SE429339B - 3-INDONYL-TERT.BUTYLAMINOPROPANOLS WITH THERAPEUTICAL PROPERTIES - Google Patents

Description

7807790-5 which independently of one another consist of alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl having 3-6 ring atoms and optionally 1 -3 alkyl substituents, cycloalkylalkyl having 3-5 ring atoms and optionally 1-3 alkyl substituents, each of the preceding groups containing up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxamido , cyano or cyanoalkyl having 2-4 carbon atoms; n is 0 or the integer 1 or 2, which denotes the number of X groups; Het is a nitrogen heterocycle, preferably a 5-membered ring having 4 carbon atoms and a nitrogen atom, having 5 or 6 ring atoms and up to 1 additional heteroatoms consisting of oxygen, sulfur or nitrogen, the heterocycle bearing 0-2 ring substituents which consists of alkyl, N- (lower alkyl) carboxamido, N, N-di (lower alkyl) carboxamido, carbalkoxy, each of the foregoing groups containing up to 8 carbon atoms, oxo or carboxamido.

The compounds of the present invention are unique as antihypertensive agents in that they combine * adrenergic beta-blocking activity with vasodilating activity. They also have utility such as antianginal agents, anti-stress agents, antiarrhythmic agents, antithrombogenic agents and in the treatment of conditions where it is desirable to reduce the oxygen requirements of the heart, such as in postmyocardial infarction. Preferred compounds have a particularly desirable combination of the above effects and minor pharmacological effects or without them, making them particularly suitable for the specific indications listed above. The compounds of formula I wherein Ar is phenyl, n = 1 and X is placed in the ortho position are preferred for antihypertensive use. The utility of the compounds of formula I and II can be illustrated by various animal experiments including isoproterenol antagonism in conscious rat treated orally (adrenergic beta-receptor blocking effect), spontaneous hypertensive rat experiments (antihypertensive effect), canine vasodilaparates, -induced ventricular tachycardia in dogs (antiarrhythmic effect), coronary artery occlusion dog test (antiarrhythmic effect), in vitro by photometric measurement of platelet aggregation in platelet-rich plasma after administration of a thrombogenic agent, such as adenosine diphosphate and collagen other animal and laboratory experiments.

For medical use, the pharmaceutically acceptable acid addition salts of the compound formulas I and II are preferred.

These acid addition salts are those in which the anion does not contribute to any great extent to the toxicity or pharmacological activity of the salt, and as such constitute the pharmacological equivalents of the bases of the above structural formulas.

In some cases, the salts have physical properties which make them desirable for pharmaceutical preparation purposes, such as solubility, absence of hygroscopicity, compressibility in tablet preparation and compatibility with other ingredients with which the substances may be mixed for pharmaceutical use.

Acid addition salts which do not meet the above criteria as regards pharmaceutical acceptability, e.g. in terms of toxicity, are sometimes useful as intermediates for the isolation and purification of the present compounds or for other chemical-synthetic purposes, such as the separation of optical isomers. Such salts also fall within the scope of the invention.

The acid addition salts are prepared by reacting a base of formula I or II above with the appropriate acid in question, preferably by reaction in solution. They can also be prepared by metathesis or treatment with an anion exchange resin, the anion in a salt of the compound being quenched with another anion under conditions which allow separation of the undesirable component, such as by precipitation from solution, vsovvoe extraction with a solvent or elution from or retention on an ion exchange resin. Pharmaceutically acceptable acids for salt preparation include hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, phosphoric acid, nitric acid, mucus acid, isethionic acid, methanesulfonic acid, p-toluenesulfonic acid, glucosaccharic acid, oxalic acid, palmitic acid, palmitic acid, palmitic acid.

The compounds of the present invention of formulas I and II above contain an asymmetric carbon atom in the propanol side chain and thus act as optically active isomers and as racemic mixtures thereof. The present invention includes both the individual optically active isomers and the racemic forms. Some of the compounds of the present invention contain an asymmetric carbon atom in the X or Het substituent, which means that diastereoisomeric racemate pairs exist. These forms also fall within the scope of the present invention.

Cleavage of the racemic mixtures to obtain the optically active isomers of the compounds of the invention is carried out, for example, by preparing a salt with an optically active acid, many of which are known to those skilled in the art, such as optically active tartaric acid, mandelic acid, cholic acid, O-di-p-toluoyltartaric acid and 0,0-dibenzoyltartaric acid and other acids commonly used for this purpose. It is therefore understood that the patent claims cover both the products in the form of the various racemic mixtures and in the form of the optically active isomers.

For therapeutic use, an effective, non-toxic amount of a compound of formula I or formula II or a pharmaceutically acceptable acid addition salt thereof is administered systemically either to a mammal having a disease state resulting from an excessive stimulation of the adrenergic beta receptors, or to a mammal, which requires vasodilation or to a mammal with hypertension. By "an effective amount" is meant a dose which exerts an adrenergic beta-receptor blocking action, a vasodilating action or an antihypertensive action in the treated animal without undue toxic side effects.

By systemic administration is meant both oral and parenteral administration. Examples of parenteral administration are intravenous injection or infusion and intraperitoneal, intramuscular or subcutaneous injection. Rectal administration with ointment or suppository may be used. The dosage varies depending on the mode of administration from about 0.1 pg to 100 mg of a compound of formula I or formula II or a pharmaceutically acceptable acid addition salt thereof per kilogram of body weight. The acute toxicity, measured in orally treated mice, ranges from 250 mg / kg to over 2000 mg / kg body weight, with non-lethal indications of drug action, such as central nervous system stimulation or depression, mydriasis or lacrimation, occurring in 1/2 to 1/10 of this dose.

The combination of pharmacological properties of the compound 1'Z 2 - (3-indolyl) -1,1-dimethylethylamino] -3- (2-methylphenoxy) -2-propanol hydrochloride according to Example 10 suggests that it is particularly suitable for antihypertensive use. It has 5 times greater adrenergic beta-receptor blocking potency than propranolol, when administered orally to rats after intravenous administration of isoproterenol. The latter compound is a well-known adrenergic beta-receptor stimulant, which gives rise to an increase in heart rate and a decrease in blood pressure. These effects of isoproterenol are antagonized by adrenergic beta-receptor blockers and the relative potency values given above were obtained by regression analysis of logarithmic dose-response data for the two compounds. For therapeutic use, the dose and frequency of the dose will vary depending on the subject being treated and the mode of administration from about 0.2 mg for intravenous administration up to about 100 mg orally, which is suitable for humans.

The compound of Example 10 differs from other adrenergic beta-receptor blocking agents in that it is effective in lowering the blood pressure of spontaneously hypertensive rats. Although adrenergic beta-receptor blockers have been widely used in human medicine for the treatment of hypertension, their mechanism of action is unknown and their antihypertensive effect cannot in most cases be demonstrated by this animal experiment. By administering the compound of Example 10 to a spontaneously hypertensive rat, a reduction in blood pressure by 25 mm Hg is achieved at an oral dose of 100 mg / kg body weight with only a minimal reduction in heart rate. This is an indication of the utility of the compound in hypertensive conditions, where other adrenergic beta-receptor blockers are ineffective or less desirable.

The compound of Example 10 also provides a lowering of blood pressure upon intravenous administration to anesthetized dog at a dose of 3.33 mg / kg body weight. The compound further differs from other similar agents in that it does not slow down the rate of the heart or the contractile force of the right ventricle, as is the case with many previous adrenergic beta-reoeptor blocking agents. The substance has both a positive inotropic and a positive chronotropic effect and these effects are also shown when the animal is first treated with an adrenergic beta-receptor blocking agent, such as sotalol. Pulmonary artery pressure remains essentially unchanged, while aortic blood flow and total peripheral resistance are reduced, as is the case with anesthetized dogs. The compound of Example 10 exhibits vasodilating action, which may partly explain its unique antihypertensive action.

In anesthetized ganglio-blocked (chloroisondamine chloride) angiotension-supported rats, direct-acting vasodilators, such as diazoxide, exert a lowering of blood pressure. The substance according to the example in this test is equivalent to diazoxide in terms of potency.

The vasodilating effect thereof can also be shown in the test with pump-fused hind leg in dogs in doses of 0.03-1.0 mg / min perfusion. Following oral administration to dishes, there is a decrease in urine volume and a decrease in sodium ion excretion, which is typical of vasodilating compounds.

The antithrombogenic activity of the substance of Example 10 is again reflected in its ability to reduce platelet aggregation in vitro in platelet-rich plasma after administration of ADP or collagen. The compound is in vitro activity comparable to suloxidil and papaverine.

There is a risk of using an overdose of adrenergic beta-receptor blockers in patients suffering from non-allergic bronchospasm, due to the tendency of these drugs to induce an asthmatic attack or to make the patient insensitive to treatment with adrenergic beta-receptor stimulants, such as isoproterenol, used in the treatment of acute attacks. The compound of Example 10 lacks the tendency to induce bronchospasm, as evidenced by the fact that the compound does not lower the pulmonary ventricular pressure and induces only a moderate increase in sensitized rats' response to immunologically induced bronchoconstriction at a dose of 0.5 mg / kg. body weight when administered intravenously. In contrast, when administered intravenously at a dose of 0.5 mg / kg body weight, propranolol lowers the pulmonary ventilator pressure and elicits an acute bronchospastic response in sensitized rats during immunologically induced bronchoconstriction. For the preparation of pharmaceutical compositions containing the compounds of formula I or formula II, in the form of dosage units for oral administration, the compound in question is mixed with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol potato starch, corn starch, amylo pectin, cellulose derivatives or gelatin, as well as with lubricants such as magnesium stearate, calcium stearate, polyethylene glycol wax or the like, and compressed into tablets. The tablets can be used uncoated or coated by known techniques for the purpose of delaying dissolution and absorption in the gastrointestinal tract and thereby giving a delayed effect over a longer period of time. If coated tablets are desired, the core prepared in the manner indicated above can be coated with concentrated sugar solution, such as e.g. may contain gum arabic, gelatin, talc, titanium dioxide or the like. The tablets may further be coated with a lacquer layer, dissolved in a volatile organic solvent or a mixture of solvents, and, if desired, dye may be added to this coating.

In the manufacture of soft gelatin capsules consisting of gelatin and e.g. glycerol and the like, the active ingredient is mixed with a vegetable oil and encapsulated in a conventional manner. Hard gelatin capsules may contain granules of the active ingredient in combination with a solid powdered carrier, such as lactose, sucrose, sorbitol, mannitol, starch (for example, potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared in the form of suppositories containing the compound in admixture with a neutral fat base, or in the form of a gelatin rectal capsule containing a mixture of vegetable oil or paraffin oil.

Liquid preparations for oral administration are suspensions, syrups and mixtures and tinctures containing from about 0.2% to about 20% by weight of the active ingredient. A suitable injectable composition comprises an aqueous solution of a water-soluble, pharmaceutically acceptable acid addition salt, which solution has been adjusted to a physiologically acceptable pH value. The compounds of formulas I and II are prepared using known procedures based on the appropriate starting materials. Representative known methods for preparing the aryloxypropanolamine compounds of the invention are described in Canadian Patent 834,751 and U.S. Patent 3,984,436. More particularly, the present invention provides a process for the preparation of the compounds of formulas I and II according to the reaction scheme set forth below. . '780? 7Û (l ~ 5 9 0 (2) ena ¿\ _. _' _ Ar'-o-cna Hce, 3-indo1yl ~ ßH = C-Nu; I en <1> ° cu, <3) (4) I,. Year '* 0H + 3'Ind ° 1Yl “cH = ç“ B ""' ä 9 Formula I and II ca, cn.c.u, in few cH = oso, R ß - -N-cH.cncH. or -N: Iz IV In the above reaction scheme, the symbol Ar 'denotes the groups ArXn and Ar flet having the meanings given in connection with formulas I and II above. The symbol B is defined by formulas III and IV, where R is a lower alkyl group having 4 or fewer carbon atoms . The preferred method is in accordance with reactions (1) and (2), wherein step (1) involves reacting the appropriately substituted phenolic compound Ar 'OH with epichlorohydrin in the presence of a catalytic amount of an amine, followed by treatment with an aqueous solution of an alkali metal hydroxide, or carrying out the reaction in an aqueous alkali metal hydroxide reaction medium, in which case the amine catalyst is not required. In step (1) an Ar 'epoxypropyl ether is formed, which in step (2) is reacted with 2- (3-indolyl) -1,1-dimethylethylamine to give a product of formula I or formula II, depending on on the nature of the Ar “OH starting material used. Each of the reaction steps (1) and (2) can be easily carried out in an ordinary laboratory or factory facility under favorable operating conditions.

Heating epichlorohydrin in a substantial molecular excess on an overnight steam bath with a phenol Ar'-OH containing one or two drops of piperidine as catalyst results in the condensation shown in step (1) above. A certain amount of the corresponding halohydrin intermediate is also formed and converted without isolation to the oxirane shown by treating the mixture with an aqueous solution of alkali metal hydroxide. Alternatively, the Ar 2 OH phenol and epichlorohydrin can be reacted in the presence of a dilute aqueous solution of an alkali metal hydroxide in an amount sufficient to neutralize the acidic Ar 'OH group at room temperature to give the desired intermediate Ar'OCH 2 C fi gH 2 . Step (2) is carried out simply by heating the oxirane intermediate obtained in step (1) with 2- (3-indolyl) -1,1-dimethylethylamine, either in the absence or presence of a reaction-inert organic solvent. - dell No catalyst or condensing agent is required. Suitable solvents include 95% ethanol, but other reaction-inert organic liquids can also be used, in which the reactants are soluble. These include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethokietane, ethylene glycol, etc. Suitable reaction temperatures are about 20 ° C.

An alternative variant of the process for the preparation of the compounds of formula I and formula II involves reacting the Ar'Ogš starting material defined above with a reactant "3 of the formula 3-indolyl-CH2ë-B according to reaction step (3) in reaction CH3 the above scheme to obtain an intermediate which is converted to the final product by hydrolysis or hydrogenolysis.

The substituent B in the reactant used in step (3) is a group of the formula III or IV shown in the reaction scheme above, which is reactive with respect to the phenolic hydroxyl group Ar'OH to incorporate with the product an initial propanolamine side chain.

The reactants for step (3) in which B has the formula III are prepared by forming the N-benzyl derivative of 2- (3-indolyl) -1,1-dimethylethylamine and reacting the latter with epichlorohydrin using the method described by L. Villa et al. and Il. Farmaco. Sci., Ed. gg, (3) (1969) 349. The reactants in which B has the formula IV are prepared by reductive alkylation of 2- (3-indolyl) -1,1-dimethylethylamine with glyceraldehyde according to known methods, t .ex. by using a catalyst of 5% palladium on carbon in a hydrogen atmosphere with methanol or other suitable non-reactive liquid as solvent.

When using an optically active form of glyceraldehyde, an optically active end product of formula I or formula II is obtained.

The aminopropanediol obtained in the above reductive alkylation reaction is then converted to the desired 2- (3-indolyl) -1,1-dimethylethyloxazolidinone reactant, wherein B has the formula IV, by reaction with formaldehyde using a 37% aqueous solution of formaldehyde in refluxing benzene, whereby the water is continuously removed by distillation. Esterification with an alkanesulfonyl chloride of the formula RSO2Cl, where R is a lower alkyl group having 1-4 carbon atoms, to the required group which is reactive with respect to Ar'OH.

The intermediate prepared in step (3) and wherein B has the formula III is converted in step (4) to a product of formula I or formula II by debenzylation in a known manner, for example by catalytic hydrogenation or reaction with sodium in liquid ammonia. The intermediates prepared in step (3), wherein B has the formula IV, are converted to the products of the formula I and the formula II in step (4) by mild acid hydrolysis. In this case, care must be taken to avoid decomposition of the reactant, as the 3-indolyl substituent is acid sensitive. Aqueous solutions of mineral acids with a concentration of 0.1 N - 1 N at temperatures of 20-100 ° C are suitable. The product is recovered in the form of the free base from the hydrolysis mixture by neutralizing it and recovering the extrudate.

The 2- (3-indolyl) -1,1-dimethylethylamine used is prepared by the method described by H.R. Snyder et al. and J. Am.

Chem. Soc., §2, (1947) 3140 starting from 3-indolylmethyldimethylamine and 2-nitropropane, followed by reduction of the obtained 2- (3-indolyl) -1,1-dimethylnitroethane.

The invention is further illustrated by means of working examples 7807709-5 12 below, in which the temperature indications refer to degrees Celsius. Regarding the melting points, these refer to, if expressly stated (corr.), Corrected values according to the U.S.P. method.

Nuclear Magnetic Resonance (NMR) spectral data refers to the chemical shift (5), expressed in parts per million (Ppm) relative to tetramethylsilane (TMS) as the reference standard. The relative surface area given for the different displacements corresponds to the number of hydrogen atoms in the particular functional group in question in the molecule, and the nature of the displacement in terms of multiplicity is given as broad singlet (bs), singlet (s), multiplet (m) , doublet (d), triplet (t) or quadruplet (q), the coupling constant (J) being given as appropriate. NMR data are given as follows: NMR (solvent): $ (relative surface area, multiplicity, J-value). Abbreviations used are MeOH (methanol), DMSO-die (deuterodimethylsulfoxide), i-ProH (isopropanol), abs.EtOH (absolute ethanol), EtOAc (ethyl acetate), EtOH (95% ethanol), i-PrOH (isopropanol) , i-PrOAc (isopropyl acetate), i-Pr2O (diisopropyl ether), s (decomposition). Other abbreviations have the usual meanings. Infrared (IR) spectral data includes only absorption wavelengths (cm_1) with identification values for functional groups. KBr was used as a diluent in all IR spectral determinations. TMS was used as the standard in the NMR spectral determinations. The elemental analyzes are expressed in% by weight.

Example 1 4- (Methylsulfonyl) -m-tolyloxymethyloxirane To a mixture of 8.1 g (0.0435 mol) of 3-methyl-4-methylsulfonylphenol and 20.0 g (0.216 mol) of epichlorohydrin was added two drops of pair of piperidine as a condensation catalyst and the mixture was heated for 18 hours at 105-58 °. The excess epichlorohydrin was then removed by distillation using toluene as an aid. A solution of 2.1 g of sodium hydroxide in 50 ml of water and 70 ml of dimethoxyethane was then added and the mixture was stirred for 2 hours with occasional heating on a steam bath to convert any phenoxychlorohydrin compound present to the oxirane. The solvent was then removed by distillation in vacuo and the residue was dissolved in a 1: 1 mixture of ether and benzene. The solution was dried over anhydrous sodium carbonate and examined by thin layer chromatography for the purity of the desired oxirane using a 9: 1 mixture of chloroform and methanol for development (Rf = 0.8). The solvent was then removed by distillation to give 10.7 g of a residue consisting of the desired oxirane. Determination of the infrared absorption spectrum was used to determine the significant absence of hydroxyl-containing impurities. The resulting material was suitable for further reaction in Example 3 below without further purification.

Example 2 2-Chlorophenoxymethyloxirane A solution of 12.9 g (0.1 mol) of 2-chlorophenol in 125 ml of water, containing 6.5 g (0.62 mol) of sodium hydroxide, and 18.5 g (0.2 mol) Epichlorohydrin was stirred for 20 hours at 250. The mixture was then extracted twice with 70 ml portions of methylene chloride. The extract was dried over anhydrous sodium carbonate and the solvent was removed by distillation in vacuo. The residue was the desired oxirane and was suitable for further conversion according to Example 4 below.

Example 3 g 1- [22- (3-indolyl) -1,1-dimethylethylamino] -3-11- (methylsulfonyl) -m-tolyloxy-2-propanol. 7. g of the oxirane from Example 1 were dissolved in 150 ml of toluene. 8.2 g (0.044 mol) of 2- (3-indolyl) -1,1-dimethylethylamine were added and the mixture was refluxed for 18 hours. The toluene was removed by distillation in vacuo and a portion of the residue was converted to the acetate salt, m.p. 142-1470. The structure was confirmed by examining infrared absorption and nuclear magnetic resonance spectra. The residue of the sample was converted to the hydrochloride salt by treating an acetonitrile solution thereof with 8 N ethanolic HCl. After recrystallization from 7807700-5 in 14 CH 3 CN / MeOH, 12.5 g of product with a melting point of 174.0-177.00 (corr.) Were obtained.

Weight Found: C, 59.40; H, 6.90; N, 5.87.

NMR (DMSO-d 6): 1.29 (6, s); - 2.52 (3, s); 3.12 (3, s); 3.16 (4, m); 4.18 (3, m); 5.95 (1.bS); 7.10 (8, m); 9.00 (2, bs) and ll, l2_ (l, bs).

IR: 740, 765, 1120, 1290, 1450, 1590 and 3270.

Example 4 1- (2-Chlorophenoxy) -3- [Z2- (3-indolyl) -1,1-dimethylethyl] amino] -2-propanol 7 g (0.033 mol) of the oxirane from Example 2 were refluxed in solution with 6 3 g (0.033 mol) of 2- (3-indolyl) -1,1-dimethylethylamine in 70 ml of ethanol. After 24 hours, the solvent was removed by distillation in vacuo and the viscous liquid residue was dissolved in 200 ml of ether and acidified with 8 N ethanolic HCl, after which the solvents were removed by distillation.

Crystallization was induced by the addition of acetonitrile and rubbing with a glass rod. Recrystallization from acetonitrile and diisopropyl ether gave 4.8 g of product, m.p. 150.5-153.50 (corr.).

Analysis Found: C, 61.54; H, 6.41; N, 6.94.

NMR (DMSOfd 6): 1.28 (6, s); 3.22 (4, m); 4.25 (3.m); 5.96 (1, bs); 7.23 (9, m); 8.84 (2, bs) and 11.12 (1, bs).

IR: 745, 1250, 1455, 1480, 1590 and 2780.

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Ingredient Amount of Lactose 79 Maize starch 10 Talc Dragant Magnesium stearate The resulting tablet base was mixed with a sufficient amount of 1- [Z2- (3-indolyl) -1,1-dimethylethyl] amino] 3 '(2-methylphylHoxy) -2-Pr0-panol-hydrochloride Example 10) to obtain tablets containing 10, 20, 40, 80, 160 and 160, respectively. 320 mg of active ingredient, and was compressed in a conventional tablet press.

Example 16 Dry-filled capsules The following ingredients were mixed in a conventional manner in the stated proportions.

Ingredient I Amount of Lactose, U.S.P. Starch 5 Magnesium stearate 2 A sufficient amount of 1- [Z2- (3-indolyl) -1,1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) was added to the mixture to obtain capsule masses. which contained, 20, 40, 80, 160 resp. 320 mg of active ingredient, which masses were then filled into hard gelatin capsules of suitable size. 7807700-5 Example Gel 17 Solution A solution of 1-βZa- (3-inhalyl) -1,1-dimethylethylamino] -3- (z-methylphenoxy) -2-propanol hydrochloride (Example 10) was prepared starting from the following ingredients.

Ingredient Mä gd Active Ingredient 20 q Sucrose, U.S.P. K 400 g Sorbitol, U.S.P. 100 g Bentonite 20 g Flavorings, q.s.

Water, q.s. to 1 liter Each milliliter of the solution contained about 20 mg of the active ingredient.

By applying the methods of Example 1 or 2 using the appropriate phenol in question or by other conventional methods, the following oxiranes were prepared, which were then converted to products of formula I or formula II by reaction with 2- (3-indolyl-1,1 -dimethylethylamine by the methods of Example 3 or 4.

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\ Nncoca. _ Ex. 24 _ '° \ OCHaQJIICI-1; : s CN EXa O š fx 0GH; CH H; Cl Cl - Ex.28 Ex. 30 21 _ F 7807700-5 \ ¶ o \ Üocuzéncn. _ s ~ cn, U Ex. 23 o / Ûocmcæån. \ cum, _ Ex.25 ø \ f * ocmcu-cza.

Ex.27 O. f: ocmcn u, / Û Ex.29 o / \ /, D OCHZCHCHQ l 1 \. "Å" GONHCH: 'Ex. 31 7307700-5 22 C0ålfC fl ø) a EX: I ca, / ° obæucnåa.

Ex. 34 0 OCHaÅI-lè fl a K i \ / CONH: CÛNH; Ex. 36 '0 O-CI-Izf- [I-QCH: 1% °' \ COaMI-1; Ex: 9. / \ Q- ocmcucn, CH; Ex. 33. O. Å \ cn = chcu = ca .. CH: Ex. 35 OV / \ OCPhCHGI-h. CHa0 _ f Ex. 37 o ocmrfxfcu. f fl ø 0 \ Ex. 39 78077ÜO-5 23 o o é \ '(l / \ \ ocn. Nen, _ / ocm Hou, G / Q 1> L \ o mmm)' Exßl o I OCHIQCH: - ocmóncn, Caacoa \ HZCN cæucxuc fl g, Ex. 42 I Ex. 43 0/0 \ Gligél-Ièl-I. OCFMCHCI-la \. / \ \ c, u, Ex. 44 -. Ex. 45 o / \ r '\ ÖCH! 'ICH gCHCH g \ “so.cn,' - cv.

Ex. 46 Ex. 47 78077Ü0-5 24 ocmca a; No; Ex.43 O - \ OCH éPCFI i - '- z OH Ex. 50 / \ ocmcncu.

Ex.52 0 ° C 5 H; HCIM NH; Ex.49 o / \ / «/ OCHgCIHCII: 0 / \ OCHICIHJI; I-Ix.53 The following physical properties have been measured: 7807 ° C10-5 Example 19 1- [Z2- (3-indolyl) -1,1-dimethylethylamino] -3- (2-propenyl) fe- nox;] - 2-propanol hydrochloride, mp 163.0-168.6 ° (corr.), recrystallized from MeOH / i-Pr 2 O.

Analysis Found: C, 69.22; H, 7.56; N, 6.70.

NMR (DMSO-d 6): 1.30 (6, s); 3.32 (6.m); 4.20 (3.m); 5.03 (2, m); 6.00 (2.m); 7.25 (9, m); 8.90 (1.bS); 9.60 (1, bs) and 11.40 (1, bs).

IR: 752, 1120, 1245, 1455, 1490, 1590, 1600, 2790, 2980 and 3350.

Example 43 1- [22- (3-indolyl) -1,1-dimethylethylamine] -3- [2- (2-methyl-1-propyl) phenoxy] -2-propanol hydrochloride, mp 163.0 -166.0 ° (corr.), recrystallized from MeOH / CH 3 CN.

Analysis Found: C, 6% 34; H, 8.19; N, 6.49.

NMR (DMSO-d 6): 0.81 (3, t, 7.0 Hz); 1.17 (3, d, 7.0 Hz); 1.32 (6, s); 1.39 (2.m); 3.28 (5.m); 4.22 (3.m); 6.04 (1, bs); 7.22 (9, m); 9.00 (l, bs); 9.60 (1, bs); 11.20 (l, bs).

IR: 750, 1100, 1240, 1450, 1490, 1582, 1600, 2780, 2960 and 3320.

Example 45 3- (2-Ethylphenoxy) -1- [22- (3-indolyl) -1,1-dimethylethylamine] -7-2-propanol hydrochloride, mp 170.0-171.5 ° (corr.), Recrystallized from EtOH.

Analysis Found: C, 68ß6; H, 7.95; N, 6.85.

NMR (DMSO-d 6): 1.21 (3.5, 7.0 Hz); 1.33 (6, s); 2.64 (2.m); 3.24 (4, m); 4.21 (3.m); 6.00 (l, bs); 7.25 (9, m); 9.00 (l, bs) and 9.55 (l, bs).

IR: 750, 1130, 1240, 1460, 1495, 1590, 1605, 2800, 2970 and 3350.

Claims (7)

7807700-5 26 Patent claims \ 1. 1. Compounds of the formula CH2 -? - NHCH CHCH-0 ~ Ar ° Xn 2 2 Formula I CH 3: EZ or CH OH m3! CH 2 -NHCH 2 CHCH 1 -O-Ar-HeC CH Formula II 3 and acid addition salts thereof, in which formulas Ar X Het represents phenyl or naphthyl, are optionally Ar-linked substituents, which independently of one another consist of alkyl, alkenyl, alkynyl , alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl having 3-6 ring atoms and 1-3 optional alkyl substituents, cycloalkylalkyl having 3-6 ring atoms and 1-3 optional alkyl substituents , each of the foregoing groups containing up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano or cyanoalkyl having 2 to 4 carbon atoms, is 0 or the whole number 1 or 2, denoting the number of X groups, and is a nitrogen heterocycle having 5-6 ring atoms and up to an additional heteroatom, consisting of oxygen, sulfur or nitrogen, the heterocycle bearing 0-2, ring substituents consisting of alkyl, N- (lower alkyl) carboxamido, N, N-di (lower alkyl) carboxa mido or carbalkoxy, each of the foregoing groups containing up to 8 carbon atoms, oxo or carboxamido. Compounds according to claim 1 having the formula I, characterized in that Ar is phenyl, X is in the ortho position and n is the integer l. Compounds according to claim 1 of the formula I, characterized in that Ar is phenyl, X is alkyl having up to 8 carbon atoms and n is the integer 1. 4. A compound according to claim 3, characterized in that X is methyl. The compound 1- [Z2- (3-indolyl) -1-ardimethylethyl] amino] -7- (2-methylphenoxy) -2-propanol according to claim 3. The compound 1- [22- (3-indolyl) -1,1-dimethylethyl] amine] 7- (2-methylphenoxy) -Z-propanol hydrochloride according to claim 3. 7. A compound according to claim 1 having the formula I, characterized in that Ar is phenyl, X is cyano and n is the whole number 1. '1807700-5 SUMMARY Compounds of the formula? H 3 OH_ _' CH2- -NHCH2CHCH2-O-Ar-Xn - Formula I CH3 NH or CH3 OH C1-NHCH2CHCH2-0 ° Ar-Hec Formula II C33 and acid addition salts thereof, in which formulas Ar is phenyl or naphthyl, X is an optional Ar- bound substituent, n is 0 or the integer 1 or 2, which indicates the number of X groups, and Het is a nitrogen heterocycle having 5 or 6 ring atoms and up to 1 additional heteroatom, which compounds are unique as antihypertensive agents by combining adrenergic ß -blocking activity with vasodilating activity and also has utility as antianginal agents, anti-stress agents, antiarrhythmic agents, antithrombogenic agents and in the treatment of conditions where it is desirable to reduce the oxygen requirements of the heart, such as in postmyocardial infarction.