Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-01-15
2003-11-11
McKane, Joseph K. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S347000
Reexamination Certificate
active
06646012
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 pharmacologic 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 modulate (e.g. block) sodium channel activity. Accordingly, the invention provides a compound of the invention, which is a compound of formula (I):
R
1
—O—R
2
—X—R
3
(I)
wherein
R
1
is aryl;
R
2
is a group of formula (II):
wherein:
A
1
, A
2
, and A
20
are each independently alkylene or substituted alkylene;
n is 0 or 1;
R
7
is hydrogen, alkyl, or substituted alkyl; and
R
8
is NR
10
R
11
, wherein each of R
10
and R
11
is independently hydrogen, alkyl, or substituted alkyl; and
X is oxygen and R
3
is aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, alkyl, or substituted alkyl; or
X is a direct bond and R
3
is an N-linked heteroaryl or an N-linked heterocycle;
wherein any aryl of R
1
-R
3
can optionally be substituted with from 1 to 5 substituents R
g
; wherein each R
g
is independently selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, cycloalkoxy, substituted cycloalkoxy, methanediol (—OCH
2
O—), ethanediol (—OCH
2
CH
2
O—), cycloalkyl, substituted alkyl, substituted alkoxy, substituted cycloalkyl, amino, substituted amino, aryl, aryloxy, carboxy, carboxylalkyl (e.g. —CO
2
Me), carboxyl(substituted alkyl) (e.g. —CO
2
(substituted alkyl)), cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, heteroaryl and trihalomethyl;
and wherein any heteroaryl of R
2
-R
3
can be optionally substituted with 1 to 5 substituents R
h
, wherein each R
h
is independently selected from the group consisting of hydroxy, alkyl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, substituted alkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, substituted cycloalkyl, amino, substituted amino, aryl, aryloxy, carboxyl (—COOH), carboxylalkyl (e.g. —CO
2
Me), carboxyl(substituted alkyl), cyano, halo, nitro, heterocyclic, and trihalomethyl.
or a pharmaceutically acceptable salt thereof.
A preferred compound of formula (I) is a compound of formula (III):
wherein:
A
6
and A
7
are each independently alkylene or substituted alkylene;
each R
20
is independently halo, alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, trifluoromethyl, cyano, nitro, hydroxy, NR
4
R
5
, or CO
2
R
6
;
R
21
is hydrogen, alkyl, or substituted alkyl;
each R
22
is independently halo, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, trifluoromethyl, cyano, nitro, hydroxy, NR
4
R
5
, or CO
2
R
6
;
y is 0, 1, 2, 3, 4, or 5;
z is 0, 1, 2, 3, 4, or 5; and
R
4
-R
6
are each independently hydrogen, alkyl, or substituted alkyl;
wherein any aryl of A
6
, A
7
, R
20
-R
22
and R
4
-R
6
can optionally be substituted with from 1 to 5 substituents R
g
; wherein each R
g
is independently selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, cycloalkoxy, substituted cycloalkoxy, methanediol (—OCH
2
O—), ethanediol (—OCH
2
CH
2
O—), cycloalkyl, substituted alkyl, substituted alkoxy, substituted cycloalkyl, amino, substituted amino, aryl, aryloxy, carboxy, carboxylalkyl (e.g. —CO
2
Me), carboxyl(substituted alkyl), cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, heteroaryl and trihalomethyl;
and wherein any heteroaryl of A
6
, A
7
, R
20
-R
22
and R
4
-R
6
can be optionally substituted with 1 to 5 substituents R
h
, wherein each R
h
is independently selected from the group consisting of hydroxy, alkyl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, substituted alkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, substituted cycloalkyl, amino, substituted amino, aryl, aryloxy, carboxyl (—COOH), carboxylalkyl (e.g. —CO
2
Me), carboxyl(substituted alkyl), cyano, halo, nitro, heterocyclic, and trihalomethyl.
or a pharmaceutically acceptable salt thereof.
Another preferred compound of formula (I) is a compound of formula (IV):
wherein:
A
8
and A
9
are each independently alkylene or substituted alkylene;
each R
23
is independently halo, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, trifluoromethyl, cyano, nitro, hydroxy, NR
4
R
5
, or CO
2
R
6
;
R
24
is hydrogen, alkyl, or substituted alkyl;
R
25
is alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, or heterocycle;
d is 0, 1, 2, 3, 4, or 5; and
R
4
-R
6
are each independently hydrogen, alkyl, or substituted alkyl;
wherein any aryl of A
8
, A
9
, R
23
-R
25
and R
4
-R
6
can optionally be substituted with from 1 to 5 substituents R
g
; wherein each R
g
is independently selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, cycloalkoxy, substituted cycloalkoxy, methanediol (—OCH
2
O—), ethanediol (—OCH
2
CH
2
O—), cycloalkyl, substituted alkyl, substituted alkoxy, substituted cycloalkyl, amino, substituted amino, aryl, aryloxy, carboxy, carboxylalkyl (e.g. —CO
2
Me), carboxyl(substituted alkyl), cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, heteroaryl and trihalomethyl;
and wherein any heteroaryl of A
8
, A
9
, R
23
-R
25
and R
4
-R
6
can be optionally substituted with 1 to 5 substituents R
h
, wherein each R
h
is independently selected from the group consisting of hydroxy, alkyl, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, substituted alkyl, arylalkyl, heteroarylalkyl, heterocyclealkyl, substituted cycloalkyl, amino, substituted amino, aryl, aryloxy, carboxyl (—COOH), carboxylalkyl (e.g. —CO
2
Me), carboxyl(substituted alkyl), cyano, halo, nitro, heterocyclic, and trihalomethyl.
or a pharmaceutically acceptable salt thereof.
Another preferred compound of formula (I) is a compound of formula (V):
wherein:
A
10
and A
11
are each independently alkylene or substituted alkylene;
each R
26
is independently halo, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycle, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, trifluoromethyl, cyano, nitro, hydroxy, NR
4
R
5
, or CO
2
R
6
;
R
27
is hydrogen, alkyl, or substituted alkyl;
R
28
is an N-linked heteroaryl or an N-linked heterocycle;
t is 0, 1, 2, 3, 4, or 5; and
R
4
-R
6
ar
Choi Seok-Ki
Fatheree Paul R.
Green David C.
Marquess Daniel
Hagenah Jeffrey A.
McKane Joseph K.
Saxon Roberta P.
Shameem Golam M. M.
Theravance Inc.
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