Dabigatran cyclic derivatives and preparation method and application thereof

A technology of dabigatran and derivatives, applied in the field of preparing thrombin inhibitors, can solve the problems of low oral bioavailability and the like, and achieve the effects of good bioavailability, improved bioavailability and good anticoagulant activity

Active Publication Date: 2016-06-08
SHENYANG POLYTECHNIC UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although its parent drug dabigatran is prepared into the form of double prodrug dabigatran etexi

Method used

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  • Dabigatran cyclic derivatives and preparation method and application thereof
  • Dabigatran cyclic derivatives and preparation method and application thereof
  • Dabigatran cyclic derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0052] Example 1

[0053] Cyclic derivatives of dabigatran (Ⅰ 1 )preparation

[0054] 1) (Z)-3-(2-(((4-(N'-((2-chloroethoxy)carbonyl)amidino)phenyl)amino)methyl)-1-methyl-N- (Pyridin-2-yl)-1H-benzimidazole-5-carboxamido)propionic acid (Ⅱ 1 )Synthesis.

[0055] Chloromethyl chloroformate (0.27 g, 2.12 mmol) was added dropwise to a solution of dabigatran (1.0 g, 2.12 mmol) and N-methylmorpholine (0.2 ml) in chloroform (10 ml), and stirred at 0°C for 1 hours, and then warmed to room temperature for 24 hours. Saturated brine (10 mL×3) was added to wash, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography to obtain pale yellow solid II 1 0.86g, yield 71.9%, 1 HNMR (400MHz, DMSO-d6): δ2.66(t, J=6.8Hz, 2H, CH 2 ),3.73(s,3H,NCH 3 ),4.18(t,J=6.8Hz,2H,CH 2 ),4.43(s,2H,CH 2 ),6.11(s,2H,CH 2 ), 6.79(d, J=8.8Hz, 2H, ArH), 6.85(d, J=8.8Hz, 1H, ArH), 7.14(m, 2H, ArH), 7.43(d, J=8.8Hz, 2H,...

Example Embodiment

[0061] Example 2

[0062] Cyclic derivatives of dabigatran (Ⅰ 2 ), other conditions are the same as in Example 1.

[0063] white solid, yield 45.2%, 1 HNMR (400MHz, DMSO-d6): δ2.60(t, J=6.8Hz, 2H, CH 2 ),3.72(s,3H,NCH 3 ),4.15(t,J=6.8Hz,2H,CH 2 ),4.23(t,J=6.8Hz,2H,CH 2 ),4.33(s,2H,CH 2 ),4.47(t,J=6.8Hz,2H,CH 2 ), 6.78(d, J=8.8Hz, 2H, ArH), 6.83(d, J=8.8Hz, 1H, ArH), 7.18(m, 2H, ArH), 7.44(d, J=8.8Hz, 2H, ArH), 7.423 (d, J=8.8Hz, 2H, ArH), 7.57 (m, 1H, ArH), 8.33 (m, 1H, ArH), 8.92 (brs, 2H, NH) 2 ); ESI-MS: m / z542[M+H] + .

Example Embodiment

[0064] Example 3

[0065] Cyclic derivatives of dabigatran (Ⅰ 3 ), other conditions are the same as in Example 1.

[0066] White solid, yield 33.8%, 1 HNMR (400MHz, DMSO-d6): δ1.85 (m, 2H, CH 2 ),2.60(t,J=6.8Hz,2H,CH 2 ),3.72(s,3H,NCH 3 ),4.15(t,J=6.8Hz,2H,CH 2 ),4.23(t,J=6.8Hz,2H,CH 2 ),4.33(s,2H,CH 2 ),4.47(t,J=6.8Hz,2H,CH 2 ), 6.78(d, J=8.8Hz, 2H, ArH), 6.83(d, J=8.8Hz, 1H, ArH), 7.18(m, 2H, ArH), 7.44(d, J=8.8Hz, 2H, ArH), 7.423 (d, J=8.8Hz, 2H, ArH), 7.57 (m, 1H, ArH), 8.33 (m, 1H, ArH), 8.92 (brs, 2H, NH) 2 ); ESI-MS: m / z556[M+H] + .

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Abstract

The invention belongs to the technical field of medicine, and mainly relates to dabigatran cyclic derivatives as shown in a universal formula I or pharmaceutically acceptable salt thereof, a medicinal composition using the compounds as active ingredients, and application of the compounds and the medicinal composition to preparation of a thrombin inhibitorby.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to dabigatran cyclic derivatives, 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 blood...

Claims

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Application Information

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IPC IPC(8): C07D498/08A61K31/4439A61P7/02
CPCC07D498/08
Inventor 于大伟侯玲胡志泉孙洪涛杨旭鹏庄殿铮蔡志强
Owner SHENYANG POLYTECHNIC UNIV
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