NO169835B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CATECHOL CARBOXYL DERIVATIVES - Google Patents

Abstract

Catechol carboxyl derivatives of formula. wherein R 2 is -C (O) OR, acetyl, H, -OH or alkanoyloxy, R 1 -C (O) OR, -OH, H or alkanoyloxy, wherein R is H, lower alkyl or - (CH) - N- (lower alkyl), R 1 H, lower alkyl or amino, R 2 H, lower alkyl, halogen or amino, A wherein R 1 is H or acyl, R 2 is H, halogen, lower alkyl, aryl or cycloalkyl, and R 7 is independently H, lower alkyl or halogen, or A is. wherein R 1 is H or acyl, R 9 is H, lower alkyl, R 2 is H, lower alkyl or halogen, R 2 is H, lower alkyl, cycloalkyl or halogen, m is 0 or 1, n is an integer from-, provided that no more than one of R or R may be -C (O) OR, and when R is H, salts thereof with pharmaceutically acceptable bases, or when R is (CH) -N- (lower alkyl), salts thereof with pharmaceutically acceptable acids. The compounds of formula They are useful in the treatment of inflammatory disorders such as arthritis, inflammatory bowel disorders such as colitis, cardiovascular disorders such as myocardial ischemia, skin disorders such as psoriasis by topical administration, and bronchopulmonary disorders such as asthma.

Description

Process for the production of phenylamino-

ethanol derivatives with therapeutic effect, particularly with affinity to beta-adrenergic receptors.

The present invention relates to a method for the production of new 1-phenyl-2-aminoethanol derivatives which possess biological activity.

The method according to the invention provides compounds of the general formula:

and physiologically acceptable acid addition salts thereof, where: means hydrogen or a straight or branched alkyl radical with

1 to 3 carbon atoms,

1*2 means hydrogen or a benzyl group,

R means a hydrogen atom or a straight or branched alkyl group with 1 to 6 carbon atoms, which may be substituted with a hydroxy group, an indolyl group or a morpholine group, or represents a cycloalkyl group with 4-8 carbon atoms, a phenalkyl or phenoxyalkyl group, where the alkyl group contains from 1-6 carbon atoms and where the phenyl or phenoxy group may be substituted with one or more hydroxy groups or one or more alkoxy groups sqm contains from 1 -

3 carbon atoms,

X means a straight or branched hydroxyalkyl group with 1-6

carbon atoms in the alkyl portion thereof, or a group of the formula

-CONI^, and the method is characterized by the carbonyl group in a ketone of the general formula: where R is hydrogen or an ether or ester-forming protecting group, and where X, R-^ and R^ have the above meanings are reduced to a -CHOH group, to give a compound of the formula: before or after the removal of a protecting group R, or for the preparation of compounds of the general formula I where X means the carbonyl group is reduced in a ketone of the general formula where R4 is a straight or branched alkyl group with 1-6 carbon atoms and R1# R2 and R3 have the same meaning as above, and before or after reduction of the carbonyl group, the -COOR^ group is converted by reaction with NH^ to a -CONH2 group or by reduction to a -CH2OH group or by reaction with methylmagnesium halide to a group

and if removal of a benzyl group or benzyl groups attached to the amino nitrogen is desired or if conversion of the compounds in which R_ and/or R3 is hydrogen or both are benzyl is desired, by reductive alkylation with carbonyl compounds to compounds where R2 is hydrogen and R3 has another of the meanings given above, and the resulting base is converted if desired into a physiologically acceptable acid addition salt or released as such.

As the compounds of the general formula I possess at least one asymmetric carbon atom, the invention also encompasses the preparation of all possible optically active forms and racemic mixtures of the compounds. The racemic mixtures can be separated using usual methods, e.g. by salt formation with an optically active acid followed by fractional crystallization. The compounds where the side chain substituents are in the para-position to the phenolic hydroxyl group or in the para-position to the substituent X are preferable.

The compounds produced according to the invention possess either stimulating or blocking effects on beta-adrenergic receptors. Compounds which have a stimulating effect on beta-adrenergic receptors are usually used as bronchodilators. Known beta-adrenergic stimulants, e.g. However, isoprenaline, which is 3,4-dihydroxy-alpha-(isopropylaminomethyl)-benzyl alcohol also affects the heart and is a potent cardiac stimulator at effective bronchodilator dosage amounts. The compounds produced according to the present invention, which possess stimulating activity on beta-adrenergic receptors, have been shown to exert a more selective effect on the bronchial muscle so that a bronchodilation or expansion is possible without excessively strong cardiac stimulation. The compound alpha^-tert-butylaminomethyl-4-hydroxy-m-xylene-alpha 1,alpha 3-diol (AH 3365) is e.g. have been investigated in asthmatic patients and it was found that doses of 100 µg of this compound administered by aerosol are at least as rapid in onset and intensity of action as isoprenaline at the same dosage amounts, and it has a longer duration of action than isoprenaline. It also turned out that AH 3365 did not affect the pulse rate or the blood pressure at four times the effective doses, while isoprenaline had a marked effect on both measurements, as can be seen from the following table i. In contrast to isoprenaline, which is not very active when administered orally, AH 3365 has been shown to be an effective bronchodilator in humans after oral administration and again to reveal cardiovascular effects.

Among the other compounds produced according to the invention, which were found to possess beta-adrenergic stimulating activity, are those listed below: 4-hydroxy-alpha^isopropylaminoethyl-m-xylene-alpha a1, alpha<3- >diol (ex. 6). Alpha"*"-(cyclopentylaminomethyl)-4-hydroxy-m-xylene-alpha1,alpha3-diol (Ex. 22) .

4-Hydroxy-alpha1-(1-isopropylaminopropyl)-m-xylene-alpha<1>,alpha<3->diol (ex. 11).

4-hydroxy-alpha<1->,/(2-indol-3-yl-1-methylethyl)-amino/- methyl-m-xylene-alpha 1 ,alpha 3-diol (Ex. 24).

4-hydroxy-alpha1- \/_(1-methyl-2-phenoxyethyl)-amino/-

) 1 3 v methyl?-m-xylene-alpha ,alpha -di1 ol ( —(ex. 15).

4-hydroxy-alpha - V(p-methoxy-alpha-methylphenethyl)-

— ) 1 v 3 amino/-methyl?' -m-xylene-alpha ,a1 lf_a -diol (ex. 18).

4-hydroxy-alpha -/_(p-hydroxy-alpha-methyl-phenethyl-

— 13

amino)-methyl/-m-xylene-alpha ,alpha -diol (ex. 16).

4-Hydroxy-alpha1-^(1-methyl-2-morpholinoethyl)-amino/-

) 13* methylj-m-xylene-alpha ,alpha -diol (ex. 19).

These compounds were tested in anesthetized guinea pigs for the relief or reversal of bronchospasm produced by injection of acetylcholine, 5-hydroxytryptamine, bradykihin and histamine.

Other uses for the compounds prepared according to the invention which possess beta-adrenergic stimulating activity may include the treatment of glaucoma, glaucoma, and also the control of gastric acid secretion in the treatment of peptic ulceration. The cardiovascular side effects of known beta-adrenergic stimulants preclude their use in these cases.

The compounds produced according to the invention which possess blocking activities on beta-adrenergic receptors are useful for the treatment or prophylactic treatment of cardiovascular disorders, e.g. arrhythmia, coronary heart disease, angina pectoris and hypertension. Known beta-adrenergic blocking agents have undesirable side effects, e.g. 3,4-dichloro-alpha-(isopropylaminomethyl)-benzyl alcohol possesses potent sympathomimetic effects, and propranolol, 1-iso-propyl-amino-3-(1-naphthyloxy)-propan-2-ol affects the central nervous system . The compounds produced according to the invention are

however, free of these side effects.

The compound 5-(2-tert-butylamino-l-hydroxyethyl)-salicylamide (this compound is designated by the inventors with the code number A 3474 and in this connection reference should be made to the article "The pharmacology of 5-(2-t-butylamino-l -hydroxyethyl) salicyl amide (AG 3474), a beta-adrenoreceptor blocking agent", published in J.PHARM. PHARMAC. , 1969, 21_, 488-497, this article also shows how the compounds prepared according to the invention excel against known compounds), proved e.g. when examined in conscious dogs, to be somewhat less active than propranolol in reducing tachycardia produced by intravenous injection of isoprenaline. For example, at 0.5 mg/kg, the orally administered compound produced a 50-60% block of the isoprenaline response, while propranolol at the same dose produced a 70-80% block, and the duration of action of the two compounds was similar . In neuropharmacological experiments, however, the compound proved to be remarkably non-toxic, and free of central nervous system depressant activity, in mice it produced e.g. only negligible adverse effects at dosages up to 400 mg/kg when administered orally, while animals treated with propranolol showed signs of depression at dosages of 100 mg/kg and at 400 mg/kg the drug caused very severe and widespread central nervous system -depressions.

Among the other compounds which are produced according to the invention and which were found to possess beta-adrenergic blocking activity when examined with regard to inhibiting the tachycardia produced by intravenous injection of isoprenaline in anesthetized dogs, the following should be mentioned:

5-(1-Hydroxy-2-isopropylaminoethyl)-salicylamide

(ex. 1).

5-(1-Hydroxy-2-[(1-methyl-2-phenoxyethyl)-amino]-ethyl)-salicylamide (Ex. 26).

5-(1-Hydroxy-2-isopropylaminoethyl)-N-methyl-salicylamide (Ex. 5).

Alpha-benzyl-tert-butylaminomethyl)-4-hydroxy-m-13 xylene-alpha,alpha-diol (Ex. 8).

Particularly preferred compounds which are prepared according to the invention are those which are specifically mentioned above.

The compounds produced according to the invention can be compounded into preparations for use in medicine for humans and animals for therapeutic and prophylactic purposes. Generally, they will be used in the form of their physiologically acceptable salts. Preferred salts include the hydrochloride, sulfates, maleates, tartrates, citrates, etc.

The reduction of the compounds of the general formula

II

where X, R 1 , R 2 and R 3 have the meaning indicated above can be carried out with suitable hydrides, e.g. sodium borohydride. When R 2 and/or R 1 are benzyl, these can be removed by catalytic hydrogenolysis. Alternatively, the reduction of the carbonyl group and the removal of any N-benzyl groups can be carried out in one step using hydrogen and a noble metal catalyst. In certain reactions, it may be advantageous to protect the phenol group, e.g. as a benzyl ether or an acetate. The protecting group can be removed by

hydrogenolysis or hydrolysis to give the desired product. Compounds where R 2 and R 1 both mean hydrogen atoms can be prepared from the benzylamino compound by catalytic hydrogenation.

The dibenzyl compound or the primary amine can then, in a subsequent step, be reductively alkylated to compounds of the formula I with aldehydes or ketones in the presence of hydrogen and a noble metal catalyst.

The compounds of the formula III where there is an alkoxycarbonyl radical of the general formula -COOR4, in the X-position where R4 has the above meaning can be prepared by allowing the ketone of the formula II where there is a carbonyl group in the X-position to react with an alcohol of the general formula R^OH, in the presence of an acid catalyst, followed by catalytic hydrogenolysis to give the 1-phenyl-2-aminoethanol deriv. These compounds can then be converted into compounds where X means GONH2, CH2OH

or

as described above. The reduction of the group COOR4 to CH2OH can be carried out simultaneously with the reduction of the carbonyl group to

the ketone, if a reducing agent, such as lithium aluminum hydride, is used.

Specific methods for preparing compounds in which x is a hydroxymethyl radical include the following.

In the first of these methods, a compound of the general formula IV, or a salt thereof, is exposed.

(where and R^ have the above meaning and Ph is a phenyl radical)

IV

for catalytic hydrogenation, preferably using a palladium oxide on bitumen catalyst to give a compound of the general formula V

Alternatively, the ketone of formula IV can be reduced with sodium borohydride to give the compound of general formula VI. This alcohol VI can also be obtained by reduction of a compound of the formula III (COOR^ in the X-position) using lithium aluminum hydride to give a compound of the formula

To prepare the alcohol v, the compound VI is then subjected to catalytic hydrogenation to remove the N-benzyl group, to give a compound of the formula V.

The use of the alcohol VI in the hydrogenation instead of the ketone IV reduces to a minimum the side reaction where

The -CH2OH group is reduced to a -CH^ group.

The complete synthesis of the compounds assuming aryl ketones is shown in the following reaction scheme. The ketone of the general formula IV can also be prepared from the compound (VII, X = -CH2OH) below where the hydroxy groups can be protected by acetylation, by condensation with a amine of the general formula R^R^NH (where R 2 and R 3 have the meaning given above) and removal of the protecting groups when these are present.

Compounds of formula i where x is an amide group of the general formula -CONH2, which can be prepared by reacting the ketone II (COOR^ in the X-position where R^ has the above meaning) or the alcohol derived from it by reduction with NH^ followed by catalytic hydrogenolysis if necessary.

The ketone of the general formula II can be prepared by condensation of an amine R^NH.CI^Ph with a halogen derivative of the general formula VII

Example 1

Preparation of 5-(hydroxy-2-isopropylaminoethyl) salicylamide hydrochloride.

Produced from starting material:

a) 5-(N-benzyl-N-isopropylglycyl)-salicylic acid methyl ester hydrochloride.

7.3 g of N-benzylisopropylamine was added to a stirred solution of 7.5 g of 5-bromoacetylsalicylic acid methyl ester in 100 ml of methyl ethyl ketone. A colorless, crystalline precipitate could immediately be observed, but stirring and reflux treatment were continued for 2J5 hours. After standing for 2 days, the solvent was evaporated under reduced pressure and dry ether was added to the remaining oil. The resulting ethereal solution was treated with dry hydrogen chloride gas to give 6 g of the hydrochloride as an oily solid. Recrystallization from methanol/ethyl acetate gave 3.55 g of the hydrochloride as a colorless powder, m.p. 168-170°C.

b) 5-(N-benzyl-N-isopropylqlycyl)- salicylamide hydrochloride

A solution of 15 g of 5-(N-benzyl-N-isopropylglycyl)-salicylic acid methyl ester hydrochloride in 125 ml of methanol and 125 ml of 0.880 ammonia solution was allowed to stand in a stoppered flask. After 6 days, the solution was evaporated to dryness and the residue was extracted three times, each time with 150 ml of ether. The free base began to precipitate from the ethereal solution. Treatment of the mixture with hydrogen chloride gas gave a white oily material which on boiling with ethyl acetate gave 12.5 g of a white solid. Recrystallization from methanol gave 11.0 g of the amide hydrochloride as colorless crystals, m.p. 217-220°C, after drying at 70°C in vacuum to constant weight.

5-(1-hydroxy-2-isopropylaminoethyl)-salicylamide hydrochloride 4.15 g of 5-(N-benzyl-N-isopropylglycyl)-salicylamide hydrochloride in 250 ml of methanol was hydrogenated at room temperature and pressure in the presence of 1 g of a 10% palladium oxide -on-bone carbon catalyst. The uptake of hydrogen ceased after 40 minutes. The solution was filtered and evaporated to dryness. The residue was recrystallized from methanol/ethyl acetate to give 2.3 g of the product, m.p. 207-208°C.

Example 2

Preparation of 5-/2-(N-benzyl-N-isopropylamino)-1-hydroxyethyl/-

salicylamide

1.3 g of 5-(N-benzyl-N-isopropylglycyl)-salicylamide was dissolved in 50 ml of tetrahydrofuran, then added to a stirred solution of 1.0 g of lithium aluminum hydride in 2 50 ml of tetrahydrofuran and heated under reflux in 3 hours. After cooling, water was added to split the excess of the hydride and the mixture was acidified with dilute hydrochloric acid. The solution was evaporated almost to dryness and the pH was adjusted to 8-9. Extraction with ether and ethyl acetate gave 0.9 g of a pale yellow gummy substance.

Chromatography on silica gel and elution with cyclohexane-ethyl acetate (1:1) gave 0.31 g of a crystalline solid, m.p. 142.5 - 144.5. Recrystallization from ether/petrol gave pure 5-(2-N-benzyl-N-isopropylamino-1-hydroxyethyl)-salicylamide, m.p. 140 - 142°C.

Example 3

Preparation of 5-(2-tert.-butylamino-1-hydroxyethyl)-salicylamide hydrochloride

1.0 g of 5-(N-benzyl-N-tert-butylglycyl)-salicylamide hydrochloride, 0.2 g of 10% palladium oxide on bone charcoal catalyst, 20 ml of ethanol and 15 ml of water were shaken at room temperature in an atmosphere of hydrogen until the absorption of hydrogen ceased. The catalyst was filtered off and the solvent was removed by

distillation. The residue was recrystallized from methanol/isopropyl acetate to give 0.56 g of a pale red solid, m.p. 203 - 204

°C.

Example 4

Preparation of 4-[1-hydroxy-2-(isopropylamino)ethyl]-salicylamide

a) 4-(2-benzylisopropylamino-1-hydroxyethyl)-salicylamide

A solution of 3.55 g of 4-(2-benzylisopropylamino-1-hydroxyethyl)-salicylic acid methyl ester hydrochloride in hot water was basified with sodium bicarbonate solution and the resulting suspension was extracted with ethyl acetate. The ethyl acetate solution was dried and evaporated and the gummy residue dissolved in 50 ml of ethanol. To this solution was added 30 ml of a 0.880 ammonia solution and the resulting mixture was allowed to stand

at room temperature for 1 week. The solution was then evaporated to dryness, and the residue extracted with ether. The ether solution was evaporated to dryness, and a whitish solid residue was obtained which, after recrystallization from benzene, gave 1.53 g of the product, m.p. 155 - 156°C.

b) 4-[1-hydroxy-2-(isopropylamino)-ethyl]-salicylamide

A solution of 0.456 g of 4-(2-benzylisopropylamino-1-hydroxyethyl)-salicylamide in methanol was hydrogenated over 0.1 g of pre-reduced 10% palladium on carbon catalyst. The uptake of hydrogen was complete within 19 minutes. After filtering off the catalyst, the methanol solution was evaporated to dryness, and a glassy residue was obtained which was allowed to recrystallize from a mixture of ether and ethyl acetate. This gave 0.236 g of white prisms, m.p. 114 - 116°C. From analysis, infrared spectrum, and equivalent weight, the compound was found to contain 0.5 mol of ethyl acetate from the recrystallization.

The benzoate derivative (prepared from a solution of the base in tetrahydrofuran and benzoic acid in ether) crystallized from isopropanol in small white prisms, m.p. 146 - 152°C.

Example 5

Preparation of 5-[1-hydroxy-2-(isopropylamino)-butyl]-salicylamide hydrochloride

Produced from starting material:

5-(alpha-isopropylamino)-butyryl/-salicylamide hydrochloride

A solution of 3.0 g of 5-/(alpha-isopropylamino)-butyryl/-salicylic acid methyl ester hydrochloride in 50 ml of ethanol and 0.880 ammonia was allowed to stand for 7 days at room temperature in a stoppered flask. The solution was evaporated to a small mass and the yellowish solid was filtered off. This was very insoluble in ether. The hydrochloride was prepared by dissolving the amide in ethanol and acidifying with dry hydrogen chloride gas to pH 4 - 6. The solvent was evaporated and the almost white solid residue was recrystallized from ethanol to give 2 g of a white solid, m.p. 300°C.

5-[l-Hydroxy-2-(isopropylamino)-butyl]-salicylamide hydrochloride

1.5 g of 5-(alpha-isopropylamino)-butyryl/-salicylamide hydrochloride in 175 ml of methanol was hydrogenated at room temperature and pressure in the presence of 10% palladium oxide on carbon catalyst for 10 hours. The solution was filtered and evaporated to dryness. The white solid residue was recrystallized from methanol/ethyl acetate as pale red prisms containing 0.5 mol of ethyl acetate from the recrystallization. The material was further recrystallized from methanol/ether and 1.0 g of pale red micro-crystals were obtained which did not contain any solvent from the recrystallization, m.p. 220 - 221°C.

Example 6

Preparation of 4-hydroxy-alpha^-isopropylaminomethyl-m-xylene-alpha a1, alpha3- diol

a) Alpha^- benzylisopropylaminomethyl- 4- hydroxy- m- xylene- alpha1, alpha3- diol

22.0 g of 5-(N-benzyl-N-benzyl-N-isopropylglycyl)-salicylic acid methyl ester hydrochloride was basified with aqueous sodium bicarbonate solution and extracted into ether. After drying over sodium sulfate, the solution was evaporated to dryness and the residue was dissolved in 150 ml of tetrahydrofuran. This solution was added dropwise to 5 g of lithium aluminum hydride in 300 ml of tetrahydrofuran. An insoluble complex was formed. The mixture was refluxed for 7 hours under nitrogen, cooled, treated with 10 ml of water and filtered. The solid together with the residue from the evaporation of the filtrate was dissolved in dilute hydrochloric acid, and this solution was made basic with aqueous sodium bicarbonate solution, and extracted continuously with ether to give the free base as a gummy substance. Crystallization from ether/petroleum gave alpha-benzylisopropyl-amino-methyl-4-hydroxy-m-xylene-alpha1,alpha3-diol as white crystals, m.p. 115 - 116°C.

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b) 4-hydroxy-alpha-isopropylaminomethyl-m-xylene-alpha, alpha-diol

5.4 g of alpha^-benzylisopropylaminomethyl-4-hydroxy-m-xylene-alpha 1 ,alpha 3-diol in 100 ml of ethanol and 10 ml of water was hydrogenated at room temperature and pressure in the presence of 1.2 g of a 10% palladium oxide on charcoal catalyst, until hydrogen uptake became markedly slower. The solution was filtered and evaporated to dryness. The oily residue solidified by allowing it to stand in 25 ml of ethyl acetate and 3.55 g of the crystalline hydroxydiol was obtained, m.p. 139 - 140°C. Purification by precipitation from a solution of tetrahydrofuran with ether raised the melting point to 143 - 145°C.

Example 7

Preparation of starting material: 4/1 -Hydroxy-2-(isopropylamino)-ethyl/-salicylic acid methyl ester, hydrochloride

a) 4-[2-benzylisopropylamino-1-hydroxyethyl]-salicylic acid methyl ester, hydrochloride

2.7 g of 4-(bromoacetyl)-salicylic acid methyl ester was dissolved in 7.5 ml of dry tetrahydrofuran and added at room temperature to a solution of 2.94 g of N-benzylisopropylamine in 7.5 ml of dry tetrahydrofuran. The resulting mixture was allowed to stand for 4 hours. After this time, the crystals of N-benzylisopropylamine hydrobromide were filtered off, and the filtrate was treated with a solution of 0.6 g of sodium borohydride in 15 ml of 90% ethanol. The resulting mixture was allowed to stand at room temperature for 3 days. The mixture was then evaporated to dryness, the residue was partitioned between ether and water, and the ether solution was dried and evaporated. The liquid residue was dissolved in 60 ml of dry ether/ethyl acetate (1:1). Stirring with a glass rod gave 2.4 g of a white solid, m.p. 150 - 160°C. Recrystallization from ethyl acetate/methanol gave 1.615 g of the product f m.p. 174 - 175°C. b) 4/1-hydroxy-2-(isopropylamino)-ethyl/-salicylic acid methyl ester,

hydrochloride

A solution of 1.0 g of 4-[2-(N-benzyl-N-isopropyl)-amino-1-hydroxyethyl]-salicylic acid methyl ester, hydrochloride in 50

ml of ethanol was hydrogenated over 0.2 g of pre-reduced 10% palladium oxide on bone charcoal catalyst. The volume of hydrogen absorbed in 10 minutes was 60 ml. The catalyst was then

filtered off, and the filtrate evaporated to dryness. Trituration of the residue with ethyl acetate gave 0.68 g of a white solid, m.p.

166 - 168°C. Recrystallization from ethyl methyl ketone gave 0.31 g of the product as large, white crystals, m.p. 171.5 - 173°C.

Example 8

Preparation of alpha^-tert.-butylaminomethyl-4-hydroxy-m-xylene-alpha1, alpha3-diol

a) Alpha1- benzyl- tert.- butylaminomethyl- 4- hydroxy- m- xylene-alpha1, alpha3- diol

3.0 g of 5-(N-benzyl-N-tert-butyl-glycyl)-salicylic acid, methyl ester, hydrochloride in 40 ml of water was basified with sodium bicarbonate solution and extracted into ether. The ether solution was dried over MgSO 4 and evaporated, and the basic residue in 20 ml of dry tetrahydrofuran was added with stirring to 1.0 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran, over 5 minutes. The slightly gelatinous precipitate that formed was stirred and refluxed for 8 hours, after which 7 ml of water was carefully added and the solvents were removed under reduced pressure.

The residue was acidified with dilute hydrochloric acid and pH brought to 8 with sodium hydroxide and sodium bicarbonate. The mixture was filtered and the filtrate and orange solid were extracted separately with chloroform. The combined dried chloroform solutions were evaporated to give 2.2 g of the crude basic triol as an orange solid by trituration with ether. Part of the material was recrystallized from ether/petrol (cf.

40 - 60°C) to give a white solid, m.p. 109 - 111°C.

In an alternative procedure, sodium borohydride was used as the reducing agent, as follows: 36 g of 2-(benzyl-tert-butylamino)-4'-hydroxy-3'-hydroxymethylacetophenone, hydrochloride was shaken with 100 ml of a 10% 's sodium carbonate solution and 100 ml of ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo.

The remaining gummy substance was dissolved in 360 ml of ethanol and cooled to 15°C in an ice/water bath. 8 g of sodium borohydride was then added in portions over 30 minutes, the temperature being maintained at 15 - 20°c. After a time period of 30 minutes at 20°C, the solution was stirred at room temperature for 2 hours. The solution was cooled again in ice, and 250 ml of 2N sulfuric acid was slowly added, then the solution was evaporated in vacuo until the ethanol had been removed. The clear aqueous solution was then treated with 250 ml of a 10% sodium carbonate solution and the precipitated oil was extracted into ethyl acetate. The ethyl acetate layer was washed with sodium carbonate solution, then with water and was dried over anhydrous sodium sulfate and evaporated in vacuo to a small volume. Petroleum ether (bp. 40 - 60°C) was added, and after standing overnight a white solid was obtained. This was filtered off to give 23 g of the product, m.p. 110 - 114

°C.

1 13

b) Alpha-tert.-butylaminomethyl-4-hydroxy-m-xylene-alpha, alpha-diol

0.8 g of alpha^-benzene-tert-butylaminomethyl-4-hydroxy-m-xylene-alpha 1 ,alpha 3-diol in 20 ml of ethanol and 2 ml of water was shaken with hydrogen in the presence of 0.50 g of reduced 10% palladium on charcoal catalyst. After the absorption of hydrogen was complete, the solution was filtered and evaporated under reduced pressure to give 0.4 g of the base as a colorless oil, which gave a white solid, m.p. 144 - 145°C after trituration with ether/cyclohexane. Recrystallization from ethyl acetate-cyclohexane gave a white solid, m.p. 147 - 149°C.

An alternative method for producing the compound according to example 8 shall be described in the following: Produced from starting material:

a) Preparation of 3-(chloromethyl)-4-hydroxyacetophenone

500 g of p-hydroxy-acetophenone, 1 liter of formaldehyde solution (40% weight/volume) and 2 liters of concentrated hydrochloric acid were stirred and cooled to 20°C, while 320 g of hydrogen chloride gas was introduced into the suspension while the temperature was maintained at 20°C. After stirring for a further 2 hours, the mixture was allowed to stand for 18 hours. 5 liters of distilled water were then added and the solid was removed by filtration, washed with hot water and hot benzene to give 480 g of a pale red solid, m.p. 164°W. (Ref. Gass. Chim., Acta., 81, 773 - 781. Chem. Ab., 46_, 8048 (1952) mp. 160 C).

Another method for the production of this compound, avoiding gaseous hydrogen chloride, was carried out as follows:

3- chloromethyl- 4- hydroxyacetophenone

10 kg of p-hydroxy-acetophenone was added to a stirred solution of 6.6 liters of a 40% formaldehyde solution (w/v) and 45 liters of concentrated hydrochloric acid (35 - 38% w/v), which had previously been heated to 45 - 50°C. The temperature was kept at 50°C for 2 hours, after which 45 liters of water were added. The red solid formed was washed with 20 liters of hot water and dried at 60°C in air to give 12 kg of the product as a red solid, m.p. 164°C.

b) Preparation of 3-(hydroxymethyl)-4-hydroxyacetophenone diacetate

470 g of 3-(chloromethyl)-4-hydroxyacetophenone, 235 g of anhydrous sodium acetate, 1100 ml of glacial acetic acid and 550 ml of acetic anhydride were stirred and refluxed for 2 hours. The acetic acid was then distilled off in a vacuum, and the residue entirely in water. The oil which separated was extracted into chloroform and the chloroform evaporated in vacuo. The residue was distilled off to give 550 g of a colorless oil, b.p. 150 - 160°C/0.3 mm Hg. n<20> = 1.517. This oil solidified and a white solid was obtained, m.p. 50°C.

c) Preparation of 3-(hydroxymethyl)-4-hydroxybromoacetophenone diacetate

555 g of 3-(hydroxymethyl)-4-hydroxyacetophenone diacetate and 2 liters of chloroform were stirred and cooled to 20°C. A solution of 118 ml of bromine dissolved in 400 ml of chloroform was added over the course of 1 hour, the temperature being maintained at 20°C. After the addition, 3 liters of ice/water were added and the chloroform layer was separated, washed with water and dried over sodium sulfate. The chloroform was evaporated in vacuo and 730 g of a pale yellow oil was obtained.

d) Preparation of 2-(N-benzyl-N-tertiary butylamino)-4'-hydroxy-3'-hydroxymethylacetophenone hydrochloride

213 g of 3-(hydroxymethyl)-4-hydroxybromoacetophenone, 220 g of benzyl tertiary butylamine and 90 ml of benzene were stirred and heated at reflux for 18 hours. After cooling, the benzyl tertiary butylamine hydrobromide was removed by filtration and washed with benzene. The benzene solution was extracted with three 200 ml portions of 2N hydrochloric acid solution. The aqueous, acidic dissolve- . ning was then extracted with 500 ml of ether, concentrated hydrochloric acid (65 ml) was added and the solution was allowed to stand for 18 hours. The precipitate was removed by filtration and washed with water. Recrystallization from water gave 90 g of the product as a white solid, m.p. 174°C.

Preparation of alpha'-tertiary butylaminomethyl-4-hydroxy-m-xylene-alpha', alpha3-diol

120 g of 2-(N-benzyl-N-tert-butylamino)-4<1->hydroxy-3<1->hydroxymethylacetophenone hydrochloride was shaken with 500 ml of 10% sodium carbonate solution and 500 ml of ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated. The remaining gummy substance was dissolved in 500 ml of ethanol and hydrogenated with 10 g of 10% palladium oxide-on-charcoal catalyst at 60°C and at atmospheric pressure. 2 moles of hydrogen were absorbed in 3% hours. The catalyst was removed by filtration and the ethanol distilled in vacuo. The remaining gummy substance was refluxed with 500 ml of ethyl acetate for a few minutes and then allowed to cool. The white solid was removed by filtration and recrystallized from ethanol/ethyl acetate to give 30 g of the diol, m.p. 151°C.

Example 9

Preparation of 4-hydroxy-alpha1-/(methylamino)-methyl/-m-xylene-alpha1, alpha3-diol a) Alpha a^-^benzylmethylamino)-methyl7-4-hydroxy-m-xylene-alpha1,

alpha3-diol

21.3 g of 5-(N-benzyl-N-methylglycyl)-salicylic acid ethyl ester was dissolved in 140 ml of tetrahydrofuran. This solution was added dropwise to a stirred suspension of 5.6 g of lithium aluminum hydride in 175 ml of dry tetrahydrofuran in an atmosphere of nitrogen. After the addition was finished, the mixture was stirred at room temperature for one hour, then 45 ml of water was added dropwise. The tetrahydrofuran was removed by distillation in vacuo, and dilute hydrochloric acid was added. The acidic solution was basified with sodium bicarbonate solution and extracted with ether (5 x 50 mL). The ethereal solution was washed three times with saline solution and after drying over anhydrous Na 2 SO 4 it was evaporated in vacuo to give 8.7 g of the product as a white solid, m.p. 132 - 134°C.

b) 4-hydroxy-alpha<1->/(methylamino)-methyl/-m-xylene-alpha<1>,alpha<3->

diol

2.0 g of alpha<1->/(benzylmethylamino)-methyl/-4-hydroxy-m-xylene-alpha 1 ,alpha 3-diol was reduced in 30 ml of ethanol containing 1 ml of triethylamine and 1 ml of water using 0.5 g 10% pal-

ladium oxide on charcoal catalyst. The hydrogen absorption was finished after 15 minutes. The catalyst was removed by filtration, and the solution was evaporated to dryness in vacuo to give 1.55 g of a brittle solid. This base in methanol was added to a solution of 0.9 g of malic acid in methanol. The solution was heated and ethyl acetate was added to effect crystallization. 1.15 g of the maleate was obtained as colorless needles, m.p. 109 - 111°C.

Example 10

Preparation of 3-hydroxy-alpha1-(isopropylamino)-methyl-p-xylene-1 4

alpha, alpha-diol

a) Alpha^-ZbenzylisopropylaminoZ-methyl-S-hydroxy-p-xylene-alpha<1>,

alpha - diol

A solution of 1.58 g of N-benzylisopropylamine in 4 ml of dry tetrahydrofuran was added all at once at approximately 10°C to a solution of 1.45 g of 4-bromoacetylsalicylic acid methyl ester in 4 ml of dry tetrahydrofuran and the flask was capped and let it stand for 3 hours. The crystalline benzylisopropylamine hydrobromide formed was filtered off and the filtrate was slowly added to a slurry of 1.7 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran with stirring. The resulting mixture was heated to boiling and stirred under reflux for 15 minutes. After cooling and standing overnight, excess lithium aluminum hydride was cleaved with a minimum amount of water and the resulting mixture was evaporated to dryness. The residue was shaken with dilute HCl and filtered. The filtrate was extracted with ether, then the aqueous layer was basified with sodium bicarbonate solution to pH 8, and extracted with ethyl acetate. The ethyl acetate solution was dried and evaporated to dryness. The residue was allowed to recrystallize from ether, and 0.99 g of yellowish crystals were obtained, m.p. 103 - 8°C.

14

b) 3-hydroxy-alpha-(isopropylamino)-methyl-p-xylene-alpha, alpha-diol

0.6 g of alpha<1-(benzylisopropylamino)-methyl-3-hydroxy-p-xylene-alpha 1,alpha 4-diol was dissolved in 30 ml of ethanol, and 0.15 g of triethylamine was added to this solution. This solution was hydrogenated over 0.15 g of pre-reduced 10% palladium on carbon catalyst. A total amount of 46.5 ml of hydrogen was absorbed in the course of 10 minutes. After filtration and evaporation to dryness, the residue was crystallized from ethyl acetate/ether, then from tetra-

hydrofuran/petrol (bp. 40 - 60°C) and was then dried in vacuum at 50°C for 3 hours and 0.3 g of a white, crystalline, solid was obtained, m.p. 103 - 105°C.

Example 11

Preparation of 4-hydroxy-alpha1-(1-isopropylaminopropyl)-m-xylene-alpha a1, alpha3-diol

Produced from starting material;

a) 5-(2-bromobutyryl)-salicylic acid methyl ester

A solution of 104 g of bromine in 1000 ml of chloroform was

added dropwise to a stirred solution of 144 g of 5-butyrylsalicylic acid, methyl ester in 300 ml of chloroform at room temperature. The reaction proceeded rather slowly at first, and only after about 1 hour was hydrogen bromide gas developed to a significant extent.

The bulk of the bromine solution was added over a further 1 hour. The solution was stirred for another 15 minutes, cooled and washed three times with cold water. The solvent was distilled off under reduced pressure, leaving a pure white solid which was recrystallized from ethanol. 200 g of the product was obtained, m.p. 83°C.' b) 5-(2-isopropylamino-butyryl)-salicylic acid methyl ester, hydrochloride

A solution of 45 g of (2-bromo-butyryl)-salicylic acid methyl ester and 30 g of isopropylamine in 30 ml of methanol was refluxed for 5 hours. The mixture was evaporated under reduced pressure, the oily residue treated with dry ether, and the insoluble hydrobromide filtered off. The ethereal solution was boiled with charcoal and filtered. Dry hydrogen chloride gas was then bubbled into the solution and the hydrochloride precipitated as a white, crystalline solid, which was recrystallized twice from methanol/ether. 20 g of the product was obtained, m.p. 250°C.

1 13 4- hydroxy- alpha -( 1- isopropylaminopropyl)- m- xylene- alpha, alpha -

diol

An aqueous suspension of 10 g of 5-(2-isopropylamino-butyryl)-salicylic acid methyl ester hydrochloride was basified with 10% sodium carbonate solution and extracted into ether. The ether solution was dried over MgSO 4 , the solvent evaporated and the gummy residue, in 60 ml of sodium-dried tetrahydrofuran, was carefully added with stirring to 3.0 g of lithium aluminum hydride in 300 ml of dry tetrahydrofuran. The mixture was heated under reflux with stirring for 30 minutes and then cooled. 21 ml of water was added dropwise with vigorous stirring and the mixture was left overnight before the solvents were evaporated. The solid residue was acidified with dilute hydrochloric acid to pH 6 and this solution was made basic with dilute sodium hydroxide and sodium bicarbonate to pH 8. The gelatinous insoluble hydroxides were then centrifuged and the filtrate was extracted continuously with chloroform. The solvent was evaporated and the oily, basic residue taken up in ether. Dry hydrogen chloride gas was introduced into the solution, and the crystalline precipitate obtained in this way was filtered off and recrystallized from ethanol, so that 5 g of the product was obtained, m.p. 199°C.

Example 12

1 13 Production of alpha - aminomethyl- 4- hydroxy- m- xylene- alpha falfa -

diol

A solution of 1.9 g of alpha-dibenzylaminomethyl-4-hydroxy-m-xylene-alpha 1 ,alpha 3-diol in 50 ml of ethanol and 5 ml of water was shaken in an atmosphere of hydrogen in the presence of 0.5 g of pre-reduced 10% palladium on bone charcoal catalyst. The uptake of hydrogen was complete within 6 hours. The catalyst was removed and the solution was evaporated to dryness under reduced pressure to give 0.9 g of the product as a cream solid, m.p. 151 - 152°C.

Example 13

Preparation of the starting material: 5-(1-hydroxy-2(methylamino)ethylsalicylic acid ethyl ester hydrochloride a) 5-(N-benzyl-N-methylglycyl)-salicylic acid ethyl ester hydrochloride 20 g 5-bromoacetylsalicylic acid ethyl ester, 15.2 g N-benzylmethylamine and 250 ml of ethyl/methyl ketone were stirred and refluxed for 1% hour. The solid product that precipitates was filtered, and the filtrate was evaporated in vacuo to leave a yellow oil.

Dry ether was added to the residue and the ether solution was filtered. The clear filtrate was treated with dry HCl gas and 13.4 g of the clear, white precipitate, m.p. 158 - 160°C, was removed by filtration. Recrystallization from ethanol/ether gave the product as colorless needles, m.p. 169 - 171°C.

b) 5-[1-Hydroxy-2-(methylamino)ethyl]-salicylic acid ethyl ester hydrochloride

3.6 g 5-(N-benzyl-N-methylglycyl)-salicylic acid-ethyl/

ester hydrochloride in 30 ml of ethanol was hydrogenated with 1 g of a 10% palladium oxide-on-bone-charcoal catalyst. Hydrogen absorption was complete after 2 3/4 hours. The solution, after removal of the catalyst by filtration, was evaporated to dryness under reduced pressure, and the residue was crystallized from ethanol/ethyl acetate to give 1.6 g of the product as colorless microneedles, m.p.

129 - 130°C.

Example 14

Preparation of 4-hydroxy-alpha-|/(2-indol-3-yl-1-methylethyl)-

_ \ 13

amino/- methylj- m- xylene- alpha, alpha - diol- hydrogen tartrate

a) 5-| l- hydroxy- 2-/( 2- indol- 3- yl- l- methylethyl) amino/ ethyl j- salicylic acid methyl ester

A solution of 0.71 g of sodium hydroxide in ethanol was added to a solution of 4.4 g of 5-(2-amino-1-hydroxyethyl)-salicylic acid methyl ester hydrochloride in ethanol. A total volume of the solution was 250 ml. Sodium chloride was then removed and the solution was hydrogenated in the presence of 1.0 g of 10% palladium-on-charcoal catalyst and 3.8 g of indol-3-yl-2-propanone. The absorption of hydrogen ceased after 25 hours. The catalyst and solvent were removed to give a straw colored oil. This was separated from the sodium chloride by dissolution in ether, followed by filtration and evaporation to give 7.1 g of the crude ester as an oil.

b) 4- hydroxy- alpha1-|/ 2- indol-3- yl-1- methylethyl) amino/ methylj- m-xylene- alpha 1, alpha 3- diol- hydrogen tartrate

6.5 g of 5-1-hydroxy-2-(T2-indol-3-yl-1-methyl-ethyl)-amino/ethyl-salicylic acid methyl ester in 100 ml of tetrahydrofuran was added to a stirred suspension of 1.4 g lithium aluminum hydride in 50 ml of tetrahydrofuran, in an atmosphere of nitrogen, at a rate sufficient to maintain reflux of the solvent. After 1 hour, 10 ml of water was carefully added and the mixture was concentrated under reduced pressure. The residue was treated with dilute hydrochloric acid and non-basic indole derivatives were removed by extraction with ethyl acetate.

The acid solution was neutralized with sodium bicarbonate and extracted four times with ethyl acetate. After drying over MgSO 4 and evaporation, the latter gave 2.0 g of a tan brittle solid. This base was dissolved in 30 ml of ethyl acetate and added to a solution of 0.8 g of racemic tartaric acid in 30 ml of methanol to precipitate a light brown gummy substance. After trituration with ethyl acetate, this slowly gave 1.6 g of a brownish, brittle, solid, m.p. about. 93 - 100°C. Recrystallization from methanol/dry ether gave a brown gum which after trituration with dry ether gave 0.8

g of the product as a brownish-yellow solid, m.p. about. 112°C, foaming from approx. 70°C.

Example 15

Preparation of 4-hydroxy-alpha1-|/(l-methyl-2-phenoxyethyl)-amino/-

) 1 3

methylj-m-xylene-alpha, alpha-diol

a) 5-| l- hydroxy- 2-/( l- methyl- 2- phenoxyethyl)- amino/- ethyl j- salicylic acid ethyl ester

5.0 g of 5-(N,N-dibenzylglycyl)-salicylic acid methyl ester hydrochloride in ethanol was reduced with hydrogen in the presence of 1.0 g of pre-reduced 10% palladium on charcoal catalyst. After 17 hours, hydrogen absorption ceased.

A solution of 0.45 g of sodium hydroxide in 20 ml of ethanol and 1.9 g of 1-phenoxy-2-propanol was added and the reduction continued in the presence of a similar amount of fresh catalyst. After 52 hours, the hydrogen uptake ceased. The catalyst and solvent were removed and the residue was partitioned between water and ether. The ether was dried and removed to leave 3.0 g of the crude ester as a pale amber oil.

b) 4- hydroxy- alpha1-|/( l- methyl- 2- phenoxyethyl) amino/- methyl|- m-

1 3

xylene-alpha, alpha-diol

2#7 9" 5" i-1-Hydroxy-2-[Jl-methyl-2-phenoxy-ethyl)-amino/— -ethyl)j-salicylic acid methyl ester dissolved in 50 ml of dry tetrahydrofuran was added to a warm, stirred suspension of 0.6 g of lithium aluminum hydride in 20 ml of tetrahydrofuran, in an atmosphere of nitrogen, at a rate such that the solvent was maintained at reflux. The resulting white, gelatinous precipitate was stirred and heated for 1 hour, then cooled and digested by the dropwise addition of 5 mL of water. The mixture was concentrated under reduced pressure, more water was added and the pH was adjusted to 8 by adding hydrochloric acid followed by sodium bicarbonate.

The mixture was extracted with ethyl acetate, which was dried and evaporated to give an amber oil. trituration with ether gave 0.9 g of the triol as a cream solid. Recrystallization from ethyl acetate/cyclohexane gave a white solid, m.p. 128 - 130°C.

Example 16

Preparation of 4-hydroxy-alpha -/(alpha-methylphenethylamino)-methyl/-

m-xylene-alpha, alpha-diol

a) 5-[1-hydroxy-2-(alpha-methylphenethylamino)-ethyl]-salicylic acid methyl ester

3.2 g of 5-(N,N-dibenzylaminoglycyl)-salicylic acid methyl ester and 1.2 g of benzyl methyl ketone in 100 ml of ethanol were shaken in an atmosphere of hydrogen in the presence of 1.0 g of 10% pre-hydrogenated palladium on charcoal catalyst. Hydrogen uptake ceased after 40 hours. The catalyst and solvent were removed to give an oil which was extracted into dilute hydrochloric acid and ether. The aqueous solution was washed with ether and treated with excess sodium bicarbonate solution. The liberated base was extracted with ether which was washed, dried over MgSO 4 and evaporated to give 1.3 g of the crude basic ester as a colorless oil.

b) 4-hydroxy-alpha<1->/(alpha-methylphentylamino)-methyl/-m-xylene-alpha , alpha - diol

1.3 g of 5-[1-hydroxy-2-(alpha-methylphenethylamino)-ethyl]-salicylic acid methyl ester in 20 ml of dry tetrahydrofuran was added to a stirred suspension of 1.5 g of lithium aluminum hydride in 50 ml of dry tetrahydrofuran at a rate which maintains back- run treatment of the solvent.

After 1 hour at reflux, the mixture was cooled and cleaved by the dropwise addition of 5 ml of water with stirring. The mixture was evaporated almost to dryness under reduced pressure and the residue was treated with excess dilute hydrochloric acid, followed by sodium bicarbonate solution.

The resulting mixture was extracted four times with ethyl acetate which was dried and evaporated to give a yellow oil. Trituration with ether gave 0.3 g of the product as a white solid. Recrystallization from ethyl acetate gave colorless crystals, m.p. 113 - 115°C.

The p-hydroxy-alpha-methyl compound has been prepared by methods analogous to the methods described above for the unsubstituted alpha-methyl compound. The structure of the p-hydroxy-alpha-methyl compound, i.e. 4-hydroxy-alpha1-/ (p-hydroxy-alpha-methylphenethylamino)-methyl/-m-xylene-13

alpha ,alpha -diol was determined by nuclear magnetic resonance and ultraviolet and infrared spectra.

Example 17

Preparation of 4-hydroxy-alpha1-|/( 3, 4, 5-trimethoxy-alpha- methyl-— ) 13 phenethyl)-amino/-methylv-m-xylene-alpha ,alpha -diol 4- hydroxy- alpha1- | /( 3, 4, 5- trimethoxy- alpha- methylphenethyl)- amino/-

) 13

methyl:- m- xylene- alpha, alpha - diol

' 1 1 3 1.7 g of alpha -aminomethyl-4-hydroxy-m-xylene-alpha , alpha - diol in 12.5 ml of methanol which contained 1 g of triethylamine, and 2.2 g of (3,4,5-trimethoxyphenyl )-2-propanone was hydrogenated in the presence of 9.25 g of pre-reduced Adams catalyst suspended in 15 ml of water. The hydrogen uptake ceased within 16 hours.

The solution was filtered and evaporated, and the resulting oil extracted with boiling benzene. On cooling the solution, a white gum precipitated which, on standing overnight in a small volume of ether followed by drying in vacuum at 40°C for 24 hours, gave 1.65 g of the product as white crystals, m.p. 90 - 98°C.

Example 18

Preparation of 4-hydroxy-alpha1-|/(p-methoxy-alpha-methylphenethyl)-_ \ 13

amino/- methylj-m-xylene-alpha, alpha-diol 1.03 g alpha<1->aminomethyl-4-hydroxy-m-xylene-alpha<1>, alpha 3-diol in 75 ml of methanol containing 10 ml water, 0.5 ml of triethylamine and 0.92 g of p-methoxyphenyl-2-propanone were hydrogenated in the presence of 0.5 g of pre-reduced Adams catalyst suspended in 25 ml of methanol.

The hydrogen uptake ceased within 15 minutes. The solution was then filtered and evaporated, and the resulting oil was extracted with boiling benzene. On cooling the solution, a white gum was precipitated, which on drying in vacuum over paraffin wax gave 0.70 g of the product as white crystals, m.p. 81 - 83°C.

Example 19

Preparation of 4-hydroxy-alpha1-|/-(1-methyl-2-morpholinethyl)-

\ 13

amino/- methylj- m- xylene- alpha, alpha - diol

1.63 g of alpha<1->aminomethyl-4-hydroxy-m-xylene-alpha<1>, alpha 3-diol in 110 ml of methanol containing 1.0 g of triethylamine, and 1.22 g of l-morpholino-2 -propanone, was hydrogenated in the presence of 0.25 g of pre-reduced Adams catalyst suspended in 15 ml of water. The hydrogen uptake ceased within 16 hours.

The solution was filtered and evaporated to give an oil which only partially solidified. Crystallization from ethyl acetate gave an oil, which when triturated gave the product as a white solid. 0.60 g of the product, m.p. 134 - 135°C, was obtained.

Example 20

Preparation of 4-hydroxy-alpha α1-,/(4-hydroxy-1-methylbutyl) -

amino/-methyl-m-xylene-alpha 1 ,alpha 3-diol 1.5 g of alpha _ -ammomethyl-4-hydroxy-m-xylene-alpha _^,alpha - diol in 85 ml of methanol containing 15 ml of water, 0.5 g of triethylamine and 0.87 g of 5-hydroxy-2-pentanone were hydrogenated in the presence of 0.16 g of pre-reduced Adams catalyst suspended in 25 ml of methanol.

After 60 hours hydrogen uptake ceased, but thin layer chromatography showed that some of the unchanged primary amine was still present. The reduction was continued in the presence of a further portion of 0.16 g of pre-reduced Adams catalyst. The uptake ceased after 25 hours, and thin-layer chromatography showed only traces of the primary amine.

The solution was filtered and evaporated to give an oil, which after rubbing with dry ether and prolonged drying in vacuum became a white, brittle, solid which readily absorbed water from the atmosphere and thereby became liquid. A preparative thin layer chromatogram (silica/methanol) containing 3% 0.880 ammonia solution on 280 mg of this solid gave two fractions at Rf 0.60 and Rf 0.80, visible under u.v. light. The former was extracted with dry methanol (2 x 50 mL) to give 140 mg of a white, brittle solid which readily absorbs water from the atmosphere and thereby liquefies. The nuclear spin resonance spectrum showed that the structure of this solid was consistent with the desired base, although it contained the approximate product of hydrogenolysis of the alpha <3->alcohol group.

Example 21

Preparation of 4- hydroxy- alpha a"* v |/( alpha a- methyl- p- ethoxyph enoxy-

\ 13

ethylamino/-methyl|-m-xylene-alpha ,alpha -diol

1 13

1.5 g of alpha-aminomethyl-4-hydroxy-m-xylene-alpha,alpha-diol in 110 ml of methanol, containing 1 g of triethylamine, and 1.63 g of (p-ethoxy-syphenoxy)-2-propanone were hydrogenated in the presence of 0.20 g of pre-reduced Adams catalyst. The hydrogen absorption ceased within 17 hours.

The solution was filtered and evaporated to give an oil which was extracted with ether (2 x 50 mL). The ether was evaporated to give a gum which was crystallized from ethyl acetate/cyclohexane to give a gummy substance which solidified after drying in vacuo for 3 days. Recrystallization from ethyl acetate/cyclohexane gave 0.30 g of the product as white prisms, m.p. 98 - 107°C.

Example 22

Preparation of alpha1-(cyclopentylaminomethyl)-4-hydroxy-m-xylene-1 3

alpha. alpha - diol

Produced from starting material:

5-(N.N-dibenzylglycyl)-salicylic acid methyl ester hydrochloride

24.1 g of dibenzylamine was added to a solution of 18.5 g of 5-(bromoacetyl)salicylic acid methyl ester in 500 ml of ethyl methyl ketone. After refluxing with stirring for 3 hours, the precipitated dibenzylamine hydrobromide was removed. The solution was evaporated to dryness and treated with ether. 2.8 g of an insoluble solid was removed by filtration and HCl gas was passed through the filtrate to precipitate 22.1 g of the product. After recrystallization from methanol/ethyl acetate, 18.0 g of a white solid was obtained, m.p. 174 - 176°C.

1 13

a) Alpha-dibenzylaminomethyl-4-hydroxy-m-xylene-alpha. alpha-diol 10 g of 5-(N,N-dibenzylglycyl)-salicylic acid methyl ester hydrochloride was basified with sodium bicarbonate solution and extracted into ether. The ether solution was dried over MgSO 4 and evaporated. The basic residue in 100 ml of dry tetrahydrofuran was added to a suspension of 1.74 g of lithium aluminum hydride in 500 ml of dry tetrahydrofuran. A white, gelatinous precipitate was formed which partially dissolved on heating. The stirred mixture was refluxed for 6 hours, then cooled and 5 ml of water was added dropwise with stirring. The cloudy residue was treated with 100 ml of 5N hydrochloric acid. The oily hydrochloride which precipitated was separated from the acidic solution, washed with a little water and treated with sodium bicarbonate solution. The liberated base was extracted into ether which was dried and evaporated to give 6.8 g of the product as a white solid, m.p. 105 - 107°C. Recrystallization from ether/petrol (bp. 40 - 60°C) gave 5.7 g of colorless rods, m.p. 110 - 111°C. 1 13

b) Alpha -(cyclopentylaminomethyl)-4-hydroxy-m-xylene-alpha. alpha diol

3.0 g of alpha -(dibenzylaminomethyl)-4-hydroxy-m-xylene-13

alpha , alpha -diol dissolved in 100 ml of ethanol and 5 ml of water was reacted in the presence of 1.0 g of triethylamine and 1.0 g of a 10% pre-reduced palladium on charcoal catalyst.

The hydrogen absorption ceased after 2^ hours and 0.76 g of cyclopentanone was then added and the reduction continued. Because of the slow hydrogen uptake, the catalyst was replaced with 0.5 g of pre-hydrogenated Adam's platinum oxide and the reaction was complete within 1 hour. After removal of the catalyst, the solution was evaporated to dryness and the resulting oil was triturated with ether to give 0.9 g of cyclopentylaminotriol as a white solid, m.p. 121 - 124°C, which was crystallized from ethyl acetate to give a white solid, m.p. 129 - 131°C.

Example 23

Preparation of beta-[5r-(2-tert.-butylamino-1-hydroxy)-ethyl-2-hydroxy]-phenyl-ethanol

Produced from starting material:

a) 3-(beta-acetoxyethyl)-4-hydroxyacetophenone

A solution of 15.0 g of beta-(o-hydroxyphenyl)-ethanol

in 120 mL of 40 w/w percent borane trifluoride-acetic acid complex was heated with stirring at 65°C for 16 h, during

at which time the color turned light brown. The solution was cooled and treated with aqueous sodium acetate, then with water and the mixture was extracted three times with ether. The combined ether extracts were dried over anhydrous sodium sulfate and evaporated to give 23 g of the product as a brown oil.

b) 4-acetoxy-3-(beta-acetoxyethyl)-acetophenone

A mixture of 23.0 g of 3-(beta-acetoxyethyl)-4-hydroxyacetophenone, 8.2 g of acetyl chloride, 46 g of anhydrous potassium carbonate

and 500 ml of ethyl methyl ketone were refluxed with stirring for 4 hours. The solids were then filtered off and the solvent evaporated to give an orange oil which was chromatographed using 600 g of silica gel. Elution with 20% ethyl acetate in benzene gave 15 g of the desired product as a mobile, straw-colored oil.

c) 4-acetoxy-3-(beta-acetoxyethyl)-phenacyl bromide

3.66 g of bromine in 75 ml of chloroform was added dropwise

during 70 minutes to a stirred solution of 6.0 g of 4-acetoc-

sy-3-(beta-acetoxyethyl)-acetophenone in 85 ml of chloroform, at room temperature. Stirring was continued for another 10 minutes, then the solution was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 7.3 g of 4-acetoxy-3-(beta-acetoxyethyl)-phenacyl bromide as a brown oil. Beta-/5-(2-benzyl-tert-butylamino-1-hydroxy)ethyl-2-hydroxy/-

phenylethanol

4.3 g of 4-acetoxy-3-(beta-acetoxyethyl)-phenacyl bromide and 4.1 g of benzyl tert-butylamine were dissolved in 20 ml of dry tetrahydrofuran and the solution was left at room temperature for 7 days. Benzyl-tert-butylamine hydrobromide was formed and filtered off. The filtrate was added dropwise over 40 minutes to a stirred suspension of 1.5 g of lithium aluminum hydride in 30 ml of tetrahydrofuran. The tetrahydrofuran was gently refluxed while the solution was added and a gelatinous solid precipitated.

Stirring was continued for 2 hours at 70°C, then the mixture was cooled to 0°C, and 15 mL of water was carefully added to the cold, stirred mixture. The mixture was stirred for 1 hour, then dilute hydrochloric acid was added until the mixture slowly turned sour. The pH value was regulated to approx. 8 by adding sodium carbonate solution. The mixture was filtered, and the filtrate was extracted four times with chloroform. The combined chloroform extracts were washed once with water and dried over anhydrous sodium sulfate and the chloroform was evaporated to give 1.8 g of a brown oil.

The oil was refluxed with 500 ml light petrol (bp. 60 - 80°C) for 10 minutes and the solution decanted and left at room temperature overnight and a white solid was obtained which was filtered off as a first part.

When treated with benzene, some of the remaining oil was dissolved. The solution was decanted, treated with charcoal and evaporated to give 0.8 g of a light brown oil. This was dissolved in ethanol and addition of water gave a whitish solid. Further recrystallization from aqueous ethanol gave a second portion of the product as an off-white solid. The titer yield of the product was 265 mg, m.p. 113 - 134.5°C.

Beta-[5-(2-tert-butylamino-1-hydroxy)-ethyl-2-hydroxy]-phenyl-ethanol^

211 mg of beta-[5-(2-benzyl-tert-butylamino-1-hydroxyethyl-2-hydroxy_/-phenylethanol) was hydrogenolyzed at room temperature in 30 ml of ethanol over a 10% palladium catalyst on bone charcoal. The hydrogen uptake ceased within 30 minutes. The catalyst was filtered off, and the filtrate evaporated to give a greenish-yellow oil, which solidified after deep freezing. However, the solid could not be recrystallized. 144 mg of the product, m.p.

54 - 60°C were obtained.

Example 24

Preparation of alpha 3-dimethyl-4-hydroxy-alpha 1-isopropylaminomethyl-m-xylene-alpha, alpha-diol

a) 4- benzyloxy- alpha 1 -( N- benzyl- N- isopropylamino)- methyl- alpha 3-1 3

dxmethyl-m-xylene-alpha, alpha-diol

A solution of 1.5 g of 2-benzyloxy-4-(2-N-benzyl-N-isopropylamino-1-hydroxyethyl)-benzoic acid methyl ester in 50 ml of tetrahydrofuran (50 ml) was treated with an excess of methylmagnesium bromide in 50 ml ether and stirred at room temperature overnight. The mixture was poured into a saturated ammonium chloride solution and the organic layer was separated, filtered through cotton and evaporated to dryness to give a gummy substance.

Trituration of a portion of this gummy substance with dilute hydrochloric acid gave a water-soluble salt which was recrystallized from tetrahydrofuran-ethyl acetate to give colorless crystals of 4-benzyloxy-alpha<1->(N-benzyl-N-isopropylamino)me-

3 13 tyl-alpha -dimethyl-m-xylene-alpha ,alpha -diol hydrochloride, m.p. 174.5 - 175°C. b). Alpha 3 - dimethyl- 4- hydroxy- alpha 1- isopropylaminomethyl- m- xylene- alpha1, alpha3- diol A solution of 1.2 g of 4-benzyloxy-alpha<1->(N-benzyl-3 13 N-isopropylamino)-methyl-alpha -dimethyl-m-xylene-alpha ,alpha -diol in 10 ml of methanol was added to 0.2 g of pre-reduced 10% palladium on charcoal in 10 ml of methanol and hydrogenated until hydrogen absorption ceased. The catalyst was filtered off and the filtrate evaporated to leave 0.9 g of a pale yellow, gummy substance.

The gummy substance was dissolved in ether and treated with an ether solution of o-benzoylbenzoic acid to give 1.08 g

of a crystalline salt, m.p. 161 - 162°c.

Recrystallization from tetrahydrofuran ether gave 0.8 g of alpha 3 -dimethyl-4-hydroxy-alpha 1 -isopropylaminomethyl-m-xylene-alpha 1, alpha<3->diol-o-benzoyl-benzoate, m.p. 162 - 164°C.

Example 25

Preparation of 5-| l- hydroxy- 2-/( l- methyl- 2- phenoxyethyl) - amino/ 7"

ethyl j- salicylic acid amide

a) 5-Il-hydroxy-2-/(1-methyl-2-phenoxyethyl)-amino/-ethyl| -salicylic acid methyl ester

5-(2-Amino-1-hydroxy)-ethyl^-salicylic acid methyl ester hydrochloride (2.53 g) in methanol (60 mL) was made basic by addition of methanolic sodium methoxide (25 mL containing 0.24

g sodium, 1 mol) and was added to 1-phenoxy-2-propanone (1.53

g, 1 mol redistilled bp. 74°/0.7 mm). The mixture was hydrogenated in the presence of pre-hydrogenated 10% PdO/C catalyst (1 g) suspended in methanol (25 mL). The hydrogen uptake was complete within 25 hours.

The solution was filtered and evaporated, and the resulting oil was separated from sodium chloride and a trace of unchanged primary amine by washing with water and extracting into ether (150 mL). The ether was dried (MgSO 4 ) and evaporated to give the crude ester as an oil (2.7 g).

b) 5- | l- hydroxy- 2-/( l- methyl- 2- phenoxyethyl)- amino/- ethyl|- salicylic acid amide

The crude ester of (a) (2.70 g) was dissolved in methanol

(20 ml) and ammonia solution - specific gravity 0.880 (20 ml) - and the whole was allowed to stand in a stoppered flask for 5 weeks.

The solution was evaporated and the remaining oily solid in methanol (7 ml) was chromatographed on a column of silicic acid (25 g) in ethyl acetate.

Elution with ethyl acetate gave the following fractions:

a) 50 ml TLC SiO2/MeOH 2 spots Rf value 0.7 and Rf value 0.9

b) 650 ml 1 spot Rf value 0.7

c) 2 spots Rf value 0.30 and 0.70

TLC = thin layer chromatography.

Fraction (b) was evaporated to give a brittle solid (ca. 0.60 g) which was recrystallized from benzene to give white crystals of the amide (260 mg), m.p. 126.5 - 128.5°C. Example 26

4- hydroxy- alpha3"- |/ T- ( p- methoxyphenyl) - 1- methylpropylamino/ methylj -

1 3

m-xylene-alpha, alpha-diol

A solution of 1.66 g of alpha-aminomethyl-4-hydroxy-m-xylene-alpha 1 , alpha 3-diol, prepared as in Example 12, and 1.79 g of 4-(p-methoxyphenyl)-2-butanone in 125 ml of methanol, and 1 g of triethylamine was added 0.30 g of Adams catalyst pre-reduced in water 10 ml and the mixture was hydrogenated. The absorption of hydrogen ceased after 4.5 hours.

The residual oil obtained after removal of the catalyst and solvent was extracted with boiling benzene. On cooling the solution, a white, gummy substance was precipitated which, when rubbed, gave! the triol as a whitish solid in an amount of 1.95 g. Recrystallization from ether/light naphtha with boiling point 40 - 60°C and drying in vacuum at room temperature gave white crystals with m.p. 91 - 98°C.

A portion was recrystallized twice from ether/light benzine boiling point 40 - 60°C and dried in vacuo to give white crystals of constant m.p. 99°C.

Example 27

4- hydroxy- alpha1- |/( 3, 4- dimethoxy- alpha- methylphenethyl) amino/ methylj 1 3

- m-xylene-alpha, alpha-diol

A solution of 1.95 g of alpha-aminomethyl-4-hydroxy-m-xylene-alpha 1,alpha 3-diol, prepared as in Example 12 and 2.59 g of (3,4-dimethoxyphenyl)-2-propanone in 100 ml of methanol and 1.5 g of triethylamine were added to 0.20 g of Adams catalyst, pre-reduced in 10 ml of water, and the mixture was hydrogenated.

The residual oil obtained after removal of the catalyst and solvent was extracted twice with 100 ml of boiling benzene. On slow cooling of the solution and contamination, white crystals were precipitated. They were dried at 40°C in vacuum for two days and 1.05 g of the triol with m.p. 71 - 94°C.

From the mother liquor, additional impure material was obtained which was recrystallized from benzene, and upon contamination, 0.75 g of white crystals with m.p. 70 - 83°C.

The pharmacological activity of compounds described in the examples will be discussed in more detail below.

The following table n lists the activity determined for compounds produced according to the present method. The structural formula for the compound is also listed with reference to the general formula. Two types of activity are indicated. The first is a beta-stimulating activity. This is examined on the bronchial muscle and on the heart muscle. The standard compound with which the activity is compared is that of isoprenaline. The activity of this compound is given a value of 100 for both bronchial and cardiac muscle. A good so-called bronchodilator is one that has a maximum effect on the bronchial muscle and a minimum effect on the heart muscle. The test methods are the usual ones. The beta-stimulatory activity on the bronchial muscle has been determined by testing anesthetized guinea pigs for the ability of the compounds to relieve or calm drug-induced bronchospasm. "Konzett, H. and Røssler, R. (1940). Versuchsanordung zu Unter-suchungen an der Bronchial musculature. Arch. exp. Patho. Pharma-kol., 195, 71-74". The beta-stimulatory activity of the heart muscle is determined in isolated guinea pig atria" Black, Duncan & Shanks (1965) Brit. J. Pharmacol., 25_, 577-591. Farmer, Levy, Kennedy & Marshall (1970) J. Pharm . Pharmacol. (to be published) . Lands, Luduena & Buzzo (1967) Life Sciences, §_, 2241-2249".

The other type of activity is a beta-blocking activity. The standard compound given a value of 100 is propranolol. The activity is determined with reference to the inhibition of tachycardia produced by intravenous injection of isoprenaline in anesthetized dogs. The unwanted side effects, which are not indicated in the table, were determined by neuropharmacological tests, particularly depression and other behavioral effects in mice. The compounds produced according to the invention possess a beta-blocking activity with very few side effects compared to isopropanol. (Cf. the literature references).

Claims (1)

Process for the preparation of new 1-hydroxyphenyl-2-aminoalkanols with therapeutic effect, particularly with affinity to beta-adrenergic receptors, and of the general formula: where means hydrogen or a straight or branched alkyl radical with 1 to 3 carbon atoms, 1*2 means hydrogen or a benzyl group, means a hydrogen atom or a straight or branched al- radical with 1 to 6 carbon atoms, which may be substituted with a hydroxy group, an indolyl group or a morpholine group, or represents a cycloalkyl group with 4-8 carbon atoms, a phenalkyl or phenoxyalkyl group, where the alkyl group contains from 1-6 carbon atoms and where the phenyl or phenoxy group may be substituted with one or more hydroxy groups or one or more alkoxy groups containing from 1-3 carbon atoms , X means a straight or branched hydroxyalkyl group with 1 - 6 carbon atoms in the alkyl part thereof, or a group of the formula -CONI^, and their acid addition salts, characterized in that the carbonyl group in a ketone of the general formula: where R is hydrogen or an ether or ester forming protecting group, and where X, R^, R^ and R^ have the above meaning, is reduced to a -CHOH group, to give a compound of the formula: before or after the removal of a protecting group R, or for the preparation of compounds of the general formula I where X means . CH, in J CONH2 or CH2OH or HO-C-CH3 the carbonyl group in a ketone of the general formula is reduced where R4 is a straight or branched alkyl group with 1-6 carbon atoms and R^, R2 and R^ have the same meaning as above, and before or after the reduction of the carbonyl group, the -COOR^ group is converted by reaction with NH^ into a -CONH2- group or by reduction to a -CH2OH group or by reaction with methylmagnesium halide to a group and if removal of a benzyl group or benzyl groups attached to the amino nitrogen is desired or if conversion of the compounds in which R2 and/or R^ is hydrogen or both are benzyl is desired, by reductive alkylation with carbonyl compounds to compounds where R2 is hydrogen and R^ has another of the meanings given above, and the resulting base is converted, if desired, into a physiologically acceptable acid addition salt or is released as such.