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Dabigatran derivatives

A technology of dabigatran and its derivatives, which is applied in the field of dabigatran derivatives and can solve the problems of further improvement of oral bioavailability

Inactive Publication Date: 2013-12-04
BEIJING MEIBEITA DRUG RES
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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 derivatives
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1N-{[2-(((4-N-hexyloxycarbonyl-amidino-phenyl)-amino)-methyl)-1-methyl-1H-benzimidazol-5-yl]-carbonyl Preparation of}-N-(pyridin-2-yl)-β-alanine (9)

[0081] Dissolve 9 g of dabigatran etexilate with 250 ml of methanol, stir at room temperature, add 80 ml of an aqueous solution containing 3.6 g of LiOH, and stir for 60 minutes. Add 150ml of water, neutralize with 1N dilute hydrochloric acid, and a solid precipitates out. Filter and dry the solid to obtain 97.4 g of the target compound. 1 H NMR δ (ppm, DMSO-d 6 ): 0.89(t, 3H), 1.31(m, 6H), 1.60(m, 2H), 2.71(t, 2H), 3.79(s, 3H), 3.98(t, 2H), 4.25(t, 2H) , 4.62(d, 2H), 6.75(d, 2H), 6.90(d, 1H), 6.97(t, 1H), 7.14(m, 2H), 7.41(d, 1H), 7.49(d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.41 (m, 1H), 8.50-9.30 (bs, 2H), 12.15 (s, 1H).

Embodiment 2

[0082] Example 2N-{[2-(((4-N-hexyloxycarbonyl-amidino-phenyl)-amino)-methyl)-1-methyl-1H-benzimidazol-5-yl]-carbonyl }-N-(pyridin-2-yl)-β-alanine acetoxymethyl ester (I 1 ) preparation

[0083]

[0084] Dissolve 0.4 g of intermediate 9 in 8 ml of DMF, blow dry nitrogen, stir at room temperature, and add 0.3 ml of triethylamine. With stirring, 0.1 ml of chloromethyl acetate was added dropwise. After the addition, the temperature was gradually raised to 50° C., and the reaction was stirred for 5 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate and washed with water; the organic layer was dried over anhydrous sodium sulfate overnight. Filter, evaporate the organic solvent under reduced pressure, separate the residue by silica gel column chromatography, elute with dichloromethane:methanol (30:1) mixed solvent, collect the required components, and evaporate to dryness under reduced pressure to obtain the target co...

Embodiment 3

[0085] Example 3N-{[2-(((4-N-hexyloxycarbonyl-amidino-phenyl)-amino)-methyl)-1-methyl-1H-benzimidazol-5-yl]-carbonyl }-N-(pyridin-2-yl)-β-alanine isobutyryloxymethyl ester (I 4 ) preparation

[0086]

[0087] With reference to the method of Example 2, 0.4g of intermediate 9 was reacted with chloromethyl isobutyrate and separated by silica gel column chromatography to obtain the target compound I 4 0.28g. 1 H NMR δ (ppm, DMSO-d 6 ): 0.89(t, 3H), 1.14(d, 6H), 1.31(m, 6H), 1.60(m, 2H), 2.53(m, 1H), 2.71(t, 2H), 3.79(s, 3H) , 3.98(t, 2H), 4.25(t, 2H), 4.62(d, 2H), 5.61(s, 2H), 6.75(d, 2H), 6.90(d, 1H), 6.97(t, 1H), 7.14(m, 2H), 7.41(d, 1H), 7.49(d, 1H), 7.56(m, 1H), 7.82(d, 2H), 8.41(m, 1H), 8.50-9.30(bs, 2H) .

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Abstract

The invention aims to provide dabigatran derivatives, which are presented by the formula I with anticoagulant activity, optical isomers, and medicinal salts thereof. R1 represents H or alkyl group with a carbon number between 1 and 3, R2 represents R3 or -OR3, and R3 represents an alkyl group with a carbon number between 1 and 8 or a naphthenic group with a carbon number between 3 and 8.

Description

technical field [0001] The present invention relates to new derivatives of dabigatran and their non-toxic pharmaceutically acceptable salts, as well as pharmaceutical compositions containing these compounds as active ingredients, and the use of the compounds and pharmaceutical compositions as thrombin inhibitors . 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 an...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/4439A61P7/02
Inventor 王建明杨振华
Owner BEIJING MEIBEITA DRUG RES