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Anticoagulant compound, preparation method and application of anticoagulant compound and drug composition containing anticoagulant compound

A compound, drug technology, applied in the field of medicinal chemistry

Active Publication Date: 2015-03-18
北京赛而生物药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

2) Monovalent thrombin inhibitors are synthetic small molecule compounds, represented by argatroban, which can only act on the active site of thrombin

Method used

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  • Anticoagulant compound, preparation method and application of anticoagulant compound and drug composition containing anticoagulant compound
  • Anticoagulant compound, preparation method and application of anticoagulant compound and drug composition containing anticoagulant compound
  • Anticoagulant compound, preparation method and application of anticoagulant compound and drug composition containing anticoagulant compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1TM 1 preparation of

[0087]

[0088] 1) Glycine methyl ester hydrochloride (37.7g, 0.3mol) was dissolved in an appropriate amount of dichloromethane, and 41.68ml of triethylamine was added under stirring conditions to produce a large number of flocs, which were filtered off, and the filtrate was concentrated to obtain a white solid Glycine methyl ester, without treatment, directly reacted.

[0089] Add 450mL dry tetrahydrofuran to the reaction flask, add N G -Nitro-N 2 -Boc-L-homoarginine (33.3g, 0.1mol, purchased from Jill Biochemical (Shanghai) Co., Ltd.), cooling the reaction solution to -20°C, adding triethylamine (10.1g, 0.1mol) in turn under stirring and isobutyl chloroformate (13.6 g, 0.1 mol). After 30 minutes, glycine methyl ester was added to the reaction solution, stirred at -20° C. for 30 minutes, and then the temperature of the reaction solution was returned to room temperature. After the reaction solution was concentrated under reduced pr...

Embodiment 2

[0104] Example 2TM 13 preparation of

[0105]

[0106] 1) Dissolve L-proline methyl ester hydrochloride (49.5g, 0.3mol) in dichloromethane, add 41.68ml triethylamine under stirring condition, white flocs are formed, filter off the precipitate, and reduce the filtrate to Concentrate under reduced pressure to obtain white solid L-proline methyl ester, which is directly used for the next reaction without further treatment.

[0107] Add 300 mL of dry tetrahydrofuran to the reaction flask, add N G -Nitro-N 2 -Boc-L-homoarginine (33.3g, 0.1mol), cooling the reaction solution to -20°C, adding triethylamine (10.1g, 0.1mol) and isobutyl chloroformate (13.6g, 0.1mol). After 30 minutes, L-proline methyl ester was added to the reaction solution, stirred at -20° C. for 30 minutes, and then the temperature of the reaction solution was returned to room temperature. After the reaction solution was concentrated under reduced pressure, 300 mL of ethyl acetate was added, and after dissol...

experiment example 1

[0118] In vitro inhibitory effect of experimental example 1 on human thrombin

[0119] Measuring principle:

[0120] The p-nitroaniline obtained by thrombin-catalyzed hydrolysis of the substrate S-2238 has an absorption at 405nm. Therefore, the absorption value of p-nitroaniline at 405 nm can directly reflect the strength of thrombin activity, and the effect of the compound on thrombin activity can be observed in vitro.

[0121] test methods:

[0122] Add 8 μM substrate S-2238 (H-D-Phe-Pip-Arg-p-nitroaniline·2HCl) and a specific concentration of compound to 1 mL of phosphate buffer containing 0.1% PEG and 1% DMSO, pH 7.2. Add 10 mU of thrombin extracted from human plasma. After 10 minutes, absorbance was measured at 405 nm.

[0123] Results: TM was determined separately 1 -TM 20 and argatroban at a final concentration of 10 -4 M, 10 -5 Inhibition rate of human thrombin at M; measure and calculate the half inhibitory concentration IC of the compound on thrombin 50 . T...

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Abstract

The invention relates to a compound shown in a general formula (I) or a general formula (II) in the specification and a stereoisomer or physiologically acceptable salts thereof and also relates to a preparation method and application of the compound. Besides, the invention also relates to a drug composition containing the compound and an application of the drug composition. The compound which is provided by the invention and can serve as a thrombin and / or blood platelet GPIIb / IIIa receptor inhibitor has good in-vitro human thrombin inhibiting activity, in-vitro blood platelet GPIIb / IIIa receptor inhibiting effects and in-vitro / in-vivo anti-platelet aggregation effects, and does not have obvious toxicity. The compound provided by the invention has a novel structure and good biological activity, is simple and convenient to synthesize and is a drug with good application prospects and anticoagulation effects.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an anticoagulant compound, its preparation method and use, and a pharmaceutical composition containing it and its use. Background technique [0002] A thrombus is a blood clot that forms in a blood vessel, impeding or blocking blood flow in the circulatory system. When a blood vessel is damaged, platelets and fibrin in the blood will aggregate to form a blood clot to repair it, so as to avoid blood loss or further damage to the blood vessel due to the impact of blood flow. But if the blood clot breaks off, it is more likely to become a thrombus. As a serious peripheral vascular disease, thrombosis is a systemic disease with a wide range of pathogenesis, which can affect upper limbs, lower limbs, visceral blood vessels and carotid arteries; when thrombosis occurs in the heart, myocardial infarction can occur; When it occurs in the head, it can cause cerebral infarction, common...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K5/11C07K1/06A61K38/08A61K38/07A61P7/02A61P9/10
CPCA61K38/00C07K5/1019C07K7/06
Inventor 马骉杜欣孔双泉
Owner 北京赛而生物药业有限公司
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