Derivatives benzopyran or their pharmaceutically acceptable salts and method of production thereof

 

(57) Abstract:

Usage: in medicine as protivogipertenzin funds. The inventive product derivatives benzopyran f-ly I, where R1, R2THAT IS, R3and R4have appropriate values. Reagent 1: compound f-ly IV, where (a) W-NH2group; W is OH - group or b) W and W together an oxygen atom and form ethoxypropan. Reagent 2: in case a) compound f-ly V, where R4indicated above; R6- C1-C4-alkyl; R7- formyl or kaleidotile, or in case b) connection f-VI crystals or VI, where R4and R5are as defined above; and --- represents a group of f-crystals, VII or VIII, where R8a, R8band R8c- C1-C4- alkyl, and get a connection f-ly Ia, where R1and R2above, and, if necessary, process connection f-ly Ia base and get a connection f-ly IB, where R1and R2as mentioned above, or, if you want the link to f-ly Ia is subjected to interaction with nitrous reagent and receive connection f-ly IC, where R1and R2above, or, if necessary, allocate the connection f-ly Ia, Ib and Ic in the form of pharmaceutically acceptable salts. The relative activity compared retina relates to new derivatives of benzopyran, which have protivogipertenzin activity and can be used in the treatment and prevention of cardiovascular disease.

The compounds of the present invention are 3,4-dihydro-2,2-dimethyl-4(1-occaisonaly-2-yl)-6 - perfluoroalkyl - sulfonyl-2H-1-benzopyran-3-ol, compound 3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-6 - trifluoromethyl - sulfonyl-2H-1-benzopyran-3-ol, nitrates of these compounds, analogues of these compounds having carbon-carbon unsaturated bond 3,4-position Pyrenophora cycle, and derivatives of these compounds and nitrates, which isoindolyl or peredelnyj cycle is substituted.

Known compounds of this type and with this type of activity [1-5] for example, 6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxo-1 - pyrrolidinyl)-2H - 1-benzopyran-3-ol of the formula A, 3,4-dihydro-2,2-dimethyl-6-trifloromethyl-4-(2-oxo-1 - pyrrole - dinyl)-2N-1-benzopyran-3-ol of the formula In and 3,4-dihydro-2,2-dimethyl-4-(1-oxiteno - Lin-2-yl)-6 - trifloromethyl-2H-1-benzopyran-3-ol of the formula:

(A)

(B)

(C)

Isomer compound, [()- 6-cyano-3,4-dihydro-2,2-dietitans-4-(2-oxo-1-PIR rollitini)-2H - 1-benzopyran-3-ol] known as Cromakalim is under study as a more feasible and useful activity, their activity duration are less than desirable.

In the present invention described a limited number of compounds that have the same class activity, the combination of 1-occaisonaly-2-ilen, or 1,2-dihydro-2-oxo-1-peredelnoj group in position 4 and perforagricultural group in position 6 and which as a result are more powerful (very active) and have a long duration of action.

The essence of the present invention are derivatives of benzopyran with vasodilator and hypoten - invasive activity.

The aim of the invention is to provide compounds having improved activity.

The compounds according to the present invention are the compounds of formula

R1SO2(I) where R1performanceline group having 1-3 carbon atoms;

R2a group of the formula

- (II) where R4a hydrogen atom or halogen, or a nitro-group, or a group of the formula

(III) where R5a hydrogen atom, an alkyl group having 1-4 carbon atoms, alkoxygroup having 1-4 carbon atoms;

a simple carbon-carbon bond (SN-SN) or a carbon-carbon double bond (C=C),

/SUB>), or when represents a double carbon-carbon bond, R3a hydrogen atom, or their pharmaceutically acceptable salts, provided that R1is not triptorelin group, when R2represents a group of formula (II), where a simple bond; R3the hydroxy-group; R4the hydrogen atom.

The invention also provides a method of producing compounds of the present invention.

In the compounds of formula (I), where R1performanceline group, the alkyl portion has 1-3 carbon atoms and may be linear or razvetvlenno-chain group, although it is preferably a linear-chain group. Such groups are triptoreline, panafcortelone, heptafluoropropyl and heptafluoroisopropyl group, of which triptoreline and panafcortelone group are preferred, and triptorelin group are more preferred.

R2can represent this group of the formula (II) or (III), from which the group of formula (II) is preferred.

When R5represents an alkyl group, it may be linear or razvetvlenno-chain alkyl group having 1-4 carbon atoms. Examples include metal is respectfully methyl, ethyl, sawn, ISO-propyl or boutelou group, most preferably a methyl group.

When R5is alkoxygroup, it can be linear or razvetvlenno-chain alkoxygroup having 1-4 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, verboeket and tertbutoxide, preferably methoxy, ethoxy-, propoxy-, isopropoxy or butoxypropyl, most preferably a methoxy group.

Preferably R5represents a hydrogen atom, methyl group, methoxy group.

When R2represents a group of formula (II), preferably so - would be a simple carbon-carbon bond and to R3would the hydroxy-group or microarthropod. In this case, it is preferable to occaisonally group would be replaced, i.e., R4would not represent a hydrogen atom. When R2represents a group of formula (III) is better that - would represent a carbon-carbon double bond.

In the compounds of formula (I), where R2a group of the formula (II), R4the hydroxy-group, the compound is an acid, so it can form a salt. Tsuchihashi use, they must be pharmaceutically acceptable. If they are not intended for therapeutic uses, for example as intermediates in obtaining other and perhaps more existing connections, it does not apply even this limitation. Examples of such salts: salts with an alkali metal such as sodium, potassium or lithium, salts with alkaline-earth metal such as barium or calcium; salts with another metal, such as magnesium or aluminium salts of organic bases, such as salt with dicyclohexylamine, and salts with basic amino acid such as lysine or arginine.

When is a simple carbon-carbon bond, the compounds of the present invention can form various stereoisomers and optical isomers. Although all of these stereoisomers and optical isomers, including racemates, represented here by the General formula (I), the present invention considers both the individual isomers and mixture of them. Preferred compounds are compounds containing 3,4-transconfiguration, in particular compounds containing (3S, 4R)-configuration. When you apply the techniques stereospecific synthesis or use of optically active compounds in cachesecs mixture of isomers, the individual isomers can be obtained by using conventional separation techniques.

Preferred classes of compounds of the present invention are those compounds of formula (I), in which

1) R1triptorelin group or panafcortelone group;

2) R2a group of the formula (II), where R4a hydrogen atom, or a nitro-group, or a group of the formula (III), where R5a hydrogen atom, a methyl group, or methoxy group.

More preferred compounds of the present invention are those compounds of formula (I) in which:

3) R2a group of the formula (II), where R4a hydrogen atom;

a simple carbon-carbon bond;

R3microarthropod,

or carbon-carbon double bond;

R3a hydrogen atom;

4) R2a group of the formula (II), where R4the nitro-group;

the carbon - carbon simple communication;

R3gidroksipropil or microarthropod,

or a carbon-carbon double bond;

R3a hydrogen atom;

5) R2a group of the formula (III), where R5a hydrogen atom;

the carbon - carbon simple communication;

R3microarthropod.

In particular those compounds in which R1and the compounds of the present invention are those compounds of formula (I), where:

6) R1triptorelin group,

particularly those compounds where R1is as defined in paragraph (6), and R2, R3and - are as defined in paragraph (4).

Examples of some compounds of the present invention is represented by the following formulas (I-1) and (I-2), in which the symbols are as defined in table. 1 and 2, i.e., PL. 1 relates to formula (I-1), and table. 2 to the formula (I-2).

(I-1)

(I-2)

Of these preferred compounds are compounds 1-2, 1-5, 1-6, 1-9, 1-13, 1-15, 1-16, 1-20, 1-21, 1-22, 1-23, 2-1, 2-2 and 2-19. The most preferred compounds are compounds under the numbers:

1-5. Nitrate 3,4-dihydro-2,2-dimethyl-4-(1-occaisonaly-2-yl)-6-trifloromethyl-2H-1-benzopyran-3-yl;

1-9. 3,4-Dihydro-2,2-dimethyl-4-(6-fluoro-1-occaisonaly-2-yl)-6-trifloromethyl-2H-1-benzopyran-3-ol;

1-13. 3,4-Dihydro-2,2-dimethyl-4-(4-nitro-1-occaisonaly-2-yl)-6 - trifloromethyl-2H-1-benzopyran-3-ol;

1-15. 3,4-Dihydro-2,2-dimethyl-4-(6-nitro-1-occaisonaly-2-yl)-6 - trifloromethyl-2H-1-benzopyran-3-ol;

1-16. 2,4-Dihydro-2,2-dimethyl-4-(4-fluoro-1-occaisonaly-2-yl)-6 - trifloromethyl-2H-1-benzopyran-3-ol;

2-1. 2,2-Dimethyl-4-(1-occaisonally of the present invention can be obtained by a number of methods, widely known for producing compounds of this type. For example, they can be obtained by reacting compounds of the formula

(IV) where R1defined above;

a) W amino group;

W' hydroxylgroups;

b) W and W' together represent an oxygen atom to form apachegroup;

in case (a) with the compound of the formula

(V) where R4defined above;

R6an alkyl group having 1-4 carbon atoms;

R7formyl group or kaleidotile group, preferably bromoethylene, chloromethylene or iodomethyl group, or,

in case b) with a compound of formula

where R4and R5defined above;

a group of the formula

N OS

or

O where R8a, R8b, R8care the same or different and each represents alkyl group having 1-4 carbon atoms; to obtain a compound of the formula

(Ia) where R1and R2defined above.

If necessary, the compound of formula (Ia) may be further formed by a base, to obtain a compound of the formula

(Ib) where R1and R2defined above.

In addition, the compound of formula (Ia) may be subjected to reaction with nitrious reageerden in salt in the usual way.

Compounds of the present invention can be obtained as shown in the following reaction schemes a and B.

The reaction scheme a (see Fig. 1) shows obtaining the compounds of formula (I), where R2a group of the formula (II);

- represents a simple bond;

R3the hydroxy-group, i.e. compounds of formula (Id),

and the corresponding compounds in which represents a double bond, i.e. compounds of formula (Ie).

In the above formulas, R1, R4and R6defined above, and R7ahalogen atom, preferably a bromine atom, chlorine or iodine.

In stage A1 of this scheme reaction aminostyrene compound of formula (IIa) is subjected to reaction with either formila - displaced difficult ether (formula Va), or galoidzamyescyennykh complex ester of the formula (Vb) to obtain the compound of formula (Id).

The reaction aminopyrrolo the compounds of formula (IIa) with ferminselmany complex ester of the formula (Va) is typically and preferably takes place in an inert solvent; it is preferably carried out in the presence of reductant.

There is no particular restriction on the nature of the employed solvent, provided that no adverse effect is Roy extent. Examples of suitable solvents are: alcohols, such as methanol, ethanol or propanol, carboxylic acids such as acetic acid or propionic acid, esters of acids, such as ethyl acetate, ketones, such as acetone or methyl ethyl ketone, water, and mixtures of any two or more of these solvents, including alcohols, in particular methanol and propanol are preferred, and propanol is preferable.

Examples of reducing agents that can be used in this reaction include borohydride and cyanoborohydride, such as cyanoborohydride sodium, borohydride sodium, cyanoborohydride zinc and borohydride zinc, of which cyanoborohydride sodium and cyanoborohydride zinc are the most preferred. If you want, zinc compounds can be obtained from the corresponding sodium compounds and zinc salts, such as cyanoborohydride zinc can be obtained from cyanoborohydride sodium and zinc chloride during the reaction.

The reaction can occur in a wide limit temperature, while the temperature of the reaction is not critical in the present invention. Determined that it is convenient to conduct the reaction at 0-150aboutWith more presioco depending on many factors, especially the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out at these conditions, the period of time is from 1 to 72 h, more preferably from 1 to 36 hours

Aminostyrene compound of formula (IIa) may be subjected to reaction in stage A1 galoidzamyescyennykh ester compound of the formula (Vb). This reaction is preferably conducted in an inert solvent, preferably in the presence of a base.

Examples of bases that can be used for this reaction include carbonates of alkali metals such as potassium carbonate, sodium carbonate or lithium, hydrogen carbonates of alkali metals such as sodium bicarbonate or potassium bicarbonate, hydrides of alkali metals, such as sodium hydride, alkali metal hydroxide, such as potassium hydroxide, tertiary amines, such as triethylamine or diisopropylethylamine. Of them preferred tertiary amines, carbonates of alkali metals and hydrogen carbonates of alkali metals.

There is no restriction on the nature of the solvent used, provided that it has no adverse effect on the reaction or involved in the reaction of the reactants and that of the NITRILES, such as acetonitrile, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, tetrahydrofuran or dioxane, halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or dichloroethane, amides, such as dimethylformamide or dimethylacetamide; NITRILES and amides are preferred.

The reaction can occur in a wide limit temperature, while the temperature of the reaction is not critical (crucial) in the present invention.

It is convenient to conduct the reaction at a temperature of from 0 to 200aboutS, more preferably from room temperature to 170aboutC. the Time required for the reaction can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out under these conditions is usually sufficient period of time from 1 to 48 h, more preferably from 1 to 10 hours

After completion of the reaction, the target compound of the invention can be extracted from the reaction mixture by conventional methods. For example, one suitable sequence retrieval readmessages water organic solvent. The extract is then dried and the solvent is removed by distillation. If necessary, the target compound can be further purified by usual method, for example by recrystallization or the various chromatography methods, especially column chromatography.

In stage A2 scheme of the reaction And the compound of formula (I), where the formula is a double bond, and R3the hydrogen atom, i.e. a compound of formula (Ie) may be obtained by treating an alcohol of compounds of formula (Id) with base in the presence of an inert solvent.

Examples of bases that can be used in this reaction include hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide, soda talc (catalogue Measurement N 1567) hydrides of alkali metals, such as sodium hydride or potassium hydride; soda talc is preferred.

There is no particular restriction on the nature of the employed solvent, provided that it has no adverse effect on the reaction or involved in the reaction reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include ethers, such as the fatty acids, such as dimethylformamide or dimethylacetamide; of those, preferred are ethers.

The reaction may proceed in a wide limit temperature, while the temperature of the reaction is not critical in the present invention. Found that the reaction is conveniently carried out at a temperature from about room temperature to 180aboutS, more preferably from 50 to 150aboutC. the Time required for the reaction can vary widely depending on many factors, particularly the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out under these conditions is usually sufficient period of time from 5 minutes to 2 hours, more preferably from 10 min to 1 h

After completion of the reaction, the target compound of the invention can be extracted from the reaction mixture by usual method. For example, one suitable method of extraction of the reaction mixture is freed from solvent by distillation or poured into water and extracted with water-immiscible organic solvent. Then the extract is dried and the solvent is removed by distillation. If necessary, the target compound can be further purified about the th chromatography.

In the reaction scheme shown how to obtain the compound of formula (I), where R2a group of the formula (III), the relationship represented by the symbol-is the carbon-carbon simple relationship, R3the hydroxy-group, i.e. the compound of formula (If), or a compound of formula (I), where R2a group of the formula (III), and the relationship represented by the symbol-is the carbon-carbon double bond, R3the hydrogen atom, i.e. a compound of formula (Ij).

In stage B1, the reaction scheme In (see Fig. 2) the compound of formula (If) can be obtained by reaction of epoxysilane formula (IVa) with a silyl ether compound of formula (VIa) or with pyridinoline compound of formula (VIb).

The reaction of the compound of formula (IVa) with a silyl ether compound of formula (VIa) is preferably carried out in the presence of desilicious reagent, and preferably in an inert solvent.

Examples desilicious reagents that can be used for this reaction include tetrabutylammonium fluoride and boron TRIFLUORIDE, of which preferred tetrabutylammonium fluoride.

There is no particular restriction on the nature of the employed solvent, provided that it has no adverse bozdo some extent. Examples of suitable solvents include ethers, such as diethyl ether, tetrahydrofuran or dioxane, hydrocarbons, in particular aromatic hydrocarbons, such as benzene, toluene or xylene, and aliphatic hydrocarbons such as hexane or pentane; of those, preferred are ethers.

The reaction may proceed in a wide limit temperature, and the temperature of reaction is not critical in the present invention. Found that the reaction is conveniently carried out at temperatures from 0 to 50aboutWith (preferably at about room temperature). The time required for the reaction may vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out under these conditions is usually sufficient period of time from 10 to 96 hours, more preferably from 12 to 80 hours

The reaction of the compound of formula (IVa) with peritoneum compound of formula (VIb) is preferably carried out in an inert solvent in the presence of a base.

There is no particular restriction on the nature of the base used in this reaction, and examples of bases that can be used is s as sodium hydride or potassium hydride, alkoxides of alkali metals such as sodium methoxide, ethoxide sodium, atoxic potassium or tertbutoxide potassium, hydroxides of Quaternary ammonium, such as hydroxide designed, hydroxide or tetrabutylammonium hydroxide of tetraethylammonium, carbonates of alkali metals such as potassium carbonate, sodium carbonate or lithium carbonate; of these, preferred hydrides of alkali metals, in particular sodium hydride, hydroxide, Quaternary ammonium compounds, in particular hydroxide designed, and amines, in particular pyridine.

There is no particular restriction on the nature of the employed solvent, provided that it has no adverse effect on the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least to some extent. When the alkali metal hydride is used in the reaction as a base, examples of suitable solvents include ethers, such as diethyl ether, tetrahydrofuran or dioxane, amides, in particular amides of fatty acids, such as dimethylformamide or dimethylacetamide, and sulfoxidov, such as dimethylsulfoxide. When the alkoxides of alkali metals, amines or hydroxides chetvertichnogo is l, ethanol or propanol as solvent. When carbonates are used for the reaction as a reason, it is preferable to use ketones, such as acetone or methyl ethyl ketone, or alcohols, such as methanol or ethanol, as solvent. In particular, when the alkali metal hydride is used as the substrate, it is preferable to use amide, in particular dimethylformamide, or sulfoxide, in particular dimethyl sulfoxide as solvent. When other bases used for the reaction, it is preferable to use the alcohol, in particular methanol or ethanol as solvent.

The reaction may proceed in a wide limit temperature, while the temperature of the reaction is not critical in the present invention. Found that the reaction is conveniently carried out at temperatures from 0 to 150aboutS, more preferably from 0 to 50aboutC. the Time required for the reaction can also vary depending on many factors, particularly the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out under these conditions is usually sufficient period of time from 30 min to 48 h, more preferably from 1 to 30 PM

After m For example, one suitable sequence extracting the reaction mixture is freed from solvent by distillation or poured into water and extracted with water-immiscible organic solvent. Then the extract was dried and the solvent is removed by distillation. If necessary, the target compound can be further purified by usual method, for example by recrystallization or the various chromatography methods, especially column chromatography.

In stage B2 of the reaction scheme, the compounds of formula (I), where R3a hydrogen atom, and the relationship represented by the symbol-is the carbon-carbon double bond, i.e. compounds of formula (Ig) can be obtained if necessary. This reaction is the same as the reaction described in stage A2 scheme of the reaction and can be carried out using the same reagents and under the same conditions.

The compound of formula (Id) or (Ie) (reaction scheme A) can be obtained according to the method described in reaction scheme B, but replacing peregrinae compound of formula (VIa) or (VIb) to the corresponding isoindoline connection formulas

where R4, R8a, R8band R8cdefined above.

Connection fistulae microarthropod (-ONO2), i.e. compounds of the formula

O2(Ih) where R1and R2defined above, can be obtained by reaction of the corresponding compounds of formula (I). where R3represents a hydroxy-group, which can be obtained by the schemes of reactions a and b, for example the compounds of formula (Id) or (If), with nitrous reagent.

Reaction with nitrous reagent is normally and preferably carried out in the presence of an inert solvent.

There is no particular restriction on the nature of the employed solvent, provided that it has no adverse effect on the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, dichloroethane, carbon tetrachloride from chloroform, ethers, such as diethyl ether, dimethoxyethane or tetrahydrofuran, hydrocarbons, particularly aliphatic hydrocarbons, such as hexane or heptane. Of them, preferred are halogenated aliphatic hydrocarbons.

Examples nitrous reagents, kotv>2BF4), hexaflurophosphate nitronium (NO2PF6or triftorbyenzola nitronium (NO2CF3SO3), and the nitric acid. Of them, preferred are salts of nitronium.

The reaction may proceed in a wide limit temperature, a reaction temperature is not crucial at a temperature of from 0 to 100aboutS, more preferably from 10 to 50aboutC. the Time required for the reaction can be varied widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out under these conditions, it is usually enough period of time from 10 min to 10 h, more preferably from 20 minutes to 3 hours

After completion of the reaction, the target compound of the invention can be extracted from the reaction mixture by usual method. For example, one method of extracting the reaction mixture is freed from solvent by distillation, or it is poured into water and extracted with water-immiscible organic solvent. Then the extract was dried and the solvent is removed by distillation. If necessary, the resulting residue can be further purified by usual method, for example PU is

In the compounds of formula (I), where the relationship represented by the symbol-is the carbon-carbon simple connection, the connection may be formed of optically active isomers. In this case, the optically active isomer can be obtained by using optically active compounds of the formula (IIa). Optically active compound of the formula (IIa) can be obtained from the racemate using a conventional method, for example by processing racemate compounds of the formula (II) optically active carboxylic acid [for example, (+)- or (-)-tartaric acid, (+)- or (-)-dibenzoyltartaric acid, (-)-malic acid or (-)-almond acid] or optically active sulfonic acid (for example, camphorsulfonic acid), followed by recrystallization of the resulting salt.

If necessary, pharmaceutically acceptable salt of the compounds of formula (I) can be obtained by treating the free acid compound with a suitable base, such as hydroxide of alkali metal such as sodium hydroxide or potassium hydroxide, or an organic amine such as triethylamine or pyridine, in the presence of an inert solvent, for example dioxane, tetrahydrofuran or diethyl ether in a suitable, rastvoritelei and, can easily be obtained from a conventional method, for example, as shown in the schemes of reactions D, E and F (see Fig. 3-5).

In the above formulas, R1is the same as defined above, and R9is aracelio group in which the alkyl portion has 1-4 carbon atoms and is substituted by one or more aryl groups, preferably with from 1 to 3 of such groups.

Aryl groups are carbocyclic aryl groups having 6-10, preferably 6-10, most preferably 6, carbon atoms substituted or unsubstituted.

Kalkilya group represented by R9is preferably a substituted or unsubstituted benzyl, diphenylmethylene (benzhydryl), triphenylmethyl (trailvoy), fenetylline, 1-phenylethylene, 2-phenylpropanol or 3-phenylpropionic group, more preferably benzene, methoxybenzene, diphenylmethylene or triphenyl - tilen group.

The reaction scheme D.

In stage D1 reaction scheme D aralkylamines formula (VIII) can be obtained by treating 4-mercaptoethanol, which has the formula (VII), alkali metal hydride such as sodium hydride, in an inert solvent, for example amide, this is and alkali metal with the compound of the formula

R9-X', (XIX) where R9defined above; X' is a halogen atom. The reaction preferably proceeds at a temperature of from 0aboutWith up to room temperature and requires a period of time from 30 min to 5 h

In stage D2 reaction scheme D, the compound of formula (IX) can be obtained by reaction of compounds of formula (VIII) with the compound of the formula

C CH (XX) where X' is defined above, in an inert solvent, e.g. a ketone, such as acetone or methyl ethyl ketone, an alcohol, such as methanol or ethanol, or a mixture of any two or more of these solvents, in the presence of a base such as a carbonate of an alkali metal such as sodium carbonate or potassium carbonate. The reaction preferably proceeds at 50-100aboutWith and usually requires a period of time from 10 to 60 hours If necessary, iodine compounds, such as potassium iodide, sodium iodide or etc., may be present in the reaction mixture.

In stage D3 reaction scheme D pernovae compound of formula (X) can be obtained by treating compounds of formula (IX) with 100-200aboutC for 1-5 h in an inert solvent, for example an aromatic hydrocarbon, such as toluene, chlorobenzene, dichlorobenzene or xylene.

In stage D4 reaction scheme D mercaptoethane is whether the acetate of mercury, in an inert solvent, for example water, organic carboxylic acid, such as aqueous acetic acid. The reaction preferably proceeds at 0-50aboutWith and usually requires a period of time from 30 minutes to 2 hours the Resulting salt of mercury is then subjected to reaction with hydrogen sulfide or with pre - owner of hydrogen sulfide such as sodium sulfide/hydrochloric acid. The reaction preferably proceeds at 0-50aboutC for from 10 min to 1 hour In the first of these stages, if necessary, the reaction mixture may also be present cationic stabilizers, such as anisole.

In stage D5 reaction scheme D, the compound of formula (XII) can be obtained by reaction of compounds of formula (XI) with the compound of the formula

R1-X', (XXI) where R1and X' are defined above, in an inert solvent, for example amide, such as dimethylformamide, or simply ether, such as tetrahydrofuran, in the presence of a base, for example alkali metal hydride such as sodium hydride, alcida alkali metal, such as tertbutoxide potassium, or organic amine such as triethylamine. The reaction preferably proceeds at 0-50aboutC for 2-10 h on the other hand, the reaction with the compound of the formula (XXI) in which R1aboutWith up to room temperature, and preferably for 1-10 hours

In stage D6 reaction scheme D, the compound of formula (IVa), which can be one of the target source substances for use in obtaining the compounds of the present invention, can be obtained by reaction of compounds of formula (XII) with an oxidant such as peroxide, such as 3-chlormadinone acid, peracetic acid or hydrogen peroxide, in an inert solvent such as halogenated hydrocarbon, such as methylene chloride or dichloroethane. The reaction preferably proceeds at 0-50aboutC for from 30 minutes to 3 hours In this reaction, the target compound of formula (IVa) is preferably obtained using about 3 mol or more of oxidant per mole of the compounds of formula (XII).

In stage D7 reaction scheme D, the compound of formula (IIa) can be obtained by the reaction of compounds of formula (IVa) c water ammonia or ethanol solution containing ammonia, LASS="ptx2">

The reaction scheme E.

The reaction scheme E shows an alternative method of obtaining the compounds of formula (XII) obtained in stage D5 reaction scheme D.

In stage E1, the reaction scheme E thiophenol formula (VII) is subjected to reaction with the compound of the formula (XXI) according to the method described in stage D5 reaction scheme D, to obtain the compound of formula (XIII).

In stage E2 reaction scheme E, the compound of formula (XIV) can be obtained by reaction of compounds of formula (XIII) with the compound of the formula (XX) according to the method described in stage D2 reaction scheme D.

In stage E3 reaction scheme E, the compound of formula (XII) can be obtained by reaction of compounds of formula (XIV) according to the method described in stage D3 reaction scheme D.

The reaction scheme F.

The reaction scheme F shows an alternative method of obtaining the compounds of formula (IVa), which is one of the starting substances which can be used in the method of the present invention, to obtain the proposed connection.

In stage F1 reaction scheme F, the compound of formula (XIV) can be obtained by reaction of compounds of formula (XV) with the compound of the formula

R1SO2-X' (XXII) where R1and X' are defined above, in an inert solvent, n is Aramean or nitrobenzene, and in the presence of a Lewis acid such as aluminum oxide or ferric chloride (3). The reaction preferably proceeds at 0-50aboutC for from 30 minutes to 24 hours

In stage F2 reaction scheme F, the compound of formula (XVII) can be obtained by reaction of compounds of formula (XVI) with a reducing agent such as sodium borohydride or sociallyengaged, in an inert solvent, for example methanol, aqueous ethanol, diethyl ether or tetrahydrofuran. The reaction preferably proceeds at 0-40aboutC for 0.5 to 3 hours

In stage F3 reaction scheme F, the compound of formula (XVIII) can be obtained by reaction of compounds of formula (XVII) with a dehydrating reagent, such as pyridine/phosphorus oxychloride, pyridine/chlorine - risty tional or paratoluenesulfonyl acid, preferably in an inert solvent, for example pyridine or benzene. The reaction preferably proceeds at a temperature of from -10 to 150aboutC for 0.5 to 3 hours

In stage F4 reaction scheme F, the compound of formula (IVa) can be obtained by reaction of compounds of formula (XVIII) according to the method described in stage D6 reaction scheme D, followed by the oxidation reaction.

After completing any of these reactions the target compounds obtained by rlineto extraction solvent Argonauts from the reaction mixture or the reaction mixture is poured into water, extracted with water-immiscible organic solvent and dried, after which the solvent Argonauts. The resulting residue, if necessary, may be further purified in the usual way, for example by recrystallization or the various chromatography methods, especially column chromatography.

Compounds of the present invention have excellent vasodilator activity, as shown in the following example tests. Thus, the compounds of the invention are useful for the prevention and treatment of a wide range of disorders for which this activity is usually indicated, including the following diseases and disorders:

hypertension, congestive heart failure, angina (angina pectoris);

reversible obstruction of the Airways, asthma;

peptic ulcer;

local alopecia (baldness);

incontinence (incontinence),

in particular for the treatment of cardiovascular diseases.

P R I m e R tests. Vasodilator activity.

The rat was put to death by exsanguination. The thoracic aorta was immediately cut. Then remove connective tissue and fat to dawat spiral narrow strips. The drug is suspended in the tube and Magnus after the drug is stable, add phenylephrine (1 x 10-6M), to cause contraction of the blood vessels. When the drug reaches steady state, the sample containing the test compound, is used collectively to observe the response of relaxation (relaxing) reaction. When the response reaches a maximum, add 10-4M papaverine and the resulting induced response is taken for 100% Experiment is carried out using each test compound at multiple doses. The magnitude of relaxation achieved at each dose (mol/l) was measured and the concentration of the test compound, indicates a 30% relaxation (IC30mol/l) is calculated.

In each trial as a control connections use Cromakalim and 3,3-dihydro-2,2-dimethyl-6-Cryptor - methylsulphonyl-4- (2-oxo-1-pyrrolidinyl)-2H-1-benzopyran-3-ol. Relative activity is shown in table. 3, where the formations of the invention are identified by numbers of examples that are shown below.

Compounds of the present invention exhibit potent anti-hypertensive effect. They also parasparam) in vivo spontaneously (spontaneous) hypertensive rats.

Compounds of the present invention can be used for the prevention and treatment of cardiovascular and other disorders, including hypertension. To this end, they can be used, if required, in a mixture with other active compounds and/or with conventional carriers, diluents, adjuvants (AIDS in the preparation of dosage forms) and/or fillers, to form a pharmaceutical drug. In addition, they can be assigned to receive no additives. The pharmaceutical form of the drug depends on the way of admission (entry), for example, for oral administration the compounds can be prepared in the form of powders, granules, syrups, tablets or capsules, for parenteral administration they may be included in the composition in the form of injection or inhalation. Though the dosage can vary depending on the symptoms of the patient, nature and severity of the disease or disorders, and ways and a way of introduction, in the case of oral administration the compounds can usually be assigned to a daily dose of 0.1 to 500 mg, in particular from 0.2 to 100 mg, and in the case of intravenous administration at a daily dose of 0.02-100 mg, in particular 0.1 to 30 mg Compounds may be assigned in a single dose or in small sponding examples.

P R I m e R 1. TRANS-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2 dimethyl - 6-trifloromethyl-2H-1-benzopyran-3-ol (compound 1-24).

< / BR>
To a solution of 1 g of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifloromethyl - 2H-1-benzopyran (obtained as described in example obtain 8) in 1.2 ml of anhydrous tetrahydrofuran added 1.63 g of 2-trimethylsilylacetamide, a solution of 2.54 g), tetrabutylammonium fluoride in anhydrous tetrahydrofuran is added to the resulting mixture with a syringe, cooling while ice and in nitrogen atmosphere. The reaction mixture was stirred at room temperature for 72 h, after which it was poured into water and extracted with ethyl acetate. Then the extract is washed with water, 5% aqueous solution of hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, after which it is dried over anhydrous magnesium sulfate. Next, the solvent is removed by distillation under reduced pressure. The resulting residue is purified by column chromatography through silica gel, using 2: 1 by volume mixture of ethyl acetate and cyclohexane as eluent to obtain 503 mg of the compounds in the form of an approximately 1:1 mixture of rotational isomers, plrpose) M. D.

1,24 (3/2H, singlet);

1,32 (3/2H, singlet);

1,47 (3/2H, singlet);

1.52m (3/2H, singlet);

as 4.02-4,13 (1/2H, multiplet);

to 4.38-4,47 (1/2H, multiplet);

5,07 (1/2H, doublet, j=10 Hz);

5,95 (1H, doublet, j=6 Hz);

6,55 /1/2H, doublet, j=10 Hz);

6,1-6,4 /2H, multiplet);

7,0-7,9 (5H, multiplet).

Infrared absorption spectrum (KBr)maxcm-1:

3270, 1663, 1580.

P R I m m e R 2. TRANS-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl) -2,2-dimethyl-6-trifloromethyl-2H-1-benzopyran-3-ol (compound 1-24).

To a suspension of 48 mg of sodium hydride (as a 55 wt. dispersion in oil) in anhydrous dimethyl sulfoxide is added 105 mg of 2-hydroxypyridine; the resulting mixture is stirred at room temperature for 15 minutes By the end of this time to the mixture under nitrogen atmosphere and at room temperature 309 mg of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifluoromethyl-sulfonyl - 2H-1-benzopyran (obtained as described in example obtain 8). The mixture is then stirred at room temperature for 24 h, after which it was poured into water and extracted with ethyl acetate. The extract is washed with water and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After that Rast is matography through silica gel, using a 3:1 by volume mixture of ethyl acetate and cyclohexane as eluent, to obtain 95 mg of the compounds.

The spectra of nuclear magnetic resonance and infrared absorption thus obtained compound is identical to example 1.

P R I m e R 3. 2,2-Dimethyl-4-(1-occaisonaly-2-yl)-6 - trifloromethyl-2H-1-benzopyran (compound 2-1).

F3CSO2

To a solution of 200 g of TRANS-3,4-dihydro-2,2-dimethyl-4-(1-occaisonaly-2-yl)-6 - trifloromethyl-2H-1-benzopyran-3 - ol (obtained as described in example obtain (13) in 6 ml of dioxane is added 200 mg soda talc (catalogue Measurement N 1567). The resulting mixture is stirred for 30 minutes, heating it while its in the oil bath, supported 140aboutC. the Reaction mixture is cooled, and then freed from insoluble substances by filtration. Next, the solvent is removed by distillation under reduced pressure. The residue is dissolved in 20 ml of methylene chloride, and the resulting solution washed with water and saturated aqueous sodium chloride. The solution is dried over anhydrous magnesium sulfate, and then under reduced pressure by distillation to remove the solvent. The oily residue obtained is when I 110-115aboutC.

Spectrum of nuclear magnetic resonance (CDCl3) memorial plaques

1,61 (6N: singlet);

the 4.65 (2H, singlet);

of 5.89 (1H, singlet);

7,07 (1H, doublet, j=8 Hz);

of 7.5 to 7.7 (4H, multiplet);

of 7.82 (1H, doublet of doublets, j=2 and 8 Hz);

7,94 (1H, doublet, j=8 Hz).

Infrared absorption spectrum (KBr)maxcm-1:

1690.

Mass spectrum (m/e): 432 (M+).

P R I m e R 4. TRANS-6-heptafluoropropyl-3,4-Ligero-2,2-dimethyl-4-(1-occaisonaly-2-yl)-2H-1-benzopyran-3-ol (compound 1-3).

F7C3SO2

The solution 0,142 g of zinc chloride and 0,065 g cyanoborohydride of sodium in 3 ml of methanol are added to a solution of 0.40 TRANS-4-amino-6-heptafluoropropyl-3,4 - dihydro-2,2-dimethyl - 2H-1-benzopyran-3-ol (obtained as described in example 4) and 0.156 g of methyl ester of 2-formylbenzoate acid in 6 ml of methanol. The resulting mixture was stirred at room temperature for 1 h and then at 50aboutWith within 24 hours By the end of this time the mixture is cooled with ice, and then mixed with a saturated aqueous solution of sodium bicarbonate. Then removed by distillation of the methanol under reduced pressure and the resulting residue diluted with water which I dried over anhydrous magnesium sulfate, then the solvent is removed by distillation under reduced pressure. The resulting residue is recrystallized from ethyl acetate to obtain 0,356 g of the indicated compound, melting at 241-249aboutC. an NMR Spectrum (hexadeuterated dimethyl sulfoxide) M. D.

of 1.32 (3H, singlet);

and 1.54 (3H, singlet);

3,9-4,2 (2H, multiplet);

4,59 (1H, doublet, j=17 Hz);

5,32 (1H, broadened singlet);

5,98 (1H, doublet, j=6 Hz);

from 7.24 (1H, doublet, j=9 Hz);

7,37 (1H, broadened singlet);

of 7.5 to 7.7 (3H, multiplet);

7,80 (1H, doublet, j=7 Hz);

7,89 (1H, doublet of doublets, j=2 and 9 Hz).

IR absorption spectrum (KBr)maxcm-1: 3478, 1667.

Mass spectrum (m/e): 541 (M+).

P R I m e R 5. 6-Heptafluoropropyl-2,2-dimethyl-4-(1-occaisonaly-2-yl) -2H-1-benzopyran (compound 2-3).

F7C3SO2

Following the example 3, but using 100 mg of TRANS-6-heptafluoropropyl-3,4-dihydro-2,2-dimethyl-4-(1-occaisonaly-2-yl)-2H-1-benzopyran-3-ol (obtained as described in example 4) and 100 mg soda talc, receive 30 mg of the indicated compound, melting at 164-166aboutC. an NMR Spectrum (CDCl3) memorial plaques

1,61 (6N, with whom 82 (1H, doublet of doublets, j=2 and 9 Hz);

of 7.95 (1H, doublet, j=7 Hz).

IR absorption spectrum (KBr)maxcm-1: 1686.

Mass spectrum (m/e): 523 (M+).

P R I m e R 6. TRANS-4-(1,2-dihydro-2-OK-with-1-pyridyl)-2,2-dimethyl-6 - trifloromethyl-2H-1-benzopyran (compound 2-11).

F3CSO2

Following the example 3, but using 406 mg of TRANS-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-6-trifloromethyl-2H-1-benzopyran-3-ol (obtained as described in example 1) and 406 mg soda talc (catalogue Measurement N 1657), obtain 124 mg of the indicated compound, melting at 214-215aboutC.

An NMR spectrum (CDCl3) memorial plaques

to 1.60 (3H, singlet);

to 1.67 (3H, singlet);

5,86 (1H, singlet);

6,28 (1H, doublet, triplet, j=1 and 7 Hz);

of 6.66 (1H, doublet, j=9 Hz);

7,06 (1H, doublet, j=9 Hz);

to 7.15 (1H, doublet of doublets, j=2 and 7 Hz);

7,27 (1H, doublet, j=2 Hz);

7,46 (1H, multiplet);

of 7.82 (1H, doublet of doublets, j= 2 and 9 Hz).

Mass spectrum (m/e): 385 (M+).

P R I m e R 7. TRANS-3,4-dihydro-2,2-dimethyl-4-(1-occaisonaly-2-yl)- 6-trifloromethyl-2H-1-benzopyran-3-yl nitrate (compound 1-5).

F3CSO2

To a solution of 300 mg of TRANS-3,4-dihydro-2,2-dimethyl-Lucene 13) in 5 ml of methylene chloride added 116 mg tetrafluoroborate nitronium and the resulting mixture was stirred at room temperature for 1.5 hours By the end of this time the reaction mixture was diluted with 20 ml of water and extracted with 15 ml of methylene chloride. The extract is washed with water and saturated aqueous sodium chloride, after which it is dried over anhydrous magnesium sulfate. Then the solvent is removed by distillation under reduced pressure and the resulting residue purified by column chromatography through silica gel, using 1:4 by volume mixture of ethyl acetate and cyclohexane as eluent to obtain 88 mg of the compounds in the form of crystals, melting at 189,5-190aboutC.

Range-NMR (CDCl3) memorial plaques

to 1.48 (3H, singlet);

to 1.61 (3H, singlet);

4,06 (1H, doublet, j=17 Hz);

to 4.33 (1H, doublet, j=17 Hz);

5,54 (1H, doublet, j=10 Hz);

of 5.92 (1H, doublet, j=10 Hz);

7,17 (1H, doublet, j=9 Hz);

of 7.4 and 7.6 (4H, multiplet);

7,8-8,0 (2H, multiplet).

Mass spectrum (m/e): 440 (M+NO2), 423 (M+HNO3).

P R I m e R 8. TRANS-3,4-dihydro-4-(1,2-dihydro-3-methyl-2-oxo-1-pyridyl)- 2,2-di - methyl-6-trifloromethyl-2H-1-benzopyran-3-ol (compound 1-41).

F3CSO2< / BR>
To a solution of 200 mg of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6 - trifloromethyl-2H-1-benzopyran (obtained as described in PR is localdata mixture then add a solution of 509 mg of fluoride tetrabutylammonium in anhydrous tetrahydrofuran, cooling when the ice and in nitrogen atmosphere. Then the reaction mixture was stirred at room temperature for 5 days, after which it is treated in the same manner as in example 1. Next, the reaction product is purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and cyclohexane as eluent to obtain 135 mg of the indicated compound, melting at 215-216aboutC. an NMR Spectrum (CDCl3) memorial plaques

of 1.41 (3H, singlet);

was 1.58 (3H, singlet);

1,0-2,2 (1H, broadened singlet);

of 2.24 (3H, singlet);

3,88 (1H, doublet, j=10 Hz);

to 6.19 (1H, triplet, j=7 Hz);

6,48 (1H, doublet, j=10 Hz);

of 6.71 (1H, doublet, j=7 Hz);

7,14 (1H, doublet, j=9 Hz);

7,28 (1H, doublet, j=7 Hz);

7,46 (1H, broadened singlet);

7,87 (1H, doublet of doublets, j=2 and 9 Hz).

IR absorption spectrum (KBr)maxcm-1:

3324, 1652, 1590, 1361.

Mass spectrum (m/e): 418 (M++1).

P R I m e R 9. TRANS-3,4-dihydro-4-(1,2-dihydro-3-methoxy-2-oxo-1-pyridyl)- 2,2-dimethyl-6-trifloromethyl-2H-1-benzopyran-3-ol (compound 1-42).

< / BR>
To a suspension of 38 mg of sodium hydride (55% dispersion in oil) in 3 ml of dimethyl sulfoxide added 98 mg of 3-methoxy-2(1H)-pyridone. The resulting Sigita-2,2-dimethyl-6 - trifloromethyl-2H-1-benzopyran (obtained, as described in the example of obtaining 8) in 1.5 ml dimethylsulfoxide at the same temperature and in a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 bottoms, after which it is treated in the same manner as described in example 2. Then the reaction product is purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and cyclohexane as eluent, to obtain 16 mg of the indicated compound, melting at 223-225aboutC.

The NMR spectrum (CDCl3) memorial plaques

of 1.42 (3H, singlet);

was 1.58 (3H, singlet);

of 3.75 (1H, doublet, j=5 Hz);

3,88 (1H, doublet of doublets, j=5 and 10 Hz);

are 3.90 (3H, singlet);

of 6.20 (1H, triplet, j=7 Hz);

to 6.43 (1H, doublet of doublets, j=1.5 and 7 Hz);

of 6.50 (1H, doublet, j=10 Hz);

6,69 (1H, doublet of doublets, j=1.5 and 7 Hz);

7,13 (1H, doublet, j=9 Hz);

was 7.45 (1H, broadened singlet);

7,86 (1H, doublet of doublets, j=2 and 9 Hz).

IR absorption spectrum (KBr),maxcm-1:

3312, 1655, 1603, 1371.

P R I m e R 10. TRANS-3,4-dihydro-2,2-dimethyl-4-(6-nitro-1-occaisonaly-2-yl) -6-trifloromethyl-2H-1-benzop-ran-3-ol (compound 1-15).

The solution 0,164 g of zinc chloride and 0.075 g of cyanoborohydride sodium in 3.3 ml of propanol is added to p is about so hydrochloride, as described in the example of a 9, and 0,224 g of methyl ester of 2-formyl-5-nitrobenzoic acid in 3.3 ml of propanol. The resulting mixture is heated at the boiling reverse drains phlegmy in an oil bath maintained during 140aboutC for 1.5 hours then the reaction mixture is diluted with 150 ml of ethyl acetate, the resulting solution washed with 1 N. aqueous solution of hydrochloric acid, water, saturated sodium hydrogen carbonate solution and saturated aqueous sodium chloride. The mixture is then dried over anhydrous sodium sulfate, then the solvent is removed by distillation under reduced pressure. The resulting residue is recrystallized from a mixture of ethyl acetate and hexane to obtain 0,424 g of the indicated compound, melting at 264-266aboutC. the NMR spectrum (hexadeuterated dimethyl sulfoxide), M. D.

of 1.34 (3H, singlet);

and 1.54 (3H, singlet);

3,86-4,24 (1H, multiplet);

4.26 deaths (1H, doublet, j=20 Hz);

4,84 (1H, doublet, j=20 Hz);

5,38 (1H, doublet, j=10 Hz);

5,86-6,16 (1H, multiplet);

7,14 (1H, doublet, j=10 Hz);

7,46-of 7.60 (2H, multiplet);

7,80-to 8.14 (2H, multiplet);

8,44-a total of 8.74 (2H, multiplet).

IR absorption spectrum (KBr),maxcm-1:

3300, 1680.

Mass spectrum (m/e)With 49,38, N 3,52, N 5,76, F 11,72, S 6,59.

Found, C 49,78, H 3,84, N 5,38, Of 11.69 F, S 6,74.

P R I m e R 11. TRANS-3,4-dihydro-2,2-dimethyl-4-(7-nitro-1-occaisonaly-yl) -6-trifloromethyl-2H-1-benzopyran-3-ol (compound 1-14).

Following the example 10, but using 0,326 g of TRANS-4-amino-3,4-dihydro-2,2-dimethyl-6-trifloromethyl - 2H-1-benzopyran-3-ol, obtained from its hydrochloride by the example of obtaining 9, 0,244 g of methyl ester of 2-formyl-6-nitrobenzoic acid, 0,164 g of zinc chloride and 0.075 g of cyanoborohydride sodium, receive 0,391 g of the indicated compound, melting at 283-284aboutC.

NMR-spectrum (hexadeuterated dimethyl sulfoxide), M. D.

of 1.34 (3H, singlet);

and 1.54 (3H, singlet);

of 3.46 (1H, broadened singlet);

as 4.02 (1H, doublet, j=10 Hz);

4,22 (1H, doublet, j=18 Hz);

was 4.76 (1H, doublet, j=18 Hz);

of 5.34 (1H, doublet, j=10 Hz);

7,29 (1H, doublet, j=8 Hz);

7,46 to 7.62 (1H, multiplet);

7,76-8,02 (4H, multiplet).

IR absorption spectrum (KBr),maxcm-1:

3440, 1670.

Mass spectrum (m/e): 486 (M+).

Elementary analysis. C20H17F3N2O7S:

Calculated C 49,39, H 3.52, The N 5,76, F 11,72, S 6,59.

Found, C 49,43, H 3,50, N 5,58, F 11,59, S 6,58.

P R I m e R 12. Tran).

To a solution of 0,367 g of ethyl ester of 2-bromomethyl-3-nitrobenzoic acid in 7.4 ml of dimethylformamide add 0,362 g of TRANS-4-amino-3,4-dihydro-2,2-dimethyl-6-trifloromethyl-2H - 1-benzopyran-3-ol, obtained from its hydrochloride by example get 9, and 0.30 ml of triethylamine. The resulting mixture was stirred at 100aboutC for 1 h in nitrogen atmosphere. Then the reaction mixture is stirred at the boiling reverse drains phlegmy solvent (152aboutC) for an additional 1 h, after which the mixture is poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. Then the extract is washed with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, after which it is dried over anhydrous sodium sulfate. Next, the solvent is removed by distillation under reduced pressure and the residue purified by column chromatography through silica gel, using 1:1:1 by volume mixture of ethyl acetate, cyclohexane and tetrahydrofuran as eluent. The reaction product obtained from the eluent, and recrystallized from a mixture of tetrahydrofuran and hexane to obtain 0,295 g of the indicated compound, melting at 292-295aboutC.

NMR spectable doublets, I=6 and 10 Hz);

4,58 (1H, doublet, j=18 Hz);

by 5.18 (1H, doublet, j=18 Hz);

5,38 (1H, doublet, j=10 Hz;

of 5.92 (1H, doublet, j=6 Hz);

7,22 (1H, doublet, j=8 Hz);

of 7.48-to 7.64 (1H, multiplet);

7,74-of 8.06 (2H, multiplet);

of 8.28 (1H, doublet, j=8 Hz);

8,54 (1H, doublet of doublets, j=2 and 8 Hz).

IR absorption spectrum (KBr),maxcm-1:

3460, 1676.

Mass spectrum (m/e): 468 (M+-18).

Elementary analysis. C20H17F3N2O7S:

Calculated C 49,39, H 3.52, The N 5,76, F 11,72, S 6,59.

Found, C 49,49, H 3,69, N 5,72, Of 11.69 F, S 6,58.

P R I m e p 13. TRANS-4-(4-fluoro-1-occaisonaly-2-yl)-3,4-dihydro-2,2-dimethyl-6 - trifloromethyl-2H-1-benzopyran-3-ol (compound 1-16).

Following the example 12, but using 0,272 g of methyl ester of 2-bromomethyl-3-fermenting acid, 0,326 g of TRANS-4-amino-3,4-dihydro-2,2-dimethyl-6-trifluoromethyl-sulfonyl-2H-1 - benzopyran-3-ol and 0.15 ml of triethylamine, obtained after purification using column chromatography through silica gel, using 1:1 by volume mixture of cyclohexane and ethyl acetate as eluent, 0,294 g of the indicated compound, melting at 259-261aboutAfter paracrystal - implementation from a mixture of ethyl acetate and hexane.

NMR-spectrum (hexadeuterated dime the years, I=18 Hz);

was 4.76 (1H, doublet, j=18 Hz);

are 5.36 (1H, doublet, j=10 Hz);

5,90 (1H, broadened singlet);

then 7.20 (1H, doublet, j=8 Hz);

of 7.36-8,02 (5H, multiplet).

IR absorption spectrum (KBr),maxcm-1:

3460, 1670.

Mass spectrum (m/e): 460 (M++1).

Elementary analysis. C20H17F4NO5S:

Calculated C 52,29, H Of 3.73, N 3,05, F 16,54, S 6,98.

Found, C 52,29, H 3,88, N 3,05, F Value Of 16,81, S 7,30.

P R I m e R a 1. 4-(Heptafluoropropyl)-thiophenol.

To a suspension of 2.4 g of sodium hydride (55% dispersion in oil) in 64 ml of dimethylformamide in a nitrogen atmosphere while cooling with ice add to 3.16 g of 4-hydroxythiophenol and the resulting mixture is stirred for 15 minutes Then added to the mixture of 3.6 ml heptafluoropropyl-1-iodide and the mixture was stirred at room temperature for 5 hours By the end of this time the reaction mixture is poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, saturated aqueous sodium hydrogen carbonate and an aqueous solution of sodium chloride, after which the solvent is removed under reduced pressure. The resulting residue cleans using column chromatography through silica gel, and is inane.

The NMR spectrum (CDCl3) memorial plaques

by 5.87 (1H, broadened singlet);

6,85 (2H, doublet, j=9 Hz);

7,52 (2H, doublet, j=9 Hz).

Mass spectrum (m/e): 294 (M+).

P R I m e R get 2. 6-(Heptafluoropropyl)-2,2-dimethyl-2H-1-benzopyran.

To the 10.8 ml of an aqueous solution containing 0,72 g of sodium hydroxide, add 11 ml of dioxane solution of 3.4 g of 4-(heptafluoropropyl)-thiophenol, obtained as described in example obtain 1), 1.85 g of 3-chloro-3-methyl-1-butyne and 2.50 g of 40 wt. an aqueous solution of hydroxide, trimethyl - benzylamine. The resulting mixture is heated at the boiling reverse drains phlegmy within 15 hours After the reaction mixture was poured into water and extracted with ethyl acetate. The extract is washed with diluted aqueous sodium hydroxide solution, water, dilute aqueous hydrochloric acid, and saturated aqueous sodium chloride, after which it is dried over anhydrous sodium sulfate. Then the solvent is removed by distillation under reduced pressure, to obtain 3,81 g of an oily material as the remainder. All of this is dissolved in 16 ml of dichlorobenzene and the resulting solution is heated at the boiling reverse drains phlegmy for 2 h in nitrogen atmosphere. Then RA is using column chromatography through silica gel, using cyclohexane as eluent, to obtain a rate of 1.67 g of the specified connection.

The NMR spectrum (CDCl3) memorial plaques

1,42 (6N, singlet);

5,64 (1H, doublet, j=10 Hz);

6,30 (1H, doublet, j=10 Hz);

7,20-7,46 (2H, multiplet);

is 6.78 (1H, doublet, j=9 Hz).

P R I m e R getting 3. 3,4-Epoxy-6-heptafluoropropyl-3,4-dihydro-2, 2-dimethyl-2H - 1-benzopyran.

To a solution of 1.65 g of 6-heptafluoropropyl-2,2-dimethyl-2H-1-benzopyran, obtained as described in example getting 2 in 33 ml of methylene chloride added and 2.79 g of 3-chlormadinone acid (85% purity). The resulting mixture was stirred at room temperature for 1.5 hours then the reaction mixture was diluted with ethyl acetate, and then washed with 1 N. aqueous solution of sodium hydroxide, water and saturated aqueous sodium chloride. RAS solution is dried over anhydrous sodium sulfate, and then the residue obtained by distillation of the solvent under reduced pressure, purified by column chromatography through silica gel, using a 5:1 by volume mixture of cyclohexane and ethyl acetate as eluent to obtain 1,21 g the specified connection.

The NMR spectrum (CDCl3) memorial plaques

of 1.32 (3H, singlet);


with 8.05 (1H, doublet, j=2 Hz).

IR absorption spectrum (liquid film)maxcm-1:

1330, 1100.

Mass spectrum (m/e): 408 (M+).

P R I m e R 4. TRANS-4-amino-6-heptafluoropropyl-3,4-dihydro-2,2-dimethyl - 2H-1-benzopyran-3-ol.

To a solution of 1,086 g of 3,4-epoxy-6-heptafluoropropyl-3,4-dihydro-2,2-dimethyl-2H-1 - benzopyran, obtained as described in example getting 3 in 30 ml ethanol add 30 ml (about 28.) aqueous ammonia and the resulting mixture is left to stand at room temperature for 3 days. By the end of this time the reaction mixture was poured into water and extracted with methylene chloride. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, and then the resulting residue purified by column chromatography through silica gel, using 1: 1 by volume mixture of cyclohexane and ethyl acetate as eluent Fractions containing the target compound, then recrystallized from a mixture of ethyl acetate and hexane, to obtain coefficient was 0.796 g of the indicated compound, melting at 186-177aboutC.

The NMR spectrum (CDCl3) memorial plaques

of 1.26 (3H, singlet);

1,54 (3 is, =8 Hz);

7,80 (1H, doublet of doublets, j=8 and 2 Hz);

to 8.12 (1H, doublet, j=2 Hz).

IR absorption spectrum (KBr)maxcm-1: 3140.

Mass spectrum (m/e): 426 (M++1).

Elementary analysis. C14H14F7NO4S:

Calculated, C 39, 54, H 3,32, N 3,29, F 31,27, S 7,54.

Found, C 39,85, H 3,51, N 3,26, F 31,23, S 7,33.

P R I m e R get 5. 6-(4-Methoxybenzylthio)-2,2-dimethyl-2H-1-benzopyran.

5 (a) 4-(4-Methoxybenzylthio)-phenol.

The solution 50,47 g parahydroxybenzoate in 250 ml of tetrahydrofuran is added to a suspension of 38.4 g of sodium hydride (55% dispersion in oil) in 380 ml of dimethylformamide while cooling with this ice and adding in a nitrogen atmosphere. The resulting mixture is stirred for 0.5 hours then the solution is 54.2 ml chloride parametersbodily in 120 ml of tetrahydrofuran is added dropwise to the resulting mixture, which was then stirred for 1 h Then the reaction mixture was neutralized by adding acetic acid, cooling the thus ice, after which it was poured into water. The mixture is extracted with ethyl acetate and the extract washed with water and saturated aqueous sodium chloride. Then the resulting solution is dried, remove the solvent peregonka is:3 by volume mixture of cyclohexane and tetrahydrofuran as eluent. Suirvey the reaction product is recrystallized from a mixture of tetrahydrofuran and hexane to obtain 88,99 g the specified connection.

IR absorption spectrum (Nujol, trade name),maxcm-1:

3380, 1450, 1250.

5 (b) 6-(4-Methoxybenzylthio)-2,2-dimethyl-2H-1-benzopyran.

The solution 73,84 g of 3-chloro-3-methyl-1-butyne in 225 ml of methanol, 11,95 g of potassium iodide and 99,50 g of potassium carbonate is added to the whole amount of 4-(4-Etxeberria)-phenol (obtained as described in stage a), in 0.9 l of methyl ethyl ketone. The resulting mixture is heated at the boiling reverse drains phlegmy for 40 h under nitrogen atmosphere. By the end of this time the reaction mixture was extracted with ethyl acetate and the extract washed with water and saturated aqueous sodium chloride. Then it is dried over anhydrous sodium sulfate, then the solvent is removed by distillation under reduced pressure. The residue is purified by column chromatography through silica gel, using a 5: 1 mixture by volume of cyclohexane and ethyl acetate as eluent to obtain 67,68 g simple ester in the form of oil. The solution of all content on this simple ether in 340 ml of orthodichlorobenzene then heated at the boiling reverse distilled under reduced pressure and the residue purified by column chromatography through silica gel, using 20:1 by volume mixture of cyclohexane and ethyl acetate as eluent. Suirvey the reaction product is recrystallized from hexane to obtain 48,74 g of the indicated compound, melting at 58-59aboutC.

The NMR spectrum (CDCl3) memorial plaques

1,38 (6N, singlet);

and 3.72 (3H, singlet);

are 3.90 (2H, singlet);

to 5.56 (1H, doublet, j=10 Hz);

to 6.22 (1H, doublet, j=10 Hz);

6,58 -7,28 (7H, multiplet).

Mass spectrum (m/e): 312 (M+).

Elementary analysis. C19H20O2S:

Calculated C 73,04; H 6,45, S 10,26.

Found, 73,33, Of 6.49 H, S Accounted For 10.39.

P R I m e R get 6. 6-Mercapto-2,2-dimethyl-2H-1-benzopyran.

In 12 ml of 80% acetic acid are dissolved with heating 0,313 g of 6-(4-methoxybenzylthio)-2,2-dimethyl-2H-1-benzopyran and to the resulting solution was added to 0.12 ml of anisole and 0,512 g trifenatate mercury. The resulting mixture was stirred at 40aboutC for 1 h, after which the reaction mixture is extracted with ethyl acetate. The extract is washed with water, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, after which it is dried over anhydrous sodium sulfate. Then remove the solvent by distillation under reduced pressure and the OS is and ethyl acetate as eluent. AluI - integration of the reaction product periostat from a mixture of hexane and ethylacetate to get 0,283 g mercury salts of the compounds in the form of crystals.

The NMR spectrum (CDCl3) memorial plaques

1,40 (6N, singlet);

to 5.58 (1H, doublet, j=10 Hz);

of 6.20 (1H, doublet, j=10 Hz);

6,60 (1H, doublet, j=8 Hz);

7,02-of 7.23 (2H, multiplet).

Mass spectrum (m/e): 584 (M++1).

Then to a solution of 2.33 g of this mercury salt in a mixture of 46 ml of tetrahydrofuran and 46 ml of methanol is added dropwise 48 ml of an aqueous solution (4,80 g) nonahydrate sodium sulphide. To the resulting mixture while cooling with ice, add 4 ml of concentrated hydrochloric acid. The mixture is then stirred at room temperature for 0.5 h, after which it is freed from a non-dissolving substances filtered through active charcoal. The filtrate is extracted with ethyl acetate. The extract is washed with water, saturated solution of sodium bicarbonate and a saturated solution of sodium chloride in water, after which it is dried over anhydrous sodium sulfate. Then the solvent is removed by distillation under reduced pressure, to obtain 1.47 g of the compounds in the form of butter.

The NMR spectrum (CDCl3) memorial plaques

1,42 (6N, the single is 2 Hz);

6,92-7,30 (2H, multiplet).

Mass spectrum (m/e): 192 (M+).

P R I m e R get 7. 2,2-Dimethyl-6-triptoreline-2H-1-benzopyran.

In 30 ml of liquid ammonia suspended 1.45 g of 6-mercapto-2,2-dimethyl-2H-1-benzopyran, obtained as described in example receive 6, and to the suspension at -60aboutC in nitrogen atmosphere add 8,23 g iodine trifloromethyl. The resulting mixture was then irradiated at -65aboutC for 2 h and then at 25aboutC for 2 h, using a mercury lamp, low pressure. Then the reaction mixture was diluted with ethyl acetate and washed with diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride. The organic layer is then dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure. The resulting residue is purified by column chromatography through silica gel, using a 20:2:1 by volume mixture of cyclohexane, chloroform and ethyl acetate as eluent to obtain 1,17 g of the compounds in the form of butter.

The NMR spectrum (CDCl3) memorial plaques

1,46 (6N, singlet);

5,62 (1H, doublet, j=10 Hz);

6,28 (1H, doublet, j=10 Hz);

6,76 (1H, doublet, j=8 Epoxy-3,4-dihydro-2,2-dimethyl-6-trifloromethyl - radioactive-2H-1-benzopyran.

Following a methodology similar to that described in example getting 3, but using 1,15 g of 2,2-dimethyl-6-triptoreline-2H-1-benzopyran, obtained as described in example receiving 7, and 4.59 g of 3-chlormadinone acid (70% purity), obtain 0.74 g of the compounds in the form of butter.

The NMR spectrum (CDCl3) memorial plaques

of 1.32 (3H, singlet);

to 1.60 (3H, singlet);

of 3.56 (1H, doublet, j=4 Hz);

4,00 (1H, doublet, j=4 Hz);

7,02 (1H, doublet, j=8 Hz);

a 7.92 (1H, doublet of doublets, j=8 and 2 Hz);

of 8.06 (1H, doublet, j=2 Hz).

Mass spectrum (m/e): 308 (M+).

P R I m e R get 9. TRANS-4-amino-3,4-dihydro-2,2-dimethyl-6-trifluoromethyl-sulfonyl-2H - 1-benzopyran-3-ol hydrochloride.

Following example 4, but using of 0.68 g of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifloromethyl-2H-1 - benzopyran, obtained as described in example receiving 8, and 28. an aqueous solution of ammonia, obtain 0.55 g of the compounds in the form of crystals, melting at 256-259aboutC.

NMR-spectrum (hexadeuterated dimethyl sulfoxide) M. D.

to 1.22 (3H, singlet);

of 1.50 (3H, singlet);

of 3.78 (1H, doublet, j=10 Hz); 4,16-of 5.26 (2H, multiplet);

then 7.20 (1H, doublet, j=8 Hz);

7,98 (1H, doublet of doublets, j=8 and 2 Hz);

8,

3330, 1360.

Mass spectrum (m/e): 326 (M++1).

Elementary analysis.

C12H15ClF3NO4S:

Calculated C 39,84, H 4,18, N A 3.87, Cl 9,80, Of 15.75 F, S 8,86.

Found, C 40,05, H To 4.41, 3,89 N, Cl 9,98, F 15,76, S 8,79.

P R I m e R 10. 2,2-Dimethyl-6-pentatration-2H-1 - benzopyran.

The solution 1,463 g of 6-mercapto-2,2-dimethyl-2H-1-benzopyran, obtained as described in example getting 6 in 15 ml of dimethylformamide is added dropwise while cooling with ice, to a suspension 0,366 g of sodium hydride (55% dispersion in oil) in 15 ml of dimethylformamide in a nitrogen atmosphere. After stirring the reaction mixture for 15 min add 5.53 g of iodine perforate. Next, the reaction mixture is stirred while cooling it with ice for 1 h and then at room temperature for 2 h then the reaction mixture is poured into 150 ml of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, after which it is dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the resulting residue purified using ke eluent, to get 1,935 g of the compounds in the form of butter.

NMR-spectrum (DCl3) memorial plaques

1,40 (6N, singlet);

5,64 (1H, doublet, j=10 Hz);

6,30 (1H, doublet, j=10 Hz);

is 6.78 (1H, doublet, j=8 Hz);

from 7.24 (1H, doublet, j=2 Hz);

7,38 (1H, doublet of doublets, j=8 and 2 Hz).

Mass spectrum (m/e): 310 (M+).

P R I m e R receiving 11. 3,4-Epoxy-3,4-dihydro-2,2-dimethyl-6-pentatration - radioactive-2H - 1-benzopyran.

Following the procedure described in the example of a 3, but using of 1.87 g of 2,2-dimethyl-6-pentatration-2H-1-benzopyran, obtained as described in example 10 and 5.35 g of 3-chlormadinone acid, obtain 1.70 g of the compounds in the form of butter.

The NMR spectrum (CDCl3) memorial plaques

of 1.34 (3H, singlet);

of 1.62 (3H, singlet);

of 3.56 (1H, signet, I=4 Hz);

4,00 (1H, doublet, j=4 Hz);

7,02 (1H, doublet, j=8 Hz);

of 8.92 (1H, doublet of doublets, j=8 and 2 Hz);

9,06 (1H, doublet, j=2 Hz).

Mass spectrum (m/e): 358 (M+).

P R I m e R 12. TRANS-4-amino-3,4-dihydro-2,2-dimethyl-6-pendaftar - ethyl-2H-1 - benzopyran-3-ol hydrochloride.

Following the procedure described in example 4, but using 0,247 g of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-pendaftar - ethylsulfonyl-2N-1 be the data connection in the form of crystals.

So pl. 250-252aboutC.

NMR-spectrum (hexadeuterated dimethyl sulfoxide), M. D.

of 1.28 (3H, singlet);

to 1.48 (3H, singlet);

3,62-to 3.92 (1H, multiplet);

4,36 (1H, doublet, j=10 Hz);

6,46-6,70 (1H, multiplet);

then 7.20 (1H, doublet, j=8 Hz);

7,94 (1H, doublet of doublets, j=8 and 2 Hz);

8,58 (1H, doublet, j=2 Hz);

8,98 (3H, broadened singlet).

IR absorption spectrum (KBr) maxcm-1:

3230, 3020, 2940, 1220, 1120.

Mass spectrum (m/e): 374 (M++1).

P R I m e R receiving 13. TRANS-3,4-dihydro-2,2-dimethyl-4-(1-occaisonaly-2-yl)-6 - trifloromethyl-2H-1-benzopyran-3-ol.

F3CSO2< / BR>
A solution of 0.18 g of zinc chloride and 0.083 g of cyanoborohydride of sodium in 3 ml of methanol are added to a solution of 0.40 TRANS-4-amino-3,4-dihydro-2,2-dimethyl-6-trifluoromethyl-sulfonyl-2H - 1-benzopyran-3-ol, obtained from its hydrochloride, as described in the example of a 9, 0.20 g of methyl ether and 2-formylbenzoate acid in 6 ml of methanol. The resulting mixture was stirred at room temperature for 1 h and then at 50aboutC for 24 h then the mixture is cooled with ice, and then mixed with a saturated aqueous solution of sodium bicarbonate. Then remove the methanol by distillation at Pont is with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent is removed by distillation under reduced pressure. The resulting residue is recrystallized from ethyl acetate to obtain 0.34 g of the indicated compound, melting at 279-281aboutC.

NMR-spectrum (hexadeuterated dimethyl sulfoxide) M. D.

of 1.35 (3H, singlet);

of 1.56 (3H, singlet);

3,98 (1H, doublet of doublets, j=6 and 11 Hz);

4,08 (1H, doublet, j=17 Hz);

4,60 (1H, doublet, j=17 Hz);

5,43 (1H, doublet, j=11 Hz);

of 5.89 (1H, doublet, j=6 Hz);

7,17 (1H, doublet, j=9 Hz);

of 7.4 and 8.1 (6N, multiplet).

IR absorption spectrum (KBr)maxcm-1:

3473, 1671.

Mass spectrum (m/e): 4411 (M+).

Elementary analysis. C20H18F3NO5S:

Calculated C 54,42, H 4,11, N 3,17.

Found, C 54,50, H Or 4.31, N 2,88.

1. Derivatives benzopyran General formula I

< / BR>
where R1C1C3-performanceline group;

R2a group of the General formula II

< / BR>
where R4hydrogen, the nitro-group or a group of the General formula III

< / BR>
where R5hydrogen, C1C4is an alkyl group, a C1- C4-alkoxygroup;

the carbon - carbon simple bond or a carbon-carbon d and a - carbon-carbon double bond R3hydrogen;

or their pharmaceutically acceptable salts, when usloviia R1not would represent triptorelin group, when R2a group of the formula II, where R4hydrogen, a simple bond, and R3the hydroxy-group.

2. Connection on p. 1, characterized in that it is a 3,4-dihydro-2-2-dimethyl-4-(1-occaisonaly-2-yl) -6-trifloromethyl-2H-1-benzopyran-3-yl nitrate, 3,4-dihydro-2,2-dimethyl-4-(6-fluoro-1-oxo-isoindoline-2-yl) -6-trifloromethyl-2H-1-benzopyran-3-ol, 3,4-dihydro-2,2-dimethyl-4-(4-nitro-1-occaisonaly-2-yl) -6-trifloromethyl-2H-1-benzopyran-3-ol, 3,4-dihydro-2,2-dimethyl-4-(6-nitro-1-occaisonaly-2-yl) -6-trifloromethyl-2H-1-benzopyran-3-ol, 3,4-dihydro-2,2-dimethyl-4-(4-fluoro-1-occaisonaly-2-yl) -6-trifloromethyl-2H-1-benzopyran-3-ol, 2,2-dimethyl-4-(1-occaisonaly-2-yl) -6-trifloromethyl-2H-1-benzopyran.

3. The method of obtaining the compounds of formula I on p. 1, characterized in that conduct the interaction of compounds of General formula IV

< / BR>
where R1has specified in paragraph 1 values

(a) W amino group, W1the hydroxy-group;

(b) W and W1together with oxygen to form apachegroup;

(c) in case (a) with the compound of the formula V

< / BR>
ormala group or kaleidotile group,

or, in the case of (b) with a compound of General formula VI or VI

< / BR>
< / BR>
where R4and R5are specified in paragraph 1 values;

< / BR>
a group of General formula

< / BR>
or formulas

< / BR>
where R8a,R8band R8c/the same or different, each C1- C4is an alkyl group;

and get the connection with the General formula Ia

< / BR>
where R1and R2are specified in paragraph 1 values

and, if necessary, treated with compounds of General formula Ia base and get a compound of General formula IB

< / BR>
where R1and R2are specified in paragraph 1 values

or, if necessary, the compounds of General formula Ia is subjected to interaction with nitrous reagent and receive compound of General formula IC

< / BR>
where R1and R2are specified in paragraph 1 values

or, if necessary, the compounds of General formulas Ia, IB and IC is isolated in the form of pharmaceutically acceptable salts.

 

Same patents:

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to methods of producing a new derived griseolus acid of the formula I

or its ether complex, is able to inhibit the activity of phosphodiesterase, specific to different cyclic nucleotides

) 6-cyano-3,4-dihydro-2,2 - dimethyl - trans-4- (2 - hydroxy-1 - pyrrolidinyl) -2h-1 - benzopyran-3 - ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining ()-6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo - 1-1-pyrrolidinyl)-2H-1-benzopyran-3-ol formula

(I) known as Cromakalim

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

The invention relates to new chemical compounds, specifically derivatives of 1-oxo-2-TRIFLUOROACETYL-3-phenyl-2,3-dihyd - ro-1H-isoindole General formula

where R = H or Cl,

which have garmentindustry activity against the enzyme system of liver microsomal cytochrome-P-450-dependent monooxygenase metabolizing foreign compounds - xenobiotics

The invention relates to a new method of obtaining alkyl(UN)substituted 2-[4-(1-oxo-2-isoindolyl)phenylacetic acids or NITRILES of General formula 1, which has anti-inflammatory and analgesic activity "Indoprofen" synonyms "Sindon", "Plaint")-2-[4-(1-oxo-2-isoindolyl)-phenyl] propiona-Wai acid - found practical use as analgesic and anti-inflammatory medication [1]

H-R1where R is H, CH3C2H5, R1Is-COOH or-SP

The invention relates to medicine, namely to pharmacology and medicinal, with interferonogenna and immunomodulatory effects

The invention relates to new chemical compounds, specifically derivatives of 1-oxo-2-TRIFLUOROACETYL-3-phenyl-2,3-dihyd - ro-1H-isoindole General formula

where R = H or Cl,

which have garmentindustry activity against the enzyme system of liver microsomal cytochrome-P-450-dependent monooxygenase metabolizing foreign compounds - xenobiotics

The invention relates to new derivatives of 2-methyl-3-etoxycarbonyl-5-(2'-cyano-3'-aminopropyl-2'-enylidene)pyrrolin - 2-it-4 or 2-(2'-cyano-3'-aminopropyl-2'-enylidene)indolinone-3 of the General formula 1

< / BR>
where, if R = COOC2H5, R1= CH3, R2+ R3= (CH2)5(a) R2+ R3= CH2CH2OCH2CH2(b) R2= H, R3= CH2C6H5(C) R2= H, R3= CH2C6H4OCH3-4 (g) R2= H, R3= CH2C6H3(OCH3)-3,4 (d) R + R1= CH = CH-CH = CH R2= R3= H (e) R2= H, R3= (CH2)6(W) R2= H, R3= CH2CH2N(C2H5)2(C) R2= H, R3= CH2CH(OH)CH2OH and R2+ R3= CH2CH2OCH2CH2(K) R2+ R3= CH2CH2N(CH3)CH2CH2(l) R2+R3=CH2CH2= H, R3= CH2C6H4OCH3-4 (o) R2= H, R3= CH2C6H3(OCH3)-3,4 (p) R2= H, R3= CH(CH3)C6H5(p) R2= H, R3= CH2CH2C6H5(c) R2= H, R3= CH2CH2C6H3(OCH3)-3,4 (t) R2= H, R3= CH(CH3)CH2C6H5(u) R2= H, R3= C6H5(f) R2= H, R3= C6H4OCH3-4 (x) with antihypertensive activity
The invention relates to medicine, namely to neurotraumatology, and can be used in the treatment of severe traumatic brain injury

The invention relates to a method for producing a lyophilized RNU, which can be easily implemented because of the small initial volume, and this method avoids deposition RNU-component and as a result to obtain a homogeneous product

FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: method involves making incision in conjunctiva and Tenon's capsule of 3-4 mm in size in choroid hemangioma projection to sclera 3-4 mm far from limb. Tunnel is built between sclera and Tenon's capsule to extrasclerally introduce flexible polymer magnetolaser implant through the tunnel to the place, the choroid hemangioma is localized, after performing transscleral diaphanoscopic adjustment of choroid hemangioma localization and size, under visual control using guidance beam. The implant has permanent ring-shaped magnet in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 2-3 mTesla units intensity. It is arranged with its north pole turned towards the choroid hemangioma so that extrascleral implant laser radiator disposition. The other end of the implant is sutured to sclera 5-6 mm far from the limb with two interrupted sutures through prefabricated openings. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. 0.1-1% khlorin solution is injected in intravenous bolus dose of 0.8-1.1 mg/kg as photosensitizer and visual control of choroid hemangioma cells fluorescence and fluorescent diagnosis methods are applied. After saturating choroid hemangioma with the photosensitizer to maximum level, transscleral choroid hemangioma laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm with total radiation dose being equal to 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the intraocular neoplasm, repeated laser irradiation of the choroid hemangioma is carried out with radiation dose of 30-60 J/cm2.

EFFECT: enhanced effectiveness of treatment.

4 cl

FIELD: medicine.

SUBSTANCE: method involves creating tunnel between sclera and Tenon's capsule in intraocular neoplasm projection. Intraocular neoplasm localization and size is adjusted by applying transscleral diaphanoscopic examination method. 0.1-0.3 ml of photosensitizing gel based on viscoelastic of hyaluronic acid, selected from group containing chealon, viscoate or hyatulon, is transsclerally introduced into intraocular neoplasm structure using special purpose needle in dosed manner. The photosensitizing gel contains khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-1% by mass. Flexible polymer magnetolaser implant is extrasclerally introduced into the built tunnel in intraocular neoplasm projection zone under visual control using guidance beam. The implant has permanent ring-shaped magnet axially magnetized and producing permanent magnetic field of 3-4 mTesla units intensity, in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The implant is arranged with its north pole turned towards the intraocular neoplasm so that implant laser radiator lens is extrasclerally arranged in intraocular neoplasm projection zone. The implant light guide is sutured to sclera 5-6 mm far from the limb with single interrupted suture. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transscleral intraocular neoplasm laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm. The treatment course being over, the flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, neodymium-iron-boron or samarium-iron-nitrogen. 0.1-1% khlorin solution as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is additionally intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg and repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2 15-20 min later during 30-90 s.

EFFECT: complete destruction of neoplasm; excluded its further growth.

4 cl

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