2-fluorofucosyl-N-aroylglucosamine derivatives, intermediates, t

Details 2-fluorofucosyl-N-aroylglucosamine derivatives, intermediates, t 2-fluorofucosyl-N-aroylglucosamine derivatives, intermediates, t

2000-01-18

2000-11-07

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514 54, 514 62, 536 172, 536124, A61K 3170, A61K 31715, C07H 1500, C07H 306, C07H 100

Patent

active

061437247

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to 2-fluorofucosyl-N-aroylglucosamine derivatives which are obtained by substituting the hydroxyl group at the 2-position with a fluorine atom in L-fucose of fucosyl-.alpha.-(1.fwdarw.3 or 1.fwdarw.4)-N-aroylglucosamine which are derivatives of Lewis X, Lewis a, sialyl Lewis X or sialyl Lewis a glycosides (or saccharides) known as the causal substances of inflammation or thrombus formation accompanied by inflammation, tissular disorder due to infiltration of inflammatory cells, asthma, rheumatism, autoimmune disease, or cancer metastasis, and their intermediates, and preparation methods thereof (herein, the aroyl group is synonymous with the arylcarbonyl group). Such derivatives are useful as medicinal components for the purpose of treatment, improvement and prevention of the said diseases.


PRIOR ART

Sialyl Lewis X glycoside, which is a oligosaccharide including fucose, has been attracting attention in recent years as a molecule involved in a homing phenomena, where leucocytes interact with selecting, an adhesion-factor on vascular endothelial cells, and are expelled from the vascular system when inflammation occurs. Further, it has been understood that another ligand of selectin, sialyl Lewis a glycoside [structural formula (IV)] is significantly involved in the liver metastasis of colon cancer [refer to Katsumoto Ito, Progress of Medical Science; 179, 223 (1996)]. Some of the above homing phenomena are initiated by the interaction between the lectinic cell-adhesion molecule called selectin and sialyl Lewis X oligosaccharide. Therefore, neutrophil (a kind of leukocyte)-dependent and selectin-dependent acute inflammation is expected to be suppressed if sialyl Lewis X oligosaccharide can be utilized as a selectin inhibitor.
As an example, a group at Michigan University showed that acute inflammation of the lung induced experimentally in rats using cobra toxin was reduced by administering sialyl Lewis X glycoside [structural formula (III)] [M. S. Mulligan et al., Nature 364, 149 (1993)], and Hayashi et al. also reported the efficacy of sialyl Lewis X derivatives in a lung disease model [Shinichiro Tojo et al., Cell 29 (2), 17 (1997)]. Further, various sialyl Lewis X derivatives have been synthesized from the entirely novel point of view of developing drugs for the inhibition of cell-adhesion. Among them interrelations between their structures and activities have been investigated by Hasegawa and Kiso et al. and their core partial structures are reportedly (1) carboxylic acid in sialic acid, (II) fucose residue, and (III) hydroxyl groups at the 4- and 6-positions in galactose [A. Hasegawa et al., Carbohydrate Research; 257, 67 (1994)]. Furthermore, it is reported that the adhesion-inhibitory activity of the glycoside deoxidized at the 1-position of the reducing terminal [structural formula (V)] to P selectin, which is a member of the selectin family, is 20 times higher than the activity of the sialyl Lewis X glycoside shown in Structural Formula (III) [H. Kondo et al., Journal of Medicinal Chemistry 39, 1339 (1996)]. In addition, synthesis of the Lewis X derivatives [structural formula (VI)] by substituting a sialic acid moiety of sialyl Lewis X with an acidic functional group such as a sulfate residue, a phosphate residue, or a carboxylic acid, and investigation of the adhesion-inhibitory activity for selectins lead to the discovery of GSC-150 as a powerful selectin blocker [refer to H. Kondo et al., Journal of Medicinal Chemistry 39, 2055 (1996); U.S. Pat. No. 5,589,465; JP Opening No. 8-99989]. ##STR1##


OBJECTS OF THE INVENTION

Lewis X or Lewis a derivatives are known as ligand moieties of P selectin or L selectin that act as cell-adhesion molecules. Although they are important compounds that function as cell recognition factors which specifically express these selecting, they are expected to easily lose their activity due to .alpha.-fucosidase existing in the human body, because they have an L-fucosyl-.alpha.-(1.fwdarw.3 or 1.fwdarw.4)-glucose sk

REFERENCES:
patent: 5604207 (1997-02-01), DeFrees et al.
patent: 5811404 (1998-09-01), DeFrees et al.
patent: 5854218 (1998-12-01), DeFrees et al.

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