DK151330B - METHOD OF ANALOGUE FOR THE PREPARATION OF AMINOAL ALCOHOL DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF - Google Patents

Description

in 151330

The present invention relates to an analogous process for the preparation of novel amino alcohol derivatives of the general formula I of claim 1, or pharmaceutically acceptable salts thereof, in which formula R1, R2, R3, R4, R5, R6 , η, X and Y also have the meanings specified in the preamble of claim 1. The process according to the invention is characterized by the characterizing part of claim 1.

The 10 compounds prepared by the process of the invention have antihypertensive and vasodilatory activity.

Some of them also have antispasmodic effects. Details of this will follow at the end of the description.

According to the invention, compounds of the general formula I, in which the halogen atoms are chlorine or fluorine, are particularly conveniently prepared.

It is particularly preferred according to the invention to prepare the following compounds having particularly high antihypertensive and vasodilatory activity: 1- (6-thiochromanyl) -2-n-octylamino-1-propanol, 1- (6-thiochromanyl) -2- (4- phenylbutylamino) -1-propanol, 1- (6-thiochromanyl) -2- [2- (phenoxy) ethylamino] -1-propanol, 1- (2,3-dihydro-5-benzo [b] thienyl) -2- n-octylamino-1-propanol, 1- (2,3-dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-propanol, 1- (2,3-dihydro-5-benzo) [b] thienyl) -2- [4- (p-chlorophenyl) butylamino] -25 1-propanol, 1- (2-methyl-2,3-dihydro-5-benzo [b] thienyl) -2- (4) -phenylbutylamino) -1-propanol, 1- (2-methyl-2,3-dihydro-5-benzo [b] furanyl) -2-n-octylamino-1-propanol, 1- (2,3,4, 5-tetrahydrobenzo [b] thienpin-7-yl) -2- (4-phenylbutylamino) -1-propanol, 1- (2,3-dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-propio-nyloxypropane, 1- (2,3-dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-cyclohexanoyloxypropane, 1- (5-indanyl) -2- (4-phenylbutylamino) -1-propanol, 1- (5-indanyl) -2- [2- (4-chlorophenoxy) ethylamino] -1-propanol and 1- (5-indanyl) anyl) -2- [2- (4-fluorobenzoyl) -propylamino3-1-propanol.

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Salts of compounds of general formula I are especially salts with inorganic acids such as hydrochlorides, phosphates and sulfates; or salts with organic acids such as oxalates, lactates, tartrates, acetates, citrates, maleate, glucuronates and gluconates.

The particularly active among the products of the invention having two asymmetric centers can be obtained as two racemates corresponding to the erythro and threo configuration, respectively, and both of these racemates can be cleaved by conventional methods, for example by forming diastereoisomeric salts. by the action of optically active acids such as tartaric acid, diacetyltartaric acid, tartranilic acid, dibenzoyltartaric acid, ditoluoyltartaric acid and separation of the diastereoisomeric mixture by crystallization, distillation, and / or chromatography, followed by release of the optically active bases from the salts.

The same methods can be used when the compounds of the present invention comprise more than two asymmetric centers.

Thus, the active derivatives can be used either in the form of racemates with erythro or threo configuration or in the form of a mixture of these forms or as optically active compounds of each of the mentioned forms.

The aforementioned amino alcohol derivatives, as mentioned, generally have an effect on the cardiovascular system, such as an antihypertensive and possibly antispasmodic action, a peripheral vasodilatory effect and possibly protective effect against myocardial anoxia, hypolipicbmic, antithrombotic, 3-lytic, platelet aggregation-inhibiting and / or central nervous system effects, e.g., a tranquilizing effect.

These properties show that the compounds of the invention may be useful in the treatment of hypertension and cardiovascular diseases, such as species iosclerosis.

In particular, it has been found that the compounds of the invention have very high antihypertensive, and several of them hypolipidemic and antithrombotic effects.

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The active compounds prepared by the process of the invention can be administered orally or parenterally with various pharmaceutical excipients.

For oral administration, coated pills, granules, tablets, capsules, solutions, juices, emulsions or suspensions containing the commonly used additives and excipients may be used. For parenteral administration, a liquid such as sterile water or an oil such as peanut oil or ethyl oleate may be used.

These active compounds can be used alone or in combination with other active products having a similar or different effect.

Thus, if the invention proceeds by reducing an α-aminoketone of formula II, wherein Q is a group 15 of the formula R3 -CO-CH-N ^ l2 \ 7 R XR7 2 3 7

20 where R and R have the meanings previously stated and R

4 has the same meaning as R or is a protecting group which can be removed later by hydrolysis or hydrogenolysis such as benzyl, butyl, trityl, acetyl, formyl or benzhydryl, the reduction can be carried out in the usual way, most conveniently for example by the action of alkali metal hydrides such as sodium borohydride, in a solvent such as methanol or ethanol, preferably at low temperature; or aluminum and lithium hydride in a solvent such as diethyl ether or tetrahydrofuran; or also by the action of an aluminum alkoxide, such as aluminum isopropoxide, in a solvent such as isopropanol, particularly advantageous at refluxing. The reduction may also be effected by hydrogenation in the presence of a catalyst such as palladium on carbon, Raney nickel or platinum oxide in a solvent such as methanol, ethanol, dioxane or acetic acid.

As mentioned, some of the products produced by the process of the invention may have two configurations, namely the erythro and threo configuration. Selection of the amino ketone used as the starting material and of the reduction conditions makes it possible to obtain any of these two forms stereoselectively. Thus 3 4

5 leads to reduction of an amino ketone where Q = CO-CH-NR R

12 and R = hydrogen, for a compound of erythro configuration under the general conditions described above.

To obtain a compound having a threo configuration, the reduction is carried out on an amino ketone where Q = CO-CH-NR R, R 2 27 where R and R have the previously defined meanings and R is a removable protecting group later by hydrolysis or hydrogenolysis, such as a benzyl group, trityl group, acetyl group, formyl group or a benzhydryl group. This reduction is preferably accomplished by the action of alkali metal hydrides, such as sodium borohydride, or aluminum and lithium hydride.

The amino ketones used as starting materials are readily available, for example, by the action of an amine R 3 R 4 NH on an α-halogen ketone in solvents such as ether, benzene, chloroform, dioxane, methanol, isopropanol or acetonitrile.

However, it is well known in the literature that reactions of this type usually yield low yields due to the formation of many secondary products and the stability of α-amino ketones. According to the present invention, a synthesis method has been found which allows the preparation of amino alcohols of the general formula I in excellent yields, and the compounds are preferably obtained without isolation of the intermediate amino ketone. A particularly suitable solvent for this reaction type has been found to be an alcohol such as methanol, ethanol or isopropanol. In this connection, according to the present invention, an α-halo ketone of formula II, 4 4 is reacted where Q = CO-CH-Z with an amine RR NH, thereby obtaining an R 2 aminoketone of the general formula II where Q = CO CH-NR2R4, \ o

Rz after which this amino ketone is reduced as described above without intermediate in solnation.

When reacting a compound II wherein Q is a group of the formula -CHOH-CH-Z 12 5 R2. 3 4? 3 4

with an amine of the type R R NH, in which formulas R, R and R

and Z has the meanings previously defined, the reaction takes place in a solvent such as an alcohol, chloroform, dioxane 1Q or carbon tetrachloride, and is most readily carried out in the presence of an agent capable of absorbing the hydrogen halide formed such as a tertiary inorganic or organic base or in the presence of an excess of amine. It is well known that in these cases the -CHOH-CH-Z group first gives an oxirane I 2

15 R

of the type

ISLAND

/ \ 2 -CH-CH-R 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 2 which react with the amino compound.

3

Thus, the present process also includes the preparation of amino alcohols from oxiranes, which method 4 can advantageously be used to prepare amino alcohol derivatives with a treo configuration.

6 7

The salts of amino alcohols of formula II can be prepared according to the invention as previously mentioned by the general procedure described above.

9

This approach allows for multiple variants. Generally, these salts can be formed by well-known methods such as, for example, reaction 11 12 of equimolefic amounts of the amino alcohol and an acid in a suitable solvent such as an alcohol, after which the salt is precipitated by the addition of another solvent which is 14 miscible with the former. solvent and wherein the salt 15 is insoluble, e.g., ether, or also by neutralizing a 16 ethereal solution of the acid or base with the base or acid. Useful acids include both organic and inorganic acids.

As inorganic acids, hydrochloric, hydrobromic, hydrochloric, sulfuric, phosphoric or perchloric acids are preferably used.

Organic acids may be carboxylic or sulfonic acids, such as formic acid, propionic acid, glycolic acid, lactic acid, citric acid, ascorbic acid, fumaric acid, maleic acid, pamoic acid, succinic acid, tartaric acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthanoic acid , salicylic acid or glucuronic acid.

Amino alcohol esters of the general formula I wherein R is an alkanoyl group or a cycloalkanoyl group are prepared by reacting an amino alcohol or salt thereof with an excess shot of a suitable acid chloride or acid anhydride, preferably at a temperature between 50 ° C and the acid chloride or acid anhydride. reflux temperature.

In another method, an amino alcohol or a salt thereof is reacted with an equimolecular amount or a small excess of an appropriate acid chloride or acid anhydride, for example in a solvent such as acetonitrile, benzene or toluene.

The process according to the invention is illustrated in the following by means of some examples.

Example 1 7 1- (6-Thiochromanyl) -2-n-octylamino-1-propanol.

a) To 35 g of aluminum chloride in 500 ml of 1,2-dichloroethylene is added 19.7 ml of propionyl chloride and then slowly with stirring 36.5 g of thiochroman in 150 ml of 1,2-dichloroethylene, keeping the temperature at approx. 10 ° C. After the addition, the mixture is stirred for 3 hours at room temperature and then decomposed by the addition of ice and hydrochloric acid.

The organic phase is separated and the aqueous phase is extracted with 1,2-dichloroethylene. The combined organic phases are dried over MgSO 4, filtered and the solvent is evaporated under vacuum. The residue thus obtained is converted to a solid by the addition of petroleum ether to give 32.5 g of 6-propionylthiochroman with m.p. 63-65 ° C in a yield of 69%.

B) To a solution of 32 g of 6-propionylthiochroman in 400 ml of anhydrous ether is added dropwise 8 ml of bromine while maintaining the temperature at 5 ° C. After the addition, the mixture is stirred for 2-3 hours at room temperature and slowly a saturated aqueous solution of NaHCO 3 is added. The aqueous phase is extracted twice with 20 100 ml of ether, the combined organic phases are dried over MgSO4 and filtered and the solvent is evaporated under vacuum. . The residue thus obtained is treated with 100 ml of petroleum ether to give 38 g of α-bromo-6-propionylthiochroman with m.p. 71-73? yield 86%.

C) 20 g of the product obtained in Example 1 (b), 15 ml of n-octylamine and 200 ml of ethanol are refluxed for 4 hours.

+ O

The mixture is cooled to -5 ° C and 5.2 g of sodium borohydride is gradually added. After the addition, the mixture is stirred for an additional 1-2 hours at room temperature, after which the solvent 30 is evaporated under vacuum. The residue is taken up in 200 ml of water and extracted with 3 x 100 ml of chloroform.

The combined organic phases are washed with water, dried over MgSO 4 and filtered and the solvent is evaporated under vacuum. The residue obtained is recrystallized from acetone. 13.3 g of 1- (6-thiochromanyl) -2-n-octylamino-1-propanol are obtained, m.p.

115-116 ° C. Yield: 60%.

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Calculated: C 71.58 8 9.91 N 4.17

Found: 71.70 9.85 4.05%.

Example 2 1- (2,3-Dihydro-5-benzo [b] thienyl-2- (4-phenylbutylamino) -1-propanol).

a) To 0.3 moles of aluminum chloride in 500 ml of 1,2-dichloroethylene is added 0.21 moles of propionyl chloride and then slowly, with stirring, 0.2 moles of 2,3-dihydrobenzo [b] thiophene are added, keeping the temperature at approx. 10 ° C. The mixture is then stirred for an additional 10 3 hours at room temperature after which it is cleaved with a mixture of ice and hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with 1,2-dichloroethylene. The combined organic phases are dried over MgSO 4 and filtered and the solvent is evaporated under vacuum. The residue obtained is transferred to a solid by the addition of petroleum ether to give 25 g of 5-propionyl-2,3-dihydrobenzo [b] thiophene with m.p. 50-52 ° C yield: 55%.

b) To 12.5 g of the product obtained in Example 2 (a) in 150 ml of anhydrous tetrahydrofuran is added dropwise with stirring at a temperature of - 10 ° C 3.3 ml of bromine. Stirring is continued for 1 hour at room temperature, after which 50 ml of 10% aqueous is added.

NaHCO-j solution. The organic phase is separated, dried and evaporated. The oily residue obtained is fixed by the addition of petroleum ether to give 30 g of 5- (a-bromopropionyl) -2,3- dihydrobenzo [b] thiophene with m.p. 64-66 ° C.

C) 15 g of 5-a-bromopropionyl-2,3-dihydrobenzo [b] thiophene, 16 g of 4-phenylbutylamine and 150 ml of methanol are refluxed for 3 hours. The solution is cooled to - 5 ° C and 5 g of sodium borohydride are slowly added. After the addition, stirring is continued for 3-4 hours at room temperature, whereupon the solvent is evaporated under vacuum. The residue is treated with 200 ml of water and extracted with chloroform. The organic phase is washed with water, dried over MgSO 4 and filtered and the solvent is evaporated under vacuum. The solid residue is recrystallized from acetone to give 9.9 g of a product of m.p. 113-115 ° C; yield: 55%.

Calc'd: C 73.85 H 7.97 N 4.10

Found: 73.50 7.95 3.90%.

EXAMPLE 3 1- (2,3,4,5-Tetrahydrobenzo [b] thienpin-7-yl) -2- (4-phenylbutylamino) -1-propanol (a) To 0.27 mole of aluminum chloride in 500 ml 1,2-dichloroethylene 5 is added 0.25 mole of propionyl chloride and then slowly with stirring 0.25 mole of 2,3,4,5-tetrahydrobenzo [b] tiepin keeping the temperature at approx. 10 ° C. The mixture is then stirred for 3-4 hours at room temperature after which it is cleaved with a mixture of ice and hydrochloric acid. The organic phase is separated and the aqueous phase is extracted with 1,2-dichloroethylene. The combined organic phases are dried over MgSO 4 and filtered and the solvent is evaporated under vacuum. The residue is distilled under vacuum to give 30 g of thick oil. Yield: 60%, boiling point 130-135 ° C / 0.4 mm Hg. The NMR (nuclear magnetic resonance spectrum) spectrum is consistent with the 7-propionyl-2,3,4,5-tetrahydro [b] tiepin structure.

b) To 11 g of the product obtained in Example 3 a) in 150 ml of anhydrous tetrahydrofuran (THF) is added dropwise at a temperature of - 10 ° C 2.6 ml of bromine. The mixture is then stirred for an additional hour at room temperature to which a 10% aqueous 20 NaHCO 3 solution is added. The organic phase is separated, dried and evaporated. There is thus obtained 13.2 g of 7- (α-bromopropionyl) -2,3,4,5-tetrahydrobenzofbiene tiepin in the form of a liquid yellow oil whose homogeneity is confirmed by TLC (thin layer chromatography).

c) 10 g of 7- (α-bromopropionyl) -2,3,4,5-tetrahydrobenzo [b] tiepin, 150 ml of methanol and 10 g of 4-phenylbutylamine are refluxed for 4 hours. The solution is then cooled to 5 ° C and 4 g of sodium borohydride are slowly added with stirring. After the addition, the mixture is allowed to stand overnight at room temperature and the solvent is evaporated under vacuum. The oily residue thus obtained is treated with 200 ml of water and extracted with chloroform. The organic phase is washed with water, dried over Na 2 SO 4 and filtered and the solvent is evaporated under vacuum. The residue thus obtained is recrystallized from acetone to give 7.5 g of product with m.p. 87-89 ° C, yield 35%.

Calculated: C 74.74 H 8.45 N 3.79

Found: 74.85 8.65 3.70%.

Example 4 1- (2-Methyl-2,3-dihydrobenzo [b] thienyl) -2- [2- (chlorophenoxy) ethylamino] -1-propanol.

To 0.15 mol of aluminum chloride, 0.11 mol of propionyl chloride 5 and 150 ml of 1,2-dichloroethylene is slowly added while maintaining a temperature of - 10 ° C 0.1 mol of 2-methyl-2,3-dihydrobenzo [b] -thio one (made according to Petropoulos, J. Am. Chem. Soc., 75, 1130, 1953). After the addition, the mixture is stirred for an additional 3 hours at room temperature, then a mixture of ice and HCl is added. The mixture is extracted with 1,2-dichloroethylene and dried over MgSO 4, then the solvent is evaporated. The oily residue is stripped under vacuum. 14 g of 5-propionyl-2-methyl-2,3-dihydrobenzo (b] thiophene with boiling point 110-115 ° C / O, 2 mm Hg, yield 70% are obtained. The NMR spectrum is in accordance with the structure .

b) To 7 g of the product obtained in Example 4 (a) dissolved in 100 ml of anhydrous THF is added dropwise 1.8 ml of bromine with stirring and maintaining a temperature of approx. 10 ° C. After the addition, the mixture is stirred for an additional hour at room temperature and then an aqueous solution of NaHCO 3 is added. The organic phase is separated and dried and then evaporated. 8.5 g of 5- (α-bromopropionyl) -2-methyl-2,3-dihydrobenzo [b] thiophene are obtained, m.p. 52-54 ° C, yield 88%. The NMR spectrum is consistent with the structure and the product is found to be homogeneous by TLC (silica gel / CgHg).

c) 16 g of the product obtained in Example 4 b), 12 g of α- (p-chlorophenoxy) -ethylamine and 200 ml of ethanol are refluxed for 3 hours. The solution is cooled to - 5 ° C and 5 g of NaBH 4 is slowly added. After the addition, the mixture is stirred for a further 2-3 hours at room temperature, the solvent is evaporated and the residue is extracted with CHCl 3. The organic phase is dried over MgSO 4, filtered and evaporated and the residue thus obtained is recrystallized from acetone. 5.5 g of a product with m.p. 108-109 ° C.

Calculated: C 63.56 H 6.40 N 3.70

Found: 63.70 6.45 3.85%.

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The structure of the product is determined by mass spectrum, NMR spectrum and IR (infrared) spectrum.

Example 5 1- (3-Methyl-6-thiochromanyl) -2- [2- (phenoxy) ethylamino] -1-propanol.

a) To 0.13 mole of AlCl3 and 0.12 mole of propionyl chloride in 150 ml of 1,2-dichloroethylene are added dropwise 0.1 mole (16.4 g) of 3-methylthiochroman at a temperature of - 5 ° C. After stirring the mixture for 3 hours at room temperature, a mixture of ice and 10 HCl is added and extracted with CHCl3. The organic phase is dried over MgSO4, filtered and evaporated. Thereby 17.3 g of 6-propionyl-3-methylthiochroman are obtained whose homogeneity is confirmed by TLC and whose structure is confirmed by the NMR spectrum.

b) To 22 g of the product obtained in Example 5 (a) in 150 ml.

15 THF is added dropwise with stirring at - 5 ° C 5.2 ml of bromine. The solution is treated according to the previously described method to give 26 g of 6- (α-bromopropionyl) -3-methylthiochroman with m.p. 60-63 ° C (methanol), yield 85%. The NMR spectrum is consistent with the structure.

C) 11 g of the product obtained in Example 5 b), 15 g of 2-phenoxyethylamine and 150 ml of ethanol are refluxed for 2 hours. The mixture is cooled to - 5 ° C and 6 g of NaBH 3 is slowly added. The solution is treated according to the method already described. After recrystallization from acetone, 5 g of product 25 is obtained with m.p. 85-87 ° C.

Calculated: C 70.54 H 7.61 N 3.91

Found: 70.42 7.60 3.90% NMR, IR and mass spectrum are consistent with structure.

Example 6 1- (8-Methyl-6-thiochromanyl) -2-n-octylamino-1-propanol.

a) 165 g of 8-methylthiochroman are treated with propionyl chloride in the presence of AlCl 3 in the 1,2-dichloroethylene according to the method already described in the previous examples. In this way 107.4 g of product with boiling point 140-155 ° C / 0.50 mm Hg is obtained. The product solidifies and has m.p. 48-51 ° C, yield 50%. The NMR spectrum is consistent with the structure.

B) 107.4 g of the product obtained in Example 6 (a) in 800 ml of THF are brominated with 25 ml of bromine according to the procedure already described. 91.7 g of 6- (α-bromopropionyl) -8-methylthiochroman are obtained with m.p. 79-80 ° C (petroleum ether), yield 5 63%. The NMR spectrum is consistent with the structure.

c) 20 g of the product obtained in Example 6 b), 20 g of n-octylamine and 300 g of methanol are refluxed for 4 hours. The mixture is cooled to 0 ° C and 9.5 g of NaBH 3 is slowly added. After usual treatment, 14 g of product with m.p.

129-130 ° C (CHCl3).

Calculated: C, 72.15; H, 10.09; N, 4.01

Found: 72.05 9.75 3.85%.

The NMR, mass and IR spectra are consistent with the structure.

Example 7 1- (2-Methyl-2,3-dihydro-5-benzo [b] furanyl-2- [4- (p-chlorophenyl) butylamino] -1-propanol) 100 g (O, 75 moles of 2-methyl-2,3-dihydrobenzo [b] furan are added at 10 ° C and with stirring to a mixture obtained by adding 108 g (0.8 mole) of aluminum chloride and 71.6 g (0.75 mole) of propionyl chloride to 1000 ml of dichloromethane. After the addition is complete, stirring is continued for 3 hours at room temperature. The obtained medium is gently poured onto ice with a small amount of concentrated hydrochloric acid. The organic phase is decanted, dried and evaporated to dryness. The oily residue is distilled off and 91.3 g (0.48 mole) of ketone derivative are collected. Boiling point 119 ° C / 0.5 mm Hg. The nuclear magnetic resonance spectrum is consistent with the structure.

B) To a solution of 57 g (0.3 mole) of 2-methyl-5-propionyl-2,3-dihydrobenzo [b] furan in 600 ml of diethyl ether maintained at 10 ° C is added a small amount of benzoyl peroxide and then 47, 9 g (0.3 mole) of bromine. Then the mixture is stirred for 2 hours at room temperature. The final medium is washed with a 10% aqueous sodium hydrogen carbonate solution, and then with water and then dried and evaporated to dryness. The solid residue is recrystallized from a 1: 1 hexane-cyclohexane mixture to give 67.3 g (0.25 mol, 83%) of brominated ketone, m.p. 79.6 ° C.

The nuclear magnetic resonance spectrum is in accordance with the expected structure.

c) A solution of 8.2 g (45 mole) of p-chlorophenylbutylamine in 100 ml of acetonitrile is boiled under reflux and stirring. Potassium carbonate (12.4 g, 90 mmol) is added and then a solution of brominated ketone obtained in Example 7 (b) in 5 ml of acetonitrile over 5 hours for 5 hours. After addition is complete, the reflux is maintained for 1 1/2 hours. To the medium is added dropwise at room temperature a solution of 1.8 g (48 mmol) of sodium borohydride in 10 ml of water made 10 alkaline by the addition of a drop of 40% aqueous NaOH. The solid is filtered off and the filtrate is evaporated to dryness. The residue is a solid. The solid residue is added to the filtered solid and recrystallized from a 1: 1 mixture of hexane and cyclohexane. 5.1 g (14 mmol, 31%) of a product of m.p. 107.8 ° C. The NMR spectrum determines the expected structure.

Calculated: C 70.70 H 7.60 N 3.72

Found: 70.40 7.60 3.60%.

Example 8 1- (2-Methyl-6-thiochromanyl) -2- (4-phenylbutylamino) -1-propanol.

a) 83 g (0.5 mole) of 2-methylthiochroman was treated with 43.2 ml of propionyl chloride (0.5 mole) in the presence of 73 g (0.55 mole) of AlCl3 in 750 ml of 1,2-dichloroethylene in the same manner as described in the previous examples. 64 g of 2-methyl-6-propionylthiochroman are obtained with m.p. 65-66 ° C (petroleum ether), yield 58%. The NMR spectrum is consistent with the structure.

b) 64 g of the product obtained in Example 8 (a) in 500 ml of abdominal solid methanol are treated with 14.9 ml of bromine as described in the preceding examples. 82 g of 6- (α-bromopropionyl) -2-methylthiochroman are obtained with m.p. 78-79 ° C, yield 95%. The NMR spectrum is consistent with the structure.

c) 15 g of the product obtained in Example 8 b), 9 g of 4-phenyl-butylamine and 200 ml of methanol are refluxed for 4 hours.

The mixture is cooled to - 0 ° C and slowly added 4 g. NaBH4 · After usual treatment and recrystallization from methanol, 6 g of 1- (2-methyl-6-thiochromanyl) -2- (4-phenylbutylamino) -1-propanol are obtained with m.p. 118-119 ° C, yield 35%.

141330 14

Calculated: C ΊΑ, ΊΑ Η 8.45 Ν 3.79

Found: 74.80 8.45 3.70%.

The NMR, mass and IR spectra are consistent with the structure.

Example 9 1- (2,3-Dihydro-5-benzo [b] furanyl) -2- (4-phenylbutylamino) -1-propanol. (A) 8.8 g of 2,3-dihydro-6- propionylbenzo [b] furan in 50 ml of aqueous free THF is treated with 2.6 ml of bromine according to the process already described. The product thus obtained is recrystallized from methanol. 8 g of 6- (α-bromopropionyl) -2,3-dihydrobenzo [b] furan are obtained with m.p. 65-66 ° C, yield 40%.

b) 10 g of the product obtained in Example 9 (a), 6 g of 4-phenyl-1 c; butylamine and 100 ml of methanol are refluxed for 3 hours. The mixture is cooled to -0 ° C and 4 g of NaBH 3 is slowly added. After usual treatment and recrystallization from acetone, 7.7 g of product are obtained with m.p. 131-133 ° C, yield 50%.

Calculated: C 77.49 H 8.36 N 4.30 2Q Found: 77.25 8.25 4.10 The NMR, mass and IR spectra are consistent with the structure.

Example 10 1 - [(1,4-Benzoditine) -6-yl] -2- (4-phenylbutylamino) -1-propanol.

A) To 0.12 mole of aluminum chloride in 250 ml of 1,2-dichloroethylene is added 0.12 mole of propionyl chloride and then slowly, with stirring and at a temperature of -15 ° C, is added 0.1 mole of 1,4-benzoditene. in 100 ml of 1,2-dichloroethylene. After the addition, the mixture is stirred for 1 hour at room temperature after which it is decomposed with a mixture of ice and hydrochloric acid. After usual treatment, 12 g of 6-propionyl-1,4-benzoditine with boiling point 145-150 ° C / 0.2 mm Hg is obtained, yield 60%.

h) To 10 g of the product obtained in Example 10 a) dissolved in 100 ml of anhydrous THF is added dropwise with stirring at a temperature of -10 ° C 2.3 ml of bromine. After usual treatment, 11 g of 6- (α-bromopropionyl) -1,4-benzoditine is obtained with m.p. 72-73 ° C, yield 80%.

c) 10 g of the product obtained in Example 10 b), 100 ml of methanol and 10 g of 4-phenylbutylamine are refluxed for 3 hours. The solution is cooled to -50 ° C and 7 g of NaBH 2 is added. Then, the solvent is evaporated and the residue is diluted with 5 water and extracted with chloroform. The organic phase is dried over MgSO4, filtered and evaporated. The solid thus obtained is recrystallized from methanol to give 7.5 g of the desired product, m.p. 138-140 ° C, yield 55%.

Calculated: C 67.50 H 7.28 N 3.75 Found: 67.25 7.45 4.00%.

Example 11 1- (2,3-Dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-propanol (threoform) -4 g of 1- (2,3-dihydro- 5-benzo [b] thienyl-2-bromo-1-propanol, 100 ml of ethanol and 20 g of 4-phenylbutylamine are refluxed for 5 hours, the solvent and excess amine are evaporated in vacuo and the residue obtained is treated with ether. Substance 20 is recrystallized from a mixture of methanol and ether and the corresponding free base is recovered by treatment with dilute NaOH solution and recrystallization from acetone to give the final product in an amount of 1.05 g, mp 85-87 ° C.

Calculated: C 73.80 H 7.95 N 4.10 Found: 73.40 7.90 4.20%.

The treoconfiguration of the product is confirmed by examination of the NMR spectrum (JH + H2 = 9 cps, δ Ηχ = 4.04 ppm, CDCl3-1% TMS).

Example 12 1- (5-Indanyl) -2- (4-phenylbutylamino) -1-propanol.

a) To 17.4 g. of 5-propionylindane in 100 ml of anhydrous THF is added dropwise at - 10 ° C 5.12 ml of bromine. Then, the mixture is stirred for an additional hour at room temperature and then added

100 ml aqueous NaHCO 3 solution. The separated organic phase is dry-35 J

, filtered and evaporated. Thereby, 13 g of liquid oil are obtained whose homogeneity is confirmed by TLC and whose structure is confirmed by the NMR spectrum.

b) 13 g of the product obtained in Example 12 a), 10 g of 4- 16 phenylbutylamine and 100 ml of methanol are refluxed for 3 hours. Then the solution is cooled to - 5 ° C and slowly 6 g of NaBH 3 is added slowly with stirring. The solvent is evaporated, the mixture is diluted with E 2 O and extracted with CHCl 3. The organic phase is dried, filtered and evaporated and the residue is recrystallized from acetone to give 4 g of product, m.p. 108-110 ° C.

Calculated: C 81.65 H 9.05 N 4.35

Found: 81.40 9.05 4.60%.

The structure of the product is determined by the mass, NMR and IR spectrum.

Example 13 1- [6- (1,2,3,4-Tetrahydronaphthyl)] - 2- (4-phenylbutylamino) -1-propanol. A mixture of 21.4 g of 6- (2-bromopropionyl) -1,2,3,4-tetrahydronaphthalene (obtained by acylation of tetralin by 2-bromopropionyl bromide, mp 60.4 ° C), 15 4 g of phenylbutylamine and 100 ml of methanol are refluxed for 3 hours. To the solution cooled to -5 ° C is added 12 g of NaBH 2. Then, 2Q is isolated and the amino alcohol is purified in the manner described in Example 12.

Weight 5.3 g, m.p. 99.7 ° C.

Calculated: C 81.9 H 9.3 N 4.2

Found: 81.7 9.3 3.9%.

The structure of the product is confirmed by mass, NMR and IR spectrum.

25

Example 14 1- (2,3-Dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-propionyloxypropane.

A mixture of 7 ml (7.4 g, 80 mol) of propionyl chloride, 10 g of 1- (2,3-dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-propanol hydrochloride and 10 ml of toluene are heated for 3 hours to reflux temperature. The final medium is evaporated to dryness under reduced pressure and the residue is recrystallized from acetonitrile.

This yields 5.9 g of the desired product whose structure is confirmed by examination of NMR and IR spectrum. Mp. 169.9 ° C

Calculated: C 66.40 H 7.40 N 3.10

Found: 66.54 7.60 3.40%.

17 151330

Example 15 15 g of 1- (2,3-dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-propanol are dissolved in 750 ml of toluene and 150 ml of chloroform and a stream of dry HCl is bubbled. gas through it for 2 hours. Then, the mixture is stirred for an additional 2 hours at room temperature, the resulting precipitate is filtered, washed with ice-cooled pen and dried. 15 g of the hydrochloride is obtained with m.p. 208-209 ° C.

Calculated: C 66.72 H 7.40 N 3.70 Pound: 66.70 7.50 3.65%.

Example 16 16 g of 1- (6-thiochromanyl) -2-n-octylamino-1-propanol are dissolved in 600 ml of toluene and a stream of anhydrous HCl is passed through it for 1 1/2 hours. The precipitate thus obtained is filtered, washed with water-cooled pentane and dried. 17 g of the hydrochloride is obtained with m.p. 227 ° C.

Calculated: C 64.60 H 9.15 N 3.77 2Q Found: 64.60 9.15 3.65%.

Example 17 2 g of 1- (6-thiochromanyl) -2- (4-phenylbutylamino) -1-propanol are dissolved in 100 ml of anhydrous ether. A stream of dry HCl gas is then passed through for 15 minutes and the resulting precipitate is filtered and dried. 2.1 g of the hydrochloride is obtained with m.p. 204-205 ° C.

Example 18 28.0 g (0.144 mole) of D-glucoronic acid are dissolved in 340 ml of water heated to 50 ° C and 34.1 g (0.1 mole) of 1- (2,3-dihydro-5-benzotheb] thienyl) -2- (4-phenylbutylamino) -1-propanol is added portionwise with vigorous stirring. Stirring is continued until complete dissolution which requires approx. 20 minutes. Thereby a clear solution is obtained which, if desired, can be diluted with distilled water.

18 151330

Example 19 1- (2,3-dihydro-5-benzo [b] thienyl 1-2 - (4-phenylbutylamino) propanol.

15 g of (5-alpha-bromopropionyl) -2,3-dihydrobenzo [b] thiophene, 25.5 g of N-benzyl-N-4-phenylbutylamine and 150 ml of methanol are refluxed for 3 hours. The solution is then cooled to 25 ° C and 1- (2,3 "dihydro-5-benzo [b] thienyl- 2- (N-benzyl-N- (4-phenylbutylamino) propiophenone is precipitated by the addition of 250 ml of ether). The precipitate is filtered and used as is without further purification to the reduction step.

10 The obtained propiophenone is dissolved in 200 ml of ethanol containing 10 ml of concentrated HCl and hydrogenated in the presence of 5 g of 10% s Pd-C until hydrogen uptake is stopped. Removal of catalyst and solvent leaves 1- (2,3-dihydro-5-benzo [b] thienyl-2- (4-phenylbutylamino) -1-propanol as a solid residue which is recrystallized from acetone to give 11.8 g product, m.p. 113-115 ° C, yield 63%.

Calculated: C 73.85 H 7.97 N 4.10

Found: C, 73.48; H, 7.82; N, 4.13%.

Example 20 a) 0¾ - about 25 ^ "fH" CH3 ^ \ CH-CH-CH3

0 Br \ J

81.3 g (0.3 mole) of brom ketone are dissolved in 750 ml of ethanol and 350 ml of ethoxyethanol. The solution is cooled to -25 ° C and then 3 g of 11.5 g of NaBH 4 dissolved in 75 ml of water is added. The mixture is allowed to reach room temperature and stirred for 90 minutes, after which 11.4 g of KOH is added in 120 ml of ethanol.

Then, stir for 30 minutes, dilute and extract with chloroform. The residue is dried and the organic solvent is evaporated. In this way, 40 g of epoxide is obtained, corresponding to a yield of 70%.

The epoxy is in the form of an oil that cannot be cleansed due to its instability. It is determined by NMR analysis in CHCl3 with TMS as internal standard: 7.33-6.8 ppm: multiplet / 3H / aromatic protons 4.06 ppm: doubled / 1H / benzyl proton 3.28 ppm: multiplet / 4H / aliphatic proton of dihydrobenzene [b] thiophene 3.13-3.83 ppm: multiplet / 1H / epoxide proton of α-methyl, and 1.05 ppm: doublet / 3H / methyl proton.

, 0 Γ8Χ1 + C6H5 (CH2UNH2 ^^ 0 ^ aji (CH) C H

- ^ 'CH-CH-CH2 ^ p ™ H (CH2) 4C6H5

V OH

Dissolve 4 g of 1- (2,3-dihydro-5-benzo [b] thienyl-1,2-epoxypropane in 100 ml of ethanol and treat with 3 g of 4-phenylbutylamine and reflux for 5 hours, after which the solvent and excess The residue is treated as described in Example 11 to give 2 g of the desired product, mp 85-87 ° C.

The melting points of the compounds described in the Examples and a variety of other compounds prepared by the process of the invention are shown in Table II below.

Pharmacological trials

Some of the compounds prepared by the process of the invention have been subjected to pharmacological tests in which their effect is compared to similar compounds, known from British Patent Specification No. 1,019,773. The results are shown in Table I, where the first six compounds are thus known reference compounds, while the others are compounds prepared by the process of the invention.

35

The experiments were performed as follows: (1) Acute toxicity was determined in fasting male mice. The test compounds were administered orally with gastric tubes as a 1% s gum mucus, 0.01 ml / g body weight. LDgQ values were calculated by Litchfield and Wilcoxon's method (J. Pharmacol, exp. Ther. 96, 94-113, 1949). The values are given in mg / kg. The results are shown in Table I below.

(2) Antihypertensive effect was measured on unaesthesized,. spontaneously hypertensive rats of the Okamoto strain. The test compounds were administered orally in an amount of 60 mg / kg. Systolic arterial pressure was measured sphygomanometrically every 30.

10 minutes for two hours before and three hours after administration of the test compound. Each compound was given to two animals, and for each day's trial the blood pressure change was similarly determined for a group of untreated control animals. The anti-hypertensive effect was assessed in three ways.

15 (a) The maximum decrease in blood pressure compared to the value before administration of the test compounds was given according to the points system below and is listed in column A of the following table 1: 0 = decrease in arterial pressure <10 mm Hg, 20 + = decrease in arterial pressure between 10 and 20 mm Hg, ++ = decrease in arterial pressure between 20 and 30 mm Hg, +++ = decrease in arterial pressure> 30 mm Hg (b) An index proportional to the duration of action is given in column S of Table I. It was calculated as follows in g d2 + 2d2 + 3 dg + 4d ^ + 5dg + 6dg 10 3q where d ^, d2, dg, d ^, d ^ and dg have decreased in blood pressure, expressed in mm Hg, after 30, 60, 90, 120, 150 and 180 minutes respectively.

(c) The therapeutic index measured on the activity in relation to the activity. It is referred to as the coefficient 35 R, is listed in column R of Table I and is calculated as

LDCn x S

E = -5 ° - 100 21 151330

The higher R is, the more valuable the compound is under even circumstances.

(3) Vasodilatory effect was measured at Level 5 femoral artery on anesthetized dogs (perfused paw technique). The test compounds were administered intra-arterially at a dose of 30 mg / kg. The results are in Table I expressed as follows in relation to the effect of papaverine tested at the same dose: 0 = no effect, + = weak effect, ++ = effect as half of the effect of papaverine, +++ = same effect as papaverine, ++ ++ = stronger effect than papaverine.

(4) Antispasmodic activity was measured in vitro on guinea pig ileum, whose contractions were induced with histamine (Hist.) Or acetylcholine (Achol). The test compounds were added to a perfusion bath at concentrations of 10 µ to 10. Contracts on the agonist were repeated every 5 minutes until the possible antagonistic effect of the test compound was maximized. Inhibitions (in%) were plotted as a function of concentration to calculate -log IC IC q listed in Table I. Reference values for papaverine were 4.70 for the histamine sample and 5.26 for the acetylcholine sample.

(5) 3-Blocking effect on adrenergic 3 receptors was assessed on isolated guinea pig chambers. Cumulative dose-response curves were obtained from the chromotropic activity of norepin-10 -4 nephrin (10 to 10 M) 20 minutes after administration of solvent 30 "6 or test compound (10 M). PD2 against norepinephrine was calculated and the optional 3-blocking activity was set to 0 when pD2 was> 6.8 and otherwise as follows: + when pD2 was between 6.8 and 6.4, 35 ++ when pD2 was between 6.4 and 6.0, +++ when pD2 was between 6.0 and 5.5 and -H - ++ when pD2 was <5.5 (as for propanolol) ".

22 151330

The results are also shown in Table I.

(6) Binding to and adrenergic receptors by in vitro experiments by direct binding studies demonstrating the ability of test compounds to "recognize" adrenergic receptors. In these studies, a known amount of receptor (present on a suitable tissue) is incubated and by a radioligand that specifically recognizes the receptor in the presence of different amounts of the test compound. The ability of a test compound to specifically recognize the receptor is judged by its ability to compete with the radioligand. From the competition curve, the amount of test compound that inhibits (the specific binding of the radioligand (IC IC q)) is calculated. The IC ^ values are also listed in Table I. The relationship between the compounds listed in the table and the following receptors was examined: adrenergic and α adrenergic receptors, both present in rat cerebral cortex.

It can be seen from Table I that the reference compounds, which are the known compounds most closely related to those produced by the process according to the invention, have no antihypertensive effect, while the compounds prepared by the process have such effect. One of the reference compounds, code number 861, was so toxic at the dose used that the test animals died before activity could be measured. All of the compounds listed in Table I have vasodilatory activity, but are generally more potent for the compounds prepared by the process of the invention than for the reference compounds. The same goes for the antispasmodic effect. The reference compounds 30 all have substantial β-blocking activity, as opposed to those prepared by the process of the invention. In contrast, those in the process of the invention have high affinity for α-adrenergic receptors, with high selectivity for type α 1.

It will be appreciated that the antihypertensive effect is surprising, and in combination with the high vasodilatory effect and the lack of β-blockade, it makes the compounds prepared by the method of the invention suitable for treating various conditions of essential hypertension where O-blockers are contraindicated. .

In addition to the comparative results set forth in Table I, a very large number of those in the process of the invention have been studied in most of the above-described respects, namely, for acute toxicity, antihypertensive, vasodilatory and antispasmodic. The test technique was in all cases the same or substantially the same as described above. The results are shown in Table III.

In terms of acute toxicity, the confidence limits of p = 95% are stated in a number of cases.

For the antihypertensive effect, only the results listed under (a) above are listed, ie the maximum decrease in blood pressure and the point system used is slightly different, namely: 0 = no decrease in arterial pressure, + = decrease in arterial pressure <10 mm Hg, ++ = decrease in arterial pressure between 10 and 20 mm Hg, 20 +++ = decrease in arterial pressure> 20 mm Hg

The point system for the vasodilatory effect is the same as in Table I.

The antispasmodic effect was in some cases also determined against the action of barium chloride-induced spasms, in Table III of the relevant column designated BaCl2.

In Table III, the compounds are identified by numbers, namely the same numbers as used in Table II.

Table III confirms for a very wide range of the compounds prepared by the process of the invention the results set forth in Table I.

Among the products of the invention, the compounds having an antihypertensive effect can be used by humans at a daily oral dose of 50-3000 mg.

In various animal species studied, the side effects observed with these 35 compounds were characterized by sedation. This effect is obtained with significantly higher doses than the therapeutic doses. The ratio of the active dose to the dose is substantially more favorable for the products of the invention compared to the corresponding ratios of known compounds such as α-methyldopa and propanolol.

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CM CM CM CM CM CM CM ^ CM CM CM

tn a aaa aaa aaa · * u uuu uuu uuu

CM CM CM CM CM CM CM CM CM CM CM

k S S S S S S δ S δ δ δ. p i i ® p “?; §sa

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(1) The recrystallization solvent is given in brackets, the melting point indicated applies to the free base unless otherwise indicated. The melting point was determined with a TOTTOLI apparatus - <· · - W '' Λ. · * '. . . _ or a METTLER FP5 apparatus.

5 (2) Melting point of the hydrochloride.

(3) Melting point of the dihydrochloride.

(4) Elemental analysis was performed for elements C, H and N and the results were found to be in accordance with the theoretical values.

(5) Treoform.

Me = CH-,

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-S n t- 7 σι id h ^ t- in S 7 7 + i A A + | i-i cm <n Λ CO (M_! pi Ar m VC5 r- co m Ο -I <N ro - = r in 1.0 i "co σ> - U ID ID lo ID · ΰ ID WN 1 'I ·· In "f" '^ 1 g _ ^^^ - 4-4-4-4. · -4 r-4 ^ -lnH r-4 - i - (r-4

Claims (4)

151330 1. Analogous Process for Preparation of Amino Alcohol Derivatives of General Formula νγ / V "5 (CP2 n R2 R3 v___L IS ^ CH-CH-N I fi r4 OR6 R10 or pharmaceutically acceptable salts thereof, in which formula r- * - is a hydrogen atom or one or two methyl groups, R2 is a straight or branched alkyl group having 1-3 carbon atoms, R 3 is a mono or polyunsaturated alkenyl group or alkynyl group having 3-18 carbon atoms, a cycloalkyl group having 3-10 carbon atoms, a straight or branched alkyl group having 2-20 carbon atoms, a straight or branched alkyl group having 2-18 carbon atoms and substituted with an atom or group selected from: (1) oxygen and sulfur, (2) C 1-6 alkoxycarbonyl groups, pyrrolidine, pyrrolidinone and imidazolidone, (3) phenyl, phenoxy, phenylthio, benzoyl, indanyloxy and naphthylpxy, (4) phenyl, phenoxy, phenylthio and benzoyl substituted with one or more alkyl or alkoxy groups, one or two halogen atoms, a nitrile group, a C2-6 alkanoyl group, an acylamino group or a C, λ alkoxycarbonyl group, 4 and R hydrogen, 34 or R and R together with the adjacent nitrogen atom, a morpholine or piperidine group substituted with a methyl, phenyl or phenylalkyl group having 1-4 carbon atoms in the alkyl moiety, or a piperazine group substituted at the 4-position with a phenyl group optionally itself substituted by (1) a methyl group of 1-4 carbon atoms or alkoxy group of 1-4 carbon atoms, (2) one or two halogen atoms or (3) a trifluoromethyl group, 5. a hydrogen atom or a methyl group , R is a hydrogen atom or a straight or branched C1-10 alkanoyl group or C3-6 cycloalkanoyl group, n is the number 1, 2 or 3, X is sulfur, oxygen or a group C1- and 10. a group CH2 or sulfur, however, such that 4 Å R does not form a substituted piperazam group together 3 with R and the adjacent nitrogen atom if all together. poem X is oxygen, Y is a group -CH 2, n = 2, R = R = hydrogen, 266 R = methyl and R is hydrogen or an alkanoyl group, characterized by starting from a compound of the general formula II - or if desired, depending on the meaning of Q, from a salt of a compound of formula II wherein R, R, X, Y and n have the meanings given above and Q is one of the following groups 0 -CH-CH-R 2; -COCH-NR 3 R 4 i -CHOH-CH-Z or -CO-CH-Z i 2 in · 2 R 30 2 3 4 wherein R, R and R have the above meanings and Z is a halogen atom such as chlorine or bromine by either a) is reduced by an α-aminoketone of the general formula II, where Q is a group of the formula R 3 -co-CH-isr I where R 2 and R have the meanings given above and R has the same 4 is as defined above for the group R or is a protecting group which can be removed by subsequent hydrolysis; b) reacting an α-halogen ketone of formula II where Q = 3 4 5 is CH-CH-Z with an amine of formula RR NH and then the obtained amino-ketone of general formula II wherein Q = -CO-CH-NR R, R 2 is reduced as described above under a) without prior isolation, 10 or c) reacting a compound of general formula II wherein Q 3 4 is a group of the formula -CHOH-CH-Z, with an amine RR NH in which É 2 2 3 4 formulas R, R, R and Z has the meanings given above, or d) reacting an oxirane of formula II wherein Q has the formula O / 2-CH-CH-R 1 3 4 with an amine RR NH upon which the compound of formula I obtained desired reaction with an organic or inorganic acid to produce a corresponding salt, or the compound obtained if it is an alcohol or a salt, if desired reacted with an acid chloride or anhydride to produce a corresponding ester. Process according to claim 1, characterized in that a compound of formula I is prepared in which the halogen atoms are chlorine or fluorine. Process according to Claim 1, characterized in that 1- (6-thiochromanyl) -2-n-octylamino-1-propanol, 1- (6-thiochromanyl) -2- (4-phenylbutylamino) -1-propanol, 1 - (6-thiochromanyl) -2- [2- (phenoxy) ethylamino] -1-propanol, 1- (2,3-dihydro-5-benzo [b] thienyl) -2-n-octylamino-1-propanol, 1- (2,3-dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-propanol, 1- (2,3-dihydro-5-benzo [b] thienyl) -2 - [4- (p-chlorophenyl) butylamino] -1-propanol, 1- (2-methyl-2,3-dihydro-5-benzo [b] thienyl) -2- (phenylbutylamino) -1-propanol, 1 - (2-methyl-2,3-dihydro-5-benzo [b] furanyl) -2-n-octylamino-1-propanol, 1- (2,3,4,5-tetrahydrobenzo [b] thienpin-7- yl) -2- (4-phenylbutylamino) -1-5 propanol, 1- (2,3-dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-propionyl-oxypropane, 1- (2,3-dihydro-5-benzo [b] thienyl) -2- (4-phenylbutylamino) -1-cyclohexa-neyloxypropane F 1- 1- (5-indanyl) -2- (4-phenylbutylamino) -1- propanol, 1- (5-indanyl) -2- [2- (4-chlorophenoxy) ethylamino] -1-propanol or 1- (5-indanyl) -2- [2- (4-fluorobenzoyl) propylamino] -1- propane beer. Process according to any one of claims 1-3, characterized in that a salt is selected from hydrochlorides, hydrobromides, phosphates, sulfates, oxalates, lactates, tartrates, acetates, citrates, maleate, gluconates and glucuronates of compounds of general formula I.