NO126437B - - Google Patents

Description

Analogy method for the production of

bronchospasmolytically active 1-(3<1>,5<1->di-

alkanoyloxyphenyl)-2-tert. butylaminoethanols.

The present invention relates to the production of orally active bronchospasmolytic 1-(3',5,-dialkanoyloxyphenyl)-2-tert.butylaminoethanols.

A large number of 1-(3<1>,4'-dihydroxyphenyl)-2-aminoethanols with bronchospasmolytic activity are known, but compounds of this type with the two hydroxyl groups in the 3,4-position of the benzene ring are attacked in the organism by certain enzymes, i.e. catechol-O-methyl-transferase, COMT, which are found, among other things, in the liver. In such an attack, the compounds are inactivated, and compounds of this type therefore have a relatively short-term effect. However, compounds with the two hydroxyl groups in the 3j5 position in the benzene ring are not attacked by COMT. Quite a few compounds of this latter type are known. These can be summarized in the general formula:

1 2

A compound of formula I where R is hydrogen and R is a methyl group is described in German patent no. 865 315. Compounds with

1 2

formula I, wherein R is hydrogen and R is a 2-hexyl, 2-heptyl, 2-octyl or n-butyl group, is described in Belgian Patent No. 635,889, and

1 2

compounds where R is hydrogen and R is the group

where R 3 is hydrogen or a methyl group, is described in Norwegian patent no. II67/63, while compounds where R"<1>" is hydrogen or a methyl group and R is an isopropyl group are described in Norwegian patent no. 108 914, These known compounds of formula I are bronchospasmolytically active compounds with a relatively long-lasting effect, but they have been found to cause an increase in the heart rate, and this effect reduces the therapeutic use of the compounds.

According to the invention, new 1-(3',5'-dialkanoyl-oxyphenyl)-2-alkylaminoethanols are provided which have a long-lasting effect and which, surprisingly, only cause a very weak effect on the heart rate.

These advantages are achieved according to the invention by preparing compounds of formula II

where R^ is an alkanoyl group with no more than 5 carbon atoms and physiologically acceptable acid addition salts thereof using known methods, namely: A. reaction of a dicarbonyl compound of formula III with tert-butylamine of formula IV during simultaneous reduction according to the following reaction scheme:

after which R , if necessary, is transferred to the group RJ, or

B. reaction of an epoxide of formula VI with a compound of formula VII according to the following reaction core:

3'. • 3 4 after which R , if necessary, is transferred to the group R , and R , if necessary, is replaced by hydrogen, or C. reduction of a compound of formula IX according to the following reaction scheme:

after which R , if necessary, is transferred to the group R , and R , if necessary, is replaced by hydrogen,

in which formulas R 3 • is hydrogen or an alkyl or alkanoyl group with no more than 5 carbon atoms or a mono- or bicyclic aralkyl group

4 with no more than 11 carbon atoms, such as benzyl or naphthylmethyl, and R is hydrogen or a mono- or bicyclic aralkyl group with no more than 11 carbon atoms,

after which the obtained compound is, if desired, converted into physiologically tolerable acid addition salts, and/or split into its optically active forms either before or after any transfer of the group R to

7 . a

the group R-' or removal of the protecting group R.

It is obvious that compounds of formula I can exist in the form of optically active isomers, which can be isolated by any method known in principle for cleaving an amine, and it is understood that such a method is covered by the present invention.

The preferred method for preparing compounds of formula II is the above-mentioned method C. The starting material of formula IX can be obtained in any desired manner, e.g. by the following reaction scheme: which can be modified in various ways known per se, such as e.g. in that the third and second steps from the end of the form can be replaced with:

whereby the bromination can be carried out using bromine at low temperature or with the help of copper (II) bromide.

The reduction of the compound of formula IX can be carried out e.g. a) by catalytic reduction, e.g. with Raney nickel or with palladium charcoal, or platinum oxide, or b) chemical reduction, e.g. with lithium aluminum hydride or sodium borohydride in which case Ry is a hydroxy protecting group,

or

c) chemical reduction of the carbonyl group, e.g. with lithium aluminum hydride or sodium borohydride, after which hydroxy-protection

3' 4

the groups R and R are removed by catalytic reduction, e.g. with palladium charcoal or platinum oxide.

If R-3^1 in formula VIII is an alkyl group, it can be replaced by hydrogen using ether-cleaving agents, e.g. by using boron tribromide at low temperature or by heating with hydrogen halides. In the latter case, the alcoholic hydroxyl group is protected against halogenation, preferably by acetylation, whereby the ether cleavage is carried out using e.g. hydrobromic acid in anhydrous glacial acetic acid or glacial acetic acid/acetic anhydride, after which the acetyl protecting group is hydrolysed. If R % t in formula VIII is one

4 acyl residue, this can be split off by treatment with acids. If R in formula VIII is an aralkyl group, this can be removed by hydrogenolysis.

The new compounds, 1-(3'>5'-dialkanoyloxyphenyl)-2-(t-butylamino)-ethanols, are very good bronchodilators and they have only very weak cardioaccelerating effects.

The new compounds can be administered in the form of salts with physiologically acceptable acids. Suitable acids that can be used are e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, citric acid, tartaric acid,

maleic or succinic acid.

Pharmaceutical preparations can be prepared containing as active ingredient the compounds produced according to the invention together with a pharmaceutical carrier. Such preparations can be designed for oral, bronchial, rectal or parenteral administration.

Liquid preparations for oral administration can be in the form of syrups, suspensions or emulsions, e.g. containing from about 0.1 to 20% by weight active compound, and, if desired, such auxiliaries as stabilizers, suspending agents, dispersing agents, flavoring agents and/or sweetening agents.

Liquid preparations for rectal administration can be in the form of water solutions containing from about 0.1 to 2 weight percent active compound and, if desired, stabilizers and/or buffer substances. v

For parenteral application by injection, the carrier can be a sterile, parenterally acceptable liquid, e.g. pyrogen-free water or an aqueous solution of polyvinylpyrrolidone or a parenterally acceptable oil, e.g. arachis oil and any stabilizer and/or buffer substances. Dosage units of the solution can preferably be enclosed in ampoules, each dosage unit preferably containing from 0.05 to 5 mg of active compound.

For administration to the bronchi, the compounds are preferably in the form of a drop or spray solution. The solution preferably contains from 0.1 to 10% by weight of the active compound.

The following examples illustrate the invention.

Example 1 Preparation of 3,5-dibenzyloxy-u)-(t-butylamino)-acetophenone used as starting material.

a) Ethyl-3j5-dihydroxybenzoate

308 g of α-resorcylic acid was dissolved in 1000 ml of absolute ethanol and 25 ml of concentrated sulfuric acid was added. The reaction mixture was refluxed for 20 hours. The ethanol was evaporated and the residue poured into water and extracted with ether. The ether phase was washed with sodium bicarbonate solution and water and dried with magnesium sulfate. After evaporation of the ether, a crystalline residue was obtained. The ester was recrystallized from water; melting point 128° - 130°C.

b) 3j5-dibenzyloxybenzoic acid

In a 2-liter three-necked flask fitted with a stirrer and a return- ■

condenser, 221 g of ethyl 3,5-dihydroxybenzoate, 750 ml of absolute ethanol, 360 ml of benzyl chloride and 210 g of potassium carbonate were introduced. reaction

the mixture was refluxed, stirred for 20 h and filtered while hot. The ethanol was evaporated and to the residue water and sodium hydroxide were added for an alkaline reaction. The aqueous phase was extracted with ether and dried with magnesium sulfate. The ether was evaporated and the remainder of benzyl chloride distilled off under reduced pressure. The remaining oil was refluxed for 3 hours on a water bath with 150 g of sodium hydroxide in 750 ml of ethanol and 50 ml of water. The ethanol was evaporated and 250 ml of water was added. When the solution was acidified with 5 N hydrochloric acid, the acid crystallized. Recrystallization from ethyl acetate: melting point 214° - 216°C.

c) 3, 5-dibenzyloxybenzoyl chloride.

167 g of dibenzyloxybenzoic acid and 400 ml of freshly distilled thionyl chloride were refluxed in an oil bath for one hour. Excess thionyl chloride was distilled off under reduced pressure and a crystalline mass remained. Recrystallization from petroleum ether, (boiling point 60° - 85°C), melting point 73° - 74°C.

d) 3,5-dibenzyloxydiazoacetophenone

Diazomethane was prepared according to known methods. 86 g of N-nitroso-p-toluene-sulfomethylamide in ether was slowly added to a solution of 24 g of potassium hydroxide in 40 ml of water and 100 ml of diethylene glycol monoethyl ether in 40 ml of ether. The reaction flask was heated to 55°-65°C on a water bath and the diazomethane formed was distilled off into a receiving flask containing 71 g of 3,5-dibenzyloxybenzoyl chloride in 250 ml of absolute ether at -25°C. The reaction mixture was slowly allowed to reach room temperature. The ether solution was used directly in the next reaction.

e) 3>5-dibenzyloxy-a)-bromoacetof enone

To the ether solution from the preceding reaction was added 300 ml of benzene

and ether saturated with hydrogen bromide added until the evolution of nitrogen ceased. After the solution was evaporated, a crystalline residue was obtained. The crystals were soluble in xylene and could be precipitated with petroleum ether (boiling point 40° - 60°C) and were washed with absolute ether, melting point 82° - 84°C.

In a similar manner, 3,5-dibenzyloxy-w-chloroacetophenone was prepared. Melting point 78° - 80°C.

f) 3,5-dibenzyloxy-a)-(t-butylamino)-acetof enone

1.5 g of t-butylamine and 85 ml of absolute ethanol were placed in a

250 ml flask fitted with a reflux condenser and the mixture heated to reflux. The reaction was carried out under nitrogen.

At the reflux temperature, 4.1 g of 3,5-dibenzyloxy-w-bromoacetophenone in 15 ml of benzene were added. The mixture was refluxed for 20 hours and after evaporation a yellow oil was obtained. This oil was shaken with absolute ether and this gave white crystals (t-butylamine hydrobromide). The crystals were filtered off and washed with ether. To the combined ether phases 10% hydrobromic acid was added and this gave a white precipitate. This precipitate was filtered off and washed thoroughly with water and ether. Recrystallization from ethanol gave a product with a melting point of 196°-198°C.

Steps d) and e) can be replaced by the following two steps:

g) 3,5-dibenzyloxy-acetophenone

70 g of 3,5-dibenzyloxybenzoyl chloride in dry benzene became slow

added to a solution of diethylethoxymagnesium malonate prepared in a known manner. The reaction mixture was refluxed overnight, and after cooling, 300 mL of benzene and 200 mL of 5 N sulfuric acid were added to hydrolyze the mixture. The benzene phase was washed three times with water and dried with magnesium sulphate, the benzene was evaporated and excess diethyl malonate distilled off under reduced pressure. To the residue, 400 ml of dioxane, 80 ml of water and 40 ml of concentrated hydrochloric acid were added. The reaction mixture was heated for 24 hours in an oil bath at 130°C. After evaporation, a brown oil was obtained and this crystallized after standing. Recrystallization from ethanol: melting point 60° - 61°C.

h) 3, 5-dibenzyloxy-ol-bromoacetof enone

11.2 g of copper (II) bromide was placed in a three-necked flask fitted with a stirrer and reflux condenser. 25 ml of ethyl acetate was added and the mixture heated to reflux with stirring. 10 g of 3,5-dibenzyloxyacetophenone in 30 ml of hot chloroform was added and refluxing was continued until the black-green color changed to light brown. The formed copper (I) bromide was filtered off and after evaporation of the filtrate a brown oil was obtained which soon crystallized. Recrystallization from ethanol: melting point 82° - 84°C.

This step h) can alternatively be replaced by i).

i) 3,5~ dibenzyloxy-cj-bromoacetof enone

Into a 250 ml three-necked flask fitted with a stirrer and a reflux condenser and a dropping funnel, 5.0 g of 3,5-dibenzyloxy-acetophenone in 90 ml of chloroform was introduced. After this, 15 drops of glacial acetic acid saturated at 0°C with hydrogen bromide were added to the solution. 4 ml of a solution prepared from 2.4 g of bromine and 25 ml of chloroform was added. The reaction mixture was heated to reflux and then cooled rapidly to 0°C. The remaining bromine solution was added slowly with stirring and cooling and then stirred for a further 1 hour at room temperature and finally heated for \ hour at reflux temperature. After cooling to room temperature, nitrogen gas was introduced to remove residual hydrogen bromide. Petroleum ether (boiling point 60°-85°C) was added and the reaction mixture was washed with cold sodium bicarbonate solution and water saturated with sodium chloride. The organic phase was dried with magnesium sulfate and evaporated. The remaining oil crystallized after standing. Recrystallization from ethanol gave a melting point of 82°-84°C.

j) 3, 5-dibenzyloxy-acetophenone

5.0 g of 50.% sodium hydride suspension and a couple of ml of benzene were added to a 500 ml three-necked flask equipped with a stirrer, cooler and a dropping funnel. 18.1 g of ethyl 3,5-dibenzyloxybenzoate in 150 ml of dry benzene was then added. The reaction mixture was stirred and heated in an oil bath (90° - 100°C), after which 4.5 g of ethyl acetate in 25 ml of dry benzene was slowly added, after which the heating and stirring were continued for 7 hours. The reaction mixture was cooled, a few ml of ethanol were added, after which the entire mixture was poured into 150 ml of 50% acetic acid solution. The acidic aqueous phase was extracted with ether, and the ether phase was washed with water, sodium bicarbonate solution and water, and then dried with magnesium sulfate. After evaporation of the solvents, an oil was obtained, which was then treated with 80 ml of dioxane, 16 ml of water and 8 ml of concentrated hydrochloric acid, after which the mixture was heated in an oil bath at 130°-140°C for 15 hours. After evaporation of the solvents, ether was added and the ether phase was washed with water, 2 N sodium hydroxide solution and water. The ether phase was then evaporated, and the residue was dissolved in hot ethanol, after which 200 ml of a 1 N sodium hydroxide solution was added. The mixture was refluxed for 5 hours to hydrolyze the remaining ethyl 3>5-dibenzyloxybenzoate. The ethanol was evaporated, after which the aqueous phase was extracted with ether, and the combined ether phases were washed with water, dried with magnesium sulfate and evaporated for solvents. The remaining oil crystallized from petroleum ether (boiling point 80° - 110°C), melting point 61.5° - 62.0°C.

k) 355- dibenzyloxy- ai-bromoacetof enone

20.0 g of 3,5-dibenzyloxy-acetophenone was dissolved in 460 ml of dry ether and cooled to 0°C. 9.7 g of bromine dissolved in 30 ml of dry, ethanol-free chloroform was then slowly added. During this addition,

the temperature was kept at 0°C. The temperature of the reaction mixture was then slowly raised to room temperature and was kept at this temperature for 2.5 hours with stirring. The ether was then evaporated at room temperature, and the remaining oil crystallized on standing. The product is identical to those obtained under example 1 i).

Example 2. Preparation of 1-(3<1>,5'-dialkanoyloxyphenyl)-2-(t-butylamino)-ethanol. ' ' a) A solution of 6.8 g of the hydrate of 1-glyoxyloyl-3>5-di-benzoyloxybenzene in 50 ml of methanol was added to 7.0 g of t-butylamine and 30

ml of benzene. The reaction mixture was refluxed for 3 hours after which the solvents were evaporated. The remaining oil crystallized when ethanol was added. Melting point 78.5° - 79.5°C. 2.5 g of this compound in 75 ml of absolute ethanol was hydrogenated under normal conditions with Raney nickel. After filtering off the catalyst and evaporating the solvents, the remaining oil was dried with ethanol/benzene. The base in ethanol was treated with hydrogen bromide in ethanol, after which the solvents were evaporated. The residue can be crystallized from glacial acetic acid/chloroform.

The IR spectrum of this product is identical to that obtained from the product in section 2 c). b) A solution of 3.5 g of 3',5'-dibenzyloxyphenyl-epoxyethane in 100 ml of ethanol was added with 2.7 g of t-butylamine in 20 ml of ethanol. The reaction mixture was refluxed for 4 hours after which the solvents were evaporated. The crystalline residue can be recrystallized from absolute ether. The melting point of 1-(3',5'-dibenzyloxyphenyl)-2-(t-butylamino)-ethanol is 119° - 122°C. The preparation of the salt and the reduction can be carried out in the same way as described under section 2 a). c) 2.4 g of 3,5-dibenzyloxy-w-(t-butylamino)-acetophenone hydrobromide in 200 ml of glacial acetic acid was hydrogenated in the presence of 0.3 g of 10% palladium charcoal at room temperature and normal pressure. Ethanol was added to dissolve the precipitated reaction product. The catalyst was filtered off, the residue evaporated to dryness after which 50 ml of absolute ethanol was added and the solution hydrogenated in the presence of 0.3 g of 10% palladium charcoal at 35°C and 5 atm. Print. The catalyst was filtered off, after which the residue was evaporated to dryness, Recrystallized from glacial acetic acid/chloroform: melting point 9 3° - 97°C for the monohydrate. The non-hydrated compound has a melting point of 205°-206°C (decomp.).

The compound 1-(3',5'-dihydroxyphenyl)-2-(t-butylamino)-ethanol obtained from one of steps a), b) or c) can then be converted into the desired final compounds by acylation. Due to the fact that with this method it is difficult to avoid the formation of by-products, in practice the method according to part C as previously defined is preferred, which method is exemplified in the examples 3, 4 and 5 below.

Example 3. Preparation of 1-(3',5'-diacetoxyphenyl)-2-(t-butylamino)-ethanol hydrobromide.

A solution of 32 g of benzyl-t-butylamine in 300 ml of absolute ethanol at reflux temperature was added to 32 g of 355-dibenzyloxy-u-bromoacetophenone in 100 ml of dry benzene. The mixture was refluxed for 20 hours and then evaporated for solvents. By adding ether, benzyl-t-butylaminohydrobromide was precipitated. The precipitated compound was filtered off, and an excess of 2 N sulfuric acid was added to the filtrate. With this addition, the hydrogen sulfate of 3,5-dibenzyloxy-(jj-(benzyl-t-butylamino)-acetofenone was precipitated. Recrystallized from acetone/ether. As the product crystallizes with different organic solvents, the melting point will vary with the type and the amount of solvent used.The hydrogen sulphate can be converted into the corresponding hydrogen bromide by means of methods known per se, which is then used as starting material in the next step.

57° S 3,5-dibenzyloxy-α-(benzyl-t-butylamino)-acetophenone hydrobromide was dissolved in 400 ml of glacial acetic acid and hydrogenated at atmospheric pressure and room temperature in the presence of 3.0 g of 10% palladium charcoal. When the calculated amount of hydrogen was taken up, the hydrogenation was terminated. Absolute ethanol was added to dissolve the formed crystalline product 3,5-dihydroxy-u-(t-butylamino)-acetophenone hydrobromide. The catalyst was filtered off and the volume of the filtrate reduced until crystallization began. Yield 20.0 g.

3.0 g of 3,5-dihydroxy-u-(t-butylamino)-acetophenone hydrobromide was refluxed and stirred with 2.5 g of acetic anhydride in 75 ml of glacial acetic acid and under a nitrogen atmosphere for 16 hours. The solvent was evaporated and the residue dissolved in ethanol. On addition of absolute ether, a crystalline product consisting of 3,5-diacetoxy-α-(t-butylamino)-acetophenone hydrobromide was formed. This was recrystallized from methanol/ether. Yield 2.0 g, melting point 191° - 193°C.

1.0 g of 3,5-diacetoxy-co-(t-butylamino)-acetophenone hydrobromide was dissolved in absolute ethanol and hydrogenated in a Parr pressure reactor at 50°C and 5 atmospheres pressure for 17 hours in the presence of 0.1 g of 10% palladium charcoal.

The catalyst was filtered and the volume of the filtrate reduced by evaporation. The hydrobromide of 1-(3',5'-diacetoxyphenyl)-2-(t-butylamino)-ethanol was brought to crystallisation by addition of absolute ether. Yield 0.7 g, melting point 108° - 111°C.

In the same way, such esters as 1-(3',5'-diisobutyryloxyphenyl)-2-(t-butylamino)-ethanol hydrobromide (melting point 168° - 170°C) and 1-(3<1>, 5'-dipropionyloxyphenyl)-2-(t-butylamino)-ethanol hydrobromide (melting point 114° - 116°C).

Example 4. Preparation of 1-(35'-diacetoxyphenyl)-2-(t-butylamino)-ethanol hydrobromide.

6.3 g of 3,5-diacetoxy-u)-bromoacetophenone dissolved in 100 ml of dry benzene was added to 7.0 g of benzyl-t-butylamine in 50 ml of dry benzene. The mixture was refluxed for 3 hours and then evaporated for solvents. When absolute ether is added, benzyl-t-butylaminohydrobromide precipitates, which was then filtered off. The ether phase was treated with hydrogen bromide in ether until the solution was slightly acidic.

The precipitated salt mixture was treated with water to dissolve benzyl-t-butylamine hydrobromide. The crystals were filtered, washed with water and recrystallized by dissolving them in ethanol and then carrying out the recrystallization in absolute ether. The hydrobromide of 3,5-diacetoxy-w-(benzyl-t-butylamino)-acetophenone has a melting point of 171° - 173°C.

1.1 g of this salt was dissolved in warm absolute ethanol after which 0.1 g of 10% palladium charcoal was added. The solution was then hydrogenated at 50°C and 5 atm. pressure overnight. The catalyst was filtered off, and the volume of the solution reduced by evaporation of the solvents. With the addition of ether, the hydrobromide of 1-(3*,5'-diacetoxyphenyl)-2-(t-butylamino)-ethanol was precipitated with 1 mol of crystal water. Melting point 108° - 111°C.

In an analogous manner, the compounds 1-(3',5'-diisobutyryl-oxyphenyl)-2-(t-butylamino)-ethanol, 1-(3',5'-dipropionyloxyphenyl)-2-(t-butylamino)- ethanol, and 1-(3', 5'-dipivaloyloxyphenyl)-2-(t-butylamino)-ethanol.

Example 5. Preparation of 1-(3<1>,5<1->dipivaloyloxyphenyl)-2-(t-butylamino)-ethanol hydrobromide.

16.0 g of 3,5-dipivaloyloxy-to-bromoacetophenone dissolved in 200 ml of dry benzene was supplied with 22.0 g of benzyl-t-butylamine. The reaction mixture was refluxed for 4 hours and then allowed to stand at room temperature for 15 hours. The benzene phase was evaporated to dryness and absolute ether added. Benzyl-t-butylaminohydrobromide crystallized out

and was filtered out. 50 ml of 10% hydrobromic acid was added to the filtrate with stirring and this gave a crystalline product consisting of 3,5-dipivaloyloxy-co-(benzyl-t-butylamino)-acetate of enone hydrobromide. Yield 11.0 g, melting point 162° - 167°C.

3.0 g of 3,5-dipivaloyloxy-w-(benzyl-t-butylamino)-acetophenone hydrobromide was dissolved in absolute ethanol and hydrogenated in a Parr pressure reactor for 20 hours at 50°C and 5 atmospheres of pressure in the presence of 0.3 g 10 % palladium coal. The catalyst was filtered off and the filtrate evaporated to dryness. The residue was crystallized from chloroform/ether/petroleum ether (boiling point 80° - 85°C). Yield 1.8 g, melting point 190° - 192°C.

Example 6. Preparation of the starting compound 1-(3',5'-dibenzyloxyphenyl)-2-(benzyl-t-butylamino)-ethanol.

18.3 g 3'»5'-dibenzyloxy-u)-(benzyl-t-butylamino)-acetophenone

in ethanol was added 2 g of sodium borohydride. The reaction mixture was allowed to stand overnight, after which methanol was added and the solution was evaporated from the solvents. Water and a 2 N sodium hydroxide solution were added to the residue, after which the water phase was extracted with ether. The ether phase was dried with magnesium sulfate, the ether was then evaporated, and the remaining oil crystallized on standing. Melting point 78° - 79°C. The recrystallized product can be converted into the corresponding 2-butylamino derivative by replacing the phenyl group with hydrogen in a known manner.

Example 7. Preparation of (-)-1-(3<»>,5'-dihydroxyphenyl)-2-(t-butylamino)-ethanol hydrobromide.

First, the starting material is prepared by cleavage of 1-(3'j5'-dibenzyloxyphenyl)-2-(benzyl-t-butylamino)-ethanol in optical antipodes. Thus, 25.0 g of 1-(3',5'-dibenzyloxyphenyl)-2-(benzyl-t-butylamino)-ethanol (the racemate form of the base) was dissolved in 375 ml of methanol by heating, after which 19.0 g of (-)-dibenzoyl- tartaric acid in 125 ml of methanol was added. The mixture was refluxed for 30 minutes. After evaporation, an oil was obtained. This was dissolved in boiling isopropanol and water was added to this mixture until a cloud appeared, after which a few ml of isopropanol were added to clear the solution. The solution was allowed to stand overnight to crystallize and 37.0 g of a white crystalline product was isolated. A further 7.0 g was obtained from the filtrate after reducing its volume. The two portions were mixed and dissolved in 1100 ml of absolute ethanol, filtered and allowed to crystallize. This product was recrystallized from absolute ethanol until the rotation remained constant (6 times) = -34.2° (1% in absolute methanol), yield 4.5 g.

4.0 g of the salt, as obtained above, was suspended in water, after which first ether was added, and then aqueous ammonia. The base was then extracted with two portions of ether. Dilute hydrobromic acid was added to the ether phase which was then stirred for 1.5 hours. This gave a white crystalline product, which was filtered off and washed with water and dry ether. Yield 2.8 g [a]p° = +33.3° (1% in absolute methanol).

This compound was dissolved in 75 ml of absolute ethanol, after which 0.15 g of 10% palladium charcoal was added and the mixture was then hydrogenated at room temperature for 4 hours at 5 atmospheres of pressure. The catalyst was filtered off and the residue evaporated to dryness. A small volume of methanol was added to dissolve the product and then ether until cloudiness occurred. The crystalline precipitate was separated after the mixture had been allowed to stand in a fume hood and dried in a drying gun for 7 hours (over boiling toluene). Yield 1.2 g Br" (calculated) = 26.1 %\ Br" (found) = 25.8 % ta]p° = -34.6° (1% in absolute methanol), melting point 24l°-242°C. Example 8. Preparation of (+)-1-(3',5'-dihydroxyphenyl)-2-(t-butylamino)-ethanol hydrobromide.

23.7 g of the base 1-(3',5'-dibenzyloxyphenyl)-2-(benzyl-t-butylamino)-ethanol obtained from the combined separated solutions from the preparation of (-)-1-(3'j5'-dibenzyloxyphenyl) -2-(benzyl-t-butylamino)-ethanol was dissolved in 250 ml of methanol and refluxed together with 18.2 g of (+)-dibenzoyl-tartaric acid dissolved in 250 ml of methanol for 60 minutes. The product was processed in the same manner as described above and recrystallized twice from absolute ethanol. [a]^<0> = +34.3° (1% in absolute methanol). Yield 10.5 g.

The hydrobromide was prepared from 9.5 g of this salt in the same manner as described above. Yield 6.2 g [a]p°= -33.0° (1% in absolute methanol). The hydrogenation of 5.5 g of this product was carried out as described above. The reaction product crystallized from ethanol/ether. Yield 2.7 g, ta]p<0> = +34.2° (1% absolute methanol). Br"

(calculated) = 26.1%, Br" (found) = 25.8%, melting point 241° - 243°C. Pharmacological experiments with 1-( 3', 5'- dialkanoyloxyphenyl)- 2- aminoethanols.

The assessed connections are indicated below with code numbers

and structural formulas. The comparisons made are made on a weight basis unless otherwise stated.

a) Bronchospasmolytic effect in vitro

Methods:

The trachea from a guinea pig was spirally cut. It was placed in a water jacketed bath (37°C) in Krebs' solution and aerated with oxygen (95%) and carbon dioxide (5%). Pilocarpine (2 µg/ml) was added. The quantity was regulated to approx. 2 g and relaxations in the trachea were recorded using a Grass force-displacement measuring transducer and a Grass polygraph model 5. The cumulative method was used. (-)-adrenaline was used as reference material. The comparisons in Table 1 are based on ED^Q values.

b) Bronchospasmolytic effect on anesthetized cats.

Methods:

Bronchospasmolytic effect was studied according to the method of Konzett & Rossler. Bronchospasms were induced by i.v. injections of histamine into the left carotid artery. Overflow was recorded using a Grass volume transducer and a Grass polygraph model 5. Changes in arterial mean pressure and heart rate were continuously recorded during the experiment. The compound KWD 2019 was used as reference in all experiments. The comparisons are based on ED^Q values. The results obtained are given in table 2 below.

Methods:

Male guinea pig (200-300 g) was used. Bronchoconstriction was produced by allowing the animals to inhale a histamine aerosol. The histamine (0.4 mg base/ml) was nebulized under standard conditions with two devices according to Rooth and Petersen (Acta. Med. Scand. Supplement 228, 1

(1949)). In these experiments, the end of the stay for the animals in the aero-sol was observed by a sudden lowering of the respiratory rate. The compound was injected intraperitoneally 15 minutes (40 animals) or administered orally 30 minutes (40 animals) before histamine treatment. The dose that protected 50% of the animals for more than 4 minutes is designated ED^q. Of untreated animals only 1-25? resist the histamine aerosol for more than 4 minutes.

To study the duration of the effect, 2.0 mg/kg was administered orally to unaffected guinea pigs at different time intervals before the histamine treatment. Eleven groups of six animals were studied and examined in histamine aerosol 10, 20, 30, 40, 50, 60, 120, 180, 240, 300 and 360 minutes after administration of the compound. The results are given in table 3 below.

All esters were examined, but KWD 20 85 is somewhat less effective than KWD 2019 when it comes to protecting guinea pigs against histamine aerosol after i.p. administration. After oral administration, however, the esters are equally or more effective than KWD 2019 with the exception of KWD 2057. The diisobutyric acid ester (KWD 2058) is 2.5 times more effective than KWD 2019 after oral administration. The duration of the compound's effect, examined when administered in equal doses, was found to be of the same order of magnitude as the duration for KWD 2019.

d) Effect on isolated guinea pig heart.

Method:

The isolated guinea pig heart was perfused according to Langendorff. The method used is described by Anden et al (Acta Pharmacol. et Toxicol. 21, 247 (1964)). Contractions in the heart were recorded at using a force-displacement measuring transducer and a Grass polygraph model 5. Cardiac recovery was examined with (-)-adrenaline between each dose of investigated compounds. KWD 2019 was used as a reference. The results are given in table 4 below.

A common feature for all the investigated esters is that they have very little direct effect on the heart muscle. With KWD 2058 no effect on heart rate was obtained at doses up to 100 µg.

e) Hemodynamic studies.

Method:

The hemodynamic effects of KWD 2058 and KWD 2019 were studied in anesthetized cats after i.v. injection into the left femoral vein.

Three attempts were made. The effects on mean arterial pressure, pulse pressure (right carotid artery) and heart rate were recorded.

In order to study the effect of the compounds on the peripheral vascular resistance, a constant current was provided in the right hind leg of two cats by means of a Sigma motor pump connected to the femoral artery. Intra-arterial injections were made and variations in the peripheral resistance were recorded as pressure changes. The results are given in table 5.

The toxicity was examined in mice (NMRI, male mice, 18-28 g) 24 hours after i.v. and oral administration. The animals were observed for 5 days, No further deaths occurred. The results are given in table 6 below.

Discussion.

The compounds KWD 2037, KWD 2057, KWD 2058 and KWD 2085 have a weaker bronchospasmolytic effect in vitro than KWD 2019 and much less direct cardiac effect than KWD 2019. In vivo, the bronchospasmolytic effect in anesthetized cats (after i.v. administration) is the same (KWD 2058) or somewhat less (KWD 2037, KWD 2057) than the effect of KWD 2019. Haemodynamic studies in cats show that the effect of KWD 205 8 on mean arterial pressure, pulse pressure, heart rate and peripheral vascular resistance is approximately half of the effect of KWD 2019. All esters show good efficacy in protecting unaffected guinea pigs against a histamine aerosol after i.p. administration as well as after p.o. administration.

The compounds KWD 2037, KWD 2057, KWD 2058 and KWD 2085 show an improved oral absorption compared to KWD 2019 which is indicated by their higher oral toxicity. The compound KWD 2058 shows a particularly good oral absorption compared to KWD 2019, which is evident from the ED 50 test result for oral administration in table 3.

The esters produced according to the present invention thus exhibit improved properties compared to the compound KWD 2019 which, according to results stated in Norwegian patent no. 120 686 in itself sqlv, has a superior effect compared to previously known compounds.

Analogous method for the preparation of bronchospasmolytically active compounds with the formula:

where R^ is an alkanoyl group with no more than 5 carbon atoms, and physiologically acceptable acid addition salts thereof, characterized by A. that a dicarbonyl compound of formula III is reacted with tert-butylamine of formula IV during simultaneous reduction according to the following reaction scheme:

3' 3

after which R , if necessary, is transferred to the group R^, or

B. that an epoxide of formula VI is reacted with a compound of formula VII according to the following reaction scheme:

31 .. x li after which R' , if necessary, is transferred to the group R , and R , if necessary, is replaced by hydrogen, or C. that a compound of formula IX is reduced according to the following reaction scheme:

3' .. "5 4 after which R , if necessary, is transferred to the group R , and R , if necessary, is replaced by hydrogen,

in which formulas R "5' is hydrogen, or an alkyl or alkanoyl group with no more than 5 carbon atoms or a mono- or bicyclic aralkyl group with no more than 11 carbon atoms, such as benzyl or naphthylmethyl, and R is hydrogen or a mono- or bicyclic aralkyl group with not more than 11 carbon atoms,

after which the obtained compound is, if desired, converted into physiologically tolerable acid addition salts, and/or split into its optically active forms either before or after possible transfer of the group R "51 to

3. 4

the group R or removal of the protecting group R .