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:
 R 1  is selected from the group consisting of C 1-8  alkyl, C 1-8  alkoxy, CN, NO 2 , amino, COOH, COOCH 3 , OH, N 3 , and halogen; and 
 R 2  is selected from the group consisting of H; OH; C 1-8  alkyl; C 1-8  alkoxy; C 2-6  alkenyl; halogen; Bn-O—; Bn- optionally substituted with C 1-8  alkyl, C 1-8  alkoxy, CN, NO 2 , amino, COOH, or halogen; and Ph- optionally substituted with C 1-8  alkyl, C 1-8  alkoxy, CN, NO 2 , amino, COOH, or halogen; 
 with the proviso that when R 1  is methoxy, R 2  is not H. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein R 2  is in α position. 
     
     
         3 . The compound according to  claim 1 , wherein R 1  is selected from the group consisting of OH, C 1-8  alkyl, C 1-8  alkoxy, and halogen. 
     
     
         4 . The compound according to  claim 1 , wherein R 1  is selected from the group consisting of OH, methyl, ethyl, methoxy, ethoxy, methylcarboxy, Cl, Br, F, and cyano. 
     
     
         5 . The compound according to  claim 1 , wherein R 2  is selected from the group consisting of H, OH, C 1-8  alkyl, C 1-8  alkoxy, C 1-8  alkenyl, and Bn. 
     
     
         6 . The compound according to  claim 1 , wherein R 2  is selected from the group consisting of H, OH, methyl, ethyl, methoxy, ethoxy, allyl, and Bn. 
     
     
         7 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of:
 3-(p-hydroxybenzyloxy)-pregnenolone,   3-(p-methylbenzyloxy)-pregnenolone,   3-(p-ethylbenzyloxy)-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-methoxybenzyloxy)-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, and   17-benzyl-3-(p-cyanobenzyloxy)-pregnenolone.   
     
     
         8 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of 3β-(p-Methoxybenzyloxy)-17α-methyl-pregnenolone, 17-benzyl-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 a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         which comprises reacting a compound of Formula III: 
       
       
         
           
           
               
               
           
         
         
           with a compound of Formula IV: 
         
       
       
         
           
           
               
               
           
         
         in the presence of methyl triflate and/or a heterogeneous acid scavenger; or
 with a compound of Formula V 
 
       
       
         
           
           
               
               
           
         
         in the presence of a heterogeneous acid scavenger;
 wherein: 
 R 1  is selected from the group consisting of C 1-8  alkyl; C 1-8  alkoxy; CN; NO 2 ; amino; COOH; COOCH 3 ; OH; N 3 ; and halogen; and 
 R 2  is selected from the group consisting of H; OH; C 1-8  alkyl; C 1-8  alkoxy; C 2-6  alkenyl; halogen; Bn-O—; Bn- optionally substituted with C 1-8  alkyl, C 1-8  alkoxy, CN, NO 2 , amino, COOH, or halogen; and Ph- optionally substituted with C 1-8  alkyl, C 1-8  alkoxy, CN, NO 2 , amino, COOH, or halogen. 
 
       
     
     
         11 . A method for treating a human or animal suffering from a pathology, comprising a step of administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a human or animal in need thereof 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of C 1-8  alkyl; C 1-8  alkoxy; CN; NO 2 ; amino; COOH; COOCH 3 ; OH; N 3 ; and halogen; and 
         R 2  is selected from the group consisting of H; OH; C 1-8  alkyl; C 1-8  alkoxy; C 2-6  alkenyl; halogen; Bn-O—; Bn- optionally substituted with C 1-8  alkyl, C 1-8  alkoxy, CN, NO 2 , amino, COOH, or halogen; and Ph- optionally substituted with C 1-8  alkyl, C 1-8  alkoxy, CN, NO 2 , amino, COOH, or halogen. 
       
     
     
         12 . The method for treating a human or animal according to  claim 11 , wherein the pathology is selected from the group consisting of psychiatric and neurological disorders; neurodegenerative disorders; metabolic disorders; drug addiction, dependence, abuse relapse and related disorders; bladder and gastrointestinal disorders; hepatic diseases; steatosis; non-alcoholic steatohepatitis (NASH), liver cirrhosis; alcoholic steatosis; inflammatory diseases; cardiovascular diseases; nephropathies; glaucoma; spasticity; cancer; osteoporosis; obesity; autoimmune hepatitis; encephalitis; pain; reproductive disorders; and skin inflammatory and fibrotic diseases. 
     
     
         13 . The process according to  claim 10 , wherein R 1  is selected from the group consisting of OH, C 1-8  alkyl, C 1-8  alkoxy, and halogen. 
     
     
         14 . The process according to  claim 10 , wherein R 2  is selected from the group consisting of H, OH, C 1-8  alkyl, C 1-8  alkoxy, C 1-8  alkenyl, and Bn. 
     
     
         15 . The process according to  claim 10 , wherein R 2  is in α position. 
     
     
         16 . The process according to  claim 10 , wherein the compound of Formula I 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. 
     
     
         17 . The method for treating a human or animal according to  claim 11 , wherein R 1  is selected from the group consisting of OH, C 1-8  alkyl, C 1-8  alkoxy, and halogen. 
     
     
         18 . The method for treating a human or animal according to  claim 11 , wherein R 2  is selected from the group consisting of H, OH, C 1-8  alkyl, C 1-8  alkoxy, C 1-8  alkenyl, and Bn. 
     
     
         19 . The method for treating a human or animal according to  claim 11 , wherein R 2  is in α position. 
     
     
         20 . The method for treating a human or animal according to  claim 11 , wherein the compound of Formula I 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.