The present invention relates to a process for the preparation of derivatives of Monosaccharides as novel Cell Adhesion Inhibitors. The compounds of this invention are useful for inhibition and prevention of cell adhesion and cell adhesion mediated pathologies including inflammatory and autoimmune diseases such as bronchial asthma, rheumatoid arthritis, type I diabetes, multiple sclerosis and psoriasis.
This invention also relates to pharmaceutical composition containing the compounds of the present invention and the methods of treating bronchial asthma, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriasis, allograft rejection, and other inflammatory and/or autoimmune disorders, using the compounds.
Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localize within the extra-cellular matrix. These interactions are mediated by specialized molecules called cell adhesion molecules (CAM). CAMs have been demonstrated to participate in various cell-cell, cell-extracellular matrix, and platelet interactions. They influence the adhesion of leukocytes to the vascular endothelium, their transendothelial migration, retention at extravascular sites and activation of T cells and eosinophils. These processes are central to the pathogenesis of inflammatory and autoimmune diseases. Therefore, adhesion molecules are considered as potential targets to treat such disorders.
CAMs can be classified into three groups - integrins, selectins and the immunoglobulin superfamily. Out of these, integrins are key mediators in the adhesive interactions between hemopoietic cells and their microenvironment. They comprise of alpha-beta heterodimers and integrate signals from outside of the cells to inside and vice versa. Integrins can be classified on the basis of the beta subunits they contain. For example, beta-1 subfamily contains beta-1 subunit noncovalently linked to one of the 10 different alpha subunits.
The alpha-4 beta-1 integrin, also known as VLA4 (very late activation antigen 4),
is a member of beta 1 integrin family and consists of alpha-4 and beta-1 subunits. It interacts with two specific ligands - the vascular cell adhesion molecule (VCAM-1) and the the CS1 region of fibronectin. Adhesion mediated by
VLA4 is central to the process of transendothelial migration of leukocytes. Ligation of VLA4 is followed by gross rearrangement of the cytoskeleton leading
to flattening of cells along the blood vessel wall followed by expression of specific
molecules which digest the endothelial cell wall and diapedesis. Once in the extraluminal region, the interactions of VLA4 with extracellular fibronectin play a
crucial role in migration to the site of inflammation, T cell proliferation, expression of cytokines and inflammatory mediators. In addition, VLA4 ligation provides
costimulatory signal to the leukocytes resulting in enhanced immunoreactivity. Therefore, it is expected that VLA4 antagonists would ameliorate the immune
response through twofold actions - inhibition of T cell recruitment at the site of inflammation and inhibition of costimulatory activation of immune cells.
In support of this concept, inhibitors of VLA4 interactions have demonstrated
beneficial therapeutic effects in several animal models of inflammatory, and allergic diseases including sheep allergic asthma (Abraham et al. J. Clin. Invest.. 93, 776 (1994)), arthritis (Wahl et al, J. Clin. Invest. 94, 655 (1994)); experimental allergic encephomyelitis (Yednock et al, Nature (Lond). 356. 63 (1992) and Baron et al, J. Exp. Med.. 177. 57 (1993)); contact hypersensitivity (Chisolm et al, Eur J. Immunol.. 23,682 (1993)); type I diabetes (Yang et al, Proc. Natl. Acad. Sci. (USA), 90, 10494 (1993)) and inflammatory bowel disease (Podolsky et al, J. Clin. Invest.. 92, 372)(1993).
Region of CS1 moiety of fibronectin involved in the interaction with VLA4 was
identified as the tripeptide Leu-Asp-Val. also known as LDV (Komoriya et al, J, Biol. Chem. 266. 15075(1991)). Taking a lead from this, several peptides
containing the LDV sequence were synthesised which have shown to inhibit the in vivo interaction of VLA4 to its ligands. (Ferguson et al, Proc. Natl. Acad.
Sci.,(USA), 88, 8072 (1991); Wahl et al, J. Clin. Invest.. 94. 655(1994); Nowlin et al. J. Biol. Chem.. 268(27). 20352(1993) and PCT publication W091/4862).
Despite these advances, there remains a need for small and specific inhibitors of VLA4 dependent cell adhesion molecules. Ideally such inhibitors should be water
soluble with oral efficacy. Such compounds would provide useful agents for
treatment, prevention or suppression of various inflammatory pathologies mediated by VLA4 binding.
The' main objective of the present invention is to provide a process for the synthesis of a new class of compounds that exhibit significant activity as VLA4
antagonists.
Thus the compounds of the present invention were screened for inhibitory activity in VLA4 mediated cell adhesion assay and the classical murine hypersensitivity
assay in mice. Several compounds exhibited significant inhibitory activity in both these tests. The salts of these compounds could be easily solubilised in water and used in treatment of chronic, cell adhesion mediated, allergic, autoimmune and inflammatory disorders such as bronchial asthma and rheumatoid arthritis. Some of the prior art describes development of peptide derivatives as cell adhesion antagonists for treatment of these diseases. However, because treatment of chronic diseases requires prolonged (mid term to long term) administration of drugs, development of small molecule, specific, orally available inhibitors of cell adhesion would be very beneficial.
Isopropylidene and benzylidene groups are the most commonly used protective groups in carbohydrate chemistry.These groups are introduced into a molecule under similar conditions; however, the location of the protection can be quite different. The reason for this difference is directly related to the stability of each protected molecule. Since protection normally occurs under conditions which allow reversibility, reaction proceeds until equilibrium is reached. The distribution of products at equilibrium is determined by their relative thermodynamic stabilities. In other words, these reactions are thermodynamically controlled. Benzylidene groups prefer to be part of six-membered ring acetals, while the ketals resulting from acetonation generally are 5-membered rings. The difference is attributed to the effect of the methyl and phenyl substituents on the stability of the particular ring systems. These blocking methods are described in the U.S. Pat. Nos. 2,715,121; 4,056,322; 4,735,934; 4,996,195; and 5,010,058 the disclosures of which are incorporated herein by reference. Other blocking methods are also described in J. Carbohydr. Chem., 4,227(1985); 3,331(1984); Methods in Carbohydr. Chem.1, 191 (1962); 1, 107 (1962); Can J. Chem., 62, 2728 (1984); 47, 1195, 1455 (1969) ; 48, 1754 (1970) all incorporated herein by reference. Literature reveals that in the case of D-glucose, which is blocked in its furanose ring structure, the 1,2- and 5,6-hydroxyl groups can be blocked using with isopropylidene or cyclohexylidene blocking group with the 3-position left
open to undergo derivatization. The therapeutic activity of hexoses and their derivatives are also disclosed in some of the above applications.
Intermediates mentioned in U.S.Pat. Nos. 4,996,195; 5,637,570; 5,367, 062; 5,360,794; 5,360,792; 5,298,494 and 5,010,058 were used as core nucleus and were prepared similarly as described in these patents.However, in the present
application, it has been discovered, that the introduction of urea moiety at various positions of pentose and hexose monosaccharides introduces VLA4 antagonism
activity. It was also discovered that the tetrapetide sequence LDVP (leucyl-aspartyl- valyl- prolyl) or any other amino acid, dipeptide or tripeptide as present
in fibronectin is not necessary for the compounds to be active as inhibitors of VLA4.
Other objects and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by the practice of the invention. The objects and the advantages of the invention may be realised and obtained by means of the mechanisms and combinations pointed out in the appended claims.
The term "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds of Formula II are modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
Accordingly the present invention provides a process for preparation of derivatives of monosaccharide as novel cell adhesion inhibitors of Formula III (as shown in the accompanied drawings) and it's pharmaceutically acceptable salts, wherein
R1 is CO-LDVP, CO-DVP, COVP or CHNHCONHR" wherein LDVP, DVP and VP have the same meaning as defined earlier, wherein R" is C6H5p-R'" wherein R'" is Cl, NO2, OCH3, CH3, CH2COOH, CH2COLDVP, CH2CODVP, CH2COVP wherein LDVP, DVP, VP have the same significance as defined earlier, which comprises treating 2,3;4,6-Di-O-isopropylidene--L-xylo-2-hexalofuranose of Formula XVI with p-toluene sulphonyl chloride to give the compound of Formula XVII (as showed in the accompanied drawings) in the presence of an organic base selected from the group consisting of pyridine, N-methylmorpholine,triethylamine or diisopropylamine at a temperature ranging from -10 to10°C followed by reaction with sodium azide to give the compound of Formula XVIII (as shown in the accompanied drawings) in an organic solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, diethyl ether or dioxane and heating the reaction mixture at a temperature ranging from 50 to 140°C, which on reduction with lithium alluminium hydride (LAH) gives the corresponding 1-aminoderivative of Formula XIX (as shown in the accompanied drawings) in an organic solvent selected from the group consisting of tetrahydrofuran, dimethylformamide, diethyl ether or dioxane, which is treated with suitable isocyanates (R'NCO) (wherein R' SO2C6H5, SO2C6H4CH3-p or S02C6H4CI-p, C6H4CH2-COOCH3, C6H4CH2COOH, C6H4R"-p and R" is Cl, NO2, OCH3, CH3, CH2COOH, CH2COOCH3) CH2COLDVP, CH2CODVP, CH2COVP, wherein LDVP, DVP and VP represent tetrapeptide (Leucyl-aspartyl-valyl-propyl), tripeptide (aspartyl-valyl-prolyl) and dipeptide (valyl-propyl) respectively) in an organic solvent selected from the group consisting of methylene chloride, ethylene chloride, chloroform or carbon tetrachloride to give the compound of Formula XX (as shown in the accompanied drawings) wherein R1 is the same as defined above, followed by selective hydrolysis of 4,6 positions to give the desired compound of Formula III.
In order to achieve the above mentioned objects and in accordance with the purpose of the invention as embodied and broadly described herein, there is provided a process for the preparation of monosaccharide derivatives having the general formula III as shown in the accompanied drawings, wherein in Formula III
R1 is SO2C6H5, SO2C6H4CH3 -p1 or SO2C6H4CI-p, phenyl or substituted phenyl, represented as C6H4-R'"-p wherein R1" is Cl, NO2, OCHs, CHs, CH2COOH, CH2COOCH3, CH2COLDVP, CH2CODVP, CH2COVP wherein
LDVP, DVP and VP represent tetrapeptide (Leucyl-aspartyl-valyl-prolyl), tripeptide (aspartyl-valyl-prolyl) and dipeptide (valyl-prolyl), respectively, which comprises reacting 2,3,4,6-Di-O-isopropylidene-a-L-xylo-2-hexalofuranose of Formula XVI with p-toluene sulphonic acid to give the compound of Formula XVII followed by reaction with sodium azide to give the compound of Formula XVIII and reduction with lithium alluminium hydride (LAH) to give the corresponding 1-aminoderivative of Formula XIX, which is treated with suitable
isocyanate R'NCO, wherein R1 is SO2C6H5, SO2C6H4CH3-p, SO2C6H4CI-p, C6H4CH2-COOCH3l C6H4CH2COOH, C6H4R"-p and R" is Cl NO2l OCH3, CH3, CH2COOH, CH2COLDVP, CH2CODVP, CH2COVP wherein LDVP, DVP and VP represent tetrapeptide (leucyl-aspartyl-valyl-prolyl), tripeptide (aspartyl-valyl-prolyl) and dipeptide (valyl-prolyl) respectively, to give the compound of Formula XX wherein R11 represents Cl, NO2, OCH3, CH3, CH2COOH, CH2COLDVP, CH2CODVP, CH2COVP followed by selectve hydrolysis of 4,6 positions to give the desired compounds of Formula III wherein R" is the same as defined earlier
In compounds of Formula XX as shown in the accompanied drawings wherein R1 is C6H4CH2COOH is also coupled with tetrapeptide [Leucyl-aspartyl (Obzl)-valyl-prolyl (Obzl)] or tripeptide [aspartyl (Obzl)-valyl-prolyl (Obzl)] or dipeptide [Valyl-prolyl) (Obzl)] in the presence of EDC or DCC and a suitable base followed by reduction with hydrogen gas in the presence of Pd/C catalyst to ascertain the VLA4 properties of these compounds. Suitable salts such as TRIS, Sodium, potassium, ammonium, etc. are prepared so as to solubilise the compound in aqueous medium for biological evaluations.
The examples mentioned below demonstrate the general synthetic procedure as well as the specific preparation for the preferred compound. The examples are given to illustrate the details of the invention and should not be constrained to limit the scope of the present invention.
Various solvents such as acetone, methanol, pyridine, ether, tetrahydrofuran, Hexanes, dichloromethane were dried using various drying reagents following the procedure as described in the literature. Wet solvents gave poor yields of the products and intermediates. IR spectra were recorded as nujol mulls or a thin neat film on a Perkin Elmer Paragon instrument. NMR (H, C) were recorded on a varian XL-300 MHz instrument using tetramethylsilane as an internal standard. CIMS were obtained on a Finnigan MAT-4510 mass spectrometer eqquipped with an INCOS data system. Generally a direct exposure probe was used and methane was used as a reagent gas ( 0.33 mm Hg, 120 OC source temp.) In the above synthesis, where specific acids, bases, solvents reducing agents etc are mentioned, it is to be understood that the other acids, bases, solvents,reducing etc. may be used. Similarly the reaction temperature and duration of the reaction may be adjusted according to the need.
An illustrative list of particular compounds according to the invention and capable of being produced by Scheme-5 include:
Compound Chemical Name
No.
1 2,3;4,6-Di-O-isopropylidene-1 -deoxy-1 -N-{[4-chlorophenyl]aminocarbonyl
amino}-,L-xylo-2-hexulofuranose
2 2,3;4,6-Di-0-isopropylidene-1 -deoxy-1 -N-{[4-methoxyphenyl]aminocarbonyl
amino}-,L-xylo-2-hexulofuranose
3 2,3;4,6-Di-O-isopropylidene-1 -deoxy-1 -N-{[4-tolyl]aminocarbonylamino}-,L-xylo-
2-hexulofuranose
4 2,3-O-isopropylidene-1 -deoxy-1 -N-{[4-(2-hydroxy-2oxoethyl))phenylamino
carbonylamino}-,L-xylo-2-hexulofuranose
5 2,3-O-isopropylidene-1-deoxy-1-N-{[4-chlorophenyl]aminocarbonylamino}-,L
xylo-2-hexulofuranose
6 2,3-O-isopropylidene-1-deoxy-1-N-{[4-methoxyphenyl]aminocarbonylamino}-,L-
xylo-2-hexulofuranose
7 2,3-O-isopropylidene-1-deoxy-1-N-{[4-tolyl]aminocarbonylamino}-,L-xylo-2-
hexulofuranose
8 2,3-O-isopropylidene-1 deoxy-1-N-{[aminocarbonylaminophenylacetyl-L- Leucyl-
,L-Aspartyl-L-Valyl-L-Proline)}-a,L-xylo-2-hexulofuranose
9 2,3-O-isopropylidene-1-deoxy-1-N-{[aminocarbonylaminophenylacetyl-,L-
Aspartyl-L-Valyl-L-Proline)}-a,L-xylo-2-hexulofuranose
10 2,3-O-isopropylidene-1 deoxy-1 -N-{[aminocarbonylaminophenylacetyl-L-Valyl-L-
Proline)}-,L-xylo-2-hexulofuranose
EXAMPLE 1
Preperation of2,3-O-lsopropylidene-1 -deoxy-1 -N-{[4-(2-methoxy-2-
oxoethyl))phenylamino carbonyl amino }-,L-xylo- 2-hexulofuranose
Step-1: 2,3;4,6-Di-O-isopropylidene-1-p-tosyl-,L-xylo-2-hexulofuranose
To a solution of 2,3;4,6-Di-O-isopropylidene-,D-xylo-2-hexulofuranose (prepared by following the method as reported in US Pat. 5,637,570) (8.0 gm 30.65 mmole) in dry pyridine (50 ml) was added p-tolune sulphonyl chloride (6.4 gm, 33.71 m mole ) portionise at 0-5°C, The reaction mixture thus obtained was stirred at room temp, for about 12 hrs. Removed pyridine under vacuum, added
water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous Na2SO4
. Removed the solvent under vacuum to get an oily product which was purified by column chromatography using 5% EtOAc in hexane. The yield of the pure product was 64% yield.
Step-2: 2,3;4,6-Di-O-isopropylidene-1 -deoxy-1 -azido-,L-xylo-2-hexulofuranose
A mixture of the tosylate obtained from step 1 ( 9.0 gm), sodium azide ( 9,0 gm ) and DMF ( 100 ml) was heated at 100°C for about 12 hrs.DMF was removed
under vacuum, added water and .extrated with ethyl acetate. The extract was washed with water, brine and dried over anhydrous Na2SO4 removed the
solvent under vacuum to get an oily product. The crude product so obtained was purified by column chromatography using 5% ethylacetate in hexane. The yield of the pure product was 84 %.
Step-3 : 2,3;4,6-Di-O-isopropylidene-1 -deoxy-1 -amino-,L-xylo-2-hexulofuranose
To a solution of sodium azide (4.0 gm) in THF (50 ml) was added LAH (3.0 gm) portionwise at 0-5°C and reaction mixture was stirred at this temp, for about 4 hrs. The excess of LAH was decomposed in ice water, the seperated solid was
filtered out and discarded. Removed the solvent under vacuum added ethyl acetate to it washed with water, brine and dried over anhydrous Na2S04 .
Removed the solvent under vacuum to get an oily product which was purified by column chromatography using 10% ethylacetate in hexane. The yield of the pure product was 86%.
Step-4 : 2,3;4,6-Di-O-isopropylidene-1 -deoxy-1 -N-{[4-(2-methoxy-
2oxoethyl))phenyl
amino carbonyl amino }-,L-xylo-2-hexulofuranose
To a solution of amine obtained from step 3 (0.5 gm , 1.92 mmole) in dry methylene chloride (10 ml) was added a solution of methyl ester of p-isocyanate-4-phenyl acetic acid (1.92 m mole) in 5 ml of dry methylene chloride at 0-5 °c. The reaction mixture was stirred at this temp, for about 2 hrs., washed with water, dried over anhydrous Na2SO4 and removed the solvent under vacuum to
get an oily product. It was purified by column chromatography by using hexane-ethylaceetate (70:30) as an eluent in 64% yield.
Similarly following compounds were prepared :
2,3;4,6-Di-O-isopropylidene-1-deoxy-1-N-{[4-chlorophenyl]aminocarbonylamino}-,L-xylo-2-hexulofuranose (Compound No. 1)
2,3;4,6-Di-O-isopropylidene-1-deoxy-1-N-{[4-methoxyphenyl]aminocarbonylamino}-,L-xylo-2-hexulofuranose (Compound No. 2)
2,3;4,6-Di-O-isopropylidene-1-deoxy-1-N-{[4-tolyl]aminocarbonylamino}-a,L-xylo-2-hexulofuranose (Compound No. 3)
Step-5:2,3-O-lsopropylidene-1 -deoxy-1 -N-{[4-(2-methoxy-2oxoethyl))phenylamino carbonylamino }-a,L-xylo- 2-hexulofuranose
To a solution of compound obtained from step 5 (O.Sgm) in THF (10 ml) was added a 30 % solution of perchloric acid (0.5 ml) dropwise at 0-5°C.. The reaction mixture was further stirred at this temp, for about 4 hrs and the reaction was quenched with a saturated solution of potassium carbonate, the solid salt formed was filtered out and discarded. Evaporated the solvent under vacuum,
dissolved the residue in ethyl acetate, washed with water and brine. The organic layer was dried ( Na2S04) removed the solvent under vacuum to get an
oily mass. This oily material was purified by column chromatography using ethylacetate-hexane (10:90) as an eluent.
Similarly following compounds were prepared:
2,3-O-isopropylidene-1 -deoxy-1 -N-{[4-chlorophenyl]aminocarbonylamino}-,L-xylo-2-
hexulofuranose (Compound No. 5)
2,3--O-isopropylidene-1-deoxy-1-N-{[4-methoxyphenyl]aminocarbonylamino}-,L-xylo-2-
hexulofuranose (Compound No. 6)
2,3-0-isopropylidene-1-deoxy-1-N-{[4-tolyl]aminocarbonylamino}-,L-xylo-2-hexulofuranose(Compound No. 7)
EXAMPLE 2
Preperation of 2,3-O-isopropylidene-1 -deoxy-1 -N-{[4-(2-hydroxy-2-
oxoethyl))phenylamino carbonyl amino }-,L-xylo- 2-hexulofuranose (Compound No. 4)
A mixture of ester as obtained in step 5 of example 1 (0.5 g) and aqueous sodium hydroxide (10 mL, 1N) was heated at 50 °C for about two hours. The reaction mixture was cooled to 0-5°C, acidified to pH-3 with 3N hydrochloric acid, and a white solid separated was filtered which got converted into oil on being
kept at room temperature. This product was extracted with ethyl acetate, washed with water, dried over anhydrous Na2SO4 and the solvent removed in vacuum to
get an oily mass. The crude product was purified by column chromatography by eluting with 35 : 65 ethyl acetate hexane mixture to get an oil in 89% yield.
EXAMPLE 3
Preparation of 2,3-O-isopropylidene -1 deoxy-1-N-{[ amino carbonyl amino phenyl acetyl-L- Leucyl- ,L-Aspartyl-L-Valyl-L-Proline)}- ,L-xylo-2-hexulofuranose (Compound No. 8)
To a suspention of 1-(3-dimethylaminepropyl)-3-ethylcarbodimide (0.23 gm) and 1-hydroxybenzotriazolehydrate (0.153 gm) in DMF (60 ml) was added triethyl amine (0.30 gm) at room temp, and the reaction mixture was stirred for about 30 min. The acid obtained from example 24 (0.43 gm) and Leu-Asp(obzl)Val-Pro(obzl) HCI (0.65 gm) were added simultaneously to the above reaction mixture and stirred for about 24 hrs. Poured the reaction mixture into water,
extracted with methylene chloride washed with saturated sodium bicarbonate solution, water, brine and dried over Na2SO4- The solvent was removed under
reduced pressure to get white foamy solid (0.72 gm) which was used for the next step without any purification.
To a solution of above benzyl ester (0.7 gm) in ethylacetate (15 ml) was added Pd/C (0.1 gm) at room temperature and subjected to hydrogenation using parr shaker for 5 hrs. Filtered the catalyst and removed the solvent under vacuum to obtain a white solid. The crude product so obtained was recrystallized from ethyl acetate-hexane mixture . The yeild of the pure product was 82% theory
The following compounds were prepared in the similar manner: 2,3-O-isopropylidene-1-deoxy-1-N-{[aminocarbonylaminophenylacetyl-,L-Aspartyl-L-Valyl-L-Proline)}- ,L-xylo-2-hexulofuranose (Compound No. 9) 2,3-O-isopropylidene-1-deoxy-1-N-{[aminocarbonylaminophenylacetyl-L-Valyl-L-Proline)}- ,L-xylo-2-hexulofuranose (Compound No. 10)

We Claim:
1. A process for preparation of derivatives of monosaccharide as novel cell adhesion inhibitors of Formula III (as shown in the accompanied drawings) and it's pharmaceutically acceptable salts, wherein R' is CO-LDVP, CO-DVP, COVP or CHNHCONHR" wherein LDVP, DVP and VP have the same meaning as defined earlier, wherein R" is C6H5p-R'" wherein R"' is Cl, NO2, OCH3) CH3, CH2COOH, CH2COLDVP, CH2CODVP, CH2COVP wherein LDVP, DVP, VP have the same significance as defined earlier, which comprises treating 2,3;4,6-Di-O-isopropylidene--L-xylo-2-hexalofuranose of Formula XVI with p-toluene sulphonyl chloride to give the compound of Formula XVII (as showed in the accompanied drawings) in the presence of an organic base selected from the group consisting of pyridine, N-methylmorpholine, triethylamine or diisopropylamine at a temperature ranging from -10 to10°C followed by reaction with sodium azide to give the compound of Formula XVIII (as shown in the accompanied drawings) in an organic solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, diethyl ether or dioxane and heating the reaction mixture at a temperature ranging from 50 to 140°C, which on reduction with lithium alluminium hydride (LAH) gives the corresponding 1-aminoderivative of Formula XIX (as shown in the accompanied drawings) in an organic solvent selected from the group consisting of tetrahydrofuran, dimethylformamide, diethyl ether or dioxane, which is treated with suitable isocyanates (R'NCO) (wherein R' SO2C6H5, SO2C6H4CH3-p or SO2C6H4CI-p, C6H4CH2-COOCH3, C6H4CH2COOH, C6H4R"-p and R" is Cl, NO2, OCH3, CH3, CH2COOH, CH2COOCH3, CH2COLDVP, CH2CODVP, CH2COVP, wherein LDVP, DVP and VP represent tetrapeptide (Leucyl-aspartyl-valyl-propyl), tripeptide (aspartyl-valyl-prolyl) and dipeptide (valyl-propyl) respectively) in an organic solvent selected from the group consisting of methylene chloride, ethylene chloride, chloroform or carbon tetrachloride to give the compound of Formula XX (as shown in the accompanied drawings) wherein R' is the same as defined above, followed by selective hydrolysis of 4,6 positions to give the desired compound of Formula III.
2. The process for the preparation of derivatives of monosaccharide derivatives of compounds of Formula III, substantially as herein described and illustrated by the example herein.