4-[2-(2-HYDROXY-2-PHENYLETHYLAMINO)ETHYL]PHENYLACETIC ACID AS BETA3-ADRENOCEPTOR-AGONIST

Abstract: Compounds of formula (I), and in vivo hydrolysable esters and pharmaceutically acceptable salts thereof are described as beta 3-adrenoceptor agonists having anti-obesity, hypoglycaemic, and related therapeutic utilities. Processes for their preparation are described as are compositions containing them.

Description: 4-[2-(2-HYDR0XY-2-PHENYLETHYLAMIN0)ETHYL]PHENYLACETIC ACID AS BETA 3 -APREN0CEPTOR-AG0NIST The present invention relates to 4-[2-(2-hydroxy-2-phenyl- ethylamino)ethyl]phenylacetic acid and bioprecursors thereof. This invention further relates to processes and intermediates for their preparation, to their use in methods of therapy and to pharmaceutical compositions containing them. The compounds of the present invention are β,-adrenoceptor agonists and are of value in disease conditions mediated through such adrenoceptors. Administration of the compounds of this invention to warm-blooded animals provides a thermogenic effect, that is ther ogenesis is stimulated and administration of the compounds is of use, for example, in the treatment of obesity and related conditions such as mature onset diabetes associated with obesity. In addition, the compounds of this invention improve glucose tolerance in warm-blooded animals and are of use in combatting disease conditions wherein such activity is beneficial for example they have hypoglycaemic activity. The compounds of this invention may also be used in the treatment of non-insulin dependent diabetes mellitus (NIDDM) and in conditions wherein insulin resistance is of importance such as hypertension, hyperlipidaemia and decreased fibrinolysis (Reaven's syndrome or Syndrome X). The present applicants have conducted substantial research into β,-adrenoceptor agonists and, in particular into their thermogenic effect. Our own United States Patent 4772631 discloses compounds of the formula (A): VθCH 2 CH(OH) 0CH 2 Z (A) 3. h e wherein R is hydrogen or fluoro; R and R are independently selected from hydrogen and C, ^ alkyl; and Z is hydroxymethyl or a group of the formula -COR in which R is hydroxy, C 1 ,alkoxy or amino. Our own United States Patent 4977148 discloses compounds of the formula (B): R c -0CH 2 CH(OH)CH 2 NHCH 2 CH 2 0 // W 0CH 2 C0NR e R f (B) a e f wherein R is hydrogen or fluoro and R and R are independently hydrogen or a variety of groups leading to secondary and tertiary amides. It is believed that compounds of the formula (A) wherein R is alkoxy or amino, and the compounds of the formula (B) , are primarily bioprecursors that are effective via the corresponding oxyacetic acid; that is the compound of the formula (A) wherein R is hydroxy. The present applicants identified the compound of the formula r_ C Q (A) wherein R -R were hydrogen and R was hydroxy as being of significant interest. However, this compound did not have an ideal profile of solubility and absorption characteristics. Accordingly, the present applicants developed a secondary amide bioprecursor of this . compound. This secondary amide was introduced into human volunteer patients. Disappointingly, there was insufficient effect on metabolic rate in the clinic and this, in effect, pointed to insufficient efficacy of the free carboxylic acid at the β-.-adrenoceptor. Further investigations were performed and we have now discovered a compound which, surprisingly, provides significant thermogenic effects at doses which cause relatively few side-effects. It is understood that selectivity of thermogenic effect, for example lack of cardiac side-effects, is an important requirement for a useful therapeutic agent in the treatment of, for example, obesity and related conditions. This compound of the present invention is a carboxylic acid and shows significant advantage over the above referred to secondary amide and free carboxylic acid. In particular, it has been shown to have full efficacy at β 3 ~adrenoceptors, whereas the compound which had been administered to man was found to have low efficacy. In addition, it has been shown to have surprisingly good solubility and absorption characteristics. This compound falls within European Patent Application 63004, published 20 October 1982, which discloses derivatives of ethanolamine of the formula: R " 1 2 3 wherein R is hydrogen or methyl; R is hydrogen or methyl; R is hydrogen, fluorine, chlorine, bromine, trifluoromethyl or C, ,alkyl; n 4 is 1 or 2; X is C._ 6 straight or branched alkylene; R is C.._,alkoxy, hydroxy, or amino optionally substituted with one or more lower alkyl groups; and A is hydrogen, fluorine, chlorine or bromine. These derivatives are stated to have anti-obesity and/or hypoglycaemic activity. We have now discovered a compound within the above formula, which exhibits particularly good thermogenic behaviour at doses which cause relatively few side-effects as referred to hereinabove. It has a particularly good profile of activity as evidenced for example by " potency in the GDP binding test, lipolytic activity, selectivity for β-adrenoceptors and effects on plasma glucose, insulin and fatty acid levels. Accordingly the present invention provides a compound of the formula (I) : Ph-CH(OH)CH 2 NHCH 2 CH 2 . . CH 2 C00H (I) or a pharmaceutically acceptable salt thereof. 4-[2-(2-Hydroxy-2-phenylethylamino)ethyl]phenylacetic acid is amphoteric and may be used in the zwitterionic form, or as a pharmaceutically acceptable acid addition salt, or as a salt with a base affording a pharmaceutically acceptable cation. Particular examples of pharmaceutically acceptable acid-addition salts include, for example, salts with inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides) , sulphates and phosphates, and salts with organic acids such as succinates, citrates, lactates, tartrates and salts derived from acidic water-soluble polymers. Particular examples of salts with bases affording a pharmaceutically acceptable cation include, for example, alkali metal and alkaline earth metal salts, such as sodium, potassium, calcium and magnesium salts, and ammonium salts and salts with suitable organic bases such as triethanolamine. The present invention also provides bioprecursors of the compound of the formula (I). Bioprecursors are those pharmaceutically acceptable compounds that are degraded in the animal body to produce the parent acid. Such compounds can be identified by administering, for example orally to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable bioprecursors include the ester, amide, secondary amide and tertiary amide derivatives of the carboxylic acid function. In addition, bioprecursors may be formed at the -CH(OH)- hydroxy function for example -CH(OCOR)- compounds wherein R is C, fi alkyl in particular methyl. Particularly suitable bioprecursors are the Cr_ β alkyl esters formed at the carboxylic acid function for example the methyl and ethyl esters. Bioprecursors of 4-[2-(2-hydroxy-2-phenyl- ethylamino)ethyl]phenylacetic acid may have a thermogenic effect in their own right and this is another aspect of the present invention. It will be appreciated that 4-[2-(2-hydroxy-2-phenylethyl- amino)ethyl]phenylacetic acid and bioprecursors thereof contain an asymmetric carbon atom and can exist as optically active enantiomers or as an optically inactive racemate. The present invention encompasses any enantiomer or racemate which when administered in a therapeutic amount provides a thermogenic effect in warm-blooded animals, it being well known in the chemical art how to prepare individual enantiomers, for example by resolution of the racemate or by stereospecific synthesis, and how to determine the thermogenic properties, for example, using the standard tests described hereinafter. It is preferred that the compounds of the present invention are provided in the (R) absolute configuration at the -CH(OH)- group (under the Cahn-Prelog-Ingold rules). In order to use a compound of the present invention or a pharmaceutically acceptable salt thereof for the therapeutic treatment of warm-blooded mammals including humans, in particular for treating obesity, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises 4-[2-(2-hydroxy-2-phenyl- ethylamino)ethyl]phenylacetic acid, or a bioprecursor thereof or a pharmaceutically acceptable, salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical compositions of this invention may be administered in standard manner for example by oral or parenteral administration. For these purposes they may be formulated by means known to the art into the form of, for example, tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions, and sterile injectable aqueous or oily solutions or suspensions. In general compositions for oral administration are preferred. The compositions may be obtained using standard excipients and procedures well known in the art. A unit dose form such as a tablet or capsule will usually contain, for example 0.1-500 mg of active ingredient, more suitably 10-250mg, and preferably 50-100mg of the compound of this invention. The compositions may also contain other active ingredients known for use in the disease conditions to be treated, for example appetite suppressants, vitamins, antihypertensives and hypoglycaemic agents such as sulphonylureas, biguanides and thiazolidinediones. It is understood that such compositions cover co-formulation, concurrent and sequential therapy of the two or more active ingredients. In one aspect of the present invention, 4-[2-(2-hydroxy-2- phenylethylamino)ethyl]phenylacetic acid or a bioprecursor thereof may be formulated for oral administration in a sustained (or delayed) release composition, for example a matrix tablet formulation comprising insoluble or swellable polymeric filler, or a coated spheroid formulation. When used to produce thermogenic effects in warm-blooded animals including man, 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]- phenylacetic acid or a bioprecursor thereof or a pharmaceutically acceptable salt thereof as appropriate, will be administered so that a dose in the general range 0.002-20 mg/kg, suitably in the range 0.02-10 mg/kg, and preferably in the range 0.5-5mg/kg is administered daily, given in a single dose or divided doses as necessary, typically one to three times a day. However, it will be appreciated by those skilled in the art that dosage will necessarily be varied as appropriate, depending on the severity of the condition under treatment and on the age and sex of the patient and according to known medical principles. In addition the compounds of the present invention lower triglyceride levels and cholesterol levels and raise high density lipoprotein (HDL) levels and are therefore of use in combatting medical conditions wherein such lowering (and raising) is thought to be beneficial. Thus they may be used in the treatment of hypertriglyceridaemia, hypercholesterolaemia and conditions of low HDL levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions. Accordingly in another aspect the present invention provides a method of lowering triglyceride and/or cholesterol levels and/or increasing HDL levels which comprises administering, to an animal in need thereof, a therapeutically effective amount of 4-[2-(2-hydroxy-2- phenylethylamino)ethyl]phenylacetic acid or a bioprecursor thereof or pharmaceutically acceptable salt thereof. In a further aspect the present invention provides a method of treating atherosclerosis which comprises administering, to an animal in need thereof, a therapeutically effective amount of 4-[2-(2-hydroxy-2-phenylethyl- amino)ethyl]phenylacetic acid or a bioprecursor thereof or pharmaceutically acceptable salt thereof. The compositions are formulated and administered in the same general manner as detailed above for producing a thermogenic effect. They may also contain other active ingredients known for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, simvastatin and pravastatin; inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA:cholesterol acyltransferase) inhibitors for example melinamide; anion exchange resins for example cholestyramine, colestipol or a dialkyla inoalkyl derivative of a cross-linked dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics. ~ In a further aspect the compounds of the present invention stimulate the "atypical" β-adrenoceptors in the gastrointestinal tract and therefore inhibit gastrointestinal motility. They may be of use in combatting medical conditions wherein stimulation of "atypical" β-adrenoceptors in the gastrointestinal tract is thought to be beneficial, such as in combatting medical conditions wherein inhibition of gastrointestinal motility is thought to be of value. Thus they may be of use for example in the treatment of inflammatory bowel disease (IBD) (such as Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), non-specific diarrhoea and dumping syndrome. Accordingly the present invention provides a method of stimulating the "atypical" β-adrenoceptors in the gastrointestinal tract which comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the present invention. In a further aspect the present invention provides methods of inhibiting gastrointestinal motility, treating IBD, treating IBS, treating non-specific diarrhoea and treating gastric emptying in dumping syndrome which comprise administering to an animal in need thereof, a therapeutically effective amount of a compound of the present invention. In a further aspect the present invention provides a process for preparing 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid or a bioprecursor thereof or a pharmaceutically acceptable salt thereof which process comprises: a) reacting a compound (II) or (III) with a compound of the formula (IV) : Ph-CH ACH 2 (II) Ph-CH(OH)CH 2 L (III) NH 2 CH 2 CH 2 -Q- CH 2 R J (IV) wherein R is carboxy or protected carboxy and L is a displaceable group; or b) hydrolysis of a compound of the formula (V) , (V) wherein R is as hereinbefore defined; or c) for 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid hydrolysing a compound of the formula (VI): wherein R is a hydrolysable group; d) reacting a compound of the formula (VII) with a compound of the formula (VIII): Ph-CH(OH)CH 2 NH 2 (VII) L' wherein R is as hereinbefore defined and L' is a displaceable group; e) deprotecting a compound of the formula (IX): wherein R is protected carboxy group as hereinabove defined; f) converting 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenyl- acetic acid into a bioprecursor, or vice versa, or converting a bioprecursor of 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid into another bioprecursor of 4-[2-(2-hydroxy-2-phenylethylamino)- ethyl]phenylacetic acid; g) reducing a compound of the formula (X): wherein R is as hereinbefore defined; h) reducing a compound of the formula (XI) wherein R is as hereinbefore defined; i) reducing a compound of the formula (XII): wherein R is as hereinbefore defined; and wherein any functional group is optionally protected and thereafter if necessary; (i) removing any protecting groups; (ii) forming a pharmaceutically acceptable salt. Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. A particular protecting group is a hydrogenolysable group present on the nitrogen atom of -CH(0H)CH 2 CH 2 CH 2 -. Suitably the protecting group is benzyl or a substituted benzyl group. Such a protecting group may be removed in conventional manner using methods of catalytic hydrogenation, for example palladium on carbon catalysts in an atmosphere of hydrogen. Suitable conditions include ambient and elevated temperatures and pressures in a solvent such as a C- , alkanol for example ethanol or propan-2-ol. Compounds corresponding to formula (I) protected with a hydrogenolysable group on the nitrogen atom may be prepared by methods analogous to those described above for formula (I). 5 The protected carboxy group R may represent the desired bioprecursor group in which case there is no need to perform a deprotection reaction. In general, where an acid addition salt of an amine is used, for example of structures (IV) or (VII) , the reaction may be carried out advantageously in the presence of an acid binding agent such as an inorganic salt, for example, sodium carbonate or potassium carbonate, or a metal alcoholate, for example, sodium methoxide, sodium ethoxide or potassium tert-butoxide, or a suitable organic amine, preferably a tertiary amine, for example, triethylamine. The reaction between a compound of the formulae (II) or (III) and a compound of the formula (IV) may be performed in a suitable solvent for example an alcohol such as methanol, ethanol or propan-2-ol, at a temperature in the range for example 10°C to 110°C and most conveniently at or near the boiling-point of the reaction mixture. In the compound of the formula (III) L may be, for example, halogen such as chloro or bromo or an arylsulphonyloxy group such as toluenesulphonyloxy or an alkanesulphonyloxy group such as methanesulphonyloxy. The compound of the formula (V) may be hydrolysed to 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid or a bioprecursor thereof under conditions known in the beta adrenergic blocker art; for example via alkaline hydrolysis in a suitable solvent for example an alkanol at an elevated temperature. The compounds of the formula (V) may be prepared by the reaction of a compound of the formula (VIII) with a compound of the formula (XIII): for example in the presence of a base in a solvent such as acetone at an elevated tempature. In an alternative the compounds of the formula (V) may be prepared by the reaction of a compound (II) with a compound of the formula (XIV): (XIV) wherein R is as hereinbefore defined and R 0- is a leaving group, for example R 0- is C._,alkoxy. In the compounds of the formula (VI) examples of hydrolysable groups R include C._ fi alkoxy and -NR a R groups so that -COR represents a C. ,alkyl ester or an amide function. Such groups may be hydrolysed (acidic, basic, enzymatic) to a group -C0~H under conventional conditions. Conversions wherein R is an in vivo hydrolysable moiety also represent examples of interconversions of a bioprecursor of 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acetic acid into 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid. Suitable acid conditions are for example a strong mineral acid such as hydrochloric, sulphuric or phosphoric acid, conveniently at a temperature in the range, for example, 20° to I10°C and in a polar solvent, such as water, a C._,alkanol (for example methanol or ethanol) or acetic acid. In such cases, the corresponding mineral acid salt of 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid may be conveniently isolated. Alternatively, base conditions may be used, for example lithium, sodium or potassium hydroxide, conveniently in a suitable solvent or diluent such as an aqueous C. .alkanol at a temperature in the range, for example, 10° to 110°C; or an alkali halide for example lithium chloride in a polar solvent such as dimethylsulphoxide. As yet further alternatives, when -COR is t-butoxycarbonyl, the decomposition may be carried out, for example, by thermolysis at a temperature in the range, for example, 100 to 220°C, alone or in the presence of a suitable diluent such as diphenyl ether. The compounds of the formula (VI) may be prepared by methods analogous to those described hereinabove for 4-[2-(2-hydroxy-2-phenyl- ethylamino)ethyl]phenylacetic acid or a bioprecursor thereof, with optional protection of the amino function for example with a benzyl group. The reaction between the compounds of the formulae (VII) and (VIII) is conveniently performed under conditions analogous to the reaction between a compound (III) and a compound of the formula (IV). L' may have similar values as recited hereinabove for L. 4-[2-(2-Hydroxy-2-phenylethylamino)ethyl]phenylacetic acid and amide bioprecursors thereof may be converted to ester precursors thereof. Suitable conditions are, for example, under reflux in the corresponding alkanol under acidic conditions, for example, with the addition of concentrated sulphuric acid as a catalyst. The reduction of the compounds (X), (XI) and (XII) may be carried out by conventional chemical or catalytic methods, such as chemical reduction using sodium borohydride or by catalytic hydrogenation using catalysts such as palladium on charcoal, or platinum. Reduction by sodium borohydride is conveniently carried out in alcohol such as methanol and the reaction is generally carried out at from 0 - 20°C. Catalytic reduction is conveniently carried out in a conventional hydrogenation solvent such as an alcohol, for example ethanol. The hydrogenation is generally carried out under hydrogen gas at about 1 to about 10 atmospheres pressure and at ambient or elevated temperature. Compounds of the formula (X) may be prepared by the reaction of a compound of the formula (IV) with a compound of the formula (XV): Ph-C0CH 2 L" (XV) wherein h' ' is a displaceable group. The reaction between a compound of the formula (XV) and a compound of the formula (IV) may be performed in a suitable solvent such as an alcohol or an ether, for example methanol or diethyl ether, at a temperature in the range, for example, -10 to 110°C and most conveniently at ambient temperature. In the compounds of the formula (XV), L ' ' may be, for example, halogen such as chloro or bromo. The resulting compounds of the formula (X) may be converted into 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid or bioprecursors thereof in situ. The compounds of the formula (XV) may be prepared by methods known in the art. Compounds of the formula (XI) may be prepared by reacting a compound (XVI) with a compound of the formula (IV) : PhCOCHO (XVI) The reaction between a compound (XVI) with a compound of the formula (IV) may be performed in a suitable solvent such as an alcohol, for example, ethanol at a temperature range, for example, 0-80°C and most conveniently at ambient temperature. The resulting compounds of the formula (XI) may be converted into 4-[2-(2-hydroxy-2-phenylethyl- amino)ethyl]phenylacetic acid or bioprecursors thereof in situ. Compounds of the formula (XII) may be prepared by reacting compounds of the formula (XVII) with a compound (VII) : The reaction between a compound of the formula (XVII) and a compound (VII) may be performed in a suitable solvent such as an alcohol, for example, ethanol, at a temperature in the range, for example, 0 - 80°C and most conveniently at ambient temperature. The resulting compounds of the formula (XII) may be converted into 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid or bioprecursors thereof in situ. Compounds of the formula (XVII) may be prepared by hydrolysis of a compound of the formula (XVIII): R 8 0 \ CHCH 2 //_ W CH 2 R J (XVIII) 9 / R*0 5 8 9 wherein R is as hereinbefore defined and R and R are independently hydrogen or C. .alkyl. Suitable conditions for hydrolysis are, for example, a strong mineral acid such as hydrochloric or sulphuric; conveniently at a temperature range, for example, 20 - 110°C, in a suitable solvent such as tetrahydrofuran, dichloromethane or diethyl ether. The compounds of the formulae (V), (VI), (IX), (X), (XI) and (XII) are novel and form another aspect of the invention. Bioprecursor esters of the hydroxy group may be prepared in conventional manner for example by reacting the hydroxy group with an activated derivative of an acid under conditions known in the beta adrenergic blocker art. Pharmaceutically acceptable salts may be prepared by reacting 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid or a bioprecursor thereof with the appropriate acid or base in conventional manner. Alternatively when a hydrogen halide salt is required, it may conveniently be obtained by hydrogenation of the free base together with a stoichiometric amount of the corresponding benzyl halide. The following biological test methods, data and Examples serve to illustrate this invention. The thermogenic effects of 4-[2-(2-hydroxy-2-phenylethyl- amino)ethyl]phenylacetic acid and bioprecursors thereof may be demonstrated using one or more of the following standard tests:- Thermogenic effects The thermogenic effects of compounds of the formula (I) and bioprecursors thereof may be demonstrated using one or more of the following standard tests:- (a) Rats are cold adapted at 4°C for 5 days to increase their capacity for thermogenesis. They are then transferred to a warm environment of 25°C for 2 days. On the following day, a test compound is administered sub-cutaneously or orally. Animals are sacrificed one hour later and the interscapular, brown adipose tissue (BAT) pad is removed. BAT mitochondria are prepared by differential centrifugation and GDP binding is determined (Holloway et al. , British J. Pharmacol. (1991), 104 97-104) as a measure of thermogenic activation. Each test includes a control which is dosed with the solution/suspension vehicle only and a positive control which is dosed with isoprenaline (as its sulphate) at lmgkg- . Test compounds are routinely dosed at 0.1, 0.3, 1.0, 3.0, and 10 mgkg and results expressed in terms of the effect on GDP binding produced by the positive control. From these results, a dose (EDco) necessary to produce 50% of the isoprenaline effect is calculated by curve fitting. Compounds are considered active in this test if they cause a significant elevation in GDP binding as compared to controls. (b) Rats are adapted to a thermoneutral environment (29°C) for 2 weeks in order to decrease their capacity for BAT mediated non- shivering thermogenesis. During the final 5 days the animals are trained to use an apparatus for measuring heart rate non-invasively via foot-pad electrodes connected to an ECG integrator giving a continuous read-out of heart rate. A test compound is administered sub-cutaneously or orally at the ED determined in test (a), and heart rate is determined 15-30 minutes after dosing. The procedure is then repeated in subsequent tests using increasing multiples of the ED determined in test (a) until the heart rate (HR) reaches or exceeds 500 beats per minute, or until the dose reaches 100 times the ED ™ determined in test (a) . The dose necessary to produce a heart rate of 500 beats per minute (D ™n dose) is estimated. The ratio of D 0 to ED in test (a) can be defined as the selectivity index (SI) and provides a measure of the selectivity of the compound for BAT as opposed to the cardiovascular system. Compounds are considered to have significant selectivity which have an SI of >1. Non^-selective compounds have an SI of <1 (for example isoprenaline = 0.06). (c) Rats are kept at 23°C for at least two days, then fasted overnight. On the following day, the basal metabolic rate of the animals is determined using a close-circuit oxygen consumption apparatus of the type described by Arundel et al. , 1984, J. Appl. Physiol. Respirat. Environ. Exercise Physiol., 1984^ 57_ (5) 1591-1593. The rats are then dosed (orally) with test compound at about 1 mgkg " as a solution or suspension in 0.025% w/v Polysorbate 80 (0.5ml/100g) . Metabolic rate is then determined for at least one hour after dosing. Compounds are considered active in this test if they cause a significant increase in metabolic rate as compared to control animals (Student's t test: p <0.05) dosed only the solution or suspension vehicle. In the above tests, the compounds of the formula (I) in general produce effects of the following order without producing overt toxicity:- test (a): sub-cutaneous or oral ED ™ for GDP binding in BAT mitochondria of 0.01-10 mgkg ; test (b): show an SI of >50; and test (c): show 2-9ml 0- min (Kg " ) at lmgkg p.o. By way of illustration, the compound described in the accompanying Example 5, produces the following effects in the above tests:- (a) oral ED ™ 1.02 mgkg ; (b) SI >50 (oral); (c) 6.4ml 0 2 min "1 (Kg 0,75 ) "1 at lmgkg "1 p.o. Effects of the compound of Example 5 on weight gain and brown adipose tissue in obese Zucker rats The potential slimming effects of the compound of Example 5 have been assessed in obese (fa/fa) Zucker rats. Obese Zucker rats continue to store fat and increase body weight for most of their life span, and most develop complications or die before a stable body weight is achieved. Therefore the effects of the compound of Example 5 on obese Zucker rats were assessed in animals which were still gaining weight at a low rate. Obese (fa/fa), male, Zucker rats were caged singly and allowed free access to powdered rat diet and water for a period of one week. Over this period the average intake of food was determined and medicated diets were prepared so as to provide intakes of the compound of Example 5 equivalent to 2.0 and 20 mg/kg/24 hours. Rats were allocated to treatments with control or the compound of Example 5 medicated diet so that the mean body weight of each group was similar at the start of the experiment. Intake of food was measured on alternate days, and body weight determined weekly. After eight weeks of treatment the rats were killed and the interscapular fat pad excised for analysis of mitochondrial protein and GDP binding. Mitochondria were prepared by differential centrifugation (Holloway et al., British J. Pharmacol. (1991), 104, 97-104), Mitochondrial protein was determined by the method of Lowry et al. , ((1951) J. Biol. Chem. 193, 265-275) and suspensions adjusted to 2 mg/ml. Specific GDP binding was determined from the total GDP binding determined as described in Holloway et al (British J. Pharmacol (1991), JO4, 97-104), after subtraction of the nonspecific GDP binding determined by the same " method but in the presence of excess (200μM) unlabelled GDP. Results Table 2 Effects of chronic treatment with the compound of Example 5 on brown adipose tissue in obese (fa/fa) rats Group n Dose Protein Specific Total (mg/kg/day) mg (mg/g tissue) GDP binding GDP binding (nmol/mg) (nmol) —Control 10 3.13 1.50 0.197 0.630 +0.27 +0.17 +0.014 +0.075 Compound 8 4.71 2.82 0.249 1.175 +0.66 +0.46 +0.027 +0.196 Compound 10 20 Results are expressed as mean +_ standard error of the mean of the number of animals in each group. Results which are significantly different from controls are indicated by asterisks: * P<0.05 ** P<0.01 *** P<0.001 approximate 24 hour intake of 'compound' Specific GDP binding = nmol GDP bound/ g mitochondrial protein Total GDP binding = nmol GDP bound/total mitochondrial protein recovered from BAT Treatment of obese male Zucker rats with 'compound' (2.0 and 20 mg/kg/day) for 8 weeks resulted in an increase in the mitochondrial content of brown adipose tissue. This was associated with a significant increase in specific GDP binding, an index of the thermogenic activity of the tissue, at 20 mg/kg/day. Treatment of obese rats at the lower dose tested, 2.0 mg/kg/day, which is twice the estimated ED ™ of this compound after an acute dose, resulted in a small, non-significant increase in specific GDP binding. However, the total GDP binding capacity of the brown adipose tissue, the capacity of BAT for thermogenesis, was significantly increased at both doses tested. Treatment of obese male Zucker rats at 20 mg/kg/day for eight weeks with the compound of Example 5 led to a decrease in body weight, whereas control animals exhibited a small weight gain. This was associated with an increase in food intake, which suggests that this group is exhibiting increased energy expenditure in relation to control rats. This is paralleled by increases in the activity of brown adipose tissue. In this experiment the compound of Example 5 did not lead to a reduction in plasma triglycerides. This is likely to be because the doses of compounds administered were insufficient to significantly affect this parameter. 24 hour fasted rat test Hale rats (125 - 150)g were allowed a one week acclimatisation period prior to a 24 hour fast. After fasting, compound of example 5. (0.5, 5-0 or 50 mg/Kg p.o.) dissolved in an aqueous solution of 0.025% polysorbate, was administered by gavage at 0.5 ml/lOOg body weight. Control rats were dosed with polysorbate solution alone. 60 minutes later, rats were anaesthetised and a cardiac blood sample taken. Plasma glucose, insulin and free fatty acid levels were determined using standard methods. [NEFA - Non-esterified fatty acids] The results are mean + S.E.M. of observations in six rats in each group. Student's t test was used to test the significance of the difference between control and treated groups- The compound of Example 5 provides a significant reduction in plasma glucose concentration and a dose dependent increase in plasma insulin and NEFA concentration, one hour after dosing. The experiments were repeated on groups of rats that had been fasted for only 5 hours prior to dosing. Significant increases in plasma insulin and NEFA levels and reductions in plasma glucose were observed. Results Results Glucose (mM) Insulin (ng/ml) NEFA (mEQ/1) Control 6.7+0.11 1.74+0.27 0.95+0.06 Compound 6.2+0.07 1.43+0.16 1.08+0.03 (0.5 mg/kg) (-8%) (-18%) (+13%) Compound 5.2+0.15 -2.72+0.62 1.35+0.26 (5.0 mg/kg) (-22%) (+56%) (+41%) Compound 5.2+0.08 4.09+0.54 1.62+0.03 (50 mg/kg) (-22%) (+135%) (+70%) Acute oral glucose tolerance test Male rats (125 - 150 g) were allowed an acclimatisation period of one week, prior to an overnight fast (18 hours). After fasting, a group of six rats was anaesthetised and a cardiac blood sample taken. Other rats were then dosed with the compound of example 5. (5.0 mg/Kg p.o.) dissolved in an aqueous solution of 0.025% polysorbate, control rats were dosed with polysorbate solution alone, at 0.5 ml/lOOg body weight. 60 minutes later, six rats from each of the two groups (control and example 5. at 5.0 mg/Kg) were anaesthetised and a cardiac blood sample taken. The remaining rats were dosed with D-glucose at lg/kg by gavage at 0.5 ml/lOOg body weight. Six rats from each of the two groups were then anaesthetised at 20 minutes, 60 minutes and 120 minutes after the administration of glucose, and a cardiac blood sample taken. Plasma glucose and insulin levels were determined using standard methods. Administration of example 5- at 5mg/Kg p.o. produced a significant improvement in oral glucose tolerance in the rat. This was associated with a large increase in plasma insulin concentration, one hour after administration of example 5, (prior to glucose). Further increases in circulating insulin concentration in example 5. treated rats, following the glucose challenge were not significantly different from those observed in control rats. 14 day oral glucose tolerance test The response to an lg/kg oral glucose challenge was measured in rats which had been treated with example 5. at 5.0 mg/Kg, dissolved in 0.025% polysorbate, twice daily for 14 days. Control rats were dosed with polysorbate solution alone, for 14 days. On day 14 rats were fasted overnight, prior to an oral glucose tolerance test. After fasting, six rats from each treatment group, (control and example 5) were anaesthetised and a cardiac blood sample taken. The remaining rats were dosed either with example 5 or control vehicle as appropriate. 60 minutes later, six rats from each group (control or example 5), were anaesthetised and a cardiac blood sample taken. The remaining rats were dosed with D-glucose at lg/kg by gavage at 0.5ml/100g body weight. Six rats from each group (control or example 5) were anaesthetised at 20 minutes, 60 minutes, and 120 minutes after the glucose administration and a cardiac blood sample taken. Plasma glucose and insulin levels were measured using standard methods. The compound of Example 5 reduced the glycaemic response to a lg/kg oral glucose challenge. The improvement in glucose tolerance after 14 days administration of Example 5, was not associated with any significant increases in plasma insulin concentration, when compared to the control rats. Effects on blood glucose levels in insulin resistant db/db mice C57BL/KsJ (db/db) female mice were divided into two groups and allowed free access to control diet or diet containing the compound of Example 5 as a dietary admix at a dose of 1, 10 and 100 mg/kg body weight/day. A group of control (+/+) mice was also included in the experiment. After 14 days treatment, blood samples were taken from the hearts of the mice for determination of blood glucose levels. Blood and plasma glucose were estimated using the glucose oxidase peroxidase system. NEFA were estimated using a WAKO NEFA C kit and plasma insulin by radio immunoassay. Results Group Blood glucose (mM) Control 5.4 + 0.20 +/+ Diabetic 18.8 + 0.45 Control db/db Compound of 4.9 + 0.62 Example 5 P*** (1 mg/kg) (-21%) Compound of 7.3 + 0.56 Example 5 P*** (10 mg/kg) (-61%) Compound of 4.6 + 0.26 Example 5 P*** (100 mg/Kg) (-76%) Results are mean ± S.E.M. of observations in groups of 15 mice. Student's t test was used to test the significance of the difference between control (+/+) and treated (db/db) groups. The compound of Example 5 significantly reduces blood glucose levels in this animal model of insulin resistance. Rat adipocyte lipolysis test Epididymal adipose tissue was excised from male rats and adipocytes prepared by digestion with collagenase. Cells were isolated by flotation and washed four times with Krebs Ringer Bicarbonate buffer (KRB) , finally washing in KRB containing 2% bovine serum albumin (KRB/BSA). Aliquots of the cell suspension were incubated in the presence of a range of concentrations of the test compound in a total volume of 1ml KRB/ 2% BSA containing 0.1 mg/ml ascorbate in an atmosphere of 95%0 2 ,5%C0,,. Incubations were also carried out in the presence of a concentration of isoprenaline (3 x 10 H) known to have a maximal effect on lipolysis. Control incubations were carried out in KRB/ 2% BSA containing ascorbate. The incubations were terminated after 90 minutes by placing the tubes on ice, and aliquots of infranatant removed for assay of free fatty acids which were measured using a WAKO NEFA-C assay kit (Alpha Laboratories). Lipolytic activity of the compounds was assessed by determining the increase in free fatty acid concentrations caused by the compounds compared to controls. The maximal effects (efficacy) of the compounds were determined and expressed as percentage of the maximal effect of isoprenaline. Test compound Efficacy Compound of Example 5 100.8 r 2.3% (mean of 7 experiments) In vitro selectivity data for activity on β..- and β^-adrenoceptors Guinea-pig right atrium (β..-adrenoceptors) Hearts were rapidly removed from guinea-pigs and placed into oxygenated Krebs solution. The right atrium was located and dissected from the the rest of the heart and mounted on a pair of platinum electrodes. Once fixed to the electrodes, the tissue was immersed into a 20 ml bath containing oxygenated Krebs solution to which had been added ICI 118551 (O.lμM, to block β2-adrenoceptors) . The electrodes were then connected to a modular cardiotachometer which counted the number of spontaneous beats in 10 sec. epochs. A computer (IBM PS 2000 or equivalent) averaged the epochs in groups of 3 and displayed these on the computer screen at 1 minutes intervals. Following equilibration of the tissues for 60 minutes concentration responses to isoprenaline were performed. Following washout, the test compound was added to the bath and left in contact with the tissues for 60 min., during which time any change in rate was measured. After this time, the concentration responses to isoprenaline were repeated. Agonist activity of the test compound was compared to the maximal increase in rate produced by isoprenaline and expressed as a percentage of this value. Antagonist activity of the test compound was determined by comparing the EC50 values of isoprenaline before and after exposure to the ICI compounds, thus: EC ™ isoprenaline after exposure '50 Concentration ratio = — EC ™ isoprenaline before exposure (The EC50 value being the response to isoprenaline that was 50% of the maximal effect). Agonist activity (% response) none detected Antagonist activity (concentration ratio) 2.74+0.53 Guinea-pig trachea (β -adrenoceptors) Trachea were removed from guinea-pigs and placed into oxygenated Krebs solution. The tissues were then cut into rings. Each preparation consisted of 5 rings sewn together. These were placed into 10 ml. organ baths containing oxygenated Krebs solution (to which had been added CGP 20712A, O.OlμM, to block βl-adrenoceptors) and left to gain spontaneous tone under a resting tension of 200 mg. When tone had stabilised, concentration responses to isoprenaline were performed. After washout, a second concentration response to isoprenaline was performed, following this second concentration response, the tissues were washed again and the test compound were was added to the tissue and left in contact for 60 min. , during which time, any effect of the test compound on resting tone could be assessed. After this time a final concentration response to isoprenaline was performed in the presence of the test compound. Agonist activity of the test compound was expressed as a percentage of the maximal relaxation produced by isoprenaline. Antagonist activity was expressed as for the atrium. Agonist activity (% response) 16.0 + 5.0% Antagonist activity (concentration ratio) 1.07 +_ 0.21% Note: Guinea-pigs were of either sex, weighing between 300-500 g. ICI 118551 and CGP 20712A are referred to inter alia by Manara et al., (1990), TIPS, 11, 229-230. The invention will now be illustrated by the following Examples in which, unless otherwise stated: a) chromatography was performed on Kieselgel (Art 9385; 230-400 Hesh) obtainable from E. Merck, Darmstadt, Federal Republic of Germany. b) evaporations were carried out under reduced pressure using a rotary evaporator. c) melting-points are uncorrected. Example 1 4-f2-(2-Hydroxy-2-phenylethylamino)ethyl]phenylacetic acid Methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenyl- acetate hydrochloride (0.32g) was heated on the steam bath for 2 hours in 2N HC1 (13ml) . The reaction mixture was filtered and cooled to give 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid as the hydrochloride (0.22g), m.p. 197-198°C: microanalysis found C, 64.0; H, 6.6; N, 4.2; Cl, 10.6%: required for C 18 H 22 C1N0 3 : C, 64.4; H, 6.6; N, 4.2; Cl, 10.6%. Example 2 Methyl 4-f2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetate A mixture of methyl 4-(2-aminoethyl)phenylacetate hydrochloride (5.0g), triethylamine (2.2g), styrene oxide (2.61g) and methanol (110ml) was heated under reflux for 72 hours. The mixture was cooled and the extract was evaporated under reduced pressure. The residue was dissolved in dichloromethane (100ml) and washed with water (3 x 30ml) , dried over MgSO, and then the solvent was removed under reduced pressure. The residue was dissolved in methyl acetate and heated with a solution of ether saturated with hydrogen chloride. The precipitated solid was crystallised from a solution of methanol and methyl acetate to give methyl 4-[2-(2-hydroxy-2-phenylethylamino)- ethyl]phenylacetate as the hydrochloride, m.p. 159-160°C. Methyl 4-(2-aminoethyl)phenylacetate hydrochloride may be made in the same way as the corresponding ethyl ester described in UK Patent Specification 1511095. The hydrochloride salt of the methyl ester was crystallised from a mixture of methanol and methyl acetate and had m.p. 200-202°C; microanalysis: found C, 57.6; H, 7.1; N, 6.0; Cl, 15.4%; required for C n H 15 N0 2 ; C, 57.5; H, 7.0; N, 6.1; Cl, 15.4%. Example 3 Methyl 4-f2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetate A mixture of methyl 4-(2-aminoethyl)phenylacetate hydrochloride (1.15 g), triethylamine (0.51 g) and phenyl glyoxal monohydrate (1.06 g) in methanol (35 ml) was heated on the steam bath for about four minutes. The mixture was cooled in an ice-bath and sodium borohydride (1.5 g) was added in small portions over .1 hour. The mixture was stirred at ambient temperature for 24 hours. The solvent was removed by evaporation under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and washed with brine (2 x 20 ml), dried over MgSO, and the solvent removed under reduced pressure. The residue (0.95 g) was dissolved in methyl acetate (20 ml) and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid was methyl 4-[2-(2-hydroxy-2-phenyl- ethylamino)ethyl]phenylacetate as the hydrochloride (0.42 g), m.p. 163-164°C, which on admixture with the product of Example 2 was not depressed. Example 4 4-f2-(2-Hydroxy-2-phenylethylamino)ethyl1phenylacetic acid A mixture of methyl 4-(2-aminoethyl)phenylacetate hydrochloride (1.15 g) , triethylamine (1.01 g) and phenacyl bromide —(0.99 g) in methanol (40 ml) was stirred at ambient temperature for three hours. The mixture was cooled in an ice-bath while sodium borohydride (1.5 g) was added in small portions over 1 hour and subsequently stirred at ambient temperature for 18 hours. The solvent was removed by evaporation under reduced pressure. The residue was dissolved in dichloromethane (70 ml), washed with water (3 x 20 ml), dried over MgSO, and the solvent removed by evaporation under reduced pressure. The residue (1.5 g) was dissolved in methyl acetate (10 ml) and treated with a solution of ether saturated with hydrogen chloride. The precipitated salt was crystallised from a mixture of methanol and methyl acetate to give 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]- phenylacetic acid as the hydrochloride (0.8 g) m.p. 196-198°C: microanalysis found C, 64.6; H, 6.7; N, 4.2; Cl, 10.5%: required for C 18 H 22 C1N0 3 : C ' 64,6; H ' 6*6; N ' 4 ' 2 ' C1 ' 10 " 6, Example 5 (R)-4-12-(2-Hydroxy-2-phenylethylamino)ethyl]phenylacetic acid (R)-Hethyl 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenyl¬ acetate hydrochloride (3.4 g) was heated on the steam bath for 2 hours in 2N HC1 (50 ml). The reaction mixture was filtered, and cooled to give (R)-4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid as the hydrochloride (2.4 g), m.p. 213-215°C; microanalysis found C, 64.2; H, 6.5; N, 4.1; Cl, 10.5%; required for C 18 H 22 C1N0 3 : C, 64.4; H, 6.6; », 4.2; Cl, 10/6% [α] 25 D = -34.5° (c = 1.0 in methanol). Example 6 (R)-Methyl 4-f2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetate A mixture of methyl 4-(2-aminoethyl)phenylacetate hydrochloride (0.995 g), triethylamine (0.437 g) and (R)-styrene oxide (0.520 g) and methanol (40 ml) was heated under reflux for 72 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was dissolved in dichloromethane (50 ml) and washed with water (2 x 20 ml) , dried over MgSO, and then the solvent . was removed under reduced pressure. The residue was dissolved in methyl acetate and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid was crystallised from a mixture of methanol and methyl acetate to give (R)-methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetate as the hydrochloride (0.26 g) m.p. 185-187°C; microanalysis found C, 64.8; H, 6.9; N, 4.0; Cl, 10.0%r required for C ιg H 24 ClN0 3 -. C, 65.2; H, 6.9; N, 4.0; Cl, 10.1%; [α] 25 D = -33.2° (c = 0.98 in methanol). Example 7 (R)-Methyl 4- \2-(2-hydroxy-2-phenylethylamino)ethyl] henylacetate A mixture of methyl 4-[2-(benzylamino)ethyl]phenylacetate hydrochloride (1.51 g) , triethylamine (0.66 g) and R-styrene oxide (0-79 g) in methanol (40 ml) was heated under reflux for 72 hours. The mixture was cooled and the solvent evaporated under reduced pressure. The residue was dissolved in dichloromethane (30 ml) and washed with water (2 x 10 ml), dried over MgSO,, and the solvent removed under reduced pressure. The residue (1.83 g) was dissolved in methanol (50 ml) and glacial acetic acid (25 ml). The mixture was hydrogenated in the presence of 10% w/w palladium on carbon (0.2 g) at about 5 bars and 60°C for 1 hour. The mixture was cooled and the filtrate was evaporated under reduced pressure. The residual oil was dissolved in methyl acetate (50 ml) and treated with a solution of ether saturated with hydrogen chloride. The precipitated solid was crystallised from a mixture of methanol and methyl acetate to give (R)-methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetate as the hydrochloride (0.32 g) m.p. 183-185°C. The melting point on admixture with the product of Example 6 showed no depression. Example 8 (R)-4-f2-(2-Hydroxy-2-phenylethylamino)ethyl]phenylacetic acid (R)-4-[2-(2-Hydroxy-2-phenylethylamino)ethyl]phenylacetic acid hydrochloride (1.0 g) was dissolved in water (20 ml). The pH of the solution was adjusted to 5.6. On standing at ambient temperature for several days, (R)-4-[2-(2-hydroxy-2-phenylethylamino)ethyl]- phenylacetic acid (0.8 g) was yielded, m.p. 210-212°C: microanalysis found: C, 72.3; H, 7.3; N, 4.6%: required for C 18 H 21 N0 3 : C, 72.2; H, 7.1; N, 4.7%; [α] = -36.0 (c = 0.98 in acetic acid). Example 9 (R)-4-f2-(2-hydroxy-2-phenylethylamino)ethylphenylacetic acid A stirred mixture of potassium carbonate (0.4 g), (R)-3-phenyl-2-oxazolidinone (0.51 g) and methyl 4-(2-bromoethyl)phenyl acetate (0.8 g) in anhydrous acetone (30 ml) was heated at reflux for 16 hours. The reaction mixture was cooled, evaporated to dryness and partitioned between ethyl acetate and water (25:10 ml). The organic layer was washed with brine (2 ml), dried over anhydrous MgSO, and evaporated to an oil. The crude product was separated by medium pressure liquid chromatography on Kieselgel 60, Art 9385 (80 g) eluting with hexane: ethyl acetate (2:1 to 1:1). Fraction 3 was evaporated to give (R)-methyl 4-[2-(2-oxo-5-phenyl- 2-oxazolidin-3-yl)ethyl]phenyl acetate as an viscous oil: NMR; CDC1., (δ), 2.89 (t, 2H), 3.32 ( , 1H), 3.57 (q, 2H), 3.60 (s, 2H), 3.69 (s, 2H), 3.77 (t, 1H), 5.40 (t, 1H), 7.1-7.45 (m, 9H) ; (M+H) 340(100%). A solution of this compound (0.37 g) in ethanol (5ml) was added to 2M aqueous NaOH (5 ml) and the resulting mixture stirred at 60°C for 6 hours. The reaction mixture was cooled to room temperature, acidified to pH 1 with concentrated HC1 and evapoated in vacuo to a white solid which after crystallising twice from water gave (R)-4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid as the hydrochloride (0.11 g), m.p. 2I4-216°C. Example 10 (R)-Methyl 4-f2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetate An ice-cold solution containing sodium nitrite (4.63 g) in water (50 ml) was added over 10 minutes to a stirred solution of methyl 4-(2-aminoethyl)phenylacetate hydrochloride (6.17 g), sodium acetate (4.63 g) and glacial acetic acid (32 ml) in water (325 ml) whilst the internal temperature was maintained between -5 and -10°C. The resulting solution was stirred at <0°C for 2 hours. Solid potassium carbonate was added to pH 9.5 and the whole extracted with dichloromethane (3 x 60 ml). The organic layers were combined, washed with water (2 ml), dried over MgSO, and evaporated in vacuo to give a pale yellow liquid. This liquid was subjected to chromatography on Kieselgel 60, Art 9385 (180 g) eluting with ethyl acetate/hexane (1:1). Fractions 3 & 4 were combined and evaporated to give methyl 4-(2-hydroxyethyl)phenyl acetate (2.8 g) as a colourless liquid: NMR; DMSO-dg (δ), 2.69 (t, 2H), 3.57 (m, 4H) , 3.6 (s, 3H), 4.58 (ϋ, 1H) , 7.15 (s, 4H); (H-H 2 0) 177(100%). Phosphorus tribromide (1.35 ml) was added over 5 minutes to a solution of 2.7 g of this liquid in dichloromethane (75 ml) maintained <30°C and under an atmosphere of argon. The mixture was stirred for 4 hours before ice (25 g) was added and stirred continued for a further 30 minutes. The organic layer was separated, washed with saturated aqueous sodium bicarbonate (10 ml) and water (2 ml) and evaporated to a yellow oil/solid mixture. The mixture was subjected to chromatography on Kieselgel 60, Art 9385 (180 g) eluting with hexane/ethyl acetate (6:4). Fraction 1 was evaporated to give methyl 4-(2-bromoethyl)phenyl acetate (1.25 g) as a colourless liquid: NMR; DNS0-d 6 (δ), 3.10 (t, 2H), 3.60 (s, 3H), 3.64 (s, 2H), 3.71 (t, 2H) , 7.21 (s, 4H); (M +NH 4 ) 274(100%). 1.0 g of the above liquid was added at room temperature to a stirred solution containing (R)-2-amino-l-phenylethanol (0.61 g) and triethylamine (0.63 ml). Stirring was continued for 1 hour before the mixture was evaporated, partitioned between ethyl acetate (25 ml) and water (10 ml), dried over anhydrous magnesium sulphate and evaporated to an oil. The mixture was subjected to chromatography on Kieselgel Art 9385 (180 g) eluting initially with dichloromethane and finally with ~ 5% methanol in dichloromethane. Fraction 3 was evaporated to give 0.37 g of a colourless oil which on dissolving in methyl acetate (15 ml) and treatment with a saturated solution of hydrogen chloride in diethyl ether gave a clear solution from which crystallised (R)-methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetate as the hydrochloride (0.28 g) as a white solid; m.p. 186.0-188.0°C. Example 11 A typical tablet formulation suitable for oral administration to warm-blooded animals comprises as active ingredient a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore (for example as described in one of the preceding Example), and may be produced by aqueous granulation or direct compression together with milled lactose containing a standard disintegrant and/or lubricant. When tablets containing small amounts of active ingreident (for example 0.5-10 mg) are required, the direct compression method may be used wherein the active ingredient is mixed with lactose in the ration of 1:10 parts by weight and/or microcrystalline cellose containing 0.5% by weight of a lubricant (such as magnesium stearate) and 5% by weight of a disintegrant (such as cross-linked sodium carboxymethyl cellulose or sodium starch glycolate). An example a tablet prepared by aqueous granulation is that containing active ingredient (50-100 mg), lactose (230 mg) , maize starch (80 mg), gelatine (2.2 mg), magnesium stearate (4 mg) and croscarmellose sodium (7 mg).

Claims: CLAIMS 1. A compound of the formula (I): (I) or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 in the form of a salt formed with hydrochloric acid. 3. A compound according to claim 1 which is: 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid, (R)-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid, (R)-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid hydrochloride, or (R)-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid hydrochloride. 4. A bioprecursor of a compound of the formula (I) (I) or a pharmaceutically acceptable salt thereof. 5. A bioprecursor according to claim 4 which is a C. , alkyl ester formed at the carboxylic acid function. 6. A bioprecursor according to claim 4 which is methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenyl acetate or methyl (R)-4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetate. 7. A pharmaceutical composition which comprises a compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 8. A pharmaceutical composition which comprises a compound according to any one of claims 4-6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 9. A process for preparing a compound according to claim 1 or claim 4 which process comprises: a) reacting a compound (II) or (III) with a compound of the formula (IV) - Ph-CH(0H)CH 2 L (III) NH 2 CH 2 CH 2 -y v cn 2 R 5 (IV) wherein -R is carboxy or protected carboxy and L is a displaceable group; or b) hydrolysis of a compound of the formula (V) : - 39 0 0 -// ' \ Ph-CH NCH 2 CH 2 W -CH 2 R' (V) \ / CH, 5 wherein R is as hereinbefore defined; or c) for 4- [2- (2-hydroxy-2-phenylethylamino)ethoxy] phenylacetic acid hydrolysing a compound of the formula (VI) : h - CH ( 0H > C W H 2 Λ CH (VI) wherein R is a hydrolysable group; d) reacting a compound of the formula (VII) with a compound of the formula (VII): Ph-CH(OH)CH 2 NH 2 (VII) , CH 2 CH 2 -r' -CH 7 R 5 (VIII) wherein -R is as hereinbefore defined and L' is a displaceable group; e) deprotecting a compound of the formula (IX): (IX) wherein R is a protected carboxy group; f) converting 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid into a bioprecursor, or vice versa, or converting a bioprecursor of 4-[2-(2-hydroxy-2-phenylethyl- amino)ethyl]phenylacetic acid into another bioprecursor of 4- [2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid; g) reducing a compound of the formula (X): wherein -R is as hereinbefore defined; h) reducing a compound of the formula (XI): wherein -R is as hereinbefore defined; i) reducing a compound of the formula (XII) (XII) wherein R is as hereinbefore defined; and wherein any functional group is optionally protected and thereafter if necessary; (i) removing any protecting groups; (ii) forming a pharmaceutically acceptable salt. 10. A compound of the formula (V), (VI), (IX), (X), (XI), (XII) as defined in claim 8. 11. The use of a compound according to claim 1 or claim 4 in a method of treating disease conditions mediated through β-.-adrenoceptors. 12. The use of a compound according to claim 1 or claim 4 in a method of stimulating thermogenesis and/or improving glucose tolerance.

Inventors: HOLLOWAY BRIAN ROY, HOWE RALPH, RAO BALBIR SINGH, HOLLOWAY, BRIAN, ROY, HOWE, RALPH, RAO, BALBIR, SINGH
Applicants: HOLLOWAY BRIAN ROY, HOWE RALPH, RAO BALBIR SINGH, ZENECA LTD, ZENECA LIMITED
Application year: 1993
Main classification: C07C229
IPC codes: C07C227, C07C229, C07D263