IMMUNOSUPPRESSIVE AND TOLEROGENIC MODIFIED LEWIS<C> AND LacNAc COMPOUNDS

Abstract: Disclosed are novel Lewis<C> and LacNAc analogues, pharmaceutical compositions containing such analogues, methods for their preparation and methods for their use.

Description: IMMUNOSUPPRESSIVE AND TOLEROGENIC MODIFIED LEWIS 0 AND LacNAc COMPOUNDS BACKGROUND OF THE INVENTION 1. Field of the Invention. The present invention is directed to Lewis c -YR and LacNAc-YR analogues, pharmaceutical compositions containing such analogues, methods for their preparation and methods for their use. 2. References The following references are cited in this application as superscript numbers at the relevant . portion of the application: 1 Horowitz, "The Glycoconjugates", Vols. I-V, Pigman, Editor, New York Academic Press (1977, 1978, 1982, 1983). 2 Ippolito, et al., U.S. Patent Application Serial No. 07/714,161, filed June 10, 1991 for "Immunosuppresive and Tolerogenic Oligosaccharide Glycosides". 3 Sialic Acids in "Cell Biology Monographs" Schauer, Editor, Vol. 10 (1982). 4 Lowe, et al. , Cell, 63:475-485 (1990). 5 Phillips, et al. , Science, 250:1130-1132 (1990) . 6 Walz, et al. , Science, 250:1132 et seq. (1990) . Larsen, et al., Cell, 62:467-474 (1990). Ratcliffe, et al., U.S. Patent No. 5,079,353, issued January 7, 1992, for "Sialic Acid Glycosides, Antigens, Immunoadsorbents, and Methods for their Preparation". Ratcliffe, et al., U.S. Patent Application Serial No. 07/278,106, filed November 30, 1988, for "Sialic Acid Glycosides, Antigens, Immunoadsorbents, and Methods for their Preparation". 10 Venot, et al., U.S. Patent Application Serial No. 07/771,007, "Methods for the Enzymatic Synthesis of Alpha-sialylated Oligosaccharide Glycosides", filed October 2, 1991. 11 Weinstein, et al., J. Biol. Chem., 257:13845- 13853 (1982). 12 Reuter, et al., Glycoconjugate J. , .5:133-135 (1988) . 13 Ippolito, et al., U.S. Patent Application Serial No. 07/889,017, filed May 26, 1992 for "Immunosuppresive and Tolerogenic Oligosaccharide Glycosides". 14 Smith, et al. , Immunology, 5_8:245 (1986). 15 Smith, et al., Infection and Immunity, 31: 129 (1980) . 16 Hindsgaul, et al., Carbohydr. Res., 109:109- 142 (1982). 17 Nicolaou, et al., J. Amer. Chem. Soc, 111:3693-3695 (1990). 18 Ekborg, et al., Carbohydr. Res., 110:55-67 (1982) . 19 Dahmen, et al., Carbohydr. Res., 118:292-301 (1983) . 20 Rana, et al., Carbohydr. Res., 91:149-157 (1981) . 21 Amvam-Zollo, et al., Carbohydr. Res., 15fj:199-212 (1986). 22 Paulsen, et al., Carbohydr. Res., 104: 195-219 (1982) . 23 Chernyak, et al., Carbohydr. Res., 128:269- 282 (1984) . 24 Fernandez-Santana, et al., J. Carbohydr. Chem., 8:531-537 (1989). 25 Lee et al., Carbohydr. Res., 3_7:193 et seq. (lb. -4). 26 Norberg, et al., Carbohydr. Res., 183:71 et seq. (1988) . 27 Petitou, et al., Carbohydr. Res., 147:221-236 (1986) . 28 Trumtez, et al., Carbohydr. Res., 191:29-52 (1989). 29 Lemieux, et al., J. Amer. Chem. Soc, £7:4076-4083 (1975). 30 Lemieux, et al.. Can. J. Chem. 60: 63-67 (1982) . 31 Oka oto, et al.. Tetrahedron, Vol. 46, No. 17, pp. 5835-5837 (1990). 32 Abbas, et al., Proc. Japanese-German Symp. Berlin, pp. 20-21 (1988) . 33 Paulsen, Agnew. Chem. Int. Ed. Eng., 21:155- 173 (1982). 34 Schmidt, Agnew. Chem. Int. Ed. Eng., 25:212- 235 (1986) . 35 Fύgedi, et al., Glycoconj . J., 4.:97-108 (1987) . 36 Kameyama, et al., Carbohydr. Res., 209∑C.-C,. (1991) . 37 Inazu, et al.. Bull. Soc. Chim. , Jap., 611:4467 (1988) . 38 Bernotas, et al., Biochem. J., 270:539-540 (1990). 39 Wollenberg, et al., U.S. Patent No. 4,612,132, for Issued September 21, 1986 for "Modified Succinimides". 40 Greig, et al., J. Chem. Soc, p. 879 (1961). 41 Piekarska-Bartowzewicz, et al., Carbohydr. Res., 2Tj3:302-307 (1990). All publications and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety. 3. State of the Art Carbohydrates and/or oligosaccharides are present on a variety of natural and pathological glycoconjugates 1 . Of particular interest are carbohydrates and oligosaccharides containing εialyl and/or fucosyl residues 3 . Such sialyl and/or fucosyl carbohydrates and oligosaccharides are present in a number of products which have been implicated in a wide range of biological phenomena based, in part, on the concept of recognition signals carried by the carbohydrate structures and by their binding to specific ligands. Specifically, a number of sialylated and sialylated/fucosylated oligosaccharide glycosides have been proposed as mediators of cell adhesion in that they are ligands for selectins (or LEC-CAM's) 4,5,6 * 7 . Sialylated, fucosylated, and sialylated and fucosylated oligosaccharide structures relating to blood group determinants having a type I or a type II core structure, including Lewis x , Lewis*, sialyl Lewis x and sialyl Lewis*, have also been shown by Ippolito et al. 2,13 to possess in vivo immunomodulating and tolerogenic properties in mammals including anti- inflammatory immunomodulating properties. In regard to the above, the DTH anti- inflammatory immunomodulating properties of Lewis x and sialyl Lewis x reported by Ippolito et al. 2,13 demonstrate that the presence of the sialyl residue on sialyl Lewis x results in enhanced anti-inflammatory activity as compared to Lewis and that the presence of a fucosyl group on sialyl Lewis x results in enhanced anti-inflammatory activity as compared the anti- inflammatory activity of sialyl LacNAc. Contrarily, oligosaccharide glycosides containing a sialyl group and/or a fucosyl group as well as related compounds are difficult to chemically synthesize in high yield. For example, synthesis of the αNeu5Ac(2→3)/3Gal disaccharide unit in compounds such as sialyl Lewis x and sialyl Lewis* with anomeric specificity for the α(2→3) is known to be difficult. Known chemical methodologies include a multistep synthesis which first generates a blocked αNeu5Ac(2→3)Gal disaccharide having a suitable leaving group at the reducing sugar terminus of the galactose 8 ' 9 . This disaccharide is then reacted with a suitably protected GlcNAc-OR saccharide glycoside and then a suitably protected L-fucose derivative which, after deprotection, provides for the sialyl Lewis glycoside [αNeu5Ac(2→3)/3Gal(1→4) [αFuc(l→3) ]-3GlcNAc-OR] or the sialyl Lewis* glycoside [i.e, α.Neu5Ac(2→3)jSGal(l→3)-[o.Fuc(l→4) ]-)3GlcNAc-OR] where R is an aglycon of at least one carbon atom. While it is well known that sialylation and fucosylation can be conducted as part of an overall chemical/enzymatic synthesis 2,9,10 of compounds such as sialyl Lewis* and sialyl Lewis", such processes require compatible sialyltransferases and fucosyltransferaseε which are not always readily available. For example, the /3Gal(l→3/4)/3GlcNAc α(2→3)sialyltransferase disclosed in the art for sialylating the 3Gal(1→4)βGlcNAc backbone is currently recovered from rat livers 11 . In any event, the inclusion of a sialyl and/or a fucosyl residue on LacNAc-OR and Lewis c -OR so as to provide for sialyl and/or fucosylated derivatives results in a more complex and costly synthesis. SUMMARY OF THE INVENTION The present invention is directed, in part, to the discovery that modified Lewis c -YR and modified LacNAc-YR compounds having a sulfate, a phosphate or a carboxylate containing group at the 2, 3 and/or 6- positions of the galactose unit possess good immunosuppressive and tolerogenic properties. Moreover, the 3-sulfate Lewis 0 -YR compound possesses approximately equivalent immunosuppressive properties as compared to sialyl Lewis x -YR. This result is particularly surprising insofar as unmodified Lewis*-YR and sialyl Lewis*-YR possess inferior immunosuppressive properties as compared to the 3-sulfate of Lewis c -YR. Additionally, these modified LacNAc-YR and modified Lewis c -YR compounds do not require formation of an α(2-+3) sialyl residue on the galactose or a fucosyl residue at the 3- or 4-position of the GlcNAc residue in order to impart biological activity. Accordingly, the synthesis of biologically active molecules is simplified and the inclusion of a required sialyl group or a required fucosyl group is avoided. However, in this regard, the optional inclusion of a sialyl group at the 6-position of the galactose having a sulfate, phosphate or -CHR 18 COOH group at the 2- or 3-position of the galactose is contemplated herein. Accordingly, in one of its composition aspects, the present invention is directed to compounds of Formula I or II: where R is selected from the group consisting of hydrogen, a saccharide-OR 19 , an oligosaccharide-OR 19 having from 2 to 7 oligosaccharide units, or an aglycon having at least 1 carbon atom where R 19 is hydrogen or an aglycon of at least one carbon atom; Y is selected from the group consisting of oxygen, sulfur, and -NH-; R. is selected from the group consisting of hydrogen, -NH 2 , -N 3 , -NHS0 3 H, -NR 5 C(0)R 4 , -N=C(R 5 ) 2 , -NHCH(R 5 ) 2 , -NHR 6 , -N(R 6 ) 2 , -OH, -OR 6 , -S(0)R 6 , -S(0) 2 R 6 and sulfate, wherein R 4 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms; -0R 7 wherein R 7 is alkyl of from 1 to 4 carbon atoms, or alkyl of from 2 to 4 carbon atoms substituted with a hydroxyl group, and "NR g R ς , wherein R 8 and R < - are independently selected from the group consisting of hydrogen and alkyl of from 1 to 4 carbon atoms, each R 5 is selected from the group consisting of hydrogen and alkyl of from 1 to 4 carbon atoms, each R 6 is alkyl of from 1 to 4 carbon atoms, R 2 is selected from the group consisting of hydrogen, -N 3 , -NH 2 , -NHS0 3 H, -NR^CfOJR^, -N=C(R ) 2 , -NHCH(R 11 ) 2 , -NHR 12 , -N(R 12 ) 2 , -OH and -0R 12 , wherein R 10 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, -0R 13 wherein R 13 is alkyl of from 1 to 4 carbon atoms, or alkyl of from 2 to 4 carbon atoms substituted with a hydroxyl group, and -NR U R 15 wherein R u and R 15 are independently selected from the group consisting of hydrogen and alkyl of from 1 to 4 carbon atoms, each R^ is selected from the group consisting of hydrogen and alkyl of from 1 to 4 carbon atoms; each R 12 is alkyl of from 1 to 4 carbon atoms, R 3 is selected from the group consisting of hydrogen, fluoro, sulfate and hydroxy; X. is selected from the group consisting of hydrogen, sialyl, sulfate, phosphate, and -CHR 18 C00H where R 18 is selected from the group consisting of hydrogen, alkyl of from 1 to 7 carbon atoms and -COOH; X 2 is selected from the group consisting of hydrogen, sulfate, phosphate, and -CHR 18 COOH where R 18 is selected from the group consisting of hydrogen, alkyl of from 1 to 7 carbon atoms and -COOH; and pharmaceutically acceptable salts thereof; and with the proviso that either at least one of X- or X 2 is sulfate, phosphate or -CHR 18 COOH or R 3 is sulfate. The compounds of Formula I and II are useful in modulating a cell-mediated immune inflammatory response and in particular a cell-mediated immune inflammatory response to an antigen. The compounds of this invention are particularly useful in reducing antigen induced inflammation in a sensitized mammal. In this regard, when the compounds of Formula I and II are administered to a sensitized mammal in response to an antigen challenge, such administration induces tolerance to later challenges from this same antigen. Preferably, administration of a compound of Formula I or II above is after initiation of the mammal's immune response but at or prior to one-half of the period of time required for the mammal to reach maximal inflammation. In another of its composition aspects, the present invention is directed to a pharmaceutical composition suitable for administration to a mammal (e.g. , human) which comprises a pharmaceutically inert carrier and an effective amount of the compound of Formula I or Formula II to modulate a cell-mediated immune inflammatory responses in said mammal. In one of its method aspects, the present invention is directed to a method for modulating a cell-mediated immune inflammatory response in a mammal which method comprises administering to said mammal an amount of a compound of Formula I or Formula II effective in modulating said immune response. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates reaction schemes for the synthesis of partially blocked N-acetyl glucosamine derivatives which are then used to prepare either modified Lewis c -OR compounds or modified LacNAc compounds. Figure 2 illustrates reaction schemes for the synthesis of partially blocked galactose derivatives which are then used to prepare either modified Lewis c - OR compounds or modified LacNAc-OR compounds. Figure 3A illustrates one method for the preparation of 3-sulfated Lewis c -OR compounds. Figure 3B illustrates one method for the preparation of 6-sulfated Lewis c -OR compounds. Figure 4 illustrates methods for preparing differentially blocked /3Gal(l→3)/3GlcNAc-OR compounds (Lewis c -OR) and derivatives thereof and methods for preparing differentially blocked SGal(l→4) ->GlcNAc-OR (LacNAc-OR) compounds. Figure 5 illustrates the synthesis of the 6-azido derivative of GlcNAc-OR. Figure 6 illustrates the synthesis of the 6- alkoxy derivatives and the 6-deoxy derivatives of GlcNAc-OR. Figure 7 illustrates the preparation of 3- hydroxy or 4-hydroxy blocked GlcNH 2 -OR where the amino group is protected as an N-phthalimido group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As noted above, the present invention is directed, in part, to the discovery of novel Lewis c -YR and novel LacNAc-YR analogues which, in mammals, including humans, are useful for in vivo modulation (e.g. , suppression) of a cell mediated immune response including cell-mediated and immune directed inflammatory responses to an antigen in a sensitized mammal (e.g., a DTH response). However, prior to discussing this invention in further detail, the following terms will first be defined. Definitions As used herein, the following terms have the definitions given below: The term "cell-mediated immune response in a mammal" refers to those mammalian immune responses which are mediated by cell-cell interactions. Included within this term are cell mediated inflammatory responses to an antigen such as DTH responses as well as cell-mediated inflammatory responses arising from injury such as frost-bite injury, reperfusion injury, adult respiratory distress syndrome, and the like. Preferably, the cell-mediated immune response is a leucocyte-mediated response. The term "antigen" refers to any protein, peptide, carbohydrate, nucleic acid or other non- endogenous substance which when exposed to a mammal induces an immune response in that mammal. Disease conditions believed to be caused by antigen exposure include, by way of example, psoriasis, asthma, dermatitis, rheumatoid arthritis, delayed type hypersensitivity, inflammatory bowel disease, multiple scelorsis, viral pneumonia, bacterial pneumonia, and the like. The term "sensitized mammal" refers to those mammals which have been previously exposed to an antigen and, accordingly, their immune systems have become educated to that antigen. Typically, initial exposure of an antigen to a mammal primes or educates the mammal's immune response to later exposure to that antigen with minimal inflammation during such initial exposure. The term "secondary immune response" refers to the effector phase of a mammal's immune response to an antigen to which it has been previously been sensitized. A mammal's secondary immune response is typically accompanied by inflammation at the point of antigen exposure. The term "period for maximal inflammation" refers to the period of time typically required to achieve maximal inflammation in a sensitized mammal due to exposure to a specific antigen or to the period of time typically required to achieve maximal inflammation in a mammal due to an injury which induces a cell- mediated inflammatory response (e.g., myocardial infarction) . This period of time depends on several factors. For example, for inflammation due to injury, the period for maximal inflammation depends on factors such as the type and extent of injury. In a sensitized mammal exposed to an antigen, this period is dependent on factors such as the specific antigen to which the mammal has been exposed, the particular mammalian species exposed to the antigen, etc. Accordingly, the period of time required to effect maximal antigen induced inflammation in-a sensitized mammal will vary for, by way of example, asthma as opposed to rheumatoid arthritis. Moreover, while the specific time required to effect maximal inflammation will vary somewhat in a given mammalian species, the time typically required to effect maximal inflammation for different antigen exposures in human and other mammals resulting in asthma, rheumatoid arthritis, psorasiε, DTH, etc. is known in the art or are readily ascertainable by the skilled artisan. For example, in the case of a DTH response in mice, maximal inflammation is typically 24 hours after antigen exposure. The term "LacNAc" refers to the disaccharide jSGal(l→4)3GlcNAc Because of its relationship to the core structure of type II blood group determinants, the βGal(1→4)βGlcNAc structure of LacNAc is often referred to as a type II structure. The term "LacNH 2 " refers to the LacNAc derivative wherein the N-acetyl group of LacNAc has been replaced with an amine (-NH 2 ) . The term "LacN 3 " refers to the LacNAc derivative wherein the N-acetyl group of LacNAc has been replaced with an azido (-N 3 ) . The term "Lewis 0 " (sometimes referred to "Le°") refers to the disaccharide øGal(l→3)/3GlcNAc. Because of its relationship to the core structure of type I blood group determinants, the 3Gal(l→3)?GlcNAc structure of Lewis 0 is often referred as a "type I structure". The terms "modified Lewis 0 glycosides (Lewis°-YR) and derivatives thereof" refer to derivatives of the Lewis 0 modified in one or both of the galactose and N-acetylglucosamine saccharide units of Lewis 0 and which have an -YR substituent as defined above. When the R substituent is an aglycon group, this group has at least one carbon atom, but nevertheless is different from glycoconjugates because such aglycon moieties are neither a protein nor a lipid capable of forming a micelle or other large aggregate structure. The term "modified LacNAc glycosides (LacNAc-YR) and derivatives thereof" refer to derivatives of the LacNAc modified in one or both of the galactose and N-acetylglucosamine saccharide units of LacNAc and which have an -YR substituent as defined above. When the R substituent is an aglycon group, this group has at least one carbon atom, but nevertheless is different from glycoconjugates because such aglycon moieties are neither a protein nor a lipid capable of forming a micelle or other large aggregate structure. The term "aglycon of at least one carbon atom" refers to non-saccharide containing residues having at least one carbon atom. Preferably, the aglycon moiety, R, is selected from the group consisting of -(A)-Z wherein A represents a bond, an alkylene group of from 2 to 10 carbon atoms, and a moiety of the formula -(CH 2 -CR 20 G) n - wherein n is an integer equal to 1 to 5; R 20 is selected from the group consisting of hydrogen, methyl, or ethyl; and G is selected from the group-consisting of hydrogen, halogen, oxygen, sulphur, nitrogen, phenyl and phenyl substituted with 1 to 3 substituents selected from the group consisting of amine, hydroxyl, ' halo, alkyl of from 1 to 4 carbon atoms and alkoxy of from 1 to 4 carbon atoms; and Z is selected from the group consisting of hydrogen, methyl, phenyl, nitrophenyl, aminophenyl and, when G is not oxygen, sulphur or nitrogen and A is not a bond, then Z is also selected from the group consisting of -OH, -SH, -NH 2 , -NHR 21 , -N(R 21 ) 2 , -C(0)0H, -C(0)OR 21 , -C(0)NH-NH 2 , -C(0)NH 2 , -C(0)NHR 21 , -C(0)N(R 21 ) 2 , and -OR 22 wherein each R 21 is independently alkyl of from 1 to 4 carbon atoms and R 22 is an alkenyl group of from 3 to 10 carbon atoms. Numerous aglycons are known in the art. For example, an aglycon comprising a para-nitrophenyl group (i.e., -YR = -OC 6 H 4 pN0 2 ) has been disclosed by Ekborg, et al. 18 At the appropriate time during synthesis, the nitro group is reduced to an amino group which can be protected as N-trifluoroacetamido. The trifluoro- acetamido group can later be removed thereby unmasking the amino group which can then be used to further functionalize the aglycon group. An aglycon containing sulfur is disclosed by Dahmen, et al. 19 . Specifically, the aglycon is derived from a 2-bromoethyl group which, in a substitution reaction with thionucleophiles, has been shown to lead to aglycons possessing a variety of terminal functional groups such as -OCH 2 CH 2 SCH 2 C0 2 CH 3 and -OCH 2 CH 2 SC 6 H A -pNH 2 . Rana, et al. 20 discloses a 6-trifluoroacet- amidohexyl aglycon (-0-(CH 2 ) 6 -NHCOCF 3 ) in which the trifluoroacetamido protecting group can be removed unmasking the primary amino group which can then be used to further functionalize the aglycon group. Other exemplification of known aglycons include the 7-methoxycarbonyl-3,6,dioxaheptyl aglycon 21 (-OCH 2 -CH 2 ) 2 OCH 2 C0 2 CH 3 ; the 2-(4-methoxycarbonylbutane- carboxamido)ethyl 22 (-OCH 2 CH 2 NHC(0) (CH 2 ) 4 C0 2 CH 3 ) ; and the allyl aglycon 23 (OCH 2 CH=CH 2 ) which, by radical co- polymerizatiσn with an appropriate monomer, leads to co-polymers; other allyl aglycons 24 are known [e.g., -0(CH 2 CH 2 0) 2 CH 2 CH=CH 2 ] . Additionally, allyl aglycons can be derivatized in the presence of 2-aminoethane- thiol 25 to provide for aglycons -OCH 2 CH 2 CH 2 SCH 2 CH 2 NH 2 . Still other aglycons are illustrated hereinbelow. Additionally, as shown by Ratcliffe et al. 9 , the R group can be an additional saccharide-OR 19 or an oligosaccharide-OR 19 containing an aglycon at the reducing sugar terminus. Preferably, the aglycon moiety is a hydrophobic group and most preferably, the aglycon moiety is a hydrophobic group selected from the group consisting of -(CH 2 ) 8 COOCH 3 , -(CH 2 ) 5 OCH 2 CH=CH 2 and -(CH 2 ) 8 CH 2 OH. The term "oligosaccharide" refers to a carbohydrate structure having from 2 to about 7 saccharide units. The particular saccharide units employed are not critical and include, by way of example, all natural and synthetic derivatives of glucose, galactose, N-acetylglucosamine, N-acetyl- galactosamine, fucose, sialic acid, 3-deoxy-D,L- octulosonic acid, and the like. In addition to being in their pyranose form, all saccharide units described herein are in their D form except for fucose which is in its L form. The term "sialic acid" or "sialyl" means all naturally occurring structures of sialic acid and analogues of sialic acid. Naturally occurring structures of sialic acid include, by way of example, 5-acetamido-3,5-dideoxy-D-glycero-D-galactononulo- pyranosylonic acid ("Neu5Ac") , N-glycoyl neuraminic acid (Neu5Gc) and 9-O-acetyl neuraminic acid (Neu5,9Ac 2 ) . Analogues of sialic acid refers to analogues of naturally occurring structures of sialic acid including those wherein the sialic acid unit has been chemically modified so as to introduce and/or remove one or more functionalities from such structures. For example, such modification can result in the removal of an -OH functionality, the introduction of an amine functionality, the introduction of a halo functionality, and the like. Certain analogues of sialic acid are known in the art and include, by way of example, 9-azido-Neu5Ac, 9-amino-Neu5Ac, 9-deoxy-Neu5Ac, 9-fluoro-Neu5Ac, 9- bromo-Neu5Ac, 7-deoxy-Neu5Ac, 7-epi-Neu5Ac, 7,8-bis- epi-Neu5Ac, 4-0-methyl-Neu5Ac, 4-N-acetyl-Neu5Ac, 4,7- di-deoxy-Neu5Ac, 4-oxo-Neu5Ac, as well as the 6-thio analogues of Neu5Ac The nomenclature employed herein in describing analogues of sialic acid is as set forth by Reuter et al. 12 The term "pharmaceutically acceptable salts" includes the pharmaceutically acceptable addition salts of the compounds of Formula I or Formula II derived from a variety of organic and inorganic counter salts well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and .the like. The term "sulfate" such as used to define the substituents -X 1 and -X 2 refers to substituents which, with the oxygen of a hydroxyl group of the galactose unit, form a sulfate group (i.e., -O-S(0) 2 -OH) . Thus, when X 1 or X 2 is a sulfate, the resulting -0X 1 and/or -0X 2 group is -0-S(0) 2 -0H, which readily forms pharmaceutically acceptable salts thereof (e.g., -0-S(0) 2 -0 " Na + ) . Contrarily, the term "sulfate" as it is used for R 3 refers to the -0-S(0 2 )-0H group, which readily forms pharmaceutically acceptable salts thereof. The term "phosphate" such as used to define the substituents -X. and -X 2 refers to substituents which, with the oxygen of a hydroxyl group of the galactose unit, form a phosphate group (i.e., -O-P(O)-(OH) 2 . Thus, when X, or X 2 is a phosphate, the resulting -OX, and/or -OX 2 group is -O-P(O)-(OH) 2 , which readily forms pharmaceutically acceptable salts thereof (e.g., -0-P(0)-(0 " Na + ) 2 . The term "removable blocking group" or "blocking group" refers to any group which when bound to one or more hydroxyl groups of the galactose and/or the N-acetylglucosamine of the Lewis°-YR and LacNAc-YR compounds prevents reactions from occurring at these hydroxyl groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as benzyl, benzoyl, acetyl, chloroacetyl, benzylidine, t-butyldiphenyl- silyl and any other group that can be introduced either enzymatically or chemically onto a hydroxyl functionality and later selectively removed either by enzymatic or chemical methods in mild conditions compatible with the nature of the product. One such contemplated blocking group is a α-galactose which can be removed enzymatically with an α-galactosidase. 2. Methodology The modified Lewis°-YR and modified LacNAc-YR compounds disclosed herein are readily prepared by complete chemical syntheses. The figures attached hereto elaborate on a variety of complete chemical synthetic schemes which result in the preparation of modified Lewis°-YR and modified LacNAc-YR compounds. Chemical synthesis is a convenient method for preparing either the complete oligosaccharide glycoside; for chemically modifying a saccharide unit which can then be chemically or enzymatically coupled to an oligosaccharide glycoside; or for chemically preparing an oligosaccharide glycoside to which can be enzymatically coupled one or more saccharide units. Several chemical syntheses of blocked intermediates exist 16,17,30 and, with suitable modifications to these synthetic routes, can be used herein. Syntheses of these intermediates or similar ones utilizing methods known in the art allow the synthesis of the modified Lewis°-YR and modified LacNAc-YR compounds disclosed herein. Chemical modifications include introduction of the sulphate or phosphate group or a -OCHR 18 COOH at the 3 and/or 6 position of the terminal galactose; the introduction of a sulfate at the 2-position of the galactose; and optionally, the introduction of modification at the 2- and 6- positions of the N-acetylglucosamine unit and/or introduction of deoxy or fluoro functionality at the 2-position of the galactose, and the like. In the description below as well as in the examples and figures, reference is made to the -OR group at the reducing sugar. However, it is understood that this group could also be -NHR or -SR, the preparation of which is well known in the art. 2A. CHEMICAL SYNTHESIS OF SACCHARIDE MONOMERS Chemical methods for the synthesis of Lewis°-YR and LacNAc-YR and some analogues thereof are known in the art. These materials are generally assembled using suitably protected individual monosaccharide intermediates. The modifications to the final structures are accomplished using known methods for sulfation or phosphorylation after appropriate selective deblocking of the to-be functionalized hydroxyl group(s) of the fully blocked Lewis°-YR or LacNAc-YR. The specific methods employed are generally adapted and optimized for each individual structure to be synthesized. In general, the chemical synthesis of all or part of the these disaccharides first involves formation of a glycosidic linkage on the anomeric carbon atom of the reducing sugar. Specifically, an appropriately protected form of a naturally occurring or of a chemically modified saccharide structure (the glycosyl donor) is selectively modified at the anomeric center of the reducing unit so as to introduce a leaving group comprising halides, trichloroacetimidate, acetyl, thioglycoside, etc. The donor is then reacted under catalytic conditions well known in the art with an aglycon or an appropriate form of a carbohydrate acceptor which possess one free hydroxyl group at the position where the glycosidic linkage is to be established. A large variety of aglycon moieties are known in the art and can be attached with the proper configuration to the anomeric center of the reducing unit. Appropriate use of compatible blocking groups, well known in the art of carbohydrate synthesis, will allow selective modification of the synthesized structures or the further attachment of additional sugar units or sugar blocks to the acceptor structures. After formation of the glycosidic linkage, the saccharide glycoside can be used to effect coupling of the galactose unit or chemically modified at selected positions. In general, chemical coupling of a naturally occurring or chemically modified saccharide unit to the saccharide glycoside is accomplished by employing established chemistry well documented in the literature. See, for example, Okamoto et al. 31 , Ratcliffe et al. 8 , Abbas et al. 32 , Paulsen 33 , Schmidt 34 , Fugedi et al. 35 , and Kameyama et al. 36 With reference to the figures. Figure 1 illustrates the synthesis of numerous blocked derivatives of glucosamine and N-acetylglucosamine which are then useful in the preparation of blocked LacNH 2 -OR [jSGal(1→4)/3GlcNH 2 -OR] , LacNAc-OR [βGal(1→4)øGlcNAc-OR] , Lewis°-OR [3Gal(1-3)3GlcNAc-OR] , Lewis°-NH 2 -OR [/3Gal(l→3) ?GlcNH 2 -OR] , etc. structures. Specifically, in Figure 1, glucosamine hydrochloride is slurried in dichloroethane containing an equivalent of anhydrous sodium acetate to which acetic anhydride is added dropwise and, after addition is completed, the solution is refluxed for a period of from about 12-16 hours to provide for the peracylated compound 10 (about 3:1 ratio of a/β) . Alternatively, the glucosamine hydrochloride is first taken up in methanol and then treated with 1 equivalent of metallic sodium to neutralize the HCl. Phthalic anhydride is then added quickly to the reaction mixture followed shortly thereafter by triethylamine to provide for the phthalimido derivative. This compound is then isolated and acetylated with acetic anhydride/pyridine using conventional techniques to provide for peracylated compound 1 having a phthalimide blocking group protecting the amine. Afterwards, the aglycon is formed by conventional techniques. For example, compound 10 is converted to 1-α-chloro compound 2 by well known chemistry which involves bubbling saturating amounts of hydrogen chloride directly into a dichloroethane solution of compound 10. In this regard, the solution used to prepare compound 10 can be used in this reaction after that solution has been quenched into water to remove acetic anhydride and sodium acetate, dried and recovered. The reaction generally proceeds over a period of about -4-6 days and hydrogen chloride is bubbled into the solution periodically (e.g., about once ever 1-2 days) . After reaction completion, the solution is quenched in aqueous sodium bicarbonate at about 0-5°C and the product is recovered after drying the organic layer and stripping the solution to provide for compound 2 (one spot on t.l.c) Compound 2 is then converted to the l-3-(CH 2 ) 8 COOCH 3 aglycon by well known chemistry which involves reaction of compound 2 with HO(CH 2 ) 8 COOCH 3 in anhydrous dichloromethane containing molecular sieves in the presence of an equivalent amount of mercuric cyanide. The reaction is generally conducted at room temperature for a period of about 12 to 24 hours. Upon reaction completion (as evidenced by t.l.c), the reaction solution is filter through silica and the resulting solution is quenched by adding the reaction solution to cold water. The organic layer is recovered and the washed twice with an aqueous potassium iodide (5 weight/vol percent) solution and then with a saturated aqueous sodium bicarbonate solution. The resulting organic solution is then dried and the solvent removed by stripping to provide for compound 3. The 3, 4, and 6 hydroxyl groups of compound 3 are then deprotected by reaction with sodium methoxide in methanol to provide for N-acetylglucosamine-OR, compound 4. This compound can reacted with C 6 H 5 CH(OCH 3 ) 2 in, for example, an acidic medium in an appropriate solvent at around 40-50°C for about 4-6 hours to provide for the 4,6-O-diprotected benzylidine compound 5. In turn, compound 5 can be reacted with p- methoxybenzyl trichloroacetimidate in an appropriate solvent (e.g., DMF, dichloromethane) in the presence of a catalytic amount of an acid (e.g. , p-toluenesulfonic acid — pTSA) to provide for the p-methoxybenzyl protected 3-hydroxy compound 6. Treatment of compound 6 with sodium cyanoborohydride in tetrahydrofuran followed by the dropwise addition of HCl saturated ether at about 0"C leads to compound 7. Alternatively, compound 5 can be blocked at the 3-hydroxyl group by reaction with, for example, allyl bromide and base (e.g., barium hydroxide/barium oxide) to provide for compound 8. Treatment of compound 8 with sodium cyanoborohydride in tetrahydro¬ furan followed by the dropwise addition of HCl saturated ether at about 0°C leads to compound 9. Because compounds 7 and 9 contain only a free hydroxyl group at the 4-position of the blocked GlcNAc-OR saccharide, subsequent reaction with an appropriately blocked galactose will result in formation of a blocked type II LacNAc-OR structure [)8Gal(l→4)3GlcNAc-OR] . Because compound 5 contains a free hydroxyl group only at the 3-position of the blocked GlcNAc-OR saccharide, subsequent reaction with an appropriately blocked galactose will result in formation of a blocked type I structure [/3Gal(l→3)/3GlcNAc-OR] . Alternatively, compound 1 can be converted to compound 11 by reaction of compound 1 with an equivalent of p-chlorothiophenol in dichloromethane at room temperature in the presence of 2 equivalents of boron trifluoride etherate (BF 3 -etherate) to provide for compound 11. In yet another embodiment, compound 1 is converted to compound 12 (or the bromo analogue) by following similar procedures set forth above for compound 2. Compound 12 is converted to compound 13 by reaction with an alcohol (e.g., ethanol, R = -CH 2 CH 3 ) in manner similar to that of compound 3 with the exception that the alcohol replaces HO(CH 2 ) 8 COOCH 3 . Compound 13 is then converted to compound 14 with sodium methoxide/methanol and is then converted to compound 15 by reaction with bis[tributyltin] oxide in refluxing toluene containing tetraethylammonium bromide followed by reaction with benzyl bromide. Because compound 15 contains free hydroxyl groups at the 3- and 4-positions of the blocked GlcNAc- OR saccharide, subsequent reaction with an appropriate- ly blocked galactose will result in formation of both a type I structure [,3Gal(l→3)3GlcNAc-OR] and type II structure [3Gal(l→4)/3GlcNAc-OR] which are readily separated by conventional techniques including chromatography. Compound 16 is prepared by treating p-chloro- thiophenol with 0.95 equivalents of potassium hydroxide in ethanol followed by heating the solution to about 40-50"C and then adding about 0.5 equivalents of compound 2 to the reaction solution. The reaction is maintained at 40-50°C for about 1-2 hours and the product 16 precipitates upon cooling the solution and is recovered by filtration. The synthesis of compounds 26 - 31 are depicted in Figure 2 and are set forth in the examples hereinbelow. In this figure, D-galactose pentaacetate 26 is produced by slurring D-galactose and about an equimolar amount (e.g., about 1.1 equivalents) of sodium acetate (NaOAc) in dichloroethane (DCE) , heating to reflux and adding at least 5 equivalents of acetic anhydride (AcOAc) dropwise to the refluxing solution (about 80-85°C) and then maintaining the reaction system at this temperature for a sufficient period of time (about 16-32 hours) to result in formation of compound 26. This procedure optimizes the yield of β-D-galactose pentaacetate 26 and controls the exotherm of heretofore known procedures. After workup of the solution, the product is treated with approximately equimolar amounts of benzyl mercaptan (Ph-CH 2 -SH) and from about 1-3 (preferably two) equivalent of boron trifluoride etherate (BF 3 -OEt 2 ) in dichloromethane. The reaction conditions are not critical and the reaction is preferably conducted at from about 0°C to about 30°C for a period abouut 6 to 16 hours to yield after crystallization from hot methanol or hot isopropanol 55-65% of benzyl 2,3,4,6- tetra-O-acetyl β-D-thiogalactopryanoside, compound 27. Deacetylation under Zemplen conditions (sodium methoxide/methanol) leads to compound 28. Deacetylation reaction conditions are not critical and the reaction is generally conducted at room temperature for a period of from about 2 to about 15 hours. After the deacetylation reaction is complete (as judged by t.l.c), the solution is neutralized with an acid ion exchange resin, filtered and evaporated to dryness to provide for compound 28. The residue is crystallized from hot acetone and the product is taken up in dimethylformamide or aoetonitrile and treated with from 1 to 2 equivalents (preferably 1.4 equivalents) of benzaldehyde dimethyl acetal and about 0.25 to 3 weight percent of p-toluenesulphonic acid (based on compound 28) . The reaction conditions are not critical and preferably the reaction is conducted at room temperature and is generally complete in about 12 to 24 hours. After neutralization, the benzyl 4,6-0- benzylidene β-D-thiogalactopyranoside, 29, is isolated and crystallized from hot isopropanol. Benzyl 4,6-0-benzylidene-3-0-chloroacetyl- β-D-thiogalactopyranoside 30 is prepared by chloroacetylation using from about 1 to 3 (preferably 2) equivalents of chloroacetylchloride which is added to a dimethylformamide (DMF) solution containing benzyl 4,6-0-benzylidene β-D-thiogalacto-pyranoside 29. The chloroacetylchloride is added dropwise while maintaining the DMF solution at from about -40° to about -15°C (preferably at -25°C) . Under these conditions, it is unexpectedly been found that the use of DMF permits selective chloroacetylation of compound 29 without the need for additional base. The reaction is generally complete in about 10-24 hours. Benzyl 4,6-0-benzylidene-3-0-chloroacetyl-β- D-thiogalactopyranoside (compound 30) is benzoylated with at least 1 equivalent (and preferably about 2 equivalents) of benzoyl chloride in a suitable solvent containing a base (e.g., pyridine/methylene chloride) with from about 0.1 to about 1 weight percent of dimethylaminopyridine [DMAP] as a catalyst. The reaction conditions are not critical and preferably the reaction is conducted at from about 0*C to about 30°C and for about 1 to about 4 hours (preferably room temperature for 2 hours, to give crystalline benzyl 4,6-0-benzylidene 2-0-benzoyl-3-0-chloroacetyl-β-D- thio-galactopyranoside, compound 31, in approximately 10-20% overall yield from galactose. The advantage of this approach is that after subsequent assembly the blocked intermediates will be simply deblocked and modified by sulfation or phosphorylation. The material is crystalline and the process obviates the need for chromatography. The sulfates and phosphates of the galactose moiety of blocked Lewis°-YR and LacNAc-YR can also be made using compound 32 in the synthesis of these compounds. This compound is made by direct benzoylation of both the 2,3-hydroxyl groups of compound 29. However, after deblocking, both the 2 and 3 hydroxyl groups of galactose are then available for sulfation and phosphorylation and the selectivity is not as efficient. Selectivity can be improved by, for example, conducting the sulfation reaction at a low temperature (e.g., -50°C) . Compound 29 can be converted to the 2,3- dibenzoyl protected compound 32 in a manner similar to that described above for the preparation of compound 31. In this case, 3-5 equivalents of benzoyl chloride are generally employed. Compounds 31 and 32 are converted to compounds 3: and 32a (shown in Figure 4) via known methodology (Norberg et al. 26 ) using bromine tetraethylammonium bromide. Alternatively, compound 31 can be converted to compound 34 by contacting compound 31 with 80% acetic acid/water at approximately 50°C for about 1-2 ho rs. Compound 34 is then converted to compound 35 by treatment with acetic anhydride/pyridine in dichloromethane. In another embodiment, compound 32 is treated with sodium cyanoborohydride and eerie chloride to provide for the benzyl-2,3-0-dibenzoyl-4-0-benzyl-/3-D- thiogalactopyranoside (not shown) . In turn, this compound is chloroacetylated at the 6-hydroxyl group. After formation of the Lewis°-0R or LacNAc-OR blocked structures, the chloroacetyl group can be selectively removed (as described above) and then either phosphorylated or sulphated so as to provide for the 6- phosphate or 6-sulfate derivative. 2B. FORMATION OF TYPE I STRUCTURES HAVING SULFATE SUBSTITUTION AT THE 3 OR 6-POSITIONS OF GALACTOSE Figure 3A illustrates one method for the preparation of 3-sulfated Lewis°-OR compounds. Specifically, in Figure 3A, compound 101, is prepared by reacting N-acetylglucosamine-OR (e.g., compound 4 in Figure 1) with C 6 H 5 CH(OCH 3 ) 2 in an acidic aoetonitrile or dimethylformamide (DMF) medium at from about 0° to about 50°C over 12-48 hours to provide for the 4,6-diprotected benzylidine compound 101. About 1 equivalent of N-iodosuccinimide is combined with about 1 equivalent of trifluoromethane- sulfonic acid in methylene chloride containing molecular sieves which remove any water present. The reaction mixture is cooled to -50"C and then compound 101 is added followed by. the addition of approximately, 1 to 1.1 equivalents of compound 32 (based on compound 101) . The reaction is allowed to equilibrate to about -20° to 0°C over about 1-3 hours. The reaction solution is then quenched by cooling to -50°C followed by the addition of triethylamine until neutral pH is reached. The solution is filtered through Celite and then washed with a saturated sodium bicarbonate solution and water. The organic layer was dried and stripped in vacuo to provide for fully protected disaccharide 102. In this reaction, compound 32a or 112 can be used in place of compound 32. Compound 112 is analagous to compound 32a but has a 4,6-p-methoxy- benzylidine protecting group on the galactose [prepared from compound 28 using (CH 3 0) 2 CH-C 6 H 4 -p-OCH 3 ] instead of the benzylidine protecting group of compound 32a. The benzoyl groups on disaccharide 102 are removed under Zemplen conditions (NaOMe/MeOH) to provide for disaccharide 103 having free hydroxyl groups at the 2,3 positions of the galactose. Disaccharide 103 is sulfated in DMF at about -30° to -50°C using about 1.1 to 1.5 equivalents of sulfur trioxide/pyridine complex to provide for the 3-sulfated disaccharide 104 as the pyridinium salt. This product contains some 2-sulfated and some 2,3-disulfated material which can be separated by chromatography. The selectivity of the sulfating step is improved by the use of colder temperatures. Alternatively, compound 103 can be chloroacetylated under typical conditions to provide for a mixture of the 2- and 3-chloroacetyl protecting groups. This mixture can be separated by chromatography and the resulting purified components can be used to prepare 2- or 3-sulfated products selectively, or for that matter, the 2-phosphorylated and 2-OCHR 18 COOH substituents (discussed below) , both of which find utility in this invention as immunomodulating compounds. Passage of a methanol solution of the 3-sulfated disaccharide pyridinium salt, 104, through Na + ion exchange resin provided for the sodium salt, 105. Compound 105 was deblocked under conventional conditions to provide for the 3-sulfated Lewis°-OR derivative, 106, not shown. A differentially protected Lewis°-OR structure can be prepared by combining compound 5 with compound 31 under suitable conditions to provide for a fully blocked Lewis°-OR structure having a 3- chloroacetyl blocking group and a 2-benzoyl blocking group on the galactose unit. This compound can then be selectively deblocked at the 3-position of the galactose and then sulfated in the manner described above to provide for the 3-sulfated blocked structure. However, deprotection of this product may lead to the generation of by products (e.g. , the 2-NH 2 of the GlcNAc) . If necessary, these by products can be separated by chromatography. Figure 3B illustrates one method for preparing the 6-sulfate Lewis°-OR compound. Specifically, compound 107 is prepared from compound 28 by treating compound 28 with p-anizaldehyde dimethylacetal under conditions otherwise identical to the preparation of compound 29. The resulting product is benzoylated under conditions similar to those employed to prepare compound 32. This compound is then ring opened using sodium cyanoborohydride in acidic medium in tetrahydrofuran which yields the free 4-OH derivative which, in turn, is acetylated under typical conditions to provide for compound 107. Compound 107 is then converted to the 1-cc-bromo derivative using Norberg 26 conditions (bromine, tetraethylammonium bromide at 0"C in methylene chloride) to provide for compound 108. Compound 108 is then combined with compound 101 in the presence of methylene chloride, silver carbonate (about 3 equivalents) , silver triflate (about 0.1 equivalents) and molecular sieves. The reaction is conducted at about 0°C to room temperature for about 5 to about 16 hours to provide for the fully protected Lewis°-0R derivative, compound 109. The p-methoxybenzyl blocking group at the 6-position of the galactose unit is selectively removed by contacting compound 109 with dichlorodicyanoquinone (DDQ) in methylene chloride and a trace of water to provide for compound 110. Compound 110 is then sulfated at the 6-position of the galactose in DMF at about -50" to 0°C using about 1.1 to 1.5 equivalents of sulfur trioxide/pyridine complex to provide for the 6-sulfated blocked Lewis°-OR as the pyridinium salt. Passage of a methanol solution of this sulfated product through a Na* ion exchange resin provided for the sodium salt, compound 111, which upon deblocking provides for compound 121. 2C. FORMATION OF TYPE II STRUCTURES HAVING SULFATE SUBSTITUTION AT THE 3 OR 6-POSITIONS OF GALACTOSE Figure 4 illustrates one method for the preparation of intermediates useful in the preparation of 3-sulfated LacNAc-OR compounds. Specifically, in Figure 4, compound 7 and approximately 1.6-1.7 equivalents of compound 32a are dissolved in dichloromethane containing molecular sieves to which is addeα about 1 equivalent (based on compound 7) of 2,6- di-t-butyl-4-methylpyridine. The reaction is stirred for 30 minutes at room temperature and then cooled to -50°C. An anhydrous toluene solution containing approximately a slight excess (e.g., about 1.2 equivalents) of silver trifluoromethanesulfonate is then added to the solution and the reaction was allowed to warm to -15°C over 2 hours and maintained at that temperature for an additional 5 hours. After reaction completion, the reaction system was worked up to provide a crude product of compound 42. This is then purified by conventional techniques such as column chromatography using silica gel and toluene-ethyl acetate (1:1) as the eluant. The benzoyl groups on the protected LacNAc-OR 42 are removed under Zemplen conditions to provide for the LacNAc-OR derivative having free hydroxyl groups at the 2,3 positions of the galactose. This disaccharide is sulfated in DMF at about -30° to -50 β C using about 1.1 to 1.5 equivalents of sulfur trioxide/pyridine complex in the manner described above to provide for the blocked 2-hydroxy-3-sulfated LacNAc-OR as the pyridinium salt. This product contains some 2-sulfated and some 2,3-disulfated material which can be separated by chromatography. The selectivity of the sulfating step is improved by the use of colder temperatures. Alternatively,, the 2,3-dihydroxy disaccharide can be chloroacetylated under typical conditions to provide for a mixture of the 2- and 3-chloroacetyl protecting groups. This mixture can be separated by chromatography and the resulting purified components can be used to prepare 2- or 3-sulfated products selectively. Passage of a methanol solution of the 3- sulfated LacNAc-OR pyridinium salt through Na + ion exchange resin provides for the sodium salt and conventional deblocking provides for the 3-sulfated LacNAc-OR derivative. Figure 4 also illustrates a differentially blocked LacNAc-OR structure which can be used to prepare 3-sulfated structures. Specifically, compound 7 and compound 33 are combined to form compound 37. This is accomplished by dissolving compound 7 and approximately 1.5 equivalents of compound 33 in dichloromethane containing molecular sieves to which is added about 1 equivalent (based on compound 7) of 2,6-di-t-butyl-4-methylpyridine. The reaction is stirred for 30 minutes at room temperature and then cooled to -50"C. An anhydrous toluene solution containing approximately a slight excess (e.g., about 1.2 equivalents) of silver trifluoromethane sulfonate is then added to the solution and the reaction is allowed to warm to -15°C over 2 hours and maintained at that temperature for an additional 5 hours. At this time, the molecular sieves are removed by filtration by passing through celite and the recove d solution is quenched by addition to a saturated sodium bicarbonate solution. The organic extract is then washed with water, with aqueous 0.5N HCl, and then with water. The organic solution is then dried and concentrated in vacuo to provide a crude product, compound 37. This is then purified by conventional techniques such as column chromatography using silica gel and hexane-ethyl acetate (1:1) as the eluant. Compound 37 is then selectively deblocked at the 3-position of the galactose and then sulfated in the manner described above to provide for the 3- sulfated blocked structure. However, deprotection of this product may lead to the generation of by products (e.g. , the 2-NH 2 of the GlcNAc) . If necessary, these by products can be separated by chromatography. The 6-sulfate derivative of LacNAc-OR is prepared in the manner described above for the 6-sulfate of Lewiε°-OR with the exception that compounds 7 or 9 are used in place of compound 101 in this reaction. 2D. FORMATION OF TYPE I AND II STRUCTURES HAVING PHOSPHATE OR -CHR 18 COOH SUBSTITUTION AT THE 3- OR 6-POSITIONS OF GALACTOSE Blocked Lewis°-OR and blocked LacNAc-OR compounds having a 2, 3- or 6-hydroxyl group (e.g., compound 103) on the galactose unit can be can be converted to the 2-, 3-, 6-phosphate group on the galactose by reaction with diphenylphosphorochloridate and 4-dimethylaminopyridine (1:1) in pyridine at 0"C 16 . The solution is allowed to warm to room temperature over 0.5 hours and stirred for 15 hours. The resulting compound is then hydrogenated under conventional conditions (first with H 2 in EtOH with Pd on carbon for 15 hours and then with H 2 in EtOH with Pt0 2 for 3 hours) to provide for the phosphate derivative at the 2-, 3-or 6-position of galactose. Deprotection leads to the modified Lewis c -OR and LacNAc-OR compounds having a phosphate substituent at the 2-, 3-, 6-position of galactose which is purified and converted to its disodium salt by contacting a solution of this compound with a sodium form of Dowex 50 x 8. In another embodiment, blocked Lewis c -OR and blocked LacNAc-OR compounds having a 2-, 3- or 6- hydroxyl group (e.g., compound 103) on the galactose unit can then be alkylated by first adding an appropriated base (e.g., silver oxide, barium hydroxide, sodium hydride) and then adding benzyl bromoacetate (BrCH 2 COOBn) or other similar acetates (e.g., BrCHR 18 ,COOBn — where R 18 , is alkyl of from 1 to 7 carbon atoms or -COOBn) to the reaction medium in an appropriate solvent such as DMF. After reaction completion, the benzyl ester(s) is (are) readily removed by conventional hydrogenation techniques which additionally removes the other benzyl protecting groups and the benzylidine protecting group. Treatment with sodium methoxide/methanol provides for a -OCH 2 COOH (or -OCHR 18 COOH where R 18 is alkyl of from 1 to 7 carbon atoms or -COOH) substituted to the 2-, 3-, 6-position of galactose. 2E. MODIFICATION ON THE 2 AND/OR 6 POSITIONS OF GlcNAc The 2,6 positions of the GlcNAc unit can be modified prior to coupling so as to provide for Lewis c -OR and LacNAc-OR structures modified at these positions which are then further modified in the manner described above to prepare the sulfated, phosphorylated or -CHR 18 COOH derivatives. In any event, function- alization of the GlcNAc unit at the 2,6 position is generally at a point in the synthesis where the to-be formed functional group does not interfere with any of the further intended reactions. For example, if an R. functional group in GlcNAc-OR would interfere with the coupling reaction with the blocked galactose, then the functional group can either be introduced at the disaccharide level or blocked at the monosaccharide level (e.g., 2-amino groups are conventionally blocked with as the N-trifluoroacetamido or the N-phthalimido group) and later deblocked. i. Modification at the 2-position of GlcNAc Modification at the 2-position of GlcNAc can be accomplished by a variety of ways. For example, the known 8,9 2-azido-2-deoxy-glucose-OR compound (prepared, for example, by azidonitration of 4,5,6- triacetylglucal) can be protected at the 6 position with a removable protecting group (i.e., Si(C 6 H 5 ) 2 tBu) by conventional techniques 8,9 and then combined with an appropriate blocked galactose compound in the manner described above to provide for the blocked 3Gal(l→3)GlcN 3 -OR and 0Gal(l→4)GlcN 3 -OR derivatives which are readily separated by conventional techniques. At the appropriate time during εynthesis of the Lewis c -OR and LacNAc-OR structures, the azido group is reduced to an amino group which can be protected, for example, as N-trifluoroacetamido. In turn, the trifluoroacetamido group is removed at the appropriate point in the synthe is thereby unmasking the amino group. The amino group can also be derivatized by conventional methods to provide for -NR^CfOJR.,-,, -NHS0 3 H, -N=C(R 11 ) 2 , -NHCH((R 11 ) 2 , -NHR 12 , and -N(R 12 ) 2 groups. For example, the -NH 2 group can be reacted, using conventional techniques: with a carboxylic acid, anhydride or chloride to provide for amides. Alternatively, the desired acid can be activated, as reported by Inazu et al 37 and then reacted with the amino group. The carboxylic acid, anhydride, chloride, or activated acid is selected so as to provide for an R 10 group (i.e., as part of the -NR 11 C(O)R 10 substituent) which is hydrogen or alkyl of from 1 to 4 carbon atoms, with an aldehyde or ketone (of from 1 to 4 carbon atoms) at controlled pH to form an i ine [-N=C(R 11 ) 2 ] which upon reduction (e.g., with sodium cyanoboro- hydride) provideε for an alkylamine substituent [i.e., -NHCH(R 11 ) 2 ] as reported by Bernotas et al. 38 , with a cyclic carbonate such as ethylene carbonate or propylene carbonate which ring opens upon reaction with the amine to form a carbamate group having an HO-alkylene-OC(0)NH- substituent where alkylene is from 2 to 4 carbon atoms as reported by Wollenberg et al. 39 , U.S. Patent No. 4,612,132, with a chloroformate [i.e., C1C(0)0R 13 ] in the manner disclosed by Greig et al. 40 . In this case, the chloroformate has an R 13 group which is alkyl of from 1 to 4 carbon atoms, with 0=C(0-C 6 H 4 -pN0 2 ) 2 which leads to an activated intermediate which is then reacted with an amine (HNR 14 R 15 ) to provide for ureas [-NHC(O)NR U R 15 ] as described by Piekarska-Bartoszewicz et al. 41 , with trimethylamine, sulfur trioxide (S0 3 ) so as to form the -NHS0 3 H group as described by Petitou 27 , and with derivatized formic acid or other materials to form a formamide (-NH-CHO) 28 which can be further functionalized to the isocyano (-N=C=0) and reduced to the deoxy derivative by tributyltin hydride (Bu 3 SnH) 28 . Alternatively, the 2-deoxy (R 2 = H) and 2- alkoxy glucoεe derivativeε [i.e., derivatives of GlcNAc where the NAc has been replaced by -H (deoxy) or by an -OR 12 (alkoxy) ] are prepared using a εynthetic scheme similar to that recited by Trumtez et al. 28 Specifically, the known 3,4,6-triacylated 1,2-ortho ester of glucose is deacylated under conventional conditions to give the 1,2-ortho ester of glucose. This compound is then converted to the 3,4,6-tribenzyl 1,2-ortho ester of glucose using conventional techniques. The 1,2-ortho ester of the resulting compound is then opened by conventional techniques to provide a protected glycosyl donor such as the l-α-bromo-2-acetyl-3,4,6-tribenzyl derivative of glucose. This 1-α-bromo derivative is then converted to the glycoside (-OR) by conventional techniques and the 2-acetyl group is then removed. The 2-position is now ready for formation of the 2-deoxy by conventional methods such as first treating with carbon disulfide and methyl iodide in the presence of one equivalent of a base to form the -C(S)SCH 3 derivative, followed by reaction with tributyltin hydride) or for the preparation of the 2-alkoxy. The remaining protecting groups are removed so as to provide for 2-deoxyglucose glycoside or a 2-alkoxyglucose glycoside which can then be derivatized in the manner described above and illustrated in Figure 1 without the need to form the aglycon. ii. Modification at the 6-Poεition of GlcNAc As shown in Figure 6, the 6-deoxy derivative of GlcNAc-OR iε εynthesized from a known benzylidene ring blocked saccharide (8-methoxycarbonyloctyl-2- acetamido-4,6-0-benzylidene-2-deoxy-3-D-gluco- pyranoεide) 29 which is protected at the 3-hydroxy position with a removable benzoyl blocking group (Bz) by reaction with benzoic anhydride in pyridine. Further conversion of this compound by reaction with N-bromosuccinimide and barium carbonate in carbon tetrachloride (CC1 4 ) at 65°C leads to the 3,4- dibenzoyl-6-bromo-GlcNAc-OR compound. This compound is, in turn, converted to the 3,4-dibenzyl-6-deoxy- GlcNAc-OR by reaction with (C 4 H 9 ) 3 SnH in the presence of AIBN (azo bis-isobutyronitrile) at 110°C followed by treatment with methanol/sodiu methoxide. This compound can then be deprotected by conventional techniques to provide for the 6-deoxyGlcNAc-OR glycoside which can then be derivatized in the manner described above and illustrated in Figure 1 without the need to form the aglycon. The 6-azido derivatives of GlcNAc-OR can be prepared in the manner described in Figure 5. Specifically, GlcNAc-OR, compound 87, is converted to the p-methoxybenzylidine blocked compound 88 by reaction with (CH 3 0) 2 CH-C 6 H 4 -p-OCH 3 . This compound is then protected at the 3-hydroxyl position by reaction with 4-CH 3 0-C 6 H 4 -CH 2 Br to provide for compound 89 where X is 4-CH 3 0-C 6 H 4 -CH 2 -. Compound 89 is partially deprotected at the 4 and 6 positions by reaction with acetic acid (AcOH) in water at about 45°C to provide for compound 90. The 6-mesylate, compound 91, is prepared by reacting compound 90 with mesyl chloride in pyridine (MsCl/py) . The 6-azido derivative, compound 92, is then formed by reaction with sodium azide in dimethylformamide (DMF) and removal of the 3-blocking group with dichlorodicyanoquinone (DDQ) yields compound 93. The 6-mesyl compound 91 can also be derivatized to any of a number of 6-substituents including alkoxy substituents, and the like by well known chemistry. The 6-azido compound 92 can be derivatized to the 6-amino at an appropriate point in the synthesiε of the Lewis c -OR or LacNAc-OR analogues in the manner described above. The 6-amino derivative can then be further functionalized by conventional methods to provide for -NR 5 C(0)R 4 , -NHS0 3 H, -N=C(R 5 ) 2 , -NHCH(R 5 ) 2 , -NHR 6 and -N(R 6 ) 2 . For example, the -NH 2 group can be reacted, using conventional techniques, with: a carboxylic acid, anhydride or chloride to provide for amides. Alternatively, the desired acid can be activated, as reported by Inazu et al 37 and then reacted with the amino group. The carboxylic acid, anhydride, chloride, or activated acid is selected so as to provide for an R 4 group (i.e., as part of the -NR 5 C(0)R 4 substituent) which is hydrogen or alkyl of from 1 to 4 carbon atoms, with an aldehyde or ketone (of from 1 to 4 carbon atoms) at controlled pH to form an imine [-N=C(R 5 ) 2 ] which upon reduction (e.g., with sodium cyanoboro¬ hydride) provides for an alkylamine substituent [i.e., -NHCH(R 5 ) 2 ] as reported by Bernotas et al. 38 , with a cyclic carbonate such as ethylene carbonate or propylene carbonate which ring opens upon reaction with the amine to form a carbamate group having an HO-alkylene-OC(0)NH- substituent where alkylene is from 2 to 4 carbon atoms as reported by Wollenberg et al. 39 , U.S. Patent No. 4,612,132, with a chloroformate [i.e., C1C(0)0R 7 ] in the manner disclosed by Greig et al. 40 . In this case, the chloroformate has an R 7 group which is alkyl of from 1 to 4 carbon atoms, with 0=C(0-C 6 H 4 -pN0 2 ) 2 which leads to an activated intermediate which is then reacted with an amine (HN g R,) to provide for ureas [-NHC OJNR^] as described by Piekarska-Bartoszewicz et al. 41 , with trimethylamine, sulfur trioxide (S0 3 ) at pH 9.5 so as to form the -NHS0 3 H group as described by Petitou 27 , and with derivatized formic acid or other materials to form a formamide (-NH-CH0) 28 which can be further functionalized to the isocyano (-N=C=0) and reduced to the deoxy derivative by tributyltin hydride (Bu 3 SnH) 28 . The 6-alkoxy derivatives of GlcNAc can be prepared in the manner described in Figure 6. Specifically, GlcNAc-OR, compound 87, is reacted with C 6 H 5 CH(OCH 3 ) 2 in an acidic medium in acetonitrile to provide for the 4,6-diprotected benzylidine compound 94. In turn, compound 94 can be reacted with benzyl (Bn) bromide and sodium hydride in the presence of dimethylformamide at around 0°C to provide for a benzyl protecting group at the 3-position, i.e., compound 95. Deprotection at the 4,6 positions by contacting compound 95 with acetic acid and water at about 80°-90 β C provides for compound 96. Reaction of compound 96 with dibutyltin oxide [(Bu) 2 SnO] and R 6 Br provides for the 6-alkoxy compound 97. Conventional deprotection of the benzyl group with hydrogen in palladium/carbon yields compound 98. In another embodiment, compound 94 can be reacted with [C 6 H 5 C(0)] 2 0 in pyridine to provide for a benzoyl protecting group (Bz) at the 3-position, i.e., compound 99. Reaction of compound 99 with N-bromo- succinimide in carbon tetrachloride yields the 6-bromo compound 100. Compound 100 can be reacted with tributyltin hydride [(Bu) 3 SnH] in toluene to provide for the 6-deoxy compound 100b which after conventional deprotection of the benzoyl groups with εodium methoxide in methanol gives the 6-deoxy compound 100c. The 6-SR 6 compounds are prepared from the 6- mesyl derivative, compound 91, by reaction with potassium thioacetate, CH 3 C(0)S " K + , to give the thioacetate derivative at the 6-position. This derivative is then treated with mild base to produce the 6-SH derivative. The 6-SH can be reacted with an alkyl halide (e.g., CH 3 Br) to provide the -SR 6 derivatives which, in turn, can be partially or fully oxidized to the 6-sulfone or the 6-sulfoxide derivatives, -S(0)R 6 and -S(0) 2 R 6 where R 6 is alkyl of from 1 to 4 carbon atoms. Figure 7 illustrates the preparation of 3- hydroxy or 4-hydroxy blocked GlcNH 2 -0R where the amino group is protected as an N-phthalimido group. Specifically, in Figure 7, compound 13 is prepared by the methods described above. This compound is then deacetylated by conventional techniques (sodium methoxide/methanol) to provide for compound 14 which is then benzylidenated under conventional techniques to provide compound 66. Compound 66 is then treated with benzyl chloride and sodium hydride in dimethylformamide at about -20°C to 20 β C to provide for compound 67. The benzylidine group of compound 67 is then removed with 80% aqueous acetic acid at about 80 β C for about 1-4 hours to provide for compound 68. This compound is then selectively acetylated at the 6-poεition by use of approximately equimolar amounts of acetyl chloride/pyridine in dichloromethane at about -10°C to provide for compound 69. As is apparent, compound 69 is useful in preparing LacNH 2 derivatives whereas compound 66 is useful in preparing Lewis-OR derivatives. The 2- or 3-sulfate, phosphate or -OCHR 18 C00H substituted LacNAc structures can be converted to the 6-sialyl derivatives by use of the known /3Gal(1→4)jSGlcNAc α(2→6)sialyltransferase in a manner similar to that described in the exampleε herein below. The 6-sialyl derivatives of Lewis c -OR can be prepared in a manner similar to that of Ratcliffe et al. 12,23 making the appropriate modifications to the blocking groups to allow for subsequent substitution with a sulfate, phosphate or -CHR 18 COOH group at the 2- or 3- positions of galactose. C. Utility Without being limited to any theory, it is believed that the modified Lewis c -YR and LacNAc-YR compounds disclosed herein affect the cell mediated immune responεe in a number of wayε. Specifically, these compounds can inhibit the ability of the immune response to become educated about a specific antigen when the compound is administered simultaneously with the first exposure of the immune system to the antigen. Also, the modified Lewis c -YR and LacNAc-YR compounds disclosed herein can inhibit the secondary immune response to an antigen in a senεitized mammal when administered after second or later exposures of the immune system to the same antigen. Additionally, the modified Lewis 0 -YR and LacNAc-YR compounds disclosed herein can induce tolerance to antigens when administered at the time of second or later expoεures of the immune system to the antigen. Tl suppression of the inflammatory component of the seconα-_ry immune response by the modified Lewis°-YR and LacNAc-YR compounds disclosed herein requires administering such compounds after initiation of the mammal's secondary immune response but at or prior to one-half the period required for maximal antigen induced inflammation. This criticality is disclosed in U.S. Patent Application No. 07/988,518 filed concurrently herewith as Attorney Docket No. 000475-045 and entitled "TIME DEPENDENT ADMINISTRATION OF OLIGOSACCHARIDE GLYCOSIDES RELATED TO BLOOD GROUP DETERMINANTS HAVING A TYPE I OR TYPE II CORE STRUCTURE IN REDUCING INFLAMMATION IN A SENSITIZED MAMMAL ARISING FROM EXPOSURE TO AN ANTIGEN" which application is incorporated herein by reference in its entirety. In this embodiment, the modified Lewis°-OR and LacNAc-OR compounds are preferably administered to the patient at least about 0.5 hours after antigen exposure, more preferably, at least about 1 to 10 hour after antigen exposure, and still more preferably, from about at least about 1 to 5 hourε after antigen exposure. Similarly, in cell-mediated inflammatory responses arising from injuries (e.g., adult respiratory distress injury (lung injury) , administration of the Lewis°-YR and LacNAc-YR is also conducted after initiation of the immune response to this injury but at or prior to one-half the period required for maximal inflammation. The modified Lewis c -YR and LacNAc-OR glycosides disclosed herein are effective in suppressing cell-mediated immune responεeε including cell-mediated immune response to an antigen (eg. the inflammatory component of a DTH response) as well as in suppressing cell-mediated inflammatory responεeε to injury (e.g., lung injury) when adminiεtered at a dosage range of from about 0.5 mg to about 50 mg/kg of body weight, and preferably from about 0.5 to about 5 mg/kg of body weight. The specific dose employed is regulated by the particular cell-mediated immune response being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the adverse immune response, the age and general condition of the patient, and the like. The modified Lewis c -YR or LacNAc-YR analogues are generally administered parenterally, such as intranasally, intrapulmonarily, transdermally and intravenouεly, although other formε of administration are contemplated. In addition to providing suppression of a mammal's secondary immune response to an antigen, administration of the modified Lewis c -YR and LacNAc-YR compounds disclosed herein also imparts a tolerance to additional challenges from the same antigen provided that the compound is administered during the critical period discussed above. In this regard, re-challenge by the same antigen weeks after administration of the modified Lewis c -YR or LacNAc-YR compoundε reεults in a significantly reduced immune responεe. Administration of the modified Lewis c -YR and LacNAc-YR compounds disclosed herein simultaneouεly with first exposure to an antigen (i.e., a non-sensitized mammal) imparts suppression of a cell- mediated immune response to the antigen and tolerance to future challenges with that antigen. In this regard the term "reducing sensitization" means that the modified Lewis c -YR or LacNAc-YR compound, when administered to a mammal in an effective amount along with a sufficient amount of antigen to induce an immune response, reduces the ability of the immune system of the mammal to become educated and thus εensitized to the antigen administered at the same time as the modified Lewis c -YR or LacNAc-YR compound. An "effective amount" of this compound is that amount which will reduce sensitization (immunological education) of a mammal, including humans, to an antigen administered simultaneously as determined by a reduction in a cell-mediated response to the antigen such as DTH responses as teεted by the footpad challenge test. Preferably the reduction in sensitization will be at least about 20% and more preferably at least about 30% or more. Generally, modified Lewis c -YR and LacNAc-YR compounds disclosed herein are effective in reducing sensitization when administered at a dosage range of from about 0.5 mg to about 50 mg/kg of body weight, and preferably from about 0.5 mg to about 5 mg/kg of body weight. The specific dose employed is regulated by the sensitization being treated as well aε the judgement of the attending clinician depending upon the age and general condition of the patient and the like. "Simultaneouε" adminiεtration of the compound with the antigen with regard to inhibiting sensitization means that the compound is administered once or continuously throughout a period of time within 3 hours of the administration of an antigen, more preferably the compound is administered within 1 hour of the antigen. The methods of this invention are generally achieved by use of a pharmaceutical composition suitable for use in the parenteral administration of an effective amount of a Lewis c -YR or a LacNAc-YR compound. These compositions comprise a pharmaceutically inert carrier εuch as water, buffered saline, etc and an effective amount of a modified Lewiε c -YR or LacNAc-YR compound εo as to provide the above-noted dosage of these compounds when administered to a patient. It is contemplated that suitable pharmaceutical compositionε can additionally contain optional components such as a preservative, etc It is also contemplated that other suitable pharmaceutical compositions can include oral compositions, transdermal compositions or bandages etc. , which are well known in the art. It is also contemplated that mixtures of these compounds can be used. The following examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. Unless otherwise stated, all temperatures are in degrees Celsius. Also, in these examples, unless otherwise defined below,- the abbreviationε employed have their generally accepted meaning: AG 1 X 8 (formate form) = ion exchange resin AG 1 x 8 (formate form) available from Bio-Rad Laboratories, Richmond, CA Dowex 50W X 8 (H + form) = ion exchange resin Dowex 50 X 8 (H + form) available from Dow Chemical, Midland, MI IR-120 resin (H + form) = amberlite resin available from Rohm & Haas, Philadelphia, PA IR-C50 resin (H * form) = ion exchange resin IR-C50 (H + form) available from Rohm & Haas, Philadelphia, PA Commercially available components are listed by manufacturer and where appropriate, the order number. Some of the recited manufacturers are as follows: Merck = E. Merck AG, Darmstadt, Germany Millipore = Millipore Corp., Bedford, MA. Waters = Waters Aεsαciates, Inc., Milford, MA. The following exampleε are divided into two parts. The first part (part I) relates to the synthetic procedures to make the recited compounds whereas the second part (part II) relates to the biological results. Part I — Synthetic Procedures Examples 1-18 illustrate syntheses of the deεcribed compounds. EXAMPLE 1 — Synthesis of Benzyl-2-0-benzoyl-4,6-0- benzylidene-3-O-chloroacetyl-β-D- thiogalactopyranoside (compound 31) Dry a 20 L stirred reactor equipped with reflux condenser, heating mantle and 1 L addition funnel. Charge to this reactor 10 L of dichloroethane. Begin to stir the reactor then charge 1 kg D-galactose and 500 g anhydrous sodium acetate to the dichloroethane. Heat this slurry to reflux. Add dropwise 4 L of acetic anhydride to the reaction mixture using the 1 L addition funnel on the reactor. Reflux is to be maintained during the 2-4 hour addition period. Continue to stir and heat the mixture at reflux overnight. When the reaction is complete as determined by t.l.c, turn off the heat to the reactor and add 250 L of water in slow dropwise fashion using the addition funnel. This reaction is quite vigorous but is controlled by slowing the addition of the water. Stir the reaction for 1-2 hours. Charge 30 L of cold water to a 50 L stirred reactor and begin stirring. Drain the contents of the 20 L reactor into a 20 L polyethylene pail and pour into the stirring ice water in the 50 L reactor. Stir this mixture for twenty minuteε. Drain the lower organic layer into a 20 L polyethylene pail. Extract the aqueouε layer in the 50 L reactor with an additional 5 L of dichloromethane. Combine the dichloromethane extract with the firεt organic layer. Drain the aqueouε layer to polyethylene pailε and diεcard as aqueous waste. Return the combined organic layers to the 50 L reactor and extract twice with 5 L portions of ice wat¬ er for 10 minutes. Drain the organic layer to a clean 20 L polyethylene pail. Drain the aqueous to waste, return the organic layer to the 50 L reactor, stir and add 1 kg of anhydrous sodium sulfate. Stir for 1-2 hours and then drain the solution into a clean 20 L polyethylene pail and filter the solution using a 4 L vacuum filtration set [or large Buchner attached to a collector] . Concentrate the filtrate to 8 L then transfer into a clean 20 L reactor equipped with stirrer, 1 L addition funnel and cooling bath. Additional solvent can be added if the level of the solution is below the thermowell. Cool the organic solution to 0°C using a cooling bath. Charge to this cool solution 724 g of benzyl mercaptan. Add a total of 1.1 L of colorless boron trifluoride etherate in slow dropwise fashion over 2 hours using the 1 L addition funnel. Stir the reaction 3-4 hours after the addition is complete maintaining the temperature at 0"C. The reaction is checked for completion by t.l.c. on silica gel. [The reaction can be left to sit overnight] . The reaction mixture is drained into a clean 20 L polyethylene pail. The 50 L reactor is charged with 15 L of saturated εodiu carbonate solution. The 20 L polyethylene pail is slowly transferred into the slowly stirring carbonate solution at such a rate that the gas evolution is not overly vigorous. Stir the solution for 20 minutes then increase the rate of stirring. When gas evolution ceaseε bubble air through the entire εolution for 24-36 hours. Drain the organic layer into a clean 20 L polyethylene pail and store in a hood. Extract the sodium carbonate solution with 3-5 L of dichloromethane and drain thiε solution into the same 20 L polyethylene pail. Once the smell has been reduced the organic εolution can be filtered using a 4 L vacuum filtration set and the filtrate evaporated under reduced preεsure on the 20 L rotovap. 7 L of methanol is introduced into the rotavap flask and the residue heated with the rotavap bath till the residue disεolves in the warm methanol. The flask is rotated and allowed to cool. Cool ice water is added to the rotavap bath and the flask slowly rotated for several hours. The flask is removed from the rotovap and the white crystalline product filtered uεing a 4 L vacuum filtration set. The benzyl 2,3,4,6-tetra-O-acetyl-β-D- thiogalactopyranoside (-1.3 kg) is charged into a clean dry 20 L reactor with stirring motor and 7 L of dry methanol is added to disεolve the material. The εolution iε treated with 3 g of freshly surfaced sodium and stirred for two hours. The reaction is checked by t.l.c on silica gel using a retained sample of the benzyl 2,3,4,6-tetra-O-acetyl-β-D-thiogalactopyranoside with 80:20 ethyl acetate: methanol (v/v) the eluant. The absence of starting material indicates the reaction is complete. 50 g of fresh methanol washed H* ion exchange resin is added, the reaction stirred for 15 minutes. The pH is checked using pH paper to ensure a neutral solution. The resin is filtered off under reduced preεsure and the methanol is removed under reduced pressure using the 20L rotovap. To the residue, 5 L of acetone is added to the 20 L flask and the solution warmed to reflux. The residue dissolveε and is allowed to cool to room temperature at which time ice is added to the bath, the solution rotated with cooling overnight. 800-900g of benzyl β-D- thiogalactopyranoεide crystallizes and is filtered and dried under vacuum. To 8 L of dry aoetonitrile is added 800 g of benzyl β-D-galactopyranose, 600 g of benzaldehyde dimethyl acetal and 2-5 g of p-tolueneεulphonic acid. The solution is εtirred at room temperature overnight. The reaction progreεε is checked fc t.l.c. When complete, the reaction is brought to pH 7 by the addition of triethylamine. The volume of acetonitrile is reduced to a minimum, 7 L of isopropanol is added and the mixture is heated to near reflux. Most of the product goes into the hot isopropanol after warming for several hours. The mixture is cooled and ice added to the bath and cooling continued overnight to give a precipitate. After filtering and drying the precipitate, 760 g of benzyl-4,6-0-benzylidene-β-D- thiogalactopyranoside is obtained. 180 g of benzyl-4,6-O-benzylidene-β-D- thiogalactopyranoεide was disεolved in dry DMF and placed in a jacketed reactor. The reactor was cooled uεing a recirculating cooling bath maintained at a temperature of -25°C and treated dropwiεe with 108 g of chloroacetyl chloride over 3 hourε while stirring the reaction mixture. - Stirring was continued 24 hours at this temperature then the reaction was quenched into several volumes of cold bicarbonate solution. The product was extracted into methylene chloride, water waεhed εeveral times, dried over sodium sulphate and evaporated to drynesε. The product waε cryεtallized from isopropanol. Yield: 125 g of benzyl 4,6-0- benzylidene-3-O-chloroacetyl-β-D-thiogalacto- pyranoside. 5 g Benzyl 4,6-0-benzylidene-3-0-chloroacetyl-β-D- thiogalactopyranoεide waε benzoylated at room temperature in methylene chloride/pyridine uεing 3 equivalentε of benzoyl chloride and a catalytic amount of dimethylaminopyridine. The εolution iε quenched into cold εodiu bicarbonate εolution, the organic layer is washed with saturated copper εulphate solution to remove the pyridine the organic layer dried and evaporated. The residue is taken up in hot isopropanol and benzyl 4,6-0-benzylidene-2-0-benzoyl-3-0- chloroacetyl-β-D-thiogalactopyranoεide cryεtallizes from solution. 1 H-n.m.r. (CDC1 3 ) : δ = 7.96, 7.4 (2m, 15H, aromatic, 5.79 (t, IH, H-2) , 5.5 (s, IH, CH) , 5.2 (q, IH, H-4, J 23 9.9 Hz, J 34 3.3 Hz), 4.5 ( , 2H) , 4.4 (d, IH) , 3.99 (m, 5H) , 3.55 (ε, IH) . Example 2 — Synthesis of 4,6-0-benzylidene-2,3-di-0- benzoyl-β-D-galactopyranoεyl bromide (compound 32A) Benzyl-4,6-0-benzylidene-3-D-thiogalacto- pyranoside (10 g) was dissolved in 100 mL dichloromethane and 6.35 g of pyridine was added. To the solution was added 9 g of benzoyl chloride in dropwise fashion and after 1 hour, 50 mg of dimethylaminopyridine was added to the solution and the mixture waε stirred for. an addition 2 to 4 hourε. The progreεε of the reaction waε checked by t.l.c on silica gel. Benzyl-4,6-0-benzylidene-2,3-di-0-benzoyl- 0-D-thiogalactopyranoside (compound 32) was iεolated by quenching the reaction mixture into εaturated sodium bicarbonate solution and washing the organic extract with water, 5% copper sulfate solution, water, drying and evaporating the solvent. The reεidue was crystallized from isopropanol to give 10.7 g of compound 32. Compound 32, benzyl-4,6-0-benzylidene-2,3-di-0- benzoyl-β-D-thiogalactopyranoεide (9.89 g) , waε dissolved in 100 L of dichloromethane, cooled to 0°C, and treated with a solution of bromine (2.85 g) in 10 mL of dichloromethane. After 15 minutes, 1.8 grams of tetraethylammonium bromide was added to the mixture and the mixture stirred for 2-3 hours at room temperature (followed by t.l.c. on silica gel). A εmall quantity of cyclohexane waε added to quench excess bromine and the reaction mixture was quenched into cold saturate sodium bicarbonate solution, washed with water, dried and volume of the solution reduced to 30 mL. This dichloromethane solution of compound 32a was used directly in the synthesis of compound 42 without further isolation and/or purification. Example 3 — Synthesis of 8-methoxycarbonyloctyl-2- acetamido-4,6-di-0-benzylidene-2-deoxy- β-D-glucopyranoεide (Compound 5) A 20L glass reactor waε charged with 8 L of dichloroethane, 1 L of acetic anhydride and 1 kg of anhydrouε εodium acetate. To the εtirring mixture was added 1 kg of glucosamine hydrochloride and the mixture was brought to reflux. A further 3.5 L of acetic anhydride was added dropwise to the refluxing εolution over 3-4 hourε and the εolution maintained at reflux for 36 hours. During the last hour of reflux 200 mL of water was added dropwise to the solution. The reaction was then cooled and added to 35 L of ice water in a 50 L stirred reactor. The organic layer was removed and then water washed a second time with an additional 20 L of water. The organic layer was dried over sodium sulphate, filtered, and saturated with anhydrous gaseous HCl for 2 hourε. The reaction was allowed to sit for 6 days being saturated with HCl for 1 hour every second day. 2-acetamido-2-deoxy-3,4,6-tri-0- acetyl-β-D-glucopyranoεyl chloride waε iεolated by quenching into ice cold sodium bicarbonate solution. The organic layer was dried over sodium sulphate and evaporated to a brown solid. Four hundred grams of 2-acetamido-2-deoxy-3,4,6- tri-O-acetyl-β-D-glucopyranoεyl chloride waε dissolved in 2 L of anhydrous dichloromethane containing 200 g of activated molecular sieves. 266 g of 8- methoxycarbonyloctanol was charged to the reaction mixture along with 317 g of mercuric cyanide. The solution was stirred rapidly at room temperature for 24 hours. After checking for reaction completion by t.l.c the reaction mixture was filtered through a buchner funnel of silica and the organic layer washed twice with water, twice with a 5% solution of potasεium iodide and twice with a saturated solution of sodium bicarbonate. The solution was dried over sodium sulphate and evaporated to dryness. The residue was taken up in anhydrouε methanol and treated with 1 g of freshly cut sodium then stirred at room temperature overnight. The solution of 8-methoxycarbonyloctyl 2- acetamido-2-deoxy-β-D-glucopyranoεide was neutralized with acid ion exchange resin and filtered and evaporated to yield 218 g of product after crystallization from isopropanol /diisopropyl ether. Two hundred grams of 8-methoxycarbonyloctyl 2- acetamido-2-deoxy-β-D-glucopyranoεide was disεolved in 1.2 L of anhydrous dimethylformamide and treated with 169 mL of dimethoxytoluene (benzylaldehyde dimethyl acetal) and 1-2 g of p-toluenesulphonic acid. The reaction waε εtirred and heated to 40°C for 5 hourε, then checked for completion by t.l.c. When the reaction appears complete the mixture was neutralized with triethylamine and quenched into several volumes of ice water, extracted into dichloromethane and backwashed several times with water. The organic layer was dried over sodium sulphate, evaporated to dryness and taken up in hot isopropanol. After cooling 8- methoxycarbonyloctyl-2-acetamido-4,6-0-benzylidene-2- deoxy-β-D-glucopyranoεide precipitates. It is filtered and dried to yield 106 g of product. 1 H-n.m.r. (CDC1 3 ) : δ = 7.41 (m,5H, aromatic), 6.11 (d, IH, NH) , 5 . 5 ( ε , IH , CH) , 4 . 63 (d , IH , H-l , J- 2 7 . 4 Hz ) , 2 . 29 (t , 2H) , 1 . 99 ( s , 3H , Ac) , 1. 58 (m , 4H) , 1. 29 (bs , 8H) Example 4 — Synthesiε of 8-Methoxycarbonyloctyl 2- acetamido-3-0-p-methoxybenzyl-4,6-0- benzylidene-β-D-glucopyranoεide (compound 6) . To a εtirred εolution of compound 5 (17.5 g, ~3 mmol) in dry dichloromethane (100 mL) and catalytic amount of p-toluenesulfonic acid (0.25 to 3 weight percent based on compound 5) was added dropwise a solution of p-methoxybenzyl trichloroacetimide (10 g in 25 mL CH 2 C1 2 ) . The reaction mixture was stirred at room temperature overnight. Triethylamine was added to quench the reaction, the organic layer was washed with sodium bicarbonate solution and the organic layer dried and evaporated to dryne ' ss, Crystallization in hot ethanol gave 20 g of the deεired product. 1 H-n.m.r. (CDC1 3 ) : <5 7.56-6.90 (m, 9H, aromatic), 5.60 (d, IH, NH) , 5.30 (s, IH, PhCH) , 4.94 (d, IH, J 12 8.0Hz, H-l), 3.80 (s, 3H, CH 3 ) , 3.60 (s, 3H, CH 3 Ph) , 2.30 (t, 2H, CH 2 C0) , 1.90 (S, 3H, AcNH) , 1.80-1.10 (m, 12H, (CH 2 ) 6 ). Example 5 — Synthesiε of 8-Methoxycarbonyloctyl 2- acetamido-2-deoxy-3-0-p-methoxybenzyl-6- O-benzyl-2-β-D-glucopyranoεide (compound 7) To a stirred solution of compound 6 (15.0 g, ~3 mmol) in 200 mL of dry THF were added, 11.0 g of sodium cyanoborohydride, 10 g of molecular sieves 4λ and 5 mg of methyl orange. The solution was cooled to -10°C and then ethereal hydrochloric acid was added dropwise until the solution remained acidic. On completion of the reaction, it was diluted with dichloromethane (200 mL) , filtered through celite and washed successively with aqueous sodium bicarbonate (2 x 100 mL) and water (2 x 100 mL) and then the εolvent dried and evaporated to give a εyrup. Purification of the mixture on column chromatography uεing silica gel as adsorbent and eluting with hexane:ethyl acetate:ethanol (20:10:1) gave 7 in 70% yield. 1 H-n.m.r. (CDC1 3 ) : 5 7.40-6.90(m, 9H, aromatic), 5.70(d, IH, NH) , 4.64(d, IH, J 12 8.0Hz, H-l), 3.86(S, 3H, CH 3 0) , 3.68(s, 3H, CH 3 0Ph) , 2.30(t, 2H, CH 2 C0) , 1.90(ε, 3H, NHAc) , 1.80-1.10(m, 12H, (CH 2 ) 6 ). Example 6 — Syntheεis of 8-Methoxycarbonyloctyl 2- acetamido-2-deoxy-3-0-p-methoxybenzyl-4- O-(4,6-0-benzylidene-2,3-O-dibenzoyl-β- D-galactopyranosyl)-6-0-benzyl-2-deoxy- β-D-glucopyranoside (compound 42) A solution of compound 7 (10.61 g, 19.7 mmol) and compound 32A (1.6-1.7 equivalents based on compound 7) and 2,6-di-t-butyl-4-methyl pyridine (3.11 g, 15.2 mmol) in 250 L of dichloromethane and 40 g of molecular sieves (4A) was stirred at room temperature for 30 minutes, and then cooled to -50°C under nitrogen. A dry solution of silver triflate (4.47 g, 17.3 mmol) in toluene (40 mL) was added to the stirred mixture. The mixture was warmed to -15°C during two hours and kept at -15°C for an additional 5 hourε. At the end of which the mixture waε warmed to room temperature and stirred overnight. 3 L of pyridine and 250 mL of dichloromethane were added to the mixture and was filtered over celite, filtrate waε washed with saturated aqueous sodium hydrogen carbonate (200 mL) and then with water (200 mL) , aqueous hydrogen chloride (0.5N, 200 mL) and water (200 mL) , concentrated in vacuo. 6.0 g of compound 8 was crystallized as white crystalε from ethyl acetate-diethyl ether-hexane. The mother liquor was concentrated, purified over chromatography (300 g silica gel, toluene:ethyl acetate, (1:1) to give 4.5 g pure compound 42. Total yield was 10.5 g (68%). Rf 0.48 (methanol:dichloromethane, 4:96). 1 H-n.m.r. (CDC1 3 ) : δ 5.80(t, IH, J 2 . 3 - 11.0Hz, H-2'), 5.52(s, IH, CHPh) , 5.25(dd, IH, J 34 4.0Hz, H-3 ' ) , 4.88(d, IH, J r<2 . 11.0Hz, H-l'), 4.70(d, IH, J 1 2 9.0HZ, H-l), 3.78(s, 2H, CH 3 0) , 3.64(S, 3H, CH 3 OPh) . Example 7 — Synthesiε of 2-0-benzoyl-4 , 6-0- benzylidene-3-O-chloroacetyl- -D- galactopyranoεyl bromide (compound 33) Compound 32, benzyl 4, 6-0-benzylidene-2-0-benzoyl- 3-chloroacetyl-/3-D-thiogalactopyranoεide (8.87 g) was disεolved in 100 mL of -dichloromethane, cooled to 0°C and treated with a solution of bromine (2.7 g) in 10 mL of dichloromethane. After 15 minutes, 1.7 g of tetraethylammonium bromide was added to the mixture and the mixture stirred for 2 to 3 hours at room temperature (followed by t.l.c on silica gel). A small quantity of cyclohexene was added to quench excesε bromine and the reaction mixture waε quenched into cold εaturate sodium bicarbonate solution, washed with water, dried, and the volume of the solution reduced to 30 L so as to provide a dichloromethane solution of compound 33. This solution was uεed directly in the synthesis of compound 37. Example 8 — Syntheεiε of 8-methoxycarbonyloctyl 2- acetamido-4-O-(2*-O-benzoyl-4• ,6'-O- benzylidene-3 ' -O-chloroacetyl-β-D- galactopyranosyl)-6-0-benzyl-2-deoxy-3- O-p-methoxybenzyl-β-D-gluco-pyranoside (compound 37) A solution of the compound 7 (5.0 g, 0.9 mmol) and compound 33 (1.4 to 1.5 equivalents — from example 7) and 2,6-di-t-butyl-4-methyl pyridine (1.78 g, 1.0 mmol) in 50 mL of dichloromethane and 20 g of molecular sieves (4A) was stirred at room temperature for 30 minutes, and then cooled to -50°C under nitrogen. A dry solution of silver triflate (3.3 g, 1.5 mL) in toluene (10 mL) was added to the stirred mixture. The mixture was warmed to -15°C over two hours and kept at -15°C for an additional 5 hourε, then allowed to warm to room temperature and εtirred overnight. 1 mL of pyridine and 100 mL of dichloromethane were added to the mixture and it waε filtered over celite, the filtrate waε washed with aqueous sodium bicarbonate (100 mL) and then with water (100 mL) , aqueous hydrogen chloride (0.5 N, 100 mL) and water (100 mL) , then concentrated in vacuo. Purification of the crude mixture on column chromatography with silica gel as adsorbent eluted with hexane:ethyl acetate (1:1) gave 5.2 g of pure compound 37. 1 H-n.m.r. (CDC1 3 ) : δ 5.85(d, lh, NH) , 5.62(t, IH, J 2 - 3 - 10.8Hz, H-2 ' ) , 5.52(ε, lH-CH-benzylidene) , 5.08 (dd, IH, J 3 - 4 . 4Hz, H-3'), 4.85 (d, IH, J r 2 - 11.0Hz, H-l ' ), 4.68 (d, IH, J, 2 9.0Hz, H-l), 3.72 and 3.64 (2ε, 6H, OCH 3 and COOCH 3 ) ; 13 C-n.m.r.: 159.0(aromatic c-p-methoxyl) 165.15(c=0, chloroacetyl) , 167.12(c-0, acetyl) , 174.2(c=0, COOCH 3 ) , 99.64(c-l), 100.26(c-1 ' ) , 101.0(PhCH) . Example 9 — Synthesis of 2-deoxy-2-phthalimido- 1,3,4,6-tetra-0-acetyl-3-D- glucopyranoεide (compound 1) (D+) Glucoεamine hydrochloride (100 g, 0.46 mol) waε added to a solution of sodium methoxide in methanol which was prepared from equimolar amount of sodium metal in methanol (0.5 L) . The resultant mixture was treated with equimolar equivalent of phthalic anhydride and triethylamine (80 mL) . The mixture was then stirred for 2 hours, filtered and the solid was dried in vacuum for 12 hours. The dry solid was dissolved in pyridine (300 mL) and treated with acetic anhydride (200 mL, 2.1 mol). The mixture was stirred at room temperature for 48 hours and then quenched in an ice- water mixture, and the resultant precipitate was filtered, concentrated and crystallized from diethylether to 98.3 g (45%) of the title compound. 1 H-n.m.r. (CDC1 3 ) : δ 7.75 (m, 4h, aromatic), 6.45 (d, IH, H-l, J 12 9.0Hz), 5.85 (t, IH) , 5.15 (t, IH) , 4.4 (t, IH) , 4.3 (q, IH) , 4.1 (q, IH) , 4.00 (m, IH) , 2.05, 2.00, 1.95, 1.80 (4s, 12H, 4Ac) . 13 C-n.m.r. (CDC1 3 ) δ 89.7 (C-l) , 72.6, 70.5, 68.3 (3C, C-3, C-4, C-5) , 61.45 (C-6) , 53.42 (C-2) . Example 10 — Synthesis of 2-deoxy-2-phthalamido- 3,4,6-tri-0-acetyl-9-D-glucopyranoεyl bromide (compound 12) 2-deoxy-2-phthalamido-l,3,4,6-tetra-0- acetyl-3-D-glucopyranoside 1 (20g, 41.9mmol) was treated with hydrogen bromide solution in acetic acid (30%, 200mL) and εtirred at room temperature for 2 hrε. The mixture waε then poured into an ice water mixture and extracted with dicloro ethane. The extract waε washed with NaHC0 3 solution and water followed by MgS0 4 drying. The mixture iε filtered, dried and concentrated in vacuo to give compound 12 as a dry syrup (compound 12) Example 11 — Synthesis of Ethyl 2-deoxy-2- phthalimido-3,4,6-tri-O-acetyl-β-D- glucopyranoside (compound 13) 2-Deoxy-2-phthalamido-3,4,6-tri-0-acetyl-,9-D- glucopyranosyl bromide (compound 12) from example 16 was taken up in dry ethanol and treated directly with dry ethanol (200 mL) , mercuric cyanide (13.7 g. 55 mmol) and stirred at room temperature for 48 hr. The mixture was then filtered and concentrated. The residue was taken up in 200 L of dichloromethane and waεi-.ed with a εolution of 10% potaεεium iodide, 5% sodium bicarbonate, water, dried over MgS0 4 and concentrated to a syrup. Example 12 — Synthesis of Ethyl 2-deoxy-2- phthalimido-β-D-glucopyranoεide (Compound 14) Ethyl 2-deoxy-2-phthalamido-3,4,6-tri-0-acetyl-/3- D-glucopyranoεyide (compound 13) from example 17 waε taken up in 100 mL of dry methanol and treated with 100 mg of εodium metal. The εolution waε εtirred at room temperature for 24 hourε and then neutralized with Ambe lite [R-120(H+) ] reεin, filtered, and evaporated to dryneεε in vacuo. This compound was uεed in the preparation of compound 15 and compound 66. Example 13 — Synthesis of Ethyl 2-deoxy-2- phthalimido-6-O-benzyl-β-D- glucopyranoεide (Compound 15) Compound 14 (2.1 g, 6.23 mmol) was taken up in 100 mL of toluene. To it was added bis(tributyl tin) oxide (2.22 mL, 4.35 mmol) and tetrabutylammonium bromide (0.983 g, 3.05 mmol). The mixture was heated at 150°C for 4 hours and then toluene (50 mL) was distilled off from the mixture. The reaction mixture was cooled to room temperature and benzyl bromide (2.17 -mL, 18.27 mmol) waε added and the reaction heated to 110°C for 36 hourε. Toluene was evaporated and the residue taken up in ethyl acetate (22 mL) , washed succesεively with aqueouε εodium bicarbonate, saturated sodium chloride solution and water. The organic layer was dried and evaporated to drynesε to give a crude solid. Purification by column chromatography on silica gel gave a crystalline solid 15 (1.4 g, 70%). 1 H- n.m.r. (CDC1 3 ) δ 7.3-8.1 (9H, aromatic), 4.5 (dd, 2H, CH 2 Ph) , 5.18 (d, IH, J 12 10.0Hz, H-l), 4.36 (dd, IH, H-3), 4.25 (dd, H, J 2(1 10.0Hz, J 23 8.0Hz, H-2) and 1.0(t, 3H, CH 3 ) . Example 14 — Syntheεis of Ethyl 2-acetamido-6-0- acetyl-3-0-benzyl-2-deoxy-β-D- glucopyranoside A solution of compound 90 (described below-2 g, 4.68 mmol) in aqueous acetic acid (80%, 150 mL) was heated at 80°C for 2 hourε. The mixture then was evaporated and the resultant solid was dried over P 2 0 5 in high vacuum. The dry solid was selectively acetylated with acetyl chloride (0.33 mL, 4.7 mmol) and pyridine (10 L) in dichloromethane (100 mL) at " 10°C to 5°C. The mixture waε then diluted with dichloromethane (50 mL) , washed with aqueous NaHC0 3 , dried over MgS0 4 and evaporated. The residue was chromatographed on a silica gel column using EToAc: hexaneε, 3:1 (v:v) as eluant to give 0.82 g (46%) of the title compound: ^-n.m.r. (300 MHz, CDC1 3 ) <57.3(m, 5H, aromatic), 5.67(bs, IH, NH) , 4.86(d, IH, H-l), 4.75(m, 2H) , 4.48(q, IH) , 4.27(d, IH) , 4.1(t, IH) , 3.85(m, IH) , 3.5(m, 3H) , 3.16(m, IH) , 2.70(bs, IH, OH), 2.1(s, 3H, AC), 1.9(s, 3H, Ac), 1.18(t, 3H, CH 3 ) , 13 C-n.m.r. (CDC1 3 ) : δ 99.45(C-1), 79.85, 74.5(CH 2 ph) , 73.7, 71.09, 65.25 (C-6) , 63.36(CH 2 -), 57.7(C-2), 23.6(AC) , 20.86(Ac), 15.06(CH 3 ) . Example 15 — Synthesis of Ethyl 6-0-acetyl-3-0- benzyl-2-deoxy-2-phthalimido-β-D- glucopyranoεide (compound 69) A εolution of ethyl 2-deoxy-2-phthalimido-j8-D- glucopyranoside (compound 14) from Example 12 was taken up in dry aoetonitrile (100 mL) and treated with benzaldehyde dimethylacetal (9.6 g) and a catalytic amount of p-toluenesulphonic acid (100 mg) . The mixture was stirred for 17 hours at room temperature and then neutralized to pH 7 with triethylamine. The mixture was evaporated and crystallized from hot hexanes to give 12.7 grams of ethyl 4,6-O-benzylidene- 2-deoxy-2-phthalimido-β-D-glucopyranoεide compound 66. Compound 66 (10 g) was dissolved in dry dimethylformamide (DMF) at -5°C and treated with 1.1 g (46.6 mol) sodium hydride and benzyl bromide (5.46 mL, 22 mmol) . The mixture was stirred at 0°C for 2 hours and then treated slowly with 20 mL methanol then slowly brought to room temperature and treated with HCl (IN) to pH 7 and then extracted three timeε with dichloromethane. The organic layer waε dried over anhydrouε magneεium sulfate then filtered, concentrated to drynesε and taken up in hot ethanol to give 7.2 g of compound 67. Compound 67 (5.43 g, 10.50 mmol) in aqueous acetic acid (80%, 200 mL) was heated at 80°C for 2 hourε. The mixture was evaporated and the resultant solid waε dried over P 2 0 5 in high vacuum. The dry solid was εelectively acetylated with acetyl chloride (0.8 mL, 11.0 mmol) and pyridine (10 mL) in dichloromethane (200 mL) at -10°C to 0 β C. The mixture waε then diluted with dichloromethane (1 0 mL) , washed with aqueous NaHC0 3 , dried over MgS0 4 and evaporated. The residue was chromatographed on a silica gel column using EtOAc:hexane, 1:2 (v:v) as eluant to give 3.5 g (71%) of the compound 69: 1 H-n.m.r. (300 MHz, CDC1 3 ) : <S 7.7 (m, 4H, aromatic), 7.0(m, 5H, aromatic) , 5.16(d, IH, H-l), 4.7(d, IH) , 4.5(m, 2H) , 4.2(m, 3H) , 3.8(m, IH) , 3.6(m, 2H) , 3.45(m, IH) , 2.9(bs, IH, OH), 2.1(s, 3H, Ac), 1.95(t, 3H, CH 3 ) . 13 C-n.m.r. (CDC1 3 ) : δ 98.09(C-1), 78.45, 74-.5, 73.9, 71.7, 65.1, 63.1, 55.5, 20.87 (Ac), 14.92 (CH 3 ) . Example 16 — Syntheεis of Ethyl 6-0-acetyl-3-benzyl- 2-deoxy-2-phthalimido-4-0-(2, 3,4,6- tetra-O-acetyl-β-D-galactosyl) -β-D- glucopyranoεide (compound 70) To a εtirred solution of compound 9 (80 mg, 0.17 mmol) in dichloromethane (10 mL) containing molecular sieveε (3A°, 1 g) , 2,6-di-tert-butyl-4-methyl-pyridine (45 mg, 0.22 mmol) and εilver triflate (57 mg, 0.22 mmol) waε added, at " 30"C under nitrogen, 2,3,4,6- tetra-O-acetyl-Cϋ-D-galactosyl bromide in dichloromethane (5 L) . The mixture was stirred at this temperature for 1 h and then warmed up to 5°C over 2h. The mixture waε then diluted with dichloromethane (10 mL) , filtered and the inεoluble material waε waεhed with dichloromethane (5 mL) . The combined filtrates were waεhed with saturated aqueous sodium hydrogen carbonate and water, dried over MgS0 4 , and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate: hexanes, 1:2 (v:v) as eluant to give 120 mg (80%) of the title compound: 1 H-n.m.r. (300 MHz, CDC1 3 ) : δ 7.68, 6.96(2m, 9H, aromatic), 5.3(m, 2H) , 5.13(d, IH, H-l ' , J r 2 - 8.0HZ), 4.99(q, IH) , 4.82(d, IH) , 4.62(d, IH, H-l, J 12 7.7Hz), 4.54(d, IH) , 4.42(d, IH) , 4.3(q, IH) , 4.15(m ,2H), 3.99(m, 2H) , 3.87(m, 2H) , 3.72(m, 2H) , 3.46(m, lh) , 2.15, 2.12, 2.09, 2.00, 1.98(5s, 15H, 5XAc) , 1.00(t, 3H, CH 3 ) . 13 C-n.m.r. (CDC1 3 ) : δ 101.2, 97.8(C-1, C-l ' ) , 14.85(CH 3 ) . In the following examples, unless indicated otherwise, R = -(CH 2 ) 8 C0 2 CH 3 Example 17 — Synthesis of 8-Methoxycarbonyloctyl 3-0- (4,6-0-benzylidene-3-0-sulfo-3-D- galactopyranoεyl)-2-acetamido-4,6-0- benzylidene-2-deoxy-3-D-glucopyranoεide (compound 105) The title compound was prepared by first generating 8-methoxycarbonyloctyl 3-0-(2,3-di-0- benzoyl-4,6-0-benzylidene- / S-D-galactopyrnosyl)-2- acetamido-4,6-O-benzylidene-2-deoxy-0-D-glucopyranoside which, in turn, was generated by coupling the 8- methoxycarbonyloctyl 2-acetamido-4,6-0-benzylidene-2- deoxy-3-D-glucopyranoεide and compound 32, the εyntheεiε of which is exemplified in example 2 above. The 8-methoxycarbonyloctyl 2-acetamido-4,6-0- benzylidene-2-deoxy-)3-D-glucopyranoside can be prepared by reacting N-acetylglucosamine-OR (e.g., compound 4 in Figure 1) with about 1.5 equivalentε of C 6 H 5 CH(OCH 3 ) 2 in an acidic (p-toluene εulfonic acid) aoetonitrile or dimethylformamide (DMF) medium at from about 0° to about 50°C over 6-48 hours to provide for the 4,6-0- protected benzylidine compound. Coupling of compound 32 with the 8-methoxycarbonyloctyl 2-acetamido-4,6-0-benzylidine-2- deoxy-3-D-glucopyranoεide ("compound A") can be achieved by first combining about 1 equivalent of N- iodosuccinimide with about 1 equivalent of trifluoromethanesulfonic acid in methylene chloride containing molecular sieves which remove any water present. The reaction mixture is cooled to -50"C and then compound A is added followed by the addition of approximately, 1 to 1.1 equivalents of compound 32 (based on compound A) . When large amounts of trifluoromethanesulfonic acid are employed, the reaction is preferably cooled to -50°C prior to the addition of the trifluoromethanesulfonic acid. The reaction is allowed to equilibrate to about -20° to 0°C over about 1-3 hourε. The reaction solution is then quenched by cooling to -50° followed by the addition of triethylamine until neutral pH is reached. The solution iε filtered through Celite and then washed with a saturated sodium bicarbonate solution and water. The organic layer was dried and εtripped in vacuo to provide for 8-methoxycarbonyloctyl 3-0-(2,3-di-0-benzoyl-4,6-0-benzylidene-3-D- galactopyranoεyl)-2-acetamido-4,6-0-benzylidine-2- deoxy-/3-D-glucopyranoεide ("compound B") . The benzoyl groupε on compound B can be removed under Zemplen conditions (NaOMe/MeOH) to provide for 8-methoxycarbonyloctyl 3-0-(4,6-0- benzyl idene-3-D-galactopyranoεyl) -2-acetamido-4 , 6-0- benzylidene-2-deoxy-3-D-glucopyranoside ("compound C") . Compound C (1 gram, 1.37 mmol) waε diεεolved in dry dimethyl formamide (5.0 mL) and sulfur trioxide- pyridine complex (267.1 mg, 1.64 mmol) was added at -30°C. The resulting solution was stirred at -30 °C for 5 hours and then 15 hours at 0 β C. Excess reagent was destroyed by the addition of methanol (2 mL) . The The reaction mixture was converted into sodium salt by passage through Dowex 50-X8 (Na+) resin in methanol. Evaporation and co-evaporation with toluene left a while solid which was purified by chromatography on silica gel using dichloromethane-methanol-pyridine (9:1:0.1) as eluant to provide the title compound as a white solid. This material was converted into sodium salt by passage through D.owex 50-X8 (Na+) resin in methanol to give the title compound (850 mg, 74.6%). Example 18 — Synthesis of 8-Methoxycarbonyloctyl 3-0- (3-0-sulfo-0-D-galactopyranosyl) -2-acetamido- 2-deoxy-0-D-glucopyranoside The product of Example 17 (800 mg, 0.96 mmol) was disεolved in methanol (10 mL) containing 5% palladium on carbon (800 mg) and was stirred under hydrogen (1 atmosphere) for 5 hours at room temperature. Catalyst was removed by filtration, washed with methanol (500 mL) and the solvent was evaporated to dryness. The residue was then purified by chromatography on silica gel using dichloromethane- methanol-water-pyridine (80:20:2:0.2) as eluant. The title compound (488 mg, 77.5%) waε obtained aε a white εolid after BioGel P-2 (200-400 meεh) filtration and converεion into its sodium salt. lH.n.m.r. (D 2 0) δ : 4.520-4.570 [m, 2h, incl. H-l(d, 4.550, J 1>2 8.0Hz and Hl'(d, 4.542, J V 2 , 7.7 Hz)], 4.277-4.343 [m, 2H, incl. H-3'(dd, 4.310, J 23 10.0Hz, J 34 3.5Hz) and H-4' (4.296) ], 3.687(s, 3H, OCH 3 ) , 2.388(t, 2H, J7.5Hz, CH 2 COO) ,2.025(ε, 3H, NHAc) , 1.570(m,4H) and 1.30(m, 8H) . The 2,3-diεulfate of Example 18 waε prepared in a εimilar manner except that εulfation waε conducted with 6 equivalentε of εulfur trioxide/pyridine complex and the reaction waε conducted at room temperature for 24 hourε. The resulting product was a mixture of 2-, 3-sulfate and predominantly 2,3-disulfate. The mixture waε purified by chromatography in the manner described and ion exchange of the resulting product provided for the 2,3-disulfate of Lewis c -0R aε the disodium salt. The 2-sulfate of Lewis c -OR waε prepared from compound C by benzoylation under conditions described above. The resulting product contained predominantly the 3-benzoyl group on the galactose unit and a small amount of the 2-benzoyl and 2,3-dibenzoyl derivatives. The products were separated by chromatography on silica gel to provide for both the 2-benzoyl and the 3-benzoyl derivatives as pure products. The 3-benzoyl derivative was sulfated in the manner described above and then deprotected to provide for the 2'-sulfo-Lewis c -OR which upon ion exchange as deεcribed above provided for the sodium salt of this product. The 3'-sulfo-LacNAc derivative was prepared from compound 42 (prepared in Example 6) wherein the dibenzoyl groups are removed via Zemplen conditions (sodium methoxide/methanol) and then sulfated under the conditions described above to provide for 3'-sulfo-Lewis c -OR. The following Examples 19-20 illustrate the immunomodulating propertieε of the compounds of this invention. Example 19 - Inhibition of DTH Inflammatory Response DTH inflammatory responεes were measured using the mouse footpad swelling asεay as described by Smith and Ziola 14 . Briefly, groups of Balb/c mice were immunized with 100 μg of the OVA antigen [Albumin, chicken egg, Sigma, St. Louis, Misεouri] containing 20μg of the DDA adjuvant (dimethyldioctadecylammonium bromide) which haε been εhown to induce a strong inflammatory DTH response. Seven days later, each group of mice was footpad-challenged with 20 μg of OVA antigen. The reεulting inflammatory footpad εwelling was measured with a Mitutoyo Engineering micrometer 24 hours after challenge. To assesε the effect of the analogueε of Lewiε c -OR and LacNAc-OR on the inflammatory DTH response, groups of mice received 100 μg of the following oligosaccharide glycosides 5 hours after foot-pad challenge with the OVA antigen. Compound A = 3 ' -Sulfo-Lewis c -OR [ 3 ' -sulf o-øGal ( 1-3 ) /ΪGlcNAc-OR] Compound B = 2 ' -Sulfo-Lewis c -OR [ 2 ' -sulf o-j3Gal ( 1-3 ) / SGlcNAc-OR] Compound C = Sialyl Lewis x -OR [αNeuδAc(2-3)jSGal(1-4)-[α-L-Fuc(1-3) ] / SGlcNAc-OR] Compound D = Sialyl Lewis*-OR (αNeu5Ac(2-*3)/3Gal(1-3) ■ [α-L-Fuc(1-4) ]-/3GlcNAc-OR] Compound E = Sialyl Lewis c -OR [αNeu5Ac(2→3) 3Gal(1-3)-3GlcNAc-OR] Percentage reduction in inflammation for this example was calculated by the following equation: "Treated mice" are those mice which receive one of the above compounds in addition to the antigen. "Untreated Mice" are those mice which do not receive any of the above compounds. Background (bkg) swelling is that level of swelling observed in mice immunized with PBS alone without antigen or compound and challenged with antigen. The results of this experiment are εet forth below: In a separate study, 3'-sulfo-LacNAc was shown to reduce inflammation by about 24% when administered to OVA sensitized mice 5 hours after OVA challenge in the manner described above. The above resultε demonstrate that the compounds of this invention are effective in treating mammalian cell mediated secondary immune responses arising from antigen challenge. Example 21 — Effect of Oligosaccharide Glycosides on LPS Caused Lung Injury LPS (lipopolysaccharide) caused lung injury is measured by weighing the lungs of sacrificed mice 24 hours after mice are given LPS intranasally. Briefly, groups of 8-10 week old Balb/c mice were sensitized with 5 μg /mouse of LPS in 50 μl of PBS intranasally under light anestheεia. The method of * administering compound intranasally is described in Smith et al. 15 , which is incorporated by reference. Briefly, mice are anetheεitized with Metofane (Pitman-Moore Ltd. , Miεεiεsauga, Ontario, Canada) and a 50 μl drop of compound is placed on the nares of the mouεe and is inhaled. Five hourε later, 100 μg/mouεe of 3'-sulfo- Lewiε c -OR in 200 μl of PBS is given to the mouse intravenously. After 24 hours, 48 hours or 72 hours, different groups of mice are εacrificed and the lungs removed and weighed. The weight of the lungs of mice treated with 3-sulfo-Lewiε c -0R are compared against control (i.e., mice treated with LPS but to which 3- sulfo-Lewis c -OR has not been administered) . The percent reduction is measured by subtracting from 100 the following: The fraction derived by a numerator whose value is the weight of the treated lungs subtracted from the weight of normal lungs (lungs from mice not exposed to LPS, 3-sulfo-Lewiε c -OR) , and whose denominator whose value is the weight of the control lungs (mice that received only LPS) subtracted from the weight of normal lungs and multiplying the resulting fraction by 100. The greater the percent reduction, the better the compound is in allevating lung damage. The resultε of this test are set forth below: The above data demonstrates that the compounds of this invention are effective in reducing cell-mediated inflammatory responεes due to injury.

Claims: WHAT IS CLAIMED IS : 1 . A compound of Formula I or II : where R is selected from the group conεiεting of hydrogen, a saccharide-OR 19 , an oligoεaccharide-OR 19 having from 2 to 7 oligosaccharide units, or an aglycon having at least 1 carbon atom where R 19 is hydrogen or an aglycon of at least one carbon atom; Y is selected from the group consisting of oxygen, sulfur, and -NH-; R 1 is selected from the group consisting of hydrogen, -NH 2 , -N 3 , -NHS0 3 H, -N j CfOJR^ -N=C(R 5 ) 2 , -NHCH(R 5 ) 2 , -NHR 6 , -N(R 6 ) 2 , -OH, -OR 6 , -S(0)R 6 , -S(0) 2 R 6 and sulfate, wherein R 4 is selected from the group consiεting of hydrogen, alkyl of from 1 to 4 carbon atoms; -OR 7 wherein R 7 is alkyl of from 1 to 4 carbon atoms, or alkyl of from 2 to 4 carbon atoms substituted with a hydroxyl group, and -NR 8 R < , wherein R 8 and -^ are independently selected from the group consisting of hydrogen and alkyl of from 1 to 4 carbon atoms, each R 5 is selected from the group consisting of hydrogen and alkyl of from 1 to 4 carbon atoms, each R 6 iε alkyl of from 1 to 4 carbon atomε, R 2 iε selected from the group consisting of hydrogen, -N 3 , -NH 2 , -NHS0 3 H, -NR n C(O)R 10 , -N=C(R 11 ) 2 , -NHCH(R--) 2 , -NHR 12 , -N(R 12 ) 2 , -OH and -OR 12 , wherein R 10 is selected from the group consiεting of hydrogen, alkyl of from 1 to 4 carbon atomε, -OR 13 wherein R 13 iε alkyl of from 1 to 4 carbon atomε, or alkyl of from 2 to 4 carbon atoms substituted with a hydroxyl group, and -NR 14 R 15 wherein R 14 and R 15 are independently selected from the group consiεting of hydrogen and alkyl of from 1 to 4 carbon atomε, each R iε selected from the group consisting of hydrogen and alkyl of from 1 to 4 carbon atoms; each R 12 is alkyl of from 1 to 4 carbon atoms, R 3 is selected from the group consiεting of hydrogen, fluoro, εulfate and hydroxy; X- iε selected from the group consiεting of hydrogen, sialyl, sulfate, phosphate, and -CHR 18 C00H where R 18 iε εelected from the group conεiεting of hydrogen, alkyl of from 1 to 7 carbon atoms and -COOH; X 2 is selected from the group conεiεting of hydrogen, sulfate, phosphate, and -CHR 18 COOH where R 18 is εelected from the group conεisting of hydrogen, alkyl of from 1 to 7 carbon atoms and -COOH; and pharmaceutically acceptable salts thereof; and with the proviso that either at least one of X 1 or X 2 iε εulfate, phosphate or -CHR 18 COOH or R 3 is sulfate. 2. A compound of Claim 1 wherein said compound is of Formula I. 3. A compound of Claim 1 wherein said compound is of Formula II. 4. A compound of Claim 1 wherein R_ is selected from the group consisting of hydroxyl, hydrogen or alkoxy of from 1 to 4 carbon atoms. 5. A compound of Claim 1 wherein R 2 is selected from the group consisting of hydroxyl, alkoxy of from 1 to 4 carbon atoms, -NH 2 , -N 3 and -NHC(O)R, 0 . 6. A compound of Claim 1 wherein R 3 is -OH. 7. A compound of Claim 1 wherein X and X j are hydrogen and X 2 is selected from the group consisting of sulfate, phosphate, and -CHR 18 COOH. 8. A compound of Claim 1 wherein X and X 2 are hydrogen and X, is selected from the group consisting of sulfate, phosphate, and -CHR 18 COOH. 9. A compound of Claim 2 wherein X, is hydrogen, X 2 is sulfate, Rj is hydroxyl, R 2 is selected from the group consisting of -NH 2 and -NHC(0)CH 3 and R 3 is hydroxyl. 10. A compound of Claim 3 wherein X_ is hydrogen, X 2 is sulfate, R j is hydroxyl, R 2 is selected from the group consisting of -NH 2 and -NHC(0)CH 3 and R 3 is hydroxyl. SUBSTITUTE £>:2ΞT 11. A pharmaceutical composition suitable for administration to a mammal which comprises a pharmaceutically inert carrier and an effective amount of the compound of Claim 1 to modulate a cell-mediated immune response in said mammal. 12. A method for modulating a cell-mediated immune response in a mammal which method comprises administering to said mammal an amount of a compound of Claim 1 effective in modulating said immune reεponse. 13. A method for reducing sensitization of a mammal to an antigen which compriseε administration of an effective amount to the mammal of a compound of Claim 1. 14. A method for reducing sensitization of a mammal to an antigen which * comprises administration of an effective amount to the mammal of a compound of Claim 2. 15. A method for reducing senεitization of a mammal to an antigen which compriεeε administration of an effective amount to the mammal of a compound of Claim 3. 16. A method according to Claim 12 wherein said suppresεion of an immune responεe comprises suppresεion of a DTH reεponεe and induction of tolerance to an antigen. SUBSTITUTESHEET

Inventors: HANNA H RIZK, HAQUE WASIMUL, IPPOLITO ROBERT M, JIANG CONG, KASHEM MOHAMMED A, NIKRAD PANDURANG V, SMITH RICHARD H, SRIVASTAVA OM P, VENOT ANDRE P, HANNA, H., RIZK, HAQUE, WASIMUL, IPPOLITO, ROBERT, M., JIANG, CONG, KASHEM, MOHAMMED, A., NIKRAD, PANDURANG, V., SMITH, RICHARD, H., SRIVASTAVA, OM, P., VENOT, ANDRE, P.
Applicants: ALBERTA RES COUNCIL, HANNA H RIZK, HAQUE WASIMUL, IPPOLITO ROBERT M, JIANG CONG, KASHEM MOHAMMED A, NIKRAD PANDURANG V, SMITH RICHARD H, SRIVASTAVA OM P, VENOT ANDRE P, ALBERTA RESEARCH COUNCIL
Application year: 1993
Main classification: C07H15
IPC codes: A61K31, A61P37, C07H3, C07H5, C07H11, C07H15, C07H19