在治療、預防或診斷應用中使用化合物時，通常期望將化合物遞送至特定位置(例如遞送至期望細胞)，以增強治療或預防效應或有利於診斷目的。當嘗試在活體內遞送治療性化合物時，常常為此種情形。此外，能夠有效地將化合物遞送至特定位置可限制或潛在地消除可能由投與化合物引起的意外後果(諸如脫靶效應)。一種有助於將化合物(諸如治療性、預防性或診斷性化合物)遞送至活體內期望位置之策略係將化合物連接(link或attach)至靶向配位體。When using compounds in therapeutic, preventive, or diagnostic applications, it is often desirable to deliver the compound to a specific location (e.g., to a desired cell) to enhance the therapeutic or preventive effect or to facilitate diagnostic purposes. This is often the case when attempting to deliver a therapeutic compound in vivo. In addition, being able to effectively deliver a compound to a specific location can limit or potentially eliminate unintended consequences (e.g., off-target effects) that may result from administering the compound. One strategy that helps deliver a compound (e.g., a therapeutic, preventive, or diagnostic compound) to a desired location in vivo is to link or attach the compound to a targeting ligand.
使用靶向配位體可靶向之一類化合物為寡聚化合物，諸如蛋白質、肽、抗體及寡核苷酸。包括與靶核酸至少部分互補之核苷酸序列(例如寡核苷酸)之寡聚化合物已顯示出在活體外及活體內改變靶標之功能及活性。當將寡核苷酸遞送至含有靶核酸(諸如mRNA或前mRNA)之細胞時，其已顯示出調節靶核酸之表現或活性。在某些情況下，寡核苷酸可藉由抑制核酸靶標之轉譯及/或觸發靶核酸之降解而減少基因表現。One class of compounds that can be targeted using targeting ligands are oligomeric compounds, such as proteins, peptides, antibodies, and oligonucleotides. Oligomeric compounds that include nucleotide sequences (e.g., oligonucleotides) that are at least partially complementary to a target nucleic acid have been shown to alter the function and activity of the target in vitro and in vivo. When oligonucleotides are delivered to cells containing a target nucleic acid (e.g., mRNA or pre-mRNA), they have been shown to modulate the expression or activity of the target nucleic acid. In certain instances, oligonucleotides can reduce gene expression by inhibiting translation of a nucleic acid target and/or triggering degradation of a target nucleic acid.
若靶核酸為mRNA，則寡核苷酸可調節mRNA靶標表現之一種機制係經由RNA干擾。RNA干擾係一種生物過程，RNA或RNA樣分子(諸如經化學修飾之RNA分子)藉由該過程能夠至少部分地經由RNA誘導之沈默複合物(RISC)路徑使基因表現沈默。另外，寡核苷酸可經由RNA酶募集機制、微小RNA機制、佔位機制及編輯機制來調節靶核酸(諸如靶mRNA)之表現。寡核苷酸可單股或雙股的。寡核苷酸可包含DNA、RNA及RNA樣分子，其亦可包括經修飾之核苷，包括一或多個經修飾之糖、經修飾之核鹼基及經修飾之核苷間鍵聯。If the target nucleic acid is mRNA, one mechanism by which an oligonucleotide can modulate the expression of an mRNA target is through RNA interference. RNA interference is a biological process by which RNA or RNA-like molecules (such as chemically modified RNA molecules) are able to silence gene expression, at least in part, through the RNA-induced silencing complex (RISC) pathway. Additionally, oligonucleotides can modulate the expression of target nucleic acids (such as target mRNA) through RNase recruitment mechanisms, microRNA mechanisms, occupancy mechanisms, and editing mechanisms. Oligonucleotides can be single-stranded or double-stranded. Oligonucleotides can comprise DNA, RNA, and RNA-like molecules, which may also include modified nucleosides, including one or more modified sugars, modified nucleobases, and modified internucleoside linkages.
使用靶向配位體可靶向之另一類化合物為小分子化合物。小分子化合物(例如分子量為約1000道耳頓或更小之有機化合物)通常顯示出改變靶標之功能及/或活性，使得疾病及/或疾病症狀得以調節或改善，或當定位置靶標時通常可用作診斷標記物。將化合物更有效地遞送至特定位置可限制或潛在地消除可能由投與該化合物引起的意外後果(諸如脫靶效應)，且提供診斷性化合物之改良定位。Another class of compounds that can be targeted using targeting ligands are small molecule compounds. Small molecule compounds (e.g., organic compounds with a molecular weight of about 1000 Daltons or less) are often shown to alter the function and/or activity of a target, such that a disease and/or disease symptom is modulated or improved, or when location-targeted, can often be used as diagnostic markers. More efficient delivery of a compound to a specific location can limit or potentially eliminate unintended consequences that may result from administration of the compound (e.g., off-target effects), and provide improved localization of diagnostic compounds.
本文所提供之實施例係關於靶向表現N-甲基-D-天冬胺酸鹽(NMDA)受體之細胞的化合物(例如本文所描繪之彼等化合物中之任一者)及方法。本文所提供之某些實施例係關於用於將劑遞送至表現NMDA受體之細胞的化合物及方法。在某些實施例中，細胞在腦中。在某些實施例中，細胞在額葉皮質中。在某些實施例中，細胞在紋狀體中。在某些實施例中，細胞在小腦中。在某些實施例中，細胞在腦幹中。在某些實施例中，細胞在海馬體中。在某些實施例中，細胞在脊髓中。在某些實施例中，該劑為治療性化合物。在某些實施例中，遞送該劑用於治療個體之疾病、病症及症狀。在某些實施例中，該劑為診斷性化合物。在某些實施例中，化合物包含NMDA受體配位體及一或多個用於連接至治療劑、預防劑或診斷劑之連接體部分。在某些實施例中，化合物包含NMDA受體配位體、一或多個連接體部分及治療劑。在某些實施例中，治療劑係選自小分子或寡聚化合物。在某些實施例中，寡聚化合物為蛋白質、肽、抗體、寡核苷酸或其組合。在某些實施例中，NMDA受體配位體為NMDA受體促效劑。在某些實施例中，NMDA受體配位體為NMDA受體拮抗劑。在某些實施例中，NMDA受體配位體為小分子、適配體、肽或抗體。在某些實施例中，NMDA受體配位體為本文所描繪之彼等配位體中之任一者或其衍生物或前藥。Embodiments provided herein relate to compounds (e.g., any of those compounds described herein) and methods for targeting cells expressingN -methyl-D-aspartate (NMDA) receptors. Certain embodiments provided herein relate to compounds and methods for delivering an agent to a cell expressing an NMDA receptor. In certain embodiments, the cell is in the brain. In certain embodiments, the cell is in the frontal cortex. In certain embodiments, the cell is in the striatum. In certain embodiments, the cell is in the cerebellum. In certain embodiments, the cell is in the brain stem. In certain embodiments, the cell is in the hippocampus. In certain embodiments, the cell is in the spinal cord. In certain embodiments, the agent is a therapeutic compound. In some embodiments, the agent is delivered for treating diseases, disorders and symptoms of an individual. In some embodiments, the agent is a diagnostic compound. In some embodiments, the compound comprises an NMDA receptor ligand and one or more linker moieties for connecting to a therapeutic, preventive or diagnostic agent. In some embodiments, the compound comprises an NMDA receptor ligand, one or more linker moieties and a therapeutic agent. In some embodiments, the therapeutic agent is selected from small molecules or oligomeric compounds. In some embodiments, the oligomeric compound is a protein, a peptide, an antibody, an oligonucleotide or a combination thereof. In some embodiments, the NMDA receptor ligand is an NMDA receptor agonist. In some embodiments, the NMDA receptor ligand is an NMDA receptor antagonist. In some embodiments, the NMDA receptor ligand is a small molecule, an aptamer, a peptide or an antibody. In some embodiments, the NMDA receptor ligand is any one of those ligands described herein or a derivative or prodrug thereof.
在某些實施例中，使表現NMDA受體之細胞(諸如腦細胞)與本文所提供之化合物接觸將該劑遞送至該細胞。在某些實施例中，使表現NMDA受體之細胞(諸如腦細胞)與本文所提供之化合物接觸治療個體之疾病、病症或症狀。在某些實施例中，與不表現NMDA受體之細胞相比，包含NMDA受體配位體之化合物選擇性地或優先靶向表現NMDA受體之細胞。在某些實施例中，與不包含NMDA受體配位體之化合物相比，包含NMDA受體配位體之化合物選擇性地或優先靶向表現NMDA受體之細胞。In certain embodiments, cells expressing NMDA receptors, such as brain cells, are contacted with compounds provided herein to deliver the agent to the cells. In certain embodiments, cells expressing NMDA receptors, such as brain cells, are contacted with compounds provided herein to treat diseases, disorders or symptoms of individuals. In certain embodiments, compared to cells that do not express NMDA receptors, compounds comprising NMDA receptor ligands selectively or preferentially target cells that express NMDA receptors. In certain embodiments, compared to compounds that do not comprise NMDA receptor ligands, compounds comprising NMDA receptor ligands selectively or preferentially target cells that express NMDA receptors.
本文所提供之某些實施例係關於用於調節核酸靶標在表現NMDA受體之細胞中之表現的化合物及方法。在某些實施例中，細胞在腦中。在某些實施例中，細胞在額葉皮質中。在某些實施例中，細胞在紋狀體中。在某些實施例中，細胞在小腦中。在某些實施例中，細胞在腦幹中。在某些實施例中，細胞在海馬體中。在某些實施例中，細胞在脊髓中。在某些實施例中，使表現NMDA受體之細胞(諸如腦細胞)與本文所提供之化合物接觸調節核酸靶標在該細胞中之表現或活性。在某些實施例中，化合物包含NMDA受體配位體、一或多個連接體部分及寡核苷酸。Certain embodiments provided herein relate to compounds and methods for modulating the expression of a nucleic acid target in a cell expressing an NMDA receptor. In certain embodiments, the cell is in the brain. In certain embodiments, the cell is in the frontal cortex. In certain embodiments, the cell is in the striatum. In certain embodiments, the cell is in the cerebellum. In certain embodiments, the cell is in the brain stem. In certain embodiments, the cell is in the hippocampus. In certain embodiments, the cell is in the spinal cord. In certain embodiments, cells expressing NMDA receptors, such as brain cells, are contacted with a compound provided herein to modulate the expression or activity of a nucleic acid target in the cell. In certain embodiments, the compound comprises an NMDA receptor ligand, one or more linker moieties, and an oligonucleotide.
應理解，本文所提供之關於較佳變數選擇之實施例可單獨或與一或多個實施例、或本文所提供之其他較佳變數選擇組合採用，如同每一組合在本文中明確列示一般。It should be understood that the embodiments provided herein regarding preferred variable selections may be employed alone or in combination with one or more embodiments, or other preferred variable selections provided herein, as if each combination were expressly listed herein.
在一態樣中，本揭示案提供式(I)化合物及其鹽：， 式(I) 其中為N-甲基-D-天冬胺酸鹽(NMDA)受體配位體； L1、L2、L3及L4中之每一者獨立地為連接體(例如視情況經取代之烷基連接體、視情況經取代之聚乙二醇(PEG)連接體、視情況經取代之雜烷基連接體或視情況經取代之雜芳基連接體)、鍵(例如碳-碳鍵、磷酸二酯鍵或硫代磷酸酯鍵)，或不存在； Y為鍵或-C(=O)-；且 R1為一或多種寡核苷酸、保護基團、小分子、蛋白質、抗體及/或肽。In one aspect, the present disclosure provides compounds of formula (I) and their salts: , Formula (I) wherein is anN -methyl-D-aspartate (NMDA) receptor ligand; each of L1 , L2 , L3 and L4 is independently a linker (e.g., an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker or an optionally substituted heteroaryl linker), a bond (e.g., a carbon-carbon bond, a phosphodiester bond or a phosphorothioate bond), or is absent; Y is a bond or -C(=O)-; and R1 is one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies and/or peptides.
在一些實施例中，NMDA受體配位體為NMDA受體促效劑。在一些實施例中，NMDA受體配位體為NMDA受體拮抗劑。在一些實施例中，NMDA受體配位體係選自由以下組成之群：、、、、、、、、、、、、、、、、、、、、、、抗NMDA受體抗體及其衍生物。In some embodiments, the NMDA receptor ligand is an NMDA receptor agonist. In some embodiments, the NMDA receptor ligand is an NMDA receptor antagonist. In some embodiments, the NMDA receptor ligand is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , anti-NMDA receptor antibodies and their derivatives.
在一些態樣中，本揭示案提供包含式(II)結構之化合物及其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(II)In some aspects, the present disclosure provides compounds comprising a structure of formula (II) and salts thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (II)
在一些實施例中，化合物包含式(II-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(II-a)In some embodiments, the compound comprises a structure of formula (II-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (II-a)
在一些態樣中，本揭示案提供包含式(III)結構之化合物及其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義，且R2為氫、鹵素、-OH或-OMe：式(III)In some aspects, the present disclosure provides compounds and salts thereof comprising a structure of formula (III), wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I), and R2 is hydrogen, halogen, -OH or -OMe: Formula (III)
在一些態樣中，本揭示案提供包含式(III-a)結構之化合物及其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義，且R2為氫、鹵素、-OH或-OMe：式(III-a)In some aspects, the present disclosure provides compounds and salts thereof comprising a structure of formula (III-a), wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I), and R2 is hydrogen, halogen, -OH or -OMe: Formula (III-a)
在一些實施例中，化合物包含式(III-b)結構或其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-b)In some embodiments, the compound comprises a structure of formula (III-b) or a salt thereof, wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-b)
在一些實施例中，化合物包含式(III-c)結構或其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-c)In some embodiments, the compound comprises a structure of formula (III-c) or a salt thereof, wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-c)
在一些實施例中，化合物包含式(III-d)結構或其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-d)In some embodiments, the compound comprises a structure of formula (III-d) or a salt thereof, wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-d)
在一些實施例中，化合物包含式(III-e)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-e)In some embodiments, the compound comprises a structure of formula (III-e) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-e)
在一些實施例中，化合物包含式(III-f)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-f)In some embodiments, the compound comprises a structure of formula (III-f) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-f)
在一些實施例中，化合物包含式(III-g)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-g)In some embodiments, the compound comprises a structure of formula (III-g) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-g)
在一些實施例中，化合物包含式(III-h)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-h)In some embodiments, the compound comprises a structure of formula (III-h) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-h)
在一些實施例中，化合物包含式(III-i)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-i)In some embodiments, the compound comprises a structure of formula (III-i) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-i)
在一些實施例中，化合物包含式(III-j)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-j)In some embodiments, the compound comprises a structure of formula (III-j) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-j)
在一些實施例中，化合物包含式(III-k)結構或其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-k)In some embodiments, the compound comprises a structure of formula (III-k) or a salt thereof, wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-k)
在一些實施例中，化合物包含式(III-l)結構或其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-l)In some embodiments, the compound comprises a structure of formula (III-1) or a salt thereof, wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-1)
在一些實施例中，化合物包含式(III-m)結構或其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-m)In some embodiments, the compound comprises a structure of formula (III-m) or a salt thereof, wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-m)
在一些實施例中，化合物包含式(III-n)結構或其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-n)In some embodiments, the compound comprises a structure of formula (III-n) or a salt thereof, wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-n)
在一些實施例中，化合物包含式(III-o)結構或其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-o)In some embodiments, the compound comprises a structure of formula (III-o) or a salt thereof, wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-o)
在一些實施例中，化合物包含式(III-p)結構或其鹽，其中Y、L1、L2、L3、L4及R1係如式(I)中所定義：。 式(III-p)In some embodiments, the compound comprises a structure of formula (III-p) or a salt thereof, wherein Y, L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (III-p)
在一些態樣中，本揭示案提供包含式(IV)結構之化合物及其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(IV)In some aspects, the present disclosure provides compounds comprising a structure of formula (IV) and salts thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (IV)
在一些實施例中，化合物包含式(IV-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(IV-a)In some embodiments, the compound comprises a structure of formula (IV-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (IV-a)
在一些實施例中，化合物包含式(XIX)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XIX)In some embodiments, the compound comprises a structure of formula (XIX) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XIX)
在一些實施例中，化合物包含式(XIX-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XIX-a)In some embodiments, the compound comprises a structure of formula (XIX-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XIX-a)
在一些態樣中，本揭示案提供包含式(V)結構之化合物及其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(V)In some aspects, the present disclosure provides compounds comprising a structure of formula (V) and salts thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (V)
在一些實施例中，化合物包含式(V-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(V-a)In some embodiments, the compound comprises a structure of formula (Va) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (Va)
在一些態樣中，本揭示案提供包含式(VI)結構之化合物及其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(VI)In some aspects, the present disclosure provides compounds comprising a structure of formula (VI) and salts thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (VI)
在一些實施例中，化合物包含式(VI-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(VI-a)In some embodiments, the compound comprises a structure of formula (VI-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (VI-a)
在一些實施例中，化合物包含式(VI-b)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(VI-b)In some embodiments, the compound comprises a structure of formula (VI-b) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (VI-b)
在一些態樣中，本揭示案提供包含式(VII)結構之化合物及其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(VII)In some aspects, the present disclosure provides compounds comprising a structure of formula (VII) and salts thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (VII)
在一些實施例中，化合物包含式(VII-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(VII-a)In some embodiments, the compound comprises a structure of formula (VII-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (VII-a)
在一些態樣中，本揭示案提供包含式(VIII)結構之化合物及其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(VIII)In some aspects, the present disclosure provides compounds comprising a structure of formula (VIII) and salts thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (VIII)
在一些實施例中，化合物包含式(VIII-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(VIII-a)In some embodiments, the compound comprises a structure of formula (VIII-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (VIII-a)
在一些實施例中，化合物包含式(IX)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(IX)In some embodiments, the compound comprises a structure of formula (IX) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (IX)
在一些實施例中，化合物包含式(IX-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(IX-a)In some embodiments, the compound comprises a structure of formula (IX-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (IX-a)
在一些實施例中，化合物包含式(X)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(X)In some embodiments, the compound comprises a structure of formula (X) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (X)
在一些實施例中，化合物包含式(X-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(X-a)In some embodiments, the compound comprises a structure of formula (Xa) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (Xa)
在一些實施例中，化合物包含式(X-b)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(X-b)In some embodiments, the compound comprises a structure of formula (Xb) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (Xb)
在一些實施例中，化合物包含式(XI)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(XI)In some embodiments, the compound comprises a structure of formula (XI) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XI)
在一些實施例中，化合物包含式(XI-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(XI-a)In some embodiments, the compound comprises a structure of formula (XI-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XI-a)
在一些實施例中，化合物包含式(XI-b)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(XI-b)In some embodiments, the compound comprises a structure of formula (XI-b) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XI-b)
在一些實施例中，化合物包含式(XI-c)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：。 式(XI-c)In some embodiments, the compound comprises a structure of formula (XI-c) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XI-c)
在一些實施例中，化合物包含式(XII)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XII)In some embodiments, the compound comprises a structure of formula (XII) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XII)
在一些實施例中，化合物包含式(XII-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XII-a)In some embodiments, the compound comprises a structure of formula (XII-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XII-a)
在一些實施例中，化合物包含式(XII-b)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XII-b)In some embodiments, the compound comprises a structure of formula (XII-b) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XII-b)
在一些實施例中，化合物包含式(XIII)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XIII)In some embodiments, the compound comprises a structure of formula (XIII) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XIII)
在一些實施例中，化合物包含式(XIII-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XIII-a)In some embodiments, the compound comprises a structure of formula (XIII-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XIII-a)
在一些實施例中，化合物包含式(XIV)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XIV)In some embodiments, the compound comprises a structure of formula (XIV) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XIV)
在一些實施例中，化合物包含式(XIV-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XIV-a)In some embodiments, the compound comprises a structure of formula (XIV-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XIV-a)
在一些實施例中，化合物包含式(XV)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XV)In some embodiments, the compound comprises a structure of formula (XV) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XV)
在一些實施例中，化合物包含式(XV-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XV-a)In some embodiments, the compound comprises a structure of formula (XV-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XV-a)
在一些實施例中，化合物包含式(XVI)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XVI)In some embodiments, the compound comprises a structure of formula (XVI) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XVI)
在一些實施例中，化合物包含式(XVI-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XVI-a)In some embodiments, the compound comprises a structure of formula (XVI-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XVI-a)
在一些實施例中，化合物包含式(XVII)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XVII)In some embodiments, the compound comprises a structure of formula (XVII) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XVII)
在一些實施例中，化合物包含式(XVII-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XVII-a)In some embodiments, the compound comprises a structure of formula (XVII-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XVII-a)
在一些實施例中，化合物包含式(XVIII)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XVIII)In some embodiments, the compound comprises a structure of formula (XVIII) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XVIII)
在一些實施例中，化合物包含式(XVIII-a)結構或其鹽，其中L1、L2、L3、L4及R1係如式(I)中所定義：式(XVIII-a)In some embodiments, the compound comprises a structure of formula (XVIII-a) or a salt thereof, wherein L1 , L2 , L3 , L4 and R1 are as defined in formula (I): Formula (XVIII-a)
在一些實施例中，L1、L2、L3及L4中之任一者可獨立地為連接體(例如視情況經取代之烷基連接體、視情況經取代之聚乙二醇(PEG)連接體、視情況經取代之雜烷基連接體或視情況經取代之雜芳基連接體)。在一些實施例中，L1、L2、L3及L4中之任一者可獨立地為鍵(例如碳-碳鍵、磷酸二酯鍵或硫代磷酸酯鍵)。在一些實施例中，L1、L2、L3及L4中之任一者可獨立地不存在。In some embodiments, any one of L1 , L2 , L3 and L4 may independently be a linker (e.g., an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, or an optionally substituted heteroaryl linker). In some embodiments, any one of L1 , L2 , L3 and L4 may independently be a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). In some embodiments, any one of L1 , L2 , L3 and L4 may independently be absent.
在一些實施例中，L1為鍵。在一些實施例中，L1為視情況經取代之烷基連接體。在一些實施例中，L1為視情況經取代之C1-C6烷基連接體。在一些實施例中，L1為經=O取代之C1-C6烷基連接體。在某些實施例中，L1包含結構。In some embodiments, L1 is a bond. In some embodiments, L1 is an optionally substituted alkyl linker. In some embodiments, L1 is an optionally substituted C1 -C6 alkyl linker. In some embodiments, L1 is a C1 -C6 alkyl linker substituted with =O. In certain embodiments, L1 comprises the structure .
在一些實施例中，L2為視情況經取代之烷基連接體。在一些實施例中，L2為視情況經取代之C1-C15烷基連接體。在一些實施例中，L2為視情況經取代之C5-C12烷基連接體。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。In some embodiments,L2 is an optionally substituted alkyl linker. In some embodiments,L2 is an optionally substituted C1-C15alkyl linker. In some embodiments,L2 is an optionally substitutedC5 -C12 alkyl linker. In certain embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure .
在一些實施例中，L2為視情況經取代之PEG連接體。在一些實施例中，L2為視情況經取代之PEG連接體，其長度包含一個、兩個、三個、四個、五個、六個、七個或八個PEG單元，其中PEG單元包含結構。在某些實施例中，L2為視情況經取代之PEG連接體，其長度包含三個PEG單元。在某些實施例中，L2為視情況經取代之PEG連接體，其長度包含四個PEG單元。在某些實施例中，L2包含結構、、、、、、或。In some embodiments,L is an optionally substituted PEG linker. In some embodiments,L is an optionally substituted PEG linker having a length of one, two, three, four, five, six, seven, or eight PEG units, wherein the PEG unit comprises the structure In some embodiments,L2 is an optionally substituted PEG linker having a length of three PEG units. In some embodiments,L2 is an optionally substituted PEG linker having a length of four PEG units. In some embodiments,L2 comprises the structure , , , , , , or .
在一些實施例中，L2為視情況經取代之雜烷基連接體。在某些實施例中，L2包含結構或。In some embodiments,L2 is an optionally substituted heteroalkyl linker. In certain embodiments,L2 comprises the structure or .
在一些實施例中，L3為視情況經取代之雜芳基連接體。在一些實施例中，L3為視情況經取代之部分不飽和雜環烷基連接體或雜芳基連接體。在某些實施例中，L3包含結構。In some embodiments, L3 is an optionally substituted heteroaryl linker. In some embodiments, L3 is an optionally substituted partially unsaturated heterocycloalkyl linker or heteroaryl linker. In certain embodiments, L3 comprises the structure .
在一些實施例中，L4為視情況經取代之雜烷基連接體。在一些實施例中，雜烷基連接體經一或多個=O取代基取代。在某些實施例中，L4包含結構，其中X為O或S。在某些實施例中，L4包含結構，其中X為O或S。In some embodiments,L4 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In certain embodiments,L4 comprises the structure , wherein X is O or S. In certain embodiments, L4 comprises the structure , where X is O or S.
在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。In some embodiments,L1 ,L2 ,L3 andL4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , where X is O or S.
在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：，及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。在某些實施例中，本揭示案提供具有如下結構之化合物：， 及其鹽，其中X為O或S。In certain embodiments, the present disclosure provides compounds having the following structure: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and salts thereof, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S. In certain embodiments, the present disclosure provides compounds having the following structures: , and its salts, wherein X is O or S.
在一些實施例中，X為O。在一些實施例中，X為S。In some embodiments, X is O. In some embodiments, X is S.
在一些實施例中，R1包含寡核苷酸。在一些實施例中，寡核苷酸在其5'端連接。在一些實施例中，寡核苷酸在其3'端連接。在一些實施例中，寡核苷酸在寡核苷酸上之內部位置連接。在一些實施例中，內部位置位於核苷間鍵聯處。在一些實施例中，R1包含與一或多種額外之NMDA受體配位體結合之寡核苷酸。在一些實施例中，寡核苷酸與兩種、三種、四種、五種或五種以上之額外NMDA受體配位體結合。在某些實施例中，額外之NMDA受體配位體在寡核苷酸之5'端、寡核苷酸之3'端、寡核苷酸上之一或多個內部位置或其任何組合處與寡核苷酸結合。在某些實施例中，寡核苷酸為經修飾之寡核苷酸。In some embodiments,R comprises an oligonucleotide. In some embodiments, the oligonucleotide is connected at its 5' end. In some embodiments, the oligonucleotide is connected at its 3' end. In some embodiments, the oligonucleotide is connected at an internal position on the oligonucleotide. In some embodiments, the internal position is located at the internucleoside bond. In some embodiments,R comprises an oligonucleotide bound to one or more additional NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to two, three, four, five or more additional NMDA receptor ligands. In certain embodiments, the additional NMDA receptor ligand is bound to the oligonucleotide at the 5' end of the oligonucleotide, the 3' end of the oligonucleotide, one or more internal positions on the oligonucleotide, or any combination thereof. In certain embodiments, the oligonucleotide is a modified oligonucleotide.
在另一態樣中，本揭示案提供組合物，其包含本文所提供之任一化合物及醫藥學上可接受之賦形劑。In another aspect, the disclosure provides a composition comprising any of the compounds provided herein and a pharmaceutically acceptable formulation.
在另一態樣中，本揭示案提供將治療性寡核苷酸遞送至個體之腦的方法，其包括向該個體投與本文所提供之任一化合物或組合物。在一些實施例中，將治療性寡核苷酸遞送至一或多個選自由以下組成之群的腦區域：紋狀體、小腦、腦幹、海馬體、額葉皮質及脊髓。在另一態樣中，本揭示案提供治療或改善個體之疾病、病症或其症狀之方法，該等方法包括向該個體投與本文所提供之任一化合物或組合物。在一些實施例中，疾病、病症或其症狀為中樞神經系統(CNS)疾病、病症或其症狀。在某些實施例中，疾病、病症或其症狀為阿茲海默氏病(Alzheimer’s disease)或其症狀。在一些實施例中，將化合物鞘內投與給個體。In another aspect, the disclosure provides methods for delivering a therapeutic oligonucleotide to the brain of an individual, comprising administering to the individual any of the compounds or compositions provided herein. In some embodiments, the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of: striatum, cerebellum, brain stem, hippocampus, frontal cortex, and spinal cord. In another aspect, the disclosure provides methods for treating or ameliorating a disease, disorder, or symptom thereof in an individual, comprising administering to the individual any of the compounds or compositions provided herein. In some embodiments, the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof. In certain embodiments, the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof. In some embodiments, the compound is administered intrathecally to the individual.
在另一態樣中，本揭示案提供製備本文所提供之任一化合物之方法，該等化合物包含本文所闡述之一或多種化合物及化學轉變，包括實例1至77。In another aspect, the disclosure provides methods of preparing any of the compounds provided herein, comprising one or more of the compounds and chemical transformations described herein, including Examples 1-77.
相關申請案Related applications
本申請案根據35 U.S.C. § 119(e)主張2023年5月12日提出申請之美國臨時申請案U.S.S.N. 63/502,035之優先權，該臨時申請案之內容係以引用的方式併入本文中。 定義This application claims priority under 35 U.S.C. § 119(e) to U.S. provisional application U.S.S.N. 63/502,035 filed on May 12, 2023, the contents of which are incorporated herein by reference.Definitions
應理解，前述一般說明及以下詳細說明均僅為例示性及解釋性的，而不限制如所主張之實施例。在本文中，除非另有明確說明，否則單數之使用包括複數。除非另有說明，否則如本文所用，使用「或」意指「及/或」。此外，術語「包括(including)」以及諸如「包括(includes及included)」等其他形式之使用不為限制性的。本文所用之章節標題僅用於組織目的，而不應解釋為限制所描述之標的物。It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of the embodiments as claimed. In this document, unless otherwise expressly stated, the use of the singular includes the plural. Unless otherwise stated, as used herein, the use of "or" means "and/or". In addition, the use of the term "including" and other forms such as "includes and included" is not limiting. The section headings used herein are used for organizational purposes only and should not be construed as limiting the subject matter described.
除非另有指示，否則以下術語具有以下含義：Unless otherwise indicated, the following terms have the following meanings:
如本文所用，術語「治療」病症涵蓋改善、減輕及/或管控該病症及/或可能引起該病症之疾患。術語「治療(treating及treatment)」係指緩和或減弱疾病及/或其伴隨症狀之方法。根據本揭示案，「治療」包括阻斷、抑制、減弱、防止(protect against)、調節、逆轉病症之效應及減少例如病症之有害效應的發生。如本文所用，「抑制」涵蓋預防、減少及停止進展。As used herein, the term "treating" a disease encompasses ameliorating, alleviating and/or managing the disease and/or the condition that may cause the disease. The terms "treating" and "treatment" refer to methods of alleviating or reducing a disease and/or its associated symptoms. According to the present disclosure, "treating" includes blocking, inhibiting, attenuating, protecting against, regulating, reversing the effects of a disease and reducing the occurrence of, for example, harmful effects of a disease. As used herein, "inhibiting" encompasses preventing, reducing and stopping the progression.
術語「分離」、「純化」或「生物純」係指材料實質上或基本上不含通常伴隨以天然狀態發現之材料之組分。通常使用分析化學技術來測定純度及均質性，諸如聚丙烯醯胺凝膠電泳或高效液相層析(HPLC)。具體而言，在某些實施例中，化合物至少85%純，更佳地至少90%純，更佳地至少95%純，且最佳地至少99%純。The terms "isolated," "purified," or "biopure" refer to a material that is substantially or essentially free from components that normally accompany the material as it is found in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis or high performance liquid chromatography (HPLC). Specifically, in certain embodiments, the compound is at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.
術語「投與(administration或administering)」包括將化合物引入個體以實現其預期功能之途徑。可使用之投與途徑之實例包括注射(皮下、靜脈內、非經腸、腹膜內、鞘內)、外用、經口、吸入、經直腸及經皮。The term "administration" or "administering" includes a route of introducing a compound into a subject to achieve its intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.
術語「有效量」包括在所需時間段內以所需劑量有效達成期望結果之量。化合物之有效量可根據諸如個體之疾病狀態、年齡及體重以及化合物在個體中引發期望反應之能力等因素而變化。可調整劑量方案以提供最佳治療反應。有效量亦為化合物之治療有益效應勝過其任何不可耐受或有害效應(例如副作用)之量。The term "effective amount" includes an amount effective to achieve the desired result at the required dosage for the required period of time. The effective amount of a compound may vary according to factors such as the disease state, age and weight of the individual and the ability of the compound to elicit the desired response in the individual. The dosage regimen may be adjusted to provide the optimal therapeutic response. An effective amount is also an amount in which the therapeutically beneficial effects of the compound outweigh any intolerable or deleterious effects (e.g., side effects).
如本文所用之片語「全身投與(systemic administration、administered systemically)」及「外周投與(peripheral administration、administered peripherally)」意指投與化合物、寡核苷酸、藥物或其他材料，使得其進入患者之循環系統且由此經受代謝及其他類似過程。As used herein, the phrases "systemic administration," "administered systemically," and "peripheral administration," "administered peripherally," refer to the administration of a compound, oligonucleotide, drug, or other material so that it enters the patient's circulatory system and thereby undergoes metabolism and other similar processes.
術語「治療有效量」係指足以防止所治療之疾患或病症之一或多種症狀發展或在一定程度上緩和該一或多種症狀的所投與之化合物之量。The term "therapeutically effective amount" refers to that amount of the compound being administered which is sufficient to prevent development of, or alleviate to some extent, one or more symptoms of the disease or condition being treated.
化合物之治療有效量(亦即有效劑量)可在約0.005 μg/kg至約200 mg/kg、較佳約0.01 mg/kg至約200 mg/kg且更佳約0.015 mg/kg至約30 mg/kg體重範圍內。在其他實施例中，治療有效量可在約1.0 pM至約10 μM範圍內。熟習此項技術者應瞭解，某些因素可能影響有效治療個體所需之劑量，該等因素包括(但不限於)疾病或病症之嚴重程度、先前治療、個體之一般健康狀況及/或年齡以及所存在之其他疾病。此外，利用治療有效量之化合物治療個體可包括單一治療，或較佳地可包括一系列治療。在一個實例中，每天、每週、每月、每季度或每年用約0.005 μg/kg至約200 mg/kg體重範圍內之化合物治療個體。在另一實例中，在慢性疾患或病恙之背景下，可每天、每週、每月、每季度或每年治療個體持續數年。亦應瞭解，用於治療之化合物之有效劑量可在特定治療之過程中增加或減少。The therapeutically effective amount of the compound (i.e., the effective dose) may be in the range of about 0.005 μg/kg to about 200 mg/kg, preferably about 0.01 mg/kg to about 200 mg/kg, and more preferably about 0.015 mg/kg to about 30 mg/kg of body weight. In other embodiments, the therapeutically effective amount may be in the range of about 1.0 pM to about 10 μM. Those skilled in the art will appreciate that certain factors may affect the dose required to effectively treat an individual, including, but not limited to, the severity of the disease or condition, previous treatments, the general health and/or age of the individual, and other diseases present. In addition, treatment of an individual with a therapeutically effective amount of a compound may include a single treatment, or may preferably include a series of treatments. In one example, a subject is treated daily, weekly, monthly, quarterly, or yearly with a compound in the range of about 0.005 μg/kg to about 200 mg/kg of body weight. In another example, a subject may be treated daily, weekly, monthly, quarterly, or yearly for several years in the context of a chronic disease or illness. It is also understood that the effective dose of the compound used for treatment may increase or decrease over the course of a particular treatment.
術語「手性」係指具有與其鏡像夥伴不可疊合之性質之分子，而術語「非手性」係指與其鏡像夥伴可疊合之分子。The term "chiral" refers to molecules that have the property of being non-superimposable with their mirror image partners, while the term "achiral" refers to molecules that are superimposable with their mirror image partners.
本揭示案之某些化合物具有不對稱碳原子(光學或手性中心)或雙鍵；鏡像異構物、外消旋物、非鏡像異構物、互變異構物、幾何異構物、就絕對立體化學而言可定義為(R)-或(S)-或對於胺基酸而言可定義為(D)-或(L)-之立體異構形式以及個別異構物涵蓋在本揭示案之範圍內。本揭示案之化合物不包括此項技術中已知之太不穩定而不能合成及/或分離之彼等化合物。本揭示案意欲包括呈外消旋及光學純形式之化合物。光學活性(R)-及(S)-或(D)-及(L)-異構物可使用手性合成子或手性試劑來製備，或使用習用技術來拆分。當本文所闡述之化合物含有烯烴鍵或其他幾何不對稱性中心時，且除非另有指定，否則預期該等化合物包括E及Z幾何異構物二者。Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; mirror isomers, racemates, non-mirror isomers, tautomers, geometric isomers, stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry or as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those compounds that are too unstable to be synthesized and/or separated as known in the art. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, it is contemplated that the compounds include both E and Z geometric isomers.
如本文所用，術語「互變異構物」係指兩種或更多種結構異構物中之一者，該等結構異構物以平衡狀態存在，且易於自一種異構形式轉化成另一種異構形式。As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another.
熟習此項技術者將明瞭，本揭示案之某些化合物可以互變異構形式存在，該等化合物之所有此等互變異構形式均在本揭示案之範圍內。It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric isomeric forms and that all such tautomeric forms of the compounds are within the scope of the present disclosure.
除非另有說明，否則本文所繪示之結構亦意欲包括該結構之所有立體化學形式(亦即，每一不對稱中心之R及S構形)。因此，本發明化合物之單一立體化學異構物以及鏡像異構及非鏡像異構混合物在本揭示案之範圍內。Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure (i.e., R and S configurations for each asymmetric center). Therefore, single stereochemical isomers as well as mirror and non-mirror isomeric mixtures of the compounds of the invention are within the scope of the present disclosure.
如本文所用，「手性富集群體」意指複數個具有相同分子式之分子，其中群體內在特定手性中心處含有特定立體化學構形之分子的數目或百分比大於在該特定手性中心為立體隨機的情況下群體內在相同特定手性中心處預期含有相同特定立體化學構形之分子的數目或百分比。在每一分子內具有多個手性中心之分子的手性富集群體可含有一或多個立體隨機手性中心。在某些實施例中，分子為經修飾之寡核苷酸。在某些實施例中，分子為包含經修飾之寡核苷酸之化合物。As used herein, "chirally enriched population" means a plurality of molecules having the same molecular formula, wherein the number or percentage of molecules within the population containing a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules within the population that would be expected to contain the same particular stereochemical configuration at the same particular chiral center if the particular chiral center were stereorandom. A chirally enriched population of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In some embodiments, the molecule is a modified oligonucleotide. In some embodiments, the molecule is a compound comprising a modified oligonucleotide.
除非另有說明，否則本文所繪示之結構亦意欲包括不同之處僅在於存在一或多個同位素富集原子之化合物。舉例而言，除用氘或氚置換氫或用13C或14C富集碳置換碳外具有本發明結構之化合物在本揭示案之範圍內。Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen with a deuterium or tritium, or the replacement of a carbon witha13Cor14C enriched carbon are within the scope of this disclosure.
如本文所用，「立體隨機手性中心」在具有相同分子式之分子群體背景下意指具有隨機立體化學構形之手性中心。舉例而言，在包含立體隨機手性中心之分子群體中，具有立體隨機手性中心(S)構形之分子的數目可與具有立體隨機手性中心(R)構形之分子的數目相同，但不一定相同。當手性中心之立體化學構形係並非為控制立體化學構形而設計之合成方法的結果時，可將其視為隨機的。在某些實施例中，立體隨機手性中心為立體隨機硫代磷酸酯核苷間鍵聯。As used herein, "stereo-random chiral center" in the context of a population of molecules having the same molecular formula means a chiral center with a random stereochemical configuration. For example, in a population of molecules comprising a stereo-random chiral center, the number of molecules with a stereo-random chiral center (S ) configuration may be the same as the number of molecules with a stereo-random chiral center (R ) configuration, but is not necessarily the same. The stereochemical configuration of a chiral center may be considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, the stereo-random chiral center is a stereo-random phosphorothioate internucleoside linkage.
術語「非鏡像異構物」係指具有兩個或更多個不對稱中心且其分子彼此不為鏡像之立體異構物。The term "non-mirror isomer" refers to stereoisomers with two or more centers of asymmetry and whose molecules are not mirror images of each other.
術語「鏡像異構物」係指彼此為不可疊合鏡像之化合物之兩種立體異構物。兩種鏡像異構物之等莫耳混合物稱為「外消旋混合物」或「外消旋物」。The term "mirror image isomers" refers to two stereoisomers of a compound that are nonsuperimposable mirror images of each other. An equimolar mixture of two mirror image isomers is called a "racemic mixture" or "racemate."
術語「異構物」或「立體異構物」係指具有相同化學組成，但原子或基團之空間排列不同之化合物。The term "isomers" or "stereoisomers" refers to compounds that have the same chemical composition but differ in the arrangement of the atoms or groups in space.
術語「前藥」意欲指示可在生理條件下或藉由溶劑分解轉化成如本文所闡述化合物之生物活性形式(例如核酸之生物活性形式)或其類似物之化合物。因此，術語「前藥」係指生物活性化合物(例如核酸)或其類似物之在醫藥學上可接受之前體。前藥在向個體投與時可為非活性的，但在活體內例如藉由水解轉化成活性化合物。前藥化合物在哺乳動物生物體中常常提供溶解性、組織相容性或延遲釋放之優點(例如，參見Bundgaard, H., Design of Prodrugs (1985)，第7-9頁，21-24 (Elsevier, Amsterdam)。關於前藥之論述提供於Higuchi, T.等人，「Pro-drugs as Novel Delivery Systems」, A.C.S. Symposium Series，第14卷及Bioreversible Carriers in Drug Design，編輯Edward B. Roche，American Pharmaceutical Association and Pergamon Press, 1987中，該兩篇文獻均係以引用方式全文併入本文中。術語「前藥」亦意欲包括任何共價鍵結之載劑，當向哺乳動物個體投與此前藥時，該等載劑在活體內釋放活性化合物。如本文所闡述之活性化合物之前藥可藉由修飾活性化合物中存在之官能基來製備，該製備方式使得該等修飾在常規操作或活體內裂解成母體活性化合物。前藥包括羥基、胺基或巰基鍵結至任何基團之如下化合物：在將活性化合物之前藥投與給哺乳動物個體時，該基團裂解而分別形成游離羥基、游離胺基或游離巰基。適宜前藥之實例包括(但不限於)磷原子修飾之核酸之麩胱甘肽、醯氧基、硫醯氧基、2-羰烷氧基乙基、二硫化物、硫胺(thiaminal)及烯醇酯衍生物。術語「前寡核苷酸」或「前核苷酸」或「核酸前藥」係指已經修飾為寡核苷酸前藥之寡核苷酸。膦酸酯及磷酸酯前藥可參見(例如) Wiener等人，「Prodrugs or phosphonates and phosphates: crossing the membrane」 Top. Curr. Chem.2015, 360:115-160，其全文係以引用的方式併入本文中。亦包括經由其他活體內機制轉化成活性形式之前藥。在態樣中，本揭示案之化合物係本文任一式之前藥。The term "prodrug" is intended to indicate a compound that can be converted under physiological conditions or by solvent decomposition into a biologically active form of a compound as described herein (e.g., a biologically active form of a nucleic acid) or an analog thereof. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound (e.g., a nucleic acid) or an analog thereof. A prodrug may be inactive when administered to a subject, but is converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility or delayed release in mammalian organisms (see, e.g., Bundgaard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). Discussions on prodrugs are provided in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems", A.C.S. Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. The term "prodrug" is also intended to include any covalently bonded carriers which release the active compound in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the active compounds as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved in conventional manipulations or in vivo to the parent active compound. Prodrugs include compounds in which a hydroxyl, amine or hydroxyl group is bonded to any group: When a prodrug of a compound is administered to a mammalian subject, the group is cleaved to form a free hydroxyl group, a free amine group or a free alkyl group, respectively. Examples of suitable prodrugs include, but are not limited to, glutathione, acyloxy, thioacyloxy, 2-carboalkoxyethyl, disulfide, thiaminal and enol ester derivatives of nucleic acids modified with phosphorus atoms. The term "pre-oligonucleotide" or "prenucleotide" or "nucleic acid prodrug" refers to an oligonucleotide that has been modified to be an oligonucleotide prodrug. Phosphonate and phosphate prodrugs can be found, for example, Wiener et al., "Prodrugs or phosphonates and phosphates: crossing the membrane" Top. Curr. Chem. 2015, 360:115-160, the entire text of which is incorporated herein by reference. Prodrugs that are converted to active forms via other in vivo mechanisms are also included. In an embodiment, the compound of the present disclosure is a prodrug of any formula herein.
術語「個體」係指動物，諸如哺乳動物，包括(但不限於)靈長類動物(例如人類)、牛、綿羊、山羊、馬、狗、貓、兔、大鼠、小鼠及諸如此類。在某些實施例中，個體為人類。The term "subject" refers to animals, such as mammals, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In certain embodiments, the subject is a human.
術語「一種/個(a、an)」及「該(the)」當在本申請案、包括申請專利範圍中使用時，係指「一或多種/個」。因此，舉例而言，除非上下文明確指示相反情形，否則對「樣品」之提及包括複數種樣品(例如複數個樣品)等。The terms "a,""an," and "the," when used in this application, including the patent claims, mean "one or more." Thus, for example, a reference to "a sample" includes a plurality of samples (e.g., a plurality of samples), etc., unless the context clearly indicates otherwise.
在整個本說明書及申請專利範圍中，除非上下文另外要求，否則詞語「包含(comprise、comprises及comprising)」係以非排他性含義使用。Throughout this specification and claims, unless the context requires otherwise, the words "comprise," "comprises," and "comprising" are used in a non-exclusive sense.
如本文所用，術語「約」在提及一值時意欲涵蓋自指定量之以下變化：在一些實施例中± 20%，在一些實施例中± 10%，在一些實施例中± 5%，在一些實施例中± 1%，在一些實施例中± 0.5%，且在一些實施例中± 0.1%，此乃因該等變化在實施所揭示之方法或採用所揭示之組合物中係適當的。As used herein, the term "about" when referring to a value is intended to encompass variations from the specified amount: in some embodiments ± 20%, in some embodiments ± 10%, in some embodiments ± 5%, in some embodiments ± 1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1%, as such variations are appropriate in practicing the disclosed methods or employing the disclosed compositions.
如本文所用，除非另有說明，否則術語「烷基」自身或作為另一取代基之一部分意指直鏈(亦即無支鏈)或具支鏈碳鏈(或碳)或其組合，其可為完全飽和的、單不飽和的(例如烯烴或烯基)或多不飽和的(例如炔烴或炔基)，且可包括具有指定碳原子數之單價、二價及多價基團。舉例而言，C1-C24意指1至24個碳原子。此範圍內之指定碳原子數包括例如C1-C20烷基(具有1-20個碳原子)、C1-C12烷基(具有1-12個碳原子)及C1-C4烷基(具有1-4個碳原子)。As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight chain (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, which may be fully saturated, monounsaturated (e.g., alkene or alkenyl) or polyunsaturated (e.g., alkynyl or alkynyl), and may include monovalent, divalent, and polyvalent groups having the specified number of carbon atoms. For example,C1 -C24 means 1 to 24 carbon atoms. The specified number of carbon atoms within this range includes, for example,C1 -C20 alkyl (having 1-20 carbon atoms),C1 -C12 alkyl (having 1-12 carbon atoms), andC1 -C4 alkyl (having 1-4 carbon atoms).
術語「烯基」係指可為直鏈或具支鏈、含有2至12個碳原子及至少一個碳-碳雙鍵之不飽和烴鏈。烯基可視情況經一或多個取代基取代。The term "alkenyl" refers to an unsaturated hydrocarbon chain which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. The alkenyl group may be optionally substituted with one or more substituents.
術語「炔基」係指可為直鏈或具支鏈、含有2至12個碳原子及至少一個碳-碳三鍵之不飽和烴鏈。炔基可視情況經一或多個取代基取代。The term "alkynyl" refers to an unsaturated hydrocarbon chain which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. The alkynyl group may be optionally substituted with one or more substituents.
術語「低碳數烷基」係指C1-C6烷基鏈。烷基之實例包括甲基、乙基、正丙基、異丙基、第三丁基及正戊基。烷基可視情況經一或多個取代基取代。The term "lower alkyl" refers to a C1 -C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, t-butyl and n-pentyl. The alkyl group may be substituted with one or more substituents as appropriate.
除非另有說明，否則術語「雜烷基」自身或與另一術語組合意指包括至少一個碳原子及至少一個雜原子(例如O、N、P、Si及/或S)之穩定直鏈或具支鏈或其組合，且其中氮原子及硫原子可視情況經氧化，且氮雜原子可視情況經四級銨化。該(等)雜原子(例如O、N、P、Si及/或S)可位於雜烷基之任何內部位置或位於烷基與分子之其餘部分連接之位置。雜烷基為非環化鏈。實例包括(但不限於)：-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH═CH-O-CH3、-Si(CH3)3、-CH2-CH═N-OCH3、-CH═CH-N(CH3)-CH3、-O-CH3、-O-CH2-CH3及-CN。最多可連續有兩個或三個雜原子，諸如-CH2-NH-OCH3及-CH2-O-Si(CH3)3。雜烷基部分可包括一個雜原子(例如O、N、S、Si、B或P)。雜烷基部分可包括兩個視情況不同之雜原子(例如O、N、S、Si、B及/或P)。雜烷基部分可包括三個視情況不同之雜原子(例如O、N、S、Si、B及/或P)。雜烷基部分可包括四個視情況不同之雜原子(例如O、N、S、Si、B及/或P)。雜烷基部分可包括五個視情況不同之雜原子(例如O、N、S、Si、B及/或P)。雜烷基部分可包括高達8個或更多個視情況不同之雜原子(例如O、N、S、Si、B及/或P)。Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched chain or combination thereof comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si and/or S), and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternary ammonated. The heteroatom(s) (e.g., O, N, P, Si and/or S) may be located at any interior position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Heteroalkyl groups are non-cyclic chains. Examples include (but are not limited to):-CH2 -CH2 -O-CH3 ,-CH2 -CH2 -NH-CH3 ,-CH2 -CH2 -N(CH3 )-CH3 ,-CH2- S-CH2-CH3 , -CH2-CH2,-S (O)-CH3 ,-CH2 -CH2 -S(O)2 -CH3 , -CH═CH-O-CH3 , -Si(CH3 )3 , -CH2 -CH═N-OCH3 , -CH═CH-N(CH3 )-CH3 , -O-CH3 , -O-CH2 -CH3 and -CN. There may be up to two or three consecutive heteroatoms, such as-CH2- NH-OCH3 and-CH2 -O-Si(CH3 )3 . The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, B, or P). The heteroalkyl moiety may include two heteroatoms that may vary depending on the circumstances (e.g., O, N, S, Si, B, and/or P). The heteroalkyl moiety may include three heteroatoms that may vary depending on the circumstances (e.g., O, N, S, Si, B, and/or P). The heteroalkyl moiety may include four heteroatoms that may vary depending on the circumstances (e.g., O, N, S, Si, B, and/or P). The heteroalkyl moiety may include five heteroatoms that may vary depending on the circumstances (e.g., O, N, S, Si, B, and/or P). The heteroalkyl moiety may include up to 8 or more optional heteroatoms (e.g., O, N, S, Si, B and/or P).
類似地，除非另有說明，否則術語「伸雜烷基」自身或作為另一取代基之一部分意指衍生自雜烷基之二價基團，例如(但不限於) -CH2-CH2-S-CH2-CH2-及-CH2-S-CH2-CH2-NH-CH2-。對於伸雜烷基而言，雜原子亦可佔據一個或兩個鏈末端(例如伸烷基氧基、伸烷基二氧基、伸烷基胺基、伸烷基二胺基及諸如此類)。此外，對於伸烷基及伸雜烷基連接基團，連接基團之式的書寫方向並不暗示該連接基團之定向。舉例而言，式-C(O)2R'-表示-C(O)2R'-及-R'C(O)2-二者。如上文所闡述，本文所用之雜烷基包括經由雜原子連接至分子之其餘部分之彼等基團，諸如-C(O)R'、-C(O)NR'、-NR'R''、-OR'、-SR'及/或-SO2R'。倘若列舉「雜烷基」，之後列舉具體之雜烷基，諸如 -NR'R''或諸如此類，應理解，術語雜烷基及-NR'R''不為多餘的或相互排斥的。相反，列舉具體雜烷基係為了更加清晰。因此，術語「雜烷基」在本文中不應解釋為排除具體雜烷基，諸如-NR'R''或諸如此類。Similarly, unless otherwise indicated, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkylene, such as, but not limited to,-CH2 -CH2 -S-CH2 -CH2- and-CH2- S-CH2 -CH2 -NH-CH2- . For heteroalkylene, heteroatoms may also occupy one or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2- . As explained above, heteroalkyl groups as used herein include those groups that are attached to the rest of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR' and/or -SO2 R'. If "heteroalkyl" is listed followed by a listing of specific heteroalkyl groups, such as -NR'R'' or the like, it is understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the listing of specific heteroalkyl groups is for the sake of clarity. Therefore, the term "heteroalkyl" herein should not be interpreted as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
術語「鹵烷基」係指經一或多個鹵基取代基取代之烷基。鹵烷基之實例包括氟甲基、二氟甲基、三氟甲基、溴甲基、氯甲基及2,2,2-三氟乙基。The term "haloalkyl" refers to an alkyl group substituted with one or more halogen substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl and 2,2,2-trifluoroethyl.
術語「芳基烯基」係指可為直鏈或具支鏈、含有2至12個碳原子及至少一個碳-碳雙鍵之不飽和烴鏈，其中烯基單元之一或多個sp2雜化碳連接至芳基部分。烯基可視情況經一或多個取代基取代。The term "arylalkenyl" refers to an unsaturated hydrocarbon chain which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond, wherein one or moresp2 hybridized carbons of the alkenyl unit are attached to the aryl portion. The alkenyl group may be optionally substituted with one or more substituents.
術語「芳基炔基」係指可為直鏈或具支鏈、含有2至12個碳原子及至少一個碳-碳三鍵之不飽和烴鏈，其中炔基單元之一或多個sp雜化碳連接至芳基部分。炔基可視情況經一或多個取代基取代。The term "arylalkynyl" refers to an unsaturated hydrocarbon chain which may be straight or branched, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond, wherein one or more sp hybridized carbons of the alkynyl unit are attached to the aryl portion. The alkynyl group may be optionally substituted with one or more substituents.
烯基及炔基之sp2雜化碳或sp雜化碳分別可視情況為烯基或炔基之連接點。The sp2- hybridized carbon or sp-hybridized carbon of the alkenyl group and the alkynyl group, respectively, can be the point of attachment of the alkenyl group or the alkynyl group, as the case may be.
術語「烷氧基」係指-O-烷基取代基。The term "alkoxy" refers to an -O-alkyl substituent.
如本文所用，術語「鹵素」、「鹵」或「鹵基」意指-F、-Cl、-Br或-I。As used herein, the term "halogen," "halogen," or "halogenyl" means -F, -Cl, -Br, or -I.
術語「烷基硫基」係指-S-烷基取代基。The term "alkylthio" refers to an -S-alkyl substituent.
術語「烷氧基烷基」係指-烷基-O-烷基取代基。The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.
術語「鹵烷氧基」係指經一或多個鹵基取代基取代之-O-烷基。鹵烷氧基之實例包括三氟甲氧基及2,2,2-三氟乙氧基。The term "haloalkoxy" refers to an -O-alkyl group substituted with one or more halogen substituents. Examples of haloalkoxy include trifluoromethoxy and 2,2,2-trifluoroethoxy.
術語「鹵烷氧基烷基」係指-烷基-O-烷基’，其中該烷基’經一或多個鹵基取代基取代。The term "haloalkoxyalkyl" refers to -alkyl-O-alkyl', wherein the alkyl' is substituted with one or more halogen substituents.
術語「鹵烷基胺基羰基」係指-C(O)-胺基-烷基，其中該烷基經一或多個鹵基取代基取代。The term "haloalkylaminocarbonyl" refers to a -C(O)-amino-alkyl group wherein the alkyl group is substituted with one or more halo substituents.
術語「鹵烷基硫基」係指經一或多個鹵基取代基取代之-S-烷基。鹵烷基硫基之實例包括三氟甲基硫基及2,2,2-三氟乙基硫基。The term "haloalkylthio" refers to an -S-alkyl group substituted with one or more halogen substituents. Examples of haloalkylthio include trifluoromethylthio and 2,2,2-trifluoroethylthio.
術語「鹵烷基羰基」係指經一或多個鹵基取代基取代之-C(O)-烷基。鹵烷基羰基之實例包括三氟乙醯基。The term "haloalkylcarbonyl" refers to a -C(O)-alkyl group substituted with one or more halogen substituents. Examples of haloalkylcarbonyl include trifluoroacetyl.
術語「環烷基」係指具有至少一個飽和環或具有至少一個非芳香族環之烴3-8員單環或7-14員雙環系統，其中該非芳香族環可具有一定程度之不飽和度。環烷基可視情況經一或多個取代基取代。在一個實施例中，環烷基之每一環之0、1、2、3或4個原子可經取代基取代。環烷基之代表性實例包括環丙基、環戊基、環己基、環丁基、環庚基、環戊烯基、環戊二烯基、環己烯基、環己二烯基及諸如此類。The term "cycloalkyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have a certain degree of unsaturation. The cycloalkyl group may be substituted with one or more substituents as appropriate. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the cycloalkyl group may be substituted with substituents. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl and the like.
術語「環烷氧基」係指-O-環烷基取代基。The term "cycloalkoxy" refers to an -O-cycloalkyl substituent.
術語「環烷氧基烷基」係指-烷基-O-環烷基取代基。The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.
術語「環烷基烷氧基」係指-O-烷基-環烷基取代基。The term "cycloalkylalkoxy" refers to an -O-alkyl-cycloalkyl substituent.
術語「環烷基胺基羰基」係指-C(O)-NH-環烷基取代基。The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.
術語「芳基」係指烴單環、雙環或三環芳香族環系統。芳基可視情況經一或多個取代基取代。在一個實施例中，芳基之每一環之0、1、2、3、4、5或6個原子可經取代基取代。芳基之實例包括苯基、萘基、蒽基、茀基、茚基、薁基及諸如此類。The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. The aryl group may be substituted with one or more substituents as appropriate. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of the aryl group may be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl and the like.
術語「芳基氧基」係指-O-芳基取代基。The term "aryloxy" refers to an -O-aryl substituent.
術語「芳基烷氧基」係指-O-烷基-芳基取代基。The term "arylalkoxy" refers to an -O-alkyl-aryl substituent.
術語「芳基烷基硫基」係指-S-烷基-芳基取代基。The term "arylalkylthio" refers to an -S-alkyl-aryl substituent.
術語「芳基硫基烷基」係指-烷基-S-芳基取代基。The term "arylthioalkyl" refers to an -alkyl-S-aryl substituent.
術語「芳基烷基胺基羰基」係指-C(O)-胺基-烷基-芳基取代基。The term "arylalkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.
術語「芳基烷基磺醯基」係指-S(O)2-烷基-芳基取代基。The term "arylalkylsulfonyl" refers to a -S(O)2 -alkyl-aryl substituent.
術語「芳基烷基亞磺醯基」係指-S(O)-烷基-芳基取代基。The term "arylalkylsulfinyl" refers to a -S(O)-alkyl-aryl substituent.
術語「芳基氧基烷基」係指-烷基-O-芳基取代基。The term "aryloxyalkyl" refers to an -alkyl-O-aryl substituent.
術語「烷基芳基」係指-芳基-烷基取代基。The term "alkylaryl" refers to an -aryl-alkyl substituent.
術語「芳基烷基」係指-烷基-芳基取代基。The term "arylalkyl" refers to an -alkyl-aryl substituent.
術語「雜芳基」係指芳香族5-8員單環、8-12員雙環或11-14員三環系統，其若為單環則具有1-4個環雜原子，若為雙環則具有1-6個雜原子，或若為三環則具有1-9個雜原子，該等雜原子選自O、N或S，且其餘環原子為碳(除非另有指示，否則具有適當氫原子)。雜芳基可視情況經一或多個取代基取代。在一個實施例中，雜芳基之每一環之0、1、2、3或4個原子可經取代基取代。雜芳基可為完全不飽和的，或其可為部分不飽和的及部分飽和的。雜芳基之實例包括吡啶基、呋喃基、噻吩基、吡咯基、噁唑基、噁二唑基、咪唑基、噻唑基、異噁唑基、喹啉基、吡唑基、異噻唑基、嗒嗪基、嘧啶基、吡嗪基、三嗪基、異喹啉基、吲唑基及諸如此類。The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system, which has 1-4 heteroatoms in the ring if it is a monocyclic ring, 1-6 heteroatoms in the bicyclic ring, or 1-9 heteroatoms in the tricyclic ring, wherein the heteroatoms are selected from O, N or S, and the remaining ring atoms are carbon (with appropriate hydrogen atoms unless otherwise indicated). The heteroaryl group may be substituted with one or more substituents as appropriate. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the heteroaryl group may be substituted with substituents. The heteroaryl group may be fully unsaturated, or it may be partially unsaturated and partially saturated. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.
術語「雜芳基烷基」係指-烷基-雜芳基取代基。The term "heteroarylalkyl" refers to an -alkyl-heteroaryl substituent.
術語「雜芳基氧基」係指-O-雜芳基取代基。The term "heteroaryloxy" refers to an -O-heteroaryl substituent.
術語「雜芳基烷氧基」係指-O-烷基-雜芳基取代基。The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.
術語「雜芳基氧基烷基」係指-烷基-O-雜芳基取代基。The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.
術語「含氮雜芳基」係指若為單環則具有1-4個環氮雜原子、若為雙環則具有1-6個環氮雜原子或若為三環則具有1-9個環氮雜原子之雜芳基。The term "nitrogen-containing heteroaryl group" refers to a heteroaryl group having 1 to 4 ring nitrogen heteroatoms if it is monocyclic, 1 to 6 ring nitrogen heteroatoms if it is bicyclic, or 1 to 9 ring nitrogen heteroatoms if it is tricyclic.
術語「雜環烷基」係指非芳香族3-8員單環、7-12員雙環或10-14員三環系統，其若為單環則包含1-3個雜原子，若為雙環則包含1-6個雜原子，或若為三環則包含1-9個雜原子，該等雜原子選自O、N、S、B、P或Si，其中非芳香族環系統係完全飽和的。雜環烷基可視情況經一或多個取代基取代。在一個實施例中，雜環烷基之每一環之0、1、2、3或4個原子可經取代基取代。代表性雜環烷基包括六氫吡啶基、六氫吡嗪基、四氫哌喃基、嗎啉基、硫嗎啉基、1,3-二氧雜環戊烷、四氫呋喃基、四氫噻吩基、硫雜環丙烯基(thiirenyl)及諸如此類。The term "heterocycloalkyl" refers to a non-aromatic 3-8 membered monocyclic, 7-12 membered bicyclic or 10-14 membered tricyclic ring system, which contains 1-3 heteroatoms if it is a monocyclic ring, 1-6 heteroatoms if it is a bicyclic ring, or 1-9 heteroatoms if it is a tricyclic ring, wherein the heteroatoms are selected from O, N, S, B, P or Si, wherein the non-aromatic ring system is fully saturated. The heterocycloalkyl group may be substituted with one or more substituents as appropriate. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of the heterocycloalkyl group may be substituted with substituents. Representative heterocycloalkyl groups include hexahydropyridinyl, hexahydropyrazinyl, tetrahydropyranyl, oxazolinyl, thiooxazolinyl, 1,3-dioxacyclopentane, tetrahydrofuranyl, tetrahydrothiophenyl, thiirenyl, and the like.
術語「雜環烷基烷基」係指-烷基-雜環烷基取代基。The term "heterocycloalkylalkyl" refers to an -alkyl-heterocycloalkyl substituent.
術語「烷基胺基」係指進一步經一個或兩個烷基取代之胺基取代基。術語「胺基烷基」係指進一步經一或多個胺基取代之烷基取代基。術語「羥基烷基(hydroxyalkyl或hydroxylalkyl)」係指進一步經一或多個羥基取代之烷基取代基。烷基胺基、胺基烷基、巰基烷基、羥基烷基、巰基烷氧基、磺醯基烷基、磺醯基芳基、烷基羰基及烷基羰基烷基之烷基或芳基部分可視情況經一或多個取代基取代。The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups. The term "hydroxyalkyl (hydroxylalkyl)" refers to an alkyl substituent further substituted with one or more hydroxy groups. The alkyl or aryl portion of alkylamino, aminoalkyl, alkylalkyl, hydroxyalkyl, alkylalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl and alkylcarbonylalkyl may be substituted with one or more substituents as appropriate.
符號「」表示化學部分與分子或化學式之其餘部分之連接點。Symbol " " indicates the point of attachment of a chemical moiety to the rest of a molecule or chemical formula.
術語「核鹼基」係指形成核苷之含氮生物化合物。其包括嘌呤鹼基及嘧啶鹼基。五種核鹼基腺嘌呤(A)、胞嘧啶(C)、鳥嘌呤(G)、胸腺嘧啶(T)及尿嘧啶(U)稱為主要或規範核鹼基。當核鹼基在式定義中列示時，其係指共價鍵結至所列舉式之部分。The term "nucleobase" refers to the nitrogen-containing biological compounds that form nucleosides. It includes purine bases and pyrimidine bases. The five nucleobases adenine (A), cytosine (C), guanine (G), thymine (T) and uracil (U) are called the principal or canonical nucleobases. When a nucleobase is listed in a formula definition, it refers to the moiety that is covalently bonded to the enumerated formula.
術語「經修飾之核鹼基」係指核鹼基之衍生物。經修飾之核鹼基之實例包括(但不限於)黃嘌呤、次黃嘌呤、7-甲基鳥嘌呤、5,6-二氫尿嘧啶、5-甲基胞嘧啶、5-羥基甲基胞嘧啶、嘌呤、2,6-二胺基嘌呤及6,8-二胺基嘌呤。當經修飾之核鹼基在式定義中列示時，其係指共價鍵結至所列舉式之部分。The term "modified nucleobase" refers to a derivative of a nucleobase. Examples of modified nucleobases include, but are not limited to, xanthine, hypoxanthine, 7-methylguanine, 5,6-dihydrouracil, 5-methylcytosine, 5-hydroxymethylcytosine, purine, 2,6-diaminopurine, and 6,8-diaminopurine. When a modified nucleobase is listed in a formula definition, it refers to the moiety that is covalently bonded to the listed formula.
術語「取代基(substituent及substituent group)」意指置換指定母體化合物之原子或基團之原子或基團。舉例而言，經修飾之核苷之取代基係與在天然核苷中所發現之原子或基團不同的原子或基團(例如，經修飾之2'-取代基係在核苷2'位處之除H或OH外之任何原子或基團)。取代基可受保護或不受保護。取代基亦可進一步經其他取代基取代，且可直接或經由連接基團(諸如烷基或烴基)連接至母體化合物。類似地，如本文所用，關於化學官能基之「取代基」意指與通常存在於指定官能基中之原子或原子團不同之原子或原子團。在某些實施例中，任何基團(諸如烷基、烯基、炔基、芳基、芳烷基、雜芳基、雜芳烷基、環烷基、雜環烷基)上之取代基可在該基團之任何原子處，其中可經取代之任何基團(諸如烷基、烯基、炔基、芳基、芳烷基、雜芳基、雜芳烷基、環烷基、雜環烷基)可視情況經一或多個取代基(其可相同或不同)取代，每一取代基置換一個氫原子。適宜取代基之實例包括(但不限於)烷基、烯基、炔基、環烷基、雜環烷基、芳烷基、雜芳烷基、芳基、雜芳基、鹵素、鹵烷基、氰基、硝基、烷氧基、芳基氧基、羥基、羥基烷基、側氧基(亦即羰基)、羧基、甲醯基、烷基羰基、烷基羰基烷基、烷氧基羰基、烷基羰基氧基、芳基氧基羰基、雜芳基氧基、雜芳基氧基羰基、硫基、巰基、巰基烷基、芳基磺醯基、胺基、胺基烷基、二烷基胺基、烷基羰基胺基、烷基胺基羰基、烷氧基羰基胺基、烷基胺基、芳基胺基、二芳基胺基、烷基羰基、或芳基胺基取代之芳基；芳基烷基胺基、芳烷基胺基羰基、醯胺基、烷基胺基磺醯基、芳基胺基磺醯基、二烷基胺基磺醯基、烷基磺醯基胺基、芳基磺醯基胺基、亞胺基、甲醯胺基、脲基、胺甲醯基、硫脲基、氰硫基、磺醯胺基、磺醯基烷基、磺醯基芳基、巰基烷氧基、N-羥基脒基或N’-芳基、N’’-羥基脒基。在某些實施例中，任何基團上之取代基包括烷基、烯基、炔基、環烷基、雜環烷基、芳烷基、雜芳烷基、芳基、雜芳基、鹵素、鹵烷基、氰基、硝基、烷氧基、芳基氧基、羥基、羥基烷基、側氧基(亦即羰基)、羧基、甲醯基、烷基羰基、烷基羰基烷基、烷氧基羰基、烷基羰基氧基、硫羰基、硫基、巰基、巰基烷基、芳基磺醯基、胺基、胺基烷基、二烷基胺基、烷基羰基胺基、烷基胺基羰基、烷氧基羰基胺基、烷基胺基、芳基胺基、二芳基胺基、烷基羰基、或芳基胺基取代之芳基；芳基烷基胺基、芳烷基胺基羰基或醯胺基。在某些實施例中，任何基團上之取代基包括烷基、鹵素、鹵烷基、氰基、硝基、烷氧基、羥基、羥基烷基、羧基、甲醯基、烷基羰基、烷氧基羰基、烷基羰基氧基、硫基、巰基、巰基烷基、胺基、胺基烷基、二烷基胺基、烷基羰基胺基、烷基胺基羰基或烷基胺基。The terms "substituent" and "substituent group" mean an atom or group that replaces an atom or group of a specified parent compound. For example, a substituent of a modified nucleoside is an atom or group that is different from the atom or group found in a natural nucleoside (e.g., a modified 2'-substituent is any atom or group other than H or OH at the 2' position of a nucleoside). Substituents may be protected or unprotected. Substituents may also be further substituted with other substituents and may be attached to the parent compound directly or through a linking group such as an alkyl or alkyl group. Similarly, as used herein, a "substituent" with respect to a chemical functional group means an atom or group of atoms that is different from the atom or group of atoms that is normally present in a specified functional group. In certain embodiments, substituents on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) may be at any atom of the group, wherein any substitutable group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) may be substituted with one or more substituents (which may be the same or different), each substituent replacing one hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, halogenalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, pendoxy (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, alkyl, alkylalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino-substituted aryl; arylalkylamino, arylalkylaminocarbonyl, amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, formamido, urea, aminoformyl, thiourea, thiocyanato, sulfonamido, sulfonylalkyl, sulfonylaryl, hydroxyalkoxy, N-hydroxyamidino, or N'-aryl, N''-hydroxyamidino. In certain embodiments, substituents on any group include alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, halogenalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, pendoxy (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, thiocarbonyl, thio, hydroxyl, alkylalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl, or amido. In certain embodiments, substituents on any group include alkyl, halogen, halogenalkyl, cyano, nitro, alkoxy, hydroxyl, hydroxyalkyl, carboxyl, formyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, thio, alkyl, alkylalkyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, or alkylamino.
術語「保護基團」或「保護部分」係指通常用於在對化合物、其衍生物或其結合物上之其他官能基實施反應時封阻或保護特定官能基之取代基，且在連接至氮原子時包括氮保護基團或在連接至氧原子時包括氧保護基團。氮及氧保護基團為此項技術中所熟知，且包括Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts，第3版，John Wiley & Sons, 1999中所詳細闡述之彼等保護基團，該文獻係以引用方式併入本文中。The term "protecting group" or "protecting moiety" refers to a substituent commonly used to block or protect a particular functional group when reacting other functional groups on a compound, its derivative, or conjugate thereof, and includes a nitrogen protecting group when attached to a nitrogen atom or an oxygen protecting group when attached to an oxygen atom. Nitrogen and oxygen protecting groups are well known in the art and include those protecting groups described in detailin Protecting Groups in Organic Synthesis , TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.
在某些實施例中，氮原子上存在之取代基為氮保護基團(亦稱為胺基保護基團)。氮保護基團包括(但不限於) -OH、-ORaa、-N(Rcc)2、-C(=O)Raa、-C(=O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(=NRcc)Raa、-C(=NRcc)ORaa、-C(=NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(=S)N(Rcc)2、-C(=O)SRcc、-C(=S)SRcc、C1-10烷基(例如芳烷基、雜芳烷基)、C2-10烯基、C2-10炔基、C3-10碳環基、3-14員雜環基、C6-14芳基及5-14員雜芳基，其中每一烷基、烯基、炔基、碳環基、雜環基、芳烷基、芳基及雜芳基獨立地經0、1、2、3、4或5個Rdd基團取代，且其中每一Raa、Rbb及Rcc獨立地為烷基、環烷基、芳基或雜芳基，其各自可視情況經1-3個獨立之Rdd取代，且每一Rdd獨立地為烷基、烯基、炔基、環烷基、雜環烷基、芳烷基、雜芳烷基、芳基、雜芳基、鹵素、鹵烷基、氰基、硝基、烷氧基、芳基氧基、羥基、羥基烷基、側氧基(亦即羰基)、羧基、甲醯基、烷基羰基、烷基羰基烷基、烷氧基羰基、烷基羰基氧基、芳基氧基羰基、雜芳基氧基、雜芳基氧基羰基、硫基、巰基、巰基烷基、芳基磺醯基、胺基、胺基烷基、二烷基胺基、烷基羰基胺基、烷基胺基羰基、烷氧基羰基胺基、烷基胺基、芳基胺基、二芳基胺基、烷基羰基、或芳基胺基取代之芳基；芳基烷基胺基、芳烷基胺基羰基、醯胺基、烷基胺基磺醯基、芳基胺基磺醯基、二烷基胺基磺醯基、烷基磺醯基胺基、芳基磺醯基胺基、亞胺基、脲基、胺甲醯基、硫脲基、氰硫基、磺醯胺基、磺醯基烷基、磺醯基芳基或巰基烷氧基。氮保護基團為此項技術中所熟知，且包括Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts，第3版，John Wiley & Sons, 1999中所詳細闡述之彼等保護基團，該文獻係以引用方式併入本文中。In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as an amine protecting group). The nitrogen protecting group includes, but is not limited to, -OH,-ORaa , -N(Rcc )2 , -C(=O)Raa , -C(=O)N(Rcc )2 , -CO2Raa, -SO2Raa, -C(=NRcc )Raa,-C (=NRcc )ORaa , -C(=NRcc)N(Rcc)2,-SO2N(Rcc )2 , -SO2Rcc, -SO2ORcc,-SORaa , -C(=S) N(Rcc )2 , -C(=O)SRcc, -C(=S)SRcc,C1-10alkyl (e.g., aralkyl, heteroaralkyl),C2-10 alkenyl,C2-10 alkynyl, C3-10 carbocyclic groups, 3-14 membered heterocyclic groups, C6-14 aryl groups and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, aralkyl, aryl and heteroaryl group is independently substituted with 0, 1, 2, 3, 4 or 5 Rdd groups, and wherein eachRaa ,Rbb andRcc is independently alkyl, cycloalkyl, aryl or heteroaryl, each of which may be substituted with 1-3 independent Rdd groups as appropriate, and each Rdd is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, halogenalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, pendoxy (i.e., carbonyl), carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, alkyl, alkylalkyl, arylsulfonyl, amino, aminoalkyl, dioxane, alkylcarbonyl, alkylcarbonylalkyl, alkyl ... The present invention further comprises an alkylamino group, an alkylcarbonylamino group, an alkylaminocarbonyl group, an alkoxycarbonylamino group, an alkylamino group, an arylamino group, a diarylamino group, an alkylcarbonyl group, or an arylamino-substituted aryl group; an arylalkylamino group, an aralkylaminocarbonyl group, an amide group, an alkylaminosulfonyl group, an arylaminosulfonyl group, a dialkylaminosulfonyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an imino group, a urea group, a carbamoyl group, a thiourea group, a thiocyanate group, a sulfonamide group, a sulfonylalkyl group, a sulfonylaryl group, or an alkylalkoxy group. Nitrogen protecting groups are well known in the art and include those described in detail inProtecting Groups in Organic Synthesis , TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.
醯胺氮保護基團(例如-C(=O)Raa)包括(但不限於)甲醯胺、乙醯胺、氯乙醯胺、三氯乙醯胺、三氟乙醯胺、苯基乙醯胺、3-苯基丙醯胺、吡啶醯胺、3-吡啶基甲醯胺、N-苯甲醯基苯丙胺醯基衍生物、苯甲醯胺、對苯基苯甲醯胺、鄰硝基苯基乙醯胺、鄰硝基苯氧基乙醯胺、乙醯乙醯胺、(N’-二硫苯甲基氧基醯基胺基)乙醯胺、3-(對羥基苯基)丙醯胺、3-(鄰硝基苯基)丙醯胺、2-甲基-2-(鄰硝基苯氧基)丙醯胺、2-甲基-2-(鄰苯基偶氮苯氧基)丙醯胺、4-氯丁醯胺、3-甲基-3-硝基丁醯胺、鄰硝基肉桂醯胺、N-乙醯基甲硫胺酸、鄰硝基苯甲醯胺及鄰(苯甲醯基氧基甲基)苯甲醯胺。Amine nitrogen protecting groups (e.g., -C(=O)Raa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridinamide, 3-pyridylformamide,N -benzylamphetamine acyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N' -dithiobenzyloxyamido)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide,N -acetylmethionine, o-nitrobenzamide and o-(benzyloxymethyl)benzamide.
胺基甲酸酯氮保護基團(例如-C(=O)ORaa)包括(但不限於)胺基甲酸甲酯、胺基甲酸乙酯、胺基甲酸9-茀基甲酯(Fmoc)、胺基甲酸9-(2-磺基)茀基甲酯、胺基甲酸9-(2,7-二溴)茀基甲酯、胺基甲酸2,7-二-第三丁基-[9-(10,10-二側氧基-10,10,10,10-四氫噻噸基)]甲酯(DBD-Tmoc)、胺基甲酸4-甲氧基苯甲醯甲酯(Phenoc)、胺基甲酸2,2,2-三氯乙酯(Troc)、胺基甲酸2-三甲基矽基乙酯(Teoc)、胺基甲酸2-苯基乙酯(hZ)、胺基甲酸1-(1-金剛烷基)-1-甲基乙酯(Adpoc)、胺基甲酸1,1-二甲基-2-鹵乙酯、胺基甲酸1,1-二甲基-2,2-二溴乙酯(DB-t-BOC)、胺基甲酸1,1-二甲基-2,2,2-三氯乙酯(TCBOC)、胺基甲酸1-甲基-1-(4-聯苯基)乙酯(Bpoc)、胺基甲酸1-(3,5-二-第三丁基苯基)-1-甲基乙酯(t-Bumeoc)、胺基甲酸2-(2’-及4’-吡啶基)乙酯(Pyoc)、胺基甲酸2-(N,N-二環己基甲醯胺基)乙酯、胺基甲酸第三丁酯(BOC)、胺基甲酸1-金剛烷基酯(Adoc)、胺基甲酸乙烯酯(Voc)、胺基甲酸烯丙酯(Alloc)、胺基甲酸1-異丙基烯丙酯(Ipaoc)、胺基甲酸桂醯酯(Coc)、胺基甲酸4-硝基桂醯酯(Noc)、胺基甲酸8-喹啉酯、胺基甲酸N-羥基六氫吡啶酯、胺基甲酸烷基二硫酯、胺基甲酸苯甲酯(Cbz)、胺基甲酸對甲氧基苯甲酯(Moz)、胺基甲酸對硝基苯甲酯、胺基甲酸對溴苯甲酯、胺基甲酸對氯苯甲酯、胺基甲酸2,4-二氯苯甲酯、胺基甲酸4-甲基亞磺醯基苯甲酯(Msz)、胺基甲酸9-蒽基甲酯、胺基甲酸二苯基甲酯、胺基甲酸2-甲基硫基乙酯、胺基甲酸2-甲基磺醯基乙酯、胺基甲酸2-(對甲苯磺醯基)乙酯、胺基甲酸[2-(1,3-二噻烷基)]甲酯(Dmoc)、胺基甲酸4-甲基硫基苯酯(Mtpc)、胺基甲酸2,4-二甲基硫基苯酯(Bmpc)、胺基甲酸2-磷基乙酯(Peoc)、胺基甲酸2-三苯基磷基異丙酯(Ppoc)、胺基甲酸1,1-二甲基-2-氰基乙酯、胺基甲酸間氯-對醯氧基苯甲酯、胺基甲酸對(二羥基氧硼基)苯甲酯、胺基甲酸5-苯并異噁唑基甲酯、胺基甲酸2-(三氟甲基)-6-色酮基甲酯(Tcroc)、胺基甲酸間硝基苯酯、胺基甲酸3,5-二甲氧基苯甲酯、胺基甲酸鄰硝基苯甲酯、胺基甲酸3,4-二甲氧基-6-硝基苯甲酯、胺基甲酸苯基(鄰硝基苯基)甲酯、胺基甲酸第三戊酯、S-硫基胺基甲酸苯甲酯、胺基甲酸對氰基苯甲酯、胺基甲酸環丁酯、胺基甲酸環己酯、胺基甲酸環戊酯、胺基甲酸環丙基甲酯、胺基甲酸對癸氧基苯甲酯、胺基甲酸2,2-二甲氧基醯基乙烯酯、胺基甲酸鄰(N,N-二甲基甲醯胺基)苯甲酯、胺基甲酸1,1-二甲基-3-(N,N-二甲基甲醯胺基)丙酯、胺基甲酸1,1-二甲基丙炔酯、胺基甲酸二(2-吡啶基)甲酯、胺基甲酸2-呋喃基甲酯、胺基甲酸2-碘乙酯、胺基甲酸異冰片酯、胺基甲酸異丁酯、胺基甲酸異菸鹼酯、胺基甲酸對(p’-甲氧基苯基偶氮基)苯甲酯、胺基甲酸1-甲基環丁酯、胺基甲酸1-甲基環己酯、胺基甲酸1-甲基-1-環丙基甲酯、胺基甲酸1-甲基-1-(3,5-二甲氧基苯基)乙酯、胺基甲酸1-甲基-1-(對苯基偶氮基苯基)乙酯、胺基甲酸1-甲基-1-苯基乙酯、胺基甲酸1-甲基-1-(4-吡啶基)乙酯、胺基甲酸苯酯、胺基甲酸對(苯基偶氮基)苯甲酯、胺基甲酸2,4,6-三-第三丁基苯酯、胺基甲酸4-(三甲基銨)苯甲酯及胺基甲酸2,4,6-三甲基苯甲酯。Carbamate nitrogen protecting groups (e.g., -C(=O)ORaa ) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothiazinyl)]methyl carbamate (DBD-Tmoc), 4- Anthoxybenzoyl methyl ester (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t -BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethyl carbamate (t- Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N -Dicyclohexylcarbamyl)ethyl ester, tert-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamic acid ester (Coc), 4-nitrocinnamic acid ester (Noc), 8-quinoline carbamate,N- -Hydroxy hexahydropyridinium ester, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfenylbenzyl carbamate (Msz), 9-anthryl methyl carbamate, diphenyl methyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2 ,4-dimethylthiophenyl ester (Bmpc), 2-phosphoethyl carbamate (Peoc), 2-triphenylphosphinoisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzoisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, tert-amyl carbamate,S -thiobenzyl carbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyvinyl carbamate, o-(N,N -dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N -dimethylformamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p' 1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,6-trimethylbenzyl carbamate.
磺醯胺氮保護基團(例如-S(=O)2Raa)包括(但不限於)對甲苯磺醯胺(Ts)、苯磺醯胺、2,3,6,-三甲基-4-甲氧基苯磺醯胺(Mtr)、2,4,6-三甲氧基苯磺醯胺(Mtb)、2,6-二甲基-4-甲氧基苯磺醯胺(Pme)、2,3,5,6-四甲基-4-甲氧基苯磺醯胺(Mte)、4-甲氧基苯磺醯胺(Mbs)、2,4,6-三甲基苯磺醯胺(Mts)、2,6-二甲氧基-4-甲基苯磺醯胺(iMds)、2,2,5,7,8-五甲基色烷-6-磺醯胺(Pmc)、甲磺醯胺(Ms)、β-三甲基矽基乙磺醯胺(SES)、9-蒽磺醯胺、4-(4’,8’-二甲氧基萘基甲基)苯磺醯胺(DNMBS)、苯甲基磺醯胺、三氟甲基磺醯胺及苯甲醯甲基磺醯胺。Sulfonamide nitrogen protecting groups (e.g., -S(=O)2 Raa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethyl ... Sulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchromane-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and benzylmethylsulfonamide.
其他氮保護基團包括(但不限於)吩噻嗪基-(10)-醯基衍生物、N’-對甲苯磺醯基胺基醯基衍生物、N’-苯基胺基硫基醯基衍生物、N-苯甲醯基苯丙胺醯基衍生物、N-乙醯基甲硫胺酸衍生物、4,5-二苯基-3-噁唑啉-2-酮、N-酞醯亞胺、N-二硫雜琥珀醯亞胺(Dts)、N-2,3-二苯基馬來醯亞胺、N-2,5-二甲基吡咯、N-1,1,4,4-四甲基二矽基氮雜環戊烷加成物(STABASE)、5-取代之1,3-二甲基-1,3,5-三氮雜環己-2-酮、5-取代之1,3-二苯甲基-1,3,5-三氮雜環己-2-酮、1-取代之3,5-二硝基-4-吡啶酮、N-甲胺、N-烯丙胺、N-[2-(三甲基矽基)乙氧基]甲胺(SEM)、N-3-乙醯氧基丙胺、N-(1-異丙基-4-硝基-2-側氧基-3-吡咯啉-3-基)胺、四級銨鹽、N-苯甲胺、N-二(4-甲氧基苯基)甲胺、N-5-二苯并環庚胺、N-三苯基甲胺(Tr)、N-[(4-甲氧基苯基)二苯基甲基]胺(MMTr)、N-9-苯基茀基胺(PhF)、N-2,7-二氯-9-茀基亞甲基胺、N-二茂鐵基甲基胺基(Fcm)、N-2-甲基吡啶基胺基N’-氧化物、N-1,1-二甲基硫基亞甲基胺、N-亞苯甲基胺、N-對甲氧基亞苯甲基胺、N-二苯基亞甲基胺、N-[(2-吡啶基)均三甲苯基]亞甲基胺、N-(N’,N’-二甲基胺基亞甲基)胺、N,N’-亞異丙基二胺、N-對硝基亞苯甲基胺、N-亞柳基胺、N-5-氯亞柳基胺、N-(5-氯-2-羥基苯基)苯基亞甲基胺、N-亞環己基胺、N-(5,5-二甲基-3-側氧基-1-環己烯基)胺、N-硼烷衍生物、N-二苯基次硼酸衍生物、N-[苯基(五醯基鉻-或鎢)醯基]胺、N-銅螯合物、N-鋅螯合物、N-硝基胺、N-亞硝基胺、胺N-氧化物、二苯基膦醯胺(Dpp)、二甲基硫基膦醯胺(Mpt)、二苯基硫基膦醯胺(Ppt)、胺基磷酸二烷酯、胺基磷酸二苯甲酯、胺基磷酸二苯酯、苯次磺醯胺、鄰硝基苯次磺醯胺(Nps)、2,4-二硝基苯次磺醯胺、五氯苯次磺醯胺、2-硝基-4-甲氧基苯次磺醯胺、三苯基甲基次磺醯胺及3-硝基吡啶次磺醯胺(Npys)。Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives,N' -toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives,N -benzoylphenylpropenylaminoacyl derivatives,N -acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one,N -phthalimide,N -dithiosuccinimide( Dts),N -2,3-diphenylmaleimide,N -2,5-dimethylpyrrole,N- -1,1,4,4-tetramethyldisilazane cyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone,N -methylamine,N -allylamine,N -[2-(trimethylsilyl)ethoxy]methylamine (SEM),N -3-acetoxypropylamine,N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salt,N -benzylamine,N -di(4-methoxyphenyl)methylamine,N -5-dibenzocycloheptylamine,N -triphenylmethylamine (Tr),N -[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N -9-phenylfluorenylamine (PhF),N -2,7-dichloro-9-fluorenylmethyleneamine,N -ferrocenylmethylamine (Fcm),N -2-methylpyridinylamineN' -oxide,N -1,1-dimethylthiomethyleneamine,N -benzylideneamine, N-p-methoxybenzylideneamine, N -diphenylmethyleneamine, N-[( 2-pyridinyl)mesityl]methyleneamine,N -(N',N' -dimethylaminomethylene)amine, N,N'-isopropylenediamine,N -p-nitrobenzylideneamine,N -salvinylamine,N -5-chlorosalvinylamine,N -(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N -cyclohexylamine,N -(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N -borane derivatives,N -diphenylboronic acid derivatives,N -[phenyl(pentaylchromium- or tungsten)acyl]amine,N -copper chelates,N -zinc chelates,N -nitroamines,N -nitrosoamines, amineN- oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphonamidates, diphenylmethylphosphonamidates, diphenylphosphonamidates, benzenesulfonamides, 2-nitrobenzenesulfonamide (Nps), 2,4-dinitrobenzenesulfonamide, pentachlorobenzenesulfonamide, 2-nitro-4-methoxybenzenesulfonamide, triphenylmethylsulfonamide, and 3-nitropyridinesulfonamide (Npys).
在某些實施例中，氧原子上存在之取代基為氧保護基團(亦稱為羥基保護基團)。氧保護基團包括(但不限於) -Raa、-N(Rbb)2、-C(=O)SRaa、-C(=O)Raa、-CO2Raa、-C(=O)N(Rbb)2、-C(=NRbb)Raa、-C(=NRbb)ORaa、-C(=NRbb)N(Rbb)2、-S(=O)Raa、-SO2Raa、-Si(Raa)3、-P(Rcc)2、-P(Rcc)3、-P(=O)2Raa、-P(=O)(Raa)2、-P(=O)(ORcc)2、-P(=O)2N(Rbb)2及-P(=O)(NRbb)2，其中Raa、Rbb及Rcc係如本文所定義。氧保護基團為此項技術中所熟知，且包括Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts，第3版，John Wiley & Sons, 1999中所詳細闡述之彼等保護基團，該文獻係以引用方式併入本文中。In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -Raa , -N(Rbb )2 , -C(=O)SRaa , -C(=O)Raa , -CO2 Raa , -C(=O)N(Rbb )2 , -C(=NRbb )Raa , -C(=NRbb )ORaa , -C(=NRbb )N(Rbb )2 , -S(=O)Raa , -SO2 Raa , -Si(Raa )3 , -P(Rcc )2 , -P(Rcc )3 , -P(=O)2 Raa , -P(=O)(Raa )2 , -P(=O)(ORcc )2 , -P(=O)2 N(Rbb )2 and -P(=O)(NRbb )2 , whereinRaa ,Rbb andRcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail inProtecting Groups in Organic Synthesis , TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.
例示性氧保護基團包括(但不限於)甲基、甲氧基甲基(MOM)、甲基硫基甲基(MTM)、第三丁基硫基甲基、(苯基二甲基矽基)甲氧基甲基(SMOM)、苯甲基氧基甲基(BOM)、對甲氧基苯甲基氧基甲基(PMBM)、(4-甲氧基苯氧基)甲基(p-AOM)、癒創木酚甲基(GUM)、第三丁氧基甲基、4-戊烯基氧基甲基(POM)、矽氧基甲基、2-甲氧基乙氧基甲基(MEM)、2,2,2-三氯乙氧基甲基、雙(2-氯乙氧基)甲基、2-(三甲基矽基)乙氧基甲基(SEMOR)、四氫哌喃基(THP)、3-溴四氫哌喃基、四氫噻喃基、1-甲氧基環己基、4-甲氧基四氫哌喃基(MTHP)、4-甲氧基四氫噻喃基、4-甲氧基四氫噻喃基S,S-二氧化物、1-[(2-氯-4-甲基)苯基]-4-甲氧基六氫吡啶-4-基(CTMP)、1,4-二噁烷-2-基、四氫呋喃基、四氫硫呋喃基、2,3,3a,4,5,6,7,7a-八氫-7,8,8-三甲基-4,7-橋亞甲基苯并呋喃-2-基、1-乙氧基乙基、1-(2-氯乙氧基)乙基、1-甲基-1-甲氧基乙基、1-甲基-1-苯甲基氧基乙基、1-甲基-1-苯甲基氧基-2-氟乙基、2,2,2-三氯乙基、2-三甲基矽基乙基、2-(苯基氧硒基)乙基、第三丁基、烯丙基、對氯苯基、對甲氧基苯基、2,4-二硝基苯基、苯甲基(Bn)、對甲氧基苯甲基、3,4-二甲氧基苯甲基、鄰硝基苯甲基、對硝基苯甲基、對鹵基苯甲基、2,6-二氯苯甲基、對氰基苯甲基、對苯基苯甲基、2-甲基吡啶基、4-甲基吡啶基、3-甲基-2-甲基吡啶基N-氧化物、二苯基甲基、p,p’-二硝基二苯甲基、5-二苯并環庚烯酮基、三苯基甲基、α-萘基二苯基甲基、對甲氧基苯基二苯基甲基、二(對甲氧基苯基)苯基甲基、三(對甲氧基苯基)甲基、4-(4'-溴苯甲醯甲基氧基苯基)二苯基甲基、4,4',4''-參(4,5-二氯苯二甲醯亞胺基苯基)甲基、4,4',4''-參(乙醯丙醯基氧基苯基)甲基、4,4',4''-參(苯甲醯基氧基苯基)甲基、3-(咪唑-1-基)雙(4',4''-二甲氧基苯基)甲基、1,1-雙(4-甲氧基苯基)-1'-芘基甲基、9-蒽基、9-(9-苯基)氧雜蒽基、9-(9-苯基-10-側氧基)蒽基、1,3-苯并二硫雜環戊烷(benzodisulfuran)-2-基、苯并異噻唑基S,S-二氧化物、三甲基矽基(TMS)、三乙基矽基(TES)、三異丙基矽基(TIPS)、二甲基異丙基矽基(IPDMS)、二乙基異丙基矽基(DEIPS)、二甲基己基矽基、第三丁基二甲基矽基(TBDMS)、第三丁基二苯基矽基(TBDPS)、三苯甲基矽基、三-對二甲苯基矽基、三苯基矽基、二苯基甲基矽基(DPMS)、第三丁基甲氧基苯基矽基(TBMPS)、甲酸酯、苯甲醯基甲酸酯、乙酸酯、氯乙酸酯、二氯乙酸酯、三氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯基甲氧基乙酸酯、苯氧基乙酸酯、對氯苯氧基乙酸酯、3-苯基丙酸酯、4-側氧基戊酸酯(乙醯丙酸酯)、4,4-(伸乙基二硫基)戊酸酯(乙醯丙醯基二硫縮醛)、新戊酸酯、金剛烷酸酯、巴豆酸酯、4-甲氧基巴豆酸酯、苯甲酸酯、對苯基苯甲酸酯、2,4,6-三甲基苯甲酸酯(均三甲苯甲酸酯(mesitoate))、碳酸第三丁酯(BOC)、碳酸烷酯甲酯、碳酸9-茀酯甲酯(Fmoc)、碳酸烷酯乙酯、碳酸烷酯2,2,2-三氯乙酯(Troc)、碳酸2-(三甲基矽基)酯乙酯(TMSEC)、碳酸2-(苯基磺醯基)酯乙酯(Psec)、碳酸2-(三苯基磷基)酯乙酯(Peoc)、碳酸烷酯異丁酯、碳酸烷酯乙烯酯、碳酸烷酯烯丙酯、碳酸烷酯對硝基苯酯、碳酸烷酯苯甲酯、碳酸烷酯對甲氧基苯甲酯、碳酸烷酯3,4-二甲氧基苯甲酯、碳酸烷酯鄰硝基苯甲酯、碳酸烷酯對硝基苯甲酯、硫代碳酸烷酯S-苯甲酯、碳酸4-乙氧基-1-萘酯、二硫代碳酸甲酯、2-碘苯甲酸酯、4-疊氮基丁酸酯、4-硝基-4-甲基戊酸酯、鄰(二溴甲基)苯甲酸酯、2-甲醯基苯磺酸酯、2-(甲基硫基甲氧基)乙基、4-(甲基硫基甲氧基)丁酸酯、2-(甲基硫基甲氧基甲基)苯甲酸酯、2,6-二氯-4-甲基苯氧基乙酸酯、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯、2,4-雙(1,1-二甲基丙基)苯氧基乙酸酯、氯二苯基乙酸酯、異丁酸酯、單琥珀酸酯、(E)-2-甲基-2-丁烯酸酯、鄰(甲氧基醯基)苯甲酸酯、α-萘甲酸酯、硝酸酯、烷基N,N,N’,N’-四甲基磷醯二胺、N-苯基胺基甲酸烷酯、硼酸酯、二甲基硫代膦醯基、2,4-二硝基苯基次磺酸烷酯、硫酸酯、甲磺酸酯(methanesulfonate、mesylate)、苯甲基磺酸酯及甲苯磺酸酯(Ts)。Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p -AOM), ethoxymethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiazol pyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxyhexahydropyridin-4-yl (CTMP), 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6, 7,7a-octahydro-7,8,8-trimethyl-4,7-oxomethylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenyloxyseleno)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halogenbenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-methylpyridyl, 4-methylpyridyl, 3-methyl-2-methylpyridyl -oxide, diphenylmethyl,p,p' -dinitrodiphenylmethyl, 5-dibenzocycloheptenone, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzylmethyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorobenzyl iminophenyl)methyl, 4,4',4''-tris(acetylpropionyloxyphenyl)methyl, 4,4',4''-tris(benzyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl 9-anthryl, 9-(9-phenyl)oxanthryl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzoisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tritylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethyl Silyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-hydroxypentanoate (acetylpropionate), 4,4-(ethylenedithio)pentanoate (acetylpropionyl dithioacetal), pivalate, adamantium ester, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), tert-butyl carbonate (BOC), alkyl methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl) ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphino) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl thiocarbonateS -Benzyl ester, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E )-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN ,N,N',N' -tetramethylphosphodiamidate,N -phenyl alkyl carbamate, borate, dimethylphosphonothioate, 2,4-dinitrophenyl alkyl sulfenate, sulfate, methanesulfonate (mesylate), benzyl sulfonate and toluene sulfonate (Ts).
在某些實施例中，硫原子上存在之取代基為硫保護基團(亦稱為硫醇保護基團)。硫保護基團包括(但不限於) -Raa、-N(Rbb)2、-C(=O)SRaa、-C(=O)Raa、-CO2Raa、-C(=O)N(Rbb)2、-C(=NRbb)Raa、-C(=NRbb)ORaa、-C(=NRbb)N(Rbb)2、-S(=O)Raa、-SO2Raa、-Si(Raa)3、-P(Rcc)2、-P(Rcc)3、-P(=O)2Raa、-P(=O)(Raa)2、-P(=O)(ORcc)2、-P(=O)2N(Rbb)2及-P(=O)(NRbb)2，其中Raa、Rbb及Rcc係如本文所定義。硫保護基團為此項技術中所熟知，且包括Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts，第3版，John Wiley & Sons, 1999中所詳細闡述之彼等保護基團，該文獻係以引用方式併入本文中。In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also known as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -Raa , -N(Rbb )2 , -C(=O)SRaa , -C(=O)Raa , -CO2 Raa , -C(=O)N(Rbb )2 , -C(=NRbb )Raa , -C(=NRbb )ORaa , -C(=NRbb )N(Rbb )2 , -S(=O)Raa , -SO2 Raa , -Si(Raa )3 , -P(Rcc )2 , -P(Rcc )3 , -P(=O)2 Raa , -P(=O)(Raa )2 , -P(=O)(ORcc )2 , -P(=O)2 N(Rbb )2 and -P(=O)(NRbb )2 , whereinRaa ,Rbb andRcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail inProtecting Groups in Organic Synthesis , TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.
術語「反義寡核苷酸」或「反義股」意指包括與靶核酸互補之區域的寡核苷酸。The term "antisense oligonucleotide" or "antisense strand" refers to an oligonucleotide that includes a region that is complementary to a target nucleic acid.
術語「組合物」或「醫藥組合物」意指適於向個體投與之物質混合物。舉例而言，組合物可包含一或多種化合物或其鹽及無菌水溶液。The term "composition" or "pharmaceutical composition" refers to a mixture of substances suitable for administration to an individual. For example, a composition may include one or more compounds or their salts and a sterile aqueous solution.
術語「核酸」係指由連接之單體核苷酸或核苷構成之分子。核酸包括(但不限於)核糖核酸(RNA)、去氧核糖核酸(DNA)、單股核酸及雙股核酸。The term "nucleic acid" refers to a molecule composed of linked monomeric nucleotides or nucleosides. Nucleic acids include (but are not limited to) ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acid and double-stranded nucleic acid.
術語「核鹼基序列」意指核酸或寡核苷酸中鄰接核鹼基之順序，該順序與任何糖或核苷間鍵聯無關。The term "nucleobase sequence" refers to the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.
術語「核苷」意指包含核鹼基及糖部分之化合物。核鹼基及糖部分各自獨立地未經修飾或經修飾。「經修飾之核苷」意指包含經修飾之核鹼基及/或經修飾之糖部分的核苷。經修飾之核苷包括缺少核鹼基之無鹼基核苷。The term "nucleoside" means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each independently unmodified or modified. "Modified nucleoside" means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides lacking a nucleobase.
術語「寡聚化合物」意指連接亞單元之聚合物。就蛋白質、肽、多肽或抗體而言，「亞單元」係指胺基酸或肽鍵。就寡核苷酸而言，「亞單元」係指如本文所提供之核苷酸、核苷、核鹼基或糖或者經修飾之核苷酸、核苷、核鹼基或糖。The term "oligomeric compound" means a polymer of linked subunits. In the case of a protein, peptide, polypeptide or antibody, a "subunit" refers to an amino acid or a peptide bond. In the case of an oligonucleotide, a "subunit" refers to a nucleotide, a nucleoside, a nucleobase or a sugar or a modified nucleotide, nucleoside, nucleobase or sugar as provided herein.
術語「寡核苷酸」意指連接核苷之聚合物(例如多核苷酸、核酸、核苷酸聚合物)，其各自可彼此獨立地經修飾或未經修飾。不受限制，寡核苷酸可包含核糖核酸(例如，包含核糖核苷)、去氧核糖核酸(例如，包含去氧核糖核苷)、經修飾之核酸(例如，包含經修飾之核鹼基、糖及/或磷酸酯基)或其組合。寡核苷酸化合物之實例包括單股及雙股化合物，諸如寡核苷酸、反義寡核苷酸、干擾RNA化合物(RNAi化合物)、靶向寡核苷酸之微小RNA (miRNA)、miRNA模擬物、佔位型化合物(例如mRNA加工或轉譯阻斷化合物及剪接化合物)及編輯化合物(例如ADAR募集分子、ADAR靶向分子、單股嚮導核酸或其組合)。RNAi化合物包括雙股化合物(例如短干擾RNA (siRNA)及雙股RNA (dsRNA))及單股化合物(例如單股siRNA (ssRNA)、單股RNAi (ssRNAi)、短髮夾RNA (shRNA)及微小RNA模擬物)，其至少部分地經由RNA誘導之沈默複合物(RISC)路徑起作用，從而經由稱為RNA干擾(RNAi)之過程導致靶核酸之序列特異性降解及/或螯合。術語「RNAi化合物」意欲等同於用於描述能夠介導序列特異性RNA干擾之核酸化合物之其他術語，例如干擾RNA (iRNA)、iRNA劑、RNAi劑、小干擾RNA、短干擾RNA、短干擾寡核苷酸、短干擾核酸、短干擾經修飾之寡核苷酸、經化學修飾之siRNA等。另外，術語「RNAi」意欲等同於用於描述序列特異性RNA干擾之其他術語。The term "oligonucleotide" means a polymer of linked nucleosides (e.g., polynucleotides, nucleic acids, nucleotide polymers), each of which may be modified or unmodified independently of one another. Without limitation, an oligonucleotide may comprise a ribonucleic acid (e.g., comprising ribonucleosides), a deoxyribonucleic acid (e.g., comprising deoxyribonucleosides), a modified nucleic acid (e.g., comprising modified nucleobases, sugars and/or phosphate groups), or a combination thereof. Examples of oligonucleotide compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA targeting oligonucleotides (miRNA), miRNA mimetics, occupier compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and editing compounds (e.g., ADAR recruitment molecules, ADAR targeting molecules, single-stranded guide nucleic acids, or combinations thereof). RNAi compounds include double-stranded compounds (e.g., short interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics) that act at least in part through the RNA-induced silencing complex (RISC) pathway, thereby causing sequence-specific degradation and/or sequestration of target nucleic acids through a process known as RNA interference (RNAi). The term "RNAi compound" is intended to be equivalent to other terms used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, such as interfering RNA (iRNA), iRNA agent, RNAi agent, small interfering RNA, short interfering RNA, short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically modified siRNA, etc. In addition, the term "RNAi" is intended to be equivalent to other terms used to describe sequence-specific RNA interference.
術語「靶核酸」、「靶RNA」及「核酸靶標」均意指能夠由本文所闡述之化合物靶向之核酸。The terms "target nucleic acid," "target RNA," and "nucleic acid target" all refer to a nucleic acid that can be targeted by the compounds described herein.
術語「治療性化合物」包括為個體提供治療益處之任何醫藥劑或化合物。治療性化合物包括核酸、寡聚化合物、寡核苷酸、蛋白質、肽、抗體、小分子及其他此類劑。The term "therapeutic compound" includes any pharmaceutical agent or compound that provides a therapeutic benefit to an individual. Therapeutic compounds include nucleic acids, oligomeric compounds, oligonucleotides, proteins, peptides, antibodies, small molecules, and other such agents.
「靶區域」意指一或多種化合物靶向之靶核酸之一部分。"Target region" means a portion of a target nucleic acid to which one or more compounds are targeted.
「靶向部分」意指例如與不存在此一部分之化合物相比，對選定靶標(例如分子、細胞或細胞類型、區室(例如細胞或器官區室)、組織、器官或身體區域)提供增強親和力之結合基團。"Targeting moiety" means a binding group that provides enhanced affinity for a selected target (e.g., a molecule, cell or cell type, compartment (e.g., a cellular or organ compartment), tissue, organ, or body region), e.g., compared to a compound without such moiety.
「末端基團」意指共價連接至寡核苷酸末端之化學基團或原子團。"Terminus group" refers to a chemical group or group of atoms covalently linked to the end of an oligonucleotide.
術語「配位體」係指與蛋白質、核酸或其他生物分子結合或以其他方式相互作用之物質。在一些實施例中，配位體為小分子。在一些實施例中，配位體結合至蛋白質(例如受體)。在某些實施例中，配位體結合至NMDA受體。The term "ligand" refers to a substance that binds to or otherwise interacts with a protein, nucleic acid, or other biomolecule. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand binds to a protein (e.g., a receptor). In certain embodiments, the ligand binds to an NMDA receptor.
術語「結合」係指兩種分子(例如如本文所闡述之寡核苷酸及配位體)藉由共價鍵接合在一起。與例如配位體或寡核苷酸之共價鍵可連接在該配位體或該寡核苷酸之任何原子處(亦即該配位體或該寡核苷酸之基團)。The term "binding" refers to the joining of two molecules (e.g., an oligonucleotide and a ligand as described herein) together by a covalent bond. The covalent bond to, for example, a ligand or an oligonucleotide can be attached to any atom of the ligand or the oligonucleotide (i.e., a radical of the ligand or the oligonucleotide).
術語「N-甲基-D-天冬胺酸鹽受體」或「NMDA受體」係指在神經元(例如人類中)發現的麩胺酸受體及離子通道。NMDA受體之許多配位體為此項技術中所已知，包括(例如)Neuropharmacology2007, 53(6), 699-723；J. Med. Chem.1990, 33(2), 789-808；Neuroscience2001, 105(3), 663-669；J. Med. Chem.2022, 65(13), 9063-9075；Drugs Fut.2004, 29(10), 992；Drugs Fut.2004, 29(10), 993；及British Journal of Pharmacology2022, 179(6), 1146-1187中所揭示之彼等配位體，該等文獻各自係以引用的方式併入本文中。The term "N -methyl-D-aspartate receptor" or "NMDA receptor" refers to the glutamate receptor and ion channel found in neurons (e.g., in humans). Many ligands for NMDA receptors are known in the art, including, for example, those disclosedin Neuropharmacology 2007, 53(6), 699-723;J. Med. Chem. 1990, 33(2), 789-808;Neuroscience 2001, 105(3), 663-669;J. Med. Chem. 2022, 65(13), 9063-9075;Drugs Fut. 2004, 29(10), 992;Drugs Fut. 2004, 29(10), 993; andBritish Journal of Pharmacology 2022, 179(6), 1146-1187, each of which is incorporated herein by reference.
術語「有義寡核苷酸」或「有義股」意指雙股化合物之股，其包括與該雙股化合物之反義股區域實質上互補之區域。The term "sense oligonucleotide" or "sense strand" refers to a strand of a double-stranded compound that includes a region that is substantially complementary to the antisense strand of the double-stranded compound.
如在本文中可互換使用之術語「微小RNA」及「miRNA」係指短的(例如長度為約20至約24個核苷酸)非編碼核糖核酸(RNA)，其藉由影響mRNA之穩定性及轉譯而參與多細胞生物體中基因表現之轉錄後調控。miRNA由RNA聚合酶II轉錄，作為加帽及多聚腺苷酸化初級轉錄物(初級miRNA)之一部分，其可為編碼蛋白質的或非編碼的。初級轉錄物由Drosha核糖核酸酶III酶裂解，產生長度為大約70個核苷酸之莖環前體miRNA (前miRNA)，其在RNAi路徑中進一步加工。作為此路徑之一部分，前miRNA由細胞質Dicer核糖核酸酶裂解，生成成熟的miRNA及反義miRNA星號(miRNA*)產物。成熟的miRNA併入至RNA誘導之沈默複合物(RISC)中，該複合物經由與miRNA之不完全鹼基配對(亦即部分互補)識別靶mRNA，且最常見的是導致靶mRNA之轉譯抑制或去穩定。此機制最常見的是經由miRNA在靶mRNA之3'非轉譯區(UTR)上結合，此可藉由抑制轉譯(例如藉由阻斷核糖體進入轉譯)或直接導致轉錄物降解而減少基因表現。該術語(亦即miRNA)在本文中可用於指個體miRNA之任何形式(例如前體、初級及/或成熟miRNA)。The terms "microRNA" and "miRNA," as used interchangeably herein, refer to short (e.g., about 20 to about 24 nucleotides in length) noncoding ribonucleic acids (RNAs) that are involved in the post-transcriptional regulation of gene expression in multicellular organisms by affecting the stability and translation of mRNA. miRNAs are transcribed by RNA polymerase II as part of a capped and polyadenylated primary transcript (primary miRNA), which may be protein-coding or noncoding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce a stem-loop precursor miRNA (pre-miRNA) of approximately 70 nucleotides in length, which is further processed in the RNAi pathway. As part of this pathway, pre-miRNAs are cleaved by the cytoplasmic Dicer ribonuclease to generate mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into the RNA-induced silencing complex (RISC), which recognizes the target mRNA through imperfect base pairing (i.e., partial complementation) with the miRNA and most commonly results in the inhibition or destabilization of the translation of the target mRNA. This mechanism is most commonly through the binding of the miRNA to the 3' untranslated region (UTR) of the target mRNA, which can reduce gene expression by inhibiting translation (e.g., by blocking ribosome entry for translation) or directly causing transcript degradation. The term (i.e., miRNA) may be used herein to refer to any form of an individual miRNA (e.g., precursor, primary and/or mature miRNA).
如在本文中可互換使用之術語「小干擾RNA」、「短干擾RNA」及「siRNA」係指以長度為約20至約24個核苷酸之非編碼雙股RNA (dsRNA)分子形式存在且可用於RNA干擾 (RNAi)中之RNA分子。siRNA常發現有磷酸化之5'端及羥基化之3'端，該等3'端通常具有超出反平行股(例如dsRNA分子之互補股) 5'端2個核苷酸之懸突。siRNA可經由結合與其互補之靶序列(例如靶核酸序列)且促進(例如有助於、觸發、啟動) mRNA之降解來干擾特定基因之表現，藉此阻止(例如抑制、沈默、干擾)轉譯。在整合且分離至RISC複合物中後，siRNA與其靶mRNA鹼基配對(例如完全互補)且裂解該靶mRNA，藉此防止該靶mRNA用作轉譯模板。如上文所論述，同樣作為RNAi路徑之一部分，miRNA裝載之RISC複合物掃描細胞質mRNA之潛在互補性(例如部分互補性)。As used interchangeably herein, the terms "small interfering RNA," "short interfering RNA," and "siRNA" refer to RNA molecules that exist as noncoding double-stranded RNA (dsRNA) molecules of about 20 to about 24 nucleotides in length and can be used in RNA interference (RNAi). siRNAs are often found with phosphorylated 5' ends and hydroxylated 3' ends, which 3' ends typically have an overhang of 2 nucleotides beyond the 5' end of the antiparallel strand (e.g., the complementary strand of the dsRNA molecule). siRNAs can interfere with the expression of specific genes by binding to their complementary target sequence (e.g., target nucleic acid sequence) and promoting (e.g., facilitating, triggering, activating) the degradation of mRNA, thereby preventing (e.g., inhibiting, silencing, interfering with) translation. After integration and dissociation into the RISC complex, the siRNA base pairs with its target mRNA (e.g., fully complementary) and cleaves the target mRNA, thereby preventing the target mRNA from being used as a translation template. As discussed above, also as part of the RNAi pathway, the miRNA-loaded RISC complex scans the cytoplasmic mRNA for potential complementarity (e.g., partial complementarity).
如本文可使用之術語「ADAR募集分子」係指一種核酸，其經構形以增加該核酸周圍位域中作用於核糖核酸之腺苷去胺酶(ADAR)酶濃度。在一些實施例中，增加之濃度係相對於不存在ADAR募集分子之給定位域中之濃度。在一些實施例中，ADAR募集分子包含雙股RNA雙鏈體。The term "ADAR recruitment molecule" as used herein refers to a nucleic acid that is configured to increase the concentration of an adenosine deaminase (ADAR) enzyme that acts on ribonucleic acid in a region surrounding the nucleic acid. In some embodiments, the increased concentration is relative to the concentration in a given region where the ADAR recruitment molecule is not present. In some embodiments, the ADAR recruitment molecule comprises a double-stranded RNA duplex.
如本文可使用之術語「ADAR靶向分子」係指經構形以將ADAR分子引導至合意位置(例如位域)之核酸。如本文所用，術語「引導」係指與不存在ADAR靶向分子情形下之濃度相比，提高ADAR在合意位置中之濃度。在一些實施例中，ADAR靶向分子可經構形以藉由改變核酸之序列及/或性質(例如藉由對核鹼基、糖、核苷間鍵聯或其他組件進行修飾)來控制合意位置。在一些實施例中，ADAR靶向分子包含ADAR募集分子及單股嚮導核酸。在一些實施例中，ADAR靶向分子包含雙股RNA雙鏈體及單股嚮導核酸。The term "ADAR targeting molecule" as used herein refers to a nucleic acid that is configured to guide the ADAR molecule to a desired position (e.g., a domain). As used herein, the term "guiding" refers to increasing the concentration of ADAR in a desired position compared to the concentration in the absence of the ADAR targeting molecule. In some embodiments, the ADAR targeting molecule can be configured to control the desired position by changing the sequence and/or properties of the nucleic acid (e.g., by modifying nucleobases, sugars, internucleoside bonds or other components). In some embodiments, the ADAR targeting molecule includes an ADAR recruitment molecule and a single-stranded guide nucleic acid. In some embodiments, the ADAR targeting molecule includes a double-stranded RNA duplex and a single-stranded guide nucleic acid.
如本文可使用之術語「單股嚮導核酸」或「嚮導RNA」係指單股核酸，其包含與靶序列至少部分互補之特異性序列。在一些實施例中，靶序列位於、毗鄰或靠近期望調節ADAR濃度之位域。在一些實施例中，互補性水準足以有助於單股嚮導核酸與靶序列之結合(例如退火)。As used herein, the term "single-stranded guide nucleic acid" or "guide RNA" refers to a single-stranded nucleic acid that includes a specific sequence that is at least partially complementary to a target sequence. In some embodiments, the target sequence is located at, adjacent to, or near a site where modulation of ADAR concentration is desired. In some embodiments, the level of complementarity is sufficient to facilitate binding (e.g., annealing) of the single-stranded guide nucleic acid to the target sequence.
本揭示案之化合物亦可在構成此等化合物之一或多個原子處含有非天然比例之原子同位素。舉例而言，化合物可經放射性同位素放射標記，該等放射性同位素諸如為氚(3H)、碘-125 (125I)或碳-14 (14C)。本揭示案化合物之所有同位素變化形式(無論是否具有放射性)均涵蓋在本揭示案之範圍內。The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium (3H ), iodine-125 (125I ), or carbon-14 (14C ). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
術語「同位素變異體」係指在構成治療劑(例如本文所揭示之化合物及/或經修飾之寡核苷酸)之一或多個原子處含有非天然比例之同位素的此一治療劑。在某些實施例中，治療劑之「同位素變異體」含有非天然比例之一或多種同位素，包括(但不限於)氫(H)、氘(2H)、氚(3H)、碳-11 (11C)、碳-12 (12C)、碳-13 (13C)、碳-14 (14C)、氮-13 (13N)、氮-14 (14N)、氮-15 (15N)、氧-14 (14O)、氧-15 (15O)、氧-16 (16O)、氧-17 (17O)、氧-18 (18O)、氟-17 (17F)、氟-18 (18F)、磷-31 (31P)、磷-32 (32P)、磷-33 (33P)、硫-32 (32S)、硫-33 (33S)、硫-34 (34S)、硫-35 (35S)、硫-36 (36S)、氯-35 (35Cl)、氯-36 (36Cl)、氯-37 (37Cl)、溴-79 (79Br)、溴-81 (81Br)、碘 123 (123I)、碘-125 (125I)、碘-127 (127I)、碘-129 (129I)及碘-131 (131I)。在某些實施例中，治療劑之「同位素變異體」含有非天然比例之一或多種同位素，包括(但不限於)氫(H)、氘(2H)、氚(3H)、碳-11 (11C)、碳-12 (12C)、碳-13 (13C)、碳-14 (14C)、氮-13 (13N)、氮-14 (14N)、氮-15 (15N)、氧-14 (14O)、氧-15 (15O)、氧-16 (16O)、氧-17 (17O)、氧-18 (18O)、氟-17 (17F)、氟-18 (18F)、磷-31 (31P)、磷-32 (32P)、磷-33 (33P)、硫-32 (32S)、硫-33 (33S)、硫-34 (34S)、硫-35 (35S)、硫-36 (36S)、氯-35 (35Cl)、氯-36 (36Cl)、氯-37 (37Cl)、溴-79 (79Br)、溴-81 (81Br)、碘 123 (123I)、碘-125 (125I)、碘-127 (127I)、碘-129 (129I)及碘-131 (131I)。The term "isotopic variant" refers to a therapeutic agent (eg, a compound and/or modified oligonucleotide disclosed herein) that contains unnatural proportions of isotopes at one or more atoms that constitute such an agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes including, but not limited to, hydrogen (H), deuterium (2H ), tritium (3H ), carbon-11 (11C ), carbon-12 (12C ), carbon-13 (13C ), carbon-14 (14C ), nitrogen-13 (13N ), nitrogen-14 (14N ), nitrogen-15 (15N ), oxygen-14 (14O ), oxygen-15 (15O ), oxygen-16 (16O), oxygen-17 (17O ), oxygen-18 (18O), fluorine-17 (17F ), fluorine-18 (18F ), phosphorus-31 (31P ), phosphorus-32 (32P), phosphorus-33 (33P) , sulfur-32 (32 S), sulfur-33 (33 S), sulfur-34 (34 S), sulfur-35 (35 S), sulfur-36 (36 S), chlorine-35 (35 Cl), chlorine-36 (36 Cl), chlorine-37 (37 Cl), bromine-79 (79 Br), bromine-81 (81 Br), iodine-123 (123 I), iodine-125 (125 I), iodine-127 (127 I), iodine-129 (129 I) and iodine-131 (131 I). In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes including, but not limited to, hydrogen (H), deuterium (2H ), tritium (3H ), carbon-11 (11C ), carbon-12 (12C ), carbon-13 (13C ), carbon-14 (14C ), nitrogen-13 (13N ), nitrogen-14 (14N ), nitrogen-15 (15N ), oxygen-14 (14O ), oxygen-15 (15O ), oxygen-16 (16O), oxygen-17 (17O ), oxygen-18 (18O), fluorine-17 (17F ), fluorine-18 (18F ), phosphorus-31 (31P ), phosphorus-32 (32P), phosphorus-33 (33P) , sulfur-32 (32 S), sulfur-33 (33 S), sulfur-34 (34 S), sulfur-35 (35 S), sulfur-36 (36 S), chlorine-35 (35 Cl), chlorine-36 (36 Cl), chlorine-37 (37 Cl), bromine-79 (79 Br), bromine-81 (81 Br), iodine-123 (123 I), iodine-125 (125 I), iodine-127 (127 I), iodine-129 (129 I) and iodine-131 (131 I).
將理解，在治療劑(例如本文所揭示之化合物及/或經修飾之寡核苷酸)中，根據熟習此項技術者之判斷，在可行之情形下，任何氫可為例如2H，或任何碳可為例如13C，或任何氮可為例如15N，或任何氧可為例如18O。在某些實施例中，治療劑之「同位素變異體」含有非天然比例之氘(D)。It will be understood that in a therapeutic agent (e.g., a compound and/or modified oligonucleotide disclosed herein), where applicable, any hydrogen may be, for example,2 H, or any carbon may be, for example,13 C, or any nitrogen may be, for example,15 N, or any oxygen may be, for example,18 O, according to the judgment of one skilled in the art. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of deuterium (D).
「經修飾之寡核苷酸」意指其中至少一個糖、核鹼基或核苷間鍵聯經修飾之寡核苷酸。"Modified oligonucleotide" means an oligonucleotide in which at least one sugar, nucleobase or internucleoside linkage has been modified.
「核鹼基序列」意指核酸或寡核苷酸中鄰接核鹼基之順序，該順序與任何糖或核苷間鍵聯無關。"Nucleobase sequence" means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkages.
術語「寡聚雙鏈體」意指由兩種具有互補核鹼基序列之寡聚化合物形成的雙鏈體。寡聚雙鏈體之每一寡聚化合物可稱為「雙鏈體化之寡聚化合物」。寡聚雙鏈體之每一寡聚化合物之寡核苷酸可包括非互補懸垂核苷。在一些實施例中，術語「雙鏈體化之寡聚化合物」及「經修飾之寡核苷酸」可互換使用。在其他實施例中，術語「寡聚雙鏈體」與「化合物」可互換使用。The term "oligoduplex" means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of the oligoduplex may be referred to as a "duplexed oligomeric compound". The oligonucleotides of each oligomeric compound of the oligoduplex may include non-complementary pendant nucleosides. In some embodiments, the terms "duplexed oligomeric compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligoduplex" and "compound" are used interchangeably.
「硫代磷酸酯鍵聯」意指經修飾之磷酸酯鍵聯，其中一個非橋接氧原子經硫原子置換。"Phosphorothioate linkage" means a modified phosphate linkage in which one of the non-bridging oxygen atoms is replaced by a sulfur atom.
術語「RNA干擾化合物」、「RNAi化合物」及/或「iRNA劑」意指至少部分地經由RNA誘導之沈默複合物(RISC)路徑或Ago2、而不經由RNA酶H起作用，以調節靶核酸及/或由靶核酸編碼之蛋白質之化合物。RNAi化合物包括(但不限於)雙股siRNA、單股siRNA及微小RNA，包括微小RNA模擬物。 某些實施例The term "RNA interference compound", "RNAi compound" and/or "iRNA agent" refers to a compound that acts at least in part via the RNA-induced silencing complex (RISC) pathway or Ago2, rather than via RNase H, to regulate a target nucleic acid and/or a protein encoded by the target nucleic acid. RNAi compounds include (but are not limited to) double-stranded siRNA, single-stranded siRNA, and microRNA, including microRNA mimetics.Certain embodiments
在某些實施例中，化合物包含NMDA受體配位體及一或多個連接體部分。在某些實施例中，化合物係選自如本文所闡述之以下各式中之任一者：I、II、II-a、III、III-a、IV、IV-a、V、V-a、VI、VI-a、VI-b、VII、VII-a、VIII、VIII-a、IX、IX-a、X、X-a，或其鹽。在某些實施例中，該一或多個連接體部分(L1、L2、L3、L4等)將NMDA受體配位體連接至治療劑、預防劑或診斷劑。在某些實施例中，化合物進一步包含一或多種治療劑、預防劑或診斷劑。在某些實施例中，治療劑、預防劑或診斷劑為小分子或寡聚化合物。在某些實施例中，寡聚化合物包含蛋白質、肽、抗體、寡核苷酸或其組合。In some embodiments, the compound comprises an NMDA receptor ligand and one or more linker moieties. In some embodiments, the compound is selected from any of the following formulae as described herein: I, II, II-a, III, III-a, IV, IV-a, V, Va, VI, VI-a, VI-b, VII, VII-a, VIII, VIII-a, IX, IX-a, X, Xa, or a salt thereof. In some embodiments, the one or more linker moieties (L1 , L2 , L3 , L4 , etc.) link the NMDA receptor ligand to a therapeutic, preventive, or diagnostic agent. In some embodiments, the compound further comprises one or more therapeutic, preventive, or diagnostic agents. In certain embodiments, the therapeutic, prophylactic or diagnostic agent is a small molecule or an oligomeric compound. In certain embodiments, the oligomeric compound comprises a protein, a peptide, an antibody, an oligonucleotide or a combination thereof.
在某些實施例中，寡聚化合物為本文所闡述之彼等寡聚化合物中之任一者。在某些實施例中，寡聚化合物之長度為約10-50個亞單元。在某些實施例中，寡聚化合物為寡核苷酸。在某些實施例中，寡核苷酸為本文所闡述之彼等寡核苷酸中之任一者。在某些實施例中，寡核苷酸之長度為8至80個連接核苷、長度為12-50個連接核苷、長度為12-30個連接核苷或長度為15-30個連接核苷。In certain embodiments, the oligomeric compound is any one of those oligomeric compounds described herein. In certain embodiments, the length of the oligomeric compound is about 10-50 subunits. In certain embodiments, the oligomeric compound is an oligonucleotide. In certain embodiments, the oligonucleotide is any one of those oligonucleotides described herein. In certain embodiments, the length of the oligonucleotide is 8 to 80 linked nucleosides, the length is 12-50 linked nucleosides, the length is 12-30 linked nucleosides, or the length is 15-30 linked nucleosides.
在某些實施例中，寡核苷酸為經修飾之寡核苷酸，其包含至少一個經修飾之核苷間鍵聯、至少一個經修飾之糖或至少一個經修飾之核鹼基。In certain embodiments, the oligonucleotide is a modified oligonucleotide comprising at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase.
在某些實施例中，寡核苷酸係單股的。在某些實施例中，寡核苷酸係雙股的。在某些實施例中，寡核苷酸在其一部分長度上係雙股的。在某些實施例中，寡核苷酸包含核糖核酸(例如包含核糖核苷)、去氧核糖核酸(例如包含去氧核糖核苷)或其組合。在某些實施例中，寡核苷酸為小干擾RNA (siRNA)、微小RNA (miRNA)拮抗劑、miRNA模擬物、ADAR募集分子、ADAR靶向分子、嚮導RNA、反義寡核苷酸、短髮夾RNA (shRNA)或其組合。In some embodiments, the oligonucleotide is single-stranded. In some embodiments, the oligonucleotide is double-stranded. In some embodiments, the oligonucleotide is double-stranded over a portion of its length. In some embodiments, the oligonucleotide comprises ribonucleic acid (e.g., comprising ribonucleosides), deoxyribonucleic acid (e.g., comprising deoxyribonucleosides), or a combination thereof. In some embodiments, the oligonucleotide is a small interfering RNA (siRNA), a microRNA (miRNA) antagonist, a miRNA mimetic, an ADAR recruiting molecule, an ADAR targeting molecule, a guide RNA, an antisense oligonucleotide, a short hairpin RNA (shRNA), or a combination thereof.
在一些實施例中，連接體為視情況經取代之烷基連接體。在一些實施例中，連接體為視情況經取代之C1-C6烷基連接體。在一些實施例中，連接體為經=O取代之C1-C6烷基連接體。在某些實施例中，連接體包含結構。在一些實施例中，連接體為視情況經取代之C1-C15烷基連接體。在一些實施例中，連接體為視情況經取代之C5-C12烷基連接體。在某些實施例中，連接體包含結構。在某些實施例中，連接體包含結構。In some embodiments, the linker is an optionally substituted alkyl linker. In some embodiments, the linker is an optionally substituted C1 -C6 alkyl linker. In some embodiments, the linker is a C1 -C6 alkyl linker substituted with =O. In certain embodiments, the linker comprises the structure In some embodiments, the linker is an optionally substituted C1 -C15 alkyl linker. In some embodiments, the linker is an optionally substituted C5 -C12 alkyl linker. In certain embodiments, the linker comprises the structure In some embodiments, the connector includes a structure .
在一些實施例中，連接體為鍵。在一些實施例中，連接體為視情況經取代之PEG連接體。在一些實施例中，連接體為視情況經取代之PEG連接體，其長度包含一個、兩個、三個、四個、五個、六個、七個或八個PEG單元，其中PEG單元包含結構。在某些實施例中，連接體為視情況經取代之PEG連接體，其長度包含三個PEG單元。在某些實施例中，連接體為視情況經取代之PEG連接體，其長度包含四個PEG單元。在某些實施例中，連接體包含結構。在某些實施例中，連接體包含結構。在某些實施例中，連接體包含結構。在某些實施例中，連接體包含結構。在某些實施例中，連接體包含結構。在某些實施例中，連接體包含結構。在某些實施例中，連接體包含結構。在某些實施例中，連接體包含結構。In some embodiments, the linker is a bond. In some embodiments, the linker is an optionally substituted PEG linker. In some embodiments, the linker is an optionally substituted PEG linker having a length comprising one, two, three, four, five, six, seven, or eight PEG units, wherein the PEG unit comprises the structure In some embodiments, the linker is an optionally substituted PEG linker comprising three PEG units in length. In some embodiments, the linker is an optionally substituted PEG linker comprising four PEG units in length. In some embodiments, the linker comprises the structure In some embodiments, the connector includes a structure In some embodiments, the connector includes a structure In some embodiments, the connector includes a structure In some embodiments, the connector includes a structure In some embodiments, the connector includes a structure In some embodiments, the connector includes a structure In some embodiments, the connector includes a structure .
在一些實施例中，連接體為視情況經取代之雜烷基連接體。在某些實施例中，連接體包含結構。在某些實施例中，連接體包含結構。In some embodiments, the linker is an optionally substituted heteroalkyl linker. In certain embodiments, the linker comprises the structure In some embodiments, the connector includes a structure .
在一些實施例中，連接體為視情況經取代之雜芳基連接體。在一些實施例中，連接體為視情況經取代之部分不飽和雜環烷基連接體或雜芳基連接體。在一些實施例中，連接體包含結構。In some embodiments, the linker is an optionally substituted heteroaryl linker. In some embodiments, the linker is an optionally substituted partially unsaturated heterocycloalkyl linker or a heteroaryl linker. In some embodiments, the linker comprises the structure .
在一些實施例中，連接體為視情況經取代之雜烷基連接體。在一些實施例中，連接體經一或多個=O取代基取代。在某些實施例中，連接體包含結構，其中X為O或S。在某些實施例中，連接體包含結構，其中X為O或S。In some embodiments, the linker is an optionally substituted heteroalkyl linker. In some embodiments, the linker is substituted with one or more =0 substituents. In certain embodiments, the linker comprises the structure , wherein X is O or S. In certain embodiments, the linker comprises a structure , where X is O or S.
在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。在一些實施例中，連接體包含結構，其中X為O或S。In some embodiments, the connector includes a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , wherein X is O or S. In some embodiments, the linker comprises a structure , where X is O or S.
在某些實施例中，化合物包含以下結構中之一者或由以下結構中之一者組成：、、、、、、、、、、、、、、、、、、、、、、、、、、、， 或其鹽，其中X為O或S。In certain embodiments, the compound comprises or consists of one of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , or a salt thereof, wherein X is O or S.
在一些實施例中，X為O。在一些實施例中，X為S。In some embodiments, X is O. In some embodiments, X is S.
在一些實施例中，R1包含寡核苷酸。在一些實施例中，寡核苷酸在其5'端連接。在一些實施例中，寡核苷酸在其3'端連接。在一些實施例中，寡核苷酸在寡核苷酸上之內部位置連接。在一些實施例中，內部位置位於核苷間鍵聯處。在一些實施例中，R1包含與一或多種額外之NMDA受體配位體結合之寡核苷酸。在一些實施例中，寡核苷酸與兩種、三種、四種、五種或五種以上之額外NMDA受體配位體結合。在某些實施例中，額外之NMDA受體配位體在寡核苷酸之5'端、寡核苷酸之3'端、寡核苷酸上之一或多個內部位置或其任何組合處與寡核苷酸結合。在某些實施例中，寡核苷酸為經修飾之寡核苷酸。In some embodiments,R comprises an oligonucleotide. In some embodiments, the oligonucleotide is connected at its 5' end. In some embodiments, the oligonucleotide is connected at its 3' end. In some embodiments, the oligonucleotide is connected at an internal position on the oligonucleotide. In some embodiments, the internal position is located at the internucleoside bond. In some embodiments,R comprises an oligonucleotide bound to one or more additional NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to two, three, four, five or more additional NMDA receptor ligands. In certain embodiments, the additional NMDA receptor ligand is bound to the oligonucleotide at the 5' end of the oligonucleotide, the 3' end of the oligonucleotide, one or more internal positions on the oligonucleotide, or any combination thereof. In certain embodiments, the oligonucleotide is a modified oligonucleotide.
某些實施例提供組合物，其包含本文任一實施例之化合物以及醫藥學上可接受之載劑或賦形劑。Certain embodiments provide compositions comprising a compound of any one of the embodiments herein and a pharmaceutically acceptable carrier or formulation.
某些實施例提供包含本文任一實施例之化合物之組合物，其用於療法中。Certain embodiments provide a composition comprising a compound of any one of the embodiments herein for use in therapy.
在某些實施例中，向細胞遞送劑之方法包括使該細胞與本文任一實施例之化合物接觸，藉此將該劑遞送至該細胞。在某些實施例中，細胞在細胞表面上表現NMDA受體。在某些實施例中，細胞為腦細胞。在某些實施例中，細胞為額葉皮質之細胞。在某些實施例中，細胞為紋狀體之細胞。在某些實施例中，細胞為小腦之細胞。在某些實施例中，細胞為腦幹之細胞。在某些實施例中，細胞為海馬體之細胞。在某些實施例中，細胞為脊髓之細胞。在某些實施例中，劑為治療劑或診斷劑。在某些實施例中，細胞在動物體內。In some embodiments, the method of delivering an agent to a cell comprises contacting the cell with a compound of any of the embodiments herein, thereby delivering the agent to the cell. In some embodiments, the cell expresses an NMDA receptor on the cell surface. In some embodiments, the cell is a brain cell. In some embodiments, the cell is a cell of the frontal cortex. In some embodiments, the cell is a cell of the striatum. In some embodiments, the cell is a cell of the cerebellum. In some embodiments, the cell is a cell of the brain stem. In some embodiments, the cell is a cell of the hippocampus. In some embodiments, the cell is a cell of the spinal cord. In some embodiments, the agent is a therapeutic or diagnostic agent. In some embodiments, the cell is in an animal.
在某些實施例中，調節核酸靶標在細胞中之表現之方法包括使該細胞與本文任一實施例之化合物接觸，藉此調節該核酸靶標在該細胞中之表現。在某些實施例中，細胞在細胞表面上表現NMDA受體。在某些實施例中，細胞為腦細胞。在某些實施例中，細胞為額葉皮質之細胞。在某些實施例中，細胞為紋狀體之細胞。在某些實施例中，細胞為小腦之細胞。在某些實施例中，細胞為腦幹之細胞。在某些實施例中，細胞為海馬體之細胞。在某些實施例中，細胞為脊髓之細胞。在某些實施例中，劑為治療劑或診斷劑。在某些實施例中，使細胞與本文任一實施例之化合物接觸抑制核酸靶標之表現。在某些實施例中，核酸靶標為前mRNA、mRNA、非編碼RNA或miRNA。在某些實施例中，細胞在動物體內。In some embodiments, the method of modulating the expression of a nucleic acid target in a cell comprises contacting the cell with a compound of any embodiment of the present invention, thereby modulating the expression of the nucleic acid target in the cell. In some embodiments, the cell expresses an NMDA receptor on the cell surface. In some embodiments, the cell is a brain cell. In some embodiments, the cell is a cell of the frontal cortex. In some embodiments, the cell is a cell of the striatum. In some embodiments, the cell is a cell of the cerebellum. In some embodiments, the cell is a cell of the brain stem. In some embodiments, the cell is a cell of the hippocampus. In some embodiments, the cell is a cell of the spinal cord. In some embodiments, the agent is a therapeutic or diagnostic agent. In some embodiments, contacting a cell with a compound of any embodiment herein inhibits expression of a nucleic acid target. In some embodiments, the nucleic acid target is a pre-mRNA, mRNA, non-coding RNA, or miRNA. In some embodiments, the cell is in an animal.
在某些實施例中，調節核酸靶標在個體中之表現之方法包括向該個體投與本文所提供之任一化合物或組合物，藉此調節該核酸靶標在該個體中之表現。在某些實施例中，調節個體之細胞中核酸之表現，該細胞在細胞表面上表現NMDA受體。在某些實施例中，調節腦細胞中核酸之表現。在某些實施例中，在表面上表現NMDA受體之細胞為腦細胞。在某些實施例中，腦細胞為額葉皮質之細胞。在某些實施例中，腦細胞為紋狀體之細胞。在某些實施例中，腦細胞為小腦之細胞。在某些實施例中，腦細胞為腦幹之細胞。在某些實施例中，腦細胞為海馬體之細胞。在某些實施例中，腦細胞為脊髓之細胞。在某些實施例中，核酸靶標為前mRNA、mRNA、非編碼RNA或miRNA。在某些實施例中，將化合物鞘內投與給個體。In certain embodiments, a method for modulating the expression of a nucleic acid target in an individual comprises administering to the individual any compound or composition provided herein, thereby modulating the expression of the nucleic acid target in the individual. In certain embodiments, the expression of nucleic acids in cells of an individual is modulated, and the cells express NMDA receptors on the cell surface. In certain embodiments, the expression of nucleic acids in brain cells is modulated. In certain embodiments, the cells expressing NMDA receptors on the surface are brain cells. In certain embodiments, the brain cells are cells of the frontal cortex. In certain embodiments, the brain cells are cells of the striatum. In certain embodiments, the brain cells are cells of the cerebellum. In certain embodiments, the brain cells are cells of the brain stem. In some embodiments, the brain cell is a cell of the hippocampus. In some embodiments, the brain cell is a cell of the spinal cord. In some embodiments, the nucleic acid target is a pre-mRNA, mRNA, non-coding RNA or miRNA. In some embodiments, the compound is administered intrathecally to the subject.
在某些實施例中，治療或改善個體之疾病、病症或其症狀之方法包括向該個體投與本文所提供之任一化合物或組合物，藉此治療、預防或改善該個體之疾病、病症或症狀。在某些實施例中，疾病、病症或其症狀為中樞神經系統(CNS)疾病、病症或其症狀。在某些實施例中，疾病、病症或其症狀為阿茲海默氏病或其症狀。在某些實施例中，將化合物鞘內投與給個體。在某些實施例中，將化合物或組合物以治療有效量投與給個體。In certain embodiments, a method of treating or ameliorating a disease, disorder, or symptom thereof in an individual comprises administering to the individual any compound or composition provided herein, thereby treating, preventing, or ameliorating the disease, disorder, or symptom of the individual. In certain embodiments, the disease, disorder, or symptom thereof is a central nervous system (CNS) disease, disorder, or symptom thereof. In certain embodiments, the disease, disorder, or symptom thereof is Alzheimer's disease or a symptom thereof. In certain embodiments, the compound is administered intrathecally to the individual. In certain embodiments, the compound or composition is administered to the individual in a therapeutically effective amount.
在某些實施例中，與不表現NMDA受體之細胞相比，包含NMDA受體配位體之化合物選擇性地或優先靶向表現NMDA受體之細胞。在某些實施例中，與不包含NMDA受體配位體之化合物相比，包含NMDA受體配位體之化合物選擇性地或優先靶向表現NMDA受體之細胞。In certain embodiments, a compound comprising an NMDA receptor ligand selectively or preferentially targets cells expressing an NMDA receptor compared to cells not expressing an NMDA receptor. In certain embodiments, a compound comprising an NMDA receptor ligand selectively or preferentially targets cells expressing an NMDA receptor compared to a compound not comprising an NMDA receptor ligand.
本文亦提供如本文所闡述之化合物之用途，其用於製造用以治療疾病或病症之藥劑。Also provided herein is the use of a compound as described herein in the manufacture of a medicament for the treatment of a disease or disorder.
在另一態樣中，本揭示案提供製備本文所提供之任一化合物之方法，該等化合物包含本文所闡述之一或多種化合物及化學轉變，包括實例1至77。 包含寡核苷酸之某些化合物In another aspect, the present disclosure provides methods for preparing any of the compounds provided herein, comprising one or more compounds and chemical transformations described herein, including Examples 1 to 77.Certain compounds comprising oligonucleotides
在某些實施例中，本文所闡述之化合物包含寡核苷酸。在某些實施例中，寡核苷酸具有與靶核酸序列(例如細胞內表現之靶核酸)至少部分互補之核鹼基序列。在一些實施例中，寡核苷酸在遞送至表現靶核酸之細胞後，能夠改進潛在基因之表現。在一些實施例中，寡核苷酸在遞送至表現靶核酸之細胞後，能夠抑制潛在基因之表現。基因表現可在活體外或活體內改進或抑制。在某些實施例中，寡核苷酸包含一或多個核糖核酸(例如一或多個核糖核苷)、去氧核糖核酸(例如一或多個去氧核糖核苷)、經修飾之核酸(例如一或多個經修飾之核鹼基、糖及/或核苷間鍵聯)或其組合。在一些實施例中，寡核苷酸包含核糖核酸(RNA)。在一些實施例中，寡核苷酸包含去氧核糖核酸(DNA)。在一些實施例中，寡核苷酸包含修飾(例如經修飾之核鹼基、經修飾之糖或經修飾之核苷間鍵聯)。In certain embodiments, the compounds described herein comprise oligonucleotides. In certain embodiments, the oligonucleotide has a nucleobase sequence that is at least partially complementary to a target nucleic acid sequence (e.g., a target nucleic acid expressed in a cell). In certain embodiments, the oligonucleotide can improve the expression of a potential gene after delivery to a cell expressing a target nucleic acid. In certain embodiments, the oligonucleotide can inhibit the expression of a potential gene after delivery to a cell expressing a target nucleic acid. Gene expression can be improved or inhibited in vitro or in vivo. In certain embodiments, the oligonucleotide comprises one or more ribonucleic acids (e.g., one or more ribonucleosides), deoxyribonucleic acids (e.g., one or more deoxyribonucleosides), modified nucleic acids (e.g., one or more modified nucleobases, sugars and/or internucleoside linkages), or combinations thereof. In some embodiments, the oligonucleotide comprises ribonucleic acid (RNA). In some embodiments, the oligonucleotide comprises deoxyribonucleic acid (DNA). In some embodiments, the oligonucleotide comprises a modification (e.g., a modified nucleobase, a modified sugar, or a modified internucleoside linkage).
在某些實施例中，寡核苷酸係單股的。在一些實施例中，單股寡核苷酸為單股RNA (ssRNA)、ssDNA或ssRNA/DNA雜合體(例如單股寡核苷酸包含核糖核苷(經修飾或未經修飾)及去氧核糖核苷(經修飾或未經修飾)二者)。在一些實施例中，寡核苷酸係雙股的(例如包含兩個單股核酸)。此類雙股寡核苷酸包含具有與靶核酸互補之區域的第一寡核苷酸及具有與該第一寡核苷酸互補之區域的第二寡核苷酸。第一寡核苷酸及第二寡核苷酸可獨立地經修飾。在某些實施例中，第一寡核苷酸連接至一或多個NMDA受體配位體。在某些實施例中，第二寡核苷酸連接至一或多個NMDA受體配位體。In some embodiments, the oligonucleotide is single-stranded. In some embodiments, the single-stranded oligonucleotide is a single-stranded RNA (ssRNA), ssDNA or a ssRNA/DNA hybrid (e.g., a single-stranded oligonucleotide comprises both ribonucleosides (modified or unmodified) and deoxyribonucleosides (modified or unmodified)). In some embodiments, the oligonucleotide is double-stranded (e.g., comprising two single-stranded nucleic acids). Such double-stranded oligonucleotides comprise a first oligonucleotide having a region complementary to the target nucleic acid and a second oligonucleotide having a region complementary to the first oligonucleotide. The first oligonucleotide and the second oligonucleotide may be independently modified. In some embodiments, the first oligonucleotide is linked to one or more NMDA receptor ligands. In some embodiments, the second oligonucleotide is linked to one or more NMDA receptor ligands.
在一些實施例中，寡核苷酸之長度為至少2個(例如2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150或更多個)核苷酸。在一些實施例中，寡核苷酸之長度為至少5個核苷酸。在一些實施例中，寡核苷酸之長度為至少10個核苷酸。在一些實施例中，寡核苷酸之長度為至少15個核苷酸。在一些實施例中，寡核苷酸之長度為至少16個核苷酸。在一些實施例中，寡核苷酸之長度為至少17個核苷酸。在一些實施例中，寡核苷酸之長度為至少18個核苷酸。在一些實施例中，寡核苷酸之長度為至少19個核苷酸。在一些實施例中，寡核苷酸之長度為至少20個核苷酸。在一些實施例中，寡核苷酸之長度為至少21個核苷酸。在一些實施例中，寡核苷酸之長度為至少22個核苷酸。在一些實施例中，寡核苷酸之長度為至少23個核苷酸。在一些實施例中，寡核苷酸之長度為至少24個核苷酸。在一些實施例中，寡核苷酸之長度為至少25個核苷酸。在一些實施例中，寡核苷酸之長度為至少26個核苷酸。在一些實施例中，寡核苷酸之長度為至少27個核苷酸。在一些實施例中，寡核苷酸之長度為至少28個核苷酸。在一些實施例中，寡核苷酸之長度為至少29個核苷酸。在一些實施例中，寡核苷酸之長度為至少30個核苷酸。在一些實施例中，寡核苷酸之長度為至少40個核苷酸。在一些實施例中，寡核苷酸之長度為至少50個核苷酸。在一些實施例中，寡核苷酸之長度為至少60個核苷酸。在一些實施例中，寡核苷酸之長度為至少70個核苷酸。在一些實施例中，寡核苷酸之長度為至少80個核苷酸。在一些實施例中，寡核苷酸之長度為至少90個核苷酸。在一些實施例中，寡核苷酸之長度為至少100個核苷酸。在一些實施例中，寡核苷酸之長度為至少150個核苷酸。In some embodiments, the length of the oligonucleotide is at least 2 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 6 0, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 ,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 1 In some embodiments, the oligonucleotide has a length of at least 5 nucleotides. In some embodiments, the oligonucleotide has a length of at least 10 nucleotides. In some embodiments, the oligonucleotide has a length of at least 15 nucleotides. In some embodiments, the oligonucleotide has a length of at least 16 nucleotides. In some embodiments, the oligonucleotide has a length of at least 17 nucleotides. In some embodiments, the oligonucleotide has a length of at least 18 nucleotides. In some embodiments, the length of the oligonucleotide is at least 19 nucleotides. In some embodiments, the length of the oligonucleotide is at least 20 nucleotides. In some embodiments, the length of the oligonucleotide is at least 21 nucleotides. In some embodiments, the length of the oligonucleotide is at least 22 nucleotides. In some embodiments, the length of the oligonucleotide is at least 23 nucleotides. In some embodiments, the length of the oligonucleotide is at least 24 nucleotides. In some embodiments, the length of the oligonucleotide is at least 25 nucleotides. In some embodiments, the length of the oligonucleotide is at least 26 nucleotides. In some embodiments, the length of the oligonucleotide is at least 27 nucleotides. In some embodiments, the length of the oligonucleotide is at least 28 nucleotides. In some embodiments, the length of the oligonucleotide is at least 29 nucleotides. In some embodiments, the length of the oligonucleotide is at least 30 nucleotides. In some embodiments, the length of the oligonucleotide is at least 40 nucleotides. In some embodiments, the length of the oligonucleotide is at least 50 nucleotides. In some embodiments, the length of the oligonucleotide is at least 60 nucleotides. In some embodiments, the length of the oligonucleotide is at least 70 nucleotides. In some embodiments, the length of the oligonucleotide is at least 80 nucleotides. In some embodiments, the length of the oligonucleotide is at least 90 nucleotides. In some embodiments, the length of the oligonucleotide is at least 100 nucleotides. In some embodiments, the length of the oligonucleotide is at least 150 nucleotides.
在一些實施例中，寡核苷酸之長度小於或等於150個(例如2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150個)核苷酸。在一些實施例中，寡核苷酸之長度小於或等於150個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於100個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於90個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於80個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於70個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於60個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於50個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於40個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於30個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於29個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於28個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於27個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於26個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於25個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於24個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於23個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於22個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於21個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於20個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於19個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於18個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於17個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於16個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於15個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於10個核苷酸。在一些實施例中，寡核苷酸之長度小於或等於5個核苷酸。In some embodiments, the length of the oligonucleotide is less than or equal to 150 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 ,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82 ,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,1 03, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 11 In some embodiments, the oligonucleotide has a length of less than or equal to 150 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 100 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 90 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 80 nucleotides. In some embodiments, the oligonucleotide has a length of less than or equal to 70 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 60 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 50 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 40 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 30 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 29 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 28 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 27 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 26 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 25 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 24 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 23 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 22 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 21 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 20 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 19 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 18 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 17 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 16 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 15 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 10 nucleotides. In some embodiments, the length of the oligonucleotide is less than or equal to 5 nucleotides.
在一些實施例中，寡核苷酸長約5個核苷酸至長約150個核苷酸。在一些實施例中，寡核苷酸長約10個核苷酸至長約100個核苷酸。在一些實施例中，寡核苷酸長約20個核苷酸至長約90個核苷酸。在一些實施例中，寡核苷酸長約30個核苷酸至長約80個核苷酸。在一些實施例中，寡核苷酸長約40個核苷酸至長約70個核苷酸。在一些實施例中，寡核苷酸長約50個核苷酸至長約60個核苷酸。In some embodiments, the oligonucleotide is about 5 nucleotides long to about 150 nucleotides long. In some embodiments, the oligonucleotide is about 10 nucleotides long to about 100 nucleotides long. In some embodiments, the oligonucleotide is about 20 nucleotides long to about 90 nucleotides long. In some embodiments, the oligonucleotide is about 30 nucleotides long to about 80 nucleotides long. In some embodiments, the oligonucleotide is about 40 nucleotides long to about 70 nucleotides long. In some embodiments, the oligonucleotide is about 50 nucleotides long to about 60 nucleotides long.
在一些實施例中，寡核苷酸為治療性寡核苷酸。治療性寡核苷酸可包含例如(但不限於)小干擾RNA (siRNA)、微小RNA (miRNA)拮抗劑、miRNA模擬物、ADAR募集分子、ADAR靶向分子、嚮導RNA、反義寡核苷酸、短髮夾RNA (shRNA)或其組合。In some embodiments, the oligonucleotide is a therapeutic oligonucleotide. The therapeutic oligonucleotide may include, for example, but not limited to, small interfering RNA (siRNA), microRNA (miRNA) antagonists, miRNA mimics, ADAR recruiting molecules, ADAR targeting molecules, guide RNA, antisense oligonucleotides, short hairpin RNA (shRNA), or a combination thereof.
在某些實施例中，miRNA為前體、初級及/或成熟miRNA。In certain embodiments, the miRNA is a precursor, pro-miRNA and/or mature miRNA.
在某些實施例中，寡核苷酸包含反義寡核苷酸或由其組成。在某些實施例中，反義寡核苷酸與mRNA互補。在某些實施例中，反義寡核苷酸與前mRNA互補。在某些實施例中，反義寡核苷酸阻斷mRNA轉錄物之轉譯且促進其降解。在某些實施例中，反義寡核苷酸募集RNA酶H且促進mRNA轉錄物之降解。在某些實施例中，反義寡核苷酸靶向miRNA，此抑制miRNA調節mRNA表現且促進miRNA之降解。某些修飾In certain embodiments, the oligonucleotide comprises or consists of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide is complementary to mRNA. In certain embodiments, the antisense oligonucleotide is complementary to pre-mRNA. In certain embodiments, the antisense oligonucleotide blocks the translation of mRNA transcripts and promotes their degradation. In certain embodiments, the antisense oligonucleotide recruits RNase H and promotes the degradation of mRNA transcripts. In certain embodiments, the antisense oligonucleotide targets miRNA, which inhibits miRNA regulation of mRNA expression and promotes the degradation of miRNA.Certain modifications
在某些態樣中，本揭示案係關於包含寡核苷酸之化合物。在某些實施例中，寡核苷酸可為未經修飾之RNA或DNA，或寡核苷酸可經修飾。在某些實施例中，寡核苷酸為經修飾之寡核苷酸。在某些實施例中，相對於未經修飾之RNA或DNA，經修飾之寡核苷酸包含至少一個經修飾之糖、經修飾之核鹼基或經修飾之核苷間鍵聯。在某些實施例中，寡核苷酸具有經修飾之核苷。經修飾之核苷可包含經修飾之糖、經修飾之核鹼基，或經修飾之糖及經修飾之核鹼基二者。經修飾之寡核苷酸亦可包括末端修飾，例如5'端修飾及3'端修飾。 糖修飾及模體In some aspects, the present disclosure relates to compounds comprising oligonucleotides. In some embodiments, the oligonucleotide can be unmodified RNA or DNA, or the oligonucleotide can be modified. In some embodiments, the oligonucleotide is a modified oligonucleotide. In some embodiments, the modified oligonucleotide comprises at least one modified sugar, modified nucleobase, or modified internucleoside linkage relative to the unmodified RNA or DNA. In some embodiments, the oligonucleotide has a modified nucleoside. The modified nucleoside can comprise a modified sugar, a modified nucleobase, or both a modified sugar and a modified nucleobase. The modified oligonucleotide can also include terminal modifications, such as a 5' terminal modification and a 3' terminal modification.Sugar Modifications and Motifs
在某些實施例中，經修飾之糖為經取代之呋喃糖基糖或經修飾之非雙環糖。在某些實施例中，經修飾之糖為經修飾之雙環或三環糖。在某些實施例中，經修飾之糖為糖替代物。糖替代物可包含本文所闡述之一或多種取代。In certain embodiments, the modified sugar is a substituted furanosyl sugar or a modified non-bicyclic sugar. In certain embodiments, the modified sugar is a modified bicyclic or tricyclic sugar. In certain embodiments, the modified sugar is a sugar surrogate. The sugar surrogate may comprise one or more substitutions described herein.
在某些實施例中，經修飾之糖為經取代之呋喃糖基糖或經修飾之非雙環糖。在某些實施例中，呋喃糖基糖為核糖基糖。在某些實施例中，呋喃糖基糖包含一或多個取代基，包括(但不限於)在2'位、3'位、4'位及5'位處之取代基。In certain embodiments, the modified sugar is a substituted furanosyl sugar or a modified non-bicyclic sugar. In certain embodiments, the furanosyl sugar is a ribosyl sugar. In certain embodiments, the furanosyl sugar comprises one or more substituents, including but not limited to substituents at the 2' position, 3' position, 4' position, and 5' position.
在某些實施例中，2'位取代基包括(但不限於) F及OCH3(「OMe」、「O-甲基」或「甲氧基」)。在某些實施例中，適於經修飾之非雙環糖之2'位取代基包括(但不限於)鹵基、烯丙基、胺基、疊氮基、SH、CN、OCN、CF3、OCF3、F、Cl、Br、SCH3、SOCH3、SO2CH3、ONO2、NO2、N3及NH2。在某些實施例中，2'位取代基包括(但不限於) O-(C1-C10)烷氧基、烷氧基烷基、O-烷基、S-烷基、N-烷基、O-烯基、S-烯基、N-烯基、O-炔基、S-炔基、N-炔基、O-烷基-O-烷基、炔基，其中該烷基、該烯基及該炔基可為經取代或未經取代之C1至C10烷基或C2至C10烯基及炔基。在某些實施例中，2'位取代基包括(但不限於)烷芳基、芳烷基、O-烷芳基及O-芳烷基。在某些實施例中，該等2'取代基可進一步經一或多個獨立地選自以下之取代基取代：羥基、烷氧基、羧基、苯甲基、苯基、硝基(NO2)、硫醇、硫烷氧基、硫烷基、鹵素、烷基、芳基、烯基及炔基。在某些實施例中，2'位取代基包括(但不限於) O[(CH2)nO]mCH3、O(CH2)nOCH3、O(CH2)nCH3、O(CH2)nONH2、O(CH2)nNH2、O(CH2)nSCH3及O(CH2)nON[(CH2)nCH3)]2，其中n及m獨立地為1至約10。在某些實施例中，2'位取代基包括(但不限於) OCH2CH2OCH3(「MOE」)、O(CH2)2ON(CH3)2(「DMAOE」)、O(CH2)2O(CH2)2N(CH3)2(「DMAEOE」)及OCH2C(=O)-N(H)CH3(「NMA」)。In certain embodiments, 2'-position substituents include, but are not limited to, F and OCH3 ("OMe", "O-methyl" or "methoxy"). In certain embodiments, 2'-position substituents suitable for modified non-bicyclic sugars include, but are not limited to, halogen, allyl, amine, azido, SH, CN, OCN, CF3 , OCF3 , F, Cl, Br, SCH3 , SOCH3 , SO2 CH3 , ONO2 , NO2 , N3 and NH2 . In some embodiments, the 2'-substituent includes, but is not limited to, O-(C1 -C10 ) alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, alkynyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C1 to C10 alkyl or C2 to C10 alkenyl and alkynyl. In some embodiments, the 2'-substituent includes, but is not limited to, alkaryl, aralkyl, O-alkaryl and O-aralkyl. In certain embodiments, the 2' substituents may be further substituted with one or more substituents independently selected from the group consisting of hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro(NO2 ), thiol, thioalkoxy, sulfanyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, 2' substituents include, but are not limited to, O[(CH2)nO]mCH3 , O(CH2 )nOCH3 , O(CH2 )nCH3 , O(CH2)nONH2, O(CH2)nNH2 , O(CH2)nSCH3 , and O(CH2 )nON [(CH2)nCH3 )]2 , wherein n and m are independently 1 to about10. In certain embodiments,the 2'-substituent includes, but is not limited to, OCH2CH2OCH3( "MOE"), O(CH2 )2ON (CH3 )2 ("DMAOE"), O(CH2 )2O (CH2 )2N (CH3 )2 ("DMAEOE"), andOCH2C (=O)-N(H)CH3 ("NMA").
在某些實施例中，適於經修飾之非雙環糖之4'位取代基包括(但不限於)烷氧基(例如甲氧基)、烷基及Manoharan等人，WO 2015/106128中所闡述之彼等取代基。在某些實施例中，適於經修飾之非雙環糖之5'位取代基包括(但不限於)甲基(「Me」) (R或S)、乙烯基及甲氧基。在某些實施例中，一或多個糖包含5'-乙烯基膦酸酯修飾。在某些實施例中，本文針對2'位、4'位及5'位所闡述之取代基可添加至糖上之其他特定位置。在某些實施例中，此等取代基可添加至3'末端核苷上糖之3'位或5'末端核苷之5'位。在某些實施例中，經修飾之非雙環糖可包含一個以上之非橋接糖取代基。在某些此類實施例中，經修飾之非雙環糖取代基包括(但不限於) 5'-Me-2'-F、5'-Me-2'-OMe (包括R及S異構物二者)。在某些實施例中，經修飾之糖取代基包括Migawa等人，WO 2008/101157及Rajeev等人，US2013/0203836中所闡述之彼等取代基。In certain embodiments, suitable substituents at the 4' position of the modified non-bicyclic sugar include, but are not limited to, alkoxy (e.g., methoxy), alkyl, and those substituents described in Manoharan et al., WO 2015/106128. In certain embodiments, suitable substituents at the 5' position of the modified non-bicyclic sugar include, but are not limited to, methyl ("Me") (R or S), vinyl, and methoxy. In certain embodiments, one or more sugars comprise a 5'-vinylphosphonate modification. In certain embodiments, the substituents described herein for the 2', 4', and 5' positions may be added to other specific positions on the sugar. In certain embodiments, these substituents may be added to the 3' position of the sugar on the 3' terminal nucleoside or the 5' position of the 5' terminal nucleoside. In certain embodiments, the modified non-bicyclic sugar may include more than one non-bridging sugar substituent. In certain such embodiments, the modified non-bicyclic sugar substituent includes, but is not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In certain embodiments, the modified sugar substituent includes those described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836.
在某些實施例中，經修飾之糖為雙環糖。雙環糖係包含兩個環之經修飾之糖，其中經由連結第一環中之兩個原子之橋形成第二環，藉此形成雙環結構。在某些實施例中，雙環糖包含橋接取代基，該橋接取代基橋接呋喃糖基環之兩個原子以形成第二環。在某些實施例中，雙環糖不包含呋喃糖基部分。「雙環核苷」(「BNA」)係具有雙環糖之核苷。在某些實施例中，雙環糖在4'與2'呋喃糖環原子之間包含橋。在某些實施例中，雙環糖在5'與3'呋喃糖環原子之間包含橋。在某些此類實施例中，呋喃糖環為核糖環。在某些實施例中，4'至2’橋接取代基包括(但不限於) 4'-CH2-2'、4'-(CH2)2-2'、4'- (CH2)3-2'、4'-CH2-O-2' (「LNA」)、4'-CH2-S-2'、4'-(CH2)2-O-2' (「ENA」)、4'-CH(CH3)-O-2' (當呈S構形時，為「約束乙基」或「cEt」)、4’-CH2-O-CH2-2’、4’-CH2-N(R)-2’、4'- CH(CH2OCH3)-O-2' (「約束MOE」或「cMOE」)及其類似物(例如美國專利第7,399,845號)、4'-C(CH3)(CH3)-O-2'及其類似物(例如美國專利第8,278,283號)、4'-CH2-N(OCH3)-2'及其類似物(例如美國專利第8,278,425號)、4'-CH2-O-N(CH3)-2' (例如美國專利公開案第2004/0171570號)、4'-CH2-N(R)-O-2' (其中R為H、C1-C12烷基或保護基團(例如美國專利第7,427,672號))、4'-CH2-C(H)(CH3)-2' (例如Chattopadhyaya等人，J. Org. Chem., 2009, 74, 118- 134)及4'-CH2-C(=CH2)-2'及其類似物(例如美國專利第8,278,426號)。前述文獻各自之全部內容在此係以引用的方式併入本文中。教示雙環核酸核苷酸之製備之其他代表性美國專利及美國專利公開案包括(但不限於)以下：美國專利第6,268,490號；第6,525,191號；第6,670,461號；第6,770,748號；第6,794,499號；第6,998,484號；第7,053,207號；第7,034,133號；第7,084,125號；第7,399,845號；第7,427,672號；第7,569,686號；第7,741,457號；第8,022,193號；第8,030,467號；第8,278,425號；第8,278,426號；第8,278,283號；US 2008/0039618；及US 2009/0012281、US 2013/0190383；及WO 2013/036868，其各自之全部內容在此係以引用的方式併入本文中。前述雙環核苷中之任一者均可製備成具有一或多種立體化學糖構形，包括例如α-L-呋喃核糖及β-D-呋喃核糖(例如，參見WO 99/14226)。除非另有指定，否則本文指定之雙環核苷係呈β-D構形。In certain embodiments, the modified sugar is a bicyclic sugar. A bicyclic sugar is a modified sugar comprising two rings, wherein a second ring is formed by a bridge connecting two atoms in the first ring, thereby forming a bicyclic structure. In certain embodiments, the bicyclic sugar comprises a bridging substituent that bridges two atoms of the furanosyl ring to form the second ring. In certain embodiments, the bicyclic sugar does not comprise a furanosyl moiety. A "bicyclic nucleoside"("BNA") is a nucleoside having a bicyclic sugar. In certain embodiments, the bicyclic sugar comprises a bridge between the 4' and 2' furanose ring atoms. In certain embodiments, the bicyclic sugar comprises a bridge between the 5' and 3' furanose ring atoms. In certain such embodiments, the furanose ring is a ribose ring. In certain embodiments, the 4' to 2' bridging substituent includes, but is not limited to, 4'-CH2-2 ', 4'-(CH2 )2-2 ', 4'-(CH2 )3-2 ', 4'-CH2 -O-2'("LNA"),4'-CH2-S -2', 4'-(CH2 )2 -O-2'("ENA"),4'-CH(CH3 )-O-2'("constrainedethyl" or "cEt" when in the S configuration), 4'-CH2-O-CH2-2 ', 4'-CH2- N(R)-2', 4'-CH(CH2OCH3 )-O-2'("constrainedMOE" or "cMOE") and the like (e.g., U.S. Patent No. 7,399,845), 4'-C(CH3 )-O-2'("constrainedethyl" or "cEt"), and the like (e.g., U.S. Patent No. 7,399,845), and 4'-CH2-S-2 '. )(CH3 )-O-2′ and its analogs (e.g., U.S. Patent No. 8,278,283), 4′-CH2 -N(OCH3 )-2′ and its analogs (e.g., U.S. Patent No. 8,278,425), 4′-CH2 -ON(CH3 )-2′ (e.g., U.S. Patent Publication No. 2004/0171570), 4′-CH2 -N(R)-O-2′ (wherein R is H, C1 -C12 alkyl or a protecting group (e.g., U.S. Patent No. 7,427,672)), 4′-CH2 -C(H)(CH3 )-2′ (e.g., Chattopadhyaya et al.,J. Org. Chem ., 2009, 74, 118- 134) and 4′-CH2 -C(═CH2 )-2' and its analogs (e.g., U.S. Patent No. 8,278,426). The entire contents of each of the foregoing documents are hereby incorporated by reference. Other representative U.S. patents and U.S. patent publications that teach the preparation of bicyclic nucleic acid nucleotides include (but are not limited to) the following: U.S. Patent Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7 ,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008/0039618; and US 2009/0012281, US 2013/0190383; and WO 2013/036868, the entire contents of each of which are hereby incorporated by reference into this document. Any of the foregoing bicyclic nucleosides can be prepared with one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see, for example, WO 99/14226). Unless otherwise specified, the bicyclic nucleosides specified herein are in the β-D configuration.
在某些實施例中，經修飾之糖為糖替代物。在某些實施例中，糖替代物之氧原子經例如硫、碳或氮原子置換。在某些此類實施例中，糖替代物亦可包含如本文所闡述之橋接及/或非橋接取代基。在某些實施例中，糖替代物包含具有不為5個原子之環。在某些此類實施例中，糖替代物包含環丁基部分代替呋喃戊糖基糖。在某些實施例中，糖替代物包含六員環代替呋喃戊糖基糖。在某些實施例中，糖替代物包含四氫哌喃(「THP」)代替呋喃戊糖基糖。在某些實施例中，糖替代物包含嗎啉基代替呋喃戊糖基糖。教示此等經修飾之糖結構之製備之代表性美國專利包括(但不限於)美國專利第4,981,957號；第5,118,800號；第5,166,315號；第5,185,444號；第5,319,080號；第5,359,044號；第5,393,878號；第5,446,137號；第5,466,786號；第5,514,785號；第5,519,134號；第5,567,811號；第5,576,427號；第5,591,722號；第5,597,909號；第5,610,300號；第5,627,053號；第5,639,873號；第5,646,265號；第5,658,873號；第5,670,633號；第5,700,920號；第7,875,733號；第7,939,677號、第8,088,904號；第8,440,803號；及第9,005,906號，前述專利各自之全部內容在此係以引用的方式併入本文中。In certain embodiments, the modified sugar is a sugar substitute. In certain embodiments, the oxygen atom of the sugar substitute is replaced by, for example, a sulfur, carbon or nitrogen atom. In certain such embodiments, the sugar substitute may also include bridging and/or non-bridging substituents as described herein. In certain embodiments, the sugar substitute includes a ring having not 5 atoms. In certain such embodiments, the sugar substitute includes a cyclobutyl moiety replacing a furanopentosyl sugar. In certain embodiments, the sugar substitute includes a six-membered ring replacing a furanopentosyl sugar. In certain embodiments, the sugar substitute includes tetrahydropyran ("THP") replacing a furanopentosyl sugar. In certain embodiments, the sugar substitute includes a morpholinyl group replacing a furanopentosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Patent Nos. 4,981,957; 5,118,800; 5,166,315; 5,185,444; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5 ,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,700,920; 7,875,733; 7,939,677; 8,088,904; 8,440,803; and 9,005,906, the entire contents of each of the foregoing patents are hereby incorporated by reference into this article.
在一些實施例中，糖替代物包含非環狀部分。在某些實施例中，糖替代物為解鎖核酸(「UNA」)。UNA係一種解鎖非環狀核酸，其中糖之任何鍵均已去除，從而形成解鎖「糖」殘基。在一個實例中，UNA亦涵蓋C1'-C4'之間的鍵(亦即C1'碳與C4'碳之間的共價碳-氧-碳鍵)已去除之單體。在另一實例中，糖之C2'-C3'鍵(亦即C2'碳與C3'碳之間的共價碳-碳鍵)已去除。教示UNA之製備之代表性美國公開案包括(但不限於)美國專利第8,314,227號；及美國專利公開案第2013/0096289號；第2013/0011922號；及第2011/0313020號，其各自之全部內容在此係以引用的方式併入本文中。在某些實施例中，糖替代物包含肽核酸(「PNA」)、非環狀丁基核酸(例如，參見Kumar等人，Org. Biomol. Chem., 2013, 11, 5853-5865)，以及Manoharan等人，US2013/130378中所闡述之核苷及寡核苷酸，該等文獻之全部內容係以引用的方式併入本文中。此項技術中已知可用於經修飾之核苷中之許多其他雙環及三環糖及糖替代物環系統。In some embodiments, the sugar surrogate comprises a non-cyclic portion. In certain embodiments, the sugar surrogate is an unlocked nucleic acid ("UNA"). UNA is an unlocked non-cyclic nucleic acid in which any bonds of the sugar have been removed, thereby forming an unlocked "sugar" residue. In one example, UNA also encompasses monomers in which the bond between C1'-C4' (i.e., the covalent carbon-oxygen-carbon bond between the C1' carbon and the C4' carbon) has been removed. In another example, the C2'-C3' bond of the sugar (i.e., the covalent carbon-carbon bond between the C2' carbon and the C3' carbon) has been removed. Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Patent No. 8,314,227; and U.S. Patent Publication Nos. 2013/0096289; 2013/0011922; and 2011/0313020, each of which is hereby incorporated by reference in its entirety. In certain embodiments, the sugar surrogate comprises a peptide nucleic acid ("PNA"), a non-cyclic butyl nucleic acid (e.g., see Kumar et al.,Org. Biomol. Chem. , 2013, 11, 5853-5865), and nucleosides and oligonucleotides as described in Manoharan et al., US2013/130378, the entire contents of which are hereby incorporated by reference. Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.
在某些態樣中，本揭示案係關於包含至少一種寡核苷酸之化合物，其中此等寡核苷酸之核苷包含一或多種類型之經修飾之糖及/或未經修飾之糖，該等糖以確定之模式或「糖模體」沿著寡核苷酸或其區域排列。在某些情況下，此等糖模體包括(但不限於)本文所闡述之糖修飾模式中之任一者。In certain aspects, the present disclosure relates to compounds comprising at least one oligonucleotide, wherein the nucleosides of such oligonucleotides comprise one or more types of modified sugars and/or unmodified sugars arranged along the oligonucleotide or a region thereof in a defined pattern or "sugar motif". In certain instances, such sugar motifs include, but are not limited to, any of the sugar modification patterns described herein.
在某些實施例中，寡核苷酸包含間隔體(gapmer)糖模體。間隔體寡核苷酸包含具有兩個外部「翼」區及一個中央或內部「空位」區之區域，或由該區域組成。空位區及翼區形成核苷鄰接序列，其中每一翼之大部分核苷糖不同於空位之大部分核苷糖。在某些實施例中，翼區包含大部分經修飾之糖，且空位包含大部分未經修飾之糖。在某些實施例中，空位之核苷為去氧核苷。具有間隔體糖模體之化合物闡述於例如美國專利第8,790,919號中，該專利之內容係以引用方式併入本文中。In certain embodiments, the oligonucleotide comprises a gapmer sugar motif. A gapmer oligonucleotide comprises or consists of a region having two external "wing" regions and a central or internal "gap" region. The gap region and the wing region form a nucleoside-adjacent sequence, wherein the majority of the nucleoside sugars of each wing are different from the majority of the nucleoside sugars of the gap. In certain embodiments, the wing region comprises a majority of modified sugars, and the gap comprises a majority of unmodified sugars. In certain embodiments, the nucleoside of the gap is a deoxynucleoside. Compounds with gapmer sugar motifs are described, for example, in U.S. Patent No. 8,790,919, the contents of which are incorporated herein by reference.
在某些實施例中，雙股化合物之一種或兩種寡核苷酸包含三聯體糖模體。具有三聯體糖模體之寡核苷酸在三個連續核苷上包含三個相同之糖修飾。在某些實施例中，三聯體位於寡核苷酸之裂解位點處或附近。在某些實施例中，雙股化合物之寡核苷酸可含有一個以上之三聯體糖模體。在某些實施例中，三聯體糖模體之相同糖修飾為2'-F修飾。具有三聯體糖模體之化合物揭示於例如美國專利第10,668,170號中，該專利之內容係以引用方式併入本文中。In certain embodiments, one or both oligonucleotides of the double-stranded compound comprise a triplet sugar motif. An oligonucleotide having a triplet sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In certain embodiments, the triplet is located at or near the cleavage site of the oligonucleotide. In certain embodiments, the oligonucleotide of the double-stranded compound may contain more than one triplet sugar motif. In certain embodiments, the identical sugar modification of the triplet sugar motif is a 2'-F modification. Compounds having a triplet sugar motif are disclosed, for example, in U.S. Patent No. 10,668,170, the contents of which are incorporated herein by reference.
在某些實施例中，雙股化合物之一種或兩種寡核苷酸包含四聯體糖模體。具有四聯體糖模體之寡核苷酸在四個連續核苷上包含四個相同之糖修飾。在某些實施例中，四聯體位於裂解位點處或附近。在某些實施例中，雙股化合物之寡核苷酸可含有一個以上之四聯體糖模體。在某些實施例中，四聯體糖模體之相同糖修飾為2'-F修飾。對於具有長度為19-23個核苷酸之雙鏈體區域之雙股化合物，反義寡核苷酸之裂解位點通常位於距5'端10、11及12個位置附近。在某些實施例中，自有義寡核苷酸5'端之第一核苷計數，或自有義寡核苷酸5'端雙鏈體區域內之第一配對核苷酸開始計數，四聯體糖模體位於有義寡核苷酸之8位、9位、10位、11位；9位、10位、11位、12 位；10位、11位、12位、13位；11位、12位、13位、14位；或12位、13位、14位、15位。在某些實施例中，自反義寡核苷酸5'端之第一核苷計數，或自反義寡核苷酸5'端雙鏈體區域內之第一配對核苷酸開始計數，四聯體糖模體位於反義寡核苷酸之8位、9位、10位、11位；9位、10位、11位、12位；10位、11位、12位、13位；11位、12位、13位、14位；或12位、13位、14位、15位。裂解位點可根據雙股化合物之雙鏈體區域長度而變化，且可相應地改變四聯體之位置。In certain embodiments, one or both oligonucleotides of the double-stranded compound comprise a quadruplex sugar motif. An oligonucleotide having a quadruplex sugar motif comprises four identical sugar modifications on four consecutive nucleosides. In certain embodiments, the quadruplex is located at or near the cleavage site. In certain embodiments, the oligonucleotides of the double-stranded compound may contain more than one quadruplex sugar motif. In certain embodiments, the identical sugar modification of the quadruplex sugar motif is a 2'-F modification. For double-stranded compounds having a duplex region of 19-23 nucleotides in length, the cleavage site of the antisense oligonucleotide is typically located near 10, 11, and 12 positions from the 5' end. In certain embodiments, counting from the first nucleoside at the 5' end of the sense oligonucleotide, or from the first paired nucleotide in the duplex region at the 5' end of the sense oligonucleotide, the quadruplex sugar motif is located at position 8, 9, 10, 11; position 9, 10, 11, 12; position 10, 11, 12, 13; position 11, 12, 13, 14; or position 12, 13, 14, 15 of the sense oligonucleotide. In certain embodiments, counting from the first nucleotide at the 5' end of the antisense oligonucleotide, or counting from the first paired nucleotide in the duplex region at the 5' end of the antisense oligonucleotide, the quadruplex sugar motif is located at position 8, 9, 10, 11; position 9, 10, 11, 12; position 10, 11, 12, 13; position 11, 12, 13, 14; or position 12, 13, 14, 15 of the antisense oligonucleotide. The cleavage site can vary depending on the length of the duplex region of the double-stranded compound, and the position of the quadruplex can be changed accordingly.
在某些實施例中，寡核苷酸包含交替性糖模體。在某些實施例中，雙股化合物之一種或兩種寡核苷酸包含交替性糖模體。具有交替性糖模體之寡核苷酸包含至少兩種不同的糖修飾，其中包含第一糖修飾之一或多個連續核苷與包含第二糖修飾之一或多個連續核苷及包含第三糖修飾之一或多個連續核苷等等交替。舉例而言，若A、B及C各自代表核苷之一種修飾類型，則交替性模體可為「ABABABABABAB...」、「AABBAABBAABB...」、「AABAABAABAAB...」、「AAABAAABAAAB...」、「AAABBBAAABBB...」或「ABCABCABCABC...」等。在某些實施例中，交替性糖模體沿著寡核苷酸重複至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23個鄰接核鹼基。在某些實施例中，交替性糖模體包含兩種不同的糖修飾。在某些實施例中，交替性糖模體包含2'-OMe及2'-F糖修飾。In some embodiments, the oligonucleotide comprises an alternating sugar motif. In some embodiments, one or both oligonucleotides of the double-stranded compound comprise an alternating sugar motif. The oligonucleotide having an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification alternate with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, and so on. For example, if A, B, and C each represent a modification type of a nucleoside, the alternating motif may be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB...", "AAABAAABAAAB...", "AAABBBAAABBB...", or "ABCABCABCABC...", and the like. In some embodiments, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 adjacent nucleobases along the oligonucleotide. In some embodiments, the alternating sugar motif comprises two different sugar modifications. In some embodiments, the alternating sugar motif comprises 2'-OMe and 2'-F sugar modifications.
在某些實施例中，寡核苷酸之每一核苷獨立地經本文所提供之一或多種糖修飾修飾。在某些實施例中，雙股化合物之每一寡核苷酸獨立地具有一或多個本文所提供之糖模體。在某些實施例中，含有糖模體之寡核苷酸完全經修飾，此乃因除包含糖模體之核苷以外的每一核苷均包含糖修飾。 核鹼基修飾及模體In certain embodiments, each nucleoside of an oligonucleotide is independently modified with one or more sugar modifications provided herein. In certain embodiments, each oligonucleotide of a double-stranded compound independently has one or more sugar motifs provided herein. In certain embodiments, an oligonucleotide containing a sugar motif is fully modified in that each nucleoside except the nucleoside containing the sugar motif contains a sugar modification.Nucleobase Modifications and Motifs
在某些實施例中，經修飾之寡核苷酸包含一或多個包含經修飾之核鹼基的核苷。在某些實施例中，經修飾之寡核苷酸包含一或多個不包含核鹼基之核苷，稱為無鹼基核苷。In certain embodiments, the modified oligonucleotide comprises one or more nucleosides comprising a modified nucleobase. In certain embodiments, the modified oligonucleotide comprises one or more nucleosides that do not comprise a nucleobase, referred to as abasic nucleosides.
在某些實施例中，經修飾之核鹼基係選自：5-取代之嘧啶、6-氮雜嘧啶、烷基或炔基取代之嘧啶、烷基取代之嘌呤以及N-2、N-6及O-6取代之嘌呤。在某些實施例中，經修飾之核鹼基係選自：2-胺基丙基腺嘌呤、5-羥甲基胞嘧啶、5-甲基胞嘧啶、黃嘌呤、次黃嘌呤、2-胺基腺嘌呤、6-N-甲基鳥嘌呤、6-N-甲基腺嘌呤、2-丙基腺嘌呤、2-硫尿嘧啶、2-硫胸腺嘧啶及2-硫胞嘧啶、5-丙炔基(C≡C-CH3)尿嘧啶、5-丙炔基胞嘧啶、6-偶氮尿嘧啶、6-偶氮胞嘧啶、6-偶氮胸腺嘧啶、5-核糖基尿嘧啶(假尿嘧啶)、4-硫尿嘧啶、8-鹵基、8-胺基、8-硫醇、8-硫代烷基、8-羥基、8-氮雜及其他8-取代之嘌呤；5-鹵基、具體而言5-溴、5-三氟甲基、5-鹵基尿嘧啶及5-鹵基胞嘧啶；7-甲基鳥嘌呤、7-甲基腺嘌呤、2-F-腺嘌呤、2-胺基腺嘌呤、7-去氮鳥嘌呤、7-去氮腺嘌呤、3-去氮鳥嘌呤、3-去氮腺嘌呤、6-N-苯甲醯基腺嘌呤、2-N-異丁醯基鳥嘌呤、4-N-苯甲醯基胞嘧啶、4-N-苯甲醯基尿嘧啶、5-甲基4-N-苯甲醯基胞嘧啶、5-甲基4-N-苯甲醯基尿嘧啶、通用鹼基、疏水性鹼基、混雜鹼基、大小擴大之鹼基及氟化鹼基。其他經修飾之核鹼基包括三環嘧啶，諸如1,3-二氮雜吩噁嗪-2-酮、1,3-二氮雜吩噻嗪-2-酮及9-(2-胺基乙氧基)-1,3-二氮雜吩噁嗪-2-酮(G夾)。經修飾之核鹼基亦可包括嘌呤或嘧啶鹼基經其他雜環置換之彼等核鹼基，該等其他雜環例如7-去氮-腺嘌呤、7-去氮鳥苷、2-胺基吡啶及2-吡啶酮。In certain embodiments, the modified nucleobase is selected from: 5-substituted pyrimidine, 6-azapyrimidine, alkyl or alkynyl substituted pyrimidine, alkyl substituted purine, and N-2, N-6 and O-6 substituted purine. In certain embodiments, the modified nucleobase is selected from: 2-aminopropyladenine, 5-hydroxymethylcytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C-CH3 )uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halogen, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxy, 8-aza and other 8-substituted purines; 5-halogen, specifically 5-bromo, 5-trifluoromethyl, 5-halogenuracil and 5-halogencytosine; 7-methylguanine, 7-methyladenine, 2 -F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, mixed bases, size-expanded bases, and fluorinated bases. Other modified nucleobases include tricyclic pyrimidines such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenathiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-H). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced by other heterocycles such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone.
其他核鹼基包括以下文獻中所揭示之彼等核鹼基：美國專利第3,687,808號；Modified Nucleosides in Biochemistry, Biotechnology and Medicine，Herdewijn, P.編輯，Wiley-VCH, 2008；The Concise Encyclopedia Of Polymer Science And Engineering，第858-859頁; Kroschwitz, J.L.編輯，John Wiley & Sons, 1990, 858-859；Englisch等人，Angewandte Chemie，國際版，1991, 30, 613；Sanghvi, Y.S.，第15章，dsRNA Research and Applications，第289-302頁；Antisense Research and Applications, Crooke, S.T.及Lebleu, B.編輯，CRC Press, 1993, 273-288；Antisense Drug Technology, Crooke S.T.編輯，CRC Press, 2008, 163-166及442-443 (第6章及第15章)，該等文獻各自係以引用方式併入本文中。Other nucleobases include those disclosed in the following references: U.S. Patent No. 3,687,808; Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed., Wiley-VCH, 2008; The Concise Encyclopedia Of Polymer Science And Engineering, pp. 858-859; Kroschwitz, JL ed., John Wiley & Sons, 1990, 858-859; Englisch et al.,Angewandte Chemie, International Edition , 1991, 30, 613; Sanghvi, YS, Chapter 15, dsRNA Research and Applications, pp. 289-302; Antisense Research and Applications, Crooke, ST and Lebleu, B. ed., CRC Press, 1993, 273-288; Antisense Drug Technology, Crooke ST ed., CRC Press, 2008, 163-166 and 442-443 (Chapter 6 and Chapter 15), each of which is incorporated herein by reference.
教示某些上述經修飾之核鹼基以及其他經修飾之核鹼基之製備的公開案包括(但不限於)美國專利申請公開案第2003/0158403號及第2003/0175906號；美國專利第4,845,205號；第5,130,302號；第5,134,066號；第5,175,273號；第5,367,066號；第5,432,272號；第5,434,257號；第5,457,187號；第5,459,255號；第5,484,908號；第5,502,177號；第5,525,711號；第5,552,540號；第5,587,469號；第5,594,121號；第5,596,091號；第5,614,617號；第5,645,985號；第5,681,941號；第5,811,534號；第5,750,692號；第5,948,903號；第5,587,470號；第5,457,191號；第5,763,588號；第5,830,653號；第5,808,027號；第6,005,096號；第6,015,886號；第6,147,200號；第6,166,197號；第6,166,199號；第6,222,025號；第6,235,887號；第6,380,368號；第6,528,640號；第6,639,062號；第6,617,438號；第7,045,610號；第7,427,672號；及第7,495,088號，該等案件各自之內容係以引用方式併入本文中。Publications that teach the preparation of some of the above-described modified nucleobases, as well as other modified nucleobases, include, but are not limited to, U.S. Patent Application Publication Nos. 2003/0158403 and 2003/0175906; U.S. Patent Nos. 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432, No. 272; No. 5,434,257; No. 5,457,187; No. 5,459,255; No. 5,484,908; No. 5,502,177; No. 5,525,711; No. 5,552,540; No. 5,587,469; No. 5,594,121; No. 5,596,091; No. 5,614,617; No. 5,645,985; No. 5,681,941; No. 5,811,534; No. 5,750,692; No. 5,948,903; No. 5,587,470; No. 5,457,191; No. 5,763,588; No. 5,830,653; No. 5,808,027; No. 6,005,096; No. 6,015,886; No. 6,147,200; No. 6,16 No. 6,197; No. 6,166,199; No. 6,222,025; No. 6,235,887; No. 6,380,368; No. 6,528,640; No. 6,639,062; No. 6,617,438; No. 7,045,610; No. 7,427,672; and No. 7,495,088, the contents of each of which are incorporated herein by reference.
在某些實施例中，寡核苷酸包含以確定之模式或模體沿著寡核苷酸或其區域排列的經修飾及/或未經修飾之核鹼基。在某些實施例中，每一核鹼基均經修飾。在某些實施例中，核鹼基均不經修飾。在某些實施例中，每一嘌呤或每一嘧啶均經修飾。在某些實施例中，每一腺嘌呤均經修飾。在某些實施例中，每一鳥嘌呤均經修飾。在某些實施例中，每一胸腺嘧啶均經修飾。在某些實施例中，每一尿嘧啶均經修飾。在某些實施例中，每一胞嘧啶均經修飾。在某些實施例中，經修飾之寡核苷酸中之一些或所有胞嘧啶核鹼基為5-甲基胞嘧啶。In certain embodiments, the oligonucleotide comprises modified and/or unmodified nucleobases arranged in a defined pattern or motif along the oligonucleotide or a region thereof. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases is modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in the modified oligonucleotide are 5-methylcytosine.
在某些實施例中，經修飾之寡核苷酸包含經修飾之核鹼基之嵌段。在某些此類實施例中，嵌段位於寡核苷酸之3'端。在某些實施例中，嵌段位於寡核苷酸之3'端的3個核苷內。在某些實施例中，嵌段位於寡核苷酸之5'端。在某些實施例中，嵌段位於寡核苷酸之5'端的3個核苷內。 核苷間鍵聯修飾及模體In certain embodiments, the modified oligonucleotide comprises a block of modified nucleobases. In certain such embodiments, the block is located at the 3' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 3' end of the oligonucleotide. In certain embodiments, the block is located at the 5' end of the oligonucleotide. In certain embodiments, the block is located within 3 nucleosides of the 5' end of the oligonucleotide.Internucleoside Linkage Modifications and Motifs
3'至5'磷酸二酯鍵聯係RNA及DNA之天然核苷間鍵聯。在某些實施例中，寡核苷酸具有一或多個經修飾(亦即非天然)之核苷間鍵聯。某些非天然核苷間鍵聯可賦予合意性質，諸如細胞攝取增強、對靶核酸之親和力增強且在核酸酶存在下穩定性增加。代表性經修飾之含磷核苷間鍵聯包括(但不限於)磷酸三酯、烷基膦酸酯(例如甲基膦酸酯)、胺基磷酸酯及硫代磷酸酯(「P=S」)及二硫代磷酸酯(「HS-P=S」)。代表性不含磷之核苷間連接基團包括(但不限於)亞甲基甲基亞胺基(-CH2-N(CH3)-O-CH2)、硫代二酯、硫羰胺基甲酸酯(-O-C(=O)(NH)-S-)；矽氧烷(-O-SiH2-O-)；及N,N'-二甲基肼(-CH2-N((CH3)-N((CH3)-)。含磷及不含磷核苷間鍵聯之製備方法為熟習此項技術者所熟知。中性核苷間鍵聯包括(但不限於)磷酸三酯、甲基膦酸酯、MMI (3'-CH2-N(CH3)-O-5')、醯胺-3 (3'-CH2-C(=O)-N(H)-5')、醯胺-4 (3'-CH2-N(H)-C(=O)-5')、甲縮醛(3'-O-CH2-O-5')、甲氧基丙基及硫基甲縮醛(3'-S-CH2-O-5')。其他中性核苷間鍵聯包括非離子鍵聯，其包含矽氧烷(二烷基矽氧烷)、羧酸酯、羧醯胺、硫化物、磺酸酯及醯胺(例如，參見Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi及P.D. Cook編輯，ACS Symposium Series 580; 第3章及第4章，40-65)。其他中性核苷間鍵聯包括包含混合之N、O、S及CH2組成部分的非離子鍵聯。3' to 5' phosphodiester bonds link the natural internucleoside linkages of RNA and DNA. In certain embodiments, the oligonucleotide has one or more modified (i.e., non-natural) internucleoside linkages. Certain non-natural internucleoside linkages can impart desirable properties, such as enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative modified phosphorus-containing internucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphonates (e.g., methylphosphonate), phosphoramidates, and phosphorothioates ("P=S") and phosphorodithioates ("HS-P=S"). Representative non-phosphorus-containing internucleoside linking groups include, but are not limited to, methylenemethylimine (-CH2- N(CH3 )-O-CH2 ), thiodiester, thiocarbamate (-OC(=O)(NH)-S-); siloxane (-O-SiH2 -O-); and N,N'-dimethylhydrazine (-CH2 -N((CH3 )-N((CH3 )-). Methods for preparing phosphorus-containing and non-phosphorus-containing internucleoside linkages are well known to those skilled in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriester, methylphosphonate, MMI (3'-CH2 -N(CH3 )-O-5'), amide-3 (3'-CH2 -C(=O)-N(H)-5'), amide-4 (3'-CH2 -N(H)-C(=O)-5'), formaldehyde (3'-O-CH2 -O-5'), methoxypropyl and thioformaldehyde (3'-S-CH2 -O-5'). Other neutral internucleoside linkages include non-ionic linkages including siloxanes (dialkylsiloxanes), carboxylates, carboxamides, sulfides, sulfonates and amides (e.g., see Carbohydrate Modifications in Antisense Research; YS Sanghvi and PD Cook, eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Other neutral internucleoside linkages include non-ionic linkages including mixed N, O, S andCH2 components.
在某些實施例中，寡核苷酸包含至少一個經修飾之核苷間鍵聯。經修飾之核苷間鍵聯可位於寡核苷酸之任何位置。對於雙股化合物，經修飾之核苷間鍵聯可位於雙股化合物之有義寡核苷酸內、反義寡核苷酸內或該兩種寡核苷酸內。In certain embodiments, the oligonucleotide comprises at least one modified internucleoside linkage. The modified internucleoside linkage may be located at any position of the oligonucleotide. For double-stranded compounds, the modified internucleoside linkage may be located in the sense oligonucleotide, the antisense oligonucleotide, or both oligonucleotides of the double-stranded compound.
在某些實施例中，核苷間鍵聯修飾可發生在寡核苷酸之每個核苷上。在某些實施例中，核苷間鍵聯修飾可沿著寡核苷酸以交替模式發生。在某些實施例中，基本上每一核苷間連接基團均為磷酸酯核苷間鍵聯(P=O)。在某些實施例中，經修飾之寡核苷酸之每一核苷間連接基團為硫代磷酸酯(P=S)。在某些實施例中，經修飾之寡核苷酸之每一核苷間連接基團獨立地選自硫代磷酸酯及磷酸酯核苷間鍵聯。在某些實施例中，雙股化合物之每一寡核苷酸上之核苷間鍵聯修飾模式係相同的。在某些實施例中，雙股化合物之每一寡核苷酸上之核苷間鍵聯修飾模式係不同的。在某些實施例中，雙股化合物包含6-8個經修飾之核苷間鍵聯。在某些實施例中，該6-8個經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或烷基膦酸酯核苷間鍵聯。在某些實施例中，有義寡核苷酸在5'端及3’端中之任一者處或在該兩個末端包含至少兩個經修飾之核苷間鍵聯。在某些此類實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或烷基膦酸酯核苷間鍵聯。在某些實施例中，反義寡核苷酸在5'端及3'端中之任一者處或在該兩個末端包含至少兩個經修飾之核苷間鍵聯。在某些此類實施例中，經修飾之核苷間鍵聯為硫代磷酸酯核苷間鍵聯或烷基膦酸酯核苷間鍵聯。In certain embodiments, the internucleoside linkage modification may occur on each nucleoside of the oligonucleotide. In certain embodiments, the internucleoside linkage modification may occur in an alternating pattern along the oligonucleotide. In certain embodiments, substantially each internucleoside linkage group is a phosphate internucleoside linkage (P=O). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is a thiophosphate (P=S). In certain embodiments, each internucleoside linkage group of the modified oligonucleotide is independently selected from thiophosphate and phosphate internucleoside linkages. In certain embodiments, the internucleoside linkage modification pattern on each oligonucleotide of the double-stranded compound is the same. In certain embodiments, the internucleoside linkage modification pattern on each oligonucleotide of the double-stranded compound is different. In certain embodiments, the double-stranded compound comprises 6-8 modified internucleoside linkages. In certain embodiments, the 6-8 modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the sense oligonucleotide comprises at least two modified internucleoside linkages at either the 5' end and the 3' end or at both ends. In certain such embodiments, the modified internucleoside linkages are phosphorothioate internucleoside linkages or alkylphosphonate internucleoside linkages. In certain embodiments, the antisense oligonucleotide comprises at least two modified internucleoside linkages at either the 5' end and the 3' end or at both ends. In certain such embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage or an alkylphosphonate internucleoside linkage.
在某些實施例中，雙股化合物包含懸突區。在某些實施例中，雙股化合物在懸突區中包含硫代磷酸酯或烷基膦酸酯核苷間鍵聯修飾。在某些實施例中，雙股化合物包含連接懸突核苷酸與靠近該懸突核苷酸之配對核苷酸之硫代磷酸酯或烷基膦酸酯核苷間鍵聯。舉例而言，在末端三個核苷之間可能存在至少兩個硫代磷酸酯核苷間鍵聯，其中該三個核苷中之兩個為懸突核苷，且第三個為靠近懸突核苷之配對核苷。該三個末端核苷可位於反義寡核苷酸之3'端、有義寡核苷酸之3'端、反義寡核苷酸之5'端或有義寡核苷酸之5'端。In certain embodiments, the double-stranded compound comprises an overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage modification in the overhang region. In certain embodiments, the double-stranded compound comprises a phosphorothioate or alkylphosphonate internucleoside linkage connecting an overhang nucleotide to a paired nucleotide proximal to the overhang nucleotide. For example, there may be at least two phosphorothioate internucleoside linkages between the terminal three nucleosides, wherein two of the three nucleosides are overhang nucleosides and the third is a paired nucleoside proximal to the overhang nucleoside. The three terminal nucleosides may be located at the 3' end of the antisense oligonucleotide, the 3' end of the sense oligonucleotide, the 5' end of the antisense oligonucleotide, or the 5' end of the sense oligonucleotide.
在某些實施例中，經修飾之寡核苷酸包含一或多個具有手性中心之核苷間鍵聯。代表性手性核苷間鍵聯包括(但不限於)烷基膦酸酯及硫代磷酸酯。可將包含具有手性中心之核苷間鍵聯的經修飾之寡核苷酸製備成包含立體隨機核苷間鍵聯的經修飾之寡核苷酸群體，或製備成包含呈特定立體化學構形之硫代磷酸酯鍵聯的經修飾之寡核苷酸群體。在某些實施例中，經修飾之寡核苷酸群體包含硫代磷酸酯核苷間鍵聯，其中所有該等硫代磷酸酯核苷間鍵聯均為立體隨機的。此等經修飾之寡核苷酸可使用可隨機選擇每一硫代磷酸酯鍵聯之立體化學構形之合成方法來生成。如熟習此項技術者所充分理解，每一個別寡核苷酸分子之每一個別硫代磷酸酯具有確定之立體構形。在某些實施例中，經修飾之寡核苷酸群體富集經修飾之寡核苷酸，該等經修飾之寡核苷酸包含一或多個呈特定獨立選擇之立體化學構形之特定硫代磷酸酯核苷間鍵聯。在某些實施例中，群體中至少65%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少70%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少80%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少90%之分子中存在特定硫代磷酸酯鍵聯之特定構形。在某些實施例中，群體中至少99%之分子中存在特定硫代磷酸酯鍵聯之特定構形。經修飾之寡核苷酸之此類富集群體可使用此項技術中已知之合成方法來生成，例如以下文獻中所闡述之方法：Oka等人，JACS125, 8307 (2003)；Wan等人，Nuc. Acid. Res.42, 13456 (2014)；及WO 2017/015555。在某些實施例中，經修飾之寡核苷酸群體富集具有至少一種呈(Sp)構形之所指示硫代磷酸酯的經修飾之寡核苷酸。在某些實施例中，經修飾之寡核苷酸群體富集具有至少一種呈(Rp)構形之硫代磷酸酯的經修飾之寡核苷酸。 NMDA受體配位體In certain embodiments, the modified oligonucleotide comprises one or more internucleoside linkages having a chiral center. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as a modified oligonucleotide population comprising stereo-random internucleoside linkages, or as a modified oligonucleotide population comprising phosphorothioate linkages in a specific stereochemical configuration. In certain embodiments, the modified oligonucleotide population comprises phosphorothioate internucleoside linkages, wherein all of the phosphorothioate internucleoside linkages are stereo-random. Such modified oligonucleotides can be generated using a synthetic method that can randomly select the stereochemical configuration of each phosphorothioate linkage. As is well understood by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereo configuration. In certain embodiments, a modified oligonucleotide population is enriched for modified oligonucleotides that contain one or more specific phosphorothioate internucleoside linkages in a specific independently selected stereochemical configuration. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, a specific configuration of a specific phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, a specific conformation of a specific phosphorothioate linkage is present in at least 99% of the molecules in the population. Such enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, such as those described in Oka et al.,JACS 125, 8307 (2003); Wanet al., Nuc. Acid. Res. 42, 13456 (2014); and WO 2017/015555. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) conformation. In certain embodiments, the population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) conformation. NMDA Receptor Ligands
在一些實施例中，本文所提供之化合物包含NMDA受體配位體。在一些實施例中，NMDA受體配位體可用於引導治療劑、預防劑或診斷劑。在某些實施例中，治療劑為寡核苷酸(例如治療性寡核苷酸)。在一些實施例中，NMDA受體配位體將寡核苷酸引導至位域。在一些實施例中，NMDA受體配位體靶向組織。在一些實施例中，組織為腦組織。在一些實施例中，NMDA受體配位體靶向細胞受體。在一些實施例中，細胞受體為NMDA受體。在一些實施例中，NMDA受體在腦中。在一些實施例中，NMDA受體在額葉皮質中。在一些實施例中，NMDA受體在紋狀體中。在一些實施例中，NMDA受體在小腦中。在一些實施例中，NMDA受體在腦幹中。在一些實施例中，NMDA受體在海馬體中。在一些實施例中，NMDA受體在脊髓中。In some embodiments, the compounds provided herein include NMDA receptor ligands. In some embodiments, NMDA receptor ligands can be used to guide therapeutic agents, preventive agents or diagnostic agents. In some embodiments, the therapeutic agent is an oligonucleotide (e.g., a therapeutic oligonucleotide). In some embodiments, the NMDA receptor ligand guides the oligonucleotide to the site. In some embodiments, the NMDA receptor ligand targets tissues. In some embodiments, the tissue is brain tissue. In some embodiments, the NMDA receptor ligand targets cell receptors. In some embodiments, the cell receptor is an NMDA receptor. In some embodiments, the NMDA receptor is in the brain. In some embodiments, the NMDA receptor is in the frontal cortex. In some embodiments, the NMDA receptors are in the striatum. In some embodiments, the NMDA receptors are in the cerebellum. In some embodiments, the NMDA receptors are in the brain stem. In some embodiments, the NMDA receptors are in the hippocampus. In some embodiments, the NMDA receptors are in the spinal cord.
本揭示案考慮在本文所提供之化合物中使用任何NMDA受體配位體。NMDA受體配位體為此項技術中所已知，且熟習此項技術者將能夠鑑別除本揭示案所明確提供之彼等配位體以外的用於本文所闡述化合物中之其他NMDA受體配位體。本揭示案亦考慮在本發明所闡述之化合物中使用本文所提供或此項技術中所已知之任何NMDA受體配位體之衍生物及前藥，且熟習此項技術者應知曉如何製備此類衍生物及前藥。The present disclosure contemplates the use of any NMDA receptor ligand in the compounds provided herein. NMDA receptor ligands are known in the art, and one skilled in the art will be able to identify other NMDA receptor ligands for use in the compounds described herein in addition to those expressly provided in the present disclosure. The present disclosure also contemplates the use of derivatives and prodrugs of any NMDA receptor ligand provided herein or known in the art in the compounds described in the present invention, and one skilled in the art will know how to prepare such derivatives and prodrugs.
在一些實施例中，NMDA受體配位體為NMDA受體促效劑。在一些實施例中，NMDA受體配位體為NMDA受體拮抗劑。在一些實施例中，NMDA受體配位體為美金剛(memantine)、MK-801、石杉鹼(huperzine) (例如石杉鹼 A、石杉鹼B)、膽固醇、拉科醯胺(lacosamide)、拉帕斯汀(rapastinel)、氯胺酮，或其結構類似物或衍生物。在一些實施例中，NMDA受體配位體為以下文獻中所揭示之彼等配位體中之任一者：Neuropharmacology2007, 53(6), 699-723；J. Med.Chem.1990, 33(2), 789-808；Neuroscience2001, 105(3), 663-669；J. Med.Chem.2022, 65(13), 9063-9075；Drugs Fut.2004, 29(10), 992；Drugs Fut.2004, 29(10), 993；及British Journal of Pharmacology2022, 179(6), 1146-1187，該等文獻各自係以引用方式併入本文中。用於本揭示案中之例示性NMDA受體配位體包括(但不限於)以下NMDA受體配位體及其衍生物中之任一者：、、、、、、、、、、、、、、、、、、、及。In some embodiments, the NMDA receptor ligand is an NMDA receptor agonist. In some embodiments, the NMDA receptor ligand is an NMDA receptor antagonist. In some embodiments, the NMDA receptor ligand is memantine, MK-801, huperzine (e.g., huperzine A, huperzine B), cholesterol, lacosamide, rapastinel, ketamine, or a structural analog or derivative thereof. In some embodiments, the NMDA receptor ligand is any of those disclosed in the following references:Neuropharmacology 2007, 53(6), 699-723;J. Med. Chem. 1990, 33(2), 789-808;Neuroscience 2001, 105(3), 663-669;J. Med. Chem. 2022, 65(13), 9063-9075;Drugs Fut. 2004, 29(10), 992;Drugs Fut. 2004, 29(10), 993; andBritish Journal of Pharmacology 2022, 179(6), 1146-1187, each of which is incorporated herein by reference. Exemplary NMDA receptor ligands for use in the present disclosure include, but are not limited to, any of the following NMDA receptor ligands and their derivatives: , , , , , , , , , , , , , , , , , , , and .
在一些實施例中，NMDA受體配位體為抗NMDA受體抗體。在某些實施例中，NMDA受體配位體為抗NMDA受體抗體片段或抗NMDA受體抗體變異體。「抗NMDA受體抗體」係指識別、結合或以其他方式與NMDA受體相互作用之免疫系統蛋白質。In some embodiments, the NMDA receptor ligand is an anti-NMDA receptor antibody. In certain embodiments, the NMDA receptor ligand is an anti-NMDA receptor antibody fragment or an anti-NMDA receptor antibody variant. "Anti-NMDA receptor antibody" refers to an immune system protein that recognizes, binds to, or otherwise interacts with an NMDA receptor.
在某些實施例中，NMDA受體配位體與一或多種劑部分結合(例如連接(link)、連結、連接(attach)、締合)。在某些實施例中，劑部分為治療劑、預防劑、診斷劑或成像劑。在某些實施例中，劑為小分子或寡聚化合物。在某些實施例中，劑部分為蛋白質、肽、抗體、寡核苷酸、小分子、大分子或其組合。In some embodiments, the NMDA receptor ligand is conjugated (e.g., linked, attached, associated) to one or more agent moieties. In some embodiments, the agent moiety is a therapeutic, prophylactic, diagnostic, or imaging agent. In some embodiments, the agent is a small molecule or an oligomeric compound. In some embodiments, the agent moiety is a protein, a peptide, an antibody, an oligonucleotide, a small molecule, a macromolecule, or a combination thereof.
在一些實施例中，一個以上之NMDA受體配位體與劑部分結合。在一些實施例中，至少兩個NMDA受體配位體(例如2、3、4、5、6、7、8、9、10或更多個NMDA受體配位體)與劑部分結合。在一些實施例中，兩個NMDA受體配位體與劑部分結合。在一些實施例中，三個NMDA受體配位體與劑部分結合。在一些實施例中，四個NMDA受體配位體與劑部分結合。在一些實施例中，五個NMDA受體配位體與劑部分結合。在一些實施例中，五個以上之NMDA受體配位體與劑部分結合。在一些實施例中，至少一個至約五個NMDA受體配位體與劑部分結合。在一些實施例中，至少一個至約四個NMDA受體配位體與劑部分結合。在一些實施例中，至少一個至約三個NMDA受體配位體與劑部分結合。在一些實施例中，至少一個至約兩個NMDA受體配位體與劑部分結合。In some embodiments, more than one NMDA receptor ligand is bound to the agent portion. In some embodiments, at least two NMDA receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more NMDA receptor ligands) are bound to the agent portion. In some embodiments, two NMDA receptor ligands are bound to the agent portion. In some embodiments, three NMDA receptor ligands are bound to the agent portion. In some embodiments, four NMDA receptor ligands are bound to the agent portion. In some embodiments, five NMDA receptor ligands are bound to the agent portion. In some embodiments, more than five NMDA receptor ligands are bound to the agent portion. In some embodiments, at least one to about five NMDA receptor ligands are bound to the agent portion. In some embodiments, at least one to about four NMDA receptor ligands are bound to the agent portion. In some embodiments, at least one to about three NMDA receptor ligands are bound to the agent portion. In some embodiments, at least one to about two NMDA receptor ligands are bound to the agent portion.
當劑部分與多個NMDA受體配位體結合時，所有NMDA受體配位體均可在劑部分上之相同位置處或附近結合，或NMDA受體配位體可與劑部分上之多個不同位置結合。When the agent moiety binds multiple NMDA receptor ligands, all of the NMDA receptor ligands may bind at or near the same location on the agent moiety, or the NMDA receptor ligands may bind to multiple different locations on the agent moiety.
在一些實施例中，寡核苷酸經由該寡核苷酸之5'端及/或3'端或在寡核苷酸中之內部位置處(亦即寡核苷酸上除5'或3'核苷酸以外之核苷酸處)與NMDA受體配位體結合(例如連結、連接、締合)。在一些實施例中，寡核苷酸經由該寡核苷酸之5'端與NMDA受體配位體結合。在一些實施例中，寡核苷酸經由該寡核苷酸之3'端與NMDA受體配位體結合。在一些實施例中，寡核苷酸經由該寡核苷酸之5'端及3'端與NMDA受體配位體結合。在一些實施例中，寡核苷酸在該寡核苷酸內之內部位置(例如在「內部修飾之寡核苷酸」中)與NMDA受體配位體結合。In some embodiments, the oligonucleotide is bound (e.g., linked, linked, associated) to the NMDA receptor ligand via the 5' end and/or 3' end of the oligonucleotide or at an internal position in the oligonucleotide (i.e., at a nucleotide other than the 5' or 3' nucleotide on the oligonucleotide). In some embodiments, the oligonucleotide is bound to the NMDA receptor ligand via the 5' end of the oligonucleotide. In some embodiments, the oligonucleotide is bound to the NMDA receptor ligand via the 3' end of the oligonucleotide. In some embodiments, the oligonucleotide is bound to the NMDA receptor ligand via the 5' end and the 3' end of the oligonucleotide. In some embodiments, the oligonucleotide is bound to the NMDA receptor ligand at an internal position within the oligonucleotide (e.g., in an "internally modified oligonucleotide").
在一些實施例中，寡核苷酸與一個以上之NMDA受體配位體結合。在一些實施例中，寡核苷酸與至少兩個NMDA受體配位體(例如2、3、4、5、6、7、8、9、10或更多個NMDA受體配位體)結合。在一些實施例中，寡核苷酸與兩個NMDA受體配位體結合。在一些實施例中，寡核苷酸與三個NMDA受體配位體結合。在一些實施例中，寡核苷酸與四個NMDA受體配位體結合。在一些實施例中，寡核苷酸與五個NMDA受體配位體結合。在一些實施例中，寡核苷酸與五個以上之NMDA受體配位體結合。在一些實施例中，寡核苷酸與至少一個至約五個NMDA受體配位體結合。在一些實施例中，寡核苷酸與至少一個至約四個NMDA受體配位體結合。在一些實施例中，寡核苷酸與至少一個至約三個NMDA受體配位體結合。在一些實施例中，寡核苷酸與至少一個至約兩個NMDA受體配位體結合。In some embodiments, the oligonucleotide is bound to one or more NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to at least two NMDA receptor ligands (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more NMDA receptor ligands). In some embodiments, the oligonucleotide is bound to two NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to three NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to four NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to five NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to more than five NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to at least one to about five NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to at least one to about four NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to at least one to about three NMDA receptor ligands. In some embodiments, the oligonucleotide is bound to at least one to about two NMDA receptor ligands.
當寡核苷酸與多個NMDA受體配位體結合時，所有NMDA受體配位體均可在寡核苷酸上之相同位置處或附近結合，或NMDA受體配位體可與寡核苷酸上之多個不同位置結合。在一些實施例中，多個NMDA受體配位體(亦即兩個、三個、四個、五個或更多個NMDA受體配位體)在寡核苷酸之5'端結合。在一些實施例中，多個NMDA受體配位體(亦即兩個、三個、四個、五個或更多個NMDA受體配位體)在寡核苷酸之3'端結合。在一些實施例中，多個NMDA受體配位體(亦即兩個、三個、四個、五個或更多個NMDA受體配位體)在寡核苷酸之一或多個內部位置處結合。在一些實施例中，寡核苷酸在該寡核苷酸之5'端與一或多個NMDA受體配位體結合，及/或在該寡核苷酸之3'端與一或多個NMDA受體配位體結合，及/或在該寡核苷酸之一個內部位置或多個內部位置處與一或多個NMDA受體配位體結合。 連接體When an oligonucleotide is bound to a plurality of NMDA receptor ligands, all NMDA receptor ligands may be bound at or near the same position on the oligonucleotide, or the NMDA receptor ligands may be bound to a plurality of different positions on the oligonucleotide. In some embodiments, a plurality of NMDA receptor ligands (i.e., two, three, four, five or more NMDA receptor ligands) are bound at the 5' end of the oligonucleotide. In some embodiments, a plurality of NMDA receptor ligands (i.e., two, three, four, five or more NMDA receptor ligands) are bound at the 3' end of the oligonucleotide. In some embodiments, a plurality of NMDA receptor ligands (i.e., two, three, four, five or more NMDA receptor ligands) are bound at one or more internal positions of the oligonucleotide. In some embodiments, the oligonucleotide is conjugated to one or more NMDA receptor ligands at the 5' end of the oligonucleotide and/or to one or more NMDA receptor ligands at the 3' end of the oligonucleotide and/or to one or more NMDA receptor ligands at one or more internal positions of the oligonucleotide.Linker
在某些實施例中，提供本文所闡述之化合物式之結合物。在某些實施例中，結合物包含與劑部分共價偶合之NMDA受體配位體。在某些實施例中，本文所提供之結合物包含一或多個連接體部分。在某些實施例中，該一或多個連接體部分將NMDA受體配位體連接至劑部分。在某些實施例中，劑部分為蛋白質、肽、抗體、核酸、小分子、大分子、治療劑、預防劑、診斷劑或成像劑。在一些實施例中，化合物與寡核苷酸結合。在某些實施例中，NMDA受體配位體與寡核苷酸結合。在某些實施例中，化合物包含一或多個NMDA受體配位體、一或多個連接體部分及一或多個劑部分，其中該等NMDA受體配位體經由一或多個連接體部分與該一或多個劑部分結合(例如連接(link)、連結、連接(attach)、締合)。In certain embodiments, a conjugate of the compound formula described herein is provided. In certain embodiments, the conjugate comprises an NMDA receptor ligand covalently coupled to an agent moiety. In certain embodiments, the conjugate provided herein comprises one or more linker moieties. In certain embodiments, the one or more linker moieties connect the NMDA receptor ligand to the agent moiety. In certain embodiments, the agent moiety is a protein, a peptide, an antibody, a nucleic acid, a small molecule, a macromolecule, a therapeutic agent, a prophylactic agent, a diagnostic agent, or an imaging agent. In certain embodiments, the compound is conjugated to an oligonucleotide. In certain embodiments, the NMDA receptor ligand is conjugated to an oligonucleotide. In certain embodiments, the compound comprises one or more NMDA receptor ligands, one or more linker moieties, and one or more agent moieties, wherein the NMDA receptor ligands are bound (e.g., linked, attached, associated) to the one or more agent moieties via the one or more linker moieties.
如本文所揭示之結合物可使用任何可用之方法來製造。當締合本文所提供之化合物與劑部分(例如NMDA受體配位體與寡核苷酸)時，該等部分可直接或間接地連接(例如，經由連接體部分；亦即，連接體共價鍵結至寡核苷酸與NMDA受體配位體中之每一者；在本文之一些式中，「-Ln-」，其中n為數字(例如L1、L2、L3、L4))。舉例而言，寡核苷酸與NMDA受體配位體可例如藉由一或多個共價鍵彼此直接締合，或可藉助於一或多個連接體締合。「連接體」係指用於使本文所提供化合物之兩種組分(例如NMDA受體配位體與寡核苷酸)彼此結合之任何化學部分(例如根據已知之化學原理具有適當化合價之原子組合)。該兩種組分中之每一者可連結至本文所提供之任何連接體之任何部分。在一些實施例中，本文所提供化合物之一種組分(例如NMDA受體配位體或寡核苷酸)藉由鍵連結至連接體之一端，且另一組分藉由鍵連結至連接體之另一端。在一些實施例中，本文所提供化合物之一種或兩種組分可藉由鍵連結至本文所闡述之任何連接體內之內部位置。舉例而言，在「烷基連接體」之背景中，NMDA受體配位體可藉由鍵接合至烷基連接體一端之碳，且寡核苷酸可藉由鍵接合至烷基連接體另一端之碳。在一些實施例中，連接體為鍵(包括例如磷酸二酯及硫代磷酸酯鍵)。在一些實施例中，連接體為視情況經取代之烷基連接體(亦即烷基鏈用於接合兩個部分，該兩個部分可各自與烷基連接體之相對端結合，或一個或兩個部分可與烷基連接體上之內部碳結合)。在一些實施例中，連接體為視情況經取代之聚乙二醇(PEG)連接體(亦即PEG鏈用於接合兩個部分，該兩個部分可各自與PEG連接體之相對端結合，或一個或兩個部分可與PEG連接體上之內部位置結合)。在一些實施例中，連接體為視情況經取代之雜烷基連接體(亦即雜烷基鏈用於接合兩個部分，該兩個部分可各自與雜烷基連接體之相對端結合，或一個或兩個部分可與雜烷基連接體上之內部位置結合)。在一些實施例中，連接體為視情況經取代之雜芳基連接體(亦即雜芳基用於接合兩個部分，該兩個部分可各自與雜芳基上之任何位置結合)。The conjugates disclosed herein can be made using any available methods. When combining the compounds provided herein with agent moieties (e.g., NMDA receptor ligands and oligonucleotides), the moieties can be directly or indirectly linked (e.g., via a linker moiety; that is, the linker is covalently bonded to each of the oligonucleotide and the NMDA receptor ligand; in some formulas herein, "-Ln- ", wherein n is a number (e.g.,L1 ,L2 ,L3 ,L4 )). For example, the oligonucleotide and the NMDA receptor ligand can be directly linked to each other, for example, by one or more covalent bonds, or can be linked with the aid of one or more linkers. "Linker" refers to any chemical moiety (e.g., a combination of atoms with appropriate valence according to known chemical principles) used to bind two components of the compounds provided herein (e.g., an NMDA receptor ligand and an oligonucleotide) to each other. Each of the two components can be linked to any portion of any linker provided herein. In some embodiments, one component of the compounds provided herein (e.g., an NMDA receptor ligand or an oligonucleotide) is linked to one end of the linker by a bond, and the other component is linked to the other end of the linker by a bond. In some embodiments, one or both components of the compounds provided herein can be linked to an internal position within any linker described herein by a bond. For example, in the context of an "alkyl linker," an NMDA receptor ligand can be attached to a carbon at one end of the alkyl linker via a bond, and an oligonucleotide can be attached to a carbon at the other end of the alkyl linker via a bond. In some embodiments, the linker is a bond (including, for example, phosphodiester and phosphorothioate bonds). In some embodiments, the linker is an optionally substituted alkyl linker (i.e., an alkyl chain is used to attach two moieties, which can each be attached to opposite ends of the alkyl linker, or one or both moieties can be attached to internal carbons on the alkyl linker). In some embodiments, the linker is an optionally substituted polyethylene glycol (PEG) linker (i.e., a PEG chain is used to join two moieties, each of which can be bound to opposite ends of the PEG linker, or one or both moieties can be bound to internal positions on the PEG linker). In some embodiments, the linker is an optionally substituted heteroalkyl linker (i.e., a heteroalkyl chain is used to join two moieties, each of which can be bound to opposite ends of the heteroalkyl linker, or one or both moieties can be bound to internal positions on the heteroalkyl linker). In some embodiments, the linker is an optionally substituted heteroaryl linker (i.e., a heteroaryl group is used to join two moieties, each of which can be bound to any position on the heteroaryl group).
在某些實施例中，本文所提供之化合物包含一或多個連接基團。在某些實施例中，L1、L2、L3及L4中之每一者包含連接基團。在某些實施例中，連接基團共價結合至NMDA受體配位體。在某些實施例中，連接基團共價結合至寡核苷酸。在某些實施例中，連接基團共價結合至可裂解部分。在某些實施例中，連接基團包含可裂解鍵。在某些實施例中，連接基團不包含可裂解部分。在某些實施例中，連接基團包含與固體支持物之共價連接。在某些實施例中，連接基團包括用於連接NMDA受體配位體之多個位置。In certain embodiments, the compounds provided herein comprise one or more linking groups. In certain embodiments, each of L1 , L2 , L3 and L4 comprises a linking group. In certain embodiments, the linking group is covalently bound to an NMDA receptor ligand. In certain embodiments, the linking group is covalently bound to an oligonucleotide. In certain embodiments, the linking group is covalently bound to a cleavable portion. In certain embodiments, the linking group comprises a cleavable bond. In certain embodiments, the linking group does not comprise a cleavable portion. In certain embodiments, the linking group comprises a covalent connection to a solid support. In certain embodiments, the linking group comprises a plurality of positions for connecting to an NMDA receptor ligand.
在某些實施例中，連接基團包含鏈結構，諸如烴基鏈，或重複單元之寡聚物或此等重複單元之組合。在某些實施例中，連接基團包含1至50個重複單元、1至40個重複單元、1至25個重複單元、1至20個重複單元、1至15個重複單元、1至10個重複單元或1至5個重複單元。在某些實施例中，連接基團為1至50個原子長、1至40個原子長、1至25個原子長、1至20個原子長、1至15個原子長、1至10個原子長或1至5個原子長。In some embodiments, the linking group comprises a chain structure, such as a alkyl chain, or an oligomer of repeating units or a combination of such repeating units. In some embodiments, the linking group comprises 1 to 50 repeating units, 1 to 40 repeating units, 1 to 25 repeating units, 1 to 20 repeating units, 1 to 15 repeating units, 1 to 10 repeating units, or 1 to 5 repeating units. In some embodiments, the linking group is 1 to 50 atoms long, 1 to 40 atoms long, 1 to 25 atoms long, 1 to 20 atoms long, 1 to 15 atoms long, 1 to 10 atoms long, or 1 to 5 atoms long.
在某些實施例中，連接基團含有碳原子。在某些實施例中，連接基團含有雜原子(例如氮、氧、硫等)。在某些實施例中，連接基團形成醯胺鍵聯、酯鍵聯或二硫鍵聯。在某些實施例中，連接基團形成腙鍵聯、肟鍵聯、亞胺鍵聯、胍鍵聯、脲鍵聯、胺基甲酸酯鍵聯、不飽和烷基鍵聯、磺醯胺鍵聯或4-8員雜環鍵聯。在某些實施例中，連接基團包含一或多個選自以下之基團：烷基、胺基、側氧基、醯胺、二硫化物、聚乙二醇、醚、硫醚及羥基胺基。在某些實施例中，連接基團包含至少一個磷基。在某些實施例中，連接基團包含至少一個磷酸酯基。在某些實施例中，連接基團包括至少一個中性連接基團。在某些實施例中，連接基團經各種取代基取代，包括(但不限於)氫原子、烷基、烯基、炔基、胺基、烷基胺基、二烷基胺基、三烷基胺基、羥基、烷氧基、鹵素、芳基、雜環基、芳香族雜環基、氰基、醯胺、胺甲醯基、羧酸、酯、硫醚、烷基硫基醚、硫醇及脲基。如熟習此項技術者應瞭解，該等基團中之每一者可繼而經取代。In some embodiments, the linking group contains carbon atoms. In some embodiments, the linking group contains heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.). In some embodiments, the linking group forms an amide bond, an ester bond, or a disulfide bond. In some embodiments, the linking group forms a hydrazone bond, an oxime bond, an imine bond, a guanidine bond, a urea bond, a carbamate bond, an unsaturated alkyl bond, a sulfonamide bond, or a 4-8 membered heterocyclic bond. In some embodiments, the linking group comprises one or more groups selected from the following: alkyl, amine, pendoxy, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamine. In some embodiments, the linking group comprises at least one phosphorus group. In some embodiments, the linking group comprises at least one phosphate group. In some embodiments, the linking group comprises at least one neutral linking group. In some embodiments, the linking group is substituted with various substituents, including but not limited to hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, amine groups, alkylamino groups, dialkylamino groups, trialkylamino groups, hydroxyl groups, alkoxy groups, halogen groups, aryl groups, heterocyclic groups, aromatic heterocyclic groups, cyano groups, amide groups, aminoformyl groups, carboxylic acids, esters, thioethers, alkylthioethers, thiols, and urea groups. As will be appreciated by those skilled in the art, each of these groups may be substituted in turn.
在某些實施例中，連接基團包括(但不限於)經取代或未經取代之C1-C10烷基、經取代或未經取代之C2-C10烯基或經取代或未經取代之C2-C10炔基，其中較佳取代基之非限制性清單包括羥基、胺基、烷氧基、羧基、苯甲基、苯基、硝基、硫醇、硫烷氧基、鹵素、烷基、芳基、烯基及炔基。在某些實施例中，連接基團為脂肪族或雜脂肪族。舉例而言，連接基團可為聚烷基連接基團。連接基團可為聚醚連接基團。連接基團可為聚乙烯連接基團，諸如PEG。In certain embodiments, the linking group includes, but is not limited to, substituted or unsubstituted C1 -C10 alkyl, substituted or unsubstituted C2 -C10 alkenyl, or substituted or unsubstituted C2 -C10 alkynyl, wherein a non-limiting list of preferred substituents includes hydroxyl, amine, alkoxy, carboxyl, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In certain embodiments, the linking group is aliphatic or heteroaliphatic. For example, the linking group may be a polyalkyl linking group. The linking group may be a polyether linking group. The linking group may be a polyethylene linking group, such as PEG.
在某些實施例中，連接基團為短的肽鏈。在某些實施例中，連接基團包含1至40個胺基酸、1至25個胺基酸、1至20個胺基酸、1至15個胺基酸、1至10個胺基酸或1至5個胺基酸。In certain embodiments, the linking group is a short peptide chain. In certain embodiments, the linking group comprises 1 to 40 amino acids, 1 to 25 amino acids, 1 to 20 amino acids, 1 to 15 amino acids, 1 to 10 amino acids, or 1 to 5 amino acids.
在某些實施例中，連接基團包含連接體核苷。在某些實施例中，連接基團包含1至40個連接體核苷、1至25個連接體核苷、1至20個連接體核苷、1至15個連接體核苷、1至10個連接體核苷或1至5個連接體核苷。在某些實施例中，此等連接體核苷可為經修飾或未經修飾之核苷。通常期望連接體核苷在化合物到達靶組織後自化合物裂解。因此，本文之連接體核苷可經由可裂解鍵彼此連接及連接至化合物之其餘部分。在本文中，連接體核苷不視為寡核苷酸有效載荷之一部分。因此，在化合物包含由指定數目或範圍之連接核苷組成及/或與參照核酸具有指定互補性百分比之寡核苷酸且化合物亦包含含有連接基團(包含連接體核苷)之NMDA受體配位體的實施例中，彼等連接體核苷不計入寡核苷酸之長度且不用於確定寡核苷酸對於參照核酸之互補性百分比。In certain embodiments, the linker group comprises a linker nucleoside. In certain embodiments, the linker group comprises 1 to 40 linker nucleosides, 1 to 25 linker nucleosides, 1 to 20 linker nucleosides, 1 to 15 linker nucleosides, 1 to 10 linker nucleosides, or 1 to 5 linker nucleosides. In certain embodiments, these linker nucleosides may be modified or unmodified nucleosides. It is generally expected that the linker nucleosides will cleave from the compound after the compound reaches the target tissue. Therefore, the linker nucleosides herein can be connected to each other and to the rest of the compound via a cleavable bond. In this article, the linker nucleosides are not considered as part of the oligonucleotide payload. Thus, in embodiments where the compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and/or having a specified percent complementarity with a reference nucleic acid, and the compound also comprises an NMDA receptor ligand containing a linker group (including linker nucleosides), those linker nucleosides are not included in the length of the oligonucleotide and are not used to determine the percent complementarity of the oligonucleotide to the reference nucleic acid.
在某些實施例中，連接基團包括蛋白質結合基團。在某些實施例中，蛋白質結合基團為脂質，諸如包括(但不限於)膽固醇、膽汁酸、金剛烷乙酸、1-芘丁酸、二氫睪固酮、1,3-雙-O(十六烷基)甘油、香葉基氧基己基、十六烷基甘油、冰片、薄荷醇、1,3-丙二醇、十七烷基、棕櫚酸、肉豆蔻酸、O3-(油醯基)石膽酸、O3-(油醯基)膽烯酸、二甲氧基三苯甲基或吩噁嗪)、維生素(例如葉酸、維生素A、維生素E、生物素、吡哆醛)、肽、碳水化合物(例如單糖、二糖、三糖、四糖、寡糖、多糖)、內體溶解組分、類固醇(例如熊果醇、龍舌蘭皂苷元(hecigenin)、薯蕷皂苷元(diosgenin))、萜烯(例如三萜烯，例如菝葜皂苷元(sarsasapogenin)、無羈萜(friedelin)、表木栓醇(epifriedelanol)衍生化之石膽酸)或陽離子脂質。在某些實施例中，蛋白質結合基團為C16至C22長鏈飽和或不飽和脂肪酸、膽固醇、膽汁酸、維生素E、金剛烷或1-五氟丙基。In some embodiments, the linking group includes a protein binding group. In some embodiments, the protein binding group is a lipid, such as, but not limited to, cholesterol, bile acid, adamantaneacetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O (hexadecyl) glycerol, geranyloxyhexyl, hexadecyl glycerol, borneol, menthol, 1,3-propylene glycol, heptadecyl, palmitic acid, myristic acid, O3-(oleyl) cholecalciferol, O3-(oleyl) cholenoic acid, dimethoxytrityl or phenoxazine), vitamins (e.g., folic acid, vitamin A, vitamin E, vitamin B12, vitamin C, vitamin B13, vitamin B14, vitamin B15, vitamin B16, vitamin B17, vitamin B18, vitamin B19, vitamin B20, vitamin B21, vitamin B22, vitamin B23, vitamin B24, vitamin B25, vitamin B26, vitamin B27, vitamin B28, vitamin B29, vitamin B29, vitamin B29, vitamin B29, vitamin B29, vitamin B21, vitamin B2 In some embodiments, the protein binding group is a C 16 to C 22 long chain saturated or unsaturated fatty acid, cholesterol, bile acid, vitamin E, adamantane or1 -pentafluoropropyl .
在某些實施例中，連接基團包括(但不限於)吡咯啶、8-胺基-3,6-二氧雜辛酸(ADO)、4-(N-馬來醯亞胺基甲基)環己烷-1-甲酸琥珀醯亞胺酯(SMCC)及6-胺基己酸(AHEX或AHA)。In certain embodiments, the linking group includes, but is not limited to, pyrrolidine, 8-amino-3,6-dioxooctanoic acid (ADO), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA).
在某些實施例中，連接基團包括(但不限於)以下參考文獻中所闡述之彼等連接基團：U.S. 5,994,517；U.S. 6,300,319；U.S. 6,660,720；U.S. 6,906,182；U.S. 7,262,177；U.S. 7,491,805；U.S. 8,106,022；U.S. 7,723,509；U.S. 9,127,276；U.S. 2006/0148740；U.S. 2011/0123520；WO 2013/033230；WO 2012/037254；Biessen等人，J. Med. Chem.1995, 38, 1846-1852；Lee等人，Bioorganic & Medicinal Chemistry2011,19, 2494-2500；Rensen等人，J. Biol. Chem.2001, 276, 37577-37584；Rensen等人，J. Med. Chem.2004, 47, 5798-5808；Sliedregt等人，J. Med. Chem.1999, 42, 609-618；Valentijn等人，Tetrahedron, 1997, 53, 759-770；Lee,Carbohydr. Res.1978, 67, 509-514；Connolly等人，J. Biol. Chem.1982, 257, 939-945；Pavia等人，Int. J. Pep. Protein Res.1983, 22, 539-548；Lee等人，Biochem.1984, 23, 4255-4261；Lee等人，Glycoconjugate J.1987, 4, 317-328；Toyokuni等人，Tetrahedron Lett.1990, 31, 2673-2676；Biessen等人，J. Med. Chem.1995, 38, 1538-1546；Valentijn等人，Tetrahedron, 1997, 53, 759-770；Kim等人，Tetrahedron Lett.1997, 38, 3487-3490；Lee等人，Bioconjug. Chem.1997, 8, 762-765；Kato等人，Glycobiol.2001, 11, 821-829；Rensen等人，J. Biol. Chem.2001, 276, 37577-37584；Lee等人，Methods Enzymol. 2003, 362, 38-43；Westerlind等人，Glycoconj. J.2004, 21, 227-241；Lee等人，Bioorg. Med. Chem. Lett.2006, 16(19), 5132-5135；Maierhofer等人，Bioorg. Med. Chem.2007, 15, 7661-7676；Khorev等人，Bioorg. Med. Chem.2008, 16, 5216-5231；Lee等人，Bioorg. Med. Chem.2011, 19, 2494-2500；Kornilova等人，Analyt. Biochem.2012, 425, 43-46；Pujol等人，Angew. Chemie Int. Ed. Engl.2012, 51, 7445-7448；Biessen等人，J. Med. Chem.1995, 38, 1846-1852；Sliedregt等人，J. Med. Chem.1999, 42, 609-618；Rensen等人，J. Med. Chem.2004, 47, 5798-5808；Rensen等人，Arterioscler. Thromh. Vase. Biol.2006, 26, 169-175；van Rossenberg等人，Gene Ther.2004, 11, 457-464；Sato等人，J. Am. Chem. Soc.2004, 126, 14013-14022；Lee等人，J. Org. Chem.2012, 77, 7564-7571；Biessen等人，FASEB J.2000, 14, 1784-1792；Rajur等人，Bioconjug. Chem.1997, 8, 935-940；Duff等人，Methods Enzymol.2000, 313, 297-321；Maier等人，Bioconjug. Chem.2003, 14, 18-29；Jayaprakash等人，Org. Lett.2010, 12, 5410-5413；Manoharan, Antisense Nucleic AcidDrug Dev.2002, 12, 103-128；Merwin等人，Bioconjug. Chem.1994, 5, 612-620；Tomiya等人，Bioorg. Med. Chem., 2013, 21, 5275-5281；國際申請案WO 1998/013381；WO 2011/038356；WO 1997/046098；WO 2008/098788；WO 2004/101619；WO 2012/037254；WO 2011/120053；WO 2011/100131；WO 2011/163121；WO 2012/177947；WO 2013/033230；WO 2013/075035；WO 2012/083185；WO 2012/083046；WO 2009/082607；WO 2009/134487；WO 2010/144740；WO 2010/148013；WO 1997/020563；WO 2010/088537；WO 2002/043771；WO 2010/129709；WO 2012/068187；WO 2009/126933；WO 2004/024757；WO 2010/054406；WO 2012/089352；WO 2012/089602；WO 2013/166121；WO 2013/165816；美國專利第4,751,219號；第7,582,744號；第8,552,163號；第8,137,695號；第6,908,903號；第6,383,812號；第7,262,177號；第6,525,031號；第5,994,517號；第6,660,720號；第6,300,319號；第7,723,509號；第8,106,022號；第7,491,805號；第7,491,805號；第8,541,548號；第8,344,125號；第8,313,772號；第8,349,308號；第8,450,467號；第8,501,930號；第8,158,601號；第7,262,177號；第6,906,182號；第6,620,916號；第8,435,491號；第8,404,862號；第7,851,615號；美國專利申請公開案第U.S. 2011/0097264號；第U.S. 2011/0097265號；第U.S. 2013/0004427號；第U.S. 2003/0119724號；第U.S. 2011/0207799號；第U.S. 2012/0035115號；第U.S. 2012/0230938號；第U.S. 2005/0164235號；第U.S. 2006/0183886號；第U.S. 2012/0136042號；第U.S. 2012/0095075號；第U.S. 2013/0109817號；第U.S. 2006/0148740號；第U.S. 2008/0206869號；第U.S. 2012/0165393號；第U.S. 2012/0101148號；第U.S. 2013/0121954號；第U.S. 2011/0123520號；第U.S. 2003/0077829號；第U.S. 2008/0108801號；及第U.S. 2009/0203132號；其各自係以引用方式併入本文中。In certain embodiments, the linking group includes, but is not limited to, those described in the following references: US 5,994,517; US 6,300,319; US 6,660,720; US 6,906,182; US 7,262,177; US 7,491,805; US 8,106,022; US 7,723,509; US 9,127,276; US 2006/0148740; US 2011/0123520; WO 2013/033230; WO 2012/037254; Biessen et al.,J. Med. Chem. 1995, 38, 1846-1852; Lee et al.,Bioorganic & Medicinal Chemistry 2011,19, 2494-2500; Rensen et al.,J. Biol. Chem. 2001, 276, 37577-37584; Rensen et al.,J. Med. Chem. 2004, 47, 5798-5808; Sliedregt et al.,J. Med. Chem. 1999, 42, 609-618; Valentijn et al.,Tetrahedron , 1997, 53, 759-770; Lee,Carbohydr. Res. 1978, 67, 509-514; Connolly et al.,J. Biol. Chem. 1982, 257, 939-945; Pavia et al.,Int. J. Pep. Protein Res. 1983, 22, 539-548; Lee et al.,Biochem. 1984, 23, 4255-4261; Lee et al.,Glycoconjugate J. 1987, 4, 317-328; Toyokuni et al.,Tetrahedron Lett. 1990, 31, 2673-2676; Biessen et al.,J. Med. Chem. 1995, 38, 1538-1546; Valentijn et al.,Tetrahedron , 1997, 53, 759-770; Kim et al.,Tetrahedron Lett. 1997, 38, 3487-3490; Lee et al.,Bioconjug. Chem. 1997, 8, 762-765; Kato et al.,Glycobiol. 2001, 11, 821-829; Rensen et al.,J. Biol. Chem. 2001, 276, 37577-37584; Lee et al.,Methods Enzymol . 2003, 362, 38-43; Westerlind et al.,Glycoconj. J. 2004, 21, 227-241; Lee et al.,Bioorg. Med. Chem. Lett. 2006, 16(19), 5132-5135; Maierhofer et al.,Bioorg. Med. Chem. 2007, 15, 7661-7676; Khorev et al.,Bioorg. Med. Chem. 2008, 16, 5216-5231; Lee et al.,Bioorg. Med. Chem. 2011, 19, 2494-2500; Kornilova et al.,Analyt. Biochem. 2012, 425, 43-46; Pujol et al.,Angew. Chemie Int. Ed. Engl. 2012, 51, 7445-7448; Biessen et al.,J. Med. Chem. 1995, 38, 1846-1852; Sliedregt et al.,J. Med. Chem. 1999, 42, 609-618; Rensen et al.,J. Med. Chem. 2004, 47, 5798-5808; Rensen et al.,Arterioscler. Thromh. Vase. Biol. 2006, 26, 169-175; van Rossenberg et al.,Gene Ther. 2004, 11, 457-464; Sato et al.,J. Am. Chem. Soc. 2004, 126, 14013-14022; Lee et al.,J. Org. Chem. 2012, 77, 7564-7571; Biessen et al.,FASEB J. 2000, 14, 1784-1792; Rajur et al.,Bioconjug. Chem. 1997, 8, 935-940; Duff et al.,Methods Enzymol. 2000, 313, 297-321; Maier et al.,Bioconjug. Chem. 2003, 14, 18-29; Jayaprakash et al.,Org. Lett. 2010, 12, 5410-5413; Manoharan, Antisense Nucleic AcidDrug Dev. 2002, 12, 103-128; Merwin et al.,Bioconjug. Chem. 1994, 5, 612-620; Tomiya et al.,Bioorg. Med. Chem. , 2013, 21, 5275-5281; International application WO 1998/013381; WO 2011/038356; WO 1997/046098; WO 2008/098788; WO 2004/101619; WO 2012/037254; WO 2011/120053; WO 2011/100131; WO 2011/163121; WO 2012/177947;WO 2013/033230; WO 2013/075035; WO 2012/083185; WO 2012/083046; WO 2009/082607; WO 2009/134487; WO 2010/144740; WO 2010/148013; WO 1997/020563;WO 2010/088537;WO 2002/043771;WO 2010/129709;WO 2012/068187;WO 2009/126933;WO 2004/024757;WO 2010/054406;WO 2012/089352;WO 2012/089602; WO 2013/166121; WO 2013/165816; U.S. Patent Nos. 4,751,219; 7,582,744; 8,552,163; 8,137,695; 6,908,903; 6,383,812; 7,262,177; 6,525,031; 5,994,517; 6,660,720; 6,300,319; 7,723,509; 8,106,022; 7,491,805 No. 7,491,805; No. 8,541,548; No. 8,344,125; No. 8,313,772; No. 8,349,308; No. 8,450,467; No. 8,501,930; No. 8,158,601; No. 7,262,177; No. 6,906,182; No. 6,620,916; No. 8,435,491; No. 8,404,862; No. 7,851,615; U.S. Patent Application Publication No. No. 2011/0097264; No. 2011/0097265; No. 2013/0004427; No. 2003/0119724; No. 2011/0207799; No. 2012/0035115; No. 2012/0230938; No. 2005/0164235; No. 2006/0183886; No. 2012/0136042; No. 2012/0095075; No. 2013/0109817; No. 2006/0148740; No. 2008/0206869; No. No. US 2012/0165393; No. US 2012/0101148; No. US 2013/0121954; No. US 2011/0123520; No. US 2003/0077829; No. US 2008/0108801; and No. US 2009/0203132; each of which is incorporated herein by reference.
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：、、、、、、、、、、及，其中每一n獨立地為1至20之整數(亦即1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)；且p獨立地為1至6之整數(亦即1、2、3、4、5或6)。In certain embodiments, L1 , L2 , L3 and L4 independently include or together form a structure selected from the following: , , , , , , , , , , and , where each n is independently an integer from 1 to 20 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20); and p is independently an integer from 1 to 6 (i.e., 1, 2, 3, 4, 5 or 6).
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：、、、、、、、及，其中每一n獨立地為1至20之整數(亦即1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)。In certain embodiments, L1 , L2 , L3 and L4 independently include or together constitute a structure selected from the following: , , , , , , , and , where each n is independently an integer from 1 to 20 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：、、、、、、、、、、、、、及，其中每一n獨立地為1至20之整數(亦即1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)。In certain embodiments, L1 , L2 , L3 and L4 independently include or together constitute a structure selected from the following: , , , , , , , , , , , , , and , where each n is independently an integer from 1 to 20 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：、、、、、、、、、、、、、及，其中每一n獨立地為1至20之整數(亦即1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)。In certain embodiments, L1 , L2 , L3 and L4 independently include or together constitute a structure selected from the following: , , , , , , , , , , , , , and , where each n is independently an integer from 1 to 20 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：、、、、、、、、、、、、、、、、、、及，其中每一L獨立地為磷連接基團；且每一n獨立地為1至20之整數(亦即1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)。In certain embodiments, L1 , L2 , L3 and L4 independently include or together constitute a structure selected from the following: , , , , , , , , , , , , , , , , , , and , wherein each L is independently a phosphorus linking group; and each n is independently an integer from 1 to 20 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：、、、、、、、、、、、、、、、、、及。In certain embodiments, L1 , L2 , L3 and L4 independently include or together form a structure selected from the following: , , , , , , , , , , , , , , , , , and .
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：、、、、、、、、、、、、及。In certain embodiments, L1 , L2 , L3 and L4 independently include or together form a structure selected from the following: , , , , , , , , , , , , and .
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：、、、、、、、、、、、、、、、、、、、及。In certain embodiments, L1 , L2 , L3 and L4 independently include or together constitute a structure selected from the following: , , , , , , , , , , , , , , , , , , , and .
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：及，其中n為1至20 (亦即1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)。In certain embodiments, L1 , L2 , L3 and L4 independently include or together form a structure selected from the following: and , wherein n is 1 to 20 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：、及。In certain embodiments, L1 , L2 , L3 and L4 independently include or together form a structure selected from the following: , and .
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：及。In certain embodiments, L1 , L2 , L3 and L4 independently include or together form a structure selected from the following: and .
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：及。In certain embodiments, L1 , L2 , L3 and L4 independently include or together form a structure selected from the following: and .
在某些實施例中，L1、L2、L3及L4獨立地包含或一起具有如下結構：。In certain embodiments, L1 , L2 , L3 and L4 independently include or together have the following structure: .
在某些實施例中，L1、L2、L3及L4獨立地包含或一起具有如下結構：。In certain embodiments, L1 , L2 , L3 and L4 independently include or together have the following structure: .
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：及。In certain embodiments, L1 , L2 , L3 and L4 independently include or together constitute a structure selected from the following: and .
在某些實施例中，L1、L2、L3及L4獨立地包含或一起構成選自以下之結構：及，其中每一n獨立地為0、1、2、3、4、5、6或7。In certain embodiments, L1 , L2 , L3 and L4 independently include or together constitute a structure selected from the following: and , where each n is independently 0, 1, 2, 3, 4, 5, 6 or 7.
在一些實施例中，L1、L2、L3及L4中之任一者可獨立地為連接體(例如視情況經取代之烷基連接體、視情況經取代之聚乙二醇(PEG)連接體、視情況經取代之雜烷基連接體或視情況經取代之雜芳基連接體)。在一些實施例中，L1、L2、L3及L4中之任一者可獨立地為鍵(例如碳-碳鍵、磷酸二酯鍵或硫代磷酸酯鍵)。在一些實施例中，L1、L2、L3及L4中之任一者可獨立地不存在。In some embodiments, any one of L1 , L2 , L3 and L4 may independently be a linker (e.g., an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, or an optionally substituted heteroaryl linker). In some embodiments, any one of L1 , L2 , L3 and L4 may independently be a bond (e.g., a carbon-carbon bond, a phosphodiester bond, or a phosphorothioate bond). In some embodiments, any one of L1 , L2 , L3 and L4 may independently be absent.
在一些實施例中，L1為鍵。在一些實施例中，L1為視情況經取代之烷基連接體。在一些實施例中，L1為視情況經取代之C1-C6烷基連接體。在一些實施例中，L1為經=O取代之C1-C6烷基連接體。在某些實施例中，L1包含結構。In some embodiments, L1 is a bond. In some embodiments, L1 is an optionally substituted alkyl linker. In some embodiments, L1 is an optionally substituted C1 -C6 alkyl linker. In some embodiments, L1 is a C1 -C6 alkyl linker substituted with =O. In certain embodiments, L1 comprises the structure .
在一些實施例中，L2為視情況經取代之烷基連接體。在一些實施例中，L2為視情況經取代之C1-C15烷基連接體。在一些實施例中，L2為視情況經取代之C5-C12烷基連接體。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。In some embodiments,L2 is an optionally substituted alkyl linker. In some embodiments,L2 is an optionally substitutedC1 -C15 alkyl linker. In some embodiments,L2 is an optionally substitutedC5 -C12 alkyl linker. In certain embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure .
在一些實施例中，L2為視情況經取代之PEG連接體。在一些實施例中，L2為視情況經取代之PEG連接體，其長度包含一個、兩個、三個、四個、五個、六個、七個或八個PEG單元，其中PEG單元包含結構。在某些實施例中，L2為視情況經取代之PEG連接體，其長度包含三個PEG單元。在某些實施例中，L2為視情況經取代之PEG連接體，其長度包含四個PEG單元。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。In some embodiments,L is an optionally substituted PEG linker. In some embodiments,L is an optionally substituted PEG linker having a length of one, two, three, four, five, six, seven, or eight PEG units, wherein the PEG unit comprises the structure In some embodiments,L2 is an optionally substituted PEG linker having a length of three PEG units. In some embodiments,L2 is an optionally substituted PEG linker having a length of four PEG units. In some embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure .
在一些實施例中，L2為視情況經取代之雜烷基連接體。在某些實施例中，L2包含結構。在某些實施例中，L2包含結構。In some embodiments,L2 is an optionally substituted heteroalkyl linker. In certain embodiments,L2 comprises the structure In certain embodiments,L2 comprises the structure .
在一些實施例中，L3為視情況經取代之雜芳基連接體。在一些實施例中，L3為視情況經取代之部分不飽和雜環烷基連接體或雜芳基連接體。在某些實施例中，L3包含結構。In some embodiments, L3 is an optionally substituted heteroaryl linker. In some embodiments, L3 is an optionally substituted partially unsaturated heterocycloalkyl linker or heteroaryl linker. In certain embodiments, L3 comprises the structure .
在一些實施例中，L4為視情況經取代之雜烷基連接體。在一些實施例中，雜烷基連接體經一或多個=O取代基取代。在某些實施例中，L4包含結構，其中X為O或S。在某些實施例中，L4包含結構，其中X為O或S。In some embodiments,L4 is an optionally substituted heteroalkyl linker. In some embodiments, the heteroalkyl linker is substituted with one or more =0 substituents. In certain embodiments,L4 comprises the structure , wherein X is O or S. In certain embodiments, L4 comprises the structure , where X is O or S.
在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。在一些實施例中，L1、L2、L3及L4一起構成結構。在一些實施例中，L1、L2、L3及L4一起構成結構，其中X為O或S。 製備化合物之方法In some embodiments,L1 ,L2 ,L3 , andL4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure , wherein X is O or S. In some embodiments, L1 , L2 , L3 and L4 together form a structure In some embodiments,L1 ,L2 ,L3 andL4 together form a structure , wherein X is O or S. Method for preparing the compound
在一些態樣中，本揭示案係關於製備包含如本文所揭示之NMDA受體配位體之化合物及組合物的方法。In some aspects, the disclosure relates to methods of making compounds and compositions comprising the NMDA receptor ligands disclosed herein.
本揭示案之化合物可藉由有機合成技術中已知之手段來製得。若需要，最佳化反應條件及最大程度地減少競爭性副產物之方法為此項技術中所已知。反應最佳化及放大可有利地利用高速平行合成設備及電腦控制之微型反應器(例如，Design and Optimization in Organic Synthesis，第2版，Carlson R編輯，2005; Elsevier Science Ltd.；Jähnisch, K等人，Angew. Chem. Int. Ed. Engl. 2004 43: 406；及其中之參考文獻)。熟習此項技術者可藉由使用市售可搜尋結構之資料庫軟體(例如SciFinder® (美國化學協會之CAS部門(CAS division of the American Chemical Society))及Reaxys® (Elsevier))，或使用網際網路搜尋引擎(諸如Google®)或關鍵字資料庫(諸如美國專利商標局文檔資料庫)藉由適當關鍵字搜尋來確定其他反應方案(scheme及protocol)。The compounds of the present disclosure can be prepared by means known in the art of organic synthesis. If necessary, methods for optimizing reaction conditions and minimizing competitive byproducts are known in the art. Reaction optimization and scale-up can advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (e.g.,Design and Optimization in Organic Synthesis, 2nd edition , Carlson R, ed., 2005; Elsevier Science Ltd.; Jähnisch, K et al., Angew. Chem. Int. Ed. Engl. 2004 43: 406; and references therein). Other reaction schemes and protocols can be identified by one skilled in the art by using commercially available searchable structure database software such as SciFinder® (CAS division of the American Chemical Society) and Reaxys® (Elsevier), or by using an internet search engine such as Google® or a keyword database such as the U.S. Patent and Trademark Office Document Database by appropriate keyword searching.
如熟習此項技術者可瞭解，合成本文各式化合物之方法對於熟習此項技術者而言將為顯而易見的，包括在本文方案及實例中。另外，各個合成步驟可以交替順序或次序實施，以得到期望化合物。另外，本文中所描繪之溶劑、溫度、反應持續時間等僅係出於闡釋目的，且熟習此項技術者將認識到，反應條件之變化可產生本揭示案之期望化合物。As will be appreciated by those skilled in the art, methods for synthesizing the various compounds herein will be apparent to those skilled in the art, including in the schemes and examples herein. In addition, the various synthetic steps may be performed in an alternate sequence or order to obtain the desired compounds. In addition, the solvents, temperatures, reaction durations, etc. described herein are for illustrative purposes only, and those skilled in the art will recognize that variations in the reaction conditions can produce the desired compounds of the present disclosure.
本文化合物亦可含有鍵聯(例如碳-碳鍵)，其中鍵旋轉限制在該特定鍵聯周圍，例如，因存在環或雙鍵而引起之限制。因此，所有順式/反式及E/Z異構物均明確地包括在本揭示案中。本文化合物亦可以多種互變異構形式表示；在該等情況下，本揭示案明確包括本文所闡述化合物之所有互變異構形式，即使可能僅表示單一互變異構形式。本文此等化合物之所有此等異構形式均明確地包括在本揭示案中。本文所闡述化合物之所有晶體形式及多晶型物均明確地包括在本揭示案中。亦體現包含本揭示案化合物之萃取物及流份。術語「異構物」意欲包括非鏡像異構物、鏡像異構物、區域異構物、結構異構物、旋轉異構物、互變異構物及諸如此類。對於含有一或多個立體源中心之化合物(例如手性化合物)，本揭示案之方法可用鏡像異構富集化合物、外消旋物或非鏡像異構物混合物來實施。本文所描繪化合物之所有異構物均明確地包括在本揭示案中。The compounds herein may also contain linkages (e.g., carbon-carbon bonds) where bond rotation is restricted around that particular linkage, e.g., due to the presence of a ring or double bond. Thus, allcis/trans andE/Z isomers are expressly included in the present disclosure. The compounds herein may also be represented in multiple tautomeric forms; in such cases, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of these compounds herein are expressly included in the present disclosure. All crystalline forms and polymorphs of the compounds described herein are expressly included in the present disclosure. Extracts and fractions comprising compounds of the present disclosure are also embodied. The term "isomer" is intended to include non-mirror image isomers, mirror image isomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like. For compounds containing one or more stereogenic centers (e.g., chiral compounds), the methods of the present disclosure can be practiced with mirror image enriched compounds, racemates, or non-mirror image isomer mixtures. All isomers of the compounds described herein are expressly included in the present disclosure.
較佳之鏡像異構富集化合物具有50%或更多之鏡像異構過量。更佳地，化合物具有60%、70%、80%、90%、95%、98%、99%或更多之鏡像異構過量。在較佳實施例中，將本揭示案之手性化合物之僅一種鏡像異構物或非鏡像異構物投與給細胞或個體。 治療方法Preferred mirror image isomer-enriched compounds have a mirror image isomer excess of 50% or more. More preferably, the compound has a mirror image isomer excess of 60%, 70%, 80%, 90%, 95%, 98%, 99% or more. In preferred embodiments, only one mirror image isomer or non-mirror image isomer of the chiral compound of the present disclosure is administered to a cell or subject.Treatment Methods
在一態樣中，提供治療患有或易患病症或疾病之個體之方法，其包括向該個體投與有效量的本文所闡述之化合物或醫藥組合物。In one aspect, a method of treating a subject suffering from or susceptible to a condition or disease is provided, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein.
在其他態樣中，提供治療患有或易患病症或疾病之個體之方法，其中該個體已鑑別為需要調節蛋白質之功能，該等方法包括向有需要之該個體投與有效量的本文所闡述之化合物或醫藥組合物，使得治療該個體之該病症。In other aspects, methods are provided for treating a subject suffering from or susceptible to a condition or disease, wherein the subject has been identified as requiring modulation of protein function, the methods comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition described herein such that the condition in the subject is treated.
在一態樣中，提供向個體之腦遞送治療性寡核苷酸之方法，該等方法包括使該個體與本文所闡述之化合物或醫藥組合物接觸，其量及條件足以靶向腦。在一些實施例中，將治療性寡核苷酸遞送至一或多個選自由以下組成之群的腦區域：紋狀體、小腦、腦幹、海馬體、額葉皮質及脊髓。In one aspect, methods of delivering a therapeutic oligonucleotide to the brain of a subject are provided, the methods comprising contacting the subject with a compound or pharmaceutical composition as described herein in an amount and under conditions sufficient to target the brain. In some embodiments, the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of: striatum, cerebellum, brain stem, hippocampus, frontal cortex, and spinal cord.
在某些實施例中，提供治療疾病、病症或其症狀之方法，其中疾病為中樞神經系統(CNS)疾病、病症或其症狀。在一些實施例中，疾病為神經退化性疾病、病症或其症狀。在一些實施例中，疾病為阿茲海默氏病或其症狀。In certain embodiments, methods of treating a disease, disorder, or symptom thereof are provided, wherein the disease is a central nervous system (CNS) disease, disorder, or symptom thereof. In some embodiments, the disease is a neurodegenerative disease, disorder, or symptom thereof. In some embodiments, the disease is Alzheimer's disease or a symptom thereof.
例示性CNS病症包括(但不限於)神經毒性及/或神經創傷、中風、多發性硬化症、脊髓損傷、癲癇、精神障礙、睡眠疾患、運動障礙、噁心及/或嘔吐、肌肉萎縮性脊髓側索硬化症、阿茲海默氏病及物質濫用或物質使用障礙(SUD)。Exemplary CNS disorders include, but are not limited to, neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, psychiatric disorders, sleep disorders, movement disorders, nausea and/or vomiting, amyotrophic lateral sclerosis, Alzheimer's disease, and substance abuse or substance use disorder (SUD).
在某些實施例中，CNS病症為神經毒性及/或神經創傷，例如，由急性神經元損傷(例如創傷性腦損傷(TBI)、中風、癲癇)或慢性神經退化性病症(例如多發性硬化症、帕金森氏病(Parkinson’s disease)、亨庭頓氏病(Huntington’s disease)、肌肉萎縮性脊髓側索硬化症、阿茲海默氏病)引起。在某些實施例中，本揭示案之化合物提供神經保護效應，例如針對急性神經元損傷或慢性神經退化性病症。In certain embodiments, the CNS disorder is neurotoxic and/or neurotraumatic, e.g., caused by acute neuron damage (e.g., traumatic brain injury (TBI), stroke, epilepsy) or chronic neurodegenerative disorders (e.g., multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease). In certain embodiments, the compounds of the present disclosure provide a neuroprotective effect, e.g., against acute neuron damage or chronic neurodegenerative disorders.
在某些實施例中，CNS病症為中風(例如缺血性中風)。In certain embodiments, the CNS disorder is stroke (eg, ischemic stroke).
在某些實施例中，CNS病症為多發性硬化症。In certain embodiments, the CNS disorder is multiple sclerosis.
在某些實施例中，CNS病症為脊髓損傷。In certain embodiments, the CNS disorder is spinal cord injury.
在某些實施例中，CNS病症為癲癇。In certain embodiments, the CNS disorder is epilepsy.
在某些實施例中，CNS病症為精神障礙，例如抑鬱症、焦慮症或焦慮症相關之疾患、學習失能、身體症狀障礙、精神分裂症或精神分裂感情型障礙。In certain embodiments, the CNS disorder is a psychiatric disorder, such as depression, anxiety or anxiety-related disorders, learning disabilities, somatic symptom disorders, schizophrenia, or schizoaffective disorder.
在某些實施例中，CNS病症為抑鬱症。「抑鬱症」包括(但不限於)抑鬱性病症或疾患，諸如重度抑鬱症(例如單極性抑鬱症)、難治性抑鬱症、心境惡劣病症(例如慢性、輕度抑鬱症)、雙極性障礙(例如躁狂抑鬱症)、季節性情感障礙及/或與物質濫用或物質濫用障礙(例如戒斷)相關之抑鬱症。抑鬱症可為臨床或亞臨床抑鬱症。抑鬱症可與經前症候群及/或經前情緒障礙相關。In certain embodiments, the CNS disorder is depression. "Depression" includes, but is not limited to, depressive disorders or conditions such as major depression (e.g., unipolar depression), refractory depression, dysthymic disorder (e.g., chronic, mild depression), bipolar disorder (e.g., manic depression), seasonal affective disorder, and/or depression associated with substance abuse or substance abuse disorder (e.g., withdrawal). Depression can be clinical or subclinical. Depression can be associated with premenstrual syndrome and/or premenstrual affective disorder.
在某些實施例中，CNS病症為焦慮症。「焦慮症」包括(但不限於)焦慮症及焦慮症相關之疾患，諸如臨床焦慮症、恐慌症、空室恐懼症、廣泛性焦慮症(GAD)、特定對象畏懼症、社會畏懼症、強迫症、急性壓力病症、創傷後壓力病症、適應障礙伴焦慮特徵、與抑鬱症相關之焦慮症、一般醫學疾患引起之焦慮症及物質誘發之焦慮症、與物質濫用或物質使用障礙(例如戒斷、依賴、恢復)相關之焦慮症及與噁心及/或嘔吐相關之焦慮症。此治療亦可誘發或促進個體(例如患有焦慮症之個體)之睡眠。In certain embodiments, the CNS disorder is anxiety. "Anxiety" includes, but is not limited to, anxiety and anxiety-related disorders, such as clinical anxiety, panic disorder, agonism, generalized anxiety disorder (GAD), object phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorder with anxious features, anxiety associated with depression, anxiety caused by general medical illness and substance-induced anxiety, anxiety associated with substance abuse or substance use disorder (e.g., withdrawal, dependence, recovery), and anxiety associated with nausea and/or vomiting. This treatment may also induce or promote sleep in individuals (such as those suffering from anxiety disorders).
在某些實施例中，CNS病症為學習障礙(例如注意力缺失症(ADD))。In certain embodiments, the CNS disorder is a learning disorder (e.g., attention deficit disorder (ADD)).
在某些實施例中，CNS病症為精神分裂症或精神分裂感情型障礙。In certain embodiments, the CNS disorder is schizophrenia or schizoaffective disorder.
在某些實施例中，CNS病症為睡眠疾患。「睡眠疾患」包括(但不限於)失眠症、嗜睡病、睡眠呼吸中止、不寧退症候群(RLS)、睡眠相位延遲症候群(DSPS)、週期性肢體運動障礙(PLMD)、呼吸減弱症候群、快速眼動行為障礙(RBD)、輪班工作睡眠疾患(SWSD)及睡眠問題(例如異睡症)，諸如夢魘、夜驚、說夢話、撞頭、打鼾及口噤不語及/或磨牙(夜間磨牙)。In certain embodiments, the CNS disorder is a sleep disorder. "Sleep disorders" include, but are not limited to, insomnia, narcolepsy, sleep apnea, restless sleep syndrome (RLS), delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD), hypopnea, rapid eye movement behavior disorder (RBD), shift work sleep disorder (SWSD), and sleep problems (e.g., parasomnias), such as nightmares, night terrors, sleep talking, head banging, snoring, and lockjaw and/or bruxism (teeth grinding at night).
在某些實施例中，CNS病症為運動障礙，例如基底神經節病症，諸如帕金森氏病、左旋多巴(levodopa)誘發之運動困難、亨庭頓氏病、日勒德拉妥瑞氏症候群(Gilles de Ia Tourette’s syndrome)、遲發性運動困難及肌張力障礙。In certain embodiments, the CNS disorder is a movement disorder, e.g., a basal ganglia disorder, such as Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, Gilles de Ia Tourette's syndrome, late-onset dyskinesia, and dystonia.
在某些實施例中，CNS病症為阿茲海默氏病。In certain embodiments, the CNS disorder is Alzheimer's disease.
在某些實施例中，CNS病症為肌肉萎縮性脊髓側索硬化症(ALS)。In certain embodiments, the CNS disorder is amyotrophic lateral sclerosis (ALS).
在某些實施例中，CNS病症為噁心及/或嘔吐。In certain embodiments, the CNS disorder is nausea and/or vomiting.
在某些實施例中，CNS病症為物質濫用或物質使用障礙(SUD) (例如對鴉片劑、尼古丁、古柯鹼、精神振奮藥物或酒精成癮)。In certain embodiments, the CNS disorder is substance abuse or substance use disorder (SUD) (e.g., addiction to opium, nicotine, cocaine, stimulants, or alcohol).
術語「神經疾病」(包括例如「神經退化性疾病)係指任何神經系統疾病，包括累及中樞神經系統(腦、腦幹及小腦)、周圍神經系統(包括腦神經)及自主神經系統(其部分位於中樞及周圍神經系統中)之疾病。神經退化性疾病係指一類以神經細胞喪失為標誌之神經疾病，包括(但不限於)阿茲海默氏病、帕金森氏病、肌肉萎縮性脊髓側索硬化症、tau蛋白病變(包括額顳葉失智症)及亨庭頓氏病。神經疾病之實例包括(但不限於)頭痛、昏睡及昏迷、失智症、癲癇發作、睡眠障礙、創傷、感染、贅瘤、神經眼科學疾病、運動障礙、去髓鞘疾病、脊髓病症以及周圍神經、肌肉及神經肌肉接點之病症。神經疾病之定義中亦包括物質濫用或物質使用障礙(SUD)及精神疾病，包括(但不限於)雙極性障礙、精神分裂症及精神分裂感情型障礙。神經疾病之其他實例包括獲得性癲癇狀失語症；急性瀰漫性腦脊髓炎；腎上腺腦白質失養症；胼胝體發育不全；失認症；艾卡迪症候群(Aicardi syndrome)；亞歷山大病(Alexander disease)；阿爾佩斯氏病(Alpers’ disease)；交替性偏癱；阿茲海默氏病；肌肉萎縮性脊髓側索硬化症；無腦畸形；安格曼症候群(Angelman syndrome)；血管瘤病；缺氧症；失語症；失用症；蜘蛛膜囊腫；蛛網膜炎；阿-希二氏畸形(Anronl-Chiari malformation)；動靜脈畸形；亞斯伯格症候群(Asperger syndrome)；共濟失調毛細血管擴張症；注意力缺失過動病症；自閉症；自主神經機能異常；背部疼痛；貝登氏病(Batten disease)；貝賽特氏病(Behcet’s disease)；貝爾氏麻痺(Bell’s palsy)；良性自發性瞼痙攣；良性病灶；肌萎縮；良性顱內高血壓；賓斯旺格氏病(Binswanger’s disease)；瞼痙攣；布洛克-蘇茲貝格症候群(Bloch Sulzberger syndrome)；臂叢神經損傷；腦膿瘍；腦損傷；腦腫瘤(包括多形性神經膠母細胞瘤)；脊髓腫瘤；布朗-斯誇症候群(Brown-Sequard syndrome)；康納丸氏病(Canavan disease)；腕隧道症候群(CTS)；灼痛；中樞性疼痛症候群；腦橋中央髓鞘溶解症；頭部病症；腦動脈瘤；腦動脈硬化；大腦萎縮；大腦巨大症；腦性麻痺；夏馬杜三氏病(Charcot-Marie-Tooth disease)；化學療法誘發之神經病變及神經病性疼痛；基亞里氏畸形(Chiari malformation)；舞蹈症；慢性發炎性去髓鞘型多發性神經病變(CIDP)；慢性疼痛；慢性區域性疼痛症候群；科芬-勞里症候群(Coffin Lowry syndrome)；昏迷，包括持續性植物狀態；先天性兩側面癱；皮質基底核退化症；顱動脈炎；顱縫線封閉過早；庫賈二氏病(Creutzfeldt-Jakob disease)；累積性創傷障礙；庫興氏症候群(Cushing’s syndrome)；巨細胞包涵體病(CIBD)；巨細胞病毒感染；舞眼舞腳症候群；丹迪-沃克症候群(Dandy-Walker syndrome)；道森氏病(Dawson disease)；狄莫西亞氏症候群(De Morsier’s syndrome)；德熱里納-克隆普克麻痹(Dejerine-Klumke palsy)；失智症；皮肌炎；糖尿病性神經病變；瀰漫性硬化；自主神經障礙；書寫障礙；失讀症；肌張力障礙；早期幼兒癲癇性腦病變；空蝶鞍症候群(empty sella syndrome)；腦炎；腦膨出；大腦三叉神經性血管瘤病；癲癇；歐勃氏麻痺(Erb’s palsy)；自發性震顫；法布瑞氏病(Fabry’s disease)；法爾氏症候群(Fahr’s syndrome)；昏厥；家族性痙攣性麻痹；熱性癲癇發作；費雪症候群(Fisher syndrome)；弗里德賴希氏共濟失調(Friedreich’s ataxia)；額顳葉失智症及其他「tau蛋白病變」；高歇氏病(Gaucher’s disease)；格斯特曼氏症候群(Gerstmann’s syndrome)；巨細胞動脈炎；巨細胞包涵體病；球狀細胞腦白質失養症；格林-巴利症候群(Guillain-Barre syndrome)；HTLV-1相關之脊髓病變；哈勒沃登-施帕茨病(Hallervorden-Spatz disease)；頭部損傷；頭痛；半面痙攣；遺傳性痙攣性截癱；多神經炎型遺傳性運動失調；耳部帶狀疱疹；帶狀疱疹；平山症候群(Hirayama syndrome)；HIV相關之失智症及神經病變(以及AIDS之神經系統表現)；全前腦無裂畸形；亨庭頓氏病及其他多麩醯胺酸重複疾病；積水性無腦；水腦症；高皮質醇症；低氧；免疫介導之腦脊髓炎；包涵體肌炎；色素失調症；嬰兒植烷酸貯積病；嬰兒雷夫蘇姆氏病(Infantile Refsum disease)；嬰兒痙攣；發炎性肌病變；顱內囊腫；顱內高血壓；朱伯特氏症候群(Joubert syndrome)；凱恩斯-沙耶症候群(Kearns-Sayre syndrome)；肯尼迪氏病(Kennedy disease)；金斯伯恩氏症候群(Kinsbourne syndrome)；克利佩爾-費爾症候群(Klippel Feil syndrome)；克拉培氏病(Krabbe disease)；庫格爾貝格-韋蘭德病(Kugelberg-Welander disease)；庫魯病(kuru)；拉弗拉病(Lafora disease)；藍伯-伊頓肌無力症候群(Lambert-Eaton myasthenic syndrome)；藍道-克里夫症候群(Landau-Kleffner syndrome)；延髓外側(瓦倫堡(Wallenberg))症候群；學習困難；雷氏病(Leigh’s disease)；雷諾島林-戈症候群(Lennox-Gustaut syndrome)；萊希-尼亨症候群(Lesch-Nyhan syndrome)；腦白質失養症；路易氏體(Lewy body)失智症；無腦迴；閉鎖症候群；盧賈里格氏病(Lou Gehrig’s disease)(亦稱為運動神經元疾病或肌肉萎縮性脊髓側索硬化症)；椎間盤疾病；萊姆病(Lyme disease)-神經系統後遺症；馬查多-約瑟夫病(Machado-Joseph disease)；巨腦畸形；大頭症；默克森-羅森泰症候群(Melkersson-Rosenthal syndrome)；梅尼爾氏病(Meniere’s disease)；腦膜炎；門默克氏病(Menkes disease)；異染性白質失養症；小頭畸形；偏頭痛；米勒-費雪症候群(Miller Fisher syndrome)；小中風；粒線體肌病變；默比厄斯氏症候群(Mobius syndrome)；單肢肌萎縮；運動神經元病；毛毛樣血管疾病(Moyamoya disease)；黏多醣貯積病；多發梗塞性失智症；多病灶性動作神經病變；多發性硬化症及其他去髓鞘病症；多系統萎縮伴體位性低血壓；肌肉營養不良症；重症肌無力；髓鞘破壞瀰漫性硬化；嬰兒肌陣攣性腦病；肌陣攣；肌病變；先天性肌強直；嗜睡病；神經纖維瘤病；抗精神病藥惡性症候群；AIDS之神經系統表現；狼瘡之神經系統後遺症；神經性肌強直；神經元蠟樣脂褐質沈積症；神經元移動異常症；尼曼-匹克病(Niemann-Pick disease)；奧沙利文-麥克勞德症候群(O’Sullivan-McLeod syndrome)；枕神經痛；隱性脊柱神經管閉合不全序列症；大田原症候群(Ohtahara syndrome)；橄欖體腦橋小腦萎縮；斜眼性眼陣攣肌陣攣；視神經炎；起立性低血壓；過度使用症候群；感覺異常；帕金森氏病；先天性副肌強直；副腫瘤性疾病；陣發性發作；帕-羅二氏症候群(Parry Romberg syndrome)；佩-梅二氏病(Pelizaeus-Merzbacher disease)；週期性癱瘓；周圍神經病變；疼痛性神經病變及神經病性疼痛；持續性植物狀態；廣泛性發育障礙；光噴嚏反射；植烷酸貯積病；皮克氏病(Pick’s disease)；神經受壓；垂體瘤；多發性肌炎；腦穿通畸形；脊髓灰質炎後症候群；疱疹後神經痛(PHN)；感染後腦脊髓炎；姿勢性低血壓；普瑞德-威利症候群(Prader-Willi syndrome)；原發性脊髓側索硬化症；普里昂疾病(prion disease)；進行性半面萎縮；進行性多病灶性腦白質病；進行性硬化性灰質營養不良；進行性核上性麻痺；假性腦瘤；侖謝-亨特症候群(Ramsay-Hunt syndrome)(I型及II型)；拉斯穆森氏腦炎(Rasmussen’s encephalitis)；反射性交感神經營養不良症候群；雷夫蘇姆氏病(Refsum disease)；重複性動作傷害；重複性應力損傷；不寧退症候群；反轉錄病毒相關之脊髓病變；蕾特氏症候群(Rett syndrome)；雷伊氏症候群(Reye’s syndrome)；聖維特斯舞蹈病(Saint Vitus dance)；山霍夫氏病(Sandhoff disease)；希爾逗氏病(Schilder’s disease)；腦裂畸形；視-隔發育不良；搖晃嬰兒症候群；帶狀疱疹；夏伊-德雷格症候群(Shy-Drager syndrome)；薛格連氏症候群(Sjogren’s syndrome)；睡眠呼吸中止；索托氏症候群(Soto’s syndrome)；痙攣狀態；脊柱裂；脊髓損傷；脊髓腫瘤；脊髓性肌萎縮；僵直人症候群(stiff-person syndrome)；中風；斯特奇-韋伯症候群(Sturge-Weber syndrome)；亞急性硬化性泛腦炎；蛛網膜下腔出血；皮質下動脈硬化性腦病變；西德納姆舞蹈症(sydenham chorea)；暈厥；脊髓空洞病；遲發性運動困難；戴-薩克斯病(Tay-Sachs disease)；顳動脈炎；脊髓拴系症候群；湯姆森氏病(Thomsen disease)；胸廓出口症候群；痛性痙攣(tic douloureux)；托德氏麻痹(Todd’s paralysis)；妥瑞氏症候群(Tourette syndrome)；暫時性腦缺血發作；傳染性海綿狀腦病變；橫貫性脊髓炎；創傷性腦損傷；顫抖；三叉神經痛；熱帶痙攣性輕截癱；結節性硬化症；血管型失智症(多發性梗塞失智症)；血管炎，包括顳動脈炎；逢希伯-林道病(Von Hippel-Lindau disease) (VHL)；瓦倫堡氏症候群(Wallenberg’s syndrome)；沃尼克-霍夫曼病(Werdnig-Hoffman disease)；韋斯特症候群(West syndrome)；外傷性頸部症候群(whiplash)；威廉姆斯氏症候群(Williams syndrome)；威爾登氏病(Wilson’s disease)；及柴爾維格氏症候群(Zellweger syndrome)。The term "neurological disease" (including, for example, "neurodegenerative disease") refers to any disease of the nervous system, including diseases affecting the central nervous system (brain, brain stem and cerebellum), the peripheral nervous system (including cranial nerves) and the autonomic nervous system (parts of which are located in the central and peripheral nervous systems). Neurodegenerative disease refers to a class of neurological diseases characterized by loss of nerve cells, including (but not limited to) Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia) and Huntington's disease. Examples of neurological diseases include (but not limited to) headaches, lethargy, and coma, dementia, epileptic seizures, sleep disorders, trauma, infection, tumors, neuro-ophthalmologic disorders, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of the peripheral nerves, muscles, and neuromuscular junctions. The definition of neurological disease also includes substance abuse or substance use disorder (SUD) and mental illness, including but not limited to bipolar disorder, schizophrenia, and schizoaffective disorder. Other examples of neurological disease include acquired epileptic aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; hypoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia-telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy palsy; benign spontaneous palsy; benign lesions; muscular atrophy; benign intracranial hypertension; Binswanger’s disease; palsy; Bloch-Sulzberger syndrome; brachial plexus nerve injury; brain abscess; brain injury; brain tumor (including neuroblastoma multiforme); spinal cord tumor; Brown-Sequard syndrome; Canavan disease disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central myelinolysis of the pons; head disease; brain aneurysm; cerebral arteriosclerosis; cerebral atrophy; megaencephaly; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin-Lowry syndrome syndrome; coma, including persistent vegetative state; congenital bilateral facial paralysis; corticomedullary degeneration; cranial arteritis; premature cranial suture closure; Creutzfeldt-Jakob disease; cumulative trauma disorder; Cushing’s syndrome; CIBD; cytomegalovirus infection; dancing eyes and feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumke palsy palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; autonomic dysregulation; dysgraphia; alexia; dystonia; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephalocele; cerebral trigeminal angiomatosis; epilepsy; Erb’s palsy; spontaneous tremor; Fabry’s disease; Fahr’s syndrome; syncope; familial spastic paralysis; febrile epileptic seizure; Fisher syndrome; Friedreich’s ataxia ataxia; frontotemporal dementia and other "tauopathies"; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1-related myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; polyneuritic hereditary movement disorder; herpes zoster oticus; herpes zoster; Hirayama syndrome syndrome; HIV-associated dementia and neuropathy (and neurologic manifestations of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine repeat disorders; hydrocephalus; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinence pigmenti; phytanic acid storage disease; infantile Refsum disease; infantile spasm; inflammatory myopathy; intracranial cysts; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning difficulties; Leigh’s disease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy bodies body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (also called motor neuron disease or amyotrophic lateral sclerosis); intervertebral disc disease; Lyme disease-neurological sequelae; Machado-Joseph disease; megalencephaly; macrocephaly; Melkersson-Rosenthal syndrome; Meniere’s disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-stroke; mitochondrial myopathy; Mobius syndrome syndrome); monolimbic myopathy; motor neuron disease; Moyamoya disease); mucopolysaccharidosis; multi-infarct dementia; multifocal movement neuropathy; multiple sclerosis and other demyelinating disorders; multisystem atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; diffuse sclerosis with myelin destruction; infantile myoclonic encephalopathy; myoclonus; myopathy; myotonia congenita; narcolepsy; neurofibromatosis; antipsychotic malignancy; AIDS-related neurological manifestations; lupus erythematosus; neuromyotonia; neurolaminoid lipofuscinosis; neuron movement abnormalities; Niemann-Pick disease disease; O’Sullivan-McLeod syndrome; occipital neuralgia; cryptic spinal canal dysfunction sequence; Ohtahara syndrome; olivopontine-cerebellar atrophy; strabismus oculomotor nystagmus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; paramyotonia congenita; paraneoplastic disease; paroxysmal seizures; Parry-Romberg syndrome; Pelizaeus-Merzbacher disease disease); periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; generalized developmental disability; photojet sneeze reflex; phytanic acid storage disease; Pick's disease; nerve compression; pituitary tumor; polymyositis; cerebral perforation; postpoliomyelitis; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion disease disease; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerotic gray matter dystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen’s encephalitis; reflex sympathetic dystrophy; Refsum disease; repetitive motion injury; repetitive stress injury; restlessness syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; herpes zoster; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; status spastic; spina bifida; spinal cord injury; spinal cord tumor; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical sclerosing encephalopathy; sydenham chorea; syncope; syringomyelia; delayed dyskinesia; Tay-Sachs disease disease; temporal artery inflammation; tethered cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; infectious cavernous encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paralysis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis, including temporal artery inflammation; Von Hippel-Lindau disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.
在某些實施例中，個體為哺乳動物，較佳為靈長類動物或人類。In certain embodiments, the subject is a mammal, preferably a primate or a human.
在另一實施例中，提供如上文所闡述之方法，其中本文所提供化合物之有效量係如上文所闡述。In another embodiment, a method as described above is provided, wherein the effective amount of a compound provided herein is as described above.
在另一實施例中，提供如上文所闡述之方法，其中鞘內、靜脈內、肌內、皮下、腦室內、經口或外用投與本文所提供之化合物。在某些實施例中，鞘內投與化合物。In another embodiment, a method as described above is provided, wherein the compound provided herein is administered intrathecally, intravenously, intramuscularly, subcutaneously, intraventricularly, orally, or topically. In certain embodiments, the compound is administered intrathecally.
在其他實施例中，提供如上文所闡述之方法，其中本文所提供各式中之任一者之化合物單獨或與一或多種其他治療劑組合投與。在另一實施例中，額外治療劑為中樞神經系統(CNS)疾病劑。In other embodiments, a method as described above is provided, wherein a compound of any of the formulae provided herein is administered alone or in combination with one or more additional therapeutic agents. In another embodiment, the additional therapeutic agent is a central nervous system (CNS) disease agent.
本揭示案之另一目標係使用如本文所闡述之化合物製造用於治療病症或疾病之藥劑。本揭示案之另一目標係使用如本文所闡述之化合物用於治療病症或疾病。 醫藥組合物Another object of the present disclosure is to use the compounds as described herein for the manufacture of medicaments for the treatment of disorders or diseases. Another object of the present disclosure is to use the compounds as described herein for the treatment of disorders or diseases.Pharmaceutical Compositions
在一態樣中，提供醫藥組合物，其包含本文所闡述之任一化合物及醫藥學上可接受之載劑或醫藥學上可接受之賦形劑。In one aspect, a pharmaceutical composition is provided, which comprises any compound described herein and a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.
如本文所闡述之化合物或組合物可與一或多種額外治療劑(例如治療及/或預防活性劑)組合投與。化合物或組合物可與額外治療劑組合投與，該等額外治療劑改良該等化合物或組合物之活性(例如在治療有需要個體之疾病、預防有需要個體之疾病及/或降低有需要個體發生疾病之風險中的活性(例如效能及/或功效))、提高生物利用度、提高安全性、降低抗藥性、降低及/或改進代謝、抑制排泄及/或改進在個體體內或細胞中之分佈。亦應瞭解，所採用之療法可針對相同病症達成期望效應，及/或其可達成不同效應。在某些實施例中，包括本文所闡述化合物及額外治療劑之本文所闡述醫藥組合物展現出協同效應，此協同效應在包括本文所闡述化合物或額外治療劑中之一者但不包括該兩者之醫藥組合物中係不存在的。The compounds or compositions as described herein may be administered in combination with one or more additional therapeutic agents (e.g., therapeutic and/or preventive agents). The compounds or compositions may be administered in combination with additional therapeutic agents that improve the activity of the compounds or compositions (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, preventing a disease in a subject in need thereof, and/or reducing the risk of a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or improve metabolism, inhibit excretion, and/or improve distribution in a subject's body or in cells. It is also understood that the therapies employed may achieve the desired effect for the same condition, and/or they may achieve different effects. In certain embodiments, pharmaceutical compositions described herein that include a compound described herein and an additional therapeutic agent exhibit synergistic effects that are not present in pharmaceutical compositions that include one but not both of the compound described herein or the additional therapeutic agent.
化合物或組合物可與一或多種額外治療劑同時、在其之前或之後投與，其可用作例如組合療法。治療劑包括治療活性劑。治療劑亦包括預防活性劑。治療劑包括有機小分子，諸如藥物化合物(例如由美國食品藥品監督管理局(U.S. Food and Drug Administration)批准用於人類或獸醫應用之化合物，如聯邦條例法典(Code of Federal Regulations，CFR)中所提供))、肽、蛋白質、碳水化合物、單糖、寡糖、多糖、核蛋白、黏蛋白、脂蛋白、合成多肽或蛋白質、連接至蛋白質之小分子、糖蛋白、類固醇、核酸、DNA、RNA、核苷酸、核苷、寡核苷酸、反義寡核苷酸、脂質、激素、維生素及細胞。在某些實施例中，額外治療劑係可用於治療及/或預防疾病(例如CNS病症)之治療劑。每一額外治療劑可按針對該治療劑所確定之劑量及/或時間表來投與。額外治療劑亦可與彼此及/或與本文所闡述之化合物或組合物以單一劑量一起投與，或以不同劑量分開投與。方案中採用之特定組合將慮及本文所闡述化合物與額外治療劑之相容性及/或欲達成之期望治療效應及/或預防效應。一般而言，預期組合使用之額外治療劑之水準不超過其在個別使用時之水準。在一些實施例中，組合使用之水準將低於個別使用時之彼等水準。The compound or composition can be administered simultaneously with, before, or after one or more additional therapeutic agents, which can be used, for example, as a combination therapy. Therapeutic agents include therapeutically active agents. Therapeutic agents also include prophylactic active agents. Therapeutic agents include organic small molecules, such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration for human or veterinary use, as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional therapeutic agent is a therapeutic agent that can be used to treat and/or prevent a disease (e.g., a CNS disorder). Each additional therapeutic agent can be administered at a dose and/or schedule determined for that therapeutic agent. Additional therapeutic agents can also be administered together with each other and/or with the compounds or compositions described herein in a single dose, or separately in different doses. The specific combination used in the regimen will take into account the compatibility of the compounds described herein with the additional therapeutic agent and/or the desired therapeutic effect and/or preventive effect to be achieved. In general, it is expected that the level of additional therapeutic agents used in combination will not exceed the level when they are used individually. In some embodiments, the levels used in combination will be lower than those when used individually.
在一態樣中，提供套組，其包含有效量的呈單位劑型之本文所提供之化合物，以及關於將該化合物投與給患有或易患疾病或病症之個體之說明書。In one aspect, a kit is provided comprising an effective amount of a compound provided herein in unit dosage form and instructions for administering the compound to a subject suffering from or susceptible to a disease or disorder.
術語「醫藥學上可接受之鹽」或「醫藥學上可接受之載劑」意欲包括用相對無毒酸或鹼製備之活性化合物之鹽，此取決於在本文所闡述化合物上所發現之特定取代基。當本揭示案之化合物含有相對酸性官能基時，可藉由使此等化合物之中性形式與足夠量之純淨或於適宜惰性溶劑中之期望鹼接觸來獲得鹼加成鹽。醫藥學上可接受之鹼加成鹽之實例包括鈉鹽、鉀鹽、鈣鹽、銨鹽、有機胺基鹽或鎂鹽，或類似鹽。當本揭示案之化合物含有相對鹼性官能基時，可藉由使此等化合物之中性形式與足夠量之純淨或於適宜惰性溶劑中之期望酸接觸來獲得酸加成鹽。醫藥學上可接受之酸加成鹽之實例包括衍生自諸如以下等無機酸之彼等鹽：鹽酸、氫溴酸、硝酸、碳酸、一氫碳酸、磷酸、一氫磷酸、二氫磷酸、硫酸、一氫硫酸、氫碘酸或亞磷酸及諸如此類；以及衍生自諸如以下等相對無毒有機酸之鹽：乙酸、丙酸、異丁酸、馬來酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富馬酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸、甲磺酸及諸如此類。亦包括胺基酸之鹽，諸如精胺酸鹽及諸如此類，以及諸如葡糖醛酸或半乳糖醛酸及諸如此類等有機酸之鹽(例如，參見Berge等人，Journal of Pharmaceutical Science66:1-19 (1977))。本揭示案之某些具體化合物含有容許將該等化合物轉化成鹼加成鹽或酸加成鹽之鹼性及酸性官能基二者。熟習此項技術者已知之其他醫藥學上可接受之載劑適於本揭示案。The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts, or a similar salt. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid or phosphorous acid, and the like; and salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids, such as arginine and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge et al.,Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present disclosure contain both basic and acidic functional groups that allow conversion of the compounds into base addition salts or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in the present disclosure.
化合物之中性形式可藉由使鹽與鹼或酸接觸且以習用方式分離母體化合物來再生。化合物之母體形式在某些物理性質(諸如於極性溶劑中之溶解性)方面與各種鹽形式不同，但在其他方面，出於本揭示案之目的，該等鹽等效於化合物之母體形式。The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the usual manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but in other respects, the salts are equivalent to the parent form of the compound for the purposes of this disclosure.
除鹽形式以外，本揭示案亦提供呈前藥形式之化合物。本文所闡述化合物之前藥係在生理條件下易於經歷化學變化以提供本揭示案化合物之彼等化合物。另外，前藥可藉由化學或生物化學方法在離體環境中轉化成本揭示案之化合物。舉例而言，當與適宜酶或化學試劑一起置於經皮貼劑貯器中時，前藥可緩慢轉化成本揭示案之化合物。In addition to salt forms, the present disclosure also provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present disclosure. In addition, prodrugs can be converted to compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir together with an appropriate enzyme or chemical reagent, the prodrug can be slowly converted to the compounds of the present disclosure.
本揭示案之某些化合物可以非溶劑化形式以及溶劑化形式(包括水合形式)存在。一般而言，溶劑化形式等同於非溶劑化形式，且意欲涵蓋在本揭示案之範圍內。本揭示案之某些化合物可以多種結晶或非晶形形式存在。一般而言，所有物理形式對於本揭示案所考慮之用途而言均係等效的且意欲在本揭示案之範圍內。Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, solvated forms are equivalent to unsolvated forms and are intended to be within the scope of the present disclosure. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
本揭示案亦提供醫藥組合物，其包含有效量的本文所闡述之化合物以及醫藥學上可接受之賦形劑。在一實施例中，使用醫藥學上可接受之調配物將本文所提供各式中之任一者之化合物投與給個體，例如在將醫藥學上可接受之調配物投與給個體後，向個體提供化合物持續遞送至少12小時、24小時、36小時、48小時、一週、兩週、三週或四週的醫藥學上可接受之調配物。The present disclosure also provides pharmaceutical compositions comprising an effective amount of a compound as described herein and a pharmaceutically acceptable formulation. In one embodiment, a compound of any of the formulae provided herein is administered to a subject using a pharmaceutically acceptable formulation, for example, after the pharmaceutically acceptable formulation is administered to the subject, the subject is provided with a pharmaceutically acceptable formulation that provides sustained delivery of the compound for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks.
本揭示案之醫藥組合物中活性成分之實際劑量水準及投與時程可變化，以便獲得針對特定個體、組合物及投與模式有效達成期望治療反應、同時個體可接受地耐受之活性成分量。Actual dosage levels and administration schedules of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, and that is acceptably tolerated by the subject.
在使用中，藉由靜脈內、鞘內、肌內、皮下或腦室內注射或藉由經口投與或外用施加，將醫藥載劑中之至少一種本揭示案化合物以醫藥學上有效之量投與給有需要之個體。根據本揭示案，本揭示案之化合物可單獨或與第二種不同的治療劑聯合投與。「與......聯合」意指一起、實質上同時或依序。在一個實施例中，急性地投與本揭示案之化合物。因此，本揭示案之化合物可在短療程內投與，諸如投與約1天至約1週。在另一實施例中，本揭示案之化合物可在更長之時間段內投與，以改善慢性病症，諸如投與約一週至數月，此取決於欲治療之疾患。In use, at least one compound of the present disclosure in a pharmaceutical carrier is administered to a subject in need thereof in a pharmaceutically effective amount by intravenous, intrathecal, intramuscular, subcutaneous or intraventricular injection or by oral administration or topical application. According to the present disclosure, the compounds of the present disclosure may be administered alone or in combination with a second different therapeutic agent. "Combined with..." means together, substantially simultaneously or sequentially. In one embodiment, the compounds of the present disclosure are administered acutely. Thus, the compounds of the present disclosure may be administered in a short course of treatment, such as for about 1 day to about 1 week. In another embodiment, the compounds of the present disclosure may be administered over a longer period of time to improve chronic conditions, such as for about one week to several months, depending on the condition to be treated.
如本文所用，「醫藥學上有效之量」意指在合理的醫學判斷範圍內，本揭示案化合物之量足夠高以顯著地積極改變欲治療之疾患，但足夠低以避免嚴重副作用(以合理的益處/風險比)。本揭示案化合物之醫藥學上有效之量將隨以下而變化：欲達成之特定目標、所治療患者之年齡及身體狀況、潛在疾病之嚴重程度、治療持續時間、並行療法之性質及所採用之具體化合物。舉例而言，根據合理醫學判斷，投與給兒童或新生兒之本揭示案化合物之治療有效量將按比例減少。因此，本揭示案化合物之有效量將為提供期望效應之最小量。As used herein, "pharmaceutically effective amount" means an amount of a compound of the present disclosure that is high enough to significantly positively alter the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The pharmaceutically effective amount of a compound of the present disclosure will vary depending on the specific goal to be achieved, the age and physical condition of the patient to be treated, the severity of the underlying disease, the duration of treatment, the nature of concurrent therapies, and the specific compound employed. For example, a therapeutically effective amount of a compound of the present disclosure administered to a child or newborn will be proportionally reduced, based on sound medical judgment. Thus, the effective amount of a compound of the present disclosure will be the minimum amount that provides the desired effect.
本揭示案之一個確定的實踐優點在於化合物可以便捷方式投與，諸如藉由鞘內、靜脈內、肌內、皮下、經口或腦室內注射途徑或藉由外用施加，諸如在乳霜或凝膠中。端視於投與途徑，可能需要將包含本揭示案化合物之活性成分包被於材料中，以保護該化合物免受酶、酸及可使該化合物不活化之其他天然條件之作用。為藉由除非經腸投與以外之模式投與本揭示案之化合物，該化合物可用防止不活化之材料包衣或與該材料一起投與。One definite practical advantage of the present disclosure is that the compounds can be administered in a convenient manner, such as by intrathecal, intravenous, intramuscular, subcutaneous, oral or intraventricular injection routes or by topical application, such as in a cream or gel. Depending on the route of administration, it may be necessary to coat the active ingredients comprising the compounds of the present disclosure in a material to protect the compound from the action of enzymes, acids, and other natural conditions that may inactivate the compound. To administer the compounds of the present disclosure by a mode other than parenteral administration, the compound may be coated with or administered with a material that prevents inactivation.
化合物可非經腸或腹膜內投與。亦可例如在甘油、液體聚乙二醇及其混合物中以及油中製備分散液。The compounds can be administered parenterally or intraperitoneally. Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.
可用作醫藥賦形劑或醫藥載劑(該等術語在本文中可互換使用)之物質之一些實例為糖，諸如乳糖、葡萄糖及蔗糖；澱粉，諸如玉米澱粉及馬鈴薯澱粉；纖維素及其衍生物，諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素；粉末狀黃蓍膠；麥芽；明膠；滑石；硬脂酸；硬脂酸鎂；硫酸鈣；植物油，諸如花生油、棉籽油、芝麻油、橄欖油、玉米油及可可油；多元醇，諸如丙二醇、甘油、山梨醇、甘露醇及聚乙二醇；瓊脂；海藻酸；無熱原水；等滲鹽水；及磷酸鹽緩衝溶液；脫脂乳粉；以及醫藥調配物中所用之其他無毒相容性物質，諸如維生素C、雌激素及紫錐菊。亦可存在潤濕劑及潤滑劑，諸如月桂基硫酸鈉，以及著色劑、矯味劑、潤滑劑、賦形劑、製錠劑、穩定劑、抗氧化劑及防腐劑。本文醫藥組合物中亦可使用增溶劑，包括例如cremaphore及β-環糊精。Some examples of substances that can be used as pharmaceutical excipients or pharmaceutical carriers (these terms are used interchangeably herein) are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; sulfuric acid calcium; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic water; and phosphate buffered solutions; skimmed milk powder; and other nontoxic compatible substances used in pharmaceutical formulations such as vitamin C, estrogen and echinacea. Wetting and lubricating agents such as sodium lauryl sulfate may also be present, as well as colorants, flavoring agents, lubricants, molding agents, tableting agents, stabilizers, antioxidants and preservatives. Solubilizing agents may also be used in the pharmaceutical compositions herein and include, for example, cremaphore and β-cyclodextrin.
包含本揭示案之活性化合物(或其衍生物或前藥)之醫藥組合物可藉助於習用混合、溶解、製粒、製糖衣、磨細、乳化、囊封、包裹或凍乾製程來製造。組合物可以習用方式使用一或多種生理學上可接受之載劑、稀釋劑、賦形劑或輔助劑加以調配，該等劑有助於將活性化合物處理成可在醫藥上使用之製劑。本文組合物可藉由將本文所描繪之化合物與一或多種適宜載劑、稀釋劑、賦形劑或輔助劑(包括本文所闡述之彼等劑，例如用於醫藥、農業或獸醫用途)組合(例如接觸、混合、溶解、製粒、製糖衣、磨細、乳化、囊封、包裹或凍乾)來製得。Pharmaceutical compositions containing the active compounds of the present disclosure (or their derivatives or prodrugs) can be manufactured by conventional mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, encapsulating, entrapping or lyophilizing processes. The compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants that facilitate processing of the active compounds into preparations that can be used in medicines. The compositions herein can be prepared by combining (e.g., contacting, mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, encapsulating, encapsulating or lyophilizing) a compound described herein with one or more suitable carriers, diluents, excipients or adjuvants (including those described herein, e.g., for medical, agricultural or veterinary uses).
本揭示案之醫藥組合物可採取適於幾乎任何投與模式之形式，包括例如鞘內、外用、經眼、經口、經頰、全身、經鼻、注射、經皮、經直腸、經陰道及諸如此類，或適於藉由吸入或吹入投與之形式。The pharmaceutical compositions of the present disclosure may take a form suitable for virtually any mode of administration, including, for example, intrathecal, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, and the like, or a form suitable for administration by inhalation or insufflation.
全身性調配物包括經設計用於藉由注射投與(例如皮下、靜脈內、肌內、鞘內或腹膜內注射)之彼等調配物，以及經設計用於經皮、經黏膜、經口或經肺投與之彼等調配物。Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.
可用之可注射製劑包括活性化合物於水性或油性媒劑中之無菌懸浮液、溶液或乳液。組合物亦可含有調配劑，諸如懸浮劑、穩定劑及/或分散劑。注射用調配物可以單位劑型呈遞(例如於安瓿中或於多劑量容器中)，且可含有所添加之防腐劑。Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound in aqueous or oily vehicles. The composition may also contain formulating agents such as suspending agents, stabilizers and/or dispersing agents. Injectable formulations may be presented in unit dosage form (e.g., in ampoules or in multi-dose containers) and may contain added preservatives.
或者，可注射調配物可以粉末形式提供，以供在使用前用適宜媒劑(包括但不限於無菌無熱原水、緩衝液、右旋糖溶液及諸如此類)重構。為此，活性化合物可藉由此項技術中已知之任何技術(諸如凍乾)來乾燥，且在使用前重構。Alternatively, injectable formulations may be provided in powder form for reconstitution with a suitable vehicle (including but not limited to sterile pyrogen-free water, buffer, dextrose solution, and the like) before use. For this purpose, the active compound may be dried by any technique known in the art (such as freeze drying) and reconstituted before use.
對於長期遞送，可將活性化合物或前藥調配成儲積製劑，以供藉由植入或肌內注射來投與。活性成分可用適宜聚合或疏水性材料(例如作為可接受油中之乳液)或離子交換樹脂來調配，或調配為微溶性衍生物(例如微溶性鹽)。For long-term delivery, the active compound or prodrug may be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient may be formulated with a suitable polymeric or hydrophobic material (for example, as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative (for example, as a sparingly soluble salt).
或者，可採用其他醫藥遞送系統。脂質體及乳液係可用於遞送活性化合物、寡核苷酸或前藥之遞送媒劑之熟知實例。亦可採用某些有機溶劑，諸如二甲亞碸(DMSO)。Alternatively, other drug delivery systems may be employed. Liposomes and emulsions are well known examples of delivery vehicles that can be used to deliver active compounds, oligonucleotides, or prodrugs. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be employed.
若期望，醫藥組合物可以包裝或分配器件來呈遞，該包裝或分配器件可含有一或多個含有活性化合物之單位劑型。該包裝可例如包含金屬或塑膠箔，諸如泡罩包裝。該包裝或分配器件可附有投與說明書。If desired, the pharmaceutical composition may be presented in a package or dispenser device which may contain one or more unit dosage forms containing the active compound. The package may, for example, comprise metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for administration.
本揭示案之活性化合物或前藥或其組合物通常將以有效達成預期結果之量使用，例如以有效治療或預防所治療之特定疾病之量使用。可治療性地投與化合物及寡核苷酸以達成治療益處，或預防性地投與以達成預防益處。治療益處意指根除或改善所治療之潛在病症及/或根除或改善與該潛在病症相關之一或多種症狀，使得患者報告感覺或狀況有所改善，儘管該患者可仍患有該潛在病症。治療益處亦包括停止或減緩疾病進展，而不管是否實現改善。The active compounds or prodrugs or compositions of the present disclosure will generally be used in an amount effective to achieve the desired result, for example, in an amount effective to treat or prevent the specific disease being treated. Compounds and oligonucleotides may be administered therapeutically to achieve a therapeutic benefit, or prophylactically to achieve a preventive benefit. A therapeutic benefit means eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more symptoms associated with the underlying disorder, such that the patient reports an improvement in feeling or condition, although the patient may still suffer from the underlying disorder. A therapeutic benefit also includes stopping or slowing the progression of a disease, regardless of whether an improvement is achieved.
對於預防性投與，可將化合物投與給處於發生先前所闡述疾病之一之風險下的患者。處於發生疾病風險下之患者可為具有將該患者置於指定的風險患者組中之特徵之患者，該風險患者組係由合適的醫學專業人士或小組界定。處於風險下之患者亦可為通常或經常處於潛在疾病有可能發展之環境中之患者。換言之，風險患者係通常或經常暴露於引起疾病或病恙之條件下或可能在有限時間內急性暴露之患者。或者，可應用預防性投與以避免診斷患有潛在病症之患者出現症狀。For prophylactic administration, the compound may be administered to a patient at risk for developing one of the previously described diseases. A patient at risk for developing a disease may be a patient having characteristics that place the patient in a designated group of patients at risk, as defined by an appropriate medical professional or panel. A patient at risk may also be a patient who is routinely or frequently exposed to an environment where a potential disease may develop. In other words, an at-risk patient is a patient who is routinely or frequently exposed to conditions that cause a disease or illness, or who may be acutely exposed for a limited period of time. Alternatively, prophylactic administration may be applied to avoid the onset of symptoms in a patient diagnosed with a potential disorder.
所投與化合物之量將取決於多種因素，包括例如所治療之特定適應症、投與模式、期望益處係預防性的抑或治療性的、所治療適應症之嚴重程度、患者年齡及體重、特定活性化合物之生物利用度及諸如此類。熟習此項技術者完全有能力確定有效劑量。The amount of compound administered will depend on a variety of factors including, for example, the specific indication being treated, the mode of administration, whether the desired benefit is preventive or therapeutic, the severity of the indication being treated, the age and weight of the patient, the bioavailability of the specific active compound, and the like. Determination of effective doses is well within the capabilities of those skilled in the art.
可自活體外分析初步估計有效劑量。舉例而言，用於動物之初始劑量可經調配以達成活性化合物之循環血液或血清濃度處於或高於特定化合物之IC50，該IC50係如在活體外分析(諸如活體外真菌MIC或MFC)及其他活體外分析中所量測。慮及特定化合物之生物利用度，熟習此項技術者完全有能力計算達成此類循環血液或血清濃度之劑量。關於指導，參見「General Principles」，Goodman及Gilman，The Pharmaceutical Basis of Therapeutics，第1章，第1-112頁，第13版，McGraw-Hill，以及其中所引用之參考文獻，該等文獻係以引用方式併入本文中。An effective dose can be initially estimated from in vitro assays. For example, an initial dose for an animal can be formulated to achieve a circulating blood or serum concentration of the active compound at or above theIC50 for the particular compound as measured in in vitro assays such as in vitro fungal MIC or MFC and other in vitro assays. One skilled in the art is well within the ability to calculate doses to achieve such circulating blood or serum concentrations, taking into account the bioavailability of a particular compound. For guidance, see "General Principles", Goodman and Gilman,The Pharmaceutical Basis of Therapeutics , Chapter 1, pages 1-112, 13th ed., McGraw-Hill, and references cited therein, which are incorporated herein by reference.
初始劑量亦可自活體內資料(諸如動物模型)估計。可用於測試化合物治療或預防上述各種疾病之功效的動物模型為此項技術中所熟知。Initial doses can also be estimated from in vivo data (eg, animal models). Animal models useful for testing the efficacy of compounds for treating or preventing the various diseases listed above are well known in the art.
劑量量通常將在約0.0001或0.001或0.01 mg/kg/天至約100 mg/kg/天範圍內，但可更高或更低，除其他因素外，此取決於化合物之活性、其生物利用度、投與模式及上文所論述之各種因素。可個別地調整劑量量及間隔，以提供足以維持治療或預防效應之化合物血漿水準。在局部投與或選擇性攝取之情形下，諸如局部外用投與，活性化合物之有效局部濃度不能與血漿濃度相關。熟習此項技術者無需過多實驗將能夠最佳化有效局部劑量。Dosage amounts will generally range from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower depending on, among other factors, the activity of the compound, its bioavailability, the mode of administration, and the various factors discussed above. Dosage amounts and intervals may be adjusted individually to provide plasma levels of the compound sufficient to maintain a therapeutic or prophylactic effect. In cases of local administration or selective uptake, such as topical administration, the effective local concentration of the active compound cannot be related to the plasma concentration. Those skilled in the art will be able to optimize the effective local dose without undue experimentation.
較佳地，化合物將提供治療或預防益處，且將具有可接受之耐受性。可使用標準醫藥程序來測定化合物及寡核苷酸之耐受性。不可耐受與治療(或預防)效應之間的劑量比率為治療指數。展現出高治療指數之化合物較佳。Preferably, the compound will provide therapeutic or preventive benefit and will have acceptable tolerability. Standard pharmaceutical procedures can be used to determine the tolerability of compounds and oligonucleotides. The dose ratio between intolerable and therapeutic (or preventive) effects is the therapeutic index. Compounds that exhibit a high therapeutic index are preferred.
在本文變數之任何定義中對化學基團清單之敘述包括將彼變數定義為任何單個基團或所列示基團之組合。本文對變數實施例之敘述包括作為任何單個實施例之實施例，或與任何其他實施例或其部分組合之實施例。本文對實施例之敘述包括作為任何單個實施例之實施例，或與任何其他實施例或其部分組合之實施例。實例The recitation of a list of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of embodiments of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. The recitation ofan embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.
為可更全面地理解本文所闡述之實施例，陳述以下實例。提供本申請案中所闡述之實例以闡釋本文所提供之化合物、組合物及方法，且不以任何方式解釋為限制其範圍。一般合成途徑In order to more fully understand the embodiments described herein, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, compositions and methods provided herein and are not to be construed in any way as limiting the scope thereof.General Synthesis Route
式(I)化合物可根據下文所闡述之一般合成途徑來製備。式(I) I 配位體合成中間體A-Y-L1-L2-N3之製備，其中Y為-C(=O)-The compounds of formula (I) can be prepared according to the general synthetic routes described below. Preparation of the ligand synthesis intermediate AYL1 -L2 -N3 of formula (I) wherein Y is -C(=O)-
通式A-Y-L1-L2-N3之配位體-連接體-疊氮化物合成中間體可根據下文所概述之一般程序中之任一者來製備。Ligand-linker-aziride synthetic intermediates of the general formula AYL1 -L2 -N3 can be prepared according to any of the general procedures outlined below.
在一些情況下，NMDA受體配位體A包含胺基，該胺基與進一步包含疊氮化物之連接體之酸基偶合。在一些情況下，胺為一級胺。在其他情況下，胺為形成環之一部分之二級胺。在一些情況下，使用活化基團達成偶合，諸如羧酸之碳二亞胺介導之修飾(例如N-羥基琥珀醯亞胺)。In some cases, the NMDA receptor ligand A comprises an amine group that is coupled to an acid group of a linker that further comprises an azide. In some cases, the amine is a primary amine. In other cases, the amine is a diamine that forms part of a ring. In some cases, coupling is achieved using an activated group, such as carbodiimide-mediated modification of a carboxylic acid (e.g.,N -hydroxysuccinimide).
在其他情況下，NMDA受體配位體A包含酸基，該酸基與進一步包含疊氮化物之連接體之胺基偶合。II 配位體合成中間體A-Y-L1-L2-N3之製備，其中Y為鍵。In other cases, the NMDA receptor ligand A comprises an acid group that is coupled to an amine group of a linker that further comprises an azide. II Preparation of the ligand synthesis intermediate AYL1 -L2 -N3 , where Y is a bond.
在一些情況下，NMDA受體配位體A包含胺基，該胺基與包含脫離基(例如Br、Cl、I、OMs及諸如此類)之連接體偶合，且其中該連接體進一步包含疊氮化物。在其他情況下，連接體包含胺基，該胺基與包含脫離基(例如Br、Cl、I、OMs及諸如此類)之NMDA受體配位體A偶合，且其中該連接體進一步包含疊氮化物。在其他情況下，NMDA受體配位體A包含醇基，該醇基與包含脫離基(例如Br、Cl、OMs及諸如此類)之連接體偶合，且其中該連接體進一步包含疊氮化物。III 合成中間體L3'-L4-R1之製備，其中L3'為L3之合成前體In some cases, the NMDA receptor ligand A comprises an amine group, which is coupled to a linker comprising an ionizing group (e.g., Br, Cl, I, OMs, and the like), and wherein the linker further comprises an azide. In other cases, the linker comprises an amine group, which is coupled to an NMDA receptor ligand A comprising an ionizing group (e.g., Br, Cl, I, OMs, and the like), and wherein the linker further comprises an azide. In other cases, the NMDA receptor ligand A comprises an alcohol group, which is coupled to a linker comprising an ionizing group (e.g., Br, Cl, OMs, and the like), and wherein the linker further comprises an azide. III Preparation of the synthetic intermediate L3 '-L4 -R1 , wherein L3 ' is the synthetic precursor of L3
通式L3'-L4-R1之R1-連接體合成中間體，其中L3'為L3之合成前體，可根據下文所概述之一般程序中之任一者來製備。R1 -linker synthetic intermediates of the general formula L3 ′-L4 -R1 , wherein L3 ′ is a synthetic precursor of L3 , can be prepared according to any of the general procedures outlined below.
在一些情況下，R1基與L4'連接體(其為L4之前體且包含胺基)偶合，形成H2N-L4'-R1。此中間體與包含酸基之L3'基偶合，其中L3'為L3之前體。在一些情況下，使用活化基團達成偶合，諸如羧酸之碳二亞胺介導之修飾(例如N-羥基琥珀醯亞胺)。IV 式(I)化合物之製備In some cases, the R1 group is coupled to a L4 'linker, which is a precursor to L4 and comprises an amine group, forming H2 NL4 '-R1 . This intermediate is coupled to a L 3 'group comprising an acid group, wherein L3 ' is a precursor to L3. In some cases, coupling is achieved using an activated group, such as carbodiimide-mediated modification of a carboxylic acid (e.g.,N -hydroxysuccinimide). IV Preparation of compounds of formula (I)
使如上文所闡述製備之通式A-Y-L1-L2-N3之配位體-連接體-疊氮化物合成中間體與L3'-L4-R1中間體偶合，形成式(I)化合物。The ligand-linker-azide synthesis intermediate of the general formula AYL1 -L2 -N3 prepared as described above is coupled with the L3 ′-L4 -R1 intermediate to form the compound of formula (I).
在一些情況下，L3'包含三鍵。在一些情況下，L3'包含環狀炔烴。In some cases, L3 ' comprises a triple bond. In some cases, L3 ' comprises a cyclic alkyne.
在一些情況下，A-Y-L1-L2-N3之疊氮化物與L3'-L4-R1之三鍵反應，形成三唑。NMDA受體配位體之合成In some cases, the aziridine of AYL1 -L2 -N3 reacts with the triple bond of L3 '-L4 -R1 to form a triazole. Synthesis ofNMDAreceptor ligands
根據下文所闡述之程序製備配位體1至23實例1：配位體1之合成(1r,3R,5S,7r)-N-(12-疊氮基十二烷基)-3,5-二甲基金剛烷-1-胺Ligands 1 to 23 were prepared according to the procedures described below. Example 1: Synthesis of Ligand 1(1r,3R,5S,7r)-N-(12-azidododecyl)-3,5-dimethyladamantan-1-amine
於密封小瓶中將美金剛鹽酸鹽(0.25 g, 1.2 mmol)、K2CO3(0.4 g, 2.9 mmol)及1-疊氮基-12-溴十二烷(0.40 g, 1.4 mmol)於DMF (3 mL)中之混合物在80℃下攪拌48小時。使反應混合物在DCM (50 mL)與水(50 mL)之間分配。分離有機相，且用DCM (2 × 50 mL)萃取水相。將合併的有機相用鹽水(20 mL)洗滌，經Na2SO4乾燥，過濾，濃縮，且藉由矽膠管柱層析(MeOH於DCM中，梯度0-10%)進行純化，得到呈黃色油狀物之標題化合物(144 mg, 32%)。A mixture of mescaline hydrochloride (0.25 g, 1.2 mmol), K2 CO3 (0.4 g, 2.9 mmol) and 1-azido-12-bromododecane (0.40 g, 1.4 mmol) in DMF (3 mL) was stirred at 80 °C for 48 h in a sealed vial. The reaction mixture was partitioned between DCM (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine (20 mL), driedoverNa2SO4 , filtered, concentrated, and purified by silica gel column chromatography (MeOH in DCM, gradient 0-10%) to give the title compound as a yellow oil (144 mg, 32%).
MS (ESI), m/z 389.3 [M+H]+MS (ESI), m/z 389.3 [M+H]+
1H NMR (500 MHz, DMSO-d6) d 8.39 (s, 1 H), 3.31 (t, J = 5 Hz, 2 H), 2.71-2.74 (m, 2 H), 2.15 (s, 1 H), 1.40-1.60 (m, 10 H), 1.30-1.45 (m, 20 H), 1.10-1.20 (m, 2 H), 0.60 (s, 6 H)實例2：配位體2之合成(1-疊氮基-15-((5S,10R)-5-甲基-10,11-二氫-5H-5,10-環亞胺基二苯并[a,d][7]輪烯-12-基)-3,6,9,12-四氧雜十五烷-15-酮)1 H NMR (500 MHz, DMSO-d6 ) d 8.39 (s, 1 H), 3.31 (t, J = 5 Hz, 2 H), 2.71-2.74 (m, 2 H), 2.15 (s, 1 H), 1.40-1.60 (m, 10 H), 1.30-1.45 (m, 20 H), 1.10-1.20 (m, 2 H), 0.60 (s, 6 H)Example 2: Synthesis of Ligand 2(1-azido-15-((5S,10R)-5-methyl-10,11-dihydro-5H-5,10-cycloiminodibenzo[a,d][7]annulen-12-yl)-3,6,9,12-tetraoxopentadecane-15-one)
將HATU (1.28 g, 3.18 mmol)添加至(+) MK-801馬來酸鹽(0.80 g, 2.37 mmol)、DIPEA (2 mL, 10.83 mmol)及1-疊氮基-3,6,9,12-四氧雜十五烷-15-酸(0.73 g, 2.51 mmol)於DCM (20 mL)中之溶液中。將混合物攪拌30分鐘，且接著傾倒至飽和NaHCO3溶液(水溶液，100 mL)中，且用DCM (300 mL × 2)萃取。使合併的有機萃取物經Na2SO4乾燥，過濾，濃縮且藉由矽膠管柱層析(乙酸乙酯於己烷中，梯度0-80%)進行純化，得到呈黃色油狀物之標題化合物(0.49 g, 42%)。HATU (1.28 g, 3.18 mmol) was added to a solution of (+) MK-801 maleate (0.80 g, 2.37 mmol), DIPEA (2 mL, 10.83 mmol) and 1-azido-3,6,9,12-tetraoxopentadecane-15-oic acid (0.73 g, 2.51 mmol) in DCM (20 mL). The mixture was stirred for 30 min and then poured into a saturated NaHCO3 solution (aq., 100 mL) and extracted with DCM (300 mL×2). The combined organic extracts were dried overNa2SO4, filtered, concentrated and purified by silica gel column chromatography (ethyl acetate in hexanes, gradient 0-80%) to give the title compound as a yellow oil (0.49 g, 42%).
MS (ESI): m/z = 495.5 [M+H]+；517.5 [M+Na]+MS (ESI): m/z = 495.5 [M+H]+ ; 517.5 [M+Na]+
1H NMR (500 MHz, CDCl3) d 7.31-7.34 (m, 2 H), 7.15-7.20 (m, 2 H), 7.07-7.12 (m, 3 H), 6.89-6.90 (m, 1 H), 5.41-5.42 (m, 1 H), 3.75-3.79 (m, 2 H), 3.56-3.66 (m, 15 H), 3.35-3.37 (m, 2 H), 2.76-2.81 (m, 3 H), 2.30-2.40 (m, 3H)實例3：配位體3之合成(1-疊氮基-N-((5R,9R,E)-11-亞乙基-7-甲基-2-側氧基-2,6,9,10-四氫-5,9-橋亞甲基環辛[b]吡啶-5(1H)-基)-3,6,9,12-四氧雜十五烷-15-醯胺)1 H NMR (500 MHz, CDCl3 ) d 7.31-7.34 (m, 2 H), 7.15-7.20 (m, 2 H), 7.07-7.12 (m, 3 H), 6.89-6.90 (m, 1 H), 5.41-5.42 (m, 1 H), 3.75-3.79 (m, 2 H), 3.56-3.66 (m, 15 H), 3.35-3.37 (m, 2 H), 2.76-2.81 (m, 3 H), 2.30-2.40 (m, 3H)Example 3: Synthesis of Ligand 3(1-azido-N-((5R,9R,E)-11-ethylidene-7-methyl-2-oxo-2,6,9,10-tetrahydro-5,9-oxomethylenecyclooctane[b]pyridin-5(1H)-yl)-3,6,9,12-tetraoxopentadecane-15-amide)
將HATU (600 mg, 1.6 mmol)添加至1-疊氮基-3,6,9,12-四氧雜十五烷-15-酸(300 mg, 1.0 mmol)、石杉鹼A (200 mg, 0.8 mmol)及DIPEA (1 mL)於DCM (5 mL)中之懸浮液中。將混合物攪拌3小時，用DCM (100 mL)稀釋且用水(50 mL)洗滌。分離有機層，經Na2SO4乾燥，過濾，濃縮且利用於己烷中之EtOH/EtOAc梯度(V/V, 1:3，0至100%)進行純化，得到呈黃色油狀物之標題化合物(128 mg, 30%)。HATU (600 mg, 1.6 mmol) was added to a suspension of 1-azido-3,6,9,12-tetraoxopentadecane-15-oic acid (300 mg, 1.0 mmol), huperzine A (200 mg, 0.8 mmol) and DIPEA (1 mL) in DCM (5 mL). The mixture was stirred for 3 h, diluted with DCM (100 mL) and washed with water (50 mL). The organic layer was separated, driedoverNa2SO4 , filtered, concentrated and purified with a gradient of EtOH/EtOAc in hexanes (V/V, 1:3, 0 to 100%) to give the title compound (128 mg, 30%) as a yellow oil.
MS (ESI): m/z = 516.6 [M+H]+；538.5 [M+Na]+MS (ESI): m/z = 516.6 [M+H]+ ; 538.5 [M+Na]+
1H NMR (500 MHz, CDCl3) d 8.25 (d, J = 10 Hz, 1H), 7.01 (d, J = 10 Hz, 1H), 5.54 (q, J = 10 Hz, 1H), 5.44-5.45 (m, 1 H), 3.82-3.83 (m, 2 H), 3.67-3.41 (m, 12 H), 3.10-3.41 (m, 2 H), 3.00-3.13 (m, 4 H), 2.19-2.25 (m, 2 H), 1.73 (d, J = 5 Hz, 3 H), 1.28 (s, 3 H), 1.30-1.40 (m, 1 H), 1.12-1.22 (m, 2 H)實例4：配位體4之合成((S)-2-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯胺基)-N-苯甲基-3-甲氧基丙醯胺)1 H NMR (500 MHz, CDCl3 ) d 8.25 (d, J = 10 Hz, 1H), 7.01 (d, J = 10 Hz, 1H), 5.54 (q, J = 10 Hz, 1H), 5.44-5.45 (m, 1 H), 3.82-3.83 (m, 2 H), 3.67-3.41 (m, 12 H), 3.10-3.41 (m, 2 H), 3.00-3.13 (m, 4 H), 2.19-2.25 (m, 2 H), 1.73 (d, J = 5 Hz, 3 H), 1.28 (s, 3 H), 1.30-1.40 (m, 1 H), 1.12-1.22 (m, 2 H)Example 4: Synthesis of Ligand 4((S)-2-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionamido)-N-benzyl-3-methoxypropionamide)
在室溫下將(2S)-2-胺基-N-苯甲基-3-甲氧基丙醯胺(168 mg, 0.81 mmol)、3-[(8-疊氮基-3,6-二氧雜辛-1-基)氧基]丙酸(199 mg, 0.81 mmol)、DIEA (208 mg, 1.61 mmol)及HATU (459 mg, 1.21 mmol)添加至DMF (4 mL)中。將所得混合物在室溫下攪拌1 h。藉由反相層析(C18矽膠管柱；移動相，CH3CN水溶液，在20 min內0%至100%梯度；偵測器，UV 254 nm)純化殘餘物，得到呈灰白色固體之標題化合物(170 mg, 45%)。(2S)-2-amino-N-benzyl-3-methoxypropionamide (168 mg, 0.81 mmol), 3-[(8-azido-3,6-dioxooct-1-yl)oxy]propanoic acid (199 mg, 0.81 mmol), DIEA (208 mg, 1.61 mmol) and HATU (459 mg, 1.21 mmol) were added to DMF (4 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by reverse phase chromatography (C18 silica gel column; mobile phase, CH3 CN in water, gradient from 0% to 100% in 20 min; detector, UV 254 nm) to give the title compound (170 mg, 45%) as an off-white solid.
MS (ESI): m/z = 460.1 [M+Na]+MS (ESI): m/z = 460.1 [M+Na]+
1H NMR (CDCl3, 500 MHz) d 7.28-7.32 (m, 2 H), 7.23-7.26 (m, 3 H), 6.90-7.01 (m, 2 H), 4.59-4.62 (m, 1 H), 4.44-4.49 (m, 2 H), 3.89-3.92 (m, 1 H), 3.74-3.76 (m, 1 H), 3.57-3.69 (m, 9 H), 3.45-3.52 (m, 5 H), 3.30-3.40 (m, 5 H)實例5：配位體5之合成((S)-2-乙醯胺基-N-(4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)苯甲基)-3-甲氧基丙醯胺)步驟1：(S)-2-乙醯胺基-N-(4-羥基苯甲基)-3-甲氧基丙醯胺1 H NMR (CDCl3 , 500 MHz) d 7.28-7.32 (m, 2 H), 7.23-7.26 (m, 3 H), 6.90-7.01 (m, 2 H), 4.59-4.62 (m, 1 H), 4.44-4.49 (m, 2 H), 3.89-3.92 (m, 1 H), 3.74-3.76 (m, 1 H), 3.57-3.69 (m, 9 H), 3.45-3.52 (m, 5 H), 3.30-3.40 (m, 5 H)Example 5: Synthesis of Ligand 5((S)-2-acetamido-N-(4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)benzyl)-3-methoxypropionamide)Step 1 : (S)-2-acetamido-N-(4-hydroxybenzyl)-3-methoxypropionamide
在0℃下向(2S)-2-胺基-N-[(4-羥基苯基)甲基]-3-甲氧基丙醯胺(300 mg, 1.33 mmol)於DCM (5 mL)中之溶液中逐滴添加三乙胺(0.30 mL, 2.7 mmol)及Ac2O (68 mg, 0.67 mmol)。將反應物在室溫下攪拌2小時，且接著濃縮並使用C18管柱層析，用CH3CN/H2O溶析進行純化，得到呈白色半固體之標題化合物(100 mg, 28%)。To a solution of (2S)-2-amino-N-[(4-hydroxyphenyl)methyl]-3-methoxypropanamide (300 mg, 1.33 mmol) in DCM (5 mL) was added triethylamine (0.30 mL, 2.7 mmol) and Ac2 O (68 mg, 0.67 mmol) dropwise at 0° C. The reaction was stirred at room temperature for 2 hours and then concentrated and purified using a C18 column eluting with CH3 CN/H2 O to give the title compound (100 mg, 28%) as a white semisolid.
MS(ESI) m/z = 267.1 [M+H]+步驟2：(S)-2-乙醯胺基-N-(4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)苯甲基)-3-甲氧基丙醯胺MS (ESI) m/z = 267.1 [M+H]+Step 2 : (S)-2-Acetamido-N-(4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)benzyl)-3-methoxypropionamide
向N-[(4S)-7-(4-羥基苯基)-5-側氧基-6-氮雜-2-氧雜庚-4-基]乙醯胺(100 mg, 0.376 mmol)於乙腈(1 mL)中之溶液中添加甲磺酸11-疊氮基-3,6,9-三氧雜十一-1-基酯(106 mg, 0.357 mmol)及Cs2CO3(244 mg, 0.751 mmol)。將混合物在60℃下攪拌2小時，且接著藉由在室溫下添加水(5 mL)淬滅，並用乙酸乙酯(100 mL)萃取。將有機層用水(10 mL)及鹽水洗滌，經Na2SO4乾燥，過濾，濃縮且利用矽膠管柱層析，利用於DCM中之MeOH (0至5%)梯度溶析進行純化，得到呈白色固體之標題化合物(84.3 mg, 47%)。To a solution of N-[(4S)-7-(4-hydroxyphenyl)-5-oxo-6-aza-2-oxahept-4-yl]acetamide (100 mg, 0.376 mmol) in acetonitrile (1 mL) was added 11-azido-3,6,9-trioxadendron-1-yl methanesulfonate (106 mg, 0.357 mmol) and Cs2 CO3 (244 mg, 0.751 mmol). The mixture was stirred at 60° C. for 2 hours and then quenched by adding water (5 mL) at room temperature and extracted with ethyl acetate (100 mL). The organic layer was washed with water (10 mL) and brine, dried overNa2SO4, filtered, concentrated and purified by silica gel column chromatography using a gradient of MeOH (0 to 5%) in DCM to give the title compound (84.3 mg, 47%) as a white solid.
MS(ESI): m/z = 468.2 [M+H]+MS(ESI): m/z = 468.2 [M+H]+
1H NMR (CDCl3, 500 MHz) d 7.10-7.20 (m, 2 H), 6.80-6.90 (m, 2 H), 6.59-6.68 (m, 1 H), 6.38-6.42 (m, 1 H), 4.49-4.53 (m, 1 H), 4.39-4.40 (m, 2 H), 4.10 (t, J = 5 Hz, 2 H), 3.85 (t, J = 5 Hz, 2 H), 3.78-3.82 (m, 1 H), 3.70-3.74 (m, 1 H), 3.65-3.70 (m, 9 H), 3.32-3.42 (m, 6 H), 3.03 (s, 3 H)實例6：配位體6之合成((S)-N-((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)-1-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯基)吡咯啶-2-甲醯胺)步驟1：(S)-2-(((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)胺甲醯基)吡咯啶-1-甲酸(9H-茀-9-基)甲酯1 H NMR (CDCl3 , 500 MHz) d 7.10-7.20 (m, 2 H), 6.80-6.90 (m, 2 H), 6.59-6.68 (m, 1 H), 6.38-6.42 (m, 1 H), 4.49-4.53 (m, 1 H), 4.39-4.40 (m, 2 H), 4.10 (t, J = 5 Hz, 2 H), 3.85 (t, J = 5 Hz, 2 H), 3.78-3.82 (m, 1 H), 3.70-3.74 (m, 1 H), 3.65-3.70 (m, 9 H), 3.32-3.42 (m, 6 H), 3.03 (s, 3 H)Example 6: Synthesis of Ligand 6((S)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)-1-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionyl)pyrrolidine-2-carboxamide)Step 1 : (S)-2-(((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)aminomethyl)pyrrolidine-1-carboxylic acid (9H-fluoren-9-yl)methyl ester
在室溫下向N-{[(9H-茀-9-基甲基)氧基]羰基}-L-脯胺酸(2.0 g, 5.9 mmol)於DCM (20 mL)中之攪拌溶液中逐滴添加(2S,3R)-2-胺基-3-羥基丁醯胺(0.70 g, 5.9 mmol)及HATU (2.7 g, 7.1 mmol)。在室溫下向上述混合物中分多次添加DIEA (1.15 g, 8.89 mmol)。將所得混合物攪拌隔夜，且接著用乙酸乙酯(3 × 250 mL)萃取。將合併的有機層用飽和NaHCO3溶液(3 × 250 mL)及鹽水(100 mL)洗滌，經Na2SO4乾燥，過濾，濃縮且藉由矽膠管柱層析，利用於DCM中之MeOH (0至10%)梯度溶析進行純化，得到呈淺黃色固體之標題化合物(1.57 g, 60%)。To a stirred solution of N-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-proline (2.0 g, 5.9 mmol) in DCM (20 mL) was added (2S,3R)-2-amino-3-hydroxybutyramide (0.70 g, 5.9 mmol) and HATU (2.7 g, 7.1 mmol) dropwise at room temperature. DIEA (1.15 g, 8.89 mmol) was added to the above mixture in portions at room temperature. The resulting mixture was stirred overnight and then extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with saturated NaHCO3 solution (3 x 250 mL) and brine (100 mL), dried over Na2 SO4 , filtered, concentrated and purified by silica gel column chromatography using a gradient of MeOH (0 to 10%) in DCM to give the title compound (1.57 g, 60%) as a light yellow solid.
MS (ESI) m/z = 438.0 [M+H]+。步驟2：(S)-N-((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)吡咯啶-2-甲醯胺MS (ESI) m/z = 438.0 [M+H]+ .Step 2 : (S)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)pyrrolidine-2-carboxamide
在室溫下向(2S)-2-({[(1S,2R)-1-胺甲醯基-2-羥基丙基]胺基}羰基)四氫吡咯-1-甲酸9H-茀-9-基甲酯(400 mg, 0.91 mmol)於DCM (4 mL)中之攪拌溶液中分多次添加六氫吡啶(0.8 mL)。將所得混合物攪拌2小時。過濾後，將濾液在減壓下濃縮，得到呈淺黃色固體之粗產物，其不經進一步純化即直接用於下一步驟中。步驟3：(S)-N-((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)-1-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯基)吡咯啶-2-甲醯胺To a stirred solution of (2S)-2-({[(1S,2R)-1-aminoformyl-2-hydroxypropyl]amino}carbonyl)tetrahydropyrrole-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (400 mg, 0.91 mmol) in DCM (4 mL) was added hexahydropyridine (0.8 mL) in portions at room temperature. The resulting mixture was stirred for 2 hours. After filtration, the filtrate was concentrated under reduced pressure to give a crude product as a light yellow solid, which was directly used in the next step without further purification.Step 3 : (S)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)-1-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionyl)pyrrolidine-2-carboxamide
在室溫下向(2S,3R)-3-羥基-2-({[(2S)-四氫-1H-吡咯-2-基]羰基}胺基)丁醯胺(220 mg, 1.02 mmol)於DCM (4 mL)中之攪拌溶液中逐滴添加3-[(8-疊氮基-3,6-二氧雜辛-1-基)氧基]丙酸(252 mg, 1.02 mmol)及HATU (583 mg, 1.53 mmol)。向上述混合物中分多次添加DIEA (396 mg, 3.07 mmol)。將所得混合物再攪拌1小時。過濾後，將濾液在減壓下濃縮。藉由反相層析(C18矽膠管柱；移動相，ACN水溶液，在20 min內10%至90%梯度；偵測器，UV 254 nm)純化粗產物，得到呈黃色油狀物之標題化合物(247 mg, 51%)。To a stirred solution of (2S,3R)-3-hydroxy-2-({[(2S)-tetrahydro-1H-pyrrol-2-yl]carbonyl}amino)butyramide (220 mg, 1.02 mmol) in DCM (4 mL) were added 3-[(8-azido-3,6-dioxooctane-1-yl)oxy]propanoic acid (252 mg, 1.02 mmol) and HATU (583 mg, 1.53 mmol) dropwise at room temperature. To the above mixture was added DIEA (396 mg, 3.07 mmol) in several portions. The resulting mixture was stirred for another hour. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (C18 silica gel column; mobile phase, aqueous ACN, gradient 10% to 90% in 20 min; detector, UV 254 nm) to give the title compound (247 mg, 51%) as a yellow oil.
MS (ESI): m/z = 445.4 [M+H]+, 467.4 [M+Na]+MS (ESI): m/z = 445.4 [M+H]+ , 467.4 [M+Na]+
1H NMR (CDCl3, 500 MHz) d 4.50-4.55 (m, 2 H), 4.40-4.45 (m, 1 H), 3.86-3.91 (m, 2 H), 3.50-3.60 (m, 12 H), 3.30-3.40 (m, 2 H), 3.25 (s, 2 H, br), 2.80-2.90 (m, 1 H), 2.48-2.51 (m, 1 H), 2.20-2.30 (m, 2 H), 2.00-2.10 (m, 2 H), 1.16 (d, J = 5.0 Hz, 3 H)實例7：以下之合成：配位體7(2-((2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)胺基)-2-(2-氯苯基)環己-1-酮(第二溶析)及配位體8N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-2-(2-氯苯基)環戊烷-1-甲醯胺(第一溶析))步驟1：甲磺酸1-(2-氯苯基)-2-側氧基環己酯1 H NMR (CDCl3 , 500 MHz) d 4.50-4.55 (m, 2 H), 4.40-4.45 (m, 1 H), 3.86-3.91 (m, 2 H), 3.50-3.60 (m, 12 H), 3.30-3.40 (m, 2 H), 3.25 (s, 2 H, br), 2.80-2.90 (m, 1 H), 2.48-2.51 (m, 1 H), 2.20-2.30 (m, 2 H), 2.00-2.10 (m, 2 H), 1.16 (d, J = 5.0 Hz, 3 H)Example 7: Synthesis of the following:Ligand 7(2-((2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2-chlorophenyl)cyclohexan-1-one (second elution) andligand 8N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(2-chlorophenyl)cyclopentane-1-carboxamide (first elution))Step 1 : 1-(2-chlorophenyl)-2-oxocyclohexyl methanesulfonate
在0℃下向2-(2-氯苯基)-2-羥基環己-1-酮(0.80 g, 3.5 mmol，如J. Org. Chem.2020, 85(13), 8656-8664中所闡述製備)於THF (0.4 mL)中之攪拌溶液中分多次添加三乙胺(1.7 mL, 12 mmol)及甲磺醯氯(1.22 g, 10.7 mmol)。將所得混合物在氮氣氣氛下在0℃下攪拌1小時。藉由在室溫下添加水(25 mL)淬滅反應，且用乙酸乙酯(2 × 250 mL)萃取。將合併的有機層用水(2 × 25 mL)及鹽水(25 mL)洗滌，經Na2SO4乾燥，過濾，且在減壓下濃縮。粗產物不經進一步純化即直接用於下一步驟中。To a stirred solution of 2-(2-chlorophenyl)-2-hydroxycyclohexan-1-one (0.80 g, 3.5 mmol, prepared as described inJ. Org. Chem .2020 , 85(13), 8656-8664) in THF (0.4 mL) was added triethylamine (1.7 mL, 12 mmol) and methanesulfonyl chloride (1.22 g, 10.7 mmol) in portions at 0°C. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 1 hour. The reaction was quenched by adding water (25 mL) at room temperature and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (2 x 25 mL) and brine (25 mL), driedoverNa2SO4 , filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.
MS (ESI): m/z = 301.0 [M-H]-。步驟2：2-((2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)胺基)-2-(2-氯苯基)環己-1-酮及N-(2-(2-(2-(疊氮基甲氧基)乙氧基)乙氧基)乙基)-2-(2-氯苯基)環戊烷-1-甲醯胺MS (ESI): m/z = 301.0 [MH]- .Step 2 : 2-((2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2-chlorophenyl)cyclohexan-1-one and N-(2-(2-(2-(azidomethoxy)ethoxy)ethoxy)ethyl)-2-(2-chlorophenyl)cyclopentane-1-carboxamide
在0℃下向甲磺酸1-(2-氯苯基)-2-側氧基環己酯(0.80 g, 2.64 mmol)於THF (1 mL)中之攪拌溶液中逐滴添加三乙胺(1.84 mL, 13.2 mmol)。在0℃下逐滴添加2-[(8-疊氮基-3,6-二氧雜辛-1-基)氧基]乙-1-胺(1.73 g, 7.93 mmol)，且將所得混合物在室溫下攪拌隔夜。藉由添加水(10 mL)淬滅反應，且用乙酸乙酯(3 × 100 mL)萃取。將合併的有機層用水(100 mL)及鹽水(100 mL)洗滌，經Na2SO4乾燥，過濾，濃縮且藉由反相急速層析(C18矽膠管柱；移動相，ACN水溶液，在20 min內10%至90%梯度；偵測器，UV 254 nm)進行純化，得到：To a stirred solution of 1-(2-chlorophenyl)-2-oxocyclohexyl methanesulfonate (0.80 g, 2.64 mmol) in THF (1 mL) was added triethylamine (1.84 mL, 13.2 mmol) dropwise at 0°C. 2-[(8-azido-3,6-dioxooct-1-yl)oxy]ethan-1-amine (1.73 g, 7.93 mmol) was added dropwise at 0°C, and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (10 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2 SO4 , filtered, concentrated and purified by reverse phase flash chromatography (C18 silica gel column; mobile phase, ACN in water, gradient from 10% to 90% in 20 min; detector, UV 254 nm) to give:
第一溶析化合物：N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-2-(2-氯苯基)環戊烷-1-甲醯胺(配位體8；181.9 mg, 15%)，呈淺黃色固體First elution compound: N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(2-chlorophenyl)cyclopentane-1-carboxamide (ligand 8; 181.9 mg, 15%), light yellow solid
MS (ESI): m/z = 425.2 [M+H]+MS (ESI): m/z = 425.2 [M+H]+
1H NMR (DMSO-d6, 400 MHz) d 7.80-7.90 (m, 1 H), 7.15-7.45 (m, 4 H), 3.20-3.70 (m, 15 H), 3.05-3.15 (m, 2 H), 2.80-2.95 (m, 1 H), 2.10-2.20 (m, 1 H), 1.90-2.05 (m, 1 H), 1.70-1.80 (m, 3 H), 1.35-1.50 (m, 1 H)1 H NMR (DMSO-d6 , 400 MHz) d 7.80-7.90 (m, 1 H), 7.15-7.45 (m, 4 H), 3.20-3.70 (m, 15 H), 3.05-3.15 (m, 2 H), 2.80-2.95 (m, 1 H), 2.10-2.20 (m, 1 H), 1.90-2.05 (m, 1 H), 1.70-1.80 (m, 3 H), 1.35-1.50 (m, 1 H)
第二溶析化合物：2-[(11-疊氮基-3,6,9-三氧雜十一-1-基)胺基]-2-(2-氯苯基)環己-1-酮(配位體7；199.9 mg, 16%)，呈淺黃色固體Second elution compound: 2-[(11-azido-3,6,9-trioxa-undecyl)amino]-2-(2-chlorophenyl)cyclohexan-1-one (ligand 7; 199.9 mg, 16%), light yellow solid
MS (ESI): m/z = 425.2 [M+H]+MS (ESI): m/z = 425.2 [M+H]+
1H NMR (DMSO-d6, 400 MHz) d 7.65-7.70 (m, 1 H), 7.25-7.40 (m, 3 H), 3.42-3.62 (m, 11 H), 3.34-3.42 (m, 2 H), 2.65-2.75 (m, 1 H), 2.50-2.60 (m, 1 H), 2.25-2.45 (m, 3 H), 2.05-2.15 (m, 1 H), 1.80-1.90 (m, 3 H), 1.60-1.75 (m, 2 H)實例8：配位體9之合成(1-疊氮基-N-((1r,3R,5S,7r)-3,5-二甲基金剛烷-1-基)-3,6,9,12-四氧雜十五烷-15-醯胺)1 H NMR (DMSO-d6 , 400 MHz) d 7.65-7.70 (m, 1 H), 7.25-7.40 (m, 3 H), 3.42-3.62 (m, 11 H), 3.34-3.42 (m, 2 H), 2.65-2.75 (m, 1 H), 2.50-2.60 (m, 1 H), 2.25-2.45 (m, 3 H), 2.05-2.15 (m, 1 H), 1.80-1.90 (m, 3 H), 1.60-1.75 (m, 2 H)Example 8: Synthesis of Ligand 9(1-azido-N-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3,6,9,12-tetraoxopentadecane-15-amide)
將疊氮基-PEG4-NHS酯(541 mg, 1.395 mmol)、美金剛鹽酸鹽(300 mg, 1.395 mmol)及DIPEA (0.43 ml, 3.1 mmol)於THF (10 mL)中之懸浮液在60℃下攪拌3 h。將反應混合物濃縮，且藉由急速層析(10 g 20微米Biotage管柱)，使用己烷及EtOAc (0-100%)純化殘餘物，得到呈米色固體之標題化合物(293 mg, 46%)。A suspension of azido-PEG4-NHS ester (541 mg, 1.395 mmol), mesothelin hydrochloride (300 mg, 1.395 mmol) and DIPEA (0.43 ml, 3.1 mmol) in THF (10 mL) was stirred at 60 °C for 3 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (10 g 20 micron Biotage column) using hexanes and EtOAc (0-100%) to give the title compound (293 mg, 46%) as a beige solid.
MS (ESI): m/z=453 [M+H]+MS (ESI): m/z=453 [M+H]+
1H NMR (499 MHz, DMSO-d6) δ 7.29 (s, 1H), 3.63 - 3.56 (m, 2H), 3.56 - 3.52 (m, 6H), 3.52 - 3.43 (m, 8H), 3.39 (dd, J = 5.6, 4.3 Hz, 2H), 2.24 (t, J = 6.6 Hz, 2H), 2.05 (p, J = 3.1 Hz, 1H), 1.73 (d, J = 3.2 Hz, 2H), 1.60 - 1.50 (m, 4H), 1.30 (dd, J = 12.3, 3.1 Hz, 2H), 1.23 (d, J = 12.1 Hz, 2H), 1.09 (s, 2H), 0.80 (s, 6H)實例9：配位體10之合成(1-疊氮基-15-((5R,10S)-5-甲基-10,11-二氫-5H-5,10-環亞胺基二苯并[a,d][7]輪烯-12-基)-3,6,9,12-四氧雜十五烷-15-酮)1 H NMR (499 MHz, DMSO-d6 ) δ 7.29 (s, 1H), 3.63 - 3.56 (m, 2H), 3.56 - 3.52 (m, 6H), 3.52 - 3.43 (m, 8H), 3.39 (dd, J = 5.6, 4.3 Hz, 2H), 2.24 (t, J = 6.6 Hz, 2H), 2.05 (p, J = 3.1 Hz, 1H), 1.73 (d, J = 3.2 Hz, 2H), 1.60 - 1.50 (m, 4H), 1.30 (dd, J = 12.3, 3.1 Hz, 2H), 1.23 (d, J = 12.1 Hz, 2H), 1.09 (s, 2H), 0.80 (s, 6H)Example 9: Synthesis of Ligand 10(1-azido-15-((5R,10S)-5-methyl-10,11-dihydro-5H-5,10-cycloiminodibenzo[a,d][7]annulen-12-yl)-3,6,9,12-tetraoxopentadecane-15-one)
將DIPEA (3.0 mL, 17 mmol)添加至(-) MK801馬來酸鹽(0.86g, 2.31 mmol)於DCM (20 mL)中之懸浮液中，獲得澄清溶液。一次性添加N3-PEG4-COOH (0.9g, 3.09 mmol)及HATU (1.2g, 3.16 mmol)。初始懸浮液變成黃色溶液。將反應物攪拌1 h，且接著傾倒至飽和NaHCO3水溶液(200 mL)中，並用DCM (500 mL)稀釋。分離有機層，經無水硫酸鈉乾燥，過濾，濃縮且藉由管柱層析(矽膠管柱80 g，利用於EtOAc中之30% EtOH溶析，於己烷中0至80%梯度)進行純化，得到呈淺黃色油狀物之標題化合物(836 mg, 58%)。DIPEA (3.0 mL, 17 mmol) was added to a suspension of (-) MK801 maleate (0.86 g, 2.31 mmol) in DCM (20 mL) to obtain a clear solution. N3 -PEG4 -COOH (0.9 g, 3.09 mmol) and HATU (1.2 g, 3.16 mmol) were added in one portion. The initial suspension became a yellow solution. The reaction was stirred for 1 h and then poured into saturated aqueous NaHCO3 solution (200 mL) and diluted with DCM (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (silica gel column 80 g, eluting with 30% EtOH in EtOAc, gradient 0 to 80% in hexanes) to give the title compound as a light yellow oil (836 mg, 58%).
MS (ESI): m/z=495.3 [M+H]+, 517.5 [M+Na]+MS (ESI): m/z=495.3 [M+H]+ , 517.5 [M+Na]+
1H NMR (499 MHz, CDCl3) δ 7.37 - 7.29 (m, 2H), 7.21 - 7.14 (m, 2H), 7.13 - 7.03 (m, 3H), 6.93 - 6.84 (m, 1H), 5.43 (s, 1H), 3.85 - 3.72 (m, 2H), 3.70 - 3.52 (m, 16H), 3.40 - 3.33 (m, 2H), 2.89 - 2.70 (m, 2H), 2.37 (s, 3H)實例10：配位體11之合成(1-疊氮基-15-(3-氯-5-甲基-10,11-二氫-5H-5,10-環亞胺基二苯并[a,d][7]輪烯-12-基)-3,6,9,12-四氧雜十五烷-15-酮)1 H NMR (499 MHz, CDCl3 ) δ 7.37 - 7.29 (m, 2H), 7.21 - 7.14 (m, 2H), 7.13 - 7.03 (m, 3H), 6.93 - 6.84 (m, 1H), 5.43 (s, 1H), 3.85 - 3.72 (m, 2H), 3.70 - 3.52 (m, 16H), 3.40 - 3.33 (m, 2H), 2.89 - 2.70 (m, 2H), 2.37 (s, 3H)Example 10: Synthesis of Ligand 11(1-azido-15-(3-chloro-5-methyl-10,11-dihydro-5H-5,10-cycloiminodibenzo[a,d][7]annulen-12-yl)-3,6,9,12-tetraoxopentadecane-15-one)
根據針對化合物12所闡述之程序，使用3-氯-5-甲基-10,11-二氫-5H-5,10-環亞胺基二苯并[a,d][7]輪烯作為起始材料(如J. Med. Chem.1996,39, 5257-5266中所闡述製備)來製備化合物13，得到呈黃色油狀物之標題化合物。Compound 13 was prepared according to the procedure described for compound 12 using 3-chloro-5-methyl-10,11-dihydro-5H-5,10-cycloiminodibenzo[a,d][7]annulene as starting material (prepared as described inJ. Med. Chem .1996 ,39 , 5257-5266) to give the title compound as a yellow oil.
MS (ESI): m/z=529.2 [M+H]+, 551.2 [M+Na]+MS (ESI): m/z=529.2 [M+H]+ , 551.2 [M+Na]+
1H NMR (400 MHz, DMSO-d6) δ 7.48 - 7.32 (m, 2H), 7.26 - 7.14 (m, 4H), 6.96 (d, J = 8.2 Hz, 1H), 5.65 (d, J = 5.4 Hz, 1H), 3.66 - 3.43 (m, 17H), 3.39 - 3.36 (m, 2H), 2.79 - 2.61 (m, 3H), 2.24 (s, 3H)實例11：配位體12之合成((4aR,5R,10bR)-1-(1-疊氮基-3,6,9,12-四氧雜十五烷-15-醯基)-12-甲基-2,3,4,4a,5,6-六氫-1H-5,10b-丙[1]烯橋-1,7-啡啉-8(7H)-酮)1 H NMR (400 MHz, DMSO-d6 ) δ 7.48 - 7.32 (m, 2H), 7.26 - 7.14 (m, 4H), 6.96 (d, J = 8.2 Hz, 1H), 5.65 (d, J = 5.4 Hz, 1H), 3.66 - 3.43 (m, 17H), 3.39 - 3.36 (m, 2H), 2.79 - 2.61 (m, 3H), 2.24 (s, 3H)Example 11: Synthesis of Ligand 12((4aR,5R,10bR)-1-(1-azido-3,6,9,12-tetraoxopentadecane-15-yl)-12-methyl-2,3,4,4a,5,6-hexahydro-1H-5,10b-prop[1]en-1,7-phenanthroline-8(7H)-one)
將石杉鹼B (486 mg, 1.90 mmol)溶解於DCM (20 mL)中，且添加DIPEA (1 mL)。添加疊氮基-PEG4-酸(694 mg, 2.38 mmol)及HATU (786 mg, 2.07 mmol)，且將溶液攪拌2小時。接著將反應混合物傾倒至飽和碳酸氫鈉溶液(100 mL)中，且用DCM (500 mL)稀釋。分離有機層，經無水硫酸鈉乾燥，過濾，濃縮且利用矽膠RediSepGold管柱(80 g，利用0至80%己烷及綠色溶劑溶析)進行純化，得到呈淺黃色油狀物之標題化合物(466 mg, 48%)。Huperzine B (486 mg, 1.90 mmol) was dissolved in DCM (20 mL) and DIPEA (1 mL) was added. Azide-PEG4-acid (694 mg, 2.38 mmol) and HATU (786 mg, 2.07 mmol) were added and the solution was stirred for 2 hours. The reaction mixture was then poured into saturated sodium bicarbonate solution (100 mL) and diluted with DCM (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated and purified using a silica gel RediSepGold column (80 g, eluted with 0 to 80% hexanes and green solvent) to give the title compound (466 mg, 48%) as a light yellow oil.
MS (ESI): m/z=530.2 [M+H]+, 552.6 [M+Na]+MS (ESI): m/z=530.2 [M+H]+ , 552.6 [M+Na]+
1H NMR (499 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 5.50 (d, J = 5.6 Hz, 1H), 3.86 (t, J = 6.3 Hz, 2H), 3.68 - 3.62 (m, 13H), 3.60 (t, J = 5.1 Hz, 2H), 3.37 - 3.23 (m, 2H), 3.02 (dd, J = 18.1, 5.7 Hz, 1H), 2.90 (t, J = 6.3 Hz, 2H), 2.85 - 2.75 (m, 1H), 2.70 - 2.56 (m, 1H), 2.51 - 2.38 (m, 1H), 2.34 - 2.14 (m, 2H), 1.90 (d, J = 16.9 Hz, 1H), 1.84 - 1.77 (m, 1H), 1.67 - 1.57 (m, 2H), 1.57 - 1.51 (m, 1H), 1.51 (s, 3H)實例12：配位體13之合成((S)-1-((2S,4R)-1-(L-蘇胺醯基)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)吡咯啶-2-羰基)-N-((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)吡咯啶-2-甲醯胺)步驟1：(2S,4R)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-1-(第三丁氧基羰基)吡咯啶-2-甲酸1 H NMR (499 MHz, CDCl3 ) δ 8.07 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 5.50 (d, J = 5.6 Hz, 1H), 3.86 (t, J = 6.3 Hz, 2H), 3.68 - 3.62 (m, 13H), 3.60 (t, J = 5.1 Hz, 2H), 3.37 - 3.23 (m, 2H), 3.02 (dd, J = 18.1, 5.7 Hz, 1H), 2.90 (t, J = 6.3 Hz, 2H), 2.85 - 2.75 (m, 1H), 2.70 - 2.56 (m, 1H), 2.51 - 2.38 (m, 1H), 2.34 - 2.14 (m, 2H), 1.90 (d, J = 16.9 Hz, 1H), 1.84 - 1.77 (m, 1H), 1.67 - 1.57 (m, 2H), 1.57 - 1.51 (m, 1H), 1.51 (s, 3H)Example 12: Synthesis of Ligand 13((S)-1-((2S,4R)-1-(L-threonamidoyl)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)pyrrolidine-2-carbonyl)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)pyrrolidine-2-carboxamide)Step 1 : (2S,4R)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid
在0℃下向含(2S,4R)-4-羥基吡咯啶-1,2-二甲酸1-第三丁酯2-甲酯(2.0 g, 8.2 mmol)之DMF (20 mL)中分多次添加NaH (0.65 g, 16.3 mmol，60%於油中)。將所得混合物在氮氣氣氛下在0℃下攪拌30 min。在0℃下逐滴添加11-疊氮基-1-碘-3,6,9-三氧雜十一烷(2.68 g, 8.15 mmol)，且將所得混合物在室溫下攪拌2小時。藉由添加冰-水淬滅反應，用乙酸乙酯(500 mL)萃取，且分離各層。將有機層濃縮，得到呈黃色油狀物之甲酯(3.4 g，10%純度)。To 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.0 g, 8.2 mmol) in DMF (20 mL) at 0°C was added NaH (0.65 g, 16.3 mmol, 60% in oil) in portions. The resulting mixture was stirred at 0°C for 30 min under nitrogen atmosphere. 11-azido-1-iodo-3,6,9-trioxaundecane (2.68 g, 8.15 mmol) was added dropwise at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding ice-water, extracted with ethyl acetate (500 mL), and the layers were separated. The organic layer was concentrated to give the methyl ester as a yellow oil (3.4 g, 10% purity).
MS(ESI) m/z= 447.3 [M+H]+。MS(ESI) m/z= 447.3 [M+H]+ .
將水層用HCl水溶液(1 N)酸化，用乙酸乙酯(500 mL)萃取，且使有機層經無水硫酸鈉乾燥，過濾並濃縮，得到含有DMF之標題化合物(4.6 g，粗製物)，其不經進一步純化即用於下一步驟中。The aqueous layer was acidified with aqueous HCl (1 N), extracted with ethyl acetate (500 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (4.6 g, crude) containing DMF, which was used in the next step without further purification.
MS (ESI，負模式) m/z= 431.0 [M-H]-。步驟2：(2S,4R)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-2-((S)-2-((苯甲基氧基)羰基)吡咯啶-1-羰基)吡咯啶-1-甲酸第三丁酯MS (ESI, negative mode) m/z = 431.0 [MH]- .Step 2 : (2S,4R)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-2-((benzyloxy)carbonyl)pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester
在室溫下向(2S,4R)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-1-(第三丁氧基羰基)吡咯啶-2-甲酸(4.6 g，來自步驟1之粗製物)及L-脯胺酸苯甲酯鹽酸鹽(1.54 g, 6.38 mmol)於DCM (46 mL)中之攪拌溶液中分多次添加HATU (2.43 g, 6.38 mmol)。在室溫下逐滴添加DIEA (3.30 g, 25.5 mmol)，且將所得混合物在室溫下攪拌隔夜。藉由添加水(10 mL)淬滅反應，且用乙酸乙酯(100 mL)稀釋。將合併的有機層用水及鹽水洗滌，經無水硫酸鈉乾燥，過濾，濃縮且藉由反相急速層析(C18矽膠管柱；移動相，ACN水溶液，在20 min內10%至90%梯度；偵測器，UV 254 nm)進行純化，得到呈褐色油狀物之標題化合物(540 mg，50%純度，26.6%)。To a stirred solution of (2S,4R)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (4.6 g, crude from step 1) and L-proline benzyl hydrochloride (1.54 g, 6.38 mmol) in DCM (46 mL) was added HATU (2.43 g, 6.38 mmol) in portions at room temperature. DIEA (3.30 g, 25.5 mmol) was added dropwise at room temperature and the resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (10 mL) and diluted with ethyl acetate (100 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by reverse phase flash chromatography (C18 silica gel column; mobile phase, aqueous ACN, gradient 10% to 90% in 20 min; detector, UV 254 nm) to give the title compound (540 mg, 50% purity, 26.6%) as a brown oil.
MS (ESI): m/z= 620.5 [M+H]+步驟3：((2S,4R)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-1-(第三丁氧基羰基)吡咯啶-2-羰基)-L-脯胺酸MS (ESI): m/z= 620.5 [M+H]+Step 3 : ((2S,4R)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)-L-proline
在室溫下向(2S,4R)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-2-((S)-2-((苯甲基氧基)羰基)吡咯啶-1-羰基)吡咯啶-1-甲酸第三丁酯(500 mg, 0.807 mmol)於THF (5 mL)中之攪拌溶液中逐滴添加NaOH (1 N, 4.03 mL, 4.03 mmol)。將所得混合物在氮氣氣氛下在室溫下攪拌隔夜，且接著用HCl溶液(1 N)酸化(pH 2)。用乙酸乙酯萃取所得混合物，且將合併的有機層用水洗滌，經無水硫酸鈉乾燥，過濾並濃縮，獲得呈黃色油狀物之標題化合物(500 mg，粗製物)，其不經進一步純化即直接用於下一步驟中。To a stirred solution of tert-butyl (2S,4R)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-2-((benzyloxy)carbonyl)pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate (500 mg, 0.807 mmol) in THF (5 mL) was added NaOH (1 N, 4.03 mL, 4.03 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere and then acidified (pH 2) with HCl solution (1 N). The resulting mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow oil (500 mg, crude), which was used directly in the next step without further purification.
MS(ESI) m/z= 530.4 [M+H]+步驟4：(2S,4R)-2-((S)-2-(((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)胺甲醯基)吡咯啶-1-羰基)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)吡咯啶-1-甲酸第三丁酯MS (ESI) m/z = 530.4 [M+H]+Step 4 : (2S,4R)-2-((S)-2-(((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)aminocarbonyl)pyrrolidine-1-carbonyl)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester
在室溫下向((2S,4R)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)-1-(第三丁氧基羰基)吡咯啶-2-羰基)-L-脯胺酸(500 mg, 0.944 mmol)於DCM (5 mL)中之攪拌溶液中分多次添加(2S,3R)-2-胺基-3-羥基丁醯胺鹽酸鹽(291.91 mg, 1.888 mmol)。在室溫下逐滴添加DIEA (366 mg, 2.83 mmol)，且將混合物在室溫下攪拌2 h。將混合物濃縮，且藉由反相急速層析(C18矽膠管柱；移動相，ACN水溶液，在20 min內10%至90%梯度；偵測器，UV 254 nm)進行純化，得到呈淺黃色油狀物之標題化合物(550 mg, 93%)。To a stirred solution of ((2S,4R)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)-L-proline (500 mg, 0.944 mmol) in DCM (5 mL) was added (2S,3R)-2-amino-3-hydroxybutyramide hydrochloride (291.91 mg, 1.888 mmol) in portions at room temperature. DIEA (366 mg, 2.83 mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse phase flash chromatography (C18 silica gel column; mobile phase, aqueous ACN, gradient 10% to 90% in 20 min; detector, UV 254 nm) to give the title compound (550 mg, 93%) as a light yellow oil.
MS (ESI) m/z= 630.5 [M+H]+步驟5：(S)-N-((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)-1-((2S,4R)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)吡咯啶-2-羰基)吡咯啶-2-甲醯胺MS (ESI) m/z = 630.5 [M+H]+Step 5 : (S)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)-1-((2S,4R)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide
在室溫下向(2S,4R)-2-((S)-2-(((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)胺甲醯基)吡咯啶-1-羰基)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)吡咯啶-1-甲酸第三丁酯(550 mg, 0.873 mmol)於DCM (5 mL)中之溶液中逐滴添加TFA (5 mL, 65 mmol)。將所得混合物在氮氣氣氛下在室溫下攪拌1 h並濃縮，獲得呈黃色油狀物之標題化合物(1.00 g，粗製物)，其不經進一步純化即直接用於下一步驟中。To a solution of tert-butyl (2S,4R)-2-((S)-2-(((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)aminocarbonyl)pyrrolidine-1-carbonyl)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)pyrrolidine-1-carboxylate (550 mg, 0.873 mmol) in DCM (5 mL) was added TFA (5 mL, 65 mmol) dropwise at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 1 h and concentrated to give the title compound (1.00 g, crude) as a yellow oil, which was used directly in the next step without further purification.
MS (ESI) m/z= 530.3 [M+H]+步驟6：((2S,3R)-1-((2S,4R)-2-((S)-2-(((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)胺甲醯基)吡咯啶-1-羰基)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)吡咯啶-1-基)-3-羥基-1-側氧基丁-2-基)胺基甲酸(9H-茀-9-基)甲酯MS (ESI) m/z = 530.3 [M+H]+Step 6 : ((2S,3R)-1-((2S,4R)-2-((S)-2-(((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)aminocarbonyl)pyrrolidine-1-carbonyl)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)pyrrolidin-1-yl)-3-hydroxy-1-oxobutyl-2-yl)carbamic acid (9H-fluoren-9-yl)methyl ester
在室溫下向(S)-N-((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)-1-((2S,4R)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)吡咯啶-2-羰基)吡咯啶-2-甲醯胺(500 mg, 0.944 mmol)於DCM (5 mL)中之攪拌溶液中分多次添加N-{[(9H-茀-9-基甲基)氧基]羰基}-L-蘇胺酸(322 mg, 0.944 mmol)。分多次添加HATU (538 mg, 1.42 mmol)及DIEA (732 mg, 5.67 mmol)，且將所得混合物在室溫下攪拌隔夜。將所得溶液濃縮，且利用C18層析(ACN/H2O)進行純化，得到呈黃色固體之標題化合物(300 mg, 37%)。To a stirred solution of (S)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-((2S,4R)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide (500 mg, 0.944 mmol) in DCM (5 mL) was added N-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-threonine (322 mg, 0.944 mmol) in portions at room temperature. HATU (538 mg, 1.42 mmol) and DIEA (732 mg, 5.67 mmol) were added in portions and the resulting mixture was stirred at room temperature overnight. The resulting solution was concentrated and purified by C18 chromatography (ACN/H2 O) to give the title compound (300 mg, 37%) as a yellow solid.
MS(ESI) m/z= 853.4 [M+H]+步驟7：(S)-1-((2S,4R)-1-(L-蘇胺醯基)-4-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙氧基)吡咯啶-2-羰基)-N-((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)吡咯啶-2-甲醯胺MS (ESI) m/z = 853.4 [M+H]+Step 7 : (S)-1-((2S,4R)-1-(L-thiocyanamidoyl)-4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)pyrrolidine-2-carbonyl)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutyl-2-yl)pyrrolidine-2-carboxamide
在室溫下向((2S,3R)-1-((2S,4R)-2-((S)-2-(((2S,3R)-1-胺基-3-羥基-1-側氧基丁-2-基)胺甲醯基)吡咯啶-1-羰基)-4-(2-(2-(2-(2-疊氮基-乙氧基)乙氧基)乙氧基)乙氧基)吡咯啶-1-基)-3-羥基-1-側氧基丁-2-基)胺基甲酸(9H-茀-9-基)甲酯(260 mg, 0.305 mmol)於DCM (3 mL)中之攪拌溶液中逐滴添加Et2NH (0.8 mL)。將所得混合物在氮氣氣氛下在室溫下攪拌2 h，且接著濃縮並用水萃取。用乙酸乙酯洗滌水層，且將合併的水層凍乾隔夜，接著與ACN共蒸發且進一步凍乾，獲得呈淺黃色固體之標題化合物(150.6 mg, 73.8%)。To a stirred solution of (9H-fluoren-9-yl)methyl ((2S,3R)-1-((2S,4R)-2-((S)-2-(((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)aminocarbonyl)pyrrolidine-1-carbonyl)-4-(2-(2-(2-(2-azido-ethoxy)ethoxy)ethoxy)ethoxy)pyrrolidin-1-yl)-3-hydroxy-1-oxobutan-2-yl)carbamate (260 mg, 0.305 mmol) in DCM (3 mL) was addedEt2NH (0.8 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h and then concentrated and extracted with water. The aqueous layer was washed with ethyl acetate and the combined aqueous layers were lyophilized overnight, then co-evaporated with ACN and further lyophilized to give the title compound as a light yellow solid (150.6 mg, 73.8%).
MS (ESI) m/z= 631.5 [M+H]+MS (ESI) m/z = 631.5 [M+H]+
1H NMR (499 MHz, DMSO-d6) δ 7.42 (d, J = 8.4 Hz, 1H), 7.10 - 7.04 (m, 2H), 4.86 (s, 1H), 4.58 (t, J = 8.0 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.22 - 4.15 (m, 1H), 4.10 - 3.98 (m, 2H), 3.85 - 3.76 (m, 1H), 3.75 - 3.65 (m, 1H), 3.67 - 3.61 (m, 1H), 3.64 - 3.57 (m, 3H), 3.60 - 3.48 (m, 12H), 3.50 - 3.42 (m, 1H), 3.42 - 3.36 (m, 2H), 3.29 - 3.23 (m, 1H), 2.34 - 2.26 (m, 1H), 2.07 - 1.97 (m, 1H), 1.97 - 1.87 (m, 3H), 1.90 (s, 1H), 1.15 - 0.97 (m, 6H)實例13：以下之合成：配位體14(N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-2-(1-((1R,2S)-1-羥基-1-(4-羥基苯基)丙-2-基)六氫吡啶-4-基)乙醯胺及配位體15N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-2-(1-((1R,2R)-1-羥基-1-(4-羥基苯基)丙-2-基)六氫吡啶-4-基)乙醯胺)步驟1：2-(1-(1-(4-((第三丁基二甲基矽基)氧基)苯基)-1-側氧基丙-2-基)六氫吡啶-4-基)乙酸乙酯1 H NMR (499 MHz, DMSO-d6 ) δ 7.42 (d, J = 8.4 Hz, 1H), 7.10 - 7.04 (m, 2H), 4.86 (s, 1H), 4.58 (t, J = 8.0 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.22 - 4.15 (m, 1H), 4.10 - 3.98 (m, 2H), 3.85 - 3.76 (m, 1H), 3.75 - 3.65 (m, 1H), 3.67 - 3.61 (m, 1H), 3.64 - 3.57 (m, 3H), 3.60 - 3.48 (m, 12H), 3.50 - 3.42 (m, 1H), 3.42 - 3.36 (m, 2H), 3.29 - 3.23 (m, 1H), 2.34 - 2.26 (m, 1H), 2.07 - 1.97 (m, 1H), 1.97 - 1.87 (m, 3H), 1.90 (s, 1H), 1.15 - 0.97 (m, 6H)Example 13: Synthesis of Ligand14(N-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(1-((1R,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)hexahydropyridin-4-yl)acetamide andLigand 15N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(1-((1R,2R)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)hexahydropyridin-4-yl)acetamide)Step 1 : Ethyl 2-(1-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-oxopropan-2-yl)hexahydropyridin-4-yl)acetate
在室溫下向2-溴-1-(4-((第三丁基二甲基矽基)氧基)苯基)丙-1-酮(1.2 g, 3.5 mmol，如Bioorg. Med. Chem. Lett.2007, 5558中所闡述製備)於乙醇(20 mL)中之攪拌溶液中分多次添加TEA (0.53 g, 5.24 mmol)及六氫吡啶-4-基乙酸乙酯(0.90 g, 5.2 mmol)。將所得混合物在氮氣下在80℃下加熱3 h，且接著在室溫下用水(5 mL)淬滅。用DCM (200 mL)萃取混合物，且將合併的有機層用鹽水洗滌，經無水硫酸鈉乾燥，過濾，濃縮且藉由矽膠管柱層析，利用PE:EA (2:1, v/v)溶析進行純化，得到呈無色油狀物之標題化合物(1.0 g, 66%)。To a stirred solution of 2-bromo-1-(4-((tert-butyldimethylsilyl)oxy)phenyl)propan-1-one (1.2 g, 3.5 mmol, prepared as described inBioorg. Med. Chem. Lett .2007 , 5558) in ethanol (20 mL) was added TEA (0.53 g, 5.24 mmol) and ethyl hexahydropyridin-4-yl acetate (0.90 g, 5.2 mmol) in portions at room temperature. The resulting mixture was heated at 80 °C under nitrogen for 3 h and then quenched with water (5 mL) at room temperature. The mixture was extracted with DCM (200 mL), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography eluting with PE:EA (2:1, v/v) to give the title compound (1.0 g, 66%) as a colorless oil.
MS(ESI) m/z= 434.2 [M+H]+MS(ESI) m/z= 434.2 [M+H]+
1H NMR (300 MHz, CDCl3) δ 8.02 (d, 2H), 6.85 (d, J = 8.3 Hz, 2H), 4.18 - 4.05 (m, 2H), 4.02 (m, 1H), 2.89 (m, 1H), 2.79 (m, 1H), 2.39 (m, 1H), 2.20 (m, 3H), 1.68 (m, 5H), 1.31 - 1.19 (m, 6H), 0.99 (s, 9H), 0.24 (s, 6H)步驟2：2-(1-(1-(4-((第三丁基二甲基矽基)氧基)苯基)-1-羥基丙-2-基)六氫吡啶-4-基)乙酸乙酯1 H NMR (300 MHz, CDCl3 ) δ 8.02 (d, 2H), 6.85 (d, J = 8.3 Hz, 2H), 4.18 - 4.05 (m, 2H), 4.02 (m, 1H), 2.89 (m, 1H), 2.79 (m, 1H), 2.39 (m, 1H), 2.20 (m, 3H), 1.68 (m, 5H), 1.31 - 1.19 (m, 6H), 0.99 (s, 9H), 0.24 (s, 6H)Step 2 : Ethyl 2-(1-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-hydroxypropan-2-yl)hexahydropyridin-4-yl)acetate
在0℃下向2-(1-(1-(4-((第三丁基二甲基矽基)氧基)苯基)-1-側氧基丙-2-基)六氫吡啶-4-基)乙酸乙酯(900 mg, 2.075 mmol)於甲醇(10 mL)中之溶液中逐批添加NaBH4(157 mg, 4.15 mmol)。將所得混合物在氮氣氣氛下在室溫下攪拌隔夜，且接著藉由添加水淬滅並用乙酸乙酯(200 mL)萃取。將合併的有機層用水及鹽水洗滌，經無水硫酸鈉乾燥，過濾並濃縮，得到呈黃色油狀物之標題化合物(1.0 g，粗製物)，其不經進一步純化即直接使用。To a solution of ethyl 2-(1-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-oxopropan-2-yl)hexahydropyridin-4-yl)acetate (900 mg, 2.075 mmol) in methanol (10 mL) was addedNaBH4 (157 mg, 4.15 mmol) portionwise at 0°C. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere, and then quenched by the addition of water and extracted with ethyl acetate (200 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.0 g, crude) as a yellow oil, which was used directly without further purification.
MS(ESI) m/z=436.3 [M+ H]+步驟3：2-(1-(1-羥基-1-(4-羥基苯基)丙-2-基)六氫吡啶-4-基)乙酸MS (ESI) m/z = 436.3 [M + H]+Step 3 : 2-(1-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)hexahydropyridin-4-yl)acetic acid
在25℃下向2-(1-(1-(4-((第三丁基二甲基矽基)氧基)苯基)-1-羥基丙-2-基)六氫吡啶-4-基)乙酸乙酯(1.0 g, 2.3 mmol)於THF (10 mL)中之攪拌溶液中逐滴添加NaOH水溶液(1 N, 13.8 mL, 13.8 mmol)。將所得混合物在室溫下攪拌隔夜，且接著藉由在室溫下逐滴添加乙酸(0.92 mL, 16 mmol)淬滅。將混合物濃縮，且藉由反相管柱層析(combi-flash C18管柱，ACN/H2O)進行純化，得到呈白色固體之標題化合物之反式/順式混合物(450 mg, 67%)。To a stirred solution of ethyl 2-(1-(1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-hydroxypropan-2-yl)hexahydropyridin-4-yl)acetate (1.0 g, 2.3 mmol) in THF (10 mL) was added aqueous NaOH (1 N, 13.8 mL, 13.8 mmol) dropwise at 25°C. The resulting mixture was stirred at room temperature overnight and then quenched by the dropwise addition of acetic acid (0.92 mL, 16 mmol) at room temperature. The mixture was concentrated and purified by reverse phase column chromatography (combi-flash C18 column, ACN/H2 O) to give a trans/cis mixture of the title compound (450 mg, 67%) as a white solid.
MS(ESI): m/z= 294.2 [M+H]+MS(ESI): m/z= 294.2 [M+H]+
1H NMR (300 MHz, DMSO-d6) δ 7.14 - 7.02 (m, 2H), 6.73 - 6.61 (m, 2H), 4.57 (d, J = 4.8 Hz, 1H，對應於順式異構物), 4.12 (d, J = 9.4 Hz, 1H，對應於反式異構物), 2.80 (t, J = 12.7 Hz, 1H), 2.65 (d, J = 13.5 Hz, 1H), 2.34 (d, J = 11.5 Hz, 0H),2.10 (m, J = 24.1, 6.4 Hz, 2H), 1.70 (d, J = 12.4 Hz, 2H), 1.56 (d, J = 11.5 Hz, 1H), 1.36 - 1.25 (m, 0H),0.88 (d, J = 6.7 Hz, 1H), 0.63 (d, J = 6.6 Hz, 2H) NMR指示順式:反式(5:7)異構物之混合物步驟4：N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-2-(1-((1R,2S)-1-羥基-1-(4-羥基苯基)丙-2-基)六氫吡啶-4-基)乙醯胺(化合物14)及 N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-2-(1-((1R,2R)-1-羥基-1-(4-羥基苯基)丙-2-基)六氫吡啶-4-基)乙醯胺(化合物15)1 H NMR (300 MHz, DMSO-d6 ) δ 7.14 - 7.02 (m, 2H), 6.73 - 6.61 (m, 2H), 4.57 (d, J = 4.8 Hz, 1H, corresponding to the cis isomer), 4.12 (d, J = 9.4 Hz, 1H, corresponding to the trans isomer), 2.80 (t, J = 12.7 Hz, 1H), 2.65 (d, J = 13.5 Hz, 1H), 2.34 (d, J = 11.5 Hz, 0H),2.10 (m, J = 24.1, 6.4 Hz, 2H), 1.70 (d, J = 12.4 Hz, 2H), 1.56 (d, J = 11.5 Hz, 1H), 1.36 - 1.25 (m, 0H), 0.88 (d, J = 6.7 Hz, 1H), 0.63 (d, J = 6.6 Hz, 2H) NMR indicated a mixture of cis:trans (5:7) isomers. Step 4 ：N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(1-((1R,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)hexahydropyridin-4-yl)acetamide (Compound 14) and N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(1-((1R,2R)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)hexahydropyridin-4-yl)acetamide (Compound 15)
向2-(1-(1-羥基-1-(4-羥基苯基)丙-2-基)六氫吡啶-4-基)乙酸(270 mg, 0.920 mmol)於DMF (3 mL)中之溶液中添加HOBt (187 mg, 1.38 mmol)、EDCI (265 mg, 1.38 mmol)及DIEA (1070 mg, 8.283 mmol)，且將混合物在氮氣氣氛下在室溫下攪拌5 min。在室溫下逐滴添加2-[(8-疊氮基-3,6-二氧雜辛-1-基)氧基]乙-1-胺(301 mg, 1.38 mmol)，且將所得混合物在30℃下攪拌36 h。將混合物濃縮，且藉由反相急速層析(C18矽膠管柱；移動相，ACN水溶液，在20 min內10%至90%梯度；偵測器，UV 254 nm)純化且藉由製備型HPLC (管柱：XBridge Prep OBD C18管柱19*150 mm, 5 m；移動相A：水(10 mmol/L NH4HCO3)，移動相B：ACN；流量：25 mL/min mL/min；梯度：等度18-28；波長：254 nm/210 nm nm)進一步純化，得到：To a solution of 2-(1-(1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)hexahydropyridin-4-yl)acetic acid (270 mg, 0.920 mmol) in DMF (3 mL) were added HOBt (187 mg, 1.38 mmol), EDCI (265 mg, 1.38 mmol) and DIEA (1070 mg, 8.283 mmol), and the mixture was stirred at room temperature under nitrogen atmosphere for 5 min. 2-[(8-azido-3,6-dioxooctane-1-yl)oxy]ethan-1-amine (301 mg, 1.38 mmol) was added dropwise at room temperature, and the resulting mixture was stirred at 30° C. for 36 h. The mixture was concentrated and purified by reverse phase flash chromatography (C18 silica gel column; mobile phase, ACN aqueous solution, gradient from 10% to 90% in 20 min; detector, UV 254 nm) and further purified by preparative HPLC (column: XBridge Prep OBD C18 column 19*150 mm, 5 m; mobile phase A: water (10 mmol/L NH4 HCO3 ), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: isocratic 18-28; wavelength: 254 nm/210 nm nm) to obtain:
配位體14：(Rt = 4.9 min, 80.3 mg, 17%，外消旋順式)，呈黃色油狀物。Ligand 14: (Rt = 4.9 min, 80.3 mg, 17%, racemic cis), yellow oil.
MS(ESI): m/z= 494.4 [M+H]+MS(ESI): m/z= 494.4 [M+H]+
1H NMR (499 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.80 (t, J = 5.7 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.68 - 6.59 (m, 2H), 4.79 (d, J = 4.5 Hz, 1H), 4.52 (t, J = 4.7 Hz, 1H), 3.60 (dd, J = 5.6, 4.3 Hz, 2H), 3.57 - 3.47 (m, 8H), 3.41 - 3.35 (m, 4H), 3.16 (q, J = 5.8 Hz, 2H), 2.77 (d, J = 11.0 Hz, 1H), 2.65 (d, J = 11.3 Hz, 1H), 2.53 (t, J = 6.7 Hz, 1H), 2.28 (td, J = 11.5, 2.3 Hz, 1H), 2.12 (td, J = 11.5, 2.3 Hz, 1H), 1.92 (d, J = 7.0 Hz, 2H), 1.40-1.60 (m, 3H), 0.90-1.00 (m, 2H), 0.88 (d, J = 6.7 Hz, 3H)1 H NMR (499 MHz, DMSO-d6 ) δ 9.13 (s, 1H), 7.80 (t, J = 5.7 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.68 - 6.59 (m, 2H), 4.79 (d, J = 4.5 Hz, 1H), 4.52 (t, J = 4.7 Hz, 1H), 3.60 (dd, J = 5.6, 4.3 Hz, 2H), 3.57 - 3.47 (m, 8H), 3.41 - 3.35 (m, 4H), 3.16 (q, J = 5.8 Hz, 2H), 2.77 (d, J = 11.0 Hz, 1H), 2.65 (d, J = 11.3 Hz, 1H), 2.53 (t, J = 6.7 Hz, 1H), 2.28 (td, J = 11.5, 2.3 Hz, 1H), 2.12 (td, J = 11.5, 2.3 Hz, 1H), 1.92 (d, J = 7.0 Hz, 2H), 1.40-1.60 (m, 3H), 0.90-1.00 (m, 2H), 0.88 (d, J = 6.7 Hz, 3H)
配位體15：(Rt =7.3 min, 119.6 mg, 25%，外消旋反式)，呈黃色油狀物。Ligand 15: (Rt =7.3 min, 119.6 mg, 25%, racemic trans), yellow oil.
MS (ESI): m/z= 494.45 [M+H]+MS (ESI): m/z= 494.45 [M+H]+
1H NMR (499 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.86 (t, J = 5.7 Hz, 1H), 7.13 - 7.07 (m, 2H), 6.72 - 6.66 (m, 2H), 4.81 (s, 1H), 4.11 (d, J = 9.4 Hz, 1H), 3.63 - 3.55 (m, 2H), 3.59 - 3.47 (m, 8H), 3.43 - 3.36 (m, 3H), 3.31 (s, 1H), 3.19 (q, J = 5.8 Hz, 2H), 2.76 (d, J = 11.3 Hz, 1H), 2.63 (d, J = 11.5 Hz, 1H), 2.51 - 2.41 (m, 2H), 2.11 - 2.03 (m, 1H), 2.01 (d, J = 6.7 Hz, 2H), 1.69 - 1.61 (m, 3H), 1.32 - 1.21 (m, 1H), 1.18 - 1.07 (m, 1H), 0.63 (d, J = 6.6 Hz, 3H)實例14：配位體16之合成1-疊氮基-15-(3-氯-5-甲基-10,11-二氫-5H-5,10-環亞胺基二苯并[a,d][7]-輪烯-12-基)-3,6,9,12-四氧雜十五烷-15-酮1 H NMR (499 MHz, DMSO-d6 ) δ 9.27 (s, 1H), 7.86 (t, J = 5.7 Hz, 1H), 7.13 - 7.07 (m, 2H), 6.72 - 6.66 (m, 2H), 4.81 (s, 1H), 4.11 (d, J = 9.4 Hz, 1H), 3.63 - 3.55 (m, 2H), 3.59 - 3.47 (m, 8H), 3.43 - 3.36 (m, 3H), 3.31 (s, 1H), 3.19 (q, J = 5.8 Hz, 2H), 2.76 (d, J = 11.3 Hz, 1H), 2.63 (d, J = 11.5 Hz, 1H), 2.51 - 2.41 (m, 2H), 2.11 - 2.03 (m, 1H), 2.01 (d, J = 6.7 Hz, 2H), 1.69 - 1.61 (m, 3H), 1.32 - 1.21 (m, 1H), 1.18 - 1.07 (m, 1H), 0.63 (d, J = 6.6 Hz, 3H)Example 14: Synthesis of Ligand 161-azido-15-(3-chloro-5-methyl-10,11-dihydro-5H-5,10-cycloiminodibenzo[a,d][7]-annulen-12-yl)-3,6,9,12-tetraoxopentadec-15-one
將DIPEA (1.0 mL, 5.74 mmol)添加至3-氯-5-甲基-10,11-二氫-5H-5,10-環亞胺基二苯并[a,d][7]輪烯(如J. Med. Chem.1990,33, 789-808中所闡述製備，90 mg, 0.35 mmol)於DCM (2 mL)中之懸浮液中。接著一次性添加HATU (201 mg, 0.53 mmol)及N3PEG4COOH (0.9 g, 3.09 mmol)，且將混合物攪拌1 h。將混合物傾倒至飽和NaHCO3水溶液(20 mL)中，且用DCM (50 mL)稀釋。分離有機層，經Na2SO4乾燥，過濾，濃縮且藉由管柱層析(矽膠管柱25 g，利用於EtOAc中之30% EtOH溶析，於己烷中之0至80%梯度)進行純化，得到呈淺黃色油狀物之標題化合物(90 mg, 49%)。DIPEA (1.0 mL, 5.74 mmol) was added to a suspension of 3-chloro-5-methyl-10,11-dihydro-5H-5,10-cycloiminodibenzo[a,d][7]annulene (prepared as described inJ. Med. Chem .1990 ,33 , 789-808, 90 mg, 0.35 mmol) in DCM (2 mL). HATU (201 mg, 0.53 mmol) andN3PEG4COOH (0.9 g, 3.09 mmol) were then added in one portion and the mixture was stirred for 1 h. The mixture was poured into saturatedaqueousNaHCO3 solution (20 mL) and diluted with DCM (50 mL). The organic layer was separated, dried overNa2SO4, filtered, concentrated and purified by column chromatography (silica gel column 25 g, eluting with 30% EtOH in EtOAc, gradient 0 to 80% in hexanes) to give the title compound as a light yellow oil (90 mg, 49%).
MS (ESI) m/z = 529.4 [M+H]+, 551.4 [M+Na]+MS (ESI) m/z = 529.4 [M+H]+ , 551.4 [M+Na]+
1H NMR (499 MHz, CDCl3) δ 7.36 - 7.28 (m, 2H), 7.24 - 7.16 (m, 2H), 7.11 - 6.99 (m, 2H), 6.83 (d,J= 8.1 Hz, 1H), 5.43 (s, 1H), 3.79 (dt,J= 9.5, 6.9 Hz, 2H), 3.71 - 3.46 (m, 15H), 3.37 (t,J= 5.0 Hz, 2H), 2.90 - 2.62 (m, 3H), 2.35 (s, 3H)實例15：配位體17之合成(5S,10R)-12-(12-疊氮基十二烷基)-5-甲基-10,11-二氫-5H-5,10-環亞胺基二苯并-[a,d][7]輪烯1 H NMR (499 MHz, CDCl3 ) δ 7.36 - 7.28 (m, 2H), 7.24 - 7.16 (m, 2H), 7.11 - 6.99 (m, 2H), 6.83 (d,J = 8.1 Hz, 1H), 5.43 (s, 1H), 3.79 (dt,J = 9.5, 6.9 Hz, 2H), 3.71 - 3.46 (m, 15H), 3.37 (t,J = 5.0 Hz, 2H), 2.90 - 2.62 (m, 3H), 2.35 (s, 3H)Example 15: Synthesis of Ligand 17(5S,10R)-12-(12-azidodecyl)-5-methyl-10,11-dihydro-5H-5,10-cycloiminodibenzo-[a,d][7]annulene
將K2CO3(1.3 g, 9.4 mmol)添加至含(+)-MK801馬來酸鹽(0.51 g, 1.5 mmol)及1-疊氮基-12-溴十二烷(0.6 g, 1.37 mmol)之DMF (5 mL)中，將混合物加熱至80℃。添加第二份1-疊氮基-12-溴十二烷(0.3g, 0.69 mmol)，且將混合物加熱至90℃持續5小時。冷卻後，用乙酸乙酯(300 mL)萃取混合物，用氯化鋰溶液(水溶液，10%)及鹽水洗滌，經Na2SO4乾燥，過濾，濃縮且經由急速管柱層析進行純化，得到呈黃色油狀物之標題化合物(340 mg, 53%)。K2CO3 (1.3 g, 9.4 mmol) was added to (+)-MK801 maleate (0.51 g, 1.5 mmol) and 1-azido-12-bromododecane (0.6 g, 1.37 mmol) in DMF (5 mL), andthe mixture was heated to 80°C. A second portion of 1-azido-12-bromododecane (0.3 g, 0.69 mmol) was added, and the mixture was heated to 90°C for 5 hours. After cooling, the mixture was extracted with ethyl acetate (300 mL), washed with lithium chloride solution (aqueous, 10%) and brine, dried overNa2SO4 , filtered, concentrated and purified by flash column chromatography to give the title compound (340 mg, 53%) as a yellow oil.
MS (ESI): m/z = 431.4 [M+H]+MS (ESI): m/z = 431.4 [M+H]+
1H NMR (499 MHz, CDCl3) δ 7.31 - 7.28 (m, 1H), 7.24 - 7.20 (m, 1H), 7.13 - 7.01 (m, 5H), 6.93 - 6.87 (m, 1H), 4.56 (d, J = 5.2 Hz, 1H), 3.37 - 3.19 (m, 3H), 2.63 - 2.52 (m, 1H), 2.50-2.45 (m, 1H), 2.40 - 2.29 (m, 1H), 1.86 (s, 3H), 1.73 - 1.54 (m, 4H), 1.41 - 1.18 (m, 16H)實例16：配位體18之合成(S)-N-(((1R,3S,5S,7S)-金剛烷-2-基)甲基)-2-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)-乙氧基)丙醯胺基)-3-甲氧基丙醯胺1 H NMR (499 MHz, CDCl3 ) δ 7.31 - 7.28 (m, 1H), 7.24 - 7.20 (m, 1H), 7.13 - 7.01 (m, 5H), 6.93 - 6.87 (m, 1H), 4.56 (d, J = 5.2 Hz, 1H), 3.37 - 3.19 (m, 3H), 2.63 - 2.52 (m, 1H), 2.50-2.45 (m, 1H), 2.40 - 2.29 (m, 1H), 1.86 (s, 3H), 1.73 - 1.54 (m, 4H), 1.41 - 1.18 (m, 16H)Example 16: Synthesis of Ligand 18(S)-N-(((1R,3S,5S,7S)-adamantan-2-yl)methyl)-2-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionamido)-3-methoxypropionamide
在室溫下向 (2S)-2-[(1-疊氮基-12-側氧基-3,6,9-三氧雜十二-12-基)胺基]-3-甲氧基丙酸(200 mg, 0.574 mmol)於DMF (3 mL)中之攪拌溶液中逐批添加金剛烷-2-基甲胺(95 mg, 0.57 mmol)、HOBt (116 mg, 0.861 mmol)及EDCI (165 mg, 0.861 mmol)。逐滴添加DIEA (371 mg, 2.87 mmol)，且將混合物在氮氣氣氛下在室溫下攪拌隔夜。用水淬滅反應，且用乙酸乙酯萃取。將合併的有機萃取物用飽和NaHCO3水溶液及鹽水洗滌，經Na2SO4乾燥，過濾，濃縮且藉由反相急速層析(SunFire C18 OBD Prep管柱19*150 mm, 5 m；移動相A：水(0.1% FA)，移動相B：CH3CN；流量：25 mL/min mL/min；梯度：在8 min內52% B至62% B；波長：254 nm/220 nm nm；RT1 (min) 4.37)進行純化，得到呈黃色油狀物之標題化合物(123 mg, 42.8%)。To a stirred solution of (2S)-2-[(1-azido-12-oxo-3,6,9-trioxadodec-12-yl)amino]-3-methoxypropanoic acid (200 mg, 0.574 mmol) in DMF (3 mL) at room temperature, adamantan-2-ylmethylamine (95 mg, 0.57 mmol), HOBt (116 mg, 0.861 mmol) and EDCI (165 mg, 0.861 mmol) were added portionwise. DIEA (371 mg, 2.87 mmol) was added dropwise, and the mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2 SO4 , filtered, concentrated and purified by reverse phase flash chromatography (SunFire C18 OBD Prep column 19*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: CH3 CN; flow rate: 25 mL/min mL/min; gradient: 52% B to 62% B in 8 min; wavelength: 254 nm/220 nm nm; RT1 (min) 4.37) to give the title compound (123 mg, 42.8%) as a yellow oil.
MS(ESI) m/z= 496.3 [M+H]+MS (ESI) m/z = 496.3 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.01 (d,J= 7.2 Hz, 1H), 6.51 (s, 1H), 4.56 - 4.47 (m, 1H), 3.87 - 3.68 (m, 3H), 3.72 - 3.59 (m, 10H), 3.46 - 3.30 (m, 8H), 2.62 - 2.43 (m, 2H), 1.94 - 1.79 (m, 7H), 1.69 (s, 6H), 1.60-1.50 (m, 2H)實例17：配位體19之合成(S)-2-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯胺基)-N-(4-氟苯甲基)-3-甲氧基丙醯胺步驟1：(2S)-2-胺基-3-甲氧基丙酸酯鹽酸鹽1 H NMR (400 MHz, CDCl3 ) δ 7.01 (d,J = 7.2 Hz, 1H), 6.51 (s, 1H), 4.56 - 4.47 (m, 1H), 3.87 - 3.68 (m, 3H), 3.72 - 3.59 (m, 10H), 3.46 - 3.30 (m, 8H), 2.62 - 2.43 (m, 2H), 1.94 - 1.79 (m, 7H), 1.69 (s, 6H), 1.60-1.50 (m, 2H)Example 17: Synthesis of Ligand 19(S)-2-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionamido)-N-(4-fluorobenzyl)-3-methoxypropionamideStep 1 : (2S)-2-amino-3-methoxypropanoate hydrochloride
在0℃下向(2S)-2-胺基-3-甲氧基丙酸鹽酸鹽(5.0 g, 32 mmol)於甲醇(50 mL)中之攪拌溶液中逐滴添加亞硫醯氯(7.65 g, 64.3 mmol)。將所得混合物在氮氣氣氛下在60℃下攪拌2小時。使混合物冷卻至室溫且接著濃縮，得到呈灰白色固體之標題化合物(6.0 g, 100%)，其不經進一步純化即直接使用。To a stirred solution of (2S)-2-amino-3-methoxypropanoic acid hydrochloride (5.0 g, 32 mmol) in methanol (50 mL) was added thionyl chloride (7.65 g, 64.3 mmol) dropwise at 0°C. The resulting mixture was stirred at 60°C under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature and then concentrated to give the title compound (6.0 g, 100%) as an off-white solid, which was used directly without further purification.
MS(ESI) m/z= 134.1 [M+H]+MS(ESI) m/z= 134.1 [M+H]+
1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 3H), 4.70 (s, 2H), 4.27 (s, 1H), 3.81 (d, J = 3.5 Hz, 2H), 3.75(s, 3H), 3.29 (s, 3H)步驟2：(2S)-2-[(1-疊氮基-12-側氧基-3,6,9-三氧雜十二-12-基)胺基]-3-甲氧基丙酸酯1 H NMR (300 MHz, DMSO-d6 ) δ 8.83 (s, 3H), 4.70 (s, 2H), 4.27 (s, 1H), 3.81 (d, J = 3.5 Hz, 2H), 3.75 (s, 3H), 3.29 (s, 3H)Step 2 : (2S)-2-[(1-azido-12-oxo-3,6,9-trioxadodec-12-yl)amino]-3-methoxypropanoate
在室溫下向(2S)-2-胺基-3-甲氧基丙酸甲酯鹽酸鹽(1.17 g, 6.88 mmol)於DMF (17 mL)中之攪拌溶液中逐批添加3-[(8-疊氮基-3,6-二氧雜辛-1-基)氧基]丙酸(1.70 g, 6.88 mmol)、HOBt (1.39 g, 10.3 mmol)及EDCI (1.98 g, 10.3 mmol)。接著逐滴添加DIEA (2.67 g, 20.627 mmol)，且將混合物在氮氣氣氛下攪拌隔夜。藉由添加水淬滅反應，且接著用乙酸乙酯萃取。將合併的有機萃取物用水、飽和NaHCO3溶液及鹽水洗滌，經Na2SO4乾燥，過濾並濃縮，得到呈黃色油狀物之標題化合物(1.6 g, 64%)，其不經進一步純化即直接用於下一步驟中。To a stirred solution of (2S)-2-amino-3-methoxypropanoic acid methyl ester hydrochloride (1.17 g, 6.88 mmol) in DMF (17 mL) were added 3-[(8-azido-3,6-dioxooct-1-yl)oxy]propanoic acid (1.70 g, 6.88 mmol), HOBt (1.39 g, 10.3 mmol) and EDCI (1.98 g, 10.3 mmol) portionwise at room temperature. DIEA (2.67 g, 20.627 mmol) was then added dropwise, and the mixture was stirred overnight under nitrogen atmosphere. The reaction was quenched by adding water, and then extracted with ethyl acetate. The combined organic extracts were washed with water, saturated NaHCO3 solution and brine, dried over Na2 SO4 , filtered and concentrated to give the title compound as a yellow oil (1.6 g, 64%) which was used directly in the next step without further purification.
MS(ESI) m/z= 349.2 [M+H]+MS (ESI) m/z = 349.2 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.04 (d,J= 8.2 Hz, 1H), 4.78 - 4.70 (m, 1H), 3.86 - 3.73 (m, 3H), 3.76 (s, 3H), 3.77 - 3.61 (m, 11H), 3.64 - 3.57 (m, 1H), 3.39 (t,J= 5.1 Hz, 2H), 3.34 (s, 3H), 2.66 - 2.50 (m, 2H)步驟3：N-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯基)-O-甲基-L-絲胺酸1 H NMR (400 MHz, CDCl3 ) δ 7.04 (d,J = 8.2 Hz, 1H), 4.78 - 4.70 (m, 1H), 3.86 - 3.73 (m, 3H), 3.76 (s, 3H), 3.77 - 3.61 (m, 11H), 3.64 - 3.57 (m, 1H), 3.39 (t,J = 5.1 Hz, 2H), 3.34 (s, 3H), 2.66 - 2.50 (m, 2H)Step 3 : N-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propanoyl)-O-methyl-L-serine
在室溫下向(2S)-2-[(1-疊氮基-12-側氧基-3,6,9-三氧雜十二-12-基)胺基]-3-甲氧基丙酸甲酯(1.6 g, 4.4 mmol)於THF (16 mL)中之攪拌溶液中逐滴添加氫氧化鈉溶液(17.7 mL, 17.7 mmol, 1 mol/L)，且將所得混合物攪拌2小時。接著將混合物用Dowex樹脂(Beijing innochem science & Technology Co. Ltd)酸化至pH 3，用乙腈洗滌，過濾且將濾液濃縮，得到呈黃色油狀物之標題化合物(1.2 g, 78%)，其不經進一步純化即直接用於下一步驟中。To a stirred solution of (2S)-2-[(1-azido-12-oxo-3,6,9-trioxadodec-12-yl)amino]-3-methoxypropionic acid methyl ester (1.6 g, 4.4 mmol) in THF (16 mL) was added dropwise a sodium hydroxide solution (17.7 mL, 17.7 mmol, 1 mol/L) at room temperature, and the resulting mixture was stirred for 2 hours. The mixture was then acidified to pH 3 with Dowex resin (Beijing innochem science & Technology Co. Ltd), washed with acetonitrile, filtered, and the filtrate was concentrated to give the title compound (1.2 g, 78%) as a yellow oil, which was used directly in the next step without further purification.
MS(ESI) m/z= 349.2 [M+H]+MS (ESI) m/z = 349.2 [M+H]+
1H NMR (300 MHz, CDCl3) δ 7.23 (d,J= 7.6 Hz, 1H), 5.37 (s, 3H), 4.76 - 4.65 (m, 1H), 3.91 - 3.81 (m, 1H), 3.82 - 3.70 (m, 3H), 3.70 - 3.55 (m, 13H), 3.44 - 3.39 (m, 2H), 3.38 (s, 3H), 2.69 - 2.40 (m, 2H)步驟4：(S)-2-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯胺基)-N-(4-氟苯甲基)-3-甲氧基丙醯胺1 H NMR (300 MHz, CDCl3 ) δ 7.23 (d,J = 7.6 Hz, 1H), 5.37 (s, 3H), 4.76 - 4.65 (m, 1H), 3.91 - 3.81 (m, 1H), 3.82 - 3.70 (m, 3H), 3.70 - 3.55 (m, 13H), 3.44 - 3.39 (m, 2H), 3.38 (s, 3H), 2.69 - 2.40 (m, 2H)Step 4 : (S)-2-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionamido)-N-(4-fluorobenzyl)-3-methoxypropionamide
在室溫下向N-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯基)-O-甲基-L-絲胺酸(200 mg, 0.574 mmol)於DMF (3 mL)中之攪拌溶液中逐批添加(4-氟苯基)甲胺(71 mg, 0.57 mmol)、HOBt (116 mg, 0.861 mmol)及EDCI (165 mg, 0.861 mmol)。接著逐滴添加DIEA (371 mg, 2.87 mmol)，且將混合物在氮氣氣氛下攪拌3小時。用水淬滅反應，且用乙酸乙酯萃取。將合併的有機萃取物用飽和NaHCO3溶液及鹽水洗滌，經Na2SO乾燥，過濾，濃縮且藉由反相急速層析(SunFire C18 OBD Prep管柱19*150 mm, 5 m；移動相A：水(0.1% FA)，移動相B：CH3CN；流量：25 mL/min mL/min；梯度：在8 min內33% B至43% B；波長：254 nm/220 nm nm；Rt (min)：5.18)進行純化，得到呈白色固體之標題化合物(99.5 mg, 38%)。To a stirred solution of N-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionyl)-O-methyl-L-serine (200 mg, 0.574 mmol) in DMF (3 mL) were added (4-fluorophenyl)methanamine (71 mg, 0.57 mmol), HOBt (116 mg, 0.861 mmol) and EDCI (165 mg, 0.861 mmol) portionwise at room temperature. DIEA (371 mg, 2.87 mmol) was then added dropwise, and the mixture was stirred under nitrogen atmosphere for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO3 solution and brine, dried over Na2 SO , filtered, concentrated and purified by reverse phase flash chromatography (SunFire C18 OBD Prep column 19*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: CH 3 CN; flow rate: 25 mL/min mL/min; gradient: 33% B to 43% B in 8 min; wavelength: 254 nm/220 nm nm; Rt (min): 5.18) to give the title compound (99.5 mg, 38%) as a white solid.
MS(ESI) m/z= 456.1 [M+H]+MS (ESI) m/z = 456.1 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.27 - 7.18 (m, 2H), 7.05 - 6.95 (m, 3H), 4.64 - 4.56 (m, 1H), 4.52 - 4.43 (m, 1H), 4.43 - 4.35 (m, 1H), 3.96 - 3.88 (m, 1H), 3.82 - 3.72 (m, 2H), 3.71 - 3.53 (m, 6H), 3.57 - 3.43 (m, 5H), 3.38 (s, 5H), 2.61 - 2.38 (m, 2H)實例18：配位體20之合成(S)-2-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯胺基)-3-甲氧基-N-(4-甲基苯甲基)丙醯胺1 H NMR (400 MHz, CDCl3 ) δ 7.27 - 7.18 (m, 2H), 7.05 - 6.95 (m, 3H), 4.64 - 4.56 (m, 1H), 4.52 - 4.43 (m, 1H), 4.43 - 4.35 (m, 1H), 3.96 - 3.88 (m, 1H), 3.82 - 3.72 (m, 2H), 3.71 - 3.53 (m, 6H), 3.57 - 3.43 (m, 5H), 3.38 (s, 5H), 2.61 - 2.38 (m, 2H)Example 18: Synthesis of Ligand 20(S)-2-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionamido)-3-methoxy-N-(4-methylbenzyl)propionamide
根據與針對(S)-2-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯胺基)-N-(4-氟苯甲基)-3-甲氧基丙醯胺所闡述類似之程序，使用對甲苯基甲胺代替(4-氟苯基)甲胺來製備(S)-2-(3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)丙醯胺基)-3-甲氧基-N-(4-甲基苯甲基)丙烯醯胺，得到呈白色固體之標題化合物，95%純。(S)-2-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionamido)-3-methoxy-N-(4-methylbenzyl)acrylamide was prepared according to a procedure similar to that described for (S)-2-(3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propionamido)-N-(4-fluorobenzyl)-3-methoxypropionamido)-N-(4-fluorobenzyl)-3-methoxypropionamido using p-tolylmethanamine instead of (4-fluorophenyl)methanamine to give the title compound as a white solid in 95% purity.
MS (ESI) m/z = 452.10 [M+H]+, 474.10 [M+Na]+實例19：配位體21之合成N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-1-(2-氯苯基)吡咯啶-2-甲醯胺步驟1：(2-氯苯基)脯胺酸MS (ESI) m/z = 452.10 [M+H]+ , 474.10 [M+Na]+Example 19: Synthesis of Ligand 21N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-1-(2-chlorophenyl)pyrrolidine-2-carboxamideStep 1 : (2-Chlorophenyl)proline
在室溫下向1-氯-2-碘苯(1.0 g, 4.194 mmol)於異丙醇(10 mL)中之攪拌溶液中添加DL-脯胺酸(0.58 g, 5.033 mmol)、碘化銅(I) (0.16 g, 0.839 mmol)、磷酸鉀(1.78 g, 8.388 mmol)及乙二醇(0.468 mL, 8.388 mmol)。將所得混合物在氮氣氣氛下在85℃下攪拌20小時。用水淬滅反應，用HCl (6 M)將pH調整至3，用乙酸乙酯萃取，用鹽水洗滌，經硫酸鈉乾燥，過濾，濃縮，且藉由矽膠層析(MeOH/DCM)進行純化，得到呈黃色油狀物之標題化合物(200 mg, 21%)。To a stirred solution of 1-chloro-2-iodobenzene (1.0 g, 4.194 mmol) in isopropanol (10 mL) was added DL-proline (0.58 g, 5.033 mmol), copper (I) iodide (0.16 g, 0.839 mmol), potassium phosphate (1.78 g, 8.388 mmol) and ethylene glycol (0.468 mL, 8.388 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 20 hours under nitrogen atmosphere. The reaction was quenched with water, the pH was adjusted to 3 with HCl (6 M), extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (MeOH/DCM) to give the title compound as a yellow oil (200 mg, 21%).
MS(ESI) m/z=226.1, [M+H]+步驟2：N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-1-(2-氯苯基)吡咯啶-2-甲醯胺MS (ESI) m/z = 226.1, [M+H]+Step 2 : N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-1-(2-chlorophenyl)pyrrolidine-2-carboxamide
在室溫下向(2-氯苯基)脯胺酸(0.22 g, 0.975 mmol)於N,N-二甲基甲醯胺(2.2 mL)中之攪拌溶液中添加HOBT (0.20 g, 1.462 mmol)、EDCI (0.28 g, 1.462 mmol)、2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙-1-胺(0.21 g, 0.975 mmol)及DIEA (0.50 g, 3.900 mmol)。將所得混合物在氮氣氣氛下在室溫下攪拌2小時。用水淬滅反應，用乙酸乙酯萃取，用鹽水洗滌，經硫酸鈉乾燥，過濾，濃縮，且藉由製備型HPLC進行純化，得到呈黃色油狀物之標題化合物(234.2 mg, 54%)。To a stirred solution of (2-chlorophenyl)proline (0.22 g, 0.975 mmol) in N,N-dimethylformamide (2.2 mL) was added HOBT (0.20 g, 1.462 mmol), EDCI (0.28 g, 1.462 mmol), 2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethan-1-amine (0.21 g, 0.975 mmol) and DIEA (0.50 g, 3.900 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by preparative HPLC to give the title compound as a yellow oil (234.2 mg, 54%).
MS(ESI) m/z=426.3 [M+H]+MS (ESI) m/z = 426.3 [M + H]+
1H NMR (300 MHz，氯仿-d) δ 7.40 - 7.27 (m, 2H), 7.24 - 7.12 (m, 1H), 7.12 - 7.02 (m, 1H), 7.01 - 6.90 (m, 1H), 4.32 - 4.21 (m, 1H), 4.01 - 3.88 (m, 1H), 3.71 - 3.59 (m, 6H), 3.59 - 3.52 (m, 2H), 3.53 - 3.44 (m, 2H), 3.44 - 3.34 (m, 4H), 3.35 - 3.25 (m, 2H), 3.06 - 2.92 (m, 1H), 2.51 - 2.34 (m, 1H), 2.21 - 1.62 (m, 4H)實例20：配位體22之合成3-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)-1-(2-(2-氯苯基)吡咯啶-1-基)丙-1-酮1 H NMR (300 MHz, chloroform-d) δ 7.40 - 7.27 (m, 2H), 7.24 - 7.12 (m, 1H), 7.12 - 7.02 (m, 1H), 7.01 - 6.90 (m, 1H), 4.32 - 4.21 (m, 1H), 4.01 - 3.88 (m, 1H), 3.71 - 3.59 (m, 6H), 3.59 - 3.52 (m, 2H), 3.53 - 3.44 (m, 2H), 3.44 - 3.34 (m, 4H), 3.35 - 3.25 (m, 2H), 3.06 - 2.92 (m, 1H), 2.51 - 2.34 (m, 1H), 2.21 - 1.62 (m, 4H)Example 20: Synthesis of Ligand 223-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-1-(2-(2-chlorophenyl)pyrrolidin-1-yl)propan-1-one
在室溫下向3-[(8-疊氮基-3,6-二氧雜辛-1-基)氧基]丙酸(300 mg, 1.213 mmol)於DMF (3 mL)中之攪拌溶液中逐批添加2-(2-氯苯基)四氫吡咯(220.42 mg, 1.213 mmol)、HOBt (245.94 mg, 1.820 mmol)及EDCI (348.90 mg, 1.820 mmol)。逐滴添加DIEA (784.13 mg, 6.067 mmol)，且將所得混合物在氮氣氣氛下在室溫下攪拌隔夜。藉由添加飽和NaHCO3水溶液淬滅反應，且接著 用乙酸乙酯萃取。將合併的有機萃取物用飽和NaHCO3溶液及鹽水洗滌，經Na2SO4乾燥，過濾，濃縮且藉由反相急速層析(SunFire C18 OBD Prep管柱19*150 mm, 5 m；移動相A：水(0.1% FA)，移動相B：CH3CN；流量：25 mL/min mL/min；梯度：等度38-61；波長：254 nm/220 nm nm；RT1 (min)：6.83)進行純化，得到呈淺黃色油狀物之標題化合物(0.2491 g, 49%)。To a stirred solution of 3-[(8-azido-3,6-dioxooctane-1-yl)oxy]propanoic acid (300 mg, 1.213 mmol) in DMF (3 mL) was added 2-(2-chlorophenyl)tetrahydropyrrole (220.42 mg, 1.213 mmol), HOBt (245.94 mg, 1.820 mmol) and EDCI (348.90 mg, 1.820 mmol) portionwise at room temperature. DIEA (784.13 mg, 6.067 mmol) was added dropwise, and the resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution, and then extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO3 solution and brine, dried over Na2 SO4 , filtered, concentrated and purified by reverse phase flash chromatography (SunFire C18 OBD Prep column 19*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: CH 3 CN; flow rate: 25 mL/min mL/min; gradient: isocratic 38-61; wavelength: 254 nm/220 nm nm; RT1 (min): 6.83) to give the title compound (0.2491 g, 49%) as a light yellow oil.
MS(ESI) m/z= 411.1 [M+H]+MS (ESI) m/z = 411.1 [M+H]+
1H NMR (300 MHz，氯仿-d) δ 7.43 - 7.29 (m, 1H), 7.28 - 7.14 (m, 2H), 7.11 - 6.99 (m, 1H), 5.35 (m, 1H), 3.83 - 3.63 (m, 13H), 3.55 - 3.53 (m, 1H), 3.39 - 3.34 (m, 2H), 2.72 - 2.36 (m, 2H), 2.18 - 2.10 (m, 1H), 2.01 - 1.72 (m, 3H)實例21：配位體23之合成N-(2-(2-(2-(2-疊氮基乙氧基)乙氧基)乙氧基)乙基)-2-(2-氯苯基)吡咯啶-1-甲醯胺1 H NMR (300 MHz, CHLOROFORM-d) δ 7.43 - 7.29 (m, 1H), 7.28 - 7.14 (m, 2H), 7.11 - 6.99 (m, 1H), 5.35 (m, 1H), 3.83 - 3.63 (m, 13H), 3.55 - 3.53 (m, 1H), 3.39 - 3.34 (m, 2H), 2.72 - 2.36 (m, 2H), 2.18 - 2.10 (m, 1H), 2.01 - 1.72 (m, 3H)Example 21: Synthesis of Ligand 23N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-(2-chlorophenyl)pyrrolidine-1-carboxamide
在0℃下向2-[(8-疊氮基-3,6-二氧雜辛-1-基)氧基]乙-1-胺(300 mg, 1.375 mmol)於DCM (6 mL)中之攪拌溶液中分多次添加碳酸二琥珀醯亞胺酯(422.53 mg, 1.649 mmol)，且將混合物在氮氣氣氛下在室溫下攪拌4 h。接著在0℃下逐滴添加DIEA (44.06 mg, 0.341 mmol)及2-(2-氯苯基)四氫吡咯(247.71 mg, 1.364 mmol)，且將所得混合物在氮氣氣氛下在室溫下攪拌隔夜 。藉由在0℃下添加飽和NaHCO3溶液淬滅反應物，且用乙酸乙酯萃取。將合併的有機萃取物用水及鹽水洗滌，經Na2SO4乾燥，過濾，濃縮且藉由製備型HPLC (SunFire C18 OBD Prep管柱19*150 mm, 5 m；移動相A：水(0.1% FA)，移動相B：ACN；流量：25 mL/min mL/min；梯度：等度37-47；波長：254 nm/220 nm nm；RT1 (min)：8.26)進行純化，得到呈無色油狀物之標題化合物(180 mg, 31%)。To a stirred solution of 2-[(8-azido-3,6-dioxooctane-1-yl)oxy]ethan-1-amine (300 mg, 1.375 mmol) in DCM (6 mL) was added disuccinimidyl carbonate (422.53 mg, 1.649 mmol) in portions at 0°C, and the mixture was stirred at room temperature under nitrogen atmosphere for 4 h. DIEA (44.06 mg, 0.341 mmol) and 2-(2-chlorophenyl)tetrahydropyrrole (247.71 mg, 1.364 mmol) were then added dropwise at 0°C, and the resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was quenched by adding saturated NaHCO3 solution at 0°C, and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, driedoverNa2SO4 , filtered, concentrated and purified by preparative HPLC (SunFire C18 OBD Prep column 19*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL/min mL/min; gradient: isocratic 37-47; wavelength: 254 nm/220 nm nm; RT1 (min): 8.26) to give the title compound (180 mg, 31%) as a colorless oil.
MS(ESI) m/z= 426.1 [M+H]+MS (ESI) m/z = 426.1 [M+H]+
1H NMR (300 MHz，氯仿-d) δ 7.36 - 7.24 (m, 1H), 7.20 - 7.15 (m, 1H), 7.15 - 7.07 (m, 2H), 5.16 - 5.00 (m, 1H), 4.01 (s, 1H), 3.71 - 3.51 (m, 8H), 3.50 - 3.38 (m, 4H), 3.37 - 3.23 (m, 5H), 2.43 - 2.26 (m, 1H), 1.89 - 1.71 (m, 3H) 總之，製備以下NMDA配位體：
屬於本揭示案範圍內之例示性配位體結合之寡核苷酸可根據以下一般程序來合成。Exemplary ligand-conjugated oligonucleotides within the scope of the present disclosure can be synthesized according to the following general procedure.
在一些情況下，一種配位體(下文所闡述之一般程序中之配位體A)與寡核苷酸之5'端結合。In some cases, a ligand (ligand A in the general procedures described below) is bound to the 5' end of the oligonucleotide.
在一些情況下，兩種相同的配位體(配位體A及配位體A)與寡核苷酸之5'端及3'端結合。In some cases, two identical ligands (Ligand A and Ligand A) are bound to the 5' and 3' ends of the oligonucleotide.
在一些情況下，兩種不同的配位體(配位體A及配位體B)與寡核苷酸之5’端及3'端結合。In some cases, two different ligands (Ligand A and Ligand B) are bound to the 5' and 3' ends of the oligonucleotide.
在一些情況下，一種配位體(配位體A)與寡核苷酸之3'端結合。實例22：配位體與有義股之5’端結合步驟1：5'-DBCO官能化之有義股In some cases, one ligand (ligand A) is bound to the 3' end of the oligonucleotide.Example 22: Ligand bound to the 5' end of the sense strandStep 1 : 5'-DBCO functionalized sense strand
將磷酸鈉緩衝液(10% V/V, 1 M, pH 7)及乙腈(20%-50% V/V)添加至5’-胺官能化之有義股之水溶液中。接著添加DBCO-NHS (1.5-3 eq)於DMSO或乙腈中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何沈澱物，且藉由反相HPLC純化水溶液，藉由凍乾乾燥且將乾燥之5'- DBCO官能化之有義股在無RNA酶之水中重構。步驟2：5’-配位體結合之有義股Sodium phosphate buffer (10% V/V, 1 M, pH 7) and acetonitrile (20%-50% V/V) were added to the aqueous solution of the 5'-amine functionalized sense strand. A solution of DBCO-NHS (1.5-3 eq) in DMSO or acetonitrile was then added and the reaction was monitored by LCMS and HPLC. Upon completion, any precipitate was removed by centrifugation and the aqueous solution was purified by reverse phase HPLC, dried by freeze drying and the dried 5'-DBCO functionalized sense strand was reconstituted in RNase-free water.Step 2 : 5'-ligand bound sense strand
將配位體A-N3(2 eq)於DMSO或THF中之溶液添加至5’-DBCO修飾之有義股(1 eq)溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-結合之有義股。實例23：配位體與有義股之5’端結合步驟1：5'-DBCO官能化之有義股A solution of ligand AN3 (2 eq) in DMSO or THF was added to a solution of 5'-DBCO modified sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 times) with a molecular weight cutoff.Example 23: Ligand conjugation to the 5' end of the sense strandStep 1 : 5'-DBCO functionalized sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP) (25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由用磷酸鈉緩衝液(100 mM, pH 7, 3×)截留分子量去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何固體，藉由反相HPLC純化溶液，藉由凍乾乾燥且將乾燥產物在無RNA酶之水中重構。步驟2：5'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 5'-(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 eq) in water (pH 7) was added, and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by using a sodium phosphate buffer (100 mM, pH 7, 3×) molecular weight cutoff. A solution of DBCO-MAL (3 eq) in DMSO was added, and the reaction was monitored by LCMS and HPLC. Upon completion, any solids were removed by centrifugation, the solution was purified by reverse phase HPLC, dried by freeze drying, and the dried product was reconstituted in RNase-free water.Step 2 : 5'-ligand-bound sense strand
向5’-DBCO官能化之有義股(1 eq)溶液中添加配位體A-N3(3 eq)於DMSO或THF中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-結合之有義股。實例24：配位體與有義股之5’端結合步驟1：5'-DBCO官能化之有義股To a solution of the 5'-DBCO functionalized sense strand (1 eq) was added a solution of ligand AN3 (3 eq) in DMSO or THF and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff.Example 24: Ligand conjugation to the 5' end of the sense strandStep 1 : 5'-DBCO functionalized sense strand
使10-(6-側氧基-6-(二苯并[b,f]氮雜環辛-4-炔-1-基)-癸醯胺基-N-乙基)-O-三乙二醇-1-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺(5'-DBCO-TEG亞磷醯胺，購自Glen research, 10-1941-02E)在標準亞磷醯胺偶合條件下與有義股之5'端偶合。步驟2：5’-配位體結合之有義股10-(6-oxo-6-(dibenzo[b,f]azanylcyclooctan-4-yn-1-yl)-decanoylamino-N-ethyl)-O-triethylene glycol-1-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphamide (5'-DBCO-TEG phosphoramide, purchased from Glen research, 10-1941-02E) was coupled to the 5' end of the sense strand under standard phosphoramide coupling conditions.Step 2 : 5'-ligand-bound sense strand
將配位體A-N3(2 eq)於DMSO中之溶液添加至5’-DBCO修飾之有義股(1 eq)溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器截留分子量來純化5’-結合之有義股。實例25：雙-同-3',5'-配位體結合之有義股步驟1：3’,5’-雙-DBCO修飾之有義股A solution of ligand AN3 (2 eq) in DMSO was added to a solution of 5'-DBCO modified sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter with a molecular weight cutoff.Example 25: Bi-homo -3',5'-ligand conjugated sense strandStep 1 : 3',5'-Bis-DBCO modified sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)及乙腈(20%-50% V/V)添加至3’,5’胺官能化之有義股之水溶液中。接著添加DBCO-NHS (3 eq)於DMSO或CH3CN中之溶液，且藉由LCMS及HPLC監測反應。完成後，藉由反相HPLC純化產物，藉由凍乾乾燥，且在無RNA酶之水中重構。步驟2：3’,5’-雙結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) and acetonitrile (20%-50% V/V) were added to the aqueous solution of the 3',5' amine functionalized sense strand. A solution of DBCO-NHS (3 eq) in DMSO or CH3 CN was then added and the reaction was monitored by LCMS and HPLC. Upon completion, the product was purified by reverse phase HPLC, dried by lyophilization, and reconstituted in RNase-free water.Step 2 : 3',5'-double conjugated sense strand
將配位體A-N3(3 eq)於DMSO或CH3CN中之溶液添加至3’,5’-雙-DBCO修飾之有義股(1 eq)溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC純化3’,5’-雙結合之有義股，藉由凍乾乾燥，在無RNA酶之水中重構，且使用Amicon®Ultra-15離心過濾器(3K，5次)去鹽。實例26：雙-同-3',5'-配位體結合之有義股步驟1：3’,5’-雙-DBCO修飾之有義股A solution of ligand AN3 (3 eq) in DMSO or CH3 CN was added to a solution of 3',5'-bis-DBCO modified sense strand (1 eq), and the reaction was monitored by HPLC and LCMS. Upon completion, the 3',5'-bis-conjugated sense strand was purified by reverse phase HPLC, dried by lyophilization, reconstituted in RNase-free water, and desalted using an Amicon® Ultra-15 centrifugal filter (3K, 5 times).Example 26: Bi-homo -3',5'-ligand conjugated sense strandStep 1 : 3',5'-Bis-DBCO modified sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’, 3’-雙(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP) (25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何固體，且藉由反相HPLC純化溶液，藉由凍乾乾燥，且將乾燥之雙-DBCO修飾之有義股在無RNA酶之水中重構。步驟2：3’,5’-雙結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 5', 3'-bis(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP) (25 eq) in water (pH 7) was added, and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added, and the reaction was monitored by LCMS and HPLC. Upon completion, any solids were removed by centrifugation and the solution was purified by reverse phase HPLC, dried by lyophilization, and the dried double-DBCO modified sense strand was reconstituted in RNase-free water.Step 2 : 3',5'-double conjugated sense strand
向5’,3’-雙-DBCO官能化之有義股(1 eq)溶液中添加配位體A-N3(3 eq)於DMSO或THF中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化雙-同-5’-, 3’結合之有義股。實例27：雙-同-3',5'-配位體結合之有義股步驟1：5'-DBCO / 3'-(C6-SS-C6)-mC官能化之有義股To a solution of 5',3'-bis-DBCO functionalized sense strand (1 eq) was added a solution of ligand AN3 (3 eq) in DMSO or THF and the reaction was monitored by HPLC and LCMS. Upon completion, the bis-homo-5'-, 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 times) with a molecular weight cutoff.Example 27: Bis-homo -3',5'-ligand conjugated sense strandStep 1 : 5'-DBCO/3'-(C6-SS-C6)-mC functionalized sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)及乙腈(20% -50% V/V)添加至5’-胺官能化之有義股之水溶液中。接著添加DBCO-NHS (1.5-3 eq)於DMSO或乙腈中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何沈澱物，且藉由反相HPLC純化水溶液。將產物流份合併，藉由凍乾乾燥，且將乾燥之N-DBCO修飾之有義股在無RNA酶之水中重構以用於步驟2。步驟2：5',3'-雙DBCO官能化之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) and acetonitrile (20% -50% V/V) were added to the aqueous solution of the 5'-amine functionalized sense strand. A solution of DBCO-NHS (1.5-3 eq) in DMSO or acetonitrile was then added, and the reaction was monitored by LCMS and HPLC. Upon completion, any precipitate was removed by centrifugation, and the aqueous solution was purified by reverse phase HPLC. The product fractions were combined, dried by freeze drying, and the dried N-DBCO-modified sense strand was reconstituted in RNase-free water for use in step 2.Step 2 : 5',3'-Bis-DBCO-functionalized sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-DBCO / 3’-(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP) (25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何固體，且藉由反相HPLC純化溶液，藉由凍乾乾燥，且將乾燥之雙-DBCO修飾之有義股在無RNA酶之水中重構以用於步驟3。步驟3：雙-同-5',3'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 5'-DBCO/3'-(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 eq) in water (pH 7) was added and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added and the reaction was monitored by LCMS and HPLC. Upon completion, any solids were removed by centrifugation and the solution was purified by reverse phase HPLC, dried by lyophilization, and the dried bis-DBCO modified sense strand was reconstituted in RNase-free water for use in step 3.Step 3 : Bi-homo -5',3'-ligand bound sense strand
向5’-, 3’-雙-DBCO官能化之有義股(1 eq)溶液中添加配位體A-N3(3 eq)於DMSO或THF中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化雙-同-5’-, 3’結合之有義股。藉由HPLC及LCMS確認產物。實例28：雙-同-3',5'-配位體結合之有義股步驟1：5'-(C6-SS-C6)-mC / 3'-DBCO官能化之有義股To a solution of 5'-, 3'-bis-DBCO functionalized sense strand (1 eq) was added a solution of ligand AN3 (3 eq) in DMSO or THF and the reaction was monitored by HPLC and LCMS. Upon completion, the bis-homo-5'-, 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 times) with a molecular weight cutoff. The product was confirmed by HPLC and LCMS.Example 28: Bis-homo -3',5'-ligand conjugated sense strandStep 1 : 5'-(C6-SS-C6)-mC/3'-DBCO functionalized sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)及乙腈(20% -50% V/V)添加至5’-胺官能化之有義股之水溶液中。接著添加DBCO-NHS (1.5-3 eq)於DMSO或乙腈中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何沈澱物，且藉由反相HPLC純化水溶液。將產物流份合併，藉由凍乾乾燥，且將乾燥之N-DBCO修飾之有義股在無RNA酶之水中重構以用於步驟2。步驟2：5',3'-雙DBCO官能化之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) and acetonitrile (20% -50% V/V) were added to the aqueous solution of the 5'-amine functionalized sense strand. A solution of DBCO-NHS (1.5-3 eq) in DMSO or acetonitrile was then added, and the reaction was monitored by LCMS and HPLC. Upon completion, any precipitate was removed by centrifugation, and the aqueous solution was purified by reverse phase HPLC. The product fractions were combined, dried by freeze drying, and the dried N-DBCO-modified sense strand was reconstituted in RNase-free water for use in step 2.Step 2 : 5',3'-Bis-DBCO-functionalized sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-DBCO / 3’-(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP) (25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何固體，且藉由反相HPLC純化溶液，藉由凍乾乾燥，且將乾燥之雙-DBCO修飾之有義股在無RNA酶之水中重構以用於步驟3。步驟3：雙-同-5',3'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 5'-DBCO/3'-(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) (25 eq) in water (pH 7) was added and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added and the reaction was monitored by LCMS and HPLC. Upon completion, any solids were removed by centrifugation and the solution was purified by reverse phase HPLC, dried by lyophilization, and the dried bis-DBCO modified sense strand was reconstituted in RNase-free water for use in step 3.Step 3 : Bi-homo -5',3'-ligand bound sense strand
向5’-, 3’-雙-DBCO官能化之有義股(1 eq)溶液中添加配位體A-N3(3 eq)於DMSO或THF中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化雙-同-5’-, 3’結合之有義股。藉由HPLC及LCMS確認產物。實例29：雙-異-3',5'-配位體結合之有義股步驟1：5’-結合之3’-(C6-SS-C6)-mC官能化之有義股To a solution of 5'-, 3'-bis-DBCO functionalized sense strand (1 eq) was added a solution of ligand AN3 (3 eq) in DMSO or THF and the reaction was monitored by HPLC and LCMS. Upon completion, the bis-homo-5'-, 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff. The product was confirmed by HPLC and LCMS.Example 29: Bis-iso -3',5'-ligand conjugated sense strandStep 1 : 5'-conjugated 3'-(C6-SS-C6)-mC functionalized sense strand
將配位體A-N3(2 eq)於DMSO中之溶液添加至5’-DBCO修飾之有義股(1 eq，關於製備參見上文)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon®Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-結合之有義股。步驟2：5’-結合之3’-DBCO修飾之有義股A solution of ligand AN3 (2 eq) in DMSO was added to an aqueous solution of 5'-DBCO-modified sense strand (1 eq, see above for preparation) and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-conjugated sense strand was purified by reverse phase HPLC or using anAmicon® Ultra-15 centrifugal filter (3K, 5 times) with a molecular weight cutoff.Step 2 : 5'-conjugated 3'-DBCO-modified sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-結合之3’-(C6-SS-C6)-mC官能化之有義股(1 eq)於水中之溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP, 25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC純化水溶液，藉由凍乾乾燥，且將乾燥之5’-結合之3’-DBCO修飾之有義股在磷酸鈉緩衝液(100 mM)中重構以用於步驟3。步驟3：雙-異-3',5'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to a solution of 5'-conjugated 3'-(C6-SS-C6)-mC functionalized sense strand (1 eq) in water. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP, 25 eq) in water (pH 7) was added and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added and the reaction was monitored by HPLC and LCMS. Upon completion, the aqueous solution was purified by reverse phase HPLC, dried by lyophilization, and the dried 5'-conjugated 3'-DBCO modified sense strand was reconstituted in sodium phosphate buffer (100 mM) for use in step 3.Step 3 : Bis-iso -3',5'-ligand conjugated sense strand
將配位體B-N3(2 eq)於DMSO中之溶液添加至5’-結合之3’-DBCO官能化之有義股(1 eq)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon®Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-, 3’-結合之有義股。實例30：雙-異-3',5'-配位體結合之有義股步驟1：5'-(C6-SS-C6)-mC, 3’-結合之有義股A solution of ligand BN3 (2 eq) in DMSO was added to an aqueous solution of 5'-conjugated 3'-DBCO functionalized sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-, 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff.Example 30: Bis-Iso -3',5'-Ligand Conjugated Sense StrandStep 1 : 5'-(C6-SS-C6)-mC, 3'-conjugated sense strand
將配位體A-N3(2 eq)於DMSO中之溶液添加至3'-DBCO修飾之有義股(1 eq，關於製備參見上文)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon®Ultra-15離心過濾器(3K，5次)截留分子量來純化3’-結合之有義股。步驟2：5’-DBCO, 3’-結合之有義股A solution of ligand AN3 (2 eq) in DMSO was added to an aqueous solution of 3'-DBCO-modified sense strand (1 eq, see above for preparation) and the reaction was monitored by HPLC and LCMS. Upon completion, the 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 times) with a molecular weight cutoff.Step 2 : 5'-DBCO, 3'-conjugated sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至5’-結合之3’-(C6-SS-C6)-mC官能化之有義股(1 eq)於水中之溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP, 25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH 7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC純化水溶液，藉由凍乾乾燥，且將乾燥之5’-結合之3’-DBCO修飾之有義股在磷酸鈉緩衝液(100 mM)中重構以用於步驟3。步驟3：雙-異-3',5'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to a solution of 5'-conjugated 3'-(C6-SS-C6)-mC functionalized sense strand (1 eq) in water. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP, 25 eq) in water (pH 7) was added and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH 7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added and the reaction was monitored by HPLC and LCMS. Upon completion, the aqueous solution was purified by reverse phase HPLC, dried by lyophilization, and the dried 5'-conjugated 3'-DBCO modified sense strand was reconstituted in sodium phosphate buffer (100 mM) for use in step 3.Step 3 : Bis-iso -3',5'-ligand conjugated sense strand
將配位體B-N3(2 eq)於DMSO中之溶液添加至5’-結合之3’-DBCO官能化之有義股(1 eq)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon®Ultra-15離心過濾器(3K，5次)截留分子量來純化5’-, 3’-結合之有義股。實例31：配位體與有義股之3’端結合步驟1：3’- DBCO修飾之有義股A solution of ligand BN3 (2 eq) in DMSO was added to an aqueous solution of 5'-conjugated 3'-DBCO functionalized sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 5'-, 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 passes) with a molecular weight cutoff.Example 31: Ligand conjugation to the 3' end of the sense strandStep 1 : 3'-DBCO modified sense strand
將磷酸鈉緩衝液(10% V/V 1 M, pH 7)添加至3’-(C6-SS-C6)-mC官能化之有義股之水溶液中。添加於水(pH 7)中之參(2-羧基乙基)膦鹽酸鹽(TCEP, 25 eq)，且藉由HPLC及LCMS監測反應。完成後，藉由MWCO用磷酸鈉緩衝液(100 mM, pH=7, 3×)去除過量TCEP。添加DBCO-MAL (3 eq)於DMSO中之溶液，且藉由HPLC及LCMS監測反應。完成後，經由離心去除任何固體，且藉由反相HPLC純化溶液，藉由凍乾乾燥，且將乾燥之3’-DBCO修飾之有義股在100 mM磷酸鈉緩衝液中重構以用於步驟2。步驟2：3'-配位體結合之有義股Sodium phosphate buffer (10% V/V 1 M, pH 7) was added to the aqueous solution of the 3'-(C6-SS-C6)-mC functionalized sense strand. Tris(2-carboxyethyl)phosphonic acid hydrochloride (TCEP, 25 eq) in water (pH 7) was added, and the reaction was monitored by HPLC and LCMS. Upon completion, excess TCEP was removed by MWCO with sodium phosphate buffer (100 mM, pH=7, 3×). A solution of DBCO-MAL (3 eq) in DMSO was added, and the reaction was monitored by HPLC and LCMS. Upon completion, any solids were removed by centrifugation and the solution was purified by reverse phase HPLC, dried by lyophilization, and the dried 3'-DBCO modified sense strand was reconstituted in 100 mM sodium phosphate buffer for use in step 2.Step 2 : 3'-ligand bound sense strand
將配位體A-N3(3 eq)於DMSO中之溶液添加至3’-DBCO官能化之有義股(1 eq)之水溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5×)截留分子量來純化3’-結合之有義股。實例32：配位體與有義股之3’端結合步驟1：3'-DBCO官能化之有義股A solution of ligand AN3 (3 eq) in DMSO was added to an aqueous solution of 3'-DBCO functionalized sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5×) with a molecular weight cutoff.Example 32: Ligand conjugation to the 3' end of the sense strandStep 1 : 3'-DBCO functionalization of the sense strand
將磷酸鈉緩衝液(10% V/V, 1 M, pH 7)及乙腈(20%-50% V/V)添加至3’-胺官能化之有義股之水溶液中。接著添加DBCO-NHS (1.5-3 eq)於DMSO或乙腈中之溶液，且藉由LCMS及HPLC監測反應。完成後，經由離心去除任何沈澱物，藉由反相HPLC純化水溶液，藉由凍乾乾燥，且將乾燥之DBCO修飾之有義股在無RNA酶之水中重構。步驟2：3’-配位體結合之有義股Sodium phosphate buffer (10% V/V, 1 M, pH 7) and acetonitrile (20%-50% V/V) were added to the aqueous solution of the 3'-amine functionalized sense strand. A solution of DBCO-NHS (1.5-3 eq) in DMSO or acetonitrile was then added, and the reaction was monitored by LCMS and HPLC. Upon completion, any precipitate was removed by centrifugation, the aqueous solution was purified by reverse phase HPLC, dried by lyophilization, and the dried DBCO-modified sense strand was reconstituted in RNase-free water.Step 2 : 3'-ligand-bound sense strand
將配位體A-N3(2 eq)於DMSO或THF中之溶液添加至3’-DBCO修飾之有義股(1 eq)溶液中，且藉由HPLC及LCMS監測反應。完成後，藉由反相HPLC或利用Amicon® Ultra-15離心過濾器(3K，5次)截留分子量來純化3’-結合之有義股。股製備之一般程序實例33：股合成A solution of ligand AN3 (2 eq) in DMSO or THF was added to a solution of 3'-DBCO modified sense strand (1 eq) and the reaction was monitored by HPLC and LCMS. Upon completion, the 3'-conjugated sense strand was purified by reverse phase HPLC or using an Amicon® Ultra-15 centrifugal filter (3K, 5 times) with a molecular weight cutoff.General Procedure for Strand PreparationExample 33: Strand Synthesis
使用寡核苷酸合成儀Oligopilot100 (Cytiva Life Sciences)在固相上合成股。將固體支持物(CPG, 80-90 μmol/g, 500A，來自LGC-Biosearch Technologies, Petaluma, CA)裝載至150-300 μmol規模。RNA及2'修飾之RNA亞磷醯胺係購自Hongene Biotech (Union City, CA)。The strands were synthesized on a solid phase using an oligonucleotide synthesizer, Oligopilot 100 (Cytiva Life Sciences). The solid support (CPG, 80-90 μmol/g, 500A, from LGC-Biosearch Technologies, Petaluma, CA) was loaded to a 150-300 μmol scale. RNA and 2'-modified RNA phosphoramidites were purchased from Hongene Biotech (Union City, CA).
所使用之2'-O-甲基亞磷醯胺為： 5'-O-(4,4'-二甲氧基三苯甲基)-N6-苯甲醯基-2'-O-甲基-腺苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-N4-乙醯基-2'-O-甲基-胞苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-N2-異丁醯基-2'-O-甲基-鳥苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-2'-O-甲基-尿苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺。The 2'-O-methylphosphoamidoamines used were: 5'-O-(4,4'-dimethoxytrityl)-N6 -benzoyl-2'-O-methyl-adenosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamido 5'-O-(4,4'-dimethoxytrityl)-N4 -acetyl-2'-O-methyl-cytidine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamido 5'-O-(4,4'-dimethoxytrityl)-N2 -isobutyryl-2'-O-methyl-guanosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamidite 5'-O-(4,4'-dimethoxytrityl)-2'-O-methyl-uridine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamidite.
所使用之2'-氟亞磷醯胺為： 5'-O-(4,4'-二甲氧基三苯甲基)-N6-苯甲醯基-2'-氟腺苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-N4-乙醯基-2'-氟胞苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-N2-異丁醯基-2'-氟鳥苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺 5'-O-(4,4'-二甲氧基三苯甲基)-2'-氟尿苷-3'-O-[(2-氰基乙基)-(N,N-二異丙基)]-亞磷醯胺。The 2'-fluorophosphamides used are: 5'-O-(4,4'-dimethoxytrityl)-N6 -benzoyl-2'-fluoroadenosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphamide 5'-O-(4,4'-dimethoxytrityl)-N4 -acetyl-2'-fluorocytidine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphamide 5'-O-(4,4'-dimethoxytrityl)-N2 -isobutyryl-2'-fluoroguanosine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamidite 5'-O-(4,4'-dimethoxytrityl)-2'-fluorouridine-3'-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoamidite.
為產生硫代磷酸酯鍵聯，使用3-((二甲基胺基-亞甲基)胺基)-3H-1,2,4-二噻唑-3-硫酮(DDTT. 來自Chemgenes, Wilmington, MA之0.1 M溶液)持續4-6分鐘。為產生磷酸二酯鍵聯，使用I2O於吡啶/水中之溶液(0.05 M，來自Sigma Aldrich, St Louis, MO)。在氧化/硫化後，使用含20% n-甲基咪唑之乙腈與含40%乙酸酐/60%二甲基吡啶之乙腈的混合物(Sigma Aldrich, St Louis, MO)使連接至CPG之任何未反應鏈乙醯化。To generate phosphorothioate linkages, 3-((dimethylamino-methylene)amino)-3H-1,2,4-dithiazole-3-thione (DDTT. 0.1 M solution from Chemgenes, Wilmington, MA) was used for 4-6 minutes. To generate phosphodiester linkages,I2O in pyridine/water (0.05 M from Sigma Aldrich, St Louis, MO) was used. After oxidation/sulfidation, any unreacted chain attached to CPG was acetylated using a mixture of 20% n-methylimidazole in acetonitrile and 40% acetic anhydride/60% lutidine in acetonitrile (Sigma Aldrich, St Louis, MO).
將亞磷醯胺溶解於無水乙腈(0.2 M)中，且添加分子篩(4A)並放置隔夜(Sigma Aldrich, St. Louis, MO)。對於寡核苷酸鏈，使用5-(乙基硫基)-1H-四唑(ETT，0.6 M於乙腈中，來自Sigma Aldrich)作為活化劑溶液。偶合時間為6分鐘，每步3.0當量進行。偶合前，使用二氯乙酸於二氯甲烷中之溶液(3% Deblock, Sigma Aldrich)處理支持物結合之寡核苷酸，且用無水乙腈洗滌。實例34：支持物結合之寡聚物之裂解及去保護The phosphoramidite was dissolved in anhydrous acetonitrile (0.2 M) and molecular sieves (4A) were added and left overnight (Sigma Aldrich, St. Louis, MO). For the oligonucleotide chain, 5-(ethylthio)-1H-tetrazole (ETT, 0.6 M in acetonitrile, from Sigma Aldrich) was used as the activator solution. The coupling time was 6 minutes and 3.0 equivalents were performed per step. Prior to coupling, the support-bound oligonucleotide was treated with a solution of dichloroacetic acid in dichloromethane (3% Deblock, Sigma Aldrich) and washed with anhydrous acetonitrile.Example 34: Cleavage and deprotection of support-bound oligomers
固相合成完成後，將支持物用AMA溶液在65℃下處理20分鐘，該AMA溶液為1:1體積之NH4OH:CH3NH2溶液(Fisher Scientific, Spectrum Chemicals)。接著使溶液蒸發。純化前，在分析型HPLC及LCMS上實施過程中分析，以測定粗純度、鑑別目標質量並監測去保護之完成。實例35：LCMS方法After solid phase synthesis, the support was treated with AMA solution at 65°C for 20 minutes. The AMA solution was a 1:1 volume ratio of NH4 OH:CH3 NH2 (Fisher Scientific, Spectrum Chemicals). The solution was then evaporated. Prior to purification, in-process analysis was performed on analytical HPLC and LCMS to determine crude purity, identify target mass, and monitor the completion of deprotection.Example 35: LCMS Method
使用Waters XBridge寡核苷酸BEH C18管柱，130 Å, 2.5 μm, 2.1 mm × 50 mm (P/N 186003952)管柱與緩衝溶液：400 mM HFIP + 15 mM TEA (緩衝液A)及100%甲醇(緩衝液B)，梯度為15%-40%或50%-75%緩衝液B，15 CV，70℃，流量為1 mL/分鐘。實例36：藉由切向流過濾(TFF)濃縮A Waters XBridge Oligonucleotide BEH C18 column, 130 Å, 2.5 μm, 2.1 mm × 50 mm (P/N 186003952) was used with buffers: 400 mM HFIP + 15 mM TEA (buffer A) and 100% methanol (buffer B), with a gradient of 15%-40% or 50%-75% buffer B, 15 CV, 70°C, and a flow rate of 1 mL/min.Example 36: Concentration by Tangential Flow Filtration (TFF)
使用Pall Minimate EVO系統(產品ID：OAPMPUNV)，使用帶有3k Omega膜之Pall Minimate TFF卡匣囊式容器濃縮粗製寡聚物。實例37：純化Crude oligomers were concentrated using the Pall Minimate EVO system (Product ID: OAPMPUNV) using a Pall Minimate TFF cartridge capsule with 3k Omega membrane.Example 37: Purification
使用反相HPLC實施純化。Waters XBridge Prep C18 5 μm OBD, 250 × 19 mm (P/N：186004021)。緩衝溶液混合物為100 mM TEAA、5% ACN，pH為7.0 (緩衝液A)及1:1乙腈:甲醇(緩衝液B)。梯度為5%-30%或30%-60%緩衝液B，60分鐘，60℃，流量為20 mL/分鐘。Purification was performed using reverse phase HPLC. Waters XBridge Prep C18 5 μm OBD, 250 × 19 mm (P/N: 186004021). The buffer mixture was 100 mM TEAA, 5% ACN, pH 7.0 (buffer A) and 1:1 acetonitrile:methanol (buffer B). The gradient was 5%-30% or 30%-60% buffer B over 60 min at 60°C with a flow rate of 20 mL/min.
純化後，藉由反相UPLC對流份進行分析。所用管柱為Waters ACQUITY UPLC寡核苷酸BEH C18 1.7 μm, 2.1 × 50 mm (P/N: 186003949)。緩衝溶液混合物為100 mM TEAA、5% ACN，pH為7.0 (緩衝液A)及1:1乙腈:甲醇(緩衝液B)。梯度設為5%-30%或30%-60%緩衝液B，5分鐘，70℃，流量為1.0 mL/分鐘。所純化匯集物(pool)之最低規格為85%。實例38：去鹽After purification, the fractions were analyzed by reverse phase UPLC. The column used was Waters ACQUITY UPLC Oligonucleotide BEH C18 1.7 μm, 2.1 × 50 mm (P/N: 186003949). The buffer solution mixture was 100 mM TEAA, 5% ACN, pH 7.0 (buffer A) and 1:1 acetonitrile:methanol (buffer B). The gradient was set to 5%-30% or 30%-60% buffer B, 5 minutes, 70°C, and a flow rate of 1.0 mL/min. The minimum specification of the purified pool was 85%.Example 38: Desalination
在匯集物確立後，即使用Pall Minimate EVO系統(產品ID：OAPMPUNV)對寡聚物進行去鹽。所用卡匣為帶有3k Omega膜之Pall Minimate TFF囊式容器(產品ID：OA003C12)。收集滲餘物進行凍乾或直接退火。實例39：退火之一般程序Once the pool is established, the oligomers are desalted using the Pall Minimate EVO system (Product ID: OAPMPUNV). The cartridge used is a Pall Minimate TFF capsule with 3k Omega membrane (Product ID: OA003C12). The raffinate is collected and either freeze-dried or directly annealed.Example 39: General procedure for annealing
藉由Nanodrop測定有義股及反義股之濃度。藉由混合等莫耳之有義股與反義股製備雙股siRNA。藉由RP-HPLC (一種非變性方法)監測退火過程。退火後，雙鏈體混合物中之反義股不超過5%。藉由在Nanodrop上量測溶液吸光度測定雙鏈體濃度。NMDA配位體-有義股結合物之製備The concentration of sense and antisense strands was determined by Nanodrop. The duplex siRNA was prepared by mixing equimolar amounts of sense and antisense strands. The annealing process was monitored by RP-HPLC (a non-denaturing method). After annealing, the antisense strand in the duplex mixture did not exceed 5%. The duplex concentration was determined by measuring the absorbance of the solution on Nanodrop. Preparation ofNMDAligand-sense strand conjugate
根據上文所闡述之製程，使如上文所闡述之配位體1至23與靶向靶標A (區域I及II)、靶標B (區域I、II及III)及靶標C之有義股結合。實例40：結合物1之製備According to the process described above, the ligands 1 to 23 described above were conjugated to the sense strands of target A (regions I and II), target B (regions I, II and III) and target C.Example 40: Preparation of conjugate 1
根據上文一般程序，使配位體1與靶向靶標A-區域I之寡有義股之5'端結合。According to the general procedure above, ligand 1 was conjugated to the 5' end of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為99%。The purity of the product was 99% as confirmed by HPLC.
LCMS：m/z：8098.6 (計算值8100.0 g/mol)實例41：結合物2之製備LCMS: m/z: 8098.6 (calculated 8100.0 g/mol)Example 41: Preparation of Conjugate 2
根據上文一般程序，使配位體2與靶向靶標A-區域I之寡有義股之5'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' end of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為98%。The purity of the product was 98% as confirmed by HPLC.
LCMS：m/z：8204.4 (計算值8206.0 g/mol)實例42：結合物3之製備LCMS: m/z: 8204.4 (calcd. 8206.0 g/mol)Example 42: Preparation of Conjugate 3
根據上文一般程序，使配位體4與靶向靶標A-區域I之寡有義股之5'端結合。According to the general procedure above, ligand 4 was conjugated to the 5' end of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為92%。The purity of the product was 92% as confirmed by HPLC.
LCMS：m/z：8147.2 (計算值8148.9 g/mol)實例43：結合物4之製備LCMS: m/z: 8147.2 (calcd. 8148.9 g/mol)Example 43: Preparation of Conjugate 4
根據上文一般程序，使配位體5與靶向靶標A-區域I之寡有義股之5'端結合。According to the general procedure above, ligand 5 was conjugated to the 5' end of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為98%。The purity of the product was 98% as confirmed by HPLC.
LCMS：m/z：8177.3 (計算值8178.9 g/mol)實例44：結合物5之製備LCMS: m/z: 8177.3 (calcd. 8178.9 g/mol)Example 44: Preparation of Conjugate 5
根據上文一般程序，使配位體6與靶向靶標A-區域I之寡有義股之5'端結合。According to the general procedure above, ligand 6 was conjugated to the 5' end of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為98%。The purity of the product was 98% as confirmed by HPLC.
LCMS：m/z：8154.2 (計算值8155.9 g/mol)實例45：結合物6之製備LCMS: m/z: 8154.2 (calcd. 8155.9 g/mol)Example 45: Preparation of Conjugate 6
根據上文一般程序，使配位體9與靶向靶標A-區域I之寡有義股之5'端結合。According to the general procedure above, ligand 9 was conjugated to the 5' end of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為97%。The purity of the product was 97% as confirmed by HPLC.
LCMS：m/z：8162.3 (計算值8164.0 g/mol)實例46：結合物7之製備LCMS: m/z: 8162.3 (calcd. 8164.0 g/mol)Example 46: Preparation of Conjugate 7
根據上文一般程序，使配位體1與靶向靶標A-區域II之寡有義股之5'端結合。According to the general procedure above, ligand 1 was conjugated to the 5' end of the oligosense strand targeting target A-region II.
經HPLC證實，產物之製備純度為95%。The purity of the product was 95% as confirmed by HPLC.
LCMS：m/z：8555.7 (計算值8557.4 g/mol)實例47：結合物8之製備LCMS: m/z: 8555.7 (calculated 8557.4 g/mol)Example 47: Preparation of conjugate 8
根據上文一般程序，使配位體2與靶向靶標A-區域II之寡有義股之5'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' end of the oligosense strand targeting target A-region II.
經HPLC證實，產物之製備純度為98%。The purity of the product was 98% as confirmed by HPLC.
LCMS：m/z：8661.6 (計算值8663.4 g/mol)實例48：結合物9之製備LCMS: m/z: 8661.6 (calculated 8663.4 g/mol)Example 48: Preparation of conjugate 9
根據上文一般程序，使配位體2與靶向靶標B-區域I之寡有義股之5'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' end of the oligosense strand targeting target B-region I.
經HPLC證實，產物之製備純度為92%。The purity of the product was 92% as confirmed by HPLC.
LCMS：m/z：8406.6 (計算值8408.1 g/mol)實例49：結合物10之製備LCMS: m/z: 8406.6 (calculated 8408.1 g/mol)Example 49: Preparation of conjugate 10
根據上文一般程序，使配位體2與靶向靶標B-區域II之寡有義股之5'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' end of the oligosense strand targeting target B-region II.
經HPLC證實，產物之製備純度為86%。The purity of the product was 86% as confirmed by HPLC.
LCMS：m/z：8440.4 (計算值8442.5 g/mol)實例50：結合物11之製備LCMS: m/z: 8440.4 (calculated 8442.5 g/mol)Example 50: Preparation of conjugate 11
根據上文一般程序，使配位體2與靶向靶標B-區域III之寡有義股之5'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' end of the oligosense strand targeting target B-region III.
經HPLC證實，產物之製備純度為94%。The purity of the product was 94% as confirmed by HPLC.
LCMS：m/z：8356.4 (計算值8358.1 g/mol)實例51：結合物12之製備LCMS: m/z: 8356.4 (calculated 8358.1 g/mol)Example 51: Preparation of conjugate 12
根據上文一般程序，使配位體1與靶向靶標C-區域I之寡有義股之5'端結合。According to the general procedure above, ligand 1 was conjugated to the 5' end of the oligosense strand targeting target C-region I.
經HPLC證實，產物之製備純度為95%。The purity of the product was 95% as confirmed by HPLC.
LCMS：m/z：7687.6 (計算值7688.7 g/mol)實例52：結合物13之製備LCMS: m/z: 7687.6 (calcd. 7688.7 g/mol)Example 52: Preparation of conjugate 13
根據上文一般程序，使配位體13與靶向靶標A-區域I之寡有義股之5'端結合。According to the general procedure above, ligand 13 was conjugated to the 5' end of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為89%。The purity of the product was 89% as confirmed by HPLC.
LCMS：m/z：8797.7 (計算值8799.5g/mol)實例53：結合物14之製備LCMS: m/z: 8797.7 (calculated 8799.5 g/mol)Example 53: Preparation of Conjugate 14
根據上文一般程序，使配位體14與靶向靶標A-區域II之寡有義股之5'端結合。According to the general procedure above, ligand 14 was conjugated to the 5' end of the oligosense strand targeting target A-region II.
經HPLC證實，產物之製備純度為90%。The purity of the product was 90% as confirmed by HPLC.
LCMS：m/z：8660.8 (計算值8662.4 g/mol)實例54：結合物15之製備LCMS: m/z: 8660.8 (calcd. 8662.4 g/mol)Example 54: Preparation of Conjugate 15
根據上文一般程序，使配位體15與靶向靶標A-區域II之寡有義股之5'端結合。According to the general procedure above, ligand 15 was conjugated to the 5' end of the oligosense strand targeting target A-region II.
經HPLC證實，產物之製備純度為94%。The purity of the product was 94% as confirmed by HPLC.
LCMS：m/z：8660.9 (計算值8662.4 g/mol)實例55：結合物16之製備LCMS: m/z: 8660.9 (calcd. 8662.4 g/mol)Example 55: Preparation of Conjugate 16
根據上文一般程序，使配位體10與靶向靶標A-區域II之寡有義股之5'端結合。According to the general procedure above, ligand 10 was conjugated to the 5' end of the oligosense strand targeting target A-region II.
經HPLC證實，產物之製備純度為90%。The purity of the product was 90% as confirmed by HPLC.
LCMS：m/z：8661.6 (計算值8663.1 g/mol)實例56：結合物17之製備LCMS: m/z: 8661.6 (calculated 8663.1 g/mol)Example 56: Preparation of Conjugate 17
根據上文一般程序，使配位體7與靶向靶標A-區域II之寡有義股之5'端結合。According to the general procedure above, ligand 7 was conjugated to the 5' end of the oligosense strand targeting target A-region II.
經HPLC證實，產物之製備純度為89%。The purity of the product was 89% as confirmed by HPLC.
LCMS：m/z：8592.0 (計算值8593.7 g/mol)實例57：結合物18之製備LCMS: m/z: 8592.0 (calcd. 8593.7 g/mol)Example 57: Preparation of Conjugate 18
根據上文一般程序，使配位體8與靶向靶標A-區域II之寡有義股之5'端結合。According to the general procedure above, ligand 8 was conjugated to the 5' end of the oligosense strand targeting target A-region II.
經HPLC證實，產物之製備純度為93%。The purity of the product was 93% as confirmed by HPLC.
LCMS：m/z：8592.0 (計算值8593.7 g/mol)實例58：結合物19之製備LCMS: m/z: 8592.0 (calcd. 8593.7 g/mol)Example 58: Preparation of Conjugate 19
根據上文一般程序，使配位體1與靶向靶標A-區域II之寡有義股之5'端結合。According to the general procedure above, ligand 1 was conjugated to the 5' end of the oligosense strand targeting target A-region II.
經HPLC證實，產物之製備純度為98%。The purity of the product was 98% as confirmed by HPLC.
LCMS：m/z：8696.2 (計算值8697.8 g/mol)實例59：結合物20之製備LCMS: m/z: 8696.2 (calcd. 8697.8 g/mol)Example 59: Preparation of Conjugate 20
根據上文一般程序，使配位體2與靶向靶標A-區域I之寡有義股之3'端結合。According to the general procedure above, ligand 2 was conjugated to the 3' end of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為97%。The purity of the product was 97% as confirmed by HPLC.
LCMS：m/z：8560.1 (計算值8561.8 g/mol)實例60：結合物21之製備LCMS: m/z: 8560.1 (calculated 8561.8 g/mol)Example 60: Preparation of Conjugate 21
根據上文一般程序，使配位體2與靶向靶標A-區域II之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' and 3' ends of the oligosense strand targeting target A-region II.
經HPLC證實，產物之製備純度為85%。The purity of the product was 85% as confirmed by HPLC.
LCMS：m/z：9132.2 (計算值9134.0 g/mol)實例61：結合物22之製備LCMS: m/z: 9132.2 (calcd. 9134.0 g/mol)Example 61: Preparation of Conjugate 22
根據上文一般程序，使配位體19與靶向靶標A-區域I之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 19 was conjugated to the 5' and 3' ends of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為85%。The purity of the product was 85% as confirmed by HPLC.
LCMS：m/z：9087.5 (計算值9088.9 g/mol)實例62：結合物23之製備LCMS: m/z: 9087.5 (calcd. 9088.9 g/mol)Example 62: Preparation of Conjugate 23
根據上文一般程序，使配位體20與靶向靶標A-區域I之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 20 was conjugated to the 5' and 3' ends of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為95%。The purity of the product was 95% as confirmed by HPLC.
LCMS：m/z：9079.4 (計算值9081.0 g/mol)實例63：結合物24之製備LCMS: m/z: 9079.4 (calcd. 9081.0 g/mol)Example 63: Preparation of Conjugate 24
根據上文一般程序，使配位體18與靶向靶標A-區域I之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 18 was conjugated to the 5' and 3' ends of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為85%。The purity of the product was 85% as confirmed by HPLC.
LCMS：m/z：9167.6 (計算值9169.2 g/mol)實例64：結合物25之製備LCMS: m/z: 9167.6 (calcd. 9169.2 g/mol)Example 64: Preparation of Conjugate 25
根據上文一般程序，使配位體17與靶向靶標A-區域I之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 17 was conjugated to the 5' and 3' ends of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為93%。The purity of the product was 93% as confirmed by HPLC.
LCMS：m/z：9037.4 (計算值9039.2 g/mol)實例65：結合物26之製備LCMS: m/z: 9037.4 (calcd. 9039.2 g/mol)Example 65: Preparation of Conjugate 26
根據上文一般程序，使配位體21與靶向靶標A-區域I之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 21 was conjugated to the 5' and 3' ends of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為96%。The purity of the product was 96% as confirmed by HPLC.
LCMS：m/z：9028.4 (計算值9029.4 g/mol)實例66：結合物27之製備LCMS: m/z: 9028.4 (calcd. 9029.4 g/mol)Example 66: Preparation of Conjugate 27
根據上文一般程序，使配位體22與靶向靶標A-區域I之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 22 was conjugated to the 5' and 3' ends of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為93%。The purity of the product was 93% as confirmed by HPLC.
LCMS：m/z：8998.7 (計算值8999.7 g/mol)實例67：結合物28之製備LCMS: m/z: 8998.7 (calculated 8999.7 g/mol)Example 67: Preparation of Conjugate 28
根據上文一般程序，使配位體23與靶向靶標A-區域I之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 23 was conjugated to the 5' and 3' ends of the oligosense strand targeting target A-region I.
經HPLC證實，產物之製備純度為93%。The purity of the product was 93% as confirmed by HPLC.
LCMS：m/z：9028.5 (計算值9029.8 g/mol)實例68：結合物29之製備LCMS: m/z: 9028.5 (calcd. 9029.8 g/mol)Example 68: Preparation of Conjugate 29
根據上文一般程序，使配位體2與靶向靶標C-區域II之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' and 3' ends of the oligosense strand targeting target C-region II.
經HPLC證實，產物之製備純度為99%。The purity of the product was 99% as confirmed by HPLC.
LCMS：m/z：9405.2 (計算值9406.9 g/mol)實例69：結合物30之製備LCMS: m/z: 9405.2 (calcd. 9406.9 g/mol)Example 69: Preparation of conjugate 30
根據上文一般程序，使配位體2與靶向靶標C-區域III之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' and 3' ends of the oligosense strand targeting target C-region III.
經HPLC證實，產物之製備純度為99%。The purity of the product was 99% as confirmed by HPLC.
LCMS：m/z：9444.3 (計算值9445.9 g/mol)實例70：結合物31之製備LCMS: m/z: 9444.3 (calcd. 9445.9 g/mol)Example 70: Preparation of conjugate 31
根據上文一般程序，使配位體2與靶向靶標C-區域IV之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' and 3' ends of the oligosense strand targeting target C-region IV.
經HPLC證實，產物之製備純度為97%。The purity of the product was 97% as confirmed by HPLC.
LCMS：m/z：9459.3 (計算值9460.8 g/mol)實例71：結合物32之製備LCMS: m/z: 9459.3 (calcd. 9460.8 g/mol)Example 71: Preparation of conjugate 32
根據上文一般程序，使配位體2與靶向靶標C-區域V之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' and 3' ends of the oligosense strand targeting target C-region V.
經HPLC證實，產物之製備純度為98%。The purity of the product was 98% as confirmed by HPLC.
LCMS：m/z：9451.3 (計算值9453.0g/mol)實例72：結合物33之製備LCMS: m/z: 9451.3 (calcd. 9453.0 g/mol)Example 72: Preparation of Conjugate 33
根據上文一般程序，使配位體2與靶向靶標B-區域I之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' and 3' ends of the oligosense strand targeting target B-region I.
經HPLC證實，產物之製備純度為76%。The purity of the product was 76% as confirmed by HPLC.
LCMS：m/z：9524.4 (計算值9526.3 g/mol)實例73：結合物34之製備LCMS: m/z: 9524.4 (calcd. 9526.3 g/mol)Example 73: Preparation of conjugate 34
根據上文一般程序，使配位體2與靶向靶標B-區域II之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' and 3' ends of the oligosense strand targeting target B-region II.
經HPLC證實，產物之製備純度為83%。The purity of the product was 83% as confirmed by HPLC.
LCMS：m/z：9558.4 (計算值9560.2 g/mol)實例74：結合物35之製備LCMS: m/z: 9558.4 (calcd. 9560.2 g/mol)Example 74: Preparation of conjugate 35
根據上文一般程序，使配位體2與靶向靶標B-區域VI之寡有義股之5'端及3'端結合。According to the general procedure above, ligand 2 was conjugated to the 5' and 3' ends of the oligosense strand targeting target B-region VI.
經HPLC證實，產物之製備純度為88%。The purity of the product was 88% as confirmed by HPLC.
LCMS：m/z：9620.6 (計算值9622.3 g/mol)LCMS: m/z: 9620.6 (calcd. 9622.3 g/mol)
總之，製備以下結合物：
在活體內評估NMDA結合物化合物。如下所指示自各個腦區域收集RNA，且量測靶標抑制。
在活體內人類靶標A基因轉殖小鼠PD研究中評估NMDA結合物化合物。動物在第1天經由腦室內注射接受單一媒劑或0.2 mg (10 mg/kg)劑量(n=3隻/組)。每天觀察動物之行為變化。在第15天收集腦區域，且將組織立即置於均質管中，快速冷凍，接著保持在-80℃以用於基因表現分析。NMDA-binding compounds were evaluated in an in vivo human target A gene transgenic mouse PD study. Animals received a single vehicle or 0.2 mg (10 mg/kg) dose (n=3/group) via intracerebroventricular injection on day 1. Animals were observed daily for behavioral changes. Brain regions were collected on day 15, and tissues were immediately placed in homogenizer tubes, snap frozen, and then kept at -80°C for gene expression analysis.
根據RNeasy Micro套組(Qiagen目錄號74004)說明書實施RNA分離。RNA分離後，將96孔板置於冰上，同時準備qRT-PCR反應。向MicroAmp光學96孔板(0.2 mL)中之含有5 μl TaqMan快速病毒1步混合母液(Thermo Fisher編號44444432)、1 μl靶標A TaqMan基因表現分析(Thermo Fisher)、1 μl小鼠GAPDH (VIC) TaqMan基因表現分析(Thermo Fisher：Mm99999915_g1, VIC)及11 μl RT-PCR級無核酸酶水之反應混合物中添加2 μl RNA。使用QuantStudio3 qPCR機，利用以下循環實施qPCR：50℃持續1分鐘，95℃持續20秒，以95℃持續15秒且60℃持續1分鐘進行40個循環。結果在下表中呈現為相對於媒劑對照之靶標A抑制百分比。
在活體內人類靶標B基因轉殖小鼠PD研究中評估NMDA結合物化合物。動物在第1天經由腦室內注射接受單一媒劑或0.2 mg (10 mg/kg)劑量(n=3隻/組)。每天觀察動物之行為變化。在第15天收集腦區域，且將組織立即置於均質管中，快速冷凍，接著保持在-80℃以用於基因表現分析。NMDA-binding compounds were evaluated in an in vivo human target B transgenic mouse PD study. Animals received a single vehicle or 0.2 mg (10 mg/kg) dose (n=3/group) via intracerebroventricular injection on day 1. Animals were observed daily for behavioral changes. Brain regions were collected on day 15, and tissues were immediately placed in homogenizer tubes, snap frozen, and then kept at -80°C for gene expression analysis.
根據RNeasy Micro套組(Qiagen目錄號74004)說明書實施RNA分離。RNA分離後，將96孔板置於冰上，同時準備qRT-PCR反應。向MicroAmp光學96孔板(0.2 mL)中之含有5 μl TaqMan快速病毒1步混合母液(Thermo Fisher編號44444432)、1 μl靶標B TaqMan基因表現分析(Thermo Fisher)、1 μl小鼠GAPDH (VIC) TaqMan基因表現分析(Thermo Fisher：Mm99999915_g1, VIC)及11 μl RT-PCR級無核酸酶水之反應混合物中添加2 μl RNA。使用QuantStudio3 qPCR機，利用以下循環實施qPCR：50℃持續1分鐘，95℃持續20秒，以95℃持續15秒且60℃持續1分鐘進行40個循環。結果在下表中呈現為相對於媒劑對照之靶標B抑制百分比。
在活體內大鼠PD研究中評估NMDA結合物化合物。動物在第1天經由腦大池內(ICM)注射接受單一媒劑或0.9 mg (3 mg/kg)劑量(n=3隻/組)。每天觀察動物之行為變化。在第15天收集腦區域，且將組織立即置於均質管中，快速冷凍，且維持在-80℃以用於基因表現分析。NMDA-binding compounds were evaluated in an in vivo rat PD study. Animals received a single vehicle or 0.9 mg (3 mg/kg) dose (n=3/group) via intracisternal (ICM) injection on day 1. Animals were observed daily for behavioral changes. Brain regions were collected on day 15, and tissues were immediately placed in homogenizer tubes, snap frozen, and maintained at -80°C for gene expression analysis.
根據RNeasy Micro套組(Qiagen目錄號74004)說明書實施RNA分離。RNA分離後，將96孔板置於冰上，同時準備qRT-PCR反應。向MicroAmp光學96孔板(0.2 mL)中之含有5 μl TaqMan快速病毒1步混合母液(Thermo Fisher編號44444432)、1 μl大鼠靶標C TaqMan基因表現分析(Thermo Fisher)、1 μl ACTB (VIC) TaqMan基因表現分析(Thermo Fisher：Rn00667869_m1, VIC)及11 μl RT-PCR級無核酸酶水之反應混合物中添加2 μl RNA。使用QuantStudio3 qPCR機，利用以下循環實施qPCR：50℃持續1分鐘，95℃持續20秒，以95℃持續15秒且60℃持續1分鐘進行40個循環。結果在下表中呈現為相對於媒劑對照之靶標C抑制百分比。
本申請案中通篇所引用之所有參考(包括參考文獻、授權專利、公開專利申請案及及共同待決之專利申請案)之內容在此均係以全文引用的方式明確地併入本文中。等效形式The contents of all references cited throughout this application (including references, issued patents, published patent applications, and co-pending patent applications) are hereby expressly incorporated herein by reference in theirentirety .
熟習此項技術者將認識到，或能夠僅使用常規實驗確定本文所闡述具體實施例之許多等效形式。以下申請專利範圍意欲涵蓋此等等效形式。實施例Those skilled in the art will recognize, or be able to ascertain using no more than routineexperimentation , many equivalents to the specific embodiments described herein. The following claims are intended to cover such equivalents.
其他實施例包括：Other embodiments include:
實施例P1. 一種包含式(I)結構之化合物或其鹽，， 式(I) 其中為N-甲基-D-天冬胺酸鹽(NMDA)受體配位體； L1、L2、L3及L4中之每一者獨立地為連接體、鍵，或不存在； Y為鍵或-C(=O)-；且 R1為一或多種寡核苷酸、保護基團、小分子、蛋白質、抗體、肽或其組合。Example P1. A compound comprising a structure of formula (I) or a salt thereof, , Formula (I) wherein is anN -methyl-D-aspartate (NMDA) receptor ligand; each of L1 , L2 , L3 and L4 is independently a linker, a bond, or absent; Y is a bond or -C(=O)-; and R1 is one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, peptides or a combination thereof.
實施例P2. 如實施例P1之化合物或其鹽，其中該NMDA受體配位體為NMDA受體促效劑。Embodiment P2. The compound or salt thereof according to Embodiment P1, wherein the NMDA receptor ligand is an NMDA receptor agonist.
實施例P3. 如實施例P1之化合物或其鹽，其中該NMDA受體配位體為NMDA受體拮抗劑。Embodiment P3. The compound or salt thereof according to Embodiment P1, wherein the NMDA receptor ligand is an NMDA receptor antagonist.
實施例P4. 如實施例P1之化合物或其鹽，其中該NMDA受體配位體係選自由以下組成之群：、、、、、、、、、、、、抗NMDA受體抗體及其衍生物。Embodiment P4. The compound or salt thereof according to Embodiment P1, wherein the NMDA receptor ligand is selected from the group consisting of: , , , , , , , , , , , , anti-NMDA receptor antibodies and their derivatives.
實施例P5. 如實施例P1之化合物或其鹽，其中該化合物包含式(II)結構：， 式(II) 或其鹽。Embodiment P5. A compound or a salt thereof according to Embodiment P1, wherein the compound comprises a structure of formula (II): , Formula (II) or a salt thereof.
實施例P6. 如實施例P5之化合物或其鹽，其中該化合物包含式(II-a)結構：， 式(II-a) 或其鹽。Embodiment P6. The compound or salt thereof of Embodiment P5, wherein the compound comprises a structure of formula (II-a): , Formula (II-a) or a salt thereof.
實施例P7. 如實施例P1之化合物或其鹽，其中該化合物包含式(III)結構，且R2為氫、鹵素、-OH或-OMe：， 式(III) 或其鹽。Embodiment P7. The compound or salt thereof according to Embodiment P1, wherein the compound comprises a structure of formula (III), and R2 is hydrogen, halogen, -OH or -OMe: , Formula (III) or a salt thereof.
實施例P8. 如實施例P7之化合物或其鹽，其中該化合物包含式(III-e)結構：， 式(III-e) 或其鹽。Embodiment P8. A compound or a salt thereof according to Embodiment P7, wherein the compound comprises a structure of formula (III-e): , Formula (III-e) or a salt thereof.
實施例P9. 如實施例P7之化合物或其鹽，其中該化合物包含式(III-f)結構：， 式(III-f) 或其鹽。Embodiment P9. A compound or a salt thereof according to Embodiment P7, wherein the compound comprises a structure of formula (III-f): , Formula (III-f) or a salt thereof.
實施例P10. 如實施例P7之化合物或其鹽，其中該化合物包含式(III-g)結構：， 式(III-g) 或其鹽。Embodiment P10. A compound or a salt thereof according to Embodiment P7, wherein the compound comprises a structure of formula (III-g): , Formula (III-g) or a salt thereof.
實施例P11. 如實施例P1之化合物或其鹽，其中該化合物包含式(IV)結構：， 式(IV) 或其鹽。Embodiment P11. The compound or salt thereof of Embodiment P1, wherein the compound comprises a structure of formula (IV): , Formula (IV) or a salt thereof.
實施例P12. 如實施例P11之化合物或其鹽，其中該化合物包含式(IV-a)結構：， 式(IV-a) 或其鹽。Embodiment P12. The compound or salt thereof of Embodiment P11, wherein the compound comprises a structure of formula (IV-a): , Formula (IV-a) or a salt thereof.
實施例P13. 如實施例P11之化合物或其鹽，其中該化合物包含式(IV-b)結構：， 式(IV-b) 或其鹽。Embodiment P13. The compound or salt thereof of Embodiment P11, wherein the compound comprises a structure of formula (IV-b): , Formula (IV-b) or a salt thereof.
實施例P14. 如實施例P1之化合物或其鹽，其中該化合物包含式(V)結構：， 式(V) 或其鹽。Embodiment P14. A compound or a salt thereof according to Embodiment P1, wherein the compound comprises a structure of formula (V): , Formula (V) or a salt thereof.
實施例P15. 如實施例P14之化合物或其鹽，其中該化合物包含式(V-a)結構：， 式(V-a) 或其鹽。Embodiment P15. A compound or a salt thereof according to Embodiment P14, wherein the compound comprises a structure of formula (Va): , Formula (Va) or a salt thereof.
實施例P16. 如實施例P1之化合物或其鹽，其中該化合物包含式(VI)結構：， 式(VI) 或其鹽。Embodiment P16. The compound or salt thereof of Embodiment P1, wherein the compound comprises a structure of formula (VI): , Formula (VI) or a salt thereof.
實施例P17. 如實施例P16之化合物或其鹽，其中該化合物包含式(VI-a)結構：， 式(VI-a) 或其鹽。Embodiment P17. A compound or a salt thereof according to Embodiment P16, wherein the compound comprises a structure of formula (VI-a): , Formula (VI-a) or a salt thereof.
實施例P18. 如實施例P16之化合物或其鹽，其中該化合物包含式(VI-b)結構：， 式(VI-b) 或其鹽。Embodiment P18. A compound or a salt thereof according to Embodiment P16, wherein the compound comprises a structure of formula (VI-b): , Formula (VI-b) or a salt thereof.
實施例P19. 如實施例P1之化合物或其鹽，其中該化合物包含式(VII)結構：， 式(VII) 或其鹽。Embodiment P19. A compound or a salt thereof according to Embodiment P1, wherein the compound comprises a structure of formula (VII): , Formula (VII) or a salt thereof.
實施例P20. 如實施例P19之化合物或其鹽，其中該化合物包含式(VII-a)結構：， 式(VII-a) 或其鹽。Embodiment P20. A compound or a salt thereof according to Embodiment P19, wherein the compound comprises a structure of formula (VII-a): , Formula (VII-a) or a salt thereof.
實施例P21. 如實施例P1之化合物或其鹽，其中該化合物包含式(VIII)結構：， 式(VIII) 或其鹽。Embodiment P21. A compound or a salt thereof according to Embodiment P1, wherein the compound comprises a structure of formula (VIII): , Formula (VIII) or a salt thereof.
實施例P22. 如實施例P21之化合物或其鹽，其中該化合物包含式(VIII-a)結構：， 式(VIII-a) 或其鹽。Embodiment P22. A compound or a salt thereof according to Embodiment P21, wherein the compound comprises a structure of formula (VIII-a): , Formula (VIII-a) or a salt thereof.
實施例P23. 如實施例P1之化合物或其鹽，其中該化合物包含式(IX)結構：， 式(IX) 或其鹽。Embodiment P23. A compound or a salt thereof according to Embodiment P1, wherein the compound comprises a structure of formula (IX): , Formula (IX) or a salt thereof.
實施例P24. 如實施例P23之化合物或其鹽，其中該化合物包含式(IX-a)結構：， 式(IX-a) 或其鹽。Embodiment P24. A compound or a salt thereof according to Embodiment P23, wherein the compound comprises a structure of formula (IX-a): , Formula (IX-a) or a salt thereof.
實施例P25. 如實施例P1之化合物或其鹽，其中該化合物包含式(X)結構：， 式(X) 或其鹽。Embodiment P25. A compound or a salt thereof according to Embodiment P1, wherein the compound comprises a structure of formula (X): , Formula (X) or a salt thereof.
實施例P26. 如實施例P25之化合物或其鹽，其中該化合物包含式(X-a)結構：， 式(X-a) 或其鹽。Embodiment P26. A compound or a salt thereof according to Embodiment P25, wherein the compound comprises a structure of formula (Xa): , Formula (Xa) or a salt thereof.
實施例P27. 如實施例P25之化合物或其鹽，其中該化合物包含式(X-b)結構：， 式(X-b) 或其鹽。Embodiment P27. A compound or a salt thereof according to Embodiment P25, wherein the compound comprises a structure of formula (Xb): , Formula (Xb) or a salt thereof.
實施例P28. 如實施例P1之化合物或其鹽，其中該化合物包含式(XI)結構：， 式(XI) 或其鹽。Embodiment P28. A compound or a salt thereof according to Embodiment P1, wherein the compound comprises a structure of formula (XI): , Formula (XI) or a salt thereof.
實施例P29. 如實施例P28之化合物或其鹽，其中該化合物包含式(XI-a)結構：， 式(XI-a) 或其鹽。Embodiment P29. A compound or a salt thereof according to Embodiment P28, wherein the compound comprises a structure of formula (XI-a): , Formula (XI-a) or a salt thereof.
實施例P30. 如實施例P28之化合物或其鹽，其中該化合物包含式(XI-b)結構：， 式(XI-b) 或其鹽。Example P30. A compound or a salt thereof according to Example P28, wherein the compound comprises a structure of formula (XI-b): , Formula (XI-b) or a salt thereof.
實施例P31. 如實施例P1至P30中任一項之化合物或其鹽，其中L1、L2、L3及L4中之每一者獨立地不存在，為鍵、視情況經取代之烷基連接體、視情況經取代之聚乙二醇(PEG)連接體、視情況經取代之雜烷基連接體、視情況經取代之雜芳基連接體、磷酸二酯鍵或硫代磷酸酯鍵。Embodiment P31. The compound or salt thereof according to any one of Embodiments P1 to P30, wherein each of L1 , L2 , L3 and L4 is independently absent and is a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, a phosphodiester bond or a phosphorothioate bond.
實施例P32. 如實施例P5至P31中任一項之化合物或其鹽，其中L1為鍵。Embodiment P32. The compound or salt thereof according to any one of Embodiments P5 to P31, wherein L1 is a bond.
實施例P33. 如實施例P5或P6之化合物或其鹽，其中L2為視情況經取代之烷基連接體或視情況經取代之PEG連接體。Embodiment P33. A compound or a salt thereof according to Embodiment P5 or P6, wherein L2 is an optionally substituted alkyl linker or an optionally substituted PEG linker.
實施例P34. 如實施例P33之化合物或其鹽，其中L2包含結構或。Example P34. A compound or a salt thereof according to Example P33, wherein L2 comprises the structure or .
實施例P35. 如實施例P7至P10中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體。Embodiment P35. A compound or a salt thereof according to any one of Embodiments P7 to P10, wherein L2 is an optionally substituted PEG linker.
實施例P36. 如實施例P35之化合物或其鹽，其中L2包含結構或。Example P36. A compound or a salt thereof according to Example P35, wherein L2 comprises the structure or .
實施例P37. 如實施例P11至P13中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體。Embodiment P37. The compound or salt thereof according to any one of Embodiments P11 to P13, wherein L2 is an optionally substituted PEG linker.
實施例P38. 如實施例P37之化合物或其鹽，其中L2包含結構或。Example P38. A compound or a salt thereof according to Example P37, wherein L2 comprises the structure or .
實施例P39. 如實施例P14或P15之化合物或其鹽，其中L2為視情況經取代之雜烷基連接體。Embodiment P39. The compound or salt thereof according to Embodiment P14 or P15, wherein L2 is an optionally substituted heteroalkyl linker.
實施例P40. 如實施例P39之化合物或其鹽，其中L2包含結構。Example P40. A compound or a salt thereof according to Example P39, wherein L2 comprises the structure .
實施例P41. 如實施例P16至P18中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體。Embodiment P41. A compound or a salt thereof according to any one of Embodiments P16 to P18, wherein L2 is an optionally substituted PEG linker.
實施例P42. 如實施例P41之化合物或其鹽，其中L2包含結構或。Example P42. A compound or a salt thereof as in Example P41, wherein L2 comprises the structure or .
實施例P43. 如實施例P19或P20之化合物或其鹽，其中L2為視情況經取代之PEG連接體。Embodiment P43. A compound or a salt thereof according to Embodiment P19 or P20, whereinL2 is an optionally substituted PEG linker.
實施例P44. 如實施例P43之化合物或其鹽，其中L2包含結構。Example P44. A compound or a salt thereof as in Example P43, wherein L2 comprises the structure .
實施例P45. 如實施例P21至P24中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體。Embodiment P45. A compound or a salt thereof according to any one of Embodiments P21 to P24, wherein L2 is an optionally substituted PEG linker.
實施例P46. 如實施例P45之化合物或其鹽，其中L2包含結構。Example P46. A compound or a salt thereof as in Example P45, wherein L2 comprises the structure .
實施例P47. 如實施例P25至P27中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體。Embodiment P47. A compound or a salt thereof according to any one of Embodiments P25 to P27, wherein L2 is an optionally substituted PEG linker.
實施例P48. 如實施例P47之化合物或其鹽，其中L2包含結構。Example P48. A compound or a salt thereof according to Example P47, wherein L2 comprises the structure .
實施例P49. 如實施例P28至P30中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體。Embodiment P49. A compound or a salt thereof according to any one of Embodiments P28 to P30, wherein L2 is an optionally substituted PEG linker.
實施例P50. 如實施例P49之化合物或其鹽，其中L2包含結構。Example P50. A compound or a salt thereof as in Example P49, wherein L2 comprises the structure .
實施例P51. 如實施例P5至P50中任一項之化合物或其鹽，其中L3為視情況經取代之雜芳基連接體。Embodiment P51. The compound or salt thereof according to any one of Embodiments P5 to P50, wherein L3 is an optionally substituted heteroaryl linker.
實施例P52. 如實施例P51之化合物或其鹽，其中L3為視情況經取代之部分不飽和雜環烷基或雜芳基連接體。Embodiment P52. The compound according to Embodiment P51 or a salt thereof, wherein L3 is an optionally substituted partially unsaturated heterocycloalkyl or heteroaryl linker.
實施例P53. 如實施例P51或P52之化合物或其鹽，其中L3包含結構。Example P53. A compound or a salt thereof according to Example P51 or P52, wherein L3 comprises a structure .
實施例P54. 如實施例P5至P53中任一項之化合物或其鹽，其中L4為視情況經取代之雜烷基連接體。Embodiment P54. The compound or salt thereof according to any one of Embodiments P5 to P53, wherein L4 is an optionally substituted heteroalkyl linker.
實施例P55. 如實施例P54之化合物或其鹽，其中該雜烷基連接體經一或多個=O取代基取代。Embodiment P55. A compound or a salt thereof according to Embodiment P54, wherein the heteroalkyl linker is substituted with one or more =0 substituents.
實施例P56. 如實施例P54或P55之化合物或其鹽，其中L4包含結構， 其中X為O或S。Example P56. A compound or a salt thereof according to Example P54 or P55, wherein L4 comprises the structure , where X is O or S.
實施例P57. 如實施例P5或P6之化合物或其鹽，其中L1、L2、L3及L4一起構成結構或， 其中X為O或S。Embodiment P57. The compound or salt thereof according to Embodiment P5 or P6, wherein L1 , L2 , L3 and L4 together form the structure or , where X is O or S.
實施例P58. 如實施例P7至P10中任一項之化合物或其鹽，其中L1、L2、L3及L4一起構成結構或， 其中X為O或S。Embodiment P58. The compound or salt thereof according to any one of Embodiments P7 to P10, wherein L1 , L2 , L3 and L4 together form the structure or , where X is O or S.
實施例P59. 如實施例P11至P13中任一項之化合物或其鹽，其中L1、L2、L3及L4一起構成結構或， 其中X為O或S。Embodiment P59. The compound or salt thereof according to any one of Embodiments P11 to P13, wherein L1 , L2 , L3 and L4 together form the structure or , where X is O or S.
實施例P60. 如實施例P14或P15之化合物或其鹽，其中L1、L2、L3及L4一起構成結構， 其中X為O或S。Embodiment P60. The compound or salt thereof according to Embodiment P14 or P15, wherein L1 , L2 , L3 and L4 together form the structure , where X is O or S.
實施例P61. 如實施例P16至P18中任一項之化合物或其鹽，其中L1、L2、L3及L4一起構成結構或， 其中X為O或S。Embodiment P61. The compound or salt thereof according to any one of Embodiments P16 to P18, wherein L1 , L2 , L3 and L4 together form the structure or , where X is O or S.
實施例P62. 如實施例P19或P20之化合物或其鹽，其中L1、L2、L3及L4一起構成結構或， 其中X為O或S。Embodiment P62. The compound or salt thereof according to Embodiment P19 or P20, wherein L1 , L2 , L3 and L4 together form the structure or , where X is O or S.
實施例P63. 如實施例P21至P24中任一項之化合物或其鹽，其中L1、L2、L3及L4一起構成結構， 其中X為O或S。Embodiment P63. The compound or salt thereof according to any one of Embodiments P21 to P24, wherein L1 , L2 , L3 and L4 together form the structure , where X is O or S.
實施例P64. 如實施例P25或P26之化合物或其鹽，其中L1、L2、L3及L4一起構成結構， 其中X為O或S。Embodiment P64. The compound or salt thereof according to Embodiment P25 or P26, wherein L1 , L2 , L3 and L4 together form the structure , where X is O or S.
實施例P65. 如實施例P1至P64中任一項之化合物或其鹽，其中該化合物包含如下結構：、、、、、、、、、、、、、、、或， 其中X為O或S。Embodiment P65. A compound or a salt thereof according to any one of Embodiments P1 to P64, wherein the compound comprises the following structure: , , , , , , , , , , , , , , , or , where X is O or S.
實施例P66. 如實施例P56至P65中任一項之化合物或其鹽，其中X為O。Embodiment P66. The compound or salt thereof according to any one of Embodiments P56 to P65, wherein X is O.
實施例P67. 如實施例P56至P65中任一項之化合物或其鹽，其中X為S。Embodiment P67. The compound or salt thereof according to any one of Embodiments P56 to P65, wherein X is S.
實施例P68. 如實施例P1至P67中任一項之化合物或其鹽，其中R1包含寡核苷酸。Embodiment P68. The compound or salt thereof according to any one of Embodiments P1 to P67, wherein R1 comprises an oligonucleotide.
實施例P69. 如實施例P68之化合物或其鹽，其中該寡核苷酸在其5'端連接。Embodiment P69. The compound or salt thereof according to Embodiment P68, wherein the oligonucleotide is linked at its 5' end.
實施例P70. 如實施例P68之化合物或其鹽，其中該寡核苷酸在其3'端連接。Embodiment P70. The compound or salt thereof according to Embodiment P68, wherein the oligonucleotide is linked at its 3' end.
實施例P71. 如實施例P68之化合物或其鹽，其中該寡核苷酸在該寡核苷酸上之內部位置連接。Embodiment P71. The compound or salt thereof according to Embodiment P68, wherein the oligonucleotide is linked at an internal position on the oligonucleotide.
實施例P72. 如實施例P71之化合物或其鹽，其中該內部位置為核苷間鍵聯。Embodiment P72. The compound or salt thereof according to Embodiment P71, wherein the internal position is an internucleoside linkage.
實施例P73. 如實施例P1至P72中任一項之化合物或其鹽，其中R1包含與一或多種額外之NMDA受體配位體結合之寡核苷酸。Embodiment P73. The compound or salt thereof according to any one of Embodiments P1 to P72, wherein R1 comprises an oligonucleotide bound to one or more additional NMDA receptor ligands.
實施例P74. 如實施例P73之化合物或其鹽，其中該寡核苷酸與兩種、三種、四種、五種或五種以上額外之NMDA受體配位體結合。Embodiment P74. The compound or salt thereof according to Embodiment P73, wherein the oligonucleotide is bound to two, three, four, five or more additional NMDA receptor ligands.
實施例P75. 如實施例P73或P74之化合物或其鹽，其中該等額外之NMDA受體配位體在該寡核苷酸之5'端、在該寡核苷酸之3'端、該寡核苷酸上之一或多個內部位置或其任何組合處與該寡核苷酸結合。Embodiment P75. A compound or salt thereof according to Embodiment P73 or P74, wherein the additional NMDA receptor ligand is bound to the oligonucleotide at the 5' end of the oligonucleotide, at the 3' end of the oligonucleotide, at one or more internal positions on the oligonucleotide, or any combination thereof.
實施例P76. 如實施例P68至P75中任一項之化合物或其鹽，其中該寡核苷酸為經修飾之寡核苷酸。Embodiment P76. The compound or salt thereof according to any one of Embodiments P68 to P75, wherein the oligonucleotide is a modified oligonucleotide.
實施例P77. 一種組合物，其包含如實施例P1至P76中任一項之化合物或其鹽以及醫藥學上可接受之賦形劑。Embodiment P77. A composition comprising a compound according to any one of Embodiments P1 to P76 or a salt thereof and a pharmaceutically acceptable excipient.
實施例P78. 一種向個體之腦遞送治療性寡核苷酸之方法，該方法包括向該個體投與如實施例P1至P76中任一項之化合物或其鹽，或如實施例P77之組合物。Embodiment P78. A method of delivering a therapeutic oligonucleotide to the brain of a subject, the method comprising administering to the subject a compound or a salt thereof according to any one of Embodiments P1 to P76, or a composition according to Embodiment P77.
實施例P79. 如實施例P78之方法，其中將該治療性寡核苷酸遞送至一或多個選自由以下組成之群的腦區域：紋狀體、小腦、腦幹、海馬體、額葉皮質及脊髓。Embodiment P79. The method of Embodiment P78, wherein the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of striatum, cerebellum, brain stem, hippocampus, frontal cortex and spinal cord.
實施例P80. 一種治療或改善個體之疾病、病症或其症狀之方法，該方法包括向該個體投與如實施例P1至P76中任一項之化合物或其鹽，或如實施例P77之組合物。Embodiment P80. A method for treating or ameliorating a disease, disorder or symptom thereof in a subject, the method comprising administering to the subject a compound or a salt thereof according to any one of Embodiments P1 to P76, or a composition according to Embodiment P77.
實施例P81. 如實施例P80之方法，其中該疾病、病症或其症狀為中樞神經系統(CNS)疾病、病症或其症狀。Embodiment P81. The method of embodiment P80, wherein the disease, disorder or symptom thereof is a central nervous system (CNS) disease, disorder or symptom thereof.
實施例P82. 如實施例P80或P81之方法，其中該疾病、病症或其症狀為阿茲海默氏病或其症狀。Embodiment P82. The method of embodiment P80 or P81, wherein the disease, disorder or symptom thereof is Alzheimer's disease or a symptom thereof.
實施例P83. 如實施例P80至P82中任一項之方法，其中將該化合物或其鹽鞘內投與給該個體。Embodiment P83. The method of any one of Embodiments P80 to P82, wherein the compound or a salt thereof is administered intrathecally to the subject.
實施例P84. 一種製備如實施例P1至P76中任一項之化合物或其鹽之方法，該化合物或其鹽包含本文所闡述之一或多種化合物及化學轉變，包括實例1。Example P84. A method of preparing a compound or a salt thereof as in any one of Examples P1 to P76, comprising one or more compounds and chemical transformations described herein, including Example 1.
實施例1. 一種包含式(I)結構之化合物或其鹽，， 式(I) 其中為N-甲基-D-天冬胺酸鹽(NMDA)受體配位體； L1、L2、L3及L4中之每一者獨立地為連接體、鍵，或不存在； Y為鍵或-C(=O)-；且 R1為一或多種寡核苷酸、保護基團、小分子、蛋白質、抗體、肽或其組合。Example 1. A compound comprising a structure of formula (I) or a salt thereof, , Formula (I) wherein is anN -methyl-D-aspartate (NMDA) receptor ligand; each of L1 , L2 , L3 and L4 is independently a linker, a bond, or absent; Y is a bond or -C(=O)-; and R1 is one or more oligonucleotides, protecting groups, small molecules, proteins, antibodies, peptides or a combination thereof.
實施例2. 如實施例1之化合物或其鹽，其中該NMDA受體配位體為NMDA受體促效劑。Embodiment 2. The compound or salt thereof according to Embodiment 1, wherein the NMDA receptor ligand is an NMDA receptor agonist.
實施例3. 如實施例1之化合物或其鹽，其中該NMDA受體配位體為NMDA受體拮抗劑。Embodiment 3. The compound or salt thereof according to Embodiment 1, wherein the NMDA receptor ligand is an NMDA receptor antagonist.
實施例4. 如實施例1之化合物或其鹽，其中該NMDA受體配位體係選自由以下組成之群：、、、、、、、、、、、、、、、、、、、、、、抗NMDA受體抗體及其衍生物。Embodiment 4. The compound or salt thereof according to Embodiment 1, wherein the NMDA receptor ligand is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , anti-NMDA receptor antibodies and their derivatives.
實施例5. 如實施例1之化合物或其鹽，其中該化合物包含式(II)結構：， 式(II) 或其鹽。Embodiment 5. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (II): , Formula (II) or a salt thereof.
實施例6. 如實施例5之化合物或其鹽，其中該化合物包含式(II-a)結構：， 式(II-a) 或其鹽。Embodiment 6. The compound or salt thereof according to Embodiment 5, wherein the compound comprises a structure of formula (II-a): , Formula (II-a) or a salt thereof.
實施例7. 如實施例1之化合物或其鹽，其中該化合物包含式(III)結構：， 式(III) 其中R2為氫、鹵素、-OH或-OMe； 或其鹽。Embodiment 7. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (III): , Formula (III) wherein R2 is hydrogen, halogen, -OH or -OMe; or a salt thereof.
實施例8. 如實施例7之化合物或其鹽，其中該化合物包含式(III-e)結構：， 式(III-e) 或其鹽。Embodiment 8. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-e): , Formula (III-e) or a salt thereof.
實施例9. 如實施例7之化合物或其鹽，其中該化合物包含式(III-f)結構：， 式(III-f) 或其鹽。Embodiment 9. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-f): , Formula (III-f) or a salt thereof.
實施例10. 如實施例7之化合物或其鹽，其中該化合物包含式(III-g)結構：， 式(III-g) 或其鹽。Embodiment 10. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-g): , Formula (III-g) or a salt thereof.
實施例11. 如實施例7之化合物或其鹽，其中該化合物包含式(III-h)結構：。 式(III-h)Embodiment 11. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-h): Formula (III-h)
實施例12. 如實施例7之化合物或其鹽，其中該化合物包含式(III-i)結構：。 式(III-i)Example 12. The compound or salt thereof according to Example 7, wherein the compound comprises a structure of formula (III-i): Formula (III-i)
實施例13. 如實施例7之化合物或其鹽，其中該化合物包含式(III-j)結構：。 式(III-j)Embodiment 13. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-j): Formula (III-j)
實施例14. 如實施例7之化合物或其鹽，其中該化合物包含式(III-k)結構：。 式(III-k)Embodiment 14. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-k): Formula (III-k)
實施例15. 如實施例7之化合物或其鹽，其中該化合物包含式(III-l)結構：。 式(III-l)Example 15. The compound or salt thereof according to Example 7, wherein the compound comprises a structure of formula (III-1): Formula (III-1)
實施例16. 如實施例7之化合物或其鹽，其中該化合物包含式(III-m)結構：。 式(III-m)Embodiment 16. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-m): Formula (III-m)
實施例17. 如實施例7之化合物或其鹽，其中該化合物包含式(III-n)結構：。 式(III-n)Embodiment 17. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-n): Formula (III-n)
實施例18. 如實施例7之化合物或其鹽，其中該化合物包含式(III-o)結構：。 式(III-o)Embodiment 18. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-o): Formula (III-o)
實施例19. 如實施例7之化合物或其鹽，其中該化合物包含式(III-p)結構：。 式(III-p)Embodiment 19. The compound or salt thereof according to Embodiment 7, wherein the compound comprises a structure of formula (III-p): Formula (III-p)
實施例20. 如實施例1之化合物或其鹽，其中該化合物包含式(IV)結構：， 式(IV) 或其鹽。Embodiment 20. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (IV): , Formula (IV) or a salt thereof.
實施例21. 如實施例20之化合物或其鹽，其中該化合物包含式(IV-a)結構：， 式(IV-a) 或其鹽。Embodiment 21. The compound or salt thereof according to Embodiment 20, wherein the compound comprises a structure of formula (IV-a): , Formula (IV-a) or a salt thereof.
實施例22. 如實施例1之化合物或其鹽，其中該化合物包含式(XIX)結構：式(XIX) 或其鹽。Embodiment 22. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (XIX): Formula (XIX) or a salt thereof.
實施例23. 如實施例22之化合物或其鹽，其中該化合物包含式(XIX-a)結構：， 式(XIX-a) 或其鹽。Embodiment 23. The compound or salt thereof according to Embodiment 22, wherein the compound comprises a structure of formula (XIX-a): , Formula (XIX-a) or a salt thereof.
實施例24. 如實施例1之化合物或其鹽，其中該化合物包含式(V)結構：， 式(V) 或其鹽。Embodiment 24. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (V): , Formula (V) or a salt thereof.
實施例25. 如實施例24之化合物或其鹽，其中該化合物包含式(V-a)結構：， 式(V-a) 或其鹽。Embodiment 25. The compound or salt thereof according to Embodiment 24, wherein the compound comprises a structure of formula (Va): , Formula (Va) or a salt thereof.
實施例26. 如實施例1之化合物或其鹽，其中該化合物包含式(VI)結構：， 式(VI) 或其鹽。Embodiment 26. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (VI): , Formula (VI) or a salt thereof.
實施例27. 如實施例26之化合物或其鹽，其中該化合物包含式(VI-a)結構：， 式(VI-a) 或其鹽。Embodiment 27. The compound or salt thereof according to Embodiment 26, wherein the compound comprises a structure of formula (VI-a): , Formula (VI-a) or a salt thereof.
實施例28. 如實施例26之化合物或其鹽，其中該化合物包含式(VI-b)結構：， 式(VI-b) 或其鹽。Embodiment 28. The compound or salt thereof according to Embodiment 26, wherein the compound comprises a structure of formula (VI-b): , Formula (VI-b) or a salt thereof.
實施例29. 如實施例1之化合物或其鹽，其中該化合物包含式(VII)結構：， 式(VII) 或其鹽。Embodiment 29. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (VII): , Formula (VII) or a salt thereof.
實施例30. 如實施例29之化合物或其鹽，其中該化合物包含式(VII-a)結構：， 式(VII-a) 或其鹽。Embodiment 30. The compound or salt thereof according to Embodiment 29, wherein the compound comprises a structure of formula (VII-a): , Formula (VII-a) or a salt thereof.
實施例31. 如實施例1之化合物或其鹽，其中該化合物包含式(VIII)結構：， 式(VIII) 或其鹽。Embodiment 31. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (VIII): , Formula (VIII) or a salt thereof.
實施例32. 如實施例31之化合物或其鹽，其中該化合物包含式(VIII-a)結構：， 式(VIII-a) 或其鹽。Embodiment 32. The compound or salt thereof according to Embodiment 31, wherein the compound comprises a structure of formula (VIII-a): , Formula (VIII-a) or a salt thereof.
實施例33. 如實施例1之化合物或其鹽，其中該化合物包含式(IX)結構：， 式(IX) 或其鹽。Embodiment 33. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (IX): , Formula (IX) or a salt thereof.
實施例34. 如實施例33之化合物或其鹽，其中該化合物包含式(IX-a)結構：， 式(IX-a) 或其鹽。Embodiment 34. The compound or salt thereof according to Embodiment 33, wherein the compound comprises a structure of formula (IX-a): , Formula (IX-a) or a salt thereof.
實施例35. 如實施例1之化合物或其鹽，其中該化合物包含式(X)結構：， 式(X) 或其鹽。Embodiment 35. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (X): , Formula (X) or a salt thereof.
實施例36. 如實施例35之化合物或其鹽，其中該化合物包含式(X-a)結構：， 式(X-a) 或其鹽。Embodiment 36. The compound or salt thereof according to Embodiment 35, wherein the compound comprises a structure of formula (Xa): , Formula (Xa) or a salt thereof.
實施例37. 如實施例35之化合物或其鹽，其中該化合物包含式(X-b)結構：， 式(X-b) 或其鹽。Embodiment 37. The compound or salt thereof according to Embodiment 35, wherein the compound comprises a structure of formula (Xb): , Formula (Xb) or a salt thereof.
實施例38. 如實施例1之化合物或其鹽，其中該化合物包含式(XI)結構：， 式(XI) 或其鹽。Embodiment 38. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (XI): , Formula (XI) or a salt thereof.
實施例39. 如實施例38之化合物或其鹽，其中該化合物包含式(XI-a)結構：， 式(XI-a) 或其鹽。Embodiment 39. The compound or salt thereof according to Embodiment 38, wherein the compound comprises a structure of formula (XI-a): , Formula (XI-a) or a salt thereof.
實施例40. 如實施例38之化合物或其鹽，其中該化合物包含式(XI-b)結構：， 式(XI-b) 或其鹽。Embodiment 40. The compound or salt thereof according to Embodiment 38, wherein the compound comprises a structure of formula (XI-b): , Formula (XI-b) or a salt thereof.
實施例41. 如實施例38之化合物或其鹽，其中該化合物包含式(XI-c)結構：， 式(XI-c) 或其鹽。Embodiment 41. The compound or salt thereof according to Embodiment 38, wherein the compound comprises a structure of formula (XI-c): , Formula (XI-c) or a salt thereof.
實施例42. 如實施例1之化合物或其鹽，其中該化合物包含式(XII)結構：， 式(XII) 或其鹽。Embodiment 42. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (XII): , Formula (XII) or a salt thereof.
實施例43. 如實施例42之化合物或其鹽，其中該化合物包含式(XII-a)結構：， 式(XII-a) 或其鹽。Embodiment 43. The compound or salt thereof according to Embodiment 42, wherein the compound comprises a structure of formula (XII-a): , Formula (XII-a) or a salt thereof.
實施例44. 如實施例42之化合物或其鹽，其中該化合物包含式(XII-b)結構：， 式(XII-b) 或其鹽。Embodiment 44. The compound or salt thereof according to Embodiment 42, wherein the compound comprises a structure of formula (XII-b): , Formula (XII-b) or a salt thereof.
實施例45. 如實施例1之化合物或其鹽，其中該化合物包含式(XIII)結構：， 式(XIII) 或其鹽。Embodiment 45. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (XIII): , Formula (XIII) or a salt thereof.
實施例46. 如實施例45之化合物或其鹽，其中該化合物包含式(XIII-a)結構：， 式(XIII-a) 或其鹽。Embodiment 46. The compound or salt thereof according to Embodiment 45, wherein the compound comprises a structure of formula (XIII-a): , Formula (XIII-a) or a salt thereof.
實施例47. 如實施例1之化合物或其鹽，其中該化合物包含式(XIV)結構：， 式(XIV) 或其鹽。Embodiment 47. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (XIV): , Formula (XIV) or a salt thereof.
實施例48. 如實施例47之化合物或其鹽，其中該化合物包含式(XIV-a)結構：， 式(XIV-a) 或其鹽。Embodiment 48. The compound or salt thereof according to Embodiment 47, wherein the compound comprises a structure of formula (XIV-a): , Formula (XIV-a) or a salt thereof.
實施例49. 如實施例1之化合物或其鹽，其中該化合物包含式(XV)結構：， 式(XV) 或其鹽。Embodiment 49. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (XV): , Formula (XV) or a salt thereof.
實施例50. 如實施例49之化合物或其鹽，其中該化合物包含式(XV-a)結構：， 式(XV-a) 或其鹽。Embodiment 50. The compound or salt thereof according to Embodiment 49, wherein the compound comprises a structure of formula (XV-a): , Formula (XV-a) or a salt thereof.
實施例51. 如實施例1之化合物或其鹽，其中該化合物包含式(XVI)結構：， 式(XVI) 或其鹽。Embodiment 51. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (XVI): , Formula (XVI) or a salt thereof.
實施例52. 如實施例51之化合物或其鹽，其中該化合物包含式(XVI-a)結構：， 式(XVI-a) 或其鹽。Embodiment 52. The compound or salt thereof according to Embodiment 51, wherein the compound comprises a structure of formula (XVI-a): , Formula (XVI-a) or a salt thereof.
實施例53. 如實施例1之化合物或其鹽，其中該化合物包含式(XVII)結構：， 式(XVII) 或其鹽。Embodiment 53. The compound or salt thereof of Embodiment 1, wherein the compound comprises a structure of formula (XVII): , Formula (XVII) or a salt thereof.
實施例54. 如實施例53之化合物或其鹽，其中該化合物包含式(XVII-a)結構：， 式(XVII-a) 或其鹽。Embodiment 54. The compound or salt thereof according to Embodiment 53, wherein the compound comprises a structure of formula (XVII-a): , Formula (XVII-a) or a salt thereof.
實施例55. 如實施例1之化合物或其鹽，其中該化合物包含式(XVIII)結構：， 式(XVIII) 或其鹽。Embodiment 55. The compound or salt thereof according to Embodiment 1, wherein the compound comprises a structure of formula (XVIII): , Formula (XVIII) or a salt thereof.
實施例56. 如實施例55之化合物或其鹽，其中該化合物包含式(XVIII-a)結構：， 式(XVIII-a) 或其鹽。Embodiment 56. The compound or salt thereof according to Embodiment 55, wherein the compound comprises a structure of formula (XVIII-a): , Formula (XVIII-a) or a salt thereof.
實施例57. 如實施例1至56中任一項之化合物或其鹽，其中L1、L2、L3及L4中之每一者獨立地不存在，為鍵、視情況經取代之烷基連接體、視情況經取代之聚乙二醇(PEG)連接體、視情況經取代之雜烷基連接體、視情況經取代之雜芳基連接體、磷酸二酯鍵或硫代磷酸酯鍵。Embodiment 57. The compound or salt thereof according to any one of Embodiments 1 to 56, wherein each of L1 , L2 , L3 and L4 is independently absent and is a bond, an optionally substituted alkyl linker, an optionally substituted polyethylene glycol (PEG) linker, an optionally substituted heteroalkyl linker, an optionally substituted heteroaryl linker, a phosphodiester bond or a phosphorothioate bond.
實施例58. 如實施例1至57中任一項之化合物或其鹽，其中L1為鍵。Embodiment 58. The compound or salt thereof according to any one of Embodiments 1 to 57, wherein L1 is a bond.
實施例59. 如實施例1至57中任一項之化合物或其鹽，其中L1為視情況經取代之烷基連接體。Embodiment 59. The compound or salt thereof according to any one of Embodiments 1 to 57, wherein L1 is an optionally substituted alkyl linker.
實施例60. 如實施例1至57中任一項之化合物或其鹽，其中L1為視情況經取代之C1-C6烷基連接體。Embodiment 60. The compound or salt thereof according to any one of Embodiments 1 to 57, wherein L1 is an optionally substituted C1 -C6 alkyl linker.
實施例61. 如實施例1至57中任一項之化合物或其鹽，其中L1為經=O取代之C1-C6烷基連接體。Embodiment 61. The compound or salt thereof according to any one of Embodiments 1 to 57, wherein L1 is a C1-C6 alkyl linker substituted with =0.
實施例62. 如實施例1至57中任一項之化合物或其鹽，其中L1包含結構。Embodiment 62. The compound or salt thereof according to any one of Embodiments 1 to 57, wherein L1 comprises the structure .
實施例63. 如實施例1至62中任一項之化合物或其鹽，其中L2為視情況經取代之烷基連接體。Embodiment 63. The compound or salt thereof according to any one of Embodiments 1 to 62, wherein L2 is an optionally substituted alkyl linker.
實施例64. 如實施例1至62中任一項之化合物或其鹽，其中L2為視情況經取代之C1-C15烷基連接體。Embodiment 64. The compound or salt thereof according to any one of Embodiments 1 to 62, wherein L2 is an optionally substituted C1 -C15 alkyl linker.
實施例65. 如實施例1至62中任一項之化合物或其鹽，其中L2為視情況經取代之C5-C12烷基連接體。Embodiment 65. The compound or salt thereof according to any one of Embodiments 1 to 62, wherein L2 is an optionally substituted C5 -C12 alkyl linker.
實施例66. 如實施例1至62中任一項之化合物或其鹽，其中L2包含結構或。Embodiment 66. The compound or salt thereof according to any one of Embodiments 1 to 62, wherein L2 comprises the structure or .
實施例67. 如實施例1至62中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體Embodiment 67. A compound or a salt thereof according to any one of Embodiments 1 to 62, whereinL2 is an optionally substituted PEG linker
實施例68. 如實施例1至62中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體，其長度包含一個、兩個、三個、四個、五個、六個、七個或八個PEG單元，其中PEG單元包含結構。Embodiment 68. The compound or salt thereof of any one of Embodiments 1 to 62, whereinL2 is an optionally substituted PEG linker having a length of one, two, three, four, five, six, seven or eight PEG units, wherein the PEG unit comprises the structure .
實施例69. 如實施例1至62中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體，其長度包含三個PEG單元，其中PEG單元包含結構。Embodiment 69. The compound or salt thereof according to any one of Embodiments 1 to 62, whereinL2 is an optionally substituted PEG linker having a length of three PEG units, wherein the PEG unit comprises the structure .
實施例70. 如實施例1至62中任一項之化合物或其鹽，其中L2為視情況經取代之PEG連接體，其長度包含四個PEG單元，其中PEG單元包含結構。Embodiment 70. The compound or salt thereof according to any one of Embodiments 1 to 62, whereinL2 is an optionally substituted PEG linker having a length of four PEG units, wherein the PEG unit comprises the structure .
實施例71. 如實施例1至62中任一項之化合物或其鹽，其中L2包含結構、、、、、、或。Embodiment 71. A compound or a salt thereof according to any one of Embodiments 1 to 62, wherein L2 comprises the structure , , , , , , or .
實施例72. 如實施例1至62中任一項之化合物或其鹽，其中L2為視情況經取代之雜烷基連接體。Embodiment 72. The compound or salt thereof according to any one of Embodiments 1 to 62, wherein L2 is an optionally substituted heteroalkyl linker.
實施例73. 如實施例72之化合物或其鹽，其中L2包含結構。Embodiment 73. The compound or salt thereof of Embodiment 72, wherein L2 comprises the structure .
實施例74. 如實施例1至73中任一項之化合物或其鹽，其中L3為視情況經取代之雜芳基連接體。Embodiment 74. The compound or salt thereof according to any one of Embodiments 1 to 73, wherein L3 is an optionally substituted heteroaryl linker.
實施例75. 如實施例1至73中任一項之化合物或其鹽，其中L3為視情況經取代之部分不飽和雜環烷基或視情況未經取代之雜芳基連接體。Embodiment 75. The compound or salt thereof according to any one of Embodiments 1 to 73, wherein L3 is an optionally substituted partially unsaturated heterocycloalkyl or an optionally unsubstituted heteroaryl linker.
實施例76. 如實施例74或75之化合物或其鹽，其中L3包含結構。Embodiment 76. The compound or salt thereof according to Embodiment 74 or 75, wherein L3 comprises the structure .
實施例77. 如實施例1至76中任一項之化合物或其鹽，其中L4為視情況經取代之雜烷基連接體。Embodiment 77. The compound or salt thereof according to any one of Embodiments 1 to 76, wherein L4 is an optionally substituted heteroalkyl linker.
實施例78. 如實施例77之化合物或其鹽，其中該雜烷基連接體經一或多個=O取代基取代。Embodiment 78. The compound or salt thereof according to Embodiment 77, wherein the heteroalkyl linker is substituted with one or more =0 substituents.
實施例79. 如實施例77或78之化合物或其鹽，其中L4包含結構， 其中X為O或S。Embodiment 79. The compound or salt thereof of Embodiment 77 or 78, wherein L4 comprises the structure , where X is O or S.
實施例80. 如實施例77或78之化合物或其鹽，其中L4包含結構， 其中X為S或OEmbodiment 80. The compound or salt thereof of Embodiment 77 or 78, wherein L4 comprises the structure , where X is S or O
實施例81. 如實施例1至80中任一項之化合物或其鹽，其中L1、L2、L3及L4一起構成結構、、、、、、、、、、、、、或， 其中X為O或S。Embodiment 81. The compound or salt thereof according to any one of Embodiments 1 to 80, wherein L1 , L2 , L3 and L4 together form the structure , , , , , , , , , , , , , or , where X is O or S.
實施例82. 如實施例1至81中任一項之化合物或其鹽，其中該化合物包含如下結構：、、、、、、、、、、、、、、、、、、、、、、、、、、、， 其中X為O或S。Embodiment 82. The compound or salt thereof according to any one of Embodiments 1 to 81, wherein the compound comprises the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , where X is O or S.
實施例83. 如實施例79至82中任一項之化合物或其鹽，其中X為O。Embodiment 83. The compound or salt thereof according to any one of Embodiments 79 to 82, wherein X is O.
實施例84. 如實施例79至82中任一項之化合物或其鹽，其中X為S。Embodiment 84. The compound or salt thereof according to any one of Embodiments 79 to 82, wherein X is S.
實施例85. 如實施例1至84中任一項之化合物或其鹽，其中R1包含寡核苷酸。Embodiment 85. The compound or salt thereof according to any one of Embodiments 1 to 84, wherein R1 comprises an oligonucleotide.
實施例86. 如實施例85之化合物或其鹽，其中該寡核苷酸在其5'端連接。Embodiment 86. The compound or a salt thereof according to Embodiment 85, wherein the oligonucleotide is linked at its 5' end.
實施例87. 如實施例85之化合物或其鹽，其中該寡核苷酸在其3'端連接。Embodiment 87. The compound or a salt thereof according to Embodiment 85, wherein the oligonucleotide is linked at its 3' end.
實施例88. 如實施例85之化合物或其鹽，其中該寡核苷酸在該寡核苷酸上之內部位置連接。Embodiment 88. The compound or salt thereof according to Embodiment 85, wherein the oligonucleotide is linked at an internal position on the oligonucleotide.
實施例89. 如實施例88之化合物或其鹽，其中該內部位置為核苷間鍵聯。Embodiment 89. The compound or salt thereof according to Embodiment 88, wherein the internal position is an internucleoside linkage.
實施例90. 如實施例1至89中任一項之化合物或其鹽，其中R1包含與一或多種額外之NMDA受體配位體結合之寡核苷酸。Embodiment 90. The compound or salt thereof according to any one of Embodiments 1 to 89, wherein R1 comprises an oligonucleotide that binds to one or more additional NMDA receptor ligands.
實施例91. 如實施例90之化合物或其鹽，其中該寡核苷酸與兩種、三種、四種、五種或五種以上額外之NMDA受體配位體結合。Embodiment 91. The compound or salt thereof according to Embodiment 90, wherein the oligonucleotide is conjugated to two, three, four, five or more additional NMDA receptor ligands.
實施例92. 如實施例90或91之化合物或其鹽，其中該等額外之NMDA受體配位體在該寡核苷酸之5'端、在該寡核苷酸之3'端、該寡核苷酸上之一或多個內部位置或其任何組合處與該寡核苷酸結合。Embodiment 92. The compound or salt thereof of Embodiment 90 or 91, wherein the additional NMDA receptor ligand is bound to the oligonucleotide at the 5' end of the oligonucleotide, at the 3' end of the oligonucleotide, at one or more internal positions on the oligonucleotide, or any combination thereof.
實施例93. 如實施例85至92中任一項之化合物或其鹽，其中該寡核苷酸為經修飾之寡核苷酸。Embodiment 93. The compound or salt thereof according to any one of Embodiments 85 to 92, wherein the oligonucleotide is a modified oligonucleotide.
實施例94. 一種組合物，其包含如實施例1至93中任一項之化合物或其鹽以及醫藥學上可接受之賦形劑。Embodiment 94. A composition comprising the compound or a salt thereof according to any one of Embodiments 1 to 93 and a pharmaceutically acceptable excipient.
實施例95. 一種向個體之腦遞送治療性寡核苷酸之方法，該方法包括向該個體投與如實施例1至93中任一項之化合物或其鹽，或如實施例94之組合物。Embodiment 95. A method of delivering a therapeutic oligonucleotide to the brain of a subject, the method comprising administering to the subject a compound or a salt thereof according to any one of Embodiments 1 to 93, or a composition according to Embodiment 94.
實施例96. 如實施例95之方法，其中將該治療性寡核苷酸遞送至一或多個選自由以下組成之群的腦區域：紋狀體、小腦、腦幹、海馬體、額葉皮質及脊髓。Embodiment 96. The method of embodiment 95, wherein the therapeutic oligonucleotide is delivered to one or more brain regions selected from the group consisting of striatum, cerebellum, brain stem, hippocampus, frontal cortex and spinal cord.
實施例97. 一種治療或改善個體之疾病、病症或其症狀之方法，該方法包括向該個體投與如實施例1至93中任一項之化合物或其鹽，或如實施例94之組合物。Embodiment 97. A method for treating or ameliorating a disease, disorder or symptom thereof in a subject, the method comprising administering to the subject a compound or a salt thereof according to any one of Embodiments 1 to 93, or a composition according to Embodiment 94.
實施例98. 如實施例97之方法，其中該疾病、病症或其症狀為中樞神經系統(CNS)疾病、病症或其症狀。Embodiment 98. The method of embodiment 97, wherein the disease, disorder or symptom thereof is a central nervous system (CNS) disease, disorder or symptom thereof.
實施例99. 如實施例97或98之方法，其中該疾病、病症或其症狀為阿茲海默氏病或其症狀。Embodiment 99. The method of embodiment 97 or 98, wherein the disease, disorder or symptom thereof is Alzheimer's disease or a symptom thereof.
實施例100. 如實施例97至99中任一項之方法，其中將該化合物或其鹽鞘內投與給該個體。Embodiment 100. The method of any one of embodiments 97 to 99, wherein the compound or a salt thereof is administered intrathecally to the subject.
實施例101. 一種製備如實施例1至93中任一項之化合物或其鹽之方法，該化合物或其鹽包含本文所闡述之一或多種化合物及化學轉變，包括實例1至77。Embodiment 101. A method of preparing a compound or a salt thereof as in any one of Embodiments 1 to 93, comprising one or more compounds and chemical transformations described herein, including Embodiments 1 to 77.
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