NO134946B - - Google Patents

Description

The present invention relates to an analogue method for the production of therapeutically active, new phenylacethydroxamic acids and their salts.

The invention relates in particular to an analogous process for the production of therapeutically active, new phenylacethydroxamic acids of formula I

where R-^, R- and R-j independently of each other mean hydrogen, lower alkyl, fluorine, chlorine or bromine to the exclusion of the simultaneous definition of the substituents R^, R2 and R^ as hydrogen, and

their salts.

In the following, the term "lower" is used in connection with alkyl residues to characterize such residues, which contain up to 6 and preferably 1 to 3 carbon atoms.

Lower alkyl residues are e.g. methyl, ethyl-> propyl, isopropyl or straight or branched butyl, pentyl or hexyl residues bound in any position.

As lower alkyl, the substituents R^, R^ and R^ are preferably an alkyl group with 1-2 carbon atoms, e.g. the methyl or ethyl group.

As lower alkoxy, a substituent is preferably the methoxy group.

The aforementioned substituents R 1 , R 2 and R 2 are preferably in the o- and/or m-position.

The invention also relates to the salts of the compounds of formula I. For use as a medicine, such salts are used which are pharmaceutically acceptable. Among these are meant in particular, salts with such bases, whose anions at the appropriate dosages show either no or a desired, special, pharmacological effect. Furthermore, it is advantageous if the salts to be used as active substance are easily crystallizable and not or slightly hygroscopic. For the salt formation with compounds of formula I, e.g. inorganic bases are used, such as e.g. aqueous or aqueous-alcoholic solutions of alkali or alkaline earth hydroxides.

The compounds according to the present invention possess valuable pharmacological properties. Thus, they exhibit antiphlogistic (anti-inflammatory), analgesic and antipyretic activity, which can be proven in animal experiments, e.g. by oral administration in doses of approx. 3 to 5o ml/kg for mice. The compounds are also characterized by relatively low toxicity and good gastro-intestinal acceptability, which can also be determined by standard testing. E.g. the analgesic effect of the new compounds of formula I can be demonstrated by oral administration to mice following that of E. Siegmund, R. Cadmus and G. Lu, Proe.Soc.Exp.Biol.Med. 95 729 (1957) described method, by; which determines the amount of substance necessary to prevent the syndrome caused by the intraperitoneal injection of 2-phenyl-1,4-benzoquinone. The antiphlogistic effect of the substituted o-anilino-phenylacethydroxamic acids of formula I can e.g. demonstrated by oral administration to guinea pigs in that of G. Wilhelmi, Schweiz.Med. Wbchenschrift 79, 577 (1949) described the UV erythema test as well as for rats in the Bolus alba edema test. according to G. Wilhelmi, Hap. J. Pharmacol. 15, 187 (1965). As further proof of the antiphlogistic effect and acceptability, the cotton granule test can be mentioned. With this, rats are implanted under ether anesthesia each with two approx. 1 cm long cotton roll pieces subcutaneously under the back skin. The test substance is then administered in equal doses on successive days. On the 11th day, the animals are killed, the developed granulomas are removed and their wet-

and dry weight is determined. By comparing the dry weight of the granulomas from rats, which received the test substance, and the granulomas from the control animals, the extent of granuloma inhibition is calculated. As a yardstick for acceptability, the weight gain of the animals is measured during the administration of the test substances.

The gastro-intestinal acceptability is measured e.g. by the ulcer-forming effect in the rat, as the active substance is used twice orally, with an interval of 15 hours, the animals are killed 21 hours after the first administration and the digestive tracts are assessed with regard to the number of ulcers that have developed as well as further changes in the mucosa.

To determine the antipyretic effect, the compounds of formula I are administered in suitable doses orally to groups of rats, which 16-18 hours before had been injected intramuscularly with a suspension of 15% baker's yeast with 1% tragacanth and 1% sodium chloride in distilled water in an amount of 1 ml per loo body weight. The fever temperatures developed with the help of the yeast are measured rectally every half hour an hour and 1/2 hour before the administration of the test substances and in the period 1/2 hour to 5 hours after the administration of the test substances. The maximum temperature depression as well as the arithmetic mean temperature drop in the 5 hours after the administration of the test substances are determined as a basis for comparison against the average of the two measurements for the administration.

The compounds of formula I absorb ultraviolet light with a wavelength range between approx. 29o and approx. 315 mu. This special property makes these substances particularly suitable for incorporation into cosmetic preparations for the prevention of sunburn.

With a suitable composition of such sun protection preparations, sunburn is avoided when using them, and yet a desired tanning of the skin is not prevented.

The new substituted o-anilino-phenylacethydroxamic acids of formula I are suitable as active substances for orally, rectally, parenterally or percutaneously applicable drugs for the relief and removal of pain and inflammation of various kinds, e.g. of a post-traumatic and post-operative nature, and for orally, rectally, parenterally or percutaneously usable drugs for the treatment of rheumatic, arthritic and other inflammatory diseases.

The following four compounds were tested comparatively with regard to their anti-inflammatory effect:

1. [o-(2,6-dichloroanilino)-phenyl]-acethydroxamic acid

2. [o-(3-chloro-o-toluidino)-phenyl]-acethydroxamic acid

3. [o-(2,6-dichloroanilino)-phenyl]-acetamide

4. [o-(3-chloro-o-toluidino)-phenyl]-acetamide

Bolus alba edema in the rat served as a test object, whereby work was carried out according to the method described by G. tfilhemi in the Japanese Journal of Pharmacol. 15, (1965), pages 187 - 198. The achieved mean reduction in swelling with the four test substances is shown in the following table:

As the table shows, the compounds 1 and 2 according to the invention, in the respective indicated amounts, after oral administration to rats, cause a much stronger reduction in swelling than compounds 3 and 4, which can be considered the closest state of the art (French patent 1 555 646 ).

Particularly noteworthy are compounds with the formula Ia

where R^, R2' and R3' mean hydrogen, methyl or fluorine, chlorine or bromine,

to the exclusion of

the simultaneous definition of R 1 , R 2' and R 3'

as hydrogen,

and salts of such compounds.

Particularly preferred are compounds of formula Ib

where R-^" means methyl or chlorine,

R2" means hydrogen, methyl or chlorine, and

R3" means hydrogen, methyl or chlorine,

and salts thereof.

Due to their particularly favorable pharmacological properties, the following should be highlighted: /o-(2,6-dichloroanilino)-phenyl7-acethydroxamic acid, /o-(2,6-dichloro-m-toluidino)-phenyl7-acethydroxamic acid, /o-(3 -chloro-o-toluidino)-phenyl7-acethydroxamic acid, /o-(6-chloro-o-toluidino)-phenyl7-acethydroxamic acid and /o-(2,6-xylidino)-phenyl7-acethydroxamic acid.

The new compounds of formula I and their salts are prepared in a manner known per se.

According to a first method, compounds of formula I and their salts with inorganic bases are prepared by reacting an amide or a preferably activated ester of an acid of formula II

where R1/R2 and R^ have it under formula I

stated meaning,

with hydroxylamine or a salt thereof in basic medium and, if desired, transferring a compound of formula I obtained

in a salt with an inorganic base.

As amides of an acid with formula II, compounds unsubstituted by the amide nitrogen are preferably used. Lower alkyl esters are preferably used as esters of an acid with formula II. As activated esters can e.g. The p-nitrobenzyl, ethoxycarbonylmethyl, methoxymethyl, p-nitrothiophenyl ester and preferably the cyanomethyl or p-nitrophenyl ester of the acids of formula II are used.

The reaction is carried out in an organic solvent, preferably at a temperature between 20° and 100°C, respectively the boiling temperature of the solvent used, and at a reaction time of between 20 minutes and 15 hours.

Suitable solvents used under the reaction conditions are inert organic solvents, such as e.g. lower alkanols, acetonitrile or chloroform. In addition, acetone can

diethyl ether, di-n-butyl ether, acetic acid ethyl ester, 1,2-dichloroethane, dimethylformamide, dimethylsulfoxide, 1,4-dioxane, methylene chloride, nitromethane, petroleum ether, tetrachloroethylene, tetrachlorocarbon or trichloroethylene, as well as benzene, nitrobenzene, pyridine or toluene are used.

The choice of the advantageous solvent in each case also depends on the nature of the starting materials used in each case. E.g. the reaction of a lower alkyl ester or an amide of an acid of formula II in a lower alkanol, preferably methanol, is carried out. In the reaction of an activated ester with formula II, e.g. acetonitrile, chloroform, dimethylformamide or acetic acid ethyl ester as solvent.

The aforementioned amides and esters" of acids with the general formula II are reacted with hydroxylamine or a salt thereof in stbchiometric amounts or with an excess of hydroxylamine. In the reaction of the aforementioned acid derivatives with hydroxylamine hydrochloride, an excess of one is added compared to the hydroxylamine stronger base.

In the reaction of lower alkyl esters or amides of acids with formula II, an amount equivalent to the hydroxylamine hydrochloride, preferably a fourfold excess of a base, such as e.g. sodium alcoholate or alcoholic caustic soda, to the reaction mixture.

Activated esters are reacted, such as e.g. the cyanomethyl ester or the p-nitrophenyl ester of an acid with formula II, then a quantity of a tertiary organic base, which is e.g. triethylamine or pyridine.

Some representatives of the lower alkyl esters and amides of an acid of formula II are known and others, corresponding to those known, can be prepared. Lower alkyl esters are produced e.g. by esterification of the corresponding acids with formula II or by alcoholysis of the corresponding nitriles. From the lower alkyl esters obtained, after reaction with ammonia, the corresponding amides are obtained in a known manner.

The substituted o-anilino-phenylacetic acid cyanomethyl esters are prepared from the corresponding substituted o-anilino-phenylacetic acids of formula II by reaction with chloroacetonitrile in the presence of the equivalent amount of triethylamine or by reaction of the Na salts of the aforementioned acids with chloroacetonitrile in a suitable solvent, such as dimethylsulfoxide. Analogously, the substituted o-anilino-phenylacetic acid p-nitrobenzyl esters, the -ethoxycarbonylmethyl ester and the -methoxymethyl ester are obtained. The substituted p-riitrophenyl esters of acids of formula II are obtained from the corresponding acids by reaction with trifluoroacetic acid p-riitrophenyl ester in the presence of pyridine. Analogously, the p-nitro-thiophenyl ester is also obtained.

If desired, the new phenylacethydroxamic acids of formula I obtained are then converted in a known manner to their salts with inorganic bases.

For salt formation with compounds of formula I, alkali hydroxides can be used, e.g. sodium or potassium hydroxide, or alkaline earth hydroxides, e.g. calcium hydroxide.

The substituted phenylacethydroxamic acids of formula I can be administered orally, rectally or parenterally. They can also be used on surfaces, e.g. incorporated into an ointment base.

The following examples illustrate the implementation of the method according to the invention in more detail,

The temperatures are indicated in degrees Celsius.

Example 1,

£o -( 2/ 6- dichloroanilino)- phenvl7- acethydroxamic acid

A solution of 17.5 g of hydroxylamine hydrochloride in 260 ml of absolute methanol is added at room temperature to a solution of 18.7 g of sodium in 400 ml of absolute methanol. The suspension is added with stirring to 77.6 g of /o-(2,6-dichloroanilino)-phenyl-7-acetic acid methyl ester (m.p. 101-102°) and is then heated under reflux for 30 minutes. The mixture is stripped and concentrated to a dryness below 11 torr at 40°. To the residue, add 4000 ml of water and 500 ml of ether, stir for 20 minutes, separate the aqueous solution and make it acidic with 6-N hydrochloric acid. The suspension is extracted with 2000 ml of ether, the ether solution is washed with 200 ml of water and 200 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated under 11 torr at 40°. The residue is crystallized twice from ethyl acetate-petroleum ether. The /o-(2,6-dichloroanilino)-phenyl7-acet-hydroxamic acid melts at 164-165°.

In an analogous manner, one obtains: /o-(2,6-dichloro-m-toluidino)-phenyl7-acethydroxamic acid, m.p. 140-145° (from ether-petroleum ether) starting from 16.2 g of /o-(2,6-dichloro-m-toluidino)-phenyl7-acetic acid methyl ester, m.p. 110-112°;

/o-(6-Chloro-o-toluidino)-phenyl7-acethydroxamic acid, m.p. 159-162°

(from ethyl acetate-petroleum ether), starting from 29.1 g of /o-(6-chloro-o-toluidino)-phenyl7-acetic acid methyl ester, m.p. 99-100° (from cyclohexane);

/o-(2,6-xylidino)-phenyl7-acethydroxamic acid, m.p. 134-36° (from ethyl acetate-petroleum ether), starting from 4.9 g of /o-(2,6-xylidino)-phenyl7-acetic acid methyl ester, m.p. 79-80° (from ether-petroleum ether);

/5_(3-Chloro-o-toluidino)-phenyl-7-acethydroxamic acid, m.p. 135-136°

(from ether-petroleum ether) starting from 7.2 g of /o-(3-chloro-o-toluidino)-phenyl7-acetic acid methyl ester, m.p. 47-48° (from ether-petroleum ether) .

The /5_(3-chloro-o-toluidino)-phenyl7-acetic acid methyl ester is obtained

e.g. as follows:

a) N-(3-chloro-o-tolyl)-anthranilic acid

A mixture of 665 g of o-bromobenzoic acid and 220 g of 85% potassium hydroxide in 1800 ml of n-pentanol is heated with stirring to 16o°C. In the course of 30 minutes, approx. 4oo ml of n-pentanol from. 940 g of 3-chloro-o-toluidine and 12.5 g of copper powder are then added and the mixture is boiled for 15 hours under reflux. The mixture is then washed off, poured into a solution of 180 g of sodium carbonate in 600 ml of water and the solution is distilled with steam. After the excess 3-chloro-o-toluidine is distilled off, the aqueous residue is filtered and the filtrate is acidified with concentrated hydrochloric acid. The separated crystals are filtered off and crystallized from ethanol-water. N-(3-chloro-tolyl)-anthranilic acid with a melting point of 212-215°C is obtained.

b) N-phenyl-3-chloro-o-toluidine

150 g of N-(3-chloro-o-tolyl)-anthranilic acid are heated for 2 J5 hours more

280°C. The cooled melt is dissolved in 700 ml of ether. The ether solution is washed twice with 150 ml of 2-n sodium carbonate solution and 150 ml of water. The ether solution is then separated, treated with sodium sulphate and concentrated to a dryness below 11 torr at 40°. The residue is distilled, whereby N-phenyl-3-chloro-o-toluidine is obtained as a yellow oil, b.p. 117°/0.0l dry.

c) N-phenyl-3'-chloro-2'-methyl-oxaniloyl chloride For a solution of 94.5 g of N-phenyl-3-chloro-o-toluidine in 560 ml

anhydrous benzene, 137 ml of oxalyl chloride is slowly added dropwise at 5°. The suspension is then stirred for 2 hours at room temperature and 1 hour at 50°, whereby the suspension dissolves. The residue is dissolved in 400 ml of anhydrous benzene and the solution is evaporated again to a dryness below 11 torr. The residue, the N-phenyl-3'-chloro-2'-methyloxaniloyl chloride, is present as an oil.

d) 1-(3-chloro-o-tolyl)-indole-2,3-dione

To a solution of 134 g of N-phenyl-3<1->chloro-2'-methyl-oxaniloyl chloride in 900 ml of tetrachloroethane, 58.6 g of powdered aluminum chloride is added in portions. The mixture is stirred for 20 hours at room temperature. It is then poured onto a mixture of 2000 g of ice and 200 ml of 2-n hydrochloric acid. Add 500 ml of chloroform and shake well. The tetrachloroethane-chloroform solution is separated, washed with 300 ml of 2-n sodium carbonate solution and then with 300 ml of water, dried over sodium sulphate and evaporated to dryness below 0.1 torr. The residue is crystallized from ethyl acetate. 1-(3-chloro-o-tolyl)-indole-2,3-dione melts at 173-174°.

e) Sodium salt of /o-(3-chloro-o-toluidino)-phenyl7-glyoxylic acid A solution of 57 g of 1-((3-chloro-o-tolyl)-indole-2, 3-dione in 800

ml of ethanol and 210 ml of sodium hydroxide solution are evaporated under 11 torr at 40° to dryness. To the residue, absolute benzene is added twice, each time 100 ml, and each time the mixture is evaporated to dryness below 11 torr at 40°, whereupon pure sodium salt of /o-(3-chloro-o-toluidino)-phenyl7- the glyoxylic acid.

f) / o-(3-chloro-o-toluidino)-phenyl7-acetic acid

A solution of 35.5 g of the sodium salt of /o-(3-chloro-o-toluidino)-phenyl-7-glyoxylic acid in 455 ml of absolute ethanol is added at 50° to 28.5 g of hydrazine hydrate and 5 minutes afterwards 66.2 g of sodium methylate . The solution is then heated in an oil bath at a bath temperature of 15o°, whereby the ethanol slowly distills off. At the same time, 455 ml of ethylene glycol monoethyl ether is added drop by drop. The temperature then rises to 130°. After completion of the addition, the solution is stirred for a further 1 hour at 150°, washed off and diluted with 3000 ml of water. The solution is extracted twice, each time with 300 ml of ether and then acidified with concentrated hydrochloric acid. The separated yellow oil is extracted with 200 ml of ethyl acetate. The ethyl acetate solution is washed with 200 ml of water. The ethyl acetate solution is washed with 200 ml of water, dried over sodium sulphate and concentrated below 11 torr at 30°, whereby the /o-(3-chloro-p-toluidino)-phenyl7-acetic acid crystallizes out. S. P. 124-125°.

q) { o -( 3-chloro-o-toluidino)-phenyl7-acetic acid methyl ester To a solution of 10 g /o-(3-chloro-o-toluidino)-phenyl7-acetic acid (m.p. 124-125°) in 100 ml ether is allowed to drip in slowly

100 ml of 2% ethereal diazomethane solution. The solution is allowed to stand for 2 hours at room temperature and then evaporated to a viscosity below 11 torr at 40°. The residue is dissolved in 100 ml of ether. The ether solution is extracted with 40 ml of 2-n sodium bicarbonate solution and water, dried over sodium sulphate and evaporated under 11 torr at 40°. The rest is crystallized from gasoline. The /5-(3-chloro-o-toluidino)-phenyl7-acetic acid methyl ester melts at 47-48°.

Example 2.

// o - ( 2, 6-dichloroanilino) - phenyl7- acethhdroxamic acid A mixture of 6.7 g /o-(2,6-dichloroanilino)-phenyl7-acetic acid cyanomethyl ester (m.p. 100-1041) and o;7 g hydroxylamine hydrochloride in 27 ml of acetonitrile, 3 drops of glacial acetic acid as well as 1.01 g of triethylamine are added. The mixture is stirred for 30 minutes at room temperature, 0.35 g of hydroxylamine hydrochloride and 0.5 g of triethylamine are again added and stirred for a further 15 hours at room temperature. The mixture is then concentrated below 11 torr at 50°. 30 ml of water and 100 ml of ethyl acetate are added to the remainder. The ethyl acetate solution is separated and evaporated under 11 torr. The residue is dissolved in 100 ml of ether and the ether solution is extracted with 10 ml of 1-1 sodium hydroxide solution, whereby the /o-(2,6-dichloro-anilino)-phenyl7-acethydroxamic acid Na salt separates from the crystalline one. The crystals are filtered off, suspended in 50 ml of ether and the suspension is shaken with 20 ml of 6-n hydrochloric acid. The clear ether phase is separated, washed over sodium sulfate and concentrated below 11 torr at 40°. The remainder is crystallized from ether. The /o-(2,6-dichloroanilino)-phenyl7-acethydroxamic acid melts at 164-165°.

in the same way one obtains: /o-(2,6-dichloro-m-toluidino)-phenyl7-acethydroxamic acid, m.p. 140-145° (from ether-petroleum ether), starting from /o-(2,6-dichloro-m-toluidino)-phenyl7-acetic acid cyanomethyl ester;

/o-(6-Chloro-o-toluidino)-phenyl7-acethydroxamic acid, m.p. 159-162° (from ethyl acetate-petroleum ether), starting from /o-(6-chloro-o-toluidino)-phenyl7-acetic acid-cyanomethyl ester;

/J5-(2,6-xylidino)-phenyl7-acethydroxamic acid, m.p. 134-136°

(from ethyl acetate-petroleum ether), starting from /o-(2,6-xylidino)-phenyl7-acetic acid cyanomethyl ester;

/o-(3-Chloro-o-toluidino)-phenyl7-acethydroxamic acid, m.p. 135-136° (from ether-petroleum ether), starting from /o-(3-chloro-o-to-luidino)-phenyl7-acetic acid-cyanomethyl ester..

The starting materials are obtained as follows:

a) / o-(2, 6- dichloroanilino)- phenyl7- acetic acid- cyanomethyl ester

A mixture of 2.96 g of /o-(2,6-dichloroanilino)-phenyl7-acetic acid

(m.p. 156-158° from ether-petroleum ether), 1.13 g of chloroacetonitrile and 1.51 g of triethylamine in 30 ml of ethyl acetate are stirred for 15 hours at 60°, cooled and separated from separated triethylamine hydrochloride. The filtrate is washed with 5 ml 1-1 hydrochloric acid, three times with 5 ml 1-1 sodium bicarbonate solution each time, as well as 5 ml water, dried over sodium sulphate and evaporated below 11 torr at 50°. The residue is crystallized from methanol, the /o-(2,6-dichloroanilino)-phenyl7-acetic acid cyanomethyl ester melts at 100-104°.

In the same way, one obtains: /o-(2,6-dichloro-m-toluidino)-phenyl7-acetic acid cyanomethyl ester, starting from /o-(2,6-dichloro-m-toluidino)-phenyl7-acetic acid , s.p. 146-149° (from ether-petroleum ether);

/o-(6-chloro-o-toluidino)-phenyl7-acetic acid cyanomethyl ester starting from /o-(6-chloro-o-toluidino)-phenyl7-acetic acid, m.p. 140-147° (from ether-petroleum ether);

/o-(2,6-xylidino)-phenyl7-acetic acid cyanomethyl ester starting from /o-(2,6-xylidino)-phenyl7-acetic acid, m.p. 112-113° (from ether-petroleum ether);

/5-(3-chloro-2-methyl)-phenyl7-acetic acid cyanomethyl ester starting from /o-(3-chloro-o-toluidino)-phenyl7-acetic acid, m.p. 124-125°

(from ether-petroleum ether).

b) /o-(2,6-dichloroanilino)-phenyl7-acetic acid-cyanomethyl ester A solution of 5.0 g of /o-(?,6-dichloroanilino)-phenyl7-acetic acid Na salt (m.p. 283-285° from water) in 30 ml of dimethyl sulphoxide is added at room temperature to 30 ml of chloroacetonitrile. The mixture is stirred for 20 minutes at room temperature, poured onto 100 g of ice. and extract with 200 ml of ether. The ether solution is washed with 30 ml of 2-n potassium hydrogen carbonate solution and three times, each time with 30 ml of water, dried over sodium sulphate and evaporated under 11 torr at 40°. The residue is crystallized from methanol, the /o-(2,6-dichloro-anilino)-phenyl-7-acetic acid cyanomethyl ester melts at 100-104°.

In the same way, one obtains: /5-(2,6-dichloro-m-toluidino)-phenyl7-acetic acid cyanomethyl ester by starting from /o-(2,6-dichloro-m-toluidino)-phenyl7-acetic acid- Na salt, s.p. 287-289° (from water);

/o-(6-chloro-o-toluidino)-phenyl7-acetic acid cyanomethyl ester starting from /5-(6-chloro-o-toluidino)-phenyl7-acetic acid K-salt, m.p. 285-300° (decomposition from methanol);

/o-(2,6-xylidino)-phenyl7-acetic acid cyanomethyl ester starting from /o-(2,6-xylidino)-phenyl7-acetic acid Na salt, m.p. 298-305°

(from water).

Example 3.

/ o-(2,6-dichloroanilino)-phenyl7-acethydroxamic acid To a suspension of 4.17 g of /o-(2,6-dichloroanilino)-phenyl7-acetic acid p-nitrophenyl ester (m.p. 105-106°) and 0, To 69 g of hydroxylamine hydrochloride in 50 ml of absolute chloroform, 2.76 g of triethylamine are added at room temperature. The clear solution is stirred for 30 minutes at room temperature and evaporated to dryness below 11 torr. 100 ml of ether and 5 ml of 2-N hydrochloric acid are added to the residue. The ether solution is separated, washed twice, each time with 40 ml of water, dried over sodium sulphate and concentrated

it grows at 40°C under 11 torr. The remainder is crystallized from ether. /o-(2,6-dichloroanilino)-phenyl7-acethydroxamic acid melts at 164-165°c.

In the same way one obtains: /o-(3-chloro-o-toluidino)-phenyl7-acethydroxamic acid, m.p. 135-136° (from ether-petroleum ether), starting from /5-(3-chloro-o-toluidino)-phenyl7-acetic acid-p-nitrophenyl ester.

The starting material is obtained as follows: /o-(2,6-dichloroanilino)-phenyl7-acetic acid-p-nitrophenyl-ester To a solution of 6.0 g of /o-(2,6-dichloroanilino)-phenyl7-acetic acid in 20 ml pyridine, 6.0 g of trifluoroacetic acid p-nitrophenyl ester (prepared according to the instructions of S. Sakakibara and N. Inukai, Bull. Chem. Soc. Jap. 1983 /I9657) is added portionwise while stirring. The mixture is stirred for 1 hour at room temperature and evaporated below 11 torr at 30-40°. To the residue, add 20 ml of water and extract with 50 ml of chloroform. The aqueous phase is separated and extracted again with 30 ml of chloroform. The combined chloroform solutions are extracted with 20 ml 1-1 hydrochloric acid, 20 ml 1-1 potassium bicarbonate solution and twice with 20 ml water each time, separated, dried over sodium sulphate and evaporated under 11 torr. The residue is crystallized from methanol, the /o-(2,6-dichloroanilino)-phenyl7-acetic acid p-nitrophenyl ester melts at 105-106°.

In the same way, one obtains: /o-(3-chloro-o-toluidino)-phenyl7-acetic acid-p-nitrophenyl ester, starting from /o-(3-chloro-o-toluidino)-phenyl7-acetic acid, m.p. 124-125° (from ether-petroleum ether).

Example 4.

/o-(2,6-dichloroanilino)-phenyl-17-acethydroxamic acid To a solution of 1.84 g of sodium in 80 ml of methanol, a solution of 1.82 g of hydroxylamine hydrochloride in 30 ml of methanol is added at 50°. The suspension is added while stirring a

solution of 5.8 g of /o-(2,6-dichloroanilino)-phenyl-17-acetamide (m.p. 188-189°) in 80 ml of methanol and then boiled for 18 hours under reflux. The rbdé suspension is stripped off and concentrated to dryness at 40° under 11 torr. The rest is shaken with 600 ml of water and 100 ml of ether. The aqueous phase is separated and acidified with 2-n hydrochloric acid. The suspension is extracted with 200 ml of ether, the ether solution is separated, washed with water, dried over magnesium sulphate and evaporated under 11 torr at 40°. The residue is crystallized from ether, thereby obtaining /o-(2,6-dichloroanilino)-phenyl-17-acethydroxamic acid with m.p. 164-165°.

In the same way one obtains: /o-(3-chloro-o-toluidino)-phenyl7-acethydroxamic acid, m.p. 135-136° from ether-petroleum ether), starting from 4.2 g of /o-(3-klbr-o-toluidino)-phenyl7-acetamide, m.p. 139-141° (from ether-petroleum ether;

/o-(2,6-dichloro-m-toluidino)-phenyl7-acethydroxamic acid, m.p. 140-145°, starting from /o-(2,6-dichloro-m-toluidino)-phenyl7-acetamide;

/o-(6-chloro-o-toluidino)-phenyl-17-acethydroxamic acid, m.p. 159-162°, starting from /o-(6-chloro-o-toluidino)-phenyl7-acetamide, m.p. 166-168°;

/o-(2,6-xylidino)-phenyl7-acethydroxamic acid, m.p. 134-136°, starting from /o-(2,6-xylidino)-phenyl7-acetamide.

The starting material is obtained as follows:

/o-(3-chloro-o-toluidino)-phenyl7-acetamide

A mixture of 7.8 g of /o-(3-chloro-o-toluidino)-phenyl7-acetic acid methyl ester (m.p. 47-48°) and 100 ml of liquid ammonia is stirred for 4 days at room temperature in the autoclave. The ammonia is then evaporated off, and the residue is chromatographed on 240 g neutral alumina. Fractions 1-15, which are eluted with ether-chloroform 1:1, contain N-(3-chloro-o-tolyl)-indolinone, fractions 16-22, which are eluted with chloroform-methanol 99:1, contain /o -(3-chloro-o-toluidino)-phenyl7-acetamide, m.p. 139-141° (from ether-petroleum ether).

Claims (6)

1. Analogy method for the preparation of therapeutically active compounds of formula i where R 1 , R 2 . and R^ independently of each other means hydrogen, lower alkyl, fluorine, chlorine or bromine to the exclusion of the simultaneous definition of the substituents R^, R 2 and R^ as hydrogen, and their salts, characterized by reacting an amide or a preferably activated ester of an acid of formula II where R1, R2 and R3 have the meaning given in formula I, with hydroxylamine or a salt thereof in basic medium and, if desired, converts a compound of formula I obtained into a salt with an inorganic base. 2. Analogous method according to claim 1, characterized in that one reacts a preferably activated ester or an amide of an acid with formula II according to claim 1, in which the phenyl radical substituted with the radicals R1~R3 is a 2,6-dichlorophenyl radical, with hydroxylamine or a salt thereof and, if desired, converting the product obtained into a salt with an inorganic base. 3. Analogous method according to claim 1, characterized in that one reacts a preferably activated ester or an amide of an acid with formula II according to claim 1, in which the phenyl radical substituted with the radicals R1~R3 is a 2,6-dichloro-3-methylphenyl radical , with hydroxylamine or a salt thereof and, if desired, converting the product obtained into a salt with an inorganic base. 4. Analogy method according to claim 1, characterized by reacting a preferably activated ester or an amide of an acid with the formula II according to claim 1, in which the phenyl radical substituted with the radicals - R 1 is a 2-methyl-3-chlorophenyl radical, with hydroxylamine or a salt thereof and, if desired, transfer the product obtained into a salt with an inorganic base. 5. Analogous process according to claim 1, characterized in that one reacts a preferably activated ester or an amide of an acid with formula II according to claim 1, in which the phenyl radical substituted with the radicals R1 - R3 is a 2-methyl-6-chlorophenyl radical, with hydroxylamine or a salt ■ thereof and, if desired, converting the product obtained into a salt with an inorganic base. 6. Analogous method according to claim 1, characterized in that one reacts a preferably activated ester or an amide of an acid with the formula I according to claim 1, in which the phenyl radical substituted by the radicals R^j^ - R3 is a 2,6-dimethylphenyl radical, with hydroxylamine or a salt thereof and, if desired, converting the product obtained into a salt with an inorganic base.