EP0139661A1 - Secondary amines - Google Patents

Abstract

Compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof, formula in which R1 represents hydrogen or halogen, R2 represents hydrogen, halogen or trifluoromethyl, R3 and R4 represent each hydrogen, C1-C6 alkyl or phenyl-C1-C6-alkyl, R5 represents hydrogen or methyl; n is 1 or 2; and R6 represents CO2H, O-R7-CO2H, in which R7 is a straight or branched alkylene chain from C1 to C6, or O-R8-R9 in which R9 represents a hydroxy, or a C1 to C6 alkoxy, or -NR10R11 in which R10 and R11 each represent hydrogen or C1 to C6 alkyl, and R8 is a straight or branched alkylene chain from C2 to C7 with at least two carbon atoms separating the hetero atoms, this compound being useful for treatment of obesity and hyperglycemia.

Description

SECONDARY AMINES

The present invention relates to a particular group of substi tuted 1 , 2-ethaned iamines which hav e anti-hyperglycaemic and/or anti-obesity activ ity, to processes for the ir production and to their use in medicine .

According to the present invention there is provided a compound of formula ( I ) :

or a pharmaceutically acceptable salt, ester or amide thereof, in which, R¹ is hydrogen or halogen;

R² is hydrogen, halogen or trifluoromethyl, each of R³ and R⁴ is hydrogen, C₁-6 alkyl or phenyl-C₁-6^-alkyl'

R⁵ is hydrogen or methyl; n is 1 or 2; and R⁶ is CO₂H, O-R⁷-CO₂H, in which R⁷ is a C₁-6 straight or branched alkylene chain, or O-R⁸-R⁹ in which R⁹ is hydroxy, or C₁-6^{-alkoxy, or} -NR¹⁰R¹¹ in which R¹⁰ and R¹¹ are each hydrogen or C₁-6 alkyl, and R⁸ is a C₂-7 straight or branched alkylene chain with at least two carbon atoms separating the hetero-atoms.

Preferably, R² is in the meta-position and is chlorine or trifluoromethyl, and R¹ is hydrogen.

R⁷ is preferably methylene, and R⁵ is preferably methyl.

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, methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid or acetylsalicylic acid.

Pharmaceutically acceptable carboxylic acid salts of compounds of formula (I) include metal salts such as aluminium, alkali metal salts such as sodium, potassium, or lithium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine. Preferred esters of the compounds of formula (I) are those wherein the CO₂H group or O-R⁷-CO₂H group is modified to a group of formula CO₂R¹² or -O-R⁷-CO₂R¹² respectively, wherein R¹² is a C₁-6 alkyl group. Preferably R¹² is methyl or ethyl.

Preferred amides of the compounds of formula (I) are those wherein the CO₂H group or O-R⁷-CO₂H group is modified to a group of formula CONR¹⁰R¹¹ or -O-R⁷-CONR¹⁰R¹¹ respectively, wherein each of R¹⁰ and R¹¹ is hydrogen or a C₁-6 alkyl group.

When R⁵ is methyl, the compounds of formula (I) have two asymmetric carbon atoms, marked with single and double asterisks in the formula. These compounds may, therefore, exist in 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 marked with a single asterisk has the R-configuration.

The most potent compounds of formula (I) are those wherein 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.

The present invention also provides a process for producing a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof, which comprises reducing the nitrogen-carbon double bond of a compound of formula (II), or an ester or amide thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁶ and n are as defined in formula (I) , and optionally thereafter forming a salt of the compound of formula (I) so formed, and/or converting the compound of formula (I) so formed into a further compound of formula (I) .

The salts of the compounds of formula (I) may be produced by treating the compounds of formula (I) with the appropriate acid or base.

The reduction of the compounds of formula (II) may be effected by conventional chemical or catalytic methods, such as chemical reduction using sodium cyanoborohydride or sodium borohydride or by catalytic hydrogenation 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.

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 atmospheric pressure to about 10 times atmospheric pressure and at ambient or elevated temperature.

Compounds of formula (I), wherein R³, R⁴ are each hydrogen, may alternatively be prepared by reducing a compound of formula (III):

wherein R¹, R², R⁵, R⁶ and n are as defined in formula (I), and optionally thereafter forming a salt of the compound of formula (I) so formed, and/or converting the compound of formula (I) so formed into a further compound of formula (I) . The reduction of the compound of formula (III) may be effected by conventional catalytic methods, using catalysts such as palladium on charcoal. The reduction is conveniently carried out in a hydrogenation solvent such as a lower alcohol, for instance methanol. The hydrogenation is generally carried out under an atmosphere of hydrogen at a pressure of from about normal atmospheric pressure to about 10 times atmospheric pressure, and at ambient or elevated temperatures.

Compounds of formula (I) may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallisation from a suitable solvent such as methanol or ethyl acetate or a mixture thereof. 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 an optically pure starting material of known configuration.

Compounds of formula (II) may themselves be prepared by treating a compound of formula ( IV ) :

wherein R¹, R², R³ and R⁴ are as defined in relation to formula (I), with the proviso that R³ and R⁴ are not simultaneously hydrogen; with a compound of formula (V) , or an ester or amide thereof:

wherein R⁵, R⁶ and n are as defined in formula (I).

The reaction of a compound of formula (IV) with a compound of formula (V) 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 or toluene, under reflux and azeotropically to remove the water using a Dean and Stark trap.

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

Compounds of formula (III) may be prepared by treating a compound of formula (VI):

wherein R¹, R², R⁵, R⁶ and n are as defined in formula (I), and Z is a leaving group, with a metal azide, suitably an alkali metal azide, preferably sodium azide.

Preferably Z is halogen, most preferably chloro. Conveniently the reaction is carried out in a organic solvent such as dimethylsulphoxide at ambient temperature.

Compounds of formula (VI) may be prepared by treating a

compound of formula (VI I ) :

wherein R¹, R², R⁵, R⁶, and n are as defined in formula (I), with a suitable reagent known to convert a hydroxyl group to a group Z.

Compounds of formula (VI) wherein Z is halogen are conveniently prepared by treating a compound of formula (VII) with a conventional reagent known to convert hydroxy to halogen, such as thionyl chloride.

Compounds of formulae (IV), (V) and (VII) are either known compounds or can be prepared from known compounds by known methods.

A compound of formula (I) or a pharmaceutically acceptable salt, ester or amide 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, ester or amide 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, binder, 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, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate, sucrose and the like.

Most suitably the composition will be provided in unit dose form. Such unit dose will normally comprise 0.1 to 1,000 mg of the drug, more usually 0.1 to 500 mg and favourably 0.1 to 250 mg .

The present invention further provides a method for treating hyperglycaemia in human or non-human animals which method comprises administering an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof to a hyperglycaemic animal.

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 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 t0 6000 mg, and more usually about 1 to 1500 mg .

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

The dose for obese humans is similar to that for hyperglycaemic humans.

In treating obese or hyperglycaemic domestic animals, especially dogs, the drug may be administered by mouth, usually once or twice a day and at about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg .

The invention will now be illustrated with reference to the following Examples, which are not intended to limit the scope in any way. Examples 1 to 8 are examples of compounds of the invention, and Examples XI to X16 are examples of intermediates.

In the Examples, the substituents in formula (I) are as shown in the following Table:

EXAMPLE 1

Methyl 4-[2-{(2-(3-chlorophenyl)-2-dimethylaminoethyl) amino}propyl]phenoxyacetate dihydrochloride

A solution of methyl 4-(2-oxopropyl) phenoxyacetate (6.30 and 2-(3-chlorophenyl)-2-dimethylaminoethanamine (5.65g) in dry toluene (200ml) was heated under reflux for 2 hours in an apparatus incorporating a water trap. The solution was cooled and the solvent removed under reduced pressure. The residue, in methanol (100ml), was hydrogenated in the presence of platinum (from platinum oxide, 50mg) until hydrogen uptake ceased. The solution was filtered through diatomaceous earth and the solvent removed under reduced pressure. Chromatography of the residue on silica-gel in 4%. methanol-dichloromethane gave an oil which on treatment with an ethereal solution of hydrogen chloride gave the title compound m.p. 92-98°C (ethyl acetate-ether) as a 47:53 mixture of diastereoisomers.

¹H nmr δ((CD₃) ₂SO) :

1.15 (3H,d), 2.75 (6H,s) , 2.8-4.6 (5H, complex) , 3.72 (3H,s) , 4.82 (2H,s) , 5.05-5.3 (1H,t) , 6.85 (2H,d) , 7.15 (2H,d) , 7.5-8.05 (4H, complex) , 9.3-10.7 (3H, broad s, exchanges with D₂0) .

EXAMPLE 2

N-Methyl 4-[2-{(2-(3-chlorophenyl]-2-dimethylamino ethyl) amino}propyl]phenoxyacetamide dihydrochloride monohydrate

Met l 4-[2-{2-(3-chlorophenyl)-2-dimethylaminoethyl)amino}propyl]phenoxyacetate (5.0g) was added to a solution of 33% methylamine in ethanol (100ml) and. this mixture was heated under reflux with stirring for 4 hours. The solvent was evaporated to give an oil which on treatment with an ethereal solution of hydrogen chloride gave the title compound m.p. 158-162°C (acetone-methanol) as a 38:62 mixture of diastereoisomers

¹H nmr δ[(CD₃) ₂SO] :

1.15 (3H,d) , 2.6-2.8 (9H, complex), 2.8-4.55 (5H, complex), 4.45 (2H,s), 4.95 (1H,t), 6.85 (2H,d) , 7.15 (2H,d), 7.5-8.0 (4H, complex), 8.15 (1H, broad s, exchanges with D₂O) , 9.3-10.7 (5H, broad s, exchange with D₂O) .

EXAMPLE 3

Methyl 4-[2-{(2-dimethylamino-2-phenylethyl)amino}propyl] phenoxyacetate dihydrochloride monohydrate

Methyl 4-(2-oxopropyl)phenoxyacetate (4.44g) and 2-dimethylamino-2-phenylethanamine (3.28g) were condensed and subsequently reduced by an analogous procedure to that described in Example 1. Chromatography on silica-gel in 5% methanol-dichloromethane gave an oil which on treatment with a solution of hydrogen chloride in ether gave the title compound m.p. 96-107°C as a 55: 45 mixture of diastereoisomers.

¹H nmr δ[(CD₃)₂SO]

1.17 (3H,d), 2.72 (6H,s), 3.1-4.35 (5H, complex), 3.70 (3H,s), 4.78 (2H,s), 4.9-5.2 (1H,t), 6.85 (2H,d), 7.15 (2H,d), 7.4-7.8 (5H,complex) , 9.3-10.5 (5H, broad s, exchanges with D₂O) .

EXAMPLE 4

Methyl 4-[2-{(2-(3-chlorophenyl)-2-methylaminoethyl)amino}propyl]phenoxyacetate dihydrochloride

Methyl 4-(2-oxopropyl)phenoxyacetate (7.86g) and 2-methylamino-2-phenylethanamine (6.55g) were condensed and subsequently reduced by an analogous procedure to that described in example 1. Chromatography on silica-gel in 5% methanol-dichloromethane gave an oil which on treatment with a solution of hydrogen chloride in ether gave the title compound, m.p. 128-136°C (methanol-ethyl acetate-ether) as a 40:60 mixture of diastereoisomers .

¹H nmr δ[(CD₃)₂SO]

1.15 (3H,d) , 2.45 (3H,s) , 2.55-4.25 (5H, complex),

3.72 (3H,s) , 4.65-5.00 (2H,s overlapping 1H,t) , 6.85 (2H, d) , 7.15 (2H,d) , 7.45-8.00 (4H, complex), 9.5-10.6 (4H, broad s, exchanges with D₂O) .

EXAMPLE 5

Methyl 4-[2-{(2-dimethylamino-2-(3-trifluoromethylphenyl)amino ethyl)amino}propyl] phenoxyacetate dihydrochloride hemi hydrate

Methy l)phenoxyacetate (6.2g) and 2-dimethyl amino-2-(3-trifluoromethylphenyl) ethanamine (6.4g) were condensed and subsequently reduced by an analogous pro cedure to that described in Example 1. Chromatography on silica-gel in 5% methanol-dichloromethane gave an oil which on treatment with a solution of hydrogen chloride in ether gave the title compound m.p. 137-145°C (acetone-ether) as a 63:37 mixture of diastereoisomers .

¹H nmr δ[(CD₃)₂SO]

1.15 (3H,d), 2.72 (6H,s), 2.80-4.40 (5H,complex) , 3.70

(3H,s), 4.80 (2H,s), 5.20 (1H,t), 6.85 (2H,d), 7.15 (2H,d), 7.60-8.25 (4H,complex) , 9.25-10.50 (4H, broad s, exchanges with D₂O) .

EXAMPLE 6

Methyl 4-[2-{(2-(3-chlorophenyl)-2-benzylaminoethyl)amino}propyl3phenoxyacetate dihydrochloride

Platinum oxide (100mg) was added to a mixture of methyl 4-(2-oxopropyl)phenoxyacetate (4.5g) and 2-(3-chlorophenyl)2-benzylaminoethanamine (5.4g) in methanol (100ml) and the mixture was reduced under hydrogen until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the solvent was removed under reduced pressure and the residual oil was chromatographed on silica gel in 5% methanol-dichloromethane. The title compound m.p. 88-95°C was obtained as a 42:58 mixture of diastereoisomers by treatment with ethereal hydrogen chloride.

¹H nmr δ(DMSO-d₆ + D₂O)

1.15 (3H,d), 2.55-4.35 (10H, complex), 4.80 (2H,s) , 5.00 (1H,t) , 6,85 (2H,d), 7.20 (2H,d) , 7.25-7.95 (9H, complex).

EXAMPLE 7

Methyl 4-[2-{(2-phenyl-2-aminoethyl)amino}propyl1 benzoate dihydrochloride

A solution of methyl 4-[2-{2-phenyl-2-azidoethylamino}propyl]benzoate (3.1g) in methanol (100ml) was hydrogenate in the presence of 5% palladium on carbon for 5 hours. The catalyst was filtered off and the solvent was evaporated under reduced pressure. The oil obtained was treated with an ethereal solution of hydrogen chloride and the solid filtered and dried under vacuum to give the title compound m.p. 249-252°C.

¹ H nmr δ(DMSO-d₆)

1.2 (3H,d) , 2.6-3.8 (5H, complex) , 3.85 (3H,s) , 5.0 (1H, complex) , 7.25-8.05 (9H, complex) , 9.0-10.5 (5H, broad s, exchanges with D₂O) .

EXAMPLE 8

Methyl 4-[2-{2-(3-chlorophenyl)-2-aminoethyl)amino}propyl]phenoxyacetate dihydrochloride

The title compound m.p. 152-65°C was prepared from methyl 4-[2-{(2-(3-chlorophenyl)-2-azidoethyl)amino}propyl]phenoxyacetate as a 65:35 mixture of diastereoisomers by an analogous procedure to that described in Example 7.

¹H nmr δ (DMSO-d₆ + D₂O)

1.15 (3H,d) , 2.80-4.25 (8H, complex), 4.75 (2H,s) , 4.85 (1H,t), 6.85 (2H,d), 7.20 (2H,d), 7.40-7.85 (4H, complex).

EXAMPLE X1

α-Bromo-α-(3-chlorophenyl) acetonitrile

α-(3-Chlorophenyl)-acetonitrile (25g) was heated to 110°C and bromine (8.6ml) was added dropwise with stirring. On completion of the addition the mixture was stirred at 110°C for a further 15 minutes. After cooling, excess bromine and hydrogen bromide were blown off under a stream of nitrogen. The residue was distilled to give the title compound b.p. 132-136°C (1.0mm).

¹H nmr δ(CDCl₃) :

5.52 (1H,s), 7.20-7.65, (4H, complex).

EXAMPLE X2

α-Bromo-α-(3-trifluoromethylphenyl)acetonitrile

The title compound was prepared from α-(3-trifluoromethylphenyl)acetonitrile as a liquid (b.p. 116-120°C at 1.5mm) by an analogous procedure to that used in Example X1.

¹H nmr δ(CDCl₃) :

5.58 (1H,s), 7.55-8.00 (4H,complex) .

EXAMPLE X3

α-(3-Chlorophenyl)-α-methylaminoacetonitrile

A solution of methylamine in ethanol (10ml of a 33% solution) was added dropwise to a stirred solution of α-bromo-α-(3-chlorophenyl) acetonitrile (2.3g) in ethanol (40ml) at room temperature. The mixture was stirred at room temperature for 90 minutes, filtered and the solvent removed under reduced pressure. The residue in ether (100ml) was washed with saturated sodium chloride solution, dried (magnesium sulphate) , filtered and evaporated. The residual oil was used in the next stage without further purification.

¹H nmr (δ; CDCl₃) :

2.48 (3H,s) , 1.7-2.6 (1H, broad s, exchanges with D₂O) , 4.72 (1H,s), 7.2-7.6 (4H, complex).

EXAMPLE X4

α-(3-Chlorophenyl)-α-dimethylamino acetonitrile

A solution of dimethylamine in ethanol (20ml of 33% solution) was added dropwise to a stirred solution of α-bromo-α-(3-chlorophenyl)acetonitrile ( 8.7g) in ethanol (70ml) with ice cooling. The mixture was stirred at room temperature for 18 hours then filtered and the solvent was evaporated under reduced pressure. The residue in ether was washed with saturated sodium chloride solution, dried (magnesium sulphate) , filtered and evaporated. The residual oil was used in the next stage without further purification.

¹H nmr δ(CDCl₃) :

2.34 (6H,s), 4.82 (1H,s), 7.20-7.60 (4H, complex).

EXAMPLE X5

α-Dimethylamino-α-(3-trifluoromethylphenyl)acetonitrile

The title compound was prepared from α-bromo-α- (3-trifluoromethylphenyl)acetonitrile by an analogous procedure to that used in Example X4.

¹H nmr δ(CDCl₃) :

2.34 (6H,s), 4.85 (1H,s), 7.4-7.75 (4H, complex).

EXAMPLE X6

α-Dimethylamino-α-phenylacetonitrile

The title compound was prepared from α-bromo-α-phenylacetonitrile by an analogous procedure to that used in Example X4.

¹H mrtr δ(CDCl₃) :

2.25 (6H,s) , 4.80 (1H,s) , 7.25-7.55 (5H,s).

EXAMPLE X7

2-(3-Chlorophenyl)-2-methylamino ethanamine

A solution of α-(3-chlorophenyl)-α-methylaminoacetonitrile (8.5g) in dry ether (40ml) was added dropwise to a suspension of lithium aluminium hydride (4.0g) in dry ether (80ml) with stirring and ice cooling under an atmosphere of nitrogen. The mixture was allowed to warm to room temperature and stirred. for 1 hour and then heated under reflux for 1 hour. After cooling, water (4ml), 10% sodium hydroxide solution (4ml), and water (4ml) were added sequentially. The mixture was filtered and evaporated to give the title compound which was used without further purification.

¹H nmr δ(CDCl₃) :

1.4-1.9 (3H, broad s, exchanges with D₂O) , 2.30 (3H,s) , 2.7-2.9 (2H, complex) , 3.2-3.4 (1H, complex) , 7.1-7.3 (4H, complex) .

EXAMPLE X8

2-(3-Chlorophenyl)-2-dimethylaminoethanamine

The title compound was prepared from α-(3-chlorophenyl)-α-dimethylaminoacetonitrile (6.7g) as an oil by an analogous procedure to that used in Example X7.

¹H nmr δ(CDCl₃) :

0.9-1.2 (2H, broad s, exchanges with D₂O) , 2.88 (6H,s) , 2.80-3.15 (3H, complex), 7.1-7.35 (4H, complex).

EXAMPLE X9

2-Dimethylamino-2-phenylethanamine

The title compound was prepared from α-dimethylamino-α-phenylacetonitrile by an analogous procedure to that used in Example χ7.

¹H nmr δ (CDC1₃) :

0.9-1.25 (2H, broad singlet, exchanges with D₂O) ,

2.18 (6H,s) , 2.85-3.20 (3H, complex), 7.1-7.3 (5H, broad s)

EXAMPLE X1 0

2-Dimethylamino-2-(3-trifluoromethylphenyl)ethanamine

The title compound was prepared from α-dimethylamino-α-(3-trifluoromethylphenyl)acetonitrile by an analogous procedure to that used in Example X7.

¹H nmr δ(CDCl₃) :

1.3-1.7 (2H, broad s, exchanges with D₂O) , 2.20 (6H,s) , 2.85-3.35 (3H, complex), 7.35-7.70 (4H, complex).

EXAMPLE X 11

α-Benzylamino-α-(3-chlorophenyl)acetonitrile

The title compound was prepared from α-bromo-(3-chloro phenyl)acetonitrile by an analogous procedure to that described in Example X 4.

¹H nmr δ(CDCl₃)

- 2.80 (1H, broad s, exchanges with D₂O) , 3.85 (2H,d), 4.60 (1H,s), 7.0-7.55 (9H, complex).

EXAMPLE X 1 2

2-Benzylamino-2-(3-chlorophenyl)ethanamine

The title compound was prepared from α-benzylairtino-α-(3-chloroρhenyl)acetonitrile by an analogous procedure to that used in Example X 7.

¹H τιmr δ(CDCl₃)

1.50 (3H,s, exchanges with D₂O) , 2.65-3.90 (5H, complex), 7.25 (9H,s).

EXAMPL E X 13

Methyl 4-[2-{2-(3-chlorophenyl)-2-azidoethylamlno} propyl]phenoxyacetate

Sodium azide (0.5g) was added to a solution of methyl 4-_.2-{2-(3-chlorophenyl)-2-chloroethylamino}propyl] phenoxyacetate hydrochloride (3.2g) in dimethylsulphoxide (100ml) and the mixture was stirred at room temperature for 2 hours. Water (500ml) was added and the solution, was extracted twice with ether. The combined organic phases was washed with saturated sodium chloride solution, dried (magnesium sulphate) , filtered and evaporated to give the title compound which was used without further purification.

¹H nmr δ(CDCl₃)

1.05 (3H,d) , 1.85 (1H, broad s, exchanges with D₂O) , 2.65-3.2 (5H, complex), 3.80 (3H,s) , 4.50 (3H,d superimposed on t) , 6.7-7.4 (8H, complex).

EXAMPLE X 14

Methyl 4-[2-{2-phenyl-2-azidoethylamino}propyl]benzoate

The title compound was prepared from methyl 4-[2-{2-phenyl-2-chloroethylamino}propyl]benzoate hydrochloride by an analogous procedure to that described in Example X 13.

¹H nmr δ(CDCl₃)

1.10 (3H,d); 2.10 (1H, broad s) ; 2.6-3.2 (5H, complex);

3.95 (3H,s); 4.60 (1H,t); 7.05-7.50 (7H, complex); 8.0 (2H,d).

EXAMPLE X 15

Methyl 4-[2-{2-(3-chlorophenyl)-2-chloroethylamino}propyl]phenoxyacetate hydrochloride

Thionyl chloride (20 ml) was added dropwise to a stirred solution of methyl 4-[2-{2-(3-chlorophenyl)-2-hydroxyethylamino}propyl]phenoxyacetate (75.6 g) in dichloromethane (250 ml) with cooling in an ice-bath. On completion of the addition. the suspension was allowed to warm to room temperature and stirred overnight.. The precipitate was filtered and dried under vacuum and was used without further purification.

¹H nmr δ(DMSO-d₆)

1.20 (3H,d); 2.3-4.1 ( 5H , complex); 3.75 (3H,s) ; 4.75 (2H s); 5.8 (1H,t); 6.7-7.85 (8H, complex); 9.0-10.3 (2H, broad s , exchanges with D₂O) .

EXAMPLE X 1 6

Methyl 4-[2-{2-phenyl-2-chloroethylamino}propyl]benzoate hydrochloride

The title compound, m.p. 192-94°C, was prepared from methyl 4-[2-{2-phenyl-2-hydroxyethylamino}propyl] zoate by an analogous procedure to that described in Example X 15.

¹H nmr δ(DMSO-d₆)

1.20 (3H,d); 2.75-4.10 (5H, complex); 3.85 (3H,s) ; 5.8 (1H,t); 7.2-8.1 (9H, complex); 9.0-10.8 (2H, broad d, exchanges with D₂O) .

Demonstration of Effectiveness of Compounds

(a) Hypoglycaemic activity

Female CFLP mice, weighing approximately 25g, 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 (10μl) was obtained from the tail for the analysis of blood glucose. Immediately after taking this blood sample, glucose (1g/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.

(b) 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 24g 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 where necessary, 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 results for each compound are expressed as a percentage of the energy expenditure of the mice dosed with water.

Claims

A compound of formula (I) :

or a pharmaceutically acceptable salt, ester or amide thereof, in which, R¹ is hydrogen or halogen;

R² is hydrogen, halogen or trifluoromethyl, each of R³ and R⁴ is hydrogen, C₁-6 alkyl or phenyl-C₁-6-^{alkyl ,}

R⁵ is hydrogen or methyl; n is 1 or 2; and

R⁶ is CO₂H, O-R⁷-CO₂H, in which R⁷ is a C₁-6 straight or branched alkylene chain, or O-R⁸-R⁹ in which R⁹ is hydroxy, or C₁-6^-alkoxy, or -NR¹⁰R¹¹ in which R¹⁰ and R¹¹ are each hydrogen or C₁-6 alkyl, and R⁸ is a C₂-7 straight or branched alkylene chain with at least two carbon atoms separating the hetero-atoms. A compound according to claim 1, in which R² is in the meta-position and is chlorine or trifluoromethyl, and R¹ is hydrogen.

3. A compound accordingy to claim 1 or claim 2, in which R⁷ is methylene.

4. A compound according to any one of claims 1 to 3, in which R⁵ is methyl.

5. A process for preparing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, ester or amide thereof, which comprises reducing the nitrogen-carbon double bond of a compound of formula (II) , or an ester or amide thereof:

wherein R¹, R², R³ R⁴, R⁵ R⁶ and n are as defined in formula (I) , and optionally thereafter forming a salt of the compound of formula (I) so formed, and/or converting the compound of formula (I) so formed into a further compound of formula (I) .

6. A process for preparing a compound of formula (I) , according to claim 1 wherein R³ , R⁴ are each hydrogen which comprises reducing a compound of formula (III) : wherein R¹ , R² , R⁵ , R⁶ and n are as defined in formula (I) , and optionally thereafter forming a salt of the compound of formula (I) so formed, and/or converting the compound of formula (I) so formed into a further compound of formula (I) .

A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, ester or amide thereof, together with a pharmaceutically acceptable carrier therefor.

A method for treating obesity or hyperglyeaemia in human or nonhuman animals, which method comprises administering an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof to an obese or hyperglycaemic animal.