Heterocyclic substituted aniline calcium channel blockers

Details Heterocyclic substituted aniline calcium channel blockers Heterocyclic substituted aniline calcium channel blockers

1999-06-14

2001-06-26

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S212010, C514S326000, C514S422000, C514S426000, C514S255030, C540S596000, C544S360000, C546S194000, C546S214000, C546S244000, C548S557000

Reexamination Certificate

active

06251919

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, asthma, amyotrophic lateral sclerosis, 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 n is independently 0 to 3;
R
1
is C
1
-C
8
alkyl, substituted C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, substituted C
3
-C
8
cycloalkyl, hetercycloalkyl, substituted hetercycloalkyl, C
2
-C
8
alkenyl, C
3
-C
8
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or arylalkyl;
Y is
X is C
1
-C
8
alkyl, C
1
-C
8
substituted alkyl, C
2
-C
8
alkenyl, substituted C
2
-C
8
alkenyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl;
R
2
is absent, —O—, (CH
2
)
n
-, O(CH
2
)
n
-, (CH
2
)
n
O—, N(R
5
)(CH
2
)
n
-, (CH
2
)
n
N(R
5
)- S(CH
2
)
n
-, (CH
2
)
n
S—, —C═C—, or —C≡C—;
R
3
is monocylic aryl, substituted monocyclic aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, C
1
-C
8
alkyl, substituted C
1
-C
8
alkyl, C
3
-C
10
cycloalkyl, substituted C
3
-C
10
cycloalkyl;
R
4
, R
5
are independently H or C
1
-C
8
alkyl; and
the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the compound of Formula I, R
2
is O(CH
2
)
n
-or -(CH
2
)
n
- and R
3
is phenyl.
In another preferred embodiment of the compounds of Formula I, X is C
2
-C
8
alkenyl or C
1
-C
8
alkyl and
Y is
In another preferred embodiment of the compounds of Formula I, R
4
is hydrogen and R
1
is 3,3-dimethylbutyl.
In another preferred embodiment of the compounds of Formula I, R
3
is phenyl;
Y is
R
4
is hydrogen;
X is 3-methyl-but-2 enyl; and
R
1
is C
1
-C
8
alkyl, substituted C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, substituted C
3
-C
8
cycloalkyl, hetercycloalkyl, substituted heteroalkyl, C
2
-C
8
alkenyl, substituted C
3
-C
8
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or arylalkyl.
In another preferred embodiment of the compounds of Formula I, Y is
In another preferred embodiment of the compounds of Formula I, X is 3-methyl-but-2 enyl or 3-methylbutyl.
In another preferred embodiment of the compounds of Formula I, R
1
is C
1
-C
8
alkyl, phenyl, pyrrolyl, piperazinyl, imidazolyl, pyridyl, or pyranyl.
In another preferred embodiment of the compounds of Formula I, R
4
is hydrogen.
In a most preferred embodiment of the present invention, the compounds are:
(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-[1-(3-methyl-butyl)-piperidin-4-yl]-amine;
(4-Benzyloxy-phenyl)-[1-(3,3-dimethyl-butyl)-piperidin-4-yl]-(3-methyl-but-2-enyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-tert-butyl-benzyl)-piperidin-4-yl]-(3-methyl-but-2-enyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-bromo-benzyl)-piperidin-4-yl]-(3-methyl-but-2-enyl)-amine;
4-{4[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin- 1-ylmethyl}-phenol;
(4-Benzyloxy-phenyl)-[1-(4-dimethylamino-benzyl)-piperidin-4-yl]-(3-methyl-but-2-enyl)-amine;
(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-[1 -(1H-pyrrol-2-ylmethyl)-piperidin-4-yl]-amine;
(4-Benzyloxy-phenyl)-[1-(1H-imidazol-4-ylmethyl)-piperidin-4-yl]-(3-methyl-but-2-enyl)-amine;
(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-(1-pyridin-2-ylmethyl-piperidin-4-yl)-amine;
(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-amine;
{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-[1-(3-methyl-butyl)-piperidin-2-yl]-methanone;
{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl }-[1-(3-methyl-butyl)-piperidin-3-yl]-methanone;
{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl }-[1-(3-methyl-butyl)-piperidin-4-yl]-methanone;
{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-[4-methyl-1-(3-methyl-butyl)-piperazin-2-yl]-methanone;
{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-[4-isopropyl-1-(3-methyl-butyl)-piperazin-2-yl]-methanone;
{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-[6-methyl-1-(3-methyl-butyl)-piperidin-2-yl]-methanone;
{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-[4-methyl-1-(3-methyl-butyl)-piperidin-2-yl]-methanone;
{4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-[3-methyl-1-(3-methyl-butyl)-piperidin-2-yl]-methanone;
(4-Benzyloxy-phenyl)-[1-(4-tert-butyl-benzyl)-piperidin-4-yl]-(3-methyl-butyl)-amine;
4-Benzyloxy-phenyl)-[1-(4-dimethylamino-benzyl)-piperidin-4-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-methoxy-benzyl)-piperidin4-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-ethoxy-benzyl)-piperidin-4-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-(3-methyl-butyl)-[1-(1H-pyrrol-2-ylmethyl)-piperidin-4-yl]-amine;
(4-Benzyloxy-phenyl)-(3-methyl-butyl)-[1-(4-methylsulfanyl-benzyl)-piperidin-4-yl]-amine;
(4-Benzyloxy-phenyl)-[1-(4-methanesulfinyl-benzyl)-piperidin-4-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-isopropoxy-benzyl)-piperidin-4-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-tert-butyl-benzyl)-piperidin-3-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-dimethylamino-benzyl)-piperidin-3-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4methoxy-benzyl)-piperidin-3-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-ethoxy-benzyl)-piperidin-3-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[(3-methyl-butyl)-[1-(1H-pyrrol-2-ylmethyl)-piperidin-3-yl]-amine;
(4-Benzyloxy-phenyl)-(3-methyl-butyl)-[1-(4-methylsulfanyl-benzyl)-piperidin-3-yl]-amine;
(4-Benzyloxy-phenyl)-[1-(4-methanesulfinyl-benzyl)-piperidin-3-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-isopropoxy-benzyl)-piperidin-3-yl]-(3-methyl-butyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-tert-butyl-benzyl)-piperidin-3-yl]-(3-methyl-but-2-enyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-dimethylamino-benzyl)-piperidin-3-yl]-(3-methyl-but-2-enyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-methoxy-benzyl)-piperidin-3-yl]-(3-methyl-but-2-enyl)-amine;
(4-Benzyloxy-phenyl)-[1-(4-ethoxy-benzyl)-piperidin-3-yl]-(3-methyl-but-2-enyl)-amine;
(4-Benzyloxy-phenyl)-(3-m

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