DK162089B - 1-PHENOXY-3-HYDROXYINDOLYLALKYLAMINO-2-PROPANOLS AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE - Google Patents

Description

in

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The present invention relates to 1-phenoxy-3-hydroxyindolyl-alkylamino-2-propanols, which compounds can be used as drugs.

There is an extensive amount of prior art available on many series of compounds classified as 3- (aryloxy) -2-hydroxypropylamines. Most of these ranks invoke utility as useful agents in the treatment of cardiovascular disease, especially β-adrenergic receptor blocking activity. Many compounds within this general group also possess a degree of vasodilating efficacy, which is sometimes due to inherent α-adrenergic receptor blocking activity. Various other cardiovascular drug effects or lack of the same cause some of these compounds to appear useful as antihypertensive agents. However, most of the prior art relates to the / J-adrenergic blocking property of these series of compounds. The prototype for structures of this type is propranolol, which is chemically referred to as 1- (isopropylamino) -3- (1-naphthyloxy) -2-propanol. Propranolol and some related naphthyloxy-propanolamines are the subject of U.S. Patent No. 3,337,628 issued August 22, 1967. Numerous subsequent patents have been granted, comprising rows 20 of compounds representing structurally modified 3- (aryloxy) -2-hydroxypropyl amines.

A variety of indol-3-yl tert-butylaminopropanols (1,2) with anti-hypertensive properties were described in Kreighbaum, et al., U.S. Patent No. 4,234,595 issued November 18, 1980, U.S. Patent No. 4,314 .943 issued February 9, 1982 and Journal of Medicinal Chemistry, 23: 3, 285-289 (1980).

O-Ar-Xn 30 08 i1 U) 35 R3 _ | A] -J ^ T "· - (2) i1 2

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In these preceding structural formulas, the symbol R 3 may be hydrogen, halogen, lower alkyl or alkoxy, but not hydroxyl.

A preferred compound encompassed by the general formula (1) is called MJ 13105, also known in the United States under the trivial name bucindolol, 5 and it is currently undergoing clinical evaluation as an antihypertensive agent.

CN

H

MJ 13105 It is of interest to the present compounds that a major metabolic pathway for MJ 13105 involves 6-hydroxylation of the indole ring. This was confirmed by comparing the metabolic solvents with the synthetically available corresponding 6-hydroxyindolyl compound of the present invention.

The compounds of formula (I) of the invention have 2-4 times stronger α-adrenergic receptor blocking activity than those described in U.S. Patent No. 4,234,595 and are thus more useful as antihypertensive agents.

The present invention comprises the compounds of formula (I) 25 and acid addition salts of these compounds.

1 CN

(I) In the preceding structural formula, R 3 and R 4 are independently selected from hydrogen and C 1-6 alkyl, and the hydroxyl group occupies the 4-, 5-, 6- or 7-position of the indole ring. In preferred compounds, R 3 and R 4 are methyl. The compounds of the present invention are useful as

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3 anti hypertensive agents, in part due to a combination of adrenergic receptor blocking and vasodilatory properties.

For medical use, the pharmaceutically acceptable acid addition salts are preferred, those salts in which the anion does not significantly affect the toxicity or pharmacological activity of their organic cation. The acid addition salts are obtained either by reacting an organic base of formula (I) with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods described in the literature and available to any person skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic, acetic, tartaric, propionic, fumaric, isethionic, succinic, pamoic, cyclamic, pavalic and the like; useful inorganic acids are hydrogen halide acids such as HCl, HBr, HI, sulfuric acid, phosphoric acid and the like.

It is to be understood that the compounds of the present invention comprise all optical isomeric forms, i.e. mixtures of enantiomers, for example racemic modifications, as well as the individual enantiomers. These individual enantiomers are generally denoted by the optical rotation they effect by (+) and (-), (1) and (d) or combinations of these symbols. The symbols (L) and (D) as well as the symbols 20 (S) and (R), which represent sinister and rectus respectively, denote an absolutely spatial configuration of the enantiomer. Where no isomer designation is given for a compound, the compound is the racemic modification.

The individual optical isomers of the group of aryloxypropanolamine derivatives to which the present compounds belong are most commonly obtained by one of four basic methods. These are: 1) fractional recrystallization from chiral acid-salt derivatives, 2) derivatization with a chiral-organic reagent, cleavage and regeneration of the optically active form, 3) synthesis of the 30 single optical isomers using of chiral intermediates, and 4) column chromatography using chiral stationary phases. Applications of these various methods are well known to those skilled in the art.

Biological testing of representative examples of compounds of the general formula (I) in animals shows that they possess biological properties which should make them useful as anti hypertensive agents. In addition to the antihypertensive activity that can be detected in animal testing, the present compounds also possess vasodilating properties along with varying degrees of adrenergic α and β receptor blocking properties.

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4 and accompanying sympathomimetic activity. A more detailed description of the specific pharmacological tests used and the criteria used to assess the current biological activity can be found in the later section entitled "Biological Assessment". Preferred representative compounds have a particularly desirable combination of the foregoing effects, and pharmacological side effects or lack thereof, which make them particularly suitable for specific cardiovascular indications, for example use as anti-hypertensive agents. The utility of the compounds of formula (I) can be demonstrated in the above-mentioned different animal models, which include antagonism of isoproterenol in the intravenously treated anesthetized dog (adrenergic / receptor activity), the spontaneous hypertensive and DOCA salt hypertensive rat. (anti-hypertensive effect), the angiotensin-maintained ganglion-blocked rat model (vasodilatory effect) and an anesthetized rat model (α-15 adrenergic blockade), and in various other animals (laboratory models) (cf. Deitchman, et al., Journal Pharmacological Methods, 3, 311-321 (1980)).

As examples, two of the representative compounds of formula (I), namely 2- [2-hydroxy-3 - [[2- (6-hydroxy-1H-indol-3-20 yl) -1,1-dimethylethyl] amino ] propoxy] benzonitrile and 2- [2-hydroxy-3 - [[2- (5-hydroxy-1H-indol-3-yl) -1,1-dimethyl ethyl] amino] propoxy] -benzonitrile, more than 20 mmHg mean systolic blood pressure in rats in one or both anti hypertensive tests when administered at a dose level of 30 mg / kg po A 3 mg / kg intravenous dose of these 25 compounds resulted in more than a 20% decrease in mean arterial blood pressure (measured 30 minutes after dosing) in the vasodilation test.

For use as anti-hypertensive agents, vasodilatory agents and / or adrenergic blocking agents, an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof is administered systemically, by both oral and parenteral route. An effective amount is to be understood as a dose exerting the desired pharmacological effect, such as those set forth above, without undesirable toxic side effects when administered to a mammal in need of such treatment. Do-35 sis will vary depending on the individual and the chosen route of administration with an expected interval of approx. 0.1 µg to 100 mg / kg body weight of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof to provide the desired

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5 stage therapeutic effect. A preferred range for an effective dose will be approx. 0.1 to 0.5 mg / kg administered intravenously and ca.

0.5 to 5 mg / kg given orally.

The compounds of the present invention can be prepared by a convenient general method. This procedure is shown below in Scheme 1.

Throughout the present specification, Me represents a methyl group and the Ac acetate, C2H302-.

10 Scheme 1 15 + ^

H

(IV) (III) * 20 r4 R3 rar

OH V

H

(II) 25

R3 R4 H

(I) wherein R3-R4 have the above meanings.

35

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6

This process involves coupling an appropriate methoxylated indole alkylamine (III) with 2 - [(2,3-epoxy) propoxy] benzonitrile (IV). The principles of synthesis necessary to reach this point in the preparation of compounds of formula (I) are analogous to a synthesis process used to prepare bucindolol, cf. U.S. Pat.

4,234,595 and 4,314,943 and J.Med.Chem., 23: 3, 285-289 (1980). However, an additional step is necessary since the resulting methoxylated indole analog (II) is converted to the desired (I) compound by cleavage of the methoxy group with boron tri bromide in methylene chloride solution. Other synthesis methods that result in conversion to hydroxylated products, for example, such as hydrogenolysis of benzyloxy precursors, are well known to the chemist and may also be adapted for use in a modified process.

The coupling of the epoxy ether intermediate (IV) with indolylalkylamine 15 (III) to form the intermediate (II) is performed simply by heating the epoxy ether either purely or in the presence of an inert organic solvent with a suitable indolylalkylamine as shown. No catalyst or condensing agent is usually required. Suitable solvents include 95% ethanol, but other organic inert liquids in which the reactants are soluble may be used. These may include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxydene, ethylene glycol, etc. Suitable reaction temperatures are from ca. 60 to approx. 200 ° C.

The intermediates necessary for the reaction (III) and (IV) can be obtained by several methods which are not limited to the following. The intermediate (IV) can be obtained by alkylation of 2-cyano-phenol (V) with epichlorohydrin as shown in Scheme 2 or in particularly complicated cases using epibromohydrin, K 2 CO 3 and dimethylformamide.

Scheme 2 (v) (IV)

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7

Although many cyanophenols (V) are commercially available, they can also be conveniently prepared from readily available phenol via the synthesis shown in Scheme 3.

5 Scheme 3

_. cho Λ CH = NOH

a.s- α .- = a.

10 ac2o 15

CN

oc.

(V) 20

This sequence essentially involves the formylation of phenol according to Reimer-Tiemann conditions to form the salicylaldehyde derivative which, via the oxime intermediate, is converted to the desired sal in -cylonitrile (V).

With respect to the indolylal chylamine intermediates of formula (III), typical synthetic methods for their preparation can be found in the above-mentioned patents of Kreighbaum, et al., And the article in J.Med.

Chem. While these mentioned methods can be used to prepare other ndolylal kylamine intermediates which may be desirable but not specifically described therein, representative syntheses of compounds of formula (III) will be given below for further exemplification of intermediates which may be necessary for the present invention.

Finally, it is of interest that a 6-hydroxyindolyl compound of formula (I) (2- [2-hydroxy-3 - [[2- (6-hydroxy-1H-indol-3-yl) -1,1] -dimethylethyl] amino] propoxy] benzonitrile) structurally similar to bucindolol (R3 and R4 are methyl) was used to confirm the identity of a major metabolite for bucindolol. It is known that 6-hydroxyl

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8 ring may be more important than 5-hydroxylation in the metabolism of tryptamine derivatives (cf. Jepson, et al., Biochim.Biophys.Acta. 62, 91 (1962), Jaccarini and Jepson, Biochim.Biophys. Acta., 156, 347 (1968)).

This knowledge suggested that 6-hydroxylation of bucindolol could be an important metabolic pathway. This has been confirmed by demonstrating that this 6-hydroxyindolyl compound of the present invention matches in mass spectrum and gas chromatographic retention time with a corresponding major hydroxymetabolite for bucindolol. In this regard, the present invention comprises 2- [2-hydroxy-3 - [[2- (6-hydroxy-10H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy] benzonitrile on purified pharmaceuticals acceptable form.

The invention also relates to unit dosage pharmaceutical compositions suitable for systemic administration to a mammal or human, comprising a pharmaceutically acceptable carrier and an antihypertensive effective but non-toxic dose of a compound of formula (I).

The compounds of formula (I) of the present invention may be formulated in accordance with conventional pharmaceutical practice to provide unit dosage pharmaceutical compositions comprising, for example, tablets, capsules, powders, granules, emulsions, suspensions and the like. The solid compositions contain the active ingredient in admixture with non-toxic pharmaceutical excipients such as inert diluents, e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, e.g., 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 in known manner to the delay of digestion and absorption in the gastrointestinal tract, thereby providing a lasting effect over a prolonged period of time. Liquid preparations suitable for parenteral administration include solutions, suspensions or emulsions of the compounds of formula (I). The aqueous suspensions of the pharmaceutical dosage forms of the compounds of formula (I) contain the active ingredient in admixture with one or more non-toxic pharmaceutical excipients known to be useful in the preparation of aqueous suspensions. Suitable excipients are, for example, suspending agents such as sodium carboxymethyl cellulose, methyl cellulase, hydroxypropylmethyl cellulase, sodium alginate, polyvinylpyrrolidone,

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9 gacanth gum, and acacia gum. Suitable distribution or wetting agents are naturally occurring phosphatides, for example, lecithin, polyoxyethylene stearate.

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

The compounds, their preparation and biological effects are set forth in the following examples. In the following preparation examples, temperatures are expressed in eC and melting points are not corrected. The values of the nuclear magnetic resonance spectra (NMR) refer to chemical shift values (6) expressed as parts per minute. million (ppm) versus tetramethylsilane (TMS) as standard reference. The relative area indicated for the different shift values in the spectral H20 NMR data corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the switches in terms of multiplicity is reported as broad singlet (bs), singlet (s), muli ti pi et (m) or doublet (d). Abbreviations used are DM $ 0-d6 (deuterodimethylsulfoxide), CDC13 (deuterochloroform), and are otherwise conventional. The 25 infrared spectral descriptors (IR) comprise only absorption wave numbers (cm- *) with functional group of identification value. IR determinations were made using potassium bromide (KBr) as diluent. The elemental analyzes are reported as weight percentages.

Synthesis of Intermediates A. Intermediates of Formula (III): General Methods

Example 1 Methoxyindol-3-yl tert-butylamine

To 15.2 ml of a cooled 25% aqueous solution of dimethylamine was added in sequence with stirring and continued cooling: 16.9 ml of acetic acid, 7.2 ml of 37% formaldehyde, 27 ml of 95% ethanol. The

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10 resulting stirred solution is maintained at 0 to -5 ° with a cooling bath, while the appropriate methoxyindole (10.0 g, 0.07 mol) is added in portions. This mixture is stirred and heated gradually to 30 ° over a period of ½ hour and then kept at 30 ° with stirring for 35 hours. Next, the reaction mixture is cooled to 10 to 15 ° and acidified with 170 ml of 2N HCl. This acidic mixture can be decolorized ("Darco G-60"), filtered, and the filtrate made basic using 245 ml of 20% NaOH with cooling and stirring. A resulting brown oily precipitate is extracted with ether and the extracts are washed with water, dried (MgSO 4) and concentrated to a brown oily residue (14 g). For example, this residue is recrystallized from isopropyl ether and hexane to give the desired methoxygramine, usually as a tan solid.

A mixture consisting of the appropriate methoxygramine (7.7 g, 0.04 mole), 2-nitropropane (26.5 g, 0.3 mole) and NaOH (1.7 g tablets, 0.04 mole) is refluxed under a nitrogen atmosphere for 3 to 5 hours. Next, the reaction mixture is cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ether extracts are washed with water, dried (MgSOJ and concentrated in vacuo to give a residue. Recrystallization of the residue, for example from isopropyl alcohol, gives a 3- (2-methyl-2-nitropropyl) methoxy-indole.

This nitropropylindole compound and activated Raney nickel (4.2 g) are combined in 80 ml of 95% ethanol and heated to reflux.

Heating is maintained by adding a solution of 85% hydrazine hydrate (7.8 g) in 8 ml of 95% ethanol. Next, the reaction mixture is heated to reflux for 2 hours, cooled to room temperature and filtered. The filtrate is concentrated to an oily residue which can be recrystallized, for example from ethyl acetate-isopropyl ether to give the desired methoxyindol-3-yl-t-bond.

Example 1a 6-Methoxyindol-3-yl tert-butylamine 35 A mixture of 6-methoxygramine (0.9 g, 0.004 mol, prepared from 6-methoxyindole by the procedure of Example 1), 3.0 g ( 0.034 mole) of 2-nitropropane and 0.19 g (0.005 mole) of NaOH tablets were stirred under reflux in an oil bath under a nitrogenate atmosphere for 2 hours, with dimethylamine escaping through the capacitor.

The resulting mixture was cooled to 25 °, treated with a solution of 0.47 ml glacial acetic acid in 4.1 ml water and extracted with ether. The ether extract was washed with 3 portions of water, dried 5 (MgSO 4) and evaporated to dryness. The remaining brown oil crystallized by rubbing and cooling in a small amount of isopropyl ether. The solid was solubilized by filtration, washed with cold isopropyl ether and dried in air to 0.6 g of tan solid which was recrystallized from isopropyl alcohol (0.52 g) (46%) 3- (2-10 methyl). 2-nitropropyl) -6-methoxyindole, m.p. 98 to 99®.

A slurry of 8.0 g (0.32 mol) of the nitro compound as prepared above, 80 ml of 95% ethanol and 4.2 g of Raney nickel (washed with water and 95% ethanol) was heated to reflux with paddle stirring. Outer heating was maintained and a solution of 7.8 g of 85% hydrazine hydrate in 8 ml of 95% ethanol was added dropwise at a rate sufficient to maintain a gentle reflux. After the addition, the mixture was heated to reflux for 2 hours and cooled to 25 °. Filtration and concentration to dryness gave a crude syrup which was chromatographed on silica gel column eluting with CH 2 Cl 2 -CH 3 OH concentrated NH 4 OH (90: 10: 1). The tan solid thus obtained (2.9 g, m.p. 125 to 128®) was recrystallized from ethyl acetate-isopropyl ether to give 1.27 g (18%) of 6-methoxyindol-3-yl-tert-butylamine, m.p. 125 to 128®.

B. The intermediate of formula (IV)

Example 2 2 - [(2,3-Epoxy) propoxy] benzonitrile A solution of 2-cyanophenol (25.0 g, 0.21 mol), epichlorohydrin (117 g, 0.26 mol) and piperidine (10 drops) were stirred and heated at 115 to 120 ° in an oil bath for 2 hours. Next, the mixture (90® / 30 Torr.) Was concentrated to remove unreacted epichlorohydrin. The residue was diluted with toluene and concentrated twice to dryness to aid in removing the last traces of volatile matter. The residual oil was dissolved in 263 ml of tetrahydrofuran and this solution was stirred at 40 to 50 for 1 hour with 263 ml of 1N NaOH. The organic layer was separated and concentrated to form

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12 of an oil which is combined with the aqueous phase. The mixture was extracted (CH 2 Cl 2), the extract dried (MgSO 4) and concentrated to give 36.6 g (100%) of oil which slowly crystallized to a waxy solid. This intermediate can be used without further purification in the preparation of compounds of formula (I).

Synthesis of compounds of the invention

Example 3 General Procedure: 2- [2-hydroxy-3 - [(hydroxyindolyl) alkylamino] propoxy] benzoni tri

A selected methoxyindolylalkylamine (III) is mixed with an equimolar or slightly excess amount of the epoxy propoxybenzonitrile (IV), and the coupling occurs either by refluxing a solution of the reactants for approx. 18 to 24 hours or by heating a pure mixture at a temperature of approx. 120 to 130 ”for approx. k to 2 hours. Ethanol and toluene are the commonly selected solvents for the reaction medium for coupling via refluxing a solution of (III) and (IV). In some cases, it is advantageous to follow the course of the reaction by TLC with the addition of additional (IV) epoxide until all indolylamine (III) has disappeared. After the reaction, the mixture is concentrated to dryness and the residue is either washed and used crude in the next step, or the methoxy intermediate can be purified by crystallization recrystallization either as the base or a suitable acid addition salt.

A solution of the methoxyindolyl product (II) is dissolved in methylene chloride and stirred under a nitrogen atmosphere at 0 to 10 °, while several times excess of 1N boron tribromide in methylene chloride is added dropwise. After addition, the reaction mixture is stirred at room temperature for approx. 6 to 8 hours. Excess boron tribromide is broken down by cooling the reaction mixture and adding excess water dropwise. The crude hydrobromide salt of formula (I) can be worked up in a number of conventional ways such as recrystallization, conversion to the base and purification, conversion to the base followed by conversion to another acid addition salt ·, etc.

The modifications necessary to adapt this process to prepare specific compounds of formula (I) are of skill to a chemist.

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13

Example 4 2- [2-Hydroxy-3 - [[2- (6-hydroxy-1H-indol-3-yl) -1,1-dimethyl ethyl] amino] propoxy] benzonitrile A solution of 6-methoxyindole 3-yl-t-butylamine (2.6 g, 0.012 mol, prepared in Example 1a), 2 - [(2,3-epoxy) propoxy] benzonitrile (2.1 g, 0.012 mol, prepared in Example 2) and 100 ml of absolute ethanol was stirred at reflux for 20 hours. Additional epoxide (0.21 g) was added and reflux was continued for 4 hours, after which the mixture was concentrated to dryness and the residue triturated in isopropyl alcohol to give crystallization. The product was collected by filtration, washed with cold isopropyl alcohol and dried in air to give 4.0 g (85%) of the methoxy product (II), mp 145 to 146 *, used directly in the next step.

A solution of the above-prepared methoxyindole product (1.5 g, 0.004 mol) in 225 ml of methylene chloride was stirred under a nitrogen atmosphere at 5 to 10 ° while 15.3 ml (0.015 mol) of 1M boron tribromide in methylene chloride was added dropwise. . After the addition, the ice bath was removed and the reaction mixture was stirred at 25 'for 6 hours before cooling to 5 to 20 10 * and dropwise addition of 47.5 ml H 2 O. The resulting mixture was decanted and the remaining rubbery solid was rinsed with 2 portions of H2 O. Dissolving this crude hydrobromide salt in 50 ml of hot H2 O followed by treatment with "Darco G-60", filtration, cooling (25 °) and basification (pH 8) with concentrated NH 4 OH gave 1.2 g of a tan colored amorphous solid, was chromatographed (silica gel 60, 230 to 400 mesh, EM reagents) on a chloroform-methanol-concentrated NH 4 OH (90: 10: 1) medium pressure system. The product thus obtained crystallized from a small amount of 95% ethanol to form, by the gradual addition of H 2 O, 1.03 g (71%) of the desired 6-hydroxyindole product (I) as a tan solid, m.p. 90 to 94 °.

Analysis. Calcd for C22H25N3O3.1 / 3H2O: C, 58.56; H, 6.67; N, 10.90; H2 O, 1.54.

Found: C, 68.69; H, 6.68; N, 10.68; H2 O, 1.80.

NMR (DMSO-d 6): 0.98 (6, s); 2.70 (4, m); 3.30 (2, bs); 3.83 (1, m); 4.11 (2, d [5.8 Hz]); 5.00 (1, bs); 6.65 (3, m); 7.20 (3, m); 7.60 (2, m); 8.71 (1, bs); 10.35 (1, bs).

IR (KBr): 760, 800, 1260, 1290, 1450, 1495, 1600, 1630, 2230 and 3300 cm -1.

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14

Example 5 2- [2-Hydroxy-3 - [[2- (5-hydroxy-1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxy] benzoni tri methoxyindol-3-yl-t-butylamine (2.7 g, 0.0125 mol, prepared from 5-methoxyindole using the procedure of Example 1), 2 - [(2,3-epoxy) propoxy] benzonitrile (2 , 2 g, 0.0125 mol) and 20 ml of acetone reflux for ½ hour. The acetone used as the solvent was then allowed to boil and the oily residue was heated at 100 ° C for 2 hours. Isopropyl alcohol (20 ml) was added and the reaction solution was refluxed for 4 hours, then cooled to room temperature, diluted with 50 ml of ether and a stirring bar used to pour a white powder, 4.7 g (96%), mp 119 to 124 °; TLC (9: 1 CHCl3-methanol) shows a single spot, R f 0.25.

This crude methoxy product can be used directly in the next step or can be purified via conversion to the HCl salt. Conversion to the HCl salt by treating an acetonitrile solution with ethanol in HCl gives a crude product which is recrystallized in butanone-95% ethanol (20: 1) to an off-white powder, mp 164 to 166®.

Analysis. Calcd for C 23 H 27 N 3 O 3 · HCl: C, 64.25; H, 6.56; N, 9.77.

Found: C, 64.14; H, 6.54; N, 9.68.

Using the procedure of Example 4 above with respect to the off-bromide cleavage of the methoxy group, but using the 5-methoxyindole intermediate product (II) prepared above, the desired 5-hydroxyindole product (I) in the form of its hydrobromide salt is obtained.

The pure hydrobromide salt is a beige colored powder, mp 219 to 221 °.

Analysis. Calcd for C 22 H 25 N 3 O 3 • HBr: C, 57.40; H, 5.70; N, 9.13.

Found 56.90; H, 5.67; N, 9.45.

NMR (DMSO-d6): 1.32 (6, s); 3.08 (2, m); 3.36 (2, m); 4.30 (3, m); 5.90 (1, bs); 7.10 (6, m); 7.71 (2, m); 8.55 (3, bs); 10.95 (1, bs).

IR (KBr): 750, 800, 1265, 1290, 1455, 1495, 1580, 1600, 2230 and 3333 cm.

Biological assessment

These biological tests are used to determine the anti-hyper-

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15 tensive profile of selected compounds of formula (I).

Example 6 The effectiveness of anti-hypertensive agents other than adrenergic 5β-5β-ββ blocking agents is normally assessed in the spontaneously hypertensive rat. Etodic pressure values are determined for test animals before and 2 and 4 hours after oral doses of 30 to 1Φ0 mg / kg of test compounds. The heart rate is also determined for each pressure measurement. A drop in blood pressure 2 or 4 hours after the single dose in the range of 15 to 20 mm Hg 10 is considered "questionable". "Active" and "inactive" designations are reductions which are slightly larger and smaller than this range.

Example 7

An arade test useful for determining the efficacy of anti-hypertensive agents uses DOCA salt hypertensive rats. These hypertensive rats are prepared as follows: male Sprague-Dawley strain rats weighing approx. 90 g are placed individually in cages with free access to feed and water for a 5 day pre-treatment period, after which the drinking water is replaced by 1% saline solution. For a 3 week treatment period 20, the rats are administered a total of 10 subcutaneous injections containing 10 mg of DOCA (deoxycorticosterone acetate) in 0.2 ml suspension vehicle (0.25% "Tween 80" and 0.125% CMC in normal saline solution). After the last injection, the 1% saline is replaced by distilled water and the animals are ready for use 1 week later.

The test is performed by selecting non-fasted animals with elevated systolic blood pressure (> 160 mmHg). Blood pressure values are determined for these test animals before and 4 hours after oral doses of 30 to 100 mg / kg of the test compounds. During the test period, the animals are placed in metabolism cages without feed or water and urine is collected for 4 hours. Heart rhythm and body weight 30 are both equally determined at each pressure measurement. A drop in blood pressure 4 hours after dosing, which is in the range of 15 to 20 mmHg, is considered "questionable". "Active" and "inactive" designations are reductions larger and smaller than this range.

Example 8

The angiotensin (II) supported ganglion-blocked rat model is used as a screening test to assess the direct vasodilator activity component. Percentage changes in blood pressure in anesthetized rats

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Determine 30 minutes after intravenous dosing. The intravenous dosing is done with test compound at 3 mg / kg. The boundary activity is defined as approx. a 10% decrease in blood pressure measured 30 minutes after dosing. "Active11 and" inactive "provisions are increases greater and 5 smaller than this.

Example 9

Rats (Wistar males) are anesthetized with a combination of urethane and chloral ase intraperitoneally. Following induction of anesthesia, 10 chlorisone diamine is injected into the peritoneal cavity to induce ganglion blockade. One femoral artery was provided with a cannula for measuring blood pressure and heart rate, and two femoral veins were equipped with a cannula for administering compounds. Trachea was intubated and rats were given the opportunity to breathe spontaneously. Animals were attacked before and 15 minutes after intravenous administration of the graduated dose of phenylephrine and the changes in blood pressure were recorded. The results were plotted to obtain dose-response curves and the dose of phenylephrine required to induce a 50 mmHg (ED50) increase in blood pressure was interpolated from the curves. Dose switching is calculated by dividing the ED50 value after 20 administration of active substance by the ED50 value before active substance.

Table 1 ----------- H3C CH3 H OH / -

CN

α-adrenergic receptor blocker (Example 9) Compound No. R (dose change) 1 H 5 ± 0 2 5-0Me 8.1 ± 1.7 3 5-OH 12 ± 1 4 6-OMe 5.9 ± 0 , 7 35 5 6-OH 23 ± 1

Claims (6)

A compound according to claims 1 to 2, characterized in that the hydroxy group occupies the 6-position of the indole ring. 4. A compound according to claim 3, characterized in that it is 2- [2-hydroxy-3 - [[2- (6-hydroxy-1H-indol-3-yl) -1,1-dimethylethyl] amino ] propoxy] benzonitrile. 5. A compound according to claim 2 characterized in that it is 2- [2-hydroxy-3 - [[2- (5-hydroxy-1H-indol-3-yl) -1,1-dimethyl ethyl] amino ] propoxy] leg zonitril. 6. A unit dose pharmaceutical composition suitable for systemic administration to a mammal or human being, characterized in that it comprises a pharmaceutically acceptable carrier and an antihypertensive but effective non-toxic dose of a compound of formula (I) according to claim 1. Pharmaceutical composition according to claim 6, characterized in that the compound of formula (I) is 2- [2-hydroxy-3 - [[2- (6-hydroxy-1H-indol-3-yl) - 1,1- dimethylethyl] ami no] propoxy] benzoni tri 1. Pharmaceutical composition according to claim 6, characterized in that the compound of formula (I) is 2- [2-hydroxy-3 - [[2- (5-hydroxy-1H-indol-3-yl) -35,1- dimethylethyl] amino] propoxy] benzonitrile.