Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-04-25
1998-12-22
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546158, A61K 3147, C07D40106
Patent
active
058520406
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to neuroprotective (excitatory amino acid 4 dihydro-2 (1H)-quinolone compounds, defined by the formula I below; the optical isomers of compounds of formula I; pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising a compound of formula I; and a method of using these compounds in the treatment of stroke, addiction, pain, epilepsy, psychosis, traumatic brain injury resulting from such things as drowning, traumatic head injury, cardiac arrest, cardiac surgery or neurosurgical procedures or CNS degenerative diseases such as senile dementia of the Alzheimer's type, multiinfarct dementia, Huntington's disease, AIDS dementia, amyotropic lateral sclerosis and Parkinson's disease.
Glutamate is recognized as a major excitatory neurotransmitter in the human central nervous system. It has also been demonstrated that exposure of neuronal cells to excessive amounts of glutamate is neurotoxic. Thus conditions which can lead to excessive glutamate release (traumatic brain injury, epilepsy, Parkinson's disease, senile dementia of the Alzheimer's type, ischemia etc.) can lead to neurodegeneration. Therefore agents which can block glutamate receptors afford protection against these diseases and conditions. This excitotoxin hypothesis and the potential utilities for excitatory amino acid receptor antagonists is well known in the art and has been described in the literature (see for example: Olney, Drug Dev. Res.,1989, 17, 299. Meldrum, Clinical Sci., 1985, 68, 113).
Ifenprodil is a racemic, so-called dl-erythro compound having the relative stereochemical formula ##STR1## which is marketed as a hypotensive agent, a utility shared by a number of close analogs; Carron et al., U.S. Pat. No. 3,509,164; Carron et al., Drug Res., v. 21, pp.1992-1999 (1971). Ifenprodil has also been shown to possess antiischemic and excitatory amino acid receptor blocking activity; Gotti et al., J. Pharm. Exp. Therap., v.247, pp.1211-21 (1988); Carter et al., loc. cit., pp. 1222-32 (1988). See also published European patent application 322,361 and French Patent 2,546,166. A goal, substantially met by the present invention, has been to find compounds possessing such neuroprotective effect in good measure, while at the same time having lowered or no significant hypotensive effect.
Certain structurally related 1-phenyl-3-(4-aryl-4-acyloxypiperidino)-1-propanols have also been reported to be useful as analgesics, U.S. Pat. No. 3,294,804; and hydroxy-alkyl)phenyl!-2-(4-hydroxy-4-tolylpiperazino)-1-alkanols and alkanones have been reported to possess analgesic, antihypertensive, psychotropic or antiinflammatory activity, Japanese Kokai 53-02,474 (CA 89:43498y; Derwent Abs. 14858A) and 53-59,675 (CA 89:146938w; Derwent Abs. 48671A).
More recently, in published European Patent Application No. 351,282, compounds which include those of the formula ##STR2## wherein R.sup.a and R.sup.b are each independently hydrogen or (C.sub.1 -C.sub.3)alkyl, R.sup.c is benzyl, phenoxy, benzyloxy or phenoxymethyl, and Z.sup.a is CH.sub.2, C(CH.sub.3).sub.2 or CH.sub.2 CH.sub.2, have been reported as having neuroprotective type activity.
PCT Application 91-101470, published Nov. 14, 1991, discloses, inter alia, compounds of the formula ##STR3## wherein A is ##STR4## n is 0 or 1; m is 0 or an integer from 1-6; (C.sub.1-C.sub.3)alkyl;
R.sup.3 and R.sup.4 are taken separately and are each hydrogen, or R.sup.3 and R.sup.4 are taken together and are ethylene; -C.sub.3)alkoxy!carbonyl; (C.sub.1-C.sub.3)alkoxy, fluoro, chloro or bromo.
SUMMARY OF THE INVENTION
The present invention is directed to the racemic mixtures and enantiomerically pure compounds of the formula ##STR5## and the pharmaceutically-acceptable acid addition salts thereof wherein R is selected from the group consisting of F, --CF.sub.3, --OCH.sub.3, --O(C.sub.1)alkyl substituted with 1 to 3 fluoro atoms, --O(C.sub.2)alkyl substituted with 1 to 5 fluoro atoms and --O(C.sub.3)alkyl substituted with 1 to 7 fluoro atoms.
The prefe
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Creagan B. Timothy
Ginsburg Paul H.
Ivy C. Warren
Mach D.Margaret M.
Pfizer Inc.
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