Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-18
2000-09-26
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514331, 546229, 546236, A01N 4340
Patent
active
061243175
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is related to 2-substituted piperidine analogs. The analogs are selectively active as antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is also directed to the use of 2-substituted piperidine analogs as neuroprotective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headaches, chronic pain, glaucoma, CMV retinitis, psychosis, urinary incontinence, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease.
2. Related Background Art
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-Aspartate (NMDA) receptor. This excitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.
Various classes of substituted piperidine analogs are known. For example, U.S. Pat. No. 5,036,077 generically discloses piperidine derivatives described by the formula: ##STR1## wherein Ar represents a phenyl group substituted by R.sub.2, R.sub.3 and R.sub.4 or a naphth-1-yl or naphth-2-yl group, substituted or unsubstituted by 1 or 2 halogen atoms; X represents an oxygen atom or sulfur atom; R.sub.1 represents H or a halogen atom; R.sub.2 represents a halogen atom, a trifluoromethyl group, a phenyl group which is unsubstituted or substituted by 1 to 3 halogen atoms, a phenoxy group which is unsubstituted or substituted by 1 to 3 halogen atoms, or a C.sub.1 -C.sub.4 alkyl group and the benzyl group substitutes the piperidine radical in the 2, 3 or 4 position. This reference does not exemplify 2-substituted piperidines. The piperidines are said to be useful as antimicrobial agents, but there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
Canadian Patent No. 696,999 is directed to N-(alkylene)aryl-2-substituted piperidines useful as vasodilators which are described by the formula: ##STR2## wherein A is an alkylene group having 2 to 3 carbon atoms. There is no mention of using the compounds of this reference as NMDA receptor antagonists or treating disorders responsive thereto.
PCT International Publication Number WO 93/15052 generically describes compounds that are said to be calcium channel antagonists represented by the formula: ##STR3## and the salts thereof, wherein R is C.sub.1-8 alkyl(phenyl)p, C.sub.2-8 alkenyl(phenyl)p, C.sub.2-8 alkynyl(phenyl)p, C.sub.3-8 cycloalkyl or C.sub.1-8 alkyl C.sub.3-8 cycloalkyl; 2-[2-(3,4-Dichlorophenoxy)ethyl]-1-cinnamylpiperidine oxalate hemihydrate and 4-[2-(2-Dibenzofuranyloxy)ethyl]-1-cinnamylpiperidine oxalate are exemplified. The compounds of this reference are said to be useful for treating anoxia, ischaemia, such as stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases and drug addiction withdrawal. This reference does not disclose or suggest NMDA receptor activity, let alone selective NMDA receptor subtype antagonism.
European Patent Application No. 235,463 generically discloses calcium antagonists represented by the formula ##STR4## wherein; p is zero, one or two; ##STR5## m is zero to six inclusive; ##STR6## d and n are selected from zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon; ##STR7## and
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Bigge Christopher F.
Cai Sui Xiong
Guzikowski Anthony P.
Keana John F. W.
Lan Nancy C.
Chang Ceila
Cocensys Inc.
Warner-Lambert & Company
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