Method of treating dermatitis comprising administering a chymase inhibitor
View Patent ↗Medicaments for the treatment of dermatitis exhibiting a biphasic inflammation reaction or dermatitis induced by repeated exposure to an antigen, having quinazolidone derivatives of formula I or II that are herein defined, are disclosed.
1. A method treatment of dermatitis exhibiting a biphasic skin reaction comprising administering to a patient in need of such treatment a chymase inhibitor in an amount effective for alleviating late-phase reaction, wherein the chymase inhibitor is a quinazolidone derivative having the formula (I) or a pharmaceutically acceptable salt thereof:
wherein the ring A represents an aryl group,
R 1 represents
a hydroxyl group,
an amino group,
a C 1 to C 4 lower alkylamino group which is optionally substituted with a carboxylic acid group,
a C 7 to C 10 lower aralkylamino group which is optionally substituted with a carboxylic acid group,
an amino group acylated with a C 1 to C 4 lower aliphatic acid which is optionally substituted with a carboxylic acid group,
an amino group acylated with an aromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group acrylated with a heteroaromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with an aromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a heteroaromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group,
a C 1 to C 4 lower alkyl group substituted with a carboxylic acid group, or
a C 2 to C 4 lower alkylene group which is optionally substituted with a carboxylic acid group;
R 2 and R 3 may be the same or different, and represent
a hydrogen atom,
an unsubstituted or substituted C 1 to C 4 lower alkyl group, wherein the substituent group of the C 1 to C 4 lower alkyl group is a carboxylic acid group, a halogen atom, a C 1 to C 4 lower alkoxy group, an amino group, a methylamino group, a dimethylamino group, a carboxymethyl amino group or a carboxyethylamino group,
a halogen atom,
a hydroxyl group,
a C 1 to C 4 lower alkoxyl group,
an amino group,
an unsubstituted or substituted C 1 to C 4 lower alkylamino group, wherein the substitutent group of the C 3 to C 4 lower alkylamino group is a carboxylic acid group, a halogen atom or a C 1 to C 4 lower alkoxyl group,
an unsubstituted or substituted C 7 to C 10 aralkylamino group, wherein the substitutent group of the C 7 to C 10 aralkylamino group is a carboxylic acid group, a halogen atom or a C 1 to C 4 lower alkoxyl group,
an amino group acylated with a C 1 to C 4 lower aliphatic acid which is optionally substituted with a carboxylic acid group,
an amino group acylated with an aromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group acylated with a heteroaromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with an aromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a heteroaromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group, or
a carboxylic acid group or
when the ring A is a benzene ring, R 1 and R 2 may form, together with the substituted benzene ring, a fused heterocyclic ring which is selected from the group consisting of a tetrahydroquinoline, a benzoxazine, a quinoxaline, a benzodioxane, a carboxytetrahydroquinoline, a carboxybenzoxazine, a carboxyquinoxaline and a carboxybenzodioxane, and R 3 is the same as defined above; and
X represents
a hydrogen atom,
a C 1 to C 4 lower alkyl group,
a C 1 to C 4 lower alkoxyl group,
a halogen atom,
a hydroxyl group,
an amino group, or
a nitro group.
2. A method according to claim 1 , wherein the dermatitis exhibiting a biphasic skin reaction is atopic dermatitis.
3. A method for alleviation of late-phase reaction of dermatitis exhibiting biphasic skin reaction comprising administering a chymase inhibitor to a patient in need of such treatment in an amount effective for alleviating late-phase reaction of dermatitis exhibiting biphasic skin reaction, wherein the chymase inhibitor is a quinazolidone derivative having the formula (I) or a pharmaceutically acceptable salt thereof:
wherein the ring A represents an aryl group;
R 1 represents
a hydroxyl group,
an amino group,
a C 1 to C 4 lower alkylamino group which is optionally substituted with a carboxylic acid group,
a C 7 to C 10 lower aralkylamino group which is optionally substituted with a carboxylic acid group,
an amino group acylated with a C 1 to C 4 lower aliphatic acid which is optionally substituted with a carboxylic acid group,
an amino group acylated with an aromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group acrylated with a heteroaromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with an aromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a heteroaromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group,
a C 1 to C 4 lower alkyl group substituted with a carboxylic acid group, or
a C 2 to C 4 lower alkylene group which is optionally substituted with a carboxylic acid group;
R 2 and R 3 may be the same or different, and represent
a hydrogen atom,
an unsubstituted or substituted C 1 to C 4 lower alkyl group, wherein the substituent group of the C 1 to C 4 lower alkyl group is a carboxylic acid group, a halogen atom, a C 1 to C 4 lower alkoxy group, an amino group, a methylamino group, a dimethylamino group, a carboxymethylamino group, or a carboxyethylamino group,
a halogen atom,
a hydroxyl group,
a C 1 to C 4 lower alkoxyl group, wherein the substituent group of the C 1 to C 4 lower alkyl group is a carboxylic acid group, a halogen atom, a C 1 to C 4 lower alkoxy group, an amino group, a methylamino group, a dimethylamino group, a carboxymethyl amino group or a carboxyethylamino group,
an amino group,
an unsubstituted or substituted C 1 to C 4 lower alkylamino group, wherein the substitutent group of the C 1 to C 4 lower alkylamino group is a carboxylic acid group, a halogen atom or a C 1 to C 4 lower alkoxyl group,
an unsubstituted or substituted C 7 to C 10 aralkylamino group, wherein the substitutent group of the C 7 to C aralkylamino group is a carboxylic acid group, a halogen atom or a C 1 to C 4 lower alkoxyl group,
an amino group acylated with a C 1 to C 4 lower aliphatic acid which is optionally substituted with a carboxylic acid group,
an amino group acylated with an aromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group acylated with a heteroaromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with an aromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a heteroaromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group, or
a carboxylic acid group or
when the ring A is a benzene ring, R 1 and R 2 may form, together with the substituted benzene ring, a fused heterocyclic ring which is selected from the group consisting of a tetrahydroquinoline, a benzoxazine, a quinoxaline, a benzodioxane, a carboxytetrahydroquinoline, a carboxybenzoxazine, a carboxyquinoxaline and a carboxybenzodioxane, and R 3 is the same as defined above; and
X represents
a hydrogen atom,
a C 1 to C 4 lower alkyl group, a C 1 to C 4 lower alkoxyl group,
a halogen atom,
a hydroxyl group,
an amino group, or
a nitro group.
4. A method according to claim 3 , wherein said dermatitis exhibiting a biphasic skin reaction is atopic dermatitis.
5. A method for treatment of dermatitis induced by repeated exposure to an antigen comprising administering a chymase inhibitor to a patient in need of such treatment in an amount effective for prevention or treatment of said dermatitis, wherein the chymase inhibitor is a quinazolidone derivative having the formula (I) or a pharmaceutically acceptable salt thereof:
wherein the ring A represents an aryl group;
R 1 represents
a hydroxyl group,
an amino group,
a C 1 to C 4 lower alkylamino group which is optionally substituted with a carboxylic acid group,
a C 7 to C 10 lower aralkylamino group which is optionally substituted with a carboxylic acid group,
an amino group acylated with a C 1 to C 4 lower aliphatic acid which is optionally substituted with a carboxylic acid group,
an amino group acylated with an aromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group acrylated with a heteroaromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with an aromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a heteroaromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group,
a C 1 to C 4 lower alkyl group substituted with a carboxylic acid group, or
a C 2 to C 4 lower alkylene group which is optionally substituted with a carboxylic acid group;
R 2 and R 3 may be the same or different, and represent
a hydrogen atom,
an unsubstituted or substituted C 1 to C 4 lower alkyl group, wherein the substituent group of the C 1 and C 4 lower alkyl group is a carboxylic acid group, a halogen atom, a C 1 and C 4 lower alkoxyl group, an amino group, a methylamino group, a dimethylamino group, a carboxymethylamino group or a carboxyethylamino group,
a halogen atom,
a hydroxyl group,
a C 1 to C 4 lower alkoxyl group,
an amino group,
an unsubstituted or substituted C 1 to C 4 lower alkylamino group, wherein the substitutent group of the C 1 to C 4 lower alkylamino group is a carboxylic acid group, a halogen atom or a C 1 to C 4 lower alkoxyl group,
an unsubstituted or substituted C 7 to C 10 aralkylamino group, wherein the substitutent group of the C 7 to C 10 aralkylamino group is a carboxylic acid group, a halogen atom or a C 1 to C 4 lower alkoxyl group,
an amino group acylated with a C 1 to C 4 lower aliphatic acid which is optionally substituted with a carboxylic acid group,
an amino group acylated with an aromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group acylated with a heteroaromatic ring carboxylic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with an aromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group,
an amino group sulfonylated with a heteroaromatic ring sulfonic acid which is optionally substituted with a carboxylic acid group, or
a carboxylic acid group or
when the ring A is a benzene ring, R 1 and R 2 may form, together with the substituted benzene ring, a fused heterocyclic ring which is selected from the group consisting of a tetrahydroquinoline, a benzoxazine, a quinoxaline, a benzodioxane, a carboxytetrahydroquinoline, a carboxybenzoxazine, a carboxyquinoxaline and a carboxybenzodioxane, and R 3 is the same as defined above; and
X represents
a hydrogen atom,
a C 1 to C 4 lower alkyl group,
a C 1 to C 4 lower alkoxyl group,
a halogen atom,
a hydroxyl group,
an amino group, or
a nitro group.