Gonadotropin releasing hormone receptor antagonists, method for the preparation thereof and pharmaceutical composition comprising the same

Patent metadata

Field	Value
Publication number	US-9481684-B2
Application number	US-201314381371-A
Country	US
Kind code	B2
Filing date	Feb 28, 2013
Priority date	Feb 28, 2012
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

Abstract

Disclosed are a gonadotropin releasing hormone receptor antagonist and a pharmaceutical composition including the same, which can be useful in preventing or treating a sex hormone-related disease such as endometriosis, amenorrhea, irregular menstruation, uterine myoma, uterine fibroids, polycystic ovarian disease, lupus erythematous, hypertrichosis, precocious puberty, short stature, acne, alopecia, gonadal steroid-dependent neoplasms, gonadotropin-producing pituitary adenoma, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, contraception, and infertility, as well as Alzheimer disease.

First claim

What is claimed is:

1. A compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt thereof:

wherein,
A is CR 8a R 8b , O, S or NR 9 ;
R 1 and R 2 , which may be the same or different, being each independently hydrogen, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, substituted (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, substituted (C 6 -C 10 )aryl, (C 6 -C 12 )aryl, (C 1 -C 10 )alkyl, substituted (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heteroaryl, substituted (C 1 -C 20 )heteroaryl, (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl, substituted (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heterocycle, substituted (C 1 -C 20 )heterocycle, (C 1 -C 20 )heterocyclyl(C 1 -C 10 )alkyl, substituted (C 1 -C 20 )heterocyclyl(C 1 -C 10 )alkyl, or —(CR 1a R 1b ) s —R 12 ;
R 3a and R 3b , which may be the same or different, being each independently hydrogen, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, substituted (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, (C 6 -C 12 )aryl, substituted (C 6 -C 12 )aryl, (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, substituted (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heteroaryl, substituted (C 1 -C 20 )heteroaryl, (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl, substituted (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heterocycle, substituted (C 1 -C 20 )heterocycle, (C 1 -C 20 )heterocyclyl(C 1 -C 10 )alkyl, substituted (C 1 -C 20 )heterocyclyl(C 1 -C 10 )alkyl, —COOR 13 or —CONR 13 R 14 or;
R 3a and R 3b , together with the carbon atom attached thereto form a homocyclic ring, a substituted homocyclic ring, a heterocyclic ring, or a substituted heterocyclic ring; or R 3a and a carbon bonded thereto, together with R 1 and a nitrogen atom bonded thereto, form a heterocyclic ring or a substituted heterocyclic ring;
R 4 is —(CR 9a R 9b ) r —Z—Y;
n is an integer of 2, 3 or 4;
s is an integer of 1, 2, 3 or 4;
r is an integer of 0, 1 or 2;
Z represents a direct bond, or —O—, —S—, —NR 11 —, —SO—, —SO 2 —, —OSO 2 —, —SO 2 O—, —SO 2 NR 11 —, —NR 11 SO 2 —, —CO—, —COO—, —OCO—, —CONR 11 —, —NR 11 CO—, —NR 11 CONR 11a —, —OCONR 11 — or —NR 11 COO—;
Y is hydrogen, halogen, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, substituted (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, substituted (C 6 -C 12 )aryl, (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, substituted (C 6 -C 12 )aryl, (C 1 -C 10 )alkyl, (C 1 -C 20 )heteroaryl, substituted (C 1 -C 20 )heteroaryl, (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl or substituted (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl;
R 6 is hydrogen, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, substituted (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, substituted (C 6 -C 12 )aryl, (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, substituted (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heteroaryl, substituted (C 1 -C 20 )heteroaryl, (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl or substituted (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl;
R 9 is hydrogen, (C 1 -C 10 )alkyl or (C 1 -C 10 )acyl;
R 12 is —CO 2 R 13 , —COOH or an acid isostere;
R 1a and R 1b , which may be the same or different, being each independently hydrogen, (C 1 -C 10 )acyl, hydroxyl, halogen, cyano, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, substituted (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, —COOR 13 — or CONR 13 R 14 —; or R 1a and R 1b , together with the atom(s) to which they are attached independently from a homocyclic ring, a substituted homocyclic ring, a heterocyclic ring or a substituted heterocyclic ring;
R 5a , R 5b , R 7a , R 7b , R 8a and R 8b , which may be the same or different, being each independently hydrogen, (C 1 -C 10 )acyl, hydroxyl, amino, halogen, cyano, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, substituted (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )aryl, substitute (C 1 -C 10 )aryl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, —COOR 13 , or —CONR 14 R 15 ; and
R 9a , R 9b , R 11 , R 11a , R 13 , R 14 and R 15 , which may be the same of different, being each independently hydrogen, (C 1 -C 10 )alkyl, (C 6 -C 12 )aryl or (C 6 -C 12 )aryl, (C 1 -C 10 )alkyl;
wherein, the heterocyclic ring, the heterocycle, the heterocyclylalkyl, heteroaryl and heteroarylalkyl contain at least one heteroatoms selected from the group consisting of N, O and S; and
“substituted” means a replacement with at least one substituent selected from the group consisting of halogen, acetylene, vinyl, hydroxy, cyano, nitro, amino, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, halo(C 1 -C 10 )alkyl, (C 6 -C 12 )aryl, (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heteroaryl, (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heterocycle, (C 1 -C 20 )heterocyclyl(C 1 -C 10 )alkyl, —NR a R b , —NR a C(═O)R b , —NR a C(═O)NR a OR b , —NR a C(═O)NR a R b , —NR a C(═O)OR b , —NR a SO 2 R b , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , —C(═O)NR a R b , —OC(═O)NR a R b , —OR a , —SR a , —S(═O) 2 R a , —OS(═O) 2 R a and —S(═O) 2 OR a , wherein R a and R b , which may be the same or different, being each independently hydrogen, (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heteroaryl, (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heterocycle, (C 1 -C 20 )heterocyclyl(C 1 -C 10 )alkyl or —(CH 2 ) z C(═O)R c , z is an integer of 1, 2, 3 or 4, and R c is hydroxyl, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl or (C 1 -C 10 )alkoxy.

2. The compound of claim 1 , wherein,
A is CH 2 , O, S or NR 9 wherein R 9 is hydrogen or methyl;
n is an integer of 2;
R 1 and R 2 being each independently hydrogen, (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, substituted (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl, substituted (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl or —(CH 2 ) s —R 12 ;
s is an integer of 1, 2, 3 or 4;
R 3a and R 3b being each independently hydrogen, (C 6 -C 12 )aryl, substituted (C 6 -C 12 )aryl, (C 1 -C 20 )heteroaryl or substituted (C 1 -C 20 )heteroaryl;
R 4 is hydrogen, (C 6 -C 12 )aryl, substituted (C 6 -C 12 )aryl, (C 1 -C 20 )heteroaryl, substituted (C 1 -C 10 )heteroaryl, (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, substituted (C 6 -C 12 )aryl, (C 1 -C 10 )alkyl, (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl, substituted (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, —C(═O)R 11 , —SO 2 R 11 or —C(═O)OR 11 ;
R 6 is (C 6 -C 12 )aryl(C 1 -C 10 )alkyl, substituted (C 6 -C 12 )aryl, (C 1 -C 10 )alkyl, (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl or substituted (C 1 -C 20 )heteroaryl(C 1 -C 10 )alkyl;
R 5a , R 5b , R 7a , R 7b , R 8a and R 8b being each independently hydrogen;
R 11 is hydrogen, (C 1 -C 10 )alkyl, (C 6 -C 12 )aryl, or (C 6 -C 12 )aryl(C 1 -C 10 )alkyl; and
R 12 is —COOH or an acid isostere selected from the group consisting of:

wherein, “substituted” means a replacement with at least one substituent selected from the group consisting of halogen, acetylene, vinyl, hydroxy, cyano, nitro, amino, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkyl, (C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, halo(C 1 -C 10 )alkyl, —NR a R b , —NR a C(═O)R b , —NR a C(═O)NR a OR b , —N

Assignees

• Sk Chemicals Co Ltd

Inventors

• Kim Seon-Mi
• Kim Jae-Sun
• Lee Minhee
• Lee So-Young
• Lee Bong-Yong
• Shin Young-Ah
• Park Euisun
• Lee Jung A
• Han Min-Young
• Ahn Jaeseung
• Yoo Taekyung
• Kim Hun-Taek

Classifications

• A61P5/04

  for decreasing, blocking or antagonising the activity of the hypothalamic hormones · CPC title

• A61P5/24

  of the sex hormones · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title