AT395849B - PHARMACOLOGICALLY ACTIVE IN POSITION 3 SUBSTITUTED ALPHA-AMINOMETHYL-2BENZOFURANMETHANOLE - Google Patents

Description

AT 395 849 B

The invention relates to a-aminomethyl-2-benzofuranmethanols substituted in position 3 and their salts, their preparation in racemic and enantiomerically pure or enantiomerically enriched form and their use.

The compounds described in the subject invention are new active ingredients with a partial benzofuranylethanolamine structure which have antiarrhythmic activity.

The subject invention relates to new compounds of the general formula

R2 1, in which R1 denotes substituted or unsubstituted lower alkyl, preferably substituted or unsubstituted arylalkyl and in which and are identical or different and independently of one another are hydrogen, branched or unbranched low molecular weight alkyl (C jC ^), cycloalkyl, aryl or arylalkyl or else R ^ and R ^ together form an alkylene group and their acid addition salts in racemic and enantiomerically pure or enantiomerically enriched form.

The present invention furthermore relates to processes for the preparation of the compounds of the general formula 1 in racemic and enantiomerically pure or enantiomerically enriched form and to their use as active pharmaceutical ingredients, preferably in the area of indication of antiarrhythmics.

The compounds described in the present invention are not yet known at the time of the filing of this patent. Especially in the area of indication of antiarrhythmics, this is a fundamentally new type of structure.

The compounds of general formula 1 can now be prepared

Al can be done in a fundamentally new way by using process 1 a benzofuran (S. Nielek. T. Lesiak, Chem. Ber. 115, 1247) of the general formula which can be prepared in a manner known per se

wherein R * has the same meaning as in the general formula 1, in position 2 in a conventional manner, for. B. formylated by reaction with POClg / DMF, the aldehyde of the general formula thus obtained

3, wherein R * has the same meaning as in the general formula 1, in a manner known per se by reaction with hydrocyanic acid in the cyanohydrin with the general formula

4, wherein R * has the same meaning as in the general formula 1, which immediately with a suitable protective group, such as. B. dihydropyran, in the compound of the general formula -2- 5,

AT 395 849 B R4

CN in which R1 has the same meaning as in the general formula 1 and R4 represents a protective group suitable for cyanohydrins, which is converted by reduction with a suitable reducing agent, such as. B. LiAlH4, in the amine of the general formula R4

6, in which the radicals have the same meaning as in general formula 5.

From the amines of the general formula 6 can by suitable methods for the substitution of primary amines, for. B. by reductive amination with a suitable carbonyl component (see Example 1), or by acylation with a suitable acid chloride and subsequent reduction of the amide (see Example 2), the corresponding amines of the general formula R +

R2 7, in which the radicals have the same meaning as in the general formulas 1 and 5, are obtained, which can then be converted into the corresponding acid addition salt after removal of the protective group by reaction with a physiologically tolerated acid. If appropriate, the protective group can be split off and the acid addition salt can be formed in one step.

The production of the secondary amines of the general formula 7 by acylation of the amine of the general formula 6 with a suitable acid chloride and subsequent reduction of the amide has the advantage over reductive alkylation with low molecular weight, unbranched aldehydes that the formation of corresponding tertiary amines as by-products is not possible.

In a process variant (see Example 3), the aldehyde of the general formula 3 is reacted with a suitable silyl compound, such as. B. t-Butyldimethylsilylcyanid or Trimethylsüylchlorid / KCN, directly into the corresponding silylated cyanohydrin of the general formula

re

wherein the radicals have the same meaning as in formula 1 and wherein R ^, and R ^ are the same or different and are branched or unbranched low molecular weight alkyl, implemented, which after reduction with a suitable reducing agent, such as. B. LiAlH ^, with simultaneous removal of the silyl protecting group into the amine of the general formula -3- 9,

AT 395 849 B

where the radicals have the same meaning as in the general formula 1, is converted, which can then optionally be converted into the compounds of the general formula 1 using the methods already discussed in process 1.

Process 1 has the advantage that the protected or unprotected amines of the general formulas 6 and 9 can be obtained in a simple manner and in good yields, which can then easily be converted into the desired compounds of the general formula 1.

In process 2 (see Example 4), the protected cyanohydrin of the all-granular formula 5 is reacted with a suitable alkali metal alcoholate, such as. B. sodium ethanolate, in the ester of the general formula R *

XR® 10, in which the radicals have the same meaning as in the general formula 5 and in which R ** means low molecular weight branched or unbranched alkyl, which, after reduction, can be reacted with a suitable reducing agent, such as e.g. B. L1AIH4, and the elimination of the protective group, which can optionally also be done in one step, in the diol of the general formula

11, in which the radicals have the same meaning as in the general formula 1, which is then reacted in a manner known per se (GB-PS 2084577) after reaction with a reagent suitable for activating primary hydroxyl groups, such as, for. B. p-tosyl chloride, by reaction with an amine of the general formula HN 12,

V wherein the radicals have the same meaning as in general formula 1, into which compounds of general formula 1 can be converted. This process represents a new approach to the compound of general formula 11, starting from compounds of general formula 5.

The preparation of the compounds of general formula 1 can also

Bl are carried out by the method 3 (see Example 5), the benzofuran of the general formula (2) by reaction with a suitable reagent for the introduction of acetyl groups, such as. B. acetic anhydride or acetyl chloride, in the ketone of the general formula -4-

AT 395 849 B

wherein the radicals have the same meaning as in the general formula 1, transferred this by a suitable method, such as. B. reaction with bromine, halogenated in position α to the carbonyl group, the compounds of the general formula thus obtained

14, in which the radicals have the same meaning as in general formula 1 and in which X is halogen, with a suitable reducing agent, e.g. L1AIH4, NaBH ^, BHg or NaCNBH ^, to the compounds of the general formula

15, in which the radicals have the same meaning as in general formula 1, and the alcohols thus obtained are converted into the compounds of general formula 1 by reaction with an amine of general formula 12.

Optionally, the alcohols of the general formula 15 obtained in the reduction can also be used with a suitable protective group, such as. B. an acetal protective group, and the compounds of the general formula thus obtained

wherein the radicals have the same meaning as in the general formulas 5 and 15, are reacted with an amine of the general formula 12 to give the compounds of the general formula 7, from which the compounds of the general formula 1 are then prepared in the manner already described can (see Example 6). This process variant has the advantage that the isomers of the general formula formed in the reaction of the compounds of the general formula 15 with the amines of the general formula 12

wherein the radicals have the same meaning as in general formula 1, do not occur.

The preparation of the compound of general formula 14 for R * = methyl is described in the work of S. Nielek (Chem. Ber. 115, 1247). The process in question is characterized in that a strong improvement in the yield (87.9% versus 52%) was achieved by using acetic anhydride as the acylating reagent and solvent and boron trifluoride etherate as the catalyst. -5-

AT 395 849 B

In one process variant, reaction of the benzofuran of the general formula 2 with a suitable acylating agent halogenated in position 2, such as, for. B. chloroacetic anhydride, the compounds of general formula 14 can be obtained directly.

The enantiomers of the compounds of general formula 1 can either be prepared in such a way that in one of the synthesis steps, preferably on the step of cyanohydrins, hydroxycarboxylic acid esters, amino alcohols or halogen alcohols, with a suitable enantiomerically pure chiral protective group, preferably an acetal protective group, such as, for. B. Noe's lactol, the diastereomers thus obtained are then separated and the protective group is removed again before or simultaneously with the formation of the acid addition salt (see Example 7), or in such a way that the compounds of the general formula 14 are reduced enantiomerically pure or enantiomerically enriched alcohols of the general formula 15 are obtained with suitable reducing agents, from which the desired enantiomerically pure or enanomerically enriched compounds of the general formula 1 can be prepared in the manner described in process 3.

Examples:

Example 1: a-Isopropylaminomethyl-3- (2-phenylethyl) -2-benzofuranmethanol-hydrochloride 15.2g 3- (2-phenylethyl) -benzofuran are dissolved in 60 ml DMF and at 5 ° C. under inert gas to a mixture of 30 ml of POCI3 and 40 ml of DMF are added dropwise. The mixture is then heated to 100 ° C. and stirred overnight. For working up, it is diluted with diethyl ether and poured into ice. After careful neutralization with NaHCÖ3, the mixture is extracted twice with diethyl ether, the combined organic phases are washed with water, dried with NajSO ^ and the solvent is removed on a rotavapor. 16.1 g of 3- (~ 2-phenol-ethvD-2-benzofurancarbaldehvd are obtained as a light yellow oil which slowly solidifies. Melting point of the dinitrophenylhydrazone: 281 ° C. (dioxane); 1H-NMR: 5ppm (CDCI3) = 2.9-3.5 (m, 4H); 7.0-7.7 (m, 9H); 9.67 (s, 1H), 5.2g of which are dissolved in 75 ml of diethyl ether and added to a solution of 5.4 g of NaCN in 50 ml of water, stirring vigorously at 5 ° C A mixture of 20 ml of 6N HCl and 1-2 ml of concentrated acetic acid is slowly added dropwise. The mixture is stirred vigorously overnight and warmed to room temperature. The organic phase is separated off and the aqueous phase is extracted twice with diethyl ether. The combined organic phases are washed with Na2SC > 4 dried and the solvent removed on a rotary evaporator 5.58 g of a-Hvdroxv-3-f2-phenvlethvlV2-benzofuran-acetonitrile as dark yellow oil. 4.47 g of which are immediately dissolved in 45 ml of CH2CI2 and mixed with 4.5 ml of 2,3-dihydropyran and something p-Toluenesulfonic acid was stirred at room temperature for 1 hour and then we d washed twice with 10% NaHCO ^ solution, the aqueous phase extracted twice with CH2Cl2 and the combined organic phases after drying with Na2SÖ4 evaporated. The remaining oil (8.39 g) is column chromatographed on silica gel (eluent: petroleum ether / diethyl ether). 4.02 g of 3-f2-PhenvlethvD-a- <, 2-tetrahvdroovranvloxvV2-benzofuranacetonitrile is obtained as a light yellow oil which slowly solidifies aH-NMR: δ (CDC13) = 1.4-1.9 (m, 6H); 2.95-3.15 (m, 4H); 3.54.1 (m, 2H); 4.5.5.1 (each m, total 1H); 5.4.5.6 (each s, total 1H); 7.1-7.7 (m, 9H), 4.0 g of which are dissolved in 20 ml of diethyl ether and added dropwise at 40 ° C. to 11 ml of an IM solution of LiAl ^ in THF. After 2 hours, the mixture is hydrolyzed with 1 ml of water, the precipitate is filtered off and washed well with diethyl ether. The filtrate is dried with Na2SO4 and the solvent is removed under reduced pressure. 3.4 g of a-aminomethvl-3 - ('2-phenvlethvl) -0 - (' 2-tetrahvdronvranvl ') - 2-benzofuranmethanol are obtained as a light yellow oil. ^ -NMR: 8ppm (CDC13) = 1.1-1.8 (m, 8H); 2.54.1 (m, 8H); 4.44.9 (m, 2H); 7.0-7.6 (m, 9H); 2 g of it are dissolved in 20 ml of methanol and mixed with 0.7 ml of acetone. After 30 min, 0.43 g of NaCNBH3 are added and the mixture is left for a further 10 min. stir. The process is then repeated with 0.5 ml acetone and 0.3 g NaCNBH3. For working up, diethyl ether is added and the mixture is washed with water. The aqueous phase is extracted once more with diethyl ether, the combined organic phases are dried with Na2SO4 and the solvent is evaporated. After column chromatography of the remaining dark yellow oil over silica gel (eluent: C ^ C ^ / methanol / conc-NH ^, 1.24 g of light yellow oil are obtained. 1.1 g of which are dissolved in diethyl ether and mixed with 6 drops of methanol and 5 ml of 1M ethereal hydrochloric acid The solvent is removed and the residue is taken up in 3 ml of ethyl acetate After heating and slowly cooling, 0.54 g of isopropylamine methyl-3- (2-phenolamine-2-benzofuran-methanol hydrochloride is obtained as light pink crystals with a melting point of 160 ° C.-163 ° C. ^ -NMR: δ.ριη (CDC13 / D2Ö) = 1.4 (dd, 6H); 2.5 (dd, 1H); 3.0 (m, 4H); 3.2 (d, 1H); 3.4 (m, 1H); 5.4 (dd , 1H); 7.0-7.6 (m, 9H); -6-

AT 395 849 B

Example 2: 3- (2-phenylethyl) -a-propylaminomethyl-2-benzofuranmethanol hydrochloride 3.0g (crude mixture) a-aminomethyl-3- (2-phenylethyl) -O- (2-tetrahydropyranyl) -2-benzofuranmethanol (Her Position see example 1) are dissolved in 30 ml of pyridine and 0.72 ml of propionic acid chloride are added at 5 ° C. The reaction mixture is placed in the refrigerator for 20 h, then diluted with diethyl ether and washed free of pyridine with HCl. After evaporating off the solvent, 3.16 g of dark oil remain. 2.19 g of this are dissolved in diethyl ether and added dropwise at room temperature to 6 ml of an IM solution of LiAlH ^ in THF. After 20 h, the mixture is hydrolyzed with 0.5 ml of water, diluted with a mixture of diethyl ether and ethyl acetate, washed five times with 2N NaOH and once with water organic phase dried with Na2S04 and the solvent removed on a rotavapor. 1.85 g of dark yellow oil are obtained. After column chromatography on silica gel (eluent: C ^ C ^ / methanol / conc. NH3), 1.4 g of 3- (2-phenylethyl) -a-propylaminomethyl-0- (2-tetrahydropyranyl) -2-benzofuranmethanol remain as a light yellow oil. 1.0 g of it is dissolved in diethyl ether and mixed with 5 ml of 1M ethereal HCl. It is diluted with isopropanol and heated. After cooling, 300 mg of non-fibrous crystals with a melting point of 150 ° C-152 ° C are obtained. ^ -NMR: önnm (CDCWDoO) = 0.9 (t, 3H); 1.8 (m, 2H); 2.33 (dd, 1H); 2.7-3.1 (m, 6H); 3.26 (t, 1H); 5.4 (dd, 1H); 7.0-7.6 (mf $ H);

Example 3: a-aminomethyl-3- (2-phenylethyl) -2-benzofuran-methanol 1 g of 3- (2-phenylethyl) -2-benzofuran-carbaldehyde (preparation see Example 1) are dissolved in 20 ml of acetonitrile and after adding 1.3 g of t -Butyldimethylsilylchloride, 1.5 g KCN and some ZnCIj16 h under protective gas atmosphere at room temperature. After removing the solvent under reduced pressure, the residue is taken up in diethyl ether, filtered, the filtrate washed with water and the diethyl ether removed on a rotavapor. 1.4 g of yellow oil remain, which is dissolved in absolute diethyl ether and added dropwise at -40 ° C. to 7 ml of an IM solution of L1AIH4 in THF. After 2 h, the precipitate is hydrolyzed with 0.6 ml of water, filtered off, washed well with diethyl ether and the solvent is evaporated off. After column chromatography of the remaining oil on silica gel (eluent: C ^ C ^ / methanol / conc-NH ^), 412 mg of a-aminomethyl-3- (2-phenylethyl) -2-benzofuranmethanol are obtained as a colorless oil. Crystallization from ethyl acetate / cyclohexane gives colorless crystals with a melting point of 92 ° C - 95 ° C. 1H-NMR: 5ppm (CDCI3) = 1.7 (s, 3H); 2.7-3.1 (m, 6H); 4.4 (dd, 1H); 7.0-7.6 (m, 9H);

Example 4: at-Butylaminomethyl-3- (2-phenylethyl) -2-benzofuranmethanol hydrochloride 10.1 g of 3- (2-phenylethyl) -a- (2-tetrahydropyranyloxy) -2-benzofuran-acetonitrile (preparation see Example 1) dissolved in 100 ml of ethanol and added to a solution of 0.77 g of sodium in 80 ml of ethanol. After stirring at room temperature for 1 h, the solution is poured into a mixture of ice water and 40 ml of 2N HCl, extracted twice with CH2Cl2 and the solvent is removed on a rotavapor. 8.7 g of the remaining oil are dissolved in THF and added dropwise at -40 ° C to 20 ml of an IM solution of LiAlH4 in THF. The mixture is stirred overnight at room temperature, hydrolyzed with 2 ml of water, washed with 2N NaOH and the combined aqueous phases are extracted twice with diethyl ether. After removing the solvent and column chromatography on silica gel, 2.9 g of a-hydroxymethyl-3- (2-phenylethyl) -2-benzofuranmethanol remain as a colorless oil. 2.4 g of this was dissolved in 40 ml of pyridine and 1.7 g of p-tosyl chloride were added at 5 ° C. The reaction mixture is placed in the refrigerator overnight, then diluted with diethyl ether and washed free of pyridine with IN HCl. 1.2 g of the oil remaining after removal of the solvent are dissolved in 5 ml of t-butylamine and heated under reflux for 2 days. The excess t-butylamine is removed, the residue is taken up in diethyl ether and washed several times with water. After removal of the solvent, 0.75 g of the remaining oil is chromatographed on silica gel (eluent: C ^ C ^ / methanol / conc.NH ^). 0.17 g of N-t-Butvl-a-hvdroxvmethvl-3-C2-nhenvlethvlV2-benzofuranmethanamine ^ -NMR: δ (CDC13) = 0.95 (s, 9H); 2.0-3.5 (broad, 2H, (NH, OH)); 2.95 (m, 4H); 3.0-3.35 (m, 2H); 3.95 (dd, 1H); 7.3-7.7 \ m, 9H); and 0.28 g at-Butvlaminomethvl-3 - ('2-phenvlethvB-2-benzofuran-methanol · 1H-NMR: δ (CDCI3) = 1.3 (s, 9H); 2.4-2.9 (m, 4H); 3.0 (m, 4H); 4.53 (dd, 1H); 7.0-7.6 (m, 9H); 0.25 g of it is dissolved in a little diethyl ether and a few drops of methanol and 1 ml of 1M ethereal HCl are added. After adding a little petroleum ether, the mixture is heated Cooling gives 0.21 g of ct-t-butaminomethvl-3- (2-phenolethvlV2-henzofuranmethanol hydrochloride as colorless crystals with a melting point of 132 ° C. -135 ° C. IR: cm'1 = 3280; 3100-2600; 1590; -7-

AT 395 849 B

Example 5: 3-methyl-a-propylaminomethyl-2-benzofuranmethanol hydrochloride 14.53 g of 3-methylbenzofuran are dissolved in 14.78 g of acetic anhydride and heated to 50 ° C. after the addition of 1.35 ml of boron trifluoride-diethyl ether complex. After the reaction has started, the heat source is removed and stirring is continued for 2 hours. The reaction mixture is then poured into water and extracted three times with diethyl ether. After evaporating off the solvent, 16.85 g of yellow oil are obtained. 8.53 g of this are dissolved in 27 ml of CHCI3 and, after adding a little AICI3, 2.53 ml of B ^ are slowly added. After the color changes to yellow, the reaction mixture is poured into ice water and stirred with NaHSC ^ until the solution is colorless. It is extracted several times with diethyl ether, the organic phases are washed with water and the solvent is evaporated off. 11.3 g of yellow oil remain. 8.5 g of it are dissolved in 50 ml of THF and slowly added dropwise to 34 ml of an IM solution of L1AIH4 in THF at -78 ° C. After 2 h, the mixture is hydrolyzed with 2.2 ml of 2N HCl, the precipitate is filtered off and washed several times with diethyl ether. After removing the solvent, 7.32 g of yellow oil remain, which are dissolved in 58 ml of n-propylamine and heated under reflux for 1 h. After the excess n-propylamine has been evaporated, 6.52 g of yellow oil remain. Column chromatography on silica gel (eluent: C ^ C ^ / methanol / conc-N ^) leads to 0.80 g a-Hvdroxvmethvl-3-methvl-N-propvl-2-benzofuran-methanamine! H-NMR: 6DDm (CDCI3) = » 0.90 (t, 3H); 1.5 (sx, 2H); 1.9-2.8 (m, 7H); 3.8 (dd, 2H); 4.0 (qu, 1H); 7.2-7.6 (m, 4H) w and to 1.01 g of 3-methylene-a-proplaminomethylene-2-benzofuran-methanol ^ -NMR:. *:, ^ (CDCI3) = 0.93 (t, 3H); 1.5 (sx, 2H); 2.33 (s, 3H); 2.6-3.3 (m, 6H); 4.96 (dd, 1H); 7.2-7.6 (m, 4H). w

The 1.01 g of 3-methyl-a-propylaminomethyl-2-benzofuranmethanol are dissolved in diethyl ether and mixed with 8.2 ml of 1M ethereal HCl. The precipitate is filtered off and recrystallized from ethyl acetate / methanol. 0.77 g of 3-methylene-ot-propylamine-methyl-2-henzofuran-methanol-hydrochloride is obtained as colorless crystals with a melting point of 143 ° C. -145 ° C.

Examples: 3-ethyl-a-propylaminomethyl-2-benzofuran-methanol-hydrochloride 4.18 g of 3-ethylbenzofuran are dissolved in 3.9 g of acetic anhydride and stirred with 0.4 g of boron trifluoride-diethyl ether complex for 1 h. The reaction mixture is poured into water and extracted three times with diethyl ether. The combined organic phases are washed acid-free with NaHCC ^ solution and the solvent is removed. 4.82 g of yellow oil remain, which is dissolved in 21 g of CHCl3 and mixed with 1.3 ml of Br2 and a little AICI3. After the solution has turned from brown to yellow, it is poured into ice water and stirred with NaHSC ^ solution until the solution is colorless. The mixture is extracted with diethyl ether, the combined organic phases are washed with water and the excess solvent is removed on a rotavapor. 6.26 g of light yellow oil remain, which is dissolved in THF and 23.7 ml of an IM LiAlH ^ solution in THF are added at -78 ° C. After 2 h, it is hydrolyzed with 1.5 ml of 2N HCl, the precipitate is filtered off and washed well with diethyl ether. After removing the solvent, 5.4 g of yellow oil are obtained. 4.1 g of this are dissolved in 50 ml of CH2Cl2 and stirred with 1.3 g of 2,3-dihydropyran and a little p-toluenesulfonic acid for 1 h. It is washed twice with 10% NaHCC ^ solution and with water. After removal of the solvent, 5.28 g of dark oil remain, which is dissolved in 8 ml of n-propylamine and heated under reflux for 2 days. After evaporating off the excess n-propylamine, 4.96 g of dark oil remain, which is purified by column chromatography (silica gel, CH2Cl2 / methanol / conc.NH3). The 0.8 g of 3-ethyl-a-propylaminomethyl-O-tetrahydropyranyl-2-benzofuranmethanol thus obtained are dissolved in diethyl ether and, after the addition of a few drops of methanol, 4.3 ml of 1M ether of hydrochloric acid are added. The resulting precipitate is filtered off and recrystallized from ethyl acetate / methanol. 270 mg of 3-ethyl-a-propylaminomethyl-2-benzofuranmethanol hydrochloride are obtained as colorless crystals with a melting point of 155 ° -158 ° C. 1H NMR: δ (CDC13 / D20) = 0.96 (t, 3H); 1.24 (t, 3H); 1.95 (sx, 2H); 2.6-3.8 (m, 6H); 5.73 (dd, 1H); 7.1-7.6 (m, 4H);

Example 7: (R) -3- (2-phenylethyl) -a-propylaminomethyl-2-benzofuranmethanol 3.2 g of a-hydroxy-3- (2-phenylethyl) -2-benzofuranacetonitrile are mixed with 3.5 g of Noe's lactol in 30 ml of 0¾¾ dissolved and stirred overnight with molecular sieve and wasp toluenesulfonic acid. For working up, dilute with C ^ C ^, filter, wash with NaHCÖ3 solution and with water, add a few drops of triethylamine and evaporate. The remaining oil (6 g) is dissolved in 60 ml of diethyl ether and added dropwise at -40 ° C. to 13 ml of an IM solution of L1AIH4 in THF. After 2 h, the mixture is hydrolyzed with 2 ml of water, the precipitate is filtered off, washed well with diethyl ether and the solvent is removed under reduced pressure. 5.47 g of dark oil are obtained. Column chromatography on silica gel (eluent: C ^ C ^ / methanol / conc-NH ^) leads to 1.12 g (ocR, 2'R- -8-

Claims (19)

AT 395 849 B (2, a, 3a, a, 4, a, 7, a, 7a, a)) - a-aminomethyl-0- (octahydro-7,8,8-trimethyl-4,7-methano- 2-benzofuranyl) -3- (2-phenylethyl) -2-benzofuranmethanol ((R) -amine), 1.25g (aS, 2'R- (2'a, 3a, a, 4'a, 7, a, 7a'a) -a-aminomethyl-0- (octahydro-7,8,8-trimethyl-4,7-methano-2-benzofuranyl) -3- (2-phenylethyl) -2-benzofuranmethanol ((S) -amine ) and 1.08 g of mixed fractions 750 mg of the (R) -amine are dissolved in 15 ml of triethylamine, 0.22 g of propionic acid chloride is added at 5 ° C. and the product is placed in the refrigerator overnight, then diethyl ether is added and the mixture is washed twice with water, the organic phase dried with Na2S04 and the solvent removed 0.82 g of the remaining oil are dissolved in 10 ml THF and added dropwise to 3 ml of an IM solution of LiAlH4 in THF at 5 ° C. The mixture is stirred for 3 h at room temperature and for 3 h under reflux , then hydrolyzed with 1 ml of water, diluted with diethyl ether, the precipitate filtered off and washed well with diethyl ether the remaining oil are dissolved in dry diethyl ether and 4 drops of methanol and 2 ml of 1M ethereal HCl are added. After removing the solvent, the remaining oil is dissolved in water, washed twice with diethyl ether, mixed with 2N NaOH, extracted three times with CH2Cl2 and the solvent is evaporated off. After column chromatography of the remaining oil on silica gel (eluent C ^ C ^ / MethanoV conc-NHo), 0.16 g of (R) -3- (2-phenylethyl) -a-propylaminomethyl-2-benzofuranmethanol is obtained as a colorless oil ^ -NMR: S -pjjj = 0.9 (t, 3H); 1.5 (sx, 2H); 2.1 (s (broad), 2H); 2.4-2.65 (m, 3H); 2.8-3.1 (m, 5H); 4.55 (dd, 1H); 7.0-7.6 (m, 9H); [a] jj = + 57.8 ° (c = 0.794 in Meüianol) The corresponding antipode can be prepared in the same way. The starting compounds (corresponding to 3-substituted benzofurans) z. B. after S. Nielek, T. Lesiak, Chem. Ber. 115.1247 (1982). Pharmacological data of 3-f2-phenvlethvlVrc-propvlatninomethvl-2-henzofuranmethanol-hydrochloride (GE 68) GE 68 leads to a concentration-dependent decrease in the beat frequency in right auricles of the guinea pig heart (exposure time in each case 60 min; EC ^ q = 7.6 mol / 1). 1 mol / 1 GE 68 does not significantly change the measured parameters of the action potential of papillary muscles (1 Hz). 5 mol / 1 GE 68 cause a decrease in the maximum slope steepness of the action potential (Vmax) (P <0.05), while they do not significantly change the repolarization times. The reduction in Vmax increases with the increase in the stimulation frequency from 0.1 to 1.2 or 3 Hz (P <0.05, P <0.01 or P <0.01). 10 mol / 1 results in a reduction of the Vmax by half (P <0.01), while the 20 and 50% (but not the 90%) action potential duration is significantly shortened (P <0.01; P <0.001). The resting potential remains unaffected. The contraction force of isolated papillary muscles of the guinea pig heart is reduced by GE 68 in a concentration-dependent manner (EC ^ q = 5.5 mol / 1). In summary, it can be said that GE 68 has negative inotropic, negative chronotropic and class I antiarrhythmic effects. PATENT CLAIMS 1. In position 3 substituted a-aminomethyl-2-benzofuranmethanols of the general formula 1. in which R ^ is substituted or unsubstituted lower alkyl, preferably substituted or unsubstituted arylalkyl, and in which R ^ and R ^ are identical or different and are, independently of one another, hydrogen, displaced form. 2. A process for the preparation of compounds of the general formula 1, characterized in »that a benzofuran of the general formula -9- AT 395 849 B wherein R * has the same meaning as in the general formula 1, in position 2 in a conventional manner, for. B. formylated by reaction with POCI3 / DMF, the aldehyde of the general formula thus obtained wherein R * has the same meaning as in the general formula 1, in a manner known per se by reaction with hydrocyanic acid in the cyanohydrin with the general formula 4, wherein R ^ has the same meaning as in general formula 1, implements this immediately with a suitable protective group, such as. B. 2,3-dihydropyran, in the compound having the general formula R4 CN 5, in which R * has the same meaning as in general formula 1 and R4 represents a protective group suitable for cyanohydrins, converts this compound obtained by reduction with a suitable reducing agent, such as e.g. B. L1AIH4, in the amine of the general formula R4 6, in which the residues have the same meaning as in the general formula 5, and this in a reductive amination, preferably with complex borohydrides, such as. B. NaBH ^ or NaCNBHg, and an aldehyde of the general formula 0 Ra-XH 18 'in which the radicals have the same meaning as in general formula 5 and in which R ^ is branched or unbranched low molecular weight alkyl (C jCy), cycloalkyl, aryl or arylalkyl , to the compounds of the general formula -10- 7, AT 395 849 B R4 wherein the radicals have the same meaning as in general formulas 1 and 5, and then the protective group is removed using a suitable method to form the desired end compound of general formula 1 or its acid addition salt with a physiologically compatible organic or inorganic acid, and if desired from an end compound of general formula 1 forms an acid addition salt with a physiologically acceptable organic or inorganic acid. 3. A process for the preparation of the compounds of general formula 1, characterized in that the compounds of general formula 6 with a carboxylic acid of general formula R® activated for amide formation 19, in which has the same meaning as in the general formula IS, the amides of the general formula thus obtained wherein the radicals have the same meaning as in general formulas 5 and 19, by reaction with a reducing agent suitable for the reduction of amides, such as. B. Li AIH4, converted into the compounds of general formula 7, which can be converted into the desired end compounds of general formula 1 in the manner mentioned in claim 2. 4. A process for the preparation of the compounds of general formula 1, characterized in that compounds of general formula 5 by reaction with a suitable alkali metal alcoholate, such as. B. sodium ethanolate, in the esters of the general formula R + vr8 10, in which the radicals have the same meaning as in the general formula 5 and in which R ^ denotes low molecular weight branched or unbranched alkyl, implemented this after reduction with a suitable reducing agent, such as. B. L1AIH4, and the splitting off of the protective group, which can optionally also be done in one step, in the diols of the general formula -11-11, AT 395 849 B. wherein the radicals have the same meaning as in the general formula 1, which, after reaction with a reagent suitable for activating primary hydroxyl groups, such as. B. p-tosyl chloride, by reaction with amines of the general formula HN 12, V in which the radicals have the same meaning as in the general formula 1 can be converted into the compounds of general formula 1. 5. A process for the preparation of the compounds of general formula 1, characterized in that a compound of general formula 2 by reaction with a suitable reagent for the introduction of acetyl groups, preferably by using acetic anhydride as reagent and solvent and a suitable catalyst, such as . B. boron trifluoride etherate, in the ketone of the general formula wherein the radicals have the same meaning as in the general formula 1, transferred this by a suitable method, such as. B. Reaction with bromine, halogenated in position α to the carbonyl group, the compounds of the general formula so obtained ü 0 14, d> 1 in which the radicals have the same meaning as in the general formula 1 and in which X is halogen, with a suitable reducing agent, such as e.g. B. L1AIH4, NaBH ^, BH3 or NaCNBHg, to the compounds of the general formula 15, in which the radicals have the same meaning as in general formula 1, and the alcohols thus obtained are converted into the compounds of general formula 1 by reaction with an amine of general formula 12 6. A process for the preparation of the compounds of general formula 1 according to claim 5, characterized in that for the acylation of the compounds of general formula 2 a suitable acylating reagent already activated in position 2, such as. B. chloroacetic anhydride used and thus directly to the compounds of general formula 14. -12- AT 395 849 B 7. A process for the preparation of the compounds of general formula 1 according to claims 5 and 6, characterized in that the alcohols of general formula 15 are reacted with a suitable protective group and wherein the radicals have the same meaning as in the general formulas 5 and 15, reacted with an amine of the general formula 12 to give the compounds of the general formula 7, which can be converted into the compounds of the general formula 1 as described in claim 2. 8. A process for the preparation of the compounds of general formula 1 according to claims 2,3,4,5,6 and 7, in which an acetal protective group, such as. B. tetrahydropyran means. 9. A process for the preparation of the compounds of general formula 1, characterized in that a compound of general formula 3 by reaction with a suitable silylve bond, such as. B. t-Butyldimethylsilyl cyanide or trimethylsilyl chloride / KCN, directly into the corresponding silylated cyanohydrin general formula Re wherein the radicals have the same meaning as in formula 1 and wherein R- \ R ^ and R ^ are the same or different and are branched or unbranched low molecular weight alkyl, reacted, which after reduction with a suitable reducing agent, such as. B. L1AIH4, with simultaneous removal of the silyl protecting group into the amine of the general formula 9, wherein the radicals have the same meaning as in general formula 1, which is then converted into the end compounds of general formula 1 using the methods already given in claims 2 and 3. 10. A process for the preparation of the enantiomers of the compounds of the general formula 1 according to Claims 2,3,4,5,6,7,8 and 9, characterized in that amino alcohols are used in one of the synthesis steps, preferably at the cyanohydrins stage or halogen alcohols use a suitable chiral enantiomeric protective group, preferably an acetal protective group, and carry out a diastereomer separation in one of the synthesis steps. 11. A process for the preparation of enantiomerically pure or enantiomerically enriched compounds of the general formula 1 according to claims 5 and 6, characterized in that the reduction of the compounds of the -13- AT 395 849 B general formula 14 with a suitable chiral reducing agent or using suitable chiral Carries out catalysts and so enantiomerically pure or enantiomerically enriched compounds of general formula 15 is obtained 12. Use of compounds according to claim 1 as active pharmaceutical ingredients, preferably in the area of indication of antiarrhythmics, with the exception of methods for the treatment of humans. 13. A compound called a-isopropylaminomethyl-3- (2-phenylethyl) -2-benzofuranmethanol hydrochloride. 10th 14. Eme Association with the name 3- (2-phenylethyl) -a-propylaminomethyl-2-benzofuran-methanol-Hydrochloride. 15. A compound called a-aminomethyl-3- (2-phenylethyl) -2-benzofuranmethanol. 16. A compound with the name a-t-butylaminomethyl-3- (2-phenylethyl) -2-benzofuranmethanol hydrochloride. 17. A compound called 3-methyl-a-propylaminomethyl-2-benzofuranmethanol hydrochloride. 18. A compound called 3-ethyl-a-propylaminomethyl-2-benzofurahmethanol hydrochloride. 20th 19. A compound named (R) -3- (2-phenylethyl) -a-propylaminomethyl-2-benzofuranmethanol and its antipode. 25 30 35 40 45 50 -14- 55