CN101240028B

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Info

Publication number: CN101240028B
Application number: CN2007100636695A
Authority: CN
Inventors: 彭师奇; 赵明; 崔国辉; 傅征然
Original assignee: Capital Medical University
Current assignee: Capital Medical University
Priority date: 2007-02-07
Filing date: 2007-02-07
Publication date: 2010-08-18
Anticipated expiration: 2027-02-07
Also published as: CN101240028A

Abstract

The invention discloses a target cationic pharmacosome with n-pentadecyl and RGD peptide as basic component, and further composed by carbonyl, methylamino and methoxy. Preparation and application is also disclosed. The inventive target cationic pharmcosome has a structure of general formula CH3(CH2)14R1, wherein R1 is carbonyl, methylamino orRGD pipetide modified by methoxy. The inventive target cationic pharmacosome has excellent target property and self-assembly property besides excellent oral antithrombotic activity, can be used as preparation material or target material for preparation of drug carrier such as microemulsion, liposomes.

Description

The conjugate that Pentadecane base and RGD peptide make up, their the synthetic and application in medical science

Technical field

The present invention relates to the target cationic pharmacome, relate in particular to Pentadecane base chain and put together the target cationic pharmacome that gets by the carboxylic end or the ammonia end of carbonyl, methylamino-and methoxyl group and RGD peptide, the invention still further relates to the preparation method of this pharmacome and this pharmacome as the application of antithrombotic agent, pharmaceutical carrier or drug targeting preparation material, belong to biomedicine field.

Background technology

Gene therapies in 5 years to 10 years in future have the ideal carrier that can be sent to gene cell.From the position of biotechnological formulation, the gene transfer system is exactly drug delivery system (DDS).The gene transfer system that has number of chemical synthetic small molecules to make up receives publicity, and wherein the gene transfer system of cation lipid formation is the focus of attention.Cation lipid at pharmaceutical field all over being used to make up liposomal delivery small molecules (comprising polypeptide) medicine.With the same in DDS, cationic-liposome has obvious benefit in the gene transfer system, for example can by electric charge absorption form mixture with DNA and effectively avoid by lysosome degraded in the cell, can with the efficient transfered cell of DNA, to the size of DNA without limits, easy and simple to handle etc.The essential structure of cation lipid is as follows:

The essential structure of cation lipid

Comprise hydrophobic arm and hydrophilic cationic head that senior aliphatic chain constitutes.

Cell adhesion plays a crucial role in the evolution of cell adhesion disease (metastasis of cancer, thrombosis, chemistry cause inflammation and osteoporosis).Modulability glycoprotein for example RGD peptide and integrin receptor has very strong binding ability, can participate in the cell adhesion process.For example the RGD peptide combines with the GP IIb/IIIa receptor-specific of thrombocyte, tumour cell and bone primary surface and can intervene thrombus, metastasis of cancer and osteoporotic evolution.This effect of RGD peptide has given the compound that contains the RGD sequence a kind of critical nature, and the compound that promptly contains the RGD sequence can be to thrombus, metastasis of cancer and osteoporotic disease sites enrichment.Under such prerequisite, RGD peptide and senior aliphatic chain are puted together, just can obtain the target pharmacome.

Summary of the invention

One of the object of the invention provides a class target cationic pharmacome.This class target cationic pharmacome is general formula CH₃(CH₂)₁₄R₁Shown in, R wherein₁Be selected from CORGDS, CORGDV, CORGDF, RGDSOCH₂, RGDVOCH₂, RGDFOCH₂, RGDSNHCH₂, RGDVNHCH₂Or RGDFNHCH₂Wherein said R is the abbreviation of arginine (Arg), and G is the abbreviation of glycine (Gly), and D is the abbreviation of aspartic acid (Asp), and V is the abbreviation of Xie Ansuan (Val), and F is the abbreviation of phenylalanine (Phe), and S is the abbreviation of Serine (Ser).

The present invention combines following understanding or foundation has been finished technique scheme.The ideal carrier (gene transfer system) that gene is sent to cell is one of mission critical of gene therapy; See that from the position of biotechnological formulation gene transfer system and drug delivery system (DDS) have identity property; The gene transfer system that cation lipid constitutes though the gene transfer system that has number of chemical synthetic small molecules to make up all receives publicity should especially pay close attention; Cationic-liposome can form mixture with DNA by electric charge absorption and also effectively avoid by lysosome degraded in the cell; Cationic-liposome can be with the efficient transfered cell of DNA, cationic-liposome to the size of DNA without limits; Thrombocyte, inflammation tissue, cancer cells and ground substance of bone show and are rich in the cell adhesion acceptor that can discern the RGD sequence that the compound that contains the RGD sequence can be to thrombus, inflammation, metastasis of cancer and osteoporotic disease sites enrichment.

The inventor is based on above-mentioned cognition, Pentadecane base chain is puted together by the carboxylic end or the ammonia end of carbonyl, methylamino-and methoxyl group and RGD peptide, make the molecule that makes obtain four kinds of performances, promptly depend on the cationic property and the wetting ability of the hydrophobicity of Pentadecane base chain, the guanidine radicals that depends on the RGD peptide and the protonated formation of alpha-amino group and depend on the target that the RGD peptide obtains GP IIb/IIIa receptor-specific affinity interaction.So, RGD peptide and Pentadecane base chain are puted together the molecule that makes and just become the target cationic pharmacome.

One of purpose of the present invention provides a kind of preparation general formula CH₃(CH₂)₁₄R₁The method of compound, wherein R₁Be selected from-CORGDS ,-CORGDV ,-CORGDF, RGDSOCH₂-, RGDVOCH₂-, RGDFOCH₂-, RGDSNHCH₂-, RGDVNHCH₂-or RGDFNHCH₂-.

One of purpose of the present invention is achieved through the following technical solutions:

(1) meets peptide technology synthetic respectively RGDS, RGDV and RGDF according to existing liquid phase;

(2) with CH₃(CH₂)₁₄COOH, CH₃(CH₂)₁₄CH₂OH and CH₃(CH₂)₁₄CH₂NH₂With RGDS, RGDV and the RGDF coupling of protecting group protection, slough protecting group, promptly respectively.

The evaluation that forms on the model at rat suppository shows that target cationic pharmacome of the present invention has the excellent oral antithrombotic acitivity, can be used as antithrombotic agent and uses; Detected these 9 kinds of target cationic pharmacomes at water and biophase and be self-assembled into performance into nano particle, test-results shows that target cationic pharmacome of the present invention has outstanding self-assembly performance, can be used as the preparation material of preparation micro emulsion, liposome etc.; Because the oral antithrombotic acitivity of these 9 kinds of target cationic pharmacomes from the RGD peptide to GP IIb/IIIa receptor-specific affinity interaction, so this antithrombotic acitivity has characterized the target of 9 kinds of target cationic pharmacomes again, so target cationic pharmacome of the present invention can be used as the targeting preparation material.

Description of drawings

Fig. 1 RGD peptide and senior aliphatic chain are puted together the synthetic route .I of preparation target cationic pharmacome) DCC, HOBt, NMM and HClGlyOMe; II) the NaOH aqueous solution (2N); III) DCC, HOBt, NMM and HClSer-OBzl or HClVal-OBzl or HClPhe-OBzl; IV) hydrogenchloride/ethyl acetate solution (4N); V) DCC, HOBt, NMM; VI) 5% palladium carbon and hydrogen (0.02Mba). AA=Phe wherein, Val, Ser.

Fig. 2 The compounds of this invention is in the stability test result of the nanometer ball of water assembling.

Fig. 3 The compounds of this invention is at the sem photograph of the nanometer ball of water assembling.

The stability test result of the nanometer ball that Fig. 4 The compounds of this invention is assembled mutually at fat.

The sem photograph of the nanometer ball that Fig. 5 The compounds of this invention is assembled mutually at fat.

In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.

Embodiment

The preparation ofembodiment 1 RGDS

1) Boc-Arg (NO₂The preparation of)-Gly-OMe

With 1.600g (5.0 mmol) Boc-Arg (NO₂)-OH is dissolved in the 20ml dry DMF, and ice bath adds 0.675g (5mmol) N-hydroxy benzo triazole (HOBt) down in the solution that obtains, and makes dissolving fully.Add 1.071g (6mmol) dicyclohexyl carbonyl diimine (DCC) after 10 minutes.Obtain reaction solution (I), stand-by.The following 0.627g of ice bath (5.0mmol) HClGly-OMe (5mmol) is suspended in the 20ml dry DMF, adds 1ml N-methylmorpholine (NMM) then, transfers pH8-9.Stirred 35 minutes, and obtained reaction solution (II), stand-by.The following reaction solution of ice bath (I) adds in the reaction solution (II), and first ice bath stirs 1h down, stirring at room 12h again, and (chloroform/methanol 10:1) shows Boc-Arg (NO to TLC₂)-OH disappears.Filtering dicyclohexylurea (DCU) (DCU), filtrate is blown away DMF.Residue dissolves with the 50ml chloroform.The solution that obtains is used saturated NaHCO successively₃The aqueous solution is washed, the saturated NaCl aqueous solution is washed, 5%KHSO₄The aqueous solution is washed with the saturated NaCl aqueous solution and is washed.The chloroform layer anhydrous Na₂SO₄Drying, filtration, filtrate decompression are concentrated into dried, obtain 3.80g (100%) title compound, are the beige solid.ESI-MS(m/z)：392[M]⁺，[α]^D₂₀＝-18.5657(c＝1，CH₃OH)。

2) Boc-Arg (NO₂The preparation of)-Gly-OH

With 0.392g (1.0mmol) Boc-Arg (NO₂)-Gly-OMe is dissolved in 10ml methyl alcohol.Under the ice bath solution that obtains is transferred pH12 and stirred 2h with NaOH (2N) aqueous solution, (chloroform/methanol 1:1) shows Boc-Arg (NO to TLC₂)-Gly-OMe disappears.Reaction mixture is transferred pH7 with dilute hydrochloric acid (2N), and concentrating under reduced pressure removes methyl alcohol.Residue is transferred pH2, is used ethyl acetate extraction (30ml * 3) with dilute hydrochloric acid (2N).The ethyl acetate that merges is washed till neutrality, anhydrous Na with the saturated NaCl aqueous solution mutually₂SO₄Dry.Filter, filtrate decompression is concentrated into dried, gets 0.339g (90%) title compound, is the beige solid.MS：375.3[M]^-，[α]^D₂₀＝-2.1644(c＝1，CH₃OH)

3) preparation of Boc-Asp (OBzl)-Ser (Bzl)-OBzl

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe gets 2.655 (99%) title compounds by 1.620g (5.0mmol) Boc-Asp (OBzl)-OH and 1.6075g (5.0mmol) TosSer (Bzl)-OBzl, is the beige solid.ESI-MS(m/z)：591.4[M]⁺，[α]^D₂₀＝-13.2108(c＝1，CH₃OH)

4) preparation of HClAsp (OBzl)-Ser (Bzl)-OBzl

0.780g (1.491mmol) Boc-Asp (OBzl)-Ser (Bzl)-OBzl is dissolved in 15ml4mol/l hydrogenchloride-ethyl acetate solution, stirring atroom 2 hours, TLC (chloroform/methanol, 3/1) shows that raw material point disappears, concentrating under reduced pressure is removed ethyl acetate, and residue adds a small amount of ether repeatedly and carries out concentrating under reduced pressure to remove hydrogen chloride gas.Add a small amount of ether at last residue is ground to form 0.570g (95.98%) title compound, be pressed powder, be directly used in next step reaction.ESI-MS(m/z)：491.3[M]⁺，[α]^D₂₀＝-55.4369(c＝1.0，CH₃OH)。

5) Boc-Arg (NO₂The preparation of)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 0.831g (3.0mmol) Boc-Arg (NO₂)-Gly-OH and 1.5795g (3.0mmol) HClAsp (OBzl)-Ser (Bzl)-OBzl gets 2.165g (85%) title compound, is the beige solid.ESI-MS(m/z)：850[M]⁺，[α]^D₂₀＝-16.3729(c＝1.0，CHCl₃)

6) HClArg (NO₂The preparation of)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.849g (1.0mmol) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl makes 0.712g (95%) title compound, is the beige solid.ESI-MS(m/z)：750.1[M]⁺，[α]^D₂₀＝-58.3196(c＝1.0，CH₃OH)。

7) preparation of RGDS

With 0.750g (1mmol) HClArg (NO₂)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl places the 50ml eggplant-shape bottle, with dissolve with ethanol, add 200mgPd/C (5%), logical H₂(0.02Mba), stirring at room to raw material point disappears.Filtering Pd/C, filtrate decompression are concentrated into dried, and residue grinds with sherwood oil repeatedly, get 0.389g (90%) title compound, are the colorless solid powder.ESI-MS(m/z)：434.4[M]⁺，[α]²⁰_D＝6.0(c＝1.0，H₂O).

The preparation ofembodiment 2 RGDV

1) preparation of Boc-Asp (OBzl)-VII l-OBzl

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe gets 2.5344g (99%) title compound by 1.620g (5.0mmol) Boc-Asp (OBzl)-OH and 1.895g (5.0mmol) TosVal-OBzl, is the beige solid.ESI-MS(m/z)：513.3[M]⁺，[α]^D₂₀＝-14.2710(c＝1，CH₃OH)

2) preparation of HClAsp (OBzl)-Val-OBzl

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, get 0.662g (99%) title compound from 0.763g (1.491mmol) Boc-Asp (OBzl)-Val-OBzl, be pressed powder, be directly used in next step reaction.ESI-MS(m/z)：413.4[M]⁺，[α]^D₂₀＝-47.8027(c＝1，CH₃OH)

3) Boc-Arg (NO₂The preparation of)-Gly-Asp (OBzl)-Val-OBzl

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 0.831g (3.0mmol) Boc-Arg (NO₂)-Gly-OH and 1.3455g (3.0mmol) HClAsp (OBzl)-Val-OBzl gets 2.08 (90%) title compounds, is the beige solid.ESI-MS(m/z)：771.6[M]⁺，[α]^D₂₀＝-30.9346(c＝1，CH₃OH)

4) HClArg (NO₂The preparation of)-Gly-Asp (OBzl)-Val-OBzl

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.771g (1.0mmol) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Val-OBzl makes 0.637g (95%) title compound, is the beige solid.ESI-MS(m/z)：672.1[M]⁺，[α]^D₂₀＝-50.8685(c＝1，CH₃OH)

5) preparation of RGDV

According to the preparation method of RGDS, from 0.672g (1mmol) HCl Arg (NO₂)-Gly-Asp (OBzl)-Val-OBzl gets 0.382g (85%) title compound, is the colorless solid powder.ESI-MS(m/z)：446.4[M]⁺，[α]²⁰_D＝3.0(c＝1.0，H₂O)。

The preparation ofembodiment 3 RGDF

1) preparation of Boc-Asp (OBzl)-Phe-OBzl

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe gets 2.77g (99%) title compound by 1.620g (5.0mmol) Boc-Asp (OBzl)-OH and 2.135g (5.0mmol) TosPhe-OBzl, is the beige solid.ESI-MS(m/z)：561.4[M]⁺，[α]^D₂₀＝-15.2842(c＝1，CH₃OH)

2) preparation of HClAsp (OBzl)-Phe-OBzl

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, get 0.703g (95%) title compound from 0.835g (1.491mmol) Boc-Asp (OBzl)-Phe-OBzl, be pressed powder, be directly used in next step reaction.ESI-MS(m/z)：461.3[M]⁺，[α]^D₂₀＝-44.8753(c＝1，CH₃OH)。

3) Boc-Arg (NO₂The preparation of)-Gly-Asp (OBzl)-Phe-OBzl

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 0.831g (3.0mmol) Boc-Arg (NO₂)-Gly-OH and 1.4895g (3.0mmol) HClAsp (OBzl)-Phe-OBzl gets 2.16g (88%) title compound, is the beige solid.ESI-MS(m/z)：819.5[M]⁺，[α]^D₂₀＝-20.3583(c＝1，CH₃OH).

4) HClArg (NO₂The preparation of)-Gly-Asp (OBzl)-Phe-OBzl

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.819g (1.0mmol) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Phe-OBzl makes 0.717g (95%) title compound, is the beige solid.ESI-MS(m/z)：719.4[M]⁺，[α]^D₂₀＝-10.6121(c＝1，CH₃OH).

5) preparation of RGDF

According to the preparation method of RGDS, from 0.719g (1mmol) HCl Arg (NO₂)-Gly-Asp (OBzl)-Phe-Obzl gets 0.443g (90%) title compound, is the colorless solid powder.ESI-MS(m/z)：494.5[M]⁺，[α]²⁰_D＝4.0(c＝2.0，H₂O).

Embodiment 4 CH₃(CH₂)₁₄The preparation of CORGDS

1) CH₃(CH₂)₁₄CO-Arg (NO₂The preparation of)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.28g (5.0mmol) CH₃(CH₂)₁₄CO₂H and 3.9275g (5.0mmol) HClArg (NO₂)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl makes 4.23g (85.7%) title compound, is yellow waxy solid.ESI-MS(m/z)：987.1[M]⁺，[α]^D₂₀＝2.3987(c＝1，CH₃OH)

2) CH₃(CH₂)₁₄The preparation of CO-Arg-Gly-Asp-Ser-OH

According to the preparation method of RGDS by 0.987g (1mmol) CH₃(CH₂)₁₄CO-Arg (NO₂)-Gly-Asp (OBzl)-Ser (Bzl)-OBzl makes 0.46g (60%) title compound, is yellow waxy solid.ESI-MS(m/z)：672.1[M]⁺，[α]^D₂₀＝-5.0968(c＝1，CH₃OH)

Embodiment 5 CH₃(CH₂)₁₄The preparation of CORGDV

1) CH₃(CH₂)₁₄CO-Arg (NO₂The preparation of)-Gly-Asp (OBzl)-Val-OBzl

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.28g (5.0mmol) CH₃(CH₂)₁₄CO₂H and 3.53g (5.0mmol) HClArg (NO₂)-Gly-Asp (OBzl)-Val-OBzl makes 3.86g (85%) title compound, is yellow waxy solid.ESI-MS(m/z)：910.5[M]⁺.[α]^D₂₀＝-13.2265(c＝1，CH₃OH)

2) CH₃(CH₂)₁₄The preparation of CO-Arg-Gly-Asp-Val-OH

According to the preparation method of RGDS by 0.910g (lmmol) CH₃(CH₂)₁₄CO-Arg (NO₂)-Gly-Asp (OBzl)-Val-OBzl makes 0.53g (78%) title compound, is yellow waxy solid.ESI-MS(m/z)：684.1[M]⁺，[α]^D₂₀＝-7.0289(c＝1，CH₃OH)。

Embodiment 6 CH₃(CH₂)₁₄The preparation of CORGDF

1) CH₃(CH₂)₁₄CO-Arg ㈩ O₂The preparation of)-Gly-Asp (OBzl)-Phe-OBzl

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.28g (5.0mmol) CH₃(CH₂)₁₄CO₂H and 3.77g (5.0mmol) HClArg (NO₂)-Gly-Asp (OBzl)-Phe-OBzl makes 3.83g (80%) title compound, is yellow waxy solid.ESI-MS(m/z)：957.5[M]⁺，[α]^D₂₀＝-8.6622(c＝1，CH₃OH)

2) CH₃(CH₂)₁₄The preparation of CO-Arg-Gly-Asp-Phe-OH

According to the preparation method of RGDS by 0.957g (1mmol) CH₃(CH₂)₁₄CO-Arg (NO₂)-Gly-Asp (OBzl)-Phe-OBzl makes 0.439g (60%) title compound, is yellow waxy solid.ESI-MS(m/z)：732.0[M]⁺，[α]^D₂₀＝-7.3279(c＝1，CH₃OH)

Embodiment 7 RGDS-OCH₂(CH₂)₁₄CH₃Preparation

1) Boc-Ser (BZl)-OCH₂(CH2)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.48g (5mmol) Boc-Ser (BZl)-OH and 1.21g (5.0 mmol) CH₃(CH₂)₁₄CH₂OH makes 2.47g (95%) title compound, is colorless oil.ESI-MS(m/z)：520.3[M]⁺

2) HClSer (Bzl)-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.52g (1.0mmol) Boc-Ser (BZl)-OCH₂(CH₂)₁₄CH₃Make 0.420g (100%) title compound, be the beige solid.ESI-MS(m/z)：420.7[M]⁺

3) Boc-Asp (OBzl)-Ser (Bzl)-OCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.615g (5mmol) Boc-Asp (OBzl)-OH and 2.10g (5.0 mmol) HClSer (Bzl)-OCH₂(CH₂)₁₄CH₃Make 3.33g (92%) title compound, be colorless oil.ESI-MS(m/z)：724.6[M]⁺

4) HClAsp (OBzl)-Ser (Bzl)-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.72g (1.0mmol) Boc-Asp (OBzl)-Ser (BZl) OCH₂(CH₂)₁₄CH₃Make 0.62g (99%) title compound, be the beige solid.ESI-MS(m/z)：624.7[M]⁺

5) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Ser (BZl)-OCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.885g (5.0mmol) Boc-Arg (NO₂)-Gly-OH and 3.12g (5.0mmol) HClAsp (OBzl)-Ser (Bzl)-OCH₂(CH₂)₁₄CH₃Make 4.23g (86%) title compound, be colorless solid.ESI-MS(m/z)：983.9[M]⁺，[α]^D₂₀＝-8.6285(c＝1，CH₃OH)

6) HClArg (NO₂)-Gly-Asp (OBzl)-Ser (Bzl)-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.984g (1.0mmol) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Ser (Bzl)-OCH₂(CH₂)₁₄CH₃Make 0.85g (96%) title compound, be the beige solid.ESI-MS(m/z)：883.9[M]⁺

7) RGDS-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of RGDS by 0.88g (1mmol) HClArg (NO₂)-Gly-Asp (OBzl)-Ser (Bzl)-OCH₂(CH₂)₁₄CH₃Make 0.52g (70%) title compound, be colorless solid.ESI-MS(m/z)：658.2[M]⁺，[α]^D₂₀＝-3.8645(c＝1，CH₃OH)

Embodiment 8 RGDV-OCH₂(CH₂)₁₄CH₃Preparation

1) Boc-Val-OCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.085g (5mmol) Boc-Val-OH and 1.21g (5.0mmol) CH₃(CH₂)₁₄CH₂OH makes 2.17g (98%) title compound, is colorless oil.ESI-MS(m/z)：442.4[M]⁺

2) HClVal-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.442g (1.0mmol) Boc-Val-OCH₂(CH₂)₁₄CH₃Make 0.318g (93%) title compound, be colorless solid.ESI-MS(m/z)：342.4[M]⁺

3) Boc-Asp (OBzl)-Val-OCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.605g (5mmol) Boc-Asp (OBzl)-OH and 1.6g (5.0 mmol) HClVal-OCH₂(CH₂)₁₄CH₃Make 2.91g (90%) title compound, be colorless oil.ESI-MS(m/z)：647.3[M]⁺

4) HClAsp (OBzl)-Val-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.647g (1.0mmol) Boc-Asp (OBzl)-Val-OCH₂(CH₂)₁₄CH₃Make 0.492g (90%) title compound, be the beige solid.ESI-MS(m/z)：547.3[M]⁺

5) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Val-OCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.885g (5.0mmol) Boc-Arg (NO₂)-Gly-OH and 2.74g (5.0 mmol) HClAsp (OBzl)-Val-OCH₂(CH₂)₁₄CH₃Make 3.604g (87%) title compound, be colorless solid.ESI-MS(m/z)：906.4[M]⁺.[α]^D₂₀＝-11.1938(c＝1，CH₃OH)

6) HClArg (NO₂)-Gly-Asp (OBzl)-Val-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.907g (1.0mmol) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Val-OCH₂(CH₂)₁₄CH₃Make 0.766g (95%) title compound, be the beige solid.ESI-MS(m/z)：806.4[M]⁺

7) RGDV-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of RGDS by 0.8lg (1mmol) HClArg (NO₂)-Gly-Asp (OBzl)-Val-OCH₂(CH₂)₁₄CH₃Make 0.536g (80%) title compound, be colorless solid.ESI-MS(m/z)：670.4[M]⁺.[α]^D₂₀＝-9.1265(c＝1，CH₃OH)

Embodiment 9 RGDF-OCH₂(CH₂)₁₄CH₃Preparation

1) Boc-Phe-OCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.325g (5mmol) Boc-Phe-OH and 1.21g (5.0mmol) CH₃(CH₂)₁₄CH₂OH makes 2.33g (95%) title compound, is colorless oil.ESI-MS(m/z)：490.6[M]⁺

2) HClPhe-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.491g (1.0mmol) Boc-Phe-OCH₂(CH₂)₁₄CH₃Make 0.37g (95%) title compound, be the beige solid.ESI-MS(m/z)：390.6[M]⁺

3) Boc-Asp (OBzl)-Phe-OCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.605g (5mmol) Boc-Asp (OBzB-OH and 1.95g (5.0 mmol) HClPhe-OCH₂(CH₂)₁₄CH₃Make 3.13g (90%) title compound, be colorless oil.ESI-MS(m/z)：695.8[M]⁺

4) HClAsp (OBzl)-Phe-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.69g (1.0mmol) Boc-Asp (OBzl)-Phe-OCH₂(CH₂)₁₄CH₃Make 0.54g (90%) title compound, be the beige solid.ESI-MS(m/z)：595.6[M]⁺

5) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Phe-OCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.885g (5.0mmol) Boc-Arg (NO₂)-Gly-OH and 2.978g (5.0mmol) HClAsp (OBzl)-Phe-OCH₂(CH₂)₁₄CH₃Make 4.0g (84%) title compound, be colorless solid.ESI-MS(m/z)：953.6[M]⁺，[α]^D₂₀＝-10.0278(c＝1，CH₃OH)

6) HClArg (NO₂)-Gly-Asp (OBzl)-Phe-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.954g (1.0mmol) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Phe-OCH₂(CH₂)₁₄CH₃Make 0.78g (92%) title compound, be the beige solid.ESI-MS(m/z)：853.6[M]⁺

7) RGDF-OCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of RGDS by 0.85g (1mmol) HClArg (NO₂)-Gly-Asp (OBzB-Phe-OCH₂(CH₂)₁₄CH₃Make 0.574g (80%) title compound, be colorless solid.ESI-MS(m/z)：718.1[M]⁺，[α]^D₂₀＝6.3946(c＝1，CH₃OH)

Embodiment 10 RGDS-NHCH₂(CH₂)₁₄CH₃Preparation

1) Boc-Ser (BZl)-NHCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.48g (5mmol) Boc-Ser (BZl)-OH and 1.20g (5.0mmol) CH₃(CH₂)₁₄CH₂NH₂Make 2.49g (96%) title compound, be colorless solid.ESI-MS(m/z)：520.2[M]⁺

2) HClSer (BZl)-NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.52g (1.0mmol) Boc-Ser (BZl)-NH₂CH₂(CH₂)₁₄CH₃Make 0.38g (90%) title compound, be the beige solid.ESI-MS(m/z)：420[M]⁺

3) Boc-Asp (OBzl)-Ser (BZl) NHCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.615g (5mmol) Boc-Asp (OBzl)-OH and 2.1g (5.0 mmol) HClSer (BZl)-NHCH₂(CH₂)₁₄CH₃Make 3.33g (92%) title compound, be colorless solid.ESI-MS(m/z)：723.8[M]⁺.

4) HClAsp (OBzl)-Ser (BZl) NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.72g (1.0mmol) Boc-Asp (OBzl)-Ser (BZl) NHCH₂(CH₂)₁₄CH₃Make 0.59g (95%) title compound, be the beige solid.ESI-MS(m/z)：623.8[M]⁺.

5) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Ser (BZl) NHCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.885g (5.0mmol) Boc-Arg (NO₂)-Gly-OH and 3.12g (5.0mmol) HClAsp (OBzl)-Ser (BZl) NHCH₂(CH₂)₁₄CH₃Make 4.17g (83%) title compound, be colorless solid.ESI-MS(m/z)：1004.3[M+Na].[α]^D₂₀＝8.3623(c＝1，CH₃OH)

6) HClArg (NO₂)-Gly-Asp (OBzl)-Ser (BZl) NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 1.004g (1.0mmol) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Ser (BZl) NHCH₂(CH₂)₁₄CH₃Make 0.79g (90%) title compound, be the beige solid.ESI-MS(m/z)：881.3[M]⁺

7) RGDS-NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of RGDS by 0.881g (1mmol) HClArg (NO₂)-Gly-Asp (OBzl)-Ser (BZl) NHCH₂(CH₂)₁₄CH₃Make 0.53g (80%) title compound, be colorless solid.ESI-MS(m/z)：657.0[M]⁺.[α]^D₂₀＝-7.5289(c＝1，CH₃OH)

Embodiment 11 RGDV-NHCH₂(CH₂)₁₄CH₃Preparation

1) Boc-Val-NHCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.085g (5mmol) Boc-Val-OH and 1.205g (5.0mmol) CH₃(CH₂)₁₄CH₂NH₂Make 2.11g (96%) title compound, be colorless solid.ESI-MS(m/z)：441.2[M]⁺

2) HClVal-NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.384g (1.0mmol) Boc-Val-NHCH₂(CH₂)₁₄CH₃Make 0.32g (95%) title compound, be the beige solid.ESI-MS(m/z)：341.6[M]⁺

3) Boc-Asp (OBzl)-Val-NHCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg ㈩ O₂The preparation method of)-Gly-OMe is by 1.615g (5mmol) Boc-Asp (OBzl)-OH and 1.7g (5.0mmol) HClVal-NHCH₂(CH₂)₁₄CH₃Make 3.10g (96%) title compound, be colorless solid.ESI-MS(m/z)：647.3[M]⁺

4) HClAsp (OBzl)-Val-NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.589g (1.0mmol) Boc-Asp (OBzl)-Val-NHCH₂(CH₂)₁₄CH₃Make 0.51g (93%) title compound, be the beige solid.ESI-MS(m/z)：547[M]⁺

5) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Val-NHCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.885g (5.0mmol) Boc-Arg (NO₂)-Gly-OH and 2.73g (5.0mmol) HClAsp (OBzl)-Val-NHCH₂(CH₂)₁₄CH₃Make 3.61g (80%) title compound, be colorless solid.ESI-MS(m/z)：904.9[M]⁺.[α]^D₂₀＝-13.3931(c＝1，CH₃OH)

6) HClArg (NO₂)-Gly-Asp (OBzl)-Val-NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.905g (1.0mmol) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Val-NHCH₂(CH₂)₁₄CH₃Make 0.76g (94%) title compound, be the beige solid.ESI-MS(m/z)：804.6[M]⁺

7) RGDV-NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of RGDS by (0.805g (1mmol) HClArg (NO₂)-Gly-Asp (OBzl)-Val-NHCH₂(CH₂)₁₄CH₃Make 0.55g (82%) title compound, be colorless solid.ESI-MS(m/z)：669.7[M]⁺.[α]^D₂₀＝-13.5230(c＝1，CH₃OH)

Embodiment 12 RGDF-NHCH₂(CH₂)₁₄CH₃Preparation

1) Boc-Phe-NHCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.325g (5mmol) Boc-Phe-OH and 1.20g (5.0mmol) CH₃(CH₂)₁₄CH₂NH₂Make 2.37g (97%) title compound, be colorless solid.ESI-MS(m/z)：489.4[M]⁺

2) HClPhe-NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.49g (1.0mmol) Boc-Phe-NHCH₂(CH₂)₁₄CH₃Make 0.39g (99%) title compound, be the beige solid.ESI-MS(m/z)：389.6[M]⁺.

3) Boc-Asp (OBzl)-Phe-NHCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.615g (5mmol) Boc-Asp (OBzl)-OH and 1.95g (5.0mmol) HClPhe-NHCH₂(CH₂)₁₄CH₃Make 3.02g (87%) title compound, be colorless solid.ESI-MS(m/z)：694.5[M]⁺

4) HClAsp (OBzl)-Phe-NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of HClAsp (OBzl)-Ser (Bzl)-OBzl, from 0.695g (1.0mmol) Boc-Asp (OBzl)-Phe-NHCH₂(CH₂)₁₄CH₃Make 0.56g (95%) title compound, be the beige solid.ESI-MS(m/z)：594.8[M]⁺.

5) Boc-Arg (NO₂)-Gly-Asp (OBzl)-Phe-NHCH₂(CH₂)₁₄CH₃Preparation

According to Boc-Arg (NO₂The preparation method of)-Gly-OMe is by 1.885g (5.0mmol) Boc-Arg (NO₂)-Gly-OH and 2.97g (5.0mmol) HClAsp (OBzl)-Phe-NHCH₂(CH₂)₁₄CH₃Make 4.05g (85%) title compound, be colorless solid.ESI-MS(m/z)：952.7[M]⁺[α]^D₂₀＝-11.1601(c＝1，CH₃OH)

6) HClArg (NO₂)-Gly-Asp (OBzD-Phe-NHCH₂(CH₂)₁₄CH₃Preparation

(preparation method of OBzB-Ser (Bzl)-OBzl is from 0.953g (1.0mmol) Boc-Arg (NO according to HClAsp₂)-Gly-Asp (OBzl)-Phe-NHCH₂(CH₂)₁₄CH₃Make 0.81g (95%) title compound, be the beige solid.ESI-MS(m/z)：852.6[M]⁺

7) RGDF-NHCH₂(CH₂)₁₄CH₃Preparation

According to the preparation method of RGDS by 0.85g (1mmol) HClArg (NO₂)-Gly-Asp (OBzl)-Phe-OCH₂(CH₂)₁₄CH₃Make 0.57g (80%) title compound, be colorless solid.ESI-MS(m/z)：717.6[M]⁺.，[α]^D₂₀＝-2.7974(c＝1，CH₃OH)

The antithrombotic acitivity test of test example 1 The compounds of this invention oral administration

1) rat operation and apparatus

(male, 220～230g) press 10nmolkg to the SD rat^-1Oral dose compound of the present invention is pressed 1200mg-kg behind the 30min^-1Dosage abdominal injection urethane solution is anaesthetized.The anesthetized rat dorsal position is fixed, and separates right common carotid artery, and in proximal part folder bulldog clamp, proximal part and distal end penetrate surgical thread respectively, and the surgical thread of distal end is clamped with mosquito forceps in fur, prepares in the distal end intubate.

2) intubate

Intubate is the polyethylene rubber tube that silanization is crossed, and divides three sections, and the stage casing is a polyethylene rubber tube, long 60.0mm, internal diameter 3.5mm; Two ends are identical polyethylene tube, and pipe range 100.0mm, internal diameter 1.0mm, an end of this pipe of external diameter 2.0mm pull into point pipe (being used to insert rat carotid artery or vein), and external diameter is 1.0mm.Be respectively charged into the long black surgical thread of 6cm in the clean penicillin bottle with the number of finishing, weigh; Take out silk thread then, put into the thicker intubate in stage casing of ready intubate according to numbering.

Open rat right side bulldog clamp, will fill with heparin-saline solution (50IUkg in the pipe by sharp pipe end with syringe^-1), then the arterial end of intubate is inserted the rat right carotid, the heparin of calculated amount is slowly injected in the rat body.

3) give drug solns

Medicine: physiological saline (3mlkg^-1, orally give), the normal saline solution, the normal saline solution of The compounds of this invention (dosage is 10nmol/kg, orally give) of Asprin (dosage is 30mg/kg, gives by the method vein of test example 1).

4) thrombus is weighed

Timing is cut off venous incubation after beginning 15 minutes, stops circulation, carefully takes out silk thread with the ophthalmology tweezer, dips in drop of blood on filter paper gently, puts into the penicillin bottle of weighing in advance, accurately weighs and record.Calculate the weight in wet base of thrombus.Each medicine repeats 11 administrations.The wet weight of thrombus of each group of statistics (X ± SD), and do the t check.

5) result

The oral administration administration, compound of the present invention all has good anti-thrombus activity.The result lists table 1 in.

The antithrombotic acitivity of table 1. The compounds of this invention oral administration administration

Compound	Wet weight of thrombus (X ± SDmg)
Compound	Wet weight of thrombus (X ± SDmg)	Physiological saline	28.03±1.40
Asprin	8.50±0.75^a	Physiological saline	28.03±1.40
Asprin	8.50±0.75^a	CH₃(CH₂)₁₄CORGDS	7.46±2.19^a
CH₃(CH₂)₁₄CORGDV	10.78±3.63^a	CH₃(CH₂)₁₄CORGDS	7.46±2.19^a
CH₃(CH₂)₁₄CORGDV	10.78±3.63^a	CH₃(CH₂)₁₄CORGDF	7.84±2.85^a
RGDS-OCH₂(CH₂)₁₄CH₃	9.97±2.99^a	CH₃(CH₂)₁₄CORGDF	7.84±2.85^a
RGDS-OCH₂(CH₂)₁₄CH₃	9.97±2.99^a	RGDV-OCH₂(CH₂)₁₄CH₃	7.25±2.81^a
RGDF-OCH₂(CH₂)₁₄CH₃	8.57±2.70^a	RGDV-OCH₂(CH₂)₁₄CH₃	7.25±2.81^a
RGDF-OCH₂(CH₂)₁₄CH₃	8.57±2.70^a	RGDS-NHCH₂(CH₂)₁₄CH₃	7.20±2.73^a
RGDV-NHCH₂(CH₂)₁₄CH₃	8.93±3.97^a	RGDS-NHCH₂(CH₂)₁₄CH₃	7.20±2.73^a
RGDV-NHCH₂(CH₂)₁₄CH₃	8.93±3.97^a	RGDF-NHCH₂(CH₂)₁₄CH₃	6.25±1.50^a

N=10; NS=physiological saline; A. compare P＜0.01 with physiological saline.

Test example 2 The compounds of this invention RGDF-NHCH₂(CH₂)₁₄CH₃The dose-effect relationship of oral administration

1) rat operation and apparatus

(male, 220～230g) press 10nmolkg to the SD rat^-1, 0.1nmolkg^-1And 0.001nmolkg^-1Oral dose RGDF-NHCH₂(CH₂)₁₄CH₃, press 1200mg-kg behind the 30min^-1Dosage abdominal injection urethane solution is anaesthetized.The anesthetized rat dorsal position is fixed, and separates right common carotid artery, and in proximal part folder bulldog clamp, proximal part and distal end penetrate surgical thread respectively, and the surgical thread of distal end is clamped with mosquito forceps in fur, prepares in the distal end intubate.

2) intubate

3) give drug solns

Medicine: with RGDF-NHCH₂(CH₂)₁₄CH₃Press 10nmolkg^-1, 0.1nmolkg^-1And 0.001nmolkg^-1Dosage configuration normal saline solution, for oral administration.

4) thrombus is weighed

5) result

The oral administration administration is at 10nmolkg^-1, 0.1nmolkg^-1, 0.001nmolkg^-1And 0.0001nmolkg^-1Under the dosage, RGDF-NHCH₂(CH₂)₁₄CH₃Dosage relies on ground performance anti thrombotic action.The result lists table 2 in.

Table 2. orally give RGDF-NHCH₂(CH₂)₁₄CH₃Dose-effect relationship

Dosage	Wet weight of thrombus (X ± SDmg)
Dosage	Wet weight of thrombus (X ± SDmg)	10nmol/Kg/3ml	6.25±1.56^a
0.1nmol/Kg/3ml	12.72±3.08^b	10nmol/Kg/3ml	6.25±1.56^a
0.1nmol/Kg/3ml	12.72±3.08^b	0.001nmol/Kg/3ml	13.52±2.79^b

A. with 0.1nmolkg^-1, 0.001molkg^-1, p＜0.05;

Test example 3 compounds of the present invention are in the test of aqueous phase assembling becoming nanometer ball

1) 9 kinds of positively charged ion pharmacomes of the present invention are configured as the aqueous solution according to the concentration of 0.5mg/ml, go up METHOD FORCONTINUOUS DETERMINATION 8 days at laser light scattering particle size analyzer (model), observe particle diameter and change of size, the results are shown in Table 3.The data that obtain show that these 9 kinds of positively charged ion pharmacomes can be self-assembled at aqueous phase and be the stabilized nano ball, thereby are the outstanding micro emulsion and the preparation material of liposome medicament.

Table 39 kinds of positively charged ion pharmacomes of the present invention are self-assembled into the grain warp into the stabilized nano ball in water

2) compound of the present invention is in the stability of the nanometer ball of water assembling

Test-results is seen Fig. 2.

3) according to the mensuration requirement of scanning electron microscope, the aqueous solution of 9 kinds of positively charged ion pharmacomes of configuration places the dry back of copper mesh Back stroke to measure the figure of compound of the present invention at the nanometer ball of water assembling.The result shows, can see uniform granular attitude by the nanometer ball of these 9 kinds of positively charged ion pharmacome assemblings under scanning electron microscope.Given here is representative compounds RGDF-NHCH₂(CH₂)₁₄CH₃Sem photograph (Fig. 3).

Test example 4 compounds of the present invention fat mutually in assembling become nanometer ball and test

1) selecting n-Octanol is the fat phase, and 9 kinds of positively charged ion pharmacomes of the present invention are configured as n-Octanol solution according to the concentration of 0.5mg/ml, goes up METHOD FORCONTINUOUS DETERMINATION 8 days at laser light scattering particle size analyzer (model), observes particle diameter and change of size, the results are shown in Table 4.The data that obtain show, these 9 kinds of positively charged ion pharmacomes can be self-assembled in mutually at fat and be the stabilized nano ball, thereby are the outstanding micro emulsion and the preparation material of liposome medicament.

Table 49 kinds of positively charged ion pharmacomes of the present invention are self-assembled into the grain warp into the stabilized nano ball in n-Octanol

2) stability of the nanometer ball assembled mutually at fat of compound of the present invention

Test-results is seen Fig. 4.

3) according to the mensuration requirement of scanning electron microscope, the n-Octanol solution of 9 kinds of positively charged ion pharmacomes of configuration places the dry back of copper mesh Back stroke to measure the figure of the nanometer ball that compound of the present invention assembles mutually at fat.The result shows, can see uniform granular attitude by the nanometer ball of these 9 kinds of positively charged ion pharmacome assemblings under scanning electron microscope.Given here is representative compounds RGDF-NHCH₂(CH₂)₁₄CH₃Sem photograph (Fig. 5).

Claims

Translated fromChinese

1.靶向阳离子药质体，其特征在于，选自以下(1)-(9)中任意一种的化合物：(1)CH₃(CH₂)₁₄CO-Arg-Gly-Asp-Ser-OH、(2)CH₃(CH₂)₁₄CO-Arg-Gly-Asp-Val-OH、(3)CH₃(CH₂)₁₄CO-Arg-Gly-Asp-Phe-OH、(4)Arg-Gly-Asp-Ser-OCH₂(CH₂)₁₄CH₃、(5)Arg-Gly-Asp-Val-OCH₂(CH₂)₁₄CH₃、(6)Arg-Gly-Asp-Phe-OCH₂(CH₂)₁₄CH₃、(7)Arg-Gly-Asp-Ser-NHCH₂(CH₂)₁₄CH₃、(8)Arg-Gly-Asp-Val-NHCH₂(CH₂)₁₄CH₃、(9)Arg-Gly-Asp-Phe-NHCH₂(CH₂)₁₄CH₃。1. Targeting cationic drug plastid, characterized in that it is a compound selected from any one of the following (1)-(9): (1) CH₃ (CH₂ )₁₄ CO-Arg-Gly-Asp-Ser- OH, (2) CH₃ (CH₂ )₁₄ CO-Arg-Gly-Asp-Val-OH, (3) CH₃ (CH₂ )₁₄ CO-Arg-Gly-Asp-Phe-OH, (4) Arg -Gly-Asp-Ser-OCH₂ (CH₂ )₁₄ CH₃ , (5) Arg-Gly-Asp-Val-OCH₂ (CH₂ )₁₄ CH₃ , (6) Arg-Gly-Asp-Phe-OCH₂ (CH₂ )₁₄ CH₃ , (7) Arg-Gly-Asp-Ser-NHCH₂ (CH₂ )₁₄ CH₃ , (8) Arg-Gly-Asp-Val-NHCH₂ (CH₂ )₁₄ CH₃ , (9) Arg-Gly-Asp-Phe-NHCH₂ (CH₂ )₁₄ CH₃ .

2.权利要求1的靶向阳离子药质体在制备抗血栓药物中的用途。2. The targeted cationic drug plasmid of claim 1 is used in the preparation of antithrombotic drugs.

3.权利要求1的靶向阳离子药质体在制备微乳或脂质体的制剂材料中的用途。3. the purposes of the targeted cationic drug plastid body of claim 1 in the preparation material of preparation microemulsion or liposome.

4.权利要求1的靶向阳离子药质体制备微乳、脂质体的靶向制剂材料中的用途。4. The targeted cationic drug plastid according to claim 1 is used in the preparation of microemulsions and liposome targeted preparation materials.