Thioureido-cyclodextrins, utilized in particular to solubilize a

Details Thioureido-cyclodextrins, utilized in particular to solubilize a Thioureido-cyclodextrins, utilized in particular to solubilize a

1998-10-20

2000-06-27

Wilson, James O.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

424 10, 536103, 549510, 549511, A01N 4304

Patent

active

060807334

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

The invention relates to thioureido-cyclodextrins, new derivatives of cyclodextrins, which can be utilized in particular to solubilize anti-tumor and antiparasitic agents in an aqueous medium, especially those of the Taxol family.
Cyclodextrins or cyclomalto-oligosaccharides, are cyclic oligosaccharides with the property of containing various molecules in their cavity, which are of a size adapted to the host structure. The generally nonpolar nature of these associations results in the preferential inclusion of hydrophobic structures that enable, in particular, the solubilization in water of compounds with little or no solubility in these media.
However, the relatively low solubility in water of cyclodextrins and, especially of .beta.-cyclodextrin (18 g/l at 25.degree. C.), the most economically accessible of them all, limits their use for this purpose.
To remedy this situation, the cyclodextrins were chemically modified to improve their solubility in water. The ramified derivatives of cyclodextrins consisting of one or more monosaccharide or oligosaccharide substituents linked to cyclodextrin by an atom of oxygen or sulfur as well as their uses were subsequently described in documents WO-A-95/19994, WO-A-95/21870 and EP-A-0 403 366. These ramified cyclodextrins are, in particular, likely to combine with Taxol and its derivatives, especially Taxotere.RTM.. These are anti-tumor and antiparasitic agents as described by P. Potier in Chem. Soc. Rev., 21, 1992, pp. 113-119, M. C. Bissery et al. in Cancer Research, 51, 1991, pp. 4845-4852 and J. Schrevel et al. in Proc. Natl. Acad. Sci. USA, vol 91, pp. 8472-8476, 1994. Inclusion complexes are thus obtained, and these enable the anti-tumor agents to be solubilized in water. By way of example, the solubility in water of Taxotere.RTM., which is 0.004 g/l, can be raised to 6.5 g/l by encapsulating it in 6.sup.I -S-.alpha.-maltosyl-6.sup.I -thiocyclo-maltaheptaose, as has been described in WO-A-95/19994.
Document EP-A-0 605 753 describes Taxol inclusion complexes that use ramified cyclodextrins such as maltosyl-cyclodextrins, to increase the solubility in water of Taxol.
Cyclodextrin derivatives consisting of one or more glycosyl or maltosyl substituents linked to cyclodextrin by a sulfur atom are also described by V. Laine et al. in J. Chem. Soc., Perkin Trans, 2, 1995, pp. 1479-1487. These derivatives have been tested to solubilize an active substance such as prednisolone.
The present invention relates to other cyclodextrin derivatives that do not only concern the solubilization of active substances, in particular anti-tumor and antiparasitic agents of the Taxol family, but also enable the targeting and vectoring of the active substance on organs to be treated.
The new cyclodextrin derivatives are thioureido-cyclodextrins that correspond to the formula: ##STR2## in which m is equal to 6, 7 or 8 and the R1s, which may be identical or different, represent OH or NH--CS--NHR.sup.2 with R.sup.2 representing an alkyl group, a group derived from a monosaccharide or an oligosaccharide that may be substituted if necessary, a glycosyl-amino acid derivative group, provided that at least one of the R.sup.1 represents NH--CS--NHR.sup.2
With these new derivatives, it is interesting to note the presence of a link or spacer of the --NH--CS--NH thiourea type instead of an oxygen or sulfur atom to bond the R.sup.2 substituent. This occurs in particular when cyclodextrin is associated with a hydrophilic pattern such as a glucide derivative and is due to the simple nature of the coupling reaction. Furthermore, thioureas are very stable compounds with well-defined structures and can be coupled to a large number of substituents, as we will see further on. In fact, Thiourea-type compounds have been used in the preparation of neoglycoconjugates as has been described by Z. J. Witczak, Adv. Carbohyr. Chem., 44, 1986, pp. 91-145 and C. M. Reichert, C. E. Hayes and I. J. Goldstein, Methods Enzymol., 242, 1994, pp. 108-117.
Thiourea-cyclodextrins corresponding to formula (I) below

REFERENCES:
patent: 5684169 (1997-11-01), Hamada et al.
P. Potier, Chem. Soc. Rev., vol. 21, pp. 113-119, "Search and Discovery of New Antitumour Compounds", 1992.
M.C. Bissery, et al. Cancer Research, vol. 51, pp. 4845-4852, "Experimental Antitumor Activity of Taxotere (RP56976, NSC 628503), A Taxol Analogue", Sep. 15, 1991.
V. Laine, et al., J. Chem. Soc., Perkin Trans., vol. 2, pp. 1479-1487, "Inclusion and Solubilization Properties of 6-S-Glycosal-6-Thio Derivatives of .beta.-Cyclodextrin", 1995.
J. Schrevel, et al., Proc. Nat. Acad. Sci. USA, vol. 91, pp. 8472-8476, "Interactions Between Docetaxel (Taxotere) and Plasmodium Falciparum-Infected Erythrocytes", Aug., 1994.
C.M. Reichert, et al., Methods in Enzymology, vol. 242, pp. 108-116, "Coupling of Carbohydrates to Proteins by Diazonium and Phenylisothiocyanate Reactions", 1994.
J.M. Garcia Fernandez, et al., Carbohydrate Research, vol. 268, pp. 57-71, "Isothiocyanates and Cyclic Thiocarbamates of .alpha..alpha.'-Trehalose, Sucrose, and Cyclomaltooligosaccharides", 1995.
R.C. Petter, et al., J. Am. Chem. Soc., vol. 112, pp. 3860-3868, "Cooperative Binding by Aggregated Mono-6-(Alkylamino)-.beta.-Cyclodextrins", 1990.
S.E. Brown, et al., Aust. J. Chem., vol. 46, pp. 953-958, "Synthesis and Properties of 6.sup.A -Amino-6.sup.A -Deoxy-.alpha.-and-.beta.-Cyclodextrin", 1993.
J.M. Garcia Fernandez, et al. J. Org. Chem., vol. 58, pp. 5192-5199, "Chiral 2-Thioxotetrahydro-1,3-O, N-Heterocycles from Carbohydrates. 2. Stereocontrolled Synthesis of Oxazolidine Pseudo-C-Nucleosides and Bicyclic Oxazine-2-Thiones", 1993.
K. Dax, et al., J. Carbohydrate Chemistry, vol. 9, No. 4, pp. 479-499, "Easy Synthesis of 1,5-Didesoxy-1,5-Imino-d-Glycitol (1-Desoxynozirimycin) and 1,6-Didesoxy-1,6-Dimino-D-Glucitol from D-Glucofuranurono-6,3-Lactone", (With English Abstract), 1990.
Z.J. Witczak, Advances in Carbohydrate Chemistry and Biochemistry, vol. 44, pp. 91-145, "Monosaccharide Isothiocyanates and Thiocyanates: Synthesis, Chemistry, and Preparative Applications", 1986.

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