Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-11-06
1994-04-26
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514323, 514324, 514312, 546126, 546198, 546201, 546153, A61K 3144, C07D20934, C07D40106, C07D26358
Patent
active
053067231
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to neuroprotective (antiischemic and excitatory aminoacid receptor blocking) 5-(1-hydroxy-2-piperidinopropyl)-2(1H,3H) -indolone analogs, defined by the formula (I), (II) and (III) below; pharmaceutically acceptable salts thereof; a method of using these compounds in the treatment of stroke, traumatic brain injury or CNS degenerative diseases such as Alzheimer's disease, senile dementia of the Alzheimer's type, 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 ##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 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 published European patent application 322,361 and 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), 53-59,675 (CA 89:146938w; Derwent Abs. 48671A) and 76,118,772 (CA 86:189738m).
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.4)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.
Also, amino ketone and amino alcohol derivatives of benzoxazolinone and their adrenergic and antihypertensive properties are described in the European Journal of Medicinal Chemistry, 25, 361-368, (1990), C.A. 113:191213f.
The nomenclature used herein is generally that of Rigaudy et al., IUPAC Nomenclature of Organic Chemistry, 1979 Edition, Pergammon Press, New York. 2(1H,3H)-Indolones are alternatively named as oxindoles.
SUMMARY OF THE INVENTION
The present invention is directed to racemic or optically active compounds of the formulas ##STR3## n is 0 or 1; m is 0 or an integer from 1-6; -C.sub.3)alkyl; and R.sup.4 are taken together and are ethylene; (C.sub.1 -C.sub.3)alkoxy, fluoro, chloro or bromo;
The preferred compounds of the present invention generally have R.sup.2 as hydrogen or methyl, most preferably as methyl, having relative stereochemistry in 1-hydroxypropyl side chain depicted as ##STR4## and which is specified either as (1S.sup.*,2S.sup.*) or (1R.sup.*,2R.sup.*).
The preferred values of A are generally ##STR5##
The present invention is also directed to intermediate compounds of the formula ##STR6## wherein the variable groups are as defined above.
The present invention is further directed to pharmaceutical compositions comprising a compound of the formula (I), (II) or (III), and to a method of treating stroke, traumatic brain injury or a CNS degenerative disease with a compound of the formula (I), (II) or (III).
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
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CA116(9):83552u Preparation . . . as Neuroprotectants, Chenard, p. 807, 1992.
Gotti et al., J. Pharmacol. Exp. Therap., vol. 247, pp. 1211-1222 (1988).
Carter et al., J. Pharmacol. Exp. Therap., vol. 247, pp. 1222-1232 (1988).
CA86:189738m Carbostyril Derivatives. Nakagawa et al., p. 592, 1977.
CA89:43498y; Derwent 14858A Piperazinyl . . . acetophenone. Muro et al., p. 644, 1978.
CA89:146938w; Derwent 48671A Aminoalcohol derivatives. Muro et al., p. 615, 1978.
Carron et al., Arneim-Forsch., vol. 21, pp. 1992-1998 (1971), Synthesis . . . Derivatives.
Bonte et al., Eur. J. Med. Chem., 25(4), pp. 361-368 (1990) Amino Ketone . . . properties.
Benson Gregg C.
Lee Mary C.
Lumb J. Trevor
McKane Joseph K.
Pfizer Inc.
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