Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1997-04-03
1998-09-15
Fonda, Kathleen K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 41, 536 179, 536 184, 536 187, 536122, 536124, 514 25, 514 54, 514 61, 514 62, C07H 1500, A61K 3170
Patent
active
058080180
DESCRIPTION:
BRIEF SUMMARY
The present application is the U.S. National Phase entry under 35 U.S.C. .sctn.371, of PCT/JP96/02250 filed on Aug. 8, 1996.
FIELD OF THE INVENTION
The present invention relates to sialyl Lewis X derivatives in which the hydroxy group at the 2 position of fucose is substituted with fluorine, and synthetic intermediates thereof and a process for the preparation thereof. These derivatives are useful in the fields of medical drugs, for example, in the fields of the treatment and prophylaxis of inflammation and thrombopoiesis associated with inflammation, asthma, rheumatism, immunological diseases and cancers.
BACKGROUND OF THE INVENTION
Sialyl Lewis X sugar chain, which is an oligosaccharide containing fucose, has recently attracted attention since it may be involved in homing phenomena in which upon inflammation leucocytes interact with endotheliocytes of blood vessels and bleed out of the blood vessels. Some of the homing phenomena start with interaction of the sialyl Lewis X oligosaccharide with a lectin-like cell adhesive molecule called selectin. Therefore, if the sialyl Lewis X oligosaccharide could be used as a selectin binding inhibitor, acute inflammations depending upon neutrophils (one of leucocytes) and upon selectin would be expected to be suppressed. In fact, is was shown by a group of Michigan University that acute pulmonic inflammation caused experimentally in rat using cobra venom factor was relieved by administration of the sialyl Lewis X sugar chain (M. S. Mulligan, et al., Nature, 364, 149 (1993)).
Thus, synthesis of various derivatives, for example, derivatives (3) (S. Hakomori, et al., WO 92/19632 (1992)) and (4) (W. Stahl, et al., Angew. Chem. Int. Ed. Engl., 33, 2096 (1994)) in which hydrogen atoms or hydroxy groups of Lewis X ganglioside (1) or sialyl Lewis X ganglioside (2) are replaced by fluorine, were studied. However, it is considered that these derivatives would lose their activity immediately since fucose is released due to .alpha.-1,3-fucosidase.
Accordingly, we have made an attempt to create a sialyl Lewis X having potent selectin adhesion inhibiting activity and metabolic stability. As such a candidate compound, a derivative of sialyl Lewis X in which a hydroxy group at the 2 position of fucose is substituted with a fluorine atom was designed. There was no method for introducing such a fluorine-containing fucose into the sugar chain streo- and position-specifically. ##STR2##
Sialyl Lewis X derivatives are known to be ligand moieties of E and L selectins having an action as a cell adhesion molecule, and are important compounds having a function as a recognition element of cells specifically expressing these selecting. It is useful to synthesize sialyl Lewis X derivatives modified with fluorine in an organic chemical manner so as to investigate the effects of chemical structures on the expression of their activity. It is also considered that such a fluorine-substituted sialyl Lewis X could be applicable to development of practical medical drugs and clinic.
Therefore, it is very meaningful to elucidate the above described sialyl Lewis X derivatives and to provide them in practical amounts.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide new fluorine-containing sialyl Lewis X derivatives which are expected to be the above described drugs, synthetic intermediates thereof and a method of their preparation.
The present inventor has studied for the purpose of synthesizing sialyl Lewis X analogs in which a hydroxy group at the 2 position of fucose is chemically modified with fluorine and, as a result, succeeded in the synthesis of such analogs leading to the present invention.
Accordingly, the present invention relates to a sialyl Lewis X derivative represented by the general formula (I-1): ##STR3## wherein R denotes an aliphatic acyl group having 2 to 6 carbon atoms; R.sup.1 denotes a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms; R.sup.20, R.sup.30 and R.sup.5 independently denote a hydrogen atom, an aliphatic acyl group havin
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Korytnyk et al. Tetrahedron 1982, 38(16), 2547-2550.
Mulligan et al., Nature, 364(Jul. 1993) 149-151.
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Iida Takao
Ohira Yutaka
Daikin Industries Ltd.
Fonda Kathleen K.
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