Pyridazinylamine derivatives and use thereof for making picornavirus inhibitors

FIELD: chemistry.

SUBSTANCE: present invention relates to derivatives of substituted pyridazinylamine of formula or to their pharmaceutically acceptable salts or hydrates, where X is C or N; Y is O or S; W is C or N; R1, R2, R3 each independently represents hydrogen or halogen; R4, R5, R6 each independently represents hydrogen, halogen, C1-C8-straight or branched alkyl, C1-C8-straight or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7; R7 independently represents hydrogen or C1-C8-straight or branched alkyl. The invention also relates to a method of producing said compounds, to pharmaceutical compositions containing said compounds and to use of the said compounds as picornavirus inhibitors for preventing and/or treating diseases caused by pircornaviruses.

EFFECT: novel compounds have useful biological properties.

10 cl, 1 tbl, 33 ex

 

·Area of technology

The present invention relates to a derivative of the substituted pyridinylamino or their pharmaceutically acceptable salts or hydrates, the method of production thereof, pharmaceutical compositions, include, and to their use as inhibitors of picornaviruses for the production of medicaments for the prophylaxis and/or treatment of diseases caused by picornaviruses.

The level of technology

The picornaviruses are the smallest known RNA viruses of animals, they include 7 genera, that is kind of rhinoviruses, enteroviruses, the genus of aphthovirus, cardiovirus, hepatovirus and rod double echoviruses and other unclassified picornaviruses. The picornaviruses can cause many diseases, such as respiratory disease, vesicular stomatitis, meningitis/encephalitis, polio, cardiovascular disease, hemorrhagic conjunctivitis, hepatitis and so on.

In the last period of 1980-ies in Virology has been a significant progress. Were described in detail several important stages in the life cycle of viruses, and many molecular targets were confirmed. In addition, some new antiviral drugs that have appeared in recent years has also contributed to the fast development of Virology. Inhibitors of picornaviruses ka the times are under active research. The target of action of these inhibitors is a viral protein 1 (VP1), which has a relatively conservative capsid structure and mediates the process of adhesion/decapetala virus. VP1 from viruses of different serotypes are highly conservative in structure, but very important for viral replication. Therefore, inhibitors acting on this target, with a high probability can be considered as medicines against picornaviruses.

The invention

The purpose of the present invention is to find a new low molecular weight compounds acting on VP1, which can prevent the adhesion/decapitation viruses, thereby allowing you to achieve the purpose of prevention and/or treatment of diseases caused by picornaviruses.

After research, the authors of the present invention have found that compounds of the following formula I can affect viral protein 1, thereby blocking the adhesion and decapitation viruses, so they can be used for the prevention and/or treatment of diseases caused by picornaviruses.

Therefore, the first aspect of the present invention relates to the compound of formula I or its pharmaceutically acceptable salt or hydrate

I

where X represents C or N;

Y of t is made by an O or S;

W represents C or N;

R1, R2, R3each independently represents hydrogen or halogen;

R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy, nitro, cyano, -COOR7, -CH2-O-R8, -CH2COOR7or-COR7;

each R7independently represents hydrogen or C1-C8is unbranched or branched alkyl;

R8represents hydrogen or cyano.

The second aspect of the present invention relates to a method for obtaining compounds of formula I or its pharmaceutically acceptable salt or hydrate.

The third aspect of the present invention relates to pharmaceutical compositions containing at least one compound of formula I or its pharmaceutically acceptable salt or hydrate and one or more pharmaceutically acceptable carrier or excipient.

A fourth aspect of the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt or hydrate to obtain drugs for prevention and/or treatment of diseases associated with infection by picornaviruses.

The fifth aspect of the present invention apply the method of prevention and/or treatment of diseases, related to infection by picornaviruses, where the method includes the introduction of a prophylactically and/or therapeutically effective amount of at least one compound of formula I or its pharmaceutically acceptable salt, or hydrate the patient who needs it.

In one implementation of the present invention, the latter relates to the compound of formula I or its pharmaceutically acceptable salt or hydrate

I

where X represents C or N;

Y represents O or S;

W represents C or N;

R1, R2, R3each independently represents hydrogen or halogen;

R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy, nitro, cyano, -COOR7, -CH2-O-R8, -CH2COOR7or-COR7;

each R7independently represents hydrogen or C1-C8is unbranched or branched alkyl;

R8represents hydrogen or cyano.

According to one preferred implementation of the present invention the compound of formula I is a compound of formula II or its pharmaceutically acceptable salt or hydrate

II

where Y represents O or S;

W represents C or N;

R1, R2, R3each independently represents hydrogen or halogen;

R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy, nitro, cyano, -COOR7, -CH2-O-R8, -CH2COOR7or-COR7;

each R7independently represents hydrogen or C1-C8is unbranched or branched alkyl;

R8represents hydrogen or cyano.

According to another preferred implementation of the present invention the compound of formula I is a compound of formula III or its pharmaceutically acceptable salt or hydrate

III

where W represents C or N;

R1, R2, R3each independently represents hydrogen or halogen;

R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy, nitro, cyano, -COOR7, -CH2-O-R8, -CH2COOR7, -COR7;

each R7independently presented yet a hydrogen or C 1-C8is unbranched or branched alkyl;

R8represents hydrogen or cyano.

According to another preferred implementation of the present invention the compound of formula I is a compound of formula IV or its pharmaceutically acceptable salt or hydrate

IV

where R1, R2, R3each independently represents hydrogen or halogen;

R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy, nitro, cyano, -COOR7, -CH2-O-R8, -CH2COOR7, -COR7;

each R7independently represents hydrogen or C1-C8is unbranched or branched alkyl;

R8represents hydrogen or cyano.

According to another preferred implementation of the present invention the compound of formula I is a compound of formula V or pharmaceutically acceptable salt or hydrate

V

where R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8-unbranched ilyuzorny alkoxy, nitro, cyano, -COOR7, -CH2-O-R8, -CH2COOR7or-COR7;

each R7independently represents hydrogen or C1-C8is unbranched or branched alkyl;

R8represents hydrogen or cyano.

According to the present invention the compound of formula I of the present invention is selected from the following compounds or their pharmaceutically acceptable salts or hydrates:

4-{4-[2-(4-butylphenoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazin,

4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenylacetic acid ethyl ester,

3,6-dichloro-4-{4-[2-(2,6-dimethylphenoxy)]piperazine-1-yl}pyridazin,

4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenylacetic acid methyl ester,

1-(4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenyl)butane-1-he,

4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy}benzoic acid methyl ester,

1-(4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenyl)heptane-1-he,

4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy}benzoic acid propyl ester,

4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy}phenylacetonitrile,

4-{4-[2-(4-bromophenoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazin,

3,6-dichloro-4-{4-[2-(4-nitrophenoxy)ethyl]piperazine-1-yl}pyridazin,

3,6-dichloro-4-{4-[2-(4-methoxyphenoxy)ethylpiperazin-1-yl]}is iridin,

4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy}benzoic acid isopropyl ester,

4-{4-[2-(4-butoxyethoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazin,

3,6-dichloro-4-{4-[2-(2-nitrophenoxy)ethyl]piperazine-1-yl}pyridazin,

3,6-dichloro-4-[4-(2-p-methylphenoxy)piperazine-1-yl]pyridazin,

3,6-dichloro-4-[4-(2-o-methylphenoxy)piperidine-1-yl]pyridazin,

1-(4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenyl)Etalon,

3,6-dichloro-4-{4-[2-(2,4-dinitrophenyl)ethyl]piperazine-1-yl}pyridazin,

4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}benzonitrile,

3-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}benzoic acid methyl ester,

4-{4-[2-(4-tert-butylphenoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazin,

3,6-dichloro-4-{4-[2-(4-ethoxyphenoxy)ethyl]piperazine-1-yl}pyridazin,

4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}benzaldehyde,

4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzonitrile,

1-(4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}phenyl)Etalon,

3,6-dichloro-4-{4-[2-(4-nitrophenyl)ethyl]piperidine-1-yl}pyridazin,

4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzoic acid methyl ester,

4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzoic acid ethyl ester,

3,6-dichloro-4-{4-[2-(4-methoxyphenoxy)ethyl]piperidine-1-yl}pyridazin,

6-{2-[4-(3,6-dichloropyridazin-4-yl)piperaz the n-1-yl]ethoxy}nicotinic acid ethyl ester; and

6-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}nicotinic acid methyl ester.

According to the present invention the compounds of the present invention receive according to the following reaction scheme.

The compound of formula VI is reacted with gaseous chlorine at 100-140°C in the presence of ferric chloride as a catalyst with the formation of the compounds of formula VII, a compound of formula VII is reacted with a compound of formula VIII in the presence of sodium carbonate at a temperature in the range from room temperature to 170°C in chloroform, acetone, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide (preferably N,N-dimethylacetamide) as a solvent to form compounds of formula IX, then the compound of formula IX is reacted with a compound of formula X by the condensation reaction at a temperature in the range from 0°C to room temperature in an organic solvent such as chloroform, dichloromethane, tetrahydrofuran, and so forth (preferably tetrahydrofuran) to give the compounds of formula I.

Thus, the method of obtaining the compounds of formula I of the present invention includes the following stages:

(i) the interaction of the compounds of formula VI with gaseous chlorine in the presence of ferric chloride as catalyst with the formation of the value of the formula VII

VI

where R1, R2, R3have the same definitions as the above formula I;

VII

where R1, R2, R3have the same definitions as the above formula I;

(ii) the interaction of the compounds of formula VII with the compound of the formula VIII with obtaining the compounds of formula IX

VIII

where X has the same definition as the above formula I;

IX

where R1, R2, R3and X have the same definitions as the above formula I;

(iii) the interaction of the compounds of formula IX with dichloromethoxy, then with a substituted phenol compound of the formula X in the condensation reaction,

X

where R4, R5, R6, W and Y have the same definitions as the above formula I, to obtain the compounds of formula I,

I

where R1, R2, R3, R4, R5, R6, X, W and Y have the same definitions as the above formula I;

(iv) optionally, a compound of formula I is transformed into its pharmaceutically acceptable salt by treatment with suitable pharmaceutically acceptable acid or base.

According to the present invention, the term “pharmaceutical is acceptable salt”, used in the present invention include acidic salts formed by the connection of the present invention with pharmaceutically acceptable inorganic acid or organic acid, or alkaline salts formed by the connection of the present invention with a pharmaceutically acceptable base, where acidic salts include named, but not limited to: hydrochloride, hydrobromide, hydroiodide, nitrates, sulphates, bisulfate, phosphates, biphosphate, acetates, propionate, butyrate, oxalates, trimethylacetate, adipate, alginates, lactates, citrates, tartratami, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, methanesulfonate, econsultancy, benzosulfimide, p-methylbenzenesulfonate and pamoate; and alkali metal salts include named, but not limited to: ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline-earth metals such as calcium and magnesium salts, organic salts, such as dicyclohexylamine and N-methyl-D-glucosamine salts and amino acid salts such as arginine or lysine salts.

According to the present invention the pharmaceutical composition of the present invention includes an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or hydrate, and one or more suitable headlight is asepticheski acceptable carrier or excipient. Pharmaceutically acceptable carriers suitable for use in the pharmaceutical compositions of the present invention include named, but not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum protein such as human serum protein, a buffering agent, such as phosphate, glycerin, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as preteenslut, intrigejosa, kalogeropoulos, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, a block polymer of polyethylene-co-polyoxypropylene and lanolin.

Compounds of the present invention are a group of strong inhibitors of picornaviruses, characterized in that it can not only prevent but also cure diseases caused by picornaviruses. These picornaviruses are rhinoviruses and enteroviruses. Disease caused by picornaviruses, in the present invention include named, but not limited to: respiratory disease, vesicular stomatitis, meningitis/encephalitis, polio, cardiovascular disease, hemorrhagic, konyu krivit, hepatitis and so on.

These respiratory diseases include named, but not limited to: the common cold (summer colds, pharyngitis, tonsillitis, croup. These diseases are usually caused by rhinoviruses families of picornaviruses.

According to the present invention the pharmaceutical composition of the present invention can be used to introduce any of the following ways: orally administered, powder inhalation, rectal introduction, nazalnam introduction, transbukkalno introduction, vaginal introduction, local introduction, parenteral introduction, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, vnutrigrudne and intracranial injection or infusion, or by introduction through explanitory reservoir, preferably by oral administration, intraperitoneal or intravenous injection. In addition, for the effective treatment of the compounds of the present invention of diseases of the Central nervous system is preferred intraventricular introduction to overcome the possible low-speed penetration cross the blood-brain barrier.

When administered orally, the compound of the present invention can be processed for the formation of any suitable dosage form for Perera inogo introduction, which includes named, but not limited to: tablets, capsules, aqueous solutions or aqueous suspension; where the media used in tablets, usually include lactose and corn starch, additionally, lubricating agents such as magnesium stearate; the thinners used in the capsules typically include lactose and dried corn starch; and in the case of aqueous suspensions of the active ingredients are usually mixed with suitable emulsifiers and suspendresume agents. If necessary, the above-mentioned oral dosage forms may further include sweeteners, flavors or dyes.

In a rectal compound of the present invention can be processed to form suppository, which is obtained by mixing the drug with a suitable not causing irritation excipients where excipient is present in solid form at room temperature and melt at rectal temperature in order to release the drug. This excipient include cocoa butter, beeswax and polyethylene glycol.

The local introduction, especially for the treatment of diseases affected surfaces or organs such as eye, skin diseases or neurogenic lesion of the lower intestine, which can be easily accessible for local injection, n is based compound of the present invention can be obtained in different dosage forms, as needed for the various affected surfaces or bodies, which are described in detail below.

The local introduction of the eye of the compound of the present invention can be processed for the formation of a finely dispersed suspension or solution, used where the carrier is a sterile isotonic saline solution with a specific pH, and can be added or not added preservative, such as Chlorobenzilate. In addition, in the case of applying the eye of the connection can form an ointment such as vaseline ointment.

The local introduction to the skin of the compound of the present invention can be processed for forming suitable ointments, lotions or creams, where the active component suspended or dissolved in one or more carriers. Here the media used in ointments include named, but not limited to: mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsified wax and water; carriers used in lotions or creams that include named, but not limited to: mineral oil, servicemonitor, tween 60, cetyl ester wax, hexadecanol, 2-octyldodecanol, benzyl alcohol and water.

The local introduction in the lower intestine connection of this izopet the deposits can be processed for forming the above-mentioned rectal suppository or appropriate enemas and in addition, can also be used by local transdermal patches.

The compound of the present invention can also be used for administration in the form of a sterile injection include sterile aqueous injection or liquid containing slurry oil, or sterile injectable solutions, where the media used and the solvents include water, ringer's solution and isotonic sodium chloride. In addition, as a solvent or suspendida environment can also be used sterilized non-volatile oil, such as monoglycerides or diglycerides.

In addition, it is necessary to take into account that a specific dosage and application in the case of different patients depend on many factors, such as age, body weight, gender, health status, nutritional status, effective force, time of administration, rate of metabolism, disease severity and subjective opinion of the physician in diagnosis and treatment. The preferred dosage is 0.01-100 mg/kg body weight/day.

Brief description of drawings

Figure 1 and figure 2 separately illustrates the activity of compounds of the present invention against picornaviruses in in vitro models in terms of preventive and therapeutic injection.

Figure 3 illustrates the results of ex vivo protivoleprosnoe level connections the example 31 of the present invention.

A specific model for carrying out the invention

The following examples represent preferred embodiment illustrating the present invention but in no way they are supposed to limit the present invention.

The melting point of the compounds was measured using the detector temperature melting RY-1, and measured uncorrected temperature. Spectra1H-NMR was measured using a nuclear magnetic resonance spectrometer JNM-ECA-400 (Japan Electronic, Inc.). Mass spectra were measured using a mass spectrometer VG-ZabSpec. All reaction solvents pre-processed by standard methods, unless otherwise noted.

The source materials used in the reactions, except 3,6-dichloropyridazine, which was purchased from Nanjing Tianzunzezhong Chemical Agents Company, was a standard reagents were purchased from well-known suppliers of chemical reagents.

Example 1: 4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenylacetic acid methyl ester

1.1. 3,4,6-trichloropyridin

In a dry three-neck flask equipped with a reflux condenser and a tube for passing the gas (connected with safety bottle), put 3,6-dichloropyridazine (Nanjingtianzunzezhong Chemical Agents) and anhydrous trichloride aluminum, the reactants were heated using outside of the deposits of the heat source, up to 120°C to melting, missed gaseous Cl2at this temperature for 3 hours, then the reaction was stopped, cooled to room temperature, was added trichlormethane to dissolve the product, trichlormethane solution was twice washed with a saturated aqueous solution of sodium chloride, the aqueous phase was twice extracted with trichloromethane, all trichlormethane the solutions were combined and dried over anhydrous sodium sulfate, and then after removal of trichlormethane by evaporation in a vacuum used distilled under reduced pressure and collecting the fraction boiling at 110-114°C/8 mm Hg or 128-129°C/18 mm Hg, solidifying in white solid in the flask-receiver. Yield: 55%, TPL 57-58°C.

1.2. 2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethanol

In a round bottom flask of 50 ml volume was placed 9,18 g (0.05 mol) of 3,4,6-trichloropyridine, 5.30 g (0.05 mol) of anhydrous sodium carbonate and 20 ml of N,N-dimethylacetamide (DMA), the reagents were mixed at room temperature, then slowly dropwise added 6,54 g (0.05 mol) of 2-(piperazine-1-yl)ethanol (dissolved in 10 ml of DMA), and the mixture was stirred over night, filtered the next day. Added 100 ml of distilled water to remaining on the filter mass and stirred, then filtered and received and 10.20 g of white solid, yield: 73.6 per cent, TPL 139-141°C.

1H-NMR (400 MHz, CDCl3 )ppm: 2.57 m (ush., 1H), 2,66~of 2.68 (t, 2H, J=5,12 Hz), 2,73~was 2.76 (t, 4H, J=4,76 Hz), 3,36~to 3.38 (t, 4H, J=4.52 Hz), 3,68~3,71 (t, 2H, J=5,04 Hz), to 6.88 (s, 1H). 13C-NMR(400 MHZ, CMOS-d6)h/million: 155,14, 149,43, 148,70, 116,64, 60,00, 58,49, 52,44, 48,90.

EI-MS m/e: 276,1 [M+, 100], 280 {[M+4]+, 100}, 245,0, 207,1, 175,1, 100,1, 70,1.

1.3. 4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenylacetic acid methyl ester

In a dry three-neck flask with a volume of 50 ml was placed 1,1085 g (0,004 mol) obtained by the authors of 2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethanol, 0.54 g (of 0.003 mol) of the ethyl ester of p-hydroxybenzoic acid and 1,224 g of triphenylphosphine and poured into the flask 15 ml of anhydrous tetrahydrofuran under cooling with ice bath and in a protective atmosphere of nitrogen gas, and then added dropwise to the flask was added 0.7 ml of diethylenediamine (DEAD)dissolved in 5 ml of anhydrous tetrahydrofuran. After adding dropwise, the temperature was raised to room temperature, and stirring was continued over night. The next day the solvent was removed using a rotary evaporator, the residue was poured into 100 ml of water, the product was extracted three times using 150 ml of dichloromethane, the extraction solutions were combined, dried over anhydrous Na2SO4concentrated and separated using column chromatography (eluent - petroleum ether:ethyl acetate:methanol=10:1:0.5),and was obtained 0.56 g of 4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenylacetic acid methyl ester as a white solid. Output: 32,9%, TPL 84-86°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 2,64~to 2.67 (m, 4H), 2,75~2,78 (t, 2H, J=5.6 Hz), 3,32~to 3.34 (m, 4H), 3,60 (c, 5H), 4,08~of 4.11 (t, 2H, J=5.6 Hz), 6.89 in~6,91 (d, 2H, J=8.7 Hz), 7,16~to 7.18 (d, 2H, J=8.7 Hz), 7,40 (c, 1H).

EI-MS m/e): 424[M+], 259, 245, 202, 175, 70,0.

In the same way as used in 1.3, received the following connections using a variety of reagents, that is, a variety of substituted phenolic compounds instead of the ethyl ester of p-hydroxybenzoic acid, used in 1.3.

Example 2: 4-{4-[2-(4-butylphenoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazin.

This compound was obtained by way of 1.3, where instead used phenol used 4-butylphenol. The named compound was obtained as a white solid, yield: 35%, TPL 83-84°C.

1H-NMR (400 MHz, CDCl3)ppm: 0,90~of 0.94 (t, 3H, J=7,3 Hz), 1,33~of 1.37 (m, 2H), 1,53~1,58 (m, 2H), 2,53~to 2.57 (t, 2H, J=7.8 Hz), 2,78~2,80 (t, 4H, J=4.5 Hz), 2,88~only 2.91 (t, 2H, J=5.3 Hz), 3,35~3,37 (t, 4H, J=4.5 Hz), 4,11~to 4.14(t, 2H, J=5.3 Hz), 6,85 (c, 1H), 6,82~at 6.84 (DD, 2H, J=8,4 Hz), 7,09~7,11 (DD, 2H, J=8.7 Hz).

EI-MS m/e: 408,0[M+], 259,0, 245,0, 201,9, 175,0, 70,0.

Example 3: 4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenylacetic acid ethyl ester

This compound was obtained by way of 1.3, where instead used phenol was used ethyl ester of 4-hydroxybenzoic acid. The named compound was obtained as a white solid prophetic is TBA, yield: 32%, TPL 128-130°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 1,29~of 1.32 (t, 3H, J=7 Hz), 2,65~of 2.68 (t, 4H, J=4,8 Hz), 2,79~2,82 (t, 2H, J=5.6 Hz), 3,32~to 3.34 (t, 4H, J=5 Hz), 4,19~4,22 (t, 2H, J=5.6 Hz), 4,25~4,30 (square, 2H, J=7,3 Hz), 7,06~was 7.08 (DD, 2H, J=8.7 Hz), 7,89~a 7.92 (DD, 2H, J=8.7 Hz).

EI-MS m/e): 424[M+], 259,0, 245,0, 201,9, 175,0, 70,0.

Example 4: 3,6-dichloro-4-{4-[2-(2,6-dimethylphenoxy)]piperazine-1-yl}pyridazin

This compound was obtained by way of 1.3, where instead used phenol was used 2,6-dimethylphenol. The named compound was obtained as a white solid, yield: 38.5 percent, TPL 94-96°C.

1H-NMR (400 MHz, CDCl3):ppm: 2,29 (c, 6H), 2,83 (USS, 4H), 2,90 (USS, 2H), 3,41 (USS, 4H, J=4.5 Hz), 2,88~only 2.91 (t, 2H, J=5.3 Hz), 3,35~3,37 (t, 4H), 3,94 (USS, 2H), 6.89 in (c, 1H), 6,91-to 6.95 (m, 1H), 7,01~7,03 (d, 2H, J=7,3 Hz).

EI-MS m/e 380[M+], 258,9, 247,0, 201,9, 175,0 91,0, 70,0.

Example 5: compound mcl040720 1-(4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenyl)butane-1-on.

This compound was obtained by way of 1.3, where instead used phenol was used 1-(4-hydroxyphenyl)butane-1-on. The named compound was obtained as a white solid, yield: 41.5 percent, TPL 140-141°C.

1H-NMR (400 MHz, CDCl3)ppm: 0,98~of 1.02 (t, 3H, J=7.4 Hz), 1,71~to 1.79 (m, 2H), 2,80~of 2.81 (m, 4H), 2,88~to 2.94 (m, 4H), 3,36~to 3.38 (m, 4H), 4,20~4,22 (t, 2H, J=5.3 Hz), 6,86 (c, 1H), 6,93~of 6.96 (DD, 2H, J=8.7 Hz), 7,93~of 7.96 (DD, 2H, J=8,7 Hz).

EI-MS m/e: 422,0 [M+], 258,9, 244,9, 201,9, 15,0, to 121.0, 70,0.

Example 6: 4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy}benzoic acid methyl ester

This compound was obtained by way of 1.3, where instead used phenol used the methyl ester of 4-hydroxybenzoic acid. The named compound was obtained as a white solid, yield: 45%, TPL 138-140°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 1,29~of 1.32 (t, 3H, J=7 Hz), 2,65~of 2.68 (t, 4H, J=4,8 Hz), 2,79~2,82 (t, 2H, J=5.6 Hz), 3,32~to 3.34 (t, 4H, J=5 Hz), 4,19~4,22 (t, 2H, J=5.6 Hz), 4,25~4,30 (square, 2H, J=7,3 Hz), 7,06~was 7.08 (DD, 2H, J=9 Hz), 7,40 (c, 1H), of 7.90-a 7.92 (DD, 2H, J=9 Hz).

EI-MS m/e: 410 [M+], 379, 259,0, 247,0, 175,1, 202,0, 92,0, 70,1.

Example 7: 1-(4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenyl)

heptane-1-it.

This compound was obtained by way of 1.3, where instead used phenol was used 1-(4-hydroxyphenyl)heptane-1-it. The named compound was obtained as a white solid, yield: 43.5%of TPL 113-115°C.

1H-NMR (400 MHz, CDCl3):ppm: 0,87~of 0.91 (t, 3H, J=6,7 Hz), 1,29~of 1.40 (m, 6H), 1,68~of 1.76 (m, 2H), 2,89~of 2.93 (m, 8H), 3,36~to 3.38 (m, 4H), 4,20~4,22 (t, 2H, J=5,32 Hz)6,86 (c, 1H), 6,94~of 6.96 (DD, 2H, J=9 Hz), 7,93~of 7.96 (DD, 2H, J=9 Hz).

EI-MS m/e: 464,0[M+], 258,9, 244,9, 201,8, 175,0, 70,0.

Example 8: 4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy]benzoic acid propyl ether

This compound was obtained by way of 1.3, where instead used phenol used and propyl ester of 4-hydroxybenzoic acid. The named compound was obtained as a white solid, yield: 47%, TPL 139-141°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 0,94~and 0.98 (t, 3H, J=7,3 Hz), 1,68-of 1.73 (m, 2H), 2,65~of 2.68 (t, 4H, J=4,8 Hz), 2,79~2,82 (t, 2H, J=5.6 Hz), 3.33 and~at 3.35 (t, 4H, J=5 Hz), 4,17~4,22 (m, 4H), 7,06~was 7.08 (DD, 2H, J=9 Hz), 7,40 (c, 1H), of 7.90~a 7.92 (DD, 2H, J=9 Hz).

EI-MS m/e: 438,1 [M+], 379, 259,0, 245,0, 175,1, 202,0, 70,1.

Example 9: 4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy]

phenylacetonitrile

This compound was obtained by way of 1.3, where instead used phenol used 4-hydroxyphenylacetonitrile. The named compound was obtained as a white solid, yield: 45.5 per cent, TPL 137-139°C.

1H-NMR (400 MHz, CDC13)ppm: 2,78-2,8l (t, 4H, J=4.5 Hz), 2,89~of 2.92 (t, 2H, J=5.3 Hz), 3,36~to 3.38 (t, 4H, J=4,8 Hz), 3,70 (c, 2H), 4,13~of 4.16 (t, 2H, J=5.3 Hz), 6,86 (c, 1H), 6,91~6,93 (m, 2H), 7.24 to~7,26 (m, 2H).

EI-MS m/e: 391,0 [M+], 259,0, 247,0, 201,9, 175,1, 77,0, 70,0.

Example 10: 4-{4-[2-(4-bromophenoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazin

This compound was obtained by way of 1.3, where instead used phenol used 4-bromophenol. The named compound was obtained as a white solid, yield: 43%, TPL 124-126°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 2,80 (USS, 4H), 2.91 in (USS, 2H), 3,37 (USS, 4H), 4,12 (USS, 2H), 6,78~PC 6.82 (m, 2H), 6,86 (c, 1H), 7,37~7,4l (m, 2H).

EI-MS m/e: 431,9[M+], 259,0, 245,0, 201,9, 175,0, 91,0, 70,1.

Prima is 11: 3,6-dichloro-4-{4-[2-(4-nitrophenoxy)ethyl]piperazine-1-yl}pyridazin

This compound was obtained by way of 1.3, where instead used phenol used 4-NITROPHENOL. The named compound was obtained as a white solid, yield: 41%, TPL 128-129°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 2,66~of 2.68 (m, 4H), 2,81~and 2.83 (t, 2H, J=5.6 Hz), 3.33 and~at 3.35 (m, 4H), 4,27~4,30 (t, 2H, J=5.6 Hz), 7,17~7,20 (d, 2H, J=9 Hz), 7,40 (c, 1H), 8,20~by 8.22 (d, 2H, J=9 Hz).

EI-MS m/e: 397,0 [M+], 259,0, 245,0, 201,9, 175,0, 70,0.

Example 12: 3,6-dichloro-4-{4-[2-(4-methoxyphenoxy)ethylpiperazin-1-yl]}pyridazin

This compound was obtained by way of 1.3, where instead used phenol used 4-methoxyphenol. The named compound was obtained as a white solid, yield: 42.5 per cent, TPL 138-140°C.

1H-NMR (400 MHz, CDCl3)ppm: 2,79 (USS, 4H), 2,87~2,90 (t, 2H, J=5.3 Hz), 3,36~to 3.38 (m, 4H), 3,78 (c, 3H), 4.09 to~of 4.11 (t, 2H, J=5.3 Hz), 6,83~6,89 (m, 5H).

EI-MS m/e: 382,1 [M+], 259,0, 245,0, 202,0, 175,1, 70,1.

Example 13: 4-{2-[4-(3,6-dichloropyridazin-4-yl)-piperazine-1-yl]ethoxy}benzoic acid isopropyl ester

This compound was obtained by way of 1.3, where instead used phenol was used isopropyl ester of 4-hydroxybenzoic acid. The named compound was obtained as a white solid, yield: 52%, TPL 135-137°C.

1H-NMR (400 MHz, DMSO-d6)ppm: of 1.29 to 1.31 (d, 6H, J=6.2 Hz) to 2.65~of 2.68 (m, 4H), 2,79~of 2.81 (t, 2H, J=5.6 Hz), 3.33 and~3,34 (who, 4H), 4,18~4,2l (t, 2H, J=5.6 Hz), 5,06~5,13 (m, 1H), 7,05~7,07 (DD, 2H, J=9 Hz), 7,40 (c, 1H), of 7.90~a 7.92 (DD, 2H, J=9 Hz).

EI-MS m/e 381 [M+], 346,0, 258,0, 229,9, 175,9, 124,0, 109,0.

Example 14: 4-{4-[2-(4-butoxyethoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazin.

This compound was obtained by way of 1.3, where instead used phenol used 4-butoxyphenol. The named compound was obtained as a white solid, yield: 40.5 per cent, TPL 135-136°C.

1H-NMR (400 MHz, CDCl3)ppm: 0,94~0,99 (t, 3H, J=7,7 Hz), 1,47~1,51 (m, 2H), 1,73~of 1.76 (m, 2H), 2,83 (USS, 4H), 2,90 (USS, 2H), 3,39 (USS, 4H), 3,90~3,93 (t, 2H, J=6.4 Hz), 4,11~of 4.12 (t, 2H, J=5 Hz), 6,84~6,85 (m, 4H), 6,86 (c, 1H).

EI-MS m/e: 424,1 [M+], 259,0, 245,0, 201,9, 175,1, 110,0, 70,1.

Example 15: 3,6-dichloro-4-{4-[2-(2-nitrophenoxy)ethyl]piperazine-1-yl}pyridazin.

This compound was obtained by way of 1.3, where instead used phenol was used 2-NITROPHENOL. The named compound was obtained as a white solid, yield: 46.5 per cent, TPL 125-126°C.

1H-NMR (400 MHz, CDCl3)ppm: 2,78~of 2.81 (t, 4H, J=4.5 Hz), 2,89~of 2.92 (t, 2H, J=5.3 Hz), 3,36~to 3.38 (t, 4H, J=4,8 Hz), 3,70 (c, 2H), 4,13~of 4.16 (t, 2H, J=5.3 Hz), 6,86 (c, 1H), 6,91~6,93 (m, 2H), 7.24 to~7,26 (m, 2H).

EI-MS m/e: 391,0 [M+], 259,0, 247,0, 201,9, 175,1, 77,0, 70,0.

Example 16: 3,6-dichloro-4-[4-(2-p-methylphenoxy)piperazine-1-yl]pyridazin.

This compound was obtained by way of 1.3, where instead used phenol used 4-METHYLPHENOL. Named connect the Addendum was received in the form of a white solid, yield: 42%, TPL 95-96°C.

1H-NMR (400 MHz, CDCl3)ppm: 2,23 (c, 3H), 2,64~of 2.66 (m, 4H), 2,74~2,77 (t, 2H, J=5.7 Hz), 3,32-to 3.34 (m, 4H), 4,05~4,08 (t, 2H, J=5.7 Hz), 6,83~6,85 (DD, 2H, J=8,4 Hz), 7,09~7,11 (DD, 2H, J=8,4 Hz), 7,40 (c, 1H).

EI-MS m/e: 438,2 [M+], 379,1, 259,1, 245,1, 175,1, 70,1.

Example 17: 3,6-dichloro-4-[4-(2-o-methylphenoxy)piperidine-1-yl]pyridazin

This compound was obtained by way of 1.3, where instead used phenol was used 2-METHYLPHENOL. The named compound was obtained as a white solid, yield: 48.5%, and TPL 106-108°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 2.13 in (c, 3H), 2,67~2,69 (t, 4H, J=4.5 Hz), 2,79~2,8l (t, 2H, J=5.6 Hz), 3,31~of 3.33 (t, 4H, J=4.5 Hz), 4,07~4,10 (t, 2H, J=5.6 Hz), 6,80~at 6.84 (m, 1H), 6.89 in~6,91 (d, 1H, J=8.1 Hz), 7,10~7,14 (m, 2H), 7,29 (c, 1H).

EI-MS m/e: 366,1 [M+], 259,0, 245,0, 202,0, 175,1, 91,0, 70,0.

Example 18: 1-(4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}

phenyl)Etalon.

This compound was obtained by way of 1.3, where instead used phenol was used 1-(4-hydroxyphenyl)Etalon. The named compound was obtained as a white solid, yield: 47.5 per cent, TPL 115-117°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 2,50~2,52 (t, 3H, J=5.6 Hz), 2,65~of 2.68 (m, 4H), 2,79~2,82 (t, 2H, J=5,9 Hz), 3.33 and~at 3.35 (m, 4H), 4,20~to 4.23 (t, 2H, J=5,9 Hz), 7,06~was 7.08 (DD, 2H, J=9 Hz), 7,4 (c, 1H), 7,92~7,94 (DD, 2H, J=8.7 Hz).

EI-MS m/e: 394,0[M+], 259,0, 247,0, 201,9, 175,0, 70,0.

Example 19: 3,6-dichloro-4-{4-[2-(2,4-dinitrophenyl)the Teal]piperazine-1-yl}pyridazin.

This compound was obtained by way of 1.3, where instead used phenol was applied 2,4-dinitrophenol. The named compound was obtained as a white solid, yield: 41.5 percent, TPL 145-146°C.

1H-NMR (400 MHz, CDCl3)ppm: 2,84 (USS, 4H), 3,01 (USS, 4H), 4,40 (USS, 4H), 6.87 in (c, 1H), 7.23 percent~of 7.25 (d, 1H, J=9,2 Hz), 8,44~of 8.47 (DD, 2H, J1=9,2 Hz, J2=2,8 Hz), 8,77-8,78 (d, 1H, J=2.5 Hz).

EI-MS m/e: 443,1 [M+], 427,1, 338,3, 245,1, 177,1, 95,1, 83,1, 68,1.

Example 20: 4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}benzonitrile.

This compound was obtained by way of 1.3, where instead used phenol used 4-hydroxybenzonitrile. The named compound was obtained as a white solid, yield: 43.5%of TPL 175-177°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 2,64~to 2.67 (m, 4H), 2,78~of 2.81 (t, 2H, J=5.6 Hz), 3,32~at 3.35 (m, 4H), 4,20~to 4.23 (t, 2H, J=5.6 Hz), 7,13~to 7.15 (DD, 2H, J=9 Hz), 7,40 (c, 1H), 7,76~7,79 (DD, 2H, J=9 Hz).

EI-MS m/e: 377 [M+], 245, 230, 201,9, 175,1, 119,0, 70,0.

Example 21: 3-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}benzoic acid methyl ester

This compound was obtained by way of 1.3, where instead used phenol used the methyl ester of 3-hydroxybenzoic acid. The named compound was obtained as a white solid, yield: 52.5 per cent, TPL 105-107°C.

1H-NMR (400 MHz, DMSO-d6)h/ml is: 2,13 (c, 3H), 2,80~2,82 (t, 4H, J=4.5 Hz), 2.91 in~to 2.94 (t, 2H, J=5.3 Hz), 3,36~to 3.38 (t, 4H, J=4.5 Hz), 3,92 (c, 3H), 4,18~is 4.21 (t, 2H, J=5.6 Hz), 6,86 (c, 1H), 7,11~7,14 (m, 1H), 7,34~7,38 (t, 1H, J=7.9 Hz), 7,58~to 7.59 (m, 1H), of 7.64~7,66 (d, 1H, J=7,8 Hz).

EI-MS m/e: 409,9 [M+], 378,9, 244,9, 201,9, 175,0, 120,9, 77,0, 70,0.

Example 22: 4-{4-[2-(4-tert-butylphenoxy)ethyl]piperazine-1-yl}-3,6-

dichloropyridazin

This compound was obtained by way of 1.3, where instead used phenol used 4-tert-butylphenol. The named compound was obtained as a white solid, yield: 49%, TPL 97-99°C.

1H-NMR (400 MHz, CDCl3)ppm: 1.30 on (c, 9H), 2,78 is 2.80 (m, 4H), 2,88~2,9l (t, 2H, J=5.6 Hz), 3,35~3,37 (m, 4H), 4,12~to 4.15 (t, 2H, J=5.6 Hz), 6,85~6,87 (DD, 2H, J=9 Hz), 6,86 (c, 1H), 7,30~to 7.32 (DD, 2H, J=9 Hz).

EI-MS m/e: 408,0 [M+], 244,9, 259,0, 175,0, 91,0, 70,0.

Example 23: 3,6-dichloro-4-{4-[2-(4-ethoxyphenoxy)ethyl]piperazine-1-yl}pyridazin.

This compound was obtained by way of 1.3, where instead used phenol used 4-ethoxyphenol. The named compound was obtained as a white solid, yield: 54.5 per cent, TPL 93-95°C.

1H-NMR (400 MHz, CDCl3)ppm: 1,38~of 1.42 (t, 3H, J=7 Hz), 3,07 (USS, 6H), 3,53 (USS, 4H), 3.96 points~to 4.01 (t, 2H, J=7 Hz), 6,85~6,92 (m, 5H).

EI-MS m/e: 396,1 [M+], 259,0, 245,0, 202,0, 175,1, 109,0, 70,1.

Example 24: 4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}benzaldehyde.

This compound was obtained by way of 1.3, where instead used phenol used 4-grams is proximinality. The named compound was obtained as a white solid, yield: 52.5 per cent, TPL 110-112°C.

1H-NMR (400 MHz, CDCl3)ppm: 2,81 (USS, 4H), 2.95 and (USS, 2H), 3,38 (USS, 4H), 4,24 (USS, 2H), 7,02~? 7.04 baby mortality (DD, 2H, J=8.7 Hz), the 7.85~7,87 (DD, 2H, J=8.7 Hz), 9,9 (c, 1H).

EI-MS m/e: 380,0[M+], 245,0, 229,9, 201,9, 175,0, 70,0.

Example 25: 4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzonitrile

25.1: 2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethanol

In a round bottom flask of 50 ml volume was placed 9,18 g (0.05 mol) of 3,4,6-trichloropyridine, 5.30 g (0.05 mol) of anhydrous sodium carbonate and 20 ml of N,N-dimethylacetamide (DMA), the reagents were mixed at room temperature, then slowly dropwise added 6,54 g (0.05 mol) of 2-(piperidine-4-yl)ethanol (dissolved in 10 ml of DMA), after adding dropwise, and the mixture was which during the night, the next day, the reaction liquid was poured into 100 ml of distilled water, the product was extracted three times using dichloromethane in a total volume of 200 ml, the extraction solutions were combined, dried over anhydrous Na2SO4concentrated and separated using column chromatography (eluent - petroleum ether:acetone=10:3), received 6 g of 2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethanol, yield: 43.6 per cent.

1H-NMR (400 MHz, DMSO-d6)ppm: 1,21~1,31 (m, 2H), 1,39~1,43 (m, 2H), 1,59~to 1.67 (m, 1H), 1,76-1,79 (dsirs, 2H, 2,82~is 2.88 (dt, 2H, J=11 Hz), 3.45 was~to 3.49 (m, 2H), 3,70-to 3.73 (dsirs, 2H), 4,40 was 4.42 (t, 1H, J=5 Hz), 7,35 (c, 1H).

25.2: 4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzonitrile

In a dry three-neck flask with a volume of 50 ml was placed 0,554 g (0.002 mol) obtained by the authors of 2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethanol, 0.20 g (0.002 mol) of p-hydroxybenzonitrile, 0,612 g of triphenylphosphine, and poured into the flask 15 ml of anhydrous tetrahydrofuran under cooling with ice bath and in a protective atmosphere of nitrogen gas, and then added dropwise to the flask was added 0.35 ml of diethylenediamine (DEAD)dissolved in 5 ml of anhydrous tetrahydrofuran. After adding dropwise, the temperature was raised to room temperature, and stirring was continued over night. The next day the solvent was removed using a rotary evaporator, the residue was poured into 100 ml of water, the product was extracted three times using in the amount of 150 ml of dichloromethane, the extraction solutions were combined, dried over anhydrous Na2SO4concentrated and separated using column chromatography (eluent - petroleum ether:ethyl acetate:methanol=10:1:0.5), and was obtained 0.26 g of 4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzonitrile in the form of a white solid. Output: 34,0%, TPL 138-139°C.

1H-NMR (400 MHz, CDCl3)ppm: 1,49~of 1.55 (m, 2H), 1,83~to 1.86 (m, 3H), 1.91 a~1,94 (dsirs, 2H), 2,82~2,87 (dt, 2H, J11,4 Hz), 3,76~3,79 (dsirs, 2H), 4,08~of 4.11 (t, 2H, J=5.8 Hz), 6,85 (c, 1H), 6,94~of 6.96 (d, 2H, J=8,8 Hz), 7,58~to 7.61 (d, 2H, J=8,8 Hz), 7,40 (c, 1H).

EI-MS m/e: 376 [M+], 258, 244, 228, 176, 119, 112.

Example 26: 1-(4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}

phenyl)alanon

This compound was obtained by way 25.2, where instead used phenol was used 1-(4-hydroxyphenyl)Etalon. The named compound was obtained as a white solid, yield: 42.5 per cent, TPL 99-100°C.

1H-NMR (400 MHz, CDCl3)ppm: 1,49~of 1.52 (m, 2H), 1,84~to 1.86 (m, 3H), 1,92~1,95 (m, 2H), 2.57 m (c, 3H), 2,81~is 2.88 (m, 2H), 3,76~with 3.79 (m, 2H), 4,11~to 4.14 (t, 2H, J=5,9 Hz), 6,85 (c, 1H), 6,92~to 6.95 (m, 2H), 7,93~of 7.96 (m, 2H).

EI-MS m/e: 393,0 [M+], 378,0, 358,0, 258,0, 227,9, 201,9, 175,9, 121,0, 77,0.

Example 27: connection of 3,6-dichloro-4-{4-[2-(4-nitrophenyl)ethyl]piperidine-1-yl}

pyridazin

This compound was obtained by way 25.2, where instead used phenol used 4-NITROPHENOL. The named compound was obtained as a white solid, yield: 30,5%, TPL 162-164°C.

1H-NMR (400 MHz, CDCl3)ppm: 1,47~of 1.56 (m, 2H), 1,82~of 1.94 (m, 5H), 2,81~2,87 (m, 2H), 3,76~with 3.79 (m, 2H), 4,11~to 4.14 (t, 2H, J=5,9 Hz), 6,85 (c, 1H), 6,93~6,97 (m, 2H), 8,18~by 8.22 (m, 2H).

EI-MS m/e 396 [M+], 258, 228, 244, 176, 109, 67.

Example 28: 4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzoic acid methyl ester

This compound was obtained by way 25.2, where instead used phenol used is the methyl ester of 4-hydroxybenzoic acid. The named compound was obtained as a white solid, yield: 36.5%, and TPL 115-117°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 1.32 to~of 1.40 (m, 2H), 1,75 (USS, 3H), 1,83~of 1.86 (d, 2H, J=12.3 Hz), 2,85~only 2.91 (m, 2H), 3.72 points~of 3.75 (d, 2H, J=12.3 Hz), 4,12~to 4.15 (t, 2H, J=6.2 Hz), 7,05~7,07 (DD, 2H, J=8.7 Hz), was 7.36 (c, 1H), of 7.90~a 7.92 (DD, 2H, J=8.7 Hz).

EI-MS m/e: 409,0[M+], 374,1, 258,0, 228,0, 175,9, 121,0.

Example 29: 4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzoic acid ethyl ester

This compound was obtained by way 25.2, where instead used phenol was used ethyl ester of 4-hydroxybenzoic acid. The named compound was obtained as a white solid, yield: 26.5 per cent, TPL 153 to 155°C.

1H-NMR (400 MHz, DMSO-d6)ppm: 1,16~1,19 (t, 3H, J=7 Hz), 1,23~of 1.40 (m, 3H), 1,75~1,76 (USS, 2H), 1,83~of 1.86 (d, 2H, J=12.3 Hz), 2,85~only 2.91 (dt, 2H, J=12.3 Hz), 3.72 points~3,76 (d, 2H, J=12.3 Hz), 4,12~to 4.15 (t, 2H, J=6.2 Hz), 4,24~4,30 (square, 2H, J=7 Hz), 7,05~7,07 (DD, 2H, J=9 Hz), was 7.36 (c, 1H), of 7.90~a 7.92 (DD, 2H, J=9 Hz).

EI-MS m/e): 423 [M+], 379,0, 351,0, 257,9, 227,9, 175,9, 120,9.

Example 30: 3,6-dichloro-4-{4-[2-(4-methoxyphenoxy)ethyl]piperidine-1-yl}pyridazin

This compound was obtained by way 25.2, where instead used phenol used 4-methoxyphenol. The named compound was obtained as a white solid, yield: 37,5%, TPL 119-120°C.

1H-NMR (400 MHz, CDCl3)ppm: 1,44~of 1.53 (m, 2H), 1.77 in~is 1.82 (m, 3H), 1.91 a~of 1.94 (d, 2H, J=12.3 Hz), 2,81~2,87 (m, 2H), 3.75 to~of 3.77 (d, 2H, J=9.8 Hz), of 3.77 (c, 3H), 3,98~to 4.01 (t, 2H, J=5.6 Hz), 6,83~6,85 (m, 5H).

EI-MS m/e 381 [M+], 346, 258, 229,9, 201,9, 175,9, 124,0, 109,0.

Example 31: the connection mcl040709 6-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}nicotinic acid ethyl ester

31.1. Ethyl ester of 6-hydroxynicotinic acid

In a three-neck flask with a volume of 100 ml were placed 0.84 g (0,006 mol) 6-hydroxynicotinic acid, 30 ml of anhydrous ethanol is slowly dropwise added 3 ml of concentrated sulfuric acid was heated overnight, evaporated in vacuum to remove excess ethanol, the residue was poured into water, the product was extracted with ethyl acetate, the extract was washed with a saturated solution of sodium bicarbonate, dried with anhydrous sodium sulfate and concentrated, obtaining 0.8 g of ethyl ester of 6-hydroxynicotinic acid. Yield: 80%, TPL 138-139°C.

31.2. 6-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}nicotinic acid ethyl ester

In a dry three-neck flask with a volume of 50 ml was placed 0,554 g (0.002 mol) obtained by the authors of 2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethanol, 0.28 g (0.002 mol) of the ethyl ester of 6-hydroxynicotinic acid, 0,612 g of triphenylphosphine and poured into the flask 15 ml of anhydrous tetrahydrofuran under cooling with ice bath and in a protective atmosphere of nitrogen gas, and then added dropwise to the flask was added 0.35 ml of diethylenediamine (DEAD), R is storengo in 5 ml of anhydrous tetrahydrofuran, after adding dropwise, the temperature was raised to room temperature, and stirring was continued over night. The next day the solvent was removed by evaporation using a rotary evaporator, the residue was poured into 100 ml of water, the product was extracted three times using in the amount of 150 ml of dichloromethane, the extraction solutions were combined, dried over anhydrous Na2SO4concentrated and separated column chromatography (eluent - petroleum ether:ethyl acetate:methanol=10:5:0.5), and getting 0.32 g of 6-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}nicotinic acid ethyl ester as a white solid. Output: 42,3%, TPL 140-141°C.

1H-NMR (400 MHz, CDCl3)ppm: 1,37~of 1.41 (t, 3H, J=7,3 Hz), 2,79 (USS, 4H), 2.91 in (USS, 2H), 3,36 (USS, 4H), 4,35~4,40 (square, 2H, J=7,3 Hz), 4,57 (USS, 2H), 6,78~to 6.80 (d, 2H, J=8.7 Hz), 6,86 (c, 1H), 8,16~8,18 (DD, 1H, J1=8,7 Hz, J2=2,2 Hz).

EI-MS m/e: 425 [M+], 258, 244,9, 223, 194,0, 175,0, 82,0, 70,0.

Example 32: 6-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}nicotinic acid methyl ester

This compound was obtained by way 31.2, where instead used phenol was used methyl ether 6-hydroxynicotinic acid. The named compound was obtained as a white solid, yield: 36.5%, and TPL 145-146°C.

1H-NMR (400 MHz, CDCl3)ppm: 2,65~of 2.66 (m, 4H), 2,77~2,80 t, 2H, J=5.6 Hz), 3.33 and~to 3.34 (m, 4H), 4,48~4,51 (t, 2H, J=5.6 Hz), 6,94~of 6.96 (d, 1H, J=8.7 Hz), 7,38 (c, 1H), 8,15~8,18 (m, 1H), total of 8.74~is 8.75 (d, 1H, J=2.2 Hz).

EI-MS m/e: 411,1 [M+], 376,1, 258,1, 245,1, 223,1, 202,1, 180,1, 82,1, 70,1.

Example 33: Activity against picornavirus compounds of the present invention in vitro models

Experimental materials:

HeLa cells (stored in the laboratory of the authors)

Rhinovirus-3 (HRV-3) (ATCC: VR-1113)

Big-eared rabbits (provided by Center of Laboratory Animals of the Military Medical Science Academy of the PLA)

Prophylactic administration:

Principle: the drug and the virus was pre-mixed and incubated to block decapitation viruses and their invasion into the cells.

Methods: the drug at a concentration of 100 ng/ml were placed in 12-well plate, then added dose of the virus with the value TCID50equal to about 100, after 0.5 h in each cell was added 500000 cells and incubated at 33°C. After three days, when the control group showed 100%cytopathic effect (CPE)was observed effects medicines to prevent phagocytosis of cells and expressed them as protection of cells (%). The results of routine introduction has shown that various compounds provide a different degree of protective effect by preventing phagocytosis of cells; and the compounds of examples 4, 13, 31 and 32 showed the best effects (see figure 1).

Terapeuticas the th introduction:

Objective: to further screening to identify drugs that were found the best preventive effects in the introduction.

Methods: 500,000 cells were added to each well, incubated at 33°C during the night for the clutch, then added dose of the virus with the value TCID50equal to about 100, after 0.5 h, the culture medium was removed by absorption, the drug was added to 12-well plate at a concentration of 100 ng/ml, the total volume of the reaction system was 2 ml. three days later, when the virus control group showed 100%, cytophagales (CPE)was observed effects medicines to prevent phagocytosis of the cells. The results showed that different compounds were provided varying degrees of protection of cells from phagocytosis; and compounds of example 31 showed the best effects (see figure 2).

Preliminary results on the determination of ex vivo level screening protivoerosionnih drugs

Preparation of tracheal rings: the rabbits were killed by an intravenous infusion of overdose phenobarbital sodium, then took the trachea, tissue and epithelial cells, associated with trachea was separated, then the trachea was divided into ring width 6-8 mm

The way therapy medicinal product: tracheal rings were placed in a nutrient medium 1640+2%FCS, at the same time added a medicinal medium spans the (final concentration: 100 μg/ml) and rhinovirus (final concentration: 106), incubated at 33°C for 90 min, then incubated at 23°C for 24 h Concentration of 10 μg/ml does not show significant therapeutic effects.

Measurement constrictional and dilatational force: tracheal rings were hung on a triangular support, brought them up to the equilibrium temperature 37°C in 20-ml bath for bodies Havard, was subjected to 10-7-10-3M Ach (acetylcholine), and each concentration was recorded maximum constrictional or maximum dilatational force, the results are shown in table 1 and figure 3.

Table 1
Experimental data (1) ex vivo levels of the compounds of Example 31
Tension (g)The concentration of Ach (log M)
-7-6-5,7-5,3-5-4,7-4,3-4was 3.70,59
Medicine 31
Average
0,000,110,350,73 1,001,301,541,72to 1.861,95
Virus
Average
0,000,110,531,061,661,922,322,622,873,05
Control
Average
0,000,130,400,610,861,291,501,792,072,34
SD (Compound of Example 31)0,000,090,310,430,450,480,520,580,590,56
SD (virus)0,120,23 0,480,560,840,920,910,961,051,12
SD (control)0,060,210,370,540,630,570,630,550,560,65

As shown in figure 3, Ach (acetylcholine) could cause increased tension of smooth muscles dependent on dosage, rhinovirus could increase the amplitude of increasing the tension of smooth muscles of the trachea induced by Ach, whereas the compound of example 31 was evidently able to inhibit an excessive increase in Ach-induced tension of smooth muscles of the trachea caused by rhinoviruses.

1. The compound of formula I, or its pharmaceutically acceptable salt, or hydrate:

where X represents C or N;
Y represents O or S;
W represents C or N;
R1, R2, R3each independently represents hydrogen or halogen;
R4, R5, R6each independently presented yet a hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7;
R7independently represents hydrogen or C1-C8is unbranched or branched alkyl.

2. The compound according to claim 1, having formula II:

where Y represents O or S;
W represents C or N;
R1, R2, R3each independently represents hydrogen or halogen;
R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7;
R7independently represents hydrogen or C1-C8is unbranched or branched alkyl.

3. The compound according to claim 1, having formula III:

where W represents C or N;
R1, R2, R3each independently represents hydrogen or halogen;
R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy or the ro, cyano, -COOR7, -CH2COOR7, -COR7;
R7independently represents hydrogen or C1-C8is unbranched or branched alkyl.

4. The compound according to claim 3, having formula IV:

where R1, R2, R3each independently represents hydrogen or halogen;
R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7;
R7independently represents hydrogen or C1-C8is unbranched or branched alkyl.

5. The compound according to claim 4, having the formula V:

where R4, R5, R6each independently represents hydrogen, halogen, C1-C8is unbranched or branched alkyl, C1-C8is unbranched or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7;
R7independently represents hydrogen or C1-C8is unbranched or branched alkyl.

6. The compound according to claim 1, which is selected from:
4-{4-[2-(4-butylphenoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazine,
4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-ylethoxy}phenylacetic acid ethyl ester,
3,6-dichloro-4-{4-[2-(2,6-dimethylphenoxy)]piperazine-1-yl}pyridazine,
4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenylacetic acid methyl ester,
1-(4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenyl)butane-1-it,
4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy}benzoic acid methyl ester,
1-(4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenyl)heptane-1-it,
4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy}benzoic acid propyl ester,
4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy}phenylacetonitrile,
4-{4-[2-(4-bromophenoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazine,
3,6-dichloro-4-{4-[2-(4-nitrophenoxy)ethyl]piperazine-1-yl}pyridazine,
3,6-dichloro-4-{4-[2-(4-methoxyphenoxy)ethylpiperazin-1-yl]}pyridazine,
4-{2-[4-(3,6-dichloropyridazin-4-yl-piperazine-1-yl)ethoxy}benzoic acid isopropyl ester,
4-{4-[2-(4-butoxyethoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazine,
3,6-dichloro-4-{4-[2-(2-nitrophenoxy)ethyl]piperazine-1-yl}pyridazine,
3,6-dichloro-4-[4-(2-p-methylphenoxy)piperazine-1-yl]pyridazine,
3,6-dichloro-4-[4-(2-o-methylphenoxy)piperidine-1-yl]pyridazine,
1-(4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}phenyl)ethanone,
3,6-dichloro-4-{4-[2-(2,4-dinitrophenyl)ethyl]piperazine-1-yl}pyridazine,
4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}benzonitrile,
3-{2-[4-(3,6-dichloropyridazin-4-the l)piperazine-1-yl]ethoxy}benzoic acid methyl ester,
4-{4-[2-(4-tert-butylphenoxy)ethyl]piperazine-1-yl}-3,6-dichloropyridazine,
3,6-dichloro-4-{4-[2-(4-ethoxyphenoxy)ethyl]piperazine-1-yl}pyridazine,
4-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}benzaldehyde,
4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzonitrile,
1-(4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}phenyl)ethanone,
3,6-dichloro-4-{4-[2-(4-nitrophenyl)ethyl]piperidine-1-yl}pyridazine,
4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzoic acid methyl ester,
4-{2-[1-(3,6-dichloropyridazin-4-yl)piperidine-4-yl]ethoxy}benzoic acid ethyl ester,
3,6-dichloro-4-{4-[2-(4-methoxyphenoxy)ethyl]piperidine-1-yl}pyridazine,
6-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}nicotinic acid ethyl ester and
6-{2-[4-(3,6-dichloropyridazin-4-yl)piperazine-1-yl]ethoxy}nicotinic acid methyl ester.

7. The method of obtaining the compounds of formula I according to claim 1, or its pharmaceutically acceptable salt, or hydrate, including:
(i) the interaction of the compounds of formula VI with gaseous chlorine in the presence of ferric chloride as a catalyst with the formation of the compounds of formula VII:

where R1, R2, R3have the same definitions as in claim 1;

where R1, R2, R3have the same definitions as in claim 1;
(ii) maintains deistvie the compounds of formula VII with the compound of the formula VIII with obtaining the compounds of formula IX:

where X has the same definition as in claim 1;

where R1, R2, R3and X have the same definitions as in claim 1;
(iii) the interaction of the compounds of formula IX with dichloromethoxy, then with a substituted phenol compound of the formula X in the condensation reaction

where R4, R5, R6, W and Y have the same definitions as in claim 1, to obtain the compounds of formula I:

where R1, R2, R3, R4, R5, R6, X, W and Y have the same definitions as in claim 1;
(iv) optionally a compound of formula I is transformed into its pharmaceutically acceptable salt by treatment with suitable pharmaceutically acceptable acid or base.

8. Pharmaceutical composition having inhibitory activity against picornaviruses, containing at least one compound of formula I, or its pharmaceutically acceptable salt, or hydrate according to any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers or excipients.

9. The use of compounds according to any one of claims 1 to 6 to obtain drugs for prevention and/or treatment of diseases caused by picornaviruses, such as rhinoviruses and enteroviruses.

10. The use according to claim 9, where the illness is s specified rhinoviruses, include the common cold, pharyngitis, tonsillitis, croup.



 

Same patents:

Novel insecticides // 2379301

FIELD: chemistry.

SUBSTANCE: compounds with formula I are described, where each of E and Z is oxygen; A is C1-C6alkylene or a 3-member monocyclic ring system, which can be monosubstituted; Y is C1-C6alkylene; p equals 0; q equals 0 or 1; B represents a 3- or 4-member ring system which is completely or partially saturated and can contain a heteroatom selected from oxygen, possibly substituted; each R1 independently represents halogen, nitro group, C1-C6alkyl; or each R1 independently represents an amino group; n equals 1, 2; each of R2 and R3 represents hydrogen; D represents a group and agronomically acceptable salts of said compounds. Also described is a method of producing formula I compounds, intermediate compounds, a pesticide composition containing a formula I compound, as well as an insect control method and a method of protecting plant propagation material.

EFFECT: novel anthranylamide derivatives have good insecticidal activity.

16 cl, 8 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: pharmacology.

SUBSTANCE: invention covers new compounds of formula I: or its pharmaceutically acceptable salt with antagonist activity to corticotrophin release factor (CRF). In formula (I) X means heteroaryl chosen of pyrazolyl and imidazolyl optionally substituted with (C1-C6)alkyl, haloid or phenyl; Y means -NRaRb where Ra means hydrogen, and Rb means phenyl optionally substituted with (C1-C6)alkyl or haloid; Z means (C1-C6)alkyl; and R1 means hydrogen, (C1-C6)alkyl or haloid.

EFFECT: compounds can find application in treatment, eg of neurodegenerative diseases, neuropsychiatric disorders and stresses.

19 cl, 1 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of common formula (I) , in which: A, if available, means (C1-C6)-alkyl; R1 means group NR6R7, (C4-C7)-azacycloalkyl, (C5-C9)-azabicycloalkyl, besides, these groups, unnecessarily, are substituted with one or more substituents, selected from (C1-C5)-alkyl or halogen; A-R1 is such that nitrogen of radical R1 and nitrogen in position 1 of pyrazole are necessarily separated at least by two atoms of carbon; R3 means radical H, OH, NH2, ORc, NHC(O)Ra or NHSO2Ra; R4 means phenyl or heteroaryl, unnecessarily, substituted with one or more substituents, selected from halogen, CN, NH2, OH, ORc, C(O)NH2, phenyl, polyfluoroalkyl, linear or ramified (C1-C6)-alkyl, besides these substituents, unnecessarily, are substituted with halogen, and moreover, heteroaryl radicals are 3-10-member, containing one or more heteroatoms, selected from sulphur or nitrogen; R5 means radical H, linear or ramified (C1-C6)-alkyl; Ra means linear or ramified (C1-C6)-alkyl; Rc means linear or ramified (C1-C6)-alkyl, (poly)fluoroalkyl or phenyl; R6 and R7, independently from each other, means hydrogen, (C1-C6)-alkyl; R6 and R7 may create 5-, 6- or 7-member saturated or non-saturated cycle, which includes one heteroatom, such as N, and which, unnecessarily, substituted with one or more atoms of halogen; to its racemates, enantiomers, diastereoisomers and their mixtures, to their tautomers and their pharmaceutically acceptable salts, excluding 3-(3-pyridinyl)-1H-pyrazole-1- butanamine, 4-(3-pyridinyl)-1H-pyrazole-1-butanamine and N-(diethyl)-4-phenyl-1H-pyrazole-1-ethylamine. Invention is also related to methods for production of compounds of formula (I) and to pharmaceutical composition intended for treatment of diseases that appear as a result of disfunction of nicotine receptors α7 or favorably responding to their modulation, on the basis of these compounds.

EFFECT: production of new compounds and pharmaceutically acceptable composition on their basis, which may find application in medicine for treatment, prophylaxis, diagnostics and observance over development of psychiatric or neurological disorders or diseases of central nervous system, when cognitive functions deteriorate or quality of sensor information processing drops.

16 cl, 106 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: medicine.

SUBSTANCE: there are described new isoindole derivatives of general formula (1), wherein A1, A2 and A4 stands for CH, and A3 means N or C-OH; n is equal to 2; R1 represents O; R2-stands for H; and a pharmaceutical composition containing thereof.

EFFECT: new compounds are inhibitors of chaperone protein Hsp90 activity and can be used in chemotherapy of cancerous diseases.

6 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives of formula I: , where: Ra is H, C1-4alkyl; one of Ra, Rc, Rd and Re is C1-4alkyl; and the other three substitutes are H; or Rb, Rd, Re are all H; and R is a radical of formula (a): , where R1 is -(CH2)n-NR3R4, where each of R3 and R4 are independently H, C1-4alkyl; n is 0, 1, 2; R2 is H; halogen; or its pharmaceutically acceptable salt.

EFFECT: wider field of use of the compounds.

8 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula (I) , Q is: (IIa) or (IIb) , R1 is chosen from a group which consists of carboxylic aryl and carboxylic aryl which is substituted with substitute(s) independently chosen from a group which consists of halogen, cyano, nitro, C1-10alkyl, C1-10alkyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-9alkoxy, C1-9alkoxy which is substituted with substitute(s) independently chosen from a group which consists of halogen, mono-C1-5alkylamino, and heterocyclyl or heterocyclyl which is substituted with substitute(s) independently chosen from a group which consists of halogen, C1-5alkyl; R2 is C1-5alkyl, C1-5alkyl which is substituted with halogen, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, -N(R2a)(R2b); where R2a and R2b are each independently hydrogen, C1-5alkyl or C1-5alkyl, substituted with substitute(s) independently chosen from a group which consists of hydroxyl, carboxylic aryl; L represents formula (IIIa); , where R3 and R4 are each hydrogen; A is a single bond, and B is a single bond or -CH2-; Z1, Z3, and Z4 are each independently hydrogen, halogen, C1-5alkyl, C1-5alkyl, substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Z2 is hydrogen, C1-5alkyl, C1-5alkyl which is substituted with carboxylic aryl, C1-5alkoxy, mono-C1-5alkylamino, di-C1-5alkylamino, carboxylic aryl, heterocyclyl or substituted heterocyclyl; Y is -C(O)NH-, -C(O)-, -C(S)NH-, -C(O)O- or -CH2-; where carboxylic aryl is phenyl; heterocyclyl is 1H-indolyl, 9H- xanthenyl, benzo[1,3]dioxolyl, furyl, imidazolyl, isoxazolyl, morpholinyl, piperazinyl, pyridyl, pyrrolidyl; halogen is fluorine, chlorine, bromine or iodine. The invention also relates to a pharmaceutical composition.

EFFECT: compounds can be used for treating central nervous system diseases, and for improving memory functioning, sleep, awakening, diabetes.

16 cl, 8 dwg, 4 tbl, 525 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: present invention concerns a derivative of pyridonecarboxylic acid presented by formula (1): or its salts where R1 represents methyl group, fluorine atom or chlorine atom; R2 represents hydrogen atom or lower alkyl group; R3 represents isopropyl group or tert-butyl group; R4 represents methyl group or halogen atom; and R5 represents fluorine atom or chlorine atom, and also an antibacterial preparation and a pharmaceutical composition, containing specified derivative or its salt as an active component. Besides the invention describes application of the compound under item 1 and the method of treating the infectious disease.

EFFECT: new compound shows excellent antibacterial activity, low toxicity, improved biological availability and low speed of binding with serum proteins.

10 cl, 4 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of aminobenzimidazole and benzimidazole of general formula (I-b-1), additive salt or stereochemically isomeric form thereof, where G is a single bond or C1-10alkanediyl; R1 is halogenphenyl, pyridyl, pyrazinyl, quinolinyl, benzimidazoly or a radical of formula (c-4), where each of the said monocyclic or bicyclic heterorings can be optionally substituted with 1, 2 or 3 substitutes, independently selected from a group consisting of halogen, hydroxy, C1-6alkyl, C1-6alkyloxy, Ar1C1-6alkyloxy, C1-6alkyloxy-CH2-CH2-O-; m equals 2; Q is hydrogen, amino or mono(C1-4alkyl)amino; R3b is hydrogen or C1-6alkyl; R4a is selected from a group of substitutes consisting of hydrogen, Ar2C1-6alkyl, Het- C1-6alkyl, hydroxy C1-6alkyl, (hydroxyC1-6alkyl)oxy C1-6alkyl, C1-6alkyl, (Ar1C1-6alkyloxy)(hydroxy)C1-6alkyl, aminoC1-6alkyl, mono- and di(C1-6alkyl)amino-C1-6alkyl, carboxyl-C1-6alkyl, C1-6alkyloxycarbonyl C1-6alkyl, aminocarbonylC1-6alkyl, (C1-4alkyloxy)2-P(=O)-C1-6alkyl, aminosulphonylC1-6alkyl; R6a is hydrogen or C1-6alkyl; R6b is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl; R6c is C1-6alkyl; Alk is C1-6alkanediyl; R9, R10, R11 are each independently selected from halogen, cyano, C1-6alkyl, Het-C1-6alkyl, Ar1C1-6alkyl, cyano C1-6alkyl, C2-6alkenyl, R6b-O-C3-6alkenyl, C2-6alkynyl, Ar1, R6b-O-, R6b-S-, R6b-O- C1-6alkyl-SO2-, polyhalo-C1-6alkyl, polyhaloC1-6alkyloxy, polyhaloC1-6alkylthio, R6c-C(=O)-, R6b-O-C(=O)-, N(R6aR6b)-C(=O)-, R6b-O-C1-6alkyl, R6b-O-C(=O)-C1-6alkyl, N(R6aR6b)-C(=O)-C1-6alkyl, R6c-C(=O)-NR6b-, N(R6aR6b)-S(=O)2-, H2N-C(=NH)-, and R10 and/or R11 can also be hydrogen; Ar1 is phenyl; Ar2 is phenyl; Het is a heteroring selected from imidazolyl or morpholinyl. The invention also relates to a pharmaceutical composition based on formula (I-b-1) compound, use of formula (I-b-1) compound to prepare a medicinal agent and a method of producing formula (I-b-1) compound.

EFFECT: novel aminobenzimidazole and benzimidazole derivatives with antiviral activity are obtained.

15 cl, 8 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I): , where: X is N or C-R6; R1 is C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluoro-C1-7alkyl, hydroxy-C1-7alkyl, CN-C1-7alkyl, R10C(O), R10OC(O)-, N(R11,R12)C(O)-; R10OC(O)C1-7alkyl, N(R11,R12)C(O)-C1-7alkyl, R10SO2, R10-SO2-C1-7alkyl, N(R11, R12)-SO2, N(R11,R12)-SO2-C1-7alkyl, aryl-C1-7alkyl, 5-member monocyclic heteroaryl containing a nitrogen atom, where the ring carbon atom can be substituted with a carbonyl group, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents an aromatic -member monocyclic ring with 1 S atom or a 6-member monocyclic ring with 1 N atom, C1-7alkoxy-C1-7alkyl, C1-7alkoxycarbonyl-C3-10cycloalkyl-C1-7alkyl or halogen substituted 4-member heterocyclyl-C1-7alkyl with one O atom; R2 is H, C1-7alkyl; R3 is aryl, aryl-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 1 S atom, a 6-member monocyclic ring with 1 or 2 N atoms, 9-, 10-member bicyclic system with 1 or 2 N atoms in one ring; R4 is H, C1-7alkyl, OH; R5, R6, R7, R8 are independently selected from a group consisting of H, halogen, C1-7alkyl, C1-7alkoxy, flouro-C1-7alkyl, fluoro-C1-7alkyloxy; R9 is aryl, heterocyclyl, heteroaryl, heterocyclyl-C(O)-; R10 is H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluro-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 4 N atoms, a 5-member heterocyclyl with 1 N atom; R11, R12 are independently selected from a group consisting of H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7 alkyl; and pharmaceutically acceptable salts thereof; where the term "aryl" represents a phenyl group which can be optionally substituted with 1 to 5 substitutes which are independently selected from a group consisting of the following: halogen, CF3, NH2, C1-7alkylsulphonyl, C1-7alkoxy, fluoro-C1-7alkyl, fluoro-C1-7 alkoxy; the term "heterocyclyl" represents a nonaromatic monocyclic 5-, 6-member heterocyclic group with 1, 2 N atoms, or with 1 N atom and 1 O atom, where the heterocyclyl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heterocyclyl group can be substituted with a carbonyl group; the term "heteraryl" represents an aromatic 5- or 6-member monocyclic ring system which can have 1, 2, 3 N atoms, or 1 N atom and 1 S atom, where the heteroaryl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heteroaryl group can be substituted with a carbonyl group. Formula I compounds have inhibitory activity towards coagulation factor Xa.

EFFECT: possibility of using said compounds in a pharmaceutical composition and for preparing a medicinal agent.

27 cl, 90 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel hydantoin derivatives of formula or pharmaceutically acceptable salt thereof, where R1 is H, halogen, CF3 or CH2CN; R2 is C1-3alkyl; each of A, A1 and B independently represents CH or N. The invention also relates to a method for synthesis of a formula I compound, to a pharmaceutical composition based a formula I compound and use thereof in making a medicinal agent.

EFFECT: obtaining novel hydantoin derivatives with inhibitory activity towards metalloproteinase.

10 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel quinoline derivatives of formula I or pharmaceutically acceptable salts thereof or esters with tyrosine kinase inhibitor properties. In formula I , R1 is selected from hydroxy, C1-C4-alkoxy, hydroxy(C2-C4-alkoxy), C1-C3-alkoxy-(C2-C4-alkoxy) or from a group of formula Q2-X3 - in which X3 is O, and Q2 is azetidin-1-yl-C2-C4-alkyl, pyrrolidin-1-yl- C2-C4-alkyl, piperidino-C2-C4-alkyl, piperazino-C2-C4-alkyl or morpholino-C2-C4-alkyl; b is 1, 2, or 3; each R2, which can be identical or different, is selected from fluorine, chlorine, bromine, C1-C4-alkyl, C2-C4-alkenyl and C2-C4-alkenyl; Q1 is piperidinyl; a is 0; X1 is CO; X2 is a group of formula: -(CR12R13)P-(Q5)m-, where m is 0 or 1, p is 0, 1, 2, 3 or 4; each of R12 and R13, which can be identical or different, is selected from hydrogen, C1-C6-alkyl, amino, C1-C6-alkylamino and di-[C1-C6-alkyl]amino, and Q5 is C3-C7cycloalkylene; Z is selected from hydroxy, amino, C1-C6-alkylamino, di-[C1-C6-alkyl]amino, C1-C6-alkoxy and a group of formula: Q6-X9-, in which X9 is a single bond and Q6 is heterocyclyl or heterocyclyl-C1-C4 alkyl; under the condition that, if m and p are equal to 0, Z is heterocyclyl.

EFFECT: proposed derivatives can be used in treating proliferative diseases, particularly for treating malignant growths.

32 cl, 4 dwg, 2 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclic compounds with the following general formula I or II and to pharmaceutically acceptable salts thereof and to all stereo isomers and optical isomers thereof:

, , where n equals 1, X and Y are NH; R1 and R2 independently represent one substitute selected from a group consisting of aryl; 2-, 3-, or 4-pyridyl; aryl substituted with one, two or three groups selected from C1-C4alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, amido, carbamide, mercapto, methylthio, ethylthio; R3 and R4 independently represent one substitute selected from a group consisting of aryl; 2-, 3- or 4-pyridyl; aryl substituted with one, two or three groups selected from C1-C4alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, amido, carbamide, mercapto, methylthio, ethylthio; 2-, 3- or 4-pyridyl, substituted with one, two or three groups selected from C1-C4alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, amido, carbamide, mercapto, methylthio, ethylthio. The invention also relates to a method of producing a range of substituted cyclic compounds and their salts in any of subclaims 1-4, to a pharmaceutical composition, to use, to a method of treating and preventing diseases as well as to an assembly.

EFFECT: obtaining new biologically active compounds suitable for treating or preventing diseases or symptoms, arising from or accompanied with violation of secretion and/or function of insulin.

13 cl, 4 ex, 3 tbl, 6 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns applications of compositions formulated as follows or its salt, solvate or prodrug of medical agent for treatment or prevention of disease state mediated by glucokinase (GLK). Besides, given invention concerns new group of composition formulated as (I) and to method of specified compositions production. The invention enables to widen range of agents used for treatment or prevention of disease conditions mediated by glucokinase (GLK) where each of R1, R2, R3, n and m has values specified in the description.

EFFECT: increased efficiency.

19 cl, 51 ex

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