Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-04-03
1998-07-14
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514725, 514844, 514859, 536 41, A61K 3170, A61K 3107, C07H 3104
Patent
active
057804435
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to water-soluble novel sugar retinoids, and to their preparation and the use thereof as medicaments and in the cosmetic sector.
Retinoic acid derivatives are commonly used in the field of dermatology. Thus keratinising epithelial tissue can be converted by retinoic acid or derivatives thereof into tissue of normally differentiated cells. The retinoids exert a protective action against chemically, photochemically or virally induced carcinogenesis and assume protective functions in cell division. Retinoic acid itself is water-insoluble and is therefore usually converted into a water-soluble form for ease of handling.
Aromatic retinoids having a saccharide or aminosaccharide radical, and which are suitable dermatalogical agents for use in pharmaceuticals and cosmetics, are disclosed in U.S. Pat. No. 4,565,863. For toxicological reasons, such aromatic retinoids are sought to be avoided.
Certain new water-soluble aliphatic derivatives of retinoic acid have now been found which are excellent dermatalogical agents for use in pharmaceuticals and cosmetics.
Accordingly, the present invention provides retinoic acid esters of formula (I) ##STR2## wherein X is a sugar residue attached at an oxygen atom, i.e. a mono-, di- or oligosaccharide, provided that X is not a glucose- or galactose sugar residue attached at the oxygen atom in the respective 1-positions of the glucose- or galactose sugar residues.
The double bonds in the retinoic acid radical may be in cis- or trans-configuration, the all-trans-form being preferred.
Oligosaccharides containing more than two sugar units may suitably be in particular compounds such as streptomycin, neuraminic acid, fucose, .alpha.,.beta.,.gamma.-cyclodextrin, raffinose or short-chain degradation products of amylose or cellulose.
The sugar radical is preferably a mono- or disaccharide which is derived from ribose, arabinose, xylose, glucose, mannose, galactose, lactose, saccharose, trehalose, cellobiose, maltose, fructose or derivatives thereof.
Suitable derivatives of these sugars include: desoxy sugars; the lactones of the corresponding sugar acids such as gluconic acid .gamma.-lactone which in turn may be esterified by C.sub.1 -C.sub.4 alkyl; uronic acids; amino sugars having an unsubstituted amino group, typically glucosamine, fructosamine, galactosamine, or having a C.sub.1 -C.sub.6 alkyl- or C.sub.1 -C.sub.6 acetyl-substituted amino group, e.g. aminoethylglucosides, aminoethyl-2-deoxy-2-aminoglucoside, N-acetylaminoglucoside; sugars in which the OH groups are substituted by one or more than one C.sub.1 -C.sub.4 alkoxy group, e.g. methyl or ethyl glucose, substitution by C.sub.1 -C.sub.4 alkylene bridges also being possible; keto-sugar acids such as ascorbic acid; sugars in which the OH groups are mono- or polyacetylated, typically glucose acetate or 2,3,4-tri-O-acetylglucose; or sugars carrying several different substituents, e.g. neuraminic acid.
Particularly preferred sugars are glucose, galactose, mannose or derivatives thereof.
The aforementioned sugar radicals may also be in the form of racemates or any mixtures of the (L)- and (D)-configuration as well as in the form of the pure (L)- or (D)-isomers. The natural (D)-configuration is preferred.
Compounds of formula Ia, Ib or Ic are of particular importance: ##STR3## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.3 alkylCOO--, or two of these radicals taken together are a O--C.sub.1 -C.sub.4 --O-alkylene bridge; saccharide moiety is in the furanose form.
The novel compounds of formula (I) are prepared by
To enhance its reactivity, the retinoic acid can be converted into a reactive derivative such as an imidazolide, a mixed anhydride or an acid chloride. The acid chloride is preferred. This conversion is preferably carried out with chloroenamine or dimethylchloroformamidinium chloride, using any solvent which is inert to the chlorinating reagent and which at least partially dissolves the retinoic acid, conveniently selected from among ethers, amides,
REFERENCES:
patent: 4457918 (1984-07-01), Holick et al.
patent: 4565863 (1986-01-01), Bollag et al.
patent: 5045533 (1991-09-01), Philippe et al.
patent: 5091522 (1992-02-01), Philippe et al.
Barua, Arum B. Methods Enzymology, vol. 189 (Retinoids, Pt. A), pp. 136-145, (1990).
Pfander et al. Helvetica Chimica Acta, vol. 63(1), 277-283, (1980).
Pfander, Hanspeter. Pure & Applied Chem., vol. 51, 565-580, (1979).
Ed. by Collins & Ferrier. Monosaccharides: Their Chemistry and Their Roles in Natural Products (John Wiley & Sons), p. 4, (1995).
Barua et al., International J. Vit. Nutr. Res. 61 258-263 (1991).
Luther Helmut
Maier Thomas
Ciba Specialty Chemicals Corporation
Kight John
Lee Howard C.
Mansfield Kevin T.
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