Crystalline dihydrochloride 3-[2-[4-(3-chloro-2-were)- 1-piperazinil]ethyl]-5,6-dimethoxy-1- (4-imidazolidinyl)-1h - indazole and a 3.5-hydrate, methods for their production

 

(57) Abstract:

Crystals 3.5-hydrate of the dihydrochloride 3-[-2-[4-(3-chloro-2-were)-1-piperazinil] ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-N-indazole having certain characteristics x-ray diffraction, have excellent characteristics as a pharmaceutical material, which has high storage stability. 5 S. and 2 C.p. f-crystals, 4 Il., table 2.

This invention relates to the dihydrochloride, which is also containing a water molecule hydrate, 3-[2-[4-(3- chloro-2-were)-1-piperazinil]ethyl]-5,6-dimethoxy - 1- (4-imidazolidinyl)-1H-indazole represented by the formula (1):

< / BR>
and to its method of production, and also refers to the use of hydrate in the treatment of humans or animals or to obtain pharmaceutical preparations.

Background of the invention

Has been disclosed, for example in U.S. patent 3362956 that certain derivatives of indazole have an effect on the Central nervous system, for example, have antianxiolytic activity, anti-epileptic activity and the like. There is also a description in Arzneim.-Forsch., 37 (4), 498-502 (1987), saying that certain derivatives of piperazine have the funk is m, its salts and hydrates are also new compounds. It was shown that this compound is represented by formula (1) and its salt can be a strong inhibiting calmodulin action and also show excellent protective effect on the brain in animal models of various cerebral disorders. As a result of this expected use of this compound for the prevention and treatment of various diseases caused by excessive activation calmodulin, and brain damage caused by ischemic disease of the brain, degenerative disease of the brain, traumatic disease of the brain, drug intoxication, hypoxia, and the like.

Anhydrous hydrochloride compounds of formula (1) can be obtained by carrying out the deposition of crystals of the free base from a mixture of organic solvent and hydrochloric acid. However, it was found that the crystals of the anhydrous compound, thus obtained, free of any organic solvent used to precipitate crystals, and the solvent contained in the crystals cannot be easily removed even by drying by heating under reduced pressure. For example, if IP is the azone from 18000 to 33,000 M. D. It was shown that the prediction of the amount of the solvent contained in the crystals, and its regulation to the specified level, it is difficult to perform.

On the other hand, when the deposition of crystals in the solvent used methanol thus obtained anhydrous hydrochloride compounds of formula (1) also contained methanol, but can be removed contained methanol almost completely when the crystals were dried by heating (120oC) under reduced pressure for several days or more. However, the anhydrous hydrochloride, obtained by removing the methanol thus demonstrated the ability to absorb moisture as a response to humidity environment at room temperature (showed the ability to absorb moisture when the humidity is high, but releases moisture when the humidity is low, see Fig. 1).

Thus, it was found that the anhydrous crystals of the hydrochloride of the compound of formula (1) cannot easily be prepared in the form of pharmaceutical preparations, because they cause different problems, so they are not suitable as pharmaceutical material.

Description of the invention

The purpose of this invention is obespecheniy free from the above problems and has excellent characteristics as a pharmaceutical material, having a high storage stability. To achieve this goal, the authors of this invention have conducted intensive research.

In the result, to our surprise, it was found that the hydrochloride hydrate 3-[2-[4-(3- chloro-2-were)-1-piperazinil]ethyl]-5, 6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole has no flaws its anhydrous hydrochloride and completely stable when stored at normal ambient conditions. This hydrate is a crystal form of a 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1 - piperazinil] ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H - indazole represented by the formula (2):

< / BR>
(sometimes referred to hereafter simply the 3.5-hydrate of the dihydrochloride).

Accordingly, the present invention relates to the crystal dihydrochloride 3-[2-[4-(3-chloro-2 - were)-1-piperazinil] ethyl]-5,6-dimethoxy-1-(4 - imidazolidinyl)-1H-indazole, which essentially has the following characteristics x-ray diffraction (x-ray).

The value of d of the lattice parameter relative intensity

28,1 - average

27,5 - average

27,0 - average

26,4 - average

25,6 - average

25,3 - strong

24,7 - average

24,3 - strong
13,8 - average

9,60 is very strong

a 9.09 - very weak

8,46 - average

This invention relates also to the above-mentioned crystal in which crystal dihydrochloride 3-[2-[4-(3-chloro-2 - were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H - indazole is a 3.5-hydrate.

This invention relates also to a method for 3.5-hydrate of the dihydrochloride 3- [2-[4-(3-chloro-2-were)-1-piperazinil]ethyl]-5,6 - dimethoxy-1-(4-imidazolidinyl)-1H-indazole, which includes

a) the processing of free-form 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazole hydrochloric acid in the presence of water or

b) processing hydrochloride hydrate 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazole, which is a hydrate and/or a hydrochloride, less than 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil]ethyl]-5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazole, water and/or hydrochloric acid, or

(C) removing water and/or hydrochloric acid from the hydrochloride hydrate 3-[2-[4-(3-chloro-2-were)-1 - piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H - indazol that Alamaty]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H - indazole, want to receive, or

(d) processing of salt 3-[2-[4-(3-chloro-2-were)-1-piperazinil]-ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole non hydrochloride, water, and hydrochloric acid.

This invention relates also to a method for producing dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] - ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole essentially has the following characteristics x-ray diffraction (x-ray).

The value of d of the lattice parameter relative intensity

28,1 - average

27,5 - average

27,0 - average

26,4 - average

25,6 - average

25,3 - strong

24,7 - average

24,3 - strong

22,0 - strong

21,4 - weak

20,9 - average

19,3 - very weak

17,8 - average

15,4 - average

13,8 - average

9,60 is very strong

a 9.09 - very weak

8,46 - average

which includes

a) the processing of free-form 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6 - dimethoxy-1-(4-imidazolidinyl)-1H-indazole hydrochloric acid in the presence of water or

b) processing hydrochloride hydrate 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1 - orida 3-[2-[4-(3-chloro-2-were)-1-piperazinil]ethyl]-5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazole, water and/or hydrochloric acid, or

c) removing water and/or hydrochloric acid from the hydrochloride hydrate 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole, which is a hydrate and/or a hydrochloride more than 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] -ethyl] -5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazol that you want to get, or

(d) processing of salt 3-[2-[4-(3-chloro-2-were)-1-piperazinil]-ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole non hydrochloride, water, and hydrochloric acid.

This invention relates to the above method of production, in which the crystal hydrochloride 3-[2-[4-(3-chloro-2 - were)-1-piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)- 1H-indazole is a 3.5-hydrate.

This invention relates also to the above method of production, in which free form 3-[2-[4-(3-chloro-2-were)-1-piperazinil]ethyl]-5,6 - dimethoxy-1-(4-imidazolidinyl)-1H-indazole treated with hydrochloric acid in the presence of water.

This invention relates also to the above method of production, in which the hydrate hydrochloride 3-[2-[4-(3-chlorine-hydrochloridum, less than 3.5-hydrate of the dihydrochloride 3-[2- [4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy - 1-(4-imidazolidinyl)-1H-indazole process water and/or hydrochloric acid.

This invention relates also to the above method of production, which removes water and/or hydrochloric acid from hydrate hydrochloride 3-[2-[4- (3-chloro-2-were)-1-piperazinil] ethyl]-5,6-dimethoxy-1-(4 - imidazolidinyl)-1H-indazole, which is a hydrate and/or a hydrochloride larger than the 3.5-hydrate of the dihydrochloride 3-[2-[4-(3- chloro-2-were)-1-piperazinil] ethyl]-5,6-dimethoxy-1-(4 - imidazolidinyl)-1H-indazol that you want to receive.

This invention relates also to the above method of production, in which salt 3-[2-[4-(3-chloro-2 - were)-1-piperazinil]ethyl]-5,6-dimethoxy-1-(4 - imidazolidinyl)-1H-indazol, which is not a hydrochloride, is treated in the presence of water and hydrochloric acid.

On the other hand, this invention relates also to the 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1 - piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1 - indazole;

the above compound, which is used in the treatment of humans and animals;

the above magkasundo connection or above the crystal, which is used in the treatment of brain diseases;

the use of the above compounds or the above-mentioned crystal in the preparation of pharmaceutical preparations;

the use of the above compounds or the above-mentioned crystal in the preparation of pharmaceutical preparations used in the treatment of brain diseases;

pharmaceutical preparation, which contains a 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole and at least one pharmaceutically acceptable carrier;

pharmaceutical preparation, which contains crystals of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1 - piperazinil] ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H - indazole essentially has the following characteristics x-ray diffraction (x-ray).

The value of d of the lattice parameter relative intensity

28,1 - average

27,5 - average

27,0 - average

26,4 - average

25,6 - average

25,3 - strong

24,7 - average

24,3 - strong

22,0 - strong

21,4 - weak

20,9 - average

19,3 - very weak

17,8 - average

15,4 - cf is re one pharmaceutically acceptable carrier;

the above-mentioned pharmaceutical preparation in which the crystal dihydrochloride 3-[2-[4-(3-chloro-2-were)-1 - piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H - indazole is a 3.5-hydrate;

the above pharmaceutical drug in which the drug is used to treat diseases caused by excessive expression of calmodulin; and

the above pharmaceutical drug in which the drug is used for treatment of brain diseases.

Below the invention is described in detail.

To our surprise, it was found that 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl]-5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazole of the present invention represented by the formula (2), has the following properties. That is, the hydrate did not show changes in its powder x-ray or detectable water content, when the relative humidity was changed in the range from about 20% to about 80% at 25oC (Fig. 2). Hardly were found changes in his appearance and were not found changes in its structure (defined IHVR) under conditions of dry heat (50oC, tightly sealed flask, 1 month) or humid heat (40Yong formula (2) compounds of formula (1) has excellent storage stability. Consequently, this means that this product can be stored for an extended period of time without changes. In particular, this product does not absorb water molecules, other than those contained a 3.5-dehydrate, so that the amount of active ingredient contained as a pharmaceutical drug, does not change during storage. In addition, it was found that it does not contain an organic solvent in the crystals as in the case of anhydrous form.

Crystals 3.5-hydrate of the dihydrochloride of the formula (2) can be characterized by their powder x-ray, for example, they demonstrate the range of Fig. 3 and its characteristic peaks.

the 3.5-Hydrate of the dihydrochloride of the formula (2) is further characterized by their elemental analysis, which corresponds to theoretical value of its molecular formula C26H31ClN6O22HCl 3,5 H2O (molecular weight: 631,00).

Calculated: 49,49%, H 6,39%; N 13,32%; Cl 16,86%.

Found: 49,22%, H 6.38 Per Cent; N To 13.09%; Cl 16,85%.

The water content of 3.5-hydrate of the dihydrochloride of the formula (2) corresponds to its theoretical value when measured by the Karl Fischer method.

Calculated: 9,99%.

Found: 10.53 per cent.

t dihydrochloride of the formula (2) can be obtained by way selected from the following methods.

a) the Way in which free form 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazole treated with hydrochloric acid in the presence of water.

b) the Way in which the hydrate hydrochloride 3-[2-[4-(3-chloro-2 - were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4 - imidazolidinyl)-1H-indazole, which is a hydrate and/or a hydrochloride smaller than 3.5-hydrate of the dihydrochloride 3-[2-[4- (3-chloro-2-were)-1-piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazol that you want to receive, process water and/or hydrochloric acid.

C) the Way in which water and/or hydrochloric acid is removed from the hydrate hydrochloride 3-[2-[4-(3-chloro-2-were) - 1-piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H - indazole, which is a hydrate and/or a hydrochloride larger than the 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were) -1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H - indazol that you want to get, for example, neutralization, drying and the like.

d) the Way in which salt 3-[2-[4-(3-chloro - 2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4 - imidazolidinyl)-1H-indazole, not everebody, processing can be performed after the connection is obtained in a free form.

When carrying out the above processing, if the occasion requires, you can use organic solvents. The most typical to use the solvents are alcohols and, when one considers the toxicity of the desired ethanol or propanol, the most desirable ethanol.

Performing the processing means to allow the compound to react with hydrochloric acid in the presence of water, to make the formation of crystals of the expected hydrochloride hydrate. It can be done in a state of suspension, but it is usually desirable to carry out the processing in solution. In this case, you can use a purification step, for example by the addition of activated charcoal.

When neutralized hydrochloride containing more hydrochloric acid than in the case dihydrochloride, or an acid additive salt, other than a hydrochloride salt can be neutralized by reaction with hydroxide, carbonate, bicarbonate, alkoxide or a similar compound of an alkali metal in solution. Therefore, a compound in the free form can be obtained commonly used way, if you wire the slots (hydrogen chloride) or water can be effective in some cases, depending on their properties, to get the first free form and then turn it into an interesting connection, and not to obtain crystals neutralization, drying and the like.

When the free form of crystals containing less hydrochloric acid into the hydrochloride, hydrochloric acid can be used in amounts that are included in the range from equal to the equivalent of up to 3 equivalentto, usually in the range from 1.5 to 2 equivalents. The amount of water that you want to use, about 2-20 times greater than the mass of crystals that you want to use, preferably exceeds the mass of crystals in 3-5 times. (When 2 ml of water are used per 1 g of the crude crystals, which means the excess of 2 times).

The preferred method of obtaining a 3.5-hydrate of the dihydrochloride is the way in which the appropriate amount of 1N hydrochloric acid and water is added to the compound of formula (1) in a free form, the mixture is dissolved by heating, and the thus obtained homogeneous solution was then cooled to room temperature under stirring, thereby effecting crystallization of the target connection is no action not only in his oral introduction, but also when it is parenteral, in particular intravenous injection. Consequently, it can be administered as oral and parenteral methods.

Dosage of 3.5-hydrate of the dihydrochloride of the present invention may optionally be changed depending on symptoms, age, weight, and similar parameters of the patient. In General, the dose for oral administration may be in the range from 1 mg to 1000 mg, preferably from 10 mg to 500 mg, per day for an adult. Examples of dosage forms include tablets, capsules, powders, granules and the like. They can be obtained by known methods for the preparation of compositions together with conventional fillers, lubricating agents, binding agents, and like additives. In the case of parenteral administration, the dose may be in the range from 1 mg to 500 mg, preferably from 10 mg to 250 mg per day for an adult, which you can enter the subcutaneous or intravenous injection or drip infusion.

The pharmaceutical preparation which contains the dihydrochloride, a 3.5-hydrate of the present invention represented by the formula (2), when used in combination with other drugs, will provide updat who's tools include a tool, improves cerebral circulation (maleate cinepazide or a similar tool), a tool that improves cerebral metabolism (idebenone, indeloxazine or a similar tool), antipsychotic agent (timiperone or a similar tool, imipramin or a similar tool, diazepam or similar tool), a tool for intracranial decompression (glycerine or a similar tool), antihypotensive drug, a vasodilator drug (trapidil or a similar tool), antipyretic-analgesic-antiinflammatory drug, an anti-inflammatory steroid, protivotromboznoe tool (ticlopidine or a similar tool), anticoagulant (heparin or a similar tool), tool, inducing fibrinolysis (tissue activator of plasminogen, or a similar tool), a diuretic, protivoepidemicheskie tool (probucol or a similar tool), antiulcer drug, the preparation of the artificial blood, a treatment for liver disease, anti-cancer drug and a similar tool.

Examples of making

the 3.5-Hydrate of the dihydrochloride of the present invention can be prepared in the form of farmatsevticheskiy technology of preparation of medicines, although the invention is not limited to these examples, as a matter of course. In the examples of formulations of medicines used recipes that used the compound obtained in inventive Example 3.

[Example 1 preparation]

(1) Compound of inventive Example 3 10 grams

(2) Lactose 50 g

(3) Corn starch 15 g

(4) Hydroxypropylcellulose 8 grams

(5) Sodium salt of carboxymethyl amylum 7 grams

(6) magnesium Stearate 1 g

The above components(1), (2), (3) and (5) put in a granulating machine fluidized bed and uniformly mixed, the mixture is turned into pellets, using a 6% aqueous solution of the component (4) as the binding solution. They are mixed evenly with the component (6) and used as a powder mixture for the manufacture of tablets. Using this mixture, prepare 100 tablets, each of which has a diameter of 8 mm and contains 100 mg (1).

[Example 2 preparation]

(1) Compound of inventive example 3, 2 g

(2) a 0.1 N hydrochloric acid and 150 ml

(3) Glucose 50 g

(4) Distilled water for injection use - up balance (see later)

Above the comp is new water for injection use. This solution is subjected to sterile filtration using a 0.2 μm filter, and then distribute portions of 10 ml in vials with a capacity of 10 ml.

Brief description of drawings

Fig. 1 is a graph showing changes in the mass of the anhydrous hydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazol, plotted as a function of humidity, Fig. 2 is a graph showing changes in the weight of 3.5-hydrate of the present invention, plotted as a function of humidity, Fig. 3 is a powder x-ray range 3.5-hydrate of the present invention and Fig. 4 is the spectrum of thermal analysis 3.5-hydrate of the present invention.

The best way of carrying out the invention

The invention hereinafter described in detail with reference to the following examples, although the invention, as a matter of course, not limited to these examples.

[Reference example 1] Ethyl-5,6-dimethoxy-1-(1-trityl - 4-imidazolyl) methyl-1H-indazol-3-carboxylate

Ethyl 5,6-dimethoxyindole-3-carboxylate (250,2 g) suspended in dimethyl sulfoxide (5000 ml) and the suspension was mixed with lithium methoxide (40,2 g) and stirred at room temperature. After peremeshivanija ml) of 4-chloromethyl-1-tritylimidazole (447,8 g) at room temperature. After stirring the resulting mixture as such at room temperature for 2 hours, mixing it with lithium methoxide (4,2 g) and 4-chloromethyl-1-tritylimidazole (44,8 g) and then stirring at room temperature for 1 hour analysis by thin-layer chromatography showed that the spot of the starting material almost disappeared on the chromatogram (chloroform/ethanol = 30/1). When the reaction solution was poured into ice-cold water (30000 ml), which was stirred during the precipitation of crystals. The crystals were collected by vacuum-filtration, washed with water (2000 ml x 3) and then dried in the air. They were dissolved in chloroform (10000 ml), the resulting solution was dried with sodium sulfate and filtered and the solvent is then evaporated under reduced pressure. The obtained residue was separated and purified on a column of silica gel (chloroform/ethanol = 50/1) and recrystallized from a mixture of chloroform-isopropyl alcohol, getting 222,0 g of colorless prismatic crystals (melting point: 184-186oC).

IR (KBr) cm-1: 1704, 1496, 1268, 1146, 1132, 1092, 748, 700.

1H NMR (M. D., CDCl3): to 1.21 (6H, d, J=5,9 Hz, Me from ISO-D), of 1.46 (3H, t, J=7,3 Hz), 3,93 (3H, s), of 3.97 (3H, s) to 4.01 (1H, m, CH from ISO-D), of 4.49 (2H, K, J=7,3 Hz), 5,61 (2H, s), 6,79 (1H, s), 7,03 (5H, m), 7,13 (1H, s), 7,28 (10H, m), 7,47 (1H, s), is ANO: 72,13%; H 6,37%; N CENT TO 8.85%.

Found: 71,53%; H 6,37%; N To 8.70%.

[Referential Example 2] 5,6-Dimethoxy-1-(1-trityl-4-imidazolyl) -methyl-1H-indazol-3-methanol

Ethyl 5,6-dimethoxy-1-(1-trityl-4-imidazolyl) methyl-1H-indazol-3-carboxylate (222,0 g) was crushed into powder using a mortar and suspended in tetrahydrofuran (1300 ml) at room temperature and the suspension was cooled with ice water. To the suspension was added natriummetasilikaatti (3.4 M solution in toluene, about 250,0 ml) for 15 minutes, then stirred in an ice bath. After 30 minutes, analysis by thin-layer chromatography showed that the spot of the starting material almost disappeared on the chromatogram (ethyl acetate/hexane = 2/1). The reaction solution was mixed with saturated aqueous solution of sodium sulfate, stirred for 1 hour, mixed with sodium sulfate and then filtered. In this case, the sodium sulfate on the filter was washed with hot chloroform (500 ml x 5). The filtrate and the washing solution were combined and the solvent evaporated under reduced pressure, obtaining a colorless solid product (to 220.1 g). It was recrystallized from chloroform, getting 181,0 g of colorless prismatic crystals (melting point: 115-120oC (Razlog.)).

NMR (M. D., CDCl3): 3,91 (3H, s) to 3.92 (3H, s), 2H,C), 5,44 (2H, s) 6,76 (1H, s), to 6.95 (1H, s), 7,05 (5H, m), 7,26 (1H, s, CHCl3), 7,28 (1H, s), 7,31 (10H,m), 7,46 (1H, s).

Elemental analysis for C33H30N4O3CHCl3:

Calculated: 62,83%; H 4,81%; N To 8.62%.

Found: 62,50%; H 4,63%; N 8,42%.

[Referential example 3] 3-Chloromethyl-5,6-dimethoxy-1- (1-trityl-4-imidazolyl) methyl-1H-indazol

5,6-Dimethoxy-1-(1-trityl-4-imidazolyl) methyl-1H-indazol - 3-methanol (180,0 g) was crushed into powder using a mortar and suspended in dichloromethane (1700 ml) at room temperature. After the suspension reaction solution was stirred while cooling in an ice bath. In this suspension for 5 minutes was added dropwise to 48.6 ml chloride tiomila. After 1 minute the analysis of thin-layer chromatography showed that the spot of the starting material almost disappeared on the chromatogram (chloroform/ethanol = 30/1). The reaction solution was poured into saturated aqueous sodium bicarbonate solution (2000 ml) and was extracted with chloroform (5000 ml) and the extract was dried with sodium sulfate, filtered and then evaporated under reduced pressure, obtaining a colorless solid (165,1 g). This solid substance was used in the next reaction as such.

example 4] 5,6-Dimethoxy-1- (1-trityl-4-imidazolyl) methyl-1H-indazol-3-acetonitrile

3-Chloromethyl-5,6-dimethoxy-1-(1-trityl-4-imidazolyl) methyl-1H-indazol (165.0 g) suspended in dimethyl sulfoxide (1200 ml) and stirred at room temperature. To the suspension was added potassium cyanate (43,6 g), which were crushed into powder using mortar. After stirring the reaction solution at 70oC for 1 hour, the solution became homogeneous and transparent, thin-layer chromatography (ethyl acetate/hexane = 2/1) showed that the spot of starting material almost disappeared. The reaction solution was cooled to room temperature and poured into water (15000 ml), which was vigorously stirred, and the mixture was stirred for 1 hour. Thus, the precipitated solid was collected by vacuum-filtration, washed with water (1000 ml x 3) and was dissolved in chloroform (5000 ml), the resulting solution was dried with sodium sulfate and filtered, then the solvent is evaporated under reduced pressure. Thus obtained residue was separated and purified on a column of silica gel (ethyl acetate), getting to 108.7 g of light brown solid. This solid is directly used in the next reaction.

1H NMR (M. D., CDCl3): to 3.92 (3H, s), of 3.94 (3H, s), of 3.97 (2H, s), 5,42 (2H, s), 6,79 (1H, s), 7,00 (1H, s), 7,02 (1H, s), 7,06 (Usna acid

5,6-Dimethoxy-1-(1-trityl-4-imidazolyl) methyl-1H-indazol - 3-acetonitrile (107,0 g) suspended in ethanol (1000 ml) at room temperature. To the suspension was added a 10N aqueous solution of sodium hydroxide (40,0 g sodium hydroxide was obtained from 100 ml of water), then the mixture was heated at the boil under reflux. 6 hours after that, with the help of analysis of thin-layer chromatography (ethyl acetate) observed that the spot of the starting material almost disappeared. The reaction solution was cooled to room temperature and poured into water (5000 ml). the pH of the mixture was set to 3-4 by addition of 10% aqueous hydrochloric acid was the precipitation of a colorless solid. It was collected by filtration and washed with water (500 ml x 3). The thus obtained solid substance was dissolved in chloroform (5000 ml), the resulting solution was dried with sodium sulfate and filtered and the solvent is then evaporated under reduced pressure. The thus obtained solid substance in the number 134,0 g directly used in the next reaction.

1H NMR (M. D., CDCl3): of 3.84 (3H, s), a 3.87 (3H, s) to 3.89 (2H, s), 5,43 (2H, s) 6,76 (1H, s), to 6.88 (1H, s), 6,93 (1H, s), 7,03 (5H, m), 7,28 (10H, m), of 7.48 (1H, s).

/Referential example 6/ 4-(3-Chloro-2-were)-1-[[5,6-dimetho the l-1H-indazol-3-acetic acid (134,0 g) suspended in dichloromethane (1000 ml). To this suspension was added 2,2-dipyridamole (63,5 g) and triphenylphosphine (75,6 g), then the mixture was stirred at room temperature (suspension became homogeneous solution). To this solution is added dropwise within 5 minutes was added a solution of 4-(3-chloro-2-were)piperazine (60,7 g) in dichloromethane (200 ml), then the mixture was stirred 5 hours at room temperature. Thin-layer chromatography (ethyl acetate/hexane = 3/1) showed that the spot of starting material almost disappeared. Dichloromethane from the reaction solution is evaporated under reduced pressure and the thus obtained residue was mixed with hot ethyl acetate and stirred until the discovery of sludge solids. It was collected by vacuum-filtration, washed with ethyl acetate (500 ml x 2) and then dried in the air. Getting 140,4 g colorless solid. A solid substance was separated and purified on a column of silica gel (chloroform/ethanol=30/1) to give 134.9 g of colorless solid product. It was recrystallized from ethanol, getting to 120.0 g of colorless prismatic crystals (so pl. 103-105oC).

IR (KBr) cm-1: 1646, 1628, 1508, 1466, 1450, 1430, 1260, 750, 702.

1H NMR (M. D., CDCl3): 1,23 (1,2 H, t, J=6.8 Hz, Me from EtOH), of 2.28 (3H, s) to 2.55 (2H, m), 2,73 (2H, m) to 3.67 (4H,m), 3,71 (0, (10H, m), 7,41 (1H, s).

Elemental analysis for C45H43N6ABOUT3ClH2ABOUT:

Calculated: 70,10%; H 5,70%; N 10,70%; Cl 4,72%.

Found: 70,02%; H 5,78%; N Or 10.60%; Cl 5,11%.

/Inventive example 1/ 3-[2-[4-(3-chloro-2-were)-1 - piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazol

4-(3-Chloro-2-were)-1-[[[5,6-dimethoxy-1-(1-trityl-4 - imidazolyl)methyl] indazol-3-yl]acetyl]piperazine (120,0 g) suspended in tetrahydrofuran (1000 ml). To this suspension was added 1.0 M of the complex of borane-tetrahydrofuran (800 ml) and then the mixture was heated at the boil under reflux. After 90 minutes, analysis by thin-layer chromatography (ethyl acetate) showed that the spot of the starting material almost disappeared. The reaction solution was cooled to room temperature and was mixed with water (30 ml) to decompose excess reagent. After evaporation of the tetrahydrofuran under reduced pressure, the thus obtained residue was mixed with concentrated hydrochloric acid (150 ml), water (200 ml) and ethanol (40 ml) and stirred at 50oC for 1 hour. The aqueous layer was cooled to room temperature, was podslushivaet potassium carbonate and was extracted with chloroform (3000 ml) and the organic layer was dried sulf the STATCOM was separated and purified column chromatography with silica gel (chloroform/ethanol = 40/1), receiving a colorless solid product. It was recrystallized from isopropyl alcohol-isopropyl simple broadcast receiving 71,0 g of colorless prismatic crystals (melting point: 143-144,5oC).

IR (KBr) cm-1: 1510, 1464, 1432, 1272, 1238, 1206, 1006.

1H NMR (M. D., CDCl3): of 2.34 (3H, s), 2,78 (4H, m), 2,90 (2H, m), of 2.97 (4H, m), 3,17 (2H, m), 3,90 (3H, c), 3,91 (3H, s), the 5.45 (2H, s), 6,83 (1H, s), at 6.84 (1H, s), 6,92 (1H, m), 7,00 (1H, s), to 7.09 (2H, m), 7,52 (1H, s).

Elemental analysis for C26H31N6Cl:

Calculated: 63,09%; H Of 6.31%; N 16,98%; Cl 7.16 Percent.

Found: 62,93%; H 6,30%; N 16.88 In%; Cl 7.16 Percent.

Inventive example 2 /1,5-hydrochloride 3-[2-[4-(3-Chloro-2-were)-1-piperazinil] ethyl] -5,6 - dimethoxy-1-(4-imidazolidinyl)-1H-indazole (anhydrous crystals)

Portion 60 g of crystals 3-[2-[4-(3-chloro-2-were)-1-piperazinil]-ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole (free form) was dissolved in 1000 ml of ethanol under heating. The resulting solution was mixed with of 182.2 ml of 1 N hydrochloric acid and was stirred for 20 minutes and then the solution is evaporated under reduced pressure. Thus obtained residue was dried at room temperature for 12 hours under reduced pressure in the presence of phosphorous pentoxide. He polycentral up to a volume of about 1000 ml by heating. Thus obtained concentrated solution was spontaneously cooled under stirring and, after the addition of the seed crystals then spontaneously cooled with stirring to room temperature. Precipitated crystals thus collected by filtration and dried by heating (60oC) for about 12 hours under reduced pressure in the presence of phosphorous pentoxide, receiving 64 g of colorless crystals (melting point: 226,5-228oC).

IR (KBr) cm-1: 2968, 2836, 2712, 2544, 2456, 1512, 1470, 1436, 1338, 1260, 1208, 1166, 1108, 1032, 1006, 862.

1H NMR (M. D., CDCl3): 2,32 (3H, s), 3,20-3,21 (3,5 H, m), 3,40-3,52 (10H, m), 3,82, 3,86 (each 3H, s), of 5.53 (2H, s), was 7.08 (1H, DD), 7,19-of 7.25 (2H, m), 7,31-7,33 (3H, m), at 8.36 (1H, s).

The HPLC analysis, it was confirmed that the obtained in this case, the crystals contained about 15,000 M. D. residual ethanol.

/Inventive example 3/ 3.5-hydrate of the dihydrochloride 3-[2- [4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazole

A portion of 4.95 g freeform 3-[2-[4-(3-chloro-2-were) -1-piperazinil] ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole was mixed with 20 ml of 1N hydrochloric acid and distilled water to a total volume of 49.5 ml Then the reaction is om, thereby completely dissolving the crystals. Thus obtained solution was cooled to room temperature under stirring with a stirrer, and then the stirring was continued all day and night. Precipitated crystals thus collected by filtration and was dried in air for 2 days, getting 5.5 g of colorless prismatic crystals (melting point: 166-167oC).

IR (KBr) cm-1: 3400, 2850, 1625, 1505, 1460, 1425, 1245, 1150, 1010, 840.

1H NMR (M. D., d6-DMSO) : 2,39 (3H, s), 3,30-3,80 (20H, m), 5,74 (2H, s), to 7.15 (1H, DD), 7,28 (1H, c), 7,30 (1H, DD), 7,43 (1H, s), 7,52 (1H, s), of 7.69 (1H, s), 9,13 (1H, s), RS 11.80 (1H, Shir. C) 14,80 (1H, Shir. C).

Elemental analysis for C26H31N6O2Cl3,5H2O:

Calculated: 49,41%; H Is 6.54%; N 13,30%; Cl Equal To 16.83%.

Found: 49,15%; H 6,44%; N To 13.29%; Cl 16,99%.

Data of powder x-ray

Measuring conditions:

The source of x-rays: the rays of Cu-K (detector side, monochromatic rays emitted by the monochromator)

Detector: scintillation counter

Voltage x-rays: 35 kV Current: 20 mA

Scanning speed: 2orpm

Angle, shielded sample: 0,010o< / BR>
Slotted system:

Crack deflection = 1,0oSlit scattering = 1, the Tr MHR-3V, made Masks Science

The characteristic peaks of the x-ray spectrum below.

The value of d of the lattice parameter (relative intensity

28,1 - average

27,5 - average

27,0 - average

26,4 - average

25,6 - average

25,3 - strong

24,7 - average

24,3 - strong

22,0 - strong

21,4 - weak

20,9 - average

19,3 - very weak

17,8 - average

15,4 - average

13,8 - average

9,60 is very strong

a 9.09 - very weak

8,46 - average

/Inventive example 4/ 3.5-hydrate of the dihydrochloride 3- [2-[4-(3-Chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazole

A portion of 5.50 g of crystals of 1,5-hydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole (anhydrous) was mixed with 5.0 ml of 1N hydrochloric acid and distilled water to a total volume of 49.5 ml Then the reaction vessel was heated at an ambient temperature of 120oC to the boiling mixture inside the vessel with reflux condenser, thereby completely dissolving the crystals. Thus obtained solution was cooled to room temperature under stirring with a stirrer, and then premasiri on the air for 2 days, obtaining 5.6 g of colorless prismatic crystals (melting point: 166-167oC).

Thus obtained crystals showed the same physical data, which is obtained in inventive example 3.

Examples of pharmacological tests of the compounds of this invention are given below, in which the results were obtained mainly using its anhydrous form (anhydride).

With regard to toxicity, toxic by single oral administration was dose 200 mg/kg or more serious adverse effects were not observed in rats in the test for toxicity at repeated oral administration for 10 days and tested for toxicity after repeated intravenous injection for 10 days.

In particular, a serious impact on hemodynamics and electrocardiogram were not observed in dogs and significant impact on the Central nervous system were observed in rhesus monkeys, even with the introduction of vnutrivennoi injection dose of 10 mg/kg /Example 1 pharmacological tests/ Inhibitory effect on calmodulin

Inhibitory effect on calmodulin was evaluated using as an indicator of inhibition effect camadulensis the test. That is, 50 mm Tris-buffer (pH 7.5, containing 5 mm MgCl2and 1 mg/ml bovine serum albumin), 1 mm CaCl2, [3H]-cGMP]-(cGMP), calmodulin (Kam, from bovine brain), Cam-PDE (calmodulinzawisimoy phosphodiesterase from bovine brain) and the test sample was mixed and incubated at 30oC for 10 minutes. The mixture was then heated for 1 minute in a bath of boiling water to stop the reaction, mixed with snake venom (1 mg/ml) and then subjected to 10 minutes of reaction at 30oC for conversion of 5'-HYPHAE formed under the action of PDE, guanosin. Next, unreacted cGMP absorbed on the ion-exchange resin (A G1-X8) and then the radioactivity of the supernatant liquid obtained by centrifugation, was measured using a liquid scintillation counter. The effect of inhibition of PDE in the calculation as the value of the IC50was 5,46 μm. On the other hand, as a control compound used compound W-7, showing the value of 33.6 ám.

/Example 2 pharmacological tests/ Influence on rat model of hypoxia in nitrogen atmosphere

This test was carried out according to the way Albert Wauguier et al. (Japan J. Pharmacol., 38, 1-7 (1985)).

1 g of the governmental funds (30 mg/kg) were placed in a transparent container (capacity 500 ml), provided with an outlet opening for air, and then the container was introduced nitrogen gas with a speed of 5.0 l/min was Measured period of time from the start of gas supply to stop breathing. When the control group was taken as 100%, the degree of increase was 15.1 per cent.

/Example 3 pharmacological tests/ Changes in the nerve cells of the hippocampus in a model of cerebral ischemia

When temporary cerebral ischemia cause gerbils, since that time, the nerve cells of the hippocampus begin to die within a few days, and this change is called delayed necrosis of nerve cells.

The following test was carried out according to the method of T. Kirino (Brain Res., 239, 57-69 (1982)). That is, each gerbil was subjected to 5-min cerebral ischemia and then squashed to count the number of nerve cells remaining in the CAl area of the hippocampus.

The nerve cells of the hippocampus CAl cerebral ischemia was lost almost completely, but oral administration of compounds (100 mg/kg) occurred within 1 hour after you create cerebral ischemia, showed a clear protective effect against necrosis of nerve cells (see tab. 1).

/Example 4 pharmacological tests/ Anti Etwee the way Nobutaka Demura et al. (Neuroscience Res., 17, 23-30) 1983)).

During anaesthesia with halothane gas rat Sic; Wis (about 300 g), which had previously entered the cannula in the caudal vein, cut the neck to rupture of the common carotid artery on the left side. Palatal artery bone and the external carotid artery on the same side was also broken and put clamps on them. Microspheres coal (5010 microns in diameter) suspended in 20% dextran and were injected with in the common carotid artery on the left side to effect the dispersion of the microspheres in the left hemisphere of the brain through the left internal carotid artery, common carotid artery immediately pinched to stop bleeding from places that were injected with microspheres, and then arterial clamp was removed to resume circulation. Since that time, the solution of each drug was continuously introduced via infusion pump of the catheter, which was inserted into the caudal vein.

Each animal was killed by decapitation 24 hours after surgery and immediately after decapitation cut the brain to measure the mass (in wet state) of the left and right hemispheres. Each fabric was then dried overnight at 150oC to measure its weight in the dry state and calculate the content Easom group for introduction of filler (only 20% dextran) (see table. 2).

Industrial applicability

This invention found that a 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1- (4-imidazolidinyl)-1H-indazole is a new crystal. This crystal is characterized by its markedly permanent storage stability. Consequently, it is useful as a pharmaceutical material.

1. Crystalline dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole, which essentially has the following characteristics x-ray diffraction (x-ray):

The value of d of the lattice parameter relative intensity

28,1 - average

27,5 - average

27,0 - average

26,4 - average

25,6 - average

25,3 - strong

24,7 - average

24,3 - strong

22,0 - strong

21,4 - weak

20,9 - average

19,3 - very weak

17,8 - average

15,4 - average

13,8 - average

9,60 is very strong

a 9.09 - very weak

8,46 - average

2. The crystal under item 1, characterized in that the crystalline dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indefini)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole, which includes the processing of free-form 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole hydrochloric acid in the presence of water.

4. The method of obtaining a 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole, which includes processing hydrochloride hydrate 3-[2-[4-(3-chloro-2-were)-1-piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole, which is a hydrate and/or a hydrochloride, less than 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole, water and/or hydrochloric acid.

5. The method of obtaining dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole essentially has the following characteristics x-ray diffraction:

The value of d of the lattice parameter relative intensity

28,1 - average

27,5 - average

27,0 - average

26,4 - average

25,6 - average

25,3 - strong

24,7 - average

24,3 - strong

22,0 - strong

21,4 - weak

20,9 - average

19,3 - very weak

which includes the processing of free-form 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole hydrochloric acid in the presence of water.

6. The method of obtaining dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil]ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole essentially has the following characteristics x-ray diffraction:

The value of d of the lattice parameter relative intensity

28,1 - average

27,5 - average

27,0 - average

26,4 - average

25,6 - average

25,3 - strong

24,7 - average

24,3 - strong

22,0 - strong

21,4 - weak

20,9 - average

19,3 - very weak

17,8 - average

15,4 - average

13,8 - average

9,60 is very strong

a 9.09 - very weak

8,46 - average

which includes processing hydrochloride hydrate 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl] -5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole, which is a hydrate and/or a hydrochloride smaller than 3.5-hydrate of the dihydrochloride 3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole, water and/or hydrochloric acid.

7. The way l]-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazole is a 3.5-hydrate.

 

Same patents:
The invention relates to a method for anticancer drug prospidina, which is used in oncological practice, as well as in the treatment of rheumatoid arthritis

The invention relates to new substituted pyrrole General formula I

< / BR>
where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain

The invention relates to the transdermal administration of drugs

The invention relates to organic chemistry and medicine and relates to new chemical compounds, namely derived pyrrolidin-2,4-dione of the formula I:

< / BR>
and drug anticonvulsant actions based on it

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: medicine; pharmaceutical engineering.

SUBSTANCE: pharmaceutical composition COMPRISES 5-(2-pyrazinyl)-4-methyl-1,2-dithyol -3-thion (oltipraze) and dimethyl-4,4'-dimetoxi-5,6,5',6'-dimethylene-dioxybiphenyl-2,2' dicarboxilate (DDB) as the main components. Oltipraze: DDB proportion is preferentially equal to 50-1:1-50, the most preferential being 5:1.

EFFECT: enhanced effectiveness of treatment.

6 cl, 6 dwg, 9 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: method relates to piperazinedione compounds of formula I wherein and are independently direct bond or double bond; F represents H or CH(RaRb), when is single bong, or C(RaRb), when is double bond; Z represents R3O-(Ar)-B, wherein B represents CH(Rc), when is single bond or C(Rc), when is double bond; Ar represents piridyl; and R3 represents alkyl, aryl, C(O)Rd, C(O)NRdRe or SO2Rd ; R1 and R2 are independently H, C(O)Rd. Compounds of formula I have antitumor activity. Methods for treatment of tumors and angiogenesis inhibition also are disclosed.

EFFECT: new compounds useful in treatment of tumors and angiogenesis inhibition.

42 cl, 23 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

Curative agent // 2283133

FIELD: medicine, medicinal agents, pharmacy.

SUBSTANCE: invention relates to a medicinal agent made as ointment, gel, vaginal or rectal suppository and designated for treatment of candidomycosis and comprising ketoconazole or fluconazole (variants) in the dose 0.01-0.4 g/1 g of agent, and recombinant alpha-interferon in the dose 150000-3000000 IU/g (for rectal and vaginal suppository) and 5-50000 IU/g (for ointment and gel). Invention provides the development of agent with prolonged effect as ointment, gel, vaginal or rectal suppository showing good penetrating capacity and possessing an antimycotic effect.

EFFECT: valuable medicinal and pharmaceutical properties of agent.

14 cl, 4 tbl, 6 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I with PGl2 receptor agonist activity. In formula R1 and R2 represent independently optionally substituted phenyl; Y represents N, N-O or CR5; Z represents N or CR6; A represents NR7; D represents alkylene or alkenylene; or A and D may together form divalent group; E represents phenylene or direct bond, or D and E may together form divalent group; G represents O, S, SO, SO2; R3 and R4 represent hydrogen atom or alkyl; Q represents carboxyl, alkoxycarboxyl, tetrazolyl, carbamoyl or -CONH-SO-R10 group. Prostaglandin I2(PGl2) is potent inhibitor of platelet aggregation and may be effectively used in treatment of vascular diseases, arteriosclerosis, hypertension, etc.

EFFECT: new compounds and drugs for platelet aggregation inhibition and treatment of vascular and other diseases.

15 cl, 3 tbl, 109 ex

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

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: medicine, hepatology, pharmacy.

SUBSTANCE: invention represents a pharmaceutical composition and its using in treatment of cirrhotic liver by regeneration of liver tissue. Proposed composition comprises the effective dose of 5-(2-pyranizyl)-4-methyl-1,2-dithiol-3-one (oltipraz) and a pharmaceutical acceptable carrier. Also, invention proposes a method for treatment of mammal with cirrhotic liver. Proposed composition induces conversion of non-differentiated liver cells to normal liver cells.

EFFECT: valuable medicinal properties of pharmaceutical composition.

5 cl, 7 dwg, 16 ex

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