Heparin derivatives having antimetastatic activity

Details Heparin derivatives having antimetastatic activity Heparin derivatives having antimetastatic activity

1996-03-05

1998-06-09

Fonda, Kathleen K.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536 21, A61K 31725, C08B 3710

Patent

active

057634211

DESCRIPTION:

BRIEF SUMMARY
This is a U.S. national stage entry under 35 U.S.C. .sctn.371 of PCT/EP94/02133, filed Jun. 30, 1994. The present invention relates to heparin derivatives, particular heparin fragments and fractions, and the use thereof as antimetastatic agents.
The antimetastatic activity of heparin has been known for some time (see, for example, Drago, J. R. et al., Anticancer Res., 4(3), 171-2, 1984), although some authors doubt its real efficacy in this field, assigning it, on the contrary, with a metastases-stimulating effect (see, for example, S. Y. Chan, and M. Pollard, J.N.C.I., 64, n. 5, May 1980). Low molecular weight heparin also has antimetastatic activity, which some authors consider higher than that of normal heparin (Green, D. et al. The Lancet, 339, Jun. 13, 1992). Nevertheless, the use of said molecules in this field is severely restricted by the marked anticoagulant and antithrombotic activities thereof.
Subsequently, studies have been directed to heparin derivatives. For example, WO 88/05301 reports data about the antimetastatic activity of heparin, of N-desulfated N-acetylated heparin and of oxidized-reduced heparins: heparin as such turns out to be the mainly active compound, whereas its derivatives have quite a lower effect, reducing the number of metastases by about 40-50%.
It should be noted, anyway, that N-desulfated N-acetylated heparin shows antithrombotic and fibrinolytic effects which could restrict its use as an antitumoral (see, EP-A-0 413 248).
Now it has surprisingly been found that other heparin derivatives and particular heparin fragments and fractions have a remarkable antimetastatic activity.
Therefore, the object of the present invention are heparin derivatives N-acylated with residues from aliphatic monocarboxylic acids having 3 to 20 carbon atoms, or with residues from aliphatic dicarboxylic acids having 3 to 10 carbon atoms, said derivatives having a molecular weight ranging from about 1,000 to about 30,000 daltons (Da), having a N-acylation degree, defined as the percent ratio of the number of N-acylated residues to the number of N-sulfated groups present in the heparin compound which they derive from, ranging from about 10 to about 100, said derivatives being further characterized in that they contain at least a unit of open D-iduronic or L-iduronic acid of formula I ##STR1## wherein X and X' are independently a --CHO or --CH.sub.2 OH group; and in that the free OH groups present on the non-open units of the D-glucuronic or L-iduronic acid and from D-glucosamine units can be acylated with the above mentioned acyl residues;
A further object of present invention relates to the use of heparin derivatives characterized in that they contain at least a unit of formula I as antimetastatic compounds.
A further object of present invention relates to the use of heparin derivatives, or of fragments and fractions thereof, having a molecular weight ranging from 1,000 to about 30,000 Da, N-acylated with residues from aliphatic monocarboxylic acids having 3 to 20 carbon atoms, or with residues from aliphatic dicarboxylic acids having 3 to 10 carbon atoms, and having a N-acylation degree, defined as the percent ratio of the number of N-acylated residues to the number of N-sulfated groups present in the heparin compound which they derive from, ranging from about 10 to about 100, and the salts thereof, as antimetastatic compounds.
A still further object of present invention is the use of particular heparin fragments or fractions having an average molecular weight equal or lower than 3,000 Da, and the salts thereof, as antimetastatic compounds. By aliphatic monocarboxylic acid residues having 3 to 20 carbon atoms, residues are meant such as those from propionic, butyric, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, crotonic, oleic, elaidic, stearolic, tetrolic, arachic acids and analogues. By aliphatic dicarboxylic acid residues having 3 to 10 carbon atoms, residues such as those from malonic, succinic, dimethylmalonic, glutaric, suberic, azelaic and sebacic acids and analogues ar

REFERENCES:
patent: 3118816 (1964-01-01), Cushing
patent: 4990502 (1991-02-01), Lormeau et al.
patent: 5280016 (1994-01-01), Conrad et al.
Carbohydrate Research, vol. 80, 1980, NL, pp. 131-145, L. A. Fransson, et al, "Periodate oxidation and alkaline degradation of heparin-related glycans" (See p. 134, l. 1-30).

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