Glycomed, Inc.

Saeed A Abbas

John H Musser

Mina A Nashed

Darwin S Asa

Falguni Dasgupta

Peng Cho Tang

Kevin R Holme

Daniel E Levy

Falguni Asgupta

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

Glyco-amino acids and glycopeptides having three-dimensionally stable configurations are described. These glyco-amino acids and glycopeptides have glycoside functional groups, such as fucose and analogues and derivatives thereof, covalently bound to an amino acid or peptide having a free carboxylic group or sulfate group in an orientation that facilitates the binding between these groups and selectin receptors. The present glyco-amino acids and glycopeptides may be used in the treatment of selectin-mediated disorders, such as inflammation, autoimmune disease and cancer.

Selectin binding glycopeptides

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

Glyco-amino acids or glycopeptides that have three-dimensionally stable configuration for the presentation of functional groups, fucose, or an analogue or derivative thereof, covalently linked to an amino acid or peptide with a free carboxylic acid group, that facilitate binding between those groups and receptors on selectins, represented by the general structural formula I.

The 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; R.sup.3 and R.sup.4 are independently H, alkyl (1-6C), aryl or R.sup.3 and R.sup.4, taken together, form a five or six-membered ring optionally containing a hetroatom selected from the group consisting of O, S, and NR.sup.1 ; wherein said five- or six-membered ring may further be substituted by one or more substituents selected from the group consisting of (CHOR.sup.1).sup.m H wherein m is 1-4, OR.sup.1, OOCR.sub.1, NR.sup.1, NCOR.sup.1 and SR.sup.1 ; Y is H, OR.sup.1, OOCR.sup.1, NR.sup.1.sub.2, NCOR.sub.1 or SR.sub.1 ; and X is --CHR.sup.5 (CHOR.sup.1).sub.2 CHR.sup.6 OR.sup.1 wherein R.sup.5 and R.sup.6 are independently H, lower alkyl (1-4C) optionally substituted with one or more R, or result in a five- or six-membered ring optionally containing a heteroatom selected from the group consisting of O, S and NR.sup.1 ; said five or six-membered ring optionally substituted with one substituent selected from the group consisting of R.sup.1, CHOR.sup.1, OR.sup.1, OOCR.sup.1, NR.sup.1.sub.2, NHCOR.sup.1, SR.sup.1 and F; or X is benzoyl or naphthoyl having 1-3 hydroxyl substituents, with the proviso that if X represents a hexose substituent R.sup.3 and R.sup.4, taken together, cannot provide a hexose substituent. These compounds are useful in the treatment of conditions characterized by excess inflammation.

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Vallejo, CA, United States of America

Saeed A Abbas