UA73557C2 - Amideoxyme derivatives of propenecarboxylic acid, a method for the preparation thereof and a pharmaceutical composition based thereon - Google Patents

Abstract

The invention refers to novel propenecarboxylic acid amidoxime derivatives, furthermore to N-oxides and/or geometrical isomers and/or optical isomers and/or pharmaceutically suitable acid addition salts and/or quaternary derivatives thereof. The novel compounds are suitable for the treatment of a state connected with oxygen deficit and/or energy deficit, or a disease based on - PARP inhibition, especially an autoimmune or neurodegenerative disease, and/or a viral disease, and/or a disease caused by a toxic effect.

Description

Description of the invention

The present invention relates to new amidoxime derivatives of propenecarboxylic acid, the method of their production, and 2 pharmaceutical compositions containing them. The new compounds have an important pharmaceutical effect due to the fact that they can be used mainly in conditions associated with energy deficiency of the cell, in conditions of oxygen deficiency in the heart and brain, in neurodegenerative diseases, in the treatment of autoimmune and/or viral diseases, in addition, in diseases caused by toxic effects.

The preparation of some derivatives of lL»- 1, 2, 4-oxadiazolin-o-one is described in the article Set. Veg., 103, 2330 2335 (1970) without any reference to possible biological effects. From the above-described compounds, the production of 5, 6-dihydro-4H-oxadiazine derivatives is discussed in the article by Spet. Veg., 108, 1911-1923 (1975) also without any reference to biological effects.

Derivatives of 1, 2, 4 - oxadiazolin-?--one, which have peripheral vasodilator, antianginal and antiarrhythmic effects are known from the patent

Hungary NO-R Mo. 179 951. Derivatives of 1, 2, 4-oxadiazine, which have peripheral vasodilator effects, blood pressure lowering effects, antiarrhythmic, weak anti-inflammatory and diuretic effects, known from the Hungarian patent HO-R Mo. 180 708. However, known derivatives of 1, 2, 4-oxadiazolin-5-one and 1, 2, 4-oxadiazine do not contain alkenyl substituents, that is, they cannot be derived from propenecarboxylic acid amidoxime.

The purpose of this invention is to obtain new compounds that have important pharmaceutical effects. Brief summary of the essence of the invention

It has been found that the above object is achieved by the present invention and, thus, the present invention relates to novel amidoxime derivatives of propenecarboxylic acid of the formula

I | and 1 mot t ov. where

K denotes a C.2o-alkyl group, a phenyl group, the last of which is optionally substituted with 1--3 substituents, where the substituent is a halogen atom and/or a C..o-alkyl group and/or C.o- an alkoxy group and/or an amino group and/or a (C..i.-alkyl) amino group and/or a di(C..i.-alkyl) amino group and/or a (C.i.o-alkanoyl) amino group , in addition, a 5- or b--linked saturated or unsaturated heterocyclic group, which contains as a heteroatom one or two nitrogen atoms or a sulfur atom, and the indicated heterocyclic group is optionally saturated with one or "In several benzene rings and/or by one or more heterocyclic groups, and

Zo K denotes a hydrogen atom, or -

K together with K forms a C ;-cycloalkyl group saturated with a benzene ring

K. and Kje independently denote a hydrogen atom, a C.5-alkyl group, a C.5-alkanoyl group or a phenyl group, the last of which is optionally substituted 1 - With substituents, where the substituent is a halogen atom and/or "

by a Si»-alkyl group and/or by a Siu-Cio-alkoxy group -, or K; and K5 form, together with the adjacent З7З70 nitrogen atom, a 5- or b-lene saturated or unsaturated heterocyclic group, which may further contain a nitrogen atom and/or an oxygen atom and/or a sulfur atom as a heteroatom c, and may be saturated with a benzene ring, and "from the heterocyclic group and/or the benzene ring may bear one or two substituents, where the substituent is a halogen atom and/or a C. o-alkyl group and/or a C. o-alkyl group,

Ku and Ko represent a hydrogen atom, and -I 15 Ez represents a hydrogen atom, a hydroxy group or a C. 5-alkoxy group, or

Ku forms, together with K2, a carbonyl group or a thiocarbonyl group, the carbon atom of which is connected to the (4) oxygen atom, which is adjacent to Ku. and with a nitrogen atom that is adjacent to Co, and Kz denotes a hydrogen atom, a halogen atom, a hydroxy group, a C. 5-alkyloxy group, a C. b-alkylthio group, a C. oo-alkanoyloxy group, a C3-oz-alkenoyloxy group, containing one or more double bonds, a methylsulfonyloxy group, a benzenesulfonyloxy group 1 90 or a toluenesulfonyloxy group, or that ER" is a hydrogen atom, and

Ku forms, together with Kz, a valence bond between the oxygen atom adjacent to

Ku and the carbon atom adjacent to Kz, in addition, their M-oxides and/or geometric isomers and/or optical isomers 59 and/or pharmaceutically acceptable acid addition salts and/or quaternary derivatives.

HF) In the description and formula, it is assumed that the C 42o -alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n- hexyl, n-heptyl, n-decyl, dodecyl, hexadecyl, octadecyl group and others similar to them. 60 The halogen atom is mainly a fluorine, chlorine or bromine atom, preferably a chlorine or bromine atom.

The C 1 -alkyl group is a methyl or ethyl group, while the C -|. -- the alkoxy group is a methoxy or ethoxy group.

C.3-alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutylose group. A C1-5-alkyl group can also be, in addition to the above groups, for example, an n-pentyl group.

(C 1 -4 alkyl)amino group is, for example, methylamino, ethylamino, isopropylamino, and so on.

Di(C1-4-alkyl) amino group is, for example, dimethylamine diethylamino, diisopropylamino group, and so on.

The C..α-alkanoyl group is preferably a formyl, acetyl, n-propionyl or n-butyryl group. cC-i-B-alkanoyl group can also be, in addition to the above groups, for example, an n-pentanoyl group. A 5- or 6-membered saturated or unsaturated heterocyclic group containing one or two nitrogen or sulfur atoms as a heteroatom is. for example, pyrrolyl, pyratolyl, imidazolyl, thienyl. pyridyl, piperidyl, pyrimidinyl, piperazinyl group and others similar to them. 70 The cycloalkyl group optionally fused to the benzene ring is, for example, a cyclopentyl, cyclohexyl, cycloheptyl, indanyl or tetranyl group. A 5- or 6-membered saturated or unsaturated heterocyclic group, which may contain, in addition to the nitrogen atom adjacent to the K and K5 substituents, a nitrogen atom and/or an oxygen atom and/or a sulfur atom as a heteroatom may be, in addition to the above heterocyclic groups, for example, a 7/5 Morpholino group.

C. The 2o-alkanoyloxy group is, for example, a formyloxy-, acetoxy-, propionyloxy-, butyryloxy-, caproyloxy-, stearoyloxy-group and the like.

The 3.oo-alkenoyloxy group can contain, in general, 1 - b double bonds and be, preferably, a linolenoyloxy-, linoleyloxy-, docosahexaenoyloxy-, ecosapentaenoyloxy- or arachidonoyloxy-group.

Pharmaceutically acceptable acid addition salts of amidoxime derivatives of propenecarboxylic acid of the formula | and their M - oxides are acid-addition salts formed from inorganic acids, such as hydrochloric, sulfuric, phosphoric and other similar acids, or from organic acids, such as acetic, fumaric, lactic, tartaric, succinic, malic, benzene sulfonic acids , p-toluenesulfonic acid and other similar acids. with

In the quaternary derivatives of compounds of the formula I! and their M-oxides, one or more nitrogen atoms of propenecarboxylic acid amidoxime are quaternized so that, for example, in the future, a C.--alkyl group or i) phenyl(C..4-alkyl) group is bound to this nitrogen atom, such thus, the specified nitrogen atom becomes positively charged. Of the nitrogen atoms that exist in the compound of formula I, respectively, one of those adjacent to the substituents K; and Ke5 is quaternized. If in formula I, K is a heterocyclic group containing an M atom

From CHNitrogen, such as a pyridyl group, then the nitrogen atom of the specified heterocyclic group can also be quaternized. i am

In M-oxides of compounds of formula I, one or more nitrogen atoms are present in an oxidized form, thus, an oxygen atom is also bound to this nitrogen atom. Of the nitrogen atoms that exist in the compound of the formula

Z, respectively, one of the adjacent to the substitutes Ku; and K5 can exist in the M-oxide form. If in formula I, K represents a heterocyclic group containing a nitrogen atom, such as a pyridyl group, then the nitrogen atom of the specified heterocyclic group can also exist in the form of an M-oxide.

Due to the presence in the formula | double bond, new propenecarboxylic acid derivatives of the formula I, as well as their M-oxides, can exist in the form of geometric isomers, that is, cis- or trans-isomers or in the form of any mixture of them. The present invention includes pure geometric isomers and any mixtures thereof. "

In addition to geometric isomerism, some compounds of formula I, as well as their M-oxides, contain one or more chiral carbon atoms, accordingly, these compounds can also exist in the form of optical isomers.

The present invention includes pure optical isomers and any mixtures thereof. with The selected subgroup of compounds of this invention consists of amidoxime derivatives of propenecarboxylic acid of the formula в песню Мн snu oni - Щ! I went

M Yaz (95) "ok s pe

Ku and Co represent a hydrogen atom, 1 20 Ez represents a hydrogen atom, a hydroxy group or a C..5-alkoxy group, or -h E, K, KA and K" are as defined above. in addition, their M-oxides and/or geometric isomers, and/"or optical isomers, and/"or pharmaceutically acceptable acid addition salts, and/or quaternary derivatives.

Another selected subgroup of the compounds of this invention consists of oxadiazoline derivatives of the formula о в: nene sonten-snin y, and yuyu У -.Х В where 60 Ku forms together with Ko a carbonyl group or a thiocarbonyl group, the carbon atom of which is bonded to an oxygen atom , which is adjacent to K., and to the nitrogen atom, which is adjacent to Ko."

Kz denotes a hydrogen atom, a halogen atom, a hydroxy group, C. a 5-alkyl group, C. a 5-alkylthio group,

Si oo-alkanoyloxy group, C33-alkenoyloxy group containing one or more double bonds, methylsulfonyloxy group, benzenesulfonyloxy group or toluenesulfonyloxy group, X denotes an oxygen atom or a sulfur atom,

E, K, KA and Kz are as defined in connection with formula I.

in addition, their M-oxides and/or geometric isomers and/or optical isomers and/or pharmaceutically acceptable acid addition salts and/or quaternary derivatives.

Another selected subgroup of compounds of this invention consists of oxadiazine derivatives of the formula

V. yan sesn-y deya

Kk ge dte is

M sn--sny - h

Who am I where c) where

ER" is a hydrogen atom, and

Ku forms, together with Kz, a valence bond between the oxygen atom adjacent to

Ku and the carbon atom adjacent to Kz,

E, K, K. and K" are as defined in connection with formula I. in addition, their M-oxides and/or geometric isomers and/or optical isomers and/or pharmaceutically acceptable acid addition salts and/or or

Amidoxime derivatives of propenecarboxylic acid of formula I are obtained as follows: a) to obtain amidoxime derivative of propenecarboxylic acid of formula Ia, where K 4 Ko and Kz denote a hydrogen atom, K, K, K,. and K" are as defined for a compound of formula I, a propene derivative of formula

Where is the cancer? ЯеснототМто Na сн шия Х В where К, К, Кз, КЕ" and К»5 are as defined above, У denotes a halogen atom or a group of the formula -ЗКе, where Ко denotes a hydrogen atom or a C..-alkyl group, react with hydroxylamine, or

B) to obtain the amidoxime derivative of propenecarboxylic acid of the formula Ia, where K 5 and Ko denote a hydrogen atom, Kz denotes a hydrogen atom or a hydroxy group, K, K, K, and K5 are as defined for He! compounds of formula i. an oxadiazoline derivative of the formula IB, where K, K, Kz, K. and K5 are as defined above, X o denotes an oxygen atom or a sulfur atom, are subjected to a reaction with an aqueous solution of alkaline hydroxide, or c) to obtain an amidoxime derivative of propenecarboxylic acid of the formula IB, where Kz denotes a hydrogen atom, X denotes an oxygen atom, E, B", Ba and B5 are as defined for the compound of the formula I, the derivative AD? - 1, 2, 4-oxadiazoline of the formula v. vd U , and рояесн--о- МН ю в и -о ИН в а Ио) where К and К' are as defined above, are subjected to reaction with aminoylkylthalide of the formula so uva 74 of the absorption of SNU

Zv o i-sn s M u

And Be M with where 7 means a halogen atom, Kz, KE. and Kb" are as stated above, or a) for obtaining the amidoxime derivative of propenecarboxylic acid of the formula IB, where Kz denotes a hydrogen atom or a hydroxy group, X denotes an oxygen atom, K, KU, K" and K5 are as follows, as defined for the compound of the formula I, the dg-1,2,A-oxadiazoline derivative of the formula I, where K and K are as indicated above, is subjected to a) c reaction with a 1,3-dihalopropane of the formula h 2-cn--cn -сС а "2" ! " ha where 7 and L independently denote a halogen atom, Kz is as stated above, and the obtained dg-1,2,4 - - 45 oxadiazolinylalkyl halide of the formula

V don b mesa on sny (95) SI ! ! mm

M Where V o To sl 50 where EK, K, KE" and 2 are as indicated above, react with the amine of the formula M

And I where Ka and K" are as indicated above, or are) to obtain the amidoxime derivative of propenecarboxylic acid of the formula IB, where K z denotes a hydroxy group, X denotes an oxygen atom, K, K, K, and K" are as follows , as defined for the compound of formula Y, a 1-1,2,4-oxadiazoline derivative of formula I, where K and K are as indicated above, are reacted with

Ф, epichlorohydrin, and the formed l--1, 2, 4-oxadiazolinylalkyl chloride of the formula in o dk svA-0-M--OH-tony cNis and ! s i | he Univ

MO b-oh! for I where K and K" are as above, react with an amine of formula MY, where K4 and K" are as above, or

C) to obtain an oxadiazoline derivative of the formula IB, where Kz denotes a hydroxy group, X denotes an oxygen atom of 65, K, K, KA. and K" are as defined for the compound of the formula |, dg-1,2,4-oxadiazolinalkyl chloride of the formula MI, where K and K are as indicated above, react with an acidic binder, and the formed epoxide of the formula o midlasn -- o M tOnui sn sn, e I ha ih ih! Trace

For where K and K' are as specified above, react with an amine of the formula MII, where K4 and K5 are as specified above, or d) to obtain an oxadiazoline derivative of the formula IB, where K z represents a hydrogen atom or hydroxy group, X represents an oxygen atom or a sulfur atom, K, K, K, and Kv are as defined for the compound of formula I, 70 amidoxime derivative of propenecarboxylic acid of formula Ia, where P, E, Kz, EK" and K; are as follows , as indicated above, are subjected to a reaction with a carboxylic acid derivative of the formula 3 х х where X is as indicated above, 75 and 73 independently denote a halogen atom, a C.i.--alkyl group or 79 C. /-alkylmercapto group, or

P) to obtain an oxadiazine derivative of the formula Is, where K, K, K; and K5 are as defined for a compound of formula I, an oxadiazoline derivative of formula IB, where K, K', K, and K" are as defined above, X represents an oxygen atom or a sulfur atom, Kz represents a halogen atom, a methylsulfonyloxy group, the benzene-sulfonyloxy group or the toluenesulfonyl-oxy group is reacted with an alkaline hydroxide in the presence of water, or i) to obtain an oxadiazine derivative of the formula II, where K, K, K 4 and K 5 are as defined for the compound of the formula I, a cyclic compound of the formula

COURTS Oh du sn i r xI

MO sveesnin" s and 2 and o where K and K are as stated above, K ; represents a halogen atom, a methylsulfonyloxy group, a benzenesulfonyloxy group or a toluenesulfonyloxy group is reacted with an amine of the formula MIII, where K and K5 are as above, or

І) to obtain the quaternary derivative formula - what would be called concrete snittons, І and р | where K, K, Ku, Ko, Kz, Ku and K" are as defined for the compound of formula I, Ka denotes a C..o-alkyl group with 5 or phenyl (S. .4-alkyl) group, X denotes a halogen atom or a group of the formula Ka-50,4, where Ka is as indicated i- above, derivative d2- where X is as indicated above, 75 and 73 independently denote a halogen atom, C.i.-- alkoxy group or

C..-alkyl mercapto group, or "

P) to obtain an oxadiazine derivative of the formula Is, where K, K, K; and K5 are as defined for a compound of formula I, an oxadiazoline derivative of formula IB, where K, K, K, and K" are as indicated above, X represents an oxygen atom or a sulfur atom, Kz represents a halogen atom, methylsulfonyloxy group, a benzene-sulfonyloxy h» group or a toluenesulfonyl-oxy group is reacted with an alkaline hydroxide in the presence of water, or "i) to obtain an oxadiazine derivative of the formula II, where K, K, K 4 and K 5 are as defined for the compound of the formula I, a cyclic compound of the formula d M, -i deton--yOBn

In OT hi o ho Dy stonytt 1 t where K and K are as stated above, K ; denotes a halogen atom, a methylsulfonyloxy group, 4! 20 a benzenesulfonyloxy group or a toluenesulfonyloxy group is reacted with an amine of the formula MII, where KA and K5 h are as indicated above, or "

І) to obtain the quaternary derivative formula shk E uut desny they on SNY, i IN : ІІ p v | And eat! that hey

Language wa Ve!

F) ov.

GI where K, K, Ki, Ko, KZ, KA and K" are as defined for the compound of the formula!, Kz denotes a C"-alkyl group or a phenyl (C-m-alkyl) group, X denotes a halogen atom or a group of the formula Ka-50,, where Ka is as indicated above, the dg-12,4-oxadiazoline derivative of the formula I, where K and K are as indicated above, are subjected to a reaction with a quaternary alkyl halide of the formula ut d--

I and ve hi 65 and Ne de Kz, Ku. K5 Ke and U are as indicated above, 7 denotes a halogen atom, or k) to obtain the M-oxide of the formula o o ditsn--rron onov Sh khm t shi | and their Co Ba ov where K, K, K., Ko, Kz, Ku and K»5 are as defined for the compound of formula I, derivative dg-1,2,A4 - oxadiazoline of formula YII, where K and K' are as indicated above, react with a compound of the formula

P where Kz, Ku and K"5 are as indicated above, 7 represents a halogen atom, and if necessary, the resulting compound of formula IB, where K" is a hydroxy group, K, K, Ku and K" are as determined for the compound of the formula I, X denotes /5 an oxygen atom or a sulfur atom, is subjected to a reaction with a halogenating agent, which gives a compound of the formula IB, where Kz is a halogen atom, or, if necessary, the obtained compound of the formula IB, where Kz is a hydroxy group, K, K, Ku and K" are as defined for the compound of formula I, X denotes an oxygen atom or a sulfur atom, react with C. "ho-alkanecarbon halide or C" 3.oo-alkenecarbon halide containing one or several double bonds, giving a compound of the formula IB, where Kz denotes a C. oo-alkanoyloxy group or a Cz oo-alkenoyloxy group, or, if necessary, the resulting compound of the formula IB, where K»z is a hydroxy group, K, K, Ku and K" are as defined for the compound of formula I, X represents an oxygen atom or a sulfur atom, is reacted with a C 5 -alkyl halide, which gives a compound of formula IB, where Kz denotes a C..5-alkoxy group, or, if necessary, the resulting compound of formula IB, where Kz denotes a halogen atom, K, KK, and K are as defined for the compound of formula i, X denotes an oxygen atom or a sulfur atom , are subjected to a reaction with an alkaline salt of C-1-5-alkanol or C-5-alkanol, which gives a compound of the formula Ir, where Kz denotes a C1-6-alkoxy group (o) or a C1-6-alkylthio group, or, if necessary, obtained a compound of formula IB, where Kz denotes a hydroxy group, K, K, K; and K5 are as defined for a compound of formula I, X represents an oxygen atom or a sulfur atom, is reacted with a methylsulfonyl halide, benzenesulfonyl halide, or toluenesulfonyl halide to give a compound of formula IB, where Kz represents a methylsulfonyloxy group, a benzenesulfonyloxy group, or a toluenesulfonyloxy group, and is) if necessary, the obtained compound of formula I! react with an inorganic or organic acid to give a pharmaceutically acceptable acid addition salt, or the base is freed from its acid addition salt, and/or one or more nitrogen atoms of the compound of formula I are quaternized with an alkylating (9 of 5 agent, and /(or the compound of formula I is subjected to a reaction with an oxidizing agent, which leads to the transformation of one or more nitrogen atoms into M-oxide.

In the method a) of this invention, the reaction of a propene derivative with hydroxyamine is carried out in a solvent or a mixture of solvents using a hydroxyamine base, which can be freed from its acid-addition salt by adding a strong base. Formed product of the formula! separated in a known, in fact, " 20 way, for example, by means of crystallization from the reaction mixture, or by evaporation of the reaction mixture, or by precipitation of It with an acid additive salt. If a propene derivative of the formula II is used, where U represents a halogen atom, the solvent is an anhydrous neutral solvent, for example, a halogenated hydrocarbon such as chloroform, dichloromethane and the like, a hydrocarbon such as benzene, toluene and the like, or any other solvent commonly used in acylation reactions, such as pyridine.

If a propene derivative of the formula II is used, where U denotes a group of the formula -5К6, in addition to the types of solvents listed above, for example, alkanols can also be used as an organic solvent. c The propene derivative of the formula YII, where U denotes a halogen atom, as a rule, a chlorine atom, the actually specified compound is imidoyl halide, as usual, imidoyl chloride, is obtained from the corresponding acid amide of formula 1. "vv HL o R where K, K, K, and Kb are as defined for the compound of formula I, where Kz denotes a hydrogen atom or

C-alkoxy group, by means of a reaction with a halogenating agent, respectively thionyl chloride, phosphorus trichloride, phosphorus pentachloride and other similar methods known from the literature. (F) A propene derivative of formula II, where M is a mercapto group, can be obtained, for example, from

GI of the corresponding acidic amine of the formula ХУ! with phosphorus pentasulfide in an organic solvent, such as toluene, xylene or pyridine, by a method known from the literature. The propene derivative of the formula II, where M is an alkylthio group, is obtained by reacting the propene derivative of the formula II, where X is a mercapto group, with an alkylating agent.

In method B) of this invention, the oxadiazoline ring is opened using the method known from Spet.

Veg., 1 03, 2330 - 2335 (1970), which involves alkaline hydrolysis in an aqueous medium. Accordingly, sodium hydroxide is used as alkaline hydroxide, and an organic solvent, preferably an aliphatic alcohol such as methanol or ethanol, is also added to the aqueous solution, if necessary. In the method of this invention, the oxadiazoline ring is opened for a short period of time at the boiling temperature of the reaction mixture, and the compound of formula Ia is obtained in good yield. The reaction product can be separated using the method described in method a).

In the method c) of this invention, the reaction is carried out in an organic solvent, which is indifferent from the point of view of the reaction, in the presence of an acidic binding agent, as a rule, at the boiling temperature of the reaction mixture.

An indifferent organic solvent is, for example, an alkanol such as methanol or ethanol, a hydrocarbon such as benzene, toluene or xylene, or a mixture thereof. Inorganic or organic bases can be used as an acidic binding agent. The reaction mixture can be processed using conventional methods, for example, the solvent is evaporated and the product is crystallized, or its acid addition salt is precipitated. 70 Derivatives of l2 - 1, 2, 4 - oxadiazoline of the formula II can be obtained from the corresponding amidoximes by reaction with carbonic acid derivatives. Representatives of amidokymi are known from the article by Spet. Chem., 62, 155 (1962). New amidoximes can be obtained from the corresponding propenecarbon nitrile by reaction with hydroxylamine, using the method described in the article. Most of the aminoalkyl halides of formula IM are known compounds that are either commercially available or can be prepared simply by reacting 1,3-75 dihalopropane with an amine of formula MI.

In the method i) of this invention, both alkylations, that is, the reaction of the derivative dl? -1,2,4 - oxadiazoline of the formula Ш with 1, З - dihalopropane of the formula M, and amination, that is, the reaction of the formed LA? - 1,2,4- oxadiazolinalkyl halide of the formula MI with an amine of the formula MiII is carried out in an organic solvent, which is indifferent from the point of view of the reaction, in the presence of an acidic binding agent, respectively an inorganic base, such as sodium hydroxide or sodium carbonate, as as a rule, at the boiling temperature of the reacting mixture. AND? - 1, 2, 4-oxadiazolinalkyl halide of the formula MI, which is formed during alkylation, is either crystallized or used after evaporation of the reaction mixture without crystallization for the amination reaction. The formed product of the reaction of the formula IB is separated using a known method, in fact, using any of the methods described above. The indifferent organic solvent can be a hydrocarbon or a halogenated /-CM aliphatic or aromatic hydrocarbon such as chloroform, an alkanol such as methanol or ethanol, a ketone such as acetone, or a mixture of the above solvents.

In the method e) of this invention, the reaction of the d2 - 1, 2, 4 - oxadiazoline derivative of the formula I with epichlorohydrin is carried out in an organic solvent that is indifferent from the point of view of the reaction, or in the absence of any solvent, preferably with an excess of epichlorohydrin, respectively at a temperature boiling of the reaction mixture. -

An indifferent organic solvent can be, for example, hydrocarbon, ether, tetrahydrofuran 0 and the like. Bases such as sodium hydroxide, sodium carbonate, and others like them are used as a catalyst. After the reaction, the solvent is evaporated and the residue is crystallized. Formed LZ? - 1,2, and 4 - oxadiazolinalkyl chloride of the formula MI! react with an amine of formula MI under conditions similar to those. with that described for the amination reaction in method 4). The formed product of the reaction of formula IB is separated in a known way, in fact, using any of the methods described above. -

In the method of the present invention, the acidic binding agent is, for example, an alkaline carbonate, such as sodium carbonate, potassium carbonate, and the like, or an alkaline hydroxide, such as sodium hydroxide, potassium hydroxide, and the like, to produce an epoxide of the formula THEM The reaction is carried out in an organic solvent, which is indifferent from the point of view of the reaction, respectively at the boiling temperature of the reaction mixture. As an indifferent organic solvent, for example, a hydrocarbon, acetone, a simple ether such as tetrahydrofuran c or dioxane, a halogenated aliphatic or aromatic hydrocarbon and others are used. The reacting mixture "c" is filtered, the filtrate is evaporated, and the formed epoxide of the formula IX is crystallized, after which it is reacted with an amine of the formula MII using the method described in method 4) during amination, preferably in alkanol. In an alternative procedure, the epoxide of formula II is not separated, but the amine of formula II is added directly to the reaction mixture in which the epoxide is prepared, and the reaction mixture is further heated. The formed product of the reaction of the formula IB is separated using a known method, in fact, using any of (95) methods described above. sl In the method e) of this invention, any derivative of carbonic acid or thiocarbonic acid can be used in the cyclization reaction as a reagent that can form a carbonyl or thiocarbonyl group, respectively, between the oxygen atom of the hydroxy group and the nitrogen atom of the amino group in drop of the part that has the formula -С (-М - ОН) - МН in the formula Ia. Acceptable compounds include carbonic acid or thiocarbonic acid halides such as phosgene or thiophosgene, halide ethers such as ethyl chloroformate or alkyl chlorothioformates, or ethers such as dialkyl carbonates, mono-, di- and tricarbonates, xanthogenates and the like.

An organic solvent, which is indifferent from the point of view of the reaction, is used for the cyclization reaction, however, the reaction can also be carried out in the absence of any solvent. The reaction mixture is cooled

HF) or heated, cyclization is performed at the boiling temperature of the reaction mixture. The formed product of reaction 7 of the formula II is separated using a known method, in fact, using any of the methods described above.

If a carbonic acid of the formula X is used in the reaction, where one or both of 75 and 73 represent a halogen atom, then, respectively, a hydrocarbon, a halogenated aliphatic or aromatic hydrocarbon, or a simple ether is used as an indifferent organic solvent. If both 7" and 73 represent an alkoxy or alkylmercapto group, then the indifferent organic solvent can also be, in addition to the above list, an alkanol.

In method n) of this invention, the oxadiazoline ring is actually converted into an oxadiazine ring. To achieve this goal, a method known from Spet is used. Veg., .108, 1911 - 1923 (1975). In accordance,

sodium hydroxide or potassium hydroxide is used as an alkaline hydroxide. The reaction is carried out in a mixture of organic solvents, such as alkanol, and an aqueous solution of alkaline hydroxide at the boiling temperature of the reaction mixture. The formed product of the reaction of the formula Is is separated using a known method, in fact, using any of the methods described above.

In method iii) of this invention, the reaction is performed in an organic solvent that is indifferent from the point of view of the reaction, or in a mixture of several such solvents, in the presence or absence of an acidic binding agent. An indifferent organic solvent is, for example, a hydrocarbon, a halogenated aliphatic or aromatic hydrocarbon, an ether or an alkanol, preferably butanol. The reaction can also be carried out in the absence of any organic solvent, in which case an excess of the amine of formula II can be used as a solvent. The formed product of the reaction of the formula Is is separated using a known method, in fact, using any of the methods described above.

In methods |) and k) of this invention, the procedure is similar to that described in method c). The quaternary alkylhalide of the formula ХП is obtained by quaternization of the corresponding aminoalkylhalide of the formula IM. 7/5 The compound of the formula XM can be obtained from the corresponding aminoalkyl halide of the formula IM with an oxidizing agent.

An oxadiazoline derivative of formula IB, where Kz represents a hydroxy group, can be converted to the corresponding compound of formula IB, where Kz is a halogen atom, by reaction with a halogenating agent. As a halogenating agent, thionyl chloride, phosphorus trichloride or phosphorus pentachloride are mainly used, and halogenation is carried out in an organic solvent, which is usually used in similar reactions, or in the absence of any solvent, for example, with an excess of halogenating agent. The reaction mixture is distilled using methods that are commonly used after halogenation reactions.

An oxadiazoline derivative of the formula IB, where Kz represents a hydroxy group, can be reacted with an active acylating derivative of an alkanecarboxylic acid Cio0 or Czoo alkenecarboxylic acid, such as a halide, anhydride, azide, and the like, or with a methysulfonyl halide, a benzosulfonyl halide, or a toluenesulfonyl halide, in an indifferent organic solvent, preferably an aromatic hydrocarbon or a halogenated aromatic or aliphatic hydrocarbon, in the presence or absence of an acidic i) binding agent. The corresponding reaction product of formula IB which is formed can be separated by the usual methods described above.

The compound of formula IB, where Kz denotes a hydroxy group, can react with a C..5-alkyl halide in a manner similar to M. In this case, one or more nitrogen atoms can be simultaneously quaternized.

The reaction of the compound of formula IB, where K represents a halogen atom, preferably a chlorine atom, with an alkaline salt of alkanol or thioalkanol can be carried out under the reaction conditions described above. yu

If necessary, a compound of the formula | converted into a pharmaceutically acceptable acid addition salt or freed from its acid addition salt. If an optically active organic acid, for example, camphoric acid, camphorsulfonic acid, tartaric acid or a derivative of tartaric acid, is used in the formation of a salt, it becomes possible to separate stereoisomers that have a chiral center. In this case, the separation is performed in a known manner, in fact, with the help of specific crystallization of acid-addition salts formed with an optically active organic acid.

If necessary, one or more nitrogen atoms of the amidoxime derivative of propenecarboxylic acid of the formula | " quaternize. For this purpose, the compound of the formula I is reacted with an alkylating agent of the formula Ka - M, where Ka denotes a C..5-alkyl group or a phenyl (C..5-alkyl) group, XU represents a halogen atom, to obtain . of the quaternary derivative formula of XII, where KaTa U are such, and? as stated above. The quaternization reaction can be carried out with a dialkyl sulfate of the formula (Ka) ZO", where Ka is as indicated above. In the latter case, the quaternary derivative of the XII formula is obtained, where U denotes

The group of the formula of the formula Ka - 5O,. The quaternization reaction is carried out in an indifferent organic solvent -I or without any solvent.

Alternatively, another nitrogen atom or an additional nitrogen atom may also be quaternized. If in the formula I, K represents a heterocyclic group containing a nitrogen atom, for example, a pyridyl group, the nitrogen atom of the pyridyl group can be quaternized, or this nitrogen atom also

Can be quaternized. o When the compound of the formula | are converted into M-oxide, correspondingly oxidize the nitrogen atom with which they are bound

And substitutes K.; and K5. In this case, the oxidation is carried out, as a rule, with hydrogen peroxide, preferably in a solution containing adanol, such as methanol, respectively, at room temperature. If in the formula I, K represents a heterocyclic group containing a nitrogen atom, for example, a pyridyl group, the nitrogen atom 5B of the pyridyl group can be at the same time or instead of a nitrogen atom transformed by an oxidizing agent into

M-oxide. In this case, the oxidizing agent is, preferably, a peroxyacid, for example, Z - chloro - (F, benzoic acid), and the oxidation reaction is carried out in an indifferent solvent, as a rule, an aromatic hydrocarbon, such as benzene or toluene, respectively, at room temperature.

It is clear that the M-oxide of the compound of the formula | can be transformed into a pharmaceutically acceptable acid-addition salt or its quaternary derivative, essentially, by a known method.

The pharmacological effect of the compounds of this invention is determined using the following tests.

Research on the inhibition of the enzyme poly (adenosine diphosphate ribose) polymerase

It is known that reactive species of oxygen, for example, hydroxy radical, peroxide, peroxynitrite, hydrogen peroxide, are continuously formed in a living organism | Kispieg, S, REV5 I ek., 241. 1 - 5 (1988)) and in small quantities they play a role role in controlling important physiological processes (VesK, K.R. ei ai., 9. Ehr.

BioI., 202, 645 - 53 (1999); Msropaid, HER. 9. apa Mygaid, R., Rhos. Boss. Ex. Vioi Meia., 211. 1 - 6 (1966)

(such as angioectasia, platelet aggregation, leukocyte adhesion). The concentration of reactive species of oxygen and nitrogen oxide significantly increases in acute and chronic diseases, for example, in most autoimmune diseases |Gagaga, S. eyi a). cat U. Ipiegp. Meia., 35, 89 - 98 (1997)), in cases of post-ischemic heart failure, cerebral ischemia (stroke) |Vgaiip RaiPoiodu, 9, 119 - 131 (1999)|).

The source of reactive species of oxygen is the cells of normal tissues due, in part, to leukocytes and macrophages that are present in affected tissues, and in part, to the inductive effect of inflammatory cytokinesis.

Reactive oxygen species destroy, among others, deoxyribonucleic acid. The complex of protection and the recovery process in the cell begins when deoxyribonucleic acid is damaged. An important element of this process is the activation of the enzyme poly (adenosine diphosphate ribose) polymerase. The enzyme poly (adenosine diphosphate ribose) polymerase is a nuclear building enzyme that is present in large quantities near every cell and catalyzes the transport of an adenosine diphosphate ribose unit from nicotinic acid adenine dinucleotide to proteins and the construction of poly (adenosine diphosphate ribose) polymerase chains. The main substrates of the enzyme include itself. SeiI. Viospet., 138. 7/5 33 - Z (1994)), nuclear proteins, histones, topoisomerase! and Ii, transcription factors. The activity of the enzyme poly (adenosine diphosphate ribose) polymerase increases by a factor of approximately 500 in the event of a chain break of deoxyribonucleic acid. My. Viol., 210. 229 - 233 (1989)). A critical decrease in the concentration of adenine dinucleotide of nicotinic acid occurs when the enzyme poly (adenosine diphosphate ribose) polymerase is activated due to excessively high damage to deoxyribonucleic acid. As a result, the synthesis of adenosine triphosphate in the cell is reduced, while the use of adenosine triphosphate is increased due to the fact that the cell attempts to restore the level of nicotinic acid adenine dinucleotide from adenosine diphosphate ribose and nicotinamide through the use of adenosine triphosphate. These biochemical processes of destruction are important in the therapy of several diseases, such as autoimmune diseases. Zsi., 19, 287 -98 (1998)), ischemic heart conditions and cerebrovascular diseases, as well as neurodegenerative diseases. The catabolism of adenine dinucleotide of nicotinic acid can be eliminated by inhibiting the enzyme poly (adenosine and) diphosphate ribose) polymerase, respectively, there is a decrease in the levels of nicotinamide and adenosine diphosphate in cells and inhibition of the consumption of adenosine trophosphate for the synthesis of adenine nucleotide; that is, the aforementioned destruction and death of cells can be eliminated by inhibiting the action of the enzyme. determination of inhibition of poly (adenosine diphosphate ribose) polymerase IP miigo, on the isolated enzyme

Poly (adenosine diphosphate ribose) polymerase was isolated from rat liver, in accordance with article 5papy, o. at

M. Iapai. Viospet., 227, 1-13 (1995)). The activity of poly (adenosine diphosphate ribose) polymerase was determined in 130 μl of the reaction mixture, which consisted of 100 mM Tris-HCl buffer, pH 8.0, 10 mM MoosIi 5, 1090 g glycerol, 1.5

MM OT, 100 μg of osha (32P) or (ZH) MAO, 10 μg of activated deoxyribonucleic acid, 10 μg of histone. me)

After 10 minutes of incubation time, the reaction was stopped with 8 95 perchloric acid, and the protein was separated by M by centrifugation (10 minutes, 10,000 X 9). The precipitate was washed three times with 8 95 perchloric acid and the limit values of protein radioactivity were measured with a scintillation counter. The results can be seen in

Tables I. " and Z are;" : z v ni i s ShY o ni nn write n: ny

Pho -4

The above data is the result of four parallel measurements.

F) In Table I, you can see that some of the tested compounds are very powerful inhibitors of poly(adenosine diphosphate ribose) polymerase (05 x 1Omg/l). Most of the tested compounds can be classified as potent inhibitors of poly (adenosine diphosphate ribose) polymerase (Id 5 x 10 - 28 mg/l). in Effect of compounds of formula I on ischemic heart failure and reperfusion arrhythmia

Damage to the heart muscle and death of heart muscle cells occurs, in most cases, due to trophic disorders. The most common form of trophic disturbance is associated with a lack of oxygen. Damage to the heart muscle leads to the development of ischemia of the heart muscle, which can be formed as a result of acute hypoxia / anoxia, coronary occlusion, spasms or chronic coronary disease. Ischemic injury 65 during an acute myocardial infarction is accompanied by an excess blood flow phase, the so-called reperfusion phase.

Arrhythmias (meaning ventricular tachycardia and fibrillation) can occur as a fatal consequence of reperfusion. They are the first manifestations of reperfusion injury. Preventing reperfusion damage to the heart muscle by administering a drug means preventing a fatal early recurrence of a heart attack.

Experiments were performed on male ZRKO rats (with an acceptable body weight in the range of 300 - Z50OG).

The animals were anesthetized using pentobarbital |5 - ethyl - 5 - (1 - methylbutyl) - 2, 4, 6 - (1H,

ЗН, 5Н) - pyrimidine-trione| (bOmg/kg intraperitoneally) and left them, giving them the opportunity to breathe on their own. Animals were ventilated with a respirator (made by Kutes (Kiiez2), Academy of Sciences 7/0 of Hungary) using a cannula in the trachea, which was inserted after tracheotomy. HER standard electrocardiogram lead (ESO II) was monitored. A catheter was placed on the right femoral artery, which was connected to a pressure sensor (VREK-C1, Ehregitija, Hungary) and a pre-amplifier.

A pulse tachometer (HO-M., Ekhregitia, Hungary) was activated using a pulsating intra-arterial blood pressure signal. A cannula was installed on the external jugular vein for the introduction of 7/5 of the drug. After thoracotomy, silk (braided, covered with 4-0) was placed under the left anterior coronary (LA) artery. After a stabilization period of several minutes, occlusion of the left anterior coronary artery was applied for 5 minutes, followed by a reperfusion period of 10 minutes. The electrocardiogram recorded data in a normal state at the beginning of the measurements and during the periods indicated above. In the data from the electrocardiogram, the time interval of ventricular tachycardia and fibrillation was determined in seconds. In addition, the percentage of survival in groups of experimental animals that were injected with the drug was recorded.

The obtained results demonstrate that the compounds of the invention are acceptable for preventing reperfusion-induced arrhythmia. For example, animals treated with the compound of Example 2 showed longer survival (by 50595) than the control group after reperfusion. high school

Study of compounds of formula I! with global cerebral ischemia

After an ischemic stroke in humans, pyramidal cells of the CAt hippocampus region are mainly (8) destroyed, other cells of the region (CA2, CAZ) are not so sensitive ISgaip, V.U. and others: Selective death of neurons after short-term cerebral ischemia in clawed Mongolian gerbil, research using silver impregnation. Neurology, 27, 402 (19881). According to some authors, memory impairment is associated with hippocampal cell death | Walker, A.E. et al.: National Stroke Review

MIMSO5, MIN: Clinical findings, Stroke, 12, Zy, irri.,, 1, 1 - 44 (1981)). The central nervous system of mammals is not equally sensitive to ischemic damage. The clawed Mongolian gerbil (Megiopez hypodistiaiv) is, as a result of an anatomical feature, more than acceptable for the study of cerebral ischemia, because this species lacks 90,906 of the main anastomotic system (Sigsciiz UMiYivii), thus has no connection me) between the carotid artery system and the vertebral artery system. Thus, large ischemia of the brain can be caused by compression of the carotid artery.

The purpose of the study is to establish whether new compounds possess the formula | protective effect in case of global ischemia of the brain. Experiments were conducted on male Mongolian gerbils.

The animals were anesthetized with a mixture of 2 90 halothane (2-bromo-2-chloro-1,1,1-trifluoro-ethane, 68,905 oxides

Nitrogen and ZO 90 oxygen. Under anesthesia, the carotid artery was compressed on both sides for 5 minutes. Nerve cells are not destroyed immediately, therefore, after compression, the reperfusion period lasted for four days (cell death of late tin). On the fourth day after the intervention, 80-90 95 cells in the CA1 pyramidal region were damaged. ;" To establish and study memory abilities as well as hyperkinesia, animals were tested in the U-maze.

The death of CA1 region cells was studied on histological sections. Animals were sprayed with buffered formaldehyde, the brain was removed and placed in formaldehyde. The growth of the destroyed SAT regions was determined on sections -I of the brain after staining.

The following substances were used for the tests: o SUKI-52466 (control material) at a dose of 40 mg/kg, intraperitoneally, administered 30 minutes after ischemia; nimodipine (1,4- dihydro - 2, 6 - dimethyl - 4 - (3 - nitrophenyl) - 3, 5 - Ридінди каробновая br Acids 2 - methoxyethyl 1 - methylethyl ether) (control material) in a dose of 10 mg / kg , intraperitoneally, 1 was administered 5 and 30 minutes after ischemia; "M new compound of the formula | in a dose of 25 mg/kg, intraperitoneally, was administered 5 and 30 minutes after ischemia;

Test groups: - ischemic control, - treatment with control material after ischemia, - treatment with the material being investigated, after ischemia, (F, - pseudo-operation. ka During the experiments, it could be established that the compounds of the formula | have a protective effect in global ischemia of the brain The effect of compounds of the formula | against autoimmune diseases In autoimmune diseases, the body's immune system reacts against the body itself | Kipd S. N. and others, Zetip. Merpgoii., 19, 25 - 33 (1999);

Tpeopyorotsios, A. M., App. M. M. Asad. 5si, 841, 225 - 235 (19981). Various autoimmune diseases differ from each other by the antigen that starts the process, but in the mechanisms of cell damage to tissues that underlie the development of the autoimmune process, a great similarity can be established (5Z2aro, S. and others, 65 Rgos. Mai). Asad si. USA, 95, 3867-3872 (19981). Autoimmune diseases include, first of all, the following: - hormonal diseases: insulin-dependent diabetes mellitus (IDDM);

- liver diseases: hepatitis; - skin diseases: bullous bullous lupus, pemphigus vulgaris, psoriasis, scleroderma, vitiligo; - diseases of hematopoietic organs: sarcoidosis; - arthropathies: rheumatoid arthritis; - vascular diseases: vasculitis, pulseless disease (Takayasu's disease), polyarthritis nodosa, ankylosing spondylitis; - gastrointestinal diseases: ulcerative colitis; 70 - diseases of the muscular and nervous system: multiple sclerosis, severe myasthenia gravis, chronic inflammatory demyelinating polyneuropathy

Of the autoimmune diseases listed above, prevention of streptozotocin-induced type I diabetes was studied in mice.

Insulin, the main regulator of carbohydrate metabolism in the body, is produced and transported to the bloodstream by 7/5 of the islet cells of Langerhans (Iapdegpapz) of the pancreas. Damage or destruction

B-cells are responsible for the reduction or cessation of insulin production, which leads to the development of type 2 diabetes

I. B-cells are particularly sensitive to oxygen free radicals and to the toxic effects of nitric oxide.

The study of deoxyribonucleic acid damage, which causes nitric oxide, led to the assumption that excessive activation of the enzyme poly (adenosine diphosphate ribose) polymerase and a decrease in the level of nicotinic acid adenine dinucleotide cause B-cell death (NePeg, V. and others, U. Vioi. Spet ., 270, 11176-180 (19951). According to a similar mechanism, streptozotocin (57) |2 - deoxy - 2 - (3 - methyl -3 - soureido) -

O-glucopyranose destroys insulin produced by B-cells, taking this into account, they proposed a model of type 1 diabetes mellitus, which was used in experiments with animals | (Matato, N. and others, Maiige, 294. 284-286 (19811). Deoxyribonucleic acid is destroyed by streptozotocin during alkylation and formation of nitric oxide, which causes activation of the enzyme poly (adenosine diphosphate ribose) polymerase, as indicated above.

The purpose of the research was to determine whether it would be possible to prevent the increase in the level of glucose in the blood, which occurred when a single dose of streptozotocin was administered to mice, with the help of the administration of a single dose of amidoxime derivatives of propenecarboxylic acid of formula I. The experiments were conducted with male CO-1 mice. The animals were randomly divided into three groups, each of which consisted of 8 animals. The first group received 160 mg/kg of streptozotocin (bBidta) intraperitoneally, the second group received 160 mg/kg of streptozotocin and 200 mg/kg of the compound of formula I, orally, and the third group was used as a control. The concentration of glucose in the blood was determined on the third day after administration. After that, the animals were killed and serological samples were taken for the determination of insulin.

The test compound of the invention was found to significantly lower blood glucose levels that had been previously elevated by the addition of streptozotocin. Cha

Effect against insulin resistance

Type II diabetes is independent of insulin. An integral part of the pathomechanism of this last type is a decrease or loss of insulin sensitivity of peripheral tissues, in particular, in striated (skeletal) muscles and adipose tissues. Naturally, this insensitivity cannot be compensated for by excessive "470 binthesis (hypersecretion) of islet B-cells of Langerhans (IGapdegpapz). It is important to pay attention to the fact that in insulin resistance, even without an attack of real diabetes, leads to some regulatory cardiovascular diseases. Therefore, insulin resistance is an independent risk factor for coronary heart disease. vascular disease. Due to the significant pathophysiological significance of insulin resistance, pharmacotherapeutic options aimed at increasing insulin sensitivity are very important in drug discovery. The only truly insulin-sensitizing drugs in clinical practice are the so-called thiazolidinediones. their toxicity (which is mainly hepatotoxicity) is a limiting factor for their use. Insulin-sensitizing agents reduce blood glucose, triglycerides, and insulin levels through a mechanism involving increased insulin sensitivity in target tissues (liver, skeletal muscle, adipocytes) Soisa, 9. K., and Mogop, 0. KK. Antihyperglycemic thiazolidines:

Ciglitazone and Its Analogues, in New Drugs for Diabetes), edited by Waiieu, S. 9. and Riai, R. Kk. 1 Ztiy-Sogdop, Mem HogkK, 1990, pages 255-2611. "M It was investigated whether treatment with the compounds of the invention of normal rabbits and rabbits with an excessive content of cholesterol in the blood is effective for insulin sensitivity. All the time, adult male white New Zealand rabbits, weighing 3 - 3.5 kg, housed in an animal house (12 hourly periods of light - dark per day, temperature 22 - 259 C, humidity 50 - 70 90), which were fed commercially available laboratory food and tap water. The experimental period began after a two-week adaptation period. The rabbits were randomly divided into two main groups. Half of the animals continued to be fed normal rabbit food, while the other group of animals was fed food enriched with 1.5 95 cholesterol for eight weeks. Each main group was divided into four treatment groups: - an untreated group, - a group that were treated with the compound of the invention, 10 mg/kg, intravenously, doses twice a day for more than 4 days, - group, which was treated with 7-nitroindazole as an inhibitor of oxygen free radicals: 65 administrations of 5 mg/kg of 7-nitroindazole over 5 minutes, previous administration of insulin with a 5-minute inter-infusion interval.

- the group treated with 7-nitroindase and the compound of the invention as described.

The animals were anesthetized, polyethylene catheters were inserted into the two main branches of the right jugular vein and the left carotid artery. Catheters were temporarily brought out through the back of the neck and filled with a physiological pain solution containing heparin.

Research on an isolated vessel

Vessel rings 4 mm long were prepared from the thoracic aorta and carotid arteries of rabbits and mounted horizontally on two small I-shaped glass hooks, each of which was connected to a force transducer (50-02,

Echretigia, London, Great Britain) for measurement and registration of isometric tension. Experiments were performed in a chamber for organs (5 ml), which was filled with Krebs solution (Ktgerv), aerated with 95 90 oxygen and 5 90 carbon dioxide. The initial tension at rest was 20 and 10 mN for carotid aortic rings, respectively. The equilibration time was 60 minutes. Subsequently, vessel rings were exposed to increase norepinephrine concentrations in a cumulative manner. After the maximal response, norepinephrine was washed out of the organ chamber until the voltage began to match the previous initial level.

To study the reactivity of blood vessels to acetylcholine, the rings were pre-compressed with EC 50 concentration of norepinephrine. After an appropriate contraction was obtained, the drugs were exposed to a cumulative increase in acetylcholine chloride.

In the second study of vascular reactivity, a separate group of rings of the carotid artery was subjected to stimulation by an electric field. After an initial stretch of 10 mN, the rings were allowed to equilibrate for more than 1 hour. Then, compressive responses to two consecutive pulses of electric field stimulation (100 pulses, 20 V, 0.1 ms and 20 Hertz) were studied. The conditions of electric field stimulation were repeated in the presence of 1 µM atropine and 4 µM guanedine ("non-adrenergic non-cholinergic" - MAMS solution). The entire procedure was performed on rings with intact endothelium and those from which the endothelial layer had been carefully removed.

The determination of cyclic guanyl monophosphate of tissue (ZMP) was provided in accordance with the 57th edition of Yimazzou (Zlimazzu, 2. and others, Sogop ag. ORiv., 4, 443 / 452 (1993); At. U. Rnuvio, 266, H2O33 - H2041 ( 19941) the following:

The muscle rings were immediately frozen using a pre-chilled Vollenberger clamp and) (UuoPepregdeg) and flashed in liquid nitrogen. The samples were then homogenized in bbo (by mass) trichloroacetic acid with a 10-fold higher amount compared to the typical weight in the solution, which was previously stored at a temperature of -702 C after thawing. M samples were processed at a temperature of 49C Sedimentation at a speed of 15,000 d for 10 minutes, which was carried out using a centrifuge K-24 Janetskyi (dChapei2Ki) (Leipzig, Germany), accompanied by the extraction of the supernatant liquid with bml of saturated ether in a Uopeh extractor for more than 5 minutes. i am

The ether fraction was separated, after which the extraction was repeated five times. Then the samples were evaporated under nitrogen and tested for the cyclic content of humnil monophosphate with the help of nador for the Ategzpat radioimmunoassay. Values are expressed as pmol/mg wet tissue mass. Research with h-

Hyperinsulinemic/euglycemic valve: Regular human insulin was infused at a constant rate (13 IU/kg) through one of the venous cannulae for over 120 minutes. This rate of insulin drug administration gave plasma insulin immunoreactivity of 100 4 5 μM/ml at steady state. Blood samples (0.3 ml) were taken from an arterial cannula to determine the concentration of glucose in the blood at 10-minute intervals.

The concentration of glucose in the blood was kept constant (5.5 4 0.5 mmol/l) by changing the rate - s of glucose infusion through the second venous cannula. When the blood glucose concentration remained stable for at least 30 minutes, this state was defined as stationary, and additional blood samples (0.5 ml) were taken to determine plasma insulin at 10-minute intervals. The rate of administration of the glucose drug during the steady state was used to determine insulin sensitivity. During the experiments, the following results were obtained: 1. The relaxation reaction to cumulative increases in the concentration of acetylcholine (1 nm - 10 μm) was not changed by using 1 μm of the compounds of the invention in the vessel of normal rabbits. 2. In an experimental study of a high cholesterol content in the blood, vasodilation by acetylcholine 1 was significantly less in the presence of the compounds of the invention. page 50 3. Stimulation with an electric field caused an increase in pressure in carotid artery rings cultured in Krebs solution (Kherv). In the non-adrenergic non-cholinergic solution, however, the relaxation response was observed as a response to the applied stimulation procedure. The compounds of the invention had no effect on the reaction. 4. Removal of the endothelium significantly increased the contraction reproduced by electric field stimulation and reduced non-adrenergic non-cholinergic relaxation. The compounds of the invention improved contraction produced by stimulation with an electric field and increased non-adrenergic non-cholinergic relaxation in endothelium-free vessel rings. 5. Electrical field stimulation-induced contractions were enhanced, taking into account what we eat) non-adrenergic non-cholinergic relaxation responses were reduced in vessel rings from animals with significantly increased blood cholesterol, compared with those observed in preparations from 60 normal rabbits. The compounds of the invention significantly reduced the stimulation induced by the electric field and enhanced the non-adrenergic non-cholinergic relaxation response in the rings of rabbits with a significantly increased blood cholesterol content, regardless of the presence of endothelium. 6. The initial concentration of cyclic guanyl monophosphate was significantly reduced in the rings of rabbits with a significantly increased blood cholesterol content, compared to the rings of normal rabbits. This decrease 65 was nearly normalized by incubation with 1 μM compounds of the invention. The tested compounds did not, however, have an effect on the average value of cyclic guanyl monophosphate content in normal rings. Stimulation with an electric field led to an increase in the concentration of cyclic guanyl monophosphate in preparations from normal animals. In rings from rabbits with significantly increased cholesterol in the blood, the applied stimulation procedure was interrupted, which did not make it possible to detect any increase in cyclic guanyl monophosphate. The compounds of the invention had no effect on the increase in the tissue content of cyclic guanyl monophosphate in normal rings, which was induced by stimulation with an electric field, but a real increase in cyclic guanyl monophosphate was observed in preparations from rabbits with a significantly increased content of cholesterol in the blood. 7. Observations on a cholesterol-enriched diet note a significant decrease in the sensitivity of 7/0 to insulin in living rabbits. Treatment with the compounds of the invention for more than 4 days almost restored insulin sensitivity in animals with increased blood cholesterol. However, the compounds of the invention acted without effect on insulin sensitivity in normal animals. 8. 7-Nitroindazole, an inhibitor of neural nitric oxide synthase, itself causes insulin resistance in normal animals. The compounds of the invention failed to modify this insulin resistance. In addition, 75.7-nitroindazole blocked insulin resistance, which increased the quality of the action of the compounds of the invention on experimental animals with increased cholesterol content.

Conclusions:

The results show that the compounds of the invention increase the hypoglycemic effect of insulin in insulin resistance, which is observed in experimental rabbits with an increased content of 2o cholesterol. The results also provide evidence that this sensitizing effect of insulin is strictly linked to nitrergic pathways, the effects of which have recently been proposed to play a major role in regulating insulin sensitivity (Zpapkag, KK et al., Diabetes, 49, 684-687 (20001). Neurohormonal regulation of peripheral insulin sensitivity of the liver can be described as follows (ats., MU. MU., Moze. y.

RNuzio., 77, 553-562 (19991): c - an increase in the level of insulin in the blood after eating. - in response to this increase in the level of insulin, the parasympathetic reflex of the liver is activated. i) - this reflex causes the splitting of acetylcholine, which initiates muscarinergic receptors. - muscarinergic disturbance leads to splitting of nitric oxide (NO). - only in the state of food intake, nitric oxide causes the cleavage of the hepatic factor of sensitization of M zo insulin (NIZ5), which has the same capabilities as insulin or gives an insulin-like effect. - the hepatic factor of insulin sensitization increases the absorption of glucose by the skeletal muscles. This mechanism of hepatic insulin sensitization factor is sensitive to the blockade of nitric oxide synthesis and can be initiated by an exogenous MO donor. It is likely that the mechanism of hepatic insulin sensitization factor is closely related to the function of hepatic sensitive fibers. An increase in the plasma level of insulin after eating a meal initiates a nitrergic subpopulation of the hepatic fibers of the sensory nerve, which cause the disconnection of its sensory neurotransmitters from the neighboring fibers. These sensory neurotransmitters, due to their hormone-like feature, reach the bloodstream and increase the insulin sensitivity of tissues.

In their recently published work, Zierrap et al. draw attention to the missing link between obesity and insulin resistance (Bierrap, S. M. et al., Maishge, 409, 307-312 (20011). In short, "the hormone , which was named resistin, is produced by adipocytes. Research has shown that resistin reduces the sensitivity of target tissues (fat and skeletal muscles), which gives a hypoglycemic effect of insulin. Therefore, pharmacological inhibition of resistin secretion is a possible new mechanism of action for pharmacological ;" use in the treatment of non-insulin-dependent diabetes mellitus and insulin resistance syndrome. Among currently known drugs, representatives of the thiazolidinediones family can slow down insulin secretion through the peroxime proliferator receptor gamma nuclear activator in adipocytes. -I Compounds of the formula | have an effect on insulin sensitivity, and they in able to improve insulin resistance due to the nitrergic mechanism and sensory neurotransmitters. insulin plays a causal role in diseases with high morbidity and mortality, such as type II diabetes, hypertension, coronary heart disease, obesity, and some endocrine diseases.

Use of compounds of the invention to prevent toxic effects o 1) Effect of compounds on lethality in mice caused by endotoxin "M" Septic shock is one of the most frequent causes of death in intensive care units. Infections caused by

Gram-negative bacteria lead to hypotension, insufficient functioning of several organs, and, finally, to the death of the organism. Thanks to the injection of lipopolysaccharide (I P5), which is a component of the bacterial membrane, a shock-like state is induced in experimental animals and, finally, death occurs. Liposaccharide initiates the family

ME-KV / Ke! transcription. which regulates the production of several transmitters that take part in the pathomechanism (F) of shock (such as TNE-A, interleukins, MO synthase) (Oiimeg, R. 9. ey a! Resistance to endotoxic shock, as a result of insufficient activation of ME-KV in poly (adenosine diphosphate ribose) polymerase - 1 mice with physical disabilities, EMVO .., 18 (16), 4446 - 4454 (19991). Gene poly (adenosine diphosphate ribose) polymerase - 1 is functionally connected to bo ME - kV , yes, in the absence of poly (adenosine diphosphate ribose) polymerase, transcription dependent on ME-KV also does not proceed, so the release of inflammatory mediators in endotoxic shock also becomes unregulated. The aim of the study is to establish Is it possible to prevent endotoxin-induced lethality by inhibiting poly(adenosine diphosphate ribose) polymerase-1 with compounds of the formula 65 C57VI/6 mice (Spapez Kimeg Vgeedipda Sha.) were used for the experiments. The dose and type were used in the study lipopolysaccharide, which were identical to those described in the article mentioned above

Olivera F.J., namely: lipopolysaccharide from EvzsPegispia soii 0111: 84 (Zidta) 3-amino-benzamide (Zidta) was also used in the experiments. A survival period of 24 hours was achieved at least twice.

Compounds of formula I were administered orally to animals 1 and b hours after the administration of lipopolysaccharide.

It was found that lethality resulting from endotoxin action was significantly reduced by the compounds of formula I which were tested. 2) Effect of compounds on hepatotoxicity caused by acetaminophen (paracetamol)

It is known that various antirheumatic non-steroidal agents (|Reyeg5, M. ei a!., Siip. Ipmev., 71, 875 - 881 (19931)) and analgesics, respectively, have significant hepatotoxicity (Kgodeg, N. ei aiY., Sep. Rpagtas, 27, 167 707170 (19961). Liver and kidney failure is a consequence of the action of a large dose of paracetamol (Megedek, T. u. eyi ai., Agsy. Ipieg. Mey., 141, 397 - 400 (19811). Recently it became obvious , that inhibitors of poly (adenosine diphosphate ribose) polymerase eliminate liver damage caused by paracetamol | Kgodeg, N. ei ai.,

Sept. Ripagtas, 27, 167 -170 (19961). It is known from the literature that paracetamol is an inducer of cytochrome P-450. The effect of paracetamol on the cytochrome P-450 system causes the formation of reactive quinone imines that bind to the 7/5 bulphyhydryl group of porteins, which, thus, results in the rapid depletion of intracellular glutathione by MoPom, 0. 9. ей айЙ, Raptasoy. 12, 251 - 271 (19741). Inactivated proteins lead, respectively, to the destruction of liver cells and liver necrosis. Intracellular glutathione is, accordingly, one of the most important antioxidants and the strongest eliminator of reactive oxygen species.

Weakening of the antioxidant protection system, which depends on glutathione, leads to an increase of 2o Intracellular level of free oxygen radicals | Miezei, MK. et al., Ipatinp, 17, 283 - 294 (1993).

Free oxygen radicals are strong inducers of poly (adenosine diphosphate ribose) polymerase, which affect the post-translation of proteins. As a result of increased activation of poly (adenosine diphosphate ribose) polymerase, the structures of adenine dinucleotide of nicotinic acid cells are depleted, and apoptosis may begin (INozspipo, U. ei ai., U. Zi(egoiy Moi. Vioi., 44, 113-119 (19931Ї) Thus, nicotinic acid amide is a selective inhibitor of the enzyme poly (adenosine diphosphate ribose) polymerase, which inhibits the dissociation of SOT and RT enzymes in the liver, as shown on the example of mice in the case of hepatitis caused by the action of i) paracetamol (| Kgodeg, N. and Engiisp, MU, in: I-Turiorpap: Current Perspectives in Medicine and Drug Safety, edited by Kospep, MU, and Ziepnagi, N., Met!. Veip, 1994).

The aim of the research was to establish whether it is possible to use new compounds of the formula ! to prevent liver damage caused by the action of paracetamol. Signs of liver damage were characterized by an increase in SOT and STR levels of enzymes caused by the action of paracetamol. The experiments were carried out on males

MMK of mice with a body weight of ZO - 40 grams. Animals were pretreated orally with compounds of the formula | within 7 days. On the 8th day, the mice were starved for 12 hours, after which they were administered an oral dose of paracetamol of 500 mg/kg and the same dose of the compound of formula I. After 16 hours, the animals bled to death and the activity of OT and SORT enzymes was measured in serum The obtained results were analyzed using the non-parametric test of Mann and Whitney (Mapp apa UMUpipeu). As for the results, the average value and the standard deviation were taken such that P « 0.05 was considered significant.

A single oral administration of paracetamol was found to increase the activity of ZOT and SORT in the serum of male MMK mice compared to saline-treated control animals. "

However, the compounds of formula I, after oral preliminary administration, which continued for 7 days, in c very significantly reduced the activity of SOT and SORT enzymes. For example, a very favorable hepatoprotective effect was observed when using the compound of Example 12, which was administered at a dose of 50 mg/kg. ;" 3) Effect of compounds on herbicide toxicity

Herbicide (1, 1i - dimethyl - 4, 4" - bipyridinium), a compound previously used as a pesticide,

Causes a toxic effect through the formation of -I radical of peroxide. Oxidoreductase enzymes, which use MAOH and MAS(P)H as electron donors, participate in the formation of the peroxide radical. (MAYU (P)H is B-nicotinamide adenine dinucleotide o phosphate, shown in the form). In the transmission of the cell's response to the lack of oxygen, which was caused by this herbicide, the rbb protein plays an important role |Mididassio, E. ei aiYi.,, Mayte, 402, 309 - 313). Mechanisms contributing to the inactivation of peroxide (such as an increase in various peroxide dismutases) effectively reduce the toxicity of the i-th herbicide. The peroxide radical plays an important role in the pathomechanism of several diseases (such as peroxygenation and ischemia, heart attack, inflammatory diseases). A simple model of the peroxide load, which is tested in these diseases, is obtained by the introduction of a herbicide.

Effect on the toxicity of the herbicide, "ip migo"

Hepa-1 hepatoma cells were grown in KRMI-1640 medium supplemented with 10 95 calf serum, while RS-12 rat pheochromocytoma cells were grown in KRMI-1640 medium supplemented with 10 95 calf serum and 5 95 horse serum at a temperature of 372 C with air containing 5 90 kO of carbon dioxide. Using 100 μl of culture medium, 5 x 103 cells were placed in the wells of a 9b-well Costar culture plate (Soziag. Part of the cultures were not treated in any way and were used as a control. The cells were partially treated with increasing concentrations of herbicide, partially with the same concentration of herbicide, and with test compounds with a concentration of 3, 10 and 30 μg/ml.

Cells were grown for the next 3 days, then stained with 5KV. The herbicide at very high concentrations resulted in cell death, while the herbicide at lower concentrations only partially slowed cell growth. The effect of the test compound was determined based on the reduction in the toxicity of the herbicide.

Effect on herbicide toxicity in natural conditions

The herbicide has significant toxicity to mice. A dose of 70 mg/kg administered intraperitoneally results in the death of animals within 2 days. Mechanisms that reduce peroxide formation, neutralization, and the effects of oxygen deficiency also have the potential to reduce herbicide toxicity under natural conditions.

CPIR mice, which had a body weight of 20 - 22 g, were divided into groups consisting of 10 animals and treated, intraperitoneally, respectively, with herbicide doses of 50 and 70 mg/kg. Some groups were also treated with the test compound for 6 hours before and after herbicide application. In the case of the use of test compounds, a dose of 100 µg/kg was used orally. The effectiveness of the test compounds was determined based on the increase in the survival time of the mice. 70 Compounds of formula I were found to significantly reduce herbicide toxicity.

Effect of compounds of formula I on neurodegenerative diseases

As mentioned earlier, as a result of damage to deoxyribonucleic acid by reactive oxygen species, the enzyme poly (adenosine diphosphate ribose) polymerase is activated, which is accompanied by the loss of adenine dinucleotide of nicotinic acid by cells, which leads to the death of 7/5 cells. The extreme importance of poly (adenosine diphosphate ribose) polymerase activation can be seen not only in nerve cell death induced by ischemia similar to cerebral ischemia, but has a proven role in other neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (| ome ei a!., MeigoraiyoI. Arri. Meiigobio!., 25, 98 -108 (1999); Eazvop ei a!., Mai. Mea., DO, 1089 -1095 (19971).

Effect on experimental amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS5) is a progressive neurodegenerative disease with fatal consequences. It is the most common manifestation of neuromotor disorders in adults in developed countries. Amyotrophic lateral sclerosis involves the degeneration of motor neurons in the cortex. brain stem and spinal cord causing skeletal muscle atrophy, paralysis and death |Komiapa, Her. R. in sch

Neurodegenerative diseases, p. 507 - 521 (19941). In some cases, amyotrophic lateral sclerosis is a hereditary disease. Hereditary cases are partially caused by a mutation with a change in the content of the gene Cy/7p peroxide i) dismutase-1 (ZO - 1) (Oepo, K. N. eyi a!., Nauka, 261, 1047 (19931). 500 - 1, a cytosolic enzyme , which is abundant in nerve tissues, plays an important role in preventing oxygen radical-induced cellular damage.The altered enzyme maintains enzyme activity near M

From Normal level. Research in laboratory conditions indicated that OO - 1 mutations lead to improved function and increased free radical generation. at

A transgenic mouse that has an altered 500-1 gene shows signs similar to those observed in right-sided amyotrophic sclerosis. To create models of the disease in overexpressed transgenic mice, several modified human BOI-1 genes (C59ZA, M1480) were used, which made it possible to screen a drug against amyotrophic lateral sclerosis. Zsi., 152 Zirri. 1, 67 - i-73 (19971).

Test of a hereditary model of amyotrophic lateral sclerosis

Transgenic mice with an overexpressed altered human 500-1 gene (993A) were used for the study. Animals were purchased from The Jackson Laboratory (askzop), USA. Treatment with compounds of formula I was started "70 before the onset of disease signs at the age of 4 weeks. The test compounds were applied once a day, orally, with three dose levels until the end of the experiment. Progression of the disease was checked by a weekly examination of motor activity (stretch reflex, loaded grid, turning test), life time and, at the end; experiment (after 120 days), histological and biochemical examination of motor neuron regions.

It was found that compounds of the formula | lead to a moderate delay in the appearance of reflexes, coordination and muscle strength deficiency in animals transgenic with amyotrophic lateral sclerosis. The effect showed dependence on -I dose. There was also a delay in the onset of paralysis and the final stage of the disease. The results of the histological examination confirmed that the clinical effect of the treatment was observed. Degeneration and loss of motoneurons and zyrgiapsia o poda of nerve cells were less common in the treated group compared to the control group. c Based on the results, it can be expected that the compounds of the formula | have a beneficial therapeutic effect in diseases such as amyotrophic lateral sclerosis. o Autoimmune Model Test of Amyotrophic Lateral Sclerosis "M In the case of temporarily occurring diseases of amyotrophic lateral sclerosis, no mutation may be detected in the 500-1 gene. This fact assumes that other causes have led to the same development of the disease. In most patients who suffer of sporadic amyotrophic lateral sclerosis, anti-calcium channel antibody can be detected.This observation supports the concept that an autoimmune process against motoneurons and calcium channels plays a major causative role in the formation of sporadic cases

F) amyotrophic lateral sclerosis. In experimental animals, Engelhard (Epdeijagai) and his co-workers induced a disease that showed specific changes of amyotrophic lateral sclerosis by immunization with a motoneuron, and then used only stable serum (Epdeijagai, 9. ei aiI.,, Synapse, 20, 185 -199 bo (19951).This model was used to study the efficacy of the compound of formula | in sporadic amyotrophic lateral sclerosis.

Hartley (Napieu) guinea pigs were immunized with homogenized bovine horn spinal cord. For immunization, motor neurons were suspended in Freund's complete adjuvant (Egeip) (CEA).

The treatment was carried out with the help of 10 subcutaneous or intradermal injections, introducing 0.1 ml of suspension each time. 65 One month later, the injections were repeated, however, incomplete adjuvant was used to prepare the suspension

Freund. Two weeks after the second immunization, within 1-3 days, the animals developed severe weakness,

especially in the lower extremities. The increase in body weight stopped, mobility decreased. During the next two weeks, the condition of the animals did not change. After that, the animals died from blood loss. The collected blood was centrifuged to obtain a serum that was used to induce amyotrophic lateral sclerosis in mice.

The research was carried out on groups consisting of 5 male albino mice (SRI P, with a body weight of 25 -

ZOg). Each animal was injected intraperitoneally with 7 ml of the above-mentioned serum in order to damage the motor neuron. One group of animals was treated with only serum, while other groups of animals were treated, in addition to serum, with the test compound of the formula! (the dose was 100 mg/kg, intraperitoneally). Subsequently, 7/0 groups of animals were treated only with the test compound of formula I without injection of serum.

The mobility of animals that were treated only with serum became slow, they could use their lower limbs only with great difficulty, then they became paralyzed. In the case when the animals were treated with both serum and the test compound of formula I, no signs of motor deficit were detected. The same tests were carried out on animals treated only with test compounds of the formula I. All this leads to the 7/5 opinion that the compounds of the formula ! prevent the development of movement disorders that can be caused by immunization.

Effects on an experimental model of Parkinson's disease

Parkinson's disease (PD) is a generalized disabling idiopathic neurodegenerative disease characterized by tremors, bradykinesia, difficulty moving from place to place, and difficulty maintaining balance. These motor abnormalities are caused by a decrease in the amount of dopamine in the brain, which eventually leads to the loss of dopaminergic neurons in the gyrus. Analysis of the action of 1 - methyl - 4 - phenyl -1, 2, 3, 6 - tetrahydropyridine (MRTP), which has selective neurotoxicity, sheds light on the possible pathomechanism of the disease

Parkinson's. 1 - methyl - 4 - phenyl - 1, 2, C, 6 - tetrahydropyridine stimulates parkinsonian motor symptoms in human and animal organisms. Messhgai., 35, 38-44 (19941). Treatment with 1 - methyl - 4 - phenyl - 1, 2, 3, 6 - tetrahydropyridine also leads to the loss of dopaminergic neurons in the brain of Zybviapiia podragae sotrasia. Body-like eosinophilic inclusions of Lewy (I eug) appear in damaged neurons and in these cells the activity of the mitochondrial complex also decreases. These changes are characteristic of i) insufficient oxygen IZNariga, A,. Hell Metzgo., 69, 161-165 (19961). The biologically active metabolite of MRTP is

MPP (1-methyl-4-phenylpyridinium)|.

MRR directly inhibits the | complex in the mitochondrion, which leads to increased generation of the anion M zo peroxide. The data indicate that oxygen deficiency plays a central role in the pathogenesis of the natural form and

MRTR of the induced form of Parkinson's disease. The enzyme poly (adenosine diphosphate ribose) polymerase is activated by insufficient oxygen, and the enzyme may play an active role in the pathomechanism of Parkinson's disease. A separate mouse poly (adenosine diphosphate ribose) polymerase shows significantly reduced sensitivity against MPTP-induced Parkinson's disease (|Mapaiig, A. ei ai., Rgos. Mai). Asad si. USA, me) 96, 5774 - 5779 (19991). These circumstances allow us to believe that inhibition of poly (adenosine diphosphate ribose) y polymerase can lead to a therapeutic effect on Parkinson's disease.

C57VI mice used in the study were purchased from Charles River Hungary. Mice weighing 20 g were treated four times with a dose of MRTP of 20 mg/kg each time with an interval of 2 hours, intraperitoneally. Test compounds were administered orally 30 minutes before MRTP injections. Control animals received the same range of treatment base. Seven days after MR TR injection, the mice were killed and the brains were quickly removed. It was separated into strips (zigiaia) on a very chilled petra dish. The cut tissues were immediately frozen and stored at a temperature of -802C to ;" the beginning of the analysis. Tissue samples were sonicated in 50 volumes of 0.1 M perchloric acid to achieve homogenization. After centrifugation (14,000 x 49, 10 minutes, 4 2C), 20 μl of the supernatant was applied to a reverse-phase catecholamine column (EZA, Vega) and the dopamine content was evaluated. -I 2 hours after the last MRTP treatment, the ventrolateral midbrain and strips (vigia(a)) were excised and homogenized in sucrose/OTT buffer, then centrifuged (14,000 X 49.5 minutes).

Mn was resuspended in buffer. After determining the protein concentration, an equal amount of protein was loaded into sodium dodecyl sulfate/electrophoresis in a polyacrylamide gel (50O5B/RACE). The protein was transferred from the gel to the nitrocellulose membrane and immunostained for poly(adenosine diphosphate ribose) and polymerase. The specific bond was visualized using chemiluminescence. "I During the examination, it was found that treatment with 1 - methyl - 4 - phenyl -1, 2, 3, 6 - tetrahydropyridine causes an intense decrease (by 80 90) in the striatal content of dopamine. The test compounds of formula I partially (by 20-40 905) slowed MRTP-induced dopamine loss. Treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine resulted in poly (adenosine diphosphate ribose) polymerase adducts in the striatal region. Co-treatment with test compounds restored the inhibition of this process (by 20 - 70 90).i) Thus, it can be expected that compounds of formula 1 may have therapeutic activity in Parkinson's disease.

Examination of the cytoprotective effect in Some drugs that are used constantly or often can cause neuronal damage, that is, have the opposite effect. Of the large number of such drugs that cause this adverse effect (chloramphenicol, dapsone, disulfiram, dichloroacetate, ethionamide, glutethimide, sodium aurothiomalate, hydralazine, isoniazid, metronidazole, nitrofurantoin, nitrous oxide, ciplatin, pyridoxine, vincristine), the best characterized and the most common discussed for the occurrence of nerve diseases are isoniazid, pyridoxine, 65 Vincristine or cisplatin. Chloramphenicol is a drug that can cause such nervous disorders, but this adverse effect may disappear after treatment is stopped. However, in almost all clinical cases, premature discontinuation of chemotherapy may prevent treatment success and may cause disease recurrence. The danger of therapeutic treatment changing due to side effects is especially high in cases of anticancer chemotherapy. This fact is of great importance for the so-called chemoprotective or cytoprotective agents, which are able to reduce the adverse side effect of life-important drugs without any reduction in therapeutic efficacy.

In cancer patients treated with cisplatin, the main side effect was damage to peripheral nerves (peripheral neuropathy). The appearance of this side effect can interfere with treatment with cisplatin, can endanger successful treatment, and weaken the quality of life resources of patients. The presence and 7/0 degree of neuronal damage can be determined by measuring nerve conduction velocity in clinical and experimental studies. The neurotoxic effect of cisplatin (cis diammine dichloroplatinum) is aimed primarily at large myelinated peripheral nerves and at the detection of sensory neuron damage (sensory neuropathy). Recently, there have been some reports of autonomic neuropathy and, occasionally, motor neuropathy secondary to cisplatin treatment. As a result of damage /5 directly to the posterior root ganglia and large sensory nerves, cisplatin can often cause a functional disorder of the sensory nerves. In rats, chronic treatment with cisplatin induces sensory neuropathy, which is reflected in a slowing of mixed-type sciatic nerve conduction velocity.

On the basis of the biochemical method of action, which is mentioned above, mainly to prevent damage, 20 which is a consequence of the action of free radicals, it is believed that the compounds of the formula | may have protective potential and may prevent organotoxic adverse effects of anticancer drugs. Therefore, in experiments on rats, cisplatin was given as a subacute treatment for 10 weeks with doses of 1 and 2 mg/kg, intraperitoneally. and monitored the development of peripheral neuropathy. In addition, it was investigated how different doses of the test compounds affect nerve function damage (nerve conduction velocity). ch 25 To find the sensory and motor neural damage caused by cisplatin, the nerve conduction velocity was measured in the tail of rats, according to the modified method of Miyoshi (Miuozpi). Modification i) consisted of measuring nerve conduction velocity at room temperature instead of 372 C. Sensory and motor nerve conduction velocities were determined before administration of cisplatin (control) and at the 5th and 10th week of administration. During the measurements, the animals were superficially anesthetized with ether, and two pairs of needle cha 3o electrodes were placed at a distance of 50 mm from each other on the tail nerve. Using the supramaximal systolic stimulus, afferent (motor) and afferent (sensory) nerve bioelectrical potentials were recorded. Nerve conduction velocity was determined autonomously, by calculating the average value of the values of bioelectric potentials, using the formula

MOM - M L (m / sec), where i.

M is the interval between the trigger and the recording electrode pairs in millimeters, and 5 is the waiting time for the appearance of the bioelectric potential in milliseconds,

IOM - nerve conduction velocity in m/second.

In tests, it was found that treatment with cisplatin for 10 weeks at doses of 1 and 2 mg/kg, intraperitoneally, significantly reduced body weight in treated animals compared to control animals. This is "

A decrease in body weight was also observed when animals were treated with compounds of formula I. There was no difference in overall behavior between treated and untreated animals, or between animals treated with cisplatin and the test compound. There was no difference in nerve conduction velocity of sensory "" and motor nerves in the control group, which was measured three times.

In animals treated with cisplatin, nerve conduction velocity was uniformly and markedly reduced at the fifth week and also at the tenth week of treatment with a dose of 1 mg/kg cisplatin. After treatment with a cisplatin dose of 2 mg/kg, a more significant decrease in nerve conduction velocity was observed. Neuropathy also developed in the motor nerves. o In the course of treatment with cisplatin for 10 weeks, the motor conduction velocity of the nerve was significantly reduced with the use of both groups of cisplatin doses of 1 and 2 mg/kg. The decrease was dose related. In the groups treated with a dose of cisplatin 1 mg/kg and the compound of the formula i, the decrease in the conduction velocity of the sensory nerve was significantly less than in the group treated only with 1 mg/kg cisplatin, thus this neuronal function "I is improved with the application of combined treatment. The degree of improvement was much higher than the degree of damage. In the group treated with cisplatin at a dose of 2 mg/kg and the compound of formula I! at various doses, at the fifth week the decrease in the conduction velocity of the sensory nerve was not different from that of the group that treated only with a dose of cisplatin 2 mg / kg. At the tenth week, however, a group of animals treated only with a dose of cisplatin 2 mg / kg, the conduction velocity of the sensory nerve further continued to decrease significantly, in iF) the same time as in the case when the animals were treated with both cisplatin and a compound of formula I, the reduction was dose-dependent compared to animals treated with 2 mg/kg cisplan alone. nerve affinity was lower at the final stage of the tenth week, especially in groups that were also treated with the compounds of the invention.

In conclusion, it can be noted that the impairment of the conduction velocity of the sensory nerve and the conduction velocity of the motor nerve caused by the treatment with cisplatin was reduced by the simultaneous treatment with the compounds of the formula I, and the progression of the impairment was prevented from the fifth to the tenth week. This protective effect was also dose dependent in some groups. Thus, the neuroprotective effect of compounds of formula | can 65 be observed both in the functions of the sensory nerve and in the functions of the motor nerve.

Biological action of carnitine - palmitoyl transferase (CRT1)

Carnitine - palmitoyl transferase is a key enzyme in the stabilization of fatty acid metabolism. There are two possibilities for coenzyme A of fatty acid esters (CoA) in the free state (EPA): 1) Triglyceride synthesis through reaction with glycerol, or 2) Oxidation, the first step of which is the formation of acylcarnitine by the enzyme carnitine - palmitoyl transferase | see MssSaigtu , in O. ei ai!., Diabetes, 5, 271 - 284 (1989); MeosSaitu, 9. O. apa Rozievg,

Oh, App. Kew. Viospit., 49, 395 - 420 (19801). The enzyme carnitine - palmitoyl transferase is localized in the outer part of the inner mitochondrial membrane (or in the outer membrane) and catalyzes the following reaction: 70 EPA - CoA i II - Carnitine -» EPA - carnitine i- CoA Inhibition of fatty acid oxidation leads to an increase in splitting glucose and oxidation. This process is extremely significant and important, especially in myocardial ischemia and diabetes; both of these pathological conditions have high morbidity and mortality. In the case of myocardial ischemia and successive peroxygenation, increased fatty acid oxidation is harmful due to additional oxygen demand and the formation of a harmful effect of /5 acyluarnitines on the membrane. SeiYi Sagaioi.,, 20, 905 - 916 (1988); Roga, 0. A. ei aI., Biochemistry, 35, 7903 - 7909 (1996); Keemev, K. A. ei aYi.,, 9). RIiagt. RPpagtasoi.,, 48, 245 - 248 (1995)).

Based on several experimental data, it can be noted and it is currently an accepted fact that the activation of glucose metabolism and the simultaneous inhibition of fatty acid oxidation have a beneficial effect from the point of view of both the restoration of the mechanical function of the myocardium and the parameters of metabolism | orazspik, o. O. ei ai,, Sigs. Kev., 66, 546 - 553 (1990); Keppeau, 9. A., ей аЙ., Viospit. РНагтасой.,, 52, 273 - 280 (19961).

This choice of the substrate of the myocardium, that is, the choice between glucose and fatty acid, can also be achieved with the help of inhibitors of carnitine - palmitoyl transferase, since the use of glucose increases and the energy of the myocardium improves (orazspikK, p. , 1036 - 1043 (1988); Satedai, M. ei ai,, Agsy. RIiuz. Viospet., 103, 45 - 49 (1995); IorazspikK, s. O. ei ai., 65, 378 - 387 (1989) ; Rashu, 0. p

E.eai., Sigs. Kev., 68, 1085-1094(19911).

Our studies show that the enzyme that catalyzes the rate-limiting reaction of fatty acid oxidation can be inhibited by compounds of the formula | in the sub-millimolar concentration range.

Studies also indicate that the test compounds affect the substrate selection of the heart and other tissues and, by altering the substrate selection, also post-ischemic tissue damage. Cha

The biological role of oxygen-sensitive genes, which are stabilized, primarily, by BNI H transcription factors

Protection against the adverse effects of hypoxia requires a series of organized protective reactions, both at the level of individual cells and at the level of the whole organism. In stabilizing the expression of genes induced by hypoxia, the NIB-1/"AKMT transcription complex plays a central, but not exclusive, role. Oxygen-sensitive, coordinately stabilized genes include erythropoietin, which stimulates the production of erythrocytes (Mapa, o. Y. i. z5 eGayi. , RMAB, 92, 5510 (19951), MESE (vascular endothelial growth factor), which stimulates tissue regeneration.

ISoidrego, M. A. apa Schneider, T. 9., U. Vioi. Spet., 269, 4355 (19941), similar to glycolytic enzymes

SARON, GON (lactate dehydrase) |Koi'i5, A. ei a!., 9. VioIi Spet., 272, 20055 (1997)), as well as the glucose transporter SIM -1.

Compounds of formula I are possibly those that bind to AKMT or NIB-1 transcription factors such that they "

Can affect the activation of genes involved in fear states (sensitive to hypoxia). It is believed that, thanks to this signal transduction pathway, the compounds of the invention display heat shock proteins, and play an important role in situations related to the state of fear. "" Synthesis of heat shock shocks (HOR) caused by various stress conditions that affect cells.

However, heat shock proteins help the survival of cells in dangerous situations and contribute to

Recovery of any damages |Sagaiomazsiag Kev., 578 (1993); Mashgovsi Hek., 163, 135-137 (19931). - and Agents that can facilitate the signaling response during adaptation to hypoxia, lead to peroxygenation and restore the exhausted adaptation response, have the potential to reduce tissue damage caused by hypoxia (hypoxia reoxygenation) in diseases such as heart attack, arteriosclerosis and diabetes. c Definition of NZR-7O0

The effect of HeP-70 was studied using a reporter gene analysis that forms a hybrid of deoxyribonucleic acid and . The protein gene, which can be detected with the help of enzyme activity, which is well amenable to measurement, was joined to the promoter sequence of NOZR-7O, which encoded a heat shock protein.

Biotechnological processes were used. The enzyme luciferase was used as a reporter gene, the action of which can be well determined by measuring luminescence. If the promoter of the luciferase enzyme gene is a promoter

NZR-70O gene, then a change in the action of the luciferase enzyme, that is, a change in the frequency of gene transcription, is correlated with the frequency of transcription of the HOR-70 gene, which continues under the given circumstances. Thus, if a substance or process iF) affects the expression of the HeP-70 gene, then the effect can be studied by measuring the enzymatic activity of the enzyme luciferase. The effect of test compounds on the expression of the HOR-70 gene was studied in such an experimental system. in a double-helical circular molecule of deoxyribonucleic acid, that is, a plasmid containing a reporter

H5P-70 gene was created in such a way that measurements could be performed. The sequence of the promoter of the NZR-70 gene of the mouse (direction 5 from the very beginning of the location of the gene) with a length of almost 600 pairs of nucleotides was joined to the coding sequence of the luciferase gene, initiated by the RPoiutiz of rugae. The used promoter sequence contained several proteins associated with sites that facilitate the expression of the HeP-70 b5 gene. The xenogeneic construct of the H5P luciferase promoter gene was inserted into the main vector of the rVK plasmid, which can be selected for neomycin. This NOR-70 luciferase plasmid was transfected into fibroblast I 929 mouse cells. Sample analysis was performed as follows:

And 929 cells containing the NZR-70 luciferase plasmid were grown in OMEM (modified medium

Dulbecco Eagles), which was fortified with 5,956 EC5 (Fetal Calf Whey). 10 7 cells were placed in wells on a 24-well Costar plate (Soviag) for cell culture in 1 ml of nutrient medium. The test substances were dissolved in PB5 (phosphate buffered saline solution) with a concentration of 10" M. After the addition of cells (3-4 hours after placing), 10 μl of the solution was added to the cultures, and the cells were created pleasant conditions for development for 30 minutes at a temperature of 379 C in a carbon dioxide thermostat. The medium was then replaced to refresh it (without the test substance), and the cells were allowed to regenerate 70 for 1 hour at 372 C, after which they were washed once with PB5. After removing the PB5, the cells were added 40 µl of 1X lysis buffer, and the samples were kept on ice for 30 minutes.After that, cells were placed in Eppendorf tubes (Errepadop) and centrifuged at 14,000 rpm for 20 minutes at 42 C. 5 µl of supernatant was added to 25 µl of buffer for luciferase assays, and the luminescence of the samples was measured in luminometers for 25 seconds.15 Quantitative content of the luciferase composition buffer: 20.00 MM tricine IM / 2 - hydroxy - 1, 1 - bis (hydroxymethyl) ethyl / aminoacetic acid), hydrogen indicator pH 7.8, 1.07 mm (MaSO»)4 Md (OH) 5 -5H2O, 2.67 mM Mo5o,, 20 0. 10 mM EOTA (ethylenediaminotetraacetic acid), 3.33 MM OT, 270 µM lithium salt of coenzyme A, 470 µM luciferin, 530 µM ATP (adenosine triphosphate). p 29 Composition of 5X lysis buffer: o 125 mM Tris - NZRO, hydrogen index pH 7.8, mm SOTA Igrans -1,2- diaminocyclohexane - M, M, M', M'- tetraacetic acid), IOtMmOTT, 50 95 glycerol, 5 96 Triton X-100.

Research of hypoxia of sensory genes -

The effectiveness of the compounds of formula I was studied on xenobiotic and hypoxia (1 95 oxygen) induced expression of the yu gene in Nera and Nerb2 cell cultures in tKMA and protein levels. It was observed that the compounds of the formula | as a result, lead to a 10-fold increase in methyl-cholanthrene, induced by HOR-70 expression in Ner about cells. In addition, the compounds of the invention increase the expression of hypoxia-sensing genes, such as MESE, ZARON, and HON, in response to hypoxia treatment in Nera and Ners2 cells.

Compounds of formula I increase hypoxia expression of several sensory genes in the case of hypoxia. This indicates that the test compounds affect the general pathway of oxygen stabilization in sensory genes. Compounds of formula and that facilitate adaptation to the stress state that occurs with hypoxia are suitable for protection against the adverse effects of hypoxia and hypoxia overoxygenation. The compounds are likely to provide therapeutic utility in conditions where tissue damage is caused by impaired circulation, compression and spasm of arteries, arteriosclerosis, heart attack, blockage of blood vessels, thrombosis, low blood pressure, shock, burns and frostbite. The compounds of the invention can also be effective in secondary hypoxic conditions associated with degenerative and metabolic diseases (Alzheimer's disease, diabetes).

Effect on the level of ION enzymes in Nerb2 cells exposed to hypoxia

Nerba2 cells were grown in OMEM medium, which was supplemented with 1095 EC5 in air containing 596 CO" - at a temperature of 372 C. 105 cells were placed in wells on a 24-well Costar plate (Sovziag) for the culture of (4) cells in iml of nutrient medium. The next day, cells were treated with test compounds at concn

ZOmkg/ml, after which the cells were treated with hypoxia (195 О 5, 596 СО) for 24 hours. A part of the control cultures was treated with water, which was used as a solvent, the other part was not subjected to hypoxia. 1 250 At the final stage of hypoxic treatment, the medium was removed, and the cells were washed twice with cold PB5. . Cell lysates were obtained in 0.05 9565 Triton X-100 containing phosphate buffer (0.05M). After processing by centrifugation (2 minutes, 20,000 X 49), the HON activity of the supernatant was determined based on the consumption of MAOH in the presence of the substrate sodium pyruvate.

The applied hypoxic treatment caused a 3-fold increase in the ION content of the cells. In addition to treating 99 hypoxia, the compounds of formula I increase the level of IOH cells in an additive manner.

GF) Antiviral efficacy t The retroviral genome consists of a single twisted molecule of ribonucleic acid, which creates a copy through a double twisted intermediate link of deoxyribonucleic acid. The introduction of double-stranded deoxyribonucleic acid into the genome of the host is a critical event in the life cycle of the virus. 60 The input mechanism is similar to the regrouping mechanism.

The enzyme reverse transcriptase makes a deoxyribonucleic acid copy of the viral ribonucleic acid. Double twisted deoxyribonucleic acid is synthesized in the cytoplasm of the infected cell.

After that, the linear deoxyribonucleic acid is transported into the nucleus, and one or more copies are integrated into the genome of the host cell. The association is mediated by the enzyme integrase. When virus-infected deoxyribonucleic acid combines, it uses host cell enzymes to make viral ribonucleic acid, which serves as gpCMA and as the genome after packaging into virions.

In the process of virus replication, an undisturbed function of reverse transcriptase is necessary. Thus, inhibition of reverse transcriptase! provides an effective way to inhibit the replication of retroviruses. Some of the currently available drugs against the human immunodeficiency virus (HIV) act by inhibiting reverse transcriptase Currently, the most effective treatments for the human immunodeficiency virus are based on combinations of different anti-HIV drugs. One or two components of these combinations are reverse transcriptase inhibitors. There are two main types of reverse transcriptase inhibitors. Some consist of nucleoside analogues, the well-known representative of this group is azidothymidine, i.e. A7T. These compounds inhibit enzymatic activity by binding to the nucleotide binding site. Non-nucleoside analogues represent another type of reverse transcription inhibitor. These compounds are also bound to the enzyme, but not at the nucleotide binding site. The connection is specific, relatively stable and leads to deformation of the active site of the enzyme, which causes a significant loss of enzymatic activity.

The performance of the compounds of this invention as reverse transcriptase inhibitors was investigated as follows. These 7/5 bpoluks can be classified as non-nucleoside analogues of reverse transcriptase inhibitors. The tests were performed on mouse reverse transcriptase of the Moloney leukemia virus (Moiopeu), which is considered a good model of the HIV reverse transcriptase enzyme. The experimental block was as follows:

The assay measures the incorporation of (ZH) aTTP into cOMA using a poly (dA) template and an oligo (at) 12-18 primer. The reaction was performed in a volume of 20 μl.

The composition of the reaction mixture: 2 μl of 10 X buffer, 20 μl of primer matrix, 5 μm of atter, 2 μCi (ZH) attev, c test compound: dissolved in 1 X buffer.

The reaction was initiated by adding 5) reverse transcriptase. and)

The composition of 10 X buffer of reverse transcriptase: 500 mM Tris - HCI, hydrogen index pH 8.3, 80 mM

MasIi", 300 mm KSI, 100 МЙОТtt.

Acceptable conditions were created for the reaction mixture for 40 minutes at a temperature of 372 C. After that, M 15 μl of the reaction mixture was loaded into a Whatman (MUpaytap) OE81 device with disk filters, which was sequentially washed with 5 95 disodium hydrogen phosphate buffer, water and 96 95 (by mass) ethanol After drying, the filter discs were placed in scintillation cocktail bml (OriPase NiZite 3, UmMaiIas), and the radioactivity was measured with a RuskKaga Tgi-Sag 2200 CE scintillation counter.

As a positive control, the experiments used two compounds with known inhibitory activity: AIT is a nucleoside analogue, while the nevirapine compound (Memigarip) is an inhibitor of the non-nucleoside type. Nevirapine was bound to the so-called benzodiazepine binding site of the enzyme.

The results of the experiments provide the following conclusions:

The compounds of the invention inhibit murine reverse transcriptase of the Moloney leukemia virus (MoiIopeu). Test compounds were used with concentrations of 0.2 - 2.Omkg/ml. On the basis of the dose-dependent reverse transcriptase inhibitory activity, it can be concluded that the inhibitory effect of the new compounds is stronger in comparison with drugs with the activity of nevirapine, but lower than the effectiveness of the nucleoside analogue of AT. Taking into account the fact that the enzyme used is considered a reliable model of HIV reverse transcription, the obtained results "" can be considered effective against human immunodeficiency virus.

Recent data show that poly (adenosine diphosphate ribose) polymerase is required for viral genome integration in the host cell, and inhibition of poly (adenosine diphosphate ribose) polymerase blocks the integration of the viral genome into deoxyribonucleic acid. For this reason, non-toxic inhibitors of poly (adenosine diphosphate ribose) polymerase can inhibit poisonous retroviruses and stop the spread of retroviruses similar to HIV and non-type B hepatitis. Based on the above experimental results, it can be established that the compounds of the invention, 5 due to their inhibitory activity on reverse transcriptase and poly (adenosine diphosphate ribose) polymerase, and can also be used as antiviral active substances with several points of application. "I Thus, new amidoxime derivatives of propenecarboxylic acid can be used as active ingredients of pharmaceutical compositions. Therefore, the invention includes a pharmaceutical composition that contains an unsaturated hydroxamic acid derivative of formula I, or its M-oxide, or a geometric isomer(s) and/or an optical isomer (isomers), or a pharmaceutically acceptable acid-addition salt, and/or a quaternary derivative, as an active ingredient and one or more commonly known carriers used "in iF) pharmaceutical compositions. The pharmaceutical composition of the invention contains, in general, 0.1 - 95 96 by weight, preferably 1 - 50 9Uo by weight, acceptable 5 - 3095 by weight of the active ingredient, and is acceptable for the treatment of diseases based on conditions of oxygen deficiency and energy deficiency, inhibition of poly (adenosine diphosphate ribose) polymerase, especially autoimmune or neurodegenerative or viral diseases, and, in addition, to prevent toxic effects.

In connection with the present invention, the term "active ingredient" includes a compound of formula I or its M-oxide, or one or more geometric or optical isomers of a compound of formula I, or its M-oxide, a pharmaceutically acceptable acid addition salt, and/or a quaternary salt of a compound of formula I, or an M-oxide, or a pharmaceutically acceptable acid addition salt, and/or a quaternary salt of isomers of a compound of formula I or an M-oxide.

The pharmaceutical composition of the invention is suitable for oral, parenteral or rectal administration or for local treatment, and may be in solid or liquid form.

Solid pharmaceutical compositions suitable for oral administration may be powders, capsules, tablets, film-coated tablets, microcapsules, and the like, and may include binders such as gelatin, sorbitol, poly(vinylpyrrolidone), and others. similar to them; fillers such as lactose, glucose, starch, calcium phosphate and others like them; excipients for the manufacture of tablets, such as magnesium stearate, talc, poly (ethylene glycol), silica and the like; wetting agents such as sodium lauryl sulfate and the like as carriers. 70 Liquid pharmaceutical compositions suitable for oral administration may be solutions, suspensions or emulsions and may include, for example, suspending agents such as gelatin, carboxymethyl cellulose and the like; emulsifiers such as sorbitol monooleate and the like; solvents such as water, oil, glycerin, propylene glycol, ethanol and others; preservatives such as methyl p-hydroxybenzoate and the like as carriers.

Pharmaceutical compositions suitable for parenteral administration generally consist of sterile solutions of the active ingredient.

The above dosage forms, as well as other dosage forms, are known in the art, see, for example,

Ketipdiopye Rpagptaseciisa! Zsiepsev, 181st Edyop, Musk Rybiizpipd So., Eaviop, OBA (1990).

The pharmaceutical composition generally contains a dosage unit. A typical dose for sick adults is daily from 0.1 to 1000 mg of the compound of formula I, or its M-oxide, or a pharmaceutically acceptable acid addition salt, and/or a quaternary derivative, per 1 kg of body weight. The daily dose can be administered as one portion or several separate portions. The actual dosage depends on many factors and is determined by the doctor.

The pharmaceutical composition is obtained by displacing the active ingredient and one carrier or from a larger number of carriers, and is converted into a mixture suitable for obtaining a pharmaceutical composition by a method known in the art. Useful methods are known from the literature, for example, Ketipdiopye Rpagtaseciisa! Zsiepsev, about which i) was mentioned above.

A preferred subgroup of the pharmaceutical composition of the invention contains an amidoxime derivative of propenecarboxylic acid of the formula Ia, where K, c", Kz, K, and K" are as defined on the compound of the formula Ia, or its M-oxide, r-zo or geometric isomer ( isomers), and/or an optical isomer (isomers), or a pharmaceutically acceptable acid addition salt, and/or a quaternary derivative thereof, as an active ingredient.

Another preferred subgroup of the pharmaceutical composition of the invention contains an amidoxime derivative of propenecarboxylic acid of the formula IB, where K, K", Kz, KA and K" are as defined on the compound of the formula II, or its M-oxide, or its geometric isomer(s), and/or optical isomer(s), or a pharmaceutically acceptable acid addition salt, and/or a quaternary derivative thereof, as an active ingredient. -

Still another preferred subgroup of the pharmaceutical composition of the invention contains an amidoxime derivative of propenecarboxylic acid of the formula 1c, where EC, B", Ku and B5 are as defined on the compound of the formula Ic, or its M-oxide, or its geometric isomer(s), and/ or an optical isomer(s), or a pharmaceutically acceptable acid addition salt, and/or a quaternary derivative thereof, as an active ingredient.

The invention includes a method of treatment in which a patient who suffers from a special condition associated with - with oxygen deficiency or energy deficiency, or diseases based on inhibition of poly (adenosine and ribose diphosphate) polymerase, especially autoimmune or neurodegenerative disease, or a viral disease, "or a disease caused by a toxic effect is treated with a non-toxic dose of an amidoxime derivative of propenecarboxylic acid of formula I, or its M-oxide, or a geometric isomer, and/or an optical isomer, or a pharmaceutically acceptable acid-addition salt, and/or a quaternary derivative Her. In addition, the invention includes the use of an amidoxime derivative of propenecarboxylic acid of formula I, or its M-oxide, or a geometric isomer, and/or an optical isomer, or a pharmaceutically acceptable acid addition salt, and/or its quaternary derivative, for obtaining a pharmaceutical composition suitable for the treatment of 1 conditions associated with oxygen deficiency or energy deficiency, or diseases based on the inhibition of sl 50 poly (adenosine diphosphate ribose) polymerase, especially an autoimmune or neurodegenerative disease, or a viral disease, or a disease caused by toxic effect." and Further, the invention is explained with the help of the following Examples.

Example 1 3 - Styryl - 4 - (C - piperidinepropyl) - And? - 1, 2, 4 - oxadiazoline - 5 - one chloride hydrate 59 0.94 grams (0.0O05mol) C - styryl - 4 - (3 - piperidinepropyl) - A? - 1, 2,

HF) 4-oxadiazolin-5-one was dissolved in 6 milliliters of acetone, 1.19 grams (0.00 bmol) of 1-chloro-Z-piperidinopropane chlorhydrate, 0.76 grams (0.0055 mol) of anhydrous potassium carbonate, 1 milliliter of methanol and 0.05 grams of potassium iodide. The reaction mixture was heated with reverse cooling for 20 hours, the inorganic salts were filtered and the solution was evaporated under reduced pressure. The residual oily crude product 60 was dissolved in isopropanol, the resulting solution was acidified by addition of hydrogen chloride in isopropanol, the reaction mixture was allowed to settle in a cooler overnight, and the precipitated crystals were filtered off. Thus, 1.05 grams of the title compound were obtained.

Melting point: 203 - 20596.

IR (KV) M o - 2550 - 2650 (MN i, 1768 (СО), 1639 (С-М) st", "Н-ММЕ (0М50-аб6) 5 1.3 - 1.85 (6Н, m, because piperidine - Z , 4, 5-CH»o), 2.11 (2H, m, propyl-CH»), 2.82 (2H, m, piperidine-CH»), 3.09 (2H, m, -CH.-M), 3.36 (2H,

m, piperidine-СНо), 3.87 (2Н, m, -О-СНо), 7.12 (1Н, d, Ag-СНАСН-), 7.4 - 7.5 (ЗН, m, Ag-Н), 7.60 (1Н, d,

Ag-SNASN), 7.8 (2Н, m, Ag), 10.3 (1Н, br, -МН).

Example 2. 3 - Styryl - 4 - (3 - piperidino - 2 - hydroxypropyl) - l2 - 1, 2, 4-oxadiazoline - 5 - well chlorohydrate

A) 2.25 grams (0.008 mol) of Z - styryl - 4 - (Z - chloro - 2 - hydroxypropyl) - d?- 1, 2, 4 - oxadiazolin-5 -one were dissolved in 10 milliliters of ethanol, 0.68 grams were added to the resulting solution (0.008 mol) of piperidine, the mixture was heated to a temperature of 50 °C with stirring and a solution of 0.32 grams (0.008 mol) of sodium hydroxide in 2 milliliters of water was added dropwise. The reaction mixture was stirred at a temperature of 50 - 55 °C for another 2 70 hours, the precipitated crystals were filtered, dried, then dissolved in ethanol when heated, and the resulting solution was acidified by adding hydrogen chloride in isopropanol. The reaction mixture was allowed to settle in a cooler overnight, and the precipitated crystals were filtered and dried. Thus, 1.09 grams of the title compound were obtained. Melting point: 234 - 235 rpm. (Z - Styryl - 4 - (Z - chloro - 2 - hydroxypropyl) - d2 -1, 2, 4 - oxadiazolin - 5 - one, which was used as a starting compound, was obtained by the reaction of Z - styryl - DA? - 1, 2, 4-oxadiazolin-5-one with epichlorohydrin according to the method described in the literature (Spet. Veg., 108, 1911 (1975)). 7"H-MME (0M50-a6) 5 - 1.3 - 1.9 (BN, m, piperidine -3, 4, 5-CH.), 2.9 - 3.6 (BN, m. ZSN»o), 3.8 (2H, m , propyl-1-CH.), 4.35 (IN, m, CH-OH), 6.3 (IN, br, OH), 7.19 (1H, d, ASN-CH), 7.37 - 7.47 (ZN, m, Ag- H), 207.57 (AN, d, A-SNASN-), 7.84 (2H, m, Ag-H), 10.25 (IN, br, "MN).

B) 0.65 grams (0.0027 mol) of З - styryl - 4 - (2, З - epoxypropyl) - ld2 - 1. 2, 4 - oxadiazolin - 5 - one was dissolved in 2 milliliters of methanol, and 0.24 grams (0.0028 mol) of piperidine.

In order for the reaction mixture to become warm, it is allowed to stand for an hour. The precipitated crystals were filtered, then dissolved in isopropanol. The solution was acidified by adding 25% hydrogen chloride in isopropyl. Thus, 0.38 grams of crystals of the title product were obtained, which is (5) identical to the compound obtained in section A. Melting point: 234 -235960. (Z-Styryl - 4 - (2, Z - epoxypropyl) - L2 - 1, 2, 4 - oxadiazolin - 5 - one, which was used as a starting compound, was obtained in the following way: 1.5 grams (0.005 Zmol) Z - styryl - 4 - (Z - chloro - 2 - hydroxypropyl) - 2. - 1, 2, 4 - oxadiazolin - 5 - one was dissolved in 5 milliliters of acetone, 0.73 - 30 grams of anhydrous potassium carbonate were added to the resulting solution, the reaction mixture was heated with reverse cooling for 16 hours, then filtered and evaporated under reduced pressure to give 1.41 grams of C-styryl-4-(2,C-epoxypropyl)-d2-1,2,4-oxadiazolin-5-one as an oil. at

C) 0.3 grams (0.0016 bmol) of C - styryl - l2 - 1, 2, 4 - oxadiazolin - 5 - one was dissolved in 3 milliliters of FO with 5 acetone, 0.41 grams (0.0019 mol) of C - piperidino - 2 - hydroxy was added to the resulting solution - 1 - ich- chloropropane chlorohydrate, 0.48 grams of anhydrous potassium carbonate, 1 milliliter of methanol and 0.05 grams of potassium iodide. The reaction mixture was refluxed for 40 hours, then filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in 5-9% aqueous hydrochloric acid, the solution was filtered, and the filtrate was made alkaline by adding a 1095% aqueous solution of sodium hydroxide. "

The precipitated product was extracted with chloroform, the solution was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in isopropanol and the resulting solution was acidified by adding isopropanol hydrogen chloride. Crystallized 0.18 grams of a product identical to the title product obtained in section A. Melting point: 234 - 23596.

Example 3. - and 3 - Styryl - 4 - (3 - pyrrolidino - 2 - hydroxypropyl) - L2 - 1, 2, 4 - oxadiazolin - 5 - one - hydrochloride with 8.4 grams (0.0 mol) C - styryl - 4 - ( 3 - pyrrolidino - 2 - hydroxypropyl) - AD? - 1, 2, 4-oxadiazolin-5-one was dissolved in 30 milliliters of ethanol, 2.55 grams (0.OZbmol) of pyrrolidine was added to the obtained solution, and then at a temperature of 60 °C, with stirring, 1.2 grams (0.0Zmol) of hydroxide solution was added dropwise sl 50 sodium in 8 milliliters of water. Further, the reaction mixture was stirred for an hour at a temperature of 609C, then ethanol was distilled under reduced pressure. The residue was acidified by adding an aqueous solution of concentrated hydrochloric acid, the solution was treated with activated carbon, filtered and made alkaline by adding a 2M aqueous solution of sodium hydroxide. The precipitated oily product was extracted with chloroform, the organic solution was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in isopropanol, the resulting solution was acidified by adding isopropanol hydrogen chloride. The crystals were filtered and dried. Thus, 1.8 grams of the title compound were obtained. Melting point: 188-18926. o 7TN-MMeE (0М5О0-46) 5 - 1.8-2.0 (4Н, m, pyrrolidine-3, 4-СНо), 3.06 - 3.55 (6Н, m, ЗСН»), 3.82 (2Н, d, propyl-1-СН.), 4.21 (1Н, m, -СН-ОН ), 6.25 (1H, d, -OH), 7.14 (IN, d, A-CH-CH-, 7.4 - 7.5 (ZH, m, Ag-H), because 7.58 (1H, d, AI-СНеСНУ -), 7.82 (2Н, m, Аг), 10.3 (IN, br, МН).

Example 4. 3 - Styryl - 4 - (3 - hexamethyleneimino - 2 - hydroxypropyl) - l2 - 1, 2, 4 - oxadiazolin - 5 - one chlorhydrate 2.8 grams (0.01 mol) C - styryl - 4 - (3 - chloro - 2 - hydroxypropyl) - d? -1, 2, 4-oxadiazolin-5-one 65 was reacted with 1.19 grams (0.012 mol) of hexamethyleneimine according to the method described in Example

C. Chlorohydrate was precipitated in an isopropanol solution by adding hydrogen chloride in isopropanol.

Thus, 1.0 grams of the title compound were obtained. Melting point: 202 - 20396. 7Н-ММЕ (СОСИЗ и- ОМ5О-96) 5 1.6 - 2.0 (8Н, m, hexamethyleneimine-3, 4, 5, 6-СНо), 3.1 - 3. 6 (6Н, m, ZCH"), 3.8 (2H, m, propyl-1-CH"), 4.35 (1H, m, -CH-OH), 6.21 (1H, d, OH), 7.11 (1H, d, Ag-SNACH-) .

Example 5. 3 - Styryl - 4 - (3 - morpholino - 2 - hydroxypropyl) - And? - 1, 2, 4-oxadiazolin-5-one chlorohydrate 4.2 grams (0.015 mol) Z - styryl - 4 - (Z - chloro - 2 - hydroxypropyl) - A? - 1, 2, 4-oxadiazolin-5-one was reacted with 1.6 grams (0.018 mol) of tetrahydrooxazine according to the method described in Example 0 3. Hydrochloric acid was precipitated in an ethanolic solution by adding hydrogen chloride in isopropanol.

Thus, 0.67 grams of the title compound were obtained. Melting point: 232 - 234 26. "H-MME (0М50-а6) 5 - 3.1 - 3.55 (6Н, m, morpholine-3, 5-СНо, propyl-3-СН2), 3.8 -4.0 (BN, m, tetrahydrooxazin -2, 6-CH»o, propyl-1-CH»), 4.37 (1H, m, -CH-OH), 6.3 (1H, br, OH), 7.12 (1H, d, Ag-CH-SNU ), 75.74 (ZH, m, Ag), 7.6 (IN, d, A-SNASN.-), 7.8 (2H, mAh), 10.6 (1H, br, "MH).

Example 6. 3 - Styryl - 4 - (3 - tert.-butylamino - 2 - hydroxypropyl) - L2 - 1, 2, 4 - oxadiazolin - 5 - one chlorhydrate 6.6 grams (0.024 mol) C - styryl - 4 - (3 - chloro - 2 - hydroxypropyl) - LD2 - 1, 2, 4 - oxadiazolin - 5 - one was subjected to a reaction with 2.63 grams (0.03 bmol) of tert.-butylamine according to the method described in Example 3. 20 Chlorohydrate was precipitated in an isopropanol solution by by adding hydrogen chloride in isopropanol.

Thus, 1.8 grams of the title compound were obtained. Melting point: 244 - 24696. 7"H-MME (0M50-96) 5 - 1.3 (9H, s, tert.-butyl), 2.9 - 3.15 (2H, m, propyl-3-CH"), 3.85 (2H , m, propyl-1-CH"), 4.15 (1H, m, CH-O), 6.08 (1H, d, OH), 7.12 (1H, d, Ag-SNACH-), 7.40 (ЗН, m, Ag -H), 7.55 (1H, a, Ag-CH-CH), 7.8 (2H, m, Ag-H), 8.55 (1H, br, MH), 8.85 (1 Н, br, MH). s 25 Example 7 H0) 3 - Styryl - 4 - |Z - (4 - methyl -1 - piperazinyl)) - 2 - hydroxypropyl) - d? - 1,2,4- oxadiazolin - 5 - one dihydrochloride 8.4 grams (0.0 mol) Z - styryl-4-(3-chloro-2-hydroxypropyl)-DL?-1,2,4-oxadiazolin-5-one M 20 was reacted with 3.6 grams (0.03 bmol) of M-methylpiperazine according to the method described in Example 3.

Chlorine hydrate was precipitated in an isopropanol solution by adding hydrogen chloride in isopropanol. / SHUT

Thus, 2.08 grams of the title compound were obtained. Melting point: 206 -20826. oyu 7"H-MME (0М50О-а6) 5 - 2.77 (ЗН, с, СНа), 3.0 - 3.1 (2Н, m, propyl-3-СН»), 3.6 (ВЗН, m, iperazine-СНо), 3.8 (2Н, m, propyl-СНо), 4.23 (IN, m, -CH-OH), 6.2 (1Н, br, ОН), 7.03 (1Н, d, Ag-СНАСН-). 7.4 (ЗН, m, Ag -H), 7.58 at 35 (1H, d, A-SNASN-), 7.77 (2H, m, Ag), 11.8 (2H, 6P, 2x"MH). -

Example 8 3 - Styryl - 4 - |Z - (1. 2, 3. 4 - tetrahydro - 2 - isoquinolyl - 2 - hydroxy - propyl) - l 2 - 1, 2. 4 - oxadiazoline - - one chloride " 2.8 grams (0.0Tmol) Z - styryl - 4 - (Z - chloro - 2 - hydroxypropyl) - To -1, 2, 4 - oxadiazolin - 5 - one was subjected to a reaction with 1.6 grams (0.012mol) 1, 2, Z, 4 - of tetrahydroisoquinoline according to the method o) c described in Example 3. Chlorohydrate was precipitated in an isopropanol solution by adding hydrogen chloride in isopropanol. Thus, 0.83 grams of the title compound were obtained. "Melting point: 208 - 21020. "Н- MME (0М50О-а46) 5 - 3.0 - 3.6 (8H, m, isoquinoline-CH»o, propyl-3-CH»), 3.84 (2H, m, propyl-1-CH»), 4.4 (1 H, m , -CH-OH), 6.3 (IN, br, OH), 7.13 (1H, d, Ag-CH-CH-), 7.2 -7.5 (7H, -1 15 m, AgH), 7.60 (1H, d, Ag-SNASN-), 7.8 (2H, m, Ag-H), 10.6 (1H, br, "MH).

Example 9 o C - Styryl - 4 - | C - (2, 6 - dimethylanilino) - 2 - hydroxypropyl - L2 - 1, 2, 4 - oxadiazolin - 5 - one chlorhydrate with 8.4 grams (0.0 mol) C - styryl - 4 - (Z - chloro - 2 - hydroxypropyl) - LD2 -1, 2, 4 - oxadiazolin - 5 -one was reacted with 4.36 grams (0.03 bmol) of 2, b-dimethylaniline in 50 milliliters of methanol instead of ethanol, according to the method , described in Example 3. Chlorohydrate was precipitated in an isopropanol solution by adding hydrogen chloride in isopropanol, then recrystallized from a mixture of one volume of isopropanol and one volume of ethanol. Thus, 1.62 grams of the title compound were obtained.

Melting point: 182-184 290. 7H-MME (OM5O-46) 5 - 2.44 (6H, s, SNU), 3.16 - 3.53 (2H, m, propyl-3-CH"), 3.86 (2H, m, propyl -1-СНо), 4.21 o (IN, m, CH-О), 6.0 (IN, br, ОН), 7.10 (1Н, d, А-СН-СН-)| " MH"). where Example 10 3 - (3, 4 - Dimethoxystyryl) - 4 - (3 - piperidino - 2 - hydroxypropyl) - A 2-1. 2. 4 - oxadiazolin - 5 - one 60 chlorhydrate 3.4 grams (0.01mol ) C - (3, 4 - dimethoxystyryl) - 4 - (3 - chloro - 2 - hydroxypropyl) - l2 - 1, 2, 4 - oxadiazolin - 5 - one was reacted with 1.02 grams (0.012 mol) of piperidine according to the method, described in Example 3. The hydrochloride was precipitated in an ethanolic solution by addition of hydrogen chloride in isopropanol. Thus, 1.8 grams of the title compound were obtained. Melting point 62: 187-188 C.

1nH-chM (SOSIZ - ЮОМ5О-ab) 5 - 1.4 - 2.0 (6Н, m, piperidine-3, 4, 5-СН»), 3.18 - 3.31 (6Н, m, piperidine - 2,6 -

CH,, propyl - Z - CH"), 3.85 - 3.92 (2H, m, propyl - 1 - CH"), 3.89 (ЗН, с, -ОСН»), 3.96 (ЗН, с, -ОСН») , 4.45 (1H, m,

CH-OH), 6.27 (1H, br, OH), 6.93 (1H, m, AgH), 6.98 (1H, d, Ag-SNACH-), 7.21 (1H, m, AgH), 7.42 (1H, m, Agn), 7.48 (1H, y, A-CH:CH-), 9.8 (1H, br, "MH).

C - (3, 4 - dimethoxystyryl) - 4 - (C - chloro - 2 - hydroxypropyl) - l2 - 1, 2, 4 - oxadiazolin - 5 - one, which was used as the starting compound, was obtained from C - (3, 4 - dimethoxystyryl) - d2 - 1, 2, 4 - oxadiazolin - 5 - one with epichlorohydrin according to the method known in the literature (Set. Veg., 108, 1911 (1975)).

Example 11 3 - Styryl - 4 - |C - (1 - methyl - 4 - piperazinyl) - 2 - hydroxypropyl - D? -1.2.4- oxadiazolin - 5 - one dihydroxychloride 2.0 grams (0.0059mol) C - (3, 4 - dimethoxystyryl) - 4 - (3 - chloro - 2 - hydroxypropyl) - Ll2 - 1, 2, 4 - 75 oxadiazolin - 5-one was reacted with 0.71 grams (0.007imole) of M-methylpiperazine according to the method described in Example 3. The hydrochloride was precipitated in an ethanolic solution by adding hydrogen chloride in isopropanol. Thus, 0.8 grams of the title compound was obtained.

Melting point: 192-193 °C. "H-MME (0M50O-a6) 5 - 2.8 (ZN, c, M-CH"), 3.2 - 3.8 (1OH, m, piperazine-CH»o, propyl-3-CH»o), 3.80 (ZN, c, methoxy), 3.83 (2H, m, ash-1-CH"), 3.86 (ZH, c, OSH"), 4.31 (1H, m, -CH-OH), 6.3 (1H, br, OH ), 7.0 (IN, m, AgH), 7.03 (1H, d, Ag-SNASN-), 7.30 (IN, m, AgH), 7.50 (1IN, m, AgH), 7.51 (1H, d,

Ag-SNESN-), 11.8 (2H, br, 2x "MH). Example 12

Amidoxime M - (Z - piperidino - 2 - hydroxypropyl) cinnamic acid Up to 1.91 g (0.00 bmol) Z - styryl - 4 - (3 - piperidino - 2 - hydroxypropyl) - dg - 1, 2, 4 - oxadiazolin - 5 - one , obtained in accordance with the method described in Example 2, 1Oml of ethanol and 1Oml of 10 95% aqueous sodium hydroxide solution were added, and the reaction mixture was boiled with reverse cooling for 2 hours. Ethanol was evaporated under reduced pressure, the pH value of the residue was set to 8 by adding hydrochloric acid. The aqueous phase was separated from the partially solid product, the residue was dissolved in methanol. Dilution with water resulted in crystallization of 0.79 g of the title compound. Melting point: 114 -115 90. 1H-yaMe (0M5O-ab) 5 - 1.7 - 1.9 (6H, m, piperidine - C, 4, 5-CH"), 2.1 - 2.3 (6H, m, piperidine - 2, 6-CH", - propyl-3-CH"), 3.2 - 3.33 (2H, m, propyl-1-CH.), 3.83 (IN, m, CH-OH), 5.6 (IN, br, OH), 6. 55 (IN, d, yuyu

Ag-SNASN-). 7.15 (1H, d, Ag-SNASNU-), 7.8 -7.32 (ZH, m, AgH), 7.44 (2H, m, AgH).

Example 13

Amidoxime dihydrogen maleate M - (Z - morpholino - 2 - hydroxypropyl) cinnamic acid with

To 2.76 g (0.007B5 mol) of C-styryl-4-(3-morpholino-2-hydroxypropyl)-Ld2-1,2,4-oxadiazolin-5-mone, obtained in accordance with the method described in Example 5, was added 10 ml of ethanol and 10 ml of 10 95 sodium hydroxide solution, and the reaction mixture was boiled with reverse cooling for 2 hours. Ethanol was evaporated under reduced pressure, the pH value of the residue was set to 8 by adding hydrochloric acid. The precipitated oily product was extracted with dichloromethane. the organic solution was dried over anhydrous sodium sulfate, and the solvent was evaporated. Maleate was precipitated in an acetone solution by adding maleic acid. Thus, 1.1 grams of the title compound were obtained. s Melting point: 128-13020. ;" 7"H-MME (SOCIz - OM50O-96) 5 - 2.8 - 3.2 (BH, morpholine-3, 5 - CH", propyl-3-CH"-); 3.3 - 3.8 (6H, m, morpholine -2, 6-CH»o, propyl-1-CHNo), 4.10 (1H, m, CH-OH), 6.05 (4H, c, maleic acid CH), 6.75 (1H, d, A-CH-SNU), 7.30 ( 1Н, и, А-СНАСНУ), 7.3 (ЗН, m, Ан), 7.50 (2Н, m, АН). - and Example 14

Amidoxime trihydrogen maleate M -- |Z - (1 - methyl - 4 - piperazinyl) -2 - hydroxypropyl cinnamic acid about 1.17g (0.0025mol) Z - styryl - 4 - |Z - (4 - methyl - 1 - piperazinyl) - 2-hydroxypropyl)-l2-1,2,4-1 oxadiazolin-5-one obtained according to the method described in Example 7 was reacted with sodium hydroxide according to the method described in Example 13. The maleate was precipitated in a solution acetone

Mn by adding maleic acid. Thus, 0.63 grams of the compound indicated in the title "i" were obtained. Melting point: 142-14390. -СН»о, propyl-3-СНо), 3.31 - 3.42 (2Н, m, propyl-1-СНо), 3.81 (IN, m, СН-ОН), 6.14 (6Н, с, maleic acid СН), 6.90 (1H, d, Ag-SNACH-), 7.28 (1H, 25 d, Ag-SNEASN), 7.4 (3H, m, AgH), 7.65 (2H, m, AgH).

F! Example 15

M - (Z - Morpholino - 2 - hydroxypropyl) - Z, 4 - dimethoxy cinnamic acid amidoxime 3.91 g (0.01 mol) Z - (3, 4 - dimethoxystyryl) - 4 - (3 - morpholino - 2 - hydroxypropyl) - Ll2 - 1,2,4-oxadiazolin-5-one was reacted with 60% sodium hydroxide in accordance with the method described in Example 13. Thus, 1.2 d was obtained as the title compound in the form of an oily product. 7"H-MME (0М50О-а6) 5 - 3.18 - 3.35 (BN, morpholine -3, 5-CH», propyl-3-СНо), 3.60 (2Н, m, propyl-1-СНо), 3.82 (ЗН . , -CH-OH), in 6.98 (1H, d, A-CH-CH-), 7.02 (1H, m, Ag-ZH), 7.24 (1H, m, Ag-2H), 7.35 (1H, d, Ag-CH-ASNU-), 7.40 (1H, m, Ag-6H).

Example 16

C - Styryl - 6 - (piperidinomethyl) - 4H - 5, 6 - dihydro - 1, 2, 4 - oxadiazine

A mixture of 33 ml of ethanol and 33 ml of a 2M aqueous solution of sodium hydroxide was added to 1.65 g (0.004 mol) of C-styryl-4-(3-piperidino-2-chloro-propyl)-LD2-1,2,4-oxadiazolin-5-one hydrochloride , the reacting mixture

Boiled with reverse cooling for 30 minutes with stirring, then evaporated under reduced pressure, and the residue was suspended in 10 ml of water. The crystals were filtered, washed with water and dried. Thus, 1.06 g of the title compound was obtained. Melting point: 147 -14996. 1nH-chM (0M5O-a6) 5 - 1.3 - 1.7 (6H, m, piperidine -3, 4, 5-CH"), 2.3 - 2.7 (BN, m, piperidine -2, 6-CH", 6 -CH»5), 3.25 - 3.6 (2H, m, oxadiazine-5-CH»o), 3.95 (1H, m, oxadiazine-6-CH), 5.0 (1H, br, oxadiazine-4-MH), 6.5 (1H, d, 70 Ag-SNACH-), 6.9 (1H, d, Ag CH-CH-), 7.2 - 7.5 (B5H, m, AgH).

C - Styryl - 4 - (3 - piperidino - 2 - chloropropyl) - AD? - 1, 2, 4-oxadiazolin-5-one chlorohydrate, used as the starting compound, was obtained from 3-styryl-4-(3-piperidino-2-hydroxypropyl)-A? -1, 2, 4-oxadiazolin-5-one chlorhydrate (obtained as described in Example 2) with thionyl chloride in accordance with the method known 75 from the literature |Spet. Veg., 108, 1911 (1975).

Example 17

C - Styryl - 6 - morpholino - methyl - 4H - 5, 6 - dihydro - 1, 2, 4 - oxadiazine dihydrogen maleate

To 1.5 g (0.003 mol) of Z-styryl-4-(3-morpholino-2-chloro-propyl)-l2-1,2,4-oxadiazolin-5-one hydrochloride was added 1 ml of ethanol and 1 ml of 1095 aqueous hydroxide solution of sodium and the reaction mixture 720 was boiled with reverse cooling for half an hour. Ethanol was evaporated under reduced pressure, the residue was acidified with 5 U6 hydrochloric acid.

The resulting solution was treated with activated carbon, filtered and made alkaline by adding a 1095% aqueous solution of sodium hydroxide. The precipitated oily substance was extracted with chloroform, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was dissolved in ethyl acetate and a solution of 0.6 mg of maleic acid in ethyl acetate was added. Go)

Thus, 1.0 g of the title product was obtained. Melting point: 137 С. 3.83 (4H, m, morpholine-2- and -6- СНо), 4.08 (IN, m, 6-СН), 6.18 (4Н, с, maleic acid CH), 6.43 (1Н, d, Ag-СНАСН-) . - chloropropyl) - d2 - 1, 2, 4 - oxadiazolin - 5 - one chlorohydrate, which was used as the starting compound was obtained from 3 - styryl - 4 - (3 - morpholino - 2 - hydroxypropyl) - 42 -1,2,4. CYU - oxadiazoline - 5 - oxy chloride (obtained according to Example 5) by heating it with thionyl chloride, then evaporating the reaction mixture.

Example 18 h-

C - Styryl -6-(1,2, 3, 4- tetrahydro - 2 - isoquinolyl) - methyl - 4H - 5, 6 - dihydro -1, 2, 4 - oxadiazine dihydrogen maleate

Up to 1.1 g (0.0025 mol) C - styryl - 6 - (1, 2, 3, 4 - tetrahydro - 2 - isoquinolyl) - 2 - chloropropyl - Al? - 1,2, 4-" oxadiazolin-5-one chlorhydrate, ml of ethanol and dml of 10 95% sodium hydroxide were added, and the reaction mixture was boiled with reverse cooling for half an hour. Ethanol was evaporated under reduced pressure, and the remainder was dissolved in 595% hydrochloric acid. The solution was treated with activated carbon, filtered, made alkaline by adding 10 95 aqueous sodium hydroxide solution, and extracted with ethyl acetate. The combined ethyl acetate solutions were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in ethyl acetate and 0.36 g of maleic acid was added to the resulting solution. Thus, 0.55 g of the title compound was obtained. Melting temperature: 151-1532C.

Ha 7"H-MME (0M50O-46) 5 - 3.10 (2H, m, isoquinoline-4-CH"), 3.15 - 3.50 (2H, m. oxadiazine-5-CHno), 3.28 - 3.39 (2H, m, oxadiazine-6-SNIM -), 3.44 - 3.6 (2H, m, isoquinoline-3-CH), 4.2 (1H, m, oxadiazine-6-CH), 4.4 (2H, c, other isoquinoline-1-CH») . Н), 7.33 - 7.52 (5Н, m, phenyl Ag-Н). -1, 2, 4 - oxadiazolin - 5 - one chlorhydrate 8.54 g (0.025mol) C - (3, 4 - dimethoxystyryl) - 4 - (3 - chloro - 2 - hydroxypropyl) - l2 -1, 2, 4 - oxadiazolin - 5 - it was dissolved in 40 ml of acetone and 3.46 g (0.025 mol) of anhydrous potassium carbonate was added to the resulting solution. The reaction mixture was boiled with reverse cooling for 6 hours, then cooled,

GI inorganic salts were removed by filtration, the solvent was evaporated under reduced pressure. The precipitate after evaporation was washed with 25 ml of methanol to stimulate crystallization. Thus, 6.5 g of C - (3, 4 - dimethoxystyryl) - 4 - (2, 3 - epoxypropyl) - dg -1, 2, 4 - oxadiazolin - 5 - one were obtained. Melting point: 113 -11596,

15ml of methanol and 0.73g (0.01mol) tert, -butylamine, the reaction mixture was boiled with reverse cooling for 4 hours, then the solvent was evaporated under reduced pressure. The residue was dissolved in 65 Oml of 5 N hydrochloric acid and the solution was filtered from the undissolved residue. The aqueous solution was made alkaline by adding 10 95 aqueous sodium hydroxide solution, the formed oily substance was dissolved in dichloromethane, the solution was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. 1.7 g of an oily product was obtained, the hydrochloride of which was precipitated from ethanol by adding isopropanol containing hydrogen chloride. Thus, 1.0 g of the title compound was obtained. Melting point: 225 - 227 96. 7"H-MME (0М50О-а46) 5 - 1.3 (9Н, с, ХХСН), 2.93 - 3.17 (2Н, m, porpyl-3-CH»о), 3.80 (ЗН, s, -OSN"), 3.85 (ZH, zv, -OSNUZ), 3.9 (2H, d, propyl-1-CH"), 4.16 (1H, m, -CH-OH), 6.12 (1H, d, - OH), 7.03 (1N, d, Ag-SNACH-), 7.51 (1N, d, Ag-SNACH-), 7.00 (1N, m, AgN), 7.29 (1N, m, AgN), 7.49 (1N, m , АН), 8.58 (IN, br, МН), 8.86 (1Н, br, МН).

Example 20 3 - (3, 4 - Dimethoxystyryl) - 4 - (3 - morpholino - 2 - hydroxypropyl) - And? -1.2.4- oxadiazolin-5-one hydrochloride 3.04g (0.01mol) C - (3, 4-dimethoxystyryl) - 4 - (2, C - epoxypropyl) -L2 - 1, 2, 4- oxadiazolin-5-one (obtained as described in Example 19) was reacted with 0.96 g (0.011 mol) of morpholine by the method described in

Example 19. Thus, 0.8 g of the title compound was obtained. Melting point: 228 - 230 20. t 7"H-MME (0М50О-а46) 5 - 3.2 - 3.34 (BN, m, morpholine-3, 5-CH», porpyl-3-CH»o), 3.82 (ЗН . 4.43 (1H, m, -CH-OH), 6.4 (1H, br, -OH), 7.0 (1H, d, AgH), 7.03 (IN, d, Ag-SNACH-), 7.29 (1H, m, AgH ), 7.48 (1H, m, AgH), 7.50 (1H, d, A-CH-CH-), 10.7 (1H, br, "MH).

Example 21

Amidoxim M -- 3 - (2, 6 - Dimethylanilino) - 2 - hydroxypropyl) - cinnamic acid

The procedure described in Example 12 was carried out, with the difference that 1.5 g (0.004 mol) of C-styryl-4-|C-(2, 6-dimethylanilino)-2-hydroxypropyl-d2-1, 2, 4-oxadiazolin-5-one (obtained according to Example 9). Thus, 0.55 g of the title compound was obtained. with

Melting point: 143-144 b. "H-MMA (0М50-а4), 5 - 2.20 (6Н, с, 2хСНа), 2.82 - 3.03 (2Н, m, o porpyl-Z3-CH.), 3.15 -3.27 (2Н, m, propyl-1- CH2), 3.64 (1H, m, -CH-OH), 3.80 (1H, m, MH-aniline), 5.15 (1H, br, -CH-OH). 5.58 (1H, br, MH-amidoxime), 6.68 (1H, d, Ag-CH-CH-), 6.69 (IN, m, AgH), 6.90 (2H, m, AgH), 7.01 (IN, d, A-CH-CH-), 7.25 - 7.55 (5H, m, AgH), 9.57 (1H, 5, -M-OH).

Example 22 -

Amidoxime M - (Z - pyrrolidino - 2 - hydroxypropyl) - cinnamic acid

The procedure described in Example 12 was performed, with the difference that 1.23 g (0.003 Bmol) of C-styryl-4-(3-pyrrolidino-2-hydroxypropyl)-LD2-1,2,4-oxadiazoline-5 was used as the starting material. - onu o (obtained in accordance with Example C). Thus, 0.65 g of the title compound was obtained. (se

Melting point: 139-141 C (from 96 96th ethanol). "H-MME (SOSIZ - OM80-ab) 5 - 1.75 (4H, m, pyrrolidine-3, 4-CH"), 2.50 - 2.64 (6H, m, pyrrolidine-2, 5-CH", propyl-3- CH»o), 3.2 - 3.35 (2H, m, propyl-1-CH»), 3.75 - (1 H, m, CH-OH), 5.6 (1H, T, MH), 6.58 (1H, d , Ag-CH-CH-) 7.08 (1H, d, Ag-SNACH-), 7.25 -7.45 (BN, m, Ag-H), 9.0 (1H, br, -M-OH).

Claims (1)

The formula of the invention is from 1. Amidoxim derivative of propenecarboxylic acid of the formula: ba on- o - - M SN o SHE ONY, s v Psh | : with Mi Ko with p 50 and "Z Kk where K means a C. 2o-alkyl group, a phenyl group, the last of which is optionally substituted with 1-3 substituents, where the substituent is a halogen atom and/or C.. o-alkyl group, and/or C. o-alkyl group, and/or amino group, and/or (C../-alkyl)amino group, and/or di(C..--alkyl)amino group, and/or ( C..-alkanoyl) amino group, or in addition, a 5- or b--linked saturated or unsaturated heterocyclic group, which contains as a heteroatom one or two nitrogen atoms or a sulfur atom, and the indicated heterocyclic group is optionally saturated with one or several benzene rings and/or one or several heterocyclic groups, and K represents a 60 hydrogen atom, or K together with EK" forms a C 1 -cycloalkyl group saturated with a benzene ring, K. and K»5 independently mean a hydrogen atom, Si 5-alkyl group, Si. a 5-alkanoyl group or a phenyl group, the latter of which is optionally substituted with 1-3 substituents, where the substituent is a halogen atom and/or Si. »-alkyl group and/or C. o-alkyl group, or 65 K; and K, together with the adjacent nitrogen atom, form a 5- or b-lane saturated or unsaturated heterocyclic group, which may contain as a heteroatom a nitrogen atom and/or an oxygen atom, and/or a sulfur atom, and may be saturated with a benzene ring, and a heterocyclic group and/or the benzene ring may bear one or two substituents, where the substituent is a halogen atom and/or a C.o-alkyl group, and/or C. o-Alkoxy group, Ku and Co mean a hydrogen atom, and Ez means a hydrogen atom, a hydroxy group or a C. 5-Alkoxy group, or Ku forms together with Co a carbonyl group or a thiocarbonyl group, the carbon atom of which is connected to an oxygen atom, which is adjacent to K/, and with a nitrogen atom which is adjacent to Ko, and Kz means a hydrogen atom, a halogen atom, a hydroxy group, a C. alkoxy group, a C. b-alkylthio group, a C4 ho-alkanoyloxy group, a C3 oz-alkenoyloxy group, / 0 containing one or more double bonds, a methylsulfonyloxy group, a benzenesulfonyloxy group or a toluene-sulfonyloxy group, or ER" is a hydrogen atom, and Ku forms, together with Kz, a valence bond between the carbon atom adjacent to K. and the carbon atom adjacent to Kz, in addition, its M-oxides and/or geometric isomers, and/or optical isomers, and/or pharmaceutically acceptable acid addition salts, and/or quaternary derivatives. 2. The derivative according to point 1, which differs in that it has the formula Ia: in ,Ia ud -ebН--0-МН-- SNU on sna, vo | | ke M pa o s On (o) where Ku and Ko mean a hydrogen atom, Ez means a hydrogen atom, a hydroxy group or a C. 5-alkoxy group, or o E, K, K, and K" are as defined in clause 1, in addition, its M-oxides and/or geometric isomers, and/or optical isomers, and/or pharmaceutically acceptable acid addition salts, and/or quaternary derivatives. Q. The derivative according to point 1, which differs in that it has the formula Ір: со в ва ,ІІ че О В-снН--Я5- МАН sny, и І | | ve: M h e - s M Y A Z . ;" where Ku forms together with Co a carbonyl group or a thiocarbonyl group, the carbon atom of which is bound to it. with an oxygen atom adjacent to K and with a nitrogen atom adjacent to Co, d) Kz means a hydrogen atom, a halogen atom, a hydroxy group, a C. alkoxy group, a C. a 5-alkylthio group, C.i.o-alkanoyloxy group, C.sub.3-alkenoyloxy group containing one or more double bonds, i.th methylsulfonyloxy group, benzenesulfonyloxy group or toluenesulfonyloxy group, "cl 20 X means an oxygen atom or a sulfur atom, E, K, K, and K » are as defined in clause 1, h. in addition, its M-oxides and/or geometric isomers, and/or optical isomers, and/or pharmaceutically acceptable acid addition salts, and/or quaternary derivatives. 4. The derivative according to point 1, which differs in that it has the formula I: , and Ku forms, together with Kz, a valence bond between the oxygen atom adjacent to K and the carbon atom adjacent to Kz, E, K, K, and K" are as defined in point 1, in addition, its M-oxides and/or geometric isomers, and/or optical isomers, and/or pharmaceutically acceptable acid addition salts, and/or quaternary derivatives. 5. The method of obtaining the amidoxime derivative of propenecarboxylic acid of formula I, where K, K, K., Ko, Kz, Ki and K5 are as defined in point 1, in addition, its M-oxides, pharmaceutically acceptable acid-addition salts and quaternary derivatives, which differs in that 70 a) to obtain the amidoxime derivative of propenecarboxylic acid of the formula Ia, where K 4, Ko and Kz mean a hydrogen atom, K, K, K,. and K" are as defined in the compound of the formula I, a propene derivative of the formula: Бе ; 5 es -zhen-yat - km -yatn-- sn -s ni-, y | | ve In zhk! where K, K, Kz, Ku and K" are as defined above, U means a halogen atom or a group of the formula -ZKv, where Ko means a hydrogen atom or a C..-alkyl group, react with hydroxylamine, or B) for obtaining the amidoxime derivative of propenecarboxylic acid of the formula Ia, where K. and Ko mean a hydrogen atom, Kz means a hydrogen atom or a hydroxy group, K, K, K,. and K" are as defined in the compound of formula I, an oxadiazoline derivative of formula IB, where K, K, Kz, K, and K" are as defined above, X represents an oxygen atom or a sulfur atom, is reacted with aqueous alkaline hydroxide solution, or o c) to obtain the amidoxime derivative of propenecarboxylic acid of the formula IB, where K z means a hydrogen atom, X means an oxygen atom, K, K, K,. and K»5 are as defined in the compound of formula I, the derivative of A21, 2, 4-oxadiazoline of the formula: h- ; 10) Ak oyu urttevtetttn so v TI M -o i - z- 20 where K and K' are as defined above, react with aminoylkylgthalide of the formula: - с m ;» "4 7-сн--сНА-с5б-- M v -I a so g 1 where 7 means a halogen atom, Kz, EK. and K" are as indicated above, or else a) to obtain the amidoxime derivative of propenecarboxylic acid of the formula Ir, where Kz means a hydrogen atom and a hydroxy group, X means an oxygen atom, K, K, Ku and Kv are as defined in the compound of the formula I, a dg-1,2,A-oxadiazoline derivative of the formula I, where K and K are as indicated above, react with 1,3-dihalopropane of the formula: о выл 7Х--сн.-с8-сНИ72 ем 6о and where 7 and 74 independently mean a halogen atom, Kz is as indicated above , and the obtained LA, 2, 4-oxadiazolinyl alkyl halide of the formula: b5 ;M Kk m s--snNA - О - - 5 - o5 Р s A - sn ;l- 2 2 M s-B-0 Kz for where E, K, KE" and 2 are as indicated above, undergo reactions with an amine of the formula: ; MI i5 Ж ke de Ka and K» are as mentioned above, or f) to obtain an amidoxime derivative of propenecarboxylic acid of the formula Ir, where K z means a hydroxy group, X means an oxygen atom, K, K, K,; and Co are as defined in the compound of formula I, the lg-1,2,4-oxadiazoline derivative of formula IS, where K and K are as indicated above, are reacted with epichlorohydrin, and the formed A21, 2, 4-oxadiazolinylalkyl chloride formula: ch 29 in UP Ge) re snK-A-s-ya-k-snU - sn sn. with! cha y ve M s-o Fe yu - a oyu so where K and K are as indicated above, react with an amine of the formula MII, where Ku, and K5 are as - indicated above, or i) to obtain a derivative oxadiazoline of the formula IB, where K z represents a hydroxy group, X represents an oxygen atom, K, K, K, and K" are as defined in the compound of the formula Y, d-1,2,4-oxadiazolinalkyl chloride of the formula MI, where "K and K' are as indicated above, are subjected to a reaction with an acidic binder, and the formed epoxide of the formula: y y di b-- sno SHUM ZsNY sn svra t Ia so M s-o sluya s 50 "and where K and K' are as indicated above, react with an amine of the formula MYI, where K/; and K" are as indicated above, or 9) to obtain an oxadiazoline derivative of the formula IB, where K z means a hydrogen atom or a hydroxy group, X means an oxygen atom or a sulfur atom, K, KK, K, and K5 are as defined in the compound of the formula I, the amidoxime derivative of the propenecarboxylic acid of the formula Ia, where K, K, Kz, Ku and Kb are as indicated above, are subjected to a reaction with the derivative of the carboxylic acid of the formula: where X is as defined above, 725 and 73 independently represent a halogen atom, a C 1 -C 1 -alkyl group, or C..-alkyl mercapto group, or P) to obtain an oxadiazine derivative of the formula Is, where K, K, K; and Co are as defined in a compound of formula I, an oxadiazoline derivative of formula IB, where K, K, K, and K5 are as defined above, X represents an oxygen atom or a sulfur atom, Kz represents a halogen atom, a methylsulfonyloxy group, a benzene- a sulfonyloxy group or a toluenesulfonyloxy group is subjected to a reaction with alkaline hydroxide in the presence of water, or i) to obtain an oxadiazine derivative of formula I, where K, K, K; and K5 are as defined in the compound of the formula I, the cyclic compound of the formula: ,х! о в / о уб--сн-с5ю кн» и TI из хуртя where K and K are as indicated above, K 7 means a halogen atom, a methylsulfonyloxy group, a benzenesulfonyloxy group or a toluenesulfonyloxy group are subjected to a reaction with an amine of the formula MIiY, where EK, Yes; are as stated above, or І) to obtain the quaternary derivative formula: Op. where K, K, Ku, Ko, Kz, Ka and K" are as defined in the compound of formula I, Ka means a C..i.-alkyl group or - phenyl (C..4-alkyl) group, X means a halogen atom or a group of the formula Ka'a-50,, where Ka is as indicated above, a dg-1,2,4-oxadiazoline derivative of the formula IS, where K and K are as indicated above, are reacted with a quaternary alkyl halide of the formula : « m" ; ЧП З с г» и ' gsnai t entsNe M | / ke -I Kz P (95) 1 where Kz, Ka, KB, Kv and U are as indicated above, 7 means a halogen atom, or sl 50 k) to obtain the M-oxide of the formula: what Ov. where K, K, Ku, Ko, Kz, Ku; and K»5 are as defined in the compound of formula I, the d-1,2,4-oxadiazoline derivative 65 of formula I, where K and K' are as defined above, is reacted with a compound of the formula: o , ХУ І /tya g-tony-en-- sny Not where Ku, Ku. and Kb are as indicated above, 7 means a halogen atom, and, if necessary, the resulting compound of formula IB, where Kz is a hydroxy group, K, K", Ku; and K"5 are as defined in the compound of formula I, X means an oxygen atom or a sulfur atom, is reacted with a halogenating agent to give a compound of formula IB, where Kz is a halogen atom, or, if desired, a compound of formula IB, where Kz is a hydroxy group, K, K,, Ku and K" are as follows , as defined in the compound of the formula I, X represents an oxygen atom or a sulfur atom, is reacted with a C.4.2o-alkanecarbon halide or a C.sub.3.oo-alkenecarbon halide containing one or more double bonds to give a compound of the formula IB, where Kz is a C1-20-alkanoyloxy group or a C3 o-alkenoyloxy group, or, if necessary, the resulting compound of formula IB, where Kz is a hydroxy group, K, K1, Ku and K" are as defined in the compound of formula I , X represents an oxygen atom or a sulfur atom, is subjected to a reaction with a C6-alkyl halide, which gives a compound of the formula IB, where Kz means C. c-alkyl groups in, or if necessary, the obtained compound of the formula IB, where Kz means a halogen atom, K, K, K, and K are as defined in the compound of the formula I X means an oxygen atom or a sulfur atom, is subjected to a reaction with an alkaline salt C.. 56-alkanol or C. 5-tiedalkanol, which gives a compound of the formula Ir, where Kz means a C 5-alkyl group or c 29 C. b-alkylthio group, or if necessary, the obtained compound of the formula IB, where Kz means a hydroxy group, K, K, K, and K are as defined in a compound of formula I, X represents an oxygen atom or a sulfur atom, is reacted with methylsulfonyl halide, benzenesulfonyl halide, or toluenesulfonyl halide to give a compound of formula II, where Kz represents a methylsulfonyloxy group, a benzenesulfonyloxy group, or a toluenesulfonyloxy group , and - if necessary, the obtained compound of formula I is subjected to a reaction with an inorganic or organic acid, which gives MU a pharmaceutically acceptable acid-addition salt, or the base is freed from its acid-addition salt, and/or one or more nitrogen atoms of the compounds of formula I are quaternized with the help of an alkylating agent, and/or the compound of formula I is subjected to a reaction with an oxidizing agent, which leads to the transformation of one or more nitrogen atoms into M-oxide. 3o 6. A pharmaceutical composition containing an amidoxime derivative of propenecarboxylic acid of formula I, where K, - K, Ku, Ko, Kz, Ku. and K5 are as defined in point 1, or its M-oxide, or geometric isomers and/or optical isomers or a pharmaceutically acceptable acid addition salt, and/or its quaternary derivative, as an active ingredient and one or more generally known carriers " 7. The pharmaceutical composition according to point 6, containing an amidoxime derivative of propenecarboxylic acid of the formula Ia, where K, K, Kz, K, and K5 are as defined in point 2, or its M-oxide, or geometric c) c isomers and /or optical isomers, or a pharmaceutically acceptable acid addition salt, and/or its quaternary derivative, as an active ingredient. " 8. The pharmaceutical composition according to item 6, containing an amidoxime derivative of propenecarboxylic acid of the formula IB, where K, K, Kz, K/, K5 and X are as defined in item C, or its M-oxide, or geometric isomers, and/or optical isomers, or a pharmaceutically acceptable acid-addition salt, and/or its quaternary X- derivative as an active ingredient. Ha 9. A pharmaceutical composition according to point b, containing an oxadiazine derivative of the formula Is, where K, K, K, . and K5 are as defined in point 4, or its M-oxide, or geometric isomers, and/or optical isomers, or a pharmaceutically acceptable acid addition salt, and/or its quaternary derivative, as an active ingredient. 50 10. Pharmaceutical use of an amidoxime derivative of propenecarboxylic acid of formula I, comprising the administration of a non-toxic amount of an amidoxime derivative of propenecarboxylic acid of formula I, where K, K, K., K»o, "M Kz, Ka and K"5 are as defined in item 1, or its M-oxide, or geometric isomers, and/or optically x isomers, or a pharmaceutically acceptable acid addition salt, and/or a quaternary derivative thereof, to a patient suffering from a condition associated with oxygen deficiency and/or energy deficiency, or a disease based on the inhibition of poly(adenosine diphosphate -ribose) polymerase, mainly autoimmune or HF) neurodegenerative disease, and/or viral disease, and/or disease arising as a result of toxic exposure. and 11. Use of an amidoxime derivative of propenecarboxylic acid of the formula I, where K, K, K., Ko, Kz, Ka and K5 are as defined in point 1, or its M-oxide, or geometric isomers, and/or optical isomers . ribose) polymerase, mainly autoimmune or neurodegenerative disease, and/or viral disease, and/or disease resulting from toxic exposure. b5 Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 8, 15.08.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s o cha yu IS) so m. shi s with -I (95) 1 s 50 what Ф) ime) 60 b5