Medicines for heart failure

 

(57) Abstract:

Cardiotonic drugs used in medicine for treatment of heart failure, contain as active ingredient at least one of the compounds of the formula I or their pharmacologically acceptable salts.

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where n = 0 or 1; a represents OH or H; represents a hydrogen atom; X represents an oxygen atom, a nitrogen atom; R1and R2represent a hydrogen atom, a C1-C4-alkyl; R3and R4represent a hydrogen atom, a C1-C6-alkyl, C2-C6alkenyl, or C(=Y)ZR6where Z=NH; Y=O,S, N-CN, or they together form a 1,4-butylene or 1,5-pentile. These compounds have high activity to strengthen contractions of the heart muscle and strong activity to reduce the rate of heart contraction. 4 C.p. f-crystals, 6 PL.

The present invention relates to the use of pharmaceutically active derivatives of benzopyran as medicines for the treatment of heart failure of mammals, including humans.

In tiled applications for patents Japan N Hei 2-4791, N Hei 2-49788, N Hei 2-152974 and N Hei 5-43432, U.S. patent N 4900752, European is estva for the treatment of diseases of the cardiovascular system, for example, hypertension, angina, arrhythmia, and so on, as well as hair growth stimulants for the treatment of baldness. However, they are not informed about the possibility of using these derivatives as a drug for the treatment of diseases associated with heart failure.

The authors of the present invention intensively studied and researched various derivatives benzopyrano to obtain derivatives with a weak ability to open potassium channels that do not have cardiomegaly activity, but rather having the ability to enhance the contraction of the heart, and as a result have found that the compounds of the following formula (I) possess strong cardiotonic activity.

Specifically, the present invention relates to compounds of the following formula (I), their optical isomers, stereoisomers and pharmaceutically acceptable salts, when they can form salts.

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where X1and X2are absent or represent an oxygen atom;

X represents an oxygen atom, a sulfur atom, a nitrogen atom (the nitrogen atom unsubstituted or substituted by an atom of hydrogen or C1-C4-alkyl), C(O), C(S) or C(N-CN);

A is an atom waters which form a single (additional) communication;

B represents a hydrogen atom or together with A forms a single bond;

R1and R2the same or different from each other, represent a hydrogen atom or a C1-C4-alkyl, or R1and R2together form a 1,4-butylene or 1,5-Panteleeva group, which is unsubstituted or substituted by one or more C1-C4-alkilani;

R3and R4the same or different from each other, represent a hydrogen atom, a C1-C6-alkyl (the alkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group), C2-C6alkenyl (this alkenyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup CH(OR)2(R presti, selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group), C2-C6-quinil (this quinil unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup CH(OR)2(R represents a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group), C3-C6-cycloalkyl (this cycloalkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup CH(OR)2(R represents a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group predstavljaet a hydrogen atom, a cyano, a nitro-group, C1-C4-alkyl, C1-C4-alkoxygroup or CO2R8(R8represents a C1-C4-alkyl)]; Z represents an oxygen atom, a sulfur atom or NR9(R9represents a hydrogen atom, a C1-C6-alkyl (alkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group), C2-C6alkenyl (this alkenyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and Bernini from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group), C3-C6-cycloalkyl (this cycloalkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group) or phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup)); and R6represents a hydrogen atom, a C1-C8-alkyl (the alkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2- 1-C4-alkyl), phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group), C2-C6alkenyl (this alkenyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group), C2-C6-quinil (this quinil unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup, formyl, ceanography and nitro group), C3-C62-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group), or phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup) or

R3and R4together form a 1,4-butylene or 1,5-Panteleeva group (the 1,4-butylene and 1.5-Panteleeva group unsubstituted or substituted by one or more substituents selected from C1-C4-alkyl, phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), halogen atom, OR10(R10represents a hydrogen atom, a C1-C4-alkyl, COR11(R11represents a C1-C4-alkyl), a nitrogroup, SO3H or PO3H2)}, or

R3and R4together form a (CH3)mX4(CH2)I[m and I SIP sulfur or NR12{ R12represents a hydrogen atom, a C1-C4is alkyl or phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup)}], or

R3and R4together form the group (CH2)nZC(=Y) (n denotes the number 2, 3 or 4, and Z and Y have the values listed above).

The present invention relates to pharmaceutical compositions for the treatment of heart failure, containing these compounds as active ingredients.

The compounds shown in the formula (1) of the present invention increases the contraction of the heart muscle, they are suitable for improving cardiac function. Therefore, they are suitable as drugs for treatment of heart failure. These compounds not only have cardiotonic activity, but also have a strong activity to reduce the rate of heart contraction.

The substituents in the compounds of formula (1) will be explained in more detail below.

In the description of the present invention "n" means normal, "i", and refers to ISO-; "sec" means secondary; "t"means tertiary; "c" means cyclo-; "Me" will obache hexyl and "Ph" means phenyl.

Examples R1and R2include a hydrogen atom. Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, sec-Bu and t-Bu. R1and R2may together form a (CH2)4or (CH2)5, resulting in spirochaetaceae kernel.

Examples include A OH, OC(O)Me, OC(O)Et, OC(O)-n, Pr, OC(O)-i-Pr, OC(O)-n-Bu, OC(O)-i-Bu, OC(O)-Sec-Bu, OC(O)-t-Bu, etc.

A and B may together form a single (additional) communication.

Examples of X include an oxygen atom, a sulfur atom, C(O), C(S) NH, NMe, NEt, N-n-Pr, N-i-Pr, N-n-Bu, N-i-Bu, N-sec-Bu, N-t-Bu, etc.

Examples R3and R4include a hydrogen atom. Me, Et, n-Pr c-Pr, n-Bu, i-Bu, sec-Bu, t-Bu, n-Pen, c-Pen, benzyl, para-chloroformate, para-performer, para-brompheniramine, phenylethyl, para-chloranilide, paracorporeal, paraproteinemic,

CH2CO2H, CH2CO2Me, CH2CO2Et, (CH2)2CO2Me, (CH2)2CO2Et, (CH2)2CH(OMe)2, (CH2)2CH(OEt)2, (CH2)3OH, (CH2)3OMe, (CH2)3OEt, (CH2)3Cl, (CH2)3Br, (CH2)3F, (CH2)3CO2H, (CH2)3CO2Me, (CH2)3CO2Et, (CH2)3CH(Me)2,

(CH2)3CH(Et)2C(O)OMe, C(O)OEt, C(O)O-n-Pr, C(O)O-i-Pr, C(O)O-c-Pr /SUB>)3Cl, C(O)O(CH2)3Br, C(O)OPh, C(O)OCH2Ph, C(O)NHMe, C(O)NHEt, C(O)NH-n-Pr, C(O)NH-i-Pr, C(O)NH-c-Pr C(O)NH-n-Bu, C(O)NH-i-Bu, C(O)NH-sec-Bu, C(O)NH-t-Bu, C(O)NH-n-Pen, C(O)NH-c-Pen, C(O)NH-n-Hex, C(O)NH-c-Hex, C(O)NH(CH2)2Cl, C(O)NH(CH2)2Br, C(O)NH(CH2)3Cl, C(O)NH(CH2)3Br, C(O)NHPh,

C(O)NHCH2Ph, C(O)NHC(O)CCl3C(S)NHMe, C(S)NHEt, C(S)NH-n-Pr, C(S)NH-i-Pr, C(S)NH-c-Pr, C(S)NH-n-Bu, C(S)NH-i-Bu, C(S)NH-sec-Bu, C(S)NH-t-Bu, C(S)NH-n-Pen, C(S)NH-c-Pen, C(S)NH-n-Hex, C(S)NH-c-Hex, C(S)NH(CH2)2Cl, C(S)NH(CH2)2Br, C(S)NH(CH2)3Cl, C(S)NH(CH2)3Br, C(S)NHPh, C(S)NHCH2Ph, C(N-CN)NHMe, C(N-CN)NHEt, C(N-CN)NH-n-Pr, C(N-CN)NH-i-Pr, C(N-CN)NH-c-Pr, C(N-CN)NH-n-Bu, C(N-CN)NH-i-Bu, C(N-CN)NH-sec-Bu, C(N-CN)NH-t-Bu, C(N-CN)NH-n-Pen, C(N-CN)NH-c-Pen, C(N-CN)NH-n-Hex, C(N-CN)NH-c-Hex, C(N-CN)NH(CH2)2Cl, C(N-CN)NH(CH2)2Br, C(N-CN)NH(CH2)3Cl, C(N-CN)NH(CH2)3Br, C(N-CN)NHPh, C(N-CN)NHCH2Ph, together with the nitrogen atom to which they are attached, form a radical of the formula Q1-Q36.

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Among drugs for the treatment of heart failure present invention the preferred drug for treatment of heart failure, containing as an active ingredient at least one of the compounds of the formula (II), their optical isomers, their stereoisomers or their pharmacologically acceptable kind, X5represents an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom unsubstituted or substituted by an atom of hydrogen or C1-C4-alkyl);

A1represents a hydrogen atom, a hydroxy-group or OC(O)R17, (R17represents a C1-C4-alkyl);

B1represents a hydrogen atom;

R13and R14the same or different from each other, represent a hydrogen atom or a C1-C4-alkyl;

R15and R16the same or different from each other, represent a hydrogen atom, a C1-C6-alkyl { the alkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C6-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro} C3-C6-cycloalkyl { this cycloalkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group}, a phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup) or C(=Y1Z1R18[Y1represents an oxygen atom,

a sulfur atom or NR19(R19represents a hydrogen atom, a cyano, a nitro-group, C1-C4-alkyl or C1-C4-alkoxygroup); Z1represents an oxygen atom, a sulfur atom or NR20(R20represents a hydrogen atom, a C1-C6-alkyl { the alkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro}, C3-Cthe volume of halogen, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro} or phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup); and R18represents a hydrogen atom, a C1-C8-alkyl {the alkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C5-alkoxycarbonyl, hydroxy-group, C1-C4-alkoxygroup, CH(OR)2(R represents a C1-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro}, C3-C6-cycloalkyl { this cycloalkyl unsubstituted or substituted by one or more substituents selected from a halogen atom, carboxypropyl, C2-C-C4-alkyl), phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), formyl, ceanography and nitro group} , or phenyl (the phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup)] or R15and R16together form a 1,4-butylene or 1,5-Panteleeva group {these 1,4-butylene and 1.5-Panteleeva group unsubstituted or substituted by one or more substituents selected from C1-C4of alkyl, phenyl (phenyl unsubstituted or substituted by one or more substituents selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup), halogen atom and OR21(R21represents a hydrogen atom, a C1-C4-alkyl, COR22(R22represents a C1-C4-alkyl), a nitrogroup, SO3H or PO3H2)}, or R15and R16together form a ((CH2)oX7(CH2)p[o and p represent the number 1, 2 or 3, and the sum of them is 3, 4 or 5; X7represents an oxygen atom, a sulfur atom or NR23(R23is what Fort worth, selected from halogen atom, hydroxy-group and C1-C4-alkoxygroup)}] ; or

R15and R16together form the group (CH2)qZ1C(=Y1) (q denotes the number 2, 3 or 4 and Z1and Y1have the values specified above).

Preferable of the above pharmaceutical compositions for the treatment of heart failure, in which R15in the formula (II) represents a hydrogen atom and R16represents the group C(=Y2)OTHER24(in which Y2represents an oxygen atom, a sulfur atom or N-CN; and R24represents phenyl, benzyl or C1-C8-alkyl which may be branched).

Preferable pharmaceutical composition for the treatment of heart failure, in which R15and R16in the formula (II) together form the group (CH2)kNHC(= Y3) (in which K represents the number 2, 3 or 4 and Y3represents an oxygen atom, a sulfur atom or N-CN).

Preferable pharmaceutical composition for the treatment of heart failure, in which R15and R16in the formula (II) simultaneously represents a C1-C6-alkili.

Predpochtitel is rule (II) together form the group (CH2)4or (CH2)5.

Below, in table/ 1, examples of compounds of formula (I) of the present invention. In the table, the sign "-" indicates the absence of X1and/or X2. Qnhas the above meaning. (Qn=(R3-)(R4-)N-).

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The compounds of formula (1) of the present invention have asymmetric carbon atoms at positions 3 and 4 cores of Piran and therefore include optically active compounds with asymmetric carbon atoms. Such optically active compounds can also be used in the present invention, like the racemic modifications. In addition, you can also apply stereoisomers by regulations 3 and 4 cores of Piran. If compounds can form salts, their pharmaceutically acceptable salts can also be used as active components of the compositions of the present invention.

Methods for obtaining compounds of formula (1) of the present invention will be described below.

Compounds of formula (1), in which X represents an oxygen atom and simultaneously R3and R4not form the group C(=Y)ZR6receive, as indicated in the following reaction scheme, the reaction of the compound of formula (3) with the compound of the formula (4) is that A forms a single (additional) communication with B, shown by formula (6).

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Solvents suitable for the reaction of the compounds (3) and compound (4) include, for example sulfoxide solvents such as dimethyl sulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, solvent type ethers, for example diethyl ether, dimethoxyethane and tetrahydrofuran, and alcohol solvents such as methanol, ethanol and isopropanol. Of these solvents, preferred alcohol solvents.

The temperature of the reaction of the compounds (3) and (4) can be from temperature, created by ice cooling to the boiling point of the employed solvent. The reaction preferably is carried out at the boiling point of the employed solvent. If necessary, the reaction can be conducted under pressure.

Starting compound (4)/(3) is used in a molar ratio ranging from 0.5 to 2.0, preferably from 1.0 to 1.1.

Depending on the reaction conditions or processing conditions of the reaction mixture after the reaction, which will be described in detail below, obtain the connection formula (5) or the compound of formula (6). The compound of formula (6) is obtained by reaction of compounds of formula (3) with the compound of the formula (4) in Tetra is about by other conditions (such as reaction time, the reaction temperature and so on).

In some cases, depending on conditions subsequent processing, the obtained compound of the formula (5) can degidratirutego. For example, if the reaction solution contains acid or alkali, and when it is immediately heated or concentrate without removal of the acid or alkali washing, formed the connection in the reaction solution is often dehydratases.

However, the result is influenced by the type of the formed compounds, reaction conditions obtain and conditions subsequent processing.

The compounds of formula (1) of the present invention, in which X is an oxygen atom and R3or R4represents the group C(=Y)ZR6receive the following reaction scheme, in which the compound of the formula (3) is treated with a compound of the formula (7) in an inert solvent to obtain compounds of formula (8) and the compound of formula (8) process connection R6NCY(R6NCO, R6NCS) or ClCO2R6to obtain the compounds of formula (9) or (10)

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In the reaction schemes Z represents N(R9or an oxygen atom or a sulfur atom; W represents a chlorine atom, a bromine atom, an iodine atom, lower alkylsulfonate R3and R4together form the core, obtained by cyclization of the compounds of formula (11).

The initial compounds of the formula (3):

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where R1and R2have the meanings specified for formula (1) can be obtained by the above reaction scheme. The full scheme of obtaining them are described below (see the end of the description).

The compound of formula (13):

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where R1and R2have the meanings specified for formula (1), treated with sodium hypochlorite (NaOCl) to obtain the compound that is represented by the formula (3) and whose X1absent and X2represents an oxygen atom (compound 3 (X1=-, X2=0)), the compound obtained is then treated with a reducing agent which is able to remove oxygen type N-oxide, for example, sodium azide (NaN3or triethylphosphite (P(OEt)3), receiving compound, which is represented by the formula (3) and whose X1and X2no (compound 3 (X= X2= -)). When the connection 3(X1=X2=-) process close to one equivalent of a suitable number of percolate (for example, m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, and these acids will be applied hereinafter), the X2missing (compound 3 (X1=0, X2=-). If the reaction is used more than one equivalent percolate, I get the connection formula (3), in which X1and X2represent oxygen atoms (compound 3 (X1=X2=0)). The compound of formula (13) can be obtained with known methods (for example, described in Med. Chem., 27, 1127 (1987)).

Connection 3(X1=0, X2=-) can also be obtained by treating compound of formula (14):

(14)

where R1and R2have the meanings specified for formula (1), with sodium hypochlorite. The compound of formula (14) can be obtained with known methods (for example, described in the above literature). Solvents suitable for the reaction of compound (8) Y=C=N-R6or ClC(O)OR6include , for example, sulfoxide solvents such as dimethyl sulfoxide, amide solvents such as dimethylformamide or dimethylacetamide, a solvent-type ethers, for example diethyl ether, dimethoxyethane or tetrahydrofuran, and the solvent type halogenated compounds such as methylene chloride or chloroform. Of these solvents, preferred halogenated compounds.

The reaction temperature La, the preferred boiling point of the employed solvent. If necessary, the reaction can be conducted under pressure.

As for the molar ratio of the starting compounds, the compound (8) and compound Y=C=N-R6or ClC(O)OR6used in a molar ratio ranging from 0.5 to 2.0, preferably from 1.0 to 1.1.

The compounds of formula (1) of the present invention, in which X represents a sulfur atom or a nitrogen atom (which is unsubstituted or substituted by an atom of hydrogen or C1-C9-alkyl), can be obtained from the compounds of formula (15) synthesis of three or four stages. The transformation of compounds of formula (15) in the compound of formula (17) is carried out, for example, known methods described in laid patents Japan N Sho 56-57785 and N Sho 56-122380. The compound of formula (17) then the usual way diasterous, such as the processing of the sodium nitrite in aqueous solution in the presence of an inorganic acid, for example hydrochloric acid or sulphuric acid, or organic acids, for example acetic acid, and then cyclist when heated at 5-100oC, preferably at 50 to 100oC, to obtain the compounds of formula (18), where X represents a nitrogen atom.

Soedineniya formula (18). Therefore, the compound of formula (1) can be obtained during the synthesis reaction of compounds of formula (18) or during subsequent processing. If desired, it can be synthesized by dehydration of compounds of formula (18) by treating the anhydride such as benzoic anhydride or acetic anhydride. or base, for example potassium carbonate.

The compound of formula (1), in which X represents alkylamino, can be obtained by reaction of compounds of formula (18) or the product of its dehydration with diazomethane or alkylhalogenide in the presence of potassium carbonate.

The compound of formula (17) by reaction with thienylene in an inert solvent, for example benzene, toluene, xylene or dichlorobenzene, to make a compound of formula (20), in which X represents a sulfur atom.

The temperature of the reaction may be from 5 to 120oC, preferably from 50 to 100oC.

The compound of formula (1), in which A and B together form a single bond, are often given simply by heating the compounds of formula (20). Therefore, the first connection can be obtained in the reaction of synthesis of the compounds of formula (20) or during subsequent processing. If desired, it can also anhydride, or base, for example potassium carbonate.

In these reaction schemes below, Z represents N(R9or oxygen atom or sulfur and W is a chlorine atom, a bromine atom, an iodine atom, lower alkylsulfonate, bansilalpet or toluensulfonate group.

Of the compounds of formula (15) a compound of the formula (24), in which R3and R4are not the group C(=Y)ZR6(R3and R4in this case, do not include both C(= Y)ZR6can be obtained by reaction of compounds of formula (23) with the compound of the formula (4) in an inert solvent.

The solvents used for the reaction of compounds of formula (23) and the compounds of formula (4) include, for example, sulfoxide solvents such as dimethyl sulfoxide, amide solvents such as dimethylformamide or dimethylacetamide, a solvent-type ethers, for example diethyl ether, dimethoxyethane or tetrahydrofuran, and alcohol solvents such as methanol, ethanol or isopropanol. Of these solvents, preferred alcohol solvents.

The reaction temperature may be the temperature that is created when ice cooling to the boiling point of the used restore. If necessary, the reaction can be conducted under pressure.

As for the molar ratio of the starting compounds, the compound (4) and the compound (23) is used in a molar ratio ranging from 0.5 to 2.0, preferably from 1.0 to 1.1.

Of the compounds of formula (15) compounds of formula (26) and (27), in which R3or R4represents the group C(=Y)ZR6can be obtained by the above reaction scheme, in which the compound of formula (23) is reacted with the compound of the formula (7) in an inert solvent with the formation of the compounds of formula (25), the reaction of which with R6NCY (R6NCO, R6NCS) or ClCO2R6get the compound of formula (26) or (27).

The compound of the formula (29), in which R3and R4together form the core, can be obtained by cyclization of the compounds of formula (28) by the following reaction scheme.

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The solvents used for the reaction of compounds of formula (25) Y= C= N-R6or ClC(Y)OR6include , for example, sulfoxide solvents such as dimethyl sulfoxide, amide solvents such as dimethylformamide or dimethylacetamide, a solvent-type ethers, for example diethyl ether, dimethoxyethane or tetr the quiet solvents, preferred solvents of the type halogenated compounds.

The reaction temperature may be the temperature that is created when ice cooling to the boiling point of the employed solvent for the reaction. The preferred reaction temperature is the boiling point of the employed solvent. If necessary, the reaction can be conducted under pressure.

As for the molar ratio of the starting compounds, the compound (25) and Y=C=N=R6or ClC(Y)OR6used in a molar ratio ranging from 0.5 to 2.0, preferably from 1.0 to 1.1.

The compounds of formula (1) of the present invention, in which A represents an acyl, can be obtained by reaction of compounds of formula (30) with acelerou reagent in an inert solvent in the presence of a suitable base in the following reaction scheme.

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The solvents used for this reaction include, for example sulfoxide solvents such as dimethyl sulfoxide, amide solvents such as dimethylformamide or dimethylacetamide, a solvent-type ethers, for example diethyl ether, dimethoxyethane or tetrahydrofuran, and halogenated solvents such compounds, for example dichloromethane, chloroform or dichloroethane. The reaction can be carried out in otsustetegemine and DBU (databaseconnect). Alleluya reagents include halides such as acid chlorides, bromohydrin, and anhydrides. The reaction temperature may be the temperature that is created by ice cooling to the boiling point of the employed solvent.

As for the molar ratio of the starting compounds, the compound (30) and allerease reagent is used in a molar ratio ranging from 0.5 to 2.0, preferably from 1.0 to 1.1.

The compounds of formula (1) of the present invention, in which R4is a group of NC(N-CN)other9can be obtained by the following reaction scheme, in which the compound of formula (32) is treated with a carbodiimide in an inert solvent, and then removing the hydrogen sulfide and then treated with cyanamide, receiving the compound of formula (33).The compound of formula (34), in which R3and R4together form the residue of a cyclic thiocarbamide, can also be converted into the compound of the formula (35) in the same way.

< / BR>
< / BR>
Optically active isomers of compounds of formula (1) of the present invention can be obtained for example by the methods of separation (splitting) of racemic modifications to the optical antipodes (see laid out a patent application in Japan is ku on the Japan patent N 5-301878, European patent N 535377).

As indicated above, the applicants of the present invention have found that the compounds of formula (1) have a strong activity to strengthen contractions of the heart muscle and also possess strong activity to reduce the rate of heart contraction. Since the compounds of the present invention does not have activity by inhibition of cardiac function, but rather have activity on strengthening the contraction of the heart muscle, they can be active to reduce the rate of heart contractions, even when put in the same amount, which is required for the expression of biological activity based on the activity of the compound of the present invention believe that they can reduce the amount of oxygen consumption of cardiac muscle, resulting in reduced load on the contractile function of the heart muscle and helps antistenocardin activity. In addition, it was also established that these compounds do not have activity on the prolongation of the effective refractory period, which contributes to the antiarrhythmic activity. Therefore, it is expected that the compounds of the present invention suitable for the treatment of cardiovascular zabolevanii ability as well as for treatment of other cardiac disorders, due to the activity of the compounds according to the decrease in the rate of heart contraction. Compounds of the present invention for example suitable as pharmaceuticals for the treatment of heart failure in mammals, including humans, as well as medicines for the treatment of cardiovascular disorders, caused by heart failure, such as medicines for the treatment of ischemic cardiopathy, medicines for the treatment of hypertension, drugs for the treatment of delayed cardiac liquids, medicines for the treatment of pulmonary hypertension, drugs for the treatment of valvulitis, medicines for the treatment of congestive cardiac disorders, drugs for treatment of cardio-muscular disorders, drugs for the treatment of pulmonary edema, medicines for the treatment of angina voltage, medicines for the treatment of myocardial infarction, drugs for arrhythmia treatment and medicines for the treatment of atrial fibrillation.

The present invention provides pharmaceutical compositions containing an effective quantity is doing compounds of the present invention it is possible to specify parenteral administration by injection (subcutaneous, intravenous, intramuscular or intraperitoneal injections, ointments, suppositories or aerosol, or oral administration in the form of tablets, capsules, granules, pills, syrups, liquids, emulsions or suspensions.

The above pharmaceutical or veterinary compositions of the present invention contain the above compounds of the present invention in an amount of from about 0.01 to 99.5 wt.%, preferably from about 0.1 to 30 wt.%, counting on the total weight of the composition.

In the compounds of the present invention or compositions containing these compounds, you can enter other pharmaceutically or veterinary active compounds. In addition, the compositions of the present invention can contain one or more compounds of the present invention.

Clinical dose of the compounds of the present invention varies depending on age, body weight, sensitivity or symptoms, etc. of the patient. In General, however, the effective daily dose is usually from about 0.003 to 1.5 g, preferably from about 0.01 to 0.6 g for an adult patient. However, if you want, you can apply a number of emerging from this limit.

Compounds of the present invention can be applied in the accordance with conventional techniques, usually applied to produce the finished pharmaceutical preparative forms.

Tablets, capsules, granules or pills for oral administration can be obtained with the use of fillers, such as white sugar, lactose, glucose, starch or mannitol; a binder such as hydroxypropylcellulose, syrups, Arabian gum, gelatin, sorbitol, tragacanth gum, methylcellulose or polyvinylpyrrolidone; disintegrators such as starch, carboxymethyl cellulose or its calcium salt, crystalline powder cellulose or polyethylene glycol; lubricants, for example talc, stearine magnesium or calcium, silicon dioxide; and means giving the homogeneity of the composition, for example laureate sodium, glycerin, etc.

Injectable compositions, solutions (liquid), emulsions, suspensions, syrups or aerosols can be obtained with the use of a solvent for the active component, for example water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butyleneglycol or polyethylene glycol; surfactants, such as fatty acid esters and anhydromannitol, of esters of fatty acids and anhydromannitol, polyoxyethylene of afirewall, such as derivatives of cellulose, such as sodium salt of carboxymethyl cellulose, or natural resins, such as tragacanth gum or Arabian gum; or preservatives, such as para-hydroxybenzoic acid, benzalkonium chloride, salts of sorbic acid, etc.

Ointments, which are percutaneous preparations can be obtained by using such as white vaseline, liquid paraffin, higher alcohols, ointment Macrogol, hydrophilic bases as ointments or hydrogel, etc.

Suppositories can be obtained using, for example, cocoa butter, polyethylene glycol, lanolin, triglycerides of fatty acids, coconut oil, Polysorbate, etc.

The best way of carrying out the invention.

Hereinafter the present invention will be explained by means of examples, but it is not limited to these examples.

Synthetic examples.

Synthetic examples of the preparation of compounds which are suitable as pharmaceuticals the present invention, is shown below.

Synthesis of optically active 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano [2,3-f]benzo - 2,1,3-oxadiazole:

300 ml of a solution of 40 g (198 mmole) 6,6-dimethyl-6H-pyrano [2,3-f] benzo-2,1,3-octadecan] manganese (III). (Getting this acetate is described in laid the patent application of Japan N Hei 5-507645 and European patent N 099 521). To the mixture was added 1.2 l of an aqueous solution of sodium hypochlorite (active chlorine: 5%). To establish the pH of the reaction mixture of 11.3 it was added 0.5 N aqueous sodium hydroxide solution. The resulting solution was stirred at room temperature for 10 hours. After stopping stirring, the solution was kept at room temperature during the night. The reaction solution was extracted with chloroform (300 ml x 1; 200 ml x 1; 50 ml x 1) and was dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was chromatographically on a column of silica gel (elution with a mixture of benzene and ethyl acetate 5: 1) and again on a column of silica gel (elution with benzene and a mixture of benzene and ethyl acetate 5:1) and the obtained crystals were recrystallize from ethanol (60 ml) to give 15.7 g of target compound (yield: 36%, optical purity more than 99%-conformer).

Column: Chirallcell OJ (Daisel Chemical Industries, Ltd.).

Mobile phase: hexane and isopropanol in the ratio of 4:1.

Detection: UV spectrum of the strip 254 nm.

Flow rate: 1 ml/min

The column temperature: 40Oia reference example 1

The enantiomer of the compound of reference example 1 was synthesized in the same manner as in reference example 1, using acetate (S, S)- [1,2-bis(3,5-di-tert-butylaniline)cyclohexane] -manganese (III). The product yield was of 20.8 g (48%).

Optical purity: more than 99%-conformer retention time: 12,5 minutes

Example of synthesis 1

Synthesis of 3-oxide-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-diethylamino-6H-pyrano[2,3-f] benzo-2,1,3-oxadiazole

< / BR>
465 mg (1.50 mmole) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4 - diethylamino-6-amino-7-nitro-2H-benzo[b] Piran, 102 mg (2,56 mmole) sodium hydroxide, 32 ml of ethanol, 6 ml of water and 0.1 ml of ethylene glycol was stirred at 40oC and the resulting solution was added 2,59 g (2,10 mmole) of 6% aqueous NaOCl solution, and was stirred for 15 minutes, the Reaction liquid was poured into water and was extracted three times with ethyl acetate. Layers of ethyl acetate were combined and then washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent is kept off and the residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and hexane, 1:1 (volume/volume)) to give 189 mg of target compound (yield 41%). Part of the thus obtained compound was dissolved in ethanol and to the solution add low. Sol had the following properties:

so pl.: 160-164oC (decomposition)

The NMR spectrum (CDCl) (mln h) to 1.15 (6H), 1.26 in(3H), of 1.52(3H), 2,64-3,14(5H), of 3.56(1H), 3,85 (1H), to 6.57(1H), 7,30(1H).

Example of synthesis 2

Synthesis of 3-oxide-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-piperidinyl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
924 mg (2.88 mmole) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (1-piperidinyl)-6-amino-7-nitro-2H-benzo[b] Piran, 0.7 ml of a 50% aqueous sodium hydroxide solution, 4 ml of dichloroethane and 10 mg Bu4N+Br-was stirred at room temperature and then the mixture was added equal to 4.97 g (a 4.03 mmole) water 6% aqueous NaOCl solution and the reaction was carried out for 9 hours at room temperature and under stirring. The organic layer was separated and the aqueous layer was extracted two times with methylene chloride. Layers of methylene chloride were combined, washed with water and dried over anhydrous sodium sulfate. After removal of the solvent the residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and hexane, 1:3, vol/vol) to give 297 mg of the target compound as oil (yield: 43%). Part of the thus obtained compound was dissolved in ethanol and the solution was added HCl-EtOH and dry simple ether to obtain the hydrochloride of the target compounds in the methyl-7-hydroxy-8-(1-piperidinyl)- 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
297 mg of 3-oxide (0,93 mmole) 7,8-dihydro-6,6-dimethyl-7-hydroxy - 8-(1-piperidinyl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole obtained in synthetic example of 2.6 ml of ethylene glycol and 60 mg (0,93 mmole) NaN3was heated at 140oC for 1.2 hours. After cooling, the reaction liquid was poured into water and was extracted three times with chloroform. Layers of chloroform were combined and dried over anhydrous sodium sulfate. After removal of the solvent by distillation, the residue was chromatographically in column (eluent: a mixture of ethyl acetate and hexane, 1:3, vol/vol) to give 84 mg of target compound (yield 30%). Part of the thus obtained compound was dissolved in a mixture of ethanol and diethyl ether and the solution was added HCl-EtOH to obtain hydrochloride of the target compound as pale yellow crystals.

So pl. 202-205 areoC.

Example of synthesis 4

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-pyrrolidinyl)- 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
150 mg (0,687 mmole) 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H - pyrano[2,3-f] benzo-2,1,3-oxadiazole, 63 μl (0,756 mmole) of pyrrolidine and 2 ml of ethanol was boiled under reflux with stirring for 31 hours. The solvent was removed by distillation and the residue was purified dispenser is soedineniya (yield 60%). Part of the thus obtained compound was dissolved in dry simple ether and the solution was added HCl-EtOH to obtain the hydrochloride of this compound as pale yellow crystals.

So pl. 208-209oC.

Example of synthesis 5.

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-methyl amino-6-pyrano[2,3-f] benzo-2,1,3-oxadiazole

< / BR>
300 mg (of 1.37 mmole) of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, of 0.53 g of aqueous 40% solution of methylamine and 15 ml of ethanol was stirred at 60oC 3 days, using the tube for a high pressure. After the reaction, the solvent is kept off and the residue was cleaned junction thin-layer chromatography (eluent: a mixture of ethyl acetate and methanol, 10: 1) to give 263 mg of target compound (yield 77%). Part of the thus obtained compound was dissolved in simple dry ether and added to a solution of HCl-EtOH to obtain hydrochloride of the target compound as colorless crystals.

So pl.: 244,5-260oC

Example of synthesis 6

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(4-fluoro benzyl)amino-6H-pyrano[2,3-f] benzo-2,1,3-oxadiazole

< / BR>
150 mg (0,687 mmole) 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 86 μl (0,756 malayali was removed by distillation and the residue was purified junction thin-layer chromatography (eluent: a mixture of ethyl acetate and hexane, 1:2) to give 204 mg of the target compound as oil (yield: 86%). Part of the thus obtained compound was dissolved in simple dry ether and added HCl-EtOH to obtain hydrochloride of the target compound as colorless crystals.

So pl. 207-210oC.

Example of synthesis of 7

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-benzylamino - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, using benzylamine received the target connection.

NMR spectrum (60 MHz, CDCl3, / million days ): to 7.77(1H), 7,37-6.92(5H), for 6.81(1H), from 3.9 to 3.8(4H), 2,73(2H) and 1.51(3H), 1,25(3H).

Example of synthesis 8

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(N-benzyl-N-methyl)amino-6H-pyrano[2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, using N-methylbenzylamine received the target connection. Hydrochloride target compound had a melting point of 148-150oC.

Example 9 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-cyclohexylamino - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, using cyclohexylamine received the target connection. Hydrochlor is hydro-6,6-dimethyl-7-hydroxy-8-(4-methyl-1-piperazinil)-6H-pyrano [2,3-f] benzo-2,1, 3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, using N-methylpiperazine received target compound as yellow crystals (yield 75%).

So pl.: 225-226oC

Mass spectrum: 70(100%), 246(56%), 318 (M+, 13%).

Example 11 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-piperazinil) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, using piperazine was obtained target compound as yellow crystals (yield 72%).

So pl. 245-246oC

Mass spectrum: 56(67%), 232(100%), 304(M+, 8%).

Example 12 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(4-phenyl-1 - piperazinil)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, using N-phenylpiperazine received target compound (yield 75%).

Mass spectrum: 132(100%), 308(36%), 380(M+, 32%)

Hydrochloride of target compound was obtained as colorless crystals

So pl. 198-201oC

Example of synthesis 13

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(4-phenyl-1 - piperidinyl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same way as described in SYN: 186(21%), 307(100%), 379(M+, 4%).

Hydrochloride of target compound was obtained as colorless crystals

So pl.: 195-197oC

Example 14 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1,2,3,4 - tetrahydroisoquinoline-2-yl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in example 6, using 1,2,3,4-tetrahydroisoquinoline received target compound (yield 80%).

Mass spectrum: 262(32%), 279(100%), 351(M+, 4%).

Hydrochloride of target compound was obtained as colorless crystals

So pl. 188,5-190oC

Example 15 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(4-morpholinyl)- 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in example 6, using the research has been the target compound (yield 11%).

So pl.: 185-186,5oC.

Example 16 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(3-methoxypropylamine) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, using 3-methoxypropylamine received target compound (yield 60%).

Mass spectrum: 177(100%), 235(100%), 289(M+-18,1%).

So pl. 175,5-178oC

Example 17 synthesis of
< / BR>
In the same manner as described in synthetic example 6, using ethyl-4-aminobutyrate received target compound (yield 38%).

Hydrochloride of target compound was obtained as colorless crystals.

So pl.: 189-191oC

Example 18 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - ethoxycarbonylmethylene-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, with the use of ethyl ester of glycine was obtained target compound (yield 5%).

Hydrochloride of target compound was obtained as an orange oil.

Example 19 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(3-chloropropylamine)- 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, using 3-chloropropylamine received target compound (yield 20%).

Hydrochloride of target compound was obtained as colorless crystals.

So pl.: 216-220oC

Synthetic example 20

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-hydroxyethylamino)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
In the same manner as described in synthetic example 6, applied in the form of colorless crystals.

So pl. 200-204oC.

Example 21 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
0,82 g (3.8 mmole) of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole was dissolved in 25 ml of 16.7% H3-EtOH and the reaction was conducted at 60oC for 48 h in a glass tube for high pressure. The solvent was removed by distillation and the residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and methanol, 5:1), receiving of 0.77 g of the target compound as a brown solid (yield 87%). Part recrystallize the product from ethanol, getting clear, colourless crystals of the target compound.

So pl.: 223-225oC.

The NMR spectrum (CDCl3+ DMSO-d6) / (million days): 1,26(3H), 1,49(3H), 2,80-3,30(5H), to 3.33(1H), 3,78(1H), PC 6.82(1H), 7,98(1H).

Mass spectrum: 133(50%), 163(100%), 235(M+, 3%).

Example 22 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-methylurea - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
200 mg (0,850 mmole)7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 20 ml dichloromethane was stirred at room temperature and the solution was added 55 μl (0,935 mmole) of methyl isocyanate and a mixture of peremeshivaete (yield 92%).

So pl. 213-215oC

Mass spectrum: 44,202(30%), 274(M+-H2O, 6%).

Example 23 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-methylthiourea - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
200 mg (0,850 mmole) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 20 ml dichloromethane was stirred at room temperature and the solution was added 68 mg (0,935 mmole) methylisothiocyanate and the mixture was stirred for 23 hours. Precipitated crystals were separated by filtration, getting 122 mg of the target compound as colorless crystals (yield 47%).

So pl. 213-215oC.

Mass spectrum: 91(62%), 202(67%), 290,308(M+, 27%).

Example 24 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-phenylurea - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
200 mg (0,850 mmole)7,8-dihydro-6,6-dimethyl-7 - hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 20 ml dichloromethane was stirred at room temperature and the solution was added 102 μl (0,935 mmole) of phenylisocyanate and the mixture was stirred for 4 hours. Precipitated crystals were separated by filtration, getting 203 mg of the target compound as colorless crystals (yield 67%).

So pl. 215-217oC

Mass spectrum: 93,163(56%), 321(20%), 354(M+, 13-f] benzo-2,1,3-oxadiazole

< / BR>
200 mg (0,850 mmole) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino - 6H-pyrano [2,3-f] benzo-2,1, 3-oxadiazole and 20 ml dichloromethane was stirred at room temperature and the solution was added 100 μl (0,935 mmole) trichloroacetimidate and the mixture was stirred 5 hours. Precipitated crystals were separated by filtration, receiving 90 mg of the target compound as colorless crystals (yield 25%).

So pl. 248-250oC

Mass spectrum: 44,163(43%), 422(M+, 2%).

Example 26 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (3-chloropropylene)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
400 mg (1,70 mmole) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 40 ml of dichloromethane was stirred at room temperature and the solution was added 192 μl (to 1.87 mmole) 3-chloropropionate and the mixture was stirred 5 hours. Precipitated crystals were separated by filtration, receiving 250 mg of the target compound as pale yellow crystals (yield 41%).

So pl. 83-85oC

Mass spectrum: 41(53%), 163,318(93%), 354(M+, 5%).

Example 27 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-chloroethylamino)- 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
400 mg (1,70 mmole) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-AOP) was added 200 μl (to 1.87 mmole)2-chlorotriazine and the mixture was stirred 6 hours. Precipitated crystals were separated by filtration, getting 480 mg of the target compound as colorless crystals (yield 83%).

So pl. 178-180oC.

Mass spectrum: 87(57%), 163,304(78%), 340(M+, 8%)

Example 28 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-isopropylamino-6H - pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
200 mg (0,850 mmole)7,8-dihydro-6,6-dimethyl-7-hydroxy - 8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 20 ml dichloromethane was stirred at room temperature and the solution was added 92 μl (0,935 mmole) isopropylmalate and the mixture was stirred 6 hours. Precipitated crystals were separated by filtration, receiving 120 mg of the target compound as colorless crystals (yield 44%).

So pl. 201-203oC

Mass spectrum: 43(40%), 202,302(20%), 320(M+, 12%).

Example 29 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-ethoxycarbonyl - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
200 mg (0,850 mmole)7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 166 μl (1,19 mmole) of triethylamine and 20 mg of dichloromethane was stirred at room temperature, the mixture was added 114 μl (1,19 mmole) ethylchloride and stirred for 21 hours. The reaction liquid was washed three times will on a column of silica gel (eluent: a mixture of ethyl acetate and methanol, 20:1, volume/volume) to give 227 mg of the target compound as a yellow oil (yield 87%).

Mass spectrum 133(48%), 235,307 (M+, 25%).

Example 30 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-chlorocarbonate)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
400 mg (1,70 mmole) 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 260 μl (to 1.87 mmole) of triethylamine and 40 mg of dichloromethane was stirred at room temperature, the mixture was added 193 μl (to 1.87 mmole)of 2 - chloroethylphosphonic and stirred for 21 hours. The reaction liquid was washed three times with water and then dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallize from chloroform, getting 507 mg of the target compound as pale yellow crystals (yield 87%).

So pl. 164-166oC

Mass spectrum: 133(48%), 235,307 (M+, 25%).

Example 31 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-oxo-3-oxazoline-1-yl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
400 mg (1,17 mmole) of the compound obtained in synthetic example 30, 3,24 g (23.4 mmole) of potassium carbonate, 388 mg (2,34 mmole) of potassium iodide and 50 ml of absolute acetone was heated under reflux at countrieslithuania, was added to the obtained filtrate ethyl acetate and washed three times with water. Thus obtained compound was dried over anhydrous magnesium sulfate. The solvent was removed by distillation and the residue was purified column chromatography on silica gel (eluent: a mixture of ethyl acetate and methanol, 10:1, volume/volume) to give 339 mg of the target compound as a brown oil (yield 94%). Part recrystallize the product from ethyl acetate, receiving yellow crystals having the following physical properties:

So pl.: 177,5-180oC

Mass spectrum: 43(25%), 272,287(65%), 305(M+, 8%).

Example 32 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-3 - imidazolin-1-yl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
The compound obtained in synthetic example 27, was treated in the same manner as in synthetic example 31, to obtain the target compound as colorless crystals (yield 34%).

So pl. 251-252,5oC.

Example 33 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-cyclohexylurea - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
The target compound in the form of colorless crystals was obtained in the same manner as in synthetic example 22, using cyclohexylsulfamate (yield 28%).
< / BR>
The target compound in the form of colorless crystals was obtained in the same manner as in synthetic example 22, using tert-utilizationa (yield 52%).

So pl. 203-205oC.

Example 35 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8 - methoxycarbonylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
The target compound in the form of a yellow oil was obtained in the same manner as in synthetic example 29, using methylchloroform (yield 19%).

Example 36 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(tert - butylthiourea)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
The target compound was obtained in the same manner as in synthetic example 23, using tert-utilizationand (yield 57%).

Example 37 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-oxohexanoate-1-yl)-6H-pyrano [2,3-f] benzo-2,1,3 - oxadiazole

< / BR>
The compound obtained in synthetic example 26, was treated in the same manner as in synthetic example 31 receiving the target compound as colorless crystals (yield 39%).

So pl. 233-234oC.

Example 38 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (3-chloropropiophenone-6H-PI is, as in synthetic example 30, using 3-chloropropylamine (yield 100%).

Example 39 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-oxotetrahydrothiophene-3-yl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
The compound obtained in synthetic example 38, was treated in the same manner as in synthetic example 31 receiving the target compound as colorless crystals (yield 34%).

So pl. 220-234oC.

Example 40 synthesis

Synthesis of 3-oxide-7,8-dihydro-6,6-dimethyl-7-acetoxy-8 - diethylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
1 ml of pyridine and 130 mg (1,27 mmole) of acetic anhydride was added 103 mg (0,34 mmole) of the compound obtained in synthetic example 1, and the mixture was stirred at 80-90oC for 2 hours. After cooling, the solvent was removed by distillation under reduced pressure and the residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and n-hexane, 1:3, vol/vol, Rf= 0,3), getting to 90.4 mg of target compound as yellow solid (yield 77%).

Example 41 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-diethyl-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
310 mg (1,01 mmole) of the compound, poluchenii was heated at 60oC for 1 hour. After cooling to room temperature thus obtained compound was stirred over night. The solvent was removed by distillation under reduced pressure and the residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and n-hexane, 1: 3, vol/vol, Rf=0,3) to give 267 mg of the target compound as yellow solid (yield 91%).

Example 42 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-acetoxy-8-diethylamino-6H - pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
2 ml of pyridine and 0.29 grams (2.8 mmole) of acetic anhydride was added 220 mg (0.75 mmole) of the compound obtained in synthetic example 41, and the mixture was heated at 80-90oC for 2 hours. After cooling, the solvent was removed by distillation under reduced pressure and the residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and n-hexane, 1:3, vol/vol, Rf= 0,3), receiving 209,1 mg of target compound as a pale yellow solid (yield 83%).

Example 43 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-acetoxy-8-(1-piperidinyl)-6H - pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
The compound obtained in synthetic example 3 was treated in the same manner as in si is o
C.

Synthetic example 44

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (4-diethoxybutane)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
The target compound in the form of a brown oil was obtained in the same manner as in synthetic example 6, using diethylacetal-4-amino aldehyde (yield 93%).

Example 45 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-hydroxypyrrolidine-1-yl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
1 ml of 2.5 N hydrochloric acid and 2 ml of 1,4-dioxane was added to 316 mg (0,832 mmole) of the compound obtained in synthetic example 44, and the reaction was carried out at room temperature for 3 hours. In the reaction mixture was added an aqueous solution of sodium carbonate to hydrate the product and formed hydrate then was extracted with diethyl ether. The solution in ether was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and n-hexane, 1:1, volume/volume, Rf=0.5) to give the target compound as a yellow oil (yield 40%).

Example 46 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (3-carboxypropyl)-6H-pyrano [2,3-f] is g (0,209 mmole) of the hydrochloride, obtained in synthetic example 17, and the reaction was conducted for 3 hours at room temperature. The reaction mixture was acidified by adding 1N hydrochloric acid and then was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, obtaining the target compound as a colourless oil.

Example 47 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-acetoxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
240 ml (1,10 mmole)-7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H - pyrano [2,3-f] benzo-2,1,3-oxadiazole was dissolved in 5 ml of dichloromethane and the solution was added 0.5 ml of the complex BF3-diethyl ether. The reaction was carried out for 30 min at room temperature. Then the reaction mixture was added saturated aqueous sodium bicarbonate solution and the reaction liquid was extracted with chloroform. After drying the extract over anhydrous sodium sulfate, the solvent is kept at reduced pressure. The residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and n-hexane, 1:1, volume/volume, Rf= 0,3) to give 152 mg of the target compound as a yellow oil (yield 50%).

Mass spectrum: 188 (100%), 277 (M+, 4%).

PR is

< / BR>
87,7 g (of 0.36 mmole) of 7,8-dihydro-6,6-diethyl-7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 61 mg (0.72 mmole) of piperidine and 2 ml of ethanol was boiled under reflux for 20 hours under stirring. After removal of the solvent the residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and n-hexane, 1:1, volume/volume, Rf=0,3), receiving 30 mg of target compound as a yellow oil (yield 25%).

Example 49 synthesis

Synthesis of 7,8-dihydro-6,6-diethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
The target compound in the form of colorless crystals was obtained in the same manner as in synthetic example 21, using 7,8-dihydro-6,6-diethyl-7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole (yield 44%).

So pl. 122-124oC.

Example of synthesis 50

Synthesis of 7,8-dihydro-6,6-diethyl-7-hydroxy-8-methyl-ureido-6H - pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
The compound obtained in synthetic example 49, was treated in the same manner as in synthetic example 22, obtaining the target compound as a brown oil (yield 89%).

Example 51 synthesis

Synthesis of 7,8-dihydro-6,6-diethyl-7-acetoxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole

< / BR>
Target taedigera-6,6-diethyl-7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole (yield 62%).

So pl. 92-95oC.

Example 52 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (2-cyano-3-tert-butyl-1-guanidino)-6H-pyrano [2,3-f] benzo-2,1,3 - oxadiazole

< / BR>
A solution containing 100 mg (0,29 mmole) of the compound obtained in synthetic example 36, 97 mg (0.37 mmole) of triphenylphosphine, 40 μl of carbon tetrachloride, 40 μl (to 0.29 mmole) of triethylamine and 1 ml of dichloromethane was heated under reflux for 4 hours. After removal of the solvent by distillation under reduced pressure, the residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and n-hexane, 1:2, vol/vol, Rf=0,1) to give 77 mg of pale yellow crystals.

The solution containing 122 mg (0,39 mmole) obtained in this way connections, 21 mg (0,50 mmole) of cyanamide, 2 ml of tetrahydrofuran and 20 mg diisopropylethylamine, was stirred 14 h at room temperature. Precipitated crystals were separated by filtration, receiving 112 mg of the target compound as yellow crystals (yield 80%).

So pl. 146-148oC.

Example 53 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-piperidinyl) -6H-pyrano [2,3-f] benzo-1,2,3-triazole

< / BR>
0.14 g (of 0.44 mmole)of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (1-piperidinyl)-amino-is and used as a catalyst 0.10 g of 5% palladium on coal. Aeration was carried out for 3 hours at room temperature and atmospheric pressure under stirring. The reaction liquid was filtered with suction to remove catalyst and the filtrate is then drove the solvent, obtaining 0.12 g (yield 95%) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-piperidinyl)-6,7 - diamino-2H-benzo[b] Piran in the form of a dark red oil. Because this connection is unstable, it was used immediately for the subsequent diazotization.

All diaminododecane obtained in the previous stage was dissolved in a mixture of 0.13 g of acetic acid and 0.23 g of water and the solution at room temperature was added a solution obtained by dissolving 35 mg (0,51 mmole) of sodium nitrite in 0.15 g of water. Upon detection of heat, the reaction mixture was heated on a water bath at 80owithin 1 min In the reaction mixture were added 20 ml of water, with 0.13 g of sodium hydroxide and 4.0 g of sodium chloride and then extracted three times with 40 ml of ethyl acetate in each case. Layers of ethyl acetate were combined, dried over anhydrous sodium sulfate and filtered. After removal of the solvent by distillation was obtained 0.10 g of a yellowish-red powder 90 mg of the powder was purified by chromatography on a column of silica gel (eluent: mixture is the overall yield after two steps was 72%.

Mass spectrum: 284(M+-H2O, 18%), 230(M+-72, 100%), 84(5%).

Example 54 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-pyrrolidinyl) -6-pyrano [2,3-f] benzo-1,2,3-triazole

< / BR>
0.20 g (0.65 mmole)of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (1-pyrrolidinyl)-6-amino-7-nitro-2H-benzo[b] Piran was dissolved in 34,9 g of ethanol and after the solution was purged with gaseous hydrogen in the presence used as a catalyst, 0.15 g of 5% palladium on coal. Aeration was carried out for 3 hours at room temperature and atmospheric pressure under stirring. The reaction liquid was filtered with suction to remove catalyst and the filtrate is then drove solvent, receiving 170 mg (yield 94%) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-pyrrolidinyl)-6,7 - diamino-2H-benzo[b]Piran in the form of a dark red oil.

All diaminododecane obtained in the previous stage was dissolved in a mixture 0,19 g of acetic acid and 0.34 g of water and the solution at room temperature was added a solution obtained by dissolving 52 mg (0.75 mmole) of sodium nitrite of 0.22 g of water. Upon detection of heat, the reaction mixture was heated on a water bath at 80owithin 3 minutes the Connection is then processed in the same obby exit after two stages was 85%.

Mass spectrum: 288 (M+, 3%), 270(M+-H2O, 3%), 216(M+-72,88%), 188(M+-100, 100%), 70(22%).

Example 55 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-diethylamino-6-pyrano [2,3-f] benzo-1,2,3-triazole

< / BR>
0.20 g (0.65 mmole)of 3,4-dihydro-2,2-dimethyl-Z-hydroxy - 4-diethylamino-6-amino-7-nitro-2H-benzo[b]Piran was dissolved in 34,9 g of ethanol and after the solution was purged with gaseous hydrogen in the presence used as a catalyst, 0.15 g of 5% palladium on coal. Aeration was carried out for 2.5 hours at room temperature and atmospheric pressure under stirring. The reaction liquid was filtered with suction to remove catalyst and the filtrate is then drove the solvent, obtaining 0.15 g (yield 83%)of 3,4 - dihydro-2,2-dimethyl-3-hydroxy-4-diethylamino-6,7-diamino-2H - benzo[b]Piran in the form of a dark brown oil.

All diaminododecane obtained in the previous stage was dissolved in a mixture 0,19 g of acetic acid and 0.34 g of water and the solution at room temperature was added a solution obtained by dissolving 52 mg (0.75 mmole) of sodium nitrite of 0.22 g of water. Upon detection of heat, the reaction mixture was heated on a water bath at 80owithin 3 minutes the Connection ZAT is brown powder. The total yield after two steps was 37%.

Mass spectrum (FAB): 291(M+H)+]

Example 56 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-piperidinyl)-6 - pyrano [2,3-f] benzo-2,1,3-thiadiazole

< / BR>
0.28 g (of 0.87 mmole)of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4- (1-piperidinyl)-6-amino-7-nitro-2H-benzo[b] Piran was dissolved in 44,8 g of ethanol and after the solution was purged with gaseous hydrogen in the presence used as a catalyst 0.20 g of 5% palladium on coal. Aeration was carried out for 3 hours at room temperature and atmospheric pressure under stirring. The reaction liquid was filtered with suction to remove catalyst and the filtrate is then drove solvent, getting 0.24 g (yield 95%) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-piperidinyl)-6,7 - diamino-2H-benzo[b]Piran in the form of a dark red oil. In the obtained oil was added 0.12 g (0,86 mmole) thienylene and 4 g of benzene and the mixture was heated under reflux for 2.5 hours. After removal of the solvent under reduced pressure the residue was chromatographically on a column of silica gel (eluent: a mixture of ethyl acetate and ethanol, 1:3) to give 60 mg (yield 23%) of target compound as a yellow solid.

Mass spectrum: 84(85%), 247(100%), 319 (Mthe sooner [2,3-f] benzo-2,1,3-thiadiazole

< / BR>
3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-pyrrolidinyl)-6-amino - 7-nitro-2H-benzo[b] Piran was treated in the same manner as in synthetic example 56, obtaining the target compound in the form of brown crystals (yield 25%).

Example 58 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-diethylamino-6H-pyrano [2,3-f] benzo-2,1,3-thiadiazole

< / BR>
3,4-dihydro-2,2-dimethyl-3-hydroxy-4-diethylamino-6-amino-7 - nitro-2H-benzo[b]Piran was treated in the same manner as in synthetic example 56, obtaining the target compound as a brown oil (yield 17%).

Example 59 synthesis

Synthesis of (-)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1-pyrrolidinyl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole (optically active (-)-isomer of the compound of synthetic example 4)

< / BR>
of 14.7 g (206,2 mmole) of pyrrolidine was added 60 ml of a solution of 15.0 g (68.7 mmole) of the compound of reference example 1 in ethanol and the mixture was heated under reflux for 2 hours. After removal of the solvent by distillation under reduced pressure, the residue was added 100 ml of water and the mixture was extracted with chloroform (100 ml x 1.30 ml x 2). After drying the solution in chloroform over anhydrous sodium sulfate, the solvent is kept at reduced pressure. The rest of chromatogra who was tallital from a mixture of benzene and hexane (1:2), obtaining 13.8 g of target compound as yellow crystals (yield 69%).

240 ml of a mixture of hydrochloric acid : methanol (10%) was added to 240 ml of a solution of 13 g (44,9 mmole) of target compound in methanol and the mixture was stirred 3 hours at room temperature. The solvent is then drove away under reduced pressure. The residue was led into a 250 ml 2-propanol, receiving of 11.5 g of the hydrochloride of the target compound as colorless crystals (yield: 78%).

So pl.: above 200oC (decomposition)

Example 60 synthesis

Synthesis of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1-pyrrolidinyl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole (optically active (+)-isomer of the compound of synthetic example 4)

In the same manner as in synthetic example 59, obtained 15.0 g (yield 58%) of target compound as yellow crystals. In the same way also received 12,9 g (yield 82%) of the hydrochloride of the target compound as colorless crystals.

So pl.: above 200oC (decomposition).

Example 61 synthesis

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-di-n-propylamino - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole:

< / BR>
219 mg (1 mmol) of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 304 mg (3 mmol) of di-n-Propylamine and 5 ml EA reaction the solvent is distilled off and the residue is subjected to chromatography on a column of silica gel (item: hexanitrate = 9: 1) to obtain 112 mg of target compound (yield 35%). Part of the thus obtained compound was dissolved in dry ethanol and add HCl-ethanol, and then formed cleaners containing hydrochloride salt of the compound in the form of colorless powder.

So pl.: from 178 to 183oC.

Example 62 synthesis:

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-n-propylamino-6H - pyrano [2,3-f] benzo-2,1,3-oxadiazole:

< / BR>
The target compound is obtained using n-Propylamine according to the method described in synthesis Example 61. Hydrochloride target compound has a melting point of from 248 to 250oC (yield: 56%).

Example 63 synthesis:

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(3'-ethoxypropan) amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole:

< / BR>
The target compound is obtained using 3-ethoxypropylamine according to the method described in synthesis Example 61. Hydrochloride target compound has a melting point of from 175 to 178oC (yield: 56%).

Example 64 synthesis:

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(N-ethyl-N-n-propyl) amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole:

< / BR>
The target compound is obtained using N-ethyl - n-Propylamine according to the method described in Example 61 synthesis of the Hydrochloride of the target compound has a melting point of from 222 to 225Ino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole;

< / BR>
The target compound is obtained using N-ethyl - n-butylamine according to the method described in synthesis Example 61. Hydrochloride target compound has a melting point of 180 to 182oC (yield: 28%).

Example 66 synthesis:

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (N,N-diallyl) -amino-6H-pyrano [2,3-f] benzo-2,1,3 - oxadiazole:

< / BR>
The target compound is obtained using diallylamine according to the method described in synthesis Example 61. Hydrochloride target compound has a melting point of from 172 to 174oC (yield: 35%).

Example 67 synthesis:

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(4'-hydroxybutyl) amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole:

< / BR>
The target compound is obtained using 4-hydroxyethylamino according to the method described in synthesis Example 61. Hydrochloride target compound has a melting point of 220 to 223oC (yield: 49%).

Example 68 synthesis:

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(di-2'-hydroxyethyl) amino-6H-pyrano [2,3-f] benzo-2,1,3 - oxadiazole:

< / BR>
The target compound is obtained using diethanolamine according to the method described in synthesis Example 61. Hydrochloride target compound has a melting point of from 108 to 110ois-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole:

< / BR>
The target compound is obtained using N-methylphenethylamine according to the method described in synthesis Example 61. Hydrochloride target compound has a melting point of from 190 to 193oC (yield: 79%).

Example 70 synthesis:

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(N-methyl-N-isobutyl) amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole:

< / BR>
The target compound is obtained using methyl-isobutylamine according to the method described in synthesis Example 61. Hydrochloride target compound has a melting point of 178 to 181oC (yield: 26%).

Example 71 synthesis:

Synthesis of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1', 1'-dimethylpentyl)amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole:

< / BR>
The target compound is obtained using 1,1-dimethylphenethylamine according to the method described in synthesis Example 61. Hydrochloride target compound has a melting point of from 190 to 192oC (yield: 34%).

Examples of the preparation of finished dosage forms.

Below are examples of the preparation of finished dosage forms of tablets, hard capsules, elastic capsules, suppositories, injection and granular funds.

1. Tablet contains 5 wt.% connection N 59, 60 wt.% l is fester.

2. Hard capsule contains 10 wt.% connection N 59, 30 wt.% lactose, 59 wt.% microcrystalline cellulose and 1 wt.% the stearate.

3. Elastic capsule contains 6.7 wt.% connection N 59, at 92.6 wt.% the triglyceride C4-10aliphatic acid and 0.7 wt.% Polysorbate 80 (i.e., polyoxyethylene 20-sorbitan of monooleate defined in the Pharmacopoeia of Japan).

4. The suppository contains 1.0 wt.% connection N 59, of 98.5 wt.% solid fat and 0.5 wt.% Polysorbate 80 ("tallow" represents a triglyceride C6-18aliphatic acid specified in the Pharmacopoeia of Japan).

5. Means for injection contains 0.01 wt.% connection N 59 and 99.99 wt.% distilled water for injection.

6. A granular product contains 5 wt.% connection N 59, 60 wt.% lactose, 20 wt.% corn starch, 5 wt.% hydroxypropylmethylcellulose and 10 wt.% CMC-Ca salt.

EXAMPLES PREPARATION PREPARATIVE FORMS

Example 1 ready preparative form.

Ready preparative form in the form of tablets:

The compound (obtained in example of synthesis 4) - 10 g

Lactose is 260 grams

Powder, crystalline cellulose - 600 g

Corn starch - 350 g

Hydroxypropylcellulose - 100 g

use components were mixed in the usual manner and the mixture is then alloy preformed, getting 10000 covered by the sugar-coated tablets, each of which contained 1 mg of the active component.

Example 2 ready preparative form:

Ready preparative form of capsules:

The compound (obtained in example of synthesis 4) - 10 g

Lactose - 440 g

Powder, crystalline cellulose - 1000 grams

Stearine magnesium - 50 g

Only 1500 grams

The above components were mixed in the usual way and then the mixture was filled in gelatin capsules, receiving 10,000 capsules, and of every of them contained 1 mg of the active component.

Example 3 ready preparative forms

Ready preparative form in the form of soft capsules:

The compound (obtained in example 4) 10 grams

PEG-400 - 479 g

Triglycerides of saturated fatty acids - 1500 g

Peppermint oil - 1 g

Polysorbate 80 - 10 g

Just - 2000

The above components were mixed and then the mixture was filled soft gelatin capsules No. 3 conventional technique, getting 10000 soft capsules, each of which contained 1 mg of the active component.

Example 4 ready preparative forms

Ready preparative form in the form of ointments:

The compound (obtained in example of synthesis 4) - 1.0 g

Liquid Parati is,0 g

The above components were mixed in the usual method, receiving 1% ointment.

Example 5 ready preparative forms

Ready preparative form of suppositories:

The compound (obtained in example of synthesis 4) 1 g

Witepsol H15x- 478 g

Witepsol W 35x- 520 g

Polysorbate 80 1 g

Only 1000 grams

(xindicates the brand name of triglyceride connection).

The above components were mixed in the melt with conventional method and poured into containers suppositories, and then cooled for solidification, receiving 1000 suppositories 1 g, each of which contains 1 mg of the active component.

Example 6 ready preparative forms

Ready preparative form of injection;

The compound (obtained in example 4), 1 mg

Distilled water for injection 5 ml

Ready preparative form is received, as required, by dissolving the compounds in distilled water.

EXAMPLES OF PHARMACEUTICAL TEST

The effect on the contractility of cardiac muscle

Test method:

Heart was removed from male Guinea pigs Harley and in fluid Krebs Henseleit aerated with a gas mixture of 95% 02//5% Lannoy nutrient liquid, which stood at the 31oC. To determine the contractility of cardiac muscle of left atrium sample transmural were subjected to electrical stimulation using platinum dipolar electrodes and record the voltage generated by the contraction of the heart muscle sample. Conditions for electrical stimulation were as follows:

Voltage: two threshold voltage to achieve reduction (B)

Time: 3 (msec)

Frequency: 1 Hz)

After equilibration of the sample when replacing nutritious liquid on the sample acumulative was applied isoproterenol to get the maximum contractile response of the sample. After washing the added isoproterenol sample was again balanced within 60 min when replacing the nutrient fluid. Then the sample was applied the following test compounds and watched them in action.

The effect caused by application of 100 μm and 300 μm of each compound is expressed as the rate of change (%), counting from the maximum reduction (100%), previously obtained from the application of isoproterenol.

The results:

The test results are given in table. 1A, confirm that the connection this is the concentration used for the connection.

The results of test 1 - effect on the contractility of the heart muscle are given in table. 1A.

The effect on the rate of heart contractions

Test method:

Heart was removed from male Guinea pigs Harley and in fluid Krebs Henseleit aerated with a gas mixture (95% O2/5% CO2), it separates the right atrium. The sample was kept at a voltage of 1 g in a bath filled organs nutritious liquid that is kept at the 31o.

After equilibration of the sample when replacing nutritious liquid on the accumulative sample was applied isoproterenol to get the maximum response of the sample. After washing the added isoproterenol sample was again balanced within 60 min when replacing the nutrient fluid. Then the sample was applied the following test compounds and watched them in action.

Received relative change (%) heart rate reduction of the sample is determined by adding the test compounds (100 μm or 300 μm), the maximum response (100%), previously obtained from the application of isoproterenol.

The results:

The results of the tests shown in the table. 2 show that the compounds of this is it on the concentration used for the connection.

The results of tests of 2 - the impact on the rate of heart contractions are presented in table. 2.

The impact on cardiac function shot dogs

Test method:

Females and males dogs mongrels were anestesiologi pentobarbital sodium and kept under artificial respiration. In the abdominal aorta through the right femoral artery was inserted cannula and blood pressure of the animal was measured with the use of the amplifier blood pressure and gauge pressure. The speed of the heartbeat of the animal was measured on the basis of the instant wave of the cardiac contraction, using a wave of blood pressure as a trigger. The catheter (sensor blood pressure) was inserted into the left ventricle from the left carotid artery and the internal pressure in the left ventricle was measured with the use of the amplifier blood pressure. The internal pressure in the left ventricle were differentiated by the differential device for receiving a primary differential value of the internal pressure in the left ventricle (this value corresponds to a major extent systolic pressure of the left ventricle, LV dp/dlmax). The test compounds shown below was dissolved in a mixed solvent of polietileno. Before the test it was found that he mixed solvent does not influence cardiac function and blood pressure of the animal.

The results:

The test results are shown in table. 3 confirm that the compounds of the present invention have a strong activity to strengthen contractions of the heart muscle and strong activity to reduce the rate of heart contractions and no effect on blood pressure.

The results of test 3:

(The effect of the compounds of example 59 synthesis of (-)-isomer of the compound of synthetic example 4), which was injected intravenously shot the dog - like change (in %) (obtained as the average of three determinations) the values obtained before the addition of test compounds.

Test 1. The effect on the contractility of the heart muscle are presented in table. 4.

Test 2. Effect on heart rate are presented in table. 5.

METHODS

Investigated the actions of the test compounds on1and2-adrenergic receptors. For experiments on the competitive binding1251-labeled iodobenzoate (specific activity, 2200 Ci/mmol; horse at the tabulated concentrations used microsomal membrane, obtained from cerebral cortex of rats. Reactions were performed in 50 mm Tris-HCl (pH 7.5) containing 150 mm NaCl, 2.5 mm MgCl2and 0.5 mm ascorbate for 30 minutes at 37oC. was finishing the reaction by rapid vacuum filtration on filters of glass fibers. By means of a counter gamma radiation was determined by the radioactivity remaining on the filters. The selectivity of the binding for1and2-adrenergic receptors was determined simultaneously in the presence of an excess of ICI-118.551 (2-selective blocker) or ICI-89.406 (1-selective blocker), respectively. Nonspecific binding was determined by adding to the sample an excess of its isoproterenol (100 μm). Specific binding was calculated as the difference between total binding minus nonspecific binding. Specific binding is from 80 to 85% of the total binding.

The results are presented as percent of maximum specific binding1251-labeled iodophenol in the absence of the test compound.

Test connection = Connection Example 59 Synthesis. Results.

As shown in the table. 6, the test compound does not bind no1and2-adrenergic of receivedany is different from the mechanism-blocker.

The effect of test compounds on the binding1and2-adrenergic receptors are presented in table. 6.

1. Drug for treatment of heart failure, characterized in that it contains as active ingredient at least one of the compounds of General formula I

< / BR>
where n is 0 or 1;

X represents an oxygen atom or a nitrogen atom (the nitrogen atom unsubstituted or substituted by a hydrogen atom);

A represents a hydrogen atom or a hydroxyl group;

In represents a hydrogen atom;

R1and R2the same or different from each other, represent a hydrogen atom or a C1-C4is an alkyl group;

R3and R4the same or different from each other, represent a hydrogen atom, a C1-C6is an alkyl group (this alkyl group is unsubstituted or substituted by one or more substituents selected from a hydroxyl group, a C1-C4-alkoxy group or phenyl group), C2-C6-Alchemilla group, or C(= Y)ZR6where Y denotes an oxygen atom, a sulfur atom or a group NR7in which R7represents a cyano, Z represents a group NR9in which R9those form a 1,4-butylene or 1,5-Panteleeva group (the 1,4-butylene and 1.5-Panteleeva group not substituted or substituted by a hydroxyl group); or R3and R4form together a group -(CH2)mX4(CH2)I- in which m and each I is 1, 2 or 3, their sum must be 3, 4 or 5; X4represents an oxygen atom or a group NR12in which R12denotes a hydrogen atom or a phenyl group; or R3and R4form together -(CH2)2ZC(=Y)- or -(CH2)3ZC(=Y)-, where Z-values indicated above;

their optical isomers, their stereoisomers or their pharmaceutically acceptable salts in amounts of from 0.01 to 99.5 wt.%.

2. Drug for treatment of heart failure under item 1, wherein R3represents a hydrogen atom and R4represents C(= Y)ZR6where Y represents an oxygen atom, a sulfur atom or the group NR7in which R7represents a cyano, Z represents a group NR9in which R9represents a hydrogen atom, R6represents C1-C8is an alkyl group.

3. Drug for treatment of heart failure under item 1, wherein R3and R4together form the group (CH2)mX4(CH2)Iin which m and each I is 1, 2 yoroi R12represents a hydrogen atom or phenyl group.

4. Drug for treatment of heart failure under item 1, wherein R3and R4are simultaneously C1-C6is an alkyl group.

5. Drug for treatment of heart failure under item 1, wherein R3and R4together form the group (CH2)4or (CH2)5.

Priorities for items:

02.04.93 and 08.03.94 - on all claims.

 

Same patents:

The invention relates to medicine and can be used in the treatment of stress lesions of the nervous system in combustionengines, traumatic, neurological and surgical hospitals

The invention relates to new chemical substances possessing valuable properties, in particular nitrogen-containing cyclic derivative of General formula

< / BR>
where X is carbinieri, unsubstituted or substituted at the nitrogen atom by alkyl, aryl, heteroaryl or cyano, carbonyl, thiocarbonyl, sulfonyl, 1-nitroethene-2,2-diyl or 1,1-dicyano-Eten-2,2-diyl,

Y is unsubstituted or substituted Rcor Rdor Rcand Rdnonbranched alkylen or albaniles with 2 to 4 carbon atoms, which may optionally be substituted by one or two alkyl groups and in which one or two methylene groups can be replaced by a carbonyl, 1,2-cycloalkyl with 5 to 7 carbon atoms, unsubstituted or substituted Rcor Rdor Rcand Rd, 1,2 - cycloalkenyl with 5 to 7 carbon atoms, unsubstituted or substituted Rcor Rdor Rcand Rd, 1,2-Allen, 1,2-phenylene, in which one or two methine groups are replaced by nitrogen atom or one or two groups-CH=CH - replaced by a group-CO-NH - or a methine group substituted by nitrogen atom and one group-CH= CH - replaced by a group-CO-NH-, and above heterocycles or substituted Rcor Rd,

the first of the residues Ra- Rdmeans A group-B-, in which A group of the formula

< / BR>
< / BR>
or

< / BR>
where pentostatin can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents R25and R26that may be the same or different and have the meanings stated below, in one bancoestado 1 - 3 methine group may be replaced by a nitrogen atom or a group-CH= CH - may be replaced by a group-CO-NR1or one methine group may be replaced by nitrogen atom and one group-CH=CH - may be replaced by a group-CO-NR1-, where R1means a hydrogen atom or alkyl,

G1and G4- bond or methylene which may be mono - or Disaese the alkyl, aryl or heteroaryl, and the substituents may be the same or different,

G2- bond or methylene, substituted residues R7and R8,

G3communication, methyl nitrogen atom or Metin, unsubstituted or substituted by alkyl, aryl or heteroaryl,

R2is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl if at least one of the groups G2and G3doesn't mean the relationship,

R3is a hydrogen atom, alkyl, aryl or heteroaryl or R3together with R2form an oxygen atom, if at least one of the groups G2and G3doesn't mean the relationship,

R4and R14is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl parts, alkyl with 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, arylalkyl, heteroallyl, alkoxycarbonyl, allmediascotland, formyl, acetyl, TRIFLUOROACETYL, allyloxycarbonyl, amidino or R11CO-0-(R12CR13)-O-CO-, where R11is alkyl with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, aryl or arylalkyl, R12is a hydrogen atom, alkyl, cycloalkyl with sweetlenny alkylen 2 - 4 carbon atoms or methylene, if G2doesn't mean the relationship,

R5is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G1no means of communication, or R4together with R5mean an additional bond, if G1means of communication,

R6is a hydrogen atom, alkyl, aryl or heteroaryl or a chlorine atom, a hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G1means linking and R4together with R5mean an additional bond, or R6together with R5mean oxygen atom, if G1doesn't mean the relationship,

R7is a hydrogen atom, alkyl, aryl or heteroaryl,

R8is a hydrogen atom, alkyl, aryl or heteroaryl or R8together with R4mean the unbranched alkylene with 2 to 5 carbon atoms,

R9is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G2doesn't mean the relationship,

R10is a hydrogen atom, alkyl, aryl or heteroaryl or R10together with R4mean the unbranched alkylene with 2 to 4 carbon atoms,

R15is a hydrogen atom or chlorine, alkyl, aryl, heteroaryl, hydroxyl, methoxyl, amino, alkylamino or dialkylamino,

R16- foelkel 1 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl or arylalkyl,

R17is a hydrogen atom or alkyl, or R16together with R17mean an additional bond, if G4means of communication,

R18is a hydrogen atom, alkyl or fluorine atom, chlorine or bromine, hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G4means linking and R16and R17together denote an additional bond,

n is the number 1 or 2,

In - line, alkylen, albaniles, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms may be associated with the remainder of A connection instead of a hydrogen atom, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or RC="http://www.fips.ru/fullimg2/rupat3/19993/003.dwl/2126002-6t.gif" ALIGN="ABSMIDDLE">replaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, the second of the residues Ra- Rdmeans a group of the formula

F - E - D-,

where D is alkylene with 1 to 6 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, sulfinil, sulfonium or the group-NR19-, where R19means a hydrogen atom, alkyl, alkylaryl, alkylsulfonyl, arylcarbamoyl or arylsulfonyl, or in which one ethylene group may be replaced by a group-CO-NR20- or-NR20-CO-, where R20means a hydrogen atom or alkyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms, together with the hydrogen atom may also be linked with the rest of E, if the latter does not mean the connection or not connected via a heteroatom or a carbonyl with the rest of D, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, indaniel, naftilan, 1,2,3,4-tetrahydronaphthalen or benzoguanamine, in which one of the be substituted by one or two alkyl groups, and the aromatic ring may be substituted by fluorine atom, chlorine, bromine or iodine, alkyl, trifluoromethyl, hydroxyl, alkoxyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl or cyano, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one groupreplaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, unsubstituted or substituted by one or two alkyl groups piperazinyl in which one adjacent to the nitrogen atom of the methylene group may be replaced by a carbonyl, or alkilenkarbonatov with the total number of carbon atoms 2-6, if E is a cyclic aminogroup, and a carbonyl linked to a nitrogen atom of a cyclic aminogroup group E, or a link, if E does not mean the relationship,

E - communication, alkylene with 1 to 6 carbon atoms which may be substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, is POI with the total number of carbon atoms of 2 10, the group HNR21- or N-alkyl-NR21-, where R21means alkylsulphonyl or alkylsulfonyl with 1 to 8 carbon atoms in the alkyl part, allyloxycarbonyl with the total number of carbon atoms 2 and 5 cycloalkylcarbonyl or cycloalkylcarbonyl with 5 to 7 carbon atoms in cycloalkyl part, arylalkylamines, arylalkylamines, arylethoxysilanes, arylcarbamoyl or arylsulfonyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one groupreplaced by a nitrogen atom linked to the carbon atom of the residue D, cycloalkyl with 4 to 7 carbon atoms in cycloalkanones part, unsubstituted or substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, a group HNR21- or N-alkyl-NR21-, where R2119-, -NR20-CO - or-CO-NR20-, where R19and R20have the above meanings, with alkylene may be optionally substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, group-HNR21- or N-alkyl-NR21where R21have the above significance, with an additional heteroatom substituent heteroatom is separated from the remainder of W by at least two carbon atoms, if D does not mean the relationship,

F - carbonyl, substituted by hydroxyl, alkoxyl with 1 to 8 carbon atoms, arialcategory or group R22O-, where R22means cycloalkyl with 4 to 8 carbon atoms and cycloalkyl with 3 to 8 carbon atoms in cycloalkyl part, in which cycloalkyl part may be substituted by alkyl, alkoxyl or dialkylamino, or alkyl and 1 to 3 methyl groups, with one methylene group in the 4 - to 8-membered cycloalkyl part may be replaced by oxygen atom or alkylaminocarbonyl, benzocyclobutene the PA R23CO-O-CHR24-O-CO-, where R23means alkyl or alkoxy with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, cycloalkyl with 5 to 7 carbon atoms in cycloalkyl parts, aryl, aryloxy, arylalkyl or Allakaket and R24is a hydrogen atom or alkyl,

the shortest distance between the residue of F and located at a maximum distance from the rest F the nitrogen atom of the group A-B - is at least 11 links,

the third of the residues Ra- Rdmeans a hydrogen atom, alkyl, perfluoroalkyl, alkoxy, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, aryl, heteroaryl or arylalkyl,

the fourth of the residue Ra- Rdmeans a hydrogen atom, alkyl or aryl, and if nothing else is mentioned,

under the above term "aryl" is to be understood phenyl, which can be monogamist the remainder R25mono-, di - or triamese the remainder R26or monogamist the remainder R25and additionally mono - or Disaese the remainder R26and the substituents may be the same or different, R25means cyano, carboxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxycarbonyl, alkylboron, the Mino, alkylamino, dialkylamino, alkylcarboxylic, phenylalkylamine, phenylcarbonylamino, alkylsulfonyl, phenylalkylamine, phenylcarbonylamino, N-alkyl-alkylcarboxylic, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, N-alkyl-alkylsulfonyl, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, R26- alkyl, hydroxyl or alkoxy, fluorine atom, chlorine, bromine or iodine, and two residue R26if they are linked to adjacent carbon atoms, may also be alkylene with 3 to 6 carbon atoms, 1,3-butadiene-1,4-deelen or methylendioxy group

under the above term "Allen" should be understood phenylene, which can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents may be the same or different and have the above values,

under the above term "heteroaryl" should read 5-membered heteroaromatic ring containing one atom of oxygen, sulfur or nitrogen, one atom of nitrogen and one atom of oxygen, sulfur is certain heteroaromatic ring, in which one or two of the groups-CH= N - can be replaced by a group-CO-NR20where R20has the above value, the heteroaromatic ring can be substituted by one or two alkyl groups or by a fluorine atom, chlorine, bromine or iodine, hydroxyl or alkoxyl in the carbon skeleton,

and, if nothing else is mentioned, the above alkyl, alkylene or CNS groups can contain 1 to 4 carbon atoms and each of the carbon atoms in the above alkilinity and cycloalkenes groups associated at least one heteroatom,

mixtures of their isomers, or individual isomers or salts

The invention relates to pharmacology and describes a new tool for the treatment of irritable bowel syndrome

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, endocrinology, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 3 tbl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention proposes the composition comprising xenon as NMDA-antagonist and alpha-2-adrenergic agonist used for treatment of tetanus or narcotics (alcohol) withdrawal syndrome, states with chronic pain syndrome. Also, invention relates to the anesthetic composition comprising xenon and alpha-2-adrenergic agonist and to a method for anesthesia. The synergistic interaction of xenon as NMDA-antagonist and alpha-2-adrenergic agonist provides reducing the dose and to maintain the prolonged effectiveness by prevention for arising the drug habitation to the claimed preparation.

EFFECT: valuable medicinal properties of composition.

9 cl, 6 dwg, 6 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with mixing water for injections, conservation agent, metronidasol till complete dissolving at 50-60 C, adding a buffer (NaOH solution) pH 4.5-6.5 at pre-estimated quantity of water, then one should sterilize the obtained medicinal form due to membranous filtration followed by sterile packaging. As a conservation agent one should apply sodium chloride at the quantity of 1.5-2.0 against metronidasol weight, then metronidasol solution should be supplemented with a half-volume of sodium chloride solution, after complete dissolving the obtained solution should be supplemented with the rest quantity of sodium chloride solution. As for membranous filtration it should be carried out by applying a capsule out of polypropylene with hydrophilic membrane of 1.2 mcm. The method provides no crystallization of an active substance during prolonged period of time.

EFFECT: higher therapeutic efficiency.

1 ex, 1 tbl

FIELD: medicine, cardiology.

SUBSTANCE: it is suggested to apply cortisol antagonists in addition to clonidine while manufacturing preparation to treat heart failure. Moreover, one should introduce cortisol antagonist or a product that includes cortisol antagonist along with the second medicinal preparation being a combined preparation to be applied either simultaneously, separately or successively. The present innovation provides decreased symptoms of heart failure at decreasing cardiac muscle's fibrosis and heart sizes due to preferable impact upon glucocorticoid receptors in patient's heart and/or kidneys.

EFFECT: higher efficiency of application.

12 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new spiroimidazolidine derivatives of the formula (1):

wherein R1 represents hydrogen atom or methyl; R2 represents phenyl or (C1-C4)-alkyl; X represents -CH2-CH2- or -CH2-CH2-CH2-; W represents isopropyl or cyclopropyl; V represents hydrogen atom or methoxy-group; E represents -CO-R3 wherein R3 represents hydroxy-group, (C1-C4)-alkoxy- or amino-group; phenyl represents unsubstituted phenyl residue or phenyl residue substituted with one or some similar or different substitutes taken among the group consisting of (C1-C4)-alkoxy-, methylenedioxy- and ethylenedioxy-group in all its stereoisomeric forms and their mixtures in all ratios, and to its physiologically acceptablesalts. Also, invention relates to a method for preparing compounds of the formula (1) and pharmaceutical composition based on these compounds. Invention provides preparing new compounds eliciting the inhibitory effect with respect o leukocytes adhesion.

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

16 cl, 1 tbl, 41 ex

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