5-aminoalkylpyrazolo[4,3-d]pyrimidines

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to 5-aminoalkylpyrazolo[4,3-d]pyrimidines of the general formula (I): wherein R1 and R2 are similar or different and represent independently of one another (C1-C8)-alkyl group; 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 groups, (C1-C8)-alkoxy-, amino-, mono-(C1-C8)-alkyl-amino-, di-[(C1-C8)-alkyl]-amino-, N-morpholino- or pyridyl groups or in common with nitrogen atom to which they are bound form unsaturated heterocyclic ring that comprises optionally one or more additional atoms of nitrogen and/or oxygen and substituted with one or more hydroxyl, (C1-C8)-alkylol, (C1-C6)-oligohydroxyalkyl, amino-, mono-[(C1-C8)-alkyl]-amino- or di-[(C1-C8)-alkyl]-amino-groups. Proposed compounds inhibit activity of cGMP-phosphodiesterase and can be used in treatment of states of cardiovascular system and for treatment in potency disturbances. Also, invention relates to a medicinal preparation used for inhibition of activity of cGMP-phosphodiesterase based on indicated compounds, a method for preparing compounds of the formula (I) and a method for preparing the medicinal preparation.

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

7 cl, 15 ex

 

The present invention relates to 5-aminoalkylindole[4,3-(1]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 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 are 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 thieno[3-d]pyrimidines for the treatment of cardiovascular conditions and impotence is described in the German application, under the code of 19644228.1.

Finally, in the German application with cipher 19942474.8 described the use of pyrazolo[4,3-d]pyrimidines having the General formula

The substituents R1for R4represent a hydroxyl group, various alkyl, alkoxy or halogen groups, or hydrogen. X represents either cycloalkyl group, or cycloalkenyl group having from 5 to 12 atoms, phenyl or phenylmethylene group, or a 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 all the groups mentioned above for the substituent X, monogamist group: -COOH, C(O)O(C1-C6-alkyl), -C(O)NH2-C(O)NH[(C1-C6-alkyl), -C(O)N(C1-C6-alkyl)2 or-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, R7are the same or different and independently from each other represent hydrogen or C1-C8is an alkyl group,

R3, R4are dinasovymi or different and independently of one another represent hydrogen, 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, C1-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 more C1-C8-alkyl, hydroxyl, C1-C8-alkoxy, C1-C8-alkylamine, C1-C8-oligosiloxane, amino, mono(C1-C8-alkyl)amino, di(C1-With8-alkyl)amino, -SO2R7or-C(O)R7groups,

R7is the th C 1-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 5-aminoalkylindole[4,3-d]pyrimidines of the formula (I), as well as their physiologically tolerated salts have advantageous pharmacological properties.

In particular, the molecules of the General formula (I) show specific inhibition of 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 can be performed, 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 and others in J.Urol., 150, p. 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, R2different and are selected from the group consisting of hydrogen and linear or branched (C1-C4)-alkyl groups, R1in particular, is a metal or ethyl group, and R2in particular, is a sawn or boutelou 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, Panteleeva, ethylenoxy, metalinox or Ethylenedioxy.

The radicals R5and R6may be the same or different and is ezavisimo from each other represent hydrogen or C 1-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 suitable salts are, 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, isonicotinamide acid, methane - and econsultancy acid, ethicality acid, naphtalene - and-disulfonate acid, and louisanna acid.

For the application of the Oia as 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 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 in the derivative solutions moreover, 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 specific activity of the applied compounds of 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 (a) according to the invention are produced by reaction of the corresponding 5-kilometersa[4,3-d]pyrimidine of the General formula (IIa) with suitable alkylamino formula (III), as shown in the following equation (1).

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 (1) 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, ethers, 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 acetamide", she dimethylacetamide, N-organic and dimethylformamide, NITRILES such as acetonitrile, sulfoxidov, such as dimethylsulfoxide, nitro compounds such as nitromethane and microbe is angry 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.

5-kilometersa[4,3-d]pyrimidines of General formula (IIa) can be obtained from the corresponding 4-chloropyrazole[4,3-d]pyrimidines 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 19942474.8. The described 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 7-(3-chloro-4-methoxybenzylamine)-5-chloromethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine in 10 ml of DMF is treated with 5 ml of 3-aminopropanol and stirred at room temperature for two hours. Then diluted with water and extracted with ethyl acetate. Received after the traditional processing of the product in the form of oil dissolved in alcohol HCl and treated with ethyl acetate is added to turbidity. The precipitated crystals are filtered with suction and recrystallized from isopropanol/ethyl acetate. 3.1 g of 7-(3-chloro-4-methoxybenzylamine)-5-(3-hydroxypropylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine receive in the form of its dihydrochloride.

TPL=207°C.

Example 2

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 7-(3-chloro-4-methoxybenzylamine)-5-(4-hydroxypiperidine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine was obtained in the form of its dihydrochloride.

TPL=206°C.

Example 3

The reaction was carried out as described in Example 1, with the equivalent of what kolichestvo 2-hydroxyethylamine instead of 3-aminopropanol.

After treatment of the corresponding acid 7-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxyethylaminomethyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine was obtained in the form of its dihydrochloride.

TPL=201°C.

Example 4

The reaction was carried out as described in Example 1 with an equivalent amount of N-(2-hydroxyethyl)piperazine instead of 3-aminopropanol.

After treatment of the corresponding acid 7-(3-chloro-4-methoxybenzylamine)-5-(N-(2-hydroxyethyl)piperidinomethyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine was obtained in the form of his trihydrochloride.

TPL=176°C.

Example 5

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 7-(3-chloro-4-methoxybenzylamine)-5-(3-methoxypropylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-dipyrimidine received in the form of his trihydrochloride.

TPL=211°C.

Example 6

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

After treatment of the corresponding acid 7-(3-chloro-4-methoxybenzylamine)-5-(N,N-diethylaminoethylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine then received in the form of his trihydrochloride.

TPL=223°C.

The following compounds were obtained analogously:

(3-chloro-4-methoxybenzyl)(1-is ethyl-3-propyl-5-{[(pyridine-3-ylmethyl)-amino]methyl}-1H-pyrazolo[4,3-d]pyrimidine-7-yl)Amin

5-{[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]amino}pentane-1-ol

3-{4-[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]piperazine-1-yl}propane-1,2-diol

(3-chloro-4-methoxybenzyl)-[4-(4-dimethylaminopyridine-1-ylmethyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7-yl]amine

2-{[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]ethylamino}ethanol

(3-chloro-4-methoxybenzyl)-{1-methyl-5-[(2-morpholine-4-ylethylamine)methyl]-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7-yl]amine

(2S,3S,4S,5R)-6-{[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-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 2N 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 compounds the Oia.

Example: Solution

A solution is prepared from 1 g of the active compounds of formula (I), 9,38 g NaH2PO4·2H2O, 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 kg of potato 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 ASEP is automatic 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

1. 5-Aminoalkylindole[4,3-d] pyrimidines of the formula (I):

in which

R1, R2are the same or different and independently of one another represent C1-C8is an alkyl group;

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 groups, C1-C8-alkoxy, amino, mono(C1-C8-alkyl)amino, di(C1-C8-alkyl) amino, N-morpholino or peredelnoj groups or together with the nitrogen atom to which they are linked, form a saturated heterocyclic ring, colorareofferte contains one or more additional nitrogen atoms and/or oxygen and which is substituted by one or more hydroxyl, With1-C8-alkylamine,1-C6-oligosiloxane, amino, mono(C1-C8alkyl)amino or di(C1-C8alkyl)amino groups.

2. The compound according to claim 1, characterized in that

R1, R2different and are selected from the group consisting of linear or branched (C1-C4)alkyl groups, R1in particular represents a methyl or ethyl group, a R2in particular represents sawn or boutelou group,

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 a linear or branched C1-C6-alkoxygroup or halogen,

R5, R6may be the same or different and independently from each other represent hydrogen, C1-C6is an alkyl group which is unsubstituted or substituted by one or more hydroxyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, peredelnoj or N-morpholinopropan, or R5, R6form together with the nitrogen atom to which they relate, piperidinyl or piperazinilnom ring, optionally substituted by one or more hydroxyl groups or With1-C2-alkylamino the sing.

3. The compound of formula (I) according to claim 1, selected from 7-(3-chloro-4-methoxybenzylamine)-5-(3-hydroxypropylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine,

7-(3-chloro-4-methoxybenzylamine)-5-(4-hydroxypiperidine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine,

7-(3-chloro-4-methoxybenzyl-amino)-5-(2-hydroxyethylaminomethyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d)pyrimidine,

7-(3-chloro-4-methoxybenzylamine)-5-(N-(2-hydroxyethyl)piperidinomethyl)-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine,

7-(3-chloro-4-methoxybenzylamine)-5-(3-methoxypropylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine,

7-(3-chloro-4-methoxybenzylamine)-5-(N,N-diethylaminoethylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine,

(3-chloro-4-methoxybenzyl)(1-methyl-3-propyl-5-{[(pyridine-3-ylmethyl)-amino]methyl}-1H-pyrazolo[4,3-d]pyrimidine-7-yl)amine,

5-{[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidine-5-ylmethyl]amino}pentane-1-ol,

3-{4-[7-(3-chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]piperazine-1-yl]propane-1,2-diol,

3-chloro-4-methoxybenzyl)[5-(4-dimethylaminopyridine-1-ylmethyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7-yl]amine,

2-{[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]ethyl-amino}ethanol

(3-chloro-4-methods dibenzyl){1-methyl-5-[(2-morpholine-4-ylethylamine)methyl]-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7-yl}amine,

(2S,3S,4S,5R)-6-{[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]-methylamino}hexane-1,2,3,4,5-pentola or one of their physiologically acceptable salts.

4. Drug comprising the compound according to one of claims 1 to 3 or one of its physiologically acceptable salts for the inhibition of C-GFM phosphodiesterase.

5. The drug according to claim 4, including a connection from the group consisting of

7-(3-chloro-4-methoxybenzylamine)-5-(3-hydroxypropylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine,

7-(3-chloro-4-methoxy-benzylamino)-5-(4-hydroxypiperidine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine,

7-(3-chloro-4-methoxybenzylamine)-5-(2-hydroxyethylaminomethyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidine,

7-(3-chloro-4-methoxybenzylamine)-5-(N-(2-hydroxyethyl)piperidinomethyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidine,

7-(3-chloro-4-methoxybenzylamine)-5-(3-methoxypropylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine,

7-(3-chloro-4-methoxybenzylamine)-5-(N,N-diethylaminoethylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine,

(3-chloro-4-methoxybenzyl)(1-methyl-3-propyl-5-{[(pyridine-3-ylmethyl)amino]-methyl}-1H-pyrazolo[4,3-d]pyrimidine-7-yl)amine,

5-{[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]AMI is about}pentane-1-ol,

3-{4-[7-(3-chloro-4-methoxybenzyl-amino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]-piperazine-1-yl]propane-1,2-diol,

(3-chloro-4-methoxybenzyl)[5-(4-dimethylaminopyridine-1-ylmethyl)-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidine-7-yl]amine,

2-{[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]ethylamino}ethanol

(3-chloro-4-methoxybenzyl){1-methyl-5-[(2-morpholine-4-ylethylamine)methyl]-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-7-yl}-amine,

(2S,3S,4S,5R)-6-{[7-(3-chloro-4-methoxybenzylamine)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine-5-ylmethyl]methyl-amino}hexane-1,2,3,4,5-pentola or one of their physiologically acceptable salts.

6. The method of obtaining 5-aminoalkylindole[4,3-d] pyrimidines according to one of claims 1 to 3, characterized in that 5-kilometersa[4,3-d] pyrimidine of the General formula (IIa)

in which the substituents R1for R4have the meanings indicated in claim 1,

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.

7. The method of obtaining a medicinal product intended for the inhibition of C-GMP phosphodiesterase, characterized in that the compound according to claims 1 to 3 is whether one of its physiologically acceptable salts of lead in a suitable dosage form, at least one suitable excipient or the media.



 

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FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes phenyl-substituted heterocyclic 1,3-ketoenols of the formula (I): wherein R1 and R3 mean independently of one another ethyl or (C1-C2)-alkoxy-group; Q means the group of the formula (Q1): or (Q2): wherein R4 and R5 in common with atoms to which they are joined form 5-7-membered cycle that can comprise additionally anellated alkylene chain consisting of 2-6 carbon atoms that, in turn, can comprise two heteroatoms taken among oxygen atom, and indicated cycle can be substituted with halogen atom, hydroxy-group, (C1-C6)-alkoxy-group, (C1-C6)-alkoxy-(C1-C6)-alkoxy-group, (C1-C4)-alkylcarbonyloxy-group, hydroxy-(C1-C4)-alkoxy-group, hydroxycarbonyl-(C1-C2)-alkoxy-group, methoxycarbonyl-(C1-C2)-alkoxy-group, methoxyimino-, methoxyethoxyethoxy-group; R6 and R7 means (C1-C10)-alkyl; R8 means hydrogen atom; X means oxygen atom; R20 means (C1-C10)-alkyl, and also agronomically acceptable salts and isomers of these compounds. Also, invention describes a method for preparing compounds of the formula (I), herbicide agent and a method for control of weed growth based on compounds of the formula (I). Invention provides preparing compounds possessing the herbicide activity.

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

5 cl, 28 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, amino acids, medicine, pharmacy.

SUBSTANCE: invention relates to using derivatives of cysteine for preparing a medicinal agent. The proposed agent is designated for treatment of diseases arising as a result of formation of heterotrimeric protein G, and to new derivatives of cysteine, and pharmaceutical composition based on thereof. Derivatives of cysteine, in particular, involve the following compounds: bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[2,2a]-pyrazine]-disulfide and bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-2-91-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo-[1,2a]-pyrazine-7-yl]-disulfide. Invention provides high effectiveness of treatment.

EFFECT: valuable medicinal properties of compounds.

6 cl, 7 dwg, 2 tbl, 7 ex

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

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to a heteroarylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone taken among of compounds order corresponding to the formula (I): wherein a subscript symbol n mans a whole number 1; R1 means (C1-C6)-alkyl (substituted with one or two substitutes taken among group involving hydroxy group, (C1-C6)-alkoxy group and others), piperidinyl-(C0-C4)-alkyl [wherein piperidinyl fragment is monosubstituted optionally with benzyl, carbamoyl, (C1-C4)-alkane sulfonyl, (C1-C6)-alkyl and so on], morpholinyl-(C0-C4)-alkyl, tetrahydropyranyl-(C0-C4)-alkyl, 2-oxoimidazolidinyl-(C0-C4)-alkyl, 2-oxopyrrolidinyl-(C0-C4)-alkyl or 1,1-dioxotetrahydrothienyl-(C0-C4)-alkyl, (C3-C6)-cycloalkyl (monosubstituted with monohydroxy group, (C1-C6)-alkoxy group and so on), 1,4-dioxaspiro[4,5]decane-8-yl, 2,4-dione-1,3-diazaspiro[4,5]decane-8-yl or (3-hydroxymethyl-3-methyl)-1,5-dioxaspiro[5,5]undecane-9-yl; R2 means (C1-C4)-alkyl, halogen atom; R3 means hydrogen atom, (C1-C6)-alkyl (optionally substituted with one or two substitutes taken among group involving (C1-C4)-alkoxy group, pyrrolidinyl, di-(C1-C4-alkyl)-amino-group and so on), phenyl, benzyl or piperidinyl (N-substituted optionally with (C1-C4)-alkyl); R4 means hydrogen atom, and also its individual isomers, racemic and nonracemic mixtures of isomers, prodrugs and its pharmaceutically acceptable salts. Also, invention proposes a pharmaceutical composition possessing inhibitory activity with respect to activity of p38 MAP kinase. The composition comprises a heteroalkylamino-derivative of dihydropyrimido[4,5-d]pyrimidinone of the formula (I), isomer, racemic or nonracemic mixture of isomers or its pharmaceutically acceptable salt in mixture with at least one pharmaceutically acceptable vehicle. Invention provides representing a heteroalkylamino-substituted derivative of dihydropyrimido[4,5-d]pyrimidinone possessing inhibitory activity with respect to activity of p38 MAP kinase.

EFFECT: valuable biochemical properties of compounds and composition.

14 cl, 4 tbl, 90 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry, pharmacy.

SUBSTANCE: invention describes alkylamino-substituted bicyclic nitrogen-containing heterocycles of the general formula (I):

wherein n = 1; R1 means (C1-C6)-alkyl; R2 means halogen atom; R3 means (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylsulfonyl-(C1-C6)-alkyl, hydroxy-(C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, N-heterocyclyl-(C1-C6)-alkyl or (C1-C6-alkylene)-C(O)R31 wherein R31 means hydroxy- or (C1-C6)-alkoxy-group, and its pharmaceutically acceptable salts. New compounds are inhibitors of protein kinase p38 and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

8 cl, 13 ex

FIELD: medicine, experimental cardiopharmacology.

SUBSTANCE: in an experiment one should intragastrically introduce APP inhibitor analapryl for laboratory animal at endothelial dysfunction, at the background of its modeling, at the dosage of 0.5 mg/kg and intraperitoneally - L-arginine at the dosage of 200 mg/kg once daily. This enables to activate correction of endothelial dysfunction due to enhancing enzymatic NO formation, L-carnitine being its donator.

EFFECT: higher efficiency of correction.

1 ex, 2 tbl

FIELD: medicine, therapy.

SUBSTANCE: invention relates to a method for treatment of arterial hypertension. Method involves administration of one or some medicinal preparations in biorhythmical sequence taken among the following order: papaverin, common wormwood tincture - at 7.00 - 9.00 a. m.; thrombo-ACC, rheopro, clopidogrel - at 9.00 - 11.00 a. m.; No-Spa - at 11.00 a. m.; trental - at 11.15 a. m.; atenolol, propranolol, metoprolol, nifedipin, verapamil, cordaron, valerian, motherwort - at 11.30 a. m.; polyvitamins, fenules - at 1.00 p. m.; No-Spa - at 4.00 p. m.; trental - at 4.15 p. m.; hypothiazid, furosemid, verospiron, captopril, enalapril, prestarium, quinapril, ramipril, losartan, valsartan - at 4.30 p. m.; No-Spa - at 7.00 p. m.; trental - at 7.15 p. m.; atenolol, propranolol, metoprolol, nifedipin, verapamil, cardura, valerian, motherwort, phenazepam, coaxil, paxil - at 7.30 p. m.; ginseng - at 9.00 p. m.; Essentiale, simvastatin, lovastatin - at 11.00 p. m. Method provides recovery of levels synchronization in organization of organ-forming systems that allows carrying out the effect on the arterial pressure value in the corresponding time of day.

EFFECT: improved treatment method.

1 tbl, 2 dwg, 1 ex

FIELD: organic chemistry of heterocyclic compounds, biochemistry.

SUBSTANCE: invention relates to new ortho-substituted and N-substituted indoles of the formula (α): or (β): or their pharmaceutically acceptable salts wherein Z1 represents -CR4 or nitrogen atom (N); R4 means hydrogen atom (H), (C1-C6)-alkyl comprising optionally oxygen atom (O) or nitrogen atom (N) possibly substituted with halogen atom, keto-group, 5-6-membered cycloaliphatic radical possibly comprising 1-2 oxygen atoms (O) or nitrogen atom (N); Z2 represents -CH or -CR wherein R means (C1-C6)-alkyl; R1 means compound of the formula: wherein X1 means -CO or its isostere; m = 0, 1; Y represents alkyl that can be substituted; or two Y form in common (C2-C3)-alkylene; n = 0, 1 or 2; Z3 represents -CH; X2 represents -CH, -CH2 or their isostere; Ar represents one or two phenyl groups bound with X2 wherein phenyl can be substituted; R2 represents hydrogen atom (H), (C1-C6)-alkyl or aryl wherein each aryl comprises, possibly, oxygen atom (O) or nitrogen atom (N) and can be substituted. Proposed compounds are selective inhibitors of p38α kinase.

EFFECT: valuable biochemical properties of compounds.

34 cl, 5 tbl, 23 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to physiologically acceptable L-carnitine and alkanoyl L-carnitine salts characterizing by nonhygroscopicity and stability used in preparing solid formulations and suitable for oral using. Invention proposes L-carnitine or alkanoyl L-carnitine salt with taurine chloride represented by the general formula (I): wherein R represents hydrogen atom or lower linear or branched alkanoyl comprising from 2 to 5 carbon atoms. Invention provides the development of stable nonhygroscopic L-carnitine and lower alkanoyl L-carnitine salts that are valuable supplements in human diet nutrition and animals under normal physiological state and good health, and also in low absorption syndrome occurring in children and adults, and in the development of the food composition supplement.

EFFECT: improved and valuable properties of compositions.

8 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for prophylaxis of oncological diseases, or infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. In the first embodiment of invention blood extracellular DNA destroying agent, such as DNAase, is administered into blood. In the second embodiment agent, binding to blood extracellular DNA, such as anti-DNA antibody is administered into blood. According to the third embodiment enzyme altering of blood extracellular DNA chemical structure is administered into blood. According to the forth embodiment agent, stimulating synthesis and/or activity of endogenic deoxyribonuclease or agent stimulating synthesis of antibody binding to blood extracellular DNA are administered into blood.

EFFECT: effective method for treatment of abovementioned diseases without side effects when prolonged using of preparation affected on blood extracellular DNA.

7 cl, 11 tbl, 18 ex, 5 dwg

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for treatment of diseases, associated with alterations of blood extracellular DNA, such as generalized infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. Method includes administering of blood extracellular DNA destroying agent into blood. As such agent DNAase is used, in particular in doses providing alteration of electrophoretic profile of blood extracellular DNA, detectable by pulse gel electrophoresis. DNAase may be administrated in doses and regimes providing exceeded levels of blood plasma DNA-hydrolytic activity, namely 150 Kuntz/l of plasma, during 12 h/day in total.

EFFECT: effective method for treatment of abovementioned diseases without side effects.

4 cl, 14 tbl, 15 ex, 5 dwg

FIELD: medicine.

SUBSTANCE: the present innovation deals with increasing life duration period due to deteriorating the onset of aging-associated sick states. For this purpose, it is necessary to introduce an agent that inactivates extra-cellular blood DNA into blood circulation. AS such an agent one should apply DNAse, antibody anti-DNA, enzymes that alter chemical structure of extra-cellular blood DNA, and, also, agents that stimulate synthesis or activity of endogenous DNAse or that of antibodies that bind extra-cellular blood DNA. The method provides high therapeutic effect in case of no direct impact upon genetic apparatus of aging cells.

EFFECT: higher efficiency.

6 cl, 8 ex, 4 tbl

FIELD: medicine, in particular cardiovascular diseases treatment.

SUBSTANCE: the object of present invention is to provide products containing polyphenols and L-arginine having healthy action of mammalians. Foodstuff and pharmaceutical composition contain procyanidins of cocoa and/or nuts in combination with L-arginine. Said composition represent effective inducers for physiological enhancement of nitrogen oxide production in mammalian. Foodstuff optionally contains chocolate or nut procyanidin. As chocolate dark or milky nut-containing chocolate is used. Natural or synthetic products may be used as procyanidins. As L-arginine sources nut mass, nut paste and/or nut flour, seeds, seed paste and/or seed flour, or gelatin may be used. Abovementioned compositions also are useful in treatment of cardiovascular diseases wherein effective dose is calculated on the base of procyanidin content.

EFFECT: composition having advantageous action of organism, in particular with vasorelaxation effect.

107 cl, 17 tbl, 19 ex

FIELD: medicinal pharmacology.

SUBSTANCE: the present innovation deals with minor peptides which could be characterized with the following formula: X-A-B-C-Y-NH2, where X - α-aminoisobutiryl, tranexamyl (i.e.4-(aminomethyl)cyclo-hexane carbonyl), isonipecotinyl, γ-aminobutiryl, hydrogen or imidazolylacetyl, A - D-2-methyltryptophan, D-β-(2-naphthyl)alanine or D-tryptophan, B - D-2-methyltryptophan, D-β-(2-naphthyl)alanine, D-tryptophan or is absent, C - D-2-methyltryptophan, phenylalanine or is absent, Y - lysine or arginine, where D means dextroisomer, or pharmaceutically acceptable salt of peptide that induces penile erection. Also, pharmaceutical composition is suggested that contains these peptides, and methods for treating erectile dysfunctions.

EFFECT: higher efficiency.

12 cl, 7 ex

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