GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO
First Claim
1. A compound having the following structure (I):
- or a stereoisomers, esters, solvates, or pharmaceutically acceptable salts thereof,wherein;
A is pyridyl, phenyl, quinolinyl, naphthyridinyl, thienopyrimidinyl, or 2-oxo-pyrimidinyl, wherein the pyridyl, phenyl, quinolinyl, thienopyrimidinyl or 2-oxo-pyrimidinyl is substituted with 0-5 R4;
R1a is H, halogen, C1-4alkyl, alkoxy or trifluoromethyl;
R1b and R1c are the same or different and are independently H, halogen, hydroxy, haloC1-4 alkyl, —
C1-6 alkyl-(R5)p, —
O—
C1-6alkyl-(R5)p, —
C1-6alkyl-O—
C1-6alkyl-(R5)p, —
NR7—
C1-6alkyl-(R5)p, or —
S(O)m—
C1-6alkyl-(R5)p;
R1d is Cl, F, methyl, CF3 or cyano;
R2 is —
C1-4alkyl-(R5)p;
R2a is phenyl substituted with 0-4 R3, heteroaryl substituted with 0-4 R3, C1-6alkyl substituted with 0-4 R3, aryl-C1-4alkyl substituted with 0-4 R3, or heteroaryl-C1-4alkyl substituted with 0-4 R3;
R3 at each occurrence is independently halogen, cyano, halo-C1-4alkyl, R5, —
C1-6alkyl —
(R5)p, —
C1-6alkyl-O—
C1-6alkyl-(R5)p, —
O—
C1-6alkyl-(R5)p, —
NR7, —
C1-6alkyl-(R5)p, —
S(O)m—
C1-6alkyl-(R5)p, —
O—
C1-6alkyl-NR7—
C1-6alkyl-(R5)p, heterocycle-(R5)p;
R4 at each occurrence is independently halogen, C1-6alkyl, haloC1-4alkyl, C1-6alkoxy, hydroxy, cyano, thioC1-6alkyl, —
C(O)NR7R8 or 5 member heteroaryl;
R5 at each occurrence is independently H, hydroxy, —
OC(O)—
C1-6alkyl, —
OC(O)O—
C1-6alkyl, —
OC(O)—
C1-6alkyl-NR7R8, —
COOR6, —
C(O)NR7R8, —
NR7C(O)NR7R8, —
S(O)2NR9R9, —
S(O)m—
C1-4 alkyl, —
NR7R8, C1-6alkoxy, —
O-heterocycle, or heterocycle wherein said heterocycle and said —
O-heterocycle are substituted with 0-4 groups selected from halogen, C1-6alkyl, C1-4haloalkyl, hydroxy, oxo, thio, —
NH2, —
S(O)2C1-4alkyl and —
COOH;
R6 at each occurrence is independently H, C1-4alkyl, C1-4alkyl-O—
C(O)—
C1-6alkyl, or C1-4alkyl-O—
C(O)—
O—
C1-6alkyl;
R7 at each occurrence is independently H, C1-4alkyl, hydroxy, or heterocycle where said heterocycle is substituted with 0-4 groups selected from halogen, C1-6alkyl, hydroxy, keto, —
NH2 and —
COOH;
R8 at each occurrence is independently H, C1-4alkyl, haloC1-4alkyl, —
C(O)—
C1-4alkyl, —
C(O)-haloC1-4alkyl, —
S(O)m-haloC1-4alkyl or —
S(O)m—
C1-4alkyl;
R9 at each occurrence is independently H, C1-4alkyl, or —
C(O)C1-4alkyl;
m is 0-2; and
p at each occurrence is independently 1-3.
3 Assignments
0 Petitions
Accused Products
Abstract
GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure, wherein R1a, R1b, R1c, R1d, R2, R2a, and A are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
28 Citations
21 Claims
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1. A compound having the following structure (I):
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or a stereoisomers, esters, solvates, or pharmaceutically acceptable salts thereof, wherein; A is pyridyl, phenyl, quinolinyl, naphthyridinyl, thienopyrimidinyl, or 2-oxo-pyrimidinyl, wherein the pyridyl, phenyl, quinolinyl, thienopyrimidinyl or 2-oxo-pyrimidinyl is substituted with 0-5 R4; R1a is H, halogen, C1-4alkyl, alkoxy or trifluoromethyl; R1b and R1c are the same or different and are independently H, halogen, hydroxy, haloC1-4 alkyl, —
C1-6 alkyl-(R5)p, —
O—
C1-6alkyl-(R5)p, —
C1-6alkyl-O—
C1-6alkyl-(R5)p, —
NR7—
C1-6alkyl-(R5)p, or —
S(O)m—
C1-6alkyl-(R5)p;R1d is Cl, F, methyl, CF3 or cyano; R2 is —
C1-4alkyl-(R5)p;R2a is phenyl substituted with 0-4 R3, heteroaryl substituted with 0-4 R3, C1-6alkyl substituted with 0-4 R3, aryl-C1-4alkyl substituted with 0-4 R3, or heteroaryl-C1-4alkyl substituted with 0-4 R3; R3 at each occurrence is independently halogen, cyano, halo-C1-4alkyl, R5, —
C1-6alkyl —
(R5)p, —
C1-6alkyl-O—
C1-6alkyl-(R5)p, —
O—
C1-6alkyl-(R5)p, —
NR7, —
C1-6alkyl-(R5)p, —
S(O)m—
C1-6alkyl-(R5)p, —
O—
C1-6alkyl-NR7—
C1-6alkyl-(R5)p, heterocycle-(R5)p;R4 at each occurrence is independently halogen, C1-6alkyl, haloC1-4alkyl, C1-6alkoxy, hydroxy, cyano, thioC1-6alkyl, —
C(O)NR7R8 or 5 member heteroaryl;R5 at each occurrence is independently H, hydroxy, —
OC(O)—
C1-6alkyl, —
OC(O)O—
C1-6alkyl, —
OC(O)—
C1-6alkyl-NR7R8, —
COOR6, —
C(O)NR7R8, —
NR7C(O)NR7R8, —
S(O)2NR9R9, —
S(O)m—
C1-4 alkyl, —
NR7R8, C1-6alkoxy, —
O-heterocycle, or heterocycle wherein said heterocycle and said —
O-heterocycle are substituted with 0-4 groups selected from halogen, C1-6alkyl, C1-4haloalkyl, hydroxy, oxo, thio, —
NH2, —
S(O)2C1-4alkyl and —
COOH;R6 at each occurrence is independently H, C1-4alkyl, C1-4alkyl-O—
C(O)—
C1-6alkyl, or C1-4alkyl-O—
C(O)—
O—
C1-6alkyl;R7 at each occurrence is independently H, C1-4alkyl, hydroxy, or heterocycle where said heterocycle is substituted with 0-4 groups selected from halogen, C1-6alkyl, hydroxy, keto, —
NH2 and —
COOH;R8 at each occurrence is independently H, C1-4alkyl, haloC1-4alkyl, —
C(O)—
C1-4alkyl, —
C(O)-haloC1-4alkyl, —
S(O)m-haloC1-4alkyl or —
S(O)m—
C1-4alkyl;R9 at each occurrence is independently H, C1-4alkyl, or —
C(O)C1-4alkyl;m is 0-2; and p at each occurrence is independently 1-3. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
or a stereoisomer, ester, solvate or pharmaceutically acceptable salt thereof, wherein; A is pyridyl, phenyl, quinolinyl, thienopyrimidinyl, or 2-oxo-pyrimidinyl, wherein the pyridyl, phenyl, quinolinyl, thienopyrimidinyl or 2-oxo-pyrimidinyl is substituted with 0-4 R4; R1a is H, halogen, alkyl, alkoxy or trifluoromethyl; R1b and R1c are the same or different and are independently H, halogen, hydroxy, haloC1-4alkyl, —
C1-6 alkyl-(R5)p, —
O—
C1-6 alkyl-(R5)p, —
C1-6alkyl-O—
C1-6alkyl-(R5)p, —
NR7—
C1-6alkyl-(R5)p, or —
S(O)m—
C1-6alkyl-(R5)p;R1d is Cl, methyl, CF3 or cyano; R2 is C1-4alkyl-(R5)p; R3 at each occurrence is independently halogen, haloC1-4alkyl, hydroxy, —
C1-6alkyl-(R5)p, —
C1-6alkyl-O—
C1-6alkyl-(R5)p, —
O—
C1-6alkyl-(R5)p, —
NR7—
C1-6alkyl-(R5)p, —
S(O)m—
C1-6alkyl-(R5)p, —
CO2R6, —
C(O)NR7R8;R4 at each occurrence is independently halogen, alkyl, haloC1-4alkyl, C1-4alkoxy, hydroxy, cyano, thioC1-4alkyl, —
C(O)NR7R8 or 5 member heteroaryl;R5 at each occurrence is independently H, hydroxy, —
OC(O)—
C1-6alkyl, —
OC(O)O—
C1-6alkyl, —
OC(O)—
C1-6alkyl-NR7R8, —
COOR6, —
C(O)NR7R8, —
S(O)2NR9R9, —
S(O)mC1-4alkyl, —
NR7R8, C1-6alkoxy, or a heterocycle selected from the group consisting ofR6 at each occurrence is independently H, C1-4alkyl, C1-4alkyl-O—
C(O)—
C1-6alkyl, or C1-4alkyl-O—
C(O)—
O—
C1-6alkyl;R7 is H, C1-4alkyl or hydroxy; R8 is H, C1-4alkyl, —
C(O)—
C1-4alkyl, —
C(O)NR7—
C1-4alkyl, or —
S(O)m—
C1-4alkyl;R9 at each occurrence is independently H, C1-4alkyl, or —
C(O)C1-4alkyl;m is 0-2; n is 0-4; and p at each occurrence is independently 1-3.
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3. A compound of claim 1 wherein A is pyridyl substituted with 0-4 R4.
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4. A compound of claim 3 wherein A is 2-pyridyl substituted with 0-4 R4.
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5. A compound of claim 3 wherein A is 3-pyridyl substituted with 0-4 R4.
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6. A compound of claim 1 wherein A is phenyl substituted with 0-4 R4.
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7. A compound of claim 1 wherein A is quinolinyl substituted with 0-4 R4.
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8. A compound of claim 1 wherein A is thienopyrimidinyl substituted with 0-4 R4.
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9. A compound of claim 1 wherein A is 2-oxo-pyrimidinyl substituted with 0-4 R4.
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10. A compound of claim 1 wherein R1a and R1c are H.
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11. A compound of claim 1 wherein R1b is —
- C1-6alkyl-(R5)p or —
O—
C1-6alkyl-(R5)p, p is 1, and R5 is H, hydroxy or COOR6.
- C1-6alkyl-(R5)p or —
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12. A compound of claim 1 wherein R2a is phenyl substituted with 1 or 2 R3, wherein one of R3 is —
- O—
C1-6alkyl-(R5)p, p is 1, and R5 is H hydroxy or COOR6.
- O—
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13. A compound of claim 1 wherein R3 is —
- C1-6alkyl-(R5)p, —
C1-6alkyl-O—
C1-6alkyl-(R5)p or —
O—
C1-6alkyl-(R5)p.
- C1-6alkyl-(R5)p, —
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14. A compound of claim 1 wherein the compound is 3-(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(4-methyl-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(4-methyl-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-propionic acid, 4-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyric acid, 2-{[4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoyl]-methyl-amino}-benzoic acid methyl ester, 4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-fluoro-6-methoxy-phenyl)-2-methoxy-N-methyl-benzamide, or a pharmaceutically acceptable salt thereof.
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15. A compound of claim 1 wherein the compound is 4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid, 3-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenoxy}-propionic acid, 4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid, 4-[5-Chloro-2-[(5-chloro-2-methoxy-phenyl)-methyl-carbamoyl]-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric acid, 2-{[2-(3-Carboxy-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-benzoic acid methyl ester, 4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[methyl-(2-oxazol-5-yl-phenyl)-carbamoyl]-phenoxy}-butyric acid, 4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-fluoro-6-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid, 4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-2-[3-(2H-tetrazol-5-yl)-propoxy]-benzamide, 4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-benzamide, or a pharmaceutically acceptable salt thereof.
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16. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
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17. A method for treating a sex-hormone related condition of a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 16.
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18. A method for treating a condition in a subject in need thereof, wherein said condition is endometriosis, uterine fibroids, polycystic ovarian disease, dysmenorrhea, dyspareunia, menorrhagia, nonmenstrual pelvic pain, pelvic tenderness, induration, general disorders of the menstrual cycle, premature ovarian failure due to chemotherapy or early menopause, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, adenomyosis, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, lower urinary tract symptoms, contraception or infertility, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 16.
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19. A method of claim 18 wherein the condition is endometriosis, dysmenorrhea, polycystic ovarian disease or uterine fibroids.
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20. A method of claim 18 wherein the condition is benign prostatic hypertrophy, lower urinary tract symptoms, myoma of the uterus, prostatic cancer, uterine cancer, breast cancer or pituitary gonadotroph adenomas.
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21-29. -29. (canceled)
Specification