Calcium channel blockers

Details Calcium channel blockers Calcium channel blockers

2001-01-25

2002-12-17

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S553000, C560S055000, C564S155000, C564S157000, C514S740000, C514S741000

Reexamination Certificate

active

06495715

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds that act to block calcium channels; methods of using the compounds to treat stroke, cerebral ischemia, pain, head trauma or epilepsy; and to pharmaceutical compositions that contain the compounds of the present invention.
BACKGROUND OF THE INVENTION
The entry of excessive amounts of calcium ions into neurons following an ischemic episode or other neuronal trauma has been well documented. Uncontrolled high concentrations of calcium in neurons initiates a cascade of biochemical events that disrupts normal cellular processes. Among these events are the activation of proteases and lipases, breakdown of neuronal membranes and the formation of free radicals, which may ultimately lead to cell death. Several types of calcium channels have been discovered and called the L, N, P, Q, R, and T types. Each type possesses distinct structural features, functional properties and cellular/subcellular distributions. Type selective calcium channel blockers have been identified. For example, SNX-111 has been shown to be a selective N-type calcium channel blocker and has demonstrated activity in a number of models of ischemia and pain (Bowersox S. S., et al.,
Drug News and Perspective,
1994:7:261-268 and references cited therein). The compounds of the present invention are calcium channel blockers that can block N-type calcium channels and can be used to treat stroke, pain, cerebral ischemia, head trauma, and epilepsy.
SUMMARY OF THE INVENTION
The present invention provides compounds having the Formula I
wherein
each m is independently 1 to 3;
each n is independently 0 to 3;
each R
a
and R
b
is independently hydrogen, C
1
-C
6
alkyl, or R
a
and R
b
together with the carbon atom to which they are bonded form a C
3
-C
6
cycloalkyl
R
5
is C
1
-C
6
alkyl, —(CH
2
)
m
-heteroaryl, —(CH
2
)
m
-substituted heteroaryl, —(CH
2
)
m
-phenyl, or —(CH
2
)-substituted phenyl;
R
2
is hydrogen, C
1
-C
8
alkenyl, C
3
-C
8
cycloalkenyl, phenyl, substituted phenyl, C
1
-C
8
alkyl, substituted C
1
-C
8
alkyl, —(CH
2
)
m
substituted C
3
-C
8
cycloalkyl, —(CH
2
)
m
-C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkyl, substituted C
3
-C
8
cycloalkyl, —(CH
2
)
m
-phenyl, or —(CH
2
)
m
substituted phenyl;
R
3
is hydrogen, C
1
-C
6
alkyl, or C
2
-C
6
alkenyl;
Q is aryl, heteroaryl, substituted heteroaryl, C
3
-C
8
cycloalkyl, substituted C
3
-C
8
cycloalkyl, C
1
-C
6
alkyl, substituted C
1
-C
6
alkyl, hydrogen, C
3
-C
8
heterocycloalkyl, C
3
-C
8
substituted heterocycloalkyl, or substituted aryl;
V is —O(CH
2
)
n
—, —C═C—, —O—,
or —(CH
2
)
n
—O—;
R
4
is hydrogen,
C
1
-C
6
alkyl, C
2
-C
8
alkenyl, C
3
-C
8
cycloalkenyl, C
3
-C
8
substituted cycloalkenyl, —(CH
2
)
m
-phenyl, —(CH
2
)
m
-heteroaryl, —(CH
2
)
m
-substituted heteroaryl, —(CH
2
)
m
-substituted phenyl, C
3
-C
8
cycloalkyl, or C
3
-C
8
substituted cycloalkyl;
or R
3
and R
4
together with the nitrogen atom to which they are bonded can form a 5-7 membered ring that can contain one or more heteroatom;
and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the compounds of Formula I, V is —OCH
2
— or CH
2
CH
2
, and Q is phenyl.
In another preferred embodiment of the compounds of Formula I, X is
and Z is
In another preferred embodiment of the compounds of Formula I, R
3
and R
4
are both hydrogen.
In another preferred embodiment of the compounds of Formula I, R
3
is hydrogen and R
4
is
In another preferred embodiment of the compounds of Formula I, V is —OCH
2
—;
Q is phenyl;
Z is
R
3
is hydrogen;
R
4
is
R
2
is C
2
-C
8
cycloalkenyl, C
2
-C
8
alkyl, or C
2
-C
8
alkenyl; and
R
5
is C
1
-C
8
alkyl.
In another preferred embodiment of the compounds of Formula I, Z is
and X is
In still another preferred embodiment of the compounds of Formula I, R
5
is isobutyl, 3-methylbutyl, 2-methylbutyl, —CH
2
-pyridyl, or —CH
2
-imidazolyl.
In a preferred embodiment of the compounds of Formula I, R
2
is 3-methyl-but-2-enyl, or 3-methylbutyl, 2-methylpropyl, methyl, CH
2
-cyclohexyl, n-butyl, or cyclohexyl.
In another preferred embodiment of the compounds of Formula I, V is —O—CH
2
—, —C═C—, —CH
2
—CH
2
, or —NH—CH
2
;
Q is pyridyl, phenyl, cyclohexyl, or C
1
-C
8
alkyl.
In a most preferred embodiment, the compounds of Formula I are:
(S)-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
[S-(R*,R*)]-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1-methyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{3-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-propylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidine-1-carbonyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-cyclohex-2-enyl-amino]-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{2-[benzyl-(4-benzyloxy-phenyl)-amino]-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-Azepane-1-carboxylic acid (1-{2-[(4-benzyloxy-phenyl)-cyclohex-2-enyl-amino]-1,1-dimethyl-ethylcarbamoyl}-3-methyl-butyl)-amide;
(S)-2-Dimethylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-but-2-enyl)-amino]-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-2-(Cyclohex-2-enyl-methyl-amino)-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
(S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide;
[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-methyl-ethyl}-amide;
[S-(R*,R*)]-4-Methyl-2-(3-methyl-but-2-enylamino)-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1-methyl-ethyl}-amide;
[S-(R*,R*)]-4-Methyl-2-(3-methyl-butylamino)-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1-methyl-ethyl}-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid {2-[(4-benzyloxy-phenyl)-cyclohex-2-enyl-amino]-1,1-dimethyl-ethyl}-amide;
[S-(R*,R*)]-2-[Bis-(3-methyl-butyl)-amino]-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-methyl-ethyl}-amide; and
[S-(R*,R*)]-2-{Bis]-(3-methyl-but-2-enylamino)-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-methyl-ethyl}-amide.
In a most preferred embodiment, the compounds of Formula I are:
2-Amino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
2-Benzylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
4-Methyl-2-(3-methyl-butylamino)-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
2-(Cyclohexylmethyl-amino)-4-methyl-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-butyl)-amino]-1,1-dimethyl-ethyl}-amide;
2-Dimethylamino-4-methyl-pentanoic acid {2-[(4-benzyloxy-phe

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