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Novel crystalline forms of an inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1

A crystalline, chlorophenyl technology is applied in the field of effective inhibitors of 11β-hydroxysterol dehydrogenase-1 enzyme, and can solve the problems of no disclosure and the like

Inactive Publication Date: 2007-02-07
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, WO 03 / 104207 does not disclose 3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-di Newly discovered crystalline monohydrate and anhydrate of cyclopropyl-r-4H-1,2,4-triazole

Method used

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  • Novel crystalline forms of an inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1
  • Novel crystalline forms of an inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1
  • Novel crystalline forms of an inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] 3-[1-(4-Chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole crystalline anhydrate

[0064] Bisulfate 2-11 (39.0 g, 90.9 mmol) slurry in IPAc (150 mL) with 10% Na 2 CO 3 (100 mL) was mixed until all solids were dissolved. The aqueous layer was removed, and the organic layer was washed twice with 50 mL of water. The organic layer was then concentrated in vacuo to 70 g (ca. 45 mL residual IPAc). Some product crystallized out during concentration. Heptane (180 mL) was added slowly and the mixture was aged for 2 hours. The product was filtered and the filter cake was washed with heptane. Air drying followed by oven drying at 40°C gave the crystalline anhydrate free base as a white solid.

Embodiment 2

[0066] 3-[1-(4-Chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole crystalline anhydrate

[0067] bisulfate 2-11 (9.75 g, 22.7 mmol) in toluene (60 mL) was added water (60 mL) and 50% NaOH (4.54 g, 56.8 mmol). The mixture was stirred until all solids dissolved. Discard the aqueous layer. The organic layer was washed with 5% aqueous NaCl (60 mL). The organic layer was concentrated by vacuum distillation to about 38 mL. The solution was then transferred through an in-line filter to a stirred suspension of free base seeds (483 mg) in heptane (135 mL) over 3 hours. The resulting mixture was cooled to 0° C., stirred for 30 minutes, then filtered, washing with 4:1 heptane-toluene (30 mL) followed by heptane (30 mL). The crystalline material was dried under vacuum at 40°C to give the crystalline anhydrate form.

Embodiment 3

[0069] 3-[1-(4-Chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole crystalline monohydrate

[0070] to 6.58g bisulfate 2-11 To a slurry in IPA (15 mL) was added water (7.5 mL) and 10N NaOH (3.2 mL). The mixture was warmed to 40°C until all solids dissolved. The aqueous layer was separated and more water (7.5 mL) was added to the organic layer. Anhydrous free alkali seeds were introduced into the mixture and aged for 0.5 hours. More water (30 mL) was slowly added via syringe pump over 3 hours. The mixture was aged overnight and filtered. The filter cake was washed with 3:1 water / IPA (20 mL), then water (40 mL). Air drying overnight gave the crystalline monohydrate form.

[0071] 3-[1-(4-Chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole crystalline anhydrate

[0072] The monohydrate was then obtained in the crystalline anhydrate form by drying the monohydrate in a vacuum oven at 40°C with a slow flow of nitrogen.

[0...

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Abstract

Novel crystalline salts of 3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole are potent inhibitors of 11beta-hydroxysteroid dehydrogenase Type 1 and are useful for the treatment of conditions associated with Metabolic Syndrome as well as cognitive impairment. The invention also relates to pharmaceutical compositions containing these novel salts, processes to prepare these salts and their pharmaceutical compositions as well as uses thereof for the treatment of Type 2 diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, and cognitive impairment.

Description

field of invention [0001] The present invention relates to new crystal forms of type 1 11-beta-hydroxysterol dehydrogenase inhibitors. More specifically, the present invention relates to 3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4- Novel crystalline anhydrates and novel crystalline monohydrates of triazoles, which are potent inhibitors of the 11β-hydroxysterol dehydrogenase-1 (11β-HSD-1) enzyme. These new crystal forms of 11β-HSD-1 inhibitors are used to prepare pharmaceutical compositions containing 11β-HSD-1 inhibitors for the treatment and prevention of diseases and diseases requiring 11β-HSD-1 inhibitors. disorders, especially type 2 diabetes, hyperglycemia, obesity, dyslipidemia, hypertension and cognitive impairment. The present invention further relates to pharmaceutical compositions comprising the novel polymorphs of the present invention; methods of preparing specific anhydrates and monohydrates and pharmaceutical compositions thereo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08A61K31/4196
CPCC07D249/08A61P3/00A61P3/04A61P3/06A61P3/10A61P5/00A61P9/12A61P25/28A61P43/00
Inventor Y·贝雷兹尼特斯基M·A·哈夫曼J·E·林奇赵芒柱
Owner MERCK & CO INC
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