Concomitant drugs

• US 20040097555A1
• Filed: 06/25/2003
• Published: 05/20/2004
• Est. Priority Date: 12/26/2000
• Status: Abandoned Application

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Naruo, Kenichi, Ohkawa, Shinegori, Miwatashi, Seiji
• Application Number:
  US10/451,839
• Publication Number:
  US 20040097555A1
• Time in Patent Office: Days
• US Class Current: 514/342
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to a pharmaceutical agent containing one or more kinds of a p38 MAP kinase inhibitor and/or a TNF-α production inhibitor and one or more kinds of drugs selected from the group consisting of (1) a non-steroidal antiinflammatory drug, (2) a disease-modifying anti-rheumatic drug, (3) an anti-cytokine drug, (4) an immunomodulator, (5) a steroid and (6) a c-Jun N-terminal kinase inhibitor in combination. This combination agent is useful as a prophylactic or therapeutic agent of the diseases such as rheumatism, arthritis and the like, and other diseases.

Claims

1. A pharmaceutical agent comprising one or more kinds of a p38 MAP kinase inhibitor and/or a TNF-α

production inhibitor and one or more kinds of drugs selected from the group consisting of (1) a non-steroidal antiinflammatory drug, (2) a disease-modifying anti-rheumatic drug, (3) an-anti-cytokine drug, (4) an immunomodulator, (5) a steroid and (6) a c-Jun N-terminal kinase inhibitor in combination.

2. The pharmaceutical agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-α

production inhibitor are/is a 1,3-thiazole compound substituted at the 5-position by a pyridyl group optionally having substituents, or a salt thereof or a prodrug thereof.

3. The pharmaceutical agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-α

production inhibitor are/is a compound represented by the formula

4. The pharmaceutical agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-α

production inhibitor are/is an optionally N-oxidized compound represented by the formula;

5. The pharmaceutical agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-α

production inhibitor are/is N-[5-(2-benzoylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3,5-dimethylphenyl)-1,3-thiazol-2-yl]acetamide, N-[4-[4-(4-methoxyphenyl)-2-methyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-butyl-4-(3-methylphenyl)-1,3thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-(4-methoxyphenyl)propionamide, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-4-phenylbutyramide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-benzyl-N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-benzyl-N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-[4-[4-(3-methylphenyl)2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]phenylacetamide, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-3-phenylpropionamide, N-benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(3-phenylpropyl)amine, N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine, N-(4-fluorobenzyl)-N-[4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine, (S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide, (R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]nicotinamide, (S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, (R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, (S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, (R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, (S)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, (R)-N-[4-(3-methylphenyl)-5-(2-(1-phenylethylamino)-4-pyridyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, N-[5-(2-benzylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]nicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methylnicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-chloronicotinamide, N-[5-(2-benzoylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]-2-methoxynicotinamide, (S)-N-(1-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[2-butyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylthiophenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (S)-N-(1-phenylethyl)-4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, (R)-N-(1-phenylethyl)-4-[2-(4-fluorophenyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine, or a salt thereof.

6. The pharmaceutical agent of claim 1, wherein the p38 MAP kinase inhibitor and/or the TNF-α

production inhibitor are/is a compound represented by the formula

7. The pharmaceutical agent of claim 1, which is a prophylactic or therapeutic agent of asthma, chronic obstructive pulmonary disease (COPD), allergic disease, inflammation, Addison'"'"'s disease, autoimmune hemolytic anemia, systemic lupus erythematosus, Crohn'"'"'s disease, psoriasis, rheumatism, cerebral hemorrhage, cerebral infarction, head trauma, spinal cord injury, brain edema, multiple sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, diabetes, arthritis, osteoporosis, toxemia, Crohn'"'"'s disease, ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, AIDS encephalopathy, meningitis, angina pectoris, cardiac infarction, congestive heart failure, chronic cardiac deficiency, acute myocardial infarction, prognosis of cardiac infarction, hypertension, acute cardiac deficiency, hepatitis, kidney failure, nephritis, malignant tumor, immunological rejection associated with transplantation, dialysis hypotension or disseminated intravascular coagulation.

8. The pharmaceutical agent of claim 1, which is a prophylactic or therapeutic agent of chronic rheumatoid arthritis or osteoarthritis.

9. A method for the prophylaxis or treatment of asthma, chronic obstructive pulmonary disease (COPD), allergic disease, inflammation, Addison'"'"'s disease;

autoimmune hemolytic anemia, systemic lupus erythematosus, Crohn'"'"'s disease, psoriasis, rheumatism, cerebral hemorrhage, cerebral infarction, head trauma, spinal cord injury, brain edema, multiple sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, diabetes, arthritis, osteoporosis, toxemia, Crohn'"'"'s disease, ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, AIDS encephalopathy, meningitis, angina pectoris, cardiac infarction, congestive heart failure, chronic cardiac deficiency, acute myocardial infarction, prognosis of cardiac infarction, hypertension, acute cardiac deficiency, hepatitis, kidney failure, nephritis, malignant tumor, immunological rejection associated with transplantation, dialysis hypotension or disseminated intravascular coagulation, which comprises administration of an effective amount of one or more kinds of a p38 MAP kinase inhibitor and/or a TNF-α

production inhibitor and an effective amount of one or more kinds of drugs selected from the group consisting of (1) a non-steroidal antiinflammatory drug, (2) a disease-modifying anti-rheumatic drug, (3) an anti-cytokine drug, (4) an immunomodulator, (5) a steroid and (6) a c-Jun N-terminal kinase inhibitor in combination to a mammal.

10. A method for the prophylaxis or treatment of chronic rheumatoid arthritis or osteoarthritis, which comprises administration of an effective amount of one or more kinds of a p38 MAP kinase inhibitor and/or a TNF-α

production inhibitor and an effective amount of one or more kinds of drugs selected from the group consisting of (1) a non-steroidal antiinflammatory drug, (2) a disease-modifying anti-rheumatic drug, (3) an anti-cytokine drug, (4) an immunomodulator, (5) a steroid and (6) a c-Jun N-terminal kinase inhibitor in combination to a mammal.

11. Use of one or more kinds of a p38 MAP kinase inhibitor and/or a TNF-α

production inhibitor and one or more kinds of drugs selected from the group consisting of (1) a non-steroidal antiinflammatory drug, (2) a disease-modifying anti-rheumatic drug, (3) an anti-cytokine drug, (4) an immunomodulator, (5) a steroid and (6) a c-Jun N-terminal kinase inhibitor for the production of a prophylactic or therapeutic agent of asthma, chronic obstructive pulmonary disease (COPD), allergic disease, inflammation, Addison'"'"'s disease, autoimmune hemolytic anemia, systemic lupus erythematosus, Crohn'"'"'s disease, psoriasis, rheumatism, cerebral hemorrhage, cerebral infarction, head trauma, spinal cord injury, brain edema, multiple sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, diabetes, arthritis, osteoporosis, toxemia, Crohn'"'"'s disease, ulcerative colitis, chronic pneumonia, pulmonary silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, cachexia, arteriosclerosis, Creutzfeldt-Jakob disease, virus infection, atopic dermatitis, AIDS encephalopathy, meningitis, angina pectoris, cardiac infarction, congestive heart failure, chronic cardiac deficiency, acute myocardial infarction, prognosis of cardiac infarction, hypertension, acute cardiac deficiency, hepatitis, kidney failure, nephritis, malignant tumor, immunological rejection associated with transplantation, dialysis hypotension or disseminated intravascular coagulation.

12. Use of one or more kinds of a p38 MAP kinase inhibitor and/or a TNF-α

production inhibitor and one or more kinds of drugs selected from the group consisting of (1) a non-steroidal antiinflammatory drug, (2) a disease-modifying anti-rheumatic drug, (3) an anti-cytokine drug, (4) an immunomodulator, (5) a steroid and (6) a c-Jun N-terminal kinase inhibitor for the production of a prophylactic or therapeutic agent of chronic rheumatoid arthritis or osteoarthritis.