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 divisiional applicatoin out of the application No.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 th '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 VUA4 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. 9A 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 (ChJsolm 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, vh 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 II as shown in the accompanied drawings,
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 acidic residues such as carboxylic acids; and the like.
A process for the preparation of derivatives of monosaccharides as novel cell adhesion inhibitors of Formula II (as shown in the accompanied drawings) and it's pharmaceutically acceptable salts, wherein
R is C1-C-15 alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl or alkylaryl,
R' is SO2C6H5, SO2C6H4CH3-p, SO2C6H4CI-p, phenyl or substituted phenyl represented as C6H4R'"-p wherein R'" is Cl, NO2, 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 2,3-0-isopropylidene-5-deoxy-1-O-alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl or alkyl aryl, with 5-tosyl--D-lyxofuranoside of 2,3-O-isopropylidene-5-deoxy-1-O-(alkyl alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl or alkyl aryl)-5-tosyl--D-lyxofuranoside (Formula XIII) with sodium azide in an organic solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, diethylether or dioxane at temperature ranging from 50-to140°C followed by reduction with Lithium Aluminium Hydride (LAH) in an organic solvent selected from the group consisting of tetrahydrofuran, dimethylformide, dioxane or diethylether 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, SO2C6H4CI-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.
Similarly, this amine is reacted with suitable sulfonyl isocyanates to give the corresponding sulfonylurido compounds of Formula II wherein R is SC^CeHg, SO2C6H4CH3-p or SO2C6H4CI-p). when R1 is -C6H4-CH2-COOCH3, the corresponding free carboxylic acid is obtained by hydrolysis with aqueous sodium hydroxide.
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, reducing agents etc. are mentioned, it is to be understood that the other acids, bases, solvents,
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 include:
Compound Chemical Name
No.
1 2,3-O-isopropylidene-1-O-methyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-a,D-lyxofuranoside
2 2,3-O-isopropylidene-1-O-butyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-,D-lyxofuranoside
3 2,3-O-isopropylidene-1-O-heptyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-,D-lyxofuranoside
4 2,3-O-isopropylidene-1-O-decyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-,D-lyxofuranose
5 2,3-O-isopropylidene-1-O-dodecyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonyl amino}-,D-lyxofuranoside
6 2,3-O-isopropylidene-1-O-methyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
amino},D-lyxofuranoside
7 2,3-O-isopropylidene-1-O-butyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
amino},D-lyxofuranoside
8 2,3-O-isopropylidene-1-O-heptyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
amino}D-lyxofuranoside
9 2,3-O-isopropylidene-1-O-decyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
amino},D-lyxofuranoside
10 2,3-O-isopropylidene-1-O-dodecyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
amino},D-lyxofuranoside
11 2,3-O-isopropylidene-1 -O-methyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl
amino},D-lyxofuranoside
12 2,3-O-isopropylidene-1 -0-butyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl
amino},D-lyxofuranoside
13 2,3-O-isopropylidene-1 -O-heptyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl
amino},D-lyxofuranoside
14 2,3-O-isopropylidene-1-O-decyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl
amino},D-lyxofuranoside
15 2,3-O-isopropylidene-1 -O-dodecyl-5-deoxy-5-N-{[4-methoxyphenyl]amino
carbonylamino}D-lyxofuranoside
15. 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl
amino},D-xylofuranose
16. 1,2-0-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino}, D-
xylofuranose
17. 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino} ,D-
xylofuranose
18. 1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino} ,D-
xylofuranose
19. 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino} ,D-
xylofuranose
20. 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},-
xylofuranose
21. 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]phenyl
cetyl-L-Leucyl-a,L-Aspartyl-L-Valyl-L-Proline}-,D-xylofuranose
22. 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]phenyl
cetyl-,L-Aspartyl-L-Valyl-L-Proline}-,D-xylofuranose
23. 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]
phenylacetyl-alyl-L-Proline}-,D-xylofuranose
24. 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
minocarbonylamino}-,D-ribofuranose
25. 1,2-0-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-,D-ribofuranose
26. 1,2-O-isopropylidene-3-O-heptyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-,D-ribofuranose
27.' 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl] aminocarbonylamino}-,D-ribofuranose
28. 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]
aminocarbonylamino}-a,D-ribofuranose
29. 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
amino},D-ribofuranose
30. 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
' amino},D-ribofuranose
31. 1,2-O-isopropylidene-3-O-heptyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
amino},D-ribofuranose
32. 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
amino},D-ribofuranose
33. 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl
. amino}a,D-ribofuranose
34. 1,2-0-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-methoxyphenyl]
aminocarbonylamino},D-ribofuranose
35. 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl
amino},D-ribofuranose
36. 1,2-O-isopropylidene-3-O-heptyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl
amino},D-ribofuranose
37. 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl
amino}.D-ribofuranose
38. 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl
amino},D-ribofuranose
39. 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino}, D-
ribofuranose
40. 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino} ,D-
ribofuranose
41. 1,2-O-isopropylidene-3-O-heptyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino} a, D-
ribofuranose
42. 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino} ,D-
ribofuranose
43. 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-
ribofuranose
44. 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylaminophenyl]
acetyl-L-Leucyl-a,L-Aspartyl-L-Valyl-L-Proline}-,D-ribofuranose
45. 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylaminophenyl]
acetyl-,L-Aspartyl-L-Valyl-L-Proline}-,D-ribofuranose
46. 12-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylaminophenyl]
acetyl-L-Valyl-L-Proline}-,D-ribofuranose
The examples mentioned below demonsrate the general synthetic procedure as well as he 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 solvent 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 various XL-300 MH2 instrument using tetramethyl silane as an intermediate standated. CIMS were obtained on a Finnigan MAT-4510 mass spectrometer equipped 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°C source temp.)
EXAMPLE 1
Preparation of 1,2-O-isopropylidene-3-0-dodecyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]amino carbonyl amino}-,D-xylofuranose
Step-1: 1,2-O-isopropylidene-3-O-dodecyl-4-carboxaldehyde-,D-glucofuranose
To a suspension of 1,2-O-isopropylidene-3-0-dodecyl-,D-gucofuranose ( 20.0g) (prepared by following the method as reported in U.S.Pat.No.5,360,792 ) in water (20 ml) at 0-5°C, was added dropwise a solution of sodium periodate 20g dissolved in 60ml of water and the reaction mixture thus obtained was stirred at room temperature for about 10 hours. Excess of ethanol was added to the reaction mixture the separated white salt was filtered out and discarded. Solvent was evaporated under vacuum and ethylacetate was added to the residue. Washed with water, dried over anhydrous sodium sulphate and solvent was removed under vacuum to get an oily product in 81% yield.
The compounds prepared similarly were as follows : 1,2-O-isopropylidene-3-O-methyl-4-carboxaldehyde-,D-glucofuranose
1,2-O-isopropylidene-3-O-butyl-4-carboxaldehyde-,D-glucofuranose 1,2-O-isopropylidene-3-O-hexyl-4-carboxaldehyde-,D-glucofuranose 1,2-O-isopropylidene-3-O-decyl-4-carboxaldehyde-,D-glucofuranose
Step-2: 1,2-O-isopropylidene-3-0-dodecyl-4-oximino-,D-glucofuranose
To a solution of hydroxylamine hydrochloride (12.0 gm) in pyridine (50 ml) at room temperature was added a solution of aldehyde in ethanol (15.0 gm in 30 ml ethanol) and heated the reaction mixture at 75 OC for about 24 hours. Pyridine was removed under vacuum, water was added to it and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate and the solvent was removed under vacuum. The crude product so obtained was purified by column chromatography using ethyl acetate (15 : 85) as an eluent to afford a pure product in 90% yield.
The other compounds prepared in the similar fashion were as follows :
1,2-O-isopropylidene-3-O-methyl-4-oximino-,D-glucofuranose
1,2-O-isopropylidene-3-O-butyl-4-oximino-,D-glucofuranose
1,2-O-isopropylidene-3-O-hexyl-4-oximino-,D-glucofuranose
1,2-O-isopropylidene-3-O-decyl-4-oximino-a,D-glucofuranose
Step-3 : 1,2-0-isopropylidene-3-O-dodecyl-5 -deoxy-5-amino-,D-xylofuranose
To a suspension of lithium aluminium hydride (6.0 g) in dry THF (50 ml) at 0-5OC , was added a solution of oxime obtained from step 2 (16.0 g dissolved in 80 ml of THF) dropwise. Once the addition was over the reaction mixture was further stirred at room temperature for about 4 hours. The excess of LAH was decomposed by addition of ice-water mixture filtered the reaction mixture through celite and washed the bed with THF. The solvent was removed under vacuum, dissolved the residue in ethyl acetate, washed with water and brine. Dried the organic layer over anhydrous sodium sulphate and removed the solvent under vacuum completely to get an oily product. This was purified by column chromatography over silica using ethylacetate as an eluent to get viscous oil in 68% yield.
The other compounds prepared similarly were as follows :

1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-amino-,D-xylofuranose 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-amino-,D-xylofuranose 1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-amino-,D-xylofuranose 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-amino-,D-xylofuranose
Step-4 : 1 ,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-(2-methoxy-2-
oxoethyl)phenyl] amino carbonyl amino}-,D-xylofuranose
To a cold (0-5°C) solution of amine obtained from Step - 3 (2.4 g, 8.12 mmol) in dry methylene chloride (10 ml), was added a solution of methyl ester of p-isocyanate-4-phenyl acetic acid (1.5 g, 8.12 mmol) dissolved in dry methylene chloride at 0-5°C dropwise and the reaction mixture was stirred at same temp.
for about 3 hours. Added excess of methylene chloride, washed with water and brine. Dried the methylene chloride layer over anhydrous Na2SO4 and removed
the solvent under vacuum to get an oily material. The product was purified by column chromatography using ethyl acetate-hexane mixture (20:80) as an eluent to get a pure white solid in 63% yield of the pure product, m. p. 74-75 OC
The compounds prepared similarly.as described in step 4 of example 1 were as follows :
1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-xylofuranose 1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-xylofuranose 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-xylofuranose 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethylphenyl]aminocarbonyl amino}-,D-xylofuranose
EXAMPLE 2
Preparation of 1 ,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]amino carbonyl amino}-,D-xylofuranose (Compound No.1)
A mixture of ester as obtained in step 4 of example 1 (2.7 gm) and aqueous sodium hydroxide (1N, 30 mL) was heated at 50 °C for about 2 hours. Cooled

the'reaction mixture to 0-5°C and acidified to pH-3 with 3N HCI to get a white solid which became oil on keeping it at room temperature. This product was extracted with ethyl acetate, washed with water, dried over anhydrous Na2SO4
and the solvent was removed under vacuum to get an oily product. The crude product was purified by column chromatography over silica using ethyl acetate-hexane (35 : 65) as an eluent to get a white solid in 87% yield, m. p. 94-95 °C
The other compounds prepared similarly were as follows: 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonylamino}-a,D-xylofuranose (Compound No.2) 1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonylamino}-,D-xylofuranose (Compound No.3) 1,2-O-isopropylidene-3-0-butyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-xylofuranose (Compound No.4) 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonylamino}-,D-xylofuranose (Compound No.5)
EXAMPLE 3
Preparation of 1,2-0-isopropylidene-3-0-alkyl or alkylaryl-5-deoxy-5-N-{[4-(chloro,methyl or methoxy)-phenyl]amino carbonyl amino}-a,D-xylofuranose
The desired amine, prepared similarly as described in step 3 of example 1 was reacted with appropriate isocyanate by using the same procedure as described in step 4 of Example 1 to get the title compound.
The compounds prepared similarly were as follows : 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-chlorophenylaminocarbonyl amino},D-xylofuranose (Compound No.6)
1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-xylofuranose (Compound No.7)
1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-xylofuranose (Compound No.8)
1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-xylofuranose (Compound No.9)
1,2-0-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonyl amino}a,D-xylofuranose (Compound No. 10) 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonylamino}DD-xylofuranose (Compound No.11) 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl amino},D-xylofuranose (Compound No. 12) 1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonylamino},D-xylofuranose (Compound No.13) 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl amino},D-xylofuranose (Compound No. 14)
1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonyl amino}a,D-xylofuranose (Compound No. 15)
1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-xylofuranose (Compound No. 16)
1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-tolyl]aminocarbonyl amino},D-xylofuranose (Compound No.17)
1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-N-{[4-tolyl]aminocarbonyl amino} a,D-xylofuranose (Compound No. 18) 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-tolyl]aminocarbonyl amino} ,D-xylofuranose (Compound No. 19)
1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-xylofuranose (Compound No.20)
EXAMPLE 4
Preparation of 1,2-O-isopropylidene -3-O-dodecyl-5-deoxy-5-N-{[aminocarbonyl amino] phenyl acetyl-L-Leucyl- ,L-Aspartyl-L-Valyl-L-Proline}- ,D-xylofuranose (Compund No: 21)
To asuspention of 1-(3-Dimethylaminopropyl)-3-ethylcarbodimide (1.6 gm) and 1-hydroxybenzotriazole hydrate (1.1 gm) in DMF (60 ml) was added triethyl amine (1.0 ml) at room temperature and the reaction mixture was stirred for about 30 min. A mixture of the acid as obtained in example 2 (3.5 gm) and Leu-Asp(oBzl)Val-Pro(oBzl) hydrochloride (4.09 gm.) were added simultaneusly to the reaction mixture and stirred for about 24 hrs. The reaction mixture was poured into water, extracted with methylene chloride followed by washing with
saturated sodium bicarbonate solution water and brine. Dried the methylene chloride layer over anhydrous Na2SO4 and solvent was removed under reduced
pressure to get white foamy solid which was used for the next step without any purification.
To a solution of above benzyl ester (0.8 gm) in ethylacetate(70 ml) was added Pd/C (0.2gm) at 25-30°C and subjected to hydrogenation using parr shaker for 5 hrs. The catalyst was filtered and solvent was removed to obtain a white solid in 56 % yield.
Similarly following compounds were prepared :
1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]phenylacetyl-,L-Aspartyl-L-Valyl-L-Proline}-a,D-xylofuranose (Compound No.22) 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylamino]phenylacetyl-L-Valyl-L-Proline}-a,D-xylofuranose (Compound No.23)
EXAMPLE 5
Preparation of 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]amino carbonyl amino}-,D-ribofuranose
Step-7: 1,2-O-isopropylidene-3-O-dodecyl-4-carboxaldehyde-,D-allofuranose
1,2-O-lsopropylidene-3-0-Dodecyl-a-D-allofuranose (prepared by the procedure known in the literature), was oxidised with sodium perroiodate by the procedure as described in step 1 of example 1 in 76 % yield.
The other compounds prepared similarly were as follows :
1,2-O-isopropylidene-3-O-methyl-4-carboxaldehyde-,D-allofuranose
1,2-O-isopropylidene-3-O-butyl-4-carboxaldehyde-,D-allofuranose
1,2-O-isopropylidene-3-O-hexyl-4-carboxaldehyde-,D-allofuranose
1,2-O-isopropylidene-3-O-decyl-4-carboxaldehyde-,D-allofuranose
Step-2: 1,2-O-lsopropylidene-3-O-dodecyl-4-oximino-,D-allofuranose
Aldehyde (obtained in step 1) was reacted with Hydroxyl amine HCI by following
the method used in step 2 of example 10 in 80 % yield.
The compounds prepared similarly were as follows :
1,2-0-isopropylidene-3-O-methyl-4-oximino-,D-allofuranose
1,2-O-isopropylidene-3-O-butyl-4-oximino-,D-allofuranose
1,2-O-isopropylidene-3-O-hexyl-4-oximino-,D-allofuranose
1,2-O-isopropylidene-3-O-decyl-4-oximino-a,D-allofuranose
Step-3 : 1,2-0-isopropylidene-3-0-dodecyl-5 -deoxy-5-amino-,D-ribofuranose
Oxime obtained from step 2 was reduced with LAH by using the same procedure as outlined in step 3 of Example 1 in 79 % yield.
The compounds prepared similarly were as follows :
1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-amino-,D-ribofuranose
1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-amino-,D-ribofuranose
1,2-O-isopropylidene-3-O-hexyl-5-deoxy-5-amino-,D-ribofuranose
1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-amino-,D-ribofuranose
Step-4:1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonylamino}-,D-ribofuranose
The amine obtained in step 4 was reacted with methyl ester of p-isocyanate 4-phenyl acetic acid by following the method as described in step 4 of example 1 to get the desired ureido compound in 68 % yield.
The compounds prepared similarly.as described in step 4 of example 5 were as follows :
1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-ribofuranose 1,2-0-isopropylidene-3-O-hexyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-ribofuranose 1,2-0-lsopropylidene-3-O-butyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-ribofuranose 1,2-O-lsopropylidene-3-O-methyl-5-deoxy-5-N-{[4-(2-methoxy-2-oxopthyl)phenyl]aminocarbonyl amino}-,D-ribofuranose
EXAMPLE 6
Preparation of 1,2-O-isopropylidene-3-0-dodecyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]amino carbonyl amino}-,D-ribofuranose (Compound No. 24)
The ester obtained in step 4 of example 5 was hydrolysed with aqueous sodium hydroxide (1N) following the same procedure as outlined in example 2 in 70% yield.
The compounds prepared similarly were as follows: 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-ribofuranose (Compound No. 25) 1,2-O-isopropylidene-3-O-hepyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-ribofuranose (Compound No. 26) 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonyl amino}-,D-ribofuranose (Compound No. 27) 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-(2-hydroxy-2-oxoethyl)phenyl]aminocarbonylamino}-,D-ribofuranose (Compound No. 28)
EXAMPLE 7
Preparation of 1,2-O-isopropylidene-3-O-alkyl or alkylaryl-5-deoxy-5-N-{[4-(chloro,methyl or methoxy)-phenyl]amino carbonyl amino}-,D-ribofuranose
The amine prepared following the same procedure as described in step 3 of example 1 was reacted with appropriate isocyanate by following the same procedure as described in step 4 of Example 1 to get the title compound.
The compounds prepared similarly were as follows : 1,2-0-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-ribofuranose (Compound No. 29) 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-ribofuranose (Compound No. 30)
1,2-O-isopropylidene-3-0-heptyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-ribofuranose (Compound No. 31)
1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-ribofuranose (Compound No. 32) 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-chlorophenyl]aminocarbonylamino},D-ribofuranose (Compound No. 33) 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonylamino},D-ribofuranose (Compound No. 34) 1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-
methoxyphenyl]aminocarbonylamino},D-ribofuranose (Compound No. 35) 1,2-O-isopropylidene-3-O-heptyl-5-deoxy-5-N-{[4-
methoxyphenyl]aminocarbonylamino},D-ribofuranose (Compound No. 36) 1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-
methoxyphenyl]aminocarbonylamino},D-ribofuranose (Compound No. 37) 1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-methoxyphenyl]aminocarbonylamino},D-ribofuranose (Compound No. 38) 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-ribofuranose (Compound No. 39)
1,2-O-isopropylidene-3-O-decyl-5-deoxy-5-N-{[4-tolyl]aminocarbonyl amino},D-
ribofuranose (Compound No. 40)
1,2-O-isopropylidene-3-O-heptyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino} ,D-
ribofuranose(CompOUnd No. 41)
1,2-O-isopropylidene-3-O-butyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-ribofuranose (Compound No. 42)
1,2-O-isopropylidene-3-O-methyl-5-deoxy-5-N-{[4-tolyl]aminocarbonylamino},D-ribofuranose (Compound No. 43)
EXAMPLE 8
Preparation of 1,2-0-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[ amino carbonyl amino phenyl ] acetyl-L-Leucyl-,L-Aspartyl-L-Valyl-L-Proline }-,D-ribofuranose (Compound No. 44)
The above compound was prepared by reacting the acid obtained in example 6 with Leu-Asp(oBzl) Val-Pro (oBzl) hydrochloride by following the procedure as described in example 4 in 74% yield.
The compounds prepared similarly were as follows:
1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylaminophenyl]acetyl-a,L-Aspartyl-L-Valyl-L-Proline}-,D-ribofuranose (Compound No. 45) 1,2-O-isopropylidene-3-O-dodecyl-5-deoxy-5-N-{[aminocarbonylaminophenyl]acetyl-L-Valyl-L-Proline }-,D-ribofuranose (Compound No. 46)

We Claim:
1. A process for the preparation of derivatives of monosaccharides as novel cell adhesion inhibitors of Formula II (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 or alkylaryl,
R' is SO2C6H5, SO2C6H4CH3-p, SO2C6H4CI-p, phenyl or substituted phenyl represented as C6H4R'"-p wherein R'" is Cl, NO2, 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-5-deoxy-1-O-alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl or alkyl aryl, with 5-tosyl--D-lyxofuranoside of 2,3-0-isopropylidene-5-deoxy-1 -O-(alkyl alkyl, alkene, alkyne (straight chain or branched), aryl, substituted aryl or alkyl aryl)-5-tosyl--D-lyxofuranoside (Formula XIII) with sodium azide in an organic solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, diethylether or dioxane at temperature ranging from 50-to140°C followed by reduction with Lithium Aluminium Hydride (LAH) in an organic solvent selected from the group consisting of tetrahydrofuran, dimethylformide, dioxane or diethylether 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, SO2C6H4CI-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 derivatives of monosaccharide compounds of Formula II, substantially as herein described and illustrated by the example herein.