CS276205B6 - Alkoxyphenylcarbamic acid 3-alkylamino-2-hydroxy-1-propyl esters - Google Patents

Abstract

New substituted 3-alkylamino-2-hydroxy-1-propyl esters of the general formula I, in which R* 1 is an unbranched alkyl with 2 to 4 carbon atoms and RZ is a pentyloxy substituent in the 0-, m- and p-position, as well as their salts with inorganic and organic acids. These compounds are characterized by pronounced antiarrhythmic activity. The solution further relates to the method of preparation of the mentioned substances.

Description

The invention relates to alkoxyphenylcarbamic acid 3-alkylamino-2-hydroxy-1-propyl esters of the formula I.

OH

KHCOOGH ₂ CHCH ₂ NHR

In which R is unbranched alkyl of 2 to 4 carbon atoms and R is a pentyloxy substituent in the o-, m- and p-position. From the point of view of chemical structure, these new compounds of the formula I, which have not been described in the literature, are among the isosteric analogues of beta-adrenolytics in which the ether oxygen between the aromatic nucleus and the linker chain is replaced by a carbamate group. Similar to other substances of the aryloxyaminopropanol type prepared with a similar pharmacotherapeutic indication / e.g. patent file no. 220 271 / i, these compounds are characterized by marked antiarrhythmic activity. They significantly increased the consumption of arrhythmogenic substances (ouabain, aconitine and adrenaline) needed to induce extrasystoles, fibrillation and lethal cardiac arrest. Some substances (ARK-5210, ARK-5211, ARK-5310 and ARK-5311) proved to be more effective than the propafenone standard / Tab. 1 to 3 /. All studied substances were mildly locally anesthetically effective during surface and infiltration anesthesia and the toxicity of the substances ranged from 100 to 400 mg.kg ^-1 / Tab. 4 /.

Fabric Consumption ouabainufAg.kg “ ¹ Arrhythmia Fibriláoia Lethality ⁴ Propafenone 198.4 t 8.6 353.6 - 8.7 479.4 and 2.2 Control 243.7 and 8.4 353.4 - 13.6 430.4 and 15.4 ARK-5210 278.5 t 24.7 422.6 t 26.7 563.1 and 18.5 ARK-5211 255.1 - 18.6 363.8 t 8.7 496.8 and 6.0 ARK-5212 304.5 and 14.0 454.1 and 32.2 606.8 t 40.7 ARK-5310 323.8 and 24.2 439.4 and 20.5 535.2 t 16.9 ARK-5311 286.3 and 15.3 362.2 t 9.3 429.2 and 12.7 ARK-5312 229.5 and 11.1 351.9 and 17.4 444.5 and 19.1

1. Arrhythmogenic, fibrillation and lethal consumption of ouabain after intravenous administration of substances in a concentration of 1.10 ^- mol% kg ^-1 .

CS 276 205 B6

Fabric Aconitine consumption ^ g.kg ”· '’ Arrhythmia Fibrillation Letality Propafenone 93.3 - 2.0 215.6 - 4.8 306.0 - 22.3 Control 113.1 and 11.0 189.8 and 21.2 324.4 - 15.4 ARK-5210 165.4 - 5.3 283.1 * 5.9 396.7 - 14.1 ARK-5211 i 154.6 and 21.5 274.1 and 20.9 369.9 t 14.1

ARK-5212 129.8 t 17.1 226.9 - 20.5 338.0 - 12.0 ARK-5310 252.4 and 7.0 356.0 and 14.8 457.7 - 6.2 ARK-5311 120.4 and 7.5 191.1 and 13.6 389.3 and 12.3 ARK-5312 108.6 t 2.8 156.3 - 4.5 423.2 and 12.9

Table 2. Arrhythmogenic, fibrillation and lethal consumption of aconitine after intravenous administration of substances with a concentration of I.IO ^- ^ mol.kg '· * ·

Fabric X 8 SE Control 56.83 10.16 4.15 ARK-5210 14.83 2.56 1.04 ARK-5211 10.62 2.83 1.01 ARK-5212 14.14 11.84 4.47 ARK & 531O 14.71 2.43 0.92 ARK-5311 6.16 1.60 0.65 ARK-5312 7.66 2.63 1.08

Table 3. Absolute amount of extrasystole after pre-application of substances in a dose

1.10'5 _and application of adrenaline intravenously 20 + 20 / jgkg ¹ .

CS 276 205 B6

Fabric Surface anesthesia / cocaine = l / Infiltration anesthesia / procaine = l / ^W 50 mg.kg ” ¹ ARK-5210 28.6 16.0 150-200 ARK-5211 40.0 16.6 150-200 ARK-5212 58.8 30.7 200-400 ABK-5310 22.2 16.0 100-150 ARK-5311 19.2 22.3 100-300 ARK-5312 19.6 13.8 200-400

Table 4. Local anesthetic activity during surface and infiltration anesthesia and acute toxicity of substances after s. c. application of 1% solution to mice.

Substituted alkoxyphenylcarbamic acid 3-alkylamino-2-hydroxy-1-propyl esters of the formula I can be prepared according to the invention in various ways, for example by reacting them in a polar solvent:

a) 1- (alkoxyphenylcarbamoyloxy) -3-bromo-2-hydroxypropane of formula II

/ II / wherein R means the same as in formula I, with a primary, linear alkyl amine of formula NI ^ R ^1, wherein R ¹ is the same as in formula I, preferably in a medium of water at room temperature for 24 hours.

b) 1- (alkoxyphenylcarbamoyloxy) -2,3-epoxypropane of formula III

(III), in which R is the same as in formula I, with a primary unbranched alkylamine of the general formula Ni 1 R ¹ , in which R ¹ is the same as in formula I, preferably in the environment of an alkanol having 1 to 4 carbon atoms, preferably ethanol at the boiling point of the reaction mixture for 8 h.

CS 276 205 B6

After completion of the reaction, the solvent is most often distilled off from the reaction product and the crude product is dissolved in dilute hydrochloric acid, shaken with ether and the base liberated from the separated aqueous phase is extracted into ether. From the ether solution, the basic ester can be converted directly to the desired salt and further crystallized from an organic solvent or from a mixture of organic solvents.

Suitable salts with organic acids suitable for the dosage forms are, for example, hydrobromide, hydrochloride, sulfate, phosphate, or salts with organic acids, for example, oxalate, maleate, fumarate, tartrate, citrate and the like.

The starting materials are commonly available chemicals such as 2,5 and 4-aminophenols, alkylamines, 2,3-epoxy-1-hydroxypropane or substances described in the literature. These are, for example, alkoxyphenyl isocyanates and anilines described in the literature / Borovanský A., Hartl I., Kopáčové L., Českoslov. farm. 20, 10 (1971).

Details of the preparation are given in the following examples:

Example 1

2-Pentyloxy-phenylcarbamic acid 3-propylamino-2-hydroxy-1-propyl ester

To 6.9 g (0.12 mol) of propylamine in 30 ml of water, 20.7 g (0.06 mol) of 1- (2-pentyloxyphenylcarbamoyloxy) -3-bromo-2-hydroxypropane are gradually added with stirring and stirred at rooms for 24 hours. Propylamine was distilled off from the reaction medium under a slight vacuum and the residue was dissolved in dilute hydrochloric acid. After shaking with ether from the separated aqueous phase, the base liberated by alkalization is taken up in ether and dried over anhydrous potassium carbonates. A white crystalline substance precipitates from the filtrate by adding an ethereal solution of dry hydrogen chloride, which is crystallized by starting / T. t. 94-97 ° C.

Example 2

2-Pentyloxy-phenylcarbamic acid 3-butylamino-2-hydroxy-1-propyl ester

To a reaction mixture of 25.1 g (0.09 mol) of 1 - [(2-pentyloxy) -phenylcarbamoyloxy] -2,3-epoxypropane in 50 ml of ethanol is added a solution of 10.5 g (0.18 mol) of butylamine in 30 ml of ethanol and heated at the boiling point of the reaction mixture for 8 h. Ethanol and butylamine are distilled off under a slight vacuum. The crude product is dissolved in dilute hydrochloric acid and shaken with ether. After alkalization of the aqueous phase, the liberated base is taken up in ether, dried over anhydrous sodium carbonate and, after addition of an ethereal solution of hydrochloric acid, a white crystalline substance precipitates, which is crystallized from acetone / T. t. 98-100 ° C.

Using the methods described above, the following new substances not yet described in the literature were prepared:

2-Pentyloxy-phenylcarbamic acid 1,3-ethylamino-2-hydroxy-1-propyl ester (ARK-5210) hydrochloride, m.p. t. 133 DEG-138 DEG C. (2-propanol)

2/3-propylamino-2 ^as hydroxy-propyl-2-pentyloxyfenylkarbámovej / ARK-5211 / hydrochloride salt, mp 94-97 ° C / acetone /.

2-Pentyloxy-phenylcarbamic acid 3-butylamino-2-hydroxy-1-propyl ester (ARK-5212) hydrochloride, m.p. t. 98-100 ° C (acetone)

3-Pentyloxy-phenylcarbamic acid 4-ethylamino-2-hydroxy-1-propyl ester (ARK-5310) hydrochloride, m.p. t. 132 DEG-134 DEG C. (2-propanol)

3-Pentyloxy-phenylcarbamic acid 5-propylamino-2-hydroxy-1-propyl ester (ARK-5311) hydrochloride, m.p. t. 120-123 ° C (2-propanol)

3-Pentyloxy-phenylcarbamic acid 6-3-butylamino-2-hydroxy-1-propyl ester (ARK-5312) hydrochloride, m.p. t. 105-108 ° C (2-propanol)

Claims (3)

1. Substituted alkoxyphenylcarbamic acid 3-alkylamino-2-hydroxy-1-propyl esters CLAIMS OF Formula I 1. 2 in which R is unbranched alkyl having 2 to 4 carbon atoms and R is a pentyloxy substituent in the o-, m- and p-position, as well as their salts with inorganic and organic acids. 2. A process for the preparation of substituted 3-alkylamino-2-hydroxy-1-propyl esters of alkoxyphenylcarbamic acid of the general formula I according to item 1, characterized in that 1- (alkoxyphenylcarbamoyloxy) -3-bromo-2-hydroxypropane of the general formula II is reacted. wherein R is the same as in formula I, with the primary unbranched alkylamine of formula NH 3 R 6, wherein R 2 is the same as in formula I, in a polar solvent at room temperature. 3. A process for the preparation of substituted 3-alkylamino-2-hydroxy-1-propyl esters of alkoxyphenylcarbamic acid of the general formula I, according to item 1, characterized in that 1- (alkoxyphenylcarbamoyloxy) -2,3-epoxypropane of the general formula III is reacted. (III) in which R is the same as in the general formula in which the alkanol at the boiling point of the reaction formula I, with the primary unbranched alkylamino means the same as in the formula I, in the medium of the mixture.