DD263287A5 - PROCESS FOR THE PREPARATION OF PHENOXYALKYLCARBONSAEUREDERIVATES - Google Patents

Abstract

Phenoxyalkylcarboxylic acid derivatives of the formula I <IMAGE> in which the sulfonylaminoalkyl group is in the ortho- or the meta-position to the phenoxyalkylcarboxylic acid group and in which R1 denotes an aryl group, aralkyl group or an aralkenyl group whose aryl radical can in each case be optionally mono- or polysubstituted by halogen, cyano, alkyl, trifluoromethyl, alkoxy, hydroxyl, nitro, amino, alkylamino, dialkylamino, acylamino, acyl, azido or can be substituted by phenyl which is optionally substituted by halogen, cyano, alkyl, trifluoromethyl or alkoxy, R2 represents hydrogen, an alkyl group, aralkyl group or an acyl group, R3 and R4, which can be identical or different, denote hydrogen or a lower alkyl group and n denotes the numbers 1-3, and their physiologically acceptable salts, esters and amides have platelet aggregation-inhibiting and/or hypolipidaemic action.

Description

3 0-C-COOH

B ¹ ₃ 0- _H (0H) - ^^ ^

in which the sulfonylaminoalkyl group is ortho or meta to the Phenoxyälkylcarbonsäure group and in which.

Ri is an aryl, aralkyl or an aralkenyl group whose aryl radical is each optionally mono- or polysubstituted by halogen, cyano, alkyl, trifluoromethyl, alkoxy, hydroxyl, nitro, amino, alkylamino, dialkylamino, acyl, azido or optionally by halogen, cyano , Alkyl, trifluoromethyl or alkoxy-substituted phenyl may be substituted,

R _{2 represents} hydrogen, an alkylCralkyl or an acyl group,

R _{3 and} R 1 are the same or different, respectively; hydrogen is one lower alkyl group and η is the numbers 1-3

mean, as well as their physiologically acceptable salts, esters and amides.

The novel compounds of the general formula I show an excellent antagonistic action against thromboxane A ₂ as well as against prostaglandin endoperoxides. They inhibit aggregation of platelets and prevent smooth muscle constriction and bronchoconstriction.

These properties make them valuable remedies for treatment such. As cardiovascular diseases and asthma and for the prophylaxis of a shock lung. They can still be used in organ transplantation and kidney dialysis and are suitable to prevent relapses in gastric ulcers. Of particular importance is the possibility of favorably influencing or preventing thrombotic processes. They are suitable for the treatment of peripheral arterial occlusive diseases and z. B. against cerebral ischemic conditions. In addition, they are able to inhibit the Acetateinbau in cholesterol and are therefore also suitable for the treatment of lipid metabolism diseases.

The term "aryl radical", alone or in combination with an alkyl or alkylene chain, is to be understood in all cases to mean aromatic hydrocarbons having 6-14 C atoms, in particular the phenyl, the biphenylyl, the naphthyl and the fluorenyl radicals Aryl radicals may be monosubstituted or polysubstituted in all possible positions, where as substituents halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxyl, Trifluormethyi, cyanogen, nitro, amino, C ₁ -C ₆ alkylamino, C C ₁ -C ₁₂ dialkylamino, C ₁ -C ₆ acylamino, C ₁ -C ₆ acyl and azide are preferred, the phenyl radical represented by halogen, preferably chlorine and bromine, cyano, methyl, trifluoromethyl, 4-chlorophenyl and Acetyl may be substituted.

Among the alkyl and alkoxy substituents of the aryl, aralkyl and aralkenyl radicals, preference is given to radicals having 1-4 C atoms, in particular the methyl, ethyl, isobutyl and tert-butyl group and the methoxy group.

Suitable aralkyl radicals R ₁ or R ₂ are those whose straight-chain or branched alkylene moiety contains 1-5 carbon atoms. Preferred aralkyl radicals R ₁ or R ₂ are the benzyl, phenethyl and the 4-chloro-phenethyl radical. Aralkenyl radicals R ₁ are to be understood as those whose alkenylene moiety contains 2-3 carbon atoms. Here, preferred are the styryl radical and the 4-chloro-styryl radical.

By halogen is meant in all cases fluorine, chlorine and bromine.

Suitable alkyl groups R ₂ are straight-chain or branched with 1-16 C atoms, preference is given to the methyl and octyl groups.

The acyl radicals R _{2 are} derived from aliphatic carboxylic acids having 2-16 C atoms, araliphatic and aromatic carboxylic acids. Preferred acyl groups are acetyl, isobutyroyl, cinnamoyl, benzoyl, 4-chlorobenzoyl and 4-aminobenzoyl, as well as n-octanoyl and n-hexadecanoyl.

The lower alkyl groups R ₃ and R ₄ may be straight-chain or branched and contain 1-6, preferably 1-4, carbon atoms, the methyl and ethyl groups being preferred, η preferably being the number 2.

Suitable esters of the carboxylic acids of the general formula I are those with lower monohydric alcohols (such as, for example, methanol or ethanol) or with polyhydric alcohols (such as, for example, glycerol), but it is also possible to include alcohols which still have other properties contain functional group, such as. For example, ethanolamine.

The amides of the invention derived from the carboxylic acids of general formula I contain as amine component e.g. Ammonia, p-aminobenzoic acid, .beta.-alanine, ethanolamine and 2-amino-propanol, the ones mentioned so far being preferred. But there are also alkylamines such. As isopropylamine or tert-butylamine, dialkylamines such as diethylamine and cyclic amines such as. As morpholine or 4-alkyl or -Aralkyl- or -Arylpiperazine, z. For example, 4-methylpiperazine, 4- (4-chlorobenzyl) -piperazine or 4- (3-methoxy-phenyl) -piperazine in question.

The above definition of the compounds of the invention is intended to include all possible stereoisomers as well as their mixtures.

The preparation of the compound of the general formula I is characterized in that an amine of the general formula II

HN- (GH ₂ ) n-

in which R ₂ and η have the abovementioned meaning,

optionally with intermediate protection of the amino or hydroxyl group in a conventional manner in any order with a sulfonic acid of the general formula IM

R ₁ -SO ₂ OH (III),

in which R _{1 has} the meaning given above,

or a derivative thereof and with a compound of general formula IV, ^R 3 ι

X-C-Y. "(IV),

I.

implements.

In formula IV, R ₃ and R ₄ are as defined above, X represents a reactive group, and Y is the group -COOR ₅ (wherein R _{5 represents} a hydrogen atom or a lower alkyl group) or an acid amide group. Y can also represent a radical which is converted after condensation into a Säureamidgruppe or in the -COOR ₅ group, whereupon, if appropriate, a certain substituent R _{5 is converted} to the condensation in a conventional manner into another substituent R ₅ , and the compounds obtained are converted into pharmacologically acceptable salts, esters or amides.

In the event that R ₃ and R _{4 are} lower alkyl groups, the phenols of the general formula II or their reaction products with a sulfonic acid of the general formula III auch.mit a mixture of an aliphatic ketone, chloroform and an alkali metal hydroxide. Preferably, this variant is used for the preparation of isobutyric acid derivatives, acetone being used as the ketone (cf., for this, Gazz. Chim., Ita L77 [1947], page 431). The process according to the invention is advantageously carried out in two stages. The condensation of the compounds of the general formula II with sulfonic acids III or derivatives thereof on the one hand and .Verbindungen the general formula IV on the other hand is preferably carried out by first blocking one of the two reactive groups of the compound Ii with a readily cleavable protecting group, the compound obtained a sulfonic acid III or a derivative thereof or reacted with a compound of general formula IV, the protective group cleaved again and then reacting this reactive intermediate with the not yet used compound of the general formula IV or III. Preference is given to a process route in which the compound II protected by the amino group is first reacted with a compound IV. After cleavage of the protective group, the reaction then takes place with a sulfonic acid III or with one of its derivatives.

Instead of the free amines II you can also use their salts.

Another possibility for the preparation of compounds of general formula I, their salts and their esters and amides is that a sulfonamide of the general formula V

R ₁ -SO 2 -NH ¹² I (V),

with a compound of general formula Vl

(Vl)

H ₄

to the compound VII '

R ₃

R ₁ -SO ₂ -IT- (CH ₂ ) T- / Vc-CY

² I (VIl),

R '· ^R 4

implements.

The symbols R ₁ , R ₂ , X, n, R ₃ , R ₄ and Y used in formulas V, VI and VIl have the meanings given above.

A third possibility of synthesis consists in a Umacylierung:

Substituting a free sulfonic acid IM with a compound of general formula VIII

H, .

in which n, R ₂ , R ₃ , R ₄ and Y have the abovementioned meaning and Ac is an easily exchangeable acyl radical, in a suitable solvent to give, also gives a sulfonamide of the general formula VII.

In the event that R _{2 represents} an acyl radical, a fourth synthesis option is preferred:

A compound of the general formula I in which R _{2 represents} a hydrogen atom is reacted with a reactive derivative of a carboxylic acid, ζ. B. with an acid chloride, in a suitable solvent. Preference is given to a procedure in which the compound I (with R ₂ = H) brought in the form of an ester of Phenoxyc.arbonsäure for implementation

Suitable reactive derivatives of the sulfonic acids IM are in particular the halides and the esters in question. The reactions of the sulfonic acid halides with compounds of general formula II are advantageously carried out with the addition of an acid-binding agent, such as. As alkali metal acetate, sodium bicarbonate, sodium carbonate, sodium phosphate, calcium oxide, calcium carbonate or magnesium carbonate but this function can also organic bases such. Pyridine or triethylamine, using as inert solvent e.g. Ether, benzene, methylene chloride, dioxane or an excess of the tertiary amine is used.

When using inorganic acid binder is used as the reaction medium z. As water, aqueous ethanol or aqueous dioxane.

For an implementation of the compound II with the compound IV, it has been found to be advantageous, first the amino group of the compound II in a protected group, for. As the phthalimido group, which after the reaction z. B. can be easily split again with hydroxylamine in a conventional manner. There may also be others from peptide chemistry

introduced known groups for the protection of the amino group and cleaved again after the reaction. Preferably, the blocking of the amino group by an acyl group, such as the formyl-o'der the acetyl group, which after the reaction with strong bases, such as. As sodium hydroxide or potassium hydroxide, but also with aqueous mineral acids, such as. As hydrochloric acid, can be easily split off again.

As the reactive compound IV is in particular that in question in which X is the anion of a strong acid, eg. B. represents a hydrogen halide or sulfonic acid. The reaction can be further promoted by reacting the phenolic hydroxyl group of the compound II e.g. converted into a phenolate by reaction with sodium alcoholate. The reaction of the two components is carried out in solvents such. Toluene or xylene, methyl ethyl ketone or dimethylformamide,

preferably carried out in the heat.

For the alkylation of the sulfonic acid amides V, preference is given to using compounds VI in which X represents an arylsulfonyloxy group. X is preferably a toluenesulfonyloxy group. As alkylating so preferably Arylsulfonsäurealkylester, a method that in their application to sulfonic acid amides z. For example, in Klamann et al., Monatshefte fur Chemie Bd.83 (1952), p 871 described. The reactions are carried out in an alkaline medium, preferred as the reaction medium is hot, concentrated sodium carbonate solution.

The umacylation reaction between a free sulfonic acid III and an acylamine VIII is carried out using preferably equimolar amounts of both reactants in a polar solvent. As such polar solvents serve z. As alcohols, especially ethanol and methanol. The reaction preferably proceeds at the boiling point of these solvents. As an easily replaceable acyl radical is z. B. to call the acetyl radical.

Suitable substituents Y of the general formula IV which can be converted into the -COOR ₅ group are, for example, the nitrile, carbaldehyde, hydroxymethyl, aminomethyl and formyl groups.

The optionally subsequent N-alkylation of a compound of the general formula I in which R ₂ = hydrogen can be carried out by known methods, preferably by reacting a compound with R ₂ = hydrogen with an alkyl halide or a dialkyl sulfate in the presence of an acid-binding agent, such as z. B.

Sodium hydroxide, reacted.

The introduction of an acyl group R ₂ into a sulfonamide of the general formula I (R ₂ = H) takes place under conditions which are customary for the acylation of amines: reaction with an active carboxylic acid derivative, eg. An acid halide, a mixed anhydride or an active ester, in an inert solvent in the presence of bases. Suitable inert solvents include, for example, methylene chloride, benzene, dimethylformamide and the like.

The conversion of the substituent R _{5 to be} carried out optionally after the condensation takes place, for example, by saponification of the carboxylic acid esters (R ₅ = alkyl) to the corresponding carboxylic acids (R ₅ = hydrogen) with mineral acids or alkali hydroxides in a polar solvent (such as water, methanol, ethanol, Dioxane or acetone).

Advantageously, the saponification is carried out with a strong base (such as sodium or potassium hydroxide) in a mixture of methanol and water at room temperature or at moderately elevated temperatures. Conversely, however, it is also possible to esterify the carboxylic acids in the customary manner or to convert esters with a certain R ₅ residue by transesterification into an ester with another R ₅ residue. The esterification of the carboxylic acids is useful in the presence of an acidic catalyst, such as

z. As hydrogen chloride, sulfuric acid, p-toluenesulfonic acid or a strong acid ion exchange resin made.

Transesterification, on the other hand, requires the addition of a small amount of a basic substance, e.g. an alkali or alkaline earth metal hydroxide or an alkali metal alkoxide. For the esterification of the carboxyl group or for a transesterification in principle all alcohols are suitable. Preferably, the lower monohydric alcohols such as methanol, ethanol or propanol, and polyhydric alcohols, eg. As glycol, or alcohols with other functional groups, such as ethanolamine or glycol ethers.

The amides of the invention derived from the carboxylic acids of the general formula I are preferably prepared by methods known per se from the carboxylic acids or their reactive derivatives (such as, for example, carboxylic acid halides, esters, azides, anhydrides or mixed anhydrides) by reaction with amines manufactured. As amino components come z. B.

Ammonia, alkylamines, dialkylamines, but also amino alcohols such. For example, ethanolamine and 2-aminopropanol and amino acids such. As p-aminobenzoic acid, ß-alanine and others in question. Other valuable amine components are alkyl, aralkyl and arylpiperazines.

For the preparation of salts with pharmacologically acceptable organic or inorganic bases, such as. B.

Sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine or ethanolamine, the carboxylic acids can be reacted with the corresponding bases. It is also possible to use mixtures of the carboxylic acids with a suitable alkali metal carbonate or bicarbonate.

For the preparation of medicaments, the compounds of general formula I are mixed in a conventional manner with suitable pharmaceutical excipients, flavoring, flavoring and coloring agents and shaped, for example, as tablets or dragees or with the addition of appropriate auxiliaries in water or oil, such as. As olive oil, suspended or dissolved.

The substances of general formula I can be administered orally and parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the stabilizing agents, solubilizers and / or buffers customary in injection solutions. Such additives are z. B. tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitol anhydrides.

Solid carriers are z. As starch, lactose, mannitol, methylcellulose, talc, fumed silica, higher molecular weight fatty acids (such as stearic acid) gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular weight polymers (such as polyethylene glycols). If desired, preparations suitable for oral administration may contain flavorings and sweeteners.

The dosage administered will depend on the age, the health and weight of the recipient, the extent of the disease, the type of concurrent other treatments that may be performed, the frequency of treatments, and the nature of the effect desired. Usually, the daily dose of the active compound is 0.1 to 50 mg / kg of body weight.

Normally, 0.5 to 40 and preferably 1.0 to 20 mg / kg / day are effective in one or more applications per day to obtain the desired results.

The following examples show some of the numerous process variants that can be used to synthesize the compounds of this invention. However, they are not intended to be limiting of the subject invention.

For example, 3- [2- (4-chloro-phenylsulfonylamino) ethyl] phenoxyacetic acid

a) 3- [2- (Aceiamino) ethyl] phenol

To a solution of 27.2 g (157 mmol) of 3-hydroxy-phenethylamine, 280m! Methylene chloride and 47.6 g (479 mmol) of triethylamine are added dropwise with cooling (ice bath) a solution of 24.6 g (313 mmol) of acetyl chloride and 30 ml of methylene chloride. The mixture is then stirred for one hour at room temperature, extracted with 2 N-HGI, water and NaHCO ₃ solution, dried with sodium sulfate and evaporated. The oily residue is mixed with 156 ml of 2 N NaOH and 320 ml of methanol and the mixture is heated to 40 ° C. under nitrogen for two hours. Then methanol is distilled off, treated with activated charcoal and acidified in the cold mitkonz. Hydrochloric acid on. The product is then extracted with methylene chloride, to which a little acetone has been added, the methylene chloride phase is dried with Na ₂ SO ₄ and evaporated. The oily crude product (yield 23.3 g, 83% of theory) is further processed without further purification.

b) Ethyl 3- [2- (acetamino) ethyl] phenoxyacetate

A mixture of 23.3 g (130 mmol) of 3- [2- (acetamino) ethyl] phenol, 230 mL of butanone, 26.1 g (156 mmol) of ethyl bromoacetate and 25.7 g (186 mmol) of powder K ₂ CO ₃ sicc , is held at reflux temperature for 8 hours, then sucked off hot and washed with butanone after. After evaporation, the product crystallizes out. It is rubbed with ligroin, filtered off and purified by digestion with ligroin. Y. 30.7 g (89% of theory), mp. 82-83 ° C.

c) 3- (2-aminoethyl) phenoxyacetic acid

A mixture of 23.6 g (89 mmol) of 3- [2- (acetamino) ethyl] -phenoxyessigsäureethy! Ester and 200 ml of 3N-HCl is maintained for 6 hours at reflux temperature, then adding activated charcoal and filtered off with suction. After adding 50 ml of cone. HCl is allowed to stand for a long time in the cold, filtered off, washed with cold 2 N HCl and dried over potassium hydroxide. Yield 12.0 g (58% of theory) of hydrochloride, mp. 216-217 ° C.

d) Ethyl 3- (2-aminoethyl) phenoxyacetate

A mixture of 10.7 g (46 mmol) of 3- (2-aminoethyl) phenoxyacetic acid, 100 ml of absolute ethanol and a spatula tip of p-toluenesulfonic acid is kept for three hours at reflux temperature, then it is strongly cooled and sucks off the precipitated crystals. After recrystallization from ethanol gives 8.3 g (69% of theory) of hydrochloride; mp. 119-120 ⁰ C.

e) Ethyl 3- [2- (4-chloro-phenylsulphonylamino) ethyl] phenoxyacetate

To a mixture of 8.3 g (32 mmol) of 3- (2-aminoethyl) phenoxyessigsäureethylester hydrochloride and 8.0 g (66 mmol) of triethylamine are added at 0 ⁰ C with stirring 6.6 g (32 mmol) of 4-chlorobenzenesulfonyl chloride and stirring more three hours at ⁰ ° C, then 4 hours at room temperature. After that is mitverd. Hydrochloric acid and water, dried with sodium sulfate and finally evaporated. After recrystallization from a toluene-heptane mixture, 10.4 g (82% of theory) of substance with the mp. 65-66 ° C.

f) 3- [2- (4-chloro-phenylsulfonylamino) ethyl] phenoxyacetic acid

A mixture of 6.2 g (15.6 mmol) of ethyl ester, 40 ml of 2N NaOH and 40 ml of ethanol is stirred for three hours at 60 ⁰ C, then the ethanol is evaporated in vac. Extracts the alkaline solution with ether and then drops by adding cone. HCI the acid. It is suctioned off, washed with water and recrystallized from 50% aqueous ethanol. Yield 5.1 g (88% of theory), mp. 119-12O ⁰ C.

In an analogous manner, obtained from 3- (2-aminoethyl) phenoxyacetic acid ethyl ester hydrochloride and

a) 4-Bromo-benzenesulfonylchloride:

3- [2- (4-Bromo-phenylsulfonylamino) ethyl] -phenoxy-acetic acid ethyl ester. 94% of theory, mp. 76-77 ° C (heptane + toluene)

and it

3- [2- (4-Bromo-phenylsulfonylamino) ethyl] -phenoxyacetic acid. Yield 97% of theory, mp 125-126 ° C. (aqueous ethanol).

b) 4-Cyano-benzenesulfonyl chloride:

Ethyl 3- [2- (4-cyano-phenylsulphonylamino) ethyl] phenoxyacetate Rohausb .: quantitative, color of oil.

and it

3- [2- (4-Cyano-phenylsulfonylamino) ethyl] phenoxyacetic acid. 81% of theory, mp, 136-137 ° C. (aqueous ethanol)

c) 3-chlorobenzenesulfochloride:

Ethyl 3- [2- (3-chloro-phenylsulphonylamino) ethyl] phenoxyacetate Rohausb. quantitatively. Colorless oil.

and it

3- [2- (3-chloro-phenylsulfonylamino) ethyl] phenoxy-acetic acid. 87% of theory, mp. 1-17-118 ⁰ C (aq. Ethanol).

d) 2-methyl-benzenesulfonyl chloride:

Ethyl 3- [2- (2-methylphenylsulfonylamino) ethyl] phenoxyacetate Est. 96% of theory, color of oil.

and it

3- [2- (2-methylphenylsulfonylamino) ethyl] phenoxyacetic acid. 91% of theory, mp. 116-117 ° C (aqueous ethanol).

e) 3-trifluoromethyl-benzenesulfonyl chloride:

Ethyl 3- [2- (3-trifluoromethyl-phenylsulfonylamino) ethyl] phenoxyacetate *

Y. 92% of theory, colorless oil.

and it

3- [2- (3-trifluoromethyl-phenylsulfonylamino) ethyl] phenoxyacetic acid. 95% of theory, mp. 114-115 ⁰ C (aq. Ethanol).

f) 4- (4-chlorophenyl) -benzenesulfochloride:

3- [2- (4- (4-chlorophenyl) phenylsulfonylamino) ethyl] phenoxyacetic acid ethyl ester. 87% of theory, mp. 93-94 ° C (ethanol)

and it

S-SS-W-W-ChlorphenyDphenylsulfonylaminolethyllphenoxyessigsäure ethyl ester

Y. 86% of theory, mp. 147-148 ° C (glacial acetic acid), g) 3-methyl-1-benzenesulfonyl chloride:

3- [2- (3-methyl-phenylsulfonylamino) ethyl] phenoxyessigsäureethylester

Yield 60% of theory, color of oil

and it

3- [2- (3-methyl-phenylsulfonylamino) ethyl] phenoxyacetic acid

Y. 79% of theory, mp 131-132 ° C (ether) h) 4-methyl-benzenesulfonychloride:

3- [2- {4-methyl-phenylsulfonylamino) ethyl] phenoxyessigsäureethylester

Y. 92% of theory, color oil.

and it

3- [2- (4-methyl-phenylsulfonylamino) ethyl] phenoxyacetic acid

Y. 82.% of theory, mp 119-12O ⁰ C (aqueous ethanol), i) 2-chloro-benzenesulfonyl chloride:

3- [2- (2-chloro-phenylsulfonylamino) ethyl] phenoxyessigsäureethylester

90% of theory, color of oil

and it

3- [2- (2-chloro-phenylsulfonylamino) ethyl] phenoxyacetic acid

Yield: 78% of theory, mp 137-138 ° C. (ligroin) k) 3-bromo-benzenesulfonyl chloride:

3- [2- (3-Bromo-phenylsulfonylamino) ethyl] phenoxyessigsäureethylester

Yield 97% of theory, color of oil

and it

3- [2- (3-Bromo-phenylsulfonylamino) ethyl] phenoxyacetic acid

Ausb.60% of theory, mp 122-123 ⁰ C (ether) I) 2.3-dichloro-benzolsuifonylchlorid.:

3- [2- (2,3-dichloro-phenylsulfonylamino) ethyl] phenoxyessigsäureethylester

65% of theory, color of oil and from it

3- [2- (2,3-dichloro-phenylsulfonylamino) ethyl] phenoxyacetic acid

Ausb.45% of theory, mp 141-142 ⁰ C (ligroin and ether), m) 3,4-dichloro-benzenesulfonyl chloride.:

S-ß-fSADichloro-phenylsulfonylaminotethyllphenoxyessigsäureethyJester Ausb.96% of theory, m.p.65-67X (aqueous ethanol)

and it

3- [2- (3,4-dichloro-phenylsulfonylamino) ethyl] phenoxyacetic acid

Yield 97% of theory, mp 143-144 ° C. (aqueous ethanol).

Example 2 3- [2- (Phenylsulfonylamino) ethyl] phenoxyacetic acid

A mixture of 11.6 g (50 mmol) of 3- (2-aminoethyl) phenacetic acid hydrochloride, 200 ml of water and 60 mmol of potassium carbonate is heated to 80 ° C. and at this temperature is slowly added with stirring 8.83 g (BO mmol) of benzenesulfonyl chloride. Thereafter, the mixture is stirred at 80 ⁰ C for a further two hours, then cooled and brought to pH 2 by means of hydrochloric acid. After standing in the cold, it is filtered off with suction, washed with ice-cold water, dried and recrystallized from an ethyl acetate-ligroin mixture. Y. 12.4 g (75% of theory), mp. 78-79 ° C.

Example 3 2- [2- (4-Chloro-phenylsulfonylamino) ethyl] phenoxyacetic acid

a) 2- [2- (acetamino) ethyl] phenol

A solution of 58 g (0.214 mmol) of o-hydroxyphenethylamine hydrobromide and 500 ml of dry pyridine is added dropwise, with stirring and ice-cooling, with 37 g (0.47 mol) of acetyl chloride. Then stir for three hours and pour on ice. The mixture is mixed with cone. Ammonia made alkaline and extracted with methylene chloride. The combined organic extracts are dried and evaporated. The residue is triturated with ligroin. Y. 30.9 g (81% of theory), mp 133-136 ° C

b) 2- [2- (acetamino) ethyl] phenoxyacetic acid, ethyl ester

24.7 g (138 mmol) of 2- [2- (acetamino) ethyl] phenol are heated at reflux with stirring for 24 hours with 38.1 g (0.276 mol) of potassium carbonate, 34.6 g (0.207 mol) of ethyl bromoacetate and 500 ml of butanone. Then the organic precipitate is filtered off and the filtrate is evaporated. The residue is taken up in methylene chloride, the solution is washed with 2N sodium hydroxide solution, dried and evaporated. Y. 31.7 g (87% of theory), colorless oil

c) 2- (2-aminoethyl) phenoxyacetic acid

A mixture of 39.5 g (148 mmol) of 2- [2- (acetamino) ethyl] phenoxyacetic acid ethyl ester, 82.9 g (1.48 mol) of caustic potash, 195 ml of ethanol and 160 ml of water are heated to reflux with stirring for 48 hours. After cooling, with cone. Hydrochloric acid to pH 5 and filtered off the precipitated potassium chloride. The fitrate is evaporated. The residue obtained is 33.2 g of hydrochloride as crude product which contains some potassium chloride.

d) ethyl 2- (2-aminoethyl) phenoxyacetate

23.4 g of the aforementioned crude product are abs. In 100 ml. Ethanol and saturated with hydrogen chloride while cooling with ice. Then the mixture is allowed to stand overnight at room temperature and then heated for one hour at reflux temperature. Then it is evaporated, the residue is taken up in water and the resulting solution is clarified with charcoal. The filtrate is evaporated and the anhydrous residue with abs. Ethanol stirred. The insoluble potassium chloride is filtered off and the filtrate is evaporated. The residue is crystallized by evaporation with a mixture of ether and acetone. This gives 23.6 g (87% of theory) of hydrochloride, mp. 76-79 ⁰ C.

-Β- £ UO Ä.O /

e) 2- [2- (4-chloro-phenylsulphonylamino) ethyl] phenoxyacetic acid ethyl ester

A mixture of 2.59 g (10 mmol) of ethyl 2- (2-aminoethyl) phenoxyacetate hydrochloride, 3.0 g (30 mmol) of triethylamine and 30 ml of methylene chloride is added with stirring at 0 to 5 ° C. with 2.11 g (10 mmol). Chlorbenzolsulfochlorid. Then remove the cooling bath and stirred for 3 hours at room temperature. Subsequently, coal is added to filter the precipitated triethylamine hydrochloride. The filtrate is washed first with 0.5N hydrochloric acid, then with 0.5 N sodium hydroxide solution and water, dried and evaporated. 4.0 g (quant. Yield) of the desired compound are obtained as the residue as a colorless oil.

f) 2- [2- (4-chloro-phenylsulphonylamino) ethyl] phenoxyacetic acid

4.0 g (10 mmol) of the ester obtained according to e) are dissolved in 50 ml of methanol and treated while stirring with 30 ml of 1 N potassium hydroxide. The mixture is stirred for 16 hours at 5O ⁰ C and then distilled in vac. the methanol from. The residue obtained aq. Solution is first washed with ether, then clarified with charcoal and finally acidified with dilute hydrochloric acid. The separated oil is extracted with methylene chloride. The combined extracts are clarified with charcoal, dried and evaporated. The residue obtained is a colorless oil which crystallizes after trituration with ligroin. Y. 2.0 g (54% of theory), mp 113-115 ° C

In an analogous manner you get out

2- (2-aminoethyl) phenoxyacetic acid ethyl ester and

a) p-toluenesulfonyl chloride:

2- [2- (4-Methylphenylsulfonylamino) ethyl] phenoxyacetic acid ethyl ester. quantitatively, colorless oil

and it

2- [2- (4-methylphenylsulfonylamino) ethyl] phenoxyacetic acid. 51% of theory, mp 120-122 ⁰ C

b) 4-methoxybenzenesulfonyl chloride:

2- [2- (4-methoxy-phenylsulfonylamino) ethyl] -phenoxyacetic acid ethyl ester. qantitative, color oil

and it

2- [2- (4-methoxyphenylsulfonylamino) ethyl] phenoxyacetic acid. 56% of theory, mp 131-133 ° C

Example 4 2- [2- (Phenylsulfonyiamino) ethyl] phenoxyessicylic acid

A solution of 17.5 g (68 mmol) of ethyl 2- (2-aminoethyl) phenoxyacetate hydrochloride and 200 ml of pyridine is added with stirring at 0-5 ° C. to 12.5 g (71 mmol) of benzenesulfonyl chloride. Then the cooling bath is removed and stirred first for 4 hours at room temperature, then for 6 hours at 60 ° C. It is then poured onto ice, the aqueous mixture is acidified and extracted with methylene chloride. The extracts are dried and evaporated. 18.6 g (76% of theory) of ethyl 2- [2- (phenylsulfonylamino) ethyl] phenoxyacetate are obtained as the residue as a colorless oil.

A mixture of 13.6 g (37mmol) of this ester, 100 ml of 1 N potassium hydroxide solution and 150 ml of methanol is stirred for 16 hours at 60 ⁰ C. The methanol is then distilled off in vacuo and acidified to the aqueous residue. This gives 8.6 g (69% of theory) of the title compound of mp. 130-133 ° C.

Example 5 3- [2- (N-Methyl-3-chloro-phenylsulfonylamino) ethyl] phenoxyacetic acid

A mixture of 8.0 g (20.1 mmol / l) of fS-chloro-phenylsulfonylaminoiethyllphenoxyacetic acid ethyl ester, 100 ml of absolute ethanol and 20.1 mmol of sodium methylate is evaporated to dryness, the residue is dissolved in 50 ml of absolute DMF and 2, 85g (20.1 mmol) of methyl iodide. After 3 hrs. stirring at 8O ⁰ C is cooled, stirred into water and extracted with methylene chloride. the organic phase with Na ₂ SO ₄ is dried, evaporated and chromatographed on a silica gel column by means of methylene chloride-methanol (99: 1 v / v), yield 7.5 g (91% of theory) of ethyl 3- [2- (N-methyl-3-chlorophenylsulphonylamino) ethyl] phenoxyacetate colorless oil ,

The saponification of this ester to the carboxylic acid is carried out in analogy to Example 1 f. Y. 90% of theory, mp 138-139 ° C (ethanol + water 2: 1) In an analogous manner is obtained from

3- [2- (3-chloro-phenylsulfonyiamino) ethyl] phenoxyacetic acid ethyl ester and benzyl chloride:

a) 3- [2- (N-benzyl-3-chloro-phenylsulphonylamino) ethyl [-phenoxyacetic acid ethyl ester. 90% of theory, colorless oil

and it

3- [2- (N-benzyl-3-chloro-phenylsulfonylamino) ethyl] phenoxyacetic acid

Y. 85% of theory, mp 134-135 ° C (ethanol + water 2: 1VoI.)

and from

3- [2- (4-Chloro-phenylsulfonyl-amine) -ethyl] -phenoxyacetic acid-ethyl ester and n-octyl chloride:

b) 3- [2- (N- (n-octyl) -4-chloro-phenylsulphonylamino) ethyl] phenoxyacetic acid ethyl ester. 69% of theory, colorless oil

and it

3- [2- (N- (n-octyl) -4-chloro-phenylsulfonylamino) ethyl] phenoxyacetic acid. 98% of theory, mp 68-69 ° C (ethanol + water 2: 1 vol.)

Example 6 3- [2- (N-Acetyl-3-chloro-phenylsulfonyl-amine) -ethyl] -phenoxy-acetic acid ethyl ester 3r To an ice-cold mixture of 8.0 g (20.1 mmol) of 3- [2- (3-chloro-phenylsulfonylamino ethyl ethyl] phenoxyacetate, 100 ml of methylene chloride and 3.1 g (30.2 mmol) of triethylamine are added dropwise within 15 min to a solution of 1.58 g (20.1 mmol).

-a £ oo e.01

Acetyl chloride and 50 ml of methylene chloride. The mixture is then stirred for two hours at room temperature, then extracted with 2 N HCl and water and dried by means of Na ₂ SO ₄ . Chromatography on a silica gel column using methylene chloride gives 4.95 g (63% of theory) of ester in the form of a colorless oil. In an analogous manner is obtained from 3- [2- (4-chloro-phenylsulfonylamino) ethyl] phenoxyessigsäureethylesterund

a) n-Octanoyl chloride:

3- [2- (N- (n-Octanoyl) -4-chloro-phenylsulphonylamino) ethyl] -phenoxyacetic acid ethyl ester. 67% of theory, colorless oil

b) n-hexadecanoyl chloride:

3- [2- (N-n-hexacecanoyl) -4-chloro-phenylsulfonylamino) ethyl] phenoxyacetic acid ethyl ester. 71% of theory, colorless oil

Claims (1)

in which the sulfonylaminoalkyl group is ortho or meta to the phenoxyalkylcarboxylic acid group and in which R _{1 is} an aryl, aralkyl or an araikenyl group whose aryl radical is in each case optionally mono- or polysubstituted by halogen, cyano, alkyl, trifluoromethyl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, acylamino, acyl, azido or optionally substituted by halogen, cyano, alkyl, trifluoromethyl or alkoxy substituted phenyl, R _{2 represents} hydrogen, an alkyl, aralkyl or an acyl group, R ₃ and R ₄ , which may be the same or different, are hydrogen or a lower alkyl group and η the numbers 1-3 mean, as well as their physiologically acceptable salts, esters and amides, thereby characterized in that a) an amine general formula II in which R ₂ and η have the abovementioned meaning, optionally with intermediate protection of the amino or hydroxyl group in a conventional manner in any order with a sulfonic acid of the general formula III R ₁ -SO ₂ OH (III), in which R _{1 has} the meaning given above, or a derivative thereof and with a compound of general formula IV X-C-Y (IV), implements, in which R ₃ and R _{4 have} the abovementioned meaning, and X represents a reactive group and Y is the-C 00 R ₅ , in which R _{5 is} hydrogen or a lower alkyl group, or Y represents an acid amido group or a residue which, after condensation has taken place is converted into an acid amido group or into the COOR ₅ group, or b) a sulfonamide of the general formula V _{(v) f} R ₂ in which R ₁ and R _{2 have} the abovementioned meanings, with a compound of the general formula Vl E ₃ OGY in which, X, Y, R ₃ and R _{4 have} the abovementioned meanings, to the compound VII (VII) in which n, R ₁ , R ₂ , R ₃ , R ₄ and Y have the abovementioned meanings, then optionally compounds of the general formula I with R = hydrogen by known methods N-alkylated or N-acylated and optionally the obtained Acid derivatives of the general formula I in the free acid or, if desired, the resulting free acid of the general formula I esterified, converted into an amide or into physiologically acceptable salts. 2. Use of the compounds according to claim 1, characterized in that they are used for the preparation of medicaments with antiplatelet and / or lipid-lowering effect. , Field of application of the invention The present invention relates to a process for the preparation of phenoxyalkylcarboxylic acids substituted on the phenyl in the 2- and 3-position, which can be used as active ingredient in medicaments. Characteristic of the known state of the art In DE-OS 2809377 Phenoxyalkylcarbonsäuren with lipidsenkender and the platelet aggregation inhibitory effect are described, which are substituted in the 4-position. Object of the invention The aim of the invention is the search for new compounds with improved pharmacological properties. Presentation of the essence of the invention - - It has now surprisingly been found that the 2- or 3-substituted phenoxyalkylcarboxylic acid derivatives also show a lipid-lowering and thromboxane A ₂ -antagonistic action. The present invention therefore relates to a process for preparing new Sulfonylphenylalkylamine the general formula I.