Water-soluble phenylpyridazine compounds and compositions containing the same

• US 6,861,428 B2
• Filed: 03/26/2003
• Issued: 03/01/2005
• Est. Priority Date: 09/26/2001
• Status: Expired due to Fees

• Current Assignee: KOWA Company Limited, Radiall SA
• 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 A
• Application Number:
  US10/396,726
• Publication Number:
  US 20040002497A1
• Time in Patent Office: 706 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: 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 represents 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 represents 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 pharmaceutical 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

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

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

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

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

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

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

4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,

2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

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

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

4-aminomethyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,

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

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

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

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

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

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

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

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

4-aminomethyl-2-[3-(4-chlorophenyl)propyl]-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,

4-(3-aminopropyl)-2-cyclopropylmethyl-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,

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

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

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

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

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

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

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

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

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

4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,

2-[2-(4-chlorophenyl)ethyl]-6 (4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

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

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

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

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

4-(3-aminopropyl)-2-cyclopropylmethyl-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,

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

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

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

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

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

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

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

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

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

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

2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-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, and

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

4. A pharmaceutical composition comprising the phenylpyridazine compound, or a salt thereof, of claim 1 and a pharmacologically acceptable carrier.

5. An oral medicament, which comprises:

the phenylpyridazine compound, or a salt thereof, of claim 1;

at least one inactive ingredient; and

water.