Novel Compounds As Antagonists Or Inverse Agonists At Opioid Receptors

Abstract

Novel compounds which are antagonists or inverse agonists at one or more of the opioid receptors, pharmaceutical compositions containing them, to processes for their preparation.

What is claimed is: 
     
         1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a salt thereof wherein: 
         ring A is selected from the group consisting of phenyl, thiophenyl, furanyl, oxazolyl, and pyridyl; 
         ring B is selected from the group consisting of phenyl, thiophenyl, furanyl, and pyridyl; 
         D is —CH 2 —, or —O—, with the proviso that D is not attached to ring B at the atom adjacent to the bond joining ring A and ring B; 
         E is selected from the group consisting of —C(O)NH 2 , imidazolidinyl, imidazolidinedionyl, imidazolyl, imidazolinonyl, triazolyl, triazolinonyl, and their tautomers; 
         R 1  and R 2  are selected independently from the group consisting of —H, —F, —Cl, —CH 3 , —CF 3 , and —OCH 3 ; m and n are each independently 0, 1, or 2; 
         J is a bond or a C 1-4 alkylene; 
         R 3  is —H, and R 4  is selected from the group consisting arylmethyl, arylethyl, heteroarylmethyl, heteroarylethyl, C 4-10 alkyl, cycloalkenyl, cycloalkyl, heterocyclylmethyl, and heterocyclylethyl. 
       
     
     
         2 . The compound of  claim 1  wherein ring A and ring B are both independently selected from the group consisting of phenyl and pyridyl. 
     
     
         3 . The compound of  claim 2  wherein ring A and ring B are both phenyl. 
     
     
         4 . The compound of  claim 2  wherein ring A is phenyl and ring B is pyridyl. 
     
     
         5 . The compound of  claim 2  wherein ring A is pyridyl and ring B is phenyl. 
     
     
         6 . The compound of  claim 2  wherein ring A and ring B are both pyridyl. 
     
     
         7 . The compound of  claim 1  wherein D is —CHr and J is a bond or C 1-2 alkylene. 
     
     
         8 . The compound of  claim 1  wherein R 4  is selected from the group consisting of 3-fluorophenylethyl, 3-fluorobenzyl, 2-trifluoromethylbenzyl, 2-trifluoromethoxybenzyl, 4-trifluoromethylbenzyl, 4-fluorobenzyl, 3-methoxyphenylethyl, 3-thiophenylmethyl, 2-thiophenylethyl, 4,4-dimethylcyclohexyl, 3,3-dimethylcyclohexyl, 2-indanyl, 5-cyano-2-indanyl, 5-methoxy-2-indanyl, 5-fluoro-2-indanyl, 4-fluoro-2-indanyl, 4-methoxy-2-indanyl, 4-methoxy-2-indanyl, 4,8-diflouro-2-indanyl, 5,6-difluoro-2-indanyl, 5,6-dimethoxy-2-indanyl, 2-methyl-2-indanyl, cyclohexylmethyl, cyclohexylethyl, 4,4-difluorocyclohexyl, 1-cyclohexenylmethyl, 1-cyclohexenylethyl, cyclooctyl, cycloheptylmethyl, 3-methylbutyl, adamantyl, morpholinoethyl, piperidinylethyl, 4-tert-butylcyclohexyl, 3,3,5,5-tetramethylcyclohexyl, 3,5-difluorobenzyl, 3,5-d ifluorophenylethyl, 2-diphenylmethyl, methoxyethyl, dimethylaminoethyl, 3-pyridinylethyl, 3-pyridinylmethyl, and phenyloxyethyl. 
     
     
         9 . The compound of  claim 8  wherein R 4  is selected from the group consisting of 2-indanyl, 5-fluoro-2-indanyl, 4,4-dimethylcyclohexyl, cyclohexylethyl, cyclohexylmethyl, 2-thiophenylethyl, 3-fluorophenylethyl, 3-methylbutyl, and 4,4-difluorocyclohexyl. 
     
     
         10 . The compound of  claim 1  selected from the group consisting of 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-3-biphenylcarboxamide; 4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylcarboxamide; N-{[3′-(1H-imidazol-2-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine; 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2-fluoro-3-biphenylcarboxamide; 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2-methyl-3-biphenylcarboxamide; 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2′-(trifluoromethyl)-3-biphenylcarboxamide; 3′-fluoro-4′-({[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}methyl)-3-biphenylcarboxamide; 1-{4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylyl}-2,4-imidazolidinedione; N-{[3′-(1H-imidazol-2-yl)-4-biphenylyl]methyl}-4,4-dimethylcyclohexanamine; N-{[3,5-difluoro-3′-(1H-imidazol-2-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine; N-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-4,4-dimethylcyclohexanamine; 2′-chloro-4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-3-biphenylcarboxamide, and salts thereof. 
     
     
         11 . The compound of  claim 10 , which compound is a citrate, phosphate, or hydrochloride salt. 
     
     
         12 . The compound of  claim 1  or a salt thereof in combination with at least one compound selected from the group consisting of a human ciliary neurotropic factor, a CB-1 antagonist, a neurotransmitter reuptake inhibitor, a lipase inhibitor, an MC4R agonist, a 5-HT2c agonist, a ghrelin receptor antagonist, a CCK-A receptor agonist, an NPY Y1 antagonist, PYY 3     —     36 , and a PPAR activator. 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1  or a salt thereof and at least one excipient. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 1  or a salt thereof. 
     
     
         15 . A method for treatment of obesity, diabetes, hypertension, depression, anxiety, drug addiction, substance addiction, or a combination thereof comprising administration of a compound of  claim 1  or a salt thereof. 
     
     
         16 . The method of  claim 15  wherein the treatment is for drug addiction or substance addiction. 
     
     
         17 . A compound of Formula I or Formula Ia 
       
         
           
           
               
               
           
         
         or a salt thereof wherein: 
         ring A is selected from the group consisting of an aryl, a 5-membered heteroaryl or 6-membered heteroaryl, with the proviso that in Formula I when (i) ring A is pyridyl, (ii) ring B is phenyl, and (iii) E is in the meta position relative to the bond joining ring A to ring B, the bond joining D to ring B is in the para position relative to the bond joining ring A to ring B and in Formula Ia, ring A is attached to the tetrahydroquinolyl ring at carbon 6 or carbon 7; 
         ring B is selected from the group consisting of an aryl, a 5-membered heteroaryl or a 6-membered heteroaryl; 
         D is —CH 3 , —O—, —CH(CH 3 )—, with the proviso that D is not attached to ring B at the atom adjacent to the bond joining ring A and ring B; 
         E is selected from the group consisting of —C(O)NH 2 , —C(O)NHC 1-3 alkyl, —C(O)NH(C 1-3 alkyl)aryl, —NHC(O)C 1-3 alkyl, a 5-membered heterocycle or 6-membered heterocycle, 5-membered heteroaryl, and 6-membered heteroaryl with the proviso that in Formula I, E is not attached to the atom adjacent to the bond joining rings A and B; 
         R 1  and R 2  are selected independently from the group consisting of —F, —Cl, —Br, —OH, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 fluoroalkyl, —OC 1-3 fluoroalkyl; m and n are each independently 0, 1, or 2; 
         J is a bond or a C 1-4 alkylene; 
         R 3  is selected from the group consisting of —H, C 1-12 alkyl, C 3-10 cycloalkyl, alkoxycarbonyl, arylalkyl, heterocyclyl, heterocycloalkyl, heteroarylalkyl, cycloalkenyl, C 2-12 fluoroalkyl, and heteroalkyl; 
         R 4  is selected from the group consisting of C 3-12 alkyl, C 3-10 cycloalkyl, arylalkyl, heterocyclyl, heterocycloalkyl, heteroarylalkyl, cycloalkenyl, C 3-12 fluoroalkyl, and heteroalkyl; or 
         R 3  and R 4  may be joined to form a substituted or unsubstituted 5-7 membered ring.