Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-23
2002-01-22
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S218000, C514S249000, C514S252110, C514S252180, C514S253010, C514S253050, C514S253060, C514S254050, C514S254080, C514S254090, C514S255010, C540S575000, C544S121000, C544S295000, C544S350000, C544S353000, C544S357000, C544S360000, C544S363000, C544S364000, C544S365000, C544S370000, C544S373000, C544S387000
Reexamination Certificate
active
06340682
ABSTRACT:
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.
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 (sensitized state), or basophil. After the sensitization, allergic chemical mediators such as histamine, leukotrienes, prostaglandins and PAF, and injuring enzymes such as triptase 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 been found and reported to date 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 EMBODIMENT
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 hydrates or solvates thereof have an excellent inhibitory effect on the production of an IgE antibody and are useful for 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 phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group which may be substituted;
B is a group of —CH═CH—, —C≡C—, —(CH═CH)
2
—, —CH═CH—C≡C— or —C≡C—CH═CH—, or a divalent residue of benzene, pyridine, pyrimidine or pyrazine; and
W is a formula
or
in which X is
or
Y
1
, Y
2
and Y
3
are the same or different from one another and are independently a hydrogen atom, —COOR
1
(R
1
is a hydrogen atom or a lower alkyl group), —CON(R
2
)R
3
(R
2
and R
3
are the same or different from each other and are independently a hydrogen atom, or a hydroxyl or lower alkyl group), —CH
2
—N(R
4
)R
5
(R
4
and R
5
are the same or different from each other and are independently a hydrogen atom or a lower alkyl group, or R
4
and R
5
may form, together with the adjacent nitrogen atom, a heterocyclic ring which may further have an oxygen, nitrogen or sulfur atom), or —CH
2
—S—R
6
(R
6
is a lower alkyl, phenyl or pyridyl group), or Y
1
and Y
2
may couple to each other to form an alkylene group which may be through an oxygen, a nitrogen or a sulfur, Z is a benzene or pyridine ring, and n is an integer of 2 or 3, with the proviso that when B is a p-phenylene group, and W is a 1,4-piperazinyl group, A is not a phenyl group, and when B is —CH═CH—, A is not a phenyl group which may be substituted,
or a salt thereof, or a hydrate or 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 amide compounds according to the present invention are represented by the general formula (1). In these compounds, 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.
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.
The halogen atoms include fluorine, chlorine, bromine and iodine atoms.
In the formula (1), A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, i-indolyl, quinolyl or i-quinolyl group. These groups may have 1-3 substituents. Here, examples of the substituents on these groups include a hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1-3 halogen atoms, lower alkoxy groups, an amino group which may be substituted by one or two lower alkyl groups, and alkylthio groups.
Particularly preferable examples of A include tri-lower alkoxy-phenyl groups.
In B, examples of the substituent on the divalent residue of benzene, pyridine, pyrimidine or pyrazine include nitro, amino, lower alkyl and lower alkoxy groups, and halogen atoms.
More preferred as B is —CH═CH—, —C≡C—, —(CH═CH)
2
—, —C≡C—CH═CH—, —CH═CH—C≡C—, or a divalent residue of benzene, pyridine, pyrimidine or pyrazine. Of these, —CH═CH—CH═CH—, —C≡C—CH═CH—, —CH═CH—C≡C— and a benzene residue (phenylene group) are particularly preferred.
In the general formula (1), preferable example of the heterocyclic ring which is formed by R
4
and R
5
together with the adjacent nitrogen atom include those having 3-10 carbon atoms. Specific examples thereof include pyrrolidine, oxazole, isoxazole, thiazole, isothiazole, imidazole, imidazoline, imidazolidine, pyridine, piperidine, piperazine, morpholine and phthalimide. The alkylene group formed by bonding Y
1
and Y
2
to each other preferably has 3-8 carbon atoms. Rings formed by the alkylene group which may be through an oxygen, a nitrogen or a sulfur include pyrrolidine, imidazolidine and piperazine. More preferred as Y
1
, Y
2
and Y
3
are a hydrogen atom, and carboxyl, aminomethyl, di-lower alkyl-amino and lower alkyl-aminomethyl groups, with a hydrogen atom, and carboxyl, aminomethyl, dimethylamino and dimethylaminomethyl groups being particularly preferred.
Particularly preferred as W is piperazine or homopiperazine ring which may be substituted by a carboxyl, aminomethyl, di-lower alkyl-amin
Hattori Yukio
Ishiwata Hiroyuki
Kabeya Mototsugu
Nagoya Takao
Nakao Hiroshi
Coleman Brenda
Kowa Co. Ltd.
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