Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-09-11
1999-12-21
Wilson, James O.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 553, 536 58, 536 62, 514 53, 514 62, C07H 504
Patent
active
060050993
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to specific glucosamine disaccharides, in particular to 2-N- and/or 2'-N-acylated glucosamine disaccharides, wherein at least one of the acyl groups is branched, and to compounds comprising these disaccharides. The present invention relates further to methods for preparing these disaccharides from starting materials comprising the lipid A moiety of lipopolysaccharides which starting material is subjected to a specific alkaline treatment. The invention relates also to pharmaceutical compositions comprising these disaccharides as an active ingredient, and finally to the use of these disaccharides in therapy and prophylaxis.
Lipopolysaccharides constitute endotoxins of micro-organisms such as Gram-negative bacteria, and comprise a polysaccharide component and a lipid component. This lipid component, also called lipid A, determines the endotoxic properties of lipopolysaccharides (Rietschel E. Th. et al. in Immunobiology, Volume 186, pages 169-190 [1993]).
In U.S. Pat. No. 4,912,094 modified lipopolysaccharides have been disclosed which exhibit reduced endotoxic properties while maintaining their antigenic and immuno-stimulating properties. These modified lipopolysaccharides are 3-O-deacylated and may be converted into 3-O-deacylated disaccharides by acid hydrolysis. Of these compounds the monophosphoryl 3-O-deacylated disaccharide is less toxic than the diphosphoryl 3-O-deacylated disaccharide.
The present invention relates to disaccharides which are 3-O-deacylated and 3'-O-deacylated or comprise at the 3-O-position and/or the 3'-O-position a short O-linked alkyl or acyl group, and comprise at least an N-linked, branched acyl group at the 2-position, 2'-position, or at both the 2-position and 2'-position. These compounds exhibit a still lower endotoxicity while maintaining biological activity (such as immunomodulation) and possess anti-cancer activity.
It was surprising that these specific glucosamine disaccharides possess the combination of lower endotoxicity and maintained biological activity, because although synthetic 3-O- and 3'-O-deacylated glucosamine disaccharides comprising an N-linked acyl group at the 2- and 2'-position (compound 307, Takada, H. et al. in CRC Critical Reviews in Microbiology, Volume 16, pages 477-523 [1989]; and compound LA-19-PP, Rietschel et al. [1993]) exhibited some immunobiological activities in in vitro assays, these activities were far weaker than those of reference bacterial lipid A specimens. They also lacked typical endotoxic activity.
Accordingly, the present invention relates to .beta.(1.fwdarw.6) glucosamine disaccharides having the general formula ##STR1## wherein R.sub.1 is a hydroxyl group,
a dihydroxyphosphonoyloxy group or its charged forms,
a (C.sub.1 -C.sub.5)acyloxy group;
a (C.sub.1 -C.sub.5)alkyloxy group, or
a group X; that at least R.sub.2 or R.sub.2 ' is the group Y;
a (C.sub.1 -C.sub.3)alkyl group, or
a (C.sub.1 -C.sub.3)acyl group;
a (C.sub.1 -C.sub.3)alkyl group, or
a (C.sub.1 -C.sub.3)acyl group;
a (C.sub.1 -C.sub.5)acyl group,
a (C.sub.1 -C.sub.5)alkyl group,
a dimethoxyphosphonoyl group, or
a phosphono group or its charged forms; and
a hydroxyl group,
a dihydroxyphosphonoyloxy group,
a hydroxysulphonyloxy group, their charged forms, or a group Z;
a carboxy (C.sub.1 -C.sub.5)alkyloxy group;
an --O--CH--[(CH.sub.2).sub.m COOH][(CH.sub.2).sub.n COOH] group,
wherein
a phosphono(C.sub.1 -C.sub.5)alkyl group;
a dimethoxyphosphonoyloxy group;
a hydroxysulphonyloxy group;
a hydroxysulphonyl(C.sub.1 -C.sub.5)alkyl group; and
charged forms of the group X;
an acyloxyacyl group,
an acylaminoacyl group,
an acylthioacyl group,
a (C.sub.1 -C.sub.24)alkyloxyacyl group,
a (C.sub.1 -C.sub.24)alkylaminoacyl group,
a (C.sub.1 -C.sub.24)alkylthioacyl group; and
a (C.sub.1 -C.sub.24)alkyloxy group;
a (C.sub.1 -C.sub.24)acyloxy group;
3-deoxy-D-manno-2-octulosonic acid (KDO);
(KDO).sub.n, wherein n=1-10;
a polysaccharide side chain, such as a side chain originating from natural lipopolysaccharide;
a core component, such as a component originati
REFERENCES:
Charon et al. "Chemistry of Bacterial Endotoxins. Part 2. A Practical Synthesis of 6-O-{4-O-Ammonio(hydrogen)phosphono-2-deoxy-2-[(3R)-hydroxytetradecanamido ]-.beta.-D-glucopyranosyl}-2-deoxy-2-[(3R)-3-hydroxytetradecanamido]-D-gluc ose," J. Chem. Soc. Perkin Trans 1, pp. 2291-2295 (1984).
Kusumoto et al., "Chemical Synthesis of 1-Dephospho Derivative of Escherichia Coli Lipid A," Tetrahedron letters, vol. 26, No. 7, pp. 909-912 (1985).
Imoto et al., "Total Synthesis of Escherichia coli Lipid A, the Endotoxically Active Principle of Cell-Surface Lipoplysaccharide," Bull. Chem. Soc. Jpn., 60, pp. 2205-2214 (1987).
Bauer Jacques
Davies John Gwynfor
Hirt Pierre
Schulthess Adrian
Laboratoires OM S.A.
Wilson James O.
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