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Novel pyridazine derivatives and medicines containing the same as effective ingredients

a technology of pyridazine and derivatives, which is applied in the direction of biocide, drug composition, immunological disorders, etc., can solve the problem that none of these compounds can exhibit sufficient inhibitory activity against interleukin-1 production

Inactive Publication Date: 2005-03-24
KOWA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a new pyridazine derivative that has strong inhibitory activity against interleukin-1β production, which is associated with various immune system diseases, inflammatory diseases, and ischemic diseases. This new compound can be used as a medicine to prevent and treat these diseases. The invention also provides a pharmaceutical composition containing the new compound and a method for treating diseases caused by interleukin-1β production.

Problems solved by technology

None of these compounds can however exhibit sufficient inhibitory activity against interleukin-1β production.

Method used

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  • Novel pyridazine derivatives and medicines containing the same as effective ingredients
  • Novel pyridazine derivatives and medicines containing the same as effective ingredients
  • Novel pyridazine derivatives and medicines containing the same as effective ingredients

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

(1) Preparation of 3,4-bis(4-methoxyphenyl)-2-hydroxy-4-oxobutanoic Acid

To a solution of sodium periodate (11.1 g, 52.0 mmol) in water (65 ml), concentrated sulfuric acid (1.12 ml) was added dropwise little by little under ice-water cooling and stirring. Subsequent to the dropwise addition, the temperature of the resulting mixture was allowed to rise to room temperature, followed by the addition of a solution of tartaric acid (7.81 g, 52.0 mmol) in water (18 ml). The mixture was stirred for 50 minutes. To the reaction mixture, an aqueous solution of sodium hydroxide and a suspension of 2-(4-methoxyphenyl)-4′-methoxyacetophenone (13.32 g, 52.0 mmol) in ethanol (160 ml) were added. The mixture was stirred at 40° C. for 5 hours and then at room temperature for 17 hours, and a reaction was then conducted at 70° C. for 1 hour. Subsequent to cooling, the ethanol was distilled off. The liquid residue was washed with ethyl acetate, acidified with hydrochloric acid, and then extracted with...

preparation example 2

Preparation of Methyl 4-(4-methoxyphenyl)-4-oxo-3-(4-pyridyl)butanoate

Under an argon, 2-(4-pyridyl)-4′-methoxyacetophenone (J. Am. Chem. Soc., 112, 2163-3168, 1990: Dimitrios Stefanidis and John W. Bunting; 9.6 g, 42.3 mmol) was suspended in tetrahydrofuran (200 ml), and under ice cooling, lithium diisopropylamide (2.0 M solution; 25 ml, 50.0 mmol) was added. At the same temperature, the mixture was stirred for 30 minutes. Methyl bromoacetate (6.0 ml, 63.4 mmol) was then added dropwise, and the mixture was stirred under ice cooling for 1 hour and then at room temperature for 2 hours. The reaction mixture was diluted with toluene. The mixture was washed successively with 2 N hydrochloric acid, water and a brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated and purified by chromatography on a silica gel column [silica gel: 100 g, hexane / ethyl acetate (1 / 2)], whereby the title compound (10.63 g, 84.1%) was obtained as a...

preparation example 3

(1) Preparation of 2-(4-chlorophenyl)-4′-(methylthio)acetophenone

A mixture consisting of para-chlorophenyl acetic acid (17.06 g, 0.1 mol), thioanisole (24.84 g, 0.2 mol) and polyphosphoric acid (67.59 g, 0.2 mol) was heated at 100° C. for 7 hours. Water was added to the solidified reaction product, and a white solid insoluble in water was collected by filtration and then washed with n-hexane. The solid was recrystallized from a mixed solvent of ethanol and ethyl acetate, whereby the title compound (21.24 g, 76.7%) was obtained. Further, the mother liquor was separated and purified by chromatography on a silica gel column (ethyl acetate). Recrystallization was then conducted from ethyl acetate, whereby the title compound (2.86 g, 10.4%) was obtained.

Colorless prisms (ethyl acetate)

Melting point: 161.1-162.1° C.

1H-NMR (CDCl3) δ: 2.51(3H,s), 4.21(2H,s), 7.19(2H,d,J=8.55 Hz), 7.26(2H,d,J=8.91 Hz), 7.29(2H,d,J=8.55 Hz), 7.89(2H,d,J=8.91 Hz).

(2) Preparation of Ethyl 3-(4-chlorophe...

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PUM

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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.

Description

TECHNICAL FIELD This invention relates to novel pyridazine derivatives, which have excellent inhibitory activity against interleukin-1β production and are useful for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases and the like, and also to medicines containing them as effective ingredients. BACKGROUND ART In many diseases, for example, rheumatism, arthritis, osteoporosis, inflammatory colitis, immune deficiency syndrome, ichorrhemia, hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease, leukemia and the like, stimulation of interleukin-1β production, an inflammatory cytokine, is observed. This interleukin-1β serves to induce synthesis of an enzyme which is considered to take part in inflammation like collagenase and PLA2 and, when intra-articularly injected to animals, causes multi-articular destruction highly resembling rheumatoid arthritis. On th...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/50A61K31/501A61P19/02A61P19/10A61P29/00A61P37/00C07D213/00C07D237/00C07D237/04C07D237/14C07D237/18C07D401/04C07D401/06
CPCC07D237/02C07D237/04C07D237/14C07D413/04C07D401/04C07D401/06C07D401/14C07D237/18A61P19/00A61P19/02A61P19/10A61P29/00A61P37/00A61P9/00C07D213/38C07D213/30C07D213/61
Inventor OHKUCHI, MASAOKYOTANI, YOSHINORISHIGYO, HIROMICHIKOSHI, TOMOYUKIKITAMURA, TAKAHIROOHGIYA, TADAAKIMATSUDA, TAKAYUKIYAMAZAKI, YUKIYOSHIKUMAI, NATSUYOKOTAKI, KYOKOYOSHIZAKI, HIDEOHABATA, YURIKO
Owner KOWA CO LTD
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