3-Azabicyclo[3.1.0]hexane derivatives

Abstract

The subject invention provides a compound of the formula 1, wherein X, Q, n, R 1 , R 2 , R 3 , R 4 , R 5 R 6 , R 7 , R 8 , R 9 , and R 10 are as defined. Compounds of formula I have activity as opioid receptor antagonists. The subject invention furthermore provides for pharmaceutical compositions and therapeutic methods comprising compounds of formula I.

1 - 27 . (canceled)  
   
   
       28 . A compound of formula II  
     
       
         
         
             
             
         
       
     
     wherein 
 X is H, halogen, —OH, —CN, —C 1 -C 4  alkyl substituted with from one to three halogen atoms, or —O(C 1 -C 4  alkyl), wherein the C 1 -C 4  alkyl of —O(C 1 -C 4  alkyl) is optionally substituted with from one to three halogen atoms;  
 Q is halogen, —OH, —O(C 1 -C 4  alkyl), —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —C(═O)NH 2 , —C(═O)NH(C 1 -C 4  alkyl), —C(═O)N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —NHS(═O) 2 H, or —NHS(═O) 2 R 11 ;  
 R 1  and R 2  are, with the carbon to which they are attached, connected to form a C 3 -C 7  cycloalkyl, wherein said C 3 -C 7  cycloalkyl formed by R 1  and R 2  can each optionally be substituted by from one to three R 12  groups, wherein the R 12  groups are selected from R 13 , R 16 , —C 1 -C 4  alkyl containing one or two unsaturated bonds, halogen, —OR 13 , —NO 2 , —CN, —C 3 -C 6  cycloalkyl, —NR 13 R 14 , —NR 13 C(═O)R 14 , —C(═O)NR 13 R 14 , —OC(═O)R 13 , —C(═O)OR 13 , —C(═O)R 13 , —NR 13 C(═O)OR 14 , —NR 13 C(═O)NR 14 R 1   5 , —NR 13 S(═O) 2 R 14 , and —S(═O) 2 R 13 ;  
 R 3  is C 1 -C 4  alkyl, wherein said C 1 -C 4  alkyl optionally contains one or two unsaturated bonds;  
 R 4 is —OH or —(C 1 -C 4  alkylene)-OH;  
 R 5  and R 8  are each independently H or methyl;  
 R 6 , R 7 , R 9  and R 10  are H;  
 R 11  is selected from C 1 -C 4  alkyl, —(C 2 -C 4  alkylene)-O-(C 1 -C 4  alkyl), —(C 1 -C 4  alkylene)-NH 2 , —(C 1 -C 4  alkylene)-NH(C 1 -C 4  alkyl), —(C 1 -C 4  alkylene)-N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl);  
 each R 13 , R 14 , and R 15  is independently selected from H, R 16 , Cl-C4 alkyl, halogen, —OH, —SH, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —O(C 1 -C 4  alkyl), —S(C 1 -C 4  alkyl), —CN, —NO 2 , —C(═O)(C 1 -C 4  alkyl), —C(═O)OH, —C(═O)O(C 1 -C 4  alkyl), —NHC(═O)(C 1 -C 4  alkyl), —C(═O)NH 2 ,and —C(═O)N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl),  
 or R 13  and R 14  when in —NR 13 R 14 , may optionally be connected to form a 4 to 6 membered heterocycloalkyl or heteroaryl group, which heterorayl group optionally comprises from 1 to 3 further hetero moieties selected from N, S, O and —C(═O);  
 each R 16  and R 17  is independently selected from C6—CI4 aryl and 5-14 membered heteroaryl, wherein said heteroaryl comprises from one to three hetero moieties selected from O, S, —C(═O), and N, and wherein said aryl and heteroaryl are optionally substituted with from one to three substituents selected from C 1 -C 4  alkyl optionally containing one or two unsaturated bonds, halogen, —OH, —SH, —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl), —O(C 1 -C 4  alkyl), —S(C 1 -C 4  alkyl), —CN, —NO 2 , —C(═O)(C 1 -C 4  alkyl), —C(═O)OH, —C(═O)O(C 1 -C 4  alkyl), —NHC(═O)(C 1 -C 4  alkyl), —C(═O)NH 2 ,and —C(═O)N(C 1 -C 4  alkyl)(C 1 -C 4  alkyl); and  
 n is an integer selected from zero, 1, 2, 3, 4, and 5;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       29 . A compound according to  claim 28 , wherein R 3  is methyl, ethyl, isopropyl, or straight-chain propyl.  
   
   
       30 . A compound according to  claim 29 , wherein R 4  is —OH, or CH 2 OH.  
   
   
       31 . A compound according to  claim 29  or 30, wherein Q is F, —OH, —C(═O)NH 2 , —NHS(═O) 2 CH 3 , —NHS(═O) 2 CH 2 CH 3 , —NHS(═O) 2 CH 2 CH 2 CH 3 , —NHS(═O) 2 CH(CH 3 )(CH 3 ), or —NHS(═O) 2 CH 2 CH 2 OCH 3 .  
   
   
       32 . A compound according to  claim 31 , wherein X is H, F, —OH, —C(═O)NH 2 , or —CN.  
   
   
       33 . A compound according to  claim 32 , wherein R 1  and R 2 , with the carbon to which they are attached, are connected to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, each optionally substituted with one or two R 12  groups.  
   
   
       34 . A compound according to  claim 32 , wherein R 1  and R 2 , with the carbon to which they are attached, are connected to form a cyclopentyl group, wherein said cyclopentyl group is optionally substituted with one or two R 12  groups.  
   
   
       35 . A compound according to  claim 32 , wherein R 1  and R 2 , with the carbon to which they are attached, are connected to form a cyclohexyl group, which cyclohexyl group is optionally substituted with one or two R 12  groups.  
   
   
       36 . A compound according to  claim 32 , wherein R 1  and R 2 , with the carbon to which they are attached, are connected to form a cyclobutyl group, which cyclobutyl group is optionally substituted from R 12 selected from F, —CN, or optionally substituted phenyl.  
   
   
       37 . A compound according to  claim 33 , wherein n is an integer selected from 1, 2, or 3.  
   
   
       38 . A compound according to  claim 28  selected from the group consisting of: 
 Exo-N-(3-{6-ethyl-3-[3-(1-hyd roxy-cyclohexyl)-propyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-phenyl)-methanesulfonamide;    Exo-N-(3-{6-ethyl-3-[3-(1-hydroxymethyl-cyclopentyl)-propyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-phenyl)-methanesulfonamide;    Exo-1-{3-[6-(3, 5-d ifluoro-phenyl)-6-ethyl-3-aza-bicyclo[3.1.0]hex-3-yl]-propyl}-cyclohexanol;    Exo-3-{6-ethyl-3-[3-(1-hydroxy-cyclohexyl)-propyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-benzamide;    Exo-2-methoxy-ethanesulfonic acid (3-{6-ethyl-3-[3-(1-hydroxy-cyclohexyl)-propyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-phenyl)-amide;    Exo-N-(3-{6-ethyl-3-[3-(1-hyd roxy-cyclohexyl )-propyl]-3-aza-bicyclo[3.1.0] hex-6-yl}-5-fluoro-phenyl)-methanesulfonamide;    Exo-3-{6-ethyl-3-[3-(1-hydroxy-cyclohexyl)-propyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-5-fluoro-benzamide;    Exo-3-{6-ethyl-3-[3-(1-hydroxy-cyclohexyl)-propyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-phenol;    Exo-3-{3-[3-(1-hydroxy-cyclohexyl)-propyl]-6-propyl-3-aza-bicyclo[3.1.0]hex-6-yl}-benzamide;    Exo-2-methoxy-ethanesulfonic acid (3-{3-[3-(1-hydroxy-cyclohexyl)-propyl]-6-isopropyl-3-aza-bicyclo[3.1.0]hex-6-yl}-phenyl)-amide;    Exo-N-{3-[6-ethyl-3-(cis-1-hydroxy-3-phenyl-cyclobutylmethyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-phenyl}-methanesulfonamide;    Exo-3-[6-ethyl-3-(cis-1-hydroxy-3-phenyl-cyclobutylmethyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-benzamide; and    Exo-ethanesulfonic acid (3-{6-ethyl-3-[3-(1-hydroxy-cyclohexyl)-propyl]-3-aza-bicyclo[3.1.0] hex-6-yl}-phenyl)-amide;    or a pharmaceutically acceptable salt thereof.    
   
   
       39 . The compound of  claim 38  selected from the group consisting of 
 Exo-N-(3-{6-Ethyl-3-[3-(1-hydroxy-cyclohexyl)-propyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-phenyl)-methanesulfonamide;    Exo-N-(3-{6-Ethyl-3-[3-(1-hydroxymethyl-cyclopentyl)-propyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-phenyl)-methanesulfonamide; and    Exo-3-[6-Ethyl-3-(cis-1-hyd roxy-3-phenyl-cyclobutylmethyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-benzamide;    or a pharmaceutically acceptable salt thereof.    
   
   
       40 . A pharmaceutical composition comprising an amount of a compound according to  claim 28  and a pharmaceutically acceptable carrier.  
   
   
       41 . A method for treating a disorder or condition mediated by an opioid receptor or receptors in a mammal comprising the step of administering to said mammal an amount of a compound according to  claim 28  effective in inhibiting an opioid receptor or receptors.  
   
   
       42 . The method of  claim 41  wherein said disorder or condition is selected from the group consisting of irritable bowel syndrome; constipation; nausea; vomiting; pruritic dermatoses, including allergic dermatitis; an eating disorder; depression, smoking addiction; drug addiction, including alcohol addiction, amphetamine addiction, cocaine addiction and addiction to an opiate, for example morphine, opium, or heroine; an opiate overdose; a sexual dysfunction, including erectile dysfunction and impotence; stroke; head trauma; traumatic brain injury; spinal damage; Parkinson's disease;. Alzheimer's disease, age-related cognitive decline; and. Attention Deficit and Hyperactivity Disorder.  
   
   
       43 . The method of  claim 42  wherein said disorder or condition is an eating disorder selected form anorexia, bulimia or obesity.  
   
   
       44 . The method of  claim 43  wherein said disorder or condition is obesity.