2-aminoalkylthieno[2,3-d]pyrimidines, method for their preparing, medicinal agent and method for its preparing

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to 2-aminomethylthieno[2,3-d]pyrimidines of the general formula (I): wherein R1 and R2 in common with C-atoms with which they are bound form 5-7-membered monounsubstituted cycloalkenyl ring; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl, (C1-C8)-alkoxy-group, amine, mono-(C1-C8-alkyl)-amine or di-(C1-C8-alkyl)-amine groups, or in common with nitrogen atom to which they are bound form a heterocyclic ring that comprises optionally one or more additional nitrogen atoms and substituted with one or more hydroxyl, (C1-C8)-alkoxy- or (C1-C8)-alkylol groups. Compounds elicit the inhibitory effect with respect to activity of phosphodiesterase V and can be used in treatment of cardiovascular system states and in disturbance in the potency injury. Also, invention describes a medicinal preparation based on compounds said, a method for its preparing and a method for preparing compounds.

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

6 cl, 1 tbl, 16 ex

 

The present invention relates to 2-aminoalkylation[2,3-d]pyrimidines of General formula (I)

in which the radicals R1for R6have the values listed in the text, and their use as pharmaceuticals, in particular as inhibitors of C-GMP phosphodiesterase.

Substances with C-GMP, phosphodiesterase-inhibiting properties have been known for several years. Pathological increase in the level of cyclo-guanosine monophosphate (C-GMP) they serve to lower it. They are used to prevent symptoms in the case of elevated levels of C-GMP, such as inhibition and prevention of inflammation, and muscle relaxation is suppressed and prevented. Inhibitors of C-GMP phosphodiesterase apply, in particular, for the treatment of cardiovascular diseases, and disorders of potency.

There are different classes of molecular compounds, known for their C-GMP, phosphodiesterase-inhibiting properties.

These are, on the one hand, heatline, which are described, for example, in J. Med. Chem. 36, str and beyond (1993) and in J. Med. Chem. 37, str and beyond (1994).

On the other hand, pyrazolopyrimidine described in WO 94/28902, are also suitable. It also describes the application of this class of compounds for the treatment of impotence.

The use of pyrazolo[4,-d]pyrimidines for the treatment of cardiovascular conditions and impotence is described in the German application under the code of 19942474.8.

Finally, in the German application with cipher 19644228.1. describe the use of thienopyrimidines having the General formula

The substituents R1for R4in this case, are different alkyl, alkoxy, Gallic or cycloalkenyl groups or hydrogen. X represents either cycloalkyl group having from 6 to 12 atoms, or linear or branched alkylenes group having 1 to 10 C atoms, in which one or two groups of CH2can be replaced by a group-CH=CH -, and in which cycloalkyl group and Allenova group, mentioned above, can be monogamist group-COOH, C(O)O(C1-C6-alkyl), -C(O)NH2, -C(O)NH(C1-C6-alkyl), -C(O)N(C1-C6-alkyl)2or-CN.

The aim of the present invention is to make available novel compounds which are used as pharmaceuticals, where, in particular, the use of an inhibitor of C-GMP phosphodiesterase is desirable. To reach this aim by using the compounds of formula

where R1, R2are the same or different and independently from each other represent hydrogen or linear or branched C1-C8-alkyl group or together with the atoms to which they are linked, form a 5-7-h is i.i.d. monounsaturated cycloalkenyl ring,

R3, R4are the same or different and independently from each other represent hydrogen, a hydroxyl group, a linear or branched C1-C8is an alkyl group, a C1-C8-alkoxygroup or hydrogen or together with the atoms to which they are attached, form a 5 - to 8-membered ring which, in addition to carbon atoms, can optionally contain one or more oxygen atoms,

R5, R6may be the same or different and independently of one another represent hydrogen, linear or branched C1-C8is an alkyl group which may be substituted by one or more hydroxyl,1-C8-alkoxy, amino, mono(C1-C8-alkyl)amine, di(C1-C8-alkyl)amine, nitrile, N-morpholino, phenyl, benzodioxole or peredelnoj groups or With4-C7cycloalkyl group, or together with the nitrogen atom to which they are linked, form a saturated heterocyclic ring which optionally contains one or more additional nitrogen atoms and/or oxygen, and which is substituted by one or more1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkylamine,1-C8-oligosiloxane, amino, mono(C1-C8 -alkyl)amino, di(C1-C8-alkyl)amino, -SO2R7or-C(O)R7groups,

R7represents a C1-C8is an alkyl group, a C1-C8-foralkyl group, phenyl group which is optionally substituted by alkyl, halogen or nitrile group, or benzodioxolyl group.

It was found that 2-aminoalkylation[2,3-d]pyrimidines of the formula (I)and their physiologically tolerated salts have advantageous pharmacological properties.

In particular, the molecules of the General formula (I) are specific ingibirovanie C-GMP phosphodiesterase. These compounds are therefore suitable for the treatment of conditions of the cardiovascular system and treatment and treatment of violations of a potentiality, which manifest in the form of erectile dysfunction.

Determination of biological activity of compounds (I) according to the invention is carried out, for example, by the method described in WO 93/06104. According to this method, the affinity of the compounds according to the invention relative to C-GMP and C-AMP phosphodiesterase determined by determining the values of the IC50. The value of the IC50here represents the concentration of inhibitor required for 50% inhibition of enzyme activity. Applied phosphodiesterase is also possible to select by means of known methods described, for example, W.J.Thompson and others in Biochem. 10, str and next (1971). Tests mo is but to hold, for example, using the modified batch method W.J.Thompson and ..Appleman described in Biochem. 18, str and forth (1979).

The effectiveness of compounds of the formula (I) according to the invention in the treatment and therapy of disorders of potency was demonstrated by inhibition caused by phenylephedrine interactions drugs corpus carvenosum hares. In this way the demonstration of biological activity mainly carried out by the method described F.Holmquist etc. in J. UroL, 150, pages 1310 at 1350 (1993).

The winning results were obtained by applying the compounds of General formula (I)in which the radicals R1for R5had the values listed below.

The radicals R1, R2are different, one of them is a hydrogen, the other is a linear or branched (C1-C4)-alkyl group, preferably a methyl or ethyl group, or R1and R2together form a propylene, butylene or Panteleeva group.

The radicals R3and R4may be the same or different and are located in positions 3 and 4 of the phenyl ring; they independently from each other represent hydrogen, linear or branched (C1-C6)alkyl group, linear or branched (C1-C6)alkoxygroup or halogen, or together form a propylene, butylene, pentile the new, ethylenoxy, metalinox or Ethylenedioxy.

The radicals R5and R6may be the same or different and independently from each other represent hydrogen or C1-C6is an alkyl group which is unsubstituted or substituted by one or more hydroxyl, methoxy, ethoxy, nitrile, methylamino, ethylamino, dimethylamino, diethylamino, peredelnoj, benzodioxole or N-morpholinopropan, or cyclopentyloxy or tsiklogeksilnogo group, or R5, R6form together with the nitrogen atom to which they relate, piperidinyl or piperazinilnom ring, optionally substituted by one or more hydroxyl, hydroxycarbonyl,1-C2-alkylamino, -SO2-R7or-C(O)-R7groups, and R7represents a C1-C3is an alkyl group, a C1-C3-foralkyl group, phenyl group, substituted with one or more alkyl or nitrile groups, or benzodioxolyl group.

Compounds according to the invention is suitable for use as a drug, it is possible to obtain medicines for human and veterinary medicine.

In these applications, the compounds according to the invention is often used in the form of their physiologically-tolerated salts. Such p is iodnymi salts, in General, are metal salts, for example salts of alkali metals and alkaline earth metals, and ammonium salts such as the ammonium or organic amines.

Another preferred form of the salts in the case of compounds according to the invention are acid-salt additive. It can be obtained using conventional methods known to the person skilled in the art, for example, by reaction of the compounds according to the invention with an appropriate acid in an inert solvent and subsequent excretion of salt, for example, by evaporation. Examples of acids which give physiologically acceptable salts, are, on the one hand, inorganic acids such as sulfuric acid, nitric acid, halogen acid, for example hydrochloric acid or Hydrobromic acid, phosphoric acid, for example, orthophosphoric acid, or sulfamic acid.

On the other hand, organic acids also form suitable salts. These are, for example, formic acid, acetic acid, propionic acid, Pavlova acid, diethyloxalate acid, malonic acid, succinea acid, Pimenova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, from cutinova acid, methane and econsultancy acid, ethicality acid, naphtalene - and-disulfonate acid, and louisanna acid.

For use as a drug compounds according to the invention or their physiologically acceptable salts are made to get a suitable pharmaceutical preparations. When they are brought into a suitable dosage form with at least one suitable carrier or one excipient, which can be solid, liquid or semi-liquid. Such pharmaceutical preparations are further subject of the invention.

Suitable carriers are conventional organic and inorganic substances known to the person skilled in the art, which are selected according to the intended receiving, i.e. enteral, parenteral or topical. Common examples of substances of this type are water, vegetable oils, benzyl alcohols, alkalophile, glycols, glyceryltrinitrate, gelatin, carbohydrates, such as lactose or starch, magnesium stearates, talc and petroleum jelly. Selecting the above carriers must, of course, that they should not enter into reaction with the substances according to the invention.

Examples of forms of acceptance for oral administration, which is the preferred form of reception according to the invention, the two who are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops.

In the case of rectal technique can be used, in particular, suppositories, and in the case of parenteral receive applied solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions and implants are also used.

Examples for topical application include ointments, creams and powders.

Another possibility is lyophilization of the compounds according to the invention. Lyophilizate can then be applied, for example, to get injectables.

Drugs are substances according to the invention can also be sterilized and/or can contain excipients, such as lubricants, preservatives, stabilizers and moisturizers, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyes and fragrances. Examples of such substances are vitamins.

The dosage of the substances according to the invention is preferably from 1 to 500 mg, in particular from 5 to 100 mg per unit dosage. The daily dosage in this case is from 0.02 to 10 mg/kg of body weight. However, it is true that the specific dose can vary greatly from patient to patient, as well as for each individual patient and depends on various factors. Such factors, for example, the R, are activity specific applicable connection age, body weight, General health, sex, food intake during reception, reception time and route of administration, the level of discharge, pharmaceutical combination and complexity of the specific state.

The compounds of formula (I) according to the invention are produced by reaction of the corresponding 2-halomethane[2,3-d]pyrimidine of the General formula (IIa) with a suitable alkyl-amine of formula (III), as shown in the following equation (I)

In formulas (IIa) and (III) the substituents R1for R6have the meanings indicated in connection with formula (I). Hal represents a halogen atom, preferably chlorine.

The reaction according to equation (I) is carried out at temperatures from -30 to 150°C, preferably from 0 to 120°C. the Reaction in this case can be performed with a pure substance, without the use of solvent or using a suitable solvent. Suitable, in General, are conventional solvents known to the person skilled in the art. Examples are hydrocarbons such as hexane, petroleum simple ether, benzene, toluene and xylene, chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform and dichloromethane, alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol, etc the simple esters, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, glycol ethers such as etilenglikolevye and monomethylamine esters, healthliteracy ether, ketones, such as acetone and butanone, amides, such as ndimethylacetamide, dimethylacetamide, N-organic and dimethylformamide, NITRILES such as acetonitrile, sulfoxidov, such as dimethylsulfoxide, nitro compounds such as nitromethane and nitrobenzene, esters such as ethyl acetate, and also mixtures of the aforementioned solvents. The solvent preferably used is dimethylformamide and/or N-organic.

After completion of the reaction, the resulting material is treated in the traditional way, for example, by extraction with an organic solvent after treatment with water, and the connection allocate the traditional way, for example, distillation of the solvent. Usually the resulting residue recrystallized for cleaning.

2-halomethane[2,3-d]pyrimidines of General formula (IIa) can be obtained from the corresponding 4-chlorotheophylline by reaction with the corresponding, optionally substituted benzylamines. Description of similar reactions, in which the pyrimidine ring is substituted by a group X, as indicated in the formula (II) above, instead of geometrinae functions described in the German patent application of the applicant with cipher one in her reaction conditions can be transferred to the substance of the present invention.

4-chloropropylamine can be obtained according to the method known from the literature, see, for example, Houben-Weyl, Methods der organischen Chemie, Georg Thieme Verlag, Stuttgart.

Further, the invention is illustrated in more detail by the following examples. Temperature specified in °and the abbreviations have the meaning known to the person skilled in the art. All products in this case were processed after completion of the reaction by adding water and the pH of the solution was set to values between about 2 and 10 depending on the received product. Then extraction was performed with ethyl acetate or dichloromethane, and the organic phase was separated and dried. The solvent was then removed by distillation and the obtained residue was purified by chromatography on silica gel and/or crystallization.

Example 1

A solution of 2 g of 4-(3-chloro-4-methoxybenzylamine)-2-chloromethyl-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine in 10 ml of DMF is treated with 5 ml of 3-aminopropanol and heated at 80°C for 1 hour. Then diluted with water and extracted with ethyl acetate. Obtained after traditional processing crystalline product is dissolved in alcoholic HCl and treated with ethyl acetate is added to turbidity. 2.1 g of 4-(3-chloro-4-methoxybenzylamine)-2-(3-hydroxypropylamino)-5,6,7,8-tetrahydrothieno[4,3-d]pyrimidine receive in the form of its dihydrochloride.

MP.=225°C.

Example 2

Re is the Ktsia conducted, as described in Example 1 with an equivalent amount of diethanolamine instead of 3-aminopropanol.

After treatment of the corresponding acid 4-(3-chloro-4-methoxybenzylamine)-2-(bis-2-hydroxyethylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine was obtained in the form of its hydrochloride.

MP.=180°C.

Example 3

The reaction was carried out as described in Example 1 with an equivalent amount of 4-piperidinol instead of 3-aminopropanol.

After treatment of the corresponding acid 4-(3-chloro-4-methoxybenzylamine)-2-(4-hydroxypiperidine)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine was obtained in the form of its dihydrochloride.

MP.=119°C.

Example 4

The reaction was carried out as described in Example 1 with an equivalent amount of 3-methoxypropylamine instead of 3-aminopropanol.

After treatment of the corresponding acid 4-(3-chloro-4-methoxybenzylamine)-2-(3-methoxypropylamine)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine was obtained in the form of its dihydrochloride.

MP.=116°C.

Example 5

The reaction was carried out as described in Example 1 with an equivalent amount of 2-hydroxyethylamine instead of 3-aminopropanol.

After treatment of the corresponding acid 4-(3-chloro-4-methoxybenzylamine)-2-(2-hydroxyethylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine was obtained in the form of its dihydrochloride.

MP.=225°C.

Example 6

<> The reaction was carried out as described in Example 1 with an equivalent amount of N,N-dimethylethylenediamine instead of 3-aminopropanol.

After treatment of the corresponding acid 4-(3-chloro-4-methoxybenzylamine)-2-(N,N-dimethylaminopropylamine)-5,6,7,8-tetrahydrothieno-[2,3-d]pyrimidine was obtained in the form of its 1.5 fumarata.

MP.=180°C.

Example 7

The reaction was carried out as described in Example 1 with an equivalent amount of N-hydroxyethylpiperazine instead of 3-aminopropanol.

After treatment of the corresponding acid 2-{4-[4-(3-chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno-[2,3-d]pyrimidine-2-ylmethyl]piperazine-1-yl}ethanol was obtained in the form of its dihydrochloride.

The following compounds were obtained analogously:

1-{4-[4-(3-Chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl]piperazine-1-yl}-2,2,2-triflora-alanon

1-{4-[4-(3-Chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl]piperazine-1-yl}alanon

(3-Chloro-4-methoxybenzyl)[2-(4-methanesulfonylaminoethyl-1-ylmethyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4-yl]amine

1-[4-(3-Chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl]piperidine-3-ol

(3-Chloro-4-methoxybenzyl)(2-{[(pyridine-2-ylmethyl)amino]methyl}-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4-yl)Amin

1-Benzo[1,3]dioxol-5-yl-1-{4-[4-(3-the loro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl]piperazine-1-yl}-metano

4-(1-{4-[4-(3-Chloro-4-methoxybenzylamine-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl]piperazine-1-yl}methanol)benzonitrile

(3-Chloro-4-methoxybenzyl){2-[4-(toluene-4-sulfonyl)piperazine-1-ylmethyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4-yl)Amin

4-{4-[4-(3-Chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl]piperazine-1-sulfonyl}benzonitrile

(2-{[(Benzo[1,3]dioxol-5-ylmethyl)amino]methyl}-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-4-yl)(3-chloro-4-methoxybenzyl)Amin

3-{[4-(3-Chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl]amino}propane-1,2-diol

(3-Chloro-4-methoxybenzyl){2-[(2-morpholine-4-ylethylamine)methyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4-yl}Amin

3-{4-[4-(3-Chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl]piperazine-1-yl}propane-1,2-diol

(3-Chloro-4-methoxybenzyl)[2-(4-dimethylaminopyridine-1-ylmethyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4-yl]amine

6-{[4-(3-Chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimid-2-ylmethyl]amino}hexane-1-ol

(3-Chloro-4-methoxybenzyl)(2-cyclohexylamino-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-4-yl)Amin

1-[[4-(3-Chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl](2-hydroxypropyl)amino]propan-2-ol

3-[[4-(3-Chloro-4-methox is benzylamino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl](2-cyanoethyl)amino]propionitrile

(2S,3S,4S,5R)-6-{[4-(3-Chloro-4-methoxybenzylamine)-5,6,7,8-tetrahydrobenzo-[4,5]thieno[2,3-d]pyrimidine-2-ylmethyl]methylamino}hexane-1,2,3,4,5-pentol

The following examples relate to pharmaceutical preparations

Example: Vials for injection

A solution of 100 g of the active compounds of formula (I) and 5 g of hydrogenphosphate disodium in 3 l of double-distilled water adjusted to pH 6.5 using 2 N hydrochloric acid, contribute in vials for injection, lyophilizer under sterile conditions and aseptically sealed. Each vial for injection includes 5 mg of active compound.

Example: Suppositories

A mixture of 20 g of active compound of the formula (I) melt with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allow to cool. Each suppository includes 20 mg of active compound.

Example: Solution

A solution is prepared from 1 g of the active compounds of formula (I), 9,38 g NaH2RHO4*2H2Oh, 28,48 g Na2HPO4*12H2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The solution is set at pH 6.8, bring to 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

500 mg of the active compounds of formula (I) is mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of active compound of formula I, 4 kg of lactose, 1.2 and chertopoloha starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in the traditional way with reception of tablets such that each tablet contains 10 mg of active compound.

Example F: coated Tablets

Analogously to Example E is pressed tablets, and then cover the traditional way by a coating of sucrose, potato starch, talc, tragakant and dye.

Example G: Capsules

2 kg of active compound of the formula (I) contribute in gelatin capsules in the traditional way, so that each capsule includes 20 mg of active compound.

Example N: Ampoules

A solution of 1 kg of active compound of the formula I in 60 l of double-distilled water is sterilized by filtration, making capsules, lyophilizer under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound.

Example I: Spray for inhalation

14 g of the active compounds of formula (I) is dissolved in 10 ml of isotonic NaCl solution, bring in commercially available spray containers, equipped with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg

Pharmacological research

Testing was conducted with the claimed compounds, illustrating their inhibitory activity against phosphodiester the s V.

The studies were conducted according to the procedures described .Hamet et al. (1983), Rapid activation od cAMP phosphodiesterase in rat platelets. Can. J. Biochem. Cell Biol. 61: 1158-65.

The results are shown in the table, which shows the tested compounds, the values of the IC50the melting temperature and the number of examples in the description, in which the above compound is obtained.

We obtained the following values IC50(concentration in nmol/l, i.e. a 50% inhibition of phosphodiesterase V) for compounds of formula I:

n is equal to 1

NR5R6IC50(nmol/l)melting point (°)example
N(CH2CH2OH)210,01802
4-hydroxypiperidine7,01193
3 methoxypropylamine21,01164
NHCH2CH2OH20,02255
NHCH2CH2CH2N(CH3)230,01806
4-hydroxyethylpiperazine-1-yl6,07
pyridine-2-ylmethylamino 9,0p.12, lines 3-4

1. The compound of formula (I)

where

R1, R2together with the atoms to which they are linked, form a 5-7-membered monounsaturated cycloalkenyl ring,

R3, R4are the same or different and independently of one another represent C1-C8-alkoxygroup or halogen,

R5, R6may be the same or different and independently of one another represent hydrogen, linear or branched C1-C8is an alkyl group which may be substituted by one or more hydroxyl, C1-C8-alkoxy, aminovymi, mono(C1-C8-alkyl)aminovymi or di(C1-C8-alkyl)aminovymi groups or together with the nitrogen atom to which they are linked, form a saturated heterocyclic ring which optionally contains one or more additional nitrogen atoms and which is substituted by one or more hydroxyl, C1-C8-alkoxy or C1-C8-alkylamine groups.

2. The compound of formula (1) according to claim 1, which represents the

4-(3-Chloro-4-methoxybenzylamine)-2-(3-hydroxypropylamino)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine,

4-(3-Chloro-4-methoxybenzylamine is)-2-(bis-2-hydroxyethylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine,

4-(3-Chloro-4-methoxybenzylamine)-2-(4-hydroxypiperidine)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine,

4-(3-Chloro-4-methoxybenzylamine)-2-(3-methoxypropylamine)-5,6,7,8-tetrahydrothieno[2,3-d]-pyrimidine,

4-(3-Chloro-4-methoxybenzylamine)-2-(2-hydroxyethylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine,

4-(3-Chloro-4-methoxybenzylamine)-2-(N,N-dimethylaminopropylamine)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine,

or one of their physiologically acceptable salts.

3. Drug, possess inhibitory activity against C-GMP phosphodiesterase, comprising the compound according to claim 1 or 2 or one of its physiologically acceptable salts.

4. The drug according to claim 3, comprising a compound of the group consisting of:

4-(3-Chloro-4-methoxybenzylamine)-2-(3-hydroxypropylamino)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine,

4-(3-Chloro-4-methoxybenzylamine)-2-(bis-2-hydroxyethylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine,

4-(3-Chloro-4-methoxybenzylamine)-2-(4-hydroxypiperidine)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine,

4-(3-Chloro-4-methoxybenzylamine)-2-(3-methoxypropylamine)-5,6,7,8-tetrahydrothieno[2,3-d]-pyrimidine,

4-(3-Chloro-4-methoxybenzylamine)-2-(2-hydroxyethylaminomethyl)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimi is in,

4-(3-Chloro-4-methoxybenzylamine)-2-(N,N-dimethylaminopropylamine)-5,6,7,8-tetrahydrothieno[2,3-d]pyrimidine,

or one of their physiologically acceptable salts.

5. A method of obtaining a compound according to claim 1 or 2, characterized in that 2-halomethane [2,3-d]pyrimidine of the General formula (IIa)

in which the substituents R1for R4have the meanings indicated in claim 1, is subjected to reaction with alkylamines General formula (III)

in which the substituents R5and R6have the meanings specified in claim 1, and the resulting substance is not necessarily clear.

6. The method of obtaining the drug, characterized in that the compound according to claim 1 or 2 or one of its physiologically acceptable salts of lead in a suitable dosage form with at least one suitable excipient or the media.



 

Same patents:

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

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

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new oxathiepino[6,5-b]dihydropyridines of the formula (I):

wherein: (a) R1, R2, R3, R4 and R5 are taken independently among group consisting of hydrogen atom (H), halogen atom, nitro-group (NO2); (b) R6 is taken among group consisting of unbranched or branched (C1-C5)-alkyl wherein indicated alkyl can be substituted with phenylacetyloxy-, hydroxy- carboalkoxy-group or group NR'R'' wherein R' and R'' are taken independently among group consisting of hydrogen atom (H), unbranched or branched (C1-C8)-alkyl, benzyl; (c) R7 is taken among group consisting of hydrogen atom (H), alkyl; (d) R9 represents oxygen atom; (e) n is a whole number from 1 to 2, or its pharmaceutically acceptable salt. Compounds are useful as antagonists of calcium channels and elicit cardiovascular, anti-asthmatic and anti-bronchoconstricting activity. Also, invention describes the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

28 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

The invention relates to compounds of the formula I

in which

R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

X is R4, R5or R6, monosubstituted R7,

R4is unbranched or branched alkylene with 1-10 atoms, in which one or two CH2groups can be substituted by a group-CH=CH-,

R5is cycloalkyl or cycloalkylation containing 5-12 With atoms

R6is phenyl or vinylmation,

R7is COOH, cooa, CONH2, CONHA, CON(A)2or CN,

And is alkyl having from 1 to 6 atoms

Hal represents F, Cl, Br or I,

where at least one of the radicals R1or R2HE is a,

and their pharmaceutically acceptable salts

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment or prophylaxis of hypertension, heart diseases, vascular disorders and kidney diseases. The composition comprises compound of the formula (1) as antagonist of angiotensin II receptors and one or some diuretics. The composition shows enhanced effectiveness.

EFFECT: valuable medicinal properties of composition.

23 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: method involves passing physiologically permissible gas mixture dispersed in blood and aqueous sclerosing liquid through one or several canals having at least one cross-section size from 0.1 to 30 mcm. Gas-to-liquid proportion is varied in a way that foamed material containing gas micro-bubbles is produced. The material has density of 0.07 g/ml to 0.19 g/ml and half-transformation period not less than 2 min. the device has casing enclosing a chamber allowing pressure to be increased and containing aqueous sclerosing liquid, canal-shaped passage having one or several outlet openings allowing liquid to be released from the chamber allowing liquid pressure to be increased or passage canal to be closed from the chamber to outer space. Fluid medium enclosed in the chamber is forced out along the passage canal through single or several outlet openings when container pressure is high and the passage canal is open. The foamed material containing gas micro-bubbles and has density of 0.07 g/ml to 0.19 g/ml and is able to flows through a needle of size 21 so that 50% and more bubbles having diameter equal to or less than 150 mcm and at least 95% of those bubbles retain diameter equal to or less than 280 mcm.

EFFECT: enhanced effectiveness of blood vessel sclerotherapy by introducing the foamed material into blood vessel.

59 cl, 11 dwg

FIELD: organic chemistry, peptides, medicine, pharmacy.

SUBSTANCE: invention relates to peptide derivatives named as memnopeptides that are used as an active component for manufacturing a medicinal preparation used in treatment of bacterial infection. Invention proposes compound of the formula (I): wherein radicals R1, R2, R3, R4, R5, R6, R7, R8 and (A)n have corresponding values, or its salt. Compounds of the formula (I) are prepared by culturing microorganism Memnoniella echinata FH 2272, DSM 13195 under suitable conditions in the nutrient medium containing at least one source of carbon atoms and at least one source of nitrogen atoms and the process is carrying out until the accumulation of at least one compound of the formula (I) in the nutrient medium followed by isolation of indicated compound. The attained technical result involves the development of a pharmaceutical composition eliciting an antibacterial activity. The development of the preparation provides expanding assortment of agents used in treatment of diseases said above.

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

10 cl, 2 tbl, 7 ex

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention proposes applying moxonidine as an active component in preparing pharmaceutical compositions designated for treatment of injuries of heart muscle caused by infarction. Indicated compositions promote to prophylaxis in the infarction progression and to treatment of its complications also.

EFFECT: valuable medicinal properties of composition.

3 cl, 1 tbl, 1 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a solid medicinal formulation eliciting an antihypertensive, anti-anginal, vasodilating, antioxidant and antiproliferative effect. The solid medicinal formulation comprises the following components: carvedilol, disaccharide, magnesium stearate, starch, calcium phosphate, hydroxypropylmethylcellulose, aerosil and carboxymethylcellulose sodium salt. Also, invention discloses a method for preparing this formulation. Invention provides preparing the formulation eliciting high rate and fullness in releasing an active substance in the human body, stability of quality indices for all fitness period and allowing the effective usage in manufacturing the medicinal agent. Invention can be used in treatment hypertension, stenocardia, myocardium ischemia and chronic cardiac insufficiency.

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

5 cl, 1 tbl, 4 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

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

21 cl, 70 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

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

21 cl, 70 ex

FIELD: medicine, chemistry of peptides.

SUBSTANCE: invention proposes a new anti-arrhythmic agent that represents a peptide ligand of opioid receptors deltorphine D - compound of the formula (I): Tyr-D-Leu-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-His-Ser-Ile-NH2 (I). The effect of this agent is associated with stimulation of opioid receptors and results to reducing frequency in arising multiple ventricular extrasystoles and episodes of ventricular tachycardia.

EFFECT: valuable medicinal properties of agent.

1 tbl, 1 ex

The invention relates to medicine, in particular to andrology, and can be used for the treatment of menopausal syndrome in men
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