IE42502B1 - Phenoxyphenylbutyric acid derivatives and process for their preparation - Google Patents

Abstract

1494462 Phenoxyphenyl-butyric acid derivatives MERCK PATENT GmbH 5 March 1976 [7 March 1975] 08980/76 Heading C2C Novel compounds I in which R1 is H, C 1-6 alkyl or C n H 2n -R3, R2 is H, Cl, Br or F, R3 is di(C 1-4 alkyl)amino, pyrrolidino, piperidino, morpholino, piperazino, N-C 1-4 alkyl-piperazino or N-C 1-4 hydroxyalkyl-piperazino and n is 2, 3 or 4, and their physiologically acceptable salts, are prepared by reducing a compound II and R5 is -C(CH 3 )R6-CH 2 -, -C(CH 3 )=CH-, -C(=CH 2 )-CH 2 -, -CH(CH 3 )-CHR7-, -(CH 3 )R6-CHR7 or -C(CH 3 )=CR7, where R6 and R7 are each OH, Oacyl, SH, NH 2 , aralkyloxy or aralkylamino, followed, if desired, by treatment of a resulting compound I with a solvolysing, esterifying or salt-forming agent. Pharmaceutical compositions having antiinflammatory, analgesic, antipyretic, antiarteriosclerotic and thrombocyte aggregationinhibiting activity for oral, parenteral, rectal or topical administration, comprise one of the above novel compounds together with a pharmaceutically acceptable carrier.

Description

The present invention is concerned vzith certain novel phenoxyphenylbutyric acid derivatives, with a process for their preparation, and vzith compositions containing them.

We have found that phenoxyphenylbutyric acid derivatives of 5 formula I: wherein is H, alkyl with 1-6 C atoms or Cj^n-^' R2 is H, F, Cl or Br, R is di-(C1_^ alkyl)amino, pyrrolidino, piperidino, morpholino, piperazino, or 4-alkylpiperazino or 4-hydroxyalkylpiperazino with 5-8 C atoms in each case, and n is 2, 3 or 4, - 2 43502 and their physiologically acceptable salts, possess valuable pharmacological properties and are well tolerated. These compounds have anti-inflammatory activity which can, for example, be demonstrated in rats, for example by the adjuvant5 arthritis test described by Newbould (Brit. F. Pharmacol., 21, (1963), pages 127-136). These compounds also have analgesic, antipyretic and anti-arteriosclerotic activity and thrombocyte aggregation-inhibiting activity; these various activities can be demonstrated by the conventional procedures and tests appropriate thereto.

The compounds of formula I and their salts can therefore be used as medicaments in human and veterinary medicine; they can also be used as intermediates in the preparation of other medicaments; for example their reduction leads to the corresponding alcohols which are also valuable anti-inflammatory and anti-arteriosclerotic agents.

The compounds of formula I and their physiologically acceptable salts are novel and constitute one aspect of the present invention.

The alkyl groups referred to herein, whether they be alkyl substituents as such or part of other substituents, viz. dialkylamino, alkylpiperazlno or hydroxyalkylpiperazino, are preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, of which the first two are particularly preferred.

R1 is preferably H, methyl, ethyl, 2-dimethylaminoethyl or 2-diethylaminoethyl, and may also be, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, isohexyl, 2-methylethylaminoethy1, 2-di-n-propylaminoethyl, 2-di-n-butylaminoethyl, 2- or 3dimethylaminopropyl, 2- or 3-diethylaminopropyl, 2-, 3- or 4dimethylaminobutyl, 2-, 3- or 4-diethylaminobutyl, 2-pyrrolidin oethyl, 2-piperidinoethyl, 2-morpholinoethyl, 2-piperazin5 oethyl, 2-(4-methylpiperazino)-ethyl, 2-(4-ethylpiperazino)ethyl, 2-(4-n-butylpiperazino)-ethyl or 2-[4-(2-hydroxyethyl) 2 piperazinoj -ethyl. R is preferably F or Cl; this radical is preferably in the p-position, but it can also be in the o3 * position or m-position. R is preferably dimethylamino or diethylamino. n is preferably 2 or 3, more preferably 2. Accordingly, CnH2n can be ' ‘‘ -CH2CH2-, -(CH2)3- or -(CH2)4~, but also -CH{CH3)-, -CHtCHgHg-, -ch(ch3)-cM2-, -ch2-ch(ch3)-, -c(ch3)2-, -CH(CH3)-CH(CH3)-, -C(CH3)2-CH2-, -CH2-C(CHg)2», -CH(CH2H5)-CH2-, -CH2-CH(C2H5)-, -CH(C3H7)- or -CH(iso-C3H?)-.

Preferred compounds according to the invention are those compounds of formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be characterised by the partial formulae Ia to If below, which correspond to formula I and wherein the radicals not defined in more detail have the meaning indicated in the formula I, but wherein: in Ia, R1 is H, CH3, CgHg, CH2CH2H(CHg)2 or CHgCHgN(CgHg)2? in lb, r1 is H, CHg, or CgHgj in Ic, R is P or Clf in Id, R1 is H, CHg or CgHg and R2 is P or Clj in Ie, R^ is H, CHg or CgHg and 2 R is Ff and in If, R1 is H, CH3 or C2Hg and R2 is Cl.

The present invention also comprises a process for the preparation of a compound of formula I or a physiologically acceptable salt thereof, which comprises reducing a compound of formula II: ΓΎ/ r5-coor1 II wherein r5 is -c(ch3)r6-ch2-, -c(ch3)=ch-, -c(c=ch2)-ch2-, -CH(CH3)-CHR7-, -C(CH3)R6-CHR7- or -C(CH3)=CR7-, 7 R and R are each OH, Oacyl, halogen, SH, NH2, or aralkyloxy or aralkylamino with up to 10 carbon atoms in each case, and 1 2 R and R have the above-stated meanings.

The compound of formula I obtained may, if desired, betreated with a solvolysing agent, an esterifying agent or a saltforming agent, to convert the R^ radical into another R^ radical. When a carboxylic acid of formula I is obtained, it may, if desired, be treated with a base to form a physiologically acceptable salt.

For the sake of simplicity, A is used in the following description to mean an alkyl group with 1-6, preferably 1-4, C atoms and Q to mean the group -CH(CH3)-CH2~.

The preparation of the compounds of formula I is carried out in other respects in accordance with known methods such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic 42S02 Reactions,John Wiley & Sons Inc., New York) and, in particular, under the reaction conditions which are known and suitable for the reactions in question. Use can also be made of variants which are in themselves known, but which are not referred to in more detail herein.

The starting materials for the preparation of the compounds of formula I are, in some cases, known. They can be prepared according to known methods, if desired, in situ, in such a way that they are not isolated from the reaction mixture, but are immediately further reacted to give the compounds of formula I.

Examples of suitable compounds of formula II are carboxylic acids of the formulae: Z-C (CH3) (OH)-CH2-COOH, Z-C(CH3)=CH-COOH, Z-C(=CH2)-CH2-COOH, Z-CC1(CH3>-CH2-COOH, Z-CH(CH3)-CHC1-COOH, Z-C(CH3)(OH)-CHC1-C00H, Z-C(CHj)-CC1-C00H and Z-C(CH3)C1-CHC1-C00H, The reduction of these starting materials is preferably carried out by catalytic hydrogenation or by chemical methods.

Catalysts which are suitable for catalytic hydrogenations are, for example, noble metal, nickel or cobalt catalysts, and also mixed catalysts, such as copper chromium oxide. Suitable noble metals are, in particular, platinum and palladium, which can be present on carriers (for example charcoal, calcium carbonate or strontium carbonate), as oxides or in the finely divided form. Nickel and cobalt catalysts are preferably employed as Raney metals. The hydrogenation reaction can be 4250^ carried out at a pressure of from 1 to 100 atmospheres and at a temperature of from -80° to +150°C, preferably from 20° to 100°C. The hydrogenation reaction is carried out in the presence of an inert solvent, for example an alcohol, such as methanol, ethanol or isopropanol; a carboxylic acid, such as acetic acid; an ester, such as ethyl acetate; or an ether, such as tetrahydrofuran (THF) or dioxan. Solvent mixtures can also be used, for example mixtures which contain water.

Reaction with nascent hydrogen is another suitable method of 10 reducing the compounds Ila. Nascent hydrogen can be produced, for example, by treating metals with acids or bases. Thus, for example, the systems zinc/acid, zinc/alkali metal hydroxide ’ 7 ? solution, iron/acid and tin/acid can be used. Suitable acids are, /'_ for example hydrochloric acid or acetic acid. An aluminium/ , ' nickel alloy in aqueous alkaline solution, if desired with the addition of methanol, or sodium amalgam or aluminium amalgam in aqueous alcoholic solution or aqueous solution are also suitable for producing nascent hydrogen. In the case of this method of reduction, the reaction is suitably carried out at 20 a temperature of from 0° to 150°C, preferably from 20°c to the boiling point of the solvent used.

A further suitable reducing agent is tin(II) chloride which is preferably used in the form of its dihydrate in aqueous-alcoholic or aqueous-acidic solution, for example in the presence of acetic acid and/or hydrochloric acid at a temperature of from 0° to 120°C.

Another suitable reducing agent is hydriodic acid, if desired, with the addition of phosphorus and/or a solvent, such as acetic acid, preferably at a temperature of from 100°C to the boiling 2q point. Hydriodic acid can also be produced In situ by using, for example, a mixture of KI, red phosphorus and phosphoric acid as the reducing agents, preferably at a temperature of from 100° yr·» '?> - 7 42502 to 150°C.

Using the above-described methods, several reducible groups in a given starting material can be reduced simultaneously, the compounds of formula Ila being passed through as intermediates which do not need to be isolated. 3 Esters of formula I (R =A or cnH2nR can solv°lYse4» in particular hydrolysed, or thermolysed to give the free carboxylic acids. The esters are preferably treated with NaOH, KOH or KjCOj in methanol, ethanol or isopropanol for from 1 to 48 hours at a temperature of from 20° to 12o°C; acidic (for example with acetic acid/hydrochloric acid at 2O-12O°C) or neutral (with water at 100-200°C, if desired under pressure)hydrolysis can also be carried out.

An acid of formula I (R^=H) can be esterified with an alcohol of the formula A-OH or R -cnH20~0Hr for example in the presence of an inorganic or organic acid, such as HCl, HBr, HI, H2SO4, H3PO4, trifluoroacetic acid or a sulphonic acid, such as benzenesulphonic acid or £-toluenesulphonic acid, or an acidic ion exchanger, and also, if desired, in the presence of an inert solvent, such as benzene, toluene or xylene, at a temperature of from 0° to 140°C. The alcohol is preferably employed in excess. The water formed in the reaction can be removed azeotropically, for which purpose it is advantageous to add a hydrocarbon (for example benzene or toluene) or a chlorinated hydrocarbon (for example chloroform or 1,2-dichloroethane) to the reaction mixture. If the water of reaction is chemically bonded by the addition of a carbodiimide (for example N,N’dicyclohexylcarbodiimide) , the esterification reaction can be carried out under mild conditions, preferably in the presence of an inert solvent, such as ether, dioxan, 1,2-dimethoxyethane, benzene, CH2C12 or CHCland a base, such as pyridine. The methyl esters and ethyl esters can also be prepared by reacting the free - 8 4 2502 acid with diazomethane or diazoethane in an inert solvent, such as ether, benzene or methanol.

Esters of formula I (r!=A) can also be prepared by reacting a metal salt of the corresponding carboxylic acid I (R1=:H), preferably the alkali metal, lead or silver salts, with a halide of the formula A-Hal or R3-CnH2n-Hal, if desired in an inert solvent, such as ether, benzene, DMF or petroleum ether.

Esterification can also be effected in several stages, for example, by first converting the acid into its halide and reacting the latter with the alcohol A-OH or R3CnH2n-,3Hr if desired in the presence of an aoid catalyst or a base, such as NaOH, KOH,Na2CO3,K2CO3 or pyridine. An excess of the alcohol and/or an inert solvent is preferably used and the reaction is preferably carried out at a temperature of from 0°C to the boiling point. Tert.-alkyl esters are obtainable, for example, from the acid chloride and potassium tert.-alcoholates.

Suitable inert solvents are, for example, ether THF or benzene.

The acids of formula I (R^=H) can be converted into one of their physiologically acceptable metal salts or ammonium salts by reaction with a base. Suitable salts are, for example, the sodium, potassium, magnesium, calcium and ammonium salts, and also substituted ammonium salts, such as, for example, dimethylammonium, diethylammonium and diisopropylammonium salts, monoethanolammonium, diethanolammonium and triethanolammonium salts, cyclohexylammonlum salts, dicyclohexylammonium salts and dibenzylethylenediammonium salts.

Conversely, acids of formula can be liberated from their metal or ammonium salts by treatment with an acid. - 9 43302 The compounds of formula I contain a centre of asymmetry and are usually obtained in the racemic form. The racemates can be separated into their optical antipodes by means of known mechanical or chemical methods, such as are described in the literature, for example, the acids I (R^H) can be separated by means of optically active bases.

The compounds of formula I and their physiologically acceptable salts can be used in human or veterinary medicine in admixture with solid, liquid and/or semi-liquid inert, physiologically acceptable carriers or excipients. Suitable carriers are organic or inorganic substances which are suitable for parenteral or enteral administration or topical application and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohol, polyethylene glycols, gelatine, lactose, starch, magnesium stearate, talc, petroleum jelly and cholesterol Compositions in the form of tablets, dragees, capsules, syrups, elixirs or suppositories are suitable for enteral administration. Compositions in the form of solutions, preferably oily or aqueous solutions, suspensions, emulsions or Implants are suitable for parenteral administration; and ointments, creams or powders for topical application. The new compounds can also be lyophilised and the resulting lyophilisates can be used, for example, for the preparation of injection formulations. Such compositions may be sterilised and/or may contain adjuvants, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for controlling the osmotic pressure, buffer substances, colorants, flavouring agents and/or aromatising agents. They can, if desired, also contain one or more further active compounds, for example vitamins.

The compounds of formula I and their salts are, in general, administered in the same way as knovm anti-inflammatory agents, such as Indomethacin. The daily dosage is preferably from 0.2 to 20 mg/kg of body-weight. Oral administration is preferred.

When compositions of the new compounds are in dosage 5 unit form, they preferably contain from 10 to 1000, more preferably 30 to 300, mg of the compound(s) per dosage unit.

In order that the invention may be more fully understood, the following examples are given by way of illustration. In these examples, all temperatures are in degrees Centigrade.

Customary working up means: water and/or an organic solvent, such as benzene chloroform or dichloromethane, is added, if necessary, to the reaction mixture, the phases are separated, the organic phase is dried over sodium sulphate and filtered the filtrate is evaporated and the residue is purified by chromatography and/or crystallisation.

Example 1 a) 1 g of 3-(4-£-chlorophenoxy-phenyl)-3-hydroxybutyric acid ethyl ester (obtainable by reacting 4-£-chlorophenoxyacetophenone with bromoacetic acid ethyl ester/zinc) (or the corresponding hydroxy-acid, obtainable by saponifying the ester, or 3-(4-£chlorophenoxyphenyl)-2-butenic acid, obtainable by dehydrating the hydroxy-acid) is heated with 2 ml of 67% hydriodic acid and 4 ml of acetic acid for 1 hour at 150°, the mixture is poured on to ice and decolorised with NaHSO3 solution to give, after the customary working up, 3-(4-p-chlorophenoxy-phenyl)-butyric acid, m.p. 81-83°. Sodium salt m.p. 200-204°.

The following are obtained analogously from the corresponding hydroxy-esters, hydroxy-acids, unsaturated esters or unsaturated acids: 42503 3-p-phenoxy-phenyl-butyric acid, m.p. 82-84°, 3-(4-o-chlorophenoxy-phenyl)-butyric acid, m.p. 95-97°, 3-(4-m-chlorophenoxy-phenyl)-butyric acid, 3-(4-o-fluorophenoxy-phenyl)-butyric acid, 3-(4-m-fluorophenoxy-phenyl)-butyric acid, 3-(4-£-fluorophenoxy-phenyl)-butyric acid, m.p. 91-93°, 3-(4-o-bromophenoxy-phenyl)-butyric acid, 3-(4-m-bromophenoxy-phenyl)-butyric acid and the cyclohexylamine salt of 3-(4-g-bromophenoxy-phenyl)-butyric acid, m.p. 157-160°. b) 1 g of 3-(4-g-chlorophenoxy-phenyl)-butyric acid is allowed to stand in 15 ml of methanolic hydrochloric acid for 24 hours at 20°. The mixture is evaporated and the residue is worked up in the customary manner to give 3-(4-g-chlorophenoxy-phenyl)butyric acid methyl ester, b.p. 150-155°/0.2 mm.

The corresponding methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, n-pentyl, isopentyl or n-hexyl esters, for example 3-(4-g-fluorophenoxy-phenyl)-butyric acid ethyl ester (b.p. 165-172°/O.l mm) and 3-(4-g-fluorophenoxy-phenyl)20 butyric acid methyl ester (n^ 1.5329), are obtained analogously (reaction times up to 3 days) from the corresponding acids by reacting with HCl in methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec.-butanol, n-pentanol, isopentanol and n-hexanol. c) 2 g of 3-(4-g-ohlorophenoxy-phenyl)-butyric acid are boiled with 1 ml of concentrated and 30 ml of n-butanol for hours. The mixture is evaporated, the residue is taken up in chloroform, and the solution washed with NaHCO3 solution, dried and evaporated to give 3-(4-g-chlorophenoxy-phenyl)butyric acid n-hutyl ester.

Example 2 3.35 g of 3-(4-g-chlorophenoxy-phenyl)-3-hydroxy-butyric acid ethyl ester are dissolved in 40 ml of acetic acid and introduced into a solution of 9 g of SnClj.CHgO in 20 ml of concentrated hydrochloric acid. The mixture is boiled for 3 hours and buffered to pH 2 with sodium hydroxide solution, hydrogen sulphide is passed in until precipitation of SnS has ended, the mixture is filtered and worked up in the customary manner to give 3-(4-p-chlorophenoxy-phenyl)-butyric acid, m.p. 81-83°.

Example 3 A mixture of 33.5 g of 3-(4-£-chlorophenoxy-phenyl)-3hydroxy-butyric acid ethyl ester, 8.7 g of potassium iodide, .2 g of red phosphorus and 45 ml of 85% phosphoric acid is heated to 130° for 7 hours, whilst stirring. The mixture is worked up in the customary manner to give 3-(4-£chlorophenoxy-phenyl)-butyric aeid ethyl ester, b.p. 165-172°/O.l mm.

Example 4 3.18 g of 3-(4-£-fluorophenoxy-phenyl)-3-hydroxy-butyric acid ethyl ester (obtainable from 4-g-fluorophenoxyacetophenone and bromacetic acid ethyl ester/zinc) are dissolved in 10 ml of dichloromethane, the solution is saturated with dry HCl gas and 1 ml of SOClj is added. The mixture is warmed to 50° for 2 hours and the solvent is removed. The residue, which consists of 3-(4-£-fluorophenoxy-phenyl)-3-chlorobutyric acid ethyl ester, is dissolved in 100 ml of methanol and hydrogenated on 100 mg of platinum oxide under normal pressure and at 25°. The mixture is filtered, a solution of 0.4 g of NaOH in 5 ml of water is added to the filtrate, the filtrate is boiled for 2 hours and evaporated, the residue is dissolved in water and worked up in the customary manner to give 3-(4-£-fluorophenoxy-phenyl)-butyric acid, m.p. 91-93°. - 13 4 3 3 0 2 Example 5 A solution of 2.9 g of 3-(4-£~fluorophenoxy-phenyl)-3-hydroxybutyric acid in 30 ml of acetic acid is hydrogenated on 0.2 g of 10% Pd/C, in the presence of 0.01 ml of HC104, at 20° and under normal pressure. The mixture is filtered and the filtrate is diluted with water to give 3-(4-g-fluorophenoxy-phenyl)-butyric acid, m.p. 91-93°.

Example 6 3.17 g of 3-(4-g-chlorophenoxy-phenyl)-2-butenic acid ethyl 10 ester are boiled in 14 ml of 1 N sodium hydroxide solution and ml of ethanol for 3 hours, 40 ml of water are added and 55 g of 2.5% sodium amalgam are introduced in portions at 25° in the course of 5 hours, whilst stirring, the mixture is stirred for a further 5 hours, warmed on a water bath and decanted from the mercury, the alcohol is distilled off and the residue is worked up in the customary manner to give 3-(4-g-chlorophenoxy-phenyl) butyric acid, m.p. 81-83°.

I Example 7 g of 3-(4-g-fluorophenoxy-phenyl)-2-butenic aoid methyl ester in 20 ml of methanol is hydrogenated on 0.1 g of 5% Pd-C at 1 atmosphere and 20° until the reaction has ended, the mixture is filtered and the filtrate is evaporated to give 3-(4-g-fluorophenoxy 20 phenyl)-butyric acid methyl ester, nD 1.5329.

The following are obtained analogously from the corresponding 2-butenic aoid esters: 3-£-Phenoxy-phenyl-butyric acid methyl ester, 3-(4-0-fluorophenoxy-phenyl)-butyric acid methyl ester, 3-(4-m-fluorophenoxy-phenyl)-butyric acid methyl ester, 3-(4-o-chlorophenoxy-phenyl)-butyric acid methyl ester, 3-(4-m-chlorophenoxy-phenyl)-butyric acid methyl ester, 3-(4-g-chlorophenoxy-phenyl)-butyric acid methyl ester, 3-(4-o-bromophenoxy-phenyl)-butyric acid methyl ester, 3-(4-m-bromophenoxy-phenyl)—butyric acid methyl ester, and 3-(4-g-bromophenoxy-phenyl)-butyric acid methyl ester.

Example 8 a) 31.7 g of 3-(4-£-chlorophenoxy-phenyl)-2-butenic acid ethyl ester in 400 ml of ethanol is hydrogenated on 18 g of Raney nickel at 25° and 1 atmosphere until the uptake of hydrogen has ended, the mixture is filtered and the filtrate is evaporated to give 3-(4-£-chlorophenoxy-phenyl)-butyric acid ethyl ester, b.p. 165-172°/O.O1 mm.

The following are obtained analogously from the corresponding 2- butenic acid esters: 3- £-Phenoxy-phenyl-butyric acid ethyl ester, 3-(4-o-fluorophenoxy-phenyl)-butyric acid ethyl ester, 3-(4-m-fluorophenoxy-phenyl)-butyric acid ethyl ester, 3-(4-£-fluorophenoxy-phenyl)-butyric acid ethyl ester, 3-(4-o-chlorophenoxy-phenyl)-butyric acid ethyl ester, 3-(4-m-chlorophenoxy-phenyl)-butyric acid ethyl ester, 3-(4-o-bromophenoxy-phenyl)-butyric acid ethyl ester, 3-(4-m-bromophenoxy-phenyl)-butyric acid ethyl ester and 3-(4-£-bromophenoxy-phenyl)-butyric acid ethyl ester, b) 3.19 g of 3-(4-£-chlorophenoxy-phenyl)-butyric acid ethyl ester is boiled with 1 g of KOH in 25 ml of ethanol for 2 hours, the mixture is evaporated, the residue is dissolved in water, and the solution is washed with ether, acidified with hydrochloric acid to pH 3 and worked up in the customary manner to give 3-(4£-chlorophenoxyphenyl)-butyric acid, m.p. 81-83°. c) 3.19 g of 3-(4-£-chlorophenoxy-phenyl)-butyric acid ethyl ester is boiled in a mixture of 25 ml of acetic acid and 25 ml of 25% hydrochloric acid for 90 minutes. Working up in the customary manner gives 3-(4£-chlorophenoxy-phenyl)-butyric acid, m.p. 81-83°. d) A mixture of 1 g of 3-(4-£-chlorophenoxy-phenyl)-butyric acid ethyl ester and 100 ml of water is heated in an autoclave for 24 hours to 180°. The mixture is cooled and worked up in the - 15 customary manner to give 3-f4-p-chlorophenoxy-phenyl)-butyric acid, m.p. 81-83°. c) 31.25 g of the sodium salt of 3-(4-p-chlorophenoxy-phenyl). butyric acid in 300 ml of DMF are heated with 13.6 g of 2diethylaminoethyl chloride to 80° for 20 hours, the mixture is evaporated and worked up in the customary manner to give 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-diethylaminoethyl ester. B.p. 2O1-2O5°/O.l mm. 3-(4-p-Chlorophenoxy-phenyl)-butyric acid 2-dimethylaminoethyl ester, fumarate, m.p. 100-102°, is obtained analogously with 2dimethylaminoethyl chloride.

The following are obtained analogously with the corresponding chlorides or bromides: 3-(4-p-Chlorophenoxy-phenyl)-butyric acid-2-methylethylaminoethyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-di-n-propyl aminoethyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-di-n-butylaminoethyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-dimethylaminopropyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 3-dimethylaminopropyl ester 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-diethylaminopropyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 3-diethylaminopropyl ester, 3-(4-g-chlorophenoxy-phenyl)-butyric acid 4-dimethylaminobutyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 4-diethylaminobutyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-pyrrolidinoethyl ester, 3-(4-p-chlorophenoxy-phenyl)butyric acid 2-piperidinoethyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-morpholinoethyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-pipera2inoethyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-(4-methylpiperazino)ethyl ester, 3-(4-p-chlorophenoxy-phenyl)-butyric acid 2-(4-ethylpiperazino)ethyl ester, - 16 43502 3-(4-£-chlorophenoxy-phenyl)-butyric acid 2-(4-n-butylpiperazino)ethyl ester and 3-(4-£-chlorophenoxy-phenyl)-butyric acid 2-(4-(2-hydroxyethyl)piperaz ino)-ethyl ester.

Example 9 a) 1 g of 3-(4-£-fluorophenoxy-phenyl)-2-butenic acid is dissolved in 25 ml of dioxan, 0.1 g of PtO2 is added and the mixture is hydrogenated at 20° and under normal pressure until the uptake of hydrogen has ended, the mixture is filtered and the filtrate is evaporated to give 3-(4-£-fluorophenoxy-phenyl)-butyric acid, m.p. 91-93°. b) 1 g of 3-(4-g-fluorophenoxy-phenyl)-butyric acid is dissolved in 10 ml of THF and ethereal diazomethane solution is added dropwise, whilst stirring, until no further evolution of nitrogen is observed. After 20 minutes, the mixture is evaporated to give 20 3-(4-£-fluorophenoxy-phenyl)-butyric acid methyl ester, nD 1.5329. Example 10 3.53 g of 3-(4-g-chlorophenoxy-phenyl)-butyric acid 2-chloroethyl ester (obtainable from the acid and 2-chloroethanol) are heated with 2 g of diethylamine in 25 ml of absolute benzene in a tube to 100° for 10 hours, the mixture is cooled, the diethylamine hydrochloride which has separated out is filtered off and the filtrate is evaporated to give 3-(4-£-chlorophenoxy-phenyl)butyric acid 2-diethylaminoethyl ester, b.p. 2O1-2O5°/O.l mm.

The following are obtained analogously from 3-(4-£-fluorophenoxyphenyl)-butyric acid 2-chloroethyl ester with the corresponding amines: 3-(4-£-fluorophenoxy-phenyl)-butyric acid 2-dimethylaminoethyl ester, 3-(4-£-fluorophenoxy-phenyl)-butyric acid 2-diethylaminoethyl ester, 3-(4-£-fluorophenoxy-phenyl)-butyric acid 2-methylethylaminoethyl ester, 3-{4—£—£luorophenoxy-phenyl)-butyric acid 2-di-n-propylaminoethyl ester, 3- (4-£-fluorophenoxy-phenyl)-butyric acid 2-di-n-butylaminoethyl ester, - 17 42502 3-(4-g-fluorophenoxy-phenyl)-butyric ester, 3-(4-g-fluorophenoxy-phenyl)-butyric ester, 3-(4-g-fluorophenoxy-phenyl)-butyric ester, 3-(4-g-fluorophenoxy-phenyl)-butyric ester, 3-(4-g-fluorophenoxy-phenyl)-butyric ester, 3-(4-g-fluorophenoxy-phenyl)-butyric ester, 3-(4-g-fluorophenoxy-phenyl)-butyric ester, 3-(4-g-fluorophenoxy-phenyl)-butyric 3“(4-g-fluorophenoxy-phenyl)-butyric 3-(4-g-fluorophenoxy-phenyl)-butyric 3“(4-g-fluorophenoxy-phenyl)-butyric ethyl ester, 3-(4-g-fluorophenoxy-phenyl)-butyric ethyl ester, 3-(4-g-fluorophenoxy-phenyl)-butyric ethyl ester, and 3-(4-g-fluorophenoxy-phenyl)-butyric piperazino)-ethyl ester. acid 2-dimethylaminopropyl acid 3-dimethylaminopropyl acid 2-diethylaminopropyl acid 3-diethylaminopropyl acid 4-dimethylaminobutyl acid 4-diethylaminobutyl acid 2-pyrrolidinoethyl acid 3-piperidinoethyl ester, acid 2-morpholinoethyl ester, acid 2-piperazinoethyl ester, acid 2-(4-methylpiperazino)acid 2-(4-ethylpiperazino)acid 2-(4-n-butylpiperazino)acid 2-(4-(2-hydroxyethy1)The following examples of pharmaceutical compositions containing active compounds of formula I are given by way of illustration: Example A: Tablets A mixture consisting of 1 kg of 3-(4-g-chlorophenoxy-phenyl)butyric acid, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in conventional manner to form tablets, each tablet containing 100 mg of the active compound.

Example Β: Dragees Tablets are pressed analogously to Example A and are subsequently coated in conventional manner with a coating consisting of sugar, maize starch, talc and tragacanth.

Example C: Capsules kg of 3-(4-£-fluorophenoxy-phenyl)-butyric acid are filled into hard gelatine capsules in conventional manner, each capsule containing 250 mg of the active compound.

Tablets, dragees and capsules which contain one or more of the 10 other active compounds of formula I or their physiologically acceptable salts can be obtained analogously.

Claims (21)

1. CLAIMS:1. Phenoxyphenylbutyric acid derivatives of formula I: wherein 5 R 1 is H, alkyl with 1-6 C atoms or c n H 2n~ R3 * R 2 is H, F, Cl or Br, R is di-(C^_ 4 alkyl)amino, pyrrolidino, piperidino, morpholino, piperasino, or 4-alkylpiperazino or 4hydroxyalkylpiperazino with 5-8 C atoms in each case, lo and n is 2, 3 or 4, and physiologically acceptable salts thereof.

2. 3-(4-g-Fluorophenoxy-pheny1)-butyric acid.

3. 3-(

4. -£-Fluorophenoxy-phenyl)-butyric acid methyl ester. 15 4. 3-(4-g-Fluorophenoxy-phenyl)-butyric acid ethyl ester.

5.

6.

7. 3-(4-o-Fluorophenoxy-phenyl)-butyric 3-(4-g-Chlorophenoxy-phenyl)-butyric 3-(4-g-Chlorophenoxy-phenyl)-butyric acid. acid. acid methyl ester.

8. 3-(4-£-Chlorophenoxy-phenyl)-butyric acid

9. 3-(4-g-Chlorophenoxy-phenyl)-butyric acid ethyl ester. ethyl ester. 2-dimethy1 amino - 20 42502

10. 3-(4-g-Chlorophenoxy-phenyl)-butyric acid 2-diethylaminoethyl ester.

11. 3-(4-o-Chlorophenoxy-phenyl)-butyric acid.

12. 3-(4-g-Bromophenoxy-phenyl)-butyric acid.

13. 3-(4-o-Bromophenoxy-phenyl)-butyric acid.

14. 3-g-Phenoxy-phenyl-butyric acid.

15. A process for the preparation of a phenoxyphenylbutyric acid derivative of formula I specified in claim I or a physiologically acceptable salt thereof, which comprises reducing a compound of formula II: II wherein R 5 is -C(CH3)R 6 -CH2-, -C(CH 3 )=CH-, -C(=CH 2 )-CH 2 ~, -CH(CH 3 )-CHR 7 -, -C(CH3)R 6 -CHR 7 - or -C(CH3)=CR 7 -, R 6 and R 7 15 are each OH, Oacyl, halogen SH, NH 2 , or aralkyloxy or aralkylamino with up to 10 carbon atoms in each case, and R^ and R2 have the meanings specified in claim 1.

16. A process according to claim 15, in which the compound of formula I obtained is treated with a solvolysing agent, an 20 esterifying agent or a salt-forming agent to convert the R^ radical into another R 1 radical.

17. A process according to claim 15 or 16, in which, when a carboxylic acid of formula I is obtained, it is treated with a base to form a physiologically acceptable salt thereof.

18. A process for the preparation of a phenoxyphenylbutyric acid derivative of formula I specified in claim 1 or a physiologically acceptable salt thereof, substantially as herein described in any of Examples 1 to 10.

19. A pharmaceutical composition which comprises at least one compound as claimed in any of claims 1 to 14 and an inert, physiologically acceptable carrier.

20. A pharmaceutical composition according to claim 19 which is in the dosage unit form, each dosage unit containing from 30 to 300 mg of acid compound(s).

21. A pharmaceutical composition substantially as herein described in any of Examples A to C.