NO121047B - - Google Patents

Description

Process for the production of hitherto unknown, substituted phenylacetic acids with therapeutic effect.

The present invention relates to a process for the production of hitherto unknown, substituted phenylacetic acids with the general formula (I), where and FLj independently of each other mean a methyl or ethyl group, or a fluorine, chlorine or bromine atom,

R^ represents hydrogen, a methyl or ethyl group, or a fluorine, chlorine or bromine atom, and

R 2 represents a hydrogen, fluorine, chlorine or bromine atom.

The method consists in heating a compound with the general formula (II),

where R-p R2, R^ and R^ have the meanings indicated under formula (I), according to Willgerodt-Kindler's method with sulfur and morpholine, and hydrolyze the first obtained morpholide with the general formula

III),

where R-p R£, R^ and R^ have the meanings indicated under formula (I). E.g. the aforementioned reaction components are boiled in an excess of morpholine for some time, e.g. about. ^ - hO hours under reflux, separates from the formed morpholide the thio acid and hydrolyzes it, e.g. by boiling with ethanolic or methanolic caustic soda or potash.

The compounds with the general formula (II), substituted o-anilino-acetophenones, which are required as starting materials, are prepared, e.g. by proceeding from correspondingly substituted N-phenyl-anthranilic acids, representatives of which are known and can further be produced analogously to the known ones. The mentioned substituted N-phenyl-anthranilic acids are first transferred to their acid chlorides and the latter are reacted with (ethoxymagnesium)-malonic acid diethyl ester in absolute ethanol, whereby substituted (N-phenyl-anthraniloyl)-malonic acid diethyl esters are obtained. From these is formed by boiling in an acidic medium, e.g. by boiling in a mixture of sulfuric acid and aqueous acetic acid during hydrolysis and subsequent splitting off of 2 molecules of carbon dioxide the desired substituted o-anilino-acetophenones of the general formula (II).

As was further found, the new acids of the general formula (I) possess valuable therapeutic properties, in particular anti-phlogistic (anti-inflammatory), analgesic and antipyretic action at a favorable therapeutic index. They can be used orally or rectally for the treatment of rheumatic, arthritic and other inflammatory diseases. The antiphlogistic effect can be demonstrated in animal experiments, e.g. in UV-Erythem in guinea pigs and in Bolus alba-bedema in rats.

Compound 1. [b-(2,6-dichloro-anilino)-phenyl]-acetic acid

" 2. (p-(2,6-dichloro-m-toluidino-phenyl)-acetic acid " 3. [o-(2,6-xylidino)-ferriyl]-acetic acid " 1+. [2-(2,6 -dichloro-m-toluidino)-5-chlorophenyl]-acetic acid

" 5-[p-(2,6-dichloro-anilino)-phenyl]-acetic acid (according to French medical patent no. h 2M+ M).

The research method below was used and the stated results obtained.

Bolus alba- bdem in rats

(Wilhelm!, G., Japanese J. Pharmacol. 15, (196?) 187-198)

White male rats weighing 110-130 g were used as test animals,

6 animals per dose. The test substance is administered orally as a suspension with tragacanth. One hour later, subcutaneous injection of 0.1 ml of a 10% suspension of Bolus alba etbdem is triggered in the sole of the foot on the right hind paw. 5 hours later, the rats are killed and the hind paws are amputated. The swelling is measured by determining the weight difference between the left, normal paw and the right, swollen paw. The mean weight of the swelling for the rats treated with the test substance is compared with that of untreated control animals. The average swelling reduction achieved with the test substance is expressed in %.

The results in the preceding table show the superior anti-inflammatory effect of the examined compounds produced according to the present invention, in comparison with a compound known from the French medical patent No. k-2kh M.

The following example explains in more detail the implementation of the method according to the invention. The temperatures are indicated in degrees Celsius.

EXAMPLE

A mixture of 2 g of o-(2,6-dichloroanilino)-acetophenone, 0.75 g of sulfur and 2.2 g of morpholine is boiled for 15 hours under reflux (bath temperature 150°). On cooling, the solution crystallizes. The crystal cake is dissolved in 50 ml of benzene, the insoluble material is filtered off and the filtrate is evaporated below 11 Torr to dryness. The remaining h-[[o-(2,6-dichloroanilino)-phenyl]-thio-acetyl]-morpholine is dissolved in 50 ml of 5% ethanolic caustic soda and the solution is refluxed for 15 hours. The solution is then cooled and evaporated below 11 Torr at ^-0° to dryness. The rest is dissolved in 100 ml of water. The aqueous solution is extracted with 30 ml of ether and then acidified with 2N hydrochloric acid. The precipitated oil is dissolved in ^0 ml of ether, the ether solution is separated, washed with a little water, dried over sodium sulphate and evaporated to dryness below 11 Torr. Co-(2,6-dichloroanilino)-phenyl3-acetic acid crystallizes from ether-petroleum ether, melting point 156-158°.

In an analogous manner, £o-(2,6-dichloro-m-toluidino)-phenylj-acetic acid is obtained with melting point 11+6-11+9° (from ether-petroleum ether).

The substituted acetophenones required as starting materials are produced, e.g. in the following way: A mixture of 0.2 g of absolute ethanol and 0.17 ml of carbon tetrachloride is added to 0.2 k g of magnesium shavings. As soon as the reaction has started, dilute with 20 ml of ether. Then a mixture of 1.5 g of malonic acid diethyl ester and 0.8 ml of absolute ethanol is added and the mixture is heated for 3 hours in the steam bath to boiling, whereby the magnesium dissolves to form (ethoxy-magnesium)-malonic acid diethyl ester. A mixture of 2.0 g of N-(2,6-dichloro-phenyl)-anthranilic acid chloride and 5 ml of absolute ether is added to the boiling solution. After 15 minutes, cool to 20° and add dilute sulfuric acid (0.96 g concentrated sulfuric acid + 8 ml water). The mixture is shaken until a solution is formed. The ether phase is then separated. The aqueous phase is extracted with 10 ml of ether. The ether solutions are combined, dried with sodium sulphate and evaporated to dryness below 11 Torr. A mixture of 2.1 ml of glacial acetic acid, 0.32 ml of concentrated sulfuric acid and 1.6 ml of water is added to the remaining crude [N-(2,6-dichlorophenyl)-anthraniloyl-malonic acid diethyl ester. The solution is heated for h hours under reflux while boiling, cooled to 5° and made alkaline by the addition of 30% caustic soda. The alkaline-aqueous suspension is extracted with ml of ether. The ethereal solution is separated, dried over sodium sulphate and evaporated below 11 Torr. The remainder is crystallized from methanol. The obtained o-(2,6-dichloro-anilino)-acetophenone melts at 115-117°.

In an analogous manner, o-(2,6-dichloro-m-toluidino)-acetophenone, melting point 10V-106<0>, is obtained from methanol.

In an analogous way, the following are also produced:

a) [o-(2,6-xylidino)-phenylD-acetic acid, m.p. 133-137°} from ether-petroleum ether; starting from o-(2,6-xylidino)-acetophenone; b) [o-(6-chloro-o-toluidino)-phenylj-acetic acid, m.p. 1^0-11+7°, from ether; starting from o-(6-chloro-o-toluidino)-acetophenone; c) L2-(2<*>,6<1->dichloroanilino)-5-chlorophenylj-acetic acid, melting point I8I-I83<0>; starting from 2-(2',6'-dichloroanilino)-5-chloro-acetophenone; d) C2-(2',6'-dichloro-m-toluidino)-5-chlorophenyl]-acetic acid, m.p. 152-156°, from ether; starting from 2-(2',6'-dichloro-m-toluidino)-5-chloroacetophenone; e) o-(2',6'-dichloro-3'-methylanilino)-phenylacetic acid, melting point 1V6-11+90; f) o-(2',6'-diethylanilino)-phenylacetic acid, melting point 88-90°.

Claims (1)

Process for the production of hitherto unknown, substituted phenylacetic acids with therapeutic effect and with the general formula (I), where R^ and R2 independently of each other mean a methyl or ethyl group, a fluorine, chlorine or bromine atom, R^ means hydrogen, a methyl or ethyl group, or a fluorine, chlorine or bromine atom, and R^ means a hydrogen, fluorine, chlorine or bromine atom, characterized by heating a pre- bond with the general formula (II), where R-p Rp, R^ and R^ have the meanings indicated under formula (I), according to the Willgerodt-Kindler method with sulfur and morpholine, and hydrolyzes the first obtained morpholide with the general formula (III), where R-p R2 , R^ and R^ have the meanings indicated under formula (I).