Tyrosine-derived compounds as calcium channel antagonists

Details Tyrosine-derived compounds as calcium channel antagonists Tyrosine-derived compounds as calcium channel antagonists

1999-09-27

2001-01-30

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C514S617000, C514S625000, C514S649000, C514S659000, C546S223000, C546S192000, C546S224000, C546S229000, C564S305000, C564S336000

Reexamination Certificate

active

06180677

ABSTRACT:

CROSS REFERENCE
This application is a 371 of PCT/US99/12276 filed Jun. 2, 1999.
BACKGROUND OF THE INVENTION
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 initiate a cascade of biochemical events that disrupts normal cellular processes. Among these events are the activation of proteases and lipases, the breakdown of neuronal membranes, and the formation of free radicals, which may ultimately lead to cell death. Several types of calcium channels, the L, N, P, Q, R, and T types, have been discovered. Each type possesses distinct structural features, functional properties and cellular/subcellular distributions. Type-selective calcium channel blockers also 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 that block calcium channels and have the Formula I:
and pharmaceutically acceptable salts, esters, and pro-drugs thereof, wherein
R
1
-R
5
are defined below.
The present invention also provides pharmaceutical compositions containing the compounds of Formula I and methods of using them to treat stroke, cerebral ischemia, head trauma, and epilepsy.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises novel calcium channel blockers having general structural Formula I:
and pharmaceutically acceptable salts, esters, and pro-drugs thereof, wherein
R
1
and R
2
are independently H, phenylcyclopentylcarbonyl, C
1
-C
7
alkyl, cyclohexylmethyl, benzyl, C
1
-C
5
alkylbenzyl or C
1
-C
5
alkoxybenzyl;
A is —C(O)— or —CH
2
—;
R
3
is H or —CH
3
;
R
4
is C
1
-C
4
alkyl or piperidin-1-ylethyl;
R
5
is phenyl-(CH
2
)
n
—, C
1
-C
4
alkylphenyl-(CH
2
)
n
—, or halophenyl-(CH
2
)
n
—; and
n is 1 or 2.
The term “alkyl” means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl, (CH
3
)
2
CHCH
2
CH
2
—, ((CH
3
)
2
CHCH
2
CH
2
)
2
CH—, and (CH
3
)
3
CCH
2
CH
2
.
The term “alkoxy” means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
The term “halo” means chlorine, fluorine, bromine, and iodine.
The symbol “—” means a bond.
Most preferably, the invention provides compounds of Formula I selected from the group consisting of:
(S)-1-Phenyl-cyclopentanecarboxylic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcar-bamoyl-ethyl]-amide;
(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-(3-methyl-butylamino)-propionamide;
(S)-3-(4-Benzyloxy-phenyl)-2-[bis-(3-methyl-butyl)-amino]-N-tert-butyl-propion-amide;
(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-[4-methyl-1-(3-methyl-butyl)-pentyl-amino]-propionamide;
(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-[cyclohexyl-methyl-(3-methyl-butyl)-amino]-propionamide;
(S)-3-(4-Benzyloxy-phenyl )-N-tert-butyl-2-[(3,3-dimethyl-butyl)-(3-methyl-butyl)-amino]-propionamide;
(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-(3,3-dimethyl-butylamino)-propionamide;
(S)-3-(4-Benzyloxy-phenyl)-2-[bis-(3,3-dimethyl-butyl)-amino]-N-tert-butyl-propion-amide;
(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-(4-tert-butyl-benzylamino)-propionamide;
(S)-3-(4-Benzyloxy-phenyl)-2-[bis-(4-tert-butyl-benzyl)-amino]-N-(2-piperidin-1-yl-ethyl)-propionamide;
3-(4-Benzyloxy-phenyl)-N
2
,N
2
-bis-(4-tert-butyl-benzyl)-N
1
-(2-piperidin-1-yl-ethyl)-propane-1,2-diamine;
3-(4-Benzyloxy-phenyl)-N
2
-(4-tert-butyl-benzyl)-N
1
-(2-piperidin-1-yl-ethyl)-propane1,2-diamine;
(S)-3-(4-Benzyloxy-phenyl)-2-(4-tert-butyl-benzylamino)-N-(2-piperidin-1-yl-ethyl)-propionamide; and
3-(4-Benzyloxy-phenyl)-N
1
-tert-butyl-N
2
-(4-tert-butyl-benzyl)-propane-1,2-diamine.
The term “patient” means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
The compounds of the invention may be readily prepared as set forth in the following reaction schemes which employ common synthetic methods well-known to those skilled in organic chemistry. The following terms are as defined:
HBTU
O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium-
hexafluorophosphate
TFA
Trifluoroacetic acid
DMC
4,4′-Dichloro-&agr;-methylbenzhydrol
DMF
N,N-Dimethylformamide
LAH
Lithium aluminum hydride
THF
Tetrahydrofuran
NaHB(Oac)
3
Sodium triacetoxyborohydride
Et
2
O
Diethyl ether
Each of R
a
—R
h
are defined to encompass all chemical moieties for which the reaction products of Schemes I through IV fall within the scope of Formula I.
Those skilled in the art are easily able to identify patients having a stroke or at risk of having a stroke, cerebral ischemia, head trauma, or epilepsy. For example, patients who are at risk of having a stroke include, but are not limited to, patients having hypertension or undergoing major surgery.
A therapeutically effective amount is an amount of a compound of Formula I that when administered to a patient, ameliorates a symptom of the disease. Typical amounts will be about 0.01 to about 200 mg/kg of body weight. Daily dose will generally be from about 5 to about 500 mg per patient.
The compounds of the present invention can be administered to a patient either alone or a part of a pharmaceutical composition. The compositions can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) bi

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