Amino- and amido-aminotetralin derivatives and related compounds as mu opioid receptor antagonists

摘要

The invention provides amino- and amido-aminotetralin compounds of formula (I):;
wherein R1, R2, R3, R4, R5, R6, R7, and n are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.

主权项

1. A method of treating opioid-induced bowel dysfunction or post-operative ileus in a mammal, the method comprising administering to the mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I): wherein R1 is —ORa or —C(O)NRbRc; R2, R3, and R4 are each independently C1-3alkyl; R5 is selected from hydrogen, —CH2-cyclohexyl, benzyl, —CH2OH, and —C(O)OH; R6 is hydrogen or C1-3alkyl; R7 is selected from hydrogen, —C(O)R8, —C(O)NHR9, —C(S)NHR10, —S(O)2R11, and C1-6alkyl, optionally substituted with —C(O)NH2, —OH, —CN, —O(CH2)2OCH3, cyclohexyl, or phenyl, wherein cyclohexyl and phenyl are each optionally substituted with one or two halo; R8 is selected from phenyl, benzyl, C5-6cycloalkyl, furanyl, thiophenyl, and C1-6alkyl, wherein phenyl, benzyl, and C5-6cycloalkyl are optionally substituted with one or two halo or with —S(O)2NH2, and C1-6alkyl is optionally substituted with one or two substituents selected from —OH, —C(O)ORa, —C(O)NH2, —S(O)2CH3, phenyl, and —OCH2OCH3; R9 is selected from C1-6alkyl, phenyl, benzyl, and —CH2-cyclohexyl, wherein phenyl and benzyl are each optionally substituted with one or two substituents selected from halo, —OCH3, and —CF3; R10 is selected from C1-6alkyl, phenyl, and benzyl, wherein phenyl and benzyl are each optionally substituted with one or two halo; R11 is selected from C1-6alkyl, cyclohexyl, and phenyl, wherein phenyl is optionally substituted with —NHC(O)CH3 or with from 1 to 5 fluoro; Ra, Rb, and Rc are each independently hydrogen or C1-3alkyl; and n is 0 or 1; wherein the substituents at the chiral centers marked by asterisks are in the trans configuration; provided that when R1 is —ORa, then at least one of R5 and R7 is not hydrogen or C1-6alkyl; or a pharmaceutically-acceptable salt thereof.