Title of Invention

NOVEL HETEROCYCLIC COMPOUNDS, PROCESS FOR THER PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract The present invention relates to novel azolidinedione derivatives and their phannaceutical acceptable salts for the treatment of type II diabetes which could be more potent at relatively lower doses and having better efficacy with lower toxicity The invention also relates to a process for the preparation of above said novel compounds and phannaceutically acceptable salts.
Full Text Field of the Invention
The present invention relates to novel antidiabetic compounds, their tautomeric forms, their derivatives, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. This invention particularly relates to novel azolidmedione derivatives of the general formula (I), and their pharmaceutically aceeptable salts, pharmaceutically acceptable solvates and pharmacetical compositions containing ther

The present invention also relates to a process for the preparation of the above said level, azolidinedione derivati/es, their tautomeric forms, their stereoisomers, their polymophs, their phannaceutically acceptable salts, pharmaceutically acceptable solvates, novel intenuediates and pharmaceutical composition? "containing them.
The azolidinedione derivatives of the general formula (I) dotined above of the presc.u invention are useful for the treatment and / or prophylaxis of diseases or conditions iis which insi-ilin resistance is the ixsiderlying pat!) physiological mechanism. Examples of ;"«.se (ii.sear.es and conditions are type II diabetes, mipaued glucose tolerance, dysi"pidaemia, hypertensioi). corona 17 heart disease and other cardiovascular disorders including atherof;clerosJs. The azolidhiedionej derivatives of the formula (I) are useful for the treatment of i"jsulin resistance associated with obesity and psoriasis. The azohdinedicyr derivatives of the formula (I) can also be used to trei.; diabetic complications and can be used for treatment and / or prophylaxis of other diseases and conditions such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nepluopathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive

nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inhibitors and for improving cognitive fiinctions in dementia.
Background of the Invention
Insulm resistance is the diminished ability of insuhn to exert its biological action across a broad range of concentrations. In insuhn resistance, the body secretes abnormally high amounts of insulin to compensate for this defect ; failing which, the plasma glucose concentration inevitably rises and develops mto diabetes. Among the developed countries, diabet&s meUitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlip demia (J. Clin. Invest., (1985) 75 : 809 - 817; N. Engl. J. Med.; (1987) 317 : 350 - 357 ; J. Clin. Endocrinol. Metab., (1988) 66 : 580 - 583; J. Clin. Invest, (1975) 68 : 957 - 969) and other renal comphcations (See Patent Application No. WO 95/21608). It is now increasingly being recognized that insulin resistance and relative hyperinsuhnemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes melUtus. The association of insulm resistance with obesity, hypertension and angina has beew described as a syndrcme having insulin resisiance as the central pathogenic link-Syndrpme-X. In addition, polycystic ovarian syndrome (Patent Application No. WO 95/07697), psoriasis (Patent AppUcatlon No. WO 95/35108), dementia (Behavioral Brain Research (1996) 75 : 1 - 11) etc, may also have iasuUu resistance as a central pathogenic feature.
A number of molecular defects have been associaced with k&ulm resistance. These include reduced expression of insulm receptors on the plasma membrane of msuUn responsive cells and alterations m the signal transduction pathways that become ac*" ited after insuhn binds to its receptor includmg glucose transport and glycogen synthesis.
Since defective insulin action is thought to be more important than failure of insulin secretion in the development of non-insulin dependent diabetes mellitus and other related complications, this raises doubts about the iutiinsic suitabihty of antidiabetic treatment that is

based entirely upon stimulation of insulin release. Recently, Takeda has developed a new class of compounds wliicb are the derivatives of 5-(4-alkoxybenzyl)-2,4-thiazolidmediones of the fonnula (n) (Ref Chem. PharntBull. 1982, 3(?, 3580-3600). In the formula (H), V represents substituted or unsubstituted divalent aromatic group and U represents various groups wliich have been reported in various patent documents.

By way of examples, U may represent the follov^ig groups:
(i) a group of the formula (Ila) where R^ is hydrogen or hydrocarbon residue or heterocyclic residue which may each be substituted, R^ is hydrogen or a lower alkyl which may be suDstituted by hydroxy group, X is an oxygen or sulphur atom, Z is i hydroxylated methylene or a carbonyl, m is 0 or 1, u is an integer of 1-3. Tlnese compounds have been disclosed in the European Patent Application No. 0 VI 353

An example of these compom\ds is shown in formula (lib)

(ii) a group of the formula (lie) wherein R^ and R^^re the same or different and each i
defined for R3 and may be the same or dififerent from R^. These compounds are disclosed in the European Patent Application No. 0 13 9 421.

An example of these compounds is shown in (lid)

iii} A group of formula (He) where A^ represents substituted or unsubstituted aromatic heterocyclic group, R^ represents a hydrogen atom, alkyl group, acyl group, an aralkyl group wherein the aryl moiety may be substituted or unsubstituted, or a substituted or luisubstituted aryl gioup, n represents an integer in the range +Tom 2 to 6. These compounds are disclosed in European Patent No. 0 306 228.

4n example of this compound is shown in formula (Ilf)

iv) A group of formula (Ilg) where Y represents N or CR^, R1, R^, R3, R4 and R^ represents ?jydrogen, halogen, alkyl and the like and R^ represents hydrogen, alkyl, aryl and the like, n represents an integer of 0 to 3. These compounds are disclosed in European Patent Application No. 0 604 983.


All example of this compound is shown in formula (Ilh)

Still another class of antihypeTglycemic agents are 5-substituted oxazolidme-2,4-diones and 2-substituted-1,2,4-oxadiazolidiue-3,5-dJones which can be represented in the fonnula (Hi),

where V represents substituted or unsubstituted divalent aryl or hetero aryl group, W represents
various groups which have been reported in vj«rious patent documents, A TP-jrretents nitrogen atom
or a CH group and B is an oxygen atom.
By way of examples, W may represent the following groups :
v) a group of fonnub (IIj), where R is (C1-C6) alkyl groups, cycloalkyl group, fui^l, thienyl,
substituted or unsubstituted phenyl group, X is hydrogen, methyl, methoxy, "-Jiloro or fluoro. These compounds have been disclosed in the US patent no. 5 037 842.

An example of these compounds is shown in fonnula (Ilk).


(vi) A group of fomiula (III) wherein A^ reiireseiits a substituted or uiisubstituted aromatic heterocyclyl group; represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or imsubstituted or a substituted or unsubstituted aryl group, n represents an integer in the range of from 2 to 6. These compounds


Some of the above referenced hitherto kiiowii antidiabetic compounds seem to possess bone marrow depression, liver and cardiac toxicities and modest potency and consequently, their regular use for the treatment and control of diabetes is becoming limited and restricted.
Summary of the Invention
With an objective of developing new compounds for the treatment of type II diabetes [non-insulin-dependent-disjbetes mellitus (NIDDM)] which could be more potent at relatively lower doses and having better efficacy with lower toxicity, we focused our research efforts in a direction of incoiporating safety and to have better eflScacy, which has resulted in the development of novel azolidinedione derivatives having the general formula (I) as defined above.
The main objective of the present invention is therefore, to provide novel azolidinedione derivatives; their tautomeric forras, their stereoisomers, their pf^lyirorphs, their phanuaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing theiti, or their mixtures.
Another objective of the present invention is to provide novel azoUdinedione derivatives, their tautomeric forms, their stereoisomers, their polymorphs, then pharmaceutically acieptable salts, tiieir pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, no toxic effect or reduced toxic effect.
Yet another objective of the present invention is to produce a process for the preparation of novel azolidinediones of the fonnula (I) as defined above, their tautomeric forms, their stereoisomers, their polymorphs, their phanoiaceutically acceptable salts and their phamiaceutically acceptable solvates.

Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), theh tautomers, their stereoisomers, their polymorphs, thek salts, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Yet another objective of the present invention is to provide a process for the preparation of the novel intermediate of the formula (III)

where G represents -CHO, -NO2, -NH2, -CH=NHOH, -CH2NHOH, -CH2N(OH)CONH2 or -CH2CH(J)-C00R, where J represents hydroxy group, halogen atom such as chlorine, bromine or iodine and R represents H or lower alkyl group such as methyl, ethyl, or propyl. X, Y, Z, R", R , R3 , n, and Ar are defined as m formula (I).


hydroxy, or nitro, or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamiiio, arylamiiio, amiuoalkyl, aryloxy, alkoxycarbouyl, alkylamiiio, alkoxyalkyl, alkylthio, tliioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives with the provision that when R^, R2 or R^ is on a nitrogen atom it does not represent hydrogen, halogen, nitro, carboxylic acid or sulfomc acid groups; or any two of R^ R2 and R3 along with the adjacent atoms to which they are attached may also form s substituted or imsubstituted cyclic stmcture of from 4 to 7 atoms vAtla one or more double bonds, the cyclic structure may be carbocyclic or may contain one or more heteroatoms selected from o:"cygen, aitrogen and sulfur; Wlten the groups representmg R^, R2 or R^ are substituted, the substituents are selected from the same groups that may represent R1, R2, and R^ such as hydroxy, halogen, or nitro, or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, arji aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamiuo, alkoxyalkyl, alkyltliio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives. The hnking group represented by (€112)11-0- in
formula (I) may be attached either through nitrogen atom or through X, Y qr Z where n is ais integer ranging from 1 - 4. Ar represents an optionally substituted divalent aromatic or heterocyclic group, R^ represents hydrogen atom, halogen or lower alkyl group or forms a bond together with the adjacent group A. A represents a nitrogen atom or a group Cfl^ where R-lepresents hydrogen, halogen or lower alkyl group such as methyl, ethyl, propyl or the like or R^ forms a bond together with R^; B represents an oxygen atom or a sulfur atom when A is CW and B represents an oxygen atom when A is a nitrogen atom.
Suitable combinations of X, Y and Z that form the ring structure containing X, Y and Z in the formula (I) are represented in the following Table:




Wlieu R^ R2 and R3 groups are attached to X, Y, and Z it is preferred that R^ R2, and R^ are selected from hydrogen, halogen atom such as fluorine, chlorine, bromine, or iodine; hydroxy, nitro; substituted or unsubstituted (Ci-Ci2)alkyl group, especially, linear or branched (Ci-C6)alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl and the like; cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; cycloalkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like; aryl group such as phenyl or naphthyl, the aryl group may foe substituted, aralkyl such as benzyl or phenethyl, the aralkyl group may be substituted; heteroaryl group such as pyridyl, thienyl, faryl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group may be substituted; heterocyclyl groups such as aziridiiiyl, pyiTolidinyl, moipholinyl, piperidinyl and the like, the heterocyclyl group may be substituted; aiyloxy such as phenoxy, naphthyloxy, the aryloxy group may be substituted; alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl; aryloxycarbonyl group such as optionally substituted phenoxycarbonyl; arylamino group such as HNC6H5; amino group; amino(Ci-C6)alkyl; hydroxy(Ci-C6)alkyl; (Cl-C6)alkoxy; t\\xo{Ci-C6)&^^yi. (Ci-C6)alkylthio; acyl group sur-h n^ acetyl, propiosiyl or benzoyl, the acyl group may be substituted; acylamino groups such as NHCOCH3, NHCOC2H5, >fHCOC3H7, NHCOC6H5, aralkoxj"carbonylamino group such as NHCOOCH2C6H5, alkoxycarbonylamino group such as NHCOOC2H5, NHCOOCH3 and the like; carboxylic acid or its derivatives such as amides, Uke CONH2, COT"lHMe, CONMei, CONHEt, C0NEt2, CONHPh and the like, the carboxylic acid derivatives may be substiti?ted; acyloxy group such as OCOMe, OCOEt, OCOPh and the like which may optionally be substit""ted; sulfonic acid or its derivatives such as SO2NH2, S02NEMe, S02NMe2, SO2NHCF3
and the like; the sulfonic acid derivatives may be substituted.
All of the prefened groups that may represent R^ R^ and R^ may be substituted or unsubstituted.





substituents on the group represented by Ar may be selected from linear or branched (Ci-C6)alkyl, (Ci-C3)alkoxy, halogen, acyl, amino, acylamino, thio, or carboxylic or sulfonic acids or their derivatives.
It is more preferred that Ar represents substituted or imsubstituted divalent phenylene, naphthylene, benzofuryl, indoUnyl, quinolinyl, azaindolyl, azamdolinyl, benzothiazolyS or benzoxazolyl.
It is still more preferred that Ar is represented by divalent phenylene or naphthylene, which may be optionally substituted by methyl, halomethyl, methoxy or halomethoxy groups.
Suitable R^ includes hydrogen; lower alkyl group such as methyl, etliyl or propyl; halogen atom such as fluorine, chlorine, bromine or iodine, or R^ together with A represents a bond.
Suitable A group may be nitrogen or CR5 where R^ may be a hydrogen atom, halogen, lower alkyl group or together with R"^ forms a bond.
Suitable B group includes a heter" atom selected from O or S, witb the provision that" when A is CR^, B is selected from sulftir or oxygen, and when A is nitrogen, B represents oxygen.
Sutiable ring structure comprising A and B include 2,4-dioxooxazolidiii-5-yl, 2,4-dioxothiazolidin-5-yl, 3,5-dioxol,2,4-oxadiazolidin-2-yl groups. Prefered ring sti-uctures comprising, A and B mclude 2,4-dioxooxazolidine-5-yl and 2,4-dioxotluazolidin-5-y! groups.
It is more prefened that the ring structure comprising A and B is a 2,4-dioxothiazolidin-5-yl group.
Phannaceutically acceptable salts forming gart of this mvention include salts of the azolidinedione 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, diethanolamine,

choline and the like, ammonium or substituted anamonium salts, salts of carboxy group wherever appropriate, such as aluminum, alkali metal salts; alkaline earth metal salts, ammonium or substituted ammonium salts. Salts may include acid addition salts which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, beuzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other snlvents of crystallization such as alcohols.
Particularly useful compounds according to the present invention includes: 5-[4-[2-[2,4-dimethyl-6-oxo-l,6-dihydro- l-pyrimidinyl]ethoxy]phenyl methyrjthiazolidine-2,4-dione and its salts, 5-[4-[2-[2-ethyl-4-methyl-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxy]phenylmethyI]thiazoIidine-2,4-
dione and its salts,
5-[4-[2-[4-metliyl-2-propyl-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-
2,4-dione and its salts,
5-[4-[2-[2-butyl-4-metliyl-6-oxo- l,6"dihydro- l-pyiimidinyl]ethoxy]phenyl methyl]thiazolidiiie-2,4-
dione and its salts,
5-[4-[2-[2-etliyl-4-phenyl-6-oxo-!,6-dihydro-l-pyiimidinyl]ethoxy]phenyl metljyl]thiazolidine-2,4"
dione and Us salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl]thiazolidine-2,4-dione
and its salts and its poIyinoriJbs,
5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-qunia2olinyl]methoxyJphenyl methyl]thiazolidine-2,4-dione
and its salts,
5-[4-[2-[2-raethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]pheoyl methyl]thiazolidine-2,4-dione
and its salts,
5-[4-[2-[2-etliyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phettyl methyl]thiazolidine-2,4-dione
and its salts,
5-[4-[2-[6,7-dimethoxy-2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl]
thiazolidine-2,4-dione and its salts,









the range of 30C to 100C. The duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.
In another embodiment of the present invention, the novel intermediate of general formula (ni), where G is a CHO or NO2 group, can also be prepared by the reaction of compound of general formula (VIII)
where X, Y, Z, R1 , R2, R3, n and L1 are as defined earlier with a compound of general formula

where G is a CHO or NO2 group and Ar is as defined earlier.
The reaction of compound of formula (VIII) with compound of formula (IX) to produce a compound of the formula (III) may be carried out in the presence of solvents such as THF, DIVIF, DMSO, DME and the like or mixtures thereof The reaction may be canied out in an inert atmosphere which may be maintamed by using inert gases such as N2, AT, or He. The reaction may be effected in the presence of a base such as K2CO3, Na2C03 or NaH or mixture?, thereof Tlve reaction temperature may range from 20 "C - 120 ^C, preferably at a temperature in the range of 30 C - 100 C. The duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours.
The present invention provides a process for the preparation of novel azolidinedione derivatives of general fonnula (I), their tautomeric forms, their stereoisomers, their polymorphs, their phanuaceutically acceptable salts and their phantiaceutically acceptable solvates wherein R",

R2, R3, X, Y, Z, n and Ar are as defined earlier and A represents CR^ where R^ together with R"^ represent a bond and B represents a sulfur or a oxygen atom, and further to a compound of formula (I) wherein R4 and R5 represent hydrogen and all symbols are as defined above, which comprises:
reacting the noVel intermediate of the general formula (III) obtained above where G represents CHO group with 2,4-thiazolidinedione or 2,4-oxazolidinedione and removing the wat^ fonned during the reaction by conventional methods to yield a compound of general formula (X)

where R\ R2, R3, X, Y, Z, n and Ar are as defined earUer and B represents sulfixr or oxygen.
The reaction between the compound of the general formula (III) where G is a CHO group with 2,4-thiazoHdinedioae or 2,4-oxazolidinedioae, to yield cortipound of genera! formula (X) wherein B represents a suliiir or an oxygen atom respectively, may be carried out neat in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, methoxyethanol or mixtures thereof. The reaction temperature may range fiom 80 ^C to 140 ^C depending upon the solvents employed and in the range from 80 ^C to 180 ^C when the reaction is carried out neat in the presence of sodium acetate. Suitable catalyst such as piperidinium acetate or benzoate, sodium acetate or mixtures of catalysts may also be employed. Sodium acetate can be used in the presence of solvent, but it is preferred tliat sodium acetate is used neat. The water produced in the reaction may be removed, for example, by using Dean Stark water separator or by using water absorbing agents like molecular selves. Oxazolidme-2-oxo-4-thiione may be used instead of 2,4-oxazohdinedioue. However, the thio group needs to be converted to oxo group by oxidation using agents such as hydrogen peroxide or peroxyacids like mCPBA.

The compound of the general formula (X) obtained in the manner described above is reduced by known method to obtain the compound of general formula (XI)

wherein R1 R2, R3 X, Y, Z, n and Ar are as defined earlier and B represents a sulfur atom or an oxygen atom. The compomid of general formula (XI) represents the compound of general fonnula (I) wherein R^ is hydrogen, A is CR5 where R5 is hydrogeri and other symbols are as defined earlier.
The reduction of compound of the fonnula (X) to yield a compomid of the general fonnula (XI) may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the like. Mixtures of catalysts may be used. The reaction may also be conducted in the presence of solvents such as dioxane, acetic acid, ethyl acetate and the like. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be 5 - 10 % Pd/C and the amount of catalyst used may range from 50 - 300 % w/w. The reaction may also be canned out by employing metal solvent reduction such as magnesium in methanol or sodium amalguu in methanol.
The compound of the general formula (XI) obtained above is converted into hs phannaceutically acceptable salts, or its phaitnaceutically acceptable solvates by conventional methods.
In another embodiment of the present invention, the compound of the general fonnula (I) can also be prepared by reacting a compound of the general fonnula (VIII) defined above with a compound of general formula (XII)


where R"*, A, B and Ar are as defined earlier and R6 is hydrogen or a nitrogen protecting group which is removed after the reaction.
The reaction of compound of formula (VIIl) with compoimd of formula (Xll) to produce a compound of the formula (I) may be carried out in the presence of solvents such as TllF, DMF, DMSO, DME and the like or mixtures thereof The reaction may be carried out in an iiieii atmosphere which is maintained by using inert gases such as N2, Ar or He. The reaction may be effected in the presence of a base such as K2CO3, Na2CO3 or NaH or mixtures thereof The reaction temperature may range from 20 "C - 120 ^C, preferably at a temperature in the range of 30 OC - 80 OC. The duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours.
In still another embodiment of the invention, the compound of the general formulu (1), wliere -(CH2)ii-0- linker is attached to nitrogen atom can be prepared by reacting the corapouad
of the general formula (IV) defined above with a compound of general fonnula (XIII)

where L1 n, Ar , A, B, R4 and R6 are as defined earlier and removal of the protecting group when R6 is a nitrogen protecting group.

The reaction of compound of general formula (IV) with a compound of general formula (XIII) to produce a compound of general formula (I) may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof The reaction may be carried out in an inert atmosphere which is maintained by using inert gases such as N2, Ar or He. The reaction may be eflfected m the presence of a base such as alkalis like sodium hydroxide, or potassium hydroxide; alkali metal carbonates like sodimn carbonate, or potassium carbonate; alkali metal hydrides such as sodium hydride; organometallic bases like n-butyl lithium; alkali metal amides Uke sodamide, or mixtures thereof Multiple solvents and bases can be used. The amount of base may range from i to 5 equivalents, preferably 1 to 3 equivalents. 1 to 3 equivalents of alkali metal halides such as iithiimi bromide may be added as an additive. The reaction temperature may be in the range of 0 C to 120 C, preferably at a temperature in the range of 20 oc to 100 0C. The duration of the reaction may range from 0.5 to 24 hours, preferably from 0.5 to 6 hours.
In yet another embodiment of the present invention, the compoimd of general formula (I), where R1, R2, R3, X, Y, Z, n and Ar are as defined earlier, R4 represents hydrogen and A is CH and B represents S or O can be prepared by the reaction of compound of general fonnula (XIV)

where R^ R2, R3, X, Y, Z, n and Ar are as defined earlier, J is a halogen atom like chlorine, bromine or iodine or a hydroxy group and R is a lower alkyl group, with urea when J is a OH group and with thiourea when J is a halogen atom, followed by treatment with an acid.
The reaction of compound of general formula (XIV) with urea or thiourea is nonnally earned out in the presence of alcoholic solvent such as methanol, ethanol, propanol, isobutanol, 2-methoxybutanol, etc or DMSO or sulfolane. The reaction may be conducted at a temperature in

the range between 20C and the reflux temperature of the solvent used. Bases such as NaOAc, KOAc, NaOMe, NaOEt etc. can be used. The reaction is normally followed by treatment with a mineral acid such as hydrochloric acid at 20 C to 100 C.
The compound of general formula (XIV) where J is hydroxy group is prepared by the hydrolysis of compound of general formula (XIV) where J is a halogen atom using aqueous alkali at a temperature rangmg from 20 C to 100 C followed by reesterification of the hydrolysed acid group by conventional methods.
The compound of general formula (XFV) where J is a OH group may also be preparea from compomid of formula (XIV) where J is a halogen atom by reacting wdtli forraamide in the presence of water. The amoxmt of formamide used in the reaction ranges from 0.5 to 15 mL and water used ranges from 20 [xL to 0.1 mL for one mmol of the halo compound (XIV). Ttie reaction is conducted at a temperature rangmg from 80 0C to 180 0C, preferably from 120 C to 150 °C, over a period ranging from 1 to 8 hours.
The compound of general formula (XIV) where J is a halogen atom gan be prepared by the diaiiotization of the annuo compound of the general formula (XV)

where all symbols are as defined earlier, using alkali metal nitrites followed by treatment with acrylic acid esters m the presence of hydrohalo acids and catalytic amount of copper oxide or copper halide.

The compound of general formula (XV) can in turn be prepared by the conventional reduction of the novel intermediate (III) where G is NO2 group and other symbols are as defined earher.
In another embodiment of the present invention, the compoimd of general formula (I), where R^, R2, R3, X, Y, Z, n and Ar are as defined earUer and A is nitrogen atom and B is oxygen atom can be prepared by a process which comprises : reaction of novel mtermediate of formula (III) where all symbols are as defined above, and G represents a CHO group with NH2OH. HCl to yield a compound of general formula (III) where G represents CH=NOH group and all symbols are as defined earlier, followed by metal borohydride reduction to yield a compound of general formula (XVI)

wlieie all symbols are as defined earlier.
The reaction of compound of general fonnula (HI), where G is CHO group and other symbols are as defined earlier, with hydroxylamine hydrochloride is canied out in solvents suck as etlianol, methanol, TilF, dioxane and the like following the conventional method to make oximes. I to 10 equivalents of NH2OH.HCI may be used, preferably, 2 to 5 equivalents. Bases such as alkali metal acetates or ammonium acetate may be used. Reaction may be carried out in the presence of water. Temperature in the range of 0 C to reflux temperature of the solvent may be used. The oxime obtained in the manner described above is reduced using reducing agents such as alkali metal borohydrides like sodium borohydride or sodium cyanoborohydride or borane reagents using conventional conditions to vield the compound of general formula (XVI).

The compound of general formula (XVI) in turn is reacted with halocarbonyl isocyanate or alkoxycarbonyl isocyanate to yield a compound of general formula (I) or with KOCN to yield a compound of general formula (IH) where G is CFr2N(OH)CONH2, followed by treatment with carbonylating agents such as alkyl haloformate to produce the compound of general fonnula (I)
wiere R , R , R , X, Y, Z, n, Ar are as defined earher, A represents nitrogen atom and B is oxygen atom.
The reaction of compound of general formula (XVI) with halocarbonyl isocyanate such as dilorocarbonyl isocyanate or alkoxycarbonyl isocyanate such as ethoxycarbonyl isocyanate may be carried out in mert solvents such as THF, dioxane, etc at a temperature in the range -15 «€ to 50 0C. The reaction may be carried out for 0.5 to 12 hours depending on the substrates used for the reaction.
Alteniatively, the compound of general formula (XVI) may be treated with excess of KOCN in organic acids such as acetic acid. Water may be used in the reaction. The reaction may be carried out at a temperature in the range of 20 oc to 120 oc The product isolated in the reaction is further treated Avith alkyl haloformate such as ethyl chloroformste in the presence of i to 10 equivalents of alkali such as sodium hydroxide, potassium hydroxide and the like to obtain compound of general formula (I) where all the symbols are as defined earlier and A represents nitogen atom and B represents oxygen atom.
In yet another embodiment of the invention, the compound of general form^ila (I), wher^ the linker -(CH2)irO- is attached througli Z, where Z represents =C, and all other syinbols are as defined eariier can be prepared by reacting the compound of general formula (XViJ)


where R1R2, and R3 are as defined earlier, X represents C=0 or C=S and Y represents C=C; or when R2 and R3 together with Y forai a cyclic structure as defined earlier, X represents C=0 or C=S, Y represents C=C and R^ is as defined earlier, with a compound of general formula (XVIII)

where Ar,R4, A, B and n are as defined earlier, D may be-CN;-C(0R"7)3 where R"^ is (Ci-C4)alkyl; -C(=0)-R8 where R8 may be selected from -OH, CI, Br, I, -NH2, -NHR, where R is a
lower alkyl group such as methyl, ethyl, propyl and the like, or R8 may be 0-(C=0)-R9, where R9 may be a hnear or branched (C1-C5)alkyl group such as methyl, ethyl, propyl, isopropy?, butyl, t-
butyl and the like, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl groups. The reaction proceeds through the intermediate foraiation of compound of general formula (XDC).

where all symbols R", R^ R^ R"*, X, Y, A, B, Ar Mid u are as defined earher.
The group X-NHR^ m formula (XIX) can also be generated by conventional methods such as amidation of an ester group (XOR) or partial hydrolysis of a CN (in a compound where CN group is present ui the place of X-NHR^) group.

Ilie reaction of compound of general formula (XVII) with a compound of general formula (XVIII) to produce a compound of general formula (I) may be carried out in neat or in the presence of solvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO and the like or mixtures thereof The reaction may be carried out in an inert atmosphere which may be maintahied by using inert gases such as N2, Ar or He. The reaction may be canied out at a
temperature in the range of 50 0C to 200 "C, preferably at a temperature in the range of 60 0 C to 180 0C. The reaction may be effected in the presence or in absence of a base or an acid. The nature of the base or the acid is not critical. Example of such bases include organic bases such as pyridine, lutidine, triethyl amine, diisopropylethyl amine and the like, metal carbonates such as K2CO3, Na2C03. Examples of acids include organic acids such as AcOH, C2H5COOH, butyric
acid, p-toluenesulfonic acid, benzenesulfonic acid and the like, mineral acids such as HCl, HBr etc. T1»e duration of the reaction may range from 0.25 to 48 hours, preferably from 0.50 to 18 hours.
Alteinatively, the novel intermediate of formula (XDC) may be isolated and then cychsed to yield a compound of fon;nula (I).
The reaction of compound of the formula (XVII) with a compoxmd of fomiula (XVill) to yield a compound of the fonnula (XIX) may be earned out neat or in presence of solvent such as xylene, toluene, dioxane, DMF, DMSO, halogenated hydrocarbons such as CH2CI2, CHCI3, CICH2CH2CI and the like or mixtures thereof The reaction may be effected in the presence or absence of a base or an acid. The nature of the base or acid is noi critical. Examples of such bases include organic bases such as pyridine, hrtidine, triethyl amine, diisopropylethyl amine and the like. Examples of acids used for tliis reaction includes CH3COOH, C2H5COOH, butyric acid, benzene^iulfouic acid, p-toluenesulfonic acid and the Uke. The reaction may be carried out ui an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He. The
reaction may be earned out at a temperature m the range of 25 C to 180 C, preferably in the range of 25 C to 100 C. The reaction is generally instantaneous and the duration of the reaction may range from 0.25 to 24 h, preferably 0.25 to 2 h.

I lie cyclisation of the compound of formula (XIX) to yield a compound of the formula (I) may be carried out neat or in the presence of solvents such as THF, toluene, xylene, 1,4-dioxane and the like or mixtures thereof The reaction temperature may range from 60 "C to 150 "C depending upon the solvent employed and in the range from 100 "C to 200 °C when the reaction is carried out neat. The reaction may be effected in presence or absence of acids. The acids normally used include acetic acid, propionic acid, butyric acid, pTsOH and the like The amount of acid used may range from 0.1 to 100 equivalents, preferably 0.1 to 10 equivalents. The reaction can also be carried out in neat acid. The reaction is preferably carried out in solvents such as THF, toluene, xylene, 1,4-dioxane or mixtures thereof in the presence of an acid such as acetic acid, propionic acid, p-TsOH and the like. The duration of the reaction may range from 3 to 48 h preferably from 4 to 18 h.
The process described in the above embodiment is novel and unique since the hetsrocycle has been built in the final step of the process. In the present process no side products are observed. The yields are high and no purification is required for any intermediate involved. The process described in the above embodiment does not uivolve any stringent conditions This process woiks well for both small scale and large scale reactions. The process described in the above embodiment is preferably used for compounds of formula (I) wherein R2 and R3 together fonn a cyclic structure as defined earlier with Y, wherein Y represents C=C.
The compound of general formula (XVIII) where D represents -COOH and all other symbols are as defined eariier is prepared from the compound of general formula (XVIO) where D represents -COOR where R is a lower alkyl group such as CH3, C2H5, C3H7 and all other svtnbols are as defined earlier by conventional hydrolysis procedures.
The hydrolysis of the compound of formula (XVIII) where D represents COOR group to yield a compound of the fonnula (XVIII) where D represents COOH group, may be earned out in the presence of solvents such as methanol; ethanol, dioxane, ether, THF, water and the like or mixtures thereof The reaction may be effected in the presence of a base such as an alkali like NaOH, KOH or alkali metal carbonates like sodium carbonate, potassium carbonate and the like. The amount of base may range from 1 to 5 equivalents. The reaction may be carried out at a

temperature m the range of 0 "C to 120 X, preferably at a temperature m the range of 15 "c to 100 X. The duration of the reaction may range from 0.25 to 24 h, preferably from 0.5 to 5 h.
The compound of general fonnula (XVIII) where D represents COCl or COBr and other symbols are as defined earher may be prepared by the reaction of compound of general fonnula (XVIII) where D represents COOH and other symbols are as defined earher with reagents such as SOCla, PCI3, PCI5, PBr3 and the like. The reaction may be carried out neat or in the presence of solvents such as benzene, xylene etc. The reaction may be carried out in the range of 0 "C to 140 X preferably m the range of 25 X tolOO X. ITie duration of the reaction may range from 0.25 to 24 h, preferably 0.5 to 5 h.
Hie compound of general fonnula (XVHI) where all symbols are as defined earlier and D represents -C(=0)-0-(C=OX where R" represents a liuear or branched (C1-C2) alkyl group, dichlorophenyl, trichlorophenyl group and the like, may be prepared by the reaction of compomid of general fonnula (XVIH) where D represents GOOH and all other symbols are as defined earher, with organic acid halides such as acetyl chloride, acetyl bromide, propanoyl chlonde, butanoyi chloride, pivaloyl chloride, trichlorobenzoylchloride and the hke in the presence of a base such as pyndine, N,N-dimethylaminopyridine, triethyl amin., dnsopropylethyl amine, lutidine and the hke or a mixture thereof Hie reaction may be earned out in solvents such as CH2Cl2, CHCl2, ClCHaCH^Cl, l,4.dioxane, xylene and the Uke. The reaction maybe canried out at a temperature in the range of 0 X to 120 X, preferably in the range of 0 X to 50 X. The duration of the reaction may range from 0.25 to 12 h, preferably 0.5 to 5 h.
Particularly useful compound of general fonnula (I) where X represents C=0, Y represents C-C, Z represents =C, n represents an integer 1, R" represents methyl group, B represents sulfur atom, R2 and R3 together with Y fonn a phenyl ring represented by fonnula (XX) can be prepared according to the process described in the above embodunent comprising :


where R10 is as defined above.
The reduction of ootnpoimd of the formula (XXI) to yield a compound if the formula (XXII) may be earned out in the presence of gaseous hydrogen and a catalyst such is Pd/C or Raney nickel. Mixtures of catalysts may be used. Solvents such as dioxane, accilc acid, ethyl acetate and the like may be used. A pressure between atmospheric pressure and 80 psi may be employed. The catalyst may be 5 - 10 % Pd/C and the amount of catalyst used may range from 50 - 300 % w/w. The reaction may also be carried out by employing metal solvent reduction such as magnesium in methanol or sodium amalgam in methanol.
b) Hydrolysis of compound of fonnula (XXII) using conventional conditions to yield a
compound of formula (XXIII)

Tlie hydrolysis of the compound of formula (XXII) to yield a compound of the formula (XXIII) may be canied out in the presence of solvents such as metlianol, ethanol, dioxane, ether, THF, water and the like or mixtures thereof The reaction may be eflFected in the presence of a base such as alkali like NaOH, KOH, alkali metal carbonates like sodium carbonate and potassium carbonate. Tlie amount of base msy range from 1 to 5 equivalents, based on the amount of the compound of foitnula (XXII). Tl\e reaction may be carried out at a temperature in the range of 0
X to 120 °C, preferably at a temperature in the range of 15 "C to 100 T. Tlie duration of the reaction may range from 0.25 to 24 h, prererabiy from 0.5 to 5 h.
c) Reacting a compound of fonnula (XXIII) v.ith acid halide or halogenating agent to obtain
a compoiuid of formula (XXFV),

where D represents COCl or COBr or -C(=0)-0-(C=0)-R^ where R" represents methyl or t-butyl group.

Hie reaction of compound of formula (XXIII) with halogenating agent such i»s SOCI2, PCI5, PBrj may be carried out neat or in presence of sohrent such as benzene, xylene etc. Tlie
reaction may be carried out at 0 ^C to 140 ^C, preferably at 25 ^C to 100 ^C. Tlie duration of the reaction may range from 0.25 to 24 h, preferably 0.5 to 5 h. The reaction of compound of formula (XXIII) with acid halide to yield mixed anhydride, may be carried out wath acid halides such as acetyl chloride or pivaloyl chloride in the presence of a base such as pyridine, triethyl amine, N,N-dimethylamino pyridme or mixtures tliereof The amount of base may range from 1 to 5 equivalents, based on the amount o*" the compound of formula (XXIII). The reaction may be carried out in solvents like dichloromethane, cliloroform, dichloroethane, 1,4-dioxane, xylene and the like, "^flie reaction may be carried cut at a temperature in the range of 0 C to 12D C, preferably at a temperature in the range of 15 °C to 50 "c. The duration of the reaction may range from 0.25 to 12 h preferably from 0.5 to 5 h.
d) Reaction of compound of formula (XXIV) with a compound of formula (XXV)

to yield a compound of formula (XX) defined above. Tlie reaction proceeds through the intennediate fonnation of compound of fonnula (XXVI).

Tl\e reaction of compound of fomiula (XXIV) with a compound of fonnula (XXV) to produce a compound of general fonnula (XX) may be carried out in neat or in tlie presence of

solvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO and the like or mixtures thereof. Tlie reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He. The reaction may be carried out at a temperature in the
range of 50 «€ to 200 OC, preferably at a temperature in the range of 80 0 C to 180 OC. Tlie reaction may be effected in the presence of an acid. The nature of the acid is not critical. Examples of acids include organi(^ acids such as AcOH, C2H5COOH, p-toluenesulfonic acid and the like, mineral acids such as HCl, HBr etc. Tlie duration of the reaction may range from 0.25 to 48 hours, preferably from 0.50 to 18 hours, based on solvent, temperature and acid used.
Alternatively, the novel intermediate of fonnula (XXVI)) may be isolated and then cyclised to yield a compound of formula (XX).
Tlie reaction of compomid of the formula (XXIV) with a compomid of formula (XXV) to yield a compound of the formuJa (XXVI) may be carried out neat or in presence of solvent such as xylene, toluene, dioxane, DMF, DMSO halogenated hydrocarbons such as CH2CI2, CHCI3, CICFI2CH2CI and the like or mixtures thereof Tlie reaction may be effected in the presence of an acid. Tlie nature of tlie acid is not critical. Examples of acids used for this reaction iiic"udes CH,COOH, C2H5COOH, butyric acid, benzenesulfonic acid, p-toluenesulfonic acid and the liku. The reaction may be carried out in an inert atmosphere which may be maintained by using inert gases such as N2, Ar or He. The reaction may be carried out at a temperature in the range of 25
"C to 180 °C, preferably in the range of 25 "C to 60 "c. Tlie reaction is generally instantaneous and the duration of tlie reaction may range from 0.25 to 12 h, preferably 0.25 to 2 h.
Tlie cyclisation of the compound of formula (XXVI) to yield a compound of the formula (XX) may be carried out neat or in the presence of solvents such as THF, toluene, xylene, 1,4-dioxaae and the like or mixtures thereof Tlie reaction temperature may range from 60 "C to 150 "C depending upon the solvent employed and in the range from 100 °C to 200 "C wlien the reaction is carried out neat. Tlie reaction may be effected in the presence of acids. Tlie acids normally used include acetic acid, propionic acid, and pTsOH. The amount of acid used may range from 0.1 to 100 equivalents, preferably 0.1 to 10 equivalents. Tlie reaction can also be

earned out in neat acid. Tlie reaction is preferably carried out in solvents such as THF, toluene, xylene, 1,4-dioxane or mixtures thereof in the presence of an acid such as acetic acid, propionic acid, p-TsOH and the like. Tlie duration of the reaction may range jfrom 3 to 48 h preferably from 4 to 18 h, based on solvent, temperature and acid used.
Tlie phannaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents liko ether, THF, methanol, t-butauol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginite, diethanolamme, choline, guanidine and their derivatives etc. may also be used. Alternatively, acid addition salts are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxytiaphthoic acid, ascorbic acid, pahnitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF. dioxarie etc. Mixture of solvents may also be used.
Tlie stereoisomers of the compounds forming pari of this invention may be prepared by using reactants in their single enantiomeric form m the process wherever possible or by conducting the reactior in the presence of reagents or catalysts in their single enantiomer fomi or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mjindelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like or chiral bases such as rucine, cinchona alkaloids and their derivatives and tlie like.
Various polymorphs of compound of general formula (I) forming part of tlvis invention may be prepared by ciystallizatiou of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at dififerent temperatures; various modes of cooling, ranghig from very fast to veiy slow cooling during ci^stallizations. Polymorphs may also be obtained by heating or melting the

compound tollowed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffractogram or such other techniques.
The present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I), as defined above, their tautomeric foitns, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed caniers, diluents and the like, useflil for tlie treatment and / or prophylaxis of diseases in which msuhn resistance is the underlying pathophysiological mechanism such as type II diabetes, impaired glucose tolerance, dyslipidaemia, hypertension, coronary heart disease and other cardiovascular disorders including atherosclerosis; insulin resistance associated with obesity and psoriasis, for treating diabetic complications and other diseases such as polycystic ovarian syndrome (PCOS), certain renal diseases including diabetic nephropatiiy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal diseases and microalbuminuria as well as certain eating disorders, as aldose reductase inliibitors and for improving cognitive fiinctions in dementia.
Tlie pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the Uke, may contain flavourants, sweeteners etc. hi suitable soUd or Uquid caniers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of act"ve compovmd, the remamder of the composition being phamiaceutically acceptable carriers, diluerits or solvents.
A typical tablet production method is exemplified below:
Tablet Production Example :



circumstances wliere the patient cannot swallow the medication, or absoiption following oral adrainistration is impaired, as by disease or other abaormahty, it is essential tliat the drug be administered pareuterally. By either route, tlie dosage is in the range of about 0.10 to about 200 mg / kg body weight of the subject per day or preferably about 0.10 to about 30 mg / kg body weight per day administered singly or as a divided dose. However, tlie optimum dosage for the individual subject being treated will be determined by tlie person responsible for treatment, generally smaller doses being admuiistered initially and thereafter uicrements made to determine the most suitable dosage.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound wiU be present in such phannaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Tlius, for oral administration, the compounds can be combined with a suitable solid or hquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like. For parenteral admmistration, the compounds can be combmed with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, ktqueous propylene glycol and the liVe can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds. Tlie injectable solutions prepared in this manner can the.? be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intrajnuscular administration being preferred in humans.
Tlie invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to hmit the scope of the invention.
Preparation 1 4-|2-[4-lVIethyl-2-propyl-6-oxo-l,6-dihydro-l-pyrimidinyllethoxylbenzaldehydc :


To a stirred suspension of NaH (570 mg, 22.57 tnmol, 95 %) in dry DMF (35 ml) at 25 OC was added a solution of 4-methyl-2-propyl-l,6-dihydro-6-pyriniidone (2.64 g, 17.36 mmol) in dry DMF. After the eflfervescence has ceased, anhydrous LiBr (3.51 Jg, 40.0 nraiol) was added followed by 4-[2-bromoetlioxy]benzaldehyde (4.37 g, 19.08 mmol) in dry DMF at the same temperature. The reaction mixture was immersed in a preheated oil bath at 70 ^C and stirred for 2 h. Tlie reaction mixture was cooled to room temperature, poured into water and extracted with FtOAc. Tlie combined EtOAc layers were washed witli brine, dried over anhydrous Na2S04 and
concentrated. Tlie crude compound was cltfomatographed over silica gel using 3 : 7 EtOAc - pet. ether as eluent to obtain tlie title compound (1.61 g, 31 %).
1H NMR (CDCI3): 5 9.80 (s, IH), 7.82 (d, J= 8.72 Hz, 2H), 6.95 (d, J = 8.72 Hz, 2H), 6.20 (s, IH), 4.45 (t, J = 5.30 Hz, 2H), 4.35 (t, J = 5.30 Hz, 2H), 2.92 (t, J = 7.50 Hz, 2H), 2.25 (s, 3H), 1.92-1.70 (m, 2H), 1.20 (t, J = 7.50 Hz, 3H).
Preparation 2
4-(2-[2,4-Dimethyl-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxylbcnzaJdehyde :

Tlie title compomid (0.8 g, 30 %) was prepared from 2,4-dimethyl-l,6-diIiydro-6-pyi-imidone (1.3 g, 10.48 mmol) and 4-[2-bromoethoxy]benzaldehyde (2.4 g, 10.48 mmol) m the presence of a base K2CO3 (2.89 g, 20.96 mmol) by a similar procedure as described in preparation 1.

"H NMR (CDCJa): 5 9.90 (s, IH), 7.80 (d, J = 8.70 Hz, 2H), 7.02 (d, J = 8.70 Hz, 2H), 6.20 (s, IH), 4.50 - 4.3Q (m, 4H), 2.70 (s, 3H), 2.20 (s, 3H).
Preparation 3 4-[2-(2-Etbyl-4-methyl-6-oxo-l,6-dihydro-l-pyriiiiidinyllethoxylbenzaIdehyde :

The title compound (1.7 g, 42 %) was prepared from 2-etliyl-4-methyl-l,6-dihydro-6-pyrimidone (2.0 g, 14.49 ramol), 4-[2-bromoetlioxy]benzaldehyde (3.32 g, 14.49 mmoi), LiBr (2.9 g, 33.33 mmol) aad NaH (0.45 g, 18.84 nunol) as base, by a simflar procedure to that described in preparation 1.
"H NMR (CDCI3): 5 9.90 (s, IH), 7.80 (d, J = 8.70 Hz, 2H), 6.98 (d, J = 8.70 Hz, 2H), 6.20 (s, IH), 4.52 - 4.25 (m, 4H), 3.02 (q, J = 7.40 Hz, 2H), 2.30 (s. 3H), 1.40 (t, J - 7.40 Hz, 3H).
Preparation 4
4_j2-[2-Butyl-4-methyl-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxy]benzaldehyde :

Tlie title compound (1.1 g, 25 %) was prepared from 2-butyl-4-methyl-I,6-dibydro-6-pyiimidone (2.3 g, 13.85 mmol), 4-[2-bromoethoxy]benzaldehyde (3,17 g, 13.85 mmol) in the presence of K2CO3 (3.82 g, 27.7 mmol) as base by a similar procedure to that described in preparation 1.

1H NMR (CDCI3): 5 9.90 (s, IH), 7.84 (d, J = 8.72 Hz, 2H), 6.98 (d, J = 8.72 Hz, 2H), 6.20 (s, IH), 4.52 - 4.30 (m, 4H), 2.96 (t, J = 7.47 Hz, 2H), 2.26 (s, 3H), 1.90 - 1.70 (m, 2H), 1.70 - 1.50 (m, 2H), l.Ol (t, J = 7.47 Hz, 3H).
Preparation 5
4-[2-I2-Benzyl-4-iMethyI->6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxy]beii.Taldchyde:

Hie title compound (2.0 g, 20.6 %) was prepared from 2-benzyl-4-iTiethyl-1,6-dihydro-6-jyrimidone (5.6 g, 28.0 mmol), 4-[2-bromoetlioxy]benzaldeliyde (17.05 g, 30.1 minol) in the )resence of 95 % NaH (873 mg, 35.0 mmol) as base by a similar procedure to that described in ireparation 1.
H NMR (CDCI3): 5 9.89 (s, IH), 7.81 (d, J = 8.72 Hz, 2H), 7.45 - 7.15 (m, 5H), 6.98 (d, J -;.72 Hz, 2H), 6.44 (s, IH), 4.70 (t, J = 4.71 Hz, 2H), 4.30 (t, J = 4.71 Hz, 2H), 4.14 (s, 2H), 2.42 (s, 3H).
Preparation 6
4-[2-[2,5-Diethyl-4-raethyl-6-oxo-l,6-dihydro-l-pyrimidinyllcthoxylbenzaldfthyde :

Hie title compound (1.42 g, 28 %) was prepared from 2,5-diethyl-4-methyl-I,6-dihydro-6-pyrimidoue (2.70 g, 16.26 mmol) and 4-[2-bromoethoxy]benzaldehyde (4.09 g, 17.86 mmol) in

the presence of 95 % NaH (508 mg, 20 mmol) as base by a similar procedure to that described in preparation 1.
"H NMR (CDCI3): 6 9.88 (s, IH), 7.82 (d, J = 8.62 Hz, 2H), 6.97 (d, J = 8.62 Hz, 2H), 4.50 -4.20 (m, 4H), 2.95 (q, J = 7.47 Hz, 2H), 2.52 (q, J = 7.47 Hz, 2H), 2.28 (s, 3H), 1.34 (t, J = 7.47 Hz, 3H), 1.09 (t, J = 7.47 Hz, 3H).
Preparation 7
4-[2-[2-Ethyl-4-phenyl-6-oxo-l,6-dihydro-l-pyriinidinyI]ethoxy]benzaIdehydc :

The title compound (2.0 g, 44 %) was prepared from 2-ethyl-4-phenyl-l,6"dihydro-6-pyrimidone (2.6 g, 13.0 mmol), 4-[2bromoethoxy]benzaldehyde (2.97 g, 13.0 mmol) and LiBr (2.59 g, 29.9 mmol) in the presence of NaH as base (0.4 g, 16.9 mmol) by a similar procedure to that described in preparation 1.
1H NMR (CDCI3) : 5 9.89 (s, IH), 8.10 - 7.95 (m, 2H), 7.83 (d, J - 8.72 Hz, 2H), 7.55 - 7.45 (m. 3H), 6.98 (d, J = 8.72 Hz, 2H), 6.78 (s, IH), 4.60 - 4.40 (m, 4H), 3.08 (q, J = 7.30 Hz, 2H), 1.48 (t, J = 7.30 Hz, 3H).
Preparation 8
4-[2-(4-N-AcetyIamiao-2-oxo-l,2-dihydro-l-pyrimidinyl]ethoxy]benzaldehyde:


iiie title compoxmd (1.8 g, 66 %) was prepared ftom 4-acetylaniino-l,2-daiydro-2-pyriraidoue (1.8 g, 11.9 mmol) and 4-[2-bromoetlioxy]ben7aldehyde (2.72 g, 11.9 mmol) in the presence of K2CO3 (3.28 g, 23.8 mmol) as base by a similar procedure to that described in preparation 1.
^H NMR (CDCI3): 8 9.90 (s, IH), 8.70 (bs, IH, D2O exchangeable), 7.85 (d, J = 8.70 Hz, 2H), 7.75 (d, J = 7.80 Hz, IH), 7.42 (d, J = 7.80 Hz, IH), 6.95 (d, J = 8.70 Hz, 2H), 4.40 - 4.20 (m, 4H), 2.30 (s,3H).
Preparation 9
4-[2-[4-Oxo-3,4-dihydro-3-quinazoIinyl]ethoxy]benzaldehyde :

The title compound (1.5 g, 73 %) was prepared from 4-oxo-3,4-dihydroquinazoline (1.03 g, 7.05 mmol) and 4-[2-bromoethoxy]ben3"aldehyde (1.77 g, 7.7 nnnol) in the presence of K2C0^ (:».0 g, 14.5 mmol) as base, by a similar procedure to that described in preparation 1.
1H NMR (CDCI3) : 5 9.88 (s, IH), 8.32 (d, J = 7.88 Hz, IH), 8.21 (s, IH), 7.88 - 7.70 (m, 2H), 7.82 (d, J = 8.72 Hz, 2H), 7.60 - 7.42 (m, IH), 7.00 (d, J = 8.72 Hz, 2H), 4.55 - 4.25 (m, 4H).
Preparation 10
4-[2-[2-MethyI-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaIdehyde :


Tlie title compovmd (0.6 g, 39 %) was prepared fiom 2-methyl-4-oxo-3,4-dihydroquiuazolme (0.8 g, 5 mmol) and 4-[2-bromoetlioxy]benzaldehyde (1.37 g, 6 ramol) m the presence of K2CO3 (1.38 g, 10.0 mmol) as base, by a similar procedure to tliat described in preparation 1.
1H NMR (CDCI3) : 5 9.85 (s, IH), 8.13 (d, J = 8.0 Hz, IH), 7.84 - 7.72 (m, 3H), 7.59 - 7.41 (m, 2H), 7.10 (d, J = 7.0 Hz, 2H), 4.50 - 4.40 (m, 2H), 4.40 - 4.30 (m, 2H), 2.76 (s, 3H).
Preparation 11
4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaldehyde:

The title compound (5.0 g, 27 %) was prepared from 2-ethyl-4-pxo-3,4-dihydroquinazoUne (9.2 g, 57.5 mmol) and 4-(2-broraoethoxy)benzaldehyde (14.5 g, 69.0 mmol) in the presence ofK2C03 (14.6 g, 115.0 mmol) as base, by a similar procedure to that de-scribed in preparation !.
"H NMR (CDCI3): 6 9.86 (s, IH), 8.14 (d, J = 8.0 Hz, IH), 7.87 - 7.76 (m, 3H), 7.65 - 4.45 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 4.60 - 4.50 (m, 2H), 4.50 - 4.40 (m, 2H), 3.07 (q, J - 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).
Preparation 12
4-[2-|8-Aza-2-methyI-4-oxo-3,4-dihydro-3-quinazoIinyl]ethoxy]benzaldehydc :


Tlie title compound (0.26 g, 41 %) was prepared from 8-aza-2-inetljyl.4-oxo-3,4-dihydro quinazolme (0.33 g, 2.0 mmol), 4-[2-broinoethoxy]betizaldehyde (0.52 g, 2.25 mmol) in the presence of K2CO3 (0.57 g, 4.1 mmol) as base by a similar procedure to that described in
preparatiou 1.
•H NMR (CDCI3) : 8 9.87 (s. IH), 9.02 - 8.90 (m, IH), 8.58 (d, J = 7.30 Hz, IH), 7.82 (d, J = 8.72 Hz, 2H), 7.48 - 7.35 (m, IH), 6.97 (d, J = 8.72 Hz, 2H), 4.58 (t, J = 4.72 Hz, 2H), 4.43 (t, J = 4.72 Hz, 2H), 2.91 (s,3H).
Preparation 13 4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazoIinyl]methoxy]benzaldehyde:

A mixture of 4-hydroxybenzaldeliyde (^3.21 g, 26.3 mmol) and K2CO3 (3.64 g, 26.3 mmol) 1H NMJl (CDCI3) : 5 9.89 (s, IH), 8.29 (d, J = 7.89 Hz, IH), 7.85 (d, J = 8.71 Hz, 2H), 7.80 -7.62 (m, 2H), 7.52 (t, J = 7.81 Hz, IH), 7.19 (d, J = 8.71 Hz, 2H), 5.27 (s, 2H), 3.74 (s, 3H).
Preparation 14

4-[(3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]niethoxy]benzaIdehyde:

The titk compound (4.24 g, 88 %) was prepared from 2-chloromethyI-3-etliyl-4-oxo-3,4-dihydro-quinazoline (3.5 g, 15.7 mmol) and 4-liydroxybenzaldehyde (2.10 g, 17.21 mmol) in the presence of K2CO3 (2.38 g, 17.26 mmol) as base by a similar procedure to that described in preparation 13,
1H NlVm (CDCI3) : 5 9.91 (s, IH), 8.31 (d, J = 7.89 Hz, IH), 7.88 (d, J = 8.72 Hz, 2H), 7.82 -7.68 (m, 2H), 7.65 - 7.45 (m, IH), 7.22 (d, J ■= 8.72 Hz, 2H), 5.28 (s, 2H), 4.28 (q, J = 7.06 Hz, 2H), 1.41(t,J = 7.06Hz,3H).
Preparation US :
4-l|l-methyl-4-oxo-l,4-dihydro-2-quinazoIinyI]methox>Jbenzaldehyde:

The title compound (364 mg, 65 %) was prepared from 2-chloromethyl-l-metliyl-4-oxo-l,4-dihydroquinazoline (416 mg, 2.0 mmol) and 4-hydroxybenzaldehyde (244 mg, 2.0 mmol) in the presence of K2CO3 (276 mg, 2.0 mmol) as base by a similar procedure to that described in
preparation 13.

1H NMR (CDCI3): 8 9.88 (s, IH), 8.34 (d, J = 7.89 Hz, IH), 7.83 (d, J = 8.71 Hz, 2H), 7.80 -7.70 (m, IH), 7.60 - 7.40 (m, 2H), 7.22 (d, J = 8.71 Hz, 2H), 5.34 (s, 2H), 3.91 (s, 3H).
Preparation 16
3-IVIethoxy-4-[(3-Methy]-4>oxo-3,4-dihydro-2-quina2olinyl]methoxylbcnznld(ihyde:

Tlie title compound (250 mg, 77 %) was obtained from 2-cWoromethyl-3-inelhyl-4-oxo-3,4-dihydroquinazoljne (209 mg, 10 inmol) and vanillin (167 mg, 1.1 mmol) in the preSeiace of K2CO3 (276 mg, 2.0 mmol) as base by a similar procedure to that described in prqoaration 13,
iH NMR (CDCI3) : 5 9.88 (s, IH), 8.29 (d, J = 8.30 Hz, IH), 7.80 - 7.62 (m, 2H), 7.58 - 7.39 (m, 2H), 7.26 (d, J - 8.30 Hz, 2H). 5.30 (s, 2H), 3.90 (s, 3H), 3.78 (s, 3H).
Preparation 17
4-[2-[2-Ethyl-4-methyl-6-oxo-l ,6-dihydro-l-pyi*imidinyl]ethoxy]bcnzaldcIiydc oxime :

To a stined solution of hydroxylamine hydrochloride (10.0 g, 143.0 mmol) and sodium acetate trihydrate (20.0 g, 146.9 mmol) in water (100 ml) at 30 ^C was added a hot solution of 4-[2-[2-ethyl-4-methyl-6-oxo-l,6-dihydro-l-pyi-imidinyl]ethoxy]benzaldehyde (5.72 g, 20.0 mmol) (obtained from preparation 3) m ethanol (100 ml). The reaction mixture was immersed in a

preheated oil bath (95 ^"C) and refluxed for 3 h. The reaction mixture was then cooled to room temperature and concentrated to a volume where crystals of oxime started separating out and the mixture was kept aside for 30 min. to 1 h at 25 ^C. The resultant crystals were filtered and washed with water and dried to obtain the title compound (5.42 g, 90 %).
^H NMR (CDCl3+DMSO-d6) : 5 10.56 (s, IH, OH, D2O exchangeable), 8.08 (s, IH), 7.55 (d, J = 8.56 Hz, 2H), 6.88 (d, J = 8.56 Hz, 2H), 6.20 (s, IH), 4.51 - 4.40 (m, 2H), 4.40 - 4.28 (m, 2H), 3.05 (q, J = 7.06 Hz, 2H), 2.30 (s, 3H), 1.40 (t, J = 7.06 Hz, 3H).
Preparation 18
4-(2-[2-Ethyl-4-methyI-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxy]benzylhydroxylaminc:

To a stirred solution of 4-[2-[2-ethyl-4-meii:liyl-6-oxo-l,6-dihvdro-l-
pyiimidinyljethoxyjben/aldehyde oxime (301 mg, 1.0 ramol) (obtained firom preparation 17) in a mixture of methanol (7 ml) and THF (3 ml) was added 4 N HCl (2 ml) in dioxane at 30 ^C and stirred for 10 min. at the same temperature. The reaction mixture was basified to pH 9 with 1 N NaOH and extracted with EtOAc (3x10 ml). The combined organic layers were washed with bniie and dried over anhydrous Na2S04 and concentrated to yield the of title compomid (272 mg,
90 %).
iH NMR (CDCI3): 5 7.23 (d, J = 8.72 Hz, 2H), 6.80 (d, J = 8.72 Hz, 2H), 6.18 (s, IH), 4.45 -4.35 (m, 2H), 4.35 - 4.20 (m, 2H), 3.98 (s, 2H), 3.01 (q, J = 7.56 Hz, 2H), 2.22 (s, 3H), 1.32 (t, J = 7.56 Hz, 3H).
Preparation 19

N-[4-[2-[2-EthyI-4-methyl-6-oxo-l,6-dihydro-l-pyrimidinyI]ethoxyJbeiizyI]N-hydroxyurea :

To a stirred solution of 4-[2-[2-ethyl-4-metliyl-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxy]benzyl hydroxylamine (303 mg, 1.0 mmol) (obtained from preparation 18) in a mixture of water (2 ml) and acetic acid (0.5 ml) was added a solution of KOCN (343 mg, 3.0 mmol) in water (1 ml) and stirred for 1 h at 30 OC. The reaction mixture was diluted with water and extracted with ethyl acetate (3x10 ml). Tlie combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to yield the compound (295 mg, 85 %).
1H NMR (CDCI3) : 5 7.18 (d, J « 8.65 Hz, 2H), 6 90 (d, J = 8.65 Hz, 2H), 6.60 (bs, IH, D2O exchangeable), 6.15 (s, IH), 5.85 (bs, IH, D2O exchangeable), 4.70 (s, 2H), 4.50 (bs, iH, D2O exchangeable), 4.40 - 4.30 (m, 2H), 4.22 - 4.10 (m, 2H), 2.92 (q, J - 7.56 Hz. 2H), 2.20 (s, 3H), 1.20 (t, J =7.56 Hz, 3H)-
Preparation 20 4-[2-[2-EtliyI-4-mcthyI-«»-oxo-l,6-dihydro-l-pyrimidinyI]ethoxy]nitrobenzene :

The title compound (5.2 g, 25 %) was prepared from 2-ethyl-4-methyl-l,6-dihydro-6-pyrimidDne (7.65 g, 55.43 mmol), 4-[2-bromoethoxy]uitrobenzene (15.0 g, 60.97 mmol), LiBr (11.09 g,

127.49 mmol) and 60 % NaH (2.76 g, 72.06 mmol) as base by a similar procedure to that described in preparation 1.
>H NMR (CDCI3) : 5 8.20 (d, J = 8.81 IIz, 2H), 6.94 (d, J = 8.81 Hz, 2H), 6.22 (s, IH), 4.55 -4.42 (m, 2H), 4.42 - 4.34 (m, 2H), 2.99 (q, J = 7.4 Hz, 2H), 2.27 (s, 3H), 1.38 (t, J = 7.4 Hz, 3H).
Preparsitioin 21
4-|2-|2-EthyI-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]nitrobenzene :

Tlie title compound (1.246 g, 64 %) was prepared from 2-ethyl-4-oxo-3,4-diliydroquinazoline (1.0 g, 5.7 mmol) and 4-[2-bromoethoxy]nitrobenzene (1.696 g, 6.3 mmol) and K2CO3 (1.58 g, 11.49
mmol) as a base by a similar procedure v.o that described in preparation 1.
hi NMR (CDCI3): 6 8.24 (d, J = 7.93 Hz, IH), 8.18 (d, J = 9.20 Hz, 2H), 7.82 - 7.61 (m, 2H), 7.46 (t, J = 7.93 Hz, IH), 6.94 (d, J = 9.20 Hz, 2H), 4.58 (t, J = 4.82 Hz, 2H), 4.44 (t, J = 4.82 Hz, 2H), 3.09 (q, J = 7.38 Hz, 2H), 1.46 (t, J = 7.38 Hz, 3H).
Preparation 22 4-(2-[2-Ethyl-4-methyl-6-oxo-l,6-dihydro-l-pyrimidinyI]ethoxy]aniline :


A solution of 4-[2-[2-ethyl-4-methyl-6-qxo-l,6-dawdro-l-pyriinidmyl]ethoxy]tutrobenzene (1.0 g, 3.3 mmol) (obtained from preparation 20) in 1,4-dioxane (20 ml) was reduced witli hydrogen in the presence of 10 % palladium on charcoal (100 mg) at 30 psi for 16 h. The mixture was filtered through a bed of celite and washed with dioxane and evaporated to dryness under reduced pressure to yield the title compound (625 mg, 70 %).
"H NMR (CDCI3) : 5 6.78 - 6.52 (m, 4H), 6.18 (s, IH), 4.38 (t, J = 4.98 Hz, 2H), 4.19 (t, J = 4.98 Hz, 2H), 2.99 (q, J = 7.47 Hz, 2H), 2.24 (s, 3H), 1.33 (t, J = 7.47 Hz, 3H).
Preparation 23
4-[2-(2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyI]ethoxy]aniIine: .

Tlie title compound (1.107 g, 98 %) was prepared from 4-i2-[i-ethyl-4"Oxo-3,4-dihydio-j-quinazolinyl]ethoxy]nitrobenzene (1.246 g, 3.67 mmol) (obtained from preparation 21) by a similar procedure to that described in preparaton 22.
»H NMR (CDCI3) : 5 8.24 (d, J - 7.93 Hz, IH), 7.80 - 7.60 (m, 2H), 7.43 (t, J = 7.93 Hz, IH), 6.80 - 6.50 (m, 4H), 4.51 (t, J = 5.19 Hz, 2H), 4.24 (t, J = 5.19 Hz, 2H), 3.10 (q, J - 7.34 Hz, 2H), 1.42 (t, J-7.34 Hz, 3H).
Preparation 24
Ethyl 2-bromo-3-[4-[2-[2-ethyl-4-methyl-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxylphenyl| propanoatc :



The title compound (671 mg, 55 %) was prepared from 4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]aiulme (800 mg, 2.58 mmol) (obtained from preparation 23), NaN02 (214 rag, 3.1 mmol) and ethyl aciylate (1.7 ml, 1.574 g, 15.74 mmol) by a similar procedure to that described in preparation 24.
^H NMR (CDCI3) : 8 8.23 (d, J = 7.88 Hz, IH), 7.80 - 7.55 (m, 2H), 7.52 - 7.30 (m, IH), 7.15 -7.01 (m, 2H), 6.77 (d, J = 8.71 Hz, 2H), 4.52 (t, J = 5.03 Hz, 2H), 4.45 - 4.30 (m, IH), 4.30 (t, J = 5.03 Hz, 2H), 4.20 - 4.00 (m, 2H), 3 35 (dd, J = 14.12, 8.71 Hz, IH), 3.20 - 3.00 (ni, 3H), 1.43 (t, J = 7.34 Hz, 3H), 1.20 (t, J = 7.34 Hz, 3H).
Preparation 26
5-|4-I2-12-Ethyl-4-metliyI-6-oxo-l,6-dihydro-l-pyrimidinyllcthoxy]phenyl methyIj-2-
iminothiazolidine-4>one hydrochloride;

A mixture of ethyl 2-bromo-3-[4-[2-[2-ethyl-4-inethyl-6-oxo-l,6-dihydro-l-
pyrimidinyl]ethoxy]pheuyl]propaneate (1.70 g, 3.89 mmol) (obtained from preparation 24), fused sodium acetate (637 mg, 7.78 mmol) and thiourea (592 mg, 7.78 mmol) in ethanol (10 ml) was refluxed for 12 h. Tlie reaction mixture was cooled to room temperature and the resultant solid was filtered and dried to afford the title compound (1.35 g, 89 %).
•H NMR (CDCI3) : 5 7.12 (d, J = 8,59 Hz, 2H), 6.76 (d, J = 8.59 Hz, 2H), 6.12 (s, IH), 4.50 -4.30 (m, 3H), 4.30 - 4.15 (m, 2H), 3.40 (dd, J = 14.11, 3.74 Hz, IH), 2.98 (q, J - 7.47 Hz, 2H), 2.85 (dd, J = 14.11, 9.43 Hz, IH), 2.23 (s, 3H), 1.32 (t, J- 7.47 Hz, 3H).

Preparation 27
5-|4-[2-I2-Ethyl-4-oxo-3,4-«iihydro-3-quinazolinyllethoxylphcnyl methyll-2-imino
tliiazoIidine-4-one hydrochloride:

Tlie title compound (329 mg, 78 %) was prepared from ethyl 2-bromo-3-[4-[2-[2-ethyl-4-oxo-3,4-diliydro-3-quinazoliuyl]ethoxy]phenyl]propanoate (473 mg, 1.0 mmol) (obtained from preparation 2S), sodium acetate (164 mg, 2.0 mmol) and thiourea (152 mg, 2.0 mmol) by a similar procedure to that described in preparation 26.
1H NMR (CDCI3) : 5 8.12 (d, J = 7.88 Hz, IH), 7.80 (t, J = 7.03 Hz, IH), 7.62 (d, J = 7.88 Hz, IH), 7.49 (t, J = 7.03 m, IH), 7.12 (d, J = 7.58 Hz, 2H), 6.84 (d, J = 7.58 Hz, 2H), 4.50(dd, J = 9.43, 3.72 Hz, IH), 4.46 (t, J = 5.31 Hz, 2H), 4.25 (d, J = 5.31 Hz, 2H), 3.25 (dd, J = 14.11, 3.72 Hz, IH), 3.04 (q, J = 7.17 Hz, 2H), 2.81 (dd, J= 14.11, 9.43 Hz, IH), 1.31 (t, J = 7.19 Hz, 3H).
Preparation 28
3-[4-|2-J2-Etliyl-4-raethyl-6-oxo-l,6-dihydro-l-pyrimidinyllcthoxylphcnyll-2-hydroxypropanoic acid :

A mixture of ethyl 2-bromo-[3-[4-[2-[2-et]iyl-4-methyl-6-oxo-l,6-dihydro-l-pyi-iniidinyl-ethoxyjphenyljpropanoate (438 mg, 1.0 inmol) (obtained from preparation 24), sodium hydroxide (44 mg, 1.1 mmol) and calcium carbonate (100 mg, 1.0 mmoH in 1,4-dioxane (2 ml) and water (3

ml) was refluxed for 10 li. The reaction mixture was cooled to room temperature and acidified to pH 4 with 2N HCl and extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine, dried over Na2S04 and concentrated to aflFord the title compound (92 mg, 27 %).
iH NMR (CDC13 + DMSO-de) : 5 7.12 (d, J = 8.61 Hz, 2H), 6.78 (d, J = 8.61 Hz, 2H), 6.19 (s,
IH). 4.50 - 4.32 (m, 2H), 4.30 - 4.05 (m, 3H), 3.10 - 2.60 (m, 4H), 2.25 (s, 3H), 1.30 (t, J = 7.20 Hz, 3H).
Preparation 29
Ethyl 3-[4-[2-[2-ethyl-4-mcthyl-6-oxo-l,6-dihydro-l-pyrimidinyIIcthoxylphenyl]-2-
hydroxypropanoate:
Method A
A solution of 3-[4-[2-[2.ethyl-4-methyl-6-oxo-l,6-dihydro-l-pyrimidinyl]etlioxy]phenyl]-2-liydroxypropanoic acid (346 mg, 1.0 mmol) (obtained from preparation 28) in ethanol (3 ml) containing concentrated hydrochloric acid (0.1 ml) was refluxed for 10 h. Tlie solution was cooled to room temperature, diluted with water and extracted with EtOAc (2 x 10 ml). Tiie combined orgajiic extracts were washed with brine, dried over anliydrous Na2S04 and concentrated to yield the title compound (97 mg, 26 %).
Method B
^ mixture of ethyl 2-bromo-3-[4-[2-[2-ethyl-4-metliyl-6-oxo-l,6-dihydro-l-
|)yiiraidinyl]ethoxy]phenyl]propanoate (1.0 g, 2.28 mmol) (obtained from preparation 24) fomiamide (225 nl) and water (45 ^il, 45 mg, 2.5 mmol) was heated at 160 oc for 3 h. Water (45

Ill) was added further and stirred for 2 h at 175 oc. Hie reaction mixture was cooled to room temperature, diluted with EtOAc (10 ml) waslied with brine, dried over anhydrous Na2S04 and concentrated to yield the crude compound which was purified by flash chromatography to afiford the title compound (306 mg, 36 %).
iH NMR (CDC13): 5 7.11 (d, J = 8.62 Hz, 2H). 6.77 (d. J = 8.62 Hz, 2H), 6.18 (s, IH). 4.50 -4.31 (m, 2H), 4.30 - 4.05 (m, 5H), 3.10 - 2.80 (m, 4H), 2.25 (s, 3H), 1.40 - 1.15 (m, 6H).
Preparation 30
5-I4-I2.I2-Ethyl.4-methyl-6-oxo-l,6-dihydro-l.pyrimidinyllethoxylphenyI methylcneI-2-thio-l,3-oxazolidine-4-one:

M intimate mixture of 4-[2.[2-ethyl-4-methyi.6.oxo-l,6-dihydro-l.pyrimidinyl3ethoxy] benzaldehyde (286 mg, 1.0 mmol) (obtained from preparation 3), 2^thio.l,3-oxazolidi.,e-4-one (175 mg, 1.5 mmol) and anhydrous sodium acetate (246 mg, 3.0 mmol) was heated at 120 oc under reduced pressure (2.0 torr.) for 90 miai. After cooling, the reaction mixture was poured into ethyl acetate (80 ml) and water (20 ml) and stirred for 30 min, the aqueous layer was separated and acidified to pH 4 with 2N HCl. Tlie solid separated was filtered and dned to yield the title compound (207 mg, 54 %).
"H NMJl (CDCI3) : 5 7.76 (d, J = 8.62 Hz, 2H), 6.93 (d, J = 8.62 Hz, 2H), 6.59 (s, IH), 6.17 (s, IH), 4.50 - 4.30 (m, 4H), 2.98 (q, J = 7.47 Hz, 2H). 2.27 (s, 3H), 1.35 (., J = 7.47 Hz, 3H). Preparation 31
















The title compound (0.98 g, 95 %) was obtained from 4-[2-[2,4-dimethyl-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxy]benzaldehyde (0.8 g, 2.8 mmol) (obtained from preparation 2) and tliia2olidine-2,4-dione (0.344 g, 2.8 mmol) by a similar procedm-e to that described in example 1, mp235 0C.
>H NMR (CDCI3): 5 8.50 (bs, IH, D2O exchangeable), 7.80 (s, IH), 7.48 (d, J = 8.40 Hz, 2H), 6.98 (d, J = 8.40 Hz, 2H), 6.21 (s, IH), 4.52 - 4.30 (m, 4H), 2.70 (s, 3H), 2.25 (s, 3H).
Example 3
5-|4-f2-f2-EthyI-4-methyl-6-oxo-l,6-dihydro-l-pyrimidinyIIethoxy]phenyl methylene!
thiazoUdine-2,4-dione :

Tlie title compound (2.13 g, 92 %) was obtained from 4-[2-[2-ethyl-4-methyl-6-oxo-I,6-diIiydro-l-pyiimidinyl]etlioxy]benzaldehyde (1.7 g, 5.94 mmol) (obtained from preparation 3) and tliiazolidine-2,4-dioue (0.695 g, 5.94 mmol) by a similar procedure to that described in example 1, mp248-250OC.


Example 4 :
5-[4-[2-I2-ButyI-4-methyl.6-oxo-l,6-dihydro-l-pyrimidmylJethoxyJphenyl methylencl
tliiazolidine-2,4-dione:

Tlie title compound (1.2 g, 83 %) was obtained from 4-[2.[2-butyl-4-metliyI-6-oxo- 1,6-diliydro-l-pyriniidinyl]et!ioxy]benzaldehyde (1.1 g, 3.5 mmol) (obtained from preparation. 4) and tliiazoIidine-2,4-dione (410 mg, 3.5 mmol) by a similar procedure to that described in example I, mp209OC.
1H NMR (CDC13) : 5 7.80 (s, IH), 7.40 (d, J = 8.63 Hz, 2H), 6.95 (d, J = 8.63 Hz, 2H), 6.21 (s, IH), 4.55 - 4.22 (m, 4H), 2.95 (t, J= 7.47 Hz, 2H), 2.25 (s, 3H), 1.85 - 1.60 (m, 2H), 1.60 - 1.40 (m, 2H), 0.99 (t, J = 7.10 Hz, 3H).
Example 5 :
5-|4-[2-[2-Benzyl-4-methyl-6-oxo-l,6-dihydro-l-pyrimidinyI]ethoxy]phenyl metliylenel
thiazolidine-2,4-dione :

nie title compound (1.70 g, 66 %) was obtained from 4-[2-[2-benzyl-4-methyl-6.oxo-l,6-dihydro- l-py,-iraiclinyl]ethoxy]benzalde]iyde (2.0 g, 5.74 mmol) (obtained from preparation 5) and

tIiiazolidine-2,4-dione (0.74 g, 6.4 mmol) by a sinular procedure to that described in example 1, mp 223 OC.
• H NMR (CDCl3+DMSO-d6) : 5 7.74 (s, IH), 7.44 (d, J = 8.71 Hz, 2H), 7.40 - 7.10 (in, 5H), 6.95 (d, J = 8.71 Hz, 2H), 6.26 (s, IH), 4.38 (s, 2H), 4.35-4.10 (m, 4H), 2.32 (s, 3H).
Example 6:
5-[4-[2-[2,5-Dicthyl-4-methyI-6-oxo-l,6-diliydro-l-pyrimidinyllethoxy]phenyl raethylene| thiazolidine-2,4-dione :

Tlie title corapomid (881 mg, 92 %) was obtained from 4-[2-[2,5-dietliyl-4-methyl-6-oxo-l,6-dihydro-i-pyrimidittyl]et]ioxy]benzaMehyde (730 mg, 2.32 mmol) (obtained from preparatioii 6) and thiaz,olidine-2,4-dione (451 mg, 2.55 mmol) by a similar procedure to that described in example 1, mp 252 - 254 oC.
•H NMR (CDCl3+DMSO-d6) : 5 12.08 (bs, IH, D2O exchangeable), 7.69 (s, IH), 7.44 (d, J = S.58 Hz, 2H), 6.97 (d, J = 8.58 Hz, 2H), 4.50 - 4 20 (m, 4H), 2.93 (q, J = 7.43 Hz, 2H), 2 50 (q, J = 7.43 Hz, 2H), 2.26 (s, 3H), 1.33 (t, J = 7.43 Hz, 3H), 1.07 (t, J - 7.43 Hz, 3H).
Example 7
5-|4-(2-i2-Ethyl-4-phenyl-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxy]phenyI niethylencl
thJazoIidinc-2,4-dione :





1H NMR (DMS0-d6) : 6 12.58 (bs, IH, D2O exctiangeable). 8.15 (d, J = 8.0 Hz, IH). 7.82 -7.44 (m,"6H), 7.08 (d, J = 8.0 Hz. 2H), 4.47 - 4.40 (m, 2H), 4.40 - 4.3O (m, 2H), 3.08 (q, J = 7.0 Hz,2H),1.37(t,J = 7.0Hz,3H).
Example 11
5-I4-[2..[8-Aza-2-methyl.4-oxo-3,4-diliydro-3-quinazolmylIetIvoxyJphcnyl niethylenel
thiazoIidiiie-2,4-dione:

Tlie title compound (0.25 g, 68 %) was obtained from 4-[2-[8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]benzaIdeliyde (0.28 g, 0.9 mmol) (obtained from preparation 12) and thiazolidine.2,4-dione (0.106 g, 0.9 mmol) by a simUar procedure to that described in example 1, mp 276 oc.
iH NMR (CDCl3+DMSO-d6) : 5 9.00 - 8.90 (m. m, 8.51 (d. J = 7.30 Hz, IH), 7.72 (s, IH), 7.51 (d, J = 8.72 Hz, 2H), 7.55 - 7.45 (m, IH), 7.05 (d, J = 8.72 Hz. 2H), 4.60 - 4.50 (m, 2H), 4.50-4.38 (m,2H), 2.85 (s,3H).
Example 12
5-|4-[|3-Metliyl-4-oxo-3,4-dihydio-2-quinazolinyllmethoxy]phenyl methylenelthiazolidine-2,4-dionc :


T!ie title compound (11.10 g, 96 %) was obtained from 4.[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]benzaldeliyde (9.0 g, 30.61 mmol) (obtained from preparation 13) and thiazoIidiae-2,4-dione (3.6 g, 30.61 mmol) by a similar procedure to that described in example I, rap 280 OC.
iH NMR (CDCl3+DMSO~d6) : 6 12.38 (bs, IH. D2O exchangeable), 8.19 (d, J =7.47 Hz, IH), 7.82 - 7.60 (ra, 2H), 7.72 (s, IH), 7.53 (d, J = 8.7 Hz, 2H), 7.60 - 7.48 (m, IH), 7.23 (d. J =- B.ll Hz, 2H), 5.35 (s, 2H), 3.68 (s, 3H).
Example 13
5-|4-f[3-Ethy!4-oxo-3,4-dihydro-2-qu5=azolinyl]methoxy]phenyl methyienelthiazolidine-2,4 dionc :

Tlie title compound (3.3 g, 83 %) was obtained from 4.[[3-ethy]-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]be„zaldehyd, (3.0 g, 9.74 minol) (obtained from preparation 14) and thiazolidine-2,4-dione (1.14 g, 9.74 mmol) by a similar procedure to that described in example 1, mp 260-261 OQ

"" NMR (CDCl3+DMSad6) : 8 ,2.58 (bs, IH. D2O e«h«>ge.ble), 8.18 (d. J = 7.88 Hz, Ifl), 7.92 - 7.74 (., ,H), 7.78 (s. IH). 7.74 - 7.54 (n^ 2H), 7.61 (d, J = 8.72 H^ 2H), 7.29 (d. J
= 8.72 Hz, 2H). 5.40 (s, 2H). 4.14 {,, J = 6.84 Hz, 2H). 1.34 (U = 6.84 Hz, 3H).
Example 14
5-H-||I-M..hyl-4-„x„.,,4.dihydro-2^„i„,z.li„j,„me.hoxylphe„yl mea,yIe„e|.htazolidmc 2,4-dionc :

TTe Utle oo.p„u.d (3,0 „,g, 79 %) wa. „b..i.ed iom 4.[I,.„eU,y,.4-„™.,.4-dihydr„-2. ,u,„azo„yl,„e.h„xy]b»za,dehyde (2,4 „g, l.o „„„,) (obtained from p.pan„i„„ ,5, and .h«zobd,„e-2,4.di„„e („7 „g, ,.o „„„„,) b, , ,i^„ p„^,„„ ,„ ,^^, _,^^^^_ ^ ^^^^^,^
"H NMR (DMS0.d6) : 5 8.09 (d, , = 7.88 H. ,H,, 8.00 - 7.04 (o, 4H), 7.58 (d, . - 8 72 Hz 2H), 7.24 (d, J . 8.72 Hz, 2H), 5.41 (s, 2H), 3.86 (5, 3H). Example 15
thiazoIidine-2,4-dione :



1H NMR (CDCl3+DMSO-d6) : 6 12.56 (bs, IH, D2O exchangeable), 10.85 (s, IH, D2O exchangeable), 8.11 (d, J = 7.2 Hz, IH), 7.74 (s, IH), 7.55 (d, J = 8.30 Hz, 2H), 7.17 (d, J = 7.20 Hz, IH), 7.11 (d, J = 8.30 Hz, 2H), 4.40 - 4.05 (m, 4H), 2.08 (s, 3H).
Example 17
5-[4-I2-(4-methyl-2-Propyl-6-oxo-l,6-diliydro-l-pyrimidinyllethoxylphenyl methyl]
thia2oIidine-2,4-dione:

A solution of 5-[4-[2-[4-methyI-2-propyl-6-oxo-l,6-dihydro-l-pvTimidinyl]ethoxy]phenyl metliylene]tluazolidine-2,4-dione (5.0 g, 12.46 mmol) obtained from example 1 in 1,4-dioxane (75 ml) was reduced with hydrogen in the presence of 10 % palladium on charcoal (12.0 g) at 60 psi pressure for 40 h. Tlie mixture was filtered through a bed of cehte. TM filtrate was evaporated to dryness under reduced pressure, purified by column chromatography (2 : 1 EtOAc / petroleum ether as elueut) followed by cystallisation (CH2CI2) to afford the title compound (4.6 g, 92 %), rap 144 - 146 oc.
iH NMR (CDCI3) : 5 8.25 (bs, IH, D2O exchangeable) 7.12 (d, J = 8.48 Hz, 2H), 6.79 (d. J = 7.48 Hz, 2H), 6.2 i (s, IH), 4.47 (dd, J = 9.36, 4.06 Hz, IH), 4.41 (t, J = 4.47 Hz, 2H), 4.26 (t, J = 4.47 Hz, 2H). 3.41 (dd, J = 14.11, 4.06 Hz, IH), 3.10 (dd, J = 14.11 9.36 Hz, IH), 2.92 (t, J = 7.63 Hz, 2H), 2.24 (s, 3H), 1.90 ^ 1.60 (m, 2H), 1.05 (t, J = 7.65 Hz, 3H).
Example 18
5-[4-|2-[2,4-Dimethyl-6-oxo-l,6-dihydro-l-pyriraidinyl]ethoxy)phenyl methyllthiazolidine-2,4-dione :














Method A:
The title compound (1.186 g, 58 %) was obtained from 5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazo]inyl]metlicxy]phenyl methylene]thJazolidme-2,4-dione (2.035 g, 3.0 ramol) (obtained from example 13) by a similar procedure to that described in example 17.
Method B :
The title compound (278 mg, 68 %) was obtained from 4-[[2,4-2,4"dioxo-l,3-thiazoUdiJ!e-5-yl]methyI]pl!euoxy]acetic acid (281 mg, 1.0 mmol) (obtained from preparation 38) and 2-amino-N*-tethyl ben/amide (164 mg, 1.0 mmol) by a similar procedure to tha: described in example 22 in method B. mp = 218 °C
1H MMPV (CDCI3) : 5 9.20 (bs, IH, D2O exchangeable) 8.30 (d, J = 7.84 Hz, IH), 7.84 - 7.64 (m, 2H), 7.60 - 7.48 (m, IH), 7.19 (d, J = 8.46 Hz, 2H), 7.02 (d, J = 8.46 Hk, 2H), 5.25 (s, 2H), 4.51 (dd, J - 9.30, 3.95 Hz, IH), 3.94 (q, J = 6.92 Hz, 2H), 3.42 (dd, J = 14.12, 3.95 Hz, IH), 3.11 (dd, J = 14.2, 9.30 Hz, IH), 1.35 (t, J = 6.92 Hz, 3H).
Example 24
5-[4-[2-[2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]cthoxy]pheD:"" methyl] thiazolidine-2,4-dione :


The title compound (173 mg, 82 %) was obtained from 5-[4-[2-[2-ethyl-4-oxo-3,4-diJiydro-3-quiiiazolinyl]ethoxy]phenyl methyl]-2-imiuotluazolidine-4-one (211 mg, 0.5 mmol) (obtained from preparation 27) by a similar procedure to that described in example 19 (Method B), mp 178 -180 OC.
in NMR (CDCI3) : S 8.24 (d, J = 7.88 Hz, IH), 7.80 - 7.60 (m, 2H), 7.43 (t, J = 7.56 Hz, IH), 7.10 (d, J = 8.63 Hz, 2H), 6.80 (d, J = 8.63 Hz, 2H), 4.54 (t, J = 5.03 Hz, 2H), 4.46 (dd, J -9.22, 3.83 Hz, IH), 4.32 (t, J = 5.03 Hz, 2H), 3.40 (dd, J = 14 3^, 3.83 Hz, IH), 3.20 2.90 (m. 3H), 1.43(t,J=7.48Hz,3H).
Example 25
2-[4-I2-I2-Ethyl-4-methyl-6-oxo-l,6 dlhydro-l-pyruiiidinyIJethoxy]plicnyI methyll-1,2,4-oxadiazoIidine-3,5-dione:

Method A
To a stirred solution of N-[4-[2-[2-etliyl-4-methyl-6-oxo-l,6-dihydro-l-
pyrimidinyl]ethoxy]benzyl]-N-hydroxyiirea (346 mg, 1.0 mmol) (obtained from preparation 19) hi water (2 ml) was added IN NaOH (3 m\) followed by ethyl chloroformate (191 ^1, 217 mg, 2.0
mmol) and stirred for 1 h at 30 ^c. The reaction mixture was diluted with water, acidified to pH 3.0 and extracted with EtOAc (3x10 ml). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to yield the title compomid (283 rag, 76 %).
Method B
To a cold (-5 °C) solution of 4-[2-[2-ethyl-4-methyl-6-oxo-l,6-dihydro-l-pyiimidinyl]etlioxy]benzyl hydroxylamiue (304 mg, 1.0 mmol) (obtained from preparation 18) in

imhydi^us THF (4.0 ml) was added N-(chlorocarbonyl)isocyanate (88 nt 116 mg. 1.1 mmol) dropwise. The mixture was stirred for 30 min. and poured into 2N HCl followed by extraction AVith EtOAc (3 X 10 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2S04 and concentrated to yield the title compound (264 mg, 71 %).
IH NMR (CDCl3+DMSO.d6) : 5 12.40 (bs. IH, D2O exchangeable), 7.25 (d, J = 8.72 Hz, 2H),
6.90 (d, J == 8.72 Hz, 2H). 6.15 (s, IH), 4.70 (s, 2H), 4.40 - 4.25 (la, 2H), 4.25 •- 4.12 (m, 2H),
2.90 (q, J - 7.56 Hz, 2H), 2.12 (s, 3H), 1.20 (t, J = 7.56 Hz, 3H).
Example 26
5-[4-I2.I2-Ethyl-4-methyI-6-oxo-l,6-dihydro-l-pyrimidinyIIethoxy]phenyl methylene]
oxazolidine-2,4-dione :

To a stirred solution of 5-[4-[2-[2-etLyl-4-methyl.6-oxo-l,u.dihydro-l-pyrimidiiiyl]ethoxyJpiien^^ methy:eue]-2-thio-l,3-oxazohdine-4-one (100 mg, 0.259 mmol) (obtained from preparation 30) in diy DMF (2 ml) was added 3-cMoroperbe«zoic acid (179 mg, 0.68 mmol, 65 %) at 0 ^C and stirred for 30 min at 0 oc to 10 oc and then at 30 OQ for 5 h. The reaction mixture was diluted mih ethyl acetate (10 ml), washed ^Mth water (5 ml) and tl^en witlt brine (5 ml); dried over auhydrius Na2S04 and concentrated. The crude product was purified by flash cliromavography to yield the title compound (72 mg, 75 %).
IH NMR (CDCl3+DMSO-d6) : 5 7.68 (d, J = 8.72 Hz, 2H), 6.91 (d, J = 8.72 Hz, 2H), 6.61 (s, IH), 6.16 (s, IH), 4.50 - 4.38 (m, 2H), 4.38 - 4.00 (m, 2H), 3.12 (q, J ^ 7.47 Hz, 2H), 2.24 (s 3H), 1.35(t,J = 7.47Hz,3H).
Example 27

5-[4-[2-I2-Ethyl-4-methyI-6-oxo-l,6-dihydro-l.pyrimidmylIethoxyIphenyl methyI]oxazoIidme-2,4-dione:

Method A :
A solution of 5-[4.[2-[2.etbyl-4-methyl.6.oxo.l,6.dihydro-l.pyriinidmyl]ethoxy]phenyl methyleue]oxazoUdine-2,4.:dione (100 mg) (obtained from example 26) in 1.4-dloxane (10 ml) was reduced with hydrogen in tl^e presence of 10 % paUadium on charcoal (20 mg) at 50 psi for 24 h. TTxenuxture was ©tered through a bed of cehte. Tlie filtrate was evaporated to do^ under reduced pressure, purified by column chromatography (2:1 EtOAc / petroleum etl.er as eluent) io aiford the title compound (90 mg, 90 %).
Method B :
A soluti™ of=fl"yI3..!4.p-(2.ea,y,.4-„e.I,yl.6.ox„-l>dil.ydro.l.pyrimidmyl]ethoxyi^^^^^^^^ hydroxy propaaoate (93 „g. 0.25 ™„„ („b,ai„ed ftom preparation 29), urea (3» mg, 0.5 ,™„., and .od™. ^eioxide (22 n,g, 0.4 ™„,) ta a mixture of mefl,.nol (0.5 ml) and ethane. (2,0 „U, was birred for 2 b at 30 oc. m.^.6 by reflux for 2 h. He reaction mixture was cooled to room temperature and acidified ™th 2N HCl ,„ pH 4 and extracted with eth,^ ac«a.,= (2x10 ml, Tie combined organic extracts were washed with water (5 mL). brine (5 mU, dried over anltydrous Na2S04 and concentrated to yield the title compom>d (35 mg, 38 »/.).
"H NMR (CDa3.DMSad5) : 6 7.14 (d, , = 8.51 H. 2H). 6.77 (d, , = 8.5 H.. 2H,. 6.17 (s •H). 4.95 (., J = 4.82 H^ IH), 4.42 (., , = 4.94 Hz, 2H). 4.24 (t, J - 4.94 Hz, 2H). 3.38 - 3 00 (m, 2H), 3.00 (q. J = 7.42 Hz. 2H), 2.25 (s, 3H), 1.34 (t, J = 7.42 Hz, 3H),
Example 28 :














Tlie title compound (1.6 g, 89 %) was obtained from 5-[4-[2-[2-methyl-4-oxo-3,4-diliydro-3-quinazolinyl]ethoxy]plienyl niethyl]-2-iitiinothiazolidine-4-one (!.8g, 4.4 mmol) (obtained fiom preparation 35) by a similar procedure to that described in exnmple 19 (mcJthad 13), a42»2444 ^c,
1H NMR (DMSO-dg) : 5 11.98 (bs, IH, D2O exchangeable), 8.11 (d, J = 7.50 Hz, IH), 7.80 (t,
J = 7.50 Hz, IH), 7.59 (d, J = 7.50 Hz, IH), 7.48 (t, J = 7.50 Hz, IH), 7.14 (d, J = 8.35 Hz, 2H), 6.89 (d, J = 8.35 Hz, 2H), 4.85 (dd, J = 9.03, 4.20 Hz, IH), 4.45 (t, J = 5.14 Hz, 2H), 4 27 (t, J = 5.14 Hz, 2H), 3.28 (dd, J = 14.12, 4.20 Hz, IH), 3.04 (dd, J= 14.12, 9.03 Hz, IH), 2.71 (s, 3H).
Example 37
5i4-[2-[2-MethyM-oxo-3,4-dihydro-3-quinazolinyl]ethoxylphenyl m ethyl] thiazoIidine-2,4-dione, sodium salt:

Tlie title compoand (348 mg, 81 Vo) was obtained from 5-[4-[2-[2-metliyl-4- cxo-3,4-diliydro-3-quinazolinyl]ethoxy]piienyl methyl]thiazolidiue-2,4-dione (409 mg, 1 mmol) (obtained from example 36) by a similar procedure to that described in example 28. mp : 317 °C.
1H NMR (DMSO-dg) : 5 8.11 (d, J = 7.88 Hz, IH), 7.79 (t, J = 7.05 Hz, IH), 7.59 (d, J = 7.88 Hz, IH), 7.48 (t, J = 7.05 Hz, IH), 7.08 (d, J = 8.40 Hz, 2H), 6.83 (d, J = 8.40 Hz, 2H), 4.44 (t, J = 5.40 Hz, 2H), 4.26 (t, J = 5.40 Hz, 2H), 4.06 (dd, J = 10.43, 3.42 Hz, IH), 3.28 (dd, J = 13.8, 3.42 Hz, IH), 2.62 (dd, J = 13.8, 10.43 Hz, IH), 2.71 (s, 3H).















We claim
1. A compound of the formula (I),

its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts or its pharmaceutically acceptable solvates where one of X, Y or Z represent C=0 or C=S and the remaining of X, Y and Z represent a group C= or C=C; R1, R2 and R3 are substituents either on X, Y or Z or on a nitrogen atom and may be the same or different and represent hydrogen, halogen, hydroxy or nitro, or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, thioalkyl, alkylthio or carboxylic acid and its derivatives or sulfonic acid and its derivatives with the provision that when R1 R2 or R3 is on a nitrogen atom it does not represent hydrogen, halogen, nitro, carboxy or sulfonic acid groups; or any two of R1, R2 and R3 along with the adjacent atoms to which they are attached may form a substituted or unsubstituted cyclic structure of 4 to 7 atoms with one or more double bonds which may be carbocyclic or may contain one or more heteroatoms selected from oxygen, nitrogen and sulfur; the linking group represented by -(CH2)n-0- may be attached either through nitrogen atom or through X, Y or Z where n is an integer ranging from 1 - 4; Ar represents an optionally substituted divalent aromatic or heterocyclic group; R4 represents hydrogen, halogen or lower alkyl group or forms a bond together with the adjacent group A; A represents a nitrogen atom or a group CR5 where R3 represents hydrogen, halogen or lower alkyl group or R5 forms a bond together with R4; B represents an oxygen or a sulfur atom when A is CR5 and B represents an oxygen atom when A is a nitrogen atom.
2. A compound according to claim 1, wherein X is a C=0 or C=S and Y and Z are selected
from =C and C=-C.

3. A compound according to claim 1, wherein Y is a C=0 or C=S and X and Z are selected from =C and C=C.
4. A compound according to claim 1, wherein Z is a C=0 or C=S and X and Y are selected from -C and C=C.
5. A compound according to claim 1, wherein R1, R2 and R3 are substituents on X, Y or Z which may be same or different and are selected from hydrogen, halogen, hydroxy, nitro, or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, thioalkyl, alkylthio or carboxy or its derivatives or sulfonic acid or its derivatives.
6. A compound according to claim 1, wherein one of R , R or R is substituent on a nitrogen atom and is selected from the group consisting of substituted or unsubstituted (Ci -C12) alkyl; substituted or unsubstituted cycloalkyl; substituted or unsubstituted aryl; substituted or unsubstituted aralkyl; substituted or unsubstituted heteroaryl; substituted or unsubstituted heterocyclyl; alkoxycarbonyl; aryloxycarbonyl; amino(Ci-C6)alkyl; hydroxy(Ci-C6) alkyl; thio(Ci -C6) alkyl and acyl groups.
7. A compound according to claim 1, wherein the cyclic structure formed by any two of R", R^ or R^ along with the adjacent atoms to which they are attached, is substituted and tile substituents are selected from the group consisting of halogen, alkyl cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl hydroxy, acyl, acyloxy, hydroxyalkyl, amino, acyl, acyloxy, acylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, carboxylic acid or its derivatives or sulfonic acid or its derivatives.
8. A process for the preparation of compound of formula (I)

where one of X, Y and Z represent C=0 or C=S and the remaining of X, Y and Z represent a group C=orC=C;R",R^andR^ are substituents either on X, Y or Z or on a nitrogen atom and may be same or different and represent hydrogen, halogen, hydroxy or nitro, or optionally

substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, thioalkyl, alkylthio or carboxylic acid or its derivatives or sulfonic acid or its derivatives with the provision that when
1 9 ^
R , R or R IS on a nitrogen atom it does not represent hydrogen, halogen, nitro, carboxy or sulfonic acid groups; or any two of R, R and R along with the adjacent atoms to which they are attached may also form a substituted or unsubstituted cyclic structure of 4 to 7 atoms with one or more double bonds, the cyclic structure may be carbocyclic or may contain one or more heteroatoms selected from oxygen, nitrogen and sulfur; the linking group represented by -(CH2)n-0- may be attached through nitrogen atom where n is an integer ranging from 1 - 4; Ar represents an optionally substituted divalent aromatic or heterocyclic group; R4 represents hydrogen, A represents CR^ where R^ represents hydrogen and B represents an oxygen or a sulfur atom when A is CR^, comprising: (a) reacting a compound of formula (IV)

where X, Y, Z, R", R^ and R^ are as defined earlier and H atom is attached to one of the nitrogen atoms of the ring, with a compound of formula (V)
L"-(CH2)n-0-Ar-G (V) where Ar and n are as defined earlier and L" is a halogen atom or a leaving group and G is a CHO group to yield a compound of formula (III)

where G represents -CHO group and X, Y, Z, R", R^, R^ n and Ar are as defined earlier, in the presence or absence of solvent, in the presence or absence of inert atmosphere at a temperature in the range of 0 °C to 150 °C, preferably from 15 °C to 100 °C for a period in the range of 0.25 to 24 hours, preferably from 0.25 to 6 hours.

(b) reacting the compound of general formula (III) obtained in step (a) above with
thiazolidine-2,4-dione or oxazolidine-2,4-dione to yield a compound of formula (X)

where R\ R^ R^ X, Y, Z, n, Ar are as defined earlier and B represents a sulfur or an oxygen atom and removing the water formed during the reaction, in the presence or absence of solvent at a temperature in the range of 80 °C to 140 °C and
(c) reducing the compound of formula (X) obtained in step (b) to obtain the compound of
formula (XI)
where R", R^, R^, X, Y, Z, n and Ar are as defined earlier and B represents a sulfur atom or an oxygen atom, in the presence or absence of hydrogen atmosphere, in the presence or absence of catalyst, in the presence or absence of solvent. The compound of general formula (XI) represents the compound of general formula (I) wherein R"* is hydrogen, A is CR^ where R^ is hydrogen, and the other symbols are as defined earlier.
9. A pharmaceutical composition which comprises a compoimd of formula (I)

as defined in claim 1 and pharmaceutically acceptable carriers, diluents, excipients or solvates.
10. A pharmaceutical composition as claimed in claim 9, in the form of a tablet, capsule,
powder, syrup, solution or suspension.

11. A compound according to claim 1 where Ar represents susbstituted or- unsubstituted divalent phenylene, naphthylene, benzofUryL indolinyl, azaindolyl, azaindolinyl or benzoxazolyl.
12. A compound according to claim 1 which is selected from the group consisting of the following compounds:
5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro- 1 -pyrimidinyl]ethoxy]phenyl methvljthiazolidine-
2.4dione and its salts,
5-[4- [2-[2-ethyl-4-methyl-6-oxo-l,6-dihydro-l-pyrimidinyl]ethoxy] phenyl methyl] thiazolidine
-2,4-dione and its salts,
5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6- dihydro-l-pyrimidinyl]ethoxy]pheny] methyl]
thiazolidine-2,4-dione and its salts,
5-[4-[2-[2-butyl-4-methyl-6-oxo-1,6-dihydro-l-pyrimidinyl]ethoxy]phenyl methyl]thiazolidine-
2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6- dihydro- l-pyrinidinyl]ethoxy]phenyl methyl]thiazolidine
2,4-dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyImethyl]thiazolidine-2,4dione
and its salts and its polymorphs,
5-[4-[[3-ethyl-4- oxo-3,4-dihydro-2-quinazolinyl]methoxy] phenyl methyl]thiazolidine-2,4-
dione and its salts,
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenyl methyl] thiazolidine-2,4-
dione and its salts,
5-[4-[2-[6,7-dimethoxy-2-ethyl-4-oxo-3,4-dihydro-3-quinazohnyl]ethoxy]phenyI
methyllthiazolidine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-methyl-6-oxo-l,6-dihydro- l-pyrimidinyl]ethoxy]phenyl methyl] oxazolidine
2,4-dione and its salts,
5-[4-[2-[4-methyl-2-propyl-6-oxo-l,6- dihydro-l-pyrimidinyl]ethoxy]phenyl methyl] oxazolidine
2,4-dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methyl] oxazolidine-2,4-
dione and its salts,
2-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1 -pyrimidinyl] ethoxy]phenyl methyl-1,2,4-
oxadiazolidine-3,5-dione and its salts.

2-[4-[2-[4-methyl-2-propyl-6-oxo- 1,6-dihydro- 1 - pyrimidinyl]ethoxyl]phenyl methyl]-
l,2,4oxadiazolidine-3,5-dione and its salts,
2-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyImethyl]-l,2,4-
oxadiazolidine-3,5-dione and its salts,
5-[4-[2-[2,4-dimethyl-6-oxo- 1,6-dihydro- l-p3aimidinyl]ethoxy]phenyl methylenejthiazolidine-
2,4-dioneand its salts,
5-[4- [2-[2-ethyl-4-methyl-6-oxo- 1,6-dihydro- l-pyrimidinyl]ethoxy]phenyl methylene]
thiazolidine-2,4-dione and its salts,
5-[4-[2-[4-methyl-2-propyl-6-oxo- 1,6- dihydro- 1 -pyrimidinyljethoxy] phenyl methylene]
thiazohdine-2,4-dione and its salts,
5-[4-[2-[2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1 -pyrimidinyl]ethoxy]phenyl methylene]
thiazolidine-2,4-dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4- dihydro-2-quinazohnyl]methoxy]phenyl methylene]thiazolidine-2,4-
dione and its salts,
5-[4-[[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenyl methylene] thiazolidine-2,4-
dione and its salts,
5-[4-[2-[2-methyl-4-oxo-3, 4-dihydro-3- quinazolinyl]ethoxy]phenyl methylene]tbiazolidine-2,4-
dione and its salts,
5-[4- [2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy] phenyl methylene]thiazolidine- 2,4-
dione and its salts,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy]-3-methoxyphenyl methylene]
thiazolidine-2,4-dione and its salts,
5[4- [[3-methyl-4-oxo-3.4-dihydro-2-quinazolinyl]methoxylphenyl methyl]thiazolidine- 2,4-
dione sodium salt and its polymorphs,
5-[4-[2-[2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl]etboxy]phenyl methyl]thiazolidine-2.4-dione, sodium salt,
5-[4-[2-[2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl]ethoxy]phenylmethyl]thiazolidine-2,4-dione,
sodium salt,
5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2.4-
dione, potassium salt.

5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazohnyl]methoxylphenylmethylenelthiazolidine-2,4dione, sodium salt.

Documents:

1150-mas-1996 abstract duplicate.pdf

1150-mas-1996 abstract.pdf

1150-mas-1996 assignment.pdf

1150-mas-1996 claims duplicate.pdf

1150-mas-1996 claims.pdf

1150-mas-1996 correspondence others.pdf

1150-mas-1996 correspondence po.pdf

1150-mas-1996 description (complete) duplicate.pdf

1150-mas-1996 description (complete)-1 duplicate.pdf

1150-mas-1996 description (complete)-1.pdf

1150-mas-1996 description (complete).pdf

1150-mas-1996 form-1.pdf

1150-mas-1996 form-18.pdf

1150-mas-1996 form-3.pdf

1150-mas-1996 form-5.pdf

1150-mas-1996 form-6.pdf


Patent Number 202816
Indian Patent Application Number 1150/MAS/1996
PG Journal Number 05/2007
Publication Date 02-Feb-2007
Grant Date 30-Oct-2006
Date of Filing 01-Jul-1996
Name of Patentee DR. REDDY’S LABORATORIES LTD
Applicant Address 7-1-27, AMEERPET, HYDERABAD, 500 016
Inventors:
# Inventor's Name Inventor's Address
1 VIDYA BHUSHAN LOHARY 302, PUSHKAR APARTEMENT, JUDGES BUNGALOW ROAD, BODAKDEV, AHMEDABAD 380 051
2 PARASELLA BHEEMA RAO S/O P. APPALA SWAMY, PATHA PONNUTURU (VILLEGE), NIVAGAM (POST) SRIKAKULAM (DIST),
3 RANJAN CHAKRAARTI 7-1-27 AMEERPET, HYDERABAD 500 016
4 BREJ BHUSHAN LOHARY 302, PUSHKAR APARTEMENT, JUDGES BUNGALOW ROAD, BODAKDEV, AHMEDABAD 380 051
5 GURRAM RANGA MADHAVAN H.NO. 47, VERTEX PREVILAGE, NEAR KOALM RAGHAV REDDY GARDEN, HYDERABAD 500 072
6 PAKALA KUMARA SAVITHRU SARMA D.NO: 15-51, SREE NAGAR COLONY, GAJULA REGA, VIZIANAGARAM 531 201,
7 RAMANUJAM RAJAGOPALAN 7-1-27 AMEERPET, HYDERABAD 500 016
PCT International Classification Number C07D 263/02
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA