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 application is a divisional of the application Np.3108/Del/98.

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 WO91/4862).
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.
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 I as shown in the accompanied drawings,
The term "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds of Formula III are modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acidic residues such as carboxylic acids; and the like.
A process for the preparation of derivatives of monosaccharides as novel cell adhesion inhibitors of compounds of Formula I (as shown in the accompanied drawings) and it's pharmaceutically acceptable salts, wherein
R is C1-C15 alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl orallylaryl,
R is SO2C6H5, SO2C6H4CH3 -p1 or SO2C6HCI-p, phenyl or substituted phenyl, represented as C6H4-R"'-p wherein R"1 is Cl, NO2, OCH3, CH3, 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 oxidising 1,2-0-isopropylidene-6-deoxy-3-0-alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl or alkylaryl, , D-glucofuranose or -D-allofuranose of Formula IV as shown in the accompanied drawings where R is same as defined above, with sodium periodate (NalO4) to give a compound of Formula VII at temperature ranging from -10°C to10°C. which is reacted with hydroxylamine (NH2ON) followed by reduction with lithium aluminium hydride (LAH) in an organic solvent selected from the group consisting of tetrahydrofuran, dimethylformamide, dioxane or diethyl ether to give a compound of Formula X as shown in the accompanied drawings wherein R is same as defined above, which is then reacted with the isocyanates R'NCO, wherein R' is same as defined earlier, in an organic solvent selected from the group consisting of methylene chloride, ethylene chloride, chloroform or carbontetrachloride to give the compound of Formula I wherein R and R' are the same as defined above and R" is H.
When R1 is -C6H4-CH2-COOCH3, the corresponding free carboxylic acid is obtained by hydrolysis with aqueous sodium hydroxide followed by acidification with dilute acid to pH 3.
The compounds of the Formula I wherein R1 is C6H4CH2COOH having the structure as shown in the accompanied drawings, are 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 1-(3-dimethylaminoprolyl)-3-ethylcarbodiimide hydrochloride (EDC) or 1,3-dicyclohexylcarbodiimide (DCC) and a suitable base followed by reduction with hydrogen gas using Pd/C as catalyst.
Soluble salts of the above compounds are obtained by the addition of various bases such as TRIS [tris(hydroxymethylaminomethane)] or alkaline hydroxides, carbonates or bicarbonates etc. and are also included in the invention.
In the above synthesis, where specific acids, bases, solvents, oxidising agents,
reducing agents etc. are mentioned, it is to be understood that the other acids,
bases, solvents, oxidising agents, reducing agents 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-ll include:
Compound Chemical Name
No.
1. 1,2-0-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-a,D-xylofuranose
2. 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-a,D-xylofuranose
3. 1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-a,D-xylofuranose
4. 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-a,D-xylofuranose
5. 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)
phenyl]aminocarbonylamino}-a,D-xylofuranose
6. 1,2-O-isopropylidene-3-0-dodecyl-5-deoxy-5-N-{[4-chlorophenyl]amino
carbonylamino}a,D-xylofuranose
7. 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-chlorophenyl]amino
arbonylamino}a,D-xylofuranose
8. 1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-N-{[4-chlorophenyl]amino
carbonylamino}cc,D-xylofuranose
9. 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-chlorophenyl]amino
carbonylamino}a,D-xylofuranose
10. 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-chlorophenyl]amino
carbonylamino}a,D-xylofuranose
11. 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-methoxyphenyl]amino
carbonylamino},D-xylofuranose
16 2,3-O-isopropylidene-1-O-methyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino}, D-
lyxofuranoside
17 2,3-0-isopropylidene-1-O-butyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino}, D-
lyxofuranoside
18 2,3-O-isopropylidene-1-0-heptyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino}, D-
lyxofuranoside
19 2,3-O-isopropylidene-1 -O-decyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino}, D-
lyxofuranoside
20 2,3-O-isopropylidene-1-0-dodecyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},
D-lyxofuranoside
21 2,3-0-isopropylidene-1-O-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]phenyl
acetyl-L-Leucyl- a,L-Aspartyl-L-Valyl-L-Proline}-,D-lyxofuranoside
22 2,3-O-isopropylidene-1-O-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]phenyl
acetyl-a,L-Aspartyl-L-Valyl-L-Proline}-a,D-lyxofuranoside
23 2,3-0-isopropylidene-1-O-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]phenyl
acetyl-L-Valyl-L-Proline}-a,D-lyxofuranoside
The examples mentioned below demonstrated the general synthetic procedure as well as the specific preparation for the preferred compound. The examples are given to illustrate the details of invention and should not be constrained to limit the scope of the present invention.
Various solvents such as acetone, methanol, pyridine, ether, tetrahydrofuran, hexane, dichloromethane were dried using various drying reagents following the procedure as described in the literature. Wet solvents gave poor yields of the product and intermediates. IR Spectra were recorded as hugol mulls or a thin neat film or a Perkin Elmer Paragon instrument. NMR (H, C) were recorded on a various X-300 MH2 instrument using tetramethylsilane as an internal standard. CIMS were obtained on a Finnigar MAT-4510 man spetrometer equipped with an I NCOS data system. Generally a direct exposure probe was used and methane was used as a reagent gas (0.033 mm Hg, 120°C source temperature).
EXAMPLE 1
Preparation of 2,3-O-isopropylidene-1 -O-dodecyl-5-deoxy-5-N-{[4-(2-methoxy-2-
oxoethyl)phenyl]amino carbonyl amino}-a,D-lyxofuranoside
Step 1 :2,3-O-isopropylidine-1 -O-dodecyl-5-deoxy-5-azido-,D-lyxofuranoside
A mixture of 2,3-O-isopropylidine-1-0-dodecyl-5-p-tosyl-,D-lyxofuranoside (prepared by following the procedure as reported in U. S. Pat. No. 5,367,062) (8.0 gm ) sodium azide ( 8.0 gm. ) and DMF (80 ml ) was heated at 100° c for about 9 hrs. The solvent was removed under vacuum, the residue obtained was
dissolved in ethylacetate and was washed with water. The organic layer was dried over anhydrous Na2S04i and evaporated the solvent completely under
vacuum. The crude material was purified by column chromatography and eluted with 2% ethyl acetate in hexane mixture to get pure oily mass in 83% yield. .
The compounds prepared similarly were as follows :
2,3-O-isopropylidine-1-O-methyl-5-deoxy-5-azido-,D-lyxofuranoside
2,3-O-isopropylidine-1-O-butyl-5-deoxy-5-azido-,D-lyxofuranoside
2,3-O-isopropylidine-1-O-heptyl-5-deoxy-5-azido-,D-lyxofuranoside
2,3-O-isopropylidine-1-O-decyl-5-deoxy-5-azido-,D-lyxofuranoside
Step 2 :2,3-O-isopropylidine-1 -O-dodecyl-5-deoxy-5-amino-,D-lyxofuranoside
To a solution of lithium aluminium hydride ( 5.0 gm) in dry THF ( 100 ml) at 0-5 °C was added the solution of the above compound (3.0 gm in 10 ml of THF) dropwise. After the addition was over, the reaction was stirred at 25-30°C for about 2 hrs. The excess of LAH was decomposed by addition of ice-water mixture and the reaction mixture was filtered through celite. The solvent was
removed under vacuum, residue was dissolved in ethyl acetate.washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and
solvent was removed under vacuum to get an oily product in 65 % yield.
The other compounds prepared similarly were as follows :
2,3-0-isopropylidine-1-O-methyl-5-deoxy-5-amino-,D-lyxofuranoside
2,3-0-isopropylidine-1-O-butyl-5-deoxy-5-amino-,D-lyxofuranoside
2,3-O-isopropylidine-1-O-heptyl-5-deoxy-5-amino-,D-lyxofuranoside
2,3-O-isopropylidine-1-O-decyl-5-deoxy-5-amino-,D-lyxofuranoside
Step-3: 2,3-O-isopropylidene-1 -O-dodecyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxo ethyl)phenyl]amino carbonyl amino}-a,D-lyxofuranoside
To a cold (0-5°C) solution of the above amine (0.5 g, 1.4 mmol) in dry methylene chloride (10 ml), was added a solution of methyl ester of p- isocyanate-4-phenyl acetic acid (260 m g, 1.4 mmol) in dry methylene chloride. The reaction mixture was stirred at the same temp, for about 3 hours. Excess of methylene chloride
was added to it, washed with water and brine. Dried the organic layer over anhydrous Na2SO4 , the solvent was removed under vacuum to get an oily
product and this was purified by column chromatography over silica using ethyl acetate-hexane (20:80) mixture as an eluent to get a white solid in 80% yield.
The compounds prepared similarly.as described in step 3 of example 1 were as follows :
2,3-O-isopropylidene-1-O-methyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-a,D-lyxofuranoside 2,3-O-isopropylidene-1-O-butyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-a,D-lyxofuranoside 2,3-O-isopropylidene-1-O-heptyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-a,D-lyxofuranoside 2,3-O-isopropylidene-1-O-decyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-a,D-lyxofuranoside
EXAMPLE 2
Preparation of 2,3-O-isopropylidene-1 -O-dodecyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]amino carbonyl amino}-a,D-lyxofuranoside (Compound No. 5).
A mixture of the ester obtained in step 3 of example 1 (0.3 g) and aqueous sodium hydroxide (1N 10 ml) was heated at 50°C for about 2 hours. The reaction mixture was cooled to 0-5°C, and acidified to pH-3 with 3N HCI. The white solid separated converted to the oily product on keeping at room temperature. This
product was extracted with ethyl acetate, washed with water and dried over anhydrous Na2SO4. The solvent was removed under vacuum to get an oily
mass. The crude oily mass was purified by column chromatography by eluting with ethyl acetate-hexane (35:60) mixture to get pure product in 71% yield.
Thecompoundspreparedsimilarlywereasfollows: 2,3-0-isopropylidene-1-0-methyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonylamino}-a,D-lyxofuranoside (Compound No.1) 2,3-O-isopropylidene-1-O-butyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonylamino}-a,D-lyxofuranoside (Compound No.2) 2,3-O-isopropylidene-1-O-heptyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonylamino}-a,D-lyxofuranoside (Compound No.3) 2,3-O-isopropylidene-1-O-decyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonylamino}-,D-lyxofuranoside (Compound No.4)
EXAMPLE 3
Preparation of 2,3-O-isopropylidene-1-0-alkyl or alkyl aryl-5-deoxy-5-N-{[4-(chloro, methyl or methoxy)-phenyl]amino carbonyl amino}-a,D-lyxofuranoside (Compound No. 5)
The desired amine, prepared similarly as described in step 2 of example 1 was reacted with appropriate isocyanate by using the same procedure as described in step 3 of Example 1 to get the title compound.
The compounds prepared similarly were as follows :
2,3-O-isopropylidene-1-O-methyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino} a.D-lyxofuranoside (Compound No.6)
2,3-O-isopropylidene-1-O-butyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-lyxofuranoside (Compound No.7)
2,3-O-isopropylidene-1-O-heptyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-lyxofuranoside (Compound No.8)
2,3-O-isopropylidene-1-O-decyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-lyxofuranoside (Compound No.9)
2,3-O-isopropylidene-1-O-dodecyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl amino}a,D-lyxofuranoside (Compound No. 10)
2,3-O-isopropylidene-1-O-methyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl amino}a,D-lyxofuranoside (Compound No.11) 2,3-O-isopropylidene-1-O-butyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonylamino}a,D-lyxofuranoside (Compound No. 12)
2,3-O-isopropylidene-1-O-heptyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl amino}a,D-lyxofuranoside (Compound No. 13)
2,3-O-isopropylidene-1-O-decyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl amino}a,D-lyxofuranoside (Compound No. 14)
2,3-O-isopropylidene-1-O-dodecyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl amino},D-lyxofuranoside (Compound No. 15)
2,3-O-isopropylidene-1-O-methyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-lyxofuranoside (Compound No. 16)
2,3-O-isopropylidene-1-O-butyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-lyxofuranoside (Compound No. 17)
2,3-O-isopropylidene-1-O-heptyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-lyxofuranoside (Compound No. 18)
2,3-O-isopropylidene-1-O-decyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-lyxofuranoside (Compound No. 19)
2,3-O-isopropylidene-1-O-dodecyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-lyxofuranoside (Compound No.20)
EXAMPLE 4
Preparation of 2,3-O-isopropylidene-1 -O-dodecyl-5-deoxy-5-N-{[aminocarbonyl amino] phenyl acetyl-L-Leucyl- ,L-Aspartyl-L-Valyl-L-Proline}-,D-lyxofuranoside (Compound No. 21)
To asuspention of 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (2.30 gm) and 1-hydroxybenzotriazolehydrate (1.53 gm) in ethylacetate (100 ml) was added triethyl amine (1 ml) at room temp, and the reaction mixture was stirred for about 30 min. A mixture of acid as obtained in example 2 (5.3 gm) and Leu-Asp(oBzl)Val-Pro(oBzl) hydrochloride (6.58 gm.) was added to it and stirred for about 24 hrs. The reaction mixture was poured into water and extracted with
methylene chloride followed by washing with saturated sodium bicarbonate solution, water and brine. Dried over anhydrous Na2SO4 and solvent was
removed under reduced pressure to get white foamy solid which was used for the next step without further purification.
To a solution of above benzyl ester (2.0 gm) in ethyl acetate (50 ml) was added Pd/C (0.2 gm) at room temperature and subjected to hydrogenation using parr
shaker for about 5 hrs. The catalyst was filtered and solvent was removed under vacuum to obtain a low melting solid in 84% yield. The product shows a single homogeneous spot on TLC. Similarly following other compounds were prepared :
2,3-0-isopropylidene-1-0-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]phenylacetyl-a,L-Aspartyl-L-Valyl-L-Proline}-,D-lyxofuranoside (Compound No. 22) 2,3-0-isopropylidene-1-O-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]phenylacetyl-L-Valyl-L-Proline}-a,D-lyxofuranoside (Compound No. 23)

We Claim:
1. ' A process for preparing compounds of Formula II (as shown in the accompanied drawings) and it's pharmaceticlly acceptable salts, Wherein
R is C1-C15 alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl or alkylaryl,
R1 is SO2C6H5, SO2C6H4CH3-p, SO2C6H4CI-p, phenyl or substituted phenyl represented as C6H4R'"-p wherein R'" is Cl, N02, OCH3, CH3 CH2COOH, CH2COOCH3, CH2COLDVP, CH2CODVP, CH2COVP wherein LDVP, DVP and VP represent (Leucyl-aspartyl-valyl-propyl) tripeptide (aspartyl-valyl-prolyl) and dipepdide (valyl-prolyl) respectively;
which comprises reacting 2,3-O-isopropylidene-O-deoxy-1-O-alkyl, alkene, alkyne (straight chain or branched), aryl substituted aryl or alkyl aryl, with 5-tosyl--D-lyxofuranoside qf Formula XllI With. sodium azide followed by reduction with Lithium Aluminium Hydride (LAH) to afford the desired amine of Formula XIV, as shown in the accompanied drawings, which is subsequently treated with suitable isocyanates, R'NCO wherein R' is SO2C6H5, SO2C6H4CH3-p, S02C6H4CI-p, C6H4CH2-COOCH3 C6H4CH2COOH, C6H4R'"-p wherein R'" is Cl, NO2, OCH3, CH3, 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 to give the compound of Formula II wherein R and R' are same as defined above.
2. The process for the preparation of compounds of Formula II, substantially as herein described and illustrated by the example herein.