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Dabigatran cyclic derivative and its preparation method and use

A technology for dabigatran and derivatives, which is 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, good transmembrane absorption, and improved bioavailability

Active Publication Date: 2017-11-21
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 etexilate, its oral bioavailability is still low (F<6.5%), still can not better meet the needs of the market

Method used

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  • Dabigatran cyclic derivative and its preparation method and use
  • Dabigatran cyclic derivative and its preparation method and use
  • Dabigatran cyclic derivative and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Dabigatran cyclic derivatives (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 (0.27g, 2.12mmol) was added dropwise to a solution of dabigatran (1.0g, 2.12mmol) and N-methylmorpholine (0.2ml) in chloroform (10ml), stirred at 0°C for 1 hours, then warmed up to room temperature for 24 hours. Add saturated brine (10mLx3) to wash, dry over anhydrous sodium sulfate and filter, the filtrate is concentrated to dryness, and the residue is purified by column chromatography to obtain light yellow solid II 1 0.86g, yield 71.9%, 1 H NMR (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, ArH), 7.48(d, J=8.8Hz, 2H, ArH), 7.58(m, 1H, ArH), 8...

Embodiment 2

[0062] Dabigatran cyclic derivatives (Ⅰ 2 ), other conditions are with embodiment 1.

[0063] White solid, yield 45.2%, 1 H NMR (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 (br s, 2H, NH 2 ); ESI-MS: m / z 542[M+H] + .

Embodiment 3

[0065] Dabigatran cyclic derivatives (Ⅰ 3 ), other conditions are with embodiment 1.

[0066] White solid, yield 33.8%, 1 H NMR(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 (br s, 2H, NH 2 ); ESI-MS: m / z 556[M+H] + .

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Abstract

The invention belongs to the field of medical technology, and mainly relates to dabigatran cyclic derivatives represented by general formula I or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds as active ingredients, and the compounds and pharmaceuticals The composition is used as the preparation of a thrombin inhibitor.

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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Patent Type & Authority Patents(China)
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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