SK81493A3 - 3-/4-phenyl-1-piperazinyl/-2-hydroxy-1-propylesters alkoxyphenyl-carbame acids - Google Patents

Abstract

Compounds of general formula 1, where R means alkoxyle with 1 to 3 carbon atoms as well as their inorganic and organic acids salts are prepared by reaction of 3-bromo-2-hydroxy-1- -propylester of alkoxyphenylcarbamic acid with N-phenylpiperazine in an aqueous medium at ambient temperature, and/or by reaction of 2,3-epoxy-1-propylester of alkoxyphenylcarbamic acid with N-phenylpiperazine in an alkanol medium at boiling point of the reaction mixture. These compounds display antidisrhytmic activity.

Description

3- (4-Phenyl-1-piperazinyl) -2-hydroxy-i-propyl esters of linyl alkoxyphenylcarbamides

Technical field

The invention relates to 3- (4-phenyl-1-piperazinyl) -2-hydroxy-1-propyl esters of alkoxyphenylcarbamic acids wherein alkyl is an aliphatic hydrocarbon radical having 1 to 3 carbon atoms.

BACKGROUND OF THE INVENTION

To date, 3-alkylamino-2-hydroxy-1-propyl esters of alkoxyphenylcarbamic acid have been known in which alkoxy is a substituent. in the 2-, 3- and 4-position of the aromatic nucleus having a carbon number of 3 to 7, and the alkyl in the basic moiety is a single unbranched or non-branched alkyl; The above compounds exhibited anti-arrhythmic activity Racanska E., Sheep P., E., Csollei J., Kulcsar Press).

wherein alkoxy

The 3- and 4- aromatic nuclei with the alkyl in the basic moiety are carbon atoms, anesthetic, and L., Bučiová L.,

276 205, Racanska

Czechoslovak Farm (Csollei J.

Turnová I .: A., up to 4 loci, Beneš • CS

Búčiová L .:

SUMMARY OF THE INVENTION

The present invention provides novel compounds which are not yet known

wherein R is alkoxy having 1 to 4 aromatic nucleus, such as inorganic acids.

The compounds according to the invention are prepared by reacting them in the polar α-3-bromo-2-hydroxy-1-propyl ester of the carbamic formula II with their carbon atoms in position with their organic clay. , u or Formula I in various ways, e.g. it is thus possible for the alkoxyphenyls to be

(II) wherein R is the same as in Formula I, with N-phenylpiperazine, preferably in a water environment at room temperature for 24 hours.

b) 2,3-epoxy-1-propyl ester of alkoxyphenylcarbamic acid of formula III

(III), wherein R is the same as in formula I with N-phenylpiperazine, preferably in a C 1 -C 4 alkanol, preferably ethanol at the boiling point of the reaction mixture for 8 hours.

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. The base liberated by alkalization from aqueous base is shaken 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 a mixture of organic solvents. Salts with inorganic acids suitable for the use forms are, for example, hydrobromide, hydrochloride, or salts with organic acids, e.g. oxalate, journalate, citrate and the like.

The starting materials are common chemicals such as e.g. 2-, 3- and 4-aminophenols, 2,3-epoxy-1-propainol or substances described in the literature. They are eg. alkoxyphenyl isocyanates and anilines described in the literature (Cižmárik 3, Borovanský A., shoemaker P .: Acta Facult Pharm Univ Comeniane 29, 53 (1976)).

The following examples illustrate but do not limit the preparation and properties of the compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 3- (4-phenyl-1-piperazinyl) -2-hydroxy-1-propyl ester of 4-ethoxyphenylcarbamic acid

To 9.7 g (0.06 mol) of N-phenylpiperazine in 15 cm @ ^{3 of} water, while stirring, 9.5 g (0.03 mol) of 4-ethoxyphenylcarbamic acid 3-bromo-2-hydroxy-1-propyl ester are gradually added. and stirred at room temperature for 24 hours. The crude product obtained is extracted three times with 30 cm @ ^{3 of} ether and dried over anhydrous potassium carbonate. Addition of an ethereal solution of dry hydrogen chloride to the filtrate precipitates a white crystalline solid.

The product is purified by crystallization from dilute ethanol. A solid product is obtained in a yield of 80% of theory.

Colorless crystals, i. t. 1.95-196 ° C.

Example 2

Preparation of 3- (4-Phenyl-1-piperazinyl) 2-methoxyphenylcarbonic acid - 1-yloxy-1-piperazinyl

To the reaction mixture, 2.2 g (.01 mol) of 2-methoxyphenylcarbonic acid in 1.6% (0.01 mol) of N-phenylpiperazine was boiled for 8 hours under gentle vacuum with crude hydrochloric acid. By basifying the aqueous phase, it is dried over an anhydrous solution of dry substance, which solid is obtained in a yield of 6 colorless crystals, the product is dissolved and the base is shaken three times with sodium carbonate. After addition of hydrogen chloride, it is purified by crystallization from eta 3% of theory.

mp 114 to 116 ° C.

Of 2,3-epoxy-1-propyl ester 30 cm ^{3 of} ethanol are added. is added and heated at a temperature. Ethanol is distilled off under dilute ether. After ether, ethereal using the following literature procedures not previously described:

3- (4-phenyl-1-piperazinyl) -2-hydroxy-1-propyl acid ester

2-methoxy phenyl lkarbárnove j (ARK 62.L) hydrochloride, mp 114-116 ^C> C (ethanol)

IR (cm -1, KBr) V / n-h 2 S 255 Vc = oz = 1740 = 1525

UV (nm, methanol) 280,240,210

NMR (see table)

3- (4-Phenyl-1-piperazinyl) -2-hydroxy-1-propyl ester

2-ethoxyphenylcarbonic (ARK-622) hydrochloride, m.p. 118-120 ° C (ethanol)

IC (cm ^-1 , KBr) V / n-hz ⁼ 8,325 ýz c = o / -l 700 i / c = c / ⁼ 1,510

UV (nm, methanol) 280,242,208

NMR (see table)

3- (4-Phenyl-1-piperazinyl) -2-hydroxy-1-propyl ester

2-Propoxyphenylcarbamic hydrochloride

IR (cnri, KBr)

UV (nm, methanol)

NMR (see table)

3- (4-phenyl-1-piperazinyl) -2-hydroxy-1-propyl ester

3-methoxyphenylcarbonic (ARK-631) hydrochloride, m.p. 195-199 ° C (ethanol)

IC (cm ^-1 , K Br) / zn-hz ⁼ 3,235 (zc = o) ⁼ 1,740 / zc-1,545

UV (nm, methanol) 278,240,214

NMR (see table)

3- (4-phenyl-1-piperazinyl) -2-hydroxy-1-propyl ester

With the following, 1 / was also spoken

2 /

3 / (ARK-622)

mp 125-126 ° C (2-propanol)

Ί / n-h / - 3 390 c-O.z-1 700

278,260,210

4 /

5 /

5 ·· 'í. 4-enenes .1-L-p. pe τ-asi ny .1. 2-Hydroxy-1-propyl L is still a 1-theta

3-ethoxyphenylcarbamate (ARK-6 32) hy d oc h t t d, l-. t. L 95 to .1. 98-- (methanol)

IC (crri '*, Klrr)

y.

.- = 1st 750 V 'S ·! d. iHTi, ni> ľ ai iol) 2'73,24.1,21 2

NMR (See also 3- (4-phenyl) -piperazine) -2-hydroxy-1-propyl ester acid. S-propoxyphenylcarbonyl-ARK (33 'hydrochloride, m.p. 1'35 at C (ethanol)

U V (. Nm, m e t a n o 1 273,241, 2 i J.

NMR see table;

7 / .3-; 4-Phenylenes-1-piperazin-2-hydroxy-1-propylenes

1-Methoxyphenylenecarbamyl (AR 1, 5'-4'-Hydrochloride, mp 198-283 ° C ^, c. ethanol)

IR (cnr ', KBr) Yz _W -h, · - = 3,210 .-. = 0, = i 710 Yc ₌ cz-L MO

UV (nm, methanol) · 286,242,208

N M P. í v í 13 b uľk a)

8 / 3- (4-phenyl-1-piperazinyl) -2-hydroxy-1-propyl ester; n-4-Etosyl enylcarbamic (ARK-642) hydrochloride, m.p. 195-196 ° C tzr. ethanol)

IR (cnr >, KBr) ΖΝ _ΖΝ -h, - = 3 '215 Y c = oz = 1710 ^ czc.-i 600

UV (nm, methanol) 228,242,206

NMR (see table)

9 / 3- (4-Phenyl-1-piperazinyl) -2-hydroxy-1-propylene, 4-propenyl-4-propylene. AR? -? - 64 3.) hyd roc l .1. o r i d, t. t. 19 5 to 20 0 3- C t e. a n o .1)

IR (α 1, K 2r) Y 2 -h 2 '3' X '. _{: s0 /} = 1710 Y-; _; = c _of 1 SOC

UV (nm, methanol) 236,242,206

NMR (see table)

Results of biological activity assays

In the study of the antioxidantic activity of 3- (4-phenyl-1-piperazinyl) -2-hydroxy-1-propyl 2-metharyphenylcarbonic acid ester (AP.K-62L), a modified method according to Páv and Seleckŕho í Páve k K., Selecký 'F. brother Listy 43 i.

/ 1960 /). The protective effect of the substance against dysrhythmic induced by iv administration was evaluated by two equal,> 0 sec. Consecutive doses of adrenaline at a total dose of 40 µg. kg- ¹ . The anti-dysrytinic effect of the compound was expressed by the number of extrasystoles induced by the couple's adrenaline dose;

control 12, -1 ± 1.9 'AP.K-621 1.3 ± 1.5, and the difference from control is fetalistically significant.

F ri & my8 a n u u u u u u u u u ^:

3- (4-Phenyl-1-piperazinyl) -2-byroxy-1-propyl esters of alkoxy sulfonylcarbamides can be used in the pharmaceutical industry and in medicine.

'h o

CN spectra of ARK series.

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Patent claims

Claims (2)

Patent claims 1. 3- (4-Phenyl-1-i-piperazinyl) -2-hydroxy-1-propyl-1-alkoxyphenylcarbamic acid esters of formula I -CH-CH 2 -N 2 OH (I) wherein P represents an alkoxy group having 1 to 3 carbon atoms in the 2-, 3 or 4-position of the aromatic ring, as well as salts thereof with organic or inorganic acids. 2. A substituted alkoxyíenyikarbámovej esters of the formula I, and in point, characterized in reacting 3-bromo - 2-hydroxy-1-propyl-lester alkoxyíenylkarbámovej of the formula II 'NH-CO-CH -0 _o - 0H-CH _of Br 4 I b OH (II) in which R is the same as in the formula With N-phenylpiperazine at room temperature. polar solvent environment with pri .3. A process for the preparation of substituted alkoxyphenyl 1 carbamic acid esters of the formula I according to claim 1, characterized in that the 2,3-epoxy-1-propyl ester of alkoxyphenyl 1-carbamic acid of the formula III is reacted. NH-C0-0-CH-CH-CH _{about 9} ¥ ² (III) wherein R is the same as in formula I, with N-íenylpiperazínorn the alkanol medium at the boiling point of the reaction mixture.