Pyrazole and imidazole compounds and uses thereof

Abstract

Compounds of Formula (I) that act as cannabinoid receptor ligands and their uses in the treatment diseases, conditions and/or disorders modulated by cannabinoid receptor antagonists in animals are described herein.

1 . A compound of Formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 X is carbon and Y is nitrogen or X is nitrogen and Y is carbon;  
 R 1  is hydrogen, (C 1 -C 6 )alkyl, halogen, or cyano;  
 R 2  and R 3  are each independently (CH 2 ) n -aryl or (CH 2 ) n -heteroaryl, where n is 0, 1 or 2, and where said aryl and said heteroaryl moieties are optionally substituted with one or more substituents;  
 L is —C(O)— or —C(R 4 )(OR 5 )—, where R 4  is hydrogen or (C 1 -C 6 )alkyl and R 5  is hydrogen, (C 1 -C 6 )alkyl, or taken together with R 8  or R 9  is —CH 2 CH 2 — or —CH 2 C(O)—;  
 R 6  and R 7  are each independently hydrogen or (C 1 -C 6 )alkyl, or R 6  and R 7  taken together form a partially or fully saturated carbocyclic ring; and  
 R 8  and R 9  taken together form a partially or fully saturated, 4- to 8-membered heterocyclic ring containing 1 to 3 heteroatoms and optionally substituted with one or more substituents;  
 a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.  
 
   
   
       2 . The compound of  claim 1 , wherein said compound of Formula (I) is a compound of Formula (IA)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydrogen or (C 1 -C 6 )alkyl;  
 R 2  and R 3  are each independently —(CH 2 ) n -aryl or —(CH 2 ) n -heteroaryl, where n is 0, 1 or 2, and where said aryl and said heteroaryl moieties are each optionally substituted with one to three substituents; and  
 R 6  and R 7  are each independently hydrogen or (C 1 -C 6 )alkyl, or R 6  and R 7  taken together form a partially or fully saturated carbocyclic ring; and  
 R 8  and R 9  taken together form a partially or fully saturated, 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms and optionally substituted with one or more substituents;  
 a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.  
 
   
   
       3 . The compound of  claim 2  selected from the group consisting of 
 1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-piperidin-1-yl-ethanone;    1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-morpholin-4-yl-ethanone;    1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-[4-(1-methyl-1H-pyrrole-2-carbonyl)-piperazin-1-yl]-ethanone;    1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-[4-(1-methyl-cyclopropanecarbonyl)-piperazin-1-yl]-ethanone;    N-(1-{2-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-oxo-ethyl}-piperidin-4-yl)-2,2,2-trifluoro-acetamide;    1-[5-(4-chloro-phenyl)-1-(2-fluoro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-morpholin-4-yl-ethanone;    1-[5-(4-chloro-phenyl)-1-(2-fluoro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-piperidin-1-yl-ethanone;    1-[5-(4-chloro-phenyl)-1-(2-fluoro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-(4-trifluoroacetyl-piperazin-1-yl)-ethanone;    1-[1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-pyrrolidin-1-yl-ethanone;    1-[1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-[1,4]oxazepan-4-yl-ethanone; and    1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-(1-oxa-8-aza-spiro[4,5]dec-8-yl)-ethanone; 
 a pharmaceutically acceptable salt thereof or a solvate or hydrate of said compound or said salt.  
   
   
   
       4 . The compound of  claim 1 , wherein said compound of Formula (I) is a compound of Formula (IB)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydrogen or (C 1 -C 6 )alkyl;  
 R 2  and R 3  are each independently —(CH 2 ) n -aryl or —(CH 2 ) n -heteroaryl, where n is 0, 1 or 2, and where said aryl and said heteroaryl moieties are each optionally substituted with one to three substituents;  
 R 4  is hydrogen or (C 1 -C 6 )alkyl;  
 R 5  is hydrogen or (C 1 -C 6 )alkyl;  
 R 6  and R 7  are each independently hydrogen or (C 1 -C 6 )alkyl, or R 6  and R 7  taken together form a partially or fully saturated carbocyclic ring; and  
 R 8  and R 9  taken together form a partially or fully saturated, 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms and optionally substituted with one or more substituents;  
 a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.  
 
   
   
       5 . The compound of  claim 4  selected from the group consisting of 
 1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-(3,5-dimethyl-piperidin-1-yl)-ethanol;    1-{2-[1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-hydroxy-ethyl}-4-isopropylamino-piperidine-4-carboxylic acid amide;    1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-(3,3-dimethyl-piperidin-1-yl)-ethanol;    1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-piperidin-1-yl-ethanol; and    1-[5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-2-morpholin-4-yl-ethanol; 
 a pharmaceutically acceptable salt thereof or a solvate or hydrate of said compound or said salt.  
   
   
   
       6 . (canceled)  
   
   
       7 . (canceled)  
   
   
       8 . The compound of  claim 1 , wherein said compound of Formula (I) is a compound of Formula (ID)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydrogen or (C 1 -C 6 )alkyl;  
 R 2  and R 3  are each independently —(CH 2 ) n -aryl or —(CH 2 ) n -heteroaryl, where n is 0, 1 or 2, and where said aryl and said heteroaryl moieties are each optionally substituted with one to three substituents;  
 R 6  and R 7  are each independently hydrogen or (C 1 -C 6 )alkyl, or R 6  and R 7  taken together form a partially or fully saturated carbocyclic ring; and  
 R 8  and R 9  taken together form a partially or fully saturated, 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms and optionally substituted with one or more substituents;  
 a pharmaceutically acceptable salt thereof, a prodrug of said compound or said salt, or a solvate or hydrate of said compound, said salt or said prodrug.  
 
   
   
       9 . The compound of  claim 8  selected from the group consisting of 
 1-[1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1H-imidazol-4-yl]-2-piperidin-1-yl-ethanone; and    1-[1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1H-imidazol-4-yl]-2-morpholin-4-yl-ethanone; 
 a pharmaceutically acceptable salt thereof or a solvate or hydrate of said compound or said salt.  
   
   
   
       10 . The compound of claims  1 ,  2 ,  4 ,  6 , or  8  wherein R 2  is p-chlorophenyl or p-fluorophenyl, and R 3  is 2,4-dichlorophenyl, 2-chlorophenyl or 2-fluororophenyl.  
   
   
       11 . A pharmaceutical composition comprising 
 (a) a compound of  claim 1 , a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt; and    (b) a pharmaceutically acceptable excipient, diluent, or carrier.    
   
   
       12 . The composition of  claim 10  further comprising a nicotine receptor partial agonist, an opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.  
   
   
       13 . The composition of  claim 12  wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY 3-36  or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a 3 adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.  
   
   
       14 . A method for treating a disease, condition or disorder modulated by a cannabinoid receptor antagonist in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of  claim 1 , a pharmaceutically acceptable salt thereof, or a solvate or hydrate of said compound or said salt.  
   
   
       15 . The method of  claim 14  wherein said cannabinoid receptor is a CB1 receptor.  
   
   
       16 . The method of  claim 15  wherein said disease, condition or disorder modulated by a cannabinoid receptor antagonist is selected from the group consisting of weight loss, obesity, bulimia, depression, bipolar disorders, psychoses, schizophrenia, alcoholism, tobacco abuse, memory loss, Alzheimer's disease, dementia of aging, seizure disorders, epilepsy, attention deficit disorder, Parkinson's disease, and type II diabetes.  
   
   
       17 . The method of  claim 15  wherein said disease is obesity, bulimia, attention deficit disorder, alcoholism, or tobacco abuse.  
   
   
       18 . A method for treating a disease, condition or disorder modulated by a cannabinoid receptor antagonist in animals comprising the step of administering to an animal in need of such treatment two separate pharmaceutical compositions comprising 
 (i) a first composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient, diluent, or carrier, and    (ii) a second composition comprising at least one additional pharmaceutical agent and a pharmaceutically acceptable excipient, diluent, or carrier.    
   
   
       19 . The method of  claim 18  wherein said at least one additional pharmaceutical agent is a nicotine partial agonist, an opioid antagonist, a dopaminergic agent, an attention deficit disorder agent, or an anti-obesity agent.  
   
   
       20 . The method of  claim 19  wherein said anti-obesity agent is selected from the group consisting of an apo-B/MTP inhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptide YY 3-36  or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a 3 adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or inverse agonist, and a neuromedin U receptor agonist.  
   
   
       21 . The method of  claim 18  wherein said first composition and said second composition are administered simultaneously.  
   
   
       22 . The method of  claim 18  wherein said first composition and said second composition are administered sequentially and in any order.  
   
   
       23 . The method of claims  18 ,  19 ,  20 ,  21 , or  22  wherein said disease is obesity, bulimia, attention deficit disorder, alcoholism, or tobacco abuse.