UA82907C2 - Amidomethyl-substituted 2-(4-sulfonilamino)-3-hidroxy-3,4-dihydro-2h-chromium-6-yl-derivatives, process and intermediates for the preparation thereof and drugs containing said compounds - Google Patents

Abstract

The invention relates to compounds of general formula (I), wherein the meaning of R1, R2, R3, R4, R5 and R6 is given in a description, to a method for producing said compounds and to intermediate products thereof. Drugs containing the inventive compounds of formula (1) are also disclosed. I

Description

Description of the invention

This invention relates to new amidomethyl-substituted derivatives of 2 2-(4-sulfonylamino)-3-hydroxy-3,4-dihydro-2H-chromen-b-yl with a blocking effect on potassium channels, primarily with an effect on the cardiovascular system, as well as medicines that contain these compounds. The invention also relates to the method of obtaining new compounds and intermediate products proposed in the invention, which are obtained by this method and used in its implementation.

From MO application 00/12077 A1 |corresponds to patent OB 6150356)| already known indanes, benzopyrans and analogs of 70 similar compounds that have a blocking effect on potassium channels, primarily an effect that positively affects the cardiovascular system.

MO application 00/58300 A1 describes chroman derivatives suitable for use as medicinal products, primarily products that have an antiarrhythmic effect.

The basis of this invention was the task of offering new active substances for the treatment of 12 diseases of the cardiovascular system, mainly cardiac arrhythmia, which would be distinguished by high efficiency with good physiological compatibility, and when used as antiarrhythmic agents - also by a pronounced selective effect in relation to the atria ( atrioselective action).

When creating the invention, it was unexpectedly established that the proposed group of new amidomethyl-substituted derivatives of 2-(4-sulfonylamino)-3-hydroxy-3,4-dihydro-2H-chromen-b-yl has properties that block potassium channels, and suitable for the treatment of diseases of the cardiovascular system, mainly for the treatment of cardiac arrhythmia. The compounds proposed in the invention are characterized by high efficiency with good physiological compatibility, and in the case of use as antiarrhythmic agents, they also have a pronounced atrioselective effect. In addition, the compounds proposed in the invention exhibit such properties that will probably allow their use to provide an additional positive effect on the immune system. c 29 According to the above, the object of this invention are new amidomethyl-substituted derivatives of he) 2-(4-sulfonylamino)-3-hydroxy-3,4-dihydro-2H-chromen-b-yl of the general formula (c) 30 5 t m - ez o

F

THEM. ON | cm 35 in | 4 with co

Z - o. « 40 o'clock E! what with what" in which

B" means S. Sualkil,

IN? means C-C alkyl, oo BZ means phenyl, optionally mono- or di-substituted by halogen, C-C alkyl, C-C alkyl or trifluoromethyl, naphthyl or biphenyl, where B" means hydrogen, C-C alkyl or C3-C4cycloalkyl-C1-C4alkyl, where B means hydrogen and 5025 means C4alkyl, phenyl-C4alkyl, the phenyl group of which is optionally monosubstituted by halogen, or furyl-C4alkyl or tetrahydronaphthyl or "and B? and 9, together with the nitrogen to which they are bound, form a piperazine ring, optionally substituted by phenyl.

The object of the invention is also medicinal products that contain compounds of formula I. The object of the invention is also a method of obtaining compounds of formula I and intermediate products obtained by this method and used in its implementation.

In those cases when the substituents in the compounds of formula I or in other compounds presented in this description and formula io) of the invention are or contain C 4 -C alkyl or C 1 alkyl, this alkyl in each case can have a straight or branched chain. 60 Each of B and B? mostly means methyl. 3 preferably means phenyl, optionally mono- or disubstituted by halogen, C.4-C.alkyl,

C.-C, alkoxy group or trifluoromethyl. First of all, KZ means phenyl monosubstituted by S.-Slalkyl.

If KZ means phenyl substituted by halogen, then fluorine, chlorine, bromine and iodine can be considered as the latter. In 65, one of the particularly preferred variants of KZ is 4-ethylphenyl.

B" preferably means hydrogen, C1-C1-alkyl or cyclopropyl-C1-C1-alkyl, primarily cyclopropylmethyl. If

B" means C-Salkyl, then this alkyl is primarily branched and is preferably neopentyl, 2,2-dimethylbutyl, 2-ethylbutyl, 3-methylbutyl or 2-methylpropyl.

VE? mostly means hydrogen. 25 preferably means phenyl-C-C-alkyl, primarily benzyl or phenethyl, or means tetrahydronaphthyl, primarily 1-tetrahydronaphthyl. The preferred value is (K)-1-tetrahydronaphthyl.

Particularly preferred compounds of formula I are selected from the group that includes 2-(4-I((4-ethylphenyl)sulfonyl|amino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromene-b- yl)-M-1,2,3,4-tetrahydrona phthalen-1-ylacetamide, 70. 2-(3554К)-4-(4-ethylphenyl)sulfonyl|amino)-3-hydroxy-2,2-dimethyl- 3,4-dihydro-2H-chromen-b-yl)-M-(1K)-1,2,3, 4-tetrahydronaphthalen-1-yl|iacetamide,

M-benzyl-2-14-I(4-ethylphenyl)sulfonyl|(neopentyl)amino|-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6b-ylsiac ethamide, 2-A -I(4-ethylphenyl)sulfonyl|(neopentyl)amino|-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-b-yl)-M-(2-phenylethyl)acetamide and 2-(4-I(4-methylphenyl)sulfonyl|amino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-b-yl)-M-1,2,3,4 -tetrahydron aphthalen-1-ylacetamide.

According to the invention, new compounds of the formula | are obtained by the interaction of compounds of the general formula HER

Z ro Mn sho M on s b 4 P (o)

With - , about; oh and

EE at which KE", B, B", B? and B? have the values indicated above, with a compound of the general formula ІІ about 4 s with X-30-K SHI, in which KZ has the values indicated above, and X means a leaving group that is removed. This reaction can be carried out by a known hydrochemical route under conditions using an inert organic solvent, primarily a dipolar aprotic solvent such as dichloromethane, or using a mixture of similar solvents and in the presence of a suitable base. Suitable bases are non-nucleophilic organic nitrogenous bases, such as tertiary (lower) alkylamines, for example, triethylamine. Liquid organic bases used in excess can also serve as solvents. If necessary, the reaction can be catalyzed by any known auxiliary agent that promotes coupling, such as 4M,M-dimethylaminopyridine (DMAP). The reaction is preferably carried out at a temperature in the range from room to 802C, for example, at 6520. The reaction can be carried out at a pressure in the range from normal to about 200 bar, for example, at a pressure of 180 bar. When using the compound of formula I in liquid form, it may be appropriate to remove the solvent used from the reaction mixture in a known way, for example, under reduced pressure, after adding the compound of formula PP to the compound of formula II dissolved in the solvent. If in the original compounds of formula II KB? is hydrogen, then it is advisable to use the compound of formula II in equimolar quantities. Halogen, preferably chlorine or bromine, is usually used as the withdrawing X group in compounds of formula I. The interaction of the compound of formula I with the compound of formula II can also be carried out in a known manner on a solid phase, primarily on a thermoplastic such as aminomethylpolystyrene (AMPS). According to this variant, the reaction should preferably be carried out to obtain small amounts of the product, for example, on the order of 1-10 mmol. When carrying out the synthesis on the solid phase, it is preferable to use the well-known methylpiperidine immobilized on the polymer (IP-) as a basis. When carrying out the synthesis in the solid phase, it is advisable to work at a temperature in the range from 10 to 402C, preferably at room temperature.

Compounds of the formula II can be obtained by the interaction of the epoxy compound 60о of the general formula IM b5, carried out according to a known method

| at

With 2 IM about Kk , I eE in which EK", K?, KZ? and VK? have the above values, with a nucleophilic organic nitrogenous base, preferably ammonia in aqueous solution, in a dipolar protic solvent such as (lower) alkyl alcohol, preferably in ethanol. The reaction can be carried out at temperatures in the range from room to 602b. If as the target product it is necessary to obtain compounds of formula I, where B" represents C -Svalkyl or

C.-C,cycloalkyl-C.-C.alkyl, then the resulting compound of formula II, where B is hydrogen, can then be alkylated in a known manner. The alkylation can be carried out as an aminoalkylation by first subjecting the compound of the formula

Ii, where B7 is hydrogen, interactions with aldehyde of the general formula M

Кк -СсСНно У, сч 7 о in which BK 7291 means hydrogen, C0-Salkyl or C4-Ccycloalkyl-C0-Salkyl, and then reducing the formed intermediate imine product by adding the appropriate reducing agent to the alkylamine compound of formula II. Complex borohydrides can be used as reducing agents, such as Mavn cm or the well-known borohydride immobilized on a polymer (IP-VN;). According to one of the options, the reaction can be carried out under conditions using an inert polar protic organic solvent, primarily methanol, while reduction of the imine is carried out without its isolation in the same solvent. The reaction according to this variant o can be carried out at temperatures in the range from room to 6б02С, for example, at 5020. According to another variant of the interaction of the compound of the formula II, where B" is hydrogen, with the aldehyde of the formula M with the formation of an intermediate imine product, it is possible to carry out in a dipolar aprotic solvent, primarily in tetrahydrofuran (THF). At the same time, to accelerate the reaction, it is advisable to add a catalytic amount of a dehydrating agent, for example, an orthoether, primarily trimethylorthoformate (TMOF). Then, the intermediate imine product can be isolated and dissolved in the polar solvent specified above for the first option to a protic solvent in order to restore it in this solvent. The reaction according to the second variant is preferably carried out at room temperature. With the help of a nucleophilic reaction with the opening of the cycle of epoxides of the formula IM, carried out according to the two variants described above, as a rule, compounds of the formula I are obtained, where -) c vicinal (adjacent) substituents in position Z and in position 4 of the pyran ring, namely, the hydroxy group and the amino group, respectively, are in the trans-configuration relative to each other. "Compounds of formula II are new and can be successfully used as intermediates for obtaining new pharmacologically active active substances, for example, for obtaining compounds of formula I.

Compounds of formula I, as well as compounds of formula M, are in principle known or they can be obtained by (ee) known methods also from known compounds. Compounds of the IM formula can be obtained by the known method of interaction of compounds of the general formula MI (Ce) 5 o "A 5" B y: 2 MI o o "

IS

60 in which 2", 2, BZ and 2? have the above values, with a peroxide compound capable of forming an epoxide, primarily with .m-chloroperbenzoic acid (MHPBK), under conditions using an inert organic polar protonic solvent, preferably dichloromethane, and in in the presence of a suitable base. An aqueous solution of sodium bicarbonate is primarily suitable as such a base 65. The reaction is preferably carried out at room temperature.

The compounds of the formula I have a chiral center at least in the vicinal carbon atoms in position C and in position 4 of the pyran ring, respectively, and therefore they can be presented in several isomeric forms.

Accordingly, the object of the invention are compounds of formula I both in the form of pure isomers and in the form of mixtures of these isomers. Optically active compounds of the formula | can be obtained, for example, from mixtures of isomers of the formula !/ or from mixtures of isomers of the formula !| using known methods, in particular, chromatographic separation into chiral materials used for these purposes. Mixtures of isomers of the formula IY can also be obtained by interaction with appropriate optically active acids, such as camphorsulfonic acid or 0- or 1-tartaric acid, and subsequent separation into the appropriate optical antipodes 7/0 by fractional crystallization of the resulting salts.

Optically active compounds of the formula | can also be obtained directly by chiral synthesis. If it is intended to obtain compounds of the formula!, where the hydroxy substituent is in position C of the pyran ring and

B"M5Oov-substituent in position 4 of the pyran ring are, according to the stereochemistry, in the trans-configuration relative to each other, then in these cases it is possible to start from epoxides of the formula IM with 75 predetermined corresponding stereochemistry. Epoxides of the formula IM with a predetermined corresponding stereochemistry can be obtained, for example, carried out in a conventional way by epoxidation of alkenes of formula MI using a chiral catalyst according to Jacobsen's method (cf., for example, EP 0521099 AT).

If, for example, it is envisaged to obtain a compound of formula I, where the chiral center in position C of the pyran ring is in the 5-configuration, and the chiral center in position 4 of the pyran ring is in

K-configuration, then the intermediate product of the MI formula can be converted in the presence of a chiral catalyst, primarily (5,5)-manganese(PI)-salen (salen is 2-I2-K2-hydroxyphenyl)methylidenamino|ethyliminomethyl| phenol), and in the presence of an oxygen donor, primarily sodium hypochlorite, under conditions using an inert organic solvent, primarily dichloromethane.

It is advisable to carry out the reaction at a pH of the order of 9.5-11.5. To set the pH value to the required pH of the reaction mixture, it is preferable to add a buffer solution, which consists of Ma "HPO" and M-oxide of pyridine. at

The reaction can be carried out at temperatures ranging from -109С7 to room temperature, preferably at 02С. If it is intended to obtain a compound of formula I, where the chiral center in position C of the pyran ring is in the K-configuration, and the chiral center in position 4 of the pyran ring is in the 5-configuration, then it is possible to work similarly to the method described above, but using (5 ,5)-manganese(III)-salen (K,K)-manganese(III)-salen. at

Compounds of the formula MI can be obtained by the known method of aminoacylation by the interaction of a compound of the general formula MIII b» no sm ee so ve UNN o 2 o E - - in which B! and 2? have the above values, with a compound of the general formula MI! p ttkto 56

NyaKk U , so in which 2? and KE? have the above values. Carboxylic acids of the formula Mi! can be used as acylating agents. or their reactive derivatives, such as halides, primarily chloro- and bromohydrides of these acids. When using acids of the formula MI! as such, their interaction with amine compounds of the formula MII should also be carried out in the presence of any known coupling agent, for example, 1,1-carbonyldiimidazole, chloroformic acid ethyl ether, or alkylcarbodiimide, such as M'-(3-dimethylaminopropyl)- M-ethylcarbodiimide (DEK), or cycloalkylcarbodiimide, such as "and dicyclohexylcarbodiimide. Acylation can be carried out under conditions using an inert organic solvent at a temperature in the range from -300 to -502C, preferably at room temperature. Halogenated hydrocarbons are acceptable as solvents for these purposes , such as dichloromethane, or simple cyclic ethers, such as 59 tetrahydrofuran and dioxane, or mixtures of these solvents.

ГФ) Compounds of the formula МИЙ can be obtained by saponification of the ester group of the compound of the general formula ИХ ko 60 b5 y carried out according to a known method; Sh-- in o; Their, about; in which K" and K? have the above values and K / stands for C.--Slalkyl. Saponification can be carried out in a polar protic solvent such as ethylene glycol by contact with a suitable base, for example a strong base such as diluted aqueous solution of caustic sodium.The reaction is preferably carried out in 5 at a temperature in the range from room to the boiling temperature of the solvent or mixture of solvents.

Compounds of formula IX can be obtained by the interaction of compounds of general formula X carried out according to a known method

KOH. ,

І о Х, он сч 7 о in which K" has the above values, with the compound of the general formula ХИ и: -о м - хи 5 ? (22) в2 s

So, in which VK and K? have the above values. This reaction can be carried out under conditions using an inert organic solvent, such as toluene or xylene, in the presence of a suitable acid with separation of water by azeotropic distillation. As an acid for the specified purposes, you can use, for example, 70% acid or propionic acid. When carrying out the reaction, it is preferable to work with the addition of a catalyst, such as a Lewis acid, for example, phenylboronic acid. The reaction is preferably carried out at a temperature in the range from to the boiling point of the solvent or mixture of solvents, for example, at and" temperature of the order of 12090.

Compounds of formula X, as well as compounds of formula XI, are in principle known or they can be obtained by a known method also from known compounds. o The presence of compounds of the formula | as pharmacologically active active substances with positive properties becomes obvious against the background of the following explanations. It is known that substances that block autogenous cardiac potassium channels can be used as active substances in cardiovascular diseases, primarily in cardiac arrhythmia. Thanks to the blockade of the flow of potassium ions from the cells of the heart, it is possible to increase the action potential of the heart, which has a positive antiarrhythmic effect. As examples of this well-known approach used in therapy (av), we can mention the use of antiarrhythmic drugs of class I. The problem associated with the use of such non-specific potassium channel blockers is the low selectivity of their action on various tissues of the heart. Thus, for a long time there has been an assumption that, first of all, antiarrhythmic drugs of class I can lead to an unwanted increase in the duration of the OT interval on the electrocardiogram (ECG) and to polymorphic ventricular tachycardia (flutter-fibrillation of the ventricles), which ultimately can cause unwanted complications, such as such as ventricular fibrillation. Therefore, attempts to create such were made and are being made

HF) blockers of potassium channels, which would be able to selectively affect the potassium currents of the atrium, not the ventricle. Since the recently discovered potassium K1.5 channels in the heart are localized exclusively in the atrium and not in the ventricle, compounds that block these K1.5 potassium channels may be used as antiarrhythmic drugs with atrioselective action. However, K,1.5 potassium channels, as well as other potassium channels, are localized not only in the heart, but also, for example, in the vessels of other parts of the body. Therefore, it is impossible to completely exclude the possibility that compounds that block K,1.5 potassium channels will not lead to an increase in blood pressure due to the blockade of potassium channels in blood vessels. Such compounds that block potassium channels Ku/1.5, which are not able to cause side effects manifested in an increase in blood pressure, are therefore preferred. Among the other unwanted side effects that may occur when some compounds are administered into the body, which have a blocking effect on K,/1.5 potassium channels, the effects accompanying the use of class I antiarrhythmic drugs and negative inotropic effects should also be mentioned.

Compounds of formula I are distinguished by a pronounced and selective cardiac effect, which blocks potassium channels

KU1.5. Along with particularly high efficiency and a pronounced atrioselective antiarrhythmic profile, compounds of formula I allow under all conditions to minimize the occurrence of undesirable side effects, such as an increase in blood pressure, effects that accompany the use of class I antiarrhythmic drugs, as well as negative inotropic effects. Accordingly, compounds of the formula | indicated for the treatment and/or prevention of cardiovascular diseases, primarily atrial fibrillation, atrial flutter and other cardiac arrhythmias, in large mammals and humans. 70 In addition, compounds of formula I have a pronounced blocking effect on K,1.3 potassium channels. Potassium channels

K/1.3 are mainly localized in cells of the immune system. Blockade of Ku/1.3 potassium channels is considered, in particular, in connection with antiproliferative and/or immunosuppressive effect | see S. Veeeip and others, Te doshigpai! oi Ittypoiodu 166, 2001, pp. 936-944). Based on this, relative to compounds capable of blocking potassium channels

KM1.3, including, for example, and in relation to the compounds of the formula !/, it can be assumed that they can /5 be used also for the treatment and/or prevention of proliferative, chronic inflammatory and autoimmune diseases, such as multiple sclerosis.

The numbers of the examples indicated in the following description correspond to the numbers of the examples described below for obtaining the compounds proposed in the invention. 1. Study of the blocking effect of compounds on K,/1.5 potassium channels in experiments of IP mygo

The presence of blocking action on K Uu1.5 potassium channels in the compounds proposed in the invention is confirmed experimentally by conducting a study on a well-known experimental model or its analogue | see

MM. We and others 9. RNAptasoi. Tokyo Meiyodz 34, 1995, pp. 1-7). When conducting research on this experimental model, a line of Chinese hamster ovary cells (CHO-cells from the English "spipeze patvzvieg omagu"), obtained from one single cell and stably expressing the KUu1.5 channel, is used. Indicated with two CHO-cells by their overnight incubation in nutrient medium containing KCl or in "loading buffer" (composition (all values are in mM) KCl 5, MaCi 140, CaCl 5 2, Mo5O, 1, (o )

M-2-hydroxyethylpiperazine-M'-2-ethanesulfonic acid (NEREZ5) 10, glucose 5) are "loaded" with KB cations under the action of ATPase, which transfers Ma"/K". Then one part of CHO cells, which is used as a comparative standard, incubated in the absence of the inhibitor, and another part of the CHO cells incubated in the presence of the corresponding tested compounds of formula I, which have an inhibitory effect. After that, the CHO cells are depolarized by increasing the extracellular concentration of potassium ions, resulting in K 1.5 potassium channels О of СНо-cells are opened. When the inhibitor is present, БЁ" ions flow through potassium channels Ku/1.5 into the liquid that surrounds them. In the presence of the tested compound of the formula I, which has an inhibitory effect, "BB" dreams remain localized inside the CHO cells. As a measure of the blocking effect of the tested compounds of the formula | on potassium channels Ku/1.5 cm

With atomic adsorption spectroscopy, the concentration of BB' ions in the liquid surrounding them is measured in comparison with a comparative standard.

Chinese hamster ovary cells (see above) were cultured in a nutrient medium known as such, which contains KCI, for the cultivation of CHO cells and then transferred to the wells of a 9b-well plate. To obtain a monolayer of CHO cells, they were left overnight for reproduction. After that, the nutrient medium was first removed with a pipette and each well was washed three times with a buffer for preliminary incubation with a low concentration of potassium ions in it (composition (all values are indicated in mM): KSI 5, Masi 140, Sasi» 2, Mazo, "» 1, NEREZ 10, glucose 5) in portions of 10O0μl. Then 5μl of a solution of the corresponding "tested compound (stock solution in DMSO, dilution with buffer for pre-incubation, final concentration in the test mixture 1μM) or only solvent (as a negative control) was added to each well ) and incubated in each case for 10 minutes at room temperature. Next, 5 Ωcl of stimulation buffer (OG) with an increased concentration of potassium ions was added to each well (composition: KSI 145 mM, mass ΩM, other components correspond to the buffer for pre-incubation), after which the samples were incubated for another 1 Ω at room temperature.

Then 8 µl of the liquid surrounding the CHO cells was transferred from each well separately from each other to the wells of the analytical tablet and the concentration of KB ions in 250 liquid samples was determined by atomic adsorption spectroscopy. Two experiments were performed with each of the tested compounds. On the spectrogram, the fragment of the signal corresponding to the component of the outflow of KB7 cations from the cells related to the channel K uU1.5 was highlighted, using as a positive control the well-known blocker of potassium channels 4-AP in a high concentration (which is 100 times higher than the value of IC 50 for channel K), 1.5). In this way, it was possible to determine which part of the flow of KB" cations from the cells depended on the effect of the A-AR blocker and therefore had to be correlated with the Ku/1.5 channel. With compounds that, at the used concentration equal to 10 μM, reduced (F) the flow of cations KB" from cells for at least 5095, conducted additional experiments in which the tested compound

F was used in lower concentrations for the possibility of determining its inhibitory concentration, which is half of the maximally effective one. As a relevant indicator in each case, the concentration of the tested compound of formula I, at which the degree of inhibition is equal to half of the maximum (IC) was determined.

Table 1 below presents the tested compounds of formula I and the IC value obtained for them based on the results of the research conducted on this experimental model. at

Example Mo ISvo vv vv vv o vv sya o 2. Study of the blocking action of compounds on K,/1.3 potassium channels in experiments of IP mygo

The presence of blocking action on K.1.3 potassium channels in the compounds proposed in the invention is confirmed experimentally by conducting a study on a known experimental model (for example, according to the method of the Sepiop company, Hamburg) or its analogue | see. U. Riavek and K. Zidieg, U. Rioiospiet. RNoiobioi. 33, 1996, pp. 101-124). When conducting research on this experimental model, known Chinese hamster ovary cells (CHO cells) stably transfected with potassium channel K 1.3 are used. Blockade in transfected cells of the intrinsic activity of K)/1.3 potassium channels is accompanied by a shift (o) of the membrane potential towards positive values from approximately -40 mV to -30 mV, while in wild-type CHO cells, which were studied in parallel, no change occurs - any significant shift in the membrane potential. The change in the membrane potential is directly related, thus, to a decrease in the activity of c o) potassium channels K/1.3. Blockade of K/1.3 potassium channels, for example, by compounds of formula I, and the resulting change in membrane potential lead to the accumulation of a membrane potential-sensitive fluorescent dye in the intracellular compartments of CHO cells and ultimately to an increase in fluorescence intensity. Thus, the change in the membrane potential of CHO cells is measured indirectly by increasing the fluorescence intensity of a membrane-potential-sensitive dye. h Cells were transfected with the K/1.3-plasmid by a known method using a commercially available transfection reagent (OMKIE-S of Sibso VK, Germany). The results of transfection were verified by immunofluorescence, as well as by studying the current of potassium ions by the patch-clamp method (potential fixation). To measure fluorescence, a fluorimeter of the Tesap Zaige type, manufactured by Tesap, Germany, was used. As an appropriate indicator in each case, the increase in fluorescence intensity caused by the blockade of K/1.3 potassium channels in CHO cells by compounds of formula I at a concentration equal to 10 µM was determined. This increase in fluorescence intensity in each case was expressed as a percentage (90) of the increase in fluorescence intensity (se) caused by margatoxin, which was used as a reference compound. Margatoxin is known as a selective blocker of K 1.3 potassium channels | see, for example, M. o Sagsia-Saimo et al., 9. Vioi. Spent 268, 1993, pp. 18866-18874). "I Table 2 below presents the tested compounds of the formula I and the percentage values obtained for them based on the results of the research conducted on this experimental model. iF) Example (Increase in fluorescence intensity (in 96 in relation to the increase in fluorescence intensity caused by com margatoxin) 5 в 1000000 вв 10000005 12 111 kny nyshishshshiiiiiii 70 Z. Study of the functional efficiency of the compounds proposed in the invention in experiments of ip mygo on the atrium of a rat

The presence of functional antiarrhythmic efficiency in the compounds proposed in the invention is confirmed experimentally by conducting research on the experimental model described below. In the study of this experimental model, the degree to which compounds of formula I, which have a blocking effect on potassium /5 Ku1.5 channels, prolong the functional refractory period in the left atrium of the rat is determined. The refractory period is the minimum possible time interval that passes from the moment of reaction to the main stimulus to the moment of reaction to an additional stimulus and during which it is possible to cause a repeated contraction of the muscle. The degree of lengthening of the functional refractory period is a measure of the antiarrhythmic effectiveness of the compounds proposed in the invention. To determine the functional refractory period on the drug that is subjected to electrical stimulation, it is checked after which the time interval from the moment of the previous contraction can cause a repeated contraction as a result of additional irritation with an electric current pulse.

Rats (Zrgadie-JuOamieu line, Spagievz-Kimeg company, Germany) had their hearts removed immediately after their death. After that, the left atria were isolated and fixed on force sensors in a thermostatically controlled (30 2) organ bath filled with a modified solution

Tyrode (composition (all values are given in mM): mass 137, KSI 2.7, Sassi»o 1.8, MoSiI»i 0.8, MansSo» 11.9, Ma?RO, 0.6, (8) glucose 5). Regular contractions were induced by adding stimulating electric current pulses to the drugs (rectangular pulses, with an intensity 3.5 times higher than the irritation threshold, a duration of 1.5ms, and a repetition rate of 1Hz). First, the initial value of the functional refractory period was determined, for which, in addition to the main stimulus, additional electric current pulses were applied to the preparations, while gradually shortening the time interval that passes from the moment of the previous "2 main stimulus to the moment of the next additional electric current pulse , until in response to the supply of another additional pulse of electric current, there was no additional contractile reaction of the drugs to it. After that, the cumulative addition of compounds of the formula | in z.

335 In increasing concentrations (from 0.1 to 1 ОмМкМ) at intervals of 20 minutes, while re-determining the refractory period after 18 minutes after each addition of compounds of the formula I. Before carrying out the measurements, the initial solutions of the tested compounds (3.2 and 0.32 mM in 10095 DMSO). In order to achieve the required final concentration of the tested compounds (0.1-10 μM) in the tub for organs (volume 100 ml), these initial solutions were then added to it in appropriate volumes. "

As a relevant indicator in each case, the prolongation in milliseconds of the functional -vs refractory period (FRP) in the left atrium of rats was determined, which was observed after adding the corresponding compound of formula I at a concentration of 10 µM to the atrial preparations. Table C below presents the tested compounds of formula I and the value of lengthening of the refractory period obtained for them according to the results of the study conducted on this experimental model, while higher values correspond to higher antiarrhythmic efficiency. so yu oh i

Fo

And now with you

F. yu vo 4. Study of the functional efficiency of the compounds proposed in the invention in the experiments of ip mimo on the b5 heart of guinea pigs

Using the example of the experimental model described below, it is demonstrated that the compounds proposed in the invention also have a slight undesirable proarrhythmic effect on the repolarization of the ventricles of the heart. For this purpose, we are investigating the effect of compounds of the formula | on the effective refractory period (ERP) and on other values that affect the work of the heart of guinea pigs. In the study on this experimental model of the use of non-selective potassium channel blockers, which do not correspond to the present invention, which also block channels

NEKO and/or CL OT1, leads to an undesirable change in ERP, as well as the duration of the OT interval on the electrocardiogram (ECG). The duration of the OT interval is also a measure of heart repolarization. Due to the use of potassium channel blockers, the increase in ERP and the duration of the OT interval in each of the two cases independently indicates the risk of unwanted ventricular flutter-fibrillation ("Togzade-de-Roipiez"). In addition, according to the ECG in 7/0, the duration of the LV complex was also determined in each case as a measure of the speed of propagation of ventricular excitation. Due to the use of the tested compound, the increase in the duration of OKO5-complex is also associated with an increased risk of unwanted proarrhythmic side effects. Therefore, in the study on this experimental model, the absence of an increase in ERP and the duration of the OT interval indicates a low risk, and the appearance of a significant increase in the ERP and the duration of the OT interval indicates an increased risk of an unwanted proarrhythmic effect. 7/5 In addition, the lack of an increase in the duration of the К3-complex due to the use of the studied compounds of the formula I means a small risk of unwanted proarrhythmic side effects, since the absence of an increase in the duration of the OK5-complex indicates an undisturbed propagation of excitation in the ventricle of the heart. | on the contrary, an increase in the duration of the OKZ-complex, which is usually caused by antiarrhythmic drugs of class I, indicates a slowing down of the speed of excitation and can contribute to the occurrence of ventricular tachycardia up to the flickering of the ventricles of the heart.

During the research, male guinea pigs (OitKip-Napeu lines, Spagez Kimeg company) were anesthetized (ketamine at a dose of 5mg/kg, xylazine at a dose of 10mg/kg) and access to one of the jugular veins was opened in each animal for the introduction of compounds of formula I through it. or just the carrier. Through another jugular vein, a bipolar catheter was inserted into the right ventricle of the guinea pigs for stimulation (stimulation frequency s dv ZHC). Arterial blood pressure was measured using a catheter inserted into the carotid artery, connected to a Stetham pressure sensor (Ziaiiat). ECG was recorded using needle electrodes. Measurement data (8) were digitized using an analog-to-digital converter, processed on a computer using the appropriate software (Ropetaipy RpPuzioiodu Riatsyogt, Socii firm, USA) and printed in parallel on a multi-channel recorder. After the end of the 45-minute period of reaching the equilibrium state, the guinea pigs were intravenously injected with compounds of the formula at 12-minute intervals

It or carrier in increasing dosage. Before the first administration and one minute after each subsequent administration of compounds of formula I in increasing dosage (from 0.1 to a maximum of ZOμmole/kg), the effective refractory period was measured. For this purpose, after the delivery of every five normal stimulating pulses of electric current, an additional pulse was delivered, while gradually increasing the time interval that passes from the moment of EM from the delivery of the previous pulse of electrical current to the moment of delivery of the next additional pulse, until the delivery of the next additional pulse an electric current pulse did not cause cardiac activity.

The registered time interval corresponds to the ventricular myocardium ERP.

In order to identify the possible effect of the tested compounds on blood pressure, in the same study, after each administration of the tested compounds, systolic and diastolic blood pressure were determined and the measured values were compared with the previous blood pressure level. Blood pressure parameters were recorded automatically after 1 and 8 minutes after each administration of the tested compounds. Table 4 below additionally presents data on the change in systolic blood pressure caused by the following compounds of formula I (with the exception of carrier-induced effects). None of these compounds led to a significant increase in blood pressure.

Table 4 below presents the tested compounds of formula I and the action they revealed in the study on this experimental model. In the table below, only statistically significant results are presented, while the i-criterion was used for statistical testing at a significance level of p "0.05. In Table 4 below, the abbreviation "s.n." ("statistically unreliable") means that the compound from the corresponding example "c" does not have any statistically significant effect on the specified measured value. at

The effect of the tested compounds (through them after intravenous administration at a dose of 1 µmol/kg) on the duration of the ERP, the duration of the OT interval and the IP mimo (abbreviation "s.n." means "statistically unreliable", negative values indicate a reduction in the indicated duration of the ERP, duration interval OT and duration of OKZ-Kcomplex, respectively, on the reduction of systolic blood pressure) e (mm.Hg) o yu in nn nn i o PO i Pot z 00010861 vk1 61788 vv vl |v |v

5. Study of the functional efficiency of the compounds proposed in the invention in ip mimo experiments on the heart of an anesthetized cat

Using the example of the experimental model described below, it is demonstrated that the compounds proposed in the invention have a pronounced selective effect on the atria. After the introduction of the compounds proposed in the invention, there is a significant increase in the threshold for the occurrence of atrial fibrillation, that is, an increase in the current at which atrial fibrillation occurs. At the same time, there is only a minimal effect on the threshold of occurrence of atrial fibrillation of the ventricles.

Live cats were anesthetized with chloralose and urethane (intravenously at a dose of 50 and ZObOmg/kg, respectively) and then their lungs were artificially ventilated with ambient air. Then, after thoracotomy, irritating electrodes were sewn to the right atrium and ventricle of the heart. The threshold for the occurrence of atrial fibrillation and ventricular arrhythmia was determined by a well-known method by applying rectangular electric current pulses of increasing strength before the onset of atrial and, respectively, ventricular fibrillation | more detailed information on the methodology of this study can be found in Vg.). Rpagtas 17, 1961, p. 167, in Nab. ex. Rpagtasoi KhMI/3, 1975, p.131, as well as t5 in РНаптасой. Kev. 25, supplement 2, 1992, p. 156). Tested compounds of the formula | dissolved in propylene glycol (8096-nom) and administered intravenously in increasing dosage (from 5 to ZOμmol/kg). In the future, the threshold for the occurrence of atrial and ventricular atrial fibrillation was determined according to the known method every time 5 minutes after the introduction of the tested compounds in the appropriate dosage. The increase in the corresponding threshold for the occurrence of atrial fibrillation due to the introduction of the studied compounds was expressed as a percentage of the value that preceded the introduction of the studied compounds, i.e. doubling the threshold for the occurrence of atrial fibrillation corresponds to its increase by 10095.

Table 5 below presents the tested compounds of formula I and the action they showed in the study on this experimental model. ch 5) (dose of ZOmcmol/kg, intravenously)

Mo (o) (o) - zv vv o

F vv with co

Particularly high tolerability of the compounds proposed in the invention can be demonstrated by conducting research on other pharmacological experimental models. So, for example, in experiments of ip mygo on preparations of the myocardium of guinea pigs, it is possible to demonstrate that the compounds of the formula | in the extreme case, they have only minor effects that accompany the use of antiarrhythmic drugs of class I. In addition, in "ip myo experiments on the heart of rats, as well as in the experiments of ip myo on the heart of guinea pigs, it is possible to demonstrate that the compounds of formula I in the extreme case cause only minor negative inotropic effects. "» Compounds of formula I can be introduced into the body in the form of conventional pharmaceutical compositions. In some cases, special dosage forms can be prescribed. The doses used depend on the individual characteristics of the patient and vary, of course, depending on the condition to be treated and on the active agent used substances. It should be noted, however, that in the treatment of humans and large mammals, it is recommended, as a rule, to use dosage forms with an active substance content from 0.2 to 50 Ωg, and primarily from 10 to 20 Ωg, based on a single dose. According to the invention compounds of formula I, together with "o conventional pharmaceutical excipients and/or carriers, can be included in solid or liquid pharmaceutical compositions. As an example of solid preparations, preparations intended for o oral administration, such as tablets, dragees, capsules, powders or granules, can be named , and are also intended for "I rectal use of suppositories. These drugs together with the usual they auxiliary pharmaceutical means, such as sliding substances or disintegrants of tablets, may contain inorganic and/or organic carriers commonly used in pharmaceuticals, such as, for example, talc, lactose or

Starch. Liquid preparations, such as suspensions or emulsions of active substances, may include conventional diluents such as water, oils and/or suspending agents such as polyethylene glycols, etc. Other excipients can be additionally added to (F.) of the indicated preparations, such as, for example, preservatives, taste improvers, etc.

The active substances can be mixed with pharmaceutical excipients and/or carriers in a known way and appropriate compositions can be prepared from the mixtures according to a known method. Thus, to obtain solid dosage forms, the active substances can, for example, be mixed with excipients and/or carriers in a conventional way and then subjected to wet or dry granulation according to known methods. The obtained granulate or powder can be directly packed into capsules or pressed from them using the usual technology of core tablets. If necessary, these latter can be used to prepare dragees using the usual technology.

Below, the invention is explained in more detail by examples, which do not limit its scope.

Example 1 2-(4-(4-ethylphenyl)sulfonyl|amino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-M-1,2,3, 4-tetrahydroronaphthalene-1-ylacetamide o more

What 70 What nm

N o

M on o yet

WITH

A) 25g of methyl-4-hydroxyphenylacetate, 14.5ml of 3-methylbut-2-enal and 18.3g of phenylboronic acid were added together to a volume of dry toluene under a nitrogen atmosphere and refluxed for 7 hours. Then, bOml of glacial acetic acid was added to this mixture at room temperature (RT) and refluxed again for 7 hours. After that, the mixture was allowed to cool to room temperature, the solvent was almost completely evaporated under reduced pressure, and the resulting residue was poured into 30 ml of a mixture of ethyl acetate (EA) and water (in a volume ratio of 1:11). By adding solid sodium bicarbonate, the pH value was set to 5, and the organic phase was separated and almost completely evaporated under reduced pressure. After chromatography of the formed residue on silica gel (mobile phase: petroleum ether/EA in a volume ratio of 10:1), 16 g of methyl (2,2-dimethyl-2H-chromen-6-yl)acetate was obtained in the form of a pale yellow oil. chn

TNA-NMR (400 MHz, SOSIz) 5 ppm: 1.15 (in, ZN), 1.27 (5 ZN), 1.43 (z, ZN), 1.60-1.85 (ZN ), 1.97 (t, 1), 2.66-2.82 (4 H), 3.20-3.29 (ZN), 3.54 (ad, yin), 423 (ad, 1), 5.06 (t, 1H), 5.28 (a, tn), 5.59 (a, o 1H), 6.55 (4, 1H), 6.66 (a, 1Hn), 6.97 ( aa, 1nH), 7.03-7.18 (4H), 7.35 (t, 2H), 7.87 (t, 2H). Gee)

SS-NMR (101 MHz, SOSIi) 5 ppm: 15.1 (4), 18.5 (4), 20.1 (0, 26.6 (4), 28.8 (0, 292 ( 0, 302 (0, 42.9 (0, 47.7 (4), 55.1 (4), 74.8 (9), 78.7 (8), 117.9 (4), 121.3 (8), 126.3 (y), 127.2 (c), 127.4 (a, c

C), 128.2 (9), 128.8 (9), 128.9 (a, 2C), 129.3 (a), 130.3 (a), 136.5 (5), 137.6 (8), 137.7 (c), 150.2 (c), 152.3(8), 170.3(8). 00

B) 46 bg of methyl (2,2-dimethyl-2H-chromen-b-yl)acetate obtained above (the total amount from several similar mixtures), 1500 ml of ethylene glycol and 400 ml of a 20956 aqueous solution of caustic sodium were boiled for 3 hours with reflux refrigerator in 44 Oml of tetrahydrofuran (THF). Then the resulting mixture was allowed to cool to room temperature, the solvent was almost completely evaporated under reduced pressure, and 200 ml of tert-butyl ether and 300 ml of water were added to the obtained residue. The mixture was left for 1 hour for mixing, after which the pH of the aqueous phase was set to 6 by adding a 2095 aqueous solution of hydrochloric acid. Then the aqueous phase was extracted twice with dichloromethane in portions of 300 ml, and the combined organic phases were dried over 20 g of sodium sulfate. Then the solvent was almost completely evaporated under reduced pressure, the obtained residue was mixed with petroleum ether, and the first formed crystalline fraction was separated by filtration from the solvent.

The filtrate was re-concentrated under reduced pressure, while the crystalline fraction again fell into the sediment. The combined crystalline fractions were dried and 33.8 g of 2,2-(dimethyl-2H-chromen-b-yl)acetic acid was obtained as a result, which was used in the next reaction without further purification. "H-NMR (400 MHz, SOSIZ) 5 ppm): 1.41 (z, 6H), 3.52 (c, 2H), 5.59 (y, yin), 6.27 (a, 1 ), 6.72 (a, so 1H), 6.88 (4, 1H), 6.99 (aa, 1n). o 50 ZS-NMR (101 MHz, SOS) 5 (pp/million) | 28.1 (4, 22), 40.2 (0, 76.3 (c), 116.5 (4), 121.4 (8), 122.1 (9), 125.3 (8), 127.2 (a), 129.9 (a), 131.1 (a), 152.3 (c), 177.8 (8).

More. B) A solution of 9.6 g of 1,1-carbonyldiimidazole (KDI) in 85 ml of THF was slowly added to a solution of 11.7 g of 2,2-(dimethyl-2H-chromen-b-yl)acetic acid obtained above in 1000 ml of THF and stirred for 30 minutes at CT. Then a solution of 8.8 ml of 1,2,3,4-tetrahydro-1-saphthylamine in 30 ml of THF was slowly added dropwise to this mixture, the resulting mixture was stirred for an hour and left to stand overnight at room temperature. Then the solvent was almost completely evaporated

HF) under reduced pressure and the obtained residue was mixed with a mixture of diethyl ether and isopropanol (in a volume ratio of 100:1) and crystallized. The formed crystals were separated by vacuum filtration and dried at a temperature of 659C and a pressure of 20 bar. After chromatography on silica gel washing liquid consisting of diethyl ether/isopropanol, an intermediate product was additionally obtained, which was combined with its main amount and dried. As a result, 17.5 g of 2-(2,2-dimethyl-2H-chromen-b6-yl)-M-1,2,3,4-tetrahydronaphthalene-1-ylacetamide was obtained in the form of a colorless solid, which was used without further purification in the following reaction.

TNA-NMR (400 MHz, SOS) 5 parts per million)|: 1.41 (in, b6H), 1.60-1.85 (ZN), 1.98-2.08 (1), 2.65 -2.80 (2H), 3.45-3.55 (2H), 5.12-5.20 (1H), 5.60 (y, 1H), 5.66 (4, 1H), 6 .26 (9, 1H), 6.71 (a, yin), 6.86 (a, tn), 6.96 (aa, 1n), 7.02-7.07 (1H), 7.08- 7.17(Z3H).

ZS-NMR (101MHz, SOS) 5 parts/million 20.2 (0, 28.0 (4, 2C), 29.2 (0, 303 (0, 43.2 (0, 47.7 (9), 76.3 (c), 116.8 (a ), 121.7 (8), 122.0 (4), 126.2 (9), 126.9 (8), 127.2 (a), 128.2 (0), 129.1 (4) , 129.8 (9), 131.3 (49), 136.7 (c), 137.5 (8), 152.2 (c), 170.7 (c).

D) 95 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to a solution of 11 g of 2-(2,2-dimethyl-2H-chromen-b6-yl)-M-1,2,3,4-tetrahydronaphthalene-1-ylacetamide obtained above in bOO ml of dichloromethane . Then, a total of 15 g of g-chloroperoxybenzoic acid (MHPBK) was added to the resulting mixture in three portions at bg with b-minute intervals and stirred at CT for 18 hours. The organic phase was separated and almost completely evaporated on a rotary evaporator at a temperature of 659C and a pressure of 20 70 bar. As a result, 2-(2,2-dimethyl-1a,7p-dihydro-2H-oxireno|c|chromen-b-yl)-M-1,2,3,4-tetrahydronaphthalene-1-ylacetamide was obtained in the form of a crude oil , which was used in the next reaction without further purification.

TNA-NMR (400 MHz, SOSI) 585 parts per million: 1.23 (in, bH), 1.56 (z, b6H), 1.63-1.85 (6H), 1.97-2, 10 (2H), 2.65-2.82 (4H), 3.43-3.56 (6H), 3.84-3.89 (2H), 5.12-5.22 (2H), 5 ,62-5-72 (2H), 6.75 (a, tn), 6.76 (a, tn), 79.7.02-7.19 (10 H), 7.23-7.27 (2H) .

ZS-NMR (101 MHz, SOSIi) 5 ppm) |: 20.1 (0, 22.6 (4), 25.7 (94), 292 (0, 30.2 (9, 431 (9, 47 ,7 (4), 50.8 (49), 62.7 (9), 73.2 (8), 118.6 (4), 120.5 (8), 126.2 (40), 126.3 ( 4), 127.2 (4), 127.3 (y), 127.5 (5), 128.2 (a), 128.3 (a), 129.2 (a), 130.5 (a ), 131.1 (a), 131.2 (a), 136.5 (8), 137.5 (8), 137.6 (c), 151.8 (8), 170.4 (c) .

D) To a solution of 16 g of 2-(2,2-dimethyl-1a,7p-dihydro-2H-oxyreno|sichromene-b-yl)-M-1,2,3,4-tetrahydronaphthalen-1-ylacetamide obtained above in 88 ml 8 ml of a 25956% aqueous solution of ammonia was added to ethanol and stirred at room temperature for 18 hours. Then 200 ml of dichloromethane and 500 ml of methanol were added and stirring was continued for another 15 min. After that, 200 ml of water was added and left for 15 minutes for further mixing. The organic phase was separated and almost completely evaporated under reduced pressure, the resulting residue was mixed with 3 ml EA, filtered and dried on a rotary evaporator at a temperature of 702C and a pressure of 20 bar. As a result, we got (U

3g 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-b-yl)-M-1,2,3, 4-tetrahydronaphthalene-1-ylacetamide in the form gray solid, which was used in the next reaction without further purification. "NA-NMR (400MHz, DMSO-O6) 5 (|fr./million|: 1.08 (in, 6H), 1.35 (z, 6H), 1.60-1.95 (12H), 2 .63-2.83 (4H), t 3.17 (9, 2H), 3.32-3.40 (4H), 349 (a, 2H), 4.90-4.98 (2H), 5 ,32-5.38 (2H), 6.62 (a, 2H), 7.01 (ad, 2n), "F 7.05-7.18 (8H), 7.47 (a, 2H), 8.32-8.35 (2H). b

ZS-NMR (101 MHz, DMSO-Ov) 5 (/ppm): 18.6 (4), 19.9 (0, 27.0 (4), 28.7 (0, 29.8 (0 , 41.7 (0, 46.2 (9), 50.8 (4), 76.6 (4), 77.8 (8), 115.6 (4), 125.5 (8), 125 ,6 (a), 125.7 (a), 126.5 (4), 127.9 (c), c 128.0 (4), 128.1 (49), 128.3 (9), 128 ,4 (4), 128.6 (4), 136.9 (c), 137.5 (8), 150.5 (c), 169.8 (c).

E) 1.67 g of 4-ethylbenzenesulfonyl chloride was added dropwise to a solution of 3.75 g of 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)- M-1,2,3,4-tetrahydronaphthalen-1-ylacetamide and 8.4 ml of triethylamine in 16 b0 ml of dichloromethane. Then another 5 ml of dimethylformamide (DMF) was added and the resulting mixture was stirred for 18 hours at room temperature. After that, 100 ml of water was added and stirring was continued for another 5 minutes. The organic phase was separated and the solvent was almost completely evaporated under reduced (73 s) pressure, the resulting residue was chromatographed on silica gel (mobile phase: EA/cyclohexane/methanol in a volume ratio of 110:140:2), and the phases containing the product were were combined and concentrated. The residue was mixed with petroleum ether/diethyl ether (in a volume ratio of 10:1). The formed crystallite was separated by vacuum filtration and dried on a rotary evaporator at a temperature of 402C and a pressure of 25 bar. As a result, 2 was obtained, 3 g of the compound indicated in the title of example 1 in the form of colorless crystals. co TN-NMR (400 MHz, SOCIv) 5 parts per million: 1.14 (in, ЗН), 1.16 (in, ЗН), 1.26 ( 5 ZN), 1.28 (ZN), 1.44 (5, with b6H), 1.60-1.85 (8H), 1.95-2.08 (2H), 2.66-2.83 (8H), 3.18-3.33 (6H), 3.53-3.63 (2H), 418-428 (2H), 5.02-5.13 (2H), 5.26-5, 37 (2H), 5.52-5.60 (2H), 6.54 (a, 2H), 6.66-6.71 (2H), 6.95-7.19 (t, 1OH), 7 ,34-7.39 (se) (4 H), 7.85-7.92 (4 H) at 20 C NMR (101 MHz, SOSIi) 5 parts/million: 15.1 ( 4), 18.4 (4), 20.1 (0, 26.6 (4), 28.8 (0, 292 (0, 302 (0, 42.9 (0, 47.7 (4), 47.8 (4), 55.1 (4), 74.9 (4), 75.0 (a), 78.6 (5), 78.7 (8), 118.0 (4), 121 ,0 (c), "and 126.2 (9), 126.3 (4), 127.2 (c), 127.4 (a), 128.2 (4), 128.8 (a), 128.9 (y), 129.2 (a), 129.3 (4), 130.3 (9), 136.5 (c), 137.6 (8), 150.3 (8), 152 ,3 (in), 170,3 (8).

Example 2 2-(3554K)-4-(4-ethylphenyl)sulfonaliamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-b-yl)-M-K1K)-1 ,

GF! 2,3,4-tetrahydronaphthalen-1-yl|iacetamide ko 60 b5 sn

With Fr

OA S

With nm

What | I'm in it

F o 6 8) from

WITH

WITH

A) 24.5 g of KDI, ZOg 2,2-(dimethyl-2H-chromen-b-yl)acetic acid (production see example 1B)) and 22.8 ml (1kK)-1,2,3,4-tetrahydro -1-n-safthylamine was subjected to interaction with each other similarly to example IV). As a result, 49 g of 2-(2,2-dimethyl-2H-chromen-b-yl)-M-|-(1K)-1,2,3,4-tetrahydronaphthalene-1-ylacetamide was obtained in the form of a colorless crystal, which without further purification was used in the next reaction.

TN-NMR (400 MHz, SOS) 5 (fr./million): 1.41 (in, 6H), 1.60-1.85 (ZH), 1.98-2.08 (1H), 2.65 -2.80 (2H), 3.45-3.55 (2H), 5.12-520 (1), 5.60 (a, 1 NN), 5.66 (a, tn), 6, 26 (a, tn), 6.71 (a, yin), 6.86 (a, tn), 6.96 s (aa, 1n), 7.02-7.07 (1H), 7.08- 7.17(Z3H).

ZS-NMR (101 MHz, SOS) 5 |fr./million)| 20.2 (9, 28.0 (4, 2C), 292 (0, 303 (0, 43.2 (9, 47.7 (9), o 76.3 (c), 116.8 (a) , 121.7 (8), 122.0 (4), 126.2 (9), 126.9 (8), 127.2 (a), 128.2 (0), 129.1 (4), 129.8 (9), 131.3 (49), 136.7 (c), 137.5 (8), 152.2 (c), 170.7 (c).

B) 5 g of dichloromethane was added to a solution of 44 g of 2-(2,2-dimethyl-2H-chromen-b-yl)-M-(1K)-1,2,3,4-tetrahydronaphthalene-1-ylacetamide obtained above in 80 Oml of dichloromethane (5,5)-manganese(II)-salen and 7g of M-oxide of pyridine. The mixture obtained in this way was cooled to - 02C and for 45 minutes a mixture of 100 ml of an aqueous solution of sodium hypochlorite (С1»1396) and 8 ml of sodium chloride was added to it.

39ZPhO aqueous solution Mag2HRO,). The mixture was stirred at 02C for 1 hour, after which the organic phase was separated and mixed with 500 g of Seyye product for 1 hour. 503. Next, the solid substance was filtered off and the filtrate was washed with dichloromethane until it was completely decolorized. After that, the filtrate was concentrated to dryness under reduced pressure. As a result, 4 g of 2-(ICha,75)-(2,2-dimethyl-1a,7p-dihydro-2H-oxyreno|c|chromen-b-yl|-IM-1,2,3,4-tetrahydronaphthalene- 1-ilacetamide In the form of crude oil, which was used in the next reaction without further purification or more detailed determination of characteristics. " c) 40 g of the above obtained Also c 2-(Ta,75)-(2,2-dimethyl-1a, 7B-dihydro -2H-oxyreno|c|chromen-b6-yl|-M-1,2,3,4-tetrahydronaphthalene-1-ylacetamide and 250 ml of 2595% aqueous ammonia solution were subjected to interaction with each other similarly to example 1D). After "" chromatography of the crude product on silica gel (mobile phase: dichloromethane/methanol/2590 aqueous ammonia solution (in a volume ratio of 75:50:2)), 13.2 g of 2-I(35.4K)-4- amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-b-yl|-M-K1K)-1,2,3,4-tetrahydronaphthalen-1-yl (se) acetamide in in the form of oil, which was used in the next reaction without further purification. with "NA-NMR (400MHz, DMSO-O6) 5 (|pp/ml|: 1.08 (in, 6H), 1.35 (z, 6H) , 1.60-1.95 (12H), 2.63-2.83 (4H), 3.17 (a, 2H), 3.32-3.40 (4H), 3.49 (a, 2H ), 4.90-4.98 (2H), 5.32-5.38 (2H), 662 (a, 2), 7.01 (aa, 2n), (Ce) 7.05-7.18 (8H), 7.47 (a, 2H), 8.32-8.35 (2H) at 250 C NMR (101 MHz, DMSO-O6) 5 ppm: 18.6 (4) , 19.9 (0, 27.0 (4), 28.7 (0, 29.8 (0, 41.7 (0, 46.2 (9), 50.8 (4), 76.6 ( 4), 77.8 (8), 115.6 (4), 125.5 (8), 125.6 (a), 125.7 (a), 126.5 (4), 127.9 (c ), "m 128.0 (49), 128.1 (4), 128.3 (49), 128.4 (a), 128.6 (a), 136.9 (c), 137.5 ( 8), 150.5 (c), 169.8 (8). d) 5.94 mL of 4-ethylbenzenesulfonyl chloride, 13.2 g of of the above 2-(3554K)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-b-yl|-M-K1K)-1,2,3,4- tetrahydronaphthalen-1-yl 25 acetamide, 8 in 8 ml of triethylamine and 4 ml of dimethylformamide were subjected to interaction with each other similarly to the example

F! 1E). As a result, 6.2 g of the compound indicated in the title of example 2 was obtained in the form of a solid amorphous foamy substance. o TN-NMR (400 MHz, SOSIz) 5 parts/million: 1.15 (in, HL), 1.26 (5 9-76 Hz, HL), 1.45 (in, HL), 1.60 -1.85 vo (ZNU, 2.01 (t, 1H), 2.65-2.82 (4H), 3.20-3.33 (ZH), 3.58 (aa, 9U-9.0 , 3.0Hz, 1), 4.23 (aa, 9-9.0, 8.7Hz, 1H), 5.04 (t, 1), 5.16 (a, 9-8.7Hz, 71) , 5.51 (a, 9-8.5 Hz, 1H), 6.54 (a, 9-2.0 Hz, 1H), 6.68 (a, 9-8.4 Hz, MH), 6.98 ( aa, 2-84, 2.0Hz, 1H), 6.95-7.19 (4H), 7.37 (t, 2H), 7.87 (t, 2H).

SS-NMR (101 MHz, SOSIv), 5 ppm: 15.1 (4), 18.4 (4), 201 (0, 26.6 (4), 28.9 (9, 29.2 ( 0, 302 (0, 43.0 (0, 47.8 (4), 55.1 (4), 75.0 (9), 78.7 (8), 118.0 (4), 121.1 (8), 126.2 (y), 127.3 (c), 127.4 (a, bv5 ZS), 128.2 (4), 128.7 (4), 129.0 (y, 2C) , 129.3 (a), 130.4 (4), 136.5 (8), 137.6 (8), 137.7 (8), 1504 (c), 152.3 (8), 170, 3 (8).

Io 9--8.32 (c-0.1, MeOH).

Example C

M-benzyl-2-14-I(4-ethylphenyl)sulfonyl(neopentyl)amino)|-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)acetamide o sn, 70 : d

NM

N y y M. o .OoNn o o KA sa

S Z

A) A solution of 16.2 g of KDI in ZOO ml of THF was slowly added to a solution of 19.7 g of 2,2-(dimethyl-2H-chromen-b-yl)acetic acid (for the preparation, see example 1B)) in ZOO ml of THF and stirred for 100 min at CT. Then, 10.9 ml of benzylamine was slowly added dropwise to this mixture, and the resulting mixture was stirred for an hour. The solvent was almost completely evaporated under reduced pressure and the resulting residue was extracted once with 500 ml of the mixture (o)

EA and water (in a volume ratio of 2:3). The organic phase was almost completely evaporated under reduced pressure and after chromatography on silica gel of the formed residue (mobile phase: EA/cyclohexane in a volume ratio of 1:1), drying of fractions containing the product on a rotary evaporator at a temperature of 70 2С and a pressure of at 20 bar, 28 g of M-benzyl-2-(2,2-dimethyl-2H-chromen-b-yl)acetamide were obtained in the form of oil, which was used in the next reaction without further purification or more detailed determination of characteristics. at

B) 980 ml of a saturated aqueous solution of sodium bicarbonate was added to the solution of 28 g obtained above F

M-benzyl-2-(2,2-dimethyl-2H-chromen-b-yl)yaoacetamide in 480 ml of dichloromethane. Then, a total of 44.1 g of MHPBK was added to the resulting mixture in three portions of 14.7 g at 5-minute intervals, and for 18 hours, EM with 5 was stirred at RT. The organic phase was separated, extracted once with 200 ml of a saturated aqueous solution of sodium bicarbonate, and then it was almost completely evaporated under reduced pressure. As a result, they received Z5g

M-benzyl-2-(2,2-dimethyl-1a,7p-dihydro-2H-oxirenoi|sichromene-b-yl)uacetamide in the form of crude oil, which was used in the next reaction without further purification or more detailed determination of characteristics. c) To the 5g solution obtained above "

M-benzyl-2-(2,2-dimethyl-1a,7p-dihydro-2H-oxirenoi|c|chromen-b-yl)lacetamide was added to 250 ml of ethanol in 250 ml of a 2590% aqueous solution of ammonia and stirred for 18 hours at CT. Then the reaction mixture was poured into 500 ml of water and extracted with 250 ml of dichloromethane. The organic phase was separated, dried over sodium sulfate and almost completely evaporated under reduced pressure, the resulting residue was mixed with 200 ml of diethyl ether.

Crystals that fell out after some time were separated by vacuum filtration and dried on a rotary evaporator

At a temperature of 60 and a pressure of 20 bar. As a result, 11 g of 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6b-yl)-M-benzylacetamide were obtained as a gray solid, which without further purification or a more detailed definition of the characteristics used in the next reaction. "se d) To a solution of 11 g of 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-"M-benzylacetamide obtained above in 200 ml of methanol was added 4 ml of trimethylacetaldehyde. Then 2.44 g of Mavn zSM was added in several portions, and the resulting suspension "M was stirred for 2 hours at 5020. After cooling to room temperature, the reaction mixture was poured into 200 ml of water. The aqueous phase was extracted once with 150 ml of EA, the combined organic phases were dried over sulfate sodium and the solvent were almost completely evaporated under reduced pressure. After chromatography of the formed residue on silica gel (mobile phase: EA/cyclohexane in a volume ratio of 1:1) and drying of the fractions containing the product on a rotary evaporator, 10.g (F. M-benzyl-2-(3-hydroxy-2,2-dimethyl-4-(neopentylamino)-3,4-dihydro-2H-chromen-6-yl|acetamide in the form of a colorless oil. "H-NMR (400 MHz , SOSIZ) 5 Parts/million): 1.15 (in, ZN), 1.25 (B ZN), 1.43 (in, ZN), 2.70 (d, 2H), 3.18-3 .31 bo (Z3H), 3.55 (aa, 1), 4.22 (da, tn), 4.30 (4, 2), 5.51 (a, yin), 5.8 1 (i l1H), 6.56 (a, tn), 6.67 (a, tn), 6.96 (aa, 1H), 7.15 (t, 2H), 7.21-7.30 ( ZN), 7.32 (t, 2H), 7.84 (t, 2H).

SS-NMR (101 MHz, SOSIv), 5 ppm: 15.1 (4), 18.5 (4), 26.6 (4), 28.8 (0, 42.7 (9, 43, 5 (0, 551 (4), 74.8 (9), 78.7 (8), 117.9 (94), 121.2 (8), 127.0 (in), 127.4 (0, 22), 127.5 (4, 3), 128.7 (j, 22), 128.9 (9, ZO), 130.4 (4), 137.6 (c), 138.1 (8) , 150.2 (5), 152.3 (5), 171.0 (5). because Example 4

M-benzyl-2-14-I(4-ethylphenyl)sulfonyl|(neopentyl)amino|-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6b-yl)acetamide sn. at;

AND

Still r: y

M Me ore,

WITH

4. ml of 4-ethylbenzenesulfonyl chloride was added dropwise to the solution of 10.8 g obtained above in example C

M-benzyl-2-|3-hydroxy-2,2-dimethyl-4-(neopentylamino)-3,4-dihydro-2H-chromen-6b-yl)acetamide and ml of triethylamine in 1000 ml of dichloromethane. Dichloromethane was immediately almost completely evaporated under reduced pressure, and the resulting mixture was stirred for 1 hour at a temperature of 652C and a pressure of 180 bar. Then the entire mixture was poured into 150 ml of water, the aqueous phase was extracted once with 200 ml of EA. The solvent was almost completely evaporated under reduced pressure, the resulting residue was dried over sodium sulfate and then chromatographed on silica gel (mobile phase: petroleum ether/EA in a volume ratio of 3:1). After drying the product-containing fractions, 3.6 of the title compound (2 conformers) were obtained as a colorless oil.

TN-NMR (400 MHz, SOSIV) major isomers, 5 |fr./ml: 0.75 (in, 9H), 1.15 (5, ЗН), 1.26 (и, ЗН), 1.46 (5 , ZH), 2.36 (1H), 2.65-2.75 (2H), 2.90-3.40 (4H), 3.86 (aa tn), 4.39 (a, 2H), 4.76 (a, 1), 5.50 (5 tn), - 6.48 (1H), 6.73 (d, 1H), 7.03 (da, 1H), 7.15-7.35 (7H), 7.81 (t, 2H). o "H-NMR (400 MHz, SOSIv) minor isomers, 5 |parts/million|: 0.86 (z, 9H), 1.19 (5, ZN), 1.24 (B ZN), 1.51 (5, ZH), 2.65-2.75 (2H), 2.81 (y, tn), 3.25-3.60 (4H), 4.25-4.61 (4H), 4, 60 (aa 1), 5.87 (i, 1H), 6.73 (a, o 1H), 6.96 (aa, 1H), 7.15-7.35 (8H), 7.66 (t , 2H). urine

ISR-NMR (101MHz, SOSIv) major isomers, 5 |pp/m|: 15.1 (4), 17.9 (4), 27.0 (4), 28.8 (4, ZS), 28 ,8 so (0, 32.0 (8), 43.0 (0, 43.7 (0, 56.3 (0, 59.0 (4), 71.2 (a), 79.1 (8), 118.4 (a), 120.7 (c), 127.0-130.4 (123), 137.2 (8), 138.1 (8), 150.4 (c), 153.0 ( 8), 170.7 (8).

ISR-NMR (101 MHz, SOSIv) minor isomers, 5 ppm): 15.1 (4), 18.6 (4), 27.2 (4), 28.0 (4, ZS), 28, 8 (0, 33.5 (8), 43.3 (0, 436 (0, 63.0 (0, 63.4 (4), 73.2 (a), 78.8 (8), 118, 0 (a), 122.0 (c), 125.7-129.8 « 20 (123), 137.3 (8), 138.3 (8), 150.2 (8), 151.8 ( 5), 171.3 (8). with c Example 5 and M-(4-chlorobenzyl)-2-(3-hydroxy-2,2-dimethyl-4-("3-methylphenyl)sulfonylamino)-3, 4-dihydro-2H-chromen-b-yl) and acetamide; o o; o We

F SI 8 hours,

NM x with M | he o o o Kz vo sn, 60 , , y , . ,

A) 175.6 g of methyl-4-hydroxyphenylacetate and 128.9 g of phenylboronic acid were added together to 3.5 l of m-xylene.

88.9 g of 3-methylbut-2-enal and 130 ml of glacial acetic acid were then added to this mixture. Further, in a nitrogen atmosphere in a Dean-Stark apparatus, after reaching approximately 7095 conversion of phenol (duration of approximately 48-72 hours), it was heated to 14020. Then the reaction mixture was allowed to cool to room temperature, filtered at 65 and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in a mixture of THF and 2595 aqueous ammonia solution (1:1 volume ratio) and stirred for 2 hours. After that, THF was almost completely evaporated under reduced pressure and EA was added. The organic phase was separated, successively washed with aqueous 7N. MassOnN and a saturated aqueous solution of table salt and finally dried over sodium sulfate. The solvent was almost completely evaporated under reduced pressure and the resulting residue was chromatographed on silica gel (mobile phase: n-hexane/EA in a volume ratio of 15:1-10:1). After drying the fractions containing the product in a vacuum created by an oil pump, 106 g of methyl (2,2-dimethyl-2H-chromen-b-yl)acetate was obtained in the form of a pale yellow oil, which, without further detailed characterization, was used in the next reaction.

B) 106g of methyl(2,2-dimethyl-2H-chromen-b-yl)acetate obtained above was dissolved in 9UOO ml of THF. A solution of 57.6 g of SHON in 900 ml of water was added to this 7/0 mixture and stirred at CT for 1 hour. THF was almost completely evaporated under reduced pressure and the aqueous residue was acidified by adding an aqueous solution of hydrochloric acid. Then the aqueous phase was extracted with EA, and the combined organic phases were successively washed with a saturated aqueous solution of table salt and water. The organic phase was dried over sodium sulfate and the solvent was almost completely evaporated under vacuum. As a result, 97.6 bg of 2,2-(dimethyl-2H-chromen-b-yl)acetic acid were obtained, which was used in the next reaction without further purification or more detailed determination of characteristics.

B) 14.0 g of 2,2-(dimethyl-2H-chromen-b-yl)acetic acid obtained above and 13.54 g of DEK-HCI were dissolved at CT in dichloromethane. Then, 10.0 g of 4-chlorobenzylamine was added dropwise to this mixture with stirring, and stirring was continued for another 16 hours at room temperature. Then the reaction mixture was successively washed with water,

Zn. with an aqueous solution of hydrochloric acid and a saturated aqueous solution of table salt, and the organic phase was dried over sodium sulfate. After evaporation of the solvent under reduced pressure and drying of the formed residue in a vacuum created by an oil pump, 21.92 g of crude

M-4-chlorobenzyl-2-(2,2-dimethyl-2H-chromen-6-yl)acetamide, which was used in the next reaction without further purification or more detailed determination of the characteristics. high school

D) 700 ml of a saturated aqueous solution of sodium bicarbonate was added to the solution of 21.92 g obtained above

M-4-chlorobenzyl-2-(2,2-dimethyl-2H-chromen-6b-yl)acetamide in bbOml of dichloromethane. Then a total of 31.6 g of MHPBK (7295-noi) was added to this mixture in portions i) and stirred at room temperature for 1 hour. The organic phase was separated, washed twice with a 596% aqueous solution of sodium bicarbonate, dried over sodium sulfate and almost completely evaporated under reduced pressure. After drying in a vacuum created by an oil pump (with a pump, //M-(4-chlorobenzyl)-2-(2,2-dimethyl-1a,7p-dihydro-2H-oxirenoi|sichromene-b-yl)dacetamide U was obtained in the form of crude oil, which was used in the next reaction without further purification or more detailed determination of its characteristics

D) The M-(4-chlorobenzyl)-2-(2,2-dimethyl-1a,7p-dihydro-2H-oxyreno|sichromene-b-yl)acetamide obtained above was immediately added to a mixture of this amount of ethanol and 2595- of an aqueous solution of ammonia (in a volume ratio of 6:5), which made it possible to obtain a 0.2-molar solution of the indicated compound, which was then stirred for 1 hour at 50 9C. After that, the compound was allowed to cool to RT and the solvent was almost completely evaporated under reduced pressure, the resulting residue was chromatographed on silica gel (mobile phase: gradient dichloromethane/methanol/2595 aqueous ammonia solution in a volume ratio varying from 97.5:2 :0.5 to 90:9.5:0.5). After drying the fractions containing the product, 7.3 g of 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6b-yl)-M-4-chlorobenzylacetamide were obtained , which was used in the next reaction without further 2 s purification. The formation of another regioisomer, i.e. 2-3-amino-4-hydroxy-2,2-dimethylchromene-b-yl|-M-4-chlorobenzylacetamide, was not observed. "» E) In the slot of the tablet for samples intended for parallel automated synthesis, to the Umg solution obtained above 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromene-b- yl)-M-4-chlorobenzylacetamide in b.5 ml of dichloromethane was successively added to 15 mg of IP-methylpiperidine and a solution of b.Omg of 3-methylbenzenesulfonyl chloride in 0.5 ml of dichloromethane. The mixture was shaken for 40 hours at RT and then 20 mg of AMPS was added to it. The shaking was continued for another 1 hour at RT, after which the liquid phase was separated from the thermoplastic and the thermoplastic was washed twice with dichloromethane in Tml portions. The solvent contained in the combined organic phases was evaporated under reduced pressure and as a result the compound indicated in the title of example 5 was obtained with a purity of 9595 (determination by РХВР-MS), MANI)" 529. - Example 6 "I M-butyl-2-A-I(2,5-dimethoxyphenyl)sulfonal|-2-"-ethylbutyl)amino|- 3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromomen-6-yl)acetamide

F) ko 60 b5

Me

IN

- With 70 MA

A lot is known; o There are

WITH

A) 10.0g of 2,2-(dimethyl-2H-chromen-6b-yl)acetic acid (see example 5B) for preparation), 9.67g of DEC.HCI and 5.41g of n-butylamine were subjected to interaction with each other similarly to example 58). As a result, 17.5 g of raw material was obtained

M-(n-butyl)-2-(2,2-dimethyl-2H-chromen-b-yl)acetamide, which was used in the next reaction without further purification or more detailed characterization. step B) 7O00Oml of a saturated aqueous solution of sodium bicarbonate, a solution of 17.5 g obtained above

M-(n-butyl)-2-(2,2-dimethyl-2H-chromen-b-yl)acetamide in bbOoml of dichloromethane and 31.6 g of MHPEK (72965-noy) were subjected to (o) interaction with each other similarly to the example of BM ). As a result, raw was obtained

M-butyl-2-(2,2-dimethyl-1a,7p-dihydro-2H-oxyreno|sichromene-b-yl)uacetamide, which was directly used in the next reaction without further purification or more detailed determination of the characteristics. cha 20 B) The above-obtained butyl-2-(2,2-dimethyl-1a,7p-dihydro-2H-oxirenoi|sichromene-b-yl)yaoacetamide was immediately added to a mixture of this amount of ethanol and a 25906 aqueous solution ammonia (in a volume ratio of 6:5), which made it possible to obtain a 0.2-molar solution of the specified compound, which was then subjected to further processing similarly to example 5D). As a result, 74 g of F 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-M-(n-butyl)acetamide were obtained, which without further The purification was used in the next reaction. The formation of another regioisomer, (se) 2-3-amino-4-hydroxy-2,2-dimethylchromen-b6-yl|-N-(n-butyl)acetamide, was not observed. d) 610 mg of 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-M-(n-butyl)acetamide obtained above was dissolved in 20 ml of 1THF and 220 μl TMOF was added. Then 197 mg of ethyl butylaldehyde was added to this mixture and shaken for 20 16 hours at room temperature. Next, the solvent was removed under reduced pressure, the resulting residue was dissolved in 20 ml of methanol, and 7.9 g of IP-VN was added to it. and the mixture was shaken for another 1 hour at RT. Then the mixture was filtered and the thermoplastic was washed with methanol. The combined filtrates were almost completely evaporated under reduced pressure, the resulting residue was dissolved in 200 ml of dichloromethane, and after that, 0.4 equivalents of the known polymer-immobilized aldehyde (IP-CHO) and 0.6 equivalents of AMPS were successively added. Then it was repeatedly shaken for 15-16 hours at CT, the liquid phase was filtered from the thermoplastic and the latter was washed with THF. The combined liquid organic phases were evaporated under reduced pressure, resulting in 572 mg of 2-I(4-(2-ethylbutylamino)-3-hydroxy-2,2-dimethylchromen-b6-yl|-M-(n-butyl) of acetamide with a purity of 9595 (definition

KkZz with the help of РХВР-MS), which was used in the next reaction without further purification or more detailed determination of characteristics. i-o 50 D) In the socket of the tablet for samples, intended for parallel automated synthesis, to the solution av | 14.8 mg of 2-I4-(2-ethylbutylamino)-3-hydroxy-2,2-dimethylchromen-b6-yl|-N-(n-butyl)acetamide obtained above in

20 mg of IP-methylpiperidine resin and a solution of /37.1 mg were successively added to 0.5 ml of dichloromethane

Another 3,5-dimethoxybenzenesulfonyl chloride in 04 ml of dichloromethane. The mixture was shaken for 168 hours at CT, the resin was filtered, and then 120 mg of IP-AMPS was added to the filtrate. It was then shaken for another 16 hours at 5°C, after which the liquid phase was separated from the resin and the resin was washed twice with dichloromethane in portions of 1 ml each. The solvent contained in the combined organic phases was evaporated under reduced pressure and the result

HF) obtained the compound indicated in the title of example 6 with a purity of 9695 (determination using РХВР-MS), NAME 591. o According to the methods described in the examples or similar to them, it is also possible to obtain compounds of formula I, presented in table 6 below. b5

Table 6: Other compounds of formula I; | App.|K | And it's co-4

Mo 4-ethylphenyl neopentyl benzyl IA 008 |Me|Me 4 ethylphenyl neopentyl benzyl 70 Me Me! 4-ethidphenyl NN NO (5)-tetrahydro-| 5 naphthalen-1-yl 4-ethylphenyl neopentyl phenylethyl trans 4-ethylphenyl benzyl. | 5 4-ethylphenyl phenylethyl | trans 13 |MeiMe) 3-fluorophenyl Hn H| (5)-tetrahydro- | trans naphthalene-1-1l 14 |Me|Me phenyl n H | (5)-tetrahydro- | trans that naphthalene-1-yl |Me|Me)| 4-methylphenyl H NI (5)-tetrahydro-| ptrans naphthalene-1-yl i s yu" 16 |Me/Me| 4-ethylphenyl DOSNo»IEMSoNH 1 tran | c 4-iodophenyl. | NN | | n-butyl trans

Me Me| 4-methylphenyl | cyclopropyl- | H benzyl trans methyl iso-4-methylphenyl | Z-methylbutyl benzyl o 21 |Me|Me| 2,5-dimethoxy- | 2-ethylbutyl |H| 2-furylmethyl trans F phenyl 22 |Me|Me| C-Methoxyphenyl| n-pentyl |H 1,2-dimethyl-trane cm propyl so 23 |Me|Me| 4-trifluoro- | 3-methylbutyl | H benzyl trans methylphenyl « liu 24 |Me|Me 33-chloro-4-2-methylpropyl | H n-propyl trans - s fluorophenyl z» 2-naphthyl 3Z-methylbutyl benzyl trane and 4-biphenyl | Z-methylbutyl n-propyl 15 Z-methoxyphenyl | 3-methylbutyl 4-chlorobenzyl trans co "Note: the term "trans" denotes the trans-configuration of substituents at the C-3 and C-4 atoms, while, however, we are talking about mixtures of stereoisomers, Me means methyl, "5" and "K" means, respectively, the absolute configuration at the corresponding carbon atom. c Example o 20 Capsules containing 2-(4-((4-ethylphenyl)sulfonaliamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro- 2H-chromen-b-yl)-M-1,2,3,4-tetrahydrona" and phthalen-1-ylacetamide

The composition of the manufactured capsules per capsule: 22 2-(A--(4-ethylphenyl)sulfonyl|amino)-Z-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-b-yl) -M-1,2,3,4-tetrahydronaphthalene-1-ylacetamide 20 mg corn starch bomg o lactose ZbOmg io) EA 4.5. 60 A homogeneous paste-like mixture is prepared from the active substance, corn starch and lactose using EA (ethyl acetate). Then this paste is crushed and the formed granulate is placed on a suitable pallet, on which it is dried to remove the solvent at 4520. The dried granulate is passed through a grinding unit and mixed in a suitable mixer with other auxiliary substances, such as using the following substances: b5 talc Bmg magnesium stearate Bmg corn starch Umg.

At the end, the obtained granules are packaged in 400-milligram capsules (capsules of size 0).

Claims (11)

The formula of the invention 0 1. Compounds of general formula I 4 o. also х и - ЯЗ-рз3 тв ве / ОН Й Z evo o (v; ry in which В" means S.-Sualalkyl, B? means S.-Sualalkyl, BZ means phenyl, optionally mono- or disubstituted by halogen , C-4-Slalkyl, C--Slalkoxy group or trifluoromethyl, naphthyl or biphenyl, si 29 B" means hydrogen, C-Salkyl or C3-Scycloalkyl-C 1-C.alkyl, ge) VE? means hydrogen and 29 means C-Salalkyl, phenyl-C4-Slalkyl, the phenyl group of which is optionally monosubstituted by halogen, furyl-S-Salkyl or tetrahydronaphthyl, or M zo B? and K9, together with the nitrogen to which they are bound, form a piperazine ring, optionally substituted by phenyl. at 2. Compounds according to claim 1, in which each of the VC! and B? means methyl. b 3. Compounds according to claim 1, in which KZ means optionally monosubstituted phenyl. 4. Compounds according to claim 1, in which B" means hydrogen, C-Sulfyl or cyclopropyl-C-Sulfyl. sia Zo 5. Compounds according to claim 1, in which KE? means phenyl-C-Slalkyl or tetrahydronaphthyl. with b. Compounds according to claim 1, in which in the pyran ring the carbon atom (C-3) carrying the hydroxy substituent is in the 5-configuration, and the carbon atom (0-4) carrying the nitrogen-containing substituent is in the K-configuration. " 7. Compounds of formula I according to any of the previous items, selected from the group that includes 2-(4-I(4-ethylphenyl)sulfonyl|amino)-3-hydroxy-2,2-dimethyl-3,4-dihydro -2H-chromen-6-yl)-M-1,2,3,4-tetrahydro-soronaphthalene-1-ylacetamide, "» 2-(3554К)-4-Ш(4-ethylphenyl)sulfonyl|amino)- 3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-M-Sh1K)-1, " 2,3,4-tetrahydronaphthalen-1-yl|acetamide, M-benzyl -2-14-I(4-ethylphenyl)sulfonyl|(neopentyl)amino|-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6b-yl (acetamide, (og) 2- 4A-I(4-ethylphenyl)sulfonyl|(neopentyl)amino|-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-b-yl)-M-(2-phe with nylethyl) acetamide and 2-(4-I(4-methylphenyl)sulfonyl|amino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-b-yl)-M-1,2,3 ,4-tetragy (Ce)dronaphthalen-1-ylacetamide. at 20 8. Medicinal product containing a pharmacologically active amount of the compound of formula I! according to claim 1 and conventional pharmaceutical excipients and/or carriers. "and 9. Application of compounds of formula I! according to claim 1 for obtaining a medicinal product intended for the treatment of cardiovascular diseases and/or for the treatment of proliferative, chronic inflammatory and autoimmune diseases. 10. The method of obtaining compounds of the formula o. 05 (F) - b-I with her ZD Z-rez3 60 re 1 On tive? (o o and b5 but in which one B" means C-Sulfylalkyl, B? means C-Sulfyl, BZ means phenyl, optionally mono- or disubstituted by halogen, C-C; alkyl, C--C-Alkoxy group or trifluoromethyl, naphthyl or biphenyl, B" " means hydrogen, C-C alkyl or C 3-C cycloalkyl-C 1-C alkyl, B means hydrogen and B means C-C alkyl, phenyl-C-C alkyl, the phenyl group of which is optionally monosubstituted by halogen, 70 furyl-C .-Salkyl or tetrahydronaphthyl, or 25 and K9, together with the nitrogen to which they are bound, form a piperazine ring, optionally substituted by phenyl, which differs in that the compound of the general formula is - 4 Z BE: o ho KE in which KE", B, B", B? and B? have the values specified above, are subjected to interaction with a compound of the general formula ЖЙ х-50.-КЗШ, cm in which ЕЗ has the values specified above, and X means a leaving group that is removed. (at) 11. Compounds of the general formula ІІІІІІІІІІІІІІІІ M t o dvyton o scho о and Zoso in which B" means S.-Sualkyl, B? means S.-Sdalkyl, "20 B" means hydrogen, C .-Salkyl or C3-SUcycloalkyl-C.-Salkyl, C7Z with VE? means hydrogen and and 25 means C.Salkyl, phenyl-C-Salkyl, the phenyl group of which is optionally monosubstituted by halogen, "" furyl-S.-Salkyl or tetrahydronaphthyl, or B? and K9, together with the nitrogen to which they are bound, form a piperazine ring, optionally substituted by phenyl. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuits", 2008, M 10, 26.05.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. o what co 60 b5