Methods and compositions utilizing quinazolinones

• US 20040254203A1
• Filed: 07/20/2004
• Published: 12/16/2004
• Est. Priority Date: 10/27/1999
• Status: Active Grant

• Current Assignee: Cytokinetics, Inc.
• Original Assignee: Cytokinetics, Inc.
• Inventors: Finer, Jeffrey T., Feng, Bainian, Chabala, John C., Smith, Whitney W., Bergnes, Gustave
• Granted Patent: US 7,294,634 B2
• Time in Patent Office: Days
• US Class Current: 514/266.2
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 239/90 with acyclic radicals attached in position 2 or 3
• CPC Class Codes: C07D 239/91 with aryl or aralkyl radicals attached in position 2 or 3

Abstract

Quinazolinones of formulae 1a, 1b, 1c and 1d are disclosed. They are useful for treating cellular proliferative diseases and disorders associated with KSP kinesin activity.

Claims

1-59. -59 (cancelled)

60. A composition comprising a taxane and a compound having the structure:

63. A composition according to claim 60, 61, or 62 wherein:

R₁ is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl;

R₂ is chosen from hydrogen, lower alkyl and substituted lower alkyl and R₂′

is hydrogen;

R_3″

is chosen from C₁-C₁₃ alkyl;

substituted lower alkyl;

phenyl;

naphthyl;

phenyl substituted with halo, lower alkyl, lower alkoxy, nitro, methylenedioxy, or trifluoromethyl;

biphenylyl, benzyl and heterocyclyl; and

R₄ is chosen from lower alkyl, substituted lower alkyl, cyclohexyl;

phenyl substituted with hydroxy, lower alkoxy or lower alkyl;

benzyl;

substituted benzyl, heterocyclyl, heteroarylmethyl;

heteroarylethyl;

heteroarylpropyl and R₁₆-alkylene, wherein

R₁₆ is di(lower alkyl)amino, (lower alkyl)amino, amino, lower alkoxy, or N-heterocyclyl.

64. A composition according to claim 63 wherein:

R₁ is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;

R₂ is hydrogen or lower alkyl;

R₂′

is hydrogen;

R_3″

is chosen from substituted phenyl, heterocyclyl and naphthyl;

R₄ is chosen from subtituted benzyl, heterocyclyl substituted lower alkyl and R₁₆-alkylene-;

R₆ and R₇ are chosen from hydrogen and halo;

R₅ and R₈ are hydrogen; and

R₁₆ is chosen from di(lower alkylamino), (lower alkyl)amino, amino, pyrrolidino, piperidino, imidazolyl and morpholino.

65. A composition according to claim 64 wherein:

R₁, is benzyl;

R₂ is ethyl;

R₂′

is hydrogen;

R_3″

is chosen from halophenyl, polyhalophenyl, tolyl, dimethylphenyl, methoxyphenyl, dimethoxyphenyl, cyanophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, bis(trifluoromethyl)phenyl, carboxyphenyl, t-butylphenyl, methoxycarbonylphenyl, piperidinyl and naphthyl;

R₄ is chosen from substituted benzyl, piperidinyl, hydroxy(lower alkyl) and R₁₆-alkylene-;

R₆ and R₇ are chosen from hydrogen and halo;

R₅ and R₈ are hydrogen; and

R₁₆ is chosen from dimethylamino, amino, pyrrolidinyl and piperidinyl.

66. A composition according to claim 60, 61, or 62 further comprising a physiologically acceptable carrier.

61. A composition comprising a vinca alkaloid and a compound having the structure:

62. A composition comprising a topoisomerase I inhibitor and a compound having the structure: