Sodium channel modulators

Details Sodium channel modulators Sodium channel modulators

2001-08-30

2004-06-29

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S519000

Reexamination Certificate

active

06756400

ABSTRACT:

FIELD OF THE INVENTION
The invention is directed to novel compounds that bind to sodium channels and modulate their activity. The invention is also directed to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with the activity of sodium channels, and processes and intermediates useful for preparing such compounds.
BACKGROUND
Voltage-gated ion channels play a critical role in the electrical activity of neuronal and muscle cells. Large families of voltage-gated ion channels (e.g. sodium channels) have been identified. These ion channels have been the target of significant pharmocologic study, due to their potential role in a variety of pathological conditions.
For example, the activity of sodium channels has been implicated in numerous pathological conditions, including neuropathic pain. Neuropathic pain is a chronic condition associated with diabetes, chronic inflammation, cancer and herpes virus infection. An estimated 75 million people worldwide are expected to suffer from neuropathic pain by the year 2010. Unfortunately, current treatment options typically provide only partial pain relief, and are limited by inconvenient dosing and by side effects, such as somnolence, ataxia, edema, gastrointestinal discomfort and respiratory depression.
Thus, despite the limited success that has been achieved using sodium channel modulators to treat pain, there continues to be a need for novel agents and methods that are useful for treating neuropathic pain, as well as other conditions associated with the activity of sodium channels. Particularly useful agents may be more potent or cause fewer side effects than existing agents.
SUMMARY OF THE INVENTION
The present invention provides novel compounds that bind to sodium channels and modulate (e.g. block) their activity. Accordingly, the invention provides a compound of the invention, which is compound of formula I:
wherein:
Q is —O—, —S(O)
m
, —(CR
5
R
6
)
p
—, —O(CR
5
R
6
)
r
O—, or —N(R
k
);
each R
1
is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R
a
;
each R
2
is independently a covalent bond or alkylene; wherein alkylene is optionally substituted with 1 to 4 substituents independently selected from R
b
;
each X is independently oxy (—O—) or —N(R
m
)—;
each Y is independently NR
n
R
p
or a heterocyclyl containing at least one nitrogen atom, wherein each nitrogen of the heterocyclyl is substituted with R
3
or is linked to R
2
, and wherein each heterocycle of Y is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R
4
;
each R
3
is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, oxo, or heterocyclyl; and each R
4
is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R
b
; or R
3
and R
4
are joined to form a C
1-4
alkylene group, wherein the alkylene group is optionally substituted with 1 to 4 substituents independently selected from R
b
;
each R
5
and R
6
is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; or R
5
and R
6
together with the carbon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionally contains 1 or 2 heteroatoms in the ring independently selected from oxygen, sulfur or nitrogen;
wherein for R
1
-R
6
, each alkyl, alkenyl, and alkynyl is optionally substituted with R
x
, or with 1, 2, 3, or 4 substituents independently selected from R
b
; for R
1
-R
6
, each aryl and heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R
c
, and for R
1
-R
6
, each cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from R
b
and R
c
;
each R
a
is independently —OR
d
, —NO
2
, halo, —S(O)
m
R
d
, —SR
d
, —S(O)
2
OR
d
, —S(O)
m
NR
d
R
e
, —NR
d
R
e
, —O(CR
f
R
g
)
n
NR
d
R
e
, —C(O)R
d
, —CO
2
R
d
, —CO
2
(CR
f
R
g
)
n
CONR
d
R
e
, —OC(O)R
d
, —CN, —C(O)NR
d
R
e
, —NR
d
C(O)R, —OC(O)NR
d
R
e
, —NR
d
C(O)OR
e
, —NR
d
C(O)NR
d
R
e
, —CR
d
(═N—OR
e
), —CF
3
, or —OCF
3
;
each R
b
is independently R
a
, oxo or ═N—OR
e
;
each R
c
is independently R
a
, alkyl, alkenyl, or alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally substituted with 1 to 4 substituents independently selected from R
b
;
each R
d
and R
e
is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from R
h
; or R
d
and R
e
together with the atoms to which they are attached form a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen;
each R
f
and R
g
is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from R
h
; or R
f
and R
g
together with the carbon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionally contains 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen;
each R
h
is independently halo, C
1-6
alkyl, C
1-6
alkoxy, aryl, (aryl)-C
1-6
alkyl, heteroaryl, (heteroaryl)-C
1-6
alkyl, hydroxy, amino, —NHC
1-6
alkyl, —N(C
1-6
alkyl)
2
, —OC(O)C
1-6
alkyl, —C(O)C
1-6
alkyl, —C(O)OC
1-6
alkyl, —NHC(O)C
1-6
alkyl, —C(O)NHC
1-6
alkyl, carboxy, nitro, —CN, or —CF
3
;
R
k
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from R
h
;
R
m
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from R
h
;
each R
n
and R
P
is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from R
h
; and
each R
x
is independently aryl, heteroaryl, cycloalkyl or heterocyclyl; wherein each aryl or heteroaryl is optionally substituted with 1 to 4 substituents selected from the group consisting of R
c
, and wherein each cycloalkyl and heterocyclyl is optionally substituted with 1 to 4 substituents selected from R
b
;
m is 0, 1, or 2;
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p is 1, 2, or 3;
r is 2, or 3; and
each w is independently 0, 1, 2, 3, or 4;
or a pharmaceutically-acceptable salt thereof;
provided that when any Y is NR
n
R
p
or a nitrogen-linked heterocyclyl, then the R
2
attached to that Y is not a covalent bond or methylene.
The invention also provides a pharmaceutical composition comprising a compound of the invention and pharmaceutically acceptable carrier.
The invention also provides a method of treating a disease or condition associated with sodium channel activity (e.g. neuropathic pain) in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention. The invention also provides a method of treating a disease or condition associated with sodium channel activity (e.g. neuropathic pain) in a mammal, comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition of the invention.
The invention also provides processes and intermediates described herein, which are useful for preparing compounds of the invention.
The invention also provides a compound of the invention as described herein for use in medical therapy, as well as the u

Affiliated with

Also associated with

Rating

Sodium channel modulators does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Sodium channel modulators, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Sodium channel modulators will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3338292