Pyrimidines as sodium channel blockers

Patent metadata

Field	Value
Publication number	US-10059675-B2
Application number	US-201715586963-A
Country	US
Kind code	B2
Filing date	May 4, 2017
Priority date	Sep 2, 2011
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

The present disclosure provides substituted pyrimidine compounds of Formula (I), and the pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein A 1 , X, A 2 , W 1 , W 2 , W 3 , E, Z, and R 4 are defined as set forth in the specification. The present disclosure 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 disclosure are especially useful for treating pain.

First claim

What is claimed is:

1. A compound having Formula XIII:

or a pharmaceutically acceptable salt, or solvate thereof, wherein
v is 1, 2, 3, or 4;
w is 1, 2, 3, or 4;
represents a single bond or a double bond;
W 1 and W 2 are N and W 3 is CR 3 ; or
W 1 and W 3 are N and W 2 is CR 3 ; or
W 2 and W 3 are N and W 1 is CR 3 ;
A 1 is selected from the group consisting of:
a) optionally substituted aryl;
b) optionally substituted heteroaryl;
c) optionally substituted cycloalkyl;
d) optionally substituted heterocyclo; and
e) aralkyl;

R 1 is selected from the group consisting of:
a) hydrogen;
b) alkyl;
c) aralkyl;
d) (heterocyclo)alkyl;
e) (heteroaryl)alkyl;
f) (amino)alkyl;
g) (alkylamino)alkyl;
h) (dialkylamino)alkyl;
i) (carboxamido)alkyl;
j) (cyano)alkyl;
k) alkoxyalkyl;
l) hydroxyalkyl; and
m) heteroalkyl;

R 2 is selected from the group consisting of hydrogen and alkyl; or
R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R 3 selected from the group consisting of:
a) hydrogen;
b) halo;
c) nitro;
d) cyano;
e) hydroxy;
f) amino;
g) alkylamino;
h) dialkylamino;
i) haloalkyl;
j) hydroxyalkyl;
k) alkoxy;
l) haloalkoxy; and
m) alkoxyalkyl;

Z is selected from the group consisting of —NR 5 — and —O—;
R 4 is selected from the group consisting of:

c) hydroxyalkyl;
d) hydroxy(cycloalkyl)alkyl; and
e) (heterocyclo)alkyl;

each of R 10a , R 10b , R 10c , and R 10d is independently selected from the group consisting of:
a) hydrogen;
b) hydroxy;
c) optionally substituted alkyl;
d) aralkyl;
e) (heterocyclo)alkyl;
f) (heteroaryl)alkyl;
g) (amino)alkyl;
h) (alkylamino)alkyl;
i) (dialkylamino)alkyl;
j) (carboxamido)alkyl;
k) (cyano)alkyl;
l) alkoxyalkyl;
m) hydroxyalkyl;
n) heteroalkyl;
o) optionally substituted cycloalkyl;
p) optionally substituted aryl;
q) optionally substituted heterocyclo; and
r) optionally substituted heteroaryl; or

R 10a and R 10b taken together with the carbon atom to which they are attached form a 3- to 8-membered optionally substituted cycloalkyl or a 3- to 8-membered optionally substituted heterocyclo;
r is 1, 2, or 3;
s is 1, 2, or 3;
R 11 is selected from the group consisting of:
a) hydroxy;
b) alkoxy; and
c) —NR 1a R 2a ;

R 1a is selected from the group consisting of:
a) hydrogen;
b) alkyl;
c) aralkyl;
d) (heterocyclo)alkyl;
e) (heteroaryl)alkyl;
f) (amino)alkyl;
g) (alkylamino)alkyl;
h) (dialkylamino)alkyl;
i) (carboxamido)alkyl;
j) (cyano)alkyl;
k) alkoxyalkyl;
l) hydroxyalkyl; and
m) heteroalkyl;

R 2a is selected from the group consisting of hydrogen and alkyl; or
R 1a and R 2a taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R 12 is selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl;
c) (amino)alkyl;
d) (alkylamino)alkyl;
e) (dialkylamino)alkyl;
f) (carboxamido)alkyl;
g) (cyano)alkyl;
h) alkoxyalkyl;
i) hydroxyalkyl; and
j) heteroalkyl;

R 5 is selected from the group consisting of:
a) hydrogen
b) alkyl;
c) hydroxyalkyl; and
d) alkylsulfonyl; or

R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
with the proviso that when R 4 and R 5 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo, then R 1 is selected from the group consisting of:
a) hydrogen;
b) (heterocyclo)alkyl;
c) (heteroaryl)alkyl;
d) (amino)alkyl;
e) (alkylamino)alkyl;
f) (dialkylamino)alkyl;
g) (carboxamido)alkyl;
h) (cyano)alkyl;
i) alkoxyalkyl;
j) hydroxyalkyl; and
k) heteroalkyl.

2. The compound of claim 1 , wherein Z is —NR 5 —, or a pharmaceutically acceptable salt, or solvate thereof.

3. The compound of claim 1 , wherein Z is —O—, or a pharmaceutically acceptable salt, or solvate thereof.

4. The compound of claim 1 , wherein:
R 4 is selected from the group consisting of:

b) hydroxyalkyl; and
c) hydroxy(cycloalkyl)alkyl;

R 10a is selected from the group consisting of:
a) hydrogen;
b) hydroxy;
c) optionally substituted alkyl;
d) aralkyl;
e) (heteroaryl)alkyl;
f) (amino)alkyl;
g) (alkylamino)alkyl;
h) (dialkylamino)alkyl;
i) (carboxamido)alkyl;
k) alkoxyalkyl; and
l) hydroxyalkyl;

R 10b is selected from the group consisting of hydrogen and alkyl; or
R 10a and R 10b taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl;
r is 1 or 2;

or a pharmaceutically acceptable salt, or solvate thereof.

5. The compound of claim 1 , wherein R 4 and R 5 taken together with the nitrogen to which they are attached form a 5- or 6-membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt, or solvate thereof.

6. The compound of claim 5 , wherein said optionally substituted 5- or 6-membered heterocyclo is selected from the group consisting of:

wherein:
R 13a , R 13b , R 13c , R 13d , R 13e , and R 13f are independently selected from the group consisting of:
a) hydrogen;
b) hydroxy;
c) hydroxyalkyl;
d) carboxy;
e) alkoxycarbonyl; and
f) carboxamido;

Y is selected from the group consisting of O, S, and NR 14 ; and
R 14 is selected from the group consisting of hydrogen and alkyl,

or a pharmaceutically acceptable salt, or solvate thereof.

7. The compound of claim 1 , wherein R 4 is:

and
R 11 is —NR 1a R 2a ,

or a pharmaceutically acceptable salt, or solvate thereof.

8. The compound of claim 1 , wherein R 4 is:

R 10a and R 10b taken together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; and
R 11 is —NR 1a R 2a ,
or a pharmaceutically acceptable salt, or solvate thereof.

9. The compound of claim 1 , wherein R 4 is selected from the group consisting of:

R 10 is selected from the group consisting of hydrogen and alkyl; and
R 10b is selected from the group consisting of:
a) hydrogen;
b) hydroxy; and
c) alkyl,

or a pharmaceutically acceptable salt, or solvate thereof.

10. The compound of claim 1 , wherein R 4 is hydroxyalkyl or hydroxy(cycloalkyl)alkyl, or a pharmaceutically acceptable salt, or solvate thereof.

11. The compound of claim 10 , wherein said hydroxyalkyl or hydroxy(cycloalkyl)alkyl is selected from the group consisting of:

Assignees

• Purdue Pharma Lp

Inventors

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

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

• A61P43/00

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

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title