N-dihydroxyalkyl-substituted 2-oxo-imidazole derivatives

Abstract

The invention provides the compounds represented by the formula (I) in which, R stands for a dihydroxy-substituted C 1 -C 6 alkyl group, and Cy stands for an optionally substituted C 6 -C 10 bi- or tri-cyclic aliphatic carbocyclic group. These compounds act as nociceptin receptor antagonist, and are useful, for example, as relievers against tolerance to narcotic analgesic, dependence on narcotic analgesic or addiction; analgesic enhancers; antiobestic or appetite suppressors; treating or prophylactic agents for cognitive impairment and dementia/amnesia; agents for treating developmental cognitive abnormality; remedy for schizophrenia; agents for treating neurodegenerative diseases; anti-depressant or treating agents for affective disorder; treating or prophylactic agents for diabetes insipidus; treating or prophylactic agents for polyuria; and remedy for hypotension and the like.

1 - 15 . (canceled)  
     
     
         16 . A method for treating a disease or disorder involving the nociceptin receptor ORL1 (Opioid receptor-like-1 receptor) by inhibiting the binding of nociceptin to the nociceptin receptor ORL1 in a human patient in need thereof which comprises administering to the patient a compound of the formula (I):  
       
         
           
           
               
               
           
         
         wherein:  
         R is a di-hydroxy-substituted C 3 -C 4  alkyl group, and  
         Cy is selected from the group consisting of: spiro[4.5]dec-6-yl; spiro[2.5]oct-4-yl; spiro[3.5]non-5-yl; bicyclo[2.2.1]hept-2-yl; and 1-spiro(bicyclo[2.2.1]heptane-2,1′-cyclopropan)-3-yl, which is unsubstituted or substituted with a substituent selected from: halogen and C 1 -C 6  alkyl; or a pharmaceutically acceptable salt thereof.  
       
     
     
         17 . The method of  claim 16  wherein the compound of formula (I): R is selected from the group consisting of: 2-hydroxy-1-(hydroxymethyl)ethyl; 2,3-dihydroxypropyl; 2,3-dihydroxy-2-methylpropyl; 2,3-dihydroxybutyl; 2,4-dihydroxybutyl; 3,4-dihydroxybutyl; 2,3-dihydroxy-1-methylpropyl; 2-hydroxy-1-(hydroxymethyl)propyl; 3-hydroxy-1-(hydroxymethyl)propyl; and 3-hydroxy-2-(hydroxymethyl)propyl.  
     
     
         18 . The method of  claim 16  wherein the compound of formula (I): R is selected from the group consisting of: 2,3-dihydroxypropyl; 2-hydroxy-1-(hydroxymethyl)ethyl; and 2,3-dihydroxy-2-methylpropyl.  
     
     
         19 . The method of  claim 16  wherein the compound of formula (I): Cy is selected from the group consisting of: spiro[4.5]dec-6-yl; spiro[2.5]oct-4-yl; spiro[3.5]non-5-yl; 3,3-dimethylbicyclo[2.2.1]hept-2-yl; and 1-spiro(bicyclo[2.2.1]-heptane-2,1′-cyclopropan)-3-yl.  
     
     
         20 . The method of  claim 16  wherein the compound of formula (I): Cy is unsubstituted.  
     
     
         21 . The method of  claim 16  wherein the compound of formula (I): Cy is substituted with a C 1 -C 4  alkyl group.  
     
     
         22 . The method of  claim 16  wherein the compound is selected from the group consisting of: 
 1-(2,3-dihydroxypropyl)-3-[1-(spiro[4.5]dec-6-ylmethyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;    1-(2,3-dihydroxypropyl)-3-[1-(spiro[2.5]oct-4-ylmethyl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;    1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-[1-(spiro[bicyclo-[2.2.1]heptane-2,1′-cyclopropan]-3-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;    1-(2,3-dihydroxy-2-methylpropyl)-3-[1-(spiro[2.5]oct-4-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; and    1-(2,3-dihydroxypropyl)-3-[1(spiro[bicyclo[2.2.1]heptane-2,1′-cyclopropan]3-ylmethyl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,    or a pharmaceutically acceptable salt thereof.    
     
     
         23 . The method of  claim 16  wherein the compound is 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(spiro[4.5]dec-6-ylmethyl)piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, or a pharmaceutically acceptable salt thereof.  
     
     
         24 . The method of  claim 16  wherein the compound is 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, or a pharmaceutically acceptable salt thereof.  
     
     
         25 . The method of  claim 16  wherein the compound is 1-[2-hydroxy-1-(hydroxymethyl)-ethyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.1]heptane-2,1′-cyclopropan-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, or a pharmaceutically acceptable salt thereof.  
     
     
         26 . The method of  claim 16  wherein the compound is 1-[2-hydroxy-1-(hydroxymethyl)ethyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo[2.2.1]heptane-2,1′-cyclopropan-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one hydrochloride.  
     
     
         27 . The method of  claim 16  wherein the compound is 1-[2,3-dihydroxy-2-methylpropyl]-3-{1-[(4S)-spiro[2.5]oct-4-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidzol-2-one, or a pharmaceutically acceptable salt thereof.  
     
     
         28 . The method of  claim 16  wherein the compound is 1-[(2R)-2,3-dihydroxypropyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo-[2.2.1]heptane-2,1′-cyclopropan]-3-ylmethyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one, or a pharmaceutically acceptable salt thereof.  
     
     
         29 . The method of  claim 16  wherein the compound is 1-[(2R)-2,3-dihydroxy-propyl]-3-{1-[(1R,3S,4S)-spiro[bicyclo-[2.2.1]heptane-2,1′-cyclopropan]-3-ylmethyl]-piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one hydrochloride.  
     
     
         30 . The method of  claim 16  wherein the disease or disorder is selected from the group consisting of: pain, cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain, neuralgia, addiction, tolerance to narcotic analgesics, dependence on narcotic analgesics, analgesic enhancement, obesity, suppressing appetite, cognitive impairment, dementia in aging, amnesia in aging, cerebrovascular disease, Alzheimer's disease, attention deficit hyperactivity disorder, learning disability, schizophrenia, neurodegenerative disease, Parkinson's disease, chorea, depression, affective disorder, diabetes insipidus, polyuria, and hypotension.