Crystalline forms of an inhibitor of 11-β-hydroxysteroid dehydrogenase type 1

#The present invention relates to novel crystalline forms of an inhibitor of 11β-hydroxysteroid dehydrogenase Type 1. More particularly, the invention relates to novel crystalline anhydrates of 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole, which is a potent inhibitor of the 11β-hydroxysteroid dehydrogenase Type 1 (11β-HSD-1) enzyme. These novel crystalline forms of the 11β-HSD-1 inhibitor are useful for the preparation of pharmaceutical compositions containing the inhibitor for the treatment and prevention of diseases and conditions for which an inhibitor of 11β-HSD-1 is indicated, in particular Type 2 diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, and cognitive impairment. The invention further concerns pharmaceutical compositions comprising the novel crystalline polymorphic forms of the present invention; processes for preparing the particular anhydrate forms and their pharmaceutical compositions; and methods of treating conditions for which an inhibitor of 11β-HSD-1 is indicated comprising administering a composition of the present invention.

#Inhibition of 11β-hydroxysteroid dehydrogenase Type 1 (11β-HSD-1), an enzyme that catalyzes regeneration of active 11-hydroxy glucocorticoids from inactive 11-keto metabolites within target tissues, represents a novel approach to the treatment of the conditions associated with the Metabolic Syndrome, including hypertension, obesity, dyslipidemia, and Type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). Inhibitors of this enzyme may also have utility to treat or prevent age-associated cognitive impairment. The therapeutic potential of inhibitors of 11β-HSD-1 has been reviewed: B. R. Walker and J. R. Seckl, “11β-Hydroxysteroid dehydrogenase Type 1 as a novel therapeutic target in metabolic and neurodegenerative disease,” Expert Opin. Ther. Targets, 7: 771-783 (2003).

#U.S. Pat. No. 6,849,636 describes a class of substituted 1,2,4-triazoles, which are potent inhibitors of the 11β-HSD-1 enzyme and therefore useful for the treatment of Type 2 diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, and cognitive impairment. Specifically disclosed in U.S. Pat. No. 6,849,636 is 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole.

#FIG. 1 is a characteristic X-ray diffraction pattern of a crystalline anhydrate, designated Form I, of Compound I of the present invention.

#FIG. 2 is a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of a crystalline anhydrate, designated Form I, of Compound I of the present invention.

#FIG. 3 is a typical differential scanning calorimetry (DSC) curve of a crystalline anhydrate, designated Form I, of Compound I of the present invention.

#This invention provides novel crystalline anhydrate polymorphic forms of 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole of structural formula I (Compound I):

#A further embodiment of the present invention provides the Compound I drug substance that comprises a crystalline anhydrate form in a detectable amount. By “drug substance” is meant the active pharmaceutical ingredient (API). The amount of crystalline anhydrate form in the drug substance can be quantified by the use of physical methods such as X-ray powder diffraction (XRPD), solid-state fluorine-19 magic-angle spinning (MAS) nuclear magnetic resonance spectroscopy, solid-state carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance spectroscopy, solid state Fourier-transform infrared spectroscopy, and Raman spectroscopy. In a class of this embodiment, about 5% to about 100% by weight of the crystalline anhydrate form is present in the drug substance. In a second class of this embodiment, about 10% to about 100% by weight of the crystalline anhydrate form is present in the drug substance. In a third class of this embodiment, about 25% to about 100% by weight of the crystalline anhydrate form is present in the drug substance. In a fourth class of this embodiment, about 50% to about 100% by weight of the crystalline anhydrate form is present in the drug substance. In a fifth class of this embodiment, about 75% to about 100% by weight of the crystalline anhydrate form is present in the drug substance. In a sixth class of this embodiment, substantially all of the Compound I drug substance is the crystalline anhydrate form, i.e., the Compound I drug substance is substantially phase pure crystalline anhydrate form.

#Another aspect of the present invention provides a novel crystalline methanol solvate of Compound I.