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

Active Publication Date: 2011-05-11
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 1N-{[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) of dabigatran ethyl ester (II 1 ) was dissolved in 2 mL of DMF, and 0.18 g of K was added 2 CO 3 (1.3 mmol), 0.15 mL (1.3 mmol) of a solution of chloromethyl propionate in 1 mL of DMF was added dropwise with stirring, and the addition was completed within 15 min; after the addition, the reaction mixture was stirred at room temperature for 20 h. The reaction solution was concentrated in vacuo, and 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 the target compound I 18 . 1 HNMRδ(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....

Embodiment 2

[0123] Example 2N-{[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 for embodiment 1, replace chloromethyl propionate and dabigatran ethyl ester (II) with chloromethyl-butyrate 1 ) reaction to obtain the target compound I 19 , the yield is 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 3N-{[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 for embodiment 1, replace chloromethyl propionate and dabigatran ethyl ester (II) with chloromethyl-isobutyrate 1 ) reaction to obtain the target compound I 20 , the yield is 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 novel ester derivatives of dabigatran and non-toxic pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing these compounds as active ingredients, and the use of said compounds and pharmaceutical compositions as thrombin inhibitors use. Background technique [0002] Dabigatran is a selective and potent thrombin inhibitor. However, due to the presence of strongly basic amidine groups, it cannot be absorbed orally. In order to improve its bioavailability, the free carboxyl group in the dabigatran molecule was converted into ethyl ester, and the amidine group was converted into hexyl carbamate to obtain its double prodrug, 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, which exerts an anticoagulant effect. Dabigatran dipivoxil was launched in 2008 as the...

Claims

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Application Information

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Patent Type & Authority Applications(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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