Substituted diarylalkyl amides as calcium channel antagonists

Details Substituted diarylalkyl amides as calcium channel antagonists Substituted diarylalkyl amides as calcium channel antagonists

1999-10-25

2002-10-01

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S239200, C514S255030, C514S453000, C514S485000, C514S522000, C514S524000, C514S617000, C514S630000, C540S529000, C544S175000, C544S391000, C546S226000, C549S356000, C558S414000, C560S027000, C564S164000, C564S168000, C564S195000

Reexamination Certificate

active

06458781

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.
SUMMARY OF THE RELATED ART
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.
Certain benzhydryl amides and benzhydryl amines have been described in the past, but their methods of use have been different from those of the present invention. For instance, U.S. Pat. No. 4,596,803 disclosed the following compound for the treatment of cardiac problems, with no mode of action specified:
European Patent Publication 333,938 refers to compounds having beta blocking activity for use in treatment of cardiovascular disorders. World Patent Publication 96/05201 refers to imidazopyridine derivatives as dual histamine and platelet activating factor antagonists. U.S. Pat. No. 4,764,514 refers to an oxothiazolidine compound. Other benzhydryl amides are mentioned in
Acta. Polon. Pharm.
34(4):371-375; 34(5):459-463; and 39(3):261-266. None of these earlier compounds have been used as N-type calcium channel blockers as described in the present invention.
The compounds of the present invention are not homologs or positional isomers of the compounds specified by Masaki et al.; therefore, one skilled in the art could not predict if these compounds would have similar biological activities.
SUMMARY OF THE INVENTION
The present invention provides compounds having the structural Formula I
or the pharmaceutically acceptable salts, thereof, wherein:
X is —NH(CH
2
)
n
—
each R
1
and R
2
are independently hydrogen, C
1
-C
6
alkyl, C
2
-C
6
alkenyl,
R
1
and R
2
together with the nitrogen atom to which they are both attached form a heterocycloalkyl group;
R
3
is hydrogen, C
1
-C
6
alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, or —(CH
2
)
n
—C
3
-C
7
cycloalkyl;
R
4
is hydrogen or C
1
-C
6
alkyl;
or R
3
and R
4
together with the carbon atom to which they are attached form a C
3
-C
7
cycloalkyl ring;
each R
5
and R
6
are independently phenyl or substituted phenyl;
R
7
is C
1
-C
6
alkyl, phenyl, or heterocycloalkyl; and
each n is independent 0 to 6.
In another preferred embodiment,
R
1
is hydrogen and
In another preferred embodiment, R
3
is hydrogen and
R
4
is 2-methylpropyl.
In another preferred embodiment, R
5
and R
6
are 4-fluorophenyl.
In another preferred embodiment, X is —NHCH
2
CH
2
CH
2
—.
In another preferred embodiment, R
5
and R
6
are phenyl.
In another preferred embodiment, R
5
and R
6
are 4-fluorophenyl or phenyl;
X is —NHCH
2
CH
2
CH
2
—;
R
3
is hydrogen; and
R
4
is 2-methylpropyl.
In a preferred embodiment of the compounds of Formula I,
X is
R
1
is hydrogen;
R
2
is
 and
R
5
and R
6
are 4-fluorophenyl or phenyl.
The present invention provides the compound (S)-Azepane-1-carboxylic acid {3-methyl-1-[3-(1-methyl-2-oxo-3-phenyl-2,3-dihydro-1H-indol-3-yl)-propylcarbamoyl]-butyl}-amide.
The present invention provides the compound (S)-Azepane-1-carboxylic acid {3-methyl-1-[(1-phenyl-1H-indazol-3-ylmethyl)-carbamoyl]-butyl}-amide.
The present invention provides the compound (S)-Azepane-1-carboxylic acid {1-[4-(9H-fluoren-9-yl)-piperazine-1-carbonyl]-3-methyl-butyl}-amide.
The present invention provides the compound (S)-(1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butyl)-carbamic acid tert-butyl ester.
The present invention provides the compound (S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butyl)-amide.
The present invention provides the compound (S)-Azepane-1-carboxylic acid [1-(benzhydryl-carbamoyl)-3-methyl-butyl]-amide.
The present invention provides the compound (S)-Azepane-1-carboxylic acid [1-(2,2-diphenyl-ethylcarbamoyl)-3-methyl-butyl]-amide.
The present invention also provides the compounds:
(S)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-amide;
(R)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-amide;
(S)-Azepane-1-carboxylic acid [1-(3,3-diphenyl-propylcarbamoyl)-3-methyl-butyl]-amide;
(S)-{1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester;
(S)-2-Amino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-(Cyclohexylmethyl-amino)-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-(3-methyl-but-2-enylamino)-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-methylamino-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-but-2-enyl)-amino]-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-Cyclohexylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-2-methyl-butyl}-amide;
(S)-4-Phenyl-piperazine-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-amide;
(S)-4-Methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-Isopropylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-Dimethylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-piperidin-1-yl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-morpholin-4-yl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-piperidin-1-yl-pentanoic acid (3,3-diphenyl-propyl)-amide;
(S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic acid (3,3-diphenyl-propyl)-amide;
(S)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-2-methyl-propyl}-amide;
(S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide;
(S)-4-Methyl-piperazine-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-amide;
(S)-Azepane-1-carboxylic acid {1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-ethyl}-amide;
(S)-Azepane-1-carboxylic acid (1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazine-1-carbon

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