FI79709C - Process for the preparation of novel therapeutically useful 1-pyridyloxy-2 or 3-indolylalkylamino-2-propanol derivatives - Google Patents

Description

1 79709

The invention relates to a process for the preparation of new therapeutically useful 1-pyridyloxy-2 or 3-indolylalkylamino-2-propanol derivatives. The invention relates to a process for the preparation of new 1-pyridyloxy-3-indol-2 or 3-yl-alkylamino-2-propanol derivatives of the formula I and their acid addition salts, - OR '

15 B

wherein X is -CHO, -CN, -CF 3, -CONR · R b or -CO 2 R c, wherein R a and R b are independently hydrogen or C x. 4-alkyl and Rc is C 1-4 alkyl, Y is hydrogen, halo

O

II

Gene, or hydroxy, R is hydrogen or -C-L, where L is lower alkyl or phenyl, R 1, R 2, A and B are each other. . independently hydrogen and lower alkyl and C is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy. These compounds have a vasodilating effect.

A relatively large number of 3- (aryloxy) -2-hydroxypropylamine compounds are known in the art as β-adrenergic receptor blockers and / or vasodilators and can be used to treat cardiovascular diseases. The model for these compounds is propranolol, the chemical name of which is 1- (isopropylamino) -3- (1-naphthyloxy) -2-propanol. Propranolol and other related naphthyloxypropanolamines are protected in U.S. Patent 3,337,628 (issued August 22, 1957). Subsequently, several patents have been granted for carboxylic ethers in which the naphthyloxy group of propranolol has been replaced by other aromatic or heterocyclic systems.

J.J. Baldwin has been granted several patents in which the pyridinyloxy group has been used in this manner.

5 These compounds and their salts have been patented and reported to have antihypertensive activity. These patents, listed below, generally describe compounds of the formula 10 tx, 0-or>

N OR

(1) wherein R is alkyl, phenylalkyl or phenoxyalkyl,

O

R 1 is H or C-L, where L is alkyl or aryl, R 2 is H,

O

CN, CF 3, OH, C-L, Cl, NO 2, F, pyrrolyl or oxadiazol-20-yl.

Baldwin's patents (Merck & Co., Inc.) are as follows: 4,000,282, December 28, 1976; 4,060,601, November 29, 1977; 4,091,104, May 23, 1978; 4,092,419, May 30, 1978; 4,144,343, March 13, 1979? 4,145,425, March 20, 1979; 4,151,284, April 24, 1979; 25 4 210 653, 01.07.1980; 4,259,327, March 31, 1981; 4,263,307, April 21, 1091; 4,279,913, July 21, 1981; and 4,329,351, May 11, 1982.

A preferred compound in this series, 2 - [(tert-butylamino) -2-hydroxypropoxy] -3-cyanopyridine-30, also known as MK-761, has been further investigated as described in the following articles:

Sweet et al. The Journal of Pharmacology and Experimental Therapeutics, 211/1, 195-296 (1979); Sweet et al., Clinical and Experimental Hypertension, 1 (4), 449-471 (1979); 35 and Vickers et al., Drug Metabolism and Disposition, 8/3, 397970 163-167 (1980). However, studies on acute effects in humans were discontinued when MK-761 was found to be teratogenic in rabbits when administered continuously at high doses (cf. Journal of Medicinal Chemist-5, 22/11, 1284-1290 (1979)).

cc - ch3) * hci

10 0H

U.S. Patent Nos. 4,234,595 (Kreighbaum et al., November 18, 1980) and 4,314,943 (Kreighbaum et al., February 15, 1982) and Journal of Medicinal Chemist Association, 23: 3, 285-289 (1980) describe a series of antihypertensive indol-2-yl tert-butylaminopropanols (2,3).

O-Ar-Xn 20 oh H1 (2)

OH

Of these, a preferred compound, which is a compound of formula (2), designated MJ 13105 as well as busindolol, is currently undergoing clinical trials for its suitability as an antihypertensive drug.

V CN

βτΓ ^ · - «

OH

B

MJ 13105 4 79709

It has now been found that the compounds of formula I and their pharmaceutically acceptable acid addition salts have an excellent vasodilating effect as well as a β-adrenergic blocking effect.

Preferred compounds of formula I are those in which the indolylalkylaminopropoxy side chain is attached at the 2-position of the pyridine ring.

The indole group is preferably attached via its 3-position to the alkylaminopropoxy chain.

Preferred pharmaceutically acceptable acid addition salts for pharmaceutical use are those in which the anion does not significantly affect the toxicity or pharmacological activity of the organic cation. Acid addition salts are obtained either by reacting an organic base of formula I with an organic or inorganic acid, preferably in solution, or by any of the standard methods described in the literature available to those skilled in the art. Examples of useful organic acids include carboxylic acids such as malic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclic acid, pivalic acid and the like; useful inorganic acids include hydrohalic acids such as HCl, HBr, HI, sulfuric acid, phosphoric acid and the like.

The group of compounds of formula I also comprises all optical isomeric forms, i. mixtures of enantiomers, e.g. racemic forms as well as different enantiomers. Enantiomers are usually denoted by the symbols (+) and (-), (1) and (d) or combinations of these symbols according to the optical rotation they cause. Symbols (L) and (D) and symbols (S) and (R) denoting sinister and rectus indicate the absolute space configuration of the enantiomer. When a compound does not have an isomeric label, it is a racemic form.

Compounds of formula I and their acid addition salts may be prepared by coupling a Z-substituted pyridine derivative of the formula wherein X and Y are as defined above and Z is hydroxyl or halogen with a W-substituted propanol precursor. of the formula 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 wherein R, R1, R2, A, B and C are as defined above and W is halogen, preferably chlorine, when Z is hydroxyl. 3 L, and W is hydroxyl when Z is halogen; 4

and, if desired, a compound of formula I wherein C

5 is lower alkoxy, is converted to a compound of formula I wherein C is hydroxy, and / or the resulting compound of formula 7 is converted to an acid addition salt.

8

When Z in the starting material of formula IV has a halo 9 gene, it is preferably chloride. In general, a hydroxyl-containing reactant is initially converted with a strong base to an oxide anion prior to reaction with a halogen-containing 12 intermediate.

13 This process uses methods known for the preparation of 1- (substituted-amino) -3-heteroaryloxy) -2-propanols known from the prior art patents and 6,79,709 disclosed above. The preparation of the compounds of formula I can be illustrated by the following reaction scheme:

Reaction 1

5 r1 R2 a .C

τ-φ ^ · ^ w «; vX) C9§i

(IV) <«> (I) B

The reaction is carried out by heating the selected substituted halopyridine with the appropriate indolylalkylaminopropanol-II intermediate (II) in the presence of a base in an inert organic liquid under mild reaction conditions. Ordinary strong bases such as potassium tert-butoxide, potassium hydroxide or sodium hydride may be used, with sodium hydride being preferred. The reaction medium may likewise be any organic inert liquid; The reaction between cyanopyridine and indolylalkylaminopropanol can also be carried out without a reaction medium in the presence of a base. Suitable solvents are, for example, benzene, toluene, tetrahydrofuran, dibutyl ether, dimethoxyethane, etc. A suitable reaction temperature is about 20 to 80 ° C. The reaction is facilitated by the addition of a suitable crown ether, such as 18-crown-6-ether.

Compounds of formula I wherein C is hydroxy are prepared by cleaving the corresponding methoxy precursor as shown in Reaction Scheme 2.

30

Reaction 2 B.

B

7 79709

The required halopyridines are commercially available or can be prepared by standard methods known in the literature. The preparation of nearby trisubstituted pyridines is described in U.S. Patent No. 4,329,351 (Baldwin et al., Issued May 11, 1982).

Preferred intermediates used in the synthesis, indolylalkylaminopropanols (II; R 1 H), are prepared by reacting an appropriately substituted indolylalkylamine (III) with 3-chloro-1,2-propanediol in alcohol in the presence of sodium carbonate at reflux temperature. This method is illustrated in Reaction Scheme 3:

Reaction 3 "T'1 *."; (III) (II) 20

In Reaction Scheme 3, R 1, R 2, A, B and C are as defined in Formula I.

Indolylalkylamines (III) are described in Kreighbaum et al. patents and 25 Journal o £ Medicinal Chemistry, which, together with the references therein, are incorporated herein by reference. Although the methods set forth in the references are also applicable to the preparation of indolylalkylamine intermediates other than those specifically described in these publications, which are required in the present invention, representative syntheses of compounds of formula III are set forth below.

Biological experiments with the compounds of the formula I show that they have a strong vasodilatory effect and a variable amount of 8 79709 β-receptor blocking activity and innate sympathomimetic activity. The preferred compounds have a particularly desirable combination of the above-mentioned effects and, in addition, pharmacological effects which make them suitable for the treatment of cardiovascular diseases, e.g. as antihypertensive drugs. The utility of the compounds of formula I can be demonstrated in various animal experiments; these include, e.g., demonstration of isoproterenol antagonism in anesthetized dogs by intravenous administration of a test compound 10 (adrenergic β-receptor effect); experiment in rats spontaneously hypertensive and hypertensive with DOCA salt (antihypertensive effect); experiment in gangliosal-stained rat under angiotensin effect (vasodilating effect), and other laboratory experiments performed on experimental animals (see Deitchman et al., Journal of Pharmacological Methods, e, 311-321 (1980)). No evidence of teratogenic or mutagenic effects has been observed with the compounds of formula I.

The following biological experiments were used to determine the cardiovascular profile of the compounds of formula I as vasodilators with β-adrenergic blocking activity.

The antihypertensive effect of an antihypertensive agent other than a β-adr-energy blocking agent is usually determined spontaneously by hypertensive experiments. The blood pressures of the experimental animals are measured before the administration of the test compound at an oral dose of 50 mg / kg and 24 hours after the administration of the compound; the% change in heart rate is also measured. A decrease in blood pressure of 30 19-24 mmHg is considered "questionable". When the compound is "active", the reduction in blood pressure is greater than 24 mmHg and when it is inactive, the reduction in blood pressure is less than 19 mmHg.

The vasodilatory effect of the compound is obtained in 35 screening experiments using gangliosalted rats exposed to angiotensin 9 79709. The% reduction in blood pressure in anesthetized rats is determined 30 minutes after intravenous dosing. The test compound is administered intravenously at a dose of 3 mg / kg. The borderline case is a 15-20 5% reduction in blood pressure 30 minutes after dosing.

"Active" and "inactive" affect more and less.

The effect on diastolic blood pressure and heart rate is determined by administering to anesthetized dogs a fixed dose of isoproterenol and determining blood pressure and heart rate before gradual intravenous administration of the test compound 15 minutes and at 3 minute intervals thereafter. Cannulas are placed in the femoral artery and vein branch to measure blood pressure and administer the test compound dissolved in saline. The vagus nerves were cut in both sides in the middle area of the neck and the dogs were oxygenated mechanically (Harvard respirator) by conducting room air (20 times min) at a stroke volume of 20 ml / kg. Heart rate was measured with a kar-20 diotachometer operated by a pressure pulse.

All measurements were recorded on a Beckman R-612 plotter. The effect of the drug has been reported as the effect of the cumulative dose (pg / kg) that causes 50% inhibition of the effect of isoprotereol.

The following table shows the results obtained with the compounds of Examples 14, 15 and 16 below.

10 79709 tr m λ: 3 ή.

m o> ι i a a_

rH O

d in o tn q <n

I M

O

B

P

nS dP dP dP

<0 -P vo o as <d n tN Tf

rH III

B

Ό

O

tn (0 dP> - i • H *

-P

G G

«D -H

> i g

«H ^ rH

aö cn (N

G -h »n r» n

0) M -P I I I

<l E> iC

H: ro φ: θ O -H Ό JG 5n

M tn> vH rH

M C tn -P - 3 0) H -P--

3 P

3 φ I

En CU Λί> ι: <Ό l

JG aö rH

(—I atj • rl · (->

-P 3 G C

:: tn + j φ φ c γη γη -h • ri-PCCO oo m cn g

C O -H -H fi I + I

fö P (Ö r- «g β aö <0 a O '¢) e -rl

P G 3 K 3 -P

G Φ Φ Φ G 3 G

0 3 P g * "" 1 Φ Φ JO

CVH Φ g 3 Φ Φ Sh

W>> - ^ M M rH

___o vo • rl n

M

M I

P

J 'j' m vo m

-. β rH rH rH

• H Π tn W * rl

pH

-, - | o cn o ro p

rr oo σν -P

«9 * r * r- G

t ~ 3 rf * r o 52 rH rH rH ^ __ * 11 79709

The compounds of formula I and their pharmaceutically acceptable acid addition salts can be administered as antihypertensive, vasodilator and / or β-adrenergic blockers in a systemically and orally and parenterally effective, non-toxic amount. An effective amount is one that has the desired pharmacological effect set forth above, without significant toxic side effects, when administered to a mammal in need of treatment. Dose 10 will vary with the recipient and the route of administration, and is expected to be from about 0.1 pg to 100 mg / kg body weight of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, at which dose will generally provide the desired therapeutic effect.

The compounds of formula I may be formulated into unit dosage pharmaceutical compositions by conventional pharmaceutical methods; such unit dosage forms include, for example, tablets, capsules, powders, granules, emulsions, suspensions, etc. Solid preparations contain the active ingredient in admixture with non-toxic pharmaceutical excipients such as inert diluents, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating and disintegrating agents such as corn starch and alginic acid, binders such as starch, gelatin or acacia; and with lubricants such as magnesium stearate, stearic acid and talc. The tablets may be uncoated or they may be coated in known manner to delay disintegration and absorption in the gastrointestinal tract and thereby provide a delayed, longer lasting effect of the drug.

Liquid preparations suitable for parenteral administration include solutions, suspensions and emulsions of a compound of formula 1. Aqueous suspensions of the compound of formula I in pharmaceutical dosage form contain the active ingredient in admixture with one or more non-toxic pharmaceutical diluents known to be suitable for the manufacture of aqueous suspensions. Suitable diluents include, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum. Suitable emulsifiers are naturally occurring phosphatides, e.g. lecithin and polyoxyethylene stearates.

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 paraffin oil. The suspension may contain a thickening agent, such as beeswax, paraffin or cetyl alcohol.

The compositions generally also contain sweetening and flavoring agents, such as saccharin, sodium cyclamate, sugar, or burnt sugar, to make them more palatable for oral use. The compositions may also contain other absorption, stabilization, emulsification and pus-20 agents.

The following examples illustrate the invention. In the examples, temperatures are expressed in degrees Celsius (eC) and melting points are uncorrected. Nuclear Magnetic Resonance Spectrum (NMR) symbols refer to chemical shift (expressed in parts per million (ppm) using tetramethylsilane (TMS) as a reference standard). The relative areas reported for the different shifts in the H NMR spectra correspond to the number of functional 1γγρ1η hydrogen atoms in the molecule in question. The nature of the transitions (multiplicity) is reported as follows: broad singlet (bs), singlet (s), multiplet (m), and doublet (d).

The abbreviations DMSO-d6 (deuterodimethylsulfoxide), CDCl3 (deuterochloroform) are common abbreviations. The infrared (IR) spectra comprise only the absorption wavelengths (cm-1) of the functional group relevant for identification. IR assays were performed using potassium bromide (KBr) as a diluent. Elemental analyzes are expressed as 13% by weight.

Synthesis of Intermediates A. Intermediates of Formula III Example 1 3- (2-Amino-2-methylpropyl) -6-methoxyindole (R 1 -R 2 -Me, A, 1a B to H, Q 6 -MeO) _ Chilled 25- To a 1% aqueous solution of dimethylamine (15.2 ml) were added, with stirring and continuous cooling, successively the following substances: 16.9 ml of acetic acid, 7.2 ml of 37% formaldehyde, 27 ml of 95% ethanol . The mixture was stirred in a cooling bath at 0-5 ° C when 6-methoxyindole (10.0 g, 0.07 mol) was added portionwise. The mixture was stirred and gradually warmed to 30 ° C over 30 minutes, where it was further stirred for 3 hours. The reaction mixture was cooled to 10-15 ° C and acidified with 170 mL of 2N HCl. The acidic mixture was decolorized (Darco G The mixture was filtered and the filtrate was basified with 245 ml of 20% NaOH solution while cooling and stirring, the resulting brown oily precipitate was extracted with ether, the extract washed with water, dried (MgSO 4) and evaporated to give a brown oily residue (14 g) was obtained, which was crystallized from isopropyl ether and hexane to give 9 g (65%) of 6-methoxygramine as a tan solid, mp 88-90 °.

A mixture of 6-methoxygramine (7.7 g, 0.04 mol), 2-nitropropane (26.5 g, 0.3 mol) and NaOH (1.7 g pellets, 0.04 mol) was refluxed. under nitrogen for 3-5 hours. The reaction mixture was cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ether extract was washed with water, dried (MgSO 4) and evaporated in vacuo. The residue was crystallized from a mixture of isopropyl alcohol and water to give 7.6 g (80%) of a tan solid 3- (2-methyl-2-nitro-35-propyl) -6-methoxyindole, m.p. 98-100 °.

A mixture of the resulting nitropropylindole, activated Raney nickel (4.2 g) and 95% ethanol (80 ml) was heated to reflux. Heating was stopped, and a solution of 85% hydrazine hydrate (7.8 g) in 8 ml of 95% ethanol was added dropwise to the mixture. The reaction mixture was then heated to reflux for 2 hours, cooled to room temperature and filtered. The filtrate was evaporated, the residual oil slowly solidified and recrystallized from a mixture of ethyl acetate and isopropyl ether to give 4.2 g of product, m.p. 125-128 *.

Example 2 2- (2-Amino-2-methylpropyl) indole (R 1 = R 2 = Me, A, B and C = H) _______

A solution of indole-2-carboxylic acid (10.0 g, 0.06 mol) and thionyl chloride (20.0 g 0.17 mol) in 130 ml of dry diethyl ether was stirred for 12-18 hours at room temperature under nitrogen. The reaction mixture was filtered and the filtrate was evaporated, the oily residue was dissolved in 150 ml of anhydrous ether. The ether solution was treated with a solution of diethylamine (80 ml) in 90 ml of diethyl ether. The reaction mixture was evaporated to dryness and the residue was crystallized from isopropyl alcohol. The solid product was isolated by filtration to give 4.0 g (34%) of the 2-indolylamide product, m.p. 181-183 °.

The resulting imide was dissolved in 100 ml of tetrahydrofuran, and the solution was added dropwise with stirring under a nitrogen atmosphere to a suspension of lithium aluminum hydride (3 g) in 50 ml of THF. The mixture was heated to reflux for 2 hours, then cooled and quenched by the addition of a small amount of water and dilute NaOH solution. The mixture was filtered, the filtrate evaporated and the residual oil dissolved in absolute ethanol. The solution was treated with a small excess of dimethyl sulfate, the mixture was stirred at room temperature for 4 hours, then the mixture was evaporated to dryness in vacuo to give a quaternary trimethylamine salt as a residue.

A mixture of crude quaternary salt (3.0 g 0.01 mol), NaOH (2.0 g pellets, 0.05 mol) and 2-nitropropane (79 ml) (15 ml) was heated to reflux under nitrogen for 1 hour. The resulting dark thick mixture was cooled, diluted with water, acidified with acetic acid to about pH 6 and then extracted with diethyl ethers. The ether extracts were combined, washed with water, dried (MgSO 4) and evaporated and the resulting dark residue chromatographed on a silica gel column using methylene chloride as solvent. Evaporation of methylene chloride and crystallization of the crude product from a mixture of isopropyl alcohol and water gave 0.4 g of 2- (2-methyl-2-nitropropyl) indole as a cream solid, m.p. 102-103 °.

Reduction of the obtained nitro compound with Raney nickel and hydrazine by the method described in Example 1 gave the desired indole alkylamine as a white solid, m.p. 130-133 °.

Other examples of indole alkylamines are given in Table 1.

table 1

Indole alkylamines; :

H-N

B 1 2 3 4 5 6

„. . (HD

2

Example 3 ki_ R1 R2 A B c 4

3 Me H 3-H Me H

5

4 Me Me 2-Me H H

6 5 Me Me 2-H H 5-Br 6 Me Me 2-H H 5-0Me

7 H Me 2-H H H

g H Me 2-Me Me 5-0? r 35 9 H Me 3-Me Me 5-Br 10 Me Me 2-HH 6-0Me 11 Me H 2 -Et H 4-Cl 12 Me H 2 -HH 7-0. ': e ie 79709 B. Formula II intermediates Example 13 3- [2- (3-Indolyl) -1,1-dimethylethylamino] -1,2,5-propanediol hydrate (II) -α, α-dimethyl-β- (3-indolyl) ethanamine .0 g, 0.05 mol), Νη2θΟ ^: η (11.3 g, 0.11 mol), 3-chloro-1,2-propanediol (7.0 g, 0.06 mol) and ethanol (250 ml) the mixture was stirred and refluxed overnight. The mixture was cooled, filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and the solution was treated with decolorizing carbon (Darco G-60), then the solution was evaporated to a volume of 100 ml.

A white solid precipitated from solution which was crystallized from ethyl acetate to give 7.7 g (55%) of product, m.p. 112-114 °. The crystals contained 0.2 moles of water.

Using other intermediates of formula III in this or a similar process, various intermediates of formula II can be readily prepared.

Synthesis of the final product Example 14 2- [2-hydroxy-3- [2- (1H-indol-3-yl) -1,1-dimethylethyl]; amine-7-propoxy-3-pyridinecarbonitrile hydrochloride (Y = H, X = CN, R = H, R1 and R2 = Me, A, B and C = H) - 3- [2- (3-indolyl) -1, 1-Dimethylethylamino-1,2-propanediol (47.3 g, 0.18 mol) and sodium hydride (7.6 g of a 57% dispersion of mineral oil, 0.18 mol) were stirred and heated at 70 ° under a nitrogen atmosphere of 2.5 ° C. per liter of toluene for 3 hours. The mixture was further stirred while allowing to cool to room temperature, 18-crown-6-ether (0.5 g), anhydrous K 2 CO 2 powder (62.1 g powder, 0.0 g) were added successively with stirring. 45 mol) and 2-chloro-3-cyanopyridine 35 (25.0 g, 0.18 mol), and stirring was continued for another 42 hours. The mixture was evaporated to dryness and the residue partitioned between 17,770,709 hot water and ethyl acetate. After the mixture was cooled, the aqueous layer was separated, washed further with ethyl acetate, and the washing solution and the original ethyl acetate extract were combined. The extract was dried (MgSO 4) and evaporated on a heat-5 club to about half volume. Upon cooling, a solid precipitated which was filtered to give about 41 g (62%) of crude product as a base.

The base was converted to the hydrochloride salt by treating the isopropyl alcohol solution of the base with HCl-ethanol solution.

Recrystallization of the crude hydrochloride salt from absolute ethanol gave a white solid, m.p. 181-183 °. Analysis calculated for C21H24N4O2'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, s), 3.20 (4, m), 3.99 (3, m), 6.02 (1, d / 4.0 Hz?), 7.30 (6.0, m), 8.31 (1, dd / 2.0, 7.6 Hz?) 8.51 (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, 20 2230, 2790, 2980 and 3400 cm-1.

..... Preparation of cyclamate salt

The cyclamate salt can be prepared by treating the synthesized crude base (2 g of crude base) with cyclamic acid (1 g) in 50 ml of methanol. The methanol solution was heated, filtered, the filtrate evaporated in vacuo and the residue obtained crystallized from 10 ml of acetonitrile. Recrystallization from a mixture of methanol and acetonitrile gave 2.0 g of a white solid, m.p. 172-174 °.

Analysis calculated for C 21 H 24 N 4 O 2 · C 6 H 13 NO 3 S 5 C 59.65 H 6.87 N 12.89 Found: C 59.74 H 6.77 N 12.82.

79709 BC

Example 15 4- [2-Hydroxy-3- [2- (1H-indol-3-yl) -1,1-dimethylethylamino] propoxy] -3-pyridinecarbonitrile By the method of Example 14 and using 3 - [2- (3- indolyl) -1,1-dimethylethylamino-1,2-propanediol (10.4 g, 0.04 mol), sodium hydride (1.7 g, 0.04 mol), toluene (550 ml) and 4-chloro 3-cyanopyridine (5.5 g, 0.04 mol) (see Wieland and Biener, Chem. Berichte, 10 96, 268-274 (1963)), 18-crown-6-ether (0.11 g) and anhydrous 1 CO 2 powder (13.7 g 0.1 mol) gave a gum (15 g). It was chromatographed on a silica gel column eluting with a mixture of methylene chloride (90 parts), methanol (10 parts) and ammonium hydroxide (1 part) to give 15 fractions. Elution of the second fraction gave 6.8 g of a gummy substance, which was crystallized from ethyl acetate to give 5 g of solid, m.p. 124-126 °. Recrystallization from ethyl acetate gave 4.2 g of a white solid, m.p. 126-128 °.

Analysis calculated 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 (DMDO-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 Hz7), 8.78 (1, s), 10.82 (1, bs).

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

Example 16 2- [2-Hydroxy-3- [2- (1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy] -3-pyridinecarboxamide

Following the procedure of Example 4, 3 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -1,2-propanediol (10.5 g, 0.04 mol), sodium hydride (1.7 g) was obtained. 0.04 mol) toluene (400 ml), 2-chloronicotinamide, (5.6 g, 0.04 mol), 18-crown-6-ether (0.11 g) and anhydrous ^ CO 2 powder 19 79709 (13.8 g 0.1 mol) to react with each other to give 17 g of a solid as an evaporation residue.

It was chromatographed on a silica gel column eluting with a mixture of methylene chloride (90 parts), methanol (10 parts) and ammonium hydroxide (1 part). The product-containing fractions were combined and evaporated and the residue crystallized from ethyl acetate to give 5.2 g of product, m.p. 68-72 °. It was recrystallized from ethyl acetate and dried in a vacuum oven to give 4 g of a white solid, m.p. 131-133 °. Analysis calculated 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 (DNAO-d6); 1.03 (6, s), 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 Hz7), 10.85 (1, bs).

IR (KBr); 740, 780, 1100, 1235, 1430, 1460, 1585, 1670, 2970, 3330 and 3470 cm-1.

Example 17 20 Conversion of Methoxy Compounds to Hydroxy Compounds - General Procedure_

The methoxy compound is dissolved in methylene chloride, and the solution is stirred under a nitrogen atmosphere while cooling in an ice bath. To the solution is added dropwise 3 equivalents of boron tribromide as a solution of methylene chloride.

At the end of the addition, the ice bath is removed and the reaction mixture is stirred at room temperature for 6-8 hours. The reaction mixture is again cooled in an ice bath and the excess reagent is decomposed by dropwise addition of water to give a gummy substance. The supernatant is decanted and the gummy substance is rinsed with two portions of water. The gum is dissolved in hot water, the solution is treated with activated carbon (Darco), filtered, the filtrate is cooled and basified to a pH of about 8 with ammonium hydroxy-35. The precipitate obtained is filtered, washed with water, dried and further purified by column chromatography on silica gel using a mixture of CHCl 3 (90 parts), methanol (10 parts) and NH 4 OH (1 part) for elution. Evaporation of the product-containing fractions and crystallization of the residue from ethanol-water gives the pure hydroxy-5 compound.

Using the appropriate pyridine and indolylalkylamine as starting materials, other compounds of formula I can be prepared by the method described above. Some of the synthesized compounds of formula I are summarized in the following Table 2. In the formulas, G represents a group r1 * 2 a c L B - * 15 which is determined by the selected intermediate of formula III (see Examples 1-12).

21 79709

Table 2 „. , Formula

examples

Example- Equation 5 kl fT ifY0 "62

'«3 OH

". 'Took. »'OC ^.

ÖH OH

»" Of "" O: a 0H OCCH3

CONH0 O

OC ^. - ‘OCr- OH ·

20 OH

s * '“OC ^” OCr -

·: 0CCH3 0H

; “OC ^ - OH <OCEt ..:. v OCPh. - * Il o '35 22 79709 Abbreviations used herein have the following meanings: Ph is a phenyl group, Pr is a propyl group, Me is a methyl group, Et is an ethyl group.

5

Claims (2)

A process for the preparation of novel therapeutically useful 1-pyridyloxy-3-indol-2 or 3-yl-alkylamino-2-5-propanol derivatives and acid addition salts thereof, OR J4 B in which formula X is -CHO, -CN, -CF3, -CONR "Rb or -CO2Rc, wherein R" and Rb independently represent hydrogen or C1-4 alkyl and Rc is C1-4 alkyl, Y is hydrogen, Q halogen or hydroxy, R is hydrogen or -CL where L is lower alkyl or phenyl, R 1, R 2, A and B are independently hydrogen or lower alkyl and C is hydrogen, halogen, lower alkyl, lower alkoxyl or hydroxy, characterized in that Z-substituted pyridinediene wherein V and X are the same as above and Z is hydroxyl or halogen, coupled to a W-substituted propanol precursor of formula 26 79709 wherein R, R1, R2, A, B and C are the same as above and W is halogen, preferably chlorine, where Z is hydroxyl, and W is hydroxyl, where Z is halogen; and, if desired, converting a obtained compound of Formula I where C is lower alkoxy into a compound of Formula I wherein C is hydroxy and / or converting a obtained compound of Formula 1 into an acid addition salt . 2. A process according to claim 1, characterized in that a compound of formula II wherein 10 W is hydroxyl and Z is halogen is used and the coupling is carried out by heating a compound of formula IV with a compound of formula II in the presence. of a base in an inert organic liquid under mild conditions. 15