CS252518B1 - 4-(3-alkylamino-2-hydroxypropoxy)-3-(alkoxymethyl)phenylalkylketones and method of their preparation - Google Patents

Description

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

OH i

R ^Z

WHAT WHERE

R ¹ is isopropyl, tert-butyl,

R ² is allyl, cyclohexyl,

R ³ is methyl, ethyl.

The invention also relates to salts of substituted aryloxyaminopropanols of the formula I as well as to processes by which the aryloxyaminopropanols of the formula I can be prepared.

Based on the literature search and the patent literature, the compounds of formula (I) are original, not yet described in the literature, which exhibit the typical effects of betalytics, as is the case with aryloxyaminopropanols substituted in other ways (U.S. Pat. No. 128,471, U.S. Pat. 3,446). 376, DOS 2645 710, 2,106,209). The prepared compounds show significant antiisoprenaline activity, comparable to the Praktolol standard. The antiarrhythmic activity is lower than the propranolol standard.

As an indicative evaluation of acute toxicity sc of applied aqueous solutions of the studied substances showed that the LD 50 of these substances is in the range of 300-600 mg.kg ^-1 , which corresponds to the toxicity in clinical practice of used beta-adrenolytics (for example Trimepranol). The compounds of the formula I can be prepared in various ways according to the invention by reacting a) a compound of the formula II

OH í O

C'CO-R '(li) in which

^R2 is the same as in formula I with a primary amine

NH ² R ¹ wherein

R ¹ is the same as in formula I b) a compound of formula III

i g

CO-R (H1) wherein

^R2 is the same as in formula I with a primary amine

NH 2 -R ¹ wherein

Rt is the same as in formula I cj of the compound of formula IV

^R2 is the same as in formula I, with 1-alkylamino-2,3-epoxypropane of the formula V

CH2 - CH - CH2 - NH - R1 (Vj)

About which

R ¹ is the same as in formula I dj a compound of formula IV wherein R ² is the same as in formula I with 1-alkylamino-3-chloro-2-propanol of formula VI

Cl — CH2 — CH — CH2 — NHR ¹ (VI)

I

OH in which

R ¹ is the same as in formula I.

In the preparation according to the invention, the reaction between the two starting materials in processes a) and b) is carried out in an alcohol medium at the boiling point of the reaction mixture. In processes cj and d), the reaction is carried out in water 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 purified by crystallization from an organic solvent or a mixture of solvents. Of the prepared salts, salts with organic acids such as fumarate, citrate, oxalate, tartrate, etc. have proven suitable. The preparation details are given in the following examples.

Example 1

4- (3-Isopropylamino-2-hydroxypropoxy) -3- (cyclohexyloxymethyl) phenylethylketone

To a solution of 0.04 mol of 4- (2-hydroxy-3-chloropropoxy) -3- (cyclohexyloxymethyl) phenylethyl ketone in 50 ml of 2-propanol is added 0.05 mol of isopropylamine and the reaction mixture is heated at reflux for 24 hours. After cooling the reaction mixture, the solvent and the unreacted amine are distilled off in vacuo, the residue is dissolved in dilute hydrochloric acid, shaken three times with ether and the base is alkalinized to give an alkaline solution which is shaken into ether. of fumarate, which is recrystallized from ethyl acetate, mp 164-165 ° C.

IR at _as coo ~ = 1580 cm ^{@ -1} ;

VArocH 2 ⁼ 1256 cm ^-1 ;

UV λ = 208, 222, 275 nm, (loge = 3.33; 3.32; 3.27 m ² mol ¹ ) ¹ H-NMR δ =

4.00 (broad band 3H; Ar-OCH 2 -CH 3,

0.95 (6H; d; CH 2 CH 2 O 2) ppnT Example 2

4- (3-Isopropylamino-2-hydroxypropoxy) -3- (allyloxymethyl) phenylethylketone

To a solution of 0.08 mol of 4- (2,3-epoxyipropoxy) -3- (allyloxymethyl) phenylethyl ketone in 100 ml of ethyl alcohol was added 0.016 mol of isopropylamine, and the reaction mixture was heated at 30 ° C for 3 hours and at reflux temperature for 4 hours. After completion of the reaction, the solvent and the unreacted amine are stripped off, 50 ml of water are added to the residue, and the base is shaken three times into ether.After drying, the so-called magnesium sulfate, —135 ° C.

ič p _as coo ~ ⁼ 1572 cm ^-1 ;

i * ArocH 2 ⁼ 1262 cm ^-1 ;

UV λ = 208, 219, 273 nm (log? = 3.66, 3.67, 3.53 m ² .mol ^_1)

@ 1 H-NMR .delta

4.00 µm (broad band 3H; Ar-OCH 2 -QH),

0.95 ppm [6H; d; CH (CH ₂ ) ₂ ]

Example 3

4- (3-Isopropylamino-2-hydroxypropoxy) -3- (allyloxymethyl) phenylmethylketone

A solution of 0.02 mol of 3-allyloxymethyl-4-hydroxyphenylmethyl ketone, 3 ml of 1-isopropylamino-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 addition of an ethereal fumaric acid solution precipitates a fumarate which is recrystallized from ethyl acetate; t. t. 131-132 ° C.

ič _{as as} coo ~ ⁼ 1576 cm - ¹ ;

»ArocH 2 ⁼ 1256 cm ^-1 ;

UV Λ = 206, 219, 273 nm, (loge = 3.63; 3.65; 3.52 m2.mol) 1 H-NMR δ =

4,00 ppm (broad band 3H; Ar-OCH 2 -CH),

0.95 ppm [6H; d; CH (CH3) 2]

Example 4

4- (3-tert-Butylamino-2-hydroxypropoxy) -3 (allyloxymethyl) phenylmethylketone

To 0.02 mol of 3-allyloxymethyl-3-hydroxyphenylmethyl ketone, 0.02 mol of 1-chloro-3-tert-butylamino-2-propanol hydrochloride was added 60 ml of 4% sodium hydroxide solution. The reaction mixture was stirred at room temperature for 24 hours. After drying, the fumarate is precipitated from the filtrate by addition of an ethereal fumaric acid solution and recrystallized from ethyl acetate; t. t. 178-180 ° C.

IR, _as coo = 1579 cm- ¹ ;

l * ArOCH 2 ⁼ 1269 cm ^-1 ;

UV λ = 204, 218, 273 cm ¹ , (loge = 3.65; 3.67; 3.52 m ² .mol ^-1 H-NMR δ =

0.07 ppm [s; 9H; C (CH 3) 3]

The following new substances were prepared using these methods:

First

4- (3-isopropylamino-2-hydroxypropoxy) -3- (cyclohexyloxymethyl) phenylmethylketone fumarate,

1.1. 164-165 ° C (ethyl acetate)

Second

4- (3-tert-butylamino-2-hydroxypropoxy) -3- (cyclohexyloxymethyl) phenylmethylketone fumarate,

t. t. 209-210 ° C (ethyl acetate)

Third

4- (3-isopropylamino-2-hydroxypropoxy) -3- (cyclohexyloxymethyl) phenylethylketone fumarate,

t. t. 171-174 ° C (ethyl acetate)

4th

4- (3-tert-butylamino-2-hydroxypropoxy) -3- (cyclohexyloxymethyl) phenylethylketone fumarate,

t. t. 217-220 ° C (ethyl acetate)

5th

4- (3-Isopropylamino-2-hydroxypropoxy) -3- (allyloxymethyl) phenylmethylketone fumarate

t. t. 131-132 ° C (ethyl acetate)

6th

4- (3-tert-butylamino-2-hydroxypropoxy) -3- (allyloxymethyl) phenylmethylketone fumarate

t. t. 178-180 ° C (ethyl acetate)

7th

4- (3-Isopropylamino-2-hydroxypropoxy) -3-allyloxymethyl) phenylethylketone fumarate

t. t. 133-135 ° C (ethyl acetate)

8th

4- (3-tert-butylamino-2-hydroxypropoxy) -3- (allyloxymethyl) phenylethylketone fumarate

4.00 ppm. (wide band 3H; Ar-OCH 2 -CH),

1.1. 175-177 ° C (ethyl acetate)

The prepared fumarates are in a 2: 1 base-fumaric acid ratio. The structure of the prepared compounds was verified by elemental analysis (carbon, hydrogen, nitrogen) and evaluation of ultraviolet, infrared and 1H-NMR spectra.

Claims (5)

1,4- (3-Alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) phenylalkyl ketones of formula I OH in which R1 is isopropyl, tert-butyl, R ² is cyclohexyl, allyl, R ³ is methyl, ethyl. 2. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) phenylalkyl ketones of the formula I according to Box 1, which comprises reacting a compound of the formula II OH O-CH 2 CH-CH ₂ Ct L / chjo-R The CO-R (II) of the invention is in which R ² and R ³ is the same as in formula with a primary amine IlžNR ¹ in which R1 is the same as in formula I in a C 1 -C 3 alcohol at the boiling point of the reaction mixture. 4. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymethyl) phenylalkyl ketones of the formula I as defined in claim 1, which comprises reacting a compound of the formula IV in which: R ² and R ³ is the same as in formula I with a primary amine HzNRi in which R &^lt; ¹ > is the same as in Formula I in an alcohol having 1 to 3 carbon atoms. 3. Method of preparation 4- (3-alkylamino-2-hydroxypropoxy) -3- (allkoxymethyl) phenylalkyliketones of general formula I according to item 1, characterized by reacting a compound of general formula III in which: R ² and R ³ is the same as in formula I with L-alkylamino-2,3-epoxypropane of the formula V ABOUT / \ CH2-CH2-CH2-NH-R1 (V) in which R 1 is the same as in formula I in water under catalysis with an alkali metal hydroxide, preferably sodium hydroxide. > 5. A process for the preparation of 4- (3-alkylamino-2-hydroxypropoxy) -3- (alkoxymeíyl) f enylalkylketónov of formula I according to claim 1, characterized in that reacting a compound of formula IV, R ² and R ³ it is the same as in formula I with 1-alkylamino-3-chloro-2-propanol of formula VI Cl-CH ₂ -CH-CH 2 NH-R ¹ (VI) OH in which R ¹ is the same as in formula I in water under the catalytic action of an alkali metal at room temperature.