Method of production of 2-[2ъ-hydroxy-3ъ-(1.1-dimethyl-propylamine)-propoxy]-beta-phenylpropiophenon

专利摘要:

公开号:SU1331424A3
申请号:SU833583671
申请日:1983-04-22
公开日:1987-08-15
发明作者:Петрик Герд；Заксе Рольф
申请人:Хелофарм В.Петрик Унд Ко,Кг (Фирма)；
IPC主号:

专利说明:

00 with
11 th

CH

This invention relates to a process for the preparation of a novel ester of β-phenylpropiophenone, namely, hydroxychloride 2-2 hydroxy-3 - (1,1-dimethylpropyl amino) propoxy-phenylpropiophenone or its salts, which have an antiarrhythmic effect.
The purpose of the invention is a method for producing a novel compound in a series of / -phenylpropiophenone derivatives having a higher antiarrhythmic effect.
Example 1 A. Preparation of 2- (2, 3-epoxypropoxy) - [9-phenyl-propiophenone, 22.6 g (0.1 mol) of 2-hydroxy-1-phenylpropiophenone is dissolved in 150 ml of 1-chloro-2,3-epoxypropane. After addition of 12 g of potassium carbonate, the reaction mixture is heated, shaken and refluxed until high pressure liquid chromatography shows the reaction is complete. The reaction mixture is cooled, the resulting potassium chloride is filtered off. The filtrate is condensed under reduced pressure, while excess 1-chloro-2,3-zpoxypropane is separated from the one obtained from 2- (2,3-epoxypropoxy) -phenylpropiophenone. The resulting crude product is a yellowish oil, which solidifies at room temperature (yield 28 g, 98%). At the next stage, the product does not need to be cleaned. The pure substance obtained by recrystallization from four times the amount of methanol has a melting point of 56 ° C.
Calculated,%: C 76.58; H 6.42.
Found,%: C 76.92; H 6.38.
B. Preparation of 2- (2 -hydroxy-3-1,1-dimethylpropylamino) -propoxy-phenylpropiophenone hydrochloride (diprafenone-HC1).
28 tons (0.1 mol) of the obtained compound in accordance with Example 1A. dissolved in 100 ml of methanol and treated with 26 g of 1,1-dimethylpropylamine (2-methyl-2-amino5utane). The mixture was then heated under reflux for 4 hours while stirring. The reaction mixture is then evaporated under reduced pressure. The resulting residue is then dissolved in 100 ml of isopropanol.
314242
simultaneously heating, and then adjusted to pH 1 with concentrated 36% hydrochloric acid. The mixture is kept at room temperature until the hydrochloride precipitates in the form of crystals. The resulting crude product is recrystallized from the same volume amount.
10 isopropanol. The hydrochloride is obtained with a yield of approximately 33.0 g (81.3% in the form of a white crystalline substance, having a melting point of from 130 to 131 C.
15 Calculated,%: C 68.05; H 7.94; N 3.45.
CijHj NOjCl
Found,%: C 67.97; H 7.91; N 3.72.
2 II p and M e r 2. 2- (2-hydroxy-3 - bromopropoxyl) - fr phenylpropiophenone is reacted with an equivalent amount of 2-methyl-2-aminobutane in the presence of dimethylformamide as a solvent and sodium carbonate as acid acceptor by distillation under reflux for several hours. After treatment of the reaction mixture in accordance with Example 1B, diprafenone-hydrochloride with m.p. 130 ° C. is obtained. EXAMPLE 3 Example 2 is repeated with 2- (2-hydroxy-3-chloropropoxy)) enylpropiophenone getting
35 diprafenone hydrochloride with mp pl. 13025
thirty
40
.
The therapeutic effect of the proposed compound was tested on dogs. Model arrhythmia, which is characterized by ventricular extrasystoles with absolute arrhythmia, was obtained by infusion of chloroform and adrenaline (epinephrine). At the onset of these rhythm disorders, an image of the shadow was administered intravenously as an aqueous solution of hydrochloride.
Such small intravenous doses of 0.05 mg / kg were fully effective after 45 minutes in all dogs that
B they were introduced, i.e. sinus rhythm on an electrocardiogram ECG has become normal.
Dogs could again be able to observe a high antiarrhythmic effect after oral administration. Rhythm disorders were achieved by closing the branches of the coronary vessels. The compound of the invention was administered internally.
Ribyushin in the form of hydrochloride the next day. The aextrasystole remained unchanged for 10 minutes after the administration of 10 mg / kg. 30 min after administration, extrasystoles were not observed. ECG remained normal for 24 hours.
The table shows the results of pharmacological tests on dogs of the proposed compound as hydrochloride and propafenone-HC1.
Systolic blood pressure mm Hg
Diastolic blood pressure
mmHg
Peak left ventricular pressure mm Hg
Maximum speed of increasing pressure
Peripheral blood volume
D P
1424
In the table, the following notation is used: D - diprafenone - a compound obtained in accordance with the invention; P - propafenone - structural analogue; O is not substantially different from the original value;
 - significant effect.
The results of the tests suggest that the compound has a higher antiarrhythmic effect at lower doses.
-13
-17 -45 O -30
-65
-sixteen
-24 -39 O -40
-60
-eight
-22 o
-24 o
-46 -25
-42
-70
about o -30
about . -29 -47
-62
About About +10 +36
Parameters of the blood circulation of the arc, the test criteria
Volume of venal blood flow
P

D
P
+
about
+
about
Compiled by L.Ioffe. Editor A.Dolynich Tehred M.Hodanich Proofreader A.T.
Order 3596/58 Circulation 371Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4
Table continuation
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I-14 30 +43 +67
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权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING 2- [2'-HYDROXY-3 ¹ - (1,1-DIMETHYL PROPYLAMINO) PROPOXY] - β-PHENYL PROPIOPHENONE OR ITS PHARMACOLOGICALLY ACCEPTABLE SALTS, characterized in that the phenol ether of the formula A o-χ ₂ -a is where: - group —CH — CH2
HE
I or CH - CH ^ - B; In - bromine or chlorine, is reacted with 1,1-dimethylpropylamine, followed by isolation of the resulting product in the form of a base or salt.
SU <„. 1331424> CH

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引用文献:

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE3133814A|DE3133814C2|1981-08-25|1981-08-25|2- [2'-Hydroxy-3 '--propoxy] -β-phenylpropiophenone, its acid addition salts and drugs|

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