Inhibitors of p38

• US 7,115,637 B2
• Filed: 08/08/2003
• Issued: 10/03/2006
• Est. Priority Date: 05/11/1998
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Galullo, Vincent, Bellon, Steven, Bemis, Guy, Cochran, John, Salituro, Francesco
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US10/638,126
• Publication Number:
  US 20040132729A1
• Time in Patent Office: 1,152 Days
• Field of Search: 546/282.1, 546/288, 546/289, 514/335, 514/345, 514/336, 514/349, 514/350, 514/183, 514/218, 514/231.5, 514/252.13, 514/332
• US Class Current: 514/332
• 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 method of treating inflammatory diseases selected from cerebral ischemia, reperfusion/ischemia in stroke, myocardial ischemia, renal ischemia, rheumatoid arthritis, or Crohn'"'"'s disease in a patient, said method comprising administering to said patient a compound of the formula:

2. The method according to claim 1, wherein said method is used to treat rheumatoid arthritis or Crohn'"'"'s disease.

3. The method according to claim 1, wherein said method is used to treat cerebral ischemia, ischemia/reperfusion in stroke, myocardial ischemia, or renal ischemia.

4. The method 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 amd wherein at least one of said substituents is in the ortho position.

5. The method according to claim 4, wherein Q₁ contains at least two substituents, both of which are in the ortho position.

6. The method according to claim 4, wherein Q₁ is selected from:

7. The method according to claim 6, 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.

8. The method 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, —

C(O)OH, —

C(O)OCH₃, —

CH₂NH₂, —

N(CH₃)₂, —

CH₂-pyrrolidine, —

CH₂OH, —

CH₂—

N(CH_{3l )2}, —

CH₂-piperazine, —

NH—

C(═

NH)—

NH₂, —

CH₂—

NH—

C(═

NH)—

NH₂, and —

CH₂—

NH-imidazoline.

9. The method according to claim 8, wherein Q₂ is selected from:

10. The method according to claim 9, 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-fluorophenyl, 2,4-difluorophenyl, 2-hydroxy-4-fluorophenyl or 2-methylenehydroxy-4-fluorophenyl, 1-naphthyl, 3-chloro-2-methylenehydroxy, 3-chloro-2-methyl, or 4-fluoro-2-methyl.

11. The method according to claim 1, wherein each R and U attached to Y is independently selected from hydrogen or methyl.

12. The method 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.

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

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

15. The method according to claim 1, wherein the compound is selected from any one of the following compounds:

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

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

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

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

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

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

wherein X=H,

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

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

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