LU85410A1 - 1-PHENOXY-3-HYDROXYINDOLYLALKYLAMINO-3-PROPANOLS AND THEIR PREPARATION - Google Patents

Description

Λ

'V

1-PHEN0XY-3-HYDR0XYIND0LYLALKYLAMIN0-3-PR0PAN0LS AND THEIR PREPARATION

The present invention relates to heterocyclic carbon compounds of the Vindole series having a friend no substituent and it relates to biologically effective drugs containing them as well as the application of these compounds to the treatment of the body.

^ There is a large amount of prior literature relating to many series of compounds classified as 3- (aryloxy) -2-hy-droxypropylamines. Most of these series include agents useful in the treatment of cardiovascular disease, particularly because of their beta-adrenergic receptor blocking activity. Many compounds in this general class also have some degree of vasodilatory efficacy due, in some cases, to their inherent alpha-adrenergic receptor blocking activity.

Various other effects of cardiovascular drugs, or lack thereof, combine to make some of these compounds useful as antihypertensive agents. Most of the documents of the prior art however relate to the property of the beta-adrenergic blocking agent of these series of compounds. The prototype of structures of this kind is propanolol; chemically, 1- (isopropylamino) - 3- (1-naphthyloxy) -2-propanol. Propanolol and some related naphthyloxypropa-nolamines form the subject of U.S. Patent No. 3,337,628 issued August 22, 1967. Numerous subsequent patents have been granted which cover series of compounds representing i 3- ( aryloxy) -2-hydroxypropylamines whose structure is modified.

Λ A series of indole-3-yl-tertio-butylaminopropanols (1,2) having antihypertensive properties is described in US Pat. No. 4,234,595 to Kreighbaum et al. issued November 18, 1980, U.S. Patent No. 4,314,943 issued February 30, 1982; and in the Journal of Medicinal Chemistry, 23/3, 285-289 (1980).

i 2 '-Ort? ^ “i1 5 (1)

CN

",> JAt — ΓΧί '" Ρ “' -“ i1 (2) 3 w 15 In these structural formulas above, the symbol R may C represent hydrogen, halogen, lower alkyl or alkoxy but is - not a hydroxyl .

A preferred compound of structural formula (1) and designated under our reference MJ 13105 is known under the name adopted in the United States of bucindolol, and it is currently under clinical evaluation as a hypertensive agent,

CN

Οθ * Τ-0

H

MJ 13105 c It is of interest with respect to the compounds according to the present invention that a main metabolic pathway of MJ 13105 involves T hydroxylation in position 6 of the indolic cycle. This is confirmed by comparison of the metabolism isolates with the corresponding 6-hydroxyindolyl obtained synthetically of the present invention.

Attention is also drawn to the application filed in the United States on September 3, 1982 by the Applicant No. 414 748 which describes a series of vasodilating agents having a certain beta-adrenergic blocking potential and having the structural formula (3 ).

3 • ^ ÿvr ^ ·

ί 'OH

5 b '(3)

While in the above structural formula (3), C may, among other substituents, represent a hydroxyl, this series differs in general from the compounds of the present invention in that the compounds of structure (3) are pyridinyloxypropanolamines.

The present invention includes the compounds of formula I and the acid addition salts of these substances.

? "

20 (H

1 5

In the previous structural formula, the symbols R to R have the following meanings. One of the radicals R and R represents a hydrogen and the other a hydrogen or a C1-C6 alkyl; R ^ and R ^, independently, are chosen between hydrogen or C 1 to C 4 alkyl, and R 5 may represent halogen, hydrogen, hydroxy or C 1 to C 6 alkyl.

4 2 3 4 and R will always be hydrogen while R and R are chosen independently and can both represent an alkyl.

5 R may represent a halogen, preferably fluorine or chlorine, or alternatively hydrogen, hydroxyl or lower alkyl. The indolyl system is attached to the side chain either in position 2 or in position 3, and the hydroxyl substituent occupies positions 4, 5, 6 or 7 of the indole cycle.

1 2 For the preferred compounds, R represents hydrogen, R

represents 2-hydrogen (the indole radical being coupled to the main side chain by its position 3); R and R represent methyl 5 and R represents hydrogen or 5-fluoro.

For medical use, the pharmaceutically acceptable acid addition salts, i.e. the salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the organic cation, are the ones you prefer. The acid addition salts are obtained either by reaction of an organic base of structure I with an organic or mineral acid, preferably by contact in solution, or by any standard method described in the technical literature and available to any experienced practitioner. Useful organic acids are, for example, carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclamic acid, pi valic acid and the like; useful mineral acids are for example hydracids such as HCl, HBr, HT, sulfuric acid, phosphoric acid, etc.

It is also understood that the compounds according to the present invention comprise all the optical isomeric forms, that is to say mixtures of enantiomers, for example racemic varieties as well as the individual enantiomers. These individual enantiomers are conventionally designated according to the optical rotation to which they give rise by (+) and (-), (1) and (d) or combinations of these symbols. The symbols (L) and (D) and the symbols (S) and (R), which signify left and right respectively, denote an absolute spatial configuration of the enantiomer. When no isomer designation is given for a compound, the compound is the racemic variety.

The individual optical isomers of the class of aryloxypropanolamine compounds, of which the compounds according to the present invention are members, were most generally obtained by one of the following four basic methods, namely: 1) fractional recrystallization chiral acid salt derivatives; 2) derivatization using a chiral organic reagent, the? 5 resolution and regeneration of the original compound in its optically active form; r- '3) synthesis of the single optical isomer using chiral intermediates; and 4) column chromatography using chiral stationary phases.

The applications of these various methods are well known to those skilled in the art.

Biological tests of representative compounds of formula I on animals demonstrate that they have biological properties making them useful as antihypertensive agents. In addition to the hypertensive activity which can be demonstrated by animal tests, the compounds according to the present invention also have vasodilator properties at the same time as, to varying degrees, blocking properties of the alpha and beta adrenergic receptors and intrinsic sympathomimetic activity. A more detailed description of the specific pharmacological tests used and the criteria used to judge the relevant biological activity is contained in the description which follows. Preferred representative members exhibit a particularly desirable combination of the foregoing actions and auxiliary pharmaceutical effects or a lack thereof which makes them particularly suitable for specific cardiovascular indications, for example, for use as an anti -hypertensives. The usefulness of the compounds of formula I can be demonstrated in various animal models, as mentioned above, including the antagonism of isoproterenol in the anesthetized dog treated intravenously (adrenergic action of the beta receptor), spontaneous rat hypertension and rat hypertension caused by DOCA salt (anti-hypertensive action), rat ganglion model maintained by angiotensin (vasodilator action) and anesthetized rat model 35 (alpha-adrenergic blocking) and on various other models of laboratory animals {cf. Deitchman et al., Journal Pharmacological Methods, 3, 311-321 (1980)}.

6 As examples, two of the representative compounds of formula I; 2- {2-hydroxy-3 - [(2- (6-hydroxy-1H-indol-3-yl) -1, 1-dimethylethyl) ami-no] propoxy) benzonitrile and 2- {2-hydroxy- 3-C (2- (5-hydroxy-1H-indol-? 3-yl) -1, 1-dimethylethyl) amino] propoxy> benzonitrile cause an average systolic blood pressure drop in rats greater than 20 mm of mercury in one or two of the antihypertensive tests when administered at a dosage level of 30 mg / kg po An intravenous dose of 3 mg / kg of these compounds produces a drop greater than 20¾ in average arterial blood pressure (taken 30 minutes after administration) in the vasodilation test.

In their use as antihypertensive agents, vasodilators and / or adrenergic blocking agents, the compounds according to the present invention are administered sysmetically, both orally and parenterally in an effective, non-toxic amount of one compound of formula I or a pharmaceutically acceptable acid addition salt thereof. An effective amount means a dose which exerts the desired pharmacological activity such as that set out above without exerting undue toxic side effects when administered to a mammal in need of such treatment. The 20 doses vary depending on the subject and the route of administration chosen, the range to be expected being from about 0.1 mcg to 100 mg / kg body weight of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof generally providing the desired therapeutic effect. The preferred effective dosing interval should be about 0.1 to 0.5 mg / kg when given intravenously and about 0.5 to 5 mg / kg when given intravenously oral.

The compounds according to the present invention can be prepared by a suitable general process. This process is described below in Scheme 1.

^ In the following application, Me means a methyl group and Ac 5 means the acetate ion 35 7 I t i

Diagram 1 + “* -1 i1 (IV) (III) 1 10 CN R4 r3 R2 ..... Çcl2 ^ - © Co- ^ gX - ^^ - oMe 0H l1 x 15 ψ (II) 2 3 4

R1 ° H CN

(I) 25 in which: 1 5 R to R are as defined above.

This process indicates the coupling of a suitable methoxylated indolalkylamine (III) with a phenoxy epoxy intermediate substituted at R ^ (IV). The synthesis methodology necessary to reach this point in the preparation of the products of formula I is analogous to a synthesis process used to prepare bucindolol. The corresponding patents of Kreighbaul et al., U.S. 4,234,595 and U.S. 4,314,943 and J. Med. Chem. 23/3, 285-289 (1980) are incorporated into the present application for reference. However, an additional step is necessary since the methoxylated indole analog (II) which results therefrom is transformed into the desired product (I) by cleavage of the methoxy group with tri boron bromide in a solution of 8 ί methylene chloride. . Other synthetic methods producing conversion to hydroxylated products, such as for example hydrogenolysis of benzyloxy precursors, are well known to confirmed chemists and they can also be adapted for use in a modified process.

5 The coupling of the intermediate epoxyether (IV) with the i ndolyl al - -L kylamine (III) to give the intermediate (II) is carried out * simply by heating the epoxyether, either pure or in presence of an inert organic solvent reacting with the appropriate indolylalkylamine as shown. No catalyst or condensing agent is usually required. Suitable solvents include 95% ethanol but other inert organic liquids for the reaction in which the reactants are soluble can also be used. These include, but are not limited to, benzene, tetrahydro-furan, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures range from about 60 to 200 ° C.

The necessary reaction intermediates, III and IV, can be obtained by various methods and are not limited to the following. The phenoxy epoxide (IV) intermediates can be obtained by alkylation of the appropriate R (V) substituted cyanophenol with epichlorohydrin as in Scheme 2; or in recalcitrant cases, using epibromohydrin, I ^ COg and dimethylformamide.

Figure 2 25 HOC — 3 - "- Owj 30 (V) (IV)

Although many cyanophenols (V) are commercially available, they can also be conveniently prepared from readily available phenols by the synthesis route described as Scheme 3.

9

Diagram 3

^ CHO CH = NOH

; s * s-O. „s-’ -oc. -oc.

Co

10 Ψ

CN

-at.

(15) This sequence essentially involves the formylation of a phenol substituted by in the Reimer-Tiemann conditions to provide the silicylaldehyde derivative which is transformed via the oxime intermediate into salicylonitrile (V). It should be noted that, when products of formula I are desired in which R represents a hydroxyl, the intermediate IV in which R represents methoxy must be used in scheme 1. Cleavage by BBrg to obtain the hydroxyl group is carried out in the last stage of the synthesis.

For indolylalkylamines, intermediates of structure III, typical synthetic procedures for their preparation are available in the patents of Kreighbaum et al 1. and the article by J. Med. Chem, cited above and incorporated into this application for reference. Although these procedures by reference are applicable to the preparation of other indolylalkylamine intermediates which may be desired but are not specifically described herein, representative syntheses of compounds of formula III will be given below, by way of more detailed examples of intermediates which may be necessary for the present invention.

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Finally, it is interesting to note that a 6-hydroxy-indolyl compound of formula I, 2- {2-hydroxy-3-L (2- (6-hydroxy-1H-indol-3-yl) - 1, 1-dimethylethylaminaminpropoxylbenzonitrile, which corresponds in structure to bucindolol (R, R and R3 represent hydrogen, and R "5 and R4 represent methyl) is used to confirm the identity i of a major metabolite of bucindolol. It is known that hydroxylation if at position 6 is perhaps more important than hydroxylation at position 5 in the metabolism of tryptamine derivatives (cf. Jepson et al!, Biochim. Biophys. Acta., 62, 91 (1962); Jaccarini and Jepson, 10 Biochim. Biophys. Acta., 156, 347 (1968). These references suggest the possibility that the 6-position hydroxylation of bucindolol may be an important metabolic pathway. This has been confirmed by the demonstration that this compound 6-hydroxyindolyl according to the present invention agrees by its mass spectrum and its retention time in j phase chromatography gas with a major hydroxy metabolite corresponding to bucindolol. In this regard, another aspect of the present invention includes 2- {2-hydroxy-3 - [(2- (6-hydroxy-1H-indol-3-yl) -1, 1-dimethylethyllaminolpropoxylbenzonitrile in its pharmaceutically purified form acceptable.

The compounds according to the present invention can be formulated according to conventional pharmaceutical practice to provide pharmaceutical compositions in the form of unit dosages comprising for example pastilles, capsules, powders, granules, emulsions, suspensions and the like. Solid preparations contain the active ingredient in admixture with non-toxic pharmaceutical excipients, such as inert diluents, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating and disintegrating agents, for example, corn, starch or alginic acid; binding agents for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The pellets may not be coated or they may be coated by known techniques so as to retard disintegration and absorption in the gastrointestinal tract and thereby provide delayed action over a longer period. 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 ingredients in admixture with one or more pharmaceutically toxic excipients known for suitable for the preparation of aqueous suspensions. Suitable excipients are, for example, suspending agents such as sodium, carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrol idone, gum tragacanth and gum acacia. Distribution agents or wetting agents j are for example naturally occurring phosphatides, lecithin, polyoxyethylene stearate.

Non-aqueous suspensions can be formulated by suspending the active ingredient in vegetable oil, for example, olive oil, sesame oil or coconut oil, or in mineral oil, for example liquid paraffin. The suspensions may contain a thickener such as beeswax, hard paraffin or cetyl alcohol. Perfumes and sweeteners generally used in pharmaceutical compositions can also be included such as saccharin, sodium cyclamate, sugar and caramel to provide a preparation with better taste. The compositions may also contain other absorbents, stabilizers, wetting agents and buffers.

The compounds constituting the present invention, their method of preparation and their biological actions will appear in more detail when considering the following examples which are given by way of illustration only and should not be understood as limiting the scope of the invention. In the following examples used to illustrate the previous synthesis methods, the temperatures are expressed in ° C and the melting points are not corrected. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical derivatives (δ) expressed in part per million (ppm) with respect to tetramethylsilane (TMS) serving as a reference standard. The relative area indicated for the various drifts in the NMR spectral data H corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the drifts when at their multiplicity is indicated in the form: broad singlet (bs), singlet (s), 'multiplet (m), or doublet (d). The abbreviations used are: DMSO-dg 35 (deuterodimethylsulfoxide), CDCl 4 (deuterrochloroform) and the others are in fact conventional.

The infrared spectrum (IR) descriptions only contain the absorption wave numbers (cnf ^) having an identification value 12 of a functional group. The IR determinations are used with the use of potassium bromide (KBr) as a diluent. The elementary analyzes are indicated in percentage by weight (¾ by weight). Synthesis of intermediates 5 A. Intermediaries of formula III: General procedures L EXAMPLE 1 s Methox.yi ndol -3-yl -terti o-butyl ami ne To 15.2 ml of a cooled 25% aqueous solution of dimethyla -mine, the following is added in sequence while stirring and continuing the cooling: 16.9 ml of acetic acid, 7.2 ml of 37% formaldehyde, 27 ml of 95% ethanol. The resulting stirred solution is kept at a temperature of 0 to 5 ° using a cooling bath while the appropriate methoxyindole (10.0 g, 0.07 mole) is added in portions. This mixture is stirred and is gradually heated to 30 ° C over a period of half an hour and is then kept at 30 ° C, with stirring, for 3 hours. The reaction mixture is then cooled β 10 to 15 ° C and it is acidified with 170 ml of 2N HCl. This acid mixture can be discolored (Darco G-60), filtered and the filtrate is made basic by using 245 ml of 20% NaOH while cooling and stirring. The resulting brown oily precipitate is extracted with ether and the extracts are washed with water, dried (MgSO 4) and concentrated, giving a brown oily residue (14 g). The residue is recrystallized, for example in isopropyl ether and hexane, to give the desired methoxygramine, usually as a brown solid.

A mixture of the appropriate methoxygramine (7.7 g, 0.04 mole), 2-nitropropane (26.5 g, 0.3 mole) and NaOH (1.7 g of lozenges, 0.04 mole) is treated at reflux under a nitrogen atmosphere for 3 to 5 hours. The reaction mixture is then cooled to room temperature, acidified with 10% acetic acid and extracted with ether. The ethereal extracts are washed with water, dried (MgSO 4) and concentrated in vacuo to give a residue. Recrystallization of the residue, for example from an isopropyl alcohol-water mixture, gives a 3- (2-methyl-2-nitropropyl) methoxyindole.

This nitropropylindole and activated Raney nickel (4.2 g) are put together in 80 ml of 95% ethanol and heated to reflux. Heating is stopped while a solution consisting of 85% hydrazine hydrate (7.8 g) in 8 ml of 95% ethanol is added dropwise. The reaction mixture is then heated at 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 an ethyl acetate-isopropyl ether mixture, which gives the desired product, methoxyindole-3-yl-t-butylamine.

- EXAMPLE 6-methoxyi ndole-3-yl-terti o-butylami does

A mixture of 6-methoxy gramine (0.9 g, 0.004 mole); prepared from 6-methoxyindole by the procedure of Example 1, 3.0 g 10 (0.034 mole) of 2-nitropropane and 0.19 g (0.005 mole) of NaOH pellets, is stirred at reflux in the bath of oil under a nitrogen atmosphere for 2 hours while dimethylamine escapes through the condenser. The resulting mixture is cooled to 25 ° C, treated with a solution of 0.47 ml of glacial acetic acid in 4.1 ml of water and extracted with ether. The ethereal extract is washed with 3 portions of water, dried (MgSO 4) and it is evaporated to dryness. The residual brown oil crystallizes out from friction and cooling in a small amount of isopropyl ether. The solid is isolated by filtration, washed with cold isopropyl ether and it is dried in air, which gives 0.6 g of a brown solid which is recrystallized from an isopropyl alcohol-water mixture, which gives 0.52 g (46%) of 3- (2-methyl-2-nitro-propyl) -6-methoxyindole, melting point 98-99 ° C.

A slurry of 8.0 g (0.32 mole) 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), is heated to reflux while stirring with blades. The outdoor heating is stopped and a solution of 7.8 g of 85% hydrazine hydrate in 8 ml of 95% ethanol is added dropwise at a speed sufficient to maintain moderate reflux. After the addition, the mixture is heated at reflux for 2 hours and then cooled to 25 ° C. Filtration and concentration of the filtrate to dryness gives a crude syrup which is passed by chromatography on a column of silica gel, elution is carried out with a concentrated mixture (CHgC 4 -CHgOH-NH 4 OH) (90/10/1). The brown solid thus obtained; (2.9 g, melting point 125-128 ° C) is recrystallized from a mixture of ethyl acetate-isopropyl ether, which gives 1.27 g (18%) of 6-methoxyindole-3-yl-tertio -butylami ne, melting point 125-128 ° C.

EXAMPLE 2 Methoxyindole-2-yl-tertio-butylamine (r \ = H, R ^, = Me)

In this general procedure, a solution comprising the appropriate methoxyindole-2-carboxylic acid (0.06 mole) and thionyl chloride (2.0 g, 0.17 mole) 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 taken up in 150 ml of dry ether. This ethereal solution is treated with 80 ml of dimethylamine in 90 ml of ether. The ethereal reaction mixture is concentrated to dryness and the residue is crystallized from isopropyl alcohol. The solid is isolated by filtration, which gives a yield of 30 to 40¾ of the product, methoxyindole-2-carboxa-mide.

The methoxyindole-2-yl-carboxamide is dissolved in 100 ml of THF ^ 15 and this solution is added dropwise to a stirred suspension consisting of 3 g of lithium aluminum hydride in 50 ml of THF under; nitrogen atmosphere. After heating at reflux for 2 hours, the reaction mixture is cooled and it is decomposed with a small amount of water and a dilute NaOH solution. This mixture is filtered and the filtrate is concentrated to a residual oil which is taken up in absolute ethanol and which is treated with a slight excess of dimethyl sulfate. The resulting alcoholic solution is stirred at room temperature for 4 hours and is then concentrated to dryness in vacuo to give a quaternary salt of trimethylamine as a residue.

The crude quaternary salt produced (0.01 mole) is combined with NaOH (2.0 g of pellets, 0.05 mole) and 2-nitropropane (15 ml) and the mixture is heated at reflux under a nitrogen atmosphere for 1 hour. The resulting thick and dark mixture is cooled, diluted with water, acidified with acetic acid to a pH of about 6 and then extracted with ether. These ethereal extracts are then combined, washed with water, dried (MgSO 4) and concentrated in a dark residue which is passed by chromatography on a column of silica gel and which is diluted; with methylene chloride. The removal of the methylene chloride solvent and the recrystallization of the raw material in an isopropyl alcohol-water mixture gives a methyloxyindole substituted in position 2 by a 2-methyl-2-nitropropyl radical.

\ 15

Reduction of this nitro compound with Raney nickel and hydrazine according to the procedure used in Example 1 above gives the desired methoxyindole-2-yl-tert-butylamine.

EXAMPLE 3 5 Methylation in position 1 of methoxyindolylalkylamines: 3- (2- - amino-2-methylpropyl) -l-meth, yl-methoxyindole (R ^, R ^, = Me, = H)

In this general process, 7 g (0.11 mole) of 85¾ KOH are ground in a mortar and quickly transferred to a 25 ml Erlenmeyer flask purged with nitrogen. DMSO (55 ml) is added and the mixture is stirred for 5 minutes. The additions of methoxyindolyl-tert-butylamine (0.27 mole) and iodomethane (3.78 g, 0.03 mole or any suitable alkylating agent) are each followed by 45 minutes of stirring, after which the suspension is soaked in 30 ml of water. Extraction of this mixture with ethyl acetate, followed by washing the extracts with water and brine, gives a clear solution which is dried (MgSO 4) and evaporates under vacuum, an oily product is obtained. This free base can be used as an intermediate without further purification. Characterization is usually obtained by transforming the oily base into the hydrochloride in order to obtain a crystalline product.

EXAMPLE 4 Methoxyi ndole-2-yl-ethylami ne

In this operating mode which is essentially that of Bhat and Siddappa, J. Chem. Soc. (C), 1971, 178-81; various methoxy-indole-2-carboxylate esters (commercially available or prepared according to literature methods) are reduced to the corresponding derivatives of 2-hydroxymethylindole by reduction with lithium aluminum hydride in ether. The conversion to indole-2-carbaldehyde is accomplished by dissolving a 2-hydroxymethyl-methoxyindole (4 g) in dichloromethane (250 ml) and by adding activated manganese dioxide (10 g) and then stirring the mixture reaction at room temperature for 20 to 30 hours. The reaction is followed by TLC, monitoring of the disappearance of the starting 2-hydroxymethylindole task. If necessary, new quantities of - manganese dioxide (2 to 3 g) can be added. The reaction mixture is filtered and the manganese dioxide residue is washed several times with a little fresh dichloromethane. The combined filtrates are evaporated to dryness, which gives the crude methoxyindole-2-carbaldehyde in the form of a pale yellow solid which is then recrystallized.

16

Methoxyindole-2-carbaldehyde (5 g), nitromethane (8 ml) and ammonium acetate (1 g) are heated at reflux for half an hour. The reaction mixture is cooled and the dark red crystals which separate are collected, washed thoroughly with water, dried and crystallized from ethanol. The nitrovinylmethoxy-indole thus prepared is then reduced to the desired methoxyindole-2-yl-ethylamine by treatment with lithium aluminum hydride in dry ether. The mixture from the reduction is gently heated at reflux for 10 hours after which the excess lithium aluminum hydride is broken down. Following filtration, the filtrate is concentrated under vacuum, which gives a residue which is crystallized from a suitable solvent to obtain the desired methoxyindole-2-yl-ethylamine.

EXAMPLE 5 ^ 15 Methoxyi ndole-2-propylami ne

By modifying the procedure of Example 4, a methoxy-> indole-2-carbaldehyde (1 g) suitable in nitroethane (0.5 ml) is treated with 4 drops of benzylamine; following this, the mixture is heated at reflux for 1 hour. At rest, the cold reaction mixture leaves dark red crystals which can be collected, washed with a little ether, dried and crystallized from ethanol. These thus prepared nitropropenylindoles are reduced with lithium aluminum hydride as described above in Example 4. The solid products are crystallized and the liquids are characterized as derivatives of benzoyl.

EXAMPLE 6 Methoxyi ndole-3-yl-ethylami ne

See Young, J. Chem. Soc., 1958, 3493-96. This synthesis starts from methoxyindole-3-aldehydes which are either commercially available, or prepared from methods of the literature. Using the procedure described in Example 4 above, a suitable methoxyindole-3-carbaldehyde is condensed with a nitromethane using ammonium acetate as catalyst. At rest, the cooled solution gradually lets deposit dark red crystals which can be recrystallized from benzene or methanol, which gives 3-nitro-vinylmethoxyindole which is reduced with lithium aluminum hydride. as above, to obtain the desired methoxyindole-2-yl-ethylami.

17 EXAMPLE 7 Methoxyi ndolo-3-yl-propylami no

A selected methoxyindole-3-carbaldehyde (5 g), nitroethane (10 ml), and ammonium acetate (1 g) are heated in the steam bath with occasional stirring for half an hour . At

cooling, the crystals are collected, washed with hot water (2 x 50 ml) and crystallized from methanol. The resulting 3- (2-nitropro-penyl) -methoxyindole is reduced to the desired 3- (2-aminopropyl) -methoxyindole by treatment with lithium aluminum hydride as explained in detail in the procedures below. above. B. Intermediaries of formula IV

EXAMPLE 8 2 - {(2,3-epoxy) propox.y} benzonitrile

A solution of 2-cyanophenol (25.0 g, 0.21 mole), epichlorohydrin (117 g, 0.26 mole) and piperidine (10 drops) is stirred and heated to 115-120 ° C in an oil bath for 2 hours. The reaction mixture is then concentrated (90 ° / 30 Torr) to remove the unreacted epichlorohydrin. The residue is diluted with toluene and concentrated to dryness twice to help remove the last 20 traces of volatiles. The residual oil is dissolved in 263 ml of tetrahydrofuran and this solution is stirred at 40 to 50 ° for one hour with 263 ml of NaOH IN. The organic layer is separated and concentrated, which gives an oil which is combined with the aqueous phase. The mixture is extracted (CHgC ^) and the extract is dried (MgSO ^) and concentrated, giving 36.6 g (100%) of an oil which slowly crystallizes into a waxy solid. This intermediate product can be used without further purification in the preparation of the products of formula I.

EXAMPLE 9 30 2 - {(2,3-epoxy) propoxy} -4-methoxybenzonitrile

The necessary 5-methoxysalicylaldehyde can be obtained from 4-methoxyphenol by the Reimer-Tiemann procedure which is well described in the literature, see for example Kappe et al., Arch. Pharm., 308/5, 339 (1975). A solution comprising 0.005 mole of the starting salt-cylaldehyde in 6 ml of pyridine and 6 ml of absolute ethanol is treated with 0.4 g (0.02 mole) of hydroxylamine hydrochloride and heated under reflux for 4 hours. The mixture is concentrated in vacuo to a gray syrup which is stirred with 50 ml of HgO and the suspension is decanted. Addition of 10 ml of water to the glassy residue, followed by cooling to 5 ° gives, by filtration, approximately 1.2 g of crude solid which is taken up in 25 ml of an ethyl-ether-isopro mixture -pylether at 50%. The ethereal solution is filtered, dried (MgSO 4), treated with Darco G-60 and celite, filtered and concentrated in vacuo to a waxy solid. Recrystallization from an ethyl ether-Skelly B mixture gives the corresponding benzaldehydeoxime.

A mixture of 0.002 mole of the oxime and 1.02 g (0.01 mole) of acetic anhydride is heated at reflux for 30 minutes and is then cooled to 25 °. Water (50 ml) is added and then 20% NaOH is added dropwise to pH 10. The resulting suspension is stirred at 25 ° for 20 hours (to hydrolyze any acetate ester from desired phenolic derivative). The pH is adjusted to approximately 2 by using 6N HCl and the resulting mixture is extracted with 40 ml m of ethyl acetate, which gives an organic layer which is separated, dried (MgSO 4) and evaporated. at 65 ° / 70 Torr to obtain a brown syrup which Ο? ' τ 'consists mainly of acetic ester. Subsequent hydrolysis of y

syrup in a mixture of 7 ml of methanol, 7 ml of water and 0.1 g of NaOH tablets at 25 ° for 3 hours is followed by the elimination of the methanol at 60 ° / 70 Torr. Dilution of the aqueous residue with 0.5N HCl

gives a precipitate which can be recrystallized from isopropyl ether and dried to obtain the intermediate benzonitrile intermediate which is desired.

A mixture of 0.015 mole of 2-hydroxy-5-methoxybenzonitrile, 4.2 g (0.03 mole) of anhydrous potassium carbonate in fine powder and 140 ml of DMF is stirred at 50 ° for 15 minutes. Epibromhy-drine (2.8 g, 0.02 mole) is added in a single portion and the 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 to 5 °. By filtering the mixture and washing the filter cake with water, the crude intermediate compound is obtained by air drying, which can be used without further purification. Likewise, by using other substituted 2-cyanophenols, as an alternative to the above procedures, the other intermediate compounds of formula IV are obtained for use in the synthesis of the various compounds of formula I according to the present invention.

19

Product summary EXAMPLE 10

General procedure: 2- {2-hydroxy-3 - [(h.ydrox, yindo1yl) alkyl-amino] propox, y} benzonitrile 5 A selected methoxyindolylalkylamine (III) is mixed with an equimolar amount or a slight excess of epoxypropoxybenzonitrile selected (IV) and coupling is carried out either by reflux treatment of a solution of the reagents for approximately 18 to 24 hours, or by heating of a pure mixture at a temperature of about 120 to 130 ° for about half an hour to two hours. Ethanol and toluene are the solvents that are usually chosen as the reaction medium for coupling by reflux treatment of a solution of III and IV. In some cases it is advantageous to follow the course of the reaction by TLC, adding additional epoxy IV ^ 15 until all Tindolylamine III is gone. Following the reaction, the mixture is concentrated to dryness and the residue is either washed and used raw in the next step, or the intermediate methoxy produced can be purified by crystallization-recrystallization either as the base or in the form of 'Addable 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 an excess of several times the required amount of IN boron tribromide is added dropwise to the methyl-25 chloride oak. Following the addition, the reaction mixture is stirred at room temperature for about 6 to 8 hours. The excess boron tribromide is decomposed by cooling the reaction mixture and adding dropwise excess water. The crude hydrobromide of the product of formula I can be produced in various conventional ways such as recrystallization, conversion to base and purification, conversion to base followed by conversion to a different acid addition salt, etc.

The variants necessary to adapt this procedure for the preparation of the specific compounds of formula I are entirely within the competence of the experienced chemist.

EXAMPLE 11 2- {2-hydroxy-3 - [(2- (6-methoxy-1H-indol-3-yl) -l, l-dimethylethyl) -ami noIpropoxy} benzoni tri 1e

A solution of 6-methoxyindol-3-yl-t-butylamine (2.6 g, 0.012 mo-5 le; prepared in example la), of 2 - {(2,3-epoxy) propoxy} benzon1trfle * ( 2.1 g, 0.012 mole; prepared in Example 8) and 100 ml of absolute ethanol is stirred at reflux for 20 hours. Additional epoxide (0.21 g) is added and reflux is continued for 4 hours, after which the mixture is concentrated to dryness and the residue 10 is triturated in isopropyl alcohol to start crystallization . The product is collected by filtration, washed with cold isopropyl alcohol and air-dried, which gives 4.0 g (85%) of the methoxy (II) product, melting point 145-146 °, that l 'we use directly in the next step.

; A solution of methoxyindole prepared above (1.5 g, 0.004 mol) in 225 ml of methylene chloride is stirred under nitrogen at 5-10 ° C while 15.3 ml is added dropwise. (0.015 mole) of IM boron tribromide in methylene chloride. Following this addition, the ice bath is removed and the reaction mixture is stirred at 25 ° for 6 hours before being refrigerated at 5-10 ° and before adding 47.5 ml of dropwise. H20. The reaction mixture is decanted and the residual rubbery solid is rinsed with two portions of H2O. Dissolution of this crude hydrobromide in 50 ml of hot HgO followed by treatment with Darco G-60, filtration, cooling (25 °) and alkalization (pH 8) with concentrated NH 4 OH gives 1.2 g of a solid. amorphous brown which is treated by chromatography (silica gel 60, 230-400 mesh, reagent EM) on a medium pressure system with a chloroform-methanol-NH ^ OH mixture concentrated (90/10/1). The product obtained in this way is crystallized from a small amount of 95% ethanol, which gives, by progressive addition of H 2 O, 1.03 g (71%) of the desired 6-methoxyindole (I ) as a brown solid, melting point 90-94 °.

** Upon analysis, it is found that the product obtained has the formula: 35 C22H25N3 ° 3'1 / 3H2 ° and the following values are obtained: CH N H20 - calculated .... 68.56 6, 67 10.90 1.54 - found ..... 68.69 6.68 10.68 1.80 21 NMR (DMSO-dg): 0.98 (6, s); 2.70 (4, m); 3.30 (2, bs); 3.83 (1, m); 4.11 (2, d C5.8 Hz3); 5.00 (b, bs); 6.65 (3, m); 7.20 (3, m); 7.60 (2, m); 8.71 (b, bs); 10.35 (l.bs).

IR (KBr): 760, 800, 1260, 1290, 1450, 1494, 1600, 1630, 2230 and 5 3300 cm "1.

-! = EXAMPLE 12 2- {2-hydroxy-3-C (2- (5-hydroxy-1H-indol-3-yl) -l, Ι-dimethylethyl) -ami noIpropoxyIbenzoni tri 1e

A solution of 5-methoxyindole-3-yl-t-butylamine (2.7 g, 0.0125 mole; prepared from 5-methoxyindole using the procedure given in Example 1), of 2- ( (2,3-epoxy) propoxy} ben-zonitrile (2.2 g, 0.0125 mol) and 20 ml of acetone is treated at reflux for half an hour, then the solvent, acetone, is left. remove by boiling and the oily residue is heated at 100 ° for 2 hours, isopropyl alcohol (20 ml) and the reaction solution are added and treated under reflux for 4 hours, whereupon it is cooled at room temperature, dilute with 50 ml of ether and an agitator is used to deposit a white powder, 4.7 g (96%), melting point 119-124 °; TLC (9/1 CHCl ^ - methanol) manifests a single task, Rf 0.25. This crude methoxy produced can be used directly in the next step or it can be purified by conversion to HCl salt. Conversion to HCl salt by treatment of a solution acetonitrile e with ethanolic HCl gives a crude product which is recrystallized from a 95% butanol-ethanol mixture (20/1) to form a white powder with a melting point of 164-166 °.

On analysis, it is found that the product obtained has the formula: C23H27N3O3.HCl and the following values are obtained:

30 C H N

- calculated .... 64.56 6.56 9.77 - found ..... 64.14 6.54 9.68 ^ Using the procedure given above in example 11 for separation at boron tribromide from the methoxy group, but by using the intermediate product 5-methoxyindole (II) prepared above, the desired 5-hydroxyindole, product (I), can be obtained in the form of its hydrobromide. Crude hydrobromide is a beige powder, melting point 219-221 °.

22 On analysis, it is found that the product obtained has the formula: C22H25N3 ° 3, HBr and the following values are obtained:

5 C H N

- calculated .... 57.40 5.70 9.13 - found ..... 56.90 5.67 9.45 NMR (DMSO-dg): 1.32 (6, s); 3.08 (2, m); 3.36 (2, m); 4.30 (3, m); 5.90 (b, bs); 7.10 (6, m); 7.71 (2, m); 8.55 (3, bs); 10.95 (b, bs).

10 IR (KBr): 750, 800, 1265, 1290, 1455, 1495, 1580, 1600, 2230 and 3300 cm "'' '.

Starting with suitable methoxyindolalkylamines (III) and suitable epoxypropoxybenzonitriles (IV), additional examples of products of formula I can be synthesized using substantially the same procedures as described above with only slight modifications which are entirely necessary. done in the skills of the experienced chemist. Some additional products of formula I which can be synthesized by these means are shown in Table 1.

20 TABLE 1

Example -0H R1 R2 R3 R4 R5

30 13 4- H 2-H Me Me H

14 7- H 2-H Me Me H

15 4- Me 2-H Me Me H

r 16 5- Me 2-H Me Me 5-F

17 6- Me 2-H Me Me 5-0H

35 18 7- Me 2-H Me Me H

19 4- Me 3-H H Me H

20 5- Me 3-H H Me 5-F

21 6- Me 3-H H Me H

23

Example -OH R1 R2 R3 R4 R5 22 7- Me 3-H H H 4-Me

23 4- H 2-Me H Me H

24 5- H 2-Me H H H

y 5 25 6- H 2-Me Me Me H

26 7- H 2-Me Me Me H

27 4- H 3-Me H H 5-OH

28 5- H 3-Me H Me 5-F

29 6- H 3-Me H Me H

10 30 7- H 3-Me H H 5-Br 31 4- H 2-H H Me 5-Me 32 5- H 2-H H Me 4-C1

33 6- H 2-H H Me H

34 7- H 2-H H Me 4-OH

15 Biological evaluation

These biological tests are used to evaluate the hyper-tensor profile of the selected compounds of formula I.

EXAMPLE 35 The efficacy of antihypertensive agents other than beta-adrenergic receptor blocking agents is commonly estimated in spontaneously hypertensive rats. The blood pressures are determined for each animal to be tested before and 2 and 4 hours after administration of oral doses of 30 to 100 mg / kg of test compounds. The pulse is also determined at the same time as each blood pressure measurement. A drop in blood pressure 2 or 4 hours after administration of a single dose in the range of 15 to 20 mm of mercury is considered "problematic". The designations "active" and "inactive" mean decreases above and below this range respectively.

EXAMPLE 36 Another test useful for determining the effectiveness of the antihypertensive agents makes use of rats hypertensive with the DOA salt. These hypertensive rats are prepared in the following manner: male Sprague-Dawley strain rats weighing approximately 90 g are individually caged with free access to food and water during a five-day pretreatment period, after which the drinking water is replaced by a 1% saline solution. During a three-week treatment period, rats are administered a total of 24 10 subcutaneous injections containing 10 mg DOCA (deoxy-corticosterone acetate) in 0.2 ml suspension vehicle (Tween 80 at 0.25 % and 0.125% CMC in normal saline). After the final injection, the 1% saline solution is replaced with distilled water and the 5 animals are available for use one week later.

The test is carried out by selecting animals which have not Γ fasted and have a high systolic blood pressure (> 160 mm of mercury).

The blood pressures are determined for these test animals before and 4 hours after administration of oral doses of 30 to 100 mg / kg of 10 compounds to be tested. During the test period, the animals are housed in metabolism cages without food or water and their urine is collected for 4 hours. Both pulse and body weight are determined at the same time as each blood pressure measurement. A drop in blood pressure 4 hours after administration in the range of 15 to 20 mm of mercury is considered to be "problematic". The designations "active" and "inactive" are decreases greater or less than this range.

EXAMPLE 37

A rat model whose lymph node blockage is supported by angiotensin II is used as a control test to estimate the direct vasodilator component of activity. Percentage changes in blood pressure in the anesthetized rat 30 minutes after IV administration are determined. The intravenous dosage is carried out with compounds to be tested at 3 mg / kg. Boundary activity is defined as being approximately a 10% decrease in blood pressure measured 30 minutes after administration. The designations "active" and "inactive" are lower and higher decreases than that.

EXAMPLE 38 The responses of diastolic blood pressure and pulse rate to a fixed control dose of isoproterenol are obtained before and ^ 15 minutes after a progressive dose of test compounds administered> intravenously over an interval of 3 minutes, anesthetized dogs. A branch of a femoral artery and a vein are provided with a cannula to record blood pressure and to administer drugs which are dissolved in saline.

We select bilaterally in the middle cervical region of the neck and mechanically ventilate the dogs (Harvard respirator) with air

J

25 ambient at a rate of 20 / minute and a volume per neck of 20 ml / kg. The pulse is monitored using a cardiotachometer triggered by the pressure pulses. All measurements are recorded on a Beckman R-612 recorder. The effect of the drug is expressed in terms of the cumulative dose (microgram / kg) causing a 50% inhibition of the response to isoproterenol.

: EXAMPLE 39

Rats (Vistar males) are anesthetized intraperitoneally with a combination of urethane and chloralase. Following induction of anesthesia, chlorisondamine is injected into the peritoneal cavity to produce blockage of the ganglion. One femoral artery is equipped with a cannula to monitor blood pressure and pulse and two femoral veins are equipped with a cannula to administer the compounds. The trachea is intubated and the rats are allowed to breathe spontaneously. The animals are excited before and 15 minutes after intravenous administration of the test compound with progressive doses of '• JC ·· phenylephrine and the blood pressure changes are recorded.

The data are recorded to obtain dose-response curves and the dose of henylephrine required to trigger an increase of 20 50 mm of mercury (ED5Q) in blood pressure is taken from the curves. Dose variations are calculated by dividing ED ^ q after medication by ED ^ q before medication.

Claims (17)

26 1. Compound having the formula: R1 CN (I) 10 and its acid addition salts, in which: i ο one of the radicals R and R represents a hydrogen and the other represents a hydrogen or an alkyl in C, to C *; OA l ** 15. and R independently, are chosen between hydrogen or 5 enΐ ° ° 4 alkyl; represents halogen, hydrogen, hydroxy or C ^ -C ^ alkyl; the phenoxypropanolaminoalkyl side chain is attached to the indolic ring either in position 2, either in position 3, and the hydroxyl-killing group occupies either positions 4, 5, 6 or 7 of the indole cycle. 2. Compound according to Claim 1, characterized in that the indolic ring is attached in its position 3 to the side chain phenoxypropanolami noalkyl e. 3. A compound according to claim 1, characterized in that R ^ and 2 R represent hydrogen. 3 4. Compound according to claim 1, characterized in that R and 4 R represent a methyl. 5 5. Compound according to claim 1, characterized in that R 30 represents hydrogen or 5-fluoro. 3 6. Compound according to claim 3, characterized in that R and 4 t R represent methyl. 5 7. Compound according to claim 6, characterized in that R represents a hydrogen or 5-fluoro. 8.- Compound according to claim 1, characterized in that the hydroxyl substituent occupies position 6 of the indole ring. ZI 9, - Compound according to claim 1, characterized in that it is 2- {2-hydroxy-3 - [(2- (6-hydroxy-1H-indol-3-yl) -1,1- dimethyl-ethyl) friend noIpropoxyIbenzonitri 1 e. 10, - Compound according to claim 1, characterized in that ^ 5 is 2- {2-hydroxy-3 - [(2- (5-hydroxy-1H-indol-3-yl) -1, 1-dimethyl- * ethyl) amino] propoxy} benzonitrile. 11, - Pharmaceutical composition in unit dosage form, suitable for systemic administration to a mammalian host, comprising a pharmaceutically acceptable vehicle and an amount of compound of formula I according to claim 1 to provide an effective but non-toxic antihypertensive dose from 0.1 mcg to 100 mg of this compound of formula I per kg of body weight of this host. 12, - Pharmaceutical composition according to claim 11, characterized in that the compound of formula I is 2- {2-hydroxy-3 - [(2- (6- λ 15 hydroxy-1H-indol-3-yl) - 1,1-dimethylethyl) amino] propoxy} benzonitrile. 13. Pharmaceutical composition according to claim 11, characterized in that the compound of formula I is 2- {2-hydroxy-3 - [(2- (5-hydroxy-ΙΗ-indol-3-yl) -1, 1-dimethylethyl) ami noIpropoxyIbenzoni tri 1e. 14.- process for preparing a compound having the formula: 2 ° R2 'A n cn R (I) and its acid addition salts, in which: 1 2 one of the radicals R and R represents a hydrogen and the other represents a hydrogen or a C 1 to C 4 alkyl. ; 3. i h R and R independently, are chosen from hydrogen or C -C · alkyl 5. V a R represents halogen, hydrogen, hydroxy or C ^ C ^ alkyl; the phenoxypropanolaminoalkyl side chain is attached to the indole ring either in position 2 or in position 3; and the hydroxyl substituent group occupies either positions 4, 5, 6 or 7 of the indole ring, this process consisting in: a) coupling a methoxylated indolalkylamine III \ / 3 f>, —I - ';> (III) * in which: 10 R1, R2, R3 and R4 are as defined above, - with an epoxy phenoxy substituted by R5 (IV) CN ~ 15 (IV) in which: ^ 19 0 Λ - R, R, R and R are such as defined above, by heating III and IV together either pure or in the presence of an inert organic reaction solvent so as to produce an intermediate II CN r3 * 25 0H (II) in which: R1, R2, R3 , R4 and R5 are as defined above, then, b) reacting intermediate II under suitable conditions so as to cleave the methoxy group into a hydroxyl group and thus form the compound of formula I; and then, y c) optionally, if a pharmaceutically acceptable acid addition salt of formula I is desired, then converting the product in step b) to said salt by conventional techniques. ψ 29 15, - Method according to claim H, characterized in that step b) consists in reacting the intermediate II with boron tribromide in a methylene chloride solution under reaction conditions such that the compound is formed of formula I. 16. A vasodilation method, characterized in that an effective dose "non-toxic vasodilator dose of a compound according to claim 1 is administered to a host mammal in need of this treatment. 17. - An adrenergic blocking method comprising administering to a host mammal in need of this treatment an effective dose of non-toxic adrenergic blocking of a compound according to claim 1. 18. Pharmaceutical composition according to claims 11, 12 or 13, characterized in that this dose of the compound of formula I is intended to be administered intravenously to mammals and in that it consists of 0.1 to 0.5 mg of this compound of formula I per kg of body weight of this mammal. 19. Pharmaceutical composition according to claims 11, 12 or: · 13, characterized in that this dose of compound of formula I is intended to be administered orally to mammals and consists of 0.5 to 5.0 mg of this compound of formula I per kg of body weight of this mammal. 20. - A method of combating hypertension, characterized in that it consists in administering to a mammalian host having hypertension an effective non-toxic antihypertensive dose of a compound according to claim 1. 21. 21. A method of fight against hypertension according to claim 11, characterized in that the compound administered is 2- {2-hydroxy-3 - [(2- (6-hydroxy-1H-indol-3-yl) -l, l -dimethylethyl) amino] -propoxyIbenzoni tri 1e. , Ά h