Water-soluble phenylpyridazine compounds and compositions containing the same

• US 6,869,954 B2
• Filed: 09/25/2002
• Issued: 03/22/2005
• Est. Priority Date: 09/26/2001
• Status: Expired due to Fees

• Current Assignee: KOWA Company Limited
• Original Assignee: KOWA Company Limited
• Inventors: Sato, Seiichi, Koshi, Tomoyuki, Takemura, Shunji, Kitamura, Takahiro, Yoshizaki, Hideo, Yasuoka, Kyoko, Kyotani, Yoshinori, Shigyo, Hiromichi, Totsuka, Junko
• Primary Examiner(s): BERNHARDT, EMILY B
• Application Number:
  US10/253,523
• Publication Number:
  US 20030119838A1
• Time in Patent Office: 909 Days
• Field of Search: 544/238, 544/239, 544/114, 514/247, 514/252.02, 514/236.5, 514/252.03
• US Class Current: 514/247
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• 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 13/12 of the kidneys
• 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 25/00 Drugs for disorders of the nervous system
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 237/14 Oxygen atoms
• CPC Class Codes: C07D 237/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

Compounds having the formula (1):
wherein R¹ represents an alkyl or alkenyl group, R² and R³ each independently represent a hydrogen atom or an alkyl, hydroxyalkyl, dihydroxyalkyl or alkynyl group, or R² and R³ may be fused together with the adjacent nitrogen atom to form a substituted or unsubstituted, nitrogen-containing, saturated heterocyclic group, X, Y and Z each independently represent a hydrogen atom, an alkyl group, a halogen atom or the like, and n stands for an integer of from 1 to 5; and also to medicinal compositions containing them. These compounds have inhibitory activity against IL-1β production, high water solubility and good oral absorbability.

Claims

1. A phenylpyridazine compound, or a salt thereof, wherein the phenylpyridazine compound is selected from the group consisting of

4-dimethylaminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,

2-cyclopropylmethyl-4-dimethylamino-methyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-benzyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

2-cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)-methyl-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)amino-methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

4-dimethyl-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one,

4-diethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,

6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one,

2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropyl-methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,

2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one,

2-isobutyl-6-[4-(methylthio)-phenyl]-4-propargylaminomethyl-2H-pyridazin-3-one,

4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one,

2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

2-cyclopentylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

4-dimethylaminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

4-aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,

6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,

2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,

2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,

2-cyclopropylmethyl-4-(3-dimethylaminopropyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one or

4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one.

2. A pharmaceutical composition comprising at least one of the phenylpyridazine compound, or a salt thereof, of claim 1 and a pharmaceutically-acceptable carrier.

3. A The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is in a form suitable for oral administration.

4. The pharmaceutical composition of claim 3, wherein the form suitable for oral administration is a tablet.