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1. US20080108623 - Substituted thieno[2,3-d]pyrimidin-2,4-dione compounds and uses thereof

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Claims

1. A compound of the formula (I):

( MOL) ( CDX)
wherein
R 1 is a C 1-4 alkyl;
R 2 is
(1) a C 1-6 alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C 1-4 alkoxy, (3′) a C 1-4 alkoxy-carbonyl, (4′) a di-C 1-4 alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C 1-4 alkyl-carbonyl and (7′) a halogen,
(2) a C 3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C 1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4 alkyl and (4′) a C 1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4 alkoxy-C 1-4 alkyl, (3′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkyl, (4′) a C 1-4 alkoxy and (5′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkoxy, or
(5) a C 1-4 alkoxy;
R 3 is a C 1-4 alkyl;
R 4 is
(1) a hydrogen atom,
(2) a C 1-4 alkoxy,
(3) a C 6-10 aryl,
(4) a N—C 1-4 alkyl-N—C 1-4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C 1-4 alkyl, (3′) a hydroxy-C 1-4 alkyl, (4′) a C 1-4 alkoxy-carbonyl, (5′) a mono-C 1-4 alkyl-carbamoyl and (6′) a C 1-4 alkylsulfonyl;
n is an integer of 1 to 4;
provided that when R 2 is a phenyl which may have a substituent, R 4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) a hydroxy-C 1-4 alkyl, (3) a C 1-4 alkoxy-carbonyl, (4) a mono-C 1-4 alkyl-carbamoyl and (5) a C 1-4 alkylsulfonyl; or a salt thereof.
2. A compound as claimed in claim 1, wherein
R 2 is
(1) a C 1-4 alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C 1-4 alkoxy, (3′) a C 1-4 alkoxy-carbonyl, (4′) a di-C 1-4 alkyl-carbamoyl and (5′) a 5 to 7-membered nitrogen-containing heterocyclic group,
(2) a C 3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C 1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4 alkyl and (4′) a C 1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4 alkoxy-C 1-4 alkyl, (3′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkyl and (4′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkoxy, or
(5) a C 1-4 alkoxy;
R 4 is
(1) a C 1-4 alkoxy,
(2) a C 6-10 aryl,
(3) a N—C 1-4 alkyl-N—C 1-4 alkylsulfonylamino or
(4) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a hydroxy-C 1-4 alkyl, (3′) a C 1-4 alkoxycarbonyl, (4′) a mono-C 1-4 alkyl-carbamoyl and (5′) a C 1-4 alkylsulfonyl.
3. A compound as claimed in claim 1, wherein R 1 is methyl.
4. A compound as claimed in claim 1, wherein R 2 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) a halogen, (2) a hydroxy group, (3) a C 1-4 alkyl and (4) a C 1-4 alkoxy.
5. A compound as claimed in claim 1, wherein R 3 is methyl.
6. A compound as claimed in claim 1, wherein R 4 is a C 1-4 alkoxy.
7. A compound as claimed in claim 1, wherein n is 2.
8. A compound as claimed in claim 1, wherein R 3 is methyl, R 4 is a hydrogen atom and n is 1.
9. N-(4-(1-(2,6-difluorobenzyl)-5(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-3-(2-pyridinyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a salt thereof.
10. N-(4-(5((2-methoxyethyl)methylamino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-methoxyphenyl)thieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a salt thereof.
11- 17. (canceled)
18. A compound of the formula (A):

( MOL) ( CDX)
wherein
R a is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl, (3) a cycloalkyl group which may have a substituent or (4) a heterocyclic group which may have a substituent;
R b is a nitrogen-containing heterocyclic group which may have a substituent;
R c is an amino group which may have a substituent;
R d is an aryl group which may have a substituent;
p is an integer of 0 to 3;
q is an integer of 0 to 3; or a salt thereof.
19. N-(4-(1-(2,6-difluorobenzyl)-3-(4-(1-hydroxy-1-methylethyl)phenyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-(1-hydroxy-1-methylethyl)phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, N-(4-(1-(2,6-difluorobenzyl)-3((1-(hydroxymethyl)cyclopropyl)methyl)-5-(((2-methoxyethyl)(methyl)amino)methyl)-2,4-dioxo1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, or a salt thereof.
20. A prodrug of the compound represented by formula (I)

( MOL) ( CDX)
wherein
R 1 is a C 1-4 alkyl;
R 2 is
(1) a C 1-6 alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C 1-4 alkoxy, (3′) a C 1-4 alkoxy-carbonyl, (4′) a di-C 1-4 alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C 1-4 alkyl-carbonyl and (7′) a halogen,
(2) a C 3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C 1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4 alkyl and (4′) a C 1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4 alkoxy-C 1-4 alkyl, (3′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkyl, (4′) a C 1-4 alkoxy and (5′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkoxy, or
(5) a C 1-4 alkoxy;
R 3 is a C 1-4 alkyl;
R 4 is
(1) a hydrogen atom,
(2) a C 1-4 alkoxy,
(3) a C 6-10 aryl,
(4) a N—C 1-4 alkyl-N—C 1-4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C 1-4 alkyl, (3′) a hydroxy-C 1-4 alkyl, (4′) a C 1-4 alkoxy-carbonyl, (5′) a mono-C 1-4 alkyl-carbamoyl and (6′) a C 1-4 alkylsulfonyl;
n is an integer of 1 to 4;
provided that when R 2 is a phenyl which may have a substituent, R 4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) a hydroxy-C 1-4 alkyl, (3) a C 1-4 alkoxy-carbonyl, (4) a mono-C 1-4 alkyl-carbamoyl and (5) a C 1-4 alkylsulfonyl; or a salt thereof.
21. A pharmaceutical composition which comprises the compound represented by formula (I):

( MOL) ( CDX)
wherein
R 1 is a C 1-4 alkyl;
R 2 is
(1) a C 1-6 alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C 1-4 alkoxy, (3′) a C 1-4 alkoxy-carbonyl, (4′) a di-C 1-4 alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C 1-4 alkyl-carbonyl and (7′) a halogen,
(2) a C 3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C 1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4 alkyl and (4′) a C 1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4 alkoxy-C 1-4 alkyl, (3′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkyl, (4′) a C 1-4 alkoxy and (5′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkoxy, or
(5) a C 1-4 alkoxy;
R 3 is a C 1-4 alkyl;
R 4 is
(1) a hydrogen atom,
(2) a C 1-4 alkoxy,
(3) a C 6-10 aryl,
(4) a N—C 1-4 alkyl-N—C 1-4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C 1-4 alkyl, (3′) a hydroxy-C 1-4 alkyl, (4′) a C 1-4 alkoxy-carbonyl, (5′) a mono-C 1-4 alkyl-carbamoyl and (6′) a C 1-4 alkylsulfonyl;
n is an integer of 1 to 4;
provided that when R 2 is a phenyl which may have a substituent, R 4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) a hydroxy-C 1-4 alkyl, (3) a C 1-4 alkoxy-carbonyl, (4) a mono-C 1-4 alkyl-carbamoyl and (5) a C 1-4 alkylsulfonyl; or a salt thereof or a prodrug thereof, and a pharmacologically acceptable carrier, excipient or diluent.
22. A pharmaceutical composition as claimed in claim 21, which is a gonadotropin-releasing hormone antagonist.
23. A pharmaceutical composition as claimed in claim 21, which is for preventing or treating a sex hormone dependent disease.
24. A pharmaceutical composition as claimed in claim 21, which is for preventing or treating sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, benign or malignant tumor which is hormone independent and LH-RH sensitive or hot flash; reproduction regulator; contraceptive agent; ovulation inducer; or for prevention of postoperative recurrence of sex hormone-dependent cancer.
25. A method for antagonizing gonadotropin-releasing hormone, which comprises administering an effective amount of the compound represented by formula (I):

( MOL) ( CDX)
wherein
R 1 is a C 1-4 alkyl;
R 2 is
(1) a C 1-6 alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C 1-4 alkoxy, (3′) a C 1-4 alkoxy-carbonyl, (4′) a di-C 1-4 alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C 1-4 alkyl-carbonyl and (7′) a halogen,
(2) a C 3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C 1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4 alkyl and (4′) a C 1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4 alkoxy-C 1-4 alkyl, (3′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkyl, (4′) a C 1-4 alkoxy and (5′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkoxy, or
(5) a C 1-4 alkoxy;
R 3 is a C 1-4 alkyl;
R 4 is
(1) a hydrogen atom,
(2) a C 1-4 alkoxy,
(3) a C 6-10 aryl,
(4) a N—C 1-4 alkyl-N—C 1-4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C 1-4 alkyl, (3′) a hydroxy-C 1-4 alkyl, (4′) a C 1-4 alkoxy-carbonyl, (5′) a mono-C 1-4 alkyl-carbamoyl and (6′) a C 1-4 alkylsulfonyl;
n is an integer of 1 to 4;
provided that when R 2 is a phenyl which may have a substituent, R 4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) a hydroxy-C 1-4 alkyl, (3) a C 1-4 alkoxy-carbonyl, (4) a mono-C 1-4 alkyl-carbamoyl and (5) a C 1-4 alkylsulfonyl; or a salt thereof to a mammal.
26. A method for manufacturing a pharmaceutical composition for antagonizing gonadotropin-releasing hormone which comprises mixing the compound represented by formula (I):

( MOL) ( CDX)
wherein
R 1 is a C 1-4 alkyl;
R 2 is
(1) a C 1-6 alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C 1-4 alkoxy, (3′) a C 1-4 alkoxy-carbonyl, (4′) a di-C 1-4 alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C 1-4 alkyl-carbonyl and (7′) a halogen,
(2) a C 3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C 1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4 alkyl and (4′) a C 1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4 alkoxy-C 1-4 alkyl, (3′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkyl, (4′) a C 1-4 alkoxy and (5′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkoxy, or
(5) a C 1-4 alkoxy;
R 3 is a C 1-4 alkyl;
R 4 is
(1) a hydrogen atom,
(2) a C 1-4 alkoxy,
(3) a C 6-10 aryl,
(4) a N—C 1-4 alkyl-N—C 1-4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C 1-4 alkyl, (3′) a hydroxy-C 1-4 alkyl, (4′) a C 1-4 alkoxy-carbonyl, (5′) a mono-C 1-4 alkyl-carbamoyl and (6′) a C 1-4 alkylsulfonyl;
n is an integer of 1 to 4;
provided that when R 2 is a phenyl which may have a substituent, R 4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) a hydroxy-C 1-4 alkyl, (3) a C 1-4 alkoxy-carbonyl, (4) a mono-C 1-4 alkyl-carbamoyl and (5) a C 1-4 alkylsulfonyl; or a salt thereof; and a pharmacologically acceptable carrier, excipient or diluent.
27. A method for preventing and/or treating diseases selected from the group consisting of sex-hormone dependent cancers, bone metastasis of the sex hormone-dependent cancers, prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome and LH-RH sensitive benign or malignant tumor which is independent of the hormone; for regulating reproduction, contraception or induction of ovulation; or for preventing postoperative recurrence of sex hormone-dependent cancers, by antagonizing gonadotropin-releasing hormone, which comprises administering an effective amount of the compound represented by formula (I):

( MOL) ( CDX)
wherein
R 1 is a C 1-4 alkyl;
R 2 is
(1) a C 1-6 alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C 1-4 alkoxy, (3′) a C 1-4 alkoxy-carbonyl, (4′) a di-C 1-4 alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C 1-4 alkyl-carbonyl and (7′) a halogen,
(2) a C 3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C 1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4 alkyl and (4′) a C 1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4 alkoxy-C 1-4 alkyl, (3′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkyl, (4′) a C 1-4 alkoxy and (5′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkoxy, or
(5) a C 1-4 alkoxy;
R 3 is a C 1-4 alkyl;
R 4 is
(1) a hydrogen atom,
(2) a C 1-4 alkoxy,
(3) a C 6-10 aryl,
(4) a N—C 1-4 alkyl-N—C 1-4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C 1-4 alkyl, (3′) a hydroxy-C 1-4 alkyl, (4′) a C 1-4 alkoxy-carbonyl, (5′) a mono-C 1-4 alkyl-carbamoyl and (6′) a C 1-4 alkylsulfonyl;
n is an integer of 1 to 4;
provided that when R 2 is a phenyl which may have a substituent, R 4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) a hydroxy-C 1-4 alkyl, (3) a C 1-4 alkoxy-carbonyl, (4) a mono-C 1-4 alkyl-carbamoyl and (5) a C 1-4 alkylsulfonyl; or a salt thereof; to a mammal.
28. A method for preventing and/or treating diseases depending on male or female hormone, diseases due to excess of these hormones, by suppressing gonadotropin secretion with its gonadotropin-releasing hormone receptor-antagonizing action to control plasma sex hormone concentrations, which comprises administering an effective amount of the compound represented by formula (I):

( MOL) ( CDX)
wherein
R 1 is a C 1-4 alkyl;
R 2 is
(1) a C 1-6 alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C 1-4 alkoxy, (3′) a C 1-4 alkoxy-carbonyl, (4′) a di-C 1-4 alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C 1-4 alkyl-carbonyl and (7′) a halogen,
(2) a C 3-8cycloallyl which may have (1′) a hydroxy group or (2′) a mono-C 1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4 alkyl and (4′) a C 1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4 alkoxy-C 1-4 alkyl, (3′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkyl, (4′) a C 1-4 alkoxy and (5′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkoxy, or
(5) a C 1-4 alkoxy;
R 3 is a C 1-4 alkyl;
R 4 is
(1) a hydrogen atom,
(2) a C 1-4 alkoxy,
(3) a C 6-10 aryl,
(4) a N—C 1-4 alkyl-N—C 1-4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C 1-4 alkyl, (3′) a hydroxy-C 1-4 alkyl, (4′) a C 1-4 alkoxy-carbonyl, (5′) a mono-C 1-4 alkyl-carbamoyl and (6′) a C 1-4 alkylsulfonyl;
n is an integer of 1 to 4;
provided that when R 2 is a phenyl which may have a substituent, R 4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) a hydroxy-C 1-4 alkyl, (3) a C 1-4 alkoxy-carbonyl, (4) a mono-C 1-4 alkyl-carbamoyl and (5) a C 1-4 alkylsulfonyl; or a salt thereof; to a mammal.
29. A method for preventing and/or treating diseases depending on sex hormone, LH-RH sensitive benign or malignant tumor which is independent of the hormone or irritable bowel syndrome; for regulating reproduction in male or females, male or female contraception, induction of ovulation, or animal estrus; for preventing postoperative recurrence of sex hormone-dependent cancers; for improving meat quality; or for promoting animal growth or fish spawning, which comprises administering an effective amount of the compound represented by formula (I):

( MOL) ( CDX)
wherein
R 1 is a C 1-4 alkyl;
R 2 is
(1) a C 1-6 alkyl which may have a substituent selected from the group consisting of (1′) a hydroxy group, (2′) a C 1-4 alkoxy, (3′) a C 1-4 alkoxy-carbonyl, (4′) a di-C 1-4 alkyl-carbamoyl, (5′) a 5- to 7-membered nitrogen-containing heterocyclic group, (6′) a C 1-4 alkyl-carbonyl and (7′) a halogen,
(2) a C 3-8 cycloalkyl which may have (1′) a hydroxy group or (2′) a mono-C 1-4 alkyl-carbonylamino,
(3) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a hydroxy group, (3′) a C 1-4 alkyl and (4′) a C 1-4 alkoxy,
(4) a phenyl which may have a substituent selected from the group consisting of (1′) a halogen, (2′) a C 1-4 alkoxy-C 1-4 alkyl, (3′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkyl, (4′) a C 1-4 alkoxy and (5′) a mono-C 1-4 alkyl-carbamoyl-C 1-4 alkoxy, or
(5) a C 1-4 alkoxy;
R 3 is a C 1-4 alkyl;
R 4 is
(1) a hydrogen atom,
(2) a C 1-4 alkoxy,
(3) a C 6-10 aryl,
(4) a N—C 1-4 alkyl-N—C 1-4 alkylsulfonylamino,
(5) a hydroxyl group, or
(6) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1′) oxo, (2′) a C 1-4 alkyl, (3′) a hydroxy-C 1-4 alkyl, (4′) a C 1-4 alkoxy-carbonyl, (5′) a mono-C 1-4 alkyl-carbamoyl and (6′) a C 1-4 alkylsulfonyl;
n is an integer of 1 to 4;
provided that when R 2 is a phenyl which may have a substituent, R 4 is a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1) oxo, (2) a hydroxy-C 1-4 alkyl, (3) a C 1-4 alkoxy-carbonyl, (4) a mono-C 1-4 alkyl-carbamoyl and (5) a C 1-4 alkylsulfonyl; or a salt thereof; to a mammal.
30. A prodrug of the compound represented by formula (A):

( MOL) ( CDX)
wherein
R a is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl, (3) a cycloalkyl group which may have a substituent or (4) a heterocyclic group which may have a substituent;
R b is a nitrogen-containing heterocyclic group which may have a substituent;
R c is an amino group which may have a substituent;
R d is an aryl group which may have a substituent;
p is an integer of 0 to 3;
q is an integer of 0 to 3; or a salt thereof.
31. A pharmaceutical composition which comprises the compound represented by formula (A):

( MOL) ( CDX)
wherein
R a is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl, (3) a cycloalkyl group which may have a substituent or (4) a heterocyclic group which may have a substituent;
R b is a nitrogen-containing heterocyclic group which may have a substituent;
R c is an amino group which may have a substituent;
R d is an aryl group which may have a substituent;
p is an integer of 0 to 3;
q is an integer of 0 to 3; or a salt thereof or a prodrug thereof, and a pharmacologically acceptable carrier, excipient or diluent.
32. A pharmaceutical composition as claimed in claim 31, which is a gonadotropin-releasing hormone antagonist.
33. A pharmaceutical composition as claimed in claim 31, which is for preventing or treating a sex hormone dependent disease.
34. A pharmaceutical composition as claimed in claim 31, which is for preventing or treating sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, benign or malignant tumor which is hormone independent and LH-RH sensitive or hot flash; reproduction regulator; contraceptive agent; ovulation inducer; or for prevention of postoperative recurrence of sex hormone-dependent cancer.
35. A method for antagonizing gonadotropin-releasing hormone, which comprises administering an effective amount of the compound represented by formula (A):

( MOL) ( CDX)
wherein
R a is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfonyl and (xi) an alkylsulfonyl, (3) a cycloalkyl group which may have a substituent or (4) a heterocyclic group which may have a substituent;
R b is a nitrogen-containing heterocyclic group which may have a substituent;
R c is an amino group which may have a substituent;
R d is an aryl group which may have a substituent;
p is an integer of 0 to 3;
q is an integer of 0 to 3; or a salt thereof to a mammal.
36. A method for manufacturing a pharmaceutical composition for antagonizing gonadotropin-releasing hormone which comprises mixing the compound represented by formula (A)

( MOL) ( CDX)
wherein
R a is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl, (3) a cycloalkyl group which may have a substituent or (4) a heterocyclic group which may have a substituent;
R b is a nitrogen-containing heterocyclic group which may have a substituent;
R c is an amino group which may have a substituent;
R d is an aryl group which may have a substituent;
p is an integer of 0 to 3;
q is an integer of 0 to 3; or a salt thereof; and a pharmacologically acceptable carrier, excipient or diluent.
37. A method for preventing and/or treating diseases selected from the group consisting of sex-hormone dependent cancers, bone metastasis of the sex hormone-dependent cancers, prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome and LH-RH sensitive benign or malignant tumor which is independent of the hormone; for regulating reproduction, contraception or induction of ovulation; or for preventing postoperative recurrence of sex hormone-dependent cancers, by antagonizing gonadotropin-releasing hormone, which comprises administering an effective amount of the compound represented by formula (A):

( MOL) ( CDX)
wherein
R a is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl, (3) a cycloalkyl group which may have a substituent or (4) a heterocyclic group which may have a substituent;
R b is a nitrogen-containing heterocyclic group which may have a substituent;
R c is an amino group which may have a substituent;
R d is an aryl group which may have a substituent;
p is an integer of 0 to 3;
q is an integer of 0 to 3; or a salt thereof; to a mammal.
38. A method for preventing and/or treating diseases depending on male or female hormone, diseases due to excess of these hormones, by suppressing gonadotropin secretion with its gonadotropin-releasing hormone receptor-antagonizing action to control plasma sex hormone concentrations, which comprises administering an effective amount of the compound represented by formula (A):

( MOL) ( CDX)
wherein
R a is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl, (3) a cycloalkyl group which may have a substituent or (4) a heterocyclic group which may have a substituent;
R b is a nitrogen-containing heterocyclic group which may have a substituent;
R c is an amino group which may have a substituent;
R d is an aryl group which may have a substituent;
p is an integer of 0 to 3;
q is an integer of 0 to 3; or a salt thereof; to a mammal.
39. A method for preventing and/or treating diseases depending on sex hormone, LH-RH sensitive benign or malignant tumor which is independent of the hormone or irritable bowel syndrome; for regulating reproduction in male or females, male or female contraception, induction of ovulation, or animal estrus; for preventing postoperative recurrence of sex hormone-dependent cancers; for improving meat quality; or for promoting animal growth or fish spawning, which comprises administering an effective amount of the compound represented by formula (A):

( MOL) ( CDX)
wherein
R a is (1) a hydrogen atom, (2) an aryl group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) nitro, (iii) cyano, (iv) amino, (v) a carboxyl group which may be esterified or amidated, (vi) an alkylenedioxy, (vii) an alkyl, (viii) an alkoxy, (ix) an alkylthio, (x) an alkylsulfinyl and (xi) an alkylsulfonyl, (3) a cycloalkyl group which may have a substituent or (4) a heterocyclic group which may have a substituent;
R b is a nitrogen-containing heterocyclic group which may have a substituent;
R c is an amino group which may have a substituent;
R d is an aryl group which may have a substituent;
p is an integer of 0 to 3;
q is an integer of 0 to 3; or a salt thereof; to a mammal.