CN101240029B

Movatterモバイル変換

Info

Publication number: CN101240029B
Application number: CN2007100636731A
Authority: CN
Inventors: 彭师奇; 赵明; 崔国辉; 李龙钰
Original assignee: Capital Medical University
Current assignee: Capital Medical University
Priority date: 2007-02-07
Filing date: 2007-02-07
Publication date: 2010-08-11
Anticipated expiration: 2027-02-07
Also published as: CN101240029A

Abstract

Translated fromChinese

本发明公开了以正庚烷基和RGD肽为基本构件，通过羰基、甲氨基及甲氧基组构的靶向阳离子药质体，公开了其制备方法及其用途。本发明靶向阳离子药质体为通式CH₃(CH₂)₆R₁所示的结构，其中R₁为羰基、甲氨基及甲氧基修饰的RGD肽。本发明的靶向阳离子药质体除具有优秀的静脉和口服抗血栓活性外，还具有优秀的靶向性能和自组装性能，可作为制备微乳、脂质体等药物载体的制剂材料或靶向制剂材料。

The invention discloses a targeted cationic drug plastid with n-heptyl and RGD peptide as basic components, organized through carbonyl, methylamino and methoxy groups, and discloses its preparation method and application. The targeting cationic drug plastid of the present invention has a structure represented by the general formula CH₃ (CH₂ )₆ R₁ , wherein R₁ is RGD peptide modified by carbonyl, methylamino and methoxy. The targeting cationic drug plasmid of the present invention has not only excellent intravenous and oral antithrombotic activity, but also excellent targeting performance and self-assembly performance, and can be used as a preparation material or target for preparing drug carriers such as microemulsions and liposomes. to preparation materials.

Description

Translated fromChinese

正庚烷基和RGD肽构建的缀合物、其合成方法和应用Conjugate constructed by n-heptyl and RGD peptide, its synthesis method and application

技术领域technical field

本发明涉及靶向阳离子药质体，尤其涉及正庚烷基链通过羰基、甲氨基及甲氧基与RGD肽的羧端或氨端缀合而得的靶向阳离子药质体，本发明还涉及该药质体的制备方法以及该药质体作为抗血栓剂、药物载体或药物靶向制剂材料的应用，属于生物医药领域。The present invention relates to targeted cationic drug plasmids, in particular to targeted cationic drug plasmids obtained by conjugating n-heptyl chains to the carboxyl or amino ends of RGD peptides through carbonyl, methylamino and methoxy groups. The method for preparing the drug substance and the application of the drug substance as an antithrombotic agent, a drug carrier or a drug targeting preparation material belong to the field of biomedicine.

背景技术Background technique

在未来的5年到10年基因治疗会有可把基因传送至细胞的理想载体。从生物制剂的立场看，基因转导系统就是药物释放系统(DDS)。有多种化学合成的小分子构建的基因转导系统受到关注，其中阳离子脂质构成的基因转导系统是关注热点。阳离子脂质在药学领域遍用于构建脂质体运载小分子(包括多肽)药物。与在DDS中一样，在基因转导系统中阳离子脂质体有明显好处，例如可通过电荷吸附与DNA形成复合物并有效避免被细胞内溶酶体降解、可将DNA高效导入细胞、对DNA的尺寸没有限制、操作简便等。阳离子脂质的基本构造如下：In the next 5 to 10 years, gene therapy will have an ideal carrier for delivering genes to cells. From a biologics standpoint, a gene delivery system is a drug delivery system (DDS). There are a variety of gene transduction systems constructed by chemically synthesized small molecules that have attracted attention, among which the gene transduction system composed of cationic lipids is the focus of attention. Cationic lipids are widely used in the pharmaceutical field to construct liposomes to carry small molecule (including polypeptide) drugs. As in DDS, cationic liposomes have obvious advantages in gene transduction systems, such as forming complexes with DNA through charge adsorption and effectively avoiding degradation by intracellular lysosomes, efficiently introducing DNA into cells, and There is no limit to the size, easy to operate, etc. The basic structure of cationic lipids is as follows:

包括高级脂肪链构成的疏水臂和亲水的阳离子头。It includes hydrophobic arms composed of higher fatty chains and hydrophilic cationic heads.

细胞黏附在细胞黏附性疾病(癌转移、血栓形成、化学致炎和骨质疏松)的发展过程中起关键作用。调节性糖蛋白例如RGD肽与整合素受体有很强的结合能力，可参与细胞黏附过程。例如RGD肽与血小板、肿瘤细胞及骨基表面的GP IIb/IIIa受体特异性结合可干预血栓、癌转移和骨质疏松的发展过程。RGD肽的这种作用赋予了含RGD序列的化合物一种重要性质，即含RGD序列的化合物可以向血栓、癌转移和骨质疏松的患病部位富集。在这样个前提下，把RGD肽与高级脂肪链缀合，便可以获得靶向药质体。Cell adhesion plays a key role in the development of cell-adhesive diseases (cancer metastasis, thrombosis, chemical inflammation, and osteoporosis). Regulatory glycoproteins such as RGD peptides have a strong binding ability to integrin receptors and can participate in the process of cell adhesion. For example, RGD peptide specifically binds to platelets, tumor cells and GP IIb/IIIa receptors on the surface of bone substrates, which can interfere with the development of thrombus, cancer metastasis and osteoporosis. This role of RGD peptide endows an important property of the compound containing RGD sequence, that is, the compound containing RGD sequence can be enriched in the diseased sites of thrombus, cancer metastasis and osteoporosis. Under such a premise, the targeted drug plastid can be obtained by conjugating the RGD peptide with a higher fatty chain.

发明内容Contents of the invention

本发明目的之一是提供一类靶向阳离子药质体。这类靶向阳离子药质体，为通式CH₃(CH₂)₆R₁所示，其中R₁选自CORGDS、CORGDV、CORGDF、RGDSOCH₂、RGDVOCH₂、RGDFOCH₂、RGDSNHCH₂、RGDVNHCH₂或RGDFNHCH₂；其中所述的R为精氨酸(Arg)的缩写，G为甘氨酸(Gly)的缩写，D为天冬氨酸(Asp)的缩写，V为缬氨酸(Val)的缩写，F为苯丙氨酸(Phe)的缩写，S为丝氨酸(Ser)的缩写。One of the objectives of the present invention is to provide a class of targeting cationic drug plastids. This type of targeted cationic drug plasmid is represented by the general formula CH₃ (CH₂ )₆ R₁ , wherein R₁ is selected from CORGDS, CORGDV, CORGDF, RGDSOCH₂ , RGDVOCH₂ , RGDFOCH₂ , RGDSNHCH₂ , RGDVNHCH₂ or RGDFNHCH₂ ; wherein R is the abbreviation of arginine (Arg), G is the abbreviation of glycine (Gly), D is the abbreviation of aspartic acid (Asp), V is the abbreviation of valine (Val), F is the abbreviation of phenylalanine (Phe), and S is the abbreviation of serine (Ser).

本发明结合了下述认识或依据完成了上述技术方案：把基因传送至细胞的理想载体(基因转导系统)是基因治疗的关键任务之一；从生物制剂的立场看基因转导系统与药物释放系统(DDS)具有等同性；虽然有多种化学合成的小分子构建的基因转导系统都受到关注但是阳离子脂质构成的基因转导系统应格外给予关注；阳离子脂质体可通过电荷吸附与DNA形成复合物并有效避免被细胞内溶酶体降解；阳离子脂质体可将DNA高效导入细胞、阳离子脂质体对DNA的尺寸没有限制；血小板、炎症组织、癌细胞和骨基质表明富含可识别RGD序列的细胞黏附受体，含RGD序列的化合物可以向血栓、炎症、癌转移和骨质疏松的患病部位富集。The present invention combines the following understandings or completes the above-mentioned technical scheme: the ideal carrier (gene transduction system) for transferring genes to cells is one of the key tasks of gene therapy; The release system (DDS) is equivalent; although there are a variety of chemically synthesized small molecule gene transduction systems that have received attention, the gene transduction system composed of cationic lipids should be given special attention; cationic liposomes can be absorbed by charge Form a complex with DNA and effectively avoid degradation by intracellular lysosomes; cationic liposomes can efficiently introduce DNA into cells, and cationic liposomes have no limitation on the size of DNA; platelets, inflammatory tissues, cancer cells and bone matrix show rich The cell adhesion receptor containing the RGD sequence can be recognized, and the compound containing the RGD sequence can be enriched in the diseased parts of thrombus, inflammation, cancer metastasis and osteoporosis.

本发明人基于上述认识，把正庚烷基链通过羰基、甲氨基及甲氧基与RGD肽的羧端或氨端缀合，使制得的分子获得四种性能，即依赖于正庚烷基链的疏水性、依赖于RGD肽的胍基和α-氨基质子化形成的阳离子性质和亲水性和依赖于RGD肽对GPIIb/IIIa受体特异亲和作用获得的靶向性。这样一来，把RGD肽与正庚烷基链缀合制得的分子便成为靶向阳离子药质体。Based on the above knowledge, the present inventors conjugated the n-heptyl chain to the carboxyl or amino end of the RGD peptide through carbonyl, methylamino and methoxy groups, so that the obtained molecule obtained four properties, namely, dependent on n-heptane The hydrophobicity of the base chain depends on the cationic properties and hydrophilicity formed by the protonation of the guanidinium and α-amino groups of the RGD peptide, and the targeting properties obtained by the specific affinity of the RGD peptide to the GPIIb/IIIa receptor. In this way, the molecule prepared by conjugating the RGD peptide to the n-heptyl chain becomes a targeted cationic pharmacosome.

本发明的目的之是二提供一种制备通式CH₃(CH₂)₆R₁化合物的方法，其中R₁选自-CORGDS、-CORGDV、-CORGDF、RGDSOCH₂-、RGDVOCH₂-、RGDFOCH₂-、RGDSNHCH₂-、RGDVNHCH₂-或RGDFNHCH₂-。The second object of the present invention is to provide a method for preparing the compound of general formula CH₃ (CH₂ )₆ R₁ , wherein R₁ is selected from -CORGDS, -CORGDV, -CORGDF, RGDSOCH₂ -, RGDVOCH₂ -, RGDFOCH₂ -,_RGDSNHCH2- ,_RGDVNHCH2- , or_RGDFNHCH2- .

本发明的目的之二是通过以下技术方案来实现的：Two of the purpose of the present invention is achieved through the following technical solutions:

(1)按照现有液相接肽技术分别合成RGDS、RGDV和RGDF；(1) Synthesize RGDS, RGDV and RGDF respectively according to the existing liquid-phase peptide connection technology;

(2)将CH₃(CH₂)₆COOH、CH₃(CH₂)₆CH₂OH或CH₃(CH₂)₆CH₂NH₂分别与保护基保护的RGDS、RGDV和RGDF偶联，脱去保护基，即得。(2) Coupling CH₃ (CH₂ )₆ COOH, CH₃ (CH₂ )₆ CH₂ OH or CH₃ (CH₂ )₆ CH₂ NH₂ with protecting group-protected RGDS, RGDV and RGDF, respectively, and removing Remove the protective group, that is.

在大鼠血栓形成模型上的评价表明，本发明靶向阳离子药质体具有优秀的静脉和口服抗血栓活性，可作为抗血栓剂应用；在水相和生物相检测了这9种靶向阳离子药质体自组装成为纳米颗粒的性能，试验结果表明，本发明靶向阳离子药质体具有优秀的自组装性能，可作为制备微乳、脂质体等的制剂材料；因为这9种靶向阳离子药质体的静脉和口服抗血栓活性来自RGD肽对GP IIb/IIIa受体特异亲和作用，所以这种抗血栓活性又表征了9种靶向阳离子药质体的靶向性，所以本发明靶向阳离子药质体可作为靶向制剂材料。The evaluation on the rat thrombosis model shows that the targeted cationic drug substance of the present invention has excellent intravenous and oral antithrombotic activity, and can be used as an antithrombotic agent; the nine targeted cationic drugs were tested in the aqueous phase and biological phase Pharmacosome self-assembles into the performance of nanoparticle, and test result shows, the target cationic drug plasmid of the present invention has excellent self-assembly performance, can be used as the preparation material of preparation microemulsion, liposome etc.; Because these 9 kinds of targeting The intravenous and oral antithrombotic activity of the cationic drug plasmid comes from the specific affinity of the RGD peptide to the GP IIb/IIIa receptor, so this antithrombotic activity characterizes the targeting of the nine cationic drug plasmids, so this paper The inventive targeted cationic drug plastid can be used as targeted preparation material.

附图说明Description of drawings

图1正庚烷基和RGD肽通过羰基、甲氨基及甲氧基缀合制备靶向阳离子药质体的合成路线。I)DCC、HOBt、NMM和HCl·GlyOMe；II)NaOH水溶液(2N)；III)DCC、HOBt、NMM和HCl·Ser-OBzl或HCl·Val-OBzl或HCl·Phe-OBzl；IV)氯化氢/乙酸乙酯溶液(4N)；V)DCC、HOBt、NMM；VI)5％钯碳和氢气(0.02Mba).其中AA＝Phe，Val，Ser。Fig. 1 The synthesis route of n-heptyl and RGD peptides prepared by conjugation of carbonyl, methylamino and methoxy groups to target cationic drug plastids. I) DCC, HOBt, NMM and HCl GlyOMe; II) NaOH aqueous solution (2N); III) DCC, HOBt, NMM and HCl Ser-OBzl or HCl Val-OBzl or HCl Phe-OBzl; IV) hydrogen chloride/ Ethyl acetate solution (4N); V) DCC, HOBt, NMM; VI) 5% palladium on carbon and hydrogen (0.02 Mba). Where AA=Phe, Val, Ser.

图2由扫描电镜描述的本发明的代表性化合物在水相组装的纳米球。Fig. 2 Nanospheres assembled in aqueous phase of representative compounds of the present invention depicted by scanning electron microscopy.

图3由扫描电镜描述的本发明的代表性化合物在脂相组装的纳米球。Figure 3 is a scanning electron microscope depiction of nanospheres assembled in lipid phase by representative compounds of the present invention.

为了进一步阐述本发明，下面给出一系列实施例。这些实施例完全是例证性的，它们仅用来对本发明进行具体描述，不应当理解为对本发明的限制。In order to further illustrate the present invention, a series of examples are given below. These examples are entirely illustrative, and they are only used to specifically describe the present invention, and should not be construed as limiting the present invention.

具体实施方式Detailed ways

实施例1 RGDS的制备The preparation ofembodiment 1 RGDS

1)Boc-Arg(NO₂)-Gly-OMe的制备1) Preparation of Boc-Arg(NO₂ )-Gly-OMe

将1.600g(5.0mmol)Boc-Arg(NO₂)-OH溶于20ml无水DMF，冰浴下往得到的溶液中加入0.675g(5mmol)N-羟基苯并三氮唑(HOBt)，并使完全溶解。10分钟后加入1.071g(6mmol)二环己基羰二亚胺(DCC)。得到反应液(I)，待用。冰浴下把0.627g(5.0mmol)HCl·Gly-OMe(5mmol)悬浮于20ml无水DMF中，然后加入1ml N-甲基吗啉(NMM)，调pH 8-9。搅拌35分钟，得到反应液(II)，待用。冰浴下把反应液(I)加入反应液(II)中，先冰浴下搅拌1h，再室温搅拌12h，TLC(氯仿/甲醇，10∶1)显示Boc-Arg(NO₂)-OH消失。滤除二环己基脲(DCU)，滤液吹去DMF。残留物用50ml氯仿溶解。得到的溶液依次用饱和NaHCO₃水溶液洗、饱和NaCl水溶液洗、5％KHSO₄水溶液洗和饱和NaCl水溶液洗。氯仿层用无水Na₂SO₄干燥、过滤、滤液减压浓缩至干，得到3.80g(100％)标题化合物，为米黄色固体。ESI-MS(m/z)：392[M]⁺，[α]_D²⁰＝-18.5657(c＝1，CH₃OH)。1.600g (5.0mmol) Boc-Arg(NO₂ )-OH was dissolved in 20ml anhydrous DMF, and 0.675g (5mmol) N-hydroxybenzotriazole (HOBt) was added to the resulting solution under ice cooling, and to dissolve completely. After 10 minutes 1.071 g (6 mmol) of dicyclohexylcarbodiimide (DCC) were added. Obtain reaction liquid (I), stand-by. Suspend 0.627g (5.0mmol) HCl·Gly-OMe (5mmol) in 20ml anhydrous DMF under ice-cooling, then add 1ml N-methylmorpholine (NMM) to adjust the pH to 8-9. Stir for 35 minutes to obtain the reaction solution (II), which is ready for use. Add the reaction solution (I) to the reaction solution (II) under ice-cooling, first stir under ice-cooling for 1 h, then stir at room temperature for 12 h, TLC (chloroform/methanol, 10:1) shows that Boc-Arg(NO₂ )-OH disappears . Dicyclohexylurea (DCU) was filtered off, and the filtrate was blown off of DMF. The residue was dissolved in 50 ml of chloroform. The obtained solution was washed successively with saturated NaHCO₃ aqueous solution, saturated NaCl aqueous solution, 5% KHSO₄ aqueous solution and saturated NaCl aqueous solution. The chloroform layer was dried over anhydrous_Na2SO4 , filtered, and the filtrate was concentrated to dryness under reduced pressure to afford 3.80_g (100%) of the title compound as a beige solid. ESI-MS (m/z): 392 [M]⁺ , [α]_D²⁰ = -18.5657 (c = 1, CH₃ OH).

2)Boc-Arg(NO₂)-Gly-OH的制备2) Preparation of Boc-Arg(NO₂ )-Gly-OH

将0.392g(1.0mmol)Boc-Arg(NO₂)-Gly-OMe溶于10ml甲醇。冰浴下将得到的溶液用NaOH(2N)水溶液调pH12并搅拌2h，TLC(氯仿/甲醇，1∶1)显示Boc-Arg(NO₂)-Gly-OMe消失。反应混合物用稀盐酸(2N)调pH7，减压浓缩除甲醇。残留物用稀盐酸(2N)调pH2、用乙酸乙酯萃取(30ml×3)。合并的乙酸乙酯相用饱和NaCl水溶液洗至中性，无水Na₂SO₄干燥。过滤，滤液减压浓缩至干，得0.339g(90％)标题化合物，为米黄色固体。MS：375.3[M]^-，[α]^D₂₀＝-2.1644(c＝1，CH₃OH)0.392 g (1.0 mmol) Boc-Arg(NO₂ )-Gly-OMe was dissolved in 10 ml methanol. The resulting solution was adjusted to pH 12 with NaOH (2N) aqueous solution under ice cooling and stirred for 2 h. TLC (chloroform/methanol, 1:1) showed that Boc-Arg(NO₂ )-Gly-OMe disappeared. The reaction mixture was adjusted to pH 7 with dilute hydrochloric acid (2N), and concentrated under reduced pressure to remove methanol. The residue was adjusted topH 2 with dilute hydrochloric acid (2N), and extracted with ethyl acetate (30ml×3). The combined ethyl acetate phases were washed with saturated NaCl aqueous solution until neutral, and dried over_anhydrous_Na2SO4 . After filtration, the filtrate was concentrated to dryness under reduced pressure to afford 0.339 g (90%) of the title compound as a beige solid. MS: 375.3 [M]^- , [α]^D₂₀ = -2.1644 (c = 1, CH₃ OH)

3)Boc-Asp(OBzl)-Ser(Bzl)-OBzl的制备3) Preparation of Boc-Asp(OBzl)-Ser(Bzl)-OBzl

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.620g(5.0mmol)Boc-Asp(OBzl)-OH和1.6075g(5.0mmol)Tos·Ser(Bzl)-OBzl得2.655(99％)标题化合物，为米黄色固体。ESI-MS(m/z)：591.4[M]⁺，[α]^D₂₀＝-13.2108(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, 2.655 (99% ) the title compound as a beige solid. ESI-MS (m/z): 591.4 [M]⁺ , [α]^D₂₀ =-13.2108 (c = 1, CH₃ OH)

4)HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备4) Preparation of HCl Asp(OBzl)-Ser(Bzl)-OBzl

将0.780g(1.491mmol)Boc-Asp(OBzl)-Ser(Bzl)-OBzl溶解在15ml 4mol/l氯化氢-乙酸乙酯溶液中，室温搅拌2小时，TLC(氯仿/甲醇，3/1)显示原料点消失，减压浓缩除去乙酸乙酯，残留物反复加少量乙醚进行减压浓缩以除去氯化氢气。最后加少量乙醚将残留物研磨成0.570g(95.98％)标题化合物，为固体粉末，直接用于下一步反应。ESI-MS(m/z)：491.3[M]⁺，[α]^D₂₀＝-55.4369(c＝1.0，CH₃OH)。0.780g (1.491mmol) Boc-Asp(OBzl)-Ser(Bzl)-OBzl was dissolved in 15ml 4mol/l hydrogen chloride-ethyl acetate solution, stirred at room temperature for 2 hours, TLC (chloroform/methanol, 3/1) showed The raw material point disappeared, concentrated under reduced pressure to remove ethyl acetate, and the residue was repeatedly added with a small amount of ether for concentration under reduced pressure to remove hydrogen chloride gas. Finally, a small amount of diethyl ether was added to grind the residue into 0.570 g (95.98%) of the title compound as solid powder, which was directly used in the next reaction. ESI-MS (m/z): 491.3 [M]⁺ , [α]^D₂₀ = -55.4369 (c = 1.0, CH₃ OH).

5)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl的制备5) Preparation of Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Ser(Bzl)-OBzl

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由0.831g(3.0mmol)Boc-Arg(NO₂)-Gly-OH和1.5795g(3.0mmol)HCl·Asp(OBzl)-Ser(Bzl)-OBzl得2.165g(85％)标题化合物，为米黄色固体。ESI-MS(m/z)：850[M]⁺，[α]^D₂₀＝-16.3729(c＝1.0，CHCl₃)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, 0.831g (3.0mmol) Boc-Arg(NO₂ )-Gly-OH and 1.5795g (3.0mmol) HCl·Asp(OBzl)-Ser(Bzl )-OBzl afforded 2.165 g (85%) of the title compound as a beige solid. ESI-MS (m/z): 850 [M]⁺ , [α]^D₂₀ =-16.3729 (c = 1.0, CHCl₃ )

6)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl的制备6) Preparation of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Ser(Bzl)-OBzl

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.849g(1.0mmol)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl制得0.712g(95％)标题化合物，为米黄色固体。ESI-MS(m/z)：750.1[M]⁺，[α]^D₂₀＝-58.3196(c＝1.0，CH₃OH)。According to the preparation method of HCl Asp(OBzl)-Ser(Bzl)-OBzl, 0.712g was prepared from 0.849g (1.0mmol) Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Ser(Bzl)-OBzl (95%) The title compound as a beige solid. ESI-MS (m/z): 750.1 [M]⁺ , [α]^D₂₀ = -58.3196 (c = 1.0, CH₃ OH).

7)RGDS的制备7) Preparation of RGDS

将0.750g(1mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl置于50ml茄形瓶中、用乙醇溶解、加200mgPd/C(5％)、通H₂(0.02Mba)，室温搅拌至原料点消失。滤除Pd/C、滤液减压浓缩至干，残留物反复用石油醚研磨，得0.389g(90％)标题化合物，为无色固体粉末。ESI-MS(m/z)：434.4[M]⁺，[α]²⁰_D＝6.0(c＝1.0，H₂O).Put 0.750g (1mmol) HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Ser(Bzl)-OBzl in a 50ml eggplant-shaped bottle, dissolve with ethanol, add 200mgPd/C (5%), pass through H₂ (0.02Mba), stir at room temperature until the raw material point disappears. Pd/C was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was repeatedly triturated with petroleum ether to obtain 0.389 g (90%) of the title compound as a colorless solid powder. ESI-MS (m/z): 434.4 [M]⁺ , [α]²⁰_D = 6.0 (c = 1.0, H₂ O).

实施例2 RGDV的制备The preparation ofembodiment 2 RGDV

1)Boc-Asp(OBzl)-Val-OBzl的制备1) Preparation of Boc-Asp(OBzl)-Val-OBzl

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.620g(5.0mmol)Boc-Asp(OBzl)-OH和1.895g(5.0mmol)Tos·Val-OBzl得2.5344g(99％)标题化合物，为米黄色固体。ESI-MS(m/z)：513.3[M]⁺，[α]^D₂₀＝-14.2710(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, 2.5344g (99%) of the title was obtained from 1.620g (5.0mmol) Boc-Asp(OBzl)-OH and 1.895g (5.0mmol) Tos·Val-OBzl Compound, as beige solid. ESI-MS (m/z): 513.3 [M]⁺ , [α]^D₂₀ =-14.2710 (c = 1, CH₃ OH)

2)HCl·Asp(OBzl)-Val-OBzl的制备2) Preparation of HCl Asp(OBzl)-Val-OBzl

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.763g(1.491mmol)Boc-Asp(OBzl)-Val-OBzl得0.662g(99％)标题化合物，为固体粉末，直接用于下一步反应。ESI-MS(m/z)：413.4[M]⁺，[α]^D₂₀＝-47.8027(c＝1，CH₃OH)According to the preparation method of HCl Asp(OBzl)-Ser(Bzl)-OBzl, 0.662g (99%) of the title compound was obtained from 0.763g (1.491mmol) Boc-Asp(OBzl)-Val-OBzl as solid powder, directly for the next reaction. ESI-MS (m/z): 413.4[M]⁺ , [α]^D₂₀ =-47.8027 (c=1, CH₃ OH)

3)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Val-OBzl的制备3) Preparation of Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Val-OBzl

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由0.831g(3.0mmol)Boc-Arg(NO₂)-Gly-OH和1.3455g(3.0mmol)HCl·Asp(OBzl)-Val-OBzl得2.08(90％)标题化合物，为米黄色固体。ESI-MS(m/z)：771.6[M]⁺，[α]^D₂₀＝-30.9346(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 0.831g (3.0mmol) Boc-Arg(NO₂ )-Gly-OH and 1.3455g (3.0mmol) HCl·Asp(OBzl)-Val-OBzl Yield 2.08 (90%) of the title compound as a beige solid. ESI-MS (m/z): 771.6 [M]⁺ , [α]^D₂₀ =-30.9346 (c = 1, CH₃ OH)

4)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Val-OBzl的制备4) Preparation of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Val-OBzl

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.771g(1.0mmol)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Val-OBzl制得0.637g(95％)标题化合物，为米黄色固体。ESI-MS(m/z)：672.1[M]⁺，[α]^D₂₀＝-50.8685(c＝1，CH₃OH)According to_the preparation method of HCl·Asp(OBzl)-Ser(Bzl)-OBzl, 0.637g (95% ) the title compound as a beige solid. ESI-MS (m/z): 672.1 [M]⁺ , [α]^D₂₀ =-50.8685 (c = 1, CH₃ OH)

5)RGDV的制备5) Preparation of RGDV

按照RGDS的制备方法，从0.672g(1mmol)HCl Arg(NO₂)-Gly-Asp(OBzl)-Val-OBzl得0.382g(85％)标题化合物，为无色固体粉末。ESI-MS(m/z)：446.4[M]⁺，[α]²⁰_D＝3.0(c＝1.0，H₂O).According to the preparation method of RGDS, 0.382 g (85%) of the title compound was obtained as a colorless solid powder from 0.672 g (1 mmol) of HCl Arg(NO₂ )-Gly-Asp(OBzl)-Val-OBzl. ESI-MS (m/z): 446.4 [M]⁺ , [α]²⁰_D = 3.0 (c = 1.0, H₂ O).

实施例3 RGDF的制备The preparation of embodiment 3 RGDF

1)Boc-Asp(OBzl)-Phe-OBzl的制备1) Preparation of Boc-Asp(OBzl)-Phe-OBzl

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.620g(5.0mmol)Boc-Asp(OBzl)-OH和2.135g(5.0mmol)Tos·Phe-OBzl得2.77g(99％)标题化合物，为米黄色固体。ESI-MS(m/z)：561.4[M]⁺，[α]^D₂₀＝-15.2842(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, 2.77g (99%) of title were obtained from 1.620g (5.0mmol) Boc-Asp(OBzl)-OH and 2.135g (5.0mmol) Tos·Phe-OBzl Compound, as beige solid. ESI-MS (m/z): 561.4 [M]⁺ , [α]^D₂₀ =-15.2842 (c = 1, CH₃ OH)

2)HCl·Asp(OBzl)-Phe-OBzl的制备2) Preparation of HCl Asp(OBzl)-Phe-OBzl

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.835g(1.491mmol)Boc-Asp(OBzl)-Phe-OBzl得0.703g(95％)标题化合物，为固体粉末，直接用于下一步反应。ESI-MS(m/z)：461.3[M]⁺，[α]^D₂₀＝-44.8753(c＝1，CH₃OH)。According to the preparation method of HCl Asp(OBzl)-Ser(Bzl)-OBzl, 0.703g (95%) of the title compound was obtained from 0.835g (1.491mmol) Boc-Asp(OBzl)-Phe-OBzl as solid powder, directly for the next reaction. ESI-MS (m/z): 461.3 [M]⁺ , [α]^D₂₀ = -44.8753 (c = 1, CH₃ OH).

3)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Phe-OBzl的制备3) Preparation of Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OBzl

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由0.831g(3.0mmol)Boc-Arg(NO₂)-Gly-OH和1.4895g(3.0mmol)HCl·Asp(OBzl)-Phe-OBzl得2.16g(88％)标题化合物，为米黄色固体。ESI-MS(m/z)：819.5[M]⁺，[α]^D₂₀＝-20.3583(c＝1，CH₃OH).According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 0.831g (3.0mmol) Boc-Arg(NO₂ )-Gly-OH and 1.4895g (3.0mmol) HCl·Asp(OBzl)-Phe-OBzl Yield 2.16 g (88%) of the title compound as a beige solid. ESI-MS (m/z): 819.5 [M]⁺ , [α]^D₂₀ =-20.3583 (c = 1, CH₃ OH).

4)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Phe-OBzl的制备4) Preparation of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OBzl

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.819g(1.0mmol)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Phe-OBzl制得0.717g(95％)标题化合物，为米黄色固体。ESI-MS(m/z)：719.4[M]⁺，[α]^D₂₀＝-10.6121(c＝1，CH₃OH).According to_the preparation method of HCl·Asp(OBzl)-Ser(Bzl)-OBzl, 0.717g (95% ) the title compound as a beige solid. ESI-MS (m/z): 719.4[M]⁺ , [α]^D₂₀ =-10.6121 (c=1, CH₃ OH).

5)RGDF的制备5) Preparation of RGDF

按照RGDS的制备方法，从0.719g(1mmol)HCl Arg(NO₂)-Gly-Asp(OBzl)-Phe-OBzl得0.443g(90％)标题化合物，为无色固体粉末。ESI-MS(m/z)：494.5[M]⁺，[α]²⁰_D＝4.0(c＝2.0，H₂O).According to the preparation method of RGDS, 0.443 g (90%) of the title compound was obtained as a colorless solid powder from 0.719 g (1 mmol) of HCl Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OBzl. ESI-MS (m/z): 494.5 [M]⁺ , [α]²⁰_D = 4.0 (c = 2.0, H₂ O).

实施例4 CH₃(CH₂)₆CORGDS的制备Example 4 Preparation of CH₃ (CH₂ )₆ CORGDS

1)CH₃(CH₂)₁₀CO-Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl的制备1) Preparation of CH₃ (CH₂ )₁₀ CO-Arg(NO₂ )-Gly-Asp(OBzl)-Ser(Bzl)-OBzl

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由0.72g(5.0mmol)CH₃(CH₂)₆CO₂H和3.9275g(5.0mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl制得3.85g(85.6％)标题化合物，为黄色蜡状固体。ESI-MS(m/z)：876.7[M]⁺，[α]^D₂₀＝-10.8309(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 0.72g (5.0mmol) CH₃ (CH₂ )₆ CO₂ H and 3.9275g (5.0mmol) HCl·Arg(NO₂ )-Gly-Asp (OBzl)-Ser(Bzl)-OBzl yielded 3.85 g (85.6%) of the title compound as a yellow waxy solid. ESI-MS (m/z): 876.7 [M]⁺ , [α]^D₂₀ =-10.8309 (c = 1, CH₃ OH)

2)CH₃(CH₂)₆CO-Arg-Gly-Asp-Ser-OH的制备2) Preparation of CH₃ (CH₂ )₆ CO-Arg-Gly-Asp-Ser-OH

按照RGDS的制备方法由0.876g(1mmol)CH₃(CH₂)₆CO-Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OBzl制得0.39g(70％)标题化合物，为黄色蜡状固体。ESI-MS(m/z)：558.1[M]⁺，[α]^D₂₀＝-9.5645(c＝1，CH₃OH)According to the preparation method of RGDS, 0.39 g (70%) of the title compound was prepared from 0.876 g (1 mmol) of CH₃ (CH₂ )₆ CO-Arg(NO₂ )-Gly-Asp(OBzl)-Ser(Bzl)-OBzl, It is a yellow waxy solid. ESI-MS (m/z): 558.1 [M]⁺ , [α]^D₂₀ =-9.5645 (c = 1, CH₃ OH)

实施例5 CH₃(CH₂)₆CORGDV的制备Example 5 Preparation of CH₃ (CH₂ )₆ CORGDV

1)CH₃(CH₂)₆CO-Arg(NO₂)-Gly-Asp(OBzl)-Val-OBzl的制备1) Preparation of CH₃ (CH₂ )₆ CO-Arg(NO₂ )-Gly-Asp(OBzl)-Val-OBzl

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由0.72g(5.0mmol)CH₃(CH₂)₆CO₂H和3.53g(5.0mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Val-OBzl制得3.27g(82％)标题化合物，为黄色蜡状固体。ESI-MS(m/z)：797.3[M]⁺.[α]^D₂₀＝-5.0652(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 0.72g (5.0mmol) CH₃ (CH₂ )₆ CO₂ H and 3.53g (5.0mmol) HCl·Arg(NO₂ )-Gly-Asp (OBzl)-Val-OBzl yielded 3.27 g (82%) of the title compound as a yellow waxy solid. ESI-MS (m/z): 797.3[M]⁺ .[α]^D₂₀ =-5.0652 (c=1, CH₃ OH)

2)CH₃(CH₂)₆CO-Arg-Gly-Asp-Val-OH的制备2) Preparation of CH₃ (CH₂ )₆ CO-Arg-Gly-Asp-Val-OH

按照RGDS的制备方法由0.797g(1mmol)CH₃(CH₂)₆CO-Arg(NO₂)-Gly-Asp(OBzl)-Val-OBzl制得0.48g(85％)标题化合物，为黄色蜡状固体。ESI-MS(m/z)：571.9[M]⁺，[α]^D₂₀＝-8.6308(c＝1，CH₃OH)According to the preparation method of RGDS, 0.48 g (85%) of the title compound was obtained as a yellow wax from 0.797 g (1 mmol) of CH₃ (CH₂ )₆ CO-Arg(NO₂ )-Gly-Asp(OBzl)-Val-OBzl shaped solid. ESI-MS (m/z): 571.9 [M]⁺ , [α]^D₂₀ =-8.6308 (c = 1, CH₃ OH)

实施例6 CH₃(CH₂)₆CORGDF的制备Example 6 Preparation of CH₃ (CH₂ )₆ CORGDF

1)CH₃(CH₂)₆CO-Arg(NO₂)-Gly-Asp(OBzl)-Phe-OBzl的制备1) Preparation of CH₃ (CH₂ )₆ CO-Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OBzl

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由0.72g(5.0mmol)CH₃(CH₂)₆CO₂H和3.77g(5.0mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Phe-OBzl制得3.28g(70％)标题化合物，为黄色蜡状固体。ESI-MS(m/z)：846.8[M]⁺，[α]^D₂₀＝-11.7641(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 0.72g (5.0mmol) CH₃ (CH₂ )₆ CO₂ H and 3.77g (5.0mmol) HCl·Arg(NO₂ )-Gly-Asp (OBzl)-Phe-OBzl yielded 3.28 g (70%) of the title compound as a yellow waxy solid. ESI-MS (m/z): 846.8 [M]⁺ , [α]^D₂₀ =-11.7641 (c = 1, CH₃ OH)

2)CH₃(CH₂)₆CO-Arg-Gly-Asp-Phe-OH的制备2) Preparation of CH₃ (CH₂ )₆ CO-Arg-Gly-Asp-Phe-OH

按照RGDS的制备方法由0.845g(1mmol)CH₃(CH₂)₆CO-Arg(NO₂)-Gly-Asp(OBzl)-Phe-OBzl制得0.39g(63％)标题化合物，为黄色蜡状固体。ESI-MS(m/z)：620.0[M]⁺，[α]^D₂₀＝-6.0986(c＝1，CH₃OH)According to the preparation method of RGDS, 0.39 g (63%) of the title compound was obtained as a yellow wax from 0.845 g (1 mmol) CH₃ (CH₂ )₆ CO-Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OBzl shaped solid. ESI-MS (m/z): 620.0 [M]⁺ , [α]^D₂₀ =-6.0986 (c = 1, CH₃ OH)

实施例7 RGDS-OCH₂(CH₂)₆CH₃的制备Example 7 Preparation of RGDS-OCH₂ (CH₂ )₆ CH₃

1)Boc-Ser(BZl)-OCH₂(CH₂)₆CH₃的制备1) Preparation of Boc-Ser(BZl)-OCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.48g(5mmol)Boc-Ser(Bzl)-OH和0.72g(5.0mmol)CH₃(CH₂)₆CH₂OH制得1.93g(95％)标题化合物，为无色油状物。ESI-MS(m/z)：408.1[M]⁺，[α]^D₂₀＝-1.2997(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, 1.93 g was prepared from 1.48 g (5 mmol) Boc-Ser(Bzl)-OH and 0.72 g (5.0 mmol) CH₃ (CH₂ )₆ CH₂ OH (95%) The title compound as a colorless oil. ESI-MS (m/z): 408.1 [M]⁺ , [α]^D₂₀ =-1.2997 (c = 1, CH₃ OH)

2)HCl·Ser(Bzl)-OCH₂(CH₂)₆CH₃的制备2) Preparation of HCl·Ser(Bzl)-OCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.41g(1.0mmol)Boc-Ser(BZl)-OCH₂(CH₂)₆CH₃制得0.29g(95％)标题化合物，为米黄色固体。ESI-MS(m/z)：308.1[M]⁺，[α]^D₂₀＝-6.9982(c＝1，CH₃OH)Following the preparation of HCl Asp(OBzl)-Ser(Bzl)-OBzl, 0.29 g (95%) of the title was prepared from 0.41 g (1.0 mmol) of Boc-Ser(BZl)-OCH₂ (CH₂ )₆ CH₃ Compound, as beige solid. ESI-MS (m/z): 308.1 [M]⁺ , [α]^D₂₀ =-6.9982 (c = 1, CH₃ OH)

3)Boc-Asp(OBzl)-Ser(Bzl)-OCH₂(CH₂)₆CH₃的制备3) Preparation of Boc-Asp(OBzl)-Ser(Bzl)-OCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.615g(5mmol)Boc-Asp(OBzl)-OH和1.72(5.0mmol)HCl·Ser(Bzl)-OCH₂(CH₂)₆CH₃制得2.81g(92％)标题化合物，为无色油状物。ESI-MS(m/z)：612.9[M]⁺，[α]^D₂₀＝-13.8921(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 1.615g (5mmol) Boc-Asp(OBzl)-OH and 1.72(5.0mmol) HCl·Ser(Bzl)-OCH₂ (CH₂ )₆ CH₃ Yield 2.81 g (92%) of the title compound as a colorless oil. ESI-MS (m/z): 612.9 [M]⁺ , [α]^D₂₀ =-13.8921 (c = 1, CH₃ OH)

4)HCl·Asp(OBzl)-Ser(Bzl)-OCH₂(CH₂)₆CH₃的制备4) Preparation of HCl·Asp(OBzl)-Ser(Bzl)-OCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.61g(1.0mmol)Boc-Asp(OBzl)-Ser(BZl)O₂CH₂(CH₂)₆CH₃制得0.46g(90％)标题化合物，为米黄色固体。ESI-MS(m/z)：512.8[M]⁺，[α]^D₂₀＝-1.3995(c＝1，CH₃OH)According to the preparation_method of HCl·Asp(_OBzl₎_-Ser (Bzl)-OBzl,_0.46 g (90%) of the title compound as a beige solid. ESI-MS (m/z): 512.8 [M]⁺ , [α]^D₂₀ =-1.3995 (c = 1, CH₃ OH)

5)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Ser(BZl)-OCH₂(CH₂)₆CH₃的制备5) Preparation of Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Ser(BZl)-OCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.885g(5.0mmol)Boc-Arg(NO₂)-Gly-OH和2.74g(5.0mmol)HCl·Asp(OBzl)-Ser(Bzl)-OCH₂(CH₂)₆CH₃制得3.74g(86％)标题化合物，为无色固体。ESI-MS(m/z)：817.2[M]⁺，[α]^D₂₀＝-19.0958(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, 1.885g (5.0mmol) Boc-Arg(NO₂ )-Gly-OH and 2.74g (5.0mmol) HCl·Asp(OBzl)-Ser(Bzl₎_-OCH2 (_CH2 )_6CH3 yielded 3.74 g (86%) of the title compound as a colorless solid. ESI-MS (m/z): 817.2 [M]⁺ , [α]^D₂₀ =-19.0958 (c = 1, CH₃ OH)

6)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OCH₂(CH₂)₆CH₃的制备6) Preparation of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Ser(Bzl)-OCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.817g(1.0mmol)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OCH₂(CH₂)₆CH₃制得0.66g(93％)标题化合物，为米黄色固体。ESI-MS(m/z)：717.9[M]⁺，[α]^D₂₀＝-2.3992(c＝1，CH₃OH)According to the preparation method of HCl·Asp(OBzl)-Ser(Bzl)-OBzl, from 0.817g (1.0mmol) Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Ser(Bzl)-OCH₂ (CH₂ )₆ CH₃ yielded 0.66 g (93%) of the title compound as a beige solid. ESI-MS (m/z): 717.9 [M]⁺ , [α]^D₂₀ =-2.3992 (c = 1, CH₃ OH)

7)RGDS-OCH₂(CH₂)₆CH₃的制备7) Preparation of RGDS-OCH₂ (CH₂ )₆ CH₃

按照RGDS的制备方法由0.75g(1mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Ser(Bzl)-OCH₂(CH₂)₆CH₃制得0.49g(90％)标题化合物，为无色固体。ESI-MS(m/z)：545.8[M]⁺，[α]^D₂₀＝-32.0584(c＝1，CH₃OH)According to the preparation method of RGDS, 0.49 g (90%) of the title compound was obtained from 0.75 g (1 mmol) of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Ser(Bzl)-OCH₂ (CH₂ )₆ CH₃ , a colorless solid. ESI-MS (m/z): 545.8 [M]⁺ , [α]^D₂₀ =-32.0584 (c = 1, CH₃ OH)

实施例8 RGDV-OCH₂(CH₂)₆CH₃的制备Example 8 Preparation of RGDV-OCH₂ (CH₂ )₆ CH₃

1)Boc-Val-OCH₂(CH₂)₆CH₃的制备1) Preparation of Boc-Val-OCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.085g(5mmol)Boc-Val-OH和0.65g(5.0mmol)CH₃(CH₂)₆CH₂OH制得1.49g(91％)标题化合物，为无色油状物。ESI-MS(m/z)：329.1[M]⁺，[α]^D₂₀＝-84.9145(c＝1，CH₃OH)According to the preparation method_of Boc-Arg(NO₂ )-Gly-OMe_,_1.49_g (91% ) the title compound as a colorless oil. ESI-MS (m/z): 329.1 [M]⁺ , [α]^D₂₀ =-84.9145 (c = 1, CH₃ OH)

2)HCl·Val-OCH₂(CH₂)₆CH₃的制备2) Preparation of HCl Val-OCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.329g(1.0mmol)Boc-Val-OCH₂(CH₂)₆CH₃制得0.288g(90％)标题化合物，为无色固体。ESI-MS(m/z)：230.2[M]⁺，[α]^D₂₀＝5.1659(c＝1，CH₃OH)Following the preparation of HCl Asp(OBzl)-Ser(Bzl)-OBzl, 0.288 g (90%) of the title compound was obtained from 0.329 g (1.0 mmol) Boc-Val-OCH₂ (CH₂ )₆ CH₃ as Colorless solid. ESI-MS (m/z): 230.2[M]⁺ , [α]^D₂₀ =5.1659 (c=1, CH₃ OH)

3)Boc-Asp(OBzl)-Val-OCH₂(CH₂)₆CH₃的制备3) Preparation of Boc-Asp(OBzl)-Val-OCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.605g(5mmol)Boc-Asp(OBzl)-OH和1.3g(5.0mmol)HCl·Val-OCH₂(CH₂)₆CH₃制得2.45g(92％)标题化合物，为无色油状物。ESI-MS(m/z)：535.1[M]⁺，[α]^D₂₀＝-12.4636(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, it is prepared from 1.605g (5mmol) Boc-Asp(OBzl)-OH and 1.3g (5.0mmol) HCl·Val-OCH₂ (CH₂ )₆ CH₃ Yield 2.45 g (92%) of the title compound as a colorless oil. ESI-MS (m/z): 535.1 [M]⁺ , [α]^D₂₀ =-12.4636 (c = 1, CH₃ OH)

4)HCl·Asp(OBzl)-Val-OCH₂(CH₂)₆CH₃的制备4) Preparation of HCl·Asp(OBzl)-Val-OCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.534g(1.0mmol)Boc-Asp(OBzl)-Val-OCH₂(CH₂)₆CH₃制得0.39g(91％)标题化合物，为米黄色固体。ESI-MS(m/z)：435.1[M]⁺，[α]^D₂₀＝-2.3327(c＝1，CH₃OH)According to the preparation method_of HCl·Asp(OBzl)_-Ser (Bzl)_-OBzl_, 0.39g (91% ) the title compound as a beige solid. ESI-MS (m/z): 435.1 [M]⁺ , [α]^D₂₀ =-2.3327 (c = 1, CH₃ OH)

5)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Val-OCH₂(CH₂)₆CH₃的制备5) Preparation of Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Val-OCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.885g(5.0mmol)Boc-Arg(NO₂)-Gly-OH和2.3g(5.0mmol)HCl·Asp(OBzl)-Val-OCH₂(CH₂)₆CH₃制According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 1.885g (5.0mmol) Boc-Arg(NO₂ )-Gly-OH and 2.3g (5.0mmol) HCl·Asp(OBzl)-Val-OCH₂ (CH₂ )₆ CH₃

3.44g(85％)标题化合物，为无色固体。ESI-MS(m/z)：793.2[M]⁺.[α]^D₂₀＝-12.0969(c＝1，CH₃OH)3.44 g (85%) of the title compound as a colorless solid. ESI-MS (m/z): 793.2[M]⁺ .[α]^D₂₀ =-12.0969 (c=1, CH₃ OH)

6)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Val-OCH₂(CH₂)₆CH₃的制备6) Preparation of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Val-OCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.793g(1.0mmol)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Val-OCH₂(CH₂)₆CH₃制得0.64g(92％)标题化合物，为米黄色固体。ESI-MS(m/z)：693.2[M]⁺，[α]^D₂₀＝-2.1663(c＝1，CH₃OH)According to the preparation method of HCl·Asp(OBzl)-Ser(Bzl)-OBzl, from 0.793g (1.0mmol) Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Val-OCH₂ (CH₂ )₆ CH₃ Yield 0.64 g (92%) of the title compound as a beige solid. ESI-MS (m/z): 693.2 [M]⁺ , [α]^D₂₀ =-2.1663 (c = 1, CH₃ OH)

7)RGDV-OCH₂(CH₂)₆CH₃的制备7) Preparation of RGDV-OCH₂ (CH₂ )₆ CH₃

按照RGDS的制备方法由0.7g(1mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Val-OCH₂(CH₂)₆CH₃制得0.47g(85％)标题化合物，为无色固体。ESI-MS(m/z)：557.1[M]⁺.[α]^D₂₀＝-7.0315(c＝1，CH₃OH)According to the preparation method of RGDS, 0.47 g (85%) of the title compound was prepared from 0.7 g (1 mmol) HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Val-OCH₂ (CH₂ )₆ CH₃ as free color solid. ESI-MS (m/z): 557.1[M]⁺ .[α]^D₂₀ =-7.0315 (c=1, CH₃ OH)

实施例9 RGDF-OCH₂(CH₂)₆CH₃的制备Example 9 Preparation of RGDF-OCH₂ (CH₂ )₆ CH₃

1)Boc-Phe-OCH₂(CH₂)₆CH₃的制备1) Preparation of Boc-Phe-OCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.325g(5mmol)Boc-Phe-OH和0.65g(5.0mmol)CH₃(CH₂)₆CH₂OH制得1.85g(98％)标题化合物，为无色油状物。ESI-MS(m/z)：378.3[M]⁺，[α]^D₂₀＝-8.3651(c＝1，CH₃OH)According to the preparation method of Boc-_Arg (NO₂ )-Gly-OMe,_1.85_g (98_% ) the title compound as a colorless oil. ESI-MS (m/z): 378.3 [M]⁺ , [α]^D₂₀ =-8.3651 (c = 1, CH₃ OH)

2)HCl·Phe-OCH₂(CH₂)₆CH₃的制备2) Preparation of HCl·Phe-OCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.377g(1.0mmol)Boc-Phe-OCH₂(CH₂)₆CH₃制得0.26g(95％)标题化合物，为米黄色固体。ESI-MS(m/z)：278.3[M]⁺.[α]^D₂₀＝-2.2326(c＝1，CH₃OH)Following the preparation of HCl Asp(OBzl)-Ser(Bzl)-OBzl, 0.26 g (95%) of the title compound was obtained from 0.377 g (1.0 mmol) Boc-Phe-OCH₂ (CH₂ )₆ CH₃ as Beige solid. ESI-MS (m/z): 278.3[M]⁺ .[α]^D₂₀ =-2.2326 (c=1, CH₃ OH)

3)Boc-Asp(OBzl)-Phe-OCH₂(CH₂)₆CH₃的制备3) Preparation of Boc-Asp(OBzl)-Phe-OCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.605g(5mmol)Boc-Asp(OBzl)-OH和1.56g(5.0mmol)HCl·Phe-OCH₂(CH₂)₆CH₃制得2.6g(90％)标题化合物，为无色油状物。ESI-MS(m/z)：583.2[M]⁺，[α]^D₂₀＝-18.0627(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, it is prepared from 1.605g (5mmol) Boc-Asp(OBzl)-OH and 1.56g (5.0mmol) HCl·Phe-OCH₂ (CH₂ )₆ CH₃ Yield 2.6 g (90%) of the title compound as a colorless oil. ESI-MS (m/z): 583.2 [M]⁺ , [α]^D₂₀ =-18.0627 (c = 1, CH₃ OH)

4)HCl·Asp(OBzl)-Phe-OCH₂(CH₂)₆CH₃的制备4) Preparation of HCl·Asp(OBzl)-Phe-OCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.58g(1.0mmol)Boc-Asp(OBzl)-Phe-OCH₂(CH₂)₆CH₃制得0.43g(95％)标题化合物，为米黄色固体。ESI-MS(m/z)：483.1[M]⁺，[α]^D₂₀＝-33.6284(c＝1，CH₃OH)According to the preparation method_of HCl Asp(OBzl)-Ser(Bzl)_-OBzl_,_0.43g (95% ) the title compound as a beige solid. ESI-MS (m/z): 483.1 [M]⁺ , [α]^D₂₀ =-33.6284 (c = 1, CH₃ OH)

5)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Phe-OCH₂(CH₂)₆CH₃的制备5) Preparation of Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.885g(5.0mmol)Boc-Arg(NO₂)-Gly-OH和2.5g(5.0mmol)HCl·Asp(OBzl)-Phe-OCH₂(CH₂)₆CH₃制得3.3g(78％)标题化合物，为无色固体。ESI-MS(m/z)：841.7[M]⁺，[α]^D₂₀＝-13.7964(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 1.885g (5.0mmol) Boc-Arg(NO₂ )-Gly-OH and 2.5g (5.0mmol) HCl·Asp(OBzl)-Phe-OCH₂ (_CH2 )_6CH3 yielded 3.3 g (78%) of_the title compound as a colorless solid. ESI-MS (m/z): 841.7 [M]⁺ , [α]^D₂₀ =-13.7964 (c = 1, CH₃ OH)

6)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Phe-OCH₂(CH₂)₆CH₃的制备6) Preparation of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.841g(1.0mmol)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Phe-OCH₂(CH₂)₆CH₃制得0.67g(90％)标题化合物，为米黄色固体。ESI-MS(m/z)：741.2[M]⁺，[α]^D₂₀＝-19.3619(c＝1，CH₃OH)According to the preparation method of HCl·Asp(OBzl)-Ser(Bzl)-OBzl, from 0.841g (1.0mmol) Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OCH₂ (CH₂ )₆ CH₃ Yield 0.67 g (90%) of the title compound as a beige solid. ESI-MS (m/z): 741.2 [M]⁺ , [α]^D₂₀ =-19.3619 (c = 1, CH₃ OH)

7)RGDF-OCH₂(CH₂)₆CH₃的制备7) Preparation of RGDF-OCH₂ (CH₂ )₆ CH₃

按照RGDS的制备方法由0.74g(1mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Phe-OCH₂(CH₂)₆CH₃制得0.54g(90％)标题化合物，为无色固体。ESI-MS(m/z)：605.1[M]⁺，[α]^D₂₀＝-17.8281(c＝1，CH₃OH)According to the preparation method of RGDS, 0.54 g (90%) of the title compound was prepared from 0.74 g (1 mmol) of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OCH₂ (CH₂ )₆ CH₃ as free color solid. ESI-MS (m/z): 605.1 [M]⁺ , [α]^D₂₀ =-17.8281 (c = 1, CH₃ OH)

实施例10 RGDS-NHCH₂(CH₂)₆CH₃的制备Example 10 Preparation of RGDS-NHCH₂ (CH₂ )₆ CH₃

1)Boc-Ser(BZl)-NHCH₂(CH₂)₆CH₃的制备1) Preparation of Boc-Ser(BZl)-NHCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.48g(5mmol)Boc-Ser(BZl)-OH和0.645g(5.0mmol)CH₃(CH₂)₆CH₂NH₂制得1.83g(90％)标题化合物，为无色固体。ESI-MS(m/z)：407.2[M]⁺.[α]^D₂₀＝-2.7657(c＝1，CH₃OH)_According to_the preparation method_of Boc-Arg(_NO₂ )-Gly-OMe,_1.83 g (90%) of the title compound as a colorless solid. ESI-MS (m/z): 407.2[M]⁺ .[α]^D₂₀ =-2.7657 (c=1, CH₃ OH)

2)HCl·Ser(BZl)-NHCH₂(CH₂)₆CH₃的制备2) Preparation of HCl Ser(BZl)-NHCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.41g(1.0mmol)Boc-Ser(BZl)-NH₂CH₂(CH₂)₆CH₃制得0.28g(92％)标题化合物，为米黄色固体。ESI-MS(m/z)：307.1[M]⁺.[α]^D₂₀＝-2.3995(c＝1，CH₃OH)According to the preparation_method of HCl Asp(OBzl)_-Ser (Bzl)_-OBzl ,_0.28g₍ 92% ) the title compound as a beige solid. ESI-MS (m/z): 307.1[M]⁺ .[α]^D₂₀ =-2.3995 (c=1, CH₃ OH)

3)Boc-Asp(OBzl)-Ser(BZl)NHCH₂(CH₂)₆CH₃的制备3) Preparation of Boc-Asp(OBzl)-Ser(BZl)NHCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.615g(5mmol)Boc-Asp(OBzl)-OH和0.171g(5.0mmol)HCl·Ser(BZl)-NHCH₂(CH₂)₆CH₃制得2.65g(87％)标题化合物，为无色固体。ESI-MS(m/z)：612.2[M]⁺.[α]^D₂₀＝-17.4510(c＝1，CH₃OH).According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, 1.615g (5mmol) Boc-Asp(OBzl)-OH and 0.171g (5.0mmol) HCl·Ser(BZl)-NHCH₂ (CH₂ )₆_CH3 yielded 2.65 g (87%) of the title compound as a colorless solid. ESI-MS (m/z): 612.2[M]⁺ .[α]^D₂₀ =-17.4510 (c=1, CH₃ OH).

4)HCl·Asp(OBzl)-Ser(BZl)NHCH₂(CH₂)₁₀CH₃的制备4) Preparation of HCl Asp(OBzl)-Ser(BZl)NHCH₂ (CH₂ )₁₀ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.61g(1.0mmol)Boc-Asp(OBzl)-Ser(BZl)NHCH₂(CH₂)₆CH₃制得0.48g(95％)标题化合物，为米黄色固体。ESI-MS(m/z)：512.2[M]⁺.[α]^D₂₀＝-3.0324(c＝1，CH₃OH)According to_the preparation_method of HCl Asp(OBzl)-Ser(_Bzl )-OBzl,_0.48g ( 95%) the title compound as a beige solid. ESI-MS (m/z): 512.2[M]⁺ .[α]^D₂₀ =-3.0324 (c=1, CH₃ OH)

5)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Ser(BZl)NHCH₂(CH₂)₆CH₃的制备5) Preparation of Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Ser(BZl)NHCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.885g(5.0mmol)Boc-Arg(NO₂)-Gly-OH和2.7g(5.0mmol)HCl·Asp(OBzl)-Ser(BZl)NHCH₂(CH₂)₆CH₃制得3.57g(82％)标题化合物，为无色固体。ESI-MS(m/z)：871.1[M+Na].[α]^D₂₀＝-6.2981(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, 1.885g (5.0mmol) Boc-Arg(NO₂ )-Gly-OH and 2.7g (5.0mmol) HCl·Asp(OBzl)-Ser(BZl )_NHCH2 (_CH2 )_6CH3 yielded 3.57 g (82%) of the title compound as_a colorless solid. ESI-MS (m/z): 871.1 [M+Na].[α]^D₂₀ =-6.2981 (c = 1, CH₃ OH)

6)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Ser(BZl)NHCH₂(CH₂)₆CH₃的制备6) Preparation of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Ser(BZl)NHCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.87g(1.0mmol)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Ser(BZl)NHCH₂(CH₂)₆CH₃制得0.69g(90％)标题化合物，为米黄色固体。ESI-MS(m/z)：770.8[M]⁺.[α]^D₂₀＝-6.5650(c＝1，CH₃OH)According to the preparation method of HCl·Asp(OBzl)-Ser(Bzl)-OBzl, from 0.87g (1.0mmol) Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Ser(BZl)NHCH₂ (CH₂ )₆ CH₃ yielded 0.69 g (90%) of the title compound as a beige solid. ESI-MS (m/z): 770.8[M]⁺ .[α]^D₂₀ =-6.5650 (c=1, CH₃ OH)

7)RGDS-NHCH₂(CH₂)₆CH₃的制备7) Preparation of RGDS-NHCH₂ (CH₂ )₆ CH₃

按照RGDS的制备方法由0.77g(1mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Ser(BZl)O₂CH₂(CH₂)₆CH₃制得0.49g(90％)标题化合物，为无色固体。ESI-MS(m/z)：545.1[M]⁺.[α]^D₂₀＝-10.8643(c＝1，CH₃OH)According to the preparation method of RGDS, 0.49 g (90%) of the title was prepared from 0.77 g (1 mmol) of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Ser(BZl)O₂ CH₂ (CH₂ )₆ CH₃ Compound, a colorless solid. ESI-MS (m/z): 545.1[M]⁺ .[α]^D₂₀ =-10.8643 (c=1, CH₃ OH)

实施例11 RGDV-NHCH₂(CH₂)₆CH₃的制备Example 11 Preparation of RGDV-NHCH₂ (CH₂ )₆ CH₃

1)Boc-Val-NHCH₂(CH₂)₆CH₃的制备1) Preparation of Boc-Val-NHCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.085g(5mmol)Boc-Val-OH和0.645g(5.0mmol)CH₃(CH₂)₆CH₂NH₂制得1.56g(95％)标题化合物，为无色固体。ESI-MS(m/z)：329.2[M]⁺.[α]^D₂₀＝-0.4332(c＝1，CH₃OH)According to the preparation method_of Boc-Arg(NO₂₎ -Gly-OMe_,_1.56 g (₉₅ %) the title compound as a colorless solid. ESI-MS (m/z): 329.2[M]⁺ .[α]^D₂₀ =-0.4332 (c=1, CH₃ OH)

2)HCl·Val-NHCH₂(CH₂)₆CH₃的制备2) Preparation of HCl·Val-NHCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.328g(1.0mmol)Boc-Val-NHCH₂(CH₂)₆CH₃制得0.22g(97％)标题化合物，为米黄色固体。ESI-MS(m/z)：229.2[M]⁺.[α]^D₂₀＝4.6555(c＝1，CH₃OH)Following the preparation of HCl Asp(OBzl)-Ser(Bzl)-OBzl, 0.22 g (97%)_of the title compound was obtained from 0.328 g (1.0 mmol) of Boc-Val-_NHCH2 (_CH2 )_6CH3 as Beige solid. ESI-MS (m/z): 229.2[M]⁺ .[α]^D₂₀ =4.6555 (c=1, CH₃ OH)

3)Boc-Asp(OBzl)-Val-NHCH₂(CH₂)₆CH₃的制备3) Preparation of Boc-Asp(OBzl)-Val-NHCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.615g(5mmol)Boc-Asp(OBzl)-OH和1.1g(5.0mmol)HCl·Val-NHCH₂(CH₂)₆CH₃制得2.42g(91％)标题化合物，为无色固体。ESI-MS(m/z)：555.1[M+Na]⁺.[α]^D₂₀＝-20.3281(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, it is prepared from 1.615g (5mmol) Boc-Asp(OBzl)-OH and 1.1g (5.0mmol) HCl·Val-NHCH₂ (CH₂ )₆ CH₃ Yield 2.42 g (91%) of the title compound as a colorless solid. ESI-MS (m/z): 555.1[M+Na]⁺ .[α]^D₂₀ =-20.3281 (c=1, CH₃ OH)

4)HCl·Asp(OBzl)-Val-NHCH₂(CH₂)₆CH₃的制备4) Preparation of HCl·Asp(OBzl)-Val-NHCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.533g(1.0mmol)Boc-Asp(OBzl)-Val-NHCH₂(CH₂)₆CH₃制得0.38g(89％)标题化合物，为米黄色固体。ESI-MS(m/z)：434.3[M]⁺.[α]^D₂₀＝-4.6660(c＝1，CH₃OH)According to_the preparation method of HCl Asp(OBzl)_-Ser (_Bzl )_-OBzl , 0.38g (89% ) the title compound as a beige solid. ESI-MS (m/z): 434.3[M]⁺ .[α]^D₂₀ =-4.6660 (c=1, CH₃ OH)

5)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Val-NHCH₂(CH₂)₆CH₃的制备5) Preparation of Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Val-NHCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.885g(5.0mmol)Boc-Arg(NO₂)-Gly-OH和2.34g(5.0mmol)HCl·Asp(OBzl)-Val-NHCH₂(CH₂)₆CH₃制得3.2g(82％)标题化合物，为无色固体。ESI-MS(m/z)：792.3[M]⁺.[α]^D₂₀＝-20.3303(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 1.885g (5.0mmol) Boc-Arg(NO₂ )-Gly-OH and 2.34g (5.0mmol) HCl·Asp(OBzl)-Val-NHCH₂ (_CH2 )_6CH3 yielded 3.2 g (82%) of_the title compound as a colorless solid. ESI-MS (m/z): 792.3[M]⁺ .[α]^D₂₀ =-20.3303 (c=1, CH₃ OH)

6)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Val-NHCH₂(CH₂)₆CH₃的制备6) Preparation of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Val-NHCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.792g(1.0mmol)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Val-NHCH₂(CH₂)₆CH₃制得0.62g(90％)标题化合物，为米黄色固体。ESI-MS(m/z)：692.2[M]⁺.[α]^D₂₀＝-13.0642(c＝1，CH₃OH)According to the preparation method of HCl·Asp(OBzl)-Ser(Bzl)-OBzl, from 0.792g (1.0mmol) Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Val-NHCH₂ (CH₂ )₆ CH₃ Yield 0.62 g (90%) of the title compound as a beige solid. ESI-MS (m/z): 692.2[M]⁺ .[α]^D₂₀ =-13.0642 (c=1, CH₃ OH)

7)RGDV-NHCH₂(CH₂)₆CH₃的制备7) Preparation of RGDV-NHCH₂ (CH₂ )₆ CH₃

按照RGDS的制备方法由0.692g(1mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Val-NHCH₂(CH₂)₆CH₃制得0.5g(90％)标题化合物，为无色固体。ESI-MS(m/z)：557.1[M]⁺.[α]^D₂₀＝-8.7977(c＝1，CH₃OH)According to the preparation method of RGDS, 0.5 g (90%) of the title compound was prepared from 0.692 g (1 mmol) of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Val-NHCH₂ (CH₂ )₆ CH₃ as free color solid. ESI-MS (m/z): 557.1[M]⁺ .[α]^D₂₀ =-8.7977 (c=1, CH₃ OH)

实施例12 RGDF-NHCH₂(CH₂)₆CH₃的制备Example 12 Preparation of RGDF-NHCH₂ (CH₂ )₆ CH₃

1)Boc-Phe-NHCH₂(CH₂)₆CH₃的制备1) Preparation of Boc-Phe-NHCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.325g(5mmol)Boc-Phe-OH和0.645g(5.0mmol)CH₃(CH₂)₆CH₂NH制得1.74g(93％)标题化合物，为无色固体。ESI-MS(m/z)：377.3[M]⁺.[α]^D₂₀＝-10.0648(c＝1，CH₃OH)According to the preparation method of Boc-Arg(_NO₂ )-Gly-OMe_,_1.74 g (93_% ) the title compound as a colorless solid. ESI-MS (m/z): 377.3[M]⁺ .[α]^D₂₀ =-10.0648 (c=1, CH₃ OH)

2)HCl·Phe-NHCH₂(CH₂)₆CH₃的制备2) Preparation of HCl·Phe-NHCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.38g(1.0mmol)Boc-Phe-NHCH₂(CH₂)₆CH₃制得0.27g(99％)标题化合物，为米黄色固体。ESI-MS(m/z)：277.2[M]⁺.[α]^D₂₀＝-3.1989(c＝1，CH₃OH)Following the preparation of HCl Asp(OBzl)-Ser(Bzl)-OBzl, 0.27 g (99%) of the title compound was obtained from 0.38 g (1.0 mmol) of Boc-Phe-NHCH₂ (CH₂ )₆ CH₃ as Beige solid. ESI-MS (m/z): 277.2[M]⁺ .[α]^D₂₀ =-3.1989 (c=1, CH₃ OH)

3)Boc-Asp(OBzl)-Phe-NHCH₂(CH₂)₆CH₃的制备3) Preparation of Boc-Asp(OBzl)-Phe-NHCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.615g(5mmol)Boc-Asp(OBzl)-OH和1.38g(5.0mmol)HCl·Phe-NHCH₂(CH₂)₆CH₃制得2.58g(89％)标题化合物，为无色固体。ESI-MS(m/z)：582.2[M]⁺.[α]^D₂₀＝-8.3651(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, it is prepared from 1.615g (5mmol) Boc-Asp(OBzl)-OH and 1.38g (5.0mmol) HCl·Phe-NHCH₂ (CH₂ )₆ CH₃ Yield 2.58 g (89%) of the title compound as a colorless solid. ESI-MS (m/z): 582.2[M]⁺ .[α]^D₂₀ =-8.3651 (c=1, CH₃ OH)

4)HCl·Asp(OBzl)-Phe-NHCH₂(CH₂)₆CH₃的制备4) Preparation of HCl·Asp(OBzl)-Phe-NHCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.582g(1.0mmol)Boc-Asp(OBzl)-Phe-NHCH₂(CH₂)₆CH₃制得0.43g(90％)标题化合物，为米黄色固体。ESI-MS(m/z)：482.2[M]⁺.[α]^D₂₀＝-4.1918(c＝1，CH₃OH)According to the preparation method of HCl Asp(OBzl₎_-Ser (Bzl)_-OBzl ,_0.43g (90% ) the title compound as a beige solid. ESI-MS (m/z): 482.2[M]⁺ .[α]^D₂₀ =-4.1918 (c=1, CH₃ OH)

5)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Phe-NHCH₂(CH₂)₆CH₃的制备5) Preparation of Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Phe-NHCH₂ (CH₂ )₆ CH₃

按照Boc-Arg(NO₂)-Gly-OMe的制备方法由1.885g(5.0mmol)Boc-Arg(NO₂)-Gly-OH和2.40g(5.0mmol)HCl·Asp(OBzl)-Phe-NHCH₂(CH₂)₆CH₃制得3.8g(85％)标题化合物，为无色固体。ESI-MS(m/z)：840.6[M]⁺.[α]^D₂₀＝-16.5293(c＝1，CH₃OH)According to the preparation method of Boc-Arg(NO₂ )-Gly-OMe, from 1.885g (5.0mmol) Boc-Arg(NO₂ )-Gly-OH and 2.40g (5.0mmol) HCl·Asp(OBzl)-Phe-NHCH₂ (_CH2 )_6CH3 yielded 3.8 g (85%) of_the title compound as a colorless solid. ESI-MS (m/z): 840.6[M]⁺ .[α]^D₂₀ =-16.5293 (c=1, CH₃ OH)

6)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Phe-NHCH₂(CH₂)₆CH₃的制备6) Preparation of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Phe-NHCH₂ (CH₂ )₆ CH₃

按照HCl·Asp(OBzl)-Ser(Bzl)-OBzl的制备方法，从0.84g(1.0mmol)Boc-Arg(NO₂)-Gly-Asp(OBzl)-Phe-NHCH₂(CH₂)₆CH₃制得0.67g(95％)标题化合物，为米黄色固体。ESI-MS(m/z)：740[M]⁺.[α]^D₂₀＝-13.9522(c＝1，CH₃OH)According to the preparation method of HCl·Asp(OBzl)-Ser(Bzl)-OBzl, from 0.84g (1.0mmol) Boc-Arg(NO₂ )-Gly-Asp(OBzl)-Phe-NHCH₂ (CH₂ )₆ CH₃ Yield 0.67 g (95%) of the title compound as a beige solid. ESI-MS (m/z): 740[M]⁺ .[α]^D₂₀ =-13.9522 (c=1, CH₃ OH)

7)RGDF-NHCH₂(CH₂)₆CH₃的制备7) Preparation of RGDF-NHCH₂ (CH₂ )₆ CH₃

按照RGDS的制备方法由0.74g(1mmol)HCl·Arg(NO₂)-Gly-Asp(OBzl)-Phe-OCH₂(CH₂)₆CH₃制得0.54g(90％)标题化合物，为无色固体。ESI-MS(m/z)：605.1[M]⁺.[α]^D₂₀＝-5.5321(c＝1，CH₃OH)。According to the preparation method of RGDS, 0.54 g (90%) of the title compound was prepared from 0.74 g (1 mmol) of HCl·Arg(NO₂ )-Gly-Asp(OBzl)-Phe-OCH₂ (CH₂ )₆ CH₃ as free color solid. ESI-MS (m/z): 605.1 [M]⁺ .[α]^D₂₀ =-5.5321 (c=1, CH₃ OH).

试验例1 本发明化合物口服给药的抗血栓活性试验Test Example 1 Antithrombotic activity test of compound of the present invention administered orally

1)大鼠手术与器械1) Rat surgery and instruments

SD大鼠(雄性，220～230g)按10nmol·kg^-1剂量口服本发明化合物，30min后按1200mg-kg^-1剂量腹腔注射乌拉坦溶液进行麻醉。麻醉大鼠仰卧位固定，分离右颈总动脉，于近心端夹动脉夹，近心端和远心端分别穿入手术线，将远心端的手术线于皮毛用止血钳夹紧，准备在远心端插管。SD rats (male, 220-230 g) were orally administered the compound of the present invention at a dose of 10 nmol·kg^-1 , and were anesthetized by intraperitoneal injection of urethane solution at a dose of 1200 mg-kg^-1 30 min later. Anesthetized rats were fixed in a supine position, the right common carotid artery was separated, and the arterial clamp was clamped at the proximal end, and the proximal and distal ends were respectively threaded into the surgical thread, and the surgical thread at the distal end was clamped on the fur with a hemostat, ready to be placed in the Intubation at the distal end.

2)插管2) Intubation

插管为硅烷化过的聚乙烯胶管，分三段，中段为聚乙烯胶管，长60.0mm，内径3.5mm；两端为相同的聚乙烯管，管长100.0mm，内径1.0mm，外径2.0mm该管的一端拉成尖管(用于插入大鼠颈动脉或静脉)，外径为1.0mm。将编好号的干净青霉素小瓶中分别装入6cm长的黑色手术线，称重；然后取出丝线，按照编号放入准备好的插管的中段较粗的插管中。The intubation tube is a silanized polyethylene hose, which is divided into three sections. The middle section is a polyethylene hose with a length of 60.0 mm and an inner diameter of 3.5 mm; both ends are the same polyethylene tube with a length of 100.0 mm, an inner diameter of 1.0 mm, and an outer diameter of 2.0 mm. mm One end of the tube is drawn into a tip tube (for insertion into a rat carotid artery or vein) with an outer diameter of 1.0 mm. Put 6cm-long black surgical thread into the numbered clean penicillin vials and weigh them; then take out the silk thread and put it into the thicker middle section of the prepared cannula according to the number.

打开大鼠右侧动脉夹，用注射器通过尖管端将管中注满肝素生理盐水溶液(50IU·kg^-1)，然后将插管的动脉端插入大鼠右侧颈总动脉，将计算量的肝素缓缓注入大鼠体内。Open the right arterial clamp of the rat, use a syringe to fill the tube with heparin saline solution (50IU·kg^-1 ) through the tip of the tube, and then insert the arterial end of the cannula into the right common carotid artery of the rat. The heparin was slowly injected into the rats.

3)给药溶液3) Dosing solution

药品：生理盐水(3ml·kg^-1，口服给予)、阿斯匹林(剂量为30mg/kg，按试验例1的方法静脉给予)的生理盐水溶液、本发明化合物(剂量为10nmol/kg，口服给予)的生理盐水溶液。Drugs: physiological saline solution (3ml·kg^-1 , administered orally), aspirin (a dose of 30 mg/kg, given intravenously according to the method of Test Example 1), a physiological saline solution of the compound of the present invention (a dose of 10 nmol/kg, Oral administration) of physiological saline solution.

4)血栓称重4) Thrombus weighing

计时开始15分钟后，剪断动静脉插管，停止循环，用眼科镊小心取出丝线，在滤纸上轻轻蘸掉血滴，放入事先称重好的青霉素小瓶中，精确称重并记录。计算出血栓的湿重。每个药品重复11次给药。统计各组的血栓湿重(X±SD)，并做t检验。15 minutes after the start of timing, cut off the arteriovenous cannula, stop the circulation, carefully take out the silk thread with ophthalmic forceps, gently dip the blood drop on the filter paper, put it into the pre-weighed penicillin vial, accurately weigh and record. Calculate the wet weight of the thrombus. Each drug was administered 11 times. The thrombus wet weight (X±SD) of each group was counted, and t test was done.

5)结果5) Results

经口服给药，本发明的化合物都具有很好的抗栓活性。结果列入表1。After oral administration, the compounds of the present invention have good antithrombotic activity. The results are listed in Table 1.

表1.本发明的化合物经口服给药的抗血栓活性Table 1. Antithrombotic activity of compounds of the present invention administered orally

化合物compound 血栓湿重(X±SD mg)Thrombus wet weight (X±SD mg) 生理盐水normal saline 17.88±0.9517.88±0.95 阿斯匹林(静脉给予)Aspirin (administered intravenously) 5.36±1.74a5.36±1.74a CH3(CH2)6CORGDSCH3(CH2)6CORGDS 9.08±2.74a9.08±2.74a CH3(CH2)6CORGDVCH3(CH2)6CORGDV 8.94±3.25a8.94±3.25a CH3(CH2)6CORGDFCH3(CH2)6CORGDF 9.90±2.83a9.90±2.83a RGDS-OCH2(CH2)6CH3RGDS-OCH2(CH2)6CH3 8.78±2.44a8.78±2.44a RGDV-OCH2(CH2)6CH3RGDV-OCH2(CH2)6CH3 9.55±3.31a9.55±3.31a RGDF-OCH2(CH2)6CH3RGDF-OCH2(CH2)6CH3 10.95±3.70a10.95±3.70a RGDS-NHCH2(CH2)6CH3RGDS-NHCH2(CH2)6CH3 12.48±1.38a12.48±1.38a RGDV-NHCH2(CH2)6CH3RGDV-NHCH2(CH2)6CH3 9.68±3.03a9.68±3.03a RGDF-NHCH2(CH2)6CH3RGDF-NHCH2(CH2)6CH3 10.96±2.52a10.96±2.52a

n＝10；NS＝生理盐水；a.与生理盐水相比，P＜0.05。n=10; NS=normal saline; a. Compared with normal saline, P<0.05.

试验例2 本发明化合物CH₃(CH₂)₆CORGDS口服给药的量效关系Test Example 2 Dose-effect relationship of oral administration of compound CH₃ (CH₂ )₆ CORGDS of the present invention

1)大鼠手术与器械1) Rat surgery and instruments

SD大鼠(雄性，220～230g)按10nmol·kg^-1，0.1nmol·kg^-1和0.001nmol·kg^-1剂量口服CH₃(CH₂)₆CORGDS，30min后按1200mg-kg^-1剂量腹腔注射乌拉坦溶液进行麻醉。麻醉大鼠仰卧位固定，分离右颈总动脉，于近心端夹动脉夹，近心端和远心端分别穿入手术线，将远心端的手术线于皮毛用止血钳夹紧，准备在远心端插管。SD rats (male, 220-230g) were given oral administration of CH₃ (CH₂ )₆ CORGDS at doses of 10nmol·kg^-1 , 0.1nmol·kg^-1 and 0.001nmol·kg^-1 , followed by a dose of 1200mg-kg^-1 after 30min Intraperitoneal injection of urethane solution for anesthesia. Anesthetized rats were fixed in a supine position, the right common carotid artery was separated, and the arterial clamp was clamped at the proximal end, and the proximal and distal ends were respectively threaded into the surgical thread, and the surgical thread at the distal end was clamped on the fur with a hemostat, ready to be placed in the Intubation at the distal end.

2)插管2) Intubation

插管为硅烷化过的聚乙烯胶管，分三段，中段为聚乙烯胶管，长60.0mm，内径3.5mm；两端为相同的聚乙烯管，管长100.0mm，内径1.0mm，外径2.0mm该管的一端拉成尖管(用于插入大鼠颈动脉或静脉)，外径为1.0mm。将编好号的干净青霉素小瓶中分别装入6cm长的黑色手术线，称重；然后取出丝线，按照编号放入准备好的插管的中段较粗的插管中。The intubation tube is a silanized polyethylene hose, which is divided into three sections. The middle section is a polyethylene hose with a length of 60.0 mm and an inner diameter of 3.5 mm; both ends are the same polyethylene tube with a length of 100.0 mm, an inner diameter of 1.0 mm, and an outer diameter of 2.0 mm. mm One end of the tube is drawn into a tip tube (for insertion into a rat carotid artery or vein) with an outer diameter of 1.0 mm. Put 6cm long black surgical thread into the numbered clean penicillin vials and weigh them; then take out the silk thread and put it into the thicker middle section of the prepared cannula according to the number.

3)给药溶液3) Dosing solution

药品：将CH₃(CH₂)₆CORGDS按10nmol·kg^-1，0.1nmol·kg^-1和0.001nmol·kg^-1剂量配置生理盐水溶液，供口服给药。Drugs: CH₃ (CH₂ )₆ CORGDS is formulated into physiological saline solution at doses of 10nmol·kg^-1 , 0.1nmol·kg^-1 and 0.001nmol·kg^-1 for oral administration.

4)血栓称重4) Thrombus weighing

计时开始15分钟后，剪断动静脉插管，停止循环，用眼科镊小心取出丝线，在滤纸上轻轻蘸掉血滴，放入事先称重好的青霉素小瓶中，精确称重并记录。计算出血栓的湿重。每个药品重复11次给药。统计各组的血栓湿重(^X±SD)，并做t检验。15 minutes after the start of timing, cut off the arteriovenous cannula, stop the circulation, carefully take out the silk thread with ophthalmic forceps, gently dip the blood drop on the filter paper, put it into the pre-weighed penicillin vial, accurately weigh and record. Calculate the wet weight of the thrombus. Each drug was administered 11 times. The thrombus wet weight (^X ± SD) of each group was counted, and the t test was performed.

5)结果5) Results

经口服给药，在10nmol·kg^-1，0.1nmol·kg^-1，0.001nmol·kg剂量下，CH₃(CH₂)₆CORGDS剂量依赖地发挥抗血栓作用。结果列入表2。After oral administration, CH₃ (CH₂ )₆ CORGDS exerts antithrombotic effect in a dose-dependent manner at doses of 10 nmol·kg^-1 , 0.1 nmol·kg^-1 , and 0.001 nmol·kg. The results are listed in Table 2.

表2.口服给予CH₃(CH₂)₆CORGDS的量效关系Table 2. Dose-effect relationship of oral administration of CH₃ (CH₂ )₆ CORGDS

剂量dosage 血栓湿重(X±SDmg)Wet weight of thrombus (X±SDmg) 10nmol/Kg/3ml10nmol/Kg/3ml 8.78±2.44a8.78±2.44a 0.1nmol/Kg/3ml0.1nmol/Kg/3ml 10.40±1.9310.40±1.93 0.001nmol/Kg/3ml0.001nmol/Kg/3ml 12.37±2.9712.37±2.97

a.与，0.001nmol·kg^-1组比，p＜0.05；a. Compared with, 0.001nmol·kg^-1 group, p<0.05;

试验例3 本发明化合物在水相中组装成为纳米球试验Test Example 3 The compound of the present invention is assembled into a nanosphere test in the aqueous phase

1)本发明的9种阳离子药质体按照mg/ml的浓度配置成为水溶液，在激光散射粒度仪(型号)上连续测定8天，观察粒径及粒径变化，结果见表3。得到的数据表明，这9种阳离子药质体在水相中可以自组装成为稳定的纳米球，因而是优秀的微乳和脂质体药物的制备材料。1) 9 kinds of cationic drug plasmids of the present invention are configured into an aqueous solution according to the concentration of mg/ml, and are continuously measured on a laser scattering particle size analyzer (model) for 8 days, and the particle size and particle size changes are observed. The results are shown in Table 3. The obtained data showed that these nine kinds of cationic drug plastids can self-assemble into stable nanospheres in the aqueous phase, so they are excellent materials for the preparation of microemulsion and liposome drugs.

表3 本发明的9种阳离子药质体在水中自组装成为稳定的纳米球的粒经Table 3 Nine kinds of cationic drug plasmids of the present invention self-assemble into stable nanosphere particles in water

样品名Sample name 粒径nmParticle size nm CH3(CH2)6CORGDSCH3(CH2)6CORGDS 54275427 CH3(CH2)6CORGDVCH3(CH2)6CORGDV 41064106 CH3(CH2)6CORGDFCH3(CH2)6CORGDF 315.23315.23 RGDS-OCH2(CH2)6CH3RGDS-OCH2(CH2)6CH3 251.7251.7 RGDV-OCH2(CH2)6CH3RGDV-OCH2(CH2)6CH3 296.7296.7 RGDF-OCH2(CH2)6CH3RGDF-OCH2(CH2)6CH3 348.9348.9

样品名Sample name 粒径nmParticle size nm RGDS-NHCH2(CH2)6CH3RGDS-NHCH2(CH2)6CH3 648.1648.1 RGDV-NHCH2(CH2)6CH3RGDV-NHCH2(CH2)6CH3 630.9630.9 RGDF-NHCH2(CH2)6CH3RGDF-NHCH2(CH2)6CH3 50955095

2)按照扫描电镜的测定要求，配置9种阳离子药质体的水溶液，置于铜网上挥发干后测定本发明的化合物在水相组装的纳米球的图。结果表明，由这9种阳离子药质体组装的纳米球在扫描电镜下可以看到均匀的粒状态。这里给出的是代表性化合物RGDF-OCH₂(CH₂)₆CH₃的扫描电镜图(图2)。2) According to the measurement requirements of the scanning electron microscope, the aqueous solution of 9 kinds of cationic drug plasmids was prepared, placed on the copper grid and volatilized to dryness, and then measured the nanosphere assembled by the compound of the present invention in the water phase. The results show that the nanospheres assembled by these nine kinds of cationic drug plasmids can be seen in a uniform particle state under the scanning electron microscope. Presented here is_a scanning electron micrograph of a representative compound RGDF-_OCH2 (_CH2 )_6CH3 (Figure 2).

试验例5 本发明化合物在脂相中组装成为纳米球试验Test Example 5 The compound of the present invention is assembled into a nanosphere test in the lipid phase

1)选择正辛醇为脂相，将本发明的9种阳离子药质体按照mg/ml的浓度配置成为正辛醇溶液，在激光散射粒度仪(型号)上连续测定8天，观察粒径及粒径变化，结果见表4。得到的数据表明，这9种阳离子药质体在脂相中可以自组装成为稳定的纳米球，因而是优秀的微乳和脂质体药物的制备材料。1) Select n-octanol as the lipid phase, configure 9 kinds of cationic drug bodies of the present invention into n-octanol solution according to the concentration of mg/ml, measure continuously for 8 days on the laser scattering particle size analyzer (model), observe the particle diameter And particle size change, the results are shown in Table 4. The obtained data showed that these nine kinds of cationic drug plasmids could self-assemble into stable nanospheres in the lipid phase, so they were excellent materials for the preparation of microemulsion and liposome drugs.

表4 本发明的9种阳离子药质体在正辛醇中自组装成为稳定的纳米球的粒经Table 4 Nine kinds of cationic drug plasmids of the present invention self-assemble into stable nanosphere particles in n-octanol

样品名Sample name 粒径(nm)Particle size (nm) CH3(CH2)6CORGDSCH3(CH2)6CORGDS 16311631 CH3(CH2)6CORGDVCH3(CH2)6CORGDV 267.4267.4 CH3(CH2)6CORGDFCH3(CH2)6CORGDF 41674167 RGDS-OCH2(CH2)6CH3RGDS-OCH2(CH2)6CH3 11211121 RGDV-OCH2(CH2)6CH3RGDV-OCH2(CH2)6CH3 58.7758.77 RGDF-OCH2(CH2)6CH3RGDF-OCH2(CH2)6CH3 261.6261.6 RGDS-NHCH2(CH2)6CH3RGDS-NHCH2(CH2)6CH3 220.2220.2 RGDV-NHCH2(CH2)6CH3RGDV-NHCH2(CH2)6CH3 15.6815.68 RGDF-NHCH2(CH2)6CH3RGDF-NHCH2(CH2)6CH3 198.1198.1

2)按照扫描电镜的测定要求，配置9种阳离子药质体的正辛醇溶液，置于铜网上挥发干后测定本发明的化合物在脂相组装的纳米球的图。结果表明，由这9种阳离子药质体组装的纳米球在扫描电镜下可以看到均匀的粒状态。这里给出的是代表性化合物RGDF-OCH₂(CH₂)₆CH₃的扫描电镜图(图3)。2) According to the measurement requirements of the scanning electron microscope, configure n-octanol solutions of 9 kinds of cationic drug plasmids, put them on the copper grid and volatilize to dryness, and measure the graph of the nanospheres assembled by the compound of the present invention in the lipid phase. The results show that the nanospheres assembled by these nine kinds of cationic drug plasmids can be seen in a uniform particle state under the scanning electron microscope. Presented here is a scanning electron micrograph of a representative compound RGDF-OCH₂ (CH₂ )₆ CH₃ ( FIG. 3 ).

Claims

1. the target cationic pharmacome is characterized in that, is selected from any one compound in following (1)-(9): (1) CH₃(CH₂)₆CO-Arg-Gly-Asp-Ser-OH, (2) CH₃(CH₂)₆CO-Arg-Gly-Asp-Val-OH, (3) CH₃(CH₂)₆CO-Arg-Gly-Asp-Phe-OH, (4) Arg-Gly-Asp-Ser-OCH₂(CH₂) 6CH₃, (5) Arg-Gly-Asp-Val-OCH₂(CH₂)₆CH₃, (6) Arg-Gly-Asp-Phe-OCH₂(CH₂)₆CH₃, (7) Arg-Gly-Asp-Ser-NHCH₂(CH₂)₆CH₃, (8) Arg-Gly-Asp-Val-NHCH₂(CH₂)₆CH₃, (9) Arg-Gly-Asp-Phe-NHCH₂(CH₂)₆CH₃

2. the target cationic pharmacome of claim 1 is in the purposes of preparation in the antithrombotic reagent.

3. the purposes of the target cationic pharmacome of claim 1 in the preparation material of preparation micro emulsion or liposome.

4. the purposes of the target cationic pharmacome of claim 1 in the targeting preparation material of preparation micro emulsion, liposome.