Polypeptide hydrous salt of direct thrombin inhibitor and synthesis method thereof

A synthesis method and inhibitor technology, applied in the pharmaceutical field, can solve problems such as pollution, toxicity, and handling difficulties

Active Publication Date: 2009-09-23
SHENZHEN SALUBRIS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] An object of the present invention is to provide a direct inhibitor of thrombin that can be used in clinical practice to solve the above-mentioned problems in the prior art that there is no polypeptide hydrate salt of a direct thrombin inhibitor, and the synthesis methods of related types of compounds are difficult to handle, pollution and toxicity are relatively large. Peptide hydrate salt of agent, and a simple, convenient and environmentally friendly synthesis method of direct thrombin inhibitor polypeptide hydrate salt

Method used

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  • Polypeptide hydrous salt of direct thrombin inhibitor and synthesis method thereof
  • Polypeptide hydrous salt of direct thrombin inhibitor and synthesis method thereof
  • Polypeptide hydrous salt of direct thrombin inhibitor and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Coupling reactions of single amino acids

[0073] 1. Deprotection of the first amino acid at the C-terminal Fmoc-Leu-Wang resin Weigh 5.0 g of Fmoc-Leu-Wang resin, 4.5 mmol (loading capacity: 0.9 mmol / g, 100-200 mesh, DVB 1%).

[0074] (a) Put the Fmoc-Leu-Wang resin in a 100ml silanized glass reactor, add 50ml DMF, completely immerse the resin in it, and swell for 30min.

[0075] (b) Suction filter off DMF, add 40ml 20% piperidine / DMF to the resin, react for 5 minutes under slight shaking, after suction filtering off the reaction solution, add 40ml 20% piperidine / DMF, and react for 15 minutes under slight shaking , remove the reaction solution.

[0076] (c) Wash the resin with DMFx2, MeOHx2, and DMFx2, take out a little resin and put it into a small glass test tube, add one drop of ninhydrin detection reagent, react at 105°C for 5 minutes, the solution and resin are dark blue, indicating that the removal of Fmoc is complete .

[0077] 2. The second amino acid at the...

specific Embodiment 2

[0118] 1. Deprotection of the first amino acid at the C-terminal Fmoc-Leu-Wang resin Weigh 5.0 g of Fmoc-Leu-Wang resin, 4.5 mmol (loading capacity: 0.9 mmol / g, 100-200 mesh, DVB 1%).

[0119] (a) Put the Fmoc-Leu-Wang resin in a 100ml silanized glass reactor, add 50ml DMF, completely immerse the resin in it, and swell for 30min.

[0120] (b) Suction filter off DMF, add 40ml 20% piperidine / DMF to the resin, react for 5 minutes under slight shaking, after suction filtering off the reaction solution, add 40ml 20% piperidine / DMF, and react for 15 minutes under slight shaking , remove the reaction solution.

[0121] (c) Wash the resin with DMFx2, MeOHx2, and DMFx2, take out a little resin and put it into a small glass test tube, add one drop of ninhydrin detection reagent, react at 105°C for 5 minutes, the solution and resin are dark blue, indicating that the removal of Fmoc is complete .

[0122] 2. The second amino acid at the C-terminal resin coupling

[0123] Reaction for...

specific Embodiment 3

[0154] Coupling reaction of two peptide fragments

[0155] 1. Coupling of 1-10 amino acids at the C-terminal:

[0156] (1) Deprotection of the first amino acid at the C-terminal

[0157]Weigh 5.0 g of Fmoc-Leu-Wang resin, 4.5 mmol (loading capacity is 0.9 mmol / g, 100-200 mesh, DVB 1%).

[0158] (a) Put the Fmoc-Leu-Wang resin in a 100ml silanized glass reactor, add 50ml DMF, completely immerse the resin in it, and swell for 30min.

[0159] (b) Suction filter off DMF, add 40ml 20% piperidine / DMF to the resin, react for 5 minutes under slight shaking, after suction filtering off the reaction solution, add 40ml 20% piperidine / DMF, and react for 15 minutes under slight shaking , remove the reaction solution.

[0160] (c) Wash the resin with DMFx2, MeOHx2, and DMFx2, take out a little resin and put it into a small glass test tube, add one drop of ninhydrin detection reagent, react at 105°C for 5 minutes, the solution and resin are dark blue, indicating that the removal of Fmoc i...

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PUM

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Abstract

The invention relates to the field of medicaments, in particular to a polypeptide hydrous salt of a direct thrombin inhibitor and a synthesis method thereof. The invention solves the problems of the prior art including lack of direct thrombin inhibitor polypeptide hydrous salts, difficult synthesis methods and post treatment of compounds of related types, heavy environmental pollution and great harm to human body, and provides a convenient-to-operate and effective polypeptide hydrous salt of a direct thrombin inhibitor and a synthesis method thereof, wherein the general formula of the polypeptide hydrous salt is C98h138N24O33.mXnH2O. The synthesis method adopts coupling single amino acids or peptide fragments. The details of the synthesis method details are described in the description. The method of the invention is simple in operation process, stable in reaction conditions and good in repeatability, allows for automatic synthesis in a synthesizer and allows a whole reaction process to be carried out in one reactor, thereby avoiding product loss caused by the transfer of intermediates and greatly saving labor and materials; and reagents used in the reaction process cause little pollution to environment and little harm to the health of operators.

Description

technical field [0001] The invention relates to the field of medicines, and relates to a polypeptide hydrated salt of a direct thrombin inhibitor and a synthesis method thereof. Background technique [0002] The polypeptide portion of the direct thrombin inhibitor has been reported (US Patent No. 5433940), but its hydrated salts have not been mentioned. In the actual synthesis process, if the final refining process of the product exists in the form of hydrated salt, since the polypeptide hydrated salt is easily soluble in water and relatively stable, especially hydrochloric acid, acetate and trifluoroacetate are used in the clinical application process. Among them, there are no toxic and side effects, and it is the best form of polypeptide products, so the research on the hydrated salts of this compound is necessary. [0003] The synthetic method of related type compound has bibliographical report abroad to be the solid-phase synthesis method (MaraganoreJM., 1989) utilizing...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/04C07K1/06
Inventor 范业梅梅世昌
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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