Derivatives of propene carboxylic acid amidooximes, method for their preparing and pharmaceutical compositions comprising thereof

FIELD: organic chemistry, chemical technology, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

9 cl, 1 tbl, 41 ex

 

The technical field of the invention

The invention relates to new derivatives amidoximes propenylboronic acids, the method of receiving and containing pharmaceutical compositions. The new compounds possess valuable pharmaceutical effect, so they can be used in conditions associated with energy shortages cells, in conditions of oxygen deficiency of the heart and the brain, neurodegenerative diseases, in the treatment of autoimmune and/or viral diseases, moreover, diseases caused by the toxic effects.

Prerequisites to the creation of inventions

Getting some derivatives Δ2-1,2,4-oxadiazole-5-it is described in the publication Chem. Ber.,103, 2330-2335 (1970) without any reference to their possible biological properties. Of the above compounds preparation of derivatives of 5,6-dihydro-4H-1,2,4-oxadiazine discussed in publications Chem. Ber.,108, 1911-1923 (1975) and again without any reference to biological properties.

Derivatives of 1,2,4-oxadiazoline-5-she has a peripheral vasodilator, antistenocardin and antiarrhythmic actions are disclosed in HU-P No. 179951. Derivatives of 1,2,4-oxadiazine with peripheral vasodilator and blood pressure-lowering, anti-arrhythmic, weak anti-inflammatory and diuretic actions, RA is covered in HU-P No. 180708. However, the known derivatives of 1,2,4-oxadiazoline-5-she 1,2,4-oxadiazine not contain any alkenyl substituents, i.e. they cannot be derived amidoxime propenylboronic acid.

The aim of the invention is to provide new compounds having valuable pharmaceutical properties.

Summary of invention

It has been found that the above objective is achievable, and, therefore, the invention relates to new derivatives amidoximes propenylboronic acids of the formula

where

R means (C1-C20)alkyl group, phenyl group, the latter optionally substituted by 1-3-substituents, where the Deputy is an atom of halogen and/or (C1-C2)alkyl group, and/or (C1-C2)alkoxygroup, and/or amino group, and/or (C1-C4)alkylamino, and/or di(C1-C4)alkylamino, and/or (C1-C4)alkanolamines, in addition, 5 - or 6-membered saturated or unsaturated heterocyclic group containing one or two nitrogen atom or a sulfur atom as a heteroatom, and said heterocyclic group optionally is condensed with one or more benzene rings and/or one or more heterocyclic groups, and

R' means and what Ohm hydrogen, or

R together with R' forms (C5-C7)cycloalkyl group optionally condensed with a benzene ring,

R4and R5independently from each other mean a hydrogen atom, (C1-C5)alkyl group, (C1-C5)alkanoyloxy group or phenyl group, the latter optionally substituted by 1-3-substituents, where the Deputy is an atom of halogen and/or (C1-C2)alkyl group, and/or (C1-C2)alkoxygroup, or

R4and R5form together with the adjacent nitrogen atom a 5 - or 6-membered

saturated or unsaturated heterocyclic group which may contain an additional nitrogen atom and/or oxygen atom and/or sulfur atom as a heteroatom and may be condensed with a benzene ring, and the heterocyclic group and/or the benzene ring may contain one or two substituent, where the Deputy is an atom of halogen and/or (C1-C2)alkyl group, and/or (C1-C2)alkoxygroup,

R1and R2means a hydrogen atom, and

R3means a hydrogen atom, a hydroxy-group or (C1-C5)alkoxygroup, or R1forms together with R2carbonyl group or thiocarbonyl group, a carbon atom which is connected with the adjacent R1an oxygen atom and adjacent to R2 the nitrogen atom, and

R3means a hydrogen atom, a halogen atom, a hydroxyl group, (C1-C5)alkoxygroup, (C1-C5)allylthiourea, (C1-C20)alkanoyloxy, (C3-C22)alkanoyloxy containing one or more double bonds, methylsulfonylamino, benzolsulfonate or toluensulfonate, or

R2means a hydrogen atom, and

R1together with R3forms a valence bond between adjacent R1an oxygen atom and adjacent to R3carbon atom, in addition to N-oxides or geometric isomers and/or optical isomers and/or pharmaceutically acceptable acid additive salts and/or their Quaternary derivatives.

Description of the preferred embodiment variants of the invention

In the description and the claims under (C1-C20)alkyl group refers to, for example, methyl, ethyl, n-sawn, ISO-propyl, n-bucilina, Deut.-bucilina, tert.-Butina, isobutylene, n-pencilina, n-exilda, n-heptylene, n-decile, Godzilla, hexadecimally, octadecyl group, etc.

The halogen atom is primarily a fluorine atom, chlorine or bromine, preferably chlorine atom or bromine.

(C1-C2)alkyl group means methyl or ethyl is the Rupp, while (C1-C2)alkoxygroup means metaxylene or ethoxyline group.

(C1-C4)alkyl group means methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, Deut.-boutelou, tert.-Botelho or isobutylene group. In addition to the above-mentioned groups (C1-C5)alkyl group may be, for example, n-Pintilei group.

(C1-C4)alkylamino means, for example, methylaminopropyl, ethylamino, isopropylamino etc. Di(C1-C4)alkylamino means, for example, dimethylaminopropyl, diethylaminopropyl, methylisoborneol etc.

(C1-C4)alcoolica group means preferably formyl group, acetyl group, n-propionyloxy group or n-butyryloxy group. In addition to the above-mentioned groups (C1-C5)alcoolica group may be, for example, n-pentanone group.

Five - or six-membered saturated or unsaturated heterocyclic group containing one or two nitrogen atom or a sulfur atom as a heteroatom, mean, for example, pyrrolidinyl group, pyrazolidine group, imidazolidinyl group, thienyl group, pyridyloxy group, piperidino group, pyramidalnou group, piperazinilnom group, etc.

(C5-the 7)cycloalkyl group optionally condensed with a benzene ring, means, for example, cyclopentyloxy group, tsiklogeksilnogo group, cycloheptyl group, indenolol group or tetralinyl group.

Five - or six-membered saturated or unsaturated heterocyclic group, which in addition to the nitrogen atom adjacent to the substituents R4and R5may contain an additional nitrogen atom, and/or an oxygen atom and/or sulfur atom as heteroatoms, in addition to the above groups may be, for example, morpholinopropan.

(C1-C20)alkanoyloxy means, for example, formyloxy, acetoxy, propionyloxy, butyryloxy, caprolactum, palmitoylated, stearylamine etc.

As a rule, (C3-C32)alkanoyloxy may contain 1-6 double bonds, and preferably means linolenicacid, lipoleiomyoma, docosahexaenoate, eicosapentaenoate or arachidonoylglycerol.

Pharmaceutically acceptable acid additive salt derivatives amidoximes propenylboronic acids of formula I and their N-oxides mean acid additive salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. or organic acids, such as acetic acid, fumaric acid, lactic acid, tartaric acid, succinic acid, malic acid, benzolsulfonat acid, p-toluensulfonate acid, etc.

In the Quaternary derivatives of the compounds of formula I and their N-oxides of one atom of nitrogen or more amidoxime propenylboronic acid quaternized, ie, for example, additional (1-C4)alkyl group or phenyl(C1-C4)alkyl group is associated with this nitrogen atom, therefore, the said nitrogen atom becomes positively charged. Of the nitrogen atoms present in the compound of formula I, respectively quaternized one nitrogen atom adjacent to the substituents R4and R5. If in the formula I the substituent R denotes heterocyclic group containing a nitrogen atom, such as Peregrina group, the nitrogen atom mentioned heterocyclic groups may also quaternization.

In the N-oxides of compounds of formula I one atom of nitrogen or more is/are present in the oxidized form, therefore, the oxygen atom is also linked to the nitrogen atom. Of the nitrogen atoms present in the compound of formula I, respectively, the nitrogen atom adjacent to the substituents R4and R5may be present as N-oxide. If in the formula I the substituent R denotes heterocyclic group, which contains asuu the nitrogen atom, such as Peregrina group, the nitrogen atom mentioned heterocyclic groups may also be present as N-oxide.

Due to the presence of double bonds in the new derivatives of the formula I propenylboronic acids of the formula I, and their N-oxides can exist in the form of geometrical isomers, i.e. CIS - or TRANS-isomers or mixtures thereof. The invention includes pure geometric isomers and any mixtures thereof.

In addition to geometric isomerism some compounds of formula I, and their N-oxides contain one or more chiral carbon atoms, therefore, these compounds may also exist in the form of optical isomers. The invention also includes the pure optical isomers and any mixtures thereof.

A preferred subgroup of compounds according to the invention are derived amidoximes propenylboronic acids of the formula

where

R1and R2means a hydrogen atom,

R3means a hydrogen atom, a hydroxy-group or (C1-C5)alkoxygroup,

R, R', R4and R5have the above meanings, in addition, their N-oxides or geometric isomers and/or optical isomers and/or pharmaceutically acceptable acid additive salts and/or Quaternary derivatives.

Another preferred subgroup connection is according to the invention are derived oxadiazoline formula

where

R1and R2together form a carbonyl group or thiocarbonyl group, a carbon atom which is linked to the oxygen atom adjacent to R1and with the nitrogen atom adjacent to R2,

R3means a hydrogen atom, a halogen atom, a hydroxy-group, (C1-C5)alkoxygroup, (C1-C5)allylthiourea, (C1-C20)alkanoyloxy, (C3-C22)alkanoyloxy containing one or more double bonds, methysulfonylmethane, benzolsulfonate or toluensulfonate,

X means an oxygen atom or a sulfur atom,

R, R', R4and R5matter in accordance with formula I,

in addition, their N-oxides or geometric isomers and/or optical isomers and/or pharmaceutically acceptable acid additive salts and/or Quaternary derivatives.

More preferred subgroup of compounds according to the invention are derived oxadiazine formula

where

R2means a hydrogen atom, and

R1and R3together form a valence bond between the oxygen atom adjacent to R1and the carbon atom adjacent to R3,

R, R', R4and R5matter in accordance with formula I, in addition, their N-oxides isogeometric isomers, and/or optical isomers and/or pharmaceutically acceptable acid additive salts and/or Quaternary derivatives.

Derivatives amidoximes propenylboronic acids of the formula I get the following:

(a) to obtain the derived amidoxime propenylboronic acid of formula Ia, where R1, R2and R3means a hydrogen atom, R, R', R4and R5matter in accordance with formula I, derived propene of the formula

where

R, R', R3, R4and R5have the meanings given above,

Y means a halogen atom or a group of the formula-SR6in which

R6means a hydrogen atom or (C1-C4)alkyl group, is reacted with hydroxylamine; or

(b) to obtain the derived amidoxime propenylboronic acid of formula Ia, where R1and R2means a hydrogen atom, R3means a hydrogen atom or a hydroxy-group, R, R', R4and R5matter in accordance with formula I, derived oxadiazoline formula Ib, where R, R', R3, R4and R5have the meanings given above, X denotes an oxygen atom or a sulfur atom, is reacted with an aqueous solution of alkali metal hydroxide; or

(C) to obtain the derived oxadiazoline formula Ib, where R3means a hydrogen atom, X denotes the atom to which Sloboda, R, R', R4and R5matter in accordance with formula I, derived Δ2-1,2,4-oxadiazoline formula

where

R and R' have the above meanings, is reacted with aminoalkylation formula

where

Z means a halogen atom,

R3, R4and R5have the above meanings; or

(g) to obtain the derived oxadiazoline formula Ib, where R3means a hydrogen atom or a hydroxy-group, X means an oxygen atom, R, R', R4and R5matter in accordance with formula I, derived Δ2-1,2,4-oxadiazoline formula III, where R and R' have the above meanings, is reacted with 1,3-dialogprepare formula

where

Z and Z1means independently of each other a halogen atom,

R3has the above value,

and received Δ2-1,2,4-oxadiazolidine formula

where

R, R', R3and Z have the above meanings, is reacted with an amine of the formula

where R4and R5have the above meanings; or

(d) to obtain the derived oxadiazoline formula Ib, where R3means a hydroxy-group, X means an oxygen atom, R, R', R4 and R5matter in accordance with formula I, derived Δ2-1,2,4-oxadiazoline formula III, where

R and R' have the above meanings, is reacted with epichlorohydrin, and the resulting Δ2-1,2,4-oxadiazolidine formula

where

R and R' have the above meanings, is reacted with an amine of the formula VII, where

R4and R5have the above meanings; or

(e) to obtain the derived oxadiazoline formula Ib, where R3means a hydroxy-group, X means an oxygen atom, R, R', R4and R5matter in accordance with formula I, Δ2-1,2,4-oxadiazolidine formula VIII

where R and R' have the meanings described above, is reacted with an agent that binds acid, and the resulting epoxide of the formula

where R and R' have the above meanings, is reacted with an amine of the formula VII, where R4and R5have the above meanings; or

(W) to obtain the derived oxadiazoline formula Ib, where R3means a hydrogen atom or a hydroxy-group, X means an oxygen atom or a sulfur atom, R, R', R4and R5matter in accordance with formula I, derived amidoxime propenylboronic acid of formula Ia, where R, R', R3, R4and R5have the meanings set is installed above reacts with a carboxylic acid derivative of the formula

where

X is above a certain value,

Z2and Z3means independently of each other a halogen atom, (C1-C4)alkoxygroup or (C1-C4)allylmercaptan; or

(C) to obtain the derived oxadiazine formula Ic, where R, R', R4and R5matter in accordance with formula I, derived oxadiazoline formula Ib, where R, R', R4and R5have the above meanings, X means an oxygen atom or a sulfur atom, R3means a halogen atom, methysulfonylmethane, benzolsulfonate or toluensulfonate, reacts with alkali metal hydroxide in the presence of water; or

(and) when deriving oxadiazine formula Ic, where R, R', R4and R5matter in accordance with formula I, a cyclic compound of the formula

where

R and R' have the meanings given above,

R7means a halogen atom, methysulfonylmethane, benzolsulfonate or toluensulfonate, reacts with the amine of formula VII, where R4and R5have the meanings stated above; or

(K) to obtain the Quaternary derivative of the formula

where

R, R', Rsub> 1, R2, R3, R4and R5matter in accordance with formula I,

R8means (C1-C4)alkyl group or phenyl(C1-C4)alkyl group,

Y means a halogen atom or a group of the formula R8-SO4in which R8has stated above values

derived Δ2-1,2,4-oxadiazoline formula III, where R and R' have the above meanings, is reacted with Quaternary alkylhalides formula

where

R3, R4, R5, R8and Y have the above values,

Z means a halogen atom; or

(l) to obtain the N-oxide of the formula

where

R, R', R1, R2, R3, R4and R5matter in accordance with formula I, derived Δ2-1,2,4-oxadiazoline formula III, where R and R' have the above meanings, is reacted with a compound of formula

where

R3, R4and R5have the above values,

Z means a halogen atom; and

if necessary, the resulting compound of formula Ib, where R3means a hydroxy-group, R, R', R4and R5matter in accordance with formula I, X represents an oxygen atom or a sulfur atom, is reacted with palodiruyut agent to obtain compounds is of formula Ib, where R3means a halogen atom; or if necessary, the resulting compound of formula Ib. where R3means a hydroxy-group, R, R', R4and R5matter in accordance with formula I, X represents an oxygen atom or a sulfur atom, reacts with halogenerator (C1-C20)alkenylboronic acid or halogenerator (C3-C22)alkenylboronic acid containing one or more double bonds, to obtain the compounds of formula Ib, where R3means (C1-C20)alkanoyloxy or (C3-C22)alkanoyloxy; or if necessary, the compound of formula Ib, where R3means a hydroxy-group, R, R', R4and R5matter in accordance with formula I, X represents an oxygen atom or a sulfur atom, is reacted with (C1-C5)alkylhalides to obtain the compounds of formula Ib, where R3means (C1-C5)alkoxygroup; or if necessary, the resulting compound of formula Ib, where R3means a halogen atom, R, R', R4and R5matter in accordance with formula I, X means

an oxygen atom or a sulfur atom, is reacted with an alcoholate of an alkali metal (C1-C5)alkanol

or (C1-C5)thioalkyl to obtain the compounds of formula Ib, where R3means (C1-C5)alkoxygroup or (C1 5)allylthiourea; or

if necessary, the resulting compound of formula Ib, where R3means a hydroxy-group, R, R', R4and R5matter in accordance with formula I, X represents an oxygen atom or a sulfur atom, reacts with methanesulfonamido, benzolsulfonate or toluensulfonate to obtain the compounds of formula Ib, where R3means methanesulfonyl group, benzosulfimide group or toluensulfonyl group; and if necessary, the resulting compound of formula I is reacted with an inorganic or organic acid to obtain a pharmaceutically acceptable acid additive salt or base is released from its acid salt additive, and/or one or more nitrogen atoms, the compounds of formula I form a Quaternary salt with an alkylating agent, and/or

the compound of formula I is reacted with an oxidizing agent to convert one or

several of their nitrogen atoms in the N-oxide.

In method (a) according to the invention the reaction of a derivative of propene of the formula II with hydroxylamine is carried out in a solvent or solvent mixture, using hydroxylamine-based, which can also be isolated in free form in situ from the acid additive salt adding strong bases. The resulting product of the formula Ia distinguish known from su is estu way for example, by crystallization from the reaction mixture or by evaporation of the reaction mixture, or by precipitation of the acid additive salt.

If using a derivative of propene of the formula II where Y represents a halogen atom, the solvent is anhydrous inert organic

solvent, e.g. halogenated hydrocarbons such as chloroform, dichloromethane and

so, hydrocarbons, such as benzene, toluene, etc. or any other solvent

commonly used in acylation reactions, such as pyridine.

If using a derivative of propene of the formula II where Y represents a group of the formula-SR6in addition to the types of the solvents listed above as the organic solvent can be used, for example, alkanols.

Derived propene of the formula II where Y represents a halogen atom, as

the rule,

the chlorine atom, - in reality, mentioned connection is midollo, as a rule, imidocloprid receive from the corresponding

amide acid of the formula

where

R, R', R4and R5matter in accordance with formula I,

R3means a hydrogen atom or (C1-C5)alkoxygroup,

reaction with palodiruyut agent, respectively, with thionyl chloride,

trichloride phosphorus, pentol the reed phosphorus, etc. according to the method known from the literature.

Derived propene of the formula II where Y means mercaptopropyl can be obtained, for example, from the corresponding acid amide of the formula XVI and pentasulfide phosphorus in an organic solvent, such as toluene, xylene or pyridine according to the method known from the literature. Derived propene of the formula II where Y means allylthiourea receive interaction derived propene of the formula II where Y means mercaptopropyl, with an alkylating agent.

In method (b) according to the invention oxadiazoline ring open, using the technique known from Chem. Ber., 103. 2330-2335 (1970), which is alkaline hydrolysis in an aqueous environment. As a hydroxide of an alkali metal, respectively, using potassium hydroxide or sodium hydroxide, to the aqueous solution which, if necessary, to add an organic solvent, preferably an aliphatic alcohol, such as methanol or ethanol. In the method according to the invention oxadiazoline ring open at the boiling temperature of the reaction mixture in the short term and the compound of formula Ia get with a good yield. The reaction product can be allocated is known for being the way as described in connection with method (a).

In method (C) according to the invention the reaction is carried out in an organic solvent, which is inert with that is key view part in the reaction, in the presence of an agent that binds acid, usually at the boiling temperature of the reaction mixture. The inert organic solvent is, for example, alkanol, such as methanol or ethanol, hydrocarbons such as benzene, toluene or xylene, or a mixture. As the acid acceptor can be used inorganic or organic bases. The reaction mixture can be processed by conventional means, for example, the solvent evaporated, and the product crystallizes or precipitates in the form of its acid salt additive.

Derivatives Δ2-1,2,4-oxadiazoline formula III can be obtained from the appropriate amidoxime interaction with derivatives of carboxylic acids. Some representatives amidoximes known from the publication Chem. Rew.,62, 155 (1962). New amidoxime can be obtained from the corresponding nitrile propenylboronic acid interaction with hydroxylamine by the method described in this article. Most of aminoalkylation formula IV are known compounds which are either commercially available or can be obtained in a simple manner by the interaction of 1,3-dialogprepare with the amine of formula VII.

In method (d) according to the invention as alkylation, i.e. the reaction of the derived Δ2-1,2,4-oxadiazoline formula III with 1,3-dialogprepare formula V, and AMI is the key, i.e. reaction formed Δ2-1,2,4-oxadiazolidine formula VI with an amine of formula VII is carried out in an organic solvent which is inert from the point of view of participation in the reaction, in the presence of an acid binding agent, respectively, inorganic bases such as sodium hydroxide or sodium carbonate, as a rule, at the boiling temperature of the reaction mixture. Formed during the alkylation Δ2-1,2,4-oxadiazolidine formula VI or crystallizes, or after evaporation of the reaction mixture is used without crystallization in the amination reaction. The obtained reaction product of formula Ib are way essentially known, using any of the techniques described above. The inert organic solvent may be a hydrocarbon or halogenated aliphatic or aromatic hydrocarbon, such as chloroform, alkanols, such as methanol or ethanol, a ketone such as acetone, or a mixture of these types of solvents.

In method (d) according to the invention the reaction of the derived Δ2-1,2,4-oxadiazoline formula III with epichlorohydrin is carried out in an organic solvent which is inert from the point of view of participation in the reaction, or in the absence of any solvent, preferably in excess of epichlorohydrin, respectively, when those whom the boiling temperature of the reaction mixture. Inert organic solvent can be, for example, a hydrocarbon, a simple ether, such as dioxane, tetrahydrofuran, etc. as the catalyst used bases such as sodium hydroxide, sodium carbonate, etc. At the end of the reaction the solvent is evaporated and the residue crystallized. Formed Δ2-1,2,4-oxadiazolidine formula VIII is reacted with an amine of formula VII in a manner similar to that described for the amination reaction in the method (g). The obtained reaction product of formula Ib are way essentially known, using any of the techniques described above.

In method (e) according to the invention upon receipt of the epoxide of formula IX acceptor acid is, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, etc. or an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc. the Reaction is carried out in an organic solvent which is inert from the point of view of participation in the reaction, respectively, at the boiling temperature of the reaction mixture. As the inert organic solvent used, for example, hydrocarbons, acetone, simple ether, such as tetrahydrofuran or dioxane, halogenated aliphatic or aromatic hydrocarbon, etc. the Reaction mixture is filtered, the filtrate evaporated and the resulting e is the oxide of formula IX is crystallized, then injected into the reaction with the amine of formula VII as described in the method (g) for amination, preferably in alkanol. As an alternative method epoxide of the formula IX are not allocated, and add the amine of formula VII directly to the reaction mixture, which was formed epoxide, and then the reaction mixture is heated. The obtained reaction product of formula Ib emit essentially known manner, using any of the techniques described above.

In method (f) according to the invention in the reaction circuit loop can be used any carboxylic acid derivative or thiocarbonic acid of formula X, the reagent capable of forming a carbonyl or thiocarbonyl group, respectively, between the oxygen atom of the hydroxy-group and the nitrogen atom of the amino group in the case when part of the formula Ia has the structure-C(=N-OH)-NH-. Such compounds include galodamadruga carboxylic acid and thiocarbonic acid such as phosgene and thiophosgene, galoidoproizvodnykh esters, such as ethyl ether of Harborview acid or alkalemia esters of chlorotaurine acid, or ethers, such as diallylmalonate, mono-, di - and trithiocarbonate, xanthates, etc. In the reaction circuit cycle using an organic solvent which is inert from the point of view of participation in the reaction,but the reaction can also be carried out in the absence of any solvent. The reaction mixture is cooled or heated, respectively, the closing cycle is carried out at the boiling temperature of the reaction mixture. The resulting reaction product of the formula Ib are separated essentially known manner, using any of the techniques described above.

If the reaction using a carboxylic acid of formula X, where one or both of the Deputy of Z2and Z3means a halogen atom, in an inert solvent using, respectively, hydrocarbons, halogenated aliphatic or aromatic hydrocarbon or a simple ester. If Z2and Z3mean alkoxygroup or allylmercaptan, in addition to the listed inert organic solvent can be also alkanol.

In method (C) according to the invention in reality oxadiazoline ring transform in oxadiazine ring. For this purpose, use the method known from Chem. Ber,108, 1911-1923 (1975). Accordingly, the sodium hydroxide or potassium hydroxide is used as alkali metal hydroxide. The reaction is carried out in a mixture of an organic solvent, such as alkanol, and an aqueous solution of alkali metal hydroxide at the boiling temperature of the reaction mixture. The resulting reaction product of the formula Ic is separated famous for being way, using any and the techniques above.

In method (I) according to the invention the reaction is carried out in an organic solvent which is inert from the point of view of participation in the reaction, or a mixture of several of such solvents in the presence or in the absence of an acid acceptor. The inert organic solvent is, for example, hydrocarbons, halogenated aliphatic or aromatic hydrocarbon, a simple ester or alkanol, preferably butanol. The reaction can also be carried out in the absence of any solvent, in this case, it is possible to use an excess of amine of the formula VII as a solvent. The obtained reaction product of formula Ic is separated known essentially a way of using any of the techniques described above.

In the methods (K) and (l) according to the invention a method similar to that described in method (b). Quaternary alkylated formula XIII is obtained by formation of the Quaternary salt of the corresponding aminoalkylated formula IV. The compound of formula XV can be obtained from the corresponding aminoalkylated formula IV and an oxidizing agent.

Derived oxadiazoline formula Ib, where R3means a hydroxy-group, can be converted into the corresponding compound of formula Ib, where R3means a halogen atom, interaction with palodiruyut agent. As halogenous and the enta preferably using thionyl chloride, trichloride phosphorus or pentachloride phosphorus and implement gorodilova in organic solvents normally used in such reactions, or in the absence of any solvent, for example, in excess halogenous agent. The reaction mixture is treated by the methods usually applied after reactions haloiding.

Derived oxadiazoline formula Ib, where R3means a hydroxy-group, can react with active allermuir derivative (C1-C20)alkenylboronic acid or (C3-C22)alkenylboronic acid such as the acid chloride, anhydride, azide, etc. or methanesulfonamido, benzolsulfonate or toluensulfonate in an inert organic solvent, preferably in an aromatic hydrocarbon or halogenated aromatic or aliphatic hydrocarbon in the presence or in the absence of an acid acceptor. The corresponding reaction product of formula Ib, which is formed, can be separated by conventional methods described above.

The compound of formula Ib, where R3means a hydroxy-group, can react with (C1-C5)alkylhalides in a similar fashion. In this case, one or more atoms of nitrogen compounds can form a Quaternary salt.

The reaction of compounds of formula Ib, where R3means the volume of halogen, preferably, a chlorine atom, can be carried out under reaction conditions described above.

If necessary, the compound of the formula I is converted into pharmaceutically acceptable acid additive salt or isolated in the free form of its acid salt additive. If salt is used optically active organic acid, such as camphoric acid, camphorsulfonic acid, tartaric acid or a derivative of tartaric acid, it becomes possible separation of the stereoisomers of the compounds having a chiral center. In this case, division by prominent substantive way by fractional crystallization of the acid additive salts formed with optically active organic acid.

Optionally one or more nitrogen atoms derived amidoxime propenylboronic acid of the formula I quaternized. To this end, the compound of formula I is reacted with an alkylating agent of formula R8-Y, where R8means (C1-C4)alkyl group or phenyl(C1-C4)alkyl group, Y represents a halogen atom, to obtain a Quaternary derivative of formula XII, where R8and Y have the above meanings. The reaction of formation of the Quaternary salt may also be diallylsulfide formula (R8)2SO4where R8 is the above value. In the latter case, receive a Quaternary derivative of formula XII, where Y represents a group of formula R8-SO4. The reaction of formation of the Quaternary salt is carried out in an inert organic solvent or in the absence of any solvent.

Alternative another nitrogen atom or an additional nitrogen atom of the compounds of formula I can also be quaternization. If in the formula I the substituent R denotes heterocyclic group containing a nitrogen atom, for example pyridyloxy group, the nitrogen atom peredelnoj group can quaternization or another nitrogen atom may also quaternization.

When the compound of formula I is transformed into N-oxide, respectively oxidized nitrogen atom, which is associated with the substituents R4and R5. In this case, the oxidation is carried out, usually with hydrogen peroxide, preferably in a solution containing alkanol, such as methanol, respectively, at room temperature. If in the formula I the substituent R denotes heterocyclic group containing a nitrogen atom, for example pyridyloxy group, the nitrogen atom peredelnoj group under the action of the oxidizing agent can simultaneously or instead of the above-mentioned nitrogen atom to become N-oxide. In this case, the oxidizing agent is preferably nagkalat, for example 3-chlormadinone acid, and the oxidation reaction of p is avodat in an inert organic solvent, typically, in an aromatic hydrocarbon such as benzene or toluene, respectively at room temperature.

Of course, the N-oxide compounds of formula I can be converted in farmatsevticheskii acceptable acid additive salt or Quaternary derivative is known essentially the way.

Pharmacological action of the compounds according to the invention is determined in the following tests.

The study of inhibition of poly(adenosinetriphosphatase)polymerase (PARP)

It is known that reactive species of oxygen (ROS)such as hydroxyl radical. superoxide, peroxynitrite, hydrogen peroxide, continuously formed in living organisms [Richter S., FEBS Lett.,241, 1-5 (1988)], and a small number of them are involved in the control of important physiological processes [Beck K.F., etc., J. Exp. Biol.202, 645-53 (1999); McDonald L.J. and Murad F., Proc. Soc. Exp. Biol. Med.,211, 1-6 (1966)] (such as vasodilation, platelet aggregation, leukocyte adhesion). The concentration of reactive oxygen species and nitric oxide significantly higher in acute and chronic inflammation, such as when the majority of autoimmune diseases [Taraza S. and others, Rom. J. Intern. Med.,35, 89-98 (1997)], in the case of postischemic heart failure, cerebral ischemia (stroke) [Brain Pathology,9, 119-131 (1999)]. Sources of ROS include cells of normal tissues blagodarya, what leukocytes and macrophages partially present in inflamed tissue, partially due to the inductive effect of inflammatory cytokines.

Reactive species of oxygen, among other things, damage and DNA. Complex protective and regenerative process is initiated in a cell with damaged DNA. An important element of this process is the activation of the enzyme poly(adenosinetriphosphatase)polymerase (PARP). PARP is a nuclear enzyme structure, which is present in large quantities in almost every cell and catalyzes the transport adenosinetriphosphatase link from negotiationtemplate (NAD) to proteins and creating circuits on the basis of poly(adenosinetriphosphatase). The main substrates of the enzyme include yourself [R. Gonzalez and others, Mol. Cell. Biochem.,138, 33-37 (1994)], nuclear proteins, histones, topoisomerase I and II, transcription factors. The activity of the enzyme PARP increases by about 500 times in the event of breakage of the DNA chain [Menissier de Murcia, J., and others, J. Mol. Biol.,210, 229-233 (1989)]. A critical decrease in the concentration of NAD is caused by activation of the enzyme PARP due to extremely heavy damage DNA. As a result in the cell decreases the synthesis of adenosine triphosphate (ATP), and at the same time, the level of use of ATP becomes higher as the cell tries to restore the level of NAD from adenosinetriphosphatase and nicotinamide way of the use of ATP. Data of biochemical reactions cause significant damage therapy of certain diseases, such as autoimmune clinical forms [C. Szabo and others, Trends Pharmacol. Sci.,19, 287-98 (1988)], ischemic States of the heart and brain, as well as neurodegenerative diseases. The catabolism of NAD can be excluded by inhibiting the enzyme PARP, thus reducing the levels of nicotinamide and adenosinetriphosphatase in cells and inhibiting the consumption of ATP for the synthesis of NAD; that is, the above-mentioned damage and death of cells can be excluded by inhibition of the enzyme.

The definition of inhibiting PARP in vitro on a dedicated enzyme

Poly(adenosinetriphosphatase)polymerase was isolated by their rat liver in accordance with the publication G.M. Shah [Anal. Biochem.,227, 1-13 (1995)]. The PARP activity was determined in 130 µl of reaction mixture consisting of 100 mm buffer Tris-HCl, pH 8.0, 10 mm MgCl2, 10% glycerol, 1.5 mm of dithiothreitol (DTT), 100 mcg32P or3H-NAD+, 10 μg of activated DNA, 10 µg of histone [Tris-HCl mean hydrochloride Tris(hydroxymethyl)aminomethane]. After 10 min incubation the reaction was stopped with 8% perchloric acid and separating the protein by centrifugation (10 min, 10000 g). The precipitate washed three times 8% perchloric acid and the radioactivity of the protein was measured with a scintillation counter. The results can be seen in the table.

Table
Compound(example no.) Inhibition of PARP, I0,5mg/l
29±2
38±1
414±2
513±2
617±3
812±2
97±1
1028±4
1218±3
1320±3
149±2
1618±3

The above data were obtained from four parallel measurements. From the table we can see that some of the investigated compounds is very good with a PARP inhibitor (l0,5<10 mg/ml). A large part of the investigated compounds can be classified as good PARP inhibitors (l0,5=10-28 mg/ml).

The effect of compounds of the formula I in ischemic heart failure, and re-perfusion fibrillation

Damage to the heart muscle and cell death of the cardiac muscle in the majority of cases occur due to violations of their power. The most common form of malnutrition is the lack of oxygen. Developing damage with technol muscle is ischemia of the heart muscle, which can be formed due to acute hypoxia/oxygen insufficiency, coronary occlusion, spasm or chronic heart disease. Ischemic part of the acute infarction of the heart muscle is accompanied by a phase of excess flow, the so-called phase of re-perfusion. As the lethal consequences of re-perfusion can happen arrhythmia called ventricular tachycardia and fibrillation). They are the first manifestations of disorders of re-perfusion. The prevention of infringement of re-perfusion of the heart muscle by injection means preventing deadly danger in the early post-infarction phase.

Experiments were performed on rats male line SPRD (range of acceptable body weight 300-350 g). Animals were given anesthesia, introducing pentobarbital [5-ethyl-5-(1-methylbutyl)-2,4,6-(1H,3H,5H)pyrimidinetrione] (60 mg/kg intraperitoneally) and left to spontaneous breathing. Animals spent an auxiliary breathing apparatus (manufactured Kutesz, Hungarian Academy of Sciences) using a tracheal cannula introduced after tracheotomy. Controlled standard lead electrocardiogram (ECG II). In the right femoral artery was injected, the catheter was connected with a sensor of blood pressure (BPR-01, Experimetria, Hungary) and preamplifier. Pillsothenet (HG-M, Experimetria, Hungary) started PR is a pulsating signal of arterial blood pressure. The external jugular vein was Coulibaly for drug injection. After thoracotomy silk thread (braided, coated 4-0) were placed under the left anterior coronary artery (LAD) artery. After a few minutes stabilization period conducted 5-minute occlusion of the LAD artery, followed by a 10-minute period of re-perfusion. Recorded ECG in normal state in the initial period and in the preceding periods. According to the ECG was determined by the length of time ventricular tachycardia and fibrillation in sec. In addition, we recorded survival rates in the groups treated animals.

The obtained results indicate that the compounds according to the invention is applicable to prevent arrhythmias induced by re-perfusion. For example, in animals treated with compound of example 2, survival after re-perfusion was 50% higher compared with the control group.

The study of the compounds of formula I in global cerebral ischemia

After ischemic stroke in humans pyramidal cells of area CA1 of the hippocampus, for the most part, destroyed, other cells area (CA2, CA) is not so sensitive [B.J. Crain and others: "the Selective death of neurons after transient ischemia forebrain clawed at the Mongolian gerbil, a study with application of silver". Neuroscience, , 402 (1988)]. In accordance with the data of some authors of memory disorders associated with cell death in the hippocampus [Walker, A.E. and others: The national survey of stroke NINCDS, NIH: Clinical findings, Stroke,12, Suppl.,1, 1-44 (1981)]. The Central nervous system of mammals is not equally sensitive to ischemic damage. Mongolian clawed gerbil (Meriones imguiculatus) due to its anatomical features more suitable for the investigation of cerebral ischemia, because this type of 90% of the system basilar anastomosis (Circuius Willisi) is not, therefore, no communication between the carotid artery and vertebral artery. Thus, extensive forebrain ischemia can be induced by pressing on the carotid artery.

The purpose of this experience is to determine whether the new compounds of formula I forms a protective effect in global cerebral ischemia. The experiments were carried out in male Mongolian clawed gerbil. Animals were given anesthesia using a mixture of 2% halothane gas [2-bromo-2-chloro-1,1,1,triptorelin], 68% nitrous oxide and 30% oxygen. Anaesthesia carotid artery squeezed from two sides for 5 minutes Neurons is not destroyed immediately, so after you followed a four-day period of re-perfusion (cell death late type). On the fourth day after the intervention 80-90% of the cells were damaged in a pyramidal participants of the e CA1.

To determine the ability to learn and remember, and hypermotility, animals were tested in a Y-maze.

The death of cells in area CA1 was studied by histological sections. Animals were perfesional buffered formalin, and the brains were removed and fixed in formalin. Distribution of destroyed areas CA1 was determined by brain sections after staining.

In the experiments used the following materials:

GYKI-52466 (1-[4-AMINOPHENYL]-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine) (control substance) at a dose of 40 mg/kg intraperitoneally introduced after 30 min after ischemia;

Nimodipin [2-methoxyethyl-1-metaliteracy ether 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)is 3.5-pyridineboronic acid] (control substance) at a dose of 10 mg / kg intraperitoneally, entered after 5 and 30 min after ischemia;

a new compound of formula I at a dose of 25 mg/kg intraperitoneally, entered after 5 and 30 min after ischemia.

Experimental group:

- ischemic control,

treated control substance after ischemia,

treated investigated the matter after ischemia,

- pseudocontractive.

In the experiments it was possible to establish that the compounds of formula I exhibit a protective effect in global cerebral ischemia.

The effect of compounds of the formula I in autoimmune diseases

Autoimmune diseases are diseases in the cat is where the body gives the immune reaction to their normal components [Ring GH and others, Semin. Nephrol.,19, 25-33 (1999); A.N. Theofilopoulos, Ann. N.Y. Acad. Sci.,841, 225-235 (1998)]. Different autoimmune diseases differ each other antigen, which starts the reaction, however, a great similarity can be installed in destroying the cellular tissue of the mechanism shown autoimmunity [Szabó C. etc., Proc. Natl. Acad. Sci. USA95, 3867-3872 (1998)]. Primary autoimmune disease include the following:

- hormonal diseases:insulin-dependent diabetes mellitus (IDDM);
- liver disease:hepatitis;
- skin diseases:bubble pemphigidae lupus, common lupus, psoriasis, scleroderma, vitiligo;
- disease of the blood forming organ:sarcoidosis;
- arthropathy:rheumatoid arthritis;
cardiovascular disease:vasculitis, Takayasu's arteritis, knotted polyarteritis, ankylosing

spondylitis;
gastrointestinal disease:ulcerative colitis;
- diseases of the muscular and nervous systems:multiple sclerosis, myasthenia pregnant, chronic inflammatory demyelinizing polyneuropathy

Of these autoimmune sableman the th investigated in mice prevention of diabetes mellitus type I, induced streptozotocin.

Insulin is the main regulator of carbohydrate metabolism in the body, is produced and transported in the bloodstream by cells of the pancreatic islets of Langerhans. Damage or destruction β-cells causes a reduction or termination of production of insulin, which leads to the development of diabetes mellitus type I. Particularly sensitive β-cells to ROS and toxic effects of nitric oxide. The study of DNA damage induced by nitric oxide, has led to the assumption that excessive activation of PARP enzyme and reduction of NAD is responsible for the deaths β-cells [Heller V. and others, J. Biol. Chem.,270, 11176-180 (1995)]. Such mechanism streptozotocin (SZ) [2-deoxy-2-(3-methyl-3-nitrosourea)-D-glucopyranose] damage producing insulin β-cells, thus presenting the model of type I diabetic for use in experiments on animals [Yamamoto H., and others, Nature,294, 284-286 (1981)]. DNA is destroyed by streptozotocin due to alkylation and formation of nitric oxide, which causes activation of the enzyme PARP, as mentioned above. Was investigated, could the effects of a single dose of streptozotocin, increase the level of blood glucose in mice can be prevented by a single dose derived amidoxime propenylboronic acid of formula I. the Experiments were conducted on m is Shah-male line CD-1. Animals were divided into three groups, each of which consisted of 8 animals. The first group received 160 mg/kg streptozotocin (Sigma) intraperitoneally, the second group received 160 mg/kg streptozotocin and 200 mg/kg of the compounds of formula I is oral, the third group served as a control. The concentration of glucose in blood was determined on the third day after treatment. Then the animals were killed and took serum samples for determination of insulin.

It was found that investigated the connection according to the invention significantly reduced the level of glucose in the blood increase when adding streptozotocin.

Impact on insulin resistance

Diabetes type II diabetes is insulin-independent. The essence of the pathological mechanism of this latter type is the reduction or loss of insulin sensitivity of peripheral tissues, especially in the striped (skeletal) muscle, and adipose tissues. Naturally, this insensitivity may not be offset by overproductive (hypersecretion) β-cells of islet of Langerhans. It is important to emphasize that resistance to insulin, even without a real beginning of diabetes, leads to some regulatory cardiovascular disorders. Thus, insulin resistance is an independent risk factor for cardiovascular disease. Owing to pathophysiologies the th value of resistance to insulin possibilities of pharmacotherapy, aimed at improving insulin sensitivity, very important in the study of drugs. The only really existing in clinical practice insulin sensitizers are the so-called preparations of thiazolidinediones. Their toxicity (which, basically, hepatotoxicity) is a limiting factor in their application. Insulin sensitizers reduce the levels of blood glucose, triglyceride and insulin mechanism, which includes an increased sensitivity to insulin in target tissues (liver, skeletal muscle, adipocytes) [Coica J.R., and D.R. Morton:

"Antihyperglycemics thiazolidine: ciglitazone and its analogues" in the "New anti-diabetic medicines," the editors C.J. Bailey and Flatt P.R., ed-Smith-Gordon, New York, 1990, str-261].

Was investigated, does treatment with compounds according to the invention on insulin sensitivity rabbits, normal and hypercholesterolemia, in consciousness. Adult white rabbits male breed New Zealand with weighing 3-3 .5 kg were placed in the room for animals (day 12-hour periods of light/dark temperature 22-25°C, humidity 50-70%), applied industrial feed for laboratory animals and tap water with free access used throughout the experience. The experimental period started after a two-week adaptation period. Rabbits p is Osvaldo was divided into two main groups. Half of the animals continued to give normal rabbit feed, while the second group of animals were fed enriched with 1.5% cholesterol over a period of eight weeks. Each main group was divided into four treated groups:

- untreated group,

the group treated with the compound according to the invention, at a dose of 10 mg/kg

intravenously twice a day for 4 days,

the group treated with 7-nitroindazole as NOS inhibitor:

introduction 5 mg/kg 7-nitroindazole for 5 min preceded the introduction

insulin with 5 minute intervals between infusions,

group, treated as 7-nitroindazole and connection

the invention as described.

Animals were given anesthesia and inserted polyethylene catheters in two main branches of the right jugular vein and left carotid artery. Catheters were introduced through the back of the neck and filled with physiological saline containing heparin.

Studies on the isolated vessel

From the thoracic aorta and carotid arteries of rabbits was preparing vascular rings with a length of 4 mm and was placed horizontally on two small L-shaped hooks, one of which was connected to a force measuring transducer (SG-02, Experimetria, London, UK) for measurement and recording of isometric tension. The experiments were performed in the camera body (5 ml)application : the United Krebs solution with a gas mixture of 95% oxygen and 5% carbon dioxide. The initial off-load voltage was set at 20 and 10 mn for rings of aorta and carotid artery, respectively. Time equilibrium was reached 60 minutes Later, the vascular rings were exposed to increasing concentrations of norepinephrine cumulative way. After the maximum response norepinephrine washed away from the camera body until such time as the voltage is returned to the previous baseline level. To explore the vascular response to acetylcholine, the ring was pre-compressed using EU50(50%effective concentration) of norepinephrine. After appropriate compression was obtained, samples were subjected to exposure to a cumulative increase in the level of acetylcholine chloride.

In the second direction of research in the reactivity of the vessels separate group rings carotid artery was subjected to induced electric fields. After the initial set voltage of 10 mn rings for 1 h led to a state of equilibrium. Then studied contractile responses of two consecutive series of excitation pulses of the electric field (100 stimuli, 20, 0.1 MS and 20 Hz). Then the Protocol field excitation was repeated in the presence of 1 μm atropine and 4 μm of guanethidine (neadrenergicheskoy neholinergichesky (NANC) solution). The entire Protocol was carried out with the rings and the stroke endothelium and rings, in which the endothelial layer was carefully removed.

The determination of the content in tissue cyclic GMP (guanosine monophosphate) in accordance with Szilvássy [Szilvássy Z. and others, Coron art. Dis.,4, 443/452 (1993). Am. J. Physiol., H2033-H2041 (1994)].

Muscle ring was immediately frozen using pre-cooled clamp of Wollenberger and were crushed in liquid nitrogen. Then the samples are homogenized in 6% (vol./about.) trichloroacetic acid in excess of 10 times the mass of the sample in a mortar, previously kept at -70°C. After thawing, the samples were treated with 4°C. Deposition at 15000 g for 10 min using a centrifuge brand Janetzki K-24 (Leipzig, Germany) was followed by extraction of the supernatant with 5 ml of water-saturated ether extractor Wortex within 5 minutes the Ether fraction was discarded and then repeated extraction five times. After that, the samples were evaporated under nitrogen and analyzed for the content of cyclic GMP using kits for radioimmunoassay analysis. Values were expressed pmash/mg mass of wet tissue.

Research hyperinsulinemia applicationscope fixation

Spent the infusion of human regular insulin at a constant speed (13 honey/kg) through a venous cannula is within 120 minutes the insulin infusion rate resulted in the immunoreactivity of Ann is Lina plasma 100± 5 μm/ml at rest. Blood samples (0.3 ml) were taken from the arterial cannula with 10-minute intervals to create a concentration of glucose in the blood. The concentration of glucose in the blood is kept constant (5,5±0.5 mmole/l) by changing the rate of glucose infusion through the second venous cannula. When the level of glucose in the blood had been kept constant for at least 30 min, the condition is defined as a state of rest and additional blood samples (0.5 ml) was taken for determination of insulin in plasma with 10-minute intervals. The glucose infusion rate at rest is used to oharakterizovat insulin sensitivity.

In the research the following results are obtained.

1. Relaxation responses to cumulative increasing concentrations of acetylcholine (1 nm -10 ám) vessel normal rabbit did not change under the influence of 1 μm of the compounds according to the invention.

2. In experimental hypercholesterolemia vascular relaxation with acetylcholine was significantly weaker in the presence of compounds according to the invention.

3. The excitation of the electric field induced voltage gain in the rings of the carotid artery, incubated in Krebs solution. However, in the NANC relaxation solution response was observed in response to the applied Protocol excitation. Neither response did not feel the influence is of the compounds according to the invention.

4. Removal of the endothelium significantly increased the compression caused by the excitation of the electric field, and weakened NANC relaxation. Compounds according to the invention softened the compression caused by the excitation of the electric field, and increased NANC relaxation in vascular rings without endothelium.

5. In vascular rings hypercholesterinemia animals compression induced by the excitation of the field were increased, whereas the response to NANC relaxation were weak compared to the reactions observed in preparations from normal rabbits. Compounds according to the invention is considerably weakened compression induced by electrical stimulation, and increased response to NANC relaxation in vascular rings rabbits with hypercholesterolemia, regardless of the presence of endothelium.

6. The baseline concentration of cyclic GMP is significantly reduced in rings from rabbits with hypercholesterolemia as compared to that in normal rings. This decrease was almost normalized by incubation with 1 μm of the compounds according to the invention. However, the compounds had no effect on the content of cyclic GMP at rest in the normal rings. The excitation electric field led to an increase in the concentration of cyclic GMP in preparations from normal animals. In rings from rabbits with hypercholesterolemia applied the initial Protocol excitation was insufficient, to install any increase in the concentration of cyclic GMP. Compounds according to the invention were ineffective in improving induced by the excitation of the field content in tissue cyclic GMP in normal rings, but in preparations from rabbits with hypercholesterolemia was observed a significant increase in the level of cyclic GMP.

7. The effect of cholesterol-enriched feed led to a marked reduction in insulin sensitivity in rabbits, in consciousness. Treatment with compounds according to the invention for 4 days almost restored insulin sensitivity in animals with hypercholesterolemia. However, the compounds according to the invention had no effect on insulin sensitivity in normal animals.

8. The neural inhibitor of NO-synthase, 7-nitroindazole as such causes resistance to insulin in normal animals. Compounds according to the invention unable to influence this state of resistance to insulin. Moreover, 7-nitroindazole blocks the improving effects on the insulin resistance shown by the compounds according to the invention in experimental hypercholesterolemia.

Conclusions

The results presented above show that the compounds according to the invention enhance the hypoglycemic effect of insulin in a state of resistance to insulin that is associated with the exposure the pilot hypercholesterolemia in rats in consciousness. The results also confirm the evidence that this effect sensitization to insulin is largely associated with netrelease metabolic pathways, the effect of which, as recently suggested, plays a major role in the regulation of insulin sensitivity [Shankar R.R., and others, Diabetes,49, 684-687 (2000)]. Hepatic neurohormonal regulation of peripheral insulin sensitivity can be described as follows [Lautt W.W., Can. J. Physiol,77, 553-562 (1999)].

- There is emerging after a meal increases insulin levels in the blood.

In response to this increased level of insulin is activated hepatic parasympathetic reflex.

This reflex causes the release of acetylcholine, which activates muscarinergic receptors.

- Muscarinergic excitation leads to the secretion of nitric oxide (NO).

Only in the excited state nitric oxide triggers the release of hepatic insulin-sensitizing factor (HISS), which has synergetik or insulin action.

- HISS increases the uptake of glucose by skeletal muscle.

This mechanism involving HISSS sensitive to blockade of the synthesis of nitric oxide and can be activated by exogenous NO donor. It is highly likely that a mechanism involving HISS is closely related to hepatic function is sensory fibers. Occur after eating increased level of insulin in the plasma activates netservices a subpopulation of hepatic sensory nerve fibres that cause the release of sensory neurotransmitters from neighboring fibers. These sensory neurotransmitters due to their hormone-like character get into the bloodstream and increase tissue sensitivity to insulin.

In a very recent work Steppan et al. were able to shed light on the missing link between obesity and insulin resistance. [Steppan C.M. and others, Nature,409, 307-312 (2001)]. In brief hormone called resistin, is produced by adipocytes. It was shown that resistin reduces the sensitivity of target tissues (adipose tissue and skeletal muscle) to the hypoglycemic action of insulin. Therefore, pharmacological inhibition of secretion of resistin is a possible new mechanism of action for use in pharmacology in the treatment of non-insulin-dependent diabetes mellitus and insulin resistance syndrome. Of the currently known drugs of the family of preparations of thiazolidinediones can suppress insulin secretion through peroxisomal proliferative activator of nuclear γ-receptor in adipocytes.

The compounds of formula I have an impact on insulin sensitivity, and they are able to reduce steadily the th to insulin using netservices mechanism and sensory neurotransmitters. Normalization of insulin sensitivity is the cause of diseases with high prevalence and mortality, such as diabetes type II, hypertension, coronary heart disease, obesity and some endocrine diseases.

The use of compounds according to the invention for the prevention of toxic effects

1) the Effect of compounds on mortality induced by endotoxin in mice

Septic shock is one of the most frequent causes of death in intensive care units. Infections caused by gram-negative bacteria, lead to hypotension, inadequate function of some organs and finally to the collapse of the body. By injection of lipopolysaccharide (LPS), a component of bacterial membranes in experimental animals causes a condition similar to shock and finally death. LPS activates transcription family of NF-KB/Rel, which regulates the production of several mediators involved in the pathological mechanism of shock (such as tumor necrosis factor α (TNF-α), interleukins, NO-synthase) [Oliver F.J., and others: "Resistance to endotoxic shock as a consequence of defective activation of NF-κIn mice with deficiency of poly(ADP-ribose)polymerase-1", EMBO J.,18, (16) 4446-4454 (1999)]. Gene PARP-1 is functionally associated with NF-κthus, the loss of PARP transcription hung is the following from the NF-κ In, also do not occur, therefore, when endotoxin shock the release of inflammatory mediators is also insufficiently regulated. The aim of the study is to find out, could the mortality induced by endotoxin, can be prevented by inhibiting PARP-1 compounds of formula I.

In our experiments we used c57BL/6 (Charles River Breeding Ltd.). In the experience of the dose and type of used LPS were identical to those described in the article F.J. Oliver mentioned above: lipopolysaccharide from Escherichia coli 0111:B4 (Sigma). In the experiments used a 3-aminobenzamide (Sigma). Survival within 24 h was monitored at least twice. The compounds of formula I was administered to animals orally after 1 and 6 h after treatment with LPS.

It was found that the mortality induced by endotoxin, significantly decreased the analyzed compounds of formula I.

2) the Effect of compounds on hepatotoxicity induced by acetaminophen (paracetamol)

It is known that various non-steroidal Antirheumatic agents [Peters, M. and others, Clin. Inves.,71, 875-881 (1993)] and painkillers, respectively, have significant hepatotoxicity [Kroger N. and others, Gen. Pharmac.,27, 167-170 (1996)]. Deficiency of liver and kidney induced by a large dose of paracetamol [Meredeth T.J., and others, Arch. Inter. Med.,141, 397-400 (1981)]. Recently, it became apparent that inhibitors of poly(HELL is-ribose)polymerase eliminate liver damage, induced by paracetamol [Kröger N. and others, Gen. Pharmac.,27, 167-170 (1996)]. From literature it is known that paracetamol is an inducer of cytochrome P-450. Effect of paracetamol on the system of cytochrome P-450 leads to the formation of reactive hinokio that bind with sulfhydryl groups of proteins, causing rapid depletion of intracellular glutathione [D.J. Jollow, etc., Pharmacol.,12, 251-271 (1974)]. Inactivated proteins lead to the destruction of liver cells and liver necrosis, respectively. Intracellular glutathione is one of the most important antioxidants and strongest liquidator reactive oxygen species, respectively. The weakening of the antioxidant defense system, which depends on glutathione leads to increased intracellular level of reactive oxygen species [R. Miesel, etc., Inflam.,17, 283-294 (1993)]. Free oxygen radicals are strong inducers PARP affecting posttranslation proteins. Due to enhanced activation of PARP stocks NAD in cells depleted and may begin apoptosis [Hoschino J. and others, J. Steroid Mol. Biol.,44, 113-119 (1993)]. Therefore, nicotinamide, a selective inhibitor of the enzyme PARP, suppresses the secretion of enzymes glutamate-oxalacetate-transaminase and glutamate-pyruvate-transaminase in the liver, as shown in mice in the case of hepatitis, in Zirovnica paracetamol [Krö ger N. and Ehrlich W. in: "L-Tryptophan: contemporary perspectives in medicine and drug safety", as amended Kochen W. and I. Steinhart, the publishing house Verlag, Berlin, 1994].

Was investigated, can be prevented liver damage induced by paracetamol, with new compounds of the formula I. a Symptom of liver damage is characterized by the increase induced by paracetamol levels of the enzymes GOT and GTP. The experiments were conducted on mice-male NMRI weighing 30-40, Animals previously given orally for 7 days, the compounds of formula I. On day 8, the mice were subjected to starvation for 12 h, was given a dose of paracetamol 500 mg/kg oral and introduced a specific dose of a compound of formula I. After 16 h the animals were killed by exsanguination and in serum was measured by the activity of the enzymes GOT and GPT. The results were analyzed using the nonparametric criterion of Mann-Whitney. As for the results, the mean and standard deviation, where the p value<0.05 is considered as significant.

It was found that a single oral administration of paracetamol increased the activity of GOT and GPT in mice male NMRI compared to control animals treated with saline. However, the compounds of formula I after the preliminary oral administration, which lasted 7 days, reduced the activity of the enzymes GOT and GPT really is considerably. For example, a very favorable hepatoprotective effect was observed in case of compound from example 12, is introduced at a dose of 50 mg/kg

3) the Effect of compounds on the toxicity of paraquat

Paraquat (1,1'-dimethyl-4,4'-bipyridine) connection, previously used as a pesticide, has a toxic effect due to the formation of superoxide radical. In the formation of superoxide radical participate oxidoreductase enzymes that use NADH and NAD(P)H as electron donor. [NAD(P)H means β-adenine dinucleotide phosphate in restored form]. In the transmission of cellular response to oxidative stress induced by paraquat, plays an important role in protein R [Migligaccio E. and others, Nature,402, 309-313]. The mechanisms that contribute to the inactivation of superoxide (such as increased levels of superoxide dismutase), effectively reduce the toxicity of paraquat. Superoxide radical plays an important role in the pathological mechanism of certain diseases (such as ischemic reoxygenate, heart attack, inflammatory diseases). A simple model of an experimental superoxide load in these diseases is produced by introduction of paraquat.

The effect on the toxicity of paraquat in vitro

Cells hepatoma HEPA-1 were grown in medium RPMI-1640 with the addition of 10% bovine serum, whereas cells PC-12 pheochromo the Toms rats were grown in medium RPMI-1640 with the addition of 10% bovine serum and 5% horse serum at 37° With air containing 5% carbon dioxide. Using 100 µl of culture medium, 5×103cells were placed in wells of 96-well culture tablet Costar. Some cultures received no treatment and was used as a control. Some cells were treated with increasing concentrations of paraquat, part of the same concentrations of paraquat and concentrations of 3, 10 and 30 μg/ml of the studied compounds. Cells were grown for an additional 3 days, and then were stained with SRB (sulforhodamine). Higher concentrations of paraquat led to cell death, whereas lower concentrations of paraquat partially inhibited the growth of cells. The effect of the compounds was determined on the basis of reducing toxicity of paraquat.

The effect on the toxicity of paraquat in vivo

Paraquat has a significant toxicity in mice. The dose of 70 mg/kg, introduced intraperitoneally, leads to death within 2 days. Mechanisms that inhibit the formation of superoxide, neutralization and exposure to oxidative stress, can also reduce the toxicity of paraquat in vivo.

CFLP mice having a body weight of 20-22 g, were divided into groups consisting of 10 animals, and treated intraperitoneally 50 and 70 mg/kg of paraquat, respectively. Part of the group also received an investigational compound for 6 h prior to the introduction of the of arquata. In the case of the compounds under study used a dose of 100 mg/kg orally. The effectiveness of the studied compounds was determined on the basis of increasing the survival rate of mice.

It has been found that the compounds of formula I significantly reduce the toxicity of paraquat.

The effect of compounds of the formula I in neurodegenerative diseases

As noted earlier, because of damage to DNA by the action of ROS activates the enzyme PARP, which is accompanied by release of cellular NAD, thus leads to cell death. Extreme speed activation of PARP can not only be observed when neuronal death caused by ischemia, like ischemia of the brain, but there is evidence of its role in other neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis [Love and other, Neuropathol. Appl. Neurobiol.,25, 98-108 (1999); Eliasson and others, Nat. Med,10, 1089-1095 (1997)].

Effect on experimental amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease. This is the most common start of motor neuron disorders in adults in developed countries. ALS involves the degeneration of motor neurons in the cerebral cortex, brain stem and spinal cord that causes atrophy of the skeletal muscles, paralysis and CME is th [Roland L.P. in Neurodegenerative diseases", str.507-521 (1994)]. In some cases of ALS disease is family. Family cases partially associated with a missense-mutation in Cu/Zn-superoxide dismutase-1 (SOD-1) [Deng, R.H., and others, Science,261, 1047 (1993)]. Cytosolic enzyme SOD-1 is abundant in nerve tissue, plays an important role in protecting cells from damage induced by oxygen radicals. The mutated enzyme retains almost normal levels of enzyme activity. In vitro studies showed that mutations in SOD-1 lead to increased enzyme function and increases the production of free radicals.

In transgenic mice with the mutated gene AOD-1, develop symptoms similar to those with ALS. Some mutated human genes SOD-1 (G93A, V148G) were sverkhekspressiya in transgenic mice, generated and disease models were used for screening drugs against ALS [M.E. Gurney, J. Neurol. Sci., 152. Suppl. 1, 67-73 (1997)].

Research on models of family ALS

The study used transgenic mice, overexpressing mutated human gene SOD-1 (G93A). Animals were purchased from Jackson Laboratory, USA. The treatment of compounds of formula (I started before the onset of symptoms at the age of 4 weeks. The investigated compounds were given once daily orally at 3 dose levels up to the end of the experiment.

Progression what the disease was controlled weekly study of motor function (the stretch reflex, charged grid, rotational test), survival time and at the end of the experiment (120 days) by histological and biochemical studies of areas of motor neurons.

It has been found that the compounds of formula I result in a moderate delay in the appearance of reflexes, lack of coordination and muscle efforts in transgenic animals with ALS. The observed effect was dose-dependent. There was also a delay in the onset of paralysis and final stage of the disease. The results of histological studies confirmed the observed clinical effects of the treatment. Degeneration and loss of motor neurons and substancia nigra were less pronounced in the treated group than in the control group. Based on the results it can be assumed that the compounds of formula I have a beneficial therapeutic effect in diseases of the ALS.

Research on autoimmune model of ALS

In the case of sporadic disease ALS gene SOD-1 failed to detect any mutations. This fact suggests that other factors lead to the same progression of the disease. Most patients suffering from sporadic ALS, it is possible to detect the antibody against calcium channels. This observation confirms the concept that autoimmune reaction against motor neurons and calcavecchia source plays a role in the development of sporadic ALS. In experimental animals Engelhardt employees induced disease with any specific changes in ALS by immunization with motor neuron, then using only the immune serum [J. Engelhardt and others, Synapse,20, 185-199 (1995)]. This model was also used to study the effectiveness of the compounds of formula I with sporadic disease ALS.

Guinea pigs, Hartley were immunized with gomogenizirovannykh bullish front corniculate process of the spinal cord. For immunization neurons suspended in complete Freund's adjuvant (CFA). Processing of data was performed by 10 subcutaneous or intradermal injection, injecting each time 0.1 ml of suspension. After a month, injections were repeated, however, for the preparation of suspensions used the incomplete beta-blockers. Two weeks after the second immunization in animals within 1-3 days developed severe weakness, especially in the lower extremities. The weight gain stopped, mobility decreased. In the next two weeks, the condition of the animals was not changed. Then, animals were scored by bloodletting. Blood was collected and centrifuged to obtain serum, which was used for the induction of ALS in mice.

Experiments were performed on groups of 5 male mice-albinos (CFLP, body weight 25-30 g). Each animal was administered by intraperitoneal injection is AI 1 ml of the above-described serum to damage the motor neuron. One group of animals was treated with only the serum, while others, in addition to serum, were treated also studied compound of formula I at a dose of 100 mg/kg intraperitoneally. Other groups of animals were treated only with investigational compound of formula I without the injection of serum.

The mobility of the animals treated only serum was slow, lower limbs could be used by them only with difficulty, then they became paralyzed. In the case of animals treated as serum and investigational compound of formula I, it was impossible to determine any deficiency syndrome mobility. The same was verified in the case of animals treated only with investigational compound of formula I. All this suggests that the compounds of formula I may also prevent the development of disorders of the locomotor abilities induced by immunization.

Effect on experimental model of Parkinson's disease

Parkinson's disease is a well-known result in the loss of ability to work idiopathic neurodegenerative disorder characterized by tremor, bradykinesia, rigidity, caused by muscle tension, and difficulty with balance. These motor abnormalities are caused by depletion of moshovos the dopamine, what is the loss of dopaminergic neurons in the substancia nigra pars compacta. Analysis steps 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MRTR)with selective neurotoxicity, sheds light on the possible pathological mechanism of Parkinson's disease. MRTR induces motor symptoms of Parkinson's disease in humans and animals [Dexter A. and others, Ann. Neurol., 35, 38-44 (1994)]. Processing MRTR also leads to the loss of dopaminergic neurons in the substancia nigra pars compacta. Eosinophilic inclusions, such calf Lewy, appear in the damaged neurons, and the activity of mitochondrial complex in these cells also decreases. These changes are characteristic of oxidative stress [Shapira A., Adv. Neurol.,69, 161 to 165 (1996)]. Biologically active metabolite MRTR is RAM (1-methyl-4-phenylpyridine). RAM directly inhibits complex I in mitochondria, leading to increased formation of superoxide anion. The data indicate that oxidative stress plays a Central role in the pathogenesis of natural forms and induced MRTR form of Parkinson's disease. The enzyme PARP is activated by oxidative stress, and the enzyme seems to play an active role in the pathological mechanism of Parkinson's disease. Mice with an extremely low level of PARP discover significantly reduced sensitivity to the action MRTR, inducing the disease is of arkinson [Mandrir F. and others, Proc. Natl. Acad. Sci. USA96, 5774-5779 (1999)]. These findings suggest that inhibition of PARP may result in a therapeutic effect on Parkinson's disease.

Mouse C57B1 used in the experiments were obtained from Charles River, Hungary. Mice weighing 20 g were treated four times with 20 mg/kg MRTR entered each time intraperitoneally with 2-hour intervals. The compounds were administered orally 30 min prior to injection MRTR. Control animals received the treatment of the filler with the same periodicity. Seven days after injection MRTR mice were killed and brains were rapidly removed. Striped body was stratified chilled on ice Petri dish. Then the tissue was rapidly frozen and stored at -80°C until analysis. Tissue samples were irradiated by ultrasound in 50 volumes of 0.1 M perchloric acid to achieve homogenization. After centrifugation (14000 g, 10 min, 4° (C) 20 μl of the supernatant was injected in oberservatory column catecholamine (ESA, Bedford) and evaluated the content of dopamine.

After 2 h after the last treatment with MRTR ventrolateral midbrain and striatum was dissected and homogenized in sucrose buffer/DTT (dithiotreitol), then centrifuged (14000 g, 5 min). The precipitate is again suspended in the buffer. After determining the protein concentration equal amounts of protein were loaded on the gel for SDS/PAGE electrophoresis in the poly is aluminum gel in the presence of sodium dodecyl sulphate). Protein was transferred from the gel to nitrocellulose membrane and stained with immune labels for the polymer poly(ADP-ribose). Specific binding was detected using chemiluminescence.

In experiments it was found that treatment with MRTR has caused a sharp decline (80%) content of dopamine in the veins of the region. The compounds of formula I in part (20-40%) inhibited the loss of dopamine induced MRTR. Treatment with MRTR led to the emergence of poly(ADP-ribose)polymer adducts veins in the area. Concomitant treatment with investigational compounds produced suppression of the symptom (20-70%). Thus, it can be expected that the compounds of formula I may possess therapeutic activity in Parkinson's disease.

The study chitosamine actions

Some drugs used constantly or frequently, can cause neuronal damage as side effects. From a large series of such drugs that cause this side effect (chloramphenicol, Dapsone, disulfiram, dichloracetate, ethionamide, glutethimide, aurothiomalate sodium, hydrazine, isoniazid, metronidazole, nitrofurantoin, nitrous oxide, cisplatin, pyridoxine, vincristine), the best characterized and most commonly discussed are neuropathy caused by isoniazid, pyridoxine, vincristine by recipelatino. Chloramphenicol may cause such a neuropathy, but its side effect may disappear after stopping treatment. However, in almost all clinical cases of premature stop chemotherapy may hinder the success of the treatment and can cause endometriosis. Especially high is the risk of changes due to adverse effects in therapeutic treatment in case of anticancer therapy. This fact gives great importance to the so-called hematodinium or cytotoxity agents that can reduce the damaging side effects important, life-saving drugs, without causing any decrease in their therapeutic efficacy.

Most cancer patients treated with cisplatin, the main side effect is damage to the peripheral nerves (peripheral neuropathy). The occurrence of this side effect may hinder the implementation of therapy with cisplatin, can jeopardize the success of the treatment and worsen the quality of life of patients. The presence and degree of neuronal damage can be determined by measuring the speed of nerve conduction both in clinical and in experimental studies. Neurotoxic effects of cisplatin include, primarily, the formation of large myelinated layer on the peripheral nerves and is manifested in incarnam damaged neurons (sensory neuropathy). Recently, several reports mentioned autonomic neuropathy and occasionally motor neuropathy accompanying treatment with cisplatin. As a result of damage directly dorsal radicular cysts and large sensory nerves cisplatin can cause functional disorders of the sensory nerves. In rats, continuous treatment with cisplatin causes sensory neuropathy, which is reflected in the slowing of the rate of sensory nerve conduction of the sciatic nerve of mixed type.

On the basis of biochemical mode of action mentioned above, mainly by preventing damage caused by free radicals, it is believed that the compounds of formula I can possess cytotoxity potential and can prevent organooxygen side effects of anticancer drugs. Therefore, in experiments with rats cisplatin was given in the form of subacute treatment for 10 weeks at doses of 1 and 2 mg/kg intraperitoneally and observed the development of peripheral neuropathy. In addition, explored how different doses of these compounds affect the damage of nerve function (speed of nerve conduction).

To determine sensory and motor neuronal damage induced by cisplatin, measured the speed of nerve conduction at the tail of the rats in the CE is provided with a modified method of Mieshi. The modification consisted in the measurement of the speed of nerve conduction at room temperature instead of 37°C. the Speed of sensory and motor conduction was determined before treatment with cisplatin (control) and on the fifth and tenth weeks of treatment. During the measurements, the animals were given a shallow ether anesthesia and two pin terminal electrode pairs were placed in the tail nerve at a distance of 50 mm from each other. Applying force incentive above the maximum recorded afferent (motor) and afferent (sensory) nerve potentials actions. The speed of nerve conduction was determined independently by averaging 10 action potentials, using the formula

NCV=v/1 [m/s], where

v means the distance between the trigger and the recording electrode pairs in mm 1 mean waiting time of occurrence of the action potential in milliseconds, NCV means the speed of nerve conduction in m/s.

In experiments it was found that a 10-week treatment with 1-2 mg/kg cisplatin intraperitoneally significantly reduces body weight in the treated animals compared with that of control animals. This weight loss was also studied in the case of animals treated with compounds of formula I. there was No difference in normal behaviour between treated and untreated animals or animals treated with cisplatin, and studies the target compound. There was no difference in NCV sensory and motor nerves in the control group in the three periods of measurement. In animals treated cisplatin, NCV decreased at all and unusually, at the fifth and tenth week due to treatment with 1 mg/kg cisplatin. After treatment with 2 mg/kg of cisplatin was investigated stronger decrease in NCV. Neuropathy was also developed in the motor nerves.

During treatment with cisplatin for 10 weeks motor NCV was significantly decreased in groups with a dose of 1 mg/kg and 2 mg/kg cisplatin. The decrease was dose-dependent. In the groups treated with 1 mg/kg cisplatin and compound of formula I, the lowering speed of sensory nerve conduction was significantly less than in the group treated with only 1 mg/kg cisplatin, therefore, the function of the neurons were improved after combined treatment. The degree of improvement was higher, the stronger was the degree of damage. In the group treated with 2 mg/kg cisplatin and compound of formula I at different doses, on the fifth week, the lowering speed of sensory nerve conduction was not different from that in the group treated with only 2 mg/kg cisplatin. However, at the tenth week in group of animals treated with only 2 mg/kg cisplatin, NCV has dropped dramatically advanced. Whereas in the case of animals treated as Cipla the other, and a compound of formula I, the decrease was dose-dependent compared to animals treated only 2 mg/kg cisplatin. The speed decrease afferent nerve conduction was less at the end of the tenth week, especially in the groups treated also by the compounds according to the invention.

Summarizing, we can state that the violation of the speed of sensory and motor nerve conduction caused by treatment with cisplatin, is reduced with the simultaneous introduction of the compounds of formula I, and the progression of the violation from the fifth to the tenth week is prevented. Protective effect in some groups was dose-dependent. Thus, the neuroprotective effect of the compounds of formula I can be demonstrated for both sensory and motor nerve functions.

Biological effect carnitinelongevity (CPTI)

A key enzyme in the regulation of fatty acid metabolism is CPTI. There are two opportunities esters on the basis of coenzyme A (COA) and free fatty acids (FFA):

(1) synthesis of triglycerides by reaction with glycerol or

(2) oxidation, the first step is the formation of acylcarnitine using enzyme CPTI [see McGarry J.D., etc.. Diabetes,5, 271-284 (1989); J.D. McGarry and Foster D. Ann. Rev. Biochem.,49, 395-420 (1980)]. The enzyme CPTI localized in the outer part of the inner m is tochondrial membrane (or in the outer membrane and catalyzes the following reaction:

FFA-CoA + L-carnitine → FFA-carnitine + COA

Inhibition of fatty acid oxidation leads to increased cleavage and oxidation of glucose. This transformation is extremely important and beneficial, especially when ischemia of the heart muscle and diabetes; both of these pathological conditions are characterized by high prevalence and mortality. Ischemia of the heart muscle and the subsequent re-oxygenation increased oxidation of fatty acids is detrimental to health because of the high oxygen demand and damaging effects on the membrane shown formed acylcarnitine [Busselen R. and others, J. Mol. Cell. Cardiol.,20, 905-916 (1988); Ford D.A., and others, Biochemistry,and35, 7903-7909 (1996); Reeves K.A., and others, J. Pharm. Pharmacol.,48, 245-248 (1995)]. On the basis of some experimental data currently recognized is the fact that the activation of glucose metabolism and the simultaneous suppression of the oxidation of fatty acids have a beneficial effect from the point of view of recovery of mechanical function of the myocardium and settings metabolism (secretion of the enzyme, lipid peroxidation) [G.D. Lopaschuk, etc., Circ. Res.,66, 546-553 (1990); Kennedy J.A., and others, Biochem. Pharmacol.,52, 273-280 (1996)]. This substrate selection of the myocardium, i.e. the choice between glucose and fatty acid, can also be achieved using inhibitors CPTI, thus, the utilization of glucose increases, the energy performance of the myocardium improved [G.D. Lopaschuk and others, Circ. Res.,63, 1036-1043 (1988); Carregal, M. and others, Arch. Phys. Biochem.,103, 45-49 (1995); G.D. Lopaschuk, etc., Circ. Res.,65, 378-387 (1989); Pauly D.F. and others, Circ. Res.,68, 1085-1094(1991)].

Research applicants have shown that the enzyme that catalyzes the rate-limiting the speed of reaction of fatty acid oxidation, may be Engibarov compounds of formula I in the range of millimolar concentrations below. Research also indicates that the compounds affect substrate selection of the heart and other tissues and by changes in substrate selection and also in postischemic tissue injury.

The biological role of the oxygen-sensitive genes, adjustable first and foremost, the bHLH transcription factors

Protection from the damaging effects of hypoxia requires some organized defensive reactions on the level of individual cells and at the level of the whole organism. In the regulation of expression of inducing hypoxia genes transcriptional complex HIF-1/ARNT plays a Central but not exclusive role. The oxygen-sensitive coordination regulated genes include erythropoietin, which stimulates the production of red blood cells [Wang G.L., and others, PNAS,92, 5510 (1995)], VEGF (vascular endothelial growth factor), which stimulates angiogenesis [Goldberg M.A. and T.J. Schneider, J. Biol. Chem.,269, 4355 (1994)], glycolytic enzymes, such GAPDH (galactose-6-fosfatados the back), LDH (lactate dehydrogenase) [Rolfs A., and others, J. Biol. Chem.,272, 20055 (1997)], and a vector of glucose Glut-1.

The compounds of formula I supposedly contacted by the transcription factor ARNT and/or HIF-1, thus, they affect the activation of genes involved in anxiety (sensitive to hypoxia) conditions. It is believed that through this way signal transmission connection according to the invention Express heat shock proteins that play an important role in anxiety.

The synthesis of heat shock proteins (HSP) is induced by various stresses, which have an effect on the cells. Heat shock proteins help cells to survive in dangerous situations and contribute to the reparation of any damage [Cardiovascular Res., 578 (1993); Neurosci. Lett.,163, 135-137 (1993)].

Agents that may promote anxiety response in adaptation to hypoxia, to the re-oxygenation and restoration of depleted adaptive response, potentially able to reduce tissue damage caused by hypoxia (hypoxia-reoxygenation) in diseases such as heart attack, arteriosclerosis and diabetes.

The definition of HSP-70

The activity of heat shock protein HSP-70 was studied by analysis of reporter gene, forming a hybrid with the DNA. Gene protein, which can be well-defined measurable enzymatic activity, hybridized with promotor follow what eTelestia HSP-70, encodes a heat shock protein. Used biotechnological methods. The enzyme luciferase was chosen as reporter gene, the activity of which may well be determined by measuring luminescence. If the promoter of the gene of the enzyme luciferase is replaced by the promoter of the gene HSP-70, the change in activity of the enzyme luciferase, i.e. the change of the frequency of transcription from a gene that correlates with the frequency of transcription of the HSP-70, which occurs in the circumstances. In this way, if the substance or reaction affects the expression of HSP-70, the effect can be studied by measuring the activity of the enzyme luciferase. The influence of the studied compounds on the expression of HSP-70 was studied in this experimental system.

Double-stranded circular DNA molecule, i.e. a plasmid containing a reporter gene HSP-70 was designed to measure. The sequence length of almost 600 BP promoter of the mouse gene HSP-70 (5'-direction from the start site of the gene) hybridized with the coding sequence of luciferase gene, derived from Photumus pyralis. Applied to the promoter sequence contains several binding protein sites that promote gene expression of HSP-70. The construction consisting of the HSP promoter and heterologous luciferase gene, was built in based on the pBR plasmid in ctor, which can be breeding for neomycin. This HSP-70-luciferase plasmid was transfusional in cells of murine L929 fibroblasts. The analysis was carried out as follows.

The L929 cells that contain plasmid HSP-70-Ls., were grown in DMEM (modified Dulbecco environment Needle) supplemented with 5% FCS (fetal bovine serum). Put 104cells in 1 ml culture medium tablet in wells of a 24-hole tablet Costar for cell cultures. The analyte was dissolved in SFR at a concentration of 10-2M After attaching cells (3-4 h after placing the tablet) made in culture, 10 μl of a solution and cells were incubated for 30 min at 37°in thermostat with CO2. Then the culture medium was replaced with fresh (without analyte) and the cells allowed to recover for 1 h at 37°With, then once washed with SFR. After removal SFR to the cells was added 40 μl of IX lisanova buffer and the sample was kept on ice for 30 minutes the cells are Then transferred into Eppendorf tubes and centrifuged at 14000 rpm for 20 min at 4°C. was Added 5 μl of supernatant to 25 µl of buffer for analysis of luciferase and measured the luminescence of the samples for 25 seconds in a luminometer.

The composition of buffer for analysis of luciferase:

20,00 mm tricin [N-{2-hidroxi-1,1-bis(hydroxymethyl)ethyl}glycine], R is 7,8,

1,07 mm (MgCO3)4Mg(OH)2.5H2O,

2,67 mm MgSO4,

0.10 mm EDTA (ethylenediaminetetraacetic acid),

of 3.33 mm DTT,

270 μm lithium salt of coenzyme a,

470 μm luciferin,

530 μm ATP (adenosine triphosphate).

The composition lisanova buffer 5X:

125 mm Tris-N3PO4, 7,8,

10 mm CDTA (TRANS-1,2-diaminocyclohexane-N,N,N',N'-tetraoxane acid),

10 mm DTT,

50% glycerin,

5% Triton X-100.

The study is sensitive to hypoxia genes

The effect of the compounds of formula I studied on xenobiotic and hypoxia (1% oxygen)induced gene expression in cell cultures Nera and HepG2 at the levels of mRNA and protein. Observed that the compounds of formula I leads to 10-fold increased expression of HSP-70 in HEPA cells induced methylcholanthrene. In addition, the compounds according to the invention enhance the expression sensitive to hypoxia genes like VEGF, GAPDH and LDH, in response to hypoxic treatment in HEPA cells and HepG2.

The compounds of formula I in the case of hypoxia enhance the expression of several sensitive to hypoxia genes. This indicates that the compounds affect the overall metabolic pathway regulation of the oxygen-sensitive genes. The compounds of formula I that promotes adaptation to stress caused by hypoxia and hypoxia-reoxygenation applicable for protection against obosnovanie hypoxia and hypoxia-re-oxygenation. It is expected that the compounds will be therapeutically useful in conditions where the tissue damage caused by poor blood circulation, contraction and spasm of the arteries, arteriosclerosis, heart attack, pulmonary embolism, thrombosis, low blood pressure, shock, burns, frostbite. Compounds according to the invention can be also effective in secondary hypoxic conditions associated with degenerative and metabolic diseases (Alzheimer's, diabetes).

Impact on the level of the enzyme LDH exposed to hypoxia cells HepG2

The HepG2 cells were cultured in DMEM with addition of 10% FCS in air containing 5% CO2at 37°C. Put 10 cells in 1 ml of medium tablet in wells of a 24-hole tablet Costar for cell cultures. The next day cells were treated with the studied compounds at a concentration of 30 μg/ml, and then the cells were subjected to hypoxic treatment (1% 02with 5% CO2in gaseous nitrogen) within 24 hours Part of the control cultures were treated water used as solvent, the other part is not subjected to hypoxia. At the end of the hypoxic treatment medium was removed and cells washed twice with cold SPR. Cell lysates were prepared in 0.05% Triton X-100 containing phosphate buffer (0.05 M). After centrifugation (2 min, 20000 g) LDH activity in the supernatant was determined on the basis of race is an ode to NADH in the presence of sodium pyruvate as a substrate.

Applied hypoxic treatment induced a 3-fold increase in the content of LDH in the cells. In addition to the treatment of hypoxia, the compounds of formula I increased the level of LDH in the cells in an additional way.

Antiviral effect

Retroviral genome consists of single-stranded RNA molecules, which is replicated from the intermediate double-stranded DNA. Inserting a double-stranded DNA into the host genome is a crucial event in the life cycle of the virus. The insertion mechanism similar to the mechanism of transposition.

The enzyme reverse transcriptase makes a DNA copy of the viral RNA. Double-stranded DNA is synthesized in the cytoplasm of infected cells. Then the linear DNA is transported into the nucleus and one or more copies integrated into the genome of the host cell. Integration is mediated by the integrase enzyme. When the proviral DNA is integrated, it uses enzymes of the host cell to produce viral RNA, which serves as mRNA and as genome after packaging into virions.

During viral replication undisturbed function of the reverse transcriptase is essential. Therefore, inhibition of reverse transcriptase provides an efficient way to suppress the replication of retroviruses. Part of the currently available HIV drugs acts by inhibiting the inverse is Oh transcriptase. Currently, the most effective therapies directed against the human immunodeficiency virus, based on combinations of different drugs against HIV. One or two components of these combinations are reverse transcriptase inhibitors. There are two main types of reverse transcriptase inhibitors. One consists of nucleoside analogues, a well-known representative of this group is azidothymidine, i.e. AZT. These compounds inhibit the enzyme activity by connecting to the nucleotide-binding site. Another type of reverse transcriptase inhibitors are nucleoside analogues. These compounds are also connected to the enzyme, but not in the nucleotide-binding site. The binding is specific, relatively stable and leads to deformation of the active centre of the enzyme, causing a significant loss of enzyme activity.

The inhibitory activity of the compounds according to the invention in respect of reverse transcriptase was investigated as follows. These compounds may be classified as non-nucleoside analogues reverse transcriptase inhibitors. The experiment was performed in the reverse transcriptase of the virus murine Moloney leukemia, which is considered a good model of HIV's reverse transcriptase enzyme. The experiment was as follows.

Using analyze who measured the incorporation of [ 3H]dTTP into cDNA using a matrix of poly(dA) and primer oligo(dT)12-18. The reaction was carried out in a volume of 20 µl.

The reaction mixture composition:

2 µl buffer 10x,

20 µl of matrix primer,

5 μm dTTP.

2 MCI of [3H]dTTP,

the analyzed compound, dissolved in buffer 1 X.

The reaction was started by adding 5 units of reverse transcriptase.

The composition of the buffer 10 X reverse transcriptase:

500 mm Tris-HCl, pH 8.3,

80 mm MgCl2,

300 mm KCl,

100 mm DTT.

The reaction mixture was incubated for 40 min at 37°C. Then, 15 μl of reaction mixture was transferred to the filter disks Whatman DE81 that sequentially washed with 5% denitrification buffer, water and 96% (vol./about.) the ethanol. After drying the filter disks were placed in 5 ml of scintillation mixture (OptiPhase HiSafe 3, Wallac) and radioactivity was measured in a scintillation counter Packard Tri-Carb CE.

As a positive control in the experiments used two compounds with known inhibitory activity: the nucleoside analogue AZT and non-nucleoside type nevirapine. Nevirapine is associated with the so-called benzodiazepine binding site of the enzyme. The results of the experiments led to the following conclusions. Compounds of the invention inhibit reverse transcriptase of the virus murine Moloney leukemia. The compounds used in conc the operations of 0.2-2.0 µg/ml Based on the dose-dependent inhibitory activity against reverse transcriptase can be concluded that the inhibitory activity of the new compounds is higher than that for the baseline, but less than the effect of nucleoside analogue AZT. Because the used enzyme is considered as a reliable model of HIV reverse transcriptase, the observed results may be considered as the impact of HIV.

Recent data indicate that PARP necessary for integration into the viral genome into the cell host and PARP inhibition blocks the viral integration into the genome of the host's DNA. For this reason, non-toxic PARP inhibitors can suppress virulent retroviruses and stop the spread of retroviruses like HIV and hepatitis viruses are not the type of Century

Based on the above experimental results it can be established that the compounds according to the invention due to its inhibitory effect on reverse transcriptase and PARP can also be used as the active antiviral substances, with a few areas of impact.

Thus, the new derivatives amidoximes propenylboronic acids can be used as active ingredients of pharmaceutical compositions.

Therefore, the invention includes a pharmaceutical composition comprising at is the quality of the active ingredient derived unsaturated hydroxamic acids of formula I or a N-oxide, or geometric isomers and/or optical isomers, or pharmaceutically acceptable acid additive salt and/or Quaternary derivative and one or more conventional carriers used in pharmaceutical compositions.

The pharmaceutical composition according to the invention usually contain 0.1 to 95% mass, preferably 1-50% mass, acceptable 5-30% of the mass of active ingredient suitable for the treatment of diseases which are based on the state of oxygen and energy deficiency, inhibition of PARP, especially autoimmune or neurodegenerative and/or viral diseases, moreover, to prevent toxic effects.

In connection with the invention, the term "active ingredient" means a compound of formula I or its N-oxide, or one or more geometrical and/or optical isomers of the compounds of formula I or a N-oxide, pharmaceutically acceptable acid additive salt and/or Quaternary salt of the compounds of formula I or a N-oxide, or pharmaceutically acceptable acid additive salt and/or Quaternary salt of isomers of compounds of formula I or N-oxide.

The pharmaceutical composition according to the invention is applicable for oral, parenteral or rectal injection or for local treatment and may be solid or liquid.

Solid pharmaceutical to the notizie, applicable for oral administration may be powders, capsules, tablets, tablets coated with microcapsules, etc. and may include binding agents such as gelatin, sorbitol, poly(vinyl pyrrolidone), etc.; fillers such as lactose, glucose, starch, calcium phosphate, etc.; excipients for tableting, such as magnesium stearate, talc, poly(ethylene glycol), silicon dioxide, etc.; moisturizing agents, such as sodium lauryl sulfate, etc. as a carrier.

Liquid pharmaceutical compositions applicable for oral administration may be solutions, suspensions or emulsions, and may include, for example, suspendresume agents, such as gelatin, carboxymethyl cellulose, etc.; emulsifiers, such as servicemanual etc.; solvents such as water, oil, glycerine, propylene glycol, ethanol and so on; preservatives, such as methyl ether n-hydroxybenzoic acid, etc. as a carrier.

Pharmaceutical compositions applicable for parenteral administration are, as a rule, sterile solutions of the active ingredient.

Dosage forms listed above, as well as other dosage forms are known, see, for example, Remington's Pharmaceutical Sciences, 18th-oe edition, Mack Publishing Co., Easton, USA (1990).

Pharmaceutical whom azizia, as a rule, contains the standard dose. The typical dose for adult patients is daily 0.1 to 1000 mg of the compounds of formula I or a N-oxide, or pharmaceutically acceptable acid additive salts and/or Quaternary derivative per 1 kg of body weight. The daily dose may be introduced in the form of one or more portions. The effective dose depends on many factors and is determined by the doctor.

The pharmaceutical composition is prepared by mixing the active ingredient with one or more carriers and converting the resulting mixture into a pharmaceutical composition is known essentially the way. The methods known from the literature, for example, the above-mentioned Remington''s Pharmaceutical Sciences.

A preferred subgroup of pharmaceutical compositions according to the invention contains as an active ingredient derived amidoxime propenylboronic acid of formula Ia, where R, R', R3, R4and R5have the meanings defined in connection with formula Ia, or a N-oxide, or geometric isomers and/or optical isomers, or pharmaceutically acceptable acid additive salt and/or Quaternary salt.

Another preferred group of pharmaceutical compositions according to the invention contains as an active ingredient derived amidoxime propenylboronic acid of the formula Ib, R, R', R3, R4, R5and X have the meanings defined in connection with formula Ib, or a N-oxide, or geometric isomers and/or optical isomers, or pharmaceutically acceptable acid additive salt and/or Quaternary salt.

An additional preferred group of pharmaceutical compositions according to the invention contains as an active ingredient derived amidoxime propenylboronic acid of the formula Ic, where R, R', R4and R5have the meanings defined in connection with formula Ic, or a N-oxide, or geometric isomers and/or optical isomers, or pharmaceutically acceptable acid additive salt and/or Quaternary salt.

The invention includes a method of treatment in which the patient is suffering particularly from States associated with oxygen deficiency and/or energy deficiency, or from disease, based on the suppression of PARP, especially autoimmune or neurodegenerative disease, and/or viral diseases and/or diseases caused by the toxic effect, undergoes therapy non-toxic dose derived amidoxime propenylboronic acid of the formula I or an N-oxide, or a geometric isomer, and/or optical isomer, or pharmaceutically acceptable acid additive salts and/or Quaternary derivative.

In addition, from retina includes the use of derivative amidoxime propenylboronic acid of the formula I or an N-oxide, or a geometric isomer, and/or optical isomer, or pharmaceutically acceptable acid additive salts and/or Quaternary derivative to obtain a pharmaceutical composition suitable for treating a condition associated with oxygen deficiency and/or energy deficiency, or disease, based on the suppression of PARP, especially autoimmune or neurodegenerative disease, and/or viral diseases and/or diseases caused by the toxic effect.

The invention is further explained by the following examples.

Examples

Example 1

Hydrochloride 3-styryl-4-(3-piperidinophenyl)-Δ2-1,2,4-oxadiazole-5-she

Dissolved 0,94 g (0,005 mol) 3-styryl-Δ2-1,2,4-oxadiazole-5-it in 6 ml of acetone, the resulting solution was added 1.19 g (0,006 mole) of the hydrochloride of 1-chloro-3-piperidinedione, 0,76 g (0,0055 mole) of anhydrous potassium carbonate, 1 ml of methanol and 0.05 g of potassium iodide. The reaction mixture was heated at boiling for 20 h, the inorganic salt was separated by filtration and the solution was evaporated under reduced pressure. The remaining oily crude product was dissolved in isopropanol, the resulting solution was acidified by addition of a solution of hydrogen chloride in isopropanol, the reaction mixture was left to stand in a refrigerator in accordance with the s night, and precipitated crystals were separated by filtration. Thus received of 1.05 g of the title compound; tPL: 203-205°C.

IR (KBr, v, cm-1): 2550-2650 (NH+), 1768 (CO), 1639 (C=N).

1H-NMR (DMSO-d6that δ): 1,3-1,85 (6N, m, 3,4,5-CH2piperidine), 2,11 (2H, m, CH2cut), 2,82 (2H, m, CH2piperidine), to 3.09 (2H, m, -CH2-N)to 3.36 (2H, m, CH2piperidine), a 3.87 (2H, m, -och2-), 7,12 (1H, d, arylbetween 7.4 to 7.5 (3H, m, aryl-H), 7,60 (1H, d, aryl7,8 (2H, m, aryl-H), AND 10.3 (1H, ush.,+NH).

Example 2

Hydrochloride 3-styryl-4-(3-piperidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she

A) Dissolving 2.25 g (0,008 mole) 3-styryl-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it in 10 ml of ethanol, the resulting solution was added 0.68 g (0,008 mole) of piperidine, the mixture was heated to 50°and with stirring was added dropwise a solution of 0.32 g (0,008 mole) of sodium hydroxide in 2 ml of water. The reaction mixture was stirred at 50-55°C for additional 2 h, the precipitated crystals were separated by filtration, dried, and then dissolved in ethanol by heating and the resulting solution was acidified by the addition of a solution of hydrogen chloride in isopropanol. The reaction mixture was left to stand in a refrigerator overnight, the precipitated crystals were separated by filtration and dried. Thus received of 1.09 g of the title compound; tPL: 234-235�B0; C.

3 Styryl-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it is used as a starting compound, was obtained by reaction of 3-styryl-Δ2-1,2,4-oxadiazole-5-she and epichlorohydrin in accordance with the methods described in the literature [Chem. Ber.,108, 1911 (1975)].

1H-NMR (DMSO-d6that δ): 1,3-1,9 (6N, m, 3,4,5-CH2piperidine), 2,9-3,6 (6N, m, SN2), 3,8 (2H, m, 1-CH2cut), 4,35 (1H, m,6,3 (1H, ush.,7,19 (1H, d, aryl7,37-7,47 (3H, m, aryl-H), EUR 7.57 (1H, d, arylto 7.84 (2H, m, aryl-H), of 10.25 (nos.,+NH).

B) was Dissolved 0.65 g (0,0027 mole) 3-styryl-4-(2,3-epoxypropyl)-Δ2-1,2,4-oxadiazole-5-it in 2 ml of methanol and the resulting solution was added 0.24 g (0,0028 mole) of piperidine. The reaction mixture, which was warm, he left at four o'clock the Precipitated crystals were separated by filtration, then dissolved in isopropanol. The solution was acidified by adding a solution of hydrogen chloride in isopropanol. Thus crystallised of 0.38 g of the title product, which is identical to the compound obtained in the section. A; tPL: 234-235°S. 3 Styryl-4-(2,3-epoxypropyl)-Δ2-1,2,4-oxadiazole-5-it is used as a starting compound, was prepared as follows: dissolve 1.5 g (0,0053 mole) 3-St the RIL-4-(3-chloro-2-hydroxypropyl)-Δ 2-1,2,4-oxadiazole-5-Oh in 5 ml of acetone, the resulting solution was added 0.73 g of anhydrous potassium carbonate, the reaction mixture was heated at boiling for 16 h, then filtered and evaporated under reduced pressure. Thus received 1,41 g 3-styryl-4-(2,3-chloro-2-epoxypropyl)Δ2-1,2,4-oxadiazole-5-it is in the form of oily substance.

C) was Dissolved 0.3 g (0,0016 mole) 3-styryl-Δ2-1,2,4-oxadiazole-5-it is in 3 ml of acetone, the resulting solution was added 0,41 g (0,0019 mole) of the hydrochloride of 3-piperidino-2-hydroxy-1-chloropropane, of 0.48 g of anhydrous potassium carbonate, 1 ml of methanol and 0.05 g of potassium iodide. The reaction mixture was heated at boiling for 40 h, then filtered and the solvent drove away under reduced pressure. The residue was dissolved in 5% aqueous hydrochloric acid, the solution was filtered and the filtrate was podslushivaet the addition of 10% aqueous sodium hydroxide solution. The precipitated product was extracted with chloroform, the solution was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was dissolved in isopropanol and the resulting solution was acidified by adding a solution of hydrogen chloride in isopropanol. Crystallized 0.18 g of product, which is identical to the title compound, obtained in section a; tPL: 234-235°C.

Example 3

Hydrochloride 3-styryl-4-(3-pyrrolidin the o-2-hydroxypropyl)-Δ 2-1,2,4-oxadiazole-5-she

Dissolved 8,4 g (0,03 mole) 3-styryl-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it in 30 ml of ethanol, the resulting solution was added 2.55 g (being 0.036 mole) of pyrrolidine, then dropwise with stirring at 60°With a solution of 1.2 g (0,03 mole) of sodium hydroxide in 8 ml of water. The reaction mixture was stirred additionally for 1 h at 60°C, the ethanol is then drove away under reduced pressure. The residue was acidified by adding concentrated aqueous hydrochloric acid, the solution was treated with activated charcoal, filtered and podslushivaet, adding 2 N. aqueous sodium hydroxide solution. The precipitated oily substance 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 a solution of hydrogen chloride in isopropanol. The crystals were separated by filtration and dried. Thus was obtained 1.8 g of the title compound; tPL: 188-189°C.

1H-NMR (DMSO-d6that δ): 1,8-2,0 (4H, m, 3,4-CH2pyrrolidine), 3,06-3,55 (6N, m, SN2), 3,82 (2H, d, 1-CH2cut), is 4.21 (1H, m,of 6.25 (1H, d,7,14 (1H, d, arylbetween 7.4 to 7.5 (3H, m, aryl-H), 7,58 (1H, d, arylof 7.82 (2H, , aryl-H), and 10.3 (1H, ush.,+NH).

Example 4

Hydrochloride 3-styryl-4-(3-hexamethyleneimino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she

Introduced in the reaction of 2.8 g (0,01 mol) 3-styryl-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she 1.19 g (0,012 mol) of hexamethylenimine in accordance with the procedure described in example 3. Hydrochloride besieged in isopropanol solution, adding a solution of hydrogen chloride in isopropanol. Thus was obtained 1.0 g of the title compound; tPL: 202-203°C.

1H-NMR (CDCl3+ DMSO-d6that δ): 1,6-2,0 (8H, m, 3,4,5,6-CH2hexamethylenimine), 3,1-3,6 (6N, m, SN2), 3,8 (2H, m, 1-CH2cut), 4,35 (1H, m,6,21 (1H, d,7,11 (1H, d, arylof 7.4 (3H, m, aryl-H), EUR 7.57 (1H, d, arylto 7.77 (2H, m, aryl-H), AND 10.0 (1H, ush.,+NH).

Example 5

Hydrochloride 3-styryl-4-(3-morpholino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she

Introduced in the reaction of 4.2 g (0,015 mol) 3-styryl-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it with 1.6 g (0,018 mole) of the research in accordance with the procedure described in example 3. Hydrochloride besieged in ethanol solution by adding a solution of hydrogen chloride in isopropanol. Thus received to 0.67 g of the title compound; tPL: 232-234°S./p>

1H-NMR (DMSO-d6that δ): 3,1-3,55 (6N, m, 3,5-CH2the research, 3-CH2cut), 3,8-4,0 (6N, m, 2,6-CH2the research, 1-CH2cut), 4,37 (1H, m,6,3 (1H. ush.,for 7.12 (1H, d, arylof 7.4 (3H, m, aryl-H), AND 7.6 (1H, d, aryl7,8 (2H, m, aryl-H), OR 10.6 (1H, ush.,+NH).

Example 6

Hydrochloride 3-styryl-4-[3-(tert.-butylamino)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-she

Was introduced into the reaction 6.6 g (0,024 mole) 3-styryl-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she 2,63 g (being 0.036 mole)of tert.-of butylamine in accordance with the procedure described in example 3. Hydrochloride besieged in isopropanole solution, adding a solution of hydrogen chloride in isopropanol. Thus was obtained 1.8 g of the title compound; tPL: 244-246 C.

1H-NMR (DMSO-d6that δ): 1,3 (N, s, tert.-butyl), 2,9-3,15 (2H, m, 3-CH2cut), 3,85 (2H, m, 1-CH2cut), is 4.15 (1H, m,between 6.08 (1H, d,for 7.12 (1H, d, aryl7,40 (3H, m, aryl-H), 7,55 (1H, d, aryl7,8 (2H, m. aryl-H), 8,55 (1H, ush., NH), cent to 8.85 (1H, ush., NH).

Example 7

The dihydrochloride of 3-styryl-4-[3-(4-methyl-1-piperazinil)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-she

Introduced in the reaction of 8.4 g (0,03 mole) 3-tis the Il-4-(3-chloro-2-hydroxypropyl)-Δ 2-1,2,4-oxadiazole-5-she 3.6 g (being 0.036 mole) of N-methylpiperazine in accordance with the procedure described in example 3. Hydrochloride besieged in isopropanole solution, adding a solution of hydrogen chloride in isopropanol. Thus received of 2.08 g of the title compound; tPL: 206-208°C.

1H-NMR (DMSO-d6that δ): 2,77 (3H, s, CH3), 3,01-3,1 (2H, m, 3-CH2cut), and 3.6 (8H, m, CH2piperazine), 3,8 (2H, m, 1-CH2cut), to 4.23 (1H, m,6,23 (1H, ush.,7,03 (1H, d, arylof 7.4 (3H, m, aryl-H), 7,58 (1H, d, arylto 7.77 (2H, m, aryl-H), AND 11.8 (2H, ush., 2+NH).

Example 8

Hydrochloride 3-styryl-4-[3-(1,2,3,4-tetrahydro-2-ethanolic)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-she

Introduced in the reaction of 2.8 g (0,01 mol) 3-styryl-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it with 1.6 g (0,012 mol) of 1,2,3,4-tetrahydroisoquinoline in accordance with the procedure described in example 3. Hydrochloride besieged in isopropanole solution, adding a solution of hydrogen chloride in isopropanol. Thus received 0,83 g of the title compound; tPL: 208-210°C.

1H-NMR (DMSO-d6that δ): 3,0-3,6 (8H, m, CH2the isoquinoline, SN2cut), a-3.84 (2H, m, 1-CH2cut), and 4.4 (1H, m,6,3 (1H, ush. 7,13 (1H, d, aryla 7.2 to 7.5 (7H, m, aryl-H), 7,60 (1H, d, aryl7,8 (2H, m, aryl-H), OR 10.6 (1H, ush.,+NH).

Example 9

Hydrochloride 3-styryl-4-[3-(2,6-dimethylaniline)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-she

Introduced in the reaction of 8.4 g (0,03 mole) 3-styryl-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she 4,36 g (being 0.036 mole) of 2,6-dimethylaniline in 50 ml of methanol in accordance with the procedure described in example 3. Hydrochloride besieged in isopropanole solution, adding a solution of hydrogen chloride in isopropanol, and then was led from a mixture of one volume of isopropanol and one volume of ethanol. Thus received of 1.62 g of the title compound; tPL: 182-184°C.

1H-NMR (DMSO-d6that δ): 2,44 (6N, s, 2CH3), 3,16-of 3.53 (2H, m, 3-CH2cut), 3,86 (2H, m, 1-CH2cut), is 4.21 (1H, m,6,0 (1H, ush.,7,10 (1H, d, aryl7,14 (3H, m, aryl-H), of 7.4-7.5 (3H, m. aryl-H), TO 7.59 (1H, d, arylfor 7.78 (2H, m, aryl-H), AND 9.0 (2H, ush.,+NH2).

Example 10

Hydrochloride 3-(3,4-dimethoxytrityl)-4-(3-piperidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she

Was introduced into the reaction 3.4 g (0,01 mol) of 3-(3,4-dimethoxytrityl)-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-ONAT 1,02 is (0,012 mol) of piperidine in accordance with the methodology described in example 3. Hydrochloride besieged in ethanol solution, adding a solution of hydrogen chloride in isopropanol. Thus was obtained 1.8 g of the title compound; tPL: 187-188°C.

1H-NMR (CDCl3+ DMSO-d6that δ): 1,4-2,0 (6N, m, 3,4,5-CH2piperidine), 3,18-3,31 (6N, m, 2,6-CH2piperidine, 3-CH2cut), 3,85-to 3.92 (2H, m, 1-CH2cut), the 3.89 (3H, s, -och3), of 3.96 (3H, s, -och3), of 4.45 (1H, m,6,27 (1H, ush,6,93 (1H, m, aryl-H), 6,98 (1H, d, aryl7,21 (1H, m, aryl-H), 7,42 (1H, m, aryl-H), OF 7.48 (1H, d, arylof 9.8 (1H, ush.,+NH).

3-(3,4-Dimethoxytrityl)-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it is used as starting compound was obtained from 3-(3,4-dimethoxytrityl)-Δ2-1,2,4-oxadiazole-5-she and epichlorohydrin in accordance with methods known from the literature [Chem. Ber,108, 1911 (1975)].

Example 11

Hydrochloride 3-styryl-4-[3-(1-methyl-4-piperazinil)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-she

Introduced in the reaction of 2.0 g (0,0059 mole) of 3-(3,4-dimethoxytrityl)-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she 0.71 g (0,0071 mole) of N-methylpiperazine in accordance with the procedure described in example 3. Hydrochloride besieged in isopropanole solution, adding to dissolve the hydrogen chloride in isopropanol. Thus was obtained 0.8 g of the title compound; tPL: 192-193°C.

1H-NMR (DMSO-d6that δ): 2,8 (3H, s, N-CH3), a 3.2 to 3.8 (10H, m, CH2piperazine, 3-CH2cut), of 3.80 (3H, s, och3), 3,83 (2H, m, 1-CH2cut), 3,86 (3H, s, -och3), or 4.31 (1H, m,6,3 (1H, ush,7,0 (1H, m, aryl-H), 7,03 (1H, d, aryl7,30 (1H, m, aryl-H), TO 7.50 (1H, m, aryl-H), 7,51 (1H, d, aryl11,8 (2H, ush., 2+NH).

Example 12

Amidoxime N-(piperidino-2-hydroxypropyl)cinnamic acid

In accordance with the procedure described in example 2, was added to 1,91 g (0,006 mole) 3-styryl-4-(3-piperidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-10 ml ethanol and 10 ml of 10% aqueous sodium hydroxide solution and the reaction mixture was heated at boiling for 2 hours, the Ethanol was evaporated under reduced pressure, the pH value of the residue is brought to 8 by addition of hydrochloric acid. Decantation of the water phase with partially solid product, the residue was dissolved in methanol. When diluted with water, crystallized 0,79 g of the title compound; tPL: 114-115°C.

1H-NMR (DMSO-d6that δ): 1.7 to 1.9 (6N, m, 3,4,5-CH2piperidine), to 2.1-2.3 (6N, m, 2,6-CH2piperidine, 3-CH2cut), 3,2-to 3.33 (2H, m, 1-CH2cut), 3,83 (1H, m,5,6 (1H ush, IT), 6,55 (1H, d, arylto 7.15 (1H, d, aryl7,8-to 7.32 (3H, m, aryl-H), 7,44 (2H, m, aryl-H).

Example 13

Demolet (nonadditivity) amidoxime N-(3-morpholino-2-hydroxypropyl)cinnamic acid

In accordance with the procedure described in example 5, was added to 2.76 g (0,0075 mole) 3-styryl-4-(3-morpholino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-10 ml ethanol and 10 ml of 10% aqueous sodium hydroxide solution and the reaction mixture was heated at boiling for 2 hours, the Ethanol was evaporated under reduced pressure, the pH value of the residue is brought to 8 by addition of hydrochloric acid. The precipitated oily product was extracted with dichloromethane, the organic solution was dried over anhydrous sodium sulfate, the solvent was evaporated. Maleate besieged in acetone, adding maleic acid. Thus was obtained the title compound; tPL: 128-130°C.

1H-NMR (CDCl3+ DMSO-d6that δ): 2,8-3,2 (6N, 3,5-CH2the research, 3-CH2cut), 3,3-3,8 (6N, m, 2,6-CH2the research, 1-CH2cut), 4,10 (1H, m,6,05 (4H, s, CH maleic acid), to 6.75 (1H, d, aryl7,30 (1H, d, arylof 7.3 (3H, m, aryl-H), TO 7.50 (2H, m, aryl-H).

Example 14

Tremolet (nonadditivity) amidoxime N-[3-(1-methyl-4-piperazinil)-2-g is droxidopa] cinnamic acid

In accordance with the procedure described in example 7, 1,17 g (0,0025 mole) 3-styryl-4-[3-(4-methyl-1-piperazinil)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-it was introduced in reaction with sodium hydroxide. Maleate besieged in acetone, adding maleic acid. Thus received to 0.63 g of the title compound; tPL: 142-143°C.

1H-NMR (DMSO-d6that δ): 2,7 (3H, s, CH3), of 2.5-3.2 (10H, m, CH; piperazine, 3-CH2cut), 3,31-of 3.42 (2H, m, 1-CH2cut), 3,81 (1H, m,6,14 (6N, s, CH maleic acid), of 6.90 (1H, d, aryl7,28 (1H, d, arylof 7.4 (3H, m, aryl-H), THE 7.65 (2H, m, aryl-H).

Example 15

Amidoxime N-(3-morpholino-2-hydroxypropyl)-3,4-dimethoxyphenol acid

In accordance with the procedure described in example 13, was introduced into the reaction 3,91 g (0,01 mol) of 3-(3,4-dimethoxytrityl)-4-(3-morpholino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-one with sodium hydroxide. Thus was obtained 1.2 g of the title compound as an oily product.

1H-NMR (DMSO-d6that δ): 3,18-3,35 (6N, 3,5-CH2the research, 3-CH2cut), of 3.60 (2H, m, 1-CH2cut), of 3.60 (2H, m, 1-CH2cut), 3,82 (3H, s, och3), 3,86 (3H, s, och3), to 3.92 (4H, m, 2,6-CH2of the research), 4,34 (1H, m,6,3 (1H, ush.,/img> 6,98 (1H, d, aryl7,02 (1H, m, aryl-3H), 7,24 (1H, m, aryl-2H), 7,35 (1H, d, aryl7,40 (1H, m, aryl-6N).

Example 16

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

To 1.65 g (0, 0043 mole) of the hydrochloride of 3-styryl-4-(3-piperidino-2-chlorpropyl)-Δ2-1,2,4-oxadiazole-5-it was added a mixture of 33 ml of ethanol and 33 ml of 2 N. aqueous sodium hydroxide solution, the reaction mixture was heated at boiling for 30 minutes with stirring, then was evaporated under reduced pressure and the residue suspended in 10 ml of water. The crystals were separated by filtration, washed with water and dried. Thus was obtained 1.06 g of the title compound; tPL: 147-149°C.

1H-NMR (DMSO-d6that δ): 1.3 to 1.7 (6N, m, 3,4,5-CH2piperidine), 2,3-2,7 (6N, m, 2,6-CH2piperidine, 6-CH2), 3,25-3,6 (2H, m, 5-CH2oxadiazine), of 3.95 (1H, m, 6-CH oxadiazine), 5,0 (1H, ush., 4-NH oxadiazine), and 6.5 (1H, d, arylof 6.9 (1H, d, aryla 7.2 to 7.5 (5H, m, aryl-H).

Used as source hydrochloride 3-styryl-4-(3-piperidino-2-chlorpropyl)-Δ2-1,2,4-oxadiazole-5-it was obtained from hydrochloride of 3-styryl-4-(3-piperidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it (obtained as described in example 2) with thionyl chloride in accordance with methods known from the literature Chem. Ber.,108, 1911 (1975)].

Example 17

Demolet (nonadditivity) 3-styryl-6-morpholinomethyl-4H-5,6-dihydro-1,2,4-oxadiazine

To 1.5 g (to 0.0039 mole) of the hydrochloride of 3-styryl-4-(3-morpholino-2-chlorpropyl)-Δ2-1,2,4-oxadiazole-5-it was added 9 ml of ethanol and 9 ml of 10% aqueous sodium hydroxide solution, the reaction mixture was heated at boiling for 30 minutes, the Ethanol was evaporated under reduced pressure, the residue was acidified with 5% hydrochloric acid. The resulting solution was treated with activated charcoal, filtered and podslushivaet by adding 10% aqueous sodium hydroxide solution. 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 was added a solution of 0.66 g of maleic acid in ethyl acetate. Thus was obtained 1.0 g of the title product; tPL:137°C.

1H-NMR (DMSO-d6that δ):3,1-3,44 (8H, m, 5-CH2, 6-CH2; 3 - and 5-CH2of the research), 3,82 (4H, m, 2 - and 6-CH2of the research), 4,08 (1H, m, 6-CH), 6,18 (4H, s, CH maleic acid), to 6.43 (1H, d, arylof 7.25 (1H, ush., 4-H), 7,33-7,51 (5H, m, aryl-H), 13-14 (ush., HE maleic acid)

Used as a starting compound hydrochloride 3-styryl-4-(3-morpholino-2-chlorpropyl)-Δ2-1,2,4-oxadiazole-5-she's got and the hydrochloride of 3-styryl-4-(3-morpholino-2-hydroxypropyl)-Δ 2-1,2,4-oxadiazole-5-it (obtained in accordance with example 5) by heating with thionyl chloride, followed by evaporation of the reaction mixture.

Example 18

Demolet (nonadditivity) 3-styryl-6-(1,2,3,4-tetrahydro-2-ethanolic)methyl-4H-5,6-dihydro-1,2,4-oxadiazine

To 1.1 g (0,0025 mole) of the hydrochloride of 3-styryl-4-[3-(1,2,3,4-tetrahydro-2-ethanolic)-2-chlorpropyl)-Δ2-1,2,4-oxadiazole-5-it was added 8 ml of ethanol and 8 ml of 10% aqueous sodium hydroxide solution and the reaction mixture was heated at boiling for half an hour. The ethanol was evaporated under reduced pressure, the residue was dissolved in 5% hydrochloric acid. The solution was treated with activated charcoal, filtered, podslushivaet by adding 10% aqueous sodium hydroxide solution and was extracted with ethyl acetate. United an ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in ethyl acetate and the resulting solution was added 0.36 g of maleic acid. Thus was obtained 0.55 g of the title compound; tPL: 151-153°C.

1H-NMR (DMSO-d6that δ): 3,10 (2H, m, 4-CH2of isoquinoline), 3,15-3,50 (2H, m, 5-CH2oxadiazine), 3,28-3,39 (2H, m,oxadiazine), 3,44-3,6 (2H, m, 3-CH2of isoquinoline)and 4.2 (1H, m,oxadiazine), 4,4 (2H, s, 1-CH2of isoquinoline), 6,13 (4H, s, CH Malei the OIC acid), 6,44 (1H, d, arylto 7.15 (1H, d, aryl7,21-7,33 (4H, m, aryl-H of isoquinoline), 7,33-7,52 (5H, m, aryl-H of phenyl).

Example 19

Hydrochloride 3-(3,4-dimethoxytrityl)-4-[3-(tert.-butylamino)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-she

Dissolved 8,54 g (0,025 mol) of 3-(3,4-dimethoxytrityl)-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it in 40 ml of acetone, the resulting solution was added of 3.46 g (0,025 mol) of anhydrous potassium carbonate. The reaction mixture was heated at boiling for 6 h, then cooled, the inorganic salt was removed by filtration, the solvent was evaporated under reduced pressure. The residue after evaporation was washed with 25 ml of methanol to cause crystallization. Thus was obtained 6.5 g of 3-(3,4-dimethoxytrityl)-4-(2,3-epoxypropyl)-Δ2-1,2,4-oxadiazole-5-it; tPL: 113-115°C.

To 3.04 from g (0,01 mol) of 3-(3,4-dimethoxytrityl)-4-(2,3-epoxypropyl)-Δ2-1,2,4-oxadiazole-5-it was added 15 ml of methanol and 0.73 g (0,01 mol) of tert.-of butylamine, the reaction mixture was heated at boiling for 4 h, then the solvent was evaporated under reduced pressure. The residue was dissolved in 10 ml of 5% hydrochloric acid and the solvent decantation from the sediment, which is not dissolved. The aqueous solution was podslushivaet by adding 10% aqueous sodium hydroxide solution, the resulting mA is lo was dissolved in dichloromethane, the solution was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure. Received 1.7 g of oily product, from which the hydrochloride was besieged in ethanol by adding isopropanol containing hydrogen chloride. Thus was obtained 1.0 g of the title compound; tPL: 225-227°C.

1H-NMR (DMSO-d6that δ): 1,3 (N, s, SN3), 2,93-3,17 (2H, m, 3-CH2cut), of 3.80 (3H, s,of 3.85 (3H, s,3,9 (2H, d, 1-CH2cut), to 4.16 (1H, m,6,12 (1H, d, HE), 7,03 (1H, d, aryl7,51 (1H, d, aryl7,00 (1H, m, aryl-H), 7,29 (1H, m, aryl-H), 7,49 (1H, m, aryl-H), 8,58 (1H, ush., NH), 8,86 (1H, ush., NH).

Example 20

Hydrochloride 3-(3,4-dimethoxytrityl)-4-(3-morpholino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she

Was introduced into the reaction 3.04 from g (0,01 mol) of 3-(3,4-dimethoxytrityl)-4-(2,3-epoxypropyl)-Δ2-1,2,4-oxadiazole-5-it (obtained as described in example 19) with 0.96 g (of 0.11 mol) of the research method described in example 19. Thus was obtained 0.8 g of the title compound; tPL:228-230°C.

1H-NMR (DMSO-d6that δ): 3,2-3,34 (6N, m, 3,5-CH2the research, 3-CH2cut), 3,82 (3H, s, -och3), 3,86 (2H, d, 1-CH2cut), 3,88 (3H, s, -och3), 3,90 (4H, m, 2,6-CH2of the research), 4,43 (H, m,of 6.4 (1H, ush-HE), a 7.0 (1H, d, aryl-H), 7,03 (1H, d, aryl7,29 (1H, m, aryl-H), of 7.48 (1H, m, aryl-H), to 7.50 (1H, d, arylof 10.7 (1H, ush.,+NH).

Example 21

Amidoxime N-[3-(2,6-dimethylaniline)-2-hydroxypropyl]cinnamic acid

Followed the procedure described in example 12 with the difference that as the starting compound used 1.5 g (0,004 mol) 3-styryl-4-[3-(2,6-dimethylaniline)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-it (obtained in accordance with example 9).so was obtained 0.55 g of the title compound; tPL: 143-144°C.

1H-NMR (DMSO-d6that δ): 2,20 (6N, s, 2CH3), 2,82-3,03 (2H, m, 3-CH2cut), 3,15-of 3.27 (2H, m, 1-CH2cut), to 3.64 (1H, m,of 3.80 (1H, m, NH aniline), of 5.15 (1H, ush.,to 5.58 (1H, ush., NH amidoxime), of 6.68 (1H, d, aryl6,69 (1H, m, aryl-H), 6,90 (2H, m, aryl-H), 7,01 (1H, d, aryl, 7,25-of 7.55 (5H, m, aryl-H), to 9.57 (1H, s,

Example 22

Amidoxime N-(3-pyrrolidino-2-hydroxypropyl)cinnamic acid

Followed the procedure described in example 12, except that as the starting compound used hydrochloride 3-styryl-4-(3-pyrrolidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it (obtained in accordance with the laws the AI with example 3). Thus was obtained 0.65 g of the title compound; tPL: 139-141°With (96% ethanol).

1H-NMR (CDCl3+ DMSO-d6that δ): 1,74 (4H, m, 3,4-CH2pyrrolidine), 2,50-2,64 (6N, m, 2,5-CH2pyrrolidine, 3-CH2cut), 3,2-to 3.35 (2H, m, 1-CH2cut in), 3.75 (1H, m,5,6 (1H, t, NH), to 6.58 (1H, d, arylwas 7.08 (1H, d, aryl7,25 was 7.45 (5H, m, aryl-H), and 9.0 (1H, ush.,

Example 23

Amidoxime N-[3-(1,2,3,4-tetrahydro-2-ethanolic)-2-hydroxypropyl]cinnamic acid

a 3.83 g (0,009 moles) of hydrochloride of styryl-4-[3-(1,2,3,4-tetrahydro-2-ethanolic)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-she received in accordance with the procedure described in example 8, is subjected to the interaction with sodium hydroxide in accordance with the procedure described in example 13. The oily product is dissolved in ethyl acetate and left to stand. Gain of 2.51 g specified in the connection header in the form of crystals containing 1 mol of ethyl acetate in the form of crystalline liquid. Tpl.: 72°C.

IR (KBr) ν=3100-3400 (NH, OH), 1730 (CO-OC2H5), 1640 (C=N) cm-1.

Example 24

Amidoxime N-(3-tert.-butylamino-2-hydroxypropyl)cinnamic acid

2.24 g (0,006 moles) of hydrochloride of styryl-4-[(3-tert.-butylamino)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-she received in accordance with the methodology described in example 6, is subjected to the interaction with sodium hydroxide in accordance with the procedure described in example 13. Get 2.0 g specified in the connection header. After recrystallization from ethyl acetate Tpl.: 152-154°C.

1H-NMR (DMSO-d6) δ=1,05 (N, s, tert.-butyl), 2,45 is 2.55 (2H, m, propyl-3-CH2), 3,11-3,26 (2H, m, propyl-1-CH2), 3,52 (1H, m,4,8 (1H, br,to 5.66 (1H, t, NH), 6,72 (1H, d, aryl7,02 (1H, d, aryl7,25-7,40 (3H, m, aryl-H), 7,50-EUR 7.57 (2H, m, aryl-H), 9,58 (1H, br, =N-OH).

Example 25

Demolet N-(3-hexamethyleneimino-2-hydroxypropyl)cinnamic acid 3,62 g (0.01 mol) of the hydrochloride of styryl-4-[(3-hexamethyleneimino-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-she received in accordance with the procedure described in example 4 is subjected to interaction with sodium hydroxide in accordance with the procedure described in example 13. Demolet precipitated in a solution of isopropanol with the addition of maleic acid. The result of 2.51 g specified in the connection header. Tpl.: 134°C.

1H-NMR (DMSO-d6) δ=of 1.5-1.9 (8H, m, hexamethylenimine-3,4,5,6-CH2), 3.1 to 3.4 (8H, m, 4×CH3), was 4.02 (1H, m,6,1 (4H, s, maleic acid CH), 6,8 (1H, d, arylto 7.18 (1H, d, and the Il 7,3 was 7.45 (3H, m, aryl-H), TO 7.59-7,63 (2H, m, aryl-H).

Example 26

Demolet amidoxime N-(3-piperidino-2-hydroxypropyl)-3,4-dimethoxyphenol acid

of 4.25 g (0.01 mol) of the hydrochloride of 3-(3,4-dimethoxytrityl)-4-(3-piperidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she received in accordance with the procedure described in example 10, is subjected to the interaction with sodium hydroxide in accordance with the procedure described in example 13. Demolet precipitated in a solution of isopropanol with the addition of maleic acid. The result of 1.14 g specified in the connection header. Tpl.: 119-121°C.

1H-NMR (DMSO-d6) δ=1,4-1,9 (6N, m, piperidine, 3,4,5-CH2), 2,8-3,6 (8H, m, piperidine-2,6-CH2, propyl 1-and 3-CH2), with 3.79 (3H, s, och3) 3,81 (3H, s, och3), 4,08 (1H, m,6,10 (4H, s, maleic acid CH), 6,69 (1H, d, aryl7,17 (1H, d, aryl6,93-of 7.23 (3H, m, aryl-H).

Example 27

Demolet amidoxime N-(3-pyrrolidino-2-hydroxypropyl)-4-methoxycatechol acid

1.5 g (0,004 mol) of the hydrochloride of 3-(4-methoxytrityl)-4-(3-pyrrolidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she received in accordance with the procedure described in example 28, is subjected to the interaction with sodium hydroxide in accordance with the procedure described in example 13. Demolet about adut in a solution of isopropanol with the addition of maleic acid. The result of 1.52 g specified in the connection header. Tpl.: 133°C.

1H-NMR (DMSO-d6) δ=1,8-of 2.05 (4H, m, pyrrolidine-3,4-CH2), a 3.1 to 3.25 (4H, m, pyrrolidine-2,5-CH2), of 3.25 to 3.35 (2H, m, propyl 3-CH2), 3,80 (2H, m, propyl-1-CH2), of 3.85 (3H, s, och3), 3,92-4,00 (1H, m,6,10 (4H, s, maleic acid SN), of 6.68 (1H, d, aryl6,98 (2H, d, aryl-H), 7,2 (1H, d, aryl7,58 (2H, d, 2 aryl-H).

Example 28

Hydrochloride 3-(4-methoxytrityl)-4-(3-pyrrolidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-he

a 10.74 g (or 0.035 moles) of 3-(4-methoxytrityl)-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it is subjected to the interaction of 3.32 g (0,047 moles) of pyrrolidine in accordance with the procedure described in example 3. The hydrochloride is precipitated in isopropanol solution by adding hydrogen chloride in isopropanol. The result is 2.67 g specified in the connection header. Tpl.: 171°C.

1H-NMR (DMSO-d6) δ=1,8-2,04 (4H, m, pyrrolidine-3,4-CH2), 3,05-of 3.06 (4H, m, pyrrolidine-2,5-CH2), 3,21-to 3.36 (2H, m, propyl 3-CH2), 3,80 (2H, m, propyl-1-CH2), 3,81 (3H, s, och3), 4,20 (1H, m,6,24 (1H, d, HE), OF 6.96 (1H, d, aryl7,52 (1H, d, aryl6,99-7,05 (1H, m, aryl-H), TO 7.77 (2H, m, aryl-H).

<> 3-(4-methoxytrityl)-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it is used as a starting compound, is produced by the interaction of 3-(4-methoxytrityl)-Δ2-1,2,4-oxadiazole-5-one with epichlorohydrin according to known literature methods (Chem. Ber.,108,1911 (1975)).

Example 29

Demolet amidoxime N-(3-piperidino-2-hydroxypropyl)-4-methoxycatechol acid

1,83 g (0.005 mol) of the hydrochloride of 3-(4-methoxytrityl)-4-(3-piperidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she received in accordance with the procedure described in example 30, is subjected to the interaction with sodium hydroxide in accordance with the procedure described in example 13. Demolet precipitated in a solution of isopropanol with the addition of maleic acid. The result is 1.77 g specified in the connection header. Tpl.: 129-132°C.

1H-NMR (DMSO-d6) δ=1,3-1,9 (6N, m, piperidine, 3,4,5-CH2), 2,98 is 3.40 (8H, m, piperidine-2,6-CH2, propyl 1,3-CH2), with 3.79 (3H, s, -och3) 4,10 (1H, m,between 6.08 (4H, s, maleic acid), 6,70 (1H, d, aryl7,0 (2H, d, aryl-H), 7,25 (1H, d, arylto 7.7 (2H, d, aryl-H).

Example 30

Hydrochloride 3-(4-methoxytrityl)-4-(3-piperidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-he

5.6 g (0,018 moles) of 3-(4-methoxytrityl)-4-(3-chloro-2-hydroxypropyl)-Δ 2-1,2,4-oxadiazole-5-it is subjected to interaction with 2,08 g (0,024 moles) of piperidine in accordance with the procedure described in example 3. The hydrochloride is precipitated in isopropanol solution by adding hydrogen chloride in isopropanol. The result is 1.24 g specified in the connection header. Tpl.: 204°C.

1H-NMR (DMSO-d6) δ=1,3-2,0 (6N, m, piperidine-3,4,5-CH2), 2,95-3,51 (6N, m, piperidine-2,6-CH2, propyl-3-CH2), with 3.79 (2H, m, propyl 1-CH2), 3,81 (3H, s, och3), to 4.33 (1H, m,6,24 (1H, d, HE), 6,98 (1H, d, arylof 6.99 (1H, m, aryl-H), 7,52 (1H, d, arylfor 7.78 (2H, m, aryl-H).

Example 31

Demolet amidoxime N-(3-pyrrolidino-2-hydroxypropyl)-3,4-dimethoxyphenol acid

1,49 g (0,004 mol) of 3-(3,4-dimethoxytrityl)-4-(3-pyrrolidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she received in accordance with the procedure described in example 32, is subjected to the interaction with sodium hydroxide in accordance with the procedure described in example 13. Demolet precipitated in a solution of isopropanol with the addition of maleic acid. The result is 0.87 g specified in the connection header. Tpl.: 125-127°C.

1H-NMR (DMSO-d6) δ=1,94 (4H, m, pyrrolidine-3,4-CH2), 3,14-to 3.35 (8H, m, pyrrolidin-2,5-CH2, propyl 1,3-CH2 ), with 3.79 (3H, s, och3), 3,81 (3H, s, och3), 3,98 (1H, m,5,90 (1H, br, OH), 6,1 (4H, s, maleic acid CH), 6,69 (1H, d, arylof 6.99 (1H, d, aryl-5H), 7,16 (1H, d, aryl7,16 (1H, m, aryl-6N), OF 7.23 (1H, d, aryl-2H).

Example 32

3-(3,4-dimethoxytrityl)-4-(3-pyrrolidino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-he

to 5.00 g (0,016 moles) of 3-(3,4-dimethoxytrityl)-4-(2,3-epoxypropyl)-Δ2-1,2,4-oxadiazole-5-it is subjected to interaction with 1.28 g (0,018 moles) of pyrrolidine in accordance with the procedure described in example 2B. Instead of formation of the salt of the crude base is used as the source of the product to the next stage of the synthesis.

Example 33

Demolet amidoxime N-(3-tert.-butylamino-2-hydroxypropyl)-3,4-dimethoxyphenol acid

3.42 g (0,009 moles) of hydrochloride of 3-(3,4-dimethoxytrityl)-4-(3-tert.-butylamino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she received in accordance with the procedure described in example 19, is subjected to the interaction with sodium hydroxide in accordance with the procedure described in example 13. Demolet precipitated in a solution of isopropanol with the addition of maleic acid. The result is 1.29 g specified in the connection header. Tpl.: 95-99°C.

1H-NMR (DMSO-d6) δ=1,27 (N, s, 3×CH3), 2,78-of 3.06 (2H, m, propyl-3-CH2), to 3.41 (2H, m, propyl-1-CH2), with 3.79 (3H, s, och3), 3,81 (3H, s, och3), the 3.89 (1H, m,6,11 (4H, s, maleic acid SN), of 6.71 (1H, d, aryl7,00 (1H, m, aryl-SN2), 7,17 (1H, m, aryl-6N), 7,19 (1H, d, arylfrom 7.24 (1H, m, aryl-2H), 10,04 (1H, br,

Example 34

Demolet amidoxime N-(3-hexamethyleneimino-2-hydroxypropyl)-4-methoxycatechol acid

4.5 g (to 0.011 mol) of the hydrochloride of 3-(4-methoxytrityl)-4-[(3-hexamethyleneimino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she received in accordance with the procedure described in example 35, is subjected to the interaction with sodium hydroxide in accordance with the procedure described in example 13. Demolet precipitated in a solution of isopropanol with the addition of maleic acid. The result 2,96 g specified in the connection header. Tpl.: 125°C.

1H-NMR (DMSO-d6) δ=1,6-2,0 (8H, m, hexamethyleneimino-3,4,5,6-CH2), 3,05 and 3.4 (8H, m, hexamethyleneimino-2,7-CH2, propyl-1,3-CH2), is 3.08 (3H, s,-och3), 4,07 (1H, m,6,0 (1H, br,6,1 (4H, s, maleic acid CH), 6,60 (1H, d, aryl6,98 (2H, m, aryl-3,5-CH), 7,14 (1H, d, aryl7,53 (2H, m, aryl-2,6-CH).

Example 35

3-(4-Methoxystyrene)--[(3-hexamethyleneimino-2-hydroxypropyl]-Δ 2-1,2,4 oxadiazoline-5-he

results were 23.08 g (0,074 moles) of hydrochloride of 3-(4-methoxytrityl)-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it is subjected to interaction from 11.42 g (0,115 moles) of hexamethylenimine in accordance with the procedure described in example 3. The hydrochloride is precipitated in isopropanol solution by adding hydrogen chloride in isopropanol. The result 8,98 g specified in the connection header. Tpl.: 200-202°C.

1H-NMR (DMSO-d6) δ=of 1.5-2.0 (8H, m, hexamethyleneimino-3,4,5,6-CH2), 3,1-3,6 (6N, m, hexamethyleneimino-2,7-CH2, propyl-3-CH2), 3,79-3,81 (2H, m, propyl 1-CH2), 3,82 (3H, s, och3), 4,36 (1H, m,6,2 (1H, br, OH), 6,98 (1H, d, aryl6,99 (2, m, aryl-3,5-H), TO 7.99 (2H, m, aryl-2,6N), of 10.4 (1H, br,+NH).

Example 36

Demolet amidoxime N-(3-hexamethyleneimino-2-hydroxypropyl)-3,4-dimethoxyphenol acid

1.5 g (of 0.003 mol) of the hydrochloride of 3-(3,4-dimethoxytrityl)-4-(3-hexamethyleneimino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she received in accordance with the procedure described in example 37, is subjected to the interaction with sodium hydroxide in accordance with the procedure described in example 13. Demolet precipitated in a solution of isopropanol with the addition of maleic acid. The result of 1.38 g specified in the connection header. sub> pl.: 120-123°C.

1H-NMR (DMSO-d6) δ=1,6-2,0 (8H, m, hexamethyleneimino-3,4,5,6-CH2), 3,4-3,6 (6N, m, hexamethyleneimino-2,7-CH2, propyl-1,3-CH2), with 3.79 (3H, s, -och3), 3,81 (3H, s,-och3), 4,1 (1H, m,5,9 (1H, br,6,1 (4H, s, maleic acid CH), 6,62 (1H, d, aryl6,98 (2H, m, aryl-5H), 7,11 (1H, d, arylfor 7.12 (1H, m, aryl-6N), 7,20 (1H, m, aryl-2H).

Example 37

Hydrochloride 3-(3,4-dimethoxytrityl)-4-[(3-hexamethyleneimino-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-5-he

13.3 g (0,039 moles) of 3-(3,4-dimethoxytrityl)-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it is subjected to interaction with the value of 4.76 g (0,048 moles) of hexamethylenimine in accordance with the procedure described in example 3. The hydrochloride is precipitated in isopropanol solution by adding hydrogen chloride in isopropanol. The result is 3.25 g specified in the connection header. Tpl.:114-116°C.

1H-NMR (DMSO-d6) δ=of 1.5-2.0 (8H, m, hexamethyleneimino-3,4,5,6-CH2), 3,15-3,50 (6N, m, hexamethyleneimino-2,7-CH2, propyl-3-CH2), of 3.84 (3H, s,-och3), and 3.31 (3H, s,-och3), a 3.87-3,91 (2H, m, propyl-1-CH2), 4,34 (1H, m,6,38 (1H, br,7,03 (1H, m, aryl-SN), 7,16 (1H, d, aryl7,34 (1H, m, aryl-6N), 7,54 (1H, d, arylto 7.59 (1H, m, aryl-2H), 10,2 (1H, br,+NH).

Example 38

Trimulean 3-styryl-6-(4-methyl-1-piperazinil)-4H-5,6-dihydro-1,2,4-oxadiazine

1.28 g (of 0.003 moles) of the dihydrochloride of 3-styryl-4-[3-(4-methyl-1-piperazinil)-2-chlorpropyl)-Δ2-1,2,4-oxadiazole-5-it is subjected to interaction with sodium hydroxide in accordance with the procedure described in example 17. The result of 1.34 g ukazannogo in the connection header. Tpl.: 153-154°C.

1H-NMR (DMSO-d6) δ=2,64 of 2.68 was 2.76 (3H, s,-CH3), 2,8-3,18 (8H, m, piperazine-CH2), 3,06-3,39 (2H, m, 5-CH2), 3,71 (1H, m, 6-CH), 6,41 (1H, d, aryl7,13 (1H, d, arylto 7.32 (3H, m, aryl-H), TO 7.50 (2H, m, aryl-H).

The dihydrochloride of 3-styryl-4-[3-(4-methyl-1-piperazinil)-2-chlorpropyl]-Δ2-1,2,4-oxadiazole-5-it is used as a source of product was obtained by interaction of the dihydrochloride of 3-styryl-4-[3-(4-methyl-1-piperazinil)-2-hydroxypropyl]-Δ2-1,2,4-oxadiazole-3-one (prepared according to the procedure described in example 7) with chloride tiomila in accordance with known literature methods. [Chem/Ber.,108, 1911 (1975)].

Example 39

Maleate 3-styryl-6-(tert.-butylaminoethyl)-4H-5,6-dihydro-1,2,4-oxadiazine

1,59 g (0,0042 moles) of hydrochloride of 3-styryl-4-[tert.-butylaminoethyl-2-chlorpropyl]-#x00394; 2-1,2,4-oxadiazole-5-it is subjected to interaction with sodium hydroxide in accordance with the procedure described in example 17. The result 0,86 g specified in the connection header. Tpl.: 201-203°C.

1H-NMR (DMSO-d6) δ=1,32 (N s, tert.-butyl), 2,86-3,55 (4H, m, oxadiazine-5-CH2, 6-CH2), 3,81 (1H, m, oxadiazine-6-CH), 6,10 (2H, s, maleic acid-CH), 6,47 (1H, d, aryl7,14 (1H, d, aryl7,22 (1H, br, 4H), 7,33 was 7.45 (3H, m, aryl-H), 7,53-7,58 (2H, m, aryl-H).

Hydrochloride 3-styryl-4-(3-tert.-butylamino-2-chlorpropyl)-Δ2-1,2,4-oxadiazole-5-it is used as a source of product was obtained by interaction hydrochloride 3-styryl-4-(3-tert.-butylamino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she (prepared in accordance with the procedure described in example 6) with chloride tiomila in accordance with known literature methods. [Chem/Ber.,108, 1911 (1975)].

Example 40

The dihydrochloride of 3-styryl-6-(hexamethylenimine)-4H-5,6-dihydro-1,2,4-oxadiazine

To 1.56 g (0,004 mol) of the hydrochloride of 3-styryl-4-(3-hexamethyleneimino-2-chlorpropyl)-Δ2-1,2,4-oxadiazole-5-ONU add a mixture of 11 ml of ethanol and 11 ml of 2n. an aqueous solution of sodium hydroxide. The reaction mixture is refluxed for 15 minutes under stirring, and then evaporated is under reduced pressure. The residue is subjected to leaching by adding 10% aqueous sodium hydroxide solution and extracted with ethyl acetate. After evaporation of the solvent the residue is dissolved in isopropanol and the resulting solution is acidified by the addition of hydrogen chloride dissolved in isopropanol. The result is precipitated 0.5 g specified in the connection header. Tpl.: 229-232°C.

1H-NMR (DMSO-d6) δ=of 1.5-2.0 (8H, m, hexamethyleneimino-3,4,5,6-CH2), 3,15 to 3.8 (8H, m, hexamethyleneimino-2,7-CH2, oxadiazine-5,6-CH2), 4,50 (1H, m, oxadiazine-6-CH), is 6.61 (1H, d, aryl7,41 (1H, t, aryl7,35-of 7.48 (2H, m, aryl-H), 7.5 to at 7.55 (3H, m, aryl-H).

Hydrochloride 3-styryl-4-(3-hexamethyleneimino-2-chlorpropyl)-Δ2-1,2,4-oxadiazole-5-it is used as a source of product was obtained by interaction hydrochloride 3-styryl-4-(3-hexamethyleneimino-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-she (prepared in accordance with the procedure described in example 4) with chloride tiomila in accordance with known literature methods. [Chem/Ber.,108, 1911 (1975)].

Example 41

Maleate 3-styryl-6-hydroxymethyl-4H-5,6-dihydro-1,2,4-oxadiazine

To of 5.83 g (0,02 mol) 3-styryl-4-(3-chloro-2-hydroxypropyl)-Δ2-1,2,4-oxadiazole-5-it is prepared in accordance with methods described in p is the iMER 2A, add 40 ml of 10% sodium hydroxide and 10 ml of ethanol. The reaction mixture is refluxed for 15 minutes, then evaporated under reduced pressure. The residue is extracted with ethyl acetate. Specified in the header maleate precipitated by adding maleic acid. Tpl.: 132-133°C.

1H-NMR (DMSO-d6) δ=3,17-3,50 (2H, m, 5-CH2), 3,53-3,59 (2H, m,3,66 (1H, m, 6-CH), 6,21 (2H, s, maleic acid-CH), 6.42 per (1H, d, aryl7,17 (1H, d, aryl7,33 was 7.45 (3H, m, aryl-H), 7,51 (2H, m, aryl-H).

1. Derived amidoxime propenylboronic acid formula

where R is a phenyl group which optionally is substituted by 1-3 substituents where the Deputy is (C1-C2)alkyl group or (C1-C2)alkoxygroup,

R' means a hydrogen atom,

R4and R5independently from each other mean a hydrogen atom, (C1-C5)alkyl group or phenyl group, the latter optionally substituted by 1-3-substituents, where the Deputy is (C1-C2)alkyl group or (C1-C2)alkoxygroup, or

R4and R5form together with the adjacent nitrogen atom a 5 - or 6-membered saturated or unsaturated heterocyclic the forge group, which may contain an additional nitrogen atom or oxygen atom as a heteroatom and may be condensed with a benzene ring, and the heterocyclic group and/or the benzene ring may contain one or two substituent, where the Deputy is (C1-C2)alkyl group or (C1-C2)alkoxygroup,

R1and R2means a hydrogen atom,

R3means a hydrogen atom or a hydroxy-group, or

R1forms together with R2carbonyl group, a carbon atom which is connected with the adjacent R1an oxygen atom and adjacent to R2the nitrogen atom,

R3means a hydrogen atom or hydroxyl group, or

R2means a hydrogen atom,

R1forms together with R3valence bond between adjacent R1an oxygen atom and adjacent to R3carbon atom,

in addition, its geometrical isomers and/or optical isomers and/or pharmaceutically acceptable acid additive salt.

2. The compound according to claim 1 of formula Ia

where R1and R2means a hydrogen atom,

R3means a hydrogen atom or a hydroxy-group,

R, R', R4and R3matter according to claim 1, furthermore, its geometrical isomer and/or optical isomers, and/or pharmaceutically acceptable acid additive salt.

3. The compound according to claim 1, which represents the derived oxadiazoline formula Ib

where R1and R3together form a carbonyl group, a carbon atom which is linked to the oxygen atom adjacent to R1and with the nitrogen atom adjacent to R2,

R3means a hydrogen atom or a hydroxy-group,

X means an oxygen atom

R, R', R4and R5matter according to claim 1, furthermore, its geometrical isomers and/or optical isomers and/or pharmaceutically acceptable acid additive salt.

4. The compound according to claim 1, which represents the derived oxadiazine formula Ic

where as according to claim 1,

R2means a hydrogen atom,

R1and R3together form a valence bond between the oxygen atom adjacent to R1and the carbon atom adjacent to R3,

R, R', R4and R5matter according to claim 1, furthermore, its geometrical isomers and/or optical isomers and/or pharmaceutically acceptable acid additive salt.

5. The method of deriving amidoxime propenylboronic acid of the formula Ia according to claim 2, where R1and R2means a hydrogen atom, R3means an atom of water is an ode or a hydroxy-group, R, R', R4and R5matter in accordance with formula I according to claim 1, and pharmaceutically acceptable acid additive salts, namely, that derived oxadiazoline formula Ib according to claim 3, where R, R', R3, R4and R5have the meanings given above, X is an oxygen atom, is subjected to contact with an aqueous alkali solution; if necessary, the resulting compound of formula Ia is subjected to interaction with an inorganic or organic acid to obtain a pharmaceutically acceptable acid salt additive, or allocate a basis in the free form of its acid salt additive.

6. The pharmaceutical composition intended for the inhibition of poly(adenosinetriphosphatase)polymerase and treat conditions based on inhibition of this enzyme, as well as for the treatment of conditions associated with oxygen deficiency in the heart and brain, including derivative amidoxime propenylboronic acid of the formula I, where R, R', R1, R2, R3, R4and R5matter according to claim 1, or its geometric isomers and/or optical isomers, or pharmaceutically acceptable acid additive salt as an active ingredient, and one or more well-known carriers.

7. The pharmaceutical composition according to claim 6, including derivative amidoxime probanker is about acid of the formula Ia, where R, R', R3, R4and R5matter according to claim 2, or its geometric isomers and/or optical isomers, or pharmaceutically acceptable acid additive salt as an active ingredient.

8. The pharmaceutical composition according to claim 6, including derived oxadiazoline formula Ib, where R, R', R3, R4, R3and X have the meanings according to claim 3, or its geometric isomers and/or optical isomers, or pharmaceutically acceptable acid additive salt as an active ingredient.

9. The pharmaceutical composition according to claim 6, including derivative oxadiazine formula Ic, where R, R', R4and R5matter according to claim 4, or its geometric isomers and/or optical isomers, or pharmaceutically acceptable acid additive salt as an active ingredient.



 

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