Benzofuran derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to the compound with the formula (1): where R1 is C1-C12 alkyl group, which can have the substitute, or C2-C12 alkenyl group, which can have the substitute represented with the C6-C14 aryl group, which can be substituted with the halogen atoms; each of R2 and R3 represent the hydrogen atom, alkyl group, hydroxyalkyl group, dihydroxyalkyl group, or R2 and R3 form with the adjacent nitrogen atoms the 5-membered, 6-membered, or 7-membered nitrogen-containing saturated heterocyclic group, which can be substituted with the alkyl group; (the dotted line means the possible double bind), or its salt, as well as to the pharmaceutical composition containing the said compound, and to its application as a pharmaceuticals and to the treatment method.

EFFECT: invented compound demonstrates inhibiting activity against the tumor necrosis factor production (TNF-α) and improved absorbability after oral administration.

16 cl, 1 tbl, 18 dwg, 1 ex

 

The present invention relates to a derivative of benzofuran, which has an excellent inhibitory efficacy against production of tumor necrosis factor (TNF-αand high re-absorption after oral administration and, therefore, is effective for prevention or treatment of allergic diseases, immune diseases, inflammatory disease or similar diseases. The present invention also relates to a medicinal product containing a specified derivative as an active ingredient.

The tumor necrosis factor (TNF-α) is an inflammatory cytokine produced by cells such as macrophages. It shows various types of physiological activity and, therefore, is indispensable for the protection of the living body and maintaining homeostasis. It is considered that excessive production of tumor necrosis factor (TNF-α) is responsible for the allergic, inflammatory or autoimmune diseases such as articular rheumatism, arthritis deformans, asthma, bronchitis, atopic dermatitis, inflammatory disease of the internal organs, ulcerative colitis, Crohn's disease and acquired immunodeficiency syndrome (AIDS), and therefore, it is assumed that compounds exhibiting inhibitory activity against producerof is of TNF-α act as a preventive or therapeutic agent for these diseases.

Recently it was reported that anti-TNF-α antibodies and soluble TNF-α receptors demonstrated superior clinical efficacy (Lancet 344 1105 (1994), Ann. Intern. Med. 130 478 (1999)), which gives a more solid Foundation for the application of anti-TNF-α therapy.

These antibodies and receptors are often referred to as biological drugs and introduction by injection is inevitable for the introduction of the patient. Thus there remains a need in connection with a low molecular weight, which exhibits inhibitory activity against the production of TNF-α and may be absorbed through oral administration.

Compounds with a low molecular weight, having inhibitory action on the production of TNF-αdescribed to date include derivatives of oxyindole (WO 0122966, JP-A-2001-511449)derived thiazolyl (WO 0164674), derivatives of pyrrole (JP-A-2001-181187, JP-A-2000-514808), derivatives of piperidinylidene (JP-A-2001-511764)derived pikolinos acid (EP 926137), derivatives of imidazopyridine (WO 0158900)derived tetrahydrothieno[2,3-c]pyridine (JP 13151779, JP 13158789, JP 13151780) and derivatives sulfonamida (WO 01/62751, WO 01/62715). However, none of these publications do not disclose specific information concerning absorption after oral administration.

Another connection is a derived dihydropyridine, has also been described as compounds having inhibitory activity against the production of TNF-α (JP-A-2000-290261), but it is significantly different from the compounds of the present invention according to the chemical structure.

The authors of the present invention discovered that by introducing pyridazinyl group in the structure of benzofuran in position 5 can be obtained compound, which exhibits good absorption after oral administration and unexpected inhibitory efficiency on the production of TNF-α and, therefore, is effective as a drug for the prophylaxis or treatment of, for example, allergic diseases, immune diseases or inflammatory diseases. The present invention is based on these data.

Thus, according to the present invention features derived benzofuran represented by the formula (1):

where R1represents an alkyl group which may have a Deputy, or alkenylphenol group which may have a Deputy;

each of R2and R3represents a hydrogen atom, alkyl group, hydroxyalkyl group, dihydroxyethylene group or alkylamino group, or R2and R3form together with the adjacent nitrogen atom asado is containing a series of saturated heterocyclic group, which may have a Deputy; and

a dashed line indicates the possible presence of a double bond

or its salt.

The present invention also provides a drug containing as an active ingredient derived benzofuran (1) or its salt.

The present invention also provides a pharmaceutical composition comprising a derivative of benzofuran (1) or its salt and a pharmaceutically acceptable carrier.

The present invention also provides a method of treatment of pathological conditions caused by excessive production of tumor necrosis factor (TNF-α), characterized by the introduction of a derived benzofuran (1) or its salt.

The present invention also provides the use of a derived benzofuran (1) or salts thereof for the manufacture of a medicinal product.

Connection (1) according to the present invention demonstrates excellent inhibitory efficacy against production of tumor necrosis factor (TNF-αand enhanced absorption after oral administration and, therefore, is effective for prevention or treatment of allergic diseases, immune diseases, inflammatory diseases or similar pathological conditions.

Brief description of drawings

The drawing shows the adsorption after oral administration of compounds is according to the invention (Examples 7, 10 and 13).

The best way of carrying out the invention

In the formula (1), if they refer to alkyl, hydroxyalkyl or dihydroxyethylene group, or an alkyl group or the alkyl portion of the hydroxyalkyl or dihydroxyethylene group represents a C1-Say, more preferably C1-Salkil. The alkyl group/the portion of the molecule may be linear, branched or cyclic, or may have a ring structure. Examples of the alkyl groups of the molecule include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

In the formula (1) is an alkyl group represented by R1represents a C1-SLR, preferably C1-Salkil, more preferably C1-Salkil. The alkyl group may be linear, branched or cyclic, or may have a ring structure. Examples of alkyl groups represented by R1include methyl, ethyl, propyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl, preferably methyl, ethyl, isobutyl, cyclopropylmethyl or cyclopentylmethyl.

Alchemilla group represented by R1that is, prefer the Ino, C2-Say, more preferably C2-Salkini, especially preferably C2-Salkini. Alchemilla group can be linear or branched, and examples alkenylphenol groups include vinyl, propenyl, butenyl and pentenyl.

Examples of the substituent, which may have alkyl or Alchemilla group represented by R1include aryl group which may have a Deputy, and a heteroaryl group which may have a substituent. Aryl group may be a C6-Sal group, and the examples mentioned aryl groups include phenyl and naphthyl, where phenyl is preferred. Heteroaryl group may be a heteroaryl group having a 5-membered or 6-membered ring containing one to three nitrogen atoms, and the examples mentioned heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyrazinyl, preferably pyridyl.

Aryl or heteroaryl group may have one to three substituents. Examples of the substituents include halogen atom, alkyl group and alkoxygroup. Examples of the halogen atom include fluorine, chlorine, bromine and iodine, where preferred are fluorine and chlorine. The alkyl group preferably represents C1-Say, more preferably C1-Salkil. Alkoxygroup preferably represents sobeys-Sax, more preferably C1-Celecoxi.

Further, the alkyl group represented by R2or R3or the alkyl portion of the hydroxyalkyl or dihydroxyethylene group represented by R2or R3preferably represents C1-Say, more preferably C1-Salkil. The alkyl group/part preferably is a linear or branched, and examples mentioned alkyl groups/parts include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxypropyl and dihydroxybutyl.

Examples alkenylphenol group represented by R2or R3include C3-San, in particular C3-Salkini, such as propargyl (2-PROPYNYL).

Examples of nitrogen-containing saturated heterocyclic group which is formed from R2, R3and the neighbouring nitrogen atom include 5-membered, 6-membered and 7-membered saturated heterocyclic group. Typical examples include pyrrolidinyl, piperidino, piperazinil, homopiperazine, morpholine where piperazinil, piperidino, morpholine are preferred.

Examples of the substituent, which may have heterocyclic group include halogen atom, alkyl group, alkoxycarbonyl group and aracelio group. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. The use of the s alkyl groups include C1-Sal group, preferably C1-Sulkily group. Examples alkoxycarbonyl groups include C1-SXL group, preferably C1-Celecoxibonline group. Kalkilya group preferably represents phenyl-C1-Sulkily groups, particularly preferred benzyl group.

In the formula (1) dotted line indicates the possible presence of a double bond. However, preferred is the absence of double bonds.

In the formula (1) R1especially preferably represents isobutyl, cyclopropylmethyl, cyclopentylmethyl, cinnamyl, getagentname, benzyl, halogenmethyl, dehalogenases or (halogenfree)propyl. Each of R2and R3preferably represents a hydrogen atom, C1-Saltillo group, C1-Cherokeecasino group or propargilovyh group. Heterocyclic group formed by R2and R3,preferably represents piperazinilnom group, piperidino, pyrrolidino or morpholinopropan, where each of the four groups optionally may be substituted by C1-C7 alkyl group or benzyl group.

The salt form of the compound (1) according to the present invention preferably is an acid additive salt. Examples of the acid additive salts include inorganic acid salts such as hydrochloride, sulfa is, nitrate and phosphate, and organic acid salts such as methanesulfonate, maleate, fumarate, citrate and oxalate.

Compounds of the present invention can be in the form of a solvate or keto-enol tautomers. The present invention also covers such solvate and tautomers. Does not provide for any specific limitations on the type of MES, since the MES does not adversely affect the inhibitory activity against the production of tumor necrosis factor (TNF-α) along with other effects and the MES can be formed from the solvent used for the receipt or on other stages, such as water or alcohol. The MES is preferably a hydrate.

Connection (1) according to the present invention can be obtained, for example, in the following way:

where R4represents an alkyl group; Hal represents a halogen atom; Ms is methanesulfonyl group; and each of R1, R2and R3has the same meaning as described above.

Next will be described the stages of the process.

First will be described the stages used to obtain compound (5) from acetophenone (2). The acetophenone (2) and diethylmalonate was heated under stirring to obtain compound (3). Provo is or the reaction of the compound (3) with hydrazine to obtain a ring with subsequent treatment with alkali (for example, sodium hydroxide) to obtain the specified connection (4). Carried out the reaction of the compound (4) with an alcohol (e.g. methanol) to obtain the specified connection (5).

Thus obtained compound (5) was subjected to interaction with R1-Hal or R1-OMs in the presence of alkali (e.g. potassium carbonate) to form compound (6). The compound (6) was subjected to hydrolysis to obtain compound (7), which was later introduced in the interaction with hareticantem, giving an acid anhydride. Acid anhydride was reduced by using a reducing agent (e.g. sodium borohydride) to obtain compound (8). Compound (8) was administered in cooperation with methanesulfonamide in the presence of a base (e.g. triethylamine) to give the compound (9), which serves as the primary intermediate compound in the process.

The target compound (1) can be obtained by reaction of the compound (9) with the required amine (R2(R3)NH). The reaction is preferably carried out in polar solvent (e.g. acetonitrile) and in the presence or absence of alkali (e.g. potassium carbonate). In the case when R2or R3Amina have the amino group, the amino group of the original amine may be protected with appropriate protecting group (for example, alkoxycarbonyl what rupai) and after completion of the reaction, the protecting group is removed.

In that case, when you get the connection (1), in which each of R2and R3represents hydrogen, can be used a process in which the compound (9) interacts with phthalimide potassium, and then with hydrazine or a similar connection.

Salt of the compounds (1) according to the present invention is produced by interaction of this compound with an organic acid or inorganic acid in the usual way.

Separation/purification of compounds (1) according to the present invention can be carried out by cleaning method commonly used in the chemistry of organic synthesis, such as filtration, extraction, washing, drying, concentration, recrystallization or chromatography. The intermediate process can be used in subsequent stages of the reaction without additional purification. Connection (1) according to the present invention can be obtained in the form of MES with a solvent, such as the reaction solvent, or by recrystallization from a solvent, in particular in the form of a hydrate.

As shown in the experimental examples described below, the compound (1) according to the present invention shows excellent inhibitory activity against the production of TNF-α and demonstrate the improved adsorption after oral administration. Therefore, with the Association (1) is effective as a drug for prevention or treatment of pathological conditions in mammals, including humans, caused by the excessive production of TNF-αsuch as allergic diseases, inflammatory diseases and autoimmune diseases. Typical examples of pathological conditions caused by excessive production of TNF-α include chronic articular rheumatism, arthritis deformans, asthma, bronchitis, atopic dermatitis, inflammatory diseases of internal organs, ulcerative colitis, Crohn's disease and acquired immunodeficiency syndrome (AIDS)

The pharmaceutical composition of the present invention contains the compound (1) as an active ingredient. The active ingredient, the compound (1)may be converted to the drug, alone or in combination with one or more pharmaceutically acceptable carriers (e.g., a solubilizer, excipient, binder and diluent). Examples of the physical form of the drug include tablets, capsules, granules, powders, injectable form and suppositories. The drug can be obtained in a known manner. For example, a drug for oral administration can be obtained by processing the compound (1) with one or more appropriately selected media, such as a solubilizer (e.g., tragacanth gum, acacia gum, sucrose esters, Le is Itin, olive oil, soybean oil or PEG400), excipients (for example, starch, mannitol or lactose), a binder (for example, carboxymethylcellulose sodium or hydroxypropylcellulose), dezintegriraat substance (for example, crystalline cellulose or carboxymethylcellulose calcium), moving substance (for example, talc or magnesium stearate) and an agent that improves the fluidity (for example, finely divided anhydrous silicic acid). The pharmaceutical composition of the present invention is administered orally or parenterally.

The dose of the pharmaceutical composition of the present invention varies depending on, among other things, on body weight, age, sex or pathological condition of the patient. The daily dose of compound (1) for an adult is usually from 0.01 to 1000 mg, preferably from 0.1 to 100 mg of the Compound (1) is preferably administered once a day, or two, or three times a day fractionally.

Examples

The present invention will be further described in more detail by way of examples, which however do not limit the invention.

Example 1: Getting 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-carboxy-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

5-Acetylcoumarin [H.C. Brown, T. Inukai, J. Am. Chem. Soc., 83 4825 (1961)] (5, g, for 30.8 mmol) and diethyl-ketomalonate (5.9 g, to 33.9 mmol) were mixed together and the mixture was stirred for 39 hours at 120°C. the Reaction mixture was dissolved in isopropanol (100 ml) and the resulting mixture was added hydrazine monohydrate (3.38 g, 67.5 mmol), followed by stirring for six hours at 100°C. To it was added 2 mol/l aqueous sodium hydroxide solution (7 ml) and the resulting mixture was stirred for four hours at 100°C. the Reaction mixture was cooled on ice and acidified with concentrated hydrochloric acid. The resulting precipitates were collected by filtration and thoroughly washed with water followed by drying to obtain 5.9 g of the named compound as a yellow powder (74,1%).

2) Obtain 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one

4-Carboxy-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one (5.9 g, of 22.8 mmol) suspended in methanol (100 ml) and to the suspension was added dropwise thionyl chloride (3 g, a 25.1 mmol) under ice cooling, followed by stirring for three hours at 80°C. the Temperature of the reaction mixture was lowered to room temperature and the solvent was removed under reduced pressure. To the residue was added water under cooling in an ice bath and the resulting precipitates were collected by filtration and washed with water followed by drying with getting 4,90 g's name is the first connection in the form of tiny pale-yellow needle crystals (78,8%).

TPL: 192-200°C

1H NMR (400 MHz, CDCl3)δ:

of 3.28 (2H, t, J=8,3 Hz)to 3.99 (3H, s), of 4.66 (2H, t, J=8,3 Hz), 6.87 in (1H, d, J=8,3 Hz), 7,56 (1H, d, J=8,3 Hz), 7,68 (1H, s), 8,31 (1H, s).

3) Obtaining 4-carboxy-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

6-(2,3-Dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one (2.0 g, 7,35 mmol) was dissolved in N,N-dimethylformamide (17 ml) and the resulting solution was added potassium carbonate (2.0 g, 14.7 mmol) and bromelicola (1.2 g, 8,8 mmol) followed by stirring for two hours at 80°C. the Temperature of the reaction mixture was lowered to room temperature and thereto was added a saturated aqueous solution of bicarbonate, followed by extraction the ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was removed by distillation to obtain 2.66 g of crude product. The crude product is suspended in methanol (20 ml) was added 2 mol/l aqueous sodium hydroxide solution (20 ml) followed by stirring for one hour at 60°C. After lowering the temperature of the reaction mixture to room temperature, thereto was added water and the mixture was acidified with concentrated hydrochloric acid followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous surfacematerial. The solvent was removed under reduced pressure and the residue was recrystallized from a mixture of chloroform-hexane to obtain 1.88 g of the named compound as a yellow powder (81,7%).

TPL: 160-165°C.

1H NMR (400 MHz, CDCl3) δ:

0,50-0,55 (2H, m), 0,60-0,66 (2H, m)of 1.46 (1H, m), 3,30 (2H, t, J=8,8 Hz), 4,22 (2H, t, J=7,3 Hz), of 4.67 (2H, t, J=8,8 Hz), 6.89 in (1H, d, J=8.5 Hz), the 7.65 (1H, DD, J=8,5, 2.0 Hz), 7,72 (1H, s), to 8.62 (1H, s).

4) to Obtain 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one

To a solution of 4-carboxy-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one (1.8 g, USD 5.76 mmol) in THF (25 ml) was added triethylamine (641 mg, 6,34 mmol) and the resulting mixture was added dropwise a solution of charitycardonate (688 mg, 6,34 mmol) in THF (1 ml) under cooling in an ice bath followed by stirring for 30 minotauromachy the triethylamine hydrochloride was removed by filtration and to the filtrate was added a solution of sodium borohydride (327 mg, 8,64 mmol) in water (2 ml) under cooling in an ice bath followed by stirring for 15 minutes at room temperature. To the reaction mixture was added aqueous hydrochloric acid (2 mol/l) and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue evaluation of the Gali separation/purification column chromatography on silica gel [silica gel 60 g, chloroform/methanol (100/1)] with getting 566 mg of the named compound as a pale yellow powder (32,9%).

TPL: 115-117°C.

1H NMR (400 MHz, CDCl3)δ:

0,46-of 0.51 (2H, m), of 0.54 to 0.60 (2H, m), USD 1.43 (1H, m), or 3.28 (2H, t, J=8,8 Hz), 4,10 (2H, d, J=7,1 Hz), with 4.64 (2H, d, J=8,8 Hz), 4,71 (2H, d, J=0,73 Hz), 6,85 (1H, d, J=8.5 Hz), 7,55 (1H, DD, J=8,5, 2.0 Hz), 7,63 (1H, s), to 7.68 (1H, s).

5) Getting 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

2-Cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one (540 mg, is 1.81 mmol) was dissolved in methylene chloride (12 ml) and to the solution was added triethylamine (238 mg, 2,35 mmol) and methanesulfonamide (249 mg, 2,17 mmol) under cooling in an ice bath followed by stirring for one hour. To the reaction mixture were added saturated aqueous bicarbonate and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from a mixture of chloroform-hexane to obtain 607 mg of the named compound as a pale yellow crystalline powder (89,1%).

TPL: 108-111°C.

1H NMR (400 MHz, CDCl3)δ:

0,45-0,50 (2H, m), of 0.53 to 0.60 (2H, m)of 1.42 (1H, m), 3,17 (3H, s), 3,29 (2H, t, J=8,8 Hz), 4,10 (2H, d, J=7,3 Hz)and 4.65 (2H, t, J=8,8 Hz), 5,28 (2H, d, J=0,97 Hz)6,86 (1H, d, J=8,3 Hz), 7,56 (1H, DD, J=8,3, 2.0 Hz), to 7.67 (1H, s), of 7.75 (1H, s).

6) Getting 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

2-Cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one (100 mg, 0.27 mmol) was dissolved in acetonitrile (1.5 ml) and to the solution was added potassium carbonate (55 mg, 040 mmol) and 1-methylpiperazine (32 mg, 0.32 mmol) followed by stirring for three hours at 80°C. the Temperature of the reaction mixture was lowered to room temperature and added to her water. The resulting mixture was extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was subjected to separation/purification using separation thin layer chromatography on silica gel [chloroform/methanol (10/1)], followed by recrystallization from a mixture of chloroform-hexane to obtain 54 mg of the titled compound as pale yellow needle crystal (53,5%).

TPL: 128-130°C.

1H NMR (400 MHz, CDCl3)δ:

0,45-0,57 (4H, m)of 1.42 (1H, m), 2,43 (3 H, s), 2,60-of 3.00 (8H, m), 3,29 (2H, t, J=8,8 Hz), 3,61 (2H, s), 4.09 to (2H, d, J=7,2 Hz), with 4.64 (2H, t, J=8,8 Hz), PC 6.82 (1H, d, J=8,3 Hz), 7,55 (1H, d, J=8,3 Hz), of 7.69 (1H, s), 7,71 (1H, s).

IR (KBr) cm-1: 1651, 1608, 1501,1242, 1168, 808.

MS m/z: 380(M+).

Example 2: Obtain 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(2,3-dihydro-benzofuran-5-yl)-2H-pyridazin-3-one

Example 1 (6) was performed using a 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine with obtaining these compounds as a yellow oil (yield: 74,5%).

1H NMR (400 MHz, CDCl3)δ:

0,40-0,65 (4H, m)of 1.42 (1H, m), 2,70 was 3.05 (4H, m), or 3.28 (2H, t, J=8,8 Hz), 3,50-4,00 (6H, m), 4,11 (2H, d, J=8.5 Hz), with 4.64 (2H, t, J=8,8 Hz), 6,85 (1H, d, J=8.5 Hz), 7,58 (1H, d, J=8.5 Hz), 7,71 (1H, s), 7,80 (1H, s).

IR (Neat) cm-1: 3392, 1645, 1602, 1516, 1238, 1047.

MS m/z: 354(M+-CH2OH).

Example 3: Getting 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-dimethylaminomethyl-2H-pyridazin-3-one

2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-ONU (120 mg, 0.32 mmol) was added 40% aqueous solution of dimethylamine (2 ml) and the mixture was stirred for two hours at 80°C. the Temperature of the reaction mixture was lowered to room temperature and the reaction mixture was added water. The resulting mixture was extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from a mixture of chloroform-hexane to obtain 53 mg (51.1 percent) of the named compound as a yellow powder.

TPL: 109-110°C.

1H NMR (400 MHz, CDCl3)δ:

0,45-0,56 (4H, m), USD 1.43 (1H, m), is 2.44 (3H, s), or 3.28 (2H, t, J=8,8 Hz), 3,62 (2H, s), 4,10 (2H, d, J=7.3 for the TS) 4,63 (2H, t, J=8,8 Hz), 6,85 (1H, d, J=8,3 Hz), a 7.62 (1H, d, J=8,3 Hz), 7,72 (1H, s), 7,92 (1H, m).

IR (KBr) cm-1: 1651, 1606, 1499, 1243, 1102, 820.

MS m/z:325(M+).

Example 4: Obtaining 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 1 (6) was repeated using 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperazine of the carboxylate with obtaining these compounds as a yellow oil (yield: 97,6%).

1H NMR (400 MHz, CDCl3)δ:

0,45-0,50 (2H, m), 0,51 is 0.58 (2H, m)of 1.42 (1H, m)of 1.47 (9H, s), 2,45-2,60 (4H, m),3,29 (2H, t, J=8,8 Hz),3,45-3,55 (4H, m)to 3.58 (2H, users), 4,10 (2H, d, J=7,1 Hz),with 4.64 (2H, t, J=8,8 Hz)6,86 (1H, d, J=8,3 Hz), 7,55 (1H, m), 7,69 (1H, s), of 7.75 (1H, m).

2) Getting 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one (121 mg, 0.26 mmol) was dissolved in triperoxonane acid (1.1 ml) under cooling with ice water and the solution was stirred for 15 minutes at the same temperature. To the reaction mixture were added water (10 ml) and the resulting mixture was made alkaline using potassium carbonate followed by extraction of chlorof ROM. The organic layer was washed with saturated saline (20 ml) and dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain 83 mg (87,4%) of the named compound as a yellow oil.

1H NMR (400 MHz, CDCl3)δ:

0,44-0,58 (4H, m), USD 1.43 (1H, m), 2,58-2,70 (5H, m), 2,99-3,10 (4H, m), 3,29 (2H, t, J=8.5 Hz), of 3.57 (2H, s), 4.09 to (2H, d, J=7,3 Hz), with 4.64 (2H, t, J=8.5 Hz), 6,86 (1H, d, J=8,3 Hz), 7,56 (1H, d, J=8,3 Hz), to 7.68 (1H, s), 7,74 (1H, m).

IR (Neat) cm-1: 1652, 1607, 1497, 1238, 1102, 821.

MS m/z: 366(M+).

Example 5: Receiving 4-aminomethyl-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

2-Cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one (140 mg, of 0.37 mmol) and phthalimide potassium (83 mg, 0,56 mmol) was added to N,N-dimethylformamide (4 ml) and the mixture was stirred for two hours at 80°C. To the reaction mixture were added water and the resulting mixture was extracted with chloroform followed by washing with saturated saline solution (20 ml) and drying over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get crude product. The crude product was dissolved in methanol (4,2 ml) and to the solution was added hydrazine monohydrate (91 mg, of 1.85 mmol) followed by heating in a flask under reflux for two hours. The methanol was removed under reduced pressure to about the TATKO was added chloroform followed by washing successively with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was subjected to separation/purification by separation thin layer chromatography on silica gel (elwen: chloroform/10%/about ammonia-methanol (20/1)), with 91 mg of the above compound (82,3%) as a yellow oil.

1H NMR (400 MHz, CDCl3)δ:

of 0.44 to 0.60 (4H, m)of 1.42 (1H, m), with 3.27 (2H, t, J=8,8 Hz)to 3.92 (2H, s), 4.09 to (2H, d, J=7,1 Hz), 4,63 (2H, t, J=8,8 Hz), at 6.84 (1H, d, J=8,3 Hz), 7,56 (1H, DD, J=8,3, 1.2 Hz), 7,69 (1H, d, J=1.2 Hz), 8,02 (1H with).

IR (Neat) cm-1: 1648, 1605, 1498, 1238, 1105, 754.

MS m/z:297(M+).

Example 6: Obtain 2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-carboxy-2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 1 (3) was performed using 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-formanilide with obtaining these compounds are in the form of a yellow powder (yield: 54.7 per cent).

TPL: 215-218°C.

1H NMR (400 MHz, CDCl3)δ:

3,30 (2H, t, J=8,8 Hz), and 4.68 (2H, t, J=8,8 Hz), 5,46 (2H, s), 6.87 in (1H, d, J=8.5 Hz),? 7.04 baby mortality-was 7.08 (2H, m), 7,50-rate of 7.54 (2H, m), 7,63 (1H, DD, J=8,5, 2.0 Hz), of 7.70 (1H, s), at 8.60 (1H, s), 14,06 (1H, s).

2) Obtaining 2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one

Example 1 (4) was performed using 4-carboxy-2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one with n is the receiving of the named compound as a yellow oil (yield: 43,4%).

1H NMR (400 MHz, CDCl3)δ:

of 3.28 (2H, t, J=8,8 Hz), with 4.64 (2H, t, J=8,8 Hz), 4,69 (2H, d, J=1.2 Hz), to 5.35 (2H, s), 6,85 (1H, d, J=8.5 Hz), 6,98? 7.04 baby mortality (2H, m), 7,46 is 7.50 (2H, m), 7,55 (1H, DD, J=8,5, 2.0 Hz), to 7.64 (1H, s), to 7.67 (1H, users).

3) Obtaining 2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Example 1 (5) was performed using 2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one with obtaining these compounds as a yellow oil (yield: 78.6 per cent).

1H NMR (400 MHz, CDCl3)δ:

as 3.14 (3H, s), 3,29 (2H, t, J=8,8 Hz)and 4.65 (2H, t, J=8,8 Hz), 5,27 (2H, d, J=1.5 Hz), to 5.35 (2H, s)6,86 (1H, d, J=8.5 Hz), 6,98-7,05 (2H, m), 7,45 is 7.50 (2H, m), 7,55 (1H, DD, J=8,5, 2.0 Hz), the 7.65 (1H, users), of 7.75 (1H, users).

4) to Obtain 2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Example 1 (6) was repeated using 2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one with obtaining these compounds are in the form of a pale yellow powder (yield: 54.8 per cent).

TPL: 179-180°C.

1H NMR (400 MHz, CDCl3)δ:

2,43 (3H, s), 2,64-2,74 (8H, m), 3,29 (2H, t, J=8,5 Hz)to 3.58 (2H, s)and 4.65 (2H, t, J=8.5 Hz), of 5.34 (2H, s)6,86 (1H, d, J=8.5 Hz), 6,98? 7.04 baby mortality (2H, m), 7,46-7,51 (2H, m), 7,54 (1H, DD, J=8,5, 2.0 Hz), to 7.67 (1H, d, J=2.0 Hz), of 7.70 (1H, s).

IR (KBr) cm-1: 1653, 1609, 1501, 1240, 1119, 819,

MS m/z:434(M+).

Example 7: Obtain 2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

To a solution of 2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one (109 mg, 0.25 mmol) in methanol (1 ml) was added dropwise 4-mol/l solution (0.15 ml) of hydrochloric acid in ethyl acetate under stirring at room temperature. The solvent was removed under reduced pressure and the residue was recrystallized from methanol-ether to obtain 112 mg (88,0%) of the titled compound as pale yellow needle crystal.

TPL: 201-204°C(decomp.).

1H NMR (400 MHz, CDCl3)δ:

and 2.79 (3H, s)to 2.99 (4H, users), of 3.13 (2H, users), 3,30 (2H, t, J=8,8 Hz), of 3.45 (2H, users), to 3.67 (2H, s)and 4.65 (2H, t, J=8,8 Hz), of 5.34 (2H, s)6,86 (1H, d, J=8,3 Hz), 7,01 (2H, DD, J=8,8, 8,8 Hz), 7,49 (2H, DD, J=of 8.8, 5.4 Hz), 7,60 (1H, users), 7,51 (1H, m), 7,66 (1H, s).

IR (KBr) cm-1: 3437, 1655, 1608, 1510, 1497, 1438, 1240,

MS m/z:434(M+).

Example 8: Obtain 2-(4-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-carboxy-2-(4-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 1 (3) was performed using 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzylchloride with obtaining these compounds are in the form of a yellow powder (yield: 89.3 per cent).

TPL: 200-210°C.

1H NMR (400 MHz, CDCl3)δ:

3,30 (2H, t, J=8,8 Hz), and 4.68 (2H, t, J=8,8 Hz), the 5.45 (2H, s), 6.89 in (1H, d, J=8.5 Hz), 7,35 (2H, d, J=8.5 Hz), 7,46 (2H, d, J=8.5 Hz), a 7.62 (1H, DD, J=8,5, 20 Hz), of 7.70 (1H, d, J=2.0 Hz), 8,61 (1H, s), 14,02 (1H, users).

2) Obtaining 2-(4-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one

Example 1 (4) was repeated using 4-carboxy-2-(4-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one with obtaining these compounds are in the form of a pale yellow powder (yield: 32.7 per cent).

TPL: 129-134°C.

1H NMR (400 MHz, CDCl3)δ:

of 3.28 (2H, t, J=8,8 Hz), with 4.64 (2H, t, J=8,8 Hz), 4,69 (2H, s), to 5.35 (2H, s), 6,85 (1H, d, J=8,3 Hz), 7,28-to 7.32 (2H, m), 7,41-the 7.43 (2H, m), 7,55 (1H, m), the 7.65 (1H, m), 7,66 (1H, users).

3) Obtaining 2-(4-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Example 1 (5) was performed using 2-(4-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one with obtaining these compounds are in the form of a yellow powder (yield: 96.6 percent).

TPL: 69-70°C.

1H NMR (400 MHz, CDCl3)δ:

a 3.15 (3H, s), 3,29 (2H, t, J=8,8 Hz)and 4.65 (2H, t, J=8,8 Hz), of 5.24 (2H, s), of 5.34 (2H, s)6,86 (1H, d, J=8,3 Hz), 7,30-to 7.32 (2H, m), 7,41-the 7.43 (2H, m), 7,55 (1H, m), the 7.65 (1H, m), of 7.75 (1H, m).

4) to Obtain 2-(4-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Example 1 (6) was performed using 2-(4-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one with obtaining these compounds are in the form of pale yellow needle crystal (yield: 46,3%).

TPL: 14-150° C.

1H NMR (400 MHz, CDCl3)δ:

to 2.55 (3H, s), of 2,75 2,95 (8H, m), 3,29 (2H, t, J=8.5 Hz), 3,61 (2H, s)and 4.65 (2H, t, J=8.5 Hz), 5,33 (2H, s)6,86 (1H, d, J=8,3 Hz), 7,29 (2H, d, J=8,3 Hz), the 7.43 (2H, d, J=8,3 Hz), 7,53 (1H, ushers, J=8,3 Hz), to 7.64-of 7.70 (2H, m).

IR (KBr) cm-1: 1654, 1609, 1499, 1241, 1118, 808,

MS m/z:450(M+), 452(M+).

Example 9: Obtaining 2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-carboxy-2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 1 (3) was performed using 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamate with obtaining these compounds are in the form of an orange powder (yield: 44.4 per cent).

TPL: 177-181°C.

1H NMR (400 MHz, CDCl3)δ:

3,29 (2H, t, J=8.5 Hz), of 4.67 (2H, t, J=8.5 Hz), 5,09 (2H, DD, J=6,7, 1.2 Hz), to 6.39 (1H, dt, J=15,9, 6,7 Hz), was 6.73 (1H, d, J=15,9 Hz), 6.89 in (1H, d, J=8.5 Hz), 7,29 (2H, d, J=8.5 Hz), 7,33 (2H, d, J=8.5 Hz), to 7.64 (1H, DD, J=8,5, 2.0 Hz), of 7.70 (1H, d, J=2.0 Hz), 8,63 (1H, s).

2) Obtaining 2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one

Example 1 (4) was performed using 4-carboxy-2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one with obtaining these compounds are in the form of a pale yellow powder (yield: 31.1%).

TPL: 131-141°C.

1H NMR (400 MHz, CDCl3)δ:

of 3.27 (2H, t, J=8.5 Hz), with 4.64 (2H, t, J=8.5 Hz), 4,71 (2H, d, J=1.2 Hz),to 4.98 (2H, DD, J=6,6 1.2 Hz), 6,41 (1H, dt, J=15,9, and 6.6 Hz), of 6.65 (1H, d, J=15,9 Hz), 6,85 (1H, d, J=8,3 Hz), 7,26 (2H, d, J=8,8 Hz), 7,31 (2H, d, J=8,8 Hz), 7,56 (1H, ushers, J=8,8 Hz), 7,66 (1H,users), to 7.68 (1H, users).

3) Obtaining 2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Example 1 (5) was repeated using 2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one with obtaining these compounds are in the form of a pale yellow powder (yield: 83,3%).

TPL: 135-140°C.

1H NMR (400 MHz, CDCl3)δ:

and 3.16 (3H, s), or 3.28 (2H, t, J=8,5 Hz)and 4.65 (2H, t, J=8.5 Hz), to 4.98 (2H, DD, J=6,6, 1.2 Hz), 5,28 (2H, d, J=1.2 Hz), to 6.39 (1H, dt, J=15,9, and 6.6 Hz), of 6.66 (1H, d, J=15,9 Hz)6,86 (1H, d, J=8.5 Hz), 7,27 (2H, d, J=8.5 Hz), 7,31 (2H, d, J=8.5 Hz), EUR 7.57 (1H, ushers, J=8.5 Hz), to 7.67 (1H, users), to 7.77 (1H, t, J=1.2 Hz).

4) to Obtain 2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Example 1 (6) was performed using 2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one, to obtain the titled compound as pale brown powder (yield: 45.8 per cent).

TPL: 112-113°C.

1H NMR (400 MHz, CDCl3)δ:

2,49 (3H, s), 2,60-2,84 (8H, m), 3,29 (2H, t, J=8.5 Hz), 3,61 (2H, users), with 4.64 (2H, t, J=8.5 Hz), equal to 4.97 (2H, d, J=6.3 Hz), 6.42 per (1H, dt, J=15,9, 6.3 Hz), of 6.66 (1H, d, J=15,9 Hz)6,86 (1H, d, J=8,3 Hz), 7,25 (2H,, d, J=8.5 Hz), 7,31 (2H, d, J=8.5 Hz), 7,54 (1H, d, J=8,3 Hz), 7,69 (1H, s), 7,72 (1H, s).

IR (KBr) cm-1: 1648, 1607, 1496, 1238, 1091, 807.

+), 478(M+).

Example 10: Obtain 2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one dihydrochloride

Example 7 was repeated using 2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one with obtaining these compounds are in the form of a pale brown crystalline powder (yield: 40.5 per cent).

TPL: 248-251°C.

1H NMR (400 MHz, DMSO-d6)δ:

of 2.81 (3H, s)of 3.25 (2H, t, J=8,8 Hz), 3,50-4,00 (10H, m), 4,60 (2H, t, J=8,8 Hz), equal to 4.97 (2H, d, J=5.6 Hz), 6.42 per (1H, dt, J=16,3, 5.6 Hz), only 6.64 (1H, d, J=16,3 Hz), 6.89 in (1H, d, J=8,3 Hz), 7,37 (2H, d, J=8,5 Hz), 7,47 (1H, m), 7,49 (2H, d, J=8.5 Hz), 766 (1H, DD, J=8,3, 2.0 Hz), 7,79 (1H, s).

IR (KBr) cm-1: 1652, 1607, 1492, 1239, 1091, 933.

Example 11: Obtain 6-(1-benzofuran-5-yl)-2-(4-terbisil)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 5-acetyl-1-benzofuran

5-acetyl-2-methoxycarbonyl-1-benzofuran [Ramachandra P. K., Cheng, T., Horton W. T., J. Org. Chem. 28 2744 (1963)] (795 mg, of 3.64 mmol) was dissolved in methanol (7 ml) and to the solution was added 20% sodium hydroxide (7 ml). The mixture was stirred for one hour at 60°C, followed by concentration under reduced pressure. Then the reaction mixture was acidified with hydrochloric acid. The resulting precipitates were collected by filtration, washed with water and dried to obtain 667 mg of the product carboxylic acid. This product was heated with quinoline (3.3 grams) and the edno powder (133 mg) in 200° C for six hours in a nitrogen atmosphere. After cooling, the mixture was dissolved in ethyl acetate followed by washing successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline solution. The mixture was dried over anhydrous sodium sulfate and the solvent was removed by distillation to obtain 517 mg of the above compound in the form of a blackish brown powder (88,7%).

1H NMR (400 MHz, CDCl3)δ:

to 2.67 (3H, s), 6.87 in (1H, DD, J=2.0 a, 1.0 Hz), 7,55 (1H, d, J=8,8 Hz), of 7.70 (1H, d, J=2.4 Hz), 7,98 (1H, DD, J=8,8, 2.0 Hz), compared to 8.26 (1H, d, J=2,4 Hz).

MS m/z:160(M+).

2) Obtain 6-(1-benzofuran-5-yl)-4-carboxy-2H-pyridazin-3-one

5-acetyl-1-benzofuran (536 mg, 3.35 mmol) and diethylmalonate (642 mg, of 3.69 mmol) were mixed together and the mixture was stirred for 34 hours at 120°C. To a solution of the reaction mixture in isopropanol (8.5 ml) was added hydrazine monohydrate (247 mg, is 4.93 mmol) and the resulting mixture was heated with stirring for six hours at 100°C. To it was added 2 mol/l aqueous solution of sodium hydroxide (5.2 ml) and the mixture was additionally stirred for four hours at 100°C. the Mixture was cooled with ice, and thereto was added concentrated hydrochloric acid, thereby podkisst heated system. The resulting precipitates were collected by filtration, thoroughly washed with water and dried to obtain 397 mg called the data connection in the form of a yellow powder (46.2%).

3) Obtain 6-(1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one

Example 1 (3) was performed using 6-(1-benzofuran-5-yl)-4-carboxy-2H-pyridazin-3-one with obtaining these compounds are in the form of a pale yellow powder (yield: 95.6%of).

TPL: 222-225°C.

1H NMR (400 MHz, CDCl3)δ:

to 4.01 (3H, s), 6,85 (1H, DD, J=2.0, the 0,98 Hz), 7,60 (1H, d, J=8.5 Hz), of 7.70 (1H, d, J=2.2 Hz), to 7.77 (1H, DD, J=8,5, 2.0 Hz), of 8.04 (1H, d, J=2.2 Hz), 8,42 (1H, s).

4) to Obtain 6-(1-benzofuran-5-yl)-4-carboxy-2-(4-terbisil)-2H-pyridazin-3-one

Example 1 (3) was performed using 6-(1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-formanilide with obtaining these compounds are in the form of a yellow powder (yield: 73.4 per cent).

TPL: 207-210°C.

1H NMR (400 MHz, CDCl3)δ:

of 5.50 (2H, s), to 6.88 (1H, DD, J=2.0, the 0,98 Hz), 7,05-to 7.09 (2H, m), 7,53-7,56 (2H, m), 7,63 (1H, d, J=8,8 Hz), 7,72 (1H, d, J=2.2 Hz), 7,82 (1H, DD, J=8,8, 2.0 Hz), 8,08 (1H, d, J=2.2 Hz), 8,72 (1H, s).

5) Obtain 6-(1-benzofuran-5-yl)-2-(4-terbisil)-4-hydroxymethyl-2H-pyridazin-3-one

Example 1 (4) was performed using 6-(1-benzofuran-5-yl)-4-carboxy-2-(4-terbisil)-2H-pyridazin-3-one with obtaining these compounds are in the form of a pale yellow powder (yield: 30.4 per cent).

TPL: 158-160°C.

1H NMR (400 MHz, CDCl3)δ:

4,72 (2H, d, J=1.2 Hz), of 5.39 (2H, s), 6,85 (1H, DD, J=2,2, of 0.98 Hz), 6,99-7,06 (2H, m), 7,49-7,53 (2H, m), to 7.59 (1H, d, J=8.5 Hz), 7,69 (1H, d, J=2.2 Hz),7,76-7,79 (2H, m), 8,02 (1H, d, J=2.2 Hz).

6) Obtained is 6-(1-benzofuran-5-yl)-2-(4-terbisil)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Example 1 (5) was performed using 6-(1-benzofuran-5-yl)-2-(4-terbisil)-4-hydroxymethyl-2H-pyridazin-3-one with obtaining these compounds are in the form of a yellow powder (yield: up 85.2%).

TPL: 162 to 165°C.

1H NMR (400 MHz, CDCl3)δ:

and 3.16 (3H, s), 5,28 (2H, d, J=1.5 Hz), of 5.39 (2H, s)6,86 (1H, DD, J=2,2, of 0.98 Hz), 7,00-7,06 (2H, m), of 7.48-7,52 (2H, m), to 7.59 (1H, d, J=8,8 Hz), of 7.70 (1H, d, J=2.0 Hz),to 7.77 (1H, DD, J=8,8, 2.2 Hz), 7,86 (1H, t, J=1.2 Hz), 8,01 (1H, d, J=2.0 Hz).

7) Obtain 6-(1-benzofuran-5-yl)-2-(4-terbisil)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Example 1 (6) was performed using 6-(1-benzofuran-5-yl)-2-(4-terbisil)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one with obtaining these compounds are in the form of pale yellow needle crystal (yield: 61.7 per cent).

TPL: 128-130°C.

1H NMR (400 MHz, CDCl3)δ:

of 2.36 (3H, s), 2,55-2,70 (8H, m)and 3.59 (2H, d, J=1.2 Hz), 5,38 (2H, s)6,86 (1H, DD, J=2,2, of 0.98 Hz), 6,99-7,05 (2H, m), 7,49-of 7.55 (2H, m), to 7.59 (1H, d, J=8.5 Hz), 7,69 (1H, d, J=2.2 Hz), to 7.77 (1H, DD, J=8,5 and 2.2 Hz), 7,83 (1H, s), 8,02 (1H, d, J=2.2 Hz).

IR (KBr) cm-1: 1651, 1605, 1511, 1241, 1118, 770.

MS m/z:432(M+).

Example 12: Obtain 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 1 (3) was performed using 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2-chloro who enyl)-1-propanol of methansulfonate with obtaining these compounds are in the form of a yellow powder (yield: 76.8%of all).

TPL: 137-140°C.

1H NMR (400 MHz, CDCl3)δ:

and 2.26-of 2.34 (2H, m),is 2.88 (2H, t, J=7.8 Hz), 3,30 (2H, t, J=8,8 Hz), 4,43 (2H, t, J=7,1 Hz), of 4.67 (2H, t, J=8,8 Hz), to 6.88 (1H, d, J=8,3 Hz), 7,12-7,24 (3H, m),7,33 (1H, m), 7,63 (1H, DD, J=9,3, 2.0 Hz), 7,71 (1H, users), 8,59 (1H, s), 14,22 (1H, users).

2) Obtain 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one

Example 1 (4) was performed using 4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one with obtaining these compounds as a yellow oil (yield: 49.6 per cent).

1H NMR (400 MHz, CDCl3)δ:

2,19-of 2.27 (2H, m),2,85 (2H, t, J=7,6 Hz), or 3.28 (2H, t, J=8.5 Hz), 4,32 (2H, t, J=7,3 Hz), with 4.64 (2H, t, J=8.5 Hz), 4,70 (2H, d, J=1.2 Hz), 6,85 (1H, d, J=8,3 Hz), 7,11-7,20 (3H, m),7,32 (1H, m), 7,55 (1H, DD, J=8,3, 1.2 Hz), 7,63 (1H, s), to 7.68 (1H, s).

3) Obtain 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Example 1 (5) was performed using 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one with obtaining these compounds as a yellow oil (yield: 95.9 per cent).

1H NMR (400 MHz, CDCl3)δ:

2,19-of 2.27 (2H, m),2,85 (2H, t, J=7,6 Hz), 3,17 (3H, s), 3,29 (2H, t, J=8,8 Hz), 4,32 (2H, t, J=7,1 Hz)and 4.65 (2H, t, J=8,8 Hz), 5,27 (2H, d, J=1.5 Hz), 6,86 (1H, d, J=8.5 Hz), 7,12-7,20 (3H, m), 7,32 (1H, m), 7,56 (1H, DD, J=8,5, 1.2 Hz), to 7.67 (1H, s), 7,74 (1H, s).

4) to Obtain 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)m is Teal-2H-pyridazin-3-one

Example 1 (6) was performed using 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one with obtaining these compounds as a yellow oil (yield: 79.3 percent).

1H NMR (400 MHz, CDCl3)δ:

2,17-of 2.26 (2H, m), to 2.57 (3H, s), 2,80-2,88 (10H, m), 3,29 (2H, t, J=8,8 Hz), 3,63 (2H, s), or 4.31 (2H, t, J=7,3 Hz)and 4.65 (2H, t, J=8,8 Hz)6,86 (1H, d, J=8.5 Hz), 7,11-to 7.18 (3H, m), 7,28-7,33 (2H, m), 7,52 (1H,s), to 7.68 (1H, s).

IR (Neat) cm-1: 1652, 1608, 1498, 1237, 1015, 753.

MS m/z:478(M+), 480(M+).

Example 13: Obtain 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one dihydrochloride

Example 7 was performed using 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one with obtaining these compounds are in the form of a pale brown crystalline powder (yield: 77.2 percent).

TPL: 228-231°C

1H NMR (400 MHz, DMSO-d6)δ:

2,05-of 2.15 (2H, m), of 2,75 2,85 (2H, m), of 2.81 (3H, s), 3,26 (2H, t, J=8,8 Hz), 3,60-4,20 (10H, m), is 4.21 (2H, t, J=7,1 Hz), br4.61 (2H, t, J=8,8 Hz), 6.89 in (1H, d, J=8.5 Hz), 7,20-7,30 (3H, m), 7,38-7,41 (2H, m), the 7.65 (1H,DD, J=8,5, 2.0 Hz), 7,78 (1H, s).

IR (KBr) cm-1: 1660, 1610, 1499, 1238, 1018, 941.

Example 14: Getting 4-aminomethyl-2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 5 was performed using 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-metasolv velocimeter-2H-pyridazin-3-one with obtaining these compounds as a yellow oil (yield: 58.3 percent).

1H NMR (400 MHz, CDCl3)δ:

2,11-of 2.26 (2H, m), 2,85 (2H, t, J=7,3 Hz), with 3.27 (2H, t, J=8,8 Hz), 3,90 (2H, s), or 4.31 (2H, t, J=7,3 Hz), 4,63 (2H, t, J=8,8 Hz), at 6.84 (1H, d, J=8.5 Hz), 7,10-7,19 (3H, m), 7,32 (1H, m), 7,56 (1H,DD, J=to 8.5, 2.0 Hz), 7,68 (1H, s), of 7.69 (1H,s).

IR (Neat) cm-1: 1652, 1606, 1498, 1238, 1108, 754.

MS m/z:395(M+),397(M+).

Example 15: Getting 2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 1 (3) was performed using 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(4-chlorophenyl)-1-propanol of methansulfonate with obtaining these compounds are in the form of a yellow powder (yield: 71.0 per cent).

TPL: 157-160°C.

1H NMR (400 MHz, CDCl3)δ:

2.21 are of 2.30 (2H, m),by 2.73 (2H, t, J=7,6 Hz), 3,03 (2H, t, J=8,8 Hz), to 4.38 (2H, t, J=7,3 Hz), and 4.68 (2H, t, J=8,8 Hz), 6.89 in (1H, d, J=8,3 Hz), 7,13 (2H, d, J=8,3 Hz),7,24 (2H, d, J=8,3 Hz), a 7.62 (1H, DD, J=to 8.3, 2.0 Hz), 7,69 (1H, s), 8,58 (1H, s), 14,19 (1H, users).

2) Obtain 2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one

Example 1 (4) was performed using 4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one with obtaining these compounds as a yellow oil (yield: 53.3 per cent).

1H NMR (400 MHz, CDCl3)δ:

2,16-of 2.24 (2H, m),2,70 (2H, t, J=7,3 Hz), or 3.28 (2H, t, J=8.8 G is), 4,27 (2H, t, J=7,3 Hz)and 4.65 (2H, t, J=8,8 Hz), was 4.76 (2H, d, J=1.2 Hz), 6,85 (1H, d, J=8.5 Hz), 7,14 (2H, d, J=8,3 Hz), 7.23 percent (2H, d, J=8,3 Hz), 7,55 (1H, DD, J=8,3, 2.2 Hz), to 7.61 (1H, s), 7,66 (1H, users).

3) Obtain 2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Example 1 (5) was repeated using 2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one with obtaining these compounds as a yellow oil (yield: 96.9 percent).

1H NMR (400 MHz, CDCl3)δ:

2,16-of 2.23 (2H, m), 2,70 (2H, t, J=7,6 Hz), 3,17 (3H, s), 3,29 (2H, t, J=8,8 Hz), 4,27 (2H, t, J=7,3 Hz)and 4.65 (2H, t, J=8,8 Hz in), 5.25 (2H, d, J=1.5 Hz), 6,86 (1H, d, J=8,3 Hz), 7,14 (2H, d, J=8,3 Hz), of 7.23 (2H, d, J=8,3 Hz), 7,55 (1H, DD, J=8,3, 2.2 Hz), to 7.64 (1H, s), 7,73 (1H, s).

4) to Obtain 2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Example 1 (6) was repeated using 2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one with obtaining these compounds as a yellow oil (yield: 62.7 percent).

1H NMR (400 MHz, CDCl3)δ:

2,15 is 2.33 (2H, m), is 2.37 (3H, s), 2,52-2,72 (10H, m), 3,29 (2H, t, J=8,8 Hz), of 3.56 (2H, d, J=1.2 Hz), 4.26 deaths (2H, t, J=7,6 Hz)and 4.65 (2H, t, J=8,8 Hz), 6.87 in (1H, d, J=8.5 Hz), 7,14 (2H, d, J=8.5 Hz), 7,22 (2H,,d, J=8.5 Hz), 7,53 (1H, DD, J=8,5, 2.0 Hz), to 7.67 (1H, d, J=2.0 Hz), 7,69 (1H, s).

IR (Neat) cm-1: 1649, 1607, 1496, 1237, 1015, 755.

MS m/z:478(M+), 480(M+).

Example 16: Getting 4-aminol the Il-2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 5 was repeated using 2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one with obtaining these compounds as a yellow oil (yield: 54.5 per cent).

1H NMR (400 MHz,CDCl3)δ:

2,15-of 2.23 (2H, m), 2,70 (2H, t, J=7,3 Hz), with 3.27 (2H, t, J=8,8 Hz), 3,90 (2H, s), 4.26 deaths (2H, t, J=7,3 Hz), with 4.64 (2H, t, J=8,8 Hz), at 6.84 (1H, d, J=8.5 Hz), 7,14 (2H, d, J=8.5 Hz), 7,22 (2H, d, J=8.5 Hz), at 7.55 (1H, DD, J=8,5, 2.0 Hz), 7,65-to 7.67 (2H, m).

IR (Neat) cm-1: 1652, 1606, 1496, 1238, 1103, 756.

MS m/z:395(M+), 397(M+).

Example 17: Obtaining 2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-carboxy-2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 1 (3) was performed using 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-chlorobenzylchloride with obtaining these compounds are in the form of yellow needle crystal (yield: 75.0 per cent).

TPL: 177, 9mm-178,6°C.

1H NMR (400 MHz, CDCl3)δ:

of 3.27 (2H, t, J=8,5 Hz)and 4.65 (2H, t, J=8.5 Hz), to 5.66 (2H, s), 6,85 (1H, d, J=8.5 Hz), 7.23 percent-7,33 (3H, m), 7,45 (1H, m), to 7.59 (1H, DD, J=8,5, 2.0 Hz), to 7.67 (1H, d, J=1.5 Hz), 8,65 (1H, s), 14,03 (1H, s).

IR (KBr) cm-1: 1756, 1638, 1577, 1499, 1476, 1456, 1435, 1303, 1244.

2) Obtaining 2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one

Example 1 (4) was repeated using 4-carboxy-2-(2-Chlorobenzyl)-6-(2,3-dihyd is about-1-benzofuran-5-yl)-2H-pyridazin-3-one with obtaining these compounds are in the form of pale yellow needle crystal (yield: 42.8 per cent).

TPL: 158,3-159,0°C.

1H NMR (400 MHz, CDCl3)δ:

of 3.23 (2H, t, J=8,8 Hz)to 4.41 (2H, t, J=8,8 Hz), 4,71 (2H, d, J=1.2 Hz), of 5.53 (2H, s), for 6.81 (1H, d, J=8.5 Hz), 7,13-7,24 (3H, m), 7,40 (1H, m), 7,53 (1H, DD, J=8,5, 2.0 Hz), the 7.65 (1H, d, J=1.5 Hz), 7,72 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 3402, 1656, 1614, 1596, 1498, 1442, 1235.

MS m/z:368(M+), 370(M+).

3) Obtaining 2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Example 1 (5) was repeated using 2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one with obtaining these compounds are in the form of pale yellow needle crystals (yield: 74.7 per cent).

TPL: 118,2-118,9°C.

1H NMR (400 MHz, CDCl3)δ:

and 3.16 (3H, s)of 3.25 (2H, t, J=8,8 Hz), 4,63 (2H, t, J=8,8 Hz), 5,28 (2H,d, J=1.5 Hz), 5,54 (2H, s), 6,83 (1H, d, J=8,3 Hz), 7,16-7,27 (3H, m),7,41 (1H, m), 7,53 (1H, DD, J=8,3, 2.0 Hz), to 7.64 (1H, d, J=1.5 Hz), 7,80 (1H, t, J=1.2 Hz),

IR (KBr) cm-1: 1655, 1608, 1398, 1444, 1356, 1242, 1166, 1040.

MS m/z:446(M+), 448(M+).

4) to Obtain 2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Example 1 (6) was repeated using 2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one with obtaining these compounds are in the form of pale yellow needle crystal (yield: 42.5 per cent).

TPL: 141,4-142,1°C.

1H NMR (400 MHz, CDCl3)δ:

of 2.35 (3H, s)of 2.64 (4H, users), 2,78 (4H, users),3,26 (2H, t, J=8,8 Hz), 3,60 (2H, d, J=1.5 Hz), 4,63 (2H, t, J=8,8 Hz)5,54 (2H, s), to 6.88 (1H, d, J=8,3 Hz), 7,14-7,24 (3H, m), 7,40 (1H, m), 7,53 (1H, DD, J=8,3, 2.0 Hz), 7,66 (1H, s), 7,78 (1H, s).

IR (KBr) cm-1: 1656, 1611, 1498, 1440, 1323, 1297, 1238,

MS m/z:450(M+), 452(M+).

Example 18: Getting 4-aminomethyl-2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one

Example 5 was repeated using 2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one with obtaining these compounds are in the form of pale yellow needle crystal (yield: 45.8 per cent).

TPL: 120,1-122,8°C.

1H NMR (400 MHz,CDCl3)δ:

3,24 (2H, t, J=8,8 Hz), 3,93 (2H, s), to 4.62 (2H, t, J=8,8 Hz), 5,28 (2H, d, J=1.5 Hz), 5,54 (2H, s), PC 6.82 (1H, d, J=8.5 Hz), 7,14-7,26 (3H, m), 7,39 (1H, m), 7,54 (1H, DD, J=8,3, 2.0 Hz), 7,66 (1H, s), 7,75 (1H, s).

IR (KBr) cm-1: 3354, 1654, 1613, 1499, 1438, 1239.

MS m/z: 367(M+), 369(M+).

Test example 1

The way to determine the inhibitory effect against the production of TNF-α

RAW264.7 cells suspended in DMEM, supplemented with 10% fetal calf serum (FBS), and the suspension was sown in the wells of a 24-hole tablet (5×105/ml/well). Each test compound (from 0 to 10 μm) was added to the wells and the mixture is incubated in an incubator in an atmosphere of CO2within 30 minutes. Then to the mixture was added lipopolysaccharide (1 μg/ml and further incubation was performed in an incubator in the atmospheres of the CO 2within eight hours. Eight hours after the start of incubation was collected culture supernatant and using enzyme-linked immunosorbent assay (ELISA) to determine the amount of TNF-αcontained in the culture fluid. The value of the IC50was determined by comparison with the quantity produced TNF-α without drugs. Results related to some typical compounds are shown in Table 1.

Table 1

Test example 2

The study of absorption after oral administration to mice

Each of the tested compounds (Examples 7, 10, and 13) suspended in 0.5% HPMC in a mortar. The suspension was administered orally to each male mouse ICR (age 6 weeks) in an amount of 10 mg/kg In each moment of 0.25, 0.5, 1 and 4 hours after administration collected samples of blood and centrifuged, the receiving plasma samples. The level of the test compound in the plasma samples was determined by HPLC. The results are shown in the drawing, where it is seen that the compounds of the present invention demonstrate good absorbability, it indicates that these compounds are effective as medicines that can be applied orally.

1. Derived benzofuran represented by the formula (1)

where R1is1-C12alkyl group which may have a Deputy, or C2-C12alkenylphenol group which may have a Deputy, where specified, the Deputy represents a C6-C14aryl group which may be substituted by halogen atoms; each of R2and R3represents a hydrogen atom, alkyl group, hydroxyalkyl group, dihydroxyethylene group, or R2and R3form, together with the adjacent nitrogen atom, 5-membered, 6-membered or 7-membered nitrogen-containing saturated heterocyclic group which may be substituted by an alkyl group; and the dotted line indicates the possible presence of a double bond,

or its salt.

2. The compound according to claim 1, where R1is cyclopropylmethyl group, cinnamyl group, halogencontaining group, benzyl group, halogenmethyl group, dehalogenation group or (halogenfree), sawn group; each of R2and R3represents a hydrogen atom, a C1-C7alkyl group or a C1-C7hydroxyalkyl group; heterocyclic group formed by R2and R3represents piperazinilnom group which may be substituted With1-C7alkyl group.

3. The compound according to claim 1, to the / establishment, which is a 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one, 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-dimethylaminomethyl-2H-pyridazin-3-one, 2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one, 4-aminomethyl-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, 2-(4-terbisil)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one, 2-(4-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one, 2-(4-chlorocinnamoyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one, 6-(1-benzofuran-5-yl)-2-(4-terbisil)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one, 2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one, 4-aminomethyl-2-[3-(2-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, 2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one, 4-aminomethyl-2-[3-(4-chlorophenyl)propyl]-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-he, 2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one or 4-aminomethyl-2-(2-Chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one.

4. Drug for prevention or treatment of a pathological condition caused by the CSOs excessive production of tumor necrosis factor (TNF-α containing as active ingredient the compound or its salt according to any one of claims 1 to 3.

5. The drug according to claim 4, which is an instrument for the prevention or treatment of immune diseases, inflammatory diseases or allergic diseases.

6. The drug according to claim 4, which is an instrument for the prevention or treatment of rheumatism, arthritis or ulcerative colitis.

7. The inhibitor of the production of tumor necrosis factor (TNF-α), containing as active ingredient the compound or its salt according to any one of claims 1 to 3.

8. Pharmaceutical composition for prevention or treatment of pathological conditions caused by excessive production of tumor necrosis factor (TNF-α)containing the compound or its salt according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, representing a pharmaceutical composition for the prevention or treatment of immune diseases, inflammatory diseases or allergic diseases.

10. The pharmaceutical composition of claim 8, representing a pharmaceutical composition for the prevention or treatment of rheumatism, arthritis or ulcerative colitis.

11. The use of compounds or salts thereof according to any one of claims 1 to 3, to obtain a medicine for prevention and or treatment of a pathological condition, caused by excessive production of tumor necrosis factor (TNF-α).

12. The application of claim 11, where the specified drug is an agent for the prevention or treatment of immune diseases, inflammatory diseases or allergic diseases.

13. The application of claim 11, where the specified drug is an agent for the prevention or treatment of rheumatism, arthritis or ulcerative colitis.

14. A method of treatment of pathological conditions caused by excessive production of tumor necrosis factor (TNF-α), characterized in that the injected compound or its salt according to any one of claims 1 to 3.

15. A method of treating immune diseases, inflammatory diseases or allergic diseases, wherein the administered compound or its salt according to any one of claims 1 to 3.

16. The method according to clause 15, which represents a method for the treatment of rheumatism, arthritis or ulcerative colitis.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel benzofuran derivatives comprising group of carbamoyl type of the formula [1]: wherein cycle Z represents group of the formula or A represents a simple bond or group of the formula -NH-; Y represents lower alkylene group, cycloalkanediyl group, phenyl group or piperidyl group; R4 and R5 are similar or different, and each represents hydrogen atom, unsubstituted lower alkyl group, lower alkyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, lower alkyl group substituted with hydroxyl group, lower alkyl group substituted with lower alkoxy group, or lower alkyl group substituted with pyridyl group; or R4 and R5 represent tetrahydropyranyl; or R4 and R are bound by ends to form in common with adjacent nitrogen atom and represent pyrrolidinyl group, morpholinyl group, pyrrolidinyl group substituted with (hydroxy)(lower alkyl) group, pyrrolidinyl group substituted with hydroxyl group, thiomorpholinyl group, piperidinyl group, piperdinyl group substituted with hydroxyl group, piperazinyl group substituted with (hydroxy)(lower alkyl) group, piperidinyl group substituted with (hydroxy)(lower alkyl) group, piperazinyl group substituted with lower alkyl group, pyrrolidinyl group substituted with lower alkoxycarbonylamino group, piperidinyl group substituted with amino group optionally substituted with 1-2 lower alkyl groups, or piperidinyl group substituted with lower alkoxycarbonyl group; R1 represents hydrogen atom, halogen atom or lower alkyl group; cycle B of the formula: represents benzene cycle optionally substituted with one or two groups chosen independently from halogen atom, optionally substituted lower alkyl group, hydroxy group, lower alkoxy group optionally substituted with alkoxycarbonyl group or amino group; carbonyl group optionally substituted with lower alkoxy group, hydroxyl group, amino group optionally substituted with 1-2 alkyl groups, morpholinyl or pyrrolidyl group; optionally substituted amino group; R3 represents hydrogen atom or lower alkyl group. Also, invention relates to it's a pharmaceutically acceptable salt that are useful as Fxa inhibitors. Also, invention relates to a pharmaceutical composition based on these compounds and their using in treatment of thrombosis.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

18 cl, 22 tbl, 143 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

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

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention proposes a method for synthesis of derivatives of piperazine, namely, N-arylpiperazines of the formula (VI): wherein R, Ar and Aryl are given in the invention claim. Method involves interaction of compound of the formula (I) with NH2R' and the following conversion of synthesized intermediate substance of the formula (II) to the end compound. Except for, invention proposes a method for synthesis of intermediate substance N1-(2'-pyridyl)-1,2-alkanediaminesulfamic acid of the formula (II) wherein R and R' have values given in the invention claim by above given the reaction scheme. Also, invention involves compound of the formula (II) and its optical isomers. Except for, invention relates to a method for synthesis of intermediate compound of the formula (V) from intermediate substance of the formula (II) and to a method for synthesis of N-arylpiperazines of the formula (VI) from intermediate compound of the formula (V). Invention provides using intermediate substance of the formula (II) for synthesis of chiral piperazine derivatives that display activity with respect to 5-HT1A receptors by the stereoselective and convergent manner.

EFFECT: improved methods of synthesis, valuable biological property of compounds.

11 cl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel nitrogen-containing aromatic derivatives of the general formula (I): wherein X1 means nitrogen atom (N) or group -CR10= wherein R10 means hydrogen atom (H), halogen atom or -CN; X2 means N or group -CR11= but X1 and X2 can't mean N simultaneously; Y means oxygen atom (O) or group -NRY- wherein RY means hydrogen atom or (C1-C6)-alkyl group; R1 means phenoxy-group, group -NR12aR12b, group , group and other values; each radical among R3, R4, R5, R6 and R11 means hydrogen atom; R7 means hydrogen atom or (C1-C6)-alkyl group; R8 means hydrogen atom or (C1-C6)-alkyl group; R10 means hydrogen atom, halogen atom or cyano-group; R9 means group -NR16aR16b or group of the formula: wherein T2 means pyrrolidine, piperazine ring possibly substituted with (C1-C6)-alkyl group, or morpholine ring; R12a and R12b mean independently hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R2 means hydrogen atom or (C1-C6)-alkyl; R16a means hydrogen atom or (C1-C6)-alkyl, and R16b means (C1-C6)-alkyl possibly substituted with phenyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or di-(C1-C6)-alkylamino-group, (C3-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl possibly substituted with halogen atom, thiazolyl or piperidinyl possibly substituted with (C1-C6)-alkyl, and their salts or hydrates. Also, invention describes a pharmaceutical composition, method for treatment or prophylaxis of tumor diseases and using the novel compounds for preparing an agent useful in treatment abovementioned diseases.

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

26 cl, 17 tbl, 221 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of nicotinamide of the general formula (I): wherein R1 is chosen from hydrogen atom, unsubstituted or substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl or heteroaryl; R2 is chosen from hydrogen atom, (C1-C6)-alkyl and group -(CH2)q-(C3-C7)-cycloalkyl, or -(CH2)mR1 and R2 in common with nitrogen atom to which they are bound form (four-six)-membered heterocyclic ring; R3 represents chlorine atom or methyl group; R4 represents group -NH-CO-R7 or -CO-NH-(CH2)q-R8; R7 is chosen from hydrogen atom, (C1-C6)-alkyl, group -(CH2)q-(C3-C7)-cycloalkyl and others; R8 is chosen from hydrogen atom, (C1-C6)-alkyl, (C3-C7)-cycloalkyl and others; each X and Y is chosen independently from hydrogen atom, methyl group and halogen atom; Z represents halogen atom; m is chosen from 0,1, 2, 3 and 4; n and q are chosen from 0, 1 and 2, and to pharmaceutically acceptable salts or their solvates. Indicated compounds possess inhibitory activity with respect to p38 kinase and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 127 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

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

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel derivatives of 1,2,4-triazole of the general formula (I): wherein A and b can be taken separately or in common being when they are taken separately then A means (C1-C6)-alkyl or phenyl, and B means (C1-C6)-alkyl; A and B taken in common mean (C2-C5)-alkanediyl, and they form with C-atoms 3-6-membered cycle optionally substituted with (C1-C4)-alkylene, oxo, ethylenedioxy group, (C1-C4)-alkyl, 1-2 halogen atoms, (C1-C3)-alkoxy-(C1-C3)-alkoxy or hydroxy group; each R1 means independently hydrogen atom, -OH, halogen atom, (C3-C6)-cycloalkyl, (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms; or two R1 groups near adjacent carbon atoms form 6-membered aryl cycle; R2 and R3 can be taken in common or separately, and when they are taken in common then they represent (C3-C8)-alkanediyl that forms condensed 5-10-membered nonaromatic cycle; when R2 and R3 are taken separately then R2 means (C1-C6)-alkyl possibly substituted with 1-3 halogen atoms or cyclopropyl, and R3 means cyclopropyl possibly substituted with (C1-C4)-alkyl, naphthyl, phenyl possibly substituted with halogen atom, -OH, (C1-C6)-alkyl wherein indicated (C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, -O-(C1-C6)-alkyl wherein indicated -O-(C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, phenyl or benzyloxy group, dihydrobenzofuranyl, benzothiadiazolyl or benzoimidazolyl possibly substituted with (C1-C6)-alkyl, their pharmaceutically acceptable salts or solvates, and pharmaceutical composition based on thereof. Proposed compounds are inhibitor of 11β-hydroxysteroid dehydrogenase I, and can be used in medicine in treatment of diabetes mellitus, obesity and dyslipidemia.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 17 tbl, 4 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel derivatives if 1,3,5-triazine of the general formula (1): wherein R1 means halogen atom, (C1-C3)-alkyl, (C1-C3)-alkoxy-group, N-(di)-(C1-C3)-alkyl, NH-(C2-C3)-alkynyl, N,N-(C1-C3)-alkyl, (C2-C3)-alkynyl or 1-pyrrolidinyl, 1-piperidinyl or 1-morpholinyl group; R2 means hydrogen atom (H), (C1-C3)-alkyl possibly substituted with hydroxy-, (C1-C3)-alkoxy- or phenoxy-group; R3 means H, -CF3, (C1-C3)-alkyl possibly substituted with hydroxy-, (C1-C3)-alkoxy-, phenoxy-group or 1-morpholinyl group; or R2 and R3 in common with phenyl group to which they are bound form benzodioxolane or naphthalene cyclic system; R4 means H, -CF3 or (C1-C3)-alkoxy-group; X means -NH, N-(C1-C3)-alkyl, -CH2, oxygen atom (O) or a bond carbon-carbon; Y means group of the general formula (A) , (B) or (C) wherein R5 means -OH or -CH2OH; R6 means H or phenyl; n = 0 or 1; R7 means (C1-C3)-alkyl; R8 means H, -OH or (C1-C3)-alkoxy-group; R9 means H or (C1-C3)-alkoxy-group; R10 and R11 mean independently H or (C1-C3)-alkyl; Z means -NOH or O, or their pharmacologically acceptable salts, pharmaceutical composition possessing (ant)agonistic activity to adenosine-A3 receptors and using novel compounds in treatment of such diseases as chronic pains, arthritis, cerebrospinal sclerosis, asthma, psoriasis and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 4 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a compound of the formula (I): , wherein carbon atom designated as * is in (R)- or (S)-configuration; R1 represents (C1-C6)-alkyl; R2 represents hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-halogenalkyl; R3 represents H or halogen atom; R4 represents phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl wherein R4 group is substituted optionally with 1-4 R14-substitutes; each among R5, R6 and R7 is chosen independently from the following group: H, halogen atom, -OR11, -CN, (C1-C4)-halogenalkyl or (C1-C6)-alkyl; or R5 and R6 taken in common can represent -O-C-(R12)2-O-; R8 represents H; R11 represents H or (C1-C4)-alkyl; R12 represents (C1-C4)-alkyl; R12 is chosen independently in each case from a substitute chosen from the following group: halogen atom, -OR11, -NR11R12, morpholinyl, (C1-C6)-alkyl and (C1-C4)-halogenalkyl, or its pharmaceutically acceptable salt or solvate. Also, invention describes a pharmaceutical composition used in blocking in reuptake of norepinephrine, dopamine and serotonin based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties, improved method of treatment.

39 cl, 2 tbl, 49 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazine of the general formula (I): and their salts wherein R1 represents hydrogen atom or halogen atom; R2 represents hydrogen atom or protected or unprotected group of monophosphoric, diphosphoric or triphosphoric acid; R3, R4, R5 and R6 can be similar or different and represent hydrogen atom, halogen atom, substituted or unsubstituted, protected or unprotected hydroxyl group or amino-group; or R4 and R6 taken in common form a simple bond; A represents oxygen atom or methylene group; n = 0 or 1; Y represents oxygen atom pr NH-group. Compounds elicit the excellent antiviral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition based on compounds of the formula (I) and derivatives of fluoropyrazine carboxamide as intermediate compounds used in synthesis of compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 6 tbl, 57 ex

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

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing inhibitory effect on activity of dipeptidyl peptidase IV (DPP IV) that can be used, for example, in treatment of diabetes mellitus type 2. In compounds of the formula (I) X means nitrogen atom (N) or -C-R5; R1 and R2 mean independently hydrogen atom, (C1-C6)-alkyl; R3 means saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, or perfluoro-(C1-C6)-alkyl; R4 means (lower)-alkyl, (lower)-alkoxy-, (lower)-alkylthio-group, saturated or aromatic 7-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-, amino-group or perfluoro-(C1-C6)-alkyl, 4-fluorophenyloxy-(C1-C6)-alkyl or (C3-C6)-cycloalkyl; R5 means hydrogen atom or (C1-C6)-alkyl. Also, invention relates to methods for synthesis of compounds of the formula (I), pharmaceutical compositions and their using for preparing medicaments used in treatment and/or prophylaxis of DPP IV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

21 cl, 93 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: medicine; immunology.

SUBSTANCE: method implies that animals' thymus, e.g. sea animals' thymus, is defatted and connective tissue cleaned, milled, lyophilised, degreased with liquid CO2, hydrated in isotonic phosphate buffer at pH 7.2-7.4, sediment is removed by centrifugation, supernatant is collected and warmed up at 80°C during 10-15 min, centrifugated, supernatant is collected and pH is reduced to 4.0-4.2, deposited with ammonium sulphate, formed sediment is removed by centrifugation, dissolved in tris-HCl buffer, pH 8.0-8.2, ammonium sulphate is removed on column with Sephadex G-15, material of column outer content is, lyophilised, dissolved in 0.01 M tris-HCl, buffer containing 0.14 M NaCl, pH 8.0-8.2, gel- chromatographed on column with Sephadex G-50, end product is collected by molecular weight 500 to 25000 dalton, lyophilised, dissolved in bidistilled water and desalted on column with Sephadex G-15, end product produced in column free content is lyophilised.

EFFECT: method provides higher product yield and storage stability.

1 tbl, 4 ex

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