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1. US20060160829 - Thienopyrimidine compounds and use thereof

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Claims

1. A compound of the formula:

( 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 alkoxy-carbonyl, (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-(((2-ethoxyethyl)(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-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or 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. A prodrug of the compound as claimed in claim 1.
12. A pharmaceutical which comprises the compound as claimed in claim 1 or a prodrug thereof.
13. A pharmaceutical as claimed in claim 12, which is a gonadotropin-releasing hormone antagonist.
14. A pharmaceutical as claimed in claim 12, which is for preventing or treating a sex hormone dependent disease.
15. A pharmaceutical as claimed in claim 12, 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.
16. A method for antagonizing gonadotropin-releasing hormone, which comprises administering an effective amount of the compound as claimed in claim 1 to a mammal.
17. Use of the compound as claimed in claim 1 for manufacturing a pharmaceutical composition for antagonizing gonadotropin-releasing hormone.
18. A compound of the formula:

( 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.