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Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor

A technology of dihydrogen and anhydrous crystals, applied in the treatment of symptoms requiring DPP-IV inhibitors, crystallization of new solvates of dihydrogen phosphate, and crystal anhydrates, which can solve undisclosed problems and achieve simplified processing, The effect of improving physical and chemical properties

Inactive Publication Date: 2006-10-11
SCHERING AG
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  • Abstract
  • Description
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Problems solved by technology

[0004] Yet the compound (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4] of newly discovered following structural formula I is not disclosed in the above-mentioned document The dihydrogen phosphate salt of triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butane-2-amine (hereinafter referred to as As the solvate crystal and crystalline anhydrate of compound I)

Method used

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  • Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
  • Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor
  • Novel crystalline forms of a phosphoric acid salt of a dipeptidyl peptidase-iv inhibitor

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Embodiment 1

[0072]

[0073] (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4, 3-α]Pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine dihydrogen phosphate Mixture of salt anhydrous forms I and III

[0074] Preparation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-α]pyrazine salt Acid (1-4)

[0075] Process 1

[0076]

[0077] Step A : Preparation of bishydrazide (1-1)

[0078] Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitrile. 31.5 g of ethyl trifluoroacetate (0.22 mol) was added over 60 min. The internal temperature of the solution was increased from 14°C to 25°C. The resulting solution was aged at 22-25°C for 60 min. The solution was then cooled to 7°C. 17.9 g of 50 wt% liquid NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride (0.22 mol) were added simultaneously below 16°C over 130 min. After the reaction was completed, the mixture was vacuum distilled to remove water and ethanol at 27-30°C u...

Embodiment 2

[0143] (2R) 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazine-7(8H )-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine free base 2-5 in isoamyl alcohol (~200 mg / g) was charged to the crystallizer. A seed crystal was then added, followed by a mixed solution of 96% isoamyl alcohol and 4% water. The mixture was aged before heating to about 50°C. A mixed solution of about 1 equivalent of phosphoric acid in 96% isoamyl alcohol and 4% water (to obtain a final batch concentration of 85 mg / g) was added to the slurry to crystallize Form I. The slurry was aged, followed by cooling to room temperature. The solid was filtered and washed with isoamyl alcohol. The wet solids were dried at 75-80°C. These crystalline solids were determined by X-ray powder diffraction and solid-state NMR spectroscopy to be a mixture of anhydrous forms I and III, with form I predominating.

[0144] X-ray powder diffraction method is widely used in characterizing molecular structure, crystalli...

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Abstract

The present invention relates to crystalline anhydrate polymorphs of the dihydrogenphosphate salt of (2R)-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 as well as a process for their preparation, pharmaceutical compositions containing these novel forms, and methods of use of the novel forms and pharmaceutical compositions for the treatment of diabetes, obesity, and high blood pressure. The invention also concerns novel crystalline solvates of the dihydrogenphosphate salt of (2R)-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 as well as a crystalline desolvated polymorph and their use for the preparation of the anhydrate polymorphs of the present invention.

Description

technical field [0001] The present invention relates to a new phosphate crystal of dipeptidyl peptidase IV inhibitor. Specifically, the present invention relates to a potential inhibitor of dipeptidyl peptidase IV (DPP-IV) (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4]Triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine phosphoric acid Dihydrogen salt neosolvate crystalline and crystalline anhydrate. These new crystalline forms of DPP-IV inhibitors are useful in the preparation of pharmaceutical compositions comprising said inhibitors for the treatment and prevention of diseases and conditions requiring treatment with dipeptidyl peptidase IV inhibitors, especially Is type 2 diabetes, hyperglycemia, insulin resistance, obesity and high blood pressure. The present invention also relates to pharmaceutical compositions comprising the novel polymorphic anhydrates of dihydrogen phosphate of the present invention, methods of preparing dihydrogen phosphate...

Claims

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Application Information

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IPC IPC(8): A01N43/58A01N43/60A61K31/495A61K31/50A61K
CPCC07D487/04A61P3/00A61P3/04A61P9/12A61P3/10
Inventor R·M·温斯罗J·D·阿姆斯特隆三世陈敏华S·赛普斯R·R·费尔利塔K·汉森C·M·林德曼E·斯帕塔利斯
Owner SCHERING AG
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