Derivatives of benzene

 

(57) Abstract:

Compounds represented by formula I, in which R1is hydrogen, hydroxyl, C1-9- acyloxy group or a lower alkoxyl; R2and R3- H, halogen, lower alkyl, alkoxyl; R4Is h or lower alkyl; And a fragment represented by formula II; R5- H, alkyl, alkoxyl, phenyl, pyrrolidin, 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum; or a fragment represented by formula (III - XVI; R6and R7- H, alkyl, aryl or heterocyclic group; n = 2,3,4,5 or 6, or their possible stereoisomers, or optical isomers, or their pharmaceutically acceptable salts. The compounds of formula I exert inhibitory effect on the calcium overload in addition to their vasodilator activity and inhibitory effect on lipid pereokislenie and are useful as preventive or therapeutic agents in cases ishemicheskikh disease and hypertension. 30 C.p. f-crystals, 37 PL.

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This invention relates to compounds of General formula I and their pharmaceutically acceptable salts or each possible is key in addition to vasodilator activity /antagonism of calcium/ and inhibitory action on lipid pereokislenie and are useful as preventive or therapeutic agents in the case of ischemic heart disease and hypertension (hypertension).

The process of cell damage due to ischemia in a broad sense is divided into two categories: 1/ damage caused by reductions in the level of intracellular ATP or increase intracellular calcium concentration and so on. when insufficient oxygen during ischemia, and 2/ damage caused by increased influx of calcium or production of free radicals, and others, with subsequent reperfusion or repair of blood vessels after ischemia (Yoshiwara et al., Metabolism and disease, 29, 379 /1992/). As typical ischemic diseases can be reduced cardiovascular disease, such as various forms of angina, unstable angina, and arrhythmia caused by restoration of coronary vessels with PTCA/PTCR/CABG etc. or cerebrovascular disease, such as transient ischemic stroke; traumatic head injuries and complications after brain surgery. In the treatment of variant angina or unstable angina are used nitro compounds, examples of which include nitroglycerin and nicorandil, and calcium antagonists, examples of which are diltiazem, nifedipine and verapamil, and to facilitate myocardial infarction or coronarias or acceptors radicals. As a preventive and therapeutic agents for cases of ischemic sosudistogo diseases has been studied and used glycol (registered trademark), ozagrel, nicotine, ticlopidine, Nicaraguan etc. to reduce cases of brain edema or spasm of cerebral vessels during acute phase of injury cerebral vessels. In the chronic phase were used amplifiers cerebral circulation, such as calcium antagonists, examples of which include nicardipine, Cinnarizine and flunarizin, amplifiers cerebral blood flow (circulation) with stimulating effect on metabolism, such as Vinpocetine, nicergoline, pentoxifylline, and ifenprodil, or cerebral metabolic activators, such as idebenone, GABA, and Rospatent calcium, in order to increase the flow of the blood or to improve the metabolic status of tissues, which have experienced ischemic damage.

On the basis of extensive and intensive studies in search of effective preventive and therapeutic agents for cases of ischemic heart disease or hypertension, which could be able to suppress the generation of active oxygen and the increase of intracellular calcium concentration, which is considered dostavlennya formula I, having vasodilator activity (calcium antagonism), inhibitory action on lipid pereokislenie and calcium overload, and as a result have created the present invention.

The present invention provides compounds of General formula I.

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where R1represents a hydrogen atom, a hydroxyl group, acyloxy group having 1-9 carbon atoms, or lower alkoxy group having 1-6 carbon atoms;

R2and R3which may be the same or different, each represents a hydrogen atom, hydroxyl group, halogen atom, lower alkyl group having 1-6 carbon atoms, or lower alkoxy group having 1-6 carbon atoms;

R4represents a hydrogen atom, a lower alkyl group having 1-6 carbon atoms;

A represents A fragment represented by formula II.

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in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1-6 carbon atoms, substituted or unsubstituted lower alkenylphenol group having 2-6 carbon atoms, substituted or unsubstituted alkoxy group having 1-6 carbon atoms, substituted or unsubstituted aryl group ilsee two or more atoms of oxygen or sulfur, in the case of which the carbon atom to which it is attached, is a Spiro atom; or a fragment represented by formula III

B,

moreover, B is a fragment selected from the group of the following fragments of formulas IV-XIV.

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R6and R7that may be the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1-6 carbon atoms, substituted or unsubstituted lower alkenylphenol group having 2-6 carbon atoms, substituted or unsubstituted aryl group or optionally substituted heterocyclic group, provided that R6and R7at the same time are not methyl groups, or R6and R7taken together with the formation of substituted or unsubstituted ring which may be condensed ring;

n = 3, 4, 5 or 6, and their pharmaceutically acceptable salts or stereoisomers or optical isomers them.

The compound represented by formula I, can be obtained by the following processes A-Q (process diagram A see at the end of the description).

On the process diagram A R1represents a hydrogen atom, a hydroxyl SUB> and R3that may be the same or different, each represents a hydrogen atom, hydroxyl group, halogen atom, lower alkyl group having 1-6 carbon atoms, or lower alkoxy group having 1-6 carbon atoms; R4represents a hydrogen atom, a lower alkyl group having 1-6 carbon atoms; R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted lower alkenylphenol group having 2-6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; R6and R7that may be the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1-6 carbon atoms, substituted or unsubstituted alkenylphenol group having 2-6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7are not simultaneously methyl group, or R6and R7taken together, form a substituted or unsubstituted ring, which may be of skondensirovannye the same values as defined previously; R8represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group; Z is a chlorine atom or a bromine atom.

Process C:

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On the process diagram C R1- R8, n and Z have the same values as previously defined.

Process D.

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On the process diagram D R1- R7and n have the same values as previously defined.

The process that is

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On the process diagram E R1- R7, n and Z have the same values as previously defined; R9represents an alkyl group having 1-6 carbon atoms: m= 1-7, an integer.

Process F.

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The diagram of the process F R1- R9n and m have the same values as previously defined.

Process G:

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In the diagram of G R2- R9n and m have the meanings previously defined.

The process H

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On the process diagram N R1- R7, Z, n and m have znaczeniu previously defined; and R10R11that may be the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 atoms of plastics technology: turning & the seal aryl group or a substituted or unsubstituted heterocyclic group, or R10and R11taken together, form a substituted or unsubstituted ring which may be condensed ring.

Process I:

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In process scheme I R1- R7, Z and m have the meanings previously defined; and R9represents substituted or unsubstituted lower alkyl group having 1-6 carbon atoms.

Process J:

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In the scheme of process J R1- R7and n have the meanings previously defined.

The process K:

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In the scheme of process K R1- R4, R6, R7and n have the meanings defined above; R12represents carboxyl group or sulfonyloxy group, and R13represents carbonyl and sulfonyloxy group

The process L:

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On the process diagram L R1- R4, R6and R7and n have the meanings previously defined; and R13- represents carbonyl group.

The process M:

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In the diagram M R1- R4, R6, R7and n have the previously specified values.

Process N:

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On the process diagram N R1- R4, R6, R7and n have the meanings previously defined; A represents A piece of the X - an atom of chlorine or bromine.

The process is ABOUT:

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To the process O R1- R4, R6and R7have the meanings previously defined.

Process P:

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In the scheme of process P R1- R4and n have the previously specified values.

Process Q:

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To the process Q R1- R4, R6and R7have the meanings previously defined.

The conditions of the reactions selected for each of the processes A - Q, are given in table. I - IX.

Process A:

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The reaction conditions for each stage of the process A, see table.I.

Note: *: Racemic mixture /5/ can be separated using optically active organic bases such as brucine, cinchonidine, ephedrine or quinine, giving optically active form of compounds /5/.

* * Although you can use any method commonly used for the recovery of carboxylic acid in the alcohol, the reaction preferably is carried out using a first transformation /5/ mixed anhydride using atilglukuronida and others, followed by reduction using sodium borohydride. Sodium borohydride is used in an amount of from 1 to 30 molar e in the presence of potassium iodide.

Process B:

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The reaction conditions for each stage of the process B, see table.II.

Note: *: the Reaction is preferably carried out in the presence of potassium iodide,

Process C: * the Reaction is preferably carried out in the presence of potassium iodide.

Process C: /8/--->/16/--->/17/--->/9/

Reaction conditions for each stage of the process C, see table.III.

Process D: /9/--->/18/

Reaction conditions of the process D.

Stage: /9/--->/18/

Solvent: water or acid (the acid is preferably acetic or hydrochloric acid).

The reaction temperature: -10oC to the temperature of reflux distilled (preferably 0-50oC).

The reaction time is from 2 to 15 days (preferably 4-10 days).

Acid: inorganic acid (preferably 47% Hydrobromic acid).

Process E: /19/--->/21/--->/22/

Reaction conditions for each stage of the process E see table.IV.

Note: *: the Reaction is preferably carried out in the presence of potassium iodide.

Process F: /22/--->/23/

Reaction conditions of the process F (/22/--->/23/)

Solvent: water or an alcoholic solvent (preferably methanol containing water or ethanol, containing about temperature reflux distilled).

Reaction time: 1-48 hours (preferably 6-24 hours)

The base or acid: an aqueous solution of an inorganic base, e.g. sodium hydroxide or potassium hydroxide or inorganic acid, for example sulphuric or hydrochloric acid.

Process G: /22/--->/24/

Reaction conditions of the process G [(22)--->(24)]

Solvent: inert solvent (preferably THF, diethyl ether or toluene)

The reaction temperature: - 78oC to the temperature of reflux distilled (preferably from -78oC to room temperature)

The reaction time is 0.1 to 24 hours, preferably 5 hours)

Reducing agent: sociallyengaged, lithium borohydride, DIBAL complex, borane-THF, etc.

The process H; /25/--->/27/--->/28/

Reaction conditions for each stage of the process H, see table. V.

Note: * the Reaction is preferably carried out in the presence of potassium iodide.

Process I: /29/--->/30/--->/31/--->/32/

Reaction conditions for each stage of the process I see in the table. VI.

Note: *: the Reaction is preferably carried out in the presence of potassium iodide.

Process J: /9/--->/33/

Reaction conditions of the process J [(9)--->(33)]

Solvent: inert solvent (suppose doctitle from 0 to 50oC)

Reaction time: 0.5 to 48 hours, preferably 2-10 hours)

Reagent: sulfurylase agent (preferably paternity phosphorus or reagent Losson)

The process K: /34/--->/35/

Reaction conditions of the process K [(34)--->(35)]

Solvent: inert solvent (preferably THF, diethyl ether, dichloromethane or chloroform)

The reaction temperature: - 10oC to the temperature of reflux distilled (preferably from 0oC to the temperature of reflux distilled)

Reaction time: 0.5 to 48 hours, preferably 1-24 hours)

Gaodirelwe agent include thionyl chloride, oxalicacid, phosphorus trichloride, tribromide phosphorus, and other (note: the Reaction is preferably carried out in the presence of catalytic amount of DMF).

Base: inorganic base or an organic base (preferably pyridine or triethylamine)

The process L; (35)--->(36)

Reaction conditions of the process L [(35)--->(36)]

Solvent: Inert solvent (preferably dichloromethane or chloroform)

The reaction temperature: -10oC - the temperature of the reflux distilled (preferably 0 to 50oC)

Reaction time: 0.5 to 48 hours, preferably 2-10 hours)

Sulfurylase agent: paternity foci: inert solvent (preferably, THF)

The reaction temperature: -10oC - the temperature of the reflux distilled (preferably, 0oC to the temperature of reflux distilled)

Reaction time: 0.5 to 48 hours (preferably 5-24 hours)

Base: inorganic or organic base (preferably sodium hydride or diisopropylamide lithium) Alkylating agent: alkylhalogenide (preferably ethyliodide)

Process N; /38/--->/40/--->/41/

Reaction conditions for each stage of the process N, see table. VII.

Note: * the Reaction is preferably carried out in the presence of potassium iodide.

The process O; /42/--->/43/ /44/--->/45/

Reaction conditions for each stage of the process O see table. VIII.

Note: *: the Reaction is preferably carried out in the presence of potassium iodide.

Process P: (9)--->(46)

Reaction conditions of the process P [(9)--->(46)]

Stage: (9)--->(46)

Solvent: an organic acid (preferably acetic acid)

The reaction temperature: -5 - 40oC (preferably room temperature)

Reaction time: 0.5 to 48 hours (preferably 6 to 12 hours)

Oxidizing agent: hydrogen peroxide or organic nagkalat

Process Q: a /1/--->/47/ /48/--->/49/

Reaction conditions on kazdin or two asymmetric carbon atom in its structure, and pure stereoisomers or optical isomers can be obtained using methods known in the art. For example, each enantiomer can be separated using chromatography using HPLC columns for optical separation, or by using fractional crystallization with an optically active acid, preferably the acid (R)-(-)-1,1'-binaphthyl-2,2'-diyl-phosphate. The above-mentioned methods of separation of optical isomers is applicable not only to final products, but also to intermediate products, which have a carboxyl group. In the latter case may apply commonly used optically active bases such as brucine. Similarly diastereomer mixture, including both CIS-and TRANS-stereoisomers can be separated into individual optical isomers, i.e. CIS(+), CIS(-) TRANS(+) and TRANS(-), using conventional methods known to experts in this field.

Needless to say, the stereoisomers and optical isomers of compounds of formula I are also included in the scope of the present invention.

The present invention will now be illustrated in more detail with reference to reference examples, examples and examples farmacologicas which was measured using a JEOL JNM-FX200 or JEOL JNM-270, unless marked with an asterisk, in which the measurements were carried out using Hitachi R-24B (60 MHz).

In the above and following tables are used symbols and abbreviations that are deciphered as follows: and - and; brs - Shire. C. (wide singlet); d - d (doublet); Hz - Hertz; m - m (multiplet); NMR NMR; q - square (Quartet); quint - Quint. (quintet); S - S. (singlet); t - so (triplet).

Referential example 1. Getting 2-(3,5-aminobutiramida 4-hydroxyphenyl)-3-(3-hydroxypropyl)- 1,3-thiazolidin-4-one,

In benzene /50 ml/ suspendibility 3,5-aminobutiramida 4 - hydroxybenzaldehyde /5.00 g/ and 3-aminopropanol /1.82 g/ in nitrogen atmosphere. To the reactor was connected trap Dean-stark, and the suspension was heated under conditions of reflux distilled (under reflux) for 1.5 hours. After leaving the mixture to cool added - mercaptoacetate acid /2.23 g/, then the mixture was further heated under reflux for 2 hours. After removal of the benzene by evaporation, to the residue was added water /50 ml, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The remainder of the PTS is unity in the form of a colorless oil, NMR (CDCl3, 60 MHz) :

1.23 (12H, d , J=6.6 Hz), 1.0-1.8 (2H, m), 2.5-3.8(7H, m), 3.73(2H, Shir.C.), 5.50 (2H, Shir.C.), 6.92 (2H, s),

Each of the alcohols shown in Tables 1-3, were obtained in accordance with the procedure of reference example 1, using in each case the corresponding substituted benzaldehyde and appropriate - aminoalkylated alcohol instead of 3,5-aminobutiramida 4-hydroxybenzaldehyde and 3-aminopropanol.

Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3 - hydroxypropyl)-1,3-thiazolidin-4-it.

In the atmosphere of nitrogen in benzene /500 ml/ suspendibility 3,5-di-tert-butyl-4-hydroxybenzaldehyde /50.0 g/ and - alanine /20.0/. To the reactor was connected trap Dean-stark, and the suspension was heated under reflux for 1 hour. After leaving the mixture to cool added - mercaptoacetate acid /23.6 g/, and the mixture was further heated under reflux for 24 hours. After removal of the benzene by evaporation, to the residue was added water /500 ml, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified using column chromatography on silica gel (eluent: chloroform-metacrysts, so pl. 164-165oC.

NMR /CDCl3, 200 MHz/ :

1.42 (18H, s ), 2.2-2.5(1H, m ), 2.5-2.8(1H, m), 3.0-3.3(1H, m), 3.5-4.0 (3H, m), 5.33 (1H, s), 5.64(1H, s), 7.09 (2H, s), 8.5 (1H, Shir. C.).

To a solution of the resulting 2-(3,5-di-tertbutyl-4-hydroxyphenyl)-3-(2-carboxyethyl)-1,3 - thiazolidin-4-it /100 mg/ tetrahydrofuran /3 ml was added dropwise a triethylamine /27 mg/ and ethylchloride /28 mg/ if -10oC in nitrogen atmosphere, followed by stirring at (-10) - (-5)oC for 1 hour. To the mixture was added sodium borohydride /100 mg), and the mixture stirred at room temperature for 3 hours, then poured into a mixture of ice and water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using column chromatography on silica gel (eluent: chloroformmethanol, 98:2) to give 70 mg (73%) of product, which was identical to the product of reference example 15.

Reference example 17. Getting 2-(3,5-aminobutiramida 4-hydroxyphenyl)-3-(3-chlorpropyl)- 1,3-thiazolidin-4-it.

To a solution in dichloromethane /50 ml/ 2-(3.5-aminobutiramida 4-hydroxyphenyl)-3-(3-hydroxypropyl)-1,3 - thiazolidin-4-it /1.97 g/ obtained in reference example 1, dubblestandart was evaporated under reduced pressure, and to the residue was added brine and chloroform. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using column chromatography on silica gel (eluent: dichloromethane) to give 1.25 g (60%) of target compound as pale-yellow crystals, so pl. 105-106oC,

NMR /CDCl3, 60 MHz/ :

1.23 (12H, d, J=6.6 Hz), 1.5-2.1 (2H, m), 2.6-3.8 (6H, m), 3.67 (2H, Shir. C.), 5.20(1H, 1H, s), 5.50 (1H, Shir. C.), 6.88 (2H, s),

Reference examples 18-28.

Each connection shown in tables 4 and 5, were obtained according to the procedure of reference example 17, using in each case the corresponding alcohol.

Reference example 29. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-bromopropyl)-1,3 - thiazolidin-4-it,

To a solution of 2-(3, 5-di-tert-butyl-4-hydroxyphenyl)-3-(3 - hydroxypropyl)-1,3-thiazolidin-4-it /2.00 g/ obtained in reference example 15, in diethyl ether /20 ml/ added trichromacy phosphorus /0.74 g/ in nitrogen atmosphere, the mixture is then stirred at room temperature for 6 hours. After completion of the reaction the mixture was poured into a mixture of ice-water /100 ml, and the product was extracted in diethyl ether. The organic layer promyvanie, and the residue was purified using column chromatography on silica gel (eluent: chloroform) to give 1.31 g (56%)of target compound in the form of blignault crystals. So pl. 130-131oC.

NMR /CDCl3, 60 MHZ/ :

of 1.43(18H, s), 1.6-2.2(2H, m), 2.6-3.6(2H, m), 3.28(2H, T., J=6.5 Hz), 3.70(2H, Shir. C.), 5.28(1H, s), 5.53(1H, Shir. C.), 7.05(2H, s)

Each of the bromides, are shown in table 6, was obtained in accordance with the procedure of reference example 29 using in each case the corresponding alcohol.

Example 1. Getting 2- (3,5-aminobutiramida 4-hydroxyphenyl) -3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]- 1,3-thiazolidin-4-it.

To a solution of 2-(3,5-aminobutiramida 4-hydroxyphenyl)-3-(3 - chlorpropyl)-1,3-thiazolidin-4-it /0.50 g/ obtained in reference example 17, and N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amine /0.30 g/ formamide /10 ml was added sodium carbonate /0.29 g/ and potassium iodide /0.30 g/ in nitrogen atmosphere, and the mixture was mixed at 80oC for 24 hours. The solvent was removed by evaporation under reduced pressure, to the residue was added water /20 ml, and the mixture was extracted with chloroform. The organic layer was washed successively with water and brine, then dried over anhydrous sulfate-her on silica gel (eluent: chloroform-methanol 97:3), giving 0.26 g (36%) of target compound as pale brown oil.

NMR (CDCl3, 60 MHz) :

1.23(12H, d, J=6.6 Hz), 1.4-1.9(2H, m), 2.17(3H, s), 2.3-3.8(8H, m), 3.67(2H, Shir.C.), 3.87(2H, T., J= 5.7 Hz), 5.00(1H, Shir. C.), 5.57(1H, s), 5.80(2H, s), 6.0-6.7(3H, m), 6.90(2H, s).

Examples 2-25. Each connection shown in Tables 7 to 10, was obtained in accordance with the procedure of example 1, using the corresponding chloride and the appropriate amine in each case.

Example 26-A. Obtaining 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-(N-methyl-N- [2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]- 1,3-thiazolidin-4-it,

To a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3 - bromopropyl)-1,3-thiazolidin-4-it /89.3 mg/ obtained in reference example 29, and N-methyl-N-[2-(3,4-methylenedioxyphenoxy) ethyl]amine /48.8 mg/ acetone /5 ml was added potassium carbonate /34.6 mg/ nitrogen atmosphere, and the mixture was heated under reflux for 10 hours. After the mixture was left to cool, the inorganic substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (eluent: chloroform-methanol, 97:3), giving 67.4 mg (60%) of target compound as colorless crystals, etc., 7-2.9 (1H, m), 3.5-3.6 (1H, m), 3.66 and 3.80 (2H, Awkw. , J= 16.0 Hz), 3.92 (2H, T., J=5.9 Hz), 5.32(1H, s), 5.66(1H, s), 5.90(2H, s), 6.2-6.7(3H, m), 7.09(2H, s).

Examples 27-34. Each connection shown in tables 11 and 12, was obtained in accordance with the procedure of example 26-A, using in each case the corresponding bromide and the appropriate amine.

Reference example 33. Getting the hydrobromide of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-(N-methylamino)propyl]- 1,3-thiazolidin-4-it.

A mixture of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-bromopropyl)- 1,3-thiazolidin-4-it /1.10 g/ obtained in reference example 29 in 40% methanol solution of methylamine /20 ml) and acetonitrile /15 ml stirred at room temperature for 15 hours under nitrogen atmosphere. After completion of the reaction the solvent and excess methylamine were removed under reduced pressure. The residue was purified using column chromatography on silica gel (eluent: chloroform-methanol, 95:5) to give 0.90 g (76%) of target compound as pale orange crystals. So pl. 195-196oC.

NMR /CDCl3, 60 MHz/ :

1.42 (18H, s ), 1.6-2.2(2H, m ), 2.67(3H, s), 2.6 to 3.6(4H, m), 3.77(2H, Shir.C.), 5.33(1H, s), 5.63 (1H, Shir.C.), 7.08 (2H, s).

Each of the compounds shown in table 13, was obtained by using procedures which/P> In the reference example 35 chromatographic purification was performed on a column of silica gel using a mixture of chloroform-methanol, 95:5, containing 1% triethylamine as eluent.

Example 26-B. To a solution of the hydrobromide of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3- (N-methylamino)propyl] -1,3-thiazolidin-4-it /380 mg/ obtained in reference example 33, and 2-(3,4-methylenedioxyphenoxy)ethylbromide /260 mg/ acetone /10 ml was added potassium carbonate /300 mg/, and the mixture was mixed for 10 hours in nitrogen atmosphere. After the reaction mixture was left to cool, the insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 97:3) to give 350 mg (64%) of the same compound, which was obtained in example 26-A.

Examples 35-37, Each connection table 14 were obtained in accordance with the procedure of example 26 In when interacting in each case, each of the compounds shown in table 13, with the corresponding bromide.

Example 38. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3- [N-methyl-N-[2-hydroxy-3-(3,4-methylenedioxyphenoxy)propyl] amino] - propyl]-1,3-thiazolidin-4-, is received in reference example 33, in acetonitrile /10 ml was added 2,C-epoxypropyl-3,4-methylendioxyphenyl ether /0.26 g/ at room temperature, and the mixture was heated under reflux for 8 hours. After leaving to cool, the mixture was poured into a mixture of ice and water and extracted with ethyl acetate. The organic layer was washed with saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified using chromatography on silicagel column (eluent: chloroformmethanol, 98:2) to give 0.72 g (95%) of target compound as a colourless oil.

NMR (CDCl3, 270 MHz) :

1.43 (18H, s), 1.4-1.8 (2H, m), 2.17(3H, s), 2.2-2.6(4H, m), 2.7-3.0(1H, m ), 3.4-3.7(1H, m,), 3.67 and 3.80 (2H, Awkw., J=16.0 Hz), 3.8-4.1 (4H, m ), 5.33(1H, s ), 5.57(1H, s), 5.91 (2H, s), 6.2-6.8 (3H, m), 7.09(2H, s).

Examples 39 and 40. Each of the compounds shown in table 15, was obtained following the procedure of example 38, using in each case the corresponding epoxide.

Reference example 36. Obtain 3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]-Propylamine.

In acetone (20 ml) was suspenderbelt N-methyl-N-[2-(3,4 - methylenedioxyphenoxy)ethyl]amine /1.0 g/, N-(3-bromopropyl)phthalimide /1.51 g/, and the carbonate is up to cool, it was filtered to remove inorganic material and the filtrate was concentrated. The residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 10:1) to give 1.82 g (93%) of N-[3-[N'-methyl-N'-/2- (3,4-methylenedioxyphenoxy)ethyl]amino]propyl]phthalimide in the form of a brown oil.

NMR (CDCl3, 60 MHz) :

1.5-2.2(2H, m), 2.28(3H, s), 2.3-2.9(4H, m), 3.72(2H, T., J=7.0 Hz), 3.90(2H, J=6.0 Hz), 5.82(2H, s), 6.0-6.8(3H, m), 7.4-8.0(4H, m).

The resulting N-[3-[N'-methyl-N'-[2-(3, 4-methylenedioxyphenoxy)ethyl] amino]propyl]phthalimide /1.82 g/ dissolved in 40% methanol solution of methylamine /10 ml, and the mixture is stirred at room temperature over night. After completion of the reaction the solvent and excess methylamine were removed under reduced pressure. The residue was purified using chromatography on silicagel column (eluent: chloroformmethanol, 1:1, containing 1% triethylamine) to give 0.74 g (62%) of target compound as pale brown oil.

NMR (CDCl3), (60 MHz) :

1.33(2H, s ), 1.1-2.1(2H, m), 2.27(3H, s), 2.2-3.0(6H, m), 3.90(2H, T., J=6.0 Hz), 5.77(2H, s), 6.0-6.8(3H, m).

Reference example 37. Getting 2-/N-methyl-N- [2-(3,4-methylenedioxyphenoxy)ethyl]amino]-ethylamine.

The target compound was obtained in solimide.

NMR(CDCl3), (60 MHz) :

2.34(3H, s ), 2.0-3.2(8H, m), 3.90(2H, T., J=6.0 Hz), 5.85(2H, s), 6.0-6.9(MN, m).

Example 41 /How-A/. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-5 - methyl-1,3-thiazolidin-4-it.

The target compound was obtained in accordance with the procedure of reference example 1, using 3-[N-methyl-N-[2- -(3,4-methylenedioxyphenoxy)ethyl]amino]Propylamine and 2-mercaptopropionic acid instead of 3-aminopropanol and d-mercaptohexanol acid.

NMR (CDCl3), (270 MHz) :

1.42 (18H, s ), 1.2-1.8(2H, m ), 1.58(3x2/5H, d, J=6.9 Hz), 1.65 (3x3/5H, d, J=6.9 Hz), 2.20 (3x3/5H, s), 2.23 (3x2/5H, s), 2.2-2.5(2H, m ), 2.6-2.9(3H, m ), 3.4-3.7(1H, m ), 3.8-4.1(3H, m), 5.29(2/5H, s), 5.30(3/5H, s ), 5.56 (3/5H, s), 5.57 (2/5H, Shir.C.), 5.90(2H, s), 6.2 - 6.8(3H, m), 7.05(2x2/5H, s), 7.11 (2x3/5H, s).

Example 42. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[2- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]ethyl]-1,3 - thiazolidin-4-it.

The target compound was obtained according to the procedure of reference example 1 using 2-[N-methyl-N-[2-(3, 4 methylenedioxyphenoxy)-ethyl]amino]ethylamine instead of 3-aminopropanol.

NMR (CDCl3), (60 MHz) :

1.40(18H, s), 2.20(3H, s), 2.5-3.0(5H, m), 3.3-4.1(3H, m), 3.65(2H, Shir.C.), 5.23(1H, s), 5.73(1H, s), 5.82(2H, s), 6.0-6.8(3H, m), 7.00(2H, S. Ino]propyl]-1,3 - thiazolidin-4-it.

In acetic acid /5 ml/ dissolved 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2- (3,4-methylenedioxyphenoxy)ethyl] amino]-propyl]-1,3-thiazolidin-4-one /0.35 g/, and added 47% Hydrobromic acid /5 ml, the mixture is then stirred at room temperature for 7 days. After completion of the reaction the mixture was poured into ice 5% aqueous sodium carbonate solution and was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 98:2) to give 0.05 g (16%) of target compound as pale brown oil.

NMR (CDCl3), (200 MHz):

1.37(9H, s ), 1.2-1.9(2H, m), 2.26(3H, s), 2.1-2.5(2H, m), 2.71(2H, T. , J=5.7 Hz), 2.6-3.0(1H, m), 3.4-3.8(1H, m), 3.67 and 3.80(2H, Awkw., J= 16.0 Hz), 3.94(2H, T., J=5.7 Hz), 5.60(1H, s), 5.82(1H, s), 5.88(2H, s), 6.1-7.0(5H, m), 7.14(1H, s).

Reference example 38. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3- (3-hydroxypropyl)-5-methyl-1,3-thiazolidin-4-one was obtained according to the procedure of reference example 1 using 2-mercaptopropionic acid instead - mercaptohexanol acid.

NMR (CDCl3), (200 MHz) :

1.43(18H, s), 1.1-1.7(2H, m), 1.60(h/4H, d, J=6.94 H, C.)

Reference examples 39 and 40. Each compound shown in table 16 were obtained in accordance with the procedure of reference example 38 using the appropriate - mercaptocarboxylic acid instead of 2-mercaptopropionic acid in each case.

Reference example 41. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3 - hydroxypropyl)-5-carboxymethyl-1,3-thiazolidin-4-it.

In benzene /200 ml/ suspendibility 3,5-di-tert-butyl-4-hydroxybenzaldehyde /23.4 g/ and 3-aminopropanol /9.01 g/ in nitrogen atmosphere. After connecting to the reactor traps Dean-stark suspension was heated under reflux for 2 hours. After the mixture was left to cool, added diablada acid /19.52 g/, then the mixture was heated under reflux for an additional period of 3 hours. The benzene was removed by evaporation, and the resulting white solid was precrystallization from water-containing methanol, yielding 10.5 g (25%) of target compound as colorless crystals, so pl. 227-228oC.

NMR (d6-DMSO) (200 MHz) :

1.37(18H, s), 1.2-1.8(2H, m), 2.3-2.8(1H, m), 3.0-3.6(5H, m), 4.0-4.2(1H, m), 4.37(1H, Shir. C.), 5.73(1H, s), 7.10(2H, s), 7.13 (1H, s).

Reference is util-4-hydroxyphenyl)-3-(3-hydroxypropyl)-5-methyl-1,3- -thiazolidin-4-in accordance with the procedure of reference example 17.

NMR (CDCl3) (60 MHz) :

1.42(18H, s), 1.1-2.2(5H, m), 2.7-4.2(5H, m), 5.23 (1H, s), 5.43(1H, Shir. C.), 6.97(2H, Shir. C.)

Reference examples 43 and 44. Each of the compounds shown in table 17 were obtained respectively from each of the compounds of reference examples 39 and 40 in accordance with the procedure of reference example 29.

Reference example 45. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3 - bromopropyl)-5-ethoxycarbonylmethyl-1,3-thiazolidin-4-it.

To a suspension of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3- (3-hydroxypropyl)-5-carboxymethyl-1,3-thiazolidin-4-it /2.45 g/ diethyl ether /30 ml/ suspenderbelt trichromacy phosphorus /3.45 g/, and the mixture is stirred at room temperature for 3 hours. To the mixture was added dropwise ethanol /30 ml/ under ice cooling, and the mixture was mixed at room temperature over night. After completion of the reaction, the reaction mixture was poured into 100 ml of a mixture of ice and water, and the product was extracted with ethyl acetate. The organic layer was washed with saline and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified using column chromatography on silica gel (eluent: ethyl acetate: n-hexane, 20:80), and then p is allow. So pl. 154-155oC.

NMR (CDCl3) (200 MHz) :

1.26(3H, T., J=7.1 Hz), 1.43 (18H, s), 1.6-2.2 (2H, m), 2.6-3.1(2H, m ), 3.2-3.6(4H, m), 4.17(2H, square, J=7.1 Hz), 4.1-4.4(1H, m), 5.33(1H, s), 5.53(1H, s), 7.14 (2H, s)

Reference example 46. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3- (3-bromopropyl)-5-isopropoxycarbonyl-1,3-thiazolidin-4-one was obtained as colorless crystals in accordance with the procedure of reference example 45 using isopropyl alcohol instead of ethanol, so pl. 170-171oC.

Yarm (CDCl3), (200 MHz) :

1.24(6H, d, J=5.7 Hz), 1.43(18H, s), 1.6-2.2(2H, m), 2.6-3.7(6H, m), 4.1 and 4.4(1H, m), 4.8-5.2(1H, m), 5.33(1H, s), 5.53 (1H, s), 7.14(2H, s)

Example 41 /method-B/. Getting 2. -(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2- (3,4-methylenedioxyphenoxy)ethyl] amino]propyl]- 5-methyl-1,3-thiazolidin-4-it.

The target compound was obtained in accordance with the procedure of example 1 using 2-(3,5-di-tert-butyl-4-hydroxyphenyl)- 3-(3-chloropropyl)-5-methyl-1,3-thiazolidin-- 4-she obtained in reference example 42. Data analysis the obtained sequences were identical to the data of the compounds obtained in example 41.

Examples 44 and 45. Each compound shown in table 18, was obtained in accordance with the procedure of examples 26 to A corresponding connection is lidin-4-it.

Example 46. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]- 5-ethoxycarbonylmethyl-1,3-thiazolidin-4-it.

The target compound was obtained as colorless crystals in the procedure of example 26-A, using 2- (3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-bromopropyl)-5 - ethoxycarbonylmethyl-1,3-thiazolidin-4-she obtained in reference example 45 instead of 2-(3,5-decret-butyl-4-hydroxyphenyl)-3-(3-bromopropyl)-1,3-thiazolidin - 4-it.

So pl. 88-89oC. NMR (CDCl3), (200 MHz) :

1.26(3H, T. , J=7.1 Hz), 1.41(18H, s), 1.4-1.9(2H, m), 2.19(3H, s), 2.3-2.5(2H, m ), 2.67(2H, T., J=5.7 Hz), 2.7-3.0(2H, m), 3.2-3.7(2H, m), 3.91(2H, T. , J = 5.7 Hz), 4.17(2H, square, J=7.1 Hz), 4.1-4.4(1H., m), 5.29(1H, s), 5.58(1H, s), 5.89(2H, s), 6.1-6.8(3H, m), 7.09(2H, s).

Example 47. According to the procedure of example 46, using 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-bromopropyl)-5-isopropoxycarbonyl-1,3-thiazolidin-4-it instead of 2-(3,5-di-tert-butyl-4 - hydroxyphenyl)-3-(3-bromopropyl)-5-ethoxycarbonylmethyl-1,3-thiazolidin - 4-it was obtained 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2- (3,4-methylenedioxyphenoxy)-ethyl] amino]propyl]-5 - isopropoxycarbonyl-1,3-thiazolidin-4-one as colourless crystals, so pl. 81-82oC.

NMR (CDCl3m), 4.8-5.2(1H, m), 5.30(1H, s), 5.57(1H, s), 5.89(2H, s), 6.1-6.8(3H, s), 7.10(2H, s)

Example 48. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-/3- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-carboxymethyl-1,3-thiazolidin-4-it.

In ethanol /5 ml/ dissolved 2-(3,5-di-tert-butyl-4 - hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy) ethyl] amino] propyl] -5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one /100 mg, obtained in example 46, and was added a solution of sodium hydroxide (200 ml) in 20% water-containing ethanol, the mixture is then stirred at room temperature over night. After completion of the reaction the mixture was kind of balanced out 1 standards. hydrochloric acid and concentrated under reduced pressure. To the residue was added a mixture of water (50 ml) and chloroform /50 ml, and the mixture was mixed. The organic layer was separated, washed with saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was pulverized with n-hexane, yielding 80 mg (84%) of target compound as a pale yellow solid.

NMR (CDCl3) (200 MHz) :

1.41(18/2H, s ), 1.42(18/2H, s ), 1.4-2.4(2H, m), 2.85 (3/2H, s), 2.90(3/2H, s), 2.7-3.8(8H, m), 4.1-4.7(3H, m), 5.2-5.4(1H, m), 5.66(1/2H, Shir. C. ), 5.81(1/2H, Shir. C.), 5.89 (2H, s), 6.2-6.7(3H, m), 7.13(2/2H, s), 7.14 (and)ethyl] amino] propyl] -5- (2-hydroxyethyl)-1,3-thiazolidin-4-it.

To a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3- [3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5 - ethoxycarbonylmethyl-1,3-thiazolidin-4-it /80 mg/ obtained in example 46, in dry tetrahydrofuran (THF /5 ml/ added alumoweld lithium /20 mg/ -78oC, and the mixture is stirred at 0oC for 3 hours. To the mixture was added water-containing tetrahydrofuran /5 ml/ s, followed by stirring at this temperature for 1 hour. The mixture was kind of balanced out 1 standards. hydrochloric acid, concentrated under reduced pressure. The residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 95:5) to give 68 mg (86%) of target compound as a colourless oil.

NMR (CDCl3) (200 MHz) :

1.41(18H, s), 1.3-1.8 (4H, m), 2.19(3H, s), 2.2-2.5(3H, m), 2.67(2H, T. , J=5.7 Hz), 2.7-2.9(1H, m), 3.4-3.6(1H, m), 3.8-4.0(2H, m), 3.91 (2H, T. , J= 5.7 Hz), 4.04 (1H, T. , J=5.7 Hz), 5.33 (1H, C.), 5.60(1H, s), 5.90(2H, s), 6.2-6.7(3H, m), 7.12(2H, s).

Reference example 47. Getting 2-(3,5-di-tert-butyl - 4-hydroxyphenyl)-3-(3-chloropropyl)-5-(1-pyrrolidinecarbonyl) -1,3-thiazolidin-4-it.

To a suspension of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3- (3-hydroxypropyl)-5-carboxymethyl-1,3-thiazolidin-4-it /0.61 g/ obtained in reference example 41, in dichloromethane /Tim refrigerator for 2 hours. After she was left to cool, the mixture was added dropwise to a solution of pyrrolidine /1.02 g/ in dichloromethane /20 ml/ under ice cooling and stirred at this temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into a mixture of ice and water and extracted with chloroform. The organic layer was washed successively 1 n hydrochloric acid and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 97:3), and then precrystallization from a mixture of chloroform and n-hexane, giving 0.65 g (92%) of target compound as colorless crystals, so pl. 193-194oC.

NMR (CDCl3) (200 MHz) :

1.43 (18H, s ), 1.4-2.2(6H, m ), 2.5-3.1(2H, m), 3.2-3.7(8H, m), 4.2-4.5(1H, m), 5.29(1H, s), 5.53(1H, s), 7.08 (2H, s)

Reference examples 48 to 50.

Each compound shown in table 19 were obtained in accordance with the procedure of reference example 47, using in each case the corresponding amine.

Example 50. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5- (1-pyrrolidinecarbonyl with the procedure of example 1, using 2-(3,5-di-tertbutyl-4-hydroxyphenyl)-3-(3-chloropropyl)-5-(1-pyrrolidin - carbonylmethyl)-1,3-thiazolidin-4-she obtained in reference example 47, instead of 2-(3,5-aminobutiramida 4-hydroxyphenyl)-3-(3-chloropropyl)-1, 3-thiazolidin-4- -it.

NMR (CDCl3) (200 MHz) :

1.41(18H, s ), 1.4-2.1(6H, m), 2.20(3H, s), 2.2 - 2.5(2H, m), 2.5-3.1(4H, m ), 3.2-3.8(6H, m ), 3.93(2H, T., J=5.7 Hz), 4.2-4.5(1H, m), 5.29(1H, s), 5.57(1H, s), 5.88(2H, s), 6.1-6.8(3H, m), 6.9-7.2(2H, m)

Examples 51 - 53. Each compound shown in table 20, were obtained according to the procedure of example 50, using each of the compounds obtained in reference examples 48 to 50, instead of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-chlorpropyl-5-(1 - pyrrolidinecarbonyl)-1,3-thiazolidin-4-it.

Reference example 51. Getting 2-(3,5-di-tert-butyl-4 - hydroxyphenyl)-3-(3-bromopropyl)-5-methoxy-1,3-thiazolidin-4-it.

To a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3 - bromopropyl)-1,3-thiazolidin-4-it /1.0 g/ obtained in reference example 29, in dichloromethane /15 ml was added dropwise sulfurylchloride /0.36 g/ cooling with a mixture of ice and water, and the mixture is stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure and to the residue was added methanol /10 ml, and the mixture peremeci the current was purified using chromatography on silicagel column (eluent: chloroform), giving 0.59 g (48%) of target compound as pale brown oil.

NMR (CDCl3) (200 MHz) :

1.42(18H, s ), 1.5-2.3(2H, m ), 2.8 to 3.6(4H, m), 3.46(3x2/5H, s), 3.52(3x3/5H, s), 5.2-6.1(3H, m), 7.08(2x2/5H, s), 7.12(3x3/5H, s)

Reference examples 52 and 53. Each of the compounds listed in table 21 were obtained in accordance with the procedure of referential example 51 by using ethylene glycol instead of methanol.

Example 54. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]- 5-methoxy-1,3-thiazolidin-4-it.

The target compound was obtained as a pale yellow oil in accordance with the procedure of example 26-A, using 2-(3,5-decret-butyl-4-hydroxyphenyl)-3-(3-bromopropyl)- 5-methoxy-1,3-thiazolidin-4-she obtained in reference example 51, instead of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-bromopropyl)-1,3-thiazolidin-4-it.

NMR (CDCl3) (270 MHz) :

1.41(18H, s ), 1.4-1.9(2H, m ), 2.18(3x2/5H, s), 2.22(3x3/5H, s), 2.2-3.1(5H, m ), 3.46(3x2/5H, s), 3.51(3x3/5H, s), 3.5-3.7(1H, m), 3.8-4.1(2H, m), 5.2-5.8(3H, m), 5.90(2H, s), 6.1-6.8(3H, m), 7.21(2x2/5H, s ), 7.26(2x3/5H, s)

Examples 55 and 56. Each of the compounds shown in table 22, were obtained in accordance with the procedure of example 54, using each of the compounds obtained in LASS="ptx2">

Example 57. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] - 1,3-thiazolidin-4-thione.

In THF /5 ml/ suspendibility 2-(3,5-di-tert-butyl-4 - hydroxyphenyl) -3-[3-[N-methyl-N-[2- (3,4-methylenedioxyphenoxy) ethyl]amino]propyl]-1,3-thiazolidin-4-one /217 mg/ and reagent Lawsona /194 mg/, and the suspension was mixed at room temperature for 5 hours. The solvent was evaporated under reduced pressure and to the residue was added water /20 ml, and then the mixture was extracted with chloroform. The organic layer was washed successively with water and brine and were dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 99:1) to give 181 mg (81%) of target compound as pale yellow oil.

NMR (CDCl3) (200 MHz) :

1.41(18H, s), 1.3-1.8(2H, m), 2.20(3H, s), 2.3 - 2.5(2H, m), 2.70(2H, T. , J= 5.7 Hz), 3.1-3.3(1H, m), 3.93(2H, T., J=5.7 Hz), 3.9-4.1(1H, m), 4.26 and 4.40(2H, Awkw., J =16.0 Hz), 5.34(1H, s), 6.18(2H, s), 6.04(1H, s ), 6.2-7.0(3H, m), 7.07(2H, s).

Example 58. Obtaining N-[3-[N-methyl-N-[2-(3,4 - methylenedioxyphenoxy)ethyl] amino]-propyl]-3,5-di-tert-butyl-4 - hydroxybenzamide.

oC and the mixture was mixed at room temperature for 1 hour. The solvent and excess oxalicacid was removed under reduced pressure and to the residue was added tetrahydrofuran /8 ml/. The resulting solution was added dropwise to a solution of 3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]Propylamine /1.01 g/ triethylamine /0.41 g/ tetrahydrofuran /13 ml/ at 0oC, and the mixture is stirred at room temperature for 6 hours. The reaction mixture was poured into cold water and the product was extracted with chloroform. The organic layer was washed with saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 97:3) to give 1.35 g (70%) of target compound as pale brown oil.

NMR (CDCl3) :

1.H/3H, s ), 1.43(h/3H, s), 1.7-1,9(2H,m), 2.41(3H, s), 2.6-2.7(2H, m), 2.8-2.9(2H, m), 3.5-3.6(2H, m), 3.9-4.1(2H, m), 5.48(1H, s ), 5.86(2x2/3H, s ), 5.88(2x1/3H, s), 6.1-6.7(3H, m), 7.64(2x2/3H,s), 7.79(2x1/3H, s), 7.8-8.0(1H, Shir. C.)

Example 59. In accordance with the procedure of example 58 was obtained 3,5 - di-tert-butyl-4-hydroxybenzenesulfonate of 3,5-di-tert-butyl-4-hydroxybenzenesulfonic acid and tianello-methylenedioxyphenoxy)ethyl]amino]propyl]-3,5-di - tertbutyl-4-hydroxybenzenesulfonate, giving a colorless oil.

NMR (CDCl3) (200 MHz) :

1.43(18H, s ), 1.3-1.8(2H, m), 2.25(3H, s), 2.51(2H, T., J=6.3 Hz), 2.72(2H, so J= 6.3 Hz), 3.07(2H, T., J= 6.3 Hz), 3.97(2H, T., J=6.3 Hz), 5.66(1H, s), 5.90(2H, s), 6.2-6.7(3H, m), 7.67(2H, s)< / BR>
Example 60. Obtaining N-[3-[N-methyl-N-[2- (3,4 - methylenedioxyphenoxy)ethyl]amino]propyl]-3,5-di-tert-butyl-4 - hydroxybenzamide.

The target compound was obtained as pale yellow crystals in accordance with the procedure of example 57 using N-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -3,5 - di-tert-butyl-4-hydroxybenzoyl obtained in example 58, instead of 2-(3,5-di-tertbutyl-4-hydroxyphenyl)- 3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)-ethyl]amino]propyl]-1,3 - thiazolidin-4-it, so pl. 114-115oC.

NMR (CDCl3) (200 MHz) :

1.42(18H, s), 1.6-2.1(2H, m), 2.21(3H, s), 2.5-2.9(4H, m), 3.80(2H, T., J=5.7 Hz), 3.8-4.1(2H, m), 5.44(1H, s), 5.82(2H, s), 5.8-6.7(3H, m), 7.5-7.8(3H, m)

Example 61. Obtaining N-cyano-N'-[3-[N-methyl-N-[2-(3,4 - methylenedioxyphenoxy)-ethyl]amino]impregnated]-3,5-di-tert-butyl-4 - hydroxybenzamide.

To a solution of N-[3-[N-methyl-N-[2-3, 4-methylenedioxyphenoxy) ethyl]amino] propyl] -3,5-di-tert-butyl-4-hydroxybenzamide /1.0 g/ obtained in example 60, in dry tetrahydrofuran was added sodium hydride /0.16 g/ at 0oC in the atmosphere azuosim by stirring at room temperature for 2 hours. The mixture was again cooled to 0oC, and to it was added cyanamide /0.84 g/ followed by stirring at room temperature for 15 hours. After completion of the reaction the mixture was poured into a mixture of ice and water, and the product was extracted with chloroform. The organic layer was washed with saline and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 99: 1) to give 0.70 g (69%) of target compound as pale yellow crystals, so pl. 129-130oC.

NMR (CDCl3) (200 MHz) :

1.45(18H, s ), 1.6-2.1(2H, m), 2.20(3H, s), 2.6-3.0(4H, m), 3.6-3.8(2H, m), 3.83(2H, T., J=5.7 Hz), 5.56(1H, s), 5.84(2H, s), 5.8-6.8(3H, m), 7.48(2H, s), 7.48(2H, s), 8.44(1H, Shir.S.).

Reference example 54. Obtaining 3-(3-bromopropyl)-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4 - oxadiazol/-2(3H)-it.

To a solution of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1, 3,4-oxadiazol-2(3H)-it /0.50 g/ dimethylformamide /8 ml was added sodium carbonate /0.36 g/ and dibromopropan /1.74 g/, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into a mixture of ice and water, and the product was extracted etnom pressure. The residue was purified using chromatography on silicagel column (eluent: chloroform), and then precrystallization from a mixture of chloroform and n-hexane, yielding 0.45 g (63%) of target compound as colorless crystals. So pl. 130-131oC.

NMR (CDCl3) (200 MHz) :

1.46(18H, s), 2.1 to 2.6(2H, m), 3.46(2H, T., J=6.6 Hz), 3.93(2H, T., J= 6.6 Hz), 5.60(1H, s), 7.63(2H, s).

Reference examples 55 to 58. Each of the compounds listed in table 23 were obtained in accordance with the procedure of reference example 54, using in each case instead of 5-(3,5-di-tert-butyl-4 - hydroxyphenyl)-1,3,4-oxadiazol-2(3H)-she of the corresponding 5-membered heterocyclic compounds.

Example 62. Getting 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-3- [3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)-ethyl] amino] propyl] - 1,3,4-oxadiazol-2/3H/she is.

The target compound was obtained as a colorless oil according to the procedure of example 26-A using 3- (3-bromopropyl)-5-(3,5-di-tert-butyl-4-hydroxyphenyl)- 1,3,4-oxadiazol-2(3H)-she obtained in reference example 54, instead of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-bromopropyl) -1,3-thiazolidin-4-it.

NMR (CDCl3) (270 MHz) :

1.45(18H, s ), 1.8-2.2(2H, m), 2.35(3H, s), 2.4-3.0(4H, m), 3.7-4.2(4H, m), 5.60(1H, s), 5.88(2H, s),following the procedure of example 62 using each of the compounds, in Table 23, instead of 3- (3-bromopropyl)-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4 - oxadiazol-2(3H)-it.

Reference example 59. Getting 5-(3,5-di-tert-butyl-4 - hydroxyphenyl)-1-(3-hydroxypropyl)imidazole,

To a solution of 3-hydroxy-N-(3,5-di-tert-butyl-4-hydroxybenzylidene) -Propylamine /1.50 g/ methanol /50 ml/ added dosimetricians /1.68 g/ and the potassium carbonate /1.43 g/, and the mixture is stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into a mixture of ice and water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude crystals were precrystallization from a mixture of chloroform and diethyl ether, giving 1.41 g /82%/ target compound in the form of blignault crystals, so pl. 166-167oC.

NMR (CDCl3) :

1.43(18H, s), 1.5-2.3(3H, m), 3.53(2H, T., J= = 6.6 Hz), 4.08(2H. so, J=6.6 Hz), 5.30(1H, Shir. C.), 6.92(1H, Shir. C.), 7.10(2H, s), 7.50(1H, s)

Reference example 60. Getting 5-(3,5-di-tert-butyl-4 - hydroxyphenyl)-1-(3-chloropropyl)imidazole.

To a solution of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-(3 - hydroxypropyl)imidazole /1.20 g/ obtained in reference primal was heated under reflux for 2 hours, After leaving to cool, the reaction mixture was poured into 5% aqueous sodium carbonate solution, a cooled mixture of ice and water, and the product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was precrystallization from a mixture of dichloromethane and diethyl ether, yielding 1.09 g (86%) of target compound as pale yellow crystals, so pl. 178-179oC,

NMR (CDCl3) (60 MHz) :

1.43(18H, s), 1.6-2.8(2H, m), 3.35(2H, T., J=6.6 Hz), 4.15(2H, T., J= 6.6 Hz), 5.45(1H, Shir. s), 6.90(1H, s), 7.05(2H, s), 7.43(1H, s)

Example 67. Getting 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-[3- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]imidazole.

The target compound was obtained as a colorless oil according to the procedure of example 1 using 5-(3, 5-di-tert-butyl-4-hydroxyphenyl)-1-(3-chloropropyl)imidazole obtained in reference example 60, instead of 2-(3,5-aminobutiramida 4-hydroxyphenyl)-3-(3-chlorpropyl)-1,3-thiazolidin-4 - it.

NMR (CDCl3) (200 MHz) :

1.43(18H, s ), 1.5-2.0(2H, m), 2.16(3H, s), 2.32(2H, T., J=6.6 Hz), 2.64(2H, T. , J= 5.7 Hz), 3.88(2H, T., J= 5.7 Hz), 3.98(2H, T., J=6.6 Hz), 5.35(1H, Shir. C.), 5.87(2H, s), 6.1-6.8(3H, m), 6.96(1H, s), 7.12(2H, s ), 7.52(1H, s is about]propyl]- 1,3-thiazolidin-4-it-1-oxide.

To a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3 - thiazolidin-4-it /0.30 g/, obtained in example 26-A and 26-B, in acetic acid /5 ml was added 35% aqueous hydrogen peroxide solution /0.20 g/, and the mixture is stirred at room temperature over night. After completion of the reaction, the reaction mixture was added to a mixture of ethyl acetate and 5% aqueous sodium carbonate solution and stirred. The organic layer was separated, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 98:2) to give 0.12 g (39%) of target compound as a colorless oil. MC (m/z):558(M+)

NMR (CDCl3) (200 MHz) :

1.41(18H, s), 1.4-2.0(2H, m), 2.28(3H, s), 2.3-2.7(2H, m), 2.72(2H, T., J=5.7 Hz), 2.9-3.2(1H, m), 3.37 and 3.69(2H, Awkw., J=16 Hz), 3.8-4.2(3H, m), 5.40(1H, s), 5.61(1H, s), 5.87(2H, s), 6.1-6.8(3H, m), 6.94(2H, s)

Reference example 61. Obtain hydrochloride of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazolidine.

In a mixed solvent consisting of methanol /100 ml and tetrahydrofuran /100 ml, was dissolved 5.0 g of 3,5-di-tertbutyl-4-hydroxybenzaldehyde /5.0 g/, and was added to a solution of 2-amiele completion of the reaction the solvent was evaporated under reduced pressure, and to the residue was added 200 ml of ice and water. The product was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and to the residue was added a mixture of methanol-hydrochloric acid /5 ml. The mixture was pulverized with diethyl ether, giving 5.81 g (82%) of target compound in the form of a white powder.

NMR (CDCl3) (200 MHz) :

1.43(18H, s ), 2.9-3.2(2H, m ), 3.6-3.8(1H, m), 3.8-4.0(1H, m), 5.20(1H, s), 5.46(1H, s), 7.2-7.4(2H, m)

Reference example 62. Getting 2-(3,5-di-tert-butyl - 4-hydroxyphenyl)-3-acryloyl-1,3-thiazolidine.

To a suspension of the hydrochloride of 2-(3,5-di-tert-butyl-4-hydroxyphenyl) -1,3-thiazolidin /1.65 g/ obtained in reference example 61, in tetrahydrofuran /20 ml was added triethylamine /1.52 g/, and to the mixture was added akriloilkhlorida /0.63 g/ at 0oC. the Mixture is stirred at this temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into a mixture of ice and water, and the product was extracted with chloroform. The organic layer was washed successively 1 standards. hydrochloric acid, saturated aqueous bicarbonate sodium and brine, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the I 0.93 g (54%) of target compound as colorless crystals, so pl. 147-149oC.

NMR (CDCl3) (200 MHz) :

1.40(18H, s ), 3.0-3.2(2H, m), 3.8-4.0(1H, m ), 4.2-4.5(1H, m), 5.20(1H, Shir. C.), 5.5-5.8(1H, m), 5.9-6.6(3H, m), 6.98(2H, Shir. C.)

Example 69. Getting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3- [N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propionyl]- 1,3-thiazolidine,

To a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-acryloyl-1,3 - thiazolidin /0.35 g/ obtained in reference example 62, in chloroform /5 ml was added N-methyl-2-(3,4-methylenedioxyphenoxy)ethylamine /0.20 g/, and the mixture was heated under reflux for 3 hours. After completion of the reaction the solvent was evaporated under reduced pressure, and the residue was purified using chromatography on silicagel column (eluent: chloroform-methanol, 98:2) to give 0.41 g 76%) of target compound as a colourless oil.

NMR (CDCl3) (200 MHz) :

1.41(18H, s ), 2.14(3H, s), 2.2-2.7(4H, m), 2.7 - 2.9(2H, m), 2.9-3.2(2H, m), 3.8-4.1(3H, m), 4.2-4.4(1H, m), 5.1-5.3(1H, m), 5.89(2H, s ), 6.02(1H, Shir. C.), 6.2-7.1(5H, m)

Example 70. Obtain (+)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3- [3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] - 1,3-thiazolidin-4-it.

The compound obtained in example 26-A and 26-B and weighing 400 mg) was subjected to HPLC using a column for optical Rasse is Xan-isopropyl alcohol, /80:20, flow rate 16 ml/min, and detectional a wavelength of 280 nm, and separated 180 mg of the target compound. The specific rotation of the hydrochloride of the resulting compounds is as follows: ()D= +36.14 (EtOH, C=0.332),

Obtaining (-)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3- [3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]- 1,3-thiazolidin-4-it.

The compound obtained in examples 26-A and 26-B, a weight of 400 mg was subjected to HPLC in the form of dozens of separate factions in the same conditions as in example 70, and was obtained 170 mg of the target compound. The hydrochloride of the resulting compound had the following specific rotation: ()D= -36.72 (ethanol, C=0.610).

Example 72. Obtaining 2,5-TRANS-2-(3,5-di-tert-butyl-4 - hydroxyphenyl)-3-[3-[N-methyl-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-it.

The compound obtained in example 41-A and 41-A, a weight of 500 mg was subjected to HPLC using silicagel column (CMD-paxil SH-043-5.2 cm (diameter) x 25 cm) in dozens of separate factions in the conditions of the mobile phase chloroform-isopropanol, /97:3, flow rate 12 ml/min, and detectional a wavelength of 280 nm, and stood out 150 mg of the target compound. The stereochemistry was established by 1.41(18H, s ), 1.5-1.9(2H, m), 1,58(3H, d, J=6.9 Hz), 2.23(3H, s), 2.3-2.5(2H, m ), 2.69(2H, T., J=5.6 Hz), 2.7-2.9(1H, m), 3.5-3.7(1H, m), 3.94(2H, T. , J = 5.6 Hz), 4.02(1H, q, j square J=1.7, 6.9 Hz), 5.28(1H, s), 5.57(1H, d, J=1.7 Hz), 5.90(2H, s), 6.2-6.8(3H, m), 7.05(2H, s)

Example 73. Obtaining 2,5-CIS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)- -3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)-ethyl] amino]propyl] -5-methyl-1,3-thiazolidin-4-it.

The compound obtained in example 41-A and 41-B, a weight of 500 mg was subjected to HPLC in dozens of factions in the same conditions as in example 72, and was obtained 140 mg of the target compound. The stereochemistry was established according to the 1H-Yarm M. R. Johnson and others (M. R. Johnson and others, J. Qrg. Chem. 48, 494 (1983)).

NMR (CDCl3) (270 MHz) :

1.43(18H, s ), 1.2-2.0(2H, m), 1.65(3H, d, J=6.9 Hz), 2.20(3H, m), 2.2-2.5(2H, m ), 2.67(2H, T., J=5.6 Hz), 2.7-3.0(1H, m), 3.4-3.8(1H, m), 3.92(2H, T., J=5.6 Hz), 4.02 (1H, square, J=6.9 Hz), 5.30(1H, s), 5.55(1H, s ), 5.91(2H, s), 6.2-6.8 (3H, m), 7.12(2H, s).

Example 74. Obtain (+)-2,5-CIS-2-(3,5-di-tert-butyl-4 - hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]-5-methyl-1,3-thiazolidin-4-it.

The compound obtained in example 73, was subjected to HPLC in dozens of separate factions in the same conditions as in example 70, for separation of the target product. The resulting compound had the following indicators attached is oxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]-5-methyl-2,3-thiazolidin-4-it.

The compound obtained in example 73, was subjected to HPLC in dozens of separate factions in the same conditions as in example 70, for separation of the target product. The resulting compound had the following indicators specific rotation: ()D= -28.39 (CDCl3with=1.000)

Below is a description of examples of tests in order to demonstrate that compounds having formula I, according to the present invention have three types of actions, i.e., inhibitory effect on lipid pereokislenie vasodilator action and the action on the inhibition of calcium overload.

The test example 1. Inhibitory effect on lipid pereokislenie in vitro:

Method A. the Test compound was added to LDL rabbits received in accordance with the method of Havel and others (Havel, R. J. et al., J. Clin, Invest., 34, 1345(1955)), and then added soybean lipoxygenase type IS (SLO) to a final concentration of 40 μg/ml Oxidation of LDL was carried out by incubation at 37oC CO2incubator for 24 hours. Oxidized LDL solution was analyzed by gel permeation chromatography, and fluorescence intensity LDL fraction was measured at a wavelength of excitation 360 nmany in table 25 (see at the end of the description).

Method B. the Test compound was added to LDL rabbit received in accordance with the method of Havel and others (Havel, R. J., et al., J. Clin. Invest., 34, 1345 (1955)), then add copper sulfate to a final concentration of 1 μm. Oxidation of LDL was carried out with shaking at 37oC for 24 hours. Generated TBARS was measured by the method of Yagi and using fluorometry (Yagi, K. , Biohem. Med., 15, 212 (1976)). The measurement results, expressed as percentage of inhibition is shown in table 26 (see end of description).

The test example 2. Vasodilator action in vitro.

Method.

In male rats Sparague-Dawley (Cry) weighing between 350 and 550 g were cut thoracic aorta was freed from surrounding connective tissue. The vessel is cut into a ring having a width of 2-3 mm of the Resulting preparation was Wednesday histological preparation for registration isometric tension (tension) in the tub with a body filled with 10 ml Krebs-Hanseleit (K-H solution, pH 7.4, 37oC), which was flushed with a mixture of 95% O2/5% CO2. Changes in isometric tension were recorded using an isometric transducer (TB-611T, manufactured by Nihon Koden Bldg.). P is the population balance at 30 minutes (K-H solution was replaced with fresh every 15 minutes). First, the preparation was subjected to preliminary compression by replacing the solution in the bath solution containing 30 mm K+. After the compression was maintained for 20 minutes, the product was filtered K-H solution. After 60 minutes (K-H solution was replaced with fresh solution every 20 minutes), the compression again were induced in the same manner as described above. After compression stabilized to the system was added to the test compound or diltiazem cumulative manner, with increments or increments semi log-unit to obtain the curve of concentration - response.

Taking compression with 30 mm K+100% had a concentration of drug at which the compression is relaxed to 50% in the form 1C50. The results are shown in table 27 (see end of description).

The test example 3. Inhibitory effect on calcium overload in vitro, Method A:

Were prepared incubated ventricular myocytes from hearts of male rats Sprogue-Dawley weighing 300-500 g, using the method of enzymatic perfusion. Thus obtained rod-shaped normal myocytes were treated test compound or diltiazem for 30 minutes, and added 100 μg/ml veratrine. After 5 the Oia. The results are shown in table 28 (see end of description).

Method B. the Effectiveness of was evaluated in the same way as in the case of method A, except using 50 μg/ml veratrine instead of 100 µg/ml veratrine. The results are shown in table 29 (see the end of the description).

Compounds of the examples cited previously shown in tables 30-37 (see the end of the description).

Industrial applicability.

As described above, the connection according to the present invention has an inhibitory action on lipid pereokislenie vasodilator action and inhibitory action on calcium overload and could be used as a preventive or therapeutic agent in the case of ischemic heart disease and hypertension.

1. Production of benzene of General formula (I)

< / BR>
in which R1represents a hydrogen atom, a hydroxyl group, alloctype having 1 to 9 atoms operad, or lower alkoxygroup having 1 to 6 carbon atoms;

R2or R3that may be the same or different, represent each a hydrogen atom, halogen atom, lower alkyl group having 1 to 6 carbon atoms, or lower alkoxygroup, amatomu carbon;

A represents A fragment of General formula (II)

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or unsubstituted phenyl; substituted or unsubstituted, pyrrolidin or 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum, or a fragment of the formula (llI)

B,

moreover, B is a fragment selected from the following group of fragments of formula (lV - XVl)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R6and R7the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4, 5 or 6,

or their possible stereoisomers, or optical isomer is th R1represents a hydroxyl group, alloctype having 1 to 9 carbon atoms, or lower alkoxygroup having 1 to 6 carbon atoms;

R2and R3identical or different, represent each a hydrogen atom, halogen atom, lower alkyl group having 1 to 6 carbon atoms, or lower alkoxygroup having 1 to 6 carbon atoms;

R4represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms;

A represents A fragment of General formula (lI)

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or unsubstituted finalnew group; substituted or unsubstituted, pyrrolidin or 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum; or a fragment of formula IlI

B,

in which B represents a fragment selected from the following group of fragments of formulas IV - XVl

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R6and R7the same or different, each represents a hydrogen atom, tamilnew group or zameshannuu or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4, 5, or 6,

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

3. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 carbon atoms, or lower alkoxygroup having 1 to 6 carbon atoms;

R2and R3identical or different, represent each a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms;

R4represents a hydrogen atom or methyl group;

A fragment of General formula lI

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or unsubstituted phenyl group; substituted or unsubstituted, pyrrolidin or 5-membered ring containing two oxygen atom, a carbon atom to which it prisoedineaiusi group of fragments of formula lV - VlIl

< / BR>
< / BR>
< / BR>
R6and R7the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4 or 5,

or its possible stereoisomers, or optical isomers, or its pharmaceutical acceptable salts.

4. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 carbon atoms, or lower alkoxygroup having 1 to 6 carbon atoms;

R2and R3identical or different, represent methyl group, ethyl group, isopropyl group or tert-boutelou group;

R4represents a hydrogen atom or methyl group;

A represents A fragment of General formula (lI)

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl pile; substituted or unsubstituted phenyl group, substituted or unsubstituted pyrrolidine or 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum; or a fragment formula

B,

in which B represents a fragment of formula lV

< / BR>
R6and R7the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4 or 5;

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

5. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 carbon atoms, or lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

odorata, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or unsubstituted finalnew group; zanesennyi or an unsubstituted pyrrolidine or 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6and R7the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4 or 5;

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

6. The compound of General formula I under item 1

< / BR>
in which R1represents hydroxy or methoxy group;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4- atomnoy or unsubstituted lower alkyl group, having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or unsubstituted phenyl group; substituted or unsubstituted, pyrrolidin or 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6and R7the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring, which may be skondensirovany ring;

n = 2, 3, 4 or 5;

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

7. The compound of General formula I under item 1

< / BR>
in which R1- hydroxyl group;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5is a; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or unsubstituted phenyl group; substituted or unsubstituted, pyrrolidin or 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6and R7the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4 or 5;

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

8. The compound of General formula I under item 1

< / BR>
in which R1- hydroxyl group;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of the General formula ll

< / BR>
in which R5represents the hydrogen atom is th lower alkoxygroup, having 1 to 6 carbon atoms; substituted or unsubstituted phenyl group; substituted or unsubstituted, pyrrolidin or 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6and R7the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 3,

or its possible stereoisomer, or optical isomers, or its pharmaceutically acceptable salt.

9. The compound of General formula I under item 1

< / BR>
in which R1- alloctype having 1 to 9 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of the General formula ll

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower carbon atoms; substituted or unsubstituted phenyl group, substituted or unsubstituted pyrrolidine or 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6and R7the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4 or 5;

or its possible stereoisomers, or optical isomers, or their pharmaceutically acceptable salts.

10. The compound of General formula I under item 1

< / BR>
in which R1- lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of the General formula ll

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl groups; amestoy or unsubstituted finalnew group; substituted or unsubstituted, pyrrolidin or 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6and R7the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4 or 5;

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

11. The compound of General formula I under item 1

< / BR>
in which R1- methoxy group;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of the General formula ll

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; Zam is the function group: substituted or unsubstituted pyrrolidine or 5-membered ring, containing two atoms of oxygen, in which case the carbon atom to which it is attached, is spirostomum;

R6and R7that may be the same or different, each represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic group, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4 or 5;

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

12. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 otomops carbon, or lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group; substituted or unsubstituted phenyl group or a 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6and R7the same or different, each represents a hydrogen atom or substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4 or 5;

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

13. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 otomops carbon, or lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or nizamudeen ring, containing two atoms of oxygen, in which case the carbon atom to which it is attached, is spirostomum;

R6and R7the same or different, each represents a hydrogen atom or substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 3;

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

14. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 otomops carbon, or lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or Neshama, to which it is attached, is spirostomum;

R6and R7the same or different, each represents a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 2, 3, 4 or 5;

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

15. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 otomops carbon, or lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or unsubstituted phenyl group or a 5-membered ring containing two atoms sour is 7 the same or different, each represents a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, provided that R6and R7both are methyl groups, or R6and R7taken together, form a substituted or unsubstituted ring which may be condensed ring;

n = 3,

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

16. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 otomops carbon, or lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or unsubstituted phenyl group or a 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is sproat is kind;

R7represents a group selected from the group consisting of 2-(3,4-methylenedioxyphenoxy)ethyl group, 3-(3,4-methylenedioxyphenoxy), sawn group, 4-(3,4-methylenedioxyphenoxy)-n-butilkoi group and 3,4-dimethoxyphenylthio group, or

-NR6R7represents a group selected from the group consisting of 4-(N-2-benzothiazolyl-N-methylamino)piperidino group, 4-femalecelebrities group, 4-(3,4-methylenedioxyphenoxy)piperidino group and 4-(2,3,4-trimethoxyphenyl)piperazinilnom group;

n = 2, 3, 4 or 5,

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

17. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 otomops carbon, or lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 atoms in which the carbon atom, to which it is attached, is spirostomum;

R6represents substituted or unsubstituted lower alkyl group having 1 to 3 carbon atoms;

R7represents a group selected from the group consisting of 2-(3,4-methylenedioxyphenoxy)ethyl group, 3-(3,4-methylenedioxyphenoxy), sawn group, 4-(3,4-methylenedioxyphenoxy)-n-butilkoi group and 3,4-dimethoxyphenylthio group, or

-NR6R7represents a group selected from the group consisting of 4-(N-2-benzothiazolyl-N-methylamino)piperidino group, 4-femalecelebrities group, 4-(3,4-methylenedioxyphenoxy)piperidino group and 4-(2,3,4-trimethoxyphenyl)piperazinilnom group;

n = 3,

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

18. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 otomops carbon, or lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5represents the hydrogen atom is s lower alkoxygroup, having 1 to 6 carbon atoms; substituted or unsubstituted phenyl group or a 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6represents a methyl or ethyl group;

R7represents a group selected from the group consisting of 2-(3,4-methylenedioxyphenoxy)ethyl group, 3-(3,4-methylenedioxyphenoxy), sawn group, 4-(3,4-methylenedioxyphenoxy)-n-butilkoi group and 3,4-dimethoxyphenylthio group, or

-NR6R7represents a group selected from the group consisting of 4-(N-2-benzothiazolyl-N-methylamino)piperidino group, 4-femalecelebrities group, 4-(3,4-methylenedioxyphenoxy)piperidino group and 4-(2,3,4-trimethoxyphenyl)piperazinilnom group;

n = 2, 3, 4 or 5,

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

19. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 otomops carbon, or lower alkoxygroup having 1 to 6 carbon atoms;

R2- tert-bucilina group;

R3- tert-bucilina group;
m is hydrogen, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; substituted or unsubstituted phenyl group or a 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6represents a methyl or ethyl group;

R7represents a group selected from the group consisting of 2-(3,4-methylenedioxyphenoxy)ethyl group, 3-(3,4-methylenedioxyphenoxy), sawn group, 4-(3,4-methylenedioxyphenoxy)-n-butilkoi group and 3,4-dimethoxyphenylthio group, or

-NR6R7represents a group selected from the group consisting of 4-(N-2-benzothiazolyl-N-methylamino)piperidino group, 4-femalecelebrities group, 4-(3,4-methylenedioxyphenoxy)piperidino group and 4-(2,3,4-trimethoxyphenyl)piperazinilnom group;

n = 3,

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

20. The compound of General formula I under item 1

< / BR>
in which R1represents a hydroxyl group, alloctype having 1 to 9 carbon atoms, or Nisshin group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; or a 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6represents a methyl group;

R7group selected from the group consisting of 2-(3,4-methylenedioxyphenoxy)ethyl group, 3-(3,4-methylenedioxyphenoxy), sawn group, 4-(3,4-methylenedioxyphenoxy)-n-butilkoi group and 3,4-dimethoxyphenylthio group, or

-NR6R7represents a group selected from the group consisting of 4-(N-2-benzothiazolyl-N-methylamino)piperidino group, 4-femalecelebrities group, 4-(3,4-methylenedioxyphenoxy)piperidino group and 4-(2,3,4-trimethoxyphenyl)piperazinilnom group;

n = 2, 3, 4 or 5,

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

21. The compound of General formula I under item 1

< / BR>
in which R1represents hydroxyl UB>2- tert-bucilina group;

R3- tert-bucilina group;

R4is a hydrogen atom;

A fragment of General formula lI

< / BR>
in which R5represents a hydrogen atom, substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms; substituted or unsubstituted lower alkoxygroup having 1 to 6 carbon atoms; or a 5-membered ring containing two oxygen atom, a carbon atom to which it is attached, is spirostomum;

R6represents a methyl group;

R7group selected from the group consisting of 2-(3,4-methylenedioxyphenoxy)ethyl group, 3-(3,4-methylenedioxyphenoxy), sawn group, 4-(3,4-methylenedioxyphenoxy)-n-butilkoi group and 3,4-dimethoxyphenylthio group, or

-NR6R7represents a group selected from the group consisting of 4-(N-2-benzothiazolyl-N-methylamino)piperidino group, 4-femalecelebrities group, 4-(3,4-methylenedioxyphenoxy)piperidino group and 4-(2,3,4-trimethoxyphenyl)piperazinilnom group;

n = 3,

or its possible stereoisomers, or optical isomers, or its pharmaceutically acceptable salt.

22. Connection on p. 1, selected from the group of the and)ethyl] amino] propyl]-1,3-thiazolidin-4-one; (+)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-1,3-thiazolidin-4-one; (-)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl] -1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[4-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] bet]-1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[5-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]pentyl] -1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[3-(3,4-methylenedioxyphenoxy)propyl] amino] propyl] -1,3-thiazolidin-4-one; 2-(3,5-aminobutiramida 4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[1-[4-(2,3,4-trimethoxybenzyl)piperazinil] ] propyl] -1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[ N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-5-methyl-1,3-thiazolidin-4-one; 2,5-CIS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one; (-)-2,5-CIS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)aticimun.exe)ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one; 2,5-TRANS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[4-(3,4-methylenedioxyphenoxy)butyl] amino] propyl] -1,3-thiazolidin-4-one; 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl] -imidazole; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-1,3-thiazolidin-4-tion; 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-ethyl-2-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-1,2,4-triazole-3-one; 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propoxy] -1,2,4-oxadiazole; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-5-(2-hydroxyethyl)-1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one; N-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]-3,5-di-tert-butyl-4-hydroxybenzenesulfonate; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-methoxy-1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N--4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-(2-hydroxyethoxy)-1,3-thiazolidin-4-one; Spiro[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-1,3-thiazolidin-4-one-5,2'-[1,3]dioxolane]; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-N, N-dimethylcarbamoyl-1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[1-(4-benzyl)piperidyl] propyl]-1,3-thiazolidin-4-one and 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[1-[4-(3,4-methylenedioxyphenoxy)piperidyl] ] propyl] -1,3-thiazolidin-4-one or its pharmaceutically acceptable salts.

23. Connection on p. 1, selected from the group consisting of the following compounds: 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -1,3-thiazolidin-4-one; (+)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-1,3-thiazolidin-4-one; (-)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl] -1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-ethyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[3-(3,4-methylenedioxyphenoxy] amino] propyl] -1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methyland the-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl] -5-methyl-1,3-thiazolidin-4-one; (-)-2,5-CIS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-5-methyl-1,3-thiazolidin-4-one; (+)-2,5 - CIS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-5-methyl-1,3-thiazolidin-4-one; 2,5-TRANS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-methyl-1,3-thiazolidin-4-one; 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -imidazole; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -1,3-thiazolidin-4-tion; 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-ethyl-2-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -1,2,4-triazole-3-one; 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propoxy]-1,2,4-oxadiazole; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-(2-hydroxyethyl)-1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-ethoxycarbonylmethyl-1,3-thiazolidin-4-one; N-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]-3,5-di-tert-butyl-4-hydroxybenzenesulfonate; 2-(3,5-di-tert-butyl-4-hydrochl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-5-isopropoxycarbonyl-1,3-thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-(2-hydroxyethoxy)-1,3-thiazolidin-4-one; Spiro[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]-1,3-thiazolidin-4-one-5,2'-[1,3] dioxolane] ; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-5-N,N-dimethylcarbamoyl-methyl-1,3 - thiazolidin-4-one; 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[1-(4-benzyl)piperidyl]propyl]-1,3-thiazolidin-4-one or its pharmaceutically acceptable salts.

24. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -1,3-thiazolidin-4-one under item 1 or its pharmaceutically acceptable salt or its possible optical isomer.

25. (+)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-1,3-thiazolidin-4-one under item 1 or its pharmaceutically acceptable salt.

26. (-)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl]-1,3-thiazolidin-4-one under item 1 or its pharmaceutically acceptable salt.

27. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino] propyl] -5-methyl-1,3-thiazolidin CLASS="ptx2">

28. 2,5-CIS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]-5-methyl-1,3-thiazolidin-4-one under item 1, or its pharmaceutically acceptable salt, or its possible optical isomer.

29. 2,5-TRANS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]-5-methyl-1,3-thiazolidin-4-one under item 1, or its pharmaceutically acceptable salt, or its possible optical isomer.

30. (-)-2,5-CIS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]-5-methyl-1,3-thiazolidin-4-one under item 1, or its pharmaceutically acceptable salt.

31. (+)-2,5-CIS-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl] amino]propyl]-5-methyl-1,3-thiazolidin-4-one under item 1, or its pharmaceutically acceptable salt.

 

Same patents:

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to the derivatives of saccharin General formula 1, where L denotes 0 or N; when L is 0, R1- 2,6-dichloro-3-[2-(4-morpholinyl)ethoxy] benzoyl, when L is N, then L together with R1represents a 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl, R2primary or secondary alkyl of 2-4 carbon atoms, R3- lower alkoxy at any of the 5-, 6 - or 7-positions, or their pharmaceutically acceptable additive salts of acids or bases, which inhibit the activity of proteolytic enzymes

The invention relates to new benzothiophen-2-carboxamide-S,S-dioxides having valuable properties, in particular to derive benzothiophen-2-carboxamide - S,S-dioxide of the General formula I

< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to optically active derivative of carboxamides with a strong analgezirutuyu activity and low toxicity, or their pharmacologically suitable salts

The invention relates to the chemistry of heterocyclic compounds exhibiting inhibitory activity against elastase

The invention relates to cyclic urethane compounds and their pharmaceutical compositions suitable for the treatment of humans and other mammals with cardiac arrhythmia and cardiac fibrillation

The invention relates to the derivatives of indole, methods and intermediates for their receipt containing their pharmaceutical compositions and to their medical use

The invention relates to new Amida 4 - oxoazetidin-2-sulphonic acids and their salts, to a process of obtaining

The invention relates to a method for 3-{ 2-[4-(6-toranzo[d]isoxazol-3-yl) piperidine-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a] pyrimidine-4-it (I) interaction of 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it (II) isoxazol derivative of the formula (III)where Y and Z represent the deleted group, such as halogen or alkyl - or arylsulfonate, in the presence of a suitable solvent and base
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