Camptothecin-skeleton compounds isolated from Mappia foetida and

Details Camptothecin-skeleton compounds isolated from Mappia foetida and Camptothecin-skeleton compounds isolated from Mappia foetida and

1998-10-06

2000-09-19

Rotman, Alan L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546 70, C07D47104, A61K 31437

Patent

active

061212776

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to camptothecin-skeleton alkaloids isolated from Mappia foetida or obtained by semi-synthesis from said alkaloids.


BACKGROUND ART

Mappia foetida, a plant growing in the Indian subcontinent, is known to contain in its various parts, mainly in the seeds, camptothecin, mappicine and foetidine I and II (EP-A-685481). Camptothecin derivatives and their preparation are also described in the Journal of Medicinal Chemistry", Vol. 22, No. 3, 1979.


SUMMARY OF THE INVENTION

The alkaloids of the invention have the following general formula: ##STR2## in which R is a hydrogen atom or a methoxy group; R.sub.1 is hydroxy, an OM group wherein M is an alkali cation, preferably sodium or potassium, a C.sub.1 -C.sub.6 alkoxy group, an optionally substituted phenoxy group, an amino, C.sub.1 -C.sub.6 monoalkylamino or C.sub.2 -C.sub.12 dialkylamino group in which the alkyl moiety is optionally substituted by amino groups, an arylamino group; R.sub.2 is a C.sub.1 -C.sub.6 alkyl group or a group of formula COR.sub.3 wherein R.sub.3 is alkyl C.sub.1 -C.sub.6 or optionally substituted phenyl or benzyl.
The phenoxy, phenyl or benzyl groups can be substituted by halogen atoms; C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, nitro, cyano, C.sub.1 -C.sub.3 haloalkyl groups.


DETAILED DESCRIPTION OF THE INVENTION

The compounds 1 in which R is hydrogen or methoxy, R.sub.1 is hydroxy or an OM group (M=sodium or potassium) and R.sub.2 is acetyl can be isolated from Mappia foetida extracting the artificially dried vegetable biomass at temperatures not higher than 50.degree. C., preferably at 35.degree. C., first with aliphatic ketones or aliphatic esters and subsequently with aliphatic alcohols. In these operative conditions, the 17-acetyl derivatives of camptothecinic and 9-methoxy-camptothecinic acids can be extracted in high yields. Although Mappia foetida has been widely studied as a camptothecin selective source, said alkaloids were not identified, due likely to their degradation to camptothecin during the extraction using unsuitable solvents. In the presence of aliphatic alcohols these alkaloids are easily converted into camptothecin even at the extraction natural pH.
The same group of compounds can be obtained by selective acetylation of the C.sub.17 hydroxyl of camptothecin in alkali medium.
The resulting compounds can in their turn be used as starting materials for the preparation of other compounds of formula 1 in which R.sub.2 is different from acetyl and/or R.sub.1 is an alkoxy, phenoxy or amino group as defined above or for the preparation of Foetidines I and II. For this purpose, conventional methods for the preparation of esters or amides can be used, for example the reaction of compounds 1 in which R.sub.1 is an OM group with alkyl halides such as ethyl or benzyl bromoacetate for the preparation of esters, or the reaction of compounds 1 in which R.sub.1 is OH with amine and dicyclohexylcarbodiimide for the preparation of amides.
Compounds 1 have cytotoxic activity against tumor cell lines. For example, Table 1 reports the cytotoxic activity against a colon carcinoma line (HCT116) and against the same line resistant to the most common chemotherapeutics (HCT116/VM46). The results evidenced how a compound of the invention is more active than camptothecin.


TABLE 1 ______________________________________ Cytotoxic activity of 17-acetyl-camptothecinic acid and of camptothecin Examples IC.sub.50 (nMoles/ml) Line HCT116 Line HCT116/VM46 ______________________________________ Camptothecin 10.5 96.7 17-Acetyl-cam- 8.2 25.3 ptothecinic acid ______________________________________
The compounds 1 can therefore be used as active principles in antitumor pharmaceutical compositions in admixture with suitable carriers, for example injectable physiological solutions. The dosages can vary within wide limits (5 to 500 mg/day) but in principle they will be about 10 mg alkaloid a day.
The following examples further illustrate the invention.


EXAMPLE 1

REFERENCES:
patent: 5525609 (1996-06-01), Bombardelli et al.
Journal of Medicinal Chemistry, vol. 22, No. 3, 1979, Washington US, pp. 310-314, "Prodrug analogues of the antitumor alkaloid camptothecin".

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