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Dabigatran derivative used as prodrug, and preparation method and application thereof

A technology of dabigatran and ester derivatives, which is applied in the field of drug synthesis and can solve the problems of low oral bioavailability of dabigatran etexilate

Inactive Publication Date: 2013-12-04
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the oral bioavailability of dabigatran etexilate is low (<6.5%), so it needs to be further improved

Method used

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  • Dabigatran derivative used as prodrug, and preparation method and application thereof
  • Dabigatran derivative used as prodrug, and preparation method and application thereof
  • Dabigatran derivative used as prodrug, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 (cis) 3-(2-(((4-fluoro-3-(N'-(methoxycarbonyl)formamidoyl)phenyl)amino)methyl)-1-methyl-N-( Pyridin-2-yl)-1H-benzimidazole-5-carboxamido)methyl propionate (Ⅰ 1 ) preparation

[0050] 1) 3-(2-(((3-cyano-4-fluorophenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzimidazole-5- Synthesis of formamido) ethyl propionate (2A)

[0051] 2-((3-cyano-4-fluorophenyl)amino)acetic acid (1.93 g, 0.0l mol), EDC1 (1.9 g, 0.01 mol), 1-hydroxybenzotriazole (1.35 g, 0.01 mol ) was dissolved in a mixture of THF (35 mL) and DMF (5 mL). Stir in an ice-water bath for 35 min, rise to room temperature, and slowly add 1 (3.1 g, 0.009 mol) in THF (15 mL) dropwise. Add and stir for 6 h. The solvent was evaporated, dichloromethane (30 mL) was added, washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to dryness, glacial acetic acid (45 mL) was added to the residue, heated Reflux for 2 h, concentrate to dryness unde...

Embodiment 2-24

[0059] With reference to the operation of Example 1, the difference is that different phenoxyacetic acids are used, and different carboxylates react with different activated ester side chains to obtain the compound of the following formula I.

[0060]

[0061]

[0062]

[0063]

[0064]

Embodiment 25

[0065] Example 25 Evaluation of Anticoagulant Activity - Determination of Activated Partial Thromboplastin Time (aPPT)

[0066] Kunming mice with a mass of 18-20 g were divided into random groups, 10 in each group, and fasted overnight. Suspend or dissolve dabigatran etexilate and the target compound to be tested in 1% aqueous solution of sodium carboxymethyl cellulose to make a concentration of 1 mg / mL, and calculate according to a dose of 10 mg / Kg (converted to dabigatran) ) for intragastric administration, half an hour later blood was collected by cardiac puncture, 4% sodium wolfberry solution was added to a final concentration of 0.4% for anticoagulation, centrifuged at 12000r / min for 5 minutes, 0.1mL of plasma was taken, 0.1mL of aPPT reagent was added, and 37°C After pre-warming for 3 minutes, add 0.1 mL of calcium chloride solution pre-warmed at 37°C, and measure the coagulation time with a platelet aggregation coagulation factor analyzer, which is the aPPT value. The ...

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Abstract

The invention relates to a preparation method of a benzimidazole derivative of a general formula I, wherein R1, R2 and R3 are defined in the specification. The invention relates to a Dabigatran derivative of the general formula I and non-toxic pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing these compounds as active components, and application of the compounds and the pharmaceutical composition as thrombin inhibitors.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to ester derivatives of dabigatran and a preparation method thereof, a pharmaceutical composition containing these derivatives and the use of the compound and the pharmaceutical composition as a thrombin inhibitor. Background technique [0002] Dabigatran etexilate is a new type of synthetic direct thrombin inhibitor, a prodrug of dabigatran, a non-peptide thrombin inhibitor, developed by Boehringer Ingelheim, Germany. In April 2008, it was first launched in Germany and the United Kingdom under the trade name of Pradaxa for the prevention and treatment of 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, and has few drug interactions. Various in vitro, in vivo and clinical studies suggest that this product has good curative effect and pharmacokinetic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/4439A61P7/02
Inventor 孔维苓蔡志强黄长江龚珉徐为人汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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