UA57885C2 - benzopyran derivative and pharmaceutical composition - Google Patents

Abstract

This invention relates a benzopyran derivative of formula (I) wherein, R1 and R2 represent each independently a hydrogen atom, a (substituted)C1-6 alkyl group or a (substituted)phenyl group, R3 represents a hydroxyl group or C1-6 alkylcarbonyloxy group, R4 represents a hydrogen atom, or R3 and R4 together form a bond, m represents an integer of 0-4, n represents an integer of 0-4, Y is absent, or represents CR11R12 in which R11 and R12 represent each independently a hydrogen atom or a C11-6 alkyl group, R5 represents an aryl group or a (substituted)heteroaryl group, R6 represents a hydrogen atom or a C1-6 alkyl group, R7 represents a hydrogen atom or a С1-6 alkyl group, X is absent, or represents C=O or SO2, R8 represents a hydrogen atom, a (substituted)C1-6 alkyl group or C3-6 cycloalkyl group, and R9 represents a nitro group, etc., or a pharmaceutically acceptable salt thereof And this invention also relates an antiarrhythmic agent having the prolongation effect on the functional refractory period comprising said compound or a pharmaceutically acceptable salt thereof as an active ingredient. (I)

Description

Description of the invention

The present invention relates to benzopyran derivatives having a prolonging effect on 2 functional refractory periods, which are used for the treatment of arrhythmia in mammals, including humans.

With regard to benzopyran derivatives, 4-acylaminobenzopyran derivatives were known, examples of which are presented by Stotak Kaiit (explanation of Japanese patent application Mo Zpo 58-67683). These 4-acylaminobenzopyran derivatives, examples of which are represented by Stotakaite, are known to open ATP-sensitive K" channels and are effective for the treatment of hypertension or asthma, but there was no mention of the treatment of arrhythmia based on the prolongation of the functional refractory period.

At this time, antiarrhythmic drugs used that have a prolonging effect relative to the functional refractory period as the main function (such as drugs of Class I according to the classification of antiarrhythmic drugs according to Mashdpap UuyPiat»ve, or d-sotalol, which belongs to Class II), have a very dangerous action that causes an arrhythmia that can lead to sudden death, such as flutter based on the prolongation of the action potential of the ventricular muscle associated with a prolonging action relative to the functional refractory period, which becomes a therapeutic problem. Thus, agents with fewer side effects are preferred.

According to this invention, intensive studies of compounds with a prolonging effect on the functional refractory period, more selective on the atrial muscles compared to the ventricular muscles, were carried out, and it was found that the compound with the general formula (I) has a prolonging effect on the functional refractory period , selective relative to the atrial muscle without any influence on the refractory period of the ventricular muscle and action potential parameters.

In connection with this invention, benzopyran derivatives were intensively studied and it was found that the compound of formula c 29 () has a strong prolonging effect on the functional refractory period, and it is useful as an antiarrhythmic agent. This invention is based on this discovery.

This invention relates to a benzopyran derivative of formula (I)

VE so (a)

In schools where V! and B2, each independently, represent a hydrogen atom, a C..v.-alkyl group, where the alkyl group may be optionally substituted by a halogen atom, a C..v.-alkyl group or a hydroxyl group; or a phenyl group, where the phenyl group can be optionally substituted by a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C. 6-alkyl group or a C) 6-alkyl group, "

BZ is a hydroxyl group or a C. b-alkylcarbonyloxy group,

БЕ" represents a hydrogen atom, or ВЗ and 7 together form a bond, - с т represents an integer from 0 to 4, "з н represents an integer from 0 to 4, " У is absent or represents SV 7872, where В !ii B, each independently, is a hydrogen atom or

С, в-"alkyl group, с 15 БЕ? represents an aryl group or a heteroaryl group, where an aryl group or a heteroaryl group can be optionally substituted 4. (KU), where KO is a halogen atom, a hydroxyl group, С 4 .in-alkyl - a group where the alkyl group can optionally be replaced by a halogen atom or a C. 86-alkyl group, or K o represents a nitro group, a cyano group, a formyl group, a formamide group, an amino group, a C 4.in-alkylamino group, di -Ci.v-alkylamino group, C..v-alkylcarbonyl amino group, C.4.d-alkylsulfonylamino group, aminocarbonyl group, (o) C.v.-alkylaminocarbonyl group, di-C.v-alkylaminocarbonyl group, C.v.-alkyl- a carbonyl group, a C 1 -C 6 -alkylsulfonyl group, an aminosulfonyl group, a C 1 -C 6 -alkylsulfonyl group, a carboxyl group, or an arylcarbonyl group, 4 is an integer from 1 to 3, and each B 79 can be the same or different if 4 is equal to 2 or 3, 25 represents a hydrogen atom or C. in-alkyl group, o B represents a hydrogen atom or C. in-a alkyl group, X is absent or is C-O or 505,

BZ represents a hydrogen atom, a C 4.6-alkyl group, where the alkyl group can be optionally substituted by a halogen atom, a hydroxyl group, or a C. 6-alkyl group, or a C 3.6-cycloalkyl group, and

VE? represents a hydrogen atom, a halogen atom, a nitro group or a cyano group; or a pharmaceutically acceptable salt thereof.

The compound according to this invention has a strong prolonging effect on the functional refractory period and can be used as a drug for the treatment of arrhythmia.

Suitable substituents for compound (I) of the present invention are specifically illustrated below.

Here "n" means normal, "ii" means iso, "vt" means secondary, "t" means tertiary, "c" means cyclo-, "o" means ortho-, "m" means meta-, and "n" " means para-.

Examples of C 1-6 alkyl groups can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,

t-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl,

C-hexyl, 1-methyl-n-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, cyanomethyl and hydroxymethyl, etc.

Methyl, ethyl, n-propyl, isopropyl and n-butyl are preferred.

Halogen atoms can be a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Fluorine atom, chlorine atom and bromine atom are preferred.

Examples of C. β-alkyl groups can be methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, isopentyloxy, /o0 Neopentyloxy, 2,2-dimethylpropoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-methyl-n-pentyloxy, 1,1,2-trimethyl-n-propoxy, 1,2,2-trimethyl-n- propoxy and 3,3-dimethyl-n-butoxy, etc.

Methoxy, ethoxy, n-propoxy and isopropoxy are preferred.

Examples of Su. γ-alkylcarbonyloxy groups can be methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, t-butylcarbonyloxy, t-butylcarbonyloxy, 1-pentylcarbonyloxy, 2-pentylcarbonyloxy, 3-pentylcarbonyloxy, isopentylcarbonyloxy, neopentyl-carbonyloxy, 1-pentyloxy, -hexylcarbonyloxy, 2-hexylcarbonyloxy, 3-hexylcarbonyloxy, 1-methyl-n-pentylcarbonyloxy, 1,1,2-tri-methyl-n-propylcarbonyloxy, 1,2,2-trimethyl-n-propylcarbonyloxy and 3,3-dimethyl -n-butylcarbonyloxy, etc.

Methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy and t-butylcarbonyloxy are preferred.

Examples of aryl groups include phenyl, biphenyl, naphthyl, anthryl and phenanthryl, etc.

Phenyl, biphenyl and naphthyl are preferred.

Examples of heteroaryl groups are 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl , b-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl,

B-benzothienyl, b-benzothienyl, 7-benzothienyl, 1-isobenzothienyl, 4-isobenzothienyl, B-isobenzothienyl, 2-chromenyl, 3-chromenyl, 4-chromenyl, 5-chromenyl, b-chromenyl, 7-chromenyl, 8- chromenyl, 1-pyrrolyl, 2-pyrrolyl,

3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 3-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,

Z-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, Z-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, co 4-pyrimidinyl, 5-pyrimidinyl, Z-pyridazinyl, 4-pyridazinyl, 1 -indolizinyl, 2-indolizinyl, Z-indolizinyl, so 5B-indolizinyl, b-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-isoindolyl, 4-isoindolyl, 5B-isoindolyl, 1-indolyl, 2-indolyl, Z- indolyl, 4-indolyl, 5B-indolyl, b-indolyl, 7-indolyl, 1-indazolyl, 2-indazolyl, c.

C-indazolyl, 4-indazolyl, b5-indazolyl, b-indazolyl, 7-indazolyl, 1-purinyl, 2-purinyl, C-purinyl, b-purinyl, and 7-purinyl, 8-purinyl, 2-quinolyl, C -quinolyl, A-quinolyl, 5B-quinolyl, b-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, C-isoquinolyl, 4-isoquinolyl, B-isoquinolyl, b-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl . -quinazolinyl, 7-quinazolinyl, « 8-quinazolinyl, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, b-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, sta) c 2-pteridinyl, 4-pteridinyl, b-pteridinyl , 7-pteridinyl and 3-furazanil, etc. . Preferred are 2-pyridyl, 3-pyridyl and 4-pyridyl, etc. and?" Examples of C. β-alkylamino groups can be methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, isobutylamino, t-butylamino, t-butylamino, cyclobutylamino, 1-pentylamino, 2-pentylamino, 3-pentylamino, isopentylamino, neopentylamino, t-pentylamino, cyclopentylamino, 1-hexylamino, c 2-hexylamino, 3-hexylamino, cyclohexylamino, 1-methyl-n-pentylamino, 1,1,2-trimethyl-n-propylamino, 1, 2, 2-trimethyl -n-propylamino and 3,3-dimethyl-n-butylamino, etc.

Sh- Preferred are methylamino, ethylamino, n-propylamino, isopropylamino and n-butylamino.

Go! Examples of /di-C..v-alkylamino groups can be dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, dicyclopropylamino, di-n-butylamino, diisobutylamino, di-tt-butylamino, di-t-butylamino, dicyclobutylamino, di -1-pentylamino, di-2-pentylamino, di-Z-pentylamino, dizzopentylamino, sp dineopentylamino, di-t-pentylamino, dicyclopentylamino, di-1-hexylamino, di-2-hexylamino, di-Z-hexylamino, dicyclohexylamino, di-(1-methyl-n-pentyl) amino, di-(1,1,2-trimethyl-n-propyl)amino, di-(1,2,2-trimethyl-n-propyl)amino, di-( 3,3-dimethyl-n-butyl)amino, methyl(ethyl)amino, methyl(n-propyl)amino, methyl(isopropyl)amino, methyl(cyclopropyl)amino, methyl(n-butyl)amino, methyl (isobutyl )amino, methyl(t-butyl)amino, methyl(t-butyl)amino, methyl(cyclobutyl)amino, ethyl(n-propyl)-amino,

F) ethyl(isopropyl)amino, ethyl(cyclopropyl)amino, ethyl(n-butyl)amino, ethyl(isobutyl)amino, ethyl(tert-butyl)amino, ka ethyl(t-butyl)amino, ethyl(cyclobutyl)amino , n-propyl(isopropyl)amino, n-propyl(icyclopropyl)amino, n-propyl(n-butyl)amino, n-propyl-(isobutyl)amino, n-propyl(t-butyl)amino, n-propyl( t-butyl)-amino, in n-propyl(cyclobutyl)amino, isopropyl(cyclopropyl)-amino, isopropyl(n-butyl)amino, isopropyl(isobutyl)amino, isopropyl(t-butyl)amino, isopropyl(t-butyl) )amino, isopropyl-(cyclobutyl)amino, cyclopropyl(n-butyl)amino, cyclopropyl-(isobutyl)amino, cyclopropyl(t-butyl)amino, cyclopropyl(t-butyl)amino, cyclopropyl(cyclobutyl)amino, n- butyl(isobutyl)-amino, n-butyl(t-butyl)amino, n-butyl(t-butyl)amino, n-butyl-(cyclobutyl)amino, isobutyl(t-butyl)amino, isobutyl(t-butyl) -amino, isobutyl(cyclobutyl)amino, 65 t-butyl(t-butyl)amino, t-butyl (cyclobutyl)amino and t-butyl(cyclobutyl)amino, etc.

Dimethylamino, diethylamino, di-n-propylamino, diisopropylamino and di-n-butylamino are preferred.

Examples of /-( C. b-alkylcarbonylamino groups can be methyl-carbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, t-butylcarbonylamino, t-butylcarbonylamino, 1-pentylcarbonylamino, 2-pentylcarbonylamino,

3-pentylcarbonylamino, isopentylcarbonylamino, neopentylcarbonylamino, t-pentylcarbonylamino, 1-hexylcarbonylamino, 2-hexylcarbonylamino, 3-hexylcarbonylamino, etc.

Preferred are methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino and n-butylcarbonylamino.

As Su c-alkylsulfonylamino groups can be methylsulfonylamino, ethylsulfonylamino, 7/0 n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, t-butylsulfonylamino, t-butylsulfonylamino, 1-pentylsulfonylamino, 2-pentylsulfonylamino,

3-pentylsulfonylamino, isopentylsulfonylamino, neopentylsulfonylamino, t-pentylsulfonylamino, 1-hexylsulfonylamino, 2-hexylsulfonylamino and 3-hexylsulfonylamino, etc.

Preferred are methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, 7/5 Isopropylsulfonylamino and n-butylsulfonylamino.

Like Su. γ-alkylaminocarbonyl groups can be methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, t-butylaminocarbonyl, t-butylaminocarbonyl, 1-pentylaminocarbonyl, 2-pentylaminocarbonyl,

3-pentylaminocarbonyl, isopentylaminocarbonyl, neopentylaminocarbonyl, t-pentylaminocarbonyl, 1-hexylaminocarbonyl, 2-hexylaminocarbonyl, 3-hexylaminocarbonyl, etc.

Methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl and n-butylaminocarbonyl are preferred.

As di-S. γ-alkylaminocarbonyl groups can be called dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, dicyclopropylaminocarbonyl, di-n-butylaminocarbonyl, sc diisobutylaminocarbonyl, di-tt-butylaminocarbonyl, di-t-butylaminocarbonyl, di-cyclobutylaminocarbonyl, di-1 pentylaminocarbonyl, di-2-pentylaminocarbonyl, di-Z-pentylaminocarbonyl, diisopentylaminocarbonyl, (8) dieopentylaminocarbonyl, di-t-pentylaminocarbonyl, dicyclopentylaminocarbonyl, di-1-hexylaminocarbonyl, di-2-hexylaminocarbonyl, di-3-hexylaminocarbonyl, etc. .

Preferred are dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, iso-diisopropylaminocarbonyl, dicyclopropylaminocarbonyl, di-n-butylaminocarbonyl.

Examples of C1.6-alkylcarbonyl groups can be methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, tert-butylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl , isopentylcarbonyl, neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl and 3-hexylcarbonyl. uh-

Methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl and n-butyl carbonyl are preferred. yu

Examples of Su. β-Alkoxycarbonyl groups can be methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, t-butoxycarbonyl, 1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl, 1-hexyloxy-carbonyl, 2-hexyloxycarbonyl and "

C-hexyloxycarbonyl, etc. with c Preferred are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and n-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl and t-butoxycarbonyl. ;" Examples of C..v.-alkylsulfonyl groups are methanesulfonyl and ethanesulfonyl.

Examples of arylcarbonyl groups are benzoyl, p-methylbenzoyl, p-t-butylbenzoyl, p-methoxybenzoyl, p-chloro-benzoyl, p-nitrobenzoyl and p-cyanobenzoyl. c Benzoyl, p-nitrobenzoyl and p-cyanobenzoyl are preferred.

Examples of C 1 -cycloalkyl groups can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Ш- cycloheptyl and cyclooctyl, etc. o Cyclopropyl, cyclobutyl and cyclohexyl are preferred.

Examples of preferred compounds used in the present invention are the following compounds. (1) A benzopyran derivative of formula (I) or a pharmaceutically acceptable salt thereof, where B and B, both, represent methyl groups, EZ represents a hydroxyl group, and KE" represents a hydrogen atom. (2) A benzopyran derivative or its pharmaceutically acceptable salt an acceptable salt, as defined in (1), where B? represents a hydrogen atom or a nitro group. 22 (3) A benzopyran derivative or a pharmaceutically acceptable salt thereof, as defined in (2), where X represents C-O, and

HF) 25 ate, both, represent hydrogen atoms. kyu (4) Benzopyran derivative or its pharmaceutically acceptable salt, defined in (3), where BE U is a benzene ring, U is absent, t is 0, ap is 1 or 2. vo (5) Benzopyran derivative or its pharmaceutically acceptable salt , defined in (3), where B C represents an alkyl group, BO represents a nitro group, and n is 2. Specific examples of compounds that can be used in the present invention are shown below, but the present invention is not limited thereto. Below, "Me" means a methyl group, "EE" means an ethyl group, "Rg" means a propyl group, "Vy" means a butyl group, "Rep" means a pentyl group, "Nex" means a hexyl group, "RY" means a phenyl group, "Ac" where means an acetyl group (PINE), and "-" means a bond, respectively.

Table 1 ; in c, proe in:

Ouch! tyu v ve v t v EE p

N Nn on N N Nn 0

Me Me on Me Nn nn 1

Me Me on E H n 2

Me Me on pARg N N Z

Me Me on Rg n H 4

Me Me on p-vy nn n 0

Me Me on iVy n i i

Me Me on You n H 2

Me Me on p-Rep n N Ki

Me Me on p-Neh N H 4 p

Me Me on N n n 2 o

Me Me on Me n H 2

Me Me on E N N Z

Me Me osSoOMe Nn n nn 2 oyu zo Me Me Oso N N MO" 2

Me Me on N N MO; 2 so

Me Me on n N MO, with (ee)

Me Me on Nn Nn MO; 4 m

RY RE on Nn IRg MO" 4

E v on No opvyo0 MO, 2 yu perg pARg on n iVy MO; 2 iRg i-Rg on N EVy MO, 2 p-Vu p-Vy OH N p-Rep MO; 2 « 20 iVy iVy ON N p-Neh MO, 2 - s Vy Vy on n Me MO, 3 "z p-Rep p-Rep on n Ins! s Z " p-Neh p-Neh on N N E Z

SEZ SEZ on Nn n Vg Kk) sl 9 snosn; stack; ОН Н Н cm z -I (ee) bo 0 sl (F) ko 5) 65

Table 2 in SN. y k nk i ve s

Go

EE! titi v v fe v V p

N n n n n n i! 0

Me Me Me H H 1

Me Me k H N 2

Me Me p-Rg H n 3

Me Me iRg H n 4

Me Me p-Vy Н Н 0

Me Me and You in! n 1

Me Me (You H x! 2

Me Me p-Rep n in! 3

Me Me p-Neh N H 4 s 29 Me Me n n Nn 2 o

Me Me Me H N 2

Me Me EE NN N Z

Me Me Ying! nn. NN 2 yu

Me Me N N MO" 2

Me Me N Me MO; 1 so

Me Me N E MO" 2 ee)

Me Me Nn pARG MO, Z i-

RE RN IRg MO; 4 oh

EE in No opy 0 MO, 2 p-Rg p-Rg N iVy MO" 2

Ir Ir; их и-Вы MO» 2 « p-Вы p-Вы Н p-Rep MO; 2 and You are them! p-Neh MO» 2 Z s You You Nn Me MO» Z

Iz» p-Rep p-Rep Hnn ns z p-Nekh p-Nekh N n E K 15 SEZ SE Nn Nn V Z sl СН»ОосНнЬ СноОСсН» nn Н CM Z -I (ee) bo o sl (F) ko 6o 65

Table 3 and c! as a dream

ES chi " y v o» 1 eE i Z o. v v v v I-y t p

Н Нн on Н Нн Н 0

Me Me on Me H n 1

Me Me Ge E N H 2

Me Me on p-Rg N N Z

Me Me on ЕРг Н Н 4

Me Me he p-You n v! 0

Me Me on i-You N n i

Me Me OH You H n 2

Me Me on p-Rep n Nn Z

Me Me ON p-Neh |! H 4th grade

Me Me ОН n n H 2 o

Me Me on Me n H 2

Me Me ON E N N 3

Me Me OosSoOMe N N N 2

Me Me OsOye n N MO» 2 o

Me Me on n Me MO" (1 Ge)

Me Me ON n E MO» 2 so

Me Me OH N p-Rg MO" 3

RA Rv on n iv MO; 4 -

E E on NO opy 0 MO; 2 yu p-Rg p-Rg on n i-Vy MO; 2

I-Rg ERg on Nn Vy MO, 2 pVy p-Vy on Nn p-Rep MO" 2 " and Vy yav on n p-Neh MO; 2 - t0 EVy EVy on them! Me MO; Z s p-Rep p-Rep on n ns z z» p-Neh p-Neh on n n E Z

SEz SEZ on n n VI Z 15 pine sSNYOsSN» Hey! NN nn CM Z 1 -I (ee) bo o sl (F) ko 6o 65

Table 4. in OS! pvvnnnnshnjayashyatntnayaayaayannay a an a a a a a a a a aa a a a OO V a v' v v V v o p

N n on N N N 0

Me Me on Me H n 1

Me Me on EE N Hn 2

Me Me on p-Rg H n 3

Me Me on IeRg n Hn 4

Me Me he v-You In! N o 720 Me Me on iVy n No

Me Me on You N Ying! 2

Me Me on p-Rep | Nn Z

Me Me on p-Neh Nn N A s 25 Me Me on NN N 2 o

Me Me on Me Nn n 2

Me Me on k N n Ki

Me Me oSoMe Nn n H 2 oyu zo Me Me oso Nn N MO, 2

Me Me on Nn Me MO" 1 so

Me Me on Nn E MO, 2 so

Me Me on Nn PAR MO» Z k

RE RI on n Rg MO» 4 35 E h on N p-Vu MO» 2 yuyu p-Rg p-Rg on n i-Ve MO» 2

IRe ERgG on n You MO" 2 p-Vy n-Vy on NO ope 0 MO" 2 "

You MVy on N p-Neh MO» 2 v s You Vy on Nn Me MO» Z y p-Rep p-Rep On n n y z ,» p-Neh 00 peNeh on t N E Z

SEZ SEZ (Fin! n NN Vg KI sl 45 bSn,osnU SNOSNI ON n N cm Z -I (ee) bo o sl (F) ko 6o 65

Table 5 she, -k c

E osv 70 nan aaaaaannny prices in vo av v v v! in: VZ in in! V p n N ОН Н n Н 0

Me Me on Me H Hn 1

Me Me on E H n 2

Me Me on p-Rg n n Z

Me Me on Rg Nn in! 4

Me Me on p-Vy H n 0

Me Me on iv Nn n 1

Me Me on You N n 2

Me Me on p-Rep n NN Z in Me Me on pNeh NN no a s

Me Me on N n n 2 i)

Me Me on Me H n 2

Me Me on EI n n Z

Me Me oSsOoMe n N n 2 o

Me Me oso I! NN MO". 2 so

Me Me on nn Me MO» 1 so

Me Me on nn E MO" 2

Me Me on N p-Ru MO» Z -

RE RE on n iRg MO» 4 yuyu

EE E on H n-Vy MO» 2 p-Rg n-Rg on Nn Vy MO, 2 iRg (Rg on n EVy MO" 2 " 20 p-Vy n-Vy on Hn p-Rep MO, 2 t s i Vy IiVy on Nn p-Neh MO" 2. iVy EVy on N Me MO" Z » p-Rep p-Rep on n nsi Z p-Neh p-Neh on n N E Z sl 15 SE. SEZ on N N In the sNoSNnu pine ОН n N cm z -I щ nota tu nn Nut» anu ЧІ Fi ennie nn NNYA, teach t t lan ach (ee) bo sl (F) ko 60 65

Table 6

In lsvzh-4 7 g in M z

NAM E

Oh

Ah! 70 pnnyazhshzhyayalshlyashlshshna a a aa a a a OO v I V v V! t a

Нн Н ОН and Н Н 0

Me Me OH Me H H 1

Me Me on is Hn H 2

Me Me on p-Rg N N Ki

Me Me on iRg Н H 4

Me Me OH p-You N n 0 that Me Me on You n no

Me Me on yVi Н H 2

Me Me ON p-Rey N N Z

Me Me on p-Neh N n 4 p

Me Me on N N Nn 2 o

Me Me OH Me H N 2

Me Me ОН ЕИ Н Н 3

Me Me OoSOoMe N N N 2 oyu

Me Me OSOye; Nn N MO" 2

Me Me on n Me MO" 1 so

Me Me on N Kk MO" 2 (ee)

Me Me ON Nn p-Rg MO» With M

Re RA ON N Rg MO" 4

E vk on No oeava o MU 2 o p-Rg pere on Nn EVy MO; 2 i-Re Rg on N Vy MO» 2 p-Vu p-Vy on N p-Rep MO» 2 h iVy iVy on N pneho mo, 2 Z s EVy Vy on n Me MO; Z "z p-Rep p-Rep Fin! n n s 3 " p-Neh p-Neh on Nn N E K

SEZ SE on n n HV z sl 35 stosn stfOosSn ОН Н N CM Z -I (ee) bo 0 sl (F) ko 6o 65

Table 7 and in Kk is

Me. M. on t m

In o СМе ravЯааааяяЮязеЮ Khana and ОО is in! in to p

N r! H p-MeO 0

Me Н H p-MeO 1 n H MO, p-MeO 2 p-Vg n H p-MeO Z

Rg H Nn p-MeOo 4 p-Vy n H t-MeO 0

You Nn Nn o-MeO 1

Vi N N r-Me 2 p-Rep N n rE Z p-Nekh N N t-E 4 s n n N o-E 2 o

N N MO" r-si 2

E Nn Nn r-E Z n N MO» r-ON 2 oyu zo n N MO» r-sOn 2 n Me Mo, r-mo, 1 so n EE MO; r-SM 2 so

Nn p-Rg MO» p-MMe» Z cha zv Nn IRg MO. r-MNMe 4 oyu

N p-Vy MO» r-on 2 I! You are about t-SOZH 2

N You MO. t-OMe 2 " n H MO" p-MNO, 2

N p-Neh MO. p-MMe» 2 Z s N Me MO, p-MNMe Z z» n H MO, p-MN» 2

Нн НЕ р-Е Кк н Н Вгр-Рг 3 «sl Н Нн СМ р-СН»ОМе З nnnozhzhaaoayaeeeoYUShvnannanana aa aa na Ва а их The compound according to this invention has asymmetric carbon atoms in position C and position 4, thus , (ee) there are their optical isomers based on asymmetric carbon atoms, which can be used in the application of this invention in the same way as its racemate. In addition, the cis- or trans-isomer may be included based on the configuration at position C and position 4, but the trans isomer is preferred. In addition, when the compounds can form salts, pharmaceutically acceptable salts can also be used as active ingredients.

Examples of pharmaceutically acceptable salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, acetates, benzoates, tartrates, phosphates, lactates, maleates, fumarates, malates, gluconates, and salicylates, etc.

Hydrochlorides and methanesulfonates are preferred. ime) Next, the method of obtaining the compound according to this invention is illustrated.

The compounds of the formula (I), in which BC represents a hydrogen atom and KZ represents a hydroxyl group, which are 60 compounds of the formula (1-a), can be obtained by the interaction of the compound of the general formula (2) with the compound (3) in an inert solvent, as shown in the following reaction scheme.

The compound of general formula (2) can be synthesized by known methods (methods described by ..M.

Emapz her a). in 9.Med4.Spet., 1984, 21, 1127; 9d. May. Spet., 1986, 29, 2194; 9.7. My dear. in 9U.Ogd.Spet, 1995, 60, 3397, as well as in the statement of the Japanese patent application No. 56-57785, the statement of the Japanese 65 patent application No. 56-57786, the statement of the Japanese patent application No. 58-188880, the statement of the Japanese patent application application Mo Nei 2-141, disclosure of Japanese patent application Mo Nei 10-87650 and disclosure of Japanese patent application Mo Nei 11-209366, etc.). - as! And in about

I am in osv (2) that is - AK snu SNI vedy Ssna u (Sv Kk Mn

НН (3) era: ptn НА /5 (acid catalyst) Е отв (К-а)

In this scheme, B", B, B?, 5, 27, b8, b, X, U, t and n have the definitions given above.

Examples of solvents used in the reaction of the compound of the general formula (2) with the compound (3) can be the following.

Sulfoxide solvents can be used, an example of which is dimethyl sulfoxide; amide-containing solvents, examples of which are dimethylformamide or dimethylacetamide; ethers, examples of which are ethyl ether, dimethoxyethane or tetrahydrofuran; halogen-containing solvents, examples of which are dichloromethane, chloroform, and dichloroethane; nitrile-containing solvents, examples of which are acetonitrile and propionitrile; and toluene; hydrocarbon solvents, examples of which are hexane and heptane; esters, an example of which is ethyl acetate. In addition to (o), the reaction can be carried out in the absence of a solvent. The preferred solvents are ethers and nitrile-containing solvents.

The reaction temperature usually ranges from -809C to the boiling point of the reaction solvent, preferably from -109C to 10020,

The molar ratio of the reaction materials is in the range of 0.5 - 20.0, preferably 1.0 - 10.0 for compound (3)/compound (2). co

An acid catalyst can be used in the reaction. Examples of acid catalysts used can be inorganic acids, examples of which are hydrochloric acid, sulfuric acid, and also -

Lewis acids, examples of which are aluminum chloride, titanium tetrachloride, boron trifluoride and diethyl ether complex, perchloric acid, lithium perchlorate, lithium bromide and ytterbium trifluoromethanesulfonate, etc.

Compounds of general formula (I), except for compounds of formula (1-4), described above (compounds of formula (I), in which

KZ her v together form a bond, and those in which K 4 represents a hydrogen atom, and Kk Z represents "

C, β-alkylcarbonyloxy group) can be obtained by methods similar to those described in Japanese patent application Mo Zpo 52-91866 and Japanese patent application Mo Nei 10-87650, etc. c) c Lithium bromide, perchloric acid and lithium perchlorate are preferred. "» The synthesis of optically active compounds included in the compounds of the general formula (I) can be carried out with "the use of optical separation methods (statement of Japanese patent application Mo Nei 3-141286, patent

USA. MO 5097037 and European patent MO 409165). In addition, the synthesis of optically active compounds of the general formula (2) can be carried out using asymmetric synthesis methods (Japanese National Publication No. Mo Nei 5-507645, Japanese Patent Application Mo Nei 5-301878, Japanese Patent Application No. 1 Mo Nei 7 -285983, the presentation of the European patent application Mo 535377 and the US patent Mo 5420314). co As described above, it was found that the compound of the general formula (I) has a strong prolonging effect

Go! 20 relative to the functional refractory period. The prolonging effect relative to the functional refractory period is one of the functions of the antiarrhythmic effect and an important indicator that can be easily extrapolated to the effectiveness relative to clinical arrhythmia. Conventional antiarrhythmic drugs, which have a prolonging action relative to the functional refractory period as the main function (such as a-sotalol, which belongs to class I according to the classification of antiarrhythmic drugs according to Matsdpap UMiShatv), have quite 22 dangerous actions that cause arrhythmia, which can lead to sudden death such as flickering on

HF) based on the prolongation of the action potential of the ventricular muscle associated with a prolonging effect on the functional refractory period, which become therapeutic problems in relation to arrhythmias associated with atrial contractions (such as supraventricular tachycardia, atrial flutter, and atrial fibrillation). In order to solve these problems, the search and study of compounds that have a prolonging effect in relation to the 60 functional refractory period, more selective in relation to the muscles of the atria than in relation to the muscles of the ventricles, and found that the compound of the general formula (I ) has a prolonging effect on the functional refractory period, selective in relation to the atrial muscles without any influence on the functional refractory period of the ventricular muscle and the action potential. The difference between the present invention and the known methods consists in providing a prolonging action in relation to the functional refractory period, selective in relation to the muscles of the atrium, with the help of this compound, which is demonstrated by means of the following tests; without any influence on the period of preservation of the action potential of the separated ventricular muscle and without influence on the OT electrocardiogram of the anesthetized animal. From the above, it follows that the compounds of this invention do not have an arrhythmia-inducing effect in the ventricular muscle, thus they can provide the possibility of a safer application of known methods in relation to arrhythmia associated with the atrial muscle. The method according to this invention is suitable for therapeutic or prophylactic use as a means against atrial fibrillation, means against atrial flutter and means against atrial tachycardia associated with paroxysmal, chronic, preoperative, operative and postoperative atrial arrhythmias, for the prevention of the phenomenon of embolism due to arrhythmia atria, prevention of the phenomenon of ventricular arrhythmia or tachycardia originating from atrial arrhythmia or tachycardia, and prevention of deterioration of life prognosis due to preventive action regarding arrhythmia or atrial tachycardia, which may turn into ventricular arrhythmia or tachycardia.

The present invention provides a pharmaceutical composition or a veterinary pharmaceutical composition containing compounds of general formula (I) in an effective amount for this treatment.

Examples of methods of administration of the compound according to this invention are parenteral administration by means of injections (subcutaneous, intravenous, intramuscular and intra-abdominal), in the form of ointments, suppositories and aerosols, or oral administration using tablets, capsules, granules, pills, syrups, solutions, emulsions and suspensions, etc.

The above-mentioned pharmaceutical or veterinary pharmaceutical composition contains the compounds of the present invention in an amount from about 0.01 to 99.595, preferably about 0.1 to 3095, of the total weight of the composition.

In addition, in addition to the compound of this invention or the composition containing this compound, the parenteral form may contain other pharmaceutically active compounds or veterinary pharmaceutically active compounds.

In addition, the compositions may contain multiple compounds according to the present invention.

The amount for clinical use varies depending on the age/weight and sensitivity of the patient, the severity of the patient's condition, etc., and the effective amount for administration is usually about 0.003 - 1.5 g, preferably 0.01 - 0.00 g per day for an adult If necessary, however, the quantity may exceed (8) the above-mentioned interval.

The compound according to this invention is produced in the form of a dosage form for administration using conventional pharmaceutical means. That is, tablets, capsules, granules and pills for oral administration are made using fillers such as sucrose, lactose, glucose, starch and mannitol; binders such as hydroxypropyl cellulose, syrup, gum arabic, gelatin, sorbitol, tragacanth, methylcellulose and (3) polyvinylpyrrolidone; disintegrants such as starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose and polyethylene glycol; lubricants such as talc , magnesium or calcium stearate and

With silicon dioxide; and such as sodium laurate and glycerin, etc. yu

Preparations for injection, solutions, emulsions, suspensions, syrups and aerosols are obtained using solvents for active components, such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol and polyethylene glycol; surfactants, such as ester of sorbitan fatty acid, ester of polyoxyethylene and sorbitan fatty acid, ester of polyoxyethylene and fatty "

ACID, polyoxyethylene ether of hydrogenated castor oil and lecithin; suspending agents such as c carboxymethyl sodium salt, cellulose derivatives such as methyl cellulose, tragacanth and natural resins such as . gum arabic; and preservatives, such as p-hydroxybenzoic acid ester, benzalkonium chloride and i? salts of sorbic acid, etc.

For ointments, which are transdermal adsorbable pharmaceutical preparations, are used,

For example, white petroleum jelly, liquid paraffin, high molecular weight alcohols, macrogol ointment bases, hydrophilic ointment bases and aqueous gel bases.

Suppositories are obtained using, for example, cocoa fat, polyethylene glycol, lanolin, triglycerides - fatty acids, coconut oil and polysorbate, etc. o The best way to implement the invention

The present invention is illustrated in detail by the following examples, but the present invention is not limited to these examples. c Examples of synthesis

Synthesis example 1. Trans-b-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-2-phenethylamino)-2H 1-benzopyran-3-ol

F) name)

NM

7 denm A ON

What at 65 To a solution of b-acetylamino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (50O0mg, 1.80 mmol) and lithium perchlorate (76bmg , 7.20 mmol) in tetrahydrofuran (15 ml) add 2-phenethylamine (904 μl, 7.20 mmol)

at room temperature and stirred at 652C for 9 hours.

Ethyl acetate is added to the mixture, and the resulting organic phase is washed twice with a saturated aqueous solution of ammonium chloride and once with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.

After the solvent is distilled off, the residue is purified by medium pressure column chromatography (hexane-ethyl acetate - 1:1) and then recrystallized from hexane-ethyl acetate to obtain the desired substance in the form of yellow crystals (yield: 6190). T.pl.: 172 - 174960,

TN-NMR (SOS) 8: 1.17(s, ЗН), 1.48(s, ЗН), 1.бО(shr.s, 2Н), 2.28(s, ЗН), 2.83 ( t, 9-7.0Hz, 2H), 2, 70 85-3.00 (m, 2H), 3.47(d4, A part of AB, 9U-10.3HzC, 1H), 3.67(d, In part AB, 9-10.3Hz, 1H), 7.21-7.33(m, 5H), 7.6O(s, 1H), 8.59(C, 1H), 9.96(s, 1H).

MS (EI) m/s: 409IM-1)", 327 (Br)

The following compounds were obtained in a similar way (Synthesis Examples 2-36).

Synthesis example 2. 75 Trans-b-acetylamino-3,4-lyhydro-2,2-dimethyl-7-nitro-4-(3-phenylpropylamino)-2H-1-benzopyran-3-ol

WE

AsNM Ha ON vva p 29 Output: 7196 Go)

TN-NMR (SOSIi) 8: 1.21(s, ЗН), 1.51(s, ЗН), 1.87 (5th, 7.4Hz 2Н), 1.94(width с, 2Н), 2 ... 9U-10.3Hz, 71), 7.16-7.23(m, ЗН), 7.25-7.217(m, 2H), 7.63(s, 1H), 8.68(s, 1H) , 10.02(s, 1H). yu zo MS (ZY) m/z: 413|Ma1)", 221 (Br)

Synthesis example 3. F

Trans-β6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-(4-phenylbutylamino)-2H-1-benzopyran-3-ol so cha

IC c)

NM « day A

M on shi s

OHM

»? at

ZO Exit: 50905

TN-NMR (SOSIV) 8: 1.20(s, ЗН), 1.52(s, ЗН), 1.55-1.60(m, 2Н), 1.63-1.75(m, 2Н ), 2.25(s, ЗН), 2.40(width, s, 1 2), 2.624(t, 9У7А4АГЦц, 2Н), 2.58-2.72 (m, 2Н), 3.57(d , А part AB, .-10.0Hz, 1Н), З,7О(d, B part AB, -1 У-10.0Hz, 1Н), 7.15-7.18 (m, ЗН), 7, 24-7.62(m, 2H), 7.62(s, 1H), 8.67(s, 1H), 10.00(s, 1H).

MS (ZY) m/z: 427 | MI", 150 (Br). so Synthesis example 4. o 50 Trans-b-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-( 2-(4-hydroxyphenyl)-ethylamino|-2H-1-benzopyran-3-ol one sl

F) t NM

ASNM MON

60 oz (in)

Output: 29905 65 TN-NMR (SOSIi) 8: 1.17(s, ZN), 1.48(s, ZN), 2.00(lat.s, ZN), 2.29(s, ZN), 2.70-2.85(m, ZN), 2.86-2.95 (m, 71), 3.51(d, A part AB, U-10.3HZ, 1H), 3.bb(d , in part AB, 9U-10.3Hz, 1H), 6.77(d, U-8.4Hz, 2H), 7.06b(d,

U-8.4АЦС, 2Н), 7.6О(s, 1Н), 8.46(s, 1Н), 9.95(s, 1Н),

MS (ZY) mi/z: 416 |M--117, 308 (Br).

Synthesis example 5. Trans-6b-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-(2-(4-methoxyphenyl)ethylamino|-2H-1-benzopyran-3-ol

Ome

NK day p ON

OM about

Output: 1895

TN-NMR (SOSIV) 5: 1.18(s, ZN), 1.49(s, ZN), 1.80 (width s, 2H), 2.27(s, ZN), 2.76- 3.00 (m, 4H), 3.56(d, A part AB, 9U-10.5HZ, 1H), Z.77(d, B part AB, 9U-10.5HZ, 1H), 3.79 (с, ЗН), b, 83З(d, 9У-8.6Hz, 2Н), 7.23(d, -8.6HZ, 2Н), 7.61(с, 1Н), 8.55(s, 1H), 9.93 (s, 1H).

MS (ZY) m/z: 430 | Ma-117, (Br).

An example of synthesis b. with

Trans-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-(2-(4-chlorophenyl)ethyl-amino|-2H-1-benzopyran-3-ol

SI (8) b o so

NM co

ASNM A ON cha b (9) iv)

Output: 6690

TN-NMR (SOSIZ) 8: 1.18(s, ЗН), 1.49(s, ЗН), 1.70 (sh.s, 2Н), 2.28(s, ЗН), 2.78( t, 9-6.8Hz, 2H), « 2.84-2.99(m, 2H), З3.50(d, A part AB, 9U-10.2HZ, 71), Zb8(dd, B part AB, 9U-102 and 1.0Hz, 1H), 7.17(d, - 10 U-8.4Hz, 2H), 7.27(d, U-8.4Hz, 2H), 7.61(s , 1H), 8.59 (s, 1H), 9.97 (s, 1H). with MS (ZY) mi/z: 434 |M.-117, 361 (year). :z" Synthesis example 7.

Trans-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-(2-(4-aminophenyl)-ethylamino|-2H-1-benzopyran-3-ol

Not 1 - And (ee) because oh still

AsNM on slom at 29 Output: 4095 (F) TNAMR (SOSI) 5: 1.17(s, ZN), 1.48(s, ZN), 1.69 (shyr.s, 4H), 2.28 (c, ЗН), 2.71(t, 9У-6.8Hz, 2Н), ko 2.79-2.92(m, 2Н), 348(d, A part AB, 9У-10.3Хц, 71 ), Z,b7/(dd, B part AB, 9U-10.3 and 1.1Hz, 1H), 6.63(d,

U-8.6Hz, 2H), 7.02(d, U-8.6Hz, 2H), 7.6O(s, 1H), 8.58(s, 1H), 9.96(s, 1H) . in MS (ZY) mi/z: 415 |M.-117, 237 (Br).

Synthesis example 8. Trans-b-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-(2-(4-nitrophenyl)ethylamino|-2H-1-benzopyran-3-ol b5

MO" nm

ASNM A aON

Gaia o z3

Output: 1995

T.pl. 211 - 21392 (decomposition).

TN-NMR (DMSO-iv) 5: 1.15 (s, ЗН), 1.45 (s, ЗН), 2.05 (s, ЗН), 3.05-3.40 (m, 5Н), 4.06 (m, 1H), 4.51 (m, 1H), 6.44 (s, 1H), 7.40 (s, 1H), 7.56 (d, U-8.8Hz, 2H) , 7.90 (s, 1H), 8.20 (d, 9-8.8 Hz, 2H), 10.14 (s, 1H).

MS (EI) m/z: 444 |MI", 371 (Br).

SYNTHESIS EXAMPLES 9-36

FROM

7

ASNK Hmm On

ХХ" s om O Me o

An example of Luo's synthesis

IS o) 9 g so (ee)

E i- 10 di IS)

KE

E « 11 re - s! ;" OoMe " di 1 OMe -I

B with A

OMe o 50 sl 14 a (F) Ve i SH bo ni i p p p o p po o oon nny b5

E in

AsSNM ho AON om Ge, Me

An example of the synthesis of Me V yuyu sho,

Me 600

Me 15

R

17

Ri 20

ОоОМе 6 Фу о сч 25 а (о) 19 ХХ а ю 30 (ге) ч- и Іо) хх " s - 22 I s re: ;" nama aa aa a a a a 1 -I (ee) bo 0 sl (F) ko 6o 65

AsyM A ON oh Oh Me

An example of the synthesis of He H t 23 sh

My MN "0078 z5 s oMe o no DY

Me oyu

You are 27 years old

OVyp m

OK oh 28

ОМе « , EE - p 29 of 1 -I (ee) bo o sl (F. ko) 60 65

Oh no

As h on and (0) Me

An example of the synthesis of Me 24 nzhnajzhzhaynzhyaaEaavanzhanVyaaVaanaaVaaaanalyeltlFsh is asked from 600 DH si she ХХ (at 32

SEZ sa s shchi 33 h o a

IS) from V so

AsNM A, ОН ож ОО Me - with shi IF)

An example of the synthesis of Le V "34 - 7 ne s;" 35 as 4) sl NM -I cha y / in 36 so im sl aa aa a a a a a V aa vo PI OO OO OO

Synthesis example 9

Red crystals

T.pl.: 176.5 - 178.0260

He) TNMR (SOSIi) 8: 1.17(s, ЗН), 148(s, ЗН), 2.27(s, ЗН), 2.86-2.98(m, 4Н), 3.46b( d, 4-10.0Hz, 1H), yuyu Z,b8(d, U-10.0Hz, 1), 7.00-7.10(m, 2H), 7.17-7.26 (m, 2H), 7.61 (s, 1H), 8.63 (s, 1H), 9.98 (s, 1H).

MS (ZY) mi/z: 418 |M.-1)", 346, 309, 179 (year).

Synthesis example 10 60 Red crystals

T.pl..: 163.5-165.0960

TN-NMR (SOSIZ) 8: 1.18 (s, ЗН), 1.49 (s, ЗН), 2.27 (s, ЗН), 2.81-2.99 (m, 4Н), 3, 49(d, 9U-101Hz, 1H),

Z,b8(d, U-10.1Hz, 1H), 6.89-6.95(m, 2H), 7.02(d, 9-7.6Hz, 1H), 7.23-7.26 (m, 1H), 7.61(s, 1H), 8.58(s, 1H), 9.96(s, 1H). 65 MS (ZY) m/z: 418 |Ma-1)", 344, 298 (yy).

Synthesis example 11

Orange crystals

T.pl.: 141.0-142.076

TNA-NMR (SOSIZ) 8: 1.18(s, ЗН), 1.49(s, ЗН), 2.27(s, ЗН), 2.78-2.97(m, 4Н), 349( d, 9-101Hz, 1H), 56 Z,bV(d, 9-10 1Hz, 1H), 6b,99(t, U-8.8Hz, 2H), 7.19(dd, uU-2.9 , 5.5Hz, 2H), 7.61 (s, 1H), 8.57(s, 1H), 9.97(s, 1H).

MS (ZY) mi/z: 417 |M.-1)", 345, 302, 176 (Br).

Synthesis example 12

Yellow crystals

T.pl.: 151.0-152.076

TNA-NMR (SOSIi) 8: 1.18 (s, ZN), 1.49(s, ZN), 2.26(s, ZN), 2.77(t, 9-6.8Hz, 2H), 2.87-2.97 (m, 2H),

Z,B1(d, U-101Hz, 7H), 3.69 (d, 9U-10.1Hz, 7), b,ZZ(d, 9U-2.2Hz, 71H), b,Z9(d, 9U -2.2Hz, 2H), 7.6O(s, 1), 8.55(s, 1H), 9.93(s, 1H).

MS (ZY) m/z: 459 |M-1)", 441, 307, 278, 193 (yy).

Synthesis example 13

Red amorphous substance

T. pl..: 176.5-178.070

TN-NMR (SOSIi) 8: 118(s, ЗН), 1.48(s, ЗН), 2.27 (s, ЗН), 2.78-2.97(m, 4Н), З.5О( d, 4-101 GHz, MN),

З,б9(d, U-10.1Hz, 1), 3.79(s, ЗН), 6.75-6.83(m, ЗН), 7.21 (t, У-7.6Hz, 1Н ), 7.6O(s, 1H), 8.56(s, 1H), 9.94(s, 1H).

MS (FAB) m/z: 430 |M--11" (br),

Synthesis example 14

Red crystals

T.pl.: 171.5-172.876

TNAMR (SOSIV) 8: 1.18(s, ЗН), 1.48(С, ЗН), 2.27(s, ЗН), 2.86-2.98(m, 4Н), З48(d, 9U-104HC, MN), p

Z, 7O(d, 9U-104HZ, 1), 7.14-7.22(m, 2H), 7.26-7.28(m, 71H), 7.Z4(dd, 9U-1.6 , 7.6Hz, 7H), 7.61(s, 1H), O,b64(s, 1H), 9.98(s, 1H). at

MS (ZY) m/z: 433|M--1)", 357, 318 (yy).

Synthesis example 15

Yellow amorphous substance IF)

TN-NMR (SOSIi) 85: l118(s, ZN), 1.49 (s, ZN), 2.28 (s, ZN), 2.79(t, 9-6.9Hz, 2H), 2, 86-2,98(m, 2H), co

Z,BO(d, 9-101Hz, 1), Z,bv(id, 9U-101Hz, 71), 7.12(d, U-82Hz, 2H), 7.42(d, 9U-8.2HzC , 2H), 7.61(s, 1), 8.6O(s, 1H), 9.98(s, 1H). co

MS (ZY) m/z: 481|M21", 479(MI", 406 (Br). cha

Synthesis example 16

From Orange Crystals Fr

T.pl.: 90.0-91.076

TN-NMR (SOSIv) 8: 1.18(s, ZN), 1.48 (s, ZN), 2.22 (s, ZN), 2.24(s, ZN), 2.27(s, ZN), 2.75-2.78(m, 2H), 2.88-2.91(m, 2H), 3.5O(d, 9U-101HC, 71H), 3.69 (d, 9U- 10.1Hz, 1), b, 9b(id, 9U-7.7Hz, 71H), 7.00(s, 1), 7.06(d, « 20 -7.7Hz, 1H), 7.6О (c, 1H), 8.61 (c, 1H), 9.97 (c, 1H). with

MS (ZY) m/z.; 428|M'-1)7, 356 (br). c p synthesis example 17 c Brown amorphous substance

TN-NMR (SOSIV) 5: 1.16(С, ЗН), 1.48 (s, ЗН), 2.29(с, ЗН), 2.82 (shr.s, 1Н), 3.25 ( dd, 9-21, 7.7Hz, 2H),

3.52 (D, 9-10.3 Hz, 1H), 3.69 (d, 9U-10.3 Hz, 1H), 7.18-7.35 (m, 1OH), 7.61 (s, 1H ), 8.61(s, 1H), 9.98(s, 1H). 1 MS (ZY) m/z: 475IMN 117, 310, 280 (yy).

Example of synthesis 18th.

Yellow crystals (ee) M.p.: 186.0-188.07C at 50 TNA-NMR (SOSIV) 8: 1.18 (s, ZN), 1.46 (t, 9U-7.1GHz, ZN) . (d, 9U-10.3Hz, 1), 4.11(q, U-7.1Hz, 2H), 6.76-6.82 (m, ЗН), 7.61(s, 1H), 8 .53 (s, sl 1H), 9.93 (s, 1H).

MS (ZY) m/z: 473|M-1)", 440, 401, 308 (yy).

Synthesis example 19 29 Brown amorphous substance

HF) TNAMR (SOSIi) 8: 119(s, ЗН), 1.49(s, ЗН), 2.27(s, ЗН), 2.84-2.95(m, 4Н), З,Б1( d, U-104Hz, 1H),

HF Z,71(d, 9U-10.4Hz, 1), 7.18(dd, 9-2.0, 8.0Hz, 1), 7.22(d, U-8.0Hz, 1), 7.36b(d, 9U-2.0Hz, 1H), 7.61(s, 1H), 8.63(s, 1H), 9.99(s, 1H). in MS (ZY) m/z: 468 |MI", 396, 353 (yy).

Synthesis example 20

Red crystals

M.p.: 156.0-157.076 "NA-NMR (SOSIVi) 8: 1.19 (s, ZN), 1.50 (s, ZN), 2.28 (s, ZN), 2.93- 3.04(M, 4H), 3.52(d, U-101HZ, 1H), вЕ Z/d, 9U-101Gu, 1H), bvv(d, 9U-3, ЗГц, 1H), b. U5 (dd, 9U-3.3, 51Hz, 1), 7.16 (d, 9U-51Hz, 1H), 7.62(s, 1H), 8.64(s, 1H), 9.98(s , 1H).

MS (ZY) m/z: 405|M)", 332, 308 (yy).

Synthesis example 21

Brown crystals

T.pl.: 172.0-174.076

TNA-NMR (SOSIV) 5: 1.19(s, ZN), 1.49 (s, ZN), 2.28(s, ZN), 2.84(t, 9-6, bHz, 2H), 2.90-3.03 (m, 2H),

З.5Z(d, 9-10.1Hz, 1), З3.71(d, 9U-10.1Hz, 1), 7.18(d, 9U-5.9Hz, 2H), 7.62 (s , 1), 849(d, 9U-5.9Hz, 2H), 8.64(s, 1H), 9.98(s, 1H),

MS (EAV) m/z: 401 | Ma-117, 171, 157 (yy).

Synthesis example 22

Brown amorphous substance "H-NMR (SOSIV) 8: 1.20 (s, ZN), 1.49 (s, ZN), 2.28 (s, ZN), 2.80-2.87 (m, ZN ), 2.93-2.96 (m, 1H), 3.58 (d,

U-10.3Hz, 1), З3.75(d, 9U-10.3Hz, 1), 7.24(m, 1H), 7.6O(s, 1H), 7.62(d, 9U- 1.5Hz, 71H), 8.42 (t, 9U-1.5Hz, 2H), 8.67(s, 1H), 9.96 (s, 1H). 19. Me (ZY) mi/z: 400 |M/", 328, 280 (br).

Synthesis example 23

Orange crystals

T.pl.: 147.0-149.076

TN-NMR (SOSIv) 85: 1.24(s, ЗН), 1.54(s, ЗН), 2.26 (s, ЗН), 2.94-3.07(m, 2Н), 3, 19-3.21 (m, 2H), 3.6b(d,

U-10.1Hz, 1), З3.7b(d, 9U-101Hz, 1H), 7.16-7.19(m, 1H), 7.22(d, 9U-7.7Hz, 1), 7.58 (s, 1H), 1.63-1.68 (m, 1H), 8.53 (s, 1H), 8.71 (s, 1H), 9.94 (s, 1H),

MS (EAV) m/z: 400|MI", 366, 328, 120 (Br),

Synthesis example 24 p

Brown amorphous substance

TN-NMR (SOSIZ) 8: 1.14 (s, ЗН), 1.45 (s, ЗН), 2.24 (s, ЗН), 2.91-3.02 (m, 4Н), 3, 51(d, 9U-10.3Hz, MN), o 3.b7(d, 9U-10.3Hz, 71), 7.10(t, 9U-7.0Hz, 71), 714(d, 9U- 2.2Hz, 1), 7.20(t, 9U-7.0Hz, 1), 7.37(d, U-8yHz, 1H), 7.57(d, U-8.1Hz, 1H), 7.59(s, 1H), 8.10(width, 1H), 8.43(s, 1H), 9.82(s, 1H).

MS (EAV) m/z: 437 |Ma-1)", 307, 278, 233, 194 (yr). Shcheo,

An example of the synthesis of 25 so

Brown amorphous substance

TNAMR (SOS) 8: 1.18 (s, ZN), 1.49 (s, ZN), 2.23 (s, ZN), 2.87 (t, 9U-6.8Hz, 2H), 2, 94-2,99(m, 2H), co

Z.52(d, 9-10.1Hz, 1), Z.7O0(d, 9U-10.1Gu, 1), 7.30-7.35(m, ZN), 741-745 (m, 2H ), 7.52-7.59(m, 4H), 7.60(s, 1H), 8.61(s, 1H), 9.96(s, 1H).

From I went)

MS (ZY) m/z: 475IMI", 442, 401 (yy).

Synthesis example 26

Red amorphous substance

TNA-NMR (SOS) 8: 1x19(s, З), 1.49(s, ЗН), 2.26 (s, ЗН), 2.76-2.79(m, 2Н), 2.84- 2.90(m, 1H), « 20 2.93-2.98(m, 1H), 3.53(d, U-10.1Htsu, 1H), 3.7O(d, U-101Gu, 1H ), З.86(s, ЗН), 3.88 (s, ЗН), 6.76-6.810m, ЗН), З с 7.6О(s, 1Н), 8.54(s, 1Н), 9.93 (s, 1H). and MS (ZY) m/z: 460|M--1)", 237, 165 (br). "" Example of synthesis 27

Output: 58905

Yellow crystals, m.p.: 2256 -I T'NA-NMR (DMSO-yv) 5: 115(s, HN), 1.45(s, HN), 2.04(s, HN), 2, 90-3.10 (m, 5H), 3.21 (width, 1H), 4.00-4.05 (m, 1), 4.47-4.51 (m, 7H), 5, 09 (s, 2H), 5.12 (s, 2H), 6.75(dd, 9U-8.2 and 1.8Hz, 1H), 6.97(d, (ee) U-8.2Hz, 1H), 7.03(d, 9U-2.0Hz, 1H), 7.28-7.46 (m, 11H), 7.96 (s, 1H), 10.20(s, 1H). at 50 MS (ZY) m/z: 611|MI", (br).

Synthesis example 28 sl Output: 3296

Yellow crystals

T.pl.: 227-22876 52 TN-NMR (DMSO-yv) 5: 1.15 (s, ZN), 1.29 (t, 9-7.0 Hz, ZN), 1.45 (s, ZN ), 2.05(s, ZN), 2.90-3.10(m, 4H),

HF) Z.25(width s, 1H), 3.74(s, ZN), 3.96b(square, U-7.0Hz, 2H), 4.00-4.05(width s, 1H ), 4.42(width s, 1H), 6b,45(width s, 1H), yuyu 6b,7Z(dd, 9-84 and 2.4HzC, 1H), 6.85(d, 9U- 2.4Hz, 1H), b, 8b(d, U-8.4Hz, 1H), 7.40(s, 1H), 7.92(s, 1H), 10.16(s, 1H).

MS (ZY) m/z: 473 |MI", 233 (Br).

Synthesis example 29 bo Output: 4095

Yellow amorphous substance

TN-NMR (SOSIi) 8: 111 (s, ZN), 1.30 (t, 9-7.0 Hz, ZN), 1.91 (s, ZN), 2.00 (s, ZN), 2, 45-2.50(m, 2H), 2.65(t, U7.1Hz, 2H), 2.75-2.85(m, 1H), З.58(dd, A part AB, 9-9 . 9U-5.3Hz, 1H), b,8O(d, 9U-8.8Hz, 2H), 7.10(d, U-8.8Hz, 2H), 7.6O(s, 1H), 8, 32(s, 1H), 9.95(s, 1H).

MS (ZY) m/z: 443 |MI", 237 (yr).

Synthesis example 30

Exit 9895

Yellow crystals

T.pl.: 214-21670

MS (ZY) m/z: 467 MI", 308 (yr).

Synthesis example 31

Yield: 96905 70 Orange Crystals

T.pl.: 133-1347S

TNA-NMR (SOSIV) 8: 1.18(s, ZN), 1.49(s, ZN), 1.60(sh,s, 1), 2.28(s, ZN), 2.75- 3.00 (m, 5H), 3.50 (d, A part AB, 9U-10.2Hz, 1H), 3.69 (dd, B part AB, 9-10.2 and 1.0Hz, 1H) , 7.05-7.20 (m, 4H), 7.61(s, 1H), 8.59(s, 1H), 9.97(s, 1H).

MS (ZY) m/z: 433|MI", (br).

Synthesis example 32

Output: 8290

Orange solid "NA-NMR (SOSIV) 8: 1.18(s, ZN), 1.48(s, ZN), 2.27(s, ZN), 2.80-3.00(m, 6Н ), 3.49(d, A part AB, U-101HZ, 720 1H), 3.69 (dd, B part AB, U-40.1 and 1.2Hz, 1H), 7.40-7.50 (m, 4H), 7.62 (s, 1H), 8.63 (s, 1H), 9.99 (s, 1H).

MS (ZY) m/z: 467|M)", 348 (br).

Synthesis example 33

Output: 8495 sh

Yellow amorphous substance

TNAMR (SOSIi) 8: 1.19(s, ZN), 1.9 (s, ZN), 1.58 (shrs, 1H), 2.27(s, ZN), 2.80-2.98( m, ЗН), o 3.08-3.23(m, 2Н), З,50(d, A part of AB, U-10.3Хц, 71Н), 3.72(d, B part of AB, 2- 10.3Hz, 1H), 7.02-7.08(m, 1H), 7.25-7.28(m, 2H), 7.61(s, 1H), 8.68(s, 1H) , 10.00 (s, 1H).

MS (ZY) m/z: 467 MI", 354 (yr). IS)

Synthesis example 34

A yellow crystalline substance

M.p.: 160.0-165.076 (ee) "NA-NMR (SOSIZ) 8: 1.33 (s, ZN), 1.53 (s, ZN), 2.14 (s, ZN), 2 .61(d, 9-2.8Hz, 1H), 3.79(dd, 9-2.8, 8.8Hz, M 1), 3.99(d, U-8.8Hz, 1H), 6 ,78(d, U-8.0Hz, 2H), 6.83 (t, 9U-7.6Hz, 1), 7.23(t, 9U-8.0Hz, 2H), 7.66(s, 1H),

From 8.59(s, 1H), 9.79(s, 1H). Shit,

MS (ZY) m/z: 371|M)", 299, 257 (yy),

Synthesis example 35

Output: 8796 "

Yellow amorphous substance, a mixture of diastereoisomers 1:1. From 70 TN-NMR (SOSIZ) 8: 1.15 (s, 6H), 1.29(d, 9U-5.5Hz, 6H), 1.45 (s, ЗН), 1.48(s, ЗН ), 2.28(s, ЗН), 2.29(s, s ЗН), 2.58(width с, 1Н), 2.75-2.90(m, 8Н), 2.95(width .s, 1H), 3.37(d, 9U-10.0Hz, 1), З.5O(d, 9-10.0Hz, 1), :z» 3.62(d, 9U-101Hz, 1 ), 3.64 (d, 9-10.1HZ, 1H), 7.20-7.38 (m, 7OH), 7.59 (s, 1H), 7.60 (s, 1H), 8, 45(s, 1H), 8.65(s, 1H), 9.95(s, 1H), 10.00(s, 1H). 415 MS (ZY) m/z: 414|Ma1)", 279 (yy), s Synthesis example 36

Yield: 2790 - Orange solid, diastereoisomer A (more polar). o TNAMR (SOSIi) 8: 1.20 (s, ZN), 1.29 (d, 9U-6.5Hz, ZN), 1.44 (s, ZN), 1.72 (shyr.s, 2H) . ... -9.7 and 1.1Hz, 1H), 7.14 (d, 9U-8.2Hz, 2H), 7.26(d, U-8.2Hz, 4 2H), 7.6O(s, 1H ), 8.84(s, 1H), 10.06(s, 1H).

MS (ZY) m/z: 447 (M117 (Br).

Output: 3290

Yellow solid, diastereoisomer B (less polar). o TNAMR (SOSIi) 8: 1.14 (d, 9U-6.0 Hz, ZN), 1.23 (s, ZN), 1.49 (s, ZN), 1.60 (shyr.s, 2H) . U-6.8 and 6b, ОГц, 1Н), 3.б5(dd, B part AB, о -10.0 and 1.0HzС, 1Н), 7.25 (s, 4Н), 7.56(s , 1H), 8.54(s, 1H), 9.91(s, 1H).

MS (ZY) m/z: 447|MI (Br). 60 b5

SYNTHESIS EXAMPLES 37-49

Kk

AHA AND HIM

OM o Me is an example of the synthesis of Lo B and Z 37 from "KI

MO;

NM

Me zv 39 "KI o

N OMe

E what DA and we so s po and hi SE, oyu

Ome voi XX -

WE - p

NK E

1 a and in VN -I (ee) because 0 sl

F) name) bo 65

KE

Nn:

M. o om o me

An example of the synthesis of Mo in 7170 Python about Chon Chi ton boring A un lpo t n nnuNOOno chunOch ОН uk nulchn

An example of the synthesis of Le E 44 "KI

NM

"SHI

WE

45 and 46 "No

NM s y (8)

NM a yu so cha

NM

IS c) 19 АХ nm « s General method of synthesis of compounds 37 - 49 "z To a solution of /b-isopropylamido-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1- To benzopyran (20 mg, 0.65 mmol) and lithium bromide (226 mg, 2.6 mmol) in tetrahydrofuran (2 ml) was added amine (1.31 mmol) at room temperature and stirred at 65 °C for 4 hours. In addition, ethyl acetate is added and the organic phase formed is washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate 1. After the solvent is distilled off, the residue is purified by column chromatography on silica gel to obtain the desired substance in the form of a crude product. Then to the solution of the desired substance in methanol (10 times the volume) add 1095 methanolic solution of hydrogen chloride (two times the volume) while cooling (ee) with ice and stir for 30 minutes. To the mixture add isopropyl ether (100 times the volume) and for 50 crystals obtained are filtered, washed with diisopropyl ether to obtain the desired g hydrochloride.

After the obtained hydrochloride is extracted with ethyl acetate and a saturated aqueous solution of sodium bicarbonate, the "H-NMR" indicators are determined.

Synthesis example 37

Output: 3390 22 Yellow crystals

Gee! T.pl.: 2287C (exp.)

MS (EAV) m/z: 414 (MANI de Synthesis Example 38

Yield: 3090 60 Yellow crystalline substance

T.p.: 2577C (exp.)

TN-NMR (SOSIi) 8: 118(s, ZN), 1.32(d, 9-6.8Hz, 6H), 1.49 (s, ZN), 1.60 (width s, 1H), 2.65 (fifth,

U-6.8Hz, 1H), 2.80 (width, 1H), 2.95-3.05 (m, 4H), Z,50(d, A part of AB, 9U-10.3 Gd, 1H), Z,68(d, B part AB,

U-10.3Hz, 1H), 7.44(d, 9-8.4Hz, 2H), 7.64(s, 1H), 8.17(d, U-8.4Hz, 2H), 8, 74(s, 1H), 10.18(s, 1H). for MS (EAV) m/z: 473IMNI".

Synthesis example 39

Output: 3390

Yellow crystals

M.p.: 244-245" (div.) "NA-NMR (SOSIV) 5: 1.18(s, ZN), 1.30(d, U-6.8Hz, 6H), 1.48 ( s, ZN), 1.60(width s, 1H), 2.63(quint, --6.8Hz, 1), 2.77(t, 9U-68Hzc, 2H), 2.95-3, 00 (m, ZN), Z,5O(d, A part of AB, .4-10,3HZ, 1H), Z,b8(d, B part of AB,

U-10.3Hz, 1H), 3.78(s, 6H), 6.32 (d, U-2.4Hz, 1H), 6.4O(d, 9U-2.4Hz, 2H), 7, 62(s, 1H), 8.71(s, 1H), 10.14(s, 1H).

MS (EAV) m/z: 488|M-NI".

Synthesis example 40

Output: 46905

Yellow crystals

T.pl.: 2397C (exp.)

MS (EAV) m/z: 446 MANI)".

Synthesis example 41

Output: 3890

Yellow crystals

T.pl.: 24972 (exp.)

MS (EAV) m/z: 496 (MANI.

Synthesis example 42

Output: 2390

Yellow crystals

T.pl.: 2287C (exp.)

MS (EAV) m/z: 458 MANI. with

An example of the synthesis of 43 Ge)

Output: 31956 Yellow crystals

T.pl.: 2437С (exp.)

MS (EAV) m/z: 446 MANI)". oyu 20 Example of synthesis 44

Output: 2690 (ee)

Yellow crystals so

T.pl.: 24270 (open)

TNA-NMR (SOSIi) 8: 1.17 (s, ZN), 1.31 (d, 9-6.9 Hz, b), 1.48 (s, ZN), 2.00 (sh.s, 2H ), 2.64 (quint, i-

Sv -6.9Hz, 71H), 2.75-3.00 (m, 4H), З.50(d, A part of AB, 4-10.0Hz, 1H), 3.69(d, B part of AB , U-10.0Hz, 71), z 7.01(t, U9-8.5Hz, 2H), 7.15-7.26(m, 2H), 7.63 (s, 1H), 8, 69(s, 1H), 10.15(s, 1H).

MC (EAV) m/z: 446 MANI.

Synthesis example 45 "

Exit: 990

Yellow crystals - with melting point: 112-1167С (dec.) and MS (EAV) m/z: 442 MENI. ," Synthesis example 46

Output: 2495

Yellow crystals 1 M.pl.: 25022 (dec.) - TNA-NMR (SOSIS) 8: 1.18 (s, ЗН), 1.32(d, 9-7.0Hz, 6Н), 1.49 ( s, ZN), 1.62 (width of s, 2H), 2.65 (quint,

U-7.0Hz, 1H), 2.81(t, U-6.6Hz, 2H), 2.88-3.00 (m, 2H), 3.48(d, A part of AB, 9U-10 ... ,3Hz, 2H), 7.63(s, 1H), 8.71(s, 1H), 10.16(s, 1H). bo about MS (EAV) m/z: 462 (MANI.

Synthesis example 47 sl Output: 3595

Yellow crystals

T.pl.: 24972 (open) 59 MS (EAV) m/z: 462 (MENI.

GF) Synthesis example 48 7 Output: 1690

Yellow crystals

T.pl.: 204-2087C (open)

MS (EAV) m/z: 443 MANI.

Synthesis example 49

Red amorphous substance

TN-NMR (SOSIi) 8: 1.17(s, ZN), 1.32(d, 9U-7.0Hz, 6H), 1.48 (s, ZN), 2.21(s, ZN), 2.65(5th, -7.0Hz, bB 1), 2.86-2.98(m, 4H), 3.46b(d, 9U-10.0Hz, 1H), C.68(d, 9 -10, OGC, 1), 7.22-7.32 (m, 5H), 7.61(s, 1H), 8.63(s, 1H), 9.98(s, 1H).

MS (ZY) m/z: 420 |Ma-1)", 344, 179 (br)

SYNTHESIS EXAMPLES 50-75

Кк 9 - что уон о Го) Meshe 70

An example of the synthesis of Lo V nt v kN zh aa aa aa aa aa

Mo, pooe A as 51 and 52 And see

E about

OMe 53 yu nm so (ee)

E but AH and ki it) in HORROR:

NK E 2 s z» s poyu AH

Nk s pop NN -I (ee) bo sl (F. ko bo 65

Kk

N I and A On at 9 Me

An example of the synthesis of Le B 70 ptn

OMe " d 15 NM OMe 8 NM Rv

MN, zo

NM s o oo yay AD

NM a yuyu so (ee) 61 Adi ge yu z AL nya « 400--------------- - - -- 525 - : yu Ya t «A - s z 1 -I ( ee) bo o sl (F) ko 6o 65

Example of Lo synthesis Structural formula

AH

NM

6 Z HA t ON om mo) 15 I: i nn t b ve A mon

KI. at 0 20 f

M

65 schi A ON sch 25 o - s | i.e

AD o 30 NM 6 6 NM A mon so va » o i; uh-

Z5 IS o) i: he F 67 n.K X lon « . vo : s li o ;z" ---5-333337777717T.-- 45 1 -I (og) oo 20 sl (F, ko 60 bo

An example of the synthesis of Mo. The structural formula of di 68 nu

AenM A, mon (optically active) o

IS

AH

69 well with AsNM A mon (optically active) vva 2b ohm o

AJDU

NI s 70 N g what A On o (optically active) o "KI ozh o

IS) " AD from the village

Still everything Mri on (optically active) z vya ge o yu o o nnknzhzhnzhNzha a a a vVNVa azh a a zh zhVNV aVn zhchzhchtantnlntayaaya go aa an a a a A a « t s ;z» 1 -I (ee) o 50 sl

F) name) 60 b5

Example of Me synthesis Structural formula

AH

WE

12 t

As OH (optically active) o o 7 3 NM. . ASND Ka (optically active) ох 0 ох 1 AsNM. no on (optically active) ХА с од о о

AH about us 75 t so

ASNM. ON EE (optically active) (ee) ож 0 и-

And AD Y

76 In you " (optically active) "ON - NO t s o om o . from VV VV OO VV

General method of synthesis of compounds 50 - 75

To a solution of b-cyclopropylamido-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (20 mg, 0.66 1 mmol) and lithium bromide (22 mg, 2, 6 mmol) in tetrahydrofuran (2 ml) add amine (1.31 mmol) at room temperature and stir at 657C for 4 hours. Ethyl acetate is added to the mixture, and the resulting organic phase is washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate (ee). After the solvent is distilled off, the residue is purified by column chromatography on silica gel to obtain the desired substance. (uh)

Synthesis example 50 sl Output: 3090

TN-NMR (SOS) 85: 0.96-0.98 (m, 2H), 1.10-1.78 (m, 5H), 1.48 (s, ЗН), 1.63-1.66 (m, 1H), 2.93-3.01(m, 4H), 3.52(d, 9U-101Hz, 7H), b,bv(id, 9U-10.1Hz, 1), 7.40 -7.42 (m, 2H), 1.63 (s, 1H), 8.14-8.17 (m, 2H), 8.66 (s, 29 1H), 10.29 (width, 1H).

F! MS (ZY) m/z: 334 (Br), 471 (MI

Synthesis example 51 o Output: 3895

TN-NMR (SOCI3) 8: 0.92-0.95 (m, 2H), 1.09-1.13 (m, 2H), 1.19 (s, ЗН), 1.50 (s, ЗН ), 1.63-1.64(m, 1H), 60 1.80-1.84(m, 2H), 2.58-2.68(m, 4H), 3.5b(id, 9U- 10.1Hz, 1), 3.71(dd, 9-09, 10.1Hz, 1H), 7.14-7.27(m, 5H), 7.61(s, 1H), 8.72( d, U-0.9Hz, 1H), 10.30 (width s, 1H).

MS (ZY) m/z: 300 (Br), 439 (MI

Synthesis example 52

Yield: 7190 65 TN-NMR (SOSIS) 85: 0.94-0.96 (m, 2H), 1.10-1.17 (m, 5H), 1.47 (s, ЗН), 1.63 -1.66 (m, 1H), 2.81-2.94 (m,

AN), 3.50(d, 9U- 10.1HzC, 1H), 3.7O(d, 9-10, 1HzC, 1H), 6.96-7.22 (m, 4H), 7.60 ( s, 1H), 8.64(s, 1H), 10.25(width, 1H).

MS (ZY) m/z: 303 (Br), 443 MI

Synthesis example 53

Yield: 47905 "NA-NMR (SOSIZ) 5: 0.93-0.96(m, 2H), 1.10-1.17(m, BN), 1.48 (s, ЗН), 1.63 -1.65(m, 1H), 2.72-2.89(m, 4H),

Z,5O(d, 9U-101Huts, 1), Z,b7(dd, 90.7, 101Gu, 71), Z3,77(s, ZN), 6.80-6.82 (m, 2H), 7.10-7.13(m, 2H), 7.6Ff(s, 1H), 8.63(s, 1H), 10.25 (width s, 1H).

MS (EAV) m/z: 121, 456 |МА1|" 70 Example of synthesis 54

Output: 5495

TN-NMR (SOS) 85: 0.95-0.97 (m, 2H), 1.10-1.17 (m, 2H), 1.26 (s, ZN), 1.48 (s, ZN ), 1.63-1.67(m, 1H), 2.76-2.94(m, 4H), 3.50 (d, 9-10, 2HC, 1H), Z,b/(dd, 9U-1.0, 10.2Hz, 71H), 6.94-6.99(m, 2H), 7.15-7.26(m, 2H), 7.61(s, 1H), 8, 61 (d, 9-1.0Hz, 1H), 10.26 (width, 1H).

MS (ZY) m/z: 260 (Br), 443 MI"

Synthesis example 55

Output: 53905

TN-NMR (SOSIV) 8; 0.94-0.97(m, 2H), 1.11-1.17 (m, 5H), 1.48 (s, ЗН), 1.63-1.65(m, 1H), 2, 79-2.94(m, 4H), 3.49 (d, 9U-10.3HZ, 1H), Z3.6b7/(dd, 9U-0.9, 10.3HZ, 71H), 6.90- 7.01 (m, ZN), 7.23-7.26 (m, 1H), 7.62 (s, 1H), v,v3(d, 2-0.9Hz, 1H), 10.27( shir.s, 1H).

MS (ZY) m/z: 301 (Br), 443 MI

Synthesis example 56

Output: 58905

TN-NMR (SOSIZ) 8: 0.87-0.90 (m, 2H), 1.11-1.14 (m, 2H), 1.17 (s, ZN), 1.48 (s, ZN ), 1.63-1.67 (m, 1H), s 2.717-2.81 (m, 2H), 2.89-2.93 (m, 2H), 3.48 (d, 9U-10, 3Hz, 1H), 3.65(d, 9U-10.3Hz, 1H), 7.16-7.26 (m, 4H), 7.62(s, o 1H), 8.65(s, 1H ), 10.28 (width c, 1H).

MS (ZY) m/z: 305 (Br), 460 (M)

Example of synthesis 57 points

Output: 56905

TNA-NMR (SOSIZ) 5: 0.92-0.95 (m, 2H), 1.09-1.18 (m, 5H), 1.49 (s, ЗН), 1.62-1.65 (m, 1H), 2.73-2.92 (m, 00 4H), 3.51 (d, 9-10, 2HC, 7H), 3.67 (d, 9U-10, 2HC, 7H), 3.77 (c, 6H), 6b.31(c, ЗН), b,Zy(c, 2H), 7.61(c, 1H), со 8.64(c, 1H), 10.26 ( shir.s, 1H).

MS (ZY) m/z: 470 (Br), 486 MI -

Example of synthesis 58 yu

Output: 5290

TNA-NMR (SOS) 8: 0.92-0.97 (m, 2H), 1.10-1.16 (m, 2H), 1.20 (s, ZN), 1.51 (s, ZN ), 1.63-1.68 (m, 1H),

Z,b4(d, 9U-10.1HzC, 1H), 3.77-3.84(m, ЗН), 7.25-7.39(m, 5H), 7.67(s, 1H), 8.88 (s, 1H), 10.34 (width, 1H). "

MS (ZY) m/z: 339 (yy), 411 MI"

Synthesis example 59 - s Yield: 5790 in TN-NMR (SOSIS) 8: 0.93-0.96 (m, 2Н), 1.11-1.17 (m, 5Н), 1.47 (s, ЗН ), 1.63-1.65 (m, 1H), 2.68-2.71 (m, nya 2H), 2.85-2.88 (m, 2H), Z46b(d, 9U-10, 1ГЦц, 1), Z,b4(d, 9U-101Gu, 1), 6.62-6.64 (m, 2H), 6.70-7.02 (m, 2H), 7.61(s, 1H), 8.64 (s, 1H), 10.26 (width s, 1H).

MS (ZY) m/z: 333 (Br), 439 MI" o Example of synthesis 60-I Output: 4290

TN-NMR (SOSIi) 8: 0.94-0.97 (m, 2H), 1.12-1.17 (m, 5H), 1.49 (s, ЗН), 1.63-1.67 (m, 1), 2.77-2.94(m, so 4H), 3.49(d, 9-10.3HzC, 1), Z,b/(dd, U-0.9, 10, 3Hz, 71), 7.10-7.22(m, 4H), 7.62 (s, 1H), 8.63Z(d, 9-0.9Hz, bo 0200 1n), 10.27(width with, 1H). sp MS (ZY) m/z: 334 (Br), 460 (M)

Synthesis example 61

Output: 61905

TN-NMR (SOSIV) 8: 0.94-0.97(m, 2H), 1.10-1.18(m, 5H), 1.48 (s, ЗН), 1.63-1.66 (m, 1), 2.85-2.96(m, 4H), 3.5Z(d, 9U-10.1Hz, 1H), 3.71(d, 9U-10.1Hz, 1), 7 ,28-7 46(m, 4H), 7.6O(s, 1H), 8.66(s, 1H), 10.26 (width s, 1H). (F. MS (ZY) m/z: 259 (yy), 494 MI z Synthesis Example 62

Red amorphous substance in TNMR (SOSIZ) 5: 0.94-0.97(m, 2H), 1.12-115(m, 2H), 1.16 (s, ЗН), 1.47(s, ЗН) ), 1.61-1.67(m, /1H), 2.719-2.96(m, 4H), 3.45 (d, U-9.9HzC, 1H), Z,b4(d, U- 9.9Hz, 1H), 7.22-7.32 (m, 5H), 7.61(s, 1H), 8.62(s, 1H), 10.26(s, 1H).

MS (ZY) m/z: 418 |M-1)", 346, 309, 179 (yr).

Synthesis example 63

Red crystals 65 M.p.: 169.0-170.07С

TN-NMR (SOSIv) 8: 1.17(s, ЗН), 1.37(s, 9Н), 1.47(s, НН), 2.81-2.85 (m, 2Н), 2, 93-2.97 (m, 2H), Z3.47 (d,

U-10.1HzC, 1H), 3.67(d, 9-10, 1HzC, 1H), 7.19-7.32(m, 5H), 7.63(s, 1H), 8.74( c, 1H), 10.44 (c, 1H).

MS (ZY) m/z: 441 |Ma1)", 322, 268 (yy).

Synthesis example 64

Red crystals

T.pl.: 176.5-178.076

TNA-NMR (SOSIZ) 8: 1.18(s, ZN), 1.54(s, ZN), 3.05-3.16 (m, ZN), 3.26-3.30(m, 71Н ), 4.06b(d, U-8.6Hz, 1H), 4.58(d, U-8.6Hz, 1H), 7.15-7.26(m, 5H), 7.73(s , 1H), 8.65(s, 1H), 10.66(s, 1H).

MS (ZY) m/z: 453 |MI" (Br).

Synthesis example 65

Red amorphous substance

TN-NMR (SOSIi) 85: 1.02 (t, 9-6.8 Hz, ZN), 1.24 (s, ZN), 1.52 (s, ZN), 1.83 (s, ZN), 2.68-2.96 (m, 4H),

З.33(kv, U-6.8Hz, 1Н), 3.6З(d, 9У-10.1Hz, 1Н), 3.74(d, У-10.1Hz, 1), 3.77-3 .90 (m, 1H), 7.19-7.39 (m, 7H),

MS (EAV) m/z: 428 MI" (Br), 268, 105. iz Example of synthesis 66

Red amorphous substance "NA-NMR (SOSIV) 8: 1.15 (s, ZN), 1.33 (t, 9-7.1 GHz, ZN), 1.46 (s, ZN), 2.82-2 ... ,b5(d, 9U-10.1Hz, 1H), 6b,58(s, 1), 7.22-7.26(m, ЗН), 7.31-7.34 (m, 20. 2H) , 7.5Z(width s, 1H), 7.6F(s, 1H).

MS (ZY) m/z: 385 |MI", 314, 266, 223 (Br).

Synthesis example 67

Yellow oil

TNA-NMR (SOS) 85: 1.18 (s, ZN), 1.48 (s, ZN), 2.75-3.00 (m, b6H), 3.52 (d, A part of AB, 4 -9.9Hz, 1H), s 25 C,7O(d, B part of AB, U-9.9Hz, 1H), 7.18-7.35(m, 5H), 7.62(s, 1H) , 8.45(s, 1H), 8.66(s, 1H), 9.98(s, 1H). (5)

MS (ZY) m/z: 385 |MI", 313 (Br).

Synthesis example 68

A derivative of ()-(3K", 4K")-6-acetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (9995 with an error within of admissibility of these or more). it) 30 Yellow amorphous substance so 26 (which is -104.6(c 0.64, EUN) so

Synthesis example 69

A derivative of ()-(3K", 4K")-6-acetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (9995 with o

Зз5 an error within the limits of admissibility (its) or more). yu

Yellow crystals (NOI salt): m.p. 246-2477C (detail). (NOI salt): (oo -71.8 (c 0.38, EUN) «

Synthesis example 70 40 Derivative of (g)-(3K", 4K")-3,4-epoxy-6-cyclopropyl-amide-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1- of benzopyran t s (9995 with an error within the permissible limit (one or more). "» (NOI salt): Yellow crystals " (NOI salt): mp. 241-2467C (dec.). 45 (NOI salt): ( o. -92.1 (s 0.45, EUN) s Synthesis example 71

A derivative of (g)-(3K", 4K)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-6-trifluoroacetamide-2H-1-benzopyran - (9995 with an error in limits of admissibility (its or more). со (NOI salt): Yellow crystals (NOI salt): m.p. 2437 (dec.). o 26 (ЧО -54.8 (с 0.5, ЕЙН) sl Example of synthesis 72

A derivative of ()-(3K", 4K")-6-acetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (9995 with an error within of admissibility of these or more).

Red amorphous substance (Ф) (x10 -64.3 (c 1.03, EUN) co Synthesis example 73

A derivative of (-)-(3K", 4E"7)-6-acetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (9995 with an error within the limits of admissibility of Ii or more). A red amorphous substance (soC 61.2 (c 0.98, EUN)

Synthesis example 74

A derivative of ()-(3K", 4K")-6-acetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (9995 with an error within of admissibility of these or more). 65 Red amorphous substance

(10 -64.6 (with 1.00, EUN)

Synthesis example 75

A derivative of (-)-(3K", 4E"7)-6-acetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (9995 from 9 an error within the limits of admissibility (its) or more).

Red amorphous substance (010 160.8 (c 0.93, EUN)

Synthesis example 76 70 To a solution of /(-3-(3K", 0 4K-3,4-epoxy-6-isopropylamide-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran ( 1.0t, 3.59 mmol) and lithium bromide (1.24g, 14.36 mmol) in acetonitrile (10 mL) add 4-fluorophenethylamine (188 mL, 14.4 mmol), corresponding to the required substituent in the 4-position, at room temperature and stirred at 65"C for 2 hours. Then ethyl acetate is added and the organic phase formed is washed with a saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution and dried /5 over anhydrous magnesium sulfate. After the solvent is distilled off, the residue is purified by column chromatography on silica gel to obtain a substance substituted by an amine in position 4. Then, concentrated hydrochloric acid (6 equivalents) is added to a solution of this substance substituted by an amine in position 4 in ethanol (10 times the volume) at room temperature and boiled with reflux for 1 day at 907. Then add a saturated solution of hydrogen carbonate at tritium and extracted with ethyl acetate, and the organic phase formed is washed once with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off to obtain the substance deamidated in position b. Then, a 4N solution of hydrogen chloride in dioxane (1.4 equivalents) is added to a solution of the substance deamidated in position 6 in dimethylformamide (20 times the volume) at room temperature and stirred for 10 minutes. Acid chloride (1.5 equivalents) corresponding to the substituent in the 6-position is added dropwise and the mixture is stirred for 1 hour, then methanol (ml) is added and stirred for another 10 minutes. Water is added to this mixture and extracted with ethyl acetate, and the organic phase formed is washed with a saturated solution of i) sodium bicarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.

After the solvent is distilled off, the residue is purified by column chromatography on silica gel to obtain the desired substance. Then, to the solution of the desired substance in methanol (10 times the volume) add 1095 methanolic hydrogen chloride solution (two times the volume) while cooling with ice and stir for 30 minutes.

Then add diisopropyl ether (100 times the volume) and the obtained crystals are filtered off, washed with diisopropyl ether to obtain the desired hydrochloride. co

Yellow crystals

T. pl.: 244-2452С (excl.) i- (o. -67.3 (c 04, EUN) Shcheo,

Examples of compositions

Example of composition 1

Tablets "

The compound according to this invention 10g - s Lactose 260g "» Powder of crystalline cellulose god " Corn starch WBOH

Hydroxypropyl cellulose 100g

KMC-cSa 1BOG o Magnesium stearate Zog -I Total 1500g so The above compounds are mixed in the usual way and then made into 10,000 sugar-coated 50 tablets, each of which contains 1mg of active ingredient per tablet.

An example of a 2-syllabic composition

Capsules

The compound according to this invention 1ohm

Lactose 440g o Powder of crystalline cellulose 1000g

Magnesium stearate God eats) Total 1500g 60 The above compounds are mixed in the usual way and then filled into gelatin capsules to make 10000 capsules, each of which contains 1mg of active ingredient per capsule.

An example of a composition by Z

Soft capsules 65 Compound according to this invention 1 g

PEG 400 Atog

Triglyceride of saturated fatty acid 1500g

Peppermint oil 1 g

Polysorbate 80 1 g

Only 2000 g

The above-mentioned compounds are mixed in the usual way and then filled with the mixture into soft gelatin capsules of Mo Z to obtain 10,000 soft gelatin capsules, each of which contains 1 mg of active ingredient per capsule. 70 Example of composition 4

Ointment

The compound according to this invention - 1.0 g

Vaseline oil 10,Og

Cetanol 20.0 g

White Vaseline 68 Ag

Ethylparaben b 1g 1-menthol OBG

Only 100, Ohm

The above-mentioned compounds are mixed in the usual way to obtain 195 ointment.

Example of composition 5

Suppositories

Compounds according to this invention 1g p

Vitepsol NIB" (Uupervoi H157). 478 g o

Vitepsol NZB" 520 g

Polysorbate 80 1g

Only 10 gods

Io) ("Vytepsol" is a trade name for compounds of the triglyceride type) so

The above-mentioned compounds are mixed in a melt in the usual way, the mixture is poured into containers for suppositories and cooled until solidification, and in this way 1000 suppositories (1 g) are obtained, each of which contains 1 mg of the active ingredient per suppository. Cha

An example of a composition b

From Injections that)

Compounds according to this invention 1 mg

Distilled water for injections 5 ml «

Water is used for dissolution during application. - c Example of a pharmacological test xz Effect of the compound on the functional refractory period in the muscle of the left atrium of the guinea pig and the papillary muscle of the right ventricle

Test method

Hearts were removed from guinea pigs and the muscles of the left atrium or the papillary muscles of the right ventricle were isolated from them and placed in Krebs-Henseleit solution, which is aerated at 9595 O o 5956 CO. The samples were stimulated -I electrically with a frequency of 1 Hz and a voltage 1.5 times higher than the limit value of the response to stimulation (baseline stimulation; 51), using the apparatus for electrical stimulation. The contraction that occurred at this time (ee) was recorded with the help of a thermal recording device through the PO receiving device and the tensile pressure amplifier. The functional refractory period is defined as the shortest time interval between 51,

Me that is obtained as a result of a defined contraction and additional stimulation (52). The time interval between 51 and sp 2 in the sample of the left atrial muscle began with 150 msec, decreased gradually by 10 msec to 100 msec and then by 5 msec to the functional refractory period. As for the right atrial papillary muscle sample, it started at 300 msec and decreased stepwise by 10 msec until the functional refractory period. Here, 52 was set to double the threshold value when a response to stimulation occurred.

The temperature during the experiment was equal to 36 and 17C. The solvent here did not affect any of the i) functional refractory periods for the left atrial muscle and the right atrial papillary muscle. ko After determining the initial value before adding the compound, compounds were added cumulatively, incubated for 15 minutes at the appropriate concentration, and then the functional refractory period was determined. 60 Results

Compounds according to this invention showed a strong prolonging effect on the functional refractory period (FRP) on the atrial muscle. two

From 40 6 1A vovi

The compounds of this invention exhibit a strong prolonging effect on the functional refractory period and, thus, they are useful for alleviating arrhythmia. Therefore, the present invention may provide useful antiarrhythmic agents.

Claims (1)

The formula of the invention is 1. The benzopyran derivative of the formula (I) in B dl Snju (sna KM M 54 Xx 2 Kk B osv where B and B2, each independently, represent a hydrogen atom, C 1-in--an alkyl group, where the alkyl the group ω may be optionally substituted by a halogen atom, a C 4.6-alkyl group, or a hydroxyl group; or a phenyl group, where said phenyl group may be optionally substituted by a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C. c-alkyl group, or C. c-alkyloxy group, BZ represents a hydroxyl group or C. c-alkylcarbonyloxy group, БЕ" represents a hydrogen atom, or BZ and 7 together form a bond, Het represents an integer from 0 to 4, n represents an integer from 0 to 4, o U is absent or represents SV 872, where B and B/?, each independently, represents a hydrogen atom or C, an alkyl group, ВЕ? represents an aryl group or a heteroaryl group, where aryl is indicated group and the indicated heteroaryl o group can be optionally substituted (K 10 ud where KO is a halo atom genu, hydroxyl group, (ee) C, c-alkyl group, where the specified alkyl group can be optionally replaced by a halogen atom or a C-Ci c-alkyl group; or BO represents a nitro group, a cyano group, a formyl group, a formamide group, an amino group, a C-alkylamino group, a di-C4-alkylamino group, a C-alkylcarbonylamino group, Si in-alkylsulfonylamino group, aminocarbonyl group, Su. γ-alkylaminocarbonyl GROUP, di-C-γ-alkylaminocarbonyl group, Su. c-alkylcarbonyl group, C-c-alkylcarbonyl group, aminosulfonyl group, C-c-alkylsulfonyl group, carboxyl group or arylcarbonyl group, d is an integer from 1 to 3, and each BO can be the same or different if 4 is equal 2 or 3, " 25 represents a hydrogen atom or a C. v-alkyl group, B represents a hydrogen atom or a C. v- alkyl group, - c X is absent or represents C-O or 505, "" BZ represents a hydrogen atom, C 4. 6-alkyl group, where the specified alkyl group can be optionally substituted by a halogen atom, a hydroxyl group or a C. 6-alkyl group, or a C 6-cycloalkyl group, and B? represents a hydrogen atom, a halogen atom, a nitro group or a cyano group; or its pharmaceutically acceptable salt 49. Mn 2. A benzopyran derivative or its pharmaceutically acceptable salt according to item 1, where B and its 22, both, represent methyl groups, EZ represents a hydroxyl group, and KE" represents a hydrogen atom. CO 3. A benzopyran derivative or its pharmaceutically acceptable salt according to item 2, where VU is a 5p hydrogen atom or a nitro group, because 4. A benzopyran derivative or a pharmaceutically acceptable salt thereof according to item 3, where X is C-O, and B?sl and 27, both, are hydrogen atoms. 5. The benzopyran derivative or its pharmaceutically acceptable salt according to item 4, where B ? is a benzene ring, Y is absent, t is 0, and n is 1 or 2. 6. Benzopyran derivative or its pharmaceutically acceptable salt according to item 5, where KZ is an alkyl HF! group, VZ is a nitro group, and n is 2. 7. A medicinal product, which is characterized by the fact that it includes a benzopyran derivative or its pharmaceutically acceptable salt according to item 1 as an active ingredient. 8. A drug for the treatment of arrhythmia, which is characterized by the fact that it includes a benzopyran derivative or its 60 pharmaceutically acceptable salt according to item 1 as an active ingredient. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 7, 15.07.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. b5