Oxadiazole ketone inhibitors of fatty acid amide hydrolase

Abstract

Certain oxadiazole ketone compounds are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as MS).

1 . A compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Ar is a 5- or 6-membered aryl or heteroaryl ring having a carbon as its point of attachment;  
 A is a straight-chain C 1-7 alkylene having a carbon as its point of attachment to the carbon in the beta position, optionally having 1 or 2 carbon atoms each replaced with a sulfur, oxygen, or nitrogen atom;  
 B is a straight-chain, branched, or cyclic C 2-10 alkylene, or, is an aryl, C 2-10 alkenyl, or C 2-10 alkynyl, where an sp 2  hybridized carbon atom in said aryl, alkenyl, or alkynyl is covalently attached to A;  
 or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of said compound.  
 
     
     
         2 . A compound as defined in  claim 1 , wherein Ar is selected from the group consisting of furanyl, pyridinyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, oxadiazolyl, and isoxazolyl.  
     
     
         3 . A compound as defined in  claim 2 , wherein A is a straight-chain C 1-7 alkylene, having no carbon atoms optionally replaced.  
     
     
         4 . A compound as defined in  claim 3 , wherein B is selected from the group consisting of ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, phenyl, ethenyl, cis-1-decenyl, trans-1-decenyl, ethynyl, and 1-decynyl.  
     
     
         5 . A compound as defined in  claim 1 , wherein A is a straight-chain C 1-7 alkylene, optionally having 1 or 2 carbon atoms each replaced with an oxygen atom.  
     
     
         6 . A compound as defined in  claim 5 , wherein B is selected from the group consisting of ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, phenyl, ethenyl, cis-1-decenyl, trans-1-decenyl, ethynyl, and 1-decynyl.  
     
     
         7 . A compound as defined in  claim 1 , wherein B is selected from the group consisting of ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, phenyl, ethenyl, cis-1-decenyl, trans-1-decenyl, ethynyl, and 1-decynyl.  
     
     
         8 . A compound as defined in  claim 7 , wherein Ar is selected from the group consisting of furanyl, pyridinyl, phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, oxadiazolyl, and isoxazolyl.  
     
     
         9 . A compound as defined in  claim 1  wherein Ar is selected from the group consisting of phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, and furanyl.  
     
     
         10 . A compound as defined in  claim 1 , wherein A is a straight-chain C 1-7 alkylene having no carbon atoms optionally replaced.  
     
     
         11 . A compound as defined in  claim 1 , wherein A is selected from the group consisting of propylene, butylene, pentylene, hexylene, propoxylene, butoxylene, and pentoxylene.  
     
     
         12 . A compound as defined in  claim 1 , wherein B is phenyl or cis-1-decenyl.  
     
     
         13 . A compound selected from the group consisting of: 
 7-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-heptan-1-one;    6-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-hexan-1-one;    8-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-octan-1-one;    9-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-nonan-1-one;    1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-octadec-9-en-1-one;    7-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-heptan-1-one;    1-(5-phenyl-1,3,4-oxadiazol-2-yl)-octadec-9-en-1-one;    6-phenyl-1-[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]-hexan-1-one;    7-phenyl-1-[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]-heptan-1-one;    7-phenyl-1-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-heptan-1-one;    1-[5-(furan-2-yl)-1,3,4-oxadiazol-2-yl]-heptan-1-one; and    6-phenoxy-1-(5-pyridin-2-yl-[1,3,4]oxadiazol-2-yl)-hexan-1-one.    
     
     
         14 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by FAAH activity, comprising administering to the subject an effective amount of a compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 Ar is a 5- or 6-membered aryl or heteroaryl ring having a carbon as its point of attachment;  
 A is a straight-chain C 1-7 alkylene having a carbon as its point of attachment to the carbon in the beta position, optionally having 1 or 2 carbon atoms each replaced with a sulfur, oxygen, or nitrogen atom;  
 B is a straight-chain, branched, or cyclic C 2-10 alkylene, or, is an aryl, C 2-10 alkenyl, or C 2-10 alkynyl, where an sp 2  hybridized carbon atom in said aryl, alkenyl, or alkynyl is covalently attached to A;  
 or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of said compound.  
 
     
     
         15 . A method according to  claim 14 , wherein the disease, disorder, or medical condition is selected from the group consisting of: anxiety, pain, sleep disorders, eating disorders, inflammation, movement disorders, HIV wasting syndrome, closed head injury, stroke, Alzheimer's disease, epilepsy, Tourette's syndrome, Niemann-Pick disease, Parkinson's disease, Huntington's chorea, optic neuritis, autoimmune uveitis, drug withdrawal, nausea, emesis, sexual dysfunction, post-traumatic stress disorder, cerebral vasospasm, glaucoma, irritable bowel syndrome, inflammatory bowel disease, immunosuppression, gastroesophageal reflux disease, paralytic ileus, secretory diarrhea, gastric ulcer, rheumatoid arthritis, unwanted pregnancy, hypertension, cancer, hepatitis, allergic airway disease, autoimmune diabetes, intractable pruritis, and neuroinflammation.  
     
     
         16 . A method according to  claim 14 , wherein the disease, disorder, or medical condition is selected from the group consisting of: anxiety, pain, inflammation, sleep disorders, eating disorders, and movement disorders.  
     
     
         17 . A pharmaceutical composition for treating a disease, disorder, or medical condition mediated by FAAH activity, comprising: 
 (a) an effective amount of an agent selected from compounds of Formula (I):                          wherein:    Ar is a 5- or 6-membered aryl or heteroaryl ring having a carbon as its point of attachment;    A is a straight-chain C 1-7 alkylene having a carbon as its point of attachment to the carbon in the beta position, optionally having 1 or 2 carbon atoms each replaced with a sulfur, oxygen, or nitrogen atom;    B is a straight-chain, branched, or cyclic C 2-10 alkylene, or, is an aryl, C 2-10 alkenyl, or C 2-10 alkynyl, where an sp 2  hybridized carbon atom in said aryl, alkenyl, or alkynyl is covalently attached to A;    and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites thereof; and    (b) a pharmaceutically acceptable excipient.    
     
     
         18 . A pharmaceutical composition according to  claim 17 , further comprising: an analgesic selected from the group consisting of opioids and non-steroidal anti-inflammatory drugs.  
     
     
         19 . A pharmaceutical composition according to  claim 17 , further comprising: an analgesic selected from the group consisting of aspirin, acetaminophen, ibuprofen, naproxen, COX-2 inhibitors, gabapentin, pregabalin, and tramadol.  
     
     
         20 . A method according to  claim 14 , wherein the compound is selected from the group consisting of: 
 7-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-heptan-1-one;    6-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-hexan-1-one;    8-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-octan-1-one;    9-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-nonan-1-one;    1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-octadec-9-en-1-one;    7-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-heptan-1-one;    1-(5-phenyl-1,3,4-oxadiazol-2-yl)-octadec-9-en-1-one;    6-phenyl-1-[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]-hexan-1-one;    7-phenyl-1-[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]-heptan-1-one;    7-phenyl-1-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]-heptan-1-one;    1-[5-(furan-2-yl)-1,3,4-oxadiazol-2-yl]-heptan-1-one; and    6-phenoxy-1-(5-pyridin-2-yl-[1,3,4]oxadiazol-2-yl)-hexan-1-one.