Biologically active bistramides, process for their production an

Details Biologically active bistramides, process for their production an Biologically active bistramides, process for their production an

1996-03-04

1998-08-25

Bond, Robert T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514453, 514451, 549334, C07D40304, A61K 3155

Patent

active

057983810

DESCRIPTION:

BRIEF SUMMARY
A subject of the invention is new derivatives of bistramides, process for their production and their applications in therapy.
Bistramides are so called by analogy with a marine organism from which they can be extracted, namely the ascidia Lissoclinum bistratum which lives in symbiosis with its prochlorons.
Several bistramides have already been described, in particular bistramides A, B and C.
Their chemical structure, which is complex, has only recently been elucidated (see article by Foster et al. in J.A.C.S. 1992, 114). It corresponds to formula (A) as follows: ##STR2## with R.sub.1 and R.sub.2 representing, respectively, ##STR3##
Interest in these products results, in a general manner, from the strong cytostatic activity they present in particular in vitro. However, their high cytotoxicity and high toxicity in vivo does not allow exploitation of their properties to be envisaged for uses such as medicaments.
The LD.sub.50 of these bistramides is in fact of the order of 1.7 mg/kg (measured in mice, after injection of the product by intravenous route as a single dose).
Work by the inventors on marine invertebrates, in particular on the ascidia Lissoclinum bistratum Sluiter, accompanied or not by its prochloron symbiotes, have lead them to perfecting the specific extraction conditions allowing new bistramides to be isolated having diverse biological activities which are of great interest.
In a surprising manner, study of these new bistramides showed that they were endowed with a cytostatic effect in vitro and therapeutic effects in vivo, but that, contrary to the bistramides mentioned above, their cytotoxicity and their toxicity in vivo were much weaker, even non-existent, which permits their use in therapy.
Therefore, an aim of the invention is to provide new derivatives having a bistramide-type structural skeleton.
It is also an aim of the invention to provide a process for the production of these products by extraction from L. bistratum and/or their prochlorons.
Also the invention relates to the biological and biochemical uses of these new bistramides, in particular for cancer therapy, in particular, for solid human tumours, or the treatment of parasitic illnesses.
The bistramides according to the invention are characterized in that the differentiation of tumoural cells, with the inhibition in vitro of the expression of the erb-2 oncogene normally expressed by the cells of the non-small cell bronchopulmonary lines. ##STR4## in which R.sub.1, X, Y and R.sub.2, identical to or different from each other, represent a saturated or unsaturated hydrocarbon chain with 1 to 20 carbon atoms, substituted by at least one --OH group and/or a ketone function, including, if appropriate, at least one ##STR5## ring, this ring being able to contain one or more unsaturations, R.sub.3, R.sub.4 and R.sub.5, identical to or different from each other, are chosen from hydrogen, alkyl or alkoxy radicals with 1 to 4 carbon atoms, a --COOH, --OH, --NH.sub.2 or --NO.sub.2 group, or a halogen atom, it being understood that when R.sub.3 and R.sub.4 each represent a hydrogen atom, R.sub.1 and R.sub.2 do not respectively represent the following chains: ##STR6##
It will be remembered that the compounds corresponding to these three exclusions are bistramides A, B and C of the prior art mentioned above.
The expression "anti-tumoral activity in vivo" as used above signifies that an inhibition of the tumoural proliferation of non-small cell bronchopulmonary cancers (80% of pulmonary tumours) has been shown, without acute toxicity to the animal. These properties permit a therapeutic plateau to be obtained allowing access to the standards of the National Cancer Institute for products with T.ltoreq.42%.
The "LD.sub.50 " of the products of the invention has been measured for mice after injection of the products by intravenous route.
Taking into account the LD.sub.50 value of the bistramides thus defined, bistramides A, B and C mentioned above are excluded from the scope of the invention. Moreover, it will be noted that due to their high toxicity

REFERENCES:
Dunkel, R. et al. Analytical Chemistry, 64, 24, Dec., 1992, pp. 3150-3160.
Foster et al, Journal of the American Chemical Society 114(3):1110-1111 (1992).
Chemical Abstracts 115(23):34 (1991), abstract No. 247630a.

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