Title of Invention

A PROCESS FOR PREPARATION OF NOVEL PHOSPHONATE DERIVATIVES

Abstract

A process for the preparation of compound of formula (I) as claimed in claim 1, comprising the following steps. i) reacting an aldehyde of formula (2), where A is as defined earlier, with a compound of formula (3), where Rl and R2 are as defined earlier to obtain a, p-unsaturated phosphonate derivative of formula (4). ii) reducing the compound of formula (4) to obtain compound of formula (1), where all symbols are as defined earlier.

Full Text

FORM 2 The PATENT ACT, 1970 (39 of 1970) Complete Specification A [PROCESS FOR PREPARATION OF NOVEL PHOSPHONATE DERIVATIVES CADILA HEALTHCARE LTD, Zydus Research Center Zydus Tower, Satellite Cross Road, Sarkhej-Gandhinagar Highway, Ahmedabad- 380015, Gujarat, India The following specification describes the nature of the invention and the manner in which it is to be performed: 8 JAN 2004 The present invention relates to novel phosphonate derivatives of formula (I), their lalogs, their tautomeric forms, their pharmaceutically acceptable salts, their larmaceutically acceptable solvates and pharmaceutically acceptable compositions ining them. The present invention also relates to a process of preparing compounds formula (I), their analogs, derivatives, their tautomeric forms, their tically acceptable salts, pharmaceutical compositions containing them, and ermediates involved in their synthesis. The compounds of the general formula (I) induce an increase in an individual's bone mass and also are found to lower or modulate triglyceride levels and/or cholesterol levels and/or low-density lipoproteins (LDL) and raise HDL plasma levels (JP 20102687) and hence are useful in the treatment of bone wasting diseases like osteoporosis (US 5508273 and in the treatment and/or prophylaxis of obesity, hypertension, atherosclerotic disease events, vascular restenosis, diabetes and many other related conditions (US 5043330). The compounds of the present invention can also be used in medical conditions like rheumatoid arthritis, asthma, cardiovascular diseases, dysmenorrhea, atherosclerosis, osteoarthritis and other similar disease conditions. The compounds have effects on different parasites (J. Med. Chem., 2001,44, 909-916). The compounds of the present invention are also useful as inhibitors of matrix-degrading metalloproteinases, reprolysin (also known as adamylsin) subfamilies and of TNF-alpha (tumor necrosis factor alpha) activity. Osteoporosis is a bone-wasting disease in which there is an imbalance or uncoupling between the rate of bone formation and resorption resulting in a decrease in total bone mass. As a result of this decrease in bone mass the skeleton becomes weakened and unable to bear the normal weight-bearing stresses. The effects of osteoporosis are generally seen in the weight-bearing part of the skeleton, especially the spine and hips, which can fracture in the absence of trauma. The current therapies for postmenopausal osteoporosis consist of treatments which are for the most part preventative but they do not induce an increase in bone mass which is needed to reduce fracture risk and pain. The present invention focuses on agents which are useful in treating bone wasting diseases by increasing an individuals bone mass and thus reducing or eliminating fracture risk. Diabetes is associated with other diseases such as obesity, hyperlipidemia, hypertension, angina and cardiovascular diseases. Recent addition of drugs in the treatment of diabetes are the thiazolidinediones, drugs having insulin-sensitizing action. These are useful in treating diabetes, lipid metabolism but are suspected to have tumor-inducing potential and cause hepatic dysfunction, which may lead to liver failure. Presently, there is a need for a safe and an effective drug, to treat insulin resistance, diabetes and hyperlipidemia [Exp. Clin. Endocrinol. Diabetes: 109(4), S548-9 (2001)]. The compounds of the present invention can be used in treatment of diabetes and the associated conditions like type 2 diabetes, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease, atherosclerosis, xanthoma, stroke, peripheral vascular diseases and related disorders, certain renal diseases such as glomerulonephritis, glomerulosclerosis, etc. Tumor necrosis factor-alpha converting enzyme (TACE) is responsible for cleavage of cell bound tumor necrosis factor-alpha (TNF-a, also known as cachectin). TNF-a is recognized to be involved in many infectious and auto-immune diseases (W. Friers, FEBS Letters, 285,199 (1991)). Further, TNF-a has been shown to be the prime mediator of the inflammatory response seen in sepsis and septic shock. Compounds, which are inhibitors of TACE, prevent the formation of TNF-a and prevent the deleterious effects of it. The compounds of the invention are also useful in the treatment of inflammatory The main objective of the present invention is to provide novel phosphonate derivatives represented by the general formula (I), their analogs, their tautomeric forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutical compositions containing them or their mixtures thereof. Another objective of the present invention is to provide novel phosphonate derivatives represented by the general formula (I), their analogs, their tautomeric forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutical compositions containing them or their mixtures thereof having enhanced activities, without toxic effects or with reduced toxic effect. Yet another objective of this invention is to provide a process for the preparation of novel phosphonate derivatives represented by the general formula (I), their analogs, their tautomeric forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates. Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions. A further objective of the present invention is to provide process for preparation of intermediates involved in the process. DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention relates to compounds of the general formula (I), their analogs, their tautomeric forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutical compositions containing them or their mixtures thereof wherein R1 represents H, substituted or unsubstituted (C1-C12)alkyl, acyl, aryl, ar(Cr C12)alkyl, heteroaryl, heteroar(C1-C6)alkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl or alkylaminoalkyl groups which may be substituted; R2 represents H, CN, linear or branched substituted or unsubstituted alkyl, substituted or unsubstituted single or fused aryl, substituted or unsubstituted single or fused alralkyl or groups selected from linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, OR3, COOR4, CONR5R6. Where R3 represents hydrogen, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, cyclo(C3-C6)alkyl, aryl, ar(C1-C12)alkyl, heteroaryl, heteroar(Ci C1-C12)alkyl, heterocyclyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl or acyl groups; R4 represents hydrogen, substituted or unsubstituted groups selected from linear or branched (CC1-C12)alkyl, aryl, ar(C1-C12)alkyl, heteroaryl, heteroar(C1-C12)alkyl, heterocylyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl or alkylaminoalkyl groups; R5 and R6 may be same or different and represents independently hydrogen, OH, or substituted or unsubstituted groups selected from (C1-C12) alkyl, aryl, ar(C1-C12)alkyl, hydroxy(C1-C12)alkyl, amino(C1-C12)alkyl, heteroaryl or heteroar(C1-C12)alkyl groups; n is 0 or 1; (—) may optionally represents a bond when n=l; A represents substituted or unsubstituted groups selected from linear or branched (Ci C1-C12)alkyl, cyclo(C1-C12)alkyl, aryl, ar(C1-C12)alkyl, heteroaryl, heteroar(C1-C12)alkyl, heterocyclyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl or acyl groups; The term "substituted" used in combination with other radicals, denotes suitable substituents on that radical such as substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted aryl, etc. mentioned anywhere in the specification. The suitable substituents include, but are not limited to the following The term "alkyl" used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing one to twelve carbons, such as methyl, ethyl, n- propyl, tso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, /-amyl, n-pentyl , w-hexyl, iso- hexyl, heptyl, octyl and the like. The term "alkenyl" used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing two to twelve carbons; such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and the like. The term "alkenyl" includes dienes and trienes of straight and branched chains. The term "alkynyl" used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing two to twelve carbons, such as ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like. The term "alkynyl" includes di- and tri-ynes. The term "cyclo(C3-C7)alkyl" used herein, either alone or in combination with other radicals, denotes a cyclic radical containing three to seven carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term "cyclo(C3-C7)alkenyl" used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbons, such as cyclopropenyl, 1- cyclobutenyl, 2-cylobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, and the like. The term "alkoxy" used herein, either alone or in combination with other radicals, denotes a radical alkyl, as defined above, attached directly to an oxygen atom, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, /-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the like. The term "alkenoxy" used herein, either alone or in combination with other radicals, denotes an alkenyl radical, as defined above, attached to an oxygen atom, such as vinyloxy, allyloxy, butenoxy, pentenoxy, hexenoxy, and the like. The term "cyclo(C3-C7)alkoxy" used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like. The term "halo" or "halogen" used herein, either alone or in combination with other radicals, such as "haloalkyl", "perhaloalkyl" etc refers to a fluoro, chloro, bromo or iodo group. The term "haloalkyl" denotes a radical alkyl, as defined above, substituted with one or more halogens such as perhaloalkyl, more preferably, perfluoro(Ci-C6)alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups. The term "haloalkoxy" denotes a haloalkyl, as defined above, directly attached to an oxygen atom, such as fluoromethoxy, chloromethoxy, fluoroethoxy chloroethoxy groups, and the like. The term "perhaloalkoxy" denotes a perhaloalkyl radical, as defined above, directly attached to an oxygen atom, trifluoromethoxy, trifluoroethoxy, and the like. The term "aryl" or "aromatic" used herein, either alone or in combination with other radicals, denotes an aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, such as phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like. The term 'aralkyl" denotes an (C1-C12) alkyl group, as defined above, attached to an aryl, such as benzyl, phenethyl, naphthylmethyl, and the like. The term "aryloxy" denotes an aryl radical, as defined above, attached to an alkoxy group, such as phenoxy, naphthyloxy and the like, which may be substituted. The term "aralkoxy" denotes an aryialkyl moiety, as defined above, such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy, and the like, which may be substituted. The term "heterocyclyl" or "heterocyclic" used herein, either alone or in combination with other radicals, denotes saturated, partially saturated and unsaturated ring-shaped radicals, the heteroatoms selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, and the like; examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, and the like. The term "heteroaryl" or "heteroaromatic" used herein, either alone or in combination with other radicals, denotes unsaturated 5 to 6 membered heterocyclic radicals containing one or more hetero atoms selected from O, N or S, attached to an aryl group, such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, and the like. The term "heterocyclyl(Ci-Ci2)alkyl" used herein, either alone or in combination with other radicals, represents a heterocyclyl group, as defined above, substituted with an alkyl group of one to twelve carbons, such as pyrrolidinealkyl, piperidinealkyl, morpholinealkyl, thiomorpholinealkyl, oxazolinealkyl, and the like, which may be substituted. The term "heteroaralkyl" used herein, either alone or in combination with other radicals, denotes a heteroaryl group, as defined above, attached to a straight or branched saturated carbon chain containing 1 to 12 carbons, such as (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1- (2-pyrimidyl)ethyl and the like. The terms "heteroaryloxy", "heteroaralkoxy", "heterocycloxy", "heterocylylalkoxy" denotes heteroaryl, heteroarylalkyl, heterocyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom. The term "acyl" used herein, either alone or in combination with other radicals, denotes a radical containing one to eight carbons such as formyl, acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted. The term "acyloxy" used herein, either alone or in combination with other radicals, denotes a radical acyl, as defined above, directly attached to an oxygen atom, such as acetyloxy, propionyloxy, butanoyloxy, wo-butanoyloxy, benzoyloxy and the like and may be substituted. The term "acylamino" used herein, either alone or in combination with other radicals, denotes an acyl group as defined earlier attached to one amino group and may be CH3CONH, C2H5CONH, C3H7CONH, C4H9CONH, C6H5CONH and the like, which may be substituted. The term "mono-substituted amino" used herein, either alone or in combination with other radicals, denotes an amino group, substituted with one group selected from (d-C6)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups. Examples of monoalkylamino group include methylamine, ethylamine, n-propylamine, «-butylamine, n-pentylamine and the like and may be substituted. The term 'disubstituted amino" used herein, either alone or in combination with other radicals, denotes an amino group, substituted with two radicals that may be same or different selected from (C1-C6)alkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, such as dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like and may be substituted. The term "arylamino" used herein, either alone or in combination with other radicals, denotes an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, such as phenylamino, naphthylamino, N-methyl anilino and the like and may be substituted. The term "aralkylamino" used herein, either alone or in combination with other radicals, denotes an arylalkyl group as defined above linked through amino having a free valence bond from the nitrogen atom e.g. benzylamino, phenethylamino, 3-phenylpropylamino, 1-napthylmethylamino, 2-(l-napthyl)ethylamino and the like and may be substituted. The term "oxo" or "carbonyl" used herein, either alone (-C=0) or in combination with other radicals, such as "alkylcarbonyl", denotes a carbonyl radical (~C=0) substituted with an alkyl radical such as acyl or alkanoyl, as described above. The term "carboxylic acid" used herein, alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic acid such as esters and amides. The term "ester" used herein, alone or in combination with other radicals, denotes -COO- group, and includes carboxylic acid derivatives, where the ester moieties are alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, and the like, which may be substituted; aryloxycarbonyl group such as phenoxycarbonyl, napthyloxycarbonyl, and the like, which may be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as defined earlier, which may be substituted. The term "amide" used herein, alone or in combination with other radicals, represents an aminocarbonyl radical (H2N-C=0), wherein the amino group is mono- or di-substituted or unsubstituted, such as methylamide, dimethylamide, ethylamide, diethylamide, and the like. The term "aminocarbonyl" used herein, either alone or in combination with other radicals, with other terms such as 'aminocarbonylalkyl", "n-alkylaminocarbonyl", "N- arylaminocarbonyl", "N,N-dialkylaminocarbonyl", "N-alkyl-N-arylaminocarbonyl", "N- alkyl-N-hydroxyaminocarbonyl", and "N-alkyl-N-hydroxyaminocarbonylalkyl", substituted or unsubstituted. The terms "N-alkylaminocabonyl" and "N,N-dialkylaminocarbonyl" denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical and with two alkyl radicals, respectively. Preferred are "lower alkylaminocarbonyl" having (C1-C6) lower alkyl radicals as described above attached to aminocarbonyl radical. The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" denote aminocarbonyl radicals substituted, respectively with one aryl radical, or one alkyl and one aryl radical. The term "aminocarbonylalkyl" includes alkyl radicals substituted with aminocarbonyl radicals. The term "hydroxyalkyl" used herein, either alone or in combination with other radicals, denotes an alkyl group, as defined above, substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like. The term "aminoalkyl" used herein, alone or in combination with other radicals, denotes an amino (-NH2) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyl. The term "alkylamino" used herein, alone or in combination with other radicals, denotes an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and di-substituted alkylamino. The term "alkoxyalkyl" used herein, alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like. The term "aryloxyalkyl" used herein, alone or in combination with other radicals, includes phenoxymethyl, napthyloxymethyl, and the like. The term "aralkoxyalkyl" used herein, alone or in combination with other radicals, includes C6H5CH2OCH2, C6H5CH2OCH2CH2, and the like. The term "(CrCi2)alkylthio" used herein, either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group of one to twelve carbon atoms, as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, such as methylthio, ethylthio, propylthio, butylthio, pentylthio and the like. Examples of cyclic alkylthio are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be substituted. The term "thio(C1-C12)alkyl" used herein, either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to a group of formula -SR', where R' represents hydrogen, alkyl or aryl group, e.g. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be substituted. The term "arylthio' used herein, either alone or in combination with other radicals, denotes an aryl group, as defined above, linked through a divalent sulfur atom, having a free valence bond from the sulfur atom such as phenylthio, napthylthio and the like. The term "(Ci-Ci2)alkoxycarbonylamino" used herein, alone or in combination with other radicals, denotes an alkoxycarbonyl group, as defined above, attached to an amino group, such as methoxycarbonylamino, ethoxycarbonylamino, and the like. The term "aryloxycarbonylamino" used herein, alone or in combination with other radicals, denotes an aryloxycarbonyl group, as defined above, attached to the an amino group, such as C6H5OCONH, C6H5OCONCH3, C6H5OCONC2H5, C6H4(CH30)CONH, C6H4(OCH3)OCONH, and the like. The term "aralkoxycarbonylamino" used herein, alone or in combination with other radicals, denotes an aralkoxycarbonyl group, as defined above, attached to an amino group C6H5CH2OCONH, C6H5CH2CH2CH2OCONH, C6H5CH2OCONHCH3, C6HsCH2OCONC2H5, C6H4(CH3)CH2OCONH, C6H4(OCH3)CH2OCONH, and the like. The term "aminocarbonylamino", "alkylaminocarbonylamino", "dialkylaminocarbonylamino" used herein, alone or in combination with other radicals, denotes a carbonylamino (-CONH2) group, attached to amino(NH2), alkylamino group or dialkylamino group respectively, where alkyl group is as defined above. The term "amidino" used herein, either alone or in combination with other radicals, denotes a -C(=NH)-NH2 radical. The term "alkylamidino" denotes an alkyl radical, as discussed above, attached to an amidino group. The term "guanidino" used herein, either alone or in combination with other radicals, denotes HN=C(NH2)NH-, suitably substituted with other radicals, such as alkylguanidino, dialkylguanidino, where the alkyl group, as defined above is attached to a guanidino group, such as methylguanidino, ethylguanidino, dimethylguanidino, and the like. The term "hydrazino" used herein, either alone or in combination with other radicals, denotes -NHNH-, suitably substituted with other radicals, such as alkyl hydrazino, where an alkyl group, as defined above is attached to a hydrazino group. The term "alkoxyamino" used herein, alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an amino group. The term "hydroxyamino" used herein, alone or in combination with other radicals, denotes - NHOH moiety, and may be substituted. The term "sulfenyl" or "sulfenyl and its derivatives" used herein, alone or in combination with other radicals, denotes a bivalent group, -SO- or RSO, where R is substituted or unsubstituted alkyl, aryl, heteroaryl, heterocyclyl, and the like. The term "sulfonyl" or "sulfones and its derivatives" used herein, either alone or in combination with other radicals, with other terms such as alkylsulfonyl, denotes divalent radical -S02-, or RS02-, where R is substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, heterocyclyl, and the like. "Alkylsulfonyl" denotes alkyl radicals, as defined above, attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like. The term "arylsulfonyl" used herein, either alone or in combination with other radicals, denotes aryl radicals, as defined above, attached to a sulfonyl radical, such as phenylsulfonyl and the like. The term "sulfonic acid or its derivatives", used herein, either alone or in combination with other radicals, denotes -SO3H group and its derivatives such as sulfonylamino(S02NH2); N-alkylaminosulfonyl and N,N-dialkylarninosulfonyl radicals where the sulfonylamino group is substituted with one and two alkyl groups respectively, such as N-methylaminosulfonyl, N-ethylaminosulfonyl, N,N-dimethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl and the like; N-arylaminosulfonyl and N-alkyl-N-arylaminosulfonyl groups where the sulfonylamino group is substituted with one aryl radical, or one alkyl and one aryl radical; -SO3R, wherein 'R' represents alkyl, aryl, aralkyl groups, as defined above, which may be substituted. The term "phosphonic acid or its derivatives", used herein, either alone or in combination with other radicals, denotes P(0)(OH)2, P(0)(0(CrC6) alkyl)2, P(0)(0 aryl)2, P(0)(OH)(0(Ci-C6)alkyl), and the like. Pharmaceutically acceptable salts forming part of this invention are intended to define but not limited to salts of the carboxylic acid moiety such as alkali metal salts like Li, Na, and K salts; alkaline earth metal salts like Ca and Mg salts; salts of organic bases such as lysine, arginine, guanidine and its derivatives, which may be optionally substituted, diethanolamine, choline, tromethamine and the like; ammonium or substituted ammonium salts and aluminium salts. Salts may be acid addition salts which defines but not limited to sulfates, bisulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, fumarates, maleiates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols. Particularly useful compounds according to the present invention includes 2-(Diethoxy-phosphoryl)-3-phenyl-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(3-hydroxy-phenyl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(4-hydroxy-phenyl)-acrylic acid ethyl ester 3-(3-Benzyloxy-phenyl)-2-(diethoxy-phosphoryl)-acrylic acid ethyl ester 3-(4-Benzyloxy-phenyl)-2-(diethoxy-phosphoryl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(4-phenethyloxy-phenyl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(4-methoxy-phenyl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(pyridin-2-ylmethoxy)-phenyl]-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(pyridin-3-ylmethoxy)-phenyl]-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(pyridin-4-ylmethoxy)-phenyl]-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(4-nitro-benzyloxy)-phenyl]-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(4-methanesulfonyloxy-benzyloxy)-phenyl]-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-{4-[4-(toluene-4-sulfonyl)-benzyloxy]-phenyl}-acrylic acid ethyl ester 3-(4-Chloro-phenyl)-2-(diethoxy-phosphoryl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(3,4-dihydroxy-phenyl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(4-methylsulfanyl-phenyl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(4-methanesulfonyl-phenyl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acrylicacid ethyl ester 2-(Diethoxy-phosphoryl)-3- {4-[2-(4a, 1 Oa-dihydro-phenothiazin-10-yl)-ethoxy]-phenyl} -acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(4-fluoro-phenyl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(3,5-dimethyl-benzyloxy)-phenyl]-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(3-phenethyloxy-phenyl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-furan-2-yl-acrylic acid ethyl ester [l-Cyano-2-(4-hydroxy-phenyl)-vinyl]-phosphonic acid diethyl ester 2-(Dimethoxy-phosphoryl)-3-(4-hydroxy-phenyl)-acrylic acid ethyl ester 3-(4-Benzyloxy-phenyl)-2-(dimethoxy-phosphoryl)-acrylic acid ethyl ester 3-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-(diethoxy-phosphoryl)-acrylic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-phenyl-propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(3-hydroxy-phenyl)-propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester 3-(4-Benzyloxy-phenyl)-2-(diethoxy-phosphoryl)-propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(4-phenethyloxy-phenyl)-propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(pyridin-3-ylmethoxy)-phenyl]-propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(pyridin-4-ylmethoxy)-phenyl]-propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-[4-(4-nitro-benzyloxy)-phenyl]-propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3- {4-[2-(4a, 1 Oa-dihydro-phenothiazin-10-yl)-ethoxy]-phenyl} -propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-(4-fluoro-phenyl)-propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-propionic acid ethyl ester 2-(Diethoxy-phosphoryl)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (Ethoxy-phenyl-methyl)-phosphonic acid diethyl ester [(4-Benzyloxy-phenyl)-ethoxy-methyl]-phosphonic acid diethyl ester 4-[(Diethoxy-phosphoryl)-ethoxy-methyl]-benzoic acid methyl ester [(4-Benzylcarbamoyl-phenyl)-ethoxy-methyl]-phosphonic acid diethyl ester {Ethoxy-[4-(2-phenothiazin-10-yl-ethoxy)-phenyl]-methyl}-phosphonic acid diethyl ester [2-(4-Benzyloxy-phenyl)-l-ethoxy-ethyl]-phosphonic acid diethyl ester [l-Ethoxy-2-(4-hydroxy-phenyl)-ethyl]-phosphonic acid diethyl ester [l-Ethoxy-2-(4-phenylsulfamoyl-phenyl)-ethyl]-phosphonic acid diethyl ester {l-Ethoxy-2-[4-(2-phenothiazin-10-yl-ethoxy)-phenyl]-ethyl}-phosphonic acid diethyl ester [l-(4-Benzyloxy-benzyl)-propyl]-phosphoric acid diethyl ester [2-(4-Benzyloxy-phenyl)-l,l-dimethyl-ethyl]-phosphonic acid diethyl ester 2-(4-Benzyloxy-benzyl)-2-(diethoxy-phosphoryl)-butyric acid ethyl ester 2-Benzyl-2-(dieihoxy-phosphoryl)-butyric acid ethyl ester 2-(Diethoxy-phosphoryl)-2-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-butyric acid ethyl ester [2-(4-Benzyloxy-phenyl)-1,1 -dimethyl-ethyl]-phosphonic acid Several synthesis routes can be employed to prepare the compounds of the present invention well known to one skilled in the art of organic synthesis. The compounds of formula (I) can be synthesized using the methods described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as appreciated by those skilled in the art. Referred methods include, but not limited to those described below. The novel compounds of this invention may be prepared using the reactions and techniques described in this section . The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. When preparing or elaborating compounds of the invention containing heterocyclic rings, those skilled in the art recognize that substituents on the ring may be prepared before, after or concomitant with the construction of the phosphonate compounds. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. Those skilled in the art will recognize that certain reactions are carried out when other potentially reactive functionality on the molecule is masked or protected to avoid undesired side reactions and/or increasing the yield of the reaction. The desired protective groups may be found T. W. Greene, P.G.M. Wuts " Protective Groups in Organic Synthesis" 2nd edition 1991, Wiley and Sons, New York. It is understood by one skilled in the art of organic synthesis that the protective groups present on various reactive functionality of the molecule must be compatible with reagents and reactions proposed and it will be readily apparent to one skilled in the art an alternate methods must be used. The reactions are performed in solvents appropriate to the reagents and materials used and are suitable for the transformations being effected. The phosphonate compounds of the present invention are prepared by methods outlined in Schemes 1 and 2. Scheme-1 illustrates the preparation of the a-carboxyphosphonate compounds. Suitably substituted aldehyde derivatives of the formula (2) where A is as defined earlier, is reacted with trialkyl phosphonoacetate of formula (3) where R2 represents COOR5 or CONR6R7 and R5, R6 and R7 are as defined earlier, in the presence of Lewis acids such as SnCU, TiCl4 and the like in the presence of organic base to get an a,p-unsaturated carboxy-phosphonate (4) where A, R1 and R2 are as defined earlier. Organic base can be used but not limited to bases such as piperidine, N-methyl morpholine and the like. Temperature of the reaction is in the range of -20 °C to 30 °C, but preferably 0 °C. An a,p-unsaturated-carboxy-phosphonate (4), on reduction with reducing agent such as NaBrLt, NaBF^CN and the like lead to its saturated derivative (I) where A, Ri and R2 are as defined earlier. The reduction may be carried out in polar protic solvent such as water, MeOH, EtOH, or mixture thereof or etheral solvent like diethyl ether, THF and the like or mixtures thereof. Scheme-II refers to the synthesis of a-alkoxy-phosphonate analogues of formula (I). Suitably substituted aldehyde derivative (5) where A is as defined earlier, was treated with suitable trialkyl orthoformate of formula (6) as an acetalization reagent in the presence of suitable acidic catalyst such as PTSA, pivalic acid and the like at 50 °C to 80 °C to yield the corresponding acetal derivative (7), where A and R4 are as discussed earlier. Suitable acetalizing agents may be selected from triethyl orthoformate, trimethyl orthoformate and the like. Reacting the compound (7) with appropriate trialkyl phosphite of formula (8) where A, R1, R2 are as discussed earlier, in the presence of suitable Lewis acid catalyst in an inert solvent such as diethyl ether, THF and the like or mixtures thereof, yields the corresponding a-alkoxy-phosphonate analogues of formula (I), where all the symbols are as defined earlier. Suitable Lewis acid catalyst may be selected from but not limited to SnCU, TiCl4 and the like. Scheme-Ill refers to the synthesis of a-alkyl-phosphonate analogues. Suitably substituted alkyl phosphonate (9) where R1 and R2 are as defined earlier, was alkylated by suitable alkyl halide of formula (10) using bases such as LDA, NaHMDS, LiHMDS, NaH and like in the presence of inert solvent like THF, diethyl ether and the like or mixtures thereof, to obtain the corresponding alkylated derivative of formula (11) where R1 and R2 are as defined earlier. Further alkylation with alkyl halide of formula (12) under similar basic conditions gave compound of formula (lb) where A, R1 and R2 are as defined earlier. Alternatively, compound of formula (9) may be alkylated with suitable alkyl halide of formula (13) under similar basic conditions to get compound of formula (la) where A, Rt and R2 are as defined earlier. SCHEME I Because a carbon-carbon double bond also exists in the compounds, the invention contemplates various geometric isomers and mixtures thereof resulting from the arrangement of substituents around these carbon-carbon double bonds. These substituents are designated as being in the E or Z configuration wherein the term "E" refers to higher order substituents on opposite sides of the carbon-carbon double bond, and the term "Z" refers to higher order substituents on the same side of the carbon-carbon double bond. A thorough discussion of E and Z isomerism is provided in "Advanced Organic Chemistry. Reaction, Mechanisms, and Structure", 4th ed., John Wiley & Sons, New York, 1992, pp. 109-112. Another aspect of the present invention comprises a pharmaceutical composition, containing at least one of the compounds of the general formula (I), their derivatives, their analogs, their tautomeric forms, their prodrugs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates thereof as an active ingredient, together with pharmaceutically employed carriers diluents and the like. Pharmaceutical compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: the Science and Practice of Pharmacy, 19th Ed., 1995. The compositions may be in the conventional forms, such as capsules, tablets, powders, solutions, suspensions, syrups, aerosols or topical applications. They may contain suitable solid or liquid carriers or in suitable sterile media to form injectable solutions or suspensions. The compositions may contain 0.5 to 20 %, preferably 0.5 to 10 % by weight of the active compound, the remaining being pharmaceutically acceptable carriers, excipients, diluents, solvents and the like. The compounds of Formula I are useful in the treatment of diseases mentioned above both in humans and other warm blooded animals, by either oral, topical or parenteral administration. Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals including mammals, rodents, and the like. More preferred animals include horses, dogs and cats. For the treatment of any of the above-mentioned diseases the compounds of formula (I) may be administered, for example, orally, topically, parenterally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention. The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition. In therapeutic use for treating bacterial infections in humans and animals that have been diagnosed with having bacterial infections, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be therapeutically active. Generally, such therapeutically effective amount of dosage of active component will be in the range of about 0.1 to about 100 mg/kg, more preferably about 0.5 to about lOOmg/kg of body weight/day. However, it should be appreciated that the dosages may vary depending upon the requirements of the patient, the severity of the bacteria] infection, and the particular compound being used. Also, it must be understood that the initial dosage administered may be increased beyond the upper level in order to rapidly achieve the desired blood level or the initial dosage may be smaller than the optimum and the and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also, be divided into multiple doses for administered, e.g. two to four times per day. The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes as previously indicated, in single or multiple doses. More specifically, the novel compounds described in the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, trochees, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. The carriers may include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents etc. Moreover, for oral consumption, the pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically effective compounds as described in the invention are present in the compositions at concentration levels ranging from 5% to 60% by weight, preferably 10% to 50% by weight. For oral administration, the tablets may be combined with various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine along with various disintegrants such as starch more preferably corn, potato or tapioca starch, alginic acid, sodium carbonate and certain complex sillicates; together with binders like polyvinylpyrrolidone, sucrose, gelatin and acacia, humectants such as for example, glycerol; solution retarding agents, such as, for example paraffin; absorption accelerators such as, for example, quartenary ammonium compounds; wetting agents like cetyl alcohol and glycerol monostearate; absorbents like kaolin and bentonite clay. Additionally, magnesium stearate, sodium lauryl sulfate, talc, calcium stearate, solid polyethylene glycols and mixtures thereof are often added as lubricating agents for tabletting purposes. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Similar type of solid compositions may also be employed as fillers and excipients in soft and hard gelatine capsules; preferred materials include lactose, milk sugar or high molecular weight polyethylene glycols. The active compounds can also be in micro-encapsulated form using one or more of the excipients noted above. The solid dosage forms of tablets, dragees, capsules, pills, and the granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings which are well known in the field of pharmaceutical formulation art. In such solid dosage forms the active compound may be admixed with atleast one inert diluent such as sucrose, lactose and starch. They may also contain, additional substances for e.g. tableting lubricants and other substances like magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the formulation may also contain buffering agents. They may also be so formulated that they release the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. The same may be achieved using embedded agents like, for example, polymeric substances and waxes. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. For such oral consumption it is desirable to combine the active ingredient with various sweetening or flavoring agents, coloring matter or dyes, if so desired. The diluents may be selected from water, ethanol, propylene glycol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, 1,3 butylene glycol, dimethyl formamide, oils for e.g. cottonseed, groundnut, corn, germ, olive, castor, sesame oils and the like, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids like sorbitan and various combination thereof. For mammals other than humans, the composition of the active substance are suitably modified. For parenteral administration, the solutions of the compound is prepared in either sesame or peanut oil or in aqueous propylene glycol. The aqueous solutions should be suitably buffered (preferably pH>8) if necessary, and the diluent should be first rendered isotonic. The aqueous solutions are suitable for intravenous injection purposes while the oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The aforesaid compositions can be readily prepared under sterile conditions following well known standard pharmaceutical techniques by persons skilled in the art. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner. For transdermal and topical administration, the dosage forms will include ointments, pastes, creams, lotions, gels, powders, solutions, sprays and inhalants. Transdermal patches may be prepared following standard drug delivery techniques and applied to the skin of a mammal, preferably a human or a dog, to be treated. Ophthalmic solutions, ear drops, eye ointments, powders can also be used as a medium of providing therapeutic dosages to the patients as will be necessary. The ointments, pastes, creams and gels may, in addition to the active ingredient, contain excipients like animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide or their mixtures. Powders and sprays may contain, in addition to the active substance, excipients like lactose, talc, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or their mixtures. Sprays will additionally contain propellants like chlorofluorohydrocarbons. The invention is explained in detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. 1H NMR spectral data given in the tables (vide infra) are recorded using a 300 MHz spectrometer (Bruker AVANCE-300) and reported in 5scale. Until and otherwise mentioned the solvent used for NMR is CDCI3 using Tetramethyl silane as the internal standard Example 1 Preparation of 2-(diethoxy-phosphoryl)-3-(4-hydroxy-phenyl)-acrylic acid ethyl ester from 4-hydroxybenzaldehyde (compound no. 3). To a solution of titanium tetrachloride (27.87 g, 146 mmol) in dichloromethane (60 ml) at 0 °C, was added 4-hydroxybenzaldehyde (6.0 g, 49 mmol). Tetraethyl methylenediphosphonate (15.53 g, 69 mmol) followed by 4-methyl morpholine (19.81 g, 195 mmol) was added to the mixture. The mixture was stirred for 3h at room temperature (tic) and partitioned between ethyl acetate and water. The ethyl acetate was dried and evaporated to dryness to get 15.4 g (95.80 %) of title compound. The crude compound was subjected to column chromatography over silica gel with 10% acetonitrile in dichloromethane to get title compound (13.12 g, 81.63 %). Example 2 Preparation of 3-(4-ben:zyloxy-phenyl)-2-(diethoxy-phosphoryl)-acrylic acid ethyl ester (compound no. 5). 2-(Diethoxy phosphoryl)-3-(4-hydroxyphenyl) acrylic acid ethyl ester (3.0 g, 9.1 mmol) was added to a mixture of 2.51 g (18 mmol) potassium carbonate and benzylbromide (1.71 g, 10 mmol) in 30 mL DMF. The reaction mixture was refluxed for 1 hour, and cooled to 26 °C-28 °C. The reaction mixture was partitioned between ethyl acetate (150 mL) and water (100 mL). The aqueous layer was separated and extracted with EtOAc (50 mL). The organic layer was washed with water (2 X 100 mL), dried over sodium sulfate and evaporated to get 3.3 g (86.75%) of the title product. Example 3 Preparation of 2-(diethoxy-phosphoryl)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (compound no. 30). 2-(Diethoxy phosphoryl)-3-(4-hydroxyphenyl) acrylic acid ethyl ester (17.4 g, 0.053 mol) was added to THF (100 mL) and 10.03 g (0.26 mol) sodium borohydride was added portion wised to the reaction mixture in an 1 hour. The reaction mixture was stirred for 30 minutes at 25 - 30 °C and partitioned between ethyl acetate (600 mL) and water (300 mL). The organic layer was dried over sodium sulfate and distilled out solvent under reduced pressure to get 12.7 g (72.6%) of desired title product Example 4 Preparation of (ethoxy-phenyl-methyl)-phosphonic acid diethyl ester (compound no. 40). OEt PO(OEt)2 Benzaldehyde diethyl acetal (7.5 g, 41.7 mmol) and triethylphosphite (9.0 mL, 54.2 mmol) were dissolved in dichloromethane (75 mL). The solution was cooled to -75 to -78 °C and to it was added a solution of TiCL (9.2 mL, 83.4 mmol) in dichloromethane (20 mL) dropwise within 5 minutes. The reaction was continued at the same temperature for 2 hours. After completion of the reaction the reaction mixture was warmed to 0 °C and added 50 mL water. The separated organic layer was washed with 50 mL water, dried over sodium sulfate and the solvent was distilled out under reduced pressure to get 11.0 g of title product (yield 97 %). Example 5 Preparation of [2-(4-benzyloxy-phenyl)-l-ethoxy-ethyl]-phosphonic acid diethyl ester (compound no. 45). ! 4-Benzyloxyphenyl acetaldehyde diethyl acetal (1.0 g, 3.3 mmol) and triethylphosphite (0.75 mL, 4.33 mmol) were dissolved in dichloromethane (1.5 mL). The mixture was cooled to -75 to -78 °C and to it was added a solution of TiCl4 (0.73 mL, 6.6 mmol) in dichloromethane (5 mL) within 5 minutes. The reaction was continued at the same temperature for 2 hours (tic). The mixture was warmed to 0 °C and added water (5 mL). The organic layer was washed with water (5 mL). The combined organic layer was dried over sodium sulfate and solvent was evaporated under reduced pressure to get 1.2 g of crude product. The crude compound was subjected to column chromatography over silica gel (200-300 mesh) using 50% EtOAc : pet. ether (1:1) to give the title product (0.56 g, yield 42.9%). Example 6 Preparation of [l-ethoxy-2-(4-hydroxy-phenyl)-ethyl]-phosphonic acid diethyl ester (compound no. 46). A mixture of [2-(4-benzyloxy-phenyl)-l-ethoxy-ethyl]-phosphonic acid diethyl ester (3.0 g, 76.5 mmol), ammonium formate (1.0 g, 15.3 mol), formic acid (1.2 mL, 30.6 mmol) and 10% Pd/C (0.6 g) in ethanol, was gently heated under stirring at 50-55 °C for 2 hours. After completion of the reaction, the mixture was cooled to 25-30 °C, filtered off the Pd/C and washed the used catalyst with EtOAc (15 mL). The combined filtrate was washed with water (20 mL) and dried over sodium sulfate. The solvent was distilled out under reduced pressure to get 2.0 g of title product (yield 86.53%). Example 7 Preparation of [l-ethoxy-2-(4-phenylsulfamoyl-phenyl)-ethyl]-phosphonic acid diethyl ester (compound no. 47). a) Chlorosulfonic acid (28.7 mL, 419 mmol) was cooled to 0-5 °C and to it was added (l-ethoxy-2-phenyl-ethyl)-phosphonic acid diethyl ester (15.0 g, 52.4 mmol) over 10 minutes. The reaction mixture was warmed to 25-30 °C and stirred for 2 hours. After completion of reaction (tic), it was poured into 300 mL of ice water mixture. The mixture was extracted with EtOAc (200 +100 mL)'. The combined EtOAc layer was washed with brine (30 mL). The solvent was distilled under reduced pressure to get 19.4 g of crude chlorosulfonyl derivative. b) A cold mixture of aniline (1.99 mL, 36 mmol) in dichloromethane (30 mL) was added dropwise to a cold solution of chlorosulfonyl derivative obtained above (7.0 g, 18.2 mmol), in dichloromethane (30 mL), at 0-5 °C over 5 minutes. Reaction was continued under stirring at the same temperature for 1 hour. After completion of reaction 50 mL water was added at once. The organic layer was washed with 10 % HC1 (50 mL) and then with water (50 mL). The organic layer was dried over sodium sulfate and the solvent was distilled out to get crude sulfonamide derivative (7.0 g, 84 % yield). The crude compound (0.4 g) was purified by treatment with 20 % EtOAc in pet. ether (20 mL) to get 0.2 g of pure product. Example 8 Preparation of [l-(4-benzyloxy-benzyl)-propyl]-phosphonic acid diethyl ester (compound no. 49) A 1.0 M solution of n-butyl lithium in hexane (8.7 mL, 8.7 mmol) was added over 30 minutes to diisopropylamine (1.22 mL, 8.7 mmol) in THF (20mL) at -78 °C. After 1 hour propyl-phosphonic acid diethyl ester (1.37 g, 7.6 mmol) was added at -78 °C. After 1 hour, 4-benzyloxy benzylbromide (2.0 g, 7.6 mmol) was added at the same temperature. After 2 hours, saturated ammonium chloride solution (10 mL), water (10 mL) and EtOAc (20 mL) were added at -50 °C. The separated aqueous phase extracted with EtOAc (15 mL). The combined organic extracts were washed with water (20 mL), brine (15 mL) and dried (Na2S04). Removal of solvent under reduced pressure provided isopropyl-phosphonic acid diethyl ester as an oil (1.0 g, yield 35%). Example 9 Preparation of [2-(4-benzyloxy-phenyl)-1,1 -dimethyl-ethyl]-phosphonic acid (compound no. 54). Trimethylsilyl bromide was added to [2-(4-benzyloxy-phenyl)-1,1 -dimethyl-ethyl] -phosphonic acid diethyl ester (compound no. 49) (0.2 g, 0.531mmol) in dichloromethane (5 mL) at 25 °C. After 5 hours, the volatile materials were removed under reduced pressure, the residue was diluted with methanol (2 mL), and the resulting solution was concentrated in vacuum to get 150 mg of title compound (88 % yield). R2n PO(OR1)2 (IV) The compounds of the present invention have been tested for their biological activities by carrageenan foot paw edema test in male as well as female Wistar rats according to standard protocol described in literature (Winter et. al, Proc. Soc. Exp. Biol. Med., Ill, 544, (1962); Otterness and Bliven, Laboratory Models for Testing NSAIDS, in Non¬steroidal Anti-inflammatory Drugs, (J. Lombardino, ed.1985). The protocol followed was as described below: Wistar rats obtained from the Experimental Animal Facility of Zydus Research. Centre. Animals were housed in an environmentally controlled rooms with food and water available ad-libitum. All the experimental protocols were approved by the Institutional Animal Ethics Committee. Animals were divided into different groups, each group comprising of five-six animals. After an overnight fast, animals of the control group received vehicle only by oral gavage whereas animals of the other groups received different doses of the test substance(s). Each rat received same volume of the formulation i.e. 2 mL/kg on body weight basis. One hour after administration of the vehicle or test substance, all the animals received sub-planter injection of carrageenan (1 % w/v in saline). Paw volume was measured at 0, 1,3 and 5 hour after carrageenan injection. Anti¬inflammatory activity, expressed as % Inhibition in paw swelling was calculated by measuring change in paw volume at different time intervals after carrageenan injection vs corresponding 0 hr values using the following formula. (PVC - PVT) % inhibition = X 100 PVC Where PVC = Average change in Paw volume of control animals PVT = Average change in Paw volume of treated animals. The compounds of the present invention inhibited 10 % - 95 % rat paw edema at a dose of 30 mg/kg. The compounds of the present invention possess analgesic property and are effective in neuropathy pain. The compounds of the present invention inhibit the COX-1 and COX-2 coenzymes to varying extents as found by human whole blood assay (C. Brideau, S. Kargman, S.Liu; Inflammation Research, 45,68-74 (1996)) The inhibitory activities of representative compounds of the present invention are given in the following table: SI. No. Compound No. Dose (mg/kg) % Inhibition of paw edema after 1 h 1. 1 30 24.04 2. 3 30 37.81 3. 5 30 39 4. 6 30 39.68 5. 13 30 18.39 6. 27 30 12.38 7. 42 30 11.71 8. 43 30 18.96 9. Celecoxib 30 33 The compounds of the present invention lowered triglyceride, total cholesterol, LDL, VLDL and increased HDL and lowered serum glucose levels. This was demonstrated by in vivo animal experiments. A) Demonstration of in vivo efficacy of compounds: i) Serum triglyceride and total cholesterol lowering activity in Swiss albino mice: Male Swiss albino mice (SAM) were bred in Zydus animal house. All these animals were maintained under 12 hour light and dark cycle at 25+1 °C. Animals were given standard laboratory chow (NIN, Hyderabad, India) and water ad libitum. SAM of 20-30 g body weight range were used. The test compounds were administered orally to Swiss albino mice at 0.001 to 50 mg / kg/ day dose for 6 days. The compound was administered after suspending it in 0.25 % CMC or dissolving it in water, when compound is water-soluble. Control mice were treated with vehicle (0.25% of Carboxymethylcellulose; dose 10 ml/kg). The blood samples were collected on 0th day and in fed state 1 hour after drug administration on 6th day of the treatment. The blood was collected in non heparinised capillary and the serum was analyzed for triglyceride and total cholesterol (Wieland, O. Methods of Enzymatic analysis. Bergermeyer, H., O., Ed., 1963. 211-214; Trinder, P. Ann. Clin. Biochem. 1969. 6: 24-27). Measurement of serum triglyceride and total cholesterol was done using commercial kits (Zydus-Cadila, Pathline, Ahmedabad, India). Formula for calculation: Percentage reduction in triglycerides/total cholesterol were calculated according to the formula: Percentage reduction (%) = OC = Zero day control group value OT = Zero day treated group value TC = Test day control group TT = Test day treated group ii) Cholesterol lowering activity in hypercholesterolemic rat models Male Sprague Dawley rats stock bred in Zydus animal house were maintained under 12 hour light and dark cycle at 25±1 °C. Rats of 100-150 g body weight range were used for the experiment. Animals were made hypercholesterolemic by feeding 1 % cholesterol and 0.5 % sodium cholate mixed with standard laboratory chow (NIN, Hyderabad, India) and water ad libitum for 5 days. The animals were maintained on the same diet throughout the experiment [Petit D., Bonnefis M. T., Rey C and Infante R., Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normal and hyperlipidemic rats, Atherosclerosis, 14, 215-225(1988)]. The test compounds were administered orally at a dose 0.03 to 50 mg/ kg/ day for 4 days, after suspending it in 0.25 % CMC or dissolving it in water when compound is water-soluble. Control group was treated with vehicle alone (0.25% of Carboxymethylcellulose; dose 10 ml/kg). The blood samples were collected in fed state on 0th and 1 hour after drug administration on 6th day of the treatment. The blood was collected from the retro-orbital sinus through non-heparinised capillary and the serum samples were analyzed for triglyceride and total cholesterol using commercial kits (Zydus-Cadila, Pathline, Ahmedabad, India). LDL and HDL by commercial kits (Point Scientific, USA). LDL and VLDL cholesterol were calculated from the data obtained for total cholesterol, HDL and triglyceride. The reduction in VLDL cholesterol is calculated according to the formula. VLDL cholesterol in mg/dl = Total cholesterol - HDL cholesterol - LDL cholesterol The compounds of the present invention are also suitable for the treatment of bone wasting diseases like osteoporosis and in the treatment and/or prophylaxis of obesity, hypertension, atherosclerotic disease events, vascular restenosis, diabetes and many other related conditions. The compounds of the present invention have morphinomimetic action and so can be used to relieve pain, to induce constipation, to treat diarrhea or dysentery, for cough suppression, to induce sleep, for sedation, for induction of euphoria or the treatment of depression. The compounds of the present invention can also be used in medical conditions like rheumatoid arthritis, asthma, cardiovascular diseases, dysmenorrhea, premature labour, nephritis, nephrosis, atherosclerosis, osteoarthritis, shock, cancer, and Alzheimer disease, wherein prostaglandins play a pathophysiological role. The compounds of the present invention are also useful as inhibitors of matrix-degrading metalloproteinases, reprolysin (also known as adamylsin) subfamilies and of TNF-alpha (tumor necrosis factor alpha) activity. We Claim: A process for the preparation of compound of formula (I) as claimed in claim 1, comprising the following steps. i) reacting an aldehyde of formula (2), where A is as defined earlier, with a compound of formula (3), where Rl and R2 are as defined earlier to obtain a, p-unsaturated phosphonate derivative of formula (4). ii) reducing the compound of formula (4) to obtain compound of formula (1), where all symbols are as defined earlier. 2) A process as claimed in claim 1 substantially as herein described with reference to foregoing examples. Dated this the 8th day of January 2004

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