Hypotensive n-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride

FIELD: chemistry.

SUBSTANCE: compound refers to new biologically active N-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride (I) of formula . The compound is produced from reacted 1-bromine-2-(2'-methylphenoxy)ethane and morpholine. The produced compound represents a white crystalline matter, soluble in hot water, ethanol, chloroform, dimethyl sulphoxide, dimethyl formamide.

EFFECT: there is produced a new long-lasting hypotensive compound.

1 tbl

 

The claimed connection relates to the field of organic chemistry, to the class of aryloxyalkyl, namely to a new biologically active N-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride (I) of the formula

which can find application in the medical and pharmaceutical industry as drug antihypertensive drug.

As standards of comparison hypotensive action taken: known anti-hypertensive drug papaverine hydrochloride and the closest structural analogue of propranolol hydrochloride (inderal) [Mashkovsky PPM Medicines: 2 so - 14th ed., Rev., Corr. and extra - M.: OOO "Publishing house New Wave", 2000].

The aim of the invention is to obtain new information not previously described N-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride (I)having an antihypertensive effect. This goal is achieved by obtaining N-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride (I) the interaction of 2-methylphenethylamine with morpholine (Fig.1):

1. The scheme for synthesis of N-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride.

Method for producing N-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride. A mixture of 15.0 g (0.07 mol) of 1-bromo-2-(2'-methylphenoxy)ethane and 12.2 g (0.14 mol) of the research upon completion of the exothermic reaction boil on the sandstones is Noah bath for 2 h, left overnight, the precipitation of the research hydrobromide is filtered off, washed with diethyl ether. The ether extract is washed with NaOH solution until the discoloration of the water layer. The organic layer is dried crystalline NaOH. After removal of the desiccant in the filtrate is passed a current of dry HCl. The precipitation of the hydrochloride of N-2-(2'-methylphenoxy)-ethylmorpholine filtered off, crystallized from toluene. The product yield 10,14 g (56.4 per cent), TPL 194-196°C.

The inventive compound is a white crystalline substance, soluble in hot water, ethanol, chloroform, DMSO, DMF. The NMR spectrum1N (BS-567A, (100 MHz) in CDCl3internal standard - GMDS) connection I have:

the singlet of three protons of the methyl group in the area and 2.14 ppm, multiplet two axial protons of two methylene groups at the nitrogen atom morpholino fragment N(CH2CH2)2In the area of 3.06 ppm, a triplet of two protons of methylene group at the nitrogen atom in the side chain in the area of 3.45 ppm, doublet of two Equatorial protons of two methylene groups at the nitrogen atom morpholino fragment N(CH2CH2)2O in the area of 3.56 ppm, doublet of two axial protons of two methylene groups at the oxygen atom morpholino fragment N(CH2CH2)2O in the field 3,93 ppm, a triplet of two Equatorial protons of the two methylene what's groups at the oxygen atom morpholino fragment N(CH 2CH2)2O in the field to 4.23 ppm, a triplet of two protons group co2in the field to 4.52 ppm, multiplet, protons of the aromatic ring in the area 6,74-to 7.15 ppm, broadened singlet proton of NH group+in the field 13,41 ppm

Acute toxicity when administered intravenously were determined by nonlinear white mice weighing 20-25 g test substance and the Comparators were injected into the tail vein in aqueous solution at a rate of 0.1 ml / 10 g weight of the animal in increasing doses. The results were processed by Prozorovsky calculation of the median lethal dose (LD50) at P=0.05 [Prozorovsky CENTURIES, Prozorovsky BTW, Demchenko V.M. Pharmacol. and toxicol., so 41, No. 4, s-502 (1978)].

The connection I investigated for the presence of anti-hypertensive activity. The experiment was performed in healthy cats of both sexes anesthetized with barbitala sodium (medial) at a dose of 400 mg/kg, intraperitoneally. Claimed the substance was administered to animals at a dose of 5 mg/kg (1/25 LD50), and the Comparators was administered at a dose of 0.1 LD50intravenously. Blood pressure was measured in the carotid artery by the direct method. In each series of experiments was used 5-6 animals. The degree of hypotensive activity of the compounds and standards of comparison expressed in mm RT. Art. relative to the original level in a certain period of time and were statistically processed once ostim method using the student coefficient [Sarnow L.N., Hazura CENTURIES, Elements of experimental pharmacology, M., s.312-313 (2000)].

The test results presented in the table.

Table
Acute toxicity, the severity and duration of the hypotensive effect of the inventive compounds (I) and reference measurement standards
ConnectionLD50mg/kgThe degree of decrease in blood pressure, %The duration of the hypotensive effect of, min
I140,040,7
(p<0,01)
660
Papaverine hydrochloride30,030,2
(p<0,01)
3
Propranolol hydrochloride22,547,2
(p<0,001)
10

As can be seen from the table, studied the connection shows high anti-hypertensive activity, significantly outperforming the Comparators in duration. The toxicity of compound I is significantly lower than the standards of comparison.

Thus, N-2-(2'-methylphenoxy)-Atila Polina hydrochloride (I) shows significantly more prolonged hypotensive effect. Therefore, the claimed compound (I) can be used in medicine as an anti-hypertensive drugs with long lasting effect.

N-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride

having hypotensive activity.



 

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