1,5-DISUBSTITUTED-3,4-DIHYDRO-1H-PYRIMIDO[4,5-D]PYRIMIDIN-2-ONE COMPOUNDS AND THEIR USE IN TREATING CSBP/P38 KINASE MEDIATED DISEASES

• US 20070238743A1
• Filed: 12/20/2006
• Published: 10/11/2007
• Est. Priority Date: 03/02/2000
• Status: Abandoned Application

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Hall, Ralph, Taggart, John, Adams, Jerry, Boehm, Jeffrey
• Application Number:
  US11/613,517
• Publication Number:
  US 20070238743A1
• Time in Patent Office: Days
• US Class Current: 514/262.100
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• 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: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Novel substituted pyrimido[4,5-d]pyrimidin-2-one compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.

Claims

1. A compound of the formula:

2. The compound according to claim 1 wherein the structure is of Formula (IV), or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein R₃ is an optionally substituted aryl, arylC_1-10alkyl, or a C_3-7cycloalkyl moiety.

4. The compound according to claim 1 wherein R₁ is an optionally substituted aryl moiety.

5. The compound according to claim 3 wherein the moiety is optional substituted one or more times, independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

6. The compound according to claim 1 wherein X is OR₂.

7. The compound according to claim 1 wherein X is S(O)_mR₂.

8. The compound according to claim 1 wherein X is (CH₂)_nNR₄R₁₄.

9. The compound according to claim 1 wherein X is (CH₂)_nNR₂.

10. The compound according to claim 1 wherein X is R₂.

14. The compound according to claim 1 wherein R₂ is an optionally substituted alkyl, heteroaryl, or heterocyclic or heterocyclic alkyl.

15. The compound according to claim 14 wherein R₂ is an optionally substituted imidazole, tetrazole, pyrrolidine, piperidine, piperazine, or morpholine ring.

16. The compound according to claim 15 wherein the ring is substituted one or more times, independently, by halogen, C_1-10alkyl, halosubstituted C_1-10alkyl, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nOR₆, or (CR₁₀R₂₀)_nC(Z)OR₆.

18. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier or diluent.

19. A method of treating, including prophylaxis, of a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound of according to claim 1.

20. The method according to claim 19 wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter'"'"'s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerularnephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.

11. to 13. (canceled)

17. (canceled)

21. to 68. (canceled)

69. A process for producing a compound of Formula (IV)

70. The process according to claim 69 wherein the compound of Formula (A) is produced by reacting a compound of the formula:

71. The process according to claim 69 wherein X₁ is methyl.

72. The process according to claim 70 wherein X₁ is methyl.

73. The process according to claim 69 wherein R₁ and R₃ are each an optionally substituted phenyl ring.

74. The process according to claim 70 wherein R₁ and R₃ are each an optionally substituted phenyl ring.

75. The process according to claim 73 wherein R₃ is an unsubstituted or substituted one or more times, independently with halogen.

76. The process according to claim 74 wherein R₃ is an unsubstituted or substituted one or more times, independently with halogen.

77. The process according to claim 70 wherein the reducing agent is a hydride reducing agent.

78. The process according to claim 77 wherein the hydride is lithium aluminium hydride or NaB₂H₇.

79. The process according to claim 77 wherein the hydride is in an ethereal solvent, THF, Et₂O, glyme or dioxane.

80. The process according to claim 78 wherein the hydride is in an ethereal solvent, THF, Et₂O, glyme or dioxane.

81. The process according to claim 70 wherein the reducing agent is samarium di-iodide in H₃PO₄, or a Raney Ni catalyzed hydrogenation, or sodium borohydride-cobaltous chloride.