PL103092B1 - METHOD OF MAKING NEW ALPHA- (AMINOPHENYL) -ALIPHATIC CARBOXYLIC ACID DERIVATIVES - Google Patents

Description

The invention relates to a manufacturing process new α- (aminophenyl) - aliphatic derivatives carboxylic acids of general formula I, -w wherein ArN is a bicyclic alkenyl group noamine with 1 to 3 double bonds and 5 to 6 members in each ring, possibly connected composed of lower alkyl groups, free, set esterified or etherified groups, hydroxyl we, or mercaptan or ketone groups. Ph oz¬ the phenylene residue is optionally substituted by 1-2 substituents of such as lower v .alkyl, free, esterified or etherified a fictitious hydroxyl or mercaptan group, trifluoromethyl, nitro; amine, low the upper group of dialkylamine soup, the lower group ... the alkane group iloamine, possibly function-transformed carboxyl group, cyano group ^ kairbainoyl- wa, lower dialkylcaribomoyl group, lower alkylsulfonyl group, _sulfone group, sulfa- mylum ', lower, dialkylsulfamyl group. or a- halogen volume, Rt is hydrogen, lower alkyl group, lower alkenyl group, cycloalk- low, cycloalkenyl,. cycloalkyl-lowalkyl Or cycloalkenyl-lowalkyl and .R is an atom hydrogen or lower alkyl group or not thereof. sycznycb, - pharmacologically acceptable salts.

The compounds according to the invention ku exhibit a particular * -remarkable anti-action inflammatory, and further anesthetic and antifungal r can be easily done suitable pharmacologically active compounds.

The terms "low" or "lower" are used before or on organic radicals, groups or compounds kach means that the defined organic radicals, groups or compounds preferably contain up to 7, especially up to 4 carbon atoms.

Lower. an alkyl group is for example methyl, ethyl, n-propyl, isopropyl, n- butyl, isbobutyyl, Il-rzejd. buitylowa, Ill-row. butyria, n-pentyl, ispentyl, neopentyl wa, n-hexyl, isohexyl, n-heptyl or isoheptyl.

A lower alkenyl group is for example a group vinyl, allyl, methylallyl, 3Hbutenyl or l * pentenyl.

A cycloalkyl group or a cycloalkenyl group it preferably contains 3-7 ring members and e- ventuamie may be substituted for no 'more Jak 4 lower -alkyl groups. Grapami -tifetmi sa for example the groups: cyldopropfrtowa / cfrfcadbuftjtowa, cyclopentyl, c-lfclohfcksyl or * cyclopho-pt * lo- wa, ^^ cyclopropene, 1-, J2- hib '3MCjrkk> peAt «y- low or 1-, 2-or 3-ohexeny, -which-may g contains up to 4, preferably 1 alpha-2, groups alkyl, and especially mile-groups.

The rest of the cycloalkite ^ low-alcohol value »afbo cfrkioalke- nyloHniispkoaSkitewa -is one of the "popree" rfo-exchange other alkyl groups are used, the use of up to 4 atoms'wegia, rw4sjz * na5 in any t> o1o- 103 092 103 092 3 It is preferable to burn the terminal carbon with one of the mentioned cycloalkyl groups or cycloalkenyl; such residues are, for example cyclopropylmethyl, 2-cyclopentylethyl- wa or 3- cyclopentenylmethyl.

Phenylene residue Ph associated with group A ^ N in position 2, preferably position 3, and in particular in position 4, it may possibly include at position 4 one or more fixed positions, preferably 1 or 2 identical or different substituents, as in for example lower alkyl groups as before listed, free, etherified or esterified important hydroxyl or mercaptan groups, such as low alkoxy groups, for example methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy or isobutoxy, low alkyl- mercaptan groups, for example methyl mercaptan groups ptane or ethyl mercaptan or chlorine atoms a groove, for example, fluorine, bromine or iodine groups peatfLuoromethyl, nitro groups, amino groups, preferably di-lowalkylamino, for example dimethylamino, N-ethyl-N-methylamino, diethylamine1, dinnipropylamine, di- isopropylamine, di-n-J-butylamine or diisobutylamino, low alkenyamino groups we, for example, pyrrolidine, piperidine, pyro linear and piperidine, and monoaza-, monoxy- or monothiaalkyleneamines, for example pi- perazin, 4H-lowalkylpiperazine, morpholine- we or thiomorpholmic or lowalkanoylamino, for example, acetylamino or pivaloyl groups amine and, if appropriate, functional transformation carboxyl groups such as carbometho- xyl or carboethoxy, optionally na example carbamoyl groups substituted with a- gold with low alkyl residues, such as locarbamoyl, for example the group of dimethyl car- bamoyl or cyano groups, low alkyl sulfo nyl groups, for example methylsulfonyl groups or ethylsulfonyl, or optionally 'functionally converted sulfo groups as optional Nn-substituted sulfamyl groups, for example diskdalkylsulfonyl, such as dimethylsulfa- rnetylpwa. The rest of Ph means groups in particular 1,3- or 1,4-phenylene, (lowalkyl) -1,3- or 1,4- phenylene, (low-alkyl, 3- or -1,4-phenylene, (mono- or dihalo) -1, 3 or -1,4-phenylenic, (trifluoromethyl) -1, 3- or -1,4-phenylene, (nitro) -1,3- or 1,4-phenylene, (amino) -1, 3- or 1,4-phenylen new, (dinipunamino) -1, 3 or -1,4-phenylene we or (low-alkylenamino) -1, 3- or -1,4-phenylen new.

The bicyclic alkyleneamino group is typically a suitable 5-6 member ring remainder shaft with 1–3 bonds in the cyclic part double, optionally substituted below with the desired substituents. The rest of this is above all benzoalkenylene amine residues either a suitable residue is dihydrogen or tetrahydro -benzoalkenylamine, in which part aclenyl- amine contains 5-6 members in the ring and which possibly in the aromatic part, for example a clade in the Ph phenylene residue, may be substituted especially by lower alkyl groups, free ne, etherified or esterified hy- . droxyl or mercaptan groups, for example groups low alkoxy or low alkanoyl, as well as not by halogen atoms, but in the aliphatic part also by ketone and thionic groups. Such for example groups are: I-indolinyl, 2- -isoindolinyl, 1, 2, 3, 4-tetrahydro-1-quinol- nylon or 1, 2, 3, 4-tetrahydro, 2-resoquinoline- low as well as 4, 5, 6, 7-tetrahydro-1-dndol- o nylon, 4, 5, 6, 7-tetrahydro-2-isoindolinyl, 4,7-dihydro-1-indoline> 4,7-dihydro-2- -isoindolinyl ^ 1, 2, 3, 4, 5, 6, 7, 8-octane -1-quinolinyl, 1, 2, 3, 4, 5, 6, 7, 8-octane -2-isoquinolinyl, 1, 2, 3, 4, 5, 8-hexahydroTl- ^ quinolinyl or 1, 2, 3, 4, 5, 8H Hexahydro-2- - isoquinolinyl which optionally, for example 'as stated, may be substituted.

The salts are for example ammonium salts or salts metals as well as acid addition salts.

From Belgian Patent Specification No. 705,869 there is There are derivatives of α-phenylalkanecanoate • in which the phenyl radical is substituted monocyclic pyrrole group. These compounds were listed I have anti-inflammatory, analgesic and anti-inflammatory effects feverish.

CNbwe compounds produced by the method according to excl the invention has better anti-inflammatory properties, a moreover, they show antifungal activity.

Pharmacological properties, especially anti-inflammatory flammability can be demonstrated by tests carried out on test animals, preferably mammals like mice, rats and guinea pigs, come on in research in yirfcro. For example, in the one described by Wintera et al., Proc. Soc. Expl. Biol. a. Med., Bd 111, p. 544 (li962), method of experimental research own anti-inflammatory carriers, manufacturing compounds have been used in the form of solutions according to the invention water formations or suspensions containing na For example carboxymethylcellulose or polyglycol Tylen as a dissolving aid. IN studies conducted on adult rats In both sexes, these compounds were introduced by a stomach probe in daily doses of approx 0.0001 to about 0.075 g / kg, preferably from about 0.0005 to about 0.05 g / kg, especially in doses between about 0.001 and about 0.025 g / kg. After about hours in the left rear paw of the animal experienced 0.06 ml of 1% of the caustic suspension was injected soragenin in an aqueous saline solution After 3-4 hours, the volume and / or the shade were compared from the rear to the right rear paw.

The differences between the two limbs are compared the difference in the control animals, where This comparison was a measure of the counteracting effect inflammation of the test compounds.

The following compounds I-III were tested and compared obtained by the method of the invention and compound IV known from the Belgian patent specification no 705 869: And a-f3-chloro-4Kl-keto-2-isoindolmyl) -pheny- acid lo] -propionic II acid a- (4- (1-k € tO'2-pheoJindolinyl) -phenyl] -ipropio- » 95 new v, 80s itotai 6 Lf acid a- [3-'chloro-4 - '(2-isoiiidolinyl) -cphenyl] -pro- vertical IV a- {p- (1-pyrryl) -phenyl] H-propionic acid Blackboard Association: 1 I II III IV ED ^ mg / kg , 6 1.3 4.2 65.0 LI> 50 mg / kg 708.9 57.64 448.13 431 Indicator now gloomy 127 44.3 107 | 6.2 1 The therapeutic index for compounds I-III is a much higher riiz for the TV compound proving that compounds I-III produced by the method of the invention lazku show a much more effective action anti-inflammatory than the known comparator IV.

-According to Hewfcouid, firit. J.

Pharmacól. GJhembtóier., Id. 21, p. 120 (1963), test arthritis, rats ii- was sensitized under ether anesthesia with 0.05 ml ! • / * injected aqueous suspension of carraigenin for all 4 hind legs of the animal. After For 24 hours, it was injected subcutaneously into the tail of the animal of 0.1 ml of lithium © suspension of Mycobacterium butyri- cum in mineral oil. Experimental compounds after 7 days, a gastric tube was administered in the middle of previously described way within 14 days. Rats weighed once a week and set three times a week worthy secondary arthritic lesions, like their li¬ and severity and compared with animal data control plans.

The antifungal action can be established on example in in vitro experiments with lamellar} dilution method for strains a fungus for example Trichophyton, Microsporum or Epidermophyton, like Trichophyton. mentagtrophy- tes, Trichophyton rubrum, Trichophyton sinii, Mi- cnwporuih canis, Microsporum gypseum or Epide rmophyton floccasum. Antifungal activity can also be shown in vivo on for example, the method described by Molinas, J. Invest.

Derm., Bd. 25, p. 33 (1965). In this method, the injection is hammered to guinea pigs to their shaved back a homogeneous agar suspension of the Tricho mushroom phyton mentagrophytes from a 10 * day culture on Sabouraud agar. Treatment with 0.5-2 * / »solutions or ointments containing test substances begins after 24 hours and repeats daily within 10 days. During this period of time, you get married fur and leather parts from 5 different surfaces infected and incubates subcultures on plates with a- a pot suitable for the cultivation of microorganisms causing mycoses and conducts research breeding development.

The analgesic effects can be determined, for example a method developed by Writhing on mice, like Siegmund and others according to Proc.

Soc. Expl. BioL Med., Bd. 95, p. 729 (1957), at break giving per os doses ranging from about 0.05- —0.2 g / jkg / day

The compounds according to the invention can be used as measures to prevent ciwgrzybiczym and relieving pain, especially as effective anti-inflammatory agents in treatment arthritic and dermatopathological symptoms.

These compounds can also be used as products indirect to produce others, pharmacologically active and valuable connections.

Produced with particularly preferred compounds the method according to the invention are compounds of a pattern at 1, in which the group A — N represents two- There are several 5-% alkenylene anine residues with 1 or 3 double bindings occurring especially in the isocyclic ring preferably a benzoalkenyleneamino group ^ 6-membered ring in the alkenylene part amine, the remainder of which may be placed, especially in a position adjacent to the by 1 to 2 ketone groups, Ph before puts the phenylene residue optionally substituted through 1-2 lowalkyl, hydroxyl, meta groups rcaplanic, nisfcoalieoxy, low alkyl mercap- tan, trifluoromethyl, nitro, amine, 2s discoalkylamino, lowalkanoylamino, carboxylic, cyano, carboxamoyl, dipolar alkylcarbamoyl, lowalkylphonyl, sulfo novel, sulfamyl, dienoalkylsulfamyl or via halogen atoms, Rt is hydrogen, a low or low alkenyl group, or a group of pe cycloalkyl, cycloalkenyl, cycloalkyl-ni- sfcoalkyl or cycloalkenyl-lowalkyl, where the cycloaliphatic rest contains 3 ^ 7 elements in pie- cutlass as well as lower alkyl esters or them salts, especially those used in pharmacy, are non-toxic salts of these compounds.

Particularly valuable compounds with properties anti-inflammatory compounds are the formula 1, in which the group A- ^ N represents a bicyclic alke residue 40 nyleneamine with 1-3 double bonds in the rest isocyclic and with 5 to 6 members in each in the ring, especially the remainder of the benzoalkenyleneamines new with a 5 ^ -6-membered ring in the cyclical part aliphatic, with residues such as one of ** two carbon atoms, adjacent to the nitrogen atom, may contain a ketone group and Ph means the rest 1,3- or -1,4-phenyne, (low alkyl) -1, 3- or -1,4- phenylene, (low alkoxy) -1, 3- or 1,4- (mono- or dihalo) -1, 3- or -1> 4-phenylene- 50 wa, (trihoromethylH, 3- or -Hl, 4-phenylene, (none tro) -! 4 - or -1,4-phenylene, (amino) -1, 3- or -1,4- phenylene or (dialkylamino) -1, 3- or -1,4 -phenylene, Rj is hydrogen, the group n1 scoalkyl, cycloalkyl with 3 to 7 ring members 55% or cycloalkyl-lowalkyl groups from 3 to 7 ring members and R is hydrogen or lower alkyl group or salts, especially suitable pharmaceutically acceptable, non-toxic ammonium salts, alkali metal and earth metal salts alkali and acid addition salts.

Particularly distinguished properties against inflammatory compounds are shown by compounds of formula 2, where Am is 1-indoMnyl, 2-isoindolinyl, 1, 2,3,4-tetrahydro-1-quinolinyl or 1,2,3,4-mm tetrahydro-2-isoquinolylic acid, wherein in re one or both of them adjacent to the atom Nitrogen in the rings may contain carbon atoms a keto group, Ra is hydrogen or an al-group kilo or alkoxy of up to 4 atoms carbon, trifluoromethyl, nitro or amino or halogen, R 6 is atom hydrogen, an alkyl group of up to 4 atoms carbon or is a cycloalkyl or cycloalkyl group alkylmethyl in which the cycloalkyl contains 3 to 4 ring and R is hydrogen or an alkyl group with up to 4 carbon atoms, like a methyl, ethyl, n-propyl, isopropyl group dust, n-butyl or isobutyl, or salts, v especially non-toxic in pharmacy ammonium salts, alkali metal salts, e.g. trace, sodium or potassium salts, or addition salts with acids.

Among these compounds we should especially replace nothing of the compounds of formula II in which Am is Dec 20 pe 2-isoindolinyl, especially 1-keto-2-isoindolinyl- nylon, as well as 1,3-biceto-2-isoindolinyl, 1-keto-1,2,3,4-tetrahydro-2-isoquinolinyl or 1,3-biceto-1,2,3,4-tetrahydro-2-isoquin- linyl, Rf1 represents a hydrogen atom or a n- & trifluoromethyl as well as trifluoromethyl, R't represents a hydrogen atom or a methyl group, eth low, n-propyl or cyclopropylmethyl> and R is a methyl or ethyl group, or salts, especially the pharmaceutically acceptable non-toxic salts of M ammonium, sodium or potassium or addition salts with acids; these compounds, in particular the acid a- [5-chloro ro-4- (1-keito-2-dzoindolinyl) -phenyl] propionic, show in the mentioned test systems, with daily doses ranging from approx 0.001 to about 0.025 g / kg, outstanding counter property inflammatory.

Process for the preparation of compounds of formula I, in which A — N, Ph, R and R1 have the meanings given above no, according to the invention, the relationship between Fr. the formula A — N — Ph — Xi, wherein X x is a group of the formula —CCRiKYi) —C - (= 0) —OR, wherein Yx denotes a carboxyl group, undergoes decarboxy lation displacing the Yt group or the bundle of formula A — N — Ph — Xj, wherein X x is a group of the formula y ^ -CtRiKYi) —Ct-OJ ^ OR, where Yt is acyl group, is strongly affected by the agent alkali by cleaving the β-keto acid and / or giving many compounds in the form of an ester or salt contain hydrogen in position a is metallized a then reacted with a reactive alcohol ester by the formula Rx-OH, and the resulting halogen compound it is at an aromatic residue marked with the symbol lem Ph and / or the obtained compound transformed into the salt or the obtained salt is converted to the free compound, compound, the resulting mixture of isomer solutions is divided into individual isomers. , Starting compounds - corresponding «¦ derivatives The melonic acid is decarboxylated on the way pyrolysis, preferably in an acidic environment The compounds obtained can be carried out in a known manner lead one into another. For example, received tWolnet ^ acids can be esterified with than * higher alkanols in the presence of esteriflicating agents 40 45 M. 55 60 substances such as strong acids such as acid Hydrochloric, sulfuric, benzene sulphonate * it or p-toluenesulfonic acid, as well as two clohexylcarbodiimide or dWuazo compounds * out.

The obtained esters can be hydrolyzed to vol by the action of, for example, appropriate acids alkaline agents, such as an aqueous solution of water alkali metal oxide, or carry out into other esters by acting with alcohols in the presence acidic or basic agents such as acids inorganic or complex compounds acidic with heavy metals, as well as in- ^ alkali metal glanamide or metal alkoxides alkaline tails.

Compounds containing ketone groups can be Carry out an example with the action of pentosulfide phosphorus to the appropriate thionic compounds. In two- with any A-N-residue not containing a keto group such groups can be new by oxidation, for example, oxygen (e.g. air) or other mild clades with oxidizing agents as previously mentioned put them into the part containing the nitrogen atom here as a member of the ring, especially in one or both positions adjacent to the nitrogen atom of the ring shadows, being obtained from the corresponding amine compounds corresponding lactate compounds speech or imide compounds.

The obtained esters or salts can be in position a with respect to the functionally converted carbon group to be metallized, for example by acting alkali metals or their derivatives, such as or organic compounds of alkali metals, na example with lithium phenyl or triphenylmethyl- sodium or alkali metal hydride such as sodium hydride, amides or alkoxides m and alkali metals, then react with a reactive ester of an alcohol of the formula Ri-OH, and with the corresponding halide, and this way put in the position a organic group R1 ( The compounds obtained can be subjected to halogenation in the aromatic part Ph, for example with using halogen, preferably in the presence of Lewis acid, for example iron halides111, aluminum, antimony 111 or tin IV, or a chlorine agent an inducing agent, for example hydrochloric acid in the presence of hydrogen peroxide or methanol alkaline thallium, for example sodium chlorate nitrosyl halide, for example nitrosyl chloride or nitrosyl bromide, a haloimide, for example bromosuccinimddu or bromophthalimide. Next you can introduce the nitro group to the rest aromatic Ph, for example by the action of acid nitrogen or nitrates under acidic conditions in the presence of sulfuric acid or trifluoroacetate wego. The resulting nitro compound can the nitro group is reduced to an amino group action of catalytically activated hydrogen or chemical reducing agents, (hydrogen in stfttu nascendi). / ¦¦ ... "f ¦ .-. * ' • * 'Reductions and other transformations should be in such a way that the compound produced contains no saturated alkehyleriamine; -: ¦'¦ ki> Compounds received with primary group a-103 092 9 10 the minefield can be reacted with reactive esters with alcohols or glycols and reactive derivatives functional acid functionalities such as halides, for example, chlorides or anhydrides and, thus) transform into compounds containing a secondary row or a tertiary amine group or a quaternary group row ammonium group, how. also acylated amino groups. Received compounds from a free group amine tactcii ^ calcane with nitric acid give a compound, - diazo lines, which, after the Sandmeyer reaction, on for example, by hydrolysis at higher temperatures by the action of copper halides11 or cyanide copper, relatively lower alkanol or lower the arylmefkaican, preferably under ambient conditions that are either slightly acidic or slightly alkaline can be converted into suitable hydro xy-, halogen-, cyano-, low alkoxy- relatively low alkylomer capto and derivatives.

In the obtained phenolic products you can etherify phenolic hydroxyl groups v and mercapitan, using the appropriate metal phenolates, "as phenolics of metals c s4kalicz- alkali metals or thiophenolates, and tact gifted or cycloalkanols, such as low alkyl halides mu or cycloalkyl, sulfates or sulfonates , us low alkyl or cycloalkyl and with two and a half compounds, like the lower hami. The obtained phenol esters can be split into for example by the action of strong acids or acid salts such as hydrobromic acid and acetic acid and pyridine hydrochloride. Aliphatic hydroxyl compounds can be dehydrated as iia the example previously described.

The resulting unsaturated compounds can be, as saturated previously described for example, catalytically acting as an asset hydrogen or reducing chemicals (hydrogen in statu nascendi) eliminating "double bonds, for example in the group Rx Wub in the ester group.

In the received relationships that can be vaccinate possibly esterified groups hydroxyl groups in the A-N residue may be such a group possibly together with hydrogen split off, it I mean introducing double bonds, in a way and above.

The free acid obtained can be carried out in a known manner converted into salt, for example by reactions with approximately a stoichiometric amount of a suitable and rinsing agent salts such as ammonia, amine or ! alkali metal or earth metal hydroxide and alkali, carbonates or acidic carbonates : alkali or alkaline earth metals. In this the ammonium salts or metal salts obtained in the process I convert into free acids by action acid, for example hydrochloric acid, sulfuric acid or acetic acid to obtain the answer lower pH.

The resulting basic compound can be processed in an acid addition salt, for example by reactions with inorganic or organic acid or by using a suitable ion exchanger salt and the isolation formed) and then conversion to addition salt. The obtained acid The word addition salt can be acted on as a rule on An example of an alkali metal hydroxide ammonium niac or ion exchanger, transform into 8 free relationship.

- Acid addition salts are used in pharmaceutical non-toxic acid addition salts, na example. inorganic acid addition salts, such as hydrochloric, hydrobromic, sulfuric acid, phosphorus, "nitrogen or perchloride," especially7 of carboxylic or sulfonic acids organic, such as formic, acetic, propionic new, amber, glycolic, lactic, apple, wine, lemon, benzoic, 4-aminobenzoic, anthranilic, 4 ^ hydroxy- benzoic, salicylic, amdnosalicicic, em- bon, nicotine, and methane sulfonic, ethanesulfonic, hydroxyethanesulfonic phonics, ethylsulfonates, benzenesulfonates, chlorobetizenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohe- ks ^ losyraminowy.

The above-mentioned as well as other salts, for example picrates, can also be used for cleaning bonding and identification of free unions; in this way you can turn free compounds into them salts, and these are separated from the crude mixture and from the separated salts are then free relationships. Due to the close relationship between the knife free and in the form of these compounds salts, the term "free compounds" or "salts" includes I am both salts and free compounds.

The resulting isomeric mixtures can be a known way to separate into individual isomers, for example by fractionated distillation or crystallizations and / or chromatography.

Racemic compounds can be broken down optically inactive isomers, for example the fractionation route significant crystallization by separation from mixtures salts that are diastereoisomers, for example acid d- or 1-tartaric sem, d-a-phenylethylamine, d-ct (1-naphthyl) ethylamine or 1-cinchonidine, and possibly or separate the free optical isomers from the salt.

The previously mentioned reactions are performed by known methods, for example possibly in in the environment of diluents, preferably those which towards the reaction components behave \ do not, and allow them to dissolve, and if it does it is the need in the presence of catalysts, interm condensing or neutralizing vessels, in the atmosphere the sphere of an inert gas, for example nitrogen, with cooling or heating and / or under a higher one pressure.

The invention also includes such variations the same, in which the starting compounds are used in salt form.

In the process according to the invention, it is preferably used get the starting relationships that lead to compounds of formula 1, which were previously written as particularly valuable.

Starting unions are known, and if they are related to me new, these compounds are made known methods. Starting compounds of formula A — N—- Ph — Xj n & knows get the barrel introduction » 40 45 50 55 6011 183 092 12 the formation of the group A — N—, for example, surrendering reaction of the appropriate compound in place of the group A — N contains a free amino group with a compound of the formula HO — A — OH or a reactive derivative thereof on. Malonic acid derivatives used as Output compounds can be obtained by synthesis method Ando, acting on the compound of formula A — N — Pb— Xlf where Xx is hydrogen, ester mesoxylic acid in the presence of tin chloride IV; the obtained adduct can be hydrogenated, on cleavage of the hydroxyl group, the obtained jac ester of a malonic acid derivative.

I have received indirect relationships and initial relationships valid according to the above-mentioned methods can also carry one into the other with methods described for the final compounds.

The compounds of formula I and their salts are useful in the pharmaceutical industry macology can be used, for example, in the manufacture of pouring pharmaceutical preparations containing an effective amount of active ingredient, optionally in mixture with inorganic or organic, solid or liquid used in nasal pharmacy suitable for internal use it, parenteral and topical. Preferably a stack eat tablets or gelatin capsules containing active substances together with a diluent, na example lactose, dextrose, sucrose, unannitol, sorbitol, cellulose and / or glycerin or agents lubricants, such as silica, talc, acid stearic acid or its salts, such as magnesium stearates or calcium and / or polyethylene glycol; tablets incl They also contain binding agents, such as a chair magnesium aluminum titers, different types of starch, like from maize, wheat, rice or Amyium Ma- rantae, gelatine, tragacanth, methylcellulose, sodium salt sodium, carboxymethylcellulose and / or polyvinylpyr rolidone, and possibly grinding agents, has an example starches, agar, alginic acid, or sodium alginate or effervescent mixtures and / who adsorption agents ing; dyes, fragrances and sweeteners. Pre¬ The injection materials are preferably aqueous solutions isotonic arms or suspensions, and suppositories and butter, primarily emulsions or suspensions us fats. Pharmaceutical preparations can be sterilized and / or contain aids Nothing like preservatives would stabilize chewing, wetting and / or emulsifying agents, hives twiajace dissolving, salts to regulate the pressure osmotic conditions and / or buffers. Pharmaceutical preparations pharmaceuticals are produced in a known manner, ma example by conventional mixing method, granulation or drazeting. Prepara¬ these include about 0.1% to about 7.5%, especially from about 1% to about 50% of the active substance and possibly other pharmacologically valuable substances substances.

The invention is illustrated by the following examples, v the temperatures of which are given in degrees Cel sius.

Example I. A mixture of 5 g of diethyl ester a -! [4- < 2-isoindoylinyl) -phenyl] -a-methyl- malonic acid, 50 ml of ethanol and 40 ml of a 25% solution the aqueous potassium hydroxide is kept constant not boiling under a reflux condenser within 4 hours one day after which it evaporated under reduced pressure not. Treat the remainder with a 50% solution aqueous sulfuric acid and the mixture is heated on the steam bath within ID minutes; the reaction is mixed nina is adjusted to pH 4 with B aqueous sodium hydroxide solution and extracted diethyl ether. Organic extract made by the water is washed, dried and evaporated. Received after * the residue was recrystallized from ethyl acetate and used acid 2 ^ 4n (2-isoiridoltoyl) ^ enyl] propdono- with a melting point of 247— ^ 5.0 ° C- The stock can be made in naisfcep ^ which way: A mixture of 25 g 4- 12.6 g of a 50% slurry of sodium hydride in a mineral oil 50 g of α-methyl diethyl ester of malonic acid and 150 ml of hexamethyltriamide acid phosphorus acid persists for 2.5 days in temperature 1-00 ° C. After cooling the mixture, stock is poured into water and extracted with ether diethyl. The extract is dried and evaporated to obtaining diethyl ester of a-methyl-a- (4- nitrophenyl- malonic acid.

A solution of 28 g of a-me- acid diethyl ester Tylor- (4-nitro-ethyl) malionic) in 150 ml of saturated A total solution of hydrogen chloride in ethanol is added 1.5 g of catalyst consisting of 10% palladium was deposited on carbon and hydrogenated under a pressure of 3 atmospheres fer. After hydrogen absorption has ceased, it is filtered off by chopping talisman, glue evaporates under reduced pressure, and the residue dissolved in water and M is made alkaline with water sodium hydroxide solution and extracted with ether with diethyl solution, the organic extract is dried and evaporates to give the acid diethyl ester a- (4-amino-phenyl) - A mixture of 5 g of M4- acid diethyl ester aminophenyl) Hot-methylnialonic acid, 5.3 g of α, α-di- bromo-o-xylene, 5 Tyloformamide, mixing, persists for 5 hours at 100 ° C. After cooling, the 40 s ^ anine passes, pass thickens under reduced pressure, and the obtained concentrate diluted with water and extracted with diethyl ether.

The organic extract is washed with water, dried and evaporates to give the diethyl ester of α- 45 and [4- {2-isoindolinyl) phenyl] malonic.

A similar method is prepared with the use of suitable starting substances and possibly after performing an additional reaction, such as for example are given in the following examples as follows 50 relationships: ai [4-i (2-isoindolinyl) -phenyl] - acid ethyl ester acetic acid, mp 118-120 ° C after recrystallization from ether; a-13-chloro-4- (1,3-dio-2-) acid ethyl ester 55 isoindolinyl) phenyl] propionic acid at a temperature of mp 107-110 ° C after recrystallization from ether ru; a- ε 4 - <(2-isoindolinyl) -phenyl] - acid ethyl ester propionic acid, m.p. 111-113 ° C 60 after recrystallization from ethanol; ethyl ester of a- (4- tetrahydro-2-isoquinolinyl) phenyl] acetic acid with a temperature of mp 89-91 ° C after recrystallization niu from ethanol; 65 α- [3-chloro-4- (1-keio-2-isoindo-103 0S2) acid ethyl ester 13 14 linyl) phenyi-propionic acid, m.p. temperature 111-113 ° C; acid x an [3 ^ 1oro-4H (1-keto-2-isoindolinyl) -phenyl] n-propionic acid, m.p. 178-180 ° C; aH [4- (1-lketo-2-isoindalinyl) -phenyl] -ootic acid with mp 206-208 ° C; a- [4- (1-keto-2-isoindolinyl) - acid ethyl ester phenylene, m.p. 111- —114 ° C; an [4n (1-toto-2-isoindolinyl) - acid methyl ester phenyl]-propionic acid, m.p. 129 —M ° C; α ^ 4- (1-keto-2-isoindolinyl) acid ethyl ester phenylH »petroleum with a melting point of 104 —1Q6 ° C; a- {4- (1-ketp-2-isoindole-) n-propyl ester nylon) phenyl] propionic acid melting point concentration 87- * 0 ° C; α ^ 4- (1-keto-2-rosoindole- acid isopropyl ester) nyk>) - phenyk>] - H-propionic acid with a melting point H 8, 121 ° C; α- (4H (1-keto-2-i! zoindolkiy-) acid isobutyl ester 1) -phenyl] -propionic acid, m.p. 110 ° C-113 ° C; an [3-chloro-4- <2-d-indolinyl) acid ethyl ester phenylol-peropionic melting point 67- -70 ° C and a boiling point of 190-200 ° C 0.4 mm h *; a- {3-chloro-4- (1-keto-2-isoindolinyl) phenyl] - acid buttery, m.p. 191-193 ° C; a- (3-chloro-4- (1-keto-2-isoin-) acid ethyl ester boiling point, dolinyl-panylol-butyl 230-24 ° C / 0.25 mm Hg; acid a- {3-chloro-4-phenyl] - - α-cyclopropyl ethanol, m.p. 242-245aC; acid ethyl ester dolinyl) phenyl] -1 -cyclopropylacetic-acetic acid bp 225-235 ° C / 0.33 mm Hg; ethyl ester of a- [4- (1,3-dioxo ^ 4, 5, 6, 7- catero «h] or (> 2-isoindolinyl) -phenyl] -acetic at the mp 197-199 ° C; a-cyclopropyl-a- (4- (1-keto-2-isoindolinyl) - -phenyl] ootic, m.p. 186- —188PC; . a-eyfklop! ropyl-a- (4- (l- * keto) acid methyl ester 2-isoindolinyl) phenyl] acetic acid at a temperature of mp 98-101 ° C; a-cyclopropyl-a- {4-keto-2- acid ethyl ester isoindolinyl) phenyl] acetic acid at a temperature of mp 111-113 ° C; Example II: Mixture; 1 g of ethyl ester aHl3Hchloro-4- (2-isoindolinyl) -phenyl) -propio- acid new, 30 µl of ethanol and 15 ml of 20% aqueous of the potassium carbonate solution is heated for 1 hour at the boiling point under the reflux condenser on and evaporates under reduced pressure. Mon. the residue is dissolved in water and a mixture of za¬ Kvass: with 6N hydrochloric acid to pH = 3 and extracted ethyl acetate. The organic extract is dried and filtered poisons and evaporates. The residue evaporates Aug. from ethyl acetate to give the acid α-[3-chloro-4- (2-Thiaokidolinyl) -phenyl] H-propionic acid at temperature mp 148-150 ° C.

Example III, Mixture of 4.5 g of ethyl ester of a-i [4- (1-keto-2-isoindolinyl) -phenyl] -pro- acid vertical and 1.6 g of potassium hydroxide in 2 ml water and 250 ml. ethanol, under nitrogen atmosphere, heat it is weighed for 2 hours at boiling point under reflux cooler. The remainder dissolves in the water day, washed with chloroform, acidified with acid salt and extracted with ethyl acetate. Organic extract the mixture is dried and evaporated under reduced pressure pressure and the residue crystallizes from acetate ethyl. The acid a- [4- (1-keto-2-isoindol- nyl) phenyl] H-propionic acid, m.p. 208-210 ° C.

Example IV. A mixture of 4.8 g of ethyl ester α- {4- (2-zoindolinyl-phenyl] -acetic acid and 80 ml of a 25% aqueous solution of hydro-oxygen of sodium is heated to reflux under reflux condenser within 3 hours, then chilled today and the water is diluted. The mixture becomes acidic hydrochloric acid, the precipitate was filtered off and recrystallized it takes with ethyl acetate. The acid a- {4- (2-isoindolinyl) phenyl] acetic acid of formula 3, which melts at 237-239 ° C.

Example 5 A mixture of 1.8 g of ethyl ester a- {4- (2-isoindolinyl) -phenyl] -propionic acid, ml of 50% strength aqueous hydroxide solution sodium chloride, 25 ml of water and 100 ml of ethanol was heated at boiling point under reflux r for 1 1/2 hours and concentrate under reduced pressure not. The concentrate was diluted with water, obtained the suspension is acidified with 6N hydrochloric acid to pH = 3 and extracted with ethyl acetate. Organic extract the mixture is dried, filtered and evaporated to a reduced temperature high pressure. The remainder crystallizes out ethyl acetate to give the acid * -a- (4- (2-isomdoli- nyl) phenyl] propionic acid of Formula 4 which melts at 247-250 ° C.

Example VI. A solution of 0.5 g of ethyl ester α- [4- <2-isoindolinyl) -phenyl} -propionic acid in 50 ml of glacial acetic acid by dropping mixed with 6 ml of saturated chlorine glacial acetic acid and the mixture is evaporated under reduced pressure. The residue dissolves in an aqueous solution of sodium bicarbonate and extracted with ether. The organic extract is dried, filters and evaporates. The residue is chromatographed on silica gel, being the eluant a mixture of benzene and hexane (1: 1) is used. Ja¬ As the main product, the ethyl ester is obtained a- {3-chloro-4- (2-isoindolinyl) -phenylo] -prqpio- acid of the new formula 5, the value of Rf = 0.30 (raw material: Rr = 0.26) and the second product is e- a- {3., 5-dichloro-4- (2-isoindole-) acid ethyl steroid nyl) phenyl] propionic acid of Formula 8; Rf = "0.395.

Example VII. By a concentrated solution of the ester e- tyl acid a- [3-chloro-4- (2-isoindolinyl) -phe nylH) oil in diethylformamclose by let go of the bubbles, stirring within 2 hours air, maintaining the temperature of 60 ° C. Received is eaten ethyl ester of a- {3-chloro-4- (l ^ keto * 2- isoindolinyl) phenyl] H-propionic acid of the formula VII, which is The rice is isolated by evaporating the reaction mixture under reduced pressure and distillation leftovers; the product is obtained as fractions boiling at 200-210 ° C / 0.4 mm Hg.

An [3 ^ h | orp-4- (5-chlQr9-l-keto-2-iz <> indplin-) acid 40 45 50 59 00 6515 103 092 16 Jto) -phenyl] H-propionic acid, and its methyl ester, ethyl or sodium or potassium salts can be obtained washing with the methods described above, using appropriate poor raw materials.

Claims (19)

Patent claims 1. A method for the preparation of new derivatives of a- (aiminolenyl) -aliphatic carboxylic acids of the general formula I, in which A-N is a bicyclic alkenyleneamino group with 1-3 double bonds and 5-6 members in each ring, optionally substituted by lower alkyl groups, free, esterified or etherified hydroxyl groups, or mercaptan groups or ketone groups. Ph is a phenylene residue optionally substituted with 1-2 substituents from such as a lower alkyl group, free, esterified or etherified hydro group xyl or mercaptan group, trifluoromethyl, nitro, amino, lower dialkylamino, lower alkanoylamino, optionally functionally converted carboxyl group, cyano, carbomoyl, lower, dialkylcarbonamoyl, lower alkyl, isanbamoyl group sulfone, sulfamyl, lower dialkylsulfamyl or halogen; R4 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group, a dialkylalkyl-lowalkyl group or a cycloalkenyl-lowalkyl group and R is a hydrogen atom or a lower alkyl group, or a pharmacologically acceptable salt thereof, characterized by , with a compound of formula A — N — Ph — XIt in which A — N and Ph are as defined above, and Xi is a group b of the formula —CCRjMYi) —C - (= "O) —OR, in which R4 and R have the meaning given above and Y is a carboxyl group, it is subjected to pyrolysis leaving the group Ylf and / or the obtained free compound is converted into a salt or the obtained salt is converted into a free compound, and / or the obtained mixture of isomers is separated into individual isomers . 2.; The method according to p. The process of claim 1, wherein the hyio] -malonic acid is reacted to give α- [4- (2-isoindolinyl) phenyl] acetic acid, which is optionally salified. 3. The method according to p. 6. A process as claimed in claim 1, characterized by reacting cw [4- (2-isoindolinyl) -phenyl] -α-methylmalonic acid to obtain α-4- (2-isoindolinyl) -phenyl] -propionic acid, which is optionally converted in salt. 4. The method according to p. A process as claimed in claim 1, characterized by reacting α- {3-chloro-4- (2-isoindolinyl) -phenylol - "- methylmalonic acid to give α- {3-chloro-4- <2-isoindolinyl) -phenyl acid ] H-propionic acid, which is optionally salified. 5. The method according to p. A process as claimed in claim 1, characterized in that α- {3-chloro-4- (1-keto-2-isoindolinyl) -phenyl] -α-methylmalonic acid is reacted to give α- (3-chloro-4- (1) -keto-2-isoindolinyl) phenyl] propionic, which is optionally salified. 6. $, A method according to claim 1, characterized by reacting α ^ [4- (1-keto-2-isoindolinyl) -phenyl] -a-methylmalonic acid to obtain α- [4- (1 N-keto-2-isoindolinyl) phenyl] propionic acid, which is optionally salified. 7. A method for the preparation of the new (aminophenyl) -aliphatic carboxylic acid derivatives of the general formula I, in which A — N is bicyclic. an alkenyleneamino group with 1 - a double bonds and 5 - 6 members in each ring, optionally substituted with lower alkyl groups, free, esterified or etherified hydroxyl or mercaptan groups or ketone groups, Ph denotes a phenylene residue optionally substituted by 1-2 substituents from such as lower alkyl, free, esterified or etherified hydroxy or mercaptan groups, trifluoromethyl, nitro, amine, lower bicoloramino, lower alkanoylamino, optionally functionally converted carboxyl group, cyano, carbamoyl, lower dialkylcarbamoyl, lower alkylsulfonyl, sulfo, sulfamyl, lower dialkylsulfamyl or halogen, Rx, lower alkyl, lower alkyl alkenyl group, cycloalkyl, cycloalkenyl, cycloalkyl-lowalkyl or cycloalkenyl-lowalkyl group and R is lower an alkyl group or a pharmacologically acceptable salt thereof, characterized in that the compound of formula A — N — Ph — Xi, wherein A — N and Ph are as defined above, and Xt is the group —C ( RiKYj) —C (= O) —OR, wherein R 1 is as defined above, Y ± is a carboxyl group, and R is a hydrogen atom, is subjected to pyrolysis to vaccinate the Yx group and the obtained acid is transformed into the lower the alkyl ester and the compound optionally obtained are salified and / or the resulting mixture of isomers is separated into the "individual isomers." 8. The method according to p. 7. A process as claimed in claim 7, characterized in that α- [4- {2-isoihdolinyl) -feriyio] -acetic acid is converted to the ethyl ester. 9. Method according to zastfz. The process of claim 7, characterized in that α- [3-chloro-4- (1,3-dio-2-isoindolinyl) phenyl] -propionic acid is converted to the ethyl ester. 10. The method according to p. The process as claimed in claim 7, characterized in that α- {4- (2-isoindoinyl) phenylol-propiol is converted to the ethyl ester. 11. The method according to p. 7. A process as claimed in claim 7 wherein the isoquinolinyl) phenyl} acetic acid is converted to the ethyl ester. 12. A method for the preparation of new d- (aminophenyl) -aliphatic carboxylic acid derivatives of the general formula I, in which A-N represents a bicyclic alkenyleneamino group with 1-3 double bonds and 5-6 members in each ring, optionally substituted by the lower alkyl groups, free, esterified or etherified hydroxyl or mercaptan groups, or ketone groups, Ph is phenylene residues optionally substituted with 1-2 substituents from such as lower alkyl, free 50 55 60 103 17, esterified or etherified hydroxy or mercaptan group, trifluoromethyl, nitro, amine, lower dialkylamino, lower alkanoylamino, optionally functionally converted carboxyl, cyano, carbamoyl, dialkyl lower carbamoyl, lower alkylsulfonylpwa, sulfo, sulfamyl, lower dialkylsulfamyl or halogen, Iii denote and a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkyl low alkyl group, or a cycloalkenyl low alkyl group, and R is a hydrogen atom, or a pharmacologically acceptable salt thereof, such as that in the formula A — N — Ph — Xi, where A — N and Ph are as defined above, and Xx is a group of the formula —CCRiKYi) —C / —OZ — OR, in which Ri is as defined above, Yx is the carboxyl group and R is lower alkyl group; it is subjected to pyrolysis, splitting the groups Y4, and the obtained ester is hydrolyzed to the free acid, and optionally the compound obtained is converted into a salt and / or the resulting mixture of isomers is separated into individual isomers. 13. Process for the preparation of new α- (aminophenyl) -aliphatic carboxylic acid derivatives of the general formula I, in which A-N denotes a dicyclic alkenyleneamino group with 1 to 3 double bonds and 5 to 6 members in each ring, optionally substituted by lower alkyl groups, free, esterified or etherified hydroxyl or mercaptan groups, or ketone groups, Ph is phenylene residues optionally substituted with 1-2 substituents from such as lower alkyl, free, esterified or etherified groups hydroxy or mercaptan, trifluoromethyl, nitro, amino, lower dialkylamino, lower alkanoylamino, optionally functionally converted carboxyl group, cyano, carbamoyl, lower dialkylcarbamoyl, nisulfonyl sulfo group, sulfamyl group, lower dialkylsulfamyl group or halogen atom, RA is lower alkyl group, lower g an alkenyl group, cycloalkyl, cycloalkenyl, cycloalkyl-lowalkyl or cycloalkenyl-lowalkyl group and R is hydrogen or a lower alkyl group, or a pharmacologically acceptable salt thereof, characterized in that the compound of the formula A —N — Ph — Xi, and Xj is a group of the formula —CfHKYi) —C - (= 0) —OR, YA is a carboxyl group and R has the meaning given above, subjected to pyrolysis leaving the Y ± group and the resulting compound, in the form of a lower alkyl ester or salt, it is metallized in the a position and then reacted with a reactive alcohol ester of the formula Rj — OH, in which R is as defined above and the compound obtained, if appropriate, is converted into the free acid and / or the resulting isomer mixtures are separated into the individual isomers. 14. Process for the preparation of new derivatives of (aminophenyl) -aliphatic carboxylic acids of the general formula (I), in which Arr-N denotes a bicyclic alkenyleneamino group with 1 - 3 - 92 and * double bonds and 5 - 6 members in each ring , optionally substituted with lower alkyl, free, esterified or etherified mercaptan or ketone groups, Ph is a phenylene residue substituted with 2 halogen atoms or a phenylene residue substituted with 1 halogen and optionally further substituted with a lower alkyl group, free , esterified or etherified hydroxyl or mercaptan group, trifluoromethyl LO group, nitro, amino group, dialkyl lower amino group, lower alkanoylamino group, optionally functionally converted carboxylate, dicarboxylate, nysocarbamoyl group lower alkylsulfonyl, sulfo, sulfamyl or lower dialkylsulfamyl, Rx o is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl, cycloalkenyl, cycloalkyl-lowalkyl or cycloalkenyl-lowalkyl group and R is a hydrogen atom or a lower alkyl group, or pharmacologically acceptable salts thereof wherein A-N is as defined above, Ph is a phenylene residue optionally substituted with a lower alkyl group, free, esterified or etherified hydroxyl group or mercaptan, trifluoromethyl, nitro, amino, lower dialkylamino, lower alkanoylamino, optionally functionally converted carboxyl group, cyano, carbamoyl, lower dialkylsulfonoyl group , sulfamyl or lower dialkylsulfamyl group, and Xj is a group of formula —C (R1) (Y1) —C (= O) —OR, where R1 and R are as defined above, and Y1 is carboxyl, p is subjected to pyrolysis, cleaving the group Yj and the obtained compound, optionally in the form of a salt, is halogenated in the aromatic residue at 40 Ph, and optionally the compound obtained is converted into a free compound or the obtained free compound is converted into salt and / or the obtained mixture of isomers is separated to individual isomers. 15. Process for the preparation of new α- (aminophenyl) -aliphatic carboxylic acid derivatives of the general formula I, in which A-N represents a dicyclic alkenyleneamino group with 1-3 double bonds and 5-6 members in each ring, optionally substituted with lower alkyl groups, free, esterified or etherified hydroxyl or mercaptan groups or ketone groups, Ph denotes phenylene residues optionally substituted with 1 - * - 2 substitutents from among such as lower alkyl group, free , esterified or etherified hydroxy or mercaptan group, trifluoromethyl, nitro, amine, lower dialkylamino, lower alkanoylamino, optionally functionally converted carboxyl, cyano, carbamoyl, lower carbamoyl, lower carbamoyl, lower alkylsulfonyl group, sulfo group, sulfamyl group, lower dialkylsulfamyl group or halogen atom, R65 is hydrogen, lower a alkyl group, n-19 O 3 092 * 0th alkenyl group, cycloalkyl, cycloalkenyl, cycloalkyl-lowalkyl, or cycloalkenyl-lowalkyl group, and R is hydrogen or lower alkyl group, or pharmacologically acceptable salts thereof, in that the compound of formula A — N — Ph — X! wherein A — N and Ph are as defined above, and Xj is a group of the formula - ^ C {R1XY1) ^ hC - ^ (= 0) - OR, in which R x and R are as defined above and Y1 is an acyl group, is subjected to the action of a strongly alkaline agent, splitting the O-keto acid and / or the obtained free compound is salified or the obtained salt is converted form a free compound, and / Or the obtained mixture of isomers is separated into individual isomers. 16. A method for the preparation of new α- (aminophenyl) -aliphatic carboxylic acid derivatives of the general formula I, in which A-N denotes a dicyclic alkenyleneamino group with 1 to 3 double bonds and 5 to 6 members in each ring, optionally substituted by lower alkyl groups, free, esterified or etherified hydroxyl or mercaptan groups or ketone groups, Ph is phenylene residues optionally substituted with 1-2 substituents from such as lower alkyl, free, esterified or etherified groups hydroxy or mercaptans, trifluoromethyl, nitro, amino, lower dialkylamino, lower alkanoylamino, optionally functionally converted carboxyl group, cyano, carbamoyl, lower dialkylcarbamoyl, lower alkyl, lower dialkylcarbamoyl group sulfo group, sulfamyl group, lower dialkylsulfamyl group or halogen atom, Ri is hydrogen atom, lower alkyl group a lead, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lowalkyl or cycloalkenyl-lowalkyl group and R is a lower alkyl group, or a pharmacologically acceptable salt thereof, characterized in that the compound of formula A - - N — Ph — Xt, where A — N and Ph are as defined above, and Xj is a group of formula —C (RiKYi) —C {= 0) —OR in which Rx is as defined above, Yt is the group acyl and R is a hydrogen atom, is subjected to the action of a strongly alkaline agent, splitting the β-keto acid, and the resulting acid is transformed into a lower alkyl ester, and optionally the compound obtained is converted into salt and / or the resulting mixture of isomers is separated into individual isomers. 17. A method for the preparation of new α- (aminophenyl) -aliphatic carboxylic acid derivatives of the general formula I, in which A-N denotes a dicyclic alkenyleneamino group with 1-3 double bonds and 5-6 members in each ring, optionally substituted with lower alkyl groups, free, esterified or etherified hydroxyl or mercaptan groups or ketone groups, Ph is a phenyl residue optionally substituted with 1-2 substituents from such as lower alkyl, free esterified or etherified hydroxyl or mercaptans, trifluoromethyl, nitro, amino, lower dialkylamino, lower alkanoylamino, optionally functionally converted carboxyl, cyano, carbamoyl, lower di-alkylcarbamoyl, lower alkylsulfonyl, n-isamyl sulfonate dialkylsulfamyl or halogen atom, Rt represents a hydrogen atom, lower alkyl group, lower an alkenyl group, cycloalkyl, cycloalkenyl, cycloalkyl-lowalkyl or cycloalkenyl-low-alkyl group and R is a lower alkyl group or their pharmacologically acceptable salts, characterized by the compound of formula A — N — Ph — XIf A — N and Ph are as defined above, and Xi is a group of the formula —CCRiKYj) —CCO) —OR, where Ri is as defined above, Yf is an acyl group and R is a lower alkyl group. is subjected to the action of a strongly alkaline agent, splitting the O-keto acid, and the obtained ester is hydrolyzed to free acid, and optionally the compound obtained is converted into a salt and / or the obtained mixture of isomers is separated into individual isomers. 18. A method for the preparation of new derivatives of a- (aminophenyl) -aliphatic carboxylic acids of general formula I, in which A-N represents a dicyclic alkenyleneamino group with 1 to 3 double bonds and 5 to 6 members in each ring, optionally substituted by lower alkyl groups, free, esterified or etherified hydroxyl groups, or mercaptan groups or ketone groups, Ph is a phenylene residue optionally substituted with 1-2 substituents from such as lower alkyl, free, esterified or etherified groups hydroxy or mercaptans, trifluoromethyl, nitro, amino, lower dialkylamino, lower alkanoylamino, optionally functionally converted carboxyl group, cyano, carbamoyl, lower dialkylcarbamoyl, lower sulfonyl sulfo, sulfamyl, lower dialkylsulfamyl or halogen, Rx is lower alkyl, lower g Rupe alkenyl, cycloalkyl, cycloalkenyl cycloalkyl low alkyl or cycloalkenyl low alkyl and R is hydrogen or a lower alkyl group or their pharmacologically acceptable salts, characterized in that the compound of formula A - - N - Ph —Xi, where A — N and Ph are as defined above and Xj is a group of formula —C (HKYi) —C - (= O) —OR, Yj is an acyl group and R is as defined above, the action of a strongly alkaline agent, splitting the fl-keto acid, and the obtained compound in the form of a lower alkyl ester or salt is metallized in the aa position, and then reacted with a reactive alcohol ester of the formula Ri-OH, in which Rt has the above-mentioned meaning that the optionally obtained compound is converted into the free acid and / or the resulting mixture of isomers is separated into the individual isomers. 19. A method for the preparation of new derivatives of (aminophenyl) -aliphatic carboxylic acids of the general formula I, in which A-N represents 15 20 25 30 35 4C 45 50 55 60 103 092 21 a bicyclic alkenyleneamino group, with 1 to 3 double bonds and 5 - 6 members in each ring, optionally substituted by lower alkyl groups, free, esterified or etherified mercaptan or ketone groups, Ph is a phenylene residue substituted with 2 halogen atoms or a phenylene residue substituted with 1 halogen atom and optionally additional Substituted by a lower alkyl group, a free esterified or etherified hydroxyl or mercaptan group, a trifluoromethyl, nitro, amine group, a lower dialkylamino group, a lower alkanoylamino group, an alternatively functionally converted carboxylic group, cyano, carbamoyl, lower dialkylcarbamoyl, lower alkylsulfonyl, sulfo, sulfamyl or lower group dialkylsulfamyl, Ri is hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lowalkyl or cycloalkenyl-lowalkyl and R is hydrogen or lower alkyl, or pharmacologically acceptable thereof 20 of these salts, characterized in that the compound of formula A — N — Ph — Xt, in which A — N is as defined above, Ph is a phenylene residue, optionally substituted with a lower alkyl group, free, esterified or etherified hydroxy or mercaptan group, trifluoromethyl, nitro, amino group, lower dialkylamino group, lower alkanoylamino group, optionally functionally converted carboxyl group, cyano group, carbamoyl group, lower dialkylsulfonyl-lowercarbomoyl group sulfamyl or lower dialkylsulfamyl group, and Xx represents a group of the formula —C (R1) (Y1) ^ C (= O) ^ OR, where R5 and R are as defined above, and Yj is the acyl group, is subjected to the action of a strongly alkaline agent, splitting the 3-acid and the resulting compound, possibly in the form of a salt, is halogenated in the aromatic Ph residue, and optionally the compound obtained is converted into the free compound or the obtained free compound the compound is salified and / or the resulting mixture of isomers is separated into the individual isomers. Ri 0 I li 0 AN-Ph-CH-C-OR Am ^ = ^ CH-C-OR formula 1 Ra Ri 0 Formula 2 (YCH2> Och2-6-oh Formula 3 ^ 2> ^> CH-C-OH Formula UN pu CH3 O / VCH2 \ Formula 5 a ch3o CH-C-0-C2H5 o Ji-o-c2H5 a CH3 Formula 7