SE460419B - SUBSTITUTED 1-PYRIDYLOXY-3-INDOLYLALKYLAMINO-2-PROPANOLS, PROCEDURES FOR PREPARING THESE AND A PHARMACEUTICAL COMPOSITION - Google Patents

Description

469Û 4419? 2 The above-mentioned patent, which has been granted to J.J. Baldwin, U.S. Patents 4,000,282, dated December 28, 1976, 4,060,601 dated November 29, 1977, 4,091,104 dated May 23, 1978, 4,092,419 dated May 30, 1978, 4,144,343 dated 13 March 1979, 4 145 425 of 20 March 1979, 4 151 284 of 24 April 1979, 4 210 653 of 1 July 1980, 4 259 327 of 31 March 1981, 4 263 307 of 21 April 1981, 4 279,913 of 21 July 1981 and 4,329,351 of 11 May 1982.

A preferred compound belonging to this series, 2- (3- (ex-butylamino) -2-hydroxypropoxy) -3-cyanopyridine, also known as NK-761, has been the subject of extensive research, and in this connection reference is made to Sweet et al. ., The Journal of Pharmacology and Experimental Therapeutics 21111 (1979) 195-296; Sweet et al., Clinical and Exgeri- mental Hypertension 1 (4) (1979) 449-471; and Vickers et al., Drug Metabolism and Disposition, 811 (1980) 163-167.

Ongoing studies in humans were discontinued, however, when MK-761 was shown to cause malformations in rats after chronic administration in high doses (see Journal of Medicinal Chemistry, 22/11 (1979) 1284-1290).

CN Û min RO /-/ ïmcwxä) 3 -Hcl-OH A series of indol-3-yl-tert-butylaminopropanol (2,3) with antihypertensive properties has been described by Kreighbaum et al.in U.S. Patent 4,234,595 of November 18. 1980, in U.S. Patent 4,314,943, issued February 9, 1982 and in Journal of Medicinal Chemistry, 23: 3 (1980) 285-289). j \ UI g..n G 419 n N _ Ra I ”fi / \ ø-Af se: N Rz OH I Rl (3) A preferred compound belonging to the series represented by the structure (2) has the designation MJ 13105 and is also known as bucindolol and is currently undergoing clinical evaluation as an antihypertensive agent.

The present invention relates to a series of vasodilators with β-adrenergic blocking potency and having the general formula I and pharmaceutically acceptable acid addition salts thereof. a1 X2 n \ N 4-> <_ i) “TH f * nya) (I) In formula I, X is -CN or CONH2 and R1 and R2 are independently hydrogen or lower alkyl; wherein the indolyl system is joined via its 2- or 3-position. Preferred compounds have the indolylalkylaminopropoxy side chain attached to the 2-position of the pyridine core. 460 44-9 '4 The indole group itself is preferably linked to the main side chain via its S-position. For medical use, the pharmaceutically acceptable acid addition salts are preferred, i.e. those salts in which the anion does not contribute to any great extent to the toxicity or pharmacological activity of the organic cation.

The acid addition salts are obtained either by reacting an organic base of structural formula I with an organic or inorganic acid, preferably by contact in solution, or by any of the other standard methods described in the literature and available to those skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclamic acid, pivalic acid and the like, useful inorganic acids are hydrohalic acids such as HCl, HBr, Hi; sulfuric acid; phosphoric acid; and similar.

It will also be appreciated that the compounds of the present invention include all optical isomeric forms, i.e. mixtures of enantiomers, for example racemic nä.

Lu 'JN 460 419 modifications as well as the individual enantiomers. These individual enantiomers are usually denoted in accordance with the optical rotation they exhibit, by (+) and (-), (l) and (d) or combinations of these symbols. The symbols (L) and (D) and the symbols (S) and (R), which stand for "sinister" and "rectus", respectively, denote the absolute space configuration of the enantiomer.When no isomer designation is given for a compound, the compound is the the racemic modification.

Biological testing of the present compounds of formula I in animals shows that they exhibit potent vasodilatory properties as well as a varying degree of adrenergic ß-receptor blocking properties and inherent sympathomimetic activity. Preferred compounds have a particularly desirable combination of the above effects and supporting pharmacological effects, or absence thereof, making them particularly suitable for specific cardiovascular indications, for example use as antihypertensives.

The utility of the compounds of formula I can be illustrated in various animal models including antagonism of isoproterenol in anesthetized dog, which has been treated intravenously (adrenergic ß-receptor activity), spontaneous hypertensive and DOCA-salt-hypertensive rat (antihypertensive activity). ), angiotensin-maintained ganglion-blocked rat model (vasodilator activity) and in various other animal and laboratory models (see Deitchman et al., Journal Pharmacological Methods å (1980) 311321). No evidence of malformation or mutagenic properties has been shown to be associated with the compounds of formula 1.

For use as antihypertensive, vasodilating and / or walking adrenergic blocking agents, the compounds of the present invention in therapeutic treatment may be administered systemically both orally and parenterally, using an effective, non-toxic amount of a compound pharmaceutically acceptable acid adjuvant. 43-9 '6 tion salts thereof. An effective amount is considered to be a dose which exerts the desired pharmacological activity, as described above, without any undesirable side effects when administered to a mammal in need of a suitable treatment. The dosage will vary according to the subject and the mode of administration chosen, with 0.1 pg to 100 mg / kg of body weight of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof generally being expected to provide the desired therapeutic effect.

The compounds of the present invention may be prepared by a conventional general procedure. This process involves coupling a Z-substituted pyridine (IV) with a suitable W-substituted propanol or a propanol precursor intermediate (II).

General procedure W / * ñ “vn i, D l (IIA) hydrolysis // X // ^ \ ï / ^ \\ § Q w» ß N, Z _ on j, (II C) I 1 In the general procedure above, D is hydrogen or preferably phenyl; G is the group ~ 5 F * á in grams. d? 460 419 Z is hydroxyl or halogen, preferably chloride; W is halogen, preferably chloride, when Z is hydroxyl and hydroxyl when Z is halogen. In general, the hydroxyl-bearing reactant is initially converted to the oxide anion with a strong base before it is reacted with the halogen-bearing intermediate.

This process utilizes methods known in the art for the preparation of 1- (substituted amino) -3- (hetaryloxy) -2-propanols as set forth in the patents and publications set forth above in the description of the prior art. The process involves reacting the appropriately substituted pyridine with either 1) one (3- (indolylalkyl) oxazolidin-5-yl) methanol (or methyl halide) of formula IIA or 2) an indolylalkylaminopropanediol (or halopropanol) of formula IIB or 3) glycidol of formula IIC.

The intermediate from the reaction of IV and IIa is converted to the product I by hydrolysis under acidic conditions.

This hydrolysis is carried out with dilute mineral acid at a concentration of 0.1N-TN at temperatures of 20-10003. The product of formula I can be recovered as the free base by neutralizing the hydrolysis mixture and recovering the precipitate. Acid addition salts can be obtained by evaporation of the hydrolysis mixture or by reacting the free base with acid. Purification is carried out in a conventional manner, such as by recrystallization.

The conversion of the epoxide intermediate resulting from the reaction of IV with IIC to the product of formula I is carried out simply by heating the epoxy ether either as such or in the presence of a reaction-inert organic solvent with an amine of formula HZNG, as shown . No catalyst or condensate is required.

Suitable solvents include 95% ethanol, but other reaction-inert organic liquids in which the reactants are soluble can be used. These include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are 60-20,000.

The process involving a one-step process involves reacting IV with IIB and this is the preferred process for synthesizing the products of the present invention.

This process is illustrated by the following specific reaction scheme, which shows the preferred method of synthesis or Reaction 1.

R1 Rz XN x 1 -2 @} ha10 + no OH tïS-aï R å UH Égf / K / (IVF (ns) (I) HI the reaction scheme above, X, R1 and R2 have the meanings given in connection with formula I. In fact, this process involves heating the selected substituted halopyridine with the appropriate indolylalkylaminopropanol intermediate (IIB) in the presence of a base and in an inert organic liquid under mild conditions. butoxide, potassium hydroxide or sodium hydride may be used, fervid sodium hydride is preferred, as well as a large number of inert organic liquids may be used as the reaction medium or the cyanopyridine and indolylalkylaminopropanol may be reacted as such in the presence of the base. benzene, toluene, tetrahydrofuran, dibutyl ether, dimethoxyethane, etc. Suitable reaction temperatures are 2 .mu.-SO2. Addition of a suitable crown ether, such as 18-crown-6-ether, facilitates the reaction process. Pyridines are commercially available or can be prepared using standard methods set forth in the literature. The preparation of related trisubstituted pyridines is disclosed in U.S. Patent 4,329,351 of May 31, 1982, which is incorporated herein by reference in its entirety.

The indolylalkylaminopropanol intermediates (IIB), the preferred synthesis intermediates, are conveniently prepared by reacting an appropriately substituted indolylalkylamine (III) with 3-chloro-1,2-propanedione in refluxing alcohol containing sodium carbonate. This procedure is illustrated by Reaction 2.

Reaction 2 to 112 g of R; HO / Y \ Cl __; HNXÛ Base 2 l H m0 fr no v d 'H 1-1 (III) (IIB) In Reaction Scheme 2 above, R1 and R2 have the meanings given in connection with formula I.

The indolylalkylamines (III) are described by Kreighbaum et al in the above cited patent and article in the Journal of Medicinal Chemistry, to which reference is made in the present context as well as references cited therein. Although these methods are applicable to the preparation of other indolylalkylamine intermediates not specifically disclosed therein but required as intermediates for the present invention, representative syntheses of the compounds of formula III are set forth below for illustrative purposes.

The compounds of the present invention may be formulated in accordance with conventional pharmaceutical practice into pharmaceutical compositions in dosage unit form comprising, for example, capsules, powders, granules, emulsions, suspensions and the like. The solid preparations contain the active ingredient in admixture with toxic pharmaceutical excipients, such as inert diluents, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn, starch or alginic acid; binder, for example starch, gelatin or acacia- Wi mi; and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques to retard dissolution and absorption in the gastrointestinal tract and thereby provide a delayed action for an extended period of time.

Liquid preparations suitable for parenteral administration include solutions, suspensions or emulsions of the compounds of formula I. Aqueous suspensions of pharmaceutical dosage forms of the compounds of formula I contain the active ingredient in admixture with one or more non-toxic pharmaceuticals. excipients which are known to be suitable for the preparation of aqueous suspensions. Suitable excipients are, for example, sus-. pension agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum. Suitable dispersing or wetting agents are naturally occurring phosphatides, for example lecithin and polyoxyethylene stearate.

Anhydrous suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example olive oil, sesame oil or coconut oil, or in a mineral oil, for example liquid paraffin. The suspensions may contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents commonly used in pharmaceutical compositions may also be incorporated, for example, saccharin, sodium cyclamate, sugar and caramel color to give appealing oral preparations. The compositions may also contain other absorbents, stabilizers, wetting agents and buffering agents.

The compounds of the present invention, the methods of preparing them and their biological effects are set forth in FIG. rl 460 419 in more detail below of the following exemplary embodiments, which are given for illustrative purposes only and are not intended to limit the invention. In the embodiments below, the temperatures refer to degrees Celsius and the melting point indications are uncorrected. Nuclear Magnetic Resonance (NMR) spectral data refer to chemical shifts (5 expressed in parts per million (ppm) relative to trimethylsilane (TMS) as the reference standard).

The relative surface area given for the different shifts in the 1 H NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the displacements in terms of multiplicity is stated as broad singlet (bs), singlet (S), multiplet (m) or doublet (Ö). Abbreviations used are DMSO-d6 (deuterodimethylsulfoxide) and CDCl3 meaning. Infrared (IR) spectral data includes only (deuterochloroform) and otherwise has conventional absorption weights (cm_1) with identification value for functional groups. The IR determinations have been performed using potassium bromide (KBr) as diluent. Elemental analysis data refers to weight percentages.

Synthesis of intermediates A. Intermediates of formula III Example 1 2- (2-amino-2-methylpropyl) indole (R1 = R2 = Me) A solution comprising 10.0 g (0.06 mol) of indole-2-carboxylic acid and 20.0 g (0.17 mol) of thionyl chloride in 130 ml of dry Et 2 atmosphere. Reaction mixture 0 was stirred for 12-18 hours at room temperature under a nitrogen filter and the filtrate was concentrated to an oily residue, which was taken up in 150 ml of dry Et 2 methylamine in 90 ml of Et 2 O. This ether solution was treated with 80 ml of di- O. The ether reaction mixture was concentrated to dryness and the residue was crystallized from isopropyl alcohol. The solid was isolated by filtration to give 4.0 (34%) of the 2-indolylamide product with a melting point of 12,460 4t9 'u: LW The amide was dissolved in 100 ml of THF and this solution was added dropwise to a stirred suspension, which contained 3 g of lithium aluminum hydride in 50 ml of THF, under a nitrogen atmosphere.

After refluxing for 2 hours, the reaction mixture was cooled and decomposed with a small amount of water and dilute sodium hydroxide solution. This mixture was filtered and the filtrate was concentrated to a residual oil, which was taken up in absolute ethanol and treated with a slight excess of dimethyl sulfate. The resulting alcohol solution was stirred at room temperature for 4 hours and then concentrated in vacuo to dryness to give the residual quaternary trimethylamine salt.

The quaternary salt crude product (3.0 g; 0.01 mol) was combined with 2.0 g (0.05 mol) of sodium hydroxide (pellets) and ml of 2-nitropropane and the mixture was refluxed for 1 hour under a nitrogen atmosphere. The resulting dark thick mixture was cooled, diluted with water, acidified with acetic acid to a pH of about 6 and then extracted with Et O. These Et O extracts were combined, washed with water, dried over magnesium sulfate and concentrated to a dark residue, which was chromatographed on a silica column and diluted with methylene chloride. The removal of the methylene chloride and recrystallization of the crude material from isopropyl alcohol-water gave 0.4 g of 2- (2-methyl-2-nitropropyl) indole as a cream solid, m.p. 102-1030. Raney nickel and hydrazine gave the desired indole alkylamine as a white solid, m.p. 130-133 °. Additional examples of an indole alkylamine are set forth in Table 1 below.

Exemgel fx)) læäàllLl Indolalkylamine FP »Fi» UI 460 M9 14 B. Intermediates of formula II Exemgel 3 3 - ((2- (3-indolyl) -1,1-dimethylethyl) amino) - 1,2-propanediol hydrate ( IIB) A mixture of 10.0 (0.05 mol) q, dr-dimethyl- (3-indolyl) -ethanamine, 11.3 g (0.11 mol) sodium carbonate, 7.0 g (0.06 mol) 3-Chloro-1,2-propanediol and 250 ml of ethyl alcohol were stirred overnight at reflux temperature. After cooling, the mixture was filtered and concentrated in vacuo. The residue was dissolved in EtOAc, decolorized (Darco G-60) and evaporated to a volume of 100 ml. The solution precipitated a white solid which was recrystallized from EtOAc to give 7.7 g (55%), m.p. 112-1140. The material crystallized with 1/5 mol of water. "Using other intermediates of formula III in this or similar processes, a variety of intermediates of formula IIB are readily obtained.

Synthesis of Brodukter Exemgel 4 2- (2-hydroxy-3 - ((2- (1H-indol-3-yl) -1,1-dimethylethyl) amino) propoxy) -3-pyridinecarbonitrile hydrochloride (x = CN, R1 and n = = ne) 47.3 g (0.18 mol) of 3 - ((2- (3-indolyl) -1,1-dimethylethyl) amino} -1,2-propanediol and 7.6 g of a 57% dispersion of sodium hydride in oil (G 18 mol} was stirred in 2.5 liters * <0 f toluene and heated 3 tin at 700 under a nitrogen atmosphere. The mixture was then allowed to cool to room temperature with stirring and G, š g 18- crown-6-ether, 62.7 g of anhydrous powdered potassium carbonate (0.5 mol) and 25.0 g of {Û, 18 mol) of 2-chloro-3-cyanopyridine were added in order 1, 460 419 to the The mixture was stirred and then stirred for a further 42 hours. Concentration to dryness gave a residue which was partitioned between hot water and EtOAc. After cooling to room temperature, the aqueous layer was separated and washed with additional EtOAc and this wash was combined with the original EtOAc layer. EtOAc was dried over magnesium sulfate and concentrated in heat to approximately half volume. Upon cooling, a solid precipitated, which was isolated by filtration to give about 41 g (62%) of the base as a crude product.

Conversion of the base to the hydrochloride salt was performed by treating an isopropyl alcohol solution of the base with ethanolic HCl. Recrystallization of the crude hydrochloride salt from absolute ethanol gave a white solid, m.p. 181-1830.

Analysis Ber. for C 21 H 24 N 4 O 2 -HCl: C 62.92 H 6.29 N 13.98 Found; c 62.85 H 6.29 N 14.04.

NMR (DMSO-d 6): 1.30 (6.5); 3.20 (4, m); 3.99 (3.m); 6.02 (1, d (4.0 HZ)); 7.30 (6, m); 8.31 (1, dd (2.0, 7.6 Hz)); 3.51 (1, dd (2.0, 5.6 Hz)); 8.82 (1, bs); 9.32 (1, bs); 11.27 (1, bs).

IR (KBr): 750, 1110, 1310, 1440, 1460, 1580, 1588, 2230, etc., 2960 and 3400 C151.

Preparation of the cyclamate salt The cyclamate salt was prepared by treating the crude base (2 g of crude base) synthesized above with 1 g of cyclamic acid in 50 ml of methylene. The methanol solution was heated and filtered and the filtrate was concentrated in vacuo to give a residue which crystallized from 10 ml of acetonitrile. Recrystallization of the crude salt from methanol-acetonitrile UT 460 44-9-16 gave 2.0 g of a white solid, m.p. 172-174 °.

Analxs Ber. for C 21 H 24 NO 2 O 2 · C 6 H 13 NO 3 S: C 59.65 H 6.87 N 12.89 Found: C 59.74 H 6.77 N 12.82. EXAMPLE 5 4- (2-Hydroxy-3 - ((2- (1H-indol-3-yl) -1,1-dimethylethyl) amino) propoxy) -3-pyridinecarbonitrile Using the procedure of Example 4 and the like using 10.4 g (0.04 mol) of 3 - ((2- (3-indolyl) -1,1-dimethylethyl) amino) -1,2-propanediol, 1.7 550 ml of toluene, 5, 5 g (0.04 mol) of chloro-3-cyanopyridine (see Wieland and Biener, Chem. Berichte go (1963) 268-274, 0.11 g of 18-crown-6-ether and 13.7 g (0, 1 mol) of anhydrous g (0.04 mol) of sodium hydride, 4 powdered potassium carbonate 15 g of a gummy material were obtained, the rubber was chromatographed on a silica column eluting with 90 parts of methylene chloride, 10 parts of methanol and 1 part of ammonium hydroxide to obtain 2 fractions. .

The second fraction eluted gave 6.8 g of gum, which was crystallized from ethyl acetate to give 5 g of solid, m.p. 124-1260. Recrystallization of this material from ethyl acetate gave 4.2 g of a white solid, m.p. 126-1280.

Analvs Ber. for C 21 H 24 N 4 O 2: C 69.21 H 6.64 N 15.38 Found: C 69.42 H 6.75 N 15.65.

NMR (DMSO-d 6): 1.00 (6, S}; 1.55 (1, bs); 2.75 (4, m); 3.90 (1, m); 4.27 (2, m ); 5.10 '(1, bS); 7.25 (6, m); 8.64 (1, d. (6.0 Hz)}; 8.78 (1, 51; 10.82 (1 , bs).

IR (KBr): 745, 1010, 1190, 1290, 1315, 1455, 1495, 1520, 1590, 2225, 2970 and 3400 cm -1; give.

U 460 419 H Example Gel 6 2- (2-Hyaroxy-3 - ((2- <1H-inazol-3-yl) -1,1-dimethylethyl) amino) propoxy) -3-pyridinecarboxamide Using a procedure similar to that of in Example 4, 10.5 g (0.4 moli) of 3-I (2- (3-inhalyl) -1,1-amethylethyl) amino> -1,2-propanoyl were reacted, 1.7 g of 4 ml) sodium hydride, 400 ml of toluene, 5.6 g of 10.04 mol) of 2-chloronicotinamide, 0.11 g of 18-crown-6-ether and 13.8 g (0.1 mol) of anhydrous powdered potassium carbonate were reacted to obtaining 17 g of a rubber. The rubber was chromatographed on a silica column eluting with 90 parts of methylene chloride, 10 parts of methanol and 1 part of ammonium hydroxide. The fractions containing the product were combined and concentrated to a residue, which was crystallized from ethyl acetate to give 5.2 g of material, m.p. 68-720. Recrystallization from ethyl acetate and drying in a vacuum oven gave 4 g of white solid, m.p. 131-1330.

Analysis Ber. for C 21 H 26 N 4 O 3: C 65.95 H 6.86 N 14.65.

Found: C 65.80 H 6.85 N 14.31.

NMR (DMSO-d 6): 1.03 (6.5); 2.77 (4, m); 3.95 (1, m); 4.46 (2.m); 7.20 (6.m); 7.81 (2, bs); 8.30 (2, d (6.1 Hzh; 10.85 (1, bs)).

IR (KBr): 740, 780, 1100, 1235, 1430, 1460, 1585, 1670, 2970, 3330 and 3470 cm -1. B8 460 44-9- Biological evaluation These biological tests were performed to determine the cardiovascular profile of a number of compounds of formula I as vasodilators with ß-adrenergic blocking activity.

Example 7 The effect of antihypertensive agents other than adrenergic ß ~ receptor blocking agents1 is usually determined by spontaneous hypertensive treatment. Blood pressure values are determined for the experimental animals before and 24 hours after oral doses of 50 mg / kg of the test compounds; the observed percentage change in heart rate is also noted. A drop in blood pressure of the order of 19-24 mm Hg is termed "doubtful".

The terms "active" and "inactive" refer to lower blood pressure drops, respectively. less than said range.

Example 8 The angiotensin-maintained ganglion-blocked rat model is used as a "screening" test to determine the activity of the vasodilator component. Percentage changes in blood pressure in anesthetized rats minutes after intravenous administration are determined. The intravenous administration is performed with the test compound at a dose of 3 mg / kg. The limit case in terms of activity is defined as a 35-20% reduction in blood pressure measured 30 minutes after administration. The terms "active" and "inactive" refer to greater blood pressure decreases, respectively. less than said range.

Example 9 Eiastolic blood pressure and heart rate response .A certain administered dose of isoproterenol is measured before and minutes after intravenous administration to anesthetics; 19 460 419 '-1 serated dogs of graded doses of the test compound over a 3-minute interval. A branch of a femoral artery and vein is cannulated to determine blood pressure and to administer the drugs, which are dissolved in saline.

The vagus nerves were sectioned bilaterally in the intercervical region of the neck and the dogs were mechanically ventilated (Ghrvard respirator) with room air at a rate of / minute and a stroke volume of 20 ml / kg. The heart rate was monitored with a cardiotachometer, which was triggered by the pressure pulse. All measurements were recorded on a Beckman R-612 printer. The drug effect is expressed as the cumulative dose in micrograms / kg that causes a 50% inhibition of the isoproterenol response.

Claims (9)

.C. Ö \ CD 1 3> _; \ O QC “2ATENT§ß5V Compounds of the formula o H (I) and acid addition salts thereof, wherein X is -CN or CONH and R and R are independently hydrogen or lower alkyl; wherein the indolyl system is joined via its 2- or 3-position. The compound 2- (2-hydroxy-3 - ((2- (1H-indol-3-yl) -1,1-dimethylethyl) amino) propoxy) -3-pyridinecarbonitrile and pharmaceutically acceptable acid addition salts thereof, preferably the cyclic acid and hydrochloric acid addition salts thereof according to claim 1. I The compound 4- (2-hydroxy-3 - ((2- (1H-indol-3-yl) -1,1-dimethylethyl) amino) propoxy) -3-pyridinecarbonitrile and pharmaceutically acceptable acid addition salts thereof according to claim l. The compound 2- (2-hydroxy-3 - ((2- (1H-indol-3-yl) -1'-dimethylethyl) amino) propoxy) -3-pyridinecarboxamide and pharmaceutically acceptable acid addition salts thereof according to claim 1 . Pharmaceutical composition in dosage unit form suitable for systemic administration to a mammal, characterized in that it comprises a pharmaceutical carrier and a compound of claim 1 having the formula I 1- - 460 419 E + oH (1) wherein X is -CN or CONH 2 and R 1 and R 2 are independently hydrogen or lower alkyl; wherein the indolyl system is joined via its 2- or 3-position, in an amount sufficient to provide an effective non-toxic dose of 0.1 micrograms - 100 mg / kg body weight. Pharmaceutical composition according to claim 5, characterized in that the compound of formula I is 2- (2-hydroxy-3 - ((2- (1H-indol-3-yl) -1,1-dimethylethyl) amino) -propoxy) -3-pyridinecarbonitrile, 4- (2-hydroxy-3 - ((2- (1H-indol-3-yl) -1,1-dimethylethyl) amino) propoxy) -3-pyridinecarbonitrile or 2- (2-hydroxy-3 - ((2- (1H-indol-3-yl) -1,1-dimethylethyl) amino) propoxy) -3-pyridinecarboxamide or a pharmaceutically acceptable acid addition salt of any of these compounds. A process for the preparation of a compound according to claim 1 having the formula "from: (OH (U) or an acid addition salt thereof, wherein X is -CN or -CONH 2 and R 1 and R 2 are independently hydrogen or lower alkyl; wherein the indole system is joined via its 2- or 3-position, characterized in that a) a Z-substituted pyridine of the formula IV gg X 'Z is added wherein X has the meaning given above and Z is hydroxyl or: 460 4-19 halogen , with an unsubstituted propanol or propanol precursor intermediate II having any of the formulas IIA, IIB and IIC W 1, O NG (IIA) D w MG OH (IIB) '0 WN (IIC) wherein D is hydrogen or phenyl and preferably phenyl; G is the group R 1, R 2, 2 2 where R and R have the meanings given above, and W is halogen and preferably chlorine when Z is hydroxyl and W is hydroxyl when Z is halogen, and (b) i) when compound IIA is reacted with compound IV, then the product thereof is converted by hydrolysis under acidic conditions to the compound of formula I or wi i) when compound ïIC is reacted with compound IV, an epoxy ether is formed and said epoxy ether is heated either as such or in the presence of a reaction-inert organic solvent with an amine of formula H2NG, where G has the meaning given above, to form a compound * D 460 419 w than b 'of formula I. Process according to claim 7, characterized in that a compound of formula IIB is used, wherein W is hydroxyl and that Z is halogen and that the coupling in step (a) involves heating the compound IV with compound IIB in the presence of a base in an inert organic liquid under mild conditions. Process according to claim 7, characterized in that the hydrolysis under acidic conditions utilizes dilute mineral acid with a concentration of 0.1N-1N and temperatures in the range 20-100 ° C also comprises recovering either (a) the product with formula I as free base by neutralizing the hydrolysis mixture and recovering the resulting precipitate or (b) the acid addition salts thereof by evaporating the hydrolysis mixture or by reacting the free base with acid.