Pyridazine derivatives and drugs containing the same as the active ingredient

• US 6,403,586 B1
• Filed: 08/31/2000
• Issued: 06/11/2002
• Est. Priority Date: 03/02/1998
• Status: Expired due to Term

• Current Assignee: KOWA Company Limited
• Original Assignee: KOWA Company Limited
• Inventors: Matsuda, Takayuki, Koshi, Tomoyuki, Ohkuchi, Masao, Kitamura, Takahiro, Yoshizaki, Hideo, Oda, Soichi, Habata, Yuriko, Kyotani, Yoshinori, Shigyo, Hiromichi, Kotaki, Kyoko
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US09/622,897
• Time in Patent Office: 649 Days
• Field of Search: 544/238, 544/239, 514/247, 514/252.03
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 237/02 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 237/22 Nitrogen and oxygen atoms
• CPC Class Codes: C07D 237/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

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

wherein R¹ represents a lower alkoxyl group, a lower alkylthio group or a halogen atom; R² represents H, a lower alkoxyl group, a lower alkylthio group or a halogen atom; R³ represents a lower alkyl or lower alkenyl group, which may be substituted by one or more OHs, CNs, lower cycloalkyl groups, (substituted) aromatic groups or (substituted) carbamoyl groups; R⁴ represents COOH, a lower alkoxycarbonyl group, a (substituted) carbamoyl group, a (substituted) amino group, or a (substituted) ureido group; 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):

wherein

R¹ represents a lower alkoxyl group, or a lower alkylthio group;

R² represents a hydrogen atom, a lower alkoxyl group, a lower alkylthio group or a halogen atom;

R³ represents a linear or branched lower alkyl or lower alkenyl group, wherein said alkyl or alkenyl group may have one or more substituents each independently selected from the group consisting of

a hydroxyl group,

a halogen atom,

a cyano group,

a lower cycloalkyl group,

a phenyl group which may be substituted,

a naphthyl group which may be substituted,

a pyridyl group which may be substituted,

wherein said phenyl, naphthyl or pyridyl groups when substituted have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a nitro group, an amino group, and a carbonylamino group substituted with a phenyl, naphthyl or pyridyl group; and

a carbamoyl group that may be substituted with one or more substituents independently selected from the group consisting of a lower alkyl group, a lower alkyl group substituted by one or more hydroxy groups, a lower alkyl group substituted with phenyl, naphthyl or pyridyl, and a phenyl, naphthyl or pyridyl group which may be substituted with one or more lower alkythio groups;

R⁴ represents a carboxyl group,

a lower alkoxycarbonyl group,

a carbamoyl group which may have one or more substituents each independently selected from a lower alkyl group, a phenyl, naphthyl or pyridyl group, or by a lower alkyl group substituted by one or more phenyl, naphthyl or pyridyl groups,

a thiocarbamoyl group which may have one or more substituents each independently selected from a lower alkyl group, a phenyl, naphthyl or pyridyl group, or by a lower alkyl group substituted by one or more phenyl, naphthyl or pyridyl groups,

a amino group which may have one or more substituents independently selected from a lower alkoxycarbonyl group which may be substituted by phenyl, naphthyl or pyridyl, a C₁-C₅ acyl group, a lower alkyl group which may be optionally substituted by phenyl, naphthyl or pyridyl, a lower alkylsulfonlyl group, or

a ureido group, which may be substituted by one or more lower alkyl groups;

wherein the dashed line in formula I indicates that the carbon-carbon bond between the 4-position and the 5-position is a single bond or a double bond;

or a salt thereof.

2. A pyridazine derivative or a salt thereof according to claim 1, wherein the carbon-carbon bond between the 4-position and the 5-position in the formula (1) is a double bond.

3. A pyridazine derivative or a salt thereof according to claim 1, wherein

R¹ represents a lower alkoxyl group or a lower alkylthio group; and

R² represents a hydrogen atom, halogen atom or a lower alkoxyl group.

4. A pyridazine derivative or a salt thereof according to claim 1, wherein:

R³ represents a linear or branched alkyl group having 1 to 6 carbon atoms or a linear or branched lower alkenyl group having 2 to 9 carbon atoms, wherein said alkyl or alkenyl groups may have one or more substituents each independently selected from the group consisting of;

a hydroxyl group,

a halogen atom,

a cyano group,

a lower cycloalkyl group;

a phenyl or pyridyl group which may have 1 to 3 substituents each independently selected from a halogen atom, a nitro group, an amino group, a carbonylamino group substituted by one or more phenyl, naphthyl or pyridyl groups; and

a carbamoyl group which may have one or more substituents each independently selected from a lower alkyl group, a hydroxy lower alkyl group, a lower alkyl group substituted by one or more phenyl, naphthyl or pyridyl groups or a lower alkylthiophenyl group; and

R⁴ represents a carboxyl group;

a lower alkoxy-carbonyl group;

a carbamoyl or thiocarbamoyl group which may have one or more substituents each independently selected from a lower alkyl group, a phenyl, naphthyl or pyridyl group or a lower alkyl group substituted by one or more phenyl, naphthyl or pyridyl groups;

an amino group which may have one or more substituents each independently selected from a lower alkoxycarbonyl group, a lower alkoxycarbonyl group substituted by one or more phenyl, naphthyl or pyridyl groups, a C₁-C₅ acyl group, a lower alkyl group, a lower alkyl group substituted by one or more phenyl, naphthyl or pyridyl groups, a lower alkylsulfonyl group;

or a ureido group which may have one or more lower alkyl groups as substituents.

7. A pharmaceutical composition or medicine comprising a pyridazine derivative or a salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

8. A method for preparing a pharmaceutical composition or a medicine comprising admixing the pyridazine derivative or a salt thereof according to claim 1 with a pharmaceutically acceptable carrier.

9. A method for inhibiting interleukin-1β

production comprising administering to a subject an effective amount of a pyridazine derivative or a salt thereof according to claim 1, wherein said subject has arthritis or rheumatism.

5. A pyridazine derivative or a salt thereof that is 2-isobutyl-6-(4-methoxy-phenyl)-4-methylcarbamoyl-2H-pyridazin-3-one, 2-cyclo-propylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one, 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one, 2-cyclopropylmethyl-4-ethylcarbamoyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one, 2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one, or 2-(4-chlorocinnamyl)-4-formylamino-6-(4-methoxy-phenyl)-2H-pyridazin-3-one.

6. A pyridazine derivative or a salt thereof that is 6-(3-chloro-4-fluorophenyl)-2-cinnamyl-4-ethoxycarbonyl-2H-pyridazin-3-one or 4-carbamoyl-6-(3-chloro-4-fluorophenyl)-2-cinnamyl-2H-pyridazin-3-one.