Combinatorial synthesis of carbohydrate libraries

A method for synthesizing a thiosaccharide derivative on a solid support, which method comprises:

• (a) providing a thiosaccharide;
• (b) providing at least a stoichiometric amount of a coupling reagent selected from Michael acceptors, .alpha.-(sulfonic ester)carbonyl compounds and .alpha.-halocarbonyl compounds wherein either the thiosaccharide or the coupling reagent is covalently attached to a solid support;
• and
• (c) contacting the thiosaccharide and the coupling reagent under conditions which provide for a thiosaccharide carbonyl compound covalently attached to a solid support.

A method for preparing a thiosaccharide derivative library produced by synthesizing on each of a plurality of solid supports a single compound wherein each compound comprises a thiosaccharide derivative, which library is synthesized in a process comprising:

• a) apportioning solid supports among a plurality of reaction vessels which supports comprise a reactive functional group covalently bound thereto which group is capable of covalently binding a thiosaccharide at a position other than the thiol group;
• b) contacting the supports in each reaction vessel with a unique thiosaccharide under conditions wherein the thiosaccharide is covalently attached to the solid supports through the reactive functional group;
• c) pooling the supports;
• d) apportioning the supports from (c) above among a plurality of reaction vessels;
• and
• e) contacting the supports in each reaction vessel from (d) above with a unique coupling reagent selected from the group consisting of Michael acceptors, .alpha.-(sulfonic ester)carbonyl compounds and .alpha.-halocarbonyl compounds under conditions which provide for a thiosaccharide carbonyl compound covalently bound to said support.

A method for preparing a thiosaccharide derivative library produced by synthesizing on each of a plurality of solid supports a single compound wherein each compound comprises a thiosaccharide derivative, which library is synthesized in a process comprising:

• a) apportioning solid supports among a plurality of reaction vessels which supports comprise a reactive functional group covalently bound thereto which group is capable of covalently binding a coupling reagent;
• b) contacting the supports in each reaction vessel with a unique coupling reagent selected from the group consisting of Michael acceptors .alpha.-(sulfonic ester)carbonyl compounds and .alpha.-halocarbonyl compounds under conditions wherein the coupling reagent is covalently attached to the solid supports through the reactive functional group;
• c) pooling the supports;
• d) apportioning the supports from (c) above among a plurality of reaction vessels;
• and
• e) contacting the supports in each reaction vessel from (d) above with a unique thiosaccharide under conditions which provide for a thiosaccharide carbonyl compound covalently bound to said support.

A library of diverse thiosaccharide derivatives comprising a plurality of solid supports having a plurality of covalently bound thiosaccharides derivatives, wherein the thiosaccharide derivative bound to each of said supports is substantially homogeneous and further wherein the thiosaccharide derivative bound on one support is different from the thiosaccharide derivatives bound on the other supports and further wherein said thiosaccharide derivative is represented by the formula (I):

• ##STR7## wherein R.sup.1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, thioalkoxyalkyl and a linking arm covalently linking the compound of formula I to the support;
• R.sup.2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, thioalkoxyalkyl and a linking arm covalently linking the compound of formula I to the support;
• R.sup.3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, thioalkoxyalkyl and a linking arm covalently linking the compound of formula I to the support;
• or R.sup.1 and R.sup.2, or R.sup.1 and R.sup.3, or R.sup.2 and R.sup.3, or R.sup.1, R.sup.2 and R.sup.3 can be joined, together with the carbon atoms to which R.sup.1 and/or R.sup.2 and/or R.sup.3 are attached, to form a cycloalkyl, cycloalkenyl or heterocyclic ring;
• R.sup.4 is selected from the group consisting of --XR.sup.5, --XC(W)R.sup.6, --XC(W)X'R.sup.7 and --C(W)XR.sup.8 ;
• wherein W is selected from the group consisting of oxygen, sulfur and NH;
• and X and X' are each independently selected from the group consisting of oxygen, sulfur and --NR.sup.9 --, wherein R.sup.9 is selected from the group consisting of hydrogen and alkyl;
• or when R.sup.4 is --XR.sup.5 and R.sup.5 is not hydrogen, X can also be selected from the group consisting of --S(O)-- and --SO.sub.2 --;
• R.sup.5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, thioalkoxyalkyl and a linking arm covalently linking the compound of formula I to the support, and when X is --NR.sup.9 --, then R.sup.9 together with X can form an amino acid;
• or R.sup.5 and R.sup.1, or R.sup.5 and R.sup.2, or R.sup.5 and R.sup.3 can be joined, together with X of the --XR.sup.5 group and the carbon atoms to which R.sup.1 and/or R.sup.2 and/or R.sup.3 are attached, to form a heterocyclic ring;
• R.sup.6 is selected from the group consisting of alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, thioalkoxyalkyl and a linking arm covalently linking the compound of formula I to the support;
• or R.sup.6 and R.sup.1, or R.sup.6 and R.sup.2, or R.sup.6 and R.sup.3 can be joined, together with the --XC(W)-- moiety of the --XC(W)R.sup.6 group and the carbon atoms to which R.sup.1 and/or R.sup.2 and/or R.sup.3 are attached, to form a heterocyclic ring;
• R.sup.7 is selected from the group consisting of alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, thioalkoxyalkyl and a linking arm covalently linking the compound of formula I to the support;
• or R.sup.7 and R.sup.1, or R.sup.7 and R.sup.2, or R.sup.7 and R.sup.3 can be joined, together with the --XC(W)X'-- moiety of the --XC(W)X'R.sup.7 group and the carbon atoms to which R.sup.1 and/or R.sup.2 and/or R.sup.3 are attached, to form a heterocyclic ring;
• R.sup.8 is selected from the group consisting of alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, thioalkoxyalkyl and a linking arm covalently linking the compound of formula I to the support;
• or R.sup.8 and R.sup.1, or R.sup.8 and R.sup.2, or R.sup.8 and R.sup.3 can be joined, together with the --C(W)X-- moiety of the --C(W)XR.sup.8 group and the carbon atoms to which R.sup.1, R.sup.2 and/or R.sup.3 are attached, to form a heterocyclic ring;
• Y is selected from the group consisting of sulfur, --S(O)-- and --S(O).sub.2 --;
• n is an integer equal to 0 or 1;
• and pharmaceutically acceptable salts thereof;
• wherein the saccharide is selected from the group consisting of a monosaccharide, an oligosaccharide, monosaccharide-Z- and oligosaccharide-Z-, wherein Z is a linking arm covalently linking the compound of formula I to the solid support;
• with the proviso that only one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8 and Z is linked to the solid support.