P38 inhibitors and methods of use thereof

• US 7,799,782 B2
• Filed: 02/02/2009
• Issued: 09/21/2010
• Est. Priority Date: 03/03/2003
• Status: Expired due to Term

• Current Assignee: Array Biopharma Incorporated (Pfizer Inc.)
• Original Assignee: Array Biopharma Incorporated (Pfizer Inc.)
• Inventors: Harvey, Darren, Munson, Mark, Gronenberg, Robert D., Rao, Chang, Kim, Youngboo, Rizzi, James P., Rodriguez, Martha, Mareska, David A., Balachari, Devan, Vigers, Guy, Kim, Ganghyeok
• Primary Examiner(s): Anderson; Rebecca L
• Application Number:
  US12/364,300
• Publication Number:
  US 20090136596A1
• Time in Patent Office: 596 Days
• Field of Search: 514/234.5, 514/322
• US Class Current: 514/234.5
• 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 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 261/20 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

This invention relates to inhibitors of p38 and methods of utilizing the inhibitors and pharmaceutical compositions thereof in the treatment and prevention of various disorders mediated by p38.

Claims

1. A method of treating a p38-mediated condition in a human or animal having said p38-mediated condition, wherein said p38-mediated condition is selected from pain, rheumatoid arthritis, osteoarthritis, stroke, endotoxemia, inflammatory bowel disease, tuberculosis, atherosclerosis, cachexia, psoriatic arthritis, gout, gouty arthritis, diabetes, sepsis, toxic shock syndrome, traumatic arthritis, rheumatid spondylitis, septic shock, endotoxic shock, gram negative sepsis, graft vs. host reaction, psoriasis, glomerulonephritis, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, bone resorption, reperfusion injury, allograft rejections, Crohn'"'"'s disease ulcerative colitis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi'"'"'s sarcoma, and multiple myeloma, said method comprising administering to said human or animal, in an amount effective to treat said p38-mediated condition, a compound of the Formula

2. The method of claim 1, wherein said p38-mediated condition is pain.

3. The method of claim 2, wherein said p38-mediated condition is selected from neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.

4. The method of claim 3, wherein said p38-mediated condition is dental pain.

5. The method of claim 1, wherein said p38-mediated condition is selected from rheumatoid arthritis, osteoarthritis, stroke, endotoxemia and/or toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, cachexia, psoriatic arthritis, gout, traumatic arthritis, and diabetes.

6. The method of claim 5, wherein said p38-mediated condition is rheumatoid arthritis.

7. The method of claim 6, wherein said compound is administered in combination with gold, methotrexate, a steroid or pencillinamine.

8. The method of claim 5, wherein said p38-mediated condition is osteoarthritis.

9. The method of claim 8, wherein said compound is administered in combination with a steroid.

10. The method of claim 1, wherein said p38-mediated condition is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, bone resorption, reperfusion injury, graft vs. host reaction, allograft rejections, and Crohn'"'"'s disease, and ulcerative colitis.

11. The method of claim 10, wherein said p38-mediated condition is rheumatoid spondylitis.

12. The method of claim 1, wherein said p38-mediated condition is selected from psoriasis, inflammatory bowel disease, cardiac and renal reperfusion injury, adult respiratory distress syndrome, and glomerulonephritis.

13. The method of claim 1, wherein said compound is administered topically and said p38-mediated condition is pain.

22. The method of claim 1, wherein said p38-mediated condition is selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi'"'"'s sarcoma, and multiple myeloma.

14. A method of treating a p38-mediated condition in a human or animal having said p38-mediated condition, wherein said p38-mediated condition is selected from pain, rheumatoid arthritis, osteoarthritis, stroke, endotoxemia, inflammatory bowel disease, tuberculosis, atherosclerosis, cachexia, psoriatic arthritis, gout, gouty arthritis, diabetes, sepsis, toxic shock syndrome, traumatic arthritis, rheumatid spondylitis, septic shock, endotoxic shock, gram negative sepsis, graft vs. host reaction, psoriasis, glomerulonephritis, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, bone resorption, reperfusion injury, allograft rejections, Crohn'"'"'s disease, ulcerative colitis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi'"'"'s sarcoma, and multiple myeloma, said method comprising administering to said human or animal, in an amount effective to treat said p38-mediated condition, a compound of the Formula

15. The method of claim 14, wherein said p38-mediated condition is pain.

16. The method of claim 15, wherein said p38-mediated condition is selected from neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.

17. The method of claim 16, wherein said p38-mediated condition is dental pain.

18. The method of claim 14, wherein said p38-mediated condition is selected from rheumatoid arthritis, osteoarthritis, stroke, endotoxemia and/or toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, cachexia, psoriatic arthritis, gout, traumatic arthritis and diabetes.

19. The method of claim 18, wherein said p38-mediated condition is rheumatoid arthritis.

20. The method of claim 14, wherein said p38-mediated condition is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, bone resorption, reperfusion injury, graft vs. host reaction, allograft rejections, and Crohn'"'"'s disease, and ulcerative colitis.

21. The method of claim 20, wherein said p38-mediated condition is rheumatoid spondylitis.

23. The method of claim 14, wherein said p38-mediated condition is selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi'"'"'s sarcoma, and multiple myeloma.