Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-05-29
1999-11-09
Huang, Evelyn Mei
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514327, 514328, 546 19, 546216, 546217, 546219, 546220, 546222, A61K 31445, C07D21142, C07D21146
Patent
active
059815396
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase under 35 U.S.C. .sctn.371 of prior PCT International Application No. PCT/EP96/04039 which has an International filing date of Sep. 13, 1996 which designated the United States of America, published as WO 97/10212 on Mar. 20, 1997, the entire contents of which are hereby incorporated by reference.
The present invention relates to pharmaceutically active compounds and their use as well as to pharmaceutical preparations comprising the compounds. The compounds of the invention possess valuable activity as calcium channel blockers which make them useful in the treatment of stroke, anoxia, ischemia, migraine, psychosis (e.g. affective disorders), epilepsy or any other convulsive disorder.
It is well known that an accumulation of calcium (calcium overload) in the brain is seen after anoxia, ischemia, migraine and other hyperactivity periods of the brain, such as after epileptic convulsions. An uncontrolled high concentration of calcium in the cells of the Central Nervous System (CNS) is known to cause most of the degenerative changes connected with the above diseases. Compounds which can block the calcium channels of brain cells will therefore be useful in the treatment of anoxia, ischemia, migraine, epilepsia and in the prevention of the degenerative changes connected with same.
Compounds blocking the so called L-type calcium channels in the CNS will be useful for the treatment of the above disorders by directly blocking the calcium uptake in the CNS.
Further, it is well known that the so called N- and P-types of calcium channels, as well as possibly other types of calcium channels, are involved in the regulation of neurotransmitter release. Compounds blocking the N- and/or P-types of calcium channels will indirectly and very powerfully prevent calcium overload in the CNS after the hyperactivity periods of the brain as described above by inhibiting the enhanced neurotransmitter release seen after such hyperactivity periods of the CNS, and especially the neurotoxic, enhanced glutamate release after such hyperactivity periods of the CNS. Furthermore, blockers of the N- and/or P-types of calcium channels will as dependent upon the selectivity of the compound in question inhibit the release of various other neurotransmitters such as aspartate, GABA, glycine, dopamine, serotonin and noradrenaline.
DE-A-2738477 discloses the use of piperidine derivatives for the preparation of antidepressants.
U.S. Pat. No. 4,994,471 discloses piperidine derivatives which are useful as analgesics.
Drug Development Research 8, pages 225-232 (1986) discloses the synthesis of cisapride, a gastrointestinal stimulant derived from cis-4-amino-3-methoxypiperidine.
WO-A-92/02502 discloses processes for preparing piperidine derivatives, pharmaceutical compositions containing said compounds and their use in therapy, in particular as calcium blocking agents.
It is an object of the present invention to provide compounds capable of blocking the L-type and/or the N-type and/or the P-type of calcium channels, and/or other types of calcium channels.
In combination with their calcium channel blocking activity certain compounds of the invention also possess valuable sodium channel blocking activity.
The main pathway for the sodium ion in excitable cells is the voltage operated Na-channels. These channels are universally distributed in excitable cells such as neurons, skeletal--and heart muscles, as well as in various gland cells. Voltage-gated sodium channels are responsible for the initial, rapid depolarization of the action potential in nerve and muscle cells. At negative membrane potentials, most sodium channels are in closed, resting states. In response to membrane depolarization, the channels open for a few hundred microseconds, resulting in sodium-ion influx through a sodium-ion selective pore, and then convert to a nonconducting inactivated state. Modulation of sodium channels is the mechanism of action of local anesthetics and class I antiarrhytmics, and several antepileptic compounds exert their effects th
REFERENCES:
patent: 4160837 (1979-07-01), Paioni
patent: 4994471 (1991-02-01), Lalinde et al.
Van Daele et al., Drug Development Research, vol. 8, pp. 225-232 (1986).
Axelsson Oskar
Christophersen Palle
Peters Dan
stergaard Nielsen Elsebet
Huang Evelyn Mei
NeuroSearch A/S
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