Pyridine compounds and the uses thereof

Patent metadata

Field	Value
Publication number	US-9611222-B2
Application number	US-201514724494-A
Country	US
Kind code	B2
Filing date	May 28, 2015
Priority date	Sep 17, 2010
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

The invention relates to substituted pyridine compounds of Formula (I) and the pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein R 1a , A 1 , A 2 , E, G, Z 1 , and Z 2 are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain.

First claim

What is claimed is:

1. A compound having Formula I:

or a pharmaceutically acceptable salt, or solvate thereof, wherein:
Z 1 is CR 1b and Z 2 is selected from the group consisting of N and N-oxide;
R 1a and R 1b , which are identical or different, are selected from the group consisting of:
a) hydrogen;
b) halogen;
c) hydroxy;
d) cyano;
e) optionally substituted alkyl;
f) alkoxy;
g) haloalkoxy; and
h) haloalkyl;
A 1 is optionally-substituted phenyl;
X is —O—;
A 2 is optionally substituted phenyl;
G is selected from the group consisting of:
a) cyano;

wherein:
R 5a and R 5b , which are identical or different, are selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl;
c) optionally substituted cycloalkyl;
d) optionally substituted heterocyclo;
e) optionally substituted aryl;
f) optionally substituted heteroaryl;
g) aralkyl;
h) hydroxyalkyl;
i) (cyano)alkyl;
j) (heterocyclo)alkyl;
k) (heteroaryl)alkyl;
l) (amino)alkyl;
m) (alkylamino)alkyl;
n) (dialkylamino)alkyl, and
o) —(CH 2 CH 2 O) m —R 15a , or
R 5a and R 5b taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo;
R 6a and R 6b , which are identical or different, are selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl;
c) optionally substituted cycloalkyl;
d) optionally substituted heterocyclo;
e) optionally substituted aryl;
f) optionally substituted heteroaryl;
g) hydroxyalkyl
h) (heterocyclo)alkyl;
i) (heteroaryl)alkyl;
j) (amino)alkyl;
k) (alkylamino)alkyl;
l) (dialkylamino)alkyl;
m) (carboxamido)alkyl;
n) (cyano)alkyl, and
o) —(CH 2 CH 2 O) n —R 15b ; or
R 6a and R 6b taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo;
R 7 is selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl;
c) optionally substituted cycloalkyl;
d) optionally substituted heterocyclo;
e) optionally substituted aryl;
f) optionally substituted heteroaryl;
g) (heterocyclo)alkyl;
h) (heteroaryl)alkyl;
i) (amino)alkyl;
j) (alkylamino)alkyl;
k) (dialkylamino)alkyl; and
l) —(CH 2 CH 2 O) o —R 15c ,
R 8a and R 8b , which are identical or different, are selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl; and
c) —(CH 2 CH 2 O) p —R 15d ,
L is selected from the group consisting of —O— and —NR 16 —;
R 9 is selected from the group consisting of hydrogen, alkyl and —(CH 2 CH 2 O) q —R 15e ;
R 15a , R 15b , R 15c , R 15d , and R 15e , which are identical or different, are selected from the group consisting of hydrogen and optionally substituted alkyl;
R 16 is selected from the group consisting of hydrogen and optionally substituted alkyl;
m, n, o, p, and q are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;
w is 0, 1, 2, 3, 4 or 5;
x and y are each independently 1, 2, 3, or 4;
E is selected from the group consisting of:
a) halogen;
b) optionally substituted heteroaryl;
c) optionally substituted heterocyclo;
d) hydroxyalkyl;

wherein:
R 17a and R 17b , which are identical or different, are selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl;
c) —SO 2 R 24a ;
d) —COR 24b ;
e) optionally substituted aryl;
f) optionally substituted heteroaryl;
g) (heterocyclo)alkyl;
h) (heteroaryl)alkyl;
i) (amino)alkyl;
j) (alkylamino)alkyl;
k) (dialkylamino)alkyl;
l) (carboxamido)alkyl;
m) (cyano)alkyl; and
n) hydroxyalkyl; or
R 17a and R 1m taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo;
R 18a and R 18b , which are identical or different, are selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl;
c) optionally substituted cycloalkyl;
d) optionally substituted aryl;
e) optionally substituted heteroaryl;
f) (heterocyclo)alkyl;
g) (heteroaryl)alkyl; and
h) (dialkylamino)alkyl; or
R 18a and R 18b taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo;
R 19 is selected from the group consisting of hydrogen and optionally substituted alkyl;
R 20a and R 20b , which are identical or different, are selected from the group consisting of hydrogen and optionally substituted alkyl, wherein at least one of R 20a and R 20b is optionally substituted alkyl;
R 21a is selected from the group consisting of hydrogen and alkyl;
R 21b and R 21b , which are identical or different, are selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl;
c) optionally substituted cycloalkyl;
d) optionally substituted aryl;
e) optionally substituted heteroaryl;
f) (heterocyclo)alkyl;
g) (heteroaryl)alkyl; and
h) (dialkylamino)alkyl; or
R 21b and R 21c taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo;
R 22 is selected from the group consisting of hydrogen and alkyl;
R 24a is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R 24b is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
t and u are each independently 0, 1, 2, or 3; and
v is 1, 2, or 3;
wherein:
1) when G is:

w is 0, and E is:

then R 17a is not hydrogen or alkyl when R 17b is hydrogen or alkyl;
2) when G is:

w is 0, and E is:

then u is 1, 2, or 3;
3) when G is:

and R 5a and R 5b taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo, then said optional substituents are selected

Assignees

• Purdue Pharma Lp

Inventors

• Ni Chiyou
• Shao Bin
• Tafesse Laykea
• Yao Jiangchao
• Yu Jianming
• Zhou Xiaoming

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/06

  Antiarrhythmics · 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

• A61P25/06

  Antimigraine agents · CPC title