NO129903B - - Google Patents

Description

Analogy method for the preparation of therapeutically active compounds.

The present invention relates to an analogous method for the production of therapeutically active compounds which, in the form of the free base, have the formula:

where Y is an alkanoyl or alkanoylmethyl group with 1-8 carbon atoms, 1-methyl-cyclopropanecarbonyl, cyclohexanecarbonyl or a benzoyl or benzylcarbonyl group, which may be substituted

with 1-3 alkyl or alkoxy groups of 1-4 carbon atoms, and Y<1 >is -OH or Y-O-where Y has the meaning given above, and, where at least one of Y and Y 1 contains at least M carbon atoms, and Y <2>

is hydrogen or acetyl, as well as acid addition salts thereof.

The compounds with formula I are produced according to the invention by a compound with the formula:

where Y and Y"*" have the meaning stated above, is reduced and, if desired, the product obtained is acylated, and/or converted into acid addition salts thereof. ;The acid addition salts can be prepared from any organic or inorganic acid. They are obtained in the usual way, e.g. either by a direct mixture of the base with the acid, or when this is not appropriate, by dissolving either the base or the acid separately in water or in an organic solvent and then mixing the two solutions, or by dissolving both the base and the acid in the same solvent . The resulting acid addition salt can be isolated by filtration, if it is insoluble in the reaction medium, or by evaporating the reaction medium so that the acid addition salt appears as a residue. The acid groups or anions in these salt forms are in themselves neither new nor critical, and can therefore be any acid anion or acid-like substance capable of forming a salt with the base. Representative acids for forming acid addition salts include formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, trifluoroacetic acid, maleic acid, fumaric acid, succinic acid, succinamic acid, tannic acid, glutamic acid, tartaric acid, oxalic acid, pyromucinic acid, citric acid, lactic acid, glucolinic acid. , gluconic acid, saccharinic acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid, 3 -indoleacetic acid, barbituric acid, sulfanic acid, metasulfonic acid, ethanesulfonic acid, isethonic acid, benzenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, methanephosphinic acid, acid resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid and arsenic acid. All types of acid addition salts can be used for the production of the free bases, e.g. by a turnover with an inorganic base. It is therefore obvious that if one or more characters such as solubility, molecular weight, physical appearance and toxicity for a given base or an acid addition salt thereof make the compound in question unsuitable for one or more purposes, then said compound can easily be converted into another and more suitable form. For pharmaceutical purposes, one naturally uses acid addition salts of the compounds of formula I with relatively non-toxic, pharmaceutically acceptable acids, e.g. hydrochloric acid, lactic acid and tartaric acid. Monoesters of formula I where Y^ is hydroxy are self-sold amphoteric, in that they have both free phenolic and basic amino groups, and they can consequently form salts with both acids and bases. It is obvious that when carrying out the reduction of the above-mentioned ester ketones of formula II to the corresponding ester alcohols, one must avoid using reducing agents which result in a reduction of the carboxylic ester groups. It is usually preferred to carry out the reduction either by a catalytic hydrogenation in the presence of a noble metal catalyst such as platinum or palladium, or by using an alkali metal borohydride and a lower alkanol. The catalytic hydrogenation can conveniently be carried out in a suitable solvent, e.g. ethyl alcohol, at 20-60°C; and under a hydrogen pressure varying from 1.5-3.5 kg/cm 2 in the presence of a palladium or platinum hydrogenation catalyst. The hydrogenation is continued until the theoretical amount of hydrogen has been absorbed so that this can be calculated in the usual way by a drop in the hydrogen pressure. Normally, a hydrogenation time of 4 hours or less will be satisfactory. After the catalyst has been removed, the ester alcohol is isolated in the usual way, e.g. by evaporating some or all of the solvent from the reaction mixture, collect the precipitated ester alcohol and purify it by recrystallization from a suitable solvent. The e»s ter-ketones with formula II which are used here as starting compounds for the reduction method described above, are obtained by mono- or di-esterification of the corresponding known and easily available unesterified ketone with the formula: ;For the production of mono-ester- ketones of formula II; where Y<1> is -OH, the starting compound can be the 3,4-dihydroxyphenyl ketone; c. (formula III) is treated with a molar equivalent of an acid anhydride or an acid halide of the carboxylic acid in question (Y-OH), optionally in the presence of an acid-absorbing medium, in any suitable manner for acylation of the fernolic hydroxyl group. In a preferred method, the 3,4-dihydroxyphenyl ketone (formula III) is treated with two molar equivalents of an alkali metal lower alkoxide, e.g. sodium methoxide, after which the resulting alkali metal phenolate is reacted with one molar equivalent of an appropriate acid halide, e.g. an acid chloride, Y-Cl. The 4-hydroxyl group in the 3,4-dihydroxyphenyl ketone (formula III) can be acylated more easily than the 3-hydroxy group, and said mono-acylation consequently gives the desired 4-acyloxy-3-hydroxyphenyl ketone (formula II where Y^ " is hydroxy). ;2 ;Preparation of esters of formula I where Y is acetyl is achieved by esterifying the corresponding ester alcohols of formula I, i.e. where Y 2 is hydrogen. This esterification can conveniently be carried out by treating an acid (strong )-addition salt of the ester alcohol, e.g. a hydrohalide or a methanesulfonate salt, ;with a suitable acid halide of formula Y-halogen, preferably the acid halide Y-Cl, where Y has the same meaning as stated above. ;Esters prepared according to the present invention, which in the free base form has formula I as stated above, can be administered orally, intratracheally, intraduodenally or intravenously to mammals, whereby it is possible to produce sympathomimetic effects with a significantly longer duration than for the corresponding unesterified sympath omimetic means. ;Usually, diesters of formula I have a longer sympathomimetic effect than the corresponding monoesters of formula I. ;Esters of formula I not only provide a longer bronchodilating effect than the corresponding unesterified bronchodilators, when administered orally, intratracheally, intraduodenally or intravenously to mammals, but also produces beneficial lower cardiovascular effects than the corresponding unesterified compounds. The prepared compounds can be used to produce sympathomimetic effects of long duration in mammals which include administering an effective amount of an ester which in the free base form has formula I as indicated above. In this connection, said esters can be administered orally in the same way as for the corresponding unesterified sympathomimetics. They can thus be used in conjunction with any known pharmaceutically acceptable carrier of the type commonly used for oral or parenteral administration of such agents. Usually they will be combined with common pharmaceutical solid or liquid diluents and carriers in tablets, capsules, syrups, emulsions, solutions or suspensions. These preparations may contain known diluents such as water, lactose, starch, magnesium stearate, talc, gelatin and calcium carbonate. A particularly preferred method of administration of these esters (formula I) is in the form of an aerosol inhalation preparation, e.g. of the type that is usually used in aerosol therapy, such as in the treatment of bronchospasm, where a sympathomimetic agent with an effective bronchodilating effect is combined: with suitable carriers or diluents and an inert propellant in a nebulization unit. A typical preparation of the aerosol type contains per weight: 0.25%; of the ester (formula I) or a suitable pharmaceutically acceptable salt thereof, 39.75% U.S.P. ethanol, 4b% dichlorotetrafluoroethane and 12.00% dichlorodifluoromethane. The individual dosage units can be varied as desired. Generally, it is preferred to incorporate from 0.1 to 100 mg of the ester (formula I) in a solid diluent, whether in tablet or capsule form, or in a liquid preparation, from 0.1 to 100 mg of the ester (formula I) per teaspoon, or in an aerosol, from 0.02 to 2 mg per time. The effective oral dose to produce bronchodilation is in the range from approx. 0.02-2.0 mg per kg. The following examples illustrate the invention. ;The compounds produced in examples 3,4,5 and 9; are preferred compounds. ;Example 1 ;A. A mixture of 25 grams of 3,4-dihydroxyphenyl tert-butyl-amino-methyl-ketone hydrochloride, 150 ml of butyric acid saturated with hydrogen chloride and 150 ml of butyryl chloride was stirred on a steam bath until a clear solution was obtained (about 6 hours), after which the solution was heated on the steam bath for a further 1 hour. About. 50 ml of the solvent were distilled off under reduced pressure from the reaction mixture when it had cooled. The mixture was then filtered to collect a crystalline solid which was washed with diethyl ether and then air dried. 31 grams of 3,4-bis(butyryloxy)phenyl tert-butyl-aminomethyl-ketone hydrochloride were thereby obtained as a white, crystalline solid with a melting point of 212-215°C (decomposition) (uncorrected). B. A mixture of 30 grams of 3,4-bis(butyryloxyJphenylxtert-butylaminomethyl ketone hydrochloride, 200 ml of 90% ethyl alcohol and 2 grams of 10% palladium-on-charcoal hydrogenation catalyst was hydrogenated for 2 hours at 50°C under an initial hydrogen pressure of approx. .. 3.5 kg/cm 2. The hydrogenation mixture was filtered to remove the catalyst. The solvent was evaporated from the filtrate under reduced pressure, and the resulting residue dissolved in 50 ml of isopropyl alcohol, left overnight at 5°C and filtered to remove 3 grams of solid. The filtrate was evaporated under reduced pressure, the residue obtained was dissolved in 50 ml of isopropyl acetate, and this solution was filtered to remove minor amounts of an insoluble solid. When the filtrate was diluted with anhydrous diethyl ether, a solid. This was collected on a filter. 20 grams of impure 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride were thus obtained. This salt was dissolved in water, after which ammonium m hydroxide was added, so that the free base was precipitated, namely 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol. This precipitate was collected on a filter paper and washed first with water and then with n-hexane. This base melting at 97-99°C (uncorrected) was dissolved in isopropyl alcohol and the solution concentrated under reduced pressure. The resulting residue was dissolved in 30 ml of isopropyl acetate and a hydrochloride solution was added. solution in ether in a sufficient quantity to give a slight excess of the necessary quantity of the hydrogen chloride to convert the base into the hydrochloride. The mixture was cooled and the inside of the vessel scraped to induce crystallization. The mixture was diluted with 100 ml of diethyl ether, and the solid precipitate was collected on a filter paper and washed with anhydrous diethyl ether and dried at 70°C. In this way, 11 grams of 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride were obtained as a white, crystalline solid which melted at 136-13b°C (uncorrected). This salt was soluble in water in amounts up to 20%. The pH in a 1% aqueous solution was 6.0, and a precipitate formed when the pH in this solution was raised to 7.0 by adding a N/10 sodium hydroxide solution. ;Example 2 ;A. To a mixture of 26 grams of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml of N,N-dimethylformamide under an atmosphere of nitrogen was added 17 grams of sodium methoxide. By distillation under reduced pressure, 50 ml of liquid was removed, and the mixture was then cooled under an atmosphere of nitrogen, after which 25 grams of isobutyryl chloride were quickly added at 5-25°C. The reaction mixture was stirred at 25°C for 1 hour and then heated to 70°C, whereupon the solvent was removed by distillation. The resulting residue was stirred in 400 ml of diethyl ether, and the suspension filtered to remove approx. 10 grams of insoluble matter. The ether layer of the filtrate was separated, washed with dilute aqueous sodium hydroxide solution and then with water. An ether solution of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone was thus obtained. This solution was added to a solution prepared by adding 4 ml. hydrochloric acid to 25 ml of water, and the The resulting mixture was then shaken. The crystalline solid formed was collected on a filter paper and dried, at -70°C. 8.5 grams of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone hydrochloride were thus obtained as a white, crystalline powder melting at 221-23°C (decomposition) (uncorrected). B. By a catalytic hydrogenation of 8.5 grams of 3,4-bis-(idobutyryloxy)phenyl tert-butylaminomethyl-ketone hydrochloride in 200 ml of 95/G's ethyl alcohol in the presence of 2 grams of 1056 palladium-on-charcoal catalyst ffkk one prepared 5, 0 grams of 3,4-bis(isobutyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white, crystalline powder with a melting point of 190°C (uncorrected^). ;Example 3 ;A. A mixture of 25 grams of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, 100 grams of isovaleryl chloride and 100 grams of isovaleric acid was stirred on a steam bath for 72 hours. The reaction mixture was left overnight at room temperature (about 25°C), then heated and filtered while hot to remove 1 lb grams of solids. The filtrate was evaporated to dryness under reduced pressure, and the resulting residue was crystallized from isopropyl acetate containing minor amounts of acetic acid. 11.2 grams of 3,4-bis(isovaleryloxy)phenyl tert-butylaminomethyl ketone hydrochloride were thus obtained as a white, crystalline solid which melted at 220-222°C (uncorrected). After recrystallization of a sample of this compound from isopropyl alcohol, the melting point was 224-225°C. B. By catalytic hydrogenation of 11.2 grams of 3,4-bis-(iso-valeryloxy)phenyl tert-butylaminomethyl-ketone hydrochloride in 250 ml of 95% ethyl alcohol in the presence of 2 grams of 10% palladium-on-charcoal catalyst, 3 was produced .6 grams of 3,4-bis(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white, crystalline powder with a melting point of 173°C (uncorrected). ;This salt was soluble in water at 25°C in amounts up to 20%. The pH in a 1% aqueous solution was 5.4 and when the pH in this solution was adjusted to 7.0 by the addition of a 10-normal sodium hydroxide solution, a precipitate was formed. ;Example 4 ;A. Using the same procedure as described in Example 2A above, 26 grams of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 17 grams of sodium methoxide, and the resulting sodium phenolate salt was reacted with 25 grams of 3,3-dimethylbutanoyl chloride, whereby prepared 7.0 grams of 3,4-bis(3,3-dimethylbutanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid, mp 225-22b°C (dec) (uncorrected). B. In a catalytic hydrogenation of 7.0 grams of 3,4-bis-(3,3-dimethylbutanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml of 95% ethyl alcohol in the presence of 2 grams of 10% palladium-on-charcoal catalyst , 6.0 grams of 3,4-bis(3,3-dimethylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride were prepared as a white, crystalline powder with a melting point of 226°C (uncorrected). This salt was soluble in water at 25°C in amounts up to 1%. ;Example 5 ;A. Under an atmosphere of nitrogen, 26 grams of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride were mixed with 17 grams of sodium methoxide in 200 ml of N,N-dimethylformamide, after which 50 ml of the solvent was distilled off below 40°C at reduced pressure. Then 31 grams of p-toluyl chloride were added dropwise at 5-10°C. The solvent was distilled from the reaction mixture under reduced pressure, and the resulting residue stirred in a mixture of water and ethyl ether, after which the whole was filtered to remove 9.5 grams of insoluble solid. The ether layer of the filtrate, which contained 3,1-bis(p-toluyloxy)phenyl tert-butyl monomethyl ketone, was separated, washed with water and dilute sodium hydroxide, and then shaken with a solution prepared by diluting 4 ml of concentrated hydrochloric acid with water to a volume of 30 ml. After the mixture had stood at room temperature for 1 hour, the precipitate was collected on a filter paper, washed with diethyl ether and recrystallized from isopropyl alcohol. 14.0 grams of 3,4-bis-(p-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride were prepared in this way as a white, crystalline solid with a melting point of 221-224°C (uncorrected). The solubility of this salt in water at 25°C was less than 0.1%. B. In a catalytic hydrogenation of 13.5 grams of 3,4-bis-(p-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 220 ml of anhydrous ethyl alcohol at room temperature in the presence of 2.0 grams of 10% palladium-on-charcoal catalyst until one mole equivalent of hydrogen had been absorbed (about 30 minutes), 8.0 grams of impure 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl) benzyl alcohol hydrochloride were produced as a powdery solid, which at a treatment with an excess of 10% ammonium hydroxide converted the free base, which weighed 4.3 grams and melted at 80-84°C. The base was converted to its methanesulfonic acid salt (4.3 grams), which was a white, crystalline powder with a melting point of 170-172°C (uncorrected). The methanesulfonate was soluble in dimethylsulfoxide in quantities of up to 1%, and when a 1% solution in dimethylsulfoxide was diluted with three volumes of water, no precipitate was formed. C. A solution of 1.1 grams of 3,4-bis(p-toluyloxy)-phenyl tert-butylaminomethyl-ketone-methanesulfonate (melting point 185-187°C' ; (uncorrected), prepared by reacting the free base with methanesulfonic acid), in 20 ml of anhydrous methyl alcohol at 5°C under nitrogen, 100 ml of dry sodium borohydride was added with stirring. After 5 minutes, the reaction mixture was cooled with approx. 15 drops of glacial acetic acid, whereby the pH of the mixture became approx. 6. It was then evaporated to dryness, diluted with 200 ml of diethyl ether and washed with 100 ml of 5% aqueous sodium bicarbonate solution, followed by washing successively with water and water saturated with sodium chloride. The aqueous wash solutions were combined and extracted with diethyl ether, and this extract was combined with the ether solution, after which the whole was dried over sodium sulfate and evaporated to approx. 1 gram of a colorless oil. This oil which was 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol was diluted with 70 ml of anhydrous diethyl ether and then 0.14 ml of methanesulfonic acid was added. A precipitate formed on cooling. The mixture was concentrated to a volume of approx. 25 ml and then filtered. The white crystalline substance obtained, weighing 1.1 grams, was 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, identical to the product described above in Part B. A treatment of this salt with ammonium hydroxide gave the free base, which was then treated with acetic acid to give the acetate salt as a white, crystalline solid, mp 110°C (uncorrected). ;Example 6 ;A. Under an atmosphere of nitrogen, 8.1 grams of sodium methoxide was added to 13 grams of 3,4-dihydroxyphenyl tert-butylaminomethyl-ketone hydrochloride in 200 ml of N,N-dimethylformamide, after which 50 ml of the solvent was distilled from the reaction mixture under reduced pressure. Under an atmosphere of nitrogen, 7.8 grams of isovaleryl chloride were then added dropwise at 20-25°C, and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue dissolved in a mixture of 500 ml water, 3 ml of a 35% aqueous sodium hydroxide solution and 200 ml of diethyl ether. The ether layer was separated and discarded. The aqueous layer was acidified with acetic acid and the precipitate formed was collected on a filter paper and washed with water and n-hexane. 12 grams of 3-hydroxy-4-(sovaleryloxy)phenyl tert-butylaminomethyl ketone were thus produced. This base was stirred in 500 ml of anhydrous ethyl alcohol, and while stirring, 6b% methanesulfonic acid was added in an amount (5 ml) until a sustained acidic reaction was produced in the suspension, which was then stirred until a heavy precipitate. This was collected on a filter and washed with ethyl alcohol and diethyl ether. 8.1 grams of 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl-ketone-methanesulfonate were thus prepared as a white, crystalline solid, melting point 242-245°C (decomposition) (uncorrected). B. In a catalytic hydrogenation of 8.1 grams of 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl-ketone-methanesulfonate suspended in 250 ml of 95% ethyl alcohol in the presence of 3.0 grams of 10% palladium-on-charcoal catalyst 4.8 grams of 3-hydroxy-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate were prepared as a white, crystalline solid, melting point 148-150°C (uncorrected). The solubility of this salt in water at 25°C was at least 5%. Example 7 A mixture of 13 grams of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, 25 ml of o-toluyl chloride and 35 ml of trifluoroacetic acid was heated for 30 minutes on a steam bath. The reaction mixture was concentrated under reduced pressure and the resulting residue crystallized. The collected solid, which was impure 3,4-bis(o-toluyloxy)phenyl tert-butylaminomethyl ketone trifluoroacetate, was stirred in anhydrous ethyl ether and the suspension made basic by treatment with ammonium hydroxide. The ether layer was separated and washed first with dilute aqueous sodium hydroxide solution and then with water. The ether solution was filtered, and the filtrate stirred with 4.5 grams of methanesulfonic acid in 50 ml of isopropyl alcohol. The solid crystalline substance was collected on a filter and recrystallized from 100 ml of isopropyl alcohol and dried at 70°C. 15.8 grams of 3,4-bis(o-toluyl-oxy)phenyl tert-butylaminomethyl-ketone-methanesulfonate were thus obtained as a white, crystalline solid with a melting point of 134-137°C (decomposition) (uncorrected). When this methanesulfonate (15.5 grams) was catalytically hydrogenated using a method as described above in Example 5B, 12.8 grams of 3,4-bis(o-toluyloxy)-alpha-tert-butylaminomethyl)benzyl alcohol was produced as a white, crystalline solid with a melting point of 151-153°C (uncorrected). Example 8: 5.3 grams of 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate in 25 ml of glacial acetic acid was added to 2.1 ml of acetyl chloride, and the resulting mixture was shaken until got a complete resolution. This solution was concentrated to a solid, which was then recrystallized from isopropyl acetate. The methanesulfonate of 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl acetate was thus obtained as a white, crystalline solid, weighing 1.2 grams and melting at 153-155°C (uncorrected). ;Example 9 ;A. A mixture of 130 grams of 3-chloromethyl-4-hydroxyacetophenone, 650 ml of acetic anhydride and 130 ml of acetyl chloride was refluxed for 3 hours, after which the reaction mixture was concentrated and fractionally distilled under reduced pressure. The fraction distilled at 135-148°C at a pressure of 0.6 mm Hg then solidified. This product, weighing 94.9 grams, was 3-chloromethyl-4-acetoxyacetophenone. B. 200 grams of pivalic acid was added to 17.1 grams of sodium methoxide in methyl alcohol, and the resulting mixture was purified from methyl alcohol under reduced pressure. The solid residue was added to 71.4 grams of 3-chloromethyl-4-acetoxyacetophenone, and the mixture was heated while stirring at the same time as 110 ml of substance was distilled off. The reaction mixture was concentrated under reduced pressure and then cooled, whereupon a mixture of water and diethyl ether was added. All but 10 grams of gummy material dissolved. The ether layer was separated and washed three times with a cold aqueous sodium bicarbonate solution and then once with water. The ether solution was then dried over anhydrous magnesium sulfate, concentrated and distilled under reduced pressure. After a precursor fraction of 4.1 grams was discarded, 44.9 grams of a fraction was obtained which distilled at 158-168°C at a pressure of 0.1 mm Hg. This product was a somewhat impure 3-(pivalyloxymethyl)-4-(pivalyloxy)-acetophenone. C. 43 grams of 3-(pivalyloxymethylJ-4-(pivalyloxy)-acetophenone in 225 ml of chloroform was gradually added over 30 minutes to a solution of bromine in 40 ml of chloroform. During the addition, the temperature of the reaction mixture was kept at 10°C at addition of solid carbon dioxide. The chloroform solution of the reaction mixture was washed twice with water, twice with dilute aqueous sodium bicarbonate solution and finally once with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue, which was 21.5 grams of impure 3- (pivalyloxy-methyl)-4-(pivalyloxy-alpha-bromo-acetophenone), a solution of 9.45 ml of tert-butylamine and 13.1 grams of triethylamine in 225 ml of dimethylsulfoxide was added while stirring. During this addition, the reaction mixture was stirred at 10 -15°C and then stirred at 20°C for half an hour. The mixture was then poured into water and extracted several times with diethyl ether. The combined ether extracts were dried and concentrated. The gummy residue obtained uum, which was impure 3-(pivalyloxymethyl)-4-(pivalyloxyJphenyl-tert-butylaminomethyl-ketone), was treated with 8.5 grams of methanesulfonic acid whereby 19.5 grams of 3-(pivalyloxymethyl)-4-(pivalyloxy)phenyl- tert-butylamine pmethyl ketone methanesulfonate as a white crystalline solid melting at 164-173°C (uncorrected). D. A solution of 2.5 grams of 3-(pivalyloxymethyl)-4-(pivalyloxy)phenyl-tert-butylaminomethyl-ketone-methanesulfonate in 30 ml of methyl alcohol at -10°C was added portionwise 0.3 grams of sodium borohydride. The reaction mixture was then stirred for 10 minutes at -10°C and glacial acetic acid was then added until the mixture was neutral. ;. The mixture was concentrated on a rotary evaporator and the resulting residue was dissolved in 25 ml of cold water. The solution was made weakly basic by adding ammonium hydroxide and extracted three times with diethyl ether. The ether extracts were combined, dried over anhydrous calcium sulfate and concentrated under reduced pressure. The resulting gummy residue was dissolved in 20 ml of isopropyl acetate, and to this solution was added 0.35 ml of methanesulfonic acid and a volume of diethyl ether. The white precipitate formed was collected on a filter. This product 1.4 grams, melting point 200-203°C (uncorrected)] was recrystallized from isopropyl acetate, whereby 1.3 grams of 3-(pivalyloxymethylJ-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol-methane was obtained - ;sulfonate as a white, crystalline solid, melting point 200-203°C (uncorrected). ;Example 10 ;A. 180 grams of isovaleric acid was added to 19 grams of sodium methoxide in methyl alcohol. The methyl alcohol and methyl isovalerate were removed from the resulting reaction mixture by evaporation under reduced pressure on a steam bath. The obtained residue was added to 68.0 grams of 3-chloromethyl-4-acetoxyacetophenone, and the mixture was heated while the acetic acid formed was distilled off. The reaction mixture was concentrated on a rotary evaporator under reduced pressure. The resulting residue was stirred in diethyl ether, and the ether layer was separated and washed three times with dilute aqueous sodium bicarbonate solution and once with water, dried over magnesium sulfate and concentrated under reduced t jerk. The residue was distilled under distilled pressure, whereby 62 grams of 3-(isovaleryloxymethyl)-4-(isovaleryloxy)acetophenone were obtained as a fraction which distilled at 158-lb8°C at a Hg pressure of 0.08-0.1 etc. B. 33.4 grams of 3-(isovaleryloxymethyl)-4-(isovaleryloxy)acetophenone in 200 ml of chloroform was added dropwise with stirring to 5.2 ml of bromine at 0°C. The reaction mixture was washed with dilute aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The obtained residue containing J>-(isovaleryloxymethyl)-4-(isovaleryloxy)-alpha-bromoacetophenone was added, while cooling, to a solution of 7.3 grams of tert-butylamine and 10.1 grams of triethylamine in 150 ml of dimethylsulfoxide. This reaction mixture was stirred at 15°C for 30 minutes and then poured into ice water and extracted with diethyl ether. The ether extract was washed once with water, dried over anhydrous calcium sulfate and concentrated. The residue, which was an impure 3-(isovaleryloxymethyl)-4-(isovaleryloxy)phenyl-tert-butylaminomethyl-ketone, was reacted with methanesulfonic acid to give 5.0 grams of 3-(isovaleryloxymethyl)-4-(isovaleryloxy)phenyl-tert-butylaminomethyl-ketone. methanesulfonate as a crystalline substance, melting point 190-215°C (uncorrected). ;C. A solution of 5.0 grams of J>-(isovaleryloxymethyl)-4-(isovaleryloxy)phenyl-tert-butylaminomethyl-ketone methanesulfonate in 60 ml methyl alcohol was added portionwise at -10°C to 0.6 grams of sodium borohydride. The reaction mixture was stirred for 15 minutes at -5 to -10°C and was then neutralized by adding acetic acid, then concentrated on a rotary evaporator. The residue obtained was dissolved in 50 ml of cold water, and the solution was then made slightly basic by adding ammonium hydroxide and the whole was extracted three times with diethyl ether. The ether extracts were combined, dried over anhydrous calcium sulfate and concentrated. The resulting gummy residue, which was impure 3-(isovaleryloxy methyl )-4-(isovaleryloxy)-alpha-(tert-butylaminomethyljbenzyl alcohol) was converted to 3.5 grams of 3-(isovaleryloxymethyl)-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white, crystalline substance, melting point 125-126°C (uncorrected). ;The following compounds are further examples of ;esters with formula I which were prepared by methods according to the present invention as described and illustrated above: ;Example 11 ;3,4-bis(2-methylbutanoyloxy)-alpha-(tert-butylaminomethyl) ) benzyl alcohol hydrochloride, melting point 163-165°C (uncorrected). Example 12: 3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride, melting point 249°C (uncorrected). Example 13 3,4-bis(3-methylpentanoyloxy)-alpha-(tert-butylaminomethyl) benzyl alcohol hydrochloride, melting point 139-140°C (uncorrected). Example 14: 3,4-bis(2,2-dimethylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, melting point 107-109°C (uncorrected). Example 15: 3,4-bis(1-methylcyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, melting point 210-212°C (uncorrected). ;Example 16 ;3,4-bis(cyclohexanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, melting point 212-213°C (uncorrected;. Example 17 ;3,4-bis(benzoyloxy)-alpha-(tert -butylaminomethyl)-benzyl alcohol hydrochloride, melting point 2l4-216°C (uncorrected). ;v ;Example IM ;3,4-bis(p-anisoyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride, melting point 165° C (uncorrected). ;Example 19 ;3-hydroxy-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol methanesulfonate, melting point 175-177°C (uncorrected). Example 20. ;3_hydroxy-4-( 3,3-dimethylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol-methanesulfonate, melting point 176-178°C (uncorrected). ;Example 21 ;3-hydroxy-4-(p-toluyloxy)-alpha-(tert- butylaminomethyl)-benzyl alcohol methanesulfonate, melting point 203-205°C (uncorrected). Example 22; 3-(isovaleryloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, melting point 202-204°C ( uncorrected).Example 23; 3,4-bis(m-toluyloxy)-alpha-(tert-butylami nomethyl)-benzyl alcohol-methanesulfonate, melting point 135°C (uncorrected). Example 24: 3,4-bis(2,4-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, melting point 170-172°C (uncorrected). Example 25 3,4-bis(2,5-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, melting point 156-158°C (uncorrected). Example 26 3,4-bis(3,4-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, melting point 212°C (uncorrected). Example 27 3,4-bis(3,5-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, melting point 190-193°C (uncorrected). ;Example 2b1 ;3,4-bis(p-tolylacetoxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride, melting point 115-117°C (uncorrected). Example 29 3,4-bis(p-methoxyphenylacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, melting point 124-127°C (uncorrected). ;Example =3P ;3~hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl) benzyl alcohol hydrochloride, melting point 211-213°C (decomposition) ;(uncorrected). Example 31 3-acetoxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl) benzyl alcohol methanesulfonate, melting point 171-173°C (uncorrected). Example 32: 3-(p-toluyloxy)-4-benzoyloxy-alpha-(tert-butylaminomethyl)benzyl alcohol-trifluoroacetate, melting point 162-166°C, and the methanesulfonate, melting point 154-156°C (uncorrected). Example 33 3-benzoyloxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, melting point 183-185°C (uncorrected). Esters of formula I produced according to the present invention have been shown to have very useful sympathomimetric activity of long duration, and the preferred compounds are further characterized by a desirable low cardiovascular stimulating effect, as can be seen from the results below. The compounds referred to in connection with these results were the following: I: 3,4-dihydroxy-alpha-(tert-butylaminomethyl)-benzyl alcohol, ;II: 3,4-dihydroxy-alpha-(isopropylaminomethyl)-benzyl alcohol, ; III: 3-hydroxymethyl-4-hydroxy-alpha-(tert-butylaminomethyl)benzyl alcohol, ;IV: 3,4-dihydroxy-alpha-[1-(isopropylamino;-propyl]-benzyl alcohol, ;V: 3,4-dihydroxy -alpha-(methylaminomethyl)benzyl alcohol, ;VI: 3,4-diacetoxy-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride, ;VII: 3,4-diacetoxy-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride, ;VIII: 3, 4-dipropionoxy-alpha-(isopropylaminomethyl)-benzyl alcohol hydrochloride. ;The bronchodilator activity was measured in anesthetized dogs (test method I) and in vitro in a guinea pig lung (test method II), using the following pharmacological methods: Experimental method I ;Dogs of both sexes weighing from 9-lb kg were anesthetized with pentobarbital sodium (30 mg per kg).Each animal with the thorax opened at the midsternum was kept under artificial ve ntillation using a constant volume pump (250 ml per strokes, 10-12; strokes per minute) connected to the tracheal cannula. The air flow was controlled using a glass or plastic valve that closed and opened respectively when the air flowed to and from the tracheal cannula. The bronchoconstriction and/or bronchodilation was measured by changes in the air pressure so that this could be measured in a small gauge placed in a side arm of the cannula. ;Control bronchoconstrictions were induced by an intravenous injection of carbachol (choline chloride carbamate) in doses varying from 4 to 6 micrograms per kg, or with the help of histamine diphosphate in doses varying from 35 to 45 micrograms per kg. In most of the test animals, the above-mentioned doses produced a 100 to 200% increase in the normal airway pressure. Solutions of the test compounds were prepared in distilled water or in a saline solution (for infusion). An addition of a stabilizing agent, namely ethylenediaminetetraacetic acid, to the solutions of compounds I, II, IV and V was necessary to stabilize them. These solutions were then tested for bronchodilator activity in three ways, namely (1) by mixing a measured dose of the test compound with a constant dose of carbachol or histamine in an injection needle and injecting the mixture into the femoral vein, (2) by first producing a bronchoconstriction and then injecting the test compound during the maximal constriction, and (3) by first injecting the test compound and then injecting carbachol or histamine over a period of from 1 to 10 minutes. The injections were repeated every 20 to 30 minutes. The bronchodilator value was obtained by measuring the areas between the baseline and the baseline on the printer associated with said meter (in the first five minute period) of the carbachol or histamine controls as well as for the mixtures using a planimeter. Any reduced area was expressed as a percentage of bronchodilation in relation to the control area for the carbachol or histamine constriction. The mean bronchodilation (reductions in constriction) was plotted against the doses administered, after which the mean effective dose (ED^Q) was calculated in micrograms/kg from the response curves for each individual dose. Blood pressure was measured in the femoral artery using an artery gauge connected to a printer. In the intratracheal studies, an animal of the same type as described above was used. A modified "aerosol releaser" was placed between the valve and the tracheal cannula, and the aerosol preparation was introduced directly into the tracheal passage as the air passed inwards. Five minutes later, the degree and duration of the bronchodilator effect was measured and then repeated at intervals of 30 to 60 minutes until a complete recovery could be observed. In the intraduodenal studies, the same dog was used as was used for the bronchodilator measurements, and the duodenal segment of the small intestine was made accessible via a small incision in the abdomen. The sample solution was injected into the duodenum using a fine needle. Five minutes later, the degree and duration of bronchodilation was measured by injecting a control dose of carbachol or histamine and then repeated at intervals of 30 to 60 minutes until a complete recovery or a near recovery could be observed. In some dogs that showed very rapid recovery, a reference substance was also tried approx. 1.5-2 hours after the first injection. Representative results obtained with anesthetized dogs are given below. ;;Bronchodilator Test Method II ;In this method, the bronchodilator activity was determined in vitro by testing the effect of varying doses of the test compounds on guinea pig bronchioles constricted by means of carbachol, using the technique described by Sollman and von Oettingen, Proe. Soc. Exp. Biol. Med., 25,692 (192b) and modified by Tainter, Pedden and James, J. Pharm. Exp. Ter., 51, 371 (193H) and by Luduena, von Euler, Tullar and Lands, Arch. internal. Pharmacol., 111, 392 (1957). ;Representative results obtained in this test are indicated in the following table. ;Cardiovascular studies ;1) The effect of a rapid intravenous injection on heart rate was measured in anesthetized dogs during normal respiration. They also tried a couple of dogs with open chests. An increase in heart rate was measured using an electrocardiograph attached to the dog. Measurements were taken every half to full minute for the first 10 minutes and then every two to five minutes until total recovery. Several doses and more than one compound were tested alternately in the same dog. 2) Doses varying from 0.125-0.5 y/kg/minute were infused over 3<*>0 minutes using an infusion pump, and change with regard until heart rate was measured as described above.

The heart rate was also measured for a further 20-30 minutes after the infusion had stopped. Blood pressure was measured at the same time. Tests carried out in this way showed that esters of formula I had far less cardiovascular stimulating effect than the corresponding unesterified phenols.

Claims (5)

1. Analogy method for the preparation of therapeutically active compounds which, in the form of the free base, have the formula: where Y is an alkanoyl or alkanoylmethyl group with 1-8 carbon atoms, 1-methyl-cyclopropanecarbonyl, cyclohexanecarbonyl or a benzoyl or benzylcarbonyl group, which may be substituted with 1-3 alkyl or alkoxy groups with 1-4 carbon atoms, and Y1 is -OH or Y-Where Y has the above meaning, and, where at least one of Y and Y"*" contains at least 4 carbon atoms, and 2 Y is hydrogen or acetyl, as well as acid addition salts thereof, characterized in that a compound with the formula: where Y and Y^ have the meaning given above, is reduced, and, if desired, the product obtained is acylated and/or converted into acid addition salts thereof. 2.. Analogous process for the production of 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol and acid addition salts thereof, characterized in that 3,4-bis(p-toluyloxy)-phenyl-tert-butylaminomethyl-ketone is reduced, and, if desired, converted into acid addition salts thereof. 3. Analogous process for the production of 3,4-bis(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol and acid addition salts thereof, characterized in that 3,4-bis(isovaleryloxy)-phenyl-tert-butylaminomethyl-ketone is reduced, and, if desired, converted to acid addition salts thereof. 4. Analogous process for the production of 3,4-bis(3,3-dimethyl-butanoyloxy)-alpha-(tert-butylaminomethyl^benzyl alcohol and acid addition salts thereof, characterized in that 3,4-bis(3,3-dimethylbutanoyloxy)phenyl- tert-butylaminomethyl ketone is reduced and, if desired, converted to acid addition salts thereof. 5. Analogous process for the production of 3_(pivalyloxymethyl)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol and acid addition salts thereof, characterized in that 3-(pivalyloxymethyl)-4-(pivalyloxy)phenyl-tert-butylaminomethyl-ketone is reduced, and, if desired, converted into acid addition salts thereof.