DE2305092C2 - - Google Patents

Description

The present invention relates to α - aminomethylbenzyl alcohol derivatives which have a hydroxyl group in the 4-position and a formylamino or carbonylamino group in the 3-position according to claims 1 to 5, processes for their preparation according to claim 6 and pharmaceutical preparations according to claim 7.

The compounds of this invention are useful as β - adrenergic stimulants and, therefore, they have great activity on smooth respiratory muscles and are useful as bronchodilator agents.

The following are known as α - alkylmethylbenzyl alcohol derivatives: 3-amino-4-hydroxy- α- isopropylaminobenzyl alcohol (Dutch patent 85 197; Chemicals Abstracts 52 , 11 121d [1958]), 3-ethoxycarbonylamino-4-hydroxy- a- isopropylaminobenzyl alcohol (cf. also Belgian patent 7 65 986), α - (isopropylaminomethyl) - 4-hydroxy-3-ureidobenzyl alcohol (Japanese patent application 2 674/1971).

In contrast, the compounds of this invention possess more excellent bronchodilator activity than these known ones Links.

In BE-PS 7 39 678 amino alcohols of the general formula

described, in which R _{1 can have} the meaning RO and where R is hydrogen, straight or branched chain alkyl, preferably having 1 to 8 carbon atoms or an alkenyl, alkynyl or acetyl radical, and R _{2 is} an amino or Acylamino group and R ₃ can represent hydrogen. As the information in BE-PS 7 39 678 on page 4, paragraphs 3 and 4 shows, the compounds described there are intended to serve against coronary diseases and for cardiac treatment for arrhythmia. In contrast, the compounds of the present invention are surprisingly usable as β - adrenergic stimulants and thereby exert great activity on the smooth respiratory muscles, so that they are used as bronchodilator agents for combating asthma. However, the compounds described in BE-PS 7 39 678 have the property of blocking the adrenaline- β- receptors, so that they have a contracting effect on the bronchial tubes and thereby trigger asthmatic attacks (see loc. Cit. Page 4, paragraph 3, lines) 1-2).

The principle of solution of the compounds of the invention differs themselves from this prior art (BE-PS 7 39 678) in that the claimed compounds in the 4-position are a hydroxy and in the 3-position a formylamino or carbonylamino group exhibit.

The compounds of this invention can be understood by the general Formula I ′

represent, the meanings of R ₁ , R ₂ and R ₃ in their respective combination can be found in Tables II and III.

The formula I ′ comprises the formula I ″ even more specifically divided

and the formula I ″

the meanings of R ₃ and R ₄ in their respective combinations are also shown in Tables II and III.

As raw materials for producing the above described connections become such connections used, wherein one or more hydrogen atoms of the monosubstituted amino group (i.e. secondary amino group) and their Hydroxyl group have been protected by a protective group, which is easily split off by reduction, like one Benzyl group, a benzyloxycarbonyl group, a p- Nitrobenzyloxycarbonyl group.

Furthermore, the starting material for those to be manufactured Compounds with the hydroxyl group adjacent to Benzene ring to be a compound that according to a carbonyl group of the following formula

owns.

The compounds of this invention can be obtained by catalytic Reduction, e.g. B. the starting material or its Salts, in a solvent, e.g. B. ethanol, isopropanol, Ethyl acetate at normal temperature or at elevated temperature, under normal pressure or high Pressure, in the presence of a catalyst, e.g. B. Palladium or platinum, according to the usual working conditions getting produced.  

Practical examples of the raw materials for the Preparation of the compounds of this invention are as follows:

• 1. 3-formamido-4-benzyloxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol;
• 2. 3-acetamido-4-benzyloxy- α - (tert-butylaminomethyl) benzyl alcohol;
• 3. 3-formamido-4-benzyloxy- α - (3-p-hydroxyphenyl-1-methylpropylamino) acetophenone;
• 4. 3-formamido-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol;
• 5. 3-acetamido-4-benzyloxy- α - [N- (1-methyl-3-m-tolylpropyl) aminomethyl] benzyl alcohol;
• 6. 3-formamido-4-benzyloxy- α - [N-benzyl-N-1,1-dimethyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol;
• 7. 3-Formamido-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-acetamidophenylethylaminomethyl] benzyl alcohol;
• 8. 3-Benzyloxyacetamido-4-hydroxy- α - [N-benzyl-N- (1-methyl-2-p-propoxyphenylethyl) amino] acetophenone;
• 9. 3-Acetamidopropionamido-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-ethoxyphenylethyl) aminomethyl] benzyl alcohol.

In Table II below, the serial number, the structural formula, the structural formula of the end product and the radicals R ₁ , R ₂ , R ₃ and R _{4 of} the end product are given for the above starting materials.

Table II

continuation

continuation

If the hydroxyl groups of groups R ₃ and R _{4 of} these starting materials for the preparation of the compounds of this invention z. B. have been substituted by benzyl groups or benzyloxycarbonyl groups, the substituents of the hydroxyl groups are split off in order to obtain the hydroxyl groups in the abovementioned reduction.

The manufactured products of the invention can be isolated and cleaned, the usual for this chemical working methods are used. Since the Compounds of this invention at least have an asymmetric carbon atom the compounds of this invention all possible optically active forms and racemic mixtures. The racemic Mixtures can be prepared by methods known per se be separated, e.g. B. optically more active by formation Acid addition salts and their separation by fractional Crystallization.

The pharmacological effects of the compounds of these Invention are illustrated by the following studies and their results clarified, these be compared with known compounds.

Investigation I Isolated smooth bronchial muscle activity (in vitro test)

The trachea was removed from guinea pigs, cut spirally and the isolated bronchial specimen was suspended in a Magnus bath. Then Tyrode liquid was used as the nutrient solution and kept at 37 ° C. Then 10 ^-5 g / ml histamine or methacholine chloride were added to the experimental set-up as agonists. After the contraction of the trachea reached a temporary state of stability, the test sample shown in Table I below was added cumulatively to the experimental set-up. A dose for 50% relaxation of the bronchial muscle was called ED ₅₀ .

Investigation II Experimental anti-asthmatic effect (in Vivo test)

A guinea pig was housed in an 11 liter glass kettle and then the bronchoconstrictor substance administered to the animal by spraying with a nebulizer. Then when 0.01% histamine or methacholine chloride solution sprayed in 10 seconds, the test animal showed symptoms by Dyspnoe. 10 mg / kg of the sample was taken orally for 30 minutes or 2 hours before the bronchoconstrictor administration Substance administered. If the guinea pig is not dyspnea Showed symptoms, the sample was considered effective.

The results obtained in the above studies are shown in Table I below.  

Table I

The known compounds used above are:

• A: 3-amino-4-hydroxy- α- isopropylaminomethylbenzyl alcohol (Dutch patent 85 197).
• B: 3-ethoxycarbonylamino-4-hydroxy- α- isopropylaminomethylbenzyl alcohol (produced based on BE-PS 7 65 986)
• C: 4-Hydroxy-3- (N'-methylureido) - α- isopropylaminomethylbenzyl alcohol (Japanese Patent Application Laid-Open No. 2 674/1971).
• D: salbutamol; 4-hydroxy-3-hydroxymethyl- α- tert-butyl-aminomethylbenzyl alcohol.
• E: trimetoquinol; l-1- (3,4,5-trimethoxybenzyl) -6.7- dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride.

From the above results it can be clearly seen that the compounds of this invention are known bronchodilator agents with similar and dissimilar ones Structures were superior.

The compounds of this invention can be in various Find forms of treatment and contraception. Generally, they are called salts of pharmacological non-toxic acids used. For example, they can as salts of such inorganic acids as hydrochloric acid, Sulfuric acid, phosphoric acid or organic acids such as fumaric acid, maleic acid, Acetic acid, lactic acid, citric acid Find use.

The compounds of this invention can be oral or parenteral be administered. In the case of oral administration can be in the form of sugar-coated Tablets, buccal tablets or capsules Find use. They can also be in the form of aerosols  Inhalation can be administered. Furthermore, they can subcutaneously, intramuscularly or intravenously as an injection be administered.

The dosage of the compounds of this invention depends on the patient's condition and age from time to time suitable oral dosage ranges are from 0.3 to 1.5 mg / day for adults.

The following reference examples relate to the production of the starting products.

Reference example 1

a) 5.4 g of 4-benzyloxy-3-nitro-acetophenone were dissolved in 60 ml of chloroform. A mixture of 3.2 g of bromine and 5 ml of chloroform was added dropwise to the solution with stirring. The mixture was continued for a further 30 minutes. The reaction product was concentrated under reduced pressure. The crystalline residue obtained was washed with 20 ml of benzene and dried. 5.5 g of 4-benzyloxy-3-nitro- α- bromoacetophenone were obtained. The product had a melting point of 135-136 ° C after recrystallization from chloroform.

b) 5.3 g of 4-benzyloxy-3-nitro- α- bromoacetophenone were dissolved in 60 ml of tetrahydrofuran. Then 4.5 g of N-benzyl-N-isopropylamine were added to the solution and the mixture was stirred overnight at room temperature. Then, after the precipitates formed had been filtered off, the filtrate was concentrated under reduced pressure and the crystalline residue obtained was washed with ethanol. 5.5 g of yellow crystalline 4-benzyloxy-3-nitro- α - (N-benzyl-N-isopropylamino) acetophenone were obtained. The product showed a melting point at 92-93 ° C after recrystallization from ethanol.

c) 3.5 g of 4-benzyloxy-3-nitro- α - (N-benzyl-N-isopropylamino) acetophenone were suspended in 35 ml of ethanol. After adding 0.4 g of sodium borohydride, the mixture was stirred at room temperature for 3 hours. After the ethanol was distilled off under reduced pressure, water was added to the residue. The mixture was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then it was concentrated under reduced pressure. 3.4 g of pale yellow crystalline 4-benzyloxy-3-nitro- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were obtained. The product had a melting point at 97 ° C. after recrystallization from ethanol.

d) 3 g of 4-benzyloxy-3-nitro- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were dissolved in 30 ml of 50% aqueous acetic acid solution. 1.5 g of iron powder was added to the solution and then refluxed for 30 minutes. After filtering off the insolubles from the reaction product, the filtrate was concentrated under reduced pressure. To the residue thus obtained, 20 ml of 5% aqueous sodium carbonate solution was added, and then the product was extracted with benzene. The extract was washed with water and then dried over anhydrous magnesium sulfate. The extract was then concentrated under reduced pressure. Brownish crystalline 3-amino-4-benzyloxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was obtained.

The product was recrystallized from benzene-n-hexane (2: 5) and then had a melting point at 63-65 ° C. The yield was 2.2 g.  

e) 1.9 g of 3-amino-4-benzyloxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were dissolved in 5 ml of a mixture of acetic anhydride and formic acid and left to stand overnight. The solution was concentrated under reduced pressure. To the residue obtained, 20 ml of 5% aqueous sodium carbonate solution was added. The product was then extracted with 30 ml of benzene. The extract was washed with water and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 4-Benzyloxy-3-formylamino- α - (N-benzyl-N-isopropylaminomethyl) - o-formylbenzyl alcohol was obtained.

The product was dissolved in 10 ml of 90% methanol (balance 10% water). 0.5 g of sodium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then the solvent was distilled off under reduced pressure and the residue obtained was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 1.9 g of brownish oily 4-benzyloxy-3-formylamino- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were obtained. The product is used in Example 1.

Reference example 2

a) 5 g of 3-amino-4-benzyloxyacetophenone were added to 30 ml of pyridine dissolved. There were 3.9 g of benzyloxyacetyl chloride added with cooling and the mixture over Stirred at room temperature overnight. The solvent was reduced from the reaction product under Pressure distilled off. The residue formed was dissolved in 50 ml of chloroform. Then the solution washed twice with 20 ml water, dried over anhydrous sodium sulfate and  the chloroform was distilled off under reduced pressure. By recrystallization of the yellow crystals 7.5 g of 4-benzyloxy-3- benzyloxyacetylaminoacetophenone with a melting point at Obtained 104-105 ° C.

b) 1.9 g of 4-benzyloxy-3-benzyloxyacetylaminoacetophenone were dissolved in 50 ml of chloroform. 0.78 g of bromine was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then chloroform and hydrogen bromide were distilled off from the reaction mixture under reduced pressure. The crystals obtained were recrystallized from chloroform-n-hexane. 1.85 g of 4-benzyloxy-3-benzyloxyacetylamino- α- bromoacetophenone with a melting point at 155-157 ° C. were obtained.

c) 4 g of 4-benzyloxy-3-benzyloxyacetylamino- α- bromoacetophenone were dissolved in 40 ml of tetrahydrofuran at 40-50 ° C. Then 2.68 g of N-benzyl-N-isopropylamine was added to the solution. The mixture was stirred overnight at the same temperature (40-50 ° C). The reaction mixture was cooled, the N-benzyl-N-isopropylamine hydrochloride formed was filtered off and then the solvent was distilled off under reduced pressure. After the yellow oily material (5 g) thus obtained was dissolved in 100 ml of ethanol, 0.5 g of sodium borohydride was added to the solution, and the mixture was stirred for 4 hours at room temperature. Then the solvent was distilled off from the reaction product under reduced pressure. The white crystals obtained were recrystallized from ethanol. 2.3 g of 4-benzyloxy-3-benzyloxyacetylamino- a - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol with a melting point at 93-95 ° C. were obtained. The product obtained is processed further in Example 2.

Reference example 3

a) 5.4 g of 4-hydroxy-3-nitroacetophenone were dissolved in 50 ml of chloroform. Then 5 ml of a chloroform solution of 4.8 g of bromine was added dropwise to the solution. Thereafter, the mixture was stirred for 15 minutes and then concentrated under reduced pressure, whereby yellow crystals were obtained. Recrystallization of the product from benzene-n-hexane gave 6.3 g of crystalline α - bromo-4-hydroxy-3-nitroacetophenone with a melting point at 69-71 ° C.

b) 5.2 g of α - bromo-4-hydroxy-3-nitroacetophenone was dissolved in 50 ml of methyl ethyl ketone. Then 9 g of N-benzylisopropylamine were added to the solution and the mixture was stirred overnight at room temperature. After the precipitated N-benzylisopropylamine hydrobromide was filtered off, the filtrate was concentrated. Crude yellowish brown oily 4-hydroxy-3-nitro- α - (N-benzyl-N-isopropylamino) acetophenone was obtained.

c) The crude 4-hydroxy-3-nitro- α - (N-benzyl-N-isopropylamino) acetophenone obtained above was dissolved in 50 ml of ethanol and then 1.5 g of sodium borohydride was added to the solution. The mixture was stirred overnight at room temperature. The reaction product was concentrated under reduced pressure. Water was then added to the residue obtained and the product extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then the solvent was distilled off and a yellow-brown oily material was obtained. The oily product was subjected to silica gel column chromatography. The product was then isolated using benzene as the eluent. 4 g of 4-hydroxy-3-nitro- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were obtained from the collected eluates.

d) 2.7 g of 4-hydroxy-3-nitro- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol (prepared as described above) were dissolved in 30 ml of methanol. Then 1 g of Raney nickel catalyst was added to the solution. The catalytic reduction of the compound was carried out at normal temperature and normal pressure. After 600 ml of hydrogen was absorbed, the reaction was stopped. After filtering off the catalyst and adding 8.2 ml of a 1N hydrogen chloride-ethanol solution to the filtrate, the reaction product was concentrated under reduced pressure. 2.7 g of yellow-brown powdery 3-amino-4-hydroxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol hydrochloride were obtained.

e) 1.2 g of the 3-amino-4-hydroxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol hydrochloride prepared above was dissolved in 20 ml of pyridine. Then 0.20 g of formic acid and 0.85 g of dicylohexylcarbodiimide were added to the solution while cooling to below 0 ° C. The mixture was stirred overnight at room temperature. The separated dicyclohexylurea was filtered off. The filtrate was concentrated. Water was added to the residue obtained, and the mixture was washed with ethyl acetate. The aqueous solution formed was neutralized by adding sodium carbonate and then extracted with ethyl acetate. The extracts were dried and concentrated. A brown residue was obtained. The residue was subjected to silica gel column chromatography. The product was obtained using a chloroform-acetone mixture (5: 1) as eluent. Then 0.5 g of yellow powdery 3-formylamino-4-hydroxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was obtained from the eluates. The compound is used in Example 8.

Reference example 4

a) 5 g of 3-amino-4-benzyloxyacetophenone were added to 15 ml of pyridine dissolved. 3 ml of acetic anhydride were added to the solution added and the mixture at 2 hours Leave room temperature. Then that became The reaction product is concentrated under reduced pressure and the crystalline residue obtained with ethanol washed. 5.3 g of white crystalline 3-acetylamino Obtained 4-benzyloxyacetophenone. The product had one after recrystallization from ethanol Melting point at 130-133 ° C.

b) 5 g of 3-acetylamino-4-benzyloxyacetophenone were dissolved in 45 ml of chloroform. Then, a solution of 2.8 g of bromine in 5 ml of chloroform was gradually added dropwise to the solution, warming the batch initially. The mixture was stirred for a further 20 minutes. Then 50 ml of benzene was added to the mixture, and the crystals thereby precipitated were separated by filtration and dried. 5.5 g of white crystalline 3-acetylamino-4-benzyloxy- α- bromoacetophenone with the melting point at 181 ° C. were obtained.

c) 1.85 g of 3-acetylamino-4-benzyloxy- α- bromoacetophenone were dissolved in 40 ml of acetonitrile and 10 ml of dimethylformamide. 1.5 g of N-benzyl-N-isopropylamine were added to the solution and the mixture was stirred at 40-50 ° C. for 2 hours. Then the mixture was left overnight at room temperature. The precipitates thus formed were filtered off and the filtrate was concentrated under reduced pressure. The residue was then dissolved in ethyl acetate and the insolubles were filtered off. An ethanol solution of hydrogen chloride was added to the filtrate, whereby crystalline deposits occurred. The precipitates were separated by filtration and dissolved in water with heating. The insoluble matters were separated by filtration and the solution was neutralized by the addition of aqueous sodium carbonate solution. The reaction product was extracted with ethyl acetate, and the extract was then washed with water, dried and concentrated under reduced pressure. 1.2 g of 3-acetylamino-4-benzyloxy- α - (N-benzyl-N-isopropylamino) acetophenone were obtained.

d) 1 g of 3-acetylamino-4-benzyloxy- α - (N-benzyl-N-isopropylamino) acetophenone was dissolved in 20 ml of ethanol. 0.2 g of sodium borohydride was added to the solution and the mixture was stirred overnight. The reaction product was concentrated under reduced pressure. Water was added to the residue obtained and the product extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 0.9 g of 3-acetylamino-4-benzyloxy- a - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was obtained, which is used in Example 3.

Reference example 5

a) 5.4 g of 4-benzyloxy-3-nitro-acetophenone were dissolved in 60 ml of chloroform. A mixture of 3.2 g of bromine and 5 ml of chloroform was added dropwise to the solution with stirring. The mixture was then stirred for a further 30 minutes. The reaction product was concentrated under reduced pressure and the crystalline residue obtained was washed with 20 ml of benzene and dried: 5.5 g of 4-benzyloxy-3-nitro- α- bromoacetophenone with a melting point of 135-136 ° C. were obtained.

b) A mixture consisting of 4.6 g of 4-benzyloxy-3-nitro- α- bromoacetophenone and 6.4 g of N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amine was mixed with 50 ml of methyl ethyl ketone heated to 70-80 ° C for 30 minutes.

After the reaction product had cooled, the precipitates formed were filtered off and the filtrate was concentrated under reduced pressure. After the addition of ethanol to the residue obtained, the product was crystallized. The crystals were separated by filtration and recrystallized from ethanol. 5.5 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone with a melting point of 84-85 ° C. were obtained.

c) 4.5 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone were suspended in 100 ml of ethanol. 0.5 g of sodium borohydride was added to the suspension. The mixture was stirred at room temperature for one hour. Then, ethanol was distilled off from the reaction product under reduced pressure, water was added to the residue, and the product was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then the extract was concentrated under reduced pressure. 4.4 g of yellowish crystalline powdery 4-benzyloxy-3-nitro- a - [N-benzyl-N- (1-methyl-2-p-hydroxyphenyl-ethyl) aminomethyl] benzyl alcohol were obtained.

d) 4.3 g of 4-benzyloxy-3-nitro- a - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were dissolved in 40 ml of 60% aqueous acetic acid solution. 1.5 g of iron powder was added to the solution. The mixture was refluxed for 30 minutes. After the insoluble constituents had been filtered off from the reaction product, the product was concentrated under reduced pressure. 10% aqueous sodium carbonate solution was added to the residue obtained and the product was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 3.7 g of brownish crystalline powdery 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were obtained.

e) In 10 ml of acetic anhydride-formic acid mixture (5: 3) 3.3 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] dissolved benzyl alcohol. After the mixture was left overnight at room temperature, the mixture was concentrated under reduced pressure. The residue obtained was dissolved in 50 ml of methanol. 3 ml of water and 3 g of sodium carbonate were added to the solution. The mixture was carried out at room temperature for one hour. Methanol was distilled off from the mixture under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off from the extract. 3.4 g of pale brown powdery 4-benzyloxy-3-formylamino- a - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were obtained. In 30 ml of benzene, 2.5 g of the pale brown powder obtained above was dissolved and the solution was left overnight at room temperature, whereby crystals were deposited. The crystals were separated and recrystallized from ethyl acetate-benzene. 1.2 g of white crystalline product with a melting point of 135-137 ° C. were obtained.

Nuclear magnetic resonance spectrum (NMR; CDCl ₃ ):

δ : 4.50 ppm (m, 1H, CH belonging to the hydroxyl group), 3.46, 3.87 ppm (AB band, q, 2H, CH ₂ belonging to N).

This product is called 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] and is used in Example 10.

Furthermore, the solvent was left behind Mother liquor of the above step distilled off and the residue obtained one Subjected to silica gel column chromatography. Then was by using benzene-ethyl acetate Mixture (10: 2) 0.8 g of white crystalline powder obtained.

NMR (CDCl ₃ ):

δ : 4.34 ppm (m, 1H, CH belonging to the hydroxyl group), 3.76 ppm (S, 2H, CH ₂ belonging to N).

This product is called 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [B] and is used in Example 11.

Reference example 6

a) 27 g of 4-benzyloxy-3-nitro-acetophenone were dissolved in 270 ml of chloroform. A mixture of 16 g of bromine and 10 ml of chloroform was added dropwise to the solution with stirring. The mixture was stirred for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure. The crystalline residue obtained was washed with a mixture of 50 ml of benzene and 50 ml of n-hexane and dried. 31 g of 4-benzyloxy-3-nitro- α - bromoacetophenone with a melting point of 135-136 ° C. were obtained.

b) A mixture of 30.5 g of 4-benzyloxy-3-nitro- α- bromoacetophenone and 28.5 g of N-benzyl-N-tert-butylamine was kept under reflux for 3 hours together with 300 ml of methyl ethyl ketone. After cooling, the precipitates formed were filtered off. The filtrate was concentrated under reduced pressure and the crystals formed were separated. Then they were recrystallized from ethanol. 30 g of 4-benzyloxy-3-nitro- α - (N-benzyl-N-tert-butylamino) acetophenone with a melting point at 99-100 ° C. were obtained.

c) 30 g of 4-benzyloxy-3-nitro- α - (N-benzyl-N-tert-butylamino) acetophenone were dissolved in a mixture of 200 ml of ethanol and 150 ml of tetrahydrofuran. After adding 3 g of sodium borohydride to the solution, the mixture was stirred for 3 hours at room temperature. The reaction product was concentrated under reduced pressure and water was added to the residue. The product was then extracted with benzene from this approach. The extract was washed with water and dried over anhydrous magnesium sulfate. Then it was concentrated under reduced pressure. 30 g of oily 4-benzyloxy-3-nitro- a - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were obtained.

d) 30 g of 4-benzyloxy-3-nitro- α - (N-benzyl-N-tert-butyl-aminomethyl) benzyl alcohol were dissolved in 150 ml of 50% aqueous acetic acid solution. Then 12 g of iron powder was added to the solution. The mixture was refluxed for 25 minutes. The reaction mixture was filtered while hot and the filtrate was concentrated under reduced pressure. Then 50 ml of 10% aqueous sodium carbonate solution was added to the residue and the product was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then this was concentrated under reduced pressure and a crystalline residue was obtained. By recrystallization of the product from a mixture of 40 ml of benzene and 60 ml of n-hexane, 23 g of 3-amino-4-benzyloxy- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol with a melting point of 68-69 ° C obtained.

e) 20 g of 3-amino-4-benzyloxy- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were dissolved in 50 ml of acetic anhydride-formic acid mixture (5: 3) and left to stand overnight. Then the solution was concentrated under reduced pressure. The residue obtained was dissolved in 120 ml of methanol. Then 5 ml of water and 7.5 g of sodium carbonate were added to the solution. The mixture was stirred at room temperature for one hour. Then the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then it was concentrated under reduced pressure. 20.5 g of oily 4-benzyloxy-3-formylamino- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were obtained.

f) 5 g of 4-benzyloxy-3-formylamino- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were dissolved in 30 ml of anhydrous tetrahydrofuran. The resulting solution was added dropwise while stirring to a solution of 20 ml of tetrahydrofuran and 20 ml of ether containing 3 g of lithium aluminum hydride. Thereafter, the resulting mixture was refluxed for one hour by heating. Then 20 ml of water was added dropwise to the reaction mixture and then stirred for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with benzene. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (with 70 ml of silica gel as a filling) using chloroform as the eluent. The third to eighth fractions (each fraction was 40 ml) were collected. Then they were concentrated under reduced pressure. 2.8 g of pale yellow oily 4-benzyloxy-3-methylamino- a - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were obtained.

g) 1.5 g of 4-benzyloxy-3-methylamino- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were dissolved in 5 ml of acetic anhydride-formic acid mixture (5: 3) and the solution was left to stand overnight . The mixture was then concentrated under reduced pressure and the residue formed was dissolved in 50 ml of methanol. After adding 3 ml of ice water and 2 g of sodium carbonate, the resulting mixture was stirred for one hour. The reaction product was concentrated under reduced pressure and the residue obtained was extracted with benzene. After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 1.5 g of brownish oily 4-benzyloxy-3- (N-methyl-N-formylamino) - α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were obtained. The compound produced is used in Example 13.

Reference example 7

a) In 200 ml of methanol, 16.0 g of 4-benzyloxy-3-formylamino- a - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] (prepared according to Reference Example 5 ) resolved. Then 30 ml of 4.8 1N hydrochloric acid was added to the solution. The mixture was refluxed for one hour and 30 minutes. After the completion of the reaction, the reaction product was cooled, and 10 g of potassium hydroxide and 50 ml of water were added. The resulting mixture was stirred for one hour. The solvent was distilled off from the reaction product under reduced pressure. The residue obtained was extracted with benzene, the extract was washed with water and dried over anhydrous magnesium sulfate. Then it was concentrated under reduced pressure. 14.5 g of crystalline powdery 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] were obtained.

b) In 20 ml of acetic anhydride, 4.0 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] (prepared according to the above Regulation). The mixture was heated to 65-80 ° C for one hour and 30 minutes and then concentrated under reduced pressure. The residue was dissolved in a mixture of 15 ml of methanol and 2.0 g of potassium hydroxide. The solution was stirred at room temperature for one hour. Then methanol was distilled off under reduced pressure. The residue obtained was mixed with water and then extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off. 3.8 g of crystalline powdery 4-benzyloxy-3-acetylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] were obtained. By recrystallization of 2.0 g of the product obtained in this way from 20 ml of ethanol, 1.6 g of crystalline pure product with a melting point of 141-143 ° C. were obtained, which is further reacted in Example 14.

Elemental analysis for C ₃₂ H ₃₆ N ₂ O ₄ :

Calculated: C 75.55%, H 6.92%, N, 34%; Found: C 75.62%, H 7.03%, N 5.21%.

Reference example 8

2 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol (prepared according to reference example 7a above) was dissolved in 20 ml of anhydrous pyridine. The solution was cooled to temperatures from -20 ° C to -30 ° C. A solution of 2.28 g of benzyloxyacetyl chloride in 5 ml of toluene was added dropwise to the solution thus kept cooled while stirring, and the temperature of the mixture was slowly brought to room temperature. After stirring the mixture overnight, the solvent was distilled off under reduced pressure. The residue obtained was mixed with 50 ml of benzene and 50 ml of water. The benzene solution was washed three times with water, and benzene was distilled off under reduced pressure, whereby a red oily material was obtained. The product was dissolved in 50 ml of ethanol. Then 5 ml of water and 10 ml of 4N sodium hydroxide solution were added to the solution, and the resulting mixture was stirred for two hours. Then the pH of the reaction mixture was adjusted to 3 by adding 1N hydrochloric acid and excess sodium carbonate was added. Then ethanol was distilled off under reduced pressure and the residue was extracted with benzene. The extract was washed three times with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby a yellow, oily material was obtained. The product was then subjected to silica gel column chromatography (65 ml). The product was eluted using a 9: 1 benzene-acetone mixture and the eluate was concentrated under reduced pressure. 3-Benzyloxyacetylamino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was obtained, which is used in Example 15.

NMR (CDCl ₃ ):

Reference example 9

4 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol hydrochloride and 3.5 g of N-acetyl- β - alanine dissolved. Then 5.5 g of dicyclohexylcarbodiimide was added to the solution with ice cooling. The mixture was stirred overnight. After the deposited precipitates were filtered off, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 30 ml of methanol. Then 10 ml of 4N sodium hydroxide solution was added to the solution and the mixture was stirred for 3 hours. Then 1N hydrochloric acid was added to adjust to pH 3 and then excess sodium carbonate was added. The resulting mixture was stirred for 30 minutes. The reaction product was concentrated under reduced pressure and the residue was then extracted with 50 ml of chloroform. The extract was washed three times with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 4 g of yellow oily material were obtained. The material obtained was subjected to silica gel column chromatography (75 ml) and a further silica gel column chromatography (35 ml). 800 mg of pure caramel-like 3- (N-acetyl- β- alanyl) amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were obtained. In the above chromatography purification treatments, 4: 2: 1 ethyl acetate-benzene-methanol was used as the developing solvent. The product obtained is processed further in Example 16.

Elemental analysis for C ₃₆ H ₄₁ N ₃ O ₅ :

Calculated: C 72.58%, H 6.94%, N 7.05%; Found: C 72.44%, H 6.98%, N 6.86%.

Reference example 10

a) A mixture of 4.1 g of 4-benzyloxy-3-nitrio- α - bromo-acetophenone, 6.6 g of N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) amine and 41 ml of methyl ethyl ketone was heated to 65-80 ° C for one hour. After the reaction mixture was cooled, the crystals formed were filtered off and the filtrate was concentrated under reduced pressure. The residue formed in this way was dissolved in 40 ml of ethanol at temperatures below 50 ° C. and the solution was left to crystallize at room temperature. The crystals were separated by filtration. 3.7 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) amino] acetophenone were obtained.

b) 2.7 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) amino] acetophenone were suspended in 30 ml of methanol. Then 0.6 g of sodium borohydride was added to the suspension with ice cooling and the mixture was stirred for 1 hour. Then water was added, methanol was distilled off under reduced pressure, and the product was extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 2.6 g of yellowish powdery 4-benzyloxy-3-nitro- a - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol were obtained.

c) 1.3 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol were dissolved in 20 ml of methanol. Then 0.7 g of iron powder, 0.6 ml of 4.8 N hydrochloric acid and 3 ml of water were added to the solution and the mixture was refluxed for 2 hours and 30 minutes. After the insolubles had been filtered off, 0.8 g of sodium carbonate was added to the mixture and the mixture was stirred for 2 hours. Water was added to the obtained reaction mixture, methanol was distilled off under reduced pressure, and then extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 1.1 g of crystalline powdery 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol were obtained.

d) In 6 ml of acetic anhydride-formic acid mixture (5: 3), 1.0 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] Dissolved benzyl alcohol and left overnight. The reaction mixture was then concentrated under reduced pressure after standing. The residue was dissolved in a mixture of 10 ml of methanol and 2 ml of water, and 0.5 g of potassium hydroxide was added to the solution. The mixture was stirred at room temperature for one hour. Then methanol was distilled off from the reaction mixture under reduced pressure, the residue was mixed with water and then extracted with benzene. The extract was then washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off therefrom and 0.9 g of crystalline powdery 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol was obtained. The product obtained is reacted further in Example 17.

NMR (CDCl ₃ ):

δ : 2.04 ppm (S, 3H, H of the methyl group from the p-acetylamino group), 8.38 ppm (S, 1H, H of the formyl group), 4.4 ppm (m, 1H, H from the methine group to the hydroxyl group proper).

In the following reference examples 11 to 14, the same Repeat the above procedure, however using different starting materials.

Reference example 11

Using 2.7 g of 4-benzyloxy-3-nitro- α - bromoacetophenone and 4.8 g of N-benzyl-N- (1-methyl-2- {3,45-trimethoxyphenyl} ethyl) amine as starting materials 1.2 g of crystalline powdery 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2- {3,4,5-trimethoxyphenyl} ethyl) aminomethyl] benzyl alcohol were obtained. Further processing takes place in example 18.

NMR (CDCl ₃ ):

δ : 3.6 ppm, 3.7 ppm (9H, H from the methyl group from the 3,4,5-trimethoxy group), 8.36 ppm (S, 1H, H from the formyl group), 4.46 ppm (m, 1H, H of the methine group belonging to the hydroxyl group).

Reference example 12

When 10.4 g of 4-benzyloxy-3-nitro- α - bromoacetophenone and 15.2 g of N-benzyl-N- (1-methyl-3-p-hydroxyphenylpropyl) amine were used as starting materials, 5.9 g of 4- Benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-3-p-hydroxyphenylpropyl) aminomethyl] benzyl alcohol, which is used in Example 19.

NMR (CDCl ₃ ):

δ: 1.76 ppm (m, 2H, H of the methylene group in the 2 position of the 3-p-hydroxyphenylpropyl group), 8.38 (S, 1H, H of the formyl group), 4.56 ppm (m, 1H, H the methine group belonging to the hydroxyl group).

Reference example 13

Using 6.75 g of 4-benzyloxy-3-nitro-α- bromoacetophenone and 9.2 g of N-benzyl-N-p-tolylisopropylamine 3.7 g of 3-formylamino 4-benzyloxy-α- (N-benzyl-N- (1-methyl-2-p-tolylethyl) aminomethyl] benzyl alcohol obtained, the Further processing in Example 20 is carried out.

NMR: (CDCl ₃ ):

δ: 2.30 ppm (S, 3H, Φ-CH ₃ ), 5.02 ppm (S, 2H, -OCH ₂ -).

Reference example 14

a) A mixture of 9.4 g of 4-benzyloxy-3-nitro-α-bromoacetophenone and 13.7 g of N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) amine was added together with 50 ml of methyl ethyl ketone Heated at 70-80 ° C for one hour. After the solution was cooled and the precipitates formed were filtered off, the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, causing crystals to be deposited. The crystals were separated by filtration and recrystallized from ethanol. There were 12.8 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2- 2-methoxyphenylethyl) amino] acetophenone with the melting point at 100-102 ° C.

b) 12.8 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) amino] acetophenone were suspended in 200 ml of ethanol. 1.8 g of sodium borohydride was added to the suspension and the mixture was stirred overnight. Then, ethanol was distilled off from the reaction product, and water was added to the residue. The product was then extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure. 10.7 g of yellow oily 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl] aminomethyl] benzyl alcohol were obtained.

c) 10.7 g of 4-benzyloxy-3-nitro- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol were dissolved in 70 ml of methanol. Then, 15 ml of 2.2 N hydrochloric acid solution, 10 ml of water and 5.4 g of iron powder were added to the solution. The mixture was refluxed for one hour. After the insoluble matters had been filtered off from the reaction mixture, the filtrate was concentrated under reduced pressure, 50 ml of benzene, 10 ml of water and 10 g of sodium carbonate were added, and the mixture was then extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure. 8.8 g of yellow caramel-like 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol were obtained.

d) In 20 ml of acetic anhydride-formic acid mixture (5: 3) 5.5 g of 3-amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] Dissolved benzyl alcohol and then the solution was left overnight at room temperature. The solution was concentrated under reduced pressure. The residue was mixed with 50 ml of methanol, 3 ml of water and 3.5 g of sodium carbonate and the mixture was stirred for 2 hours at room temperature. Then methanol was distilled off under reduced pressure and the residue formed was extracted with benzene. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. 5.1 g of crystalline powdery 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol were obtained. Then 4.9 g of the product was dissolved in 20 ml of methanol and 1 g of fumaric acid was added to the solution. The mixture was concentrated under reduced pressure. The residue was dissolved in 80 ml of ethyl acetate and the solution was left overnight to crystallize out. The crystals formed were filtered off and recrystallized from isopropanol. 3.2 g of white crystalline 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol-1-fumarate with a melting point of 173 ° C. receive.

In 30 ml of 90% methanol, 3 g of the above manufactured product suspended to the Suspension added 1.5 g of sodium carbonate and Stirred for 30 minutes. The mixture was reduced Pressure reduced. The residue was treated with 10 ml Mixed water and extracted with 30 ml of benzene. The Extract was washed with water and over anhydrous Magnesium sulfate dried. Then the extract concentrated under reduced pressure. 2.3 g of one obtained white powder.

NMR (CDCl ₃ ):

δ : 4.52 ppm (m, 1H, CH belonging to the hydroxyl group), 348 ppm, 3.87 ppm (AB Type Quartet, 2H, CH ₂ belonging to N).

This product is referred to as 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenyl) aminomethyl] benzyl alcohol [A] and processed further in Example 21.

Furthermore, the solvent was distilled off from the mother liquor, which, after the crystals had been separated off from 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol-1- fumarate [A] had been obtained in the above step. The residue was dissolved in 30 ml of methanol. Then 3 ml of water and 1.5 g of sodium carbonate were added to the solution and the mixture was stirred for 30 minutes. The mixture was then concentrated under reduced pressure. The residue was mixed with 10 ml of water and extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. Then the solvent was distilled off. 2.3 g of slightly brownish powdery 4-benzyloxy-3-formylamino- a - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol were obtained. The product was subjected to silica gel column chromatography using benzene: ethyl acetate (10: 1) as an eluent, which was concentrated under reduced pressure. A white powder was obtained.

NMR (CDCl ₃ ):

δ : 4.40 ppm (m, 1H, CH belonging to the hydroxyl group), 3.73 ppm (S, 2H, CH ₂ belonging to N).

This is referred to as 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [B] and is used in Example 22.

Reference example 15

a) A mixture of 2.7 g of 4-benzyloxy-3-acetylamino- α - bromo-acetophenone and 4.0 g of benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amine was added together with 80 ml of methyl ethyl ketone Room temperature stirred for 4 hours. After the precipitates formed were filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was then separated using a 10: 2 benzene / ethyl acetate mixture as the eluent. 2.2 g of yellowish crystalline powdery 4-benzyloxy-3-acetylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone were obtained.

b) 0.9 g of 4-benzyloxy-3-acetylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone was dissolved in 18 ml of ethanol. Then 0.1 g of 10% palladium carbon was added to the solution. Thereafter, the catalytic reduction was carried out at normal temperature and pressure until 78 ml of hydrogen was absorbed. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography. From the eluate, using a 4: 2: 1 ethyl acetate-benzene-methanol mixture, 0.5 g of yellowish crystalline powdery 3-acetylamino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl ) amino] acetophenone obtained and used in Example 23.

NMR (D ₆ -DMSO):

δ : 2.12 ppm (S, 3H, H on the methyl group of the 3-acetylamino group), 0.98 ppm (d, 3H, H on the 1-methyl group), 4.10 ppm (2H, H on the methylene group between Carbonyl group and amino group).

The invention is now practically illustrated by the following examples. Table III shows the structural formulas of the starting and end products and the radicals R ₁ , R ₂ , R ₃ and R _{4 of} the end products.

Table III

continuation

continuation

continuation

continuation

continuation

continuation

Example 1

1.4 g of 4-benzyloxy-3-formylamino- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were dissolved in 20 ml of ethanol. 0.2 g of 10% palladium-carbon was added to the solution and the catalytic reduction was carried out at normal temperature and normal pressure. After the consumption of 165 ml of hydrogen, the reaction was stopped. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue formed was dissolved in a small amount of ethanol. Then a small amount of ether was added to the solution and the solution was left to stand, whereby crystals were precipitated. By separating the crystals by filtration, 0.7 g of 3-formylamino-4-hydroxy- α - (isopropylaminomethyl) benzyl alcohol was obtained.

When 120 mg of the product obtained above was added to 2 ml of ethanol solution containing 30 mg of fumaric acid and the mixture was left to stand, white crystals were deposited. The crystals were separated by filtration. There was obtained 3-formylamino-4-hydroxy- α - (siopropylaminomethyl) benzyl alcohol ½ fumarate with a melting point at 179-190 ° C (with decomposition).

Elemental analysis for C ₁₄ H ₂₀ N ₂ O ₅ :
Calculated: C 56.75%, H 6.80%, N 9.45%; Found: C 56.71%, H 6.76%, N 9.70%.

Example 2

2.3 g of 4-benzyloxy-3-benzyloxyacetylamino- a - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol were dissolved in 100 ml of methanol. To the solution was added 4.3 ml of 1N hydrochloric acid in ethanol, then 0.3 g of 10% palladium-carbon was added. The catalytic reduction was carried out at normal pressure and normal temperature. When 300 ml of hydrogen was absorbed, the reaction was stopped. Thereafter, the catalyst was filtered off and then the solvent was distilled off under reduced pressure. White crystals were obtained as a residue. By recrystallization from methanol-n-hexane, 600 mg of 4-hydroxy-3-hydroxyacetylamino- α - (isopropylaminomethyl) benzyl alcohol hydrochloride with a melting point at 188-190 ° C. were obtained.

Elemental analysis for C ₁₃ H ₂₀ N ₂ O ₄ · HCl:
Calculated: C 51.23%, H 6.95%, N 9.19%; Found: C 50.79%, H 7.03%, N 9.03%.

Example 3

1 g of 3-acetylamino-4-benzyloxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was dissolved in 20 ml of ethanol. 0.2 g of 10% palladium carbon was added to the solution. The catalytic reduction was carried out at normal pressure and normal temperature. After the consumption of 115 ml of hydrogen, the reaction was stopped. Then the catalyst was filtered off and the reaction product was concentrated under reduced pressure, whereby an oily material was obtained. The oily material was dissolved in ethyl acetate and then 3N hydrochloric acid-ethanol solution was added to the solution, whereby crystals were deposited. The solvent was removed by decantation and the crystals were washed with ethyl acetate and dried. 0.5 g of crystalline powdery 3-acetylamino-4-hydroxy- a - (isopropylaminomethyl) benzyl alcohol hydrochloride was obtained.

Elemental analysis for C ₁₃ H ₂₀ N ₂ O ₃ · HCl
Calculate: C 54.07%, H 7.33%, N 9.70%; Found: C 53.81%, H 7.28%, N 9.63%.

Example 4

2.5 g of 4-benzyloxy-3-formylamino- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol were dissolved in 30 ml of ethanol. 0.2 g of 10% palladium-carbon was added to the solution and the catalytic reduction was carried out at normal temperature and normal pressure. After 280 ml of hydrogen had been absorbed, the reaction was terminated. After filtering off the catalyst, the reaction product was concentrated under reduced pressure. 1.3 g of crystalline powdery 3-formylamino-4-hydroxy- α - (tert-butylaminomethyl) benzyl alcohol were obtained. 1.2 g of the product obtained was added to 15 ml of ethanol containing 0.3 g of fumaric acid dissolved therein, and the mixture was left overnight at -4 ° C, whereby white crystals separated. By separating the crystals by filtration, 1.14 g of 3-formylamino-4-hydroxy- α - (tert-butylaminomethyl) benzyl alcohol ½-fumarate with a melting point at 195-196 ° C. was obtained.

Elemental analysis for C ₁₅ H ₂ N ₂ O ₅ :
Calculated: C 58.05%, H 7.15%, N 9.03%; Found: C 58.03%, H 7.21%, N 8.94%.

Example 5

1 g of 3-acetylamino-4-benzyloxy- α - (N-benzyl-N-isopropylamino) acetophenone was dissolved in 15 ml of ethanol. 0.2 g of 10% palladium carbon was added to the solution. Then the catalytic reduction was carried out at normal temperature and normal pressure. After absorbing 168 ml of hydrogen, the reaction was stopped. The catalyst was filtered off and the reaction product was concentrated under reduced pressure. 0.45 g of crude 3-acetylamino-4-hydroxy- α - (isopropylaminomethyl) benzyl alcohol was obtained. When 250 mg of the obtained product was added to 5 ml of ethanol containing 60 mg of fumaric acid in a dissolved form, crystals were formed after standing. After the crystals had been separated off by filtration, 150 mg of 3-acetylamino-4-hydroxy- α - isopropylaminomethyl) benzyl alcohol ½ fumarate with a melting point of 189-192 ° C. were obtained.

Elemental analysis for C ₁₅ H ₂₂ N ₂ O ₅ :
Calculated: C 58.05%, H 7.15%, N 9.03%; Found: C 57.72%, H 7.26%, N 8.93%.

Example 6

0.7 g of 4-benzyloxy-3-formylamino- α - (N-isopropyl-N-benzylamino) acetophenone was dissolved in 10 ml of methanol. Then 0.2 g of 10% palladium-carbon was added and the catalytic reduction was carried out at normal temperature and normal pressure. When 120 ml of hydrogen was absorbed, the reaction was stopped. The catalyst was filtered off. The reaction product was concentrated. 0.3 g of crude 3-formylamino-4-hydroxy- α - (N-isopropylaminomethyl) benzyl alcohol was obtained. 240 mg of the product was dissolved in 3 ml of ethanol and then 60 mg of fumaric acid was added. The mixture was left to stand at room temperature, whereby crystals were deposited. These were filtered off. There were 75 mg of 3-formylamino-4-hydroxy- α - (isopropylaminomethyl) benzyl alcohol ½ fumarate with the melting point at 179-181 ° C.

The product had the same infrared absorption spectrum as the product obtained according to Example 1.

Example 7

1 g of 4-benzyloxy-3-formylamino- α - (N-benzyl-N-tert-butylamino) acetophenone was dissolved in 20 ml of ethanol. 0.2 g of 10% palladium-carbon was added to the solution and the catalytic reduction was carried out at normal temperature and normal pressure. As soon as 165 ml of hydrogen had been absorbed, the reaction was terminated. After filtering off the catalyst, the reaction product was concentrated. 0.5 g of crude 3-formylamino-4-hydroxy- α - (tert-butylaminomethyl) benzyl alcohol was obtained. 250 mg of the product was added to 5 ml of ethanol containing 60 mg of fumaric acid dissolved, and then the mixture was left to stand at room temperature, whereby crystals were deposited. These were separated by filtration. 100 mg of 3-formylamino-4-hydroxy- α - (tert-butylaminomethyl) benzyl alcohol ½ fumarate were obtained with the melting point at 195-196 ° C.

The product had the same infrared absorption spectrum as the compound prepared according to Example 4.

Example 8

0.45 g of 3-formylamino-4-hydroxy- α - (N-benzyl-N-isopropylaminomethyl) benzyl alcohol was dissolved in 10 ml of ethanol. Then 0.1 g of 10% palladium carbon was added to the solution. The catalytic reduction was carried out at normal temperature and normal pressure. As soon as 36 ml of hydrogen were absorbed, the reaction was terminated. After filtering off the catalyst, the reaction product was concentrated under reduced pressure. 0.32 g of white crystalline powdery 3-formylamino-4-hydroxy- α - (isopropylaminomethyl) benzyl alcohol was obtained. 240 mg of the product were dissolved in 3 ml of ethanol and 60 mg of fumaric acid were added. The mixture was allowed to stand at room temperature for crystal deposition. 250 mg of white crystalline 3-formylamino-4-hydroxy- α - (isopropylaminomethyl) benzyl alcohol ½ fumarate were obtained.

The product had the same infrared absorption spectrum like that for the compound according to Example 1 was obtained.  

Example 9

0.9 g of 3-formylamino-4-hydroxy- α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol was dissolved in 10 ml of ethanol. 0.1 g of 10% palladium-carbon was added to the solution. Then the catalytic reduction was carried out at normal temperature and normal pressure. After 65 ml of hydrogen was absorbed, the reaction was stopped. The catalyst was filtered off and the reaction product was concentrated under reduced pressure. 0.65 g of white crystalline powdery 3-formylamino-4-hydroxy- α - (tert-butylaminomethyl) benzyl alcohol was obtained. 500 mg of the product was dissolved in 5 ml of ethanol and then 120 mg of fumaric acid was added to the solution. The mixture was left at room temperature until crystals were deposited. These were filtered off. 520 mg of 3-formylamino-4-hydroxy- α - (tert-butylaminomethyl) benzyl alcohol ½-fumarate were obtained.

The product showed the same infrared absorption spectrum like the product produced according to Example 4.

Example 10

1.1 g of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] (prepared according to Reference Example 5) were suspended in 20 ml of ethanol . Then 0.1 g of 10% palladium-carbon was added to the suspension and the catalytic reduction was carried out at normal temperature and normal pressure until 105 ml of hydrogen had been absorbed. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. 0.7 g of white crystalline powdery 3-formylamino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] was obtained.

0.34 g of the product prepared above was dissolved in 95% ethanol together with 0.06 g of fumaric acid and the solution was left to form crystals. The crystals were separated. 0.33 g of 3-formylamino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [A] -½ fumarate with a melting point of 151.8-153 ° C. was obtained .

Elemental analysis for C ₂₀ H ₂₄ N ₂ O ₆ :
Calculated: C 61.85%, H 6.23%, N 7.21%; Found: C 61.52%, H 6.31%, N 7.31%.

Example 11

1.0 g of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [B] (prepared according to Reference Example 5) was dissolved in 10 ml of ethanol . Then 0.1 g of 10% palladium-carbon was added to the solution. The catalytic reduction was carried out at normal temperature and normal pressure until 95 ml of hydrogen had been absorbed. Then the catalyst was filtered off and the reaction product was concentrated under reduced pressure. 0.65 g of pale brownish powdery 3-formylamino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [B] was obtained.

0.34 g of the product obtained above was dissolved in 95% ethanol together with 0.06 g of fumaric acid. Then the solution was left to crystallize. The crystals formed were separated. 0.3 g of 3-formylamino-4-hydroxy- a - [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol [B] 1/2 fumarate with a melting point of 154.1-155 ° C. was obtained.

Elemental analysis for C ₂₀ H ₂₄ N ₂ O ₆ :
Calculated: C 61.85%, H 6.23%, N 7.21%; Found: C 61.73%, H 6.27%, N 7.19%.

The compounds obtained in Examples 10 and 11 represent diastereoisomers.

Example 12

1.5 g of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-3-cyclohexylpropyl) aminomethyl] benzyl alcohol were dissolved in 20 ml of ethanol. 0.2 g of 10% palladium-carbon was added to the solution and the catalytic reduction was carried out at normal temperature and normal pressure until 140 ml of hydrogen had been absorbed. After filtering off the catalyst, the reaction product was concentrated under reduced pressure. 0.9 g of white crystalline powdery 3-formylamino-4-hydroxy- α - [N- (1-methyl-3-cyclohexylpropyl) aminomethyl] benzyl alcohol was obtained.

470 mg of the product obtained above was dissolved in 7 ml of 0.2 N acetic acid, dissolved in ethanol. The solution was concentrated to 2-3 ml. Ether was added and the mixture was left to crystallize. The white crystals formed were filtered off. 0.5 g of 3-formylamino-4-hydroxy- α - [N- (1-methyl-3-cyclohexylpropyl) aminomethyl] benzyl alcohol acetate with a melting point of 138-140 ° C. was obtained.

Elemental analysis for C ₂₁ H ₃₄ N ₂ O ₅ :
Calculated: C 63.94%, H 8.69%, N 7.10%; Found: C 64.31%, H 8.92%, N 7.46%.

Example 13

1.4 g of 4-benzyloxy-3- (N-methyl-N-formylamino) - α - (N-benzyl-N-tert-butylaminomethyl) benzyl alcohol (prepared according to Reference Example 6) were dissolved in 20 ml of ethanol. 0.1 g of 10% palladium-carbon was added to the solution and the catalytic reduction was carried out until 150 ml of hydrogen had been absorbed. The catalyst was filtered off and the reaction product was concentrated under reduced pressure. 0.8 g of white crystalline powdery 4-hydroxy-3- [N-methyl-N-formylamino) - α - tert-butylaminomethylbenzyl alcohol was obtained. 360 mg of the product were dissolved in 6 ml of ethanol together with 85 mg of fumaric acid and the solution was left to stand for crystal deposition. The deposited white crystals were separated by filtration. There were 390 mg of 4-hydroxy-3- (N-methyl-N-formylamino) - a-tert-butylaminomethylbenzylalkohol ½fumarat obtained with the melting point at 188 ° C.

Elemental analysis for C ₁₆ H ₂₄ N ₂ O ₅ :
Calculated: C 59.24%, H 7.46%, N 8.64%; Found: C 59.16%, H 7.47%, N 8.34%.

Example 14

1.2 g of 4-benzyloxy-3-acetylamino- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol (prepared according to Reference Example 7) were dissolved in 12 ml of ethanol. Then 0.2 g of 10% palladium carbon was added to the solution. Thereafter, the catalytic reduction was carried out at normal temperature and pressure until 110 ml of hydrogen was absorbed. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. 0.75 g of crystalline powdery 3-acetylamino-4-hydroxy- a - [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was obtained.

Elemental analysis for C ₁₉ H ₂₄ N ₂ O ₄ :
Calculated: C 66.26%, H 7.02%, N 8.13%; Found: C 66.43%, H 6.81%, N 7.88%.

Example 15

1.2 g of 3-benzyloxyacetylamino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was dissolved in 50 ml of ethanol. 0.5 g of 10% palladium-carbon was added to the solution. The catalytic reduction was carried out at normal temperature and normal pressure until 137 ml of hydrogen had been absorbed. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. 0.8 g of white caramel-like 3-hydroxyacetylamino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was obtained.

NMR: (D ₆ -DMSO):

Example 16

In 30 ml of methanol, 800 mg of 3- (N-acetyl- β- alanyl) amino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol (prepared according to Reference example 9) resolved. Then 50 mg of 10% palladium carbon was added to the solution. The catalytic reduction was carried out at normal temperature and pressure until 65 ml of hydrogen had been absorbed. Then the catalyst was filtered off. The filtrate was concentrated under reduced pressure. 470 mg of white caramel-like 3- (N-acetyl- β- alanyl) amino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol were obtained.

NMR (D ₆ -DMSO):

δ : 0.90 ppm (d, 3H, CHCH ₃ ), 1.80 ppm (S, 3H -COCH ₃ ), 4.45 ppm (m, CHOH).

Example 17

0.7 g of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol was dissolved in 7 ml of ethynol. 0.15 g of 10% palladium-carbon was added to the solution. The catalytic reduction was carried out at normal temperature and pressure until 61 ml of hydrogen had been absorbed. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. 0.34 g of crystalline powdery 3-formylamino-4-hydroxy- α - [N- (1-methyl-2-p-acetylaminophenylethyl) aminomethyl] benzyl alcohol was obtained.

NMR (D ₆ -DMSO):

δ : 2.04 ppm (S, 3H, H on the methyl group from the p-acetylamino group), 8.30 ppm (S, 1H, H on the formyl group), 4.48 ppm (m, 1H, H on the methine group) belonging to the hydroxyl group).

Example 18

1.2 g of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-2- {3,4,5-trimethoxyphenyl} ethyl) aminomethyl] benzyl alcohol (prepared according to Reference example 11) resolved. After adding 0.2 g of 10% palladium-carbon, the catalytic reduction was carried out until 110 ml of hydrogen was absorbed. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure. 0.7 g of crystalline powdery 3-formylamino-4-hydroxy- a - [N-1-methyl-2- {3,4,5-trimethoxyphenyl} ethyl) aminomethyl] benzyl alcohol was obtained.

Elemental analysis for C ₂₁ H ₂₈ N ₂ O ₆ :
Calculated: C 62.36%, H 6.98%, N 6.93%; Found: C 61.99%, H 6.98%, N 6.66%.

Example 19

2.2 g of 4-benzyloxy-3-formylamino- α - [N-benzyl-N- (1-methyl-3-p-hydroxyphenylpropyl) aminomethyl] benzyl alcohol (prepared according to Reference Example 12) were dissolved in 40 ml of ethanol. 0.3 g of 10% palladium-carbon was added to the solution and the catalytic reduction was carried out at normal temperature and normal pressure until 195 ml of hydrogen had been absorbed. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. 1.3 g of crystalline powdery 3-formylamino-4-hydroxy- α - [N- (1-methyl-3-p-hydroxyphenylpropyl) aminomethyl] benzyl alcohol were obtained. 0.60 g of the product obtained and 0.102 g of fumaric acid were dissolved in 95% ethanol and the solution was left to crystallize, with white crystals separating out. The crystals were filtered off. 0.55 g of 3-formylamino-4-hydroxy- α - [N- (1-methyl-3-p-hydroxyphenylpropyl) aminomethyl] benzyl alcohol ½ fumarate monohydrate was obtained.

Elemental analysis for C ₂₁ H ₂₈ N ₂ O ₇ :
Calculated: C 59.99%, H 6.71%, N 6.66%; Found: C 60.07%, H 6.81%, N 6.74%.

Example 20

1.62 g of 3-formylamino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-tolylethyl) aminomethyl] benzyl alcohol (prepared according to Reference Example 13) was dissolved in 50 ml of ethanol. 0.3 g of 10% palladium-carbon was added to the solution and the catalytic reduction was carried out at normal pressure and normal temperature until 154 ml of hydrogen had been absorbed. The catalyst was filtered off, and 8 ml of water and 186 mg of fumaric acid were added to the remaining ethanol solution. The solvent was removed from the obtained solution under reduced pressure. The residue was dissolved in ethanol and benzene was added to the solution until the solution became slightly cloudy. When the batch was left in the freezer, 550 mg of white crystals were formed. The crystals were filtered off and recrystallized from ethanol-benzene. 3-Formylamino-4-hydroxy- α - [N- (1-methyl-2-p-tolylethyl) aminomethyl] benzyl alcohol ½ fumarate · ½ hydrate with the melting point at 132-133 ° C. (with decomposition) was obtained.

Elemental analysis for C ₂₁ H ₂₆ N ₂ O ₅ ·½H ₂ O:
Calculated: C 63.78%, H 6.88%, N 7.08%; Found: C 63.99%, H 6.70%, N 6.82%.

Example 21

0.52 g of 3-formylamino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [A] (prepared according to reference example 14) was dissolved in 10 ml of ethanol . 0.2 g of 10% palladium-carbon was added to the solution, and then the catalytic reduction was carried out at normal temperature and pressure until 48 ml of hydrogen was absorbed. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. 0.35 g of white crystalline powdery 3-formylamino-4-hydroxy- α - [N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [A] was obtained. 0.35 g of the product was dissolved in 7 ml of 95% ethanol together with 0.06 g of fumaric acid and the solution was left to crystallize. The crystals were separated by filtration. 0.34 g of white, crystalline 3-formylamino-4-hydroxy- α - [N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [A] · ½ fumarate with a melting point of 138-140 ° C. (with decomposition).

Elemental analysis for C ₂₁ H ₂₆ N ₂ O ₆ · H ₂ O:
Calculated: C 59.99%, H 6.71%, N 6.66%; Found: C 59.63%, H 6.65%, N 6.71%.

Example 22

0.79 g of 3-formylamino-4-benzyloxy- α - [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [B] (prepared according to reference example 14d) was dissolved in 30 ml of ethanol . Then 0.2 g of 10% palladium-carbon was added to the solution and the catalytic reduction was carried out at normal pressure and normal temperature until 73 ml of hydrogen had been absorbed. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. 0.57 g of white powdery 3-formylamino-4-hydroxy- α - [N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [B] was obtained. 0.57 g of the product was dissolved in 8 ml of 95% ethanol together with 0.087 g of fumaric acid. Then 0.5 ml of water was added to the solution and left to crystallize. The white crystals formed were separated by filtration. 0.3 g of 3-formylamino-4-hydroxy- α - [N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol [B] -½ fumurate with a melting point of 154-155 ° C. (with decomposition ) receive.

Elemental analysis for C ₂₁ H ₂₆ N ₂ O ₆ ² / ₃H ₂ O:
Calculated: C 60.89%, H 6.65%, N 6.76%; Found: C 60.94%, H 6.69%, N 6.77%.

The compounds obtained in Examples 21 and 22 are very excellent drugs with particularly valuable therapeutic properties.

Example 23

0.28 g of 3-acetylamino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl) amino] acetophenone was dissolved in 3.5 ml of ethanol. Then 0.16 g of 10% palladium-carbon was added to the solution and the catalytic reduction was carried out at normal temperature and normal pressure until 20 ml of hydrogen had been absorbed. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. 0.21 g of crystalline powdery 3-acetylamino-4-hydroxy- α - [N- (1-methyl-2-p-hydroxyphenylethyl) aminomethyl] benzyl alcohol was obtained. The infrared absorption spectrum of this product coincided with the infrared absorption spectrum of the product produced according to Example 14.

Example 24 (tablets)

Formulation:
3-Acetamido-4-hydroxy- α - (isopropylaminomethyl) benzyl alcohol ½ fumarate 100 mg lactose 100.0 g starch 35.0 g talcum 5.0 g

The above formulation became 1000 tablets manufactured, each tablet had a diameter of 7 mm. If necessary, these can be covered with a coating be provided.

Example 25 (injection)

Formulation:
3-Acetamido-4-hydroxy- α - (isopropylaminomethyl) benzyl alcohol ½ fumarate 50 mg sodium chloride 8.5 g citric acid 1.0 g made up to 1000 ml pH 4.0-6.0 with water

1000 injection vials were made from the above formulation each with 1 ml content. The injection preparation was by dissolving the above Components in water, sterilization by filtration, Filled in ampoules and fused.

Claims (7)

1. Compounds of the general formula as well as their acid addition salts of pharmaceutically acceptable non-toxic inorganic or organic acids, in which R _{3 represents the} following radicals: 2. Compounds of the general formula and their acid addition salts of pharmaceutically acceptable non-toxic inorganic or organic acids, in which R ′ _{3 represents the} following radicals: 3. Compounds of the general formula and their acid addition salts of pharmaceutically acceptable non-toxic inorganic or organic acids, in which R ″ _{3 represents the} following radicals: 4. Compounds of the general formula and their acid addition salts of pharmaceutically acceptable non-toxic inorganic or organic acids, in which Y represents a hydrogen atom or an ethyl radical. 5. Compound of the formula as well as their acid addition salts of pharmaceutically acceptable non-toxic inorganic or organic acids. 6. A process for the preparation of α - aminomethylbenzyl alcohols according to Claims 1 to 5, characterized in that compounds or their acid addition salts of the formulas mentioned in Claims 1 to 5 in which one or more hydrogen atoms of secondary amino groups and / or hydroxyl groups are used a benzyl group, a benzyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group is protected, freed from these protective groups by reduction with hydrogen and optionally converted into the acid addition salts by adding non-toxic inorganic or organic acids. 7. Pharmaceutical preparations, characterized by a content on one of the compounds according to claims 1 to 5 as Active ingredient.