Phenylpyridazine compounds and medicinal agents comprising thereof

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 scope of the invention

The present invention relates to compounds phenylpyridazin having excellent inhibitory activity against the production of interleukin-1βmethods of prevention and treatment of diseases of the immune system, inflammatory diseases, ischemic diseases and the like with the use of these compounds and drugs containing these compounds as active ingredients.

Prior art

In many diseases, such as rheumatism, arthritis, osteoporosis, inflammatory colitis, immunodeficiency syndrome, pyemia, 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 the inflammatory cytokine known as interleukin-1β. Interleukin-1β and serves to induce the synthesis of the enzyme, such as collagenase and PLA2, which is reputed to be involved in inflammation and intra-articular introduction to animals causes multiple sustavnoi destruction, highly similar to rheumatoid arthritis. On the other hand, in normal vivo activity of interleukin-1β control the receptors of interleukin-1 soluble receptor of interleukin-1 receptor antagonists of interleukin-1.

From the research the project, were carried out using recombinant data of inhibiting the biological activity of substances, anti-interleukin-1β antibodies, anti-receptor antibodies and mice with a shock dose of models of various diseases, found that interleukin-1β plays a Central role in the body, leading to increased efficiency of substances with anti-interleukin-1β-inhibitory activity as therapeutic agents for such diseases.

For example, it is reported that immunosuppressants and steroids, used to treat rheumatism, inhibit the production of interleukin-1β. It is reported that even among drugs currently in development, CE derived benzoylpropionic acid [The Japanese Society of Inflammation (11th), 1990], for example, has inhibitory activity against the production of interleukin-1βeven though it is immunoregulation. Inhibitory activity against the production of interleukin-1β see also in the group of compounds called "MOR-2 selective inhibitors, including, for example, nimesulide, as derived phenoxycarbonylamino (DE 2333643), T-614, as derived phenoxybenzophenone (US 4954518), and tenidap (derived oxyindole), as dual inhibitors (COX-1/5-LO).

However, for all these compounds the activity of inhibiting the production of interleukin-1&x003B2; is not the primary action, so their inhibitory activity against the production of interleukin-1β below their primary activity.

In recent years, studies are progressing with increasing activity and focused on the inhibitory activity against the production of interleukin-1β. Inhibitors of production can be classified under the group of compounds which inhibit the transfer process of the inflammatory signal to the cell nucleus and the process of transcription and translation, and another group of compounds which inhibit the enzyme ICE, which operates in the conversion of precursor interleukin-1β. Well-known examples of compounds which are believed to have a primary action, include SB203580 [laid patent application (Kokai) Japanese (PCT) No. HEI 7-503017], FR167653 (Eur. J. Pharm., 327, 169-175, 1997), T-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), while there are examples of compounds which are believed to have a secondary action, include VE-13045, which is a peptide compound (Cytokine, 8(5), 377-386, 1996).

However, none of these compounds does not demonstrate sufficient inhibitory activity against the production of interleukin-1β.

On the other hand, it is known that various derivatives of 5,6-diphenylpyrazine OK is to provide analgesic and anti-inflammatory effect (Eur. J. Med. Chem., 14, 53060, 1979). However, absolutely nothing is known about inhibitory activity of these derivatives of 5,6-diphenylpyrazine against the production of interleukin-1β.

In recent years, in JP 7-69894, WO 9841511, WO 9910331, WO 9910332, WO 9925697 and WO 9944995 revealed some derivatives pyridazine, as having inhibitory activity against the production of interleukin-1β. However, they differ in chemical structure from the compounds of the present invention.

Thus, one purpose of the present invention is the provision of compounds having excellent inhibitory activity against the production of interleukin-1β.

Brief description of the invention

The present invention relates to compounds of pyridine represented by the General formula (I)having excellent inhibitory activity against the production of interleukin-1β and are useful as drugs for the prevention and treatment of diseases of the immune system, inflammatory diseases and ischemic diseases.

Namely, the present invention relates to the connection phenylpyridazin, which is represented by the following formula (I):

where R1represents a substituted or unsubstituted phenyl group or a substituted or unsubstituted pyridyloxy group;

R2predstavljaet lower alkoxygroup, the lower allylthiourea, lower alkylsulfonyl group or lower alkylsulfonyl group;

R3represents a hydrogen atom or a lower alkoxygroup;

or R2and R3together can be condensed, forming alkylenedioxy;

R4represents hydrogen, halogen, cyano, carboxyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted lower alkylsulfanyl, substituted or unsubstituted lower alkylsulfonyl, substituted or unsubstituted lower alkylsulfonate, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocycle, substituted or unsubstituted, phenoxy, substituted or unsubstituted, phenylthio, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted, pyridyloxy, substituted or unsubstituted, morpholino, substituted or unsubstituted morpholinoethyl, substituted or unsubstituted piperidinylcarbonyl, substituted or unsubstituted 1-piperazinylcarbonyl or substituted or unsubstituted amino, and

n is 0 or 1,

provided that, if R1is 4-metoksifenilny group, R2represents a methoxy group, and R3represents a hydrogen atom,R 4cannot be hydrogen or halogen, and R1cannot be 4-(methylsulphonyl)phenyl or 4-(aminosulfonyl)phenyl;

or its salt.

The present invention relates to a medicinal product, comprising as active ingredient a compound phenylpyridazin (I) or its salt.

The present invention also relates to an inhibitor of the production of interleukin-1βcomprising as an effective ingredient the compound phenylpyridazin (I) or its salt.

The present invention relates also to pharmaceutical compositions comprising a compound phenylpyridazin (I) or its salt as an effective ingredient and a pharmacologically acceptable carrier.

The present invention relates also to a method of treatment of a disease caused by stimulation of the production of interleukin-1βthat is distinguished by the introduction connections phenylpyridazin (I) or its salt to the needy in this patient.

In addition, the present invention relates also to the use of compounds phenylpyridazin (I) or salts thereof for the manufacture of a medicinal product.

A detailed description of the preferred options

Examples of lower alkyl groups and lower alkyl fragments in the lower alkoxygroup, lowest allylthiourea, lower alkylsulfonyl group, lower alkyls Honiley group and lowest alkylsulfonates, used in this description, are linear, branched or cyclic lower alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, cyclopentyl, cyclohexyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. Examples of the halogen atoms may include fluorine atoms, chlorine, bromine and iodine.

Examples of one or more groups of substituents in the substituted phenyl or peredelnoj group denoted by R1in the formula (I)include halogen, hydroxyl, alkyl, lower alkoxy and phenylthiourea, and particularly preferred halogen, lower alkoxy and phenylthiourea. Among the preferred Halogens fluorine and chlorine, and among the lowest alkoxygroup methoxy group is preferred. These groups of the substituents are preferably in position 4 of the phenyl group, although, if required, can be placed in any other position. A preferred group R1is a phenyl group, or Peregrina group, or a group substituted by one or more halogen, lower alkoxygroup or phenylthiophene. Preferred groups R1are 4-methoxyphenyl, 4-pyridyl, phenyl, 4-forfinal, 4-chlorophenyl or 4-(phenylthio)phenyl.

As the lower alkyl is of ragment lower alkoxy, lower alkylthio, lower alkylsulfonyl or lower alkylsulfonyl the groups denoted by R2particularly preferred is a methyl group. The most preferred R2are methoxy, methylthio or methylsulfonyl group.

As the lower alkoxygroup denoted by R3particularly preferred is a methoxy group.

In addition, if R2and R3United, forming alkylenedioxy, the preferred atlantoxerus.

Examples of one or more groups of substituents in the substituted lower alkyl groups denoted by R4include halogen, hydroxy, cyano, nitro, amino, carboxy and substituted or unsubstituted aminocarbonyl group. Illustration of one or more groups of substituents in aminocarbonyl group is hydroxyl and lower alkyl groups. Examples of one or more groups of substituents in the substituted lower alkenylphenol group denoted by R4include halogen and aryl groups. Examples of the lower alkenylphenol groups include linear, branched or cyclic lower alkeneamine group having 1-6 carbon atoms, and particularly preferred allyl group. Examples of one or more groups of substituents in the substituted lower allylthiourea, substituted lower alkylsulfonyl group, Sames the authorized lowest alkylsulfonyl group, or substituted lower alkylsulfonates, denoted by R4include aryl groups. Illustration of one or more groups of substituents in the substituted aryl group or substituted aromatic heterocyclic group denoted by R4is halogen, lower alkyl, lower alkoxy, cyano, nitro and amino groups, and particularly preferred halogen and lower alkyl groups.

Examples of aryl groups include phenyl and groups with 6-10 carbon atoms, such as naphthyl, and particularly preferred phenyl. Examples of aromatic heterocyclic groups include 5 - or 6-membered ring containing nitrogen, and particularly preferred pyridyl. Examples of one or more groups of substituents in substituted fenoxaprop denoted by R4include halogen, cyano, nitro, amino, lower alkyl and lower alkoxygroup, among which particularly preferred halogen, cyano, nitro and lower alkoxygroup. Illustration of one or more groups of substituents in substituted phenylthio, substituted phenylsulfonyl or substituted phenylsulfonyl the groups denoted by R4is halogen, lower alkyl, lower alkoxy, cyano, nitro and amino groups, and particularly preferred halogen. Illustration of one or more groups of substituents in substituted pyridyloxy denoted by R4is halogen, lower alkyl, lower alkoxy, cyano, n the tro and an amino group. Illustration of one or more groups of substituents in substituted morpholine, substituted morpholinosydnonimine or substituted piperidinecarboxylic the groups denoted by R4is halogen, lower alkyl, lower alkoxygroup, cyano and nitro. Illustration of one or more groups of substituents in the substituted 1-piperazinylcarbonyl group denoted by R4is halogen, lower alkyl, lower alkoxy, cyano, nitro and amino groups, and particularly preferred lower alkyl groups. Illustration of one or more groups of substituents in the substituted amino group denoted by R4is lower alkyl, substituted or unsubstituted phenyl, benzyl or acyl group, among which the preferred lower alkyl, substituted or unsubstituted phenyl and benzyl. Examples of groups of substituents in the phenyl group include halogen, cyano, nitro, amino and lower alkoxygroup, preferably halogen and alkoxygroup.

Preferred groups R4are hydrogen; halogen; cyano; carboxyl; lower alkyl which may be substituted by one or more groups selected from hydroxyl, carboxyl or substituted or unsubstituted aminocarbonyl groups; lower alkenyl; lower alkylthio; lower alkylsulfonyl; lower alkylsulfonate; phenyl; phenoxy, which can be substituted by the one or more groups, selected from halogen, cyano, nitro or lower alkoxygroup; penalty, which may be substituted by one or more halogen atoms; pyridyloxy; morpholino; morpholinoethyl; 1-piperazinylcarbonyl, which may be substituted by one or more lower alkyl groups; or an amino group which may be substituted by one or more groups selected from lower alkyl, substituted or unsubstituted phenyl or benzyl groups.

In derivatives phenylpyridazin formula (I) of the present invention R1represents a substituted or unsubstituted phenyl or pyridyloxy group, R2represents lower alkoxy, lower alkylthio or lower alkylsulfonyl group, R3represents hydrogen or lower alkoxygroup, or R2and R3together can be condensed, forming alkylenedioxy. R4represents hydrogen, halogen, cyano, carboxyl, substituted or unsubstituted lower alkyl, lower alkenyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonate, substituted or unsubstituted aryl, substituted or unsubstituted, phenoxy, substituted or unsubstituted lower phenylthio, pyridyloxy, morpholino, morpholinoethyl, 1-piperazinylcarbonyl or a substituted or an unsubstituted amino group, and n is 0 or 1, provided that excluded the derived fenspiride the Zina of the formula (I), in which R4represents a hydrogen atom or halogen, R1is 4-methoxyphenyl, R2represents a methoxy group, and R3represents hydrogen; or that excluded derived phenylpyridazin formula (I)in which R1is 4-(methylsulphonyl)phenyl or 4-(aminosulfonyl)phenyl. More preferred specific examples of compounds phenylpyridazin (I) of the present invention include:

3,4-bis(4-methoxyphenyl)-6-(phenoxy)pyridazine,

3,4-bis(4-methoxyphenyl)-6-(2,3-divergence)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(2,5-divergence)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(2,6-divergence)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(3,4-divergence)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(2,3,5,6-tetraterpenes)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(2,3,4,5,6-Pantothenate)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(3,4,5-trichlorophenyl)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(4-methoxyphenoxy)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(4-nitrophenoxy)pyridin,

3,4-bis(4-methoxyphenyl)-6-(2-cianfrocca)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(3-cianfrocca)pyridazin,

6-(2,4-divergence)-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine,

6-(2,3-divergence)-3-(4-methoxyphenyl)-4-phenylpyridazin,

6-(2,4-divergence)-3-(4-methoxyphenyl)-4-phenylpyridazin,

3-(4-methoxyphenyl)-6-(2,3,4,5,6-Pantothenate)-4-FeNi is pyridazin,

3-(4-methylthiophenyl)-6-phenylthio-4-(4-phenylthiophene)pyridazin,

4-(4-chlorophenyl)-6-(2,4-divergence)-3-[4-(methylthio)phenyl]pyridazine,

3,4-bis(4-methoxyphenyl)-6-cyanopyridine and

6-cyano-3-(4-methoxyphenyl)-4-phenylpyridazin.

The way to obtain

The method of obtaining compounds of phenylpyridazin (I) of the present invention or its salt has no particular restrictions, and you can use different methods which are usually used for the synthesis of derivatives of pyridazine, and their modifications. For example, the connection phenylpyridazin (I) of the present invention or its salt can be obtained by the reaction schemes of any of the following methods to obtain 1-5.

(Method of obtaining 1)

where R1, R2and R3have the same meanings as defined above, R5represents a substituted or unsubstituted, morpholino, substituted or unsubstituted piperidine, substituted or unsubstituted 1-piperazinil or the like, R6and R7each independently represents hydrogen, hydroxyl, lower alkyl or the like.

The following methods of obtaining suggest suitable solvents, reagents, catalysts and conditions for each reaction. However, it is clear that they are merely illustrative in nature and do not limit the present invention.

In the method of obtaining vhodnye compounds (II) and (III) can be obtained by known methods (WO 9925697).

(1) Obtaining the compound (I1), in which R4denotes halogen:

The compound (I1) can be obtained by the interaction of the halogenation agent with compound (II) in a solvent.

Suitable solvents applicable in this reaction include benzene, toluene and N,N-dimethylformamide (DMF). Suitable halogenation agents are phosphorus oxychloride and thionyl chloride. Preferably the interaction at a temperature of from 20 to 150°C for 0.5-10 hours, more preferably at a temperature of from 50 to 130°C for 1-5 hours.

(2) Obtaining the compound (I2), in which R4denotes a substituted or unsubstituted fenoxaprop, compound (I3), in which R4denotes a substituted or unsubstituted phenylthiourea, compound (I4), in which R4denotes a substituted or unsubstituted pyridyloxy, compound (I5), in which R4denotes a substituted or unsubstituted morpholinopropan, or compound (I6), in which R4denotes a substituted or an unsubstituted amino group:

The compound (I2-I6each can be obtained by interaction of the corresponding compounds (I1) with R4'N, in which R4'denotes a substituted or unsubstituted fenoxaprop, substituted or unsubstituted phenylthiourea, zameshennoj the unsubstituted pyridyloxy, substituted or unsubstituted morpholinopropan or a substituted or an unsubstituted amino group, in the presence of a base in a solvent.

Suitable bases include inorganic bases such as potassium carbonate, sodium carbonate and sodium hydride; and organic bases such as alkoxides of metals. Examples of suitable solvents include DMF, dimethylsulfoxide, acetone and methyl ethyl ketone. Preferably the interaction with 20-150°C for 1-20 hours, more preferably at 50-130°C for 2-10 h.

(3) Obtaining the compound (I7), in which R4denotes a substituted or unsubstituted aryl:

The compound (I7) can be obtained by dissolving the respective compounds (I1in the solvent, the sequential addition of the palladium catalyst and arellanobond and their interaction.

Suitable for this reaction solvents include diethyl ether, tetrahydrofuran (THF), dimethoxyethane, benzene and toluene. Examples of the palladium catalyst include palladium chloride and tetrakis(triphenylphosphine)palladium. Preferably the interaction with 20-100°C for 0.5 to 2 hours, more preferably at 40-80°C for 1-1 .5 hours.

(4) Obtaining the compound (I8), in which R4denotes allylthiourea:

Connection ( 8) can be obtained by the interaction of alkylhalogenide with the corresponding compound (III) in the presence of sodium hydride in a solvent.

Suitable for this reaction solvents include DMF, dimethylsulfoxide, acetone, THF, dioxane and methyl ethyl ketone. Preferably the interaction with stirring and the temperature from 0 to 50°C for 0.5 to 2 hours, more preferably at 5-20°C for 1 hour.

(5) Obtaining the compound (I9), in which R4means alkylsulfonyl:

The compound (I9) can be obtained by oxidation of the corresponding compounds (I8in the solvent.

Suitable oxidizing agents include a mixture of osmium tetroxide-periodate sodium or metallocarborane acid. The solvent can be used chloroform, acetone, butanol or the like, or their mixture. Preferably the interaction with stirring and at a temperature of from -40 to 50°for 1-40 hours, more preferably at a temperature of from -10 to 20°C for 10-30 hours.

(6) Obtaining the compound (I10), in which R4denotes alkylsulfonates:

The compound (I9) can be obtained by interaction of the corresponding compound (II) with alkylsulfonamides in the solvent.

Suitable solvents include pyridine, picoline and lutidine. Preference is sustained fashion to interact with 10-40° C for 1-10 days, more preferably at 20-30°C for 3-5 days.

(7) Obtaining the compound (I11), in which R4denotes hydrogen:

The compound (I11) can be obtained by subjecting the corresponding compound (I1) catalytic recovery in the presence of a catalyst in a solvent.

Suitable solvents include methanol, ethanol, THF, ethyl acetate and acetic acid. As a catalyst, you can use 10% palladium on coal. It is preferable to conduct the reaction in a stream of hydrogen gas at room temperature and atmospheric pressure for 1 to 10 hours, more preferably for 4 to 5 hours.

(8) Obtaining the compound (I12), in which R4denotes hydrogen, namely, pyridazin oxide compounds:

The compound (I12) can be obtained by interaction of the corresponding compounds (I11) with hydrogen peroxide in the solvent.

A suitable solvent is acetic acid. Preferably the interaction with 20-80°C for 2-10 hours, more preferably at 40-60°C for 4-6 hours.

(9) Obtaining the compound (I13), in which R4denotes a cyano:

The compound (I13) can be obtained by interaction of the corresponding compounds (I12with allermuir agent and alkaline cyanide is atalla in the solvent.

Suitable cyanides of alkali metals include sodium cyanide and potassium cyanide. As Alliluyeva agent can be used acetic anhydride, acetylchloride, benzoyl chloride or the like. Preferably the interaction with 10-40°C for 10-40 hours, more preferably at 20-30°C for 20-30 hours.

(10) Obtaining the compound (I14), in which R4denotes carboxyl:

The compound (I14) can be obtained by hydrolysis of the corresponding compounds (I13in the presence of an inorganic acid or alkali in a solvent.

Suitable solvents include water, ethanol, methanol and mixtures thereof. As the inorganic acid can be used hydrochloric, sulphuric, nitric acid or the like. As the alkali can be used sodium hydroxide, potassium hydroxide or the like. It is preferable to conduct the reaction under stirring at a temperature of 60-140°C for 0.5 to 2 hours, more preferably at 80-120aboutC.

(11) Obtaining the compound (I15), in which R4means-COR5:

The compound (I15) can be obtained by the interaction of the compound that is represented by the formula, R5H, where R5has the same meaning as defined above, with a corresponding compound (I14in the presence of condensing agent.

Coming up is the development of condensing agents include 50% solution of cyclic anhydride 1-papapetrou acid (n=3) in ethyl acetate. The solvent can be used THF, DMF or mixtures thereof. Preferably the interaction with stirring and the temperature 10-40°C for 1-7 hours, more preferably at 20-30°C for 3-5 hours.

(12) Obtaining the compound (I16), in which R4means of alkenyl:

The compound (I16) can be obtained by the interaction of alkenylsilanes with the corresponding compound (I1in the presence of palladium catalyst in a solvent and the inert gas.

Suitable solvents include THF, benzene and toluene. As a preferred palladium catalyst tetrakis(triphenylphosphine)palladium or the like. Preferably the interaction at a temperature of 20-40°C for 0.5 to 4 hours, more preferably at a temperature of-10-10°for 0.5-1.5 hours, continuing the reaction at 20-30°C for 1-3 hours.

(13) Obtaining the compound (I17), in which R4denotes hydroxyalkyl:

The compound (I17) can be obtained by subjecting alkenylphenol group of the corresponding compounds (I16reactions of hydroporinae.

The reaction hydroporinae can be, for example, adding a solution of 9-borabicyclo[3.3.1]nonane (9-BBN) or its salt to the solvent in which the compound (I16), in an atmosphere of inert gas, such as and the gon or nitrogen, stirring the mixture at 10-40°C for 5-30 hours, preferably at 20-30°C for 10-20 hours, then adding to the reaction mixture water, an aqueous solution of alkali and hydrogen peroxide solution while cooling with ice water and subsequently mixing the thus obtained mixture at 10-40°C for 1-4 hours, preferably at 20-30°C for 1.5 to 3 hours.

(14) Obtaining the compound (I18), in which R4denotes carboxyethyl:

The compound (I18) can be obtained by subjecting compound (I17) oxidation by the oxidizing agent in a solvent.

Suitable solvents include acetone and acetic acid. As a preferred oxidant reagent Jones. Preferably the interaction with 10-40°C for 4-12 hours, more preferably at a temperature of 20-30°C for 6-10 hours.

(15) Obtaining the compound (I19), in which R4denotes alkyl, substituted substituted or unsubstituted aminocarbonyl:

The compound (I19) can be obtained by interaction of the corresponding compounds (I18and compounds represented by the formula, R6R7NH in which R6and R7have the same meanings as defined above, similarly to obtain the compound (I15).

(Method of obtaining 2)

Obtaining the compound (I20), in which R2denotes a lower alkylsulfonyl:

The compound (I20) can be obtained by oxidation of the corresponding compounds (IV) in a solvent.

In this case you can apply a reaction similar to the reaction used to obtain the compound (I9). Alternatively, as an oxidizer, you can use hydrogen peroxide and the solvent acetic acid or the like. In this case, it is preferable to carry out the interaction with 40-100°C for 0.5 to 6 hours, more preferably at 60-80°C for 2-4 hours.

(Method of obtaining 3)

Obtaining the compound (I21), in which R1denotes phenylthiophene, and R4denotes phenylthiourea:

The compound (I21) can be obtained by interaction of the corresponding compounds (I1), in which R1means halogenfrei group, with thiophenols in the presence of a base in a solvent.

Suitable bases include inorganic bases such as potassium carbonate, sodium carbonate and sodium hydride; and organic bases such as alkoxides of metals. The solvent can be used DMF), dimethyl sulfoxide, acetone, methyl ethyl ketone or the like. Preferably the interaction of p and 50-300° For 5-40 hours, more preferably at 100-200°C for 10-30 hours.

(Method 4)

In the process for 4 to obtain the compound (VII) interaction of acetone with compound (V) in the presence of a base in a solvent.

Suitable solvents include acetone, ethanol, methanol and mixtures thereof. Examples of bases include piperidine, morpholine and Diisopropylamine. Preferably the interaction with stirring and the temperature 10-40°C for 10 min-1 hour, more preferably within 20-40 minutes Alternative, as compound (VII) can be used a commercial product from Lancaster.

(1) Obtaining the compound (I22), in which R4denotes alkyl:

The compound (I22) can be obtained by the interaction of the compounds (VI) and compound (VII) in the presence of alkali metal cyanide in a solvent to obtain the compound (VIII), the interaction of hydrazine hydrate is added with the compound (VIII) in a solvent and subsequent dehydrogenization.

Suitable solvents for the interaction between the compounds (VI) and compound (VII) include DMF) and dimethylsulfoxide, and examples of the cyanide of an alkali metal include potassium cyanide and sodium cyanide.

Suitable solvents for interaction with hydrazinehydrate include ethanol and isopropanol.

Predpochtite the flax to interact with stirring and the temperature of 50-100° C for 4-10 hours, more preferably at 70 to 90°C for 6-8 hours. The reaction dehydrogenization can be made by air oxidation in a solvent such as chloroform.

(2) Obtaining the compound (I23), in which R2means alkylsulfonyl, and R4denotes alkyl:

The compound (I23) can be obtained by interaction of the corresponding compounds (I22), in which R2denotes allylthiourea, similar to the method of obtaining the compound (I20).

(Method of obtaining 5)

In the method of obtaining 5 compound (IX) can be obtained by the known method (WO 9925697). The compound (X) can be obtained by adding sitedisability (LDA) at -20°to a solution of the compound (IX) in THF, then holding interaction at room temperature for 20 min, add Allilueva and followed by their interaction at room temperature for 30 minutes, the Compound (XI) can be obtained by oxidation of compound (X) with osmium tetroxide, similar to the above method.

(1) Obtaining the compound (I24), in which R1denotes halogenfree and R4denotes hydrogen:

The compound (I24) can be obtained by the interaction of the compounds (XI) according to a similar method of obtaining the compound (I22).

(2) receipt of the compounds (I 25), pyridazine 1-oxide, in which R1denotes halogenfree and R4denotes hydrogen:

The compound (I25) can be obtained by the interaction of the compound (I24) according to a similar method of obtaining the compound (I12).

(3) Obtaining the compound (I26), in which R1denotes halogenfree and R4denotes a cyano:

The compound (I26) can be obtained by the interaction of the compound (I25) according to a similar method of obtaining the compound (I13).

The intermediate and target compounds obtained in the above-described specific reactions, you can select and clear purification methods commonly used in synthetic organic chemistry, including, but not limited to, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographic methods. Intermediate products can be used in the following reaction without purification or can be cleaned, if necessary, using conventional cleaning methods. In addition, you can get them in the form of a solvate solvent, such as reaction solvents or solvent recrystallization, in particular hydrates.

Examples of salts phenylpyridine compounds of the present invention are the hydrochloride, nitrate, hydrobromide, acetate, sulfate, para-Tolu is sulfonate, methanesulfonate, fumarate, succinate, lactate, salt, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt methylamine, salt dimethylammonio and trimethylammonium.

Phenylpyridine compounds (I) and their salts corresponding to the present invention have excellent inhibitory activity on the production of interleukin-1β and useful for the prevention and treatment of diseases caused by stimulation of the production of interleukin-1β. Stimulation of the production of interleukin-1β is the cause of many diseases, such as diseases of the immune system, inflammatory diseases, ischemic diseases, osteoporosis and pyemia. These compounds or their salts are particularly useful as medicines, such as drugs for prevention and treatment of rheumatic fever, immunodeficiency syndrome, arthritis, inflammatory colitis, ischemic heart disease, ischemic encephalopathy, ischemic nephritis, ischemic hepatitis, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease and leukemia, or inhibitors of the production of interleukin-1β.

The pharmaceutical compositions of the present invention contain as the active ingredient phenylpyridine the compound (I) or their salts. These compositions can be applied to any smooth surface shall be any ways introduction including but not limited to, oral administration in the form of tablets, capsules, granules, powders or syrups, and parenteral administration by intravenous injection, intramuscular injection, suppository, inhalation, transdermal preparations, eye drops or nasal drops. Upon receipt of pharmaceutical compositions in the form of various standard dosage forms, the active ingredients can be used alone or, if required, in combination with the usual pharmaceutically acceptable excipients, binders, substitutes, leavening agents, surfactants, lubricating agents, dispersing agents, buffers, preservatives, modifiers, flavoring agents, coating agents, solvents, diluents and/or carriers.

The dosage of each of the pharmaceutical compositions of the present invention varies depending on the body weight, age, sex and condition of the patient. But for adults, it is generally preferable oral or parenteral administration of the compounds represented by formula (I) in an amount of from about 0.01 to 1000 mg, preferably from 0.1 to 100 mg per day, in single or multiple portions.

Examples

After describing the present invention in General terms, we can obtain additional insight when referring to some specific when the EPAM, which are presented here only to illustrate and not to limit, if not stated otherwise.

Example 1

Obtaining 3,4-bis(4-methoxyphenyl)-6-phenylpyridazin

3,4-Bis(4-methoxyphenyl)-6-chloropyridazine [Eur. J. Med. Chem.-Chimica Therapeutica, 14, 53-60 (1979)] (309,3 mg, 0.95 mmol) dissolved in benzene (2 ml). Add sequentially tetrakis(triphenylphosphine)palladium [Pd(Ph3P)4] (90,6 mg, 0.08 mmol) and phenylmagnesium (1.0 M tertrahydrofuran ring solution (1.5 ml) and further stirred at 60°C for 75 minutes After adding to the reaction mixture water-methylene chloride mixture is extracted with methylene chloride and the organic layer is dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is separated and purified by chromatography on a column of silica gel [silica gel (10 g), hexane/ethyl acetate (2/1)], it is mentioned in the title compound as a pale yellow amorphous solid (129 mg, 36,9%).

1H-NMR (CDCl3) δ: a 3.83 (3H, s), of 3.84 (3H, s)6,86 (2H, d, J=9,04 Hz), make 6.90 (2H, d, J=9,04 Hz), 7,22 (2H, d, J=9,04 Hz), 7,45-of 7.55 (5H, m), 7,79 (1H, s), 8,15-to 8.20 (2H, m).

IR (film) cm-1: 1609, 1514, 1392, 1252, 1178.

Example 2

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2,4-differenlty)pyridazine

3,4-Bis(4-methoxyphenyl)-6-chloropyridazine (440 mg, 1.35 mmol) dissolved in N,N-dimethylformamide (5 ml). Added sequentially potassium carbonate (400 mg, 2,90 mmol) and 2,4-giftart OpenAL (300 mg, 2.05 mmol) and then stirred at 80°C for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue is extracted with chloroform and the organic layer is dried over anhydrous sodium sulfate. The solvent is distilled off, the residue is separated and purified preparative thin-layer chromatography on silica gel [manifesting solvent: hexane/ethyl acetate (8/1)], the obtained crystals are recrystallized from a mixture of chloroform-diethyl ether-hexane, obtaining colorless needles (RUR 219.7 mg, 37.4 per cent). TPL 112,0-level 113.0°C.

1H-NMR (CDCl3) δ: of 3.80 (3H, s), 3,81 (3H, s), to 6.80 (2H, d, J=8,79 Hz), 6,83 (2H, d, J=8,79 Hz), 6,95-7,02 (3H, m), was 7.08 (2H, d, J=8,79 Hz), was 7.36 (2H, d, J=8,79 Hz), of 7.70 (1H, DDD, J=1,71, 6.35mm, 8,79 Hz).

IR (KBr) cm-1: 1608, 1509, 1487, 1387, 1297, 1251, 1178.

Example 3

Obtaining 3,4-bis(4-methoxyphenyl)-6-(phenylthio)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (160 mg, 0,490 mmol) and phenol as starting substances in 120°C for 22 h and carry out further processing, receiving specified in the title compound as colourless needles (133,1 mg, 70.7 percent).

TPL 198,8-199,5°With (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: 3,81 (3H, s), 3,83 (3H, s), for 6.81 (2H, d, J=9,04 Hz), 6,85 (2H, d, J=8,79 Hz), to 7.09 (1H, s), to 7.15 (2H, d, J=8,79 Hz), 7,21-7,31 (3H, m), 7,34 (2H, d, J=9,04 Hz), 7,35-7,46 (2H, m).

IR (KBr) cm-1: 1608, 1512, 1489, 1419, 1397, 1251, 1216, 1174.

Note the p 4

Obtaining 3,4-bis(4-methoxyphenyl)-6-(phenoxy)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (AZN 352.5 mg, of 1.08 mmol) and thiophenol as starting substances in 100°C for 7 h and carry out further processing, receiving specified in the title compound as a colorless crystalline powder (55,8 mg, 12.9 percent). TPL 176,9-of 177.8°With (chloroform-diethyl ether).

1H-NMR(CDCl3) δ: with 3.79 (3H, s), of 3.80 (3H, s), to 6.80 (2H, d, J=8,79 Hz), for 6.81 (2H, d, J=8,79 Hz), 7,00 (2H, d, J=8,79 Hz), 7,02 (1H, s), 7,34 (2H, d, J=8,79 Hz), 7,42-7,46 (3H, m), 7,65-of 7.69 (2H, m).

IR (KBr) cm-1: 1607, 1508, 1387, 1219, 1174.

Example 5

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2,3-divergence)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (180 mg, 0,551 mmol) and 2,3-diferena as starting substances at 150°C for 19 h and carry out further processing, receiving specified in the title compound as a colorless crystalline powder (of 208.3 mg, 90,0%). TPL 157,5-159,0°With (chloroform-hexane).

1H-NMR (CDCl3) δ: of 3.80 (3H, s), 3,83 (3H, s), for 6.81 (2H, d, J=8,79 Hz), to 6.88 (2H, d, J=8,79 Hz), 7,07-7,17 (3H, m), 7,18 (1H, d, J=8,79 Hz), 7,22 (1H, s), 7,34 (2H, d, J=8,79 Hz).

IR (KBr) cm-1: 1609, 1513, 1478, 1420, 1396, 1372, 1295, 1251, 1201, 1176.

Example 6

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2,4-divergence)pyridazine

Oppo is ichno method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0,613 mmol) and 2,4-diferena as starting substances in 120°C for 13 h and carry out further processing, receiving specified in the title compound as a colorless crystalline powder (136 mg, 52.5 per cent). TPL 141,7-142,5° (diethyl ether-hexane).

1H-NMR (CDCl3) δ: of 3.80 (3H, s), 3,83 (3H, s), to 6.80 (2H, d, J=8,79 Hz), 6.87 in (2H, d, J=8,79 Hz), 6.90 to-7,02 (2H, m), 7,17 (2H, d, J=8,79 Hz), 7,19 (1H, s), 7,32 (1H, s), 7,33 (2H, d, J=8,79 Hz).

IR (KBr) cm-1: 1610, 1506, 1395, 1299, 1249, 1208, 1179.

Example 7

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2,5-divergence)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0,613 mmol) and 2,5-diferena as starting substances at 150°C for 24 hours and carry out further processing, receiving specified in the title compound as a colorless crystalline powder (235,5 mg, 91.5 per cent). TPL of 174.4-175,2°With (chloroform-hexane).

1H-NMR(CDCl3) δ: of 3.80 (3H, s), 3,83 (3H, s), for 6.81 (2H, d, J=8,79 Hz), 6.87 in (2H, d, J=8,79 Hz)6,94 (1H, m), 7,09-7,17 (2H, m), 7,18 (2H, d, J=8,79 Hz), 7,20 (1H, s), 7,34 (2H, d, J=8,79 Hz).

IR (KBr) cm-1: 1608, 1507, 1419, 1398, 1372, 1301, 1250, 1209, 1173.

Example 8

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2,6-divergence)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0,613 mmol) and 2,6-diferena as starting substances, the ri 150° C for 72 h and carry out further processing, receiving specified in the title compound as a colorless crystalline powder (101,0 mg, 39.3 per cent). TPL 204,7-206,4°With (chloroform-hexane).

1H-NMR (CDCl3) δ: of 3.80 (3H, s), 3,83 (3H, s), to 6.80 (2H, d, J=8,79 Hz), 6.87 in (2H, d, J=8,79 Hz), 7,03 (2H, t, J=EUR 7.57 Hz), 7,18 (1H, m), 7,19 (2H, d, J=8,79 Hz), 7,27 (1H, s).

IR (KBr) cm-1: 1609, 1513, 1499, 1479, 1394, 1295, 1251, 1221, 1178.

Example 9

Obtaining 3,4-bis(4-methoxyphenyl)-6-(3,4-divergence)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0,459 mmol) and 3,4-diferena as starting substances at 150°C for 14 h and carry out further processing, receiving specified in the title compound as a pale yellow amorphous solid (190,2 mg, 99.1 per cent).

1H-NMR (CDCl3)δ: 3,81 (3H, s), 3,83 (3H, s), for 6.81 (2H, d, J=8,79 Hz)6,86 (2H, d, J=8,79 Hz), 7,05 (1H, m), 7,11-of 7.23 (5H, m), 7,33 (2H, d, J=8,79 Hz).

IR (KBr) cm-1: 1610, 1587, 1574, 1506, 1419, 1394, 1373, 1298, 1251, 1209, 1179.

Example 10

Obtaining 3,4-bis(4-methoxyphenyl)-6-(3,5-divergence)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (250 mg, 0,766 mmol) and 3,5-diferena as starting substances at 150°C for 6 hours and carry out further processing, receiving specified in the title compound as colourless needles(315,0 mg, 98,0%). TPL 135,1-137,5°With (ethyl acetate-diethyl ether-hexane).

1H-NMR (CDCl3) δ: 3,81 (3H, s), 3,83 (3H, s)6,70 (1H, TT, J=1,20, 9,03 Hz), 6,80-6,90 (6N, m), to 7.15 (1H, s), 7,16 (2H, d, J=8,79 Hz), 7,35 (2H, d, J=8,79 Hz).

IR (KBr) cm-1: 1609, 1514, 1466, 1394, 1373, 1253, 1212, 1182.

Example 11

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2,3,5,6-tetraterpenes)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0,613 mmol) and 2,3,5,6-tetrafluorophenol as starting substances at 150°C for 12 h and carry out further processing, receiving specified in the title compound as a colorless crystalline powder (105,7 mg, 37.8%, respectively).

TPL 172,5-of 174.5°C (hexane).

1H-NMR (CDCl3) δ: 3,81 (3H, s), of 3.84 (3H, s), PC 6.82 (2H, d, J=8,79 Hz), to 6.88 (2H, d, J=8,79 Hz), 7,03 (1H, TT, J=7,08, 10,01 Hz), 7,19 (2H, d, J=8,79 Hz), 7,31 (1H, s), 7,34 (2H, d, J=8,79 Hz).

IR (KBr) cm-1: 1610, 1526, 1515, 1484, 1393, 1264, 1250, 1203, 1181.

Example 12

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2,3,4,5,6-Pantothenate)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0,613 mmol) and 2,3,4,5,6-pentafluorophenol as starting substances at 150°C for 24 hours and carry out further processing, receiving specified in the title compound as a colourless amorphous solid (covers 175.6 mg, 60.5 per cent).

1H-NMR (CDCl3) ´ : 3,81 (3H, s), of 3.84 (3H, s), PC 6.82 (2H, d, J=8,79 Hz), to 6.88 (2H, d, J=8,79 Hz), 7,19 (2H, d, J=8,79 Hz), 7,31 (1H, s), 7,33 (2H, d, J=8,79 Hz).

IR (film) cm-1: 1610, 1520, 1472, 1395, 1371, 1298, 1253, 1205, 1180.

Example 13

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2,4-dichlorphenoxy)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0,495 mmol) and 2,4-dichlorphenol as starting substances at 150°C for 15 h and carry out further processing, receiving specified in the title compound as a colorless crystalline powder (195,5 mg, 93.9 per cent). TPL 152,2-152,8°With (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: of 3.80 (3H, s), 3,83 (3H, s), to 6.80 (2H, d, J=8,79 Hz), 6.87 in (2H, d, J=8,79 Hz), 7,18 (2H, d, J=8,79 Hz), 7,20 (1H, s), 7,29-7,33 (2H, m), 7,34 (2H, d, J=8,79 Hz), 7,51 (1H, d, J=1,71 Hz),

IR (KBr) cm-1: 1608, 1513, 1473, 1420, 1394, 1372, 1255, 1231, 1179.

Example 14

Obtaining 3,4-bis(4-methoxyphenyl)-6-(3,4,5-tryptophanate)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0,613 mmol) and 3,4,5-trichlorophenol [Ger. Offen. DE 2515699 19751023 (Dow Chemical Co., U.S.A.)] as starting substances in 100°C for 72 hours and carry out further processing, receiving specified in the title compound as a colourless amorphous solid (125,3 mg, 40.6 per cent).

1H-NMR (CDCl3) δ: with 3.79 (3H, s), 3,81 (3H, s), for 6.81 (2H, d, J=8,79 Hz), at 6.84 (2H, d, J=8,79 Hz), 7,10 (2 is, d, J=8,79 Hz), 7,27 (1H, s), of 7.36 (2H, d, J=8,79 Hz), 7,68 (2H, s).

IR (film) cm-1: 1608, 1510, 1385, 1298, 1252, 1179.

Example 15

Obtaining 3,4-bis(4-methoxyphenyl)-6-(4-methoxyphenoxy)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0,459 mmol) and 4-methoxyphenol as starting substances at 150°C for 24 hours and carry out further processing, receiving specified in the title compound as colorless prisms (180,1 mg, 94.7 percent). So pl. 146,7-148,2°With (ethyl acetate-diethyl ether-hexane).

1H-NMR (CDCl3) δ: of 3.80 (3H, s), 3,82 (3H, s), 3,83 (3H, s), to 6.80 (2H, d, J=9,03 Hz), 6,85 (2H, d, J=9,03 Hz)6,94 (2H, d, J=9,03 Hz), 7,05 (1H, s),7,13 (2H, d, J=9,03 Hz), 7,20 (2H, d, J=9,03 Hz), 7,33 (2H, d, J=9,03 Hz).

IR (KBr) cm-1: 1610, 1512, 1504, 1396, 1252, 1219, 1180.

Example 16

Obtaining 3,4-bis(4-methoxyphenyl)-6-(3-nitrophenoxy)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (106,9 mg, 0,327 mmol) and 3-NITROPHENOL as a source of substances at 150°C for 17 h and carry out further processing, receiving specified in the title compound as light yellow prisms (140,4 mg of 99.9%). TPL 172,2-174,0°With (ethyl acetate-diethyl ether-hexane).

1H-NMR (CDCl3) δ: 3,81 (3H, s), of 3.84 (3H, s), PC 6.82 (2H, d, J=8,79 Hz), 6.89 in (2H, d, J=8,79 Hz), 7,18 (2H, d, J=8,79 Hz), 7,21 (1H, s), 7,34 (2H, d, J=8,79 Hz), 7,60 (1H, DD, J=7,82, 8,30 Hz), to 7.67 (1H, d is d, J=1,22, 2,20, 8,30 Hz)to 8.12 (1H, DDD, J=1,22, 1,95, of 7.82 Hz), 8,17 (1H, DD, J=1,95, 2.20 Hz).

IR (KBr) cm-1: 1610, 1528, 1514, 1395, 1347, 1253, 1227, 1178.

Example 17

Obtaining 3,4-bis(4-methoxyphenyl)-6-(4-nitrophenoxy)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0,495 mmol) and 4-NITROPHENOL as a source of substances at 150°C for 15 h and carry out further processing, receiving specified in the title compound as a pale yellow crystalline powder (146,1 mg, 74.1 per cent).

TPL 197,7-201,1°With (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: 3,81 (3H, s), 3,83 (3H, s), for 6.81 (2H, d, J=8,79 Hz), 6,85 (2H, d, J=8,79 Hz), 7,03 (2H, s), 7,11 (2H, d, J=8,79 Hz), 7,19 (2H, d, J=8,79 Hz), 8,08 (2H, d, J=9,04 Hz), a 8.34 (2H, d, J=9,04 Hz).

IR (KBr) cm-1: 1675, 1608, 1590, 1515, 1488, 1345, 1296, 1250, 1181.

Example 18

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2-cianfrocca)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (110 mg, of 0.337 mmol) and 2-cyanoprop as starting substances at 150°C for 24 hours. and carry out further processing, receiving specified in the title compound as a pale yellow amorphous solid (121,4 mg, 88.1 per cent). TPL 197,7-201,1°With (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: 3,81 (3H, s), of 3.84 (3H, s), PC 6.82 (2H, d, J=8,79 Hz), to 6.88 (2H, d, J=8,79 Hz), 7,19 (2H, d, J=8,79 Hz), 7,29 (1H, s), 7,34 (2H, d, J=8,79 G is), to 7.35 (1H, DDD, J=1,71, 7,51, 8,79 Hz), 7,54 (1H, DD, J=0,98, 8,79 Hz), to 7.67 (1H, DDD, J=1,22, 7,51, 8,79 Hz), 7,73 (1H, DD, J=1,22, to 7.32 Hz).

IR (KBr) cm-1: 3233, 1609, 1514, 1486, 1395, 1252, 1235, 1179.

Example 19

Obtaining 3,4-bis(4-methoxyphenyl)-6-(3-cianfrocca)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (175 mg, 0,536 mmol) and 3-cyanoprop as starting substances at 150°C for 19 h and carry out further processing, receiving specified in the title compound as colorless prisms (165 mg, 75.2 per cent). TPL 169,9-172,7°With (ethyl acetate-diethyl ether-hexane).

1H-NMR (CDCl3) δ: 3,81 (3H, s), 3,83 (3H, s), PC 6.82 (2H, d, J=8,79 Hz), to 6.88 (2H, d, J=8,79 Hz), 7,17 (2H, d, J=8,79 Hz), 7,18 (1H, s), 7,34 (2H, d, J=8,79 Hz), 7,52-to 7.61 (4H, m).

IR (KBr) cm-1: 2236, 1608, 1514, 1255, 1242, 1179.

Example 20

Obtaining 3,4-bis(4-methoxyphenyl)-6-(4-cianfrocca)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0,459 mmol) and 4-cyanoprop as starting substances at 150°C for 13 h and carry out further processing, receiving specified in the title compound as a pale yellow crystalline powder (108,0 mg, 57.5%, respectively). TPL 167,3-170,5°With (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: 3,81 (3H, s), 3,83 (3H, s), 6,83 (2H, d, J=8,79 Hz), 6.89 in (2H, d, J=8,79 Hz), 7,17 (2H, d, J=8,79 Hz), 7,19 (1H, s), 7,35 (2H, d, J=8,79 Hz), 7,42 (2H, d, J=8,55 G IS),7,73 (2H, d, J=8,55 Hz).

IR (KBr) cm-1: 2228, 1608, 1584, 1513, 1501, 1421, 1394, 1372, 1298, 1254, 1224, 1177.

Example 21

Obtaining 3,4-bis(4-methoxyphenyl)-6-(4-pyridyloxy)pyridazine

Similar to the method of example 2 subjected to the interaction of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0,613 mmol) and 4-hydroxypyridine as starting substances at 150°C for 22 h and carry out further processing, receiving specified in the title compound as a pale yellow crystalline powder (201,6 mg, up 85.2%).

1H-NMR (CDCl3) δ: of 3.84 (3H, s), 3,85 (3H, s), to 6.58 (2H, d, J=8,06 Hz), 6.87 in (2H, d, J=8,79 Hz), make 6.90 (2H, d, J=8,79 Hz), 7,20 (2H, d, J=8,79 Hz), 7,42 (2H, d, J=8,79 Hz), 7,49 (1H, s), 8,31 (2H, d, J=8,06 Hz).

IR (KBr) cm-1: 1637, 1609, 1567, 1514, 1254, 1190.

Example 22

Obtaining 6-chloro-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine

The phosphorus oxychloride (100 ml) are added to 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-ONU [WO 9925697] (3.00 g, the 10.8 mmol) and stirred at 90°C for 1 hour. The reaction mixture was concentrated under reduced pressure and add to the residue water. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium carbonate and then dried over anhydrous sodium sulfate. The extract was concentrated under reduced pressure, the residue is crystallized from a mixture of ethyl acetate-diethyl ether, obtaining mentioned in the title compound as light-W is ltyh prisms, TPL which is 186,2-188,9° (2,88 g, 90,0%).

1H-NMR (CDCl3) δ: is 3.82 (3H, s), 6,85 (2H, d, J=8,55 Hz), to 7.15 (2H, d, J=6,10 Hz), 7,33 (2H, d, J=8,55 Hz), 7,49 (1H, s)8,64 (2H, d, J=6,10 Hz).

IR (KBr) cm-1: 1608, 1579, 1562, 1520, 1387, 1254, 1182.

Example 23

Getting 6-(2,4-divergence)-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine

Similar to the method of example 2 subjected to the interaction of 2,6-chloro-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine (150 mg, 0,504 mmol) and 2,4-diferena as starting substances at 150°C for 25 hours and carry out further processing, receiving specified in the title compound as a pale yellow amorphous solid (157,0 mg, 79.6%of).

1H-NMR (CDCl3) δ: of 3.80 (3H, s), for 6.81 (2H, d, J=8,78 Hz), 6,1-7,03 (2H, m), 7,18 (2H, d, J=6,11 Hz), 7,24 (1H, s), 7,28 (2H, d, J=8,78 Hz), 7,29 (1H, m)8,64 (2H, d, J=6,11 Hz).

IR (film) cm-1: 1610, 1586, 1506, 1399, 1374, 1250, 1212, 1178.

Example 24

Obtaining 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridazin

6-(4-Methoxyphenyl)-5-phenyl-2H-pyridazin-3-one [WO 9925697] (2.76 g, 9,60 mmol) and phosphorus oxychloride (2.8 ml) was stirred at 90°C for 5 h in benzene. The reaction mixture was treated similarly to the method of example 22, receiving specified in the title compound in the form of light yellow-brown oil (1,83 g, 64.3 per cent).

1H-NMR (CDCl3) δ: 3,86 (3H, s), PC 6.82 (2H, d, J=8,79 Hz), 7,19-7,22 (2H, m), 7,33-7,39 (5H, m), of 7.48 (1H, s).

IR (film) cm-1: 1609, 1579, 1558, 152, 1499, 1386, 1337, 1298, 1253, 1177.

Example 25

Getting 6-(2,3-divergence)-3-(4-methoxyphenyl)-4-phenylpyridazin

Similar to the method of example 2 subjected to the interaction of 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridazin (210 mg, 0,708 mmol) and 2,3-diferena as starting substances at 150°C for 20 h and carry out further processing, receiving specified in the title compound as colorless prisms (230,3 mg, 83.4%of). So pl. 155, 2mm-of 156.6aboutWith (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: with 3.79 (3H, s), 6,79 (2H, d, J=8,8 Hz),? 7.04 baby mortality-to 7.18 (2H, m), 7,21-7,42 (8H, m).

IR (KBr) cm-1: 1608, 1508, 1478, 1399, 1371, 1362, 1255, 1224, 1207, 1182, 1033, 1014, 849.

Mass spectrum m/z: 390(M+)

Example 26

Getting 6-(2,4-divergence)-3-(4-methoxyphenyl)-4-phenylpyridazin

Similar to the method of example 2 subjected to the interaction of 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridazin (215 mg, 0,725 mmol) and 2,4-diferena as starting substances at 150°C for 20 h and carry out further processing, receiving specified in the title compound as colourless needles (169,7 mg, 60,0%). So pl. 169,0-169,9aboutWith (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: with 3.79 (3H, s), is 6.78 (2H, d, J=8,79 Hz), to 6.88-7.03 is (2H, m), 7,19-7,42 (N, m).

IR (KBr) cm-1: 1508, 1396, 1249, 1213.

Mass spectrum m/z: 390(M+)

Example 27

Obtaining 3-(4-methoxyphenyl)-6-(2,3,4,5,6-Pantothenate)-4-phenylpyridazin

Similar to the method of example 2 p will gorhaut the interaction of 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridazin (200 mg, 0,675 mmol) and 2,3,4,5,6-pentafluorophenol as starting substances at 150°C for 48 hours and carry out further processing, receiving specified in the title compound as a colorless crystalline powder (to 91.2 mg, 30.5 per cent). So pl. 133,1-133,9aboutWith (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: of 3.78 (3H, s), 6,79 (2H, d, J=8,79 Hz), 7.24 to 7,40 (8H, m).

IR (KBr) cm-1: 1612, 1519, 1399, 1369, 1207, 1178.

Example 28

Obtaining 6-chloro-4-(4-forfinal)-3-[4-(methylthio)phenyl]pyridazine

5-(4-Forfinal)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one [WO 9925697] (510 mg, 1,633 mmol) and phosphorus oxychloride (8 ml) was stirred at 100°C for 2 hours. The reaction mixture was treated similarly to the method of example 22. Thus obtained crystals are recrystallized from a mixture of ethyl acetate-hexane, obtaining mentioned in the title compound as light-yellow needles (367 mg, 69.2 per cent). So pl. 130,9-to 131.4aboutC.

1H-NMR (CDCl3) δ: 2,49 (3H, s), 7,06 (2H, d, J=8,67 Hz), 7,15-7,22 (2H, m), 7,32 (2H, d, J=8,55 Hz), 7,49 (1H, s).

IR (KBr) cm-1: 1603, 1595, 1503, 1385, 1221, 1137, 1109, 843, 828, 784.

Mass spectrum m/z: 330(M+), 331(M+), 332(M+), 333(M+), 334(M+).

Example 29

Getting 6-(2,4-divergence)-4-(4-forfinal)-3-[4-(methylthio)phenyl]pyridazine

Similar to the method of example 2 subjected to the interaction of 6-chloro-4-(4-forfinal)-3-[4-(methylthio)phenyl]pyridazine (198 mg, 0,599 mmol) and 2,4-diferena in the quality of the ve initial substances at 150° C for 20 h and carry out further processing, receiving specified in the title compound as light yellow crystals (197 mg, 77.4 percent). So pl. 140,6-143,4°With (acetone-water).

1H-NMR (CDCl3) δ: 2,47 (3H, s), 6,58-7,33 (N, m).

IR (KBr) cm-1: 1638, 1606, 1505, 1393, 1213, 1140, 1101, 965, 849.

Mass spectrum m/z: 424(M+), 425(M+), 426(M+).

Example 30

Obtain 3-[4-(methylthio)phenyl]-6-phenylthio-4-[4-(phenylthio)phenyl]pyridazine

Similar to the method of example 2 subjected to the interaction of 6-chloro-4-(4-forfinal)-3-[4-(methylthio)phenyl]pyridazine (198 mg, 0,599 mmol) and thiophenol (165 mg, 1.5 mmol) as starting compounds at 150°C for 20 h and carry out further processing, receiving specified in the title compound as a yellow oil (217 mg, 73.1 per cent).

1H-NMR (CDCl3) δ: 2,47 (3H, s), 6,95-7,02 (3H, m), 7,10-7,16 (4H, m), 7,29-7,46 (10H, m), 7,65-to 7.68 (2H, m).

IR (KBr) cm-1: 1674, 1594, 1475, 1439, 1379, 1336, 1106, 824.

Mass spectrum m/z: 494(M+), 496(M+).

Example 31

Obtaining 6-chloro-4-(4-chlorophenyl)-3-[4-(methylthio)phenyl]pyridazine

5-(4-Chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one [WO 9925697] (700 mg) is subjected to interaction as starting material at 100°C for 2 hours.

Similar to the method of example 22, receiving specified in the title compound as colorless crystals (dichloromethane-hexane) to yield 93,4%.

TPL 145,0-145,8aboutC.

H-NMR (CDCl3) δ: 2,49 (3H, s), 7,16 (2H, d, J=8.6 Hz), 7,18 (2H, d, J=8,3 Hz), 7,32 (2H, d, J=8,3 Hz), 7,34 (2H, d, J=8.6 Hz), of 7.48 (1H, s).

IR (KBr) cm-1: 3436, 1595, 1489, 1383, 1107, 1091, 833, 825.

Mass spectrum m/z: 346(M+), 348(M+).

Example 32

Obtain 3-[4-(methylthio)phenyl]-6-phenylthio-4-[4-(phenylthio)phenyl]pyridazine

Similar to the method of example 2 subjected to the interaction of 6-chloro-4-(4-chlorophenyl)-3-[4-(methylthio)phenyl]pyridazine (150 mg, 0,303 mmol) and thiophenol (119 mg) as starting compounds at 150°C for 20 h and carry out further processing, receiving specified in the title compound as a pale yellow crystalline powder (85,0 mg, 39.8 per cent).

TPL 53,3-56,2° (diethyl ether-hexane).

1H-NMR (CDCl3) δ: 2,48 (3H, s), 6,98 (2H, d, J=8,8 Hz), 7,02 (1H, s), 7,12 (2H, d, J=8.5 Hz), 7,14 (2H, d, J=8.5 Hz), 7,28-7,58 (10H, m), 7,65-of 7.69 (2H, m).

IR (KBr) cm-1: 1594, 1489, 1475, 1439, 1379, 1336, 1106, 1083, 824, 748, 691.

Mass spectrum m/z: 494(M+), 496(M+).

Example 33

Getting 4-(4-chlorophenyl)-6-(2,4-divergence)-3-[4-(methylthio)phenyl]pyridazine

Similar to the method of example 2 subjected to the interaction of 6-chloro-4-(4-chlorophenyl)-3-[4-(methylthio)phenyl]pyridazine (230,0 mg, to 0.662 mmol) and 2,4-diferena as starting substances at 150°C for 20 h and carry out further processing, receiving specified in the title compound as colourless plates (dichloromethane-hexane, to 216.2 mg, 74,0%).

TPL 16,2-164,0° C.

1H-NMR (CDCl3) δ: 2,47 (3H, s), 6.89 in-7,03 (3H, m), 7,14 (2H, d, J=8,8 Hz), 7,19 (2H, d, J=8,8 Hz), 7,21 (1H, s), 7,28 (2H, d, J=8,8 Hz), 7,34 (2H, d, J=8,8 Hz).

IR (KBr) cm-1: 1596, 1506, 1492, 1411, 1389, 1372, 1247, 1212, 1142, 1096.

Mass spectrum m/z: 440(M+), 442(M+).

Example 34

Getting 4-(4-chlorophenyl)-6-(2,4-divergence)-3-[4-(methylsulphonyl)phenyl]pyridazine

4-(4-Chlorophenyl)-6-(2,4-divergence)-3-[4-(methylthio)phenyl]pyridazine (108 mg, 0.24 mmol) was dissolved in a mixed solvent of chloroform (5 ml)-acetone (30 ml) and the resulting solution was added a solution of periodate sodium (210 mg, 0.98 mmol) in water (10 ml). After cooling, ice water is added a solution (0.16 ml) of osmium tetroxide (1 g, 0,0 3 mmol) in butanol (25 ml) and stirred for 20 hours. To the reaction mixture, water is added, the resulting mixture is extracted with chloroform and the organic layer is dried over anhydrous sodium sulfate. The solvent is distilled off, the residue is purified by chromatography on a column of silica gel [hexane/ethyl acetate (2/1)]. Select the desired fraction and optionally purified preparative thin-layer chromatography on silica gel [manifesting solvent: benzene/ethyl acetate (4/1)] and then crystallized from a mixture of diethyl ether-hexane, obtaining mentioned in the title compound as a colorless crystalline powder (71,5 mg, 61.7 per cent). TPL 115,2-117,3aboutC.

1H-NMR (CDCl3δ : a 3.06 (3H, s), 6,91-7,05 (2H, m), to 7.15 (2H, d, J=8,8 Hz), 7,28-7,34 (2H, m), 7,37 (2H, d, J=8.5 Hz), 7,58 (2H, d, J=8.5 Hz), 7,88 (2H, d, J=8,5 Hz).

IR (KBr) cm-1: 1507, 1493, 1411, 1390, 1316, 1304, 1210, 1154, 1093.

Mass spectrum m/z: 472(M+), 474(M+).

Example 35

Obtaining 6-chloro-3-(3,4-acid)-4-(4-methoxyphenyl)pyridazine

6-(3,4-Acid)-5-(4-methoxyphenyl)-2H-pyridazin-3-one [WO 9925697] (231 mg, 0,683 mmol) is treated similarly to the method of example 22, receiving specified in the title compound as a brown amorphous solid (112 mg, 46,0%).

1H-NMR (CDCl3) δ: 3,71 (3H, s), 3,82 (3H, s)to 3.89 (3H, s),

to 6.80 (2H, d, J=8,55 Hz), 6.87 in (2H, d, J=9,04 Hz),

of 6.96-7,00 (2H, m), to 7.15 (2H, d, J=9,04 Hz), 7,47 (1H, m).

IR (KBr) cm-1: 1607, 1511, 1418, 1382, 1252, 1176, 1141, 1025, 889, 834, 754.

Mass spectrum m/z: 456(M+), 458 (M+).

Example 36

Obtaining 3-(3,4-acid)-4-(4-methoxyphenyl)-6-(phenylthio)pyridazine

To a solution of 6-chloro-3-(3,4-acid)-4-(4-methoxyphenyl)pyridazine (112 mg, 0,314 mmol) in N,N-dimethylformamide (2 ml) is added potassium carbonate (87 mg, 0,628 mmol) and thiophenol (42 mg, 0,377 mmol) and stirred for 8 hours in a bath at a temperature of 100aboutC. the Reaction mixture was extracted with ethyl acetate, the organic layer washed successively with water and saturated aqueous sodium chloride (saturated salt solution), and then dried over anhydrous sodium sulfate. The solvent is distilled off. Receive the TES brown oil (162 mg) was separated and purified preparative thin-layer chromatography on silica gel [manifesting solvent: hexane/ethyl acetate (2/1)], getting listed in the title compound as a brown amorphous solid (98 mg, 72,5%).

1H-NMR (CDCl3) δ: of 3.69 (3H, s), with 3.79 (3H, s), a 3.87 (3H, s), 6.73 x-6,83 (3H, m)6,94 (1H, DD, J=2,20, 8,54 Hz), 7,00-7,05 (4H, m), 7,42-7,46 (3H, m), 7,65-of 7.70 (2H, m).

IR (KBr) cm-1: 1605, 1510, 1375, 1250, 1024, 832, 749.

Mass spectrum m/z: 430(M+), 429(M+-1).

Example 37

Getting 6-(2,4-divergence)-3-(3,4-acid)-4-(4-methoxyphenyl)pyridazine

Similar to the method of example 2 interact 6-chloro-3-(3,4-acid)-4-(4-methoxyphenyl)pyridazine (203 mg, 0,589 mmol) and 2,4-differenoe as starting substances at 150°C for 20 h and carry out further processing, receiving specified in the title compound as a yellow amorphous solid (260 mg, quantitative).

1H-NMR (CDCl3) δ: 3,70 (3H, s), 3,83 (3H, s), a 3.87 (3H, s), 6,74 (1H, d, J=8,55 Hz), 6,66? 7.04 baby mortality (7H, m), 7,13-7,21 (3H, m).

IR (KBr) cm-1: 1609, 1506, 1391, 1251, 1210, 1178, 1140, 1026.

Mass spectrum m/z: 450(M+).

Example 38

Obtaining 6-chloro-3-(3,4-atlanticcity)-4-(4-methoxyphenyl)pyridazine

6-(3,4-Atlanticcity)-5-(4-methoxyphenyl)-2H-pyridazin-3-one (202 mg, 0,601 mmol) is treated similarly to the method of example 22, receiving specified in the title compound as a yellow amorphous solid (207 mg, 97.1 per cent).

1H-NMR (CDCl3) δ: a 3.83 (3H, s), 4,23-the 4.29 (4H, m), 6,74-to 6.80 (2H, m), 6.87 in (2H, d, J=8,79 Hz), 7,06 (1H, d, J=1,96 Hz), to 7.15 (2H, d, J=8,79 Hz), 7,45 (1H, s).

IR (KBr) cm-1: 1608, 1510, 1286, 1247, 1067, 897, 831, 747.

Mass spectrum m/z: 354(M+), 356 (M+).

Example 39

Getting 6-(2,4-divergence)-3-(3,4-atlanticcity)-4-(4-methoxyphenyl)pyridazine

Similar to the method of example 2 interact 6-chloro-3-(3,4-atlanticcity)-4-(4-methoxyphenyl)pyridazine (136 mg, 0,383 mmol) and 2,4-differenoe as starting substances in 120°C for 8 hours and carry out further processing, receiving specified in the title compound as colorless prisms (113 mg, 65.7 per cent). TPL 158,0-159,5°With (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: of 3.84 (3H, s), 4,21-4,27 (4H, m), 6,07-to 6.80 (2H, m), 6,83-7,02 (5H, m), 7,18 (1H, s), 7,18 (2H, d, J=8,79 Hz), 7,30-7,34 (1H, m).

IR (KBr) cm-1: 1610, 1505, 1391, 1244, 1211, 1062, 897, 829.

Example 40

Obtaining 3,4-bis(4-methoxyphenyl)-6-(dimethylamino)pyridazine

Similar to the method of example 2 interact 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (140 mg, 0.43 mmol) and 40% (mass/volume) aqueous solution of dimethylamine as the starting substances at 45°C for 30 hours and carry out further processing, receiving specified in the title compound as colorless prisms (139 mg, 96.5 per cent). TPL 109,6-to 110.7°With (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: 3,23 (6N, C), with 3.79 (3H, s), 3,81 (3H, s)6,70 (1H, s), is 6.78 (2H, d, J=9,03 Hz), at 6.84 (2H, d, J=8,79 Hz), 7,13 (2H, d, J=9,04 G is), 7,31 (2H, d, J=8,79 Hz).

IR (KBr) cm-1: 1610, 1591, 1517, 1402, 1248, 1173, 1023, 830.

Example 41

Getting 6-benzylamino-3,4-bis(4-methoxyphenyl)pyridazine

Similar to the method of example 2 interact 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (300 mg, 0,918 mmol) and benzylamine as starting substances in 120°C for 19 h and carry out further processing, receiving specified in the title compound as colorless prisms (365 mg, quantitative). TPL 125,4-126,3°With (ethyl acetate-hexane).

1H-NMR (CDCl3) δ: of 3.78 (3H, s), with 3.79 (3H, s), and 4.68 (2H, d, J=5,62 Hz), 5,18-5,32 (1H, SIRM), 6,51 (1H, s), is 6.78 (2H, d, J=8,79 Hz), to 6.80 (2H, d, J=8,78 Hz), 7,05 (2H, d, J=8,79 Hz), 7,26-7,46 (7H, m).

IR (KBr) cm-1: 3400, 3236, 1611, 1516, 1247, 1177, 832.

Mass spectrum m/z: 397 (M+).

Example 42

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2,4-dipertanyakan)pyridazine

Similar to the method of example 2 interact 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (AZN 264.2 mg, 0,809 mmol) and 2,4-diferencia as starting substances in 100°C for 12 h and carry out further processing, receiving specified in the title compound as a colorless crystalline powder (328,8 mg, 97,0%). TPL 177,4-178,0°With (chloroform-diethyl ether-hexane).

1H-NMR (CDCl3) δ: of 3.80 (3H, s), 3,81 (3H, s), to 6.67 (1H, Sirs), for 6.81 (2H, d, J=8,79 Hz), at 6.84 (2H, d, J=8,79 Hz), 6,85 (1H, s), 6,86-6,97 (2H, m), 7,11 (2H, d, J=8,79 Hz), 7,33 (2H, d J=8,79 Hz), 8,17 (1H, m).

IR (KBr) cm-1: 3419, 1609, 1511, 1492, 1250, 1175.

Example 43

Obtaining 3,4-bis(4-methoxyphenyl)-6-[N-(n-propyl)-2,4-diptiranjan]pyridazine

(1) preparation of 2',4'-deformationand

2,4-Diptiranjan (5.0 g, of 38.7 mmol) dissolved in chloroform (30 ml), then added propionic anhydride (6.0 g, 46,1 mmol). The resulting mixture was stirred at room temperature for 16 hours. After adding to the reaction mixture of methanol (10 ml) thus obtained mixture is concentrated under reduced pressure. The residue is dissolved in chloroform. The resulting solution was washed with saturated aqueous sodium bicarbonate and then dried over anhydrous sodium sulfate. The solvent is evaporated, the residue is crystallized from a mixture of toluene-hexane, obtaining mentioned in the title compound as colourless, leaves like crystals (7,17 g, quantitative). TPL 66,9-67,4aboutC.

1H-NMR (CDCl3) δ: of 1.26 (3H, t, J=7,33 Hz), 2,44 (2H, q, J=7,33 Hz), 6,82-6,91 (2H, m), 7,20 (1H, W), of 8.28 (1H, m).

IR (KBr) cm-1: 3289, 1676, 1613, 1546, 1503, 1210.

(2) Obtaining N-(n-propyl)-2,4-diferencia

2,4-Deformationand (7,17 g of 38.7 mmol) was dissolved in tetrahydrofuran (30 ml), then add sociallyengaged (7 g, 184 mmol). The resulting mixture was stirred at 70°C for 7 hours. When the cooling water with ice add methanol (10 ml) to decompose wt is the tissue of sociallyengaged. Then to the reaction mixture is added saturated aqueous solution of ammonium chloride (100 ml) and the precipitate filtered off. The filtrate is extracted with chloroform and dried the organic layer over anhydrous sodium sulfate. The solvent is distilled off, the residue was separated and purified by chromatography on a column of silica gel (silica gel 5 g, chloroform), getting mentioned in the title compound in the form of a light reddish-brown oil (5.7 g, 86,0%).

1H-NMR (CDCl3) δ: of 1.00 (3H, t, J=7,32 Hz)of 1.66 (2H, sextet, J=to 7.32 Hz), of 3.07 (2H, t, J=to 7.32 Hz), 3,68 (1H, W), 6,59 (1H, m), 6,70-to 6.80 (2H, m).

IR (film) cm-1: 3431, 2965, 2936, 2877, 1603, 1521, 1479, 1430, 1264, 1206, 1147, 1130, 1092.

(3) Obtaining 3,4-bis(4-methoxyphenyl)-6-[N-(n-propyl)-2,4-diptiranjan]pyridazine

Similar to the method of example 2 is stirred 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (180 mg, 0,551 mmol) and N-(n-propyl)-2,4-diptiranjan as starting substances in 100°C for 12 h, then interact with 170°C for 10 h and carry out further processing, receiving specified in the title compound in the form of light yellow-brown amorphous solid (137,5 mg, 54.1 per cent).

1H-NMR (CDCl3) δ: 0,86 (3H, t, J=7,32 Hz)to 1.79 (2H, sextet, J=to 7.32 Hz), of 3.77 (3H, s), with 3.79 (3H, s), 4,11 (2H, t, J=to 7.32 Hz), to 6.43 (1H, s)6,76 (2H, d, J=8,79 Hz), 6,78 (2H, d, J=8,79 Hz), of 6.96 (2H, d, J=8,79 Hz), 7,14 (2H, dt, J=2,45, of 8.06 Hz), 7.23 percent-7,31 (2H, m), 7,32 (1H, d, J=8,79 Hz).

IR (KBr) cm -1: 1610, 1589, 1510, 1460, 1426, 1297, 1249, 1178.

Example 44

Obtaining 3,4-bis(4-methoxyphenyl)-6-(3,4,5-trimethoxyaniline)pyridazine

Similar to the method of example 2 interact 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150,0 mg, 0,459 mmol) and 3,4,5-trimethoxyaniline as starting substances at 140°C for 5 hours and carry out further processing, receiving specified in the title compound as a pale yellow crystalline powder (155,0 mg, 71.3 per cent). TPL 125,4-126,3°With (chloroform-hexane).

1H-NMR (CDCl3) δ: of 3.80 (3H, s), 3,81 (3H, s), 3,85 (3H, s), 3,86 (6N, (C), 6,69 (2H, s), for 6.81 (2H, d, J=8,79 Hz), PC 6.82 (2H, d, J=8,79 Hz), 7,00 (1H, s), 7,06 (1H, Sirs), was 7.08 (2H, d, J=8,79 Hz), 7,31 (2H, d, J=8,79 Hz).

IR (KBr) cm-1: 3343, 1609, 1593, 1574, 1508, 1452, 1436, 1249, 1128.

Example 45

Obtaining 3,4-bis(4-methoxyphenyl)-6-(morpholino)pyridazine

Similar to the method of example 2 interact 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (output reached 125.5 mg, 0.384 mmol) and the research as a source of substances with 100°C for 15 h and carry out further processing, receiving specified in the title compound as a pale yellow crystalline powder (115,2 mg, 79,5%). TPL 188,0-190,3°With (chloroform-diethyl ether).

1H-NMR (CDCl3) δ: is 3.82 (3H, s), 3,83 (3H, s), 3,88 (8H, Sirs), 6,85 (2H, d, J=8,79 Hz), 6.87 in (2H, d, J=8,79 Hz), 7,13 (2H, d, J=8,79 Hz), 7,28 (1H, s), 7,34 (2H, d, J=8,79 Hz).

IR (KBr) cm-1: 1627, 1606, 1518, 1303,1251, 1189.

Example 46

Getting 4-(4-forfinal)-6-methylthio-3-[4-(methylthio)phenyl]pyridazine

A solution of 55% sodium hydride (4.3 mg, 0,097 mmol) in N,N-dimethylformamide (1 ml) cooled on ice in the atmosphere of gaseous argon, then add a solution of 5-(4-forfinal)-6-{4-(methylthio)phenyl]-2H-pyridazin-3-thione [WO 9925697] (32 mg, 0,097 mmol) in N,N-dimethylformamide (2 ml) and then add a solution of methyliodide (13.9 mg, 0,097 mmol) in N,N-dimethylformamide (1 ml). Next, the resulting mixture is stirred for 1 hour. Dilute the reaction mixture with ethyl acetate and the resulting mixture is washed successively with an aqueous solution of sodium thiosulfate solution, water and saturated salt solution. The organic layer is dried over anhydrous sodium sulfate. The solvent is distilled off, the residue was separated and purified by chromatography on a column of silica gel [silica gel, 2 g, hexane/ethyl acetate (2/1)], then the desired fraction is crystallized from a mixture of ethyl acetate-hexane, obtaining crude crystals (38,1 mg). The crude crystals are recrystallized from a mixture of ethyl acetate-hexane, obtaining mentioned in the title compound as yellow prisms (from 20.9 mg, 62.9 per cent). TPL is 165.8-169, 5mmaboutC.

1H-NMR (CDCl3) δ: 2,48 (3H, s), and 2.79 (3H, s), 7,03 (2H, t, J=8,55 Hz), 7,13-7,19 (4H, m), 7,29 (1H, s), 7,32 (2H, d, J=8,30 Hz).

IR (KBr) cm-1: 1604, 1508, 1387, 1227, 1107, 839.

Mass spectrum m/z: 342(M+), 343(M+), 344 (M+).

the example 47

Obtaining 3,4-bis(4-methoxyphenyl)-6-(methylsulphonyl)pyridine

3,4-Bis(4-methoxyphenyl)-6-(methylthio)pyridazine (0.18 g, of 0.53 mmol) is treated similarly to the method of example 34, receiving a light brown oil (0.20 g, quantitative). This oil is crystallized from a mixture of ethyl acetate-hexane, obtaining mentioned in the title compound as a pale brown prisms.

TPL 137-140°C.

1H-NMR (CDCl3) δ: 3,49 (3H, s), of 3.84 (3H, s), to 6.88 (2H, d, J=8,8 Hz), 6,92 (2H, d, J=8,8 Hz), 7,20 (2H, d, J=8,8 Hz), 7,47 (2H, d, J=8,8 Hz), of 8.09 (1H, s).

IR (KBr) cm-1: 1607, 1513, 1501, 1323, 1256, 1155.

Example 48

Obtaining 3,4-bis(4-methoxyphenyl)-6-(methylsulfonylamino)pyridazine

Methylsulfonylamino (10 μl, 1.44 mmol) are added to a solution of 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (11 mg, 0.36 mmol) in pyridine (3 ml), then stirred at room temperature for 5 days. The pyridine is distilled off and to the residue is added a mixture of water-chloroform. The resulting mixture is extracted with chloroform and dried the organic layer over anhydrous sodium sulfate. The solvent is distilled off, the residue is separated and purified preparative thin-layer chromatography on silica gel [manifesting solvent: hexane/ethyl acetate (2/1)], obtaining a colorless oil (93 mg, 66.9 per cent). This oil is crystallized from a mixture of ethyl acetate-hexane, obtaining specified in the title compound in the form of bright purple-red prisms 59 mg).

TPL 150,0-151,0aboutC.

1H-NMR (CDCl3) δ: 3,66 (3H, s), 3,83 (3H, s), 3,63 (3H, s), 6,85 (2H, d, J=9,03 Hz), 6.87 in (2H, d, J=8,79 Hz), to 7.15 (2H, d, J=8,79 Hz), 7,30 (1H, s), 7,37 (2H, d, J=9,04 Hz).

IR (KBr) cm-1: 1609, 1513, 1395, 1372, 1256, 1180, 1162, 909, 816.

Example 49

Getting 4-(4-(chlorophenyl)-6-methyl-3-[4-(methylthio)phenyl]pyridazine

(1) preparation of 4-(4-(chlorophenyl)-3-butene-2-it

Piperidine (1.5 ml) are added to a mixed solvent of acetone (1.1 ml)-ethanol (5 ml). After stirring the mixture for 5 min add 4-chlorobenzaldehyde (700 mg, 5.0 mmol). Thus obtained mixture was stirred at room temperature for 30 minutes Then add acetic acid (two drops, 0.2 ml) and then heated at the boil under reflux for 6 hours. The solvent is distilled off, the residue (879 mg) was separated and purified by chromatography on a column of silica gel [silica gel 40 g, hexane/diethyl ether (10/1)], getting mentioned in the title compound as a pale yellow oil (375 mg, 41.7 per cent).

1H-NMR (CDCl3) δ: of 2.38 (3H, s)of 6.71 (1H, d, J=16,11 Hz), 7,34-7,05 (5H, m).

(2) Obtaining 4-(4-(chlorophenyl)-5-[4-(methylthio)phenyl]pentane-2,5-dione

Sodium cyanide (90 mg, of 1.87 mmol) are added to a solution of 4-(methylthio)benzaldehyde (300 mg, 1.97 mmol) in N,N-dimethylformamide (2 ml). Stirring the mixture at 30-40aboutC, was added dropwise a solution of 4-(4-chlorophenyl)-3-butene-2-she (370 mg, 1.97 mmol) of the N,N-dimethylformamide (3 ml). Thus obtained mixture was stirred at the same temperature for 90 minutes is Added to the reaction mixture water, then extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, then dried over anhydrous sodium sulfate. The solvent is distilled off, the obtained brown oil (762 mg) was separated and purified preparative thin-layer chromatography on silica gel [manifesting solvent: hexane/diethyl ether (2/1)], getting mentioned in the title compound as a pale yellow oil (317 mg, 48,3%).

1H-NMR (CDCl3) δ: to 2.18 (3H, s), 2,47 (3H, s), of 2.72 (1H, DD, J=4,15, 18,07 Hz), 3,57 (1H, DD, J=9,77, 18,07 Hz), 5,04 (1H, DD, J=4,15, 9,76 Hz), 7,18 (2H, d, J=8,78 Hz), 7,19-of 7.25 (4H, m), a 7.85 (2H, d, J=8,79 Hz).

(3) Obtaining 4-(4-(chlorophenyl)-6-methyl-3-[4-(methylthio)phenyl]pyridazine

Hydrazinehydrate (72 mg, 1.44 mmol) are added to a solution of 4-(4-chlorophenyl)-5-[4-(methylthio)phenyl]pentane-2,5-dione (317 mg, 0,953 mmol) in ethanol (6 ml) and the resulting mixture is stirred for 7 hours in a bath at a temperature of 80aboutC. is Added to the reaction mixture water and then extracted with ethyl acetate. The extract is washed successively with water and saturated salt solution and then dried over anhydrous sodium sulfate. The solvent is distilled off, the residue is dissolved in chloroform. Thus obtained solution was stirred at room temperature during the 7 hour conducting the oxidation by air. The solvent is distilled off, the residue (296 mg) was separated and purified preparative thin-layer chromatography on silica gel (manifesting solvent: chloroform), getting mentioned in the title compound as a pale yellow oil (200,5 mg, 64.3 per cent).

1H-NMR (CDCl3) δ: 2,48 (3H, s), 2,80 (3H, s), 7,14 (2H, d, J=8,30 Hz), 7,17 (2H, d, J=8,30 Hz), 7,28 (1H, s), 7,32 (2H, d, J=8,30 Hz), 7,34 (2H, d, J=8,30 Hz).

Mass spectrum m/z: 325(M+-1), 326 (M+), 328 (M+).

Example 50

Getting 4-(4-(chlorophenyl)-6-methyl-3-[4-(methylsulphonyl)phenyl]pyridazine

Hydrazine monohydrate (206 mg, 4.1 mmol) are added to a solution of 4-(4-chlorophenyl)-5-[4-(methylthio)phenyl]pentane-2,5-dione (661 mg, 2.0 mmol) in ethanol (12 ml) and the resulting mixture is stirred for 3 hours in a bath at a temperature of 80aboutC. the Solvent is distilled off and the residue is dissolved in chloroform (30 ml). Thus obtained solution was stirred at room temperature for 24 hours, conducting the oxidation by air. The solvent is distilled off, the residue is dissolved in acetic acid (10 ml) and then added a 31% solution of hydrogen peroxide. The resulting mixture was stirred for 3 hours in a bath at a temperature of 70aboutC. After neutralization of the reaction mixture is diluted with an aqueous solution of caustic soda, the reaction mixture was extracted with ethyl acetate. The organic layer is washed successively 3%aqueous races is the thief of sodium sulfite and saturated salt solution, then dried over anhydrous sodium sulfate. The solvent is distilled off, the residue is separated and purified preparative thin-layer chromatography on silica gel [manifesting solvent: chloroform/methanol (35/1)], getting mentioned in the title compound as slightly yellow prisms (330 mg, 46.3 per cent). TPL 205-209°With (ethyl acetate).

1H-NMR (CDCl3) δ: 2,84 (3H, s), of 3.07 (3H, s), 7,11 (2H, d, J=8,30 Hz), 7,34 (2H, d, J=8,79 Hz), 7,37 (1H, s), 7,63 (2H, d, J=8,55 Hz), to $ 7.91 (2H, d, J=8,55 Hz).

IR (KBr) cm-1: 1596, 1391, 1311, 1303, 1151, 1091, 856, 840.

Mass spectrum m/z: 357(M+-1), 358 (M+), 359 (M+), 360 (M+).

Example 51

Obtaining 3,4-bis(4-methoxyphenyl)-6-cyanopyridine

A solution of 3,4-bis(4-methoxyphenyl)pyridazine 1-oxide [Eur. J. Med. Chem.-Chimica Therapeutica, 14, 53-60 (1979)] (5,01 g, 16,25 mmol) and potassium cyanide (3,17 g, 48,75 mmol) in water (90 ml) cooled on ice. After the addition of benzoyl chloride (to 7.77 g, 55,25 mmol), drop by drop under vigorous stirring in an atmosphere of nitrogen gas, the resulting mixture was stirred at room temperature for 20 hours. Add to the reaction mixture water-chloroform, then alkalinized and thus obtained mixture is extracted with chloroform. The organic layer is washed with water and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, the residue (oil) is separated and purified by chromatography on a column with silicagel who eat [hexane/ethyl acetate (5/1)]. The desired fraction is crystallized from a mixture of ethyl acetate-diethyl ether-hexane, obtaining mentioned in the title compound as slightly yellow prisms (3,30 g, 64,0%).

TPL 113-115°C.

1H-NMR (CDCl3) δ: a 3.83 (3H, s), of 3.84 (3H, s)6,86 (2H, d, J=8,2 Hz), make 6.90 (2H, d, J=8,2 Hz), 7,17 (2H, d, J=8,2 Hz), 7,46 (2H, d, J=8,2 Hz), 7,72 (1H, s).

Example 52

Obtaining 3,4-bis(4-methoxyphenyl)-6-carboxamidine

10% aqueous solution of caustic soda (9 ml) was added to a solution of 3,4-bis(4-methoxyphenyl)-6-cyanopyridine (1.47 g, 4,63 mmol) in ethanol (12 ml) and stirred at 100°C for 1 hour. After removal of the solvent the residue is acidified with dilute hydrochloric acid and extracted with chloroform. The organic layer is washed with water and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, the residue is crystallized from a mixture of ethyl acetate-diethyl ether, obtaining mentioned in the title compound as light-yellow needles (1.48 g, 95,0%). TPL 157-158aboutC.

1H-NMR (CDCl3) δ: of 3.84 (3H, s), 6,83 (2H, d, J=8,79 Hz), 6.89 in (2H, d, J=8,79 Hz), 7,21 (2H, d, J=8,79 Hz), 7,47 (2H, d, J=8,79 Hz), compared to 8.26 (1H, s).

Example 53

Obtaining 3,4-bis(4-methoxyphenyl)-6-(4-methyl-1-piperazinylcarbonyl)pyridazine

3,4-Bis(4-methoxyphenyl)-6-carboxypeptidases (0.10 g, 0.30 mmol) and N-methylpiperazine (0.375 g, 3.7 mmol) is suspended in a mixed solvent of N,N-dimethylformamid is (2 ml)-tetrahydrofuran (3 ml), where add 50% solution of cyclic anhydride 1-papapetrou acid (n=3) (0.33 g) in ethyl acetate while cooling on ice. After stirring the thus obtained mixture at room temperature for 4 hours, water is added. The resulting mixture was extracted with ethyl acetate. The organic layer is washed with water and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, the residue was washed with diethyl ether, obtaining mentioned in the title compound as light brown crystals (49 mg, 39.4 percent). Slightly yellowish powder (chloroform-hexane).

TPL 178-181aboutC.

1H-NMR (CDCl3) δ: to 2.41 (3H, s), 2.57 m (4H, dt, J=7,8, 5.0 Hz), 3,85 (6N, (C), of 3.94 (4H, t, J=5.0 Hz), make 6.90 (2H, d, J=8,4 Hz), 6,93 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz)to 7.50 (2H, d, J=8,4 Hz), 7,87 (1H, s).

IR (KBr) cm-1: 3436, 1736, 1645, 1610, 1514, 1401, 1300, 1254.

Example 54

Obtaining 3,4-bis(4-methoxyphenyl)-6-(morpholinylcarbonyl)pyridazine

Using 3,4-Bis(4-methoxyphenyl)-6-carboxypeptidases (0.25 g, of 0.74 mmol), morpholine (0.65 g, 7.4 mmol), tetrahydrofuran (7 ml) and 50% solution of cyclic anhydride 1-papapetrou acid (n=3) (1.2 g) in ethyl acetate (weight. %, product of Hoechst AG), repeat the procedure of example 53, receiving oil (0,208 g, 69,0%). Carry out crystallization from a mixture of ethyl acetate-hexane, obtaining mentioned in the title compound as a colorless crystalline powder(0,155 g, 51,4%).

TPL 126-128aboutC.

1H-NMR (CDCl3) δ: of 3.77-3,98 (8H, m), 3,83 (6N, C)6,86 (2H, d, J=8,8 Hz), 6.87 in (2H, d, J=9.0 Hz), 7,19 (2H, d, J=8,8 Hz), was 7.45 (2H, d, J=9.0 Hz), 7,86 (1H, s).

IR (KBr) cm-1: 3447, 1645, 1608, 1514, 1389, 1251.

Example 55

Getting 6-allyl-3,4-bis(4-methoxyphenyl)pyridazine

To a solution of 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (1.2 g, 3.7 mmol) in tetrahydrofuran (24 ml) is added tetrakis(triphenylphosphine)palladium (0.21 g, 0.18 mmol). While cooling with ice water in the atmosphere of gaseous argon was added a drop of 1M solution (11 ml) allylanisole in diethyl ether. After stirring the resulting mixture at the same temperature for 1 hour the temperature of the mixture is allowed to rise to room temperature and then stirred for further 2 hours. To the reaction mixture is added a mixture of water-ethyl acetate and the resulting mixture extracted with ethyl acetate. The organic layer is washed with water and then dried over anhydrous sodium sulfate. The extract was concentrated under reduced pressure and the residue left for three days at room temperature. The residue was separated and purified by chromatography on a column of silica gel [hexane/ethyl acetate (4/1)], getting mentioned in the title compound as a light brown oil (0.85 grams, 69,8%).

1H-NMR (CDCl3) δ: 3,76-are 3.90 (2H, m), 3,83 (3H, s), 3,85 (3H, s), 5,20 lower than the 5.37 (2H, m), 6,18 (1H, m), 6,83-to 6.95 (4H, m), 7,18 (2H, d, J=8.1 Hz), 7,33 (1H, s), 7,44 (2H, q, j =8,1 Hz).

IR (film) cm-1: 1609, 1512, 1397, 1251, 1179.

Example 56

Obtaining 3,4-bis(4-methoxyphenyl)-6-(3-hydroxypropyl)pyridazine

To a solution of 6-allyl-3,4-bis(4-methoxyphenyl)pyridazine (0,58 g, 1.7 mmol) in tetrahydrofuran (3 ml) is added drop by drop to 0.5 M solution (8.7 ml) 9-borabicyclo[3.3.1]nonane in an atmosphere of gaseous argon while cooling the reaction system water with ice. Then the resulting mixture was stirred at room temperature for 15 hours. To the reaction mixture are added water (1 ml), then 3N solution of caustic soda (3 ml) and 31% solution of hydrogen peroxide (3 ml) under ice cooling and then stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, the organic layer washed successively with water, saturated aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate. The extract was concentrated under reduced pressure and the resulting mixture was left for three days at room temperature. The residue was separated and purified by chromatography on a column of silica gel (ethyl acetate), obtaining mentioned in the title compound as a light brown oil (0.54 g, 88.3 per cent).

1H-NMR (CDCl3) δ: 2,12 (2H, q, J=6.5 Hz), is 3.08 (1H, Sirs), and 3.16 (2H, t, J=7,3 Hz), 3,80 (2H, t, J=6.5 Hz), 3,82 (3H, s), 3,83 (3H, s), 6,85 (2H, d, J=9,2 Hz), to 6.88 (2H, d, J=9,2 Hz), 7,16 (2H, d, J=9,2 Hz), 7,33 (1H, s), 7,41 (2H, d, J=9,2 Hz).

<> IR (film) cm-1: 3366, 1609, 1513, 1400, 1299, 1252, 1179.

Example 57

Obtaining 3,4-bis(4-methoxyphenyl)-6-(2-carboxyethyl)pyridazine

3,4-Bis(4-methoxyphenyl)-6-(3-hydroxypropyl)pyridazin (0.54 g, 1.5 mmol) dissolved in acetone (6 ml), added Jones reagent (4,2 ml) and the resulting mixture was stirred at room temperature for 8 hours. After adding isopropanol to decompose the excess reagent water is added and the resulting mixture extracted with ethyl acetate. The organic layer is washed with water and hold back extraction of saturated aqueous sodium bicarbonate. Reverse the extract is acidified with hydrochloric acid and then extracted with chloroform. The organic layer is washed with water and then dried over anhydrous sodium sulfate. The solvent is distilled off, the residue was separated and purified by chromatography on a column of silica gel [chloroform/methanol (40/1)], getting mentioned in the title compound as a light brown oil (0.21 g, 37.4 per cent).

1H-NMR (CDCl3) δ: 3,05 (2H, t, J=6.8 Hz), the 3.35 (2H, t, J=6.8 Hz), 3,80 (3H, s), 3,81 (3H, s), 5,14 (1H, Sirs), 6,83 (2H, d, J=9.0 Hz), at 6.84 (2H, d, J=9.0 Hz), 7,13 (2H, d, J=9.0 Hz), 7,35 (2H, d, J=9.0 Hz), 7,40 (1H, s).

IR (CHCl3) cm-1: 1727, 1610, 1514, 1477.

Example 58

Obtaining 3,4-bis(4-methoxyphenyl)-6-(N-hydroxy-N-methyl-2-carbamoylethyl)pyridazine

3,4-Bis(4-methoxyphenyl)-6-(2-carboxyethyl)pyridazin the (0,136 g, of 0.37 mmol) and the hydrochloride of N-methylhydroxylamine (0.156 g, of 1.87 mmol) was dissolved in N,N-dimethylformamide (4 ml). While cooling with ice, add one drop of the triethylamine (0,77 g 7,608 mmol) and then a 50% solution of cyclic anhydride 1-papapetrou acid (n=3) (0.39 g, 0,613 mmol) in ethyl acetate. After stirring for 1 hour the temperature of the obtained mixture is allowed to rise to room temperature at which the mixture is stirred for 15 hours. Add to the reaction mixture water and the resulting mixture extracted with ethyl acetate. The organic layer is washed successively with a saturated aqueous solution of sodium bicarbonate and water, then dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is crystallized from a mixture of ethyl acetate-hexane, obtaining mentioned in the title compound as light brown needles (17 mg, 13,0%). TPL 85-87aboutC.

1H-NMR (CDCl3) δ: 1,71 (1H, Sirs), 3,21 (2H, t, J=6,7 Hz), 3,24 (3H, s), of 3.48 (2H, t, J=6,7 Hz), 3,84 (6N, (C), to 6.88 (4H, d, J=9,2 Hz), 7,16 (2H, d, J=9,2 Hz), 7,34 (2H, d, J=9,2 Hz), 7,44 (1H, s).

IR (KBr) cm-1: 3436, 1736, 1645, 1610, 1514, 1401, 1300, 1254.

Example 59

Obtaining 6-chloro-3-[4-(methylthio)phenyl]-4-phenylpyridazin

6-[4-(Methylthio)phenyl]-5-phenyl-2H-pyridazin-2-[WO 9925697] (500 mg) is treated as the initial substance similar to the method of example 22 (interaction at 100°C for 2 hours), receiving specified in the header is Obedinenie with quantitative yield as a pale brown prisms (ethyl acetate-hexane). TPL 157,7-158,3aboutC.

1H-NMR (CDCl3) δ: 2,47 (3H, s), to 7.15 (2H, d, J=8.5 Hz), 7.18 in-of 7.23 (2H, m), 7,33 (2H, d, J=8.5 Hz), 7,35-7,42 (3H, m)to 7.50 (1H, s).

IR (KBr) cm-1: 1592, 1401, 1386, 1339, 1323, 1136, 1107, 834, 788, 702, 585.

Mass spectrum m/z: 312(M+), 314 (M+).

Example 60

Obtaining 6-chloro-4-(4-chlorophenyl)-3-[4-methylsulphonyl)phenyl]pyridazine

6-Chloro-4-(4-chlorophenyl)3-[4-(methylthio)phenyl]pyridazine (230 mg) is treated as the initial substance similar to the method of example 34, receiving specified in the title compound in quantitative yield as a colourless plates (ethyl acetate-hexane). TPL 189,6-to 190.5aboutC.

1H-NMR (CDCl3) δ: is 3.08 (3H, s), 7,12 (2H, d, J=8.5 Hz), 7,37 (2H, d, J=8.5 Hz), 7,58 (1H, s), a 7.62 (2H, d, J=8,8 Hz), to 7.93 (2H, d, J=8,8 Hz).

IR (KBr) cm-1: 1490, 1312, 1304, 1152, 1134, 1090, 852, 846, 776, 585.

Mass spectrum m/z: 378(M+), 380 (M+).

Example 61

Getting 4-(4-chlorophenyl)-3-[4-(methylsulphonyl)phenyl]pyridazine

(1) preparation of 2-(4-chlorophenyl)-1-[4-(methylthio)phenyl]-4-penten-1-it

After adding a 2.0m solution of sitedisability (LDA) (36.2 ml, to 72.4 mmol) at -20°to a solution of 2-(4-chlorophenyl)-1-[4-(methylthio)phenyl]-1-ethanone (20 g, to 72.3 mmol) in anhydrous tetrahydrofuran (200 ml) the resulting mixture is stirred for 20 minutes while heating to room temperature. The mixture is then cooled to -20aboutTo add allergodil in (6.67 ml, with 72.9 mmol) and then stirred for 30 minutes under load, the processes to room temperature. Add to the reaction mixture water and the resulting mixture extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. The solvent is distilled off, the residue was separated and purified by chromatography on a column of silica gel [silica gel, 100 g, hexane/ethyl acetate (2/1)]. The desired fraction is crystallized from a mixture of diethyl ether-hexane, obtaining mentioned in the title compound as colorless prisms (22,85 g, 99.8 per cent).

1H-NMR (CDCl3) δ: 2,48 (3H, s), 2,53 (1H, TD, J=7,32, 15,38 Hz), 2,90 (1H, TD, J=7,32, 13,92 Hz), of 4.54 (1H, t, J=to 7.32 Hz), equal to 4.97 (1H, DD, J=0,92, 10,26 Hz), 5,02 (1H, DD, J=0,92, 17,58 Hz), 5,71 (1H, m), 7.18 in-7,28 (6N, m), to 7.84 (2H, DD, J=1,95, 6,83 Hz).

IR (CHCl3) cm-1: 1663, 1588, 1553, 1340, 1322, 1306, 1285, 1264, 1210, 1172, 1118.

(2) Obtaining 3-(4-chlorophenyl)-4-[4-(methylsulphonyl)phenyl]-4-oxobutyraldehyde

2-(4-Chlorophenyl)-1-[4-(methylthio)phenyl]-4-penten-1-he (5.7 g, 18.0 mmol) is treated similarly to the method of example 34, receiving specified in the title compound as a yellow amorphous solid (4,50 g, 71.3 per cent).

1H-NMR (CDCl3) δ: 2,88 (1H, DD, J=3,90, 18,55 Hz), 3.04 from (3H, s), the 3.65 (1H, DD, J=9,77, 18,55 Hz), to 5.08 (1H, DD, J=3,90, 9,77 Hz), 7,19 (2H, d, J=8,79 Hz), 7,29 (2H, d, J=8,79 Hz), of 7.97 (2H, d, J=8,79 Hz), of 8.09 (2H, d, J=8,79 Hz), 9,79 (1H, s).

IR (film) cm-1: 1718, 1689, 1493, 1317, 1153.

(3) Obtaining 4-(4-chlorophenyl)-3-[4-(methylsulphonyl)phenyl]pyridazine

Hydrazinehydrate (0.8 ml, 16.5 mmol) are added to a solution of 3-(4-chlorophenyl)-4-[4-(matilal is of IMT)phenyl]-4-oxobutyraldehyde (4.5 g, 12.8 mmol) in ethanol (100 ml) and then stirred at room temperature for 1 hour. To the reaction mixture add a 31% solution of hydrogen peroxide (6 ml) and the resulting mixture was stirred at 60°C for 18 hours. This mixture is concentrated under reduced pressure, the residue was separated and purified by chromatography on a column of silica gel [silica gel, 70 g, chloroform/methanol (50/1)], getting mentioned in the title compound as a pale yellow amorphous solid (2,60 g, 58.8 per cent).

1H-NMR (CDCl3) δ: is 3.08 (3H, s), 7,13 (2H, d, J=8,55 Hz), 7,35 (2H, d, J=8,55 Hz), 7,54 (1H, d, J=of 5.53 Hz), 7,66 (2H, d, J=8,55 Hz), to 7.93 (2H, d, J=8,55 Hz), 9,29 (1H, d, J=5,35 Hz).

IR (film) cm-1: 1733, 1684, 1597, 1492, 1313, 1153.

Example 62

Getting 4-(4-chlorophenyl)-3-[4-(methylsulphonyl)phenyl]pyridazin-1-oxide

The hydrogen peroxide solution (31%, and 5.2 ml) are added to a solution of 4-(4-chlorophenyl)-3-[4-(methylsulphonyl)phenyl]pyridazine (2.6 g, at 7.55 mmol) in acetic acid (30 ml) and then stirred at 50°C for 6 hours. The reaction mixture was concentrated under reduced pressure and add to the residue aqueous solution of potassium carbonate. Thus obtained mixture is extracted with chloroform and dried the organic layer over anhydrous sodium sulfate. The solvent is distilled off, the residue was separated and purified by chromatography on a column of silica gel [silica gel, 100 g benzene/ethyl acetate (1/1)], receiving the decree of the TES in the title compound as a pale yellow amorphous solid (1.2 g, 44,1%).

1H-NMR (CDCl3) δ: of 3.07 (3H, s), was 7.08 (2H, d, J=8,55 Hz), 7,34 (2H, d, J=8,55 Hz), to 7.59 (2H, d, J=8,55 Hz), to 7.68 (1H, d, J=6,59 Hz), of 7.90 (2H, d, J=8,55 Hz), compared to 8.26 (1H, d, J=6,59 Hz).

IR (film) cm-1: 1683, 1592, 1525, 1492, 1314, 1152.

Example 63

Getting 4-(4-chlorophenyl)-6-cyano-3-[4-(methylsulphonyl)phenyl]pyridazine

To a solution of 4-(4-chlorophenyl)-3-[4-(methylsulphonyl)phenyl]pyridazin-1-oxide (1.1 g, of 3.05 mmol) in anhydrous tetrahydrofuran (50 ml) are added successively water (30 ml), potassium cyanide (1,008 g of 15.5 mmol) and benzoyl chloride (6 ml, of 51.7 mmol), then stirred at room temperature for 24 hours. The reaction mixture is extracted with chloroform and dried the organic layer over anhydrous sodium sulfate. The solvent is distilled off, the residue was separated and purified by chromatography on a column of silica gel [silica gel, 30 g, chloroform/methanol (40/1)]. The desired fraction is crystallized from a mixture of ethyl acetate-diethyl ether, obtaining mentioned in the title compound as light yellow prisms (310 mg, 27.5 per cent). TPL 211,4-212,5aboutC.

1H-NMR (CDCl3) δ: to 3.09 (3H, s), 7,14 (2H, d, J=8,79 Hz), 7,41 (2H, d, J=8,79 Hz), 7,69 (2H, d, J=8,3 Hz), 7,88 (1H, s), of 7.97 (2H, d, J=8,30 Hz).

IR (KBr) cm-1: 2248, 1597, 1494, 1386, 1313, 1151.

Example 64

Obtaining 3-(4-methoxyphenyl)-4-phenylpyridazin

10% Palladium on coal (1.1 g) is added to a solution of 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridine (1,53 g, 5,16 mmol) in acetic acid (25 ml), and the current of nitrogen gas, catalytic reduction is carried out at room temperature and atmospheric pressure for 5 hours. The catalyst is filtered off, the solvent is distilled off and add to the residue saturated aqueous solution of sodium bicarbonate. Thus obtained mixture is extracted with chloroform and dried the organic layer over anhydrous sodium sulfate. The solvent is distilled off and the residue crystallized from hexane, getting mentioned in the title compound as light-yellow needles (1.28 g, 94.7 percent).

TPL 116,1-119,6aboutC.

1H-NMR (CDCl3) δ: 3,81 (3H, s), 6,83 (2H, d, J=8,79 Hz), 7,20-7,24 (2H, m), 7,32-7,45 (6N, m), 9,16 (1H, d, J=5.12 in Hz).

IR (KBr) cm-1: 1607, 1514, 1428, 1352, 1300, 1248, 1181.

Example 65

Obtaining 3-(4-methoxyphenyl)-4-phenylpyridazin-1-oxide

3-(4-Methoxyphenyl)-4-phenylpyridazin (1,15 g, 4,39 mmol) is treated similarly to the method of example 62 and the residue crystallized from a mixture of chloroform-diethyl ether, obtaining mentioned in the title compound as light yellow prisms (1.01 g, 82,8%). TPL 117,1-118,0aboutC.

1H-NMR (CDCl3) δ: of 3.80 (3H, s), is 6.78 (2H, d, J=8,79 Hz), 7,11-7,21 (2H, m), to 7.32 and 7.36 (5H, m), EUR 7.57 (1H, d, J=6,59 Hz), 8,16 (1H, d, J=6,59 Hz).

IR (KBr) cm-1: 1607, 1509, 1428, 1377, 1346, 1252, 1173, 1150.

Example 66

Getting 6-cyano-3-(4-methoxyphenyl)-4-phenylpyridazin

3-(4-methoxyphenyl)-4-phenylpyridazin-1-oxide (1,11 g, with 3.79 mmol) is treated similarly to the method of example 63 the residue is crystallized from a mixture of diethyl ether-hexane, getting listed in the title compound as light-yellow needles (593 mg, 51,7%). TPL to 131.4-132,2aboutC.

1H-NMR (CDCl3) δ: is 3.82 (3H, s), at 6.84 (2H, d, J=8,79 Hz), 7,24 (2H, DD, J=1,95, with 8.05 Hz), of 7.36-the 7.43 (3H, m), 7,44 (2H, d, J=8,79 Hz), 7,76 (1H, s).

IR (KBr) cm-1: 2245, 1575, 1489, 1381, 1259, 1184, 1180.

Experiment 1 (inhibitory activity against the production of interleukin-1β)

Inhibitory activity of the compounds of the present invention represented by the formula (I), against the production of interleukin-1β examined in the following experiment:

Cells HL-60 cultivate 4 days prior to fusion medium RPMI 1640 with the addition thereto of 10% fetal calf serum (FBS). Wednesday centrifuged. Supernatant discarded, the cells are suspended concentration 1×106cells/ml in RPMI medium 1640 with 3% FBS and add lipopolysaccharide, receiving a final concentration of 10 ág/ml Culture were seeded in 1 ml/well in 24-well plate. Add the studied compound in the amount of 1 μl/well and then cultured for 3 days. After three days, determine the amount of Il-1β in each culture using ELISA method. Each value IC50determined by comparing the output with the control, which does not add the analyzed compound. The results for some typical compounds are shown in table 1.

Table 1
The analyzed compound (No. of example)IL-β (IC50μm)
30,10
50,12
70,18
80,35
90,46
110,19
120,04
140,20
150,45
170,63
180,15
190,16
230,96
250,32
260,31
270,01
320,94
330,26
510,09
660,68
Comparative example 132,10
Comparative example 24,16

The possibility of application in the industry.

Connection phenylpyridine (I) and their salts, which relate to the present invention have excellent inhibitory activity against the production of interleukin-1β and are useful as medicines such as tools for p is opractice and treatment of diseases of the immune system, inflammatory and ischemic diseases.

1. Connection phenylpyridazin, represented by the following formula (I):

where R1represents a substituted or unsubstituted phenyl, where the substituents are selected from the group consisting of halogen, lower alkyl, lower alkoxy, phenylthio; or pyridyl;

R2is lower alkoxygroup, lower allylthiourea, lower alkylsulfonyl or lower alkylsulfonyl;

R3represents hydrogen or lower alkoxygroup;

or R2and R3together can be condensed, forming the lower alkylenedioxy;

R4represents cyano; carboxyl; substituted or unsubstituted lower alkyl, where the substituents are selected from the group consisting of hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio; lower alkylsulfonyl; lower alkylsulfonyl; lower alkylsulfonate; substituted or unsubstituted, phenoxy, where the substituents are selected from the group consisting of halogen, lower alkoxy, nitro, cyano; unsubstituted, phenylthio or phenylthio, substituted with halogen; pyridyloxy; morpholino; morpholinoethyl; 1-piperazinylcarbonyl, substituted lower alkyl; substituted or unsubstituted amino, where the substituents selected from the group contains the lowest is lcil, benzyl, phenyl which may be substituted by halogen atoms or lower alkoxygroup,

n=0;

or its salt.

2. The intermediate connection for connection phenylpyridazin according to claim 1, represented by formula (I), where this intermediate compound selected from the group including

4-(4-chlorophenyl)-3-[4-(methylsulphonyl)phenyl]pyridazin;

4-(4-chlorophenyl)-3-[4-(methylsulphonyl)phenyl]pyridazin-1-oxide;

3-(4-methoxyphenyl)-4-phenylpyridazin-oxid.

3. Connection phenylpyridazin or its salt according to claim 1 where the compound is selected from the group including

3,4-bis(4-methoxyphenyl)-6-(phenoxy)pyridazine,

3,4-bis(4-methoxyphenyl)-6-(2,3-divergence)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(2,5-divergence)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(2,6-divergence)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(3,4-divergence)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(2,3,5,6-tetraterpenes)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(2,3,4,5,6-Pantothenate)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(3,4,5-trichlorophenyl)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(4-methoxyphenoxy)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(4-nitrophenoxy)pyridin,

3,4-bis(4-methoxyphenyl)-6-(2-cianfrocca)pyridazin,

3,4-bis(4-methoxyphenyl)-6-(3-cianfrocca)pyridazin,

6-(2,4-divergence)-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine,

6-(2,3-divergence)-3-(4-methoxyphenyl)-4-phenylpyridazin,

6-(2,4-divergence)-3-(4-methoxyphenyl)-4-phenylpyridazin,

3-(4-methoxyphenyl)-6-(2,3,4,5,6-Pantothenate)-4-phenylpyridazin,

3-(4-methylthiophenyl)-6-phenylthio-4-(4-phenylthiophene)pyridazin,

4-(4-chlorophenyl)-6-(2,4-divergence)-3-[4-(methylthio)phenyl]pyridazine,

3,4-bis(4-methoxyphenyl)-6-cyanopyridine and

6-cyano-3-(4-methoxyphenyl)-4-phenylpyridazin and their salts.

4. Drug, inhibiting the production of interleukin-1βcomprising as an effective ingredient the compound phenylpyridazin or its salt according to any one of claim 1 or 3.

5. The inhibitor of the production of interleukin-1βcomprising as an effective ingredient the compound phenylpyridazin or its salt according to any one of claim 1 or 3.

6. The pharmaceutical composition inhibiting the production of interleukin-1βcomprising as an effective ingredient the compound phenylpyridazin or its salt according to any one of claim 1 or 3 and a pharmaceutically acceptable carrier.

7. Connection phenylpyridazin (I) or salts thereof for production of a drug that inhibits the production of interleukin-1β.



 

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EFFECT: valuable biochemical and medicinal properties of compounds.

6 cl, 1 tbl, 30 ex

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EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

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