FI69835C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA 3-NDOLYL-TERTIAERBUTYLAMINOPROPANOLDERIVAT - Google Patents

Description

γβΙ Π1 AD CQO-7C »tSTl? ^ UTLÄGGNINGSSKRIFT Oy O OD

C (45) Pate Λ tl rayjr-.stty (51) Kv.lk//lnt.ci. «E 07 D 209/1 **, ** 03/12 FINLAND —FINLAND (21) Patent application - Patentansökning 782205 (22 ) Date of application - Ansökningsdag 10.07-78 (23) Starting date —Giltighetsdag 10.07-78 (41) Made public - Blivit offentlig 1 ^ 4.01.79

National Board of Patents and Registration of Finland Date of publication and publication 31 31 85

Patent and registration authorities '' Ansökan utlagd och utl.skriften publicerad (32) (33) (31) Privilege requested — Begärd priority 13-07-77 USA (US) 815138 (71) Bristol-Myers Company, 3 ** 5 Park Avenue, New York, New York 10022, USA (72) William E. Kreighbaum, Evansville, Indiana,

William T. Comer, Evansville, Indiana, USA (US) (7 * 0 Oy Koi ster Ab (5 * i) Process for the preparation of therapeutically useful 3 "indolyl-tertiary-butylaminopropanol derivatives - For the preparation of 3" indolyl-tert-butylaminopropanol derivatives tertiary-ty1 am inopropanolder i vat

This invention relates to a process for the preparation of heterocyclic amino-substituted indole derivatives. The method of the invention provides therapeutically useful compounds of formula I or II

ch3 OH

,: -t-CH -C-NHCH-CHCH -O-Ar-X I

1; ; 2, 22 n k CH_ * / (K 3

B

or

ch3 OH

, - --------------- CH -C-NHCH „CHCH_-O-Ar-Het II

i I 1 2, 2 2 k! i CH3

OF

B

2,68935 and pharmaceutically acceptable acid addition salts thereof. In the above structural formulas, Ar is phenyl or naphthyl, X represents a lower alkyl, alkenyl, alkynyl, alkoxy, alkanoyl or alkylsulfonyl group or halogen, n is 0, 1 or 2, indicating X groups which may be the same or different, number, and

Het is an N-containing heterocyclic ring having 5 or 6 ring atoms and optionally substituted by up to two oxo and / or carboxamide groups.

The compounds of formula I or II are unique antihypertensive agents in that they combine an adrenergic γ-blocking effect with a vasodilating effect. They are also useful as anti-angina agents, anti-stress agents, anti-pulse agents, anticoagulants, and in the treatment of conditions where the amount of oxygen required by the heart must be reduced, such as in the treatment of post-myocardial infarction. The preferred compound members have a particularly desirable combination of the above effects, and pharmacological side effects, or lack thereof, which makes them particularly suitable for certain of the therapeutic topics listed above. Compounds of formula I in which Ar is phenyl, n = 1 and X is in the ortho position are recommended for use primarily as antihypertensive agents. The utility of the compounds of formulas I and II can be demonstrated in a variety of animal models, including isoproterenol antagonism in an orally treated conscious rat (adrenergic β-receptor blocking effect), spontaneously hypertensive rat (hypotensive effect), antihypertensive effect) ), ouabain-induced ventricular tachycardia in dogs (antiarrhythmic effect), coronary artery occlusion in dogs (antiarrhythmic effect), by in vitro photometric measurement of platelet aggregation

II

3 69835 (antiplatelet effect), and using various other animal and laboratory models.

The invention includes a process for the preparation of compounds of the above structural formulas and their acid addition salts. The use of pharmaceutically acceptable acid addition salts for pharmaceutical use is recommended. Pharmaceutically acceptable acid addition salts are those in which the anion does not significantly affect the toxicity or pharmacological activity of the salt, and as such are pharmaceutically equivalent to the bases of the above structural formulas. In some cases, the salts have physical properties that make them most desirable for pharmaceutical prescription purposes such as solubility, lack of hygroscopicity, compressibility for tablet formation, and miscibility with other ingredients with which the agents can be used for pharmaceutical purposes. Acid addition salts which do not meet the above pharmaceutical suitability requirements, for example in terms of toxicity, are sometimes useful as intermediates in the isolation and purification of the substances of the invention or for other chemical synthetic purposes such as the separation of optical isomers.

Acid addition salts are prepared by reacting a base of the above structural formula with an acid by contacting them with one another in solution. They can also be prepared by an exchange reaction or by treatment with an anion exchange resin, in which case the anion of the salt of the substance is replaced by another anion under conditions which allow isolation of the undesired part, such as precipitation from solution or solvent extraction, or elution from or coupling with anion exchange resin. For salt formation purposes, pharmaceutically acceptable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, phosphoric acid, nitric acid, succinic acid, isethionic acid, methanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid acids.

The compounds represented by the above structural formulas have an asymmetric carbon atom in the propanolamine side chain and compounds 69835 exist as their optically active isomers as well as racemic mixtures thereof. The present invention encompasses the preparation of all optically active and racemic forms. The X or Het substituent of some of the materials prepared in accordance with this invention has an asymmetric carbon atom, and thus diastereoisomeric pairs of racemates exist. The invention also encompasses the manufacture of these forms.

The resolution of racemic mixtures into components to give optically active isomers of the above compounds is accomplished, for example, by salt formation with an optically active acid, many of which are known to those skilled in the art, such as optically active tartaric acid, mandelic acid, bile acid, O, di-p-toluoyl tartaric acid, and with O, O-dibenzoyltartaric acid or other acids commonly used for this purpose. The claims are therefore considered to cover the preparation of products in the form of several racemic mixtures as well as suitable products in the form of optically active isomers.

Therapeutic methods include the systemic administration of a compound of formula I or a compound of formula II, or a pharmaceutically acceptable acid addition salt thereof, in an effective, non-toxic amount to a mammal having a disease caused by excessive stimulation of adrenergic receptors, or by a mammal. with too much blood pressure. An effective amount is considered to mean a dose that produces an adrenergic '' receptor blocking effect, a vasodilating effect, or an antihypertensive effect in a patient with the disease without causing unduly toxic side effects. Systemic administration includes both oral and parenteral routes of administration. Examples of parenteral administration include intravenous injection or "injection" and intraperitoneal, intramuscular or subcutaneous injection. The method of administration may be rectal administration in the form of an ointment or suppository. The dosage will vary depending on the route of administration, from about 0.1 microgram to 100 mg per kilogram of body weight of the compound of formula I or formula II or a pharmaceutically acceptable acid addition agent thereof.

II

5,698,35 salts generally give the desired therapeutic effect. Acute toxicity, as determined in mice, when administered orally is in the range of about ALC ^ 250 mg -> 2000 mg per kilogram body weight, in the presence of non-lethal drug symptoms such as central nervous system stimulation or depression, space blackness, or tear production. dosage 1 / 2-1 / 10.

The combination of the pharmacological properties of the compound of Example 8, 1- [72- (3-indolyl) -1,1-dimethylethyl] amino] -S- (2-methylphenoxy) -2-propanol hydrochloride, indicates that it is particularly desirable for hypertension. for use as a depressant. It has a 5-fold adrenergic 3-receptor blocking effect compared to propranolol, which has been demonstrated by oral administration to rats after exposure of animals to isoproterenol given as a booster injection. The latter is a well-known adrenergic / receptor stimulant that causes an increase in heart rate and a decrease in blood pressure. These effects of isoproterenol are counteracted by adrenergic β-receptor blockers, and the relative efficacy values mentioned above are based on the logs obtained for the two compounds. for regression analysis of dose-response values. When used for treatment, the dosage amount and frequency of administration will vary depending on the subject and the route of administration, with a suitable amount for a human being ranging from 0.2 mg for intravenous injection to about 100 mg for oral administration.

The agent of Example 8 differs from other adrenergic receptor blocking drugs in that it causes a decrease in blood pressure in a rat with spontaneous hypertension. Although adrenergic / 'receptor blockers have been widely used as human drugs in the treatment of hypertension, their mechanism of action is unknown and in most cases their effect as antihypertensive agents cannot be detected in this animal experiment. When the agent of this invention is administered to a rat with spontaneously hypertension, the blood pressure is reduced at a dose of 25 mmHg orally at 100 mg per kilogram of body weight, with only a minimal decrease in heart rate. This is considered to indicate its utility in cases of hypertension in which other adrenergic receptor blockers are ineffective or less desirable.

6 69835

The agent of Example 8 also causes a reduction in blood pressure when administered intravenously to an anesthetized dog at a dose of 3.33 mg per kilogram of body weight. It is also characterized by the fact that it does not reduce the heart rate or the intensity of the right ventricular contractile activity, as is the case with many previous adrenergic β-receptor blockers. The substance exhibits both a positive inotropic and a positive pulse-regulating effect, and these effects also occur when the animal is first treated with an adrenergic k-receptor blocking agent such as sotalol. Pulmonary arterial blood pressure remains essentially unchanged as aortic blood flow and peripheral circulatory resistance decrease, all of the above seen in an anesthetized dog.

The compound of Example 8 has a vasodilatory effect, which may be attributed in part to its unique antihypertensive effect. In an anesthetized nerve node-blocked (chlorosondamine chloride), in a hypertensive rat, direct vasodilators such as diazoxide cause a decrease in blood pressure. The material of Example 8 is similar in potency to the diazoxide in this experiment. Its vasodilatory effect can also be demonstrated in a pump-perfused dog's hind limb at doses of 0.03-1.0 mg / perfusion-min. Following oral administration to rats, current volume decreases and sodium vascular excretion decreases, a characteristic feature of vasodilators.

The anticoagulant effect of the agent of Example 8 is manifested in its ability to reduce platelet aggregation in vitro in platelet-containing plasma after exposure to ADP or collagen. Its in vitro activity can be compared to that of suloctilil or papaverine.

Excessive administration of adrenergic / 'receptor blocking agents to patients suffering from non-allergic bronchospasm may be dangerous if these agents attempt to initiate an asthma attack or render the patient unable to receive adrenergic therapy. 'receptor stimulants such as isoproterenol, which are used to treat sudden seizures. The agent of Example 8 does not tend to cause bronchospasm, as evidenced by the fact that it does not lower the pressure in the bronchial chamber and causes only a slight increase in response to immunologically induced bronchospasm in rats given an intravenous dose of 0.5 mg per kg body weight. In contrast, propranolol, given as an intravenous dose of 0.5 mg per kilogram of body weight, lowers pressure in the bronchial chamber and accelerates a sudden bronchospasm reaction in rats sensitized to immunologically induced bronchospasm.

For the preparation of pharmaceutical compositions in dosage unit form containing a compound of formula I or formula II, the compound is mixed with a solid, powdered carrier such as lactose, cane sugar, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose, amylopectin, , as well as glidants such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like and compressed into tablets. The tablets may be used uncoated or coated by known methods to allow disintegration and absorption in the gastrointestinal tract and thereby maintain the effect for a relatively long time. If coated tablets are desired, the core part prepared above may be coated with a concentrated sugar solution, which solution may contain e.g. gum arabic, gelatin, talc, titanium dioxide or the like. Furthermore, the tablets may be coated with a varnish dissolved in a volatile organic solvent or solvent mixture, and if desired, a colorant may be added to this coating.

In preparing soft gelatin capsules containing gelatin and e.g. glycerin and the like, the active ingredient is mixed with a vegetable oil and encapsulated in the usual manner. Hard gelatin capsules may contain granules of the active ingredient in combination with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

-

II

69835

Dosage units for suppository administration may be prepared in the form of suppositories containing the compound in admixture with a neutral fat-based substance, or in the form of gelatin suppositories in admixture with vegetable oil or paraffin oil.

Liquid preparations suitable for oral administration include suspensions, syrups and elixirs containing from about 0.2% to about 20% by weight of active ingredient.

A suitable injectable mixture comprises an aqueous solution of a water-soluble pharmaceutically acceptable acid addition salt, the pH of which is adjusted to be physiologically acceptable.

Compounds of formula I and formula II are prepared by applying known methods to suitable starting materials.

Representative known methods for preparing aryloxypropanolamine compounds are disclosed, for example, in CA Patent 834,751 (Troxler) and U.S. Patent 3,984,436 (Jaeggi, et al.). The production method of this invention is illustrated by the following reaction scheme: ch3

O 3-indolyl-CH 2 C-NH

Ar'-OH - and Ar '-O-CH_CHCH_ CH 2, I, II

(1) 2 2 ---------------------- * ------> (2)

In the above reaction scheme, the symbol Ar 'corresponds to the groups ArX1 and ArHet as defined in connection with formula I and formula II. Step (1) involves the reaction of an appropriately substituted phenolic compound Ar'-OH with epichlorohydrin in the presence of a catalytic amount of amine, followed by treatment with an aqueous alkali metal hydroxide solution, or reaction in an aqueous alkali metal hydroxide reaction medium without the need for an amine catalyst. In step (1), an Ar 1 epoxypropyl ether is prepared, which is reacted in step (2) with 2- (3-indolyl) -1-dimethylethylamine to give a product of formula I or formula II, depending on the nature of the starting Ar'OH. Reaction steps (1) and (2) each easily take place in conventional laboratory or factory equipment under appropriate working conditions.

9,69835 Heating the substantially used molar excess of epichlorohydrin with phenol Ar'OH, which includes a drop or two of piperidine as a catalyst, in a water bath overnight results in the condensation described in step (1). In this case, some of the corresponding halohydrin intermediate is also formed and this is converted without isolation to the oxirane shown by treating the mixture with an aqueous alkali metal hydroxide solution. Alternatively, the Ar'-phenol and epichlorohydrin can be reacted at room temperature to neutralize the acidic Ar'-OH group in the presence of a dilute aqueous solution of a sufficient amount of alkali metal hydroxide to form the desired intermediate Ar'-OCH ^ 'CHCH2. Step (2) is carried out simply by heating the oxirane intermediate formed in step (1) with 2- (3-indolyl) -1,1-dimethylethylamine either as such or in the presence of a reaction-neutral organic solvent. No catalyst or condensing agent is required. A suitable solvent is 95% ethanol, but other reaction-neutral organic liquids in which the reactants are soluble may be used. These include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures range from about 60 to 200 ° C.

The 2- (3-indolyl) -1,1-dimethylethylamine used is prepared by H.R. By the method of Snyder et al., J. Am. Chem. Soc., 69, 3140 (1947), from 3-indolylmethyldimethylamine and 2-nitropropane, followed by reduction of the resulting 2- (3-indolyl) -1,1-dimethylnitroethane.

In the following methods, temperatures are reported in degrees Celsius (°). Melting points are corrected values according to the U.S.P. method when correlation is used. Nuclear magnetic resonance (NMR) spectral properties refer to the chemical change (-3) expressed in parts per million (ppm) compared to the tetramethylsilane (TMS) used as a reference standard. The relative area reported for the various changes corresponds to the number of hydrogen atoms in a particular functional type of molecule, and the nature of the change as well as the multiplicity is reported as a wide singlet 69835 10 (bs), singlet (s), multiplet (m), doublet (d), triplet ), or as a quadruplet (q), in which case the coupling constants (J) are given when appropriate. The formula is NMR (solvent): ε (relative area, multiplicity, J value). The abbreviations used are MeOH (methanol), DMSO-dg (deuterodimethylsulfoxide), i-PrOH (isopropanol), sbs. EtOH (absolute ethanol), EtOAc (ethyl acetate), EtOH (95% ethanol), i-PrOH (isopropanol), 1-PrOAc (isopropyl acetate), 1-Pr 2 O (diisopropyl ether), d (decomposition). Other abbreviations have the usual established meanings. Infrared (IR) spectral imaging includes only absorption wave numbers (cm 2) with a functional group identification value. KB has been used as a diluent in all IR spectral assays. TMS was used as an internal reference in NMR spectral assays. Elemental analysis values are expressed as percentages by weight.

Method 1. 4- (Methylsulfonyl) -m-tolyloxymethyloxirane (Starting material)

To a mixture of 3-methyl-4-methylsulfonylphenol, 8.1 g (0.0435 moles) and 20.0 g (0.216 moles) of epichlorohydrin, two drops of piperidine are added as a condensation catalyst and the mixture is heated at 105-108 ° for 18 hours. . Excess epichlorohydrin is then removed by distillation using toluene as the propellant. A solution of 2.1 g of sodium hydroxide in 50 ml of water and 70 ml of dimethoxyethane is then added and the mixture is stirred for 2 hours by occasional heating in a water bath to completely convert the phenoxychlorohydrin compound to oxirane. The solvent is then removed by distillation in vacuo and the residue is dissolved in a mixture of ether and benzene (v / v 1: 1). The solution is dried over anhydrous sodium carbonate and the purity of the desired oxirane is examined by plate chromatography using a mixture of chloroform and methanol (9: 1) for development (R = 0.8). The solvent is then removed by distillation to give 10.7 g of a residue which is the desired oxirane. An infrared absorption spectral assay is used to verify the absence of essential hydroxyl-containing impurities. This material is suitable without further purification for use in the further reaction in Example 1.

B

69835 11

Method 2. 2-Chlorophenoxymethyl-oxirane (Starting material)

A solution of 12.9 g of 2-chlorophenol (0.1 mol) in 125 ml of water containing 6.5 g (0.162 mol) of sodium hydroxide and 18.5 g (0.2 mol) of epichlorohydrin is stirred at 25 ° at 20 hours. The mixture is then extracted twice with 70 ml portions of methylene chloride. The extract is dried over anhydrous sodium carbonate and the solvent is removed by distillation in vacuo. The residue is the desired oxirane and is suitable for further modification as described in Example 2.

Example 1. 1- [2- (3-Indolyl) -1,1-dimethylethyl] amino] -3- [3- (methylsulfonyl) -m-tolyloxy] -2-propanol

The oxirane of Method 1, 10.7 g, was dissolved in 150 ml of toluene, 8.2 g (0.044 mol) of 2- (3-indolyl) -1,1-dimethylethylamine were added and the mixture was boiled for 18 hours. The toluene was removed by distillation in vacuo and part of the residue was converted to the acetate salt, m.p. 142-147 ° C. The structure was confirmed by studying infrared absorption and nuclear magnetic resonance spectra. The remainder of the sample was converted to the hydrochloride salt by treating its acetonitrile solution with 8-norm. With ethanolic HCl solution. Recrystallization from CH 2 CN / MeOH gave the product, m.p. 174.0-177.0 ° (corr.).

Analysis found: C, 59.40; H, 6.90; N, 5.87.

NMR (DMSO-d 6): 1.29 (6, s); 2.52 (3, s); 3.12 (2, s); 3.16 (4, m); 4.18 (3 m); 5.95 (l, bs); 7.10 (8, m); 9.00 (2, bs); and 11.12 (lfbs).

IR. 740, 765, 1120, 1290, 1450, 1590 and 3270.

/ Example 2. 1- (2-chlorophenoxy) -3- [2- (3-indolyl) -1,1-dimethylethyl] amino] -2-propanol

A portion of the oxirane product of Method 2, 7 g (0.033 moles), was boiled as a solution with 6.3 grams (0.033 moles) of 2- (3-indolyl) -1,1-dimethylethylamine in 70 mL of ethanol. After 24 hours, the solvent was removed by distillation in vacuo and the viscous liquid residue was dissolved in 200 ml of ether, acidified to 8-norm. HCl in ethanol and the solvents were removed again by distillation. Crystallization was initiated by the addition of acetonitrile and trituration with a glass rod. Recrystallization from acetone from triil and diisopropyl ether gave 4.8 g of 69835 12 products, m.p. 150.5-153.5 ° C (corr.).

Analysis found: C, 61.54; H, 6.41; N, 6.94.

NMR (DMSO-d 6): 1.28 (6, s); 3.22 (4, m); 4.25 (3, m); 5.96 (1, bs); 7.23 (9, m); 8.84 (2, bs); and 11.12 (1.1 bs).

IR: 745, 1250, 1455, 1480, 1590 and 2780.

Using the above methods, the products listed in the following table were prepared.

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By applying Method 1 or 2 to the appropriate phenol, or other conventional methods, the following oxiranes are prepared and then converted to products of formula I or II by reacting them with 2- (3-indolyl) -1,1-dimethylethylamine in Example 1 or 2. in accordance with.

The physical properties of the final products obtained from these starting materials were determined as follows:

Example 13 1- [72- (3-Indolyl) -1,1-dimethylethyl] amino] -3- [2- (propenyl) phenoxy] -2-propanol hydrochloride m.p. 163.0-168.6 ° (corr.), Recrystallized from MeOH / i-P 2 O.

Analysis found: C, 69.22; H, 7.56; N, 6.70.

NMR (DMSO-d 6). 1.30 (6, s); 3.32 (6, m); 4.20 (3, m); 5.03 δ (2, m); 6.00 (2, m); 7.25 (9, m); 8.90 (l, bs); 9.60 (l, bs); and 11.40 (1.1 bs).

IR: 752, 1120, 1245, 1490, 1590, 1600, 2790, 2980 and 3350.

Example 14 1- [7,2- (3-Indolyl) -1,1-dimethylethyl] amino] -3-72- (2-methyl-1-propyl) phenoxy] -2-propanol hydrochloride, m.p. 163.0-166.0 ° (cor.), Recrystallized from MeOH / CH 2 Cl 2.

Analysis found: C, 69.34; H, 8.19; N, 6.49.

NMR (DMSO-d 6): 0.81 (3, t, 7.0 Hz); 1.17 (3, d, 7.0 Hz); 1.32 (6, s); 1.39 (2, m); 3.28 (5, m); 4.22 (3, m); 6.04 (1.1 bs); 7.22 (9, m); 9.00 (l, bs); 9.60 (l, bs); 11.20 (l, bs).

IR: 750, 1100, 1240, 1450, 1490, 1582, 1600, 2780, 2960 and 3320.

Example 15 3- (2-ethylphenoxy) -1-772- (3-indolyl) -1,1-dimethylethyl-7-amino-2-propanol hydrochloride, m.p. 170.0-171.5 ° (corr.), Recrystallized from EtOH.

Analysis; received; C, 68.36; H, 7.95; N, 6.85.

NMR (DMSO-d 6); 1.21 (3.5, 7.0 Hz); 1.33 (6, s); 2.64 (2, m); 3.24 (4, m); 4.21 (3, m); 6.00 (l, bs); 7.25 (9, m); 9.00 (l, bs); and 9.55 (1, bs).

IR: 750, 1130, 1240, 1460, 1495, 1590, 1605, 2800, 2970 and 3350.

Claims (5)

18 69835 Pat en tt ivaa t tins A process for the preparation of therapeutically useful 3-indolyl-tert-butylaninopropanol derivatives of the formula CH 1 3 OH --------------- CH 2 -C-NHCH-CHCH 7 -O- Ar-X, T, Γ i. £ - t ^ zn \ J · j kA -; i CH3 H or f 3 OH II ί -------------- CHn-C-NHCR ^ CHCH 2 -O-Ar-Het (II) 1 I 2. ^ s ί I li '/ CH. H in which Ar is phenyl or naphthyl, X represents a lower alkyl, alkenyl, alkynyl, alkoxy, alkanoyl or alkylsulfonyl group or halogen, n is 0, 1 or 2, indicating X groups which may be the same or different , and Het is an N-containing heterocyclic ring having 5 or 6 ring atoms and optionally substituted by up to two oxo and / or carboxyamide groups and for the preparation of their pharmaceutically acceptable acid addition salts, characterized in that the phenol of the formula Ar'-OH reacting with epichlorohydrin to form an Ar'-epoxypropyl ether of formula Ar'-O-CH 2 CHCH 0, which is reacted with 2- (3-indolyl) -1,1-dimethylethylamine to give a compound of formula (I) or (II), and optionally converting the resulting compound of formula (I) or (II) into a pharmaceutically acceptable acid addition salt. Process according to Claim 1, characterized in that a compound of the formula (I) is prepared in which Ar is phenyl, X is in the ortho position and n is 1. II 69835 19 Process according to Claim 1, characterized in that a compound of formula (I) is prepared in which Ar is phenyl, X is lower alkyl and n is 1. Process according to Claim 3, characterized in that X is methyl. Process according to Claim 3, characterized in that 1- [N, N-indolyl] -N 1 -dimethylethyl] amino] -7- (2-methylphenoxy) -2-propanol or its hydrochloride is prepared. 20 69835