Benzopyrane derivative and a drug based on it

 

(57) Abstract:

The invention relates to new derivatives of benzopyran formula (I)

where R1and R2each independently represent a hydrogen atom, a C1-6-alkyl group, where this alkyl group may be optionally substituted by a halogen atom, a C1-6-alkoxygroup or a hydroxyl group; R3represents a hydroxyl group or a C1-6-alkylcarboxylic; R4represents a hydrogen atom, or R3and R4together form a bond, m is an integer from 0 to 4, n represents an integer from 0 to 4, Y is absent or represents CR11R12where R11and R12each independently represents a hydrogen atom or a C1-6is an alkyl group, R5represents an aryl group or heteroaryl group, such as thienyl, pyridyl or indolyl, where this aryl group may be optionally substituted (R10), where R10represents a halogen atom, a hydroxyl group, a C1-6-alkyl group, where this alkyl group may be optionally substituted by a halogen atom or C1-6-alkoxygroup is nogroup, C1-6-alkoxycarbonyl group, carboxyl group, q is an integer from 1 to 3, and each R10may be the same or different when q is 2 or 3, R6represents a hydrogen atom or a C1-6is an alkyl group, R10represents a hydrogen atom or a C1-6is an alkyl group, X is absent or represents C=O or SO2; R8represents a hydrogen atom, a C1-6-alkyl group, where this alkyl group may be optionally substituted by a halogen atom, or WITH3-6-cycloalkyl group, and R9represents a halogen atom, a nitro-group, or cyano; or their pharmaceutically acceptable salts, as well as a drug on the basis of these compounds with anti-arrhythmic activity. The technical result - obtaining new derivatives benzopyran for the treatment of arrhythmia. 3 s and 5 C.p. f-crystals, 9 PL.

The technical field

This invention relates to benzopyranones derivatives which are prolonging effect on the functional refractory period, which is used to treat arrhythmia in mammals, including humans.

The level of technology

That cases the Lena Cromakalim (display Japanese patent application No. Sho 58-67683). These 4-arylaminobenzothienoand derivatives, examples of which are presented Cromakalim, as is well known, open-sensitive ATP TO+channels and effective for the treatment of hypertension or asthma, but there was no mention in the treatment of arrhythmia based on prolonging the action on the functional refractory period.

Currently used anti-arrhythmic means having a prolonging effect on the functional refractory period as the main functions (such as medicines of the Class I according to the classification of antiarrhythmic drugs on Vaughan Williams, or d-sotalol, belonging to Class III), have a very dangerous causing arrhythmia effect, which can lead to sudden death, such as atrial flutter based on the lengthening of the action potential of the muscle of the ventricles, associated with prolonging effect on the functional refractory period, which is therapeutic problems. Thus, the desired funds, with fewer side effects.

Description of the invention

This invention conducted intensive studies of compounds with Strait is rudseti compared with the muscles of the ventricles, and found that the compound with the General formula (I) has a prolonging effect on the functional refractory period selective in relation to the muscles of the Atria without any effect on the refractory period of the muscle of the ventricles and the parameters of the action potential.

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

This invention relates to benzopyrano derivative of the formula (I)

where R1and R2each independently represent a hydrogen atom, a C1-6-alkyl group, where the alkyl group can be optionally substituted by a halogen atom, a C1-6-alkoxygroup or a hydroxyl group; or phenyl group where the phenyl group can be optionally substituted by a halogen atom, a hydroxyl group, a nitrogroup, cyano, C1-6is an alkyl group or a C1-6-alkoxygroup,

R3is hydroxyl the3and R4together form a bond,

m represents an integer from 0 to 4,

n represents an integer from 0 to 4,

Y is absent or represents CR11R12where R11and R12each independently represents a hydrogen atom or a C1-6is an alkyl group,

R5represents an aryl group or heteroaryl group, where the aryl group or heteroaryl group can be optionally substituted q(R10), where R10represents a halogen atom, a hydroxyl group, a C1-6-alkyl group, where the alkyl group can be optionally substituted by a halogen atom or C1-6-alkoxygroup; or R10is a nitro-group, a cyano, formyl group, formamide group, an amino group, a C1-6-alkylamino, di-C1-6-alkylamino, C1-6-alkylcarboxylic, C1-6-alkylsulfonamides, aminocarbonyl group, C1-6-alkylaminocarbonyl group, di-C1-6-alkylaminocarbonyl group, C1-6-alkyl-carbonyl group, a C1-6-alkoxycarbonyl group, aminosulfonyl group, C1-6-alkylsulfonyl group, carboxyl who are treated alike or different, if q is 2 or 3,

R6represents a hydrogen atom or a C1-6is an alkyl group,

R7represents a hydrogen atom or a C1-6is an alkyl group,

X is absent or represents C=O or SO2,

R8represents a hydrogen atom, a C1-6-alkyl group, where the alkyl group can be optionally substituted by a halogen atom, a hydroxyl group or a C1-6-alkoxygroup or3-6-cycloalkyl group, and

R9represents a hydrogen atom, a halogen atom, a nitro-group, or cyano;

or its pharmaceutically acceptable salt.

The connection 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.

Appropriate substituents for the compound (I) according to this invention is specifically illustrated below.

Here “n” means normal, “I” means ISO, “W” means secondary, “t” means tertiary, “C” means cyclo-, “o” means ortho, “m” means meta-, and “p” means para-.

Examples of the Tyl, 2 pentyl, 3-pentyl, isopentyl, neopentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 3,3-dimethyl-n-butyl, trifluoromethyl, triptorelin, pentafluoroethyl, cyanomethyl and hydroxymethyl, etc.

Preferred are methyl, ethyl, n-propyl, isopropyl and n-butyl.

As atoms of halogen can be fluorine atom, chlorine atom, bromine atom and iodine atom. Preferred are a fluorine atom, a chlorine atom and a bromine atom.

Examples of C1-6-alkoxygroup can be methoxy, triptoreline, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, W-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, isopentylamine, neopentylene, 2,2-DIMETHYLPROPANE, 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.

Preferred are methoxy, ethoxy, n-propoxy, isopropoxy.

Examples of C1-6-alkylcarboxylic can be methylcarbonate, ethylcarbonate, n-propylmalonate, isopropylcarbonate, n-BUTYLCARBAMATE, isobutyryloxy, W-BUTYLCARBAMATE, t-BUTYLCARBAMATE, 1-intercorporal is iloxi, 1 hexylcaine, 2-hexylcaine, 3 hexylcaine, 1-methyl-n-intercorporate, 1,1,2-trimethyl-n-propylmalonate, 1,2,2-trimethyl-n-propylmalonate and 3,3-dimethyl-n-BUTYLCARBAMATE etc.

Preferred are methylcarbonate, ethylcarbonate, n-propylmalonate, isopropylcarbonate, n-BUTYLCARBAMATE and t-BUTYLCARBAMATE.

Examples of aryl groups can be phenyl, biphenyl, naphthyl, antril and tenantry, etc.

Preferred are phenyl, biphenyl and naphthyl.

Examples of heteroaryl groups can be 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzothiazyl, 3-benzothiazol, 4-benzothiazyl, 5-benzothiazyl, 6-benzothiazyl, 7-benzothiazyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-chromanol, 3-chromanol, 4-chromanol, 5-chromanol, 6-chromanol, 7-chromanol, 8-chromanol, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-oxazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-isoindolyl, 4-isoindolyl, 5-isoindolyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-indazole, 2-indazole, 3-indazoles, 4-indazole, 5-indazole, 6-indazole, 7-indazole, 1-purines, 2-purinol, 3-purinol, 6-purinol, 7-purinol, 8-purines, 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 6-chinolin, 7-chinolin, 8-chinolin, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 6-ethanolic, 7-ethanolic, 8-ethanolic, 1-phthalazine, 5-phthalazine, 6-phthalazine, 2-naphthyridines, 3-naphthyridines, 4-naphthyridine, 2-honokalani, 5-honokalani, 6-honokalani, 2-hintline, 4-hintline, 5-hintline, 6-hintline, 7-hintline, 8-hintline, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, 8-indolinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl and 3-furutani etc.

Preferred are 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.

Examples of C1-6-alkylamino can be methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, isobutylamino, W-butylamino, t-b is ylamino, cyclopentylamine, 1 hexylamino, 2-hexylamino, 3 hexylamino, cyclohexylamino, 1-methyl-n-pentylamine, 1,1,2-trimethyl-n-propylamino, 1,1,2-trimethyl-n-propylamino and 3,3-dimethyl-n-butylamino etc.

Preferred are methylamino, ethylamino, n-propylamino, isopropylamino and n-butylamine.

Examples of di-C1-6-alkylamino may be dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, Dicyclopentadiene, di-n-butylamino, diisobutylamine, di-W-butylamino, di-t-butylamino, Dicyclopentadiene, di-1-pentylamine, di-2-pentylamine, di-3-pentylamine, diisobutylamine, dineopentyl, di-t-pentylamine, Dicyclopentadiene, di-1-hexylamine, di-2-hexylamino, di-3-hexylamino, dicyclohexylamine, 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(W-butyl)amino, methyl(t-butyl)amino, methyl(cyclobutyl)amino, ethyl(n-propyl)-amino, ethyl(isopropyl)amino, ethyl(cyclopropyl)amino, ethyl(n-butyl)amino, ethyl(isobutyl)amino, ethyl(W-butyl)amino, ethyl(t-butyl)amino, ethyl(cyclobutyl)ampil(W-butyl)amino, n-propyl(t-butyl)amino, n-propyl(cyclobutyl)amino, isopropyl(cyclopropyl)amino, isopropyl(n-butyl)amino, isopropyl(isobutyl)amino, isopropyl(W-butyl)amino, isopropyl(t-butyl)amino, isopropyl(cyclobutyl)amino, cyclopropyl(n-butyl)amino, cyclopropyl(isobutyl)amino, cyclopropyl(W-butyl)amino, cyclopropyl(t-butyl)amino, cyclopropyl(cyclobutyl)amino, n-butyl(isobutyl)amino, n-butyl(W-butyl)amino, n-butyl(t-butyl)amino, n-butyl(cyclobutyl)amino, isobutyl(W-butyl)amino, isobutyl(t-butyl)amino, isobutyl(cyclobutyl)amino, W-butyl(t-butyl)amino, W-butyl(cyclobutyl)amino and t-butyl(cyclobutyl)amino, etc.

Preferred are dimethylamino, diethylamino, di-n-propylamino, diisopropylamino and di-n-butylamino.

Examples of C1-6-alkylcarboxylic can be methylcobalamine, ethylcarbodiimide, n-propylnitrosamine, isopropylcarbodiimide, n-BUTYLCARBAMATE, isobutylamino, W-butylcarbamoyl, t-butylcarbamoyl, 1 intelcorporation, 2-intelcorporation, 3 intelcorporation, isopentenyladenine, neopentylene, t-intelcorporation, 1 paxilonline, 2-paxilonline, 3 paxilonline etc.

Pre is Ino and n-BUTYLCARBAMATE.

As C1-6-alkylsulfonamides can be methylsulfonylamino, ethylsulfonyl, n-propylsulfonyl, isopropylaniline, n-butylmethylamine, isobutylparaben, W-butylsulfonyl, t-butylsulfonyl, 1 pentylaniline, 2-pentylaniline, 3 pentylaniline, isopentenyladenine, neopentylene, t-pentylaniline, 1 hexylaniline, 2-hexylaniline and 3 hexylaniline etc.

Preferred are methylsulfonylamino, ethylsulfonyl, n-propylsulfonyl, isopropylacrylamide and n-butylmethylamine.

As C1-6-alkylaminocarbonyl groups can be methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl, n-butylaminoethyl, isobutylparaben, W-butylaminoethyl, t-butylaminoethyl, 1-intramyocardial, 2-intramyocardial, 3-intramyocardial, isopentylamine, neopentylglycol, t-intramyocardial, 1-mexiletineciclovir, 2-mexiletineciclovir, 3-mexiletineciclovir etc.

Preferred are methylaminomethyl, ethylaminomethyl, n-propylaminoethyl groups can be named dimethylaminoethyl, diethylaminoethyl, di-n-propylaminoethyl, diisopropylaminoethanol, dicyclopentadienyl, di-n-butylaminoethyl, diisobutylamine-carbonyl, di-W-butylaminoethyl, di-t-butylaminoethyl, dicyclopentadienyl, di-1-intramyocardial, di-2-intramyocardial, di-3-intramyocardial, diisobutylamine, diaopen.filename, di-t-intramyocardial, dicyclopentadienyl, di-1-mexiletineciclovir, di-2-mexiletineciclovir, di-3-mexiletineciclovir etc.

Preferred are dimethylaminoethyl, diethylaminoethyl, di-n-propylaminoethyl, diisopropylaminoethanol, dicyclopentadienyl, di-n-butylaminoethyl.

Examples of C1-6-alkylcarboxylic groups can be methylcarbamyl, ethylcarbazole, n-propylboronic, isopropylcarbonate, n-butylcarbamoyl, isobutylketone, W-butylcarbamoyl, t-butylcarbamoyl, 1-internabonal, 2-internabonal, 3-internabonal, isopentylamine, neopentylene, t-internabonal, 1-hexylcaine, 2-hexylcaine and 3-hexylcaine.

Preferred are methylcarbamyl, ethylcarbazole, n-propylboronic, isopropylcarbonate and n-butylcarbamoyl.

Preferred are methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and n-butoxycarbonyl, isobutoxide, W-butoxycarbonyl and t-butoxycarbonyl.

Examples of C1-6-alkylsulfonyl groups can be methanesulfonyl and econsultancy.

Examples arylcarboxylic groups may be benzoyl, p-methylbenzoyl, p-t-butylbenzoyl, p-methoxybenzoyl, p-chlorobenzoyl, p-nitrobenzoyl and p-cyanobenzoyl.

Preferred are benzoyl, p-nitrobenzoyl and p-cyanobenzoyl.

Examples3-6-cycloalkyl groups can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl etc.

Preferred are cyclopropyl, cyclobutyl and cyclohexyl.

Examples of preferred compounds used in this invention are the following compounds.

both represent a methyl group, R3represents a hydroxyl group, and R4represents a hydrogen atom.

(2) Benzopyrane derivative or its pharmaceutically acceptable salt as defined in (1), where R9represents a hydrogen atom or a nitro-group.

(3) Benzopyrane derivative or its pharmaceutically acceptable salt as defined in (2), where X represents C=O, and R6and R7both represent hydrogen atoms.

(4) Benzopyrane derivative or its pharmaceutically acceptable salt as defined in (3), where R5represents a benzene ring, Y is absent, m is 0, n is a 1 or 2.

(5) Benzopyrane derivative or its pharmaceutically acceptable salt as defined in (3), where R8represents an alkyl group, R9is the nitro-group, and n is 2.

Specific examples of compounds that can be used in this invention are shown below, but the invention is not limited to them. Below “Me” means methyl group, “Et” means ethyl group, “RG” means through the group, “VI” means boutelou group, “Pen” means pentelow group, “Hex” means the city of the AET communication, respectively.

The connection according to this invention have asymmetric carbon atoms at position 3 and position 4, there is, thus, their optical isomers based on asymmetric carbon atoms, which can be used when applying this invention, like its racemate. Additionally, there may be included CIS - or TRANS-isomer based on the configuration at position 3 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 can be hydrochloride, hydrobromide, sulphates, methansulfonate, acetates, benzoate, tartratami, phosphates, lactates, maleate, fumarate, malate, gluconate and salicylates, etc.

Preferred are hydrochloride and methanesulfonate.

The following illustrates a method of obtaining compounds of this invention.

The compounds of formula (I) in which R4represents a hydrogen atom, and R3represents a hydroxyl group, which are compounds of formula (I-a), can be obtained interaction is AI.

The compound of General formula (2) can be synthesized by known methods (methods described by J. M. Evans et al. in J. Med.Chem., 1984, 27, 1127; J. Med.Chem., 1986, 29, 2194; J. T. North et al. in J. Org.Chem., 1995, 60, 3397, as well as in the distribution of Japanese patent application No. Sho 56-57785, the display of Japanese patent application No. Sho 56-57786, the display of Japanese patent application No. Sho 58-188880, the display of Japanese patent application No. Hei 2-141, the display of Japanese patent application No. Hei 10-87650 and layout of Japanese patent application No. Hei 11-209366 and so on).

In this scheme, R1, R2, R5, R6, R7, R8, R9X, Y, m and n have the definitions given above.

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

Can be used sulfoxide solvents such as dimethyl sulfoxide; amesterdam solvents, examples of which include dimethylformamide or dimethylacetamide; ethers, examples of which include ethyl ether, dimethoxyethane or tetrahydrofuran; halogenated solvents, examples of which include dichloromethane, chloroform and dichloroethane; nitrosobenzene solvents, examples of which include acetone is nye esters, an example is ethyl acetate. In addition, the reaction may be conducted in the absence of solvent. Preferred solvents are ethers, and nitrosobenzene solvents.

The reaction temperature is usually from 80 ° C to the boiling point of the reaction solvent, preferably from-10C to 100C.

The molar ratio of the reaction materials is in the range of 0.5 to 20.0, preferably 1.0 to 10.0 for compounds (3)/ connections (2).

The reaction can be used an acid catalyst.

Examples of the used acid catalysts can be inorganic acids, examples of which are hydrochloric acid, sulfuric acid, and Lewis acid, examples of which include aluminum chloride, titanium tetrachloride, a complex of boron TRIFLUORIDE and diethyl ether, Perlina acid, lithium perchlorate, lithium bromide and triftorbyenzola ytterbium, etc.

Compounds of General formula (I), except for compounds of the formula (I-a) described above (compounds of formula (I) in which R3and R4together form a bond, and those in which R4represents a hydrogen atom, and R3represents C1-6-alkylcarboxylic), may be the patent application No. Hei 10-87650 etc.

Preferred are lithium bromide, Perlina acid and lithium perchlorate.

Synthesis of optically active compounds included in the compounds of General formula (I) may be carried out using methods of optical separation (display Japanese patent application No. Hei 3-141286, U.S. patent No. 5097037 and European patent No. 409165). In addition, synthesis of optically active compounds of General formula (2) can be carried out using methods of asymmetric synthesis (Japanese national publication No. Hei 5-507645, spreading Japanese patent application No. Hei 5-301878, spreading Japanese patent application No. Hei 7-285983, merchandising European patent application No. 535377 and U.S. patent No. 5420314).

As described above, it was found that the compound of General formula (I) has a strong prolonging effect on the functional refractory period. The prolonging effect in relation to the functional refractory period represents one of the functions of the antiarrhythmic action and is an important indicator, which can be extrapolated for efficacy against clinical arrhythmia. Conventional antiarrhythmic agent with prolonged action on the function of the classification of antiarrhythmic drugs on Vaughan Williams), they have very dangerous causing arrhythmia actions, which can lead to sudden death, such as the flicker on the basis of the lengthening of the action potential of the muscle of the ventricles, associated with prolonging effect on the functional refractory period, which become therapeutic challenges in relation to arrhythmia associated with contractions of the Atria (such as supraventricular tachycardia, atrial flutter and atrial fibrillation). To solve these problems, conducted the search and study of compounds with prolonging effect on the functional refractory period of 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 General formula (I) has a prolonging effect on the functional refractory period selective in relation to the muscles of the Atria without any effect on the functional refractory period of the muscle of the ventricles and the action potential. The difference between this invention and the known methods consists in the provision of prolonged action in relation to the functional refractory period selective towards muscle is any effect on the retention period of the action potential of the separated muscle ventricle and without affecting electrocardiogram QT shot the animal. From the above it follows that the compounds of this invention do not possess inducing fibrillation effect in the muscle of the ventricles, so they can provide more secure against arrhythmia associated with muscle fibrillation, use than known methods. The method according to this invention are suitable for therapeutic or prophylactic use as anti-atrial fibrillation, anti-atrial flutter and anti-tachycardia fibrillation associated with paroxysmal, chronic, preoperative, operating and post-operative atrial fibrillation for the prevention of the phenomenon of the pitch as a result of fibrillation, prevention of the phenomenon of ventricular fibrillation or tachycardia originating from arrhythmia or tachycardia fibrillation, and prevention of deterioration of living forecast in the preventive action against arrhythmia or tachycardia fibrillation, which can go into ventricular fibrillation or tachycardia.

This invention is a pharmaceutical composition or veterinary pharmaceutical composition comprising a compound of General formula (I) in an effective amount for this leczenie by injection (subcutaneous, intravenous, intramuscular and intraperitoneal), in the form of ointments, suppositories or aerosol, or oral administration using tablets, capsules, granules, pills, syrups, solutions, emulsions and suspensions, etc.

The above-mentioned pharmaceutical or veterinary pharmaceutical composition containing the compound according to this invention in an amount of from about 0.01 to 99.5% pure, preferably about 0.1-30% of the total weight of the composition.

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

In addition, the composition can contain a number of compounds according to this invention.

Quantity for clinical application varies depending on age, weight and sensitivity of the patient, severity of patient's condition and so on, and an effective amount for administration is usually about 0.003 to 1.5 g, preferably 0.01 to 0.6 g per day for an adult. If necessary, however, may go beyond the above-mentioned interval.

The connection according to this invention Isrotel the TB pills, capsules, granules and pills for oral administration are made using fillers, such as sucrose, lactose, glucose, starch and mannitol; binders such as hydroxypropylcellulose, syrup, Arabian gum, gelatin, sorbitol, tragakant, methylcellulose and polyvinylpyrrolidone; disintegrators such as starch, carboxymethyl cellulose or its calcium salt, microcrystalline cellulose and polyethylene glycol; lubricants, such as talc, magnesium stearate or calcium and silicon dioxide; and such as sodium laurate and glycerol, etc.

Preparations for injections, solutions, emulsions, suspensions, syrups and aerosols receive, using solvents for the active ingredients, such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butyleneglycol and polyethylene glycol; surfactants such as esters sorbinovoj fatty acid esters of polyoxyethylene and sorbinovoj fatty acid esters of polyoxyethylene and fatty acids, polyoxyethylene simple ester of hydrogenated castor oil and lecithin; suspendresume agents, such as carboxymethylation salt, derivatives of cellulose, such as methylcelluloses acid, benzalkonium chloride and salts of sorbic acid, etc.

For ointments, which are percutaneous adsorbed pharmaceutical preparations are used, for example, white petrolatum, liquid paraffin, high molecular weight alcohols, macrogalleria ointment bases, hydrophilic ointment bases and aqueous gel base.

Suppositories are getting, using, for example, fats, cocoa butter, polyethylene glycol, lanolin, triglycerides of fatty acids, coconut oil, and Polysorbate, and so on

The best way of carrying out the invention

This invention is illustrated in detail with examples below, but the invention is not limited to these examples.

Examples synthesis

Example of synthesis 1

TRANS-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-(2-phenethylamine)-2H-1-benjaporn-3-ol

To a solution of 6-acetylamino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (500 mg, of 1.80 mmol) and lithium perchlorate (766 mg, 7.20 mmol) in tetrahydrofuran (15 ml) is added 2-phenethylamine (904 μl, 7.20 mmol) at room temperature and stirred at 65 degree Celsius for 9 hours.

To the mixture are added ethyl acetate and the resulting organic phase is twice PI dried over anhydrous magnesium sulfate.

After the solvent is distilled off, the residue is purified column chromatography medium pressure (hexane:ethyl acetate = 1:1) and then recrystallized from hexane-ethyl acetate to give the desired substance in the form of yellow crystals (yield: 61%). So pl.: 172-S.

1H-NMR (Dl3) : 1,17 (s, 3H), of 1.48 (s, 3H), 1,60 (Shir.s, 2H), 2,28 (s, 3H), and 2.83 (t, J=7,0 Hz, 2H), 2,85-3,00 (m, 2H), 3,47 (d, a part of AB, J=10.3 Hz, 1H), 3,67 (d, a part of AB, J=10.3 Hz, 1H), 7,21-7,33 (m, 5H), 7,60 (s, 1H), 8,59 (s, 1H), 9,96 (s, 1H).

MS (EI) m/z: 400[M+1]+, 327 (bp)

The following compounds were obtained in a similar fashion (examples of synthesis 2-36).

Example of synthesis 2

TRANS-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-(3-phenylpropylamine)-2H-1-benzopyran-3-ol

Yield: 71%

1H-NMR (Dl3) : to 1.21 (s, 3H) and 1.51 (s, 3H), of 1.87 (Quint, 7,4 Hz, 2H), 1,94 (Shir.s, 2H), and 2.27 (s, 3H), 2,63-by 2.73 (m, 4H), 3,54 (d, a part of AB, J=10.3 Hz, 1H), 3,71 (d, a part of AB, J=10.3 Hz, 1H), 7,16-of 7.23 (m, 3H), 7,25-7,27 (m, 2H), 7,63 (s, 1H), 8,68 (s, 1H), 10,02 (s, 1H).

MS (EI) m/z: 413[M+1]+, 221 (bp)

Example of synthesis 3

TRANS-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-(4-phenylbutyramide)-2H-1-benzopyran-3-ol

Yield: 50%

1H-NMR (Dl3) : of 1.20 (s, 3H), of 1.52 (s, 3H), 1.55V, J=10.0 Hz, 1H), 7,15-to 7.18 (m, 3H), 7.24 to a 7.62 (m, 2H), 7.62mm (s, 1H), 8,67 (s, 1H), 10,00 (s, 1H).

MS (EI) m/z: 427[M+1]+, 150 (bp).

Example of synthesis 4

TRANS-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-[2-(4-hydroxyphenyl)-ethylamino]-2H-1-benzopyran-3-ol

Yield: 29%

1H-NMR (Dl3) : 1,17 (s, 3H), of 1.48 (s, 3H), 2.00 (evens Shire.s, 3H), to 2.29 (s, 3H), 2,70-to 2.85 (m, 3H), 2,86-2,95 (m, 1H), 3,51 (d, a part of AB, J=10.3 Hz, 1H), 3,66 (d, a part of AB, J=10.3 Hz, 1H), 6,77 (d, J=8,4 Hz, 2H), 7,06 (d, J=8,4 Hz, 2H), 7,60 (s, 1H), 8,46 (s, 1H), for 9.95 (s, 1H).

MS (EI) m/z: 416[M+1]+, 308 (bp).

Example of synthesis of 5

TRANS-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-[2-(4-methoxyphenyl)ethylamino]-2H-1-benzopyran-3-ol

Yield: 18%

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,49 (s, 3H), 1,80 (Shir.s, 2H), and 2.27 (s, 3H), was 2.76 3.00 for (m, 4H), of 3.56 (d, a part of AB, J=10.5 Hz, 1H), of 3.77 (d, a part of AB, J=10.5 Hz, 1H), 3,79 (s, 3H), 6,83 (d, J=8.6 Hz, 2H), 7.23 percent (d, J=8.6 Hz, 2H), to 7.61 (s, 1H), 8,55 (s, 1H), to 9.93 (s, 1H).

MS (EI) m/z: 430[M+1]+, (b).

Example of synthesis 6

TRANS-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4- [2-(4-chlorophenyl)ethylamino]-2H-1-benzopyran-3-ol

Yield: 66%

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,49 (s, 3H), 1.70 to (Shir.s, 2H), 2,28 (s, 3H), 2,78 (t, J=6,8 Hz, 2H), 2,84-to 2.99 (m, 2H), 3,50 (d, part2">

MS (EI) m/z: 434[M+1]+, 361 (bp).

Example of synthesis of 7

TRANS-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-[2-(4-AMINOPHENYL)-ethylamino]-2H-1-benzopyran-3-ol

Yield: 40%

1H-NMR (Dl3) : 1,17 (s, 3H), of 1.48 (s, 3H), 1.69 in (Shir.s, 4H), of 2.28 (s, 3H), 2,71 (t, J=6,8 Hz, 2H), 2,79 of 2.92 (m, 2H), 3,48 (d, a part of AB, J=10.3 Hz, 1H), to 3.67 (DD, a part of AB, J= 10,3 and 1.1 HZ, 1H), 6,63 (d, J=8.6 Hz, 2H), 7,02 (d, J=8.6 Hz, 2H), 7,60 (s, 1H), 8,58 (s, 1H), 9,96 (s, 1H).

MS (EI) m/z: 415[M+1]+, 237 (bp).

Example 8 synthesis

TRANS-6-acetylamino-3,4-dihydro-2,2-dimethyl-7-nitro-4-[2-(4-nitrophenyl)ethylamino]-2H-1-benzopyran-3-ol

Yield: 19%

So pl. 211-C (decomposition).

1H-NMR (DMSO-d6) : to 1.15 (s, 3H), 1,45 (s, 3H), 2, 05 (s, 3H), 3,05 is 3.40 (m, 5H), 4,06 (m, 1H), 4,51 (m, 1H), 6,44 (s, 1H), 7,40 (s, 1H), 7,56 (d, J was 8.8 Hz, 2H), of 7.90 (s, 1H), to 8.20 (d, J=8,8 Hz, 2H), 10,14 (s, 1H).

MS (EI) m/z: 444[M+1]+, 371 (bp).

Example 9 synthesis

Red crystals

So pl.: 176,5-178,0

1H-NMR (Dl3) : 1,17 (s, 3H), of 1.48 (s, 3H), and 2.27 (s, 3H), 2,86 are 2.98 (m, 4H), of 3.46 (d, J=10.0 Hz, 1H), 3,68 (d, J=10.0 Hz, 1H), 7,00-7,10 (m, 2H), 1,17-7,26 (m, 2H), to 7.61 (s, 1H), 8,63 (s, 1H), 9,98 (s, 1H).

MS (EI) m/z: 418[M+1]+, 346, 309, 179 (bp).

3) : of 1.18 (s, 3H), 1,49 (s, 3H), and 2.27 (s, 3H), 2,81-to 2.99 (m, 4H), 3,49 (d, J=10.1 Hz, 1H), 3,68 (d, J=10.1 Hz, 1H), 6.89 in-to 6.95 (m, 2H), 7,02 (d, J=7,6 Hz, 1H), 7.23 percent-7,26 (m, 1H), to 7.61 (c, 1H), 8,58 (c, 1H), 9,96 (c, 1H).

MS (EI) m/z: 418[M+1]+, 344, 298 (bp).

Example 11 synthesis

Orange crystals

So pl.: 141,0-142,0

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,49 (s, 3H), and 2.27 (s, 3H), 2,78-of 2.97 (m, 4H), 3,49 (d, J=10.1 Hz, 1H), 3,68 (d, J=10.1 Hz, 1H), 6,99 (t, J=8,8 Hz, 2H), 7,19 (DD, J=2,9, and 5.5 Hz, 2H), to 7.61 (s, 1H), to 8.57 (s, 1H), becomes 9.97 (s, 1H).

MS (EI) m/z: 417[M+1]+, 345, 302, 176 (bp).

Example 12 synthesis

Yellow crystals

So pl.: 151,0-to 152.0

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,49 (s, 3H), and 2.26 (s, 3H), 2,77 (t, J=6,8 Hz, 2H), 2,87-of 2.97 (m, 2H), 3,51 (d, J=10.1 Hz, 1H), 3,69 (d, J=10.1 Hz, 1H), 6,33 (d, J=2.2 Hz, 1H), to 6.39 (d, J=2.2 Hz, 2H), 7,60 (s, 1H), 8,55 (s, 1H), to 9.93 (s, 1H).

MS (EI) m/z: 459[M+1]+, 441, 307, 278, 193 (bp).

Example 13 synthesis

Red amorphous substance

So pl.: 176,5-178,0

1H-NMR (Dl3) : of 1.18 (s, 3H), of 1.48 (s, 3H), and 2.27 (s, 3H), 2,78-of 2.97 (m, 4H), 3,50 (d, J=10.1 Hz, 1H), 3,69 (d, J=10.1 Hz, 1H), 3,79 (s, 3H), 6.75 in-6,83 (m, 3H), 7,21 (t, J=7,6 Hz, 1H), 7,60 (s, 1H), 8,56 (s, 1H), 9,94 (s, 1H).

MC (FAB) m/z: 430[M+1]+(bp).

Example 14 synthesis

Red crystals

So pl.: which is 171,5-172,8

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,8,64 (s, 1H), 9,98 (s, 1H).

MS (EI) m/z: 433[M+1]+, 357, 318 (bp).

Example 15 synthesis

Yellow amorphous substance

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,49 (s, 3H), of 2.28 (s, 3H), and 2.79 (t, J=6.9 Hz, 2H), 2,86 are 2.98 (m, 2H), 3,50 (d, J=10.1 Hz, 1H), 3,68 (d, J=10.1 Hz, 1H), 7,12 (d, J=8,2 Hz, 2H), 7,42 (d, J=8,2 Hz, 2H), to 7.61 (s, 1H), at 8.60 (s, 1H), 9,98 (s, 1H).

MS (EI) m/z: 481[M+2]+, 479[M]+, 406 (bp).

Example 16 synthesis

Orange crystals

So pl.: 90,0-91,0

1H-NMR (Dl3) : of 1.18 (s, 3H), of 1.48 (s, 3H), 2,22 (s, 3H), 2,24 (s, 3H), and 2.27 (s, 3H), 2,75-2,78 (m, 2H), 2,88-only 2.91 (m, 2H), 3,50 (d, J=10.1 Hz, 1H), 3,69 (d, J=10.1 Hz, 1H), of 6.96 (d, J=7.7 Hz, 1H), 7,00 (s, 1H), 7,06 (d, J=7.7 Hz, 1H), 7,60 (s, 1H), 8,61 (s, 1H), becomes 9.97 (s, 1H).

MS (EI) m/z: 428[M+1]+, 356 (bp).

Example 17 synthesis

Brown amorphous substance

1H-NMR (Dl3) : of 1.16 (s, 3H), of 1.48 (s, 3H), to 2.29 (s, 3H), 2,82 (Shir.s, 1H), 3,25 (DD, J=2,1, 7.7 Hz, 2H), 3,52 (d, J=10.3 Hz, 1H), 3,69 (d, J=10.3 Hz, 1H), 7.18 in-7,35 (m, 10H), to 7.61 (s, 1H), 8,61 (s, 1H), 9,98 (s, 1H).

MS (EI) m/z: 475[M+1]+, 310, 280 (bp).

Example 18 synthesis

Yellow crystals

So pl.: of 186.0-188,0

1H-NMR (Dl3) : of 1.18 (s, 3H), of 1.46 (t, J=7,1 Hz, 3H), 1,49 (s, 3H), and 2.27 (s, 3H), 2,78-to 3.02 (m, 4H), 3,55 (d, J=10.3 Hz, 1H), 3,76 (d, J=10.3 Hz, 1H), 4,11 (kV, J=7,1 Hz, 2H), 6,76-PC 6.82 (m, 3H), to 7.61 (s, 1H), 8,53 (s, 1H), to 9.93 substance

1H-NMR (Dl3) : 1,19 (s, 3H), 1,49 (s, 3H), and 2.27 (s, 3H), 2,84-2,95 (m, 4H), 3,51 (d, J=10.4 Hz, 1H), 3,71 (d, J=10.4 Hz, 1H), 7,18 (DD, J=2,0,8,0 Hz, 1H), 7,22 (d, J=8.0 Hz, 1H), was 7.36 (d, J=2.0 Hz, 1H), to 7.61 (s, 1H), 8,63 (s, 1H), 9,99 (s, 1H).

MS (EI) m/z: 468[M]+, 396, 353 (bp).

Example 20 synthesis

Red crystals

So pl.: 156,0-157,0

1H-NMR (Dl3) : 1,19 (s, 3H), 1,50 (s, 3H), of 2.28 (s, 3H), 2,93 totaling 3.04 (m, 4H), 3,52 (d, J=10.1 Hz, 1H), 3,71 (d, J=10.1 Hz, 1H), to 6.88 (d, J=3.3 Hz, 1H), 6,95 (DD, J=3.3, then a 5.1 Hz, 1H), 7,16 (d, J=5,1 Hz, 1H), 7.62mm (s, 1H), 8,64 (s, 1H), 9,98 (s, 1H).

MS (EI) m/z: 405[M]+, 332, 308 (bp).

Example 21 synthesis

Brown crystals

So pl.: 172,0-174,0

1H-NMR (Dl3) : 1,19 (s, 3H), 1,49 (s, 3H), of 2.28 (s, 3H), 2,84 (t, J=6.6 Hz, 2H), 2, 90-3,03 (m, 2H), 3,53 (d, J=10.1 Hz, 1H), 3,71 (d, J=10.1 Hz, 1H), 7,18 (d, J=5,9 Hz, 2H), 7.62mm (s, 1H), 8,49 (d, J=5,9 Hz, 2H), 8,64 (s, 1H), 9,98 (s, 1H).

MS (FAB) m/z: 401[M+1]+, 171, 157 (bp).

Example 22 synthesis

Brown amorphous substance

1H-NMR (Dl3) : of 1.20 (s, 3H), 1,49 (s, 3H), of 2.28 (s, 3H), 2,80-2,87 (m, 3H), 2,93-2,96 (m, 1H), to 3.58 (d, J=10.3 Hz, 1H), 3,75 (d, J=10.3 Hz, 1H), 7,24 (m, 1H), 7,60 (s, 1H), 7.62mm (d, J=1.5 Hz, 1H), 8,42 (t, J=1.5 Hz, 2H), 8,67 (s, 1H), 9,96 (s, 1H).

MS (EI) m/z: 400[M]+, 328, 280 (bp).

Example 23 synthesis

Orange crystals

So pl.: 147,0-of 149.0 is,1 Hz, 1H), 7,16-7,19 (m, 1H), 7,22 (d, J=7.7 Hz, 1H), 7,58 (s, 1H), 7,63-to 7.68 (m, 1H), 8,53 (s, 1H), 8,71 (s, 1H), 9,94 (s, 1H).

MS (FAB) m/z: 400[M]+366, 328, 120 (bp).

Example 24 synthesis

Brown amorphous substance

1H-NMR (Dl3) : to 1.14 (s, 3H), 1,45 (s, 3H), 2,24 (s, 3H), 2.91 in-to 3.02 (m, 4H), 3,51 (d, J=10.3 Hz, 1H), to 3.67 (d, J=10.3 Hz, 1H), 1,10 (t, J=7,0 Hz, 1H), 7,14 (d, J=2.2 Hz, 1H), 7,20 (t, J= 7,0 Hz, 1H), 7,37 (d, J=8,1 Hz, 1H), EUR 7.57 (d, J=8,1 Hz, 1H), to 7.59 (s, 1H), 8,10 (Shir.s, 1H), 8,43 (s, 1H), 9,82 (s, 1H).

MS (FAB) m/z: 437[M-1]+, 307, 278, 233, 194 (bp).

Example 25 synthesis

Brown amorphous substance

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,49 (s, 3H), of 2.23 (s, 3H), 2,87 (t, J=6,8 Hz, 2H), 2,94-to 2.99 (m, 2H), 3,52 (d, J=10.1 Hz, 1H), 3,70 (d, J=10.1 Hz, 1H), 7,30-7,35 (m, 3H), 7,41 was 7.45 (m, 2H), 7,52-to 7.59 (m, 4H), 7,60 (s, 1H), 8,61 (s, 1H), 9,96 (s, 1H).

MS (EI) m/z: 475[M]+, 442, 401 (bp).

Example 26 synthesis

Red amorphous substance

1H-NMR (Dl3) : 1,19 (s, 3H), 1,49 (s, 3H), and 2.26 (s, 3H), was 2.76-and 2.79 (m, 2H), 2,84-2,90 (m, 1H), 2.93 which are 2.98 (m, 1H), 3,53 (d, J=10.1 Hz, 1H), 3,70 (d, J=10.1 Hz, 1H), 3,86 (s, 3H), 3,88 (s, 3H), 6,76-for 6.81 (m, 3H), of 7.60 (s, 1H), 8,54 (s, 1H), to 9.93 (s, 1H).

MS (EI) m/z: 460[M+1]+, 237, 165 (bp).

Example 27 synthesis

Yield: 58%

Yellow crystals

So pcs.: S

1H-NMR (DMSO-d6) : to 1.15 (s, 3H), 1,45 (s, 3H), 2,04 (s, 3H0 Hz, 1H), 7,28-7,46 (m, 11N), of 7.96 (s, 1H), and 10.20 (s, 1H).

MS (EI) m/z: 611[M]+, (b).

Example 28 synthesis

Yield: 32%

Yellow crystals

So pl.: 227-S

1H-NMR (DMSO-d6) : to 1.15 (s, 3H), of 1.29 (t, J=7.0 Hz, 3H), 1,45 (s, 3H), of 2.05 (s, 3H), 2,90-3,10 (m, 4H), 3,25 (Shir.s, 1H), 3,74 (s, 3H), 3.96 points (kV, J=7,0 Hz, 2H), 4,00-4,05 (Shir.s, 1H), 4,42 (Shir.s, 1H), 6,45 (Shir.s, 1H), 6.73 x (DD, J=8.4 and 2.4 Hz, 1H), 6,85 (d, J=2.4 Hz, 1H), 6,86 (d, J=8,4 Hz, 1H), 7,40 (s, 1H), 7,92 (s, 1H), 10,16 (s, 1H).

MS (EI) m/z: 473 [M]+, 233 (bp).

Example 29 synthesis

Yield: 40%

Yellow amorphous substance

1H-NMR (Dl3) : a 1.11 (s, 3H), of 1.30 (t, J=7.0 Hz, 3H), 1.91 a (s, 3H), from 2.00 (s, 3H), 2,45-of 2.50 (m, 2H), 2,65 (t, J=7,1 Hz, 2H), 2,75-to 2.85 (m, 1H), to 3.58 (DD, a part of AB, J=9.6 and a 5.3 Hz, 1H), 3,65 (d, a part of AB, J=9.6 Hz, 1H), of 3.97 (q, J=7,0 Hz, 2H), 5,43 (d, J=5.3 Hz, 1H), 6,80 (d, J=8,8 Hz, 2H), 7,10 (d, J=8,8 Hz, 2H), 7,60 (s, 1H), 8,32 (s, 1H), 9,95 (s, 1H).

MS (EI) m/C, 443 [M]+, 237 (bp).

Example 30 synthesis

Exit 98%

Yellow crystals

So pl.: 214-S

MS (EI) m/z: 467 [M]+, 308 (bp).

Example 31 synthesis

Yield: 96%

Orange crystals

So pl.: 133-S

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,49 (s, 3H), 1,60 (Shir.s, 1H), 2,28 (s, 3H), 2,75-3,00 (m, 5H), 3,50 (d, a part of AB, J=10,2 Hz, 1H), 3ASS="ptx2">

Example 32 synthesis

Yield: 82%

Orange solid

1H-NMR (Dl3) : of 1.18 (s, 3H), of 1.48 (s, 3H), and 2.27 (s, 3H), 2,80-3,00 (m, 6N), 3,49 (d, a part of AB, J=10.1 Hz, 1H), 3,69 (DD, a part of AB, J=10.1 and 1.2 Hz, 1H), 7,40-to 7.50 (m, 4H), a 7.62 (s, 1H), 8,63 (s, 1H), 9,99 (s, 1H).

MS (EI) m/z: 467 [M]+, 348 (bp).

Example 33 synthesis

Yield: 84%

Yellow amorphous substance

1H-NMR (Dl3) : 1,19 (s, 3H), 1,49 (s, 3H), 1,58 (Shir. s, 1H), and 2.27 (s, 3H), 2,80 are 2.98 (m, 3H), is 3.08 is 3.23 (m, 2H), 3,50 (d, a part of AB, J=10.3 Hz, 1H), and 3.72 (d, a part of AB, J=10.3 Hz, 1H), 7,02-was 7.08 (m, 1H), 7,25-7,28 (m, 2H), to 7.61 (s, 1H), 8,68 (s, 1H), 10,00 (s, 1H).

MS (EI) m/z: 467 [M]+, 354 (bp).

Example 34 synthesis

A yellow crystalline substance

So pl.: 160,0-165,0

1H-NMR (Dl3) : of 1.33 (s, 3H), of 1.53 (s, 3H), and 2.14 (s, 3H), 2,61 (d, J=2,8 Hz, 1H), 3,79 (DD, J=2,8, 8,8 Hz, 1H), 3,99 (d, J= 8,8 Hz, 1H), 6,78 (d, J=8.0 Hz, 2H), 6,83 (t, J=7,6 Hz, 1H), 7.23 percent (t, J=8.0 Hz, 2H), 7,66 (s, 1H), 8,59 (s, 1H), 9,79 (s, 1H).

MS (EI) m/z: 371[M]+, 299, 257 (bp).

Example 35 synthesis

Yield: 87%

Yellow amorphous substance, a mixture of diastereoisomers 1:1.

1H-NMR (Dl3) : 1,15 (C, 6N), of 1.29 (d, J=5.5 Hz, 6N), 1,45 (s, 3H), of 1.48 (s, 3H), of 2.28 (s, 3H), to 2.29 (s, 3H), 2,58 (Shir.s, 1H), 2,75-2,90 (m, 8H), 2.95 and (Shir.s, 1H), 3,37 (d, J=10.0 Hz, 1H), N).

MS (EI) m/z: 414[M+1]+, 279 (bp).

Example 36 synthesis

Yield: 27%

Orange solid, diastereoisomer And (more polar).

1H-NMR (Dl3) : of 1.20 (s, 3H), of 1.29 (d, J=6.5 Hz, 3H), of 1.44 (s, 3H), 1,72 (Shir.s, 2H), and 2.26 (s, 3H), 2,61 (DD, a part of AB, J=13,4 and 7.1 Hz, 1H), 2,86 (DD, a part of AB, J=13,4 and 6.5 Hz, 1H), 3,28-to 3.36 (m, 1H), 3,34 (d, a part of AB, J=9.7 Hz, 1H), 3,63 (DD, a part of AB, J=9.7 and 1.1 Hz, 1H), 7,14 (d, J=8,2 Hz, 2H), 7,26 (d, J=8,2 Hz, 2H), 7,60 (s, 1H), 8,84 (s, 1H), 10,06 (s, 1H).

MS (EI) m/z: 447[M+1]+(bp).

Yield: 32%

Yellow solid, diastereoisomer (less polar).

1H-NMR (Dl3) : to 1.14 (d, J=6.0 Hz, 3H), of 1.23 (s, 3H), 1,49 (s, 3H), 1,60 (Shir.s, 2H), to 2.29 (s, 3H), was 2.76 (d, J=6,8 Hz, 2H), 3,52 (d, a part of AB, J=10.0 Hz, 1H), 3,51 (DQC, J=6.8 and 6.0 Hz, 1H), 3,65 (DD, a part of AB, J=10,0 and 1.0 Hz, 1H), 7,25 (s, 4H), 7,56 (s, 1H), 8,54 (s, 1H), to 9.91 (s, 1H).

MS (EI) m/z: 447[M]+, (bp).

General methods of synthesis of compounds 37-49

To a solution of 6-isopropylamino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (200 mg, of 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 degree Celsius for 4 hours. In addition, add ethyl acetate and education is essential magnesium sulfate. After the solvent is distilled off, the residue is purified column chromatography on silica gel to give the desired substance in the form of product-raw. Then to a solution of the desired substance in methanol (10-fold volume) add 10% methanol solution of hydrogen chloride (double volume) under cooling with ice and stirred for 30 minutes. To the mixture is added diisopropyl ether (100-fold volume) and the resulting crystals filtered off, washed with diisopropyl ether to give the desired hydrochloride. After the resulting hydrochloride is extracted with ethyl acetate and saturated aqueous sodium bicarbonate, determine 1H-NMR indicators.

Example 37 synthesis

Output: 33%

Yellow crystals

So pl.: C (decomp.)

MS (FAB) m/z: 414 [M+H]+.

Example 38 synthesis

Yield: 30%

A yellow crystalline substance

So pl.: C (decomp.)

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,32 (d, J=6,8 Hz, 6N), for 1.49 (s, 3H), 1,60 (Shir.s, 1H), 2,65 (Quint, J=6, 8 Hz, 1H), 2,80 (Shir.s, 1H), 2.95 and was 3.05 (m, 4H), 3,50 (d, a part of AB, J=10.3 Hz, 1H), 3,68 (d, a part of AB, J=10.3 Hz, 1H), 7,44 (d, J=8,4 Hz, 2H), to 7.64 (s, 1H), 8,17 (d, J=8,4 Hz, 2H), total of 8.74 (s, 1H), 10,18 (s, 1H).

MS (FAB) m/z: 473 [M+H]+LASS="ptx2">

1H-NMR (Dl3) : of 1.18 (s, 3H), of 1.30 (d, J=6,8 Hz, 6N), to 1.48 (s, 3H), 1,60 (Shir.s, 1H), 2.63 in (Quint, J=6,8 Hz, 1H), 2,77 (t, J=6,8 Hz, 2H), 2.95 and 3.00 for (m, 3H), 3,50 (d, a part of AB, J=10.3 Hz, 1H), 3,68 (d, a part of AB, J=10.3 Hz, 1H), 3,78 (C, 6N), 6,32 (d, J=2.4 Hz, 1H), 6,40 (d, J=2.4 Hz, 2H), a 7.62 (s, 1H), 8,71 (s, 1H), 10,14 (s, 1H).

MS (FAB) m/z: 488[M+H]+.

Example 40 synthesis

Yield: 46%

Yellow crystals

So pl.: C (decomp.)

MS (FAB) m/z: 446[M+H]+.

Example 41 synthesis

Yield: 38%

Yellow crystals

So pl.: C (decomp.)

MS (FAB) m/z: 496 [M+H]+.

Example 42 synthesis

Yield: 23%

Yellow crystals

So pl.: C (decomp.)

MS (FAB) m/z: 458 [M+H]+.

Example 43 synthesis

Yield: 31%

Yellow crystals

So pl.: C (decomp.)

MS (FAB) m/z: 446 [M+H]+.

Example 44 synthesis

Yield: 26%

Yellow crystals

So pl.: C (decomp.)

1H-NMR (Dl3) : 1,17 (s, 3H), of 1.31 (d, J=6,9 Hz, 6N), to 1.48 (s, 3H), 2.00 (evens Shire.s, 2H), 2,64 (Quint, J=6,9 Hz, 1H), 2,75-3,00 (m, 4H), 3,50 (d, a part of AB, J=10.0 Hz, 1H), 3,69 (d, a part of AB, J=10.0 Hz, 1H), 7,01 (t, J=8.5 Hz, 2H), 7,15-7,26 (m, 2H), 7,63 (s, 1H), 8,69 (s, 1H), 10,15 (s, 1H).

MS (FAB) m/z: 446 [M+H]+.

The AB) m/z: 442 [M+H]+.

Example 46 synthesis

Yield: 24%

Yellow crystals

So pl.: C (decomp.)

1H-NMR (Dl3) : of 1.18 (s, 3H), 1,32 (d, J=7,0 Hz, 6N), for 1.49 (s, 3H), 1,62 (Shir.s, 2H), 2,65 (Quint, J=7,0 Hz, 1H), 2,81 (t, J=6.6 Hz, 2H), 2,88-3,00 (m, 2H), 3,48 (d, a part of AB, J=10.3 Hz, 1H), 3,66 (d, a part of AB, J=10.3 Hz, 1H), 7,18 (d, J=8,3 Hz, 2H), 7,26 (d, J=8,3 Hz, 2H), 7,63 (s, 1H), 8,71 (s, 1H), 10,16 (s, 1H).

MS (FAB) m/z: 462 [M+H]+.

Example 47 synthesis

Yield: 35%

Yellow crystals

So pl.: C (decomp.)

MS (FAB) m/z: 462 [M+H]+.

Example 48 synthesis

Yield: 16%

Yellow crystals

So pl.: 204-C (decomp.)

MS (FAB) m/z: 443 [M+H]+.

Example 49 synthesis

Red amorphous substance

1H-NMR (Dl3) : 1,17 (s, 3H), 1,32 (d, J=7,0 Hz, 6N), to 1.48 (s, 3H), and 2.27 (s, 3H), 2,65 (Quint, J=7,0 Hz, 1H), 2, 86-2, 98 (m, 4H), of 3.46 (d, J=10.0 Hz, 1H), 3,68 (d, J=10.0 Hz, 1H), 7,22-to 7.32 (m, 5H), to 7.61 (s, 1H), 8,63 (s, 1H), 9,98 (s, 1H).

MS (EI) m/z: 420 [M+1]+, 344, 179 (bp)

General methods of synthesis of compounds 50-75

To a solution of 6-cyclopropylamino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (200 mg, 0.66 mmol) and lithium bromide (226 mg, 2.6 m is of 4 hours. To the mixture are added ethyl acetate and the resulting organic phase is washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After the solvent is distilled off, the residue is purified column chromatography on silica gel to give the desired substance.

Example of synthesis 50

Yield: 30%

1H-NMR (Dl3) : 0,96-0,98 (m, 2H), 1,10-of 1.78 (m, 5H), to 1.48 (s, 3H), 1,63-of 1.66 (m, 1H), 2,93-a 3.01 (m, 4H), 3,52 (d, J=10.1 Hz, 1H), of 6.68 (d, J=10.1 Hz, 1H), 7,40-7,42 (m, 2H), 7,63 (s, 1H), 8,14-8,17 (m, 2H), 8,66 (s, 1H), 10,29 (Shir.s, 1H).

MS (EI) m/z: 334 (bp), 471 [M]+

Example 51 synthesis

Yield: 38%

1H-NMR (Dl3) : 0,92-of 0.95 (m, 2H), 1,09 is 1.13 (m, 2H), 1,19 (s, 3H), 1,50 (s, 3H), 1,63-of 1.64 (m, 1H), 1,80-of 1.84 (m, 2H), 2,58 of 2.68 (m, 4H), of 3.56 (d, J=10.1 Hz, 1H), 3,71 (DD, J=0,9, 10.1 Hz, 1H), 7,14-7,27 (m, 5H), to 7.61 (s, 1H), 8,72 (d, J=0.9 Hz, 1H), 10.30 a.m. (Shir.s, 1H).

MS (EI) m/z: 300 (bp), 439 [M]+

Example 52 synthesis

Yield: 71%

1H-NMR (Dl3) : 0,94-0,96 (m, 2H), 1,10-1,17 (m, 5H), of 1.47 (s, 3H), 1,63-of 1.66 (m, 1H), 2,81-to 2.94 (m, 4H), 3,50 (d, J=10.1 Hz, 1H), 3,70 (d, J=10.1 Hz, 1H), of 6.96-7,22 (m, 4H), 7,60 (s, 1H), 8,64 (s, 1H), of 10.25 (Shir.s, 1H).

MS (EI) m/z: 303 (bp), 443 [M]+

Example 53 synthesis

Yield: 47%

1H-NMR (Dl3) : 0,93-0,96 (m, 2H), 1,10-1,17 1H), 8,63 (s, 1H), of 10.25 (Shir.s, 1H).

MS (FAB) m/z: 121, 456 [M+1]+

Example 54 synthesis

Yield: 54%

1H-NMR (Dl3) : 0,95-0,97 (m, 2H), 1,10-1,17 (m, 2H), 1.26 in (s, 3H), of 1.48 (s, 3H), 1,63-to 1.67 (m, 1H), was 2.76 vs. 2.94 (m, 4H), 3,50 (d, J=10,2 Hz, 1H), to 3.67 (DD, J=1,0, 10,2 Hz, 1H), 6,94-of 6.99 (m, 2H), 7,15-7,26 (m, 2H), to 7.61 (s, 1H), 8,61 (d, J=1.0 Hz, 1H), 10,26 (Shir.s, 1H).

MS (EI) m/z: 260 (bp), 443 [M]+

Example 55 synthesis

Yield: 53%

1H-NMR (Dl3) : 0,94-0,97 (m, 2H), 1,11-1,17 (m, 5H), to 1.48 (s, 3H), 1,63-of 1.65 (m, 1H), 2,79-to 2.94 (m, 4H), 3,49 (d, J=10.3 Hz, 1H), to 3.67 (DD, J=0,9, 10,3 Hz, 1H), 6.90 to-7,01 (m, 3H), 7.23 percent-7,26 (m, 1H), 7.62mm (s, 1H), 8,63 (d, J=0.9 Hz, 1H), 10,27 (Shir.s, 1H).

MS (EI) m/z: 301 (bp), 443 [M]+

Example 56 synthesis.

Yield: 58%

1H-NMR (Dl3) : of 0.87-0.90 (m, 2H), 1,11-to 1.14 (m, 2H), 1,17 (s, 3H), of 1.48 (s, 3H), 1,63-to 1.67 (m, 1H), 2.77-to of 2.81 (m, 2H), 2,89-of 2.93 (m, 2H), 3,48 (d, J=10.3 Hz, 1H), 3,65 (d, J=10.3 Hz, 1H), 7,16-7,26 (m, 4H), a 7.62 (s, 1H), 8,65 (s, 1H), 10,28 (Shir.s, 1H).

MS (EI) m/z: 305 (bp), 460 [M]+

Example 57 synthesis

Yield: 56%

1H-NMR (Dl3) : 0,92-of 0.95 (m, 2H), 1,09-of 1.18 (m, 5H), for 1.49 (s, 3H), 1,62-of 1.65 (m, 1H), 2,73 of 2.92 (m, 4H), 3,51 (d, J=10,2 Hz, 1H), to 3.67 (d, J=10,2 Hz, 1H), of 3.77 (s, 6N), of 6.31 (s, 3H), 6,37 (s, 2H), to 7.61 (s, 1H), 8,64 (s, 1H), 10,26 (Shir.s, 1H).

MS (EI) m/z: 470 (bp), 486 [M]+

Example 58 synthesis

NR), of 3.77-a-3.84 (m, 3H), 7,25-7,39 (m, 5H), to 7.67 (s, 1H), 8,88 (s, 1H), 10,34 (Shir.s, 1H).

MS (EI) m/z: 339 (bp), 411 [M]+

Example 59 synthesis

Yield: 57%

1H-NMR (Dl3) : 0, 93-0, 96 (m, 2H), 1,11-1,17 (m, 5H), of 1.47 (s, 3H), 1,63-of 1.65 (m, 1H), 2,68-a 2.71 (m, 2H), 2,85-is 2.88 (m, 2H), 3.46 in (d, J=10.1 Hz, 1H), 3,64 (d, J=10.1 Hz, 1H), 6,62-only 6.64 (m, 2H), 6,70-7,02 (m, 2H), to 7.61 (s, 1H), 8,64 (c, 1H), 10,26 (Shir.s, 1H).

MS (EI) m/z: 333 (bp), 439 [M]+

Example 60 synthesis

Yield: 42%

1H-NMR (Dl3) : 0,94-0,97 (m, 2H), 1,12-1,17 (m, 5H), for 1.49 (s, 3H), 1,63-to 1.67 (m, 1H), 2.77-to to 2.94 (m, 4H), 3,49 (d, J=10.3 Hz, 1H), to 3.67 (DD, J=0,9, 10,3 Hz, 1H), 7,10-7,22 (m, 4H), a 7.62 (s, 1H), 8,63 (d, J=0.9 Hz, 1H), 10,27 (Shir.s, 1H).

MS (EI) m/z: 334 (bp), 460 [M]+

Example 61 synthesis

Yield: 61%

1H-NMR (Dl3) : 0,94-0,97 (m, 2H), 1,10-of 1.18 (m, 5H), to 1.48 (s, 3H), 1,63-of 1.66 (m, 1H), 2,85-2,96 (m, 4H), 3,53 (d, J=10.1 Hz, 1H), 3,71 (d, J=10.1 Hz, 1H), 7,28-7,46 (m, 4H), 7,60 (s, 1H), 8,66 (s, 1H), 10,26 (Shir.s, 1H).

MS (EI) m/z: 259 (bp), 494 [M]+

Example 62 synthesis

Red amorphous substance

1H-NMR (Dl3) : 0,94-0,97 (m, 2H), 1,12-of 1.15 (m, 2H), 1,16 (s, 3H), of 1.47 (s, 3H), 1,61-to 1.67 (m, 1H), 2,79-2,96 (m, 4H), of 3.45 (d, J=9.9 Hz, 1H), 3,64 (d, J=9.9 Hz, 1H), 7,22-to 7.32 (m, 5H), to 7.61 (s, 1H), to 8.62 (s, 1H), 10,26 (s, 1H).

MS (EI) m/z: 418 [M+1]+, 346, 309, 179 (bp).

Example 63 synthesis

MS (EI) m/z: 441 [M+1]+, 322, 268 (bp).

Example 64 synthesis

Red crystals

So pl.: 176,5-178,0

1H-NMR (Dl3) : of 1.18 (s, 3H), and 1.54 (s, 3H), 3,05-and 3.16 (m, 3H), 3,26-3,30 (m, 1H), 4,06 (d, J=8.6 Hz, 1H), 4,58 (d, J=8.6 Hz, 1H), 7,15-7,26 (m, 5H), 7,73 (s, 1H), 8,65 (s, 1H), 10,66 (s, 1H).

MS (EI) m/z: 453 [M]+(bp).

Example 65 synthesis

Red amorphous substance

1H-NMR (Dl3) : of 1.02 (t, J=6.8 Hz, 3H), 1,24 (s, 3H), of 1.52 (s, 3H) and 1.83 (s, 3H), 2,68-2,96 (m, 4H), 3.33 and (kV, J=6,8 Hz, 1H), 3,63 (d, J=10.1 Hz, 1H), 3,74 (d, J=10.1 Hz, 1H), of 3.77-3,90 (m, 1H), 7,19-7,39 (m, 7H).

MS (FAB) m/z: 428 [M]+(bp), 268, 105.

Example 66 synthesis

Red amorphous substance

1H-NMR (Dl3) : to 1.15 (s, 3H), of 1.33 (t, J=7,1 Hz, 3H), of 1.46 (s, 3H), 2,82-of 2.86 (m, 3H), 2.91 in-2,96 (m, 1H), is 3.08-3,13 (m, 2H) and 3.59 (d, J=10.1 Hz, 1H), 3,65 (d, J=10.1 Hz, 1H), return of 6.58 (s, 1H), 7,22-7,26 (m, 3H), 7,31-7,34 (m, 2H), 7,53 (Shir.s, 1H), 7,60 (s, 1H).

MS (EI) m/z: 385 [M]+, 314, 266, 223 (bp).

Example 67 synthesis

Yellow oil

1H-NMR (Dl3) : of 1.18 (s, 3H), of 1.48 (s, 3H), 2,75-3,00 (m, 6N), 3,52 (d, a part of AB, J=9.9 Hz, 1H), 3,70 (d, a part of AB, J=9.9 Hz, 1H), 7.18 in-7,35 (m, 5H), a 7.62 (s, 1H), 8,45 (s, 1H), 8,66 (s, 1H), 9,98 (s, 1H).

MS (is-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (99% error tolerance [her] or more).

Yellow amorphous substance

[]26D+104,6 (from 0.64, EtOH)

Example 69 synthesis

Derived from (+)-(3R*,4R*)-6-ndimethylacetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (99% error tolerance [her] or more).

Yellow crystals

(HCl salt): so pl. 246-247C (decomp.).

(HCl salt): []26D-71,8 (from 0.38, EtOH).

Example 70 synthesis

Derived from (+)-(3R*,4R*)-3,4-epoxy-6-cyclopropylamino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (99% error tolerance [her] or more).

(HCl salt): Yellow crystals

(HCl salt): so pl. 241-C (decomp.).

(HCl salt): []26D-92,1 (from 0.45, EtOH).

Example 71 synthesis

Derived from (+)-(3R*,4R*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-6-triptorelin-2H-1-benzopyran (99% error tolerance [her] or more).

(HCl salt): Yellow crystals

(HCl salt): so pl. C (decomp.).

[]26D-54,8 (0.5, EtOH)

Example 72 synthesis

Derived from (+)-(3R*,4R*)-6-ndimethylacetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (99% error tolerance [her] or more).

Red amorphous substance

Red amorphous substance

[]26D+61,2 (from 0.98, EtOH)

Example 74 synthesis

Derived from (+)-(3R*,4R*)-6-ndimethylacetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (99% error tolerance [her] or more).

Red amorphous substance

[]26D-64,6 (from 1.00, EtOH)

Example of synthesis 75

Derived from (-)-(3R*,4R*)-6-ndimethylacetamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (99% error tolerance [her] or more).

Red amorphous substance

[]26D+60,8 (0,93, EtOH)

Example 76 synthesis

To a solution of (+)-(3R*,4R*)-epoxy-6-isopropylamino-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (1.0 g and 3.59 mmol) and lithium bromide (1.24 g, 14,36 mmol) in acetonitrile (10 ml) is added 4-fortuneteller (of 1.88 ml, 14.4 mmol), corresponding to the desired substituent in position 4, at room temperature and stirred at 65 degree Celsius for 2 hours. Then add ethyl acetate and the resulting organic phase is washed with a saturated solution of sodium bicarbonate and aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After the solvent is distilled off, the residue is purified is the thief of the substance, substituted with the amine at position 4, in ethanol (10-fold volume) is added concentrated hydrochloric acid (6 equivalents) at room temperature and refluxed at 90 ° C for 1 day. Then add a saturated solution of sodium bicarbonate and extracted with ethyl acetate, and the resulting organic phase is washed once with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled with obtaining the substance, dezaminirovanie in position 6. Then the solution of the substance, dezaminirovanie in position 6, in dimethylformamide (20-fold volume) is added 4n solution of hydrogen chloride in dioxane (1.4 equivalent) at room temperature and stirred for 10 minutes. Added dropwise to the acid chloride of acid (1.5 equivalent), corresponding to the substituent in the 6 position, and stirred for 1 hour, then add methanol (1 ml) and stirred for 10 minutes. To this mixture are added water and extracted with ethyl acetate and the resulting organic phase is washed with saturated sodium hydrogen carbonate solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After solvent is a solution of the desired substance in methanol (10-fold amount) add 10% methanol solution of hydrogen chloride (double volume) under cooling with ice and stirred for 30 minutes. Then added diisopropyl ether (100-fold volume) and the resulting crystals filtered off, washed with diisopropyl ether to give the desired hydrochloride.

Yellow crystals

So pl.: 244-C (decomp.)

[]26D-67,3 (0.4, EtOH)

Examples of compositions

Example compositions 1

Tablets, g:

The connection according to this invention 10

Lactose 260

Powder, crystalline cellulose 600

Corn starch 350

Hydroxypropylcellulose 100

CMC-CA 150

Magnesium stearate 30

Only 1500

The above compounds are mixed in the usual way and then make 10000 covered sugar tablets, each containing 1 mg of active ingredient per tablet.

Example composition 2

Capsules, g:

The connection according to this invention 10

Lactose 440

Powder crystal

pulp 1000

Magnesium stearate 50

Only 1500

The above compounds are mixed in the usual way and then fill gelatin capsules with getting 10,000 capsules each containing 1 mg of the act is giving this invention 10

PEG 400 479

Triglyceride rich

fatty acids 1500

Peppermint oil 1

Polysorbate 80 10

Only 2000

The above compounds are mixed in the usual way and then fill with a mixture of soft gelatin capsules No. 3 with obtaining 10000 soft gelatin capsules, each containing 1 mg of active ingredient per capsule.

An example of the composition 4

Ointment, g:

The connection according to this invention 1,0

Vaseline oil 10,0

Cetanol 20,0

White petrolatum 68,4

Ethylparaben 0,1

1-menthol 0.5

Just 100,0

The above compounds are mixed in the usual way with getting 1% ointment.

An example of the composition 5

Suppositories, g:

The connection according to this invention 1

Witepsol n* (Witepsol H15*) 478

Witepsol N* 520

Polysorbate 80 1

Only 1000

(* "Witepsol" is a trading name for connections triglyceride type).

The above-mentioned compounds are mixed in the melt in the usual way, the mixture was poured into containers for suppositories and cooled to harden and get that abrasion composition 6

Injection

The connection according to this invention 1mg

Distilled water for injection 5 ml

Water is used for dissolving in the application.

An example of pharmacological trials

Action connection in the functional refractory period of the muscle of the left atrium of the Guinea pig and papillary muscle of right ventricle

Test method

The Guinea pigs were removed heart and one of them was isolated muscles of the left atrium or papillary muscle of the right ventricle and placed in Krebs solution-Henseleit, aerated with 95% O2+5% CO2. The samples were electrically stimulated with a frequency of 1 Hz and a voltage of 1.5 times above the threshold response to stimulation (basal stimulation; S1), using the apparatus for electrical stimulation. The reduction that occurred at this time, registered by termotopliwego device through FD receiving device and the amplifier pressure stretching. The functional refractory period is defined as the shortest time interval between S1 obtained from the designated reduction, and additional stimulation (S2). The time interval between S1 and S2 in the sample of the muscles of the left preaching period. As for the sample papillary muscle of the right atrium, it began with 300 MS and decreased speed for 10 msec to the functional refractory period. Here S2 installed on a dual threshold value, when there was a reaction to the stimulation. The temperature during the experiment was equal to S. The solvent here does not affect any of the functional refractory periods for the muscles of the left Atria and papillary muscle of the right ventricle. After defining the initial values before adding the connection was added cumulatively, were incubated for 15 minutes at the appropriate concentration and then determined the functional refractory period.

Results

Compounds according to this invention showed strong prolonging action in respect of the functional refractory period (FER) on the muscle of the Atria (see tab. 8).

Example pharmacological test 1

The effect of compounds on effective refractory period.

Test method

The hounds were anestesiologi pentobarbital sodium and thoracotomy was performed along the middle line under breathing apparatus and was made the cut on perevernete free wall of the right atrium, the appendage of the right atrium and the free wall of the right ventricle. Vagusnye nerve is stimulated using the device for electrostimulation with nichrome wire, introduced in wagusnye nerve in the neck from both sides. Conditions of electrical stimulation vagusnye nerve was created so that RR intervals of the ECG were 100 msec longer than intervals before stimulation.

Effective refractory period of the Atria and ventricle were determined by the method of additional stimulation S1-S2 if the length of the main loop 300 msec during bilateral stimulation vagusnye nerve using a programmable electrical stimulator. For a series of 10 major stimulus (S1) was performed premature additional stimulation (S2) using a dual-threshold diastolic pressure. The interval S1-S2 progressively increased to 2 msec, and the effective refractory period was defined as the point at which the S2 did not give a long response.

To evaluate the effectiveness of a drug action effective refractory period of the ventricle and atrium were determined before administration of a medicinal product, then the compounds were administered intravenously at a dose of 0,ASS="ptx2">

The results were presented as a time of lengthening the effective refractory periods of the atrium and ventricle, namely [the effective refractory period after administration of the medicinal product] - [effective refractory period before the introduction of the medicinal product] (msec).

The data obtained are presented in Table 9.

The compounds of this invention show a strong prolonged activity against functional and effective refractory period, and thus, they are useful to facilitate arrhythmia. Therefore, this invention can provide useful antiarrhythmic agents.

1. Benzopyrane derivative of the formula (I)

where R1and R2each independently represent a hydrogen atom, a C1-C6alkyl group, where this alkyl group may be optionally substituted by a halogen atom, a C1-C6alkoxygroup or a hydroxyl group;

R3represents a hydroxyl group or a C1-C6alkylcarboxylic;

R4represents the 0 to 4;

n represents an integer from 0 to 4;

Y is absent or represents CR11R12where R11and R12each independently represents a hydrogen atom or a C1-C6alkyl group;

R5represents an aryl group or heteroaryl group, such as thienyl, pyridyl or indolyl, where this aryl group may be optionally substituted (R10), where R10represents a halogen atom, a hydroxyl group, a C1-C6alkyl group, where this alkyl group may be optionally substituted by a halogen atom or WITH1-C6alkoxygroup; or R10is a nitro-group, an amino group, a C1-C6alkylamino group, di-C1-C6alkylamino, C1-C6alkoxycarbonyl group, carboxyl group, q is an integer from 1 to 3, and each R10may be the same or different when q is 2 or 3;

R6represents a hydrogen atom or a C1-C6alkyl group;

R7represents a hydrogen atom or a C1-C6alkyl group;

X is absent or represents C=O or SO2; the other group may be optionally substituted by a halogen atom or WITH3-C6cycloalkyl group;

R9represents a halogen atom, a nitro-group, or cyano;

or its pharmaceutically acceptable salt.

2. Benzopyrane derivative or its pharmaceutically acceptable salt p. 1, where R1and R2both represent a methyl group, R3represents a hydroxyl group, and R4represents a hydrogen atom.

3. Benzopyrane derivative or its pharmaceutically acceptable salt according to p. 2, where R9represents a hydrogen atom or a nitro-group.

4. Benzopyrane derivative or its pharmaceutically acceptable salt according to p. 3, where X represents C=O, a, R6and R7both represent hydrogen atoms.

5. Benzopyrane derivative or its pharmaceutically acceptable salt according to p. 4, where R5represents a benzene ring, Y is absent, m is 0 and n is 1 or 2.

6. Benzopyrane derivative or its pharmaceutically acceptable salt p. 5, where R8represents an alkyl group, R4is a nitro-group, and n is 2.

7. Drug, possess antiarrhythmic activity, which on the enta.

8. Drug for the treatment of arrhythmia, which includes benzopyrane derivative or its pharmaceutically acceptable salt under item 1 as an active ingredient.

 

Same patents:

The invention relates to new biologically active compounds

The invention relates to new derivatives of 2-aminopyridine of General formula (I)

where And denotes the radical

in which R1, R2and R3mean hydrogen, halogen, HE, alkyl or alkoxy and the other,

or radical

in which R8means hydrogen, x is the radical -(CH2)m-Q, m is an integer from 0 to 6, Y represents alkyl, alkenylphenol or alkenylphenol chain or other, R10is hydrogen or alkyl, or their salts

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to new derivatives chromane General formula I,

,

where R is hydrogen, halide or NR1R1group; R1means hydrogen or alkyl group with 1-10 carbon atoms; R2means R1or NR1R1; R3means hydrogen or CO2R1; Ar1means a phenyl group or a 5-or 6-membered heterocyclic ring containing as the heteroatom atom N; m = 1, 2, or 3; n = 1, when this symbol is the group -(CO)nand n is 0, 1 or 2, when this symbol is the group (X); X is alkyl group with 1-4 carbon atoms; R4means hydroxyl or CNS group with 1-10 carbon atoms; and their pharmaceutically acceptable salts, having agonistic activity against beta-3-adrenergic receptor

The invention relates to 4-oxocyclohexyl the urea compounds of General formula (I), where X, Y, R, R1, R2, R3, R4, R5And L, such as defined in the claims

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new optically active proizvodnim of benzopyran formula

< / BR>
where R and R are independently selected from the group consisting of hydroxyl and a moiety that can be converted in vivo in hydroxyl, such as acyloxy, -OR4, -OC(O)R7or-OC(O)OR4(where R4represents alkyl, alkenyl, quinil or aryl; and R7represents amino, alkylamino, aminoalkyl and alkylsulfonyl); and R3represents-CH2- or-CH2CH2-; or its pharmaceutically acceptable salt, where the specified compound or salt is optically active because they contain more than 50% (by weight relative to all stereoisomers) 2S stereoisomers

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

The invention relates to new derivatives of tocopherol, tocotrienol and other derivative Romana and the side chains of the formula 1:,

where X represents oxygen; R1represents a group-C1-10alkylene-COOH, -C1-4alkylene-CONH2, -C1-4alkylene-COO-C1-4alkyl, -C1-4alkylene-CON(C1-4alkylene-COOH)2- 1-4alkylene-OH, -CH2(CH2)2-NH3-CI or-C1-4alkylen-OSO3NH(C1-4alkyl)3; R2and R3represent hydrogen or methyl; R4represents methyl; and R5represents a group-C7-17alkyl, -COOH, -C7-16-olefinic group containing from 3 to 5 ethylene linkages, -C=C-COO-C1-4alkyl or-C1-4alkylene-COO-C1-4alkyl; provided that R1may not represent any group-FROM2-4alkylene-COOH or-C1-4alkylene-CONH2or-C1-4alkylen HE, when each of R2, R3and R4represents methyl, and R5represents-C16alkyl, as well as to a method of treating cellular proliferative diseases and method of induction of apoptosis cells

The invention relates to new organic compounds, namely 3-amido-Germanischer(thio)ureas of the formula (I)

< / BR>
in which R(1) denotes hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms; R(2a), R(2b) and R(2c), which are identical or different, denote hydrogen or alkyl with 1 or 2 carbon atoms; R(3) means hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; Z denotes sulfur or oxygen; And means phenyl, which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen, alkyl with 1 or 2 carbon atoms and alkoxyl with 1 or 2 carbon atoms; or a represents a residue of a saturated or unsaturated lactam of the formula

< / BR>
where In means albaniles or alkylene with 3, 4, 5 or 6 carbon atoms, which is not substituted or is substituted by up to three identical or different alkyl groups with 1, 2, 3 or 4 carbon atoms; in all their stereoisomeric forms and mixtures thereof in any ratio; and their physiologically acceptable salts, which are valuable pharmaceutical active substances is I sudden death from cardiac arrest or impact of reduced contractility of the heart, and method of production thereof, and containing pharmaceuticals

The invention relates to bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIb/IIIa, to prevent thrombosis

The invention relates to new sulfadimethoxine benzopyranones derivative of the formula I

< / BR>
where R(5) is in one of positions 5, 6, 7 and 8, and R(1) and R(2) independently of one another denote hydrogen or alkyl with 1-6 carbon atoms, R(3) means R(10)-CnH2nR(10) means a hydrogen atom or methyl, n denotes an integer equal to 0-10, R(4) means R(13)- CrH2rand one of CH2group can be replaced by-CO-O - or-O-CO - group, R(13) denotes methyl or trifluoromethyl, r is an integer equal 0-12, R(5) means-Y-CsH2s-R(18), Y represents-O-, s indicates an integer equal to 1-8, R(18) denotes hydrogen, trifluoromethyl or phenyl, R(6) means-OR(10d) or-OCOR(10d) group, R(10d) denotes hydrogen or alkyl with 1-3 carbon atoms, denotes hydrogen or R(6) and together form a bond; and their physiologically acceptable salts

The invention relates to new sulfadimethoxine compounds of formula I, where R(1)-R(9) and have the values listed in the description with+channel blocking action, as well as pharmaceutical compositions based on them
Up!