Etoposide derivatives, process for preparing them, their use as

Details Etoposide derivatives, process for preparing them, their use as Etoposide derivatives, process for preparing them, their use as

1995-06-21

1997-07-01

Peselev, Elli

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514 25, 536 171, 536 181, 536 182, A61K 3170, C07H 1526

Patent

active

056438850

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to etoposide derivatives, to a process for preparing them and to their use as an anticancer medicinal product.
Etoposide a and some of its derivatives such as teniposide b ##STR2## are known to have antitumor activities which are useful in human clinical medicine. They are derived, on the one hand from a natural stock, especially from podophyllotoxin ##STR3## and on the other hand from a glycosylated portion, especially a 4,6-ethylidene-.beta.-D-glucopyranose.
The synthesis of etoposide has been described in U.S. Pat. No. 3,524,844. It has also been the subject of many publications (J. Med. Chem. (1971), 14, 936; J. Org. Chem. (1981), 46, 2826 and more recently: Heterocycles (1991), 32, 859; Tetrahedron (1991), 47, 4675; Synthesis (1991), 275).
Etoposide and its analog teniposide are commercially available as medicinal products for the treatment of a number of cancerous tumors, as well as in acute leukemias in relapse.
The major drawback of these medicinal products lies in the fact that they give rise to a large number of undesirable side effects, such as leukopenia or thrombocytopenia.
A large number of etoposide derivatives have been proposed in the literature, in particular in Patent Applications EP-A-0,401,800, EP-A-0,461,556, EP-A-0,455,159, EP-A-0,433,678, EP-A-0,358,197, EP-A-0,415,453, EP-A-0,320,988, EP-A-0,423,747, EP-A-0,394,907 or EP-A-0,445,021.
Some of these derivatives are, in particular, described as intermediate products in the synthesis of etoposide.
In point of fact, it was found, unexpectedly, that some etoposide derivatives displayed improved anticancer activity while showing lower toxicity, enabling these products to be administered on a chronic basis as medicinal products.
The present invention hence relates to a compound of general formula I: ##STR4## in which R' represents a hydrogen atom or a radical R, and ##STR5## or an acyl residue of formula C.sub.1 -C.sub.4 alkyl ) and naphthyl radicals and these same radicals substituted with one to three substituents chosen from hydroxyl radicals, linear or branched C.sub.1 -C.sub.4 alkoxy radicals optionally perhalogenated with chlorine or fluorine atoms, benzyloxy, phenyl and linear or branched C.sub.1 -C.sub.4 alkyl radicals and halogen atoms, especially chlorine or fluorine, 4-fluorophenoxyacetyl, 4-benzyloxyphenoxyacetyl, 4-hydroxyphenoxyacetyl, 4-methylphenoxyacetyl, 3,4,5-trimethoxyphenoxyacetyl, 3,4-methylenedioxyphenoxyacetyl, 2,3-dimethoxyphenoxyacetyl, 4-(trifluoromethoxy)phenoxyacetyl, 4-phenylphenoxyacetyl, 2-naphthoxyacetyl, 1-naphthoxyacetyl, cyclohexylacetyl, 4-methylphenoxyacetyl and 3,4-dimethoxyphenoxyacetyl radicals.
Linear or branched C.sub.1 -C.sub.4 alkyl will preferably be understood to mean methyl, ethyl, propyl and butyl radicals, these same definitions applying to the alkyl residues of the phenyl alkyl and alkoxy radicals.
Advantageously, the compounds of general formula I will be chosen with R' representing a hydrogen atom.
For its part, R will preferably be chosen from ethoxyacetyl, phenoxyacetyl, 4-methoxyphenoxyacetyl, 2-methoxyphenoxyacetyl, 4-nitrophenoxyacetyl, 2-nitrophenoxyacetyl, 2,4-dichlorophenoxyacetyl, 2,4,5-trichlorophenoxyacetyl, 2,4,6-trichlorophenoxyacetyl, 4-fluorophenoxyacetyl, 2-fluorophenoxyacetyl, 4-hydroxyphenoxyacetyl, 4-benzyloxyphenoxyacetyl, 4-methylphenoxyacetyl, 3,4,5-trimethoxyphenoxyacetyl, 3,4-methylenedioxyphenoxyacetyl, 2,3-dimethoxyphenoxyacetyl, 4-(trifluoromethoxyphenoxyacetyl, 4-phenylphenoxyacetyl, 2-naphthoxyacetyl, 1-naphthoxyacetyl, cyclohexylacetyl, 4-methylphenoxyacetyl and 3,4-dimethoxyphenoxyacetyl radicals.
The present invention also relates to a process for preparing a compound of general formula I, for which a glycosyl intermediate of general formula 2 ##STR6## is reacted with an intermediate of formula 3 ##STR7## for which formulae R and R' are defined above, and the phenol functions of the compound of formula I obtained are, where appropriate, deprotected.
The general scheme of synthesis of the compounds according to the invention an

REFERENCES:
patent: 5206350 (1993-04-01), Wang et al.

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