Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

• US 8,481,738 B2
• Filed: 11/10/2011
• Issued: 07/09/2013
• Est. Priority Date: 04/06/2007
• Status: Active Grant

• Current Assignee: Neurocrine Biosciences Inc.
• Original Assignee: Neurocrine Biosciences Inc.
• Inventors: Beaton, Graham, Chen, Mi, Coon, Timothy Richard, Ewing, Todd, Jiang, Wanlong, Lowe, Richard, Moree, Willy, Smith, Nicole, Wade, Warren, Zhao, Liren, Zhu, Yun-fei, Rowbottom, Martin, Ashweek, Neil
• Primary Examiner(s): CHANDRAKUMAR, NIZAL S
• Application Number:
  US13/293,943
• Publication Number:
  US 20120122891A1
• Time in Patent Office: 607 Days
• Field of Search: 546/114, 546/122
• US Class Current: 546/114
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• 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 15/14 for lactation disorders, e.g. galactorrhoea
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
• CPC Class Codes: A61P 5/08 for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: C07C 233/88 having nitrogen atoms of carboxamide groups bound to an acyclic carbon atom and to a carbon atom of a six-membered aromatic ring wherein at least one ortho-hydrogen atom has been replaced
• CPC Class Codes: C07C 235/42 having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 255/57 containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/58 Amidines
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/70 : Sulfur atoms
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/84 : Nitriles
• CPC Class Codes: C07D 213/89 : with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 215/14 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 215/54 : attached in position 3
• CPC Class Codes: C07D 239/36 : as doubly bound oxygen atom or as unsubstituted hydroxy radical
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : 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
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

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):

2. The compound of claim 1 having the following structure (Ia):

3. The compound of claim 1 wherein A is naphthyridinyl.

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

5. The compound of claim 1 wherein R_1a and R_1c are H.

6. The compound of claim 1 wherein R_1b is —

C_1-6alkyl-(R₅)_p or —

O—

C_1-6alkyl-(R₅)_p, p is 1, and R₅ is H, hydroxy or —

COOR₆.

7. The compound of claim 1 wherein R_2a is phenyl substituted with 1 or 2 R₃, wherein one of R₃ is —

O—

C_1-6alkyl-(R₅)_p, p is 1, and R₅ is H, hydroxy, or —

COOR₆.

8. The compound of claim 1 wherein R₃ is —

C_1-6alkyl-(R₅)_p, —

C_1-6alkyl-O—

C_1-6alkyl-(R₅)_p or —

O—

C_1-6alkyl-(R₅)_p.

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