Steroid derivative regulators, method for preparing the same, and uses thereof

Patent metadata

Field	Value
Publication number	US-2022017565-A1
Application number	US-201916969137-A
Country	US
Kind code	A1
Filing date	Jan 31, 2019
Priority date	Feb 11, 2018
Publication date	Jan 20, 2022
Grant date	—

Abstract

Steroid derivative regulators, a method for preparing the same, and uses thereof are described. Specifically, a compound as shown in formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and uses thereof as a regulator of GABA A receptor for treating depression, convulsion, Parkinson's disease, and nervous system diseases are described, wherein the substituents of the formula (I) are as defined in the description.

First claim

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

wherein:
X is selected from the group consisting of —CR 17 — and —N—;
Y is selected from the group consisting of —CR 23 R 24 —, —S(CH 2 ) n1 —, —P(CH 2 ) n1 —, —O(CH 2 ) n1 —, —(CH 2 ) n1 NR 22 —,

R x , R y , R z and R f are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 23 , —(CH 2 ) n1 OR 23 , —(CH 2 ) n1 SR 23 , —(CH 2 ) n1 C(O)R 23 , —(CH 2 ) n1 C(O)OR 23 , —(CH 2 ) n1 S(O) m1 R 23 , —(CH 2 ) n1 NR 23 R 24 , —(CH 2 ) n1 C(O)NR 23 R 24 , —(CH 2 ) n1 NR 23 C(O)R 24 and —(CH 2 ) n1 NR 23 S(O) m1 R 24 , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH 2 ) n1 R 25 , —(CH 2 ) n1 OR 25 , —(CH 2 ) n1 SR 25 , —(CH 2 ) n1 C(O)R 25 , —(CH 2 ) n1 C(O)OR 25 , —(CH 2 ) n1 S(O) m1 R 25 , —(CH 2 ) n1 NR 25 R 26 , —(CH 2 ) n1 C(O)NR 25 R 26 , —(CH 2 ) n1 C(O)NHR 25 , —(CH 2 ) n1 NR 25 C(O)R 26 and —(CH 2 ) n1 NR 25 S(O) m1 R 26 ;
or, any two adjacent or non-adjacent groups or two identical groups of R x , R y , R z and R f are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH 2 ) n1 R 23 , —(CH 2 ) n1 OR 23 , —(CH 2 ) n1 SR 23 , —(CH 2 ) n1 C(O)R 23 , —(CH 2 ) n1 C(O)OR 23 , —(CH 2 ) n1 S(O) m1 R 23 , —(CH 2 ) n1 NR 23 R 24 , —(CH 2 ) n1 C(O)NR 23 R 24 , —(CH 2 ) n1 NR 23 C(O)R 24 and —(CH 2 ) n1 NR 23 S(O) m1 R 24 ;
or, any two adjacent groups of R x , R y , R z and R f form a double bond;
R 21 is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 23 , —(CH 2 ) n1 OR 23 , —(CH 2 ) n1 SR 23 , —(CH 2 ) n1 C(O)R 23 , —(CH 2 ) n1 C(O)OR 23 , —(CH 2 ) n1 S(O) m1 R 23 , —(CH 2 ) n1 NR 23 R 24 , —(CH 2 ) n1 C(O)NR 23 R 24 , —(CH 2 ) n1 NR 23 C(O)R 24 and —(CH 2 ) n1 NR 23 S(O) m1 R 24 , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH 2 ) n1 R 25 , —(CH 2 ) n1 OR 25 , —(CH 2 ) n1 SR 25 , —(CH 2 ) n1 C(O)R 25 , —(CH 2 ) n1 C(O)OR 25 , —(CH 2 ) n1 S(O) m1 R 25 , —(CH 2 ) n1 NR 25 R 26 , —(CH 2 ) n1 C(O)NR 25 R 26 , —(CH 2 ) n1 C(O)NHR 25 , —(CH 2 ) n1 NR 25 C(O)R 26 and —(CH 2 ) n1 NR 25 S(O) m1 R 26 ;
when X is —CR 17 —, then R 17 is selected from the group consisting of a bond, hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
or, R 17 and any group of R x , R y , R z and R f are bonded to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH 2 ) n1 R 23 , —(CH 2 ) n1 OR 23 , —(CH 2 ) n1 SR 23 , —(CH 2 ) n1 C(O)R 23 , —(CH 2 ) n1 C(O)OR 23 , —(CH 2 ) n1 S(O) m1 R 23 , —(CH 2 ) n1 NR 23 R 24 , —(CH 2 ) n1 C(O)NR 23 R 24 , —(CH 2 ) n1 NR 23 C(O)R 24 and —(CH 2 ) n1 NR 23 S(O) m1 R 24 ;
R 22 is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 23 , —(CH 2 ) n1 OR 23 , —(CH 2 ) n1 SR 23 , —(CH 2 ) n1 C(O)R 23 , —(CH 2 ) n1 C(O)OR 23 , —(CH 2 ) n1 S(O) m1 R 23 , —(CH 2 ) n1 NR 23 R 24 , —(CH 2 ) n1 C(O)NR 23 R 24 , —(CH 2 ) n1 NR 23 C(O)R 24 and —(CH 2 ) n1 NR 23 S(O) m1 R 24 , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH 2 ) n1 R 25 , —(CH 2 ) n1 OR 25 , —(CH 2 ) n1 SR 25 , —(CH 2 ) n1 C(O)R 25 , —(CH 2 ) n1 C(O)OR 25 , —(CH 2 ) n1 S(O) m1 R 25 , —(CH 2 ) n1 NR 25 R 26 , —(CH 2 ) n1 C(O)NR 25 R 26 , —(CH 2 ) n1 C(O)NHR 25 , —(CH 2 ) n1 NR 25 C(O)R 26 and —(CH 2 ) n1 NR 25 S(O) m1 R 26 ;
R 23 , R 24 , R 25 and R 26 are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
m is an integer of 0, 1, 3, 4, 5, 6, 7, 8, 9 or 10;
n is an integer of 0, 1, 2 or 3;
o is an integer of 0, 1, 2, 3, 4 or 5;
p is an integer of 0, 1, 2, 3, 4, 5 or 6;
q is an integer of 0, 1, 2, 3, 4, 5 or 6;
m 1 is an integer of 0, 1 or 2; and
n 1 is an integer of 0, 1, 2, 3, 4 or 5.

2 . The comp

Assignees

• Jiangsu Hansoh Pharmaceutical Group Co Ltd
• Shanghai Hansoh Biomedical Co Ltd

Inventors

• Su Yidong
• Chen Xiaopo
• Wang Jun
• Bao Rudi

Classifications

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• C07J41/005 Primary

  the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives · CPC title

• A61P27/16

  Otologicals · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title