|Inventor(s): ||Brooks, Carl; Cheung, Mui; Eidam, Hilary Schenck; Goodman, Krista B.; Hammond, Marlys; Hilfiker, Mark A.; Patterson, Jaclyn R.; Stoy, Patrick; Ye, Guosen |
The invention relates to spirocarbamate analogs of formula I, pharmaceutical compns. containing them and their use as TRPV4 antagonists. Compds. of formula I wherein n is 1, 2 and 3; X is CR4 and N; R1 is H, C1-3 alkyl, CH2OH, CH2OMe, CH2OBn, etc.; each R2 is independently H, CN, CF3, halo, etc.; R3 is H, C1-2 alkyl, CF3 and OH; R4 is H, halo, and C1-3 alkyl; A is (CH2)0-2-Ph, (CH2)0-2-naphthyl, (CH2)0-2-CO-Ph, etc.; and pharmaceutically acceptable salts thereof, are claimed. Example compound II was prepared by amination and ring opening of 1-[(3S,5S)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile with 3-bromobenzylamine; the resulting 1-[[(1S,SS)-3-((((3-bromophenyl)methyl)amino)methyl)-3-hydroxycyclohexyl]methyl]-1H-benzimidazole-6-carbonitrile, which underwent cyclization with CDI to give compound II. All the invention compds. were evaluated for their TRPV4 antagonistic activity. It was determined that the invention compds. exhibited IC50 values in the range of 0.001 nM to 1.
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Note: Titles and abstracts for patent records in CAplus are routinely enhanced to better describe the claimed invention. In this example, CAS enhanced both the abstract and title using additional information found in the patent. The original title of the PCT patent publication is TRPV4 antagonists. For the CAplus record, this title was enhanced to read Spiro[cyclohexane-oxazolidinone] derivatives as TRPV4 antagonists and their preparation.