Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-10-23
1993-02-09
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514364, 546 18, 546124, 546125, 546129, 546131, A61K 3146, C07D45102, C07D45106
Patent
active
051853434
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to neuroprotective (antiischemic and excitory aminoacid receptor blocking) 2-piperidino-1-alkanol derivatives defined by the formulas (I), (II) and (III) below; pharmaceutically acceptable salts thereof; a method of using these compounds in the treatment of stroke or CNS degenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease; and to certain intermediates therefor.
Ifenprodil is a racemic, so-called dl-erythro compound having the relative stereochemical formula ##STR2## which is marketed as a hypotensive agent, a utility which is marketed as a hypotens 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). More recently, ifenprodil has been shown to possess antiischemic and excitory aminoacid 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 French Patent 2546166. 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 1-[4-(amino- 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).
SUMMARY OF THE INVENTION
The present invention is directed to compounds of the formula ##STR3## wherein R is H, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl or (C.sub.2 -C.sub.6)alkynyl; CO.sub.2 R.sup.1, SR.sup.1, NHR.sup.1, NHCOR.sup.1, CONH.sub.2 or CN; ##STR4## Y and Y.sup.1 are taken separately, and Y is hydrogen or OH, and Y.sup.1 is ##STR5## Y is hydrogen and Y.sup.1 is ##STR6## n is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; ##STR7## wherein D is ##STR8## Y.sup.2 and Y.sup.3 are taken together and are ##STR9## Y.sup.2 and Y.sup.3 are taken separately, and Y.sup.2 is OH and Y.sup.3 is ##STR10## Y.sup.9 is ##STR11## and R, R.sup.1, X, X.sup.1, Q, Q.sup.1, n and m are as defined above; and compounds of the formula ##STR12## wherein Y.sup.4 is H; and pharmaceutically acceptable acid addition salts of these compounds.
The expression "pharmaceutically acceptable acid addition salts" is intended to include but is not limited to such salts as the hydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulfate, dihydrogen phosphate, mesylate, maleate, and succinate. Such salts are conventionally prepared by reacting the free base form of the compound (I), (II) or (III) with an appropriate acid, usually one molar equivalent, and in a solvent. Those salts which do not precipitate directly are generally isolated by concentration of the solvent and/or addition of a non-solvent.
The preferred compounds of the present invention generally have R as methyl and possess 1S*,2S* or threo relative stereochemistry at the 1- and 2-positions of the propanol chain, i.e., ##STR13##
Furthermore, regardless of the value of R, preferred compounds of the present invention are of the formula (I) or (II) having Y and Y.sup.1 or Y.sup.2 and Y.sup.3 taken separately, further having Y or Y.sup.2 as OH, or Y.sup.1 as --Z(C.sub.4 H.sub.3 Q.sup.1 ; or are of the formula (III). The preferred value of Z in all cases is S.
The present invention is also directed to pharmaceutical compositions and to methods of treating a mammal, particularly man, suffering a central nervous disorder, which comprises administering to said mammal a neuroprotective effective amount of a compound of the formula (I), (II) or (III). Said compositions and methods are particularly valuable in the treatment of stroke, Alzheimer's disease, Parkinson's disea
REFERENCES:
patent: 3294804 (1966-12-01), Carabateas
patent: 3509164 (1970-04-01), Carron et al.
patent: 4393069 (1983-07-01), Langbein et al.
Carron, et al., Arzneim-Forsch. (Drug Res.), 21, 1992-1999(1971).
Carter, et al., Journal of Pharmacology and Experimental Therapeutics, 247, 1222-1232 (1989).
Gotti, et al., Journal of Pharmacology & Experimental Therapeutics, 247, 1211-1222 (1988).
Dentz Bernard
Lumb J. Trevor
Pfizer Inc.
Richardson Peter C.
Ronau Robert T.
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