CH472404A - Process for the production of new indole derivatives - Google Patents

Description

  

  



  Process for the production of new lidol derivatives
The present invention relates to a process for the preparation of new indole derivatives of the formula I,
EMI1.1
 where Rl is hydrogen or methyl and R2 is the isopropyl, cyclopropyl, sec. Butyl or tert-butyl group, and their acid addition salts. If R is a methyl group, this can be in the 1-, 2- or 3-position of the indole structure.



   The compounds of the formula I have not yet been described in the literature; they are characterized by interesting pharmacodynamic properties with low toxicity. In particular, they have a pronounced, long-lasting bradycardia and a certain antihypertensive effect. They do not influence the adrenaline effects on blood pressure, but inhibit the tachycardia produced by adrenaline. The compounds have an inhibitory effect on the circulatory effects of isoprenaline [1- (3 4-dihydroxyphenyl) -2-isopropylaminoethanol] and accordingly have a blocking effect on the receptors of the adrenergic nervous system.



   In appropriate doses, they also have x-receptor-stimulating activity as well as adipokinetic and glucokinetic properties (i.e. they influence the transport of lipoids or I carbohydrates in the organism).



   The properties mentioned above are particularly evident in the case of 2-methyl-4- (2-hydroxy-3-isopropylaminopropoxy) indole and 4- (2-hydroxy-3-isopropylaminopropoxy) indole. The new compounds are clearly superior to known preparations with a similar direction of action.



   The compounds can be used as medicaments, in particular for the prophylaxis or treatment of coronary diseases and anginal complaints, for the treatment of cardiac arrhythmias and arrhythmias associated with tachycardia, and for the therapy of hypertension.



   The method according to the present invention is characterized in that epichlorohydrin with amines of the formula II
EMI1.2
 converts the reaction products in alkaline solution and with exclusion of oxygen with hydroxyindoles of the formula III
EMI1.3
 condensed, then the benzyl group is split off hydrogenolytically and, if appropriate, the compounds obtained are converted into the corresponding salts by reaction with inorganic or organic acids.



   The method according to the invention is explained in more detail below:
The reaction of epichlorohydrin with the amine of the formula II is carried out by heating the components, preferably in an inert solvent such as benzene or toluene. The temperature is approx. 50-1100, the reaction time 1 to several hours. The addition of an acid binding agent, e.g. a tertiary organic base such as pyridine or triethylamine, or an inorganic base such as potassium carbonate, can be advantageous. however, it is not necessary.



   For the reaction with the reaction product obtained above, the hydroxyindole of the formula III is preferably used in the form of an alkali or ammonium salt. To do this, it is dissolved in an equimolar alcoholic or preferably aqueous alkali metal hydroxide or ammonia solution, mixed with 1 to 3 equivalents of the above-mentioned intermediate and the mixture is stirred for several hours at 20-500.



   According to a variant of the process, an alcoholic solution of the alkali metal salt of the l: hydroxyindole of the formula III is evaporated to dryness and the residue is suspended in dimethoxyethane or the hydroxyindole of the formula III is placed in an inert organic solvent such as benzene, toluene, etc. with the equimolar amount of an alkali metal alcoholate, amide or hydride; then - as above - 1 to 3 equivalents of the reaction product of epichlorohydrin with the amine II are added and the mixture is stirred for several hours at 20-500.



   Hydroxyindoles are extremely sensitive to oxidation in alkaline solutions; the measures described above are therefore carried out with the exclusion of oxygen, e.g. in a nitrogen atmosphere. The benzyl group is removed by treatment with catalytically excited hydrogen, preferably in a lower alkanol in the presence of a palladium catalyst.



   The end products of the process can be isolated and purified as free bases or in the form of their salts by known methods. They are colorless, mostly crystalline substances that are only slightly soluble in water and mostly well soluble in organic solvents. With the Keller reagent (glacial acetic acid and conc. Sulfuric acid containing ferric chloride) and the Van Urk reagent (p-dimethylaminobenzaldehyde and dilute sulfuric acid) they generally give characteristic colors.



   The invention also encompasses the preparation of acid addition salts of the new compounds, e.g. with inorganic acids such as hydrogen chloride, hydrogen bromide or sulfuric acid, or with organic acids such as fumaric acid, maleic acid, tartaric acid, benzoic acid, methane, ethane or p-toluenesulphonic acid etc. 4-hydroxyindole is known. Derivatives which have a methyl group in the pyrrole ring can be obtained, for example, as follows:
1. Methyl group in position 1: 4 -benzyloxyindole is methylated, for example by reaction with methyl iodide in liquid ammonia with the addition of sodium amide, and the benzyl group is then split off hydrogenolytically, e.g. by shaking with palladium and hydrogen in methanol.



   2. Methyl group in position 3: 4-Benzyloxyindole is converted into the corresponding benzyloxygramine with formaldehyde and dimethylamine in weakly acidic solution and this is hydrogenated over palladium in methanol, the dimethylamino and benzyl groups being split off at the same time.



   3. Methyl group in position 2: 4-Benzyloxyindole-2-carboxylic acid is converted into dimethylamide via the acid chloride, and this is reduced with lithium aluminum hydride to give the corresponding dimethylamine. which is quaternized with a methyl halide. 2-Cyanomethyl-4-benzyloxyindole is obtained from this by heating with aqueous sodium cyanide solution. hydrolyzes this and decarboxylates the acid obtained; the benzyl group is split off by hydrogenolysis.



   In the following example all temperatures are given in degrees Celsius, without corrections.



   Example 4 - (- Hydroxy-3-isoprnpy [atiinoprnpoxy) idol
A mixture of 18.4 g of epichlorohydrin and 29.8 g of N-benzylisopropylamine in 100 ml of benzene is refluxed for 24 hours, the solvent is then evaporated and the residue is distilled in a high vacuum; Bp. 107-1100 / 0.03 mm mm Hg.



   14.6 g of this distillate are added to a nitrogen-flushed solution of 7.3 g of 4-hydroxyindole and 2.25 g of sodium hydroxide in 50 ml of water. The mixture is stirred for 24 hours at 4 (each time, the reaction mixture is extracted 4 times with methylene chloride and the combined organic layers, dried over magnesium sulfate, are evaporated under reduced pressure. The residue is shaken 3 times between ethyl acetate and 1N tartaric acid solution, and the combined tartaric acids are then added Phases up to an alkaline reaction with sodium hydroxide solution: Shake out with ethyl acetate, dry the organic phase over potash, add 1 g of a palladium catalyst (5% on sole) and shake with hydrogen until absorption stops.



  The catalyst is filtered off, the filtrate is evaporated to dryness and the residue is ligated recrystallized from ethanol, giving the compound named in the title with a melting point of 171-1730 (needles).



   Keller's color reaction (0.2 mg): olive green
Van Urk's color reaction (1 mg): before exposure purple, afterwards dark purple-purple.



   The following compounds can also be prepared by the same process: 1-methyl-4- (2-hydroxy-3-isopropylaminopropoxy) indole mp 79-810 (from ethyl acetate / ether); 3-methyl-4- (2-hydroxy-3-isopropylaminopropoxy) indole m.p. 95-970 (from benzene / ligroin); 4- (2-hydroxy-3-cyclopropylaminopropoxy) indole m.p. 118-1200 (needle drums from ethyl acetate); 4- (2-hydroxy-3-sec-butylaminopropoxy) indole mp 154-1560 (prisms from methanol / ethyl acetate); 2-methyl-4- (2-hydroxy-3-isopropylaminopropoxy) indole m.p. 95-970 (from ethyl acetate); 2-methyl-4- (2-hydroxy-3-tert-butylaminopropoxy) indole. Mp. 131-1330 (from ethyl acetate).

 

Claims (1)

PATENT CLAIM Process for the preparation of new indole derivatives of the formula I, EMI2.1 where R1 is hydrogen or methyl and R is the isopropyl, cyclopropyl, sec-butyl or tert-butyl group. and their acid addition salts, characterized in that epichlorohydrin with amines of the formula II EMI2.2 converts the reaction products in an alkaline medium and with exclusion of oxygen with hydroxyindoles of the formula III EMI3.1 reacted, thereupon the benzyl group is split off hydrogenolytically and, if appropriate, the compounds obtained are converted into the corresponding salts by reaction with inorganic or organic acids. SUBCLAIMS 1. The method according to claim, characterized in that the reaction of the epichlorohydrin with the amines of the formula II is carried out in the presence of an acid-binding agent. 2. The method according to claim, characterized in that the hydroxyindoles of the formula III are initially introduced in an equimolar aqueous alkali metal hydroxide solution.