Dabigatran derivatives as well as preparation method and application thereof

A technology of dabigatran and its derivatives, which is applied in the field of medicine and can solve the problems of low oral bioavailability

Active Publication Date: 2015-05-06
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, after research, we found that dabigatran etexilate also has many shortcomings, and its oral bioavailability is low (<6.5%)

Method used

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  • Dabigatran derivatives as well as preparation method and application thereof
  • Dabigatran derivatives as well as preparation method and application thereof
  • Dabigatran derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 13

[0048] Preparation Example 13-(2-((4-methoxyphenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzimidazole-5-carbonylamino)propane Acid (III)

[0049]

[0050] Step (1): To 3-(2-(chloromethyl)-1-methyl-N-(pyridin-2-yl)-1H-benzimidazole-5-carbonylamino)propionic acid ethyl ester (I) (8.02g, 20mmol) in a stirred solution of acetonitrile (50ml), sequentially added 4-methoxyaniline (2.96g, 24mmol), potassium carbonate (5.53g, 40mmol), potassium iodide (0.34g, 2mmol). The mixture was stirred at 80°C for 5 hours. The solution was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (200 mL) and water (150 mL), and the organic layer was separated. The aqueous phase was further extracted with dichloromethane (150 mL) and the combined organic extracts were combined. Dry over anhydrous sodium sulfate, filter and concentrate to give crude 3-(2-((4-methoxyphenylamino)methyl)-1-methyl-N-(pyridin...

preparation Embodiment 2

[0053] Preparation Example 2: 3-(2-((2-chlorothiophene-5-carbonylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzimidazole-5-carbonyl Preparation of amino)propionic acid

[0054]

[0055] Step (1) At 0-5°C, slowly add dropwise to a stirred solution of 2-aminoacetic acid (IV) (5g, 66mmol) in aqueous sodium hydroxide solution (3.8mol / L) and tetrahydroimidazole (40ml) Boc anhydride (14.5g, 66mmol), after the dropwise addition, rise to room temperature (about 25°C) for 24 hours, then lower to 0-5°C, adjust the pH to about 3 with 2N hydrochloric acid, dichloromethane (80mL*3) The aqueous phase was extracted, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 10 g of crude product 2-(tert-butoxycarbonylamino)acetic acid (V).

[0056] Step (2) At room temperature (around 25°C), slowly add carbonyldiimidazole ( 5.4g, 33.3mmol), stirred for 0.5 hours, added 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl) benzamido) propionic a...

preparation Embodiment 3

[0061] Preparation Example 3: 3-(2-((1H-indol-6-ylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzimidazole-5-carbonyl The preparation of amino)propionic acid (XV)

[0062]

[0063] Step (1): To 3-(2-(chloromethyl)-1-methyl-N-(pyridin-2-yl)-1H-benzimidazole-5-carbonylamino)propionic acid ethyl ester (I) (8.02g, 20mmol) in a stirred solution of acetonitrile (50ml), were added successively 6-aminoindole (XII) (3.17g, 24mmol), potassium carbonate (5.53g, 40mmol), potassium iodide (0.34g, 2mmol). The mixture was stirred at 80°C for 2 hours. The solution was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (200 mL) and water (150 mL), and the organic layer was separated. The aqueous phase was further extracted with dichloromethane (200 mL) and the combined organic extracts were combined. Dry over anhydrous sodium sulfate, filter and concentrate to give crude 3-(2-((1H-indol-6-ylamino)...

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PUM

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Abstract

The invention belongs to the field of medicines, and specifically relates to dabigatran derivatives or the pharmaceutical salts thereof, a preparation method for the derivatives, a medicine composition containing the dabigatran derivatives, and an application of the derivatives and the medicine composition in preparation for anticoagulant medicines and treatment for related diseases.

Description

technical field [0001] The invention belongs to the field of medicine, in particular, the invention relates to a dabigatran derivative or a pharmaceutically acceptable salt thereof, a preparation method of the derivative, a pharmaceutical composition containing the b derivative, and the derivative and the application of the pharmaceutical composition in the preparation of anticoagulant drugs and the treatment of related diseases. Background technique [0002] Dabigatran etexilate is a new type of synthetic direct thrombin inhibitor, which is a prodrug of dabigatran and belongs to non-peptide thrombin inhibitors, developed by Berlinger Ingelheim, Germany. In April 2008, it was first launched in Germany and the United Kingdom under the trade name of Pradaxa, which is used to prevent and treat acute venous thrombosis (VTE). This is the first new oral anticoagulant drug to be marketed in the past 50 years after warfarin. It is powerful, does not require special drug monitoring,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D409/14C07D417/14C07D401/12A61K31/4439A61K31/444A61K31/4545A61P7/02
CPCC07D401/12C07D401/14C07D409/14C07D417/14
Inventor 杜曰雷杨广兴杨琰王文峰白沙沙刘蕴秀
Owner CHINA RESOURCES SAIKE PHARMA
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