CH455777A - Process for the production of new indole derivatives - Google Patents

Description

  

  
 



  Process for the production of new kdol derivatives
The present invention relates to a process for the preparation of new IndoIderivaten and their salts with valuable pharmacological properties.



   Derivatives of indole-2-acetic acid according to formula I,
EMI1.1
 in which R1 is a lower alkyl or alkoxy radical, the trifluoromethyl radical or a halogen atom and X is the methylene, ethylidene or carbonyl group, have not yet become known. As has now been found, these compounds have valuable pharmacological properties, in particular anti-inflammatory (anti-inflammatory), analgesic and antipyretic activity with a favorable therapeutic index. The compounds of the formula I can be used orally or rectally or, if they are water-soluble salts according to the meaning of R2, also parenterally, in particular intramuscularly, for the treatment of rheumatic, arthritic and other inflammatory diseases.



   In the compounds of the formula I and the corresponding starting materials mentioned below, R1 is z. B. chlorine, fluorine, bromine, trifluoromethyl or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. Butyl, methoxy, sithoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy radical.
The compounds of the formula I are prepared by adding a compound of the formula II,
EMI1.2
 in which R2 is a lower alkyl radical or the benzyl radical and R1 and X have the meaning given under formula I, converted into the free acid of formula I by hydrolysis or hydrogenolysis and, if desired, the latter with an inorganic or organic base to form a salt. The hydrolysis can be carried out in a conventional manner, e.g.

   B. by heating with alkanolic potassium hydroxide solution or sodium hydroxide solution, or by means of aqueous hydrochloric acid at room temperature. The hydrogenolysis is also carried out under common conditions, e.g. B. in the presence of noble metal catalysts such as palladium on carbon or alkaline earth metal carbonates, in suitable organic solvents such as ethanol or dioxane, at room temperature and normal pressure, or in the presence of Raney nickel in the same solvents and, if necessary, at moderately elevated pressure.



   The starting materials of the formula II are themselves new compounds. You can for example by cyclization, in the presence of a dehydrating agent, a derivative of levulinic acid of the formula III,
EMI2.1
 in which R1, R2 and X have the meaning given above.



   Lewis acids in organic solvents at about 0 to 2000 are particularly suitable as dehydrating agents. For example, the compound of the formula III is boiled with anhydrous zinc chloride in ethanol.



   The daily doses of compounds of formula I for the treatment of rheumatic, arthritic and other inflammatory diseases range between 20 and 300 mg for adult patients. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 5 to 100 mg of a compound of the formula I, in particular a free acid or a pharmacologically acceptable salt thereof.



   The following example is intended to explain the implementation of the method according to the invention in more detail. The temperatures are given in degrees Celsius.



   example
270 mg of ethyl 1 - (p-chlorobenzyD-5-methoxy-3-methykndol-2-acetic acid ester are refluxed with 290 mg of potassium hydroxide in 8 ml of 50% aqueous ethanol for one hour under nitrogen. The reaction mixture is cooled, diluted with 25 ml of water and extracted with ethyl acetate. The aqueous phase is acidified with 2N hydrochloric acid and extracted with ethyl acetate. The product obtained after evaporation is recrystallized from ethyl acetate / pentane.



  The l- (p-chlorobenzyl) -5-methoxy-3-methylindole-2-acetic acid thus obtained melts at 132-1340.



   The starting material of this example can be prepared as follows: a) 123 g of p-anisidine are refluxed with 80.5 g of p-chlorobenzyl chloride in 350 ml of xylene for 36 hours and then allowed to cool. The crystal slurry is filtered off with suction, the filtrate is concentrated and ethanol is added, and the precipitated N- (p-chlorobenzyl) -panisidine is filtered off with suction. After recrystallization from methanol, it melts at 69-700. b) 50.0 g of N- (p-chlorobenzyl) -p-anisidine are stirred with 22.5 g of ethyl 3-bromolevulinate under nitrogen, first for 24 hours at 250, then for 4 hours at 600. The reaction mixture is mixed with 100 ml of ether and suction filtered.

   The filtrate is shaken with 5N hydrochloric acid, suction filtered again and washed neutral. The ether is then evaporated and the residue is distilled under high vacuum. The fractions below 0.01 torr to 1500 are discarded. The crude 3- [N- (p-chlorobenzyl) -p-anisidino] levulinic acid ethyl ester remains as a residue, which can be further processed directly. c) 2 g of ethyl 3- [N- (p-chlorobenzyl) p-anisidino] levulinate (cf. Example 1b) are heated to 1500 for 2 minutes with 2 g of anhydrous zinc chloride under nitrogen.

   The reaction mixture is partitioned between 5N hydrochloric acid and ethyl acetate, the organic phase is evaporated, applied to 45 times the amount of silica gel and eluted with a mixture of benzene / ethyl acetate / glacial acetic acid (94: 5: 1). The eluate is recrystallized from ethanol, whereupon the l- (p-chlorobenzyl) 5-methoxy-3-methyl-indole-2-acetic acid ethyl ester obtained melts at 110-110.50.

 

Claims (1)

PATENT CLAIM Process for the preparation of new indole derivatives of the formula I, EMI2.2 in which R1 is a lower alkyl or alkoxy radical, the trifluoromethyl radical or a halogen atom and X is the methylene, ethylidene or carbonyl group, characterized in that a compound of the formula II, EMI2.3 in which R2 denotes a lower alkyl radical or the benzyl radical and R1 and X have the meaning given under formula I, by hydrolysis or hydrogenolysis into the free acid of formula I and, if desired, the latter with an inorganic or organic base to form a salt.