SU1160933A3 - Method of obtaining 3-aminopropaxyphenyl derivatives or their pharmaceutically acceptable salts - Google Patents

Abstract

The method of obtaining Z-aminopropoxyphenyl derivatives of general formula (I) OH O-CHg-CH-CHg-Sh-t -Sh CONHK 0- (CH2) gO-H2 or their pharmaceutically acceptable salts J where A is alkylene containing 2-5 atoms carbon; R is phenyl, phenyl substituted by hydroxyl, cyano cyano;} R-- C —C is alkyl, cyclopropylmethyl, characterized in that the compound of the general formula (y) -L axis is -CN-CH2 where R and RI have the indicated values is reacted with a compound of the general formula (III) O H m A NH-CO-NH-f i o where A and R have the indicated meanings, CO and the desired product are obtained in free form or in the form of a pharmaceutically acceptable salt.

Description

This invention relates to a process for the preparation of novel biologically active chemical compounds, specifically to a process for the preparation of 3-aminopropoxyphenyl derivatives of the general formula O-CHg-CH-CH-Br-L-W CONHR 0- (CH2) 2-0-R2, their pharmaceutically acceptable, and alkylene, containing 2-5 carbon atoms; In phenyl, phenyl substituted by hydroxyl, cyano, R,. Cyano, R,, cyclopropylmethyl, which have adrenoceptor blocking activity. derivatives of phenyl urea formulas in charcoal are known. A solution of bromine in chloroform at 0 ° C is added to a solution of the 4- (2-cyclopropyl-Vtoxy-ethoxy) phenol in methanol, and the mixture is stirred for 2 hours. After chromatography on silica gel, the resulting 2-bromo-4- (2-cyclopropylmethoxyethoxy) phenol subjected to interaction for 60 hours with a mixture of potassium carbonate, acetone and benzyl bromide. After chromatography on silica gel, the resulting 1-benzyloxy2-bromo-4- (2-cyclopropanemethoxyethoxy) benzene is reacted for 5 hours with copper cyanide. The reaction is carried out in dimethylformamide. After purification by distribution between an aqueous solution of hydrochloric acid and ethyl acetate, the resulting 2-benzyloxy-5- (2-cyclopropylmethoxyistoxy) benzonitrile is subjected to debenzylation, which is carried out in methanol in the presence of 10% palladium on charcoal. Formed with 2-hydroxy-5- (2-cyclopropylmethoxyethoxy) benzonitrile is reacted at 100 ° C with epichlorohydrin in the presence of catalytic amounts of piperidine. The result is 2- (2,3-epoxypropoxy) -5 (2-cyclopropylmethoxyethoxy) benzonitrile. Analogously to Example 1. Using the corresponding compounds of formula (O) and (III) as starting materials, compounds of formula (t) given in Table 1 can be obtained (examples 2-6). Table 1

Ethylene Phenyl 0-CN

Ethylene h-OH-phenyl 0-CH

Ethylene Phenyl 0-Vg Cyclopropyl Ethylene g yy MSO-phenyl 0-CN

Ethylene p-OH-phenyl .0-CN Cyclopropyl Example 7. 2- (2-hydroxy-3) -2 (3-phenylureido-ethylamino) -propoxy-. 5- (2-methoxyethoxy) -benzonitrile-acid malonate.

100 g of 2- (2-hydroxy-3-) 2- (3-phenylureido-ethylamino) -propoxy-5- (2-methoxyethoxy) -benzonitrile and 24.3 g of malonic acid are dissolved by heating in 750 ml of methanol. After filtration, the resulting salt is evaporated to dryness and the residue is dissolved in 100 ml of ethyl acetate, and then simple sufir is added until the crystallization process begins. The result is a salt whose melting point is 94-96 ° C. The output is 99% of theoretical.

methyl

142-144

Methyl 91-93

methyl

Compounds according to the invention have a particularly high adrenoreceptor blocking activity. For example, in the case of spontaneous contractions of the atrium of guinea pigs, these compounds inhibit the positive chronotropic effect of isopropalin at a concentration of from about 10 M to about 10 M, and in spinal tests on cats, at a dose of from about 0.02 mg / kg to 1 mg / kg

In tab. 2 shows the hormone-receptor blocking activity of compound-. formula. Table 2 Consequently, the compounds of formula () can be recommended for use as blocking agents - adrenoreceptors, for example, for the prevention and treatment of coronary diseases, for example, angina, under conditions associated with excessive sympathetic stimulation, for example, cardiac arrest, myocardial infarction, overpressure, for the intermediate treatment of migraine and for the treatment of glaucoma and thyrotoxicosis. The compounds of formula (T), in view of their antiarrhythmic effects, are useful as antiarrhythmic agents for the treatment of cardiac arrhythmias, for example, in the case of pre-gastric tachycardia. . Prescribed daily doses of lying, ranging from about 10 mg to about 500 mg / they are usually administered in partial doses from 2 to 4 times per day in single doses containing about 2.5 to 250 mg of the active ingredient, or in the form of long-term drugs. The novel compounds have more pronounced and pharmacological indicators lying in a wider range than those that would be expected from compounds having a structure of this type. Thus, in particular, their activity in relation to the effect on heart activity is more selective than might have been expected - based on the results of similar known compounds. The indicated selectivity in relation to the effect on heart activity can be demonstrated in vitro using marine fabrics. pigs according to standard tests. Thus, samples of the tissues of the left ventricle of the heart and lung membranes are obtained according to standard methods of pharmacological studies, after which they are introduced into the reaction with exogenously administered radioactive f / 3 ligand, for example, 3- (251) isocyanopindolol (1-SUR) to determine the efficacy of the test compounds with respect to y9 and .j-adrenoreceptors. Thus, in the case of the listed compounds (Table 3), the affinity for β-adrenoreceptors exceeds the affinity for β2-adrenoreceptors by a specified number of times. . Table 3 Ratio of indications Compound of the selection of the effects of the action on the activity of the heart High selectivity of the new compounds in relation to blocking is essential in the treatment of hypertension, since the known compounds used for this purpose

7 1160933. "

may cause exacerbation of asthmatic-optically active isomers of those

diseases. of these, in which the 2C compounds of the formula (j) may have the position of the carbon atom of the Stock 3 3, also affect the congenital-aminopropoxy-chain (8) -conjective excitability of the sympathetic figure, have a greater farne system. This is their property of mo-magical activity,. than

It can be used to prevent the corresponding (P) - enantiomeric excess delayed activity.

hearts as well.

To improve the suddenness of cardiac arrest, it is preferable to use the nose in persons suffering from disease compounds for the treatment of vascularisteal muscle, these diseases and hypertension.

Claims (1)

The method of obtaining 3-aminopropoxife Strong derivatives of General formula (I) HE o-ch ₂ -sn-ch ₂ -n-l-nn hundred o ~ no.) go-k ₂ or their pharmaceutically acceptable salts _? where a is alkylene containing 2-5 carbon atoms; H - phenyl, phenyl, substituted by hydroxyl, cyano; B, - cyano group; K _g - C, -C ^ -alkyl, cyclopropylmethyl, wherein the compound of general formula (s) where K, and C _g have the indicated meanings, are reacted with a compound of the general formula (F) Η ₂ Ν _ A-ΝΗ — CO — ΝΗ -Y where A and β have the indicated values, and the target product is given in free form or as a pharmaceutically acceptable salt. 1160933 one 1160933