5-phenyl-3-pyridazinone derivatives and drug composition...

Details 5-phenyl-3-pyridazinone derivatives and drug composition... 5-phenyl-3-pyridazinone derivatives and drug composition...

1998-12-11

2001-05-22

Bernhardt, Emily (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252030, C514S252010, C514S252010, C514S252050, C544S238000, C544S239000

Reexamination Certificate

active

06235739

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel 5-phenyl-3-pyridazinone derivative having a type IV phosphodiesterase (PDE) inhibitory activity and a pharmaceutical composition containing the same.
BACKGROUND ART
Intracellular second messenger cAMP is synthesized by adenylate cyclase, and hydrolysed to 5′-AMP by a family of phosphodiesterase(PDE) isozymes. Up to now, at least five isozymes of PDE have been identified, and their distributions have been studied in variety of tissues [Trends Pharm. Sci., 12, 19, (1991)]. Among five PDE subtypes, type IV PDE was found to be a dominant isozyme in inflammatory cells. Increase in intracellular concentration of CAMP by inhibition of cAMP degradation with PDE inhibitors has been shown to inhibit several kind of inflammatory cells. In addition, airway smooth muscle tone are regulated by cAMP, increase in intracellular concentration of cAMP result in relaxation of airway smooth muscles [Thorax, 46, 512, (1991)]. Thus, a compound which inhibit type IV PDE may exhibit beneficial effects on inflammatory disease such as asthma [J. Pharmacol. Exp. Ther., 266, 306 (1993)], dermatitis [Br. J. Pharmacol., 112, 332 (1994)], and autoimmune diseases including multiple sclerosis [Nature Medicine, 1, 244 (1994)], and rheumatoid arthritis [Clin. Exp. Immunol., 100, 126 (1995)]. Because distribution of PDE isozymes are not same in different organs, specific inhibitor of type IV PDE may also decrease some adverse effects observed in nonspecific PDE inhibitor such as theophylline. Rolipram having the following formula (JP-A-50-157360 publication) is known as a compound having a specific inhibitory action against type IV PDE.
Other compounds having a specific inhibitory action against type IV PDE are known (WO 94/10118, WO 94/12461, JP-A-5-117259, JP-A-7-101861, WO 95/03794, WO 95/08534, etc.). However they have not been clinically applied up to now, and therefore, development of more useful compounds is desired.
JP-A-60-89421 discloses a compound having the following formula (II):
wherein R
1
represents an isopropyl group or t-butyl group; R
2
represents a hydrogen atom, C
1
to C
4
alkyl group, C
1
to C
4
alkoxy group, hydroxy group, or amino group; and R
3
represents a hydrogen atom or methyl group, as a &bgr;-adrenergic receptor antagonist. JP-A-4-234369 discloses a compound having the following formula (III):
wherein Ar represents a phenyl group substituted with two groups, a pyridyl group, or thienyl group; and R
3
represents a C
1
to C
5
alkyl group, —CH
2
Ph group, or —CH
2
CH
2
Ph group, as a synthesis intermediate of a pharmaceutical composition. JP-A-50-37800 discloses a compound having the following formula (IV):
wherein R
1
, R
2
, R
3
, and R
4
represent a hydrogen atom or lower alkyl group; and A represents a hydrogen atom or oxygen atom, as a synthesis intermediate of a compound exhibiting an analgesic action. WO 92/06963 discloses a compound having the following formula (V):
wherein R
1
and R
2
represent a methoxy group, difluoromethoxy group, ethoxy group, C
4
to C
7
cycloalkoxy group, or C
3
to C
7
cycloalkylmethoxy group, as a synthesis intermediate of a compound exhibiting a bronchospasm relieving action. However, the fact that the compound having the above formula (V) per se exhibits the bronchospasm relieving action is not described at all.
DISCLOSURE OF INVENTION
Accordingly, an object of the present invention is to provide a novel compound having a type IV PDE inhibitory activity, especially strong bronchodilator and anti-inflammatory effects, and a pharmaceutical composition containing the same.
In accordance with the present invention, there is provided a 5-phenyl-3-pyridazinone derivative having the following general formula (I):
wherein R
1
represents an unsubstituted or substituted C
1
to C
8
alkyl, C
3
to C
7
cycloalkyl or indanyl group; R
2
represents a C
1
to C
4
alkyl group; R
3
represents a hydrogen atom; an unsubstituted or substituted C
1
to C
5
alkyl group; a C
3
to C
7
cycloalkyl group; or an aryl group which may contain at least one heteroatom selected from the group consisting oxygen atom, nitrogen atom, and sulfur atom; R
4
and R
5
independently represent a hydrogen atom, a C
1
to C
6
alkyl group, an unsubstituted or substituted phenyl or a monocyclic aryl group which may contain at least one heteroatom selected from the group consisting of an oxygen atom, nitrogen atom, and sulfur atom; a dotted line represents a single or double bond, provided that when the dotted line represents a single bond, R
6
represents a hydrogen atom or C
1
to C
6
alkyl group), an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in detail below.
As R
1
of the above formula (I), a C
1
to C
8
linear or branched alkyl group (for example, a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-ethylbutyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, n-heptyl, and n-octyl) may be mentioned. These may contain a substituent (for example, a phenyl; a cycloalkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and a cycloalkyl substituted with an alkyl group such as a methyl, ethyl, and propyl. As a specific substituted C
1
to C
8
alkyl group, for example, a cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, (1-methylcyclopropyl)methyl, and (1-phenylcyclopropyl)methyl may be mentioned. As R
1
, a C
3
to C
7
cycloalkyl group (for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) and indanyl may be mentioned. As R
1
, preferably a C
1
to C
6
alkyl group, a C
1
to C
5
alkyl group which is substituted with a phenyl, C
3
to C
7
cycloalkyl group, or C
3
to C
7
cycloalkyl group substituted with a C
1
to C
3
alkyl group; C
4
to C
6
cycloalkyl group; or an indanyl group may be mentioned. More preferably a cyclopentyl, cyclopropylmethyl, or 2-indanyl may be mentioned.
As R
2
, a C
1
to C
4
linear or branched alkyl group (for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and t-butyl) may be mentioned. Preferably a methyl or ethyl, more preferably a methyl, may be mentioned.
As R
3
, a hydrogen atom; a C
1
to C
5
linear or branched alkyl group (for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl and n-pentyl) may be mentioned. These may be substituted with an aryl group which may contain at least one heteroatom selected from an oxygen atom, nitrogen atom, and sulfur atom (for example, a phenyl, pyridyl, thiazolyl, furyl, thienyl, naphthyl, and quinolyl). As the specific C
1
to C
5
alkyl group which may be substituted, for example a benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, pyridylmethyl, furylmethyl, thiazolylmethyl, 1-naphthylmethyl, and 4-quinolylmethyl may be mentioned. Further, as R
3
, a C
3
to C
7
cycloalkyl group (for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl) and an aryl group which may contain at least one heteroatom selected from an oxygen atom, nitrogen atom, and sulfur atom (for example, a phenyl, pyridyl, thiazolyl, furyl, thienyl, naphthyl, and quinolyl) may be mentioned. As R
3
, preferably a hydrogen atom, a C
1
to C
3
alkyl group, an aryl group, and a C
1
to C
2
alkyl group substituted with an aryl group may be mentioned. More preferably, a hydrogen atom, methyl, ethyl, phenyl, or benzyl may be mentioned.
As R
4
and R
5
, a hydrogen atom; C
1
to C
6
linear or branched alkyl group (for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, and hexyl); a phenyl which may be substituted (for example, a phenyl, 4-methylphenyl, and 4-chlorophenyl); a monocyclic aryl group having at least one heteroatom selected from an oxygen atom, nitrogen atom, and sul

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