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

1. A compound of Formula I or a pharmaceutically acceptable salt thereof,

wherein:

R1 is selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, CN, NO 2 , amino, COOH, COOCH 3 , OH, N 3 , and halogen and

R2 is selected from the group consisting of H, OH, C1-8 alkyl, C1-8 alkoxy, C2-C6 alkenyl, halogen, Bn-O—, Bn- and Ph-.

2. The compound according to claim 1 wherein R2 is in a position.

3. The compound according to claim 1 wherein R1 is selected from the group consisting of OH, C1-8 alkyl, C1-8 alkoxy and halogen.

4. The compound according to claim 1 wherein R1 is selected from the group consisting of OH, methyl, ethyl, methoxy, ethoxy, methylcarboxy, CI, Br, F and cyano.

5. The compound according to claim 1 wherein R2 is selected from the group consisting of H, OH, C1-8 alkyl, C1-8 alkoxy, C2-6 alkenyl and Bn.

6. The compound according to claim 1 wherein R2 is selected from the group consisting of H, OH, methyl, ethyl, methoxy, ethoxy, allyl and Bn.

7. The compound according to claim 1 wherein said compound is selected from the group consisting of:

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-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 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. The compound according to claim 1 wherein Bn- is substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO 2 , amino, COOH or halogen.

10. The compound according to claim 1 wherein Ph- is substituted with C1-8 alkyl, C1-8 alkoxy, CN, NO 2 , amino, COOH or halogen.

11. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

12. 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 in claim 1 ,

with a compound of Formula IV:

wherein R1 is as defined in claim 1 ,

in the presence of methyl triflate and of a heterogeneous acid scavenger

or

with a compound of Formula V

wherein R1 is as defined in claim 1 ,

in the presence a heterogeneous acid scavenger.