CS238943B1 - Processing of 4-alkalamine-2-hydrxypropoxy)-3-(acoxymethpropyofenone - Google Patents

Abstract

The present invention relates to novel 1-aryloxy-3- -amino-2-propanols of formula I OH / 9 CHjj-O-CH-CH-NHR * coch2ch3 wherein R 1 is saturated or branched alkyl with 1-10 carbon atoms and R2 * represents branched alkyl having 3-4 carbon atoms / isopropyl, target. butyl / and 4 methods of preparing these compounds. Prepared substances show betalytic and antiarrhythmic activity. Higher analogues, surface localization was found anesthetic and antimicrobial activity. 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, 2

O-CH ₂ -CH-CH ₂ —NH-R 'CH 2 -O-R ¹

(1) co-ch ₂ -ch ₃ and 2 wherein R is a saturated or branched alkyl of 1-10 carbons and R is a branched alkyl of 3-4 carbons / isopropyl, tert. butyl /. The invention also relates to salts of substituted aryloxyaminopropanols of formula I as well as methods by which the aryloxyaminopropanols derivatives of formula I can be prepared.

Based on the literature search as well as the patent literature, the compounds of formula (I) are original, not yet described in the literature, which exhibit the typical effects of betalytics, such as the aryloxyaminopropanols substituted in other ways by Cs. pat.

128,471, US. pat. 3,446,376, GER. Offen 2,645,710, 2,106,209, CH. pat. 451 114, 453 363].

The substances studied exhibit antisisrenaline and antiarrhythmic activity. When evaluating antiisoprenaline activity on spontaneously throbbing guinea pigs, substance no. 5 with working designation FP33. The pA _{2 of} this substance is similar to that of the Praktolol Standard.

For analogs with a higher number of carbons than 5 in the alkoxy group, surface local anesthetic and antimicrobial activity was confused. Substance no. 25 with the working designation FP93 on Gram-positive strains of Staphylocoocus aureus and yeast Candida albicans shows higher activity than Standard benzododecinium chloride.

Indicative assessment of acute toxicity s.c. applied aqueous solutions of the studied substances showed that the LDjq of these substances is in the range of 300-600 mg.kg \, which corresponds to the toxicity in the clinical practice of used betalytics e.g. metipranolol.

The 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) propiophenones of the formula I can be prepared according to the invention in various ways, for example, by reacting a) a compound of the formula II

OH on the CH-CH ₂ -CH ₂ -C H ₂ nT ^c - ο ^R-1/11 / _{co-CH2 -CH3}

2 in which R is the same as in formula I with a primary amine of the formula NH ₉ R, in which R is the same as in formula I / 111 / b / a compound of formula III

O o-ch ₂ -ch — ch ₂ φ-ΟΗ, -Οco-ch ₂ ch ₃ > 1? in which R is the same as in formula I with a primary amine of the formula NH, R in which R is the same as in formula I c / a compound of formula IV

OH

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

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 formula VI ₂ -ch-ch ₂ -nh-r ²

OH / VI /

In which R is the same as in formula I.

In the preparation according to the methods of the invention, the reaction between the two starting components takes place in methods a and / and b) in an alcohol medium at the boiling point of the reaction mixture. In processes c) and d), the reaction is carried out in a water medium under the catalytic action of an alkali metal hydroxide, for example sodium hydroxide, at room temperature.

After completion of the reaction, the reaction mixture is worked up by distilling off the organic solvent by shaking 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.

Of the prepared salts, salts with organic acids e.g. fumarate, citrate, oxalate, tartrate, etc. Details of preparation are given in the following examples:

Example 1

4- (3-isopropylamino-2-hydroxypropoxy) -3- (propoxymethyl) propiophenone (FP33)

To a solution of 0.04 mol of 4- (2-hydroxy-3-chloropropoxy) -3- (propoxymethyl) propiophenone in 50 ml of isopropyl alcohol is added 0.05 mol of isopropylamine. The reaction mixture is heated at the boiling point of the reaction mixture for 24 hours.

*

After cooling the reaction mixture, the solvent and unreacted amine were distilled off in vacuo, the residue was dissolved in dilute hydrochloric acid, shaken three times with ether, and the base separated from the aqueous layer by alkalization and shaken into ether.

After drying bzv. magnesium sulfate, the fumarate is precipitated from the filtrate by addition of an ethereal fumaric acid solution and recrystallized from ethyl acetate. T. t. 137-9 ° C.

Example 2

4- (3-isopropylamino-‘2-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 is added 0.16 mol of isopropylamine. The reaction mixture is heated at 30 ° C for 3 hours and refluxed for 4 hours.

After completion of the reaction, the ethanol and unreacted amine were distilled off in vacuo, 50 ml of water were added to the residue, and the base was shaken three times into ether. After drying over anhydrous magnesium sulfate, fumarate is precipitated from the filtrate by addition of an ethereal fumaric acid solution, which is recrystallized from isopropyl alcohol / m.p. 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 of water with 0.2 ml conc. of sodium hydroxide solution was stirred at room temperature for 6 hours.

From the oily layer formed, the corresponding base is obtained by shaking the reaction mixture with ether. After drying the ethereal solution, the so-called " magnesium sulfate, the fumarate is precipitated from the filtrate by addition of an ethereal fumaric acid solution and recrystallized from ethyl acetate / m.p. 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 4% sodium hydroxide solution is added 0.02 mol of 1-chloro-3-tert-hydrochloride. 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. sulfate. magnesium fumarate is precipitated from the filtrate by addition of an ethereal fumaric acid solution, which is recrystallized from ethyl acetate / m.p. 183-4 ° C;

The following new substances were prepared using these methods:

1. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (methoxyethyl) propiophene fumarate 129-31 ° C (ethyl acetate) (FP13)

2. 4- / 3-tert. butylamino-2-hydroxypropoxy (-3-) methoxyniethyl) propiophenone fumarate, mp 135-7 ° C (isopropyl alcohol) (FP14)

3. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (ethoxymethyl) propiophenone fumarate m.p. 142-4 ° C / ethyl acetate / (FP23)

4. 4- / 3-tert. butylamino-2-hydroxypropoxy (-3-) ethoxymethyl) propiophenone fumarate m.p. 179-82 ° C / ethyl acetate-ethanol / (FP24)

5. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (propoxymethyl) propiophenone fumarate m.p.

137-8 ° C (ethyl acetate) (FP33)

6. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (propoxymethyl) proplophenone fumarate m.p.

183-5 ° C / isopropyl alcohol / / FP34 /

7. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (isopropoxymethyl) propiophenone fumarate m.p. 160-2 ° C / isopropyl alcohol / / FP 313 /

8. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (isopropoxymethyl) propiophenone fumarate m.p. 201-3 ° C / isopropyl alcohol / / FP3 / 4 /

9. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (butoxymethyl) propiophenone fumarate m.p. 137-9 ° C / ethyl acetate / (FP43)

10. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (butoxymethyl) propiophenone fumarate m.p. 182-5 ° C / isopropyl alcohol / / FP44 /

11. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (isobutoxymethyl) propiophenone fumarate m.p. 150-3 ° C (ethyl acetate / FP4i3)

12. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (isobutoxymethyl) propiophenone fumarate m.p. 199-202 ° C / isopropyl alcohol / / FP414 /

13. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- [sec. butoxymethyl / propiophenone fumarate m.p. 157-9 ° C (ethyl acetate) / (FP4s3)

14. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (sec-butoxymethyl) propiophenone fumarate m.p. 198-201 ° C / isopropyl alcohol / / FP4s4 /

15. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (pentyloxymethyl) propiophenone fumarate m.p. 145-6 ° C (ethyl acetate) / (FP53)

16. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (pentyloxymethyl) propiophenone fumarate m.p.

184- 7 ° C / isopropyl alcohol / / FP54 /

17. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (isopentyloxymethyl) propiophenone fumarate m.p. 145-6 ° C / ethyl acetate / (FP5i3)

18. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (isopentyloxymethyl) propiophenone fumarate mp 193-4 ° C (isopropyl alcohol) (FP514)

19. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (hexyloxymethyl) propiophenone m.p. 119-121 ° C (ethyl acetate) (FP63), fumarate

20. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (hexyloxymethyl) propiophenone fumarate m.p. 165-8 ° C (ethyl acetate) / (FP64)

21. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (heptyloxymethyl) propiophenone fumarate m.p. 120-2 ° C / ethyl acetate / (FP73)

22. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (heptyloxymethyl) propiophenone fumarate m.p. 169-71 ° C (ethyl acetate-ethanol) / (FP74)

23. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (octyloxymethyl) propiophenone fumarate m.p. 106-8 ° C / ethyl acetate / (FP83)

24. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (octyloxymethyl) propiophenone fumarate m.p. 160-2 ° C / ethyl acetate / (FP84)

25. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (nonyloxymethyl) propiophenone. fumarate m.p. 122-5 ° C / ethyl acetate / (FP93)

26. 4- (3-tert-Butylamino-2-hydroxypropoxy) -3- (nonyloxymethyl) propiophenone fumarate m.p. 169-71 ° C / ethyl acetate / (FP94)

27. 4- (3-Isopropylamino-2-hydroxypropoxy) -3- (decyloxymethyl) propiaphenone fumarate m.p.

84-6 ° C / ethyl acetate / (FP103)

Prepared fumarates / no. 1-26 / sd in base: fumaric acid ratio 2: 1, fumarate no. 27 is 1: 1 in Domere. Structures of the prepared compounds was confirmed by analysis elementárncu / carbon, hydrogen, nitrogen and / evaluating the infrared, ultraviolet, ¹ H NMR and mass spectra.

Claims (5)

1. 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) propiophene OH O-CH ₂ CH ₂ NH -ÍH- - R ² -CH ₂ On ¹ / Tl COCH ₂ CH ₃ and R 2 in which R is a saturated or branched alkyl of 1-10 carbons and R is a branched alkyl of 3-4 carbon atoms. 2. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkomethyl) propiophenones of the formula I according to claim 1, characterized in that a compound of the formula II is reacted, OH O-CH ₂ -CH-CH ₂ -CH air '' ⁰ '/.v _COCH2 CH ₃ wherein R ¹ and R ² is the same as in formula I with a primary amine H ₂ NR ^2, wherein R ² is the same as in formula I, in a C 1 -C 3 alcohol medium 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 / propiophenone of formula I according to claim 1, characterized in that reacting a compound of formula III, _{O-CH2-CH-CH 2} R £ v-CH ₂ o _R '/ 111 / coch ₂ ch ₃ Wherein R and R are the same as in Formula I with the primary amine of Formula 2 2 H ₂ NR, in which R is the same as in formula I, in an alcohol having 1 to 3 carbon atoms at the boiling point of the reaction mixture. 4. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) propiophenones of the formula I according to claim 1, which comprises reacting a compound of the formula IV. OH (O ^ fCHjOR ¹ coch ₂ ch ₃ / IV) In which R and R are the same as in formula I, with an alkylamino-2,3-epoxypropane of the general formula (V) ₍ CH ₂ -CH-CH ₂ -NHR) in which R is the same as in of the formula I, in an aqueous medium with an alkali metal catalysis, preferably sodium hydroxide. 5. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) propiophenones of the formula I, characterized in that a compound of the formula IV is reacted in which R1 is the same as in formula I with 1-alkylamino-3-chloro-2-propanol of formula VI OH C CH ₂ -CH ₂ -CH ² -NHR / VI / wherein R means the same as in Formula I in a water to the catalytic action of an alkali metal hydroxide at room temperature.