CA1136158A - Phenoxyalkylcarboxylic acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
New phenoxyalkylcarboxylic acid derivatives and their preparation are provided of the formula (I)

Description

1136i158 The present invention is concerned with phenoxy-alkylcarboxylic acid derivatives and their preparation.
West German Patent 2,149,070, Ernst-Christian Witte et al, issued November 21, 1977, and West German Offenlegungsschriften 2,405,622, Hans Peter Wolff et al, published August 14, 1975, and 2,541,342, Ernst-Christian Witte et al, published March 31, 1977.`
describe phenoxyalkylcarboxylic acid derivatives with a lipid-sinking action, the phenyl radical of which is substituted by 10 various types of acylaminoalkyl radicals.
It has now, surprisingly, been found that analogous phenoxyalkylcarboxylic acid derivatives, the phenyl radical of which is substituted by a sulphonylamino or sulphonyl-aminoalkyl radical, also display a ~3ignificant lipid-sinking action but essentially exhibit an outstanding inhibiting action on thrombocyte aggregation, According to the invention there is provided phenoxyalkylcarboxylic acid derivatives of the formula (I) Rl-sO2-l (CH2)n~ O-C-COOH (I) 20 wherein R is a hydrogen atom or a lower alkyl radical, Rl is an alkyl radical or an aryl, aralkyl or aralkenyl radical, the aryl moiety of which is unsubstituted or substituted one or more times ~y halogen atoms, hydroxyl groups, tri-fluoromethyl radicals or lower alkyl, lower alkoxy or acyl radicals, R2 and R3, which may be the same or different, are hydrogen atoms or lower alkyl radicals and n is 0, 1, 2 or 3;
and the pharmaceutically acceptable,physiologically compatible salts, esters and amides thereof.

113~158 The new derivatives of formula (I) and their pharmaceutically acceptable physiologically compatible salts, esters and amides, display, in vitro, an outstanding inhibition of induced thrombocyte aggregation. Furthermore, they prove to be effective lipid sinking agents.
The alkyl radicals Rl have straight or branche~
chains containing 1 to 16 carbon atoms, preferred alkyl radicals including methyl, ethyl, octyl and hexadecyl.
The aralkyl radicals are those in which the alkyl moiety contains 1 to 5 carbon atoms, which can be straight-chained or branched, the phenethyl and 4-chlorophenethyl radicals being preferred.
Tha aralkenyl radicals are those in which the alkenyl moiety contains 2 or 3 carbon atoms, the styryl and 4-chloro-styryl radicals being preferred.
The aryl radicals and the aryl moieties of the aralkyl and aralkenyl radicals are aromatic hydrocarbon radicals containing 6 to 14 carbon atoms, the phenyl, bi-phenylyl, naphthyl and fluorenyl radicals being preferred, These aryl radicals and moieties can be substituted one or more times in all possible positions, the substituents thereby being selected from halogen atoms, hydroxyl groups and lower alkyl, lower alkoxy, trifluoromethyl and acyl radicals~
The halogen atoms are preferably fluorine, chlorine or bromine atoms.
The lower alkyl and lower alkoxy substituents on the aryl moieties suitably contain 1 to 5 carbon atoms, and can be straight-or branched-chain radicals The straight-chain alkyl radical is preferably methyl, the branched-chain alkyl radical is preferably tert.-butyl and the alkoxy radical is preferably methoxy.

113b;15~

The acyl radical is suitably an aliphatic radical comprising a straight or branched chain lower alkyl radical of up to 5 carbon atoms. The preferred acyl radical is acetyl.
The lower alkyl radicals R, R2 and R3 can be straight-chain or branched-chain and contain up to 6 and preferably up to 4 carbon atoms.
The ester derivatives of carboxylic acids of formula (I) suitably contain, as the alcohol component, a lower monohydroxy alcohol of 1 to 6 carbon atoms of which methanol, ethanol and propanol are preferred, as well as polyhydroxy alcohols of 2 to 6 carbon atoms, for example glycol and glycerol, or alcohols with other functional groups, for example, ethanolamine or glycol ethers.
The amide derivatives of the carboxylic acids of formula (I) suitably contain, as amine component, ammonia, E~
aminobenzoic acid, ~-alanine, ethanolamine and 2-amino-propanol, as well as the amino acid of the formula:-H2N_CH2_CH2~3 o cH2 cooH

the hitherto mentioned ones being preferred. However, loweralkylamines, for example, iscpropylamine and tert.-butylamine, di-lower-alkylamines, for example, diethylamine, as well as cyclic amines, for example, morpholine and 4-lower-alkyl- or -ar-lower-alkyl- or arylpiperazines, for example, 4-methyl-piperazine, 4-(4-chlorobenzyl)-piperazine and 4-(3-methoxy-phenyl)-piperazine can also be used.
The above-given definitions of the compounds accord-ing to the present invention are also to include all possible stereoisomers, as well as mixtures thereof.

113~158 In another aspect of the invention there are provided processes for preparing the derivatives of formula (I) in which a first process comprises reacting an amine of the formula (II):-I ( 2)n ~ ~ (II)R

in which R has the same meaning as above, possibly with intermediate protection of the amino or hydroxyl group, in known manner and in any order with a sulphonic acid of the formula (III):-Rl-SO2OH (III) in which Rl has the same meaning as above, or with a derivative thereof, and with a compound of the formula (IV):-lR2 X - C - Y (IV) wherein R2 and R3 have the same meanings as above, X is a reactive group ar.d Y is a -COOR4 group (R4 being a hydrogen atom or a lower alkyl radical) or an acid amide group.
However, Y can also represent a residue which, after con-densation has taken place, can be converted into an acid amide group or into a -COOR4 group, whereupon, if desired, a parti-cular substituent R4 is subsequently converted, after thecondensation, in known manner, into a different substituent R4 and, if desired, a compound obtained is converted into a 113f~158 pharmaceutically acceptable, pharmacologically or physio-logically compatible salt.
When R2 and R3 signify lower alkyl radicals, the phenols of formula (II) or the reaction products thereof with a sulphonic acid of formula (III) can also be reacted with a mixture of an aliphatic ketone of formula -R2-Co-R3 chloroform and suitably in the presence of an alkali metal hydroxide. This process variant is preferably used for the preparation of isobutyric acid derivatives, acetone thereby being used as the ketone (cf. in this regard Gazz. Chim. ital , 77, 431/1947).
The process according to the present invention is preferably carried out in two steps. The condensation of a compound of formula (II) with a sulphonic acid of formula (III) or with a derivative thereof, on the one hand, and with a compound of formula (IV), on the other hand, is preferably carried out in such a manner that first one of the two xeactive groups of the compound (II) is blocked with a pro-tecting group which can easily be split off, the compoundobtained is reacted with a sulphonic acid (III) or with a derivative thereof or with a compound of formula (IV), the protecting group is split off and the reactive intermediate thus obtained is subsequently reacted with the compound of formula ~IV) or (III) which has not already been used. A
synthesis route is preferred in which a compound (II~ pro-tected on the amino group is first reacted with a compound (IV).
After removing the protecting group to produce a compound of formula(IX):-~13~58 Hl-(CH2)n ~ ~ ~ O - C - Y (IX) wherein R, R2, R3, Y and n are as defined above. The step of removing the protecting group, which con-veniently is an acid or alkaline hydrolysi~ may also convert an ester (IX), wherein Y is said group -COOR4 and R4 is lower alkyl, to the free acid in which R4 is hydrogen; if desired the carboxylic acid group may be re-esterified prior to the reaction with the sulphonic acid (II) or a reactive derivative thereof, the reaction with a sulphonic acid (III) or with a derivative thereof,is then carried out.
Instead of the free amines (II), it is also possible to employ the salts thereof.
Instead of the amine (II), there may be employed a corresponding nitro compound of formula (X):-02N- (CH2 ) n~--~OH (X ) wherein n is 0, 1, 2 or 3, which can be reacted with a compound of formula (IV), whereafte~the nitro group in the resulting compound of formula (XI):-O2N-(CH2)n ~ / ~ ~ O - C - y (XI) wherein R2, R3, Y and n are as defined above, is hydrogenated with, for example, hydrogen over a catalyst and a compound obtained of formula (IX) in which R is hydrogen is thereafter reacted with the sulphonic acid, or a reactive derivative thereof, of formula (II).
A further possibility within the invention for the preparation of compounds of formula (I), or their salts, as well as of their esters and amides, consists in reacting a sulphonamide of the formula (V):-Rl - S02 - NH (V) R

wherein R and Rl have the same meanings as above, with a compound of the formula (VI):-X-(CH2) ~ O - C - y (VI) wherein R2, R3, X, Y and n have the same meanings as above, to give a compound of the formula (VII):-Rl-S2-N-(CH2) ~ O - C - y (VII) in which R, Rl, R2, R3, Y and n have the same meanings as above.

1~3~i158 A further possibility of synthesis, in accordance with the invention, consists in a transacylation: if a free sulphonic acid (III) is reacted with a compound of the formula (VIII):-Ac-l-(CH2)n ~ 0-C-Y (VIII) wherein n, R, ~ , R3 and Y have the same meanings as above and Ac is a readily exchangeable acyl radical, in an appropriate solvent, then there is again obtained a sulphon-amide of formula (VII).
The reactive derivatives of the sulphonic acids (III) are suit~bly halides, or estere.
The reaction of a sulphonic acid halide with a com-pound of formula (II) is preferably carried out with the addition of an acid-binding agent, for example, an alkali metal acetate, sodium bicarbonate, sodium carbonate, sodium phosphate, calcium oxide, calcium carbonate or magnesium carbonate. This function can, however, be undertaken by an organic base, for example, pyridine or triethylamine, using, as inert solvent, for example, diethyl ether, benzene, methylene chloride, dioxan or an excess of the tertiary amine.
When using an inorganic acid-binding agent, the reaction medium used can be, for example, water, aqueous ethanol or aqueous dioxan.
For the reaction of a compound (II) with a compound (IV), it has proved to be advantageous first to convert the amino group of the compound (II) into a protected group.

113~1~8 Blocking groups for amino are well known and, by way of example, there may be mentioned a phthalimido group which after the reaction, can easily be removed again in known manner with, for example, hydroxylamine. Other groups known from peptide chemistry can also be used for protecting the amino group and then removed again after the reaction.
It is also preferred to block the amino group with an acyl radical, for example, a formyl or acetyl radical, which, after the reaction, can easily be removed again with a strong base, for example, sodium hydroxide or potassium hydroxide or with an aqueous mineral acid, for example hydrochloric acid.
In the compounds (IV~, X is a leaving group in an SN nucleophilic substitution reaction displaceable by a phenoxy group.
As reactive compounds (IV~, those are especially preferred in which X represents an anion of a strong acid, for example, of a hydrohalic or sulphonic acid. The reaction can be further promoted by converting the phenolic hydroxyl group of the compound (II) into a phenolate, for example, by reaction with a sodium alcoholate. The reaction o~ the two components is suitably carried out in a solvent, for example, toluene, xylene, methyl ethyl ketone or dimethylformamide, preferably at an elevated temperature.
For the alkylation of the sulphonic acid amides (V), to produce compounds (VI), it is preferable to use com-pounds (VI), wherein X is an arylsulphonyloxy radical, X more preferably being a-toluene-sulphonyloxy radical. Thus, as alkylation agents, there are preferably employed alkyl aryl-sulphonates, a method for the use of which for sulphonic acidamides, is described by Klamann et al., in Monatshefte fur Chemie, 83, 871/1952~ The suitable reaction takes place in ~3~158 an alkaline medium, a hot, concentrated aqueous solution of sodium carbonate being the preferred reaction medium.
The transacylation reaction between a free sulphonic acid (III) and an acylamine (VIII) is preferably carried out with the use of equimolar amounts of the two reaction components in a polar solvent, examples of such polar sol-vents including alcohols and especially ethanol and methanol.
The reaction is preferably carried out at the boiling temperature of the solvent. An example of a readily exchange-able acyl radical is the acetyl radical.
As substituents Y in the compounds of formula (IV)which can be converted into the -COOR4 group, there may be mentioned, for example, the nitrile, carbaldehyde, hydroxy-methyl, aminomethyl and formyl groups.
A possible subsequent N-alkylation of a compound of formula (I), in which R is a hydrogen atom, can be carried out in known manner, preferably by reacting a com-pound in which R is a hydrogen atom with an alkyl halide or a dialkyl sulphate in the presence of an acid-binding agent, for example, sodium hydroxide.
A conversion of a substituent R4 into a different substituent R4 can be carried out after the condensation takes place, for example, by hydrolysis or saponification of the carboxylic acid esters (R4 = alkyl) to give the correspond-ing carboxylic acids (R4 = hydrogen) with a mineral acid or an alkali metal hydroxide in a polar solvent, for example, water, methanol, ethanol, dioxan or acetone. Hydrolysis or saponification is advantageously carried out with a strong base, for example, sodium or potassium hydroxide, in a mixture of methanol and water at ambient temperature or at a moderately elevated temperature. On the other hand, however, t~e carboxylic 113~S8 acids can also be esterified in the usual manner or esters with a particular residue R4 can be transesterified to give an ester with a different residue R4. The esterification of the carboxylic acids is preferably carried out in the presence of an acidic catalyst, for example, hydrogen chloride, sulphuric acid, P-toluenesulphonic acid or a strongly acidic ion exchange resin. Transesterifications, on the other hand, require the addition of a small amount of a basic substance, for example, of an alkali metal or alkaline earth metal hydroxide or of an alkali metal alcoholate. For the esterification of the carboxylic acids or for the trans-esterification, there can, in principle, be used all alcohols.
It is preferable to use lower monohydroxy alcohols, for example, methanol, ethanol or propanol, as well as poly-hydroxyl alcohols, for example, glycol, Or alcohols with other functional groups, for example ethanolamine or glycol ethers.
The amides according to the present invention derived from the carboxy~ic acids of formula (I) are preferably prepared by known methods from the carboxylic acids or their reactive derivatives, for example, carboxylic acid halides, esters, azides, anhydrides or mixed anhydrides, by reaction with amines. The amino component can be, for example, ammonia, a lower-alkylamine or a di-lower-alkylamine, as well as an amino-lower-alkanol, for example, ethanolan~ne or 2-amino-propanol, and also an amino acid, for example p-aminobenzoic acid, ~-alanine or the like. Other useful amine components include the alkyl-, aralkyl- and arylpiperazines For the preparation of salts with non-toxic pharma-cologically compatib~e organic or inorganic bases, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine or ethanolamine, the carboxylic acids can be reacted with the appropr~ate bases.

113~158 Mixtures of the carboxylic acids with an appropriate alkali metal carbonate or bicarbonate can also be used.
It will be understood that when a salt of a derivative of formula (I) is employed in a pharmaceutical composition, that the salt should suitably be both pharma-ceutically acceptable and physiologically or pharmaco-logically compatible.
In this specification, it will be understood that the qualification that the salts are "pharmaceutically acceptable" means that the salts have the necessary physical characteristics, for example, stability, to render them suitahle for formulation into pharmaceutical compositions.
The qualification that the salts be "physiologically or pharmacologically compatible" is to be understood as extend-ing to salts of the carboxylic acids of formula (I) with non-toxic inorganic or organic bases which have no adverse affects to the extent that such salts would be unsuitable for administration to living bodies.
Salts of acids of formula (I) which are not pharmacologically compatible and/or pharmaceutically accept-able form a useful aspect of the invention of the novel derivatives, in as much as they can be readily converted to different salts having the required physical and chemical characteristics to make them suitable for administration in pharmaceutical compositions to living bodies.
For the preparation of pharmaceuticals, the com~
pounds according to the present invention are mixed in the usual way with appropriate pharmaceutical carrier materials and aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, for example, olive oil.

113b~1S8 The new derivatives according to the present invention can be administered orally or parenterally in liquid or solid form. As injection medium, it is preferred to use water which contains the stabilising agents, solubilising - agents and/or buffers usual in the case of injection solutions, Additives of this type include, for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide, complex-forming agents (such as ethylene-diamine-tetraacetic acid), high molecular weight polymers (such as liquid poly-ethylene oxide) for viscosity regulation and polyethylene derivatives of sorbitol anhydrides.
Solid carrier materials can be, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phos-phate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Compo~itions suitable for oral administration can, if desired, contain flavouring and sweetening agents.

The derivatives of the invention will generally be administered in daily dosages of 1 to 3 g, for example, 1.5 -

2 g. and are preferably administered in dosage units of 250 or 500 mg. However, the regular dosage would depend on the particular condition being treated and the state of health of the patient as will be clearly understood.

The new derivatives of the invention may be employed in the same dosages and for treatment of the same ailments as Colfarit* (acetylsalicylic acid).

For example, the derivatives (I) may be employed in tablet dosages of 500 mg in the treatment of thrombophlebitis by administration of two tablets, three times daily until *trademark subsidence of the acute symptoms whereafter the treatment may be reduced to one tablet, three times daily. In the treatment of rheumatic fever, the treatment may co~prise administration of two tablets, three times daily, at intervals of 6 to 8 hou~s.
The activity of the compounds (I) in inhibiting thrombocyte aggregation is demonstrated by the following illustrative experiments:
In a series of determinations utilizing the Born test, venous blood from rnetabolically healthy persons was mixed with sodium citrate in a ratio of 9:1 and the erythro-cytes precipitated by centrifuging at 150 g. The filtrate is enriched in thrombocytes and this filtrate is designated a~ platelet-rich plasma (PRP). One aliquot of the PRP is placed in the cuvette of an aggregometer (Universal Aggregometer, manufactured by Braun Melsungen, West Germany) and stirred with a magnetic stirrer. The substance to be tested is added in the form of an aqueous sol~tion at a pH of about 7.
Changes in the light transmiqsion of the suspension are continuously recorded. After spontaneous aggregation ceases, further aggregation is induced by the addition of 5 X 10 6 m adrenalin, forming larger thrombocyte aggreaates and increasing the light transmission through the suspension.
The adrenalin induced aggregation takes place in two phases, i.e., the light transmission initially increases, then stagnates temporarily, and then increases again. Only the second phase of the aggregation can be influenced by aggregation inhibitors. For an evaluation o~ the results there is first established, in a control experiment using no test compound, the angle of the second aggregation phase against the horizontal for adrenalin induced aggregation and this is designated as G% inhibition.

- 14 _ 1~36158 Utilizing the same P~P, the test compound is added and aggregation is induced with adrenalin, and the course of aggregation continuously recorded. The angle of the second aggregation phase against the horizontal is again determined and the relationship of this angle against the angle deter-mined in the control experiment yields the percent inhibition of the second phase of the thrombocyte aggregation.
The standard material "Colfarit"* (acetylsalicylic acid) yields 100% inhibition at a concentration of 10 4 m and ~% inhibition at a concentration of 5- x 10 5 m. At the latter concentration compounds (I) of the invention yielded the results shown in Table (I) below.
TABLE (I) Percent Inhibition of Thrombocyte Aggregation (at 5 x Te~t Compound 10 5 m 4-[2-(benz~sulfonylamino)-ethyl]-phenoxyacetic acid 100%

4-[2-(benz~sulfonylamino)-ethyl]
phenoxyacetic acid-isopropyl e~terlOG%

4-[2-(4-fluorobenzosulfonyl-amino)-ethyl]-phenoxyacetic acid 100%

4-[2-(p-toluolsulfonylamino)-ethyl]-phenoxyacetïc acid lOG%

4-[2-(1-naphthalenesulfonylamino)-ethyl~-phenoxyacetic acid 10~/o 4-[2-(4-chlorobenzosulfonylamino)-ethyl]-phenoxyacetic acid 10~/o 4-(benzo~ul~onylamino-methyl)-phenoxyacetic acid 20%

2-~4-[2-(4-chlorobenzo~ulphonyl-amino)-ethyl~-phenoxy3-2-methyl-pro-pionic acid 100%

2-~4-[2-(benzo~ulphonylamino)-ethyl]-phenoxy~-2-methylpropionic acid 2C%

*trademark _ 15 -113~158 (Table I Continued) Percent Inhibition of Thrombocyte Aggregation (at 5 x Test Compound lO S m) 4-[2-(benzolsulfonylamino~-ethyl]-phenoxyacetic acid-(2-ethoxy-carbonyl-ethylamide 10~/o 4-[3-(4-acetylbenzolsulfonylamino)-ethyl]-phenoxyacetic acid 10~/o 4-~2-(benzolsulfonylamino)-ethyl]-phenoxyacetic acid-(l-hydroxy-2-propylamide) l~/o 4-[3-(benzolsulphonylamino)-propyl]-phenoxyacetic acid 10~/o Table (I) shows that compounds (I) of the invention are far superior to the standard comparison substance, acetylsalicylic acid, in that compounds (I) demonstrate a substantial and often 10~/o inhibition at a concentration where the comparison substance yields ~/o inhibition.
The novel compounds (I) may be administered by themselves or in conjunction with carriers which are pharma-cologically acceptable, either active or inert. The dosage unit~ are similar to those of the heretofore known thrombo-cyte aggregation inhibitors, for example, 2 to 3 grams per day for thrombo-phlebitis or 1 to 1.5 grams per day for ~enous thromboses, although higher and lower dosages can be used. The dosage should be lowered after the acute symptoms of thrombo-phlebitis have moderated. ~ather than administering a single dosage, it is preferable that the compounds are dosed evently over the course of the day, e.g., in applications of 0.5 g. to 1 g, three times a day.

113f~158 The following Examples, which are given for the purpose of illustrating the present invention, describe some of the numerous process variants which can be used for the synthesis of the new derivatives of the invention, it will be evident that variations of the procedures, for example, variation in the starting materials will result in different compounds of the invention.
Example 1 4-r2-(Benzenesulphonylamino)-ethyll-phenoxYacetic acid Process I
a) A mixture of 240 g. (1.34 mol) N-acetyl-tyramine, 370 g. (2.68 mol) anhydrous powdered potassium carbonate and 2.5 litres butan-2-one are heated to reflux temperature for 2 hours, while stirring. 266 g. (1.47 mol) ethyl bromoacetate and 1.5 g. potassium iodide are then added thereto and the reaction mixture again heated to reflux temperature. After about 6 hours, the reaction is complete.
The reaction mixture is then filtered, the filter cake is washed with acetone and the combined filtrates are evaporated in a vacuum. The residue is taken up in 1.75 litres methylene chloride. The methylene chloride phase is washed three times with 300 ml. amounts of 0.5N aqueous sodium hydroxide solution and once ~ith 300 ml. water, dried with anhydrous sodium sulphate and then evaporated in a vacuum. There are thus obtained 321 g. (98~/~ of theory) ethyl 4-(2-acetylaminoethyl)-phenoxyacetate; m.p. 85C.
Using the same synthesis route, ethyl 4-(2-acetyl-aminoethyl)-phenoxyacetate can also be prepared from N-acetyltyramine and ethyl chloroacetate. The reaction time is 9 hours and the yield i~ quantitative, m.p. 83 - 84.5C.

113~158 b) A mixture of 489.6 g. (1.845 mol) ethyl 4-(2-acetylaminoethyl)-phenoxyacetate and 2.77 litres (5.55 mol) 2N hydrochloric acid is stirred for 8 hours at reflux temperature, then cooled and the solution adjusted to pH 6 with about 460 ml. lON aqueous sodium hydroxide solution.
After cooling in an ice-bath, the reaction mixture is filtered with suction. The filter cake is treated twice with 250 ml.
amounts of water, sharply filtered off with suction and dried in a vacuum at 50C. There are obtained 299.5 g. (83% of theory) 4-(2-aminoethyl)-phenoxyacetic acid; m.p. 292C~
(decomp.).
c) 280 g. (1.435 mol) 4-(2-Aminoethyl)-phenoxy-acetic acid are suspended in a solution of 2.85 litres water and 436 g. (3.157 mol) anhydrous potassium carbonate and, while stirring, 266 g. (1.507 mol) benzenesulphochloride allowed to run in in the course of 45 minutes. The reaction mixture is subsequently stirred for 2.5 hours at 80C.
After cooling, 1 litxe ethyl acetate is added to the reaction mixture and this then acidified, while stirring, with 800 ml, 6N hydrochloric acid. The organic phase is then separated off and the aqueous phase is extracted with 1 litre ethyl acetate. The organic phases are combined and extracted with an amount of saturated aqueous sodium bicarbonate solution which is sufficient for salt formation. The aqueous phase is filtered and, while stirring, adjusted to pH 1 with 6N
hydrochloric acid, the product thereby precipitating out in the form of a brownish granulate. This is filtered off with suction, washed with some water and dried in the air. The suhstance is now dissolved in about 3 litres warm diethyl ether, a greasy, dark brown residue thereby remaining undis-solved. The clear ethereal phase is decanted off and evaporated.

There are obtained 312 g. (65% of theory) colourless 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetic acid; m.p. 117 -118~C. After recrystallisation from toluene, the product melts at 119 - 120C.
For the preparation of the N-acetyltyramine used as starting material, there can be used the following methods:
1. While stirring, 64.0 g. (0.466 mol) tyramine are mixed with 200 ml. acetic anhydride, whereby, with spontaneous heating, a clear solution results. This solution is seeded with a few crystals of ~-acetyltyramine, whereafter crystallisation takes place immediately. The reaction mixture is rapidly cooled, filtered with suction, washed with diethyl ether and water and dried. There are obtained 59 g. (71%
of theory) N-acetyltyramine; m.p. 124 - 126C. By evaporating the mother liquor, dissolving the residue in dilute aqueous sodium hydroxide solution, filtering and acidfying the filtrate, there are obtained a further 5.5 g. (6% of theory) of product; m.p~ 122 - 124C. After recrystallisation from ethyl acetate, N-acetyltyramine melts at 129 - 131C.
2. 65.8 g. (0.84 mol) Acetyl chloride are added dropwise to a solution of 54.9 g. (0.4 mol) tyramine and 200 ml. pyridine, while stirring at 30 - 35C. The reaction mixture is subsequently heated for 15 minutes on a boiling water-bath, then cooled and poured into an ice-water mixture.
By the addition of concentrated hydrochloric acid, it is rendered distinctly acidic and subsequently extracted with chloroform. The chloroform phase is washed with water, dried over anhydrous calcium chloride and then evaporated.
There are obtained 88.5 g. (quantitative yield) of a residue of diacetyltyramine, m.p. 99 - 100C., after recrystallisation from benzene. The diacetyltyramine is now dissolved in 500 ml.

113~i~S8 methanol. 800 ml. (0.8 mol) lN aqueous potassium hydroxide solution are added dropwise thereto, the temperature thereby increasing to about 30C., and then maintained for 2 hours at an internal temperature of 50C. The reaction mixture i5 then cooled, rendered weakly acidic with concentrated hydrochloric acid and the methanol evaporated off in a vacuum. The product which crystallises out is filtered off with suction, thoroughly washed with water and then dried.
The yield of N-acetyltyramine is 58.3 g. t81% of theory);
m.p. 131C., after recrystallisation from ethyl acetate.
Process II
19.3 g. (0.11 mol) Benzenesulphonyl chloride are added dropwise to a mixture of 15.0 g, (0.11 mol) tyramine, 18.0 g. (0.22 mol) anhydrous sodium acetate and 250 ml. 97%
ethanol and subsequently heated to reflux temperature for 2 hours. The reaction mixture is then freed from ethanol in a vacuum, the residue i5 mixed with water and the aqueous phase acidified with 2N hydrochloric acid. The precipitated product is taken up in diethyl ether, extracted several times with diethyl ether and the combined ethereal phases dried with anhydrous sodium sulphate. The diethyl ether is then distilled off and the residue triturated with ligroin. For purification, the product is dissol~ed in 2N aqueous sodium hydroxide solution, the solution is treated with active char-coal and the phenolic compound then precipitated out again with dilute hydrochloric acid. After washing with water and drying, there are obtained 23.5 g. (7P/O of theory) 4-[2-(benzenesulphonylamino)-ethyl]-phenol; m.p. 131C.
11.9 g. ~71.5 mMol) Ethyl bromoacetate are added dropwise, while stirring at the boiling temperature, to a mixture of 18.0 g. (65 mMol) 4-~2-(benzenesulphonylamino)-113~i158 ethyl]-phenol, 8.95 g. (65 mMol) anhydrous powdered potassium carbonate and 250 ml. ethanol and the reaction mixture then further kept for 2.5 hours at reflux temperature. The reaction mixture is then evaporated in a vacuum, the residue is extracted several times with diethyl ether and the ethereal extracts are evaporated. The product remaining behind is recrystallised from a mixtur~ of ethyl acetate and ligroin.
There are obtained 9.8 g. (42% of theory) ethyl 4-[2-(benzene-sulphonylamino)-ethyl~-phenoxyacetate; m.p. 68 - 70C.
A mixture of 22.1 g. (61 mMol) ethyl 4-[2-(benzene-sulphonylamino)-ethyl~-phenoxyacetate, 183 ml. (183 mMol) lN aqueou~ potassium hydroxide solution and 250 ml. methanol i9 kept for 2 hours at 35C. It is then acidified with 2N
hydrochloric acid, the methanol is evaporated off and the remaining aqueous phase is extracted several times with methylene chloride. The combined methylene chloride phases are washed with water, dried over anhydrous sodium sulphate and evaporated. The evaporation residue is triturated with ligroin and filtered with suction. There are obtained 17.6 g (86% of theory) 4-[2-(benzenesulphonylamino)-ethyl]-phenoxy-acetic acid; m.p. 116 - 118C, Process III
13.3 g. (75 mMol) Benzene-sulphochloride are added dropwise, while stirring, over the course of one hour to an ice-cooled solution of 19.5 g. (75 mMol) ethyl 4-(2-aminoethyl)-phenoxyacetate hydrochloride, which may be prepared from tyramine and ethylbromoacetate followed by conversion to the hydrochloride acid addition salt. The cooling bath is then removed and the reaction mixture stirred for 2 hours at ambient temperature. Subsequently, it is poured into ice water and acidified with concentrated hydrochloric _ 21 -acid, whereby an oil separates out which is taken up in diethyl ether. The aqueous phase is further extracted several timeswith diethyl ether and the combined ethereal phases are dried with anhydrous sodium sulphate and subsequently evaporated. There are obtained 22.3 g. (82% of theory) ethyl 4-~2-(benzenesulphonylamino)-ethyl3-phenoxyacetate; m,p. 76 -Saponification of this ethyl ester to give the free 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetic acid is carried out in the manner described above, a) Isopropyl 4-r2-(benzenesulphonylamino)-ethYll-phenoxyacetate A mixture of 7.28 g. (20 mMol) ethyl 4-[2-(benzene-sulphonylamino)-ethyl]-phenoxyacetate obtained in accordance with process I, II or III, 75 ml. isopropanol and about 50 mg. sodium isopropylate is heated for 12 hours at reflux temperature and subsequently the isopropanol is distilled off. The residue is treated with 0.5N hydrochloric acid and dieth~yl ether and the ethereal phase is dried and evaporated.
The oil which remains behind is triturated with ligroin to give 4.5 g. (67% of theory) isopropyl 4-[2-(benzenesulphonyl-amino)-ethyl]-phenoxyacetate, m.p. 56 - 57C.
Example 2 4-r2-(4-Methoxybenæenesulphonylamino)-ethYll-phenoxyacetic acid A mixture of 10.35 g. (50 mMol) 4-methoxybenzene-sulphonyl chloride and 50 ml. pyridine is added dropwise at O - 10C. in the course of 5 minutes to a solution of 11.2 g.
(50 mMol) ethyl 4-(2-aminoethyl)-phenoxyacetate, which may be prepared from tyramine and ethyl bromoacetate, in 125 ml, anhydrous pyridine. The reaction mixture is allowed to warm - ~13~i158 up to ambient temperature and then kept at 60C. for 45 minutes. Subsequently, the reaction mixture is evaporated to half its volume in a vacuum, then poured into ice-water and acidified with hydrochloric acid. The precipitated viscous mass is dissolved in toluene and the toluene phase successively extracted with dilute hydrochloric acid, an aqueous solution of sodium bicarbonate and water. After dry-ing over anhydrous calcium chloride, the solution is evaporated in a vacuum and the residue triturated with some diethyl ether, crystallisation thereby taking place. The product is filtered off with suction and recrystallised from a very small amount of diethyl ether. There are thus obtained 13.0 g. (66% of theory) ethyl 4-~2-(4-methoxybenzenesulphonyl-amino)-ethyl]-phenoxyacetate, m.p. 82 - 83C.
In the case of the availability of 4-[2-(4-methoxy-benzenesulphonylamino)-ethyl]-phenoxyacetic acid, its ethyl ester can also be synthesised in the following way:
The acid is dissolved in twenty times its quantity by weight of absolute ethanol and the surface of the solution gassed with dry hydrogen chloride, the temperature thereby being maintained at 50 to 60C., until saturation is achieved.
The reaction mixture is then maintained for 30 minutes at 50 to 60C., subsequently evaporated in a vacuum and the yellowish, initially oily residue obtained recrystallised from diethyl ether. The yield is about 9G% of theory.
70 ml. ~70 mMol) lN Aqueous potassium hydroxide solution is added dropwise to a solution of 11.8 g. (30 mMol) ethyl 4-~2-~4-methoxybenzene sulphonylamino)-ethyl]-phenoxy-acetate and 70 ml. ethanol and the reaction mixture then kept for 5 hours at 35 to 40DC. The ethanol is subsequently distilled off in a vacuum and the aqueous phase extracted with - 113f~58 diethyl ether. The addition of 35 ml. 2N hydrochloric acid leads to the precipitation of a colourless material which is filtered off with suction and recrystallised from dilute acetic acid. There are obtained 8.66 g. (79/O of theory) 4-[2-(4-methoxybenzenesulphonylamino)_ethyl]-phenoxyacetic acid;
m.p. 103C.
The preparation of the ethyl 4-(2-aminoethyl)-phenoxyacetate or of its hydrochloride required for the reaction can take place in two ways:
A. From 4-(2-aminoethyl)-phenoxyacetic acid and ethanol:
Dry hydrogen chloride gas is passed, while stirring, on to a cooled (5 - 10C.) solution of 67.2 g. 4-(2-amino-ethyl)-phenoxyacetic acid and 672 ml. anhydrous ethanol until the solution is saturated. After standing overnight, the reaction mixture is evaporated at 30C. The crystalline residue is then left to dry first in the air and then over potassium hydroxide. There are obtained 85.6 g. (96% of theory) ethyl 4-(2-a~inoethyl)-phenoxyacetate hydrochloride which, after recrystallisation from isopropanol, melts at 158 - 160C. The free base, which is a viscous oil, condenses very quickly.
B. Via 4-[2-(phthalimido)-ethyl]-phenol:
A mi~ture of 137.1 g. (1 mol)tyramine, 148.1 g.
(1 mol) phthalic anhydride, 13 ml. triethylamine and 2 litres toluene is heated under reflux on a water separator until the theoretical amount of water has separated, The reaction mixture is then allowed to cool and the precipitate obtained filtered off. There are obtained 259 g. (9P/O of theory) 4-{2-(phthalimido)-ethyl~-phenol; m.p. 223 - 226C. After recrystallisation from isopropanol, the compound melts at 228 - ~30~C.

_ ~4 -1~3~i1S8 34.7 g. ~C.13 mol) 4-[2-(phthalimido)-ethyl]-phenol and 35.9 g. (0.26 mol) anhydrous, powdered potassium carbonate are heated under reflux, while stirring, for 2 hours in 300 ml. dry acetone. 31.8 g. (0.19 mol) Ethyl bromoacetate and 0.2 g. potassium iodide are then added thereto and the reaction mixture maintained at reflux temperature for a further 8 hours.
The inorganic precipitate is filtered off, washed with acetone and the combined filtrates evaporated in a vacuum. The residue is taken up in chloroform, the solution washed with 0.5N aqueous sodium hydroxide solution and water, dried and evaporated. The residue is recrystallised from isopropanol.
There are obtained 38.8 g. (83% of theory) ethyl 4-[2-(phthalimido)-ethyl]-phenoxyacetate m.p. 104 - 106C.
35.3 g. (0.1 mol) of this ester are dissolved in 1 litre of boiling ethanol and mixed, while hot, with 7.5 g.
(0.15 mol3 hydrazine hydrate. The solution is left to stand overnight, acidified with a little concentrated hydrochloric acid and then evaporated. The residue is stirred into 1 litre water, insoluble material is filtered off and the aqueous 2~ filtrate is evaporated. With the addition of charcoal, the evaporation residue is recrystallised from isopropanol. There are obtained 17.2 g. (66% of theory) ethyl 4-(2-aminoethyl)-phenoxyacetate hydrochloride; m.p. 157 - 160C.
Example 3 4-r2-(4-Fluorobenzenesulphonylamino)-ethyll-phenoxyacetic acid 16.35 g. (84 mMol) 4-Fluorobenzenesulphonyl chloride are added dropwise at 10 to 15C. to a mixture of 160 ml.
anhydrous pyridine, 11.1 g. (80 mMol) pulverised, anhydrous potassium carbonate and 20.8 g. (80 mMol) ethyl 4-(2-amuno-ethyl~-phenoxyacetate hydrochloride, which may be prepared from tyramine and ethylbromoacetate and conversion to the ~13f~158 hydrochloride salt. The reaction mixture is subsequently stirred for 30 minutes at 20C. and for 5 minutes at 80C.
and then cooled and poured into ice-water. ~rhe solution is acidified with concentrated hydrochloric acid and the precipitated material extracted with methylene chloride.
After drying over anhydrous sodium sulphate, the methylene chloride phase is evaporated and the evaporation residue recrystallised from a methanol-water mixture. There are thus obtained 25.5 g. (84% of theory) ethyl 4- [2-(4-fluoro-benzenesulphonylamino)-ethyl]-phenoxyacetate; m.p. 75 - 78C.
By hydrolysis of the ethyl ester in a manner analogous to that described in Example 2, there is obtained a yield of 8P/o of theory of 4- [2-(4-fluorobenzenesulponylamino)-ethyl~-phenoxyacetic acid; m.p. 206 - 208C.
For the preparation of the sodium salt, 7.46 g.
(21.1 mMol) of the acid are suspended in 150 ml. methanol, warmed to about 40C. and 21.1 ml. lN aqueous sodium hydroxide solution added thereto. Thereafter, the solution is evaporated in a vacuum and the residue is triturated with acetone, filtered off with suction and washed with acetone.
There are obtained 7.8 g. of the sodium salt; m.p. 260 - 270C.
(decomp.).
In an analogous manner, by the reaction of ethyl 4-(2-aminoethyl)-phenoxyacetate hydrochloride with the appropriate sulphonyl chlorides in the presence of pyridine and potassium carbonate, there are obtained:
a3 ethYl 4-r2-(methanesulphonylamino)-ethyll-phenoxyacetate from methanesulphonylchloride as a viscous oil; yield 65% of theory;
~R maxima: 3290 cm ; 1750 cm 1; 1608 cm 1;
and from this, by hydrolysis:

_ 26 --113~158 4-r2-(methanesulphonylamino)-ethyll-phenoxyacetic acid m.p. 142 - 143C.: yield 77% of theory, sodium salt: m.p. 330C. (deco~p.).
b) ethyl 4-r2-(p-toluenesulphonylamino)-ethYll-phenoxY-acetate from ~toluenesulphonylchloride m.p. 66 - 67C. (recrystal-lised from ethanol), yield 74% of theory, and from this, by hydrolysis:
4-r2-( ~toluenesulphonylamino)-ethyll-phenoxyacetic acid m.p. 119 - 120C.; yield 93% of theory, sodium salt as monohydrate; m.p. 245 - 247C.
c) ethyl 4-r2-(1-naphthalenesulphonylamino)-ethYll-phenoxyacetate from l-naphthalenesulphGnylchloride m.p. 105 - 106C.
(recrystallised from ethanol); yield 65% of theory, and from this, by hydrolysis:
4- r2-(l-naphthalenesulphonylamino)-ethyll-p-henoxyacetic acid m.p. 119 - 120C. (recrystallised from ethyl acetate +
20 ligroin), yield 92% of theory;
sodium salt: m.p. 238 - 239C.
d) ethyl 4-r2-(styrenesul~honylamino~-ethyll-phenoxY-acetate from styrenesulphonylchloride m.p. 62 - 63~C. (recrystallised from ethyl acetate + ligroin), yield 71% of theory, and from this, by hydrolysis:
4-~2-(styrenesulphonylamino~-ethyll-phenoxyacetic acid m.p. 141 - 142C. (recrystallised from acetone f water) yield 85% of theory.
30 e) ethyl 4-r2-(4-chlorostyrenesulphonylamino)-ethyll-~enoxYacetate from 4-chlorostyrenesulphonyl chloride m.p. 91 - 92~C.

~136158 (recrystallised from ethyl acetate + ligroin), yield 76% of theory and from this, by hydrolysis:
4-r2-(4-chlorostYrenesulphonylamino)-ethyll-phenoxyacetic acid m.p. 147 - 148C. (recrystallised from ethyl acetate +
ligroin); yield 69% of theory.
f) ethyl 4-r2-(4-chlorobenzenesulphonylamino)-ethyll-phenoxyacetate from 4-chlorobenzenesulphonyl chloride m.p. 61 - 62C.
(recrystallised from diethyl ether); yield 66% of theory and from this, by hydrolysi~:
4-r2-(4-chlorobenzenesulphonylamino)-ethyll-phenoxvacetic acid m.p. 127 - 128C. (recrystallised from acetone + water);
yield 62% of theory.
Example 4 4=~BenzenesulphonylaminomethYl)-phenoxyacetic acid.
15.7 g. (0.2 mol) Acetyl chloride are added dropwise, while cooling, to a solution of 15.9 g (0.1 mol) 4-hydroxybenzylamine hydrochloride in 100 ml. anhydrous pyridine. The reaction mixture is subsequently stirred for 1 hour at 20~C., then heated for 15 minutes on a boiling water-bath and, while still warm, poured into ice water and acidified with concentrated hydrochloric acid. It is then extracted with chloroform and the chloroform phase is dried with anhydrous ~odium sulphate and evaporated. The crude product is dis-solved in ethyl acetate. After the addition of ligroin, pure 4-acetaminomethyl phenyl acetate precipitates out, yield 18.86 g. ~91% of theory); m.p. 78 - 79C.

113~i158 A mixture of 106.8 g. (0.515 mol) 4-acetaminomethyl phenyl acetate, 800 ml. methanol and 1030 ml. IN aqueous potassium hydroxide solution is heated for 2 hours at 50C.
and the methanol is distilled off in a vacuum, followed by acidification with hydrochloric acid. After concentration of the aqueous phase, the solid product is filtered off with suction and washed with ethanol. There are thus obtained 55.8 g. (66% of theory) 4-(acetaminomethyl)-phenol, m.p.
132 - 133C.
A mixture of 150.0 g. (0.908 mol) 4-(acetamino-methyl)-phenol, 250.9 g. (1.816 mol) anhydrous, pulverised potassium carbonate and 3 litres butan-2-one is heated for 2 hours at reflux temperature, then cooled somewhat and 5 g.
potassium iodide and 244.1 g. (1.462 mol) ethyl bromoacetate added thereto. The reaction mixture is subsequently stirred for 4 hours at reflux temperature, then cooled, filtered and the filter cake washed with acetone. The combined filtrates are evaporated in a vacuum. The evaporation residue is triturated with diethyl ether, filtered off with suction and recrystallised from isopropanol. The yield is 211.2 g.
(92% of theory) ethyl 4-(acetaminomethyl)-phenoxyacetate;
m.p. 93 - 94C.
A mixture of 725 ml. ethanol, 125 g. (0.5 mol) ethyl 4-(acetaminomethyl)-phenoxyacetate, 280 g. (5.0 mol) potassium hydroxide and 600 ml. water is maintained at reflux temperature for 14 hours, then cooled and adjusted to pH 4 with con-centrated hydrochloric acid. The reaction mixture is filtered with suction and the filter cakQ is washed with water and recrystallised from aqueous ethanol. There are obtained 73.4 g. (81% of theory) 4-(aminomethyl)-phenoxyacetic acid; m.p. 260C. (decomp.). The hydrochloride has a melting point of 252 - 253~C.

_ 29 -113~i158 While cooling in an ice-bath, dry hydrogen chloride is passed on to a mixture of 89.0 g. (0.491 mol) 4-(amino-methyl)-phenoxyacetic acid and 890 ml. anhydrous ethanol until the nixture is saturated. The reaction mixture is sub-sequently stirred for 12 hours at ambient temperature, a clear solution thereby being slowly formed, whereafter it is evaporated in a vacuum, There are obtained 115.3 g.
(96% of theory) ethyl 4-(aminomethyl)-phenoxyacetate hydrochloride; m.p. 189 - 190C.
35.32 g. (0.2 mol) Benzenesulphonyl chloride are added dropwise, while stirring at O~C., to a solution of 24.57 g. (0.10 mol) ethyl 4-(aminomethyl)-phenoxyacetate hydrochloride in 250 ml. anhydrous pyridine, whereafter the reaction mixture is stirred for 2 hours at ambient temperature and then poured into ice water. The aqueous phase is acidified with concentrated hydrochloric acid and then extracted with diethyl ether and chloroform. The co~bined extracts are washed with dilute hydrochloric acid, dried and evaporated in a vacuum. After recrystallisation of the evaporation residue from isopropanol, there are obtained 30.0 g. (86%
of theory) ethyl 4-(benzenesulphonylaminomethyl~-phenoxyacetate;
m.p. 110 - 111~.
20.96 g. (60 mMol) Ethyl 4-(benzenesulphonylamino-methyl)-phenoxyacetate are mixed with 250 ml. methanol and 180 ml. (0.18 mol) lN aqueous potassium hydroxide solution.
The dar~ red solution is stirred for 2 hours at ambient temperature and then acidified with hydrochloric acid. The methanol is now distilled of~ in a vacuum and cooled. The precipitated crystals are filtered off with suction, washed with water, dried and subsequently recrystallised from iso-propanol. There are obtained 13.84 g. (72% of theory) 4-113~i158 ~enzenesulphonylaminomethyl)-phenoxyacetic acid, m.p. 142-143C.
In an analogous manner, by the reaction of ethyl 4-aminophenoxyacetate obtained by reacting 4-nitrophenol with ethylbromoacetate and hydrogenating the resulting compound with the appropriate sulphonyl chloride in the presence of pyridine, there is obtained:
ethyl 4-(benzenesul~honYlamino)-phenoxyacetate from 4-benzenesulphonyl chloride m.p. 127 - 128C. (recrystallised from ethyl acetate);
yield 74% of theory, and from this, by hydrolysis:
4-(benzenesulphonylamino)-phenoxyacetic acid m.p. 157 - 158C. (recrystallised from acetone + water):
yield 92% of theory.
Ex m~le 5 2-~4-r2-(4-Chlorobenzenesulphony-amino~ethyll-phenoxy~--2-methyl~ropionic acid A mixture of 44.8 g. (0.25 mol) N-acetyltyramine, 69.5 g. (0.5 mol) anhydrous, pulverised potassium carbonate and 750 ml. anhydrous butan-2-one is heated for 2 hours, while stirring, at reflux temperature, then 73.2 g. (0.375 mol) ethyl 2-bromo-2-methylpropionate and 1 g. potassium iodide æ e added thereto and the reaction mixture again heated at reflux temperature.
After 40 to 70 hours boiling, there are, in each case, additionally added 35 g potassium carbonate and 36.6 g. ethyl 2-bromo-2-methylpropionate After a total reaction time of 130 hours, the reaction mixture is evaporated in a vacuum, poured into ice water and extracted with diethyl ether.
The ethereal extract i~ washed three times with 0. SN aqueous sodium hydroxide solution and then with water and finally dried over anhydrous calcium chloride and evaporated. There are obtained 83.8 g. of an oily residue which still contains ethyl 2-bromo-2-methylpropionate, The oil is kept for 5 hours at a vacuum of 0.1 mm.Hg, and at a temperature of 70C.
The resultant crystalline slurry is washed with ligroin and dried. There are obtained 69.8 g. (95% of theory) of not quite pure ethyl 2-[4-(2-acetaminoethyl)-phenoxy]-2-methyl-propionate; m.p. 51 - 52C.
A solution of 119.1 g. (0.407 mol) ethyl 2-~4-(2-acetaminoethyl)-phenoxy]-2-methylpropionate in 750 ml. ethanol is mixed with a solution of 224,4 g. (4.0 mol) potassium hydroxide in 800 ml. water and heated to reflux temperature for 8 hours. While cooling, there are added exactly 4.0 ml.
hydrogen chloride (for example, in the form of 2N hydro-chloric acid), cooling is intensified and, after some time, the precipitated crystals are filtered off with suction, These are washed with water and dried. The yield is 48.4 g.
(53% of theory); m.p. 274C. (decomp.), From the mother liquor there are obtained, by dis-tilling off the ethanol and cooling, a further 32.5 g. (36%
of theory) of product; m.p. 263 - 270C. The crude 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionic acid thus obtained is recrystallised from alcohol-water (4:1 v/v) and then has a melt-ing point of 284C. The hydrochloride melts at 137 - 189C.
A solution of 58 g. (0.26 mol) of this carboxylic acid in 600 ml, absolute ethanol is gassed, while stirring and cooling with ice, on the surface with dry hydrogen chloride until the solution is saturated. The reaction mixture is then left to stand for 12 hours in a closed vessel. Subsequently, the ethanol and hydrogen chloride are removed in a vacuum.
Water is added to the residue, followed by extracting three times with diethyl ether. The aqueous phase is rendered distinctly alkaline and extracted three times with chloroform.
The chloroform extract is washed with a little water, dried over anhydrous potassium carbonate and evaporated. By dis-tillation of the residue, there are obtained, between 125 and 128C./0.1 mm.Hg., 53.2 g. (82% of theory) colourless ethyl 2-~4-(2-aminoethyl)-phenoxy]-2-methylpropionate. The gas chromatographically pure product has a refractive index nD = 1.5075.
By the reaction of ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate with 4-chlorobenzenesulphonyl chloride in a manner analogous to that described in Example 2, there is obtained, in a yield of 69% of theory, colourless ethyl 2-~4-[2-(4-chlorobenzenesulphonylamino)-ethyl~-phenoxy~-2 methylpropionate in the form of a viscous oil. From this there is obtained, by hydrolysis:
2-~4-r2-(4-chlorob~ s~læhonylamino)-ethyll-phenoxy~-2 methylpropionic acid yield 67% of theory, m.p. 116C, (recrystallised from acetone).
In an analogous manner, there is obtained:
ethYl 2-~4-r2-(benzenesulphonylamino)-ethyll-phen 2-methylpropionate from ethyl 2-E4-~2-aminoethyl)-phenoxy]-2-methylpropionate and benzenesulphonyl chloride, m.p. 66 - 67C. (recrystallised from isopropanol +
ligroin); yield 71% of theory, and from this, by hydrolysis:
2-~4-r2-(benzenesulphonylamino~-ethyll-phenoxy~-2-methylpropionic acidm.p. 12B - 129C. (recrystallised from ethyl acetate +

ligroin), yield 85% of theory.

~3~i~58 Example 6 4-r2-~benzenesulphonylamino)-ethyll-phenoxyacetamide A mixture of 67 g. (0.2 mol) 4-[2-(benzenesulphonyl-amino)-ethyl]-phenoxyacetic acid, which may be obtained as described in Example 1, 400 ml. benzene and 71.5 g. (0.6 mol) thionyl chloride is heated for 4 hours at reflux temperature.
The benzene and excess thionyl chloride are then distilled off in a vacuum. The yield of crude product is quantitative.
After recrystallisation from methylene chloride, there are obtained 61 g. (86% of theory) 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetyl chloride; m.p. 78.5 - 79C. With equal success, it is possible to omit the use of benzene, i.e., to use pure thionyl chloride alone.
A solution of 10.6 g. (30 mMol) 4-~2-(benzene-sulphonylamino)-ethyl]-phenoxyacetyl chloride and 100 ml.
anhydrous dioxan is mixed at ambient temperature with 3.3 ml.
concentrated aqueous ammonia solution, then briefly warmed to 40C. and subsequently coole~. The reaction mixture is then poured into ice water. The reaction mixture is filtered with suction and the filter cake is washed with water and digested with an aqueous solution of sodium bicarbonate.
After suction filtration and washing with water, the product is recrystallised from acetone to gi~e 7.2 g. (72% of theory) 4-~2-(benzenesulphonylamino)-ethyl]-phenoxyacetamide, m.p. 118 - 119C.
By the reaction of 4-E2-(benzenesulphonylamino)-ethyl~-phenoxyacetyl chloride or the free acid with the appropriate amines, there are obtained the following amides:

a) 4-r2-(benzenesulphonylamino)-ethyll-phen acetanilide

3.73 g. (40 mMol) Aniline are added dropwise, with stirring, to a solution of 7.08 g. (20 mMol) acid chloride and 35 ml. anhydrous benzene. The reaction mixture is briefly warmed with 40C. and the benzene then distilled off.
Methylene chloride and dilute hydrochloric acid are added to the residue, followed by vigorous stirring, whereafter the phases are separated. The methylene chloride phase is washed with 2N hydrochloric acid and water, dried and evaporated.
After recrystallisation from ethyl acetate, there are obtained 5~58 g~ (6~/o of theory) of the desired product; m.p. 123C.
b) 4-L2-~Benzenesulphonylamino)-ethyll-phenoxyacetic acid 2-ethoxycarb nylethylami e A mixture of 4.6 g~ (30 mMol) ethyl ~-aminopropionate hydrochloride, 4.1 g. (30 mMoI) pulverised potassium carbonate and 100 ml. anhydrous pyridine are stirred for 20 minutes, with ice cooling, and then 10~6 g~ (30 mMol) of the acid chloride are added dropwise thereto. The reaction mixture is subsequently allowed to warm up to 20C., then heated for 30 minutes to 50C., cooled and poured into about 500 ml.
ice water. By the addition of hydrochloric acid, the pH is adjusted to 5.5 and the reaction mixture then extracted with methylene chloride. The methylene chloride phase is washed several times with dilute hydrochloric acid and water, dried with anhydrous sodium sulphate and evaporated. There are obtained 10.5 g. (81% of theory) of oily 4-[2-(benzenesulphonyl-amino)-ethyl]-propionic acid 2-ethoxycarbonylethylamide with a refractive index of 3 = 1.5490.
By hydrolysis thereof in a manner analogous to that described in E~ample 2, there is obtained:

_ 35 -` 1~3~158

4-r2-(benzenesulphonylamino)-ethyll-phenoxyacetic acid-2-carboxyethylamide m.p. 64 - 65C. (recrystallised from acetone + water);
yield 86% of theory.
c) 4-r2-(benzenesulphonylamino)-ethyll-phenoxyacetic -, acid 4-ethoxYcarbonYlanilide in a manner analogous to that described àbove in b) from the acid chloride and ethyl 4-aminobenzoate hydrochloride; m.p.
157 - 158C. (recrystallised from ethyl acetate); yield - 72% of theory;
and from this, by hydrolysis:
4-r2-(benzenesulphonylamino)-ethyll-phenoxyacetic acid - 4-carboxyanilide m,p, 185 - 186C. (recrystallised from acetone + water), yield 65% of theory;
d) 4-~2-(benzenesulphonYlamino)-ethYll-phenoxyacetic acid 4-(ethoxycarbonylmethyleneoxy)-phenethylamide in a manner analogous to that described above in b) from the acid chloride and ethyl 4~(2-aminoethyl)-phenoxyacetate;
m.p. 97 - 98C. (recrystallised from ethyl acetate); yield 68% of theory, and from this, by hydrolysis:
4-r2-(benzenesulphonylamino)-ethyll-phenoxyacetic acid -tcarbo~ymethYleneoxY)-PhenethYlamide m.p. 148 - 149C. (recrystallised from water + acetone);
yield 60% of theory.

_ 36 ~

Example 7 4-r2-(n-octanesulphonylamino)-ethyll-phenoxyacetic acid 26.1 g. (0.1 mol) Ethyl 4-(2-aminoethyl)-phenoxy-acetate hydrochloride, which may be prepared from tyramine and ethylbromoacetate followed by conversion to the hydro-chloric acid addition salt, and 21.3 g. (0.1 mol) n-octane-sulphonyl chloride are suspended in 400 ml. benzene, a solution of 27.6 g. tO.2 mol) potassium carbonate and 400 ml.
water is added dropwise thereto, with very vigorous stirring, stirring is continued for 10 minutes and the phases are then separated, The benzene phase is washed with water, dried over anhydrous sodium sulphate and evaporated in a vacuum.
After recrystallisation of the residue from ethyl acetate, there are obtained 32.6 g. ( 82% of theory) ethyl 4-~2-(n-octanesulphonylamino)-ethyl]-phenoxyacetate; m.p. 65 - 66C~
(after recrystallisation from ethyl acetate).
A mixture of 15.4 g. ( 38 mMol) of this ethyl ester, 38 ml. 2N a~ueous potassium hydroxide solution and 38 ml.
ethanol is kept at 40C. for 3 hours. The ethanol is then distilled off in a vacuum and the residue is acidified with hydrochloric acid, filtered with suction and the product thus obtained recrystallised from a water-dioxan mixture. ~here are obtained 12.4 g. (8~/o of theory) 4-[2-(n-octanesulphonyl-amino)-ethyl]-phenoxy-acetic acid, m.p. 128 - 129~C.
Example 8 4-r-2---(n-Hexadecanesulphonylamino)-ethyll-phenoxyacetic acid

5.5 g. (16.9 mMol) _-Hexadecanesulphonyl chloride are added at 0C., with visorous stirring, to a mixture of 4.4 g. (16.9 mMol) ethyl 4-~2-aminoethyl)-phenoxyacetate hydrochloride, obtained as described previously, 50 ml. benzene and 6.8 g. (68 mMoll triethylamine. The reaction mixture is stirred for a further 2 hours in an ice-bath and then left to stand overnight at 20C. The reaction mixture is -` 1136158 then poured on to ice water, acidified with hydrochloric acid and extracted with diethyl ether. The ethereal phase is washed with water, dried with anhydrous sodium sulphate, evaporated and the residue recrystallised from ethanol to give 5.8 g. (6P/o of theory) ethyl 4-~2-(n-hexadecanesulphonyl-amino)-ethyl]-phenoxyacetate; m.p. 91 - 92C.
Hydrolysis of the ester is carried out analogously to Example 7 with aqueous potassium hydroxide solution in methanol. There is obtained a yield of 68% of theory of 4-[2-(n-hexadecanesulphonylamino)-ethyl]-phenoxyacetic acid;
m.p. 137.5 - 138C. (recrystallised from ethanol).
Example 9 In a manner analogous to that described in Example 3, by the reaction of ethyl 4-[2-(aminoethyl)-phenoxyacetate hydrochloride with the appropriate sulphonyl chloride in the presence of pyridine, there are obtained the following compounds:
a) ethYl 4-r2-(2-phenylethanesulphonylamino)-ethYll-phenoxyacetate from 2-phenylethane sulphonyl chloride as a viscous oil (crude product); yield 76% of theory, and from this, by hydrolysis:
4-r2-( ~ th~ g~ lamino)-eth ~ enoxY-acetic acid m.p. 124 - 125C. (recrystallised from ethanol + lC% water);
yield 74% of theory.
b) ethYl 4-~2-r2-~4-chl~ nyl)-ethanesulphonylamin ethv~ phenoxyacetate from 4-chlorophenylethanesulphonyl chloride as a viscous oil (crude product), yield 5P/O of theory; and from this, by hydrolysis:

4-~2-r2-t4-chlorophenyl)-ethanesulPhonylaminol-eth phenoxyacetic acid m.p. 128 - 130C. (recrystallised from ethyl acetate +
ligroin), yield 73% of theory.
c) Ethvl 4-~2-(4-acetylbenzenesulphonylamino)-eth phenoxyacetate from 4-acetylbenzenesulphonyl chloride m.p. 113.5 - 114C.
(recrystallised from e~hyl acetate + ligroin), yield 52%
of theory, and from this, by hydrolysis:
4-r2-(4-acetYlbenzenesulphonylamino)-ethyl1-phenoxy-acetic acid m.p. 162C. (recrystallised from acetone); yield 63% of theory.
Examole 10 4-r2-(Benzenesul~honylamino)-ethyll-phenoxyacetic acid l-hydroxy-2-propylamide A solution of 6.4 g. (18 mMol) 4-[2-tbenzene-sulphonylamino)-ethyl~-phenoxyacetyl chloride, which may be obtained as described in Example 6, and 25 ml. anhydrous benzene is added dropwise at 0 to 5C., over the course of 2 hours, to a mixture of 5.4 g. (72 mMol) l-hydroxy-2-amino-propane and 35 ml. water, a precipitate thereby forming slowly. After standing overnight at 20C,, the precipitate i4 filtered off with suction and the filter cake is washed with dilute aqueous sodium hydroxide solution and then with water and dried. After recrystallisation from ethyl acetate, there are o~tained 5.2 g. (74% of theory) o the desired pro-duct; m.p. 90 - 91~C.

_ 39 -1136~58 Example 11 4-r2-(N-Methylbenzenesulphonylamino)-ethyll-phen acetic acid 0.6 g. (25 mMol) Sodium hydride (suspension in mineral oil) are added to a mixture of 9.1 g. (25 mMol) ethyl 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetate, 50 ml. hexamethylphosphoric acid triamide and 50 ml. anhydrous toluene and the reaction mixture subsequently stirred for 2 hours at 80C. The reaction mixture is then cooled, mixed with a mixture of 10.6 g. (75 mMol) methyl iodide and 10 ml.
hexamethylphosphoric acid triamide, stirred for 15 minutes at 20C, and then kept for 3 hours at 80C. After cooling, the reaction mixture is poured on to ice water, adjusted to pH 3 by means of hydrochloric acid and extracted several times with toluene, The toluene phase is evaporated and the evaporation residue chromatographed on silica gel with the use of toluene. There are obtained 3.9 g. (41% of theory) pure ethyl 4-[2-(N-methylbenzenesulphonylamino)-ethyl]-phenoKy-acetate in the form of a colourless oil with the refractive index nD = 1.5440.
~his compound can also be obtained in the following manner:
9.25 g, (54 mMol) Benzenesulphonic acid monomethyl-amide are dissolved in 75 ml hexamethylphosphoric acid tri-amide, 1,3 g, (54 mMol) sodium hydride (in the form of a mineral oil suspension) is added thereto, the reaction mixture is stirred for 20 minutes at 20~C. and then 14.9 g.
(54 mMol) ethyl 4-(2-~romoethyl)-phenoxyacetate are added thereto. The reaction mixture is stirred for 24 hours at 50C., cooled and poured into ice water. The pH is adjusted to 3 by means of dilute hydrochloric acid and extracted several times with toluene. The toluene phase is washed with - 4~ -113~158 water and dried with anhydrous sodium sulphate. The product is then chromatographed on silica gel with toluene to give 9.2 g. (45% of theory) of the desired ester, From this there is obtained, by hydrolysis with lN
aqueous potassium hydroxide in ethanol, 4-[2-(N-methyIbenzene sulphonylamino)-ethyl]-phenoxyacetic acid, m.p. 103 - 104C.
(recrystallised from ethyl acetate + ligroin), yield 91% of theory.
Example 12 4-r3-(Benzenesulphonylamino)-propyll-~henoxyacetic acid.
A mixture of 14.5 g. (75 mMol) 4-(3-acetaminopropyl)-phenol, 16.8 g. (122.5 mMol) pulverised potassium carbonate and 150 ml. butan-2-one is maintained at reflux temperature for 2 hours, then 20.6 g. (122.5 mMol) ethyl bromoacetate and a spatula tip of potassium iodide are added thereto and the reaction mixture maintained at 80C.for 6 hours. The reaction mixture is then filtered with suction and the filtrate evaporated in a vacuum and, for the separation of excess ethyl bromoacetate, finally at oil pump vacuum. The evaporation residue is taken up in methylene chloride and extracted with cold 0.5N aqueous sodium hydroxide solution and then with water. ~fter drying with anhydrous sodium sulphate, the solution is e~raporated and, by cooling and adding diethyl ether, crystallisation is brought about. After recrystallis-ation from diethyl ether, there are obtained 14.9 g (71% of theory) ethyl 4-(3-acetaminopropyl)-phenoxyacetate, m p 57 - 58C, A mixture of 16.2jg, (58 mMol) ethyl 4-(3-acetamino-propyl3-phenoxyacetate, 100 ml. ethanol, 100 ml water and 32 5 g. (0.58 mol) potassium hydroxide is ~ept at reflux temperature for 16 hours The reaction mixture is then cooled, adjusted to pH 6.5 with 6N hydrochloric acid and the resultant sand-coloured precipitate filtered off with suction. After washing with water and drying, there are obtained 12.0 g.
(quantitative yield) 4-(3-aminopropyl)-phenoxyacetic acid;
m.p. 248C.
A mixture of g.7 g. (46.5 n~ol) 4-(3-aminopropyl)-phenoxyacetic acid, 6.9 g. (50 ~ol) potassium carbonate and 100 ml. water is heated to 80C. and 8.5 g. (48 n~ol) benzenesulphochloride added dropwise thereto at this 10 temperature. Thereafter, the reaction mixture is kept at 80C. for a further 2 hours, then cooled and adjusted to ~iH
2 with 2N hydrochloric acid. The precipitate obtained is filtered off with suction, dried and crystallised from ethyl acetate and then from glacial acetic acid to give 8.26 g.
(51% of theory) 4- [3-(benzenesulphonylamino)-propyl]-phenoxy-acetic acid; m.p. 146 - 147C.
Example 13 2- ~4- r2-(Benzene~ul~honylamino)-ethyll-phenoxy~-2-methylPropionic acid 20 (using the chloroform-acetone method) 9.4 g. (235 ~ol) Sodium hydroxide are added to a mixture of 4.45 g. (16.1 mMol) 4-[2-(benzenesulphonylamino)-ethyl]-phenol (which may be obtained from benzenesulphochloride and tyramine) and 77 ml. acetone at 20C., while stirring With-in 2 hours, 8.7 g. (72.9 mMol) chloroform are added dropwise, whereby by occasi<:nal cooling, the internal temperature is kept at 30 to 35C. The reaction mixture is then further stirred for 30 minutes at 30aC. and then heated at reflux temperature for 2.5 hours. The reaction mixture is then evaporated in a vacuum 30 and the residue is taken up in water and extracted with diethyl ether. The aqueous phase is acidified and extracted with ethyl acetate.

113~i158 The ethyl acetate phase is dried with anhydrous sodium sulphate and evaporated in a vacuum. The residue is mixed with 50 ml.
water and 5 g. sodium bicarbonate and stirred, a clear solution thereby being obtained. This is again extracted with diethyl ether. The aqueous phase is now acidified and extracted with ethyl acetate. After evaporation of ethyl acetate, the residue is recrystallised from an ethyl acetate-ligroin mixture, with the addition of charcoal, to give 2.64 g. (45% of theory) of the desired acid which, in all physical properties, is identical with the product obtained in Example 5.
Example 14 2-r4-~4-Chlorobenzenesulphonylamino)-phenoxvl-2-methYl proE~onic acid A mixture of 139.1 g. (1 mol) 4-nitrophenol, 1 litre butan-2-one and 207,3 (1.5 mol) pulverised, anhydrous potassium carbonate is stirred for 2 hours at reflux temperature, then 292.5 g. (l.S mol) ethyl 2-bromo-2-methylpropionate are added thereto and the reaction mixture maintained at reflux temperature for a further 92 hours. After the addition of a further 69.1 g. (0.5 mol) potassium carbonate and 97,5 g.
(0.5 mol) ethyl 2-bromo-2-methyl-propionate, the reaction mixture is stirred for a further 20 hours at reflux temperature.
The reaction mixture is then filtered with suction and the filtrate is evaporated in a vacuum (for the removal of excess ethyl ester, finally at a high vacuum). The residue is ta~en up in diethyl ether, filtered and the ethereal phase now extracted several times with lN aqueous sodium hydroxide solution.
After washing until neutral and drying, it is evaporated, 153 g~ (6~/o of theory) of an oily crude product being obtained.
After distillation at 155.5 - 156C~/0.05 mm.Hg., there is obtained a yield of 46% of theory of pure ethyl 2-methyl-2~(4-113~1S8 nitrophenoxy)-propionate in the form of a yellow oil with a refractive index of nD = 1.5288.
A mixture of 50.6 g. (0.2 mol) ethyl 2-methyl-2-(4-nitrophenoxy)-propionate, 500 ml, ethanol and about 20 g, 5% palladium charcoal is hydrogenated in a shaker at ambient temperature and atmospheric pressure until the necessary amount of hydrogen has been taken up. The reaction mixture is subsequently filtered with suction and the liquid phase is evaporated to give a quantitative yield of crude ethyl 2-(4-aminophenoxy)-2-methylpropionate in the form of a distillable oil (b.p. 134 - 135C./0.05 mm.Hg.);
nD = 1.5035; m.p. of the hydrochloride 153 - 154C~
10.6 g. (50 mMol) 4-Chlorobenzenesulphochloride are added within the course of 30 minutes at 0 - 5C. to a mixture of 13.0 g. (50 mMol) ethyl 2-(4-aminophenoxy)-2-methylpropionate hydrochloride and 200 ml. anhydrous pyridine.
The reaction mixture is then stirred for 1 hour at 5C. and finally maintained for 2 hours at 80C. The reaction mixture is then cooled, stirred into ice water and acidified with hydrochloric acid to pH 5.5, an oily product thereby separating out. This is taken up in diethyl ether. The ethereal phase is successively washed with 6N hydrochloric acid, water, aqueous sodium bicarbonate solution and again with water, dried and evaporatéd in a vacuum. There are ob-tained 18.8 g. (95% of theory) crude ethyl 2-[4-(4-chloro-benzenesulphonylamino)-phenoxy3-2-mRthyl-propionate in the form of a colourless oil. By saponification of the crude ester by means of lN aqueous potassium hydroxide solution in ethanol in a manner analogous to that described in Example 2, there is obtained a yield of 91% of theory of crystalline 2-[4-(4-chlorobenzenesulphonylamino)-phenoxy]-2-methylpropion-ate; m.p. 146.5 - 147C. (after recrystallisation from ethyl - 4~ -~136158 acetate + ligroin).
The following compounds are obtained in an analogous manner:
a) ethYl 2-r4-(4-chlorostyrenesul~honylamino)-phen 2-methvlpropionate from P-chlorostyrene~ulphonyl chloride and ethyl 2-(4-aminophenoxy)-2-methylpropionate;
m.p. 130 - 131C. (~ecrystallised from ethyl acetate);
yield 87% of theory, and from this, by hydrolysis:
2r4-(4-chlorostyrenesulphonvlamino)-phenoxyl-2-methyl-E~ionic acidm.p. 172 - 173C. (recrystallised from ethyl acetate):
yield 73% of theory.
b) ethYl 2-~4-r2-(4-chlorostyrenesulphonylamino)-ethy phenoxv~-2-methYlpropionate from P-chlorostyrenesulphonyl chloride and ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate, obtained frvm 4-(2-nitroethyl)phenol and bromo-2-methylpropionate followed by hydrogenation of the nitro to amino:
colourless oil, nD = 1.5625;
and from this, by hydrolysis:
2-~4-r2-(4-Chlorostyrenesulphonylamino)-ethyll-phenoxy3-2-methylpropionic acid m.p. 148 - 149C. (recrystallised from benzene); yield 76%
of theory.
c) ethYl 2-t4-~2-r2-(4-chlorophenvl)-ethanesulphonyl-aminol-ethYl~-phenoxy~-2-methylpropionate from 2-(4-chlorophenyl)-ethanesulphonyl chloride and ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate, obtained as described above;

113~158 colourless oil; yield 7~ of theory, and from this, by hydrolysis:
2-5~4-~2=r2-~4-chloro~henyl)-ethanesulPhonylaminol-ethYl~-E~henoxy~-2-methylpropionic acid m.p. 138 - 139C. (recrystallised from ethyl acetate +
ligroin), yield 53% of theory.
Example 15 2- ~ hlorobenzenesulphony~lamino)-ethyll-phen n-hexanoic acid A mixture of 17.92 g. (0.1 mol) 4-(2-acetamino-ethyl)-phenol, 17.3 g, (0,125 mol) pulverised potassium carbonate and 150 ml, butan-2-one is stirred for 2 hours at reflux temperature, then 27.9 g. (0.125 mol) ethyl 2-bromohexanoate and a spatula tip of potassium iodide are added thereto and the reaction mixture kept at reflux temperature for a further 28 hours. The reaction mixture is then filtered with suction and the filtrate evaporated in a vacuum, The residue is taken up in diethyl ether and the ethereal phase is extracted with 2N hydrochloric acid, water, 0.5N aqueous sodium hydroxide solution and again with water, dried over anhydrous sodium sulphate and evaporated to give 32.1 g. (quantitative yield) ethyl 2-[4-(2-acetamino-ethyl)-phenoxy]-n-hexanoate in the form of a colourless oil with a refractive index nD = 1.5010.
A mixture of 25.7 g. (80 mMol) ethyl 2-~4-(2-acetaminoethyll-phenoxy~-_-hexanoate, 150 ml. water, lS0 ml.
ethanol and 44.9 g. (0.8 mol) ~otassium hydroxide is ~ept at reflux temperature for 16 hours and the alcohol subsequently distilled off in a vacuum. After the addition of 150 ml.
water, the reaction mixture is acidified to p~ 4 with hydro-chloric acid and the resultant precipitate is filtered off with 113~8 suction, washed with water and dried. There are obtained 12.5 g. (62% of theory) 2-[4-(2-aminoethyl)-phenoxy]-_-hexanoic acid; m.p. 274 - 276C.
By the reaction of 2-[4-(2-aminoethyl)-phenoxy]-_-hexanoic acid with 4-chlorobenzenesulphonyl chloride in the presence of aqueous potassium carbonate solution, in a manner analogous to that described in Example 1, there is obtained a yield of 32% of theory of 2-~4-[2-(4-chlorobenzenesulphonyl-amino)-ethyl]phenoxy~-n-hexanoic acid, m.p. 138 - 139C.
(recrystallised from ethyl acetate and cyclohexane).

Claims (88)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for the preparation of a phenoxyalkyl-carboxylic acid derivative of the formula (I):- (I) in which R is a hydrogen atom or a lower alkyl of 1 to 6 carbon atoms; R1 is an alkyl of 1 to 16 carbon atoms, or an aryl of 6 to 14 carbon atoms, aralkyl in which the aryl moiety con-tains 6 to 14 carbon atoms and the alkyl moiety contains 1 to 5 carbon atoms or aralkenyl in which the aryl moiety contains 6 to 14 carbon atoms and the alkenyl moiety contains 2 or 3 carbon atoms, the aryl moiety of said aryl, aralkyl or ar-alkenyl being unsubstituted or substituted one or more times by halogen, hydroxyl, trifluoromethyl, lower alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, or aliphatic acyl of up to 5 carbon atoms, R2 and R3, which may be the same or different, are hydrogen atoms or lower alkyl of 1 to 6 carbon atoms and n is 0, 1, 2 or 3, and the pharmaceutically acceptable, physiologically compatible salts, esters and amides thereof, comprising:

a) reacting an amine of the formula (II):-(II) or an acid addition salt thereof, wherein R and n are as defined above, with intermediate protection of the amino or hydroxyl group, if desired, in any sequence with a sulphonic acid of the formula (III):-R1-SO2OH (III) in which R1 is as defined above, or with a derivative thereof, and with a compound of the formula (IV):- (IV) in which R2 and R3 are as defined above, X is a reactive group and Y is a -COOR4 radical, R4 being a hydrogen atom or a lower alkyl radical or Y is an acid amide group or a residue which, after condensation, can be converted into a -COOR4 radical or into an acid amide group, or b) when R2 and R3 signify lower alkyl radicals reacting said amine of formula (II), with intermediate protection of the amino or hydroxyl group if desired, in any sequence with said sulphonic acid of formula (III), or a derivative thereof and with an aliphatic ketone R2-CO-R3 and chloroform; or c) reacting a sulphonamide of the formula (V) (V) in which R and R1 are as defined above with a compound of the formula (VI):- (VI) in which n, R2, R3, X and Y are as defined above, to give a compound of formula (VII):- (VII) in which R1, R2, R3, R, Y and n are as defined above, or d) transacylating a compound of formula (VIII) (VIII) wherein n, R, R2, R3 and Y are as defined above, and Ac is a readily exchangeable acyl radical, with a free sulphonic acid of formula (III) R1-SO2OH (III) in which R1 is as defined above, to produce said compound of formula (VII), as defined above, or e) reacting a compound of formula (IV), as defined above with a compound of the formula (X):- (X) wherein n is 0, 1, 2 or 3, hydrogenating the resulting nitro product to produce the corresponding amino derivative and reacting said amino derivative with a sulphonic acid, or a reactive derivative thereof, of formula (II), as defined above, whereafter, when Y is said residue, converting said residue into said -COOR4 radical or said acid amide group, and, if desired, a derivative (I) obtained in which R is a hydrogen atom is N-lower-alkylated or, if desired, an ester or amide derivative (I) obtained is converted into the free acid or, if desired, an ester derivative (I) obtained is transesterified to a different ester (I), or if desired, a free acid obtained is esterified or converted into an amide or into a pharmaceutically acceptable, physiologically compatible salt with a non-toxic inorganic or organic base.

2. A process according to claim 1a) comprising reacting said amine(II), or an acid addition salt thereof, with inter-mediate protection of the amino or hydroxyl group if desired, in any sequence with said sulphonic acid (III), or a reactive derivative thereof,and said compound (IV).

3. A process according to claim 2, comprising reacting said amine (II), in which the amino group is protected,with said compound (IV), removing the protecting group on the amino in the reaction product, and reacting the resulting compound with said sulphonic acid (III), or a reactive derivative thereof.

4. A process according to claim 3, wherein said amine (II) and said compound (III), are reacted in a solvent at an elevated temperature.

5. A process according to claim 1b) comprising reacting said amine of formula (II), with intermediate protection of the amino or hydroxyl group, if desired, in any sequence with said sulphonic acid of formula (III), or a derivative thereof and with said aliphatic ketone and chloroform.

6. A process according to claim 5, wherein said ketone is acetone.

7. A process according to claim 1c), comprising reacting said sulphonamide(V) with said compound (VI).

8. A process according to claim 7, wherein X is an arylsulphonyloxy radical and said reacting is carried out in an alkaline medium.

9. A process according to claim 1d), comprising transacylating said compound (VIII), with qaid free sulphonic acid (III).

10. A process according to claim 9, carried out with equimolar amounts of said compound (VIII) and said acid (III) in a polar solvent, at the boiling temperature of the solvent.

11. A process according to claim 1, including the step of converting a free acid (I), into a pharmaceutically acceptable, pharmacologically compatible salt with a non-toxic inorganic or organic base.

12. A process according to claim 1, including a final step selected from:
i) hydrolysing or saponifying an ester or amide (I) to obtain a corresponding free acid (I), ii) esterifying a free acid (I) to obtain a corresponding ester (I), iii) transesterifying a first ester (I) to obtain a different ester (I), iv) reacting a free acid (I), or a reactive derivative thereof, with an amine to obtain a corresponding amide(I).

v) N-lower-a]kylating a derivative (I) in which R is hydrogen to produce a corresponding derivative (I) in which R is lower alkyl.

13. A process according to claim 1, in which there is produced a compound with said radical Y, in which Y is nitrile, carbaldehyde, hydroxymethyl, aminomethyl or formyl, and including a step of converting Y into said radical -COOR4-or said acid amide group.

14. A process according to claim 3, for preparing 4-[2-benzenesulphonylamino)-ethyl]-phenoxyacetic acid comprising reacting N-acetyltyramine with ethyl bromoacetate, removing the acetyl protecting group on the amino group and hydrolyzing the ester reaction product, and reacting the resulting free acid with benzenesulphochloride.

15. A process according to claim 2, for preparing 4-[2-(benezenesulphonylamino)-ethyl]-phenoxyacetic acid comprising reacting tyramine with benzenesulphonylchloride, reacting the reaction product with ethyl bromoacetate and hydrolyzing the resulting ethyl 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetate to obtain the free acid.

16. A process according to claim 3, for preparing 4-[2-(benzenesulphonylamino)-ethyl3-phenoxyacetic acid comprising reacting N-acetyl-tyramine with ethyl bromoacetate, removing the protecting acetyl group on amino in the reaction product, and reacting the resulting ethyl 4-(2-aminoethyl)-phenoxy-acetate, in the form of its hydrochloride acid addition salt, with benzenesulphochloride, and hydrolyzing the resulting ethyl ester to give the free acid.

17. A process according to claim 12 iii), for preparing isopropyl 4-[2-(benzenesulphonylamino)-ethyl]-phenoxy acetate, comprising transesterifying ethyl 4-[2-(benzene-sulphonylamino)-ethyl]-phenoxy acetate with isopropanol.

18. A process according to claim 2, for preparing 4-[2-(4-methoxybenzenesulphonylamino)-ethyl]-phenoxy-acetic acid, comprising reacting ethyl 4-(2-aminoethyl)-phenoxy acetate, the reaction product ofan amine II with a compound IV, with 4-methoxybenzenesulphonyl chloride, and hydrolyzing the obtained ethyl 4-[2-(4-methoxybenzenesulphonylamino)-ethyl]-phenoxy acetate to obtain the free acid.

19. A process according to claim 2, for preparing 4-[2-(4-fluorobenzenesulphonylamino)-ethyl]-phenoxy-acetic acid, comprising reacting ethyl 4-(2-aminoethyl)-phenoxy acetate hydrochloride, the reaction product of an amine II with a compound IV, with 4-fluorobenzenesulphonyl chloride, and hydrolyzing the resulting ethyl ester to obtain the free acid.

20. A process according to claim 19, including the step of converting the free acid to the corresponding sodium salt.

21. A process according to claim 2, for preparing 4-[2-(methanesulphonylamino)-ethyl]-phenoxy acetic acid comprising reacting ethyl 4-(2-aminoethyl)-phenoxy acetate, the reaction product of an amine IT with a compound IV, with methyanesulphonyl chloride and hydrolyzing the resulting ethyl ester.

22. A process according to claim 2, for preparing 4-[2-(p-toluenesulphonylamino)-ethyl]-phenoxy acetic acid, comprising reacting 4-(2-aminoethyl)-phenoxy acetate, the reaction pro-duct of an amine II with a compound IV, with p-toluene-sulphonyl chloride, and hydrolyzing the resulting ethyl ester to obtain the free acid.

23. A process according to claim 2, for preparing 4-[2-(1-naphthalenesulphonylamino)-ethyl]-phenoxyacetic acid, comprising reacting ethyl 4-(2-aminoethyl)-phenoxy acetate, the reaction product of an amine II with a compound IV, with 1-naphthalenesulphonyl chloride, and hydrolyzing the result-ing ethyl ester to obtain the free acid.

24. A process according to claim 2, for preparing 4-[2-styrenesulphonylamino)-ethyl]-phenoxyacetic acid, comprising reacting ethyl 4-(2-aminoethyl)-phenoxyacetate, the reaction product of an amine II with a compound IV, with styrene-sulphonyl chloride, and hydrolyzing the resulting ethyl ester to obtain the free acid.

25. A process according to claim 2, for preparing 4-[2-(4-chlorostyrenesulphonylamino)-ethyl]-phenoxyacetic acid, comprising reacting ethyl 4-(2-aminoethyl)-phenoxyacetate, the reaction product of an amine II with a compound IV, with 4-chlorostyrenesulphonyl chloride and hydrolyzing the result-ing ethyl ester to obtain the free acid.

26. A process according to claim 2, for preparing 4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-phenoxyacetic acid, comprising reacting ethyl 4-(2-aminoethyl)-phenoxyacetate, the reaction product of an amine II with a compound IV, with 4-chlorobenzenesulphonyl chloride, and hydrolyzing the result-ing ethyl ester to obtain the free acid.

27. A process according to claim 3, for preparing 4-(benzenesulphonylaminomethyl)-phenoxyacetic acid, comprising reacting 4-(acetaminomethyl)-phenol with ethyl bromoacetate, removing the acetyl protecting group, reacting the resulting compound with benzenesulphonyl chloride and hydrolyzing the resulting ethyl ester to obtain the free acid.

28. A process according to claim 1 e), for preparing 4-(benzenesulphonylamino)-phenoxyacetic acid, comprising reacting ethyl 4-aminophenoxyacetate with 4-benzenesulphonyl chloride and hydrolyzing the thus obtained ethyl ester to obtain the free acid.

29. A process according to claim 3, for preparing 2-{4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-phenoxy} 2-methyl-propionic acid, comprising reacting N-acetyltyramine with ethyl 2-bromo-2-methylpropionate, removing the protective acetyl group on amino, reacting the obtained ethyl ester with 4-chlorobenzenesulphonyl chloride, and hydrolyzing the thus obtained ethyl ester to product the free acid.

30. A process according to claim 3, for preparing 2-{4-[2-(benzenesulphonylamino)-ethyl]-phenoxy}2-methylpropionic acid, comprising reacting ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate,the reaction product of an amine II with a compound IV, with benzenesulphonyl chloride, and hydrolyzing the resulting ethyl ester to obtain the free acid.

31. A process according to claim 12 iv), for preparing 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetamide, compris-ing reacting 4-[2-(benzenesulphonylamino)-ethyl]-phenoxy-acetic acid, or an acid chloride derivative thereof, with ammonia.

32. A process according to claim 12 iv), for preparing 4-[2-(benzenesulphonyl)-ethyl]-phenoxyacetanilide comprising reacting 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetyl chloride with aniline.

33. A process according to claim 12 iv), for preparing 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetic acid 2-ethoxycarbonylethylamide comprising reacting 4-[2-(benzene-sulphonylamino)-ethyl]-phenoxyacetyl chloride with ethyl .beta.-aminopropionate hydrochloride.

34. A process according to claim 33, including the step of hydrolyzing said ethylamide to obtain 4-[2-(benzene-sulphonylamino)-ethyl]-phenoxyacetic acid 2-carboxyethylamide.

35. A process according to claim 12 iv), for preparing 4-[2-(benzenesulphonylamino)-ethyl]-phenoxy acetic acid 4-carboxyanilide comprising reacting 4-[2-(benzenesulphonyl-amino)-ethyl]-phenoxyacetyl chloride with ethyl 4-aminobenzoate hydrochloride, and hydrolyzing the resulting 4-ethoxycarbonyl-anilide to obtain the corresponding 4-carboxyanilide.

36. A process according to claim 12 iv), for preparing 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetic acid 4-(car-boxymethyleneoxy)-phenethylamide, comprising reacting 4-[2-(benzenesulphonylamido)-ethyl]-phenoxyacetyl chloride with ethyl 4-(2-aminoethyl)-phenoxyacetate, and hydrolyzing the resulting 4-(ethoxycarbonylmethyloxy)-phenethylamide to obtain the 4-(carboxymethyleneoxy)-phenethylamide.

37. A process according to claim 2, for preparing 4-[2-(?-octanesulphonylamino)-ethyl]-phenoxyacetic acid comprising reacting ethyl 4-(2-aminoethyl)-phenoxyacetate hydrochloride, the reaction product of an amine II with a compound IV, with ?-octanesulphonyl chloride, and hydrolyzing the resulting ethyl ester to obtain the free acid.

38. A process according to claim 2, for preparing 4-[2-(?-hexadecanesulphonylamino)-ethyl]-phenoxyacetic acid, comprising reacting ethyl 4-(2-aminoethyl)-phenoxyacetate hydrochloride, the reaction product of an amine II with a compound IV, with ?-hexadecanesulphonyl chloride, and hydrolyzing the resulting ethyl ester to obtain the free acid.

39. A process according to claim 2, for preparing 4-[2-(2-phenylethanesulphonylamino)-ethyl]-phenoxyacetic acid com-prising reacting ethyl 4-[2- aminoethyl)-phenoxyacetate hydro-chloride with 2-phenylethanesulphonyl chloride and hydrolyzing the resulting ethyl ester to obtain the free acid.

40. A process according to claim 2, for preparing 4-[2-[2-(4-chlorophenyl)-ethanesulphonylamino]-ethyl}-phenoxy-acetic acid comprising reacting ethyl 4-(2- aminoethyl)-phenoxyacetate hydrochloride, the reaction product of an amine II with a compound IV, with 4-chlorophenyl-ethane-sulphonyl chloride and hydrolyzing the resulting ethyl ester to obtain the free acid.

41. A process according to claim 2, for preparing 4-[2-(4-acetylbenzenesulphonylamino)-ethyl]-phenoxyacetic acid comprising reacting ethyl 4-t2 aminoethyl)-phenoxy acetate hydrochloride, the reaction product of an amine II with a compound IV, with 4-acetylbenzenesulphonyl chloride and hydrolyzing the resulting ethyl ester to obtain the free acid.

42. A process according to claim 12 iv), for preparing 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetic acid 1-hydroxy-2-propylamide comprising reacting 4-[2-(benzene-sulphonylamino)-ethyl]-phenoxyacetyl chloride with 1-hydroxy-2-aminopropane.

43. A process according to claim 12 v), for preparing 4-[2-(N-methylbenzenesulphonylamino)-ethyl]-phenoxyacetic acid comprising N-methylating ethyl 4-[2-benzenesulphonyl-amino)-ethyl]-phenoxyacetate and hydrolyzing the ethyl ester to obtain the free acid.

44. A process according to claim 7, for preparing 4-[2-(N-methylbenæenesulphonylamino)-ethyl]-phenoxyacetic acid comprising reacting benzenesulphonic acid monomethyl-amide with ethyl 4-(2-bromoethyl)-phenoxyacetate, and hydrolyzing the thus obtained ethyl ester to produce the free acid.

45. A process according to claim 3, for preparing 4-t3-(benzenesulphonylamino)-propyl]-phenoxyacetic acid comprising reacting 4-(3-acetaminopropyl)-phenol with ethyl bromoacetate, removing the protective acetyl group from the resulting methyl ester and hydrolyzing the ester to obtain the free acid, and reacting the free acid with benzenesulpho-chloride.

46. A process according to claim 5, for preparing 2{4-[2-(benzenesulphonylamino)-ethyl]-phenoxy}-2-methylpropionic acid comprising reacting 4-[2-(benzenesulphonylamino)-ethyl]-phenol, obtained by reacting an amine II with a sulphonic acid III, with acetone and chloroform.

47. A process according to claim 1 e), for preparing 2-[4-(4-chlorobenzenesulphonylamino)-phenoxy]-2-methyl propionic acid comprising reacting 4-nitrophenol with ethyl 2-bromo-2-methylpropionate, hydrogenating the resulting ethyl ester to convert the 4-nitro group to a 4-amino group, reacting the resulting ethyl ester with 4-chlorobenzene-sulpho chloride and hydrolyzing the thus obtained ethyl ester to produce the free acid.

48. A process according to claim 1 e), for preparing 2-[4-(4-chlorostyrenesulphonylamino)-phenoxy]-2-methyl propionic acid comprising reacting ?-chlorostyrenesulphonyl chloride with ethyl 2-(4-aminophenoxy)-2-methylpropionate, and hydrolyzing the thus obtained ethyl ester to produce the free acid.

49. A process according to claim 1 e), for preparing 2-{4-[2-(4-chlorostyrenesulphonylamino)-ethyl]-phenoxy}-2-methyl propionic acid comprising reacting 4-(2-nitroethyl)-phenol with bromo-2-methyl-propionate, hydrogenating the resulting ethyl ester to convert the 2-nitro-ethyl group to a 2-amino ethyl group, reacting the resulting ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methyl propionate with ?-chloro-styrenesulphonyl chloride and hydrolyzing the resulting ethyl ester to obtain the free acid.

50. A process according to claim 1 e), for preparing 2-{4-{2-[2-(4-chlorophenyl)-ethanesulphonylamino]-ethyl}-phenoxy} -2-methylpropionic acid comprising reacting 4-(2-nitro-ethyl)-phenol with bromo-2-methyl-propionate, hydrogenating the resulting compound at the nitro group, reacting the resulting ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate with 2-(4-chlorophenol)-ethanesulphonyl chloride, and hydrolyzing the resulting ethyl ester to obtain the free acid.

51. A process according to claim 3, for preparing 2-{4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-phenoxy)-?-hexanoic acid comprising reacting 4-(2-acetamino-ethyl)-phenol with ethyl 2-bromohexanoate, removing the protective acetyl group on amino and converting the ethyl ester to the free acid, and reacting the free acid with 4-chlorobenzenesulphonyl chloride.

52. A phenoxyalkylcarboxylic acid derivative of the formula (I):- (I) in which R is an hydrogen atom or a lower alkyl of 1 to 6 carbon atoms, R1 is an alkyl of 1 to 16 carbon atoms, or an aryl of 6 to 14 carbon atoms, aralkyl in which the aryl moiety contains 6 to 14 carbon atoms and the alkyl moiety contains 1 to 5 carbon atoms, or aralkenyl in which the aryl moiety contains 6 to 14 carbon atoms and the alkenyl moiety contains 2 or 3 carbon atoms, the aryl moiety of said aryl, aralkyl or aralkenyl being unsubstituted or substituted one or more times by halogen, hydroxyl, trifluoromethyl, lower alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, or aliphatic acyl of up to 5 carbon atoms, R2 and R3, which may be the same or different, are hydrogen atoms or lower alkyl of 1 to 6 carbon atoms and n is 0, 1, 2 or 3; and of the pharmaceutically acceptable, physiologically compatible salts, esters and amides thereof, whenever prepared by the process of claim 1, 2 or 3, or by an obvious chemical equivalent.

53. A pharmaceutically acceptable,physiologically com-patible salt of a derivative of formula (I) as defined in claim 1, with a non-toxic inorganic or organic base, whenever prepared by the process of claim 11, or by an obvious chemical equivalent.

54. 4-[2-(benzenesulphonylamino)-ethyl]-phenoxy acetic acid, whenever prepared by the process of claim 14, 15 or 16, or by an obvious chemical equivalent.

55. Isopropyl 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetate, whenever prepared by the process of claim 17, or by an obvious chemical equivalent.

56. 4-[2-(4-Methoxybenzenesulphonylamino)-ethyl]-phenoxyacetic acid, whenever prepared by the process of claim 18, or by an obvious chemical equivalent.

57. 4-[2-(4-Fluorobenzenesulphonylamino)-ethyl]-phenoxy-acetic acid, whenever prepared by the process of claim 19, or by an obvious chemical equivalent.

58. The sodium salt of 4-[2-(4-fluorobenzenesulphonyl-amino)-ethyl]-phenoxyacetic acid, whenever prepared by the process of claim 20, or by an obvious chemical equivalent.

59. 4-t2-(methanesulphonylamino)-ethyl]-phenoxyacetic acid, whenever prepared by the process of claim 21, or by an obvious chemical equivalent.

60. 4-[2-(?-toluenesulphonylamino)-ethyl]-phenoxy-acetic acid, whenever prepared by the process of claim 22, or by an obvious chemical equivalent.

61. 4-[2-(1-naphthalenesulphonylamino)-ethyl]-phenoxy-acetic acid, whenever prepared by the process of claim 23, or by an obvious chemical equivalent.

62. 4-[2-(styrenesulphonylamino)-ethyl]-phenoxyacetic acid, whenever prepared by the process of claim 24, or by an obvious chemical equivalent.

63. 4-[2-(4-chlorostyrenesulphonylamino)-ethyl]-phenoxxy-acetic acid, whenever prepared by the process of claim 25, or by an obvious chemical equivalent.

64. 4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-phenoxy-acetic acid, whenever prepared by the process of claim 26, or by an obvious chemical equivalent.

65. 4-(Benzenesulphonylaminomethyl)-phenoxyacetic acid, whenever prepared by the process of claim 27, or by an obvious chemical equivalent.

66. 4-(Benzenesulphonylamino)-phenoxyacetic acid, when-ever prepared by the process of claim 28, or by an obvious chemical equivalent.

67. 2-{4-[2-(4-Chlorobenzenesulphonylamino)-ethyl]-phenoxy}-2-methylpropionic acid, whenever prepared by the process of claim 29, or by an obvious chemical equivalent.

68. 2-{4-[2-(benzenesulphonylamino)-ethyl]-phenoxy}-2-methylpropionic acid, whenever prepared by the process of claim 30 or 46, or by an obvious chemical equivalent.

69. 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetamide, whenever prepared by the process of claim 31, or by an obvious chemical equivalent.

70. 4-[2-(benzenesulphonylamino)-ethyl]-phenoxy-acetanilide, whenever prepared by the process of claim 32, or by an obvious chemical equivalent.

71. 4-[2-(Benzenesulphonylamino)-ethyl]-phenoxyacetic acid 2-ethoxycarbonylethylamide, whenever prepared by the process of claim 33, or by an obvious chemical equivalent.

72. 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetic acid 2-carboxyethylamide, whenever prepared by the process of claim 34, or by an obvious chemical equivalent.

73. 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetic acid 4-carboxyanilide, whenever prepared by the process of claim 35, or by an obvious chemical equivalent.

74. 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetic acid 4-(carboxymethyleneoxy)-phenethylamide, whenever pre-pared by the process of claim 36, or by an obvious chemical equivalent.

75. 4-[2-(?-Octanesulphonylamino)-ethyl]-phenoxy-acetic acid, whenever prepared by the process of claim 37, or by an obvious chemical equivalent.

76. 4-[2-(?-Hexadecanesulphonylamido)-ethyl]-phenoxyacetic acid, whenever prepared by the process of claim 38, or by an obvious chemical equivalent,

77. 4-[2-(2-phenylethanesulphonylamino)-ethyl]-phenoxy-acetic acid, whenever prepared by the process of claim 39, or by an obvious chemical equivalent.

78. 4-{2-[2-(4-chlorophenyl)-ethanesulphonylamino]-ethyl}-phenoxyacetic acid, whenever prepared by the process of claim 40, or by an obvious chemical equivalent.

79. 4-[2-(4-acetylbenzenesulphonylamino)-ethyl]-phen acetic acid, whenever prepared by the process of claim 41, or by an obvious chemical equivalent.

80. 4-[2-(Benzenesulphonylamino)-ethyl]-phenoxyacetic acid 1-hydroxy-2-propylamide, whenever prepared by the process of claim 42, or by an obvious chemical equivalent.

81. 4-[2-(N-methylbenzenesulphonylamino)-ethyl]-phenoxy-acetic acid, whenever prepared by the process of claim 43 or 44, or by an obvious chemical equivalent.

82. 4-[3-(Benzenesulphonylamino)-propyl]-phenoxyacetic acid, whenever prepared by the process of claim 45, or by an obvious chemical equivalent.

83. 2{4-[2-(benzenesulphonylamino)-ethyl]-phenoxy}-2-methylpropionic acid, whenever prepared by the process of claim 46 or by an obvious chemical equivalent.

84. 2-[4-(4-chlorobenzenesulphonylamino)-phenoxy]-2-methyl propionic acid, whenever prepared by the process of claim 47, or by an obvious chemical equivalent.

85. 2-[4-(4-chlorostyrenesulphonylamino)-phenoxy]-2-methyl propionic acid, whenever prepared by the process of claim 48, or by an obvious chemical equivalent.

86. 2-{4-[2-(4-chlorostyrenesulphonylamino)-ethyl]-phenoxy}-2-methyl propionic acid, whenever prepared by the process of claim 49, or by an obvious chemical equivalent.

87. 2-{4-{2-[2-(4-chlorophenyl)-ethanesulphonylamino]-ethyl}- phenoxy}-2-methylpropionic acid, whenever prepared by the process of claim 50 or by an obvious chemical equivalent.

88. 2-{4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-phenoxy}-n-hexanoic acid, whenever prepared by the process of claim 51, or by an obvious chemical equivalent.