Heterocyclic compounds having antidiabetic hypolipidemic antihypertensive properties process for their preparation and pharmaceutical compositions containing them

The present invention relates to novel antidiabetic compounds, their tautomeric forms, their analogues, 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 azolidinedione compounds of the general formula (I), and their analogues, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. ##STR1##

FIELD OF THE INVENTION 
The present invention relates to novel antidiabetic compounds, their 
tautomeric forms, their analogues, 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 
azolidinedione compounds of the general formula (I), and their analogues, 
their derivatives, their tautomeric forms, their stereoisomers, their 
polymorphs, their pharmaceutically acceptable salts, pharmaceutically 
acceptable solvates and pharmaceutical compositions containing them. 
##STR2## 
The present invention also relates to a process for the preparation of the 
above said novel azolidinedione compounds, their analogues, their 
derivatives, their tautomeric forms, their stereoisomers, their 
polymorphs, their pharmaceutically acceptable salts, pharmaceutically 
acceptable solvates, and pharmaceutical compositions containing them. 
This invention also relates to novel intermediates, processes for preparing 
the intermediates and processes for using intermediates. 
The azolidinediones of the general formula (I) defined above of the present 
invention are useful for the treatment and/or prophylaxis of 
hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, 
obesity, glucose intolerance, insulin resistance and also diseases or 
conditions in which insulin resistance is the underlying 
pathophysiological mechanism. Examples of these diseases and conditions 
are type II diabetes, impaired glucose tolerance, dyslipidaemia, 
hypertension, coronary heart disease and other cardiovascular disorders 
including atherosclerosis. The azolidinediones of the formula (I) are 
useful for the treatment of insulin resistance associated with obesity and 
psoriasis. The azolidinediones of the formula (I) can also be used to 
treat 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 nephropathy, 
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 functions in dementia. 
BACKGROUND OF THE INVENTION 
Insulin resistance is the diminished ability of insulin to exert its 
biological action across a broad range of concentrations. In insulin 
resistance, the body secretes abnormally high amounts of insulin to 
compensate for this defect; failing which, the plasma glucose 
concentration inevitably rises and develops into diabetes. Among the 
developed countries, diabetes mellitus is a common problem and is 
associated with a variety of abnormalities including obesity, 
hypertension, hyperlipidemia (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 
complications (See Patent Application No. WO 95/21608). It is now 
increasingly being recognized that insulin resistance and relative 
hyperinsulinemia have a contributory role in obesity, hypertension, 
atherosclerosis and type 2 diabetes mellitus. The association of insulin 
resistance with obesity, hypertension and angina has been described as a 
syndrome having insulin resistance as the central pathogenic 
link-Syndrome-X. In addition, polycystic ovarian syndrome (Patent 
Application No. WO 95/07697), psoriasis (Patent Application No. WO 
95/35108), dementia (Behavioral Brain Research (1996) 75: 1-11) etc. may 
also have insulin resistance as a central pathogenic feature. Recently, it 
has also been reported that insulin sensitizers improve the bone mineral 
density and thus may be useful for the treatment of osteoporosis 
(EP-783888). 
A number of molecular defects have been associated with insulin resistance. 
These include reduced expression of insulin receptors on the plasma 
membrane of insulin responsive cells and alterations in the signal 
transduction pathways that become activated after insulin binds to its 
receptor including 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 
intrinsic suitability of antidiabetic treatment that is based entirely 
upon stimulation of insulin release. Recently, Takeda has developed a new 
class of compounds which are the derivatives of 
5-(4-alkoxybenzyl)-2,4-thiazolidinediones of the formula (II) (Ref. Chem. 
Pharm. Bull. 1982, 30, 3580-3600). In the formula (II), V represents 
substituted or unsubstituted divalent aromatic group B represents a sulfur 
atom or an oxygen atom and U represents various groups which have been 
reported in various patent documents. 
##STR3## 
By way of examples, U may represent the following groups: (i) a group of 
the formula (IIa) where R.sup.1 is hydrogen or hydrocarbon residue or 
heterocyclic residue which may each be substituted, R.sup.2 is hydrogen or 
a lower alkyl which may be substituted by hydroxy group, X is an oxygen or 
sulphur atom, Z is a hydroxylated methylene or a carbonyl, m is 0 or 1, n 
is an integer of 1-3. These compounds have been disclosed in the European 
Patent Application No. 0 177 353 
##STR4## 
An example of these compounds is shown in formula (IIb) 
##STR5## 
(ii) a group of the formula (IIc) wherein R.sup.1 and R.sup.2 are the same 
or different and each represents hydrogen or C.sub.1 -C.sub.5 alkyl, 
R.sup.3 represents hydrogen, acyl group, a (C.sub.1 -C.sub.6) 
alkoxycarbonyl group or aralkyloxycarbonyl group, R.sup.4 -R.sup.5 are 
same or different and each represent hydrogen, C.sub.1 -C.sub.5 alkyl or 
C.sub.1 -C.sub.5 alkoxy or R.sup.4, R.sup.5 together represent C.sub.1 
-C.sub.4 alkenedioxy group, n is 1, 2, or 3, W represents CH.sub.2, CO, 
CHOR.sup.6 group in which R.sup.6 represents any one of the items or 
groups defined for R.sup.3 and may be the same or different from R.sup.3. 
These compounds are disclosed in the European Patent Application No. 0 139 
421. 
##STR6## 
An example of these compounds is shown in (IId) 
##STR7## 
iii) A group of formula (IIe) where A.sup.1 represents substituted or 
unsubstituted aromatic heterocyclic group, R.sup.1 represents a hydrogen 
atom, alkyl group, acyl group, an aralkyl group wherein the aryl moiety 
may be substituted or unsubstituted, or a substituted or unsubstituted 
aryl group, n represents an integer in the range from 2 to 6. These 
compounds are disclosed in European Patent No. 0 306 228. 
##STR8## 
An example of this compound is shown in formula (IIf) 
##STR9## 
iv) A group of formula (IIg) where Y represents N or CR.sup.5, R.sup.1, 
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represents hydrogen, halogen, alkyl 
and the like and R.sup.6 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. 
##STR10## 
An example of this compound is shown in formula (IIh) 
##STR11## 
v) a group of formula (IIi), where R is (C.sub.1 -C.sub.6) alkyl groups, 
cycloalkyl group, furyl, thienyl, substituted or unsubstituted phenyl 
group, X is hydrogen, methyl, methoxy, chloro or fluoro. These compounds 
have been disclosed in the U.S. Pat. No. 5,037,842. 
##STR12## 
An example of these compounds is shown in formula (IIj). 
##STR13## 
(vi) a group of formula (Ilk) wherein A.sup.1 represents a substituted or 
unsubstituted aromatic heterocyclyl group; R.sup.1 represents a hydrogen 
atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl 
moiety may be substituted or unsubstituted or a substituted or 
unsubstituted aryl group, n represents an integer in the range of from 2 
to 6. These compounds have been disclosed in the patent application No. WO 
92/02520. 
##STR14## 
An example of these compounds is shown in formula (II l). 
##STR15## 
Some of the above referenced hitherto known 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-diabetes 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 
incorporating safety and to have better efficacy, which has resulted in 
the development of novel azolidinedione compounds having the general 
formula (I) as defined above. 
The main objective of the present invention is therefore, to provide novel 
azolidinediones, their derivatives, their analogues, their tautomeric 
forms, their stereoisomers, their polymorphs, their pharmaceutically 
acceptable salts, their pharmaceutically acceptable solvates and 
pharmaceutical compositions containing them, or mixtures thereof. 
Another objective of the present invention is to provide novel 
azolidinediones, their derivatives, their analogues, their tautomeric 
forms, their stereoisomers, their polymorphs, their pharmaceutically 
acceptable salts, their pharmaceutically acceptable solvates and 
pharmaceutical compositions containing them or mixtures thereof 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 formula (I) as defined 
above, their derivatives, their analogues, their tautomeric forms, their 
stereoisomers, their polymorphs, their pharmaceutically acceptable salts 
and their pharmaceutically acceptable solvates. 
Still another objective of the present invention is to provide 
pharmaceutical compositions containing compounds of the general formula 
(I), their derivatives, their analogues, their tautomers, their 
stereoisomers, their polymorphs, their pharmaceutically acceptable salts, 
solvates or mixtures thereof in combination with suitable carriers, 
solvents, excipients, diluents and other media normally employed in 
preparing such compositions. 
Yet another objective of the present invention is to provide a novel 
intermediate of the formula (III) 
##STR16## 
where G represents --CHO, --NO.sub.2, --NH.sub.2 or --CH.sub.2 
CH(J)--COOR, where J represents halogen atom such as chlorine, bromine or 
iodine and R represents H or lower alkyl group such as a (C.sub.1 
-C.sub.6) alkyl, preferably a (C.sub.1 -C.sub.3) alkyl group such as 
methyl, ethyl, or propyl; and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, 
X, W, n and Ar are defined as in formula (I) and a process for the 
preparation thereof. 
DETAILED DESCRIPTION OF THE INVENTION 
Azolidinediones of the present invention have the general formula (I) 
##STR17## 
In the above formula (I), X represents O or S; the groups R.sup.1, 
R.sup.2, R.sup.3, R.sup.4 may be same or different and represent hydrogen, 
halogen, hydroxy, cyano, nitro; optionally substituted groups selected 
from alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aralkyl, heteroaryl, 
heteroaralkyl, heterocyclyl, aryloxy, alkoxycarbonyl, aryloxycarbonyl, 
aralkoxycarbonyl, arylamino, amino, alkylamino, aminoalkyl, hydroxyalkyl, 
alkoxyalkyl, thioalkyl, alkylthio, acyl, acylamino, aryloxycarbonylamino, 
aralkoxycarbonylamino, alkoxycarbonylamino, carboxylic acid or its 
derivatives, acyloxy, sulfonic acid or its derivatives; "----" represents 
a bond or no bond; W represents oxygen atom or nitrogen atom, with the 
provision that when W represents nitrogen atom, "----" represents a bond 
and when W represents a oxygen atom "----" represents no bond; when 
R.sup.5 is present on a carbon atom, it represents hydrogen, hydroxy, 
halogen, nitro, cyano, optionally substituted groups selected from amino, 
alkyl, cycloalkoxy, cycloalkyl, acylamino, aryl, aralkyl, heterocyclyl, 
heteroaryl, heteroaralkyl, acyl, hydroxyalkyl, aminoalkyl, alkoxy, 
aryloxy, aralkoxy, acyloxy, alkoxycarbonyl, aryloxycarbonyl, 
aralkoxycarbonyl, alkoxyalkyl, alkylthio, thioalkyl, alkylamino, 
arylamino, alkoxycarbonylamino, aryloxycarbonylamino, 
aralkoxycarbonylamino, carboxylic acid and its derivatives, sulfonic acid 
and its derivatives; when R.sup.5 is present on a nitrogen atom, it 
represents hydrogen, optionally substituted groups selected from alkyl, 
cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, 
hydroxyalkyl, aminoalkyl, alkoxy, aryloxy, aralkoxy, acyloxy, 
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, alkylthio, 
thioalkyl, carboxylic acid derivatives, or sulfonic acid derivatives; n is 
an integer ranging from 1-4; Ar represents an optionally substituted 
divalent aromatic or heterocyclic group; R.sup.6 and R.sup.7 may be same 
or different and individually represent hydrogen atom, hydroxy, halogen or 
lower alkyl group or together form a bond; B represents an oxygen atom or 
a sulfur atom. 
Suitable groups represented by R.sup.1, R.sup.2, R.sup.3, R.sup.4 may be 
selected from hydrogen, halogen atom such as fluorine, chlorine, bromine, 
or iodine; hydroxy, cyano, nitro; substituted or unsubstituted (C.sub.1 
-.sub.2)alkyl group, especially, linear or branched (C.sub.1 
-C.sub.6)alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 
iso-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; cycloalkyl 
group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the 
like, the cycloalkyl group may be substituted; cycloalkyloxy group such as 
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, 
the cycloalkoxy group may be substituted; aryl group such as phenyl or 
naphthyl, the aryl group may be substituted; aralkyl such as benzyl or 
phenethyl, the aralkyl group may be substituted; heteroaryl group such as 
pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, 
oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the 
heteroaryl group may be substituted; heteroaralkyl wherein the heteroaryl 
moiety is as defined earlier and is attached to (C.sub.1 -C.sub.3) 
alkylene moiety such as furanmethyl, pyridinemethyl, oxazolemethyl, 
oxazolethyl and the like; heterocyclyl groups such as aziridinyl, 
pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like, the 
heterocyclyl group may be substituted; aryloxy such as phenoxy, 
naphthyloxy, the aryloxy group may be substituted; alkoxycarbonyl such as 
methoxycarbonyl or ethoxycarbonyl, the alkoxycarbonyl group may be 
substituted; aryloxyvcarbonyl group such as phenoxycarbonyl or naphthyloxy 
carbonyl, the aryloxycarbonyl group may be substituted; aralkoxycarbonyl 
wherein the aryl moiety is phenyl or naphthyl; aralkoxycarbonyl group such 
as benzyloxycarbonyl, phenethyloxycarbonyl, napththylmethyloxycarbonyl and 
the like, the aralkoxycarbonyl group may be substituted; linear or 
branched (C.sub.1 -C.sub.6)alkylamino, the alkylamino group may be 
substituted; arylamino group such as HNC.sub.6 H.sub.5, NCH.sub.3 C.sub.6 
H.sub.5,--NHC.sub.6 H.sub.4 --CH.sub.3,--NHC.sub.6 H.sub.4 -halo and the 
like, the arylamino group may be substituted; amino group; amino(C.sub.1 
-C.sub.6)alkyl group, the aminoalkyl group may be substituted; 
hydroxy(C.sub.1 -C.sub.6)alkyl group, the hydroxyalkyl group may be 
substituted; (C.sub.1 -C.sub.6)alkoxy group, the alkoxy group may be 
substituted; thio(C.sub.1 -C.sub.6)alkyl group, thioalkyl group may be 
substituted; (C.sub.1 -C.sub.6)alkylthio group, the alkylthio group may be 
substituted; acyl group such as acetyl, propionyl or benzoyl, the acyl 
group may be substituted; acylamino group such as NHCOCH.sub.3, 
NHCOC.sub.2 H.sub.5, NHCOC.sub.3 H.sub.7, NHCOC.sub.6 H.sub.5, the 
acylamino group may be substituted, aryloxycarbonylamino group such as 
NHCOOC.sub.6 H.sub.5, --NCH.sub.3 COOC.sub.6 H.sub.5, --NC.sub.2 H.sub.5 
COOC.sub.6 H.sub.5,--NHCOOC.sub.6 H.sub.4 CH.sub.3,--NHCOOC.sub.6 H.sub.4 
OCH.sub.3 and the like, the aryloxycarbonylamino may be substituted, 
aralkoxycarbonylamino group such as NHCOOCH.sub.2 C.sub.6 H.sub.5, 
--NHCOOCH.sub.2 CH.sub.2 C.sub.6 H.sub.5, --NCH.sub.3 COOCH.sub.2 C.sub.6 
H.sub.5, --NC.sub.2 H.sub.5 COOCH.sub.2 C.sub.6 H.sub.5, --NHCOOCH.sub.2 
C.sub.6 H.sub.4 CH.sub.3, --NHCOOCH.sub.2 C.sub.6 H.sub.4 OCH.sub.3 and 
the like, aralkoxycarbonylamino may be substituted; alkoxycarbonyl amino 
group such as, NHCOOC.sub.2 H.sub.5, NHCOOCH.sub.3 and the like, 
alkoxycarbonyl group may be substituted; carboxylic acid or its 
derivatives such as amides, like CONH.sub.2, CONHMe, CONMe.sub.2, CONHEt, 
CONEt.sub.2, CONHPh and the like, the carboxylic acid derivatives may be 
substituted; acyloxy group such as MeCOO, EtCOO, PhCOO and the like, the 
acyloxy which may optionally be substituted; sulfonic acid or its 
derivatives such as SO.sub.2 NH.sub.2, SO.sub.2 NHMe, SO.sub.2 NMe.sub.2, 
SO.sub.2 NHCF.sub.3 and the like, the sulfonic acid derivatives may be 
substituted. 
When the groups represented by R.sup.1, R.sup.2, R.sup.3, R.sup.4 are 
substituted, the substituents may be selected from halogen, hydroxy, cyano 
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, alkylthio, 
thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, 
aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic 
acid or its derivatives. The substituents are as defined above. 
It is preferred that R.sup.1 -R.sup.4 represent hydrogen, halogen atom such 
as fluorine, chlorine, bromine; alkyl group such as methyl, ethyl, 
isopropyl, n-propyl, n-butyl and the like which may be halogenated; 
optionally halogenated groups selected from cycloalkyl group such as 
cyclopropyl; aryl group such as phenyl; aralkyl group such as benzyl; 
(C.sub.1 -C.sub.3)alkoxy, aryloxy group such as benzyloxy, hydroxy group, 
acyl or acyloxy groups. Acyl and acyloxy groups are as defined above. 
When R.sup.5 is attached to carbon atom, suitable groups represented by 
R.sup.5 are selected from hydrogen, halogen atom such as fluorine, 
chlorine, bromine, or iodine; hydroxy, nitro, cyano; substituted or 
unsubstituted (C.sub.1 -C.sub.12)alkyl group, especially, linear or 
branched (C.sub.1 -C.sub.6)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, the 
cycloalkyl group may be substituted; cycloalkyloxy group such as 
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, 
the cycloalkoxy group may be substituted; aryl group such as phenyl or 
naphthyl, the aryl group may be substituted; aralkyl such as benzyl or 
phenethyl, the aralkyl group may be substituted; heteroaryl group such as 
pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, 
tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group 
may be substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl, 
morpholinyl, piperidinyl and the like, the heterocyclyl group may be 
substituted; aryloxy such as phenoxy, naphthyloxy, the aryloxy group may 
be substituted; alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl; 
aryloxycarbonyl group such as optionally substituted phenoxycarbonyl; 
aralkoxycarbonyl wherein the aralkyl moiety is as defined earlier; 
arylamino group such as HNC.sub.6 H.sub.5, --NCH.sub.3 C.sub.6 H.sub.5, 
--NHC.sub.6 H.sub.4 --CH.sub.3,--HNC.sub.6 H.sub.4 --halo and the like; 
amino group; amino(C.sub.1 -C.sub.6)alkyl; hydroxy(C.sub.1 -C.sub.6)alkyl; 
(C.sub.1 -C.sub.6)alkoxy; thio(C.sub.1 -C.sub.6)alkyl; (C.sub.1 
-C.sub.6)alkylthio; acyl group such as acetyl, propionyl or benzoyl, the 
acyl group may be substituted; acylamino groups such as NHCOCH.sub.3, 
NHCOC.sub.2 H.sub.5, NHCOC.sub.3 H.sub.7, NHCOC.sub.6 H.sub.5, 
aryloxycarbonylamino group such as NHCOOC.sub.6 H.sub.5, --NCH.sub.3 
COOC.sub.6 H.sub.5, --NC.sub.2 H.sub.5 COOC.sub.6 H.sub.5, --NHCOOC.sub.6 
H.sub.4 CH.sub.3, --NHCOOC.sub.6 H.sub.4 OCH.sub.3 and the like; 
aralkoxycarbonylamino group such as NHCOOCH.sub.2 C.sub.6 H.sub.5, 
NHCOOCH.sub.2 CH.sub.2 C.sub.6 H.sub.5, NCH.sub.3 COOCH.sub.2 C.sub.6 
H.sub.5, --NC.sub.2 H.sub.5 COOCH.sub.2 C.sub.6 H.sub.5, --NHCOOCH.sub.2 
C.sub.6 H.sub.4 CH.sub.3, --NHCOOCH.sub.2 C.sub.6 H.sub.4 OCH.sub.3 and 
the like; alkoxycarbonylamino group such as NHCOOC.sub.2 H.sub.5, 
NHCOOCH.sub.3 and the like; alkylamino group such as methylamino, 
ethylamino, propylamino and the like; aralkoxy group such as benzyloxy, 
phenethyloxy and the like; alkoxyalkyl group such as methoxymethyl, 
methoxyethyl, ethoxymethyl, ethoxyethyl and the like; heteroaralkyl group 
such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the 
like; carboxylic acid or its derivatives such as amides, like CONH.sub.2, 
CONHMe, CONMe.sub.2, CONHEt, CONEt.sub.2, CONHPh and the like, the 
carboxylic acid derivatives may be substituted; acyloxy group such as 
OCOMe, OCOEt, OCOPh and the like which may optionally be substituted; 
sulfonic acid or its derivatives such as SO.sub.2 NH.sub.2, SO.sub.2 NHMe, 
SO.sub.2 NMe.sub.2, SO.sub.2 NHCF.sub.3 and the like; the sulfonic acid 
derivatives may be substituted. 
When R.sup.5 is attached to nitrogen atom, suitable groups represented by 
R.sup.5 are selected from (C.sub.1 -C.sub.12)alkyl group, especially 
linear or branched (C.sub.1 -C.sub.6)alkyl group, such as methyl, ethyl, 
n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl groups and the like; 
cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 
and the like, the cycloalkyl group may be substituted; aryl group such as 
phenyl or naphthyl; aralkyl such as benzyl or phenethyl; heteroaryl group 
such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, 
oxadiazolyl, tetrazolyl and the like; heterocyclyl groups such as 
aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl and the like; 
alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl; aryloxycarbonyl 
group such as phenoxycarbonyl or naphthyloxycarbonyl; amino(C.sub.1 
-C.sub.6)alkyl; hydroxy(C.sub.1 -C.sub.6)alkyl; thio(C.sub.1 
-C.sub.6)alkyl; or acyl group such as acetyl, propionyl, benzoyl, and the 
like; carboxylic acid derivatives such as amides, like CONH.sub.2, CONHMe, 
CONMe.sub.2, CONHEt, CONEt.sub.2, CONHPh and the like, the carboxylic acid 
derivatives may be substituted; acyloxy group such as OCOMe, OCOEt, OCOPh 
and the like which may optionally be substituted; sulfonic acid 
derivatives such as SO.sub.2 NH.sub.2, SO.sub.2 NHMe, SO.sub.2 NMe.sub.2, 
SO.sub.2 NHCF.sub.3 and the like; the sulfonic acid derivatives may be 
substituted; aryloxy such as phenoxy or naphthyloxy and the like; the 
aryloxy group may be substituted; (C.sub.1 -C.sub.6)alkoxy; aralkoxy group 
such as benzyloxy, phenethyloxy and the like; alkoxyalkyl group such as 
methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl and the like; 
aralkoxycarbonyl wherein the aralkyl moiety is as defined earlier; 
heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, 
oxazolethyl and the like. 
All the groups that may represent R.sup.5 may be substituted or 
unsubstituted. 
When the groups represented by R.sup.5 are substituted, the substituents 
selected are from the same groups as those groups that represent R.sup.5 
attached to carbon atom and may be selected from halogen, hydroxy, cyano 
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, alkylthio, 
thioalkyl, carboxylic acid or its derivatives, or sulfonic acid or its 
derivatives. 
When the groups represented by R.sup.5 are substituted, preferred 
substituents are selected from halogen such as fluorine, chlorine; 
hydroxy, acyl, acyloxy, amino, alkyl, aralkyl, aryl, alkoxy, aralkoxy 
groups. 
The substituents are defined as above. 
n is an integer ranging from 1-4. It is preferred that n be 1 or 2. 
It is preferred that the group represented by Ar be substituted or 
unsubstituted groups selected from divalent phenylene, naphthylene, 
pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, indolyl, 
indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, 
benzoxazolyl and the like. The substituents on the group represented by Ar 
may be selected from linear or branched (C.sub.1 -C.sub.6)alkyl, (C.sub.1 
-C.sub.3)alkoxy, halogen, acyl, amino, acylamino, thio, or carboxylic or 
sulfonic acids or their derivatives. 
It is more preferred that Ar represents substituted or unsubstituted 
divalent phenylene, naphthylene, benzofuryl, indolyl, indolinyl, 
quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl 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. 
When Ar is substituted the substituents are as defined above. 
Suitable R.sup.6 includes hydrogen, hydroxy, lower alkyl group such as a 
(C.sub.1 -C.sub.6) alkyl such as methyl, ethyl, propyl and the like; 
halogen atom such as fluorine, chlorine, bromine or iodine; or R.sup.6 
together with R represents a bond. 
It is preferred that R.sup.6 represents hydrogen or a bond together with 
R.sup.7. 
Suitable R.sup.7 may be a hydrogen atom, halogen, lower alkyl group such as 
(C.sub.1 -C.sub.6) alkyl such as methyl, ethyl, propyl and the like; or 
together with R.sup.6 forms a bond. 
When R.sup.6 or R.sup.7 is lower alkyl, the lower alkyl may be substituted 
by groups such as halogen, methyl or oxo group. 
Suitable B group includes a hetero atom selected from O or S. 
Suitable ring structure comprising B include 2,4-dioxooxazolidinyl, or 
2,4-dioxothiazolidinyl. 
It is more preferred that the ring structure comprising B is a 
2,4-dioxothiazolidinyl group. 
The groups represented by R.sup.1 -R.sup.7 and any substituent on these 
groups may be defined as disclosed anywhere in the specification. 
Pharmaceutically acceptable salts forming part of this invention 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 ammonium 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, benzenesulfonates, ascorbates, 
glycerophosphates, ketoglutarates and the like. Pharmaceutically 
acceptable solvates may be hydrates or comprising other solvents of 
crystallization such as alcohols. 
Particularly useful compounds according to the present invention include: 
5-[4-[2-[4-Methyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl 
methylene]thiazolidin-2,4-dione and its salts; 
5-[4-[2-[1-Oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl 
methylene]thiazolidin-2,4-dione and its salts; 
5-[4-[2-[4-Ethyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl 
methylene]thiazolidin-2,4-dione and its salts; 
5-[4-[2-[4-Phenyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl 
methylene]thiazolidin-2,4-dione and its salts; 
5-[4-[[2-Methyl-1-oxo-1,2-dihydro-phthalazin-4-yl]methoxy]phenyl 
methylene]thiazolidin-2,4-dione and its salts; 
5-[4-[2-[4-Methyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl methyl] 
thiazolidin-2,4-dione and its salts; 
5-[4-[2-[1-Oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl 
methyl]thiazolidin-2,4-dione and its salts; 
5-[4-[2-[4-Ethyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl 
methyl]thiazolidin-2,4-dione and its salts; 
5-[4-[2-[4-Phenyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl 
methyl]thiazolidin-2,4-dione and its salts; 
5-[4-[[2-Methyl-1-oxo-1,2-dihydro-phthalazin-4-yl]methoxy]phenyl 
methyl]thiazolidin-2,4-dione and its salts; 
5-[4-[2-[4-Oxo-3,4-dihydro-1H-2,3-benzoxazin-3-yl]ethoxy]phenyl 
methylene]thiazolidin-2,4-dione and its salts; 
5-[4-[2-[4-Oxo-3,4-dihydro-1H-2,3-benzoxazin-3-yl]ethoxy]phenyl 
methyl]thiazolidin-2,4-dione and its salts; 
5-[4-[2-[4-Hydroxy-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl 
methylene]thiazolidin-2,4-dione and its salts; and 
5-[4-[2-[4-Hydroxy-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl 
methyl]thiazolidin-2,4-dione and its salts. 
According to a feature of the present invention, there is provided a novel 
intermediate of the general formula (III) 
##STR18## 
where X represents O or S; the group R.sup.1, R.sup.2, R.sup.3, R.sup.4 
may be same or different and represent hydrogen, halogen, hydroxy, cyano, 
nitro; optionally substituted groups selected from alkyl, cycloalkyl, 
alkoxy, cycloalkyloxy, aryl, aralkyl, heteroaryl, heteroaralkyl, 
heterocyclyl, aryloxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, 
arylamino, amino group, alkylamino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, 
thioalkyl, alkylthio, acyl, acylamino, aryloxycarbonylamino, 
aralkoxycarbonylamino, alkoxycarbonylamino, carboxylic acid or its 
derivatives, acyloxy, sulfonic acid or its derivatives; "---" represents a 
bond or no bond; W represents oxygen atom or nitrogen atom, with the 
provision that when W represents nitrogen atom; "----" represents a bond 
and when W represents a oxygen atom "----" represents no bond; when 
R.sup.5 is present on carbon atom, it represents hydrogen, hydroxy, 
halogen, nitro, cyano, optionally substituted groups selected from amino, 
alkyl, cycloalkoxy, cycloalkyl, acylamino, aryl, aralkyl, heterocyclyl, 
heteroaryl, heteroaralkyl, acyl, hydroxyalkyl, aminoalkyl, alkoxy, 
aryloxy, aralkoxy, acyloxy, alkoxycarbonyl, aryloxycarbonyl, 
aralkoxycarbonyl, alkoxyalkyl, alkylthio, thioalkyl groups, alkylamino, 
arylamino, alkoxycarbonylamino, aryloxycarbonylamino, 
aralkoxycarbonylamino, carboxylic acid and its derivatives, sulfonic acid 
and its derivatives; when R.sup.5 is present on a nitrogen atom, it 
represents hydrogen, optionally substituted groups selected from alkyl, 
cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, 
hydroxyalkyl, aminoalkyl, alkoxy, aryloxy, aralkoxy, acyloxy, 
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, alkylthio, 
thioalkyl groups, carboxylic acid derivatives, sulfonic acid derivatives; 
n is an integer ranging from 1-4; Ar represents an optionally substituted 
divalent aromatic or heterocyclic group; G represents --CHO, --NO.sub.2, 
--NH.sub.2 or --CH.sub.2 CH(J)--COOR, where J represents halogen atom such 
as chlorine, bromine or iodine and R represents H or lower alkyl group. 
The lower alkyl group may be a (C.sub.1 -C.sub.6)alkyl group, preferably a 
(C.sub.1 -C.sub.3)alkyl group such as methyl, ethyl or propyl. 
According to a feature of the present invention, there is provided a 
process for the preparation of novel intermediate of the general formula 
(III) 
##STR19## 
where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, W, n, and Ar are as 
defined earlier and G represents --CHO or --NO.sub.2 group which 
comprises: reacting a compound of the general formula (IV) 
##STR20## 
where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, W, and n are as 
defined earlier, with a compound of general formula (V) 
EQU L.sup.1 --Ar--G (V) 
where L.sup.1 is a halogen atom such as fluorine or chlorine, G is a CHO or 
a NO.sub.2 group and Ar is as defined earlier. 
The reaction of a compound of formula (IV) with a compound of formula (V) 
to produce a compound of formula (III) may be carried out in the presence 
of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof. 
The inert atmosphere may be maintained by using inert gases such as 
N.sub.2, Ar or He. The reaction may be effected in the presence of a base 
such as K.sub.2 CO.sub.3, Na.sub.2 CO.sub.3, NaH and the like. Mixture of 
bases may be used. The reaction temperature may range from 20.degree. C. 
to 150.degree. C., preferably at a temperature in the range of 30.degree. 
C. to 100.degree. C. 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 (III), where G is a CHO or NO.sub.2 group, can also be 
prepared by the reaction of compound of general formula (VI) 
##STR21## 
where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, W, and n are as 
defined earlier and L.sup.2 may be a halogen atom such as Cl, Br, I or a 
leaving group such as methanesulfonate, trifluoromethanesulfonate, 
p-toluenesulfonate with a compound of general formula (VII) 
EQU HO--Ar--G (VII) 
where G is a CHO or NO.sub.2 group and Ar is as defined earlier. 
The reaction of a compound of formula (VI) with a compound of formula (VII) 
to produce a compound of the formula (III) 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 may 
be maintained by using inert gases such as N.sub.2, Ar, or He. The 
reaction may be effected in the presence of a base such as K.sub.2 
CO.sub.3, Na.sub.2 CO.sub.3 or NaH or mixtures thereof. The reaction 
temperature may range from 20.degree. C.-120.degree. C., preferably at a 
temperature in the range of 30.degree. C.-100.degree. C. The duration of 
the reaction may range from 1-12 hours, preferably from 2 to 6 hours. 
In yet another embodiment of the present invention, the novel intermediate 
of general formula (III), where G is CHO or NO.sub.2 group can also be 
prepared by the reaction of compound of general formula (VIII) 
##STR22## 
where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X and W are as defined 
earlier, with the compound of formula (IX) 
EQU L.sup.2 --(CH.sub.2).sub.n --O--Ar--G (IX) 
where L.sup.2, n, Ar and G are as defined earlier. 
The reaction of a compound of formula (VIII) with a compound of formula 
(IX) to produce a compound of the formula (III) 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 may 
be maintained by using inert gases such as N.sub.2, Ar, or He. The 
reaction may be effected in the presence of a base such as K.sub.2 
CO.sub.3, Na.sub.2 CO.sub.3 or NaH or mixtures thereof The reaction 
temperature may range from 20.degree. C.-120.degree. C., preferably at a 
temperature in the range of 30.degree. C.-100.degree. C. The duration of 
the reaction may range from 1-48 hours, preferably from 2 to 24 hours. 
Alternatively, a compound of general formula (III) can also be prepared by 
the reaction of compound of general formula (IV) defined earlier with a 
compound of general formula (VII) defined earlier. 
The reaction of compound of general formula (IV) with a compound of general 
formula (VII) may be carried out using suitable coupling agents such as 
dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such as 
PPh.sub.3 /DEAD and the like. The reaction may be carried out in the 
presence of solvents such as THF, DME, CH.sub.2 Cl.sub.2, CHCl.sub.3, 
toluene, acetonitrile, carbontetrachloride and the like. The inert 
atmosphere may be maintained by using inert gases such as N.sub.2, Ar, He. 
The reaction may be effected in the presence of DMAP, HOBT and they may be 
used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 
equivalents. The reaction temperature may be in the range of 0.degree. C. 
to 100.degree. C., preferably at a temperature in the range of 20.degree. 
C. to 80.degree. C. The duration of the reaction may range from 0.5 to 24 
hours, preferably from 6 to 12 hours. 
The present invention provides a process for the preparation of novel 
azolidinedione derivatives of general formula (I), their tautomeric forms, 
their stereoisomers, their polymorphs, their pharmaceutically acceptable 
salts and their pharmaceutically acceptable solvates wherein R.sup.1, 
R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, W, n, Ar and B are as defined 
earlier and R.sup.6 together with R.sup.7 represent a bond 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 water formed during the reaction by 
conventional methods to yield a compound of general formula (X) 
##STR23## 
where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, W, n, Ar are as 
defined earlier and B represents sulfur or oxygen. 
The reaction of the compound of the general formula (III) where G is a CHO 
group with 2,4-thiazolidinedione or 2,4-oxazolidinedione, to yield 
compound of general formula (X), wherein B represents a sulfur 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 
from 80.degree. C. to 140.degree. C. depending upon the solvents employed 
and in the range from 80.degree. C. to 180.degree. 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 that 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 
seives. Oxazolidine-2-oxo-4-thione may be used instead of 
2,4-oxazolidinedione, wherein the thio group may 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 above is converted into 
its pharmaceutically acceptable salts, or its pharmaceutically acceptable 
solvates by conventional methods. 
The compound of the general formula (X) obtained in the manner described 
above is reduced by known methods to obtain the compound of general 
formula (XI). 
##STR24## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, W n, Ar and B are as 
defined earlier. The compound of general formula (XI) represents the 
compound of general formula (I), wherein R.sup.6 and R.sup.7 represents 
hydrogen atom and other symbols are as defined earlier. 
The reduction of compound of the formula (X) to yield a compound of the 
general formula (XI) may be carried out in the presence of gaseous 
hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney Nickel, 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 carried out by 
employing metal solvent reduction such as magnesium in methanol or sodium 
amalgam in methanol. The reaction may also be carried out with alkali 
metal borohydrides such as LiBH.sub.4, NaBH.sub.4, KBH.sub.4 and the like 
in the presence of cobalt salt such as CoCl.sub.2 and ligands, preferably 
bidentated ligands such as 2,2'-bipyridyl, 1,10-phenanthroline, bisoximes 
and the like. 
The compound of the general formula (XI) obtained above is converted into 
its pharmaceutically acceptable salts, or its pharmaceutically acceptable 
solvates by conventional methods. 
In yet another embodiment of the present invention, the compound of the 
general formula (I) can also be prepared by reacting a compound of the 
general formula (VI) defined above with a compound of general formula 
(XII) 
##STR25## 
where R.sup.6, R.sup.7, B and Ar are as defined earlier and R.sup.8 is 
hydrogen or a nitrogen protecting group which is removed after the 
reaction. 
The reaction of compound of formula (VI) with compound of formula (XII) to 
produce a compound of the 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 may be 
maintained by using inert gases such as N.sub.2, Ar or He. The reaction 
may be effected in the presence of a base such as K.sub.2 CO.sub.3, 
Na.sub.2 CO.sub.3 or NaH or mixtures thereof. The reaction temperature may 
range from 20.degree. C.-150.degree. C., preferably at a temperature in 
the range of 30.degree. C.-80.degree. C. The duration of the reaction may 
range from 1-12 hours, preferably from 2 to 6 hours. 
Alternatively, compound of the general formula (I) can also be prepared by 
reacting a compound of general formula (IV) defined earlier with a 
compound of general formula (XII) defined above. 
The reaction of compound of general formula (IV) with a compound of general 
formula (XII) may be carried out using suitable coupling agents such as 
dicyclohexyl urea, triarylphosphine/dialkylazadicarboxylate such as 
PPh.sub.3 /DEAD and the like. The reaction may be carried out in the 
presence of solvents such as THF, DME, CH.sub.2 Cl.sub.2, CHCl.sub.3, 
toluene, acetonitrile, carbontetrachloride and the like. The inert 
atmosphere may be maintained by using inert gases such as N.sub.2, Ar, He. 
The reaction may be effected in the presence of DMAP, HOBT and they may be 
used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 
equivalents. The reaction temperature may be in the range of 0.degree. C. 
to 100.degree. C., preferably at a temperature in the range of 20.degree. 
C. to 80.degree. C. The duration of the reaction may range from 0.5 to 24 
hours, preferably from 6 to 12 hours. 
In another embodiment of the present invention, the compound of general 
formula (I), where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, W, n, 
Ar are as defined earlier and R.sup.6 and R.sup.7 represents hydrogen 
atom, B represents S can be prepared by the reaction of compound of 
general formula (XIII) 
##STR26## 
where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X, W, n, Ar are as 
defined earlier, J is a halogen atom like chlorine, bromine or iodine and 
R is a lower alkyl group with thiourea followed by treatment with an acid. 
The reaction of compound of general formula (XIII) with thiourea is 
normally carried out in the presence of alcoholic solvent such as 
methanol, ethanol, propanol, isobutanol, 2-methoxybutanol and the like or 
DMSO or sulfolane. The reaction may be conducted at a temperature in the 
range between 20.degree. C. and the reflux temperature of the solvent 
used. Bases such as NaOAc, KOAc, NaOMe, NaOEt and the like may be used. 
The reaction is normally followed by treatment with a mineral acid such as 
hydrochloric acid at 20.degree. C.-100.degree. C. 
The compound of general formula (XIII) where all the symbols are as defined 
earlier can be prepared by the diazotization of the amino compound of the 
general formula (XIV) 
##STR27## 
where all symbols are as defined earlier, using alkali metal nitrites 
followed by treatment with acrylic acid esters in the presence of 
hydrohalo acids and catalytic amount of copper oxide or copper halide. 
The compound of general formula (XIV) can in turn be prepared by the 
conventional reduction of the novel intermediate (III) where G is NO.sub.2 
group and other symbols are as defined earlier. 
In still another embodiment of the present invention the compound of 
general formula (I) may be prepared by reacting a compound of general 
formula (VIII) defined above with a compound of general formula (XV) 
##STR28## 
where L.sup.2, n, Ar, R.sup.6, R.sup.7, B are as defined earlier and 
R.sup.8 is hydrogen or a nitrogen protecting group which is removed after 
the reaction. 
The reaction of a compound of formula (VIII) with a compound of formula 
(XV) to produce a compound of the formula (III) 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 may 
be maintained by using inert gases such as N.sub.2, Ar, or He. The 
reaction may be effected in the presence of a base such as K.sub.2 
CO.sub.3, Na.sub.2 CO.sub.3 or NaH or mixtures thereof. The reaction 
temperature may range from 20.degree. C.-120.degree. C., preferably at a 
temperature in the range of 30.degree. C.-100.degree. C. The duration of 
the reaction may range from 1-12 hours, preferably from 2 to 6 hours. 
The pharmaceutically 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 like ether, THF, methanol, 
t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be 
used. Organic bases like lysine, arginine, diethanolamine, 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, hydroxynaphthoic acid, ascorbic acid, 
palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric 
acid and the like in solvents like ethyl acetate, ether, alcohols, 
acetone, THF, dioxane etc. Mixture of solvents may also be used. 
As used in this application the term neat means the reaction is carried out 
without the use of solvent. 
The stereoisomers of the compounds forming part of this invention may be 
prepared by using reactants in their single enantiomeric form in the 
process wherever possible or by conducting the reaction in the presence of 
reagents or catalysts in their single enantiomer form 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 mandelic acid, camphorsulfonic 
acid, tartaric acid, lactic acid and the like or chiral bases such as 
brucine, cinchona alkaloids and their derivatives and the like. 
Various polymorphs of compound of general formula (I) forming part of this 
invention may be prepared by crystallization of compound of formula (I) 
under different conditions. For example, using different solvents commonly 
used or their mixtures for recrystallization; crystallizations at 
different temperatures; various modes of cooling, ranging from very fast 
to very slow cooling during crystallizations. Polymorphs may also be 
obtained by heating or melting the compound followed 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 diffraction or such other techniques. 
The present invention also provides a pharmaceutical composition, 
containing compounds of the general formula (I), as defined above, their 
derivatives, their analogues, their tautomeric forms, their stereoisomers, 
their polymorphs, their pharmaceutically acceptable salts, their 
pharmaceutically acceptable solvates or mixtures thereof in combination 
with the usual pharmaceutically employed carriers, diluents and the like, 
useful for the treatment and/or prophylaxis of hyperlipemia, 
hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose 
intolerance, insulin resistance and also diseases or conditions in which 
insulin 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 
nephropathy, 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 functions in dementia. 
The pharmaceutical composition may be in the forms normally employed, such 
as tablets, capsules, powders, syrups, solutions, suspensions and the 
like, may contain flavourants, sweeteners etc. in suitable solid or liquid 
carriers 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 active compound, the remainder of 
the composition being pharmaceutically acceptable carriers, diluents, 
excipients, or solvents. 
A typical tablet production method is exemplified below: 
Tablet Production Example: 
______________________________________ 
a) 1) Active ingredient 
30 g 
2) Lactose 95 g 
3) Corn starch 30 g 
4) Carboxymethyl cellulose 
44 g 
5) Magnesium stearate 
1 g 
200 g for 1000 tablets 
______________________________________ 
The ingredients 1 to 3 are uniformly blended with water and granulated 
after drying under reduced pressure. The ingredient 4 and 5 are mixed well 
with the granules and compressed by a tabletting machine to prepare 1000 
tablets each containing 30 mg of active ingredient. 
______________________________________ 
b) 1) Active ingredient 
10 g 
2) Calcium phosphate 
90 g 
3) Lactose 50 g 
4) Corn starch 45 g 
5) Polyvinyl pyrrolidone 
3.5 g 
6) Magnesium stearate 
1.5 g 
200 g for 1000 tablets 
______________________________________ 
The ingredients 1-4 are uniformly moistened with an aqueous solution of 
ingredient 5 and granulated after drying under reduced pressure. 
Ingredient 6 is added and granules are compressed by a tabletting machine 
to prepare 1000 tablets containing 10 mg of ingredient 1. 
The compound of the formula (I) as defined above are clinically 
administered to mammals, including man, via either oral or parenteral 
routes. Administration by the oral route is preferred, being more 
convenient and avoiding the possible pain and irritation of injection. 
However, in circumstances where the patient cannot swallow the medication, 
or absorption following oral administration is impaired, as by disease or 
other abnormality, it is essential that the drug be administered 
parenterally. By either route, the dosage is in the range of about 0.10 mg 
to about 200 mg/kg body weight of the subject per day or preferably about 
0.10 mg to about 30 mg/kg body weight per day administered singly or as a 
divided dose. However, the optimum dosage for the individual subject being 
treated will be determined by the person responsible for treatment, 
generally smaller doses being administered initially and thereafter 
increments 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 
will be present in such pharmaceutical compositions in the amounts 
sufficient to provide the desired dosage in the range as described above. 
Thus, for oral administration, the compounds can be combined with a 
suitable solid or liquid 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 
administration, the compounds can be combined with sterile aqueous or 
organic media to form injectable solutions or suspensions. For example, 
solutions in sesame or peanut oil, aqueous propylene glycol and the like 
can be used, as well as aqueous solutions of water-soluble 
pharmaceutically-acceptable acid addition salts or salts with base of the 
compounds. The injectable solutions prepared in this manner can then be 
administered intravenously, intraperitoneally, subcutaneously, or 
intramuscularly, with intramuscular administration being preferred in 
humans. 
The 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 limit the scope of the invention. 
Preparation 1 
4-[[2-Methyl-1-oxo-1,2-dihydro-phthalazin-4-yl]methoxy]benzaldehyde: 
##STR29## 
To a stirred solution of 4-hydroxymethyl-2-methyl-1(2H)-pthalazinone (350 
mg, 1.84 mmol) (prepared according to the procedure described in Chem. 
Pharm. Bull., 28 (1980) 2763) in dry DMF (30 mL) was added NaH (88 mg, 
3.68 mmol) in portions over 30 min at 25-30.degree. C., followed by 
4-fluorobenzaldehyde (228 mg, 1.84 mmol) added dropwise, keeping the 
temperature between 0-15.degree. C. The reaction mixture was stirred at 
room temperature further for 6 h. Ice (200 g) was added to the reaction 
mixture and extracted with EtOAc. The EtOAc layer was washed with water, 
dried over anhydrous Na.sub.2 SO.sub.4 and concentrated to obtain the 
title compound (300 mg, 50%). mp: 168-170.degree. C. 
.sup.1 H NMR (CDCl.sub.3): .delta.9.92 (s, 1H), 8.48 (d, J=8.10 Hz, 1H), 
8.0-7.72 (m, 5H), 7.18 (d, J=8.72 Hz, 2H), 5.39 (s, 2H), 3.88 (s, 3H). 
Preparation 2 
4-[2-[4-Methyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]benzaldehyde: 
##STR30## 
To a stirred suspension of K.sub.2 CO.sub.3 (11.3 g, 82.5 mmol) in dry DMF 
(50 mL) at 25-30.degree. C. was added a solution of 
4-methyl-1(2H)-phthalazinone (6.6 g, 41.25 mmol) (Ref: Chemistry of 
Heterocyclic Compounds; Condensed Pyridazines including Cinnolines and 
Phthalazines, edited by R. N. Castle; John Wiley and Sons, 27, (1973) 
375-441) in dry DMF (100 mL). The reaction mixture was stirred for 30 min 
at 25.degree. C. and 4-(2-bromoethoxy)benzaldehyde (9.4 g, 41.25 mmol) was 
added. The reaction mixture was immersed in a pre-heated oil bath at 
70.degree. C. and stirred at 65-70.degree. C. for 24 h. The reaction 
mixture was cooled to room temperature and water (50 mL) was added. The 
reaction mixture was extracted with EtOAc (3.times.50 mL). The combined 
organic layers were washed with brine, dried over anhydrous Na.sub.2 
SO.sub.4 and concentrated. The crude compound was recrystallised from 
methanol to obtain the title compound (9.7 g, 77%). mp: 90.degree. C. 
.sup.1 H NMR (CDCl.sub.3): .delta.9.85 (s, 1H), 8.46 (d, J=8.10 Hz, 1H), 
7.90-7.20 (m, 5H), 7.03 (d, J=8.50 Hz, 2H), 4.64 (t, J=5.66 Hz, 2H), 4.50 
(t, J=5.66 Hz, 2H), 2.50 (s, 3H). 
Preparation 3 
4-[2-[1-Oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]benzaldehyde: 
##STR31## 
The title compound (700 mg, 44%) was prepared from 1(2H)-phthalazinone 
(800 mg, 5.48 mmol) (Ref: Chemistry of Heterocyclic Compounds; Condensed 
Pyridazines including Cinnolines and Phthalazines, edited by R. N. Castle; 
John Wiley and Sons, 27, (1973) 375-441), 4-[2-bromoethoxy]benzaldehyde 
(1.25 g, 5.48 mmol) and K.sub.2 CO.sub.3 (1.5 g, 10.96 mmol) by a similar 
procedure to that described in preparation 2, mp: 104-106.degree. C. 
.sup.1 H NMR (CDCl.sub.3): .delta.9.87 (s, 1H), 8.46 (d, J=8.10 Hz, 1H), 
8.19 (s, 1H), 7.87-7.69 (m, 5H), 7.04 (d, J 8.72 Hz, 2H), 4.69 (t, J=5.70 
Hz, 2H), 4.53 (t, J=5.70 Hz, 2H). 
Preparation 4 
4-[2-[4-Ethyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]benzaldehyde: 
##STR32## 
The title compound (450 mg, 54%) was prepared from 
4-ethyl-1(2H)-phthalazinone (450 mg, 2.6 mmol) (Ref: Chemistry of 
Heterocyclic Compounds; Condensed Pyridazines including Cinnolines and 
Phthalazines, edited by R. N. Castle; John Wiley and Sons, 27, (1973) 
375-441), 4-[2-bromoethoxy]benzaldehyde (600 mg, 2.6 mmol) and K.sub.2 
CO.sub.3 (720 mg, 5.2 mmol) by a similar procedure to that described in 
preparation 2. mp: 110.degree. C. 
.sup.1 H NMR (CDCl.sub.3): .delta.9.91 (s, 1H), 8.51 (d, J=8.10 Hz, 1H), 
7.92-7.70 (m, 5H), 7.02 (d, J=8.72 Hz, 2H), 4.68 (t, J=5.70 Hz, 2H), 4.50 
(t, J=5.70 Hz, 2H), 2.98 (q, J=7.05 Hz, 2H), 1.36 (t, J=7.05 Hz, 3H). 
Preparation 5 
4-[2-[4-Phenyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]benzaldehyde: 
##STR33## 
The title compound (2.0 g, 85%) was obtained from 
4-phenyl-1(2H)-phthalazinone (1.30 g, 5.85 mmol) (prepared according to 
the procedure described in J. Med. Chem., 36 (1993) 4052), 
4-(2-bromoethoxy)benzaldehyde (1.34 g, 5.85 mmol) and K.sub.2 CO.sub.3 
(1.6 g, 11.7 mmol) by a similar procedure to that described in preparation 
2. mp: 136.degree. C. 
.sup.1 H NMR (CDCl.sub.3): .delta.9.86 (s, 1H), 8.55 (d, J=8.10 Hz, 1H), 
7.85-7.65 (m, 5H), 7.55 (bs, 5H), 7.03 (d, J=8.72 Hz, 2H), 4.75 (t, J=5.70 
Hz, 2H), 4.56 (t, J=5.70 Hz, 2H). 
Preparation 6 
4-[2-[4-Oxo-3,4-dihydro-1H-2,3-benzoxazin-3-yl]ethoxy]benzaldehyde: 
##STR34## 
The title compound (370 mg, 66%) was prepared from 
4-oxo-3,4-dihydro-1H-2,3-benzoxazine (280 mg, 1.87 mmol) (prepared 
according to the procedure described in Tetrahedron, 22 (1966) 2107) and 
4-(2-bromoethoxy)benzaldehyde (430 mg, 1.87 mmol) and K.sub.2 CO.sub.3 
(520 mg, 3.74 mmol). mp: 102.degree. C. 
.sup.1 H NMR (CDCl.sub.3): .delta.9.89 (s, 1H), 8.10 (d, J=7.20 Hz, 1H), 
7.80 (d, J=8.70 Hz, 2H), 7.60-7.40 (m, 2H), 7.10 (d, J=7.0 Hz, 1H), 7.04 
(d, J=8.70 Hz, 2H), 5.11 (s, 2H), 4.35 (t, J=5.0 Hz, 2H), 4.23 (t, J=5.0 
Hz, 2H). 
Preparation 7 
4-[2-[4-Hydroxy-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]benzaldehyde: 
##STR35## 
To a stirred suspension of NaH (76 mg, 3.0 mmol, 95%) in dry DMF (10 mL) 
was added 2,3-dihydropththalazine-1,4-dione (486 mg, 3.0 mmol) (prepared 
according to the procedure described in Bull. Soc. Chim. Belges., 74 
(1965) 91-100) at 25-30.degree. C. and immersed in a preheated oil bath at 
60.degree. C. and stirred for 30 min at 60.degree. C. A solution of 
4-(2-bromoethoxy)benzaldehyde (636 mg, 3.0 mmol) in dry DMF (3 mL) was 
added dropwise and stirred further for 12 h at 60.degree. C. The reaction 
mixture was cooled to room temperature and water (15 mL) was added. The 
reaction mixture was extracted with EtOAc (3.times.10 mL). The combined 
organic layers were washed with brine, dried over anhydrous Na.sub.2 
SO.sub.4 and concentrated. The crude compound was chromatographed on 
silicagel using EtOAc: pet. ether (1:2) as eluent to obtain the title 
compound (465 mg, 48%). 
.sup.1 H NMR (CDCl.sub.3): .delta.10.05 (s, 1H, D.sub.2 O exchangable), 
9.91 (s, 1H), 8.48-8.32 (m, 1H), 8.08-7.92 (m, 1H), 7.92-7.65 (m, 4H), 
7.08 (d, J 8.68 Hz, 2H), 4.71 (t, J=4.56 Hz, 2H), 4.49 (t, J=4.56 Hz, 2H).