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Dabigatran derivatives and preparation method thereof

A technology of ester derivatives and dabigatran, applied in the field of medicine, can solve the problems of low oral bioavailability and the like

Inactive Publication Date: 2013-01-16
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

Method used

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  • Dabigatran derivatives and preparation method thereof
  • Dabigatran derivatives and preparation method thereof
  • Dabigatran derivatives and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzene Preparation of ethyl imidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionate (dabigatran etexilate)

[0066] 1) Synthesis of 3-(pyridine-2-imine)-ethyl propionate (2)

[0067] Under the protection of nitrogen, ethyl acrylate (13.8g, 0.14mol) was added to compound 2-aminopyridine (11.2g, 0.12mol), stirred and refluxed at 10°C for 24h, the precipitate was filtered off, the residue was concentrated and purified by column chromatography 10 g of a white solid were obtained.

[0068] 2) Synthesis of 4-aminomethyl-3-nitro-benzoic acid (4)

[0069] 50 mL of 33% methylamine aqueous solution was added to 4-chloro-3-nitrobenzoic acid (10.0 g, 0.05 mol), and the system was reacted at 110° C. for 6 hours. The pH was adjusted to 4 by adding glacial acetic acid. After standing overnight, a large amount of yellow solid precipitated out, and the solution was filtered off to obtain 7...

Embodiment 2

[0082] Example 2: N-[[2-(((4-(((2-aminopropyl)oxy)amidino)-phenyl)-amino-methyl)-1-methyl-1H-benzo Preparation of imidazol-5-yl)-carbonyl]N-(pyridin-2-yl)-β-alanine methyl ester (I1)

[0083] 1) N-[[2-(((4-cyano-phenyl)-amino-methyl)-1-methyl-1H-benzimidazol-5-yl)-carbonyl]N-(pyridine-2 Synthesis of -yl)-β-alanine methyl ester (10a)

[0084] Dissolve 5.0 g of intermediate 8 in 200 mL of ethanol, add 10 mL of 1N sodium hydroxide solution, stir the reaction at room temperature until hydrolysis is complete, evaporate to dryness, dissolve in 20 mL of DMF, add 1.76 g of methyl iodide, stir at room temperature for 24 hours, concentrate, and column 4.0 g of the target intermediate were isolated.

[0085] 2) N-[[2-(((4-(N-hydroxyamidino)-phenyl)-amino-methyl)-1-methyl-1H-benzimidazol-5-yl)-carbonyl]N Synthesis of -(pyridin-2-yl)-β-alanine methyl ester (11a)

[0086] Dissolve 4.0g of intermediate 10a in 100mL of ethanol, cool to 0°C, pass in dry hydrogen chloride gas to saturation,...

Embodiment 3

[0097] Example 3: Evaluation of Anticoagulant Activity - Determination of Activated Partial Thromboplastin Time (aPPT)

[0098] Kunming mice with a mass of 18-20 g were divided into random groups, 10 in each group, and fasted overnight. Dabigatran etexilate and target compound to be tested are suspended or dissolved in the aqueous solution of 1% sodium carboxymethyl cellulose, made into the concentration of 1mg / mL, according to the dose of 10mg / Kg (converted into dabigatran calculation) ) for intragastric administration, half an hour later blood was collected by cardiac puncture, 4% sodium lyciate 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 va...

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Abstract

The invention relates to Dabigatran derivatives and pharmaceutically acceptable salts thereof, which are shown in a general formula I, a preparation method for the derivatives in the formula I, medical compositions comprising the compounds as active ingredients, and use of the compounds and the medical compositions as thrombin inhibitors. In the formula I, R1 and R2 are respectively defined in the specifications.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates 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 (Dabigatran) is a new type of anticoagulant drug developed by Boehringer Ingelheim in 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 50 years after warfarin, and it is another milestone in the field of anticoagulation therapy and the prevention of potentially fatal thrombosis. The U.S. Food and Drug Administration approved Pradaxa capsules (dabigatran etexilate) on October 19, 2010 for the prevention of stroke and bl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14A61K31/4439A61P7/02
Inventor 蔡志强袁静黄长江刘洪强张伟光徐为人邹美香汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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