CH642066A5 - 3-INDOLYL-TERT.-BUTYLAMINOPROPANOLE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING IT. - Google Patents

Description

35 The present invention relates to heterocyclic compounds of the indole series which have an amino substituent, processes for their preparation and medicaments containing them.

The invention relates to the compounds of the general 40 formulas I and II and their acid addition salts:

CH.

OH

CH2-C-NHCH2CHCH2-0-Ar-X. ch.,

n

(D

ch3

Oh

CH2-C-NHCH2CHCH2-0-Ar-Het (II) CH,

wherein

Ar represents phenyl or naphthyl,

X relates to substituents which are optionally present on the group Ar and which independently of one another have the following meanings: alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkyl sulfonyl, alkylsulfinyl alkylthio, alkanamido, cycloalkyl with 3 to 6 ring members and optionally 1 to 3 alkyl-65 substituents, cycloalkylalkyl with 3-6 ring members and optionally 1 to 3 alkyl substituents, each of the above groups containing up to 8 carbon atoms, phenyl, cyclopentenyl, trifluoromethyl, nitro, amino, Hy -

3rd

642066

droxyl, halogen, carboxamido, cyano and cyanoalkyl with 2 to 4 carbon atoms,

n stands for the integers zero, 1 or 2 and indicates the number of groups X, and

Het represents a nitrogen heterocycle with 5 or 6 ring members, preferably a 5-membered ring with 4 C atoms and one nitrogen atom, and contains up to 1 further heteroatom, selected from oxygen, sulfur and nitrogen, the heterocycle being zero to 2 ring members has substituents selected from alkyl, N-lower alkyl-carboxamido, N, N-di-lower alkyl-carboxamido, carb-alkoxy, where each of the aforementioned groups can contain up to 8 carbon atoms, oxo and carboxamido.

As antihypertensive agents, the compounds according to the invention have the special feature that they combine β-adrenergic blocking action and vasodilatory action. They are also useful as anti-angina agents, anti-stress agents, anti-arrhythmia agents, anti-thrombotic agents, and for treating conditions where it is desirable to reduce heart oxygen demand, such as in post-myocardial infarction treatment. Preferred compounds have a particularly desirable combination of these effects and possibly pharmacological side effects which make them particularly suitable for some of the indications listed above. Those compounds of the general formula I in which Ar is phenyl, n is 1 and X is in the ortho position are preferred as antihypertensive agents. The usefulness of the compounds of the general formulas I and II can be shown by various animal model experiments, such as antagonism activity against isoproterenol in the conscious rat, in the case of oral treatment (adrenergic β-receptor blocking action), in the spontaneously hypertensive rat ( antihypertensive effect), the hind leg preparation in the dog (vasodilatory effect), ouabain-induced ventricular tachycardia in the dog (antiarrhythmic effect), in dogs in which the coronary artery was closed (antiarrhythmic effect), in vitro by the platelet aggregation plasma in platelets measures after having been treated with a thrombogenic agent such as adenosine diphosphate or collagen (anti-thrombogenic effect), and with the aid of various other animal and laboratory model tests.

The invention relates to the compounds of the above general structural formulas and their acid addition salts. The pharmaceutically acceptable acid addition sets are preferred for medical purposes. Pharmaceutically acceptable acid addition salts are those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt and as such are the pharmacological equivalents of the bases of the general structural formulas above. In some cases the salts have physical properties which make them more suitable for pharmaceutical formulations, for example in terms of solubility, the lack of hygroscopicity, the suitability for pressing tablets, etc., or also the compatibility with other constituents with which the compounds according to the invention can be used together for pharmaceutical purposes. Acid addition salts which do not meet the above criteria with regard to pharmaceutical compatibility, for example toxicity, are sometimes useful as intermediates for the isolation and purification of the substances according to the invention or for other chemical synthesis purposes, such as the separation of optical isomers.

The acid addition salts are prepared by reacting a base of the above structural formula, preferably by contacting it in solution. They can also be prepared by metathesis or treatment with an anion exchange resin, replacing the anion of a salt of the substance with another anion, 5 the conditions being such that separation of the undesired species is possible, such as by precipitation a solution or extraction in a solvent or elution from or retention in an anion exchange resin. Suitable pharmaceutically acceptable salts for salt formation are e.g. Hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, phosphoric acid, nitric acid, mucic acid, isethionic acid, methanesulfonic acid, p-toluenesulfonic acid, glucosaccharic acid, palmitic acid, heptanoic acid, 15 oxalic acid, cyclamic acid and other acids.

The compounds of the above general structural formula according to the invention contain an asymmetric carbon atom in the propanolamine side chain and occur both as optically active isomers and as race-mixed mixtures thereof. The invention encompasses both the optically active and the racemic forms. Some of the compounds according to the invention contain an asymmetric carbon atom in the substituent X or Het and there are diastereoisomeric pairs of racemas. These also fall within the scope of the invention.

The racemic mixtures for the preparation of the optically active isomers of the above compounds are separated, for example, by forming a salt with an optically active acid, many of which are known to the person skilled in the art, such as optically active tartaric acid, mandelic acid, cholic acid, 0-di-p-toluoyl tartaric acid and 0.0-dibenzoyl tartaric acid, or other acids conventionally used for this purpose. The invention thus encompasses the products in the form of the various racemi-35 mixtures and, where appropriate, in the form of the optically active isomers.

The compounds according to the invention of the general formulas I or II or their pharmaceutically acceptable acid addition salts are systemically administered in an effective ^ 40 non-toxic amount to mammals who suffer from disease states which result from excessive stimulation of the adrenergic β-receptors, or also to mammals, who need vasodilation or who have hypertension. An effective dose is understood to be a dose which exerts an adrenergic β-receptor blocking effect, a vasodilation or an anti-hypertensive effect on the living being concerned, without undesired toxic side effects occurring. Systemic administration means both oral and parenteral administration. Examples of parenteral administration are intravenous injection or infusion, and intraperitoneal, intramuscular or subcutaneous injections. Rectal administration using ointments or suppositories can also be used. The dosage is 55, depending on the mode of administration, of about 0.1 to 100 mg / kg body weight of a compound of the general formulas I or II or pharmaceutically acceptable acid addition salts thereof.

Acute toxicity values, measured in the orally treated mouse, are in the range of an ALD, 0 from 250 mg / kg to> 2000 mg / kg body weight, with non-lethal signs of drug action, such as stimulation or depression of the central nervous system, mydriasis or lacrimation -Nominal flow from about V2 to V10 of this dose occur. 65 The combination of the pharmacological properties of the compound according to Example 10 shows l - {[2- (3-indolyl) -l, l - dimethylethyl] -amino} -3- (2-methylphenoxy) -2-propanoI - hydrochloride that they are especially for use

642066

4th

is suitable as an antihypertensive agent. It has five-fold adrenergic β-receptor blocking of propanolol, as was shown by oral administration to rats and subsequent treatment of the animals with isoproterenol. The latter compound is a 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 efficacy values given above are established by regression analysis of the log dose response values for the two compounds. In therapeutic use, the size and frequency of dosing depend on the mode of administration and ranges from 0.2 mg for intravenous administration to about 100 mg orally in humans.

The compound according to Example 10 differs from other adrenergic β-receptor blocking agents in that it is effective in lowering the blood pressure of the spontaneously hypertensive rat. Although adrenergic β-receptor blocking agents are now widely used in the treatment of hypertension in human medicine, their mechanism of action is unknown and their antihypertensive activity cannot be demonstrated in most cases by this animal experiment. If the compound according to the invention is used, the spontaneously hypertensive rat has a reduction in blood pressure of 25 mm Hg at a dose of 100 mg / kg of body weight when administered orally, the heart rate being reduced only minimally. This is considered evidence of utility in hypertension indications where other adrenergic beta-receptor blocking agents are ineffective or less desirable.

The compound according to Example 10 also causes a reduction in blood pressure when administered intravenously to anesthetized dogs in a dose of 3.33 mg / kg body weight. It is further characterized in that it does not reduce the heart rate or the right ventricular contraction force, as is the case with many other known β-receptor blocking agents. The substance shows both positive inotropic and positive chronotropic effects, and these effects show 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 overall peripheral resistance are reduced, all of the above effects being measured on the anesthetized dog.

The compound of Example 10 has a vasodilatory effect, which is probably partly due to its special anti-hypertensive effect. In the anesthetized, ganglion-blocked rat (with chlorisondamine chloride) kept in angiotension, immediate-acting vasodilators such as diazoxide have a hypotensive effect. The compound according to Example 10 of the present invention is equivalent to the diazoxide in terms of the effect in this test. The vasodilatory effect can also be demonstrated by pump perfusion on the hind leg of dogs, where perfusion doses of 0.03 to 1.0 mg / min. be used. After oral administration to rats, there is a decrease in urine volume and a decrease in sodium ion excretion, which is typical of vasodilatory compounds.

The antithrombogenic effect of the compound of Example 10 is demonstrated by its ability to reduce platelet aggregation in vitro in platelet-rich plasma after administration of ADP or collagen. The in vitro activity of this compound corresponds to that of sul-octidil or papaverine.

There is a risk of primarily using adrenergic ß-receptor blocking agents in patients suffering from non-allergic bronchospasm, as these agents tend to cause an asthma attack or stimulate the patient for treatment with adrenergic ß-receptor agents such as Make isoproterenol, which are used in the treatment of acute seizures, refractory. The compound of Example 10 does not have a bronchospastic effect, which is shown by the fact that it does not reduce the lung ventricular pressure and only slightly increases the response of sensitized rats to immunologically induced bronchoconstriction upon intravenous administration of 0.5 mg / kg body weight. In contrast, propanolol at a dose of 0.5 mg / kg body weight, administered intravenously, respiratory lung pressure and causes an acute bronchospastic reaction in rats which were immunologically sensitized to bronchial constriction.

In the preparation of the pharmaceutical compositions which contain the compounds of the formulas I or II in the form of dosage units and are intended for oral administration, the compound is mixed with a solid, powdery carrier, such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch , Amylopectin, cellulose derivatives or gelatin, and with lubricants such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like and presses them into tablets. The tablets can be used without a coating or coated using known methods to delay the decomposition and absorption in the gastrointestinal tract and thereby achieve a lasting effect over a longer period of time. If coated tablets are desired, the core prepared as described above can be coated with a concentrated sugar solution, which may optionally contain gum arabic, gelatin, talc, titanium dioxide or the like. The tablets can also be coated with a varnish dissolved in a volatile organic solvent or in a solvent mixture and, if desired, dyes can also be added to this coating.

In the production of soft gelatin capsules, which consist of gelatin and, for example, glycerin or the like, the active ingredient is mixed with a vegetable oil and encapsulated in a conventional manner. Hard gelatin capsules can contain granules of the active ingredient with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration can be prepared in the form of suppositories which contain the compound in a mixture with a neutral fat base or in the form of rectal gelatin capsules with a mixture of vegetable oil or paraffin oil.

Liquid preparations suitable for oral administration are suspensions, syrups and elixirs, which contain about 0.2% by weight of the active ingredient.

Agents suitable for injection are aqueous solutions of a water-soluble, pharmaceutically acceptable acid addition salt, which are adjusted to a physiologically acceptable pH.

The compounds of formulas I and II are prepared by treating suitable starting materials by known methods. Representative known processes for the preparation of aryloxypropanolamine compounds are described in the following patents:

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

5

642066

Canadian Patent No. 834,751 and U.S. Patent 3,984,436. The present invention also relates to processes for the preparation of the compounds of formulas I and II according to the following reaction scheme:

0 / \

Ar -O-CHaCHCHj

CH3

I.

3-indolyl-CH2C-B CH3

Ar'-OH

(2)

CH3

3-indolyl-CH2C-NH2

f

CH3

(4) Connections of the

Formulas I and II

CH2C6Hs i a

-N-CH2CHCHa or

—N

-CH20S02R

III

IV

In this reaction scheme, Ar 'represents the groups ArX "and ArHet, as defined in claim 1 for the formulas I and II, and B is defined by the formulas III and IV, wherein R represents a lower alkyl group having 4 or less C atoms . Reactions (1) and (2) are preferred, wherein in step (1) the suitably substituted phenol compound Ar'-OH is reacted with epichlorohydrin in the presence of a catalytic amount of an amine and then treated with an aqueous alkali metal hydroxide, or the reaction in an aqueous Performs alkali metal hydroxide reaction medium, whereby the amine catalyst is not required. In step (1) an Ar'-epoxypropyl ether is obtained, which is reacted in step (2) with 2- (3-indolyl) - 1,1-dimethylethylamine, depending on the type of Ar'OH used - Starting materials receives a compound of formula I or formula II. Each of steps (1) or (2) can be easily carried out with conventional laboratory or factory equipment under pleasant working conditions.

If epichlorohydrin is heated in a substantially molar excess with a phenol Ar'OH, which contains one or two drops of piperidine as catalyst, overnight in a steam bath, the condensation shown in step (1) takes place. Some of the corresponding halohydrin intermediate also results and is converted into the oxiram shown without isolation 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 a dilute aqueous alkali metal hydroxide to neutralize the acidic Ar'OH group at room temperature, then the desired intermediate

/ ° \

Ar'OCH2CHCH2

results.

Step (2) simply consists in that the intermediate oxirane produced in step (1) is made with 2- (3-indolyl) -l, l-

30 -dimethyl-ethylamine, either undiluted or in the presence of an inert organic solvent. 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 intended to be limiting, benzene, tetrahydrofuran, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are between about 60 ° C and 200 ° C.

Another process for the preparation of the compounds of the formulas I or II is that the starting material Ar'OH as defined above is reacted with a reactant of the formula

45 CH.,

3-indolyl-CH2C-B

CH.

in accordance with reaction (3) of the above scheme, whereby an intermediate product is obtained which is converted into the end product by hydrolysis or hydrogenolysis. The 55 substituent B in the reactant used in step (3) comprises the groups defined by the formulas III or IV, which react with the phenolic hydroxyl group Ar'OH, so that a propanolamine side chain is first introduced into the product.

m The reactants for stage (3) in which B corresponds to the formula III are prepared by preparing the N-benzyl derivative of 2- (3-indolyl) -l, l-dimethylethylamine and this with epichlorohydrin with adaptation of that from L. Villa et al., II. Farmaco. Sci- Ed., 24, (3) 349 (1969) 65.

The reactants in which B corresponds to formula IV are known by reductive alkylation of 2- (3-indolyl) -1, l-dimethylethylamine with glyceraldehyde

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6

Processes, e.g. using 5% palladium on activated carbon catalyst in a hydrogen atmosphere with methanol or other suitable, non-reactive liquids as a solvent. If an optically active form of glyceraldehyde is used, an optically active end product of the formula I or II is obtained. The aminopropanediol which results from the above reductive alkylation is then converted into the desired 2- (3-indolyl ) - 1,1-Dimethyläthyloxazolidinon compound transferred, wherein B corresponds to the formula IV by reacting with formaldehyde, using 37% aqueous formaldehyde in refluxed benzene with constant distilling off the water. By esterification with an alkanesulfonyl chloride of the formula RS02C1, in which R stands for a lower alkyl group with 1 to 4 carbon atoms, the necessary group is introduced, which reacts with Ar'OH.

The intermediate product produced in stage (3), in which B corresponds to formula III, is converted in stage (4) into a product of formula I or II by debenzylation in a known manner, for example by catalytic hydrogenation or reaction with sodium in liquid ammonia . The intermediates prepared in stage (3), in which B corresponds to formula IV, are preferably converted into the products of the formulas I and II in stage (4) by mild, acidic hydrolysis. In this case, care must be taken to avoid decomposition of the reactant since the 3-indolyl substituent is sensitive to acid.

Aqueous, inorganic acids in a concentration of 0.1 N to In are suitable at temperatures of 20 to 100 ° C. The product is obtained in the form of the free base from the hydrolysis mixture by neutralizing and collecting the precipitate.

The 2- (3-indolyl) -1, l-dimethylethylamine used is prepared by the method of H.R. Snyder, et al., J. Am. Chem. Soc., 69, 3140 (1947) from 3-indolylmethyldimethylamine and 2-nitropropane and reduction of the 2- (3-indolyl) -1,1-dimethylnitroethane obtained.

In the examples below, the temperatures are measured in ° C. The melting point values are, where indicated (corr.) According to U.S.P. Procedure corrected. The nuclear magnetic resonance spectra (NMR) relate to the chemical shift (5) expressed as parts per million (ppm) compared to tetramethylsilane (TMS) as a comparison standard. The relative area of the different shifts corresponds to the number of hydrogen atoms of the specific functional type in the molecule, and the type of shift is specified in terms of its multiplicity with broad singlet (bs), singlet (s), multiplet (m), doublet (i.e. ), Triplet (t) or quadruplet (q), where the coupling constants (J) are given, if appropriate. The data are listed as follows:

NMR (solvent): 6 (relative range, multiplicity,

J value).

The following abbreviations are used: MeOH (methanol), DMSO-ds (deuterodimethyl sulfoxide), i-PrOH (isopropanol), abs. EtOH (absolute ethanol), EtOAc (ethyl acetate), EtOH (95% ethanol), i-PrOH (isopropanol). i-PrOAc (isopropyl acetate), i-Pr20 (di-isopropyl ether), d [decomposition (decomposition)]. Other abbreviations used are already generally known. The information regarding the infrared spectra (IR) only include the absorption wave numbers (cm-1) which are of value for the identification of functional groups. KBr is used as a diluent for all IR spectral data. TMS is used as an internal standard. The values of the elementary analyzes are given as percentages by weight.

example 1

4- (methylsulfonyl) m-tolyloxyniethyl oxirane

To a mixture of 8.1 g (0.0435 mol) of 3-methyl-4-5 -methylsulfonylphenol and 20.0 g (0.216 mol) of epichlorohydrin, two drops of piperidine are added as a condensation catalyst and the mixture is heated at 105-108 for 18 hours ° C. Then the excess epichlorohydrin is distilled off using toluene as a tractor. Then a solution of 2.1 g of sodium hydroxide in 50 ml of water and 70 ml of dimethoxyethane is added and the mixture is stirred for 2 hours, occasionally heating on a steam bath in order to convert all of the phenoxychlorohydrin to the oxirane. The solvent is then removed by distillation in vacuo and the residue is dissolved in a 1: 1 mixture (vol / vol) of ether and benzene. The solution is dried over anhydrous sodium carbonate and thin layer chromatography is carried out to determine the purity of the oxirane, using a 20 9: 1 mixture of chloroform and methanol as developer (Rf = 0.8). The solvent is then removed by distillation, giving 10.7 g of a residue which consists of the desired oxirane. The IR absorption measurement is then carried out in order to virtually confirm the absence of impurities containing hydroxyl groups. The material obtained can be used in Example 3 without further purification.

30th

Example 2 2-chlorophenoxymethyl oxirane

A solution of 12.9 g (0.1 mol) of 2-chlorophenol in 35 125 ml of water containing 6.5 g (0.162 mol) of sodium hydroxide and 18.5 g (0.2 mol) of epichlorohydrin is stirred together 20 Hours at 25 ° C. 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 consists of the desired oxirane and is suitable for further conversion, as described in Example 4.

45

Example 3

l - {[2- (3-indolyl) -1, l-dimethylethyl] -amin0 ^ -3- [4-methyl-sulfonyl) -m-tolyloxy] -2-propanol

50

10.7 g of the oxirane according to Example 1 are dissolved in 150 ml of toluene, 8.2 g (0.044 mol) of 2- (3-indolyl) -l, l-dimethyl-ethylamine are added and the mixture is heated under reflux for 18 hours. The toluene is removed by distillation in a Va-55 vacuum and part of the residue is converted into the acetate salt, mp. 142-147 ° C. The IR and NMR spectra are consistent with the desired structure. The rest of the sample is converted to the hydrochloride salt by treating an acetonitrile solution of the compound with 8N ethanolic HCl. After recrystallization from CH3CN / MeOH, 12.5 g of product are obtained, mp. 174.0 to 177.0 ° C (corr.).

Analysis:

Found: C 59.40 H 6.90 N 5.87% 65 NMR (DMSO-d6): 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.

7

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Example 4

I- (2-chlorophenoxy) -3 - {[2- (3-indolyl) -1, l-dimethylethyl] - aminoy-2-propanol

A portion of the oxirane prepared in Example 2, 7 g (0.033 mol) is heated in solution with 6.3 g (0.033 mol) of 2- (3-indolyl) -l, l-dimethyl-ethylamine in 70 ml of ethanol to reflux. 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 8N ethanolic HCl and the solvent is removed again by distillation. Crystallization is induced by adding acetonitrile and rubbing with a glass rod. After recrystallization from acetonitrile and diisopropyl ether, 4.8 g of product are obtained, mp. 150.5-153.5 ° C (corr.). s analysis:

found: C 61.54 H 6.41 N 6.94% NMR (DMSO-de): 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.

io By adapting the above procedures you get the products listed in the table below.

Compound of formulas I and II Examples 5-14

Example ArXn or ArHet mp. ° C (corr.) Solvent for elementary NMR (DMSO-de) IR

No recrystallization analysis

1-naphthyl

232.0-233.0 hydrochloride

MeOH / CH, CH

C H N

70.47 7.07 6.47

1.28 (6, s) 3.24 (4, m) 4.28 (3, m) 6.01 (l, d,

4.4 Hz) 7.39 (12, m) 8.90 (2, bs) 11.00 (l, bs)

750, 800, 1270, 1460,

775, 1110, 1400, 1580, 2780

3-methylphenyl

165.0-167.0 hydrochloride

MeOH / i-PrOH

C H N

67.76 7.62 7.05

1.30 2.28 3.18 4.13 5.93 7.10 8.72 9.12 11.00

(6, s) (3, s)

(4, m) (3, m) (l.bs) (9, m) (l, bs) (l, bs) (l.bs)

745, 770, 1160, 1260, 1450, 1490, 1580, 1600, 2780

3-chlorophenyl

197.0-198.0 hydrochloride

MeOH / abs.EtOH

C H N

a

61.34 6.36 6.75 17.14

1.30 (6, s)

3.20 (4.m)

4.17 (l, d,

6.03 (l, d,

5.0 (Hz)

7.20 (9, m)

8.86 (l, bs)

9.30 (l, bs)

750, 770,

1110, 1230,

1275, 1475,

1580, 1590,

2800, 3340

2-ethoxyphenyl

173.0-175.0 hydrochloride

MeOH / i-PrOH

2-acetylphenyl

161.0-163.0 hydrochloride

CHSCN

C.

65.86

1.30 (6, s)

740.

755.

H

7.51

1.32 (3, t,

1130.

1215.

N

6.63

7.0 Hz)

1260.

1510,

3.29 (4.m)

1580,

1590,

4.11 (5, m)

2800

5.99 (l, bs)

7.22 (9, m)

8.90 (l, bs)

9.31 (l, bs)

C.

65.73

1.30 (6, s)

745.

755.

C.

65.59

2.65 (3, s)

1240.

1450.

H

7.10

3.20 (4.m)

1485.

1590,

H

6.94

4.30 (3. m)

1665,

2780

N

7.05

6.04 (l, bs)

N

7.03

7.41 (9, m)

8.86 (l, bs)

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Example ArXn or ArHet Mp. ° C (corr.) No.

Solvent for recrystallization

Elemental analysis

NMR (DMSO-ck) IR

10 *

2-methylphenyl

11

2- (1H-pyrrole-1-yl) phenyl

12

(4-methylsulfonyl) phenyl

13

14

conh,

(2-methylsulfonyl) phenyl

173.0-174.5

MeOH / EtOAc

C.

68.09

1.30 (6, s)

750, 1170,

Hydrochloride

H

7.77

2.20 (3, s)

1250, 1460,

N

7.16

3.28 (4.m)

1500, 2800,

4.15 (3, m)

3300

6.02 (l, d,

4.2 Hz)

7.22 (9, m)

9.15 (2, bs)

11.30 (l, bs)

124.0-126.0

EtO Ac / i-PrO Ac

C.

74.40

1.10 (6, s)

740, 1100,

base

H

7.32

2.33 (l, bs)

1230, 1450,

N

10.38

2.80 (4.m)

1510, 1590,

3.96 (3.m)

3160, 3400

5.92 (l, bs)

6.33 (2.m)

7.19 (11, m)

8.10 (l, bs)

217.0-220.0

MeOH / abs.EtOH

C.

58.32

1.30 (6, s)

760, 780,

Hydrochloride

H

6.62

3.16 (3, s)

1155, 1300,

N

6.90

3.35 (4.m)

1510, 1600,

4.26 (3.m)

2800

6.07 (l, bs)

7.0-8.0 (9, m)

8.85 (l, bs)

9.25 '(l, bs)

224.5-227.5

abs.EtOH / EtOAc

C.

61.41

1.30 (6, s)

760, 1430,

Hydrochloride

C.

61.24

2.55 (2.m)

1510, 1600,

Hemihydrate

H

6.90

3.25-4.25

1680, 3400

H

6.59

(10, m)

N

10.81

6.05 (l, bs)

N

10.72

7.35 (11, m)

Cl

7.34

8.90 (l, bs)

9.31 (l, bs)

175.0-179.0

Me0H / i-Pr20

C.

57.23

1.39 (6, s)

750, 1130,

Hydrochloride

C.

57.37

3.60 (3, s)

1150, 1300,

Hemihydrate

H

6.91

3.62 (4.m)

1450, 1485,

H

6.61

4.42 (3, m)

1590, 1625

N

5.90

6.22 (l, m)

N

5.94

7.42 (9, m)

9.00 (l, bs)

9.51 (l, bs)

* In Example 10, the 2- (3-indolyl) -l, l-dimethylethylamine and the oxirane intermediate were reacted with one another at 140 ° C. for 1/2 hour without solvent or diluent.

Example 15

Tablets

The following constituents are mixed in the 55 parts by weight indicated by conventional pharmaceutical processes, whereby a tablet base is obtained.

Components

amount

Lactose

Cornstarch

talc

Tragacanth

Magnesium stearate

79 10 6 4 1

65 This tablet base is mixed with so much l - {[2- (3-indolyl) -l, l-dimethylethyl] -amino} -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) that tablets are obtained which contain 10, 20, 40, 80, 160 and 320 mg of active ingredients

9

642066

Contain fabric and presses it in a conventional tablet press.

Example 16

Capsules filled dry

The following ingredients are conventionally mixed in the parts by weight indicated.

0

Components

Set ch3ch = chc ^

0 / \

och2chch2

Example 20

Components

amount

Lactose, USP

50

Strength

5

Magnesium stearate

2nd

ch3so

15 Example 21

0 / \

och2chch2

Then so much l - {[2- (3-indolyl) -1, l-dimethyl-ethyl] -amino} -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) is added to the mixture that capsules are obtained which contain 10, 20, 40, 80, 160 and 320 mg of active ingredient, filled into hard gelatin capsules of a suitable size.

Example 17

solution

A solution of l - {[2- (3-indolyl) -1, l-dimethylethyl] -amino} -3- (2-methylphenoxy) -2-propanol hydrochloride (Example 10) is prepared from the following Ingredients:

20th

active ingredient 20 g

Sucrose, USP 400 g 35

Sorbitol, USP 100 g

Bentonite 20 g

Flavorings, fill up as much as 40 with water to 1 liter.

P \

och2chch2

Example 22

Example 23

O / \

- och2chch2

s-ch.

O / \

och2chch2

nhcoch.

Example 24

Each milliliter of this solution contains approximately 20 mg of active material.

If one uses the processes according to Examples 1 or 2, or other conventional processes with suitable phenols, the following oxiranes are obtained, which are then reacted with 2- (3-indolyl) -l, l-dimethyl-ethylamine according to the Examples 3 or 4 are converted into the corresponding compounds of the formulas I or II.

c = ch

O / \

_o-ch2chch2

Example 18

0 / \

0-ch2chch2 ch2ch = ch2

Example 25

O / \

och2chch2

conh,

O / \

oh chch

Example 26

O / \

och2chch2

och2ch = ch2

Example 19

Example 27

642066

10th

Cl

O / \

och2chch2

Cl

Example 28

O / \

och2chch2

Example 29

O / \

och2chch2

Br

O / \

och2chch2

o / \

och2chch2

20th

Example 35

O / \

och2chch2

conh,

Example 30

O / \

, och chch2

N

"conhch:

Example 31

30th

35

conh,

à

Example 36

ch30

o / \

0chochch.

Z à

Br

Example 37

O

och2chch2

O

n '

con (ch3) 2

Example 32

O / \

och2chch2

C02C2n5

Example 38

// w-och2c4h2

ch,

a

0

och2chch2

o n v_ /

Example 33

Example 39

11

642066

/ \

O / \

, och2chch2

s n

V

Example 40

O / \

och2chch2

so2ch3

Example 46

wwu2 ^ HCH2

Example 41

O

/ \

^ fX / OCHjCHCHj ch3co2

CH, CN

Example 42

O / \

och2chch2

ch2ch (ch3)

Example 43

- "2jhch2

30th

40

Example 47

O / \

och2chch2

cf.

O / \

och2chch2

Example 48

Example 49

no,

O / \

och chch2

nh,

O

/ \

och2chch2

Example 50

O / \

■ och chch

Example 44

O / \

oh chch

Example 45

Example 51

O

/ \

och chch2

Example 52

642066

12

O

The physical properties were determined as follows:

Example 19

l - {[2- (3-indolyl) -1, l-dimethylethyl] amino} -3- [2- (2-propenyl) phenoxy] -2-propanol hydrochloride, mp 163.0- 168.6 ° C, (corr.), Recrystallized from MeOH / i-PraO.

Analysis:

found: C 69.22 H 7.56 N 6.70% NMR (DMSO-de): 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

l - {[2- (3-indolyl) -1, l-dimethylethyl] amino} -3- [2- (2-methyl-l-propyl) phenoxy] -2-propanol hydrochloride, mp. 163.0-166.0 ° C (corr.), Recrystallized from MeOH / CH3CN. j Analysis:

found: C 69.34 H 8.19 N 6.49% NMR (DMSO-de): 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, io bs).

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

15

Example 45

3- (2-Ethylphenoxy) -l - {[2- (3-indolyl) -l, l-dimethylethyl] - amino} -2-propanol hydrochloride, mp. 170.0-171.5: IC (corr .), recrystallized from EtOH.

20 Analysis:

found: C 68.36 H 7.95 N 6.85% NMR (DMS0-d6): 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).

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

Claims (9)

642066 , 2 6 5 / \ -n - ch2 - ch - ch. or for 20th CH20S02R n O wherein R represents a lower alkyl group with 1 to 4 carbon atoms-25 ,, stands, implemented and the compound obtained is subjected to hydrolysis or hydrogenolysis. 2. Compounds according to claim 1, wherein Ar is phenyl, X is in the ortho position and n is the integer 1. 2nd PATENT CLAIMS 1. Indole derivatives of general formulas I or II OH- i J OH CH2-C-NHCH2CHCH2-0-Ar-Xn (I) CH., ? h3 OH implements. 3-indolyl-CH2 - C - NH2 ch " i5 CH ^ -C ^ Hc. <3 3. Compounds according to claim 1, wherein Ar is phenyl, X is alkyl having up to 8 carbon atoms and n is the integer 1. 3-indolyl-CH ^ - c ~ b, ^ I 10th CH2-C-NHCH2CHCH2-0-Ar-Het (H) CH_ ch. wherein B for and their acid addition salts, wherein Ar represents phenyl or naphthyl, X relates to substituents which are optionally present on the group Ar and which independently of one another have the following meanings: alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkanoyl, alkenoyl, alkanoyloxy, alkenoyloxy, alkylsulfonyl, alkylsulfinyl, alkylthio, alkanamido, cycloalkyl with 3 to 6 ring members and optionally 1 to 3 alkyl substituents, cycloalkylalkyl with 3 to 6 ring members and optionally 1 to 3 alkyl substituents, each of the above groups containing up to 8 carbon atoms; Phenyl, cyclopentenyl, trifluoromethyl, nitro, amino, hydroxyl, halogen, carboxamido, cyano and cyanoalkyl with 2 to 4 carbon atoms, n stands for the integers zero, 1 or 2 and indicates the number of groups X, and Het represents a nitrogen heterocycle which contains 5 or 6 ring members and up to 1 further heteroatom, selected from oxygen, sulfur and nitrogen, the heterocycle containing zero to 2 ring substituents, selected from alkyl, N-lower alkyl carboxamido, N, N-Di - lower alkyl carboxamido, carbalkoxy, where each of the aforementioned groups can contain up to 8 carbon atoms; Oxo and carboxamido. 4. Compounds according to claim 3, wherein X is methyl. 5. l - {[2- (3-indolyl) -1, l-dimethylethyl] amino} -3- (2-methylphenoxy) -2-propanol, and its hydrochloride as compounds according to claim 1. 6. Compounds according to claim 1, wherein Ar is phenyl, X is cyano and N is the integer 1. 7. A process for the preparation of a compound according to claim 1, characterized in that a compound of the general formula Ar'-OH wherein Ar 'is ArXn or ArHet with the meanings given in claim 1, first with epichlorohydrin and then with a compound of formula ch3 8. A process for the preparation of a compound according to claim 1, characterized in that a compound of the formula Ar'-OH, in which Ar 'is ArXn or ArHet s with the meanings given in claim 1, with a compound of the formula ch3 9. Pharmaceutical agent, characterized in that it contains at least one compound according to one of claims 1 to 6 in a pharmaceutical carrier.