DE2135145A1 - Process for the production of new indolylacetic acid derivatives and pharmaceutical preparations containing such derivatives - Google Patents

Description

6G03 hcrik.u?} Om Main
Annasfraijo 19 phone 555061 2135145

Frankfurt (Main), June 13, 1971

Chinoin Gyogyszer- es Vegyeszeti Termekek Gyara RT,
Budapest IV, To utca 1-5 - Hungary

PROCESS FOR MANUFACTURING NEW INDOLYL ACID EDERI VATEN AND MEDICINAL PRODUCTS CONTAINED BY SOLOHE DERIVATIVES

PARATEN

The present invention relates to new
chemical compounds and their production, as well as medicinal products containing such compounds

The present invention relates to a process for the preparation of new compounds of the general formula

77/167 old. -1-

109887/1907

2135H5

CH ₂ COOR ²

(in which formula R is one with a halogen atom or one Oxygen, sulfur and / or substituted nitro group fc nitrogen-containing heterocyclic group, R is a hydrogen atom or an alkyl group,

R is a hydrogen atom or an alkyl group, R ^{3 is} a hydrogen atom, an alkyl or alkoxy group),

characterized in that one

a) by the direct acylation of aryl hydrazines or their derivatives by treatment with a Oxo compound obtained hydrazines or hydrazones prepared compounds of the formula

(in which formula R and R- * have the meaning given above, while R ^ means two hydrogen atoms or alkylidene group)
with compounds of the formula

R ³ ^ -CO-CH ₉ -CH ₉ -COOR ² (Hl)

Cm C *

-2-109887 / 1907

,, 2135Η5

(in which formula R and R have the meaning given above to have)

converts, whereupon the free acid is desired
the product obtained, or
b) compounds of the formula

ι ^{2 2} (IV)

NN = OR ¹

(in which formula R, R and R have the meaning given above, X is -CHO, -CH ₉ OH, -CH ₉ OR ⁷ , -CN, ACJOOH

7 7

or -CH / OR '/ o group, while R' denotes an alkyl group)

cyclized, or
c) compounds of the formula

N-NH-SO _x H

(in which formula R and R * have the meaning given above) with a compound of formula III (in weleher Formula R and R have the meaning given above) lets react

then optionally converting the compound obtained in this way into a salt, or liberating it from its salts.

The manufactured according to the present invention

-3-

109887/1907

^H 2135U5

th products are used as active ingredients in anti-inflammatory, analgesic, fever-relieving and arteriosclerosis inhibitory medicinal preparations applicable.

In the products according to the invention, the group R denotes a 5 or 6-membered heterocyclic ring substituted with a halogen atom or a nitro group, ζ.B, a pyrrole, pyrazole, furan, purazole, imidazole, thiazole, thiadiazole , Pyridine « ₉ pyrimidine or pyridazine ring.

An advantageous embodiment of the invention Method offers variant a), which, in addition to its simplicity and economy, has the advantage of that it supplies intermediate products that are easy to isolate or that are directly introduced into the indole synthesis v / ground, and moreover also effective in themselves Connections are.

1 2

In our production of N -acyl-N -aryl-

hydrazines developed method one can use the. about special Isopropylidene group possessed by properties derived from

Acetone can be obtained, use as a protective group of the N atom.

ρ This offers the following advantages: the K -Iso-

Propylidene-arylhydrazine is easy - without separating the itself aerosolizing and difficult-to-treat intermediates -

can also be produced simply and easily on an industrial scale, it enables selective N acylation under simple circumstances? it is inherently suitable for indole synthesis} it can be combined with other oxo compounds suitable for indole synthesis easily exchanged? it can be introduced directly into the indole synthesis.

After the! ^ - acylation, it can be converted into N - (acylJ-ff ¹ - ^ aryl) hydrazine or into its hydrochloride by removing the isopropylidene group in a simple manner - without damaging the IT ^ acyl group.

-4-

109887/1907

The ring closure of the N -substituted phenylhydrazones iat under moderate circumstances, even at room temperature feasible, and this leads to a considerable increase in the yield.

Most Aryliiydrazines - and so also the p- -Methoxyphenylhydrazine - are quite easily decomposable Compounds, the desired intermediates can also be obtained through their separation and through hydrazone formation separated product can only be produced much more laboriously. However, we found that - after hydrolysis of the p- -Methoxyphenylhydrazinesulfonic acids sodium in an aqueous-alcalic acid System and subsequent neutralization of the reaction mixture with soda solution - the hydrazone by adding The selected oxo compound, acetone, can be selected from the aqueous-ethanolic solution. Will it be like that? If the hydrazone obtained is dissolved in a suitable solvent, the F acylation can be carried out immediately after drying of the solution.

The acetone-5-acyl-N -arylhydraon obtained by processing the reaction mixture is used for indole tea can also be used immediately.

Another advantage of this process is that after the acylation, the isopropylidene group can be easily eliminated by adding aqueous hydrochloric acid to the reaction mixture, and when using a polar one Solvent the F ^ -acyl-N -arylhydrazine hydrochloride can be recovered.

The desired N-acyl-indole-3-acetic acid derivative can either be prepared directly from the N-acyl-A ^ -aryl-hydrazine hydrochloride obtained, or the desired N-acylindole-3-acetic acid derivative can be prepared from that which can be released from the hydrochloride N ¹ acyl-N ¹ aryl hydrazine

The present invention further relates to new compounds of the formula I that have hitherto been used in chemical

-.5 «.
109887/1907

* 2135H5

see literature not yet described, so look at it as new. These yerbindangen can be delivered in eich or as your .organotropic Sals®, with tablets, drag | es, capsules, suppositories, powder mixes, emulsions, suspensions etc. si «? pareateraleiio cralen or rectal © n administration "v®ras" beit®tp Verw © M «"& be.

Crewiss © representatives of these associations can in the veterinary Hei !! made or · for contraception vöh ! Pier diseases to Psfemix-ütattargead, see dosed, applied «

In order to explain the © -Forllegend © invention who « here are some examples ^ ox ^ danger, @ hn © jedooh ours Invention on di® methods described in the examples 212 limit

80 g

-hydrason are dried in 700 ml of © ines III mixture of benzene and feluene listed ₆ on MatriaaisiElfat, filtered, and the filtrate is washed with 50 ®1 Benaol *. After cooling the liSsiimg mi £ Q ⁰ Q v / ground 40 ml Pyridia added, then at 0 »9 ° ö 87 _e 5 ml (0.5 mol) of S-nitro ~ 2 ~ furancarbonsäureshlorid added dropwise. After stirring for 50 minutes, the precipitated pyristine hydrochloride is filtered off, the solvent phase is washed since water, then shaken with 160 ml 6N hydrochloric acid.The precipitated substance is filtered through a suction filter, washed with benzene, then dissolved in water and neutralized with sodium carbonate. After filtering the precipitated N - (5-nitro-2-furoly) -N ¹ - (p-methoxyphenyl) hydrazine through a suction filter, it is washed with water. Yield: 67.5 g, Schmp.s 163-164 ⁰ CJ,

The mixture τοη 45.1 g (0.162 g-mol) N - (5- -Hitro-2-furoyl) -H ^ - (p- ⁱ inethoJ3rphenyl) -hydraziii _# 160 ml acetic acid, 27.8 ml larulinic acid and 2, 8 ml more concentrated

-6-

109887/1907

7-2135H5

Schwofelsäure is heated and a half hours at 00-85 ⁰ C. After cooling, ea is diluted with 158 ml of water and the resulting 1- (5-nitro-2-furoyl) -2-raethyl-5-methoxy-indol-3-yl-acetic acid is recrystallized from ethanol. Yield: 35.8 g, m.p .: 183-184 ⁰ , 62 #, calculated on N ¹ - - (5-nitro-2-furoyl) -N- (p-methoxyphenyl) hydrazine

Example 2

A solution of 30 g of suction-moist acetone (p-methoxyphenyl) hydraonone in 300 ml of benzene is dried over sodium sulfate and filtered, and the filtrate is washed with 30 ml of benzene. After cooling the solution to 5 C ⁰ 8 ml oC-picoline A solution of 24.8 g (0.08 g-mol) are added, then at 0-5 ⁰ C 2-bromothiazole-4-carboxylic acid chloride poured in 200 ml of toluene . The reaction mixture is stirred for 2 hours, then filtered, washed with water and shaken with 120 ml of 1: 1 dilute hydrochloric acid.After the aqueous phase has been separated off, the solvent phase is concentrated to almost dryness in vacuo -Bromothiazol-4-yl-carbonTl) -N - (p-methoxyphenyl) -hydrazine hydrochloride filtered off through a suction filter, washed with a little benzene, dried in air, then dissolved in water and neutralized with sodium carbonate. Yield 12.6 g, m.p .: 125-126 ⁰ C,

The 12.6 g of N ¹ - (2-bromothiazol-4-yl-carbonyl) -N- (p-methoxyphenyl) hydrazine prepared according to the above description is dissolved in 50 ml of acetic acid, 14 ml of levulinic acid and 2.4 ml of concentrated sulfuric acid solution are added, then the mixture is heated for 2 hours at 80-85 ⁰ C. After cooling, the reaction mixture is diluted with 50 ml water, the precipitated l- (2-Bromt ^v iiazol-4-yl-carbonyl) -2-methyl-5-methoxy-idol-3-yl -essi ". Eäure by filtered off a suction filter and recrystallized from ethanol. Yield: 8.18 g (13.7 SO »m.p .:

169-17I ⁰ C.

109887/1907

Example 3

A solution of 21.5 g of suction-moist acetone- (p- -methoxyphenylj-hydrazone in 150 ml of benzene is ^{dried over sodium sulfa-1} ; 4 ml of K-picoline are added, and the mixture at 5 ³ C with a solution of 12 g (0.045 mol) of 2-chlorothiazole-4-carboxylic acid chloride in 80 ml of benzene are added. After stirring for two hours, the reaction mixture is filtered, washed with water and shaken with 50 ml of hydrochloric acid diluted with water. The precipitated substance is filtered through a suction filter, dissolved in water and neutralized with sodium carbonate The excluded w various N- (2-Chloro-thiazol-4-yl-carbonyl) -N -. (p-methoxyphenyl) hydrazine (. 5> 8 g, m.p. 126 ⁰ C) is in 16 ml of acetic acid, after adding 6 ml of levulinic acid and 0.7 ml of concentrated sulfuric acid, heated for 2 hours at 80-85 ° C. After dilution with water, the precipitated substance is recrystallized from ethanol. Yield: 5.22 g (19.4 # )! - (^ - Ohlorthiazol ^ -yl-carbonylJ ^ -methyl-S-methoxy-indol- -3-yl-acetic acid, S. chmp ·: 158-160 ⁰ C,

Example 4

A suspension of 128 g (0.5 g-mole) of p-methoxyphenylhydrazinsulfonsaures sodium monohydrate in 500 ml Methancl is treated at 60-65 ⁰ C with 94 ml concentrated hydrochloric acid is added poured in about 10 minutes with stirring. After stirring for a further ten minutes, the mixture is cooled to room temperature and neutralized with 318 g of 20% sodium carbonate solution. 87 ml of acetone are poured into the aqueous solution obtained, after 30 minutes the crystalline acetone (pH-diethoxypheynl) hydrazone is filtered through a suction filter, and successively with 1 : 1 methanol diluted with water and the following washed with water. (After drying in vacuo, 80 g of acetone (p-methoxyphenyl) -hydraEon yield. Yield: 90 #, mp 95 -98 ⁰ C, with decomposition.)

-8th-

109887/1907

2135H5

The product is used in the after-moist state as the starting substance in Examples 1 to 3.

Example 5

About 100 g of moist acetone (p-methoxyphenyl) hydrazone obtained from 128 g (0.5 g mol) of p- * nethoxyphenylhydrazinesulfonic acid sodium monohydrate are dissolved in 700 ml of a 1: 1 mixture of benzene and toluene on sodium sulfate dried, filtered and the filtrate washed with 50 ml of benzene. After cooling the solution to ⁰ ° C., 40 ml of pyridine are added, then 87.5 ml (0.5 g-mol) of S-nitro-furancarboxylic acid chloride are added dropwise. After stirring for 30 minutes, the solvent phase is washed with 400 ml of water, dried over sodium sulfate and concentrated in vacuo. The acetone-N - (5- * nitro ~ 2-furoyl) -N - (p- -methoxyphenyl) -hydrazone remaining as an oily residue is dissolved in 300 ml of acetic acid, 40 ml of ivulinic acid and soon 5 »5 ml of concentrated sulfuric acid are added, and the mixture heated for an hour at 80-85 ⁰ C. After cooling, the mixture is diluted with water and the precipitated 1- (5-nitro-2-furoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid is recrystallized from ethanol. Yield 43 g ( $ 24, calculated on p-methoxyphenylhydrazinesulfonic acid sodium monohydrate), m.p .: 179 ⁰ G.

Example 6

20 ml of levulinic acid are added to a solution of 27.7 g (0.1 g mol) of ^ - (S-nitro- -2-furoyl) -N ¹ - (p-methoxyphenyl) hydrazine in 150 ml of acetic acid. After half an hour standing, 5.5 ml of concentrated sulfuric acid to the solution of Lävulin3öure ^N-1 are - (5-nitro-2-furoyl) -N - (p-methoxyphenyl) hydrazone was added dropwise, the mixture for one hour at 80-85 ⁰ C stirred, then cooled and 100 ml of water poured in. The excreted l- (5-nitro-2-furoyl) -

109887/1907

10 2135U5

is filtered off through a suction filter, and washed with 100 ml of 60 # acetic acid, soon with 100 ml of water. The crude 1- (5-nitro-2-furoyl) -2-methyl-5-methoxy-indol-3-yl-acetic acid is extracted from 220 ml of 88% tert. Recrystallized butanol. Yield: 21.6 g (60.6%), mp ..: 178-180 ⁰ O.

Example 7

To a solution of 25.8 g (0.1 mol) of p-methoxyphenylhydrazinsulfonsaurem sodium monohydrate in a mixture of 112 ml of water and 48 ml of tert-butanol is allowed to _e 17β4 g (0.1 mole) of 5-nitrofuran-2-carboxylic acid chloride flow in. Of the product, without separation - - After einstöndigem tubes at room temperature and einetündigem tubes at 70-80 ° C-water bath, 17 ml aqueous Iiävulinsäure and 4.5 ml of concentrated sulfuric acid dropwise eye, quilted one hour at 80-85 ⁰ O, abgekflhlt, and 80 rals of water were poured in. The precipitated 1- (5-nitro-2-furoyl) -2-methyl- -5- * netho:) cy-indol ~ 3-yl-acetic acid is filtered off through a suction filter, and then with 80 ml of 60% acetic acid washed with 100 ml of water. The crude product is made from 170 ml of 88 ^ igem tert. Recrystallized butanol, clarified with 5 l » " Norit "activated carbon, crystallized after cooling, filtered off through a suction filter, with 20 ml 88% tert. ! Butanol and dried at 80 ⁰ C to obtain 17.7 g of 1- (5-HITRO-2-furoyl) -2-methyl-5-methoxy-indole-3-acetic acid y obtained, yield: 73.5 5 *, mp. \ 178-180 ⁰ C.

Example 8

To a solution of 25.8 g (0.1 mol) of pnnethoxyphenylhydraainsulfonsaurem sodium monohydrate in a mixture of 112 ml of water and 48 ml of tert. Butanol is added to 20 g (0.11 mol) of 2-chlorothiazole-4-carboxylic acid chloride. The mixture is stirred for one hour at room temperature and then for one hour at 70 ^° C., and

-ΙΟΙ 09887/1907

2135H5

the following - without separating off the product - 43 »5 ml of levulinic acid and 5 ml of concentrated sulfuric acid were added. After four hours of heating at 80 ^° C., the result is obtained
The reaction mixture is diluted with water, the product which has separated out is filtered off through a suction filter and extracted from tert. Recrystallized butanol, 23 g of l- (2-chlorothia

re surrendered. Yield: 65 #, Schmp.i 158-160 ⁰ O.

-11-109887 / 1907

Oct 28, 1971

Example 9

A suspension of 63.24 g (0.2448 mol) of p-methoxyphenylhydrazinesulfonic acid sodium monohydrate in 275 ml of water is a solution of 39 »8 g (0.305 mol) of IFuran ^ -carboxylic acid chloride in 117 ml of tert. Butanol added. The resulting clear solution after a few minutes for an hour at room temperature, afterwards at 70 - 80 ⁰ C stirred. The reaction mixture is cooled again to room temperature and made alkaline with 123 ml of 5 ^ sodium hydroxide. At the end of the alkalization, the initially oily precipitate solidifies. The mixture is stirred for a further 90 minutes, filtered, washed with 250 ml of water and dried at 80 ⁰ G.

46.8 g (82.25%) of the 1-, / 2-furoyl (-1-) 4-methoxyphenyl7- hydrazine are obtained. Melting point: 108_ - 110 ⁰ O. are 34,8g (0.15 mol) of 1- £ 2 Buroyl-(-1) 4-methoxyphenyl7 hydrazine in 76.5 ml (0.765 mol) of levulinic acid and 8.2 dissolved ml of sulfuric acid are added dropwise, the mixture is ^{stirred for 3 »5 hours at 70 8O 0} O, cooled to room temperature, whereupon 350 ml of water are added. The solid substance is stirred for a few hours, then filtered, covered with 30 ml of water, decanted with 120 ml of water and repeatedly covered with 30 ml of water, finally ^{dried at 80 °} C., 42.59 S (90.6 %) the crude 1- (2-I ¹ uroyl) -2methyl'-5-Biethoxyindole-3-acetic acid obtained. Melting point; 140 - 144 ⁰ O, the crude product is made from an 8-fold amount of 88 ^ igen tert. Butanol recrystallized with 2 g activated charcoal with clarification

The yield is 30 * 99 S (57.18 %) - calculated on the 1- ^ S-furoyl-Oi-) 4-methoxyphe
Melting point ι 144 - 147 * 0,

109887/190

2135U5

P 21 35 Ghinoin

Oct 28 1971

The following derivatives were investigated:

A = * 1- (5-nitro-2-furoyl) -2-methyl-5-methoxyindolyl-3-acetic acid

B a 1- (2-bromo-4-thiazolylcarbonyl) -2-met] iyl-5-niet] ioxyindolyl-3- - acetic acid

C = 1- (2-chloro-4-thiazolylcarboriyl) -2-methyl-5-methoxyindolyl-3-acetic acid

D = 1- (2-S ¹ UJJOyI) -2-methyl-5-ra.ethoxyindolyl-3-acetic acid.

1. Toxiζibat

The toxicity was investigated in mice of both sexes (weight: 22-25 g). The test compound was administered orally and mortality was observed for 24 hours. S ¹ 5 mice were used for each dose. The LDj-Q values were determined using the Behrens formula.

Link .

A> 1000

B> 1000 G 750

D 975

2. The determination of the anti-inflammatory effect. a) Inhibition of kaolin edema

The experiments were carried out with female rats ( 110-130 g) which were starved for 24 hours. 0.1 ml of a 5% kaolin suspension was injected intraplanterally into the right hind leg and the change in the diameter of the upper feet was measured. Under the influence of kaolin, the upper foot of the animals was swollen. The diameters of the upper feet were measured in the 2nd and 5th hours.

The test compound was administered orally to a group of 10 animals for 60 minutes

109887/1907

BATH ORIGINAL

2135U5

utes given before the kaolin is injected. The diameter the upper feet of the control animals and the treated animals and the degree of inhibition was determined by the differences in the magnification the upper feet of the control and treated animals are determined. The significance was calculated with the hourly best. Only the significantly different values are given. - ·

7bond B causes 18%. One dose inhibition of 100 mg / kg (significant).

Bond C causes 23% inhibition in one dose of 50 mg / kg (significant).

7erbinding D causes 18.1% inhibition in one dose of 25 mg / kg (significant).

At the same time it should be mentioned that sodium salicylate, a well-known antiflogistic.es commercial product in one dose - voxi 50 · mg / kg is ineffective.

b) Inhibition of carragenin edemies

The test was carried out on female rats (110-130 g) that were starved for 24 hours. 0.1 ml of a 0.5% carragenin suspension was injected intraplant more into the right hind leg. and the change in the diameter of the thigh was measured. Similar to kaolin, the thighs were essentially swollen. The evaluation of the test was carried out as with the kaolin-te; st. The significant values are summarized in the, following Ta _ _{V /} belle :. . _: . . -. <■■■ ., ■ ■;

7erbinding,,; Dosi, s, mg / kg, -..., Inhibit lon % .; ■ -...

C.ν- 100 ι: · 18.4 D 50 ...: 29.9

The minimum effective dose of sodium salicylate is IQO "mg / kg .., _ _VVj ........

The tests were carried out on male rats (1 ^ 0--16Og.) In ether anesthesia, 25 mg were applied under the dorsal skin of the animals

10 988 ^771907? '''

sterile cotton balls placed. A piece was placed on either side of the spine. After 8 were the animals were slaughtered, the cotton balls were taken out and dried for 5 hours at 5O ⁰ C. The animals were treated daily with the test compound. Each dose was studied in 10-10 animals. Each group contained a control animal that received no substance. Fracture tissue forms on the balls in the organism, which is prevented by antiflogists. The signification of the difference was determined using a student test. The significant inhibition values are summarized in the following table:

Test connection Dose mg / kg ■■ inhibition % C. 100 18.4 D. 50 28.8 Sodium salicylate 100 29 UV erythema test

The tests were carried out on male and female albino guinea pigs (400 - 600 g) carried out. The back of the animals was depilated and subjected to UV radiation for 3 »5 minutes after 24 hours. At the point of irradiation, inflammation develops on the skin, which becomes most intense after 2 hours. the Inhibition of inflammation was studied. The intensity of the change was designated with points and the evaluation of the The difference between the control groups and the treated groups occurred according to the chi method. For each dose there were 10 animals used., the doses were given orally. The significant inhibition values are summarized in the following table:

Test compound dose mg / kg inhibition %

C 100 33

V 100 59.7

5. Antipyretic effect

The test was carried out on female rats (1JO - 150 g). The temperature of the animals was measured in the rectum, a 20% yeast suspension was administered subcutaneously. After 17 hours a significant increase in temperature was noticeable,

109887/1907

- # From

Each dose was examined in 10-10 animals, the substance was administered 60 minutes before the measurement and the reduction the temperature was measured. Each dose was used for 10 animals. The temperature change was equal to the temperature of the commanding animals put in relation. The significant antipyretic values obtained are summarized in the following table:

Compound dose mg / kg

C 50

D 25

&. Reduction in inflammatory pain

The test was carried out on female rats (60-80 g). It the Randall-Selito method was used. 0.1 ml of 5% suspension of yeast was administered intraplanterally into the right hind leg. Under the influence of the yeast, the sensitivity of the Foot against pressure larger. The increase in sensitivity or their reduction under the influence of the test compound measured with an apparatus and evaluated the analgesic effect. A significant analgesic effect was found with Compounds C and D at an oral dose of 50 mg / kg.

109887/1907

Claims (6)

PATENT CLAIMS Process for the preparation of compounds of the general formula CH ₂ COOR ' (D (in which formula R is an oxygen, sulfur and / or substituted with a halogenator or a nitro group nitrogen-containing heterocyclic group, R is a hydrogen atom or an alkyl group, R is a hydrogen atom or an alkyl group, R ^ is a hydrogen atom, an alkyl or alkoxy group), and of the salts of these compounds, characterized in that one a) the compounds of the formula prepared by the direct acylation of hydrazines or hydrazones obtained from aryl hydrazines or their derivatives by treatment with an oxo compound N-N = R-0 (II) (in which formula R and R ^{5 have} the meaning given above -12- 109887/1907 2135H5 5
have direction, while 1ΐ / two hydrogen atoms or Al- kyli lengruppen means) irit compounds of the formula R ¹ ^ -CH ₂ -CH ₂ -COOR ² (III) "L 2 (in which formula R and R have the meaning given above to have) lets react, then, if necessary, the free acid aua releases the product obtained, or b) compounds of the formula CH ₂ -CH ₂ -X (IV) (in which formula R, R and R? have the meaning given above, X is a -CHO, -CH ₀ OH, -CH ₀ OR ', -CN, -COOH or -CH (OR *) ₂ group, while R' means an alkyl group),
cyclized, or
c) / connections of the formula (V) -NH-SO ₃ H (in which formula R and R ^{3 have} the meaning given above) -13- 109887/1907 2135H5 rait a compound of the formula III given above • ι η (in which R and R have the meaning given above) Then the compounds obtained in this way, if necessary in their salts converts »or releases them from their salts. 2. The method according to variant a) of claim I _9, characterized in that the isopropylidene derivative is used as the compound of formula II, and at the same time the acetone formed is removed from the system. 3. The method according to claim 2, characterized in that the isopropylidene group in the polar solvent, removed using aqueous hydrochloric acid. 4. Therapeutic preparations, characterized in that they are used as active ingredients at least one of the compounds of general formula I - wo-12 ^ 5 for R, R, R and R the meaning given in claim 1 - or their salts, with suitable inert, solid or liquid diluents or carriers and if necessary mixed with other additives. 5. Compounds of the formula I and their salts, in which R is an oxygen-, sulfur- and / or nitrogen-containing heterocyclic group substituted by a halogen atom or a nitro group,
R ¹ denotes a hydrogen atom or an alkyl group, R ² denotes a hydrogen atom or an alkyl group, r 'denotes a hydrogen atom, an alkyl or alkoxy group. 6. l- (5-Nitro-2-furoyl) -2-methyl-5-methoxy-yne dol-3-yl-efjnir: snure, -14- 109887/1907 BAD LOCAL l- (2-Chl ort hi as ο 1-4-y l-o aodboxyl i ο) - 2-methyl -5-mo- thoxy-indol-3-yl-eßsisfjU 1- (2-bromothiazol-4-yl-carbon3-l) -2-nietliyl-5-nie ~ thoxy-indol-3-yl-acetic acid, 1- (2-Chlorthiajüol-4-yl-carbonyl) -2-met] iyl-5-methoxy-jndol-3-yl-acetic acid and their salts. - 15 - 109887/1907 BATH ORIGINAL