Piperazinyl-and piperidinyl-cyclohexanols

• US 5,387,593 A
• Filed: 02/17/1994
• Issued: 02/07/1995
• Est. Priority Date: 12/13/1991
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Briston-Myers Squibb
• Inventors: Mattson, Ronald J., Catt, John D.
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US08/198,165
• Time in Patent Office: 355 Days
• Field of Search: 546/194, 546/197, 546/208, 546/213, 546/214, 546/234, 546/236, 546/240, 546/232, 514/317, 514/318, 514/321, 514/326, 514/331
• US Class Current: 514/326
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 45/59 in five-membered rings from ozonides C07C45/40
• CPC Class Codes: C07C 49/747 containing six-membered aromatic rings
• CPC Class Codes: C07D 211/14 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/18 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 295/096 with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 317/54 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 317/58 Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 405/08 linked by a carbon chain containing alicyclic rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

Novel piperazinyl- and piperidinyl-cyclohexanols of the following formula are useful as anxiolytic agents and have other psychotropic properties ##STR1##

Claims

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

##STR87## wherein R₁ and R₂ are independently selected from H, halogen, CF₃, or C_1-4 alkoxy groups except that R₁ and R₂ cannot both be H simultaneously, or R₁ and R₂, when on adjacent carbon atoms, can be taken together to form a ##STR88## bridge with n being an integer from 1 to 3;

R₃ is H or C_1-4 alkyl;

R₄ and R₅ are each independently selected from H, C_1-4 alkyl or phenyl;

Y is CH; and

Ar is an unsubstituted phenyl ring;

a substituted phenyl ring of structure II;

##STR89## wherein Xp and Xq may be halogen, nitro, amino, carboxamido, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkyl, C_1-4 alkylthio or Xp and Xq can be taken together to form a ##STR90## (n=1-3);

or a heteroaryl group selected from 3-pyridinyl, 4-pyridinyl, 2-thienyl, 2-furanyl, and 1-methyl-2-pyrrolyl moieties.

2. The compound of claim 1 wherein R₁ and R₂ taken together form the bridge ##STR91## (n=1-3).

3. The compound of claim 2 wherein each of R₃, R₄ and R₅ is H.

4. The compound of claim 1, Z-1-(1,3-benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol.

5. The compound of claim 1, Z-1-(4-fluorophenyl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]-cyclohexanol.

6. The compound of claim 1, Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piperidine.

7. The compound of claim 1, Z-1-(4-methoxyphenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol.

8. The compound of claim 1 selected from the group consisting of:

Z-1-1-(1,3-benzodioxol-5-yl)-4-[4(phenylmethyl )-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5-difluorophenyl)methyl]-1piperidinyl]cyclohexanol; and

Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piperidine.

9. The compound of claim 1 selected from the group consisting of:

Z-1-(1,4-benzodioxan-6-yl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piperidine;

Z-1-[4-(1,4-benzodioxan-6-yl)-4-methoxy-1-cyclohexyl]-4-[3-(methoxyphenyl)methyl]piperidine fumarate; and

Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl-4-[(2,5-difluorophenyl)methyl]piperidine fumarate.

11. The compound according to claim 1 selected from the group consisting of:

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-[4-(1,3-benzodioxol-5-yl)-4-[4-(methoxy-1-cyclohexyl]-4-(3-methoxyphenyl)methyl]piperidine; and

Z-1-(4-fluorophenyl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol.

12. A pharmaceutical composition comprising an effective anxiolytic amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

13. The composition of claim 12 wherein the compound is Z-1-(1,3-benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol.

14. The composition of claim 12 the compound is selected from the group consisting of:

Z-1 -(1,3-benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piperidine;

Z-1-(4-fluorophenyl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol; and

Z-1-(4-fluorophenyl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol.

15. A method of treating anxiety comprising administering to a patient in need therof an effective amount of a compound of claim 1.

16. The method of claim 15 herein the compound is selected from the group consisting of:

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol; and

Z-1-(4-methoxyphenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol.

17. The method of claim 15 wherein the compound is

Z-1-(4-fluorophenyl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]-cyclohexanol.

18. The method of claim 15 wherein the compound is Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piperidine.

19. The method of claim 15 wherein the compound is selected from the group consisting of:

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]-piperidine; and

Z-1-(4-fluorophenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol.

20. The method of claim 19 wherein the compound is selected from the group consisting of:

Z-1-(1,4-benzodioxan-6-yl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piperidine;

Z-1-]4-(1,4-benzodioxan-6-yl)-4-methoxy-1-cyclohexyl]-4-[3-(methoxyphenyl)methyl]piperidine fumarate; and

Z-1-]4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(2,5-difluorophenyl)methyl]piperidine fumarate.

22. A method for the prophylactic treatment of migraines comprising administering to a patient in need thereof an effective amount of a compound of claim 1.

23. The method of claim 22 wherein the compound is selected from the group consisting of:

Z-1-(1,3-benzodioxol-5-yl)-4-[(phenylmethyl)-1-piperidinyl]cyclohexanol; and

Z-1-(4-methoxyphenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol.

24. The method of claim 22 wherein the compound is selected from the group consisting of:

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol; and

Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piperidine.

10. The compound of claim I selected from the group consisting of:

Z-1-(4-fluorophenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol; and

Z-1-(4-fluorophenyl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol.

21. The method of claim wherein the compound is selected from the group consisting of:

Z-1-(4-fluorophenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(4-fluorophenyl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol; and

Z-1-(4-fluorophenyl)-4-[4-[(2,5-difluorophenyl)methyl]-1-piperidinyl]cyclohexanol.