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RU2418003C2 - Antiangiogenic compounds - Google Patents

Antiangiogenic compoundsDownload PDF

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Publication number
RU2418003C2
RU2418003C2RU2009117290/10ARU2009117290ARU2418003C2RU 2418003 C2RU2418003 C2RU 2418003C2RU 2009117290/10 ARU2009117290/10 ARU 2009117290/10ARU 2009117290 ARU2009117290 ARU 2009117290ARU 2418003 C2RU2418003 C2RU 2418003C2
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Russia
Prior art keywords
substituted
antibody
targeted delivery
delivery agent
group
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RU2009117290/10A
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Russian (ru)
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RU2009117290A (en
Inventor
Курт БРЭДШОУ (US)
Курт БРЭДШОУ
Абхиджит БХАТ (US)
Абхиджит БХАТ
Джинг-Ю ЛЭЙ (US)
Джинг-Ю ЛЭЙ
Венката ДОППАЛАПУДИ (US)
Венката ДОППАЛАПУДИ
Динггуо ЛИУ (US)
Динггуо ЛИУ
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КовЭкс Текнолоджиз Айэлэнд Лимитед
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Abstract

FIELD: medicine.
SUBSTANCE: in accordance with the described invention claimed are antiangiogenic (AA) compounds of targeted delivery, which include conjugates AA of targeted delivery agent with a linker, which are bound with antigen-binding site of antibody. Claimed are various applications of compounds, including methods of treating disorders associated with abnormal angiogenesis. Invention makes it possible to obtain compounds for targeted impact on Ang2 and demonstrates advantageous properties in comparison with existing Ang2-targeted agents.
EFFECT: in some aspects of invention useful agents and compounds in accordance with invention ensure attractive balance between period of half-life and IC50 values.
26 cl, 41 dwg, 10 tbl, 29 ex

Description

Translated fromRussian

Текст описания приведен в факсимильном виде.

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Claims (26)

Translated fromRussian
1. Антиангиогенный (АА) агент направленной доставки, содержащий пептид, включающий последовательность:
Figure 00000357

где R1 представляет собой СН3, С(O)СН3, С(O)СН3, С(O)СН2СН3, С(O)СН2СН2СН3, С(O)СН(СН3)СН3, С(O)СН2СН2СН2СН3, С(O)СН(СН3)СН2СН3, С(O)С6Н5, С(O)СН2СН2(CH2CH2O)1-5Ме, дихлорбензоил (DCB), дифторбензоил (DFB), пиридинилкарбоксилат (РуС) или амидо-2-полиэтиленгликоль (амидо-2-PEG), защитную группу для амино, жирнокислотную группу липидов или углевод; и
R2 представляет собой ОН, NH2, NH(СН3), NHCH2CH3, NHCH2CH2CH3, NHCH(СН3)СН3, NHCH2CH2CH2CH3, NHCH(СН3)СН2СН3, NHC6H5, NHCH2CH2OCH3, NHOCH3, NHOCH2CH3, защитную группу для карбокси, жирнокислотную группу липидов или углевод, и
где один из Q1, Е8, (АсК)9, К11, Т12, D15, Q16, M18, L19 или G22 замещен соединяющим остатком, содержащим нуклеосрильную боковую цепь, которая может быть ковалентно связана с антигенсвязывающим сайтом антитела непосредственно или через промежуточный линкер, где соединяющий остаток выбран из группы, содержащей К, Y, ТС, гомоцистеин, гомосерин, диаминопропионовую кислоту (Dap) и диаминомасляную кислоту (Dab).1. Antiangiogenic (AA) targeted delivery agent containing a peptide comprising the sequence:
Figure 00000357

where R1 represents CH3 , C (O) CH3 , C (O) CH3 , C (O) CH2 CH3 , C (O) CH2 CH2 CH3 , C (O) CH (CH3 ) CH3 , C (O) CH2 CH2 CH2 CH3 , C (O) CH (CH3 ) CH2 CH3 , C (O) C6 H5 , C (O) CH2 CH2 (CH2 CH2 O)1-5 Me, dichlorobenzoyl (DCB), difluorobenzoyl (DFB), pyridinylcarboxylate (PyC) or amido-2-polyethylene glycol (amido-2-PEG), a protective group for amino, lipid fatty acid group or carbohydrate; and
R2 represents OH, NH2 , NH (CH3 ), NHCH2 CH3 , NHCH2 CH2 CH3 , NHCH (CH3 ) CH3 , NHCH2 CH2 CH2 CH3 , NHCH (CH3 ) CH2 CH3 , NHC6 H5 , NHCH2 CH2 OCH3 , NHOCH3 , NHOCH2 CH3 , a carboxy protecting group, a fatty acid group of lipids or a carbohydrate, and
where one of Q1 , E8 , (AsK)9 , K11 , T12 , D15 , Q16 , M18 , L19 or G22 is replaced by a connecting moiety containing a nucleosril side chain, which may be covalently linked to an antigen binding the antibody site directly or via an intermediate linker, where the connecting residue is selected from the group consisting of K, Y, TC, homocysteine, homoserin, diaminopropionic acid (Dap) and diaminobutyric acid (Dab).2. АА агент направленной доставки по п.1, где соединяющий остаток выбран из группы, состоящей из К, Y, Т, Dap и Dab.2. AA targeted delivery agent according to claim 1, where the connecting residue is selected from the group consisting of K, Y, T, Dap and Dab.3. АА агент направленной доставки по п.2, где соединяющий остаток представляет собой К.3. AA targeted delivery agent according to claim 2, where the connecting residue is K.4. АА агент направленной доставки по любому из пп.1-3, где один из (АсК)9, К11, Т12, D15, Q16, M18 и L19 замещен соединяющим остатком.4. AA targeted delivery agent according to any one of claims 1 to 3, where one of (AsK)9 , K11 , T12 , D15 , Q16 , M18 and L19 is replaced by a connecting residue.5. АА агент направленной доставки по п.1, где К11 замещен соединяющим остатком.5. AA targeted delivery agent according to claim 1, where K11 is replaced by a connecting residue.6. АА агент направленной доставки по п.1, где R1 представляет собой С(O)СН3.6. AA targeted delivery agent according to claim 1, where R1 represents C (O) CH3 .7. АА агент направленной доставки по п.1, где R2 представляет собой NH2.7. AA targeted delivery agent according to claim 1, where R2 represents NH2 .8. Соединение, имеющее формулу:
L-[AA агент направленной доставки] или L'-[AA агент направленной доставки], где [АА агент направленной доставки] представляет собой АА агент направленной доставки по любому из пп.1-7, и L представляет собой линкерную группировку, имеющую формулу -X-Y-Z-, и L' представляет собой линкерную группировку, имеющую формулу -X-Y-Z', и где Х присоединен к АА агенту направленной доставки через аминоконец, карбоксиконец или боковую цепь соединяющего остатка и представляет собой биологически совместимую соединяющую цепь, включающую любой атом, выбранный из группы, состоящей из С, Н, N, О, Р, S, F, Cl, Br и I, и может содержать полимер или блок-сополимер; Y представляет собой возможно присутствующую распознающую группу, содержащую по меньшей мере кольцевую структуру; и Z представляет собой реакционноспособную группу, способную к образованию ковалентной связи с боковой цепью аминокислоты в антигенсвязывающем сайте антитела; и Z' представляет собой соединяющую группировку, включающую ковалентную связь с боковой цепью аминокислоты в антигенсвязывающем сайте антитела.8. The compound having the formula:
L- [AA targeted delivery agent] or L '- [AA targeted delivery agent], where [AA targeted delivery agent] is an AA targeted delivery agent according to any one of claims 1 to 7, and L is a linker moiety having the formula -XYZ-, and L 'is a linker moiety having the formula -XY-Z', and wherein X is attached to an AA targeted delivery agent through an amino terminus, a carboxy terminus or a side chain of a connecting residue, and is a biocompatible connecting chain including any atom, selected from the group, with standing of C, H, N, O, P, S, F, Cl, Br and I, and may comprise a polymer or block copolymer; Y represents a possibly present recognition group containing at least a ring structure; and Z represents a reactive group capable of forming a covalent bond with the amino acid side chain at the antigen binding site of an antibody; and Z 'is a connecting moiety comprising a covalent bond with an amino acid side chain at the antigen binding site of an antibody.9. Соединение по п.8, где кольцевая структура Y имеет возможно замещенную структуру:
Figure 00000358
или
Figure 00000359

где а, b, с, d и е независимо представляют собой углерод или азот; f представляет собой углерод, азот, кислород или серу; Y присоединен к Х и Z независимо по любым двум кольцевым положениям подходящей валентности; и не более четырех из а, b, с, d, e или f одновременно представляют собой азот, и предпочтительно а, b, с, d и е в кольцевой структуре каждый представляет собой углерод.9. The compound of claim 8, where the ring structure Y has a possibly substituted structure:
Figure 00000358
or
Figure 00000359

where a, b, c, d and e independently represent carbon or nitrogen; f represents carbon, nitrogen, oxygen or sulfur; Y is attached to X and Z independently at any two ring positions of suitable valency; and not more than four of a, b, c, d, e or f simultaneously represent nitrogen, and preferably a, b, c, d and e in the ring structure each represents carbon.10. Соединение по п.8, где кольцевая структура Y представляет собой фенил.10. The compound of claim 8, where the ring structure of Y is phenyl.11. Соединение по п.8, где Z или Z', если присутствует, представляет собой замещенный алкил, замещенный циклоалкил, замещенный арил, замещенный арилалкил, замещенный гетероциклил или замещенный гетероциклилалкил, где по меньшей мере один заместитель представляет собой 1,3-дикетоновую группировку, ацил-бета-лактам, активированный сложный эфир, альфа-галогенокетон, альдегид, имид малеиновой кислоты, лактон, ангидрид, альфа-галогеноацетамид, амин, гидразид или эпоксид.11. The compound of claim 8, where Z or Z ', if present, is substituted alkyl, substituted cycloalkyl, substituted aryl, substituted arylalkyl, substituted heterocyclyl or substituted heterocyclylalkyl, where at least one substituent is 1,3-diketone a group, acyl-beta-lactam, activated ester, alpha-halo ketone, aldehyde, maleic imide, lactone, anhydride, alpha-haloacetamide, amine, hydrazide or epoxide.12. Соединение по п.11, где по меньшей мере один заместитель выбран из группы, состоящей из замещенных 1,3-дикетонов или ацил-бета-лактамов.12. The compound according to claim 11, where at least one substituent is selected from the group consisting of substituted 1,3-diketones or acyl-beta-lactams.13. Соединение по любому из пп.8-12, где Z, если присутствует, имеет структуру:
Figure 00000360
или
Figure 00000361
,
и где Z', если присутствует, имеет структуру:
Figure 00000362

или
Figure 00000363
,
где q равно 0-5, и Антитело-N-, если присутствует, указывает на ковалентную связь с боковой цепью в антигенсвязывающем сайте антитела.13. The compound according to any one of paragraphs.8-12, where Z, if present, has the structure:
Figure 00000360
or
Figure 00000361
,
and where Z ', if present, has the structure:
Figure 00000362

or
Figure 00000363
,
where q is 0-5, and Antibody-N-, if present, indicates a covalent bond to the side chain at the antigen binding site of the antibody.14. Соединение по любому из пп.8-12, где Х присоединен к соединяющему остатку, является замещенным или незамещенным и выбран из -R22-[CH2-CH2-O]t-R23-, -R22-циклоалкил-R23-, -R22-арил-R23- или -R22-гетероциклил-R23-, где R22 и R23 независимо представляют собой ковалентную связь, -O-, -S-, -NRb-, замещенный или незамещенный прямой или разветвленный С1-50алкилен, замещенный или незамещенный прямой или разветвленный С1-50гетероалкилен, замещенный или незамещенный прямой или разветвленный С2-50алкенилен либо замещенный или незамещенный C2-50гетероалкенилен; Rb в каждом случае независимо представляет собой водород, замещенный или незамещенный С1-10алкил, замещенный или незамещенный С3-7циклоалкил-С0-6алкил либо замещенный или незамещенный арил-С0-6алкил; t равно 2-50; и размер R22 и R23 выбран таким, что длина основной цепи Х остается примерно 200 атомов или меньше.14. The compound according to any one of paragraphs.8-12, where X is attached to the connecting residue, is substituted or unsubstituted and is selected from -R22 - [CH2 -CH2 -O]t -R23 -, -R22 -cycloalkyl -R23 -, -R22 -aryl-R23 - or -R22 -heterocyclyl-R23 -, where R22 and R23 independently represent a covalent bond, -O-, -S-, -NRb -, substituted or unsubstituted straight or branched C1-50 alkylene, substituted or unsubstituted straight or branched chain C1-50 heteroalkylene, substituted or unsubstituted straight or branched C2 -50 alkenylene, or substituted or unsubstituted C2-50 heteroalkenyl; Rb in each case independently represents hydrogen, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C3-7 cycloalkyl-C0-6 alkyl, or substituted or unsubstituted aryl-C0-6 alkyl; t is 2-50; and the size of R22 and R23 is chosen such that the length of the main chain X remains about 200 atoms or less.15. Соединение по любому из пп.8-12, где
Х представляет собой:
Figure 00000364
,
где v и w выбраны такими, что длина основной цепи Х составляет 6-12 атомов, и Rb в каждом случае независимо представляет собой водород, замещенный или незамещенный С1-10алкил, замещенный или незамещенный С3-7циклоалкил-С0-6алкил либо замещенный или незамещенный арил-С0-6алкил.15. The compound according to any one of paragraphs.8-12, where
X represents:
Figure 00000364
,
where v and w are selected such that the length of the main chain X is 6-12 atoms, and Rb in each case independently represents hydrogen, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C3-7 cycloalkyl-C0- 6 alkyl or substituted or unsubstituted aryl-C0-6 alkyl.16. Соединение по п.15, где X-Y представляет собой:
Figure 00000365
,
v равно 1 или 2; w равно 1 или 2; Rb представляет собой водород.16. The compound of claim 15, wherein XY is:
Figure 00000365
,
v is 1 or 2; w is 1 or 2; Rb represents hydrogen.17. Соединение по любому из пп.8-12, содержащее пептид, соответствующий SEQ ID NO: 139.17. The compound according to any one of paragraphs.8-12, containing a peptide corresponding to SEQ ID NO: 139.18. Соединение по любому из пп.8-12, имеющее формулу
Figure 00000366
18. The compound according to any one of claims 8 to 12, having the formula
Figure 00000366
19. Соединение по любому из пп.8-12, где группа Z ковалентно связана с антигенсвязывающим сайтом Антитела.19. The compound according to any one of paragraphs.8-12, where the Z group is covalently linked to the antigen binding site of the Antibody.20. Соединение по п.19, имеющее структуру:
Figure 00000367
20. The compound according to claim 19, having the structure:
Figure 00000367
21. Соединение по п.19, где Антитело представляет собой каталитическое антитело и, предпочтительно, альдолазное каталитическое антитело.21. The compound according to claim 19, where the Antibody is a catalytic antibody and, preferably, an aldolase catalytic antibody.22. Соединение по п.19, где указанное Антитело представляет собой полноразмерное антитело, Fab, Fab', F(ab')2, Fv, dsFv (двухцепочечный Fv), scFv(одноцепочечный Fv), VH, диатело или минимальное антитело (minibody), содержащее VH и VL домены из h38c2, или представляет собой антитело, содержащее VH и VL домены из h38c2 и константный домен, выбранный из группы, состоящей из lgG1, lgG2, lgG3 и lgG4.22. The compound of claim 19, wherein said Antibody is a full-length antibody, Fab, Fab ', F (ab')2 , Fv , dsFv (double-stranded Fv ), scFv (single-stranded Fv ), VH , a diabody or minimal antibody (minibody) containing the VH and VL domains of h38c2, or is an antibody containing the VH and VL domains of h38c2 and a constant domain selected from the group consisting of logG1, IgG2, IgG3 and IgG4.23. Соединение по п.19, где Антитело представляет собой h38c2 lgG1.23. The compound according to claim 19, where the Antibody is h38c2 logG1.24. Антиангиогенная фармацевтическая композиция, содержащая терапевтически эффективное количество соединения по любому из пп.8-23 или АА агента направленной доставки по любому из пп.1-7.24. An anti-angiogenic pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 8-23 or AA of a targeted delivery agent according to any one of claims 1 to 7.25. Фармацевтическая композиция по п.24, дополнительно содержащая терапевтически эффективное количество одного или более чем одного химиотерапевтического агента, предпочтительно представляющего собой соединение, выбранное из группы, состоящей из 5-фторурацила, иринотекана, оксалиплатина, бевацизумаба и цетуксимаба.25. The pharmaceutical composition of claim 24, further comprising a therapeutically effective amount of one or more chemotherapeutic agents, preferably a compound selected from the group consisting of 5-fluorouracil, irinotecan, oxaliplatin, bevacizumab and cetuximab.26. Применение АА агента направленной доставки по любому из пп.1-7 или соединения по любому из пп.8-23, или фармацевтической композиции по любому из пп.24-25 в способе ингибирования или ослабления ангиогенеза или для лечения или предупреждения заболевания или симптома, ассоциированных с ангиогенным расстройством.26. The use of an AA targeted delivery agent according to any one of claims 1 to 7 or a compound according to any one of claims 8 to 23, or a pharmaceutical composition according to any one of claims 24 to 25, in the method of inhibiting or attenuating angiogenesis or for treating or preventing a disease or symptom associated with angiogenic disorder.
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RU2560589C2 (en)*2011-05-202015-08-20Яньтай Жунчан Байотекнолоджиз Ко., Лтд.Antiangiogenic inducer fusion protein and using it

Cited By (1)

* Cited by examiner, † Cited by third party
Publication numberPriority datePublication dateAssigneeTitle
RU2560589C2 (en)*2011-05-202015-08-20Яньтай Жунчан Байотекнолоджиз Ко., Лтд.Antiangiogenic inducer fusion protein and using it

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