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Novel salts for the manufacture of pharmaceutical compositions

A technology for medicines and mixtures, applied in the field of new salts for preparing pharmaceutical compositions, can solve the problems of not providing dabigatran etexilate crystalline properties and the like

Inactive Publication Date: 2013-01-02
EGIS GYOGYSZERGYAR NYILVANOSAN MUKODO RESZVENYTARSASAG (EGIS PHARMA PLC)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In said specification, no information is provided about the crystalline nature of dabigatran etexilate base

Method used

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  • Novel salts for the manufacture of pharmaceutical compositions
  • Novel salts for the manufacture of pharmaceutical compositions
  • Novel salts for the manufacture of pharmaceutical compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0236] Dabigatran etexilate phosphate (1:1) of Formula 1 was prepared (Form III).

[0237] 486mg (0.77mmol) dabigatran etexilate, 1.0ml N,N-dimethyl-formamide and 89mg 85w / w% phosphoric acid (0.77mmol) were measured into 10cm 3 in a round bottom flask. While stirring, the suspension was warmed to 65°C. The mixture was completely dissolved at this temperature. Then, it was cooled to room temperature within 2 hours and kept at 5°C overnight. The crystalline suspension was filtered, washed with a little N,N-dimethyl-formamide and acetonitrile, and dried under vacuum at room temperature to constant weight.

[0238] Yield: 590 mg (81.3%).

[0239] Melting point: 154-156°C.

[0240] HNMR (DMSO, 500MHz): 8-10(b, 5H), 8.38(m, 1H), 7.92(m, 2H), 7.54(m, 1H), 7.48(d, J=1.1Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.16 (dd, J1=1.5Hz, J2=8.4Hz, 1H), 7.12(m, 1H), 7.0(b, 1H), 6.89(m, 1H), 6.78 (m, 2H), 4.60(bs, 2H), 4.23(t, J=7.0Hz, 2H), 4.00(m, 2H), 3.98(q, J=7.1Hz, 2H), 2.68(t, J= 7.2Hz, 2H)...

Embodiment 2

[0243] Dabigatran etexilate fumarate (1:1) of Formula 2 was prepared (Form V).

[0244] Add 636mg (1.0mmol) of dabigatran etexilate, 2.5ml of ethanol and 116mg (1.0mmol) of fumaric acid into the 10cm 3 in a round bottom flask. While stirring, the suspension was warmed to 60°C. The mixture was completely dissolved at this temperature. The mixture was cooled to room temperature over 2 hours and kept at 5 °C overnight. The crystalline suspension was filtered, washed with a small amount of ethanol, and dried under vacuum at room temperature to constant weight.

[0245] Yield: 673mg (90.5%)

[0246] Melting point: 113-115°C.

[0247]HNMR (DMSO, 500MHz): 9(b), 8.39(m, 1H), 7.80(~d, J=8.8Hz, 2H), 7.54(m, 1H), 7.48(d, J=1.1Hz, 1H) , 7.40(d, J=8.4Hz, 1H), 7.16(dd, J1=1.5Hz, J2=8.6Hz, 1H), 7.12(m, 1H), 6.94(bt, 1H), 6.89(m, 1H) , 6.77(~d, J=8.8Hz, 2H), 6.62(s, 2H), 4.60(d, J=5.1Hz, 2H), 4.23(t, J=7.2Hz, 2H), 3.98(m, 2H ), 3.98(q, J=7.0Hz, 2H), 3.77(s, 3H), 2.68(t, J=7.1Hz, 2H), ...

Embodiment 3

[0250] Preparation of dabigatran etexilate sulfate (1:1) of Formula 3 (Form I).

[0251] Add 630mg (1.0mmol) of dabigatran etexilate, 1.1ml of ethanol and 8.0ml of ethyl acetate into the 25cm 3 in a round bottom flask. 0.2 g of 50 w / w% sulfuric acid (1.0 mmol) was added to the suspension. The mixture was kept at 5°C overnight. The crystalline suspension was filtered, washed with a small amount of a mixture of ethyl acetate and ethanol (10:1 ), and dried under vacuum at room temperature to constant weight.

[0252] Yield: 543mg (74.6%)

[0253] Melting point: 171-173°C.

[0254] HNMR (DMSO, 500MHz): 11.84 (b, 1H), 10.59 (b, 1H), 9.99 (b, 1H), 8.39 (m, 1H), 7.65 (~d, J=9.0Hz, 1H), 7.59 ( b, 1H), 7.55(m, 1H), 7.47(m, 1H), 7.42(d, J=8.4Hz, 1H), 7.17(dd, J1=1.5Hz, J2=8.4Hz, 1H), 7.12( m, 1H), 6.91(m, 1H), 6.87(~d, J=9.2Hz, 2H), 4.69(d, J=3.3Hz, 2H), 4.25(m, 2H), 4.22(t, J= 7.1Hz, 2H), 3.98(q, J=7.1Hz, 2H), 3.78(s, 3H), 2.68(t, J=7.1Hz, 2H), 1.68(m, 2H), 1.38(m, 2H) , 1.30(m...

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Abstract

The present invention relates to novel polymorphous salts of dabigatran etexilate of the formula 11 and process for the preparation thereof.

Description

technical field [0001] 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]methyl}-1-methyl-1H-benzimidazole-5-carbonyl) of the formula -Pyridin-2-yl-amino]-propionic acid ethyl ester (INN: dabigatran etexilate) [0002] [0003] It is an oral anticoagulant with direct thrombin inhibitor action. [0004] The object of the present invention is to provide new salts of dabigatran etexilate, their polymorphs, dehydrates, hydrates, solvates and methods for preparing the new salts of dabigatran etexilate. The present invention also relates to pharmaceutical formulations containing novel salts of dabigatran etexilate and their use for the prevention and treatment of postoperative deep vein thrombosis and stroke. [0005] In more detail, the object of the present invention is to provide new and morphologically uniform polymorphic compounds of the salts of dabigatran etexilate and phosphoric acid, sulfuric acid, maleic acid, methanesulfonic acid, oxalic acid, hydrochloric a...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/4439A61P7/02
CPCC07D401/12A61P7/02
Inventor I·基拉伊P·特林卡B·沃尔克L·蓬戈J·鲍尔科齐P·什莱格尔M·欧布赖灿A·东乔M·迈泽瓦里T·绍博G·鲁日奇L·斯拉维克G·卢卡奇A·博扎
Owner EGIS GYOGYSZERGYAR NYILVANOSAN MUKODO RESZVENYTARSASAG (EGIS PHARMA PLC)
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