Compounds

A compound of formula (I): ##STR1## or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein: PA0 A.sup.1 represents a substituted or unsubstituted aryl group; PA0 A.sup.2 represents a benzene ring having in total up to five substituents; PA0 X represents O, S or NR.sup.1 wherein 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; PA0 Y represents O or S; PA0 R.sup.2 represents hydrogen; PA0 R.sup.3 represents hydrogen or an alkyl, aralkyl or aryl group or R.sup.2 together with R.sup.3 represents a bond; and PA0 n represents an integer in the range of from 2 to 6; a process for preparing such a compound, a pharmaceutical composition comprising such a compound and the use of such compound and composition in medicine.

This invention relates to certain substituted thiazolidinedione 
derivatives, to a process for preparing such compounds, to pharmaceutical 
compositions containing such compounds and to the use of such compounds 
and compositions in medicine. 
European Patent Applications, Publication Numbers 0008203, 0139421, 
0155845, 0177353, 0193256, 0207581, 0208420 and 0306228 relate to 
thiazolidinedione derivatives which are disclosed as having hypoglycaemic 
and hypolipidaemic activity. Chem. Pharm. Bull 30 (10) 3580-3600 also 
relates to certain thiazolidinedione derivatives having hypoglycaemic and 
hypolipidaemic activities. 
It has now surprisingly been discovered that certain novel 
substituted-thiazolidinedione derivatives show improved blood-glucose 
lowering activity and are therefore of potential use in the treatment 
and/or prophylaxis of hyperglycaemia and are of particular use in the 
treatment of Type II diabetes. 
These compounds are also indicated to be of potential use for the treatment 
and/or prophylaxis of other diseases including hyperlipidaemia, 
hypertension, cardiovascular disease and certain eating disorders. 
Accordingly, the present invention provides a compound of formula (I): 
##STR2## 
or a tautomeric form thereof and/or a pharmaceutically acceptable salt 
thereof, and/or a pharmaceutically acceptable solvate thereof, wherein: 
A.sup.1 represents a substituted or unsubstituted aryl group; 
A.sup.2 represents a benzene ring having in total up to five substituents; 
X represents O, S or NR.sup.1 wherein 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; 
Y represents O or S; 
R.sup.2 represents hydrogen; 
R.sup.3 represents hydrogen or an alkyl, aralkyl or aryl group or R.sup.2 
together with R.sup.3 represents a bond; and n represents an integer in 
the range of from 2 to 6. 
Favourably, A.sup.1 represents a phenyl group. 
Suitably R.sup.2 represents hydrogen and R.sup.3 represents an alkyl group, 
in particular a C.sub.1-6 alkyl group, for example a methyl group. 
Suitably, R.sup.2 and R.sup.3 each independently represent hydrogen. 
Suitable substituents for the moiety A.sup.2 include halogen, substituted 
or unsubstituted alkyl or alkoxy. 
Favourably, A.sup.2 represents a moiety of formula (a): 
##STR3## 
wherein R.sup.4 and R.sup.5 each independently represent hydrogen, 
halogen, substituted or unsubstituted alkyl or alkoxy. 
Suitably, R.sup.4 and R.sup.5 each independently represent hydrogen, 
halogen, alkyl or alkoxy. 
Preferably, R.sup.4 and R.sup.5 each represent hydrogen. 
An example of X is O. 
An example of Y is O. 
In one preferred aspect the present invention provides a class of 
compounds, which fall wholly within the scope of formula (I), of formula 
(II): 
##STR4## 
or a tautomeric form thereof, and/or a pharmaceutically acceptable salt 
thereof and/or a pharmaceutically acceptable solvate thereof, wherein 
A.sup.1, X, Y, R.sup.2, R.sup.3 and n are as defined in relation to 
formula (I) and R.sup.4 and R.sup.5 are as defined in relation to formula 
(a). 
Suitably, n represents an integer 2, 3 or 4, notably 2 or 3 and especially 
2. 
Suitably in the moiety NR.sup.1, R.sup.1 represents hydrogen, alkyl, acyl, 
especially acetyl, or benzyl. 
Preferably in the moiety NR.sup.1, R.sup.1 represents a methyl group. 
As indicated above a compound of formula (I) may exist in one of several 
tautomeric forms, all of which are encompassed by the present invention. 
It will be appreciated that the present invention encompasses all of the 
isomeric forms of the compounds of formula (I) and the pharmaceutically 
acceptable salts thereof, including any stereoisomeric forms thereof, 
whether as individual isomers or as mixtures of isomers. 
When used herein the term `aryl` includes phenyl and naphthyl, suitably 
phenyl, optionally substituted with up to five, preferably up to three, 
groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, 
amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, 
alkylcarbonyloxy, or alkylcarbonyl groups. 
When used herein the term `halogen` refers to fluorine, chlorine, bromine 
and iodine; preferably chlorine. 
When used herein the terms `alkyl` and `alkoxy` relate to groups having 
straight or branched carbon chains, containing up to 12 carbon atoms. 
Suitable alkyl groups are C.sub.1-12 alkyl groups, especially C.sub.1-6 
alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl 
or tert-butyl groups. 
Suitable substituents for any alkyl group include those indicated above in 
relation to the term "aryl". 
Suitable pharmaceutically acceptable salts include salts of the 
thiazolidinedione moiety, and, where appropriate, salts of amine groups or 
salts of carboxy groups. 
Suitable pharmaceutically acceptable salts include metal salts, such as for 
example aluminium, alkali metal salts such as sodium or potassium, 
alkaline earth metal salts such as calcium or magnesium and ammonium or 
substituted ammonium salts, for example those with lower alkylamines such 
as triethylamine, hydroxyalkylamines such as 2-hydroxyethylamine, 
bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)amine, cycloalkylamines 
such as bicyclohexylamine, or with procaine, dibenzylpiperidine, 
N-benzyl-.beta.-phenethylamine, dehydroabietylamine, 
N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the 
pyridine type such as pyridine, collidine or quinoline. 
In a further aspect the present invention also provides a process for the 
preparation of a compound of formula (I), or a tautomeric form thereof, 
and/or a pharmaceutically acceptable salt thereof, and/or a 
pharmaceutically acceptable hydrate thereof, which process comprises 
reacting a compound of formula (III): 
##STR5## 
wherein R.sup.2, R.sup.3 and A.sup.2 are as defined in relation to formula 
(I), R.sup.z is hydrogen or a nitrogen protecting group and R.sup.a is a 
moiety convertible to a moiety of formula (b): 
EQU A.sup.1 -X-(CH.sub.2).sub.n -Y- (b) 
wherein A.sup.1, X, Y and n are as defined in relation to formula (I), with 
an appropriate reagent capable of converting R.sup.a into the said moiety 
(b) and thereafter, if required, carrying out one or more of the following 
optional steps: 
(i) converting a compound of formula (I) into a further compound of formula 
(I); 
(ii) removing any protecting group; 
(iii) preparing a pharmaceutically acceptable salt of the compound of 
formula (I) and/or a pharmaceutically acceptable solvate thereof. 
Suitably, R.sup.a represents HY- wherein Y is as defined in relation to a 
compound of formula (I). 
A compound of formula (III), wherein R.sup.2 and R.sup.3 each independently 
represent hydrogen or R.sup.2 and R.sup.3 together represent a bond, may 
be prepared from a compound of formula (IV): 
##STR6## 
wherein A.sup.2 is as defined in relation to the compound of formula (I) 
and R.sup.b is a moiety of formula R.sup.a or a moiety convertible into a 
moiety R.sup.a, by reaction of the compound of formula (IV) with 
2,4-thiazolidinedione; and thereafter, if required, converting a compound 
of formula (III) wherein R.sup.2 together with R.sup.3 represents a bond 
into a compound of formula (III) wherein R.sup.2 and R.sup.3 each 
represent hydrogen and/or converting a moiety R.sup.b into a moiety 
R.sup.a. 
The reaction between the compound of formula (IV) and 2,4-thiazolidinedione 
will of course be carried out under conditions suitable to the nature of 
the compound of formula (IV), in general the reaction being carried out in 
a solvent such as toluene, suitably at an elevated temperature such as the 
reflux temperature of the solvent and preferably in the presence of a 
suitable catalyst such as piperidinium acetate or benzoate. Favourably, in 
the reaction between the compound of formula (IV) and 
2,4-thiazolidinedione, the water produced in the reaction is removed from 
the reaction mixture, for example by means of a Dean and Stark apparatus. 
Suitably, R.sup.b represents R.sup.c Y- wherein Y is as defined above and 
R.sup.c is a protecting group, for example a benzyl group. 
A compound of formula (III), wherein R.sup.2 represents hydrogen and 
R.sup.3 represents hydrogen, an alkyl, aralkyl or aryl group, may be 
prepared by reacting a compound of formula (V): 
##STR7## 
wherein R.sup.b is as defined in relation to formula (IV) and X.sup.2 is a 
halogen atom, with a compound of formula (VI): 
##STR8## 
wherein R.sup.3a represents hydrogen, an alkyl, aralkyl or aryl group and 
R.sup.z is as defined in relation to formula (III); and thereafter if 
required, converting a moiety R.sup.b into a moiety R.sup.a. 
The reaction between the compounds of formula (V) and (VI) may be carried 
out in any suitable solvent, such as 1,2-dimethoxyethane, at any 
temperature providing a convenient rate of formation of the required 
product, suitably at ambient temperature and preferably in the presence of 
a base such as an alkali metal base, for example potassium amide in liquid 
ammonia. 
Suitably, X.sup.2 represents a chlorine atom. 
A compound of formula (V) may be prepared from a compound of formula (VII): 
##STR9## 
wherein A.sup.2 and R.sup.b are as defined in relation to formula (IV), by 
reaction of the compound of formula (VII) with a halogenating reagent. 
Suitable halogenating agents are conventional halogenating agents, for 
example when X.sup.2 represents a chlorine atom, a suitable halogenating 
agent is thionyl chloride. 
The conditions for the reaction between the compound of formula (VII) and 
the halogenating agent will of course depend largely upon the nature of 
the particular halogenating agent chosen, but the conditions are generally 
the conventional conditions appropriate to the particular halogenating 
agent used, for example suitable conditions when the halogenating agent is 
thionyl chloride involve the use of methylene chloride or chloroform as 
solvent and at low to medium temperature for example a reaction 
temperature of between 0.degree. and 30.degree. C. 
The compounds of formula (IV), (V) and (VII) are generally known 
commercially available compounds or are prepared using methods analogous 
to those used to prepare such compounds. 
Suitable protecting groups in any of the abovementioned reactions are those 
used conventionally in the art for example those disclosed in `Protective 
Groups in Organic Synthesis`, Wiley Interscience, 1981, T. W. Greene. 
Thus, for example, a suitable nitrogen protecting group is a benzyl group 
or a benzyloxycarbonyl group and a suitable hydroxyl or thiol protecting 
group is a benzyl group or a p-methoxybenzyl group. 
The methods of formation and removal of such protecting groups are those 
conventional methods appropriate to the molecule being protected and 
includes those methods disclosed in the abovementioned `Protective Groups 
in Organic Synthesis`. 
A compound of formula (I), or a tautomeric form thereof, and/or a 
pharmaceutically acceptable salt thereof and/or a pharmaceutically 
acceptable solvate thereof, may also be prepared by reacting a compound of 
formula (VIII): 
##STR10## 
wherein A.sup.1, A.sup.2, X, Y and n are as defined in relation to formula 
(I), R.sup.6 represents hydrogen and R.sup.7 represents a halogen atom or 
R.sup.6 together with R.sup.7 represents an oxo group, with a compound of 
formula (IX): 
##STR11## 
wherein R.sup.8 represents hydrogen or a group R.sup.3a, as defined in 
relation to formula (VI), and R.sup.z is as defined in relation to formula 
(III), providing that R.sup.8 represents only hydrogen when R.sup.6 
together with R.sup.7 in compound (VIII) represent an oxo group and 
providing that R.sup.8 represents only the group R.sup.3a and R.sup.z 
represents only a protecting group when R.sup.6 represents hydrogen and 
R.sup.7 represents a halogen atom; and thereafter if required carrying out 
one or more of the following optional steps: 
(i) converting a compound of formula (I) into a further compound of formula 
(I); 
(ii) removing any protecting group; 
(iii) preparing a pharmaceutically acceptable salt of a compound of formula 
(I) and/or a pharmaceutically acceptable solvate thereof. 
When R.sup.6 and R.sup.7 in the compound of formula (VIII) together 
represent an oxo group and R.sup.8 in the compound of formula (IX) 
represents hydrogen, the reaction between the compounds of formulae (VIII) 
and (IX) may conveniently be carried out under analogous conditions to 
those described above for the reaction between compounds of formulae (IV) 
and thiazolidinedione. When R.sup.6 represents hydrogen and R.sup.7 
represents a halogen atom in the compound of formula (VIII) and R.sup.8 
represents R.sup.3a in the compound of formula (IX), then the reaction 
between the compounds of formulae (VIII) and (IX) may be carried out using 
analogous conditions to those in the reaction between the compounds of 
formulae (V) and (VI). 
When R.sup.7 represents a halogen atom, it is favourably a chlorine atom. 
A compound of formula (VIII), when R.sup.6 together with R.sup.7 represent 
an oxo group, may be prepared by reacting a compound of formula (X): 
##STR12## 
wherein A.sup.2 is as defined in relation to formula (I) and R.sup.a is as 
defined in relation to formula (III), with an appropriate reagent capable 
of converting R.sup.a into a moiety of the above defined formula (b). 
Suitably R.sup.a represents -YH. 
When R.sup.a represents a hydroxyl group or a thiol group in the compound 
of formula (X) (or a compound of formula (III)), a particularly 
appropriate reagent is a compound of formula (XI): 
EQU A.sup.1 -X-(CH.sub.2).sub.n -R.sup.d (XI) 
wherein A.sup.1, X and n are as defined in relation to a compound of 
formula (I) and R.sup.d represents a displaceable group. 
Suitable displaceable groups include leaving groups or atoms or groups or 
atoms convertible into leaving groups or atoms. 
Suitable leaving groups or atoms include mesyl or tosyl groups and halogen 
atoms such as chlorine or bromine atoms. 
Suitable groups convertible into leaving groups include hydroxy groups. 
Preferably, when X represents -NR.sup.1, R.sup.d represents a hydroxyl 
group. 
The reaction between the compound of formula (X) (or a compound of formula 
(III)) wherein R.sup.a is a hydroxyl group and the reagent of the above 
defined formula (XI) may suitably be carried out in an aprotic solvent, 
such as tetrahydrofuran, at low to medium temperature, for example at 
ambient temperature, and preferably in the presence of a coupling agent 
such as that provided by triphenylphosphine and diethyl azodicarboxylate. 
The reaction between the compound of formula (X) (or a compound of formula 
(III)) wherein R.sup.a is a hydroxyl group or a thiol group, and the 
reagent of the abovedefined formula (XI) may be carried out in an aprotic 
solvent, such as dimethylformamide, at a low to elevated temperature, for 
example in the range of from 50.degree. C. to 120.degree. C. and 
preferably in the presence of a base, such as sodium hydride. 
The reagent of formula (XI) may be prepared by reacting a compound of 
formula (XII): 
A.sup.1 -X-H (XII) 
wherein A.sup.1 and X as defined in relation to formula (I), with a 
compound of formula (XIII): 
EQU R.sup.d -(CH.sub.2).sub.n -R.sup.e (XIII) 
wherein R.sup.d is as defined in relation to formula (XI) and R.sup.e 
represents R.sup.d or a group OR.sup.f wherein R.sup.f is hydrogen or a 
hydroxyl protecting group; and thereafter where necessary removing any 
protecting group. 
Suitably, R.sup.d represents a halogen atom such as a chlorine or a bromine 
atom. 
The reaction between the compounds of formulae (XII) and (XIII) may be 
carried out in any suitable solvent, such as ethanol at any temperature 
providing a convenient rate of formation of the required product, such as 
a temperature in the range of from 30.degree. C. to the reflux temperature 
of the solvent. 
In one alternative aspect, a compound of formula (XI) when X represents 
NR.sup.1, n is 2 and R.sup.d is a hydroxyl, mesyl or tosyl group may be 
prepared by reacting a compound of the above defined formula (XII) with 
epoxyethane and thereafter if required converting the hydroxyl group to 
the mesyl or tosyl group. 
The reaction between the compound of formula (XI) and epoxyethane may be 
carried out in any suitable solvent, such as toluene at any temperature 
providing a convenient rate of formation of the required product, such as 
a temperature in the range of from 0.degree. to 30.degree. C. 
The compounds of formula (VI) and (IX) are known available compounds or 
they may be prepared according to methods used to prepare such compounds, 
for example those methods disclosed in DE 3045059. 
The compounds of formula (X) are known compounds or they are compounds 
prepared by methods analogous to those used to prepare known compounds, 
for example 4-hydroxybenzaldehyde is a known commercially available 
compound and 4-mercaptobenzaldehyde may be prepared as outlined in 
Beilstein 8.I.533. 
Conveniently, the compounds of formula (XI) wherein R.sup.d represents a 
mesyl or tosyl group may be prepared from the corresponding compound 
wherein R.sup.d is a hydroxy group, by means of known mesylation or 
tosylation methods. 
The compounds of formula (XI) wherein X represents O or S and n represents 
2 are either commercially available, as for example are those wherein 
R.sup.d represents chlorine, bromine or a hydroxy group and A.sup.1 is 
phenyl. 
When X represents NR.sup.1 in the compounds of formula (III) or (X), a 
suitable value for R.sup.a is a group A.sup.1 -NR.sup.1 
-CO-(CH.sub.2).sub.n-1 -Y- wherein A.sup.1, R.sup.1, Y and n are as 
defined in relation to formula (I), but especially when n represents 2. 
The group A.sup.1 -NR.sup.1 -CO-(CH.sub.2).sub.n-1 -Y- may be converted 
into a moiety of the abovedefined formula (b) by conventional reducing 
methods, for example by using complex metal hydride reduction using such 
as lithium aluminiium hydride in an aprotic solvent, such as 
tetrahydrofuran, at any temperature providing a convenient rate of 
formation of the required product, suitably at an elevated temperature for 
example at the reflux temperature of the solvent, and where appropriate in 
an inert atmosphere. 
When R.sup.a represents a group A.sup.1 -NR.sup.1 -CO-(CH.sub.2).sub.n-1 
-Y-, a suitable value for R.sup.b is a group of formula X.sup.3 
-CO-(CH.sub.2).sub.n-1 -Y- wherein Y and n are as defined in relation to 
formula (I), but preferably n is 2, and X.sup.3 represents a halogen atom, 
preferably a chlorine atom. 
A suitable reagent for converting a group X.sup.3 -NR.sup.1 
-CO-(CH.sub.2).sub.n-1 -Y- into A.sup.1 -NR.sup.1 -CO-(CH.sub.2).sub.n-1 
-Y- is a compound of formula (XIIA) 
EQU A.sup.1 -NR.sup.1 H (XIIA) 
wherein A.sup.1 and R.sup.1 are as defined in relation to formula (I). 
Reaction conditions are conventional conditions appropriate to the reacting 
compounds: Thus a compound of formula (X), wherein X represents the 
abovedefined group A.sup.1 -NR.sup.1 -CO-(CH.sub.2).sub.n-1 -Y-may be 
prepared by reacting a compound of formula (IVA): 
##STR13## 
wherein A.sup.2, X.sup.3, Y and n are as defined above, with a compound of 
the abovedefined formula (XIIA). 
Preferably, the --CHO group of the compound of formula (IVA) is in 
protected form. Formation and removal of the protected --CHO group being 
effected by conventional reagents and procedures. 
The reaction between compounds of formulae (IVA) and (XIIA) may be carried 
out in an inert solvent, such as benzene, at any temperature providing a 
convenient rate of formation of the required product, suitably at an 
elevated temperature, such as the reflux temperature of the solvent. 
A compound of formula (IVA) may be prepared by halogenation of a compound 
of formula (IVB): 
##STR14## 
wherein A.sup.2, Y and n are as defined above, but preferably n is 2. 
The halogenation of (IVB) may be carried out using conventional 
halogenation procedures, for example by the use of a thionyl halide in an 
inert solvent such as benzene. 
In the halogenation of (IVB) the --CHO group is generally transformed into 
a dihalomethyl group. In our hands this was a suitable protected form of 
the --CHO group as preferred in the reaction between compound of formula 
(IVA) with the compound of formula (XIIA). The --CHO group is suitably 
regenerated by hydrolysis with a mild base suitably by treatment with an 
aqueous solution of an amine, for example hexamine, at an elevated 
temperature, conveniently the reflux temperature of the solvent. 
A compound of formula (VIII) wherein R.sup.6 represents hydrogen and 
R.sup.7 represents a halogen atom, may be prepared by reacting a compound 
of formula (XIV): 
##STR15## 
wherein A.sup.1, A.sup.2, X, Y and n are as defined in relation to formula 
(I), with a halogenating agent. 
Suitable halogenating agents are conventional halogenating agents, for 
example when R.sup.7 represents a chlorine atom, a suitable halogenating 
agent is thionyl chloride. 
The conditions for the reaction between the compound of formula (XIV) and 
the halogenating agent will of course depend largely upon the nature of 
the particular halogenating agent chosen, but the conditions are generally 
the conventional conditions appropriate to the particular halogenating 
agent used, for example suitable conditions when the halogenating agent is 
thionyl chloride involve the use of methylene chloride or chloroform as 
solvent and at low to ambient temperature, for example a reaction 
temperature of between 0.degree. and 30.degree. C. 
A compound of formula (XIV) may be prepared by reacting a compound of 
formula (XV): 
##STR16## 
wherein A.sup.2 and R.sup.a are as defined in relation to formula (III), 
with an appropriate reagent capable of converting a moiety R.sup.a into a 
moiety of the above defined formula (b). 
The nature of the moiety R.sup.a, the nature of the appropriate reagent and 
suitable reaction conditions for the reaction between the compound of 
formula (XV) and the appropriate reagent are as described above for the 
reaction between a compound of formula (III) and the appropriate reagent. 
Where necessary a compound of formula (XV) may be prepared from a compound 
of the abovedefined formula (VII), by converting a moiety R.sup.b into a 
moiety R.sup.a, using methods hereinbefore described. 
The abovementioned conversion of a compound of formula (I) into a further 
compound of formula (I) includes the following conversions: 
(a) reducing a compound of formula (I) wherein R.sup.2 and R.sup.3 together 
represent a bond, to a compound of formula (I) wherein R.sup.2 and R.sup.3 
each represent hydrogen; 
(b) converting one group R.sup.1 into another group R.sup.1 ; and 
(c) converting a compound of formula (I) wherein R.sup.3 represents 
hydrogen into a compound of formula (I) wherein R.sup.3 represents an 
alkyl, aralkyl or aryl group. 
The conversion of a compound of formula (I) into a further compound of 
formula (I) may be carried out by using any appropriate conventional 
procedure. 
A suitable reduction method for the abovementioned conversion (a) includes 
catalytic reduction or the use of a metal/solvent reducing system. 
Suitable catalysts for use in the catalytic reduction are palladium on 
carbon catalysts, preferably a 10% palladium on charcoal catalyst; the 
reduction being carried out in a solvent, for example dioxan, suitably at 
ambient temperature. 
Suitable metal/solvent reducing systems include magnesium in methanol. 
The abovementioned reduction of a compound of formula (III) wherein R.sup.2 
and R.sup.3 together represent a bond to a compound of formula (III) 
wherein R.sup.2 and R.sup.3 each represent hydrogen, may be carried out 
under analogous conditions to those referred to above in conversion (a) of 
the compound of formula (I). 
In the abovementioned conversion (b), suitable conversions of one group 
R.sup.1 into another group R.sup.1 includes converting a group R.sup.1 
which represents hydrogen into a group R.sup.1 which represents an acyl 
group. 
The conversion of a compound of formula (I) wherein R.sup.1 represents 
hydrogen into a compound of formula (I) wherein R.sup.1 represents acyl 
may be carried out using any appropriate conventional acylation procedure, 
such as by treating an appropriately protected compound of formula (I) 
with an acylating agent. For example acetic anhydride may be used to 
prepare the compound of formula (I) wherein R.sup.1 is acetyl. 
In the abovementioned conversion (c), a compound of formula (I) wherein 
R.sup.3 represents hydrogen may be converted into a compound of formula 
(I) wherein R.sup.3 represents an alkyl, aralkyl or aryl group by reacting 
the appropriate compound of formula (I) with a compound of formula (XVI): 
EQU R.sup.3a -X.sup.2 (XVI) 
wherein R.sup.3a represents an alkyl, aralkyl or an aryl group and X.sup.2 
represents a halogen atom, such as a chlorine atom. 
The reaction between the appropriate compound of formula (I) and the 
compound of formula (XVI) may be carried out in any suitable solvent, such 
as 1,2-dimethoxyethane, at any temperature providing a convenient rate of 
formation of the required product, suitably at ambient temperature, and 
preferably in the presence of a base such as an alkali metal base, for 
example potassium amide in liquid ammonia. 
It will be appreciated that in the abovementioned conversions (a), (b) and 
(c) any reactive group in the compound of formula (I) may be protected 
where necessary, according to conventional chemical practice. 
Where appropriate the isomeric forms of the compounds of formula (I) and 
the pharmaceutically acceptable salts thereof may be prepared as 
individual isomers using conventional chemical procedures. 
The compounds of formula (III), (VIII) and (XIV) are believed to be novel 
compounds and as such form a further aspect of the invention. 
The compounds of formula (XII), (XIII), (XV) and (XVI) are known 
commercially available compounds or they may be prepared according to 
methods analogous to those used to prepare known compounds. 
As mentioned above the compounds of the invention are indicated as having 
useful therapeutic properties: The present invention accordingly provides 
a compound of formula (I), or a tautomeric form thereof and/or a 
pharmaceutically acceptable salt thereof and/or a pharmaceutically 
acceptable solvate thereof, for use as an active therapeutic substance. 
Thus the present invention provides a compound of formula (I), or a 
tautomeric form thereof and/or a pharmaceutically acceptable salt thereof 
and/or a pharmaceutically acceptable solvate thereof, for use in the 
treatment of and/or prophylaxis of hyperglycaemia. 
In a further aspect the present invention also provides a compound of 
formula (I), or a tautomeric form thereof and/or a pharmaceutically 
acceptable salt thereof and/or a pharmaceutically acceptable solvate 
thereof, for use in the treatment and/or prophylaxis of hyperlipidaemia. 
As indicated hereinbefore the present invention also provides a compound of 
formula (I) or a tautomeric form thereof and/or a pharmaceutically 
acceptable salt thereof and/or a pharmaceutically acceptable solvate 
thereof for use in the treatment of hypertension, cardiovascular disease 
and certain eating disorders. 
A compound of formula (I), or a tautomeric form thereof and/or a 
pharmaceutically acceptable salt thereof and/or a pharmaceutically 
acceptable solvate thereof, may be administered per se or, preferably, as 
a pharmaceutical composition also comprising a pharmaceutically acceptable 
carrier. 
Accordingly, the present invention also provides a pharmaceutical 
composition comprising a compound of the general formula (I), or a 
tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or 
a pharmaceutically acceptable solvate thereof, and a pharmaceutically 
acceptable carrier therefor. 
As used herein the term `pharmaceutically acceptable` embraces compounds, 
compositions and ingredients for both human and veterinary use: for 
example the term `pharmaceutically acceptable salt` embraces a 
veterinarily acceptable salt. 
The composition may, if desired, be in the form of a pack accompanied by 
written or printed instructions for use. 
Usually the pharmaceutical compositions of the present invention will be 
adapted for oral administration, although compositions for administration 
by other routes, such as by injection and percutaneous absorption are also 
envisaged. 
Particularly suitable compositions for oral administration are unit dosage 
forms such as tablets and capsules. Other fixed unit dosage forms, such as 
powders presented in sachets, may also be used. 
In accordance with conventional pharmaceutical practice the carrier may 
comprise a diluent, filler, disintegrant, wetting agent, lubricant, 
colourant, flavourant or other conventional adjuvant. 
Typical carriers include, for example, microcrystalline cellulose, starch, 
sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, 
magnesium stearate, sodium lauryl sulphate or sucrose. 
Most suitably the composition will be formulated in unit dose form. Such 
unit dose will normally contain an amount of the active ingredient in the 
range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more 
especially 0.1 to 250 mg. 
The present invention further provides a method for the treatment and/or 
prophylaxis of hyperglycaemia in a human or non-human mammal which 
comprises administering an effective, non-toxic, amount of a compound of 
the general formula (I), or a tautomeric form thereof and/or a 
pharmaceutically acceptable salt thereof and/or a pharmaceutically 
acceptable solvate thereof to a human or non-human mammal in need thereof. 
The present invention further provides a method for the treatment of 
hyperlipidaemia and/or hypertension and/or cardiovascular disease and/or 
certain eating disorders in a human or non-human mammal, which comprises 
administering an effective, non-toxic, amount of a compound of formula 
(I), or a tautomeric form thereof and/or a pharmaceutically acceptable 
salt thereof and/or a pharmaceutically acceptable solvate thereof, to a 
human or non-human mammal in need thereof. 
Conveniently, the active ingredient may be administered as a pharmaceutical 
composition hereinbefore defined, and this forms a particular aspect of 
the present invention. 
In the treatment and/or prophylaxis of hyperglycaemia in humans, and/or the 
treatment and/or prophylaxis of hyperlipidaemia in humans, the compound of 
the general formula (I), or a tautomeric form thereof and/or a 
pharmaceutically acceptable salt thereof and/or a pharmaceutically 
acceptable solvate thereof, may be taken in doses, such as those described 
above, one to six times a day in a manner such that the total daily dose 
for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, 
and more usually about 1 to 1500 mg. 
In the treatment and/or prophylaxis of hyperglycaemia in non-human mammals, 
especially dogs, the active ingredient may be administered by mouth, 
usually once or twice a day and in an amount in the range of from about 
0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg. Similar dosage 
regimens are suitable for the treatment and/or prophylaxis of 
hyperlipidaemia in non-human mammals. 
The dosages regimens for the treatment of hypertension, cardiovascular 
disease and eating disorders will generally be those mentioned above in 
relation to hyperglycaemia. 
In a further aspect the present invention provides the use of a compound of 
formula (I), or a tautomeric form thereof and/or a pharmaceutically 
acceptable salt thereof and/or a pharmaceutically acceptable solvate 
thereof, for the manufacture of a medicament for the treatment and/or 
prophylaxis of hyperglycaemia. 
The present invention also provides the use of a compound of formula (I), 
or a tautomeric form thereof and/or a pharmaceutically acceptable salt 
thereof, and/or a pharmaceutically acceptable solvate thereof, for the 
manufacture of a medicament for the treatment and/or prophylaxis of 
hyperlipidaemia, hypertension, cardiovascular disease or certain eating 
disorders.

The following Procedures and Examples illustrate the invention but do not 
limit it in any way. 
PROCEDURE 1 
4-[2-Phenoxyethoxy]benzaldehyde 
##STR17## 
4-Hydroxybenzaldehyde (7.4 g) was dissolved in dry dimethylformamide (200 
ml) and sodium hydride (2.42 g; 60% dispersion in oil) was added 
portionwise. After stirring under nitrogen for one hour at room 
temperature, a solution of .gamma.-bromophenetole (12.16 g) in dry 
dimethylformamide (50 ml) was added and the reaction mixture was heated 
overnight at 80.degree. C. The mixture was cooled and excess solvent 
evaporated off. The residue was added to 10% sodium hydroxide solution and 
extracted with ethyl acetate (3.times.200 ml). The combined organic 
extracts were washed with 10% sodium hydroxide solution (200 ml), water 
(2.times.200 ml), brine (2.times.200 ml) dried (MgSO.sub.4,) filtered and 
evaporated to dryness to give the title product. 
.sup.1 H NMR.delta.(CDCl.sub.3) 
4.35 (4H, s); 6.9-7.4 (7H, complex); 8.9 (2H, d); 10.0 (1H, s). 
PROCEDURE 2 
4-[(N-Methyl-N-phenylamino)carbonylmethoxy]benzaldehyde 
##STR18## 
(i) Thionyl chloride (36.7 g, 22.5 ml) was added dropwise to a stirred, 
ice-cooled suspension of 4-carboxymethoxybenzaldehyde (9.00 g) in dry 
benzene (100 ml) containing pyridine (2.5 ml). The resulting mixture was 
heated at reflux for 2 hours, then cooled and the solvent evaporated. The 
residue containing impure 4-(dichloromethyl)phenoxyacetyl chloride was 
used in the next stage of the procedure without further purification. 
(ii) A solution of N-methylaniline (5.44 g, 5.5 ml) in dry benzene (100 ml) 
was added dropwise to a stirred suspension of the acid chloride (part (i) 
above) in benzene (100 ml). The resulting mixture was heated at reflux for 
16 hours, then cooled and the solvent evaporated. The residue was 
dissolved in N,N-dimethylformamide (120 ml) at 60.degree. C., and a 
solution of hexamine (8.4 g) in water (100 ml) added. The mixture was 
heated at reflux and stirred vigorously for 1 hours, cooled and diluted 
with water (1l), acidified with dilute hydrochloric acid and extracted 
with ethyl acetate (3.times.300 ml). The combined organic solutions were 
washed with water (4.times.1l) and the brine (1l), dried (MgSO.sub.4) and 
evaporated. The resulting gum was chromatographed on silica gel with 1% 
methanol in dichloromethane to afford the title compound, mp 97-100&lt;C. 
.sup.1 H NMR (CDCl.sub.3) 
3.22 (3H, s); 4.50 (2H, s); 6.80 (2H, d); 6.90-7.80 (7H, complex); and 9.75 
(1H, s). 
PROCEDURE 3 
4-[2-(N-Methyl-N-phenylamino)ethoxy]benzyl alcohol. 
##STR19## 
A solution of 4-[N-Methyl-N-phenylamino)carbonylmethoxy]-benzaldehyde (8.25 
g) in dry tetrahydrofuran (300 ml) was added dropwise to a mechanically 
stirred, ice-cooled slurry of lithium aluminium hydride (5.90 g) in dry 
tetrahydrofuran (100 ml) under a nitrogen atmosphere. The resulting 
mixture was heated at reflux for 9 hours and then cooled in ice and 
cautiously quenched by the addition of water (6 ml), sodium hydroxide 
solution (10% w/v, 6 ml) and water (18 ml). After being refluxed for a 
further 30 minutes, the mixture was filtered through a Soxhlet thimble and 
the residue extracted with refluxing tetrahydrofuran for 3 hours. The 
solvent was evaporated and the residue chromatographed on silica gel with 
1.5% methanol in dichloromethane as solvent to yield the title compound as 
an oil. 
.sup.1 H NMR (CDCl.sub.3) 
1.80 (1H,s, exchanges with D.sub.2 O); 3.10 (3H,s); 3.75 (2H,t); 4.15 
(2H,t); 4.60 (2H,s); and 6.70-7.40 (9H, complex). 
PROCEDURE 4 
4-[2-(N-Methyl-N-phenylamino)ethoxy]benzaldehyde 
##STR20## 
A mixture of 4-[2-(N-methyl-N-phenylamino)ethoxy]benzyl alcohol (3.36 g), 
manganese (IV) oxide (11.3 g) and dichloromethane (150 ml) were stirred at 
room temperature overnight. The mixture was filtered through a Soxhlet 
thimble and the residue extracted with refluxing dichloromethane for 2.5 
hours. The solvent was evaporated to afford the title compound, an oil, 
which was used without further purification. 
.sup.1 H NMR (CDCl.sub.3) 3.10 (3H,s); 3.80 (2H,t); 4.27 (2,t); 6.70-7.50 
(7H, complex); 7.90 (2H, d); and 10.00 (1H,s). 
EXAMPLE 1 
5-[4-2-Phenoxyethoxy)benzylidene]-2, 4-thiazolidinedione 
##STR21## 
A solution of 4-[(2-phenoxyethoxy]benzaldehyde (14.2 g) and 
2,4-thiazolidinedione (7.9 g) in toluene (400 ml) containing a catalytic 
amount of piperidiniumacetate was boiled under reflux in a Dean and Stark 
apparatus for 2 hours. The mixture was cooled and filtered and the 
filtered solid was dried to give the title compound (mp 223.degree. C.). 
.sup.1 H NMR.delta.(DMSO-d.sub.6) 4.35 (4H,s); 6.9-7.75 (10 H, complex); 
12.0 (.sup.1 H, broad s, exchanges with D.sub.2 O). 
EXAMPLE 2 
5-[4-(2-Phenoxyethoxy)benzyl]-2,4-thiazolidinedione 
##STR22## 
5-[4-(2-Phenoxyethoxy)benzylidene]-2,4-thiazolidinedione (4 g) in dry 
1,4-dioxan (200 ml) was reduced under hydrogen in the presence of 10% 
palladium on charcoal (8 g) at ambient temperature and atmospheric 
pressure until hydrogen uptake ceased. The solution was filtered through 
diatomaceous earth, the filter pad was washed exhaustively with dioxan and 
the combined filtrates were evaporated to dryness under vacuum. The title 
compound (mp 133.degree. C.) was obtained after crystallisation from 
methanol. 
.sup.1 H NMR.delta.(DMSO-d.sub.6) 3.0-3.4 (2H, complex); 4.3 (4H, s); 4.85 
(1H, complex); 6.9-7.35 (9H, complex); 12.0 (1H, broad s, exchanges with 
D.sub.2 O). 
EXAMPLE 3 
5-(4-[2-N-Methyl-N-phenylamino)ethoxy]benzylidene)-2, 4-thiazolidinedione. 
##STR23## 
A mixture of 4-[2-(N-methyl-N-phenylamino)ethoxy]-benzaldehyde (2.99 g), 
2,4-thiazolidinedione (1.50 g), piperidine (0.18 ml) and benzoic acid 
(0.18 g) were heated at reflux in toluene (250 ml) in a Dean and Stark 
apparatus for 3.5 hours. The mixture was cooled and the resulting solid 
filtered off, washed with cold toluene an dried under vacuum to afford the 
title compound, mp 162.degree.-163.degree. C. 
.sup.1 H NMR (CDCl.sub.3 :DMSO-d.sub.6 1:1) 3.05 (3H,s); 3.72 (2H,t); 4.20 
(2H,t); 6.50-7.80 (10 H, complex); and 12.40 (1H, br s, exchanges with 
D.sub.2 O). 
EXAMPLE 4 
5-(4-[2-(N-Methyl-N-phenylamino)ethoxy]benzyl-2,4-thiazolidinedione. 
##STR24## 
5-(4-[2-(N-Methyl-N-phenylamino)ethoxy]benzylidene)-2,4-thiazolidinedione 
(3.2 g) was suspended in dioxan (300 ml) and hydrogenated over 10% 
palladium-charcoal (3.4 g) for 7.25 hours at room temperature and 
pressure. A further portion of catalyst (3.4 g) was added, and reduction 
continued for a total of 48 hours. The reaction mixture was filtered 
through diatomaceous earth and the solvent evaporated. The resulting gum 
was chromatographed on silica gel with 1% methanol in dichloromethane to 
afford the title compound as a low-melting foam. 
.sup.1 H NMR (CDCl.sub.3) 3.00 (3H,s); 3.05 (1H,dd); 3.37 1H,dd); 3.70 
(2H,t); 4.15 (2H,t); 4.47 (1H,dd); 6.65-7.40 (9H, complex); and 9.00 (1H, 
br s, exchanges with D.sub.2 O). 
EXAMPLE 5 
5(4-[2-(N-Methyl-N-phenylamino)ethoxy]benzyl)-2,4-thiazolidinedione, sodium 
salt. 
Sodium hydride (60% dispersion in oil; 0.27 g) was added to a stirred, 
ice-cooled solution of 
5-(4-[2-(N-Methyl-N-phenylamino)ethoxy]benzyl-2,4-thiazolidinedione (2.39 
g) in methanol (10 ml). The mixture was stirred for 5 minutes at 0.degree. 
C., then filtered. The resulting solid was washed with dry diethyl ether 
and dried under vacuum at 40.degree. C. The title compound darkens at 
270.degree. C., and decomposes above 290.degree. C. 
.sup.1 H NMR (DMSO-d.sub.6) 2.58 (1H,dd); 2.96 (3H,s); 3.31 (1H,dd); 3.69 
(2H,t); 4.07 (3H, complex); and 6.55-7.45 (9H, complex). 
DEMONSTRATION OF EFFICACY OF COMPOUNDS 
Obese Mice, Oral Glucose Tolerance Test 
C57bl/6 obese (ob/ob) mice were fed on powdered oxoid diet. After at least 
one week, the mice continued on a powdered oxoid diet or were fed powered 
oxoid diet containing the test compound. After 8 days on the supplemented 
diet all of the mice were fasted for 5 hours prior to receiving an oral 
load of glucose (3 g/kg). Blood samples for glucose analysis were taken 0, 
45, 90 and 135 minutes after glucose administration and the results appear 
below as the percentage reduction in area under the blood glucose curve 
where test compound treated groups are compared with the control groups. 7 
mice were used for each treatment. 
______________________________________ 
LEVEL IN DIET % REDUCTION IN 
EXAMPLE (.mu.mol kg.sup.-1 of 
AREA UNDER BLOOD 
NO: DIET) GLUCOSE CURVE 
______________________________________ 
2 300 19 
5 300 48 
______________________________________ 
Toxicology 
No toxicological effects were indicated for any of the compounds of the 
invention in any of the abovementioned tests.