NO164471B - ANALOGUE PROCEDURE FOR PREPARING 1-PHENOXY-3-HYDROXYINDOLYLALKYLAMINO-3-PROPANOLS. - Google Patents

Description

The present invention relates to the production of therapeutically active heterocyclic carbon compounds in the indole series with an amino substituent.

More specifically, the invention relates to an analogue method for the production of therapeutically active 1-phenoxy-3-hydroxy-indolylalkylamino-3-propanols.

There is an extensive prior art regarding many series of compounds classified as 3-(aryloxy)-2-hydroxypropylamines. Most of these ranges are claimed to be useful in the treatment of cardiovascular diseases, especially with e-adrenergic receptor blocking action. Many compounds within this general group also have a vasodilating effect to a certain extent, which in some cases is due to cx-adrenergic receptor blocking action. Various other cardiovascular drug effects or lack thereof combine to make some of these compounds appear useful as antihypertensive agents. However, most of the prior art concerns the e-adrenergic blocking properties of these series of compounds. The prototype for structures of this type is propranolol with the chemical name 1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol. Propranolol and some related naphthyloxy-propanol amines are disclosed in US-PS 3,337,628. Numerous subsequent patents have been granted covering a wide range of compounds representing structurally modified 3-(aryloxy)-2-hydroxypropylamines.

A number of indol-3-yl-tert-butylaminopropanols (1,2) with antihypertensive action are described in US-PS 4,234,595, 4,314,943 as well as in "Journal of Medicinal Chemistry", 23:3, 285-289 (1980 ).

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

A preferred compound covered by the general formula (1) is called MJ 13105 and in the USA also goes by the trivial name bucindolol, and the compound is currently subject to clinical evaluation as an antihypertensive agent.

MJ 13105

It is of interest with respect to the present compounds that a major metabolic pathway for MJ 13105 involves 6-hydroxylation of the indole ring. This has been confirmed by comparing metabolic isolates with the synthetically available corresponding 6-hydroxyindolyl compound which is produced according to the present invention.

Attention should also be drawn to US-SN 414 748 which deals with a number of vasodilating agents with a certain extent of β<->adrenergic blocking action and with the structural formula (3).

Although C in the preceding structural formula (3) can be hydroxyl among other substituents, this series of compounds can usually be distinguished from the present invention in that the compounds of formula (3) are pyridinyloxypropanol amines.

As indicated above, the present invention accordingly relates to compounds of formula (I)

and acid addition salts thereof, there

one of R<*> and R<2> is hydrogen and the other is hydrogen or C^_4-alkyl, preferably hydrogen, R<3> and R<4> are independently selected from hydrogen or C^_4-alkyl, preferably methyl, and R5 means halogen, hydrogen, hydroxy or C1-4-alkyl, preferably hydrogen or 5-fluorine, the phenoxypropanol-aminoalkyl side chain being attached to the indole ring in either the 2- or 3-position, preferably in the 3-position, and

the hydroxy substituent group occupies either the 4-, 5-, 6- or 7-position of the indole ring, preferably the 6-position.

The compounds obtained according to the invention are useful as antihypertensive 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 where the anion does not significantly affect the toxicity or the pharmacological properties of the organic cation. The acid addition salts are obtained either by reaction of 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 which are 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 HC1, HBr, HI, sulfuric acid, phosphoric acid and the like.

The individual optical isomers of the group of aryloxy-propanolamine derivatives to which the present compounds belong have most often been obtained by one of four principle methods. These are: 1) fractional recrystallization from chiral acid-salt derivatives, 2) derivatization with a chiral-organic reagent, cleavage and regeneration of the original compound in optically active form, 3) synthesis of the individual optical isomer using 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 general formula (I) in animals shows that they have biological properties that would make them useful as antihypertensive agents. Besides the antihypertensive effect which can be demonstrated in animal testing, the present compounds also have vasodilatory properties together with varying degrees of adrenergic a- and e-receptor blocking properties as well as accompanying sympathomimetic action. A more detailed description of the specific pharmacological tests used and the criteria used to assess the relevant biological activity can be found below. Preferred representative compounds have a particularly desirable combination of the above-mentioned effects and the pharmacological side effects or lack thereof which make them particularly suitable for specific cardiovascular indications, for example use as antihypertensive agents. The utility of the compounds of formula (I) can be demonstrated in the various animal models mentioned above, which include antagonism of isoproterenol in the intravenously treated anesthetized dog (adrenergic 3-receptor action), the spontaneous hypertensive and DOCA-salt hypertensive rat (antihypertensive action), the angio -tensin-maintained ganglion-blocked rat model (vaso-dilatory effect) and an anesthetized rat model (α-adrenergic blockade) as well as 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-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 mm Hg mean fall in systolic blood pressure in rats in one or both antihypertensive tests at a dose level of 30 mg/kg p.o. A 3 mg/kg intravenous dose of these compounds resulted in more than a 20% fall in mean arterial blood pressure (measured 30 minutes after dosing) in the vasodilation test.

For use as hypertensive agents, vasodilator 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 both orally and parenterally. An effective amount is to be understood as a dose which constitutes the desired pharmacological effect such as those indicated above, without undesirable toxic side effects when administered to a mammal in need of such treatment. The dose 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 therapeutic effect. A preferred interval for an effective dose would be approx. 0.1 to 0.5 mg/kg is administered intravenously and approx. 0.5 to 5 mg/kg is administered orally.

The compounds of formula (I) are prepared according to the invention by

i) connects a methoxylated indolealkylamine of formula (III)

where R<1>, R<2>, R3 and R<4> have the above meaning, with an R^ substituted phenoxyepoxide (IV)

where r<5> has the above meaning,

by heating (III) and (IV) either without a solvent or in the presence of an organic solvent inert for the reaction to form an intermediate product (II)

where R<1>, R<2>, R<3>, R<4> and R<5> have the above meaning,

li) reacts the intermediate (II) under suitable conditions for cleavage of the methoxy group to a hydroxyl group, preferably by reaction with boron tribromide in methylene chloride solution to form a compound of formula (I), and

ili) if desired, to obtain a pharmaceutically acceptable acid addition salt of a compound of formula (I), convert the compound from step (II) into the corresponding salt in a manner known per se.

This procedure involves the coupling of an appropriately methoxylated indolealkylamine (III) with an R<5-> substituted phenoxyepoxide intermediate (IV). The synthesis principles necessary to reach this point in the preparation of compounds of formula (I) are analogous to a synthesis process used for the preparation of bucindolol. However, a further step is necessary when the resulting methoxylated indole analogue (II) is converted to the desired (I) compound by cleavage of the methoxy group with boron tribromide in methylene chloride solution. Other synthetic methods which result in conversion to hydroxylated products, for example such as hydrogenolysis of benzyloxy precursors, are well known to the chemist and can also be adapted for use in a modified procedure.

The coupling of the epoxy ether intermediate (IV) with indolylalkylamine (III) to form the intermediate (II) is easily accomplished by heating the epoxyether either neat or in the presence of a reaction-inert organic solvent with an appropriate indolylalkylamine as shown. Catalysts or any condensing agent are usually not required. Suitable solutions include 9556 ethanol, but other reaction-inert organic solvents in which the reactants are soluble can be used. These may include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol", methanol, dimethoxyethane, ethylene glycol and so on. Suitable reaction temperatures are from about 60 to about 200°C.

The intermediates (III) and (IV) necessary for the reaction can be obtained by various methods which are not limited to the following. The phenoxyepoxide intermediates (IV) can be obtained by alkylation of the appropriate R<*>->substituted cyanophenol (V) with epichlorohydrin as shown in scheme 2 or in particularly complicated cases by using epibromohydrin, K2CO3 and dimethylformamide.

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

This sequence essentially involves the formulation of an R^-substituted phenol according to Reimer-Tiemann conditions to form the salicylaldehyde derivative which is converted via the oxime intermediate to the desired salicylonitrile (V). It should be noted that in order to obtain compounds of formula (I) where R<5> is hydroxyl, in scheme 1 the intermediate (IV) product where R<5> is methoxy must be used. Cleavage using BBr3 to the hydroxyl group takes place in the last synthesis step.

With regard to the indolylalkylamine intermediates of formula (III), typical synthetic methods for their preparation can be found in the above-mentioned patents as well as in the article in "J. Med. Chem.". Although these discussed methods can be used for the preparation of other indolylalkylamine intermediates which may be desirable but which are not specifically described, representative syntheses of compounds of formula (III) will be provided below to further exemplify 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-dlmethylethyl] amino]propoxy]benzonitrile) and which structurally corresponds to bucindolol (R<1>, R<2>, R<5> are hydrogen and R<3>, R<4> are methyl), are used to confirm the identity of a main metabolite of bucindolol. It is known that 6-hydroxylation is possibly 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 led to the assumption that 6-hydroxylation of bucindolol could be an important metabolic pathway. This has been confirmed by demonstrating that this 6-hydroxylindolyl compound according to the present invention agrees in mass spectrum and gas chromatographic retention time with a corresponding main hydroxy metabolite of bucindolol. In this respect, the present invention comprises 2-[2-hydroxy-3-[[2-(6-hydroxy-1H-indol-3-yl)-1,1-dimethyl 1 ethyl 1 ]amino]-propoxy]-benzonitrile on purified pharmaceutically acceptable form.

The compounds produced according to the present invention can be formulated according to conventional pharmaceutical practice to provide pharmaceutical preparations in unit dosage form, for example in the form of tablets, capsules, powders, granules, emulsions, suspensions and the like. The solid preparations contain the active ingredient in a mixture with non-toxic pharmaceutical excipients such as natural diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. The tablets can be coated or they can be coated in a known manner to delay breakdown and absorption in the gastrointestinal tract, thereby providing a lasting effect over a longer 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 mixture. with one or more non-toxic pharmaceutical excipients which are known to be suitable in the preparation of aqueous suspensions. Suitable emollients are, for example, suspension agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum. Suitable dispersing or wetting agents are naturally occurring phosphatides, for example lecithin or polyoxyethylene stearate.

Non-aqueous suspensions can 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. Sweetening and flavoring agents commonly used in pharmaceutical preparations may also be added, for example saccharin, sodium cyclamate, sugar and caramel, to provide a palatable product. The preparations may also contain other absorbents, stabilizers, humectants and buffers.

The compounds in question which are produced according to the invention and their biological effect are shown in more detail in the following examples which are only intended to illustrate the invention.

In the following manufacturing examples, temperatures are expressed in °C and the melting points have not been corrected. The values for the nuclear magnetic resonance spectra, NMR, refer to chemical slope values (S) expressed as ppm with tetramethylsilane, TMS, as standard reference. The relative area that is listed for the different slope values in the spectral H-NMR data corresponds to the number of hydrogen atoms for a specific functional type in the molecule. The nature of the shifts for purposes of multiplicity is indicated as broad singlet (bs), singlet (s), multiplet (m) or doublet (d). Abbreviations used are DMSO-d^ (deutero-dimethylsulphoxide), CDCl3 (deuterochloroform) and are otherwise conventional. The infrared spectral descriptions (IR) include only absorption wavenumbers (cm-<1>) with functional group of identification value. The IR determinations were carried out using potassium bromide as diluent. The element analyzes are indicated as weight-56.

SYNTHESIS OF INTERMEDIATE PRODUCTS.

A. Intermediates of formula (III): general methods.

Example 1

Methoxyl-indole-3-yl-tert-butylamine

To 15.2 ml of a cooled 25% aqueous solution of dimethylamine, 16.9 ml of acetic acid, 7.2 ml of 37% formaldehyde, 27 ml of 97% ethanol were added in order and with stirring and continued cooling . The resulting stirred solution is kept at 0 to 5°C with a cooling bath while the appropriate methoxyindole 1 in an amount of 10.0 g or 0.07 mol is added in 1 portions. This mixture is stirred and gradually heated to 30°C over the course of one hour and then kept at 30°C with stirring for 3 hours. The reaction mixture is then cooled to 10 to 15°C and acidified with 170 ml of 2N HCl. This acidic mixture can be decolorized ("Darco G-60"), filtered and the filtrate basified using 245 ml of 20 µg NaOH with cooling and stirring. A resulting brown oil-like precipitate is extracted with ether, the extracts are washed with water, dried over MgSO4 and concentrated to a brown oily residue of 14 g. This is recrystallized for example from isopropyl ether and hexane to form the desired methoxygramine, usually as an amber solid.

A mixture consisting of the appropriate methoxygramine (7.7 g, 0.04 mol), 2-nitropropane (26.5 g, 0.3 mol) and NaOH (1.7 g

tablets, 0.04 mol) were refluxed under a nitrogen atmosphere for 3 to 5 hours. The reaction mixture was then cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ether extract is washed with water, dried over MgSO 4 and concentrated in vacuo to a residue. Recrystallization of the residue, for example from isopropyl alcohol-water gives a 3-(2-methyl-2-nitropropyl)methoxyindole.

This nitropropylindole compound and 4.2 g of activated Raney nickel are combined in 80 ml of 95% ethanol and heated to reflux. The heating is continued as a solution consisting of 7.8 g of 85% hydrazine hydrate in 8 ml of 95% ethanol is added dropwise. The reaction mixture is then 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 form the desired methoxyindol-3-yl-t-compound.

Example la

6- methoxysvindol- 3- vl- tert-butvlamine

A mixture of 6-methoxyframine (0.9 g, 0.004 mol, prepared from 6-methoxyindole using method 1 Example 1), 3.0 g (0.034 mol) of 2-nitropropane and 0.19 g (0.005 mol) of NaOH -tablets were stirred under reflux in an oil bath under a nitrogen atmosphere for 2 hours, dimethylamine escaping through the condenser. The resulting mixture is cooled to 25°C, treated with a solution of 0.47 ml of acetic acid in 4.1 ml of water and extracted with ether. The ether extract is washed with 3 portions of water, dried over MgSO4 and evaporated to dryness. The remaining brown oil was crystallized by trituration and cooling in a small amount of isopropyl ether. The solid was isolated by filtration, washed with cold isopropyl ether and dried in air to give 0.6 g of amber solid which was recrystallized from isopropyl alcohol-water to give 0.52 g (465É) of 3-(2-methyl-2-nitro-propyl) )-6-methoxyindole with melting point 98-99'C.

A slurry of 8.0 g or 0.32 mol of the nitro compound 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. The external 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 mild reflux. After addition, the mixture was heated again to reflux for 2 hours and cooled to 25°C. Filtration and concentration to dryness gave a crude syrup which was chromatographed on a silica gel column eluting with CH 2 Cl 2 :Cl 2 OH concentrated NH 4 OH in the ratio 90:10:1. The thus obtained amber-colored solid in an amount of 2.9 g and with a melting point of 125-128°C was recrystallized from ethyl acetate:isopropyl ether whereby 1.27 g (18$) of 6-methoxyindol-3-yl-tert-butylamine was obtained with melting point 125-128°C.

Example 2

Methoxyindole- 2- y.- tert-butylamine ( R- l. R-2- = H. R-3-. R-4- ° Me)

In this general procedure, a solution comprising the appropriate methoxyindole-2-carboxylic acid (0.06 mol) and thionyl chloride (2.0 g, 0.17 mol) in 130 mL of dry ether is stirred for 12 to 18 hours at room temperature under a nitrogen atmosphere. The reaction mixture is filtered and the filtrate is concentrated to an oily residue which is collected in 150 ml of dry ether. This ether solution was treated with 80 ml of dimethylamine in 90 ml of ether. The ethereal reaction mixture is concentrated to dryness and the residue is crystallized in isopropyl alcohol. The solid is isolated by filtration to obtain a $30-$40 yield of the methoxyindole-2-carboxamide product.

The methoxyindol-2-yl-carboxamide is dissolved in 100 ml of THF and this solution is added dropwise to a stirred suspension consisting of 3 g of lithium aluminum hydride in 50 ml of THF under a nitrogen atmosphere. After heating to reflux for 2 hours, the reaction mixture is cooled and decomposed with a small amount of water and dilute NaOH solution. This mixture is filtered and the filtrate is concentrated to a residual oil which is collected in absolute ethanol and treated with a small excess of dimethyl sulphate. The resulting alcoholic solution is stirred at room temperature for 4 hours and then concentrated in vacuo to dryness, forming a quaternary trimethylamine salt as a residue.

The impure quaternary salt product in an amount of 0.01 mol is combined with NaOH (2.0 g tablets, 0.05 mol) and 15 ml of 2-nitropropane and the mixture is heated to reflux under a nitrogen atmosphere for 1 hour. The resulting dark thick mixture is cooled, diluted with water, acidified with acetic acid to a pH value of approx. 6 and then extracted with ether. These ether extracts are combined, washed with water, dried over MgSO 4 and concentrated to a dark residue which is chromatographed on a silica column and diluted with methylene chloride. Removal of the methylene chloride solvent and recrystallization of the impure material from isopropyl alcohol water gives a methoxyindole which is substituted in the 2-position with a 2-methyl-2-nitropropyl moiety.

Reduction of this nitro product with Raney nickel and hydrazine in accordance with the method described in example 1 gives the desired methoxyindol-2-yl-tert-butylamine.

Example 3

1- methylation of methoxyindolylalkylaroins: 3-(2-amino-2-methylpropyl)-1-methylmethoxyindole (R^. R3-. R-4- = Me, R-<2-> = - H) By this general procedure, 7.0 g or 0.11 mol of 85$ K0H was finely divided in a mortar and quickly transferred to a nitrogen-flushed 25 ml Erlenmeyer flask. Then 55 ml of DMSO was added and the mixture was stirred for 5 minutes. Addition of methoxyindole-tert-butylamine (0.27 mol) and iodomethane (3.78 g, 0.03 mol or any other suitable alkylating agent) are each followed by 45 minutes of stirring, after which the suspension is cooled in 300 ml of water. Extraction of the mixture with ethyl acetate followed by washing the extracts

with water and brine gives a clear solution which is dried over MgSO4 and evaporated under vacuum to an oily product. This free base can be used as an intermediate without further purification. The characterization usually takes place by converting the oily base to the hydrochloride salt to obtain a crystalline product.

Example 4

Methoxyindol-2- ylethylamine

In this method, which corresponds substantially to Bhat and Siddappa, "J. Chem. Soc", (C), 1971, 178-81, various methoxyindole-2-carboxylate esters (commercially available or prepared by methods from the literature) are reduced to the corresponding 2-hydroxymethylindole derivative by reduction with lithium aluminum hydride in ether. Conversion to the indole-2-carbaldehyde takes place by dissolving a 2-hydroxymethyl-methoxyindole (4 g) in 250 ml of dichloromethane and adding 10 g of activated manganese dioxide, followed by stirring the reaction mixture at room temperature for 20-30 hours. The reaction is followed by means of TLC while determining the disappearance of the spot from the starting 2-hydroxymethyl indole. If necessary, fresh amounts of manganese dioxide (2-3

g) is added. The reaction mixture is filtered and the remaining manganese dioxide is washed repeatedly with a small amount

fresh dichloromethane. The combined filtrate is evaporated to dryness to give the crude indole-2-carbaldehyde as a pale yellow solid which is then recrystallized.

The methoxyindole-2-carbaldehyde (5 g), nitromethane (8 ml) and 1 g of sodium acetate are heated under reflux for 10 hours. The reaction mixture is cooled and the dark red crystals that separate are collected, washed thoroughly with water, dried and crystallized from ethanol. The nitrovinylmethoxy-indole produced in this way is then reduced to the desired methoxyindol-2-ylethylamine by treatment with lithium aluminum hydride in dry ether. The reaction mixture is gently heated under reflux for 10 hours, after which excess lithium aluminum hydride is decomposed. After filtration, the filtrate is concentrated in vacuo to form a residue which is crystallized from a suitable solvent to form the desired methoxyindol-2-ylethylamine.

Example 5

Methoxyindol-2-ylpropyl amine

In a modification of the procedure in example 1, a suitable methoxyindole-2-carbaldehyde (1 g) is treated in 0.5 ml of nitroethane with 4 drops of benzylamine, after which the mixture is heated to reflux for <x>h hour. The cold reaction mixture deposits on standing dark red crystals which can be collected, washed with some ether, dried and crystallized from ethanol. The thus produced nitropropenylindoles are reduced with lithium aluminum hydride as described above in example 4. Solid products are crystallized and the liquids are characterized as benzoyl derivatives.

Example 6

Methoxyindol-3- ylethylamine

Reference is made to "J. Chem. Soc", 1958, 3493-96. This synthesis begins with methoxyindole-3-aldehydes that are either commercially available or prepared using literature methods. Using the method in Example 4 above, a suitable methoxyindole-3-carbaldehyde is condensed with a nitromethane using ammonium acetate as catalyst. On standing, the cooled solution gradually deposits dark red crystals which can be recrystallized from benzene or methanol to form the 3-nitro-vinyl-methoxyindole which is reduced with lithium aluminum hydride as above to form the desired methoxyindol-2-ylethylamine.

Example 7

Methoxyindol-3-ylpropylamine

A selected methoxyindole-3-carbaldehyde (5 g), nitroethane (10 ml) and 1 g of sodium acetate are heated on a steam bath with occasional shaking for one hour. After cooling, the crystals are collected, washed with 2 x 50 ml of hot water and crystallized from methanol. The resulting 3-(2-nitropropenyl)-methoxyindole is reduced to the desired 3-(2-aminopropyl)-methoxyindole by treatment with lithium aluminum hydride as described in detail in connection with the above-mentioned methods.

B. Intermediates of formula ( IV)

Example 8

2-f(2.3-epoxy)propoxy"lbenzonl tr in 1

A solution of 2-cyanophenol (25.0 g, 0.21 mol) apple chlorohydrin (117 g, 0.26 mol) and 10 drops of piperidine is stirred and heated to 115-120°C in an oil bath for 2 hours. The mixture is then concentrated (90°/30 Torr) to remove unreacted epichlorohydrin. The residue is diluted with toluene and concentrated twice to dryness to support the removal of the last traces of volatile material. The residual oil is dissolved in 236 ml tetrahydrofuran and this solution is stirred at 40-50°C for 1 hour with 263 ml IN NaOH. The organic layer is separated and concentrated to form an oil which is combined with the aqueous phase. The mixture is extracted (CH 2 Cl 2 ), the extract is dried over MgSO 4 and concentrated to give 36.6 g corresponding to 100$ of oil which slowly crystallized into a wax-like solid. This intermediate can be used without further purification in the preparation of compounds of formula (I).

Example 9

2- f2. 3- epoxy ) propoxyvl- 4- methoxybenzonltrile The appropriate 5-methoxysalicylaldehyde can be obtained from 4-methoxyphenol by the Reimer-Tlemann method which is well known in the literature, see for example Kappe et al., "Arch. Pharm." 308/5, 339 (1975). A solution comprising 0.005 mol of the starting salicylaldehyde in 6 ml of pyridine and 6 ml of absolute

ethanol was treated with 0.4 g (0.02 mol) hydroxylamine hydrochloride and heated to reflux for 4 hours. The mixture was concentrated in vacuo to a gray syrup which was stirred with 50 ml of H 2 O and the suspension was decanted. Addition of 10 ml of HgO to the remaining glassy material followed by cooling to 5°C gives, by filtration, approx. 1.2 g of impure solid which is collected in 25 ml of 50% lg ethyl ether-isopropyl ether. The ether solution was filtered, dried with MgSO 4 , treated with "Darco G-60" and "Celite", filtered and concentrated in vacuo to a waxy solid. Recrystallization from ethyl ether "Skelly B" gives the corresponding benzaldehyde oxlm.

A mixture of 0.002 mol of the oxime and 1.02 g (0.01 mol) of acetic anhydride is heated to reflux for 30 minutes and then cooled to 25°C. 50 ml of water is added followed by the dropwise addition of 20 µg of NaOH to pH 10. The resulting suspension is stirred at 25°C for 20 hours (to hydrolyse any acetate ester of the desired phenol derivative). The pH value is set to approx. 2 using 6N HCl and the resulting mixture is extracted with 40 ml of ethyl acetate before forming an organic layer which is separated, dried over MgSO 4 and evaporated at 65°/70 Torr. Dilution of the aqueous residue with 0.5N HCl gives a precipitate which is recrystallized from isopropyl ether and dried to form the desired benzonitrile intermediate.

A mixture of 0.015 mol of 2-hydroxy-5-methoxybenzonitrile, 4.2 g (0.03 mol) of finely powdered anhydrous potassium carbonate and 140 ml of DMF was stirred at 50°C for 15 minutes. Epibromohydrin (2.8 g or 0.02 mol) was added in one portion and stirring continued for 3 days. The reaction mixture was poured into brine and the resulting suspension stirred for 3 hours at 0-5°C. Filtration of the mixture and washing of the filter cake with water gave, on drying in air, the impure intermediate product which could be used without further purification. In a similar way, the use of other substituted 2-cyanophenols by modifications of the above-mentioned methods will give the other intermediate products of formula (IV) which can be used for the synthesis of the various compounds of formula (I).

SYNTHESIS OF END PRODUCTS

Example 10

General procedure: 2-r2-hydroxy-3-r(hydroxylndole)-alkylaminopropoxylbenzonitrile

A selected methoxyindolylalkylamine (III) is mixed with an equimolar or somewhat larger amount of a selected epoxy-propoxybenzonitrile (IV) and the coupling takes place either by refluxing a solution of the reactant 1 approx. 18-24 hours or by heating a pure mixture at a temperature of approx. 120-130° C for approx. We - 2 hours. Ethanol and toluene are the usually chosen solvents for the reaction medium for coupling via reflux coupling of a solution of (III) and (IV). In some cases, it is advantageous to follow the course of the reaction by TLC while adding further (IV)-epoxide until all the indolyl group (III) has disappeared. After the reaction, the mixture is concentrated to dryness and the residue can either be 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 methoxyindole products (II) is dissolved in methylene chloride and stirred under a nitrogen atmosphere at 0-10°C, while a several-fold excess of IN boron tribromide in methylene chloride is added dropwise. After addition, the reaction mixture is stirred at room temperature for approx. 6-8 hours. Excess boron tribromide is broken down by cooling the reaction mixture and adding an excess of water dropwise. The impure hydrobromide salt of formula (I) can be worked up in a number of conventional ways such as recrystallization, conversion to base and purification, conversion to base followed by conversion to another acid addition salt, and so on.

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

Example 11

2-r2-hydroxy-3-f T2-(6-methoxy-1H-indol-3-yl)-l.1-dimethyl-ethyllaminolpropoxylbenzonitrile

A solution of 6-methoxyindol-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 8) and 100 ml of absolute ethanol, was stirred under reflux for 20 hours. A further 0.21 g of epoxide is added and the reflux is continued for 4 hours after which the mixture is concentrated to dryness and the residue is triturated with 1 isopropyl alcohol to induce crystallization. The product is collected by filtration, washed with cold isopropyl alcohol and dried in air to form 4.0 g or 8556 of the methoxy product (II) with melting point 145-146°C which was then used directly in the next step.

A solution of the above-prepared methoxyindole product (1.5 g, 0.004 mol) in 225 ml methylene chloride was stirred under a nitrogen atmosphere at 5-10°C while 15.3 ml or 0.015 mol IM boron tribromide in methylene chloride was added dropwise. After the addition, the ice bath was removed and the reaction mixture stirred at 25°C for 16 hours for cooling to 5-10°C and subsequent dropwise addition of 47.5 ml of H2O. The resulting mixture was decanted and the remaining gummy solid was rinsed with 2 portions of EtO. The dissolution of this impure hydrobromide salt in 50 ml of hot H2O followed by treatment with "Darco G-60", filtration, cooling to 25°C and basification to pH 8 with concentrated NH4OH gave 1.2 g of an amber solid which was chromatographed ( slllkagel 60, 230-400 mesh, EM reagents) on a medium pressure system with chloroform:methanol:concentrated NH4OH in the ratio 90:10:1. The product thus obtained crystallized from a small amount of 95% ethanol to give, by gradual addition of I 2 O, 1.03 g or 71% of the desired 6-methoxyindole product (I) as an amber solid substance with melting point 90-94°C.

Analysis for C22<H>25<N>303-1/3H20:

NMR (DMS0-d6): 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>.

Example 12

2-r2-hydroxy-3-r T2-(5-hydroxyl-1H-lndol-3-l)-l. 1-dlmethyl-ethyllamlnolpropoxylbenzonltrile

A solution of 5-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 were refluxed for 11 h. The solvent acetone was then allowed to evaporate and the oily residue was heated cleanly at 100°C for 2 hours. 20 ml of isopropyl alcohol was added and the reaction solution was refluxed for 4 hours, after which it was cooled to room temperature, diluted with 50 ml of ether and a stirring rod was used to rub out 4.7 g corresponding to 96$ of a white powder. where the melting point of 119-124°C; TLC (9:1 CHCl 3 -methanol) shows a single spot, Rf 0.25. This impure 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 treatment of an acetonitrile solution with ethanolic HCl gives an impure product which is recrystallized in butanone-9556 ethanol (20:1) to form an off-white powder with a melting point of 164-166'C.

Analysis for C23<H>27N303"HC1:

Using the method in example 11 above with a view to boron tribromide cleavage of the methoxy group, but using the 5-methoxyindole intermediate (II) prepared above, the desired 5-hydroxyindole product (I) in the form of the hydrobromide salt can be obtained. The pure hydrobromide salt is a beige-coloured powder with a melting point of 219-221'C.

Analysis for C22H25<N>303<*>HBr:

NMR (DMS0-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 3300 cm-<1>.

From suitable methoxyindolealkylamines (III) and epoxy-propoxybenzonitriles (IV), further examples of compounds of formula (I) can be prepared using essentially the same method as described above with only minor technical modifications. Some additional compounds of formula (I) which can be synthesized in this way are shown in Table 1.

BIOLOGICAL ASSESSMENT

These biological samples are used to determine the antihypertensive profile of selected compounds of formula (I).

Example 35

The efficacy of hypertensive agents other than adrenergic B-receptor blocking agents is usually assessed in the spontaneously hypertensive rat. Blood pressure values are determined for test animals before and 2 and 4 hours after oral doses of 30 to 100 mg/kg of the test compounds. The heart rate is also determined for each pressure measurement. A drop in blood pressure 2 or 4 hours after the individual dose in the range of 15-20 mm Hg is considered "doubtful". "Active" and "inactive" designations are forms that are greater and less than this interval, respectively.

Example 36

Another test useful in determining the effectiveness of antihypertensive agents uses DOCA-salt hypertensive rats. These hypertensive rats are prepared as follows: male rats of the Sprague-Dawley strain and 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 156 saline solution. In a 3-week treatment period, the rats are given a total of 10 subcutaneous injections containing 10 mg DOCA (deoxycorticosterone acetate) in 0.2 ml suspension vehicle {0.25% "Tween 80" and 0.12556 CMC in normal saline solution). After the last injection, the salt water is replaced by distilled water and the animals are ready for use one week later. The test is carried out by selecting non-fasting animals with elevated systolic blood pressure (>160 mm Hg). The blood pressure value is determined for these test animals before and 4 hours after oral doses of 30-100 mg/kg of the test compounds. During the trial period, the animals are housed in metabolism cages without a lining or water and urine are collected for 4 hours. Heart rate and body weight are also determined with each pressure measurement. A drop in blood pressure 4 hours after dosing and which is in the range of 15-20 mm Hg is considered "doubtful". "Active" and "inactive" designations are requirements larger or smaller than this interval.

Example 37

The angiotensin(II)-supported ganglion-blocked rat model is used in a screening test to assess the direct vasodilator activity component. Percentage changes in blood pressure in anesthetized rats 30 minutes after intravenous dosing are determined. The intravenous dosage is carried out with test compounds at 3 mg/kg. The limit action is defined as an approx. 1056 reduction of blood pressure measured 30 minutes after dosing. "Active" and "inactive" determination are increments greater or less than this.

Example 38

Responses in diastolic blood pressure and heart rate to a fixed loading dose of isoproterenol are obtained before and 15 minutes after graded doses of test compound administered intravenously over a 3 minute interval to anesthetized dogs. A branch of a femoral artery and vein was equipped with a cannula to record the blood thickness and to administer the active compounds dissolved in 1 saline. Vagl was sectioned bilaterally in the midcervical region of the back and the dogs were mechanically ventilated ("Harvard" respirator) with room air at a rate of 20/min. and a stroke volume of 20 ml/kg. Heart rate is measured with a cardiotachometer which is activated by the pressure pulse. All measurements are recorded on a "Beckman R-612" printer. The action of the active compound is expressed as a cumulative dose in jjg/kg which causes 5056 inhibition of the reaction to isoproterenol.

Example 39

Male Wlstar rats were anesthetized with a combination of urethane and chloralase by the intraperitoneal route. After induction of anaesthesia, chlorisondamln was injected into the peritoneal cavity to induce ganglion blockade. A femoral artery was equipped with a cannula for measuring blood pressure and heart rate and two femoral veins were equipped with a cannula for administration of compounds. The trachea was intubated and the rats were allowed to breathe spontaneously. The animals were challenged before and 15 minutes after intravenous administration of the test compounds with graduated doses 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 produce a 50 mm Hg (ED50) increase in blood pressure was interpolated from the curves. Dose changes were calculated by dividing the ED5Ø value after administration of an active substance by the EDsg value before active substance.

Claims (1)

1. Analogous process for the preparation of therapeutically active 1-phenoxy-3-hydroxyindolylalkylamino-3-propanols of the formula and acid addition salts thereof, there one of R<1> and R<2> is hydrogen and the other is hydrogen or C^_4-alkyl, preferably hydrogen, R<3> and R<4> are independently selected from hydrogen or C^_4~alkyl, preferably methyl, and R 5 means halogen, hydrogen, hydroxy or C 1-4 alkyl, preferably hydrogen or 5-fluorine, the phenoxypropanol-amlnoalkyl side chain being attached to the indole ring in either the 2- or 3-position, preferably in the 3-position, and the hydroxy substituent group occupying either the 4-, 5-, 6- or 7-position, preferably the 6-position, characterized by i) connecting a methoxylated indolealkylamine of formula (III) where R<1>, R<2>, R<3> and R<4> have the above meaning, with an R<5> substituted phenoxyepoxide (IV) where R<5> has the above meaning, by heating (III) and (IV) either without a solvent or in the presence of an organic solvent inert for the reaction to form an intermediate product (II) where R<1>, R<2>, R<3>, R<4> and R<5> have the meaning given above, ii) reacts the intermediate product (II) under suitable conditions for cleavage of the methoxy group to a hydroxyl group, preferably by reaction with boron tribromide in methylene chloride solution to form a compound of formula (I), and lii) if desired, for' obtaining a pharmaceutical accept- table acid addition salt of a compound of formula (I), converts the compound from step (II) into the corresponding salt in a manner known per se.