Colchicine derivatives and the therapeutical use thereof

Details Colchicine derivatives and the therapeutical use thereof Colchicine derivatives and the therapeutical use thereof

1997-03-21

1998-12-01

Peselev, Elli

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514629, 536 41, 536 179, 560 10, 560 28, A61K 3170, A61K 3116, C07H 1500, C07C32100

Patent

active

058439102

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel colchicine derivatives having antiproliferative, antitumoral and antiinflammatory activities, the methods for the preparation thereof and the pharmaceutical formulations containing them.


BACKGROUND OF THE INVENTION

Colchicine is a known pseudo-alkaloid widely used for a very long time in therapy for the treatment of gout; it acts very quickly and specifically, even though it should be used for short times due to its toxicity. In addition, colchicine is a very potent antiblastic agent, whose action is connected with a mechanism blocking the formation of the mitotic spindle in cell division; this latter aspect has been investigated thoroughly for any antitumoral activity and a great deal of colchicine derivatives have been prepared for this purpose.
Colchicine as such and a number of its prepared derivatives cannot be used due to its high toxicity in terms of risk/benefit ratio. Only one colchicine derivative, demecolcine, is used in some degree in oncology for the treatment of some leukemia forms. As far as the use in the antiinflammatory field is concerned, the only marketed colchicine derivative is thiocolchicoside, bearing a thiomethyl moiety at C.sub.10 and a glucose molecule at the hydroxyl in C.sub.3 ; the therapeutical uses of this derivative are related to the muscle relaxant and antiphlogistic effects. The products of the invention differ from those of the prior art in the high therapeutical index. In the antitumoral field, researches have been focused on the research of products having, besides a normal cytotoxicity, a cytotoxicity aimed at cell lines resistant to the usual antiblastic medicaments.


SUMMARY OF THE INVENTION

The derivatives of the present invention have the general formula 1 ##STR1## wherein: X can be an oxygen or sulfur atom; branched alkyl groups or cycloalkyl groups, containing 1 to 6 carbon atoms; or saturated or unsaturated acyl groups, containing 16 to 22 carbon atoms, or a .beta.-D-glucose residue as such or a .beta.-D-glucose residue wherein the hydroxyl in positions 4 and 6 are protected as chetals with aliphatic or aromatic or heteroaromatic aldehydes; Y is a --CH.sub.2 --CH--NH--R.sub.3 group, the methylene group of which being bound to the carbon in position 5 and the methine group, having the same absolute configuration as colchicine, is bound to the tropolone ring, or a --CH--CH.sub.2 OR.sub.4 group, the methine group of which being bound to the carbon in position 5 and to the tropolone ring and having absolute configuration S; three halogen atoms, preferably fluorine or chlorine, or an acyl group from a natural amino acid, wherein the amino group can be free or protected as trifluoroacetamide or benzamide; atoms, or an acyl residue of a natural amino acid, wherein the colchicine amino group can be free or protected as trifluoroacetamide or benzamide, or a glycoside residue consisting of D-glucose, D-galactose, L-fucose or L-rhamnose. In this case, the sugars act as chemotactic for melanocytes, hepatocytes, fibroblasts or they give the derivative the characteristic of a pro-drug.
Preferred compounds of formula 1 are those wherein X is sulfur.
R.sub.1 and R.sub.2, which are the same or different, are preferably hydrogen or C.sub.1 -C.sub.6 alkyl.
Y is preferably a group of formula --CH.sub.2 --CH--NHR.sub.3 as defined above.


DETAILED DESCRIPTION OF THE INVENTION

For the preparation of the products of the invention, the starting products used are the natural substances colchicine (1; X.dbd.O; R.sub.1 .dbd.R.sub.2 .dbd.Me; Y.dbd.CH.sub.2 --CH--NHAc), 2-O-demethylcolchicine (1; X.dbd.O; R.sub.1 .dbd.H; R.sub.2 .dbd.Me; Y.dbd.CH.sub.2 --CH--NHAc), 3-O-demethylcolchicine (1; X.dbd.O; R.sub.1 .dbd.Me; R.sub.2 .dbd.H; Y.dbd.CH.sub.2 --CH--NHAc), colchicoside (1; X.dbd.O; R.sub.1 .dbd.Me; R.sub.2 .dbd..beta.-D-glucose; Y.dbd.CH.sub.2 --CH--NHAc) which can be recovered from vegetable materials according to procedures known in literature. These natural substances, by treatment with methylmercaptan in alkali solution

REFERENCES:
Liebigs Annalen Der Chemie, vol. 758, 12 Jul. 1972 Weinheim, DE. pp. 185-189, H. Lettre, et al.
Journal of Medicinal Chemistry, vol. 24, No. 3, Mar. 1981 Washington, DC pp. 251-256, F.R. Quinn et al.
Journal of Medicinal Chemistry, vol. 36, No. 5, 5 Mar. 1993 Washington, DC U.S. pp. 554-551, L.Sun et al.

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