COMPOUNDS

Abstract: Compounds of formula (I), wherein R<1> is hydroxy or C1-10alkyl, and in vivo hydrolysable esters and salts thereof are described as agents for the treatment of obesity and related conditions. Processes for their preparation and intermediates are described.

Description: COMPOUNDS The present invention relates to 2-hydroxy-3- phenoxypropylamino compounds and in particular to such compounds containing a phenylacetyl group and certain derivatives 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. Administration of the compounds of this invention to warm-blooded animals provides a thermogenic effect, that is thermogenesis is stimulated and administration of the compounds is of use, for example, in the treatment of obesity and related conditions such as obesity associated with mature onset diabetes. UK Patent 1245148 claims compounds of the general formula: R' XCH 2 CH(0H)CH2-mf-rC*tR>d α Roe e - wherein R a is hydrogen, halogen, or a lower al yl, phenyl, lower alkoxy or phenyl substituted lower alkyl group; R is hydrogen or up to two halogen, lower alkyl or lower alkoxy substituents; R c is an electron-withdrawing polar substituent which may include groups such as carboxy, lower alkoxycarbonyl, formyl, lower alkanoyl, carbamoyl, sulpho, sulphino, alkoxysulphonyl, alkoxysulphinyl, sulphamoyl, cyano, azido, nitro or trifluoromethyl or any such group separated from the phenyl ring by a methylene or ethylene group; R d and R e each represent hydrogen or a lower alkyl group; R represents hydrogen or a lower alkyl, alkanoyl or benzyl group; either of the benzene rings A and B may be optionally substituted further by a -CH-CH-CH--CH- radical to form a naphthyl group; SUBSTITUTE SHEET X is oxygen or sulphur; and either Y is oxygen, sulphur or a sulphinyl, sulphonyl or imino group and n is 1, 2 or 3; or Y is a direct bond and n is 0,1,2,3 or 4: wherein the term "lover" means up to 4 carbon atoms. These compounds are described as having the ability to block the beta-adrenergic receptors and are stated to be useful in the curative or prophylactic treatment of cardiac disorders such as angina pectoris and cardiac arrhythmias and in the treatment of hypertension. Biological data are reported describing the cardiac effects of various compounds vithin the claims. Ve have nov discovered a small class of compounds related to those of the above general formula which compounds, surprisingly, provide 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. Accordingly the present invention provides a compound of the formula (I): wherein R is hydroxy or C. ..-alkyl, or an in vivo hydrolysable ester or a pharmaceutically acceptable salt thereof. In one aspect R is hydroxy. In another aspect R is C 1 _ 1Q alkyl for example methyl, ethyl, n-propyl, isopropyl, n-butyl, n- pentyl, n-hexyl and n-heptyl. Preferably R is C. g alkyl for example methyl, ethyl, n-propyl, isopropyl, n-butyl and n-hexyl. The compounds of the formula (I) are basic and may be isolated and used either in the form of the free base or of a pharmaceutically acceptable acid-addition salt thereof. In addition, compounds wherein R is hydroxy are amphoteric and may be used in the zvitterionic 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, oxalates 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. In vivo hydrolysable esters may be formed at the carboxy group (-C00H) and/or at the hydroxy group (-0H). In vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyse in the human or animal body to produce the parent hydroxy compound. Such esters can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include the C. -alkyl esters. Suitable in vivo hydrolysable esters for hydroxy include the C- ..alkanoyl esters. It will be appreciated that the compounds of the formula (I) contain one or more asymmetric carbon atoms and can exist as optically active enantiomers or as optically inactive racemates. The present invention encompasses any enantiomer, racemate and/or (when two or more asymmetric carbon atoms are present) diastereoisomer, 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 (S) absolute configuration at the -CH(OH)- group (under the Cahn-Prelog-Ingold rules) which generally corresponds to the laevorotatory optically active form (-) in this class of compounds. Particular compounds of the present invention include: 4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid, (S)-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid, 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]propan-2-one, (S)-1-[ -(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]- propan-2-one, l-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]butan-2-one, (S)-l-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]butan-2-one, l-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyllpentan-2-one, (S)-1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)pheny1]- pentan-2-one, 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenylJ-3-methylbutan-2 -one, l-[4-(2-(2-hydroxy-3-phenox propylamino)ethox )phenyl]hexan-2-one, l-[4-(2-(2-hydroxy-3-phenoxy ropylamino)ethoxy)phenyl]-4-methylpentan- 2-one, l-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]heptan-2-one, 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]octan-2-one and 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl1nonan-2-one. In order to use a compound of the present invention or an in vivo hydrolysable ester or 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 a compound of the formula (I) or an in vivo hydrolysable ester 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 0.1-250 mg of active ingredient. The compositions may also contain other active ingredients known for use in the treatment of obesity and related conditions, for example appetite suppressants, vitamins and hypoglycae ic agents. In one aspect of the present invention, a compound of the formula (I) may be formulated for oral administration in a sustained (or delayed) release composition, for example a matrix tablet formulation comprising insoluble or svellable polymeric filler, or a coated spheroid formulation. When used to produce thermogenic effects in warm-blooded animals including man, a compound of the formula (I) or an in vivo hydrolysable ester or pharmaceutically acceptable salt thereof as appropriate, will be administered so that a dose in the general range 0.002-20 mg/kg, and preferably in the range 0.02-10 mg/kg, is administered daily, given in a single dose or divided doses as necessary. However, it vill be appreciated by those skilled in the art that dosage vill 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 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 (high density lipoprotein) 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 high density lipoprotein levels which comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or in vivo hydrolysable ester 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 a compound of the formula (I) or in vivo hydrolysable ester 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 dialkylaminoalkyl derivatives of a cross-linked dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics. In a further aspect the present invention provides a process for preparing a compound of the formula (I) or an in vivo hydrolysable ester or a pharmaceutically acceptable salt thereof vhich process comprises: a) reacting a compound of the formula (II) or (III) vith a compound of the formula (IV): < OCH 2 CH(0H)CH 2 L (III) Ϊ-CH-CH-O-// -CH-COR 3 (IV) vherein R is as hereinbefore defined and L is a displaceable group; or b) hydrolysis of a compound of the formula (V): G*t<_•<>•«' (v) vherein R is as hereinbefore defined; or _ _ c) for compounds of the formula (I) vherein R is hydroxy, hydrolysing a compound of the formula (VI) : 2 vherein R is a hydrolysable group; d) reacting a compound of the formula (VII) vith a compound of the formula (VIII): f -<0CH 2 CH(0H)CH 2 NH 2 (VII) vherein R is as hereinbefore defined and L' is a leaving group; or e) deprotecting a compound of the formula (IX): / ^ OθCCHH 22 CCHH((O0HH))CCHH 22 HHCCHH 22 CCHH 22 00-- '' Λ YVCH 2 R"' (IX) 3 1 vherein R is a protected derivative of a group -COR ; and if necessary thereafter forming an in vivo hydrolysable ester or a pharmaceutically acceptable salt. 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 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 sulphonyloxy such as toluenesulphonyloxy or methanesulphonyloxy. The compounds of the formula (IV) are prepared in any convenient manner knovn to those skilled in the art. For example they may be conveniently prepared by reacting compound (X) vith a compound of the formula (XI): NH-CH-CH-OH (X) For example this reaction may be performed using the Mitsunobu reaction vith diethyl azodicarboxylate and triphenylphosphine. Desirably the amino function (and carboxy-function, if present) is protected during this reaction and subsequently deprotected in conventional manner. Examples of suitable protecting groups for the amino function include the phthaloyl and t-butoxycarbonyl groups. The compounds of the formula(XI) may be prepared according to the methods described in the Examples hereinafter. The compound of the formula (V) may be hydrolysed to a compound of the formula (I) under conditions knovn in the beta-blocker art; for example via alkaline hydrolysis in a suitable solvent. The compounds of the formula (V) may be prepared by the reaction of a compound of the formula (XI) vith a compound of the formula (XII): vherein R is a group -CH-CH-OH. This reaction may be performed in any conventional manner for example by a method analogous to the reaction of the compounds of the formulae (X) and (XI). In an alternative the compounds of the formula (V) may be prepared by the reaction of a compound of the formula (XII) vherein R is hydrogen vith a compound of the formula (VIII) as hereinbefore described. In a further alternative the compounds of the formula (V) may be prepared by the reaction of a compound of the formula (II) vith a compound of the formula (XIII): vherein R is as hereinbefore defined and R 0- is a leaving group, for example R 0- is C. ,alkoxy. 4 The compound of the formula (XII) vherein R is -CH-CH-OH may be prepared for example by reaction of a compound of the formula (II) vith an N-alkoxycarbonyl derivative of a compound of the formula (X) vherein the hydroxy group is optionally protected, for example the tetrahydropyranyl ether of t-butoxycarbonylaminoethanol. The 4 compounds of the formula (XII) vherein R is hydrogen are obtainable in conventional manner. The compounds of the formulae (VIII) and (XIII) may be obtained by alkylation of the compounds of the formula (XI) in conventional manner. The reaction betveen the compounds of the formulae (VII) and (VIII) is conveniently performed under conditions analogous to the reaction betveen compounds of the formulae (III) and (IV). L' may have similar values as recited hereinabove for L. In the compounds of the formula (VI) examples of 2 hydrolysable groups R include C. , alkoxy and -NH„ groups so that -COR represents a C. galkyl ester or primary amide function. Such groups may be hydrolysed (acidic, basic, enzymatic) to a group -CO-H under conventional conditions. 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 110°C and in a polar solvent, such as vater, a C, .alkanol (for example methanol or ethanol) or acetic acid. In such cases, the corresponding mineral acid salt of the compound of formula (I) vherein R is hydroxy 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 2 further alternatives, vhen -COR is J 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 the compounds of the formula (I), vith optional protection of the amino function for example vith a benzyl group. Compounds of the formula (VI) also provide a thermogenic 2 effect, in particular compounds of the formula (VI) vherein R is - H j . Accordingly in another aspect the present invention provides compounds of the formula (VI), their use in methods of therapy (in particular in the treatment of obesity and related conditions) and pharmaceutical compositions containing them. The compounds of the formula (VI) are used and formulated in a manner analogous to that described for the compounds of the formula (I). 3 In the deprotection of a compound of the formula (IX) R may for example be an acetal such as 2-methyl-l,3-dioxolan-2-yl or 2-ethyl-l,3-dioxolan-2-yl. Such groups may be readily converted to a group -COR vherein R is alkyl by acid hydrolysis. The compounds of the formula (IX) may be prepared by methods analogous to those described herein for the preparation of the compounds of the formula (I). Certain of the compounds of the formulae (IV) and (VIII) are novel. Therefore, in another aspect the present invention provides a compound of the formula (XIV): vherein Z is amino, protected amino or a leaving group such la as halo or sulphonyloxy and R is C. - 0 alkyl. In vivo hydrolysable esters may be prepared in conventional manner for example by reacting the carboxy group vith an 2 alcohol. It vill also be realised by the skilled man that groups R 3 and R in formulae (VI) and (IX) respectively, may be in vivo hydrolysable. Pharmaceutically acceptable salts may be prepared by reacting the compound of the formula (I) vith the appropriate acid in conventional manner. Alternatively vhen a hydrogen halide salt is required, it may conveniently be obtained by hydrogenation of the free base together vith 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 the compound of the formula (I) may be demonstrated using one or more of the following standard tests:- (a) Rats are cold adapted by being placed in a cold environment (4 β C) for 10 days in order to increase their capacity for thermogenesis. They are then transferred to a thermoneutral environment (29°C). Three hours later the core temperature is measured to determine a base-line reading and the test compound is administered sub-cutaneously or orally as a solution or suspension in 0.45% v/v aqueous sodium chloride, 0.25% v/v Polysorbate 80. After one hour, the core temperature is again measured. In this test, a compound which causes a statistically significant increase in the core temperature of about 0.3°C (or more) at a sub-cutaneous dose of 15 mg/kg (or less) is considered to be significantly active. The test acts as a model for the depressed thermogenesis vhich occurs during dieting. (b) Rats are cold adapted at 4°C for 4 days to increase their capacity for thermogenesis. They are then transferred to a varm environment of 23°C for 2 days. On the following day, a test compound is administered sub-cutaneously or orally as described in (a). 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 (Hollovay e_t al. , International Journal of Obesity, 1984, 8, 295) as a measure of thermogenic activation. Each test includes a control vhich is dosed vith the solution/suspension vehicle only and a positive control vhich is dosed vith isoprenaline (as its sulphate) at 1 mg/kg. Test compounds are routinely dosed at 0.1, 0.3, 1.0, 3.0, and 10 mg/kg and results expressed in terms of the effect on GDP binding produced by isoprenaline. From these results, a dose (ED 50 ) necessary to produce 50% of the isoprenaline effect is calculated by linear regression analysis. Compounds are considered active in this test if they cause a significant elevation in GDP binding as compared to controls. This test serves to indicate that the thermogenic effects observed in test (a) are mediated through an increase in effect on BAT rather than by some non-specific or toxic mechanism. (c) Rats are adapted to a thermoneutral environment (29°C) for 2 veeks in order to decrease their capacity for BAT mediated non- shivering thermogenesis. During the final 3 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 go determined in test (b), and heart rate is determined 15-30 minutes after dosing. The procedure is then repeated in subsequent tests using increasing multiples of the ED_ Q determined in test (b) until the heart rate (HR) reaches or exceeds 500 beats per minute, allowing the dose necessary to produce a heart rate of 500 beats per minute e 00 dose) to be calculated. The ratio of D 5 Q 0 to ED,.-, in test (b) 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 vhich have an SI of >1. Non-selective compounds have an SI of <1 (for example isoprenaline = 0.06). (d) Rats are cold adapted at 4°C for four days to increase their capacity for thermogenesis. They are then transferred to a var environment at 23°C for tvo days. On the folloving 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 or sub-cutaneously) vith test compound at about (10 mg/kg) as a solution or suspension in 0.45% v/v aqueous sodium chloride, 0.25% v/v Polysorbate 80. 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 <0.5) dosed only the solution or suspension vehicle. In the above tests, the compounds of the formula (I) in general produce effects of the folloving order vithout producing overt toxicity:- test (a): increase in core temperature of about 0.5°C (or more) folloving a sub-cutaneous dosage of <15 mgkg- ; test (b): sub-cutaneous or oral ED--, for GDP binding in BAT mitochondria of 0.01-10 mgkg " ; and test (c): shov an SI of >50. By vay of illustration, the compound described in the accompanying Example 5, produced the folloving effects in the above tests:- (b) sub-cutaneous (oral) ED 50 0.23mgkg~ ; (c) D 50() : > 23 mgkg -1 (oral); SI >100 (oral), (d) 6.6 ml 0 2 min _1 Kg' 75 at lmgkg "1 p.o. The invention will now be illustrated by the folloving Examples in vhich, unless othervise stated: a) nuclear magnetic resonance (NMR) spectra vere determined at 200MHz in dg-dimethylsulphoxide/d.-acetic acid as solvent unless othervise stated, using tetramethylsilane (TMS) as an internal standard and are expressed in delta values (parts per million) for protons relative to TMS, using conventional abbreviations to describe signal types. b) chromatography vas performed on Merck Kieselgel (Art 7736) (for Example 1) or Kieselgel (Art 9385; 230-400 Mesh) (for Examples 2 - 13) obtainable from E. Merck, Darmstadt, Federal Republic of Germany. c) vhere noted, solutions vere taken to pH values as judged by moist indicator paper. d) evaporations vere carried out under reduced pressure using a rotary evaporator. e) melting-points are uncorrected. Example 1 4-[2-(2-Hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid. 4-[2-(2-Hydroxy-3-phenoxypropylamino)ethoxy]phenylacetamide (0.3g) vas heated on the steam-bath for 4 hours in 2N HCl (10ml). The reaction mixture vas cooled and the solid collected by filtration. The solid vas crystallised from aqueous acetone to give 4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid as the hydrochloride (O.lδg), m.p. 190 β C; microanalysis: found C,59.6; H,6.3; N,3.6; Cl,9.2%; required for C 19 H 24 C1N0 5 : C,59.8; H,6.3; N,3.7; Cl,9.3%; NMR 3.10 (dd,lH, one H of -CH(OH)CH-NH); 3.20(m,lH, the other H of -CH(OH)CH-NH); 3.40(t,2H,NHCH 2 CH 2 ); 3.51(s,2H,CH-C00H); 4.00(m,2H,0CH 2 CH(0H)-); 4.2-4.35(m,3H,-CH(0H)- and -OCH j CH j -) 5.87(d,lH,0H); 6.95-7.30(m,9H, aromatic H); 8.7-9.3(br,2H,NH 2 ). The starting material vas obtained as follovs: A mixture of 4-(2-N-benzylaminoethoxy)phenylacetamide (OLS 2135678) (3.38g), phenylglycidyl ether (1.79g) and ethanol (150ml) vas heated under reflux for 18 hours. The mixture vas cooled and the solvent evaporated under reduced pressure. The residue vas purified by dry, flash column chromatography. Elution vith 10% methanol in dichloromethane gave 4-[2-(N-benzyl-N-(2-hydroxy-3- phenoxypropyl)amino)ethoxyJphenylacetamide as an oil (4.98g). This vas dissolved in methanol (70ml) and acetic acid (30ml). The solution obtained vas hydrogenated in the presence of 10% v/v palladium on carbon (0.5g) at about 20 bar and 60 β C for 48 hours. The mixture vas cooled, filtered and the filtrate vas evaporated under reduced pressure. The residual oil vas dissolved in methanol and heated vith a solution of ether saturated vith hydrogen chloride. The precipitated solid vas crystallised from methanol to give 4-[2-(2-hydroxy-3- phenoxypropylamino)ethoxy]phenylacetamide hydrochloride (4.3g), m.p. 249 β C; microanalysis: found C, 60.0; H, 6.6; N, 7.4; Cl, 9.3%; required for C ιg H 25 ClN-0 4 : C, 59.9; H, 6.6; N, 7.4; Cl, 9.3%. Example 2 1-[4-(2-(2-Hydroxy-3-phenoxypropylamino)ethoxy)phenyl]propan-2-one. 4-(2-Phthalimidoethoxy)phenylpropan-2-one (lOg) in ethanol (40ml) vas treated at 0°C vith 40 vt% aqueous methylamine solution (10ml). The reaction mixture vas stirred for 45 minutes at room temperature, treated vith vater (20ml) and stirring vas continued for a further 45 minutes. Ethanol vas evaporated under reduced pressure and the residue vas basified vith 30% NaOH. Vater (100ml) vas added and the mixture extracted vith ethyl acetate (3 x 100ml). The combined organic extracts vere dried, evaporated to dryness and subjected to chromatography using methanol:ethyl acetate (30:70) as eluant. The desired fractions vere combined, collected, evaporated and heated for 3 hours in propan-1-ol (100ml) vith an equimolar quantity of phenylglycidyl ether. The reaction solution vas evaporated to dryness under reduced pressure and the residue vas subjected to chromatography as before using 5% methanol in dichloromethane as eluant. The appropriate fraction vas crystallised from ethanol 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]- propan-2-one m.p. 105-106 β C; microanalysis: found C, 69.7; H, 7.2; N, 4.2%; required for C 2() H 25 0 4 :C, 70.0; H, 7.3; N, 4.1%; NMR (CDC1-) 2.13(s,3H, CH 3 ), 2.80-3.10(m,4H, CH-NCH-), 3.62(s,2H,CH 2 ), 3.97-4.12(m,5H, 0C§ 2 , CH 2 0 and CHOH), 6.83-7.32(m,9H, aromatic H). The starting material vas obtained as follows: A solution of 4-hydroxyphenylpropan-2-one (22.5g), N-(2- hydroxyethyl)phthalimide (28.6g) and triphenylphosphine (38.5g) in tetrahydrofuran (1L) vas treated dropvise at -5°C vith diethyl azodicarboxylate (23ml). The reaction mixture vas stirred at room temperature overnight, evaporated to dryness and treated vith ether (500ml). The solution vas kept overnight at about 4°C and the solid vas collected and recrystallised from ethanol to give 4-(2- phthalimidoethoxy)phenylpropan-2-one, m.p. 116-117 β C; microanalysis: found C, 70.5; H, 5.4; N, 4.4%; required for C ις ,H 17 N0 4 : C, 70.6; H, 5.2; N, 4.3%. Example 3 1-[4-(2-(2-Hydroxy-3-phenoxypropylamino)ethoxy)phenyl]propan-2-one. l-[4-((2-Methyl-l,3-dioxolan-2-yl)methyl)phenoxy]-2-(£- toluenesulphonyloxy)ethane (lg) and l-phenoxy-3-aminopropan-2-ol (0.4g) vere heated at 65 β C for 12 hours in dimethylsulphoxide (10ml). The cooled reaction mixture vas treated vith ice-cold 2N HCl (50ml) at ambient temperature for 1 hour. The mixture vas basified vith solid sodium carbonate and extracted vith ether (2 x 50ml). The combined ether extracts vere dried, evaporated to dryness and the residue treated vith a small volume of acetone to yield a solid, identical in all respects to the product of Example 2. The starting-material vas obtained as follows: A solution of 2-[4-[(2-methyl-l,3-dioxolan-2- yl)methyl]phenoxy]ethanol (EP-A-70133) (30g) in anhydrous pyridine (500ml) was treated at 0 β C with £-toluenesulphonyl chloride (25g) in portions. The reaction mixture was stirred at 0°C for 2 hours and at ambient temperature for 2 hours. Most of the pyridine was evaporated under reduced pressure. Vater (1.5L) was added, followed by sufficient saturated sodium hydrogen carbonate solution to take the pH of the solution to approximately 9. The mixture was extracted with ether (3 x 500ml) and the combined organic extracts were washed with N HCl (100ml) and with saturated sodium hydrogen carbonate solution (several times) until the extracts were alkaline. The ether solution was dried and evaporated to dryness to yield l-[4-((2-methyl- l,3-dioxolan-2-yl)methyl)phenoxy]-2-(£-toluenesulphonyloxy)ethane, m.p. 80°C (from ethanol); microanalysis: found: C, 61.0; H, 6.1%; required for C 20 H 24°6 S: C ' 61,2 » H > 6 ' 1 ^- Example 4 1-[4-(2-(2-Hydroxy-3-phenoxypropylamino)ethoxy)phenyl]butan-2-one l-[2-(4-(2-Ethyl-l,3-dioxolan-2-ylmethyl)phenoxy)ethylamino] -3-phenoxypropan-2-ol (2.0g) in a mixture of methanol (38ml) and concentrated hydrochloric acid (38ml) vas stirred at 65°C for 1 1/2 hours. The reaction mixture was cooled, poured into water (120ml), basified with sodium hydroxide solution and extracted into ethyl acetate (3 x 50ml). The ethyl acetate extracts vere vashed vith brine (2 x 50ml), dried and the solvent removed under reduced pressure. The residual solid vas converted to the hydrochloride and the salt crystallised from ethanol to yield white crystals of the title compound in the form of the hydrochloride (1.70g); m.p. 167-169 β C; microanalysis: found C, 63.9; H, 7.2; N, 3.4%; required for C 21 H 2g Cl 0 4 , C,64.0; H, 7.1; N, 3.6%; NMR 0.93(t,3H,C0CH-CH 3 ), 2.48(q,2H,C0CH-CH 3 ), 3.06-3.47(m,4H,CH-NHCH 2 ), 3.68(s,2H,ArCH 2 CO), 3.92-4.08(m,2H,Ph0CH 2 CH), 4.22-4.38(m,3H,CH0H and CH-CH-OAr), 6.88-7.35(m,9H, aromatic H). The starting material was prepared as follows: a) l-(4-Hydroxyphenyl)butan-2-one was prepared by the action of diethylcadmium on 4-methoxyphenylacetyl chloride in toluene followed by demethylation in a mixture of hydrobromic acid and acetic acid as described by V R Biggerstaff et al. J. Med. Chem. 1964,7, 110-113. b) A solution of l-(4-hydroxyphenyl)butan-2-one (10.Og), 1,2- ethanediol (7.5ml) and p-toluenesulphonic acid (lOOmg) in toluene (200ml) was stirred under reflux in a Dean and Stark apparatus for 2 hours in an atmosphere of argon. The reaction mixture was cooled, washed with 5% aqueous sodium bicarbonate (150ml), washed with water (2 x 100ml), vashed vith brine (100ml) and dried. Toluene vas removed under reduced pressure and the residual oil triturated vith hexane to give a light brown solid which was crystallised from toluene to give 4-[(2-ethyl-l,3-dioxolan-2-yl)methyl]phenol as white crystals (10.2g) m.p. 88-90°C; microanalysis: found C, 69,3; H, 7.8%; required for C 12 H 16°3 : C ' 69,2; H ' 7*7 * * c) Diethyl azodicarboxylate (9.7ml) was added dropwise to a stirred solution of 4-[(2-ethyl-l,3-dioxolan-2-yl)methyl]phenol (lO.Og), N-t-butoxycarbonylaminoethanol (13.3g) and triphenylphosphine (16.3g) in anhydrous tetrahydrofuran (300ml), at ice-bath temperature, under argon. The reaction mixture was left for 64 hours at 20 β C and then the solvent was removed under reduced pressure. The residue was dissolved in ether (600ml) and the ethereal solution washed with 2N aqueous sodium hydroxide (2 x 150ml), water (2 x 100ml) and saturated brine (100ml). The aqueous washings were in turn extracted with ether (100ml). The ethereal solutions were combined, dried, and the ether removed under reduced pressure. The residue was purified by chromatography using 35% ethyl acetate in hexane as eluant. Combining the appropriate fractions and crystallisation from hexane yielded 1-t- butoxycarbonylamino-2-[4-(2-ethy1-1,3-dioxolan-2-y1) ethy1]- phenoxy]ethane as white crystals (11.lg) m.p 64-66°C; microanalysis: found C, 65.4; H, 8.0; N, 4.2%; required for C. Q HJ Q NO-: C, 65.0; H, 8.3; N 4.0%. d) The product from c) above (11.Og) was added to a stirred suspension of sodium hydride (1.50g of a 50% dispersion in mineral oil) in dry dimethylformamide (220ml) under argon. The reaction mixture was stirred at 50°C for 11/2 hours. The mixture was cooled to 0 β C, phenylglycidyl ether (4.3ml) was added and the reaction mixture then stirred at 50°C for 13/4 hours. The reaction mixture was cooled, poured into water (1.2L) and the product extracted into ethyl acetate (400ml, 250ml, 200ml). The combined ethyl acetate extracts were washed with water (500ml), dried and the solvent removed under reduced pressure. The residue was purified by chromatography using 60% ethyl acetate in hexane as eluant. The appropriate fractions were combined, evaporated and the residue triturated with hexane to give a solid which was crystallised from cydohexane to give 3-[2(4-(2-ethyl-l,3-dioxolan-2-ylmethyl)phenoxy)ethyl]-5- (phenoxymethyl)oxazolidin-2-one as white crystals (4.0g), m.p. 88-90 β C; microanalysis: found C, 67.4; H, 7.0; N, 3.2%; required for C 24 H 29 N0 6 ! C ' 67,4; H ' 6 ' 8; N ' 3 ' 3X ' e) A solution of product from d) above (4.0g) in a mixture of 2N aqueous sodium hydroxide (12ml) and ethanol (60ml) was heated under reflux under argon for 8 hours. The reaction mixture was cooled, poured into water (100ml) and the product extracted into dichloromethane (3 x 60ml). The combined extracts were washed with brine (60ml), dried, and the solvent removed under reduced pressure. The residual solid was crystallised from ethanol to yield l-[2-(4-(2- ethyl-l,3-dioxolan-2-ylmethyl)phenoxy)ethylamino]-3-phenoxypropan-2-ol as white crystals (3.0g) m.p. 101-103 β C; microanalysis: found C, 69.1; H, 7.8; N, 3.4%; required for C 23 H 31 0 5 : C, 68.8; H,7.7; N, 3.5%. Examples 5 and 6 In a manner similar to that of Example 4, the following compounds as the hydrochloride salts were prepared from l-(4- hydroxyphenyl)pentan-2-one and l-(4-hydroxyphenyl)-3-methylbutan-2-one respectively. PhOCH-CH(OH)CH 2 NHCH-CH 2 ° _ 3_-, CH-COR Example | R | m.p. | Microanalysis/NMR | | (solvent) | 5 | -CH 2 CH-CH 3 | 165-7°C |Found: C, 64.9; H, 7.5; N, 3.3%; | |(ethanol) |required for C 2 -H 30 C1N0 4 : C, 64.8; | | |H, 7.4; N, 3.4%; | | |NMR 0.83(t,3H,C0CH-CH-CH 3 ), | | |1.49(sextet, 2H, COCH-C^CH,-), | | |2.44(t,2H, C0CH 2 CH 2 CH 3 ), 3.11- | | |3.50(m,4H, CH 2 NHCH 2 ), | | |3.67(s,2H, ArCH j CO-), 3.95- | | |4.09(m,2H,PhOCH 2 CH-), 4.22- | | |4.38(m,3H,CH0H and CH 2 CH 2 0Ar), | | |6.90-7.34(m,9H,aromatic H). Example R m.p. | Microanalysis/NMR (solvent) 1 6 -CH(CH 3 ) 2 175-7 β C |Found: C, 64.9; H, 7.4; N, 3.3%; (ethanol) |required for C 22 H 3Q C1N0 4 : C, 64.8; |H, 7.4; N, 3.4%; |NMR 1.05(d,6H,C0CH(CH 3 ) 2 ), |2.74(septet, IH, C0CH(CH 3 ) 2 ), |3.18-3.54(m,4H,CH 2 NHCH 2 ), |3.74(s,2H,ArCH 2 C0), 3.98- |4.11(m,2H,PhOCH 2 CH-), 4.29- |4.40(m,3H,CH0H and CH j CH j OAr), |6.90-7.34(m,9H, aromatic H). 1 For convenience the scheme for the preparation of the compounds of Examples 4-6 is set out below (wherein R is ethyl, n- propyl or isopropyl). Scheme 1 (5) PhOCH 2 CH( OH ) (6) Footnotes to scheme: A. l-(4-Hydroxyphenyl)pentan-2-one (compound(l): R = -CI CH-CH,,) was prepared as follows: 1-Bromopropane (33.2ml) in anhydrous ether (100ml) vas added dropvise over 30 minutes to a stirred suspension of lithium slices (6.0g; 0.86 gm atoms) in ether (150ml) under argon, maintaining the internal temperature at 0 β to -10°C. The reaction mixture vas stirred for 1 1/2 hours at 0-5°C and added to a stirred solution of 4- hydroxyphenylacetic acid (5.6g) in anhydrous tetrahydrofuran (300ml) at 0 - 10 β C under argon, leaving behind any unreacted lithium. The reaction mixture vas stirred for 40 hours at 22°C, then cooled in an ice-bath and chlorotrimethylsilane (50ml) vas added over 15 minutes. The temperature vas allowed to rise to 22°C. and the reaction mixture was poured into IN hydrochloric acid (600ml) and stirred for 1/2 hour. The product was extracted into ethyl acetate (3 x 200ml) and the combined extracts washed with aqueous sodium bicarbonate (2 x 300ml), washed with brine (100ml), dried and the solvent removed under reduced pressure. The procedure was repeated three times on the same scale and the combined crude ketone was purified by chromatography using 22% ethyl acetate in hexane as eluant. The appropriate fractions were combined and evaporated to yield l-(4-hydroxyphenyl)pentan-2-one (3.4g) as a yellow oil. (A similar procedure for the preparation of methyl ketones is described by G M Rubottom and Chong-Van Kim, J.O.C. 1983, 48, 1550-1552). B. l-(4-Hydroxyphenyl)-3-methylbutan-2-one (compound (1): R - -CH(CH 3 )„) was prepared as follows: A solution of isopropyl magnesium bromide (prepared from magnesium (1.75g) and 2-bromopropane (8.9g)) in dry tetrahydrofuran (100ml) was added dropwise over 30 minutes to a stirred solution of 4- methoxyphen lacetyl chloride (26.6g) in tetrahydrofuran (75ml) under argon, maintaining the internal temperature at -65 β to -70°C. The reaction mixture was allowed to warm up to 20°C over 1 hour and then poured into water (150ml). The product was extracted into ether (2 x 70ml). The ether extracts were washed with IN aqueous sodium hydroxide (2 x 70ml), brine (70ml), dried, and the solvent removed under reduced pressure. The residue was purified by chromatography using 10% ethyl acetate in hexane as eluant. The appropriate fractions were combined and the solvent removed under reduced pressure to yield l-(4-methoxyphenyl)-3-methylbutan-2-one (2.5g) an oil. l-(4-Methoxyphenyl)-3-methylbutan-2-one (10.2g) was added to a stirred melt of pyridine hydrochloride (36ml) at 140°C under argon. The reaction mixture was heated to 220 β C for 2 hours. The mixture was cooled, water (400ml) was added and the product extracted into ether (3 x 150ml). The combined ethereal extracts were washed with brine (100ml), dried, and the solvent removed under reduced pressure. The residual oil was purified by chromatography using 25% ethyl acetate in hexane as eluant. The appropriate fractions were combined to give l-(4-hydroxyphenyl)-3-methylbutan-2-one (7.9g) as an oil. C. Physical Data for Intermediates in the preparation of the compounds of Examples 5 and 6. Example 5 m.p. Microanalysis (solvent) Compound (2) oil Compound (3) 80-2 β C Found C, 65.6; H, 8.6; N, 3.8%; required (cydohexane) for C 2() H 31 N0 5 :C, 65.8; H, 8.5; N, 3.8% Compound (4) 90-l β C Found C, 67.0; H, 7.1; N, 3.3%; required (cydohexane) for C 25 H 31 N0 6 1/2H 2 0:C, 66.7; H, 7.1; N,3.1% Compound (5) 104-6°C Found C, 69.4; H, 8.0; N, 3.2%; required (ethanol) for C 24 N 33 N0 5 :C, 69.4; H, 8.0; N, 3.4% Example 6 m.p. | Microanalysis (solvent) Compound (2) 84-6 β C Found C, 70.8; H, 8.5%; required for (cydohexane) C 13 H 18°3 C ' 70,3; H ' B ΛX Compound (3) 113-5 β C Found C, 65.7; H, 8.5; N, 3.7%; required (cydohexane) for C 2Q H 31 N0 5 C, 65.8 H, 8.5; N, 3.8% Compound (4) 128-9 β C Found C, 67.6; H, 6.8 , N, 3.1%; required (toluene) for C 25 H 31 N0g C, 68.0 ; H, 7.0; N, 3.2% Compound (5) | 98-100 β C Found C, 69.2; H, 7.9 ; N, 3.3%; required (ethanol) for C 24 H 33 N0 5 C, 69.4 ; H, 8.0; N, 3.4% Example 7 l-[4-(2-(2-Hydroxy-3-phenoxypropylamino)ethoxy)phenyl]butan-2-one. A solution of 3-[2-(4-(2-oxobutyl)phenoxy)ethyl]-5- (phenoxymethyl)oxazolidin-2-one (200mg) in hot ethanol (4ml) was treated with 2N aqueous sodium hydroxide (0.75ml) and the reaction mixture was stirred under reflux for 4 hours under argon. The reaction mixture was cooled, poured into water (20ml) and the product was extracted into dichloromethane (3 x 20ml). The dichloromethane extracts were washed with brine (20ml), dried, and the solvent was removed under reduced pressure. The residue was converted to the hydrochloride and crystallised from ethanol to yield the title compound in the form of the hydrochloride (150mg); m.p. 166-8°C. The starting material was prepared as follows: a) A solution of N-t-butoxycarbonylaminoethanol (2.0g), dihydropyran (1.7ml) and pyridinium p-toluenesulphonate (310mg) in anhydrous dichloromethane (90ml) was stirred at room temperature for 2 1/2 hours. Ether (150ml) was added, the solution was washed with water (2 x 50ml), dried, and the solvent removed under reduced pressure to give 2-(2-(N-t-butoxycarbonylamino)ethoxy)tetrahydropyran (3.0g) as a yellow oil. b) The product from a) above (2.9g) was added to a stirred suspension of sodium hydride (570mg of a 50% dispersion in mineral oil, 0.012 moles) in anhydrous dimethylformamide (100ml) under argon. The reaction mixture vas stirred at 55°C for 1 1/2 hours. The mixture was cooled to 0°C, phenylglycidyl ether (1.6ml) was added and the reaction mixture then stirred at 20°C for 2 1/2 hours. The reaction mixture was poured into water (500ml) and the product extracted into ethyl acetate (350ml, 100ml, 100ml). The combined ethyl acetate extracts vere vashed vith vater (200ml), dried, and the solvent removed under reduced pressure. The residue vas subjected to chromatography using 60% ethyl acetate in hexane as eluant. The appropriate fractions vere combined to yield 5-phenoxymethyl-3-(2-(tetrahydropyran-2-yloxy)ethyl)oxazolidin-2-one (l.Og) m.p. 78-80°C (cydohexane); microanalysis: found C, 63.3; H, 7.2; N, 4.3%; required for C- H- -O-: C, 63.6; H, 7.2; N, 4.4%. c) A solution of the product of b) above (0.88g) and pyridinium p-toluenesulphonate (70mg) in a mixture of vater (1.0ml) and ethanol (24ml) vas stirred at 65°C for 4 hours. Ethanol vas removed under reduced pressure and the residue partitioned betveen vater (30ml) and ethyl acetate (30ml). The organic layer vas separated and the aqueous layer re-extracted vith ethyl acetate. The ethyl acetate extracts vere vashed vith vater (20ml), dried, and the solvent removed under reduced pressure. Trituration of the residue vith ether followed by crystallisation from propan-2-ol yielded 5-phenoxymethyl-3-(2- hydroxyethyl)oxazolidin-2-one (0.52g) m.p 89-91 β C; microanalysis: found C, 60.8; H, 6.3; N, 5.8%; required for C 12 H 15 N0 4- C, 60.8; H, 6.3; N, 5.9%. d) Diethyl azodicarboxylate (0.33ml) vas added dropvise to a stirred solution of l-(4-hydroxyphenyl)butan-2-one (0.35g), part of the product from c) above (0.50g) and triphenylphosphine (0.55g) in anhydrous tetrahydrofuran (13ml), at ice-bath temperature, under argon. The reaction mixture vas left for 100 hours at 20 β C and then the solvent removed under reduced pressure. The residue vas dissolved in ethyl acetate and the solution seeded vith 1,2-dicarbethoxyhydrazine. The solution vas allowed to stand for 2 hours, the solid vas collected and the filtrate vas, subjected to chromatography using 50% ethyl acetate in hexane as eluant. The appropriate fractions vere combined, evaporated, and the residue vas crystallised from ethyl acetate/cyclohexane to give 3-[2-(4-(2-oxobutyl)phenoxy)ethyl]-5-(phenoxymethyl)oxazolidin-2-one (280mg) ; m.p 67-69°C; microanalysis found C, 68.9; H, 6.6; N, 3.7%; required for C 22 H 2 _N0 5 : C, 68.9; H, 6.5; N, 3.7%. Examples 8 - 12 In a manner similar to that of Example 7, the folloving compounds as the hydrochloride salts vere prepared from l-(4-hydroxy- pheny1)hexane-2-one, 1-(4-hydroxyphenyl)-4-methylpentan-2-one, 1-(4-hydroxypheny1)heptan-2-one, 1-(4-hydroxypheny1)octan-2-one and l-(4-hydroxyphenyl)nonan-2-one respectively. 1 Example1 R | m.p. | Microanalysis/NMR | | (solvent) | 8 | -(CH 2 ) 3 CH 3 | 173-5 β C | Found: C,65.1; H,7.6; N,3.3%; | | (ethanol) | required for C 23 H 32 C1N0 4 : C,65.5; | | | H,7.6; N, 3.3%; | | | NMR 0.84(t,3H, C0CH 2 CH 2 CH 2 CH 3 ) | | | 1.23(sextet, 2H, C0CH 2 CH 2 CH 2 CH 3 ) | | | 1.46(quintet, 2H, COCH j CH-C^CH.,); | | | 2.46(t,2H, C0CH 2 CH 2 CH 2 CH 3 ); | | | 3.09-3.47(m,4H, CI -NHCHj); | | | 3.68(s,2H,ArCH-C0); | | | 3.95-4.09(m,2H,PhOCH 2 CH); | | | 4.22-4.36(m,3H,CH0H and CH 2 CH 2 0Ar ; | | | 6.90-7.36(m,9H, aromatic H). 9 |CH-CH(CH 3 ) 2 | 176-8°C | Found: C,65.1; H,7.5; N, 3.1%; | | (ethanol) | required for C 23 H 32 C1N0 4 ; C, 65.5; | | | H,7.6; N, 3.3%; | | | NMR 0.84(d,6H, C0CH 2 CH(CH 3 ) 2 ); | | | 2.04(m,lH, C0CH 2 CH(CH 3 ) 2 ); | | | 2.35(d,2H,C0CH 2 CH(CH 3 ) 2 ); | | | 3.10-3.50(m,4H,CH 2 NHCH 2 ); | | | 3.66(s,2H ArCH j CO); | | | 3.95-4.10(m,2H,PhOCH 2 CH); | | | 4.22-4.36(m,3H,CH0H and CH-CH-OAr); | | | 6.92-7.35(m,9H, aromatic H). Example| R | m.p. | Microanalysis/NMR I |(solvent) | 10 | CH 2 ) 4 CH 3 | 172-4 β C | Found: C,65.8; H,7.8; N,3.4%; | | (ethanol)| required for C 24 H 34 C1N0 4 : C,66.1; I | | H,7.8; N,3.2%; I | | NMR 0.84(t,3H, CH 2 CH 2 CH 2 CH 2 CH 3 ) | | | 1.10-1.35(m,4H, CH 2 CH 2 CH-CH 2 CH 3 ); 1 | | 1.48(quintet, 2H, CH 2 CH-.CH 2 CH-,CH 3 ); | | [ 2.46(t,2H, C0CH 2 CH 2 CH 2 CH 2 CH 3 ); | | | 3.12-3.50(m,4H,CH-NHCH 2 ); 3.67(s,2H, | t | ArCH 2 C0); 3.95-4.10(m,2H,Ph0CH 2 CH); | | | 4.24-4.39(m,3H,CH0H and CH-CH-OAr); I | | 6.90-7.36(m,9H, aromatic H) 11 | (CH 2 ) 5 CH 3 | 172-4 β C | Found: C,66.8; H, 8.3; N, 3.0%; I [ (ethanol)| required for C 25 H 36 C1N0 4 : C,66.7; | | | H,8.0; N, 3.1%; | | | NMR 0.85(t,3H, CH j CH^H-CH j C^CHg); | | | 1.15-1.32(m,6H, CH 2 CH 2 CH-CH 2 CH 2 CH 3 ); I | | 1.46(quintet,2H,CH 2 CH 2 CH 2 CH-CH 2 CH 3 ); | | | 2.46(t,2H,C0CH 2 CH 2 ); I | | 3.08-3.50(m,4H, CH-NHCH 2 ); [ | | 3.67(s,2H,ArCH 2 C0); I | | 3.94-4.10(m,2H PhOCH- H); | | [ 4.23-4.38(m,3H,CH0H and CH 2 CH 2 0Ar); | | | 6.90-7.36(m,9H, aromatic H) For convenience the scheme for the preparation of the compounds of Examples 7-12 is set out belov (vherein R is ethyl, n-butyl, isobutyl, n-pentyl, n-hexyl or n-heptyl. Scheme 2 (8) Ph0CH 2 CH(0H)CH 2 NHCH 2 CH 2 •0_— '- N - CH 2 C0R (9) Footnotes to scheme 2 D. In a manner similar to that described in footnote A to Scheme 1, l-(4-hydroxyphenyl)hexan-2-one vas prepared from commercially available n-butyllithium. E. In a manner similar to that described in footnote B to Scheme 1, l-(4-hydroxyphenyl)-4-methylpentan-2-one, l-(4-hydroxyphenyl)heptan-2-one, l-(4-hydroxyphenyl)octan-2-one and l-(4-hydroxyphenyl)nonan-2-one vere prepared from the appropriate alkyl bromide. F. Physical Data for Intermediates in the preparation of the compounds of Examples 8-12. Example 8 m.p. Microanalysis (solvent) Compound (7) oil Compound (8) 77-9 β C Found C, 69.8; H, 7.1; N, 3.4%; (Cydohexane) required for C 24 H 2g N0-:C, 70.1; H, 7.1; N, 3.4%. Example 9 Compound (7) oil Compound (8) 93-5 β C Found C, 70.0; H, 7.2; N, 3.4%; (ethyl acetate/ required for C 24 H 29 N0 5 : C ■ 70.1; cydohexane) H, 7.1; N, 3.4%. Example 10 Compound (7) Oil Compound (8) 76-8 β C Found C, 70.8; H, 7.6; N, 3.3%; (ethyl acetate/ required for C-, 5 H-,-N0 5 : C , 70.6; cydohexane) H, 7.3; N, 3.3%. Example 11 Compound (7) Oil Compound (8) 81-3°C Found C, 71.1; H, 7.5; N, 3.1%; (ethyl acetate/ required for C 26 H,-N0c C , 71.1; cydohexane) H, 7.5; N, 3.2%. Example 12 Compound (7) 44-6°C Found C, 77.0; H, 9.7%; (cydohexane) required for c i5 H 22°2 ! C ' ''6-9; H, 9.4%. Compound (8) 83-5 β C Found C, 71.3; H, 7.7; N, 3.0%; (ethyl acetate/ required for C 27 H 5 N0 5 ! c » 71.5; cydohexane) H, 7.7; N, 3.1%. Example 13 (S)-l-[4-(2-(2-Hydroxy-3-phenoxy ropylamino)- ethoxy)phenyl]pentan-2-one. In a manner similar to that of Example 7, (S)-5-phenoxymethyl-3-(2-hydroxyethyl)oxazolidin-2-one vas reacted vith l-(4-hydroxyphenyl)pentan-2-one to give (S)-3-[2-(4-(2-oxopentyl)phenoxy)ethyl]-5-(phenoxymethyl)oxazolidin-2- one vhich vas hydrolysed to the title compound in the form of the hydrochloride; m.p. 166-7 β C (ethanol); [α] D 28 __ -11.3° (c = 1.0, methanol); microanalysis: found C, 64.9; H, 7.5; N, 3.7%; required for C 22 H 30 C1N0 4 ! C ' 64,8; H ' 7,4; N ' 3ΛX' ' NHR < DMS °- « V °- 82 < t»3H» CH 2 CH 2 CH 3 ) 1.49(sextet, 2H, CH 2 CH 2 CH 3 ); 2.44(t,2H,CH 2 CH 2 CH 3 ); 3.20-3.48(m,4H,CH 2 NHCH 2 ); 3.66(s,2H, ArCg 2 C0); 3.92-4.07(m,2H PhOCH 2 CH); 4.22-4.38(m,3H, CHOH and CH 2 C§ 2 0Ar) 5.90(1H,OH); 6.90-7.34(m,9H, aromatic H); 9.13 and 9.35(2H, NH 2 + ). The starting material vas prepared as follows: a) (S)-5-Phenoxymethyloxazolidin-2-one vas prepared from (S)-phenylglycidyl ether and urea using the procedure described by W. J. Kauffman and J. E. Herveh, J. Org. Chem. 1972, 3_7, 1842-1845. b) Sodium hydride (2.2g of a 50% dispersion in mineral oil) vas added to a stirred solution of 2-bromoethyl acetate (5ml) and (S)-5-phenoxymethyloxazolidin-2-one (8.0g) in anhydrous dimethylformamide (150ml), under argon, at 20 β C. When the effervescence had ceased, the reaction mixture vas heated to 45-50°C for 2 hours. The reaction mixture vas cooled, poured into vater (750ml) and the product extracted into ethyl acetate (3 x 400ml). The combined ethyl acetate extracts vere vashed vith vater (300ml), dried, and the solvent removed under reduced pressure. The residue vas subjected to chromatography using ethyl acetate in hexane as eluant (gradient elution; 60% to 70% ethyl acetate). The appropriate fractions vere combined to yield (S)-5-phenoxymethyl-3-(2-acetoxyethyl)oxazolidin-2-one (4.6g). c) A solution of the product from b) above (4.5g) and sodium methoxide (l.Og) in methanol (50ml) vas stirred at 20°C for 1 hour. Methanol vas removed by evaporation and the residue partitioned betveen ethyl acetate and vater. The ethyl acetate layer vas separated, dried, and the solvent removed under reduced pressure. The residue vas subjected to chromatography using 2% methanol in dichloromethane as eluant. The appropriate fractions vere combined to yield (S)-5-phenoxymethyl-3-(2-hydroxyethyl)oxazolidin-2-one (2.2g).

Claims: CLAIMS 1. A compound of the formula (I): /' -0CH 2 CH 0H)CH 2 NHCH 2 CH 2 0- -CH j COR 1 (I) vherein R is hydroxy or C. - 0 alkyl, or an in vivo hydrolysable salt or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 vherein R is hydroxy. 3. A compound according to claim 1 vherein R is C. ..alkyl. 4. A compound according to claim 3 vherein R is methyl, ethyl, n-propyl, isobutyl, n-butyl or n-hexyl. 5. A compound according to claim 1 vhich is: 4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid or (S)-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid. 6. A compound according to claim 1 vhich is: l_[4_(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]propan-2-one, (S)-l-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]propan-2- one, 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]butan-2-one, (S)-1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)pheny1]butan-2-one, l-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]pentan-2-one, (S)-l-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]pentan-2- one, 1-[ -(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phen l]-3-methylbutan-2 -one, 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]hexan-2-one, 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]-4-methylpentan- 2-one, 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy) henyl]heptan-2-one, 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)pheny1]octan-2-one or 1-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]nonan-2-one. 7. A compound according to any one of claims 1 to 6 vhen in (S) absolute configuration at the -CH(OH)- group. 8. A pharmaceutical composition vhich comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition vhich comprises a compound according to claim 7 and a pharmaceutically acceptable carrier. 10. A process for preparing a compound of the formula (I) or in vivo hydrolysable ester or pharmaceutically acceptable salt thereof as defined in claim 1 vhich comprises: a) reacting a compound of the formula (II) or (III) vith a compound of the formula (IV): (III) (IV) vherein R is as defined in claim 1 and L is a displaceable group; or b) hydrolysis of a compound of the formula (V): vherein R is as hereinbefore defined; or c) for compounds of the formula (I) vherein R is hydroxy, hydrolysing a compound of the formula (VI): /^ θCH 2 CH(OH)CH 2 NHCH 2 CH 2 0--^_ N CH 2 COR 2 (VI) 2 vherein R is a hydrolysable group; d) reacting a compound of the formula (VII) vith a compound of the formula (VIII): (VIII) vherein R is as hereinbefore defined and L' is a leaving group; or e) deprotecting a compound of the formula (IX) : 1 3 vherein R is as hereinbefore defined and R is a protected derivative of -COR 1 : and if necessary thereafter forming an in vivo hydrolysable ester or a pharmaceutically acceptable salt. 11. A compound of the formula (VI): 2 vherein R is a hydrolysable group. 2 12. A compound according to claim 11 vherein R is C. .alkoxy or amino (-NH-). 13. A compound of the formula (V): or of the formula (IX): Q - 0CχH_ 2 C^H(0-H)eCH_ 2 N-HCH_ 2 ^CH 2 0--^«f/ Λ --CH 2 R J (IX) 1 3 vherein R is defined as in claim 1 and R is a protected derivative of -COR . 14. A compound of the formula (XIV): ZCH 2 CH 2 0 >o- ' -CH 2 C0R la (XIV) vherein Z is amino, protected amino or a leaving group such as halo or la sulphonyloxy and R is C- - Q alkyl.

Inventors: HOWE RALPH, LE COUNT DAVID JAMES, RAO BALBIR SINGH, HOWE, RALPH, LE COUNT, DAVID, JAMES, RAO, BALBIR, SINGH
Applicants: ICI PLC, IMPERIAL CHEMICAL INDUSTRIES PLC
Application year: 1990
Main classification: C07C217
IPC codes: A61K31, A61P3, C07C49, C07C213, C07C217, C07C235, C07C237, C07C271, C07C309, C07D263