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Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor

A dihydro and trifluoromethyl technology, applied in the field of effective dipeptidyl peptidase-IV inhibitors, can solve the problems of no specific disclosure

Active Publication Date: 2008-11-05
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, there is no specific disclosure of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine in the above documents -7(8H)-yl]-1-(2,4,5-trifluorophenyl)butane-2-amine is a newly discovered monobasic dihydrogen phosphate salt whose structural formula I is shown below

Method used

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  • Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
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  • Phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor

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Embodiment Construction

[0074]

[0075] (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazole And[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butane-2- Amine dihydrogen phosphate monohydrate

[0076] 3-(Trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a] Preparation of pyrazine hydrochloride (1-4)

[0077] plan 1

[0078]

[0079] Step A: bishydrazide ( 1-1 ) preparation

[0080] Hydrazine (20.1 g in water, 35% by weight, 0.22 mol) was mixed with 310 ml of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) were added over 60 minutes. The internal temperature increased from 14°C to 25°C. The resulting solution was aged at 22-25°C for 60 minutes. The solution was cooled to 7°C. At a temperature below 16° C., 17.9 g of a 50% by weight aqueous NaOH solution (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously over 130 minutes. After the reaction was complete, the mixture was vacuum distilled at 27-30°C and 26-27 mercury vacuum...

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Abstract

The dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-alpha]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine is a potent inhibitor of dipeptidyl peptidase-IV and is useful for the prevention and / or treatment of non-insulin dependent diabetes mellitus, also referred to as type 2 diabetes. The invention also relates to a crystalline monohydrate of the dihydrogenphosphate salt as well as a process for its preparation, pharmaceutical compositions containing this novel form and methods of use for the treatment of diabetes, obesity, and high blood pressure.

Description

technical field [0001] The present invention relates to specific salts of dipeptidyl peptidase-IV inhibitors. More specifically, the present invention relates to 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine -7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine dihydrogen phosphate, which is a potent inhibitor of dipeptidyl peptidase-IV . This new salt and its crystalline hydrate are useful in the treatment and prevention of diseases and conditions requiring inhibitors of dipeptidyl peptidase-IV, especially type II diabetes, obesity and hypertension. The present invention further relates to a pharmaceutical composition comprising the dihydrogen phosphate and its crystalline hydrate, the pharmaceutical composition can be used for the treatment of type II diabetes, obesity and hypertension; and the preparation of the dihydrogen phosphate, its crystalline Hydrates and methods of pharmaceutical compositions thereof. Background technique [0002] Inhibiti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/4985A61P3/10A61K31/498
CPCC07D487/04A61P3/00A61P3/04A61P9/12A61P3/10
Inventor S·H·西普斯陈敏华R·R·费尔利塔K·汉森I·李V·K·维德拉R·M·小温斯罗
Owner MERCK SHARP & DOHME BV