IP Library › Granted Patent US 10,273,243
Granted Patent B2
US 10,273,243 · App. 14/775,532 · Granted Apr 30, 2019

4-phenylpiperidines, their preparation and use

Inventors: Konstantin Petrukhin (New Windsor, NY); Christopher Cioffi (Troy, NY); Graham Johnson (Sanbornton, NH); Nicoleta Dobri (New York, NY); Emily Freeman (Voorheesville, NY); Ping Chen (Slingerlands, NY); Michael Conlon (Schenectady, NY); Lei Zhu (Glenmont, NY)
Assignee: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
C07D498/04C07D401/06C07D405/14C07D409/06C07D471/04C07D487/04C07D491/052C07D495/04
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Quick Facts
Patent No.
US 10,273,243
App. No.
14/775,532
Granted
Apr 30, 2019
Kind
B2
Abstract

The present invention provides a compound having the structure: (structurally represented) 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; R 6 is H, OH, or halogen; B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterobicycle is other than chloro substituted indole; and the pyrazole, when substituted, is substituted with other than trifluoromethyl, or a pharmaceutically acceptable salt thereof.

Claims (51)

1. A compound having the structure:

wherein

R 1 , R 2 , R 3 and R 4 are each independently H, halogen, CF 3 or C 1 -C 4 alkyl and R 5 is halogen, CF 3 or C 1 -C 4 alkyl;

R 6 is H, or halogen;

B is a substituted or unsubstituted heterobicycle having the structure:

wherein

n is 1;

Y 1 and Y 4 are each CH 2 ; and

one of Y 2 or Y 3 is CH 2 and the other of Y 2 or Y 3 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 4 alkyl) , SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—(C 1 - C 4 alkyl) , C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—(C 1 -C 4 alkyl)-OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl) , C(O)—N (C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-C(O)OH, C(O)—NH 2 or oxetane, or

B has the structure:

wherein

Y 1 ,Y 2 ,Y 3 and Y 4 are each independently CR 8 or N,

wherein each R 8 is independently H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O(C 1 -C 4 alkyl ), CN, CF 3 ,C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , or NHC(O)—N(CH 3 ) 2 ,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

4. The compound of claim 1 , wherein B has the structure:

wherein

Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 8 or N,

wherein each R 8 is independently H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, O(C 1 -C 4 alkyl), CN, CF 3 , C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , or NHC(O)—N(CH 3 ) 2 .

5. The compound of claim 4 , wherein B has the structure:

6. The compound of claim 5 ,

wherein each R 8 is independently H, Cl, Br, F, OCH 3 , OCH 2 CH 3 , CF 3 , CN, CH 3 , CH 3 CH 3 , C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , SO 2 —NHCH 3 or SO 2 —N(CH 3 ) 2 .

7. The compound of claim 1 , wherein B has the structure:

wherein

n is 1;

Y 1 and Y 4 are each CH 2 ; and

one of Y 2 or Y 3 is CH 2 and the other of Y 2 or Y 3 is O, SO 2 , or N—R 10 ,

wherein

R 10 is H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, (C 1 -C 4 alkyl)-CF 3 , (C 1 -C 4 alkyl)-OCH 3 , (C 1 -C 4 alkyl)-halogen, SO 2 —(C 1 -C 4 alkyl) , SO 2 —(C 1 -C 4 alkyl)-CF 3 , SO 2 —(C 1 -C 4 alkyl)-OCH 3 , SO 2 —(C 1 -C 4 alkyl)-halogen, C(O)—( C 1 -C 4 alkyl), C(O)—(C 1 -C 4 alkyl)-CF 3 , C(O)—( C 1 -C 4 alkyl) -OCH 3 , C(O)—(C 1 -C 4 alkyl)-halogen, C(O)—NH—(C 1 -C 4 alkyl), C(O)—N(C 1 -C 4 alkyl) 2 , (C 1 -C 4 alkyl)-C(O)OH, C(O)—NH 2 or oxetane,

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 , wherein B has the structure:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein R 10 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , t-Bu, CH 2 OCH 3 , CH 2 CF 3 , CH 2 Cl, CH 2 F, CH 2 CH 2 OCH 3 , CH 2 CH 2 CF 3 , CH 2 CH 2 Cl, CH 2 CH 2 F, or

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising the compound of claim 12 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.

Assignments (1)
CONFIRMATORY LICENSE Recorded Sep 26, 2016
From: COLUMBIA UNIV NEW YORK MORNINGSIDE
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 040144/0414 →
Continuity (2)
Provisional Application 61785187 · Mar 14, 2013
Related Publication 20160046648A1 · Feb 18, 2016
Cited By (1)
US 12,440,486