DK156568B - ANALOGY PROCEDURE FOR THE PREPARATION OF 3-CONTENT DERIVATIVES - Google Patents

Description

1 DK 156568 B

The present invention relates to an analogous process for the preparation of 3-indole derivatives, and the process is not endormic to the characterizing part of claim 1.

The oxen-treated compounds have the general formulas I and II or are acid addition salts thereof: CH 3

-j-pCH2-C-NHCH2CHCH2-O-Ar-Xn I

JL JJ CH.

H

ch3 OH

- rCH9-C-NHCHoCHCHo-0-Ar-Het II

CH3 i

2 DK 156568 B

In the above formulas, the symbols Ar, X, n and Het have the following meanings:

Ar represents phenyl or naphthyl; X represents optional substituents on Ar which may be the same or different groups selected from alkyl, alkenyl, alkynyl, alkoxy; alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl of 3-6 ring members and 1-3 optional alkyl substituents, cycloalkylalkyl of 3-6 ring members and 1-3 optional alkyl substituents, each of the preceding groups have up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano and cyanoalkyl having from 2 to 4 carbon atoms, denote 0, 1 or 2 as the number of X groups, and

Het represents a nitrogen-containing heterocyclic group above the N atom, which heterocyclic group carries from 0 to 2 ring substituents in the form of C 1-6 alkyl, oxo or carboxamido.

From US Patent No. 3,946,009 and Norfek Pat.

110,557 are known respectively. 2- (3-substituted amino-2-hydroxypropoxy) -3 - substituted pyrazines and substituted naphthalene derivatives with adrenergic β-blocking activity. These known compounds are different from the compounds of the present invention and, on the basis of these known compounds, it is not possible to predict anything about the activity of the compounds of the invention.

The present compounds are unique as antihypertensive agents in that they combine adrenergic β-blocking and vasodilatory activity. They also have utility as antianginal agents, antistress agents, antiarrhythmic agents, antithrombogenic agents and in the treatment of conditions where it is desirable to reduce the oxygen demand of the heart, such as post-myocardial infarction. Preferred compounds have a particularly desirable combination of the aforementioned effects and pharmacological linkage effects or deficiencies thereof, which makes them particularly suitable for specific indications among those listed. Compounds of formula I, wherein Ar represents phenyl, η = 1 and X are in the ortho position, are preferred for antihypertensive use. The utility of the compounds of formulas I and II can be demonstrated in various animal models, including antagonism of isoproterenol in orally treated non-conscious rats (

DK 156568 B

nergic β-receptor blocking effect), spontaneously hypertensive rats (antihypertensive effect), canine hindpaw preparation (vasodilatory effect), ouabain-induced ventricular tachycardia in dogs (antiarrhythmic effect), coronary artery occluded (antiarrhythmic) activity, in vitro by measuring platelet aggregation in plate-rich plasma photometrically after exposure to a thrombogenic agent, such as adenosine diphosphate or collagen (antithrombotic effect), and in various other animal and laboratory models.

For medical use, the pharmaceutically acceptable acid addition salts are preferred. The pharmaceutically acceptable acid addition salts are those salts in which the anion does not significantly contribute to the toxicity or pharmacological activity of the salt and as such are the pharmacologically equivalent to the bases of the above structural formulas. In some cases, the salts have physical properties that make them more desirable for pharmaceutical preparations, such as solubility, lack of hygroscopicity, compressibility with respect to tablet preparation, and compatibility with other ingredients with which the substances can be used for pharmaceutical purposes. Acid addition salts that do not meet the foregoing criteria for pharmaceutical acceptance, e.g. in terms of toxicity, are sometimes valuable as intermediates for isolating and purifying the various compounds or for other chemical synthesis purposes, such as separation of optical isomers. The preparation of such salts also falls within the scope of the invention.

The acid addition salts are prepared by reacting a base of the above general formula with the acid, preferably by contact in solution. They can also be prepared by metathesis or treatment with an anion exchange resin, whereby the anion of one site of the compound is replaced by another anion under conditions which allow separation of the undesirable substances, such as by precipitation from solution or extraction in a solvent or elution from or retention. on an anion exchange resin. Pharmaceutically acceptable acids for salt formation include hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, phosphoric, nitric, mucic, isethionic, methanesulfonic, p-toluenesulfonic, glucosaccharic, palmitic, heptanoic, others.

The compounds of the general formulas shown contain an asymmetric carbon atom in the propanolamine side chain and appear as optically active isomers, as well as racemic mixtures thereof. The present invention comprises the production of both the optically active

4 DK 156568 B

and racemic forms. Some of the compounds of the present invention contain an asymmetric carbon atom in the X or Het substituent and diastereoisomeric pairs of racemates exist. The manufacture of these forms is also included.

Cleavage of racemic mixtures to prepare the optically active isomers of the aforementioned compounds is carried out e.g. by forming a site with an optically active acid, many of which are known to those skilled in the art, such as optically active wine, almond, choline, 0.0-di-p-toluoyl tartaric acid and Ο, Ο-dibenzoyl tartaric acids or other acids conventionally used for this purpose. The invention includes both the preparation of the compounds in the form of the various racemic mixtures and in the form of the optically active isomers where possible.

For therapeutic purposes, an effective non-toxic amount of a compound of Formula I or Formula II or a pharmaceutically acceptable acid addition salt of one of these can be administered to either a mammal, including human, with a disease state due to excessive stimulation of the adrenergic β-receptors, or to a mammal, including human requiring vasodilation, or to a mammal, including human with hypertension. An effective amount should mean a dose that exerts an adrenergic β-receptor blocking effect, a vasodilatory effect or an antihypertensive effect in the affected animal without significant toxic side effects. By systemic administration is meant administration comprising both oral and parenteral routes. Examples of parental administration are intravenous injection or infusion and intraperitoneal, intramuscular or subcutaneous injection. Rectal administration by ointment or suppository may be used. The dosage will vary depending on the route of administration with from approx. 0.1 µg to about 100 mg / kg / body weight of the compound of formula I or II or a pharmaceutically acceptable acid addition salt thereof, as a dose which generally provides the desired therapeutic effect. Acute toxicities measured in orally treated mice range from approx. ALD ^ g 250 mg / kg to> 2000 mg / kg body weight, with non-lethal signs of drug action, such as central nervous system stimulation or depression, mydriasis or lacrimation at 1/2 to 1/10 of this dose.

The combination of pharmacological properties of the compound 1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10 below) shows that it is particularly suitable for antihypertensive use. It has 5 times as much adrenergic β-receptor

, DK 156568 B

blocking potency as propranolol demonstrated by oral administration to rats followed by exposure of the animals to intravenously administered isoproterenol. The latter is a well-known adrenergic β-receptor stimulant which causes an increase in heart rate and a decrease in blood pressure. These effects of isoproterenol are antagonized by adrenergic β-receptor blocking agents and the relative strength values stated above were obtained by regression analysis of log dose-response data for the two compounds. For therapeutic use, the dose size and frequency will vary with the individual and the route of administration, 0.2 mg by intravenous administration until approx. 100 mg orally is appropriate for man.

The compound of Example 10 differs from other adrenergic β-receptor blocking drugs in that it is effective in lowering blood pressure in the spontaneously hypertensive rat. Although adrenergic β-receptor blocking agents have found widespread use in human medicine for the treatment of hypertension, their mechanism of action is unknown and in most cases their antihypertensive effect cannot be demonstrated in this animal test. With the present compound in the spontaneously hypertensive rat, a blood pressure reduction of 25 mm Hg occurs at a dose of 100 mg / kg body weight orally with only a minimal reduction in heart rate. This may be thought to be useful for hypertensive indications where other adrenergic β-receptor blocking drugs are inoperative or less desirable.

The compound of Example 10 also causes a blood pressure reduction by intravenous administration to anesthetized dogs at a dose of 3.33 mg / kg body weight. It can be further distinguished by the fact that it does not slow heartbeat or increase ventricular contractile force, as is the case with many known adrenergic β-receptor blocking agents. The compound exhibits both a positive inotropic and a positive chronotropic effect, and these effects can be observed even when the animal is first treated with an adrenergic β-receptor blocking agent, such as sotalol. Pulmonary artery pressure remains essentially unchanged while aortic blood flow and total peripheral resistance decrease, albeit in the anesthetized dog.

The compound of Example 10 possesses vasodilatory activity that can at least partially explain its unique antihypertensive effect. In anesthetized ganglia-blocked (chloroisone amine chloride) angiotensin-supported rats, in addition to directly acting vasodilators, such as diazoxide, a blood pressure reduction. The compound according to Example 10

6 DK 156568B

is strength equivalent to deazoxide in this test. The vasodilatory effect of the compound can also be demonstrated in the pump-perfused dog-back paw at doses of 0.03 to 1.0 mg / min. perfusion. Following oral administration to rats, a decrease in urine volume and a decrease in sodium ion excretion are typical of vasodilatory compounds.

The antithrombogenic effect of the compound of Example 10 is reflected in its ability to reduce platelet aggregation in vitro in plate-rich plasma after exposure to ADP or collagen. It is comparable in in vitro activity to suloctidil or papaverine.

There is a danger in extensive use of adrenergic β-receptor blocking agents for patients suffering from non-allergic bronchospasm because of these agents' tendency to provoke an asthmatic attack or to make the individual resistant to adrenergic β-receptor therapy. stimulants, such as isoproterenol, used to treat acute attacks. The compound of Example 10 lacks bronchospastic tendency, which is shown to not reduce pulmonary ventricular pressure and only induce moderate increase in the response of sensitized rats to immunologically induced broncho-constriction at a dose of 0.5 mg / kg body weight intravenously. . In contrast, at a dose of 0.5 mg / kg body weight, propranolol reduces intravenous pulmonary valve pressure and induces an acute bronchospastic response in sensitized rats to immunologically induced bronchoconstriction.

For the preparation of pharmaceutical compositions containing the compounds of formula I or formula II in dosage units for oral administration, the compound is admixed with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine. and with lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like, and pressed into tablets. The tablets may be used uncoated or coated in known manner to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a prolonged period of time. When coated tablets are desired, the core thus prepared can be coated with a concentrated solution of sugar, which solution may contain e.g. gum arabic, gelatin, talc, titanium dioxide or the like. Furthermore, the tablets may be coated with a varnish dissolved in a slightly volatile organic solvent or a mixture of such solvents and, if desired, dye may be added to this coating.

7 DK 156568 B

For the preparation of soft gelatin capsules, consisting of gelatin and e.g. glycerine and the like, the active ingredient is mixed with a vege-tabilic 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 (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration can 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 with a mixture of vegetable oil or paraffin oil.

Liquid compositions suitable for oral administration are suspensions, syrups and elixirs containing from ca. 0.2 to approx.

20% by weight of the active ingredient.

A suitable injection composition comprises an aqueous solution of a water-soluble pharmaceutically acceptable acid addition salt adjusted to a physiologically acceptable pH.

The compounds of formulas I and II are prepared using methods known per se to suitable starting materials. Representative processes known per se for preparing the aryloxypropanolamine compounds are disclosed in the following patents: Canadian Patent No. 834,751 (Troxler) and ü.S.A. patent no.

3,984,436 (Jaeggi, et al). More particularly, the present invention provides a process for preparing the compounds of formulas I and II according to the following reaction scheme.

O (2) CH3

Ar'-O-CH 2 CHCH 2 3-indolyl-CH 2 C-NH 2 / '' W ch.,

Ar'-OH formulas I and II

DK 156568 B

8 In the above reaction scheme, the symbol Ar 'for the groups ArXn and ArHet denotes as defined in formulas I and II. The present process proceeds according to reactions (1) and (2) wherein step (1) involves reacting the appropriately substituted phenol compound Ar'-OH with epichlorohydrin in the presence of a catalytic amount of an amine followed by treatment. with an aqueous alkali metal hydroxide or carrying out the reaction in an aqueous alkali metal hydroxide reaction medium where the amine catalyst is not required. There, in step (1), an Ar 'epoxypropyl ether is prepared which in step (2) is reacted with 2- (3-indolyl) -1,1-dimethylethylamine to form a product of formula I or II depending on the species of the Ar'OH used as starting material. Each of the reaction steps (1) and (2) readily takes place in conventional laboratory or plant apparatus under appropriate operating conditions.

Heating epichlorohydrin in substantially molar excess with a phenol Ar'OH containing one or two drops of piperidine as a catalyst in a steam bath overnight results in the condensation shown in step (1). A certain amount of the corresponding halohydrin intermediate is also formed and converted without isolation to the oxirane shown by treating the mixture with aqueous alkali metal hydroxide. Alternatively, the phenol Ar'OH and epichlorohydrin can be reacted in the presence of a sufficient amount of dilute aqueous alkali metal hydroxide to neutralize the acidic Ar'OH group at room temperature to form the desired intermediate Ar'OŒ ^ CHCl3. Step (2) is carried out simply by heating the oxirane intermediate formed in step (1) with 2- (3-indolyl) -1,1-dimethylethylamine, either purely or in the presence of an organic solvent inert for the reaction. No catalyst or condensing agent is required. Suitable solvents. contains 95% ethanol, but other inert organic liquids in which the reactants are soluble may be used. These include, but are not limited to, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are from ca. 60 to approx. 200 ° C.

9

DK 156568 B

In the following examples, the temperatures are in ° C. The melting points are corrected values according to U.S.P. The method where indicated by (corr.) · The nuclear magnetic resonance spectral values (NMR) refer to chemical shift (S) expressed as parts per million (ppm) to tetramethylsilane (TMS) as the reference standard. The relative area reproduced for the different shift values corresponds to the number of hydrogen atoms in the particular function type in the molecule and the nature of the shift value with respect to multiplicity is represented as broad singlet (bs), singlet (s), multiplet ( m), doublet (d), triplet (t) or quadruplet (q) with coupling constants (J) listed where appropriate. The arrangement is NMR (solvent): g (relative area, multiplicity, J value). Abbreviations used are MeOH (methanol), DMSO-dg (deutero-dimethyl sulfoxide), i-PrOH (isopropanol), abs.EthOH (absolute ethanol), EtOAc (ethyl acetate), EtOH (95% ethanol), i-PrOAc (isopropyl acetate) , iP 2 O (di-isopropyl ether), d (decomposition). André abbreviations have conventional established meanings. The infrared spectral descriptions (IR) include only absorbance numbers (cm 2) of value for the identification of functional groups. KBr was used as a diluent for all IR spectral determinations. TMS was used as internal reference for NMR spectral determination. The elemental analyzes are reproduced 'as weight percentages.

DK 156568 B

Preparation of Starting Compounds Example 1 4- (methylsulfonyl) -m-tolyloxymethyloxirane

To a mixture of 3-methyl-4-methylsulfonylphenol, 8.1 g (0.0435 mol and 20.0 g (0.216 mol) of epichlorohydrin is added 2 drops of piperidine as a condensation catalyst and the mixture is heated at 105-108 ° for 18 hours. Excess epichlorohydrin is then removed by distillation using toluene as a collector A solution of 2.1 g of sodium hydroxide in 50 ml of water and 70 ml of dimethoxyethane is then added and the mixture is stirred for 2 hours with occasional heating on a steam bath to convert any phenoxychloride compound. The solvent is then removed by distillation in vacuo and the residue is dissolved in a 1: 1 (v / v) mixture of ether and benzene. The solution is dried over anhydrous sodium carbonate and assayed by thin layer chromatography for purity of the desired oxirane under using a 9: 1 mixture of chloroform and methanol for development (R 2 = 0.8), the solvent is then removed at distillation to give 10.7 g of a residue which is: the 0 spoon an oxirane. Measurement of the infrared absorption spectrum is used to confirm the essential absence of hydroxyl-containing contaminants. This material is suitable for further reaction in Example 3 without further purification.

Example 2 2-Chlorophenoxymethyloxirane

A solution of 12.9 g of 2-chlorophenol (0.1 mole) in 125 ml of water containing 6.5 g (0.162 mole) of sodium hydroxide and 18.5 g (0.2 mole) of epichlorohydrin is stirred together at 25 ° C. 20 hours. The mixture is then extracted twice with 70 ml portions of methylene chloride. The extract is dried over anhydrous sodium carbonate and the solvent is removed by distillation in vacuo. The residue is the desired oxirane and is suitable for further conversion as described in Example 4.

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DK 156568 B

Preparation of End Products Example 3 1- [[2- (3-Indolyl) -1,1-dimethylethyl] amino] -3- [4- (methylsulfonyl) -m-tolyloxy] -2-propanol

The oxirane of Example 1, 10.7 g, is dissolved in 150 ml of toluene, 8.2 g (0.044 mole) of 2- (3-indolyl) -1,1-dimethylethylamine is added, and mixtures are refluxed for 18 hours. The toluene is removed by distillation in vacuo and a portion of the residue is converted to the acetate salt, mp 142-147 ° C. The structure is confirmed by examining the infrared absorption and nuclear magnetic resonance spectra. The remainder of the sample is converted to the hydrochloride salt by treatment with an acetonitrile solution thereof with 8N ethanolic HCl. After recrystallization from CH 2 CN / MeOH, 12.5 g of product is obtained, mp 174.0-177.0 ° (corr.)

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 11.12 (1, bs).

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

Example 4 1- (2-Chlorophenoxy) -3 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -2-propano A portion of the oxirane prepared in Example 2, 7 g (0.033 mol), is 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 is removed by distillation in vacuo and the viscous liquid residue is dissolved in 200 ml of ether, acidified with 8 N ethanolic HCl and the solvent is again removed at destination. Crystallization is caused by the addition of acetonitrile and rubbing with a glass rod. Recrystallization from acetonitrile and di-isopropyl ether to give 4.8 g of product, mp 150.5-153.5 ° C (corr.).

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

i2 DK 156568 B

NMR (DMSO-d 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.

Using the aforementioned methods, the products listed in the following table are prepared.

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17 DK 156568 B

Example 15 - Tablets Following ingredients are mixed in the weight ratio according to conventional pharmaceutical methods for preparing a tablet base.

Quantity of Ingredients

Lactose 79

Corn starch 10

Talc 6

Tragant 4

Magnesium stearate 1

This tablet base is mixed; with sufficient 1 - [[2- (3-indolyl) -1 / 1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) to prepare tablets containing 10, 20, 40, 80, 160 and 320 mg of the active ingredient, and pressed into a conventional tablet press.

Example 16 - Dry filled capsules The following ingredients are mixed in a conventional manner in the specified weight ratio.

Quantity of Ingredients

Lactose, U.S.P. 50

Starch 5

Magnesium stearate 2

Sufficient 1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) is added to the mixture to make capsules containing 10, 20 , 40, 80, 160 and 320 mg of the active ingredient are loaded into hard gelatin capsules of appropriate size.

Example 17 - Solution

A solution of 1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) is prepared from the following ingredients.

18 DK 156568 B

Quantity of Ingredients

Active ingredient 20 g

Sucrose, U.S.P. 400 g

Sorbitol, U.S.P. 100 g

Bentonite 20 g

Flavors, q.s.

Water, q.s. up to 1 liter

Each milliliter of solution contains approx. 20 mg of the active ingredient.

By applying the methods of Examples 1 or 2 to a suitable phenol or by other conventional methods, the following oxiranes are prepared which are then converted to the products of Formula I or II by reaction with 2- (3-indolyl) -1,1-dimethylethyl -amine according to Examples 3 and 4.

° l \ n

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CH (CH3) 2

Example 18

Example 20 Λ Λ ° o

Example 21

19 DK 156568 B

Physical properties are determined as follows:

Example 19 1- [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2- (2-propenyl) phenoxy] -2-propanol, hydrochloride, m.p. 163.0-168.6 ° (corr.), Recrystallized from MeOH / i-P 2 O.

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 (l, bs) and 11.40 (l, bs).

IR: 752, 1120, 1245, 1455, 1490, 1590, 1600, 2790, 2980 and 3350. Example 20 1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2- (2-methyl-1-propyl) -phenoxy] -2-propanol, hydrochloride, m.p. 163-166.0 ° (corr.), Recrystallized from MeOH / CH 2 CN.

Found: C, 69.34; 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 (1, bs); 9.60 (1, bs); 11.20 (1, bs).

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

Example 21 3- (2-Ethylphenoxy) -1 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -2-propanol, hydrochloride, m.p. 170.0-171.5 ° (corr.) Recrystallized from EtOH.

Found: C, 68.36; 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 (1, bs); 7.25 (9, m); 9.00 (1, bs) and 9.55 (1, bs).

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

DK 156568 B

The biological activity of compounds of the present invention is given below in the table. The compounds of Examples 22-32 are respectively.

Ex. no.

2- 2- [2-hydroxy-3 - [[2- (3-indolyl) -1H-dimethylethyl] amino] propoxy] -benzonitrile, hydrochloride, m.p. 185-187 ° C, 23 1- (2,3-Dimethylphenoxy) -3 - [[2- (3-indolyl) -1,1-dimethyl-ethyl] -amino) -2-propanol, hydrochloride, m.p. 173.5-175.5 ° C (corr.) 24 1- (4-Chloro-2-methylphenoxy) -3 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -2- propanol, oxalate (2: 1), hemihydrate, mp, 168-172 ° C (dec., corr.), 1- (2,4-dimethylphenoxy) -3 - [[2- (3-indolyl) -1 , 1-dimethylethyl] amino] -2-propanol, hydrochloride, m.p. 161.5-164.5 ° C (corr.) 26 1- [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2-methyl-4r (methylsulfonyl) phenoxy ] -2-propanol, oxalate (2: 1), hydrate, m.p. 209.5-211 ° C (dec., Corr.) 27 1-t [2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2- (1-methylpropyl) phenoxy] -2-propanol, hydrochloride, m.p. 163-166 ° C (corr.) 28 1- (2-Cyclohexylphenaphcy) -3 - [[2- (1H-indol-3-yl) -1,1-dimethylethyl] amino] -2-propanol, hydrochloride, mp.

189.5-191.5 ° C (corr.) 29 1- (2-fluorophenoxy) -3 - [[2- (3-indolyl) -1,1-dimethbylethyl] amino] -2-propanol, oxalate, mp. 203-205 ° C (dec., Corr.)

DK 156568 B

21 1- [[2- (3-indolyl) -1,1-dimethylethyl] amino] -3- [2- (trifluoromethyl) phenoxy] -2-propanol, oxalate, hemihydrate, m.p. 202.5 ° C (dec.) 31 1- [[2- (3-indolyl) -1,1-dimethyl] ethyl] amino] -S-Uni trophenoxy) -2-propanol, m.p. 127-128 ° C (corr.) 32 1- (2-Aminophenoxy) -3 - [[2- (3-indolyl) -1,1-dimethylethyl] amino] -2-propanol, dihydrochloride, m.p. 253.5-255.5 ° C (dec. Corr.) ·

The activity of the above compounds was investigated as given below.

The β-adrenergic blocking activity of the compounds of the present invention was compared with propranolol in bed-ridden rats as the ability to prevent isoproterenol-induced attenuation of heart rate 2 and 4 hours after oral dosing. The dose of propranolol needed to produce the same β-blocking activity as a test compound was determined and the ratio of propranolol to the test compound expressed the relative activity of the test compound.

The antihypertensive activity of the compounds of this invention was determined in spontaneously hypertensive rats. In the test animals, the blood pressure is measured fpr and 22 hours after oral dosing with 100 mg / kg of the subject compounds. The values in the table {A mmHgj indicate the change in pressure (positive or negative), also indicating the percentage change in heart rate (% Δ H.R.).

The vasodilatory effect was determined using angiotensin-treated, ganglia-blocked rats. The values in the table (% Δ blood pressure) indicate the change in blood pressure in the bed rats 30 minutes after intravenous administration with 3 mg / kg of the compounds.

Finally, the acute lethal dose (ALD5Q) was measured using orally treated mice.

22 DK 156568 B

Table

Adrenergic β-receptor blocking and vasodilatory effect -14 - 125-250 38 -3 -23 -> 2000 47 0 -22 -> 2000 57 0 -20 67 0 -21 - 250-500 7 - -12 0 - 500 8 10 -25 -12 -221 2 125 -250 9 10 7 -13 -10 11 12 ca.10 -24 -25 +19 125 13 5-10 -22 -14 -27 500 14 2-5 -5 -8 -30 500-100 15 5-10 - 12 -11 -29 250-500 22 5 -44 -14 -25 125-250 23> 10 -37 -13 +8> 2000 24 1 -14 -25 +11> 2000 25 10 -30 -22 +13 2000 26 2 -23 -19 -8> 2000: n 27 5-10. -24 -20 +22 500 28 6 -13 -23 +18> 1200 29> 10 -19 -5 -33 500-1000 30 10 -37 -3 -34 125 31 2-5 -22 -5 -38 125 32 1-3 -40 -19 -11 500-1000

Approximate value for orally treated mice 2

Dose 10 mg / kg intravenous

Claims (3)

23 DK 156568 B 1. Analogous Process for Preparation of 3-Indole Derivatives of General Formula I or II CH3 OH -rpCH2-C-NHCH2CHCH2-0 “Ar-Xn I <s -O-Ar-Het I 2, 2 2 k Ji U CH-, II H and acid addition salts thereof, wherein Ar represents phenyl or naphthyl, X represents optional substituents on Ar which may be the same or different groups selected from alkyl, alkenyl , alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanoamido, cycloalkyl of 3-6 ring linking and 1-3 optional alkyl substituents, cycloalkylalkyl of 3-6 ring linking and 1-3 optional alkyl substituents wherein each of the foregoing groups has up to 8 carbon atoms, phenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano and cyanoalkyl having from 2 to 4 carbon atoms, n represents 0, 1 or 2 as the number of X and Het represents a nitrogen-containing heterocyclic group containing 5 ringl ed, which heterocyclic group carries from 0 to 2 ring substituents in the form of C 1-6 alkyl, oxo or carboxamido, characterized by reacting a substituted phenol compound of the general formula Ar or ArHet having the aforementioned meaning with epichlorohydrin to form an epoxy propyl ether of the general formula: Λ Ar'-O-CH 2 CHCH 2 wherein Ar , the epoxypropyl ether is reacted with 2- (3-indolyl) -1,1-dimethylethylamine to form a compound of formula I or II and then a desired compound is converted to an acid addition salt thereof. A process according to claim 1, characterized in that the reaction is carried out between the phenolic compound and epichlorohydrin in the presence of a catalytic amount of an amine followed by treatment with aqueous alkali metal hydroxide. A process according to claim 1, characterized in that the reaction is carried out between the phenolic compound and epichlorohydrin in an aqueous alkali metal hydroxy medium. Copenhagen, June 19, 1989