Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-17
2003-06-10
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C514S332000, C514S414000, C514S616000, C546S140000, C546S175000, C546S265000, C548S455000, C564S155000, C564S158000
Reexamination Certificate
active
06576642
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel diamide compounds and medicines useful in preventing and treating allergic immunological diseases, comprising such a compound as an active ingredient.
2. Description of the Background
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 the 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; and Japanese Patent Application Laid-Open No. 92216/1996]. However, the object has been not always sufficiently achieved under the circumstances.
SUMMARY OF THE INVENTION
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.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
With the foregoing circumstances in view, the present inventors have carried out an extensive investigation. As a result, it has been found that novel diamide 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 prophylactic and therapeutic agents for various allergic immunological diseases, 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 phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group which may be substituted;
X is 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 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; and
R is a hydrogen atom, or a lower alkyl, cycloalkyl, aryl or aralkyl group, with the proviso that A is not a phenyl group, a 4-chlorophenyl group nor a 4-methoxyphenyl group when X is an ethylene group, Y is a single bond, Z is —C≡C—, and R is a hydrogen atom; A is not a 3,4-dichlorophenyl group when X is a trimethylene group, Y is a single bond, Z is —(CH═CH)
2
—, and R is a hydrogen atom; and A is not a 3,4-dihydroxyphenyl group, a 3-hydroxy-4-methoxyphenyl group, a 3-methoxy-4-hydroxyphenyl group nor a 3,4-dimethoxyphenyl group when X is a tetramethylene group, Y is a single bond, Z is —CH═CH— or —(CH═CH)
2
—, and R is a hydrogen atom, a salt thereof, or a solvate thereof.
According to the present invention, there is also provided a medicine comprising the above compound as an active ingredient.
According to the present invention, there is further provided a medicinal composition comprising the above compound and a pharmaceutically acceptable carrier.
According to the present invention, there is still further provided use of the above compound 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 an effective amount of the above compound.
BEST MODE FOR CARRYING OUT THE INVENTION
The diamide compounds according to the present invention are represented by the general formula (1). As compounds similar to these compounds, 5-phenyl-2,4-pentadiene derivatives are described in J. Med. Chem., 1968, 11, 1073. However, these compounds are described only as antimalarial drugs, not as antiallergic agents. Japanese Patent Application Laid-Open No. 214766/1985 also describes compounds similar to the compounds (1) according to the present invention. However, the publication describes these compounds as 5-lipoxygenase inhibitors, but does not describe anything about the fact that they have an inhibitory effect on the production of an IgE antibody.
In the present invention, “alkyl” in alkyl groups, alkylamino groups, dialkylamino groups and the like means linear or branched alkyl generally having 1-12 carbon atoms, and lower alkyl groups are preferred. The lower alkyl groups include linear or branched alkyl groups having 1-8 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl groups. Of these, those having 1-6 carbon atoms, for example, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl and n-hexyl groups, are particularly preferred.
“Alkoxy” in alkoxy groups, alkoxycarbonyl groups and the like means linear or branched alkoxy generally having 1-12 carbon atoms, and lower alkoxy groups are preferred. The lower alkoxy groups include linear or branched alkoxy groups having 1-8 carbon atoms. Specific examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy groups. Of these alkoxy groups, those having 1-6 carbon atoms are preferred.
Lower alkylene groups include linear or branched alkylene groups having 1-8 carbon atoms. Specific examples thereof include methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene groups.
Alicyclic compounds include saturated alicyclic hydrocarbons having 3-8 carbon atoms, for example, cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane.
Aromatic compounds include aromatic compounds having 6-14 carbon atoms, such as benzene and naphthalene.
Heterocyclic compounds include 5- to 7-membered heterocyclic compounds containing 1-3 nitrogen atoms, such as pyrrolidine, pyridine, piperidine, piperazine and homopiperazine.
Cycloalkyl groups include cycloalkyl groups having 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
Aryl groups include aromatic groups having 6-14 carbon atoms, such as phenyl and naphthyl groups. Aralkyl groups include C
6-14
-aryl-C
1-8
-alkyl groups such as benzyl, phenylethyl and naphthylmethyl groups.
Alkylthio groups include alkylthio groups having 1-8 carbon atoms.
Halogen atoms include fluorine, chlorine
Hattori Yukio
Ishiwata Hiroyuki
Kabeya Mototsugu
Nagoya Takao
Nakao Hiroshi
Kowa Co. Ltd.
Raymond Richard L.
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