Conjugate formed by conjugating one Arg-Gly-Asp-Val chain and two fatty alcohol chains by Asp, synthesis thereof and medical application thereof

A technology of arg-gly-asp-val-asp and conjugates, applied in the field of biomedicine, can solve the problems of short half-life, low immunogenicity, and small side effects

Inactive Publication Date: 2010-12-08
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although the Arg-Gly-Asp peptide has the advantages of low immunogenicity and small toxic and side effects, it has the disadvantages of short half-life and the like.

Method used

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  • Conjugate formed by conjugating one Arg-Gly-Asp-Val chain and two fatty alcohol chains by Asp, synthesis thereof and medical application thereof
  • Conjugate formed by conjugating one Arg-Gly-Asp-Val chain and two fatty alcohol chains by Asp, synthesis thereof and medical application thereof
  • Conjugate formed by conjugating one Arg-Gly-Asp-Val chain and two fatty alcohol chains by Asp, synthesis thereof and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0044] Embodiment 1Arg-Gly-Asp-Val-Asp[OCH 2 (CH 2 ) 6 CH 3 ] 2 Preparation of (9a)

[0045] 1) Boc-Arg (NO 2 )-Gly-OBzl:

[0046] 1.600g (5.0mmol) Boc-Arg (NO 2 ) was dissolved in 20ml of anhydrous THF to form a white emulsion, 0.745g (5.5mmol) of N-hydroxybenzotriazole (HOBt) was added under ice cooling, and 1.23g (6mmol) of dicyclohexylcarbonyldioxide was added after 10 minutes Amine (DCC), to obtain the reaction solution A, stand-by. Suspend 1.61g (5.25mmol) TOSH·Gly-OBzl in 20ml anhydrous THF under ice-cooling, then add N-methylmorpholine (NMM) to adjust the pH to 8-9. Stir for 35 minutes to obtain reaction solution B, which is ready for use. Add reaction solution A to reaction solution B under ice bath, first stir under ice bath for 1 h, then stir at room temperature for 12 h, TLC (chloroform / methanol, 10:1) showed that Boc-Arg (NO 2 )disappear. Dicyclohexylurea (DCU) was filtered off, and the filtrate was concentrated under reduced pressure to obtain a yellow...

Embodiment 2A

[0067] Example 2Arg-Gly-Asp-Val-Asp[-OCH 2 (CH 2 ) 8 CH 3 ]-OCH 2 (CH 2 ) 8 CH 3 Preparation of (9b)

[0068] 1) Boc-Asp[-OCH 2 (CH 2 ) 8 CH 3 ]-OCH 2 (CH 2 ) 8 CH 3 (1b)

[0069] According to the preparation method of 1a, by 1.165g (5mmol) Boc-Asp and 1.659g (10.5mmol) CH 3 -(CH 2 ) 9 -OH yielded 2.565 g (99.9%) of the title compound as a colorless oil. ESI-MS (m / z): 536[M+Na] + ,

[0070] 2) HCl·Asp[-OCH 2 (CH 2 ) 8 CH 3 ]-OCH 2 (CH 2 ) 8 CH 3 (2b)

[0071] Using the same method as in the preparation of 2a, 0.449 g (99.9%) of the target compound was prepared from 0.513 g (1 mmol) of 1 b as a colorless oil, which was directly used in the next reaction. ESI-MS(m / z): 414[M+H] + .

[0072] 3) Boc-Val-Asp[-OCH 2 (CH 2 ) 8 CH 3 ]-OCH 2 (CH 2 ) 8 CH 3 (3b)

[0073] Following the procedure of 3a, 3.06 g (99.9%) of the title compound were obtained as a colorless oil from 1.139 g (5.25 mmol) Boc-Val and 2.247 g (5.0 mmol) 2b. ESI-MS (m / z): 6...

Embodiment 3A

[0086] Example 3Arg-Gly-Asp-Val-Asp[-OCH 2 (CH 2 ) 10 CH3 ]-OCH 2 (CH 2 ) 10 CH 3 Preparation of (9c)

[0087] 1) Boc-Asp[-OCH 2 (CH 2 ) 10 CH 3 ]-OCH 2 (CH 2 ) 10 CH 3 (1c)

[0088] According to the preparation method of 1a, by 1.165g (5mmol) Boc-Asp and 1.953g (10.5mmol) CH 3 -(CH 2 ) 10 CH 2 -OH yielded 2.854 g (99.9%) of the title compound as a colorless oil. ESI-MS (m / z): 593[M+Na] + ,

[0089] 2) HCl·H-Asp[-OCH 2 (CH 2 ) 10 CH 3 ]-OCH 2 (CH 2 ) 10 CH 3 (2c)

[0090] Using the same method as in the preparation of 2a, 0.506 g (99.9%) of the target compound was obtained from 0.569 g (1 mmol) of 1c as a colorless oil, which was directly used in the next reaction. ESI-MS(m / z): 471[M+H] + .

[0091] 3) Boc-Val-Asp[-OCH 2 (CH 2 ) 10 CH 3 ]-OCH 2 (CH 2 ) 10 CH 3 (3c)

[0092] Following the preparation method of 3a, 3.34 g (99.9%) of the title compound were obtained as a colorless oil from 1.139 g (5.25 mmol) of Boc-Val and 1.07 g (5.0 m...

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Abstract

The invention discloses a conjugate of a peptide chain and two fatty alcohol chains, a preparation method thereof and medicinal application thereof. The conjugate is formed by conjugating one Arg-Gly-Asp-Val chain and two fatty alcohol chains by Asp and has a general formula of Arg-Gly-Asp-Val-Asp[OCH2(CH2)nCH3]2, wherein n may be 6, 8, 10 or 12. The conjugate of the invention has high oral antithrombotic activities, high self-assembling property and can be used as preparation materials for preparing medicament carries such as micro emulsion and liposome.

Description

technical field [0001] The invention relates to a conjugate of a peptide chain and a double fatty alcohol chain, in particular to a conjugate of an Arg-Gly-Asp-Val chain through Asp and two fatty alcohol chains, a preparation method thereof and the coupling The application of the drug as an antithrombotic agent, a drug carrier or a preparation material belongs to the field of biomedicine. Background technique [0002] Cardiovascular disease is one of the three major diseases that endanger the health of our people, and vascular embolism is an important disease that endangers people's life and health. [0003] Platelets play an important role in the process of thrombus formation. When platelets are activated by inducers, the surface membrane glycoprotein GPIIb / IIIa receptors are exposed and combine with fibrinogen to form thrombus. It has been reported in the literature that the Arg-Gly-Asp-Ser, Arg-Gly-Asp-Phe and cryptic Arg-Gly-Asp-Val sequences in the fibrin α and γ chai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/02A61K38/08A61K47/48A61P7/02A61K47/42A61K9/107A61K9/127A61K47/62
Inventor 赵明彭师奇姜文花
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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