CS238943B1

CS238943B1 - 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) propiophenones and processes for their preparation

Info

Publication number: CS238943B1
Application number: CS841802A
Authority: CS
Inventors: Ruzena Cizmarikova; Alois Borovansky; Jan Kozlovansky; Pavel Svec; Eva Bederova; Anna Dingova
Original assignee: Ruzena Cizmarikova; Alois Borovansky; Jan Kozlovansky; Pavel Svec; Eva Bederova; Anna Dingova
Priority date: 1984-03-13
Filing date: 1984-03-13
Publication date: 1985-12-16
Also published as: CS180284A1

Abstract

Vynález sa týká nových l-aryloxy-3- -amino-2-propanolov všeobecného vzorca I OH / 9 O-CHjj—CH—CHj—NHR* coch2ch3 kde R1 je nasýtený alebo rozvětvený alkyl s 1-10 atómami uhlíka a R2 *znamená rozvětvený alkyl s 3-4 atómami uhlíka /izopropyl, terč. butyl/a 4 sposobov pripravy týchto zlúčenín. Připravené látky vykazujú betalytickú a antiarytmickú účinnost. O vyšších analógov bola zistená povrchová lokálno anestetická a antimikróbna aktivita. Využitie týchto látok sa předpokládá v oblasti biologicky účinných látok.The invention relates to new 1-aryloxy-3- -amino-2-propanols of the general formula I OH / 9 O-CHjj—CH—CHj—NHR* coch2ch3 where R1 is a saturated or branched alkyl with 1-10 carbon atoms and R2 * means a branched alkyl with 3-4 carbon atoms /isopropyl, tert. butyl/ and 4 methods of preparing these compounds. The prepared substances exhibit betalytic and antiarrhythmic activity. Surface local anesthetic and antimicrobial activity was found in higher analogues. The use of these substances is expected in the field of biologically active substances.

Description

The invention relates to novel 1-arvloxy-3-amino-2-propanols of the general formula I 238943 O-CH 2 -CH-CH 2 -NH-R 1 CH 2 -O-R 1

wherein R is saturated or branched alkyl having 1-10 carbon atoms and R is branched alkyl of 3-4 carbon atoms / isopropyl, tert. butyl/. The invention also relates to salts of substituted aryl oxyaminopropanols of the general formula I as well as processes by which the aryloxy-aminopropanols derivatives of the general formula I can be prepared.

Based on the literature search as well as the patent literature, the compounds of the general formula (I) are originally, so far, not described in the literature. typical effects of a beta-alkylate such as aryloxyaminopropanols substituted by other substituted Cs. pat. 128, 471, US. pat. 3 466 376, GER. Offen 2,645,710, 2,106,209, CH. pat. 451,114, 453,363].

The substances studied show anti-isoprenaline and antiarrhythmic activity. Substance 5 with the working name FP33 has been shown to be significant in the evaluation of santioprenaline activity on spontaneously beating atria of guinea pigs. The pA £ value of this substance is similar to the Practolol Standard. For analogs with a carbon number greater than 5 in the alkoxy group, surface local anesthetic and antimicrobial activity was found. Compound 25 with the designation FP93 on gram-positive strains of Staphylococcus aureus and yeast Candida albicans shows higher activity than Standard benzododecnium chloride.

By way of indication, the acute toxicity assessment of sc applied aqueous solutions of the study fluids showed that the LD50 of these substances ranged from 300-600 mg.kg to the corresponding toxicity in the clinical practice of betalytics such as metipranolol. The 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) propiophenones of formula (I) can be prepared according to the invention in various ways, e.g.

a / a compound of formula II

Wherein OH is also as in formula (I) with a primary amine of the formula NH 9 R 12, wherein R is CH 2 Cl 2 CH 3 CH 2 2.

in which R is the same as in formula I 3 238943/111 /

b / a compound of formula III

In which R is the same as in Formula I with a primary amine of the general formula NH, R12;

wherein R is the same as in Formula I

c / a compound of formula IV

OH

/ IV / co-ch2ch3

wherein R 1 is the same as in Formula I with 1-alkylamino-2,3-epoxypropane of the general formula in CH, -CH-CH, -NH-R 2

O / 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 the formula VI c 1 -CH 2 -CH 2 CH 2 -H 2 R 2 OH / VI / 2 wherein R is the same as in Formula I .

In the preparation of the methods of the invention, the reaction between the two starting components proceeds in the methods a / b and / or in the alcohol medium at the boiling point of the reaction mixture. The reaction is carried out in an aqueous medium under the catalytic action of an alkali metal hydroxide such as sodium hydroxide at room temperature.

After the reaction is complete, the reaction mixture is worked up after distilling off the organic solvent by washing the base into ether. From this solution, a salt can be prepared directly, which can be further purified by crystallization from an organic solvent or a mixture of solvents. Among the salts prepared, salts with organic acids such as fumarate, citrate, oxalate, tartrate, etc. have been shown to be suitable. The following examples illustrate the preparation: 238943 Example 1 4- (3-isopropylamino-2-hydroxypropoxy) -3- (propoxymethyl) propiophenone / FP33 / 0.05 mol of isopropylamine is added to a solution of 0.04 mol of 4- (2-hydroxy-3-chloropropoxy) -3- (propoxymethyl) propiophenone in 50 ml of isopropyl alcohol. The reaction mixture is heated for 24 hours by boiling the reaction mixture. *

After the reaction mixture had cooled, the solvent and the unreacted amine were distilled off under vacuum, the residue was dissolved in dilute hydrochloric acid, shaken three times with ether, and the base was liberated from the aqueous layer and the base was taken up in ether.

After sowing bzv. The fumarate is removed from the filtrate by the addition of an ethereal solution of fumaric acid, which is recrystallized from ethyl acetate. Mp 137-9 ° C. Example 2 4- (3-isopropylamino-12-hydroxypropoxy) -3- (isopropoxymethyl) propiophenone FP3i3 To a solution of 0.08 mol of 4- (2,3-epoxypropoxy) -3- (isopropoxymethyl) propiophenone in 100 ml of ethyl alcohol isopropylamine (0.16 mol) is added. The reaction mixture was heated at 30 ° C for 3 hours and refluxed for 4 hours.

After completion of the reaction, ethyl alcohol and unreacted amine were distilled off under vacuum, 50 ml of water was added to the evaporation residue and the base was extracted three times into ether. After drying over anhydrous magnesium sulfate, a fumarate is added from the filtrate by adding an ethereal solution of fumaric acid to recrystallize from isopropyl alcohol (mp 160-2 ° C). Example 3 4- (isopropylamino-2-hydroxypropoxy) -3- (hexyloxymethyl) propiophenone (FP63)

A solution of 0.02 mol of 3-hexyloxymethyl-4-hydroxypropiophenone, 3 ml of 1-tert. butylamino-2,3-epoxypropane and 20 ml water with 0.2 ml conc. sodium hydroxide solution was stirred for 6 hours at room temperature. From the oil layer formed, the appropriate base is obtained by shaking the ether mixture. After drying the ethereal solution, b. magnesium fumarate was added from the filtrate by adding an ethereal solution of fumaric acid, which was recrystallized from ethyl acetate (mp 119-21 ° C).

Example 4 4- (tert-butylamino-2-hydroxypropoxy) -3- (propoxymethyl) propiophenone (FP34) To a solution of 0.02 mol of 3-propoxymethyl-4-hydroxypropiophenone in 60 ml of a 4% solution of hydroxide is added 0.02 mol of hydrochloride. -chloro-3-tert. butylamino-2-propanol. The reaction mixture was stirred at room temperature for 24 hours. The appropriate base is obtained by shaking the reaction mixture into ether. After drying bzv. sulphate. The fumarate was removed from the filtrate by the addition of ethereal solution of fumaric acid, which was recrystallized from ethyl acetate (mp 183-4 ° C). Using the above methods, the following new compounds were prepared: 1. 4- (3-isopropylamino-2-hydroxypropoxy) -3- (methoxyl) propionium fumarate 129-31 ° C / ethyl acetate / FP13 / 5 238943 2. 4- / 3-tert. butylamino-2-hydroxypropoxy) -3- (methoxyethyl) propiophenone fumarate tt, 135-7 ° C / isopropanol / (FP14) 3. 4- (3-isopropylamino-2-hydroxypropoxy) -3- (ethoxymethyl) propiophenone fumarate tt 142 -4 ° C / ethyl acetate (FP23) 4. 4- / 3-tert. butylamino-2-hydroxypropoxy) -3- (ethoxymethyl) propiophenone fumarate mp179-82 ° C / ethyl acetate-ethanol / FP24 / 5. 4- (3-isopropylamino-2-hydroxypropoxy) -3- / propoxymethyl / propiophenone fumarate tt 137 -8 ° C / ethyl acetate / FP33 / 6. 4- (3-tert-butylamino-2-hydroxypropoxy) -3- (propoxymethyl) propiophenone fumarate mp 183-5 ° C / isopropyl alcohol / / FP34 / 7. 4- / 3-isopropylamino-2-hydroxypropxy / -3- (isopropoxymethyl) propiophenone fumarate tt 160-2 ° C / isopropanol / (FP 313) 8. 4- (3-tert-butylamino-2-hydroxypropoxy) -3- (isopropoxymethyl) propiophenone tf201-3 ° C fumarate / isopropanol / (FP 3/4/9) 4- (3-isopropylamino-2-hydroxypropoxy) -3- (butoxymethyl) propiophenone fumarate mp 137-9 ° C / ethyl acetate / FP43 / 10. 4- [3-tert-butylamino-2-hydroxypropoxy] -3- (butoxymethyl) propiophenone fumarate mp 182-5 ° C / isopropanol / (FP44) 11. 4- (3-isopropylamino-2-hydroxypropoxy) -3- (isobutoxymethyl) / propiophenone fumarate tt 150-3 ° C / ethyl acetate / FP4,3 / 12. 4- (3-tert-butylamino-2-hydroxypropoxy) -3- (isobutoxymethyl) propiophene enon fumarate tt199-202 ° C / isopropanol / (FP414 / 13) 4- (3-isopropylamino-2-hydroxypropoxy) -3- / sec. butoxymethyl / propiophenone fumarate tt157-9 ° C / ethyl acetate / / FP4s3 / 14. 4- (3-tert-butylamino-2-hydroxypropoxy) -3- (sec-butoxymethyl) propiophenone fumarate tt198-201 ° C / isopropyl alcohol / / FP4s4 15. 4- (3-isopropylamino-2-hydroxypropoxy) -3- (pentyloxymethyl) propiophenone fumarate mp 145-6 ° C / ethyl acetate (FP53) 16. 4- (3-tert-butylamino-2-hydroxypropoxy) -3 - (pentyloxymethyl) propiophenone fumarate mp 184-7 ° C / isopropanol / (FP54) 17. 4- (3-isopropylamino-2-hydroxypropoxy) -3- (isopentyloxymethyl) propiophenone fumarate mp 145-6 ° C / ethyl acetate (FP 51) 18. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (isopentyloxymethyl) propiophenone fumarate mp 197-4 ° C (isopropyl alcohol) (FP 5/4) 19. 4- (3-isopropylamino-2-hydroxy-propoxy) - 3- (hexyloxymethyl) propiophenone mp 119-121 ° C / ethyl acetate (FP63), fumarate 20. 4- (3-tert-butylamino-2-hydroxypropoxy) -3- (hexyloxymethyl) propiophenone fumarate mp 165-8 ° C / ethyl acetate / FP64 / 21. 4- (3-isopropylamino-2-hydroxy-propoxy) -3- / heptyloxymethyl / propiophenone fumarate tt120 -2 ° C / ethyl acetate / FP73 / 22. 4- (3-tert-butylamino-2-hydroxypropoxy) -3- / heptyloxymethyl / propiophenone fumarate mp 169-71 ° C / ethyl acetate-ethanol / FP74 / 23. 4- [3-isopropylamino-2-hydroxypropoxy] -3- (octyloxymethyl) propiophenone fumarate t106-8 ° C / ethyl acetate (FP83) 24. 4- (3-tert-butylamino-2-hydroxypropoxy) -3- (octyloxymethyl) propiophenone 160-2 ° C fumarate / ethyl acetate (FP84) 25. 4- (3-isopropylamino-2-hydroxypropoxy) -3- (nonyloxymethyl) propiophenone. t122-5 ° C fumarate / ethyl acetate / FP93 / 26. 4- (3-tert-butylamino-2-hydroxypropoxy) -3- (nonyloxymethyl) propiophenone fumarate mp 169-71 ° C / ethyl acetate / FP94 / 27. 4- [3-isopropylamino-2-hydroxypropoxy] -3- (decyloxymethyl) propiaphenone fumarate mp 84-6 ° C / ethyl acetate / (FP103) Prepared fumarates / no. 1-26 / base in base: fumaric acid 2 s 1, fumarate. 27-is 1: 1 in Domere. The structure of the prepared compounds was verified by elemental analysis (carbon, hydrogen, nitrogen) and evaluation of infrared, ultraviolet, 1H-NMR and mass spectra.

Claims

the subject of the invention is: 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) propiophenes of general formula (I): 238943 OH O-CH 2 -H-CH 2 -NH - R 2 f -CH 2 -on / Tl COCH 2 CH 3 2 in which R is saturated or branched alkyl having 1-10 carbon atoms and R is branched alkyl of 3-4 carbon atoms.

2. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkomethyl) propiophenone of the general formula (I) according to claim 1, wherein the compound of formula (II), OH is O-CH2-CH-CH2-Cl. wherein R 1 and R 4 are the same as in Formula I with a primary amine of the formula H 2 NR 2, wherein R 2 is the same as in Formula I, in an alcohol environment of 1-3 carbon atoms for 24 hours at the boiling point of the reaction mixture.

3. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxytyl) propiophene &amp; general formula (I) according to claim 1, wherein the compound of formula (III) is reacted. wherein R and R are the same as in Formula I with a primary amine of Formula 2 H2NR, wherein R is the same as in Formula I, in an alcoholic environment of 1 to 3 carbon atom at the boiling point of the phthalic mixture.

4. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) propiophenone of the general formula (I) according to claim 1, characterized in that the compound of the formula (IV) OH is reacted (O.f. Wherein R and R are the same as in Formula I, with an alkylamino-2,3-epoxypropane of the general formula VZ 2 2 CH 2 -CH-CH 2 -NH / V / 2 wherein R is the same as in of formula I, in an environment of water under alkali metal catalysis, preferably sodium hydroxide.

5. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) propiophenone of general formula (I), characterized in that a compound of formula (IV) is reacted in which R @ 1 is the same as in formula (I) with an alkylamino-3-chloro-2-propanol of the general formula (VI) OH in which R is the same as in formula (I), in an environment of water under catalytic action of an alkali metal hydroxide at room temperature .