Novel pyridazine derivatives and medicines containing the same as effective ingredients

• US 20020123496A1
• Filed: 11/30/2001
• Published: 09/05/2002
• Est. Priority Date: 11/19/1997
• Status: Abandoned Application

• Current Assignee: KOWA Company Limited
• Original Assignee: KOWA Company Limited
• Inventors: Matsuda, Takayuki, Koshi, Tomoyuki, Ohgiya, Tadaaki, Ohkuchi, Masao, Kitamura, Takahiro, Yamazaki, Yukiyoshi, Yoshizaki, Hideo, Habata, Yuriko, Kyotani, Yoshinori, Shigyo, Hiromichi, Kumai, Natsuyo, Kotaki, Kyoko
• Application Number:
  US09/996,804
• Publication Number:
  US 20020123496A1
• Time in Patent Office: Days
• US Class Current: 514/247
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 237/02 not condensed with other rings
• CPC Class Codes: C07D 237/04 having less than three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 237/14 Oxygen atoms
• CPC Class Codes: C07D 237/18 Sulfur atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond

Abstract

This invention relates to pyridazine derivatives represented by the formula (1):

wherein R¹ represents a (substituted) aryl group, R² represents a phenyl group substituted at 4-position by a lower alkoxyl group or a lower alkylthio group, R³ represents a lower alkoxyl group, a halogenated lower alkyl group, a lower cycloalkyl group, a (subsituted) aryl group, a (substituted) aryloxy group, a (substituted) nitrogen-containing heterocyclic ring residue, a (substituted) aminocarbonyl group or a lower alkylcarbonyl group, A represents a single bond, a lower alkylene group or a lower alkenylene group, X represents O or S, and the dashed line indicates that the carbon-carbon bond between the 4-position and the 5-position is a single bond or a double bond, or salts thereof; and also to medicines containing them as effective ingredients. These compounds have excellent inhibitory activity against interleukin-1β production, and are useful as preventives and therapeutics for immune system diseases, inflammatory diseases, ischemic diseases and the like.

Claims

1. A pyridazine derivative represented by the following formula (1):

2. A pyridazine derivative or a salt thereof according to claim 1, wherein R¹ represents a substituted or unsubstituted phenyl or pyridyl group.

3. A pyridazine derivative or a salt thereof according to claim 1, wherein R¹ represents a phenyl or pyridyl group which may be substituted by 1 to 3 substituents selected from halogen atoms and lower alkoxy groups;

R² represents a phenyl group, which may be substituted at 4-position by a lower alkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, and at the other positions by 1 or 2 substituents selected from halogen atoms, lower alkoxyl groups, lower alkylthio groups, lower alkylsulfinyl groups and lower alkylsulfonyl groups;

R³ represents a hydrogen atom, a lower alkoxyl group, a halogenated lower alkyl group, a lower cycloalkyl group, a phenyl, pyridyl or phenyloxy group which may be substituted by 1 to 3 substituents selected from halogen atoms, lower alkyl groups, lower alkoxyl groups, carboxyl group, lower alkoxycarbonyl groups, nitro group, amino group, lower alkylamino groups and lower alkylthio groups, a substituted or unsubstituted piperidino, piperidyl, piperazino or morpholino group, a substituted or unsubstituted aminocarbonyl group, or a lower alkylcarbonyl group; and

A represents a linear or branched lower alkylene group having 1 to 6 carbon atoms or a linear or branched alkenylene group having 2 to 9 carbon atoms.

4. A pyridazine derivative or a salt thereof according to claim 1, which is a compound represented by the following formula (1A):

5. A pyridazine derivative or a salt thereof according to claim 1, which is 5,6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one, 2-allyl-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-cyclopropyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazine-3-thione, 5,6-bis(4-methoxyphenyl)-2-cyclopentyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-cyclopentylmethyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazin-3-one, 5-(4-chlorophenyl)-6-(4-methylthiophenyl)-2-benzyl-2H-pyridazin-3-one, 5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazine-3-thione, or 5,6-bis(3-fluoro-4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one;

or a salt thereof.

6. A medicine comprising, as an effective ingredient, a pyridazine derivative or a salt thereof according to any one of claims 1-5.

7. A medicine according to claim 6, which is an interleukin-1β

production inhibitor.

8. A medicine according to claim 6, which is a preventive or therapeutic for a disease caused by stimulation of interleukin-1β

production.

9. A medicine according to claim 6, which is a preventive or therapeutic for an immune system disease, an inflammatory disease, an ischemic disease, osteoporosis or ichorrhemia.

10. A medicine according to claim 6, which is a preventive or therapeutic for rheumatism, arthritis or inflammatory colitis.

11. An interleukin-1β

production inhibitor comprising, as an effective ingredient, a pyridazine derivative or a salt thereof according to any one of claims 1-5.

12. A pharmaceutical composition comprising a pyridazine derivative or a salt thereof according to any one of claims 1-5 and a pharmaceutically acceptable carrier.

13. Use of a pyridazine derivative or a salt thereof according to any one of claims 1-5 as a medicine.

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

production, which comprises administering a pyridazine derivative or a salt thereof according to any one of claims 1-5.