PL103087B1 - METHOD OF MAKING NEW ALPHATIC DERIVATIVES OF ALPHA- (AMINOPHENYL) ALIPHATIC CARBOXYLIC ACIDS - Google Patents

Description

The invention relates to a manufacturing process new derivatives my carboxylic acids of general formula I, in which the group A-N is bicyclic pe alkenylene amine with 1-3 double bonds and 5-6 members in each ring, possibly optionally substituted with lower alkyl groups free, esterified or etherified groups hydroxyl or mercaptan groups or keto groups tone, Ph denotes a phenylene residue, possibly substituted with 1-2 substituents thereof as a lower alkyl group, free, esterified or a etherified hydroxyl group or a mer- captan, trifluoromethyl, nitro, amino, dialkylamino lower, lower alkanoylamino, optionally functionally transformed carboxyl group, cyano- wa, carbamoyl, dialkyl lower carbohydrate group moyl, lower alkylsulfonyl group, group sulfo, sulfamyl, dialkyl lower group sulfamyl or halogen, Rx is atom hydrogen, lower alkyl, lower alkene nylon, cycloalkyl, cycloalkenyl, cycloalkyl lowalkyl or cycloalkenyl-lowalkyl, a R is a hydrogen atom or a lower alkyl group, or they are non-toxic, pharmacologically acceptable salt. Compounds produced by the process of the debts of the invention show a particularly outstanding anti-inflammatory, and further anesthetic and antifungal and can be easily treated lead to appropriate pharmacologically active relationships.

The term "low" or "lower" is 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.

A lower alkyl group is for example a group methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, tertiary. butyl, n-pentyl, isopentyl, neopentyl- wa, n-hexyl, isohexyl, n-heptyl or isoheptyl.

A lower alkenyl group is for example a group vinyl, allyl, methylallyl, 3-butenyl or 1-pentenyl, A cycloalkyl group or a cycloalkenyl group preferably it has 3-7 members in the ring and possibly it may be substituted with no more than 4 lower alkyl groups. Groups like this there are, for example, groups: cykiopropyl, cyclobuty- low, digital, cyclohexyl or cyclohexyl heptyl, 2-cyclopropenyl, 1-, 1- or 3-cycl- pentyl or 1-, 2- or 3-cyclohexenyl, which may be up to 4, preferably 1 or 2 lower alkyl groups, especially methyl groups.

A cycloalkyl-lowalkyl or cycloalkyl residue nyl-low alkyl is one of the previously mentioned changed lower alkyl groups, preferably containing up to 4 carbon atoms, bonded to 103 087 103 078 3. 4 free, etherified or esterified groups hydroxyl or mercaptan, for example cl p low alkoxy or, low alkanoyl, such as also by halogen atoms, and partly aliphatic also by ketone and thionic groups.

Such groups are, for example: 1-indolines- low, "2-isoindolinyl, 1,2,3,4-tetrahydro-1-chi nolinyl or 1,2,3,4-tetrahydro-2-isoquinolines- lowa, j: k also 4,5,6,7-tetrahydro-1-indolines- Iowa, 4,5,6,7 ^ tetrahydro-2-isoindolinyl, 4,7- - dihydrogen-1-indolinyl, 4,7-dihydro-2-iso- indolinyl, 1,2,3,4,5j 6,7,8-octane-quinoline- Iowa, 1,2,3,4,5,6,7,8-octahydro-2-isoquinolines, 1,2,3,4,5,8-hexahydro-1Hquinolinyl or 1,2,3,4, .. 5,8-hexahydro-2-isoquinolinyl, which possibly possibly they can be substituted.

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

Belgian Patent Specification No. 705 869 shows There are derivatives of α-phenylalkanecarboxylic acids in which the phenyl radical is substituted monocyclic pyrrole group. These compounds were shown consumes anti-inflammatory, analgesic and antipyretic.

Npwe compounds produced by the method of invention have better anti-inflammatory properties, and, moreover, they exhibit antifungal activity.

Pharmacological properties, especially against inflammation can be demonstrated in studies conducted on experimental animals, not mammals, such as mice, rats and guinea pigs, further in in vitro studies. For example in the description by Winter et al., Proc. Soc. Expl.Biol.a.Med., Bd 111, p. 544 (1962), the experimental method dishes of anti-inflammatory properties used the compounds according to the invention in the form of aqueous solutions or suspensions, e.g. containing, for example, carboxymethylcellulose or polyethylene glycol as a facilitator 40 dissolving. In studies conducted on Adult rats of both sexes introduced these compounds knitted gastric probe in daily doses having about 0.0001 to about 0.075 g / kg, preferably not from about 0.0005 to about 0.05 g / kg, and especially. 45 at doses ranging from about 0.001 to about 0.025 g / kg. After it will take about an hour for the left rear paw of the animal The experimental body was injected with 0.06 ml of a 1% strength a suspension of carrageenan in an aqueous saline solution ziological. After 3 to 4 hours, the 50 weight and / or weight off the left hind leg with right rear paw. The differences between the two horses the deeds were compared with the difference in the horses trolls, and this comparison constituted a measure anti-inflammatory activity of the test compounds. 55 The following compounds I-III were tested and compared obtained according to the invention and compound IV known from Belgian Patent No. 705-869.

And acid a- [3-chloro-4- (1-keto-2-isoindolinyl) -phe nyl] propionic 60 II acid a- [4- (1-keto-2-isoindolinyl) -phenyl] -pro- free position, preferably at the extreme end coal, with one of the cyclo- alkyl * or cycloalkenyl; the rest mi are, for example, cyclopropylmethyl groups, 2-cyclopentylethyl or 3-cyclopentenylmethyl- wa.

A phenylene residue Ph associated with the A — N group in position 2, preferably in position 3, especially in position 3 link in position 4, may possibly include w one or more other positions, preferably 1 or 2, same or different substituents as in for example lower alkyl groups such as the former none specified, free, etherified or esters fictitious hydroxyl or mercaptan groups, such as low alkoxy groups, for example methoxy low, ethoxy, n-propoxy, isopropoxy wa, n-butoxy or isobutoxy groups, low- coalkyl mercapto groups, for example methyl mercaptan or ethyl mercaptan or atoc we halogen, for example fluorine, bromine or iodine, trifluoromethyl groups, nitro groups, groups amino, preferably dinipalkylamino, na example dimethylamino, N-ethyl-N-methyl- amine, diethylamine, di-n-propylamino- wa, diisopropylamine, di-n-butylamine or diisobutylamino, low alkenyl- amine, for example pyrrolidine, piperidine- wa, pyrroline and piperidine, and monoaza-, monooxy- or monothiaalkyleneamine, e.g. clade of piperazine groups, 4-low alkylpiperazine- morpholine or thiomorpholine or low alkanoylamino groups, for example acetylamino groups ijic or pivaloylamine, and optionally functionally transformed carboxyl groups, like group. carbomethoxy or carboethoxy, possibly for example carbamoyl groups substituted on nitrogen with low alkyl residues, such as discoalkylcarbamoyl, e.g. dimethylcarbamoyl py or cyano groups, low alkylsulfonyl groups, for example methyl- sulfonyl or ethylsulfonyl, or optionally functionally modified sulfo groups like optionally N-substituted sulfamyl groups, na example dienoalkylsulfamyl, such as tylsulfamyl. The remainder of Ph means in particular ci 1,3- or 1,4-phenylene, (lowalkyl) -1,3- or -1,4-phenylene, (lowalkoxy) -1,3- or 1,4-phe nylene, (mono or dihal) -1, 3- or 1,4- -phenylenes, (trifluoromethyl) -1, 3- or 1,4-phenylenes new, (nitro) -1, 3- or 1,4-phenylene, (amino) -1, 3- or -1,4-phenylene, (discoalkylamino) -1, 3- or -1,4-phenylene or (lowalkyleneamino) -1,3 or -1,4-phenylene.

There is a bicyclic alkenyleneamino group especially the appropriate 5-6 member breast rest shadow with 1-3 winds in the cyclic part doubled, optionally substituted below with the listed substituents. The rest is trans de all a benzoalkenylene amine residue either a suitable residue is dihydrogen or tetrahydro -benzene-alkenylamine, part of which is alkenes- lamino z. contains 5-6 rings in the ring and which possibly in the aromatic part, as per for example in a phenylene residue Ph, may be under made especially by lower alkyl groups, vertical III acid a- [3-chloro-4- (2-isoindolinyl) -phenyl] - -propionic IV a- [p- (1-pyrryl) -phenyl] -propionic acid 40 45 50 55 605 103 087 6 Blackboard and the Union AND II III 1 iv ED40 mg / kg , 6 1.3 4.2 65.0 LD50 mg / kg 708.9 57.64 448.13 431 Indicator therapist manual 127 44.3 107 6.2 The therapeutic index for compounds I-III is much higher than for compound IV, which proves with compounds I-III produced by the method of of the invention show much more effective operation not anti-inflammatory than the known comparative compound or IV.

According to a Newbould compilation, Brit.I.

Pharmacol. Chemother., Bd 21, p. 126 (1963), test induced arthritis, rats sensitized under ether anesthesia with 0.05 ml ltyo aqueous suspension of injected carrageenan for all 4 hind legs of the animal. After For 24 hours, it was injected subcutaneously into the tail of the animal after 0.1 ml of a 1% Macobacterium butyri suspension cum in mineral oil. Experimental compounds administered after 7 days, a gastric tube v previously described method within 14 days. Rats weighed once a week and fixed three times in a week of secondary arthritic lesions like them number and severity and compared with the data for control animals.

The antifungal action can be established on example in in vitro experiments with the plate dilution method for strains a fungus for example Trichophyton, Microsporum or Epidermophyton, as Trichophyton mentagrophy- tes, Trichophyton rubrum, Trichophyton siniL Microsporum canis, Microsporum gypseum or Epidermophyton floceusum. Antifungal action douches can also be indicated in in vivo studies, for example, the method described by Molinas, J. Invest. Derm., Bd 25, p. 33 (1965). In this method is injected into guinea pigs into the shaven ridge homogeneous agar suspension of the fungus Trichophyton mentagrophytes from 10 days culture on the Sabouraud agar. Action 0.5-2% of the solution or ointments containing the test substance the action starts after 24 hours and repeats something daily for 10 days. During this period of time after It uses fur and leather parts from 5 different places contaminated area and incubates subculture on agar plates suitable for the cultivation of poultry mycosis causing organisms and carried out breeding development research.

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

Expl. Biol. Med., Bd 95, p. 729, p. 729 (1957), at orally administered doses ranging from approx 0.05-0.2 g / kg / day.

The compounds according to the invention can be used as measures to prevent fungus and relieving pain, especially I io 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 way according to the invention are compounds of Formula 1, wherein the group A-N represents a bicyclic alkenyleneamine residue by 5-6 members in rings and with special Cha in an isocyclic ring of 1-3 doubles linkages, preferably a benzene alkenylene group amine with a 5-6 membered ring in part alkenyleneimaine, the rest of which may be substituted, especially in an adjacent position with nitrogen atom, through 1-2 ketone groups, Ph represents a phenylene residue, possibly subs substituted by 1-2 lowalkyl groups, hydro xyl, mercaptan, low alkoxy, low alkyl mercaptan, trifluoromethyl, nitro, amino, double alkylamino. low alkanoyl- amine, carboxyl, cyano, carbamoyl, dialkylcarbamoyl, lowalkylsulfonyl- we, sulfonic, sulfamyl, dinipalkylsulfa- atoms or halogen atoms, Ri is hydrogen hydrogen, low coalkyl or low alkenyl group or cycloalkyl, cycloalkenyl, cyclo- alkyl-lowalkyl or cycloalkenyl-lowalkyl- wa, where the cycloaliphatic residue contains 3-7 people new moon in the ring, as well as their lower esters are alkyl or their salts, in particular suitable for non-toxic salts of these for pharmaceutical use relationships.

Particularly valuable compounds with properties anti-inflammatory are the compounds of formula 1 in which- j5 The group A — N represents a bicyclic alke residue. nyleneamine with 1-3 double bonds in an isocyclic residue and 5-6 members in each ring in the cycloaliphatic part, being in such residues one of the two carbon atoms, 40 adjacent to a nitrogen atom may contain a group ketone, and Ph means the rest of the 1,3- or 1,4-phenyl- new, (lowalkyl) -1, 3- or -1,4-phenylene, (low- coalkoxy) -1, 3- or -1,4-phenylene, (mono- or dihalo) -1, 3- or -1,4-phenylene, (trifluoro 45 'orome1; yl) -1, 3- or 1,4-phenylene, (nitro) -1, 3- or -1,4-phenylene, (amino) -1, 3- or -1,4-phenylene or (dialkylamino) -1, 3- or -1,4-phenylene wa, Ri represents a hydrogen atom, a low alkyl group, cycloalkyl with 3 to 7 ring members or A cycloalkyl-lowalkyl group of 3 to 7 members is in the ring and R is hydrogen or less alkyl group or salts, especially suitable ' non-toxic ammonium salts for pharmaceutical use new, salts of alkali metals, alkaline earth metals J5 numerous and acid addition salts.

Particularly distinguished properties against inflammatory compounds are shown by compounds of formula 2, where Am is a 1-indolinyl, 2-isoindolinyl residue, 1,2,3,4-tetrahydro-1-quinolinyl or 1,2,3,4-four- 50 hydroisoquinolinyl with residues in one or both of them adjacent to the nitrogen atom in the ring, the carbon atoms may contain a group ketone, Ra is hydrogen or a group alkyl or alkoxy of up to 4 atoms ._ carbon, trifluoromethyl, nitro or7 103087 8 amino or halogen, Rx is atom hydrogen, an alkyl group of up to 4 atoms carbon or is a cycloalkyl or cycloalkyl group allkylmethyl wherein the cycloalkyl contains 3 to 4 ring bound and R is hydrogen or an alkyl group of up to 4 n atoms gla, like methyl, ethyl, n-propyl groups, isopropyl, n-butyl or isobutyl, or salts, especially those used in pharmacy toxic ammonium salts, alkali metal salts, for example sodium or potassium salts, or salts acid addition.

Among these compounds we should especially exclude change compounds of Formula II where Am is 2-isoindolinyl group, especially 1-keto-2-isoin- valley, as well as 1,3-biceto-2-isoindolines- low, l-keto-l, 2,3,4-tetrahydro-2-isoindolinyl or 1,3-biceto-1,2,3,4-tetrahydro-2-isoquinolines- Iowa, Ra is a hydrogen atom or a nitro group or amine as well as trifluoromethyl, a Rj is a hydrogen atom or a methyl group, ethyl, n-propyl or cyclopropylmethyl, and R is methyl or ethyl, or salts, especially those used in pharmacy, are non-toxic ammonium, sodium or potassium salts or additive salts with acids; these compounds, especially acid a - [3-chloro-4- (1-keto-2-isoindolinyl) -phenyl] -pro- vertical, show the test in the mentioned systems at daily doses of approx. 0.001 to approx. 0.025 g / kg, outstanding properties anti-inflammatory.

Method for the preparation of compounds of formula 1, v which A — N, Ph R, and Ri are given above meaning, according to the invention, is that a compound of the formula A — N — Ph — Xu wherein X! represents a moiety of the formula —C (= O) —CHfRi) - —Hal where Rx is as defined above and Hal is halogen and is operable pouring away a strong alkaline or solvent of the silver salt and, if appropriate, the resulting compound The formula 1 is transformed into a lower alkyl ester low and / or obtained ester compound or a salt containing hydrogen at the downstream position can be metallized and then reacted with with the same alcohol ester of the formula Rx-OH and / or obtained from the mana compound is halogenated in the rest of the aroma marked with the symbol Ph, and / or obtained the compound is salified or the salt obtained is converted into a free compound, and the tub is obtained the mixture of isomers is separated into each individual general isomers. the a-Haloacetyl starting compound is transformed into is carried out in a compound of formula I via route grouping method of the Faworski reaction (Wall- cha), for example by acting as a strong measure an alkali metal hydroxide or a soluble silver salt such as nitrate silver.

The compounds obtained can be converted in a known manner leading one into another. For example, received the free acids can be esterified using higher alkanols esterify in the presence of agents substances such as strong acids such as acid hydrochloric, sulfuric, benzene sulphonate- it or p-toluenesulfonic acid as well as bi- ' cyclohexylcarbodiimide or b compounds of di- azo.

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

Compounds containing ketone groups can be for example, carry out the action of pentosulfide- phosphorus to the appropriate thionic compounds. In two- a cyclic A — N residue not containing a group A ketone group can be such groups, by oxidation, on for example oxygen (eg air) or other la¬s decent oxidants, as before listed, introduce to the section containing nitrogen atom as a ring member, especially in unit or both positions adjacent to the atom ring nitrogen, which is obtained from suitable amine compounds are suitable lactam compounds or imide compounds.

The resulting esters or salts can be treated with metals position in position and with respect to functionally a shaped carboxyl group, for example by treatment with alkali metals or their derivatives mi, such as organic alkali metal compounds substances, for example lithium phenyl or three sodium phenylmethylide or metal hydride alkali such as sodium hydride, amides or alkali metal alkoxides, and then react with a reactive alcohol ester of * with the formula Rx-OH as well as with the corresponding halogen place and thus bring to position a organic group Rv 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, antimony111 or tin, or a chlorine a working agent, for example hydrochloric acid it in the presence of hydrogen peroxide or chlorate, an alkali metal, such as sodium chlorate it, a nitrosyl halide, for example nihloride troyl or nitrosyl bromide, haloimide, na. an example of bromosuccinrmide 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. In the resulting 'nitro compound, you can reduce the nitro group to an amino group the action of catalytically activated hydrogen or chemical reducing agents (hydrogen / in sitatu nascendi).

Reductions as well as other transformations should be requested in such a way that the compound produced contains no saturated alkenyleneamino group.

Received ties with the primary group, the amine can react with the reactive esters of alcohols or glycols and with reactive ones functional derivatives of acids such as ha lo -40 45 50 55 60103087 9 10 logenides, for example chlorides or anhydrides, and v thus transform into compounds containing secondary or tertiary amino group or a quaternary ammonium group as well acylated amino group. Received compounds slowly (amino group treated with azo acid this is given by diazonium compounds, which after reaction Sandmeyer, for example by hydrolysis in the following formula: lower temperatures, the action of copper halides DZ11 or copper cyanide11, a relatively lower alkaline nol or lower aryl mercaptan, preferably w under neutral or slightly acidic conditions either also weakly alkaline, can be carried out in od¬ suitable hydroxy-, halogen-, cyano-, low- alkoxy or low alkyl mercapto derivatives.

In the obtained phenolic products you can etherify phenolic hydroxyl groups and mercaptans, with appropriate use metal phenates, such as alkali metal phenates alkali metals or thiophenolates of alkali metals and tr with reactive low alkali esters nols or cycloalkanols, such as low alkyl halides low or cycloalkyl, "sulfates or sulfates." low alkyl or cycloalkyl phonates and two-phase compounds as well as lower two- azoalkanes. The phenol ethers obtained can be dissolved vaccinate, for example, by the action of strong acids or acidic salts such as hydrobromic acid and acetic acid and pyridine hydrochloride.

The aliphatic hydroxyl compounds can be dehydrated niac, for example, as previously described.

The resulting unsaturated compounds can be, as previously described, convert to saturation caused, for example, by a catalytically active hydrogen or reducing agents chemical (hydrogen in statu nascendi) eliminating double bonds, for example in the group Rx and / or in the ester group.

In the received relationships that can be vaccinate possibly esterified groups hydroxyl in the A-N residue can be such groups possibly split together with hydrogen, that is, by introducing double bonds, v the above-mentioned method.

The free acid obtained can be carried out in a known manner convert to salt, for example by reactions with an approximately stoichiometric amount of suitable a salt-forming agent such as ammonia, amine or an alkali metal or earth metal hydroxide alkali, carbonates or acidic carbonates alkali or alkaline earth metals. In this the method obtained ammonium salts or metal salts can be converted into free acids for action acid, for example hydrochloric acid, acid sulfuric acid or acetic acid to obtain a proper 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 and isolating the salt formed, and then conversion to addition salt. The obtained acid The word addition salt can be acted on by a base, on an example of an alkali metal hydroxide, ammonium niac or ion exchanger, transform into free relationship.

Acid addition salts are used in pharmacy, non-toxic acid addition salts, for example, inorganic acid addition salts such as hydrochloric acid, hydrobromic acid, sulfur phosphoric, nitrogenous or perchloric it, especially carboxyl or sulfone compounds - organic acids, such as formic and acetic acids, and propionic, amber, glycol, milk wine, apple, wine, lemon, benzo esic, 4-aminobenzoic, anthranilic, 4- -hydroxybenzoic, salicylic, aminosalic- embonic, pamoate or nicotine, as well as non-methanesulfonic, ethanesulfonic, hydro xyethanesulfonate, ethylene sulfonate, benzene sulfonic acid, halobenzene sulfonic acid, tolu- enesulfonic, naphthalenesulfonic, sulfanil- or cyclohexylsulfamic acid.

The above-mentioned as well as other salts, for example picrates can also be used for the eyes pissing and identifying free relationships; in this way you can transform free compounds into their salts, and these separate from the crude mixture and then from the isolated salts to obtain a vol new relationships. Due to the strict dependence between new compounds in free form and in form their salts, the term "free compounds" or "salts" they include both salts and free compounds.

The resulting mixtures of isomers may be known another way to separate into individual isomers, na for example by fractionated distillation or crystalline talizations and / or chromatographs.

Racemic compounds can be broken down into optically inactive isomers, for example the fractionation route significant crystallization by separation from mixtures dlastereoisomeric salts, for example with d- or 1-tartaric acid or d-a-phenylethyl- amine, d-a- (1-naphthyl) ethylamine or 1-cinchoni- Dyin, and optionally isolate the free isomers from the salt optical.

The previously mentioned reactions are carried out using known methods, for example possibly in the environment of diluents, preferably those 45 which behave obey the reaction components do not, and allow them to dissolve, and if necessary in the presence of catalysts, interm condensing or neutralizing vessels, in the atmosphere the sphere of an inert gas, e.g. nitrogen, current 50 cooling or heating and / or under increased pressure.

The invention also includes such variations each other in which the original relationships are used in the form of salt. In the process according to the invention, preferably a table there are starting relationships that they lead to the compounds of formula I which have been preceded by not described as particularly valuable.

The starting compounds are known, and if they are 60 m and new, these compounds are made known methods.

The α-halo ketone compounds are obtained as in an example with a suitable alkanophenone compound by halogenation or with the compound a-di- 65 of the azoketone obtained by the reaction ha- 6011 103 087 12 benzoic acid logenide from R ^ diazonium by reaction with a hydrohalic acid dim.

In intermediate products containing v place of group A — N primary group ami¬ new, you can create a group A — N reaction path with a compound of the formula HO-A-ON or a re-thereof active derivative.

I have received indirect relationships and initial relationships valid according to the above-mentioned methods can also carry them one after another the power of the 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, to exclude preparation of pharmaceutical preparations, incl with an effective amount of active ingredient, possibly possibly in admixture with inorganic or organic compounds liquid, solid or liquid used in pharmacy carriers suitable for use internal, parenteral and local.

Preferably, tablets or capsules are used Latin, containing a total of active substances with a diluent, for example lactose, dextrose for, sucrose, mannitol, sorbitol, cellulose and / or glycerin or lubricants such as silica, talc, stearic acid or its salts, such as stearates of magnesium or calcium and / or glycol polyethylene; tablets also contain the remedies binding, for example magnesium aluminum silicate different types of starch, such as corn starch, wheat starch rice, rice or Amylum Marantae, gelatine, tra- gacanth, methylcellulose, sodium carboxymethyl locelluloses and / or polyvinylpyrrolidone and optionally grinding agents, for example starches, agar, acid alginate or sodium alginate or mixtures effervescent and / or adsorptive agents; dyes, Wednesday aromatic and sweeteners. Injection preparations are preferably aqueous zotonic solutions or suspensions, and most of all suppositories and mastic fat emulsions or suspensions. Preparations pharmaceuticals can be sterilized and / or contained Load auxiliaries, for example, a measure of horse serving, stabilizing, wetting and / or emulsifying jace, solubilizers, salt for reconstitution regulating osmotic pressure and / or buffers.

The listed pharmaceutical preparations are manufactured in a known way, for example conventional different way of mixing, granulating or relatively drazeting. These preparations contain about 0.1% up to about 75%, especially from about 1% to about 50% of the active ingredient and possibly other pharmaceuticals macologically valuable substances.

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

Example I. Solution 6 g of a-chloro-4- (2-iso- indolinyl) propiophenone in 50 ml of diethyl ether 100 ml of a 20% solution of aqueous hydroxide are added tassic in ethanol. Heat the reaction mixture it weighs within 2 hours at the boiling point under a reflux cooler, then diluted water. The reaction mixture was brought to a value of pH 4 with hydrochloric acid and extracted with stirring nine with diethyl ether. The organic extract was processed by water is washed, dried and evaporated, and the remainder crystallizes from ethyl acetate to give acid α- [4- (2-isoindolinyl) -phenyl] -propionic acid, temp mp 247-250 ° C. Yield 35%.

The output product can be obtained as follows what: A mixture of 15.2 g of 4-fluoropropiophenone, 23.8 g isoindoline and 80 ml of dimethyl sulfoxide heats up in 16 hours on a steam bath, then poured over ice and sipped. Leftover after on filtration it is dissolved in diethyl ether and the solution is dried and evaporated. This is how he got 4- (2-isoindolinyl) propiophenone, which can be used for further processing without purification.

For a solution of 25 g of 4- (2-isoindolinyl) -propiophen- nu in 100 ml of benzene is added dropwise while stirring and cooling, 13.5 g. sulfuryl chloride in 50 ml. petrol zenu. After 2 hours, the mixture is evaporated shanine under reduced pressure, remainder It was mixed with water and the mixture was extracted with ether ethyl. The organic extract is dried and evaporated rises, yielding a-chloro-4- (2-isoindolinyl) -pro.- pyofenone.

Similarly, it is prepared with the use of * "suitable starting substances and possibly after carrying out an additional reaction as on, an example is given in the following examples, na stepujace compounds: ethyl ester of a- [4- <24zo- indolinyl) phenyl] acetic acid, m.p. 118-120 ° C after recrystallization from ether; a- [3-chloro-4- {1,3-diceto- -2-isoindolinyl) phenyl] propionic acid, temp mp 107-110 ° C after recrystallization from ether; a- [4- (2-isoindolinyl) -pheny- acid ethyl ester l] -propionic acid, m.p. 111- -113 ° C after recrystallization from ethanol; a- [4- (1,3-biceto-1,2,3,4-te- tern-2-isoquinolinyl-phenyl] -acetic tetrahydro-2-isoquinolinyl mp 89-91 ° C after recrystallization niu from ethanol; a- [3-chloro-4 ^ (1-keto-2-ispin- acid ethyl ester dolinyl) phenyl] propionic acid, m.p. 11-113 ° C acid a- [3-chloro-4- (1-keto-2-isoindolinyl) -pheny- lo] j-propionic acid, m.p. 178— —180 ° C; a- [4- (1, keto-2-isoindolinyl) -phenyl] -acetic acid with mp 206-208 ° C; α- [4Hl-keto-2-isoindolinyl] - acid ethyl ester -phenyl] -acetic acid, m.p. 111- —114 ° C; a- [4- (1-keto-2-isoindoline- acid methyl ester- 1) -phenyl] -propionic acid, m.p. 129- 132 ° C; a- [4- (1-keto-2-isoindolinyl) - acid ethyl ester -phenyl] -propionic acid, m.p. 104-106 ° C; a- [4- (1-keto-2-isoindole- acid n-propyl ester) nyl) phenyl] propionic acid, m.p. temperature 87-89 ° C; a- [4- (1-ketO'-24, zoindo) acid isopropyl ester linyl) phenyl] propionic acid, m.p. temperature 118-121 ° C; acid isobutyl ester linyl) phenyl] propionic acid, m.p. temperature 110-113 ° C; 40 45 50 55 60 103 087 13 14 a- [3-chloro-4- (2-isoindoline- acid ethyl ester- 1) -phenyl] -propionic acid, m.p. 67-70 ° C and bp 190-200 ° C / 0.4 mm Hg; acid a- [3-chloro-4- (1-keto-2-isoindolinyl) -pheny- butylol, m.p. 191-193 ° C; a- [3-chloro-4- (1-keto-2-iso- iridolinyl) phenyl] butyl butyl at boiling point nations 230-240 ° G / 0.35 mm Hg; acid a- [3-chloro-4- (1-keto-2-isoindolinyl) -pheny- Io] -a-cyclopropylacetic acid, m.p. 242-245 ° C; a- [3-chloro-4- (1-keto-2-iso- indolinyl) -phenyl] -α-cyclopropylacetic acid, temp boiling point 225-235 ° C / 0.33 mm Hg; a- [4- (1,3-dio-4,5,6,7- acid ethyl ester - tetrocryloro-241-azoindolinyl) -phenyl] -acetic o mp 197-199 ° C; a-cy1klopropyl-a- [4- (1Hketo-2-isoindoline- Io) phenyl] acetic acid, m.p. 186- —188 ° C; α-cyclopropyl-α- [4- (1-ke- to-2-isoindolinyl) phenyl] acetic acid at temperature mp 98-101aC; α-cyclopropyl-α- [4-keto-2- ethyl ester -isoindolinyl) -phenyl] -acetic acid temperature mp 111-113 ° C.

Example II. A mixture of 1 g of ethyl ester α- [3-chloro-4- (2-isoindolinyl) -phenyl] -pro acid vertical, 50 ml of ethanol and 15 ml of 20% strength aq of the potassium carbonate solution is maintained for 1 hour boiling under reflux on and evaporates under reduced pressure.

The residue is dissolved in water and a mixture it is acidified with 6N hydrochloric acid to pH = 3 and extracted them with ethyl acetate. The organic extract is dried, traps and evaporates. The residue crystallizes from of ethyl acetate to give a- [3-chloro-4- (2-iso- indoline) phenyl] propionic acid mp between 148 and 150 ° C.

Example III. A mixture of 4.5 g of ethyl ester acid a- [4- (1, keto-2-isohdolinyl) -phenyl] - -propionic acid, 1.6 g of potassium hydroxide v 2 ml of water and 250 ml of ethanol under nitrogen atmosphere, it remains boiling for 2 hours under a reflux condenser, then evaporated under reduced pressure. The residue dissolves in water, washed with chloroform, acidified hydrochloric acid and extracted with ethyl acetate. Ex the organic mixture is dried and evaporated to the residue it crystallizes from ethyl acetate. I get a- [4 ^ (1-iceto-2-isoindolinyl) -phenyl] -propion- acid mp 208-210 ° C.

Example IV. A mixture of 4.6 g of ethyl ester α- [4- (2-isoindolinyl) -phenyl] -acetic acid and 80 ml of a 25% aqueous hydroxide solution sodium is maintained for 3 hours in the state boiling, under a reflux condenser, then cooled water and dilute / The mixture becomes acidic hydrochloric acid, the precipitate is desiccated and recrystallized from ethyl acetate. The acid a [4- (2-isoindo linyl) phenyl] acetic acid of formula 3 which is melting at 237-239 ° C.

Example 5 Mixture of 1.8 g of ethyl ester a- [4- (2-isoindolinyl) -phenyl] -propio-Thio- acid 5 ml of a 50% aqueous aqueous solution sodium hydroxide, 25 ml of water and 100 ml of ethanol it remains boiling for 1 1/2 hours under the reflux condenser and concentrate under reduced pressure. The concentrate is diluted with water, and the result is The mana suspension is acidified with 6N hydrochloric acid to pH = 3 and extracted with ethyl acetate. Extract the organic is dried, filtered and evaporated reduced pressure. The residue crystallizes from ethyl acetate to give the acid a- [4- (2-iso- indolinyl) 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 chlorine-saturated ice cold acetic acid and the mixture was evaporated under reduced pressure. The residue dissolves in an aqueous solution of sodium bicarbonate and extracted with ether. The organic extract is dried, traps and evaporates. The residue is chromatographed on silica gel, being the eluent a mixture of benzene and hexane (1: 1) is used.

The main product is the ethyl ester acid: a - [3-chloro-4- (2-isoindolinyl) phenyl] propion - of formula -5; Rf value = 0.30 (raw material: Rf = 0.26) and obtained as the second product acid ethyl ester N α- [3,5-dichloro-4- (2-isoindolinyl) phenyl] prop vertical with formula 6; Rf = 0.395.

Example VII. Through a concentrated ester solution ethyl acid a- [3-chloro-4- (2-isoindolinyl) -phe nyl] propionic acid in dimethylformamide by bubbles of air bubble within 2 hours, while stirring and maintaining the temperature of 60 ° C, Obtained the ethyl ester of α- [3-chloro-4- (ljke- t-2-isoindolinyl) -phenyl] -propionic acid of Formula 7, which is isolated by evaporation of the mixture reaction nine under reduced pressure i residual distillation; the product is obtained as the fractions boiling at 200-210 ° C / 0.4 mm Hg; A- [3-chloro-4- (5-chloro-1-keto-2-isoindol- acid) nyl) phenyl] propionic acid, and its methyl ester you, ethyl or sodium salts Can potassium be obtained by the methods described above using appropriate starting raw materials.

In a similar manner, using the appropriate pro ¬ ters output ducts, the following compounds are obtained: acid a- [3-methyl-4- (1-keto-2-isoindolinyl) -pheny- lo] -pyopionic, m.p. 203— —207 ° C after recrystallization from a mixture of eta nol and diethyl ether; a- [3-methyl-4- (1-keto-2-iso- -isoindolinyl) -phenyl] -propionic acid, temp mp 121-122 ° C after recrystallization from diethyl ether; acid a- [3-methoxy-4- (1-keto-2-isoindolinyl) -phie- nylon, melting point 221- —224 ° C after recrystallization from ethanol; a- [3-methoxy-4- (1-keto-2-) acid ethyl ester -isoindolinyl) -phenyl] -propionic acid, temp mp 154-156 ° C after recrystallization from ethyl acetate; 40 45 50 55 6015 103 087 16 acid a- [3-methylthio-4- (1-keto-2-isoindolinyl) -phe nyl] -propionic, m.p. 214- —217 ° C after recrystallization from ethyl acetate; a- [3-Methylthio-4- (1, keto-2-) acid ethyl ester -isoind'olinyl) -phenyl] -propionic acid, temp mp 146-149 ° C after recrystallization from ethyl acetate; acid a [3-trifluoromethyl-4- (1-keto-2-isoindol- nyl) -phyl] -propionic, m.p. 181-184 ° C after recrystallization from ethyl ether wego, and acid ethyl ester of keito-2-isoindolinyl) phenyl] propionic acid with a temperature of mp 123-125 ° C after recrystallization from diethyl ether.

Claims (13)

Patent claims 1. A method for the preparation of new derivatives of α- (aminophenyl) -aliphatic carboxylic acids of formula I, in which A-N represents a bicyclic alkenyleneamino group with 1 to 3 double bonds and 5 to 6 members in each ring lower alkyl groups, free esterified or etherified hydroxyl or mercaptan groups or ketone groups, Ph denotes a phenylene residue, optionally substituted with 1-2 substituents from among such lower alkyl groups, free, a esterified or etherified hydroxy or mercaptan group, trifluoromethyl, nitro, amine, lower dialkylamino, lower alkanoylamino, optionally functionally converted carboxyl, cyano, carbamoyl, lower di-sulfonyl sulfonyl alkyl sulfo group, sulfamyl group, dialkyl lower sulfamyl group or halogen atom, Rx is hydrogen atom, lower alkyl group, lower and an alkenyl group, cycloalkyl, cycloalkenyl, cycloalkyl-nscoalkyl or cycloalkenyl-lowalkyl group and R is hydrogen, or a pharmacologically acceptable salt thereof, characterized by wherein A — N and Ph are as defined above, and Xx is a moiety of the formula C (= O) —CH (Ri) —Hal, in which Ri is as defined above and Hal is a halogen atom, by the action of a strong alkaline agent or a soluble silver salt, and / or the obtained free compound is converted into a salt or the obtained salt is converted into the free compound, and / or the obtained mixture of isomers is separated into individual isomers. 2. The method according to claim A process as claimed in claim 1, characterized in that the starting compound is α-halo-4- (2-isoindolinyl) -acetophenone to give & - - [4- (2-isoindolinyl) -phenyl] -acetic acid, which is optionally converted to in salt. 3. The method according to p. The process of claim 1, wherein the starting compound is α-halo-1- (2-isoindolinyl) -propiophenone to obtain α- [4- (2-isoindolinyl) -phenyl] -propionic acid, which is e-ventually converted in salt. 4. The method according to p. The process of claim 1, wherein the starting compound is α-chloro-3-chloro-4- (2-isoindolinyl) -propiophenone to obtain α- [3-chloro-4- (2-isoindolinyl) -phenyl] -propio acid - new, possibly salted. 5. The method according to p. A process according to claim 1, characterized in that the starting compound is α-halo-3-chloro-4- (1-keto-2-isoindolinyl) -propiophenone to give the acid α- [3-chloro-4- (1-keto) -2-isoindolinyl) phenyl] propionic acid, optionally salified. 6. The method according to p. The process of claim 1, wherein the starting compound is a-halo-4- - (1-keto-2-isoindolinyl) -propiophenone to give the acid a- [4- (1-keto-2-isoidolinyl) -phenyl] -propionized -! 5 you, which is possibly salted. 7. Process for the preparation of new derivatives of a- (aminophenyl) -aliphatic carboxylic acids of formula I, in which A-N represents a bicyclic alkenyleneamino group with 1 to 3 double bonds and 5 to 6 members in each breast In the shade, optionally substituted with lower alkyl groups, free, esterified or etherified hydroxyl or mercaptan groups or ketone groups, Ph is a phenylene residue, optionally substituted with 1-2 substituents, such as lower alkyl, free, esterified or etherified hydroxyl or mercaptan group, trifluoromethyl, nitro, amino group, lower dialkylamino group, lower alkanoylamino group, optionally functionally converted carboxyl group, cyano group, carbamoyl group, lower disarbamoyl alkyl group, lower diarbamoyl group - nylon, sulfo, sulfamyl, lower dialkylsulfamyl or halogen, Ri is hydrogen, lower alkyl a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkyl low alkyl group or a digital alkenyl low alkyl group, and R is a lower alkyl group, or a pharmacologically acceptable salt thereof, characterized by the compound of formula A — N— Ph — X1? wherein A-N and Ph are as defined above, and Xi is a group of the formula —C (= G) —CH (Ri) —Hal, in which Rx is as defined above and Hal is a halogen atom, is subjected to by the action of a strong alkaline agent or a soluble silver salt and the resulting acid is transformed into a lower alkyl ester and the optionally obtained compound is converted into a salt and / or the resulting mixture of isomers is separated into individual isomers. 8. The method according to p. The process of claim 7, wherein α- [4- (2-isoindolinyl) phenyl] acetic acid is converted into the ethyl ester. 55 - 9. The method according to p. The process of claim 7, wherein α- [3-chloro-4- (1,3-dio-2-isoindolinyl) -phenyl] -propionic acid is converted to the ethyl ester. 10. The method according to p. 7. The process of claim 7, wherein α- [4- (2-isoindolinyl) phenyl] propionic acid is converted to the ethyl ester. 11. The method according to p. 7. The process of claim 7, wherein α- [4- (1,3-diceto-1,2,3,4-tetrahydro-2-isoquinolinyl) -phenyl] -acetic acid is converted into the ethyl ester. 65 12. Method for the preparation of new derivatives 17 103087 18 a- (aminophenyl) -aliphatic carboxylic acids of formula I, in which A-N represents a bicyclic alkenyleneamino group with 1 to 3 double bonds and 5 to 6 members in each ring In the shade, optionally substituted with lower alkyl groups, free, esterified or etherified hydroxyl or mercaptan groups or ketone groups, Ph is a phenylene residue, optionally substituted with 1-2 substituents, such as a lower alkyl group, free, esterified or etherified hydroxyl or mercaptan group, trifluoromethyl, nitro, amino group, lower dialkylamino group, lower alkanoylamino group, optionally functionally converted carboxyl group, cyano group, carbamoyl group, lower disarbamoyl alkyl group, lower diarbamoyl group nylon, sulfo, sulfamyl, lower dialkylsulfamyl or halogen and Rx is lower alkyl, lower as alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lowalkyl or cycloalkenyl-low-alkyl groups and R is hydrogen or lower alkyl, or their pharmacologically acceptable salts, characterized by the compound of formula A — N — Ph— X1? wherein A — N and Ph are as defined above and Xx is a group of the formula —C (=) - CH2 — Hal, in which Hal is a halogen atom, is treated with a strong alkali or soluble silver salt, and the compound obtained, in the form of a lower alkyl ester or salt, is metallized aa and then reacted with a reactive alcohol ester of formula Rx-OH, in which R 1 is as defined above, and the compound obtained is converted to the free acid and / or the obtained mixture of isomers are separated into the 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, and 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 mercaptane group, trifluoromethyl, nitro, amino group, lower dialkylamino group, lower alkanoylamino group, optionally functionally converted carboxyl group, cyanide group, nebuloischaramoyl group The allkylsulfonyl group, the sulfone group, the sulfamyl group or the lower dialkylsulfame group yl, Ri is hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lowalkyl or cycloalkenyl-inscoalkyl and R is hydrogen or lower alkyl, or pharmacologically acceptable salts thereof, characterized by from the compound of formula A — N — Ph — X1? in which A-N is as defined above, Ph is a phenylene residue optionally substituted with a lower alkyl group, free, esterified or etherified hydroxyl or mercaptan group, trifluoromethyl, nitro, amine, lower dialkylamino group, lower group alkanoylamino, optionally functionally converted carboxyl, cyano, carbamoyl, lower dialkylcarbamoyl, lower alkylsulfonyl, sulfonate, sulfamyl or lower dialkylsulfamyl group, and Xx is —CH (= -CH) ) —Hal in which R x is as defined above and Hal is a halogen atom, is treated with a strong alkaline agent or a soluble silver salt and the compound obtained; optionally in the form of a lower alkyl ester or salt, it is halogenated in the aromatic residue Ph, and the optionally obtained compound is converted to the free acid and / or the resulting mixture of isomers is separated into the individual isomers. 10 15 20 25 30 35 103 087 ^ F19 9 N-Ph-CH-C-OR Am ^ 3 ^ CH-C-OR v-y 11 and formula 1 Ra Ri 0 Formula 2 CH; : n -> CH2-c-oh Formula 3 <RTI ID = 0.0> 1, </RTI> N CH30 and II CH-C-OH CHF CH2 Formula U.x, 'H. CH3O 'V ^ n2 \ ^^^ i ° ii ^ N - ^> CH-C-O-C2Hs 12' a Formula 5. r Cl CH3O rAs / CH2 \ L ^ I II U1 XHj II Formula 6 O N2 OCH-C-O-C2H5 Cl CH3 Formula 7 OZ Graph. Lz. 574 (95+ 17) Price PLN 45