Glycomed, Inc.

Falguni Dasgupta

John H Musser

Saeed A Abbas

Darwin S Asa

Mina A Nashed

Peng Cho Tang

Daniel E Levy

Compounds that are synthetically inexpensive to make relative to the naturally occurring selectin ligands and that retain selectin binding activity are described that have a three-dimensionally stable configuration for sialic acid and fucose, or analogs or derivatives of these groups, such that sialic acid and fucose are separated by a non-carbohydrate linker that permits binding between those groups and the selectins, such compounds being represented by the following general structure formula I(a): ##STR1## wherein m and n are independently an integer of from 1 to 5, Y and Z are independently a connecting moiety selected from the group consisting of --CH.sub.2 --, --O--, --S--, --NR'and --NR'R'--(wherein R' and R' are independently H or an alkyl containing 1 to 4 carbon atoms); X is a connecting moiety which is selected from the group consisting of --O--, --S-- and --N--; and --R' may be --R'' or any moiety which does not interfere with the three-dimensional configuration of A or B so as to interfere with selectin binding and is preferably a moiety selected from the group consisting of --OR', --SR', --I, --N.sub.3, and --NR'R', and A is selected from the group consisting of .alpha. and .beta. forms of sialic acid, Kemp's acid. Quinic acid, Glyceric acid, Lactic acid and acetic acid, and esters thereof and B is selected from the group consisting of .alpha. and .beta. forms of L-Fucose and esters and substituted forms thereof wherein one or more of the --OH groups is independently --F, or --NR.sup.IV, R.sup.V wherein R.sup.IV and R.sup.V are independently an alkyl contain 1 to 5 carbons.

Sialic acid/fucose based medicaments

Compounds and methods of making them having the following formula are described which bind to selectin receptors and thus modulate the course of inflammation, cancer and related diseases by modulating cell-cell adhesion events: ##STR1## wherein each R.sup.1 is independently H or lower alkyl (1-4C); R.sup.2 is H, OH or lower alkyl (1-4C), or a lipophilic group such as a higher alkyl group (5-15C), alkylaryl or one or more additional saccharide residues;

Methods of treating inflammation using cell adhesion inhibitors

Compounds that are synthetically inexpensive to make relative to the naturally occurring selectin ligands and that retain selectin binding activity are described that have a three-dimensionally stable configuration for sialic acid and fucose, or analogs or derivatives of these groups, such that sialic acid and fucose are separated by a non-carbohydrate linker that permits binding between those groups and the selectins, such compounds being represented by the following general structural formula I(a): ##STR1## wherein m and n are independently an integer of from 1 to 5, Y and Z are independently a connecting moiety selected from the group consisting of --CH.sub.2 --, --O--, --S--, --NR' and --NR'R'-- (wherein R' and R' are independently H or an alkyl containing 1 to 4 carbon atoms); X is a connecting moiety which is selected from the group consisting of --O--, --S-- and --N--; and --R'' may be --R' or any moiety which does not interfere with the three-dimensional configuration of A or B so as to interfere with selectin binding and is preferably a moiety selected from the group consisting of --OR', --SR', --I, --N.sub.3, and --NR'R', and A is selected from the group consisting of .alpha. and .beta. forms of sialic acid, Kemp's acid, Quinic acid, Glyceric acid, Lactic acid and acetic acid, and esters thereof and B is selected from the group consisting of .alpha. and .beta. forms of L-Fucose and esters and substituted forms thereof wherein one or more of the --OH groups is independently --F, or --NR.sup.IV, R.sup.V wherein R.sup.IV and R.sup.V are independently an alkyl contain 1 to 5 carbons.

Compounds that are synthetically inexpensive to make relative to the naturally occurring selectin ligands and that retain selectin binding activity are described that have a three-dimensionally stable configuration for sialic acid and fucose, or analogs or derivatives of these groups, such that sialic acid and fucose are separated by a non-carbohydrate linker that permits binding between those groups and the selectins, such compounds being represented by the following general structural formula I(a): ##STR1## wherein m and n are independently an integer of from 1 to 5, Y and Z are independently a connecting moiety selected from the group consisting of --CH.sub.2 --, --O--, --S--, --NR' and --NR'R'-- (wherein R' and R' are independently H or an alkyl containing 1 to 4 carbon atoms); X is a connecting moiety which is selected from the group consisting of --O--, --S--and --N--; and --R'' may be --R' or any moiety which does not interfere with the three-dimensional configuration of A or B so as to interfere with selectin binding and is preferably a moiety selected from the group consisting of --OR', --SR', --I, --N.sub.3, and --NR'R' and A is selected from the group consisting of .alpha. and .beta. forms of sialic acid, Kemp's acid, Quinic acid, Glyceric acid, Lactic acid and acetic acid, and esters thereof and B is selected from the group consisting of .alpha. and .beta. forms of L-Fucose and esters and substituted forms thereof wherein one or more of the --OH groups is independently --F, or --NR.sup.IV, R.sup.V wherein R.sup.IV and R.sup.V are independently an alkyl contain 1 to 5 carbons.

Sialic acid/fucose based assay reagents and assay methods

Compounds that exhibit selectin binding activity are described and have the following structural formula: ##STR1## where W is selected from a group including structures a-d below ##STR2## wherein p is an integer of from 0-2, q is an integer of from 0-3, and r is an integer of from 0-5;

Compounds and methods of making them having the following formula are described which bind to selectin receptors and thus modulate the course of inflammation, cancer and related diseases by modulating cell-cell adhesion events: ##STR1## wherein each R.sup.1 is independently H or lower alkyl (1-4C); R.sup.2 is H, OH or lower alkyl (1-4C), or a lipophilic group such as a higher alkyl group (5-15C), alkylaryl or one or more additional saccharide residues; R.sup.3 is a negatively charged moiety including SO.sub.4.sup.2-, PO.sub.4.sup.2-, or related group; Y is H or lower alkyl (1-4C); and X is H or --CHR.sub.4 (CHOR.sup.1).sub.2 CHR.sup.5 OR.sup.1 wherein R.sup.4 and R.sup.5 are each independently H, lower alkyl (1-4C), or taken together result in a five- or six-membered ring optionally containing a heteroatom selected from the group consisting of O, S, and NR.sup.1 ; the five- or six-membered ring optionally substituted with one substituent selected from the group consisting of R.sup.1, CH.sub.2 OR.sup.1, OR.sup.1, OOCR.sup.1, NR.sup.1.sub.2, NHCOR.sup.1, and SR.sup.1 with the proviso that if X represents a hexose substituent R.sup.3 and R.sup.4, taken together, cannot provide a hexose substituent.

Substituted lactose derivatives

Simple lactose or lactosamine related compounds which behave as ligands for the ELAM-1 and related receptors are described. These compounds are useful in the treatment of conditions characterized by excess inflammation. These compounds are of the formula ##STR1## wherein each R.sup.1 is independently H or lower alkyl (1-4C); R.sup.2 is H, lower alkyl (1-4C), alkylaryl or one or more additional saccharide residues;

Substituted lactose and lactosamine derivatives as cell adhesion

Reaction schemes for carrying out a variety of chemical synthesis are disclosed. The reactions produce .alpha.-(X)-sialosides wherein X is O, S, N or another compatible electron donating atom or molecular moiety. The reaction schemes include a relatively small number of steps to provide a yield with a relatively small amount of undesired .beta.-configuration product. Compounds synthesized are encompassed by the following general structural formula I. ##STR1## wherein R, R' and R' are each independently H, CH.sub.3, acetyl, or a disaccharide which is preferably lactose.

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Alameda, CA, United States of America

Falguni Dasgupta