Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-07-23
1994-10-18
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514304, 514319, 546124, 546126, 546128, 546196, 546206, A61K 31445, C07D21114, C07D40504
Patent
active
053569059
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is directed to neuroprotective (antiischemic and excitory aminoacid receptor blocking) 3-piperidino-1-chromanol derivatives and analogs, defined by the formula (I), 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 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 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) and 53-59,675 (CA 89:146938w; Derwent Abs. 48671A).
The nomenclature used herein is generally that of Rigaudy et al., IUPAC Nomenclature of Organic Chemistry, 1979 Edition, Pergammon Press, New York. Chromans are alternatively named as 3,4-dihydro-1(2H)-benzopyrans.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of the formula ##STR3## wherein A and B are taken together and are --CH.sub.2 CH.sub.2 -- or A and B are taken separately and are each H; salts thereof.
For their ease of preparation and valuable biological activity, preferred compounds of the formula (I) have A and B taken separately (and so are each hydrogen ), Z i s H, F, Cl or OH; Z.sup.1 is H and m is 0, 1 or 2. When X is 0 and n is 1, the more preferred compounds have the cis relative stereochemical formula ##STR4## particularly those compounds wherein Z is OH and substituted at the 7-position of the chroman ring system. Most preferred compounds of the formula (Ia) are those wherein m is 0 or 2. When X is CH.sub.2 and n is 1, the more preferred have the trans relative stereochemical formula ##STR5## those compounds wherein Z is OH substituted at the 6-position of the 1,2,3,4-tetrahydronaphthalene ring system being of particular value. Most preferred compounds of the formula (Ib) are those wherein X.sup.1 is OH and m is O. When n is 0, the more preferred compounds have X as CH.sub.2, X.sup.1 as OH, Z as OH substituted at the 5-position of the indane ring system and m as O.
The present invention is also directed to intermediate compounds of the formula ##STR6## wherein A and B, X, X.sup.1, Z.sup.1, m and n are as defined above; and J are taken separately and G is H and J is hydroxy; when G and J are taken separately, Z.sup.3 is OR.sup.1 and R.sup.1 is a conventional hydroxy protecting group; ##STR7## wherein the variable groups are as defined above.
The present invention is further directed to pharmaceutical compositions comprising a compound of the formula (I) and to a method of treating stroke or a CNS degenerative disease with a compound of the formula (I).
The above reference to "pharmaceutically acceptable salts" in all instant cases refers to conventional acid addition salts. Thus the compounds of the formula (I) contain an amine group which is basic, and so are capable of forming such salts. Said salts include, but are not limited to, those
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Chemical Abstracts 89, (43498) 1978.
Chemical Abstracts 89, (146938w) 1978.
Carter, et al., J. Pharmacology & Experimental Therapeutics 247, 1222 (1988).
Gotti, et al., J. Pharmacology & Experimental Therapeutics 247, 1211 (1988).
Benson Gregg C.
Brokke Mervin E.
Haley Jacqueline
Pfizer Inc.
Ramsuer Robert W.
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