Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-12-12
1997-07-01
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546196, A61K 31445, C07D40512
Patent
active
056439270
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/01008 filed Mar. 17, 1995.
The present invention relates to new chromene compounds having the general formula (I): ##STR2## wherein R.sub.1 and R.sub.2 are hydrogen, alkyl having from 1 to 4 carbon atoms, halogen, trifluoromethyl, optionally substituted phenyl, or hydroxymethyl, as well as their pharmaceutically acceptable addtion salts.
Among the pharmaceutically acceptable salts, hydrochloride is preferred.
Said phenyl group may be substituted with 1 to 3 substituents independently selected from C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, halogen, amino, mono or di-C.sub.1 -C.sub.4 alkyl-amino and nitro.
The compounds of the general formula (I) are obtained according to Scheme I. In effect, the alkylation of 4-(p-fluorobenzoyl)-piperidine (II) with a 7-(3-halopropoxy)chromen-4-one of general formula (III), wherein X is chlorine, bromine or iodine and R.sub.1 and R.sub.2 are as defined for (I), provides the compounds of the invention. The reaction occurs conveniently in a nonpolar solvent and in the presence of a base.
Acetonitrile is appropriate as a nonpolar solvent, and as a base it is useful to employ an alkali metal carbonate or hydrogen carbonate. Potassium iodide can be used as a catalyst. The reaction occurs under heating, preferably at the boiling temperature of the mixture. Intermediate (II) can be purchased from commercial source. This reaction can be illustrated according to Scheme 1. ##STR3##
The intermediates of the general formula (III) wherein X is chlorine, bromine or iodine and R.sub.1 and R.sub.2 are hydrogen, alkyl having from 1 to 4 carbon atoms, halogen, trifluoromethyl, optionally substituted phenyl, may be prepared, although not in a limitative manner, a) by alkylation of the corresponding 7-hydroxy-chromen-4-ones of general formula (IV) wherein R.sub.1 and R.sub.2 are as defined in (I) with 1-bromo-3-halopropane of general formula (V) wherein X is as defined in (III), or b) by cyclization from the corresponding 4-(3-halopropoxy)-2-hydroxyacetophenones of general formula (VI) wherein X is as defined in the preceding structure, all of this according to Scheme 2. In this scheme, [Y] is a halogenating agent which is able to introduce a chlorine, bromine or iodine atom, such as tert-butyl hypochlorite, chlorine, bromine or iodine. The spontaneous intramolecular cyclization of the intermediates of general formula (VIII) in the reaction medium leads to the intermediates of general formula (III) when R.sub.1 is hydrogen and R.sub.2 is as defined for Y. ##STR4##
The intermediates of the general formula (III) wherein X is chlorine, bromine or iodine, R.sub.1 is hydrogen and R.sub.2 is hydroxymethyl may be prepared through two steps from the 4'-(halopropoxy)-2'-hydroxy-acetophenones of general formula (VI) by alkylation in dimethylformamide with phosphoryl chloride followed by addition on ice and subsequent reduction of the so-formed 7-(3-halopropoxy)-3-formyl-chromen-4-ones of general formula (IX) wherein X is as defined in the preceding structures with sodium borohydride according to conventional procedures of organic chemistry as shown in Scheme 2'. ##STR5##
In turn, the raw material required for performing the reactions shown in these schemes may be obtained either from commercial sources or according to conventional procedures of organic chemistry.
Chromene compounds containing amine groups are known in the patent literature, and their use for treating various diseases is recommended. EP Patent No. 546389 discloses substituted piperidyl-methyl chromanes as dopamine and serotonin receptor inhibitors which are potentially useful for treating CNS diseases, such as anxiety, depression, psychosis, Alzheimer's disease, etc. EP Patent No. 441506 discloses 3-piperidino-4-hydroxy-chromanes that can be used in the treatment of CNS diseases, such as stroke, Alzheimer's disease, Parkinson's disease and Huntington's disease. PCT Patent application No. 9012795 discloses substituted chromanes that are potentially useful for treating CNS diseases, suc
REFERENCES:
patent: 3576810 (1971-04-01), Duncan
patent: 5424318 (1995-06-01), Sugimoto
Tomino et al. "Preparation of benzofuranyloxyalkylamine derivatives as antiarrhythmics and psychotropics" CA 114:81563. 1991.
Dorland "Medical Dictionary" Saunders Co., p. 499. 1982.
Katritzky et al "Heterocyclic chemistry" Cambridge, pp. 78, 91, 190. 1964.
Bolos Jordi
Foguet Rafael
Ortiz José A.
Sacristan Aurelio
Chang Ceila
Ferrer Internacional S.A.
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