Naphthyridine derivatives, their methods of preparation and phar

Details Naphthyridine derivatives, their methods of preparation and phar Naphthyridine derivatives, their methods of preparation and phar

1995-11-29

1997-09-02

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546122, A61K 3144, C07D47102

Patent

active

056631812

DESCRIPTION:

BRIEF SUMMARY
The present invention relates, by way of novel products, to the naphthyridine derivatives of general formula (I) below and their addition salts, in particular the pharmaceutically acceptable addition salts.
The compounds of the invention, which possess antiproliferative properties, can be used in the treatment of cancer, psoriasis, atherosclerosis, restenosis phenomena or any other pathological condition due to cell proliferation in mammals and especially in man.
The present invention further relates to the method of preparing said products and to their applications in therapeutics.
These naphthyridine derivatives have general formula (I): ##STR2## in which: X is: ##STR3## in which n is an integer from 0 to 5 and R" is the hydrogen atom, a halogen atom or a lower alkyl radical having 1 to 6 carbon atoms, radical having 1 to 6 carbon atoms, ##STR4## in which m is an integer from 0 to 5 and Z.sub.1 and Z.sub.2 are independently:
a lower alkyl radical having 1 to 6 carbon atoms,
In the description and the claims, lower alkyl is understood as meaning a linear or branched hydro-carbon chain having from 1 to 6 carbon atoms. A lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl radical.
C.sub.3 --C.sub.7 --Cycloalkyl radical is understood as meaning a saturated cyclic hydrocarbon radical, preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical.
Halogen is understood as meaning a chlorine, bromine, iodine or fluorine atom.
The following abbreviations have been used in the description:
Advantageously, within the framework of the present invention, a compound of formula (I) will be used in which at least one of the following conditions is satisfied:
The particularly preferred compounds of the invention are selected from the products of the formulae: ##STR5##
According to the invention, the compounds of formula (I) may be synthesized in the following manner:
The reaction of a 2-chloronicotinic acid of formula (II): ##STR6## or one of its esters, in which X is as defined above, with an amine of formula (III):
NH.sub.2 --R.sub.2
Formula (III) solvent such as, for example, toluene or xylene or an alcohol, will give the 2-aminonicotinic acids of formula (IV): ##STR7## or one of their esters, in which X and R.sub.2 are as defined above, according to a method known in the literature: U.S. Pat. No. 3,415,834; C. Hoffmann, A. Faure, Bull. Soc. Chim. France 1966, 2316.
The reduction of an acid of formula (IV) or one of its esters, for example the methyl or ethyl ester, with a conventional reducing agent such as, for example, lithium aluminum hydride, in an organic solvent such as, for example, tetrahydrofuran or ethyl ether, will give the alcohols of formula (V): ##STR8## in which X and R.sub.2 are as defined above.
In the case where R.sub.2 carries a substituent sensitive to certain reducing agents, such as nitro or cyano, for example, the reducing agent chosen for reducing the ester will be one which does not affect this substituent, for example lithium borohydride prepared in situ from potassium borohydride and lithium chloride in tetrahydrofuran, or else sodium borohydride in dioxane.
The oxidation of an alcohol of formula (V) with a mild oxidizing agent such as, for example, MnO.sub.2, in an organic solvent such as dichloromethane, chloroform, toluene or xylene, at a temperature between 20 and 80.degree. C., will give the nicotinaldehydes of formula (VI): ##STR9## in which X and R.sub.2 are as defined above.
The reaction of the aldehydes of formula (VI) with an alkyl dialkoxypropionate of formula (VII): ##STR10## in which R"' is a lower alkyl radical having 1 to 6 carbon atoms, optimally the methyl radical, or else with a dialkoxypropionitrile of formula (VII'): ##STR11## in which R"' is as defined in formula (VII), in tetrahydrofuran, in the presence of a sodium or potassium alcoholate, will give the derivatives of formula (VIII): ##STR12## in which X, R.sub.2 and R"' are as defined above and Y' is an oxygen

REFERENCES:
patent: 5302606 (1994-04-01), Spada
Bilder GE, Krawiec JA, McVety K, Gazit A, Gilon C, Lyall R, Zilbertstein A, Levitski A, Perrone MH, Schrieber AB. Am. J. Physiol. 260, pp. C721-C730 1991.

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