Substituted 4-phenylpiperidines, their preparation and use
The present invention provides a compound having the structure: wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 or C 1 -C 4 alkyl, wherein two or more of R 1 , R 2 , R 3 , R 4 , or R 5 are other than H; R 6 is H, OH, or halogen; and B is a substituted or unsubstituted heterobicycle, wherein when R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is H, R 2 is CF 3 , R 3 is H, R 4 is CF 3 , and R 5 is H, or R 1 is Cl, R 2 is H, R 3 is H, R 4 is F, and R 5 is H, or R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or R 1 is Cl, R 2 is F, R 3 is H, R 4 is H, and R 5 is H, then B is other than or a pharmaceutically acceptable salt thereof.
1. A method for the preparation of Compound 81:
by conversion from Compound 33:
2. The method of claim 1 comprising treatment of Compound 33:
with an acid, followed by coupling with an acid chloride.
3. The method of claim 2 , wherein the acid is trifluoroacetic acid.
4. The method of claim 1 comprising treatment of Compound 34:
with an acid chloride.
5. The method of claim 2 , wherein the method comprises treatment with trifluoroacetic acid in methylene chloride followed by coupling with acetyl chloride.
6. The method of claim 1 , wherein compound 81 is purified by chromatography.
7. The method of claim 1 , wherein the method further comprises forming a pharmaceutical composition of compound 81, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
8. The method of claim 1 , wherein Compound 33 is prepared by reacting 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine:
with 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid:
under coupling conditions.
9. The method of claim 8 , wherein 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine:
is prepared from Compound 8:
and an acid.
10. The method of claim 9 , wherein the acid is trifluoroacetic acid.
11. The method of claim 9 , wherein 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine:
is prepared from Compound 6:
12. A method for the preparation of Compound 65:
by conversion from 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate:
13. The method of claim 11 comprising treatment of Compound 5:
with lithium 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate:
under coupling conditions.
14. The method of claim 12 comprising treatment of 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylic acid:
with lithium hydroxide.
15. The method of claim 11 comprising treatment of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl) (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone:
with zinc cyanide and a palladium catalyst.
16. The method of claim 11 , wherein Compound 65 is purified by chromatography.
17. The method of claim 11 , wherein the method further comprises forming a pharmaceutical composition of Compound 65, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
18. The method of claim 11 , wherein Compound 5:
is prepared from Compound 4:
and an acid.
19. The method of claim 18 , wherein the acid is trifluoroacetic acid.
20. The method of claim 18 , wherein Compound 5:
is prepared from Compound 1: