Heterocyclic antiviral compounds

• US 7,332,500 B2
• Filed: 02/10/2005
• Issued: 02/19/2008
• Est. Priority Date: 02/10/2004
• Status: Expired due to Fees

• 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
• Primary Examiner(s): Wilson; James O.
• Assistant Examiner(s): LEESER, ERICH A
• Application Number:
  US11/055,642
• Publication Number:
  US 20050176703A1
• Time in Patent Office: 1,104 Days
• Field of Search: None
• US Class Current: 514/277
• 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 Ie wherein

11. 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;

or,

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.

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