Derivative pyridazin-3-one and medicines containing them

 

(57) Abstract:

The purpose of the invention is to provide compounds, which are characterized by excellent activity against the production of interleukin-1, as well as medicines, including them as effective ingredients. Describes the derivative pyridazin-3-one represented by the following formula (1):

in which Ar1represents the lower alkoxyphenyl group, Ar2represents a phenyl group having a lower alkoxy, at least in its 4-position, R1represents a linear or branched alkyl group having 2-11 carbon atoms, cycloalkyl group having 3-7 carbon atoms, a lower alkyl group substituted by one or more cycloalkyl groups containing 3 to 7 carbon atoms, or phenyl or phenyl(lower alkyl) group which may be substituted by one or more halogen atoms, lower alkyl groups and lower alkoxygroup, and R2represents a cyano, a carboxyl group, a (lower alkoxy)carbonyl group, a lower alkyl group which may be substituted by one or more halogen atoms, hydroxy groups and phthalimidopropyl, or carbamoyl or lower alkyl groups, substituted phenyl or peredelnoj group, or their salts and medicines containing them as effective ingredients. 5 c. and 3 C.p. f-crystals, 1 table.

The technical field

The present invention relates to new derivatives of pyridazin-3-one, which have excellent inhibitory activity against the production of interleukin-1 and useful for the prevention or the prophylaxis and treatment of diseases of the immune system, inflammatory diseases, ischemic diseases, etc. and also to medicines containing them as effective ingredients.

Background of the invention

In many diseases, such as rheumatism, arthritis, osteoporosis, inflammatory colitis, immunodeficiency syndrome, pyemia (or septicemia), hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease, leukemia, etc., there is a stimulation of the production of interleukin-1, an inflammatory cytokine. The role of interleukin-1 in the induction of synthesis of the enzyme, which is reputed to be involved in inflammation, like collagenase and PLA2, and intraarticular the another hand, in healthy vivo activity of interleukin-1 is regulated by the receptor of interleukin-1 soluble receptor of interleukin-1 receptor antagonist interleukin-1.

In studies using recombinant these inhibiting the biological activity of substances, anti-interleukin-1 antibodies and anti-receptor antibodies against various disease models, it was found that Il-1 plays an important role in the body, leading to an increased potential for substances with inhibitory interleukin-1 activity, as therapeutic agents for such diseases.

For example, it was reported that the immunosuppressants and steroids are used to treat rheumatism (the example of so many diseases) inhibit the production of interleukin-1. For example, it was reported that even among the drugs that are being developed currently, CE derived benzoylpropionic acid [The Japanese Society of Inflammation (11th), 1990], has inhibitory activity against the production of interleukin-1, although it is immunoregulation. Inhibitory activity against the production of interleukin-1 is also observed for a group of compounds that is of nelida (DE 2333643), T-614 as derived phenoxybenzophenone (US 4954518) and tenidap (derived hydroxyindole) as a dual inhibitor (SOH-1/5-LO).

For all these compounds, however, inhibiting the production of interleukin-1 activity is not their main activity, and therefore inhibiting the production of interleukin-l activity lower than their main action.

In recent years, an increasingly active research synthesis focused on the inhibitory activity against the production of interleukin-1. Inhibitors of the production can be divided into a group of compounds that inhibit the process of migrating inflammatory signal to the cell nucleus, and another group of compounds which inhibit the enzyme ICE, which is involved in processing of precursor interleukin-1. Well-known examples of compounds which are believed to have first action include SB203580 [tiled publication in Japanese (Kokai) application (PCT) no NE 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 97/05878), although there are examples of compounds which are believed to have the last one of these compounds does not show sufficient inhibitory activity against the production of interleukin-1.

On the other hand, it is known that various derivatives of 5,6-diphenylpyrazine have analgesic and anti-inflammatory action (Eur. J. Med. Chem., 14, 53-60, 1979). However, absolutely nothing was known regarding inhibitory activity of these derivatives of 5,6-diphenylpyridine in relation to the production of interleukin-1.

Accordingly, the present invention is the provision of compounds having excellent inhibitory activity against the production of interleukin-1, and medicines containing it as an effective ingredient.

Description of the invention

Under the circumstances, the authors undertook intensive research. In the result it was found that the derived pyridazin-3-one represented by the following formula (1), have excellent inhibitory activity against the production of interleukin-1 and are useful as drugs for the prevention and treatment of diseases of the immune system, inflammatory diseases and ischemic diseases, which led to completion of the present invention.

Namely, the present invention provides derivatives of the t substituted or unsubstituted aromatic group, AG2represents a phenyl group with the Deputy, at least in its 4-position, R1represents a linear or branched alkyl group, the alkyl group of a cyclic structure, a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenyl (lower alkyl) group, and R2represents a cyano, a carboxyl group, a (lower alkoxy)carbonyl group, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted karbamoilnuyu group, or their salts.

The present invention also provides a drug comprising as an effective ingredient derived pyridazin-3-one (1) or its salt.

Further, the present invention also provides an inhibitor of production of interleukin-1, comprising as an effective ingredient derived pyridazin-3-one (1) or its salt.

In addition, the present invention also provides a pharmaceutical composition comprising a derivative pyridazin-3-one (1) or its salt and a pharmaceutically acceptable carrier.

In addition, the present invention also provides the use of a derived pyridazin-3-one (1) or EOB treatment of disease, caused by stimulation of the production of interleukin-1, which includes the introduction of derived pyridazin-3-one (1) or its salt.

The preferred method of carrying out the invention

Derived pyridazin-3-she of the present invention represented by formula (1).

In the formula (1) examples of the aromatic group represented by AG1can include all aromatic hydrocarbon group and heterocyclic aromatic groups such as phenyl, naftalina, Peregrina and kinolinna group, and particularly preferred phenyl group. Examples one or more substituents, which may have an aromatic group include halogen atoms, lower alkoxygroup, low allylthiourea, lower alkylsulfonyl group and lower alkylsulfonyl group. Examples of halogen atoms may include fluorine atoms, chlorine, bromine and iodine. Examples of the lower alkyl fragments in the lower alkoxy, the lower alkylthio, lower alkylsulfonyl and lower alkylsulfonyl groups may include linear, branched or cyclic alkyl group containing from 1 to 6 carbon atoms, for example methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, osobenno preferred methoxy group.

Examples of substituents, which has a substituted phenyl group represented by the symbol AG2in the 4-position, are lower alkoxy, lower alkylthio, lower alkylsulfonyl and lower alkylsulfonyl group. More specifically, mention may be made of groups similar to those examples which are presented earlier in connection with AG1, preferably lower alkoxygroup, especially the methoxy group. Further, the substituted phenyl group can be substituted in the other position or positions of the atoms by halogen, lower alkoxygroup or similar. Examples of halogen atoms and lower alkoxygroup can be similar to those mentioned as examples in connection with AG1.

Examples of the linear or branched alkyl groups represented by R1are group having 2-11 carbon atoms, for example ethyl, n-sawn, ISO-propyl, n-bucilina, isobutylene, tert-bucilina, pentilla, exilda and heptylene group. Examples of alkyl groups with cyclic structures are cycloalkyl group containing 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentolate and tsiklogeksilnogo group and the lower alkyl group is ry groups of substituents in substituted phenyl or phenyl(lower alkyl) group, presents R1may include halogen atoms, lower alkyl groups and lower alkoxygroup. Examples of these halogen atoms, lower alkyl groups and lower alkoxygroup can be similar to those described above as examples in connection with AG1.

Examples of the substituents in the substituted lower alkyl groups represented by R2may include halogen atoms, hydroxy-group and substituted or unsubstituted of phthalimidopropyl. Examples of the substituents at phthalimidopropyl are atoms of halogen, nitro, lower alkoxygroup and amino groups, which may contain as substituents of lower alkyl groups, lower alkylsulfonyl group or lower alkylcarboxylic group. Examples of the substituent or substituents in substituted carbamoyl group represented by R2serve as lower alkyl groups, aromatic groups and lower alkyl groups, substituted aromatic groups. Examples of the lower alkyl fragment or fragments substituted lower alkyl or lower alkoxycarbonyl group represented by R2atom or halogen atoms as a substituent or substituents in the substituted lower alkyl or neoliberalnej, lower alkylcarboxylic and lower alkyl groups, substituted aromatic group, and aromatic fragments aromatic group and a lower alkyl group, a substituted aromatic group may be similar to those described above as examples in connection with AG1. As the aromatic group is particularly preferred phenyl or Peregrina group.

Preferred specific examples of the derivatives pyridazin-3-one (1) of the present invention can include the

5,6-bis(4-methoxyphenyl)-4-carbarnoyl-2-cyclopropylmethyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-cyano-2-ethyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-cyano-2-cycloprop-palmityl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopentylmethyl-2H-pyridazin-3-one,

2-benzyl-5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2-isopropyl-2H-pyridazin-3-one and

5,6-bis(4-methoxyphenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one.

Examples of salts derived pyridazin-3-one (1), which also belong to the present invention, are the hydrochloride, nitrate, hydrobromide, acetate, sulfate, pairs of the I, salt ammonium salt methylamine, salt dimethylammonio and trimethylammonium. In addition, derivative pyridazin-3-one (1) or its salt of the present invention can exist in the form of keto-enol tautomers and solvate. Such tautomers and solvate are also covered by the scope of the present invention.

Regarding the method of obtaining pyridazin-3-one (1) or salts thereof in accordance with the present invention has no specific limitation, and can use different methods which are usually used for the synthesis of derivatives of pyridazine, and their modifications. Derived pyridazin-3-one (1) of the present invention can be obtained, for example, in accordance with the following reaction scheme:

where Ar1, Ar2, R1and R2have the same value, R3and R4may be the same or different, and each independently represents a hydrogen atom, a lower alkyl group, an aromatic group or a lower alkyl group, a substituted aromatic group, X represents a halogen atom, R5and R6may be the same or different, and each independently represents a hydrogen atom, a halogen atom, a nitro-group, a lower alkoxygroup or amino group, which m the global group and the lowest alkylsulfonyl group, and R7represents a lower alkyl group.

The raw materials, i.e. compounds represented by formulas (2) and (3) respectively, can be obtained by known methods (J. Med. Chem., 23, 1398-1405, 1980; Eur. J. Med. Chem., 14, 53-60, 1979).

(A) obtaining the compound (1a) in which R2represents a cyano

This lanzamiento derived pyridazin-3-it can be obtained by the reaction of a compound that is represented by the formula, R1-Y, in which R1has the above values, Y represents a halogen atom or a reactive closeattention hydroxyl group, with a compound represented by the formula (2) in the presence of a base in a solvent.

Examples of bases used in the reaction may include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as alkoxides of metals. Examples of solvents may include N,N-dimethylformamide, dimethylsulfoxide, acetone and methyl ethyl ketone. The reaction may be conducted preferably at 20 to 150 C for 1-20 hours, especially at 50-130C for 2-10 hours.

(B) obtaining the compound (1b) in which R2is karbamoilnuyu

(C) obtaining the compound (1C) in which R2is ethoxycarbonyl group

This ethoxycarbonylpyrimidine derived pyridazin-3-one (1C) can be obtained by the interaction of R1-Y, which is also used in (A), with the compound represented by formula (3), in the presence of a base in a solvent.

Examples of bases used in the reaction may include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as alkoxides of metals. Examples of solvents may include N,N-dimethylformamide, dimethylsulfoxide, acetone and methyl ethyl ketone. The reaction can preferably carried out at 20-150C for 1-20 hours, especially at 50-130C for 2-10 hours.

(D) obtaining the compound (Id) in which R2represents carboxyl group

This carboxyethylidene derived pyridazin-3-one (1d) can be obtained by hydrolysis of compound (1C) in the presence of a base such as sodium hydroxide or potassium hydroxide, in a solvent known in the art methods.

(E) Obtaining soem carbamoyl derived pyridazin-3-one (1E) can be obtained by transformation of a compound (Id) by its carboxyl group to a reactive derivative, and then by reaction with the appropriate amine3R4NH in which R3and R4have the above values.

Examples of the reactive derivative of the carboxyl group may include galodamadruga and mixed anhydrides of the acids. The transformation in this galoyanized acid can be performed using oxalicacid, thionyl chloride, tiniversity or similar. The transformation into a mixed acid anhydride may be carried out with acetic anhydride, trimethyloxonium (paulinum) anhydride, methanesulfonyl anhydride, para-toluensulfonate or similar. The fusion reaction of the reactive derivative may be carried out preferably in the presence or in the absence of a base, at 10-150C for 1-20 hours, especially at 0-130C for 1-10 hours, in a solvent, such as tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, pyridine, chloroform, methylene chloride, toluene or benzene.

(F) obtaining the compound (1f) in which R2is hydroxymethylene group

This hydroxymethylamino derived pyridazin-3-one (1f) can be obtained by the reaction alkylhalogenide connection, takabatake mixed acid anhydride, and then by the interaction of sodium borohydride with mixed acid anhydride.

Examples of the solvent may include tetrahydrofuran, dioxane, diethyl ether and ethyl acetate. The reaction can be conducted preferably at 20 to 50 ° C for 0.5-10 hours, especially at 0-30 ° C for 0.5-3 hours.

(G) obtaining the compound (1g) in which R2represents a halogenated methyl group

Substituted halogenated stands derived pyridazin-3-one (1g) in which X represents a chlorine atom or a bromine atom, can be obtained by the interaction of the halogenation agent such as thionyl chloride, thienylboronic, phosphorus trichloride, Piatigorsky phosphorus or trichromacy phosphorus, with the compound (1f) in the solvent. In addition, substituted halogenated stands derived pyridazin-3-one (1g) in which X represents an iodine atom, can be obtained by the interaction of sodium iodide, potassium iodide or similar with the above compound in the solvent.

Examples of solvents for the halogenation (chlorination, synthesized) can include benzene, toluene, tetrahydrofuran, dioxane, diethyl ether, ethyl acetate and chloroform. The reaction is preferably mV which X represents an iodine atom, the solvent may be acetone, methyl ethyl ketone, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, chloroform or similar.

The reaction may be conducted preferably at 40-150C for 0.5-10 hours, especially at 50-120C within 1-5 hours.

(H) obtaining the compound (1h) in which R2represents (substituted) phthalimidomethyl group

This compound (1h), which is (substituted) phthalimidomethyl group in 4-position, can be obtained by the reaction of phthalimide potassium or substituted phthalimide potassium compound (1g) in a solvent.

Examples of solvents may include N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, benzene and toluene. The reaction may be conducted preferably at 50-150C for 0.5-5 hours, especially when 70-120C for 1-3 hours.

(I) obtaining the compound (1i), in which R2represents (lower alkoxy)carbonyl group

This substituted (lower alkoxy)carbonyl derivative pyridazin-3-one (1i) can be obtained by the interaction of the lower alcohol R7-OH, in which R7has the above values, with reactive derivatives of compounds of the base solvent, such as tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, pyridine, chloroform, methylene chloride, toluene or benzene. As an alternative it can also be obtained in a regular way obtain a complex ether, namely the interaction of the lower alcohol R7-OH with a compound (1d) in the presence of an acid catalyst in a solvent.

Intermediate and target compounds obtained by the above individual reactions can be extracted and cleaned using cleaning methods that are commonly used in organic synthesis, for example by exposure to their filtration, extraction, washing, drying, concentration, recrystallization, various chromatographic techniques processing and similar methods. Intermediate compounds can be used in subsequent reactions without any special treatment. In addition, they can also be obtained in the form of a solvate solvent, such as reaction solvents or solvent recrystallization, especially in the form of hydrates.

Derivative pyridazin-3-one (1) and their salts of the present invention, which are available as described above, have excellent inhibitory activity plebani immune system, inflammatory diseases, ischemic diseases, osteoporosis, pyemia, rheumatism, arthritis and inflammatory colitis.

Drugs of the present invention include derivatives pyridazin-3-one (1) or its salt as an effective ingredient. When used separately or in combination with pharmacologically acceptable carriers, such as agents that promote the dissolution, excipients, binders, or extenders (fillers, substitutes), they can be made in the form of various forms of pharmaceutical preparations such as tablets, capsules, granules, powders, injections and suppositories. These pharmaceutical preparations can be obtained by known methods. For example, oral preparations can be obtained by using the manufacturing appropriate formulations derived pyridazin-3-one (1) or their salts in combination with agents that promote solubility, such as resin tragakant, Arabian gum, esters of sucrose, lecithin, olive oil, soybean oil and PEG400; excipients such as starch, mannitol and lactose; binders, such as sodium carboxymethyl cellulose and hydroxypropylcellulose; leavening agents, such as crystalline cellulose and forging sintering, such as light anhydrous silicic acid.

The dose of each drug according to the present invention vary depending on body weight, age, sex, status, etc., However, it is generally preferable to introduce the drug orally or parenterally to adults in an amount of about 0.01 to 1000 mg, preferably 0.1 to 100 mg, of the compounds represented by formula (1) per day, in the form of one or more portions.

Hereinafter the present invention will be described in more detail in the following examples. However, it should be borne in mind that the present invention is not limited to these examples.

Example 1

Getting 5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopropylmethyl-2H-pyridazin-3-it

(Chloromethyl)cyclopropane (0.6 ml, 6,36 mmol) are added to a solution of 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one (1,71 g, 5,10 mmol) and potassium carbonate (2,02 g, 14,62 mmol) in N,N-dimethylformamide (5 ml) followed by stirring at a bath temperature of 80 ° C for 6 hours. Then to the reaction mixture, water is added, then extracted with ethyl acetate (300 ml). The organic layer is washed successively with water and saturated aqueous sodium chloride (brine), and zatemnenie (1,413 g, 71,5%) as yellow crystals, pale yellow prisms (chloroform-diethyl ether), so pl. covers 175.6-176,1 C.

1H-NMR (Dl3) : 0,47-of 0.54 (2H, m), 0,54 is 0.67 (2H, m), 1,36-of 1.52 (1H, m), with 3.79 (3H, s), 3,83 (3H, s) to 4.15 (2H, d, J=7,33 Hz), 6,77 (2H, d, J=9,04 Hz), to 6.88 (2H, d, J=9,04 Hz),? 7.04 baby mortality (2H, d, J=9,04 Hz), 7,16 (2H, d, J=9,03 Hz).

IR (KBR), cm-1: 2235, 1667, 1608, 1512, 1255, 1179, 1024, 837.

Example 2

Getting 5,6-bis(4-methoxyphenyl)-4-carbarnoyl-2-cyclopropylmethyl-2H-pyridazin-3-it

2 N. aqueous sodium hydroxide solution (4 ml) was added to a solution of 5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopropylmethyl-2H-pyridazin-2-she (171 mg, 0.44 mmol) in methanol (2 ml), then stirred at a bath temperature of 70 C for 8 hours. Then add a mixture of 2 N. aqueous sodium hydroxide solution (1 ml) and methanol (2 ml), then stirred at a bath temperature of 70 C for 12 hours. After the methanol is distilled off, the residue is extracted with ethyl acetate. The extract is successively washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent is distilled off. The residue (197 mg) was separated and purified using preparative chromatography on silica gel [developer: chloroform/methanol (10/1)], and then crystallized from a mixture of chloroform-diethyl ether-hexane, produces the (Dl3) : 0,43-of 0.53 (2H, m), 0,53-0,66 (2H, m), 1,38-of 1.53 (1H, m), of 3.77 (3H, s), with 3.79 (3H, s), 4,13 (2H, d, J=7,33 Hz), 5,74 (1H, Shir.C) of 6.73 (2H, d, J=8,79 Hz), 6,79 (2H, d, J=8,79 Hz), 7,00 (2H, J=8,30 Hz), 7,05 (2H, J=8,31 Hz).

IR (KBr), cm-1: 3371, 3331, 3173, 1682, 1635, 1610, 1583, 1252, 1177, 1027, 828.

Mass spectrum (m/z): 405 (M+).

Example 3

Getting 5,6-bis(4-methoxyphenyl)-4-cyano-2-ethyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and ethyliodide as starting materials, again in a similar manner the procedure of example 1, to deliver specified in the title compound with yield of 76.8%, yellow prisms (ethyl acetate), so pl. 170,5-which is 171,5 C.

1H-NMR (Dl3) : to 1.48 (3H, t, J=7,33 Hz), with 3.79 (3H, s), 3,83 (3H, s), 4,35 (2H, q, J=7,33 Hz), 6,76 (2H, d, J=8,79 Hz), to 6.88 (2H, d, J=9,03 Hz),? 7.04 baby mortality (2H, d, J=9,03 Hz), to 7.15 (2H, d, J=9,03 Hz).

IR (KBr), cm-1: 2232, 1660, 1602, 1516, 1255, 1174, 1024, 840.

Mass spectrum (m/z): 361 (M+).

Example 4

Getting 5,6-bis(4-methoxyphenyl)-4-carbarnoyl-2-ethyl-2H - pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2-ethyl-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 2, to deliver specified in the header of the connection to the output 69,8%, pale yellow is, ,34 (2H, q, J=to 7.32 Hz), 5,69 (1H, Shir.C) of 6.73 (2H, d, J=8,79 Hz), 6,79 (2H, d, J=9,03 Hz), 6,9-7,05 (1H, W), 7,01 (2H, d, J=9,03 Hz), 7,02 (2H, d, J=9.0 Hz).

IR (KBr), cm-1: 3428, 3316, 1660, 1647, 1610, 1520, 1512, 1249, 1183, 1026, 839.

Example 5

Getting 5,6-bis(4-methoxyphenyl)-4-cyano-2-n-propyl-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and 1-bromopropane as starting materials, again in a similar manner the procedure of example 1, to deliver specified in the title compound with yield of 72.6%, pale yellow scales (ethyl acetate-diethyl ether), so pl. 151,4-151,9 C.

1H-NMR (Dl3) : of 1.03 (3H, t, J=7,6 Hz), was 1.94 (2H, Sextus, J=7,6 Hz), with 3.79 (3H, s), of 3.80 (3H, s), 4,25 (2H, t, J=7,6 Hz), 6,77 (2H, d, J=9.0 Hz), to 6.88 (2H, d, J=9.0 Hz), 7,03 (2H, d, J=9.0 Hz), 7,14 (2H, d, J=8,8 Hz).

IR (KBr), cm-1: 1665, 1608, 1609, 1512, 1252, 1178, 834.

Mass spectrum (m/z): 375 (M+).

Example 6

Getting 5,6-bis(4-methoxyphenyl)-4-carbarnoyl-2-n-propyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2-n-propyl-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 2, to deliver specified in the header of the connection to the output of 67.6%, colorless needles (ethyl acetate-hexane), so pl. 167,3-180,,69 (1H, Shir.), of 6.73 (2H, d, J=9.0 Hz), 6,79 (2H, d, J=8,8 Hz), of 6.99 (2H, d, J=8,3 Hz), 7,02 (2H, d, J=8.5 Hz), was 7.08 (1H, Shir.).

IR (KBr), cm-1: 3428, 1675, 1637, 1611, 1585, 1516, 1252, 1179.

Mass spectrum (m/z): 393 (M+).

Example 7

Getting 5,6-bis(4-methoxyphenyl)-4-cyano-2-isopropyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and isopropylchloride as starting materials, again in a similar manner the procedure of example 1, to deliver specified in the title compound with yield of 72.6%, pale yellow crystals (ethyl acetate-diethyl ether), so pl. 196,7-197,6 C.

1H-NMR (Dl3) : 1,46 (6N, d, J=6.6 Hz), with 3.79 (3H, s), of 3.84 (3H, s) 5,41 (1H, Sept, J=6, 6 Hz), 6,77 (2H, d, J=8.5 Hz), 6.89 in (2H, d, J=8.5 Hz), 7,05 (2H, d, J=8.5 Hz), 7,17 (2H, d, J=8,5 Hz).

IR (KBr), cm-1: 2118, 1667, 1609, 1516, 1383, 1364, 1254, 1180, 843.

Mass spectrum (m/z): 375 (M+).

Example 8

Getting 5,6-bis(4-methoxyphenyl)-4-carbarnoyl-2-isopropyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2-isopropyl-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 2, to deliver specified in the header of the connection to the output 72,0%, slightly yellow needles (chloroform-ethylacetate, J=6.6 Hz), to 5.66 (1H, W), of 6.73 (2H, d, J=9.0 Hz), to 6.80 (2H, d, J=8,8 Hz), 6,93 (1H, W), 7,01 (2H, d, J=8,8 Hz),? 7.04 baby mortality (2H, d, J=8,8 Hz).

IR (KBr), cm-1: 3348, 1681, 1636, 1610, 1514, 1384, 1365, 1251, 1180, 834.

Mass spectrum (m/z): 393 (M+).

Example 9

Getting 5,6-bis(4-methoxyphenyl)-2-n-butyl-4-cyano-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and n-butyl chloride as starting materials, again in a similar manner the procedure of example 1, to deliver specified in the title compound with yield of 72.6%, pale yellow scales (ethyl acetate-diethyl ether), so pl. RUR 134.4-135,5 C.

1H-NMR (Dl3) : 0,99 (3H, t, J=7,6 Hz) of 1.44 (2H, Sextus, J=7,6 Hz), 1,89 (2H, Quint, J=7,6 Hz), with 3.79 (3H, s), 3,83 (3H, s), the 4.29 (2H, t, J=7,6 Hz), 6,77 (2H, d, J=8,8 Hz), to 6.88 (2H, d, J=9.0 Hz), 7,03 (2H, d, J=8,8 Hz), to 7.15 (1H, d, J=8,8 Hz).

IR (KBr), cm-1: 2962, 2934, 2838, 2223, 1663, 1607, 1512, 1252, 1178, 836.

Mass spectrum (m/z): 389 (M+).

Example 10

Getting 5,6-bis(4-methoxyphenyl)-2-n-butyl-4-carbarnoyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-2-n-butyl-4-cyano-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 2, to deliver specified in the header of the connection vyhoda the J=7,6 Hz), to 1.45 (2H, Sextus, J=7,6 Hz), a 1.88 (2H, Quint, J=7,6 Hz), of 3.77 (3H, s), with 3.79 (3H, s), 4,28 (2H, t, J=7,6 Hz), 5,70 (1H, W), of 6.73 (2H, d, J=8,8 Hz), 6,79 (2H, d, J=8,8 Hz), 7,00 (2H, d, J=8,3 Hz), 7,01 (2H, d, J=8,8 Hz), was 7.08 (1H, Shir.).

IR (KBr), cm-1: 3427, 1688, 1631, 1610, 1515, 1253, 1179, 833.

Mass spectrum (m/z): 407 (M+).

Example 11

Getting 5,6-bis(4-methoxyphenyl)-4-cyano-2-isobutyl-2H-pyridazin-3-one

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and isobutylene as starting materials, again in a similar manner the procedure of example 1, to deliver specified in the header of the connection to the output 71,8%, pale yellow scales (ethyl acetate-hexane).

1H-NMR (Dl3) : 1,02 (6N, d, J=6.6 Hz), is 2.37 (1H, Sept, J=6.8 Hz), with 3.79 (3H, s), 3,83 (3H, s), of 4.12 (2H, d, J=7,3 Hz), 6,77 (2H, d, J=9.0 Hz), to 6.88 (2H, d, J=8,8 Hz), 7,03 (2H, d, J=8,8 Hz), 7,16 (2H, d, J=8,8 Hz).

IR (KBr), cm-1: 2227, 1664, 1607, 1383, 1363, 1256, 1180, 834.

Mass spectrum (m/z): 389 (M+).

Example 12

Getting 5,6-bis(4-methoxyphenyl)-4-carbarnoyl-2-isobutyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2-isobutyl-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 2, to deliver specified in the header of the connection is B>3) : 1,02 (6N, d, J=6.8 Hz), of 2.38 (1H, Sept, J=6.8 Hz), of 3.77 (3H, s), with 3.79 (3H, s), 4,11 (2H, d, J=7,3 Hz), 5,71 (1H, W), of 6.73 (2H, d, J=9.0 Hz), 6,79 (2H, d, J=8,8 Hz), of 6.99 (2H, d, J=9.0 Hz),? 7.04 baby mortality (2H, d, J=9.0 Hz), 7,12 (1H, Shir.).

IR (KBr), cm-1: 3410, 1685, 1641, 1611, 1512, 1255, 1178, 830.

Mass spectrum (m/z): 407 (M+).

Example 13

Getting 5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopentylmethyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and cyclopentylmethyl as starting materials, again in a similar manner the procedure of example 1, to deliver specified in the header of the connection to the output 42,4%, yellow needles (ethyl acetate-diethyl ether), so pl. 180,2-180,7 C.

1H-NMR (Dl3) : 1,36-of 1.44 (2H, m), 1.56 to 1,81 (6N, m) of 2.56 (1H, Sept, J=7,6 Hz), with 3.79 (3H, s), 3,83 (3H, s), 4,24 (2H, d, J=7,6 Hz), 6,77 (2H, d, J=8,8 Hz), to 6.88 (2H, d, J=8,8 Hz), 7,03 (2H, d, J=8,8 Hz), 7,16 (2H, d, J=8,8 Hz).

IR (KBr), cm-1: 2221, 1655, 1607, 1512, 1254, 1175, 835.

Mass spectrum (m/z): 415 (M+).

Example 14

Getting 5,6-bis(4-methoxyphenyl)-4-carbarnoyl-2-cyclopentylmethyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopentylmethyl-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of the use of the new ether), so pl. 183,8-184,6 C.

1H-NMR (Dl3) : 1,19-to 1.82 (8H, m), 2,59 (1H, Sept, J=7,6 Hz), of 3.77 (3H, s), with 3.79 (3H, s) to 4.23 (2H, d, J=7,6 Hz), of 5.68 (1H, W), of 6.73 (2H, d, J=8,8 Hz), 6,79 (2H, d, J=8,8 Hz), of 6.99 (2H, d, J=8.5 Hz), 7,02 (2H, d, J=8.5 Hz), 7,12 (1H, Shir.).

IR (KBr), cm-1: 3432, 1688, 1631, 1610, 1515, 1254, 1178, 830.

Mass spectrum (m/z): 433 (M+).

Example 15

Getting 5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclohexylmethyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and cyclohexylmethanol as starting materials, again in a similar manner the procedure of example 1, to deliver specified in the title compound with yield of 45.0%, yellow needles (chloroform-ethyl acetate), so pl. to 185.0-186,8 C.

1H-NMR (Dl3) : of 1.05 to 1.33 (5H, m) of 1.65 and 1.80 (5H, m), 2.00 in a 2.12 (1H, m), with 3.79 (3H, s), 3,83 (3H, s), 4,14 (2H, d, J=7,3 Hz), 6,77 (2H, d, J=9.0 Hz), to 6.88 (2H, d, J=9.0 Hz), 7,03 (2H, d, J=8,8 Hz), 7,16 (2H, d, J=9,0 Hz).

IR (KBr), cm-1: 2223, 1658, 1607, 1512, 1254, 1175, 835.

Mass spectrum (m/z): 429 (M+).

Example 16

Getting 5,6-bis(4-methoxyphenyl)-4-carbarnoyl-2-cyclohexylmethyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclohexylmethyl-2H-pyridazin-3-one as starting material, repeating the same period the s needles (ethyl acetate-hexane), so pl. 183,9-184,5 C.

1H-NMR (Dl3) : 1,06-1,32 (5H, m), 1.55V to 1.76 (5H, m), 2,03-of 2.08 (1H, m), of 3.77 (3H, s), with 3.79 (3H, s), of 4.12 (2H, d, J=7,3 Hz), 5,69 (1H, W), of 6.73 (2H, d, J=8,8 Hz), 6,79 (2H, d, J=8.5 Hz), of 6.99 (2H, d, J=8.5 Hz), 7,02 (2H, d, J=8.5 Hz), 7,12 (1H, Shir.).

IR (KBr), cm-1: 3432, 1690, 1629, 1609, 1515, 1253, 1177, 830.

Mass spectrum (m/z): 447 (M+).

Example 17

Getting 2-benzyl-5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and benzylchloride as starting materials, again in a similar manner the procedure of example 1, to deliver specified in the title compound with yield of 65.4%, orange needles (chloroform-diethyl ether), so pl. 178,8-179,2 C.

1H-NMR (Dl3) : with 3.79 (3H, s), 3,82 (3H, s), 5,43 (2H, s) 6,76 (2H, d, J=9.0 Hz), 6,86 (2H, d, J=9.0 Hz), 7,01 (2H, d, J=8,8 Hz), 7,12 (2H, d, J=9.0 Hz), 7,32-7,40 (3H, m), 7,55-7,58 (2H, m).

IR (KBr), cm-1: 2228, 1662, 1609, 1513, 1253, 1179, 836.

Mass spectrum (m/z): 423 (M+).

Example 18

Getting 2-benzyl-5,6-bis(4-methoxyphenyl)-4-carbarnoyl-2H-pyridazin-3-it

Using 2-benzyl-5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 2, obtaining as a result a CLASS="ptx2">

1H-NMR (Dl3) : of 3.77 (3H, s), of 3.78 (3H, s), 5,43 (2H, s), 5,62 (1H, W), of 6.73 (2H, d, J=9.0 Hz), 6,78 (2H, d, J=8,8 Hz), 6,93 (1H, W), of 6.99 (4H, d, J=8,8 Hz), 7,30-7,40 (3H, m), 7,54-7,56 (2H, m).

IR (KBr), cm-1: 3402, 1676, 1640, 1611, 1513, 1255, 1179, 834.

Mass spectrum (m/z): 441 (M+).

Example 19

Getting 5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2H-pyridazin-3-it

Potassium carbonate (2,72 g) and isobutyramide (1.08 g) are added to a solution of 5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2H-pyridazin-3-one (1.50 g, of 3.94 mmol) in N,N-dimethylformamide (15 ml), followed by stirring at 80 ° C for 4 hours. After the reaction mixture is concentrated, water is added, then extracted with ethyl acetate. The extract is dried over anhydrous sodium carbonate, the solvent is distilled off under reduced pressure and the residue is crystallized from a mixture of ethyl acetate-hexane, obtaining mentioned in the title compound (1.54 g, 89.4 per cent) in the form of colorless prisms, so pl. 134,3-134,7 C.

1H-NMR (Dl3) : 1,02 (6N, d, J=6.6 Hz), of 1.09 (3H, t, J=7,1 Hz), 2,39 (1H, nonet, J=6,8 Hz), of 3.77 (3H, s), with 3.79 (3H, s), 4.09 to (2H, d, J=7,3 Hz) to 4.17 (2H, q, J=7,1 Hz), 6,74 (2H, d, J=8,8 Hz), 6,79 (2H, d, J=8,8 Hz), 7,03 (2H, d, J=8,8 Hz),? 7.04 baby mortality (2H, d, J=8,8 Hz).

IR (KBr), cm-1: 1732, 1651, 1610, 1516, 1293, 1253, 1183, 1027, 841.

Mass spectrum (m/z): 436 (M+)2">

2 N. aqueous sodium hydroxide solution (50 ml) was added to a solution of 5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2-isobutyl-2H-pyridazin-3-one (1.4 g, is 3.21 mmol) in ethanol (50 ml) followed by heating under conditions of reflux distilled for 3 hours. The ethanol is distilled off under reduced pressure and to the residue add hydrochloric acid to neutralize him. Precipitated precipitated crystals are collected by filtration, and then recrystallized from a mixture of ethanol-hexane, obtaining mentioned in the title compound (1.07 g, 81,3%) as yellow prisms, so pl. 186,5-187,0 C.

1H-NMR (Dl3) : 1,06 (6N, d, J=7,1 Hz) to 2.41 (1H, nonet, J=7,1 Hz), of 3.77 (3H, s), of 3.80 (3H, s), 4,20 (2H, d, J=7,1 Hz), 6.73 x (2H, d, J=8,8 Hz), for 6.81 (2H, d, J=8,8 Hz), 6,92-6,98 (4H, m).

IR (KBr), cm-1: 1745, 1610, 1578, 1561, 1514, 1464, 1292, 1252, 1180, 1027, 834.

Mass spectrum (m/z): 408 (M+).

Example 21

Getting 5,6-bis(4-methoxyphenyl)-2-isobutyl-4-methylcarbamoyl-2H-pyridazin-3-it

p-Toluensulfonate (84 mg) are added to a solution of 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one (150 mg, and 0.37 mmol) in pyridine (5 ml) followed by stirring at room temperature for 30 minutes Then add methylaminopropane (124 mg) and the mixture is stirred for sodium. The solvent is distilled off under reduced pressure. The residue was separated and purified using chromatography on a column of silica gel. Carry out crystallization from a mixture of chloroform-hexane, to deliver specified in the header connection (to 76.4 mg, 49,4%) as slightly yellow needles, so pl. 88,9-89,7 C.

1H-NMR (Dl3) : 1,01 (6N, d, J=6.6 Hz), a 2.36 (1H, Sept, J=6.8 Hz), 2,82 (3H, d, J=4.9 Hz), of 3.77 (3H, s), of 3.78 (3H, s), 4.09 to (2H, d, J=7,3 Hz), 6,72 (2H, d, J=8.5 Hz), 6,78 (2H, d, J=8.5 Hz), 6,98 (2H, d, J=8.5 Hz), of 6.99 (2H, d, J=8.5 Hz), 7,32 (1H, Shir.kV, J=4,9 Hz).

IR (KBr), cm-1: 1629, 1611, 1515, 1292, 1251, 1179, 1030.

Mass spectrum (m/z): 421 (M+).

Example 22

Getting 5,6-bis(4-methoxyphenyl)-4-dimethylcarbamoyl-2-isobutyl-2H-pyridazin-3-it

Thionyl chloride (43,7 mg) are added to a solution of 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one (100 mg, 0.24 mmol) in benzene (5 ml) followed by stirring at 75S for 2 hours. The reaction mixture is distilled under reduced pressure. To the residue is added benzene (5 ml) and dimethylaminohydrolase (100 mg) and the mixture is then heated overnight under conditions of reflux distilled. To the reaction mixture are added water and then extracted with ethyl acetate. The extract is washed with water and then dried over anhydrous Sul who ate chromatography on silica gel (developer: ethyl acetate), and then crystallized from a mixture of chloroform-hexane, to deliver specified in the title compound in quantitative yield as a colourless needles, so pl. RUR 188.6-189,2 C.

1H-NMR (Dl3) : and 1.00 (3H, d, J=6.6 Hz), of 1.03 (3H, d, J=6.6 Hz), 2,31 is 2.46 (1H, m), of 2.72 (3H, s), is 2.88 (3H, s), of 3.77 (3H, s), with 3.79 (3H, s) 4,08 (1H, DD, J=12,4; 7,1 Hz), 4,10 (1H, DD, J=12,4; and 7.6 Hz), 6,74 (2H, d, J=9.0 Hz), 6,78 (2H, d, J=9.0 Hz), 7,00-7,14 (4H, m).

IR (KBr), cm-1: 1645, 1609, 1513, 1466, 1309, 1302, 1291, 1251, 1183, 1027.

Mass spectrum (m/z): 435 (M+).

Example 23

Getting 5,6-bis(4-methoxyphenyl)-2-isobutyl-4-phenylcarbamoyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one and aniline as starting materials, again in a similar manner the procedure of example 22, to deliver specified in the header of the connection to the output 89,0%, pale yellow needles (chloroform-hexane), so pl. of 105.5-106,2 C.

1H-NMR (Dl3) : 1,02 (6N, d, J=6.8 Hz), 2,39 (1H, Sept, J=6.8 Hz), of 3.77 (3H, s), of 3.78 (3H, s), 4,10 (2H, d, J=7,1 Hz), 6,74 (2H, d, J=8,8 Hz), 6,78 (2H, d, J=8,8 Hz), 6,98 (2H, d, J=8,8 Hz), 7,03 (2H, d, J=8,8 Hz), 7,19-7,27 (3H, m) to 7.50 (2H, d, J=7,6 Hz), 10,00 (1H, Shir.C).

IR (KBr), cm-1: 1624, 1610, 1582, 1552, 1516, 1500, 1444, 1292, 1253, 1179, 1030.

Mass spectrum (m/z): 483 (M+).

Example 24

1H-NMR (Dl3) 1,01 (6N, d, J=6.6 Hz), 2,28 is 2.43 (1H, m) 3,778 (3H, s) 3,784 (3H, s), Android 4.04 (2H, d, J=7,3 Hz), 6,74 (2H, d, J=8,8 Hz), to 6.80 (2H, d, J=8,8 Hz), 6,98 (2H, d, J=8,8 Hz), 7,01 (2H, d, J=8,8 Hz), 7,42 (2H, d, J=6.3 Hz), at 8.36 (2H, d, J=6.3 Hz), 10,81 (1H, Shir.C).

IR (KBr), cm-1: 1701, 1610, 1594, 1516, 1337, 1292, 1252, 1179, 1032, 832.

Mass spectrum (m/z): 484 (M+).

Example 25

Getting 5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2-isopropyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2H-pyridazin-3-one and Isopropylamine as starting materials, again in a similar manner the procedure of example 19, to deliver specified in the title compound with yield of 92.3% as colorless prisms (chloroform-hexane), so pl. 163,0-163,2 C.

1H-NMR (Dl3) : a 1.08 (3H, t, J=7,1 Hz), 1,44 (6N, d, J=6.6 Hz), of 3.78 (3H, s), of 3.80 (3H, s) to 4.17 (2H, q, J=7,1 Hz), 5,35-5,46 (1H, m), 6,74 (2H, d, J=8,8 Hz), to 6.80 (2H, d, J=8,8 Hz), 7,05 (2H, d, J=8,8 Hz), 7,06 (2H, J=8,8 Hz).

IR (KBr), cm-1: 2974, 2938, 1732, 1645, 1611, 1516, 1254, 1029, 840.

Mass spectrum (m/z): 422 (M+).

Example 26

On the l)-4-etoxycarbonyl-2-isopropyl-2H-pyridazin-3-one as starting material, repeating in a similar manner the procedure of example 20, to deliver specified in the header of the connection to the output is 97.9%, slightly yellow prisms (chloroform-hexane), so pl. 213,7-214,9 C (With decomposition).

1H-NMR (Dl3) : 1,50 (6N, d, J=6.8 Hz), of 3.78 (3H, s), of 3.80 (3H, s), 5.40 to-the 5.51 (1H, m), 6.73 x (2H, d, J=8,8 Hz), PC 6.82 (2H, d, J=8,8 Hz), to 6.95 (2H, d, J=8,8 Hz), 6,97 (2H, d, J=8,8 Hz), 14,50 (1H, Shir.).

IR (KBr), cm-1: 1740, 1610, 1560, 1514, 1251, 1178.

Mass spectrum (m/z): 394 (M+).

Example 27

Getting 5,6-bis(4-methoxyphenyl)-2-isopropyl-4-methylcarbamoyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isopropyl-2H-pyridazin-3-one and methylaminopropane as starting materials, again in a similar manner the procedure of example 22, to deliver specified in the title compound with yield of 92.3% as colorless prisms (chloroform-hexane), so pl. to 244.6-245,7 C.

1H-NMR (Dl3) : 1,44 (6N, d, J=6.6 Hz), of 2.81 (3H, d, J=4.9 Hz), of 3.77 (3H, s), with 3.79 (3H, s), 5,34-of 5.45 (1H, m), 6.73 x (2H, d, J=8,8 Hz), 6,78 (2H, d, J=8,8 Hz), of 6.96? 7.04 baby mortality (5H, m), [7,009 (2H, d, J=8,8 Hz) 7,014 (2H, d, J=8,8 Hz), 1H, Shir.].

IR (KBr), cm-1: 3302, 1660, 1625, 1610, 1585, 1512, 1251, 1177.

Example 28

Getting 5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-4-etoxycarbonyl-2H-pyridazin is the quality of raw materials, repeating in a similar manner the procedure of example 19, to deliver specified in the title compound with yield of 89.1%, colorless needles (ethyl acetate-hexane), so pl. 149,9-to 150.7 C.

1H-NMR (Dl3) : 0,46-of 0.53 (2H, m), 0.55 to to 0.62 (2H, m) a 1.08 (3H, t, J=7,1 Hz), 1,47 (1H, TTT, J=7,8; to 7.6 and 4.9 Hz), of 3.77 (3H, s), with 3.79 (3H, s), of 4.12 (2H, d, J=7,6 Hz) to 4.17 (2H, q, J=7,1 Hz), 6,74 (2H, d, J=9.0 Hz), to 6.80 (2H, d, J=9.0 Hz), 7.03 is-7,07 (4H, m).

IR (KBr), cm-1: 1734, 1648, 1516, 1293, 1254, 1183, 1026, 843.

Mass spectrum (m/z): 434 (M+).

Example 29

Getting 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-cyclopropylmethyl-4-etoxycarbonyl-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 20, to deliver specified in the title compound in quantitative yield, pale yellow prisms (chloroform-hexane), so pl. 196,5-197,8 C.

1H-NMR (Dl3) : 0,46-of 0.56 (2H, m), of 0.58 and 0.68 (2H, m), 1,49 (1H, TTT, J=7,8; 7,6; and 4.6 Hz), 3,76 (3H, s), with 3.79 (3H, s), 4,22 (2H, d, J=7,6 Hz), 6.73 x (2H, d, J=8,8 Hz), for 6.81 (2H, d, J=8,8 Hz), 6,97 (4H, d, J=8,8 Hz).

IR (KBr), cm-1: 1738, 1646, 1610, 1582, 1563, 1515, 1465, 1291, 1252, 1180.

Mass spectrum (m/z): 406 (M+).

Example 30

Getting 5,6-bis(4-methox is hydroxy-2-cyclopropylmethyl-2H-pyridazin-3-one and methylaminopropane as starting materials, repeating in a similar manner the procedure of example 22, to deliver specified in the header of the connection to the output 88,2%, pale yellow prisms (chloroform-hexane), so pl. 195,8-196,3 C.

1H-NMR (Dl3) : 0,42-0,50 (2H, m), 0,53-0,61 (2H, m) of 1.44 (1H, TTT, J=8,1; to 7.3 and 4.9 Hz), of 2.81 (3H, d, J=4.9 Hz), of 3.77 (3H, s), of 3.78 (3H, s), 4,10 (2H, d, J=7,3 Hz), 6.73 x (2H, d, J=9.0 Hz), 6,78 (2H, d, J=9.0 Hz), of 6.99 (2H, d, J=9.0 Hz), 7,01 (2H, d, J=9.0 Hz), 7,22 (1H, Shir.).

IR (KBr), cm-1: 1664, 1629, 1610, 1583, 1513, 1292, 1252, 1179, 1030, 835.

Mass spectrum (m/z): 419 (M+).

Example 31

Getting 4-benzylcarbamoyl-5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-one and benzylamine as starting materials, again in a similar manner the procedure of example 22, to deliver specified in the title compound in quantitative yield, slightly yellow needles (chloroform-hexane), so pl. 166,9-167,5 C.

1H-NMR (Dl3) : 0,46-0,52 (2H, m), 0,53-0,61 (2H, m) of 1.46 (1H, TTT, J=7,8; to 7.6 and 4.9 Hz), 3,76 (3H, s), of 3.80 (3H, s), of 4.12 (2H, d, J=7,6 Hz), 4,47 (2H, d, J=5,9 Hz), 6.73 x (2H, d, J=8,8 Hz), 6,77 (2H, d, J=8,8 Hz), 6,98-7,05 (7H, m), 7,20-of 7.25 (3H, m).

IR (KBr), cm-1: 1645, 1610, 1586, 1515, 1455, 1292, 1252, 1179, 1029, 834.

Mass spectrum (m/z): 495 (M+

Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-one and 2- (aminomethyl)pyridine as starting materials, again in a similar manner the procedure of example 22, to deliver specified in the title compound in quantitative yield, slightly yellow needles (chloroform-hexane), so pl. 205,2-KZT 205.7 C.

1H-NMR (Dl3) : 0,45-0,52 (2H, m), 0,53-of 0.62 (2H, m) to 1.48 (1H, TTT, J=7,8; to 7.6 and 4.9 Hz), 3,74 (3H, s), of 3.77 (3H, s), 4,14 (2H, d, J=7,6 Hz), 4,58 (2H, d, J=5.4 Hz), 6,70 (2H, d, J=8,8 Hz), 6.73 x (2H, d, J=8,8 Hz), 7,01 (2H, d, J=8,8 Hz), 7,03 (2H, d, J=8,8 Hz), 7,09-to 7.15 (2H, m), EUR 7.57 (1H, DDD, J=7,8; 7,6; and 1.7 Hz), a 7.62 (1H, Shir. t, J=5.4 Hz), to 8.45 (1H, DDD, J=4,9; 1,7; 1.0 Hz).

IR (KBr), cm-1: 1661, 1639, 1611, 1572, 1517, 1253, 1180.

Mass spectrum (m/z): 496 (M+).

Example 33

Getting 2-benzyl-5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2H-pyridazin-3-one and benzylchloride as starting materials, again in a similar manner the procedure of example 22, to deliver specified in the title compound with yield of 99.1%, colorless prisms (chloroform-hexane), so pl. 159,4-159,9 C.

1H-NMR (Dl3) : of 1.06 (3H, t, J=7,1 Hz), of 3.77 (3H, s), of 3.78 (3H, s) to 4.15 (2H, q, J=7,1 Hz), 5,41 (2H, s), 6,74 (2H, d, J=8,8 Hz), 6,78 (2N 1287, 1251, 1227, 1184, 1143, 1029, 837.

Mass spectrum (m/z): 470 (M+).

Example 34

Getting 2-benzyl-5,6-bis(4-methoxyphenyl)-4-carboxy-2H-pyridazin-3-it

Using 2-benzyl-5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 20, to deliver specified in the title compound with yield of 89.4 per cent, yellow prisms (chloroform-methanol-hexane), so pl. 192,0-192,9 C.

1H-NMR (Dl3) : 3,47 (1H, s), of 3.77 (3H, s), of 3.78 (3H, s), of 5.50 (2H, s), 6.73 x (2H, d, J=8,8 Hz), 6,79 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz) 6,94 (2H, d, J=8,8 Hz), 7,33-7,42 (3H, m), 7,55 (2H, DD, J=7,8; 1,7 Hz).

IR (KBr), cm-1: 1744, 1611, 1559, 1514, 1292, 1253, 1183, 1028.

Mass spectrum (m/z): 442 (M+).

Example 35

Getting 2-benzyl-5,6-bis(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-it

Using 2-benzyl-5,6-bis(4-methoxyphenyl)-4-carboxy-2H-pyridazin-3-one and methylaminopropane as starting materials, again in a similar manner the procedure of example 22, to deliver specified in the header of the connection to the output 90,9%, slightly yellow prisms (chloroform-hexane), so pl. 183,5-184,3 C.

1H-NMR (Dl3) : 2,78 (3H, d, J=4.9 Hz), 3,76 (3H, s), of 3.77 (3H, s), 5.40 to (2 is 1.5 Hz).

IR (KBr), cm-1: 1654, 1636, 1610, 1515, 1293, 1250, 1179, 834.

Mass spectrum (m/z): 455 (M+).

Example 36

Getting 2-benzyl-5,6-bis(4-methoxyphenyl)-4-ethylcarboxyl-2H-pyridazin-3-it

Using 2-benzyl-5,6-bis(4-methoxyphenyl)-4-carboxy-2H-pyridazin-3-one and etilamingidrokhlorida as starting materials, again in a similar manner the procedure of example 22, to deliver specified in the title compound with yield of 59.0%, colorless needles (chloroform-hexane), so pl. 187,2-187,8 C.

1H-NMR (Dl3) : 0,99 (3H, t, J=7,3 Hz), 3,24 (2H, DQC, J=7,3; 5,9 Hz), 3,76 (3H, s), of 3.77 (3H, s), of 5.40 (2H, s), 6,68-to 6.80 (5H, m) 6,988 (2H, d, J=8,8 Hz) 6,990 (2H, d, J=8,8 Hz), 7,28-7,38 (3H, m), 7,53 (2H, DD, J=8,1; 1.5 Hz).

IR (KBr), cm-1: 1682, 1659, 1643, 1633, 1610, 1563, 1514, 1289, 1254, 1182, 1029, 842, 701.

Mass spectrum (m/z): 469 (M+).

Example 37

Getting 2-benzyl-5,6-bis(4-methoxyphenyl)-4-dimethylcarbamoyl-2H-pyridazin-3-it

Using 2-benzyl-5,6-bis(4-methoxyphenyl)-4-carboxy-2H-pyridazin-3-one and dimethylaminohydrolase as starting materials, again in a similar manner the procedure of example 22, to deliver specified in the title compound with yield of 42.1%, and pale yellow prisms (chloroform-hexane), so pl. 176,9-177,2 C.

IR (KBr), cm-1: 1645, 1609, 1512, 1302, 1293, 1253, 1181, 1026, 838.

Mass spectrum (m/z): 469 (M+).

Example 38

Getting 5,6-bis(4-methoxyphenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-it

The triethylamine (278,7 mg) and ethylchloride (to 298.9 mg) is added under ice cooling to a solution of 5,6-bis(4-methoxyphenyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one (750 mg, of 1.84 mmol) in tetrahydrofuran (8 ml) followed by stirring for 1 hour. The reaction mixture is filtered. Under ice cooling to the filtrate add borohydride sodium (277,8 mg) and stirred for 1 hour. The mixture is stirred at room temperature for another 2 hours. The reaction mixture was concentrated, add saturated aqueous solution of ameriglide. After the mixture is extracted with ethyl acetate, the extract washed successively with saturated aqueous sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure. The residue was separated and purified by chromatography on a column of silica gel, and then crystallized from a mixture of ethyl acetate-hexane, obtaining specified in the header of the connection (of 383.0 mg, the output is, C) of 3.80 (3H, s), 4,11 (2H, d, J=7,3 Hz), 4,39 (1H, dt, J=6,6; 1.2 Hz), 4,51 (2H, d, J=6, 6 Hz), 6,72 (2H, d, J=9.0 Hz), 6,83 (2H, d, J=9.0 Hz), 6,94 (2H, d, J=9.0 Hz), 7,00 (2H, d, J=9.0 Hz).

IR (KBr), cm-1: 3346, 2960, 1634, 1611, 1585, 1571, 1515, 1466, 1292, 1252, 1180, 1035.

Mass spectrum (m/z): 394 (M+).

Example 39

Getting 5,6-bis(4-methoxyphenyl)-4-chloromethyl-2-isobutyl-2H-pyridazin-3-it

Thionyl chloride (306,1 mg) are added to a solution of 5,6-bis(4-methoxyphenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one (203 mg, 0.51 mmol) in benzene (10 ml) followed by stirring at 75S for 2 hours. To the reaction mixture, water is added, then extracted with chloroform. After the extract is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The residue was separated and purified using preparative chromatography on silica gel (developer: hexane/ethyl acetate (2/1)), getting mentioned in the title compound (180,8 mg, 85.1%) are in the form of a yellow resin.

1H-NMR (Dl3) : 1,03 (6N, DD, J=6,8; 1.0 Hz), 2,32-2,49 (1H, m), of 3.73 (3H, d, J=1.5 Hz), 3,80 (3H, d, J=1.5 Hz), 4,12 (2H, d, J=7,3 Hz), and 4.40 (2H, s) of 6.71 (2H, DD, J=8,8; 1.0 Hz), 6,86 (2H, DD, J=8,8; 0,7 Hz), 7,02 (2H, DD, J=8,8; 0,7 Hz), 7,10 (2H, DD, J=8,8; 1.0 Hz).

IR (KBr), cm-1: 1636, 1615, 1515, 1466, 1292, 1252, 1186, 1035, 1029.

Mass spectrum (m/z): 412 (M+

Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 38, to deliver specified in the title compound with yield of 47.7%, colorless prisms (ethyl acetate-hexane), so pl. 124,5 was 124.9 C.

1H-NMR (Dl3) : 0,46-of 0.53 (2H, m), of 0.55 to 0.63 (2H, m), 1,47 (1H, TTT, J=8,1; to 7.3 and 4.9 Hz), 3,76 (3H, s), 3,81 (3H, s), 4,14 (2H, d, J=7,3 Hz), and 4.40 (1H, t, J=6.6 Hz), to 4.52 (2H, d, J=6, 6 Hz), of 6.71 (2H, d, J=8,9 Hz), 6,83 (2H, d, J=8,9 Hz) 6,94 (2H, d, J=8,9 Hz), 7,01 (2H, d, J=8,9 Hz).

IR (KBr), cm-1: 1621, 1582, 1563, 1513, 1292, 1251, 1182, 1036, 835.

Mass spectrum (m/z): 392 (M+).

Example 41

Getting 5,6-bis(4-methoxyphenyl)-4-chloromethyl-2-cyclopropylmethyl-2H-pyridazin-3-it

Using 5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-4-hydroxymethyl-2H-pyridazin-3-one as starting material, is repeated in a similar manner the procedure of example 39, to deliver specified in the title compound in quantitative yield, colorless prisms (chloroform-hexane), so pl. 117,8-118,6 C.

1H-NMR (Dl3) : 0,48-of 0.54 (2H, m), 0.56 to to 0.62 (2H, m), 1,49 (1H, TTT, J=7,8; to 7.6 and 4.9 Hz), 3,76 (3H, s), 3,83 (3H, s) to 4.15 (2H, d, J=7,6 Hz) to 4.41 (2H, s), 6,72 (2H, d, J=9.0 Hz), 6.87 in (2H, d, J=9.0 Hz), 7,02 (2H, d, J=9.0 Hz), 7,10 (2H, d, J=9.0 Hz).<>the example 42

Getting 5,6-bis(4-methoxyphenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-it

Phthalimide potassium (324,4 mg) are added to a solution of 5,6-bis(4-methoxyphenyl)-4-chloromethyl-2-isobutyl-2H-pyridazin-3-one (180,8 mg, 0.44 mmol) in N,N-dimethylformamide (6 ml) followed by stirring at 80 ° C for 2 hours. After the reaction mixture is concentrated, water is added, then extracted with ethyl acetate. The resulting extract is then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure. The residue was separated and purified by chromatography on a column of silica gel, and then crystallized from a mixture of ethyl acetate-hexane, obtaining specified in the header connection (215,8 mg, 94,1%) as colourless needles, so pl. 74,3-76,6 C.

1H-NMR (Dl3) : 0,95 (6N, d, J=6.6 Hz), 2,28-to 2.40 (1H, m), 3,70 (3H, s), 3,74 (3H, s), a 4.03 (2H, d, J=7,6 Hz), 4,80 (2H, s), 6,69 (2H, d, J=8.5 Hz), of 6.71 (2H, d, J=8.5 Hz), of 6.99 (2H, d, J=8.5 Hz),? 7.04 baby mortality (2H, d, J=8.5 Hz), to 7.64 (2H, DD, J=5,4; 3,2 Hz), 7,72 (2H, DD, J=5,4; 3,2 Hz).

IR (KBr), cm-1: 1717, 1642, 1611, 1515, 1467, 1396, 1290, 1250, 1179, 1031, 835, 722, 714.

Mass spectrum (m/z): 523 (M+).

Test 1. Inhibitory activity against the production of interleukin-1

Conduct the following test, the results of which are played is ucirvine interleukin-1.

Cells HL-60 cultured for 4 days prior to confluently in RPMI 1640 medium with addition thereto 10% fetal bovine serum (FBS). Wednesday centrifuged. The supernatant is removed, the cells are then suspended at a concentration of 1106cells/ml in RPMI 1640 medium with 3% FBS and add the lipopolysaccharide to obtain a final concentration of 10 μg/ml Culture inoculant 1 ml/well in 24-well plate. Add a test compound in the amount of 1 ml/well and then cultured for 3 days. Three days later using ELISA to determine the number of interleukin-1 in every culture. Each value IR50determine, by comparing the output with the control, to which was added a test sample. The results for some representatives of the compounds presented in the table.

As can be seen from the table, it was found that the compounds of the present invention have an extremely high inhibitory activity against the production of interleukin-1 in comparison with the comparative compounds, which are compounds described in Eur. J. Med. Chem., 14, 53-60, 1979.

The ability of the industrial implementation

Derivative pyridazin-3-one and their salts, which unsaturation-1 and are useful as drugs for the prevention and treatment of diseases of the immune system, inflammatory diseases and ischemic diseases.

1. Derived pyridazin-3-one represented by the following formula (1):

in which AG1represents the lower alkoxyphenyl group;

AG2represents a phenyl group having a lower alkoxy at least in its 4th position;

R1represents a linear or branched alkyl group having 2-11 carbon atoms, cycloalkyl group having 3-7 carbon atoms, a lower alkyl group substituted by one or more cycloalkyl groups containing 3 to 7 carbon atoms, or phenyl or phenyl(lower alkyl) group which may be substituted by one or more halogen atoms, lower alkyl groups and lower alkoxygroup;

R2represents a cyano, a carboxyl group, a (lower alkoxy)carbonyl group, a lower alkyl group which may be substituted by one or more halogen atoms, hydroxy groups and phthalimidopropyl, or carbomoyl group which may be substituted by one or two lower alkyl groups, phenyl, peredelnyj or lower alkyl groups, substituted phenyl or peredelnoj Setenil)-4-carbarnoyl-2-cyclopropylmethyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-cyano-2-ethyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopropylmethyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-cyano-2-cyclopentylmethyl-2H-pyridazin-3-one,

2-benzyl-5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2H-pyridazin-3-one,

5,6-bis(4-methoxyphenyl)-4-etoxycarbonyl-2-isopropyl-2H-pyridazin-3-one, or

5,6-bis(4-methoxyphenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one.

3. Drug for inhibiting the production of interleukin-1, comprising as an effective ingredient derived pyridazin-3-one or its salt according to any one of paragraphs.1 and 2.

4. Drug under item 3, which is a prophylactic or therapeutic agent against diseases caused by stimulation of the production of interleukin-1.

5. The inhibitor of the production of interleukin-1, comprising as an effective ingredient derived pyridazin-3-one or its salt according to any one of paragraphs.1 and 2.

6. Pharmaceutical composition having inhibitory activity against the production of interleukin-1, including derived pyridazin-3-one or its salt according to any one of paragraphs. 1 and 2, and the pharmaceutically preelementary production of interleukin-1.

8. A method of treating diseases caused by stimulation of the production of interleukin-1, which includes the introduction of derived pyridazin-3-one or its salts according to any one of paragraphs.1 and 2.

 

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< / BR>
where Z denotes a group of General formula II

< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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