3-(4'-substituted)-benzyl-ether derivatives of pregnenolone

Abstract

The invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein R1 is C1-8 alkyl, C1-8 alkoxy, CN, NO 2 , amino, COOH, COOCH 3 , OH, N 3 , or halogen and R2 is H, OH, C1-8 alkyl, C1-8 alkoxy, C2-C6 alkenyl, halogen, Bn-O—, Bn- optionally substituted, or Ph- optionally substituted.

1 . A compound of Formula I or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein:
 R1 is: 
 
         C1-8 alkyl, 
         C1-8 alkoxy, 
         CN, 
         NO 2 , 
         amino, 
         COOH, 
         COOCH 3    
         OH, 
         N 3 , 
         or 
         halogen 
         and
 R2 is: 
 
         H, 
         OH, 
         C1-8 alkyl, 
         C1-8 alkoxy, 
         C2-C6 alkenyl, 
         halogen, 
         Bn-O-Bn- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO 2 , amino, COOH or halogen or 
         Ph- optionally substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO 2 , amino, COOH or halogen. 
       
     
     
         2 . The compound according to  claim 1  wherein R2 is in a position. 
     
     
         3 . The compound according to  claim 1  wherein R1 is OH, C1-8 alkyl, C1-8 alkoxy or halogen. 
     
     
         4 . The compound according to  claim 3  wherein R1 is OH, methyl, ethyl, methoxy, ethoxy, methylcarboxy, Cl, Br, F or cyano. 
     
     
         5 . The compound according to  claim 1  wherein R2 is H, OH, C1-8 alkyl, C1-8 alkoxy, C1-8 alkenyl or Bn. 
     
     
         6 . The compound according to  claim 5  wherein R2 is H, OH, methyl, ethyl, methoxy, ethoxy, allyl or Bn. 
     
     
         7 . The compound according to  claim 1  is:
 3-(p-hydroxybenzyloxy)-pregnenolone, 
 3-(p-methylbenzyloxy)-pregnenolone, 
 3-(p-ethylbenzyloxy)-pregnenolone, 
 3-(p-methoxybenzyloxy)-pregnenolone, 
 3-(p-ethoxybenzyloxy)-pregnenolone, 
 3-(p-methylcarboxybenzyloxy)-pregnenolone, 
 3-(p-fluorobenzyloxy)-pregnenolone, 
 3-(p-chlorobenzyloxy)-pregnenolone, 
 3-(p-bromobenzyloxy)-pregnenolone, 
 3-(p-cyanobenzyloxy)-pregnenolone, 
 17-hydroxy-3-(p-hydroxybenzyloxy)-pregnenolone, 
 17-hydroxy-3-(p-methylbenzyloxy)-pregnenolone, 
 3-(p-ethylbenzyloxy)-17-hydroxy-pregnenolone, 
 17-hydroxy-3-(p-methoxybenzyloxy)-pregnenolone, 
 3-(p-ethoxybenzyloxy)-17-hydroxy-pregnenolone, 
 17-hydroxy-3-(p-methylcarboxybenzyloxy)-pregnenolone, 
 3-(p-fluorobenzyloxy)-17-hydroxy-pregnenolone, 
 3-(p-chlorobenzyloxy)-17-hydroxy-pregnenolone, 
 3-(p-bromobenzyloxy)-17-hydroxy-pregnenolone, 
 3-(p-cyanobenzyloxy)-17-hydroxy-pregnenolone, 
 3-(p-hydroxybenzyloxy)-17-methyl-pregnenolone, 
 17-methyl-3-(p-methylbenzyloxy)-pregnenolone, 
 3-(p-ethylbenzyloxy)-17-methyl-pregnenolone, 
 3-(p-methoxybenzyl oxy)-17-methyl-pregnenolone, 
 3-(p-ethoxybenzyloxy)-17-methyl-pregnenolone, 
 17-methyl-3-(p-methylcarboxybenzyloxy)-pregnenolone, 
 3-(p-fluorobenzyloxy)-17-methyl-pregnenolone, 
 3-(p-chlorobenzyloxy)-17-methyl-pregnenolone, 
 3-(p-bromobenzyloxy)-17-methyl-pregnenolone, 
 3-(p-cyanobenzyloxy)-17-methyl-pregnenolone, 
 17-ethyl-3-(p-hydroxybenzyloxy)-pregnenolone, 
 17-ethyl-3-(p-methylbenzyloxy)-pregnenolone, 
 17-ethyl-3-(p-ethylbenzyloxy)-pregnenolone, 
 17-ethyl-3-(p-methoxybenzyloxy)-pregnenolone, 
 3-(p-ethoxybenzyloxy)-17-ethyl-pregnenolone, 
 17-ethyl-3-(p-methylcarboxybenzyloxy)-pregnenolone, 
 17-ethyl-3-(p-fluorobenzyloxy)-pregnenolone, 
 3-(p-chlorobenzyloxy)-17-ethyl-pregnenolone, 
 3-(p-bromobenzyloxy)-17-ethyl-pregnenolone, 
 3-(p-cyanobenzyloxy)-17-ethyl-pregnenolone, 
 3-(p-hydroxybenzyloxy)-17-methoxy-pregnenolone, 
 17-methoxy-3-(p-methylbenzyloxy)-pregnenolone, 
 3-(p-ethylbenzyloxy)-17-methoxy-pregnenolone, 
 17-methoxy-3-(p-methoxybenzyloxy)-pregnenolone, 
 3-(p-ethoxybenzyloxy)-17-methoxy-pregnenolone, 
 17-methoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone, 
 3-(p-fluorobenzyloxy)-17-methoxy-pregnenolone, 
 3-(p-chlorobenzyloxy)-17-methoxy-pregnenolone, 
 3-(p-bromobenzyloxy)-17-methoxy-pregnenolone, 
 3-(p-cyanobenzyloxy)-17-methoxy-pregnenolone, 
 17-ethoxy-3-(p-hydroxybenzyloxy)-pregnenolone, 
 17-ethoxy-3-(p-methylbenzyloxy)-pregnenolone, 
 17-ethoxy-3-(p-ethylbenzyloxy)-pregnenolone, 
 17-ethoxy-3-(p-methoxybenzyloxy)-pregnenolone, 
 17-ethoxy-3-(p-ethoxybenzyloxy)-pregnenolone, 
 17-ethoxy-3-(p-methylcarboxybenzyloxy)-pregnenolone, 
 17-ethoxy-3-(p-fluorobenzyloxy)-pregnenolone, 
 3-(p-chlorobenzyloxy)-17-ethoxy-pregnenolone, 
 3-(p-bromobenzyloxy)-17-ethoxy-pregnenolone, 
 3-(p-cyanobenzyloxy)-17-ethoxy-pregnenolone, 
 17-allyl-3-(p-hydroxybenzyloxy)-pregnenolone, 
 17-allyl-3-(p-methylbenzyloxy)-pregnenolone, 
 17-allyl-3-(p-ethylbenzyloxy)-pregnenolone, 
 17-allyl-3-(p-methoxybenzyloxy)-pregnenolone, 
 17-allyl-3-(p-ethoxybenzyloxy)-pregnenolone, 
 17-allyl-3-(p-methylcarboxybenzyloxy)-pregnenolone, 
 17-allyl-3-(p-fluorobenzyloxy)-pregnenolone, 
 17-allyl-3-(p-chlorobenzyloxy)-pregnenolone, 
 17-allyl-3-(p-bromobenzyloxy)-pregnenolone, 
 17-allyl-3-(p-cyanobenzyloxy)-pregnenolone, 
 17-benzyl-3-(p-hydroxybenzyloxy)-pregnenolone, 
 17-benzyl-3-(p-methylbenzyloxy)-pregnenolone, 
 17-benzyl-3-(p-ethylbenzyloxy)-pregnenolone, 
 17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone, 
 17-benzyl-3-(p-ethoxybenzyloxy)-pregnenolone, 
 17-benzyl-3-(p-methylcarboxybenzyloxy)-pregnenolone, 
 17-benzyl-3-(p-fluorobenzyloxy)-pregnenolone, 
 17-benzyl-3-(p-chlorobenzyloxy)-pregnenolone, 
 17-benzyl-3-(p-bromobenzyloxy)-pregnenolone or 
 17-benzyl-3-(p-cyanobenzyloxy)-pregnenolone. 
 
     
     
         8 . The compound according to  claim 1  which is selected from the group consisting of 3β-(p-Methoxybenzyloxy)-17α-methyl-pregnenolone, 17-benzyl-3-(p-methoxybenzyloxy)-pregnenolone, 3-(p-methoxybenzyloxy)-pregnenolone, 3-(p-bromobenzyloxy)-pregnenolone, 3-(p-methylcarboxybenzyloxy)-pregnenolone, 3-(p-methylbenzyloxy)-pregnenolone, 3-(p-fluorobenzyloxy)-pregnenolone and 3-(p-cyanobenzyloxy)-pregnenolone. 
     
     
         9 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         10 . A process for the manufacture of the compound of Formula I according to  claim 1 , which comprises reacting a compound of Formula III: 
       
         
           
           
               
               
           
         
         wherein R2 is as defined above,
 with a compound of Formula IV: 
 
       
       
         
           
           
               
               
           
         
         wherein R1 is as defined above, 
         in the presence of methyl triflate and of a heterogeneous acid scavenger 
         or
 with a compound of Formula V 
 
       
       
         
           
           
               
               
           
         
         wherein R1 is as defined above, 
         in the presence a heterogeneous acid scavenger. 
       
     
     
         11 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof for use in a method for treatment of the human or animal body. 
     
     
         12 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof for use in a method for treatment of a pathology selected from the group consisting of psychiatric and neurological disorders; neurodegenerative disorders; metabolic disorders; addiction, dependence, abuse relapse and related disorders; bladder and gastrointestinal disorders; hepatic diseases such as steatosis; non-alcoholic steatohepatitis (NASH), liver cirrhosis; alcoholic steatosis; inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma; spasticity; cancer; osteoporosis; obesity; autoimmune hepatitis and encephalitis; pain or reproductive disorders and skin inflammatory and fibrotic diseases.