Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-03-16
1995-12-05
Datlow, Philip I.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 18, A61K 3147, C07D21704
Patent
active
054729688
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel spiro[cycloalkylbenzene-1,1'-(1',2',3',4'-tetrahydroisoquinolines)], processes for their preparation, pharmaceutical formulations containing them and their neuroprotective properties.
BACKGROUND
Compounds which possess N-methyl-(d)-aspartate (NMDA) blocking properties are useful in the treatment and/or prevention of neurodegeneration in pathological conditions such as stroke, cerebral ischaemia, cerebral palsy, hypoglycaemia, epilepsy, Alzheimer's disease, Huntington's chorea, Olivo-ponto-cerebellar atrophy, perinatal asphyxia and anoxia.
Kametani et al. [J. Chem. Soc.(C) 112-118 (1968) investigated isoquinoline alkaloid derivatives and obtained 1',2',3',4'-tetrahydro-6'-hydroxy-5,6,7'-trimethoxyspiro[indane-1,1'-isoqu inoline] as a product of phenolic cyclization.
Spiro[indane-1,1'-isoindoline] was disclosed by Robinson et al[Tet. Letts. 30. 5203-5206 (1989)]. No biological data were reported.
DETAILED DESCRIPTION
According to the invention, we provide compounds of the formula I: ##STR2## wherein R.sub.1 and R.sub.2, independently represent H or C.sub.1-6 alkyl; from H, OH, NH.sub.2, NO.sub.2, halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; carbon-carbon bond; R.sub.4 is other than 5,6,7-trimethoxy; R.sub.4 is other than 5,6,7 -trimethoxy; R.sub.4 is other than 4,5-dimethoxy; R.sub.4 is other than 5,6-dimethoxy.
Pharmaceutically acceptable derivatives include pharmaceutically acceptable acid addition salts and compounds which will be suitable bioprecursors (prodrugs) of the compound of formula I.
Pharmaceutically acceptable acid addition salts of the compounds of formula I include salts of mineral acids, for example, hydrohalic acids, eg hydrochloric or hydrobromic; or organic acids, for example, formic, acetic or lactic acids. The acid may be polybasic, for example sulphuric, fumaric, maleic or citric acid.
Suitable bioprecursors of the compounds of formula I include C.sub.1-6 alkanoyl amides, urethane derivatives and amino acid amide derivatives of one or more of the amino groups, and when a compound of formula I bears a hydroxyl group, esters of alkanoic and amino acids. Urethane derivatives include C.sub.1-6 alkoxycarbonyl groups. Amino acid amide and ester derivatives may be formed from alpha-amino acids.
Alpha-amino acids may be represented by the formula II: ##STR3## in which, R.sub.5 represents hydrogen, C.sub.1-6 alkyl, hydroxy- C.sub.1-2 alkyl, mercaptomethyl, (methylthio)C.sub.1-2 alkyl, carboxy-C.sub.1-2 alkyl, 2-(C.sub.1-3 alkoxy)ethyl, (aminocarbonyl)C.sub.1-2 alkyl, amino-C.sub.1-4 alkyl, 3-imidazolylmethyl, phenylmethyl or (4-hydroxyphenyl)methyl, or in addition, R.sub.5 together with the adjacent nitrogen may represent a piperidine, pyrrolidine or a 2-pyrrolidinone ring; and alkyl, or in addition, R.sub.7 and R.sub.8 taken together with the nitrogen to which they are attached may represent a C.sub.4-5 N heterocyclic ring;
Certain compounds of formula I and II may exist in different stereoisomeric forms, including optical enantiomeric forms. All are included within the scope of the invention.
According to another aspect of the invention, there is provided a process for the preparation of the compounds of formula I or pharmaceutically acceptable derivatives thereof, which comprises: cyclizing the corresponding compound of formula III: ##STR4## in which R.sub.1, R.sub.3, R.sub.4 and n are as defined above, and X is a suitable leaving group, or by reacting the corresponding compound of formula I in which R.sub.2 is hydrogen with an alkylating agent of the formula, C.sub.1-6 alkyl-Y in which Y is a suitable leaving group, or by reducing the corresponding compound of formula I in which R.sub.2 represents a C.sub.1-6 alkanoyl group or a urethane group, or reacting the corresponding compound of formula I in which R.sub.2 represents hydrogen with formaldehyde and formic acid, or either or both of the spiro rings by halogenation-dehydrohalogenation of the corresponding compound of formula I, or by removing a protecting group from a compound of formula I in which
REFERENCES:
patent: 3886163 (1975-05-01), Kadin
Grelan, Chemical Abstract vol. 74, No. 141571b (1971).
Kametani et al, J. Chem. Soc. (c), (1971), pp. 1032-1043.
Griffith Ronald C.
Matz James R.
Napier James J.
Datlow Philip I.
Fisons Corporation
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