Methods and compositions utilizing quinazolinones

• US 6,630,479 B1
• Filed: 11/28/2000
• Issued: 10/07/2003
• Est. Priority Date: 10/27/1999
• Status: Expired due to Term

• Current Assignee: Cytokinetics, Inc.
• Original Assignee: Cytokinetics, Inc.
• Inventors: Finer, Jeffrey T., Feng, Bainian, Chabala, John C., Smith, Whitney W., Bergnes, Gustave
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US09/724,713
• Time in Patent Office: 1,043 Days
• Field of Search: 514/266.2, 514/266.3, 514/266.31, 544/284, 544/287, 544/290
• US Class Current: 514/266.3
• 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. A composition comprising, as an active ingredient for inhibition of KSP activity, a therapeutically effective dose of a compound, or a pharmaceutically acceptable salt thereof, having the following structure

and a physiologically acceptable carrier or diluent wherein:

R₁ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

R₂ and R₂′

are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

or R₂ and R₂′

taken together form a 3- to 7-membered ring;

R_3′

is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R₁₅—

NH—

;

R₄ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R₁₆-alkylene-;

R₅, R₆, R₇ and R₈ are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;

R₁₅ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

R₁₆ is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl.

2. The composition according to claim 1 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;

phenyl;

naphthyl;

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

biphenylyl, benzyl and heteroaryl; and

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

phenyl substituted with hydroxy, lower alkoxy or lower alkyl;

benzyl;

heteroarylmethyl;

heteroarylethyl;

heteroarylpropyl and R₁₆-alkylene, wherein

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

3. The composition according to claim 2, 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 and naphthyl;

R₄ is R₁₆-alkylene-, hydroxy(lower alkyl) or carboxy (lower alkyl);

R₇ is hydrogen, fluoro, chloro or methyl;

R₅, R₆ and R₈ are hydrogen;

R₁₆ is chosen from di(lower alkyl)amino, (lower alkyl)amino, amino, pyrrolidinyl and piperidinyl.

4. The composition according to claim 1 wherein the stereogenic center to which R₂ and R_2′

are attached is of the R configuration.

16. A composition according to claim 1, wherein said composition further comprises a taxane.

17. A composition according to claim 1, wherein said composition further comprises a vinca alkaloid.

18. A composition according to claim 1, wherein said composition further comprises a topoisomerase I inhibitor.

5. A method of treating cellular proliferative diseases comprising administering a compound of the formula:

wherein;

R₁ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

R₂ and R₂′

are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

or R₂ and R₂′

taken together form a 3- to 7-membered ring;

R_3′

is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R₁₅—

NH—

;

R₄ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R₁₆-alkylene-;

R₅, R₆, R₇ and R₈ are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;

R₁₅ is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and

R₁₆ is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl.

7. A method according to claim 5 wherein the stereogenic center to which R₂ and R_2′

are attached is of the R configuration.

8. A method according to claim 5 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;

phenyl;

naphthyl;

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

biphenylyl, benzyl and heteroaryl; and

R₄ is chosen from lower alkyl;

substituted lower alkyl;

cyclohexyl;

phenyl substituted with hydroxy, lower alkoxy or lower alkyl;

benzyl;

heteroarylmethyl;

heteroarylethyl;

heteroarylpropyl; and

R₁₆-alkylene, wherein

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

9. A method according to claim 5 wherein

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

R₂ is hydrogen or lower alkyl;

R₂′

is hydrogen;

R₃ is chosen from substituted phenyl and naphthyl;

R₄ is R₁₆-alkylene-hydroxy lower alkyl or carboxy lower alkyl;

R₆ and R₇ are chosen from hydrogen and halo;

R₅ and R₈ are hydrogen;

R₁₆ is chosen from di(lower alkylamino), (lower alkyl)amino, amino, piperidinyl, azetidinyl pyrrolidinyl and morpholinyl.

10. A method according to claim 5 wherein said disease or disorder is chosen from the group consisting of cancer, hyperplasia, restenosis, cardiac hypertrophy, immune disorders and inflammation.

11. The composition according to claim 5, wherein the stereogenic center to which R₂ and R₂′

are attached is of the R configuration.

13. A method according to claim 5 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;

phenyl;

naphthyl;

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

biphenylyl, benzyl and heteroaryl; and

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

phenyl substituted with hydroxy, lower alkoxy or lower alkyl;

benzyl;

heteroarylmethyl;

heteroarylethyl;

heteroarylpropyl and R₁₆-alkylene, wherein

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

6. A method of treating a disorder associated with KSP kinesin activity comprising administering a compound of the formula:

wherein;

R₁ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

R₂ and R₂′

are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

or R₂ and R₂′

taken together form a 3- to 7-membered ring;

R_3′

is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl and R₁₅—

NH—

;

R₄ is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R₁₆-alkylene-;

R₅, R₆, R₇ and R₈ are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;

R₁₅ is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;

R₁₆ is chosen from alkoxy, amino, alkylamino, dialkylamino, N-heterocyclyl and substituted N-heterocyclyl.

12. A method according to claim 6 wherein the stereogenic center to which R₂ and R₂′

are attached is of the R configuration.

14. A method according to claim 6 wherein

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

R₂ is hydrogen or lower alkyl,

R₂′

is hydrogen;

R₃ is chosen from substituted phenyl and naphthyl;

R₄ is R₁₆-alkylene-hydroxy lower alkyl or carboxy lower alkyl;

R₆ and R₇ are chosen from hydrogen and halo;

R₅ and R₈ are hydrogen;

R₁₆ is chosen from di(lower alkylamino), (lower alkyl)amino, amino, piperidinyl, azetidinyl pyrrolidinyl and morpholinyl.

15. A method according to claim wherein 6 said disease or disorder is chosen from the group consisting of cancer, hyperplasia, restenosis, cardiac hypertrophy, immune disorders and inflammation.