Triaza-spiropiperidine derivatives

• US 20050107373A1
• Filed: 10/18/2004
• Published: 05/19/2005
• Est. Priority Date: 10/23/2003
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Pinard, Emmanuel, Stalder, Henri, Ceccarelli, Simona Maria
• Granted Patent: US 7,189,850 B2
• Time in Patent Office: Days
• US Class Current: 514/227.800
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/10 Spiro-condensed systems

Abstract

The invention relates to compounds of the general formula wherein

• A-A is —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—O— or —O—CH₂—; and
• X, R¹, R², R³, R⁴, R⁵, R⁶, n, and p are as defined herein, or a pharmaceutically acceptable salt thereof for the treatment of psychoses, pain, neurodegenerative dysfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer'"'"'s disease.

Claims

1. A compound of formula

2. A compound of formula I in accordance with claim 1, wherein A-A is —

CH₂—

CH₂—

.

3. A compound of formula I′

in accordance with claim 2,

4. A compound of formula I′

in accordance with claim 3, selected from (rac,cis)-1-phenyl-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (1R,2R)-1-phenyl-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(4-chloro-phenyl)-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-phenethyl-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(3,4-dichloro-phenyl)-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-8-(2-phenyl-cyclohexyl)-1-(4-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,trans)-1-phenyl-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,trans)-8-(2-hydroxy-2-phenyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(4-methoxy-phenyl)-8-(2-phenyl-cyclohexyl) -1,3,8-triaza-spiro[4.5]decan-4-one and (rac,cis)-8-(2-hydroxy-2-phenyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.

5. A compound of formula I′

as described in claim 2, wherein X is hydrogen or hydroxy and R² is lower alkyl or —

(CH₂)_n-cycloalkyl.

6. A compound of formula I′

in accordance with claim 5, selected from (rac,cis)-1-isobutyl-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-pentyl-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(3-methyl-butyl)-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-cyclohexylmethyl-8-(2-phenyl-cydohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(2-cyclohexyl-ethyl)-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-hexyl-8-(2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one and (rac,cis)-1-cyclohexylmethyl-8-(2-hydroxy-2-phenyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one.

7. A compound of formula I″

in accordance with claim 1

8. A compound of formula I″

in accordance with claim 7, selected from (rac,cis)-1-phenyl-8-(2-p-tolyl-cydohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-8-[2-(4-fluoro-phenyl)-cyclohexyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-8-[2-(4-chloro-phenyl)-cyclohexyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-8-[2-(3,4-dichloro-phenyl)-cyclohexyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-8-[2-(4-chloro-phenyl)-cyclohexyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(4-fluoro-phenyl)-8-(2-p-tolyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(4-fluoro-phenyl)-8-[2-(4-fluoro-phenyl)-cyclohexyl]-1,3,8-triaza-spiro[4.5]decan-4-one, and (rac,cis)-8-[2-(4-fluoro-phenyl)-2-hydroxy-cyclohexyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.

9. A compound of formula I″

in accordance with claim 7, selected from (rac,cis)-8-(2-hydroxy-2-o-tolyl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-8-[2-(4-chloro-phenyl)-2-hydroxy-cyclohexyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(4-fluoro-phenyl)-8-[2-(4-fluoro-phenyl)-2-hydroxy-cyclohexyl]-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-8-[2-(4-chloro-phenyl)-2-hydroxy-cyclohexyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(4-chloro-phenyl)-8-[2-(4-fluoro-phenyl)-2-hydroxy-cyclohexyl]-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-1-(4-chloro-phenyl)-8-[2-(4-chloro-phenyl) -2-hydroxy-cyclohexyl]-1,3,8-triaza-spiro[4.5]decan-4-one, (rac,cis)-8-[2-(4-fluoro-phenyl)-2-hydroxy-cyclohexyl]-1-p-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and (rac,cis)-8-[2-(4-chloro-phenyl)-2-hydroxy-cyclohexyl]-1-(4-methoxy-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one.

10. A compound of formula I in accordance with claim 1, wherein X is hydrogen or hydroxy, and R¹ is pyridin-4-yl and R².

11. A compound of formula I in accordance with claim 10, wherein the compound is (rac,cis) 8-(2-hydroxy-2-pyridin-4-yl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.

12. A compound of formula I in accordance with claim 1, wherein A-A is —

O—

CH₂—

.

13. A compound of formula I in accordance with claim 12, wherein the compound is (rac,cis)-8-(3-hydroxy-3-phenyl-tetrahydro-pyran-4-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.

14. A compound of formula I in accordance with claim 1, wherein A-A is —

CH₂—

O—

.

15. A compound of formula I in accordance with claim 14, selected from (rac,cis)-8-(4-hydroxy-4-phenyl-tetrahydro-pyran-3-yl)-1-(3,3,3-trifluoro-propyl)-1,3,8-triaza-spiro[4.5]decan-4-one and (rac,cis)-8-(4-hydroxy-4-phenyl-tetrahydro-pyran-3-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one.

16. A compound of formula I in accordance with claim 1, wherein A-A is —

(CH₂)₃—

.

17. A process for preparation of a compound of formula I

18. A process for preparation of a compound of formula I

19. A process for preparation of a compound of formula I

20. A process for preparation of a compound of formula I

21. A process for the preparation of a compound of formula I

22. A process for the preparation of a compound of formula I

23. A process for the preparation of a compound of formula I

24. A process for the preparation of a compound of formula I

25. A process for the preparation of a compound of formula I

26. A composition comprising one or more compound of formula I

27. A method of treating Alzheimer'"'"'s disease in a patient comprising administering a therapeutically effective amount of a compound of formula I

28. A method of treating senile dementia in a patient comprising administering a therapeutically acceptable amount of a compound of formula I

29. A method of treating schizophrenia in a patient comprising administering a therapeutically effective amount of a compound of formula I