SE455865B - 1-PHENOXI-3-HYDROXIINDOLYLALKYLAMINO-3-PROPANOLS, METHOD OF PREPARING IT AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE - Google Patents

Description

455 10 15 20 25 30 35 865 - In the above structural formulas, the symbol R 3 may be hydrogen, halogen, lower alkyl or alkoxy but not hydroxyl.

A preferred compound of the above formula (1) is designated MJ 13105 and is also known as bucindolol and is currently undergoing clinical trials as an antihypertensive agent HJ 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 455,865 corresponding to the 6-hydroxyindolyl compound of the present invention.

Reference is also made to U.S. Patent Application 414,748 of September 3, 1982, which discloses a series of vasodilators having a spectrum of beta-adrenergic blocking potency and the structural formula (3).

A c Y (3) Although in the above structural formula (3) C may be, inter alia, hydroxyl, the series generally differs from the compounds of the present invention in that the compounds of structure (3) are giridinyloxypropanolamines.

The present invention relates to compounds of formula I and acid addition salts of these substances. 2 g R Ra Ra H0 imo N // ÛH f R1 (I) In the structural formula above, the symbols R1 - R5 have the following meaning. One of R 1 and R 2 is hydrogen and the other is hydrogen or C 1-4 alkyl, R 3 and R 4 are independently hydrogen or C 1-4 alkyl and R may be halogen, hydrogen, hydroxy or C 1-4 alkyl. For preferred compounds, R 1 is H, R 2 is 2-H, R 3 and R 4 are methyl and R 5 is hydrogen or 5-fluoro. The compounds of the present invention are useful as antihypertensive agents in part due to a combination of their adrenergic receptor blocking and vasodilating properties.

The invention thus relates to compounds of the above structural formula (I) and the acid addition salts thereof. In structural formula I, R 2, R 2, R 3 and R 4 may be hydrogen or alkyl of 1 to 4 carbon atoms. One of R 1 and R 2 is always hydrogen, while R 3 and R 4 may independently be alkyl. R 5 may be halogen, preferably fluorine or chlorine, hydrogen, hydroxyl or lower alkyl. The indolyl system is attached to the side chain either in the 2- or 3-position and the hydroxyl substituent occupies either the 4-, S-, 6- or 7-ring position in indole.

For preferred compounds, R 1 is hydrogen, R 2 is 2-hydrogen (the indole group is attached to the main side chain via its 3-position), R 3 and R 4 are methyl and R 5 is hydrogen or 5-fluoro.

For medical use, the pharmaceutically acceptable acid addition salts are preferred, i.e. such salts where the anion does not significantly contribute to the toxicity or pharmacological activity of the organic cation. The acid addition salts are obtained either by reacting an organic base of structure 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 those skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids are hydrohalic acids such as HCl, HBr, HI, sulfuric acid, phosphophic acid and the like.

It will also be appreciated that all compounds of the present invention include all optically isomeric forms, i.e. mixtures of enantiomers, for example racemic modifications, as well as individual enantiomers. These individual enantiomers are usually designated after the optical rotation they produce, with (+) and (-), (1) and (d), or combinations of these symbols. The symbols (L) and (D) and the symbols (S) and (R), which stand for sinister and rectus, respectively, indicate the absolute space configuration of the enantiomer. Unless an isomer designation is given for a compound, the compound is the racemic modification.

The individual optical isomers of the compounds of the aryloxypropanolamine class to which the present compounds belong have generally been obtained by any of the following four basic methods. These are: 1) fractional recrystallization of chiral acid salt derivatives; 2) derivatization with a chiral organic reagent, cleavage and regeneration of the original compound into optically active form; 3) synthesis of the simple optical isomer using chiral intermediates; and 4) column chromatography using chiral stationary phases. The application of these various methods is well known to those skilled in the art.

Biological testing of representative compounds of formula I on animals has shown that they have biological properties, which could make them useful as antihypertensive agents.

In addition to the antihypertensive activity that can be demonstrated in animal testing, the present compounds also exhibit vasodilating properties as well as varying degrees of adrenergic alpha and beta receptor blocking properties and inherent sympathomimetic activity. A more detailed description of the specific pharmacological tests used and the criteria used to assess the biological activity in question can be found in the section that follows later with the heading "Description of specific embodiments" under the subheading "Biological evaluation". Preferred representative compounds have a particularly desirable combination of the above effects and pharmacological support effects or absence thereof, which make them particularly suitable for specific cardiovascular indications, for example use as antihypertensives. The utility of the compounds of formula I can be demonstrated in various animal models including antagonism of isoproterenol in anesthetized dog, treated intravenously (adrenergic beta-receptor action), spontaneous hypertensive and DOCA salt -hypertensive rat (antihypertensive effect), angiotensin-induced ganglion-blocked rat model (vasodilatory effect) and an anesthetized rat model (alpha-adrenergic blocking) and in various other animal laboratory models (see Deitchman, et.als., Journalac, Journalac, Journalac. , 311-321 (1980)).

By way of example, two representative compounds of formula I, namely 2- [2-hydroxy-3- [2- (6-hydroxy-1-indol-3-yl) -1,1-dimethylethyl] amine] propoxy) 7benzonitrile and 2- [2-hydroxy-3- [Z2- (5-hydroxy-Ig-indol-3-yl) -1,1-dimethylethyl / aminopropoxy] benzonitrile gave rise to more than 20 mm Hg mean systolic blood pressure drop in rats in one or both of the antihypertensive tests at a dose level of 30 mg / kg per oral. A 3 mg / kg intravenous dose of these compounds resulted in more than a 20% mean mean arterial blood pressure drop (measured 30 minutes after dosing) in the vasodilation test.

The use as antihypertensive agents, vasodilators and / or adrenergic blocking agents in therapeutic methods involves systemic administration, both orally and parenterally, of an effective non-toxic amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. An effective amount means a dose which exerts the desired pharmacological activity, as indicated above, without any undue toxic side effects when administered to a mammal in need of such treatment. The dosage varies depending on the subject and the mode of administration chosen from about 0.1 pg to 10 mg / kg body weight of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. A preferred range for an effective dose would be about 0.1 - 0.5 mg / kg when administered intravenously and about 0.5 - 5 mg / kg when administered orally. The compounds of the present invention may be prepared by a convenient general method. This procedure is outlined in Reaction Scheme 1 below.

In this specification, Me refers to the methyl group and Ac refers to the acetate ion, C 2 H 3 O 2.

Reaction Scheme 1 4 3 2 CN 3 R ~ O / \\ 1 R (IV) (III) t CN al '3 xz 55153 RS R CH Cl. o '. om z 2 '1 R (II): <2 123 n ”5 H Mo R N H ou. eel CN R1-RS has the meanings given above.

This process involves coupling a suitable methoxylated indole alkylamine (III) with an R 5 -substituted phenoxy epoxide intermediate (IV). The synthesis methodology required to reach this stage in the preparation of the products of formula I is analogous to a synthesis process used to prepare bucindolol. In this context, reference is again made to U.S. Patents 4,234,595 and 4,314,943 and to the article in J. Med. Chem., 23: 3, 285-289 (1980). However, a further step is required since the resulting methoxylated indole analog (II) is converted to the desired product (I) 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 hydrogenolysis of benzyloxy precursor compounds, are well known to those skilled in the art and can also be applied in a modified process.

The coupling of the epoxy intermediate (IV) with the indolylalkylamine (III) to obtain the intermediate (II) is carried out simply by heating the epoxy ether either as such or in the presence of a reaction-inert organic solvent with a suitable indolylalkylamine, e.g. as shown above. No catalyst or condensing agent is usually required. Suitable solvents include 95% ethanol but other reaction-inert organic liquids in which the reactants are soluble may be used. These may include benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc., but are not limited thereto. Suitable reaction temperatures are about 50 ° C.

The required reaction intermediates III and IV can be obtained by several methods and are not limited to the following. The phenoxy oxide intermediates (IV) can be obtained by alkylating the appropriately RS-substituted cyanophenol (V) with epichlorohydrin, as shown in Reaction Scheme 2, or in reluctant cases using epibromohydrin, K 2 CO 3 and dimethylformamide. 10 15 20 25 30 455 865 Reaction Scheme 2 CN 115 + c1 / \ ¿j ___, n ot ox (v) uví Although many cyanophenols (V) are commercially available, they can also be conveniently prepared from readily available phenols via the synthesis which outlined in Reaction Scheme 3.

Reaction Scheme 3 x * C 5 '5__® \ en 1 CEO H non 0 ,, Naon of; CH = NOH OH u This sequence essentially involves the formulation of an RS- -substituted phenol according to the Reimer-Tiemann conditions to obtain the salicylaldehyde derivative, which is converted via the oxy intermediate to the desired salicylonitrile (V). 455 865. 10 15 20 25 30 35 10 It should be noted that when desiring products of formula I, wherein R is hydroxyl, the intermediate IV, 5 is methoxy must be used in Reaction Scheme 1. Cleavage wherein R ning by BBr3 to the hydroxyl group is achieved in the final step of the synthesis.

For the indolylalkylamine intermediates of structural formula III, typical synthetic procedures for their preparation can be found in the two U.S. Patents cited above and in the J. Med. Article cited above. Chem., To which reference is again made. Although these processes are applicable to the preparation of other indolylalkylamine intermediates, which may be desirable but not specifically disclosed in said references, representative syntheses of the compounds of formula III will be given below as a further example of the intermediates required by present invention.

Finally, it is of interest that a 6-hydroxyindolyl compound of the formula 1 (2-β-hydroxyxy-3-β-β- (6-hydroxy-1G-indol-3-yl) -1,1-dimethylethyl] amine97propox 7benzonitrile), which structurally corresponds to bucindolol (R1, R2, R5 R3, R4 a major metabolite of bucindolol. It is known that 6-hydroxy- is hydrogen and is methyl) was used to confirm the identity of clay is perhaps more important than 5- hydroxylation in the metabolism of tryptamine derivatives (see Jepson, et al., Biochem. Biophys. Acta., 62, 91 (1962); Jaccarini and Jepson, Biochim. Biophys. Acta., 156, 347 (1968)). This knowledge has suggested the possibility that 6-hydroxylation of bucindolol would be an important metabolic pathway. This has been confirmed by the demonstration that this 6-hydroxyindolyl compound of the present invention is consistent with a corresponding major hydroxymetabolite of bucindolol in terms of mass spectrum and gas chromatographic retention time. In this regard, a further aspect of the present invention relates to 2-β-hyaroxy-3-β- (6-hydroxy-Ig-inaol-3-yl) -1,1-methylethyl] amine] propoxyphenyl. benzonitrile in purified, pharmaceutically acceptable form. The compounds of the present invention may be formulated according to conventional pharmaceutical practice for the provision of pharmaceutical compositions in unit dosage form comprising, for example, tablets, capsules, powders, granules, emulsions, suspensions and the like. The solid preparations contain the active ingredient in admixture with non-toxic pharmaceutical excipients such as inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, 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 they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a delayed action for an extended period of time. Liquid preparations suitable for parenteral administration include solutions, suspensions or emulsions of the compounds of formula I.

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 which are known to be useful in the preparation of aqueous suspensions. Suitable excipients are, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia. Suitable dispersing or wetting agents are naturally occurring phosphatides, for example lecithin and polyoxyethylene stearate.

Anhydrous suspensions can be prepared by suspending the active ingredient in a vegetable oil, for example olive oil, sesame oil or coconut oil or in a mineral oil, for example liquid paraffin. The suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents commonly used in pharmaceutical compositions may also be incorporated as saccharin, sodium cyclamate, sugar and caramel to provide a palatable oral preparation.

The compositions may also contain other absorbents, stabilizers, wetting agents and buffering agents.

The invention is described in more detail below by means of the following exemplary embodiments. In these examples, the temperature indications refer to degrees Celsius and the melting points are uncorrected. Nuclear Magnetic Resonance (NMR) spectral data refers to the chemical shifts (S), expressed as parts per million (ppm) relative to tetramethylsilane (TMS) as the reference standard. The relative surface areas specified for the different shifts in 1 H NMR spectral data correspond to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the displacements with respect to the multiplicity is stated as broad singlet (bs), singlet (s), multiplet (m) or doublet (d).

Abbreviations used are DMSO-ds (deuterodimethylsulfoxide), CDCl3 (deuterochloroform) and otherwise have conventional meanings. Infrared (IR) spectral data include only absorption wavelengths (cm-1) with functional group identification value. The IR determinations were made using potassium bromide (KBI) as diluent. The elemental analyzes are expressed as a percentage by weight.

Synthesis of intermediates A. Intermediate products of formula III: General procedures Example 1 Methoxyindol-3-yl-tert-butylamine To 15.2 ml of a cooled 25% aqueous solution of dimethylamine are added the following components in turn with stirring and further cooling : 16.9 ml acetic acid, 7.2 ml 37% formaldehyde, 27 ml 95% ethanol. The resulting stirred solution is stirred via 0 ° to -s ° by means of a quench bath while adding the appropriate methoxy indole (10.0 g, 0.07 mol) portionwise. This mixture is stirred and gradually heated to 300 over a period of 0.5 hours and then kept at 30 ° for 3 hours with stirring. The reaction mixture is then cooled to 10-15 ° and acidified with 170 ml of 2N HCl. This acidic mixture can be decolorized (Darco G-60) and filtered and the filtrate alkalized using 245 ml of 20% NaOH under cooling and stirring. A brown oily precipitate obtained is extracted with ether and the extracts are washed with water, dried over magnesium sulphate and concentrated to a brown oily residue (14 g). The residue is recrystallized, for example from isopropyl ether and hexane, to give the desired methoxigramine, usually as a tan solid.

A mixture consisting of 7.7 g (0.04 mol) of the appropriate methoxigramine, 26.5 g (0.3 mol) of 2-nitropropane and 1.7 g (0.04 mol) of NaOH pellets is refluxed under a nitrogen atmosphere. for 3 - 5 hours. The reaction mixture is then cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ether extracts are washed with water, dried over magnesium sulfate 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 activated Raney nickel (4.2 g) are combined in 80 ml of 95% ethanol and heated to reflux. The heating is stopped when a solution consisting of 85% hydrazine hydrate (7.8 g) in 8 ml of 95% ethanol is added dropwise. The reaction mixture is then refluxed 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-butylamine product. Exemplary gel 1a 6-methoxyindol-3-yl-tert-butylamine A mixture of 0.9 g (0.004 mol) of 6-methoxigramine, prepared from 6-methoxyindole by the method of ex. Example 1), 3.0 g (0.034 mol) of 2-nitropropane and 0.19 g (0.005 mol) of NaOH pellets were refluxed with stirring in an oil bath under a nitrogen atmosphere for 2 hours, with dimethylamine escaping through the condenser. The resulting mixture was cooled to 250, treated with a solution of 0.47 ml of glacial acetic acid in 4.1 ml of water and extracted with ether. The ether extracts were washed with three portions of water, dried over magnesium sulphate and evaporated to dryness. The remaining brown oil crystallized on scraping 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 a brown solid which was recrystallized from isopropyl alcohol-water to give 0.52 g (46%). ) 3- (2-methyl-2-nitropropyl) -6-methoxyindole, m.p. 98-990.

A slurry of 8.0 g (0.32 mol) of the nitro compound, prepared as above, 80 ml of 95% ethanol and 4.2 g of Raney nickel (washed with water and 95% ethanol) was refluxed. while stirring. The external heating was stopped 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 proper reflux. After the addition, the mixture was refluxed again for 2 hours and then cooled to 259. Filtration and concentration of the filtrate were carried out on a silica gel column eluting with CH 2 Cl 2 -CH 3 OH-concentrated NH 4 OH (90: 10: 1). The brown solid thus obtained (2.9 g, m.p. 125-1280) was recrystallized from ethyl acetate-isopropyl ether to give dryness to give a crude syrup which chromatographed on 1.27 g (18%) of 6-methoxyindole. 3-yl-tert-butylamine, m.p. 125 DEG-1280 DEG. Example 15 Methoxyindol-2; yl-tert-butylamine (R1, R2 = H, R3, R4 = Me) In this general The process is stirred with a solution consisting of the appropriate methoxyindole-2-carboxylic acid (0.06 mol) and 2.0 g (0.17 mol) of thionyl chloride in 130 ml of dry ether 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 taken up in 150 ml of dry ether. This ether solution is treated with 80 ml of dimethylamine in 90 ml of ether.

The ether reaction mixture is concentrated to dryness and the residue is crystallized from isopropyl alcohol. The solid material is isolated by filtration to give the methoxyindole-2-carboxamide product in a yield of 30-40%.

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 refluxing 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 taken up in absolute ethanol and treated with a slight excess of dimethyl sulphate. The resulting alcoholic solution is stirred at room temperature for 4 hours and then concentrated in vacuo to dryness to give a quaternary trimethylamine salt which remains.

The quaternary crude salt product (0.01 mol) is combined with 2.0 g of 60.05 mol) of NaOH pellets and 15 ml of 2-nitropropane and the mixture is refluxed for 1 hour under a nitrogen atmosphere. The resulting dark thick mixture is cooled, diluted with water, acidified with acetic acid to a pH of about 6 and then extracted with ether. These ether extracts are combined, washed with water, dried over magnesium sulfate and concentrated to a dark residue, which is chromatographed on a silica gel and diluted with methylene chloride. Removal of the methylene chloride solvent and recrystallization of the crude material from isopropyl alcohol-water gives a methoxyindole, which is substituted in the two-position with a 2-methyl-2-nitropropyl group. this nitro compound with Raney nickel and hydrazine by the method of Example 1 gives the desired methoxyindol-2-yl-tert-butylamine.

Example 3 1-methylation of methoxyindolylalkylamines: 3- (2-amino-2-methylpropyl) -1-methylmethoxyindole 121, 1: 3, 114 = me, R2 = H In this general procedure, 7 g (0.11 mol) are ground 85% KOH in a mortar and transferred rapidly to a nitrogen-purged 25 ml Erlenmeyer flask. 55 ml of DMSO are added and the mixture is stirred for 5 minutes. Additions of methoxyindolyl-tert-butylamine (0.27 mol) and 3.78 g (0.03 mol) of iodomethane or other suitable alkylating agent are each followed by stirring for 45 minutes, after which the suspension is poured into 300 ml of water. Extraction of the mixture with ethyl acetate, followed by washing of the extracts with water and brine, gives a clear solution, which is dried over magnesium sulphate and evaporated in vacuo to an oily product. This free base can be used as an intermediate without further purification. Characterization usually takes place by converting the oily base to the hydrochloride salt in order to obtain a crystalline product.

Example 4 Methoxyindol-2-ylethylamine In this process, which is essentially the process as (C), 1971, 178-81, various methoxyindole-2-carboxylate esters (commercialized by Bhat and Siddappa, J. Chem. Soc. available or prepared by literature methods) to the corresponding 2-hydroxymethylindole derivatives by reduction with lithium aluminum hydride in ether. Conversion to the indole-2-carbaldehyde is accomplished by dissolving 4 g of a 2-hydroxymethylmethoxyindole in 250 ml of dichloromethane and adding 10 g of activated manganese dioxide, followed by stirring the reaction mixture for 20-30 hours at room temperature.

The reaction is monitored by TLC to monitor the disappearance of the 2-hydroxymethylindole starting spot. If required, fresh amounts of manganese dioxide (2 - 3 g) can be added.

The reaction mixture is filtered and the remaining manganese dioxide is washed repeatedly with a small amount of fresh dichloromethane. The combined filtrate is evaporated to dryness to give crude methoxyindole-2-carbaldehyde as a pale yellow solid, which is then recrystallized. 5 g of the methoxyindole-2-carbaldehyde, 8 ml of nitromethane and 1 g of ammonium acetate are refluxed for 0.5 hours. The reaction mixture is cooled and the dark red crystals which precipitate are collected, washed thoroughly with water, dried and crystallized from ethanol. The nitrovinylmethoxyindole thus prepared is then reduced to the desired methoxyindol-2-ylethylamine by treatment with lithium aluminum hydride in dry ether. The reduction mixture is gently heated to reflux for 10 hours, after which the excess lithium aluminum hydride decomposes. After filtration, the filtrate is concentrated in vacuo to give a residue which is crystallized from a suitable solvent to give the desired methoxyindol-2-ylethylamine.

Example 5 Methoxyindol-2-ylpropylamine By modifying the procedure of Example 4, an appropriate methoxyindole-2-carbaldehyde (1 g) is treated in 0.5 ml of nitroethane with 4 drops of benzylamine; then the mixture is refluxed for 1 hour. The cold reaction mixture gives a precipitate of dark red crystals when it is allowed to stand, which can be recovered, washed with a small amount of ether, dried and crystallized from ethanol. These nitropropenylindoles prepared in this way are reduced with lithium aluminum hydride as described above in Example 4. East products are crystallized and liquids are characterized as benzoyl derivatives.

Example Gel 6 Methoxyindol-3-ylethylamine See Young, J. Chem. Soc., 1958, 3493-96. This synthesis is based on methoxyindole-3-aldehydes, which are either commercially available or can be prepared by literature methods. Using the procedure outlined in Example 4 above, a suitable methoxyindole-3-carbaldehyde is condensed with a nitromethane using ammonium acetate as catalyst. When the cooled solution is allowed to stand, dark red crystals, which can be recrystallized from benzene or methanol, gradually precipitate to give the 3-nitrovinylmethoxyindole, which is reduced with lithium aluminum hydride as above to obtain the desired methoxyindol-2-ylethylamine.

Example 7 Methoxyindol-3-ylpropylamine A selected methoxyindole-3-carbaldehyde (5 g), 10 ml of nitroethane and 1 g of ammonium acetate are heated on a steam bath with occasional shaking for 0.5 hours. Upon cooling, the crystals are recovered, which are 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 indicated above.

B. Intermediates of Formula IV Example Gel 8 2-112,3-Epoxy) propoxybenzonitrile A solution of 25.0 g (0.21 mol) of 2-cyanophenol, 117 g (0.26 mol 15 45 455 865 19 mol ) epichlorohydrin and 10 drops of piperidine were stirred and heated on an oil bath for 2 hours at 115 - 1200. The reaction mixture was then concentrated (190 ° / 30 torr) to remove unreacted epichlorohydrin. The residue was diluted with toluene and concentrated to dryness twice for to remove the last traces of volatile material.

The residual oil was dissolved in 263 ml of tetrahydrofuran and this solution was stirred for 1 hour at 40-500 with 263 ml of 1N sodium hydroxide. The organic layer was separated and concentrated to give an oil which was combined with the aqueous phase. The mixture was extracted (CH 2 Cl 2) and the extract was dried over magnesium sulfate and concentrated to give 36.6 g (100%) of an oil which slowly crystallized to a waxy solid. This intermediate can be used without further purification in the preparation of products of formula I.

Example 9 2- [YZ, 3-epoxy) propoxy] -4-methoxybenzonitrile The required 5-methoxyalicylaldehyde can be obtained starting from 4-methoxyphenol by the Reimer-Tiemann method, which is well described in the literature; see, e.g., 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 is treated with 0.4 g (0.02 mol) of hydroxylamine hydrochloride and refluxed for 4 hours. The mixture is concentrated in vacuo to a gray syrup, which is stirred with 50 ml of water and the suspension is decanted.

Addition of 10 ml of water to the resulting glassy material, followed by cooling to 50, gives after filtration about 1.2 g of solid raw material, which is taken up in 25 ml of 50% ethyl ether-isopropyl ether. The ether solution is filtered, dried over magnesium sulphate, 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 oxime. A mixture of 0.002 mol of the oxime and 1.02 g (0.01 mol) of acetic anhydride is refluxed for 30 minutes and then cooled to 25 °. 50 ml of water are added, followed by dropwise addition of 20% sodium hydroxide to pH 10. The resulting suspension is stirred for 20 hours at 250 (to hydrolyze any acetate ester of the desired phenol derivative). The pH was adjusted to about 2 using 6N hydrochloric acid and the resulting mixture was extracted with 40 ml of ethyl acetate to give an organic layer which was separated, dried over magnesium sulphate and evaporated at 650/70 dry to give a brown syrup which was still mainly consists of the acetate ester. Further hydrolysis of the syrup in a mixture of 7 ml of methanol, 7 ml of water and 0.1 g of NaOH pellets at 250 for 3 hours is followed by removal of the methanol at 600/70 torr. Dilution of the aqueous residue with 0.5N hydrochloric acid gives a precipitate which can be crystallized from isopropyl ether and dried to give 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 is stirred for 15 minutes at 500. 2.8 g (,02 mol ) epibromohydrin is added in one portion and stirring is continued for 3 days. The reaction mixture is poured into 1 liter of brine and the resulting suspension is stirred for 3 hours at 0-50. Filtration of the mixture and washing of the filter cake with water gives on drying in air the crude intermediate which can be used without further purification.

By similarly using other substituted 2-cyanophenols in modifications of the above processes, other intermediates of formula IV are obtained, which can be used in the synthesis of various compounds of formula I according to the present invention. 10 15 20 25 30 35 -., 4g55-865 21 Synthesis of products Example 10 General procedure: 2- [E-hydroxy-3-hydroxyindolyl) alkylamine] propoxy7benzonitrile A selected methoxyindolylalkylamine (III) is mixed with an equimolar amount or a slight excess of a selected epoxy-propoxybenzonitrile (IV) and the coupling is carried out by either refluxing a solution of the reactants for about 18 - 24 hours or heating a pure mixture at a temperature of about 120 - 1300 for about 0.5 - 2 hours. Ethanol and toluene are the solvents usually chosen as 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, adding additional epoxide IV 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 subsequent steps or the methoxy intermediate can be purified by crystallization-recrystallization either as the base or as a suitable acid addition salt.

A solution of the methoxyindolyl product (II) is dissolved in methylene chloride and stirred under a nitrogen atmosphere at 0-100 while a multiple excess of 1N boron tribromide in methylene chloride is added dropwise. After the addition, the reaction mixture is stirred for about 6-8 hours at room temperature. The excess boron tribromide is decomposed by cooling the reaction mixture and adding dropwise an excess of water. The crude hydrobromide salt of the product 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 and so on.

The modifications necessary to adapt this process to the preparation of specific compounds of formula I are well within the skill of the art.

Example 11 2- [2-hydroxy-3- [2- (6-methoxy-1H-indol-3-yl) -1,1-dimethylethyl] amino] propoxyphenzonitrile A solution of 2.6 g (0.012 mol) of 6- methoxyindol-3-yl-t-butylamine (prepared according to Example 1a), 2.1 g (0.012 mol) of 2- - [Y2,3-epoxy) propoxy] benzonitrile (prepared according to Example 8) and 100 ml of absolute ethanol refluxed with stirring for 20 hours. Additional epoxide (0.21 g) was added and refluxing was continued for 4 hours, after which the mixture was concentrated to dryness and the residue was triturated in isopropyl alcohol to induce 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), m.p. 145 DEG-146 DEG, which was used directly in subsequent steps.

A solution of 1.5 g (0.004 mol) of the above-prepared methoxyindole product in 225 ml of methylene chloride was stirred under a nitrogen atmosphere at s-10 ° while 15.3 ml (0.01 mol) of 1N 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 being cooled to 5-1 °, 47.5 ml of water being added dropwise. The resulting mixture was decanted and the resulting gummy solid was rinsed with two portions of water. Dissolution of this crude hydrobromide salt in 50 ml of hot water, followed by treatment with Darco G-60, filtration, cooling (250) and alkalization (ph 8) with concentrated ammonium hydroxide gave 1.2 g of a brown amorphous solid, which was chromatographed (silica gel 60, 230 - 400 mesh, EM reagent) on a medium pressure system with chloroform-methanol-concentrated ammonium hydroxide (90: 10: 1). The product thus obtained was crystallized from a small amount of 95% ethanol, whereby by gradual addition of water, 1.03 g (71%) of the desired 6-methoxyindole product were obtained. (I) as a brown solid with a melting point of 90 - 940.

Analysis Ber. for C 22 H 25 N 3 O 3 -1 / 3H 2 O: C 68.56 H 6.67 N 10.90 H 2 O 1.54 Found: C 68.69 H 6.68 N 10.68 H 2 O 1.80 NMR (nmso-d 6) = 0, 98 (6, s); 2.70 (4, m); 3.30 (2, bs); 3.83 (1, m); 4.11 (2, a [B, s H57), 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, 1 2230 and 3300 cm

Example 12 12 [1'-hydroxy-3- [Z2- (5-hydroxy-1H-indol-3-yl) -1,1-dimethylethylamino] propoxy] benzonitrile A solution of 2.7 g (0.0125 mol) of 5- methoxyindol-3-yl-t-butylamine (prepared from 5-methoxyindole using the procedure set forth in Example 1), 2.2 g (0.0125 mol) of 2- [X2,3-ethoxy propoxy] benzonitrile and 20 ml of acetone were refluxed for 0.5 hours. The acetone solvent was then boiled off and the oily residue was heated clean at 100 ° 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 and diluted with 50 ml of ether and a stir bar was used to rub a white powder, 4.7 g (96%), mp 119-124 °; Trc (9 = 1 cnc13-methanol) showed a single spot, Rf 0.25. This methoxirâ product can be used directly in subsequent steps or can be purified via conversion to the hydrochloride salt. Conversion to the hydrochloride salt by treatment of an acetonitrile solution with ethanolic hydrogen chloride gave a crude product, which was recrystallized from butanone ~ 95% ethanol (20: 1) to a off-white powder, m.p. 164 DEG-166 DEG. . 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 given in Example 11 for the removal of the boron tribromide cleavage of the methoxy group, but using the 5-methoxyindole intermediate (II) prepared as above, the desired 5-hydroxyindole product (I) could be obtained in the form of its hydrobromide salt. The pure hydrobromide salt is a beige powder with a melting point of 219-221 °.

Analysis Ber. for C 22 H 25 N 3 O 3 · HBr: C 57.40 H 5.70 N 9.13 Found: C 56.90 H 5.67 N 9.45.

NMR (DMSO-d 6): 1.32 (6, s); 3.08 (2, m); 3.36 (2.m); 4.30 (3.m): 5.90 (1.sB); 7.10 (6.m): 7.71 (2.m); 3.55 (3, bS); 10.95 (1, bs); IR (KBr): 750, 800, 1265, 1290, 1455, 1495, 1580, 1600, 2230 and 3300 cm -1.

Based on the appropriate methoxyindole alkylamines (III) and epoxypropoxybenzonitriles (IV), additional products of formula I can be synthesized using essentially the same procedures as indicated above with only minor modifications which are well within the skill of the art.

Some of the additional products of formula I that can be synthesized in this way are shown in Table 1 below. 10 15 20 25 30 Biem- pel 13 11. 15 16 1-7 18 19 2o \ _ 22. 23. 214 25., ze_ 27 »za 29 so 31 sz 33 34 455 865 25 Table 1 m2 RB å N / \ / \ o Rs N H- OH _ 1 Rl (I) CN R X2 RR RS H 2-3 Me He HB 2-1! He He E Me 2-1! “Me Me H Me 2-H - Me Me SF He 2-3 Me Ne S-OH Me 2-H Me Me H Me 3-13 H Me H Me 3-HH Me SF Me 3-HH He H Me SH HH Å-He H Z-Me H Me HE _2-Me HHHH 2-He He He HIH z-ne ne ne nn 3-14; nn s-on H B-Me H He SF H B-Me H Me HH 3-Me HH 5-31 'H 2-11 H Me S-Me H ZH H Me Å-Cl 11 zn n uee u_ H zH H Me ß-on 10 15 20 25 30 35 455 865 26 Biological evaluation The following biological tests were used to determine the antihypertensive profile of selected compounds of formula I.

Exemgel 35 The efficacy of antihypertensive agents other than adrenergic beta-receptor blockers is usually determined in spontaneously hypertensive rats. Blood pressure values are determined in the experimental animals before and 20 hours 4 hours after orally administered doses of 30-100 mg / kg of the test compounds.

The heart rate is determined simultaneously with each pressure measurement. A drop in blood pressure of 15 - 20 mm Hg 2 or 4 hours after administration of a single dose is considered "questionable". The terms "active" and "inactive" refer to reductions greater and less than this range, respectively.

Example Gel 36 Another test useful in determining the efficacy of antihypertensive agents utilizes DOCA-salt hypertensive rats. These hypertensive rats are prepared as follows: Male rats belonging to the Sprague Dawley strain weighing about 90 g are kept individually in cages with free access to food and water for a pre-treatment period of 5 days, after which the drinking water is replaced. with a 1% saline solution. During a three-week treatment period, the dishes are given a total of ten subcutaneous injections containing 10 mg of DOCA (deoxycorticosterone acetate) in 0.2 ml of suspension vehicle (0.25% Tween 80 and 0.125% CMC in normal saline). After the final injection, the 1% saline solution is replaced with distilled water and the animals are then available for testing 1 week later.

The test is performed by selecting animals which have not fasted and which have an elevated cystolic blood pressure (> 160 10 15 20 25 30 35 455 865 27 mm Hg). The blood pressure values are determined for these test animals before and 4 hours after orally administered doses of 30 - 100 mg / kg of the test compounds. During the experimental period, the animals are kept in metabolic cages without food or water and the urine is collected for 4 hours. Heart rate and body weight are determined simultaneously with each pressure measurement. A drop in blood pressure 4 hours after dosing in the range of 15 - 20 mm Hg is considered "questionable". The terms "active" and "inactive" refer to reductions greater and less than this range, respectively.

Example 37 The angiotensin II-supported ganglion-blocked rat model is used as a screening test to evaluate the vasodilator component of the activity. The percentage changes in blood pressure of anesthetized rats are measured 30 minutes after intravenous dosing. The intravenous dosing is performed with 3 mg test compound / kg. The borderline activity is defined as approximately a 10% reduction in blood pressure, measured 30 minutes after dosing. The terms "active" and "inactive" refer to increases greater or less than this.

Example 38 The diastolic blood pressure and heart rate response to an established administered dose of isoproterenol are measured before and 15 minutes after graduated doses of the test compound, which is administered intravenously to anesthetized dogs within a three minute interval. A branch of a femoral artery and vein is cannulated to detect blood pressure and to administer the drug, which is dissolved in saline. The vagus nerves are sectioned bilaterally in the intercervical region of the neck and the dogs are mechanically ventilated (Harvard respirator) with room air at a speed of 20 / min. and a stroke volume of 20 ml / kg. The heart rate is monitored with a cardiotachometer triggered by the pressure pulse. All measurements are recorded on a Beckman-R-612 printer. The drug effect is expressed as the cumulative dose (pg / kg) which causes 50% inhibition of the isoproterenol response.

Exemgel 39 Male rats (Wistar) are anesthetized with a combination of urethane and chloralase intraperitoneally. After induction of anesthesia, chlorisondamine is injected into the peritoneal cavity to induce ganglion blockage. One femoral artery is cannulated to measure blood pressure and heart rate and two femoral veins are cannulated for administration of the compounds. Trachea is intubated and the rats are allowed to breathe spontaneously. The animals are administered pre- and 15 minutes after intravenous administration of the test compound graded doses of phenylephrine and the changes in blood pressure are recorded. Data are plotted in a dose-response curve and the dose of phenylephrine required to induce a 50 mm Hg (ED50) increase in blood pressure is interpolated from the curves. Dose shifts are calculated by dividing the ED50 value after drug delivery by the ED50 value before drug delivery.

COMPARATIVE EXPERIMENTS The blocking activity of three compounds of U.S. Patent 4,234,595 (designated as Compounds 1, 2 and 4 in the table below) was compared with the corresponding activity of two representative compounds of the present invention (Compounds 3 and 5 in the table below). , which are otherwise the compounds specified in claim 5. The experiments were performed in accordance with Example 39.

The results of the pharmacological comparative tests are presented in the table below. 10 15 20 455 865 29 RHN OH H cN 0 & blocking (ex. 39) Compounds no. R (dose shift) 1 H 5 i 0 2 s-ome 8.1 i 1.7 3 5-OH l2 il 4 ß-ome 5, 9 in 0.7 5 6-OH 23 1 1 From these results it can be concluded that the compounds 3 and 5 of the present invention are about 2-4 times more potent as blockers than the compounds of the prior art. This is an unexpected and surprising effect that is achieved when a hydroxy substituent is introduced into the 6-ring of the indole group.

Claims (9)

10 15 20 25 30 4§5 ses 3G Patentkrav Compounds of formula 2 R 3 R 3 R 3 S R m, .X j. 'Mo R OH I R 1 CN' (1) and acid addition salts thereof, wherein one of RT and R 2 is hydrogen and the other is hydrogen or C 1-4 alkyl; R 3 and R 4 are independently hydrogen or C 1-4 alkyl; and R 5 is halogen, hydrogen, hydroxy or C 1-4 alkyl; wherein the phenoxypropanolaminoalkyl side chain is attached to the indole ring in either the 2- or 3-position and the hydrocyl substituent occupies either the 4-, S-, 6- or 7-membered position of the indole. Compounds according to claim 1, characterized in that the indolyl ring is attached in its 3-position to the phenoxypropanolaminoalkyl side chain. Compounds according to claim 1, characterized in that R and R 2 are hydrogen, R 3 and R 4 are methyl and R 5 is hydrogen or 5-fluoro. Compounds according to claim 1, characterized in that the hydroxyl substituent occupies the 6-ring position of the indole. s. The compounds z-phenylaroxy-z- [Q- (s-hyaroxy-uhindol-s--yl) -1,1-dimethylethyl] amine propoxybenzonitrile and 2-β-hydroxy-3-β-2- (5- hydroxy-1H-indol-3-yl) -1,1-dimecylethyl] - amine Q7propoxybenzonitrile according to claim 1. A pharmaceutical composition in unit dosage form for the treatment of hypertension, characterized in that it comprises a pharmaceutically acceptable carrier and from 0.1 to 100 mg per kg of body weight of a compound of formula I according to claim 1. Pharmaceutical composition according to Claim 6, characterized in that it contains the compound 2-12--hydroxy-3- [ZÉ- (6-hydroxy-1H-indol-3-yl) -1,1-dimethylethyl] amine propoxybenzononitrile of the formula or z- [E-hyaroxy-α- [β- (s-hydroxy-nq- -indol-3-yl) -1,1-dimethylethyl] -amino] propoxybenzonitrile of the formula CH3 CH3 H0 / \\ | u on N CN H v 10 15 20 25 30 455 865 sl A process for the preparation of a compound according to claim 1 of formula 2. R. Ra Ra s ~ R no ~% - '\ §' / ~ \ 1 “/ \ * ou« f 'on' 1 cs R (I) or an acid addition salt thereof, in which formula one of R1 and R2 is hydrogen and the other is hydrogen or C 1-4 alkyl; R 3 and R 4 are independently hydrogen or C 1-4 alkyl; and R 5 is halogen, hydrogen, hydroxy or C 1-4 alkyl; wherein the phenoxypropanolaminoalkyl side chain is attached to the indole ring in either the two- or 3-position and the hydroxyl substituent occupies either the 4-, 5-, 6- or 7-ring position of the indole, characterized in that a) a methoxylated indole alkylamine is coupled III R, 3 Rz. nzn 'I R. '(111)' wherein R 1, R 2, R 3 and R 4 have the meanings given above, with a (R 5 -substituted phenoxy oxide) IV 455 865 wherein R 5 has the meanings given above, by heating the compounds III and IV together either as such or in the presence of a reaction-inert organic solvent, for the preparation of an intermediate II R1 Ra R3 R2 wherein R 1, R 2, R 3, R 4 and R 5 having the above meanings, wherein- (b) reacting intermediate II under appropriate conditions so that the methoxy group is cleaved to a hydroxyl group and so that a compound of formula I is formed and then c) optionally, if a pharmaceutically acceptable acid addition salt of formula If desired, the product in step (b) converts to said salt by methods known per se. 30 9. A process according to claim 8, characterized in that step (b) comprises reacting the intermediate II with boron tribromide in methylene chloride solution under such reaction conditions that a compound of formula I is formed. r