Quinazoline derivatives and pharmaceutical applications thereof

1. A quinazoline derivative having the following formula (1) or a pharmaceutically acceptable salt thereof:

wherein the ring A represents an aryl group:

R 1 represents (a) hydroxyl group, (b) an amino group, (c) a C 1 to C 4 lower alkylamino group which may be substituted with a COOH group, (d) a C 7 and C 10 lower aralkylamino group which may be substituted with a COOH group, (e) an amino group acylated with a C 1 to C 4 lower aliphatic acid which may be substituted with a COOH group, (f) an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a COOH group, (g) an amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a COOH group, (h) an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which may be substituted with a COOH group, (i) an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a COOH group, (j) an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a COOH group, (k) a C 1 to C 4 lower alkyl group substituted with a COOH group, or (l) a C 2 to C 4 lower alkenyl group which may be substituted with a COOH group;

R 2 represents (a) a C 1 to C 4 lower alkyl group substituted with a COOH 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, (b) a halogen atom, (c) a hydroxyl group, (d) a C 1 to C 4 lower alkoxyl group, (e) an amino group, (f) a C 1 to C 4 lower alkylamino group which may be substituted with a COOH group, a halogen atom or a C 1 to C 4 lower alkoxy group, (g) a C 7 to C 12 aralkylamino group which may be substituted with a COOH group, a halogen atom or a C 1 to C 4 lower alkoxy group, (h) an amino group acylated with a C 1 to C 4 lower aliphatic acid which may be substituted with a COOH group, (i) an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a COOH group, (j) an amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a COOH group, (k) an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which may be substituted with a COOH group, (l) an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a COOH group, (m) an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a COOH group, or (n) a COOH group or

R 3 represents (a) a hydrogen atom, (b) a C 1 to C 4 lower alkyl group which may be substituted with a COOH 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, (c) a halogen atom, (d) a hydroxyl group, (e) a C 1 to C 4 lower alkoxyl group, (f) an amino group, (g) a C 1 to C 4 lower alkylamino group which may be substituted with a COOH group, a halogen atom or a C 1 to C 4 lower alkoxy group, (h) a C 7 to C 12 aralkylamino group which may be substituted with a COOH group, a halogen atom or a C 1 to C 4 lower alkoxy group, (i) an amino group acylated with a C 1 to C 4 lower aliphatic acid which may be substituted with a COOH group, (j) an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a COOH group, (k) an amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a COOH group, (l) an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which may be substituted with a COOH group, (m) an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a COOH group, (n) an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a COOH group, or (o) a COOH group or

when the ring A is benzene ring, R 1 and R 2 may form, together with the substituting benzene ring, (a) a tetrahydroquinoline ring or (b) a benzoxazine ring which may be substituted with a COOH group and in which the carbon atom in the ring may form a carbonyl group and R 3 is the same as defined above; and

X represents (a) a hydrogen atom, (b) a C 1 to C 4 lower alkyl group, (c) a C 1 to C 4 lower alkoxy group, (d) a halogen atom, (e) a hydroxyl group, (f) an amino group, or (g) a nitro group.

2. A quinazoline derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein, in the formula (1), R 1 is a hydroxyl group, an amino group, a C 1 to C 4 lower alkylamino group substituted with a COOH group, or an amino group acylated with a C 1 to C 4 lower aliphatic acid substituted with a COOH group.

3. A quinazoline derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein, in the formula (1), R 2 is a COOH group.

4. A quinazoline derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein R 3 in the formula (1) is a hydrogen atom.

5. A pharmaceutical composition comprising as an effective ingredient a pharmaceutically effective amount of a quinazoline derivative or the pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier therefor.

6. A chymase composition inhibitor having as an effective ingredient a quinazoline derivative or its pharmaceutically acceptable salt according to claim 1 , and a pharmaceutically acceptable carrier therefor.

7. A method for treatment of allergic diseases or rheumatic diseases comprising administering to a patient in need of such treatment an effective amount of a quinazoline derivative or salt thereof according to claim 1 .

8. A method for treatment of bronchial asthma, eczema, atopic dermatitis, mastocytosis, scleriasis or rheumatoid arthritis comprising administering to a patient in need of such treatment an effective amount of a quinazoline derivative or salt thereof according to claim 1 .

9. A method for treatment of cardiac and circulatory system diseases due to the abnormal exacerbation of Angiotensin II production comprising administering to a patient in need of such treatment an effective amount of a quinazoline derivative or salt thereof according to claim 1 .

10. A method for treatment of cardiac insufficiency, hypercardia, stasis cardiac diseases, hypertension, arteriosclerosis, peripheral circulatory diseases, revasoconstriction after PTCA, diabetic renal disorders or non-diabetic renal disorders, cardiac infarction, angioendothelia or vascular disorders accompanying arterialization and atheroma comprising administering to a patient in need of such treatment an effective amount of a quinazoline derivative or salt thereof according to claim 1 .

11. A pharmaceutical composition comprising as an effective ingredient a pharmaceutically effective amount of a quinazoline derivative or a pharmaceutically acceptable salt thereof as claimed in claim 2 , and a pharmaceutically acceptable carrier therefor.

12. A pharmaceutical composition comprising as an effective ingredient a pharmaceutically effective amount of a quinazoline derivative or a pharmaceutically acceptable salt thereof as claimed in claim 3 , and a pharmaceutically acceptable carrier therefor.

13. A pharmaceutical composition comprising as an effective ingredient a pharmaceutically effective amount of a quinazoline derivative or a pharmaceutically acceptable salt thereof as claimed in claim 4 , and a pharmaceutically acceptable carrier therefor.

14. A quinazoline derivative having the following formula (1) and a pharmaceutically acceptable salt thereof:

wherein the ring A represents an aryl group:

R 1 represents (a) hydroxyl group, (b) a C 1 to C 4 lower alkylamino group which may be substituted with a COOH group, (c) a C 7 and C 10 lower aralkylamino group which may be substituted with a COOH group, (d) an amino group acylated with a C 1 to C 4 lower aliphatic acid which may be substituted with a COOH group, (e) an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a COOH group, (f) an amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a COOH group, (g) an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which may be substituted with a COOH group, (h) an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a COOH group, (i) an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a COOH group, (j) a C 1 to C 4 lower alkyl group substituted with a COOH group, or (k) a C 2 to C 4 lower alkenyl group which may be substituted with a COOH group;

R 2 and R 3 may be the same or different and represent (a) a hydrogen atom, (b) a C 1 to C 4 lower alkyl group which may be substituted with a COOH 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, (c) a halogen atom, (d) a hydroxyl group, (e) a C 1 to C 4 lower alkoxyl group, (f) an amino group, (g) a C 1 to C 4 lower alkylamino group which may be substituted with a COOH group, a halogen atom or a C 1 to C 4 lower alkoxy group, (h) a C 7 to C 12 aralkylamino group which may be substituted with a COOH group, a halogen atom or a C 1 to C 4 lower alkoxy group, (i) an amino group acylated with a C 1 to C 4 lower aliphatic acid which may be substituted with a COOH group, (j) an amino group acylated with an aromatic ring carboxylic acid which may be substituted with a COOH group, (k) an amino group acylated with a heteroaromatic ring carboxylic acid which may be substituted with a COOH group, (l) an amino group sulfonylated with a C 1 to C 4 lower alkanesulfonic acid which may be substituted with a COOH group, (m) an amino group sulfonylated with an aromatic ring sulfonic acid which may be substituted with a COOH group, (n) an amino group sulfonylated with a heteroaromatic ring sulfonic acid which may be substituted with a COOH group, or (o) a COOH group or

when the ring A is benzene ring, R 1 and R 2 may form, together with the substituting benzene ring, (a) a tetrahydroquinoline ring or (b) a benzoxazine ring which may be substituted with a COOH group and in which the carbon atom in the ring may form a carbonyl group and R 3 is the same as defined above; and

X represents (a) a hydrogen atom, (b) a C 1 to C 4 lower alkyl group, (c) a C 1 to C 4 lower alkoxy group, (d) a halogen atom, (e) a hydroxyl group, (f) an amino group, or (g) a nitro group.

15. A quinazoline derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein said compound is selected from the group consisting of

3-(3-amino-4-chlorobenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione,

3-(4-amino-3,5-dichlorobenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione,

4-[(7-chloro-2,4(1H,3H)quinazolinedion-3-yl)sulfonyl]anthranilic acid,

4-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid monosodium salt,

3-(3-amino-4-methoxybenzenesulfonyl)-7-chloro-2,4(1H,3H)-quinazolinedione,

5-[(7-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid,

4-[(7-methoxy-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid,

4-[(7-hydroxy-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid and

4-[(6-chloro-2,4(1H,3H)-quinazolinedion-3-yl)sulfonyl]anthranilic acid.

16. A pharmaceutical composition comprising as an effective ingredient a pharmaceutically effective amount of a quinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 14 and a pharmaceutically acceptable carrier therefore.

17. A chymase composition inhibitor having as an effective ingredient a quinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 14 and a pharmaceutically acceptable carrier therefore.