Water-soluble derivatives of epipodophyllotoxin, process for the

Details Water-soluble derivatives of epipodophyllotoxin, process for the Water-soluble derivatives of epipodophyllotoxin, process for the

1997-04-21

2000-08-22

Peselev, Elli

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514 33, 536 171, 536 172, 536 175, 536 176, 536 181, A61K 3170, C07H 1524

Patent

active

061072842

DESCRIPTION:

BRIEF SUMMARY
Among the class of epipodophylloids, certain compounds such as etoposide or teniposide, which are semisynthetic compounds derived from epipodophyllotoxin, obtained from natural lignan, are used in the preparation of medicinal products for treating many forms of cancer. They are currently considered as major products of the therapeutic arsenal.
Among the various cancers treated with compounds of this type, mention may be made of alveolar lung cancer, embryonic tumors, neuroblastomas, cancer of the kidney, lymphomas, Hodgkin's disease, acute leukemias, and even breast cancer. Etoposide is advantageously used in combination with other anticancer products and in particular platinum derivatives such as cisplatin.
The major drawback of this derivative, and likewise of its related derivative teniposide, is its lack of water-solubility. No water-soluble forms for intravenous administration exist on the market. On the contrary, the dissolution is currently carried out in partially non-aqueous solvents, requires administration by slow infusion and gives rise to certain undesirable or even toxic effects. There is thus a need for water-soluble forms for products derived from this class of compounds in order to improve the administration to the patient, as well as its bioavailability. The present invention thus relates to etoposide derivatives which are water-soluble by means of the presence of phosphate or carboxylate functional groups whose organic or inorganic addition salts form soluble species in water. This aqueous formulation has the advantage of being less toxic and easier to administer than the forms currently marketed.
The preparation of etoposide derivatives has given rise to considerable research and many patient, and in particular 2" and 3" diester and 2", 3" and 4' triester derivatives of etoposide have been claimed in patent FR 2,699,535-A1. Some of these derivatives have shown activity equal to or greater than etoposide and less toxicity. An additional improvement is now provided by means of a solubility in water which imparts to them ease of administration and leads to the expectation of increased bioavailability by better passage across the various biological membranes.
The literature mentions patents relating to compounds similar to etoposide in which it is sought to improve the water-solubility, in particular (U.S. Pat. No. 4,904,768, EP 0,369,369-A2, EP 0,196,618-A1, EP 0,320,988, EP 0,415,453-A2).
The advantage of modifying the water-solubility of the compounds by means of phosphate groups has been used favorably in a few cases both in the field of anticancer agents WO 8707609 and in the field of analgesics (BE 893,563) but, despite everything, there is nothing to suggest that the compound thus obtained can fully retain an advantageous biological activity of its own as well as the activity of the derivative from which it is obtained.
It has been found that phosphate and carboxylate derivatives possess a water-solubility which allows administration via an injectable route, and moreover exhibit improved anticancer activity relative to etoposide. The present invention therefore relates to a compound of general formula I ##STR1## in which R' represents either a hydrogen atom or a phosphate monester group or a carbamate group of --CO--N-- (R.sub.1 R.sub.2) type where N(R.sub.1 R.sub.2) represents aminodiacetic groups and a polycyclic amine such as 3-aminoquinuclidine or an acyl group of phosphonoacetic type H.sub.2 O.sub.3 P--CH.sub.2 --CO or a radical R, R represents an acyl group of formula or branched C.sub.1-4 alkylene, in this case A represents a substituted or unsubstituted phenyl ring, on condition that: aromatic ring possessing a salifiable function, with the exception of 4-hydroxyphenyl, heteroaryl or phenyl residue which is substituted or unsubstituted, it being possible in this case for the phenyl to be substituted one, two, three, four or five times, irrespective of their position on the aromatic ring, with identical or different groups chosen from groups such as halogens, F, Cl, Br, linear

REFERENCES:
patent: 5041424 (1991-08-01), Saulnier et al.

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