5-aryl-4,5-dihydro-(1h)-pyrazolines as cannabinoid cb1 receptor agonists

Abstract

The invention is directed to 5-(hetero)aryl-4,5-dihydro-(1H)-pyrazole (pyrazoline) derivatives as cannabinoid CB 1 receptor agonists, to pharmaceutical compositions comprising these compounds, to methods for their syntheses, methods for preparing novel intermediates useful for their syntheses, and methods for preparing compositions. The invention also relates to the uses of such compounds and compositions, administered to patients to achieve a therapeutic effect in disorders in which CB 1 receptors are involved, or that can be treated via manipulation of those receptors. Compounds of the present invention include compounds of formula (I): wherein the substituents have the definitions given in the specification.

1 - 10 . (canceled) 
     
     
         11 . A compound of formula (Va): 
       
         
           
           
               
               
           
         
       
       or a tautomer, stereoisomer, N-oxide, isotopically-labelled analogue, or a pharmacologically acceptable salt of any of the foregoing, 
       wherein:
 R 1  is chosen from:
 C 3-10  linear alkyl, C 4-10  branched alkyl, C 4-10  alkenyl, C 4-10  alkynyl, C 3-10 -heteroalkyl, C 5-8 -cycloalkyl-C 1-5 -alkyl, and C 5-8 -heterocycloalkyl-C 1-5 -alkyl, each of which may be optionally substituted with 1-5 substituents, wherein the substituents are the same or different, and are chosen from methyl, ethyl, hydroxy, amino, cyano and fluoro, 
 aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 1-3 -heteroalkyl, and heteroaryl-C 1-3 -heteroalkyl, wherein the aryl or heteroaryl groups are optionally substituted with 1-5 substituents Y, wherein each Y is the same or different, and is chosen from C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1-2 )-amino, mono- or dialkyl (C 1-2 )-amido, (C 1-3 )-alkyl sulfonyl, dimethylsulfamido, C 1-3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, phenyl, and acetyl, and 
 2-cyano-ethyl; 
 
 R 2  is chosen from aryl and heteroaryl, each of which may be optionally substituted with 1-5 substituents Y as defined above; 
 R 5  is chosen from hydrogen and C 1-2  alkyl, optionally substituted with 1-3 fluorine atoms; and 
 R 6  is chosen from hydrogen and C 1-2  alkyl, optionally substituted with 1-3 fluorine atoms; and 
 R 8  is chosen from chloro and OR 7 , where R 7  is C 1-3  alkyl; 
 
       provided that if R 2  is phenyl and R 1  is benzyl, then R 7  is not ethyl. 
     
     
         12 . A compound of formula (VI): 
       
         
           
           
               
               
           
         
       
       or a sodium, potassium, lithium, or cesium salt thereof, 
       wherein:
 R 1  is chosen from:
 C 3-10  linear alkyl, C 4-10  branched alkyl, C 4-10  alkenyl, C 4-10  alkynyl, C 3-10 -heteroalkyl, C 5-8 -cycloalkyl-C 1-5 -alkyl, and C 5-8 -heterocycloalkyl-C 1-5 -alkyl, each of which may be optionally substituted with 1-5 substituents, wherein the substituents are the same or different, and are chosen from methyl, ethyl, hydroxy, amino, cyano and fluoro, 
 aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 1-3 -heteroalkyl, and heteroaryl-C 1-3 -heteroalkyl, wherein the aryl or heteroaryl groups are optionally substituted with 1-5 substituents Y, wherein each Y is the same or different, and is chosen from C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1-2 )-amino, mono- or dialkyl (C 1-2 )-amido, (C 1-3 )-alkyl sulfonyl, dimethylsulfamido, C 1-3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl, phenyl, and acetyl, and 
 2-cyano-ethyl; 
 
 R 2  is chosen from aryl and heteroaryl, each of which may be optionally substituted with 1-5 substituents Y as defined above; 
 R 5  is chosen from hydrogen and C 1-2  alkyl, optionally substituted with 1-3 fluorine atoms; and 
 R 6  is chosen from hydrogen and C 1-2  alkyl, optionally substituted with 1-3 fluorine atoms; 
 
       provided that if R 2  is phenyl then R 1  is not benzyl. 
     
     
         13 . (canceled)