Antagonists of cb1 receptor

Abstract

The invention relates to an antagonist of CB1 receptor for use in the treatment of a pathologic condition or disorder selected from the group consisting of bladder and gastrointestinal disorders; inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma; spasticity; cancer; osteoporosis; metabolic disorders; obesity; addiction, dependence, abuse and relapse related disorders; psychiatric and neurological disorders; neurodegenerative disorders; autoimmune hepatitis and encephalitis; pain; reproductive disorders and skin inflammatory and fibrotic diseases.

1 . A method for the treatment of a pathologic condition or disorder comprising administering to a subject in need thereof a compound of formula (A), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein: 
          denotes that the bond is a single or a double bond, 
         R1 denotes that C3 is substituted with
 —H,   halogen,   —OH,   C1-8 alkoxy,   Bn-O—   Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen,   Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen,   ═O,   —NR5R6 wherein R5 and R6 each independently is H, C1-8 alkyl, Bn or Ph,   —O—CO—R7 wherein R7 is alkyl,   —O—CO—C 2 H 4 —COOH, or   —N 3 ,   
       —R2 denotes that C17 is substituted with
 —H, 
 —OH, 
 halogen, 
 C1-8 alkyl, 
 C1-8 alkoxy, 
 C2-6 alkenyl, 
 Bn optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, 
 Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, carboxyl or halogen, or 
 Bn-O—, 
 
         R3 denotes that C20 is substituted with
 —H,   —OH,   C1-8 alkyl,   Bn,   —NR8R9 wherein R8 and R9 each independently is H, C1-8 alkyl or Bn,   ═CR10R11 wherein R10 and R11 each independently is H or C1-7 alkyl, or   ═O     R4 denotes that C16 is substituted with   —H,   —OH, or   ═O,   
       with the proviso that
 when the bond between C16 and C17 is double, R2 is absent and the bond between C17 and C20 is single, and 
 when the bond between C17 and C20 is double, C20 is substituted with —H or —OH and R2 is absent, 
 when the bond between C4 and C5 is double, the bond between C5 and C6 is single and inversely, 
 wherein the pathologic condition or disorder is selected from the group consisting of bladder and gastrointestinal disorders; inflammatory diseases; cardiovascular diseases; nephropathies glaucoma; spasticity; cancer; osteoporosis; metabolic disorders; obesity; addiction, dependence, abuse and relapse related disorders; psychiatric and neurological disorders; neurodegenerative disorders; autoimmune hepatitis and encephalitis; pain; reproductive disorders; and skin inflammatory and fibrotic diseases. 
 
     
     
         2 . The method of  claim 1 , wherein the compound of formula (A) is a compound of formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein: 
          denotes that the bound is a single or a double bond, 
         R1 denotes that C3 is substituted with 
       —H, 
       halogen, 
       —OH, 
       C1-8 alkoxy, 
       Bn-O— 
       Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, 
       Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, 
       ═O, 
       —NR5R6 wherein R5 and R6 each independently is H, C1-8 alkyl, Bn or Ph, 
       —O—CO—R7 wherein R7 is alkyl, or 
       —O—CO—C 2 H 4 —COOH, 
       —R2 denotes that C17 is substituted with 
       —H, 
       —OH, 
       halogen, 
       C1-8 alkyl, 
       C1-8 alkoxy, 
       C2-6 alkenyl, 
       Bn optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, 
       Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, carboxyl or halogen, or 
       Bn-O—, 
         R3 denotes that C20 is substituted with 
       —H, 
       —OH, 
       C1-8 alkyl, 
       Bn, 
       —NR8R9 wherein R8 and R9 each independently is H, C1-8 alkyl or Bn, 
       ═CR10R11 wherein R10 and R11 each independently is H or C1-7 alkyl, or ═O, 
         R4 denotes that C16 is substituted with 
       —H, 
       —OH, or 
       ═O, 
       with the proviso that 
       when the bond between C16 and C17 is double, R2 is absent and the bond between C17 and C20 is single, and 
       when the bond between C17 and C20 is double, C20 is substituted with —H or —OH and R2 is absent. 
     
     
         3 . The method of  claim 1 , wherein the compound is pregnenolone, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein said compound is not substantially converted into an active pregnenolone downstream derivative after administration to the subject. 
     
     
         6 . (canceled) 
     
     
         7 . The method  claim 1 , wherein the compound of formula (A) is a compound of formula (B) 
       
         
           
           
               
               
           
         
       
       wherein
   R1 denotes that C3 is substituted with —OH or ═O, 
 —R2 denotes that C17 is substituted with —H, —OH, C1-8 alkyl, halogen or Bn, 
   3 denotes that C20 is substituted with —OH or ═O, 
   R4 denotes that C16 is substituted with —H, 
 
     
     
         8 . The method of  claim 1 , wherein the compound of formula (A) is a compound of formula (C): 
       
         
           
           
               
               
           
         
         wherein 
       
         R1 denotes that C3 is substituted with ═O or —OH 
       —R2 denotes that C17 is substituted with —H 
         R3 denotes that C20 is substituted with ═O, and 
         R4 denotes that C16 is substituted with —H, 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the compound of formula (A) is a compound of formula (D): 
       
         
           
           
               
               
           
         
       
       wherein 
         R1 denotes that C3 is substituted with
 Halogen, Bn-O or, —N 3 ,   
       —R2 denotes that C17 is substituted with —H, 
         R3 denotes that C20 is substituted with ═O, and 
         R4 denotes that C16 is substituted with —H, 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the compound of formula (A) is a compound of formula (D): 
       
         
           
           
               
               
           
         
       
       wherein 
         R1 denotes that C3 is substituted with C1-8 alkoxy, halogen or Bn-O—, or N 3    
       —R2 denotes that C17 is substituted with Bn, —CH 3  or C2-6 alkenyl, 
         R3 denotes that C20 is substituted with ═O, and 
         R4 denotes that C16 is substituted with —H, 
     
     
         13 . The method of  claim 1 , wherein: 
         R1 denotes that C3 is substituted with —OH 
       —R2 denotes that C17 is substituted with
 —OH, halogen, C1-8 alkyl, C1-8 alkoxy, C2-6 alkenyl, 
 Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, 
 Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, carboxyl or halogen, or 
 Bn-O—, 
 
         R3 denotes that C20 is substituted with ═O, and 
         R4 denotes that C16 is substituted with —H, 
     
     
         14 . The method of  claim 1 , wherein the compound of formula (A) is a compound of formula (D): 
       
         
           
           
               
               
           
         
       
       wherein 
         R1 denotes that C3 is substituted with —OH, 
       —R2 denotes that C17 is substituted with C1-8 alkyl, C1-8 alkoxy or Bn-, 
         R3 denotes that C20 is substituted with ═O, and 
         R4 denotes that C16 is substituted with —H, 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the compound of formula (A) is a compound of formula (D): 
       
         
           
           
               
               
           
         
       
       wherein 
         R1 denotes that C3 is substituted with —OH, 
       —R2 denotes that C17 is substituted with —H, 
         R3 denotes that C20 is substituted with —H, —OH or —NR8R9 wherein R8 and R9 each independently is H or C1-8 alkyl, and 
         R4 denotes that C16 is substituted with —H, 
     
     
         17 - 19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the pathologic condition or disorder is a gastrointestinal disorder. 
     
     
         21 . The method of  claim 1 , wherein the pathologic condition or disorder is obesity or a metabolic disorder. 
     
     
         22 . The method of  claim 1 , wherein the pathologic condition or disorder is addiction, dependence abuse, or a relapse related disorder. 
     
     
         23 . The method of  claim 22 , wherein the pathologic condition or disorder is  cannabis  addiction, dependence, abuse, intoxication, or relapse related disorder. 
     
     
         24 . The method of  claim 1 , wherein the pathologic condition or disorder is a neurodegenerative or psychiatric disorder. 
     
     
         25 . The method of  claim 1 , wherein the pathologic condition or disorder is a skin inflammatory or fibrotic disease. 
     
     
         26 . A compound of formula (II) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutical salt thereof, wherein: 
          denotes that the bond is a single or a double bond 
         R1 denotes that C3 is substituted with —OH, and 
       —R2 denotes that C17 is substituted with
 C3-8 alkyl, 
 C2-8 alkoxy, 
 Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, 
 Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, carboxyl or halogen, or 
 Bn-O—, 
 
       or wherein 
         R1 denotes that C3 is substituted with
 C1-8 alkoxy,   Bn-O, or   Halogen, and   
       —R2 denotes that C17 is substituted with
 C1-8 alkyl, 
 C2-6 alkenyl, 
 C1-8 alkoxy, 
 Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, amino, carboxyl or halogen, 
 Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, cyano, nitro, carboxyl, or halogen, or Bn-O—. 
 
     
     
         27 . The compound of  claim 26 , wherein the compound is 3β-fluoro-17α-methylpregnenolone, 17α-benzyl-3 O-fluoropregnenolone, 17α-benzyl-3β-benzyloxypregnenolone, 3β-benzyloxy-17α-methylpregnenolone, 17α-benzylpregnenolone, 3β-methoxy-17α-methylpregnenolone, 17α-allyl-3β-methoxypregnenolone, or 17α-benzyl-3β-methoxypregnenolone. 
     
     
         28 . A pharmaceutical composition comprising a compound of  claim 26 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         29 - 30 . (canceled)