DE1543522A1 - Therapeutically effective acylaminophenol alkanols and processes for their preparation - Google Patents

Description

Therapeutically effective acylaminophenol alkanols and processes for their preparation

The invention relates to acylaminophenol alkanols of the general formula

CH - CH - NH - Ac, ι t

EAR

(D

in which R is hydrogen or lower alkyl with one to four carbon atoms and Ac is the acyl radical of an aliphatic saturated or unsaturated mono- or dicarboxylic acid, an aromatic or heterocyclic acid or a more complex organic acid with optionally physiological intrinsic effect, such as theophyllinetic acid, mean. Also relates the invention relates to a process for the preparation of such Ac ylaminophenolalkanoIe.

909836 / U92

BATH ORIGINAL

It is known that therapeutically effective hydroxyphenylalkanolamines are broken down into ineffective compounds fairly quickly in the organism. In many cases it is rapid dismantling is desirable. But there are circulatory diseases that require therapy with less rapidly decaying pharmaceuticals.

It has now been found that the previously unknown compounds of type I.

- Cii - CiI - NH - Ac,

f I

OH II

where K is hydrogen or lower alkyl with one to four carbon atoms and Ac is an acyl radical, are excellently suited for such a therapy. Thus, for example the N-acetyl-l- ^(1: 3 -hydroxyphenyl) -2-aminoethanol, although orally in animal experiments in the cat and parenterally in contrast to l- (3 ^{L-hydroxyphenyl)} -2-aminoethanol virtually no pressor effect. It was therefore surprising that N-acetyl-l- (3 x hydroxyphenyl) -2-aminoethanol certain in Schellongtest in humans after oral administration hypotonic W affected states very favorable; Therapy-resistant hypotonic patients showed a stabilization of the circulatory system just 24 to 36 hours after the start of treatment.

It is of particular advantage that the toxicity of the substance is significantly lower than that of the related, not N-acylated sympathicomiraetica commonly used in therapy.

The increased compatibility of the compounds according to the invention with an excellent effect on the circulation compared to known compounds Connections represent a significant advance in therapy.

909836 / U92

BATH ORIGINAL

According to the invention, these compounds are prepared by using amines of the formula

- CHOH - CH - NII ₀ (II),

1 ^Λ .

where it has the meaning given for formula (I), or their acid addition salts in a manner known per se with reactive derivatives of the carboxylic acids mentioned v / ie converting halides, anhydrides or esters, or that the amines of the formula (II) are reacted with corresponding carboxylic acids with the addition of dehydrating agents, such as, for example Carbonyldiimidazole or üicyclohexylcarbodiimid, or reacts at an elevated temperature.

The amines to be reacted according to the invention include, for example, JL- (3 ^f -hydroxyphenyl) -2-aminoethanol and m-hydroxy-norephedrine. Acetyl, butyryl, benzoyl and nicotinoyl chloride, but also propionyl bromide, are used as acid halides. As part of the. Anhydrides to be used in the invention are, for example, acetic, succinic, maleic, glutaric and benzoic anhydrides. As esters, propionic, benzoin, nicotine, pivaline, quinoline-2-carbon or theophylline-7-acetic acid methyl or ethyl ester and many others can be used.

When the acid halides or anhydrides are reacted in pyridine solution, their acid addition salts, such as hydrochlorides or bromides, can also be reacted instead of the amines of the formula (II). When converting carboxylic acid esters, an excess of ester is preferably used for quantitative conversion. If you set

909836 / U92 bad original

the amines, on the other hand, with acid halides, then for To achieve uniform reaction products, it is advisable to work with molar quantities in the cold. The condensation of amines with carboxylic acids are expediently carried out in inert solvents, those with water are not are miscible, and removes the water of reaction by azeotropic distillation. The condensation with the help of dicyclohexylcarbodiimide is in alcohols, methylene chloride, tetrahydrofuran, pyridine or other solvents performed.

The preparation of the compounds according to the invention is explained in more detail in the examples below.

example 1

15.3 g of 1- (3 · -Hydroxyphenyl) -2-aminoethanol were in 150 ml of pyridine dissolved. While stirring and cooling with ice, 12.1 g of pivaloyl chloride were added dropwise over the course of 20 minutes. It was Stirred for a further two hours at 25 ° C. and then brought to dryness in vacuo. The residue was with 0.05 mol Soda and 25 ml of water worked through and again brought to dryness, whereupon the residue formed Amide was withdrawn with alcohol. The evaporation residue was used to separate off unreacted starting compound Dissolved in n-butanol and repeatedly with phosphate buffer (pH 8) shaken out. The substance contained in the butanol was recrystallized from ethyl acetate and resulted 11.8 g (50% of theory) N-pivaloyl-1- (3 * -hydroxyphenyl) -2-aminoethanol in the form of white crystals with a melting point of 115 to 117 ° C, which can be found by thin-layer chromatography consistently proven.

^C lAe ^N0 3 - ²³⁷ ' ³ calculated " ⁵ ' ⁹³ *

"found - 5.95 %

8AD ORIGINAL 909836 / U92

Example 2

56, t) g l- (3 * hydroxyphenyl) -2-aminoethanol hydrochloride was dissolved in 150 ml of pyridine and added dropwise under Kühren at 20 ⁰ C over two hours 30 ο g of acetic anhydride. After standing overnight, the mixture was concentrated to dryness, the residue was dissolved with 31.8 g of anhydrous soda and 100 ml of water and again evaporated. The residue was extracted three times with 250 ml of isopropanol; the combined extracts yielded 52.4 g of solid residue after evaporation. This was recrystallized twice from isopropanol and gave 31 g (52 % of theory ) N-acetyl-1- (3 ^f -hydroxyphenyl) -2-aminoethanol with a melting point of 113 ° to 119 ° C., which was uniform by thin layer chromatography.

^C x0 ^H 13 ^NÜ 3 - ¹⁹⁰ ' ² . »Calculated ^{= 7} ' ^{1β %}

found " ⁷ ' ^{0β %}

Example 3

16.4 g of 1- (3 ^t -hydroxyphenyl) -2-aminoethanol monohydrate were stirred under reflux in 35 g of propionate for 24 hours. It was then concentrated to dryness in vacuo. The residue was recrystallized from isopropanol / ethyl acetate. 12.1 g (58 % of theory ) of N-propionyl-1- (3'-hydroxyphenyl) -2-aminoethanol with a melting point of 112 ° to 114 ° C. were obtained.

^C LAoE ^NÜ 3 - ^{2Ü9> 25} "calculated" ^{6 '69%}

found = ^{6 '68} -

BATH ORIGINAL 90 9836 / U92

Example 4

1.67 g of l- (3 ^l -hydroxyphenyl) -2-aminopiOpanoi were refluxed with 20 ml of n-butyl acetate for 12 hours. After concentration to dryness, it was chromatographed on silica gel with benzene / methanol (4 + 1). The main fraction is dünnschichtchroüiatographisch uniform and gave after crystallization from acetone / (d ¹ 42 Jo. Th.) Iither 0.88 g .N-acetyl-1-1- (3'-hydroxyphenyl) -2-aminopropanol from the melting point to 115 ° C llö .

^c lA5 ^NO 3 ^{= 2Ο9} ' ^ύ calculated " ^ö ' ⁶⁹ *

found ~ ^{u '52%}

Example 5

8.55 g of l- (3 ^f -iiydroxyphenyi) -2-aminoethanol monohydrate were dissolved in 100 ml of acetone and mixed with 6 g of succinic anhydride dissolved in 10 ml of acetone. After standing for one hour, the mixture was heated to the reflux for a further 10 minutes and then brought to dryness. The oily residue crystallized on trituration with ethyl acetate. For analysis, it was recrystallized again from acetone. Yield: 12.1 g (96 % of theory ) of N-succinyl-l- (3 ^l -hydroxyphenyl) -2-aminoethanol with a melting point of 133 ° to 134 ° C. in the form of white crystals that dissolve easily in water, methanol and ethanol were soluble.

^C 12 ^H 15 ^NO 5 ^{= 25ΰ} ' ³ calculated ^{= 5} ' ⁵ ^ * -

found "5, ^%

Example 6

In the same way as in Example 5, 17.1 g of 1- ( δ * -hydroxyphenyl) -2-aminoethanol monohydrate were reacted with 9.8 g of maleic anhydride. Manferistallized from "! Ethanol and obtained 12.1 g of N-maleinyl-1- (3'-hydroxyphenyl) -2-aminoethanol with a melting point of 181 to 13 ° C (decomp.). The substance dissolved in lower alcohols and aqueous bicarbonate solution .

909836 / U92 ^ I £

^C 12 ^H ia ^NO 5 - ²⁵¹ ' ² »calculated " ⁵ ' ^{58 %}

Found- * δ, 4β%

Example 7

17.1 g of 1- (3 * -hydroxyphenyl) -2-aminoethanol monohydrate were melted with 50 g of methyl nicotinate and stirred at 160 ° C. for four hours. Excess nicotinic acid ester was then largely distilled off in vacuo. The residue was dissolved in 250 ml of water, extracted three times with ether and again brought to dryness. The vapor residue was chromatographed on silica gel with benzene / methanol (4 + 1) and gave the main fraction 12.5 g (48 % of theory ) of N-nicotinoyl-1- (3-hydroxyphenyl) -2-aminoethanol with a melting point of 146 up to 148 ° C ₁ which was recrystallized from ethanol / ether for analysis.

^C LAA ° 3 - ²⁵⁸ ' ³ »calculated" ¹⁰ ' ^{85 %}

N - lü, 5ii %

found

Example 8

15, bg 1- (3 * -hydroxyphenyl) -2-aminoethanol and 25.2 g of theophylline-7-acetic acid methyl ester were melted in the bottom flask and kept at 120 to 125 ° C. for two hours with the riser tube attached. After cooling, the crystalline cake was redissolved from copious amounts of methanol. There were 22.7 g (61% d. Th.) N-theophylline-7-acetyll- ^(t 3 -hydroxyphenyl) -2-aminoethanol in a white form, obtained by thin layer chromatography uniform crystals of melting point 210 to 212 ° C.

^C 17 ^H 19 ^N 5 ° 5 * ³⁷³ ' ⁴ »calculated" ¹⁸ ' ^{78 %}

Viunden - ".« *

909836/1492

Example 9

8.55 g of 1 - (. 3 · -Hydroxyphenyl) -2-aminoethanol monohydrate and 6.1 g of benzoic acid were concentrated with the addition of 1 drop. Sulfuric acid in 200 ml of xylene with the interposition boiled under reflux in a water separator. After about 2 ml of water had separated off, the reaction was complete. Most of the xylene was removed in vacuo, taken up in methylene chloride, washed three times with water and concentrated Dry up. The residue was recrystallized from ethyl acetate. 11.4 g of N-benzoyl- (3 · hydroxyphenyl) -2-aminoethanol were obtained from a melting point of 149 to 150 ° C. The substance formed colorless crystals, which were insoluble in water, acids and alkalis and easily soluble in lower alcohols.

^C 15 ^H 15 ^NO 3 - ²⁵⁷ x ³ . »Calculated" ^{5 '45 %}

»Found- - 5.24 *

Example 10

15.3 g of 1- (3'-hydroxyphenyl) -2-aminoethanol and 12.2 g Benzoic acid was dissolved in 100 ml of pyridine, and at -10 ° C. 20.6 g of dicyclohexylcarbodiimide were added in portions registered. The mixture was allowed to warm to room temperature over the course of five hours and the dicyclohexylurea was sucked off away. The filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate. One received in 72% yield N-benzoyl-1- (3 · hydroxyphenyl) -2-aminoethanol, that in melting point, mixed melting point and analysis with the substance obtained according to Example 9 was identical.

The invention includes everything that is contained in the description, including everything that deviates of the specific exemplary embodiments are obvious to the person skilled in the art.

Claims: 909836 / U92

BATH ORIGINAL

Claims (15)

Patent to s ρ r ti c h e: 1. Acylaminophenolalkanols of the general formula - Cxi - CH - NH - ac, in which H is hydrogen or lower alkyl with one to four carbon atoms and Ac is the acyl radical of an aliphatic saturated or unsaturated mono- or dicarboxylic acid, an aromatic or heterocyclic acid or a more complex organic acid with possibly a physiological intrinsic effect, such as for example theophyllinetic acid. 2. N-Pivaloy1-1- (J ¹ -hydroxyphenyl) -2-aminoethanol. 3. N-Acetyl-1- ( ¹ -hydroxyphenyl) -2-aminoethanol. 4. N-propionyl-1- (J ^l -hydroxyphenyl) -2-aminoethanol. 5. N-Acety 1-1- (Li-hydroxyphenyl) -2-aminopropanol. ΰ. N-Succinoyl-1-Cb'-hydroxyphenyl): * 2-aminoethanol. 7. N-Maleiny1-1-Ca ^f -hydroxyphenyl) -2-aminoethanol. BATH ORIGINAL 9 0983 6 / U92
: ie documents (Art. 7 sn /**.2 N- .: _t .. _te ,. ousAnderunflsge .. _Y .4.9. at »} 8. N-nicotinoyl-1- (3'-hydroxyphenyl) -2-arainoethanol. 9. N-Theophylline-T-acetyl-1-iS'-hydroxyphenyl) -2-aminoethanol 10. N-Benzoy1-1- (3'-hydroxyphenyl) -2-aminoethanol. 11. A process for the preparation of Äcylaminophenolalkanolen according to claim 1 to 10 of the general formula - CH - CH - NH - ac (I), I I OH Λ in the II hydrogen or lower alkyl with one to four carbon atoms and Ac the acyl radical one aliphatic saturated or unsaturated mono- or dicarboxylic acid, an aromatic or heterocyclic acid or a more complex organic acid with possibly a physiological inherent effect, such as for example theophyllinetic acid, characterized in that amines of the formula - CHOH - CH - NH ₀ (II), ι ^Λ It where H has the meaning given above for formula (D, or its acid addition salts are known per se Way with reactive derivatives of the carboxylic acids mentioned, such as halides, anhydrides or esters or that the amines of the formula (II) are reacted with the corresponding carboxylic acids with the addition of dehydrating agents Agents such as caibonyldiimidazole 909836 / U92 BATH ORIGINAL or dicyclohexylcarbodiimide or at elevated temperature to react. 12. The method according to claim 11, characterized in that amines of the formula (II) with excess Ester boils on reflux. 13. The method according to claim 11, characterized in that 1 mol of the acid halides or anhydrides in Pyridine in the cold with 1 mole of amine or amine hydrochloride implements. 14. The method according to claim 11, characterized in, that when amines and carboxylic acids are reacted, the water of reaction formed is distilled by azeotropic means with solvents such as benzene, toluene, xylene or halogenated hydrocarbons. 15. The method according to claim 11, characterized in that the reaction of amines with carboxylic acids with the addition of carbonyldiimidazole or cyclohexylcarbodiimide in a solvent such as methanol, Methylene chloride, tetrahydrofuran or pyridine -. possibly at elevated temperature - works. 908836/1492