Heterocyclic antiviral compounds

• US 20050176703A1
• Filed: 02/10/2005
• Published: 08/11/2005
• Est. Priority Date: 02/10/2004
• Status: Active Grant

• Current Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Original Assignee: Roche Palo Alto LLC (Roche Holding AG)
• Inventors: Gabriel, Stephen Deems, Rotstein, David Mark
• Granted Patent: US 7,332,500 B2
• Time in Patent Office: Days
• US Class Current: 514/230.500
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/4747 spiro-condensed
• CPC Class Codes: A61K 31/537 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 498/10 Spiro-condensed systems

Abstract

This invention relates to piperidine derivatives of formulae Ia and Ib with substituents as defined herein useful in the treatment of a variety of disorders, including those in which the modulation of CCR5 receptors is implicated. More particularly, the present invention relates to 1-oxa-3,8-diaza-spiro[4.5]decan-2-one and 1-oxa-3,9-diaza-spiro[5.5]undecan-2-one compounds and related derivatives, to compositions containing and to uses of such derivatives. Disorders that may be treated or prevented by the present derivatives include HIV and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS), diseases of the immune system and inflammatory diseases.

Claims

1. A compound according to formula Ia or Ib,

2. A compound according to claim 1 having a formula Ia″

or Ib″

,

3. A compound according to claim 1 with formula Ic,

4. A compound according to claim 3 wherein R⁷ is hydrogen or methyl.

5. A compound according to claim 4 wherein

R¹ is COR⁴;

R^2a is C_1-10 alkyl, C_1-10 heteroalkyl or C_1-10 alkyl wherein 2 or 3 nonadjacent carbon atoms in the alkyl chain optionally can be independently replaced with —

O—

, —

S(O)_p—

, —

NH—

or NR⁵;

R⁴ is optionally substituted aryl or optionally substituted heteroaryl; and

,

R¹⁰ is N.

6. A compound according to claim 5 wherein R⁴ is optionally substituted aryl.

7. A compound according to claim 6 wherein R⁴ is optionally substituted phenyl, 1-naphthyl or 2-naphthyl.

8. A compound according to claim 5 wherein R⁴ is optionally substituted heteroaryl.

9. A compound according to claim 8 wherein R⁴ is optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl or optionally substituted pyrrolyl.

10. A compound according to claim 1 with the formula Id wherein

11. A compound according to claim 10 with the formula Id wherein A is (CH₂)₂.

12. A compound according to claim 1 with the formula Ie wherein

13. The compound of claim 1, wherein said compound is selected from:

5-Butyl-9-[1-(4,6-dimethyl-2-trifluoromethyl-pyrimidine-5-carbonyl)-4-methyl-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

5-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)₄-methyl-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

5-Butyl-3-(4,4-difluoro-cyclohexylmethyl)-9-[1-(4,6-dimethyl-2-trifluoromethyl-pyrimidine-5-carbonyl)₄-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

5-Butyl-3-(4,4-difluoro-cyclohexylmethyl)-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)₄-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

5-Butyl-9-{1-[1-(4-fluoro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carbonyl]4-methyl-piperidin-4-yl}-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

5-Butyl-9-{1-[3-(4-methoxy-phenyl)-5-methyl-isoxazole-4-carbonyl]4-methyl-piperidin-4-yl}-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

(S)-5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one

(R)-5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one

5-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)₄-methyl-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

5-Butyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid 5-Butyl-3-cyclohexylmethyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

5-Butyl-3-cyclohexylmethyl-9-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

5-Butyl-9-[1-(4,6-dimethyl-pyrimidine-5-carbonyl)-piperidin-4-yl]-3-(tetrahydro-pyran-4-ylmethyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one;

compound with trifluoro-acetic acid

14. A method for treating or preventing an human immunodeficiency virus (HIV) infection, or treating AIDS or ARC, in a patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1.

15. A method according to claim 14 further comprising co-administering a therapeutically effective amount of one or more compounds selected from the group consisting of HIV nucleoside reverse transcriptase, HIV nonnucleoside reverse transcriptase, HIV protease inhibitor and viral fusion inhibitors and a therapeutically effective amount of a compound of claim 1.

16. A method according to claim 15 wherein said reverse transcriptase inhibitor is selected from the group consisting of zidovudine, lamivudine, didanosine, zalcitabine, stavudine, rescriptor, sustiva and viramune, efavirenz, nevirapine or delavirdine, and/or said nucleoside reverse transcriptase inhibitor is selected from the group consisting of zidovudine, didanosin, zalcitabine, stavudine, lamivudine, abacavir, adefovir and dipivoxil, and/or said protease inhibitor is selected from the group consisting of saquinavir, ritonavir, nelfinavir, indinavir, amprenavir, lopinavir.

17. A method for treating a mammal having a disease state that is alleviated by treating the mammal with a CCR5 receptor antagonist said disease selected from the group consisting of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies and multiple sclerosis which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1.

18. A method of claim 17 further comprising co-administering at least one other immune system modulator.

19. A method of claim 17 where the mammal is a human.

20. A pharmaceutical composition for the comprising a compound according to either claim 1 admixed with at least one pharmaceutical acceptable carrier, diluent or excipient.