Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-11-17
1996-03-12
Robinson, Douglas W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 54, 514 61, 514 62, 536 173, 536 174, 536 187, 536 53, 536 55, 546184, 546192, 546207, A61K 3170
Patent
active
054986044
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a new sialyl Lewis X (hereinafter abbreviated SLe.sup.x) type and sialyl Lewis A (hereinafter abbreviated SLe.sup.a) type ganglioside sugar chain derivatives represented by the following formula (I), which are useful in pharmaceutical fields such as treatment and prevention of inflammation, intimation-associated thrombosis, asthma, rheumatism, immunological diseases and cancer: ##STR2## wherein R.sup.1 represents hydrogen, a lower alkyl, a lower alkenyl or a lower alkynyl; R.sup.2 and R.sup.3 independently represent galactosyl, sialylgalactosyl or fucosyl; R.sup.4 represents a hydroxyl or acetamido.
BACKGROUND ART
Recent studies have demonstrated that the sugar chains of glycolipids and glycoproteins function as receptors of hormones, bacterial toxins, viruses and others and are profoundly involved in basic dynamic biological phenomena such as cell recognition, differentiation/proliferation, adhesion, transformation, immunity and aging.
Cell surface sugar chains, closely associated with blood group substances such as those of the ABO (H antigen), Lewis (Le antigen) and Ii blood types, are also detected as cancer-related sugar chain antigens. For this reason, there have been studies to apply monoclonal antibodies, that specifically recognize this series of sugar chains, to cancer diagnosis and treatment.
The sialyl Le type sugar chain antigen, a tetrasaccharide sugar chain antigen basically composed of .alpha.(2.fwdarw.3) sialyl and .alpha.(1.fwdarw.3 and 1.fwdarw.4) fucosylated lactosamine, and found in sialoglycoprotein sugar chains as well as in gangliosides, has been used in serologic diagnosis of cancer as a sugar chain antigen for pulmonary adenocarcinoma and digestive tract cancer. Also, sialyl Le.sup.x sugar chains have very recently been reported as functioning as sugar chain ligands for the leukocyte adhesion factor appearing on vascular endothelial cells during intimation [Lowe, J. B., et al., Cell, 63, 475-484 (1990)].
It is very difficult, however, to obtain these sugar chains as a pure single compound from the living body because they are present in the cell surface layer only in trace amounts.
Against this background various synthetic compounds, including derivatives, have been studied, but none have been known to have moranoline (1-deoxynojirimycin) as a sugar chain component like the compounds of the present invention.
The object of the present invention is to provide a sugar chain derivative that is useful as a pharmaceutical and has a new structure.
DISCLOSURE OF INVENTION
Through extensive research, the present inventors found that the object of the present invention can be accomplished by four types of compounds represented by general formula (I): i. SLe.sup.x -type sugar chain derivatives, ii. Le.sup.x -type sugar chain derivatives, iii. SLe.sup.a -type sugar chain derivatives, which are isomers of the derivatives of terms i. and ii. and have a very similar three-dimensional structure, and iv. Le.sup.a -type sugar chain derivatives. The inventors made further investigations based on this finding, and developed the present invention.
The essence of the present invention exists in the structure of the compounds of represented by general formula (I). The compounds of the invention are new compounds not described in literatures, and possess excellent pharmacologic action as stated later.
The lower alkyl for R.sup.1 in the formula (I), is preferably a linear or branched alkyl having 1 to 7 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl or isoheptyl.
The lower alkenyl for R.sup.1 is preferably a linear or branched alkenyl having i to 7 carbon atoms, such as vinyl, propenyl, butenyl, pentenyl, hexenyl or heptenyl.
The lower alkynyl for R.sup.1 is preferably a linear or branched alkynyl having 1 to 7 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl or heptynyl.
The compounds of the present invention are exemplified by the following c
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Furui et al. Carbohydr. Res. 1992, 229, C1-C4.
Dumas et al. Bioorg. Med. Chem. Lett. 1991, 1(8), 425-428.
Ichikawa et al. J. Am. Chem. Soc. 1992, 114, 9283-9298.
Kiso et al. J. Carbohydr. Chem. 1993, 12(4-5), 673-7.
Hasegawa Akira
Kiso Makoto
Yoshikuni Yoshiaki
Fonda Kathleen Kahler
Hasegawa Akira
Nippon Shinyaku Company Limited
Robinson Douglas W.
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