EP0118489A1

EP0118489A1 - Secondary arylethanolamines

Info

Publication number: EP0118489A1
Application number: EP19830902757
Authority: EP
Inventors: Richard Mark Hindley; Barrie Christian Charles Cantello
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1982-08-27
Filing date: 1983-08-22
Publication date: 1984-09-19
Also published as: WO1984000956A1

Abstract

Composés correspondant à la formule (I) et leurs sels, où R1 est de l'hydrogène, de l'halogène ou du trifluorométhyl, R2 est de l'hydrogène ou de l'halogène, R3 est de l'hydrogène ou du méthyle, n vaut 1 ou 2, A est de l'oxygène ou du soufre, R5 est un phényle ou un phényle substitué par un halogène, un alkyle inférieur ou un alcoxy inférieur, un benzyle ou un alkyle à chaîne droite ou ramifiée et comportant de 1 à 6 atomes de carbone. Ces composés peuvent être utilisés dans le traitement de l'hyperglycémie ou de l'obésité.Compounds corresponding to formula (I) and their salts, where R1 is hydrogen, halogen or trifluoromethyl, R2 is hydrogen or halogen, R3 is hydrogen or methyl, n is 1 or 2, A is oxygen or sulfur, R5 is phenyl or phenyl substituted by halogen, lower alkyl or lower alkoxy, benzyl or straight or branched chain alkyl containing 1 to 6 carbon atoms. These compounds can be used in the treatment of hyperglycemia or obesity.

Description

SECONDARYARYLETHANOLAMINES.

The present invention relates to derivatives of ethanolamine which have anti-obesity and/or anti-hyperglycaemic activity, to processes for their production and to their use in medicine.

It has now been discovered that a class of novel ethanolamine derivatives have anti-obesity and/or anti-hyperglycaemic activity.

Accordingly, the present invention provides a compound of formula (I): 3

and salts thereof, wherein;

R¹ is hydrogen, halogen or trifluoromethyl,

R² is hydrogen, or halogen,

R³ is hydrogen or methyl, n is 1 or 2,

A is oxygen or sulphur. R⁵ is C_1-6 straight or branched alkyl, benzyl, phenyl or phenyl substituted with halogen, lower alkyl or lower alkoxy.

As used herein the terms 'lower alkyl' and 'lower alkoxy' include C_1-6 alkyl and C_1-6 alkoxy.

Pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts formed with a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, orthophosphoric acid, sulphuric acid, methane sulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid or acetylsalicyclic acid.

The salts of compounds of formula (I) need not be pharmaceutically acceptable as they are also useful in the separation of stereoisomers of compounds of formula (I) when the salt ion is also optically active.

Compounds of formula (I) have at least one asymmetric carbon atom, ie the carbon atom bearing the hydroxyl and substituted phenyl groups, and, when R³ is methyl, the carbon atom bearing R³ is also asymmetric. The compounds may, therefore, exist in at least two and often four stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds of formula (I) whether free from other stereoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixtures of enantiomers.

Preferably, the carbon atom bearing the hydroxyl and substituted phenyl groups has the R-configuration. The most potent compounds of formula (I) are those wherein R³ is methyl and both asymmetric carbon atoms are in the R-configuration.

The absolute configuration of any compound of formula (I) may be determined by conventional X-ray crystallographic techniques.

It is believed that, in the 13C nmr spectrum of compounds of formula (I) wherein R³ is methyl, the diastereoisomer having the greater anti-obesity and anti-hyperglycaemic activity is that for which the signal of the methyl group carbon atom appears at higher field (the lower numerical value when expressed in ppm) in d₆Dimethyl sulphoxide solution. The paired resonances often appear at approximately 20 ppm (less active) and slightly below 20 ppm (more active) down field from tetramethylsilane. Other paired resonances can occur for the carbon atoms attached directly to the nitrogen atom and the carbon which carries the hydroxyl and phenyl groups. Again the paired resonances of the more active diastereoisomer of the investigated compounds appear at the higher field position.

The present invention provides a process for producing a compound of formula (I), or a salt thereof, which process comprises reducing an oxo-group and/or

double bond and/or cleaving an N-benzyl group of a compound of formula (II):

wherein R¹, R², R³, A, R⁵ and n are as defined in relation to formula (I),

R⁶ is hydrogen or together with R⁷ forms a bond, R⁷ is hydrogen or benzyl or together with R⁶ or R⁸ forms a bond, R⁸ is hydrogen or together with R⁹ forms an oxo-group or together with R⁷ forms a bond, R⁹ is hydrogen or together with R⁸ forms an oxo-group, R¹⁰ is hydroxyl or together with R¹¹ forms an oxo-group, R¹¹ is hydrogen or together with R¹⁰ forms an oxo-group provided that there is no more than one oxo-group represented by any of R ⁸ to R¹¹; and optionally thereafter forming a salt of the compound of formula (I) so formed.

Where there are two or more reducible moieties in the compound of formula (II) these may be reduced separately in any order or simultaneously.

The aforementioned reductions may be effected by conventional chemical methods or by catalytic methods. Suitably, chemical reduction may be effected with lithium aluminium hydride, borane methyl sulphide, sodium cyanoborohydride or sodium borohydride. Catalytic hydrogenation may be carried out using catalysts such as palladium on charcoal, or platinum, for instance, as platinum oxide.

Reduction by sodium borohydride is conveniently effected in a lower alkanolic solvent such as methanol or ethanol. The reaction is generally carried out at from 0-20°C.

Reduction by lithium aluminium hydride is conveniently effected in a dry, ether solvent such as diethyl ether or tetrahydrofuran at ambient or elevated temperatures.

Catalytic reduction is conveniently effected in a conventional hydrogenation solvent such as a lower alkanol, for instance ethanol. The hydrogenation is generally carried out under hydrogen gas at about 1 atmosphere pressure and at ambient or elevated temperatures.

Reduction of a compound of formula (II) wherein R⁷ is benzyl is conveniently effected by catalytic hydrogenation, preferably using palladium on charcoal.

Preferred aspects of the process comprise reducing a compound of formula (IIA):

or reducing a compound of formula (IIB):

or reducing a compound of formula (IIC):

or reducing a compound of formula (IID) or reducing a compound of formula (IIE):

R

wherein R¹, R², R³, R⁵, A and n are as defined in relation to formula (I) and R¹⁰ and R¹¹ are as defined in relation to formula (II). The present invention also provides another process for producing a compound of formula (I) or a salt thereof, which process comprises reacting a compound of formula (III):

wherein R³, R⁵, A and n are as defined in relation to formula (I);

with a compound of formula (IV):

wherein R¹ and R² are as defined in relation to formula (I), and Y is a group capable of reacting with the amine of formula (III) thus forming a compound of formula (I), and optionally thereafter forming a salt of the compound of formula (I) so formed. Typical examples of compounds of formula (IV) are compounds of formulae (IVA) and (IVB):

wherein R¹ and R² are as defined in relation to formula (I) and Z¹ is a leaving group, preferably halogen or tosyloxy.

The reaction of a compound of formula (III) with a compound of formula (IVA) is conveniently effected in a solvent such as a lower alkanol, preferably ethanol or methanol.

The reaction of a compound of formula (III) with a compound of formula (IVB) is conveniently conducted in a solvent, such as dimethyl sulphoxide, at elevated temperature, preferably about 50°C, for about 3 days.

The present invention provides a further process for the production of compounds of formula (I) or salts thereof, which process comprises reacting a compound of formula (V): (V ) wherein R¹ and R² are as defined in relation to formula (I);

with a compound of formula (VI):

wherein R³, R⁵, A and n are as defined in relation to formula (I) and Z² is a leaving group preferably halogen or tosyloxy.

The preparation of compounds of formula (V) is described in Published European Patent Application No. 0 021 636.

The reaction of a compound of formula (V) with a compound of formula (VI) is conveniently effected in a solvent such as dimethyl sulphσxide at an elevated temperature, preferably about 50°C for about two or three days.

A preferred process for producing compounds of formula (I) comprises the reduction of a compound of formula (IIA), especially using sodium borohydride in methanol at ambient temperatures.

The salts of compounds of formula (I) may be produced by treating the compound of formula (I) with the appropriate acid. Compounds of formula (I) and salts thereof, produced by the above processes, may be recovered by conventional methods.

Compounds of formula (II) may be produced by reacting a compound of formula (III) as hereinbefore defined.

with a compound of formula (VII):

wherein R¹ and R² are as defined in relation to formula (I) and Z³ is a group which is capable of reacting with the amine of formula (III) thus forming a compound of formula (II). Typical examples of compounds of formula (VII) are:

or its hydrate or hemi-acetal of a lower alkanol;

wherein Z⁴ is a leaving group, preferably bromine,

(

wherein R¹ and R² are as defined in relation to formula (I).

Conventional conditions suitable for use with the particular compound of formula (VII) may be used for this reaction. Thus the reaction of a compound of formula (VIIA) with a compound of formula (III) is conveniently conducted at elevated temperatures under conditions resulting in the removal of the water formed during the reaction. A particularly suitable method is to perform the reaction in a solvent, such as benzene, under reflux and to remove the water azeotropically using a Dean and Stark trap.

The reaction of a compound of formula (VIIB) with a compound of formula (III) is conveniently conducted in a polar organic solvent such as acetonitrile or butanone, at an elevated temperature, for instance under reflux.

The reaction of a compound of formula (VIIC) with a compound of formula (III) is conveniently conducted under standard peptide formation reaction conditions. Alternatively a compound of formula (II) may be prepared by reacting a compound of formula (VIII):

wherein R¹, R², R¹⁰ and R¹¹ are as defined in relation to formula (II); and Z⁵ is a leaving group, preferably halogen or tosyloxy;

with a compound of formula ( IX ) : „

wherein R³, R⁵, A and n are as defined in relation to formula (I).

A particularly preferred process for producing certain compounds of formula (II) is by reacting a compound of formula (V) as hereinbefore defined with a compound of the formula (X):

wherein R³, R⁵, A and n are as defined in relation to formula (I).

The reaction of a compound of formula (V) with a compound of formula (X) is conveniently effected under conditions which result in the removal of water formed during the reaction. A particularly suitable method is to perform the reaction in a solvent, such as benzene, under reflux and to remove the water azeotropically using a Dean and Stark trap.

It is often convenient to prepare the compound of formula (II) and reduce it, in situ, to the desired compound of formula (I) without isolation of the compound of formula (II).

Compounds of formula (I) having a single asymmetric carbon atom may, if desired, be separated into individual enantiomers by conventional means, for example, by the use of an optically active acid as a resolving agent. Compounds of formula (I) having two asymmetric carbon atoms may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallisation from a suitable solvent such as ethyl acetate. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means such as by the use of an optically active acid as a resolving agent.

Suitable optically active acids which may be 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 formula (I) may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.

By using single enantiomers of a compound of formula (III) and of a compound of formula (VIIC) a stereospecific synthesis of a compound of formula (II) is achieved. This may then be reduced to a compound of formula (I) without altering the configuration of the two asymmetric carbon atoms. Thus, for example, reaction of a compound of formula (III) with the R-absolute configuration and a compound of formula (VIIC) with the R-absolute configuration would afford a compound of formula (II) and, on reduction, a compound of formula (I) with the RR-absolute configuration.

By reacting a single enantiomer of a compound of formula (III) with a single enantiomer of a compound of formula (IVA) or (IVB), the direct stereospecific synthesis of a single enantiomer of a compound of formula (I) is effected. Thus, for example, reaction of a compound of formula (III) with the R-absolute configuration with a compound of formula (IVA) with the R-absolute configuration would afford a compound of formula (I) with the RR-absolute configuration.

A compound of formula (I) or a pharmaceutically acceptable salt thereof (hereinafter "the drug") may be administered as the pure drug, however, it is preferred that the drug be administered 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 thereof with a pharmaceutically acceptable carrier therefor.

As used herein the terms "pharmaceutical composition" and "pharmaceutically acceptable" embrace compositions and ingredients for both human and veterinary use.

Usually the compositions of the present invention will be adapted for oral administration although compositions for administration by other routes, 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 the like.

Typical carriers may, therefore, comprise such agents as microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinyl-polypyrrolidone, magnesium stearate, sodium lauryl sulphate, sucrose and the like.

Most suitably the composition will be provided in unit dose form. Such unit doses will normally comprise 0.1 to 500 mg of the drug, more usually 0.1 to 250 mg and favourably 0.1 to 100 mg. The present invention provides a method for treating hyperglycaemia in humans and domestic mammals which method comprises administering an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to humans or domestic mammals.

The present invention further provides a method for treating obesity in humans or domestic mammals, which method comprises administering an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to obese humans or domestic mammals.

Conveniently, the drug may be administered as a pharmaceutical composition as hereinbefore defined, and this forms a particular aspect of the present invention.

In treating hyperglycaemic or obese humans the drug 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 about 0.1 to 1000 mg, and more usually about 1 to 500 mg.

In treating hyperglycaemic or obese animals, especially dogs, the drug may be administered by mouth, usually once or twice a day and at about 0.025 mg/kg to 10 mg/kg, for example 0.1 mg/kg to 2 mg/kg.

Conveniently, the drug may be administered as a pharmaceutical composition as hereinbefore defined, and this forms a particular aspect of the present invention. The drug may be taken in doses such as those described above for treating obese humans.

The invention will now be illustrated with reference to the following Examples, which are not intended to limit the scope in any way.

As used in the Examples, the term 'diastereoisomer' refers to a pair of enantiomers.

EXAMPLE 1 N-[2-(4-[2-Methoxyothoxy]phenvl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl) ethanamine

1-[4-(2-Methoxyethoxy)phe.nyl]propan-2-One (3.7g) and 2-(3-chlorophenyl)-2-hydroxy ethanamine (2.4g) were mixed in dry benzene (100ml) and the solution was boiled under reflux in an apparatus incorporating a water trap until no more water was produced. The solution was cooled, the solvent evaporated and the residue, in methanol (50ml), was hydrogenated in the presence of platinum (from platinum oxide 50mg), until hydrogen uptake ceased. The mixture was filtered through diatomaceous earth and the solvent evaporated to give an oil. Chromatography on silica-gel in 4% methanol-dichloromethane gave N-[2-(4-[2-methoxy-ethoxy]phenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl) ethanamine, mp 42-48ºC (diethylether-hexane) as a 63:37 mixture of diastereoisomers.

'H nmr δ(CDCl₃):

1.1 (3H,d); 1.8-3.1 (7H,complex, 2H exchange with D₂O); 3.45 (3H,s); 3.8 (2H,t); 4.1 (2H,t); 4.5 (1H,m); 6.9 (2H, d); 7.1 (2H,d); 7.3 ( 4H,complex).

EXAMPLE 2

N-[2-(4-[2-Phenoxyethoxy]ohenyl)-1-methylethyl]-2-hydroxy- 2-(3-chlorophenyl)ethanamine

1-[4-(2-phenoxyethoxy)phenyl]propan-2-one (2.9g) and 2- (3-chlorophenyl)-2-hydroxy ethanamine (1.7g) in toluene (100ml) were boiled for 4h and the water produced was removed with a Dean and Stark trap. The solution was coole and the toluene evaporated, the crude imine was dissolved in methanol (50ml) cooled to 0°C and 1.6g of sodium boro-hydride added portionwise. After completion of addition the solution was allowed to stand at room temperature for 1 hour. The solvent was evaporated, the residue dissolved in dichloromethane and the organic phase washed with sodium carbonate solution. Drying and evaporation of the solvent gave the crude product which was crystallized from diethyl ether/ethanol to yield the title compound as a 51:49 mixture of diastereoisomers, mp 104- 108°C.

'H nmr δ(CDCl₃)

1.1 (3H,d) ; 2.0-3.1 ( 7H , complex m, 2H exchange with D₂O); 4.40 (4H,s); 4.5-4.7 (1H,m); 6.8-7.5 ( 13H , complex m).

EXAMPLE 3

N-[2-(4-[2-Thiophenoxyethoxy]phenyl)-1-methylethyl]-2-hydroxy-2-(3-chiorophenyl)ethanamine

The title compound, mp 119-123°C, (diethylether/ethanol) was prepared as a 17:83 mixture of diastereoisomers from 1-[4-(2-thiophenoxyethoxy)phenyl]propan-2-one (3.7g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (2.1g) by an analogous procedure to that described in Example 1.

'H nmr δ (CDCl₃):

1.1 (3H,d); 2.4-3.1 (7H, complex m, 2H exchange with D₂O); 3.3 (2H,t); 4.1 (2H,t); 4.3 (1H,g); 6.8 (2H,d); 7.1 (2H, d); 7.2-7.6 (9H, complex m).

EXAMPL E 4

N-[2-(4-[2-Phenoxyethoxy]phenyl)-1-methylethyl]-2-hydroxy- 2-(3-trifluoromethylphenyl)ethanamine

The title compound, mp 109-112°c (diethylether/ethanol), was prepared as a 53:47 mixture of diastereoisomers from 1-[4-(2-phencxyethoxy)phenyl]propan-2-one (2.1g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (1.5g) by an analogous procedure to that described in Example 1.

'H nmr δ (CDCl₃):

1.1 (3H,d); 2.5-3.1 ( 7H, complex m, 2H exchange with D₂O); 4.3 (4H,m); 4.5-4.8 (1H,m); 6.8-7.8 (13H, complex m).

EXAMPLEX1

1-[4-(2-Methoxyethoxy) phenyl] propan-2-one

To a solution of sodium (0.5g) in methanol (80ml) was added 1-[4-(2-hydrcxyethoxy) phenyl]propan-2-one ethylene ketal 4-toluenesulphonic acid ester (7.84g) and the mixture was boiled under reflux for 6 hours. The solvent was evaporated, the residue dissolved in water, extracted with dichloromethane, dried (magnesium sulphate) and evaporated. The residue in methanol (50ml) was stirred with 10% hydrochloric acid (50ml) at room temperature for 1 hour. Water (100ml) was added, the solution was extracted with ethyl acetate, the organic extracts dried (magnesium sulphate), filtered and evaporated to give an oil which was used without further purification.

'H nmr δ(CDCl₃):

2.2 (3H,s); 3.45 (3H,s); 3.7 (2H,s), 4.2 (4H,complex) 6.8 (2H,d), 7.3 (2H,d).

EXAMPLE X2

1-[4-(2-Phenoxyethoxy)phenyl]propan-2-one

To a solution of sodium ethoxide (prepared from 0.46g of sodium) in 200ml of boiling ethanol was added phenol (2.0g in ethanol (10ml). The mixture was boiled for 0.5h under an atmosphere of nitrogen, and 1-[4-(2-hydroxyethoxy)-phenyl]propan-2-one ethylene ketal 4-toluene sulphonic acid ester (7.0g) in ethanol (10ml) was added dropwise. After 14h under reflux the mixture was cooled, filtered and evaporated. The residue was dissolved in diethyl ether an and organic phase washed with 10% (w/v) sodium hydroxide solution. The solution was dried and evaporated to give the crude product. Deketalization was acheived by treatment with hydrochloric acid in methanol for 18h at room temperature. The methanol was evaporated and the residue dissolved in dichloromethane, washed with saturated sodium carbonate solution, dried and evaporated to give 1-[4- (2-phenoxyethoxy)phenyl] propan-2-one as a crystalline solid.

'H nmr δ(CDCl₃):

2.14 (3H,s); 3.65 (2H,s); 4.35 (4H,s); 6.5-7.4 (9H,complex m). EXAMPLE X3

1-[4-(2-Thiophenoxyethoxy)phenyl]propan-2-one

1-[4-(2-Thiophenoxyethoxy)phenyl]propan-2-one was prepared from 1-[4-(2-hydroxyethoxy)phenyl]propan-2-one erhylene ketal 4-toluenesulphonic acid ester (7.0g) and thiophenol (2.5g) by an analogous procedure to that reported in Example X2.

'H nmr δ (CDCl₃):

2.1 (3H,s); 3.25 (2H,t); 3.6 (2H,s); 4.1 (2H,t); 6.5-7.5 (9H, complex m).

Demonstration of Effectiveness of Compounds

(1) Effect on energy expenditure

The effect of the compounds on the energy expenditure of mice was demonstrated by means of the following procedure:

Female CFLP mice each weighing approximately 24 g, were given food and water ad lib before and during the experiment. The compounds were dissolved in water by addition of one mole of hydrochloric acid per mole of compound and these solutions were administered orally to each of 12 mice. A further 12 mice were dosed orally with water. The mice were placed in boxes through which air was drawn and the oxygen content of the air leaving the boxes was measured. The energy expenditure of the mice was calculated for 21 hours after dosing from the volume of air leaving the boxes and its oxygen content, following the principles described by J.B. de V. Weir, J. Physiol. (London) 109, 1-9 (1949). The food intake of the mice was measured over this same period of 21 hours. The results are expressed as a percentage of the mean food intake or rate of energy expenditure of the mice dosed with water.

ME

(ii) Anti-hyperglycaemic activity

Female CFLP mice, weighing approximately 25 g, were fasted for 24 hours prior to the study. The compounds under study were administered orally as an aqueous solution to each of 6 mice. 30 Minutes later a blood sample (10 μl) was obtained from the tail for the analysis of blood glucose. Immediately after taking this blood sample, glucose (1 g/kg body weight) was administered subcutaneously to each mouse. 6 Mice were given water as a control. Blood samples were then obtained from each mouse at 30 minute intervals for 120 minutes.

Compounds that produced a significant (P 0.05) reduction of blood glucose, compared with control mice given water, at any time interval, were considered active. The area under the blood glucose curve over the 2 hour period after the administration of the glucose was calculated for each compound and compared with the value for control animals.

Claims

A compound of formula (I)

and salts thereof, wherein;

R¹ is hydrogen, halogen or trifluoromethyl,

R² is hydrogen, or halogen,

R³ is hydrogen or methyl, n is 1 or 2,

A is oxygen or sulphur,

R⁵ is C_1-6 straight or branched alkyl, benzyl, phenyl or phenyl substituted with halogen, lower alkyl or lower alkoxy.

A compound as claimed in claim 1 wherein R³ is methyl and both asymmetric carbon atoms are in the R-configuration.

3. A compound as claimed in claim 1 selected from

N- [ 2-( 4- [2-methoxyethoxy]phenyl ) -1-methylethyl] 2-hydroxy-2- ( 3-chlorophenyl ) ethanamine ;

N- [2-( 4- [2-phenoxyethoxy]phenyl)-1-methylethyl] 2-hydroxy-2-(3-chlorσphenyl)ethanamine;

N-[2-(4-[2-thiophenoxyethoxy]phenyl)-1-methyl ethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine;

N-[2-(4-[2-phenoxyethoxy]phenyl)-1-methylethyl]-2- hydroxy-2-(3-trifluoromethylphenyl)ethanamine;

4. A process for producing a compound of formula (I), or a salt thereof, as defined in claim 1 which process comprises reducing an oxo-group and/or double bond and/or cleaving an N-benzyl group of a compound of formula (II):

wherein R¹, R², R³, A, R⁵ and n are as defined in relation to formula (I),

R⁶ is hydrogen or together with R⁷ forms a bond,

R⁷ is hydrogen or benzyl or together with R⁶ or R⁸ forms a bond,

R⁸ is hydrogen or together with R⁹ forms an oxo- group or together with R⁷ forms a bond,

R⁹ is hydrogen or together with R⁸ forms an oxo- group,

R¹⁰ is hydroxyl or together with R¹¹ forms an oxo- group, R¹¹ is hydrogen or together with R¹⁰ forms an oxo-group provided that there is no more than one oxo-group represented by any of R⁸ to R¹¹; and optionally thereafter forming a salt of the compound of formula (I) so formed.

5. A process for producing a compound of formula (I) or a salt thereof, as defined in claim 1 which comprises reacting a compound of formula (III):

wherein R³, R⁵, A and n are as defined in relation to formula (I);

with a compound of formula (IV):

wherein R¹ and R² are as defined in relation to formula (I), and Y is a group capable of reacting with the amine of formula (III) thus forming a compound of formula (I), and optionally thereafter forming a salt of the compound of formula (I) so formed.

6. A process for the production of a compound of formula (I) or a salt thereof, which process comprises reacting a compound of formula (V):

wherein R¹ and R² are as defined in relation to formula (I);

with a compound of formula (VI):

wherein R³, R⁵, A and n are as defined in relation to formula (I) and Z² is a leaving group.

A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

A compound of formula (I) as defined in claim 1 for use in treating the human or animal body.

9. A compound of formula (I) as defined in claim 1 for use in treating hyperglycaemia or obesity.