RU1063059C - Hydrochloride of derivatives of 2-carbethohy-4-oxibenzofurane possessing antiarrhythmic and antifiblrillatoring activity - Google Patents

Description

and g

vp

where R has the indicated meanings, with a primary or secondary amine of the general formula 3

RH.

wherein R is as indicated, in a non-polar solvent, preferably benzene, and the resulting base is treated with hydrochloric acid.

The structure of compounds of the general formula 1 is proved spectral1 and data and confirmed by elemental analysis data.

Example. Preparation of 2-carbethoxy-3-allylaminomethyl-4-hydroxybenzofuran hydrochloride (1a) ..

A mixture of 10.23 g (R.OZ mole) of 2-carbethoxyZ-bromomethyl-4-acetoxybenZofuran, 6.85 g

(0.12 mol) of allylamine and 50 ml of benzene were kept at 20-25 ° C for 5-6 hours. The precipitated precipitate was filtered off. The mother liquor is washed with water, dried over magnesium sulfate and evaporated. The residue was dissolved in acetone (50 ml), concentrated hydrochloric acid was added to the solution to pH 4-5. Upon cooling, crystals precipitate. The precipitate formed is filtered off, washed with acetone and dried.

4.02 g (43%) of 2-carbethoxy-3-allylaminomethyl-4-hydroxybenzofuran hydrochloride are obtained in colorless crystals soluble in water and alcohol, i.e. 194196 ° C (ethyl alcohol).

Found,%: C 58.00: H 5.80.- N 4.BO; C 11.48.

СшН1бС1МО4.

Calculated,%: C 57.79; H 5.82.- N 4.49; C1 11.37.

Under conditions analogous to example, compounds 1 b are obtained. 1 century yield and physico-chemical characteristics of which are given in table 1.

These compounds are

colorless crystalline substances, stable in air, soluble in water and alcohol.

The UV spectra of these compounds are characterized by two absorption maxima,

located at 248-250 and 304-305 tffA.

In the IR spectra of the compounds of general formula 1, there are absorption bands in the regions of I700-1720 and 3400-3430 cm, indicating the presence of

hydroxy groups.

The experiments were performed on healthy laboratory animals, having reached puberty.

Single dose toxicity

determined on 75 white mice of both sexes weighing 18-25 g with intraperitoneal administration of the compounds. Toxicity indicators calculated according to Behrens.

Antiarrhythmic properties were revealed in the model of aconitine arrhythmia in experiments on 50 rats in comparison with novohainamide and cordarone ...

The first of these was taken as a comparison, as a well-known drug tested in a clinical experiment, Corderon, as well as compounds of the general formula t, is a benzofuran derivative exhibiting the same deist

WIA, ..

The antifibrillator effect was studied in experiments with tia 16 cats, in which ventricular fibrillation of the heart was induced using a rectangular electric pulse with a duration of 100 cm and an apparent electrocardiogram period. The fibrillation threshold was determined before administration of the compounds and then after intravenous administration after 5.15.30 and 40 minutes.

. Research results. The toxicity of compounds with a single administration to mice is presented in table 2. Toxicity 4E (0zy caused inhibition of mice.

From table 2 it follows that compound 1c b is 2.5 times less toxic than corlarst, LD50 of which is 35V g / kg and is 8 times less toxic with procaine / soybeans, and 8 times less toxic with novocaines /: 140 mgMg, Compounds 1a and t € are also less than 1 x 1 lh than Novocainamide

The results of the research of Ratt & sarhhythmic activity are presented in Table 3.

. As can be seen from the table, 3,151 counterarrhythmic activity of compounds of Shi fQ in doses of 10% LDB corresponds to that of procainamide, taken in a dose of 20% LDE, and koshcharon used in the optimal dose of Ш mg / kg. Higher doses disrupt oventricular conduction. Compound 1a was more active than drugs,

Physico-chemical characteristics of the compounds of General formula 1

Taken ALA comparisons; it restored the disturbed rhythm in 8 out of 10 rats, while novocainamide and cordarone were found in only two rats. At a dose of 10% LDB, compound 1a increased the fibrillation threshold of cats' ventricles by 1.7 times.

When comparing the antiarrhythmic activity of compounds (1a. 16 and 1c) with the known compounds A and B and antiarrhythmic drugs cordarone and nicotinamide, it was found that compounds Tb and 1c have the same activity as maxo / I tc at the level of cordarone and novocainamide, and compound 1a is superior to compounds A and B, So. compound ta has a protioarrhythmic effect in 8 out of 10 rats, and the known compounds A and B in B out of 10 rats and in 7 out of 40, respectively.

It should be noted that compound 1a also has antifibril tornby activity, which is less pronounced compared with the previously described compounds A and B.

In addition, it should be noted that the compounds of the general formula I epachel + 1O are less toxic than the known compounds A and &.

So, the LDBb of compounds 1a, 1bi 1 and its composition is 121, $, respectively; 176.0 and 890.0 mg / kg, and the dosage of known compounds A and B, respectively, is 5t, 0 and 135.0 mg / kg.

Thus, the compounds of the general formula t are comparable in biological activity to known compounds of a similar structure and are, in addition, less toxic.

(56) Copyright certificate of the USSR Mg 3412453 / 23-04 class. C 07 D 307/81; C 07 D 307/84, 03/26/82 unbroken "forged".

Table 1

.sh

wei

t & n ....- V ... . ...,. , - :. - - .. Table 2 ; .Toxicity of 2-carbethoxy-4-hydroxybnzofurand derivatives for mice in a single dose

,. ; ./ vyer nt: / „- g-. :, l ,,,

 ...:.,.;,. ; : ..,.:, J .; /. . :,. .-; ; . abli c a 3

The effect of derivatives of 2-carbztoxy-4-hydroxybenzofuran, Nbvocainamide and cordarone on

aconity: New rat arrhythmia

Continuation of the table. 1