DE2012327A1 - Anti-inflammatory alpha-aminophenyl carboxylic acids - Google Patents

Abstract

Preparation of alpha(-aminophenyl) carboxylic acids having the formula: (in which R represents an opt. functionally modified carboxylic acid group, R1 is H lower alkyl or -Delta, R2 is H, halogen or -CF3 and represents a 5 or 6 membered heterocyclic moiety unsatd. at the 3 position of the rings) by a) reaction of where X1 is a replaceable group with a cpd. which will replace X1 by -CH(R1)-R b) reaction of where X2 replaceable with a cpd. which will replace X2 by c) reaction of a X3-CH(R1)-R in which X3 is a phenyl residue opt. partially saturated carrying at its 4 position and R2 at is 3 position to produce the required material of formula (I) or (d) reaction of in which R degrees 2 is transformable with a cpd. which substitutes H, Hal, or -CF3 for R degrees 2. The cpds. (I) are useful in the treatment of arthritic and dermatopathological inflammation).

Description

Tertiary amino acids the subject of application no. P 1913743.0 (Case SU 511 / 1-3 / A / E) are α- (aminophenyl) -aliphatic carboxylic acids, in which the Amino group represents a cyclic tertiary amino group, and its acid derivatives. These compounds show anti-inflammatory properties and can accordingly be used.

It has now been found that compounds of the formula wherein R represents an optionally functionally modified carboxyl group, R1 represents a hydrogen atom, a lower alkyl radical or a cyclopropyl group, R2 represents a hydrogen atom, a halogen atom or a trifluoromethyl group, and stands for a 5- to 6-membered 3-alkenyleneamino radical, as well as functional amine derivatives thereof, have particularly pronounced anti-inflammatory properties or can be easily converted into corresponding pharmacologically active compounds.

A 3-alkenylene amino group is primarily the 3-pyrrolin-l-yl group, but can also be the 1,2,5,6-tetrahydro-l-pyridyl group.

A halogen atom is primarily a fluorine or in particular a chlorine atom.

Functionally modified carboxyl groups R are primarily esterified Carboxyl groups, in particular optionally substituted carbo-lower alkoxy groups, as functionally modified carboxyl groups in which the carbon atom is substituted by at least one nitrogen atom, such as optionally, e.g. optionally substituted lower alkyl groups, by optionally heteroatoms as chain links containing lower alkylene groups or mono- or di-, substituted carbamyl or thiocarbamyl groups, as well as cyano groups, furthermore in salt -, e.g. I3. carboxyl groups present in metal or ammonium salt form. Functional Amine derivatives are e.g. acid addition salts or N-oyds.

A lower alkyl group preferably contains up to 4 carbon atoms and stands, for example, for a methyl, ethyl, n-propyl, iopropyl, n-butyl, isobutyl, sec-butyl or tert -butyl group, A substituted lower alkyl group contains as Substituents -z.13. Hydroxy, lower alkoxy or optionally substituted, preferably tert-amino groups, such substituted preferably by at least one carbon atom from the linking carbon atom of the lower alkyl group are away.

A lower alkoxy group preferably contains up to 4 carbon atoms and represents, for example, a methoxy, ethoxy, n-propyloxy, isopropyloxy or n-butyloxy group.

An optionally substituted amino group contains, for example, lower alkyl, Lower alkylene, lower oxaalkylene or Niederazaalkylenreste as Substituents and stands, for example, for a lower alkylamino or di-lower alkylamino, such as a methylamino, dimethylamino, ethylamino or diethylamino group, a Alkylenamino group with 3-7 ring members, such as a pyrrolidino or piperidino group, a morpholino group or one, optionally in the 4-position, for example by a Lower alkyl radical, substituted piperazino group. The above, if applicable substituted amino groups can also use the nitrogen moiety of amide or thioamide groups form.

The anti-inflammatory properties can be based on animal experiments can be detected, preferably acid animals, such as rats, as test animals used.

According to, for example, Winter et al., Proc. Soc. Exptl. Biol. & Med., Pd. 111, 5. 544 (1962), described experimental method, the compounds of present invention in the form of aqueous solutions or suspensions, which e.g. contain carboxymethyl cellulose or polyethylene glycol as a solubilizer, with the aid of feeding tubes to adult, male and female rats in daily doses von et O, OCC1 to about 0.07 g / kg, preferably from about 0.0005 to about 0.05 g / kg and administered primarily from about 0.001 to about 0 5 .gr. About an hour later, 0.06 ml of a 1% suspension of carrageenin in an aqueous physiological Saline solution is injected into the left hind paw of the experiment. After 3-4 hours be volume and / or weight of the. edemaic left hind paw with one the right hind paw compared.

The difference between the two extremities will be with one compared in untreated control animals; this comparison serves as a measure of anti-inflammatory effect of the test compounds.

According to that of Newbould, Brit. J. Pharmacol. Chemotherap., Vol. 21, pp. 127 (1963), developed adjuvant arthritis test, rats are placed under ether anesthesia by administering 0.05 ml liter of aqueous carrageenin suspension to all 4 Paws sensitized. After 24 hours, 0.1 ml of the above suspension is injected of Mycobacterium butyricum between the tail skin. The trial connections are after 7 days in the above-mentioned manner for 14 days with the help of gastric tubes administered. The rats are weighed once a week; be three times a week The number and severity of secondary arthritic lesions were determined.

The compounds of the present invention can therefore be used as anti-inflammatory Agents in the treatment of arthritic and dermatopathological phenomena, as well as intermediate products in the manufacture of other valuable products, e.g. pharmacological active, compounds -be used.

Compounds of the formula I in which R represents the carboxyl group, hydrogen, or the methyl or cyclopropyl group R2 represents hydrogen or a chlorine atom, show particularly pronounced pharmacological, in particular anti-inflammatory properties, and stands for a 3-pyrrolin-1-yl group, or salts, in particular pharmaceutically acceptable, non-toxic alkali metal, alkaline earth metal or ammonium salts dayon, and in particular the α- [3-chloro-4- (3-pyrrolin-yl) - phenyl] propionic acid and its salts, such as its pharmaceutically acceptable, non-toxic alkali metal, alkaline earth metal and ammonium salts, which in the test systems described above have excellent anti-inflammatory properties at talin doses of about 0.001 to about 0.025 g / kg.

The compounds of the present invention can be prepared by processes known per se, for example by a) in a compound of the formula in which X1 is a radical which can be converted into the grouping of the formula CH (R1) -R (IIa), the group X1 is converted into a grouping of the formula IIa, or b) in a compound of the formula wherein X2 is one in the 3-alkenyleneamino group represents transferable radical, X2 converted into this group, or c) in a compound of the formula wherein S3 is a group in the 4-position and in the 3-position represents the radical R2 2, optionally only partially, saturated phenyl radical, X3 in the radical of the formula converted, or (d) in a compound of the formula wherein R2 represents a radical which can be converted into a group R2, O converts R2 into a group R2, and, if desired, converts a compound obtained within the defined scope into another compound of the invention.

After process modification a), the compounds of the present Invention either by replacing group X1 with the whole grouping of Formula IIa or part thereof, especially the carboxyl part, or then through Release of the grouping of the formula IIa from a suitable radical which already has the contains the necessary number of carbon atoms, e.g. by converting a potential Carboxy group or an alkylidene residue.

X1 can be a hydrogen atom, a metallic group or mean a reactive esterified hydroxyl group. A metallic grouping is e.g. an alkali metal, such as lithium atom, or a substituted alkaline earth metal, Zinc or cadmium atom, such as a halogen magnet, as well as a lower alkyl zinc or lower alkyl cadmium, e.g. chlorine, bromine or iodine magnesium, as well as methyl or Ethyl zinc - or cadmium group. A reactive esterified one The hydroxyl group is preferably formed by a strong mineral or organic sulfonic acid such as a hydrogen halide, sulfuric, lower alkanesulfonic or benzenesulfonic acid, e.g.

Salt, hydrogen bromide, methanesulfone, ethanesulfone, benzenesulfone or p-toluenesulfonic acid> esterified hydroxyl group. The corresponding starting material of the formula II is with a compound of the formula Y1-CH (R1) -R (IIb), wherein R is the has the meaning given above, but especially one in salt form represents esterified or amidated carboxy group or a cyano group. In the above compounds of the formulas II and IIb, one of the radicals X1 and Y1 -a metallic group and the other a reactive esterified hydroxyl group, or X1 denotes a hydrogen atom and Y1 denotes a free or reactive, esterified one Hydroxy group The above reaction can be carried out according to the Arignard or Friedel-Crafts reaction, in which a new carbon-carbon bond from two different reactants is formed. The Friedel-Crafts reaction is in the presence a Lewis acid, such as an aluminum, as well as boron, antimony V, iron III or Zinc salt, especially chloride, or of hydrogen fluoride, sulfur or preferably Polyphosphoric acid, the latter being carried out primarily with compounds of the formula IIb or derivatives of which is used in which Y1 represents a hydroxyl group.

The radical X1 in compounds of the formula II can also represent a group of the formula -CH (R1) -v2 (IIc), in which Y2 is a metallic radical, such as a of the above, also an ammonium, such as a tri-lower alkyl-ammonium or di-lower alkyl-aryl-lower-alkyl-ammonium, e.g. trimethylammonium or dimethylbenzylammonium group, or a free or reactive, functionally modified, such as esterified or etherified, as well as Hydroxy group present in salt form, for example one esterified as indicated above Hydroxy group, or one etherified with a lower alkanol or an aryl-lower alkanol Hydroxy group, or one, an alkali or alkaline earth metal, e.g. sodium, potassium or calcium, containing as a cation, converted to the descaling salt form Means hydroxyl group.

Such a metal, ester, ether or alcoholate compound of Formula II can be used with a reactive derivative of carbonic or formic acid be implemented, with only one of the two reactants being a metallic Contains grouping. A metal or Grignard compound of the formula II can with a suitable metal-free carbonic acid or formic acid derivative> preferably with carbon dioxide, but also with a corresponding carbonate or haloameinic acid ester, e.g. diethyl carbonate, orthoformic acid lower alkyl, such as ethyl ester or prepyl ester, or haloformic acid lower alkyl, phenyl or phenyl lower alkyl ester, in which a lower alkyl-> Phenyl or phenyl-lower alkyl radical, if appropriate can be substituted, such as ethyl chlorameinate, tert-butyl ester -allyl ester, 2-methoxyethyl ester, phenyl ester or benzyl ester, or with a cyanogen halide or carbamoyl halide such as cyanogen bromide or diethyl carbamoyl chloride.

A starting material of the formula II with a grouping of the formula IIc, where Y2 is an ammonium or a free or reactive, functionally modified, particularly esterified and etherified hydroxyl group is preferred with a metal cyanide such as alkali metal cyanide, e.g. Sodium or potassium cyanide, implemented. A starting material, wherein Y2 in a group of the formula IIe is a free, is esterified or present in salt form, or a corresponding dehydrated compound of the formula II, in which X1 is a 1 l-lower alkenyl radical can also be reacted with carbon monoxide. The latter will be under neutral or basic, preferably acidic conditions, e.g.

in the presence of sulfuric acid, and under high pressures and / or temperatures, e.g. at up to 400 atmospheres. and 3000C, preferably in the presence of a heavy metal catalyst, such as a nickel or cobalt salt or a carbonyl derivative thereof. Carbon monoxide can also be obtained from suitable reagents, such as formic acid in the presence from high-boiling mineral acids such as sehwerel or phosphoric acid.

Another group X1 can also be a grouping of the formula -CH (R1) -Y3 (IId) be> where Y3 is a free or functionally modified carboxyl group represents transferable residue; the desired conversion of Y3 to an optional one Functionally modified carboxyl groups can be carried out by oxidation or rearrangement. An oxidatively convertible group Y3 is e.g. a methyl, hydroxymethyl, borylmethyl, Hydroxyiminomethyl or formyl group, as well as a l-lower alkenyl or 1-lower alkynyl group, a 1,2-dihydroxy-lower alkyl group or an acyl, such as lower alkanoyl, lower alkenoyl or a free or functionally modified, e.g. esterified, carboxycarbonyl group.

In a corresponding starting material of the formula II with a Grouping of the formula IId, in which Y3 is an oxidatively convertible potential carboxy group represents, V3 can with the help of standard oxidation methods in a free or functional modified carboxy group can be converted, e.g. by treatment with oxygen (either in pure form or in the form of air)> preferably in the presence of one suitable catalyst, such as a silver, manganese, iron or Kolbalt catalyst, or with oxidizing agents, such as hydrogen peroxide or a nitrogen oxide (nitrogen oxide), or oxidizing acids or salts thereof, such as hypohalous acids, periodic acid, Nitric acid or percarboxylic acids or corresponding salts, such as alkali metal salts thereof, e.g., sodium hypochlorite or sodium periodate, peracetic acid, Perbenzoic acid or monoperphthalic acid, heavy metal salts or oxides, such as alkali metal, e.g. sodium or potassium chromates or permanganates, chromium III or copper II salts, e.g. halides or sulfates, or silver, mercury, vanadium V, chromium VI or manganese IV oxides, in an acidic or alkaline medium. Usually receives one after the above oxidation methods as products of the formula I, the free acids or salts thereof.

For example, if you use a starting material with a group X1 of the formula IId, where Y represents a hydroxyiminomethyl group 3, i.e. an oxime, and leads the Beckmann rearrangement by, for example, treatment with sulfuric acid, p-toluenesulfonyl chloride or phosphorus pentachloride, or subject it to oxidation, e.g. with hydrogen peroxide or one of the above percarboxylic acids, or is a compound with a formyl or Acyl group Y3 in a radical of the formula IId, i.e. an aldehyde or ketone, and treats them with hydrazoic acid according to Schmidt's reduction, e.g. in the presence of sulfuric acid, or treats a compound with a formyl group Y3 with a sulfonyl or nitro hydroxamate, the product obtained is a nitrile, an amide or

a hydroxamic acid compound.

A starting material of the formula II with the above group of. formula lid, in which Y3 is an optionally functionally modified, in particular esterified one Carboxycarbonyl, such as carbo-lower alkoxycarbonyl group, means can either by oxidation, e.g. with hydrogen peroxide in an acidic medium, such as in the presence of a mineral acid, or by l) ecarbonylierwen, primarily by pyrolysis, preferably in the presence of copper or glass powder, into the desired Compound of formula I are converted.

A group X1 in a starting material of the formula II can also represent a radical which is primarily the grouping of the formula -CH (R1) - (IIe) results. Such a radical is, for example, a group of the formula -G (R1) (Y4) -R (IIf) or of the formula -C - (# Y5) -R (IIg), in which the radical Y4, for example, by reducing, decarboylating, Deacylators. or desulfurization into hydrogen and Y5 by reduction into the group R1 can be converted together with hydrogen.

So the radical Y4 can be free or reactive esterified or etherified hydroxy or mercapto groups, e.g. one of the above-mentioned corresponding groups Groups, or the corresponding mercapto equivalents, e.g. a hydroxy, as well as a mercapto group, a chlorine, bromine or iodine atom, a benzyloxy or benzylmereapto group, also for a disubstituted amino, such as di-lower alkylamino group, e.g.

a dimethylamino or diethylamino group; Y5 can be a Lower alkylidene or cyclopropylidene group or an optionally ketalized group Mean oxo or thiono group. Starting materials with such groups or corresponding quaternary o-or p-quinone methides, which can be obtained by splitting off the elements of a compound c.cr Formula Y4-H from a starting material of the formula II with a group of the formula IIf, e.g. when treating with strong mineral acids or alkali metal hydroxides, can be obtained by reduction, e.g. by treating with catalytically activated Hydrogen, such as hydrogen in the presence of a nickel, palladium or platinum catalyst, with electrolytically generated hydrogen or with a chemical reducing agent (nascent hydrogen), such as reducing metals, preferably in the presence a hydrogen donating agent such as an acid, a base, e.g. Alkali metal hydroxide, or an alcohol, e.g. with zinc, amalgamated zinc; iron or tin, preferably in the presence of aqueous mineral or organic carboxylic acids, z. B. hydrochloric acid or acetic acid, with zinc-nickel or aluminum-nickel alloys, preferably in the presence of an aqueous alkali metal hydroxide with an alkali metal, such as sodium or potassium, or a corresponding amalgam in the presence of a lower alkanol, converted in the desired manner.

In the reduction of a starting material with a mercapto or a free or ketalized thiono group is preferably used desulphurizing agents, such as mercury or copper oxide, as well as Raney nickel.

If Y4 represents a free hydroxyl group, one can.

also an aqueous suspension of phosphorus and iodine, hydriodic acid, Tin (II) chloride or an alkali metal, e.g. sodium sulfite or dithionite, and if Y4 denotes an esterified hydroxyl group, such as a halogen atom, a lower alkyl or Cyclopropyl metal compound, like the corresponding lithium or Grignard compound, use as reducing agent.

The above metal compounds are also suitable for reduction of the above ghinone methide compounds.

If Y5 stands for an oxo group, you can use the Clemmensen- or use Wolff-Kishner reduction (including the Huang-Minlon modification), in which a chemical reducing agent (nascent hydrogen) or hydrazine is used, the latter preferably being used in the presence of a strong alkali metal hydroxide, such as a sodium or potassium hydroxide, e.g. in an aqueous or high-boiling one glycolic medium.

Y4 stands for a carboxy group and thus represents the starting material is primarily a corresponding malonic acid derivative, such a starting material can be used be decarboxylated by pyrolysis, preferably in an acidic medium. If Y4 for an acyl group other than a carboxy group, such as a lower alkanoyl, Aroyl or aryl-lower alkanoyl, e.g. acetyl or benzoyl group, so can the corresponding R-keto acid starting material of the acid cleavage by action a strong alkaline agent such as one of the above-mentioned alkali metal hydroxides subject.

Another substituent X1> which is also the one mentioned above Grouping of the formula iie provides is an optionally substituted acetyl group, wherein substituted acetyl groups z. B. those of the formulas -C (#O) -C (# N2) -R1 (IIh) or -C (#O) -CH (R1) -Met (IIi) where Hal is a halogen atom means. An acetyl starting material can after the Willgerodt-Kindler reaction, - e.g. by Treating with sulfur in the presence of ammonia or a primary or secondary Amine, especially of morpholine, and preferably an acid such as an organic one Sulphonic acid, e.g. p-toluenesulphonic acid, can be converted as products Thioamides or amides (the latter when carrying out the reaction in an aqueous medium) receives. A corresponding α-diazoacetyl starting material is made according to the Wolff reaction (Arndt-Eistert), e.g. by hydrolysis, alcoholysis, ammonolysis or aminolysis, preferably with irradiation or heating in the presence of heavy metal, e.g. copper or Silver catalysts; and a corresponding α-haloacetyl starting material according to the Favorskii (Wallach) rearrangement, e.g. by treating with a strong alkaline Agents such as an alkali metal hydroxide or a soluble silver salt such as silver nitrate, can be converted into a compound of the present invention.

According to method b), the group can either introduced into the phenyl radical or an existing one into the group transferable radical, such as a primary, secondary or tertiary amino group, for example an acyclic tertiary amino group or one of the radicals corresponding alkyleneamino group having a group which can be split off with introduction of a double bond in the alkyleneamino radical is in the t- or t-position, into the desired group To be transferred.

So X2 can d- in a starting material. Formula III e.g. B.

represents a hydrogen atom and a metallic group or an optionally reactive esterified hydroxyl group, such as one of the above-mentioned groups, preferably represents an alkali metal or halogen atom. The corresponding starting material of the formula III can be mixed with a compound of the formula (IIIa), where one of the radicals X2 and Y6 is a 1st hydrogen atom or the metallic group, e.g. lithium or sodium, and the other is a free or reactive esterified hydroxyl group, e.g. a fluorine or chlorine atom.

When X2 is hydrogen and Y6 is a halogen atom, then becomes the reaction analogous to the above Friedel-Crafts reaction, e.g. in the presence of a Lewis acid, or, if Y6 is a hydroxyl group, in the presence of an alkaline one By means of e.g. potassium hydroxide. If X2 is a hydroxy or lower alkanoyloxy group, then one works preferably in the presence of a dehydrating or dehydrating agent, such as a mineral acid or a salt thereof, e.g. B. hydrochloric acid, ammonium sulfite or Sodium hydrogen sulfite, activated aluminum oxide, Raney nickel or palladium on carbon. An Ilalogen atom X2 is particularly a fluorine atom.

The conversion of a primary or secondary, as well as, for example, acyclic or saturated, tertiary amino group X2 in a starting material of the formula III into the group can, for example, by transaminating with a compound of the formula (IIIb) can be carried out. The latter is used in excess and in the absence or presence of a catalyst, for example one of the abovementioned dehydrating or dehydrating agents, and under elevated temperature and / or elevated pressure.

A starting material of formula III wherein X2 is a primary amino group means, can also -with a glycol of the formula HO-A-OH (IIIc) or preferably with a reactive derivative such as a reactive ester e.g. corresponding t) ihalide, such as dichloride or dibromide.

This reaction is preferably carried out in the presence of a water or acid binding agent Means, such as an alkali metal or a corresponding alcohol or carbonate, carried out.

One of the rest corresponding alkylenamino group X contains, for example, in the β or position as a removable group

a free or reactive etherified or esterified hydroxyl group, such as a lower alkoxy, e.g. ethoxy or tert-dutyloxy group, or a through a strong acid, such as esterified by a mineral or strong organic sulfonic acid Hydroxyl group, e.g. a halogen, such as chlorine, bromine or iodine atom, or a lower alkylsulronyloxy or arylsulfonyloxy, e.g. methylsulfonyloxy, 4-tolylsulfonyloxy or 4-bromophenylsulfonyloxy, furthermore a hydroxyl group esterified by a strong organic carboxylic acid, such as a lower alkanoyloxy, e.g. acetyloxy and benzoyloxy group, or a through a suitable carbonic acid half-derivative, such as by a dithiocarbonic acid lower alkyl half-ester esterified hydroxy group such as a lower alkyl mercapto-thiocarbonyloxy, e.g. Methyl mercapto-thiocarbonyloxy group.

These groups can be used together with hydrogen in a manner known per se be split off, a free or etherified hydroxyl group e.g. under dehydrating Conditions such as in the presence of strong acids, usually in concentrated form Form such as mineral acids, e.g.

Hydrohalic acid such as hydrochloric or hydrobromic acid, sulfuric acid or phosphoric acid (e.g. as polyphosphoric acid), also of carboxylic acid anhydrides, such as acetic anhydride, or of non-ionic acidic acids, preferably at elevated temperature, a reactive esterified hydroxyl group in basic Medium, for example in the presence of basic agents such as inorganic bases, e.g. metals, such as alkali metal hydroxides, e.g. sodium or potassium hydroxide, or corresponding carbonates, e.g. potassium or sodium carbonate, or.

organic phase, such as amines e.g. Pyridine, and optionally at elevated temperature, or then pyrolytically, and an etherified mercapto-thiocarbonyloxy group pyrolytically, in the absence of a solvent or in the presence of a high-boiling one Solvent, such as di- or triethylene glycol dimethyl ether, if desired, unte.r reduced pressure (Tschugaeff reaction).

Further removable groups in an alkyleneamino radical X2 are e.g. optionally reactive esterified or etherified mercapto groups which one by dehydrosulfation, e.g. in the presence of a heavy metal oxide, e.g. mercury.

silver or lead oxide can split off together with hydrogen.

Furthermore, ammonium groups, such as the trimethylammonium group, are the can also be introduced in situ by quaternizing amino groups, furthermore disubstituted aminoxy groups such as di-lower alkyl, e.g. B. diethylamine oxide groups, cleavable residues; ' they are usually pyrolytic, for example by heating in the absence of a solvent, e.g. under reduced pressure, or in the presence a high-boiling solvent, e.g. di- or triethylene glycol dimethyl ether, preferably split off under reduced pressure, together with hydrogen.

Further residues that can be split off from an alkyleneamino residue x2 are suitable, e.g. sulfonyl, substituted hydrazone groups such as N'-lower alkyl or especially N'-arylsulronylhydrazono-, e.g., N'-phenylsulfonyl-, N'-4-methylphenylsulfonyl - or N '-4-bromophenylsulfonylhydrazone groups. Such groups become pyrolytic, preferably in the absence of a diluent, or then in the presence of one High-boiling solvent, if appropriate under reduced pressure, split off.

Furthermore, substituted sulforlyl and ternary sulfonium groups, such as lower alkylsulphonyl, e.g.

Methylsulfonyl, or di-lower alkylsulfonium, e.g. dirnethylsulfonium groups, pyrolytic in an alkyleneamino radical X2, e.g. like an ammonium or disubstituted one Aminoxide group, in the presence or absence of a solvent, optionally under under reduced pressure, split off together with hydrogen.

In a starting material of the formula IV, the can be wholly or partially saturated phenyl radical by dehydration in a manner known per se, e.g. by pyrolysis in the presence of a catalyst, e.g. a hydrogenation catalyst mentioned above, or using a dehydrating agent such as sulfur or selenium or a derivative thereof, e.g. a di-lower alkyl sulfide or selenium dioxide, and a quinone compound, e.g.

Chloranil, can be converted into the desired phenyl radical.

A radical RO in a starting material that can be replaced by a group R2 of Formula V is, for example, a diazonium group; it can with the help of the Sandmeyer reaction, e.g. by treating the corresponding starting material with, preferably aqueous, Hypophosphorous acid (H3PO2), if necessary in present from copper sulphate, and at low temperatures (below 100 C) from hydrogen, or by treating the appropriate starting material with a. Copper-I -habgenid, like copper-I-chloride, or with copper powder in the presence of hydrohalic acid, such as hydrochloric acid, can be replaced by halogen such as chlorine. By treating of the diazonium starting material of Formula V with fluoboric acid followed by heating of the boron fluoride salt obtained (Schiemann reaction), R2 ° can also be replaced by fluorine will.

Compounds obtained can intermingle in a known manner be transferred. For example, free acids obtained can be obtained using Alcohols in the presence of esterifying agents, such as strong acids, z..B. Hydrochloric acid, Sulfuric acid or p-toluenesulfonic acid, as well as dicyclohexylcarbodiimide, or of Esterify diazo compounds, furthermore by treatment with halogenating agents, such as Thionyihalobeniden, e.g. 3. Thionyl chloride, or phosphorus halides or oxyhalides, z. B. convert chloride or oxychloride into acid halides.

The esters obtained can, for example, by treatment with suitable basic Agents, such as aqueous alkali metal hydroxides, hydrolyzed to free acids or with alcohols in the presence of acidic or alkaline agents such as heavy metal acids, as well as alkali metal carbonates or alcoholates are transesterified; by treating with ammonia or corresponding amines can convert esters into amides will.

Acid halides obtained can be obtained by treating with alcohols, as well Ammonia or amines in esters or

Amides, and metal salts of acids obtained by treatment with alcohols or corresponding halides, e.g.

Chlorides or bromides, or with suitable organic halogen sulfites> how lower alkyl chlorosulfites can also be converted into esters. Metal salts obtained when treated with halogenating agents such as phosphorus halides, for example, e.g., phosphorus pentachloride, or phosphorus oxyhalides, e.g., phosphorus oxychloride the corresponding acid halides, while treating the ammonium salts obtained with dehydrating agents such as phosphorus pentoxide, thionyl halides, phosphorus halides or can form phosphorus oxyhalides, amides and nitriles. Sulfur-containing compounds, such as thioamides, can be obtained from the corresponding oxygen analogues, e.g. by treating with phosphorus pentasulfide obtained.

Amides or thioamides obtained (e.g. the products of the Willgerodt-Kindler reaction) can under acid or alkaline conditions, e.g. by treating with aqueous Mineral and / or carboxylic acids, or alkali metal hydroxides, hydrolyzed, as well as alcoholysed or transaminated, furthermore, e.g. by treatment with mercury-II-oxide and lower alkyl halides, followed by hydrolysis, are desulfurized.

Nitriles obtained can e.g. by treating with concentrated aqueous or alcoholic acids or with alkaline agents such as alkali metal hydroxides, as well as alkaline hydrogen peroxide are hydrolyzed or alcoholized.

Obtained esters, salts or nitriles, in which the group R1 for Is hydrogen, can in a-position to the functionally modified carboxy group, e.g. as described above, metallized and then with a reactive ester an alcohol of the formula R1-OH are implemented. You can do a in a-position - introduce organic group R1.

Compounds obtained in which R2 is hydrogen can e.g. using halogen, especially chlorine, preferably in the presence of a Lewis acid, e.g. an iron (III), aluminum, antimony (III) or tin (IV) halide, or a halogenating agent, e.g. hydrochloric acid in the presence of hydrogen peroxide, or an alkali metal, e.g. sodium chlorate, a nitrosyl halide, such as nitrosyl chloride, or an N-halo, e.g., N-chloride imide such as succinimide or phthalimide, in ) Position halogenated, in particular chlorinated.

A free acid obtained can be used in a manner known per se, e.g. by reacting with an approximately stoichiometric amount of a suitable salt-forming Means, such as ammonia, an amine or an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, into a salt being transformed. Obtained ammonium or metal salts of this type can be treated with a acid, e.g. hydrochloric acid, sulfuric acid or acetic acid, e.g. until the necessary pH value, transfer into the free compound.

A basic compound obtained can, for example, by reacting with an inorganic or organic acid or a corresponding anion exchanger and isolating the salt formed, converted into an acid addition salt. An acid addition salt obtained can be treated by treating with a base, e.g. Alkylimetallhydroxyd, ammonia or a Hydroxyioncnaustauscher, in the free Compound to be converted. Acid addition salts, such as pharmaceutically acceptable, non-toxic acid addition salts are e.g. those with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, especially organic carboxylic or sulfonic acids, such as Ant, vinegar, propion, amber, glycol, milk, apple, wine, lemon, Ascorbic, maleic, hydroxymalein, pyruvic, phenyl acetic, benzoin, 20-aminobenzoic, Anthranil, 4-hydroxybenzoic, salicylic, aminosalicylic, embon or micotin, as well as Methanesulfone, ethanesulfone, 2-hydroxyethanesulfone, ethylene sulfone, benzenesulfone, 4-chlorobenzenesulfonic, 4-toluenesulfonic, naphthalenesulfonic, sulfanil or cyclohexylsulfamic acid.

These and other salts, e.g. the picrates, can also be used to identify, as well as purification of the free compounds can be used; so can free connections converted into their salts, these separated from the crude mixture and from the isolated Salts then the free compounds are obtained.

In terms of the close relationships between the new connections in free form and in the form of their salts are above and below among the free compounds or the salts, appropriately and appropriately, if appropriate the corresponding salts or compounds are to be understood.

N-oxides can be prepared in a manner known per se, e.g.

by reacting with hydrogen peroxide or an inorganic or organic peracid, especially percarboxylic acid, such as peracetic, trifluoroperacetic or perbenzoic acid.

Isomer mixtures obtained can be used in a manner known per se, e.g. by fractionated distillation or crystallization and / or by chromatography, can be separated into the individual isomers. Racemic products can, n.B. by Formation and separation, such as fractional crystallization, of mixtures of diastereoisomers Salts, e.g. with d- or? -Tartaric acid, or with d-phenylethylamine, d-a- (l-naphthyl ) ethyl amine or {-Cinch.onidinJ and, if desired, release of the antipodes separated from the salts into the optical antipodes.

The above reactions are carried out according to methods known per se, e.g. in the absence or presence of diluents, preferably those facing each other behave inertly to the reaction particles and be able to dissolve them, if necessary, in the presence of catalysts, condensation or neutralizing agents, in an inert gas, e.g. nitrogen atmosphere, with cooling or heating and / or carried out under increased pressure.

The invention also relates to those modifications of the above method, after which a compound formed at some stage as an intermediate as a starting material is used and the remaining stage (s) is (are) carried out with this, or the process is interrupted at any stage, or after which starting materials formed under the reaction conditions or in the form of derivatives, such as salts, be used. For example, in most of the above-mentioned oxidation methods, in which Y3 converted into a free or functionally modified carboxyl group is, the corresponding aldehyde compounds, in which Y3 stands for a formyl group stands, intermediately formed. In the Haloærormreaktion with starting materials of the formula II, in which X1 is a radical of the formula lid and Y is an acetyl group Trthalogenacetylverbindungen formed intermediately in the alkaline medium, each according to the reaction conditions, directly to the salts or esters of the resulting Acids reduced. Furthermore, quaternary o- or p-quinone methides can also be used as intermediates from the corresponding starting materials in which Y4 is a grouping of the formula IIf represents a free or reactive esterified hydroxy group, e.g. under strongly acidic or alkaline conditions,. or from the corresponding starting materials, in which Y5 represents an oxo or thiono group, formed during the reduction will. Furthermore, one can use the a-diazoketones, which are usually produced by the Arndt-Eistert method are formed from the acid halides by reaction with diazo compounds without to use to isolate in the Wolff rearrangement. In addition, when building up the 3-alkenyleneamino group various intermediate products from the corresponding starting materials of the formula III are formed.

For example, the group X2 represents a primary amino group and becomes a corresponding starting material of the formula III with a glycol of the formula IIIc or a reactive functional derivative thereof reacted, so one obtains usually an intermediate product with a secondary amino group X2 of the formula -NH-A-OH (IIId) or a reactive derivative thereof.

Furthermore, a starting material of the formula V) wherein R2 ° for a Diazonium group, usually without. to be isolated from the appropriate Amino compound produced, for example by treating with nitrous acid or a Salt thereof, such as sodium nitrite, in the presence of an acid, e.g. acetic acid, as Hydrochloric acid, where) 1 last e z -jr 11 preparation of compounds of the formula I is used, where R2 is chlorine.

According to the process, those starting materials are preferably used which lead to those compounds of the invention which are identified above as being particularly are preferred.

The starting materials are known or, if new, can be prepared in a manner known per se. Thus, starting materials of the formula II can generally analogously to process b), ie by introducing or building up the group can be obtained. If X1 represents, for example, a reactive esterified hydroxyl group, this can be introduced by halogenation or nitration, followed by reduction, diazotization and Sandmeyer reaction. The starting material obtained can subsequently be converted into a metallic compound, for example by reaction with an alkali or alkaline earth metal, such as lithium or magnesium, or with a di-lower alkyl zinc or cadmium.

Starting materials in which Y2 represents a metallic group can be prepared in an analogous manner, for example by reacting the reactive ester of a corresponding benzyl alcohol compound with an alkali or alkaline earth metal or a di-lower alkyl zinc or cadmium. On the other hand, for example, the compounds of the formula which can be easily prepared by the Friedei-Crafts method with lithium aluminum hydride or, when R1 represents hydrogen, with an organic magnesium halide compound in which the organic radical represents one of the corresponding radicals R1, reduced, or Grignard compounds with the radical of the formula be reacted with an aldehyde of the formula R1-CHO (IIm), and the corresponding benzyl alcohol compounds are obtained in this way.

In the latter, the hydroxyl group can be used in a manner known per se, e.g. e.g. by treating with a phosphorus halide, thionyl halide or sulfonyl halide or an alkali or alkaline earth metal into a reactive esterified or be stirred into a hydroxyl group present in salt form. Obtained esters or salts can be obtained by treatment with alcohols or alcoholates or reactive ones Convert esters of alcohols into ethers. Starting materials in which Y2 is an ammonium group means can from the above reactive esters by reaction with tertiary Amines or then with secondary amines, followed by quaternizing the received tertiary amines according to the usual methods, e.g.

by reaction with lower alkyl or aryl-lower alkyl halides, can be obtained.

Starting materials with a group Y3 can be selected from the aforementioned Starting materials with a metallic group Y2 by treatment with a methyl halide, Formaldehyde, a formyl halide, a lower alkanal, lower alkenal or hydroxy-lower alkanal, or a lower alkanoyl, lower alkenoyl or oxalyl halide, especially chloride, obtained, if desired alcohols obtained e.g.

by treatment with acidic agents such as sulfuric acid or phosphorus pentoxide, dehydrate and convert to the corresponding unsaturated compounds can. The latter, e.g. methylene compounds, can be combined with boranes to form borylmethyl compounds be implemented, while aldehydes when treated with hydroxylamine the corresponding Hydroxyiminomethyl, i.e., oxime compounds. Aldehyde starting materials in which Y represents a 3 formyl group can also be obtained from ketones of the formula IIk by reaction with dimethylsulfonium methylide or dimethyloxysulfonium methylide (obtained from the corresponding trimethylsulronium salts) and rearrangement of the ethylene oxides obtained to the corresponding aldehydes by reaction with Lewis acids, such as p-toluenesulfonic acid or boron trifluoride.

You can also treat them after Darzens condensation by treating Ketones of the formula IIk with a-halogen-alkane or a- Halo-alkenecarboxylic acid esters in the presence of suitable alkali metal alcoholates, e.g. potassium tert. -butyloxyd ,. -Soap the obtained glycidic acid ester, rearrange the resulting acids and decarboxylating the intermediates, preferably in an acidic medium, e.g. with sulfuric acid.

The starting materials with a free, esterified or etherified Hydroxy or mercapto group Y4 can be obtained by the cyanohydrin method or analogously. Syntheses, e.g.

by reaction of a compound of the formula IIk or a thiono analog thereof with an aqueous alkali metal e.g.

Potassium cyanide, under acidic conditions and, if desired, converting a nitrile obtained in another acid derivative and / or a received Hydroxy in a corresponding mercapto compound or in a corresponding reactive one Ester or ether, or dehydration to form a corresponding unsaturated one Connection, received. Starting materials in which Y4 is a disubstituted amino, e.g. dimethylamino group, can be obtained from starting materials of the formula II, in which X1 represents an acetyl group, can be formed, for example by treatment with a Alkali metal cyanide and ammonium carbonate followed by a base or acid and Disubstitution of the free amino group, e.g. with formaldehyde and formic acid.

Compounds in which Y5 is an oxo or thiono group can, according to the Friedel-Crafts reaction, using compounds of the formula and oxalyl halides, e.g., chloride, are formed. A phenylglyoxylic acid ester obtained can then be reduced by treating with an R1 Grignard compound and, if desired, dehydrated. They are also obtained after the Ando synthesis, for example when treating a compound of the formula IIn with a mesoxalic acid ester in the presence of a Lewis acid, such as tin-IV chloride; In the adduct obtained, the hydroxyl group can be removed reductively and the malonic acid ester compound formed can be metallized and then reacted with a reactive ester of an alcohol of the formula R1-OH or saponified and decarboxylated.

Furthermore, α-diazoketone compounds can be obtained if a corresponding benzoic acid halide is treated with an R1-diazo compound. α-Haloketone compounds are obtained, for example, when a corresponding lower alkanoylbenzene compound is halogenated or an α-diazoketone compound is reacted with a hydrohalic acid. Starting materials of the formula III can be formed analogously to method a) if starting materials are used in which (iie group by the remainder X2 or one of these in a simple manner, e.g. B. by reduction, transferable group, preferably a nitro group, is replaced.

Starting materials of the formula IV, in which one, if appropriate only partially, saturated Ph.enylrest a cyclohexyl, cyclohexenyl or cyclohexadienyl group represents, z. B.

are obtained when the aforementioned quaternary o- or p-chtnon methide compounds be over-reduced.

Starting materials of the formula V can, for example, according to that shown under a) Earth method using starting materials and intermediates, where R2 is replaced by the radical R2 ° or preferably a group which can be converted into this, such as an amino or, in particular, nitro group, is replaced. The latter can, e.g. by treatment with catalytically activated hydrogen or with chemical reducing agents (nascent hydrogen) to be reduced to the amino group.

Treated with a nitrous column gives intermediate products obtained with two amino groups, the diazonium salts, which are used as starting materials of the formula V can be.

The pharmacologically acceptable compounds of the present invention can be used, for example, for the production of pharmaceutical preparations which an effective amount of the active ingredient together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers containing the are suitable for enteral, parenteral or topical administration. Preferably one uses tablets or gelatin capsules, which the active ingredient together with Diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binding agents, e.g. magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatine, tragacanth, methyl cellulose, Sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, Disintegrants, e.g. starches, agar, alginic acid or sodium alginate, or effervescent mixtures and / or adsorbents, dyes> odorants or sweeteners. Injectable Preparations are preferably isotonic aqueous solutions or suspensions, suppositories and ointments, primarily fat emulsions or emulsions. The pharmaceutical Preparations can be sterilized and / or auxiliary materials, e.g. B. Preservatives, $ stabilizers -, Wetting and / or emulsifying agents, solubilizers, salts for regulating the osmotic Pressure and / or buffer included. The present pharmaceutical preparations are in a manner known per se, e.g. by means of conventional mixing, granulating or Coating process produced and containing from about 0.1% to about 75%, in particular from about 1% to about 50% of the active ingredient, and may, if desired, further pharmacologically contain valuable substances.

The following. Examples serve to illustrate the invention. Temperatures are given in degrees Celsius.

Example 1: A mixture of 85.5 g of a-t4-amino-3-chlorophenyl) propionic acid ethyl ester hydrochloride, 142 g of sodium carbonate and 600 ml of dimethylformamide is added dropwise with stirring with 107 g of 1,4-dibromo-2-butene added, then refluxed for 5 hours and left to stand at room temperature for 16 hours. The reaction mixture is filtered, the filtrate is evaporated under reduced pressure and the residue is triturated with hexane and filtered, the filter residue is washed with petroleum ether. The filtrate is evaporated and the residue containing the ethyl α- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionate of the formula treated with 280 ml of an aqueous sodium hydroxide solution and refluxed for 8 hours. After cooling, it is diluted with water and washed with ether; the pH of the aqueous phase is adjusted to 5-5.2 with hydrochloric acid and extracted with ether The organic extract is dried, filtered and evaporated and the residue is recrystallized from a mixture of benzoyl and hexane, giving the α- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionic acids formula which melts at 94-96 °.

The starting material can be prepared as follows: A solution of 52 g of 4-nitrophenyl-acetic acid ethyl ester in 550 ml of cirles 1: 1 mixture of Dimethylformamid.und toluene is added in portions with stirring and cooling with 9.5 g of a 50% suspension of sodium hydride in mineral oil. After 1t / 2h Stirring at room temperature, 25 g of methyl iodide are added dropwise and that The mixture was stirred at room temperature for 16 hours. You give water carefully to and extract with ether; the organic extract is dried, filtered and evaporated. The residue is taken up in 100 ml of ethanol, the solution becomes inoculated with some crystals of starting material and in the cold stand calmly. The resulting precipitate is filtered off and the filtrate is evaporated; the residue represents ethyl a- (4-nitrophenyl) propinate.

A mixture of 50 g of a- (4-nitrophenyl) propionic acid ethyl ester in 200 ml of 95% aqueous ethanol is in the presence of 0.4 g of a palladium on Hydrogenated coal catalyst until hydrogen uptake ceases. The mixture is filtered and the filtrate is evaporated. The a- (4-aminophenyl) propionate ethyl ester is obtained in this way, its hydrochloride melts at 137-140 °.

A mixture of 25 g of ethyl α- (4-aminophenyl) propionate prepared with stirring and cooling and 100 ml of acetic anhydride will stand for one hour at room temperature left and then evaporated under reduced pressure. The residue is made from ether recrystallized; the α- (4-acetylaminophenyl) propionic acid ethyl ester is obtained in this way, which melts at 88-90.

Chlorine gas is passed through a solution of while stirring and cooling 25 g of α- (4-acetylamino-phenyl) propionic acid ethyl ester, where the Course of the chlorination by means of thin layer chromatography (silica gel; 1: 4 mixture of hexane and ether). After no more starting material was found if the mixture is evaporated under reduced pressure, the residue is taken in 150 ml of ethanol and lets hydrogen chloride gas through the solution for 45 minutes parlen. Then for 15 hours under Riielfluss cooked and evaporated; the residue is recrystallized from a mixture of ethanol and ether; the α- (4-amino-3-chlorophenyl) propionic acid ethyl ester hydrochloride is obtained in this way rid, m. 164-168 °.

The starting material can also be prepared as follows: Man passes dry hydrogen chloride gas through with stirring for 51/2 hours refluxing mixture of 5000 ml of anhydrous ethanol and 1000 g of 4-aminophenylacetic acid; the mixture is stirred and cooked for a further 4 hours.

After 16 hours of cooling at 10 °, the mixture is filtered and the The filter residue is washed with cold anhydrous ethanol and 8000 ml of water solved. A 50% aqueous sodium hydroxide solution is added in 50 ml portions with stirring until mixture is basic, and stir for one hour at room temperature. The received. Precipitate is filtered off and washed with water. You get so the 4-aminophenyl-acetic acid ethyl ester, mp 47-49 °.

A solution of 200 g of ethyl 4-aminophenylacetate in 250 ml Acetic anhydride is left to stand for 10 minutes, then with stirring 1500 ml of a mixture of ice and water poured out. D, e, r obtained precipitate is filtered off and washed with water; the ethyl 4-acetylaminophenylacetate is obtained in this way, F.

A solution of 170 g of 4-acetylamino-phenylacetic acid ethyl ester in 25 ml of ether becomes one of 20.38 g of sodium, 2000 ml within 25 minutes anhydrous ammonia and some crystals of ferric nitrate nonahydrate Mixture given with stirring. Then they are added dropwise over the course of 20 minutes a mixture of 120.28 g of methyl iodide and 50 ml of ether and stirred for one Hour. The mixture is treated with 50 g of ammonium chloride, then evaporated and the residue is dissolved in ether and a dilute aqueous sodium hydroxide solution recorded. The basic solution is extracted with ether and the combined organic solutions are evaporated. The ethyl a- (4-acetylaminophenyl) propionate is obtained in this way, F. 8486o. The approximately 90% pure material is in a short path distillation apparatus distilled and collected the fraction boiling at 170-183 ° / 0.15 mm Hg.

A solution of 72 g of ethyl a- (4-acetylamino-phenyi) propionate in 200 ml of acetic acid is treated with gaseous chlorine, which is stirred with stirring and let it bubble through the solution at a temperature of 15-20 °. The course of the The reaction is followed by means of thin layer chromatography, one being called mobile Phase a 4: 1 mixture of ether and hexane used, in which the product a Rr value of 0.8 and the starting material has an Rf value of 0.51. After completion the chlorination becomes the mixture evaporated and the residue distilled. The fraction boiling at 155-160 ° / 10.7 mm lig represents the ethyl α- (4-acetylamino-3-chlorophenyl) propionate the.

A mixture of 60 g of ethyl u- (4-acetylamino-3-chlorophenyl) propionate and 200 ml of ethanol is saturated with gaseous hydrogen chloride and during refluxed for one hour, then evaporated under reduced pressure. Of the The residue is taken up in an aqueous sodium hydroxide solution and the mixture extracted with ether. The organic extract is evaporated and the residue chromatographed on aluminum oxide, using a 95: 5 mixture of cyclohexane and ethyl acetate eluted, the ethyl α- (4-amino-3-chlorophenyl) propionate thus obtained melts -at 168-170 °.

Example 2: A solution of 25.1 g-des following the procedure of the example 1 available d, C-α- [3-chloro-4- (3-pyrrolin-l-yl) -phenyl-propionic acid in 450 ml of ether are mixed with 17.1 g of d - (l-naphthyl) ethylamine while stirring; the The mixture is evaporated under reduced pressure and the residue is extracted seven times recrystallized from a mixture of ethanol and ether.

A solution of 5 g of the salt so obtainable, mp 133-135 °, in a minimal amount of a salt aqueous solution of sodium hydroxide will washed with ether, the pH value adjusted to 5.5 with hydrochloric acid and with ether extracted. The organic extract is dried, filtered and evaporated and this gives d-a- [3-chloro-4- (3-pyrrolin-l-yl) phenyl] propionic acid, [α] 25D = + 34.8 ° (ethanol).

Example 3: A mixture of 11.3 g of pure cis-1,4-dichloro-2-butene, 15.7 g of ethyl α- (4-aminophenyl) propionate, 100 ml of dimethylformamide and 10.6 g of sodium carbonate is refluxed with stirring for 5 hours and then left to stand for 16 hours at room temperature. Filter; the filtrate is evaporated under reduced pressure and the residue containing the ethyl a- [4- (3-pyrrolin-l-yl) phenyl] propionate of the formula taken up in 260 ml of a 25% aqueous IIatriunhydroxydlösung and refluxed for 8 hours. After cooling, it is diluted with water, washed with ether and the pH is adjusted to about 5 with hydrochloric acid. The mixture is extracted with ether; the organic extract is dried and evaporated and the residue is recrystallized from ethanol. The α- [4- (3-pyrrolin-1-yl) phenyl] propionic acid of the formula is obtained in this way which melts at 197-199 °.

The starting material can be prepared as follows: A solution of 52 g of ethyl 4-nitro-phenylacetate in 350 ml of a 1: 1 mixture of dimethylformamide and toluene is added in portions to 9.5 g of a 59% suspension of sodium hydride in mineral oil, stirring and cooling. After stirring for 1 1/2 hours at room temperature 26 g of methyl iodide are added dropwise and the mixture over 16 hours stirred at room temperature. Water is carefully added to the mixture; man extracted with diethyl ether, the organic extract is dried, filtered and evaporated. The residue is taken up in 100 ml of ethanol, the solution becomes inoculated with some crystals of starting material and left to stand in the cold, The precipitate obtained is filtered off and the filtrate is evaporated; you get so den-a- (4-nitrophenyl ) ethyl propionate.

A mixture of 50 g of a- (4-nitrophenyl) propionic acid ethyl ester in 200 ml of 95% aqueous ethanol is added in the presence of 0.4 g of a palladium-on-carbon catalyst hydrogenated until waascrstoffabsorption ceases. The mixture is filtered and the filtrate evaporated. The ethyl a- (4-aminophenyl) propionate is obtained in this way / its hydrochloride melts at 137-1400.

Example 4: A mixture of 24 g of a- (4-amino-3-chloro-phenyl) -butyric acid ethyl ester, 21 g of sodium carbonate and 25 g of cis-1,4-dichloro-2-butene in 250 ml of dimethylformamide is used for 12 Boiled under reflux for hours. After cooling, it is diluted with diethyl ether, filtered and the filtrate is evaporated. 11 g of the residue containing the a- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] butyric acid ethyl ester of the formula are taken up in 100 ml of ethanol and 20 ml of 25% aqueous sodium hydroxide; the mixture is refluxed for 6 hours and evaporated under reduced pressure. The residue is taken up in water, the solution is washed with diethyl ether, its pII value is adjusted to 5.5 with hydrochloric acid and then extracted with diethyl ether. The organic extract is dried and evaporated and the residue is recrystallized from hexane. The α- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] butyric acid of the formula is obtained in this way de melts at 103-105 °.

The starting material can be produced as follows. A mixture of 104 g g of ethyl 4-nitrophenyl acetate in 350 ml of dimethylformamide and 350 ml of toluene is at 10 ° and with stirring within 45 minutes with 10 g of a 50% suspension of sodium hydride in mineral oil. After 1 1/2 hours 78 g of ethyl iodide are added with stirring over the course of one hour and afterwards further A small amount of water is added dropwise for 1-1 / 2 hours. The mixture will then acidified with 10% hydrochloric acid and extracted with diethyl ether. The organic one The extract is dried and evaporated; the α- (4-nitrophenyl) butyric acid ethyl ester is obtained in this way.

A mixture of 115 g of a- (4-nitrophenyl) butyric acid ethyl ester, 400 ml of 95% ethanol and 1.5 g of a palladium-on-carbon catalyst is used in an initial pressure of about 3 atmospheres and hydrogenated at room temperature.

After the hydrogen uptake has ceased, the mixture is filtered, the filtrate is evaporated and the residue is in 2-n. Hydrochloric acid added. It is washed with diethyl ether and made basic with an aqueous sodium hydroxide solution and extracted with diethyl ether. The organic extract is evaporated and gives the a- (4-aminophenyl) butyric acid ethyl ester.

A mixture of 35 g of ethyl a- (4-aminophenyl) -butyric acid ester and 100 ml of acetic anhydride is stirred for one hour on the steam bath and evaporated. The ethyl α- (4-acetylamino-phenyl) -butyric acid is obtained in this way.

It is left through a solution of 35 g of a- (4-acetylaminophenyl) butyric acid ethyl ester in 200 ml of acetic acid while stirring i at a temperature of 15-20 ° chlorine gas bubble; the course of the reaction is monitored by means of thin layer chromatography on Silica gel (mobile phase: hexane / diethyl ether 1: 4) followed. After using the The entire starting material is evaporated and the reaction mixture is obtained the hydrochloride of α- (4-acetyl-amino-3-chlorophenyl) -butyric acid ethyl ester.

One leaves through a solution of 36 g of a- (4-acetylamino-3-chlorophenyl) -butyric acid ethyl ester hydrochloride in 200 ml of ethanol for 45 minutes and bubbling hydrogen chloride gas with stirring. The mixture is under for -20 hours Boiled under reflux, then left to stand for 24 hours at room temperature and evaporated. The residue is taken up in water, the solution with an aqueous Made sodium hydroxide solution basic and extracted with diethyl ether. The organic one The extract is dried and evaporated and the residue is distilled; those at 130-132 ° / 0.4 The fraction boiling mm Hg is the ethyl α- (4-amino-3-chloro-phenyl) -butyric acid ester the.

Example 5: A mixture of 0.63 g of a- (4-amino-3-chloro-phenyl) -a-cyclopropyl-acetic acid methyl ester hydrochloride, 0.55 g of cis-1,4-butene-2-butene, 0.7 g of sodium carbonate and 50 ml of "-dirnethylformamide is carried out for 10 hours in a nitrogen atmosphere under return flow boiled and evaporated for 2 days at room temperature, then filtered.

The filtrate is evaporated and the residue is taken up in water and extracted with diethyl ether and the organic extract under reduced pressure evaporated.

The residue containing the a- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] -α-cyclopropyl-acetic acid ethyl ester is taken up in 35 ml of ethanol, 0.5 ml of water and 0 , 28 g of potassium hydroxide, the mixture is sir for 2 hours. Boiled to reflux and then evaporated under reduced pressure. The residue is taken up in water, the solution is washed with diethyl ether, the pH is adjusted to 4 to 4.5 with hydrochloric acid and the mixture is extracted with ethyl acetate. The organic extract is dried and evaporated and the residue is crystallized from diethyl ether. The «- [3-chloro-4- (3-pyrrolin-1-yl) -phenyl] -α-cyclopropyl-acetic acid of the formula is obtained in this way which melts at 152-156 °.

The starting material can be prepared as follows: A solution of 200 g of a-cyclopropyl-phenylacetic acid in 200 ml of trifluoroacetic acid is added dropwise with a mixture of 73 ml of 70% aqueous nitric acid and 9.1 ml of 96% Aqueous sulfuric acid is added to about 3 ° with stirring and cooling. After 1-1 / 2 The mixture is allowed to warm to room temperature for hours and is stirred.

for 3 more hours and then poured to 3200 while stirring g of ice and 300 ml of water. The mixture is filtered, the filter residue becomes washed with 600 ml of water and dried and yields. an approximately 2: 1 mixture of -α-cyclopropyl-α- (4-nitrophenyl) acetic acid and α-cyclopropyl-α- (2-nitrophenyl) acetic acid.

A mixture of 50 g of the above mixture of α-cyclopropyl-α- (4-nitrophenyl) acetic acid and α-cyclopropyl-α- (5-nitrophenyl) acetic acid, 5 g of a 10% palladium on carbon catalyst and 550 ml of 95% aqueous ethanol is added under atmospheric pressure until uptake hydrogenated by 15,000 ml of hydrogen. After filtering, the filtrate is added. concentrated, the precipitate formed in the cool is separated and once from ethanol recrystallized; the pure α- (4-aminophenyl) -α-cyclopropyl-acetic acid is thus obtained.

A mixture of 10 g of α- (4-aminophenyl) -α-cyclopropyl acetic acid and 75 ml of methanol is added with stirring and cooling in an ice bath a saturated solution of hydrogen chloride in methanol is added. After 30 Minutes the mixture is warmed for one hour at 380 and with 100 ml of water treated. While cooling and stirring, 105 ml of a 20% aqueous sodium hydroxide solution are added admitted. The resulting precipitate is filtered off, washed with water and dried. The α (4-aminophenyl) -α-cyclopropyl-acetic acid methyl ester is obtained in this way, F. 68-690 A mixture of 12 ga- (4-aminophenyl) -a-cyclopropyl-acetic acid methyl ester and 100 ml of acetic anhydride is heated on the steam bath for one hour and then evaporated. The residue is taken up in benzene and the mixture again evaporated. This gives the c- (4-acetylaminophenyl) -a-cyclopropyl-acetic acid methyl ester, 159-162 °.

A solution of 1.6 g of a- (4-acetylaminophenyl) -α-cyclopropyl-acetic acid methyl ester in 50 ml of acetic acid is added dropwise with stirring with 30 ml of a saturated solution mixed with chlorine in acetic acid. The mixture is then under reduced pressure evaporated and the residue taken up in twice the volume of benzene. The mixture it is evaporated and the methyl α- (4-acetylamino-3-chlorophenyl) -a-cyclopropyi-acetic acid is obtained.

Hydrogen chloride gas is passed through a solution for 15 minutes of 1.6 ga44-acetylamino -) - chlorophenyl) -α-cyclopropyl-acetic acid methyl ester pearl in 200 ml of methanol; the mixture is then refluxed for 21 hours boiled and evaporated under reduced pressure. The residue is in 6-n. hydrochloric acid taken up, the mixture is washed with diethyl ether with an aqueous sodium hydroxide solution made basic and extracted with diethyl ether. The organic extract is dried and evaporated; the residue is taken up in diethyl ether and washed with a solution acidified by hydrogen chloride in ether. The precipitate obtained is filtered off and gives the a- (4-amino-3-chlorophenyl) -α-cyclopropyl-acetic acid methyl ester hydrochloride, 164-169 °.

Example 6: A mixture of 5 g of a- [3-chloro-4- (9-pyrrolin-l-yl) -phenyl-propic acid, 200 ml - 1,2-dichloroethane and 42.6 anhydrous disodium phosphate within.

40 minutes with stirring and at a temperature of up to 0 ° with a trirluoric acid solution formed from 2.1 ml of 90% aqueous hydrogen peroxide and 12.6 ml of trifluoroacetic anhydride in 50 ml of 1,2-dichloroethane. After 2 hours, 300 g of ice are added, the organic phase is separated off and the aqueous layer is extracted with methylene chloride. The combined organic solutions are dried, filtered and concentrated, giving the α- [3-chloro-4- (3-pyrrolin-yl) phenyl] propionic acid N-oxide of the formula that melts at 140-142 °.

Example 7: In Examples 1 and 3, 1,4-dibromo-2-butene is replaced or the cis-1,4-dichloro-2-butene drch the 1,5-dibromo-2-pentene and sets the latter with α- (4-amino-3-chlorophenyl) propionic acid ethyl ester or α- (4-amino-phe nyl) -propionic acid ethyl ester to obtain the (t- [3- Ethyl chloro-4- (1,2,5,6-tetrahydro-1-pyridyl) phenyl] propionate or the ethyl α- [4- (1,2,5,6-tetrahydro-1-pyridyl) phenyl] propionate. By means of hydrolysis, .13. after the process shown in Examples 1 and 3, i.e., treatment with 25% aqueous sodium hydroxide solution gives these Ester the a- [3-chloro-4- (1,2,5,6-tetrahydro-1-pyridyl) -phenyl] -propionic acid or

α- [4- (1,2,5,6, -tetrahydro-1-pyridyl) -phenyl] -propionic acid.

Example 8: A mixture of 5.5 g of 4- (3-pyrrolin-l-yl) -phenyl acetic acid ethyl ester, 100 ml of dimethylethylformamide and 100 ml of toluene are added in portions with stirring mixed with 1.25 g of a 54% strength suspension of sodium hydride in mineral oil; man stir for 2-82 hours at room temperature.

A solution is then added dropwise over a period of 20 minutes of 6.8 g of methyl iodide in 25 ml of toluene, the stir.

Reaction mixture for 16 hours at room temperature and evaporated then under reduced pressure. The residue - containing the ethyl 2- [4- (3-pyrrolin-1-yl) phenyl] propionate is taken up in 75 ml of an aqueous solution of potassium hydroxide and 10; Mix for 2 hours heated on the steam bath, then cooled, adjusted to pH 5 with hydrochloric acid and extracted with diethyl ether. The organic one The extract is dried and concentrated, the concentrate is diluted with petroleum ether and the precipitate formed is filtered off. The a-U4- (3-pyrrolin-1-yl) -phenyl] -propionic acid is thus obtained, which melts after recrystallization from ethanol at 197-1Q90.

The starting material can be obtained as follows: A mixture of 10.8 g of ethyl 4-aminophenylacetate hydrochloride, 32.4 g of 1,4-dibromo-2-butene and 84 g of sodium hydrogen carbonate in 500 ml of dimethylformamide is stirred while Boiled under reflux for 6 hours and filtered hot. The filtrate is reduced under Evaporated pressure and gives the 4- (3-pyrrolin-l-yl) -phenylacetic acid ethyl ester, which is used without cleaning.

Example 9: A suspension of 4.37 g of α- [3-chloro-4- (3-pyrrolin-1-yl) -phenyl-propionure in 30 ml of water is added dropwise until completely dissolved with a 50% aqueous sodium hydroxide solution added; the pH is about 12.5. The solution will be under a pressure of 0.8 mm i <g evaporated, the residue taken up in isopropanol, the mixture filtered and the filtrate concentrated. Of the The precipitate formed on cooling and inoculation is filtered off and stored for 16 Dried at 90 ° / 0.8 mm Hg for hours; the sodium salt of α- [3-chloro-4-83-pyrrolin-1-yl) phenyl] propionic acid is thus obtained, 207-210 °.

Example 10: 3 g of the lithium salt of the 4-tolylsulfonylhydrazone of 4- (4-oxopiperidino) phenylacetate is slowly heated, first to 30-40? / 0.3 mm, Hg in order to achieve complete drying, then for 45 minutes 801350 / o, 3 mm Hg. The residue is in a minimal. Amount of ethanol taken up, the solution drawn up on a small column of silica gel and eluted with benzyl. The first eluate is evaporated and gives the ethyl 4- (1,2,5,6-tetrahydropyridyl) phenylacetate of the formula which has characteristic bands in the infrared absorption spectrum at 5.86 and.

By hydrolysis, e.g. as described in Example 1, one obtains from the ethyl 4- (1,2,5,6-tetrahydropyridyl) phenylacetate the 4- (1,2,5,6-tetrahydropyridyl) acetic acid.

The starting material can be obtained as follows: A mixture of 89.6 g of ethyl 4-aminophenyl ester, 400 g of ethyl acrylate and 100 ml of acetic acid is refluxed for 19 hours and then under reduced pressure Pressure restricted. The concentrate is poured onto 500 ml of ice water; the mixture is made basic with an aqueous sodium hydroxide solution and with diethyl ether extracted. The organic extract is dried, filtered and evaporated and the residue is distilled; the fraction boiling at 211-215 ° / 0.6 mm Hg represents the 4- (N, N-bis-carbäthoxyäthyl-amino) -phenylacetic acid-ethyl ester.

A solution of 38 g of ethyl 4- (N, N-bis-carbäthoxyäthylamino) phenylacetate in 100 ml of ethanol is added dropwise with a solution of 3.4 g of sodium in 100 ml Ethanol added; the mixture is refluxed for 7 hours, then evaporated under reduced pressure. The residue is taken up in water, the mixture extracted with diethyl ether and the organic extract dried and filtered and evaporated; the 4- (3-carbethoxy-4-oxo ~ piperidino) phenylacetic acid is thus obtained ester.

A mixture of 30> 5 g of ethyl 4 - () - carbethoxy-4-oxopiperidino) phenylacetate and 300 ml of a 50% aqueous sodium hydroxide solution is added for 12 hours heated on the steam bath, then cooled and acidified with concentrated hydrochloric acid. The mixture is heated for 6 hours and evaporated under reduced pressure; the residue is taken up in a solution of chlorine water, rstoff in ethanol, the mixture evaporated again and the residue taken up in water. The aqueous mixture is made basic with an aqueous sodium hydroxide solution and with diethyl ether extracted; the organic extract is dried and evaporated and one obtains so the 4- (4-oxo-piperidino) -phenylacetic acid ethyl ester.

A mixture of 5.2 g of ethyl 4- (4-oxo-piperidino) phenylacetate, 2.1 g of 4-toluenesulfonylhydrazide, 3 ml of vinegar and 50 ml of ethanol are used for 30 Boiled at reflux for minutes, then chilled. The resulting precipitate is filtered off and added in a minimal amount of tetrahydrofuran. The solution is below a nitrogen atmosphere with 13 ml of a 1.6N n-butyllithium solution dropwise added in hexane, the temperature being kept at 0-50.

After 30 minutes the mixture is at a temperature below 35 ° evaporated to give the lithium salt of 4-tolylsulfonylhydrazone des 4- (4-Oxo-piperidino) -phenylacetic acid ethyl ester, which is further processed without purification will.

Example 11: Tablets with 0.025 g each of the active substance can be used as are prepared as follows: Composition (for 10000 tablets): α- [3-chloro-4- (3-pyrrolin-yl) -phenylpropionic acid 250 g lactose 1956 g corn starch 90 g polyethylene glycol 6000 90 g talc powder 90 g Magnesium stearate 24 g purified water q.s.

The powdery ingredients are passed through a sieve with a 0.6 mm sieve opening driven. The CL-E3-chloro-4- (3-pyrrolin-lyl) -phenyl] -propionic acid, the milk sugar, the talc, the magnesium stearate and half of the corn starch are in a suitable Mixer mixed. The other half of the corn starch is suspended in 45 ml of water and the suspension is added to the boiling solution of polyethylene glycol in 180 ml of water.

The paste obtained is used to granulate the powder mixture, adding a further amount of water if necessary. The granules will dried for 16 hours at 350, on a sieve with sieve openings of 1.2 mm crushed and using punches 7.1 mm in diameter (the upper with score line) processed into tablets.

Example 12: The starting material used in the procedure of Example 1. can also be prepared as follows: 100 ml of hexamethylphosphoramide is under Stir and under a nitrogen atmosphere with 4.8 g of a 50% dispersion added sodium hydride in mineral oil, followed by 17.1 g of α-methyl-malonic acid diethyl ester. The mixture is slowly heated to 1000 and then with a solution dropwise of 19.2 g of 2,4-dichloronitrobenzene in 20 ml of hexamethylphosphoramide treated the is added within 30 minutes; the temperature is for 7 hours at Maintained 100 °. After cooling, the mixture is diluted with water and taken under evaporated under reduced pressure, the residue is taken up in water and with Benzene extracted. The organic extract is washed with water, dried, filtered and evaporated and the residue distilled; - those at 147-1480 / Q, 25 The fraction boiling mm Hg is the α- (3-chloro-4-nitrophenyl) -α-methyl-malonic acid diethyl ester the; the corresponding α- (3-chloro-4-nitro-phenyl) -α-ethylmalonic acid diethyl ester boils at 170-174 ° / 1 mm Hg.

Hydrogen chloride gas is passed through a solution for 5 minutes of 4 g of a- (3-chloro-4-nitro-phenyl) -a-methyl-malic acid diethyl ester in 50 ml of anhydrous Ethanol beads, then gives 0.5 g of a 10% palladium-on-carbon catalyst and hydrogenated the mixture for 10 minutes under an initial pressure of 3 atmospheres. Filter; the filtrate is evaporated under reduced pressure, the residue taken in a 5% sodium hydroxide solution and washed with diethyl ether extracted. The organic extract is dried, filtered and evaporated and the α- (4-amino-3-chlorophenyl) -α-methyl-malonic acid-di is thus obtained ethyl ester> that characteristic in the infrared spectrum at 1720, 3370 and 3460 cm 1 Has bands.

A mixture of 75 g of a- (4-amino-3-chlorophenyl) -a-methyl-malonic acid diethyl ester and 150 ml of a 50% aqueous sodium hydroxide solution is added for 16 hours boiled under reflux, cooled, diluted with water and washed with diethyl ether, then acidified with concentrated hydrochloric acid. The mixture will turn during Boiled under reflux for 16 hours and evaporated under reduced pressure. The residue is taken up in an anhydrous solution of hydrogen chloride in ethanol, the mixture was refluxed for 6 hours and evaporated, and the residue recrystallized from a mixture of ethanol and diethyl ether; you get so das .c- (4-Amino-3-chloro-phenyl) -propionic acid ethyl ester-hydrochlorld, F. 164-1680.

Example 13: A mixture of 10> 8 g of ethyl 4-aminophenylacetate hydrochloride, 32.4 g of 1,4-dibromo-2-butene, 84 g of sodium hydrogen carbonate and 500 ml of dimethylformamide is refluxed for 6 hours with stirring boiled, then filtered hot. The filtrate is evaporated under reduced pressure; the residue containing the ethyl 4- (3-pyrrolin-1-yl) phenylacetate of the formula it is taken up in 150 ml of a 25% strength aqueous sodium hydroxide solution and the mixture is boiled under reflux for one hour, cooled and washed with ether, then adjusted to pH 5 with hydrochloric acid and extracted with ether. The organic extract is dried, filtered and evaporated, whereby the 4- (3-pyrrolin-1-yl) -pehylacetic acid of the formula which melts at 162-165 °.

If ethyl 4-aminophenyl acetate, ethyl α- (4-aminophenyl) propionate is used, 4-Amino-3-chlorophenylacetic acid ethyl ester or a- (4-Amino-3-chlorophenyl) propionic acid ethyl ester with 1,4-dibromo-2-butene - or 1,5-dibromo-2-pentene according to the method described above to get the'4- (3-pyrrolin-l-yl) -phenyi ethyl acetate, 4- (1,2,5,6-tetrahydro-1-pyridyl) -phenylacetic acid ethyl ester, α- [4- (3-Pyrrolin-1-yl) -phenyl] -propionic acid ethyl ester, α- [4- (1,2,5,6-Tetrahydro-1-pyridyl) -phenyl] -propionic acid ethyl ester, α- [3-Chloro-4- (3-pyrrolin-1-yl) -phenyl] -acetic acid ethyl ester, α- [3-chloro-4- (1,2,5,6-tetrahydro-1-pyridyl) -phenyl ] ossetic acid ethyl ester, α- [3-chloro-4- (3-pyrrolin-1-yl) -phenyl] -propionic acid ethyl ester or α- [3-chloro-4- (1,2,5,6-tetrahydro-1-pyridyl) - phenyl] propionic acid ethyl ester.

Claims (197)

Claims 1. A process for the preparation of α- (aminophenyl) -aliphatic carboxylic acid compounds of the formula wherein R- represents an optionally functionally modified carboxyl group, R1 represents a hydrogen atom or a lower alkyl or the cyclopropyl group, R2 represents hydrogen, a halogen atom or the. Means trifluoromethyl group, and represents a 5- to 6-membered 3-alkenyleneamino radical, and also functional amino derivatives thereof, characterized in that; that one a) in a compound of the formula in which X1 is a radical which can be converted into the grouping of the formula -CH (R1) -R (IIa), the group X1 converts into a grouping of the formula IIa, or b) in a compound of the formula wherein X2 is one in the 3-alkenyleneamino group represents convertible radical, X2 is converted into this group, or c) in a compound of the formula wherein X3 is a group in the 4-position and in the 3-position represents the radical R2 containing, optionally only partially, a saturated phenyl radical, X3 in the radical of the formula converted, or (d) in a compound of the formula wherein R2 ° represents a radical which can be converted into a group R2, R2 ° converts into a group R2, and, if desired, converts a compound obtained within the defined scope into another compound of the invention, and / or, if desired, a free compound obtained The compound is converted into a salt or a salt obtained into a free compound or into another salt, and / or, if desired, a mixture of isomers obtained is separated into the individual isomers. 2. A process for the preparation of α- (aminophenyl) aliphatic carboxylic acid compounds of the formula I according to Claim 1, in which R1, n, urid R have the meanings given in claim 1, or salts thereof, with the proviso that in a compound in which R1 and R2 are a hydrogen atom and R is a free carboxy group or a carbethoxy group, the group. stands for the 3-alkenyleneamino group with 6 ring members, characterized in that a) in a compound dei 'formula wherein X1 is a radical convertible into a grouping of the formula - (CH (R1) -R (IIa), where R has the meaning given in claim 1, converting the group X1 into a grouping of the formula IIa, or b) in a compound the formula wherein R has the meaning given in claim 1 and X is one in the group represents convertible radical, X2 is converted into this radical, or c) in a compound of the formula wherein R has the meaning given in claim 1, and X3 is a group in the 4-position and is optionally only partially saturated phenyl radical containing the radical R2 in the 3-position, the latter in the radical of the formula and, if desired, converting a compound obtained into another compound of the invention within the defined scope, and / or, if desired, converting a free compound obtained into a salt or a salt obtained into a free compound or into another salt , and / or, if desired, separating a mixture of isomers obtained into the individual isomers. 3. A process for the preparation of a- (aminophenyl) aliphatic carboxylic acid compounds of the formula I according to claim 1, wherein R1, R2 and R have the meanings given in claim 1 or salts thereof, characterized in that a) in a compound of the formula wherein X1 is a radical convertible into a grouping of the formula -CH (R1) -R (IIa), where R has the meaning given in claim 1, converting the group X1 into a grouping of the formula IIa, or b) in a compound of the formula wherein R has the meaning given in claim 1, and X2 is one in the group Is convertible radical, X2 converted into this radical, and, if desired, a compound obtained within the defined scope converted into another compound of the invention, and / or, if desired, a free compound obtained into a salt or a salt obtained into a free compound or converted into another salt, and / or, if desired, separates a mixture of isomers obtained into the individual isomers. 4. A process for the preparation of α- (aminophenyl) aliphatic carboxylic acid compounds of the formula I according to claim 1, wherein has the meaning given in claim 1, R1 represents a hydrogen atom or the methyl group, R2 represents a hydrogen atom or a chlorine atom, and R represents the carb.ethoxy group or, when R1 and R2 each represent a hydrogen atom, represents a carboxy group, or salts thereof, characterized in that a) in a compound of the formula in which X3 is a radical which can be converted into a group of the formula -CH (R1) -R (IIa), in which R has the meaning given in claim 1, the group X1 converts into a group of the formula IIa, or in a compound of the formula wherein R has the meaning given in claim 1, and one in the group X2 is converted into this radical, and in a compound obtained which contains a functionally modified carboxy group different from the carbethoxy group, this is converted into a carboxy or carbethoxy group, and, if desired, one obtained. Compound within the defined framework converted into another compound of the invention, and / or, if desired, converting a free compound obtained into a salt or a salt obtained into a free compound or into another salt, and / or, if desired, separating a mixture of isomers obtained into the individual isomers. Method according to claim -1, characterized in that 1 in the starting material of formula II represents a hydrogen atom and the corresponding starting material with a compound of the formula Y1-CH (R1) -R (IIb), wherein Y1 is a free or reactive one represents pre-esterified hydroxyl group, is implemented. 6. The method according to claim 2, characterized in that X1 in the starting material of formula II represents a hydrogen atom and the corresponding starting material with a compound of the formula Y1-CH (R1) -R (IIb), in which R is given in claim 1 Has meaning, and Y1 represents a free or reactive esterified hydroxyl group, is implemented. 7. The method according to claim 3, characterized in that X1 is in the starting material Formula II represents a hydrogen atom and the corresponding starting material with a compound of the formula Y1-CH (R1) -R (IIb), in which R is given in claim 1 Has meaning, and Y1 is a free or reactive esterified Ilydroxygruppe represents, is implemented. 8. The method according to claim 11, characterized in that X1 im Starting material of the formula II represents a hydrogen atom and the corresponding Starting material with a compound of the formula Y1-CH (R1) -R (IIb), wherein R is the has the meaning given in claim 1, and Y1 is a free or reactive esterified one Represents hydroxyl group, is implemented. 9. The method according to claim 5, characterized in that the reaction is carried out in the presence of a Lewis acid. 10. The method according to claim 6, characterized in that the reaction is carried out in the presence of a Lewis acid. 11. The method according to claim 7, characterized in that the reaction is stirred in the presence of a Lewis acid. 12. The method according to claim 8, characterized in that the reaction is carried out in the presence of a Lewis acid. 13. The method according to claim 1, characterized in that X1 im Source material. of the formula II represents a metallic grouping and the corresponding Starting material with a compound of the formula Y1-CH (R1) -R (IIb), wherein Y1 is a represents reactive esterified hydroxy group, is implemented. 14. The method according to claim 2, characterized in that X1 im Starting material of the formula II represents a metallic grouping and that corresponding starting material with a compound of the formula Y1-ClI (R1) -R (IIb), wherein R has the meaning given in claim 1, and Y1 is a reactive esterified Represents hydroxyl group, is implemented. 15. The method according to claim 3, characterized in that X1 im Starting material of the formula 11 represents a metallic group and the corresponding Starting material with a compound of the formula Y1-CII (R1) -R (IIb), wherein R is the has the meaning given in claim 1, and Y1 is a reactive esterified hydroxyl group represents, is implemented. 16. The method according to claim 4, characterized in that X1 im Starting material of the formula II represents a metallic group and the corresponding Starting material with a compound of the formula Yl-CH (Rl) -R (IIb), wherein R is the has the meaning given in claim 1, and Y1 is a reactive esterified hydroxyl group represents, is implemented. 17. The method according to claim 1, characterized in that X1 im Starting material of the formula II is a reactive esterified hydroxyl group and the corresponding starting material with a compound of the formula Y1-CH (R1) -R (IIb), in which Y1 represents a metallic grouping, is reacted. 18. The method according to claim 2, characterized in that X1 im Starting material of the formula II is a reactive esterified hydroxyl group and the corresponding starting material with a compound of Formula Y1-ClI (R1) -R (IIb), in which R has the meaning given in claim 1, and Y1 represents a metallic grouping, is implemented 19. The method according to claim 3, characterized in that X1 in the starting material of the formula II is a reactive represents esterified Ilydroxygruppe and the corresponding starting material with a Compound of the formula Y1 -C !! (H1) 4 (lib), in which R is as defined in claim 1 hata and Y1 represents a metallic grouping, is implemented. 20. The method according to claim 1, characterized in that the X1 in the starting material of formula II di. e, grouping of the formula -CH (R1) -Y2 (IIc) signifies, in which Y2 is a represents a metallic residue, and the corresponding starting material with a metal-free, reactive derivative of carbonic or formic acid is implemented. 21. The method according to claim 2, characterized in that the X1 in the starting material of the formula II is the grouping of the formula -CH (R1) -Y2 (IIc), in which Y2 is a represents a metallic residue, and the corresponding starting material with a metal-free, reactive derivative of carbonic or formic acid is implemented. 22. The method according to claim 3, characterized in that X1 im Starting material of the formula II is the grouping of the formula -CH (R1) -Y2 (IIc), where Y2 represents a metallic radical, and the corresponding starting material reacted with a metal-free, reactive derivative of carbonic or formic acid will. 23. The method according to claim 4, characterized in that X1 im Starting material of the formula II the grouping of the formula -CH (R1) -Y2 (IIc) J in which Y2 represents an alkali metal atom or a halogenomagnesium group, and the corresponding Starting material with a metal-free, reactive derivative of the carbon or Formic acid is converted. 24. The method according to claim 1, characterized in that X1 im Starting material of the formula II is the grouping of the formula -CH (R1) -Y2 (IIc), wherein Y2 represents an ammonium group, and the corresponding starting material with a metal cyanide is implemented. 25. Verrahren according to claim 2, characterized in that X1 im Starting material of the formula II is the grouping of the formula -CH (R1) -Y2 (IIc), wherein Y2 represents an ammonium group, and the corresponding starting material with a Retallcyanid is implemented. 26. The method according to claim 3, characterized in that X1 im Starting material of the formula II is the grouping of the formula -CH (R1) -Y2 (IIc), wherein Y2 represents an ammonium group, and the corresponding starting material with a metal cyanide is implemented. 27. The method according to claim 4, characterized in that X1 im Starting material of the formula II is the grouping of the formula -CH (R1) -Y2 (IIc), where Y2 represents an ammonium group5 and the corresponding starting material with a metal cyanide is implemented. 28. The method according to claim 1, characterized in that X1 the Grouping of the formula -CH (R1) -Y2 (IIc) denotes, in which Y2 is a free or reactive, represents functionally modified hydroxyl group, and the corresponding starting material is reacted with a metal cyanide. 29. The method according to claim 2, characterized in that X1 im Starting material of the formula 11 is the grouping of the formula -CH (R1) -Y2 (IIc), where Y2 is a free or reactive> functionally modified. Represents hydroxyl group, and the corresponding starting material with a metal cyanide is implemented. 30. The method according to claim 3, characterized in that X1 im Starting material of the formula II is the grouping of the formula -CH (R1) -Y2 (IIc), wherein Y2 is a free or reactive, functionally modified hydroxyl group represents, and reacted the corresponding starting material with a metal cyanide will. 31. The method according to claim 4, characterized in that X1 im Starting material of the formula II is the grouping of the formula -CH (R1) -Y2 (IIc), wherein Y2 represents a reactive esterified hydroxy group, and the corresponding Starting material is reacted with a metal cyanide. 32. The method according to claim 1, characterized in that X1 im Starting material of the formula II for the grouping of the formula -CH (R (IIc) is, wherein Y2 is a free, esterified or present in salt form hydroxyl group or represents a l-lower alkenyl group, and the corresponding starting material with Carbon monoxide is implemented. 33. The method according to claim 2, characterized in that X1 im Starting material of the formula II represents the grouping of the formula -CH (R1) -Y2 (IIc), wherein Y2 is a free, esterified or in salt form hydroxyl group or represents a 1-nicderalkenyl group, and the corresponding starting material with Carbon monoxide is implemented. The method according to claim 3, characterized in that the'-; X1 in the output, material of the formula II for the grouping of the formula -CH (R1) -Y2 (IIe), in which Y2 cinc free, esterified or present in salt form hydroxyl group or a 1-lower alkenyl group represents, and the corresponding starting material is reacted with carbon monoxide. 35 The method according to claim 1, characterized in that X1 im Starting material of the formula II is the grouping of the formula -CH (H1) -Y3 (IId), in which Y3 can be converted into a free or functionally modified carboxyl group Represents the remainder, and in a corresponding starting material Y3 by oxidation or rearrangement converted into a free or functionally modified carboxyl group will. 36. The method according to claim 2, characterized in that X1 im Starting material of the formula II denotes the group of the formula -CH (R1) -Y3 (IId), in which Y3 can be converted into a free or functionally modified carboxyl group Represents remainder, and in a corresponding Starting material Y3 by oxidation or rearrangement into a free or functionally modified carboxy group is converted. 37. The method according to claim 3, characterized in that X1 im Starting material of the formula II means the grouping of the formula -CH (R1) -Y3 (led), in which Y3 can be converted into a free or functionally modified carboxyl group Represents the remainder, and in a corresponding starting material Y3 by oxidation or rearrangement converted into a free or functionally modified carboxy group will. 38. The method according to claim 4, characterized in that X1 in the Starting material of the formula II is the grouping of the formula -CH (R1) -Y3 (IId), in which Y3 can be converted into a free or functionally modified carboxyl group Represents the remainder, and in a corresponding starting material Y3 by oxidation is converted into a free carboxyl group. 39. The method according to claim 35, characterized in that Y is a Methyl, hydroxymethyl, borylmethyl, 3 hydroxyiminomethyl, formula, 1-lower alkenyl, 1-lower alkynyl, 1,2-dihydroxy-lower alkyl or an acyl group, the by oxidation into a free CarboXy, a cyano, a carbamyl or a hydroxycarbamyl group is convicted. 40. The method according to claim 36, characterized in that Y3 is a Methyl, hydroxymethyl, borylmethyl, hydroxyiminomethyl, formula, 1-lower alkenyl, l-lower alkynyl, 1,2-dihydroxy-lower alkyl or an acyl group which is represented by Oxidation to a free carboxy, a cyano, a carbamyl or a hydroxycarbamyl group is convicted. 41. The method according to claim 37, characterized in that Y3 is a Methyl, hydroxymethyl, borylmethyl, hydroxyiminomethyl, formyl, 1-lower alkenyl, 1-lower alkynyl, 1,2-dihydroxy-lower alkyl or an acyl group which is represented by Oxidation to a free carboxy, a cyano, a carbamyl or a hydroxycarbamyl group is convicted. 42. The method according to claim 38, characterized in that Y3 is a Hydroxymethyl, borylmethyl, formyl, l-lower alkenyl, lower alkenoyl or carboxycarbony'l group represents, which is stirred into the carboxy group by oxidation. 43. The method according to claim 1, characterized in that X1 im Starting material of the formula II represents the grouping of the formula -CH (R1) -Y3, wherein Y3 is an optionally functionally modified carboxycarbonyl group, and Y3 by decarbonylation into an optionally functionally modified carboxy group is converted. 44. The method according to claim 2, characterized in that X1 im Starting material of the formula II represents the grouping of the formula -CH (R1) -Y3, where Y3 is an optionally functionally modified carboxycarbonyl group, and Y3 by decarbonylation into an optionally functionally modified carboxy group is converted. 45. The method according to claim 3, characterized in that X1 im Starting material of the formula II represents the grouping of the formula -CH (R1) -Y3, wherein Y3 denotes an optionally esterified carboxycarbonyl group, and Y denotes by Decarbonylation is converted into an optionally esterified carboxy group. 46. The method according to claim ß, characterized in that X1 in Starting material of the formula II represents the grouping of the formula -CH (R1) -Y3, wherein Y3 is a carboxycarbonyl group means, and Y3 by decarbonylation is converted into a carboxy group. 47. The method according to claim 1, characterized in that X1 im Starting material of the formula II is a group of the formula -C (R1) (Y4) -R (IIf) or the Formula (Ig) represents in which Y4 is reduced by reducing, decarboxylating, deacylating or desulfurization in hydrogen, and Y together by reduction into group R1 is converted with hydrogen. 48. The method according to claim 2, characterized in that X1 im Starting material of the formula II is a group of the formula -X (R1) (Y4) -R (IIf) or the Formula -C (= Y5) -R (IIg) represents, in which R has the meaning given in claim 1, and Y4 by reducing, decarboxylating, deacylating or desulfurizing in hydrogen, and Y5 is converted into the group R1 together with hydrogen by reduction. 49. The method naeli claim 3, characterized in that X1 im Starting material of the formula II is a group of the formula -C (R1) (Y4) -R (IIf) or the Formula -C (= Y5) -R (IIg) represents, in which R has the meaning given in claim 1, and Y4 by reducing, decarboxylating, Deacylicrer 'or desulfurizing in hydrogen, and Y5 through Reduction to group R1 together with hydrogen is convicted. 50. The method according to claim 4, characterized in that X1 im Starting material of the formula II is a group of the formula -C (R1) (Y4) -R (IIf) or the Formula -C (= Y5) -R (IIg) is where R is as defined in claim. 1 given meaning has, and wherein Y4 represents a hydroxyl or carboxy group which is obtained by reduction or decarboxylation in hydrogen, and where Y5 is a methylene group, which is converted into the methyl group together with hydrogen by reduction. 51. The method according to claim 47, characterized in that Y4 is a free or reactive esterified or etherified hydroxyl or islercapto group or is a disubstituted amino group, and Y5 is a lower alkylidene or Cyclopropylidene group or an optionally ketalized oxo or thiono group represents, and such starting materials or corresponding quaternary o- or p-quinone methide compounds by treatment with catalytically activated or electrolytically generated hydrogen or with a chemical reducing agent, optionally in the presence of a desulfurizing agent, converts. 52. The method according to claim 48, characterized in that Y4 is a free or reactive esterified. ' or etherified hydroxy or mercapto group or one disubstituted amino group, and Y5 is a lower alkylidene or cyclopropylidene group or an optionally ketalized oxo or thiono group represents, and one such starting materials or corresponding quaternary p-quinone methide compounds by treatment with catalytically activated or electrolytically generated hydrogen or with a chemical reducing agent, optionally in the presence of a desulfurizing agent, converts. 53. The method according to claim 49, characterized in that YX is a free or reactive esterified or etherified hydroxyl or mercapto group, and Y5 is a lower alkylidene or cyclopropylidene group, or where appropriate represented ketalized oxo or thiono group and one such starting materials or corresponding o- or p-quinone methide compounds by treating with catalytically activated or electrolytically generated hydrogen or with metals in the presence of acids, alkaline agents or alcohols, optionally in the presence of one Desulphurizing agent>. converts. 54. The method according to claim 50, characterized in that Y4 or Y5 converted by treatment with catalytically activated or nascent hydrogen will. 55. The method according to claim 51, characterized in that one free hydroxyl group Y4 by treatment with phosphorus and iodine, hydriodic acid, Tin-IS-chloride or an alkali metal sulfite or dithionite reduced. 56. The method according to claim 52, characterized in that one free hydroxyl group Y4 by treatment with phosphorus and iodine> hydriodic acid, Tin-IT-chloride or an alkali metal sulfite or dithionite reduced. 57. The method according to claim 53, characterized in that one free hydroxyl group Y4 by treatment with phosphorus and iodine; Hydriodic acid, Tin (II) chloride or an alkali metal sulfite or dithionite reduced. 58. The method according to claim 50, characterized in that one free hydroxyl group Y4 by treatment with phosphorus and iodine, hydriodic acid or reduced tin (II) chloride. 59. The method according to claim 47, characterized in that one Oxo group Y5 reduced by treatment with hydrazine. 60. The method according to claim 48, characterized in that one Oxo group Y5 reduced by treatment with hydrazine. 61. The method according to claim 49, characterized in that one Oxo group Y reduced by treatment with Hydra-5 in. 62. The method according to claim 47, characterized in that in a starting material in which Y4 represents a carboxy group, this by pyrolysis splits off. 63. The method according to claim 48, characterized in that in a starting material in which Y4 represents a carboxy group, this by pyrolysis splits off. 64. The method according to claim 49, characterized in that one in a starting material in which Y4 represents a carboxy group, this by pyrolysis splits off. G5. Method according to claim 50, characterized in that an in a starting material in which Y4 represents a carboxy group, this by pyrolysis splits off. 66. The method according to claim 47, characterized in that one Starting material in which Y4 represents an acyl group by treating with a Subjects strongly alkaline agents to ß-keto acid cleavage. 67. Procedure. according to claim 48, characterized in that one a starting material wherein Y4 represents an acyl group by treating with a Subjects strongly alkaline agents to ß-keto acid cleavage. 68. The method according to claim 49, characterized in that one Starting material in which Y4 represents an acyl group by treating with a Subjects strongly alkaline agents to ß-keto acid cleavage. 69. The method according to claim. 1, characterized in that X1 in Starting material of the formula II represents an acetyl group and the corresponding Starting material with sulfur in the presence of ammonia or a primary or secondary amine is treated. 70. The method according to claim 2, characterized in that X1 im Starting material of the formula II represents an acetyl group and the corresponding Starting material with sulfur in the presence of ammonia or a primary or secondary amine is treated. 71. The method according to claim 3, characterized in that X1 im Starting material of the formula II represents an acetyl group and the corresponding Starting material with sulfur in the presence of ammonia or a primary or secondary amine is treated. 72. The method according to claim 4, characterized in that X1 im Starting material of the formula II represents an acetyl group and the corresponding Starting material with sulfur in the presence of ammonia or a primary or secondary amine is treated. 73. The method-according to claim 1, characterized in that X1 im Starting material of the formula 11 a grouping of the formula -C (#O) -C (# N2) -R1 (IIh) represents and the corresponding starting material by hydrolysis, alcoholysis, ammonolysis or aminolysis is converted0 74. The method according to claim 2, characterized in that that X1 in the starting material of the formula II is a grouping of the formula -C (= O) -C (= N2) -R1 (lih) -represents and the corresponding starting material by hydrolysis alcoholysis, Ammonolysis or aminolysis is converted. 75. The method according to claim 3 »characterized in that X1 im Starting material of the formula II is a grouping of the formula. -C (= O) -c '(= N2) -R1 (IIh) represents and the corresponding starting material 'by hydrolysis alcoholysis, ammonolysis or aminolysis is converted0 76. The method according to claim 4, characterized in that X1 is a group in the starting material of the formula II of the formula -C (= O) -C (= N2) -R1 (IIh) and the corresponding starting material is converted by hydrolysis, alcoholysis, ammonolysis or aminolysis. 77. The method according to claim 1, characterized in that X1 im Starting material of the formula II a grouping of the formula -C (#O) -CH (R1) -Hal (IIi) represents wherein Hal represents a halogen atom, and the corresponding starting material treated with a strong alkaline agent or a soluble silver salt. 78. The method according to claim 2, characterized in that X1 im Starting material of the formula II a Gxoppierung of the formula -C (= O) -CH (R1) -Hal (Ili) represents wherein Hal represents a halogen atom, and the corresponding starting material treated with a strong alkaline agent or a soluble silver salt. 79. The method according to claim 3, characterized in that X1 im Starting material of the formula II a grouping of the formula -C (= O) -CH (R1) -Hal (IIi) represents wherein Hal represents a halogen atom, and the corresponding starting material treated with a strong alkaline agent or a soluble silver salt. 80. The method according to claim 1, characterized in that a starting material of the formula III with a compound of the formula (IIIa) is reacted, wherein one of the radicals X2 and Y6 represents a hydrogen atom or a metallic group and the other represents a free or reactive esterified hydroxyl group. 81. The method according to claim 2, characterized in that a starting material of the formula III, wherein R dic has the meaning given in claim 1, with a compound of the formula (IIIa) is reacted, wherein one of the radicals X2 and Y6 represents a hydrogen atom or a metallic group and the other represents a free or reactive esterified hydroxyl group. Process according to claim 3, characterized in that a starting material of the formula III, wherein i? has the meaning given in claim 1, with a compound of the formula (IIIa) is set> where one of the radicals X2 and Y6 represents a hydrogen atom or a metallic group and the other represents a free or reactive esterified hydroxyl group. 83. The method according to claim 4, characterized in that a starting material of the formula III, wherein R has the meaning given in claim 1 and X2 stands for a reactive hydroxyl group, with a compound of the formula or an alkali metal derivative is reacted. 84. The method according to claim 1, characterized in that in a starting material of the formula III, in which X2 is a primary, secondary or tertiary amino group, X2 is by transamination with an amine of the formula is converted. 85. Verrahren according to claim 2, characterized in that in a starting material of the formula IIL, wherein R has the meaning given in claim 1 and X2 is a primary, secondary or tertiary amino group, X2 is transaminating with an amine of the formula is converted. 86. The method according to claim 3, characterized in that in a starting material of the formula III, wherein R has the meaning given in claim 1, and X2 is a primary, secondary or tertiary amino group, X2 by transamination with an amine of the form] is converted. 009847/1913 87. The method according to claim 1, characterized characterized in that a starting material of the formula III, wherein X2 is a primary Amino group means with its glycol of the formula HO-A-OH (IIIb) or a reactive one Derivative thereof implemented. 88. The method according to claim 2, characterized in that one Starting material of the formula III, in which R has the meaning given in claim 1, and X2 is a primary amino group, with a glycol of the formula HO-A-OH (IIIb) or a reactive derivative thereof. 89. The method according to claim 3, characterized thereby. net that a starting material of the formula III, wherein R is the -im Claim 1 has the given meaning, and X2 denotes a primary amino group, with a glycol of the formula HO-A-OH (IIIb) or a reactive derivative thereof implemented. 90. The method according to claim 4 *, characterized in that one Starting material of the formula III, in which R has the meaning given in claim 1 has, and X2 has a primary amino group means with a reactive Ester of a glycol of the formula HO-A-OH (IIIb). 91. The method according to claim 1, characterized in that a starting material of the formula III is used in which X2 represents one, the remainder corresponding alkyleneamino group having a group which can be split off with introduction of a double bond in the alkyleneamino radical is in the β or γ position. 92. The method according to claim 2, characterized in that X2 in a starting material of the formula III, in which R has the meaning given in claim 1, is the remainder of the formula corresponding alkyleneamino group, in which the ß- or ring carbon atom contains an optionally esterified hydroxyl group, and the starting material is converted by dehydrating or splitting off the elements of an acid. 93. The method according to claim 91, characterized in that a free or reactive etherified hydroxyl group represents the removable group, which is split off together with hydrogen under dehydrating conditions. 94. The method according to claim 91, characterized in that a The reactive esterified hydroxyl group represents the removable group, which together is split off with hydrogen in a basic medium or pyrolytically. 95. The method according to claim 94, characterized in that a etherified mercapto-thiocarbonyloxy group is a reactive esterified hydroxyl group represents, which is split off pyrolytically together with hydrogen. 96. The method according to claim 91, characterized in that a optionally reactive esterified or etherified Hercapto group the cleavable Group means which are split off by dehydrosulfation together with hydrogen will. 97. The method according to claim 91, characterized in that a Ammonium group or a disubstituted aminoxyl group represents the split-off group, which is split off pyrolytically together with hydrogen. 96. The method according to claim 91, characterized in that a Sulfonyl-substituted hydrazo groups represents the split-off group which is pyrolytic be split off. 99. The method according to claim 91, characterized in that a substituted sulfonyl or ternary sulfonium group represents the removable group, the pyrolytic is split off together with hydrogen. 100. The method according to claim 1, characterized in that in one Starting material of the formula IV is the, optionally only partially, saturated phenyl radical by means of dehydration by pyrolysis or by treatment with a dehydrating agent is converted into the phenyl radical. 101. The method according to claim 2, characterized in that in one Starting material of the formula IV, in which R has the meaning given in claim 1, the, optionally only partially, saturated phenyl radical by means of dehydration Pyrolysis or converted into the phenyl radical by treatment with a dehydrating agent will. 102. The method according to claim 1, characterized in that R2 ° in a starting material of the formula V represented a diazonium group by Vlassstoff or halogen is exchanged. 103. The method according to claim 1, characterized in that one obtained Esters, amides, thioamides or NiS trile hydrolyzed to the free acids. 104. The method according to claim 2, characterized in that one obtained Esters, amides, thioamides or nitriles are hydrolyzed to the free acids. 105. The method according to claim 3, characterized in that one obtained Esters, amides, thioamides or nitriles are hydrolyzed to the free acids. 106. The method according to claim 4, characterized in that one obtained Esters, amides, thioamides or nitriles hydrolyzed to the free acids. 107. The method according to claim 1 or 103> characterized in that that in a compound obtained with a free carboxy group, this is esterified into one Carboxy group converts. 108. The method according to claim 2 or 104, characterized in that in a compound obtained with a free carboxy group, this is esterified into one Carboxy group converts. 109. The method according to claim 3 or 105, characterized in that in a compound obtained with a free carboxy group, this is esterified into one Converted to carboxy group. 110. The method according to claim 4 or 106, characterized in that in a compound obtained with a free carboxy group, this is converted into a carbethoxy group converts. 111. The method according to claim 1 or 103, characterized in that one obtained compound having a free carboxyl group into an acid halide convicted. 112. The method according to claim 2 or 104J, characterized in that one obtained compound having a free carboxyl group into an acid halide convicted. 113. The method according to claim 3 or 105, characterized in that one obtained compound having a free carboxyl group into an acid halide convicted. 114. The method according to claim 4 or 106, characterized in that one obtained compound having a free carboxyl group into an acid halide convicted. 115. The method according to claim 111, characterized in that one acid halides obtained treated with alcohols, ammonia or amines. 116. The method according to claim 112, characterized in that one treated an acid halide obtained with alcohols. 117. The method according to claim 113, characterized in that one treated an acid halide obtained with alcohols, ammonia or amines. 118. The method according to claim 114, characterized in that one treated an acid halide obtained with ethanol. 119. The method according to any one of claims 1, 107 and 11 », characterized in that that the esters, salts or nitriles obtained, in which R1 is hydrogen, are in the a-position metallized and with a reactive ester of an alcohol of the formula R1-OH converts, wherein R1 has the meaning given in claim 1. 120. The method according to any one of claims 2, 108 and 116> thereby characterized in that one obtained esters, salts or nitriles, wherein Rl is hydrogen is, metallized in a-position and with a reactive ester of an alcohol of the formula R1-OH, in which R1 has the meaning given in claim 2. 121. The method according to any one of claims 3, 109 and 117, characterized in that that the esters, salts or nitriles obtained, in which R1 is hydrogen, are in the a-position metallized and with a reactive ester of an alcohol of the formula R1-OH converts, wherein R1 has the meaning given in claim 3. 122. Method according to one of Claims 4, 110 and 119, characterized in that that the esters, salts or nitriles obtained, in which R1 is hydrogen, are in the a-position metallized and with a reactive ester of an alcohol of the formula, Rl-OH converts, wherein R1 has the meaning given in claim 4. 123. The method according to claim 1, characterized in that a compound formed at any stage as an intermediate as a starting material is used and the remaining stage (s) is (are) carried out with this, or the proceedings are interrupted at any stage. 124. The method according to claims 2 and 124, characterized in that a compound formed at some stage as a Tsar product as a starting material is used and the remaining stage (s) carried out with this will be), or the proceedings are interrupted at any stage. 125. Ve-method according to claim 3, characterized in that a compound formed at any stage as an intermediate as a starting material is used and the remaining stage (s) is (are) carried out with this, or the proceedings are interrupted at any stage. 126. The method according to claim 4, characterized in that a compound formed at any stage as an intermediate as a starting material used -is carried out and the remaining stage (s) is (are) carried out with this, or the proceedings are interrupted at any stage. 127. The method according to claim 1, characterized in that starting materials formed under the reaction conditions or in the form of salts or reactive Derivatives are used. 128. The method according to claim 2, characterized in that starting materials formed under the reaction conditions or in the form of salts or reactive Derivatives are used. 129. The method according to claim 3, characterized in that starting materials formed under the reaction conditions or in the form of salts or reactive Derivatives are used. 130. The method according to claim 4, characterized in that starting materials formed under the reaction conditions or in the form of salts or reactive Derivatives are used. 131. The method according to any one of claims 2, 6, 10, 14, 18, 21, 25, 29, 33, 36, 40, 44, 48, 52, 56, 60, 63, 67, 70, 74, 78, 81 , 85, 88, 88> i2, 102, 104, io 112, 116, 120, 124 and 128, characterized in that α- (aminophenyl) -aliphatic carboxylic acid compounds of the formula I according to claim 1, in which has the meaning given in claim 1, R1 is a hydrogen atom or a methyl or cyclopropyl group, R2 is a hydrogen atom or a chlorine atom, and R is a free or esterified carboxy group, or salts thereof prepared, with the proviso that in a Compound in which Rl and R2 are hydrogen atoms and R is a free carboxy group or a carbethoxy group, the group represents the 3-alkenyleneamino group with 6 ring members. 132. The method according to any one of claims 1, 5, 9, 13, 17, 21, 25, 28, 32, 35, 39, 43, 47, 51, 55, 59, 62, 66, 69, 73, 77, 80, 84, 91, 93-100, 102, 103, 107, 113, 117, 123 and 1.27, characterized in that the in claim 131 compounds shown or salts thereof. 133. The method according to any one of claims 3, 7, 11, 15, 19, 23, 27, 30, 34, 37, 41, 45, 49, 53, 57, 61, 64, 69, 71, 75, 79, 82, 86, 89, 105, 109, 113, 117, 121; 125 and 19, characterized in that one a- (aminophenyl). aliphatic carboxylic acid compounds of the formula I according to claim 1, wherein represents the 3-pyrrolin-yl group, R1 represents a hydrogen atom or the methyl or cyclopropyl group, R2 represents a hydrogen atom or a chlorine atom, and R represents the free carboxy group or the carbomethoxy or carbethoxy group, or ammonium, sodium or potassium salts or pharmaceutically acceptable acid addition salts thereof. 134. The method according to one of claims 2, 6, 10, 14, 18, 21, 25, 29, 33, 36, 40, 44, 48, 52, 56, 60, 63, 67, 70, 74, 76, 81, 85, 89, 92, 102, 104, 108, 112, 116, 120, 124 and 126, characterized in that one of claims 153 prepares the compounds shown or salts thereof, with the proviso, that in compounds in which R is the free carbethoxy group, at least one the radicals R1 and R2 are different from hydrogen. 135. The method according to any one of claims 1, 5, 9, 13, 17, 21, 25, 28, 32, 35, 39, 43, 47, 51, 55, 59, 62, 66, 69, 73, 77, 80, 84, 87, 91, 93-100, 102, 103, 107, 111, 115, 119, 123 and 125, characterized in that in claim 133 or salts thereof. 136. The method according to any one of claims 1, 5, 9, 13, 17, 21, 25, 28, 32, 35, 39, 43, 47, 51, 55, 59, 62, 66, 69, 73, 77, 80 , 84, 87, 91, 93-100, 102, 103, 123 and 127, characterized in that α- (aminophenyl) -aliphatic carboxylic acid compounds of the formula I according to Claim 1 in which represents the 3-pyrrolin-1-yl radical, R1 represents a hydrogen atom or the methyl or cyclopropyl group, R2 represents a hydrogen atom or a chlorine atom and R represents the carboxy group, or salts thereof. 137. The method according to any one of claims 4, 8, 12, 16, 23, 27, 31, 38, 42, 46, 50, 54, 56, 65, 72, 76, 83, 90, 106, 110, 114, 118, 122, 126 and 130, characterized in that the α- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionic acid ethyl ester or make a salt from it. 138. The method according to any one of claims 3, 7, 11, 15, 19, 23, 27, 30, 34, 37, 41, 45, 49, 53, 57, 61, 64, 69, 71, 75, 79, 82, 86, 89, 105, 109, 113, 117, 121, 125 and 129, characterized in that the ethyl a- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionate or make a salt from it. 139. The method according to any one of claims 2, 6, 10, 14, 18, 21, 25, 29, 33, 36, 40, 44, 48, 52, 56, 60, 63, 67, 70, 74, 78, 81, 85, 88, 92, 102, 104, 108, 112, 116, 120, 124 and 128, characterized in that the ethyl α- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionate or make a salt from it. 140. The method according to any one of claims 1, 5, 9, 13, 17, 21, 25, 28, 32, 35, 39, 43, 47, 51, 55, 59, 62, 66, 69, 73, 77, 80, 84, 87, 91, 93-100, 102, 103, 107, 111, 115, 119, 123 and 127, characterized in that the ethyl α- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionate or make a salt from it. 141. The method according to any one of claims 3, 7, 11, 15, 19, 23, 27, 30, 34, 37, 41, 45, 49, 53, 57, 61, 64, 69, 71, 75, 79, 82, 86, 89, 105, 125 and 129, characterized in that the α- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionic acid or making salts thereof. 142. The method according to any one of claims 2, 6, 10, 14, 18, 21, 25, 29, 33, 36, 40, 44, 48, 52, 56, 60, 63, 67, 70, 74, 78, 81, 85, 88, 88> 92, 102, 104, 124 and 128, characterized in that the α- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionic acid or making salts thereof. 143. The method according to any one of claims 1, 5, 9, 13, 17, 21, 25, 28, 32, 35, 39, 43, 47, 51, 55, 59, 62, 66, 69, 73, 77, 80, 84, 87, 91, 93-100, 102, 103, 123 and 127, characterized in that a- [3-chloro-4- (3-pyrrolin-l-yl) phenyl] propionic acid or making salts thereof. 144. The procedure described in Example 13. 145. The procedure described in Examples 1-3. 146. The procedure described in Example 7. 147. The procedure described in Examples 4-6 and 8-10. 148. The according to the method of claims 4, 8, 12, 16, 23, 27, 31, 38, 42, 46, 50, 54, 58, 65, 72, 76, 83, 90, 106, 110, 114, 118, 122, 126, 130, 137 and 144 available compounds. 149. The according to the method of claims 3, 7, 11, 15, 19, 23, 27, 30, 34, 37, 41, 45, 49, 53, 57, 61, 64, 69, 71, 75, 9, 82, 86, 89, 105, 109, 113, 117, 121, 125, 129, 133, 138, 141 and 145 available compounds. 150. The according to the method of claims 2, 6, 10, 14, 18, 21, 25, 29, 33, 36, 40, 44, 48, 52, 56, 60, 63, 67, 70, 74, 78, 81, 85, 88, 92, 101, 104, 108, 112, 116, 120, 124, 128, 131, 134, 139, 142 and 146 compounds available. 151. The according to the method of claims 1, 5, 9, 13, 17, 21, 25, 28, 32, 35, 39, 43, 47, 51, 55, 59, 62, 66, 69, 73, 77, 80, 84, 87, 91, 93-100, 102, 103, 107, 111, 115, 119, 123, 127, 132, 135, 136, 140, 143 and 147 available Links. 152. α- (Aminophenyl) aliphatic carboxylic acid compounds of the formula wherein R represents an optionally functionally modified carboxyl group, R1 represents a hydrogen atom or a lower alkyl or the cyclopropyl group, R2 represents hydrogen, a halogen atom or the trifluoromethyl group, and represents a 5- to 6-membered 3-alkenyleneamino chain. 153. Functional amine derivatives of compounds according to claim 152. 154. a- (aminophenyl) -aliphatic carboxylic acid compounds of the formula I according to claim 152, in which R1, R2 and R have the meanings given in claim 152, with the proviso that in compounds in which R is the free carboxy group or the carbethoxy group and each of the radicals R1 and P2 is a hydrogen atom, the group represents the 3-alkenyleneamino group with 6 ring members. 155. Salts of compounds according to claim 154. 156. a- (Aminophenyl) -aliphatic carboxylic acid compounds of the formula I according to claim 152, in which has the meaning given in claim 152, R1 is a hydrogen atom or a methyl or cyclopropyl group, R2 is a hydrogen atom or a chlorine atom, and R is a free or esterified carboxy group, with the proviso that in a compound in which R1 'and R2 represent a hydrogen atom and R represents a free carboxy group or the carbethoxy group, the group represents the 3-alkenyleneamino group with 6 ring members. 157. Salts of compounds according to claim 156. 158. a- (Aminophenyl) -aliphatic carbonic acid compounds of the formula I according to claim 152, in which represents the 3-pyrrolin-1-yl group, R1 represents a hydrogen atom or the methyl or cyclic propyl group, R2 represents a hydrogen atom or a chlorine atom and R represents the free carboxy group or the carbomethoxy or carbethoxy group. 159. Ammonium-> sodium or potassium salts or pharmaceutically acceptable Acid addition salts of compounds according to claim 158. 160. a- (aminophenyl) -aliphatic carboxylic acid compounds of the formula I according to claim 152, in which for the 3-pyrrolin-1-yl radical, R1 for a hydrogen atom or the methyl or cyclopropyl group, R2 r for a hydrogen atom or a chlorine atom and R for the carboxy group. 161. Salts of compounds according to claim 160. 162. Ethyl 4- (3-pyrrolin-1-yl) phenylacetate. 163. 4- (3-pyrrolin-1-yl) phenylacetic acid. 164. Ethyl 4- (1,2,5,6-tetrahydro-1-pyridyl) phenylacetate. 165. Ethyl α- [4- (3-pyrrolin-1-yl) phenyl] propionate. 166. Ethyl α- [4- (1,2,5,6-tetrahydro-1-pyridyl) phenyl] propionate. 167. Ethyl α- [3-chloro-4- (3-pyrrolin-1-yl) -phenyl] -acetate. 168. Ethyl α- [3-chloro-4- (1,2,5,6-tetrahydro-1-pyridyl) phenyl] acetic acid ester. 169. Ethyl α- [3-chloro-4- (3-pyrrolin-1-yl) phenyl] propionate. 170. Ethyl α- [3-Chlo-4- (1,2,5,6-tetrahydro-1-pyridyl) phenyl] propionate. 171. α- [3-Chloro-4- (3-pyrrolin-1-yl) -phenyl] -propionic acid. 172. d-α- [3-Chloro-4- (3-pyrrolin-1-yl) -phenyl] -propionic acid. 173. α- [4- (3-Pyrrolin-1-yl) phenyl] propionic acid. 174. α- [3-Chloro-4- (1,2,5,6-tetrahydro-1-pyridyl) phenyl] propionic acid. 175. α- [4- (1,2,5,6-Tetrahydro-1-pyridyl) phenyl] propionic acid. 176. Ethyl a- [3-Chloro-4- (3-pyrrolin-1-yl) -phenyl] -butyric acid ester. 177. α- [3-Chloro-4- (3-pyrrolin-1-yl) -phenyl] -butyric acid. 178. α- [3-Chloro-4- (3-pyrrolin-1-yl) -phenyl] -α-cyclopropyl acetic acid ethyl ester. 179. α- [3-Chloro-4- (3-pyrrolin-1-yl) -phenyl] -α-cyclopropylacetic acid. 180. α- [3-Chloro-4- (3-pyrrolin-1-yl) -phenyl] -propionic acid, N-oxide. 181. 4- (1,2,5,6-Tetrahydro-1-pyridyl) phenylacetic acid. 182. Salts of compounds of claims 162-170. 183. Salts of compounds of claims 171-113. 184. Salts of compounds of claims 174-175. 185. Salts of compounds of claims 176-181. 186. Pharmaceutically usable salts of compounds of the claims 162-170. 187. Pharmaceutically usable salts of compounds of the claims 152, 153 and 171-173. 188. Pharmaceutically acceptable salts of compounds of claims 154, 156, 174 and 175. 189. Pharmaceutically usable salts of compounds of the claims 160 and -176-181. 190. Pharmaceutical preparations, characterized by a content of a compound of any of claims 162-170 and 186. 191. Pharmaceutical preparations, characterized by a content on a compound of any one of claims 152, 153> 159, 171-173 and '187. 192. Pharmaceutical preparations characterized by a content of a compound of any of claims 154, 156, 174, 175 and 188. 193. Pharmaceutical preparations characterized by a content of a compound of any one of claims 160, 176-181 and 189. 194. The new compounds described in Example 13. 195. The new compounds described in Examples 1-3. 196. The new compounds described in Example 7. 197. The new compounds described in Examples 4-6, 8-10 and 12.