Water-soluble phenylpyridazine derivatives and therapeutical agents containing them

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to phenylpyridazine derivative of general formula I , wherein R1 represents C1-C12-alkyl optionally comprising cyclic C3-C6-alkyl structures and optionally substituted by phenyl, which may be substituted by 1-2 halogen atoms; or C1-C12-alkenyl substituted by optionally halogen-substituted phenyl; R2 and R3, independently form each other, represent hydrogen, C1-C12-alkyl, C1-C12-hydroxyalkyl, C1-C12-dihydroxyalkyl, or C1-C12-alkynyl; or R2 and R3, together with adjacent nitrogen atom form 5-6-membered saturated heterocyclic group containing 1-2 nitrogen atoms and optionally oxygen atom, indicated heterocyclic group being optionally substituted by C1-C12-alkyl group, C1-C12-alkoxydicarboxylic group or phenyl-C1-C7-alkyl group; X, Y, and Z, independently form each other, represent hydrogen, halogen, optionally halogen(s)-substituted C1-C12-alkyl, C1-C12-alkoxy, C1-C12-alkylthio, C1-C12-alkylsulfinyl, C1-C12-alkylsulfonyl, or phenyl; and n is a number from 0 to 5; provided that R2 and R3 cannot be simultaneously hydrogen atoms or identical C1-C3-alkyl groups when R1 is benzyl or C1-C3-alkyl group; and salts of compounds I. Foregoing compounds manifest inhibitory activity against production of interleukin IL-1β being well dissoluble in water and characterized by good oral absorption. Invention also relates to therapeutical agent inhibiting production of interleukin 1β, pharmaceutical composition, employment of above-defined compounds, a method for treating disease caused by interleukin 1β production stimulation as well as methods for treating immune system disturbances, inflammatory conditions, ischemia, osteoporosis, or septicemia using above compounds.

EFFECT: expanded therapeutical possibilities.

22 cl, 4 dwg, 2 tbl, 217 ex

 

The scope of the invention

The present invention relates to water-soluble derivatives phenylpyridazin which exhibit excellent activity in inhibiting the production of interleukin-1βhave a high solubility and oral assorbimento and are useful, for example, for the prevention and treatment of diseases of the immune system, inflammatory diseases and ischemic diseases, and medicines containing these compounds as the active ingredient.

Background of the invention

In many diseases, such as rheumatism, arthritis, osteoporosis, inflammatory colitis, immunodeficiency syndrome, septicemia, hepatitis, nephritis, ischemic heart disease, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease and leukemia, there is a stimulation of the production of interleukin-1β, inflammatory cytokine. Such interleukin-1β induces the synthesis of the enzyme, which is thought to be involved in inflammation, such as collagenase and PLA2, and the introduction by intra-articular injection of animals causes mnogoslovye damage, much like rheumatoid arthritis. On the other hand, in a healthy organism the activity of interleukin-1β controlled by the receptor of interleukin-1, soluble prescriptions what PR interleukin-1 receptor antagonist interleukin-1.

As a result of research conducted using recombinant variants of these inhibiting the biological activity of substances, antiinterleukin-1β antibodies and antibodies against the receptor directed against various disease models, as well as in the research conducted with the use of "knockout" mice, it was found that interleukin-1β plays an important role in the body, such studies can lead to increased potential of substances having activity of inhibiting interleukin-1βas therapeutic agents for the treatment of such diseases.

For example, there were reports that the immunosuppressants and steroids used to treat rheumatism, inhibit the production of interleukin-1β. Developed in the present compounds, KE298 derived benzoylpropionic acid [The Japanese Society of Inflammation(11th), 1990], for example, as reported, shows inhibitory activity against the production of interleukin-1βeven though it is immunoregulation. Inhibitory activity against the production of interleukin-1β also observed in the group of compounds called selective COX-2 inhibitors such as nimesulide, which is a derivative of phenoxycarbonylamino (DE 2333643), T-614, which is a derivative of phenoxybenzophenone (US atent 4954518), and tenidap (derived oxyindole), which is a dual inhibitor (COX-1/5-LO).

However, activity on the inhibition of production of interleukin-1β is not the primary effect of any of these compounds, therefore, the inhibitory activity against the production of interleukin-1β less than their main action.

Recently conducted extensive research in the field of synthesis, mainly aimed at the study of inhibitory activity against the production of interleukin-1β. Inhibitors of the production can be classified into (1) a group of compounds that inhibit the process of signal transmission inflammation of the nuclei of cells, and (2) another group of compounds which inhibit the enzyme ICE, functioning in the processing of precursor interleukin-1β. Well-known examples of compounds which are believed to have first action (1), include SB203580 [Japanese Language Laid-Open (Kohyo) Publication (PCT) No. HEI 7-503017], FR167653 (Eur. J. Pharm.,327, 169-175, 1997), E-5090 (EP 376288), CGP47969A (Gastroenterology,109, 812-828, 1995), derivatives of hydroxyindole (Eur. J. Med. Chem.31, 187-198, 1996), and derivatives triadimenol (WO 9705878), while there are examples of compounds which are believed to have the second action (2)include VE-13,045, which is a peptide compound (Cytokine,8(5), 377-386, 1996).

However, none of these is of dinani does not show sufficient inhibitory activity against the production of interleukin-1β .

On the other hand, it is known that derivatives of 5,6-diphenylpyrazine exhibit analgesic and anti-inflammatory (Eur. J. Med. Chem.,14, 53-60, 1979). In addition, 6-phenylpyridine, as reported, are useful as cardiotonic compounds (US Patent 4404203). However, there were no reports on the inhibitory activity of these pyridazinone compounds against production of interleukin-1β.

Previously, in WO 99/44995, the authors of the present invention have reported that high inhibitory activity against the production of interleukin-1β watched the derivatives phenylpyridazin. Recently reported on some connections phenylpyridazin possessing inhibitory activity against the production of interleukin-1β (JP 7-69894 A, WO 98/41511, WO 99/10331, WO 99/10332, WO 99/25697, WO 00/50408). However, these in these applications, the compounds differ in their chemical structure from the compounds of the present invention.

Description of the invention

Compounds disclosed in WO 99/44995, show strong inhibitory activity against the production of interleukin-1β. However, the solubility of such compounds is so low that their formulation into pharmaceutical preparations such as tablets, is almost impossible. In further studies, the authors present invention found Thu the introduction of substituted or unsubstituted aminoalkyl group in position 4 6-phenylpyridazin-3-it gives compound, useful as a preventive or therapeutic agent for the treatment of diseases of the immune system, inflammatory diseases and ischemic diseases, for example, thanks to its significantly improved water solubility, good oral namely excellent inhibitory activity against the production of interleukin-1βthat led to the creation of the present invention.

Thus, in one aspect the present invention provides a connection phenylpyridazin represented by the formula (1):

where:

R1represents a substituted or unsubstituted alkyl group or substituted or unsubstituted alkenylphenol group;

R2and R3each independently represents a hydrogen atom or an alkyl, hydroxyalkyl, dihydroxyethylene or alkylamino group, or R2and R3together with the adjacent nitrogen atom, may form a substituted or unsubstituted nitrogen-containing saturated heterocyclic group;

X, Y and Z, each independently, represents a hydrogen atom or halogen, substituted or unsubstituted alkyl, alkoxy, alkylthio, alkylsulfonyl or alkylsulfonyl group or a substituted or unsubstituted aryl group; and

n has a value from 1 to 5;

the ri condition, what R2and R3at the same time may not represent hydrogen atoms or the same C1-C3alkyl groups, when R1represents a benzyl group or a C1-C3alkyl group; or its salt.

In another aspect of the present invention also provides a drug comprising the compound phenylpyridazin (1) or its salt as an active ingredient.

The following aspect of the present invention also provides a pharmaceutical composition comprising the compound phenylpyridazin (1) or its salt and a pharmaceutically acceptable carrier.

In another aspect of the present invention also provides for the connection phenylpyridazin (1) or its salt to obtain the drug.

In one aspect of the present invention also provides a method of treating diseases caused by stimulation of the production of interleukin-1β, which includes the introduction of connection phenylpyridazin (1) or its salt.

BRIEF DESCRIPTION of FIGURES

In Fig. 1 graphically presents oral absorbiruyaci compounds of the present invention (Example 83) and comparative compound 3;

Figure 2 graphically presents oral absorbiruyaci other compounds of the present invention (Example 23);

Figure 3 graphicinteractive oral absorbiruyaci another compound of the present invention (Example 25);

Figure 4 graphically presents oral absorbiruyaci another compound of the present invention (Example 143).

The BEST WAYS of carrying out the INVENTION

In the above formula (1), the alkyl fragments alkyl, hydroxyalkyl, dihydroxyacetone, alkoxy, alkylthio, alkylsulfonyl and alkylsulfonyl groups represent fragments containing from 1 to 12 carbon atoms, more preferably from 1 to 7 carbon atoms. Such alkyl fragments can include linear, branched and cyclic alkyl groups and alkyl groups containing a cyclic structure, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

In the above formula (1), the alkyl group represented by R1preferably contains from 1 to 12 carbon atoms, more preferably from 1 to 7 carbon atoms, for example, from 4 to 7 carbon atoms. Examples of such alkyl groups are linear, branched and cyclic alkyl groups and alkyl groups containing a cyclic structure. Preferred examples may include methyl, ethyl, propyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl is, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl, with methyl, ethyl, isobutyl, cyclopropylmethyl and cyclopentylmethyl are particularly preferred.

Alchemilla group represented by R1preferably contains from 2 to 12 carbon atoms, with the number of carbon atoms from 2 to 7 is particularly preferred. Examples of such alkenyl groups include linear and branched alkeneamine groups, in particular vinyl, propenyl, butenyl and pentenyl.

Examples of the group (groups), which alkyl or alkeneamine group represented by R1can contain as substituent (s), are substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl group. Examples of aryl groups include aryl groups containing from 6 to 14 carbon atoms, in particular phenyl and naphthyl, with phenyl is especially preferred. Examples of heteroaryl groups, on the other hand, include 5 - or 6-membered heteroaryl group, containing 1 to 3 nitrogen atoms, in particular pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl, and the pyridyl is especially preferred.

Such aryl or heteroaryl group can contain from 1 to 3 substituents, such as halo atom is s, alkyl group or alkoxy group. Examples of the halogen atom include fluorine, chlorine, bromine and iodine, with fluorine and chlorine are particularly preferred. These alkyl and alkoxy groups preferably contain from 1 to 12 carbon atoms, with the number of carbon atoms from 1 to 7 is particularly preferred.

Alkyl, hydroxyalkyl and dihydroxyethylene group represented by R2and R3preferably contain from 1 to 12 carbon atoms, with the number of carbon atoms from 1 to 7 is particularly preferred. Preferably, such groups can be linear or branched. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, dihydroxypropyl and dihydroxybutyl.

Alkyline group represented by R2and R3preferably contain from 3 to 12 carbon atoms, with the number of carbon atoms from 3 to 7 is particularly preferred. Examples are propargyl (2-PROPYNYL).

Examples of nitrogen-containing saturated heterocyclic group, which may be formed in the connection R2and R3with the adjacent nitrogen atom, are a 5-7-membered saturated heterocyclic group, in particular pyrrolidinyl, piperidino, piperazinil, d is piperazinil, morpholino, this piperazinil, piperidino, morpholino are particularly preferred.

Examples of the group (groups)that these heterocyclic groups can contain as substituent (s)are halogen atom, alkyl group, alkoxycarbonyl group and kalkilya group. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Alkyl groups can contain from 1 to 12 carbon atoms, preferably from 1 to 7 carbon atoms. Examples alkoxycarbonyl groups are C1-C12allyloxycarbonyl group, while C1-C7allyloxycarbonyl group are preferred. Examples Uralkalij groups are phenyl group (C1-C7alkyl), especially preferred is benzyl.

Examples of halogen atoms represented by X, Y and Z are fluorine, chlorine, bromine and iodine. Alkyl groups can contain from 1 to 12 carbon atoms, with the number of carbon atoms from 1 to 7 is particularly preferred. Of these alkyl groups, linear or branched groups are especially preferred. Examples of the group (groups), which alkyl group may contain as substituent (s)are halogen atoms and alkoxygroup. Alkoxy, alkylthio, alkylsulfonyl and alkylsulfonyl group can contain from 1 is about 12 carbon atoms, the number of carbon atoms from 1 to 7 is particularly preferred. Such alkoxy, alkylthio, alkylsulfonyl and alkylsulfonyl groups, linear or branched groups are especially preferred. Specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, methylsulfinyl, ethylsulfinyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl and butylsulfonyl. Examples of aryl groups are aryl groups containing from 6 to 14 carbon atoms, in particular phenyl and naphthyl, with phenyl is especially preferred. Examples of the group (groups), which aryl group may contain as substituent (s)are halogen atoms, alkyl groups and alkoxygroup.

n is a number from 1 to 5, more preferably from 1 to 3, and most preferably 1 or 3.

When R1represents a benzyl group or a C1-C3alkyl group, R2and R3at the same time are not hydrogen atoms or the same C1-C3alkyl groups.

In the formula (1) as R1especially preferred are isobutyl, cyclopropylmethyl, cyclopentylmethyl, cinnamyl, Gal is sentinnel, benzyl, halogenmethyl, dehalogenases and (halogenarenes)propyl. As R2and R3preferred are hydrogen, C1-7alkyl, C1-7hydroxyalkyl and propargyl. As the heterocyclic group formed by R2and R3preferred are piperazinil, piperidino, pyrrolidinyl, morpholino, each of which is optionally substituted by one or more C1-7alkyl or benzyl groups. As X preferred are methyl, methoxy, methylthio and halogen-free. As Y preferred are hydrogen, methyl and halogen. As Z preferred is hydrogen. Preferred values of n are 1 and 3.

As the salt of compound (1) according to the present invention, it is preferable acid additive salt. Examples of the acid additive salts include salts of inorganic acids such as hydrochloride, sulfate, nitrate and phosphate, and organic acid salts such as methanesulfonate, maleate, fumarate, citrate and oxalate.

Compounds of the present invention may also exist in the form of a solvate or keto-enol tautomers. Such solvate and tautomers are included in the scope of the present invention. Examples of the solvate include a solvate, which are formed by adding solvent p and the formation of compounds, for example, water and alcohols. There are no particular restrictions on the solvent, provided that they do not adversely affect or similar inhibitory activity of the compounds of the present invention against the production of interleukin-1β. As MES is preferred hydrate.

Connection phenylpyridazin (1) of the present invention can be obtained, for example, using the following methods of obtaining (a) - (d).

The method of obtaining compounds of formula (1),

in which n=1

where R4represents an alkyl group, Hal represents a halogen atom, Ms is methanesulfonyl group, and R1, R2, R3X, Y and Z have the meanings given above.

Hereinafter will be described in a separate phase reactions.

On stages from acetophenone (2) to compound (5) acetophenone (2) and diethylmalonate heated under stirring to obtain compound (3). The connection is exposed to hydrazine for the implementation of the cyclization reaction and then the reaction product is treated with alkali, for example sodium hydroxide or the like, to obtain the compound (4). Then, the compound (4) is subjected to interaction with alcohol, such as methanol, to obtain the compound (5).

R1-Hal is subjected to interaction of the compound (5) in the presence of alkali, such as potassium carbonate, to obtain the compound (6). Connection (6) hydrolyzing to obtain compound (7). After exposure to the compound (7) atilglukuronida to convert it to the acid anhydride, acid anhydride restore using a reductant such as sodium borohydride, to obtain the compounds (8). The interaction of methanesulfonanilide with compound (8) in the presence of a base, such as triethylamine, gives compound (9), which is the key intermediate compound in the reaction scheme.

The reaction of the desired amine (R2(R3)NH) with compound (9) gives the target compound (1a). This reaction preferably takes place, for example, in a polar solvent such as dimethylformamide, in the presence or in the absence of alkali, such as potassium carbonate. If the group R2or R3in Amina contains amino group, the reaction may be carried out using the original substance, protected with suitable protecting group, for example alkoxycarbonyl group, with the subsequent removal of the protective group.

To obtain the compounds (1a)in which R2and R3are hydrogen atoms, phthalimide potassium is subjected to interaction with compound (9) and then the reaction product is subjected to interaction with hydrazine or the like

The compound (1a)in which X, Y and/or Z made the focus of methylsulfinyl group or methylsulfonylamino group, can be obtained by oxidation of the corresponding compounds in which X, Y and/or Z represents metalcorp, percolate, such as perbenzoic acid. This methylsulfonylamino or methylsulfonylamino can be done at the stage of intermediate compounds (9).

The method of obtaining compounds of formula (1),

in which n=3

where Hal, Ms, R1, R2, R3X, Y and Z have the meanings given above.

In accordance with the method get (b) tetravalent carbon, such as tetrabromide carbon, is first subjected to interaction with compound (8), in the presence of triphenylphosphine with getting halide (10) with the subsequent interaction of this compound with malonate in the presence of sodium hydride to obtain the compound (11). The compound (11) is subjected to interaction with acid, such as triperoxonane acid, to convert it to a dicarboxylic acid followed by heating to obtain compound (12). The compound (12) is exposed to atilglukuronida for conversion to the acid anhydride, which is then restored using a reductant such as sodium borohydride, to obtain the compounds (13). The compound (13) is subjected to interaction with methanesulfonamide in the presence of a base, such as triethylamine, with receipt is m connection (14), the key intermediate compound in the method according to the present invention.

The target compound (1b) can be obtained by the interaction of the appropriate amine (R2R3NH) with compound (14). This reaction can preferably be realized, for example, in the presence or in the absence of alkali, such as potassium carbonate, in a polar solvent such as dimethylformamide. When the group R2or R3amine contains amino group, the reaction may be carried out using the original substance, in which the amino group protected with a suitable protecting group (for example, alkoxycarbonyl group), with the subsequent removal of the protective group.

To obtain the compound (1b)in which R2and R3both represent hydrogen atoms, this compound can be obtained by the interaction of phthalimide potassium with compound (14) and then the interaction with hydrazine or the like

(c) a Method of obtaining compounds of formula (1),

in which n=2

where M represents a metal atom, and Hal, Ms, R1, R2, R3X, Y and Z have the meanings given above.

In accordance with the method of obtaining (c) cyanide such as sodium cyanide, is subjected to the interaction with the halide (10) to be converted into a nitrile derivative (15), which is then hydrolized with getting connected to the I (16). From compound (16) of the target compound (1c) can be obtained through the derivative of the alcohol (17) and methyloxirane (18) using a procedure analogous to that used to obtain the compounds, each of which contains three methylene groups.

(d) the Method of obtaining compounds of formula (1),

in which n=4 or 5

These compounds can be obtained by combining the methods of synthesis (b) and (c).

Salt of the compounds (1) according to the present invention can be obtained by the action of an organic or inorganic acid by a method known from the prior art.

Connection (1) according to the present invention can be selected and cleared through clearing, usually held in the chemistry of organic synthesis, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographic methods and/or the like, Each of the intermediate product can be used in subsequent reactions without further purification. The compound (1) can be obtained in the form of MES, in particular in the form of a hydrate, when using a solvent such as the solvent used in the reaction, or the solvent for recrystallization.

Connection (1) according to the present invention has excellent solubility in water, it is also well absorbed when administered orally and has inhibitore the activity against the production of interleukin-1β and is therefore useful as a preventive or therapeutic agent for the treatment of diseases of the immune system, inflammatory diseases, ischemic diseases, osteoporosis, ischemia, etc. are Examples of ischemic diseases include ischemic heart disease, ischemic encephalopathy, ischemic jade and ischemic hepatitis.

The pharmaceutical composition of the present invention contains as an active ingredient the compound (1) or its salt. The active ingredient can be used alone or together with a pharmacologically acceptable carrier, such as a solubilizer, excipient, binder or filler, to obtain pharmaceutical preparative forms, such as tablets, capsules, granules, powders, injections and suppositories. Such pharmaceutical preparations can be obtained by the known methods. For example, preparations for oral administration can be obtained by formulating compositions of the compounds (1) or its salts in combination with solubilization, such as gum tragakant, Arabian gum, esters of sucrose, lecithin, olive oil, soybean oil and PEG 400; excipients such as starch, mannitol and lactose; binders, such as sodium carboxymethylcellulose and hydroxypropylcellulose; leavening agents, such as crystallic the Skye cellulose and calcium carboxymethylcellulose; lubricating agents such as talc and magnesium stearate; agents against adhesion, such as light anhydrous silicic acid. The pharmaceutical compositions of the present invention lead oral or parenteral.

Injected dose of the pharmaceutical composition of the present invention varies depending on the body weight, age, sex, conditions, etc. of each patient. However, as a rule, preferably the introduction of an adult from about 0.01 to 1000 mg, preferably from 0.1 to 100 mg of the pharmaceutical composition of the present invention based on the compound (1), day 1 to 3 portions.

EXAMPLES

Hereinafter the present invention will be described with reference to examples. The examples are presented solely for purposes of illustration, and in no way should be construed as limiting the invention.

Example 1

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one

1) Poluchenie-(1-hydroxyethyl)-2-Tortolla

It chilled with ice to a solution of 3-fluoro-4-methylbenzaldehyde (50 mg, 0.36 mmol) in THF (0.5 ml) was added dropwise 0,93 M solution of 0.47 ml) methylacrylamide (0.44 mmol) in THF. The mixture was again allowed to warm to room temperature at which the reaction mixture was stirred for 1 hour. Then added 2 mol/l of chlorine is stevedorage acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compounds as a pale yellow oil (55,8 mg, quantitative yield).

1H NMR (400 MHz, CDCl3) δ: of 1.46 (3H, d, J=6.4 Hz), and 2.26 (3H, d, J=1,8 Hz), is 4.85 (1H, square, J=6.4 Hz), 6,99-7,06 (2H, m), 7,14 (1H, DD, J=7,8, 7,8 Hz).

2) Obtain 3'-fluoro-4'-methylacetophenone

To a solution of 4-(1-hydroxyethyl)-2-portaluri (55,8 mg, 0.36 mmol) in methylene chloride (1 ml) was added molecular sieves 4A (56,0 mg) and PCC 94,0 mg (0.43 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the title compounds as a pale yellow oil (47,5 mg, 86,0%).

1H NMR (400 MHz, CDCl3) δ: 2,32 (3H, d, J=1,8 Hz), of 2.56 (3H, s), 7,26 (1H, DD, J=7,6, 7,6 Hz), 7,56 (1H, DD, J=1,6, 10.4 Hz), a 7.62 (1H, DD, J=1,6, 7,8 Hz).

3) to Obtain ethyl 2-etoxycarbonyl-4-(3-fluoro-4-were)-2-hydroxy-4-oxobutanoate

A mixture of 3'-fluoro-4'-methylacetophenone (4,92 g, and 32.3 mmol) and diethylmalonate (to 6.19 g of 35.6 mmol) was stirred at 120°C for 48 hours. The temperature of the reaction mixture was allowed to drop to room temperature and the mixture was purified column chromatography on silica gel [forces the Kagel 100 g, chloroform/ethyl acetate (10/1)] to obtain specified in the title compound as yellow crystals (to 8.41 g, 79.3 percent).

Melting point: 68,7-69,0°

1H NMR (400 MHz, CDCl3) δ: 1,30 (6N, t, J=7,1 Hz), was 2.34 (3H, s), of 3.78 (2H, s), 4,25 (1H, s), or 4.31 (4H, square, J=7,1 Hz), 7,29 (1H, DD, J=7,6 Hz), to 7.59 (1H, d, J=10,2 Hz), the 7.65 (1H, DD, J=1.5 and 7.8 Hz).

IR (KBr) cm-1: 3485, 1740, 1684, 1253, 856, 577.

4) to Obtain 4-carboxy-6-(3-fluoro-4-were)-2H-pyridazin-3-one

To a solution of ethyl 2-etoxycarbonyl-4-(3-fluoro-4-were)-2-hydroxy-4-oxobutanoate (to 8.41 g of 25.8 mmol) in isopropanol (100 ml) was added hydrazinoacetate (2,84 g of 56.8 mmol) and the mixture was heated under stirring at 100°C for 6 hours. Then added 2 mol/l sodium hydroxide and the mixture continued to stir at the same temperature for 4 hours. The reaction mixture was cooled on ice and added concentrated hydrochloric acid for acidification system. The precipitate was filtered, thoroughly washed with water and dried to obtain specified in the connection header in the form of a yellow crystalline powder (5,67 g, 87.7 per cent).

Melting point: 281,3-282,0°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 2,28 (3H, d, J=1.0 Hz), 7,41 (1H, DD, J=8,1, 8.1 Hz), to 7.67-7,73 (2H, m), 8,49 (1H, s), 14,09 (1H, usher.).

IR (KBr) cm-1: 1736, 1641, 1441, 1125, 926, 806.

5) Obtain 6-(3-fluoro-4-were)-4-methoxycarbonyl-2H-pyridazin-3-one

To about lardenoy ice suspension of 4-carboxy-6-(3-fluoro-4-were)-2H-pyridazin-3-one (5.50 g, of 22.2 mmol) in methanol (100 ml) was added dropwise thionyl chloride (2,72 g, 24.4 mmol) and the mixture was stirred at 80°C for 8 hours. The temperature of the reaction mixture was allowed to drop to room temperature and the solvent is kept at reduced pressure. To a chilled on ice to the residue was added water. The precipitate was filtered, washed with water and dried to obtain specified in the title compounds as pale yellow thin needle-shaped crystals (5,43 g, 92.7%of).

Melting point: 206,0-207,3°

1H NMR (400 MHz, CDCl3) δ: of 2.33 (3H, d, J=1.7 Hz), of 4.00 (3H, s), 7,29 (1H, DD, J=7,9, 7.9 Hz), 7,46-7,53 (2H, m), 8,32 (1H, s), of 11.61 (1H, s).

IR (KBr) cm-1: 1715, 1671, 1266, 1177, 1091, 812.

6) Obtain 6-(3-fluoro-4-were)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

To a solution of 6-(3-fluoro-4-were)-4-methoxycarbonyl-2H-pyridazin-3-one (5,28 g, 20.0 mmol) in N,N-dimethylformamide (40 ml) was added potassium carbonate (5.53 g, 40.0 mmol) and isobutylamine (3,29 g, 24,0 mmol) and the mixture was stirred at 80°C for 1 hour. The temperature of the reaction mixture gave again to drop to room temperature. Was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was purified column chromatography on silica compound is a gel [silica gel 100 g, chloroform/methanol (100/1→50/1)to obtain specified in the title compound as an orange oil (5,41 g, 84,9%).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,32-to 2.42 (1H, m), of 2.33 (3H, s), 3,98 (3H, s), of 4.12 (2H, d, J=7,4 Hz), 7,28 (1H, DD, J=7,8, and 7.8 Hz), 7,46 (1H, DD, J=1,6, 7,8 Hz)to 7.50 (1H, DD, J=1,6 and 10.7 Hz), 8,21 (1H, ).

7) Getting 4-carboxy-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one

To a suspension of 6-(3-fluoro-4-were)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one (5,27 g of 16.6 mmol) in methanol (50 ml) was added 2 mol/l aqueous sodium hydroxide solution (50 ml) and the mixture was stirred at 60°C for 15 minutes the Temperature of the reaction mixture gave again to drop to room temperature and then added water. After acidification system of concentrated hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was recrystallized from a mixture of chloroform-hexane to obtain specified in the title compounds as colorless fine needle-shaped crystals (4,73 g, 93.8%of the respondents).

Melting point: 159,0-159,5°

1H NMR (400 MHz, CDCl3) δ: 1,02 (6N, d, J=6,7 Hz), 2,33-to 2.42 (1H, m), 2,35 (3H, d, J=1.6 Hz), is 4.21 (2H, d, J=7,4 Hz), 7,32 (1H, dd, J=7,8,7,8 Hz), 7,52 (1H, dd, J=1,8,8,0 Hz), 7,55 (1H, DD, J=1,8, a 10.6 Hz), 8,63 (1H, s), 14,13 (1H, C).

IR (KBr) cm1 : 2960, 1742, 1633, 1574, 1425, 1101, 820.

8) Obtain 6-(3-fluoro-4-were)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

To a solution of 4-carboxy-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one (4,53 g, 14.9 mmol) in THF (40 ml) was added triethylamine (1.66 g, 16.4 mmol). To ice the mixture was added dropwise a solution of atilglukuronida (1.78 g, 16.4 mmol) in THF (5 ml) and the mixture was stirred for 30 minutes Hydrochloride of triethylamine was filtered. To the filtrate was added a solution of sodium borohydride (564 mg, 14.9 mmol) in water (1 ml) and the mixture was stirred at room temperature for 10 min. Then the reaction mixture was added 2 mol/l hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel [silica gel 300 g, chloroform/methanol (100/1>50/1)to obtain specified in the title compounds as a colorless crystalline powder (1.08 g, 25,0%).

Melting point: 147,3-147,5°

1H NMR (400 MHz, CDCl3)δ: 0,99 (6N, d, J=6.6 Hz), 2,29-2,39 (1H, m), 2,32 (3H, d, J=1,8 Hz), 3,05 (1H, t, J=6.0 Hz), 4,08 (2H, d, J=7,4 Hz), 4,71 (2H, DD, J=1,2, 6,0 Hz), 7,26 (1H, DD, J=7.8 Hz), 7,46 (1H, DD, J=7,8, 7,8 Hz), to 7.50 (1H, DD, J=1,8, and 10.8 Hz), the 7.65 (1H, s).

IR (KBr) cm-1: 3330, 1644, 1596, 1514, 1226, 1087, 824.

9)Obtain 6-(3-fluoro-4-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

It chilled with ice to a solution of 6-(3-fluoro-4-were)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one (1.08 g, 3.73 mmol) in methylene chloride (20 ml) was added triethylamine (491 mg, is 4.85 mmol) and methanesulfonamide (513 mg, 4,48 mmol) and the mixture was stirred for 1 hour. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and then the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was recrystallized from a mixture of chloroform-hexane to obtain specified in the title compounds as a colorless crystalline powder (964 mg, 70,4%).

Melting point: 142,7-143,4°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,30-of 2.34 (1H, m), 2,33 (3H, d, J=1,8 Hz), 3,17 (3H, s)4,08 (2H, d, J=7,4 Hz), 5,27 (2H, d, J=1.4 Hz), 7,27 (1H, DD, J=7,8, and 7.8 Hz), was 7.45 (1H, DD, J=1,8, 8.0 Hz), 7,50 (1H, DD, J=1,8, up 10.9 Hz), 7,76 (1H, t, J=1.4 Hz).

IR (KBr) cm-1: 3435, 2964, 1658, 1610, 1354, 1165, 875.

10) Obtaining 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one

To a solution of 6-(3-fluoro-4-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one (100 mg, 0.27 mmol) in acetonitrile (1 ml) was added potassium carbonate (56,3 mg, 0.41 mmol) and tert-butyl 1-piperidinecarboxylate (60,7 mg, 0.33 mmol) and the mixture was stirred at 80&x000B0; C for 2 hours. The temperature of the reaction mixture gave again to drop to room temperature and then added water. The mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel [chloroform/methanol (40/1)] to obtain specified in the title compound as a yellow oil (115 mg, 92.4 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=3,4 Hz), 1,47 (N, C), 2,28-to 2.40 (1H, m), of 2.33 (3H, s), 2,52 (4H, t, J=4,7 Hz), 3,51 (4H, t, J=4,7 Hz)to 3.58 (2H, s)4,07 (2H, d, a 4.1 Hz), 7,27 (1H, DD, J=7,6, 7,6 Hz), 7,44-7,52 (2H, m), to 7.77 (1H, s).

Example 2

Getting dihydrochloride 6-(3-fluoro-4-were)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one

To a solution of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one (115 mg, 0.25 mmol) in ethyl acetate (2 ml) was added 4 mol/l solution (2 ml) of hydrochloric acid in ethyl acetate and the mixture was stirred at 50°C for 1 hour. The temperature of the reaction mixture gave again to drop to room temperature and then was added diethyl ether. The precipitate was separated with obtaining specified in the title compounds as a colorless crystalline powder (81,1 mg, 75.0 per cent).

Melting point: 186,2-195,0°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.8 Hz), 2,22 is 2.33 (1H, m)to 2.29 (3H, d, J=2.0 Hz), 3,15 (4H, usher.), of 3.32 (4H, t, J=5,2 Hz), 3,93 (2H, s), was 4.02 (2H, d, J=7,1 Hz), 7,40 (1H, DD, J=8,1, 8.1 Hz), to 7.59-7,66 (2H, m), 8,21 (1H, s).

IR (KBr) cm-1: 1656, 1610, 1425, 1306, 956.

Mass m/z: 358 (M+)

Example 3

Getting 6-(3-fluoro-4-were)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-fluoro-4-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 93.4%as).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,28-to 2.40 (1H, m), 2,33 (6N, (C), 2,52 (4H, usher.), 2,62 (4H, usher.), to 3.58 (2H, s)4,07 (2H, d, J=7,4 Hz), 7,27 (1H, DD, J=7,9, 7.9 Hz), 7,46-7,52 (2H, m), of 7.75 (1H, d, J=1.0 Hz).

Example 4

Getting dihydrochloride 6-(3-fluoro-4-were)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

To a solution of 6-(3-fluoro-4-were)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one (94,4 mg, 0.25 mmol) in methanol (1 ml) was added dropwise at room temperature with stirring, 4 mol/l solution (0.15 ml) of hydrochloric acid in ethyl acetate. The solvent is kept at reduced pressure. The residue was recrystallized from methanol-diethyl ether to obtain specified in the title compounds as a colorless crystalline powder (71,9 mg, 63.7 per cent).

Melting point: 248,5252,0° C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6,8 Hz)to 2.29 (3H, d, J=1,8 Hz), 2,22 is 2.33 (1H, m), 2,77 (3H, s)3,18 (4H, usher.), to 3.38 (4H, usher.), 3,91 (2H, s), was 4.02 (2H, d, J=7,0 Hz), 7,40 (1H, DD, J=8,0, 8.0 Hz), to 7.59-the 7.65 (2H, m), 8,16 (1H, s).

IR (KBr) cm-1: 1653, 1609, 1451, 1425, 951.

Mass m/z: 372 (M+)

Example 5

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-fluoro-4-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 84.8%of).

1H NMR (400 MHz, CDCl3) δ: 0,96 (6N, d, J=6.6 Hz), 2,27 of 2.38 (1H, m), is 2.30 (3H, s), 2,70 (4H, t, J=5.0 Hz), 3,66 (4H, t, J=5,2 Hz), of 3.69 (2H, s)4,06 (2H, d, J=7,2 Hz), 7.23 percent (1H, DD, J=7,9,7,9 Hz), 7,46-7,52 (2H, m), 7,79 (1H with).

Example 6

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 85,9%).

Melting point: 159,7-160,7°

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.6 Hz), 2,20-of 2.34 (1H, m), 2,30 (3H, d, J=1.7 Hz), the 3.35 (4H, t, J=5,1 Hz), a-3.84 (4H, t, J=5,1 Hz), of 4.05 (2H, d, J=,0 Hz), of 4.45 (2H, s), 7,42 (1H, DD, J=8,2, 8,2 Hz), 7,62-to 7.68 (2H, m), of 8.47 (1H, s).

IR (KBr) cm-1: 1663, 1613, 1427, 1087, 1052, 821.

Mass m/z: 359 (M+-H2O)

Example 7

Getting 4-dimethylaminomethyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one

To 6-(3-fluoro-4-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-ONU (100 mg, 0.27 mmol) was added 40% aqueous solution of dimethylamine (1 ml) and the mixture was stirred at 80°C for 2 hours. The temperature of the reaction mixture gave again to drop to room temperature and then added water. The mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel [chloroform/methanol (40/1)] to obtain specified in the title compound as a yellow oil (69,7 mg, 80.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,23-to 2.41 (1H, m), 2,31 (3H, s), 2,35 (6N, (C)a 3.50 (2H, d, J=1.2 Hz), 4,08 (2H, d, J=7,4 Hz), 7,26 (1H, DD, J=7,9,7,9 Hz), 7,47-rate of 7.54 (2H, m), 7,76 (1H, d, J=1.4 Hz).

Example 8

Getting hydrochloride 4-dimethylaminomethyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-dimethylaminomethyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 85.4 percent.

Melting point: 246,5-248,5°

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.6 Hz), 2,23-of 2.34 (1H, m), is 2.30 (3H, s), 2,81 (6N, (C), of 4.05 (2H, d, J=7,0 Hz), 4,27 (2H, s), 7,41 (1H, DD, J=8,0,8,0 Hz), 7,22-to 7.68 (2H, m), charged 8.52 (1H, s).

IR (KBr) cm-1: 1648, 1607, 1422, 1227, 1110, 1051.

Mass m/z: 317 (M+)

Example 9

Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

1) preparation of 4-carboxy-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compound as yellow crystals (yield: 98.9 per cent).

Melting point: 169,1-170,7°

1H NMR (400 MHz, CDCl3) δ: from 0.50 to 0.67 (4H, m ), of 1.40-1.50 (1H, m), of 3.97 (3H, s)to 4.23 (2H, d, J=7,3 Hz), 7,07 (1H, DD, J=8.5 a, 8.5 Hz), EUR 7.57 (1H, DDD, J=1,2, 2,2, 8.5 Hz), the 7.85 (1H, DD, J=2,2, and 12.2 Hz), 8,63 (1H, s), 14,20 (1H, s).

IR (KBr) cm-1: 1761, 1629, 1521, 1476, 1461.

Mass m/z: 318 (M+).

2) Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compound as a yellowish thin needle crystals (yield: 21.3 per cent).

Melting point: 119,4-122,° With

1H NMR (400 MHz, CDCl3) δ: 0,45-0,60 (4H, m), of 1.36 to 1.47 (1H, m), 3,12 (1H, t, J=6.0 Hz), of 3.95 (3H, s), 4,10 (2H, d, J=7,3 Hz), 4.72 in (2H, DD, J=1,2, 5,9 Hz), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,51 (1H, DDD, J=1,2, 2,2, 8.5 Hz), 7,62 (1H, DD, J=2,2, and 12.4 Hz), the 7.65 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 3431, 1652, 1604, 1524.

Mass m/z: 304 (M+).

3) Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellowish thin needle crystals (yield: 80.4%to).

Melting point: 156,9-to 158.4°

1H NMR (400 MHz, CDCl3) δ: 0,45-0,61 (4H, m), 1,36 of 1.46 (1H, m), 3,18 (3H, s), of 3.95 (3H, s), 4,10 (2H, d, J=7,3 Hz), 5,28 (2H, d, J=1.2 Hz), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,51 (1H, DDD, J=1,2, 2,2, 8.5 Hz), a 7.62 (1H, DD, J=2,2, and 12.2 Hz), 7,76 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 1656, 1612, 1523, 1358, 1177.

Mass m/z: 382 (M+).

4) to Obtain 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-one

A solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one (160 mg, 0.42 mmol) in 30% methylamine/ethanol (5 ml) was stirred at 80°C for 4 h in a sealed tube. The solvent is kept under reduced pressure and the residue was purified preparative thin-layer chromatography on what silicagel [manifesting solvent: chloroform/methanol (10/1)] to obtain specified in the title compound as yellow oil (87 mg, 65,5%).

1H NMR (400 MHz, CDCl3) δ: 0,45-0,59 (4H, m), of 1.36 to 1.47 (1H, m), of 1.85 (1H, usher.), 2,52 (3H, s), 3,80 (2H, d, J=1.2 Hz), of 3.95 (3H, s), 4,10 (2H, d, J=7,3 Hz), 7,01 (1H, DD, J=8.5 a, 8.5 Hz), 7,52 (1H, DDD, J=1,2, 2,2, 8.5 Hz), a 7.62 (1H, DD, J=2,2, and 12.4 Hz), 7,66 (1H, t, J=1.2 Hz).

Mass m/z: 317 (M+).

Example 10

Getting hydrochloride 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellowish thin needle crystals (yield: 93.8%of the respondents).

Melting point: 220,8-224,3°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,44-0,54 (4H, m), 1,29-of 1.40 (1H, m)to 2.66 (3H, s), 3,91 (3H, s), of 4.05 (2H, d, J=7,3 Hz), of 4.12 (2H, s), 7,33 (1H, DD, J=8.5 a, 8.5 Hz), 7,70-7,79 (2H, m), 8,39 (1H, s).

IR (KBr) cm-1: 1645, 1599, 1521, 1437.

Example 11

Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 73,8%).

1H NMR (400 MHz, CDCl3) δ: 0,45-0,59 (4H, m), of 1.36 to 1.47 (1H, m), of 2.33 (3H, s), 2,52 (4H, usher.), 2,62 (4H, usher.), of 3.80 (2H, d, J=1.2 Hz), 3,8 (2H, d, J=1.0 Hz), of 3.95 (3H, s), 4.09 to (2H, d, J=7,3 Hz),? 7.04 baby mortality (1H, DD, J=8.5 a, 8.5 Hz), 7,53 (1H, DDD, J=1,2, 2,2, 8.5 Hz), to 7.61 (1H, DD, J=2,2, and 12.4 Hz), 7,74 (1H, t, J=1.2 Hz).

IR (Pure) cm-1: 1652, 1608, 1520, 1456, 1440.

Mass m/z: 386 (M+).

Example 12

Getting dihydrochloride 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow needle crystals (yield: 81,0%).

Melting point: 237,4-238,4°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,47-0,58 (4H, m), 1,31-of 1.41 (1H, m), of 2.33 (3H, s), 2,52 (4H, usher.), 2,62 (4H, usher.), 2,90-3,85 (10H, m), 3,91 (3H, s), a 4.03 (2H, d, J=7,3 Hz), 7,30 (1H, DD, J=8.5 a, 8.5 Hz), 7,70 for 7.78 (2H, m), of 8.28 (1H, users).

IR (KBr) cm-1: 1653, 1608, 1523, 1438.

Example 13

Getting 2-cyclopropylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compound as a yellow oil (yield: 88.1 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,45-0,59 (4H, m), of 1.37 to 1.48 (1H, m), 2,36 (6N, (C), 3,51 (2H, s), of 3.95 (3H, s), 4,10 (2H, d, J=7,3 Hz), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,53-EUR 7.57(1H, m)to 7.64 (1H, DD, J=2.2, while the 12.7 Hz), of 7.75 (1H, s).

IR (Pure) cm-1: 1652, 1608, 1523, 1456, 1438.

Mass m/z: 331 (M+).

Example 14

Getting hydrochloride 2-cyclopropylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 89,0%).

Melting point: 233,6-235,0°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,41-0,54 (4H, m), of 1.27 to 1.37 (1H, m), 2,83 (6N, C)to 3.92 (3H, s)4,06 (2H, d, J=7,3 Hz), 4,30 (2H, s), 7,33 (1H, DD, J=8,8, 8,8 Hz), 7,69-to 7.77 (2H, m), 8,51 (1H, s).

IR (KBr) cm-1: 1648, 1584, 1522, 1439.

Example 15

Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(2-hydroxyethyl)aminomethyl-2H-pyridazin-3-one

Following the procedure of example 9 (4)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 2-aminoethanol obtaining specified in the title compound as a yellow oil (yield: 72.1 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,44-0,59 (4H, m), of 1.36 to 1.47 (1H, m), of 2.86 (2H, t, J=5,1 Hz), to 3.73 (2H, t, J=5,1 Hz), a-3.84 (2H, d, J=1.0 Hz), of 3.94 (3H, s), 4,10 (2H, d, J=7,3 Hz), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,50-rate of 7.54 (1H, m,), a 7.62 (1H, DD, J=2.2, while the 12.7 Hz), to 7.67 (1H, s).

IR (Pure) cm-1: 3411, 1651, 1605, 1523, 1439.

Mass m/z: 347 (M ).

Example 16

Getting hydrochloride 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(2-hydroxyethyl)aminomethyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-N-(2-hydroxyethyl)-aminomethyl-2H-pyridazin-3-one to obtain specified in the title compounds as a pale brown needle crystals (yield: 79,2%).

Melting point: 166,8-169,3°C (decomp.)

1H NMR (400 MHz, CDCl3) δ: 0,40-0,54 (4H, m), of 1.27 to 1.37 (1H, m), of 3.13 (2H, usher.), of 3.28 (2H, usher.), 3,74 (3H, s), of 4.05 (2H, d, J=7,1 Hz), 4,18 (2H, s), 5,31 (1H, usher.), 7,33 (1H, DD, J=8,8, 8,8 Hz), 7,69-7,79 (2H, m), 8,40 (1H, s).

IR (KBr) cm-1: 3334, 1654, 1616, 1604, 1523, 1441.

Example 17

Getting 4-(4-benzyl-1-piperazinil)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-benzylpiperazine with obtaining specified in the title compound as a yellow oil (yield: 97.7 percent).

1H NMR (400 MHz, CDCl3) δ: 0,44-0,58 (4H, m), 1,36 of 1.46 (1H, m), of 2.56 (4H, usher.), 2,62 (4H, usher.), of 3.56 (2H, s)to 3.58 (2H, d, J=1.0 Hz), of 3.95 (3H, s), 4.09 to (2H, d, J=7,1 Hz),? 7.04 baby mortality (1H, DD, J=8.5 a, 8.5 Hz), 7.23 percent and 7.36 (5H, m), 7,50-of 7.55 (1H, m), to 7.61 (1H, DD, J=2.2, while the 12.7 Hz), of 7.75 (1H, s).

IR (Pure) cm-1: 1652, 1608, 1522, 1438, 1289, 1237.

Mass m/z: 462 (M+).

Por what measures 18

Getting dihydrochloride 4-(4-benzyl-1-piperazinil)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-(4-benzyl-1-piperazinil)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compounds as yellow prismatic crystals (yield: 85.7 percent).

Melting point: 253,0-257,9°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,41-0,55 (4H, m), 1,27-to 1.38 (1H, m), 3,06-3,49 (10H, usher.), of 3.56 (2H, s), 3,91 (3H, s), was 4.02 (2H, d, J=7,3 Hz), 4,39 (2H, users), 7,30 (1H, DD, J=8.5 a, 8.5 Hz), 7,44-of 7.48 (3H, m), to 7.59-to 7.64 (2H, m), 7,69-to 7.77 (2H, m), 8,30 (1H, users).

IR (KBr) cm-1: 1656, 1616, 1523, 1439, 1292, 1271.

Example 19

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compounds as a pale brown oil (yield: 98.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,44-0,59 (4H, m), 1,47 (N, C), 1,38 of 1.46 (1H, m), of 2.53 (4H, t, J=4.9 Hz), 3,51 (4H, t, J=4,9 Hz)to 3.58 (2H, d, J=1.2 Hz), of 3.95 (3H, s), 4,10 (2H, d, J=7,3 Hz), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,51 (1H, DDD, J=1,2, 2,2, 8.5 Hz), to 7.61 (1H, DD, J=2.2, while the 12.7 Hz), 7,76 (1H, s).

IR (Pure) cm-1

Mass m/z: 472 (M+).

Example 20

Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

4-(4-tert-Butoxycarbonyl-1-piperazinil)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one (220 mg, 0.47 mmol) was dissolved in ice triperoxonane acid (2 ml) and at the same temperature and the mixture was stirred for 15 minutes To the reaction mixture were added water (10 ml). The mixture was podslushivaet potassium carbonate and was extracted twice with chloroform (20 ml). The extracts were washed with saturated saline (20 ml) and dried over anhydrous sodium sulfate. The solvent drove away. The residue was recrystallized from a mixture of chloroform-hexane to obtain specified in the title compounds as pale yellow prismatic crystals (120 mg, 69.2 per cent).

Melting point: 111,5-118,0°

1H NMR (400 MHz, CDCl3) δ: 0,45-0,59 (4H, m), of 1.36 to 1.47 (1H, m)to 2.55 (4H, usher.), 2,96 (4H, t, J=4.9 Hz), of 3.56 (2H, d, J=1.5 Hz), of 3.95 (3H, s), 4.09 to (2H, d, J=7,3 Hz),? 7.04 baby mortality (1H, DD, J=8.5 a, 8.5 Hz), 7,53 (1H, DDD, J=1,2, 2,2, 8.5 Hz), a 7.62 (1H, DD, J=2.2, while the 12.7 Hz), 7,76 (1H, t, J=1.5 Hz).

IR (KBr) cm-1: 3328, 1648, 1605, 1520, 1437.

Mass m/z: 372 (M+).

Example 21

Getting dihydrochloride 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to interaction cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as yellow prismatic crystals (yield: 94.5%of).

Melting point: 139,1-142,4°

1H NMR (400 MHz, DMSO-d6) δ: 0,42-0,56 (4H, m), 1,29-of 1.39 (1H, m), 3,40 (4H, usher.), 3,70 (4H, usher.), 3,91 (3H, s)to 4.16 (2H, d, J=7,3 Hz)to 4.16 (2H, users), 7,31 (1H, DD, J=8.5 a, 8.5 Hz), 7,71-7,73 (2H, m), to 8.41 (1H, users).

IR (KBr) cm-1: 3435, 1660, 1610, 1526, 1440, 1291.

Example 22

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxy-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compounds as a pale brown oil (yield: 83.0 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,43-0,58 (4H, m), 1,35 of 1.46 (1H, m), a 2.71 (4H, t, J=4,9 Hz)to 3.67 (4H, t, J=4.9 Hz), 3,71 (2H, s), 3,85 (2H, usher.), of 3.94 (3H, s), 4,10 (2H, d, J=7,3 Hz), 7,01 (1H, DD, J=8.5 a, 8.5 Hz), 7,51-7,56 (1H, m), to 7.61 (1H, DD, J=2,2, and 12.4 Hz), 7,73 (1H, t, J=1.5 Hz).

IR (Pure) cm-1: 3616, 3476, 3275, 1648, 1601, 1529.

Mass m/z: 391 (M+).

Example 23

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow prismatic crystals (yield: 75,9%)./p>

Melting point: 175,2-176,8°

1H NMR (400 MHz, DMSO-d6) δ: 0,42-0,55 (4H, m), 1,28-of 1.39 (1H, m)to 3.36 (4H, usher.), is 3.82 (4H, usher.), to 3.92 (3H, s)4,06 (2H, d, J=7,3 Hz), 4,49 (2H, users), 7,33 (1H, DD, J=8.5 a, 8.5 Hz), 7,71-7,79 (2H, m), of 8.47 (1H, users).

IR (KBr) cm-1: 3162, 1652, 1604, 1531.

Example 24

Getting 4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

1) preparation of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one

To a solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one (220 mg, or 0.57 mmol) in N,N-dimethylformamide (5 ml) was added phthalimide potassium (160 mg, 0.87 mmol) and the mixture was stirred at 80°C for 2 hours. To the reaction mixture were added water (30 ml). After stirring under cooling over water with ice, the precipitated crystals were filtered off, dried in air and recrystallized from a mixture of chloroform-hexane to obtain specified in the connection header in the form of colorless needle-like crystals (202 mg, 81,0%).

Melting point: 241,7-243,6°

1H NMR (400 MHz, CDCl3) δ: 0,45-0,59 (4H, m), of 1.37 to 1.47 (1H, m), 3,90 (3H, s), 4,10 (2H, d, J=7,1 Hz), 4,91 (2H, d, J=1.2 Hz), to 6.95 (1H, DD, J=8.5 a, 8.5 Hz), 7,29 (1H, t, J=1.2 Hz), 7,38 (1H, DDD, J=1,2, 2,2, 8.5 Hz), of 7.48 (1H, DD, J=2,2, and 12.4 Hz), 7,76-7,81 (2H, m), of 7.90-of 7.95 (2H, m).

IR (KBr) cm-1: 1712, 1653, 1614, 1524.

Mass m/z: 433 (M+).

2) Getting 4-amine is Teal-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

To a solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one (190 mg, 0.43 mmol) in methanol (5 ml) was added hydrazine monohydrate (110 mg, of 2.20 mmol) and the mixture was heated at the boil under reflux for 2 hours. Methanol and drove to the residue was added chloroform (20 ml). The mixture is then washed with water (10 ml) and saturated saline (10 ml) in that order and then dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was purified preparative thin-layer chromatography on silica gel [manifesting solvent: chloroform/10% wt./about. a solution of methanol in ammonia (20/1)] to obtain specified in the title compound as yellow crystals (130 mg, 97.8 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,45-0,59 (4H, m), of 1.37 to 1.47 (1H, m)and 1.51 (2H, usher.), the 3.89 (2H, d, J=1.2 Hz), of 3.95 (3H, s), 4,11 (2H, d, J=7,1 Hz), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,53 (1H, DDD, J=1,2, 2,4, 8.5 Hz), 7,63 (1H, DD, J=2.2, while the 12.7 Hz), 7,68 (1H, s).

IR (KBr) cm-1: 3393, 1651, 1606, 1523, 1438, 1293.

Mass m/z: 303 (M+).

Example 25

Getting hydrochloride 4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow holca what's crystals (81,0%).

Melting point: 188,2-194,2°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,42-0,55 (4H, m), 1,29-of 1.39 (1H, m)to 3.92 (3H, s)to 4.01 (2H, s)4,06 (2H, d, J=7,1 Hz), 7,34 (1H, DD, J=8.5 a, 8.5 Hz ), 7,71 for 7.78 (2H, m), 8,31 (1H, s).

IR (KBr)cm-1: 3507, 3440, 1644, 1581, 1522, 1438.

Example 26

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 94.3%of).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 1,46 (N, C), 2,27-to 2.40 (1H, m), 2,52 (4H, t, J=5,2 Hz), 3,50 (4H, t, J=5,2 Hz), of 3.57 (2H, s), of 3.95 (3H, s)4,06 (2H, d, J=7,4 Hz), 7,03 (1H, DD, J=8,6, 8.6 Hz), 7,51 (1H, DD, J=1,2, 8,4 Hz), 7,60 (1H, DD, J=2,2, 12,5 Hz), of 7.75 (1H, s).

Example 27

Getting dihydrochloride 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 58.5 per cent).

Melting point: 163,0-177,0°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.8 Hz), 2,22 is 2.33 (M, m), 3,17 (4H, usher.), of 3.33 (4H, t, J=5.3 Hz), to 3.92 (3H, s), of 3.96 (2H, s)to 4.01 (2H, d, J=7,1 Hz), 7,27 (1H, DD, J=8,9, and 8.9 Hz), to 7.67-7,72 (2H, m), by 8.22 (1H, s).

IR (KBr) cm-1: 1656, 1608, 1522, 1440, 1291, 1113.

Mass m/z: 374 (M+)

Example 28

Getting 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 80.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,28-to 2.40 (1H, m), of 2.34 (3H, s)to 2.55 (4H, usher.), 2,63 (4H, usher.), to 3.58 (2H, d, J=1.4 Hz), of 3.95 (3H, s)4,06 (2H, d, J=7,4 Hz),? 7.04 baby mortality (1H, DD, J=8,6, 8.6 Hz), 7,53 (1H, DD, J=1,2, 8.6 Hz), to 7.61 (1H, DD, J=2,2, 12,5 Hz), 7,73 (1H, s).

Example 29

Getting dihydrochloride 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 73.3 per cent).

Melting point: EUR 236.9-237,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.8 Hz), 2,21 of-2.32 (1H, m), 2,77 (3H, s), 3,14 (4H, usher.), to 3.36 (4H, usher.), a 3.87 (2H, s), 3,91 (3H, s), 4.00 points (2H, d, J=7,1 Hz), 7,26 (1H, DD, J=8.5 a, 8.5 Hz), 7,66-7,71 (2H, m)to 8.12 (1H).

IR (KBr) cm-1: 1655, 1606, 1524, 1440, 1291, 1113, 1022.

Mass m/z: 388 (M+)

Example 30

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 87.2%of total).

1H NMR (400 MHz, CDCl3) δ: 0,96 (6N, d, J=6.8 Hz), 2,27-2,39 (1H, m), a 2.71 (4H, t, J=5.0 Hz), to 3.67 (4H, t, J=5.0 Hz), 3,70 (2H, s), 3,93 (3H, s)4,07 (2H, d, J=7,4 Hz), 7,01 (1H, DD, J=8,6, 8.6 Hz), 7,53 (1H, DD, J=1,4, and 8.4 Hz), to 7.61 (1H, DD, J=2,2, 12,5 Hz), 7,72 (1H, s).

Example 31

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless flakes (yield: 89,0%).

Melting point: 129,8-133,1°

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.8 Hz), 2,23-of 2.34 (1H, m)to 3.34 (4H, t, J=5,1 Hz), 3,83 (4H, t, J=5,2 Hz)to 3.92 (3H, s), a 4.03 (2H, d, J=7,0 Hz), of 4.44 (2H, s), 7,29 (1H, DD, J=8,7, to 8.7 Hz), 7,69 to 7.75 (2H, m), 8,46 (1H, s).

IR (KBr) cm-1: 1652, 1601, 1525, 1440, 1277.

Mass m/z: 362 (M+-CH2OH)

Example 32

Getting 4-dimethylamino ethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction 6-3-(fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compound as a yellow oil (yield: 88.6 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,30-to 2.40 (1H, m), 2,36 (6N, (C)a 3.50 (2H, s), 3,93 (3H, s)4,07 (2H, d, J=7,2 Hz), 7,02 (1H, DD, J=8,6, 8.6 Hz), 7,55 (1H, d, J=8.6 Hz), 7,63 (1H, DD, J=2,1, 12,5 Hz), of 7.75 (1H, s).

Example 33

Getting hydrochloride 4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 81,0%).

Melting point: 212,4-212,8°

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.8 Hz), 2,23 is 2.33 (1H, m), 2,81 (6N, C)to 3.92 (3H, s), Android 4.04 (2H, s, J=7,1 Hz), 4,27 (2H, s), 7,29 (1H, DD, J=8,1, 8.1 Hz), 7,70 to 7.75 (2H, m), 8,51 (1H, s).

IR (KBr) cm-1: 1652, 1607, 1522, 1439, 1292, 1112.

Mass m/z: 333 (M+)

Example 34

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

1) preparation of 4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 1(5)were subjected to interaction of 4-carboxy-6-phenyl-2H-pyridazin-3-one to obtain specified in the header with the unity in the form of pale yellow crystals (yield: 98.9 per cent).

Melting point: 202,5-206,2°

1H NMR (400 MHz, CDCl3) δ: 4,01 (3H, s), 7,45-rate of 7.54 (3H, m), 7,78-a 7.85 (2H, m), scored 8.38 (1H, s), up 11,86 (1H, usher.).

IR (KBr) cm-1: 1717, 1670, 1443, 1259.

Mass m/z: 230 (M+).

2) Getting 2-isobutyl-4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 94,1%).

1H NMR (400 MHz, CDCl3) δ: 1,00 (6N, d, J=6.6 Hz), 2,33 is 2.44 (1H, m), 3,98 (3H, s), 4,14 (2H, d, J=7,4 Hz), 7,42-7,51 (3H, m), 7,79-7,83 (2H, m), of 8.27 (1H, s).

3) Obtaining 4-carboxy-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-isobutyl-4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless fine needle crystals (yield: 82.5 per cent).

Melting point: of 120.5-to 121.0°

1H NMR (400 MHz, CDCl3) δ: 1,03 (6N, d, J=6.6 Hz), 2,34 at 2.45 (1H, m)to 4.23 (2H, d, J=7,4 Hz), 7,49-rate of 7.54 (3H, m), 7,84-7,89 (2H, m), 8,69 (1H, s), 14,20 (1H, s).

IR (KBr) cm-1: 3448, 2956, 1741, 1636, 1418, 1116.

Mass m/z: 272 (M+)

4) to Obtain 4-hydroxymethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-isobutyl-6-phenyl-2H-pyridazin-3-one to obtain specified in the title compound as a colourless tone is their needle-like crystals (yield: 22.3 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,29-to 2.40 (1H, m)to 3.67 (1H, usher.), 4,08 (2H, d, J=7,4 Hz), 4.72 in (2H, d, J=3,9 Hz), 7,39-7,49 (3H, m), 7,76 (1H, t, J=1.4 Hz), 7,79-to 7.84 (2H, m).

5) Getting 2-isobutyl-4-methanesulfonylaminoethyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 4-hydroxymethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless fine needle crystals (yield: 68,4%).

Melting point: 129,7°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,30-to 2.41 (1H, m), 3,17 (3H, s), 4,10 (2H, d, J=7,2 Hz), 5,28 (2H, d, J=1.2 Hz), 7,43-7,52 (3H, m), 7,79-of 7.82 (3H, m).

IR (KBr) cm-1: 3442, 2963, 1658, 1611, 1355, 1165, 872.

Mass m/z: 336 (M+)

6) Obtain 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 1(10), 2-isobutyl-4-methanesulfonate-6-phenyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate subjected interaction in N,N-dimethylformamide is used as solvent, to obtain specified in the title compound as a yellow oil (yield: 83.5 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 1,47 (N, C)of 2.53 (4H, t, J=4.9 Hz), 3,50 (4H, t, J=4,9 Hz)and 3.59 (2H, d, J=1.0 Hz), 4.09 to (2H, d, J=7,2 Hz), 7,40-to 7.50 (3H, m), 7,80-to 7.84 (3H, m).

Example 35

Getting dihydrochloride 2-isobutyl-6-phenyl-4-(1-piperazinil)methyl-2H-pyridazin the-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one to obtain specified in the title compounds as white solids (yield: 67.9 percent).

Melting point: 154,3-159,5°

1H NMR (400 MHz, CDCl3) δ: 0,94 (6N, d, J=6.8 Hz), 2,20 of-2.32 (1H, m), of 2.86 (4H, usher.), is 3.21 (4H, usher.), 3,71 (2H, s)to 4.01 (2H, d, J=7,2 Hz), 7,42-7,53 (3H, m), 7,84-7,89 (2H, m), of 7.96 (1H, s).

IR (KBr) cm-1: 1656, 1610, 1445, 694.

Mass m/z: 326 (M+)

Example 36

Getting 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-phenyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 77.1 percent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,30-to 2.40 (1H, m), of 2.34 (3H, s)to 2.55 (4H, usher.), of 2.64 (4H, usher.), 3,59 (2H, d, J=1.4 Hz), 4,08 (2H, d, J=7,2 Hz), 7,40-to 7.50 (3H, m), 7,78-to 7.84 (3H, m).

Example 37

Getting dihydrochloride 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-phenyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 66.3 per cent).

Temperature plvl the tion: 243,8-244,3° With

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.8 Hz), 2,22-of 2.34 (1H, m), was 2.76 (3H, s), 3,01 (4H, usher.), 3,30 (4H, usher.), of 3.77 (2H, s), was 4.02 (2H, d, J=7,2 Hz), 7,43-7,53 (3H, m), a 7.85-7,89 (2H, m), 8,02 (1H, s).

IR (KBr) cm-1: 2960, 1653, 1610, 1446.

Mass m/z: 340 (M+)

Example 38

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-phenyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 38.7 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,97 (6N, d, J=6.6 Hz), 2,29-to 2.40 (1H, m), and 2.79 (4H, usher.), 3,70 (4H, usher.), of 3.80 (2H, s), 4.09 to (2H, d, J=7,4 Hz), 7,39-of 7.48 (3H, m), 7,81-7,87 (3H, m).

Example 39

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless flakes (yield: 68,4%).

Melting point: 131, 6mm-132,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.6 Hz), of 2.25 to 2.35 (1H, m)to 3.35 (4H, t, J=5,1 Hz), a-3.84 (4H, t, J=5.4 Hz), 4,06 (2H, d, J=7,1 Hz), 4,47 (2H, s), 7,45-rate of 7.54 (3H, m), of 7.90-7,94 (2H, m), 8,48 (1H, s).

IR (KBr) cm-1: 1655, 1610, 1421, 1053.

Mass m/z: 314 (M+-CH2OH)

Example 40

Getting 4-emailmyname-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-phenyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compound as a yellow oil (yield: 81.1%of).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,32-to 2.41 (1H, m), 2,35 (6N, (C), 3,51 (2H, d, J=1.2 Hz), 4.09 to (2H, d, J=7,2 Hz), 7,38-of 7.48 (3H, m), 7,80-7,87 (3H, m).

Example 41

Getting hydrochloride 4-dimethylaminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-dimethylaminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow flakes (yield: 71.5%of).

Melting point: 221,7-222,3°

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.8 Hz), 2,24 to 2.35 (1H, m), 2,82 (6N, C)4,06 (2H, d, J=7,1 Hz), the 4.29 (2H, s), 7,44-rate of 7.54 (3H, m), of 7.90-7,94 (2H, m), 8,54 (1H, s).

IR (KBr) cm-1: 1648, 1610, 1460, 1052.

Mass m/z: 285 (M+)

Example 42

Getting 4-(4-benzyl-1-piperazinil)methyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

1) preparation of 2-isobutyl-4-methoxycarbonyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 4-methoxycarbonyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: to 91.6%).

Melting point: 67,0-70,1°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,32 is 2.43 (1H, m), is 2.41 (3H, s), 3,98 (3H, s), 4,13 (2H, d, J=7,3 Hz), 7,28 (2H, d, J=8,3 Hz), of 7.70 (2H, d, J=8,3 Hz), 8,24 (1H, s).

IR (KBr) cm-1: 1718, 1663, 1605.

Mass m/z: 300 (M+).

2) Getting 4-carboxy-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-isobutyl-4-methoxycarbonyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 86.7 per cent).

Melting point: 162,1-165,4°

1H NMR (400 MHz, CDCl3) δ: 1,02 (6N, d, J=6.8 Hz), 2,34 is 2.44 (1H, m), 2,47 (3H, s), is 4.21 (2H, d, J=7,3 Hz), 7,31 (2H, d, J=8,3 Hz), of 7.75 (2H, d, J=8,3 Hz), 8,66 (1H, s), 14,26 (1H, s).

IR (KBr) cm-1: 1740, 1633, 1571, 1425.

Mass m/z: 286 (M+).

3) Obtaining 4-hydroxymethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-isobutyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 46,0%).

Melting point: 121,9-123,5°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,30-to 2.40 (1H, m), is 2.40 (3H, s), up 3.22 (1H, usher.), 4,08 (2H, d, J=7,3 Hz), 4,71 (2H, s), 7,27 (2H, d, J=8,3 Hz), to 7.77 (1H, s), of 7.70 (2H, d, J=8,3 Hz).

IR (KBr) cm-1: 3334, 1645, 1596, 1522.

Mass m/z: 272 (M+).

4) to Obtain 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-methylp the Nile)-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 4-hydroxymethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 87.4 per cent).

Melting point: 132,0-135,5°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,29-2,39 (1H, m), is 2.41 (3H, s), 3,17 (3H, s)4,08 (2H, d, J=7,6 Hz), 5,27 (2H, t, J=1.5 Hz), 7,27 (2H, d, J=8,3 Hz), 7,72 (2H, d, J=8,3 Hz), 7,79 (1H, t, J=1.5 Hz).

IR (KBr) cm-1: 1656, 1609, 1355, 1166.

Mass m/z: 350 (M+).

5) Obtain 4-(4-benzyl-1-piperazinil)methyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-were)-2H-pyridazin-3-one and 1-benzylpiperazine with obtaining specified in the title compounds as a pale yellow oil (yield: 97.7 percent).

1H NMR (400 MHz, CDCl3) δ: 0,97 (6N, d, J=6.8 Hz), 2,29-2,39 (1H, m), is 2.41 (3H, s)to 2.55 (4H, usher.), 2,61 (4H, usher.), of 3.54 (2H, s), 3,57 (2H, d, J=1.5 Hz), 4,07 (2H, d, J=7,3 Hz), 7,22 and 7.36 (7H, m), of 7.70 (2H, d, J=8,3 Hz), to 7.77 (1H, t, J=1.5 Hz).

IR (Pure) cm-1: 1657, 1652, 1518, 1455.

Mass m/z: 430 (M+).

Example 43

Getting dihydrochloride 4-(4-benzyl-1-piperazinil)methyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-(4-benzyl-1-piperazinil)methyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-he is getting at is asanoha in the title compounds as colorless needle crystals (yield: 91.8%of).

Melting point: 253,5-260,1°

1H NMR (400 MHz, DMSO-d6) δ: 0,92 (6N, d, J=6.6 Hz), 2,18-of 2.28 (1H, m), of 2.34 (3H, s), 3.43 points (10H, usher.), to 3.99 (2H, d, J=7,3 Hz), 4,36 (2H, users), 7,22 (2H, d, J=8.1 Hz), 7,43-7,49 (3H, m), 7,58-the 7.65 (2H, m), 7,78 (2H, d, J=8.1 Hz), 8,30 (1H, users).

IR (KBr) cm-1: 1660, 1617, 1452.

Example 44

Getting 4-dimethylaminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-were)-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compound as a yellowish oil (yield: 96.6 percent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,38-to 2.41 (1H, m), 2,35 (6N, (C), is 2.40 (3H, s), 3,50 (2H, d, J=1.5 Hz), 4,08 (2H, d, J=7,3 Hz), 7,26 (2H, d, J=8.1 Hz), 7,73 (2H, d, J=8.1 Hz), 7,78 (1H, t, J=1.5 Hz).

IR (Pure) cm-1: 1652, 1609, 1518, 1455.

Mass m/z: 299 (M+).

Example 45

Getting hydrochloride 4-dimethylaminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-dimethylaminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 91.8%of).

Melting point: 237,6-239,6°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.8 Hz), 2,19-of 2.30 (1H, m), is 2.37 (3H, s), 2,81 (6N, (C), was 4.02 (2H, d, J=7,0 Hz), 4,30 (2H, s), 7,34 (2H, d, J=8.1 Hz), 7,8 (2H, d, J=8.1 Hz), 8,46 (1H, s).

IR (KBr) cm-1: 1648, 1605, 1460, 1421.

Example 46

Getting 4-diethylaminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 9 (4)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-were)-2H-pyridazin-3-one and diethylamin obtaining specified in the title compounds as a pale yellow oil (yield: 95,0%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 1,07 (6N, t, J=7,1 Hz), 2,30-to 2.42 (1H, m), is 2.40 (3H, s), 2,60 (4H, square, J=7,1 Hz), 3,60 (2H, d, J=1.5 Hz), 4,08 (2H, d, J=7,3 Hz), 7,26 (2H, d, J=8.1 Hz), 7,73 (2H, d, J=8.1 Hz), 7,89 (1H, t, J=1.5 Hz).

IR (Pure) cm-1: 1652, 1609, 1518, 1465, 1455.

Mass m/z: 327 (M+).

Example 47

Getting hydrochloride 4-diethylaminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-diethylaminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 93.8%of the respondents).

Melting point: the amount of 203.9-207,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 1.27mm (6N, t, J=7.2 Hz), 2,20-of 2.30 (1H, m), is 2.37 (3H, s), 3,09-3,24 (4H, m), a 4.03 (2H, d, J=7,1 Hz), 4,28 (2H, d, J=5.4 Hz), 7,34 (2H, d, J=8.1 Hz), 7,82 (2H, d, J=8,1 Hz), 8,55 (1H, s).

IR (KBr) cm-1: 1652, 1610, 1523, 1481, 1468.

Example 48

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-were)-2-isobutyl-2-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-were)-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compounds as a pale yellow oil (yield: 95,0%).

1H NMR (400 MHz, CDCl3) δ: 0,97 (6N, d, J=6.6 Hz), 2,28-to 2.41 (1H, m), is 2.40 (3H, s), a 2.71 (4H, t, J=5.0 Hz), 3,66 (4H, t, J=5.0 Hz), 3,70 (2H, s), of 3.78 (2H, usher.), 4.09 to (2H, d, J=7,6 Hz), 7,26 (2H, d, J=8.1 Hz), 7,68 (1H, s), of 7.70 (2H, d, J=8,1 Hz).

IR (Pure) cm-1: 3392, 1645, 1600, 1520.

Mass m/z: 341 (M+-H2O).

Example 49

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 86.4 per cent).

Melting point: 158,9-161,5°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 2,19-of 2.30 (1H, m), is 2.37 (3H, s), 3.27 to of 3.46 (4H, m), of 3.77-of 3.85 (4H, m), was 4.02 (2H, d, J=7,3 Hz), 4,50 (2H, users), to 5.35 (2H, usher.), 7,34 (2H, d, J=8.1 Hz), 7,81 (2H, d, J=8.1 Hz), 8,46 (1H, s).

IR (KBr) cm-1: 3292, 1664, 1615, 1423.

Example 50

Getting 4-aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

1) preparation of 2-isobutyl-6-(4-were)-4-phthalimidomethyl-2H-pyridazin-3-one

Following the procedure of example 24 (1), evaluation of the Gali to the interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 98.2 per cent).

Melting point: 221,6-223,8°

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,27-to 2.41 (1H, m), a 2.36 (3H, s)4,08 (2H, d, J=7,3 Hz), 4,91 (2H, d, J=1.5 Hz), 7,20 (2H, d, J=8.1 Hz), 7,32 (1H, t, J=1.5 Hz), 7,56 (2H, d, J=8.1 Hz), 7,75-7,80 (2H, m), 7,89-7,94 (2H, m).

IR (KBr) cm-1: 1767, 1721, 1655, 1616.

Mass m/z: 401 (M+).

2) Getting 4-aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 24 (2), were subjected to interaction of 2-isobutyl-6-(4-were)-4-phthalimidomethyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless prismatic crystals (yield: 98.1 per cent).

Melting point: 74,9-77,9°

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.9 Hz), 1,68 (2H, usher.), 2,28-to 2.42 (1H, m), is 2.40 (3H, s), a 3.87 (2H, d, J=1.2 Hz), 4,07 (2H, d, J=7,3 Hz), 7,26 (2H, d, J=8.0 Hz), 7,69 (1H, t, J=1.5 Hz), 7,71 (2H, d, J=8.0 Hz).

IR (KBr) cm-1: 3363, 3289, 1648, 1604, 1519.

Mass m/z: 271 (M+).

Example 51

Getting hydrochloride 4-aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow prismatic crystals (yield: 93.1%of).

Melting point: 207,4-209,4°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,93 (6N, d, J=6.6 Hz), 2,19-of 2.30 (1H, m), is 2.37 (3H, s)to 4.01 (2H, d, J=7,1 Hz), was 4.02 (2H, s), 7,34 (N, d, J=8.1 Hz), 7,80 (2H, d, J=8.1 Hz), compared to 8.26 (1H, s).

IR (KBr) cm-1: 1655, 1616, 1520, 1467.

Example 52

Getting 4-(1,3-dihydroxypropyl-2-yl)aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-were)-2H-pyridazin-3-one and 2-amino-1,3-propandiol with obtaining specified in the title compounds as colorless needle crystals (yield: 83.7 percent).

Melting point: 134,1-to 135.2°

1H NMR (400 MHz, CDCl3) δ: 0,97 (6N, d, J=6.6 Hz), 2,29-2,39 (1H, m), is 2.40 (3H, s), 2,60 (3H, usher.), 2,82-2,87 (1H, m)to 3.64 (2H, DD, J=5,6, 11.2 Hz), 3,80 (2H, DD, J=4,5, 11.2 Hz), 3,86 (2H, d, J=1.0 Hz), 4,07 (2H, d, J=7,3 Hz), 7,26 (2H, d, J=8.1 Hz), 7,71 (2H, d, J=8.1 Hz), 7,74 (1H, s).

IR (KBr) cm-1: 3408, 3293, 1641, 1592, 1520.

Mass m/z: 345 (M+).

Example 53

Obtain hydrochloride of 4-(1,3-dihydroxypropyl-2-yl)aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N-(1,3-dihydroxypropyl-2-yl)aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 95.7 per cent).

Melting point: 191,2-193,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,93 (6N, d, J=6.6 Hz), 2,19-of 2.30 (1H, m), is 2.37 (3H, s), 3,29 (1H, usher.), 3,60-of 3.78 (4H, m), was 4.02 (2H, d, J=7,1 Hz), the 4.29 (2H, s), of 5.40 (2H, users), 7,34 (2H, d, J=8.1 Hz) 7,81 (2H, d, J=8.1 Hz), scored 8.38 (1H, s).

IR (KBr) cm-1: 3392, 1652, 1610.

Example 54

Getting 2-isobutyl-4-methylaminomethyl-6-(4-were)-2-pyridazin-3-one

Following the procedure of example 9 (4)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-were)-2H-pyridazin-3-one and methylamine with obtaining specified in the title compound as a yellowish oil (yield: 94.5%of).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), to 1.87 (1H, usher.), 2,29-to 2.42 (1H, m), is 2.40 (3H, s)of 2.50 (3H, s), 3,76 (2H, d, J=1.2 Hz), 4,07 (2H, d, J=7,3 Hz), 7,26 (2H, d, J=8.1 Hz), to 7.67 (1H, t, J=1.2 Hz), 7,71 (2H, d, J=8,1 Hz).

IR (Pure) cm-1: 3317, 1652, 1607.

Mass m/z: 285 (M+).

Example 55

Obtain hydrochloride of 2-isobutyl-4-methylaminomethyl-6-(4-were)-2-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-isobutyl-4-methylaminomethyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 97.5%of).

Melting point: 198,3-201,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.8 Hz), 2,20-2,31 (1H, m), is 2.37 (3H, s)to 2.65 (3H, s), was 4.02 (2H, d, J=7,3 Hz), of 4.12 (2H, s), 7,34 (2H, d, J=8.1 Hz), 7,80 (2H, d, J=8.1 Hz), 8,35 (1H, s).

IR (KBr) cm-1: 3085, 1652, 1612.

Example 56

Getting 4-(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 9 (4), were subjected to the EOI is modestia 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-were)-2H-pyridazin-3-one and 2-aminoethanol obtaining specified in the title compound as a yellowish oil (yield: 80.3 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,20-of 2.38 (3H, m), 2,39 (3H, s)2,84 (2H, t, J=5,1 Hz), and 3.72 (2H, t, J=5,1 Hz), 3,82 (2H, d, J=1.2 Hz), 4,07 (2H, d, J=7,3 Hz), 7,26 (2H, d, J=8.1 Hz), 7,68 (1H, s), of 7.70 (2H, d, J=8,1 Hz).

IR (Pure) cm-1: 3429, 1652, 1601, 1519.

Mass m/z: 315 (M+).

Example 57

Obtain hydrochloride of 4-(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N-(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 93.4%as).

Melting point: 190,8-191,9°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 2,20-2,31 (1H, m), is 2.37 (3H, s), of 3.12 (2H, t, J=5.4 Hz), 3,70 is 3.76 (2H, m), was 4.02 (2H, d, J=7,3 Hz), 4,18 (2H, s), and 5.30 (1H, usher.), 7,34 (2H, d, J=8,3 Hz), 7,81 (2H, d, J=8,3 Hz), at 8.36 (1H, s).

IR (KBr) cm-1: 3491, 1652, 1611.

Example 58

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one

1) preparation of ethyl 2-etoxycarbonyl-2-hydroxy-4-(4-triptoreline)-4-oxobutanoate

Following the procedure of example 1(3)were subjected to interaction of 4'-(trifluoromethyl)acetophenone with obtaining specified in the title compounds as pale yellow crystals (yield: 80.8%of).

1H NMR (400 MHz, CDCl3) δ: 1,30 (6N, t, J=7,1 Hz), 3,85 (2H, s), 4,22 (1H, s, or 4.31 (4H, square, J=7,1 Hz), 7,76 (2H, d, J=8.6 Hz), 8,07 (2H, d, J=8.6 Hz).

IR (KBr) cm-1: 3446, 1750, 1727, 1691.

Mass m/z: 343 (M+-H2O).

2) Getting 4-carboxy-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 1(4)were subjected to interaction of ethyl 2-etoxycarbonyl-2-hydroxy-4-(4-triptoreline)-4-oxobutanoate with obtaining specified in the title compounds as a pale brown crystalline powder (yield: 91.4 per cent).

3) Obtaining 4-methoxycarbonyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 1(5)were subjected to interaction of 4-carboxy-6-(4-triptoreline)-2H-pyridazin-3-one to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 88.5 percent).

1H NMR (400 MHz, CDCl3) δ: was 4.02 (3H, s), of 7.75 (2H, d, J=8,2 Hz), 7,95 (2H, d, J=8,2 Hz), 8,39 (1H, s), of 11.69 (1H, usher.).

IR (KBr) cm-1: 3218, 3140, 3097, 1720, 1678, 1326.

Mass m/z: 298 (M+).

4) to Obtain 2-isobutyl-4-methoxycarbonyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 4-methoxycarbonyl-6-(4-triptoreline)-2H-pyridazin-3-one to obtain specified in the title compound as yellow crystals (yield: 82.2 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,00 (6N, d, J=6.6 Hz), 2,32 is 2.43 (1H, m)to 3.99 (3H, s)to 4.15 (2H, d, J=7,2 Hz), 7,74 (2H, d, J=8,4 Hz), to 7.93 (2H, d, J=8,4 Hz)to 8.12 (1H, s).

IR (Pure) cm- : 2961, 1746, 1670, 1327, 1115, 1068.

Mass m/z: 354 (M+).

5) Obtaining 4-carboxy-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-isobutyl-4-methoxycarbonyl-6-(4-triptoreline)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless fine needle crystals (yield: to 91.6%).

Melting point: 184,4-to 185.0°

1H NMR (400 MHz, CDCl3) δ: 1,03 (6N, d, J=6.6 Hz), 2,34 at 2.45 (1H, m), 4,25 (2H, d, J=7,2 Hz), 7,78 (2H, d, J=8,2 Hz), to 7.99 (2H, d, J=8,2 Hz), to 8.70 (1H, s), 14,02 (1H, s).

IR (KBr) cm-1: 3447, 1739, 1631, 1570, 1330, 1174, 1114, 1070, 847.

Mass m/z: 340 (M+)

6) Receiving 4-hydroxymethyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless fine needle crystals (yield: 28,1%).

Melting point: 145,8-146,5°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,30-to 2.41 (1H, m), 2,96 (1H, t, J=5,9 Hz), 4,11 (2H, d, J=7,4 Hz), 4,74 (2H, DD, J=1,4, 5,8 Hz), 7,70-7,74 (3H, m), 7,94 (2H, d, J=8,2 Hz).

IR (KBr) cm-1: 3339, 1646, 1596, 1328, 1131, 1070, 848.

7) Getting 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 4-hydroxymethyl-2-isobut is l-6-(4-triptoreline)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless fine needle crystals (yield: 89.9 percent).

Melting point: 122,9-123,8°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,29-to 2.40 (1H, m), 3,18 (3H, s), 4,11 (2H, d, J=7,2 Hz), from 5.29 (2H, d, J=1.4 Hz), 7,73 (2H, d, J=8,2 Hz), 7,83 (1H, t, J=1.4 Hz), to 7.93 (2H, d, J=8,2 Hz).

IR (KBr) cm-1: 3447, 1659, 1613, 1359, 1329, 1169, 1123, 1071, 846.

Mass m/z: 404 (M+)

8) Obtain 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-triptoreline)-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 83.5 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 1,47 (N, C), 2,29-to 2.41 (1H, m), of 2.53 (4H, t, J=4.9 Hz), 3,51 (4H, t, J=4,8 Hz), of 3.60 (2H, s), 4,10 (2H, d, J=7,4 Hz), 7,72 (2H, d, J=8,2 Hz), to 7.84 (1H, s), 7,94 (2H, d, J=8,2 Hz).

Example 59

Getting dihydrochloride 2-isobutyl-4-(1-piperazinil)methyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 95,0%).

Melting point: 210,8-212,5°

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.6 Hz), 2,22 to 2.35 (1H, m), of 3.12 (4H, usher.), 3,30 (4H, t, J=52 Hz), to 3.92 (2H, s), of 4.05 (2H, d, J=7,1 Hz), to 7.84 (2H, d, J=8,3 Hz), 8,11 (2H, d, J=8.1 Hz), of 8.25 (1H, s).

IR (KBr) cm-1: 1656, 1608, 1328, 1125, 1069.

Mass m/z: 394 (M+)

Example 60

Getting 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-triptoreline)-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 81.1%of).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,30-to 2.41 (1H, m), of 2.33 (3H, s), 2,53 (4H, usher.), 2,63 (4H, usher.), of 3.60 (2H, s), 4,10 (2H, d, J=7,2 Hz), 7,72 (2H, d, J=8,2 Hz), 7,83 (1H, s), 7,94 (2H, d, J=8,2 Hz).

Example 61

Getting dihydrochloride 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-(4-triptoreline)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless flakes (yield: 88.6 per cent).

Melting point: 249,9-252,8°

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.8 Hz), 2,22 to 2.35 (1H, m), 2,77 (3H, s), 3,14 (4H, usher.), the 3.35 (4H, usher.), 3,88 (2H, s), of 4.05 (2H, d, J=7,2 Hz), to 7.84 (2H, d, J=8,2 Hz), 8,10 (2H, d, J=8.0 Hz), 8,19 (1H, s).

IR (KBr) cm-1: 2966, 1653, 1610, 1328, 1125, 1069.

Mass m/z: 408 (M+)

Example 62

Getting 4-N,N-bis(2-HYDR shall xitil)aminomethyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-triptoreline)-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 79.5%of).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,29-to 2.40 (1H, m), of 2.72 (4H, usher.), to 3.67 (4H, t, J=4, 2 Hz), and 3.72 (2H, s), 4,10 (2H, d, J=7,4 Hz), of 7.70 (2H, d, J=7,6 Hz), 7,82 (1H, s), 7,94 (2H, d, J=8,2 Hz).

Example 63

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 58.2 per cent).

Melting point: 134,9-135,4°

1H NMR (400 MHz, DMSO-d6) δ: 0,97 (6N, d, J=6.6 Hz), 2,25-of 2.36 (1H, m)to 3.34 (4H, usher.), a 3.83 (4H, t, J=5,1 Hz), 4,07 (2H, d, J=7,0 Hz), to 4.46 (2H, s), 7,86 (2H, d, J=8,2 Hz), 8,13 (2H, d, J=8,2 Hz), 8,55 (1H, s).

IR (KBr) cm-1: 1653, 1605, 1319, 1125, 1069.

Mass m/z: 395 (M+-H2O)

Example 64

Getting 4-dimethylaminomethyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-(4-triptoreline)-2H-pyridazin-3-one with a receipt in which the head of the compound as a yellow oil (yield: 80.7 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,31-to 2.40 (1H, m), 2,36 (6N, (C), 3,51 (2H, d, J=1.2 Hz), 4,10 (2H, d, J=7,4 Hz), 7,71 (2H, d, J=8,4 Hz), 7,83 (1H, t, J=1.4 Hz), of 7.97 (2H, d, J=8,2 Hz).

Example 65

Getting hydrochloride 4-dimethylaminomethyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-dimethylaminomethyl-2-isobutyl-6-(4-triptoreline)-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow flakes (yield: 93,0%).

Melting point: 242,2-242,3°

1H NMR (400 MHz, DMSO-d6) δ: 0,97 (6N, d, J=6.6 Hz), 2,25-of 2.36 (1H, m), 2,83 (6N, C)4,07 (2H, d, J=7,3 Hz), 4,30 (2H, s), 7,86 (2H, d, J=8,3 Hz)to 8.14 (2H, d, J=8.0 Hz), 8,61 (1H, s).

IR (KBr) cm-1: 2963, 1646, 1606, 1321, 1115, 1069.

Mass m/z: 353 (M+)

Example 66

Getting 6-(4-biphenylyl)-4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-2H-pyridazin-3-one

1) preparation of ethyl 4-(4-biphenylyl)-2-etoxycarbonyl-2-hydroxy-4-oxobutanoate

Following the procedure of example 1(3)were subjected to interaction of 4-acetylbiphenyl obtaining specified in the title compounds as colorless flakes (yield: 83,3%).

Melting point: 88,0 to 88.3°

1H NMR (400 MHz, CDCl3) δ: 1,31 (6N, t, J=7,1 Hz), a 3.87 (2H, s), 4,32 (4H, square,7,1 Hz), 7,41 (1H, TT, J=1,4,7,2 Hz), of 7.48 (2H, DD, J=7,2, 7,2 Hz), 7,63 (2H, d, J=7,0 Hz), of 7.70 (2H, d, J=8.6 Hz), of 8.04 (2H, d, J=8.6 Hz).

IR (KBr) is m -1: 3449, 1736, 1680, 1604, 1301, 1244, 1204, 763.

2) Obtain 6-(4-biphenylyl)-4-carboxy-2H-pyridazin-3-one

Following the procedure of example 1(4)were subjected to interaction of ethyl 4-(4-biphenylyl)-2-etoxycarbonyl-2-hydroxy-4-oxobutanoate with obtaining specified in the title compound as a yellow crystalline powder (yield: 90.2 per cent).

Melting point: to 299.7-300,8°

1H NMR (400 MHz, DMSO-d6) δ: 7,40 (1H, t, J=7.4 Hz), 7,49 (2H, DD, J=7,4, 7,4 Hz), 7,74 (2H, d, J=7,2 Hz), 7,82 (2H, d, J=8,4 Hz), 8,03 (2H, d, J=8,4 Hz), 8,54 (1H, s).

IR (KBr) cm-1: 1753, 1652, 1590, 1446, 1201, 768.

3) Obtain 6-(4-biphenylyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(5)were subjected to interaction of 6-(4-biphenylyl)-4-carboxy-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 90.4 percent).

Melting point: 277,0-277,9°C (decomp.)

1H NMR (400 MHz, CDCl3) δ: 4,01 (3H, s), 7,39 was 7.45 (3H, m), of 7.64 (2H, d, J=7,2 Hz), 7,72 (2H, d, J=8,2 Hz), 7,89 (2H, d, J=8.0 Hz), 8,42 (1H, s)to 10.7 (1H, s).

IR (KBr) cm-1: 2954, 1727, 1671, 1594, 1265, 1098, 768.

4) to Obtain 6-(4-biphenylyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(4-biphenylyl)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compound as yellow crystals (yield: 62.7 percent).

Melting point: 186,2-15,0° With

1H-NMR (400 MHz,CDCl3) δ: 1,01 (6N, d, J=6.8 Hz), 2,34 at 2.45 (1H, m)to 3.99 (3H, s)to 4.16 (2H, d, J=7,4 Hz), 7,39 (1H, TT, J=1,4,7,4 Hz), of 7.48 (2H, DD, J=7,2, 7,2 Hz), to 7.64 (2H, d, J=7,0 Hz), 7,71 (2H, d, J=8.6 Hz), 7,89 (2H, d, J=8.6 Hz), 8,31 (1H, s).

5) Obtain 6-(4-biphenylyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 6-(4-biphenylyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 79,2%).

Melting point: 156,9-157,6°

1H NMR (400 MHz, CDCl3) δ: 1,04 (6N, d, J=6.6 Hz), 2,36 is 2.46 (1H, m), 4,24 (2H, d, J=7,4 Hz), 7,41 (1H, t, J=7.4 Hz), 7,49 (2H, DD, J=7,4, 7,4 Hz), the 7.65 (2H, d, J=7,0 Hz), 7,74 (2H, d, J=8,4 Hz), 7,95 (2H, d, J=8,4 Hz), 8,73 (1H, s), 14,22 (1H, s).

IR (KBr) cm-1: 2963, 1749, 1631, 1565, 1470, 735.

6) Obtain 6-(4-biphenylyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 6-(4-biphenylyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as white solids (yield: 15.6%).

Melting point: 146,4-147,5°

1H NMR (400 MHz, CDCl3) δ: 1,01 (6N, d, J=6.8 Hz), 2,32 is 2.43 (1H, m), 3,13 (1H, t, J=6.2 Hz), 4,11 (2H, d, J=7,4 Hz), 4,74 (2H, DD, J=1,2, 6.2 Hz), 7,39 (1H, t, J=7,3 Hz), of 7.48 (2H, DD, J=7,4, 7,4 Hz), to 7.64 (2H, d, J=7,0 Hz), of 7.70 (2H, d, J=8.6 Hz), 7,74 (1H, t, J=1.2 Hz), of 7.90 (2H, d, J=8.6 Hz).

IR (KBr) cm-1: 3431, 2961, 1647, 1596, 1077, 769.

7) Obtain 6-(4-biphenylyl)-2-isobutyl-4-methane-sulfonyloxy-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 6-(4-biphenylyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 79.3 percent).

Melting point: 121,3-122,0°

1H NMR (400 MHz, CDCl3) δ: 1,01 (6N, d, J=6.8 Hz), 2,33-to 2.42 (1H, m), 3,18 (3H, s), of 4.12 (2H, d, J=7,4 Hz), and 5.30 (2H, d, J=1.2 Hz), 7,39 (1H, t, J=7.4 Hz), of 7.48 (2H, DD, J=7,6 Hz), to 7.64 (2H, d, J=7,4 Hz), 7,71 (2H, d, J=8,4 Hz), a 7.85 to $ 7.91 (3H, m).

IR (KBr) cm-1: 2964, 1658, 1610, 1354, 1165, 874, 529.

8) Obtain 6-(4-biphenylyl)-4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(4-biphenylyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 87.7 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,00 (6N, d, J=6.6 Hz), 1,47 (N, C), 2,30 is 2.43 (1H, m), of 2.54 (4H, t, J=4.9 Hz), 3,51 (4H, t, J=4.9 Hz), 3,60 (2H, d, J=1.4 Hz), 4,10 (2H, d, J=7,4 Hz), 7,38 (1H, TT, J=1,4,7,2 Hz), 7,47 (2H, DD, J=7,4, 7,4 Hz), to 7.64 (2H, d, J=7,0 Hz), of 7.70 (2H, d, J=8.6 Hz), the 7.85-a 7.92 (3H, m).

Example 67

Getting dihydrochloride 6-(4-biphenylyl)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 6-(4-biphenylyl)-4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-2H-pyridazin-3-he shall receive the drug specified in the title compounds as a colorless crystalline powder (yield: 51.5 per cent).

Melting point: 226,8-228,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,97 (6N, d, J=6.8 Hz), 2,25-of 2.36 (1H, m), 3,19 (4H, usher.), to 3.34 (4H, t, J=5,1 Hz), 3,98 (2H, s), of 4.05 (2H, d, J=7,1 Hz), 7,39 (1H, t, J=7,3 Hz), 7,49 (2H, DD, J=7,7, 7,7 Hz), 7,71 (2H, d, J=7.8 Hz), 7,79 (2H, d, J=8,3 Hz), to 7.99 (2H, d, J=8,3 Hz), 8,29 (1H, s).

IR (KBr) cm-1: 1653, 1604, 1446, 771.

Mass m/z: 402 (M+)

Example 68

Getting 6-(4-biphenylyl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(4-biphenylyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 68.2%)of.

1H NMR (400 MHz, CDCl3) δ: 1,00 (6N, d, J=6.6 Hz), 2,30 is 2.43 (1H, m), of 2.34 (3H, s)to 2.55 (4H, usher.), to 2.65 (4H, usher.), 3,61 (2H, d, J=1.2 Hz), 4,10 (2H, d, J=7,2 Hz), 7,38 (1H, t, J=7,3 Hz), 7,47 (2H, DD, J=7,5, 7.5 Hz), to 7.64 (2H, d, J=7,2 Hz), of 7.70 (2H, d, J=8,4 Hz), to 7.84 (1H, s), of 7.90 (2H, d, J=8,4 Hz).

Example 69

Getting dihydrochloride 6-(4-biphenylyl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(4-biphenylyl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 69.9 per cent).

Melting point: 262,2-263,6°

1H NMR (400 MHz, DMSO-d6) δ: 0,97 (6N, d, J=6.6 for the TS) of 2.26 to 2.35 (1H, m), 2,77 (3H, s), 3,10 (4H, usher.), to 3.34 (4H, usher.), of 3.85 (2H, s), Android 4.04 (2H, d, J=7,1 Hz), 7,39 (1H, t, J=7,6 Hz), 7,49 (2H, DD, J=8,0, 8.0 Hz), 7,71 (2H, d, J=8.0 Hz), 7,78 (2H, d, J=8,3 Hz), 7,89 (2H, d, J=8,3 Hz), 8,13 (1H, s).

IR (KBr) cm-1: 1652, 1607, 1465, 1050.

Mass m/z: 416 (M+)

Example 70

Getting 6-(4-biphenylyl)-4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(4-biphenylyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 62.4 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,30 is 2.43 (1H, m), 2,73 (4H, t, J=4,8 Hz)to 3.67 (4H, t, J=4,8 Hz), to 3.73 (2H, s), of 4.12 (2H, d, J=7,4 Hz), 7,38 (1H, t, J=7.2 Hz), 7,47 (2H, DD, J=7,2, 7,2 Hz), 7,63 (2H, d, J=7,4 Hz), to 7.68 (2H, d, J=8,2 Hz), 7,79 (1H, s), 7,89 (2H, d, J=8,2 Hz).

Example 71

Obtain hydrochloride of 6-(4-biphenylyl)-4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(4-biphenylyl)-4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 63.9 per cent).

Melting point: 218,3-of 218.6°

1H NMR (400 MHz, DMSO-d6) δ: 0,98 (6N, d, J=6.8 Hz), 2.26 and-is 2.37 (1H, m)to 3.36 (4H, t, J=5,1 Hz), 3,85 (4H, t, J=5,1 Hz), 4,08 (2H, d, J=7,3 Hz), 4,48 (2H, s), 7,40 (1H, TT, J=1,2, 7,3 Hz), 7,49 (N, DD, J=7,3 Hz), 7,72 (2H, DD, J=1,2, 7,3 Hz), 7,81 (2H, d, J=8,3 Hz), 8,01 (2H, d, J=8,3 Hz), charged 8.52 (1H, s).

IR (KBr) cm-1: 1654, 1607, 1053, 847, 769.

m/z (EI): 403 (M+-H2O)

Example 72

Getting 6-(4-biphenylyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 6-(4-biphenylyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 87.7 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,00 (6N, d, J=6.6 Hz), 2,36 (6N, (C), 2,29 is 2.43 (1H, m), 3,52 (2H, d, J=1.0 Hz), 4,10 (2H, d, J=7,2 Hz), 7,37 (1H, t, J=7.4 Hz), 7,46 (2H, DD, J=7,4, 7,4 Hz), 7,63 (2H, d, J=7,2 Hz), 7,68 (2H, d, J=8,4 Hz), the 7.85 (1H, s), 7,92 (2H, d, J=8,4 Hz).

Example 73

Obtain hydrochloride of 6-(4-biphenylyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(4-biphenylyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless flakes (yield: 58.2 per cent).

Melting point: 243,9-to 244.1°

1H NMR (400 MHz, DMSO-d6) δ: 0,98 (6N, d, J=6.6 Hz), 2.26 and-is 2.37 (1H, m), 2,83 (6N, (C), a 4.03 (2H, d, J=7,1 Hz), 4,30 (2H, s), 7,39 (1H, TT, J=1,2, 7,3 Hz), 7,49 (2H, DD, J=7,3, 7,3 Hz), 7,72 (2H, DD, J=1,2, 7,1 Hz), 7,81 (2H, d, J=8,8 Hz), 8,02 (2H, d, J=8.6 Hz), to 8.57 (1H, s).

IR (KBr) cm-1: 1647, 1604, 1460, 1409, 1052.

Mass m/z: 361 (M+)

Example 74

Getting 4-(4-tert-butoxycarbonyl the l-1-piperazinil)methyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 89,0%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 1,47 (N, C), 2,27-to 2.40 (1H, m), 2,52 (4H, t, J=4.9 Hz), 3,50 (4H, t, J=5.0 Hz), 3,57 (2H, d, J=1.4 Hz), of 3.96 (3H, s)4,07 (2H, d, J=7,2 Hz), 7,00 (1H, d, J=8.6 Hz), 7,66 (1H, DD, J=2,4, 8.6 Hz), 7,74 (1H, t, J=1.3 Hz), 7,86 (1H, d, J=2,4 Hz).

Example 75

Getting dihydrochloride 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3-chloro-4-metoxyphenyl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as white solids (yield: 70.2 per cent).

Melting point: 203,6-204,5°

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.6 Hz), 2,20-of 2.34 (1H, m), 3,14 (4H, usher.), of 3.31 (4H, t, J=5,2 Hz), 3,93 (5H, s)to 4.01 (2H, d, J=7,0 Hz), 7,26 (1H, d, J=8,8 Hz), to 7.84 (1H, DD, J=2,4, 8.6 Hz), to $ 7.91 (1H, d, J=2.4 Hz), 8,19 (1H, s).

IR (KBr) cm-1: 1654, 1608, 1507, 1289, 1065.

Mass m/z: 390 (M+), 392 (M+).

Example 76

Getting 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-chloro-methoxyphenyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 76,1%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,28-to 2.40 (1H, m), of 2.33 (3H, s), 2,53 (4H, usher.), 2,63 (4H, usher.), to 3.58 (2H, d, J=1.2 Hz), of 3.96 (3H, s)4,06 (2H, d, J=7,2 Hz), 7,01 (1H, d, J=8.6 Hz), to 7.67 (1H, DD, J=2,2, 8.6 Hz), 7,72 (1H, s), 7,86 (1H, d, J=2.2 Hz).

Example 77

Getting dihydrochloride 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 67,5%).

Melting point: 235,8-236,7°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 2,25 of-2.32 (1H, m), 2,77 (3H, s), 3,15 (4H, usher.), to 3.36 (4H, usher.), 3,88 (2H, s), 3,93 (3H, s)to 4.01 (2H, d, J=7,0 Hz), 7,26 (1H, d, J=8.6 Hz), 7,83 (1H, DD, J=2,2, 8.6 Hz), to $ 7.91 (1H, d, J=2.2 Hz), to 8.12 (1H, s).

IR (KBr) cm-1: 1653, 1608, 1507, 1289, 1064.

Mass m/z: 404 (M+), 406 (M+).

Example 78

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 79.6%of).

1H NMR (400 MHz, CDCl3) δ: 0,96 (6N, d, J=6.6 Hz), 2,28-2,39 (1H, m), a 2.71 (4H, t, J=4 Hz), 3,66 (4H, t, J=4.9 Hz), 3,70 (2H, s), of 3.94 (3H, s)4,07 (2H, d, J=7,4 Hz), 6,98 (1H, d, J=8,8 Hz), to 7.68 (1H, DD, J=1,8, and 8.7 Hz), 7,72 (1H, s), a 7.85 (1H, d, J=2.1 Hz).

Example 79

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 60.1 percent).

Melting point: 153,0-153,5°

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.6 Hz), 2,23-of 2.34 (1H, m)to 3.34 (4H, t, J=5,1 Hz), 3,83 (4H, t, J=5,1 Hz), of 3.94 (3H, s), Android 4.04 (2H, d, J=7,1 Hz), of 4.44 (2H, s), 7,28 (1H, d, J=8,8 Hz), the 7.85 (1H, DD, J=2,4, 8,6 Hz), 7,94 (1H, d, J=2.4 Hz), to 8.45 (1H, s).

IR (KBr) cm-1: 1652, 1607, 1508, 1421, 1293, 1062.

Mass m/z: 391 (M+-H2O)

Example 80

Getting 6-(3-chloro-4-methoxyphenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 84.8%of).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,31-2,39 (1H, m), 2,35 (6N, (C)a 3.50 (2H, s), of 3.95 (3H, s)4,07 (2H, d, J=7,2 Hz), of 6.99 (1H, d, J=8.6 Hz), of 7.70 (1H, DD, J=1,4, 8.6 Hz), 7,88 (1H, d, J=1.4 Hz).

Example 81

Obtaining GI is rochloride 6-(3-chloro-4-methoxyphenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(3-chloro-4-methoxyphenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as white solids (yield: 69.4 per cent).

Melting point: 213,6-214,3°

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.8 Hz), 2,22-of 2.34 (1H, m), 2,81 (6N, (C), of 3.94 (3H, s), Android 4.04 (2H, d, J=7,1 Hz), 4,27 (2H, s), 7,28 (1H, d, J=8,8 Hz), 7,87 (1H, DD, J=2,2, 8,8 Hz), 7,95 (1H, d, J=2.2 Hz), 8,53 (1H, s).

IR (KBr) cm-1: 1652, 1608, 1508, 1289, 1064.

Mass m/z: 349 (M+), 351 (M+).

Example 82

Getting 6-(4-fluoro-3-were)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of ethyl 2-etoxycarbonyl-4-(4-fluoro-3-were)-2-hydroxy-4-oxobutanoate

Following the procedure of example 1(3)were subjected to interaction of 5-acetyl-2-vtortola obtaining specified in the title compounds as pale yellow prismatic crystals (yield: 95.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,30 (6N, t, J=7,1 Hz), 2,33 (3H, d, J=1.7 Hz), with 3.79 (2H, s), the 4.29 (1H, s), or 4.31 (4H, square, J=7,1 Hz), was 7.08 (1H, DD, J=8,8, 8,8 Hz), 7,78-a 7.85 (2H, m).

2) Getting 4-carboxy-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 1(4)were subjected to interaction of ethyl 2-etoxycarbonyl-4-(4-fluoro-3-were)-2-hydroxy-4-oxobutanoate with obtaining specified in the title compounds as a pale yellow crystalline then the scale (output: 88,9%).

Melting point: 213,6-214,3°

1H NMR (400 MHz, DMSO-d6) δ: of 2.51 (3H, d, J=1.7 Hz), 7,26 (1H, DD, J=9,1, 9.1 Hz), to 7.77-7,81 (1H, m), 7,89 (1H, d, J=7,3 Hz), 8,49 (1H, s), 13,99 (1H, usher.).

3) Obtain 6-(4-fluoro-3-were)-4-methoxy-carbonyl-2H-pyridazin-3-one

Following the procedure of example 1(5)were subjected to interaction of 4-carboxy-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 76.8%of all).

1H NMR (400 MHz, CDCl3) δ: 2,35 (3H, d, J=2.0 Hz), 3,99 (3H, s), 7,10 (1H, DD, J=8,9, and 8.9 Hz), 7,58 to 7.62 (1H, m), 7,60 (1H, d, J=7,3 Hz), 8,31 (1H, s).

4) to Obtain 6-(4-fluoro-3-were)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(4-fluoro-3-were)-2-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow prismatic crystals (yield: 86,3%).

Melting point: 71,4-73,8°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,31-to 2.42 (1H, m), 2,35 (3H, d, J=2.0 Hz), 3,98 (3H, s), of 4.12 (2H, d, J=7,3 Hz), 7,10 (1H, DD, J=8,8, 8,8 Hz), EUR 7.57-the 7.65 (2H, m), 8,21 (1H, s).

5) Obtaining 4-carboxy-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow needle crystals (yield: 90.0%of).

Melting point: to 129.3-132,1°

1H NMR (400 MHz, CDCl3) δ: 1,02 (6N, d, J=6.8 Hz), 2,33 is 2.44 (1H, m), is 2.37 (3H, d, J=2, 0 Hz), is 4.21 (2H, d, J=7,3 Hz), 7,13 (1H, DD, J=8,8, 8,8 Hz), of 7.64-7,71 (2H, m), 8,63 (1H, s).

IR (KBr) cm-1: 1742, 1636, 1537, 1422.

Mass m/z: 304 (M+).

6) Obtain 6-(4-fluoro-3-were)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 24.7 per cent).

Melting point: 107,4-110,4°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,29-to 2.40 (1H, m), 2,35 (3H, d, J=1.7 Hz), 3,14 (1H, t, J=5,9 Hz), 4,08 (2H, d, J=7,6 Hz), 4,71 (2H, d, J=5,9 Hz), was 7.08 (1H, DD, J=8,8, 8,8 Hz), 7,56-the 7.65 (3H, m).

IR (KBr) cm-1: 3401, 1658, 1648, 1618, 1602, 1501.

Mass m/z: 290 (M+).

7) Obtain 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 6-(4-fluoro-3-were)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 91.4 per cent).

Melting point: 114,6-117,1°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,29-to 2.40 (1H, m), a 2.36 (3H, s), 3,17 (3H, s)4,08 (2H, d, J=7,6 Hz), 5,27 (2H, d, J=1.5 Hz), to 7.09 (1H, DD, J=8,9, and 8.9 Hz), 7,56-of 7.69 (2H, m), of 7.75 (1H, t, J=1.5 Hz)

IR (KBr) cm-1: 1656, 1611, 1505, 1354, 1166.

Mass m/z: 368 (M+).

8) Obtain 6-(4-fluoro-3-were)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellowish oil (yield: 79,1%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,27-to 2.40 (1H, m), 2,32 (3H, s), a 2.36 (3H, d, J=2.0 Hz), of 2.51 (4H, usher.), 2,62 (4H, usher.), to 3.58 (2H, d, J=1.5 Hz), 4,07 (2H, d, J=7,3 Hz), to 7.09 (1H, DD, J=8,8, 8,8 Hz), 7,58 (1H, DDD, J=2.0 a, 4,9, 8,8 Hz), to 7.64 (1H, DD, J=2.0 a, 7,3 Hz), 7,73 (1H, t, J=1.5 Hz).

IR (Pure) cm-1: 1652, 1609, 1503.

Mass m/z: 372 (M+).

Example 83

Getting dihydrochloride 6-(4-fluoro-3-were)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless prismatic crystals (yield: 95.9 per cent).

Melting point: 234,8-237,4°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,93 (6N, d, J=6.8 Hz), 2,19-of 2.30 (1H, m), 2,32 (3H, d, J=2.0 Hz), of 2.81 (3H, s), 2,89-3,62 (10H, osirm), of 4.00 (2H, d, J=7,3 Hz), 7,29 (1H, DD, J=9,0, 9.0 Hz), 7,72 for 7.78 (1H, m), 7,83 (1H, DD, J=2,4, a 7.6 Hz), 8,31 (1H, users).

IR (KBr) cm-1: 1660, 1609, 1504.

Example 84

Getting 6-(4-fluoro-3-were)-2-isobutyl-4-methylaminomethyl-2H-pyridazin-3-one

Following the procedure of example 9 (4)were subjected to interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow oil (yield: 96,2%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), of 1.65 (1H, usher.), 2,29-to 2.42 (1H, m), 2,34 (3H, d, J=1.7 Hz), of 2.51 (3H, s), of 3.77 (2H, d, J=1.2 Hz), 4,07 (2H, d, J=7,3 Hz), 7,07 (1H, DD, J=8,8, 8,8 Hz), 7,54-7,63 (2H, m), of 7.64 (1H, t, J=1.2 Hz).

IR (Pure) cm-1: 3306, 1653, 1605, 1507.

Mass m/z: 303 (M+).

Example 85

Obtain hydrochloride of 6-(4-fluoro-3-were)-2-isobutyl-4-methylaminomethyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methylaminomethyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless prismatic crystals (yield: 86.6 per cent).

Melting point: 196,8-199,7°

1H NMR (400 MHz, DMSO-d6) δ: 0,93 (6N, d, J=6.8 Hz), 2,19-2,31 (1H, m), 2,32 (3H, s)to 2.65 (3H, s), was 4.02 (2H, d, J=7,3 Hz), of 4.12 (2H, s), 7,31 (1H, DD, J=8.5 a, 8.5 Hz), 7,72 for 7.78 (1H, m), 7,80-a 7.85 (1H, m), 8,32 (1H, s).

IR (KBr) cm-1: 2722, 1652, 1615, 1505.

Example 86

Getting 4-(4-benzyl-1-piperazinil)methyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10), subjected cooperation is to work 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-benzylpiperazine with obtaining specified in the title compounds as a pale yellow oil (yield: 98.6 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,97 (6N, d, J=6.8 Hz), 2,29-2,39 (1H, m), a 2.36 (3H, d, J=1.7 Hz), to 2.55 (4H, usher.), 2,61 (4H, usher.), 3,55 (2H, s), 3,57 (2H, d, J=1.2 Hz), 4,06 (2H, d, J=7,6 Hz), to 7.09 (1H, DD, J=8,9, and 8.9 Hz), 7.23 percent-7,34 (5H, m), 7,51 (1H, DDD, J=2,4, 4,8, and 8.9 Hz), 7,63 (1H, DD, J=2,4, 7,2 Hz), 7,72 (1H, s).

IR (Pure) cm-1: 1652, 1608, 1505.

Mass m/z: 448 (M+).

Example 87

Getting dihydrochloride 4-(4-benzyl-1-piperazinil)methyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-(4-benzyl-1-piperazinil)methyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 95.3 per cent).

Melting point: 259,1-263,1°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,93 (6N, d, J=6.6 Hz), 2,17-to 2.29 (1H, m), 2,32 (3H, s)to 2.55 (4H, usher.), 3,23 of 3.56 (8H, br), of 4.00 (2H, d, J=7,3 Hz), 4,11 (2H, users), to 4.38 (2H, users), 7,29 (1H, DD, J=9,0, 9.0 Hz), 7,43-of 7.48 (3H, m), to 7.59-the 7.65 (2H, m), 7,72-to 7.77 (1H, m), 7,79-to 7.84 (1H, m), 8,35 (1H, users).

IR (KBr) cm-1: 1660, 1618, 1612, 1453.

Example 88

Getting 4-dimethylaminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellowish oil (yield: 96.4 per cent).

1H NMR (400 MHz, CDCl ) δ: 0,98 (6N, d, J=6.8 Hz), 2,28-2,39 (1H, m), 2,35 (3H, d, J=2.2 Hz), 2,56 (6N, (C)a 3.50 (2H, d, J=1.2 Hz), 4,07 (2H, d, J=7,3 Hz), 7,07 (1H, DD, J=8,9, and 8.9 Hz), to 7.59-to 7.67 (2H, m), 7,74 (1H, t, J=1.2 Hz).

IR (Pure) cm-1: 1652, 1608, 1506.

Mass m/z: 317 (M+).

Example 89

Getting hydrochloride 4-dimethylaminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-dimethylaminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 97.2 per cent).

Melting point: 208,5-213,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 2,19-of 2.30 (1H, m), 2,32 (3H, s), 2,81 (6N, (C), a 4.03 (2H, d, J=7,0 Hz), 4,30 (2H, s), 7,30 (1H, DD, J=9,0, 9.0 Hz), 7,74-7,80 (1H, m), a 7.85 (1H, m), 8,51 (1H, s).

IR (KBr) cm-1: 1648, 1608, 1507.

Example 90

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellowish oil (yield: 91.5 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,97 (6N, d, J=6.8 Hz), 2,27-to 2.40 (1H, m), 2,34 (3H, d, J=2.0 Hz), 2,70 (4H, t, J=5.0 Hz), 3,66 (4H, d, J=5.0 Hz), of 3.69 (2H, s), 3,91 (2H, usher.), 4,07 (2H, d, J=7,6 Hz), 7,07 (1H, DD, J=8,9, and 8.9 Hz), 7,60 (1H, DDD, J=2,2, 5,1, 89 Hz), to 7.64 (1H, DD, J=2,2, 7,3 Hz), 7,71 (1H, s).

IR (Pure) cm-1: 3391, 1654, 1371, 1505.

Mass m/z: 359 (M+-H2O).

Example 91

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 92.4 per cent).

Melting point: 155, 1mm-157,3°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 2,20-2,31 (1H, m), 2,32 (3H, d, J=1.2 Hz), the 3.35 (4H, user., overlaps with H2O), 3,82 (4H, usher.), as 4.02 (2H, d, J=7,3 Hz), 4,50 (2H, s), lower than the 5.37 (2H, usher.), 7,30 (1H, DD, J=9,0, 9.0 Hz), 7,78 (1H, DDD, J=2.0 a, 4,9, 9.0 Hz), the 7.85 (1H, DD, J=2.0 a, 7,3 Hz), 7,71 (1H, s).

IR (KBr) cm-1: 3281, 1655, 1606.

Example 92

Getting 6-(4-fluoro-3-were)-2-isobutyl-4-(piperidino)methyl-2H-pyridazin-3-one

6-(4-Fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one (80 mg, 0.22 mmol) and piperidine (55 mg, of 0.65 mmol) was dissolved in ethanol (0.5 ml), and the mixture was heated at 80°C for 1 hour under stirring. The solvent drove away. The residue was purified preparative thin-layer chromatography on silica gel [manifesting solvent: chloroform/methanol (10/1)] to obtain specified in the connection header in the form of VC is autogo oil (73 mg, 94,0%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.9 Hz), 1,45-of 1.53 (2H, m), 1,61 by 1.68 (4H, m), 2,28-to 2.41 (1H, m), a 2.36 (3H, d, J=2.0 Hz), 2,47 of $ 2.53 (4H, m), 3,52 (2H, d, J=1.5 Hz), 4,07 (2H, d, J=7,3 Hz), was 7.08 (1H, DD, J=8,9, the 8.9 Hz), to 7.59 (1H, DDD, J=1,7, 4,9, a 8.9 Hz), the 7.65 (1H, DD, J=1,7, 7,3 Hz), 7,76 (1H, t, J=1.5 Hz).

IR (Pure) cm-1: 1652, 1616, 1506.

Mass m/z: 357 (M+).

Example 93

Obtain hydrochloride of 6-(4-fluoro-3-were)-2-isobutyl-4-(piperidino)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-(piperidino)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as yellow prismatic crystals (yield: 90.7 percent).

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), of 1.34 to 1.47 (1H, m), 1,64-of 1.73 (1H, m), 1,74 of-1.83 (4H, m), 2,20-of 2.30 (1H, m), 2,32 (3H, s), 2,95-to 3.02 (2H, m), 3,36 is-3.45 (1H, m), was 4.02 (2H, d, J=7,3 Hz), 4,25 (2H, d, J=5,1 Hz), 7,30 (1H, DD, J=9,0, 9.0 Hz), 7,75-7,80 (1H, m), 7,83-7,87 (1H, m), 8,59 (1H, s).

IR (KBr) cm-1: 2532, 1652, 1616, 1505, 1433.

Example 94

Getting 6-(4-fluoro-3-were)-2-isobutyl-4-(morpholino)methyl-2H-pyridazin-3-one

Following the procedure of example 92, subjected to the interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and morpholine with obtaining specified in the title compound as a yellowish oil (yield: 97,4%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,28-to 2.41 (1H, m), a 2.36 (3H, d, J=2.0 Hz), 2,58 (4 is, t, J=4.6 Hz), 3,57 (2H, d, J=1.2 Hz), of 3.78 (4H, t, J=4.6 Hz), 4,07 (2H, d, J=7,3 Hz), to 7.09 (1H, DD, J=8,8, 8,8 Hz), 7,58 (1H, DDD, J=2.0 a, 4,9, 8,8 Hz), to 7.64 (1H, DD, J=2.0 a, 7,3 Hz), of 7.75 (1H, t, J=1.5 Hz).

IR (Pure) cm-1: 1659, 1606, 1503.

Mass m/z: 359 (M+).

Example 95

Obtain hydrochloride of 6-(4-fluoro-3-were)-2-isobutyl-4-(morpholino)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-(morpholino)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless prismatic crystals (yield: 92.4 per cent).

Melting point: 215,4-216,6°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 2,19-of 2.30 (1H, m), 2,32 (3H, s), 3,21 (2H, usher.), 3,79-3,98 (6N, m), was 4.02 (2H, d, J=7,3 Hz)to 4.33 (2H, users), 7,30 (1H, DD, J=9,0, 9.0 Hz), 7,74-7,79 (1H, m), 7,81-7,86 (1H, m), 8,56 (1H, users).

IR (KBr) cm-1: 2392, 1647, 1607.

Example 96

Getting 4-aminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

1) preparation of 6-(4-fluoro-3-were)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one

Following the procedure of example 24 (1), was subjected to interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 93.7%of).

Melting point: 181,2-187,2°

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,29-240 (1H, m)of 2.30 (3H, s)4,07 (2H, d, J=7,3 Hz), 4,91 (2H, s), 7,01 (1H, DD, J=9,0, 9.0 Hz), 7,31 (1H, s), 7,41-7,46 (1H, m), 7,50-7,53 (1H, m), 7,76-7,81 (2H, m), of 7.90-of 7.95 (2H, m).

IR (KBr) cm-1: 1720, 1656, 1619, 1611.

Mass m/z: 419 (M+).

2) Getting 4-aminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 24 (2), were subjected to interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellowish oil (yield: 99.6 percent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6,8 Hz)of 1.64 (2H, usher.), 2,30-to 2.40 (1H, m), 2,35 (3H, d, J=2.0 Hz), with 3.89 (2H, d, J=1.2 Hz), 4,07 (2H, d, J=7,3 Hz), 7,07 (1H, DD, J=8,8, 8,8 Hz), 7,60 (1H, DDD, J=2,1, 4,9, 8,8 Hz), to 7.64 (1H, DD, J=2.1 a, 7,4 Hz), to 7.67 (1H, t, J=1.2 Hz).

IR (Pure) cm-1: 3372, 3301, 1655, 1605, 1504.

Mass m/z: 289 (M+).

Example 97

Getting hydrochloride 4-aminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-aminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 79.8 per cent).

Melting point: 217,5-220,5°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,93 (6N, d, J=6.6 Hz), 2,20-of 2.30 (1H, m), 2,32 (3H, d, J=1.7 Hz), 4,01 (2H, d, J=2.2 Hz), was 4.02 (2H, d, J=7,3 Hz), 7,31 (1H, DD, J=9,0, 9.0 Hz), of 7.75 (1H, DDD, J=2,1, 4,9, 9.0 Hz), 7,83 (1H, DD, J=2,1, 7,4 Hz), of 8.28 (1H, s).

IR (KBr) cm-1: 2960, 297, 2872, 1656, 1614, 1507.

Example 98

Getting 4-diethylaminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 9 (4)were subjected to interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethylamin obtaining specified in the title compound as a yellowish oil (yield: 94.7 percent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 1,07 (6N, t, J=7,1 Hz), 2,30-to 2.41 (1H, m), 2,35 (3H, d, J=1.5 Hz), 2,61 (4H, square, J=7,1 Hz), 3,60 (2H, d, J=1.7 Hz), 4,08 (2H, d, J=7.5 Hz), was 7.08 (1H, DD, J=8,9, a 8.9 Hz), 7,60 (1H, DDD, J=2,2, 4,9, a 8.9 Hz), the 7.65 (1H, DD, J=2,2, 7,3 Hz), the 7.85 (1H, t, J=1.5 Hz).

IR (Pure) cm-1: 1652, 1609, 1506.

Mass m/z: 345 (M+).

Example 99

Getting hydrochloride 4-diethylaminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-diethylaminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 70.1 percent).

Melting point: 154,3-157,3°

1H NMR (400 MHz, CDCl3) δ: 0,92 (6N, d, J=6.8 Hz), 1,29 (6N, t, J=7.2 Hz), 2,20-of 2.30 (1H, m), 2,32 (3H, d, J=1.2 Hz), 3,09 is 3.25 (4H, m), a 4.03 (2H, d, J=7,3 Hz), 4,28 (2H, d, J=5.6 Hz), 7,30 (1H, DD, J=9,0, 9.0 Hz), 7,80 (1H, DDD, J=2.0 a, 4,9, 9.0 Hz), 7,87 (1H, DD, J=2.0 a, 7,3 Hz), the 7.85 (1H, t, J=1.5 Hz).

IR (KBr) cm-1: 2559, 2491, 1652, 1613, 1507.

Example 100

Getting 4-(4-tre is-butoxycarbonyl-1-piperazinil)methyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellowish oil (yield: 97.5%of).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 1,46 (N, C), 2,28-to 2.40 (1H, m), a 2.36 (3H, d, J=1.7 Hz), 3,50 (4H, t, J=4,9 Hz)to 3.58 (2H, d, J=1.0 Hz), 4,08 (2H, d, J=7,3 Hz), to 7.09 (1H, DD, J=8,9, and 8.9 Hz), 7,58 (1H, DDD, J=2.0 a, 4,9, a 8.9 Hz), 7,63 (1H, DD, J=2.0 a, 7,3 Hz), of 7.75 (1H, s).

IR (Pure) cm-1: 1695, 1652, 1608, 1506.

Example 101

Getting 6-(4-fluoro-3-were)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow oil (yield: quantitative).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 1,47 (1H, usher.), 2,28-to 2.40 (1H, m), a 2.36 (3H, d, J=1.7 Hz), of 2.56 (4H, t, J=4.9 Hz), 2,97 (4H, t, J=4.9 Hz), of 3.56 (2H, d, J=1.4 Hz), 4,07 (2H, d, J=7,3 Hz), to 7.09 (1H, DD, J=8,8, 8,8 Hz), 7,58 (1H, DDD, J=2.0 a, 4,9, 8,8 Hz), of 7.64 (1H, DD, J=2.0 a, 7,3 Hz), of 7.75 (1H, t, J=1.4 Hz).

Example 102

Getting dihydrochloride 6-(4-fluoro-3-were)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(4-fluoro-3-were)-2-isobutyl-4-(1-PIP is retinyl)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow prismatic crystals (yield: 87.2%of total).

Melting point: 154,9-158,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.8 Hz), 2,19-of 2.30 (1H, m), 2,32 (3H, d, J=1.7 Hz), 3.04 from (4H, usher.), 3,71 (4H, usher.), to 4.01 (2H, d, J=7,3 Hz), 7,28 (1H, DD, J=8,8, 8,8 Hz), 7,76 (1H, DDD, J=2.0 a, 4,9, 8,8 Hz), 7,83 (1H, DD, J=2.0 a, 7,3 Hz), 8,40 (1H, users).

IR (KBr) cm-1: 1659, 1610, 1504, 1422.

Example 103

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3,4-differenl)-2-isobutyl-2H-pyridazin-3-one

1) preparation of ethyl 4-(3,4-differenl)-2-etoxycarbonyl-2-hydroxy-4-oxobutanoate

Following the procedure of example 1(3)were subjected to interaction of 3',4'-defloration obtaining specified in the title compounds as a pale yellow oil (yield: 81.6 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,30 (6N, t, J=7,1 Hz), of 3.78 (2H, s), 4,22 (1H, s), or 4.31 (4H, square, J=7,1 Hz), 7.24 to 7,30 (1H, m), 7,73-of 7.82 (2H, m).

IR (Pure) cm-1: 3483, 1740, 1695, 1612.

Mass m/z: 312 (M+-H2O).

2) Getting 4-carboxy-6-(3,4-differenl)-2H-pyridazin-3-one

Following the procedure of example 1(4)were subjected to interaction of ethyl 4-(3,4-differenl)-2-etoxycarbonyl-2-hydroxy-4-oxobutanoate with obtaining specified in the title compounds as a pale yellow crystalline powder (yield: 88,9%).

3) Obtaining 4-methoxycarbonyl-6-(3,4-differenl)-2H-pyridazin-3-one

Following the procedure of example 1(5)were subjected to interaction of 4-carboxy-6-(3,4-differenl)-2H-pyridazin-3-one to obtain the specified title compound as a pale yellow crystalline powder (yield: 85,8%).

1H NMR (400 MHz, CDCl3) δ: 4,01 (3H, s), 7,25-to 7.32 (1H, m), 7,53-EUR 7.57 (1H, m), to 7.67-7,73 (1H, m), 8,31 (1H, s), 11,70 (1H, usher.).

IR (KBr) cm-1: 3223, 3159, 1722, 1676, 1659.

Mass m/z: 266 (M+).

4) to Obtain 6-(3,4-differenl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(3,4-differenl)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: quantitative).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,30-to 2.41 (1H, m), 3,98 (3H, s), 4,13 (2H, d, J=7,2 Hz), 7.23 percent-7,30 (1H, m), 7,49-of 7.55 (1H, m), 7,68 (1H, DDD, J=2,2, 7,6 and 11.1 Hz), to 8.20 (1H, s).

5) Obtaining 4-carboxy-6-(3,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 6-(3,4-differenl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless fine needle crystals (yield: 91.4 per cent).

Melting point: 163,4-163,70°

1H NMR (400 MHz, CDCl3) δ: 1,02 (6N, d, J=6.6 Hz), 2,33 is 2.43 (1H, m), 4,22 (2H, d, J=7,4 Hz), 7,27-to 7.35 (1H, m), 7,56 to 7.62 (1H, m), 7,74 (1H, DDD, J=2,4, 7,6, 11.2 Hz), to 8.62 (1H, s), 14,05 (1H, s).

IR (KBr) cm-1: 3436, 1737, 1635, 1522, 1434, 1276, 1102, 806.

Mass m/z: 308 (M+)

6) Receiving 6-(3,4-differenl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-6-(3,4-deltorphin the l)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless fine needle crystals (yield: 25,0%).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,29-2,39 (1H, m), 2,96 (1H, t, J=5,9 Hz), 4,08 (2H, d, J=7,4 Hz), 4.72 in (2H, DD, J=1,2, 5.8 Hz), 7,22-7,28 (1H, m), 7,51-of 7.55 (1H, m), of 7.64-7,71 (2H, m).

7) Obtain 6-(3,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 6-(3,4-differenl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless fine needle crystals (yield: 81.4 per cent).

Melting point: 113,3-113,40°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,27-to 2.40 (1H, m), 3,18 (3H, s)4,08 (2H, d, J=7,4 Hz), 5,28 (2H, d, J=1.6 Hz), 7.23 percent-7,30 (1H, m), 7,50-rate of 7.54 (1H, m), 7,68 (1H, DDD, J=2,2, 7,6 and 11.1 Hz), of 7.75 (1H, t, J=1,4 Hz).

IR (KBr) cm-1: 3447, 1656, 1613, 1522, 1354, 1167, 1049, 877.

Mass m/z: 372 (M+)

8) Obtain 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 85,5%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 1,47 (N, C), 2,28-of 2.38 (1H, m), 2,52 (4H, t, J=4,7 Hz), 3,51 (4H, t, J=4,7 Hz)to 3.58 (2H, s)4,07 (2H, d, J=7,2 Hz), 7,21-7,29 (1H, m), 7,50-of 7.55 (1H, m), of 7.64-7,71 (1H, m), 7,76 (1H, d, J=1.0 Hz).

Example 104

Receiving the hydrochloride 6-(3,4-differenl)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3,4-differenl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as white solids (yield: 72,5%).

Melting point: 182,5-of 186.0°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 2,22 is 2.33 (1H, m), 3,11 (4H, usher.), 3,30 (4H, t, J=5,1 Hz), 3,90 (2H, s), was 4.02 (2H, d, J=7,1 Hz), 7,52 (1H, DDD, J=8,6, 8,6, 10.5 Hz), 7,73 for 7.78 (1H, m), of 7.90 (1H, DDD, J=2,2, 8,0, 11.7 Hz), to 8.20 (1H, s).

IR (KBr) cm-1: 1656, 1609, 1522, 1436, 1276, 1112.

Mass m/z: 362 (M+)

Example 105

Getting 6-(3,4-differenl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 79,1%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,28-2,39 (1H, m), of 2.34 (3H, s)to 2.55 (4H, usher.), 2,63 (4H, usher.), to 3.58 (2H, s)4,07 (2H, d, J=7,2 Hz), 7,22-7,29 (1H, m), 7,50-EUR 7.57 (1H, m), of 7.64-7,72 (1H, m), 7,74 (1H, s).

Example 106

Getting dihydrochloride 6-(3,4-differenl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(3,4-differenl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-he is getting at is asanoha the title compound as a colorless crystalline powder (yield: 70.3 per cent).

Melting point: 242,5-243,40°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.8 Hz), 2,22 is 2.33 (1H, m), 2,77 (3H, s), 3,11 (4H, usher.), to 3.34 (4H, usher.), of 3.84 (2H, s), was 4.02 (2H, d, J=7,1 Hz), 7,52 (1H, DDD, J=8,6, 8,6, 10.5 Hz), 7,72-to 7.77 (1H, m), 7,89 (1H, DDD, J=2,2, 7,9, 11.7 Hz), to 8.12 (1H, s).

IR (KBr) cm-1: 1652, 1607, 1522, 1435, 1278.

Mass m/z: 376 (M+)

Example 107

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 75.8 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,97 (6N, d, J=6.6 Hz), 2,25-of 2.38 (1H, m), 2,70 (4H, usher.), 3,64-3,70 (6N, m)4,06 (2H, d, J=7,4 Hz), 7,15-of 7.25 (1H, m), 7,54-7,58 (1H, m), to 7.67-7,73 (1H, m), 7,88 (1H, s).

Example 108

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-differenl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as white solids (yield: 70.3 per cent).

Melting point: 127,5-128,30°

1H NMR (400 MHz, DMSO6) δ: 0,95 (6N, d, J=6.8 Hz), 2,23-of 2.34 (1H, m)to 3.35 (4H, t, J=5,1 Hz), a-3.84 (4H, t, J=5,1 Hz), of 4.05 (2H, d, J=7,1 Hz), of 4.45 (2H, s), 7,54 (1H DDD, J=8,6, 8,6, 10.5 Hz), 7,76-7,81 (1H, m), to 7.93 (1H, DDD, J=2,2, 7,8, 12.0 Hz), 8,53 (1H, s).

IR (KBr) cm-1: 1653, 1604, 1521, 1437, 1275.

Mass m/z: 363 (M+-H2O)

Example 109

Getting 6-(3,4-differenl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 6-(3,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 85,5%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,29-to 2.40 (1H, m), 2,35 (6N, (C)a 3.50 (2H, s)4,07 (2H, d, J=7,4 Hz), 7,20-7,30 (1H, m), 7,53-of 7.60 (1H, m), to 7.67-7,73 (1H, m), 7,74 (1H, s).

Example 110

Obtain hydrochloride of 6-(3,4-differenl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(3,4-differenl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one to obtain specified in the connection header yellowish flakes (yield: 85,9%).

Melting point: 226,5-227,70°

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.8 Hz), 2,23-of 2.34 (1H, m), 2,81 (6N, (C), of 4.05 (2H, d, J=7,1 Hz), 4,28 (2H, s), 7,54 (DDD, J=8,7, 8,7, 10.5 Hz), 7,76-7,81 (1H, m), to 7.93 (1H, DDD, J=2,2, 7,9, 12.0 Hz), to 8.57 (1H, s).

IR (KBr) cm-1: 1648, 1607, 1525, 1437, 1288, 1112.

Mass m/z: 321 (M+)

Example 111

Getting 4-aminomethyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one

1) preparation of ethyl 4-(2,4-differenl)-2-ethoxy arbonyl-2-hydroxy-4-oxobutanoate

Following the procedure of example 1(3)were subjected to interaction of 2',4'-defloration obtaining specified in the title compounds as a pale yellow oil (yield: 76.8%of all).

1H NMR (400 MHz, CDCl3) δ: 1,30 (6N, t, J=7,1 Hz), 3,81 (2H, d, J=3,4 Hz), 4,18 (1H, s), 4,30 (4H, square, J=7,1 Hz), make 6.90 (1H, DDD, J=2,4, 8,5, 10,0 Hz), 6,94-7,00 (1H, m), 7,94 (1H, DDD, J=6,6, and 8.5, 8.5 Hz).

IR (Pure) cm-1: 3491, 1743, 1692, 1612.

Mass m/z: 312 (M+-H2O)

2) Getting 4-carboxy-6-(2,4-differenl)-2H-pyridazin-3-one

Following the procedure of example 1(4)were subjected to interaction of ethyl 4-(2,4-differenl)-2-etoxycarbonyl-2-hydroxy-4-oxobutanoate with obtaining specified in the title compounds as a pale yellow crystalline powder (yield: 95.2 percent).

3) Obtain 6-(2,4-differenl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(5)were subjected to interaction of 4-carboxy-6-(2,4-differenl)-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 81.2 per cent).

1H NMR (400 MHz, CDCl3) δ: 3,99 (3H, s), of 6.96 (1H, DDD, J=2,4, 8,8, 10.1 Hz), 6,99? 7.04 baby mortality (1H, m), to 7.77 (1H, DDD, J=6,3, 8,8, 8,8 Hz), 8,30 (1H, d, J=2.0 Hz), a 12.05 (1H, usher.).

IR (KBr) cm-1: 3217, 3148, 1721, 1673, 1611.

Mass m/z: 266 (M+).

4) to Obtain 6-(2,4-differenl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(2,4-difthe who yl)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow oil (yield: 84.8%of).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,29-to 2.42 (1H, m), of 3.97 (3H, s), of 4.12 (2H, d, J=7,3 Hz)6,94 (1H, DDD, J=2,4, 8,8, 11.2 Hz), 6,98? 7.04 baby mortality (1H, m), 7,73 (1H, DDD, J=6,3, 6,3, 8,8 Hz), 8,18 (1H, d, J=2.0 Hz).

IR (Pure) cm-1: 1755, 1748, 1668, 1620, 1506.

Mass m/z: 322 (M+).

5) Obtaining 4-carboxy-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 6-(2,4-differenl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the connection header yellowish needle-like crystals (yield: 92.7%of).

Melting point: 126,5-128,20°

1H NMR (400 MHz, CDCl3) δ: 1,02 (6N, d, J=6.6 Hz), 2,31 is 2.43 (1H, m), 4,22 (2H, d, J=7,6 Hz), of 6.96-7,07 (2H, m), 7,74 (1H, DDD, J=6,3, 6,3, 8,8 Hz), 8,61 (1H, d, J=2.2 Hz), 14,02 (1H, s).

IR (KBr) cm-1: 1739, 1636, 1618, 1573, 1465.

Mass m/z: 308 (M+).

6) Receiving 6-(2,4-differenl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow oil (yield: 45.0%in).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,27-to 2.40 (1H, m)and 3.15 (1H, t, J=6,1 Hz), 4,08 (2H, d, J=7,3 Hz), 4,69 (2H, DD, J=1,2, 6,1 Hz), 6,93 (1H, DDD, J=2,4, 8,8, 11.2 Hz), of 6.96-7,02 (1H, m), to 7.61-7,63 (1H, m), 7,72 (1H, DDD, J=6,3, 6,3, 8,8 Hz).

IR (Pure) cm-1: 3412, 1652, 1620, 1507.

Mass m/z: 294 (M+).

7) Obtain 6-(2,4-debtor enyl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 6-(2,3-differenl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 96,3%).

Melting point: 86,7-88,6°

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2.26 and-2,39 (1H, m), and 3.16 (3H, s)4,08 (2H, d, J=7,3 Hz), 5,26 (2H, d, J=1.2 Hz), 6,94 (1H, DDD, J=2,4, 8,8, 11.2 Hz), 6,97-7,03 (1H, m), 7,71 (1H, DDD, J=6,3, 6,3, 8,8 Hz), 7,73 to 7.75 (1H, m).

IR (KBr) cm-1: 1659, 1612, 1508, 1359, 1166.

Mass m/z: 372 (M+).

8) Obtain 6-(2,4-differenl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one

Following the procedure of example 24 (1), was subjected to interaction of 6-(2,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 91.1%of).

Melting point: shall be 152.3-155,6°

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,28-2,39 (1H, m), 4,07 (2H, d, J=7,3 Hz), 4,89 (2H, d, J=1.0 Hz), 6,83 (1H, DDD, J=2,4, 8,8, and 11.0 Hz), 6,91-6,97 (1H, m), 7,27-7,31 (1H, m), 7,66 (1H, DDD, J=6,3, 6,3, 8,8 Hz), 7,74-7,80 (2H, m), 7,86-7,94 (2H, m).

IR (KBr) cm-1: 1773, 1720, 1650, 1617, 1509, 1418, 1389.

Mass m/z: 423 (M+).

9) Getting 4-aminomethyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 24 (2), were subjected to interaction of 2-isobutyl-6-(2,4-differenl)-4-phthalimidomethyl-2H-pyridazin-3-one with the receipt indicated the data in the title compound as a yellowish oil (yield: 98.4 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6,8 Hz)of 1.66 (2H, usher.), 2,24-to 2.41 (1H, m), a 3.87 (2H, s)4,08 (2H, d, J=7,3 Hz), 6,92 (1H, DDD, J=2,4, 8,8, 11.2 Hz), 6,97-7,02 (1H, m), 7,63 (1H, t, J=1.1 Hz), 7,71 (1H, DDD, J=6,3, 6,3, 8,8 Hz).

IR (Pure) cm-1: 3381, 3307, 1652, 1611, 1508.

Mass m/z: 293 (M+).

Example 112

Getting hydrochloride 4-aminomethyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-aminomethyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 94,9%).

Melting point: 161,4-163,9°

1H NMR (400 MHz, DMSO-d6) δ: 0,93 (6N, d, J=6.8 Hz), 2,18-of 2.34 (1H, m)to 4.01 (2H, s), was 4.02 (2H, d, J=7,3 Hz), 7.24 to 7,31 (1H, m), 7,46 (1H, DDD, J=2,4, 8,8, and 11.5 Hz), 7,76 (1H, DDD, J=6,3, 6,3, 8,8 Hz), 7,95 (1H, s).

IR (KBr) cm-1: 1652, 1616, 1597, 1509.

Example 113

Getting 6-(2,4-differenl)-4-dimethyl-aminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 6-(2,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellowish oil (yield: 94,1%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 2,27-of 2.38 (1H, m), 2,34 (6N, C)to 3.49 (2H, d, J=1.5 Hz), 4,07 (2H, d, J=7,6 Hz), 6,92 (1H, DDD, J=2,4, 8,8, 11.2 Hz), 6,95-7,01 (1H, m), of 7.70 (1H, t, J=1.5 Hz), 7,71 (1H, DDD, J=6,3, 6,3, 8,8 Hz).

IR (Net settled) cm -1: 1652, 1612, 1508.

Mass m/z: 321 (M+).

Example 114

Obtain hydrochloride of 6-(2,4-differenl)-4-dimethyl-aminomethyl-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(2,4-differenl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow prismatic crystals (yield: 89,8%).

Melting point: USD 170.1-173.5 metric°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.8 Hz), 2,18-to 2.29 (1H, m), 2,80 (6N, (C), a 4.03 (2H, d, J=7,3 Hz), 4,30 (2H, s), 7,25-7,31 (1H, m), 7,45 (1H, DDD, J=2,4, 8,8, 11.2 Hz), 7,81 (1H, DDD, J=6,3, 6,3, 8,8 Hz). of 8.15 (1H, d, J=1.7 Hz).

IR (KBr) cm-1: 1648, 1612, 1523, 1510.

Example 115

Getting 4-diethylaminomethyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 9 (4)were subjected to interaction of 6-(2,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethylamin obtaining specified in the title compounds as a pale yellow oil (yield: quantitative).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 1.06 a (6N, t, J=7,1 Hz), 2,27-2,39 (1H, m), 2,59 (4H, square, J=7,1 Hz)and 3.59 (2H, d, J=1.7 Hz), 4,07 (2H, d, J=7,3 Hz), 6,92 (1H, DDD, J=2,4, 8,8, 11.2 Hz), 6,95-7,01 (1H, m), 7,72 (1H, DDD, J=6,3, 6,3, 8,8 Hz), 7,83 (1H, TD, J=1,5, 2,9 Hz).

IR (Pure) cm-1: 1656, 1613, 1508.

Mass m/z: 349 (M+).

Example 116

Getting hydrochloride 4-diethylamino the Teal-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-diethylaminomethyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 80.9 per cent).

Melting point: 128,9-131,7°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.8 Hz), 1.28 (in the 6N, t, J=7.2 Hz), 2,18-to 2.29 (1H, m), 3,10-of 3.23 (4H, m), a 4.03 (2H, d, J=7,3 Hz), the 4.29 (2H, d, J=5.4 Hz), 7,28 (1H, DDD, J=2,2, 8,8, 8,8 Hz), was 7.45 (1H, DDD, J=2,2, 8,8, 8,8 Hz), 7,81 (1H, DDD, J=6,3, 8,8, 8,8 Hz), 8,24 (1H, d, J=1.5 Hz).

Example 117

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(2,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellowish oil (yield: 97,6%).

1H NMR (400 MHz, CDCl3) δ: 0,97 (6N, d, J=6.6 Hz), 2.26 and-2,40 (1H, m), 2,70 (4H, t, J=5.0 Hz), the 3.65 (4H, t, J=5.0 Hz), 3,70 (2H, s), 4.09 to (2H, d, J=7,3 Hz), 6,92 (1H, DDD, J=2.7, and an 8.8, 11.2 Hz), 6,97-7,03 (1H, m), 7,63 (1H, d, J=2.4 Hz), of 7.75 (1H, DDD, J=6,3, 6,3, 8,8 Hz).

IR (Pure) cm-1: 3401, 1648, 1597, 1508.

Mass m/z: 363 (M+-H2O).

Example 118

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(2,differenl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compounds as yellow prismatic crystals (yield: 89,0%).

Melting point: 161,8-163,9°

1H NMR (400 MHz, DMSO-d6) δ: 0,93 (6N, d, J=6.6 Hz), 2,18-to 2.29 (1H, m), 3.27 to is 3.40 (4H, user, overlaps with H2O), 3,76-a-3.84 (4H, m), a 4.03 (2H, d, J=7,3 Hz), 4,51 (2H, users), of 5.34 (2H, usher.), 7,24-7,31 (1H, m), 7,41-of 7.48 (1H, m), 7,76-to 7.84 (1H, m), 8,15 (1H, m).

IR (KBr) cm-1: 3233, 3172, 1645, 1613, 1593, 1421.

Example 119

Getting 6-(2,4-differenl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(2,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compounds as a pale yellow oil (yield: 94,0%).

1H NMR (400 MHz, CDCl3) δ: 0,97 (6N, d, J=6.6 Hz), 2,28-of 2.38 (1H, m), 2,31 (3H, s)of 2.50 (4H, usher.), 2,61 (4H, usher.), of 3.57 (2H, d, J=1.5 Hz), 4,07 (2H, d, J=7,3 Hz), 6,93 (1H, DDD, J=2,4, 8,8, 11.2 Hz ), of 6.96-7,02 (1H, m), 7,69 to 7.75 (2H, m).

IR (Pure) cm-1: 1655, 1616, 1596, 1508.

Mass m/z: 376 (M+).

Example 120

Getting dihydrochloride 6-(2,4-differenl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(2,4-differenl)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 90.4 percent).

Melting point: 248,1-251,7°C (decomp.).

1H NMR (400 MHz, DMSO-d 6, 100° δ: 0,93 (6N, d, J=6.8 Hz), 2,20-to 2.29 (1H, m), was 2.76 (3H, s)to 3.09 (4H, user., overlaps with H2O), with 3.27 (4H, usher.), 3,74 (2H, s), 4.00 points (2H, d, J=7,1 Hz), 7,14-7,29 (2H, m), 7,71-7,79 (2H, m).

IR (KBr) cm-1: 1652, 1612, 1514.

Example 121

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(2,4-differenl)-2-isobutyl-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellowish oil (yield: 97.5%of).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), 1,47 (N, C), 2,28-2,39 (1H, m), 2,52 (4H, t, J=4.9 Hz), 3,49 (4H, t, J=4.9 Hz), 3,57 (2H, d, J=1.2 Hz), 4,07 (2H, d, J=7,3 Hz), 6,93 (1H, DDD, J=2,4, 8,8, 11.2 Hz), of 6.96-7,02 (1H, m), 7,69 to 7.75 (2H, m).

IR (Pure) cm-1: 1695, 1655, 1613, 1508, 1425.

Mass m/z: 462 (M+).

Example 122

Getting 6-(2,4-differenl)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 20 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(2,4-differenl)-2-isobutyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: quantitative).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.8 Hz), is 1.81 (1H, usher.), 2,27-2,39 (1H, m), 2,50-of 2.56 (4H, osirm), to 2.94 (4H, t, J=4,8 Hz), 3,54 (2H, d, J=1.2 Hz), 4,07 (2H, d, J=7,3 Hz), 6,93 (1H, DDD, J=2,4, ,8, 11.2 Hz), 6,94-7,02 (1H, m), 7,69-7,76 (2H, m).

IR (Pure) cm-1: 3314, 1655, 1613, 1508.

Mass m/z: 362 (M+).

Example 123

Getting dihydrochloride 6-(2,4-differenl)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 6-(2,4-differenl)-2-isobutyl-4-(1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 90,8%).

Melting point: 136,3-140,9°

1H NMR (400 MHz, DMSO-d6) δ: 0,93 (6N, d, J=6.6 Hz), 2,20-of 2.30 (1H, m), 2.95 and (4H, t, J=5.0 Hz), to 3.02 (4H, t, J=5.0 Hz), 3,76 (2H, s), 4.00 points (2H, d, J=7,3 Hz), 7,14-7,20 (1H, m), 7,26 (1H, DDD, J=2.7, and an 8.8, 11.2 Hz), 7,86 (1H, DDD, J=6,6, 6,6, 8,8 Hz), 7,81 (1H, s).

IR (KBr) cm-1: 1656, 1616, 1597, 1509, 1426.

Example 124

Getting 2-benzyl-4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

1) preparation of 2-benzyl-6-(4-fluoro-3-were)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(4-fluoro-3-were)-4-methoxycarbonyl-2H-pyridazin-3-one and benzylchloride obtaining specified in the connection header in the form of yellow needle crystals (yield: 71.0 per cent).

Melting point: 109,0-110,5°

1H NMR (400 MHz, CDCl3) δ: 2,35 (3H, d, J=1.7 Hz), of 3.96 (3H, s), 5,44 (2H, s), 7,10 (1H, DD, J=8,8, 8,8 Hz), 7,28-7,37 (3H, m), 7,52 (2H, d, J=6.3 Hz), EUR 7.57-to 7.64 (2 is, m), 8,21 (1H, s).

IR (KBr) cm-1: 1750, 1744, 1657, 1278, 1233, 1123,

Mass m/z: 352 (M+).

2) Getting 2-benzyl-4-carboxy-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-benzyl-6-(4-fluoro-3-were)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 65.2 percent).

Melting point: 191,2-192,3°

1H NMR (400 MHz, CDCl3) δ: is 2.37 (3H, d, J=2.0 Hz), 5,52 (2H, s), 7,13 (1H, DD, J=8,8, 8,8 Hz), 7,33-7,41 (3H, m), of 7.48-7,52 (2H, m), of 7.64-of 7.70 (2H, m), to 8.62 (1H, s), 14,01 (1H, usher.).

IR (KBr) cm-1: 1739, 1633, 1569, 1457, 1423, 1240.

Mass m/z: 338 (M+).

3) Getting 2-benzyl-6-(4-fluoro-3-were)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 2-benzyl-4-carboxy-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 28.4 percent).

Melting point: 119,5-120,6°

1H NMR (400 MHz, CDCl3) δ: of 2.34 (3H, d, J=1.7 Hz), 3,01 (1H, t, J=5,9 Hz), 4,70 (2H, DD, J=1,2, 5,9 Hz), 5,41 (2H, s), was 7.08 (1H, DD, J=8,8, 8,8 Hz), 7,27-7,37 (3H, m), of 7.48 (1H, d, J=6.6 Hz), EUR 7.57-the 7.65 (2H, m), 7,66 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 3330, 1657, 1643, 1611, 1597, 1506, 1239.

Mass m/z: 324 (M+).

4) to Obtain 2-benzyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the methodology applied is 1(9), subjected to the interaction of 2-benzyl-6-(4-fluoro-3-were)-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 98.9 per cent).

Melting point: 147,6-148,3°

1H NMR (400 MHz, CDCl3) δ: 2,35 (3H, d, J=2.0 Hz)and 3.15 (3H, s), of 5.26 (2H, d, J =1.2 Hz), 5,41 (2H, s), to 7.09 (1H, DD, J=8,8, 8,8 Hz), 7,27-7,37 (3H, m), 7,47 (2H, d, J=6.6 Hz), a 7.62 (1H, d, J=7,3 Hz), EUR 7.57-of 7.60 (1H, m), of 7.75 (1H, s).

IR (KBr) cm-1: 1656, 1617, 1507, 1355, 1168, 1033, 879.

Mass m/z: 402 (M+).

5) Getting 2-benzyl-4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-benzyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 91.8%of).

1H NMR (400 MHz, CDCl3) δ: 1,46 (N, C)to 2.35 (3H, d, J=1,8 Hz), 2,50 (4H, t, J=4.9 Hz), 3,49 (4H, t, J=4.9 Hz), of 3.56 (2H, d, J=1.4 Hz), of 5.40 (2H, s), 7,26 and 7.36 (4H, m), 7,49 (2H, d, J=6.6 Hz), 7,55-of 7.60 (1H, m), 7,63 (1H, DD, J=1,8, 7,2 Hz), 7,74 (1H, s).

Example 125

Getting dihydrochloride of 2-benzyl-6-(4-fluoro-3-were)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 2-benzyl-4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in sialometaplasia in the form of a colorless crystalline powder (yield: 60,9%).

Melting point: 162,7-180,7°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 2,31 (3H, d, J=2.0 Hz), to 3.09 (4H, usher.), of 3.28 (4H, t, J=5,2 Hz)to 3.89 (2H, s), are 5.36 (2H, s), 7,21-7,40 (6N, m), 7,70-7,76 (1H, m), 7,79 (1H, DD, J=1,7, 7,3 Hz), 8,16 (1H, s).

IR (KBr) cm-1: 1656, 1607, 1505, 1239, 1126, 700.

Mass m/z: 392 (M+)

Example 126

Getting 2-benzyl-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-benzyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 81,3%).

1H NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), a 2.36 (3H, d, J=1,8 Hz), 2,53 (4H, usher.), 2,61 (4H, usher.), of 3.57 (2H, d, J=1.4 Hz), of 5.40 (2H, s), was 7.08 (1H, t, J=8,9 Hz), 7,26 and 7.36 (3H, m), 7,49 (2H, d, J=6.8 Hz), 7,56-of 7.60 (1H, m), of 7.64 (1H, DD, J=1,8, 7,2 Hz), 7,73 (1H, s).

Example 127

Getting dihydrochloride of 2-benzyl-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-benzyl-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 78.6 per cent).

Melting point: 240,0-242,5°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 2,31 (3H, d, J=1.7 Hz), was 2.76 (3H, s), 3,10 (4H, usher.), of 3.33 (4H, usher.), 3,84 (2 is, C)are 5.36 (2H, s), 7,21-7,39 (6N, m), 7,69-7,74 (1H, m), 7,78 (1H, DD, J=2,1, 7,8 Hz), of 8.09 (1H, s).

IR (KBr) cm-1: 1653, 1607, 1504, 1454, 1240, 1127.

Mass m/z: 406 (M+)

Example 128

Getting 2-benzyl-4-N,N-bis(2-hydroxyethyl)-aminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-benzyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 87.6 per cent).

1H NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,69 (4H, t, J=4,9 Hz)to 3.64 (4H, t, J=5.0 Hz), 3,68 (2H, s), of 5.40 (2H, s), 7,06 (1H, t, J=8,9 Hz), 7,26-7,38 (3H, m), 7,45 (2H, d, J=7,0 Hz), 7,58-to 7.68 (2H, m), of 7.75 (1H, s).

Example 129

Obtain hydrochloride of 2-benzyl-4-N,N-bis(2-hydroxyethyl)-aminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-benzyl-4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 75,9%).

Melting point: over 161.7-163,0°

1H NMR (400 MHz, DMSO-d6) δ: 2,31 (2H, d, J=2.0 Hz), to 3.34 (4H, t, J=5,2 Hz), 3,83 (4H, t, J=5.4 Hz), 4,47 (2H, s), of 5.39 (2H, s), 7.23 percent-7,40 (6N, m), 7,73-to 7.77 (1H, m), 7,82 (1H, DD, J=1,7, 7,3 Hz), of 8.47 (1H, s).

IR (KBr) cm-1: 1602, 1503, 1239, 1088.

Mass m/z: 393 (M+-H2O)

Example 130

Getting 2-Ben the Il-4-dimethylaminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-benzyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compound as a yellow oil (yield: 92.7%of).

1H NMR (400 MHz, CDCl3) δ: 2,34 (N, C)to 3.49 (2H, s), of 5.40 (2H, s), 7,06 (1H, t, J=8,9 Hz), 7,25-to 7.35 (3H, m), 7,49 (2H, d, J=7,4 Hz), 7,58-to 7.67 (2H, m), of 7.75 (1H, s).

Example 131

Obtain hydrochloride of 2-benzyl-4-dimethylaminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-benzyl-4-dimethylaminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the title compounds as colorless flakes (yield: 72.6 per cent).

Melting point: 225,3-226,0°

1H NMR (400 MHz, DMSO-d6) δ: 2,31 (3H, d, J=2.0 Hz), of 2.81 (6H, s), 4,28 (2H, s), of 5.39 (2H, s), 7,21-7,41 (6H, m)

7,73-7, 78 (1H, m), 7,83 (1H, DD, J=2,2, 7,6 Hz), charged 8.52 (1H, s).

IR (KBr) cm-1: 1652, 1610, 1506, 1240, 1126, 702.

Mass m/z: 351 (M+)

Example 132

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-cinnamyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

1) preparation of 2-cinnamyl-6-(4-fluoro-3-were)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(3-fluoro-4-were)-4-methoxycarbonyl-2H-pyridazin-3-one and senamirmir obtaining specified in the header connect the Oia in the form of pale yellow needle crystals (yield: 58.7 percent).

Melting point: 95,9-96,7°

1H NMR (400 MHz, CDC13) δ: 2,35 (3H, d, J=1.7 Hz), 3,99 (3H, s), 5,04 (2H, DD, J=1,2, 6,8 Hz), of 6.45 (1H, dt, J=15,9 that 6.8 Hz), to 6.75 (1H, d, J=15,GC), 7,10 (1H, DD, J=8,9, and 8.9 Hz), 7,20-7,33 (3H, m), 7,39 (2H, d, J=7,1 Hz), 7,58-7,66 (2H, m), 8,23 (1H, s).

IR (KBr) cm-1: 1724, 1661, 1603, 1501, 1292, 1234, 1123.

Mass m/z: 378 (M+).

2) Getting 4-carboxy-2-cinnamyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-cinnamyl-6-(4-fluoro-3-were)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow needle crystals (yield: 85.1%)are.

Melting point: of 142.8-143,6°

1H NMR (400 MHz, CDC13) δ: a 2.36 (3H, d, J=2.0 Hz), 5,12 (2H, DD, J=1,2, 6,8 Hz), 6.42 per (1H, dt, J=15,9 that 6.8 Hz), to 6.80 (1H, d, J=15,9 Hz), 7,13 (1H, DD, J=8,8, 8,8 Hz), 7,22 and 7.36 (3H, m), 7,40-the 7.43 (2H, m), 7,65-7,72 (2H, m), 8,64 (1H, s), 14,04 (1H, usher.).

IR (KBr) cm-1: 3438, 3061, 2688, 1747, 1637, 1567, 1463, 1244.

Mass m/z: 364 (M+).

3) Getting 2-cinnamyl-6-(4-fluoro-3-were)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-cinnamyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 20.1 percent).

Melting point: 139,9-140,9°

1H NMR (400 MHz, CDC13) δ: of 2.34 (3H, d, J=1,5Hz), of 3.00 (1H, usher.), to 4.73 (2H, s), 5,01 (2H, d, J=6.6 Hz), 6,44 1H, dt, J=15,9, and 6.6 Hz), 6,72 (2H, d, J=15,9 Hz), was 7.08 (1H, DD, J=8,9, and 8.9 Hz), 7,24 (1H, t, J=7,3 Hz), 7,30 (2H, DD, J=7,3, 7,3 Hz), 7,39 (2H, d, J=7,3 Hz), 7,58 to 7.62 (1H, m), of 7.64 (1H, d, J=7,3 Hz), to 7.67 (1H, ).

IR (KBr) cm-1: 3393, 1655, 1648, 1602, 1505, 1451, 1238, 1077.

Mass m/z: 350 (M+).

4) to Obtain 2-cinnamyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-cinnamyl-6-(4-fluoro-3-were)-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 91,9%).

Melting point: 78,4-80,5°

1H NMR (400 MHz, CDC13) δ: 2,35 (3H, d, J=2.0 Hz), 3,17 (3H, s), 5,10 (2H, DD, J=1,2, 6,8 Hz), 5,28 (2H, d, J=1.2 Hz), 6.42 per (1H, dt, J=15,9 that 6.8 Hz), was 6.73 (1H, d, J=15,9 Hz), to 7.09 (1H, DD, J=8,9, and 8.9 Hz), 7,21-7,33 (3H, m), 7,40 (2H, d, J=8,8 Hz), EUR 7.57 to 7.62 (1H, m), of 7.64 (1H, d, J=8,8 Hz), to 7.77 (1H, t, J=1.3 Hz).

IR (KBr) cm-1: 1663, 1612, 1508, 1355, 1241, 1167, 988, 958, 873.

Mass m/z: 428 (M+).

5) Obtain 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-cinnamyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cinnamyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 87.7 per cent).

1H NMR (400 MHz, CDC13) δ: of 1.47 (9H, s), 2,35 (3H, d, J=1.6 Hz), 2,52 (4H, t, J=5.0 Hz), 3,51 (4H, t, J=4,9 Hz)and 3.59 (2H, d, J=1.4 Hz), 500 (2H, DD, J=1,0, and 6.6 Hz), of 6.45 (1H, dt, J=15,8, and 6.6 Hz), 6,12 (1H, d, J=15,8 Hz), was 7.08 (1H, DD, J=8,9, and 8.9 Hz), 7,22 (1H, t, J=7.2 Hz), 7,29 (2H, DD, J=7,0, 7,0 Hz), 7,38 (2H, d, J=7,7 Hz), 7,56-to 7.61 (1H, m), the 7.65 (1H, DD, J=1,8, 7,2 Hz), to 7.77 (1H, s).

Example 133

Getting dihydrochloride 2-cinnamyl-6-(4-fluoro-3-were)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-cinnamyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 96,0%).

Melting point: RUB 171.1-187,1°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 2,31 (3H, d, J=2.0 Hz), 3,21 (4H, t, J=4,9 Hz)to 3.34 (4H, t, J=5,1 Hz)to 3.99 (2H, s), of 4.95 (2H, DD, J=1,3, 6.4 Hz), of 6.45 (1H, dt, J=16,1, 6.3 Hz), of 6.68 (1H, d, J=16.1 Hz), 7,20-7,26 (2H, m), 7,29-7,34 (2H, m), 7,41 was 7.45 (2H, m), 7,73-7,79 (1H, m), 7,83 (1H, DD, J=1,7, 7,3 Hz), compared to 8.26 (1H, s).

IR (KBr) cm-1: 1656, 1605, 1505, 1239, 962.

Mass m/z: 418 (M+)

Example 134

Getting 2-cinnamyl-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cinnamyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 80.1%of).

1H NMR (400 MHz, CDCl3) δ: 2,32 (3H, s), 2,35 (3H, d, J=1,8 Hz), of 2.51 (4H, usher.), 2,62 (4H, usher.), 3,59 (2H, d, J=14 Hz), at 4.99 (2H, DD, J=1,1, 6,6 Hz), of 6.45 (1H, dt, J=15,8, 6,0 Hz), 6,72 (1H, d, J=15,8 Hz), was 7.08 (1H, DD, J=8,9, and 8.9 Hz), 7,22 (1H, TT, J=1,6, 7,2 Hz), 7,29 (2H, DD, J=7,2, 7,2 Hz), 7,39 (2H, DD, J=1,4, 7,2 Hz), 7,56-to 7.61 (1H, m), the 7.65 (1H, DD, J=1,8, 7,2 Hz), of 7.75 (1H, t, J=1.4 Hz).

Example 135

Getting dihydrochloride 2-cinnamyl-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cinnamyl-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 66.3 per cent).

Melting point: 236,1-237,1°

1H NMR (400 MHz, DMSO-d6) δ: 2,32 (3H, d, J=2.2 Hz), was 2.76 (3H, s), is 3.08 (4H, usher.), of 3.32 (4H, usher.), a 3.83 (2H, s), 4,94 (2H, DD, J=1,2, 6.4 Hz), of 6.45 (1H, dt, J=16,1, 6.3 Hz), to 6.67 (1H, d, J=15,8 Hz), 7,19-7,26 (2H, m), 7,29-7,34 (2H, m), 7,41-7,44 (2H, m), 7,71-7,76 (1H, m), 7,81 (1H, DD, J=2,2, 7,6 Hz), 8,07 (1H with).

IR (KBr) cm-1: 1652, 1607, 1505, 1239, 1129.

Mass m/z: 432 (M+)

Example 136

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cinnamyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cinnamyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 83.7 percent).

1H NMR (400 MHz, CDCl3) δ: 2,32 (3H, s), 2,69 (4H, t, J=4.9 Hz), the 3.65 (4H, d, J=4.9 Hz), of 3.69 (2H), to 4.98 (2H, d, J=6.6 Hz), 6,41 (1H, dt, J=15,8, 6.5 Hz), of 6.68 (1H, d, J=15,8 Hz), 7,05 (1H, DD, J=8,9, and 8.9 Hz), 7,21 (1H, t, J=7.2 Hz), 7,28 (2H, DD, J=7,2, 7,2 Hz), 7,37 (2H, d, J=7,6 Hz), 7,58-7,63 (1H, m), 7,66 (1H, DD, J=1,8, 7,2 Hz), 7,81 (1H, s).

Example 137

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cinnamyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cinnamyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 63,2%).

Melting point: 112,5-of 113.2°

1H NMR (400 MHz, DMSO-d6) δ: 2,32 (3H, d, J=1.9 Hz), the 3.35 (4H, t, J=5,1 Hz), a-3.84 (4H, t, J=5,1 Hz), to 4.46 (2H, s), to 4.98 (2H, DD, J=1,5, 6,1 Hz), of 6.45 (1H, dt, J=15,8, 6,1 Hz), 6,69 (1H, d, J=16.0 Hz), 7,21-7,27 (2H, m), 7,29-7,34 (2H, m), 7,41-7,44 (2H, m), 7,757,80 (1H, m), a 7.85 (1H, DD, J=2.0 a, 7,3 Hz), of 8.47 (1H, s).

IR (KBr) cm-1: 1652, 1604, 1505, 1241, 971.

Mass m/z: 419 (M+-H2O)

Example 138

Getting 2-cinnamyl-4-dimethylaminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-cinnamyl-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compound as a yellow oil (yield: 90.9 per cent).

1H NMR (400 MHz, CDCl3) δ: of 2.34 (3H, d, J=2.0 Hz), 2,36 (6N, (C),3,51 (2H, d, J=1.4 Hz), 5,00 (2H, DD, J=1,3,6,8 Hz), 6,46 (1H, dt,J=15,8, and 6.6 Hz), 6,72 (1H, d, J=15,8 Hz), 7,07 (1H, DD, J=8,9,8,9 Hz), 7,22 (1H, TT, J=1,4, 7,2 Hz), 7,29 (2H, DD, J=7,2, 7,2 Hz), 7,39 (2H, DD, J=1,6, 7,0 Hz), 7,60-the 7.65 (1H, m), to 7.67 (1H, DD, J=2,2, 7,2 Hz), 7,76 (1H, s).

Example 139

Getting hydrochloride 2-cinnamyl-4-dimethylaminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cinnamyl-4-dimethylaminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 81.1%of).

Melting point: 183,6-184,5°

1H NMR (400 MHz, DMSO-d6) δ: 2,32 (3H, d, J=2.0 Hz), 2,83 (6N, (C), the 4.29 (2H, s), to 4.98 (2H, DD, J=1,3, 6.4 Hz), 6,46 (1H, dt, J=16,1,6,3 Hz), 6,69 (1H, d, J=16.1 Hz), 7,22-7,27 (2H, m), 7,297,35 (2H, m), 7,41-7,44 (2H, m), 7,76-7,81 (1H, m), 7,86 (1H, DD, J=2,2, 7,3 Hz)and 8.50 (1H, s).

IR (KBr) cm-1: 1652, 1607, 1505, 1240, 965.

Mass m/z: 377 (M+)

Example 140

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-2H-pyridazin-3-one

1) preparation of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(3-fluoro-4-were)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamate obtaining specified in the connection header in the form of yellow needle crystals (yield: 71.7%of).

Melting point: 137,8-138,8°

1H NMR (400 is Hz, CDCl3) δ: 2,35 (3H, d, J=1.7 Hz), 3,99 (3H, s), of 5.03 (2H, d, J=6.6 Hz), to 6.43 (1H, dt, J=the 15.6, 6.6 Hz), 6,70 (1H, d, J=15.6 Hz), 7,10 (1H, d, J=8,8 Hz), 7,27 (2H, d, J=8,8 Hz), 7,31 (2H, d, J=8,8 Hz), 7,58-7,63 (1H, m), of 7.64 (1H, DD, J=2,1, 7,0 Hz), 8,24 (1H, s).

IR (KBr) cm-1: 1724, 1709, 1667, 1506, 1291, 1236, 1126, 831.

Mass m/z: 412 (M+), 414 (M+).

2) Getting 4-carboxy-2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow crystalline powder (yield: 86.2 per cent).

Melting point: of 186.0-186,6°

1H NMR (400 MHz, CDCl3) δ: a 2.36 (3H, d, J=2.0 Hz), 5,11 (2H, DD, J=1,2, 6,8 Hz), to 6.39 (1H, dt, J=15,9 that 6.8 Hz), to 6.75 (1H, d, J=15.6 Hz), 7,13 (1H, DD, J=8,8, 8,8 Hz), 7,29 (2H, d, J=8.5 Hz), 7,33 (2H, d, J=8.5 Hz), 7,65-7,71 (2H, m)8,64 (1H, s), 13,98 (1H, usher.).

IR (KBr) cm-1: 3471, 1738, 1631, 1566, 1490, 1467, 1403, 1242, 812, 802.

Mass m/z: 398 (M+), 400 (M+).

3) Obtaining 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 17.2 per cent).

Melting point: 131,8-133,1°

1H NMR (400 MHz, CDCl3) δ: of 2.34 (3H, d, J=2.0 Hz), to 4.73 (2H, q, j =1.2 Hz), at 4.99 (2H, DD, J=1,0, and 6.6 Hz), 6,40 (1H, dt, J=15,9, and 6.6 Hz), to 6.75 (1H, d, J=15,9 Hz), was 7.08 (1H, DD, J=8,9, and 8.9 Hz), 7,26 (2H, d, J=8,8 Hz), 7,31 (2H, d, J=8,8 Hz), EUR 7.57 to 7.62 (1H, m), of 7.64 (1H, DD, J=2,2, 7,3 Hz), of 7.69 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 3359, 1653, 1598, 1506, 1492, 1240, 1091, 1076.

Mass m/z: 384 (M+), 386 (M+).

4) to Obtain 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the title compounds as colorless needle crystals (yield: 94,9%).

Melting point: 117,8-119,5°

1H NMR (400 MHz, CDCl3) δ: 2,35 (3H, d, J=2.0 Hz), 3,17 (3H, s), 4,99 (2H, DD, J=1,2, and 6.6 Hz), 5,28 (2H, d, J=1.2 Hz), 6,38 (1H, dt, J=15,9, and 6.6 Hz), to 6.75 (1H, d, J=15,9 Hz), 7,10 (1H, DD, J=8,8, 8,8 Hz), 7,27 (2H, d, J=8,5 Hz), 7,32 (2H, d, J=8,5 Hz), EUR 7.57-the 7.65 (2H, m), 7,78 (1H, t, J=1.3 Hz).

IR (KBr) cm-1: 1663, 1619, 1506, 1492, 1346, 1240, 1172, 960, 830.

Mass m/z: 462 (M+), 464 (M+).

5) Obtain 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-2H-pyridazinone

Following the procedure of example 1(10)were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 87.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,7 (N, C)to 2.35 (3H, d, J=1.6 Hz), 2,52 (4H, t, J=4.9 Hz), 3,50 (4H, t, J=5.0 Hz)and 3.59 (2H, d, J=1.2 Hz), 4,99 (2H, DD, J=1,0, and 6.6 Hz), 6.42 per (1H, dt, J=15,8, and 6.6 Hz), to 6.67 (1H, d, J=16.0 Hz), to 7.09 (1H, DD, J=8,9, a 8.9 Hz), 7,25 (2H, d, J=8,8 Hz), 7,31 (2H, d, J=8.6 Hz), 7,55-to 7.61 (1H, m), of 7.64 (1H, DD, J=2.0 a, 7,2 Hz), to 7.77 (1H, s).

Example 141

Getting dihydrochloride of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the title compounds as a pale brown crystalline powder (yield: 84.7 per cent).

Melting point: 186,7-197,0°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 2,31 (3H, d, J=2.0 Hz), 3,15 (4H, usher.), of 3.31 (4H, t, J=5,2 Hz), of 3.94 (2H, s), of 4.95 (2H, DD, J=1,3,6,3 Hz), 6,47 (1H, dt, J=15,9, 6,1 Hz), of 6.66 (1H, d, J=15,9 Hz), 7,22 (1H, DD, J=9,0, 9.0 Hz), 7,34 (2H, d, J=8.6 Hz), was 7.45 (2H, d, J=8.6 Hz), 7,73 for 7.78 (1H, m)of 7.82 (1H, DD, J=1,9, a 7.6 Hz), 8,21 (1H, s).

IR (KBr) cm-1: 1656, 1606, 1240, 1090, 964.

Mass m/z: 452 (M+), 454 (M+).

Example 142

Obtaining 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow wt is a (output: 71,8%).

1H NMR (400 MHz, CDCl3) δ: 2,32 (3H, s)to 2.35 (3H, s), of 2.51 (4H, usher.), 2,62 (4H, usher.),3,59 (2H, s), 4,99 (2H, d, J=6.6 Hz), 6.42 per (1H, dt, J=15,8,6,4 Hz), of 6.66 (1H, d, J=15,9 Hz),to 7.09 (1H, DD, J=8,9, and 8.9 Hz),7,24 (2H, d, J=8.6 Hz), 7,30 (2H, d, J=8.6 Hz), 7,56 to 7.62 (1H, m), the 7.65 (1H, DD, J=1,8, 7,2 Hz), 7,76 (1H, s).

Example 143

Getting dihydrochloride of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 80.4%to).

Melting point: 229,7-243,3°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 2,31 (3H, d, J=1,8 Hz), was 2.76 (3H, s)to 3.09 (4H, usher.), of 3.33 (4H, usher.), a 3.83 (2H, s), 4,94 (2H, DD, J=1,2, 6,0 Hz), 6.42 per (1H, dt, J=16,0, 6.2 Hz), of 6.65 (1H, d, J=16.0 Hz), 7,22 (1H, DD, J=9,1, 9.1 Hz), 7,34 (2H, d, J=8.6 Hz), was 7.45 (2H, d, J=8.6 Hz), 7,71-7,76 (1H, m), 7,80 (1H, DD, J=2,2, 7,0 Hz), 8,08 (1H, s).

IR (KBr) cm-1: 1652, 1608, 1492, 1239, 1130.

Mass m/z: 466 (M+), 468 (M+).

Example 144

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the connection header in view of the yellow oil (yield: 76.6 percent).

1H NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,70 (4H, t, J=4.5 Hz), 3,66 (4H, t, J=4.9 Hz), 3,70 (2H, s), to 4.98 (2H, d, J=6.6 Hz), 6,36 (1H, dt, J=15,8, 6.5 Hz), 6,63 (1H, d, J=15,8 Hz), 7,06 (1H, DD, J=8,6, 8.6 Hz), 7,24 (2H, d, J=8.6 Hz), 7,30 (2H, d, J=8,2 Hz), 7,58-7,63 (1H, m), the 7.65 (1H, DD, J=1,8, 7,2 Hz), 7,78 (1H, s).

Example 145

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 76,1%).

Melting point: 151,9-153,4°

1H NMR (400 MHz, DMSO-d6) δ: 2,32 (3H, d, J=1.7 Hz), the 3.35 (4H, t, J=5,1 Hz), 3,83 (4H, t, J=5.4 Hz), to 4.46 (2H, s), equal to 4.97 (2H, DD, J=1,2, 6,1 Hz), 6.48 in (1H, dt, J=15,9, 6.2 Hz), to 6.67 (1H, d, J=15,9 Hz), 7,24 (1H, DD, J=9,1, 9,1 Hz), 7,35 (2H, d, J=8,8 Hz), was 7.45 (2H, d, J=8.6 Hz), 7,75-7,80 (1H, m), a 7.85 (1H, DD, J=1,7,7,9 Hz), 8,48 (1H, s).

IR (KBr) cm-1: 1652, 1604, 1492, 1240, 1090, 968.

Mass m/z: 440 (M+), 442 (M+).

Example 146

Obtaining 2-(4-chlorocinnamoyl)-4-dimethylaminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 84.6 per cent).

sup> 1H NMR (400 MHz, CDCl3) δ: of 2.33 (3H, d, J=1.6 Hz), 2,36 (6N, (C), 3,52 (2H, d, J=1.2 Hz), 4,99 (2H, DD, J=1,0, and 6.6 Hz), to 6.43 (1H, dt, J=15,8, and 6.6 Hz), of 6.66 (1H, d, J=15,8 Hz), 7,07 (1H, DD, J=8,9,8,9 Hz), 7,24 (2H, d, J=8.6 Hz), 7,30 (2H, d, J=8.6 Hz), 7,60-to 7.68 (2H, m), to 7.77 (1H, s).

Example 147

Obtain hydrochloride of 2-(4-chlorocinnamoyl)-4-dimethylaminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-(4-chlorocinnamoyl)-4-dimethylaminomethyl-6-(4-fluoro-3-were)-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 34.4 percent).

Melting point: 201,3 reach 201.9°

1H NMR (400 MHz, DMSO-d6) δ: 2,32 (3H, d, J=1.7 Hz), 2,83 (6N, (C), 4,28 (2H, s),to 4.98 (2H, DD, J=1,3, 6,1 Hz), 6.48 in (1H, dt, J=16,1, 6,1 Hz), to 6.67 (1H, d, J=16.1 Hz), 7,24 (1H, DD, J=9,3, and 9.3 Hz), 7,35 (2H, d, J=8.6 Hz), 7,45 (2H, d, J=8.6 Hz), 7,75-7,80 (1H, m), a 7.85 (1H, DD, J=2,3, 7,6 Hz), of 8.47 (1H, s).

IR (KBr) cm-1: 1652, 1608, 1491, 1239, 968.

Mass m/z: 411 (M+), 413 (M+).

Example 148

Getting 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

1) preparation of 4-carboxy-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-cyclopropylmethyl-4-methoxycarbonyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellow crystalline p the Rosca (yield: 98.2 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,50-0,66 (4H, m), 1,40-of 1.53 (1H, m), of 2.54 (3H, s), 4,24 (2H, d, J=7,4 Hz), 7,34 (2H, d, J=8.6 Hz), 7,78 (2H, d, J=8.6 Hz), 8,66 (1H, s), 14,22 (1H, s).

IR (KBr) cm-1: 3430, 1752, 1631, 1472, 1452, 1403, 1093, 825.

Mass m/z: 316 (M+)

2) Getting 2-cyclopropylmethyl-4-hydroxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 22.6 percent).

1H NMR (400 MHz, CDCl3) δ: 0,45-0,60 (4H, m), 1,37 of 1.46 (1H, m), of 2.53 (3H, s)to 3.09 (1H, t, J=6,1 Hz), 4,11 (2H, d, J=7,2 Hz), 4.72 in (2H, d, J=6.0 Hz), 7,32 (2H, d, J=8.6 Hz), to 7.67 (1H, s), 7,74 (2H, d, J=8.6 Hz).

IR (KBr) cm-1: 3393, 1657, 1602, 1514, 1095, 822.

Mass m/z: 302 (M+).

3) Getting 2-cyclopropylmethyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-cyclopropylmethyl-4-hydroxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow thin needle crystals (yield: 78.6 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,45-to 1.61 (4H, m), of 1.37 to 1.47 (1H, m), of 2.53 (3H, s), 3,17 (3H, s), 4,11 (2H, d, J=7,2 Hz), 5,28 (2H, s), 7,33 (2H, d, J=8,4 Hz), 7,74 (2H, d, J=8,4 Hz), 7,79 (1H, s).

IR (KBr) cm-1: 3446, 1652, 1607, 1359, 1178, 1024, 829.

Mass m/z: 380 (M+).

4) Receiving cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 85.7 percent).

1H NMR (400 MHz, CDCl3) δ: 0,44-0,58 (4H, m), 1,36 is 1.48 (1H, m), of 2.33 (3H, s), of 2.53 (3H, s), 2,47-2,66 (8H, m)and 3.59 (2H, s), 4,10 (2H, d, J=7,3 Hz), 7,33 (2H, d, J=8,3 Hz), of 7.75 (2H, d, J=8,3 Hz), 7,78 (1H, s).

Example 149

Getting dihydrochloride 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-methylthio)-phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 69.1 per cent).

Melting point: 234,6-239,2°

1H NMR (400 MHz, DMSO-d6) δ: 0,40-0,45 (2H, m), from 0.50 to 0.56 (2H, m), 1,30-1,40 (1H, m), of 2.53 (3H, s), 2,77 (3H, s), of 2.97 (4H, usher.), of 3.28 (4H, usher.), and 3.72 (2H, s), of 4.05 (2H, d, J=7,1 Hz), 7,39 (2H, d, J=8.6 Hz), 7,82 (2H, d, J=8,3 Hz), of 7.96 (1H, s).

IR (KBr) cm-1: 3438, 1651, 1606, 1402, 1095.

Mass m/z: 384 (M+).

Example 150

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)Fe is Il]-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 78.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,44-0,59 (4H, m), 1,36-of 1.45 (1H, m), of 2.53 (3H, s), 2,73 (4H, usher.), to 3.67 (4H, t, J=4.9 Hz), to 3.73 (2H, s), 4,13 (2H, d, J=7,3 Hz), 7,32 (2H, d, J=8,3 Hz), of 7.70 (1H, s), 7,74 (2H, d, J=8,3 Hz).

Example 151

Obtain hydrochloride of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellowish solid (yield: 75.1%of).

Melting point: 169,2-171,7°

1H NMR (400 MHz, DMSO-d6) δ: 0,42-0,46 (2H, m), 0,52-0,57 (2H, m), 1,30-1,40 (1H, m), of 2.53 (3H, s), and 3.31 (4H, usher.), 3,81 (4H, t, J=5.3 Hz), 4,42 (2H, s), 7,41 (2H, d, J=8,8 Hz), the 7.85 (2H, d, J=9.0 Hz), of 8.37 (1H, s).

IR (KBr) cm-1: 3242, 1652, 1604, 1420, 1094, 1059, 823.

Mass m/z: 358 (M+-CH2OH).

Example 152

Getting 2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-cyclopropylmethyl-4-methanesulfonylaminoethyl-6-[4-methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 98.6 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,44-0,58 (4H, m), 1,36 is 1.48 (1H, m), 2,35 (6N, (C), 3,51 (2H, s), 4,51 (2H, d, J=7,3 Hz), 7,31 (2H, d, J=8,3 Hz), to 7.77 (2H, d, J=7.8 Hz), 7,78 (1H, s).

Example 153

Getting hydrochloride 2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 75,5%).

Melting point: 230,2-232,3°

1H NMR (400 MHz, DMSO-d6) δ: 0,42-0,46 (2H, m), 0,52-of 0.58 (2H, m), 1,31-of 1.40 (1H, m), of 2.53 (3H, s), 2,82 (6N, s), 4.09 to (2H, d, J=7,1 Hz), 4,25 (2H, s), 7,41 (2H, d, J=8.6 Hz), to 7.84 (2H, d, J=8.5 Hz), a 8.34 (1H, s).

IR (KBr) cm-1: 3435, 1646, 1604, 1402, 1093, 829.

Mass m/z: 329 (M+).

Example 154

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one

1) preparation of 4-carboxy-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

To a solution of 4-methoxycarbonyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one (8.00 g, 29,0 mmol) in N,N-dimethylformamide (80 ml) was added potassium carbonate (8,02 g, 58,0 mmol) and isobutylamine (4,76 g, 34.8 mmol) and the mixture was stirred at 80°C for 2 hours. The temperature of the reaction mixture gave again to drop to room temperature and was added saturated aqueous solution of sodium bicarbonate. Then the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. RA is the maker of the drove. Following the procedure of example 1(7), the residue was subjected to interaction with obtaining specified in the title compound as a yellow solid [yield: 65,1% (stage 2)].

1H NMR (400 MHz, CDCl3) δ: 1,01 (6N, d, J=6.6 Hz), 2,33 is 2.46 (1H, m), of 2.54 (3H, s), is 4.21 (2H, d, J=7,4 Hz), 7,34 (2H, d, J=8,4 Hz), 7,80 (2H, d, J=8,4 Hz), 8,68 (1H, s), 12,72 (1H, s).

Mass m/z: 318 (M+).

2) Getting 4-hydroxymethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 35.3 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,27-2,39 (1H, m), of 2.53 (3H, s)4,08 (2H, d, J=7,4 Hz), 4,71 (2H, d, J=5,9 Hz), 7,26 (2H, d, J=8,4 Hz), 7,66 (1H, s), 7,73 (2H, d, J=8.6 Hz).

3) Getting 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 4-hydroxymethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 73.2 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,28-to 2.40 (1H, m), of 2.53 (3H, s), 3,17 (3H, s)4,08 (2H, d, J=7,4 Hz), 5,27 (2H, d, J=1.2 Hz), 7,32 (2H, d, J=8,4 Hz), 7,73 (2H, d, J=8,4 Hz), of 7.75 (1H, d, J=1.4 Hz).

Mass m/z: 382 (M+).

4) to Obtain 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-6-4-methanesulfonylaminoethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 88,0%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 1,47 (N, C), 2,28-to 2.40 (1H, m), 2,50 is 2.55 (4H, m), of 2.53 (3H, s)a 3.50 (4H, t, J=4,8 Hz)to 3.58 (2H, s)4,07 (2H, d, J=7,4 Hz), 7,32 (2H, d, J=8,4 Hz), 7,73 (2H, d, J=8.6 Hz), 7,78 (1H, s).

Example 155

Getting dihydrochloride 2-isobutyl-6-[4-(methylthio)phenyl]-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellow crystalline powder (yield: 70,5%).

Melting point: 248,5 is 253.7°C (decomp.).

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.6 Hz), 2.21 are of 2.33 (1H, m), 2,52 (3H, s), 3,10 (4H, t, J=4,8 Hz), 3,30 (4H, t, J=5,2 Hz), 3,90 (2H, s)to 4.01 (2H, d, J=7,3 Hz), 7,39 (2H, d, J=8,3 Hz), 7,83 (2H, d, J=8,3 Hz), 8,15 (1H, s).

IR (KBr) cm-1: 2961, 2442, 1640, 1596, 1511, 1433, 1406, 1089, 912.

Mass m/z: 372 (M+).

Example 156

Getting 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)is enyl]-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 68,3%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,29-2,39 (1H, m), 2,32 (3H, s), of 2.51 (4H, usher.), of 2.53 (3H, s), 2,62 (4H, usher.), to 3.58 (2H, d, J=1.4 Hz), 4,07 (2H, d, J=7,4 Hz), 7,33 (2H, d, J=8.6 Hz), 7,74 (2H, d, J=6.8 Hz), 7,76 (1H, s).

Example 157

Getting dihydrochloride 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 86.4 per cent).

Melting point: 242,6-243,7°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 2.21 are of 2.33 (1H, m), 2,52 (3H, s), was 2.76 (3H, s)to 3.09 (4H, usher.), of 3.33 (4H, usher.), a 3.83 (2H, s)to 4.01 (2H, d, J=7,1 Hz), 7,39 (2H, d, J=8.6 Hz), 7,82 (2H, d, J=8.5 Hz), 8,07 (1H, s).

IR (KBr) cm-1: 3432, 2957, 2437, 1652, 1607, 1090, 953.

Mass m/z: 386 (M+).

Example 158

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 71.2 percent).

1H NMR (400 MHz, CDCl3) δ: 0,96 (6N, d, J=6.6 Hz), 2,27-2,39 (1H, m), of 2.51 (3H, s), a 2.71 (4H, t, J=5,1 Hz), 3,66 (4H, t, J=5,1 Hz), 3,70 (2H, s)4,08 (2H, d, J=7,2 Hz), 7,30 (2H, the, J=8.6 Hz), 7,71-7,76 (3H, m).

Example 159

Getting oxalate of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

To a solution of 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (69,7 mg, 0.18 mmol) in methanol (1 ml) was added at room temperature, the dihydrate of oxalic acid (22,4 mg, 0.18 mmol). The solvent drove away. The residue was recrystallized from a mixture of chloroform-diethyl ether to obtain specified in the title compounds as white solids (59,5 mg, 69.4 per cent).

Melting point: 116,4-118,1°

1H NMR (400 MHz, DMSO-d6) δ: 0,94 (6N, d, J=6.6 Hz), 2,20-of 2.33 (1H, m), 2,52 (3H, s), 2.91 in (4H, t, J=5.8 Hz), 3,61 (4H, t, J=5.6 Hz), of 3.94 (2H, s)to 4.01 (2H, d, J=7,3 Hz), 7,39 (2H, d, J=8.6 Hz), 7,81 (2H, d, J=8.6 Hz), to 8.14 (1H, s).

IR (KBr) cm-1: 3344, 2927, 1659, 1611, 1402, 1049, 721.

Mass m/z: 360 (M+-CH2OH).

Example 160

Getting 4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 73,9%).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,29-to 2.41 (1H, m), 2,36 (6N, (C), 2,52 (3H, s), 3,52 (2H, d, J=1.2 Hz), 4,07 (2H, d, J=7,4 Hz), 7,31 (2H, d, J=8.6 Hz), to 7.77 (2H, d, J=8,4 Hz), 7,79 (1H, s).

Example 61

Getting hydrochloride 4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 82.3 per cent).

Melting point: 216,8-218,4°

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.8 Hz), 2,23-of 2.36 (1H, m), of 2.53 (3H, s), 2,82 (6N, (C), of 4.05 (2H, d, J=7,1 Hz), 4,27 (2H, s), 7,41 (2H, d, J=8,3 Hz), to 7.84 (2H, d, J=8,3 Hz), 8,42 (1H, s).

IR (KBr) cm-1: 3485, 1740, 1684, 1253, 856, 577.

Mass m/z: 331 (M+).

Example 162

Getting 2-isobutyl-6-[4-(methylthio)phenyl]-4-propargylamine-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and propargylamine obtaining specified in the title compound as a yellow oil (yield: 52.2 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), and 2.26 (1H, t, J=2.3 Hz), 2,29-to 2.40 (1H, m), 2,52 (3H, s), 3,51 (2H, d, J=2.4 Hz), 3,90 (2H, s)4,07 (2H, d, J=7,4 Hz), 7,31 (2H, d, J=8,4 Hz), of 7.70 (1H, s), 7,73 (2H, d, J=8,4 Hz).

Example 163

Obtain hydrochloride of 2-isobutyl-6-[4-(methylthio)phenyl]-4-propargylamine-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-isobutyl-6-[4-(methylthio)phenyl]-4-propargyl isomethyl-2H-pyridazin-3-one to obtain specified in the title compounds as white solids (yield: 73.6 per cent).

Melting point: 197,5-198,4°

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.6 Hz), 2,23-of 2.36 (1H, m), of 2.53 (3H, s), 3,48 (1H, t, J=2.4 Hz), 3,95 (2H, d, J=2.4 Hz), a 4.03 (2H, d, J=7,1 Hz), 4,17 (2H, s), 7,41 (2H, d, J=8,3 Hz), 7,82 (2H, d, J=8.6 Hz), of 8.28 (1H, s).

IR (KBr) cm-1: 3447, 3207, 2958, 2122, 1651, 1607, 1441, 1093.

Mass m/z: 341 (M+).

Example 164

Getting 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

1) preparation of 2-cyclopropylmethyl-4-methanesulfonate-methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

To a solution of 2-cyclopropylmethyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (300 mg, 0.79, which mmol) in methylene chloride (10 ml) was added dropwise at -20°With a solution of 3-chloroperbenzoic acid (204 mg, 1.12 mmol) in methylene chloride (2 ml) and at the same temperature and the mixture was stirred for 30 minutes To the reaction mixture was added 10% Hydrosulphite solution of the sodium and then the mixture was extracted with chloroform. The extract was sequentially washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was recrystallized from a mixture of chloroform-hexane to obtain specified in the title compounds as a colorless crystalline powder (139 mg, 44.5 percent).

13) δ: of 0.48 to 0.63 (4H, m), 1,37 of 1.46 (1H, m), 2,77 (3H, s)3,18 (3H, s), 4,14 (2H, d, J=7,3 Hz), and 5.30 (2H, d, J=1.4 Hz), 7,76 (2H, d, J=8.6 Hz), to 7.84 (1H, t, J=1.4 Hz), 7,98 (2H, d, J=8,8 Hz).

Mass m/z: 396 (M+).

2) Getting 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropyl-4-methanesulfonylaminoethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 60.6 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,46-0,60 (4H, m), 1,37-1,49 (1H, m), of 2.34 (3H, s)to 2.54 (4H, usher.), of 2.64 (4H, usher.), 2,78 (3H, s), 3,61 (2H, s), 4,13 (2H, d, J=7,2 Hz), of 7.75 (2H, d, J=8,2 Hz), to 7.84 (1H, s), to 7.99 (2H, d, J=8,2 Hz).

Example 165

Getting dihydrochloride 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 64.3 per cent).

Melting point: 80°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,41-0,57 (4H, m), 1.30 and of 1.41 (1H, m), was 2.76 (3H, s), 2,77 (3H, s), 3,01 (4H, usher.), of 3.31 (4H, usher.), of 3.77 (2H, s)4,08 (2H, d, J=6.8 Hz), 7,80 (2H, d, J=8,3 Hz), 8,05-of 8.09 (3H, m).

IR (KBr) cm-1: 3430, 3005, 1652, 1607, 1458, 101, 1010, 838.

Mass m/z: 400 (M+).

Example 166

Getting 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

1) preparation of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 164 (1)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 54,3%).

1H NMR (400 MHz, CDCl3) δ: 1,00 (6N, d, J=6.8 Hz), 2,29-to 2.41 (1H, m), 2,77 (3H, s)3,18 (3H, s), 4,11 (2H, d, J=7,3 Hz), from 5.29 (2H, d, J=1.5 Hz), 7,76 (2H, d, J=8,8 Hz), 7,83 (1H, t, J=1.2 Hz), 7,98 (2H, d, J=8.6 Hz).

Mass m/z: 398 (M+).

2) Getting 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 61.8 percent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,30-to 2.41 (1H, m), of 2.34 (3H, s)to 2.54 (4H, usher.), of 2.64 (4H, usher.), 2,77 (3H, s), of 3.60 (2H, s), 4,10 (2H, d, J=7,4 Hz), of 7.75 (2H, d, J=8,2 Hz), 7,82 (1H, s), to 7.99 (2H, d, J=8,2 Hz).

Example 167

Getting dihydrochloride 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one/p>

Following the procedure of example 4 was subjected to the interaction of 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulfinyl)-phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 76,1%).

Melting point: 224,5-229,1°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.6 Hz), 2,22 to 2.35 (1H, m), was 2.76 (3H, s), 2,77 (3H, s), 3,14 (4H, usher.), the 3.35 (4H, usher.), a 3.87 (2H, s), Android 4.04 (2H, d, J=7,1 Hz), 7,80 (2H, d, J=8,3 Hz), 8,07 (2H, d, J=8,3 Hz), 8,18 (1H, s).

IR (KBr) cm-1: 3426, 2960, 1656, 1608, 1459, 1400, 1044, 1011.

Mass m/z: 402 (M+).

Example 168

Getting 4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 46,2%).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,30 is 2.43 (1H, m), 2,38 (6N, (C), was 2.76 (3H, s), of 3.54 (2H, s), 4,10 (2H, d, J=7,4 Hz), 7,74 (2H, d, J=8,2 Hz), 7,87 (1H, s), 8,02 (2H, d, J=8,2 Hz).

Example 169

Getting hydrochloride 4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfinyl)-phenyl]-2H-pyridazin-3-one to obtain specified in the header of the is placed in the form of a colorless crystalline powder (yield: 77.4 percent).

Melting point: 204,2-206,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,97 (6N, d, J=6.6 Hz), 2,24-of 2.36 (1H, m), 2,78 (3H, s), 2,83 (6N, C)4,07 (2H, d, J=7,1 Hz), 4,28 (2H, s), of 7.82 (2H, d, J=8,3 Hz), of 8.09 (2H, d, J=8,3 Hz), 8,49 (1H, s).

IR (KBr)cm-1: 3438, 2961, 1652, 1607, 1467, 1400, 1047.

Mass m/z: 347 (M+).

Example 170

Getting 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

1) preparation of 2-cyclopropylmethyl-4-methanesulfonylaminoethyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

To a solution of 2-cyclopropylmethyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (226 mg, 0.59 mmol) in methylene chloride (10 ml) was added dropwise at -20°With a solution of 3-chloroperbenzoic acid (410 mg, of 2.38 mmol) in methylene chloride (2 ml) and at the same temperature and the mixture was stirred for 30 minutes To the reaction mixture were added 10% aqueous Hydrosulphite solution of the sodium and then the mixture was extracted with chloroform. The extract was sequentially washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was recrystallized from a mixture of chloroform-hexane to obtain specified in the title compounds as a colorless crystalline powder (209 mg, 85,3%).

1H NMR (400 MHz, CDCl3/sub> ) δ: 0,46-0,63 (4H, m), 1,37 of 1.46 (1H, m), 3,10 (3H, s)3,18 (3H, s), 4,20 (2H, d, J=7,3 Hz), 5,31 (2H, d, J=1.2 Hz), 7,86 (1H, t, J=1.2 Hz), 8,02 (2H, d, J=8,8 Hz), of 8.06 (2H, d, J=9.0 Hz).

Mass m/z: 412 (M+).

2) Getting 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropyl-4-methanesulfonylaminoethyl-6-[4-methylsulphonyl)-phenyl]-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 80.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,46-0,61 (4H, m), to 1.38 to 1.48 (1H, m), of 2.34 (3H, s)to 2.54 (4H, usher.), of 2.64 (4H, usher.), 3,10 (3H, s), 3,61 (2H, d, J=1.2 Hz), 4,13 (2H, d, J=7,1 Hz), the 7.85 (1H, t, J=1.2 Hz), 8,03 (2H, d, J=9.0 Hz), with 8.05 (2H, d, J=9.0 Hz).

Example 171

Getting dihydrochloride 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 76.8%of all).

Melting point: 209,0-211,4°

1H NMR (400 MHz, DMSO-d6) δ: 0,41-0,46 (2H, m), 0,52-0,57 (2H, m), 1,31-of 1.41 (1H, m), 2,77 (3H, s), 3.04 from (4H, usher.), is 3.21 (3H, s), and 3.31 (4H, usher.), of 3.80 (2H, s), 4.09 to (2H, d, J=7,1 Hz), of 8.04 (2H, d, J=8,3 Hz)to 8.12 (1H, s)to 8.14 (2H, d, J=8,3 Hz).

IR (KBr) cm -1: 3434, 3012, 1652, 1596, 1458, 1402, 1302, 1150.

Mass m/z: 416 (M+).

Example 172

Getting 2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-4-methanesulfonylaminoethyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compound as a yellow oil (yield: 65.6 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,45-0,62 (4H, m), 1,39-1,49 (1H, m), 2,38 (6N, C)to 3.09 (3H, s), 3,55 (2H, s), 4,14 (2H, d, J=7,2 Hz), 7,89 (1H, s), 8,02 (2H, d, J=8,4 Hz), of 8.06 (2H, d, J=8.6 Hz).

Example 173

Getting hydrochloride 2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylsulphonyl)-phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 63.4 per cent).

Melting point: 239,5-240,7°

1H NMR (400 MHz, DMSO-d6) δ: 0,43-0,59 (4H, m), 1,33 was 1.43 (1H, m), 2,83 (6N, (C), 3,23 (3H, s), 4,13 (2H, d, J=7,1 Hz), the 4.29 (2H, s), of 8.06 (2H, d, J=7.8 Hz), 8,17 (2H, d, J=8,3 Hz), to 8.57 (1H, s).

IR (KBr) cm-1: 3447, 2674, 1646, 1608, 1596, 1306, 1150, 777.

Mass m/z: 361 (M+).

Example 174

Getting 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-[4-(methyl-sulfonyl)the dryer is l]-2H-pyridazin-3-one

1) preparation of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the method of example 170 (1)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 97.8 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,29-to 2.41 (1H, m), 3,10 (3H, s)3,18 (3H, s), of 4.12 (2H, d, J=7,3 Hz), from 5.29 (2H, d, J=1.2 Hz), the 7.85 (1H, t, J=1.4 Hz), 8,02 (2H, d, J=8,8 Hz), with 8.05 (2H, d, J=8,8 Hz).

Mass m/z: 414 (M+).

2) Obtain 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 75,9%).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 1,47 (N, C), 2,29-to 2.41 (1H, m), of 2.54 (4H, usher.), to 3.09 (3H, s), 3,51 (4H, usher.), of 3.60 (2H, s), 4,11 (2H, d, J=7,2 Hz), 7,86 (1H, s), 8,02 (2H, d, J=8,8 Hz), with 8.05 (2H, d, J=8,8 Hz).

Example 175

Getting dihydrochloride 2-isobutyl-6-[4-(methylsulphonyl)phenyl]-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 2 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-isobutyl-6-[4-(METI sulfonyl)phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 88,2%).

Melting point: 222,4-224,2°

1H NMR (400 MHz, DMSO-d6) δ: 0,96 (6N, d, J=6.8 Hz), 2,22 to 2.35 (1H, m), 3,06 (4H, usher.), is 3.21 (3H, s), or 3.28 (4H, t, J=5,2 Hz), a 3.87 (2H, s), of 4.05 (2H, d, J=7,1 Hz), of 8.04 (2H, d, J=8.6 Hz), 8,14 (2H, d, J=8,3 Hz), by 8.22 (1H, s).

IR (KBr) cm-1: 3421, 2957, 1656, 1611, 1597, 1305, 1149, 961.

Mass m/z: 404 (M+).

Example 176

Getting 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 88.5 percent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.8 Hz), 2,28-to 2.40 (1H, m), is 2.37 (3H, s), 2,53 (4H, usher.), 2,63 (4H, usher.), 3,10 (3H, s), of 3.60 (2H, s), 4,10 (2H, d, J=7,3 Hz), to 7.84 (1H, s), 8,02 (2H, d, J=9.0 Hz), with 8.05 (2H, d, J=8,8 Hz).

Example 177

Getting dihydrochloride 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-isobutyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylsulphonyl)-phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 62,0%).

Melting point: 224,5-228,0°

1H NMR (400 MHz, DMSO-d6) δ: 0,95 (6N, d, J=6.8 Hz), 2,23 to 2.35 (1H, m), was 2.76 (3H, s), and 3.8 (4H, user.), is 3.21 (3H, s), 3,32 (4H, usher.), a 3.83 (2H, s), of 4.05 (2H, d, J=7,1 Hz), of 8.04 (2H, d, J=8,3 Hz), 8,13 (2H, d, J=8.5 Hz), 8,15 (1H, s).

IR (KBr) cm-1: 3447, 2958, 1652, 1610, 1596, 1319, 1152, 955.

Mass m/z: 418 (M+).

Example 178

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 51.1 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,98 (6N, d, J=6.6 Hz), 2,28-to 2.40 (1H, m), 2,73 (4H, t, J=4,8 Hz), is 3.08 (3H, s), 3,68 (4H, t, J=4.9 Hz), to 3.73 (2H, s), 4,11 (2H, d, J=7,4 Hz), to 7.93 (1H, s), of 8.00 (2H, d, J=8.6 Hz), with 8.05 (2H, d, J=8,8 Hz).

Mass m/z: 392 (M+-CH2OH).

Example 179

Getting 4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-isobutyl-4-methanesulfonylaminoethyl-6-[4-(methylsulphonyl)phenyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 82.1 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,99 (6N, d, J=6.6 Hz), 2,30-to 2.41 (1H, m), 2,37 (6N, C)to 3.09 (3H, s), 3,52 (2H, s), 4,11 (2H, d, J=7,2 Hz), 7,86 (1H, s), 8,02 (2H, d, J=8,8 Hz), with 8.05 (2H, d, J=8,8 Hz).

Example 180

Getting hydrochloride 4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulphonyl)phenyl]-2H-PIR is dazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulphonyl)-phenyl]-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 58.6%of).

Melting point: 221,4-223,3°

1H NMR (400 MHz, DMSO-d6) δ: 0,97 (6N, d, J=6.6 Hz), 2,25-of 2.36 (1H, m), 2,82 (6N, (C), up 3.22 (3H, s)4,08 (2H, d, J=7,3 Hz), 4,28 (2H, s), of 8.06 (2H, d, J=8,3 Hz), 8,15 (2H, d, J=8.5 Hz), 8,55 (1H, s).

IR (KBr) cm-1: 3447, 2963, 1653, 1609, 1597, 1307, 1152, 777.

Mass m/z: 363 (M+).

Example 181

Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-pyrrolidinyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and pyrrolidine obtaining specified in the title compound as a yellow oil (yield: 75,9%).

1H NMR (400 MHz, CDCl3) δ: 0,44-0,61 (4H, m)of 1.42 (1H, m), 1.85 to a 2.00 (4H, m), 2.70 height is 3.00 (4H, m), 3,83 (2H, users), of 3.94 (3H, s), 4,10 (2H, d, J=7,3 Hz), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,60 (1H, d, J=8.5 Hz), the 7.65 (1H, DD, J=to 8.5, 2.0 Hz), 8,00 ( 1H, users).

IR (Pure) cm-1: 1652, 1608, 1523, 1438, 1286, 758.

Mass m/z: 357 (M+).

Example 182

Getting 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and cyclopentylmethyl {J. Org. Chem.,36, 3103 (1971)} with obtaining specified in the connection header in the form of yellow needle crystals (yield: 72,0%).

Melting point: 56-66°

1H NMR (400 MHz, CDCl3) δ: 1,30-1,45 (2H, m), 1,53-of 1.65 (2H, m)of 1.65 and 1.80 (4H, m), to 2.57 (1H, m), of 3.95 (3H, s), 3,98 (3H, s), 4,24 (2H, d, J=7.8 Hz), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), to 7.50 (1H, d, J=8,8 Hz), to 7.61 (1H, d, J=10,2 Hz), 8,19 (1H, s).

2) Getting 4-carboxy-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow powder (yield: 71,1%).

Melting point: 159-161°

1H NMR (400 MHz, CDCl3) δ: 1,33-to 1.45 (2H, m), 1,58-of 1.65 (2H, m), 1,68-to 1.82 (4H, m), to 2.57 (1H, m), of 3.97 (3H, s), 4,32 (2H, d, J=7,6 Hz), 7,06 (1H, DD, J=8.5 a, 8.5 Hz), 7,56 (1H, d, J=8.5 Hz), to 7.68 (1H, DD, J=12,2, 2.0 Hz), 8,61 (1H, s).

3) Getting 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compound as a yellow powder (yield: 47,3%).

Temperature PL is the exercise: 130-133° With

1H NMR (400 MHz, CDCl3) δ: 1,30-of 1.42 (2H, m), 1,50-of 1.62 (2H, m), 1,62 and 1.80 (4H, m), of 2.54 (1H, m), of 3.95 (3H, s), 4,19 (2H, d, J=7,6 Hz), 4,71 (2H, s), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,51 (1H, d, J=8.5 Hz), a 7.62 (1H, DD, J=12,8, 1.5 Hz), 7,63 (1H, s).

4) to Obtain 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow powder (yield: 75.3%of).

Melting point: 108-116°

1H NMR (400 MHz, CDCl3) δ: 1,25-1,32 (2H, m), 1.32 to to 1.45 (2H, m), 1,65-to 1.77 (4H, m), of 2.54 (1H, m), 3,17 (3H, s), of 3.95 (3H, s), 4,19 (2H, d, J=7,6 Hz), at 5.27 (2H, s), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), to 7.50 (1H, d, J=8.5 Hz), 7,62 (1H, DD, J=12,2, 2.2 Hz), 7,74 (1H, s).

5) Getting 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 61.4 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,32-of 1.42 (2H, m), 1,50-1,60 (2H, m)of 1.65 and 1.80 (4H, m), 2,38, 2,40 (each s, total 3H), of 2.54 (1H, m), 2,60-of 2.75 (8H, m)and 3.59 (2H, s), of 3.95 (3H, s), 4,18 (2H, d, J=7,6 Hz),? 7.04 baby mortality (1H, DD, J=8.5 a, 8.5 Hz), rate of 7.54 (1H, d, J=8.5 Hz), to 7.61 (1H, DD, J=8,5 and 2.2 Hz), 7,72 (1H, s).

IR (Pure) cm-1 : 1652, 1608, 1523, 1439, 1286, 760.

Mass m/z: 414 (M+).

Example 183

Getting dihydrochloride 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as a pale brown crystalline powder (yield: 59.6 per cent).

Melting point: 234-236°C (decomp.)

1H NMR (400 MHz, DMSO-d6) δ: 1,28-of 1.40 (2H, m), 1,48-of 1.56 (2H, m), 1.60-to of 1.73 (4H, m), 2,46 (1H, m), 2,82 (3H, s), 3,50-3,75 (10H, m), 3,91 (3H, s), 4,10 (2H, d, J=7,6 Hz), 7,31 (1H, DD, J=8,8, 8,8 Hz), 7.68 per-7,76 (2H, m), 8,25 (1H, s).

IR (KBr) cm-1: 1652, 1606, 1523, 1439, 1292, 764.

Example 184

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 54,9%).

1H NMR (400 MHz, CDCl3) δ: 1,30-1,45 (2H, m), 1,50-of 1.62 (2H, m), 1,62 and 1.80 (4H, m), 2,53 (1H, m), 2,75-2,90 (4H, m), 3,70 of 3.75 (4H, m), 3,80-of 3.85 (2H, m), of 3.94 (3H, s), 4,20 (2H, d, J=7,6 Hz), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,56 (1H, d, J=8.5 Hz), 7,63 (1H, DD, J=8,5, 2.0 Hz), the 7.65 (1H, m).

IR (Pure) cm-1: 1648, 1598, 1523, 149, 1267, 728.

Mass m/z: 383 (M+-2H2O).

Example 185

Getting 2-cyclopentylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compound as a yellow oil (yield: 63.7 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,30-1,45 (2H, m), 1,50-to 1.63 (2H, m), 1,63 and 1.80 (4H, m), 2,43 (6N, C)to 2.55 (1H, m), 3,61 (2H, s), of 3.94 (3H, s), 4,19 (2H, d, J=7,6 Hz), 7,20 (1H, d, J=8.5 a, 8.5 Hz), 7,58 (1H, d, J=8.5 Hz), 7,65 (1H, DD, J=8,5 and 2.2 Hz), to $ 7.91 (1H, users).

IR (Pure) cm-1: 1652, 1608, 1523, 1438, 1288, 762.

Mass m/z: 359 (M+).

Example 186

Getting 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 78.8 per cent).

1H NMR (400 MHz,CDCl3) δ: 1,35 was 1.43 (2H, m), 1,47 (N, C), 1,55-1,60 (2H, m)of 1.65 and 1.75 (4H, m), 2,45-2,60 (5H, m), 3,45-3,55 (4H, m), of 3.95 (3H, s), 4,18 (2H, d, J=7,6 Hz), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,52 (1H, m), 762 (1H, d, J=12,4 Hz), 7,74 (1H, m).

2) Getting 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 20 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 88,0%).

1H NMR (400 MHz, CDCl3) δ: 1,33 was 1.43 (2H, m), 1,50-of 1.62 (2H, m), 1,62 and 1.80 (4H, m)to 2.55 (1H, m), 2.57 m) 2.63 in (4H, m)3,00-3,02 (4H, m), of 3.56 (2H, users), of 3.95 (3H, s), 4,18 (2H, d, J=7,6 Hz),? 7.04 baby mortality (1H, DD, J=8.5 a, 8.5 Hz), 7,52 (1H, d, J=8.5 Hz), a 7.62 (1H, DD, J=8,5 and 2.2 Hz), 7,73 (1H, s).

IR (Pure) cm-1: 1652, 1608, 1523, 1439, 1287, 761.

Mass m/z: 400 (M+).

Example 187

Getting 4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 24 (1), was subjected to interaction of 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain the crude product. The crude product was subjected to further interaction without purification in accordance with the procedure of example 24 (2) obtaining specified in the title compound as a yellow oil (yield: 53.7 percent).

1H NMR (400 MHz, CDCl3) δ: 1,30-1,45 (2H, m), 1,50-to 1.63 (2H, m), 1,63 and 1.80 (4H, m), of 2.54 (1H, m), 3,91 (2H, s), 3,93 (3H, s), 4,17 (2H, d, J=7,6 Hz), 7,01 (1H, DD, J=8.5 a, 8.5 Hz), 7,52 (1H, d, J=8.5 Hz), a 7.62 (1H, DD, J=an 8.5 and 2.2 Hz), 7,71 (1H, users).

IR (Chi is th) cm -1: 3376, 1649, 1606, 1523, 1439, 1285, 761.

Mass m/z: 331 (M+).

Example 188

Getting hydrochloride 4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 59,0%).

Melting point: 193-196°

1H NMR (400 MHz, DMSO-d6) δ: 1,29-of 1.40 (2H, m), 1,45-of 1.57 (2H, m), 1,60-1,70 (4H, m), of 2.45 (1H, m), 3,91 (3H, s), of 4.00 (2H, s), of 4.12 (2H, d, J=7,6 Hz), 7,34 (1H, DD, J=8.5 a, 8.5 Hz), 7,69-7,72 (2H, m), of 8.47 (1H, users).

IR (KBr) cm-1: 3436, 1656, 1617, 1521, 1438, 1295, 763.

Example 189

Obtaining 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-tormentilla obtaining specified in the connection header in the form of a yellow crystalline powder (yield: 86.6 per cent).

1H NMR (400 MHz, CDCl3) δ: of 3.95 (3H, s), of 3.97 (3H, s), of 5.39 (2H, s), 7,00-7,06 (3H, m), of 7.48-7,63 (4H, m), 8,19 (1H, s).

2) Getting 4-carboxy-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the methodology in the EPA 1(7), subjected to the interaction of 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow powder (yield: 97.7 percent).

Melting point: 222-224°

1H NMR (400 MHz, CDCl3) δ: of 3.97 (3H, s), vs. 5.47 (2H, s), 7.03 is-7,10 (3H, m), 7,49-7,56 (3H, m), to 7.67 (1H, DD, J=12.1 is of 2.2 Hz), at 8.60 (1H, s).

3) Obtaining 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compound as a yellow powder (yield: 27,0%).

Melting point: 127-130°

1H NMR (400 MHz, CDCl3) δ: of 3.95 (3H, s), 4,79 (2H, d, J=1.5 Hz), are 5.36 (2H, s), 6,98-7,05 (3H, m), 7,46-7,52 (3H, m), to 7.61 (1H, DD, J=12,2, 2.2 Hz), the 7.65 (1H, s).

4) to Obtain 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow powder (yield: 49,4%).

Melting point: 125-133°

1H NMR (400 MHz, CDCl3) δ: 3.15 in (3H, s), of 3.95 (3H, in), 5.25 (2H, d, J=1.2 Hz), to 5.35 (2H, s), 7,00-7,06 (3H, m), 7,45-of 7.55 (3H, m), to 7.61 (1H, DD, J=12,4, 2.2 Hz), 7,74 (1H, s).

5) Obtaining 2-(4-terbisil)-6-(3-FPO is-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the connection header in the form of a brown crystalline powder (yield: 45.8 per cent).

Melting point: 112-113°

1H NMR (400 MHz, CDCl3) δ: 2,39 (3H, s), 2,60-2,90 (8H, m), of 3.60 (2H, s), of 3.95 (3H, s), of 5.34 (2H, s), 6,99-7,06 (3H, m), 7,47-7,51 (3H, m), to 7.59 (1H, DD, J=12,4, 2.0 Hz), 7,71 (1H, s).

IR (KBr) cm-1: 1651, 1608, 1518, 1439, 1289, 764.

Mass m/z: 440 (M+).

Example 190

Getting 4-dimethylaminomethyl-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 60.8 per cent).

Melting point: 127-129°

1H NMR (400 MHz, CDCl3) δ: 2,41 (6N, C)to 3.58 (2H, s), of 3.94 (3H, s), to 5.35 (2H, s), 6,98-7,05 (3H, m), 7,46-7,52 (2H, m), 7,56 (1H, d, J=8,8 Hz), to 7.64 (1H, DD, J=12,4, 2.2 Hz), of 7.90 (1H, users).

IR (KBr) cm-1: 1652, 1612, 1519, 1439, 1291, 763.

Mass m/z: 385 (M+).

Example 191

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 66,1%).

1H NMR (400 MHz, CDCl3) δ: 2,70 of 2.92 (4H, m), 3,70-3,85 (6N, m), 3,93 (3H, s), to 5.35 (2H, s), 6,99? 7.04 baby mortality (3H, m), 7,45 is 7.50 (2H, m), 7,55 (1H, d, J=8,3 Hz), 7,63 (1H, DD, J=12,4, 2.0 Hz), of 7.90 (1H, m).

IR (Pure) cm-1: 1652, 1606, 1520, 1435, 1281, 762.

Mass m/z: 385 (M+-CH2OH).

Example 192

Obtaining 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 78.8 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,46 (N, C), 1,55-1,65 (4H, m), 3,40-of 3.60 (4H, m), of 3.95 (3H, s), of 5.34 (2H, s), of 6.96-7,05 (3H, m), 7,47-to 7.50 (3H, m), 7,41 (1H, d, J=12,4 Hz), 7,74 (1H, users).

2) Obtaining 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 20 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 63.4 per cent).

Melting point: 142-143°

1H NMR (400 MHz, CDCl3) δ: 2,50-2,60 (4H, m), 2,96-to 3.02 (4H, m) of 3.54 (2H, d, J=1.2 Hz), of 3.95 (3H, s), of 5.34 (2H, s), 6,98-7,06 (3H, m), 7,46-7,53 (3H, m), to 7.61 (1H, DD, J=12,5 and 2.2 Hz), 7,74 (1H, users).

IR (KBr) cm-1: 1652, 1609, 1523, 1437, 1290, 762.

Mass m/z: 426 (M+).

Example 193

Getting dihydrochloride of 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one to obtain specified in the title compounds as a colorless crystalline powder (yield: 76,9%).

Melting point: 153-156°

1H NMR (400 MHz, DMSO-d6) δ: 3,30-3,75 (10H, m), 3,90 (3H, s)5,33 (2H, s), 7,15-7,21 (2H, m), 7,30 (1H, m), 7,43-7,49 (2H, m), 7,69 for 7.78 (3H, m).

IR (KBr) cm-1: 1660, 1609, 1524, 1439, 1292, 766.

Example 194

Getting 4-aminomethyl-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 24 (1), was subjected to interaction of 2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain the crude product. The crude product was subjected to further interaction without purification in accordance with the procedure of example 24 (2) obtaining specified in the title compounds as a pale brown crystalline powder (yield: 50.4 percent).

Melting point: 145-149°

1H NMR (400 MHz, CDCl3) δ: to 3.92 (3H, s), of 3.94 (2H), 5,31 (2H, s), 6,95-7,03 (3H, m), 7,40-7,52 (3H, m), 7,60 (1H, DD, J=12,5 and 2.2 Hz), of 7.75 (1H, users).

IR (KBr) cm-1: 3391, 1648, 1606, 1519, 1437, 1292, 761.

Mass m/z: 357 (M+).

Example 195

Getting hydrochloride 4-aminomethyl-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-aminomethyl-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 72,5%).

Melting point: 210-214°

1H NMR (400 MHz, DMSO-d6) δ: 3,91 (3H, s)to 4.01 (2H, s), to 5.35 (2H, s), 7,16-7,21 (2H, m), 7,34 (1H, DD, J=8,8, 8,8 Hz), 7,45-7,49 (2H, m), 7.68 per for 7.78 (2H, m), 8,29 (1H, s).

IR (KBr) cm-1: 3429, 1653, 1612, 1522, 1439, 1292, 764.

Example 196

Getting 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and mesylate derived 3-(4-forfinal)-1-propanol {J. Med. Chem., 19, 461 (1976)} with obtaining specified in the title compound as a yellow oil (yield: 90.1%of). Mesylate derivative was obtained in accordance with the procedure of example 1(9).

1H NMR (400 MHz, CDCl3) δ: 2,16-and 2.26 (2 is, m)a 2.71 (2H, t, J=7,3 Hz), of 3.95 (3H, s), 3,98 (3H, s), 4,32 (2H, t, J=7,3 Hz), 6,93-7,06 (3H, m), 7,14-to 7.18 (2H, m), 7,49 (1H, m), 7,60 (1H, DD, J=13,2, 2.2 Hz), 8,17 (1H, s).

2) Getting 4-carboxy-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow powder (yield: 89.2%of).

Melting point: 185-187°

1H NMR (400 MHz,CDCl3) δ: 2,20-of 2.30 (2H, m), is 2.74 (2H, t, J=7,3 Hz), of 3.97 (3H, s), and 4.40 (2H, t, J=7,3 Hz), 6,94-7,17 (5H, m), 7,55 (1H, d, J=8.5 Hz), 7,66 (1H, DD, J=12,2, 2.2 Hz), 8,58 (1H, s).

3) Obtain 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellow powder (yield: 37,0%).

Melting point: 130-133°

1H NMR (400 MHz, CDCl3) δ: 2,15-2,22 (2H, m), a 2.71 (2H, t, J=7,3 Hz), of 3.95 (3H, s), 4,27 (2H, t, J=7,3 Hz), 4,70 (2H, d, J=1.2 Hz), 6,93-7,06 (3H, m), 7,14-to 7.18 (2H, m)to 7.50 (1H, d, J=8,8 Hz), to 7.61 (1H, DD, J=12,7, 2,2 Hz), 7,63 (1H, s).

4) to Obtain 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 6-(3-fluoro-4-netoxygen the l)-2-[3-(4-forfinal)propyl]-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow powder (yield: 92.3 per cent).

Melting point: wing 112-116°

1H NMR (400 MHz, CDCl3) δ: 2,15 was 2.25 (2H, m), a 2.71 (2H, t, J=7,3 Hz), 3,17 (3H, s), of 3.95 (3H, s), 4,27 (2H, t, J=7,3 Hz in), 5.25 (2H, d, J=1.2 Hz), 6,93-7,05 (3H, m), 7,14-to 7.18 (2H, m), 7,49 (1H, d, J=8.5 Hz), to 7.61 (1H, DD, J=13,4, 2.0 Hz), 7,72 (1H, s).

5) Obtain 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 79.3 percent).

1H NMR (400 MHz, CDCl3) δ: 2,15 was 2.25 (2H, m), is 2.41 (3H, s), 2,60-2,75 (10H, m)to 3.58 (2H, in), 3.75 (3H, s), 4,27 (2H, t, J=7,3 Hz), 6,92-7,06 (3H, m), 7,14-to 7.18 (2H, m), 7,51 (1H, d, J=8.5 Hz), 7,60 (1H, DD, J=12,4, 2.0 Hz), of 7.69 (1H, s).

IR (Pure) cm-1: 1652, 1608, 1511, 1439, 1284, 758.

Mass m/z: 468 (M+).

Example 197

Getting 4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 61.8 percent).

Melting point: 97-100°

1H NMR (400 MHz, CDCl3) δ: 2,15 was 2.25 (2H, m), 2,43 (6N, (C), a 2.71 (2H, t, J=73 Hz), of 3.60 (2H, s), of 3.94 (3H, s), 4,27 (2H, t, J=7,3 Hz), 6,93-7,05 (3H, m), 7,15-to 7.18 (2H, m), EUR 7.57 (1H, d, J=8.5 Hz), to 7.64 (1H, DD, J=12,6, 2.2 Hz), of 7.90 (1H, users).

IR (KBr) cm-1: 1653, 1611, 1510, 1436, 1296, 763.

Mass m/z: 413 (M+).

Example 198

Getting 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 67.3 per cent).

1H NMR (400 MHz, CDCl3) δ: 2,14-2,22 (2H, m), 2,70 (2H, t, J=7,6 Hz), of 2,75 2,95 (4H, m), 3,70-3,80 (6N, m), of 3.94 (3H, s), 4,28 (2H, t, J=7,6 Hz), 6,93-7,05 (3H, m), 7,15-to 7.18 (2H, m), 7,56 (1H, m), 7,63 (1H, m), a 7.85 (1H, m).

IR (Pure) cm-1: 1645, 1601, 1510, 1439, 1277, 763.

Mass m/z: 473 (M+).

Example 199

Getting 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-(1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 72.6 per cent).

1H NMR (400 MHz, CCl 3) δ: 1,40 (N, C)2,07-of 2.16 (2H, m), 2.40 a-2,50 (4H, m), 2.63 in (2H, t, J=7,6 Hz), 3,36-of 3.46 (4H, m) of 3.48 (2H, users), 3,88 (3H, s), 4,20 (2H, t, J=7,6 Hz), 6,84-6,98 (3H, m), 7,07-7,11 (2H, m), the 7.43 (1H, d, J=8.1 Hz), 7,53 (1H, d, J=12,4 Hz), the 7.65 (1H, users).

2) Obtain 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-(1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 20 was subjected to the interaction of 4-(4-tert-butoxycarbonyl-1-piperazinil)methyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 97.2 per cent).

1H NMR (400 MHz, CDCl3) δ: 2,12-2,22 (2H, m), 2,50-2,60 (4H, m), a 2.71 (2H, t, J=7,3 Hz), 2,92-to 3.02 (4H, m), 3,53 (2H, s), of 3.95 (3H, s), 4,27 (2H, t, J=7,3 Hz), 6,91-7,06 (3H, m), 7,15-to 7.18 (2H, m), 7,51 (1H, d, J=8,8 Hz), to 7.61 (1H, DD, J=12,5 and 2.2 Hz), 7,73 (1H, s).

IR (Pure) cm-1: 1650, 1607, 1510, 1439, 1275, 758.

Mass m/z: 454 (M+).

Example 200

Getting 4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one

Following the procedure of example 24 (1), was subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain the crude product. The crude product was subjected to interaction without purification in accordance with the procedure of example 24 (2) obtaining specified in the title compounds as a pale yellow crystalline powder (yield: 41.7 per cent).

Melting point: 2-84° With

1H NMR (400 MHz, CDCl3) δ: 2,12-2,22 (2H, m), 2,70 (2H, t, J=7,6 Hz)to 3.89 (2H, s), of 3.94 (3H, s), 4,27 (2H, t, J=7,6 Hz), 6,93? 7.04 baby mortality (3H, m), 7,15-to 7.18 (2H, m), 7,51 (1H, d, J=7,3 Hz), to 7.61 (1H, DD, J=12,4, 2.0 Hz), to 7.67 (1H with).

IR (KBr) cm-1: 3366, 1651, 1605, 1509, 1436, 1273, 764.

Mass m/z: 385 (M+).

Example 201

Getting hydrochloride 4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 73.1 per cent).

Melting point: 160-165°

1H NMR (400 MHz, DMSO-d6) δ: 2,05-of 2.15 (2H, m)to 2.66 (2H, t, J=7,3 Hz)to 3.92 (3H, s)to 3.99 (2H, s), 4,19 (2H, t, J=7,3 Hz), 7,05 for 7.12 (2H, m), 7.23 percent-7,30 (2H, m), 7,34 (1H, DD, J=8,8, 8,8 Hz), 7,66-7,76 (2H, m), of 8.25 (1H, s).

IR (KBr) cm-1: 3430, 1652, 1515, 1436, 1269, 763.

Example 202

Obtaining 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzylchloride obtaining specified in the connection header in the form of yellow needle crystals (yield: 97,6%).

The temperature of prawle the Oia: 170,5-RUB 171.1° With

1H NMR (400 MHz, CDCl3) δ: of 3.95 (3H, s)to 3.99 (3H, s)5,38 (2H, s), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,31 (2H, d, J=8.5 Hz), 7,47 (2H, d, J=8.5 Hz), 7,49 (1H, m), 7,60 (1H, DD, J=12,2, 2.2 Hz), to 8.20 (1H, s)

IR (KBr) cm-1: 1723, 1670, 1526, 1271, 1128.

Mass m/z: 402 (M+), 404 ( M+).

2) Getting 4-carboxy-2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compounds as a pale yellow crystalline powder (yield: 96,0%).

Melting point: 228,3-229,1°

1H NMR (400 MHz, CDCl3) δ: of 3.97 (3H, s), 5,46 (2H, s), 7,07 (1H, DD, J=8.5 a, 8.5 Hz), 7,35 (2H, d, J=8,3 Hz), 7,46 (2H, d, J=8,3 Hz), 7,55 (1H, d, J=8,4 Hz), to 7.67 (1H, DD, J=12,2, 2.2 Hz), 8,61 (1H, s).

IR (KBr) cm-1: 1745, 1635, 1456, 1447, 1431, 1298, 1273.

Mass m/z: 388 (M+), 390 (M+).

3) Obtaining 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow needle crystals (yield: 20.4 percent).

Melting point: 164,6-165,3°

1H NMR (400 MHz, CDCl3) δ: of 3.94 (3H, s), 4,69 (2H, s), of 5.34 (2H, s), 7,01 (1H, DD, J=8.5 a, 8.5 Hz), 7,30 (2H, d, J=8.5 Hz), 7,42 (2H, d, J=8.5 Hz), 7,50 (1H, m), 7,63 (1H, DD, J=12,4, 2.2 G is), to 7.67 (1H, s).

IR (KBr) cm-1: 3373, 1653, 1610, 1527, 1291, 1135,

Mass m/z: 374 (M+), 376 (M+).

4) to Obtain 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow needle crystals (yield: 81.6 per cent).

Melting point: 156,5-157,4°

1H NMR (400 MHz, CDCl3) δ: 3.15 in (3H, s), of 3.95 (3H, s), with 5.22 (2H, d, J=1.5 Hz), to 5.35 (2H, s), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,31 (2H, d, J=8.5 Hz), 7,42 (2H, d, J=8.5 Hz), 7,49 (1H, m), to 7.61 (1H, DD, J=12,2, 2.2 Hz), 7,75 (1H, s).

IR (KBr) cm-1: 1658, 1616, 1358, 1183, 1017,

5) Obtaining 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compounds as a pale-brown prismatic crystals (yield: 39.5 per cent).

Melting point: 128,7-130,2°

1H NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,52 (4H, users), 2,60 (4H, users), 3,55 (2H, s), of 3.95 (3H, s), of 5.34 (2H, s),? 7.04 baby mortality (1H, DD, J=8.5 a, 8.5 Hz), 7,30 (2H, d, J=8.5 Hz), the 7.43 (2H, d, J=8.5 Hz), 7,51 (1H, m), 7,60 (1H, DD, J=12,4, 2.0 Hz), 7,73 (1H, s).

IR (KBr) cm-1: 1652, 1607, 1524, 1516, 1438, 1288, 1135,

p> Example 203

Obtaining 2-(4-Chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 74.7 per cent).

Melting point: 95,3-96,7°

1H NMR (400 MHz, CDCl3) δ: 2,33 (6N, (C), 3,47 (2H, d, J=1.2 Hz), of 3.94 (3H, s), of 5.34 (2H, s), 7,01 (1H, DD, J=8.5 a, 8.5 Hz), 7,30 (2H, d, J=8.5 Hz), 7,44 (2H, d, J=8.5 Hz), 7,53 (1H, DDD, J=8,5, 2,0, 1.2 Hz), a 7.62 (1H, DD, J=12,4, 2.2 Hz), 7,74 (1H, s).

IR (KBr) cm-1: 1652, 1609, 1524, 1515, 1436, 1289, 1264, 1017,

Mass m/z: 401 (M+), 403 (M+).

Example 204

Obtain hydrochloride of 2-(4-Chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-(4-Chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 59.7 per cent).

Melting point: 193,4-194,7°

1H NMR (400 MHz, CD3OD) δ: 2,96 (6N, (C), of 3.94 (3H, s)to 4.33 (2H, s), 5,43 (2H, s), 7,22 (1H, DD, J=8.5 a, 8.5 Hz), was 7.36 (2H, d, J=8.5 Hz), 7,46 (2H, d, J=8.5 Hz), to 7.67-7,72 (2H, m), to 8.20 (1H, s).

IR (KBr) cm-1: 1655, 1616, 1529, 1327, 1279.

Example 205

Getting 4-aminomethyl-2-(4-shall Lorenzi)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

1) preparation of 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one

Following the procedure of example 24 (1), was subjected to interaction of 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 75.4 per cent).

Melting point: 212,5-213,9°

1H NMR (400 MHz, CDCl3) δ: 3,90 (3H, s), 4,88 (2H, d, J=0,73 Hz), to 5.35 (2H, s), to 6.95 (1H, DD, J=8.5 a, 8.5 Hz), 7,29 (1H, s), 7,31 (2H, d, J=8.5 Hz), was 7.36 (1H, m), 7,44 (2H, d, J=8.5 Hz), 7,47 (1H, DD, J=12,2, 2.0 Hz), 7,76-7,81 (2H, m), 7,89-7,94 (2H, m).

IR (KBr) cm-1: 1773, 1713, 1651, 1610, 1522, 1439, 1419, 1393, 1300.

Mass m/z: 503 (M+), 505 (M+).

2) Getting 4-aminomethyl-2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 24 (2), were subjected to interaction of 2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 48,8%).

Melting point: 128,5-to 131.4°

1H NMR (400 MHz, CDCl3) δ: 3,88 (2H, s), of 3.94 (3H, s), of 5.34 (2H, s), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,30 (2H, d, J=8.5 Hz), the 7.43 (2H, d, J=8.5 Hz), 7,51 (1H, DDD, J=8,5, 2,2, 1.2 Hz), to 7.61 (1H, DD, J=12,4, 2.2 Hz), 7,69 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 3392, 1615, 1604, 1520, 1434, 1292, 1133, 1018.

Mass m/z: 373 (M+), 375 ( (M+).

Example 206

Getting hydrochloride 4-amino shall ethyl-2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-aminomethyl-2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 66.0%of).

Melting point: 202,0-205,5°

1H NMR (400 MHz, CD3OD) δ: of 3.94 (3H, s), of 4.13 (2H, s)5,41 (2H, s), 7,21 (1H, DD, J=8,8, 8,8 Hz), 7,35 (2H, d, J=8.5 Hz), 7,46 (2H, d, J=8.5 Hz), 7,65-7,71 (2H, m), 8,08 (1H. C).

IR (KBr) cm-1: 2940, 1655, 1616, 1526, 1439, 1292.

Example 207

Obtain 2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3,4-differenziale obtaining specified in the title compound as a yellow crystalline powder (yield: 92.1 per cent).

Melting point: 144-148°

1H NMR (400 MHz, CDC13) δ: of 3.96 (3H, s), of 3.97 (3H, s), to 5.35 (2H, s),? 7.04 baby mortality (1H, DD, J=8,5, 8,5Hz), 7,12 (1H, m), 7,28 (1H, m), of 7.36 (1H, m)to 7.50 (1H, m), 7,60 (1H, DD, J=12,2, 1.5 Hz), 8,21 (1H, s).

IR (KBr) cm-1: 1756, 1656, 1609, 1518, 1439, 1239, 1293, 1278, 1204.

Mass m/z: 404 (M+).

2) Getting 4-carboxy-2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-(3,4-d is tormentil)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compound as a yellow crystalline powder (yield: 97,6%).

Melting point: 194,4-197,0°

1H NMR (400 MHz, CDC13) δ: of 3.97 (3H, s), 5,44 (2H, s), 7,07 (1H, DD, J=8.5 a, 8.5 Hz), 7,17 (1H, m), 7,27 (1H, m), of 7.36 (1H, DDD, J=8,1, to 8.1 and 2.2 Hz), 7,56 (1H, m)of 1.66 (1H, DD, J=12,2, 2.2 Hz), 8,61 (1H, s), 13,83 (1H, s).

IR (KBr) cm-1: 1757, 1636, 1567, 1518, 1463, 1440, 1284.

Mass m/z: 390 (M+).

3) Obtain 2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 7.7 percent).

Melting point: 154,1-155,5°

1H NMR (400 MHz, CDC13) δ: 2,85 (1H, t, J=5,GC), of 3.95 (3H, s), 4,71 (2H, d, J=5.6 Hz), 5,33 (2H, s), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,12 (1H, m), 7.23 percent (1H, m), 7,31 (1H, DDD, J=11,0, 7,6, 2.2 Hz), 7,51 (1H, DDD, J=8,5, 2,2, 1.2 Hz), to 7.61 (1H, DD, J=12,4, 2.2 Hz), to 7.68 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 3390, 1648, 1602, 1518, 1440, 1285, 1141.

Mass m/z: 376 (M+).

4) to Obtain 2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the connection header in the form of yellow needle crystals (yield: 91.5 per cent).

Melting point: 145,6-146,6°

1H NMR (400 MHz, CDC13) δ: and 3.16 (3H,s), of 3.96 (3H, s), of 5.26 (2H, d, J=1.2 Hz), 5,32 (2H, s),? 7.04 baby mortality (1H, DD, J=8,5 8,5 Hz), 7,13 (1H, m), 7.23 percent (1H, m), 7,32 (1H, m)to 7.50 (1H, m), to 7.61 (1H, DD, J=12,4, 2.2 Hz), 7,76 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 1656, 1612, 1522, 1440, 1352, 1277, 1163.

Mass m/z: 454 (M+).

5) Obtain 2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the connection header in the form of yellow needle crystals (yield: 55,0%).

Melting point: 135,4-136,0°

1H NMR (400 MHz, CDC13) δ: of 2.33 (3H, s), of 2.51 (4H, users), 2,62 (4H, users), of 3.56 (2H, d, J=1.5 Hz), of 3.95 (3H, s), 5,31 (2H, s),? 7.04 baby mortality (1H, DD, J=8.5 a, 8.5 Hz), 7,11 (1H, m), 7.23 percent (1H, m), 7,32 (1H, DDD, J=11,0, to 7.6, 2.0 Hz), 7,52 (1H, DDD, J=8,5, 2,2, 1.2 Hz), to 7.59 (1H, DD, J=12,2, 2.2 Hz), 7,74 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 1652, 1608, 1522, 1437, 1291, 1273, 1139.

Mass m/z: 458 (M+).

Example 208

Obtain 2-(3,4-diferensial)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and dimethylamine to obtain specified in the connection header in the form of yellow needle crystals (yield: 77.1 percent).

Melting point: 129, 9mm-130,4°

1H NMR (400 M is C, CDCl3) δ: 2,35 (6N, C)to 3.49 (2H, s), of 3.95 (3H, s), 5,32 (2H, s), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,11 (1H, m), 7,24 (1H, m), 7,32 (1H, DDD, J=11,0, 7,6, 2.2 Hz), 7,54 (1H, DDD, J=8,5, 2,2, 1.2 Hz), a 7.62 (1H, DD, J=12,4, 2.2 Hz), to 7.77 (1H, s).

IR (KBr) cm-1: 1653, 1610, 1519, 1437, 1291, 1283, 1267, 1138, 1114.

Mass m/z: 403 (M+).

Example 209

Obtaining 2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

1) preparation of 2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Following the procedure of example 1(6)were subjected to interaction of 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamate obtaining specified in the title compounds as a pale yellow crystalline powder (yield: 51.1 per cent).

Melting point: 117-119°

1H NMR (400 MHz, CDCl3) δ: of 3.95 (3H, s), 3,98 (3H, s), 5,02 (2H, DD, J=6,8, 1.2 Hz), to 6.43 (1H, dt, J=15,9 that 6.8 Hz), 6,70 (1H, d, J=15,9 Hz), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,25 (2H, d, J=8,8 Hz), 7,31 (2H, d, J=8,8 Hz), 7,50 (1H, dt, J=8,5 and 2.2 Hz), a 7.62 (1H, DD, J=12,2, 2.2 Hz), by 8.22 (1H, s).

IR (KBr) cm-1: 1724, 1709, 1667, 1506, 1291, 1236, 1126, 831,

Mass m/z: 412 (M+), 414 (M+).

2) Getting 4-carboxy-2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(7)were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale as the addition of crystalline powder (yield: 98.2 per cent).

Melting point: 217,2-218,5°

1H NMR (400 MHz, CDCl3) δ: of 3.97 (3H, s), 5,10 (2H, d, J=6.8 Hz), to 6.39 (1H, dt, J=15,9 that 6.8 Hz), to 6.75 (1H, d, J=15,9 Hz), 7,06 (1H, DD, J=8.5 a, 8.5 Hz), 7,30 (2H, d, J=8.5 Hz), 7,34 (2H, d, J=8.5 Hz), EUR 7.57 (1H, m), 7,69 (1H, DD, J=12,2, 2.2 Hz), 8,63 (1H, s), 13,99 (1H, s).

IR (KBr) cm-1: 3059, 1744, 1629, 1523, 1480, 1438, 1426, 1296, 1272.

Mass m/z: 414 (M+), 416 (M+).

3) Obtaining 2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-carboxy-2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow crystals (yield: 17,0%).

Melting point: 158,2-160,5°

1H NMR (400 MHz, CDCl3) δ: 2,95 (1H, t, J=5,9 Hz), of 3.94 (3H, s), to 4.73 (2H, DD, J=5,9, 1.2 Hz), to 4.98 (2H, DD, J=6,6, 1.2 Hz), 6,40 (1H, dt, J=15,9, and 6.6 Hz), to 6.67 (1H, d, J=15,9 Hz), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,27 (2H, d, J=8,5 Hz), 7,32 (2H, d, J=8.5 Hz), 7,51 (1H, DDD, J=8,8, 2,2, 1.2 Hz), 7,63 (1H, DD, J=12,4, 2.2 Hz), to 7.67 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 3392, 1648, 1603, 1523, 1440, 1284, 1273, 1140.

Mass m/z: 400 (M+), 402 (M+).

4) to Obtain 2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one to obtain specified in the title compounds as pale yellow needle to the of istalol (yield: 90.7 percent).

Melting point: br135.8-to 136.4°

1H NMR (400 MHz, CDCl3) δ: 3,17 (3H, s), of 3.95 (3H, s), to 4.98 (2H, DD, J=6,6, and 0.98 Hz), 5,28 (2H, d, J=1.5 Hz), to 6.39 (1H, dt, J=15,9, and 6.6 Hz), to 6.67 (1H, d, J=15,9 Hz), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,27 (2H, d, J=8.5 Hz), 7,32 (2H, d, J=8.5 Hz), 7,50 (1H, m), a 7.62 (1H, DD, J=12,2, 2.2 Hz), to 7.77 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 1660, 1615, 1523, 1436, 1360, 1335, 1287, 1273, 1179.

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

5) Obtaining 2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compounds as a pale brown needle crystals (yield: 66.3 per cent).

Melting point: 123,9 output reached 125.5°

1H NMR (400 MHz, CDCl3) δ: of 2.33 (3H, s), 2,52 (4H, users), 2,62 (4H, users), to 3.58 (2H, d, J=1.2 Hz), of 3.95 (3H, s), to 4.98 (2H, DD, J=6,8, 1.2 Hz), 6,41 (1H, dt, J=15,9 that 6.8 Hz), of 6.66 (1H, d, J=15,9 Hz),? 7.04 baby mortality (1H, DD, J=8.5 a, 8.5 Hz), 7,26 (2H, d, J=8.5 Hz), 7,32 (2H, d, J=8.5 Hz), 7,53 (1H, DDD, J=8,5, 2,0, 1.2 Hz), a 7.62 (1H, DD, J=12,4, 2.2 Hz), of 7.75 (1H, t, J=1.2 Hz).

IR (KBr) cm-1: 1647, 1606, 1522, 1439, 1282, 1270.

Mass m/z: 482 (M+), 484 (M+).

Example 210

Obtaining 2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinil]methyl-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-(4-chlorocinnamoyl)-6-(3-what Thor-4-methoxyphenyl)-4-methanesulfonylaminoethyl-2H-pyridazin-3-one and 1-piperazineethanol obtaining specified in the connection header in the form of yellow needle crystals (yield: 65,1%).

Melting point: 133,1-134,9°

1H NMR (400 MHz, CDCl3) δ: 2.57 m-2,62 (11N, m)to 3.58 (2H, d, J=1.2 Hz), 3,63 (2H, t, J=5.4 Hz), of 3.94 (3H, s), equal to 4.97 (2H, d, J=6.6 Hz), 6,41 (1H, dt, J=15,9, and 6.6 Hz), to 6.67 (1H, d, J=15,9 Hz), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,26 (2H, d, J=8.5 Hz), 7,32 (2H, d, J=8.5 Hz), 7,53 (1H, m), to 7.61 (1H, DD, J=12,4, 2.2 Hz), of 7.75 (1H, s).

IR (KBr) cm-1: 3451, 1647, 1605, 1523, 1438, 1285, 1274, 1137.

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

Example 211

Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinil)propyl]-2H-pyridazin-3-one

1) preparation of 4-methyl bromide-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

2-Cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one (185 mg, 0.61 mmol), tetrabromide carbon (404 mg, 1.2 mmol) and pyridine (48 mg, 0.61 mmol) was dissolved in tetrahydrofuran (3 ml) and with stirring under ice cooling was added a solution of triphenylphosphine (319 mg, 1.2 mmol) in tetrahydrofuran (3 ml). The mixture was stirred under ice cooling for 1 hour and then stirred overnight at room temperature. Any insoluble matter was filtered, the solvent is kept under reduced pressure and the residue was isolated and purified column chromatography on silica gel (hexane/ethyl acetate=2/1) to obtain the specified title compound as a yellow powder (yield: 155 mg, 69.5 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,4-0,60 (4H, m)was 1.58 (1H, m), of 3.95 (3H, s), of 4.12 (2H, d, J=7,3 Hz), of 4.49 (2H, s), 7,03 (1H, DD, J=8.5 a, 8.5 Hz), 7,50 (1H, m), 7,60 (1H, DD, J=13,4, 2.2 Hz), to 7.77 (1H, s).

2) Getting 2-cyclopropylmethyl-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

After you have added 55% sodium hydride (322 mg, 7,38 mmol) to a solution of di-tert-butylmalonate (970 mg, 4,48 mmol) in N,N-dimethylformamide (10 ml) under ice cooling was added 4-methyl bromide-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one (1.8 g, of 4.90 mmol). The reaction mixture was stirred at room temperature for 1 hour, poured into water and was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure. The residue was isolated and purified by chromatography on silica gel (hexane/ethyl acetate=3/1) to obtain the specified title compound as a yellow powder (yield: 1.39 mg, 61.8 percent).

1H NMR (400 MHz, CDCl3) δ: 0,44-of 0.50 (2H, m), 0.50 to EUR 0.58 (2H, m), 1.41 to (N, C), and 1.56 (1H, m), of 3.12 (2H, d, J=7.8 Hz), a 3.87 (1H, t, J=7.8 Hz), of 3.94 (3H, s), 4.09 to (2H, d, J=7.8 Hz), 7,01 (1H, DD, J=8.5 a, 8.5 Hz), the 7.43 (1H, d, J=8.5 Hz), to 7.50 (1H, s), EUR 7.57 (1H, DD, J=12,4, 2,2 Hz).

3) Obtain 4-(2-carboxyethyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

2-cyclopropylmethyl-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-ONU (1.39 g, 2.77 mmol) was added triflorum usnow acid (21 ml) and the mixture was stirred at room temperature for 30 minutes The solvent is kept under reduced pressure and then added toluene and subsequent azeotropic boiling. The residue was heated at 190 - 200°C for 30 min in nitrogen atmosphere to obtain specified in the title compounds as a pale brown powder (yield: 907 mg, 94.7 percent).

1H NMR (400 MHz, CDCl3)δ: 0,45-0,50 (2H, m), 0.50 to 0.60 (2H, m)of 1.41 (1H, m), 2,80 (2H, t, J=7,1 Hz), of 2.97 (2H, t, J=7,1 Hz), of 3.94 (3H, s), 4,10 (2H, d, J=7,3 Hz), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,47 (1H, d, J=8.5 Hz), at 7.55 (1H, s), to 7.59 (1H, DD, J=12,4, 2,2 Hz).

4) to Obtain 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one

Following the procedure of example 1(8)were subjected to interaction of 4-(2-carboxyethyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compound as a brown oil (yield: 82.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,44-0,52 (2H, m), 0,52-0,60 (2H, m)of 1.42 (1H, m), 1,88-of 1.94 (2H, m), of 2.81 (2H, t, J=6,1 Hz), 3,63 (2H, t, J=5,9 Hz), of 3.95 (3H, s), of 4.12 (2H, d, J=7,3 Hz), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,50 (1H, m), 7,52 (1H, s), 7,60 (1H, DD, J=12,4, 2,2 Hz).

5) Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonylaminoethyl)-2H-pyridazin-3-one

Following the procedure of example 1(9)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one to obtain specified in the title compounds as a pale brown powder (yield: 82,0%)./p>

1H NMR (400 MHz, CDCl3) δ: 0,44-of 0.51 (2H, m), of 0.51 to 0.60 (2H, m)of 1.41 (1H, m), 2,13-of 2.21 (2H, m), 2,80 (2H, t, J=7,1 Hz), 3.04 from (3H, s), of 3.94 (3H, s), 4.09 to (2H, d, J=7,3 Hz), or 4.31 (2H, t, J=6,1 Hz), 7,02 (1H, DD, J=8,5, 8.5 Hz), 7,49 (1H, d, J=8.5 Hz), 7,53 (1H, s), to 7.61 (1H, DD, J=12,4, 2,2 Hz).

6) Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinil)propyl]-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonylaminoethyl)-2H-pyridazin-3-one and 1-methylpiperazin obtaining specified in the title compound as a yellow oil (yield: 62,0%).

1H NMR (400 MHz, CDCl3) δ: 0,44-of 0.50 (2H, m), 0.50 to 0.60 (2H, m)of 1.41 (1H, m), 1,90-2,00 (2H, m), of 2.45 (3H, s), 2,50-3,00 (N, m), of 3.94 (3H, s)4,08 (2H, d, J=7,3 Hz), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), of 7.48 (1H, s)to 7.50 (1H, d, J=8.5 Hz), of 7.70 (1H, DD, J=12,3, 2.0 Hz).

IR (Pure) cm-1: 1648, 1607, 1524, 1286, 1122, 1022, 755.

Mass m/z: 414 (M+).

Example 212

Getting 2-cyclopropylmethyl-4-(3-dimethylaminopropyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 7 were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonylaminoethyl)-2H-pyridazin-3-one and dimethylamine to obtain specified in the title compound as a yellow powder (yield: 64.7 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,44-of 0.50 (2H, m), of 0.53 to 0.60 (2H, m)of 1.40 (1H, m), 2,24 to 2.35 (2H, m), 2,75 is 2.80 (2H, m), 2,79 (6N, (C), 3,03 (2H, t, J=7,3 Hz), 3,94 3H, C)4,08 (2H, d, J=7,1 Hz),? 7.04 baby mortality (1H, DD, J=8.5 a, 8.5 Hz), EUR 7.57 (1H, d, J=8.5 Hz), the 7.65 (1H, DD, J=12,4, 2.2 Hz), 7,72 (1H, s).

IR (Pure) cm-1: 1649, 1608, 1524, 1288, 1122, 1022, 761.

Mass m/z: 359 (M+).

Example 213

Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinil)propyl]-2H-pyridazin-3-one

1) preparation of 2-cyclopropylmethyl-4-[3-(4-tert-butoxycarbonyl-1-piperazinil)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonylaminoethyl)-2H-pyridazin-3-one and tert-butyl 1-piperidinecarboxylate obtaining specified in the title compound as a yellow oil (yield: 76,9%).

1H NMR (400 MHz, CDCl3) δ: 0,44-of 0.50 (2H, m), 0,52-0,60 (2H, m)of 1.44 (1H, m), 1,46 (N, s), 2.00 in to 2.40 (2H, m), 2,50-2,80 (6N, m), 3,50-3,75 (6N, m), of 3.94 (3H, s)4,08 (2H, d, J=7,1 Hz), 7,02 (1H, DD, J=8.5 a, 8.5 Hz), 7,47-the 7.65 (3H, m).

2) Getting 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinil)propyl]-2H-pyridazin-3-one

Following the procedure of example 20 was subjected to the interaction of 2-cyclopropylmethyl-4-[3-(4-tert-butoxycarbonyl-1-piperazinil)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the title compound as a yellow oil (yield: 78.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,43-of 0.50 (2H, m), 0,50-0,59 (2H, m)of 1.42 (1H, m), 1,82-of 1.92 (2H, m), 2.40 a-2,50 (6N, m), 2,68 (2H, t, J=7,6 Hz), 2,93-2,95 (4H, m), of 3.94 (3H, s)4,08 (2 is, d, J=7,3 Hz), 7,01 (1H, DD, J=8.5 a, 8.5 Hz), 7,45 (1H, s)of 7.48 (1H, d, J=8.5 Hz), to 7.59 (1H, DD, J=11,4, 2.0 Hz).

IR (Pure) cm-1: 1648, 1607, 1523, 1288, 1122, 1023, 760.

Mass m/z: 400 (M+).

Example 214

Getting dihydrochloride 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinil)propyl]-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinil)propyl]-2H-pyridazin-3-one to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 83.1%of).

Melting point: 174-178°

1H NMR (400 MHz, DMSO-d6) δ: 0,39-of 0.45 (2H, m), 0,45-0,55 (2H, m), 1,32 (1H, m), 2,00-2,25 (2H, m), 2,62-of 2.66 (2H, m), 3,20-3,85 (10H, m), 3,90 (3H, s)to 4.01 (2H, d, J=7,1 Hz), 7,28 (1H, DD, J=8,8, 8,8 Hz), 7,72-7,80 (2H, m), of 7.96 (1H, s).

IR (KBr) cm-1: 1647, 1604, 1523, 1297, 1123, 1020, 762.

Example 215

Getting 4-[3-[N,N-bis(2-hydroxyethyl)amino]propyl]-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 1(10)were subjected to interaction of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonylaminoethyl)-2H-pyridazin-3-one and diethanolamine obtaining specified in the title compound as a yellow oil (yield: 13.1 per cent).

1H NMR (400 MHz, CDCl3) δ: 0,44-of 0.50 (2H, m), 0.50 to 0.60 (2H, m)of 1.41 (1H, m), 2,10-of 2.20 (2H, m), was 2.76 (2H, t, J=7,3 Hz)of 3.00-3.15 in (6N, m), a 3.87-to 3.92 (4H, m), of 3.94 (3H, s)4,08 (2H, d, J=7,3 Hz), 7,02 (1H, d is, J=8.5 a, 8.5 Hz), 7,53 (1H, d, J=8.5 Hz), 7,60 (1H, s), a 7.62 (1H, DD, J=12,4, 2,2 Hz).

IR (Pure) cm-1: 1645, 1602, 1524, 1288, 1123, 1024, 756.

Mass m/z: 400 (M+-CH2OH).

Example 216

Getting 4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 24 (1), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonylaminoethyl)-2H-pyridazin-3-one was subjected to interaction with obtaining a crude product. The crude product was subjected to further interaction without purification in accordance with the procedure of example 24 (2) obtaining specified in the title compound as a yellow oil (yield: 67,8%).

1H NMR (400 MHz, CDCl3) δ: 0,44-of 0.50 (2H, m), 0.50 to 0.60 (2H, m)of 1.41 (1H, m), 1,84 is 1.96 (2H, m), 2,67 is 2.80 (4H, m), 2,87 (2H, t, J=6,1 Hz), of 3.94 (3H, s)4,08 (2H, d, J=7,3 Hz), 7,01 (1H, DD, J=8.5 a, 8.5 Hz), 7,49 (1H, d, J=8.5 Hz), to 7.50 (1H, s), to 7.59 (1H, DD, J=12,4, 2,2 Hz).

IR (Pure) cm-1: 3370, 1648, 1606, 1523, 1289, 1122, 1023, 760.

Mass m/z: 331 (M+).

Example 217

Obtain hydrochloride of 4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Following the procedure of example 4 was subjected to the interaction of 4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one to obtain specified in the connection header in the form of a yellow crystalline powder (yield: 70.6 per cent).

Melting point: 183-185°

1 H NMR (400 MHz, DMSO-d6) δ: 0,40-0,45 (2H, m), 0,45-0,55 (2H, m), 1,32 (1H, m), 1,88-of 1.93 (2H, m)of 2.64 (2H, t, J=7,3 Hz), 2,78-is 2.88 (2H, m), 3,90 (3H, s), 4.00 points (2H, d, J=7,3 Hz), 7,28 (1H, DD, J=8.5 a, 8.5 Hz), 7,70 for 7.78 (2H, m)of 7.96 (1H, s).

IR (KBr) cm-1: 3437, 1648, 1608, 1526, 1273, 1122, 1021, 762.

Reference Example

Obtaining 3-(2,6-dichlorophenyl)-1-propenolatomethyl

1) preparation of ethyl 2,6-dichlorocinnamic

To a solution of 2,6-dichlorobenzaldehyde (350 mg, 2.0 mmol) and triethylphosphite (448 mg, 2.6 mmol) in THF (5 ml) under ice cooling was added tert-piperonyl potassium (291 mg, 2.6 mmol), and at the same temperature and the mixture was stirred for 2 hours. To the reaction mixture were added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Next, the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate=50/1) to obtain specified in the title compounds as a colorless syrup (yield: 65,1%).

1H NMR (400 MHz, CDCl3) δ: of 1.35 (3H, t, J=7.2 Hz), 4,30 (2H, square, J=7,2 Hz), 6,59 (1H, d, J=16.4 Hz), 7,19 (1H, t, J=8.0 Hz), was 7.36 (2H, t, J=8.0 Hz), 7,79 (1H, d, J=16.4 Hz).

2) Obtaining 3-(2,6-dichlorophenyl)-1-propanol

Sociallyengaged (98,8 mg, 2,60 mmol) was added in THF (5 ml) and with stirring under ice cooling was added dropwise a solution of ethyl 2,6-dichlorocinnamic (mg, of 1.30 mmol) in THF (5 ml). The mixture was then stirred at room temperature for 30 minutes To the reaction mixture was added a small amount of saturated aqueous solution of ammonium chloride, and then dried over anhydrous magnesium sulfate. After filtration through celite, the mixture was concentrated under reduced pressure and then purified by chromatography on a column of silica gel (hexane/ethyl acetate=10/1) to obtain specified in the title compounds as a pale yellow syrup (yield: 46.9 per cent).

1H NMR (400 MHz, CDCl3) δ: 1,83-of 1.93 (2H, m), to 3.02 (2H, t, J=7.8 Hz), to 3.73 (2H, t, J=6.3 Hz), to 7.09 (1H, t, J=8,3 Hz), 7,27 (2H, d, J=8,3 Hz).

3) Obtaining 3-(2,6-dichlorophenyl)-1-propenolatomethyl

To a solution of 3-(2,6-dichlorophenyl)-1-propanol (125 mg, 0.61 mmol) and triethylamine (123 mg, 1,22 mmol) in methylene chloride (3 ml) was added under ice cooling methanesulfonanilide (105 mg, 0,915 mmol) followed by stirring at room temperature for 2 hours. To the reaction mixture were added a saturated salt solution. The organic layer was separated, collected and dried over anhydrous sodium sulfate. After concentration under reduced pressure the residue was purified by chromatography on a column of silica gel (hexane/ethyl acetate=10/1) to obtain specified in the title compounds as a pale yellow syrup (yield: quantitative).

1H NMR (400 MHz, CDCl3) δ : 2,02-2,12 (2H, m), 3.00 and-3,10 (5H, m), 4,32 (2H, t, J=6.3 Hz), 7,10 (1H, t, J=8,3 Hz), 7,28 (2H, d, J=8,3 Hz).

Experiment 1

Inhibitory activity against the production of interleukin-1β

Cells HL-60 were cultured for 4 days prior to confluency on medium RPMI 1640, to which was added 10% fetal bovine serum (FBC). The medium was centrifuged. The supernatant liquid was decanted, the cells are then suspended at a concentration of 1 x 106cells/ml in RPMI medium 1640 containing 3% FBS was added lipopolysaccharide obtaining a final concentration of 10 μg/ml of Culture was inoculable in a 24-well plate at 1 ml/well. The test compound was added in the amount of 1 μl/well followed by cultivation for 3 days. Three days later by ELISA method determined the amount of interleukin-1β in every culture. Determined each value IR50by comparing the outputs with the control sample, to which was added the test compound. The results for some representative compounds are shown in Table 1.

Experiment 2 (Test solubility in water)

Test method

Each test compound was weighed in the amount indicated in Table 3, was added to distilled water in the aliquot of 0.05 ml solubility (%) compounds were determined on the basis of the number in the water, necessary for its dissolution.

Results

As shown in Table 2, the compounds of the present invention showed better solubility in water than the comparative compounds.

Table 2
Example No.Mascolino (mg)The quantity of water added (ml)Solubility (%)
142,0480,250,8
181,0480,11
2110,470,05>20
2310,820,110
251,0250,250,4
4510,370,254
4710,470,05>20
8910,570,05>20
1089,750,045>20
1493,090,03>10
1532,950,60,5
1882,0082,50,08
1935,03 0,15
195UAH 5,0722,20,2
2062,0423,50,06
2145,0610,0510
2175,0610,0510
comparative compound 10,677100

(insoluble)
<0,001
comparative compound 20,742100

(insoluble)
<0,001
comparative compound 30,740100

(insoluble)
<0,001
comparative compound 40,95100

(insoluble)
<0,001

Experiment 3 (Test namely, when administered orally to rats)

The compound of Example 83 and comparative compound 3 suspended, respectively, at 2 mg/ml with 0.5% solution of MS in mortar and oral was administered to male SD rats at a dose of 10 mg/5 ml/kg At the end of time 0,25, 0,5, 1, 2, 4, 6 and 8 hours after administration took blood samples and centrifuged to obtain plasma samples. The levels in plasma corresponding compounds was determined by HPLC. As is provided in Fig. 1, for comparative compound 3 did not observe any significant absorption, but good absorption was observed for the compound of Example 83, having high solubility. The compound of Example 83 is therefore useful as an oral input of a medicinal product.

Experiment 4 (Test namely, when administered orally to rats and/or mice)

In the same way as described in Experiment 3, the test compounds of Examples 23, 25 and 143 administered orally to mice and/or rats for testing namely, these substances when administered orally. As shown in Fig.2-4, good absorbiruyaci observed for all tested compounds, thus, they are useful as an oral input of medicines.

After reviewing the description of the present invention, a specialist should understand, there are many changes and modifications of the above-described embodiment variants of the invention without departure from the essence and scope.

1. Derived phenylpyridazin formula (1):

where

R1represents a C1-C12alkyl, optionally containing3-C6cyclic alkyl structure or optionally substituted by phenyl which can be substituted by 1-2 atoms halog is on, or1-C12alkenyl substituted by phenyl which can be substituted by a halogen atom;

R2and R3each independently represents hydrogen or C1-C12alkyl, C1-C12hydroxyalkyl,1-C12dihydroxyethyl or3-C12quinil, or R2and R3together with the adjacent nitrogen atom, form a 5-6-membered saturated heterocyclic group containing 1-2 nitrogen atom and optionally containing an oxygen atom, with the specified heterocyclic group optionally substituted C1-C12alkyl, C1-C12alkoxycarbonyl or panels1-C7alkyl group;

X, Y and Z each independently represents hydrogen or halogen, With1-C12alkyl which may be substituted atom(s) halogen, C1-C12alkoxy, C1-C12alkylthio,1-C12alkylsulfonyl or1-C12alkylsulfonyl or phenyl; and

n denotes a number from 1 to 5;

provided that R2and R3simultaneously are hydrogen or the same C1-C3alkyl groups, where R1represents a benzyl group or a C1-C3alkyl group; or its salt.

2. The compound according to claim 1, where R1is an alkyl containing about is 1 to 7 carbon atoms, optionally substituted by phenyl which can be substituted by 1-2 halogen atoms or alkenyl containing from 2 to 7 carbon atoms, substituted phenyl which can be substituted by a halogen atom.

3. The compound according to claim 1, where R2and R3each independently represents hydrogen, C1-C12alkyl, C1-C12hydroxyalkyl,1-C12dihydroxyethyl or3-C12quinil or R2and R3together with the adjacent nitrogen atom, form a 5-6-membered saturated heterocyclic group containing 1-2 nitrogen atom and optionally containing an oxygen atom, with the specified heterocyclic group optionally substituted C1-C12alkyl, C1-C12alkoxycarbonyl or panels1-C12alkyl group;

4. The compound according to claim 1, where X, Y and Z each independently represents hydrogen or halogen, With1-C12alkyl which may be substituted atom(s) halogen, C1-C12alkoxy, C1-C12alkylthio,1-C12alkylsulfonyl or1-C12alkylsulfonyl or phenyl.

5. The compound according to claim 1, where R1represents isobutyl, cyclopropylmethyl, cyclopentylmethyl, cinnamyl, halogenosilanes, benzyl, halogenmethyl or dehalogenases or (halogenfree)propyl; R2and R3each is ezavisimo represents hydrogen, With1-7alkyl, C1-7hydroxyalkyl or propargyl; specified heterocyclic group formed by R2and R3represents piperazinil, piperidino or morpholino, optionally substituted C1-7the alkyl or benzyl; X represents methyl, methoxy, methylthio or halogen; Y is hydrogen, methyl or halogen; Z represents hydrogen; n has a value of 1 or 3.

6. The compound according to claim 1, including

4-dimethylaminomethyl-6-(3-fluoro-4-were)-2-isobutyl-2H-pyridazin-3-one,

2-cyclopropylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-benzyl-1-piperazinil)methyl-2H-pyridazin-3-one,

2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

4-dimethylaminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one,

4-diethylaminomethyl-2-isobutyl-6-(4-were)-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-were)-2-isobutyl-2H-pyridazin-3-one,

6-(4-fluoro-3-were)-2-isobutyl-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one,

4-dimethylaminomethyl-6-(4-fluoro-3-were)-2-isobutyl-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-differenl)-2-isobutyl-2H-pyridazin-3-one,

2-(4-chlorocinnamoyl)-6-(4-fluoro-3-were)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one,

2-cyclopropylmethyl-4-(4-methyl-1-piperazinil)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropyl-methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,

2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one,

2-isobutyl-6-[4-(methylthio)-phenyl]-4-propargylamine-2H-pyridazin-3-one,

4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,

2-(4-Chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one,

2-cyclopentylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one,

4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one,

4-dimethylaminomethyl-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinil)methyl-2H-pyridazin-3-one,

4-aminomethyl-2-(4-terbisil)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

4-aminomethyl-2-(4-Chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-(3,4-diferensial)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one,

2-(3,4-diferensial)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one,

4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one,

4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one,

6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-4-(1-piperazinil)methyl-2H-pyridazin-3-one,

4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-forfinal)propyl]-2H-pyridazin-3-one,

2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinil]methyl-2H-pyridazin-3-one,

2-(4-chlorocinnamoyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinil)methyl-2H-pyridazin-3-one,

2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinil)propyl]-2H-pyridazin-3-one,

2-cyclopropylmethyl-4-(3-dimethylaminopropyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

2-cycloprop ylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinil)propyl]-2H-pyridazin-3-one, or

4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one.

7. Drug, inhibitory stimulation of the production of interleukin-1βcomprising as active ingredient a compound according to any one of claims 1 to 6, or its salt.

8. The drug according to claim 7 for the prevention or treatment of diseases caused by stimulation of the production of interleukin-1β.

9. The drug according to claim 7 for the prevention or treatment of diseases of the immune system, inflammatory diseases, ischemic diseases, osteoporosis or septicemia.

10. The drug according to claim 7 for the prevention or treatment of rheumatism, arthritis or inflammatory colitis.

11. The inhibitor of the production of interleukin-1βcomprising as active ingredient a compound according to any one of claims 1 to 6, or its salt.

12. The pharmaceutical composition inhibiting the stimulation of the production of interleukin-1βcomprising the compound according to any one of claims 1 to 6, or its salt and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to item 12, which is a pharmaceutical composition for the prevention or treatment of diseases caused by stimulation of the production of interleukin - 1β.

14. The pharmaceutical composition according to item 12, which is a pharmaceutical is a mini-composition for the prevention or treatment of diseases of the immune system, inflammatory diseases, ischemic diseases, osteoporosis or septicemia.

15. The pharmaceutical composition according to item 12, which is a pharmaceutical composition for the prevention or treatment of rheumatism, arthritis or inflammatory colitis.

16. The use of compounds according to any one of claims 1 to 6, or its salt to obtain a drug that inhibits stimulation of the production of interleukin-1β.

17. The application of article 16, where the specified drug is an agent for the prophylaxis or treatment of a disease caused by stimulation of the production of interleukin-1β.

18. The application of article 16, where the specified drug is an agent for the prevention or treatment of diseases of the immune system, inflammatory diseases, ischemic diseases, osteoporosis or septicemia.

19. The application of article 16, where the specified drug is an agent for the prevention or treatment of rheumatism, arthritis or inflammatory colitis.

20. A method of treating diseases caused by stimulation of the production of interleukin-1β, which includes introducing the compound according to any one of claims 1 to 6, or its salt.

21. The method of treatment of diseases of the immune system, inflammatory diseases, ischemic diseases, osteoporosis or septicemia, which includes the maintenance compound according to any one of claims 1 to 6, or its salt.

22. The method according to item 21, where the disease that is treated is a rheumatism, arthritis or inflammatory colitis.



 

Same patents:

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

The invention relates to the derivatives of pyridazine General formula I, in which R1represents phenyl or pyridyloxy group which may be substituted by 1-3 substituents selected from halogen and lower alkoxygroup; R2represents a phenyl group which may be substituted at the 4th position of the lower alkoxygroup, lower alkylthiol, lower alkylsulfonyl or lower alkylsulfonyl group and in other positions 1 or 2 substituents selected from halogen atoms, lower CNS groups, lower alkylthio, lower alkylsulfonyl groups and lower alkylsulfonyl groups;3represents a hydrogen atom; a lower CNS group; halogenated lower alkyl group; a lower cycloalkyl group; phenyl, pyridyloxy or fenoxaprop, which may be substituted by 1-3 substituents selected from halogen atoms, lower alkyl groups, lower CNS groups, carboxyl groups, lower alkoxycarbonyl groups, nitro, amino, lower alkylamino and lower alkylthio; unsubstituted or substituted lower alkyl group piperidino, piperidinyl, piperazine derivatives or morpholinopropan; unsubstituted or zameshannuu lower alkylamino group piperazinylcarbonyl group; A represents a linear or branched lower alkylenes or lower alkynylamino group having 1-6 carbon atoms; or And can mean single bond when R3represents the lower cycloalkyl or halogenated lower alkyl group; X represents an oxygen atom or a sulfur atom; provided that the following combinations are excluded: R1and R2represent 4 metoksifenilny, X represents an oxygen atom, a represents a single bond, and R3represents a hydrogen atom or 2-chloraniline group; or their salts

The invention relates to heterocyclic-benzoylpyridine formula (I):

< / BR>
where R1and R2each independently of one another, denote hydrogen, fluorine, chlorine, bromine, iodine

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides novel compounds of general formula I: (I), in which R1, R2, independently from each other, represent H, OH, OR5, or Hal; R3, R3', independently from each other, represent H or Hal; R4 represents CN or group ; R5 is A or cycloalkyl having 3 to 6 carbon atoms optionally substituted by 1-5 F and/or Cl atoms, or -(CH2)-Ar group; A represents C1-C10-alkyl optionally substituted by 1-5 F and/or Cl atoms; Ar is phenyl; n = 0, 1 or 2; Hal is F, Cl, Be, or I; and pharmaceutically acceptable derivatives thereof, solvates, and stereoisomers, including their mixtures in any proportions. Invention also relates to a method of preparing compounds I, pharmaceutical agent manifesting inhibitory activity relative to phosphodiesterase IV, application areas, and intermediate compounds of formula I-I.

EFFECT: expanded synthetic possibilities in novel biologically active compounds areas.

14 cl, 4 tbl, 19 ex

FIELD: medicine, experimental medicine.

SUBSTANCE: starting since the 7th to the 28th d after modeling a patient's limb's ischemia it is necessary to inject L-arginine intraperitoneally at the dosage ranged 30-200 mg/kg body weight. The innovation provides optimal dosages and the mode for injecting L-arginine as NO donator.

EFFECT: higher efficiency.

1 tbl

FIELD: medicine, surgery.

SUBSTANCE: it is necessary to obtain surgical access to femoral arteries and aorta to squeeze the latter with its branches to remove the main arteries and collaterals out of circulation. Then the interference on aorta and femoral arteries should be fulfilled followed by reconstruction of circulation along aorta and femoral arteries. Moreover, 12 h before the onset of surgical interference a patient should be intravenously injected with perfluorane at the dosage of 5 ml/kg body weight, moreover, a patient should inhale oxygen-enriched air mixture (for 40-50%) during 12 h. In the course of surgical interference it is necessary to additionally introduce oxygenated perfluorane intra-aortally - 70 ml and into common femoral arteries from both sides - per 50 ml. After operation patients should inhale the above-mentioned oxygen-enriched air mixture during 12 h. The innovation provides prophylaxis of post-ischemic syndrome in case of prolonged surgical interferences upon squeezed arteries.

EFFECT: higher efficiency of protection.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes acylated 6,7,8,9-tetrahydro-5H-benzocycloheptenylamines of the general formula (I): wherein R1 and R4 mean independently hydrogen atom (H), (C1-C10)-alkyl monosubstituted with fluorine atom (F); R2 and R3 mean independently H and (C1-C10)-alkyl; A means -CH, -CHOH; each among B, C and D means -CH2; R5 means possibly substituted phenyl or group Hetar. Also, invention describes method for synthesis of indicated compounds and a pharmaceutical preparation designated for stimulation of expression of endothelial NO-synthase. Nitrogen oxide (NO) released by endothelial tissue displays important significance in function of some main mechanisms of cardiovascular system. Nitrogen oxide exerts the vasodilating effect and inhibits platelets aggregation, adhesion of leukocytes to endothelial tissue and proliferation of smooth muscle cells in internal envelope of blood vessels.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparations.

16 cl, 1 tbl, 152 ex

FIELD: medicine, experimental cardiopharmacology.

SUBSTANCE: method involves modeling the endothelial dysfunction by every day intraperitoneal administration of L-nitroarginine methyl ester in rats (Wistar strain) in the dose 25 mg/kg for 7 days. On background of dysfunction modeling its correction is carried out by simultaneous intragastric administration of enalapril in the dose 0.5 mg/kg and by intraperitoneal administration of resveratrol in a single dose 2 mg/kg per 24 h. Degree of dysfunction development and activation of its correction are evaluated by the ratio endothelium-independent and endothelium-dependent vasodilation. Method provides possibility for study of endothelium-protective effects of resveratrol and activation of endothelial NO-synthase at stage of modeling endothelial dysfunction and their evaluation by the above given ratio endothelium-independent and endothelium-dependent vasodilation. Invention can be used in correction of endothelial dysfunction.

EFFECT: improved method of correction.

2 tbl, 1 ex

FIELD: medicine, medicine of catastrophes, toxicology, resuscitation.

SUBSTANCE: it is necessary to puncture any available artery, then centripetally under the pressure in flow mode one should introduce oxygenated blood substitute of gas-transport function - perfluorane at the dosage of about 10-30 ml/kg. Immediately after introducing perfluorane it is important to inject adrenaline intra-arterially. Then it is necessary to fulfill indirect cardiac massage, defibrillation, artificial pulmonary ventilation at oxygen supply and intravenous injection of infusion solutions. The innovation enables to reconstruct cardiac function in short terms and, thus, correspondingly, improve cerebral circulation due to providing direct supply of oxygenated blood substitute into the system of cerebral and coronary vessels and, also, maintain the functions reconstructed during the period of transporting a patient into medical center.

EFFECT: higher efficiency of reconstruction.

5 dwg, 1 ex

FIELD: medicine, bioactive agents.

SUBSTANCE: claimed agent for parantheral administration represents peptide complex containing 70-90 % of low molecular fraction comprising peptide components with molecular mass 72-678 Da, and peptide concentration of 2.5-2.9 mg/ml. Said agent is obtained from blood vessel of calf not older than 12 months or hog by extraction with acetic acid in presence of zinc chloride. Calf or hog blood vessels are frozen at not less -40°C, conditioned at -20-22°C for at least two months, and ground. Then 3 % acetic acid solution in volume ratio of 1:5 is added at 20±5°C. Extraction is carried out under continuous stirring to produce homogenous mixture. Then 1 % zinc chloride solution is added into mixture in volume ratio of 50:1; mixture is cooled under continuous stirring to 7-16°C; stirred during 1 h after each 4 h defecation for 48 hours. Extract is separated from ballast substances; acetone is added to extract in volume ratio of 1:5, followed by conditioning at 3-5°C for 4 hours. Obtained homogenized deposition is deposited again with acetone two time or more. Further active substance containing precipitate is washed on gravity filter with two-fold volumes of acetone cooled to 7-16°C to produce light-gray precipitate. Precipitate is passed through metal sieve, dried, dissolved in distilled water at room temperature and continuous stirring to produce polypeptide concentration of 2.5-2.9 mg/ml. Solution is centrifuged, filtered, subjected to ultrafiltration purification under back pressure of 1.0 kgf/cm2 or less trough materials with retentiveness of 15000 Da. Glycocol is added into ultrafiltrate up to finish concentration of 10-20 mg/mg at pH 5.6-6.6. Solution is subjected to sterilizing filtration under pressure of 2.0 kgf/cm2 or less, poured in 2 ml ampoules, and autoclaved for 8 min, at 120°C and atmospheric pressure of 1.1 kgf/cm2.

EFFECT: method of increased yield, non-toxic and apirogenic agent of improved purity.

2 cl, 4 ex, 3 tbl, 1 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinoline that can be used as ligands of neuropeptide Y (NPY) receptors and being first of all as neuropeptide Y (NPY) antagonists. Invention describes compounds of the formula (I): wherein R1 means -O-R4 or -NR5R6; R2 means hydrogen atom, alkyl, alkoxy-group or halogen atom; R3 means alkyl or halogen atom; R means hydrogen atom, alkyl, phenyl, phenyl substituted with 1-3 substitutes chosen independently of one another from group comprising alkyl, cyano-group, trifluoromethyl, alkoxy-group, halogen atom, pyrrolidinylcarbonyl and nitro-group, alkoxyalkyl or heterocyclyl that means saturated or aromatic 4-10-membered heterocycle comprising one heteroatom chosen from nitrogen, oxygen atoms; R5 and R6 are chosen independently of one another from group comprising hydrogen atom, alkyl or phenyl; or R5 and R6 in common with nitrogen atom (N) to which they are added form 5-10-membered heterocyclic ring comprising nitrogen atom optionally; A1 means 5-7-membered saturated heterocyclic ring comprising nitrogen atom added to quinoline ring and the second nitrogen atom optionally and wherein ring is substituted optionally with 1-3 substitutes chosen independently of one another from group comprising alkyl, alkoxy-, hydroxy-group, hydroxyalkyl, alkoxyalkyl, tetrahydropyranyloxyalkyl and cycloalkylalkoxy-group; A2 means -CH2- or -C(O)- wherein alkyl individually or in combination means alkyl group with a direct chain that comprises 1-8 carbon atoms; and their pharmaceutically acceptable salts and alkyl esters. Also, invention describes methods for synthesis of compounds of the formula (I) and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 117 ex

FIELD: medicine, cardiology.

SUBSTANCE: invention relates to a method for enhancing effectiveness of nitrates in treatment of heart ischemic disease. In case of reducing effectiveness of nitrates, arising adverse effects and detecting immune insufficiency polyoxidonium is administrated by sublingual route in the dose 0.012 g, 3 times per a day for 10 days. Proposed method provides enhancing effectiveness of nitrates effect based on correcting effect of polyoxidonium on monocyte-phagocyte link of immune system.

EFFECT: improved method of treatment.

3 tbl, 2 ex

FIELD: medicine, cardiology.

SUBSTANCE: in carrying out coronary angioplasty method involves administration of 2-ethyl-6-methyl-3-oxypyridine succinate solution in the dose 50-1500 mg into infarction-damaged artery. Method for treatment of acute myocardial infarction involves intracoronary administration of 2-ethyl-6-methyl-3-oxypyridine succinate solution into infarction-damaged artery in carrying out the coronary angioplasty and wherein the dose of 2-ethyl-6-methyl-3-oxypyridine succinate solution is 50-1500 mg. Method provides prophylaxis of re-perfusion complications and myocardium ischemia degree based on cardioprotective effect of the preparation in the infarction zone directly. Invention can be used in treatment of acute myocardial infarction.

EFFECT: improved and enhanced effectiveness of treatment method.

4 cl, 4 dwg, 4 ex

FIELD: medicine, biology.

SUBSTANCE: the present innovation deals with the technology for manufacturing the series of preparations being of immunoregulating action and could be applied for manufacturing vaccines and preparations for the purposes mentioned. It is necessary to dissolve 3000 g sugar in bidistilled water up to saturated syrup to sterilize it due to boiling followed by cooling it up to about 45-50°C, then one should add as a basis 30 g protein bile fraction of two ad more even-toes animals dissolved in 200 g bidistilled water, the mixture should be thoroughly mixed to dry it up to the end in oven drier at 45-50°C, then the mixture should be ground to sterilize the powder obtained that contains a target product with quartz irradiation to be packed into gelatinous capsules NN 1-3 at 0.5-1.5 g dosage. The innovation provides the development of reliable, economically profitable technology for manufacturing native preparations of immunoregulating action that enables to shorten terms of therapy, prolong terms of remission, achieve complete recovery in case of viral diseases and intoxications and decrease lethality percentage in case of the diseases mentioned.

EFFECT: higher efficiency.

6 ex

FIELD: medicine, peptides, pharmacy.

SUBSTANCE: invention relates to medicinal agents used in prophylaxis and correction of age disorders in cellular and humoral immunity. Invention proposes a pharmaceutical composition possessing immunogeroprotective effect and containing the effective amount of peptide glutamyl-aspartyl-proline of the general formula: H-Glu-Asp-Pro-OH of the sequence 1 [SEQ ID NO:1] as an active component. Invention proposes peptide glutamyl-aspartyl-proline of the general formula: H-Glu-Asp-Pro-OH of the sequence 1 [SEQ ID NO:1] that possesses immunogeroprotective effect. Also, invention proposes a method for prophylaxis and correction of age disorders in cellular and humoral immunity by stimulation of processes of proliferation and differentiation of lymphocytes. Method involves administration in a patient a pharmaceutical composition containing peptide glutamyl-aspartyl-proline of the formula: H-Glu-Asp-Pro-OH of the sequence 1 [SEQ ID NO:1] in the dose 0.01-100 mcg/kg of body mass as an active component at least once per a day for period necessary for providing the therapeutic effect. Invention provides creature of peptide possessing immunogeroprotective effect and pharmaceutical composition containing this peptide as an active component that stimulates processes of proliferation and differentiation of lymphocytes based on recovery in synthesis of tissue-specific proteins, normalization of metabolic and molecular-genetic indices in age disorders of cellular and humoral immunity. Proposed peptide can be used as an agent possessing immunogeroprotective effect.

EFFECT: valuable medicinal and biological properties of peptide.

6 cl, 4 tbl, 2 dwg, 8 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel condensed derivatives of imidazole that are inhibitors of dipeptidyl peptidase IV. Invention describes compound represented by the following formula (I): or its salt or hydrate wherein T1 represents monocyclic 5-6-membered heterocyclic group comprising one or two nitrogen atoms in ring that can comprise one or more amino-groups as substitutes; X represents (C2-C6)-alkenyl group that can comprise one or more substitutes, (C2-C6)-alkynyl group, phenyl group that can comprise one or some substitutes chosen from alkyl group or halogen atom or phenyl-(C1-C6)-alkyl group; each Z1 and Z2 represents independently nitrogen atom or group of the formula -CR2=; each R1 and R2 represents independently group of the formula -A0-A1-A2 wherein A0 represents a single bond or (C1-C6)-alkylene group that can comprise 1-3 substitutes chosen from group B consisting of given below substitutes; A1 represents a single bond, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, carbonyl group, group represented by formula -O-CO-, group represented by formula -CO-O-, group represented by formula -NRA-, group represented by formula -CO-NRA-, group represented by formula -NRA-CO-, group represented by formula -SO2-NRA-, or group represented by formula -NRA-SO2-; each A2 and RA represents independently hydrogen atom, halogen atom, cyano-group, (C1-C6)-alkyl group, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, 5-10-membered heteroaryl-(C1-C6)-alkyl group, (C6-C10)-aryl-(C1-C6)-alkyl group or (C2-C7)-alkylcarbonyl group wherein each A2 and RA can comprise independently 1-3 substitutes chosen from the given below group of substitutes D: when Z2 represents group of the formula -CR2= then R1 and R2 can form in common 5-7-membered ring with exception cases when: [1] R1 represents hydrogen atom; Z1 represents nitrogen atom, and Z2 represents group -CH=; and [2] Z1 represents nitrogen atom and Z2 represents group -C(OH)=; <group of substitutes B>. Group of substitutes B represents group comprising: hydroxyl group, mercapto-group, cyano-group, nitro-group, halogen atom, trifluoromethyl group, (C1-C6)-alkyl group that can comprise one or some substitutes, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocyclic group, (C1-C)-alkoxy-group, (C1-C6)-alkylthio-group, group represented by formula -SO2-NRB1-RB2, group represented by formula -NRB1-CO-RB2, group represented by formula -NRB1-RB2 (wherein each RB1 and RB2 represents independently hydrogen atom or (C1-C6)-alkyl group), group represented by formula -CO-RB3 (wherein RB3 represents 4-8-membered heterocyclic group), group represented by formula -CO-RB4-RB5, and group represented by formula -CH2-CO-RB4-RB5 wherein RB4 represents a single bond, oxygen atom or group represented by formula -NRB6- wherein each RB5 and RB6 represents independently hydrogen atom, (C1-C6)-alkyl group, (C3-C8)-cycloalkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C6-C10)-aryl group, 5-10-membered heteroaryl group, 4-8-membered heterocycle-(C1-C6)-alkyl group, (C6-C10)-aryl-(C1-C6)-alkyl group or 5-10-membered heteroaryl-(C1-C6)-alkyl group. Also, invention describes inhibitor, pharmaceutical composition, method of treatment and using based on thereof. Invention describes novel compounds possessing useful biological properties.

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

33 cl, 3 tbl, 352 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to an agent eliciting immunomodulating, antitumor, bacteriostatic and anti-aggregation properties and representing 1-hexadecyl-R-(-)-3-oxy-1-azoniabicyclo[2.2.2]octane bromide and a method for its synthesis. Method involves quartenization of R-(-)-azabicyclo[2.2.2]octane-3-ol with hexadecyl bromide at heating in organic solvent medium. Agent shows low toxicity, high effectiveness, it doesn't cause allergic effect and doesn't possess cumulative effect.

EFFECT: valuable medicinal properties of agent.

3 cl, 9 dwg, 6 tbl, 2 ex

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