Substituted pyridines as sodium channel blockers

Patent metadata

Field	Value
Publication number	US-9656959-B2
Application number	US-201113996082-A
Country	US
Kind code	B2
Filing date	Dec 21, 2011
Priority date	Dec 22, 2010
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

The invention relates to substituted pyridine compounds of Formula I: (I) and the pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein R 1a , R 1b , R 2a , R 2b , R 2c , A 1 , A 2 , and X 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 of Formula III:

or a pharmaceutically acceptable salt or solvate thereof,
wherein:
A 1 -X-A 2 - is:

Wherein
R 12a and R 12e are hydrogen;
R 12b , R 12c , and R 12d , which can be identical or different, are selected from the group consisting of:
a) hydrogen;
b) halo;
c) cyano; and
d) haloalkyl;

R 1a is selected from the group consisting of:
a) (heterocyclo)alkyl;
b) heterocyclo optionally substituted by carboxyalkyl;
c) —SO 2 R 6 ; and
d) —COR 7 ;

R 6 is selected from the group consisting of:
a) alkyl;
b) cycloalkyl;
c) heteroaryl optionally substituted by alkyl;
d) amino; and
e) alkenyl optionally substituted by aryl;

R 7 is selected from the group consisting of:
a) heteroaryl optionally substituted by one or two substituents independently selected from the group of hydroxy, alkyl, amino, alkylamino, and dialkylamino;
b)

 and
c) hydroxyalkyl;

wherein:
p is 0, 1, or 2;
each R 8a and R 8b , which can be identical or different, are selected from the group consisting of:
a) hydrogen;
b) alkyl;
c) aralkyl;
d) (heteroaryl)alkyl;
e) (carboxamido)alkyl;
f) hydroxyalkyl;
g) aryl optionally substituted by alkyl;
h) heteroaryl optionally substituted by alkyl; and
i) carboxamido;

R 9a is selected from the group consisting of:
a) hydrogen;
b) alkyl optionally substituted by one or two substituents independently selected from the group consisting of (alkoxy)carbonyl, carboxamido, and heteroaryl, wherein said heteroaryl is further optionally substituted by alkyl;
c) —COR 10 ;
d) —SO 2 R 11 ; and
e) —R 25 ;

wherein:
R 19 is selected from the group consisting of:
a) alkyl;
b) alkoxyalkyl;
c) hydroxyalkyl;
d) heteroalkyl;
e) cycloalkyl;
f) aryl optionally substituted by alkyl or haloalkyl;
g) heterocyclo optionally substituted by carbonylalkyl;
h) heteroaryl optionally substituted by alkyl;
i) amino;
j) alkylamino;
k) dialkylamino;
l) alkoxy; and
m) haloalkyl

R 11 is alkyl;
R 9b is selected from the group consisting of hydrogen and alkyl; or
R 1b is selected from the group consisting of:
a) hydrogen; and
b) hydroxyalkyl; or

R 1a and R 1b taken together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclo optionally substituted by one or two substituents independently selected from the group of hydroxy, carboxy, and carboxyalkyl;
R 2a , R 2b , and R 2c , which can be identical or different, are selected from the group consisting of:
a) hydrogen;
b) halo;
c) haloalkyl;
d) hydroxyalkyl; and
e) carboxamido;

R 25 is:

R 8c and R 8d , which can be identical or different, are selected from the group consisting of:
a) hydrogen;
b) alkyl;
c) aralkyl;
d) (heterocyclo)alkyl;
e) (heteroaryl)alkyl; and
i) (carboxamido)alkyl;

R 26 is selected from the group consisting of:
a) hydroxy;
b) alkoxy;
c) amino;
d) alkylamino; and
e) dialkylamino.

2. The compound of claim 1 , wherein R 1a is —SO 2 R 6 , or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 , wherein R 1a is —COR 7 and R 7 is:

and wherein p is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 1 having Formula V:

or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 4 , wherein R 9a is —COR 10 , or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 1 having Formula IX:

wherein R 7 is hydroxyalkyl, or a pharmaceutically acceptable salt or solvate thereof.

7. The compound of claim 1 having Formula X:

or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of claim 1 wherein A 1 -X-A 2 - is:

wherein:
R 12a , and R 12e are hydrogen;
R 12b , R 12c , and R 12d , which can be identical or different, are selected from the group consisting of:
a) hydrogen;
b) halo;
c) cyano; and
d) haloalkyl;

or a pharmaceutically acceptable salt or solvate thereof.

9. A compound selected from the group consisting of:
(S)-2-acetamido-N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-4-methylpentanamide;
(S)-2-acetamido-N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-3-phenylpropanamide;
(S)—N-(1-((6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)amino)-4-methyl-1-oxopentan-2-yl)picolinamide;
(S)—N-(1-((6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)amino)-4-methyl-1-oxopentan-2-yl)cyclopropanecarboxamide;
(S)—N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-2-(2-(2-methoxyethoxy)acetamido)-4-methylpentanamide;
(S)—N-(1-((6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)amino)-4-methyl-1-oxopentan-2-yl)nicotinamide;
(S)—N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-2-(3-isopropylureido)-4-methylpentanamide;
(S)—N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-4-methyl-2-ureidopentanamide;
N-(4-chloro-6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)methanesulfonamide;
(S)—N-(4-chloro-6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-N-(2,3-dihydroxypropyl) methanesulfonamide;
N-(4-chloro-6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)sulfamide;
(S)—N-(4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)
methanesulfonamide;
(S)—N-(4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide;
N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)methanesulfonamide;
N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)cyclopropanesulfonamide;
N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-1-methyl-1H-imidazole-4-sulfonamide;
(S)-2-amino-N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-3-(1H-imidazol-4-yl) propanamide;
(S)-2-acetamido-N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-3-(1H-imidazol-4-yl)propanamide;
(S)—N-(1-((6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)amino)-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl)cyclopropanecarboxamide;
(S)-1-acetyl-N-(1-((6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)amino)-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl)piperidine-4-carboxamide;
(S)—N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-3-(1H-imidazol-4-yl)-2-(2-methoxyacetamido)propanamide;
(S)—N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-2-(2-hydroxyacetamido)-3-(1H-imidazol-4-yl)propanamide;
(S)—N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-2-(2-hydroxy-2-methylpropanamido)-3-(1H-imidazol-4-yl)propanamide;
(S)—N-(6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)-3-(1H-imidazol-4-yl)-2-(methylsulfonamido)propanamide;
(S)-tert-butyl(1-amino-4-((6-(4-(4-fluorophenoxy)phenyl)pyridin-2-yl)amino)-1,4-dioxobutan-2-yl)carbamate;
(S)-tert-butyl(4-amino-1-((6-(4-(4-fluo

Assignees

• Ni Chiyou
• Park Minnie
• Shao Bin
• Tafesse Laykea
• Yao Jiangchao
• Youngman Mark A
• Zhou Xiaoming
• Purdue Pharma Lp

Inventors

• Ni Chiyou
• Park Minnie
• Shao Bin
• Tafesse Laykea
• Yao Jiangchao
• Youngman Mark A
• Zhou Xiaoming

Classifications

• 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

• A61P25/18

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

• A61P25/06

  Antimigraine agents · 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