Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-01
2001-06-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S096000, C544S097000
Reexamination Certificate
active
06251897
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel 6-phenyltetrahydro-1,3-oxazin-2-one derivative having a type IV phosphodiesterase (PDE) inhibitory activity and a pharmaceutical composition containing the same.
BACKGROUND ART
Intracellular second messenger cAMP is involved in relaxation of airway smooth muscles and regulation of the functions of inflammatory cells. cAMP is broken down by phosphodiesterase (PDE) and becomes inactive 5′-AMP. It is considered that an increase in intracellular concentration of cAMP due to suppression of cAMP metabolism by PDE would give bronchodilating and anti-inflammatory actions and would exhibit a therapeutic effect on inflammatory diseases such as asthma [Eur. Respir. J., 7, 579 (1994)]. Up to now, PDE has been classified into five isozymes (i.e., types I to V PDE). Their distributions differ among on the tissue [Trends Pharm., Sci., 12, 19 (1991)]. This suggests a possibility that selective inhibitors of PDE isozymes would result in tissue specific increase of intracellular cAMP concentration.
It is reported that a selective inhibitor of type IV PDE isozyme suppresses inflammatory cells functions [Thorax, 46, 512 (1991)] and is useful for inflammatory diseases such as asthma [J. Pharmacol. Exp. Ther., 266, 306 (1993)] and dermatitis [Br. J. Pharmacol., 112, 332 (1994)] and autoimmune diseases such as multiple sclerosis [Nature Medicine, 1, 244 (1994)] and rheumatoid arthritis [Clin. Exp. Immunol., 100, 126 (1995)]. In addition, it is thought that cardiovascular side effect caused by non-selective PDE inhibitors such as theophylline could be reduced by using selective type IV PDE inhibitor. Rolipram having the following formula (Japanese Unexamined Patent Publication (Kokai) JP-A-50-157360) is known as a compound having a specific inhibitory activity against type IV PDE.
Other compounds having a specific inhibitory activity against type IV PDE are known (JP-A-62-281864, U.S. Pat. No. 5128358, WO 94/10118, WO 94/12461, JP-A-5-117239, JP-A-7-101861, WO 95/03794, WO 95/08534, etc.), but they have not been clinically applied up to now. Development of more useful compounds is desired. Further, JP-A-5-213893,discloses, as an antifungal agent, a compound having the following formula (II):
wherein, Ar represents an unsubstituted or substituted aryl group or heterocycle and n is 1 or 2. JP-A-6-1777 discloses, as an antifungal agent, a compound the following formula (III):
wherein, Ar represents an unsubstituted or substituted aryl group or a heterocyclic ring, n is 1 or 2, and Z is N or CH. JP-A-5-148248 discloses a compound having the following formula (IV):
wherein, R
1
and R
2
may be the same or different and represents a hydrogen atom or an unsubstituted or substituted phenyl group, R
4
is an unsubstituted or substituted C
1
to C
10
alkyl group, R
5
represents a C
1
to C
10
alkyl group, and n is 0 or 1, as a compound useful for the production of a carbapenem based antibiotic or carbacephem based antibiotic. JP-A-7-17946 discloses a compound having formula (V):
wherein, R
1
to R
6
each independently represent hydrogen; a C
1
to C
4
alkyl group; a hydroxy group; a C
1
to C
4
alkoxy group or a C
1
to C
4
alkyl group substituted with a —SO
3
H group; a phenyl group; a benzyl group; a halogen atom; a phenyl group substituted with a C
1
to C
4
alkoxy group or a —SO
3
H group; a benzyl group; and n is 0 or 1, as a starting material, when producing 2-(2′-aminoalkylmercapto)ethanol useful as a synthesis intermediate for a dye.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a novel compound having a type IV phosphodiesterase (PDE) inhibitory activity and a pharmaceutical composition containing the same.
In accordance with the present invention, there are provided a 6-phenyltetrahydro-1,3-oxazin-2-one derivative having the formula (I):
wherein, R
1
represents an unsubstituted or substituted C
1
to C
8
alkyl group; an unsubstituted or substituted C
3
to C
7
cycloalkyl group; an unsubstituted or substituted heterocycle; or a polycyclic hydrocarbon, R
2
represents a C
1
to C
4
alkyl group, R
3
is a hydrogen atom; an unsubstituted or substituted C
1
to C
5
alkyl group; an unsubstituted or substituted C
3
to C
7
cycloalkyl group; an unsubstituted or substituted aryl group; an unsubstituted or substituted heteroaryl group which contains at least one hetero atom selected from the group consisting of an oxygen atom, nitrogen atom, and sulfur atom; or acyl group, R
4
is a hydrogen atom; an unsubstituted or substituted C
1
to C
6
alkyl group; an unsubstituted or substituted aryl group; an unsubstituted or substituted heteroaryl group which contains at least one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom, and R
5
and R
6
are independently a hydrogen atom; an unsubstituted or substituted C
1
to C
5
alkyl group; an unsubstituted or substituted C
3
to C
7
cycloalkyl group; or an unsubstituted or substituted aryl group which may contain at least one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom an optical isomer or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof.
In accordance with the present invention, there is provided a pharmaceutical composition comprising, as an essential ingredient, the above derivative, an optical isomer or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof, specifically an agent for the prevention or treatment of inflammatory diseases or an antiasthmatic agent.
BEST MODE FOR CARRYING OUT THE INVENTION
The present inventors conducted a search for a novel compound having a type IV PDE inhibitory activity and, as a result, found that the above 6-phenyltetrahydro-1,3-oxazin-2-one derivative had a strong type IV PDE inhibitory activity and had a bronchodilator and antiinflammatory effects, whereby the present invention was completed.
The present invention will now be explained in detail.
As the C
1
to C
8
linear or branched alkyl group of R
1
of the compound having the above formula (I), methyl, ethyl, propyl, isopropyl, n-butyl, 2-methylpropyl, sec-butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, 2-ethylbutyl, n-heptyl, n-octyl group, etc. may be mentioned. These may be substituted with a halogen atom; a hydroxy group; a nitro group; a cyano group; an amino group; a carboxyl group; an aryl group such as phenyl, tolyl or napthyl; a heteroaryl group such as pyridyl, thiazolyl, thienyl, furyl, or quinolyl; a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; haloalkyl; carbamoyl; alkoxy; alkylcarbonyl, etc. As the substituted C
1
to C
8
alkyl group, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-methylcyclopropylmethyl, 1-phenylcyclopropylmethyl, benzyl, phenethyl, 4-fluorophenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-(1-naphthyl)ethyl, 2-(2-pyridyl)ethyl, 2-(4-methyl-5-thiazolyl)ethyl, 2-(benzyloxy)ethyl, 2-(phenethyloxy)ethyl, 2-(methoxy)ethyl, 3-(methoxy)propyl, 4-(methoxy)butyl, 2-(ethoxy)ethyl, 3-(ethoxy)propyl, 2-(butoxy)ethyl, 2-(cyclopropylmethyloxy)ethyl, 2-(cyclopentyloxy)ethyl, 2-(4-methyl-1-piperazinyl)ethyl, 3-(4-benzyl-1-piperazinyl)propyl, etc. may be mentioned.
As the C
3
to C
7
cycloalkyl group of R
1
, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. may be mentioned. This may be substituted with an alkyl group; a halogen atom; a hydroxy group; a nitro group; a cyano group; an amino group; a carboxyl group; an aryl group such as phenyl, tolyl or napthyl; a heteroaryl group such as pyridyl, thiazolyl, thienyl, furyl, or quinolyl; a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; a haloalkyl group; a carbamoyl group; an alkoxy group; an alkylcarbonyl group, etc. As the substituted C
3
to C
7
cycloalkyl group, fo
Ina Shinji
Noda Kyoji
Yamana Kenjirou
Balasubramanian Venketaraman
Christie Parker & Hale LLP
Nikken Chemicals Co., Ltd
Raymond Richard L.
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