CS235175B1

CS235175B1 - 4- (3-Alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) acetophenones and their preparation

Info

Publication number: CS235175B1
Application number: CS785083A
Authority: CS
Inventors: Ruzena Cizmarikova; Alois Borovansky; Jan Kozlovsky; Pavel Svec; Eva Bederova; Anna Dingova
Original assignee: Ruzena Cizmarikova; Alois Borovansky; Jan Kozlovsky; Pavel Svec; Eva Bederova; Anna Dingova
Priority date: 1983-10-26
Filing date: 1983-10-26
Publication date: 1985-05-15

Abstract

Vynález sa týká nových l-aryloxy-3-amino-2-propanolov všeobecného vzórca I 2 OH CH^CH-CH~HH-R2 .ch^o-r'1 Oέ co-cw3 íl) kde R1 a R2 je alkyl a 4 sposoboch přípravy týchto zlúčenín. Připravené látky vykazujú betalytickú a antiarytmickú účinnost. U vyšších analógov bola zistená povrchová lokálno anestetická a antimikróbna aktivita.The invention relates to new 1-aryloxy-3-amino-2-propanols of the general formula I 2 OH CH^CH-CH~HH-R2 .ch^o-r'1 Oέ co-cw3 íl) where R1 and R2 are alkyl and 4 methods of preparing these compounds. The prepared substances show betalytic and antiarrhythmic activity. Surface local anesthetic and antimicrobial activity was detected in higher analogues.

Description

3 4 233175

The invention relates to novel 1-aryloxy-3-amino-2-propamols of the general formula I,

OH Q-CH 1 -CH-CH-NH-R 2 -CH 2 -O-R 1 -CO-CH 2 (I) wherein R 1 is a linear but branched alkyl of 1 to 9 carbon atoms and R 2 is a branched alkyl of 3 or 4 carbon atoms, in particular The invention also relates to the solubilized aryloxyaminopropanol of the general formula I as well as the processes by which the aryloxyaminopropanoic derivatives of the formula I can be prepared.

Based on the literature searches and patent literature of the compounds of the general formula (I), the substances previously described in the literature which exhibit the typical effects of betalytics, such as those aryloxyaminopropanols of other substituents (see U.S. Pat. No. 128,471, U.S. Pat. 3 466 376, DOS 26 45 710, 2 106 209, CH Pat.451 114, 453 363). The substances studied show anti-isoprenal and antiarrhythmic activity.

In evaluating the anti-isoprenaline activity, the stimulated contractility of the left atrium of guinea pigs has been found to be significant depending on; dose. Substance 21, shown below, showed an activity higher than that of atenolol. In evaluating the anti-isoprenaline activity on spontaneously intestinal guinea pig atria, the following substances have been shown to be significant. 5, 6 and 19.

In evaluating the antiadrenaline arrhythmia, Compound # 5 exhibited atenolol-like activity. In the case of analogs with a carbon number greater than 5 in the alkoxy group, the surface-localized anesthetic surface and the antimicrobial activity unknown to date are similar.

By way of indication, the acute toxicity assessment of sc applied aqueous solutions of the study compounds showed that the LD 50 of these substances is in the range of 300 to 600 mg / kg, corresponding to the toxicity in the clinical practice of the beta-adrenolytics used, for example Trimanol. For example, 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) acetophenones of the general formula I can be prepared according to the invention in various ways, e.g.

a) a compound of formula II

OH

O-CH 2 CH-CH 2 ClCH-O-R 1

CO-CH * 3 (II) wherein R 1 is the same as in Formula I, with a primary amine of Formula NH 2 R 2 in which R 2 is the same as in Formula I,

b) a general compound; of Formula III

ω-CH 3 (III) wherein R 1 is the same as in Formula I, with a primary amine of Formula NH 2 R 2 in which R 2 is the same as in Formula I,

c) a compound of formula IV

OH

CO-CH3 (IV)

wherein R 1 is the same as; in formula I, with 1-alkylamino-2,3-epoxypropane of general formula V

CH / CH-CHRNH-R Z 0 (V) wherein R 2 is the same as in formula I, d) a compound of formula IV,

wherein R 1 is the same as in Formula I, with 1-alkylamino-3-chloro-2-propanol of formula VI

Cl-CH-CH-CH-NH-R 2

OH (VI) 5 235173 wherein R 2 is the same as in Formula I.

In the preparation according to the invention, the reaction between the two starting components in processes a) and b) proceeds in an environment of a C 1 -C 3 alcohol at the temperature of the reaction mixture. In processes c) and d), the reaction proceeds in a water medium under the catalytic effect of an alkali metal hydroxide, for example sodium hydroxide at room temperature.

After the reaction was complete, the reaction was worked up after distilling off the organic solvent by shaking the base into ether. From this solution, a salt which can be further purified by crystallization from an organic solvent or from a mixture of solvents can be prepared directly. Salts with organic acids such as fumarate, citrate, oxalate, tartrate, etc., have been found to be suitable from the salts prepared. The following examples illustrate the preparation: Examples Example 1 4- (3-isopropylamino-2-hydroxypropoxy) - -3- (propoxymethyl) acetophenone (FA33) To a solution of 0.04 mol of 4- (2-hydroxy-3-chloropropoxy) -3- (propoxymethyl) acetophenone in 50 ml of isopropyl alcohol was added 0.05 molisopropylamine. The reaction mixture is heated at reflux temperature for 24 hours. After the reaction mixture has cooled, the solvent is dissolved and the unreacted amine is distilled off under vacuum, the residue is dissolved in dilute hydrochloric acid, shaken three times with ether and basified with an aqueous layer. After drying with anhydrous magnesium sulfate, a fumarate precipitates from the filtrate of the ethereal solution of fumaric acid, which is recrystallized from ethyl acetate (mp 120-122 ° C). Example 2 4- (3-isopropylamino-2-hydroxypropoxy) -3- (methoxymethyl) acetophenone (FA13) To a solution of 0.06 mol of 4- (2,3-epoxypropoxy) -3- (methoxymethyl) acetophenone in Isopropylamine (0.016 mol) was added to ethyl alcohol (100 ml). The reaction mixture was heated at 30 ° C for 3 hours and the reaction mixture refluxed for 4 hours. Upon completion of the reaction, ethyl alcohol and unreacted amine were distilled off under vacuum, 50 ml of water was added to the residue and the base was shaken into ether several times. After drying with anhydrous magnesium sulfate, the fumarate is removed from the filtrate by the addition of an ethereal solution of fumaric acid, which is recrystallized from isopropyl alcohol (mp 150-152 ° C). Example 3 4- (3-Isopropylatino-2-hydroxypropyl) - -3- (hexyloxymethyl) acetophenone (FA63)

A solution of 0.02 mol of 3-hexyloxymethyl-4-hydroxyacetophenone, 3 ml of 1-tert-butylamino-2,3-epoxypropane and 20 ml of water with 0.2 ml of conc. sodium hydroxide solution was stirred at room temperature for 6 hours. From the oil layer formed, the corresponding base is obtained by shaking the reaction mixture with ether. After drying the ethereal solution with anhydrous magnesium sulfate, a fumarate is precipitated from the filtrate by adding an ethereal solution of fumaric acid, which is recrystallized from ethyl acetate (mp 123-125 ° C). Example 4 4- (3-tert-butylamimo-2-oxypropoxy) -3- (propoxymethyl [acetophenone (FA34) 0.02 mol of 3-propoxymethyl-4-hydroxyacetophenone, 0.02 mol of hydrochloride 1- Chloro-3-tert-butylamino-2-propanol is added with 60 ml of 4% sodium hydroxide solution and the reaction mixture is stirred at room temperature for 24 hours, and the appropriate base is extracted from the reaction mixture into ether and dried over anhydrous magnesium sulfate. the fumarate solution, which was recrystallized from ethyl acetate (mp 183-18-4 ° C), using the following methods, the following new compounds were prepared: 1. 4- (3-isopropylamino-2) -hydroxypropoxy) -3- (methoxymethyl) acetophenone fumarate, mp 150-152 ° C (isopropyl alcohol) (FA13) 2. 4- (3-tert-butylamino-2-oxypropoxy) -3-methoxymethyl [acetophenone fumarate, mp 188-189 ° C (ethanol-ether) (FA 14) 3. 4- (3-isopropylamino-2-hydroxypropoxy) -3- (ethoxymethoxy) acetophenone fumarate, mp 140-142 ° C (ethanol-ether) er) (FA 23) 4. 4- (3-tert-butylamino-2-hydroxypropoxy) -3-ethoxymethyl) acetophenone fumarate, mp 170-172 ° C (ethyl acetate-etamol) (FA 24) 5. 4- (3-isopropylamino-2-oxypropoxy) -3- (propoxymethyl) acetophenone fumarate, mp 120-122 ° C (ethyl acetate (FA 33) 6. 4- (3-tert-butylamino-2-hydroxypropoxy) -3 - (propoxymethyl) acetophenone fumarate, m.p. 183-184 ° C (ethyl acetate) (FA34) 7. 4- (3-isopropylamino-2-hydroxypropoxy) -3- (isopropoxymethyl) acetophenone fumarate. m.p. 150-151 ° C (ethyl acetate) (FA313) 8. 4- (3-tert-butylamino-2-hydroxypropoxy) -3- (isopropoxymethyl) acetophenone fumarate, mp 193-194 ° C (ethyl acetate (FA3i4)) 9. 4- (3-isopropylamino-2-oxypropoxy) -3- (butoxymethyl) acetophenone fumarate, mp 117-120 1C (ethyl acetate) (FA43) 10. 4- (3-tert-butylamino-2- hydroxypropoxy) -3- (butoxymethyl) acetophenone fumarate, mp 172-173 ° C (ethyl acetate) (FA44) 11. 4- (3-isopropyl-amino-2-hydroxypropoxy) -3- (isobutoxymethyl) acetophenone fumarate, 1.1 .150 to 153 QC (ethyl acetate) (FA4i3)

Claims

SUBJECT

We claim:

1. 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) acetofenomes of the general formula I

OH

O-CH 2 CH-NH-R 2 ^from CH 2 -R ¹ co-cw ₃ (I) wherein R ¹ is alkyl of 1 to 9 carbon atoms and R ² is branched alkyl of 3 or 4 carbon atoms.

2. A process for the preparation of 4- (3-amino-2-hydroxypropoxy) -3- (alkoxymethyl) acetophenone of the formula I according to ^one claim 1 characterized in that the reaction of a compound of formula II,

OH

I

O-CH 2 CH-CH 2 -C 1 (of ^CH * ^OR

CO-CH.

^J (II) wherein R ¹ is the same as in formula I, with the primary amine of the formula HaNR ² , wherein R ² is the same as VO 'of formula I, in a C 1 -C 3 alcohol medium at the boiling point of the reaction mixture.

3. A process for the preparation of 4- (3-alkylamines-2-hydroxypropoxy) -3- (alkoxymethyl) acetophenone of the formula I according to claim 1, wherein reacting zlúčetnina of formula III wherein ^R1 is the same as in formula I, with a primary amine of the formula H ² NR ² , in which R ² is the same as in formula I, in a C 1 -C 3 alcohol medium at the boiling point of the reaction mixture.

4. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3-alkoxymethyl) acetophenones of the formula I as claimed in claim 1, which comprises reacting with a compound of the formula IV

OH (ur ^CH x co-ch ₃ (IV) wherein R ¹ is the same as in formula I) with 1-alkylamino-2,3-epoxypropane of formula V

CH 2 CH-CH-NH-R (V) wherein R ² is the same as in Formula I, in a water environment under catalysis with an alkali metal hydroxide, preferably sodium hydroxide.

5. A process for the preparation of 4- (3-alkylamiino-2-hydroxypropoixy) -3-alkoxymethyl) acetofenónoiv formula I according to claim 1, characterized in that reacting a compound of formula IV, wherein R ¹ is the same as Vo- of formula I, with 1-alkylamino-3-chloro-2-propanol of formula VI

C-Cha- CH-CH 2 -NH-R ²

OH (VI) wherein R ² is the same as in Formula I, in a water environment under the catalytic action of an alkali metal hydroxide at room temperature.