Pyrimidinone derivatives and their use in the treatment of atherosclerosis

• US 7,169,924 B2
• Filed: 10/05/2001
• Issued: 01/30/2007
• Est. Priority Date: 10/10/2000
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham PLC
• Original Assignee: Smithkline Beecham PLC
• Inventors: Smith, Stephen Allan, Hickey, Deirdre Mary Bernadette, Pinto, Ivan Leo, Elliott, Richard Leonard, Leach, Colin Andrew, Ife, Robert John
• Primary Examiner(s): McKenzie; Thomas C.
• Application Number:
  US10/398,977
• Publication Number:
  US 20040058941A1
• Time in Patent Office: 1,943 Days
• Field of Search: 514/260.1, 514/262.1, 514/264.1, 514/266.3, 514/269, 514/258.1, 544/262, 544/278, 544/279, 544/287, 544/319, 544/253
• US Class Current: 544/253
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 239/36 as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 239/70 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 239/91 with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

Compound of formula (I):

are disclosed in which:

• • R¹ is an aryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C_(1-6)alkyl, C_(1-6)alkoxy, C_(1-6)alkylthio, hydroxy, halogen, CN, and mono to perfluoro-C_(1-4)alkyl;
  • R² is halogen, C_(1-3)alkyl, C_(1-3)alkoxy, hydroxyC_(1-3)alkyl, C_(1-3)alkylthio, C_(1-3)alkylsulphinyl, aminoC_(1-3)alkyl, mono- or di-C_(1-3)alkylaminoC_(1-3)alkyl, C_(1-3)alkylcarbonylaminoC_(1-3)alkyl, C_(1-3)alkoxyC_(1-3)alkylcarbonylaminoC_(1-3)alkyl, C_(1-3)alkylsulphonylaminoC_(1-3)alkyl, C_(1-3)alkylcarboxy, C_(1-3)alkylcarboxyC_(1-3)alkyl, and
  • R³ is hydrogen, halogen, C_(1-3)alkyl, or hydroxyC_(1-3)alkcyl; or
  • R² and R³ together with the pyrimidone ring carbon atoms to which they are attached form a fused 5-or 6-membered carbocyclic ring; or
  • R² and R³ together with the pyrimidone ring carbon atoms to which they are attached form a fused benzo or heteroaryl ring ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from halogen, C_(1-4)alkyl, cyano, C_(1-6)alkoxy, C_(1-6)alkylthio or mono to perfluoro-C_(1-4)alkyl;
  • R⁴ is hydrogen, C_(1-6)alkyl which may be unsubstituted or substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁹R¹⁰, NR⁷COR⁸, mono- or di-(hydroxyC_(1-6)alkyl) amino and N-hydroxyC_(1-6)alkyl-N—C_(1-6)allkylamino; or
  • R⁴ is Het-C_(0-4)alkyl in which Het is a 5- to 7- membered heterocyclyl ring comprising N and optionally O or S, and in which N may be substituted by COR⁷, COOR⁷, CONR⁹R¹⁰, or C_(1-6)alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰ or NR⁹R¹⁰, for instance, piperidinyl-4-yl, pyrrolidin-3-yl;
  • R⁵ is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selectd from C_(1-6)alkyl, C_(1-6)alkoxy, C_(1-6)alkylthio, arylC_(1-6)alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, NR⁷COR⁸, CONR⁹R¹⁰, SO₂NR⁹R¹⁰, NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C_(1-4)alkyl and mono to perfluoro-C_(1-4)alkoxy;
  • R⁶ is an aryl or a heteroaryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C_(1-18)alkyl, C_(1-18)alkoxy, C_(1-6)alkylthio, C_(1-6)alkylsulfonyl, arylC_(1-6)alkoxy, hydroxy, halogen, CN, COR⁷, carboxy, COOR⁷, CONR⁹R¹⁰, NR⁷COR⁸, SO₂NR⁹R¹⁰, NR⁷SO₂R⁸, NR⁹R¹⁰, mono to perfluoro-C_(1-4)alkyl and mono to perfluoro-C_(1-4)alkoxy, or C_(5-10)alkyl; These compound are useful for treating diseases associated with abnormal activity of the phospholipase A₂ enzyme, for example athereosclosis.

Claims

1. A compound which is N-(2-diethylaminoethyl)-2-[2-(2-(2,3-difluorophenyl)ethyl)-4-oxo-4,5,6,7-tetrahydro-cyclopentapyrimidin-1-yl]-N-(4′

-trifluoromethyl-biphenyl-4-ylmethyl)acetamide

2. The compound of claim 1 in the form of its bitartrate salt.

3. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thererof, and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition according to claim 3 suitable for oral administration.

5. A pharmaceutical composition according to claim 4 which further comprises a therapeutically effective amount of a cholesterol lowering agent.

6. A pharmaceutical composition according to claim 5 wherein said cholesterol lowering agent is a statin.

7. A method of treating atherosclerosis comprising administrating a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof, alone or in combination with a pharmaceutically acceptable carrier.

8. The method of claim 7 wherein the compound of claim 1 or a pharmaceutically acceptable salt thereof is administered with a cholesterol lowering agent.

9. The method of claim 8 wherein the cholesterol lowering agent is a statin.

10. A process for preparing a compound of claim 1 comprising:

reacting a compound of formula (II);