Pyridazin-3-one derivatives and medicines containing the same

• US 6,680,316 B1
• Filed: 08/20/2001
• Issued: 01/20/2004
• Est. Priority Date: 02/26/1999
• Status: Expired due to Fees

• Current Assignee: KOWA Company Limited
• Original Assignee: KOWA Company Limited
• Inventors: Furuyama, Tomoko, Matsuda, Takayuki, Koshi, Tomoyuki, Ohkuchi, Masao, Kitamura, Takahiro, Yoshizaki, Hideo, Yasuoka, Kyoko, Kyotani, Yoshinori, Shigyo, Hiromichi
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US09/926,040
• Time in Patent Office: 883 Days
• Field of Search: 544/238, 544/239, 514/247, 514/252.03, 514/252.06
• US Class Current: 514/247
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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: C07D 237/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

Objects of the invention are to provide compounds having excellent activity against interleukin-1β production and also medicines comprising them as effective ingredients.

Pyridazin-3-one derivatives represented by the following formula (1):

wherein Ar¹ represents a substituted or unsubstituted aromatic group, Ar² represents a phenyl group having a substituent at least at the 4-position thereof, R¹ represents a linear or branched alkyl group, an alkyl group having a cyclic structure, a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenyl(lower alkyl) group, and R² represents a cyano group, a carboxyl group, a (lower alkoxy)carbonyl group, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted carbamoyl group, or salts thereof; and medicines comprising them as effective ingredients.

Claims

1. A pyridazin-3-one compound represented by the following formula (1):

wherein Ar¹ represents a lower alkoxyphenyl group, Ar² represents a phenyl group having a lower alkoxy at least at the 4-position thereof, R¹ represents a linear or branched alkyl group having 2 to 11 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a lower alkyl group substituted by one or more cycloalkyl groups having 3 to 7 carbon atoms, or a phenyl or phenyl (lower alkyl) group which may be substituted by one or more of halogen atoms, lower alkyl groups and lower alkoxy groups, and R² represents a cyano group, a carboxyl group, a (lower alkoxy)carbonyl group, a substituted lower alkyl group or a substituted or unsubstituted carbamoyl group;

or a salt thereof.

2. A pyridazin-3-one compound or a salt thereof according to claim 1, wherein R² is a cyano group;

a carboxyl group;

a lower alkoxycarbonyl;

a lower alkyl group substituted by one or more of halogen atoms, hydroxy groups, and substituted or unsubstituted phthalimido groups;

or a carbamoyl group which may be substituted by one or two of lower alkyl groups, aromatic groups and aromatic-group-substituted lower alkyl groups.

3. A pyridazin-3-one compound according to claim 1, which is

5,6-bis(4-methoxyphenyl)-4-carbamoyl-2-cyclopropylmethyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-cyano-2-ethyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopropylmethyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopentylmethyl-2H-pyridazin-3-one,

2-benzyl-5,6-bis(4-methoxyphenyl)-4-ethoxycarbonyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-ethoxycarbonyl-2-isopropyl-2H-pyridazin-3-one, or

5,6-bis(4-methoxyphenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one.

4. A pharmaceutical composition comprising a pyridazin-3-one compound or a salt thereof according to claim 1, and at least one pharmaceutically acceptable carrier or diluent.

5. A composition according to claim 4, wherein the pyridazin-3-one compound is present in an amount effective for inhibiting interleukin-1β

production.

6. A composition according to claim 4, wherein the pryidazin-3-one compound is present in an amount effective for therapeutic treatment of a disease caused by stimulation of interleukin-1β

production.

7. A composition according to claim 4, wherein the pyridazin-3-one compound is present in an amount effective for therapeutic treatment of an immune system disease, an inflammatory disease, an ischemic disease, osteoporosis or ichorrhemia.

8. A composition according to claim 4, wherein the pyridazin-3-one compound is present in an amount effective for therapeutic treatment of rheumatism, arthritis or inflammatory colitis.

9. A method for the treatment of a disease caused by stimulation of interleukin-1β

production, which comprises

administering a pyridazin-3-one compound or a salt thereof according to claim 1.

10. The method of claim 9, wherein the disease is selected from the group consisting of rheumatism, arthritis, osteoporosis, inflammatory colitis, immune system diseases, ichorrhemia, and ischemic disease.

11. A method for the treatment of a disease caused by stimulation of interleukin-1β

production comprising

administering a composition comprising the pyridazin-3-one compound of claim 1 to a mammal in need thereof.

12. The method of claim 11, wherein the pyridazin-3-one compound is administered in an amount of from 0.1 to 100 mg per day.

13. The method of claim 11, wherein the pyridazin-3-one compound is administered in an amount effective for inhibiting interleukin-1β

production.

14. The method of claim 11, wherein the pyridazin-3-one compound is administered in one portion each day.

15. The method of claim 11, wherein the pyridazin-3-one composition is administered in a plurality of portions each day.

16. The method of claim 11, wherein the pyridazin-3-one composition is administered orally or parenterally.

17. The method of claim 11, wherein the mammal is in need of inhibitory activity against interleukin-1β

production.

18. The method of claim 11, wherein the mammal is a human.