Heteroaryl alkyl alpha substituted peptidylamine calcium...

Details Heteroaryl alkyl alpha substituted peptidylamine calcium... Heteroaryl alkyl alpha substituted peptidylamine calcium...

2000-09-18

2002-10-22

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S204000

Reexamination Certificate

active

06469038

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, amyotropic 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, asthma, amyotropic lateral sclerosis, and epilepsy.
SUMMARY OF THE INVENTION
The present invention provides compounds having the Formula I
wherein
* denotes a first chiral center when R
3
and R
4
are different;
@ denotes a second chiral center;
R
1
and R
2
are independently hydrogen, C
1
-C
8
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
8
substituted alkyl, C
1
-C
6
alkoxy, hydroxy, C
3
-C
7
cycloalkenyl, C
3
-C
7
substituted cycloalkenyl, C
3
-C
7
substituted cycloalkyl, —(CH
2
)
n
-aryl, —(CH
2
)
n
-substituted aryl, C
2
-C
8
alkenyl, C
2
-C
8
substituted alkenyl, —(CH
2
)
n
-heteroaryl, —(CH
2
)
n
-substituted heteroaryl, —(CH
2
)
n
—C
3
-C
7
cycloalkyl, —(CH
2
)
n
—C
3
-C
7
heterocycloalkyl, —(CH
2
)
n
-substituted C
3
-C
7
heterocycloalkyl, or R
1
and R
2
may be taken together to form a 5- to 7-membered ring which may contain a heteroatom, provided that R
1
and R
2
are not both hydrogen;
R
3
, R
5
, and R
6
are independently hydrogen or C
1
-C
8
alkyl;
R
4
is —(CH
2
)
n
-heteroaryl or —(CH
2
)
n
-substituted heteroaryl;
Y is —(CH
2
)
n
—, O(CH
2
)
n
—, —(CH
2
)
n
O—, —N(R
7
)(CH
2
)
n
—, —(CH
2
)
n
N(R
7
)—, —S(CH
2
)
n
—, —(CH
2
)
n
S—, —C═C—, or —C≡C—;
R
7
is hydrogen, methyl, or ethyl;
Z is aryl, substituted aryl, heteroaryl, substituted heteroaryl, C
3
-C
7
cycloalkyl, substituted C
3
-C
7
cycloalkyl, C
1
-C
8
alkyl, —C
3
-C
7
heterocycloalkyl, or substituted C
3
-C
7
heterocycloalkyl;
X is OR
8
, NHR
8
, or NR
8
R
9
;
R
8
and R
9
are independently C
1
-C
12
alkyl, C
1
-C
12
substituted alkyl, —(CH
2
)
n
—C
3
-C
8
heterocycloalkyl, C
3
-C
7
cycloalkyl, substituted C
3
-C
7
cycloalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, or NR
8
R
9
can together with the nitrogen atom form a ring having from 4 to 7 atoms;
each n is 0 to 5, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the compound of Formula I, R
1
is 3-methylbutyl.
In another preferred embodiment of the compounds of Formula I, R
3
, R
5
, and R
6
are hydrogen.
In another preferred embodiment of the compounds of Formula I,
 —(CH
2
)
n
piperidine, or aminoethylpiperidine.
In another preferred embodiment of the compounds of Formula I, Y is —OCH
2
—, —CH
2
CH
2
—, or
In another preferred embodiment of the compounds of Formula I, Z is phenyl.
In another preferred embodiment of the compounds of Formula I,
R
1
is 3-methylbutyl;
R
3
, R
5
, and R
6
are hydrogen;
R
4
is —CH
2
pyridyl;
X is
Y is —OCH
2
—; and
Z is phenyl.
In another preferred embodiment of the compounds of Formula I, R
5
and R
6
are hydrogen.
In another preferred embodiment of the compounds of Formula I, R
2
is C
1
-C
8
alkyl, cyclohexyl, substituted cyclohexyl, —CH
2
-phenyl, or CH
2
-substituted phenyl.
In another preferred embodiment of the compounds of Formula I, X is
In another preferred embodiment of the compounds of Formula I, R
2
is C
3
-C
7
cycloalkenyl.
In another more preferred embodiment of the compounds of Formula I,
R
1
is 3-methylbutyl;
R
2
is C
1
-C
8
alkyl, substituted cyclohexyl, cyclohexyl, cyclohexenyl, —CH
2
-phenyl, —CH
2
-substituted phenyl, —CH
2
-cyclohexyl, C
1
-C
8
alkenyl, —CH
2
-pyridyl;
R
3
, R
5
, and R
6
are hydrogen;
R
4
is —CH
2
pyridyl;
X is
 —(CH
2
)
n
piperidine, or aminoethylpiperidine;
Y is —O—CH
2
—; and
Z is phenyl.
In another more preferred embodiment of the compounds of Formula I, Y is —O—CH
2
— or
Z is phenyl;
X is
R
3
and R
5
are hydrogen;
R
4
is —CH
2
pyridyl;
R
1
is 3-methylbutyl; and
R
2
is C
1
-C
8
alkyl, —(CH
2
)
n
substituted phenyl, or cyclohexyl.
In a most preferred embodiment of the present invention, the compounds are:
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enylamino)-3-pyridin-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-3-pyridin-3-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enylamino)-3-pyridin-3-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(3-methyl-butylamino)-3-thiazol-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enylamino)-3-thiazol-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-cyclohexylamino-3-thiazol-4-yl-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohexylmethyl-amino)-3-(1H-imidazol-4-yl)-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(1-methylethyl-amino)-3-(1H-imidazol-4-yl)-propionamide;
[S-(R*,R*)]-N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohexyl-methyl-amino)-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(isobutyl-methyl-amino)-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(3,3-dimethyl-butyl)-methyl-amino]-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-(cyclohex-2-enyl-methyl-amino)-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(4-dimethylamino-benzyl)-methyl-amino]-3-pyridin-4-yl-propionamide;
N-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-2-[(4-methoxy-benzyl)-methyl-amino]-3-pyridin-4-yl-propionamide;
N-{-tert-Butylcarbamoyl-2-[4-(3,3-dimethyl-butyl)-phenyl]-ethyl}-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(3,3-dimethyl-butyl)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-2-(3-methyl-butylamino)-3-pyridin-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-ethyl}-2-[methyl-(3-methyl-butyl)-amino]-3-pyridin-4-yl-propionamide;
N-{1-tert-Butylcarbamoyl-2-[4-(pyridin-3-ylmethoxy)-pheny

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