Dabigatran ester derivatives as prodrug

A technology of ester derivatives and pharmacy, which is applied in the field of ester derivatives of dabigatran as a prodrug, and can solve the problems that oral bioavailability needs to be further improved

Inactive Publication Date: 2014-04-02
北京弘生医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the oral bioavailability (6.5%) of dabigatran diester still needs to be further improved

Method used

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  • Dabigatran ester derivatives as prodrug
  • Dabigatran ester derivatives as prodrug
  • Dabigatran ester derivatives as prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Example 1 N-{[2-(((4-(N-propionyloxymethyl-)amidino-phenyl)-amino)-methyl)-1-methyl-1H-benzimidazole-5 -yl]-carbonyl}-N-(pyridin-2-yl)-β-alanine ethyl ester (I 18 ) preparation

[0122] 0.65 g (1.3 mmol) dabigatran ethyl ester (II 1 ) was dissolved in 2mL DMF, and 0.18 g of K was added 2 CO 3 (1.3mmol), a solution of 0.15mL (1.3mmol) chloromethylpropionate in 1mL DMF was added dropwise under stirring, and the addition was completed within 15min; after the addition, the reaction mixture was stirred at room temperature for 20h. The reaction solution was concentrated in vacuo, the residue was separated by silica gel column chromatography, and eluted with a mixed solvent of dichloromethane:methanol (5:1) to obtain 0.48 g of target compound I 18 . 1 H NMRδ (ppm, DMSO-d 6 ): 1.08(t, 3H), 1.14(t, 3H), 2.34(q, 2H), 2.69(t, 2H), 3.78(s, 3H), 3.99(q, 2H), 4.24(t, 2H) , 4.68(d, 2H), 5.75(s, 2H), 6.90(d, 1H), 6.99(t, 1H), 7.15(m, 2H), 7.42(d, 1H), 7.49(d, 1H), 7.56 (dt, 1H)...

Embodiment 2

[0123] Example 2 N-{[2-(((4-(N-butyryloxymethyl-)amidino-phenyl)-amino)-methyl)-1-methyl-1H-benzimidazole-5 -yl]-carbonyl}-N-(pyridin-2-yl)-β-alanine ethyl ester (I 19 ) preparation

[0124] With reference to the method of embodiment 1, replace chloromethyl propionate and dabigatran ethyl ester (II) with chloromethyl-butyrate 1 ) reaction to obtain target compound I 19 , yield 62%. 1 H NMRδ (ppm, DMSO-d 6 ): 0.85(t, 3H), 1.14(t, 3H), 1.51(m, 2H), 2.28(t, 2H), 2.69(t, 2H), 3.78(s, 3H), 3.99(q, 2H) , 4.24(t, 2H), 4.68(d, 2H), 5.75(s, 2H), 6.90(d, 1H), 6.99(t, 1H), 7.15(m, 2H), 7.42(d, 1H), 7.49 (d, 1H), 7.56 (dt, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.58-9.30 (bs, 2H).

Embodiment 3

[0125] Example 3 N-{[2-(((4-(N-isobutyryloxymethyl-)amidino-phenyl)-amino)-methyl)-1-methyl-1H-benzimidazole- 5-yl]-carbonyl}-N-(pyridin-2-yl)-β-alanine ethyl ester (I 20 ) preparation

[0126] With reference to the method of Example 1, chloromethyl-isobutyrate was used to replace chloromethyl propionate and dabigatran ethyl ester (II1) to react to obtain target compound I 20 , yield 71%. 1 H NMRδ (ppm, DMSO-d 6 ): 1.05(d, 6H), 1.14(t, 3H), 2.55(m, 1H), 2.69(t, 2H), 3.78(s, 3H), 3.99(q, 2H), 4.24(t, 2H) , 4.68(d, 2H), 5.75(s, 2H), 6.89(m, 3H), 7.12(m, 2H), 7.36-7.60(m, 4H), 7.68(d, 2H), 8.41(m, 1H ), 8.68 (s, 2H), 8.58-9.30 (bs, 2H).

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Abstract

The invention relates to dabigatran ester derivatives as shown in a constitutional formula I, pharmaceutically acceptable nontoxic salts thereof, medical composite containing the compounds as active components, and application of thrombin inhibitor of the compounds and medical composites, wherein R1 represents H or C1 to C5 alkyl; R2 represents H, or C1 to C3 alkyl; and R3 represents C1 to C8 alkyl or substituted alkyl.

Description

technical field [0001] The present invention relates to new ester derivatives of dabigatran and their non-toxic pharmaceutically acceptable salts, as well as pharmaceutical compositions containing these compounds as active ingredients, and the compounds and pharmaceutical compositions as thrombin inhibitors use. Background technique [0002] Dabigatran is a selective and highly effective thrombin inhibitor. However, due to the presence of a strong basic amidine group, it cannot be absorbed orally. In order to improve its bioavailability, the free carboxyl group in the dabigatran molecule is converted into ethyl ester, and the amidine group is converted into hexyl carbamate to obtain its double prodrug dabigatran diester (Dabigatran Etexilate). After oral administration, dabigatran diester is absorbed from the gastrointestinal tract, and then converted into the active form of dabigatran in the body to exert anticoagulant effect. Dabigatran diester was launched in 2008 and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D401/14A61K31/4439A61P7/02A61P23/00
Inventor 李建军郭春龙
Owner 北京弘生医药科技有限公司
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