CS220794B2 - Method of making the derivatives of the phenylacetic acid - Google Patents

Abstract

Phenylacetic acid derivs. of formula (I) and their physiologically acceptable salts, esters, and amides are new: (n=2-5; A-B- is CH-CH2-, C=CH- or CH.CO-; R1=H, halo, CF3, NO2 or NH2; R2 and R3=H, lower alkyl or together are ethylene; X1 = 2H or oxo; Y1 = CN, hydroxyamido-carbonyl, carbamoyl, 5-tetrazolyl or COOH). (I) are antiinflammatories well tolerated by the stomach and with relatively low toxicity. Some have a rapid onset of action, prolonged effect and favourable resorption capacity. They are useful in treatment of e.g. polyarthritis, neurodermatitis, bronchial asthma or hay fever, and usual oral dosage forms contain 1-250 mg. In an example, 2-(4-cyclopentylmethylphenyl)propionitrile was prep. from 4-(cyclopentylmthyl)acetophenone and p-toluenesulphonylmethyl isocyanide.

Description

The invention relates to a process for the preparation of new phenylacetic acid derivatives. Also · se ·. They describe pharmaceutical compositions containing these phenylacetic acid derivatives.

The nonionic phenylacetic acid derivatives correspond to the general formula te

where n stands for 1 to 5, the grouping, v ·.

A — B /

ch-ch groups—, \

C — CH—

Z or

CH — CO—,

OF

Rx is hydrogen, halogen, trifluoromethyl, nitro or amino,

R2 and R3 are hydrogen, methyl, or together an ethylene group,

Xj is two hydrogen atoms or oxo; and

Yt is a hydroxyamidocarbonyl group, a carbamoyl group, a carboxyl group, its salts with physiologically tolerable earth, its esters with physiologically compatible alcohols, or its amides with physiologically compatible amines.

Below the term halogen atom means a · ^E is preferably uoгu f ^l, a chlorine atom or a bromine atom.

The invention also relates to the racemic ^ ^alkyl Rivato selrn ^y íenýoctové ^eh of general formula Ia as well as their optically active antípodíi.

Suitable physiologically acceptable salts comprises no carboxylic group Y _t can be mentioned, for example, salts with alkali metals or alkaline earth metals such as sodium or calcium salt, ammonium salts, copper salts, piperazine salts or methylglucamine salt, and salts thereof with amino acids .

Physiologically compatible alcohols with which the carboxyl group may be esterified are, for example, straight, branched or cyclic, saturated or unsaturated hydrocarbon radicals, which may optionally be interrupted by an oxygen or nitrogen atom, or may be substituted by a hydroxyl, amino or carboxyl group such as, for example, alkanols (especially having 1 to 6 carbon atoms), alkenols, alkyinols, cycloalkanols, cyclloalkylallkanols, phenylalkanols, phenylalkenols, alkanediols, hydroxycarboxylic acids, aminoalkanols or alkylaminoalkanols and dialkylaminoalkanols having 1 to 4 carbon atoms in alkyl.

Alcohols which are suitable for the esterification of a carboxyl group are, for example, those containing the following radicals:

methylcarboxymethyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-carboxyethyl, propyl, allyl, cyclopropylmethyl, isopropyl, 3-hydroxypropyl, propynyl, 3-aminopropyl, butyl, sec-butyl, tert. butyl, 2-butyl, cyclobutyl, pentyl, isopenityl, t-pentyl, 2-methylbutyl, cyclopentyl, hexyl, cyclohexyl, cyclo-2-enyl, cyclopentylmethyl, heptyl, benzyl, 2-phenylethyl, octyl, bornyl, isobornyl, menthyl, n'onyl, decyl, 3-phenylpropyl, 3-phenyl-2-propenyl, undecyl or dodecyl.

Suitable alcohols suitable for esterification are also those alcohols (which lead to labile, i.e. physiologically cleavable esters, such as 5-hydroxyindane, acyloxymethanols, in particular acetoxymethanol, pivaloyloxymethanol, 5-indanyloxycarbonylmethanol, glycolic acid, dialkylaminoalkanols, especially dimethylaminalkanols, in particular dimethylaminoalkanols. as well as hydroxyphthalide.

Suitable physiologically compatible amines with which the carboxyl group can be amidated are preferably alkylamines, dialkyl amines, alkanolamines, dialkanolamines having 1 to 6 carbon atoms in the alkyl or alkanol moiety or five- or six-membered nitrogen heterocycles. Suitable amines include, for example:

methylamine, ethylamine, isopropylamine, ethanolamine, dimethylamine, diethylamine, diethanolamine, pyrrolidine, piperidine, morpholine or N-methylpiperazine.

(The process for the preparation of the novel phenylacetic acid derivatives of the formula Ia according to the invention consists in the hydrogenation of a compound of the formula X in a known manner

(X) where \

n, A - B -, X _b Y _t , R 2, and R ₂ are as defined above and

R ₅ represents a methylene group or when the moiety \

A — B— /

indicates group \

C = CH—, /

then also denotes two hydrogen atoms or one hydrogen atom and one methyl group, and optionally a compound of the formula Ia, where R _t denotes a halogen atom, dehalogenates, optionally a compound of the formula Ia in which R _t denotes a hydrogen atom, halogen is or nitrates and the resulting nitro compound is reduced to an amino compound, and optionally the obtained carboxylic acid or its reactive derivatives is converted to its salts, esters, amides, or hydroxamic acids.

The method of the invention is carried out in a known manner.

Thus, for example, compounds of formula X may be hydrogenated in an inert solvent in the presence of hydrogenation catalysts such as Raneyt nickel, platinum catalysts, palladium catalysts and the like with hydrogen gas. Suitable inert solvents are, for example, lower esters (ethyl acetate and the like), lower carboxylic acids (such as acetic acid and the like), lower alcohols (such as methanol, ethanol, isopropyl alcohol and the like), cyclic ethers (such as dioxane, tetrahydrofuran and the like). similarly) or water.

For example, the compounds of formula X needed as starting materials can be prepared from ketones of formula XX

wherein n, R _n R 2 and R ₃ have the meanings given above and a grouping \

А, —В, - /

represents a group CH ₂ -CH ₂ -, a group

or a group

by reacting these ketones with p-toluenesulfonic acid hydrazide, treating the resulting hydrazone with butyllithium and quenching the resulting lithium salt with carbon dioxide (Tetrahedron Letters 34, 1976, 2947). For example, the preparation of the starting material is also carried out under conditions commonly used in the Wittig reaction ("Organikum", Organisch Chemicals Grundpraktikum - VEB Deutscher Verlag der Wissenschaften, Berlin, 1976, 492).

Thus, for example, it can be prepared from a cycloalkyltriphenylphosphonium halide in an inert solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran or dimethylsulfoxide with the aid of a hase such as sodium hydride or butyllithium corresponding to triphenylphosphincycloalkylene and reacted at -20 to 120 ° C. with an aldehyde of formula XIII wherein

R ₁ , R ₂ and R ₃ are as defined above and

Re represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

If desired, the subsequent dehalogenation is also carried out in a conventional manner, for example by hydrogen halide cleavage. This can be accomplished by hydrogenating the compounds in, for example, ethanol or acetic acid in the presence of platinum or palladium catalysts.

Optionally, the subsequent resolution of the acid racemates takes place in known manner by reacting them with optically active bases and separating the obtained dlastereomeric mixtures by fractional crystallization.

Suitable optically active bases are, for example, optically active amino acids d- or 1-1-phenylethylamine, d- or 1-1-naphthylethylamine, brucine, strychnine or quinine.

Optionally, the subsequent halogenation of compounds of formula (Ia) wherein R ₂ is hydrogen is carried out in a conventional manner by treating the compound in an inert solvent (e.g. dichloroethane, methylene chloride, chloroform, nitrobenzene, and the like) in the presence of a Friedel-Craf printing catalyst. reacting (e.g., ferric chloride, ferric bromide, aluminum chloride, and the like) a halogen (e.g., chlorine or bromine).

Optionally, the subsequent nitration of the compounds of formula (Ia) wherein R 1 is hydrogen is carried out in a known manner by treating the compounds with nitric acid in a mixture with sulfuric acid.

Optionally, the subsequent reduction of the nitro group present is carried out under conditions known to those skilled in the art (Houben-Weyl, Vol. XI / 1, 1957, 360).

Optionally, the subsequent esterification of the free acids also takes place according to known methods. Thus, for example, acids can be reacted with, for example, diazomethane or diazoethane to give the corresponding methyl or ethyl esters. A generally applicable method is also the reaction of acids with alcohols in the presence of carbonyldiimidazole or dicyclohexylcarbodiimide.

It is furthermore possible, for example, to react the acids in the presence of copper oxide or silver oxide with alkyl halides.

Another method is to convert the free acids with the corresponding dimethylformamidalkylacetals into the corresponding alkyl esters of acids. Furthermore, the acids can be reacted in the presence of strongly acidic catalysts such as hydrogen chloride, sulfuric acid, perchloric acid, trifluoromethylsulfonic acid or p-toluenesulfonic acid, with alcohols or esters of lower alkanecarboxylic acid alcohols.

However, it is also possible to convert carboxylic acids into acid chlorides or mixed acid nitrides and to react with alcohols in the presence of basic catalysts such as pyridine, collidine, lutidine or 4-dimethylaminopyridine.

WMIS carboxylic acids, such as from the saponification - esters with the aid of basic catalysts, or at neutralizing acid with potassium hydroxide or- alíkahckých tovů such as ^IKL and ^d sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate or potassium hydroxide.

It is also possible to react the ester of ^{s b s} ECN it under Formula Ia ^ darkness acidic or basic catalysts -s finally desired alcohol. The acidic or basic catalysts used are preferably hydrogen chloride, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, p-toluenesulfonic acid, alkali metal alkoxides, alkaline earth metal alkoxides or aluminum alkoxide.

Optionally, the following preparation of amides or hydroxamic acids from free carboxylic acids or reactive derivatives thereof is also carried out according to known methods. Thus, for example, carboxylic acids can be reacted under known conditions with amines or hydroxylamine in the presence of di-cyclohexylcarbodiimide to give the corresponding aminocarbonyl compounds.

It is furthermore possible, for example, to convert the corresponding carboxylic acids, mixed anhydrides or esters into carboxylic acids under known conditions by treatment with ammonia, amines or hydroxylamine into the corresponding amides or hydroxamic acids.

For example, the following compounds of formula Ia may be prepared by the process of the invention:

2- (3-chloro-4-cyclohexyl ^and thylfenylpropionovou acid, 6-chlгr-4-L-cyklгpentylkarbгnyliπdaπ karbгxylQvгuι acid, 6-chloro-5-cyklohexylidenmethylindan-l- ^ k ^ a ^ b ^ ^^^^ xyl 6-chloro-5-cyclopropylpropylidenemic acid 6-chloro (5- (5-cyclopropylcarbonyl) -indol-11-carboxylic acid 6-chloro-5-fluoro-5-cyclopropylmethyl) -ylindyl-1-carboxylic acid -5 cyclopentylmethyl-6-L-nitrгmdaπ kaгbгxylгvгu acid - 6-aminг-5-L-cyklopentylmethylindan karboxylDvou acid ^'5-yl entylmeth cyklг ^p - ⁶ - ^{fl-L-uггindaπ} kaгboxylovгu acid, 6-chloro or- · cоklohept ^{5-yl-L-lmethylmdaп} karboxylovгu acid 2- (3-chloro-4-cyklгheptylmethylfeпylprгpiг) novгu acid 2- (3-chlгr-4-enyl cyklгheptylideпmethy LF 1) propionic acid, ^6-chloro-5-i cykloheptylidenmethyl n ^d L-aп karbbxyloιvгu ^acid 2- (3-chloro-c-plated cyklopentylidenmethylfenyl) propionic acid 2- (3 ^^! ^^^^ R ^^ 4) ^^: ^ ltylmethylfenyl lob) propionic acid 6-chloro-5-cyclobutylme thylindane-1-carboxylic acid,.

k ^y selrnu ⁶ -chlΌr 5-c ^о Caps ^Ly1 ylidenemethyl mdaп ^hyl-l-yl kaгbгx lгvгu acid 2- [B-chloro-en cyklopropylmethylf ^y lj propionic acid, 2- [3-4-chlгr -c ^y en klгprгpylideпmethylf ^yl) propionic acid 6-chiгr-5-L-cyklгpentylmethyliпdan karЬoh dгoxamovou ^yl, 2- ^{(3-chloro-4-yl} klгpen c · t ^y lmethylfeπyl) pгoplohydгoxamгvгu and 2-dimethylaminoethyl. 6-chloro-5-cyclopentylmethylindane-1-carboxylic acid thylamino ester.

The novel phenylacetic acid derivatives of the general formula (Ia) - are, as mentioned above, pharmacologically active compounds or intermediates for their production. In particular, the pharmacological activity of these compounds is manifested in that they exhibit considerable anti-inflammatory activity, are well acceptable to the stomach and exhibit only relatively low toxicity. In addition, these compounds are characterized by rapid často- - onset of high intensity and ^the implication desire duration of action. Furthermore, these compounds have very good resorbability.

The anti-inflammatory activity of the compounds of the invention can be determined using the known Adjuvans-Arthritis test, which is carried out as follows:

Female Lewis (LEW) rats weighing between 110 and 190 g are used. Drinking water and pressed altromine feed are administered ad libitum.

10 rats are used for each test group.

Mycobbacterium butyricum is used as an irritant. A suspension of 0.5 mg ^ cobacterium butyrmum in ^0.1 m ^l k ^{s p} ato him paraffin (DAB 7) was subplantarly injected into the right hind paw _.

The test substance is administered orally from day 11 of the experiment daily for 4 days. The substance is administered as a clear aqueous solution or as a crystal suspension with the addition of Myrj 53 (85 ^mg %) in isotonic ^; sodium chloride solution.

Po.stup attempt

Kr ^y with ^y ^ h is extended even as possible ^p ccording ^{WORLD of} IESNA ^s weight to ^the various type of ^H can be clamped. After plethysmographic measurement of the right hind paw volume, 0.1 ml of adjuvant is injected into the paw by subplantar injection. The right hind paw from day 14 until the experiment: ukoničern ^P on ^the usu m ^{ERI. P} to ^B and nibbling thereby three weeks.

Specifies the size of the dose of the test substance which ^p s ^d os ^oh no zahojern ^40% (= ED40).

Frequent complication in the therapy of steroidal-t ^ ^l něthvýmd atka ^and the height ^{T ≥} aludečních ulcers. These side effects may -flats dock Z ^{and p} ny of ^the US ^y on the reversal being oužije ^p j ^{and k can be} in a solubilizing amount ^for a test substance at which is observed at Acljuvans-Arthntis test ^40% Raven uz ^d.

Tries ^{to p} and the Eq vředovitostt ^Adi Umto manner:

They are males ^and Wistar rats ^y (SPF). ^From the ^IR ata ^s owner ^and the weight range ^{of 130} ± ^{10 g,} 16 hours before the start of the experiment rats were administered the feed stops but receive <water ad libitum.

5 animals are used per dose. The substance is applied once orally, dissolved in saline or as a suspension for krystate P ^CMD avku ⁸⁵ mg% Myrj 53rd

hours after application of the substance, 1 ^{ml of} 3% a1 is injected ^{. The} organic solution in the dye t ^ype in pure ^d and ^f enyl blue intravenously and the animals were US-i'tí. ^{Thanks to} grief in jmou and mterosko ^y ^ C ^ examines the number of epithelial damage and number of tumors that stand out using dyes.

The results obtained in these tests with compounds 5 to 8 according to the invention in comparison with known compounds 1 to 4 are shown in the table below.

Table

Number; ^With lantern

Adjuvant Arthritis Test (mg / kg animal)

Number ^of the ^stomach; e ^du at the same dose

1 2- (4-isopropylphenyl) propionic acid 100 ALIGN! 6.8 2 2- (4-cyclohexylphenyl) propionic acid 40 7 ^, 6 3 5-cyclohexyl- , .alpha., .alpha 50 8.3 4 ^{6-chloro-5-cyclopropyl-l-yl-cyclohex-l-indane} carboxylic acid 4 ^, 0 7 ^, 8 5 Selina ^alkyl 2- (4-cyclo ^p ent ^ylphenyl) propionic acid 10.0 0.6 6 2- (3-chloro-4-cyclopennylphenyl) propionic acid 3.0 0.6 7 6-chloro-5-cyclopentylmethylindane-1-carboxylic acid 30 2.2 8 6-chloro-5-cyclophenyl- 40 0 ^, 7

idenmeehylindan-l-carboxylic acid ^N b ^s compounds are ^h o ^{n e} in tombinaci with supporting means conventional in the pharmaceutical galenlcké palikaci instance in acute and chronic arthritldě, neurodermatitis, bronchial asthma, pollinosis and the like.

The preparation of special medicaments is carried out in a conventional manner by treating the active substances with suitable additives, carriers and flavoring agents into the desired application forms, such as tablets, dragees, capsules, solutions, detergents and the like.

For oral administration, especially tablets, -dražé and capsules containing for example 1 to a 250 mg of active ingredient and 50 ing to 2 g of the pharmacologically inactive carriers, such as lactose, amylose, talc, magnesium steaitát after Dad obné ^d, i ^{oZ and} common PNAS ^d y.

^Farther Uve e ^d ene pnMa ^ ^Gd compounds ^for clarification ^of the method of the invention.

P nk la dl

a) 1.18 kg hlinttého chloride was suspended by stirring in 2.40 liters of methylene chloride, the reaction mixture was cooled to 0 ° C -Temperature and 'over one hour is treated with an acid ethyl ester 790 g oxa ew ^{l, 8} 95 GC ^YKL o ^p en and ^the lmethylbenzenu ^{3 3} 6 L methylenchlotidu. The reaction mixture is left stirring at 20 DEG C. for 2 hours, poured onto 9 kg of ice / water (pH is adjusted to 3) and the organic phase is separated, the aqueous phase is extracted twice more. 2.5 l of methylene chloride and the combined organic extracts rom ^{p y} j ^L solution clilorteu sotoého until neutral, dried and evaporated. 1476 g of ethyl (4-cyclopentylmethylphenyl) glycoxylic acid ester are obtained in the form of an oily product.

b) 1016 g of potassium hydroxide are dissolved with stirring in 5 liters of methanol was added 1355 g of ethyl (4-cyklopentylmethylfenyljglyoxylové so long, the reaction mixture is stirred at a temperature of 20 ° ^C until precipitation-salt. This salt was dissolved in 8 liters of water, the solution is concentrated to half its volume and washed three times with 2 liters of ether. the aqueous phase was acidified with concentrated hydrochloric acid and extracted three times with 2 liters of ether. the organic phases are washed with a sodium chloride ^{é him} su ^Si odpan . ^{hexaneether kA} with 1026 g of (4-cyclo ^p entylmethylfenyl) glyoxylic acid as an oily product.

c) Under argon, a freshly prepared Grignard solution of 259 g ua bitter ^to 8 ²⁰ m ^l of methyl iodide in ^4,5-Шг all of ether with vigorous stirring, added dropwise to 519 grams of ⁽⁴ -cyklopentylmethylfenyl Jglyoxylové dissolved in 4 L of ether, dropwise addition is conducted during 2 ^d in it ^at that ^p ture in the range of ^{0 s t o} 5 ° C. ^{R p} eakčrn mixture of those -PO ^{d b} dalšmh for 2 hours at te ^p ture ^{of 20} ° C then added dropwise a mixture of 10 kg of ice water acidified with 4 liters of concentrated acid the hydrochloric ^s and phase odděh. ^V o ^{d F} Aze with them ^with the extracted four times with 2 liters of ether, the combined organic ^heavy phase is ^p rom ^{y is i} in ^d ou ^d about neutral, dried and evaporated. the resulting dry residue is washed with petrol, and finally ^stirred for a period of a ^{n e} him ^di n ^{y at} te ^pl rotatably 0 degrees Celsius, and then filtered with suction. yield ⁴ 04 ^g K ^y Selin ^2- ( ⁴ - [( ^R ) -benzyl] -2-hydroxypropion-2- ^yl ] -2-hydroxypropionic acid melting point 111 ° C.

d) 726 g of 2- (4-cyklopentylmethylfenyl) -2-h ^yd rox ^y propionic acid is boiled for 2 hours in 15 liters of dioxane with 1 liter of concentrated sulfuric acid. · After cooling to ²⁰ ° C, ^of omal ^{added 35 kg} of ice water. After one hour of stirring and cooling, the resulting product is filtered off with suction and recrystallized from gasoline. ^{OBTAINING A} was ^{376 g} carbamic acid ² - ^{(yk 4} -C lo ^p ent ^{ylmethyl y} butylphenyl ^yl) nominal acre ^yl mp 100 ° C.

e): ³²⁰ g of an acid ^{y 2} - ^(4-c KLR ^{y y p} ent ^lmet: h ^yl-phenyl) acrylic acid was reconcentrated in 3 liters of dioxane and the solution was hydrogenated at atmospheric ^to EM thia with ^{the 30 g of} palladium on charcoal (10 why.). After filtering off the catalyst, the filtrate was evaporated to an oil. 322 g of 2- (4-cyclopentylmethyl-phenyl) -propionic acid are obtained.

Example 1 -and d 2

a) 7.45 g of cyclopentyl bromide and 19.7 g of triphenylphosphine was heated in a pressure vessel ^P from argon to ^p o u ^b ^ ⁶ hourly -teplotě bath at 160 ^o C. After cooling the solid -rea ^ rn ^p genus ^{It is} boiled several times with benzene and then dried. -Se give 15.7 g ^cyclo- LR ^{p entyltrffenyfrosfonшm,} brrmi ^d u.

b) ^4, 1 ^{1 g} c k ^{l y} r ^{y p} ent ltIifen ^yi fosfrniumbrrmidu the -suspenduje in tetrahydrofuran under argon -atmosférou at 20 ° C was added 4.3 ml ^{of 3} M solution butylllthia in n-hexane. After 2 hours -míchání at ²⁰ ° C at 5 ° C was added a solution of ^{BC 2,} 24 grams of acid B-chloro-S-form / indan-carboxamide ^yl b ^s in ¹⁵ m ^l tetrahydro ^yd ro ^f ui ^ anu. ^P by 16 hours of stirring at 20 ° C, the reaction mixture is evaporated, the residue is mixed -with dilute ^ga Nou to ^{y-bismethylenesalicylic} chtorov odíkovou and extracted with ether. The ether-phase was washed and evaporated and the residue (2 g) -with chromatographed on silica (eluant: cyclohexane, 325 parts + 160 parts toluene, 190 parts + e ^ethyl ester to Selin ^y + ^y acetate ¹⁹ parts. Petroleum jelly ^alkyl acetate).

After přeikrystalování from petrol to give 1 g of i-chloro-S ^^^ ^ i ^^ ^ & lklop ^{ltylidenmethylindan-l-yl} karbrx lrvé -O-, mp 112 ° C.

c) ^{1, 5} to 8 ^{g y y} Selin 6 ^ - ^ IHO '- ⁵ ^ - ^ j ^] knocking ^ 1 ^{y y} lidenmeth lindane L-kaг ^b ox ^y lrvé -se hydrogenated at 20 ° C At atmospheric pressure in 32 ml of ethanol after addition of 158 mg of platinum oxide. The catalyst is filtered off, the filtrate is evaporated and the residue is recrystallized from petrol. 0.89 g of 6-chloro (trans-5-cyclopentylmethylindane-1-carboxylic acid), m.p. 126 DEG C., is obtained.

Claims (1)

I will invent the object A process for the preparation of phenylacetic acid derivatives of the general formula Ia wherein n = 1 to 5 is IN A — B— groups \ CH — CH3—,% \ с = сн— У or \ сн — со—, / R @ ₁ is hydrogen, halogen, trifluoromethyl, nitro or amino, R ₂ and R ₃ are hydrogen, methyl, or together ethylene, X1 is hydrogen or oxo, and Yi a hydroxyamidocarbonyl group, a carbamoyl group, a carboxyl group, its salts with physiologically compatible bases, its esters with physiologically compatible alcohols or its amides with physiologically compatible amines, characterized in that the compound of formula X is hydrogenated wherein n, A - B -, X _b R 1, R ₂ and Y, are as defined above and a R ₅ denotes a methylene group or when the group \ A — B— / indicates group \ C = CH—, / also denotes two hydrogen atoms or one hydrogen atom and one methyl group, and optionally the compounds of formula Ia wherein R 1 is a halogen atom are dehalogenated, compounds of formula Ia wherein R 1 is a hydrogen atom are halogenated or nitrated and the resulting nitro compounds are reduced to the amino compounds and, optionally, the obtained carboxylic acids or their reactive derivatives are converted into their salts, esters, amides or hydroxamic acids.