DE1643296C3 - l-Aryl-2-alkylaminoethanols and their physiologically acceptable acid addition salts, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

where R is a tertiary butyl or cyclobutyl group and R ^{1 is} a hydrogen atom or an aliphatic acyl group having up to 5 carbon atoms, and their physiologically acceptable acid addition salts.

2. A method for the preparation of compounds according to claim 1, characterized in that a diketo compound of the general formula is used in a manner known per se

15th

R ¹ O

R ¹ O

-CH

Il ο

R ¹ O

R ¹ O

with an amine of the general formula H ₂ N — R or a compound of the general formula

R ¹ O

R ¹ O

reduced and the base optionally converted into physiologically acceptable acid addition salts. 3. Medicinal products with bronchospasmolytic action, containing at least one compound according to claim 1.

A large number of l- (3 ', 4'-dihydroxyphenyl) -2-aminoethanols with bronchospasmolytic activity are known, but these compounds are inactivated in the organism by certain enzymes, such as Katediöl-O-methyltfansferase, so that they are only briefly Time are effective. 1- (3 ', 5'-Dihydroxynhenvft-2-aminoethanols, such as the known from the German patent 865315 \ - (3', 5 '- dihydroxyphenyl) -2 · methylaminoHtbanol, the analogous 2nd known from the Belgian patent 635 889 Hexylamino, 2-heptylamino, 2-octylamino and n-butylamino derivatives and the 1- (3 ', 5'-dibydroxyphenyl) -2-isopropylaroinoSthanol known from British patent specification 920623 are not attacked by Kattcbol-O-raethyltransferase , but they cause an increase in the heart rate, so that they are only of limited therapeutic value

are useful.
The task on which the invention is based exists

now in getting new bronchospasmolytic compounds that are "as low as possible Cause cardiac stimulation.

The invention relates to compounds which have bronchospasmolytic activity and therefore to Treatment of bronchospastic symptoms of various origins and specifically for treating fever asthmatic phenomena are suitable.

These compounds are 1-aryl-2-alkylaminoethanols the general formula

R ¹ O

R ¹ O

CH-CH, -N-R

reduced in the presence of an areine of the general formula H ₂ N — R or an epoxy compound of the general formula

.10

35

40

45 where R is a tertiary butyl or cyclobutyl group and R ^{1 is} a hydrogen atom or an aliphatic acyl group with up to 5 carbon atoms, and their physiologically acceptable acid addition salts.

These compounds have long-lasting bronchospasmolytic activity and cause Surprisingly, only a very small increase in heart rate. This means that the invention Compounds have a different affinity for the / ^ receptors in the heart and in the Bronchial muscles, which is probably due to the fact that the // receptors are not identical in these two organs.

The invention also relates to processes for the preparation of these compounds, which in per se be carried out in a known manner. According to a first method in a manner known per se Diketo compound of the general formula

R ¹ O

R ¹ O

C-CH

(K) reduced in the presence of an amine of the general formula H ₁ N - R. Another method is to use an epoxy compound of the general formula

R ¹ O

R ¹ O

, with an amine of the general formula H ₂ N — R

implemented, and a third method is a compound of the general formula

R ¹ O

reduced. It can be useful for all three meadows or the hydrogen atoms of the hydroxyl groups may be required on the phenyl ring and in the second and third methods also a hydrogen atom on the Amino group by a protecting group such as a mono- or acyclic aralkyl group with no more as 1 i carbon atoms as a protective group, such as a benzyl or naphthylmethyl group, to substitute.

In all cases, the bases obtained in this way can optionally be converted into their acid addition salts in the customary manner be transferred.

The compounds according to the invention are in the form of optically active isomers, which per se for the separation of amines can be isolated in a known manner.

The most convenient method of making the connections is the third method listed above. The reduction can, for example, with Raney nickel or palladium carbon or platinum oxide or but take place with lithium alanate or sodium borohydride, in the latter case optionally subsequently the protective groups by catalytic reduction, for example with palladium carbon or platinum oxide. When the protective groups of the hydroxyl groups are alkyl groups on the phenyl radical, these can be mixed with ether-splitting compounds such as Boron bromide can be split off at low temperature or by heating with hydrogen halides. When using hydrobromic acid one works expediently in anhydrous glacial acetic acid or in a mixture of glacial acetic acid and acetic anhydride, which is then hydrolyzed. If the If protective groups are acyl radicals, these can be split off with acids. Aralkyl protecting groups can be removed by hydrogenolysis.

The new 1 - (3 \ 5 '- dihydroxyphenyl) - 2 - alkylaminoethanols have a very good bronchodilator effect and only a very low cardiac accelerating effect. The compound 1 - (3 ', 5' - dihydroxyphenyl) - 2 - (tert-butyl) -aminoj-ethanol was found to be a more effective bronchodilator than 1- (3'.5'-dihydroxyphenyl both in vitro and in vivo) ) -2- (isopropylamino) ethanol, and the duration of the activity is longer than that of this known compound, and in an experiment on the isolated rabbit heart the cardiac accelerating effect is only ¹ Z ₁₅ of that of the analogous isopropylamino compound. The relationship between the cardiac stimulating effect and the bronchodilating effect was also demonstrated in spontaneously beating guinea pig atrial atrial preparations and spirally cut tracheal preparations when both preparations were placed in the same bath. When the compound of the invention was slowly poured into the bath solution, a bronshodilation was obtained without any effect on the cardiac muscle preparation. The weak cardiac accelerating effect of the tert-butylamino compound has also been observed in periodic studies of the compound with anesthetized cats.

The new compounds according to the invention can be more physiologically compatible in the form of salts Acids are administered. Suitable acids which are used for the production of such salts are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, citric acid, Tartaric acid, maleic acid, or succinic acid.

Finally, the subject matter of the invention is drugs with bronchospasmolytic action, the at least one of the compounds according to the invention, optionally in combination with a pharmaceutical carrier. You can use for oral, bronchial, rectal or parenteral administration may be provided.

The pharmaceuticals are manufactured in the usual way.

example 1

i- (3 ', 5'-dihydroxyphenyl) -2- (tert-butylamino) ethanol and its salts

a) To a solution of 6.8 g of the hydrate of l-glyoxyloyl-S.S-dibenzyloxybenzene in 50 ml of methanol 7.0 g of tert-butylamine and 30 ml of benzene were added. The reaction mixture was 3 hours heated to reflux and evaporated. The remaining oil crystallized when ethanol was added would. F. = 78.5 to 79.5 ° C. 2.5 g of this compound in 75 ml of absolute ethanol were used under normal conditions hydrogenated with Raney nickel. After filtering off the catalyst and evaporation the remaining oil was dried with ethanol / benzene. The base in ethanol was made with hydrogen bromide treated in ethanol and evaporated. The residue can be recrystallized from glacial acetic acid or chloroform will. F. = 93 to 96 "C.

The IR spectrum of this product was identical with that of the product of the method listed under c).

b) To a solution of 3.5 g of 3'.5'-dibenzyloxyphenylepoxyethane 2.7 g of tert-butylamine in 20 ml of ethanol were added in 100 ml of ethanol. The reaction mixture was refluxed for 4 hours boiled and then evaporated. The crystalline residue can be recrystallized from absolute ether. The melting point of 1- (3 ', 5'-dibenzyloxyphenyl | -2- (tert-butylamino) ethanol is 119 to 122 C. The hydrogenation was carried out in the same way as described under 2a). F. = 93 to 97 "C.

c) 2.4 g of 3,5 - dibenzyloxy - <·> - (tert-butyiamino) -acetophenone hydrobromide in 200 ml of glacial acetic acid were

hydrogenated in the presence of 0.3 g of 10% palladium carbon at room temperature and normal pressure. Ethanol was added to dissolve the precipitated reaction product. The catalyst was filtered off and the remainder of the dryness evaporated (F. = 205

fo to 206 "C). 50 ml of absolute ethanol were added, and the solution was in the presence of 0.3 10% palladium carbon at 35 ° C and. 5 atmospheres hydrogenated. the Catalyst was filtered off and the residue evaporated to dryness. Then glacial acetic acid became

f> 5 chloroform recrystallized: m.p. = 93 to 97 ° C for the monohydrate.

d) 15 g of 3,5 - dibenzyloxy - m - (benzyl - lert. - butylamino) acetophenone hydrogen sulfate in 200 ml of glacial acetic acid

were in a pressure reaction apparatus in the presence of 1.5 g of 10% palladium carbon at 50 "C and 5 atli hydrogenated. The reaction time was 5 hours. The catalyst was filtered off, the filtrate was evaporated to dryness and obtained the hydrogen sulfate of 1- (3 ', 5'-dihydroxyphenyl) -2- (tert-butylamino) -ethano]. This compound is hygroscopic, but it can be converted to the non-hygroscopic sulfate in the following manner will:

The hydrogen sulfate was dissolved in water and the pH of the solution was adjusted to 5.6 (pH meter) with 0.1 N sodium hydroxide solution set. The water solution was evaporated to dryness and the residue was dried with absolute ethanol / benzene and again evaporated to dryness. The remaining crystal mixture was extracted in a Soxhlet extraction apparatus with absolute methanol. The sulfate of 1- (3, 5'-dihydroxyphenyl) -2- (tert-butylamino) ethanol crystallized from the methanol phase. F. = 246 to 248'C.

The 3,5-dibenzyloxy - c <used as starting material - (Benzyl - tert - butylamino) - acetophenone - hydrogen sulfate was manufactured as follows:

To a solution of 32 g of benzyl tert-butylamine in 300 ml of absolute ethanol at reflux temperature were 32 g of S.S-dibenzyloxy-fi-bromoacetophenone in 100 ml of dry benzene were added. The mixture was refluxed for 20 hours and then evaporated. When absolute ether was added to the residue, benzyl lert-butylamine hydrobromide fell out. The precipitated compound was nitrated off and the filtrate became an excess added to 2 η-sulfuric acid. With this addition, the hydrogen sulfate of 3,5-dibenzyloxy) - ('i- (benzyl-tert-butylamino) -acetophenone failed. It was recrystallized from acetone / ether. Since that Product crystallizes with different organic solvents, the melting point varies with it the type and amount of crystal solvate. however, the product can be used directly for the hydrogenation will.

e) 1.1 g of 3,5-diacetoxy-ei- (benzyl-tert-butylamino) -acetophenone, mp = 171 to 173 C, were dissolved in warm absolute ethanol, whereupon 0.1 g of 10% palladium carbon was added. The solution was then stirred at 50 ⁰ C and hydrogenated 5atü overnight. The catalyst was filtered off and the volume of the solution was reduced by evaporation. The hydrobromide of 1 - (3 ', 5' - diacetoxyphenyl) -2 - (tert-butylamino) -iithanol with 1 mol of water of crystallization was precipitated on addition of ether. F. = 108 to MI C. The protective acetyl groups were removed by boiling the 1- (3 \ 5 '- diacetoxyphenyl) -2 - (tert-butylamino) -ulhanol hydrobromide with 1% hydrobromic acid for 3 hours. After evaporation and drying, the product was recrystallized as described under 2c). F. - 94 to 97 C.

Example 2

1- (3 ', 5'-dihydroxyphenyl) -2- (cyclobutylamino) ethanol hydrobromide

4.2 g of 3,5-dibenzyloxy-ff »- (benzylcyclobutylamino) acetophenone hydrobromide were dissolved in ethanol and 0.5 g of 10% palladium carbon was added. The hydrogenation was carried out in a pressure reaction apparatus at about 50 ° C. and 5 atm. the Response time is around 15 hours. The catalyst was then filtered off, and on evaporation the 1- (3 ', 5'-dihydroxyphenyl) -2- (cyclobutylamino) 4Uhanolhydrobrimid crystallized out. This was

from ethanol / ether (1: 1) to crystallize. F. = 227 to 228 ° C.

The 3,5-dibenzylox y - κ, - (benzylcyclobutylamino) - acetophenone hydrobromide used as starting material was prepared as follows:

5.5 g of benzylcyclobutylamine were in 100 ml of absolute Dissolved ethanol, and 7.0 g of 3,5-dibenzyloxyr.j-bromoacetophenone in 30 ml of dry benzene was added to this solution. The reaction mixture was refluxed overnight

and then evaporated. When absolute ether was added to the residue, the benzylcyclobutylamine hydrobromide fell and was filtered off. When 10% hydrobromic acid was added to the filtrate, the 3,5-dibenzyloxy - ». I- (benzylcyclobutylaminoj-acetophenone hydrobromide) fell out. It was recrystallized from acetone / ether. F. = 85 to 88 ° C

Example 3

1- (3 ', 5'-Dipivaloyloxyphenyl) -2- (tert-b' <tylamino) ethanol hydrobromide

3.0 g of 3,5 - dipivaloyloxy - (benzyl - tert - butylamino) acetophenone hydrobromide were dissolved in absolute ethanol and placed in a pressure reactor for 20 hours at 50 ° C. and 5 atm in the presence of 0.3 g Palladium hydrogenated on activated carbon (10%). The catalyst was filtered off and the filtrate to Evaporated to dryness. The residue turned off

vs chloroform / ether / petroleum ether (bp. 60 to 85 ⁰ C) recrystallized. Yield 1.8g. F. = 190 to 192 ° C.

Used as a starting material 3,5-Dipivaloyloxy - m - (. Benzyl - tert - butylamino) - acetophenonhyJrobromid was prepared as follows:

To 16.0 g of 3,5-dipivaloyloxy - "" - bromoacetophenone 22.0 g of benzyl tert-butylamine were added in 200 ml of dry benzene. The reaction mixture was refluxed for 4 hours and then left to stand at room temperature for 15 hours. the Benzene phase was evaporated to dryness and absolute ether was added. Benzyl tert-butylamine hydrobromide crystallized out and was filtered off. 50 ml of 10% hydrobromic acid were added

so added to the filtrate with stirring, whereupon 3,5-dipivaloyloxy - ■ ·> - (benzyl - tert - butylamino) - acetophenone hydrobromide crystallized out. Yield '. 1, above. F. = 162 to 167 ° C.

B e i s ρ i e 1 4

1- (3 ', 5'-diacetoxyphenyl) -2- (tert-butylamino) ethanol hydrobromide

1.0 g of 3,5 - diacetoxy - ω - (tert -. Butylamino) - acetophenonhydrobfomid was dissolved in absolute ethanol and in a pressure reactor at 50 ⁰ C and 5 atm in the presence of 0.1 g of palladium carbon (10% strength) 17 Hydrogenated for hours. The catalyst was filtered off and the volume of the filtrate was concentrated by evaporation. After the addition of absolute ether, the hydrobromide of 1- (3 ', 5'-diacetoxyphenyl) -2- (tert-butylamino) ethanol crystallized out. Yield 0.7g. M.p. = 108 to 111 ° C

Used as a starting material 3,5-diacetoxy - in - (tert - butylamino.) - acetophenonhydrobromid was prepared as follows:

57.0 g of 3,5 - dibenzyloxy - m - (benzyl - tert -. Butylaminoj-acetophenonhydrobromid were dissolved in 400 ml of glacial acetic acid and hydrogenated at atmospheric pressure and room temperature in the presence of 3.0 g of palladium carbon (IO% strength) After receiving the. The hydrogenation was stopped after the calculated amount of hydrogen. Absolute ethanol was added until the crystalline product formed was dissolved. The catalyst was filtered off and the volume of the filtrate was reduced until crystallization began. Yield 20.0 g.

3.0 g of the 3,5-dihydroxy-ci- (tert-butylamino) acetophenone hydrobromide obtained in this way were mixed with 2.5 g of acetic anhydride in 75 ml of glacial acetic acid; refluxed under a nitrogen atmosphere for 16 hours. The solvent was evaporated, and the reflux was dissolved in ethanol. After the addition of absolute ether crystallized! 3,5 - diacetoxy - r,> - (tert - butylamino) - acetophenone hydrobromide and was recrystallized from methanol / ether. Yield 2.0g. F. = 191 to 193 ° C The esters 1- (3 ', 5'-Diisobutyryloxyphenyl) -2- (tert. Butylamino) -ethanol hydrobromide (M. = 168 to 170 ⁰ C) and 1- (3', 5 ' Dipropionyloxyphenyl) -2- (terl. Butylamino) -ethanol hydrobromide (F. = 114 bi: 117 ⁰ C) can be prepared by the same method as for I - (3 ', fi'-diacetoxyphenyl) -2- (tert. butylamino) ethanol hydrobromide described.

Claims (1)

; Patent claims: . J, l-Aryl ^ -alkylnminoSthanoie of the general formula R ¹ O R ¹ O CH-CH, -Ν-R
OH 'H