DE1695111C - Indoldenvate - Google Patents

Description

and their pharmaceutically acceptable salts with inorganic or organic acids.

2.2-Benzoyl - 3 - [2 - (1 - pyrrolidiny 1) - ethoxy] indole hydrochloride.

3. 5,6 - methylenedioxy - 2 - benzoyl - 3 - [2 - (1 - pyrrolidinyl) ethoxy] indole hydrochloride.

4. Therapeutic agent consisting of a compound of the general given in claim 1 Formula or its pharmaceutically acceptable salt and customary excipients.

35

The present invention relates to new indole * derivatives with valuable pharmacological properties of the general formula I

O - CH ₂ - CH, - N

45

(D

in which

R _{1 is} hydrogen, the hydroxy or the methoxy group,

R _{2 is} hydrogen and, if R is the hydroxyl group, the hydroxyl group, and, if R _{1 is} the methoxy group, the methoxy group, or

R ₁ and R ₂ together represent the methylenedioxy group,

and their pharmaceutically acceptable salts with inorganic and organic acids.

These new compounds have valuable pharmacological properties Properties, especially analgesic, anti-inflammatory as well as antitussive, tranquilizing, antiallergic, antiedematous, adrenolytic and narcosis-potentiating effectiveness. Simultaneously they have relatively low toxicity and are therefore suitable as active ingredients in pharmaceuticals Preparations for relieving and relieving pain, for treating inflammation, Circulatory disorders caused by the periphery, irritation of the throat, certain mental disorders related to the treatment are accessible with tranquilizers, as well as for anesthetic potency

The new compounds of general formula I and their salts are made in a manner known per se prepared by adding an indole derivative of the general formula II

(II)

in which R ₁ and _R; is as defined above, ydroxygruppen except H, are reacted with a reactive ester of the 2-Pyrrolidinoäthanols optionally dne compound of general formula I, in welchor R ₁ or R ₁ and R ₂ each mean a methoxy group, is converted in a manner known per se into the 5-monohydroxy or the 5,6-dihydroxy compound of the general formula I and, if desired, a compound of the general formula I into a pharmaceutically acceptable salt with an inorganic or organic acid convicted.

The reaction described is preferably carried out in a solvent, such as. B. acetone, dioxane, ethyl acetate, Diinethylsulfoxyd or dimethylformamide, or in> .: a mixture of these solvents carried out, optionally in the presence of a condensing agent, such as. B. potassium carbonate.

As reactive !: Esters of 2-pyrrolidinoethanol chloride, hromide, benzenesulfonate or p-toluenesulfonai are used.

An optionally desired ether cleavage in the event that R ₁ or R ₁ and R ₂ each represent the methoxy group is carried out in a manner known per se, for. B. carried out with 48% hydrobromic acid, the 5 monohydroxy or the 5,6-dihydroxy compound of the general formula I is obtained.

The new indole derivatives of the general formula I are, if desired, in pharmaceutically acceptable form Salts with inorganic and organic acids, such as. B. hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid. Ethanesulphonic acid, 2-hydroxy-ethanesulphonic acid, acetic acid, Lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, ascorbic acid, Benzoic acid, salicylic acid, phenylacetic acid, mandelic acid or emboxylic acid transferred. The production the salts mentioned and other salts can be carried out in the customary manner. For example, you move a if desired, heated solution of an amine of the general formula I in an organic solvent, such as diethyl ether, methanol, ethanol, isopropanol, acetone or butanone, or in water, with the acid desired as the salt component or

a solution of the same and separates it immediately or after cooling, concentrating or adding a second organic liquid, e.g. diethyl ether, to one of the solvents mentioned Salt off.

The starting materials of the general formula II

(Π)

as defined above in which R ₁ and R _2, with the exception of the hydroxy groups have to be prepared in a known manner according to the following general process: The starting material is a according to the meanings of R, and R ₂ N-substituted phenacyl anthranilic acid, which is converted into its methyl ester, for example by means of diazomethane in ether, and is recrystallized from methanol or ethanol. The ring closure to a compound of the general formula II takes place by boiling the respective methyl ester in ethanol in the presence of sodium as a condensing agent. By working up, for example by pouring the reaction mixture into a mixture of ice and hydrochloric acid, the reaction product is isolated and removed from a suitable medium, such as. B. ethanol, recrystallized.

The present invention is illustrated in more detail by the following examples.

example 1

a) 4.74 g (2OmMoI) 2-benzoyl-3-hydroxy-indole, 3.76 g (22 mmol) of 2-pyrrolidinoethyl chloride hydrochloride and 6.07 g (44 mmol) of finely powdered PoUasche are in 100 ml of ethyl acetate and 1 ml of water during Heated under reflux for 15 hours.

The mixture is cooled to 15 ° C., 100 ml of water are added and the mixture is separated the organic phase and washes it twice with 25 ml of 1 η sodium hydroxide solution each time. Now you extract twice with 100 ml of 0.5 η hydrochloric acid each time and the combined extracts are washed with 50 ml of ether. By adding the base is precipitated from 2N ice-cold sodium hydroxide solution and extracted three times with 50 ml of methylene chloride each time. After drying the combined organic phases over potash, evaporation and addition the residue with a solution of hydrogen chloride in isopropanol becomes the 2-benzoyl-3- [2- (l-pyrrolidinyl) ethoxy] indole hydrochloride from, melting point 216 ° C obtained.

The 2-benzoyl-3-hydroxy-indole required as starting material is made as follows:

b) 30 g (15OmMoI) phenacyl bromide and 50 g (330 mmol) of methyl anthranilate are allowed to stand for 20 hours at 20 ⁰ C. Die'entstandene crystalline mass is heated for 2 hours at 90 ⁰ C, allowed to cool and dissolves .the reaction mixture in 300 ml of absolute ethanol. Now a solution of 6.9 g (300 mmol) of sodium in 400 ml of absolute ethanol is added and the mixture is heated for 30 minutes.

. long reflux. The reaction mixture is evaporated and the residue is dissolved in 500 ml Water and 150 ml of methylene chloride and filtered through a filter aid based on cellulose and activated charcoal. The aqueous phase is separated off and extracted four times with 150 ml of methylene chloride each time finally adjusts the aqueous layer to pH 1 with 100 ml of 2η hydrochloric acid. The precipitate obtained is filtered off, washed with 50 ml of water and recrystallized from ethanol, pure 2-benzoyl-3-hydroxyindole obtained with a melting point of 126 ° C.

Example 2

a) Analogously to Example 1 a), 4.86 g (0.20 mmol) of 2-benzoyl-3-hydroxy-5-methoxy-indole-hydrochloride are used 2-benzoyl-3- [2- (l-pyrrolidinyl) ethoxy] -5-methoxy-indole hydrochloride with a melting point of 244 ° C.

b) The 2-benzoyl-3-hydroxy-5-methoxy-indole required as the starting product is analogous to Example 1 b), starting from 59.7 g (33OmMoI) 1-Carbomethox} -2-amino-5-methoxybenzene, manufactured; Melting point 154 ° C.

Example 3

A mixture of 200 mg (0.5 mmol) of the 2-benzoyl-3- [2- (l-pyrrolidinyl) ethoxy] obtained according to Example 2 a) - 5 - methoxy - indole - hydrochloride and 3 ml of 48% hydrobromic acid are left for 48 hours stand at 20 ° C. 12 ml are added to the clear solution Ether, decanted from the undissolved material and dissolve the residue in 7 ml of warm methanol. The received The solution is poured into 25 ml of 0.3 N sodium bicarbonate solution, a light yellow precipitate separating out, the suctioned off, washed with water and then with a little cold methanol and finally in 6 ml of hot ethanol is dissolved. A few drops of conc. Hydrochloric acid, cools to 0 ° C and filtered, the precipitate was washed with isopropanol, then with ether, 2-benzoyl-3- [2- (l-pyrroltdinyl) ethoxy] - 5-hydroxy-indole hydrochloride with a melting point of 255 ° C is obtained.

Example 4

Analogously to Example 1 a), 2-benzoyl-3- [2- (l-pyrrolidinyl) - is obtained from 5.46 g (0.20 mmol) of 2-benzoyl-3-hydroxy-5,6-dimethoxy-indole hydrochloride ethoxy] -5,6 - dimethoxy - indol - hydrochloride of melting 224-226 ⁰ C (dec.).

Example 5

a) Analogous to example la), 5.14g (0.2OmMoI) 2 - Benzoyl - 3 - hydroxy - 5,6 - methylenedioxy - indole hydrochloride 2-Benzoyl-3- [2- (I -pyrrolidinyl) -ethoxy] - 5,6 - methylenedioxy - indole - hydrochloride with a melting point of 240 ° C (decomp.).

b) The 2-benzoyl-3-hydroxy-5,6-methylenedioxy-indole hydrochloride required as starting material is analogous to Example 1 b) starting from 64.4 g (330 mmol) of 1-carbomethoxy-2-amino-4,5-methylenedioxy-benzene receive; Melting point 215 ° C.

⁶ S test report

The following compounds were used to determine their effectiveness on test animals

I 695 11

the anti-inflammatory activity and toxicity tested:

I. 2-Benzoyl-3- [2- (l-pyrrohtlinyl) ethoxy] indole

hydrochloride
II. 5,6 - Methylenedioxy - 2 - benzoyl - 3 - [2 - (1 - pyrrolidinyl) ethoxy] indole hydrochloride.
III. l- (p-chlorobenzoy!) - 5-methoxy-2-methyl-indole-3-acetic acid (INDOMETHACIN);
(described in J. Amer. Chem. Soc, 81 [1963], pp. 488 and 489).

Experimental methodology
1st method - serotonin edema

The anti-inflammatory effect was based on serotonin edema the rat checked.

Serotonin (5 HTP) was used to induce edema subcutaneously on the plantar side of the left hind paw of Injected into rats. The injection amount was 0.1 ml of a 0.05% aqueous solution of serotonin-creatinine sulfate. 2 hours after application of the phlogistic, the animals were sacrificed, both hind paws amputated and the severity of the swelling by comparing the weight of the untreated right and of the left paw treated with serotonin was determined. The test substances were in the form of their chlorohydrates administered in doses of 5, 10 and 25 mg / kg orally 5 minutes before the application of the 5 HTP. Each substance was tested on a group of 18 rats weighing 120 to 150 g. A control group, which had received no test substance was treated with serotonin in the same way. The influence on the development of edema achieved with the test substances was expressed as a percentage change the mean swelling values of the individual groups are determined. The relevant values of the control series were assumed to be 100%.

Results

Veining of edema 5 10 in % connection dose 32 54 25th I. -60 II -30 - III -28

2. Acute toxicity (DL ₅₀ )

The test substances were phased out. male and female rats administered once orally, after which the test animals were observed for 8 days. To determine the DL ₅₀ , the values on the probability ^{grid (Schleicher and Schüll No. 298 1} / ·,) were intrapolated.

Results

Connection

DL ₅ ,, perorally on rats

144 I. 349 II 25th III

3. Conclusions

Compound I turns out to be about 6-fold and compound II to 14-fold lower more toxic than the known compound III.

The two tables show that the compounds I and II over the known compound III ;;. superior due to the more favorable therapeutic index are.

Claims (1)

Patent references: 1. Indole derivatives of the general formula I Ο —CH ₂ -GH ₂ -N (1) in which R _{1 is} hydrogen, the hydroxy or the methoxy group,
R _{2 is} hydrogen and, if R _{1 is} the hydroxyl group, the hydroxyl group, and if R ₁ stent for the methoxy group, the methoxy group, or
R ₁ and R ₂ together represent the methylenedioxy group,