##STR1## A compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, wherein R.sup.0 represents a substituted or unsubstituted aryl group; R.sup.1 represents hydrogen or an alkyl group; R.sup.2 represents a moiety of formula (a) wherein R.sup.4 and R.sup.5 each independently represent hydrogen, alkyl, hydroxyalkyl, cycloalkyl or R.sup.4 together with R.sup.5 represents (CH.sub.2).sub.n wherein n is 2, 3 or 4; T represents hydrogen, nitrile or a group --CO.R.sup.s wherein R.sup.s represents hydroxy, alkoxy or a group --NR.sup.t R.sup.u wherein R.sup.t and R.sup.u independently represent hydrogen, alkyl or R.sup.t and R.sup.u together with the nitrogen to which they are attached represent a saturated heterocyclic group; and R.sup.3 represents hydrogen, halogen, alkyl or alkoxy; a process for the preparation of such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine.

This application was filed under 35 U.S.C. 371 and is a continuation of PCT 
International Application No. PCT/GB93/01554, filed on Jul. 22, 1993. 
This invention relates to novel compounds, to a process for preparing such 
compounds, to pharmaceutical compositions containing such compounds and to 
the use of such compounds and compositions in medicine and agriculture. 
European patent application, publication number 0455006 discloses certain 
arylethanolamine derivatives which are stated to possess anti-diabetic 
and/or anti-hyperglycaemic and/or anti-obesity activity. 
It has been discovered that a series of novel phosphonated arylethanolamine 
derivatives have good .beta.-adrenoreceptor agonist activity and in 
particular show good selectivity for .beta..sub.3 -adrenoreceptors versus 
.beta..sub.1 - or .beta..sub.2 -adrenoreceptors. These compounds are 
therefore indicated to have good anti-hyperglycaemic and/or anti-obesity 
activity coupled with especially good selectivity from cardiac and 
tremorigenic side effects. 
They are also indicated to have potential in the treatment of 
gastrointestinal dims such as irritable bowel syndrome. 
These compounds also have potential as grog promoters for livestock and for 
decreasing birth mortality rate and increasing the post-natal survival 
rate in livestock. These compounds may also be of use in increasing the 
high-density-lipoprotein (HDL) cholesterol concentration and decreasing 
the triglyceride concentration in human blood serum and are therefore of 
potential use in the treatment and/or prophylaxis of atherosclerosis. They 
are also indicated to be useful for the treatment of hyperinsulinaemia. 
Accordingly the present invention provides a compound of formula (I): 
##STR2## 
or a pharmaceutically acceptable salt, ester or amide thereof, or a 
pharmaceutically acceptable solvate thereof, 
wherein, 
R.sup.o represents a substituted or unsubstituted aryl group; 
R.sup.1 represents hydrogen or an alkyl group; 
R.sup.2 represents a moiety of formula (a): 
##STR3## 
wherein R.sup.4 and R.sup.5 each independently represent hydrogen, alkyl, 
hydroxyalkyl, cycloalkyl or R.sup.4 together with R.sup.5 represents 
(CH.sub.2).sub.n wherein n is 2, 3 or 4; 
T represents hydrogen, nitrile or a group --CO.R.sup.s wherein R.sup.s 
represents hydroxy, alkoxy or a group --NR.sup.t R.sup.u wherein R.sup.t 
and R.sup.u independently represent hydrogen, alkyl or R.sup.t and R.sup.u 
together with the nitrogen to which they are attached represent a 
saturated heterocyclic group; and 
R.sup.3 represents hydrogen, halogen, alkyl or alkoxy. 
Suitably, R.sup.o represents a phenyl group optionally substituted with 
halogen or a hydroxy, examples include chlorophenyl, especially 
3-chlorophenyl, and hydroxyphenyl, especially 3,4-bis-hydroxyphenyl. 
Suitably, R.sup.1 is an alkyl group. 
When R.sup.1 is alkyl, it is favourably a C.sub.1-6 alkyl group, especially 
a methyl group. 
Suitably, R.sup.4 and R.sup.5 each independently represent alkyl, for 
example ethyl propyl, or butyl. 
Preferably, R.sup.4 is alkyl, for example ethyl, propyl or butyl, 
especially ethyl, and R.sup.5 is hydrogen. 
Suitably, R.sup.3 represents hydrogen. 
Suitably, T represents hydrogen or a group --CO.R.sup.s wherein R.sup.s is 
hydroxy or alkoxy. 
Preferably, T represents hydrogen. 
The compounds of formula (I) have one or two asymmetric carbon atoms, 
marked with an asterisk (*) or two asterisks (**) in the formula. These 
compounds may therefore exist in up to four stereoisomeric forms. The 
present invention encompasses all stereoisomers of the compounds of the 
general formula (I) whether free from other isomers, or admixed with other 
isomers in any proportion, such as mixtures of diastereoisomers and 
racemic mixtures of enantiomers. 
Preferably, the asymmetric carbon atom indicated by a single asterisk (*) 
is in the R-configuration. 
Preferably, the asymmetric carbon atom indicated by two asterisks (**) is 
in the R-configuration. 
One suitable form of a compound of formula (I) is a diastereomeric mixture 
of the RR and SS enantiomers. 
One preferred form of a compound of formula (I) is the RR enantiomer. 
The term `alkyl` when used alone or when forming part of other groups (such 
as the `alkoxy` group) includes straight- or branched-chain alkyl groups 
containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples 
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or 
tert-butyl group. 
The term `cycloalkyl` includes C.sub.3-8 cycloalkyl groups, especially 
C.sub.5 or C.sub.6 cycloalkyl groups. 
When used herein the term "halogen" refers to fluorine, chlorine, bromine 
and iodine, preferably chlorine. 
When used herein the term `aryl` includes phenyl and naphthyl optionally 
substituted with up to five, preferably up to three, groups selected from 
halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, 
nitro, carboxy and pharmaceutically acceptable salts, esters and amides 
thereof, alkoxycarbonylalkyl, alkylcarbonyloxy and alkylcarbonyl groups. 
A preferred aryl group is a substituted or unsubstituted phenyl group. 
Preferred optional substituents for the aryl group include up to three 
substituents selected from halogen, hydroxy, alkoxy, hydroxyalkyl and 
amino. 
Suitable pharmaceutically acceptable esters of carboxyl groups include 
alkyl esters, especially C.sub.1-6 alkyl esters such as methyl. 
Suitable pharmaceutically acceptable amides are those of formula 
--CONR.sup.x R.sup.y wherein R.sup.x and R.sup.y each independently 
represent hydrogen, alkyl or alkoxyalkyI. 
Suitable pharmaceutically acceptable salts include acid addition salts, 
salts of carboxy groups and salts of phosphonic acid groups. 
Suitable pharmaceutically acceptable acid addition salts include salts with 
inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, 
orthophosphoric acid or sulphuric acid, or with organic acids such, for 
example, as methanesulphonic acid, toluenesulphonic acid, acetic acid, 
propionic acid, lactic acid, citric acid, fumaric acid, malic acid, 
succinic acid, salicylic acid, maleic acid or acetylsalicylic acid. 
Suitable pharmaceutically acceptable salts of carboxy groups or phosphonic 
acid groups 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 C.sub.1-6 alkylamines such as methylamine, 
hydroxy-C.sub.1-6 alkylamines such as 2-hydroxyethylamine, his-(2- 
hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such 
as bicyclohexylamine, or with procaine, dibenzylpiperidine, 
N-benzyl-.beta.-phenethylamine, deehydroabietylamine, 
N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the 
pyridine type such as pyridine, collidine or quinoline. 
Suitable pharmaceutically acceptable solvates are conventional solvates, 
preferably hydrates. 
The invention also provides a process for the preparation of a compound of 
formula (I), or a pharmaceutically acceptable salt, ester or amide thereof 
or a pharmaceutically acceptable solvate thereof, which process comprises 
reducing a compound of formula (II): 
##STR4## 
wherein R.sup.o, R.sup.1, R.sup.2 and R.sup.3 are as defined in relation 
to formula (I), and thereafter, if necessary, carrying out one or more of 
the following optional steps: 
(i) converting one compound of formula (I) to another compound of formula 
(I); and 
(ii) preparing a pharmaceutically acceptable salt, ester or amide thereof 
of a compound of formula (I) or a pharmaceutically acceptable solvate 
thereof. 
The reduction of the compound of formula (II) may be carried out using any 
suitable reduction procedure, for example by using catalytic reduction in 
the presence of hydrogen. 
Suitable catalysts include platinum oxide or 10% palladium on charcaol. 
Suitable reduction conditions include using an alkanolic solvent such as 
methanol, at any temperature providing a convenient rate of formation of 
the required product, for example when using the platinum catalyst the 
reaction may conveniently be carried out at ambient temperature or when 
using the palladium catalyst the reaction may be carried out at a medium 
temperature such as 50.degree. C., under a pressure of 1-5 atmospheres of 
hydrogen. 
The compound of formula (II) may be prepared by reacting a compound of 
formula (III): 
##STR5## 
wherein R.sup.o is as defined in relation to formula (I) with a compound 
of formula (IV): 
##STR6## 
wherein R.sup.2 and R.sup.3 are as defined in relation to formula (I). 
The reaction between compounds of formulae (III) and (IV) may be carried 
out under conventional amination conditions, for example in a solvent such 
as methanol or toluene. 
Conveniently, the compound of formula (II) is prepared in-situ by reacting 
a compound of the above defined formula (III) with a compound of the above 
defined formula (IV) under reductive amination conditions. 
Suitable reductive amination conditions include reacting the compounds of 
formula (III) and (IV) in an alkanolic solvent, such as methanol, in the 
presence of a suitable reduction catalyst. 
Suitable reduction catalysts and reaction conditions are as described above 
for the reduction of the compound of formula (II). 
A compound of formula (IV) may be prepared by reducing a compound of 
formula (V): 
##STR7## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in relation to formula 
(I). 
The reduction of the compound of formula (V) may conveniently be carried 
out using iron powder in the presence of acetic acid in an aqueous solvent 
such as aqueous methanol, at any temperature providing a suitable rate of 
formation of the required product, generally at an elevated temperature 
and conveniently at the reflux temperature of the solvent. 
A compound of formula (V) may be prepared by reacting a compound of formula 
(VI): 
##STR8## 
wherein, R.sup.2 and R.sup.3 are as defined in relation to formula (I), 
with nitroalkane. 
Generally, the carbon atom of the --CHO group of compound of formula (VI) 
is in an activated form, a suitable activated form being provided by 
forming an imine of the said carbonyl group: The imine may be prepared by 
reacting the compound of formula (VI) with an amine, suitably a primary 
alkyl amine such as n-butylamine. The reaction of the compound of formula 
(VI) and the amine may be carded out in any suitable solvent, such as 
toluene, at any temperature providing a suitable rate of formation of the 
required product, generally at an elevated temperature such as the reflux 
temperature of the solvent; and preferably in the presence of a catalytic 
amount of toluenesulphonic acid. 
The reaction between the compound of formula (VI), and when it is in the 
form of an imine, and nitroalkane may be carried out in glacial acetic 
acid, preferably in the presence of an ammonium acetate catalyst, 
generally at an elevated temperature such as in the range of from 
60.degree. C. to 120.degree. C., for example 100.degree. C. 
A compound of formula (VI), wherein T is hydrogen, may be prepared from a 
compound of formula (VII): 
##STR9## 
wherein R.sup.3 is as defined in relation to formula (I) and L.sup.1 is a 
leaving group or atom, generally a fluorine atom, with an activated form 
of a compound of formula (VIII): 
##STR10## 
wherein R.sup.4 and R.sup.5 are as defined in relation to formula (I). 
A suitable activated form of a compound of formula (VIII) is an ionic form, 
such as a salted form, for example an alkali metal salted form. 
An activated form of a compound of formula (VIII) may be prepared by use of 
the appropriate conventional procedure, for example a salted form may be 
prepared by treating the compound of formula (VIII) with a base such as an 
alkali metal hydride, for example sodium hydride. 
The reaction between the compounds of formulae (VII) and (VIII) may be 
carried out in any suitable solvent, generally an aprotic solvent such as 
dimethylformamide or N-methylpyrrolidinone at a low to ambient 
temperature, for example in the range of from -15.degree. C. to 20.degree. 
C., such as 5.degree. C. 
A compound of formula (IV) may also be prepared by the reaction of a 
compound of formula (IX): 
##STR11## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in relation to formula 
(I) and J represents an oxo group or a protected oxo group, for example an 
ethan-1,2-dioxy group, with a compound of formula (X): 
##STR12## 
wherein R.sup.4, R.sup.5 and T are as defined in relation to formula (I) 
in the presence of a rhodium salt, and thereafter, as required, removing 
any protecting group. 
A suitable rhodium salt is rhodium acetate. 
The reaction between the compound of formula (IX) and the compound of 
formula (X) may be carried out under conventional carbene insertion 
conditions, in an inert solvent, such as benzene at any temperature 
providing a convenient rate of formation of the required product, 
generally at an elevated temperature, such as the reflux temperature of 
the solven; preferably the reaction is carried out under an inert 
atmosphere such as nitrogen. 
When J is a protected oxo group such as an ethan-1,2-dioxy group it may be 
removed by treatment with an aqueous acid, such as aqueous hydrochloric 
acid. 
A compound of formula (I) wherein either the *CH.sub.2 or the **CH.sub.2 
carbon is a chiral carbon may be prepared using conventional 
stereoselective chemistry from appropriate starting materialsis. 
One process for the preparation of a compound of formula (I) wherein both 
the *CH.sub.2 and the **CH.sub.2 carbon are chiral carbon atoms, or a 
pharmaceutically acceptable salt, ester or amide thereof or a 
pharmaceutically acceptable solvate thereof, comprises reacting a compound 
of formula (XI): 
##STR13## 
wherein R.sup.o is as defined in relation to formula (I), with a compound 
of formula (XII): 
##STR14## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in relation to formula 
(I); and thereafter, if necessary, carrying out one or more of the 
following optional steps: 
(i) convening one compound of formula (I) to another compound of formula 
(I); and 
(ii) preparing a pharmaceutically acceptable salt, ester or amide thereof 
of a compound of formula (I) or a pharmaceutically acceptable solvate 
thereof. 
Suitably, both the *CH.sub.2 and the **CH.sub.2 carbon atoms have the R 
stereochemistry. 
Suitable reaction conditions for the reaction between the compounds of 
formulae (XI) and (XII) include using an aprotic solvent such as 
dimethylsulphoxide, at any temperature providing a convenient rate of 
formation of the required product, for example at an elevated temperature 
such as in the range of from 30.degree. C. to 100.degree. C., for example 
75.degree. C.: preferably the reaction is carried out under an inert 
atmosphere such as nitrogen. 
A compound of formula (XII) may be prepared by the hydrogenolysis of a 
compound of formula (XIII): 
##STR15## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in relation to formula 
(I) and the **CH carbon and ***CH carbon atoms are chiral carbon atoms. 
Suitably, catalytic hydrogenolysis is used, using for example 10% palladium 
on charcaol in the presence of ammonium formate, suitably in an alkanolic 
solvent such as methanol, at any temperature providing a convenient rate 
of formation of the required product, for example at ambient temperature; 
preferably the reaction is carried out in an inert atmosphere, generably 
under nitrogen. 
The compound of formula (XIII) may be prepared by stereoselective reduction 
of a compound of formula (XIV): 
##STR16## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in relation to formula 
(I) and the ***CH carbon is a chiral carbon. 
The reduction of the compound of formula (XIV) may be carried out using 
catalytic reduction in the presence of hydrogen. 
A preferred catalyst is platinum oxide. 
Suitable reduction conditions include using an alkanol solvent such as 
methanol or ethanol, at any temperature providing a convenient rate of 
formation of the required product, conveniently at ambient temperature 
using a pressure of 1-5 atmospheres of hydrogen. 
The compound of formula (XIV) may be prepared by reacting a compound of the 
above defined formula (IV) with R-.alpha.-methylbenzylamine. 
The reaction between compounds of formulae (IV) and 
R-.alpha.-methylbenzylamine may be carried out under conventional 
amination conditions, for example those described above for the reaction 
between the compounds of formula (III) and (IV). Conveniently, as for the 
above defined compound of formula (II), the compound of formula (XIV) is 
prepared in-situ by reacting a compound of the above defined formula (IV) 
with R-.alpha.-methylbenzylamine under reductive amination conditions as 
described in relation to the compounds of formulae (III) and (IV). 
Suitable conversions of one compound of formula (I) into another compound 
of formula (I) include convening one group OR.sup.4 into another group 
OR.sup.4 and/or converting one group OR.sup.5 into another group OR.sup.5. 
Suitable conversions of one group OR.sup.4 into another group OR.sup.4 
include: 
(i) converting OR.sup.4 as hydroxy into OR.sup.4 as alkoxy; 
(ii) converting OR.sup.4 as alkoxy into OR.sup.4 as hydroxy; 
(iii) converting OR.sup.4 as alkoxy into OR.sup.4 as another alkoxy group. 
The abovementioned conversion (i) my be carried out under conventional 
phosphonate alkylation methods, using for example the appropriate alcohol 
(R.sup.4 OH) in the presence of hydrogen chloride. 
The abovementioned conversion (ii) may be carried out using conventional 
phosphonate hydrolysis methods, for example by treating the appropriate 
compound of formula (I) with an alkaline metal hydroxide, such as sodium 
or lithium hydroxide. This reaction is especially useful when converting 
OR.sup.4 alkoxy into OR.sup.4 as hydroxy while leaving OR.sup.5 as alkoxy. 
Alternatively, and especially when it is required to convert both OR.sup.4 
and OR.sup.5 from alkoxy into hydroxy, acidic hydrolysis may be used using 
for example hydrochloric acid. 
The abovementioned conversion (iii) may be carried out by first converting 
OR.sup.4 as alkoxy into OR.sup.4 as hydroxy using the conditions set out 
in respect of the abovementioned conversion (ii), followed by converting 
the hydroxy group so formed into another alkoxy group, using the 
conditions set out in respect of the abovementioned conversion (i). 
The abovementioned conversion (iii) is of particular use for preparing 
compounds of formula (I) wherein OR.sup.4 represents methoxy: such 
compounds are generally prepared from compounds of formula (I) wherein 
OR.sup.4 represents an alkyloxy group other than methoxy (suitably ethoxy) 
by first hydrolysing the relevant OR.sup.4 group (via conversion (ii)) to 
prepare a compound of formula (I) wherein OR.sup.4 represents hydroxy and 
thereafter methylating (via conversion (i)) to provide the required 
compound wherein OR.sup.4 represents methoxy. 
Suitable conversions of one group OR.sup.5 into another group OR.sup.5 
include analogous conversions to those mentioned above in regard to 
converting one group OR.sup.4 into another group OR.sup.4. 
The protection of any reactive group or atom such as the variables R.sup.o, 
R.sup.1, R.sup.2 and R.sup.3, may be carried out at any appropriate stage 
in the aforementioned processes. 
Suitable protecting groups include those used conventionally in the art for 
the particular group or atom being protected. For example a keto group may 
be protected as an ketal. 
Protecting groups may be prepared and removed using the appropriate 
conventional procedure. For example a keto group may be protected as an 
ketal by reaction with an appropriate alcohol, for example ethan-1,2-diol, 
in the presence of an acid catalyst, such as 4-toluenesulphonic acid. The 
said ketal may be removed by use of acidic hydrolysis, for example 
treatment with hydrochloric acid. 
A leaving group or atom is any group or atom that will, under the reaction 
conditions, cleave from the starting material, thus promoting reaction at 
a specified site. Suitable examples of such groups unless othewise 
specified are halogen atoms, mesyloxy groups and tosyloxy groups. 
The compounds of formulae (III) and (VIII) are known compounds or they may 
be prepared by processes analogous to those used to prepare known 
compounds, for example the compounds of formula (III) may be prepared 
according to methods disclosed in J. Org. Chem., 1974, 39, 914; and the 
compounds of formula (VIII) may be prepared according to methods disclosed 
in Phosphorus and Sulphur, 1978, 5, 455. 
The compounds of formula (IX) are known compounds or they may be prepared 
by methods analogous to those used to prepare known compounds, for example 
those methods disclosed in European application, publication number 
0052963 and United Kingdom patent number 2084577. 
The compounds of formulae (X) are either known commercially available 
compounds or they may be prepared from such compounds by conventional 
procedures for example those disclosed in the Chem. Berichte 1968, 101, 
3734 and The Chemistry of Phosphorus, (J. Emsley and D. Hall), Published 
by Harper and Row, London, 1976. For example the compounds wherein T 
represents --CO.R.sup.t R.sup.u may be prepared from the commercially 
available compounds wherein T is carboxyl or an ethyl ester thereof, by 
conventional amination reactions. The compounds of formula (X) wherein T 
is a nitrile group are conveniently prepared from 
.alpha.-chloroacetonitrile and P(OR).sub.3 whereto R is alkyl, suitably 
ethyl, and thereafter interconverting R into R.sup.4 and or R.sup.5 as 
required. 
The compounds of formula (XI) are known compounds or they may be prepared 
by methods analogous to those used to prepare known compounds, for example 
those methods disclosed in European application, publication number 
0262785. 
The salts, esters, amides and solvates of the compounds mentioned herein 
may be produced by methods conventional in the art: For example, salts may 
be prepared by treating a compound of formula (I) with the appropriate 
acid. 
Esters of carboxylic acids may be prepared by conventional esterification 
procedures, for example alkyl esters may be prepared by treating the 
required carboxylic acid with the appropriate alkanol, generally under 
acidic conditions. 
Amides may be prepared using conventional amidation procedures, for example 
amides of formula CONR.sup.s R.sup.t may be prepared by treating the 
relevant carboxylic acid with an amine of formula HNR.sup.s R.sup.t, 
wherein R.sup.s and R.sup.t are as defined above. Alternatively, a 
C.sub.1-6 alkyl ester such as a methyl ester of the acid may be treated 
with an amine of the above defined formula HNR.sup.s R.sup.t to provide 
the required amide. 
Compounds of formula (I) and pharmaceutically acceptable salt, ester or 
amide thereofs thereof; or a pharmaceutically acceptable solvate thereof, 
produced by the above processes, may be recovered by conventional methods. 
If required mixtures of isomers of the compounds of the invention may be 
separated into individual stereoisomers by conventional means, for example 
by the use of an optically active acid as a resolving agent. Suitable 
optically active acids which maybe used as resolving agents are described 
in `Topics in Stereochemistry`, Vol. 6, Wiley Interscience, 1971, 
Allinger, N. L. and Eliel, W. L. Eds. 
Alternatively, any enantiomer of a compound of the invention may be 
obtained by stereospecific synthesis using optically pure starting 
materials of known configuration. 
The absolute configuration of compounds may be determined by conventional 
X-ray crystallographic techniques. 
As previously indicated, the compounds of the present invention have 
valuable pharmacological properties: 
The present invention accordingly provides a compound of formula (I) or a 
pharmaceutically acceptable salt, ester or amide thereof thereof, or a 
pharmaceutically acceptable solvate thereof, for use as an active 
therapeutic substance. 
In one aspect, the present invention provides a compound of formula (I), or 
a pharmaceutically acceptable salt, ester or amide thereof thereof, or a 
pharmaceutically acceptable solvate thereof, for use in the treatment of 
hyperglycaemia in human or non-human animals. 
The present invention further provides a compound of formula (I), or 
pharmaceutically acceptable salt, ester or amide thereof thereof, or a 
pharmaceutically acceptable solvate thereof, for use in the treatment of 
obesity in human or non-human animals. 
A compound of formula (I), or a pharmaceutically acceptable salt, ester or 
amide thereof thereof, 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 formula (I), or a pharmaceutically 
acceptable salt, ester or amide thereof 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 mums, such as by injection, 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 careers include, for example, microcrystalline cellulose, starch, 
sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, 
magnesium stearate or sodium lauryl sulphate. 
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 2-100 mg or 0.1 to 500 mg, and 
more especially 0.1 to 250 mg. 
The present invention further provides a method for treating hyperglycaemia 
in a human or non-human mammal, which comprises administering an 
effective, non-toxic, amount of a compound of formula (I), or a 
pharmaceutically acceptable salt, ester or amide thereof thereof, or a 
pharmaceutically acceptable solvate thereof, to a hyperglycaemic human or 
non-human mammal in need thereof. 
The present invention further provides a method for treating obesity or for 
the treatment and/or prophylaxis of atherosclerosis in a human or 
non-human mammal, which comprises administering an effective, non-toxic, 
amount of a compound of formula (I), or a pharmaceutically acceptable 
salt, ester or amide thereof, 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 treating hyperglycaemic or obese humans the compound of formula (I), or 
a pharmaceutically acceptable salt, ester or amide thereof; 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. 
The treatment regimens for atherosclerosis are generally as described for 
hyperglycaemia. 
In treating non-human mammals, especially dogs, the active ingredient may 
be adminstered 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. 
In a further aspect the present invention also provides a method for 
increasing weight gain and/or improving the feed utilisation efficiency 
and/or increasing lean body mass and/or decreasing birth mortality rate 
and increasing post/natal survival rate; of livestock, which method 
comprises the administration to livestock of an effective non-toxic amount 
of a compound of formula (I) or a veterinarily acceptable salt, ester or 
amide thereof thereof, or a veterinarily acceptable solvate thereof. 
Whilst the compounds of formula (I) and the veterinarily acceptable salts 
thereof or a veterinarily acceptable solvate thereof, may be administered 
to any livestock in the abovementioned method, they are particularly 
suitable for increasing weight gain and/or feed utilisation efficiency 
and/or lean body mass and/or decreasing birth mortality rate and 
increasing post-natal survival rate; in poultry, especially turkeys and 
chickens, cattle pigs and sheep. 
In the preceding method the compounds of formula (I) or veterinarily 
acceptable salt, ester or amide thereof will normally be administered 
orally although non-oral modes of administration, for example injection or 
implantation, are also envisaged. Suitably the compounds are administered 
in the feed-stuff or drinking water provided for the livestock. 
Conveniently these are administered in the feed-stuff at from 10-.sup.3 
ppm-500 ppm of total daily fed intake, more usually 0.01 ppm to 250 ppm, 
suitably less than 100 ppm. 
The particular formulations used will of course depend upon the mode of 
administration but will be those used conventionally in the mode of 
administration chosen. For administration in feed-stuff the drugs are 
conveniently formulated as a premix in association with a suitable 
carrier. 
Accordingly, the present invention also provides a veterinarily acceptable 
premix formulation comprising a compound of formula (I), or a veterinarily 
acceptable salt, ester or amide thereof thereof; or a veterinarily 
acceptable solvate thereof, in association with a veterinarily acceptable 
career therefore. 
Suitable carriers are inert conventional agents such as powdered starch. 
Other conventional feed-stuff premix carriers may also be employed. 
No unacceptable toxicological effects am expected when compounds of the 
invention are administered in accordance with the present invention.