Inhibitors of p38

• US 20040132729A1
• Filed: 08/08/2003
• Published: 07/08/2004
• Est. Priority Date: 05/11/1998
• Status: Active Grant

• Current Assignee: Francesco Salituro, Guy Bemis, John Cochran, Steven Bellon, Vincent Galullo
• Original Assignee: Francesco Salituro, Guy Bemis, John Cochran, Steven Bellon, Vincent Galullo
• Inventors: Galullo, Vincent, Bellon, Steven, Bemis, Guy, Cochran, John, Salituro, Francesco
• Granted Patent: US 7,115,637 B2
• Time in Patent Office: Days
• US Class Current: 514/241
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• 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 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• 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 27/02 : Ophthalmic agents
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• 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 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• 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: C04B 35/01 : based on oxide ceramics
• CPC Class Codes: C07D 213/56 : Amides
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 217/22 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring

Abstract

The present invention relates to inhibitors of p38, a mammalian protein kinase involved cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.

Claims

1. A compound of the formula:

2. The compound according to claim 1, wherein Q₁ is selected from phenyl or pyridyl containing 1 to 3 substituents independently selected from chloro, fluoro, bromo, —

CH₃, —

OCH₃, —

OH, —

CF₃, —

OCF₃, —

O(CH₂)₂CH₃, NH₂, 3,4-methylenedioxy, —

N(CH₃)₂, —

NH—

S(O)₂-phenyl, —

NH—

C(O)O—

CH₂-4-pyridine, —

NH—

C(O)CH₂-morpholine, —

NH—

C(O)CH₂—

N(CH₃)₂, —

NH—

C(O)CH₂-piperazine, —

NH—

C(O)CH₂-pyrrolidine, —

NH—

C(O)C(O)-morpholine, —

NH—

C(O)C(O)-piperazine, —

NH—

C(O)C(O)-pyrrolidine, —

O—

C(O)CH₂—

N(CH₃)₂, or —

O—

(CH₂)₂—

N(CH₃)₂ and wherein at least one of said substituents is in the ortho position.

3. The compound according to claim 2, wherein Q₁ contains at least two substituents, both of which are in the ortho position.

4. The compound according to claim 2, wherein Q₁ is selected from:

5. The compound according to claim 4, wherein Q₁ is selected from 2-fluoro-6-trifluoromethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-chloro-4-hydroxyphenyl, 2-chloro-4-aminophenyl, 2,6-dichloro-4-aminophenyl, 2,6-dichloro-3-aminophenyl, 2,6-dimethyl-4-hydroxyphenyl, 2-methoxy-3,5-dichloro-4-pyridyl, 2-chloro-4,5 methylenedioxy phenyl, or 2-chloro-4-(N-2-morpholino-acetamido)phenyl.

6. The compound according to claim 1, wherein Q₂ is selected from phenyl, pyridyl or naphthyl and wherein Q₂ optionally contains up to 3 substituents, each of which is independently selected from chloro, fluoro, bromo, methyl, ethyl, isopropyl, —

OCH₃, —

OH, —

NH₂, —

CF₃, —

OCF₃, —

SCH₃, —

OCH₃, —

C(O)OH, —

C(O)OCH₃, —

CH₂NH₂, —

N(CH₃)₂, —

CH₂-pyrrolidine and —

CH₂OH.

7. The compound according to claim 6, wherein Q₂ is selected from:

8. The compound according to claim 7, wherein Q₂ is selected from phenyl, 2-isopropylphenyl, 3,4-dimethylphenyl, 2-ethylphenyl, 3-fluorophenyl, 2-methylphenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 2-carbomethoxylphenyl, 2-carboxyphenyl, 2-methyl-4-chlorophenyl, 2-bromophenyl, 2-pyridyl, 2-methylenehydroxyphenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, 2-chloro-4-fluorphenyl, 2,4-difluorophenyl, 2-hydroxy-4-fluorphenyl or 2-methylenehydroxy-4-fluorophenyl, 1-naphthyl, 3-chloro-2-methylenehydroxy, 3-chloro-2-methyl, or 4-fluoro-2-methyl.

9. The compound according to claim 1, wherein each Y is C.

10. The compound according to claim 9, wherein each R and U attached to Y is independently selected from hydrogen or methyl.

11. The compound according to claim 1, wherein U, W or both U and W are a 0-4 atom chain terminating in an alcohol, amine, carboxylic acid, ester, amide or heterocycle.

12. The compound according to claim 11, wherein U, W or both U and W are selected from:

13. The compound according to claim 12, wherein U, W, or both U and W are selected from:

14. The compound according to claim 1, wherein the compound is selected from any one of the compounds depicted in Tables 1 to 6.

15. The compound according to claim 1, wherein the compound is

16. The compound according to claim 1, wherein the compound is

17. The compound according to claim 1, wherein the compound is

18. The compound according to claim 1, wherein the compound is

19. The compound according to claim 1, wherein the compound is

20. The compound according to claim 1, wherein the compound is

21. The compound according to claim 1, wherein the compound is

22. The compound according to claim 1, wherein the compound is

23. The compound according to claim 1, wherein the compound is

24. The compound according to claim 1, wherein said compound is selected from any one of

25. A pharmaceutical composition comprising an amount of a compound according to any one of claims 1 to 24 effective to inhibit p38, and a pharmaceutically acceptable carrier.

26. A method of treating or preventing inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation or conditions associated with prostaglandin endoperoxidase synthase-2 in a patient, said method comprising administering to said patient a composition according to claim 25.

27. The method according to claim 26, wherein said method is used to treat or prevent an inflammatory disease selected from acute pancreatitis, chronic pancreatitis, asthma, allergies, or adult respiratory distress syndrome.

28. The method according to claim 26, wherein said method is used to treat or prevent an autoimmune disease selected from glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves'"'"' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn'"'"'s disease, psoriasis, or graft vs. host disease.

29. The method according to claim 26, wherein said method is used to treat or prevent a destructive bone disorders selected from osteoarthritis, osteoporosis or multiple myeloma-related bone disorder.

30. The method according to claim 26, wherein said method is used to treat or prevent a proliferative disease selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi'"'"'s sarcoma, or multiple myeloma.

31. The method according to claim 26, wherein said method is used to treat or prevent an infectious disease selected from sepsis, septic shock, or Shigellosis.

32. The method according to claim 26, wherein said method is used to treat or prevent a viral disease selected from acute hepatitis infection, HIV infection or CMV retinitis.

33. The method according to claim 26, wherein said method is used to treat or prevent a neurodegenerative disease selected from Alzheimer'"'"'s disease, Parkinson'"'"'s disease, cerebral ischemia or neurodegenerative disease caused by traumatic injury.

34. The method according to claim 26, wherein said method is used to treat or prevent ischemia/reperfusion in stroke or myocardial ischemia, renal ischemia, heart attacks, organ hypoxia or thrombin-induced platelet aggregation.

35. The method according to claim 26, wherein said method is used to treat or prevent a condition associated with prostaglandin endoperoxide synthase-2 selected from edema, fever, analgesia or pain.

36. The method according to claim 35, wherein said pain is selected from neuromuscular pain, headache, cancer pain, dental pain or arthritis pain.

37. The method according to claim 26, wherein said method is used to treat or prevent an angiogenic disorder selected from solid tumors, ocular neovasculization, or infantile haemangiomas.