Triazospiro compounds having nociceptin receptor affinity

Abstract

Disclosed are compounds of the formula (I) wherein A, R 1 , R 2 , R 3 , R 4 and X 1 are as disclosed herein. The compounds have affinity for the ORL1 receptor and are useful in the treatment of chronic and acute pain.

What is claimed is:  
     
         1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 2  is selected from the group consisting of hydrogen, C 1-10  alkyl, C 3-12  cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;  
 Z 1  is selected from the group consisting of a C 1-10  straight or branched alkyl substituted with an oxo or a carbonyl, said carbonyl optionally substituted on the carbon with halogen, C 1-5 alkyl, C 3-5 cycloalkyl, phenyl or phenyl-C 1-3 alkyl; alkenyl or alkenylene, wherein said substituted alkyl, alkenyl or alkenylene is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10  alkyl, C 1-10  alkyoxy, phenyl, phenyl(C 1-3 )alkyl, said phenyl and phenylalkyl optionally substituted with 1-3 halogen or C 1-10  alkyl;  
 R 1  is selected from the group consisting of hydrogen, C 3-12  cycloalkyl, C 3-12  cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, and a bicyclic ring system of the formula (II)  
                     
 wherein A is a saturated, unsaturated or partially unsaturated ring and X 1  and X 2  are independently selected from the group consisting of NH, O, S and CH 2 , wherein said C 3-12  cycloalkyl, C 3-12  cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, and a bicyclic ring system of the formula (II) optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10  alkyl, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 halogen or C 1-10  alkyl; and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound of  claim 1  wherein the halogen substituent of the Z 1  phenyl is fluoride.  
     
     
         3 . A compound of  claim 1  wherein Z 1  is butyl or propyl.  
     
     
         4 . A compound of  claim 1  wherein R 1  is cycloalkyl and is selected from the group consisting of cyclobutyl, cyclopropyl or cyclohexyl.  
     
     
         5 . A compound of  claim 1  wherein R 1  cycloalkylene.  
     
     
         6 . A compound of  claim 1  wherein R 1  is a bicyclic ring system selected from the group consisting of tetrahydronaphthyl, benzodioxane and decalin.  
     
     
         7 . A compound of  claim 1  wherein R 1  is a monocyclic ring system selected from the group consisting of pyridyl and phenyl.  
     
     
         8 . A compound of  claim 1  wherein R 1  is furan.  
     
     
         9 . A compound of  claim 1  wherein R 1  is a bicyclic aromatic ring selected from the group consisting of quinoline or naphthyl.  
     
     
         10 . A compound of  claim 1  wherein R 1  is dibenzocycloheptyl.  
     
     
         11 . A compound of  claim 1  wherein R 1  is piperazine.  
     
     
         12 . A compound of  claim 1  selected from 
 8-[4,4-Bis(p-fluorophenyl)-3-carbonyl-butyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[3,3-Bis(phenyl)-2-carbonyl-propyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[3,3-Bis(phenyl)-3-carbonyl-butyl]-1-phenyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-(1,2,3,4 tetrahydronaphthyl)-1-carbonyl-methyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-propylcyclohexyl-1-carbonyl-methyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-(1,2,3,4 tetrahydronaphthyl)-1-carbonyl-methyl]-3-[1-oxo-ethyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[3-(fluorophenyloxy)-2-carbonyl-propyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-benzodioxane-1-carbonyl-methyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-(2-quinoline-1-carbonyl-methyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-dibenzocycloheptyl-1-carbonyl-methyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-(2-pyridyl)-1-carbonyl-methyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[2-phenyl-1-carbonyl-ethyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[4-phenyl-α-carbonyl-benzyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[4-benzyloxy-α-carbonyl-benzyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-(2-naphthyl)-1-carbonyl-methyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[4-trifluoromethyl-α-carbonyl-benzyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-benzylpiperadine-1-carbonyl-methyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[phenyl-1-oxo-ethyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[4(p-fluorophenyl)-4-oxo-butyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[1-decalin-1-carbonyl-methyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8[1,4 dimethyl-1-carbonyl-pentyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;  
 8-[α-carbonyl-furfuryl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one; and pharmaceutically acceptable salts thereof.  
 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1  and at least one pharmaceutically acceptable excipient.  
     
     
         14 . A method of treating pain comprising administering to a patient in need thereof, an effective amount of a compound according to  claim 1 .  
     
     
         15 . A method of modulating a pharmacological response from the ORL1 receptor comprising administering an effective amount of a compound according to  claim 1 .  
     
     
         16 . A compound selected from the group consisting of 
 8-[4,4-Bis(p-fluorophenyl)butyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-[3,3-Bis(phenyl)propyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-[3,3-Bis(phenyl)-4-oxo-butyl]-1-phenyl-1-phenyl-1,3,8-triazospiro[4.5] decan-4-one;    8-[1,2,3,4 tetrahydronaphthyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-propylcyclohexyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-[1,2,3,4 tetrahydronaphthyl]-3-[1-oxo-ethyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-fluorophenyloxypropyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-benzodioxane-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-quinoline-methyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-dibenzocycloheptyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-pyridyl-methyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-phenyl-ethyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-phenyl-benzyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-benzyloxybenzyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-naphthylmethyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-trifluoromethylbenzyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-benzylpiperadine-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-[phenyl-1-oxo-ethyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-[4(p-fluorophenyl)-4-oxo-butyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-nitrofurfuryl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-dacalin-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    [1,4 dimethylpentyl]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    [3-oxo-5-phenyl-1,2 cyclohexene]-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;    8-furfuryl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one and pharmaceutically acceptable salts thereof.    
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 16  and at least one pharmaceutically acceptable excipient.  
     
     
         18 . A method of treating pain comprising administering to a patient in need thereof, an effective amount of a compound according to  claim 16 .  
     
     
         19 . A method of modulating a pharmacological response from the ORL1 receptor comprising administering an effective amount of a compound according to  claim 16 .  
     
     
         20 . A method of modulating a response from opioid μ receptors comprising administering a compound having a binding affinity for the μ receptor of less than about 5.0 K i  (nM).  
     
     
         21 . The method of  claim 20  wherein said compound has a binding affinity for the μ receptor of less than about 1.0 K i  (nM).  
     
     
         22 . The method of  claim 20  wherein said compound has a binding affinity for the μ receptor of less than about 0.5 K i  (nM).  
     
     
         23 . The method of  claim 20  wherein said compound has a binding affinity for the μ receptor of less than about 0.1 K i  (nM).  
     
     
         24 . The method of  claim 20  wherein said compound has a binding affinity for the receptor of less than about 0.06 K i  (nM).  
     
     
         25 . A method of reducing side effects associated with the administration of opioid analgesics in a human patient comprising administering to said human patient an analgesically effective amount of a non-opioid compound which exhibits a binding affinity for the μ receptor of less than about 5.0 K i  (nM).  
     
     
         26 . The method of  claim 20  wherein said compound has a binding affinity for the ORL1 receptor of less than 100 K i  (nM).  
     
     
         27 . The method of  claim 20  wherein said compound has a binding affinity for the ORL1 receptor of less than 70 K i  (nM).  
     
     
         28 . The method of  claim 20  wherein said compound has a binding affinity for the ORL1 receptor of less than 20 K i  (nM).  
     
     
         29 . The method of  claim 20  wherein said compound has a binding affinity for the ORL1 receptor of less than 5.0 K i  (nM).  
     
     
         30 . A method of reducing side effects associated with the administration of opioid analgesics in a human patient comprising administering to said human patient an analgesically effective amount of a non-opioid compound which exhibits a binding affinity specificity for the μ receptor as compared to the δ 2  receptor (K i  (nM) at the δ 2  receptor/K i  (nM) at the μ receptor) of greater than about 10,000.  
     
     
         31 . The method of  claim 30  wherein said specificity is greater than about 12,000.  
     
     
         32 . The method of  claim 30  wherein said specificity is greater than about 14,775.