Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-21
2002-09-10
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S218000, C514S252020, C514S252110, C514S255050, C514S256000, C514S385000, C514S252120, C514S403000, C540S470000, C540S480000, C540S481000, C540S575000, C540S553000, C544S295000, C544S357000, C544S239000, C544S296000, C544S298000, C544S322000, C544S333000
Reexamination Certificate
active
06448242
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel cyclic amide compounds and medicines useful in preventing and treating allergic immunological diseases or the like, comprising such a compound as an active ingredient.
BACKGROUND ART
IgE, which is a kind of immunoglobulin (Ig), is an allergen-specific molecule produced by an IgE producing cell differentiated from a B cell. This process is triggered by the contact of an immunocyte with an allergen in vivo.
IgE is produced in a target organ for an allergy and binds to a receptor on the surface of a mast cell, which is a central effector cell in an allergic reaction, or a basophil (sensitized state). After the sensitization, allergic chemical mediators such as histamine, leukotrienes, prostaglandins and PAF, and injuring enzymes such as tryptase are released from the mast cell stimulated by the reaction of the specific IgE and an allergen which invades in the living body, so that immediate responses such as vascular permeability acceleration, smooth muscle constriction and vasodilation are elicited. Further, cytokines such as IL-4, which directly activate other immune system cells, are also secreted from the stimulated mast cell. As a result, eosinophils, basophils and the like infiltrate into a tissue, and the allergic chemical mediators and tissue injuring proteins such as MBP, which are secreted by these inflammatory cells, induce a late response, so that the allergic symptom is lingered and taken seriously ill.
From this, IgE is considered a substance fundamentally participating in the attack of an allergic immunological disease.
Therefore, several compounds having an inhibitory effect on the production of an IgE antibody have heretofore been found and reported with a view toward developing antiallergic agents [Pharmacology and Therapy, 1994, 22(3), 1369; Japanese Patent Application Laid-Open No. 106818/1989; Japanese Patent Publication No. 17506/1995; Japanese Patent Application Laid-Open Nos. 92216/1996 and 109177/1996; and WO 96/11682]. However, the object has been not always sufficiently achieved under the circumstances.
Accordingly, it is an object of the present invention to find a compound having a strong inhibitory effect on the production of an IgE antibody so as to provide a medicine effective for allergic immunological diseases, comprising this compound as an active ingredient.
DISCLOSURE OF THE INVENTION
With the foregoing circumstances in view, the present inventors have carried out an extensive investigation. As a result, it has been found that novel cyclic amide compounds represented by the general formula (1), which will be described subsequently, salts thereof, or solvates thereof have an excellent inhibitory effect on the production of an IgE antibody and are useful as medicines such as antiallergic agents, thus leading to completion of the present invention.
According to the present invention, there is thus provided a compound represented by the following general formula (1):
wherein A is a residue of an alicyclic compound which may be substituted, an aromatic compound which may be substituted, or a heterocyclic compound which may be substituted;
X is a single bond; a lower alkylene group which may be substituted; a divalent residue of an alicyclic compound which may be substituted, an aromatic compound which may be substituted, or a heterocyclic compound which may be substituted; an imino group which may be substituted; or a sulfur atom or an oxygen atom;
Y is a single bond, or a lower alkylene, imino or lower alkylimino group;
Z is a group of —CH═CH—, —C≡C—, —(CH═CH)
2
—, —C≡C—CH═CH— or —CH=CH—C≡C—, or a divalent residue of benzene, pyridine, pyrimidine or pyrazine which may be substituted;
B is a nitrogen atom or ═CH—; and
m and n are the same or different from each other and independently an integer of b
1
to 4 a salt thereof, or a solvate thereof.
According to the present invention, there is also provided a medicine comprising the above compound (1) as an active ingredient.
According to the present invention, there is further provided a medicinal composition comprising the above compound (1) and a pharmaceutically acceptable carrier.
According to the present invention, there is still further provided use of the above compound (1) for a medicine.
According to the present invention, there is yet still further provided a method of treating an allergic immunological disease, which comprises administering the above compound (1).
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, examples of the alicyclic compound represented by A or X include saturated or unsaturated alicyclic compounds having 3 to 14 carbon atoms, for example, cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane; cycloalkenes such as cyclopentene and cyclohexene; and bicyclic fused cycloalkenes such as indene, indane, dihydronaphthalene and tetrahydronaphthalene.
Examples of the aromatic compound include aromatic compounds having 5 to 14 carbon atoms, such as benzene and naphthalene.
Examples of the heterocyclic compound include 5- to 7-membered heterocyclic compounds containing 1 to 3 nitrogen atoms, such as pyrrolidine, pyridine, piperidine, piperazine and homopiperazine.
Examples of the lower alkylene group represented by X or Y include linear or branched alkylene groups having 1 to 8 carbon atoms, and specifically, methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene groups.
In the formula (1), it is particularly preferred that A be a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group. These groups may have 1 to 3 substituents. Here, examples of the substituents on these groups include a hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, an amino group, monoalkylamino groups, dialkylamino groups, and lower alkylthio groups. As A, a phenyl group substituted by 1 to 3 substituents selected from among lower alkyl groups and lower alkoxy groups is particularly preferred.
The lower alkylene group represented by X is preferably a linear or branched alkylene group having 1 to 8 carbon atoms. A linear alkylene group having 2 to 4 carbon atoms is more preferred. These groups may have substituents such as halogen atoms, or hydroxyl, lower alkoxy, amino, monoalkylamino, dialkylamino, carboxyl or lower alkoxycarbonyl groups. Of these, a lower alkylene group which may be substituted by an amino, monoalkylamino, dialkylamino, carboxyl or lower alkoxycarbonyl group is particularly preferred.
The divalent residue of the alicyclic compound, which is represented by X, is preferably a divalent residue of a cycloalkane having 5 to 8 carbon atoms. Examples of the divalent residue of the aromatic compound, which is represented by X, include phenylene and naphthylene groups, with the phenylene group being particularly preferred. Here, the phenylene group may be any of 1,2-phenylene, 1,3-phenylene and 1,4-phenylene groups, with the 1,2-phenylene or 1,4-phenylene group being particularly preferred. Preferable examples of the divalent residue of the heterocyclic compound, which is represented by X, include divalent residues of pyridine, pyrrolidine, piperidine, piperazine and homopiperazine. The divalent residue of the alicyclic compound, aromatic compound or heterocyclic compound, or the imino group, which is represented by X, may be substituted by a halogen atom, a hydroxyl group, a lower alkyl group which may be substituted by an amino, monoalkylamino or dialkylamino group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, an amino group, an alkylamino group, a dialkylamino group, a nitro group, a cyano group, an aralkyl group, or the like. Here, examples of the alkylamino and dialkylamino groups include lower alkylamino groups and di-lower alkylamino groups, respectively.
It is preferred that X be the alkylene group h
Hattori Yukio
Ishiwata Hiroyuki
Kabeya Mototsugu
Nagoya Takao
Nakao Hiroshi
Kowa Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Seaman D. Margaret
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