NL8303038A - SUBSTITUTED 1-PYRIDYLOXY-3-INDOLYL ALKYLAMINO-2 PROPANOLS, THEIR PREPARATION, THEIR USE. - Google Patents

Description

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V.O.5060

Substituted 1-pyridyloxy-3-indolylalkylainlno-2-propanols, their preparation, their use.

The present invention relates to heterocyclic carbon compounds of the indole series with an amino substituent, as well as to pharmaceutical preparations and methods of bioliquid using drugs and for treating living creatures using these compounds.

There is quite a large amount of literature regarding compounds from the 3- (aryloxy) -2-hydroxypropylamine series which have an S-adrenergic receptor blocking activity and / or vasodilatory properties and are useful in the treatment of cardiovascular diseases. Much of this literature concerns the class of β-an-drenergic blocking agents of this series of compounds. The prototype of these structures is propranolol; chemically 1- (isopropylamino) -3- (1-naphthyloxy) -2-propanol propranolol and some related naphthyloxypropanol amines form it on the way of U.S. Patent 3,337,628, published August 22, 1967. Many subsequent patents have been issued which include carbocyclic ethers in which other aromatic rings or heterocyclic systems replace the naphthyloxy group of propranolol.

A series of patents have been issued to J.J. Baldwin, which describes the use of the pyridinyloxy group in this manner. These compounds and their salts are described as useful antihypertensive agents. These patents listed below generally disclose the general structure of formula 7, wherein R represents alkyl, phenalkyl, phenoxyalkyl; R * represents hydrogen, C (O) L wherein L is alkyl or aryl; 2 R stands for H, CN, CF ^, OH, C (0) L, Cl, F, pyrrolyl, oxadiazolyl.

25 The series of Baldwin patents assigned to Merck & Co, Ine. Includes; 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; 4,210,653, July 1, 1980; 4,259,327, March 31, 1981; 4,263,307, April 21, 1981, 4,279,913 July 21, 1981, and 4,329,351, May 11, 1982.

A preferred compound of this series, 2- [3- (tert.-butylamino) -2-hydroxypropoxy] -3-cyanopyridine, also known as MK-761, has been studied to a significant degree as described in: Sweet, et al.

The Journal of Pharmacology and Experimetal. Therapeutics, 211/1, -7: 7038-2-195-296 (1979); Sweet, et al., Clinical and Experimental Hypertension, 1 (4), 449-471 (1979) and Vickers, et al., Drug Metabolism and Disposition, 8/3, 163-167 (1980). However, studies in humans were abruptly terminated when MK-761 was shown to be teratogenic in rabbits after chronic dosing in 5 high doses (see Journal of Medicinal Chemistry, 22/11, 1284-1290 (1979)). The MK-761 is shown on the formula sheet with formula 8.

A series of indol-3-yl-tert-butylaminopropanols (formulas 9, 10) with antihypertensive properties has been described by Kreighbaum, et al. 10 U.S. Patent No. 4,234,595 published November 18, 1980; in U.S. Patent No. 4,314,943 published February 9, 1982; and in Journal of Medicinal Chemistry, 23: 3, 285-289 (1980).

A preferred compound of the formula 9 series is designated MJ 13105, also known as bucindolol, and is currently being critically investigated as an antihypertensive agent. This compound is shown on the formula sheet of formula 11.

The present invention relates to a range of vasodilators having a range of S-adrenergic blocking activity and corresponding to the general formula 1, as well as to the pharmaceutically acceptable acid addition salts thereof.

In formula 1, X stands for CHO, CH ^ OH, CN, CF ^, C0NRaR ^ or CO ^ R0 si ϋ c where R and R are independently selected from hydrogen or R, and

wherein R represents lower alkyl, aryl or arylalkyl; Y represents hydrogen, halogen, acyloxy, alkoxy, aralkyloxy, aryloxy, or hydroxyl; R

25 represents hydrogen or C (0) L, wherein L is selected from alkyl, aryl, substituted aryl, or arylalkyl; R, R, A and B are independently selected from hydrogen or alkyl; and C may be halogen, hydrogen, hydroxy, alkyl or alkoxy. Preferred compounds have X at the 3-position of the pyridine ring and the indolylalkylaminopropoxy side chain attached at the 2-position of the pyridine core.

The invention includes compounds of the above formula 1 as well as the acid addition salts thereof. In formula 1, X can be -CHO, -CN, -CFy -C0NRaRb, or -CO ^ R0 · R & R and Rb are independently selected from hydrogen or R, wherein R is lower alkyl (C -C ^); aryl; or may be aryl-lower alkyl, wherein aryl is preferably phenyl. It is also preferred that X is attached to the 3 position in the pyridine ring -λ jg é t -3 system. Y represents a second substituent on the pyridine ring and may be hydrogen, halogen, lower (C 1 -C 6) alkoxy, azyl-lower alkoxy, hydroxy, or C (O) -O-alkyl, wherein alkyl is C 1 -C 6 alkyl . The entire pyridinyl group is linked to the indolylalkylaminopropoxy side chain at the pyridine 5 2 position. R represents hydrogen or C (O) L, wherein L is selected from 1 2 C 1 -C 12 alkyl, phenyl, substituted phenyl, or phenylalkyl. R, R, A, and B are independently selected from hydrogen or lower alkyl. C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy. The indooΙ-ΙΟ group itself is preferably linked to the main side chain by its 3-position.

For medical use, the pharmaceutically acceptable acid addition salts are those salts in which the anion makes no significant contribution to toxicity or pharmacological activity of the organic cation. The acid addition salts are obtained by reaction of an organic base of the formula 1 with an organic or inorganic acid, preferably by contact in solution, or by any standard method described in detail in the literature and available to anyone 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, tartaric acid, pamoic acid (4,4 * methylene bis (3-hydroxy-2-naphthoic acid)), cyclamic acid, pivalic acid, and of such; useful inorganic acids are hydrogen halide acids such as HCl, HBr, Hl? sulphuric acid; phosphoric acid; and such. It will also be understood that compounds of the present invention include all optical isomer forms, ie mixtures of enantiomers, eg racemic modifications, as well as the individual enantiomers. These individual enatiomers are usually indicated according to the optical rotation they effect, by (+) and (-), (1) and (d) or combinations of these symbols. The symbols (L) and (D) and the symbols (S) and (R), which represent sinister and rectus, respectively, indicate an absolute spatial configuration of the enantiomer. When no isomer designation is given for a compound, the compound is the racemic modification.

Biological examination of the present compound of formula 1 in animals shows that they have strong vasodilatory properties. 5 ~ r; ö · -, O Ö

J I

-4- together with varying degrees of adrenergic 3-receptor blocking properties and intrinsic sympathomimetic activity. Preferred members of the group have a particularly desirable combination of the above actions and minor pharmacological actions or lack thereof, making them particularly suitable for specific cardiovascular indications, for example, use as antihypertensive agents. The utility of the compounds of formula 1 can be demonstrated in several animal models, including isoproterenol antagonism in intravenously treated anesthetized dogs (adrenergic β-receptor activity), the spontaneous hyper-tensive and DOCA salt hypertensive rats (antihypertensive activity) ), the angiotensin-maintained ganglion-blocked rat model (vasodilatory action), and in several other animal and laboratory models (see Deitchman, et al., Journal Pharmacological Methods, 3, 3-11321, (1980). no evidence of teratogenicity or mutagenicity of the compounds of formula 1 was found.

For use as antihypertensive agents, vasodilators, and / or β-adrenergic blocking agents, therapeutic methods of the invention comprise a systemic administration, by oral or parenteral routes, of an effective, non-toxic amount of a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof. By an effective amount is meant a dose which exerts the desired pharmacological activity such as the above actions, without intolerable toxic side effects when administered to a mammal in need of such treatment. The dosage will vary with the treated living being and the chosen route of administration, expecting a range from about 0.1 mcg to 100 mg / kg body weight of a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof in generally will provide the desired therapeutic effect.

*

The compounds of the present invention can be prepared by an appropriate general method. This method involves coupling a Z-substituted pyridine of formula 4 with a suitable * 35 W-substituted propanol or starting propanol intermediate of formula 2. This general method is shown in scheme A on the for-, -x · λ - -> -? λ

"'J -j' j 0 U

«I -5- muleblad. In this general method, D represents hydrogen or preferably phenyl; G represents the group of formula 5; Z represents hydroxyl or halogen, preferably chloride; state. W for halogen preferably chloride when Z is hydroxyl and for hydroxyl when Z 5 is halogen. Generally, the hydroxy-bearing reactant is first converted to the oxide anion with a strong base before the reaction is carried out with the halogen-bearing intermediate.

In this method, methods known per se for the preparation of 1- (substituted amino) -3 (hetaxyloxy) -2-10 propanols are used, for which reference is made to the patents and publications mentioned in the preamble. The method comprises reacting the appropriately substituted pyridine with either 1) an [3- (indolylalkyl) oxazolidin-5-yl] methanol (or methyl halide) of the formula 2a, or 2) an indolylalkylaminopropanediol or (halopropanol) of the formula 2b, the -15 side 3) glycidol of formula 2c.

The intermediate of the reaction of the compound of formula 4 and the compound of formula 2a is converted into the product of formula 1 by hydrolysis under acidic conditions. This hydrolysis is accomplished with dilute anergenic acid at a concentration of 0.1 to IN at temperatures of about 20 to 100 ° C. The product of formula 1 can be recovered as a free base by neutralizing the hydrolysis mixture and collecting the precipitate. Acid addition salts can be obtained by evaporating the hydrolysis mixture or by reacting the free base with acid. Purification is accomplished by conventional means such as by recrystallization.

The conversion of the epoxide intermediate, which results from the reaction of the compound of formula 4 with the compound of formula 2c, to the product of formula 1 is simply carried out by the epoxy ether either as such or in the presence of a reaction inert heating organic solvent with an amine of the formula H ^ NG as shown. No catalyst or condensing agent 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, dimethyl butyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures range from about 60 to about 200 ° C.

The one-stage process route involves the reaction of the compound of formula 4 and the compound of formula 2b and this is the preferred route for the synthesis of the products of the invention.

This method is illustrated by the specific reaction equation, shown in Scheme B, which shows the preferred synthetic method in reaction 1.

1 2

In scheme B, the symbols X, Y, R, R, R, A, B, and C have the meanings defined in formula 1. The process essentially comprises heating the selected substituted halo pyridine with the appropriate indolylalkylaminopropanol intermediate of formula 2B in the presence of a base, all in an inert organic liquid under mild conditions. Standard strong bases such as potassium tert-butoxide, potassium hydroxide or sodium hydride can be used, but sodium hydride is preferred. Also any of a number of inert organic liquids may be selected as the reaction medium or the cyanopyridine and indolylalkylamino propanol may be reacted as such in the presence of the base. Suitable solvents include, but are not limited to, benzene, toluene, tetrahydrofuran, di-20-butyl ether, dimethoxyethane, etc. Suitable reaction temperatures range from about 20 to 80 ° C. Addition of a suitable crown ether such as 18-crown-6 ether promotes the reaction process.

Products of formula 1 wherein Y and / or C represent hydroxy are prepared by cleavage of the corresponding methoxy precursor as shown in scheme C, which reaction is referred to as reaction 2.

Other synthetic methods which lead to conversion to hydroxylated products, for example hydrogenolysis of benzyloxy precursors, are well known to the chemist and can also be used in these cases.

Required halo pyridines are commercially available or can be prepared by standard methods for their preparation as described in the literature. Preparation of related triple substituted pyridines is described in U.S. Patent 4,329,351, published May 11, 1982, to Baldwin et al., The entire contents of which are hereby incorporated by reference.

The intermediate indolylalkylamino-propanols (formula: ---. Jd <1-7-2b; R stands for hydrogen), which are preferred synthesis intermediates, are conveniently prepared by leaving an appropriately substituted indolylalkylamine of formula III react with 3-chloro-1,2-propanediol in refluxing alcohol containing sodium carbonate.

This process is illustrated in Scheme D by reaction equation 3. In this scheme B, the symbols R ^, Rj, A, B, and C have the meanings defined in formula 1.

Products of formula 1 of the present invention in which R does not represent hydrogen are suitably prepared by treating the corresponding product of formula 1 in which R represents hydrogen with an appropriate acylating agent such as an acyl halide, eg undecanoyl chloride; pivaloyl chloride, benzoyl chloride, paramethoxybenzoyl chloride, or anhydride, for example acetic anhydride and the like. The reaction is illustrated by Scheme E and designated as reaction 4.

The indolylalkylamines of formula 3 are described in the aforementioned patents of Kreighbaum et al. And in the Journal of Medicinal Chemistry article, the contents of which, including certain references cited therein, are to be incorporated by reference. While these referenced procedures are applicable to the preparation of other indolylalkylamine intermediates which are not specifically disclosed therein but are required as intermediates for the present invention, representative syntheses of compounds of formula 3 are given below for further explanation.

The compounds of the present invention can be formulated according to conventional pharmaceutical practice to obtain pharmaceutical preparations in the form of dosage units comprising, for example, tablets, capsules, powders, granules, emulsions, suspensions and the like. The solid preparations containing active ingredient mixed with non-toxic pharmaceutical excipients such as inert diluents, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate? granulating agents and disintegrants, for example, corn, starch, or alginic acid; binders, for example starch, gelatin or acacia; and lubricants, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated according to known techniques to prevent disintegration and absorption in the gastrointestinal tract and thereby sustained action over a longer period of time. to provide.

Liquid preparations suitable for parenteral administration include solutions, suspensions or emulsions of the compounds of formula 1. The aqueous suspensions of the pharmaceutical dosage forms of the compounds of formula 1 contain the active ingredient mixed with one or more non-toxic pharmaceutical excipients known to be suitable for making aqueous suspensions.

Suitable excipients are, for example, suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum transformer, and gum acacia. Suitable release agents or wetting agents are naturally occurring phosphatides, for example lecithin, polyoxyethylene stearate.

Non-aqueous suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example olive oil, sesame oil or coconut oil, or in a mineral oil, for example liquid paraffin. The suspension may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavors commonly used in pharmaceutical preparations may also be included, such as saccharin, sodium cyclamate, sugar and caramel to provide a palatable oral preparation. The compositions may also contain other absorbents, stabilizers, wetting agents and buffers.

The compounds constituting the invention, their method of preparation and their biological actions will become more fully apparent from a consideration of the following examples and the claims, which are illustrative only and are not intended to limit the invention in scope. In the following examples used to illustrate the above-mentioned syntheses, the temperatures are expressed in ° C and the melting points are not corrected. The nuclear magnetic Λ resonance (NMR) spectral properties refer to chemical shifts (S expressed as parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative surface area reported in the H NMR spectral data for the various shifts corresponds to with the number of hydrogen atoms of a given functional *. '' * 'p - r'> ♦ · -9- type in the molecule The nature of the shifts in terms of their multiplicity is indicated as broad singlet (bs), singlet (s), multiplet (m) or doublet (d). Abbreviations used are DMSO-dg (deuterodimethylsulfoxide), CDCl ^ (deuterochloroform) and are further 5. The infrared spectrum data (IS) contain only absorption wave numbers (cm * j with a functional group of identification values The IS assays were performed with potassium bromide (KBr) as a diluent The elemental analyzes are expressed in% by weight.

Synthesis of intermediates.

10 A. Intermediates of formula 3.

Example I

1 2 3- (2-amino-2-methylpropyl) -6-methoxyindole (R = R * methyl; A and B = hydrogen, C = 6-methoxy)

To 15.2 ml of a cooled 25% aqueous solution of di-methylamine were added successively with stirring and continued cooling: 16.9 ml of acetic acid, 7.2 ml of 37% formaldehyde, 27 ml of 95% ethanol. The resulting stirred solution was kept at 0-5 ° C with a cooling bath while adding 10.0 g, 0.07 mole of 6-methoxyindole in portions. This mixture was stirred and gradually heated to 30 ° C over a period of half an hour and then kept at 30 ° C with stirring for 3 hours. The reaction mixture was then cooled to 10-15 ° C and acidified with 170 ml of 2N HCl. This acidic mixture was decolorized (Darco G-60), filtered and the filtrate made basic with 245 ml 20% NaOH while cooling and stirring. A resulting brownish oily precipitate was extracted with ether, and the extracts washed with water, dried over MgSO4 and concentrated to 4 g of a brown oily residue. The residue was recrystallized from isopropyl ether and hexane to obtain 9 g (65%) of 6-methoxygramine as a tan solid with a melting point of 83-90 ° C.

The mixture was heated under reflux for 3 to 5 hours under a nitrogen atmosphere, containing 7.7 g, 0.04 mole of 6-methoxygramine, 26.5 g, 0.03 mole of 2-nitropropane and 1.7 g, 04 mol of NaOH as granules. The reaction mixture was cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ether extracts were washed with water, dried over MgSO4, and concentrated to a residue under reduced pressure. Recrystallization of the residue from isopropyl alcohol-water gave 7.6 g (80%) of 3- (2-methyl-2-nitropropyl) -6-methoxy- - 3 -10- * indole as a tan solid with a melting point of 98-100 ° C.

The nitropropyl indole compound and 4.2 g of activated Raney nickel were combined in 80 ml of 95% ethanol and refluxed. The heating was then terminated in a solution containing 7.8 g of 85%. hydrazine hydrate in 8 ml of 95% ethanol, was added dropwise. The reaction mixture was then refluxed for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated to a residual oil, which slowly solidified and recrystallized from ethyl acetate isopropyl ether to yield 4.2 µg of product, mp 125-128 ° C.

4

Example II

2- (2-amino-2-methylpropyl) indole (R * = R ^ = methyl; a = B = C = hydrogen)

A solution containing 10.0 g, 0.06 mole indole-2-carboxylic acid and 20.0 g 0.17 mole thionyl chloride in 130 ml dry Et 2 O was stirred for 12-18 hours at room temperature under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate concentrated to an oily residue which was taken up in 150 ml dry Et 2 O. This ether solution was treated with 80 ml of dimethylamine in 90 ml of Et 2 O. The ether reaction mixture was concentrated to dryness and the residue was crystallized in isopropyl alcohol. The solid was isolated by filtration to yield 4.0 g (34%) of the 2-indole amide product, mp 181-183 ° C.

The amide was dissolved in 100 ml of THF and this solution was added dropwise under a nitrogen atmosphere to a stirred suspension comprising 3 g of lithium aluminum hydride in 50 ml of THF. After refluxing for two hours, the reaction mixture was cooled and decomposed with a small amount of water and dilute NaOH 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 small excess of dimethyl sulfate. The resulting alcoholic solution was stirred at room temperature for 4 hours and then concentrated under reduced pressure to a dry state to give the trimethylamine quaternary salt as a residue.

3.0 g, 0.01 mole of the crude quaternary salt product is combined with 2.0 g, 0.05 mole of NaOH in the form of granules and 15 ml of 2-nitro [mu] m. -Joo -11- * propane and the mixture was refluxed under a nitrogen atmosphere for one hour. 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 2 O. These Et 2 O extracts were combined / washed with water, dried over MgSO 2, and concentrated to a dark residue which was chromatographed on a silica column and diluted with methylene chloride. Removal of the methylene chloride and recrystallization of the crude from iso-propyl alcohol-water gave 0.4 g of 2- (2-methyl-2-nitropropyl) indole as a cream-colored solid, mp 102-103 ° C.

Reduction of this nitro product with Raney nickel and hydrazine according to the procedure used in Example I gave the desired indolealkylamine as a white solid, m.p. 130-133 ° C.

Additional examples of indole alkyl amines are shown in Table A.

15 TABLE A

Indolealkylamine of formula 3 1 2

Example R R A B_ C_

III Me Η 3-H Me H

20 IV Me Me 2-Me Η H

V Me Me 2-H H 5-Br VI Me Me 2-H H 5-OMe

VII H Me 2-H Η H

VIII Ξ Me 2-Me Me 5-0? R 25 IX H Me 3-Me Me 5-Br X Me Me 2-HH 6-OMe XI Me H 2-Et H 4-Cl XII Me H 2-HH 7- Uncle

B. Intermediates of Formula 2 Example XIII

3 - [[2- (3-indOlyl) -1,1-dimethylethyl] amino] -1,2-propanediol hydrate of formula 2b.

A mixture of 10.0 g 0.05 mol α, α-dimethyl-s- (3-indolyl) ethane-25 amine, 11.3 g, 0.11 mol Na 2 CO 2, 7.0 g 0.06 mole 3-chloro-1,2-propanediol and 250 ml EtOH was refluxed with stirring overnight. After cooling, the mixture was filtered and concentrated under reduced pressure # 3 # -12- third. The residue was dissolved in EtOAc, decolorized (Darco G-60), and evaporated to a volume of 100 ml. The solution deposited a white solid which was recrystallized from EtOAc to give 7.7 g (55%) of a product melting at 112-114 ° C. The material crystallized with 1/5 mol of water.

Using other intermediates of formula 3 in this or a similar procedure, several intermediates of formula 2b could easily be obtained.

Synthesis of products.

Example XIV

2- [2-hydroxy-3 - [[2- (1H-indol-3-yl) -1,1-dimethylethy 1] amino] propoxy] 3-1 pyridine carbonitrile hydrochloride (Y = H; X = CN; R = H, R and R = Me, A, B and C = H Stirring 3 - [[2- (3-indolyl) -1,4-dimethylethyl] amino-1,2-propanediol (47.3 g, .0 , 18 mol) and 7.6 g of a 57% dispersion in oil, 0.18 mol sodium hydride in 2.5 l of toluene and heated under nitrogen atmosphere for 3 hours at 70 ° C. The mixture was then allowed to cool to room temperature while stirring, and 0.5 g of 18-crown-6 ether, 62.1 g, 0.45 mole of K 2 Cl 4 powder and 25.0 g, 0.18 mole 2-chloro-3- were added successively. cyanopyridine to the stirred mixture and then stirred for a further 42 hrs. Concentration to dryness gave a residue which was partitioned between hot H 2 O and EtOAc. After cooling to room temperature, the water layer was separated, washed with additional Et © Ac and this washing liquid combined with the original EtOAc layer The EtOAc solution was dried over MgSO4 and concentrated hot to t 25 about half the volume. After cooling, a solid precipitated and was isolated by filtration to yield about 41 g (62%) of the crude product base.

Conversion of the base to the hydrochloride salt was accomplished by treating a solution of the base in isopropyl alcohol with ethanolic HCl. Recrystallization of the crude hydrochloride salt from absolute ethanol gave a white solid, mp 181-183 ° C.

Analysis calculated for C21H24N4 ^ 2 * SC ^: C'2, ^ 2; 3 '®'29; N, 13.98.

Found: C, 62.85; H, 6.29; N, 14.04.

NMR (DMSO-dJ: 1.30 (6, s); 3.20 '(4, m); 3.99 (3, m); 6.02 (1, od [4.0 Hz]); 7.30 (6, m); 8.31 (1, dd [2.0, 7.6]); 8.51 (1, dd [2.0, 5.6Hz]); o - n - r ~ a * v -13- 8.82 (1, bs), 9.32 (1, bs), 11.27 (1, bs).

IR (Kbr): 750, 1110, 1310, 1440, 1460, 1580, 1588, 2230, 2790, 2980 and 3400 cm -1.

Preparation of the cyclamate salt.

The cyclamate salt could be prepared by treating the crude base as prepared above (2 g crude base) with 1 g cyclamic acid in 50 ml methanol. The methanol solution was heated, filtered and the filtrate was concentrated under reduced pressure to give a residue which crystallized in 10 ml of acetonitrile. Recrystallization of the crude salt from methanol-acetonitrile gave 2.0 g of a white solid, mp 172-174 ° C.

analysis: Calculated for - C21H24N4 ^ 2'C6313N ° 3S: C, 59.65; H, 6.87; N, 12.89.

Found: C, 59.74, H, 6.77; N, 12.82.

Example XV

4- [2-Hydroxy-3 - [[2- (1H-indol-3-yl) -1,1-dimethylethyl] amino-propoxy] -3-pyridine carbonitrile.

Using the procedure of Example XIV and 3 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -1,2-propanediol (10.4 g, 0.04 mol) 20. sodium hydride (1.7 g, 0.04 mol), 550 ml of toluene, 4-chloro-3-cyanopyridine (5.5 g, 0.04 mol), Cf: Wieland and Biener, Chem. Berichte, 96, p. .

268-274 (1963); 18-crown-6 ether (0.11 g) and anhydric K 2 CO 2 (13.7 g, 0.1 mol), 15 g of a gummy material were obtained. The gum was chromatographed on a silica column eluting 25 with 90 parts of methylene chloride, 10 parts of methanol and 1 part of ammonium hydroxide to give two fractions, the second fraction to be eluted gave 6.8 g of gum which was crystallized in ethyl acetate to give 5 g of solid, m.p. 124-126 ° C was obtained.

Recrystallization of this material from ethyl acetate gas 4.2 g of a white solid with a melting point of 126-128 ° C.

Analysis. Calculated for ^ 21 ^ 24 ^ 4 ^ 21 ^ '69, 21; H, 6/64; N, 15.38.

Found: C, 69.42; H, 6.75; N, 15.65.

NMR (DMSO-d.): 1.00 (6, s); 1.55 (l, bs); 2.75 (4, m); 3.90 (1. m); 6 4.27 (2.2 m); 5.10 (1, bs); 7.25 (6, m); 8.64 (1, d [6.0 Hz]); 8.78 (1, s) 35 10.82 (1, bs).

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

-I 'Ί - »- ar» ^: 8 -14-

Example XVI

2- [2-Hydroxy-3 - [[2- (1H-indol-3-yl) -1,1-dimethylethyl 3 amino] propoxy] -3-pyridine carboxamide.

Using a procedure as described in Example IV, 5, 3 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -1,2-propanediol (10.5 g, 0.04 mol) , sodium hydride (1.7 g, 0.04 mol), 400 ml toluene, 2-chloronicotinamide (5.6 g, 0.04 mol), 18-crown-6 ether (0.1 µg) and anhydrous K2Ct ^ 2 powder (* 3.8 g, 0.1 mol) reacted to yield 17 g of a residual gum. The gum 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 in ethyl acetate to obtain 5.2 g of material, mp 68-72 ° C. Recrystallization from ethyl acetate and drying in a vacuum oven gave 4 g of a white solid, mp 131-133 ° C.

Aanlyse. Calculated for 0. c, 65.95; H, 6.86; N, 14.65 Z1 Sun 4 y

Found C, 65.80; H, 6.85; N, 14.31.

NMR (DMSO-d.): 1.03 (6, s); 2.77 (4, m); 3.95 (1.1m); 4.46 (2. m); 52Q 7.20 (6, m); 7.81 (2, bs); 8.30 (2.1 d [6.1 Hz]); 10.85 (1, bs).

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

Example XVII

Conversion of methoxy products to hydroxy products - general procedure. The methoxy product is dissolved in methylene chloride and stirred under a nitrogen atmosphere while kept cold in an ice bath. 3 equivalents of boron tribromide in a methylene chloride solution are added dropwise. After this addition, the ice bath is removed and the reaction mixture is allowed to stir at room temperature for 6-8 hours. Again, the reaction mixture is cooled with an ice bath and excess reagent is decomposed by adding excess H 2 O dropwise to precipitate a gummy material. The supernatant is decanted from the gummy material which is rinsed with 2 portions of water. The gum is dissolved in hot water, treated with activated charcoal (Darco) filtered, the filtrate cooled and made basic with ammonium hydroxide to a pH of about 8. The resulting precipitate is filtered, washed with water, 8 ': S3 φ -15- dried and further purified by column chromatography over silica gel eluting with CHCl 3 (90 parts) -methanol (10 parts) - NH 2 OH (1 part). Concentration of product-containing fractions gives a residue which is recrystallized from ethanol-water to yield pure hydroxy product.

Starting from the appropriate pyridine and indolylalkylamine, additional examples of product of formula 1 can be synthesized according to essentially the same procedures as described above. Some additional products of formula 1 that can be synthesized are shown in Table B. G in the formulas represents the group of formula 5, as determined by the selected intermediate of formula 3 (compare examples 1-12).

TABLE B

15 Example formula Example formula XVIII 12 XXV 19 IXX 13 XXVI 20 XX 14 XXVII 21 XXI 15 XXVIII 22 20 XXII 16 IXXX 23 XXIII 17 XXX 24 XXIV 18

Biological evaluation.

These biological tests were used to gauge the cardiovascular profile of a number of compounds of formula 1 as vasodilators with a range of β-adrenergic blocking activity.

Example XXXI

The effectiveness of antihypertensive agents, other than andrenergic S receptor blocking agents, is generally valued in the spontaneous hypertensive rat. Blood pressure values are determined for laboratory animals before and 24 hours after the oral dose of 50 mg / kg of the test compounds; the observed percentage change in heart rate is also noted. A drop in blood pressure in the ^ 7 ^ 7 g -16- range of 19-24 mm Hg is considered "questionable1. Indications of" active "and" inactive "indicate larger and smaller decrease than said range.

Example XXXII

The angiotensin-maintained ganglion-blocked rat model is used as a test to assess the activity of the vasodilator component. Percent changes in blood pressure in anesthetized rats are determined 30 minutes after intravenous administration. The intravenous administration is performed with 3 mg test compound / kg. Boundary activity is defined as a 15-20% decrease in blood pressure, measured 30 min after administration. Indications of 'active' and 'inactive' indicate larger and smaller decreases than the mentioned range.

Example XXXIII.

Diastolic blood pressure and heart rate responses to a fixed test dose of isoproterenol are obtained before and 15 min after intravenous administration over a 3 min interval to anesthetized step-dose dogs of the test compound. A lateral branch of a thigh artery and vein is connected to a cannula to record blood pressure and to administer the drugs dissolved in saline. The vagias were cut bilaterally in the mid-cervical region of the neck and the dogs were mechanically ventilated (Harvard respirator) with room air at a rate of 20 / min. and a swept volume of 20 ml / kg. Heart rate was monitored with a cardiotachometer agitated by the drops. All measurements are recorded on a Beckmann R-612 recorder. The drug effect is expressed in terms of a cumulative dose (micrograms / kg) causing 50% inhibition of the isoproterenol response.

The following abbreviations used herein have the following meanings: Ph represents phenyl group, Pr represents propyl group, Me represents methyl group, and Et represents ethyl group.

Furthermore, an acceptable convention in modern organic chemistry has been used throughout this description. For alkyl structures, concatenated line segments replace an explicit notation of C and H groups in short designation. For example, Formula 1 can also be described in the form of Formula 1a.

Λ · "· - *" ».- *>” ö - ·. ; -j 0 Ö

Claims (26)

A compound of the formula (I) of the formula sheet, and the acid addition salts thereof, wherein X is selected from the group consisting of -CHO, -CN, -CF-, -CONRaR 3, os Id or -CO 2 R, wherein R and R are independently selected from cc hydrogen or R, and wherein R is a lower alkyl (C 1 -C 12), aryl, or aryl-lower alkyl comb; Y represents a second substituent on the pyridine ring and represents hydrogen, halogen, lower (C 1 -C 6) alkoxy, aryl-lower alkoxy, hydroxy, or -COOalkyl wherein alkyl is C 1 -C 8 alkyl; 10 'the indolylalkylaminopropoxy side chain is linked to the 2 or 4 position of the pyridine group? R represents hydrogen or C (O) L, wherein L is selected from C 1 -C 12 alkyl, phenyl, or phenalkyl; 1 2 R, R, A and B are independently selected from hydrogen or lower alkyl; 15. represents a substituent in the benzo ring of indole, and is selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; and the indolyl system is connected through its 2 or 3 position. The compound of claim 1, wherein the indolylalkylamino-propoxy-side chain is linked to the 2-position of the pyridine group. The compound of claim 1, wherein the indolyl ring is attached at its 3 position. A compound according to claim 2 or 3, wherein X is cyano or amido; 1 2 Y is hydrogen; R is hydrogen; R. and R are lower alkyl; A and B hydrogen; and C represents halogen, hydrogen, hydroxy, alkyl, or alkoxy. The compound of claim 1, which is 2- [2-hydroxy-3 - [[2- (1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy] -3-pyridine carbonitrile or a pharmaceutically acceptable acid addition salt thereof. The cyclamic acid addition salt of the compound according to claim 5. The HCl acid addition salt of the compound according to claim 5. The compound of claim 1, which is 4- [2-hydroxy-3 - [[2- (1H-indol-3-yl) 1,1-dimethylethyl] amino] propoxy] -3-pyridine carbonitrile or a pharmaceutically acceptable acid addition salt thereof. '".33 -18- The compound of claim 1, which is 2- [2-hydroxy-3- [[2-1H-indol-3-yl) 1,1-dimethylethyl] amino] propoxy] -3-pyridine carboxamide or a pharmaceutically acceptable acid addition salt thereof. A method of exerting a vasodilatory effect in a mammal, wherein a mammal having a state in which therapeutic benefit is derived from vasodilation is administered a non-toxic active vasodilator dose of a compound according to claim 1. 11. A method of treating hypertension, wherein a hypertensive mammal is administered a non-toxic anti-hypertensive active dose of a compound according to claim 1. % 12. A pharmaceutical composition in the form of a dosage unit suitable for systemic administration to a mammal, which composition comprises a pharmaceutical carrier and an amount of a compound of Formula 1 according to claim 1, whereby an effective non-toxic dose of 0.1 micrograms to 100 mg / kg of body weight of the host is obtained. Pharmaceutical composition according to claim 12, wherein the compound of formula 1 contains the compound 2 [2-hydroxy-3 - [[2- (1H-indol-3-yl) -1,1,1-dimethylethyl] amino] propoxy] - 3-pyridine carbonitrile or a pharmaceutically acceptable acid addition salt thereof. A pharmaceutical composition according to claim 12, wherein the compound of formula 1 contains the compound 4- [2-hydroxy-3 - [[2- (1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy] -3- pyridine carbonitrile or a pharmaceutically acceptable acid addition salt. of which is. A pharmaceutical composition according to claim 12, wherein the compound of formula 1 contains the compound 2- [2-hydroxy-3 - [[2- (1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy] -3- pyridine carboxamide or a pharmaceutically acceptable acid addition salt thereof. A process for preparing a compound of formula 1 as well as the acid addition salts thereof wherein X is selected from the group consisting of -CHO, -CN, -CF ^, -C0NRaRk, or -CO2RC, wherein Ra and Rb are independently selected cc from hydrogen or R, and wherein R may be lower alkyl (C 1 -C 12), aryl or aryl-lower alkyl; Y represents a second substituent on the pyridine ring and "- n · · * ί l \. S -." · *! * -13- stands for hydrogen, halogen, lower (C 1 -C 6 alkoxy, aryl -lower alkoxy, hydroxy, or COOalkyl wherein alkyl is C 1 -C 8 alkyl; the indolylalkylaminopropoxy side chain is linked to the pyridine 2 or 4 position; 5. represents hydrogen or C (0) L, where L is selected from C -C 1 -alkyl, phenyl, or phenalkyl; 12 1 1U R, R, A, and B are independently selected from hydrogen or lower alkyl; C represents a substituent in the benzo ring of indole and are selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; and the indolyl system is connected through its 2 or 3 position, wherein (a) is a Z-substituted pyridine of formula 4, wherein X and Y are as defined above and wherein Z is hydroxyl or halogen, is coupled with a W-substituted propanol or starting propanol intermediate of formula 2 selected from the group consisting of the formulas 2a, 2b and 2c, wherein D is hydrogen or phenyl and preferably phenyl; G represents the 1 2 group of the formula 5 wherein R, R, A, B and C are as defined above; wherein W is halogen and preferably is chloride when Z represents hydroxyl and blows W is hydroxyl when Z is halogen; and (b) i) when a compound of formula 2a is reacted with a compound of formula 4, the product thereof is then converted to a compound of formula 1 by hydrolysis under acidic conditions; ii) when a compound of formula 2c is reacted with a compound of formula 4, an epoxy ether is formed and a further step is taken, heating this epoxy ether either as such or in the presence of a reaction inert organic solvent with a amine of the formula H 2 NG, wherein G is as defined above to form the compound of formula 1. The process according to claim 16, wherein the compound of formula 2b is used, wherein W is hydroxyl, wherein Z is halogen, and the .7 nu nu J w * J J coupling in step (a) comprises heating a compound of formula 4 with the compound of formula 2b in the presence of a base, all in an inert organic liquid under mild conditions. 18. The method of claim 16, wherein the hydrolysis under acidic conditions uses dilute inorganic acid having a concentration of 0.1-IN and temperatures in the range of about 20-100 ° C, and also performing the step wherein either a) the product of formula I is recovered as a free base by neutralizing the hydrolysis mixture and collecting the precipitate, or (b) the acid addition salts thereof are recovered by evaporation of the hydrolysis mixture or by adding the free base with the acid let them respond. 19. A method according to claim 16, wherein Y and / or C in the products of formula 1 is or are hydroxy, and wherein the compound of formula 2b is used and also the step in which the corresponding methoxy precursor is split by the reaction indicated as reaction 2 is shown in scheme C. 20. A compound of formula 6c as well as its acid addition salts wherein: X is selected from the group consisting of -CHO, -CN, -CF ^, -CONRaR ^, or -CO_RC, wherein Ra and R * 5 are independently selected c c from hydrogen or R and wherein R may be lower alkyl (C 1 -C 12), aryl, or aryl-lower alkyl; Y represents a second substituent on the pyridine ring and represents hydrogen, halogen, lower (C 1 -C 6) alkoxy, aryl-lower alkoxy, hydroxy or -COOalkyl wherein alkyl is C 1 -C 8 alkyl and the indolylalSylamLnopropoxy side chain is linked to the pyridine 2 or 4 position. 21. A compound of the formula 6a as well as its acid addition salt 30 wherein X is selected from the group consisting of = -CHO, -CN, -CF ^, -CONRaRt1, or -CO ^ R0, wherein Ra and Rb are independently selected cc from hydrogen or R and wherein R may be lower alkyl (C 1 -C 6), aryl, or aryl-lower alkyl? & ^ 0 "η ΐ Ë '%> ^ -J tv tj V =» 35. A second substituent on the pyridine ring represents and represents hydrogen, halogen, lower (C ^ -C ^) alkoxy, aryl-lower alkoxy, hydroxy or -COOalkyl in which alkyl is C 1 -C 4 S 4 -D 21- the indolylalkylaminopropoxy side chain linked to the pyridine 2- or 4-position, D is hydrogen or phenyl and preferably phenyl is the group of formula 5 wherein R, R, A and BS are independently selected from hydrogen or lower alkyl? C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy? And the indolyl system is connected by means of its 2 or 3 position. A method of preparing the compound of claim 20, wherein a Z-substituted pyridine of formula 4 wherein X and Y are as defined in claim 20 and wherein Z is hydroxyl or halogen is coupled with a W-substituted propanol or starting propanol intermediate of formula 2a wherein D is hydrogen or phenyl and preferably is phenyl? where G represents the group of formula 5? wherein 1 2 R., R, A and B are independently selected from hydrogen or lower alkyl? C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy; and wherein W is halogen and preferably is chloride when Z represents hydroxyl and wherein W is hydroxyl when Z represents halogen. A process for the preparation of the compound of claim 21, wherein a Z-substituted pyridine of formula 4 wherein X and Y are as defined in claim 21 and wherein Z is hydroxyl or halogen is coupled with a W-substituted propanol or starting propanol intermediate of formula 2c wherein W is halogen, and preferably is chloride when Z represents hydroxyl and wherein W is hydroxyl when Z is halogen. 24. A compound of the formula 2b wherein W is a halogen or hydroxyl group? R is hydrogen or C (O) L wherein L is selected from C 1 -C 6 alkyl, phenyl, substituted phenyl, or phenalkyl, and wherein G represents the formula 1 formula wherein R, R, A and B are independently selected from hydrogen or lower alkyl and wherein C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, lower alkyl, lower alkoxy, or hydroxy. Γ "'” 2' - * - - V v Ö -22- a% 25. Process for the preparation of a compound of formula 2b wherein W is a halogen or hydroxyl group? R represents hydrogen or C (O) L, wherein L is selected from C 1 -C 8 alkyl, phenyl, substituted phenyl, 1 12 or phenalkyl? and wherein G is the group of formula 5 wherein R, R, A and 5. are independently selected from hydrogen or lower alkyl and wherein C represents a substituent in the benzo ring of indole and is selected from hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, wherein 1 2 a compound of formula 3 wherein A, BenR, R and C are as defined above is reacted with 3-chloro-1,2-propane-10 diol in refluxing alcohol and a base which is preferably sodium carbonate. «1» r7 ^ * - * Λ. y J ^ 'J ^ \