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 - 30 . (canceled) 
     
     
         31 . A method for the treatment of a pathologic condition or disorder selected from the group consisting of bladder and gastrointestinal disorders; inflammatory diseases; cardiovascular diseases; osteoporosis; metabolic disorders; obesity; psychiatric and neurological disorders; neurodegenerative disorders; pain; skin inflammatory and fibrotic diseases in a subject in need thereof comprising administering to said subject an effective amount of a pregnenolone derivative compound chosen among:
 a compound of formula (B)   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof 
         wherein
   R1 denotes that C3 is substituted with —OH or ═O, 
 —R2 denotes that C17 is substituted with C1-8 alkyl, halogen or Bn-, 
   R3 denotes that C20 is substituted with —OH or ═O, and 
   R4 denotes that C16 is substituted with —H, 
 
         a compound of formula (D): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein
   R1 denotes that C3 is substituted with halogen, NH2, 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. 
 
         or
   R1 denotes that C3 is substituted with C1-8 alkoxy, halogen, 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, 
 
         or
   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, 
 
         or
   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, 
 
         or 
         a compound of formula (E): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
   R1 denotes that C3 is substituted with —H, 
   R3 denotes that C20 is substituted with —H, —OH or ═O, and 
   R4 denotes that C16 is substituted with —H, 
 
         provided that in formulas B, C, D, and E when the bond between C3 and R1 is single, R1 is in β position. 
       
     
     
         32 . The method according to  claim 31 , wherein said compound is not substantially converted into active pregnenolone down stream derivatives after administration to a subject. 
     
     
         33 . The method according to  claim 31 , wherein said compound is of formula (B) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof wherein:
   R1 denotes that C3 is substituted with —OH in β position or ═O, 
 —R2 denotes that C17 is substituted with C1-8 alkyl, halogen or Bn-, 
   R3 denotes that C20 is substituted with —OH, and 
   R4 denotes that C16 is substituted with —H 
 
         or
   R1 denotes that C3 is substituted with ═O, 
 —R2 denotes that C17 is substituted with C1-8 alkyl, halogen or Bn-, 
   R3 denotes that C20 is substituted with ═O, and 
   R4 denotes that C16 is substituted with —H. 
 
       
     
     
         34 . The pregnenolone derivative compound according to  claim 33 , wherein said compound is 17α-Methylprogesterone or 17α-Benzylprogesterone. 
     
     
         35 . The method according to  claim 31 , wherein said compound is of formula (D): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein
   R1 denotes that C3 is substituted with —NH2, Bn-O— or —N 3  in β position, 
 —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. 
 
       
     
     
         36 . The method according to  claim 35 , wherein said compound is 5-pregnen-3β-O-benzyl-20-one , 3β-Aminopregnenolone or 5-pregnen-3β-azido-20-one. 
     
     
         37 . The method to  claim 31 , wherein said compound is of formula (D): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein
   R1 denotes that C3 is substituted with C1-8 alkoxy, halogen, Bn-O— or N 3  in β position, 
 —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. 
 
       
     
     
         38 . The method according to  claim 37 , wherein said compound is 17α-Allyl-3β-methoxypregnenolone, 17α-Benzyl-3β-fluoropregnenolone, 3β-Fluoro-17α-methylpregnenolone, 3β-Methoxy-17α-methylpregnenolone, 17α-Benzyl-3β-methoxypregnenolone, 3β-Benzyloxy-17α-methylpregnenolone or 17α-Benzyl-3β-benzyloxypregnenolone. 
     
     
         39 . The method according to  claim 31 , wherein said compound is of formula (D): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
   R1 denotes that C3 is substituted with —OH in β position, 
 —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. 
 
       
     
     
         40 . The method according to  claim 39 , wherein said compound is 17α-Benzylpregnenolone, 17α-Ethylpregnenolone, 17α-Methylpregnenolone or 17-Methoxypregnenolone. 
     
     
         41 . The method according to  claim 31 , wherein said compound is of formula (D): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
   R1 denotes that C3 is substituted with —OH in β position, 
 —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. 
 
       
     
     
         42 . The method according to  claim 41 , wherein said compound is 20-Deoxypregnenolone or 20-Methylamino-5-pregnen-3β-ol. 
     
     
         43 . The method according  claim 31 , wherein said compound is of formula (E): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
   R1 denotes that C3 is substituted with —H, 
   R3 denotes that C20 is substituted with —H, —OH or ═O, and 
   R4 denotes that C16 is substituted with —H. 
 
       
     
     
         44 . The method according to  claim 43  wherein said compound is 5,16-Pregnadien-20-one. 
     
     
         45 . The method according to  claim 31  wherein the bladder and gastrointestinal disorder is selected from the group consisting of liver fibrosis; liver steatosis; non-alcoholic steatohepatitis (NASH); liver cirrhosis; alcoholic steatosis; hepatic ischemic reperfusion injury complicated by endotoxaemia; acute pancreatitis; overactive and painful bladder disorders and motility alteration of contractile visceral organs. 
     
     
         46 . The method according to  claim 31 , wherein the inflammatory disease is selected from the group consisting of inflammation associated with obesity, arthritis associated with obesity, chronic-immune inflammatory diseases, ulcer. 
     
     
         47 . The method according to  claim 31  wherein the cardiovascular disease is selected from the group consisting of cardiomyopathy, endothelial dysfunction and cell death involved in the development of vascular dysfunction associated with congestive heart failure, hypertension, coronary artery diseases, myocardial infarction, diseases resulting from lipid accumulation, pathologies derived by increased angiogenesis and diseases involving angiogenesis. 
     
     
         48 . The method according to  claim 31 , wherein osteoporosis is menopause associated osteoporosis. 
     
     
         49 . The method according to  claim 31  wherein the metabolic disorder is selected from the group consisting of dyslipidemia, diabetes and diabetic complications. 
     
     
         50 . The method according to  claim 31  wherein the psychiatric and neurological disorder is selected from the group consisting of schizophrenia, mood disorders, L-DOPA induced dyskinesia, memory disorders. 
     
     
         51 . The method according to  claim 31  wherein the neurodegenerative disorder is selected from the group consisting of Parkinson and Alzheimer. 
     
     
         52 . The method according to  claim 31  wherein skin inflammatory and fibrotic diseases are selected from the group consisting of skin inflammation, skin inflammation induced by UV, skin cancer, skin fibrosis, wound healing.