GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO

• US 20100184741A1
• Filed: 04/04/2008
• Published: 07/22/2010
• Est. Priority Date: 04/06/2007
• Status: Active Grant

• Current Assignee: Neurocrine Biosciences Inc.
• Original Assignee: Neurocrine Biosciences Inc.
• Inventors: Jiang, Wanlong, Zhu, Yun-fei, Yu, Jinghua, Chen, Mi, Ewing, Todd, Wade, Warren, Beaton, Graham, Rowbottom, Martin, Zhao, Liren, Coon, Timothy Richard, Ashweek, Neil, Moree, Willy
• Granted Patent: US 8,263,588 B2
• Time in Patent Office: Days
• US Class Current: 514/213.10
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/84 Nitriles
• CPC Class Codes: C07D 239/36 as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

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 R_1a, R_1b, R_1c, R_1d, R₂, R_2a, 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.

Claims

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;

R_1a is H, halogen, C_1-4alkyl, C_1-4alkoxy or trifluoromethyl;

R_1b and R_1c are the same or different and are independently H, halogen, hydroxy, haloC_1-4alkyl, —

C_1-6alkyl-(R₅)_p, —

O—

C_1-6alkyl-(R₅)_p, —

C_1-6alkyl-O—

C_1-6alkyl-(R₅)_p, —

NR₇—

C_1-6alkyl-(R₅)_p, or —

S(O)<sub>m—

C1-6</sub>alkyl-(R₅)_P;

R_1d is F, Cl, methyl, CF₃ or cyano;

R₂ is C_1-4alkyl-(R₅)_p;

R_2a is phenyl substituted with 0-4 R₃, heteroaryl substituted with 0-4 R₃, C_1-6alkyl substituted with 0-4 R₃, aryl-C_1-4alkyl substituted with 0-4 R₃, or heteroaryl-C_1-4alkyl substituted with 0-4 R₃;

or R₂ and R_2a taken together with the nitrogen to which they are attached form a heterocycle which is substituted with 0-4 R₃;

R₃ at each occurrence is independently halogen, cyano, halo-C_1-4alkyl, R₅, —

C_1-6alkyl-(R₅)_p, C_1-6alkyl-O—

C_1-6alkyl-(R₅)_p, —

O—

C_1-6alkyl-(R₅)_p, —

NR₇—

C_1-6alkyl-(R₅)_p, —

S(O)_m—

C_1-6alkyl-(R₅)_p, —

O—

C_1-6alkyl-NR₇—

C_1-6alkyl-(R₅)_p, heterocycle-(R₅)_p;

R₄ at each occurrence is independently halogen, C_1-6alkyl, haloC_1-4alkyl, C_1-6alkoxy, hydroxy, cyano, thioC_1-6alkyl, —

C(O)NR₇R₈ or 5 member heteroaryl;

R₅ at each occurrence is independently H, hydroxy, —

OC(O)—

C_1-6alkyl, —

OC(O)O—

C_1-6alkyl, —

OC(O)—

C_1-6alkyl-NR₇R₈, —

COOR₆, —

C(O)NR₇R₈, —

NR₇C(O)NR₇R₈, —

S(O)₂NR₉R₉, —

S(O)_m—

C_1-4alkyl, —

NR₇R₈, C_1-6alkoxy, —

O-heterocycle, or heterocycle wherein said heterocycle and said —

O-heterocycle are substituted with 0-4 groups selected from halogen, C_1-6alkyl, C_1-4haloalkyl, hydroxy, oxo, thio, —

NH₂, —

S(O)₂C_1-4alkyl and —

COOH;

R₆ at each occurrence is independently H, C_1-4alkyl, C_1-4alkyl-O—

C(O)—

C_1-6alkyl, or C_1-4alkyl-O—

C(O)—

O—

C_1-6alkyl;

R₇ at each occurrence is independently H, C_1-4alkyl, hydroxy, or heterocycle where said heterocycle is substituted with 0-4 groups selected from halogen, C_1-6alkyl, hydroxy, keto, —

NH₂ and —

COOH;

R₈ at each occurrence is independently H, C_1-4alkyl, haloC_1-4alkyl, —

C(O)—

C_1-4alkyl, —

C(O)-haloC_1-4alkyl, —

S(O)_m-haloC_1-4alkyl or —

S(O)_m—

C_1-4alkyl;

R₉ at each occurrence is independently H, C_1-4alkyl, or —

C(O)C_1-4alkyl;

m is 0-2; and

p at each occurrence is independently 1-3.

2. A compound of claim 1 having the following structure:

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 are substituted with 0-4 R₄;

R_1a is H, halogen, C_1-4alkyl, C_1-4alkoxy or trifluoromethyl;

R_1b and R_1c are the same or different and are independently H, halogen, hydroxy, haloC_1-4alkyl, —

C_1-6alkyl-(R₅)_p, —

O—

C_1-6alkyl-(R₅)_p, —

C_1-6alkyl-O—

C_1-6alkyl-(R₅)_p, —

NR₇—

C_1-6alkyl-(R₅)_p, or —

S(O)_m—

C_1-4alkyl-(R₅)_p;

R_1d is Cl, methyl, CF₃ or cyano;

R₂ is C_1-4alkyl-(R₅)_p;

R_2a is phenyl substituted with 0-4 R₃;

or R₂ and R_2a taken together with the nitrogen to which they are attached form a heterocycle which is substituted with 0-4 R₃;

R₃ at each occurrence is independently halogen, haloC_1-4alkyl, hydroxy, —

C_1-6alkyl-(R₅)_p, —

C_1-6alkyl-O—

C_1-6alkyl-(R₅)_p, —

O—

C_1-6alkyl-(R₅)_p, —

NR₇—

C_1-6alkyl-(R₅)_p, —

S(O)_m—

C_1-6alkyl-(R₅)_p, —

CO₂R₆, or —

C(O)NR₇R₈;

R₄ at each occurrence is independently halogen, C_1-6alkyl, haloC_1-4alkyl, C_1-4alkoxy, hydroxy, cyano, thioC_1-4alkyl, —

C(O)NR₇R₈ or 5 member heteroaryl;

R₅ at each occurrence is independently H, hydroxy, —

OC(O)—

C_1-6alkyl, —

OC(O)O—

C_1-6alkyl, —

OC(O)—

C_1-6alkyl-NR₇R₈, —

C(O)OR₆, —

C(O)NR₇R₈, —

S(O)₂NR₉R₉, —

S(O)_mC_1-4alkyl, —

NR₇R₈, C_1-6alkoxy, or a heterocycle selected from the group consisting of

R₆ at each occurrence is independently H, C_1-4alkyl, C_1-4alkyl-O—

C(O)—

C_1-6alkyl, or C_1-4alkyl-O—

C(O)—

O—

C_1-6alkyl;

R₇ is H, C_1-4alkyl or hydroxy;

R₈ is H, C_1-4alkyl, —

C(O)—

C_1-4alkyl, —

C(O)NR₇—

C_1-4alkyl, or —

S(O)_m—

C_1-4alkyl;

R₉ at each occurrence is independently H, C_1-4alkyl, or —

C(O)C_1-4alkyl;

m is 0-2; and

p at each occurrence is independently 1-3.

3. A compound of claim 1 wherein A is pyridyl substituted with 0-4 R₄.

4. A compound of claim 3 wherein A is 2-pyridyl substituted with 0-4 R₄.

5. A compound of claim 3 wherein A is 3-pyridyl substituted with 0-4 R₄.

6. A compound of claim 1 wherein A is phenyl substituted with 0-4 R₄.

7. A compound of claim 1 wherein A is quinolinyl substituted with 0-4 R₄.

8. A compound of claim 1 wherein A is thienopyrimidinyl substituted with 0-4 R₄.

9. A compound of claim 1 wherein A is 2-oxo-pyrimidinyl substituted with 0-4 R₄.

10. A compound of claim 1 wherein R_1a and R_1c are H.

11. A compound of claim 1 wherein R_1b is —

C_1-6alkyl-(R₅)_p or —

O—

C_1-6alkyl-(R₅)_p.

12. A compound of claim 1 wherein R₂ and R_2a taken together with the nitrogen to which they are attached form a heterocycle which is substituted with 0-4 R₃.

13. A compound of claim 12 wherein the heterocycle is a 9-12 member heterocycle.

14. A compound of claim 1 wherein R₃ is —

O—

C_1-6alkyl-(R₅)_p.

15. A compound of claim 1 wherein the compound is 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-butyric acid, [5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-acetic acid, 5-[2-Chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-hydroxy-butoxy)-phenyl]-2-trifluoromethyl-isonicotinonitrile, 5-[2-Chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(2-hydroxy-ethoxy)-phenyl]-2-trifluoromethyl-isonicotinonitrile, 4-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butyric acid, [5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-acetic acid, 3-[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-propionic acid, 5-[2-Chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-methoxy-phenyl]-2-trifluoromethyl-isonicotinonitrile, 5-[2-Chloro-4-methoxy-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-2-trifluoromethyl-isonicotinonitrile, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

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.

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.

19. A method of claim 18 wherein the condition is endometriosis, dysmenorrhea, polycystic ovarian disease or uterine fibroids.

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.

21-29. -29. (canceled)