EP1575587A1

EP1575587A1 - Iminosugar derivatives as glucosidase inhibitors

Info

Publication number: EP1575587A1
Application number: EP02808072A
Authority: EP
Inventors: Jasbir Singh Arora; Nidhi Gupta; Mohammad Salman; Geeta Sharma; Jang Bahadur Gupta; Upendra Kumar Pandit
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2002-10-29
Filing date: 2002-10-29
Publication date: 2005-09-21
Also published as: WO2004039373A1; AU2002368314A1

Abstract

Bis- and trisazasugar derivatives and processes for the preparation thereof are disclosed herein. The disclosed compounds have α-glucosidase inhibiting properties, and are useful in the treatment of diabetes. Pharmaceutical compositions containing the disclosed compounds and their use as anti-diabetic agents is also disclosed (Formula I).

Description

IMINOSUGAR DERIVATIVES AS GLUCOSIDASE INHIBITORS

Field of the Invention

The present disclosure relates to iminosugar derivatives and processes for the preparation thereof. The disclosed compounds have c-glucosidase inhibiting properties, and are useful in the treatinent of diabetes. The present disclosure also relates to pharmaceutical compositions containing the disclosed compounds and to their use as anti- diabetic agents.

Background of Invention Carbohydrates mainly in the form of poly- or di-saccharides are major dietary constituents. Enzymatic degradation of these complex carbohydrates to monosaccharides is an essential prerequisite for their absorption and is mediated by a class of enzymes known as glucosidases. Other than intestinal digestion, glucosidases are involved in a wide range of important biological processes such as post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. α-Glucosidase is one such member of this class responsible for the breakdown of sucrose, maltose, trehalose and starch into simple sugars for absorption. This enzyme is present at the brush border membrane of enterocytes in the small intestine. Modulation of carbohydrate absorption via inhibition of the luminal α-glucosidase enzyme effectively reduces postprandial hyperglycaemia and thus, improves glycaemic control in patients with Non-Insulin

Dependent Diabetes Mellitus (NTDDM or Type-II diabetes). Other than its therapeutic role in NIDDM, α-glucosidase inhibitors may be useful in inhibition of tumour metastasis and viral replication.

1-Azasugars are a very potent class of glucosidase inhibitors. Pyranoses and furanoses with the ring oxygen replaced by an imino group are useful as potent glucosidase inhibitors. A review on glycosylation in Drug Discovery, I, 66-75 (2002) describes the potential of imino sugars and their mechanism of action.

A large number of α-glucosidase inhibitors were originally isolated from cultures of various species of streptomyces and strains of the genus Bacillus, but are now synthesized.

Deoxynojirimycin (DNJ) and several of its derivatives potently inhibit both α- and β-glucosidases and exhibit interesting biological activities. Several of its derivatives have been described in United States Patent Nos 5,273,981 to German et al, 5,451,679 to Barta et al, 5,595,981 to Bart et al., 5,663,342 to Barta et al., and WO 00/39140.

There are three α-glucosidase inhibitors (AGI's) which are currently being used. Acarbose, which is an oligosaccharide slows down the breakdown of disaccharides and polysaccharides and other complex carbohydrates into monosaccharides. The enzymatic generation and subsequent absorption of glucose is delayed and the postprandial blood glucose values, which are characteristically high in patients with type II diabetes, are reduced with acarbose. AGIs do not prevent the absorption of carbohydrates and complex sugars, but they do delay their absorption. Besides acarbose, other AGI's include miglitol and voglibose. Miglitol, which is a pseudomonosaccharide (hydroxyethyl derivative of deoxynojirimycin) and acarbose appear to be equally effective, but miglitol is generally preferred. Acarbose has occasionally been associated with liver toxicity and requires liver monitoring, whereas miglitol does not. Neither appears to have any significant drug interactions. Voglibose (3,4-dideoxy-4-[[2-hydroxy-l-(hydroxymethyl) ethyl] amino] -2-C-(hydroxymethyl)-D-epi-inositol), disclosed for example in United States Patent No. 4,701,559 to Horii et al., is a potent α-glucosidase inhibitor, the therapeutic dosage being 0.1 and 0.2 mg as compared to 50 mg and 100 mg for acarbose and miglitol.

Glucosidase inhibitors have the potential to produce several beneficial therapeutic effects including reduction of rise in postprandial blood glucose levels (See United States Patent No. 4,634,765), inhibition of tumour metastasis (See Dennis J.W„ Cancer Research, 46, 5131 (1986)), and inhibition of viral replication (see Tyms et al., EEES Eett., 237, 128 (1988)).

A combinatorial approach towards the synthesis of five membered imino-cyclitols with inhibitory activities against glyco-enzymes have been discussed in Chemistry and Biology, 8, 1061-1070 (2001). Several aza-C-disaccarides acting as glucosidase inhibitors have been described mJ.Am. Chem. Soc. 119, 4856-4865 (1997). Syntheses of diverse scaffolded bis-1,1 '-C-linked azasugars has been discussed in Tet. Lett. 39, 749- 752 (1998). Syntheses of polyhydroxy 6-oxa-nor-tropanes, a new class of glucosidase inhibitors have been disclosed in J. Org. Chem._z 66, 7604-7614 (2001). Several other glucosidase inhibitors and their preparations are described in J Chem. Soc. 123, 5116- 5117, (2001); Bioorg. Med. Chem._^ Z 1241-1246 (1999); J. Org. Chem, 65, 4871-4882 (2000); Tetrahedron, 56, 971-978, (2000); BioorgMed. Chem. Lett., 9, 615-618 (1999); Tetrahedron, 57, 8773-8778 (2001); and Bioorg. Med. Chem. 9, 1091-1095 (2001). The therapeutic activities of some of the compounds are also disclosed in the above cited literature. There is still a need for the discovery of new and improved glucosidase inhibitors.

Summary of the Invention

The present invention results from the recognition that particular bis- and tris- azasugars can be useful as glucosidase inhibitors. In particular, bis- and tris-azasugars coupled with urea, thiourea or other linkage at C-6 are useful glucosidase inhibitors. The present invention also results from the recognition that these azasugar compounds can be used to treat diabetes in mammals, and can be used to selectively antagonize - glucosidase receptors in mammals.

It is also an aspect of the invention to provide a process for synthesis of these azasugar compounds .

It is a further aspect of the invention to provide compositions containing these azasugar compounds which are useful in the treatment of diabetes.

It is a still further aspect of this invention to provide methods of treatment for diabetes, involving these azasugar compounds. The present invention also includes within its scope prodrugs of these azasugar compounds. In general, such prodrugs will be functionalized derivatives of these azasugar compounds, which are readily converted in vivo into these azasugar compounds. For example, carboxylic acid esters can be formed from free hydroxyl groups on the azasugar compounds described herein, by reaction with carboxylic acids. Alternatively, carboxylic acid esters can be formed from carboxylic acid groups on the azasugar compounds described herein, by reaction with alcohols. Also, amide linkages can be formed between either amino groups on the azasugar compounds and carboxylic acids, or between carboxylic acid groups on the azasugars and amines. These ester and amide linkages can be hydrolyzed by particular esterases and amidases known to those of ordinary skill in the art.

The invention also includes the enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these azasugar compounds as well as metabolites having the same type of - glucosidase inhibiting activity as these azasugar compounds.

The invention further includes pharmaceutical compositions comprising these azasugar compounds, their prodrugs, metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carriers and optionally included excipients.

In order to achieve the above mentioned objectives and in accordance with purpose of the invention as embodied and described herein, there are provided azasugar derivatives represented by Formula I:

FORMULA I and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein; A represents hydrogen, lower (CrC ) alkyl, lower (C₂-C₄) alkenyl, lower (C₂-C ) alkynyl; X-G represents C=O or CH₂;

R represents hydrogen, alkyl (d-C₆), acyl, aryl, aralkyl such as benzyl; Y represents O or NH;

Z represents C=O, di- or trivalent (CrC₁ ) alkylene, for example linear or branched (Ci-C₆) alkyl; di- or trivalent arylalkyl such as -CFb-CeBL , -CKfe-CeH -CFb, trivalent - (CH₂)₂-C₆H₃-CH₂-, and the like, in all various possible isomers, which may be substituted at the aryl ring or on the alkyl portion; di- or trivalent arylene such as phenylene, naphthalene and the like, which may be substituted at the aryl ring or on the alkyl portion, where the substituent can be a further azasugar ring, as shown, for example, in Scheme IN, for example, Formula XV; di- or trivalent cycloalkyl (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; di- or trivalent 5 to 7 membered heterocyclyl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen, including aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, triazinyl and the like, which may be substituted; di- or trivalent heteroaryl group containing 1 to 4 hetero atoms (nitrogen, sulphur or oxygen), including pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, thiazinyl, tetrazolyl, benzopyranyl, and the like;

B B

|| || , wherein B is selected from sulphur and oxygen and Ri C— NH— Ft,— NH— C is selected from the group consisting (CH₂)_m, where m is an integer ranging from 1-6; di- or trivalent cycloalkylene (C -C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; di- or trivalent arylene such as phenylene, naphthylene and the like, which may be substituted; di- or trivalent 5-7 membered heterocyclyl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen suphur and oxygen, including aziridinyl, pyrrolidinyl, moφholinyl, piperidinyl, piperazinyl and the like, which may be substituted; di- or trivalent 5-7 membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen, including pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, triazinyl, tetrazolyl, benzopyranyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl and the like, which may be substituted; C₆H₄-(CH )_m-C₆H₄-, wherein m is an interger ranging from 1 to 6;

Z further represents the following structures:

wherein the group Ar includes substituted or unsubstituted di- or trivalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, benzopyranyl, pyrazolyl and the like; o o

_ll _ II

I-_* CH₂ R₂ CH c wherein R₂ is selected from the group consisting of the di- and trivalent 5-7- 1 membered heterocyclyl group containing 2 or more hetero atoms selected from the group consisting of nitrogen, sulphur and oxygen, including aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like; and o o

II II

— c— R₃— c — wherein R₃ is selected from the group selected from (CH₂)_m where m is an integer ranging from 1 to 6; di- or trivalent cycloalkylene (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; and di- or trivalent arylene such as phenylene, naphthylene and the like, which may be substituted. Z can also represent R₃ directly. included among the disclosed compounds are derivatives of the particular iminosugars, for example, derivatives of bis-[2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ- lactam], bis-[2,3,4-trihydroxy-N-propyl-D-gluco-δ-lactam], bis-[N-allyl-2,3,4-tri-O- benzyl-l,5-dideoxy-l,5-imino-D-glucitol], tris-[2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ- lactam], and tris [2,3,4-trihydroxy-N-propyl-D-gluco-δ-lactam]. One of ordinary skill in the art will recognize that other amino sugars will be useful in the compounds described herein, for example, those described in Winchester et al., Glycobiology, 2, no. 3, (1992), 199-210, which is hereby incorporated by reference in its entirety. For example, polyhydroxylated piperidines, polyhydroxylated pyrrolidines, polyhydroxylated indolizidines, polyhydroxylated pyrrolizidines, and other derivatives with substituents at the anomeric position, such as aldonolactams of L-fucose, D-galactose, D-glucose, D- glucouronic acid, D- and L-mannose, N-acetyl-D-galactosamine, N-acetyl-D- glucosamine, and D- and L-rhamnose, to name a few examples.

Unless otherwise defined, all technical and scientific terms used herein have the same ordinary meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. Detailed Description of the Invention

The compounds of the present invention may be prepared, for example, according llowing reaction sequences (Schemes I-NII) to yield the compounds of Formula I.

Scheme I

Formula VII

(Formula I, when A=CH₂CH₂CH₃, X-G=C0, R=Bn, Y=NH, Z=C— NH— Rp- NH— C-; where B and R₁ are the same as defined earlier) _{B B} In Scheme I, compounds of Formula I (with A as CH₂CH₂CH₃, X-G as C=O, R as H, Y as NH, and Z as

Z = C- NH— Ri - NH— C — II II

B B wherein B and Rγ are the same as defined earlier) may be prepared by reacting a compound of Formula II (available according to procedures disclosed in Tetrahedron, 50 (14), 4215-4224 (1994), and Tet. Lett, 37 (4), 547-50 (1996)) with ^-toluene sulphonyl chloride in an organic solvent for a period varying between 2-24 hours to give the compound of Formula III. This reaction is carried out in the presence of a base such as triethylamine or diisopropylamine. The organic solvent can be, for example, a chlorinated solvent, such as dichloromethane, dichloroethane or chloroform.

The compound of Formula III, on reaction with sodium azide in a polar aprotic solvent (such as, for example, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), or dimethylacetamide) at a temperature ranging from 10-100°C for a period ranging from one to several hours, gives the compound of Formula IV. The preferred temperature conditions are 70-80°C.

This compound, on catalytic reduction in a polar solvent, yields the corresponding amine of Formula V. The catalyst preferably used in the reduction of azide of Formula TV is Palladium/carbon, the reduction being suitably carried out in, for example, polar protic solvents such as methanol or ethanol. The compound of Formula V, on subsequent reaction with compounds of Formula VI (B=C=N-R₁-N=C=B, wherein B and R_\ are the same as defined earlier) in an aprotic solvent (for example, acetone or acetonitrile) for a period varying between 1 to 30 hours, gives a compound of Formula VII (Formula I, when A is CH₂CH₂CH₃, X-G is CO, R is H, and Y is NH, ^{z= " NH_ Rl " NH_} fi^~ 5

B B wherein B and R_\ are the same as defined earlier). On debenzylation in a polar protic solvent (such as methanol and ethanol) for a period varying between 2-40 hours, compounds of Formula VII give the compounds of Formula VIII (Formula I, when A is CH₂CH₂CH₃, X-G is CO, R is H, Y is NH, ^ ^C- ^NH- _RI-^NH-^C-

B B wherein B and R_\ are the same as defined earlier).

The specific compounds depicted in Scheme I, or any other scheme presented herein, do not limit the scope of the invention as defined by the appended claims.

Starting materials for Schemes I- VII may be readily chosen by one of ordinary skill in the art to produce any of the specific compounds of Formula I. Scheme II

la X in -Xylene, p-Xylene) Formula IX

Formula XI (Formula I, A = CH2CHCH₂ X-G=CH₂, R=Bn, Y=0, Z=R₃ as defined earlier)

Compounds of Formula XI (Formula I, where A is CH₂CH=CH₂, X-G is CH₂, R is Bn, Y is O, and Z is R₃, wherein R₃ is, for example, m-xylene or/?-xylene) can be prepared by methods which are exemplified in Scheme II. Compounds of Formula II are reduced in organic solvents such as tetrahydrofuran or diethylether to give compounds of Formula IX. The reaction is carried out at about 20-70°C for a time period of 2-20 hours. The preferable temperature range is 30-50°C. The reducing agent preferably used in the reaction is lithium aluminium hydride.

Compounds of Formula IX, on condensation with compounds of Formula X (R₃Br₂ wherein R₃ is as defined earlier) in the presence of a base and a polar aprotic solvent, yield compounds of Formula XL The condensation reaction is carried out in presence of an inorganic base, for example, sodium hydride, cesium carbonate, sodium carbonate or potassium carbonate. Suitable organic solvents include dipolar aprotic solvents, such as DMSO, DMF and dimethylacetamide. Preferable temperature conditions for the reaction can be, for example, 0°-25°C.

Scheme III

Formula XII Cl

(Formula I, A = CH₂CH₂CH₃ X-G=CO, R=Bn, Y=NH, Z= I ϊ )

/ N ^

Scheme III exemplifies some syntheses of compounds of Formula XII (Formula

include condensing compounds of Formula V with cyanuric chloride (also known as chlorotriazine, trichlorocyanidine, tricyanogen chloride, cyanuric acid trichloride, or 2,4,6-trichloro-s-triazine) in the presence of abase in a suitable solvent (such as, for example, acetone and acetonitrile) at a temperature ranging from 0° to 80°C to yield the compound of Formula XII. The base can be an inorganic or organic base, such as potassium carbonate, sodium carbonate, triethylamine and diisopropylamine. Scheme IN

Formula XV

(Formula I, A = CH₂CH₂CH_3j X-G=CO, R=H, Y=NH, Z=

Compounds of Formula I (more specifically, compounds of Formulas XIN and

XN) can also be prepared by methods illustrated in Scheme IN. The methods include condensation of Formula N with a compound of Formula XIII in presence of an organic base (for example, triethylamine or diisopropylamine) in a suitable solvent (such as an organic solvent, for example chlorinated solvents such as dichloromefhane, dichloroethane or chloroform) at a temperature ranging from 0° to 50°C preferably at 10-

s

which on debenzylation in a solvent for a period varying between 2-40 hours yields a compound of Formula CH₂CH₃, X-G is CO, R is H, Y is

The debenzylation of compounds of Formula XIV can be carried out in polar protic solvents, such as methanol or ethanol.

Scheme V

Formula XVI

Solvent/base

Formula XVII

(Formula I, A = CH2CH₂CH_3; X-G=CO, R=Bn, Y=NH, Z= — c— CH₂-N N— CH₂-C- o ^ — o

Debenzylation

Formula XVIII (Formula I, when A = C4>CH₂CH_3j X-G=CO, R=H, Y=NH, Z= C— CH₂— N / λ N— CH₂— C — )

O O Scheme N can be used to illustrate transformations resulting in compounds of

Formula XNII and XNIII, which correspond to particular examples of Formula I. In

Scheme N, compounds of Formula N are reacted with bromoacetyl bromide in presence of an organic base (for example, triethylamine or diisopropylamine) in a solvent (for example, an organic solvent such as chlorinated solvents like dichloromethane, dichloroethane and chloroform) at a temperature ranging from 0° to 60°C, preferably at

0 -15°C for a period varying from one to several hours to yield a compound of Formula

XNI which is further condensed with piperazine in the presence of a base (for example, potassium carbonate or sodium carbonate) and a phase transfer catalyst (such as, for example, tetrabutylammonium bromide or potassium iodide) in a solvent (for example, in an aprotic solvent such as acetone or acetonitrile) for a period ranging from 10 to 45 hours to give a compound of Formula XNII (Formula I, when A is CH CH CH₃, X-G is

CO, R is Bn, Y is ΝH, Z is — c— CH₂-Ν N— CH₂-C — )₃ this on debenzylation in a solvent o — o for a period ranging from 2 to 40 hours in converted to a compound of Formula XNIII (Formula I, when A is CH₂CH₂CH₃, X-G is CO, R is H, Y is ΝH, Z is

— C— CH_λ— Ν Ν — CH₂— C _o ^ — / o )• The debenzylation of compound of Formula XVII can be carried out in polar protic solvents such as methanol or ethanol.

Scheme VI

Formula XIX

Formula V

Solvent/base

Formula XXI (Formula I, A = CH₂CH₂CH_3j X-G=CO, R=Bn, Y=NH, Z=CO)

Debenzylation

Formula XXII

(Formula 1, A = CH₂CH₂CH_3! X-G=CO, R=H, Y=NH, Z=CO) Scheme NI illustrates exemplary syntheses of compounds of Formula XXI and XXII, which are themselves specific examples of compounds of Formula I. In Scheme- NI, compounds of Formula N are reacted with compounds of Formula XIX in presence of an organic base (such as triethylamine or diisopropylamine) in a suitable solvent (such as, for example, chlorinated solvents like dichloromethane, dichloroethane and chloroform) at temperatures ranging from about -60°C to 60°C, preferably from about -60°C to 0°C, for a period of one to several hours to yield a compound of Formula XX, which is further condensed with the compound of Formula N in presence of a base (such as for example an organic base such as triethylamine or diisopropylamine) and a suitable organic solvent (such as chlorinated solvents, for example, dichloromethane, dichloroethane or chloroform) to yield a compound of Formula XXI (Formula I, when A is CH CH₂CH₃, X- G is CO, Y is ΝH, R is Bn, Z is CO), which on debenzylation in a solvent for a period of 2-40 hours yields a compound of Formula XXII (Formula I, A is CH CH₂CH₃, X-G is CO, R is H, Y is ΝH, Z is CO). The debenzylation of the compound of Formula XXI can be carried out in a protic polar solvent such as, for example, methanol or ethanol.

II

e, naphthylene)

Formula XXIV

(Formula I, A=CH₂CH₂CH₃, X-G=CO, R=Bn, Y=NH, Z= -C— H — RA— NH— C ■ R is the same as defined earlier) II II ' o o

Scheme VII illustrates exemplary synthesis of compounds of Formula XXIN (Formula I, where A is CH₂CH₂CH₃, X-G is CO, R is Bn, Y is ΝH, and Z is C— ΝH— ₄— ΝH — C

II II wherein R is phenylene or naphthylene). Preparations of such compounds involve condensing compounds of Formula XX with compounds of

Formula XXIII in the presence of a base (for example, organic base, for example, triethylamine or diisopropylamine) and a solvent (such as chlorinated solvents, for example, dichloromethane, dichloroethane or chloroform) at temperatures ranging from about 20-60°C for a period varying between 1-24 hours to produce the corresponding compound of Formula XXIN (Formula I, A is CH₂CH₂CH₃, X-G is CO, R is Bn, Y is

ΝH, Z is c— ^ΝH— ^R4— ^ΝH— c _wherein Rι is phenylene or naphthylene). o o

In the above schemes, where specific starting materials, reagents, bases, solvents, phase transfer catalysts, catalysts, temperatures, times, etc. are mentioned, it is to be understood that other starting materials, reagents, bases, solvents, phase transfer catalysts, temperatures, times, etc. known to those skilled in the art may also be used. Similarly, the reaction temperature and duration of the reaction may be adjusted according to the desired needs. Specific compounds according to the invention include the following. These compounds may also be considered to be preferred embodiments of the invention: -

6,6'-[l,3-benzene-{diyl-bis-(iminocarbonylimino)-4-methyl}]-bis-[2,3,4-tri-O- benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.l)

6,6 ' -[ 1 ,4-cyclohexane-diyl-bis-(iminocarbonylimino)] -bis-[2,3 ,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.2)

6,6'-[l,3-benzene-{diyl-bis-(iminocarbonylimino)-4-chloro-6-methyl}]-bis-[2,3,4- tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.3)

6,6'-[4,4-bisphenyl}methyl-{diyl-bis-(iminocarbonylimino)]-bis-[2,3,4-tri-O- benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.4) 6,6'-[l,3-benzene-{diyl-bis-(iminocarbonylimino)-2-methyl}]-bis-[2,3,4-tri-O- benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.5)

6,6'-[l,4-benzene-{diyl-bis-(iminothiocarbonylimino)]-bis-[2,3,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.6)

6,6'-[l,4-butanediyl-bis-(immothiocarbonylimino)]-bis-[2,3,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.7)

6,6'-[l,3-benzene-{diyl-bis-(iminocarbonylimino)]-4-methyl}]-bis-[2,3,4- trihydroxy-N-propyl-D-gluco-δ-lactam] (Compound No.8)

6,6'-[l,4-cyclohexane-diyl-bis-(iminocarbonylimino)]-bis-[2,3,4-trihydroxy-N- propyl-D-gluco-δ-lactam] (Compound No.9) 6,6'-[l,3-benzene-{diyl-bis-(iminocarbonylimino)]-2-methyl}]-bis-[2,3,4- trihydroxy-N-propyl-D-gluco-δ-lactam] (Compound No.10)

6,6'-[4,4'-{bisphenyl}-methyl-diyl-bis-(iminocarbonylimino)]-bis-[2,3,4- trihydroxy-N-propyl-D-gluco-δ-lactam] (Compound No.l 1)

6,6'-[l,3-xylenediyl-bis-(oxo)]-bis-(N-allyl-2,3,4-tri-O-benzyl-l,5-dideoxy-l,5- imino-D-glucitol] (Compound No .12)

6,6 ' - [ 1 ,4-xylenediyl-bis-(oxo)] -bis-(N-allyl-2,3 ,4-tri-O-benzyl- 1 ,5-dideoxy- 1,5- imino-D-glucitol] (Compound No.13) 6,6'-[l,5-triazine-{diyl-bis-(iminocarbonylimino)-3-chloro}]-bis-[2,3,4-tri-O- benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.14)

6,6'-[l,3-benzene-diyl-bis-(iminocarbonyl)-bis-[2,3,4-tri-O-benzyl-N-propyl-D- gluco-δ-lactam] (Compound No.15) 6,6 ' 6"- [ 1 ,3 ,6-benzene-triyl-tris-(iminocarbonyl)-tris-[2,3 ,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.16)

6,6 ' 6"- [ 1 ,3 ,6-benzene-triyl-tris-(iminocarbonyl)-tris-[2,3,4-trihydroxy-N-propyl- D-gluco-δ-lactam] (Compound No.17)

6,6'-[l,4-piperazinediyl-bis-(acetylimino)]-bis-[2,3,4-tri-O-benzyl-N-propyl-D- gluco-δ-lactam] (Compound No.18)

6,6'-[l,4-piperazinediyl-bis-(acetylimino)]-bis-[2,3,4-trihydroxy-N-propyl-D- gluco-δ-lactam] (Compound No.19)

6,6'-bis-(imino)-carbonyl)-bis-[2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.20) 6,6'-bis-(imino)-carbonyl)-bis-[2,3,4-trihydroxy-N-propyl-D-gluco-δ-lactam]

(Compound No.21)

6,6'-[l,3-benzenediyl-bis-(iminocarbonylimino)]-bis-[2,3,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.22)

6,6'-[l,4-benzenediyl-bis-(iminocarbonylimino)]-bis-[2,3,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.23)

6,6'-[l,8-napthalenediyl-bis-(iminocarbonylimino)]-bis-[2,3,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.24)

Each of the compounds disclosed herein can be created with other azasugars, such as N-containing fructo-, glucofurano-, arabinofurano-, mannofurano-, furano-, arabino-, or manno-δ-lactams, as would be understood by those of ordinary skill in the art upon inspection of the present disclosure. Bis-azasugars can contain identical or different sugar groups. Further the compounds disclosed herein can involve trivalent central bridging moieties, and can thus contain three azasugar groups (tris-azasugar compounds), the sugar groups of which can be all the same or not all the same. The invention also provides for pharmaceutical compositions including a therapeutically effective amount of a compound of Formula I, or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, as described herein, along with a pharmaceutically acceptable carrier, and optionally but desirably, pharmaceutically acceptable excipients.

The invention also provides for methods of selectively antagonizing α-glucosidase receptors in a mammal. The methods include administering to a mammal a therapeutically effective amount of a compound having the structure of Formula I, or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, as described herein.

The invention also provides for methods of treating diabetes in a mammal. The methods include administering to a mammal a therapeutically effective amount of a compound having the structure of Formula I, or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, as described herein.

The administration of pharmaceutical compositions can be by injection or by gradual infusion over time. The compositions can be administered intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. Preferred methods for delivery of the compositions include orally, by encapsulation in microspheres or proteinoids, by aerosol delivery to the lungs, or transdermally by iontophoresis or transdermal electroporation. Other methods of administration will be known to those skilled in the art.

Preparations for parenteral administration of the pharmaceutical compositions described herein include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

Formulation of the pharmaceutical compositions may be carried out in conventional manner using one or more physiologically and/or pharmaceutically acceptable carriers or excipients. Thus, the compounds and their pharmaceutically acceptable salts and solvates may be formulated for administration by inhalation or insufflation (either through the mouth or the nose) or oral, buccal, parenteral, or rectal administration. For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (for example, pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (for example, lactose, macrocrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or sodium starch glycolate); or wetting agents (for example, sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a sdry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventionsl means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehchles (for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example, methyl or propyl-p-hdroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds mahy be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspension, solutions or emulsions in oily or aqueous vehicles, and may contain formuatory agents such as suspending, stailizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen- free water, before use.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds may also be formuated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchance resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The therapeutic compositions of the invention also contain a carrier or excipient, many of which are known to skilled artisans. Excipients which can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, and glycerol. Methods for making such formulations are well-known and can be found in, for example, "Remington's Pharmaceutical Sciences."

By "therapeutically effective amount" is meant the quantity of a compound or composition according to the invention necessary to prevent, cure or at least partially arrest the symptoms of the disorder and its complications. Amounts effective to achieve this goal will, of course, depend on the severity of the disease and the weight and general state of the patient. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models maybe used to determine effective dosages for treatment of particular disorders. Various considerations are described, for example, in Gilman et al., eds., 1900, "Goodman and Gilman's: The Pharmaceutical Bases of Therapeutics," 8^th ed., Pergamon Press; and Remington's Pharmaceutical Sciences," 1990, 17^th ed., Mack Publishing Co., Easton, Pa., each of which is hereby incorporated by reference.

The invention will be further described in the following examples, which demonstrate general synthetic procedures, as well as specific preparations of some peferred compounds. The examples do not limit the scope of the invention described in the claims.

EXAMPLES Example 1: Preparation of 6,6'-[ 3-benzene-{diyl-bis(iminocarbonylimino -4-methyl1- bis-[^"2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.1

Step 1: Preparation of N-Allyl-6-O-(p-toluenesulfonyI)-2,3,4-tri-O-benzyl-D- gluco-δ-lactam

N-allyl-2,3,4-tri-O-benzyl-D-gluco-δ-lactam (0.487 gm) (prepared by the method reported in Tetrahedron, 50 (14), 4215-4224 (1994), Eet. Eett., 37 (4), 547-50 (1996)) was dissolved in dichloromethane (10 ml). To this was added triethylamine (1.01 gm) and cooled to 0°C. p-Toluenesulphonyl chloride (1.143 gm) was added to the reaction mixture, which was then concentrated at room temperature and stirred for additional 2 hours. The contents of the reaction mixture were poured into ice cold water (50 ml). The compound was extracted with dichloromethane. The oganic layer was dried over anhydrous sodium sulphate (Na₂SO₄) and the solvent was evaporated under vacuum. The crude material was purified by column chromatography using ethylacetate - hexane (2:8) mixture as eluent.

Step 2: Preparation of 6-Azido-N-allyl-2,3,4-tri-O-benzyl-D-gluco-δ-Iactam. The product obtained from Step 1 (0.641 gm) was dissolved in N,N- dimethylformamide (DMF) (10 ml). To this was added sodium azide (NaN₃) (0.390 gm) and ammonium chloride (NH₄C1) (catalytic amount) and the reaction mixture was stirred at 40°C for 5 hours. The reaction mixture was poured into cold water (50 ml). The product was extracted with ethyl acetate (2 times 25 ml) and the organic layer was washed with brine (50 ml). The organic layer was dried over anhydrous Na₂SO₄ and the solvent was distilled off under reduced pressure. The compound was purified using column chromatography and ethylacetate - hexane (15:85) as the eluent. Step 3: Preparation of 6-Amino-N-propyl-2,3,4-tri-O-benzyl-D-gluco-δ- lactam

The product from the preceding step (0.512 gm) was dissolved in 10 ml ethanol and Pd/C (Palladium/carbon) (10%, 0.102 gm) was added and the system was placed under a hydrogen atmosphere using hydrogen balloon. The reaction was stirred at room temperature for 5 hours. The reaction mixture was then filtered through celite, washed with methanol (50 ml) and the solvent removed under vacuum. The compound obtained was used as such for the next step without further purification.

Step 4: Preparation of 6,6'-[l,3-benzene-{diyl-bis(iminocarbonylimino)-4- methyl}]-bis-[2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam]

To a solution of the preceding amine product (0.488 gm) in acetonitrile (CH₃CN) (10 ml) was added 4-methyl-l,3-phenylenediisocyanate (0.087gm) and the reaction was allowed to run at room temperature for 2 hours. The solvent was distilled off and the product obtained was purified by column chromatography using ethylacetate - hexane (6:4) as the eluent. The product exhibited m.p.:96-98°C, and the following spectral identification confirmed product formation: ΓR (CH₂C1₂) : v 1671, 1649 cm^"1; NMR (CDC1₃) : δ 0.82-0.87 (m, 6H, 2xCH₃), 1.54-1.56 (m, 4H, 2xCH₂), 2.06 (s, 3H, CH₃), 2.81-2.99 (m, 4H, 2xCH₂), 3.43-3.96 (m, 10H, 2xCH₂+6xCH), 4.00-4.02 (d, J=6Hz, 1H, CH), 4.07-4.09 (d, J=6Hz, 1H, CH), 4.40-4.44 (d, J=12Hz, 2H, 2xPhCH), 4.48-4.67 (m, 4H, 4xPhCH), 4.69-4.73 (d, J=12Hz, 2H, 2xPhCH), 5.04-5.08 (d, J=12Hz, 2H, 2xPhCH), 5.10-5.14 (d, J=12Hz, 2H, 2xPhCH), 5.51 (bis, 2H, NH), 6.24 (brs, 2H, NH), 6.90-7.53 . (m, 33H, ArH); Mass: m/z 1151 (M⁺+l).

The following compounds were prepared analogously to those described immediately above. Example 1A: Preparation of 6.6'ri,4-cvclohexane-diyl-bis(iminocarbonylimino ]-bis- r2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.2)

The title compound was prepared by using 1,4-cyclohexyl diisocyanate in place of 4-methyl- 1,3 -phenylene diisocyanate in Step 4 to get the title compound in a semi-solid state, with the following spectral information: IR (CH₂C1₂) : v 1647 cm^"1; NMR (CDCI₃): δ 0.86-0.90 (t, J=12Hz, 6H, 2xCH₃), 1.57-1.62 (m, 8H, 4xCH₂), 1.90-1.92 ( , 4H, 2xCH₂), 2.97 (m, 2H, 2xCH), 3.13 (m, 2H, 2xCH), 3.47 (m, 4H, 4xCH), 3.66-3.75 (m, 4H, 4xCH), 3.86 (m, 2H, 2xCH), 3.99-4.01 (m, 2H, 2xCH), 4.20-4.22 (d, J=6Hz, 2H, 2xCH), 4.51-4.75 ( , 10H, lOxPhCH), 5.06-5.09 (m, 2H, 2xPhXCH), 6.99-.7.53 (m, 30H, ArH); Mass m/z 1143 (M⁺+l).

Example IB: Preparation of 6,6'-rL3-benzene-{diyl-bis(iminocarbonylimino -4-chloro- 6-methyl) 1-bis~r2,3 ,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.3) The title compound was prepared by using 4-chloro-6-methyl-l,3-phenylene diisocyanate in place of 4-methyl- 1,3 -phenylene diisocyanate in Step 4 to get the title compound in semi solid state, with the following spectral information: IR (CH₂C1₂) : v 1670, 1645 cm^"1; NMR (CDC1₃): δ 0.82-0.87 (m, 6H,2xCH₃), 1.60 (m, 4H, 2xCH₂), 1.94 (s, 3H, CH₃), 2.95-3.00 (m, 2H, 2xCH), 3.34 (m, 2H, 2xCH), 3.44 (m, 2H, 2xCH), 3.65- 3.85 (m, 8H, 8xCH), 4.01-4.06 (m, 2H, 2xCH), 4.53-4.71 (m, 10H, lOxPhCH), 5.02-5.07 (m, 2H, 2xPhCH), 5.8 (bra, 2H, NH), 6.99(brs, 2H, NH), 7.19-7.35 ( (m, 32H, ArH); Mass : m/z 1185 (M⁺+l).

Example 1C: Preparation of 6,6'-[4,4'- {bisphenyllmethyl-diyl-bis- (iminocarbonylimino)]-bis-[2,3,4-tri-O-benyl-N-propyl-D-gluco-δ-lactam] (Compound No.4

The title compound was synthesised by using 4,4'-(bisphenyl)methyl diisocyanate in place of 4-methyl-l,3-phenylene diisocynate in Step 4 to get the title compound in semisolid state, with following spectral information: IR (CH₂C1₂) : v 1671, 1646 cm^"1; NMR (CDCI₃): δ 0.82-0.87 (t, J=7H₃, 6H, 2xCH₃), 1.57 (m, 4H, 2XCH₂), 2.95 (m, 2H, 2xCH), 3.22 (m, 2H, 2xCH), 3.50 (m, 2H, 2xCH), 3.66-3.86 (m, 4H, 2xPhCH), 4.48-4.67 (m, 10H, lOxPhCH), 4.98-5.02 (d, J=12Hz, 2HxPhCH), 5.25 (m, 2H, 2xCH), 6.61 (m,2H, 2xNH), 7.02-7.36 ( (m, 38H, ArH); Mass: m/z 1227 (M⁺+l). Example ID: Preparation of 6,6'-|^"1.3-benzene-(diyl-bis(iminocarbonylimino -2- methyl|-bis-[2,3,4-tri-O-benzyl-N-proρyl-D-gluco-δ-lactam] (Compound No.5) The title compound was prepared by using 2-methyl- 1 ,3 -phenylene diisocyanate instead of 4-methyl- 1,3 -phenylene diisocynate in Step 4 to get the title compound in semisolid state, with the following spectral information: IR (CH₂C1₂) : v 1645 cm^"1; NMR (CDCI3): δ 0.83-0.88 (t, J=7Hz, 6H,2xCH₃), 1.52-1.57 (m, 4H, 2xCH₂), 2.00 (s, 3H, CH₃), 2.95-3.00 (m, 2H, 2xCH), 3.44 (m, 2H, 2xCH), 3.55 (m, 2H, 2xCH), 3.64-3.84 (m, 8H, 8xCH), 3.99-4.01 (d, J=6Hz, 2H, 2xPhCH), 4.65-4.85 (m, 10H, lOxPhCH), 4.97- 5.01 (d, J=12Hz, 2H, 2xPhCH), 5.55 (brs, 2H, 2xNH), 6.56 (brs, 2H, 2xNH), 7.16-7.36 (m, 33H, ArH); Mass: m/z 1151 (M⁺+l). Example IE: Preparation of 6,6' -[1, 4-benzene-diyl-bis(iminothiocarbonylimino^]-bis- [2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No. 6)

The title compound was synthesized by using 1,4-phenylene diisothiocyanate instead of 4-methyl- 1,3 -phenylene diisocyanate in Step 4 to get the title compound in semisolid state, with the following spectral information: IR (CH₂C1₂) : v 1654.6 cm^" _; NMR (CDC1₃): δ 0.83-0.87 (t, J=7Hz, 6H, 2xCH₃) 1.52-1.57 (m, 4H, 2xCH₂), 2.92-2.97 (m, 2H, 2xCH), 3.53-3.57 (m, 4H, 4xCH), 3.70-3.75 (m, 4H, 4xCH), 3.81-3.83 (m, 6H, 6xCH), 4.45-4.67 (m, 10H, lOxPhCH), 4.94-4.98 (d, J=12Hz, 2H, 2xPhCH), 6.57 (brs, NH), 7.06-7.31 (m, 34H, ArH), 8.12 (brs, NH); Mass: m z 1169 Ov +1). Example IF: Preparation of 6,6' -[1, 4-butanediyl-bis(iminothiocarbonylimino 1-bis- [2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.7

The title compound was. obtained by using 1,4-butane diisothiocyanate in place of 4-methyl-l,3-phenylene diisocyanate in Step4 to get the title compound in semisolid state, with the following spectral information: IR (CH₂C1₂) : v 1654 cm^NMR (CDC1₃): δ 0.82-0.87 (m, 6H,2xCH₃), 1.38 (m, 4H, 2xCH₂), 1.52-1.59 (m, 4H, 2xCH₂) 2.04-2.06.. (m,2H, 2xCH), 2.98 (m,4H, 4xCH), 3.25 (m, 2H, 2xCH), 3.66-3.87 (m, 10H, lOxCH), ^'. . 4.16-4.18 (d, J=6Hz, 2H, 2xCH), 4.50-4.70 (m, 10H, lOxCH) 4.95-4.99 (d, J-12Hz, 2xCH), 6.58 (brs, NH), 6.79 (brs, NH), 7.19-7.37 (m, 30H, ArH); Mass: m/z 1149 (M⁺+l). Example 2: Preparation of 6,6'-[ 3-benzene-|diyl-bis(iminocarbonylimino -4-methyl>]- bis-[2,3,4-trihvdroxy-N-propyl-D-gluco-δ-lactam] (Compound No.8)

The ester obtained in Example 1, Step 4 (lmmoi) was dissolved in ethylalcohol (5 ml). To this was added palladium/carbon (Pd/C) (0.641mg, 10% dry) and cyclohexene (10 ml) and the reaction mixture was heated to reflux temperature. Stirring was continued for another 12 hours at this temperature. The reaction mixture was then filtered tlirough celite, washed with methanol and the mother liquor removed under vacuum. The residue obtained was purified by column chromatography using chloroform - methanol (8:2) as eluent mixture. The product had m.p.: 196-198°C. The following spectral information lead to confirmation of product formation: IR (KBr) : v 1671, 1640, 1637 cm^"1; NMR (D₂O): δ 0.69-0.73 (m, 6H, 2xCH₃), 1.06-1.12 (m, 4H, 2xCH₂), 2.01 (s, 3H, CH₃), 2.83-2.88 (m, 2H, 2xCH), 3.39-3.90 (m, 14H, 14xCH), 6.91-7.10 (m, 3H, ArH); Mass: m/z 611 (M⁺+1). The following compounds were prepared analogously, as will be apparent to one of ordinary skill in the art:

Example 2A: Preparation of 6,6'-[l,4-cvclohexanediyl-bis(iminocarbonylimino)]-bis- [2,3,4-teihvdroxy-N-propyl-D-gluco-δ-lactaml (Compound No.9) The title compound had m.p. :264-266°C, and the following spectral information was obtained: IR (CH₂C1₂) : v 1646.5 cm^"1; NMR (D₂O): δ 0.87-0.92 (t, J=6Hz, 6H, 2xCH₃) 1.19-1.21 (m, 6H, 6x CH), 1.51-1.66 (m, 4H, 2xCH), 1.91-1.96 (m, 4H, 4xCH), 2.96-3.05 (m, 2H, 2xCH), 3.50 (m, 6H, 6xCH), 3.59-3.69 (m, 2H, CH), 3.71-3.76 (m, 4H, 4xCH), 4.01-4.04 (d, 2H, 2xCH), 3.71-3.76 (m, 4H, 4xCH), 4.01-4.04 (d, 2H, 2xCH); Mass: m/z 603 (M⁺+l).

Example 2B: Preparation of 6,6'-[l,3-benzene-(diyl-bis(iminocarbonylimino -2- methyl>1-bis-[2,3,4-trihydroxy-N-propyl-D-gluco-δ-lactam] (Compound No .10)

The title compound had m.p.: 117°C; TR (KBr) : v 1650 cm^"1; NMR (DMSO+D₂O): δ 0.83-0.85 (m, 6H, 2xCH₃), 1.16-1.24 (m, 4H, 2xCH₂), 2.01 (s,3H, CH₃), 2.94 (m,2H, 2xCH), 3.33-3.37 (m, 6H, 6xCH), 3.40-3.46 (m, 6H, 6xCH), 3.60-3.78 (d, J=6Hz, 2H, 2xCH), 7.07-7.33 (m, 3H, ArH); Mass: m/z 611 (M⁺+l). Example 2C: Preparation of 6,6'-[^"4,4'-{bisphenyl)methyldiyl-bis- (iminocarbonylimino ]-bis- 2,3,4-trihydroxy-N-propyl-D-gluco-δ-lactam (Compound No.11) The title compound had m.p.: 96°C, and the following spectral information was obtained: IR (KBr) : v 1680.6 cm^"1; NMR (DMSO+ D₂O): δ 0.79-0.84 (m, 6H, 2xCH₃), 1.43-1.52 (m, 4H, 4xCH), 2.94 (m, 2H, 2xCH), 3.33-3.37 (m, 8H, 8xCH), 3.40-3.46 (m, 4H, 4xCH), 3.54-3.59 (m, 4H, 4xCH), 7.08-7.10 (d, J=6Hz, 4H, 4xArH), 7.24-7.26 (d, J=6Hz, 4H, 4xArH), 8.38 (brs, NH); Mass: m/z 687 (M⁺+l). Example 3: Preparation of 6.6'-r 3-xylenediyl-bis(oxo)]-bis-[^"N-allyl-2,3,4-tri-O-benzyl- 1.5-dideoxy-1.5-imino-D-glucitol] (Compound No.12)

Step 1: Preparation of N-AUyl-2,3,4-tri-O-benzyl-l,5-dideoxy-l,5- iminoglucitol

N-allyl-2,3,4-tri-O-benzyl-D-gluco-δ-lactam (prepared by the method reported in Tetrahedron, 50 (14), 4215-4224 (1994), Eet. Eett., 37 (4), 547-50 (1996)) (0.486 gm) was dissolved in tetrahydrofuran (THF) (15 ml). LAH (0.114gm) was added to the above solution and the reaction mixture was heated to 40°C. Once the addition was complete, the reaction was stirred at 40°C for 2 hours. The reaction mixture was cooled to O°C and ethyl acetate (10 ml) and water (2 ml) were added. The reaction mixture was then stirred for another 1 hour at room temperature. The product was extracted with ethylacetate (2 times 25 ml). The organic layer was dried over sodium sulphate (Na₂SO₄) and the solvent was evaporated under reduced pressure. Crude product obtained was purified by column " chromatography using ethylacetate - hexane mixture (4:6) as an eluent.

Step 2: Preparation of 6,6'-[l,3-xylenediyI-bis-(oxo)]-bis-{N-alIyl-2,3,4-tri-O- benzyl-l,5-dideoxy-l,5-imino-D-glucitoI]

To a solution of product obtained from Step 1 (0.486 gm) in DMF (10 ml) was added sodium hydride (NaH) (0.072 gm, 50%) at 0°C and the reaction mixture was stirred for 1.5 hour. To this was added m-xylylene dibromide (0.132 gm) and stirred the reaction at room temperature for additional 4 hours. Methanol (5 ml) was added to the reaction mixture and stirred for 1 hour. DMF was removed under reduced pressure and the residue obtained was diluted with water (25 ml) and extracted with ethylacetate (2 times 25 ml). The organic layer was dried over anhydrous sodium sulphate (Na₂SO₄) and solvent was distilled off under reduced pressure. The crude material was purified by column chromatography using an ethylacetate-hexane mixture (2:8) as eluent to obtain the desired compound. The product had m.p.: 85-86°C. The following spectral information was used to confirm product formation: IR (CH₂C1₂) : v 1495, 1453 cm^"1; NMR (CDC1₃): δ 2.12-2.20 (m, 2H, 2xNCH), 2.25-2.28 (m, 2H, 2xNCH), 3.11-3.16 (m, 4H, 4xCH), 3.34 (m, 2H, 2xCH), 3.47-3.54 (m, 2H, 2xCH), 3.57-3.65 (m, 8H, 8xCH), 4.38-4.41 (m, 6H, 6xCH), 4.65 (m, 4H, 4xCH), 4.77-5.14 (m, 10H, lOxCH), 5.82-5.84 (m, 2H, 2xCH), 7.10-7.30 (m, 34H, ArH); Mass: m/z 1049 (M⁺+l).

The following compound was prepared analogously: Example 3 A: Preparation of 6,6'-[l,4-xylenediyl-bis-(oxo 1-bis-rN-allyl-2, 3,4-tri-O- benzyl-L5-dideoxy-l,5-imino-D-glucitol] (Compound No.13)

The title compound was prepared by using j^-xylylenedibromide instead of m- xylylene dibromide in Step 2. The product had m.p.: 109°C. The following spectral information was obtained: IR (CH₂C1₂) : v 1447, 1453.4 cm^"1; NMR (CDCI₃): δ 2.12- 2.19 (m, 2H, 2xCH), 2.24-2.27 (d, J=9Hz, 2H, 2xCH), 3.08-3.16 (m, 4H, 4xCH), 3.32 3.34 (m, 4H, 4xCH), 3.41-3.64 (m, 8H, 8xCH), 4.36-4.39 (m, 6H, 6xCH), 4.65-4.66 (m, 4H, 4xCH), 4.77-4.87 (m, 4H, 4xCH), 4.93-4.97 (d, J=12Hz, 2H, 2xCH), 5.11-5.15 (m, 4H, 4xCH), 5.82 ( , 2H, 2xCH), 7.09-7.12 (m, 4H, ArH), 7.25-7.30 (m, 30H, ArH); Mass: m/z 1049 (M⁺+l). Example 4: Preparation of 6,6'- 1.5-triazine-{diyl-bis(iminocarbonylimino -3-chloro}]- bis- 2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.14)

To the amine product prepared as described in Example 1, Step 3, (0.488 gm) in acetone (20 ml) was added cyanuric chloride (0.092 gm), potassium carbonate (K₃CO₃) (0.829 gm) and triethylamine (0.101 gm) at 0°C. The reaction mixture was heated to 40°C and stirred for 3 hours. Acetone was removed under vacuum and the residue obtained was diluted with water (25 ml). The compound was extracted with ethylacetate (2 x 25 ml). Organic layer was dried and solvent was removed under reduced pressure. The compound was further purified by column chromatography using ethylacetate - hexane (7:3) as eluent mixture to yield the title compound in semisolid state. The following spectral information verified product formation: IR (CH₂C1₂) : v 1663 cm^"1; NMR (CDCI3): δ 0.88-0.90 (m, 6H, 2xCH₃), 1.54-1.58 (m, 4H, 2xCH₂), 3.05 (m, 2H, 2xCH), 3.59-3.89 (m, 14H, 14xCH) 4.49-4.78 (m, 10H, PhCH), 5.12-5.17 (m, 2H, 2xPhCH), 7.16-7.44 (m, 30H, ArH); Mass: m/z 1088 (VT+1). Example 5: Preparation of 6,6'-[l,3-benzenediyl-bis-(iminocarbonyl)]-bis-[2,3,4-tri-O- benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.15)

To a cold solution of product amine (0.488 gm) obtained as described in Example 1, Step 3 in dichloromethane (DCM) (15 ml) was added triethylamine (0.622 gm) and isophthaloyl dichloride (0.101 gm). The reaction was allowed to come at room temperature and stirred for 2 hours. The reaction mixture was diluted with water (25 ml) and product extracted with dichloromethane (2 times 25 ml). The organic layer was dried and the solvent was removed under vacuum. The product was purified by column chromatography using ethylacetate-hexane (6:4) as an eluent to get the title compound in semisolid state. The following spectral information verified product formation: IR (CH2CI2) : v 1654.4 cm^"1; NMR (CDCI3): δ 0.88-0.93 (m, 6H, 2xCH₃), 1.59 (m, 4H, 2xCH₂), 3.02-3.09 (m, 3H, 3xCH), 3.44-3.48 (m, 3H, 3xCH) 3.68-3.83 (m, 4H, 4xCH), 3.93-3.94 (m, 3H, 3xCH), 4.07-4.09 (d, J=6Hz, 2H), 4.46-4.56 (m, 6H, 6xPhCH), 4.70- 4.74 (d, J=12Hz, 4H, 4xPhCH), 5.11-5.15 (d, J=12Hz, 2H, 2xPhCH), 6.55 (brs, NH), 7.14-7.62 (m, 32H, ArH), 7.59-7.62 (d, J=9Hz, 2H, ArH); Mass: m/z 1107 (M⁺+l). The following compound was prepared analogously: Example 5A: Preparation of 6,6'.6"-ri.3,6-benzeneniyl-tris-(iminocarbonv ]tris-(2,3,4- tri-O-benzyl-N-propyl-D-gluco-δ-lactaml (Compound No.16)

The title compound was synthesized by using 1,3,5-benzenetricarbonyl chloride instead of isophthaloyl chloride in the above example to obtain the title compound in a semisolid state. The following spectral information was obtained as verification of product formation: IR (CH₂C1₂) : v 1648.4 cm^"1; NMR (CDC1₃): δ 0.89-0.94 (m, 9H, 3xCH₃), 1.64-1.70 (m, 6H, 3xCH₂), 3.02-3.07 (m, 3H, 3xCH), 3.73-3.74 (m, 3H, 3xCH) 3.81-3.84 (m, 12H, 12xCH), 3.95-3.96 (m, 3H, 3xCH), 4.12-4.14 (d, J=6Hz, 3H, 3xCH), 4.52-4.64 ( , 9H, 9xPhCH) 4.70-4.74 (d, J=12Hz, 3H, 3xPhCH), 4.77-4.81 (d, J=12Hz, 3H, PhCH), 5.12-5.16 (d, J=12Hz, 3H, 3xPhCH), 6.806 (brs, NH), 7.16-7.44 (m, 48H, ArH); Mass: m/z 1621 (M⁺+l).

Example 6: Preparation of 6,6\6"-[l,3,6-benzene-triyl-tris-(iminocarbony ]-tris- 2,3,4- trihydroxy-N-propyl-D-gluco-δ-lactam] (Compound No.17) The ester obtained in Example 5 was debenzylated as described in Example 2 to give the desired product having a m.p.: 211°C. The following spectral information verified product formation: IR (KBr) : v 3422, 1653.9 cm^"1; NMR (CDC1₃): δ 0.77-0.82 (m, 9H, 3xCH₃), 1.45-1.51 (m, 6H, 3xCH₂), 2.98 (m, 3H, 3xCH), 3.39-3.43 (m, 3H, 3xCH) 3.52-3.61 (m, 12H, 12xCH), 3.76 (m, 3H, 3xCH), 3.88-3.91 (m, 3H, 3xCH), 7.02- 7.22 (m, 3H, ArH); Mass: m/z 811 (M⁺+l).

Example 7: Preparation of 6,6'- l,4-piperazinediyl-bis-(acetylimino)]-bis-r2,3,4-tri-O- benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.18)

Step 1: Preparation of 6-N-{2-(bromo)-acetyl}-N-propyl-2,3,4-tri-O-benzyl- D-gluco-δ-lactam The amine (0.488 gm), obtained as described in Example 1, Step 3, was dissolved in dichloromethane (DCM) (15 ml) and the reaction mixture was cooled to 0°C. Triethylamine (TEA) (0.203 gm) was added, followed by dropwise addition of bromoacetylbromide (0.186 gm) to the reaction mixture and it was allowed to come to room temperature. The reaction mixture was stirred for one hour at this temperature. The contents of the reaction mixture were dilluted with cold water (25 ml), extracted with dichloromethane (2 times 50 ml), organic layer dried with anhydrous Na₂SO₄, solvent removed under vacuum. The compound was purified by column chromatography, using ethyl acetate as eluent. Step 2: Preparation of 6,6'- [l,4-piperazinediyl-bis-(acetylimmo)] -bis- [2,3,4- tri-O-benzyl-N-propyl-D-gluco-δ-lactam]

To a solution of product obtained immediately above (0.611 gm) in acetone (20 ml) was added piperazine (0.086g), potassium carbonate (K2CO₃) (0.277 gm), and TBABr (Catalyst). The reaction mixture was stirred overnight at room temperature. Acetone was removed under reduced pressure. The residue obtained was diluted with water (25 ml). The product was extracted with ethylacetate (2 times 25 ml). Organic layer was dried over anhydrous sodium sulphate (Na₂SO₄) and the solvent was removed under vacuum. The crude material was purified by column chromatography using ethylacetate as eluent to get the title compound in semisolid state. The following spectral information was obtained: IR (CH₂C1₂) : v 1666.7 cm^"1; NMR (CDC1₃): δ 0.88-0.91 (m, 6H,2xCH₃), 1.62 (m, 4H, 2xCH₂), 2.17-2.20 (m, 8H, 4xCH₂) 2.85 (s, 4H, 2xCH₂), 2.98- 3.00 (m, 2H, 2xCH) 3.25 (m, 2H, 2xCH), 3.57-3.59 (m, 2H, 2xCH), 3.69-3.72 (m, 6H, 6xCH), 3.88-3.91 (m, 2H, 2xCH), 4.02-4.05 (d, J=9Hz, 2H, 2xCH), 4.49-4.62 (m, 6H, 6xPhCH), 4.70-4.74 (d, J=12Hz, 4H, 4xPhCH), 5.13-5.17 (d, J=12Hz, 2H, 2xPhCH), 7.12-7.14 (m, 2H, NH), 7.24-7.44 (m, 30H, ArH); Mass: m/z 1143 (M⁺+l). Example 8: Preparation of 6,6'-ri,4-piperazinediyl-bis-(acetylimino)1-bis-r2,3,4- trihvdroxy-N-propyl-D-gluco-δ-lactam] (Compound No. 19)

The ester obtained in Example 7, was debenzylated as described in Example 2, to give the title compound having a m.p.: 63-68°C. The following spectral information verified product formation: IR (KBr) : v 1651.7 cm^"1; NMR (D₂O): δ 0.86-0.91 (m, 6H,2xCH₃), 1.28-1.34 (m, 4H, 4xCH), 2.05-2.08 (m, 2H, 2xCH) 2.41-2.44 (m, 2H, 2xCH), 2.84 (s, 3H, 3xCH) 3.04 (m, 6H, 6xCH), 2.84 (s, 3H, 3xCH), 3.04 (m, 6H, 6xCH), 3.37-3.88 (m, 2H, 2xCH), 3.49-3.84 (m, 11H, llxCH), 3.99-4.02 (m, 2H, 2xCH); Mass: m/z 603 (M⁺+l).

Example 9 : Preparation of 6,6 ' -Bis-(imino carbonyl-bis-(2,3.4-tri-O-benzyl-N-prop yl-D- gluco-δ-lactam) (Compound No .20)

Step 1: Preparation of 2,3,4-Tri-O-benzyl-6-N-(p-nitrophenyl carbamate)-N- propyl-D-gluco-δ-lactam The product amine (0.488 gm) obtained in Example 1, Step 3, was dissolved in dichloromethane (DCM), (15 ml) and the reaction mixture was cooled to -60°C. To this was added triethyalmine (TEA) (0.202 gm) and p-nitrophenyl chloroformate (0.653gm) and allowed the reaction to come to room temperature. The reaction was stirred for 2 hours at the same temperature and the reaction mixture was diluted with water (25 ml). The product was extracted with dichloromethane (2 times 25 ml) and washed with water, dried over anhydrous Na₂SO₄ and the solvent was removed under vacuum. The product was purified by column chromatography and eluted with ethylacetate-hexane mixture (6:4).

Step 2: Preparation of 6,6'-Bis(imino)carbonyl-bis (2,3,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam)

The compound obtained immediately above in Step 1 (0.653 gm) was dissolved in dichloromethane (DCM) (10 ml). To this was added triethylamine (TEA) (0.202 gm) and the reaction mixture was cooled to 0°C and then added 6-amino-N-propyl-2,3,6-tri-O- benzyl-D-gluco-δ-lactam (0.488 gm). The reaction mixture was allowed to come to room temperature and stirred for additional 2 hours at this temperature. The reaction mixture was diluted with water (25 ml), extracted with dichloromethane (2 times 25 ml), dried over anhydrous Na₂SO₄ and the solvent was removed under vacuum to obtain the desired product.

Example 10: Preparation of 6,6'-Bis(imino carbonyl-bis-(2,3,4-trihydroxy-N-propyl-D- gluco-δ-lactam (Compound No.21)

The ester obtained in Example 9, Step 2 was debenzylated as described in Example 2 to yield the desired compound, having a m.p.: 78°C. The following spectral information confirmed product formation: IR (KBr) : v 1652.7 cm^"1; NMR (D₂O): δ

0.87-0.92 (m, 6H, 2xCH₃), 1.51-1.65 (m, 4H, 2xCH₂), 3.02-3.04 (m, 2H, 2xCH) 3.38 (m, 6H, 6xCH), 3.47-3.75 (m, 6H, 6xCH) 3.98-4.01 (d, J=9Hz, 2H, 2xCH), 3.75 (m, 6H, 6xCH), 3.98-4.01 (d, J=9Hz, 2H, 2xCH); Mass: m/z 463 (M⁺+l). Example 11: Preparation of 6,6'-[ 3-benzenediyl-bis-(iminocarbonylimino)]-bis-[2,3,4- tri-O-benzyl-N-propyl-D-gluco-δ-lactaml (Compound No.22)

2,3,4-tri-O-benzyl-6-N-(p-nitrophenyl chloroformate)-N-propyl-D-gluco-δ-lactam (0.653 gm), prepared as described in Example 9, Step 1 was dissolved in dichloromethane (DCM) (10 ml). To this solution was added triethylamine (TEA) (0.202 gm) and m- phenylene diamine (0.054 gm) and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was washed with 2N HC1 (15 ml), product was extracted with dichloromethane (DCM), dried over anliydrous Na₂SO and the solvent was removed under reduced pressure. The residue was purified by column chromatography using ethylacetate - hexane (6:4) as eluent to yield the title compound in semisolid state. The following spectral information was obtained, confirming product formation: IR (CH₂C1₂) : v 1644.3 cm^'1; NMR (CDC1₃): δ 0.82-0.88 (t, J=9Hz, 6H, 2xCH₃), 1.50-1.58 (m, 4H, 2xCH₂), 2.90 (m, 2H, 2xCH) 3.20 (m, 2H, 2xCH), 3.47 ( , 2H, 2xCH) 3.66 (m, 4H, 4xCH), 3.74-3.84 (m, 4H, 4xCH), 4.03-4.06 (d, J=9Hz, 2H, 2xCH), 4.51-4.67 (m, 10H, lOxPhCH), 4.94-4.97 (d, J=9Hz, 2H, 2xPhCH), 5.51 (brs, NH), 7.19-7.34 (m, 34H, ArH); Mass: m/z 1137 (M'+l).

The following compounds were prepared analogously, as would be apparent to one of ordinary skill in the art: Example 11A: Preparation of 6,6'-[l,4-benzenediylbis(iminocarbonylimino ]-bis-r2,3,4- tri-O-benzyl-N-propyl-D-gluco-δ-lactaml (Compound No. 23)

The title compound was prepared by using j9-phenylene diamine instead of m- phenylene diamine in the above Example 11 to get the title compound in semisolid state. The following spectral information was obtained: IR (CH₂θ₂) : v 1646.9 cm^"1; NMR (CDCI₃): δ 0.80-0.86 (t, J=9Hz, 6H, 2xCH₃), 1.51-1.58 (m, 4H, 2xCH₂), 2.81 (m, 2H, 2xCH) 3.26 (m, 2H, 2xCH), 3.55 (m, 2H, 2xCH) 3.68-3.85 (m, 8H, 8xCH), 4.04 (m, 2H, 2xCH), 4.50-4.65 (m, 10H, lOxPhCH), 4.95 (m, 2H, 2xPhCH), 5.45 (brs, NH), 6.45 (brs, NH), 6.52 (m, 1H, ArH), 6.88 (m, 1H, ArH), 7.13-7.35 (m, 32H, ArH); Mass: m/z 1137 (M⁺+l). Example 11B: Preparation of 6,6'-|^"l,8-napthalenediylbis(iminocarbonylimino)]-bis- [2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.24)

The title compound was obtained.by using 1,8-diamino napthalene in place of m- phenylene diamine in the above Example 11 to get the title compound in semisolid state. The following spectral information was obtained: IR (CH₂θ₂) : v 1655.9 cm^"1; NMR (CDCI₃+D₂O): δ 0.81-0.86 (t, J=9Hz, 6H, 2xCH₃), 1.49-1.56 (m, 4H, 2xCH₂), 2.84-2.89 (m, 2H, 2xCH) 3.27-3.30 (m, 2H, 2xCH), 3.43-3.49 (m, 2H, 2xCH) 3.62 (m, 4H, 4xCH), 3.72 (m, 4H, 4xCH), 3.95-3.97 (d, J=6Hz, 2H, 2xCH), 4.33-4.37 (d, J=12 Hz, 2H, 2xPhCH), 4.43-4.53 (m, 6H, 6xPhCH) 4.56-4.60 (d, J=12Hz, 2H, 2xPhCH), 4.99-5.03 (d, J=12Hz, 2H, 2xPhCH), 7.12-7.69 (m, 36H, ArH); Mass: m/z 1187 (M⁺+l). Example 12: Pharmacolo ical Testing Results: α-glucosidase inhibition activity The α-glucosidase inhibition activity was determined by modifing an assay procedure described by Evans et. al. Phytochemistry, 22, 768-770 (1983). The activity of yeast α-glucosidase was measured at pH 7.4 in N-2-hydroxyethylρiperazine-N-ethane sulfonic acid (HEPES) buffer in a 96-well microtiter plate. The release of -nitrophenol from the the substrate -nitrophenylglycoside by yeast α-glucosidase was measured spectrophotometrically in the presence and absence of the test compound at different concentrations. Each assay included inhibitor of the enzyme as a standard. Results are expressed as IC₅₀ value of the test compound. The specific methodology was as follows: to 100ml of 50 mM HEPES buffer, pH

7.4, in a microtitre plate, 20 ml test compound in DMSO (DMSO alone in control) and 40 μl (0.03 units) yeast α-glucosidase (Sigma) in HEPES buffer were added and preincubated at room temperature for 15 minutes. 40μl of 1.5mM -nitrophenyl-α-D- glucopyranoside (Lancaster) in HEPES buffer, as substrate was added and the absorbance change at 405 mm was monitored in a Biotek EIA reader. Absorbance change was measured at 25 minutes (reaction is linear over a 30 minute period). Each concentration vs. percent inhibition curve was obtained from 5 data points using PRISM graph pad software. Deoxynojirimycin and Acarbose was used as standards.

Acarbose is an alphaglucosidase inhibitor which is already in the market and being used in patients of type II diabetes. Our stategy was to identify compounds that were equal to or more potent than acarbose in an in vitro enzyme assay using yeast alpha glucosidase. It may be noted that a Kj of 77.9μm (ICso ≡ 127 μM) has been reported for acarbose using yeast alpha glucosidase in an in vitro enzyme inhibition assay (Archives of Biochemistry and Biophysics, 371, No. 8, (1999), pp. 277-283). For table entries given with an asterisk, the percent inhibition at the given concentration was more than 30%, and could not be quantitatively checked beyond this concentration because of precipitation.

Table 1

Based on the assay results, the disclosed compounds are predicted to have the characteristic of speifically inhibiting the activity of α-glucosidase (an enzyme which breaks down disaccharides, etc.) at intestinal levels. Accordingly, these compounds can effectively inhibit the production of monosaccharides, which cause high blood sugar levels.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

We claim:

1. A compound having the structure of Formula I:

Formula I and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-Oxides, polymorphs, prodrugs, metabolites, wherein;

A represents lower (C₁-C₄) alkyl, lower (Ci-C₄) alkenyl, lower (CrC₄) alkynyl;

X-G represents C=O or CH₂; R represents hydrogen, alkyl ( - ₅), acyl, aryl, aralkyl such as benzyl;

Y represents O or NH;

Z represents C=O, divalent (Cι-C₁₂) alkenyl, especially linear or branched ( -Ce) alkenyl; the divalent aralalkenyl such as -CH₂-C₆H₄-, -CH₂-C₆H -CH2, the divalent aralalkenyl group may be substituted at the aryl ring; the divalent arylene such as phenylene, naphthylene, the divalent arylene group may be substituted; the divalent cycloalkylene (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the divalent cycloalkylene (C₃-C₆) group may be substituted; the divalent 5 to 7 membered heterocyclyl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen such as aziridinyl, pyrrolidinyl morpholinyl, piperidinyl, piperazinyl, triazinyl, the divalent (5 to 7 membered) heterocyclyl may be substituted; the divalent heteroaryl group containing 1 to 4 hetero atoms such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl thiazolyl, oxadiazolyl, thiazinyl, tetrazolyl, benzopyranyl, the divalent 5-7 membered heterocyclyl group may be substituted; B B

— C — H — R₁— NH — C — , wherein B is selected from sulphur and oxygen and,

Ri is selected from the group consisting (CH₂)_m where m is an integer ranging from 1-6; divalent cycloalkylene (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the divalent cycloalkylene (C₃-C₆) may be substituted; the divalent arylene such as phenylene, naphthylene, the divalent arylene group may be substituted; the divalent 5-7 membered heterocyclyl group containing 1 to

4 heteroatoms selected from the group consisting of nitrogen suphur and oxygen such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, the divalent

5-7 membered heterocyclyl group may be substituted; the divalent 5-7 membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, triazinyl, tetrazolyl, benzopyranyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, the divalent 5-7 membered heteroaryl group may be substituted; C₆H -(CH₂)m C₆H₄- wherein m is an interger ranging from substituted or unsubstituted divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, benzopyranyl, o o pyrazolyl Jl__CH2__R2__CH2_Jl , wherein R₂ is selected from the group consisting of the divalent 5-7-membered heterocyclyl group containing 2 or more hetero atoms selected from the group consisting of nitrogen, sulphur and oxygen such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl; o o jl__R _]1 wherein R₃ is selected from the group selected from (CH₂)m where m is an integer ranging from 1 to 6; divalent cycloalkylene (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the divalent arylene such as phenylene, naphthylene; the divalent arylene group may be substituted.

2. A compound selected from the group consisting of:

6,6'-[l,4-cyclohexane-diyl-bis-(iminocarbonylimino)]-bis-[2,3,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.2) 6,6'-[l,3-benzene-{diyl-bis-(iminocarbonylimino)-4-chloro-6-methyl}]-bis-[2,3,4- tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.3)

6,6 ' -[4,4-bisphenyl} methyl- {diyl-bis-(iminocarbonylimino)] -bis- [2,3 ,4-tri-O- benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.4) 6,6'-[l,3-benzene-{diyl-bis-(iminocarbonylimino)-2-methyl}]-bis-[2,3,4-tri-O- benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.5)

6,6'-[l,4-buntanediyl-bis-(iminothiocarbonylimino)]-bis-[2,3,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.7)

6,6'-[l,3-benzene-{diyl-bis-(iminothiocarbonylimino)]-4-methyl}]-bis-[2,3,4- trihydroxy-N-propyl-D-gluco-δ-lactam] (Compound No.8)

6,6'-[l,3-xylenediyl-bis-(oxo)]-bis-(N-allyl-2,3,4-tri-O-benzyl-l,5-dideoxy-l,5- imino-D-glucitol] (Compound No.12)

6,6 ' -[ 1 ,4-xylenediyl-bis-(oxo)] -bis-(N-allyl-2,3 ,4-tri-O-benzyl- 1 ,5-dideoxy- 1,5- imino-D-glucitol] (Compound No.13)

6,6'-[l,5-triazine-{diyl-bis-(iminocarbonylimino)-3-chloro}]-bis-[2,3,4-tri-O- benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.14) 6,6'-[l,3-benzene-diyl-bis-(iminocarbonyl)-bis-[2,3,4-tri-O-benzyl-N-propyl-D- gluco-δ-lactam] (Compound No.15)

6,6 ' 6"-[ 1 ,3 ,6-benzene-triyl-tris-(iminocarbonyl)-tris-[2,3 ,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.16) 6,6'6"-[l,3,6-benzene-triyl-tris-(iminocarbonyl)-tris-[2,3,4-trihydroxy-N-propyl- D-gluco-δ-lactam] (Compound No.17)

6,6'-[l,4-piperazinediyl-bis-(acetylimino)]-bis-[2,3,4-tri-O-benzyl-N-propyl-D- gluco-δ-lactam] (Compound No.18) 6,6'-[l,4-piperazinediyl-bis-(acetylimino)]-bis-[2,3,4-trihydroxy-N-propyl-D- gluco-δ-lactam] (Compound No.19)

6,6'-bis-(imino)-carbonyl)-bis-[2,3,4-tri-O-benzyl-N-propyl-D-gluco-δ-lactam] (Compound No.20)

6,6'-bis-(immo)-carbonyl)-bis-[2,3,4-trihydroxy-N-propyl-D-gluco-δ-lactam] (Compound No.21)

6,6'-[l,4-benzenediyl-bis-(iminocarbonylimino)]-bis-[2,3,4-tri-O-benzyl-N- propyl-D-gluco-δ-lactam] (Compound No.23) 6,6'-[l,8-napthalenediyl-bis-(iminocarbonylimino)]-bis-[2,3,4-tri-O-benzyl-N- propyl-D-gmco-δ-lactam] (Compound No.24)

A method of inhibiting α-glucosidase receptors in mammals comprising administering to said mammal a therapeutically effective amount of a compound having the structure of Formula I:

and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-Oxides, polymorphs, prodrugs, metabolites, wherein;

A represents lower (Cι-C₄) alkyl, lower (Cι-C₄) alkenyl, lower (Ci-C₄) alkynyl;

X-G represents C=O or CH₂;

R represents hydrogen, alkyl (d-C₆), acyl, aryl, aralkyl such as benzyl;

Y represents O or NH;

Z represents C=O, divalent (Cι-Cu) alkenyl, especially linear or branched (Cι-C₆) alkenyl; the divalent aralalkenyl such as -CH₂-C₆H₄-, -CH₂-C₆H₄-CH₂, the divalent aralalkenyl group may be substituted at the aryl ring; the divalent arylene such as phenylene, naphthylene, the divalent arylene group may be substituted; the divalent cycloalkylene (C3-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the divalent cycloalkylene (C₃-C₆) group may be substituted; the divalent 5 to 7 membered heterocyclyl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, triazinyl, the divalent (5 to 7 membered) heterocyclyl may be substituted; the divalent heteroaryl group containing 1 to 4 hetero atoms such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, thiazinyl, tetrazolyl, benzopyranyl, the divalent 5-7 membered heterocyclyl group may be substituted; B B

— C — _N — R _ NH — c — , wherein B is selected from sulphur and oxygen and R_\ is selected from the group consisting (CH₂)m where m is an integer ranging from 1-6; divalent cycloalkylene (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the divalent cycloalkylene (C₃- ) may be substituted; the divalent arylene such as phenylene, naphthylene, the divalent arylene group may be substituted; the divalent 5-7 membered heterocyclyl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, suphur and oxygen such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, the divalent 5-7 membered heterocyclyl group may be substituted; the divalent 5-7 membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, triazinyl, tetrazolyl, benzopyranyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, the divalent 5-7 membered heteroaryl group may be substituted; C₆H₄-(CH₂)m C₆H₄- wherein m is an integer ranging from 1 to 6; further Z represents II ( \ II wherein the group Ar includes C— NH NH— C substituted or unsubstituted divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, benzopyranyl, o o pyrazolyl j! „_u _, „„ J! , wherein R₂ is selected from the group consisting of the divalent 5-7-membered heterocyclyl group containing 2 or more hetero atoms selected from the group consisting of nitrogen, sulphur and oxygen such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl; o o jl__R _! wherein R₃ is selected from the group selected from (CH₂)m where m is an integer ranging from 1 to 6; divalent cycloalkylene (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the divalent arylene such as phenylene, naphthylene; the divalent arylene group may be substituted.

A method for treating diabetes in a mammal comprising administering to said mammal a therapeutically effective amount of a compound having the structure of Formula I:

A represents lower ( -C₄) alkyl, lower ( -C₄) alkenyl, lower (CrC₄) alkynyl;

X-G represents C=O or CH2;

R represents hydrogen, alkyl ( -C_ό), acyl, aryl, aralkyl such as benzyl;

Y represents O or NH; Z represents C=O, divalent (Ci-C₁₂) alkenyl, especially linear or branched (C Cβ) alkenyl; the divalent aralalkenyl such as -CH₂-C₆H₄-, -CH₂-C₆H4-CH2, the divalent aralalkenyl group may be substituted at the aryl ring; the divalent arylene such as phenylene, naphthylene, the divalent arylene group may be substituted; the divalent cycloalkylene (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the divalent cycloalkylene (C₃-C₆) group may be substituted; the divalent 5 to 7 membered heterocyclyl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen such as aziridinyl, pyrrolidinyl morpholinyl, piperidinyl, piperazinyl, triazinyl, the divalent (5 to 7 membered) heterocyclyl may be substituted; the divalent heteroaryl group containing 1 to 4 hetero atoms such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, thiazinyl, tetrazolyl, benzopyranyl, the divalent 5-7 membered heterocyclyl group may be substituted;

B B

— C — NH — R.,— NH — C — , wherein B is selected from sulphur and oxygen and Ri is selected from the group consisting (CH₂)m where m is an integer ranging from 1-6; divalent cycloalkylene (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the divalent cycloalkylene (C₃-C₆) may be substituted; the divalent arylene such as phenylene, naphthylene, the divalent arylene group may be substituted; the divalent 5-7 membered heterocyclyl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, suphur and oxygen such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, the divalent

5-7 membered heterocyclyl group may be substituted; the divalent 5-7 membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulphur and oxygen such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, triazinyl, tetrazolyl, benzopyranyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, the divalent 5-7 membered heteroaryl group may be substituted; C₆H₄-(CH₂)m C₆B - wherein m is an integer ranging from 1 to 6; further Z represents j[ ( j[ wherein the group Ar includes substituted or unsubstituted divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, benzopyranyl, o o pyrazolyl _{L_CH __R2__CH2_ __ , wherein R₂ is selected from the group consisting of the divalent 5-7-membered heterocyclyl group containing 2 or more hetero atoms selected from the group consisting of nitrogen, sulphur and oxygen such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl; o o — c— _R3-_C — wherein R₃ is selected from the group selected from (CH )m where m is an integer ranging from 1 to 6; divalent cycloalkylene (C₃-C₆) group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the divalent arylene such as phenylene, naphthylene; the divalent arylene group may be substituted.

A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1 or 2 and a pharmaceutically acceptable carrier.

6. A method of selectively antagonzing α- glucosidase receptors in a mammal comprising the step of administering to said mammal a therapeutically effective amount of the pharmaceutical composition according to claim 5.

7. A method for treating diabetes in a mammal comprising the step of administering to said mammal a therapeutically effective amount of the pharmaceutical composition according to claim 5.

8. A process for preparing a compound of Formula Nil, (Formula I, when A is _{and Rχ} are the same as defined earlier and ts acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-Oxides, polymorphs, prodrugs or metabolites, which comprises reacting a compound of Formula II with p-toluene sulphonyl chloride to give the compound of Formula III which on azidation yields the compound of Formula IN, which is further reduced to yield the amine of Formula N, which on condensation with a compound of Formula NI gives a compound of Formula Nil (Formula I, when A is CH₂CH₂CH₃, X-G is

CO, R is Bn, Y is ΝH, Z is || ¹ || ; wherein B and Ri are the

B B same as defined earlier, wherein B and Ri are the same as defined earlier) as shown below:

aryl, aralkyl)

(Formula I, when A=CH2CH₂CH₃, X-G=CO, R=Bn, Y=NH, Z=C— NH— R.,— NH— C-; where B and R^ are the same as defined earlier) _B „

9. The process of Claim 8 wherein the reaction of compound of Formula II and p- toluene sulfonyl chloride is carried out in a suitable solvent wherein the solvent is selected from the group consisting of dichloromethane, dichloroethane and chloroform.

10. The process of Claim 8 wherein the reaction of compound of Formula II and p- toluene sulfonyl chloride is carried out in the presence of a suitable base wherein the base is selected from the group consisting of triethylamine and diisopropylamine.

11. The process of claim 8 wherein the azidation of compound of Formula III is carried out in a suitable solvent wherein the solvent is selected from the group consisting of dimethylsulfoxide, N,N-dimethylformamide and dimethylacetamide.

12. The process of claim 8 wherein the reduction of azide intermediate of Formula IN to give the compound of Formula N is carried out in a suitable solvent, wherein the solvent is selected from the group consisting of methanol and ethanol.

13. The process of claim 8 wherein the condensation of compound of Formula N and a compound of Formula NI is carried out in a suitable solvent wherein the solvent is selected from the group consisting of acetone and acetonitrile to give a compound of Formula NIL

Formula Nil

4. The process of claim 8 wherein the debenzylation of a compound of Formula Nil to give a compound of Formula NIII (Formula I, wherein A is CH₂CH₂CH₃, X-G is CO, R is H, Y is ΝH, Z is ^_ f ^{— ΝH_ R}ι^~"NH~~ f^~ where B and R_x are the

B . B same as defined earlier) is carried out in a suitable solvent which is selected from the group consiting of methanol and ethanol

Formula VIII

15. A process for preparing a compound of Formula XI (Formula I, A is CH₂CHCH2,

X-G is CH₂, R is Bn, Y is O, Z is R₃ as defined earlier) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, thereof which comprises reduction of the compound of Formula II to give the compound of

Formula IX which on condensation with a compound of Formula X yields a compound of Formula XI as shown below:

la X in -Xylene, p-Xylene) Formula IX

Formula XI (Formula I, A = CH₂CHCH₂ X-G=CH₂, R=Bn, Y=0, Z=R₃ as defined earlier)

16. The process of claim 15 wherein the reduction of compound of Formula II is carried out in a suitable solvent wherein the solvent is selected from the group consisting of tetrahydrofuran and diethyl ether.

17. The process of claim 15 wherein the condensation of Formula IX with a compound of Formula X is carried out in a suitable solvent wherein the solvent is selected from the group consisting of dimethylsulfoxide, N,N-dimethyl formamide and dimethylacetamide.

18. The process of claim 15 wherein the consensation of compound of Formula IX with a compound of Formula X is carried out in the presence of a suitable base wherein the base is selected from the group consisting of sodium hydride, cesium carbonate, potassium carbonate and sodium carbonate.

19. A process for preparing a compound of Formula XII (Formula I, A is CH₂CH₂CH₃, X-G is CO, R is Bn, Y is NH, Z is 1 )

and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, thereof, which comprises with cyanuric chloide to give the compound of Formula XII as shown below;

Formula XII

.A X...

(Formula I, A = CH2CH₂CH_3> X-G=CO, R=Bn, Y=NH, Z= 1 j^ )

20. The process of claim 19 wherein the condensation of the compound of Formula V and cyanuric chloride to give the compound of Formula XII is carried out in a suitable solvent wherein the solvent is selected from the group consisting of acetone and acetonitrile.

21. The process of claim 19, wherein the reaction of compound of Formula N with cyanuric chloride is carried out in the presence of a inorganic or organic base selected from the group consisting of potassium carbonate, sodium carbonate, triethylamine and diisopropylamine.

22. A process for preparing a

CH₂CH₂CH₃, X-G is CO, defined earlier) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, thereof, comprising reacting the compound of Formula V with a compound of Formula XIII as shown below:

23. The process of claim 22 wherein the reaction of the compound of Formula N and a compound of Formula XIII is carried out in a suitable solvent wherein the solvent is selected from the group consisting of dichloromethane, dichloroethane and chloroform.

24. The process of claim 22 wherein the reaction of compound of Formula N and compound of Formula XIII to give a compound is of for XIN is carried out in the presence of suitable base wherein the base is selected from the group consisting of

Formula XIN

25. The process of claim 22 wherein the debenzylation of a compond of Formula XIN to give a compound of Formula XN (Formula I, A is CH₂CH₂CH₃, X-G is CO, R is H, Y is ΝH, Z is , E is the same as defined earlier) is carried out for a suitable solvent which is selected from the group consisting of methanol and

Formula XV

6. A process of preparing a compound of Formula XNII (Formula I, A is

CH₂CH₂CH₃, X-G is CO, R is Bn, Y is ΝH, Z is — C-CH₂-Ν N-CH₂-C— ) and o — o its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites there of, which comprises reacting a compound of Formula V with bromoacetyl bromide to give a compound of Formula XVI which condenses with piperazine to yield the compound of Formula XNII as shown below:

Formula XVI

Solvent/base

Formula XVII

(Formula I, A = CH₂CH₂CH_3ιX-G=C0, R=Bn, Y=ΝH, Z= — c— CH₂-N r^~\ N— CH₂-C — ) o — o

Debenzylation

(Formula I, when A = CH₂CH₂CH_3ι

27. The process of claim 26 wherein the reaction of compound of Formula N and bromoacetylbromide is carried out in a suitable solvent wherein the solvent is selected from the group consisting of dichloromethane, dichloroethane and chloroform.

28. The process of claim 26 wherein the reaction of compound of Formula N and bromoacetyl bromide is carried out in the presence of a suitable base wherein the base is selected from the group consisting of triethylamine and diisopropylamine.

29. The process of claim 26 wherein the condensation of compound of Formula XNI and piperazine is carried out in a suitable solvent wherein the solvent is selected from the group consisting of acetone and acetonitrile.

30. The process of claim 26 wherein the condensation of compound of Formula XNI and piperazine to give the compound of Formula XNII is carried out in the presence of a base which is selected from the group consisting of potassium carbonate and sodium carbonate.

Formula XNII

31. The process of Claim 26 wherein the debenzylation of the compund of Formula XNII to give the compound of Formula XNIII (Formula I, A is CH₂CH₂CH₃, X-G is CO, R is H, Y is ΝH, Z is 9 ^CH2 ^Ν _χ ^N— ^CH ₂-^C ) j_{s car}ried out in a suitable o — o solvent which is selected from the group consisting of methanol and ethanol.

Formula XVIII

2. A process of preparing a compound of Formula XXI (Formula I, A is CH₂CH2CH₃, X-G is CO, R is Bn, Y is NH, Z is CO) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, thereof which comprises reacting the compound of Formula V with the compound of Formula XIX to give the compound of Formula XX which further reacts with the compound of Formula N to yield the compound of Formula XXI as shown below:

Formula XXI (Formula I, A = CH2CH₂CH_3F X-G=CO, R=Bn, Y=NH, Z=CO)

(Formula I, A = CH.CH₂CH₃ X-G=CO, R=H, Y=NH, Z=CO)

33. The process of claim 32 wherein the reaction of compound of Formula N and the compound of Formula XIX is carried out in a suitable solvent wherein the solvent is selected from the group consisting of dichloromethane, dichloroethane and chloroform.

34. The process of claim 32 wherein the reaction of compound of formula N and the compound of Formula XIX is carried out in the presence of a suitable base wherein the base is selected from the group consisting of triethylamine and diisopropylamine.

35. The process of claim 32 wherein the reaction of compound of formula XX and the compound of Formula N is carried out in a suitable solvent wherein the solvent is selected from the group consisting of dichloromethane, dichloroethane and chloroform.

36. The process of claim 32 wherein the reaction of compound of Formula XX and the compound of Formula N to give the compound of Formula XXI is carried out in presence of a suitable base wherein the base is selected from the group consisting of triethylamine and diisopropylamine.

Formula XXI

37. The process of claim 32 wherein the debenzylation of the compound of Formula XXI to give the compound of Formula XXII (Formula I, A is CH₂CH₂CH₃, X-G is CO, R is H, Y is ΝH, Z is CO) is carried out in presence of a suitable solvent which is selected from the group consisting of methanol and ethanol.

Formula XXII

39. A process for preparing a compound ofFormula XXIN where R₄ is the same as defined earlier (Formula I, A is CH₂CH₂CH₃, X-G is CO, R is Bn, Y is ΝH, Z is r* MU. p H_' f*

II ^ 11 where Ri is phenylene or naphthylene) and its o o pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, Ν-oxides, polymorphs, prodrugs, metabolites, thereof which comprises condensing the compound ofFormula XX with a compound of

Formula XXIII to give a compound ofFormula XXIN as shown below:

II

e, naphthylene)

Formula XXIV

(Formula I, A=CH₂CH₂CH₃, X-G=CO, R=Bn, Y=NH, Z= jf^{— NH} — R4—NH— C-

R₄ is the same as defined earlier) _Q o

40. The process of claim 38 wherein the reaction of compound of Formula XX and a compound ofFormula XXIII is carried out in a suitable solvent wherein the solvent is selected from the group consisting of dichloromethane, dichloroethane and chloroform.

41. The process of claim 38 wherein the reaction of compound of Formula XX and the compound ofFormula XXIII is carried out in the presence of a suitable base wherein the base is selected from the group consisting of triethylamine and diisopropylamine.