4-substituted piperidine analogs and their use as subtype select

Details 4-substituted piperidine analogs and their use as subtype select 4-substituted piperidine analogs and their use as subtype select

1998-09-16

2000-09-26

Rotman, Alan L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546229, 546230, 546232, 546237, 546236, 546240, 514327, 514331, A01N 4340, C07D21126, C07D21160, C07D21118, C07D21120

Patent

active

06124323&

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention is related to 4-substituted piperidine analogs, including hydroxypiperidine and tetrahydropyridine 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 4-substituted piperidine analogs as neuroprotective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, psychosis, glaucoma, CMV retinitis, urinary incontinence, aminoglycoside antibiotics-induced hearing loss, convulsions, migraine headache, chronic pain, 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, EP 0648744 generically discloses phenylalkanol derivatives described by the formula ##STR1## wherein R is hydrogen, hydroxy, or aryl lower alkyloxy; X is hydrogen; Y is hydroxy or hydrogen; or both X and Y taken together are oxygen; Z is aryl lower alkyl; and m is an integer from 1 to 4. The phenylalkanol derivatives of this reference are indicated to be NMDA receptor antagonists that are useful to reduce toxic injury to central neurons and may be used to treat ischemia, stroke or hypoxia. This reference does not disclose or suggest the 4-substituted piperidine analogs of this invention or their use as selective NMDA receptor subtype antagonists.
Other piperidine derivatives having aryl alkanol functionality are disclosed by PCT International Publication No. WO 93/11107 (for treating hypoxia and ischaemia), International Publication No. WO 94/10166 (for treating stroke, addiction, pain, epilepsy, psychosis, traumatic brain injury and CNS degenerative diseases), EP 0398578 (for treating stroke or CNS degenerative diseases, Alzheimer's disease, Huntington's disease and Parkinson's disease) and PCT International Publication No. WO 93/02052 (for treating stroke, traumatic injury to the brain and spinal cord, and neuronal degenerative diseases). Similar to EP 0648744, each of these references requires a piperidine derivative having an alkyl hydroxy or keto group alpha to the aryl group of the N-1 substituent. The 4-substituted piperidine analogs of this invention differ in kind from the piperidine derivatives of these references.
EP 0445701 generically discloses tetrahydropyridine a derivatives described by the formula ##STR2## wherein Ar is phenyl or thienyl which may have identically or differently one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, substituted or unsubstituted phenyl, trifluoromethyl and hydroxy; n is an integer of from 2 to 6; R is hydroxy or a group of the formula: ##STR3## wherein R.sup.1 is hydrogen or lower alkyl; R.sup.2 and R.sup.3 each is hydrogen or lower alkyl or taken together with the adjacent nitrogen atom may form a 5- or 6-membered heterocyclic group, which may be condensed with a benzene ring, where the heterocyclic group may identically or differently have 1 to 3 substituents selected from the group consisting of lower alkyl, halogen, oxo, pyrimidine, and substituted or unsubstituted phenyl; R.sup.4 is NH

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