Derivatives of pyrazole or their pharmaceutically acceptable salts

 

(57) Abstract:

The invention relates to pyrazole derivative of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts. These compounds possess anti-inflammatory, Antirheumatic and pain-soothing activity. 3 C. p. F.-ly, 3 tables.

The present invention relates to new derivatives of pyrazole and their acceptable from a pharmaceutical point of view salts. More specifically, the present invention relates to new derivatives Pitalua and antithrombotic activities, the method of production thereof, to pharmaceutical compositions containing the above compounds and to methods of using these compounds for therapeutic purposes in the treatment and/or prevention of inflammatory diseases, various pains, collagen diseases, autoimmune diseases, various diseases of the immune system and the brain in a human body or an animal, and more specifically, to methods for treating and/or preventing inflammation and pain in the connective tissue and muscle /for example, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, etc./, inflammatory diseases of the skin, e.g. sunburn, eczema, etc./, inflammatory diseases of the eye /for example, conjunctivitis, etc./, lung diseases that involve inflammation /for example, asthma, bronchitis, diseases of the "pigeon fancier", "farmer's lung", etc./, diseases of the gastrointestinal tract associated with inflammation /for example, ulcers of the mucous membrane, Crohn's disease, offset gastritis, odpowiedniego gastritis, ulcerative colitis, regional ileitis, irritable bowel syndrome, etc./ gingivitis, inflammation, pain and swelling after surgery or genase and cyclooxygenase are factors common lupus lupus, scleroderma, polymyositis, periarteritis nodosa, rheumatic fever, syndrome Sorgen, diseases of Meseta, thyreoiditis, diabetes type 1, nephrotic syndrome, gipoplasticheskaya anemia, myasthenia gravis, uveitis, contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, etc. in Addition, as can be expected, the proposed connection will be effective as a therapeutic and/or preventing agent for diseases of the cardiovascular or cerebrovascular diseases caused by hyperglycemia and hyperlipemia.

The purpose of the present invention is to provide new and useful derivatives of pyrazole and their acceptable from a pharmaceutical point of view salts, which possess anti-inflammatory, pain management and antithrombotic activities.

Another objective of the present invention is to provide a method of obtaining the above-mentioned derivatives of pyrazole and their salts.

Another objective of the present invention is to provide a pharmaceutical composition comprising as an active ingredient the above-mentioned derivatives of pyrazole and their acceptable pharmaceutical t the definition of the method of treatment and/or prevention of inflammatory diseases, various pains and other disorders mentioned above, using the above-mentioned derivatives of pyrazole and their acceptable from a pharmaceutical point of view of salt.

Some pyrazole derivatives having anti-inflammatory and pain-soothing activities that were previously known, see, for example, patent Canada N 1 130 808 and the patent EP NN 272 704, 293 220 and 418 845.

Target pyrazole derivatives which are the subject of the present invention are new and can be represented by the following General formula I:

< / BR>
in which R1is aryl, which is substituted by the Deputy /deputies/ selected from the group consisting of lower alkylthio, cyclo/lower/alkyl, hydroxy, hydroxy/lowest/ the alkyl, cyano, lower alkylenedioxy, acyl, acyloxy, aryloxy and lower alkoxy, optionally substituted by acyl or lower alkoxy,

R2is halogen, halo/lowest/the alkyl, cyano or acyl, and

R3is aryl, substituted nitro, hydroxy, lower alkoxy, lower alkylthio, lower alkylsulfonyl or lower alkylsulfonyl, provided that when R3is aryl, substituted nitro, hydroxy or lower alkoxy, then R1is aryl, substituted ness the rhenium salt.

The target connection /1/ or its salt can be obtained by the following reactions:

Reaction 1.

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Reaction 2.

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Reaction 3.

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Reaction 4.

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Reaction 5.

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Reaction 6.

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Reaction 7.

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Reaction 8.

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Reaction 9.

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Reaction 10.

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Reaction 11.

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Reaction 12.

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Reaction 13.

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Reaction 14.

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Reaction 15.

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Reaction 16.

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in which R1, R2and R3have already been defined above,

R2ais the halo/lowest/the alkyl, cyano or acyl,

R3ais aryl, substituted lower alkylthio,

R3bis aryl, substituted lower alkylsulfonyl go lower alkylsulfonyl,

R2bis halogen,

R1ais aryl, substituted carboxy,

R1bis aryl, substituted carbamoyl, which can be substituted by the Deputy /deputies/ selected from the group consisting of lower alkyl, aryl, cyclo/lowest/ the alkyl and hydroxy, or N-containing heterocycle what stitely/, selected from the group consisting of lower alkyl, aryl, cyclo/lowest/the alkyl and hydroxy, or N-containing heterocyclic carbonyl,

R1cis aryl, substituted carbamoyl,

R1dis aryl, substituted cyano,

R1eis aryl substituted by acetyl,

R4is lower alkyl,

R1fis aryl, substituted esterified carboxy,

R1gis aryl, substituted carboxy or esterified carboxy,

R1his aryl, substituted oximation,

R1iis aryl, substituted hydroxy,

R1jis aryl, substituted lower alkoxy, optionally substituted by acyl or lower alkoxy,

R1kis aryl, substituted acyloxy,

R1lis aryl, substituted lower alkoxy, which is substituted esterified carboxy,

R1mis aryl, substituted lower alkoxy, which is substituted by carboxy,

R2dis esterified carboxy,

R1nis aryl, substituted lower alkylthio, and

R1o/

The term "lower" refers to a group containing from 1 to 6 carbon atoms, unless stated otherwise.

The term "lower alkyl" and lower alkyl component in the phrases "lower alkylthio", "lower alkylsulfonyl", "lower alkylsulfonyl", "oxy/lower/alkyl" and "halo/lower/alkyl" refers to linear or branched alcelam, such as methyl, ethyl, propyl, isopropyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., among which preferred is methyl.

Suitable "cyclo/lower/alkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., among which the cyclohexyl is preferred.

Suitable "lower alkoxy" may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert - butoxy and so on, and in the preferred embodiment, use of methoxy, ethoxy or isopropoxy.

Suitable "aryl" and aryl component in the term "aryloxy" may be phenyl, naphthyl, etc., and preferred is phenyl.

Suitable "halogen" may be fluorine, chlorine, bromine and iodine, preferably is bromine.

The corresponding "halo/Nissi foradil etc., moreover, it is preferable to deformity or trifluoromethyl.

Suitable "lower alkylenedioxy" may be linear or branched, such as methylenedioxy, Ethylenedioxy, trimethylenediamine, dimethylethylenediamine, Propylenediamine, etc.

Suitable "acyl" and allowa component in the term "acyloxy" may be carboxy; esterified carboxy: carbamoyl, optionally substituted Deputy /deputies/ selected from the group consisting of lower alkyl, cyclo/lowest/the alkyl, aryl and hydroxy; lower alkanoyl; Arola; lower alkylsulfonyl; lower alkylsulfonyl; N-containing heterocyclic carbonyl; etc.

Esterified carboxy may be substituted or unsubstituted lower alkoxycarbonyl /for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxyphenyl, 2-idatastream, 2,2,2-three - chlorocarbonates etc./, substituted or unsubstituted aryloxyalkyl [for example, phenoxycarbonyl, 4-nitrophenoxyacetic, 2-naphthalocyanine etc], substituted or unsubstituted ar/lower/alkoxycarbonyl [for example, benzyloxycarbonyl, ventilatsioonile, bailom, the acetyl, propionyl, Boutillon, isobutyryl, Valerian, isovaleryl, pivaloyl, hexanoyl etc.

Aroyl may be benzoyl, naftilan, benzoyl, substituted lower alkyl [e.g., talwara, xylene, etc.], etc. /N-containing heterocyclic carbonyl may be substituted 5 or 6-cell N-, or N - and S-, or N - and O-containing heterocyclic carbonyl such as pyrrolidinylcarbonyl, imidazolidinedione, piperidinylcarbonyl, piperazinylcarbonyl, N-/low/alkylpiperazine [for example, N-methylpiperazine, N-ethylpiperazine, and so on], morpholinoethyl, thiomorpholine, thiomorpholine, etc. Corresponding "lower alkylthio" may be methylthio, ethylthio, propylthio and so on, is preferably methylthio.

The corresponding "lower alkylsulfonyl" can be methylsulphonyl, ethylsulfonyl, propylsulfonyl and so on, and in the preferred embodiment, use methylsulphonyl.

The corresponding "lower alkylsulfonyl" can be methylsulfinyl, ethylsulfinyl, propylsulfonyl, etc. in which it is preferable to methylsulfinyl.

The preferred connection /1/ is the m or lower alkoxy for R1, halogen or halo/lowest/the alkyl for R2and aryl /in a more preferred embodiment, the phenyl/ substituted lower alkylthio, lower alkylsulfonyl or lower alkylsulfonyl for R3.

The preferred compound of the formula /1/ is a compound containing aryl /in a more preferred embodiment, the phenyl/ substituted methoxy or cyano for R1, bromine, deformation or trifluoromethyl R2and aryl /in a more preferred embodiment, the phenyl/ substituted methylthio, methylsulfinyl or methylsulfonyl for R3or aryl /in a more preferred embodiment, the phenyl/ substituted methoxy for R1, bromine or deformation for R2and aryl /in a more preferred embodiment, the phenyl/ substituted methylthio, methylsulfinyl or methylsulfonyl for R3.

The most preferred compound of the formula /1/ is a compound that contains 4-methoxyphenyl for R1, bromine or deformity for R2or 4-cyanophenyl for R1, trifluoromethyl R2and 4/methylthio/phenyl, 4-/methylsulfinyl/phenyl or 4-/methylsulphonyl/phenyl for R3.

Appropriate acceptable from a pharmaceutical standpoint salt target soy /for example, sodium salt, potassium salt, etc./, salt alkaline earth metal such as calcium salt, magnesium salt and so on/ and so forth

The reaction to obtain the target compound /1/ described in detail below.

Reaction 1

Connection /1A/ or its salt can be obtained through the interaction of the compound (II) or its salt with the compound (III or its salt.

Such salts are compounds /Ia/ and /II/ can be the same as those listed as examples of compounds /I/.

The corresponding salt of compound (III can be the same that was given as an example of a combination of /I/, and attached the salt of the acid, such as attached salt of an inorganic acid [e.g. hydrochloride, bromohydrin, sulfate, phosphate, etc.] attached salt of an organic acid [e.g. formate, acetate, triptorelin, methanesulfonate, bansilalpet, toluensulfonate etc.], etc.

This reaction is in General carried out in a known solvent, such as alcohol /for example, methanol, ethanol, etc.,/, dioxane, tetrahydrofuran, acetic acid, N,N-dimethylformamide, a mixture thereof or any other organic solvent which does not adversely affect the reaction.

The reaction of 2

Connection /Ic/ or its salt can be obtained through the interaction connections /Ib/ or its salt with an oxidizing agent.

Such salts are compounds /Ib/ and /Ic/ can be the same as those listed as examples for the connection /I/.

Appropriate oxidizing agent may be hydrogen peroxide, Gidropress hydroperoxide, tert-butyl Gidropress, Jones reagent, nagkalat [e.g., peracetic acid, natantia acid, m-chlormadinone acid, etc.], chromic acid, potassium permanganate, periodic alkali metal [e.g., periodate sodium, etc.], etc.

This reaction is in General carried out in a solvent that does not adversely affect the reaction such as acetic acid, dichloromethane, acetone, ethyl acetate, chloroform, water, alcohol [e.g. methanol, ethanol, etc.], their mixture, etc.

The reaction temperature is not the decisive factor and the reaction is in General carried out at the cooling - heating.

In this reaction, when the connection /Ib/, containing aryl, substituted lower alkylthio, for R1use as the source connection /Ic/, containing aristei with the reaction conditions. This case is included in the scope of claims of the applicant.

Reaction 3

Connection /Id/ or its salt can be obtained using the following procedure.

Namely, I/ connection /IV/ or its salt, first, interacts with the connection nitrite, and then 2/ charged in the product interacts with the halide monovalent copper.

The corresponding salt of the compound /Id/ can be the same as those listed as examples for the connection /I/.

The corresponding salt of the compound /IV/ may be the same as those listed for the connection /III/ in reaction 1.

Appropriate connection of nitrite may be a nitrite of an alkali metal [e.g. sodium nitrite, potassium nitrite, and so on], the alkyl nitrite [e.g. tert-butyl nitrite, etc.], etc.

The corresponding halide monovalent copper may be monovalent chloride copper bromide monovalent copper, etc.

In the first stage reaction in the preferred embodiment, is carried out in the presence of acid [for example, sulfuric acid, etc].

This reaction is in General carried out in a solvent such as water, tetrahydrofuran, dioxane, acetonitrile or any other organic RNA temperature is not a critical factor and the reaction may be carried out at the cooling-heating.

In the second stage reaction in the preferred embodiment, is carried out in the presence of a halide of an alkali metal [e.g. sodium bromide and so on] and inorganic acids [for example, Hydrobromic acid, etc.].

This reaction is in General carried out in a solvent such as water, tetrahydrofuran, dioxane or any other organic solvent which does not adversely affect the reaction.

The reaction temperature is not the decisive factor, and the reaction can be performed under heating.

Reaction 4

Connection /If/ or its salt can be obtained by the reaction of compounds /Ie/ or its reactive derivative in carboxypropyl, or its salt with an amine or with formamide and an alcoholate of an alkali metal.

Such salts are compounds /If/ and /Ie/, and its reactive derivative in carboxypropyl may be the same as those listed as examples for the connection /I/.

The "amine" may be ammonia, lower alkylamines, arylamines, cyclo/lower/alkylamino, lower alkylhydroxylamines, N-containing heterocyclic compound, etc.

Lowest alkylamine can utilman, pentylamine, hexylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, Diisopropylamine, dimentianon, digoxigenin etc.

Arylamine can be aniline, naphthylamine, etc., Cyclo/lower/alkylamine can be cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine etc.

Lowest alkylhydroxylamines can be methylhydroxylamine, ethylhydroxylamine, propylhydroxybenzoate, butylhydroxyanisole, isopropylacrylamide etc.

N-containing heterocyclic compound may be saturated 5 or 6-Allemagne N-, or N - and S-, or N - and O-containing heterocyclic compound, such as pyrrolidine, imidazolidine, piperidine, piperazine, N-/low/ alkylpiperazine [for example, N-methylpiperazine, N-ethylpiperazine etc.] , morpholine, thiomorpholine etc.

Corresponding to the alcoholate of an alkali metal may be sodium methylate, sodium ethylate, tert-butyl potassium, etc.

The corresponding reactive derivative in carboxypropyl connection /Ie/ may include ester, galoyanized, acid anhydride, etc., Relevant examples of the reactive derivatives may be galoyanized [e.g., chloride CIS is midazolam or acid, such as aliphatic acid [e.g. acetic acid, pivaloyloxy acid, etc.], substituted phosphoric acid [e.g. dialkylphosphinate acid, diphenylphosphoryl acid and so on];

ester such as lower alkilany ester [e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, etc.], substituted or unsubstituted ar/lower/alkilany ester [e.g. benzyl ester, benzhydryl ester, para-chlorbenzoyl ester, etc.], substituted or unsubstituted arrowy ester [for example, phenyl ester, tallowy ester, 4-nitrophenyloctyl ester, 2,4-dinitrophenoxy ester, pentachlorphenol ester, nattily ester, etc.] or an ester with N,N-dimethylhydroxylamine, N-oxysuccinimide, N-acceptilation or 1-hydroxy-6-chloro-1H-benzotriazole etc.

The reaction is in General carried out in a known solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, formamide, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely vozrast">

When the connection /Ie/ is used in the form of the free acid in the reaction, its in the preferred embodiment, is carried out in the presence of a known condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinylcarbonyl, N-ethyl - N'-/3-dimethylaminopropyl/carbodiimide, thionyl chloride, oxalyl chloride, lower alkoxycarbonyl the halide [for example, ethyl chloroformate, isobutyl chloroformate etc.], 1-/para-chlorobenzenesulfonate/-6-chloro-1H-benzotriazole, etc., This reaction also in the preferred embodiment, is carried out in the presence of known bases such as triethylamine, pyridine, hydrate of sodium oxide, etc.

The reaction temperature is not the decisive factor, and the reaction may be carried out at the cooling-heating.

Reaction 5

Connection /Ih/ or its salt can be obtained by the interaction of compounds /Ig/ or its reactive derivative in carboxylate or its salt with an amine, or with formamide and an alcoholate of an alkali metal.

The corresponding salts of the compounds /Ih/ and/Ig/ and their reactive derivatives in carboxypropyl can be the same as those listed as examples for the connection /I/.

Atolina reactions and reaction conditions [e.g., the solvent, reaction temperature, etc.] this reaction can be found in the description of reaction 4.

Reaction 6

Connection /Ij/ or its salt can be obtained by the interaction of compounds (Ii) or its salt with a dehydrating agent.

Relevant soname connections /Ii/ and /Ij/ can be the same salts as those listed as examples for the connection /I/.

Appropriate dehydrating agent may be a compound of phosphorus [e.g., pathiakis phosphorus, pentachloride phosphorus oxychloride phosphorus, etc. ] , thionyl chloride, anhydride acid [e.g. acetic anhydride, etc.], phosgene, arylsulfonate [for example, benzazolyl chloride, paratoluenesulfonyl chloride etc.], metalfoil chloride, sulfamic acid, sulpham ammonium, N, N' -dicyclohexylcarbodiimide, lower alkoxycarbonyl the halide [for example, ethyl chloroformiate etc.], etc.

The reaction is in General carried out in a known solvent, such as acetonitrile, methylene chloride, ethylene chloride, benzene, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction.

In addition, when the above-mentioned P> The reaction temperature is not the decisive factor and the response in the preferred embodiment, is carried out with heating.

Reaction 7

Union /Il/ or its salt can be obtained through the interaction connections /Ik/ or its salt drying agent. Such salts are compounds /Ik/ and /Il/ can be the same salts as those listed as examples for the connection /I/.

This reaction can be performed essentially as described for reactions 6 and, consequently, the reaction procedure and reaction conditions [e.g. solvent, reaction temperature, etc.] the reaction described in reaction 6.

Reaction 8

Connection /Im/ can be obtained using the following procedures.

Namely, I/ connection /Ie/ or its reactive derivative in carboxypropyl, or its salt, first, interacts with the connection /V/, then 2/ the resulting product is subjected to hydrolysis.

The corresponding salts of the compounds /Ie/ and its reactive derivative in carboxypropyl can be the same as those given as examples for the connection /I/.

The corresponding chemically active PTY etc.], etc.

At the first station the reaction in the preferred embodiment, is carried out in the presence of a base such as an alkali metal [e.g., lithium, sodium, potassium, etc. ], alkaline earth metal [e.g. calcium, magnesium, and D.], alkali metal hydride [e.g. sodium hydride, etc.], hydride alkaline earth metal [e.g. calcium hydride, etc.], an alcoholate of an alkali metal [e.g. sodium methylate, sodium ethylate, tert-butyl potassium, and so on], the alcoholate of alkaline earth metal [e.g. magnesium methylate, the magnesium ethylate and so on], etc.

This reaction is in General carried out in a solvent that does not adversely affect the reaction, such as diethyl simple ether, tetrahydrofuran, dioxane, etc.

The reaction temperature is not the decisive factor, and the reaction may be carried out at the cooling-heating.

In this reaction can be obtained compound of the formula:

< / BR>
in which R2and R3have already been defined above,

R1pis aryl, substituted di/low alkoxycarbonyl/acetyl.

The corresponding salt of the compound /IV/ may be the same as those listed as examples for the connection /I/.

This acid may be an organic acid [e.g. formic acid, acetic acid, propionic acid, triperoxonane acid, trichloroacetic acid, and so on ] , an inorganic acid [e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, etc.] and Lewis acid [for example, tribromide boron and so on].

This reaction is in General carried out in a solvent such as water, alcohol [e.g. methanol, ethanol, etc.] methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely affect the reaction. Liquid base or acid can also be used as solvent. The reaction temperature is not the decisive factor and the reaction is in General carried out at the cooling-heating.

Reaction 9

Connection /In/ or its salt can be obtained through the interaction connections /Ie/ or its reactive derivative in carboxylate or its salt with oxycontintear.

Such salts are compounds /In/ and /Ie/ and their reactive derivative in carboxypropyl can be the same as those listed in example DL which may be halogenerator [for example, the acid chloride, acid bromide, etc.], etc.

Appropriate oxycoedone may be an alcohol [e.g. methanol, ethanol, propanol, benzyl alcohol, etc.] phenol, naphthol, etc.,

This reaction is in General carried out in a known solvent, such as diethyl simple ether, Petraitiene, dioxane go any other solvent which does not adversely affect the reaction.

In addition, when the above-mentioned oxycoedone contains a liquid, it can also be used as solvent.

The reaction temperature is not the decisive factor and the reaction is in General carried out at the cooling-heating. When the connection /Ie/ is used in the form of the free acid in the reaction, this reaction in the preferred embodiment, is carried out in the presence of acid.

The corresponding acid may be an inorganic acid, is shown as an example in the above-mentioned reaction 8.

Reaction 10

Connection /Ip/ or its salt can be obtained through the interaction connections /Ie/ or its salts with a regenerating agent.

Such salts are compounds /Io/ the existing regenerating agent may be DIBORANE, aluminum lithium hydride, etc.

This reaction is in General carried out in a known solvent, such as diethyl simple ether, tetrahydrofuran, or any other organic solvent which does not adversely affect the reaction.

The reaction temperature is not the decisive factor, and the reaction may be carried out at the cooling-heating.

Reaction 11

Connection /Ir / or its salt can be obtained through the interaction connections /Iq/ or its salt with an alkylating agent.

Such salts are compounds /Iq/ and /Ir/ can be the same compounds that have been shown as an example for the connection /I/.

Appropriate alkylating agent may be a lower alkyl halide in which the alkyl may be substituted by lower alkoxy or acyl [e.g., methyl iodide, ethyl bromide, chloromethyl methyl simple ether, ethyl bromoacetate and so on ].

The reaction in the preferred embodiment, is carried out in the presence of a base such as an alkali metal [e.g. sodium, potassium, etc.], alkaline earth metal [e.g. magnesium, calcium and so on], it hydride or hydroxide, or a carbonate or bicarbonate.

Atlve to the reaction, such as water, dioxane, alcohol [e.g. methanol, ethanol, etc.], acetonitrile, tetrahydrofuran, N, N-dimethylformamide or mixtures thereof.

In addition, when the above-mentioned alkylating agents are in liquid, they can be used as a solvent.

The reaction temperature is not the decisive factor, and the reaction can be carried out with cooling-heating.

In this reaction in the case when the connection is /Iq/, containing aryl, substituted oxide as R3use as the source connection /Ir/ containing aryl, substituted lower alkoxy as R3can be obtained according to reaction conditions. This case is included in the scope of claims of the applicant.

Reaction 12

Connection /Is/ or its salt can be obtained through the interaction connections /Iq/ or its salts with allermuir agent.

Such salts are compounds /Iq/ and /Is/ can be the same as those listed as examples for the connection /I/.

Allerease agent may be an organic acid represented by the formula: R5HE, in which R5is acyl, as it was pollastri organic acids can be such a connection, as galoyanized [e.g. acid chloride, acid bromide, etc.], acid azide, acid anhydride, activated amide, an activated ester, etc.

When the free acid is used as Alliluyeva agent, the acylation reaction in the preferred embodiment, is carried out in the presence of a known condensing agent such as N,N'-dicyclohexylcarbodiimide etc.

The reaction is in General carried out in a known solvent such as water, acetone, dioxane, chloroform, methylene chloride, acetonitrile, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction, or their mixtures.

The reaction temperature is not the decisive factor, and the reaction may be carried out at the cooling-heating.

Reaction 13

Compound /Iu/ or its salt can be obtained by subjecting compound /It/ or its salt reaction deesterification.

Such salts are compounds /It/ and /Iu/ can be the same as those listed as examples for the connection /I/.

The reaction is carried out in accordance with known techniques otsutstvie base or acid, including the Lewis acid. Appropriate base may include an inorganic base and organic base such as an alkali metal [e.g. sodium, potassium, etc.], alkaline earth metal [e.g. magnesium, calcium and so on] their hydroxides, carbonates or bicarbonates, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo[5.4.0] undec-7-ene, etc., the Corresponding acid include organic acids, [for example, formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane acid and so on], an inorganic acid [e.g. hydrochloric acid, Hydrobromic acid, idiscovered acid, sulfuric acid, etc.], and Lewis acid [e.g., tribromide boron and so on].

This reaction is in General carried out in a solvent such as water, alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely affect the reaction. Liquid base or acid can also be used as solvent. The reaction temperature is not the decisive factor is prevalent in the preferred embodiment, to exclude part of ester, such as 4-nitrobenzyl, 2-Iodate, 2,2,2-trichloroethyl, etc., the recovery Procedure is applicable for the reaction exceptions may include chemical reduction and catalytic reduction.

Appropriate reducing agents used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc. ] or metallic compound [e.g. chromium chloride, chromium acetate, and so on] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, triperoxonane acid, para-toluene/mono/sulfonic acids, hydrochloric acid, Hydrobromic acid, etc.].

Appropriate catalysts that can be used in catalytic reduction are well-known catalysts such as a platinum catalyst [e.g. platinum plate, porous platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, and so on], palladium catalyst [for example, porous palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], Nickel catalyst [h is undertaken cobalt, cobalt the struggle of renée and so on ] , the iron catalyst [e.g. reduced iron, iron the struggle of renée and so on ], the copper catalyst [for example, the recovered copper, copper struggle of renée, copper of Ullman etc.], etc.

Recovery in General carried out in a known solvent that does not adversely affect the reaction, such as water, alcohol [e.g. methanol, ethanol, propanol, etc.], N,N-dimethylformamide or a mixture thereof. In addition, when the above-mentioned acids, which are used in chemical reduction are in liquid, they can be used as solvent. In addition, an appropriate solvent which can be used in catalytic reduction may be the above-mentioned solvent and another solvent such as diethyl simple ether, dioxane, tetrahydrofuran, etc., and mixtures thereof.

The reaction temperature in this recovery is not the decisive factor and the reaction is in General carried out at the cooling-heating.

Reaction 14

Connection /Ig/ or its salt can be obtained by subjecting compound /IV/ or its salt reaction deesterification.

Such salts are compounds /Ig/ and /IV/westwith essentially using the same procedure what was used in the reaction 13, and therefore, the procedure of the reaction and reaction conditions [e.g. solvent, reaction temperature, etc.] the reaction described in reaction 13.

Reaction 15

Connection /Ig/ or its salt can be obtained by exposing the connection /Ir/ or its salt dealkylation reactions.

Such salts are compounds /Ig/ and /Ir/ can be the same as the one shown as an example for the connection /I/.

The reaction is carried out in accordance with known methods such as hydrolysis, etc.

Hydrolysis in the preferred embodiment, is carried out in the presence of an acid including Lewis acid [e.g. hydrochloric acid, Hydrobromic acid, idiscovered acid, tribromide boron, trichloride boron, etc.] or three of lower alkyl/silicided [for example, trimethylsilylmethyl and so on].

The reaction is in General carried out in a solvent such as water, acetic acid, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely affect the reaction.

The reaction temperature is not the decisive factor and the reaction is carried out at hohlakov, as R3use as source material, the connection /Iq/ with aryl, substituted hydroxy, as R3can be obtained according to reaction conditions. This case is included in the claims of the applicant.

Reaction 16

Link /Ix/ or its salt can be obtained by the reaction of compounds /Iw/ or salt with an oxidizing agent.

Such salts are compounds /Iw/ and /Ix/ can be the same as those listed as examples for the connection /I/.

This reaction can be performed essentially using the same procedure that was described for reaction 2, and, consequently, the implementation of the reaction and reaction conditions [e.g. solvent, reaction temperature and so on] of this reaction are consistent with those that have been described in reaction 2.

In this reaction in the case when the connection is /Iw/ with aryl, substituted lower alkylthio, for R3use as a source of connection, the connection /Ix/, containing aryl, substituted lower alkylsulfonyl or lower sulfonium, as R3can be obtained according to reaction conditions. This case is included in the scope of claims of the applicant.

Soemhow, such as sputtering, recrystallization, chromatographic column, re-deposition, etc.

It should be noted that the connection /I/ and other compounds can include one or more stereoisomers due to the presence of asymmetric carbon atoms and all of such isomers and mixtures thereof are included in the scope of claims of the applicant.

The target connection /I/ or acceptable from a pharmaceutical point of view salts possess strong anti-inflammatory, pain management and antithrombotic activities and can be used for the treatment and/or prevention of inflammatory diseases, various pains, collagen diseases, autoimmune diseases, various immune diseases and thrombosis in humans or in animals, and more specifically can be used in the treatment and/or prevention of inflammation and pain in the connective tissue and muscle [e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and so on ], inflammatory skin diseases [for example, sunburn, eczema and so on]. inflammatory eye diseases [e.g., conjunctivitis, etc.], pulmonary disorders involving inflammation [e.g., asthma, brejcha, associated with inflammation [e.g., ulcers of the mucous membrane, Crohn's disease, offset gastritis, odpowiedniego gastritis, ulcerative colitis, regional ileitis, irritable bowel syndrome and so on], gingivitis, inflammation, pain and swelling after surgery or injury, pyresis, pain and other diseases associated with inflammation, in particular those factors which are the products of the lipoxygenase and cyclooxygenase, General lupus lupus, scleroderma, polymyositis, periarteritis nodosa, rheumatic fever, syndrome Sjogren, disease Becket, thyroiditis, diabetes type 1, nephrotic syndrome, gipoplasticheskaya anemia, myasthenia gravis, uveitis, contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, etc. in Addition, it can be expected that the target compound of the present invention may be useful as a therapeutic and/or prophylactic agents for the treatment of cardiovascular diseases cerebrovascular diseases caused by hyperglycemia and hyperlipemia.

In order to illustrate the effectiveness of the target compounds /I/, the following data pharmacological testing of compounds /I/.

/A/ Propitanie:

Ten female rats Sprat-Dole used in each group. Dose in 0.5 ml of Mycobacterium tuberculosis /strain Aoyama B/, suspended in 0.05 ml of liquid paraffin was injectively pasture way in the right hind paw. Injection of mycobacterial adjuvant was caused by a local inflammatory lesions /primary lesion/, and then after about 10 days secondary lesions on the paws, which were made of injection and legs, in which injections did not. The difference in the volumes of both legs before and after the injection of adjuvant served as a measure of arthritis. The drug was given tematicheskim way once a day for 23 days, from day 1.

(II) the test Results (see tab. 1).

/B/ Analgesic activity

Inflammatory hyperalgesia caused by yeast brewer in rats:

/I/ test Procedure:

Each group used a ten male rats sprag-Dole. In the right hind paw was injectively 0.1 ml of 5% yeast brewer in 0.5% methylcellulose. The threshold of pain was determined 3 hours after injection of the yeast through the application of pressure to the foot and recording the pressure at which the rat tries to release the foot.

Lekarstvennye treated animals was compared with that of control animals.

(II) the test Results (see tab. 2).

/C/ Antirheumatic activity:

The effect is caused by collagen arthritis in mice:

/I/ test Procedure:

Used eight male mice DBA/1 in each group. Bovine collagen type II was dissolved in 0.1 M acetic acid and emulsiable in complete Freund's adjuvant /CFA/. First, the mice were injected with 0.2 mg of collagen type II in CFA through the skin at the base of the tail. Mice did injection after 21 days using the same procedure. 10 days after this introduction drug used tematicheskim way once a day for 3 weeks and mice were examined every week for visual signs of arthritis. Arthritic index was used to assess the condition of the limbs on a scale of 0-3: swelling of joints and erythema /score 1/, visual neoplastic disorders /2/ and find ankylosis of joints /3/.

(II) the test Results (see tab. 3).

For therapeutic purposes the connection /I/ and it is acceptable from a pharmaceutical point of view of salt, which is the subject of the present invention can be used in the form of pharmaceutical preparati containing one of the aforementioned compounds as activepolicies solid or liquid filler, suitable for tematicheskoe, parenteral or external /local/ applications. Pharmaceutical preparati can be in the form of capsules, tablets, pills, granules, inhalations, suppositories, solution, lotion, suspension, emulsion, ointment, gel, etc., If necessary, in spooling can be included auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers, and others used in this area supplements.

Although the dosage of the compounds (I) may vary depending on the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1,000 mg of compound (I) may be effective for the treatment of the aforementioned diseases. In General, the day you can apply from 0.1 mg to 1000 mg/patient.

The following spooling and examples are given to illustrate the present invention.

Preparation 1

A mixture of ethyl 1-/4-methoxyphenyl/-5-[4-/methylthio/phenyl]pyrazole-Z-carboxylate /10.2 g/ and hydrate potassium oxide /3.7 g/ methanol /60 ml/ was subjected to reflux distilled for 30 minutes. The solvent is evaporated, and the residue was dissolved in water and washed with toluene. The aqueous layer was acidified, and the precipitation was collected is islote /8.8 g/.

The melting-point: 238-239oC /Razlog./

IR /Nujol/: 2750, 2600, 1700, 1600, 1510 cm-1< / BR>
The mass spectrum of the /m/z/: 340 /M+/

Preparation of 2

A mixture of 1-/4-methoxyphenyl/-5-[4-/methylthio/phenyl] pyrazole-3 - carboxylic acid /3,4 g/ and pentachloride phosphorus /2.3 g/ dichloromethane /20 ml was stirred at ambient temperature for 1 hour. The solvent is evaporated to obtain an oil of the appropriate acid chloride.

A solution of the obtained oil in acetone /10 ml was added dropwise to a cooled ice mixture of sodium azide /0.65 g/, water /10 ml and acetone /10 ml/. During adding the above solution, the reaction mixture was maintained at pH 8 to 9 by adding an aqueous solution of sodium bicarbonate. The mixture was stirred at ambient temperature for 30 minutes, concentrated under vacuum and was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to obtain an oil of the corresponding acid azide.

The above oil was dissolved in toluene /50 ml/. The solution was heated to 100oC for 1 hour and then concentrated to obtain a solid of the corresponding isocyanate.

A mixture of the above solid and ContentControl. To the residue was added a solution of hydrate of sodium oxide and the mixture was extracted with chloroform. The extract was washed with water, dried and concentrated under vacuum. The residue was subjected to purification on a chromatographic column on silica gel, elwira chloroform, and the purified product was subjected to recrystallization from ethanol to obtain crystals of 1-/4-methoxyphenyl/-5-[4-/methylthio/phenyl]pyrazole-3-amine /0.8 g/.

The melting-point: 120-129oC.

IR /Nujol/: 3450, 3300, 3200, 1630, 1610, 1565, 1520 cm-1< / BR>
NMR /CDCl3: 2,46 /3H, singlet/, 3,32 /2H, broad singlet/, 3,80 /3H, singlet/, by 5.87 /1H, singlet/, 6,7-7,2 /8H, multiplet/

The mass spectrum of the /m/z/: 311 /M+/

Example 1

A mixture of 4,4-debtor-1-[4-/methylthio/phenyl] -butane-1,3-dione /2.4 g/ hydrochloride and 4-methoxyphenylhydrazine /1,9 g/ acetic acid /10 ml was stirred at a temperature of 100oC for 1 hour. The solvent is evaporated and the residue was subjected to purification on a chromatographic column on silica gel /30g/, elwira toluene. Purified oil product has led from ethanol to obtain crystals of 3-/deformity/-1-/4-methoxyphenyl/-5-[4-/methylthio/phenyl]pyrazole /2.5 g/.

The temperature of the melting point: 100-101oC

IR /Nujol/: 1610, 1520, 1500 cm-1
Example 2

A mixture of 3-/deformity/-1-/4-methoxyphenyl/-5-[4-/methylthio - phenyl]pyrazole /1 g/ and meta-chlormadinone acid /0.56 g/ dichloromethane /23 ml/ was stirred at ambient temperature for 1 hour. The mixture was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated. Oily residue was led from ethanol to obtain crystals of 3-/deformity/-1-[4-methoxyphenyl/-5-[4-/methylsulfinyl/ phenyl] pyrazole /0,82 g/.

The temperature of the melting point: 123-124oC

IR /Nujol/: 1615, 1590, 1520 cm-1< / BR>
NMR /CDCl3/: 2,74 /3H, singlet/, 3,83 /3H, singlet/, 6,5-7,7 /10H, multiplet/

Example 3

A mixture of 3-/deformity/-1-/4-methoxyphenyl/-5-[4-/methylthio - phenyl]pyrazole /2 g/, 30% hydrogen peroxide /2 ml/ and sulfuric acid /2 drops/ acetic acid /5 ml was stirred at 60oC for 1 hour. The solvent is evaporated, and the residue was subjected to recrystallization from ethyl acetate, to obtain crystals of 3-/deformity/-1-/4-methoxyphenyl)/-5-[4-methylsulphonyl/phenyl] pyrazole /0,86 g/.

The temperature of the melting point: 135oC

IR /Nujol/: 1605, 1520 cm-1< / BR>
NMR /CDCl3, /: 3,07 /3H, singlet/, 3,84 /3H, singlet/, 6,1-8,0 /10H, multiplet/.

The mass spectrum of the /m/z/: 378 /M+/,-5-[4-/methylthio - phenyl] pyrazole-C-Amin /2 g/ and sulfuric acid /1,2 ml/ water /3 ml and acetonitrile /6 ml at a temperature of 5oC, and the mixture was stirred at the same temperature for 1 hour. This mixture was added in portions to a mixture of bromide monovalent copper /1,25 g/, sodium bromide /1.2 g/ and Hydrobromic acid /3,3 ml/ water /6/ ml at a temperature of 70-80oC for 15 minutes and the resulting mixture was stirred at 80oC for 30 minutes. The aqueous layer was removed by decantation, and the oily residue was extracted with toluene. The extract was washed with water, dried and concentrated under vacuum. Balance /1.1 g/ was subjected to purification using chromatographic column on silica gel /20g/, elwira with a mixture of chloroform and n-hexane /2:1/, to obtain crystals of 3-bromo-1-/4-methoxyphenyl/-5- [4-/methylthio/phenyl]pyrazole /0,62 g/.

The temperature of the melting point: 144-145oC

IR /Nujol/: 1605, 1510 cm-1< / BR>
NMR /CDCl3, /: 2,47 /3H, singlet/, 3,81 /3H, singlet/, 6,47 /1H, singlet/, 6,8-7,3 /8H, multiplet/

The mass spectrum of the /m/z/: 376 /M+/

Example 5

A mixture of 1-[4-/methylthio/phenyl]-4,4,4-triptorelin-1,3-Zion /1.8 g/ hydrochloride and 4-cyanobenzylidene /1.2 g/ acetic acid /30 ml and N,N-dimethylformamide /1 ml/ was stirred at 110oC for 3 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. The extract was washed in the-/methylthio/phenyl] -3-/trifluoromethyl/pyrazole /2.5 g/.

The melting-point: 145-147oC

IR /Nujol/: 2230, 1610, 1595, 1515 cm-1< / BR>
NMR /CDCl3, /: 2,50 /3H, singlet/, 6,75 /1H, singlet/, 7,0-7,8 /8H, multiplet/

The mass spectrum of the /m/z/: 359 /M+/

Example 6

The following compounds were obtained according to a similar procedure to that used in the dreamer 5.

1/ 3/deformity/-1-[3,4-/methylendioxy/phenyl] -5-/4-/methylthio/ phenyl/pyrazole

IR /film/: 1605, 1520, 1485 cm-1< / BR>
NMR /CDCl3, /: 2,48 /3H, singlet/, 5,99 /2H, singlet/, 6,6-7,3 /9H, multiplet/.

The mass spectrum of the /m/z/: 360 /M+/

2/ 1-/4-carboxyphenyl/-3-/deformity/-5-[4-/methylthio/ phenyl]pyrazole

The melting-point: 195-200oC /Razlog./

IR /Nujol/: 2650 2520, 1700, 1640, 1610, 1515 cm-1< / BR>
NMR /DMSO-d6, /: 2,47 /3H, singlet/, 6,9-8,1 /10H, multiplet/

The mass spectrum of the /m/z/: 360 /M+/

3/1-/4-carboxyphenyl/-5-[4-/methylthio/phenyl]-3-/trifluoromethyl/ pyrazole

The temperature of the melting point: 148-151oC

IR /Nujol/: 2650, 1700, 1610, 1500 cm-1< / BR>
NMR /DMSO-d6, /: of 2.51 /3H, singlet/, 7,2-8,2 /9H, multiplet/, 13,2 /1H, singlet/

The mass spectrum of the /m/z/: 378 /M+/

4/5-[4-/methylthio/phenyl]-1-/4-phenoxyphenyl/-3-/trifluoromethyl/pyrazole

IR /film/:1590 cm-1< / BR>
NMR /CDCl3, /: 2,48 /3H/phenyl] -5-/4-/methylthio/phenyl/-3-/ trifluoromethyl/pyrazole

IR /film/: 1590, 1490 cm-1< / BR>
NMR /CDCl3, /: 2,48 /3H, singlet/, 6,02 /2H, singlet/, 6,6-7,3 /8H, multiplet/

The mass spectrum of the /m/z/: 3,78 /M+/

6/ Ethyl 1-/4-carboxyphenyl/-5-[4-/methylthio/phenyl]pyrazole and 3 - carboxylate

The temperature of the melting point: 145-146oC

IR /Nujol/: 1720, 1695, 1610, 1515 cm-1< / BR>
NMR /CDCl3, /: 1,43 /3H, triplet, J = 7 Hz/, 2,49 /3H, singlet/, 4,47 /2H, Quartet, J = 7 Hz/, 7,03 /1H, singlet/, 7,1-7,3 /4H, multiplet/, 7,47 /2H, doublet, J = 8 Hz/, 8,10 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 382 /M+/

7/ Ethyl 1-[3,4-/methylendioxy/phenyl]-5-/4-/methylthio/phenyl/ pyrazole-3-carboxylate

NMR /CDCl3, /: 1,42 /3H, triplet, J = 7 Hz/, 2,48 /3H, singlet/, of 4.44 /2H, Quartet, J = 7 Hz/, 6,02 /2H, singlet/, 6,7-7,4 /8H, multiplet/

The mass spectrum of the /m/z/: 382 /M+/

Example 7

A mixture of 1-/4-cyanophenyl/-5-[4-/methylthio/phenyl] -3-/trifluoromethyl/ pyrazole /2.5 g/ and meta-chlormadinone acid /3.2 g/ dichloromethane /100 ml was stirred at ambient temperature for 2 hours. The mixture was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. Oily residue /3 g/ was subjected to purification on a chromatographic column on silica gel, elwira with a mixture of chloroform and methanol /40:1/. The purified product was subjected to recrystallization from a mixture of isopropanol /1.3 g/.

The temperature of the melting point: 140-142oC

IR /Nujol/: 2230, 1610, 1515, 1500 cm-1< / BR>
NMR /CDCl3, /: 3,11 /3H, singlet/, 6,89 /1H, singlet/, 7,4-8,0 /8H, multiplet/

The mass spectrum of the /m/z/: 391 /M+/

Example 8

The following compounds were obtained in accordance with the same procedure as used in example 7.

1/3-/deformity/-1-[3,4-/methylendioxy/phenyl] -5-/4-/ methylsulphonyl/phenyl/pyrazole

The temperature of the melting point: 120-121oC

IR /Nujol/: 1600, 1505, 1490 cm-1< / BR>
NMR /CDCl3/: is 3.08 /3H, singlet/, 6,05 /2H, singlet/, 6,5-7,1 /5H, multiplet/, 7,45 /2H, doublet, J = 8 Hz/, to $ 7.91 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 392 /M+/

2/1-/4-carbamoylmethyl/-3-/deformity/-5-[4-/methylsulphonyl/ phenyl] pyrazole

The melting-point: 245-246oC

IR /Nujol/: 3430, 3370, 3250, 1650, 1615, 1575, 1520 cm-1< / BR>
NMR /DMSO-d6/: 3,26 /3H, singlet/ and 7.1-8.1 README /12H, multiplet/

The mass spectrum of the /m/z/: 391 /M+/, 375

3/1-/4-cyanophenyl/-3-/deformity/-5-[4-methylsulphonyl - phenyl]pyrazole

The temperature of the melting point: 140-141oC

IR /Nujol/: 2230, 1610, 1515 cm-1< / BR>
NMR /CDCl3, /: 3,11 /3H, singlet/, 6,5-7,5 /6H, multiplet/, 7,70 /2H, doublet, J = 8 Hz/, of 7.96 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 373 /M+/

4/1-/4-acetylphenyl/: 1685, 1600, 1515 cm-1< / BR>
NMR /CDCl3, /: 2,63 /3H, singlet/, 3,10 /3H, singlet/, 6,7-7,5 /6H, multiplet/, a 7.9-8.1 README /4H, multiplet/

The mass spectrum of the /m/z/: 390 /M+/, 375

5/5-[4-/methylsulphonyl/phenyl]-1-/4-phenoxyphenyl/-3-/trifluoromethyl/ pyrazole

The temperature of the melting point: 132-133oC

IR /Nujol/: 1590, 1515, 1500 cm-1< / BR>
NMR /CDCl3, /: is 3.08 /3H, singlet/, 6,85 /1H, singlet/, 6,9-8,0 /13H, multiplet/

The mass spectrum of the /m/z/: 458 /M+/

6/1-/4-acetylphenyl/-5-[4-/methylsulphonyl/phenyl]-3-/trifluoromethyl/ pyrazole

The temperature of the melting point: 120-122oC

IR /Nujol/: 1690, 1605, 1500 cm-1< / BR>
NMR /CDCl3, /: 2,63 /3H, singlet/, 3,10 /3H, singlet/, 6,64 /1H, singlet/, 7,1-8,0 /8H, multiplet/

The mass spectrum of the /m/z/: 408 /M+/

7/1-[3,4-/methylendioxy/phenyl]-5-/4-/methylsulphonyl/phenyl/-3- /trifluoromethyl/pyrazole

The temperature of the melting point: 110-111oC

IR /Nujol/: 1605, 1510 cm-1< / BR>
NMR /CDCl3, /: 3,09 /3H, singlet/, 6,06 /2H, singlet/, 6,6-6,9 /4H, multiplet/, 7,45 -/2H, doublet, J = 8 Hz/, 7,92 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 410 /M+/

8/N-methyl-1-/4-cyanophenyl/-5-[4-/methylsulphonyl/phenyl] - pyrazole-3-carboxamide

The temperature of the melting point: 228-230oC

NMR /CDCl3, /: 3.04 from /3H, doublet, J = 5 Hz/, 3,10 /3H, singlet/, 6,9-8,0 /10H, multiplet/at

IR /Nujol/: 1720, 1685, 1605, 1510 cm-1< / BR>
NMR /CDCl3, /: 1.44MB /3H, triplet, J = 7 Hz/, 2,63 /3H, singlet/, 3,09 /3H, singlet/, 4,48 /2H, Quartet, J = 7 Hz/, 7,15 /1H, singlet/, 7,3-7,5 /4H, multiplet/, 7,8 - 8,0 /4H, multiplet/

The mass spectrum of the /m/z/: 412 /M+/

10/ Ethyl 1-[3,4-/methylendioxy/phenyl]-5-/4-methylsulphonyl/phenyl/ pyrazole-3-carboxylate

The temperature of the melting point: 188-190oC /Razlog./

IR /Nujol/: 1715, 1605, 1505 cm-1< / BR>
NMR /CDCl3, /: 1,43 /3H, triplet, J = 7 Hz/, is 3.08 /3H, singlet/, 4,46 /2H, Quartet, J = 7 Hz/, 6,05 /2H, singlet/, 6,7-8,0 /8H, multiplet/

The mass spectrum of the /m/z/: 414 /M+/

11/ 1-/4-methoxyphenyl/-5-[4-/methylsulphonyl/phenyl]-3- /trifluoromethyl/pyrazole

The temperature of the melting point: 155-156oC

IR /Nujol/: 1600, 1500 cm-1< / BR>
NMR /DMSO-d6, /: 3,25 /3H, singlet/, 3,80 /3H, singlet/, 7,03 /2H, doublet, J = 8 Hz/, 7,2-7,6 /5H, multiplet/, 7,93 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 396 /M+/

12/3-/chloromethyl/-1-/4-methoxyphenyl/-5-[4-/methylsulphonyl/phenyl]pyrazole

The temperature of the melting point: 115-116oC

IR /Nujol/: 1600, 1510 cm-1< / BR>
NMR /CDCl3, /: 3,07 /3H, singlet/, 3,83 /3H, singlet/, 4,70 /2H, singlet/, 6,68 /1H, singlet/, 6,8-7,9 /8H, multiplet/

The mass spectrum of the /m/z/: 376 /M+/

13/ 3-/deformity/-1-/2-methoxyphenyl/-5-[4-/methylsulphonyl/ CDCl3, /: 3.04 from /3H, singlet/, 3.46 in /3H, singlet/, 6,5-7,5 /8H, multiplet/, a 7.85 /2H, doublet, J =8 Hz/

The mass spectrum of the /m/z/: 378 /M+/

14/ 1-/4-methoxyphenyl/-5-[2-/methylsulphonyl/phenyl]-3- -/trifluoromethyl/pyrazole

The temperature of the melting point: 128-129oC

IR /Nujol/: 1615, 1590, 1520, 1495 cm-1< / BR>
NMR /CDCl3, /: 2,87 /3H, singlet/, 3,75 /3H, singlet/, 6,7-6,9 /3H, multiplet/, 7,2-8,2 /6H, multiplet/

The mass spectrum of the /m/z/: 396 /M+< / BR>
/15/ 3/deformity/-1-/4-methoxyphenyl/-5-[2-/methylsulphonyl/ phenyl]pyrazole

The temperature of the melting point: 124-125oC

IR /Nujol/: 1615, 1595, 1520, 1495 cm-1< / BR>
NMR /CDCl3, /: 2,90 /3H, singlet/, 5,75 /3H, singlet/, 6,5-7,4 /7H, multiplet/, 7,5-8,2 /3H, multiplet/

The mass spectrum of the /m/z/: 378 /M+/

16/1-cyclohexyl-5-[4-/methylsulphonyl/phenyl]-3-/trifluoromethyl/ pyrazole

The temperature of the melting point: 180-181oC

IR /Nujol/: 1610, 1505 cm-1< / BR>
NMR /CDCl3, /: 1,1-2,2 /10H, multiplet/, 3,14 /3H, singlet/, 3,9-4,2 /1H, multiplet/, 6,55 /1H, singlet/, EUR 7.57 /2H, doublet, J = 8 Hz/, 8,08 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 372 /M+/, 291

Example 9

A mixture of 3-/deformity/-1-[3,4-/methylendioxy/phenyl]-5- [4-/methylthio/phenyl] pyrazole /2.7 g/ and meta-chlormadinone acid /1,8 g/ in dichloromethane // 80 ml was stirred at a temperature of 5o< is /2.9 g/ was subjected to purification on a chromatographic column on silica gel, elwira with a mixture of chloroform and methanol /25:1/. The purified product /1.3 g/ subjected to recrystallization from isopropanol, to obtain 3-/deformity/-1-[3,4-/methylendioxy/phenyl]-5-[4-/methylsulfinyl/ phenyl]pyrazole /0,85 g/.

The temperature of the melting point: 104-105oC

IR /Nujol/: 1610, 1510, 1490 cm-1< / BR>
NMR /DMSO-d6, /: 2,77 /3H, singlet/, 6,12 /2H, singlet/, 6,7-7,8 /9H, multiplet/

The mass spectrum of the /m/z/: 376 /M+/, 359

Example 10

A suspension of 1-/4-carboxyphenyl/-3-/deformity/-5-[4- -/methylthio/phenyl]pyrazole /3.6 g/ thionyl chloride /40 ml/ subjected delegacia for 4 hours, and then concentrated under vacuum. A solution of the residue in tetrahydrofuran /30 ml) was added to stir the mixture of hydroxide ammonium /28%, 50 ml) and tetrahydrofuran /50 ml at a temperature of 5oC and the resulting mixture was stirred at the same temperature for 1.5 hours. The mixture was acidified using hydrochloric acid and was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to obtain 1-/4-carbamoylmethyl/-3-/deformity/-5-[4-/methylthio/phenyl] pyrazole /3.6 g/.

The melting-point: 198-201oC /Razlog./

IR /Nujol/: 3450, 3360, 1650, 1610, 1575 cm-1< / BR>
NMR /DMSO-d6, /: 2,47 /3H, sale in accordance with the same procedure, in example 10.

1/ Ethyl 1-/4-carbamoylmethyl/-5-[4-/methylthio/phenyl]pyrazole and 3-carboxylate

The temperature of the melting point: 172-174oC

IR /Nujol/: 3450, 3200, 1715, 1660, 1615 cm-1< / BR>
NMR /CDCl3, /: 1,43 /3H, triplet, J = 7 Hz/, 2,48 /3H, singlet/, 4,46 /2H, Quartet, J = 7 Hz/, 6,0 /2H, broad peak/, 7,0-7,9 /9H, multiplet/.

Mass /m/z/: 381 /M+/

2/1-/4-carbamoylmethyl/-5-[4-/methylsulphonyl/phenyl]-3- /trifluoromethyl/pyrazole

The temperature of the melting point: 210-215oC /Razlog./

IR /Nujol/: 3430, 3300, 3190, 1660, 1620, 1580 cm-1< / BR>
NMR /DMSO-d6, /: 3,26 /3H, singlet/, 7,3-8,2 /11H, multiplet/

The mass spectrum of the /m/z/: 409 /M+/, 393

3/N-methyl-1-/4-cyanophenyl/-5-[4-/methylthio/phenyl]pyrazole-3 - carboxamide

The melting-point: 210-220oC /Razlog./

NMR /CDCl3, /: 2,50 /3H, singlet/, 3,02 /3H, doublet, J = 4 Hz/, 6,9-7,7 /9H, multiplet/

The mass spectrum of the /m/z/: 348 /M+/

4/ 1-/4-carbamoylmethyl/-5-[4-/methylsulphonyl/phenyl] pyrazole-3-carbonitrile

The temperature of the melting point: 222-224oC

IR /Nujol/: 3470, 3350, 2250, 1660, 1610, 1510 cm-1< / BR>
NMR /DMSO-d6, /: 3,26 /3H, singlet/, 7,4-7,6 /6H, multiplet/, 7,9-8,2 /5H, multiplet/

The mass spectrum of the /m/z/: 366 /M+/, 350

Example 12

A solution of phosphorus oxychloride /1.7 g/ N,N-zimet olvanil/-3-/deformity/-5-[4-/ methylsulphonyl/phenyl]pyrazole /2 g/. The resulting mixture was stirred at a temperature of 5oC for 2 hours, poured into ice-water and was extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract was washed with water, dried and evaporated to obtain an oil of 1-/4-cyanophenyl/-3-/deformity/-5-[4-/methylthio/phenyl]pyrazole /2.0 g/.

IR /Nujol/: 2240, 1610, 1515, 1500 cm-1< / BR>
NMR /CDCl3, /: 2,50 /3H, singlet/, 6,5-7,7 /10H, multiplet/

The mass spectrum of the /m/z/: 341 /M+/

Example 13

The following compounds were obtained according to the procedure similar to that described in example 12.

1/ Ethyl 1-/4-cyanophenyl/-5-[4-/methylthio/phenyl]-pyrazole-3 - carboxylate

The temperature of the melting point: 143-145oC /Razlog./

IR /Nujol/: 2250, 1725, 1605, 1510 cm-1< / BR>
NMR /CDCl3, /: 1,43 /3H, triplet, J = 7 Hz/, 2,50 /3H, singlet/, 4,46 /2H, Quartet, J = 7 Hz/, 7,0-7,7 /9H, multiplet/

The mass spectrum of the /m/z/: 363 /M+< / BR>
2/ 1-/4-carboxyphenyl/-5-[4-/methylsulphonyl/phenyl]pyrazole-3 - carbonitrile

The melting-point: 185-190oC /Razlog./

IR /Nujol/: 2250, 1720, 1610, 1515 cm-1< / BR>
NMR /DMSO-d6, /: 3,26 /3H, singlet/, 7,4-8,1 /9H, multiplet/

The mass spectrum of the /m/z/: 367 /M+/

3/ 1-/4-cyanophenyl/-5-[4-/methylsulphonyl/phenyl]pyrazole-3 - carbonitrile

Point temperature is the singlet/, 7,4-8,0 /8H, multiplet/

The mass spectrum of the /m/z/: 348 /M+/

4/ 1-/4-acetylphenyl/-5-[4-methylsulphonyl/phenyl]-pyrazole - 3-carbonitrile

The temperature of the melting point: 155-156oC

IR /Nujol/: 2250, 1695, 1605, 1510 cm-1< / BR>
NMR /CDCl3, /: 2,64 /3H, singlet/, 3,10 /3H, singlet/, 6,99 /1H, singlet/ and 7.1-8.1 README /8H, multiplet/

The mass spectrum of the /m/z/: 365 /M+/, 350

5/ 1-[3,4-/methylendioxy/phenyl]-5-[4-/methylsulphonyl/phenyl] mirasol-3-carbonitril

The temperature of the melting point: 182-183oC

IR /Nujol/: 2250, 1605, 1495 cm-1< / BR>
NMR /CDCl3, /: 3,09 /3H, singlet/, 6,07 /2H, singlet/, 6,6-6,9 /3H, multiplet/, 6,94 /1H, singlet/, 7,43 /2H, doublet, J = 8 Hz/, 7,93 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 367 /M+/

Example 14

A mixture of 1-/4-carboxyphenyl/-3-/deformity/-5-[4-/methylthio - phenyl]pyrazole /2 g/ and thionyl chloride /20 ml/ was subjected to reflux distilled for 3 hours, and then concentrated under vacuum, obtaining the resulting 1-[4-/chloroformyl/phenyl] -3-/deformity/-5-[4-/methylthio/phenyl] pyrazole. A solution of diethyl malonate /1.4 g/ ethanol /0.3 ml/ diethyl simple ether /15 ml was added dropwise to stirred mixture of magnesium /0.16 g/ ethanol /0.2 ml/ carbon tetrachloride /0,36 ml/ diethyl simple air /5 ml, the resulting mixture was subjected delightprincipal at ambient temperature for 1 hour and was delegirovali 1 hour. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. Mix balance /4 g/, acetic acid /40 ml/ 20% sulfuric acid /20 ml/ was subjected to reflux distilled 3.5 hours, and then concentrated. The residue was dissolved in ethyl acetate and the solution washed with water, dried and concentrated. The residue was subjected to purification on a chromatographic column on silica gel, elwira mixture of toluene and ethyl acetate /4:1/ to obtain crystals of 1-/4-acetylphenyl/-3-/deformity/-5-[4-/methylthio/ phenyl]pyrazole /0.4 g/.

The temperature of the melting point: 143-145oC

IR /Nujol/: 1680, 1600 cm-1< / BR>
NMR /CDCl3, /: 2,49 /3H, singlet/, 2,61 /3H, singlet/, 6,5-7,5 /8H, multiplet/, 7,95 /2H, doublet, J = 7 Hz/

The mass spectrum of the /m/z/: 358 /M+/

Example 15

The following compounds were obtained in accordance with the procedure of example 14.

1/1-/4-acetylphenyl/-5-[4-/methylthio/phenyl]-3-/trifluoromethyl/pyrazole

IR /film/: 1690, 1610, 1500 cm-1< / BR>
NMR /CDCl3, /: 2,49 /3H, singlet/, 2,61 /3H, singlet/, 6,75 /1H, singlet/, of 7.1-8.2 /8H, multiplet/

The mass spectrum of the /m/z/: 376 /M+/

2/ Ethyl 1-/4-acetylphenyl/-5-[4-/methylthio/phenyl]pyrazole-3 - carboxylate

IR /film/: 1725, 1690, 1, ,02 /1H, singlet/, 7,1-7,2 /4H, multiplet/, 7,46 /2H, doublet, J = 8 Hz/, 7,95 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 380 /M+/

Example 16

A mixture of 1-/4-carboxyphenyl/-5-[4-/methylthio/phenyl]-3-/trifluoromethyl/ pyrazole /3,55 g/ and 30% hydrogen peroxide /5.5 ml/ acetic acid /25 ml/ was stirred at 45oC for 2 hours. The mixture was poured into a mixture of ice-water and the precipitate was collected, washed with water and subjected to recrystallization from ethanol to obtain 1-/4-carboxyphenyl/-5-[4-/methylsulphonyl/Peniel] -3-/trifluoromethyl/ pyrazole /3.2 g/.

The melting-point: 250-252oC /Razlog./

IR /Nujol/: 3450, 2650, 1700, 1615, 1500 cm-1< / BR>
NMR /DMSO-d6, /: 3,26 /3H, singlet/, 7,4-8,3 /9H, multiplet/

The mass spectrum of the /m/z/: 410 /M+/

Example 17

The following compound was obtained according to a procedure similar to the one used in example 16.

Ethyl 1-/4-carboxyphenyl/-5-[4-/methylsulphonyl/phenyl]pyrazole and 3 - carboxylate

The melting-point: 267-268oC

IR /Nujol/: 1720, 1610, 1515 cm-1< / BR>
NMR /DMSO-d6, /: 1,33 /3H, triplet, J = 7 Hz/, 3,26 /3H, singlet/, 4,36 /2H, Quartet, J = 7 Hz/, 7,34 /1H, singlet/, 7,4-7,6 /4H, multiplet/, a 7.9-8.1 README /4H, multiplet/, 13,2 /1H, singlet/

The mass spectrum of the /m/z/: 414 /M+/

Example 18

Mix l/ was subjected to reflux distilled 6 hours. The solvent is evaporated and the residue was subjected to recrystallization from ethanol to obtain crystals of 1-[4-/etoxycarbonyl/phenyl]-5-[4-/methylsulphonyl/phenyl]-3-/ trifluoromethyl/pyrazole /2.3 g/.

The temperature of the melting point: 159-161oC

IR /Nujol/: 1730, 1610, 1510 cm-1< / BR>
NMR /DMSO-d6, / /: 1,36 /3H, triplet, J = 7 Hz/, 3,27 /3H, singlet/, to 4.38 /2H, Quartet, J = 7 Hz/, 7,5-8,3 /9H, multiplet/

The mass spectrum of the /m/z/: 438 /M+/, 406

Example 19

A mixture of 1-[4-/etoxycarbonyl/phenyl] -5-[4-/methylsulphonyl/- phenyl] -3-/trifluoromethyl/pyrazole /2.4 g/ and aluminum lithium hydride /0.25 g/ tetrahydrofuran /20 ml was stirred at a temperature of 55oC for 2 hours. The reaction was stopped with methanol and water, and the mixture was filtered. The filtrate was concentrated and the residue was dissolved in a mixture of ethyl acetate and tetrahydrofuran. The solution was washed with water, dried and evaporated. The residue was subjected to purification using chromatographic column on silica gel, elwira with a mixture of chloroform and methanol /20: 1/ to obtain a white powder of 1-[4-/oximeter/phenyl]-5-[4-/methylsulphonyl/phenyl]-3-/trifluoromethyl/ pyrazole /1.3 g/.

The melting-point: 129-133oC.

IR /Nujol/: 3450, 1610, 1520, 1500 cm-1< / BR>
NMR /CDCl3, /: 3,09 /3H, singlet/, 4,7-4,17 g/ are added to a solution of 1-/4 oksifenil/-5-[4-/methylsulphonyl/phenyl] -3-/trifluoromethyl/pyrazole /1.5 g/ N,N-timeinformation /15 ml/ 5oC. the Mixture was stirred at ambient temperature for 30 minutes. To this mixture was added chloromethyl methyl simple ether /0.4 g/ N,N - dimethylformamide /2 ml/ 5oC. the resulting mixture was stirred at 5oC for 2 hours, at ambient temperature for 1 hour, poured into a mixture of ice and dilute hydrochloric acid and was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. Balance /1.3 g/ subjected to recrystallization from isopropanol to obtain crystals of 1-[4-/methoxyethoxy/phenyl]-5-[4-/methylsulphonyl/phenyl]-3-/ trifluoromethyl/pyrazole /1.3 g/.

The melting-point: 96-97oC

IR /Nujol/: 1610, 1520, 1500 cm-1< / BR>
NMR /CDCl3, /: is 3.08 /3H, singlet/, 3,49 /3H, singlet/, 5,20 /2H, singlet/, 6,84 /1H, singlet/, 7,0-8,0 /8H, multiplet/

The mass spectrum of the /m/z/: 426 /M+/

Example 21

The following compounds were obtained in accordance with the procedure similar to the one used in example 20.

1/ Ethyl 4-{ 5-[4-/methylsulphonyl/phenyl]-3-/trifluoromethyl/- 1-pyrazolyl} phenoxyacetate.

The temperature of the melting point: 87-89oC

IR /Nujol/: 1755, 1610, 1520, 1500 cm-1< / BR>
NMR /CDCl3, /: 1,30 /3H, triplet, J= 7 Hz/, is 3.08 /3H, singlet/, 4,28 /2H, triplet, J = 7 Hz/, 4,65 /2H, single of the si/phenyl] -5-[4-/methylsulphonyl/ phenyl]pyrazole

The temperature of the melting point: 95-96oC

IR /Nujol/: 1610, 1520 cm-1< / BR>
NMR /CDCl3, /: is 3.08 /3H, singlet/, 3,49 /3H, singlet/, 5,19 /2H, singlet/, 6,5-7,5 /8H, multiplet/, 7,92 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 408

3/ 1-/4-ethoxyphenyl/-5-[4-/methylsulphonyl/phenyl] -3-/trifluoromethyl/ pyrazole

The temperature of the melting point: 140oC

IR /Nujol/:1610, 1600, 1520, 1500 cm-1< / BR>
NMR /CDCl3, /: 1,43 /3H, triplet, J = 7 Hz/, 3,07 /3H, singlet/, 4,05 /2H, Quartet, J = 7 Hz/, 6,8-7,5 /7H multiplet/, to $ 7.91 /2H, doublet, J = 8 Hz/

4/1-/4-isopropoxyphenyl/-5-[4-/methylsulphonyl/phenyl]-3- /trifluoromethyl/pyrazole

The temperature of the melting point: 99-100oC

IR /Nujol/: 1610, 1525, 1510 cm-1< / BR>
NMR /CDCl3, /: 1,35 /6H, doublet, J = 6 Hz/, 3,07 /3H, singlet/, 4,4-4,7 /1H, multiplet/, 6,8-7,5 /7H, multiplet/, of 7.90 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 424 /M+/

5/ 3-/deformity/-1-/4-ethoxyphenyl/-5-[4-/methylsulphonyl/ phenyl]pyrazole

The temperature of the melting point: 105-107oC

IR /Nujol/: 1605, 1520, 1500 cm-1< / BR>
NMR /CDCl3, /: 1,43 /3H, triplet, J = 7 Hz/, 3,07 /3H, singlet/, 4,05 /2H, Quartet, J = 7 Hz/, 6,5-7,5 /8H, multiplet/, 7,89 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 392 /M+/

6/ 3/deformity/-1-/4-isopropoxyphenyl/-5-[4-/methylsulphonyl/ phenyl] pyrazole

Temperature is t/, 3,07 /3H, singlet/, 4,4-4,7 /1H, multiplet/, 6,5-7,5 /8H, multiplet/, 7,89 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 406 /M+/

Example 22

Acetyl chloride /0,31 g/ was added dropwise to a cooled with ice a solution of 1-/4 oksifenil/-5-[4-/methylsulphonyl/phenyl] - 3-/trifluoromethyl/pyrazole /1 g/ pyridine /10 ml/. The mixture was stirred at 5oC for 3 hours, poured into water and acidified with hydrochloric acid. Precipitation was filtered and subjected to purification using chromatographic column on silica gel, elwira with a mixture of chloroform and methanol /20:1/ to obtain a yellow powder of 1-/4-acetoxyphenyl/-5-[4-/methylsulphonyl/phenyl]-3-/trifluoromethyl/ pyrazole /0.9 g/.

The temperature of the melting point: 142-145oC

IR /Nujol/: 1760, 1605, 1500 cm-1< / BR>
NMR /CDCI3, /: 2,32 /3H, singlet/, is 3.08 /3H, singlet/, 6,85 /1H, singlet/, 7,1-7,5 /6H, multiplet/, 7,93 /2H, doublet, J = 8 Hz/

The mass spectrum of the /m/z/: 424 /M+/, 382

Example 23

A mixture of ethyl 4-{5-[4-/methylsulphonyl/phenyl]-3-/trifluoromethyl/-1-pyrazolyl} phenoxyacetate /1.7 g/, 10% of hydrate of sodium oxide /10 ml/ tetrahydrofuran /10 ml and ethanol /40 ml/ was subjected to reflux distilled for 3 hours. The solvent is evaporated, and the residue was dissolved in water and acidified with hydrochloric acid. Precipitation was filtered and subjected to the-/methylsulphonyl/phenyl] -3-/trifluoromethyl/-1-pyrazolyl}Phenoxyethanol acid /1.1 g/.

The melting-point: 245-250oC /Razlog./

IR /Nujol/: 1720, 1610, 1520, 1500 cm-1< / BR>
NMR /DMSO-d6, /: 3,25 /3H, singlet/, 4,43 /2H, singlet/, 6,9-8,0 /9H, multiplet/.

The mass spectrum of the /m/z/: 440 /M+/

Example 24

A mixture of ethyl 1-/4-cyanophenyl/-5-[4-/methylthio/phenyl]pyrazole-3 - carboxylate /2.8 g/ 1 N solution of hydrate of sodium oxide /10 ml/ ethanol /50 ml and tetrahydrofuran /20 ml was stirred at ambient temperature for 3 hours. The solvent is evaporated, and the residue was dissolved in water, acidified with hydrochloric acid and was extracted with ethyl acetate.

The extract was washed with water, dried and evaporated to obtain 1-/4-cyanophenyl/-5-[4-/methylthio/phenyl]pyrazole-3-carboxylic acid /2.5 g/.

The melting-point: 168-173oC /Razlog./

IR /Nujol/: 2240, 1710, 1605, 1510 cm-1< / BR>
NMR /CDCl3, /: 2,50 /3H, singlet/, 7,0-7,7 /9H, multiplet/

The mass spectrum of the /m/z/: 335 /M+/

Example 25

A mixture of ethyl 1-/4-carboxyphenyl/-5-[4-/methylsulphonyl/phenyl] pyrazole-3 - carboxylate /3,9 g/ and sodium methylate /3 g/ formamide /40 ml/ was stirred at a temperature of 45oC for 3 hours. The mixture was poured into a mixture of ice-water and hydrochloric acid. Precipitation was collected, washed with water, SS="ptx2">

The melting-point: 292-293oC

IR /Nujol/: 3430, 3350, 3200, 1715, 1695, 1650, 1590 cm-1< / BR>
NMR /DMSO-d6, /: 3,26 /3H, singlet/, 7,19 /1H, singlet/, 7,4-8,1 /10H, multiplet/, 13,2 /1H, singlet/

The mass spectrum of the /m/z/: 385 /M+/

Example 26

The following compounds were obtained using the same procedure as used in example 25.

1/ 1-/4-acetylphenyl/-5-[4-/methylsulphonyl/phenyl]pyrazole-3 - carboxamide

The melting-point: 242-245oC /Razlog./

IR /Nujol/: 3480, 3200, 1685, 1605 cm-1< / BR>
NMR /DMSO-d6, /: 2,61 /3H, singlet/, 3,26 /3H, singlet/, 7,18 /1H, singlet/, 7,4-8,1 /10H, multiplet/

The mass spectrum of the /m/z/: 383 /M+/, 368

2/ 1-[3,4-/methylendioxy/phenyl]-5-[4-/methylsulphonyl/phenyl] pyrazol-3-carboxamid

The melting-point: 283-285oC

IR /Nujol/: 3500, 3300, 1670, 1585, 1510 cm-1< / BR>
NMR /DMSO-d6, /: 3,25 /3H, singlet/, 6,13 /2H, singlet/, 6,7-8,0 /10H, multiplet/.

The mass spectrum of the /m/z/: 385 /M+/

Example 27

The following compounds were obtained according to a similar procedure to that used in example 1.

1/ 1-/4-methoxyphenyl/-5-[4-/methylthio/phenyl]-3-trifluoromethyl/ pyrazole

The temperature of the melting point: 98-100oC

IR /Nujol/: 1605, 1520, 1500 cm-164 /M+/

2/ 3-/chloromethyl/-1-4-methoxyphenyl/-5-[4-/methylthio/phenyl]-pyrazole

IR /film/: 1600, 1510 cm-1< / BR>
NMR /CDCl3, /: 2,47 /3H, singlet/, 3,82 /3H, singlet/, 4,70 /2H, singlet/, 6,5-7,7 /9H, multiplet/

The mass spectrum of the /m/z/: 344 /M+/

3/ 3/deformity/-1-/2-methoxyphenyl/-5-[4-/methylthio - phenyl]pyrazole

The melting-point: 38-100oC

IR /Nujol/: 1605, 1515, 1500 cm-1< / BR>
NMR /CDCl3, /: 2,44 /3H, singlet/, 3,50 /3H, singlet/, of 6.4-7.5 /10H, multiplet/

The mass spectrum of the /m/z/: 346 /M+/

4/ 1-/4-methoxyphenyl/-5-[2-/methylthio/phenyl]-3-/trifluoromethyl/ pyrazole

The temperature of the melting point: 78-80oC

IR /Nujol/: 1610, 1590, 1520, 1490 cm-1< / BR>
NMR /CDCl3, /: 2,34 /3H, singlet/, of 3.77 /3H, singlet/, compared to 6.6-7.4 /9H, multiplet/

The mass spectrum of the /m/z/: 364 /M+/

5/ 3-/deformity/-1-[4-methoxyphenyl/-5-[2-/methylthio/phenyl] pyrazole

The temperature of the melting point: 79-81oC

IR /Nujol/: 1615, 1590, 1520, 1490 cm-1< / BR>
NMR /CDCl3, /: 2,33 /3H, singlet/, 3,78 /3H, singlet/, 6,5-7,4 /10H, multiplet/

The mass spectrum of the /m/z/: 346 /M+/

6/ 3/deformity/-5-/4-methoxyphenyl/-1-[4-/methylthio/ phenyl]pyrazole

Temperature boiling point: 90-92oC

IR /Nujol/: 1610, 1545, 1495 cm-1< / BR>
NMR /CDCl3, /: 2,49 /3H, singlet/, 3,81 /3H, singlet/Teal/- pyrazole

IR /Nujol/: 1605, 1595, 1545 cm-1< / BR>
NMR /CDCl3, /: 1,1-2,1 /10H, multiplet/, 2,53 /3H, singlet/, 4,0-4,2 /1H, multiplet/, 6,45 /1H, singlet/, 7,2-7,4 /4H, multiplet/

The mass spectrum of the /m/z/: 340 /M+/

8/ 1-[4-/methylthio/phenyl]-5-/4-nitrophenyl/-3-/trifluoromethyl/pyrazole

The temperature of the melting point: 156-157oC

IR /Nujol/: 1600, 1520, 1490 cm-1< / BR>
NMR /CDCl3, /: 2,50 /3H, singlet/, 6,87 /1H, singlet/, 7,1-7,5 /6H, multiplet/, 8,15 to 8.3 /2H, multiplet/

The mass spectrum of the /m/z/: 380 //M+1/+/

Example 28

The following compounds were obtained according to the procedure described in example 2.

1/ 3-bromo-1-/4-methoxyphenyl/-5-[4-/methylsulfinyl/phenyl]- pyrazole

The temperature of the melting point: 140-142oC

IR /Nujol/: 1610, 1585, 1515 cm-1< / BR>
NMR /DMSO-d6, /: 2,75 /3H, singlet/, 3,83 /3H, singlet/, 6,60 /1H, singlet/, 6,85-7,63 /3H, multiplet/

The mass spectrum of the /m/z/: 392, 390, 377

2/ 1-/4-cyanophenyl/-5-[4-/methylsulfinyl/phenyl]-3-/trifluoromethyl/ pyrazole

Temperature melting point: 121-122oC

IR /Nujol/: 1605, 1510, 1495 cm-1< / BR>
NMR /CDCl3, /: 2,78 /3H, singlet/, 6,85 /1H, singlet/, 7,3-7,8 /8H, multiplet/

The mass spectrum of the /m/z/: 375 /M+/

3/ 1-/4-acetylphenyl/-5-[4-/methylsulfinyl/phenyl] -3-/trifluoromethyl/ pyrazole

Point temperature Plav /1H, the singlet/, 7,3-8,0 /8H, multiplet/

The mass spectrum of the /m/z/: 393 //M+1/+/

4/ 3/deformity/-5-/4-methoxyphenyl/-1-[4-/methylsulfinyl/phenyl] pyrazole

The temperature of the melting point: 123-124oC

IR /Nujol/: 1610, 1550, 1500 cm-1< / BR>
NMR /CDCl3, /: 2,74 /3H, singlet/, 3,83 /3H, singlet/, from 6.4 to 7.7 /10H, multiplet/

The mass spectrum of the /m/z/: 363 //M+1/+/

Example 29

The following compounds were obtained in accordance with the procedure of example 3.

1/ 3-bromo-1-/4-methoxyphenyl/-5-[4-/methylsulphonyl/phenyl] pyrazole

The temperature of the melting point: 177-178oC

IR /Nujol/: 1610, 1515 cm-1< / BR>
NMR /DMSO-d6, /: 3,13 /3H, singlet/, 3,79 /3H, singlet/, 6,97-7,93 /9H, multiplet/

The mass spectrum of the /m/z/: 408, 406

2/ 3/deformity/-5-/4-methoxyphenyl/-1-[4-/methylsulphonyl/phenyl] pyrazole

The temperature of the melting point: 118-120oC

IR /Nujol/: 1615, 1595, 1500 cm-1< / BR>
NMR /CDCl3, /: 3,07 /3H, singlet/, 3,84 /3H, singlet/, 6,4-8,0 /10H, multiplet/

The mass spectrum of the /m/z/: 379 //M+1/+/

3/ 1-[4-/methylsulphonyl/phenyl]-5-/4-nitrophenyl/-3-/trifluoromethyl/ pyrazole

The temperature of the melting point: 201-203oC

IR /Nujol/: 1595, 1515 cm-1< / BR>
NMR /CDCl3, /: 3,09 /3H, singlet/, 6,92 /1H, singlet/, 7,4-7,8 /4H, multiplet/, is 7.3-8.3 /4H, multiplet/

Mass with the house a solution of 1-/4-methoxyphenyl/-5-[4-/methylsulphonyl/ phenyl]-3-/trifluoromethyl/pyrazole /1.4 g/ dichloromethane /30 ml/. The mixture was stirred at 5oC for 2 hours and concentrated under vacuum. The residue was washed in dilute hydrochloric acid. The obtained powder was subjected to recrystallization from ethanol to obtain colorless crystals of 1-/4 oksifenil/-5-[4-/methylsulphonyl/phenyl]-3-/trifluoromethyl/pyrazole /0,91 g/.

The melting-point: 243-244oC

IR /Nujol/: 3370, 1605, 1525, 1505 cm-1< / BR>
NMR /DMSO-d6, /: 3,25 /3H, singlet/, 6,83 /2H, doublet, J = 8 Hz/, 7,1-7,6 /5H, multiplet/, 7,92 /2H, doublet, J = 8 Hz/, 10,0 /1H, singlet/

The mass spectrum of the /m/z/: 382 /M+/

Example 31

The following compound was obtained using a procedure similar to the one used in example 30.

1-/4 oksifenil/-5-[4-/methylsulphonyl/phenyl]-3-/deformity/pyrazole

The melting-point: 170-180oC

IR /Nujol/: 1595, 1500 cm-1< / BR>
NMR /DMSO-d6, /: 3,25 /3H, singlet/, 5,7-7,6 /8H, multiplet/, 7,92 /2H, doublet, J = 8 Hz/, 9,29 /1H, singlet/

The mass spectrum of the /m/z/: 364 /M+/

Example 32

To a solution of L -/+/-diethyl tartrate /3,71 g/ in dichloromethane /75 ml/ added isopropyl titanium /IV/ /2.7 oz/ in nitrogen atmosphere. After stirring for 5 minutes the mixture was added water /162 ml/. After the mixture was vigorously stirred 25 is -30oC, and was stirred for another 40 minutes at a temperature of from -30 to -20oC. To this mixture was added dropwise Gidropress cumene /3,00 ml/. Even after 10 minutes the reaction mixture was tightly closed and kept overnight at a temperature of -23oC. To the mixture was added water /3,03/ ml and was stirred at ambient temperature for 90 minutes. The reaction mixture was filtered and to the filtrate was added a 2 N solution of hydrate of sodium oxide /48 ml/ and saline /24 ml/. After stirring for 1 hour at ambient temperature, the organic layer was separated, dried over magnesium sulfate and concentrated under vacuum. The residue was subjected to purification on a chromatographic column on silica gel /450 g/, elwira a mixture of dichloromethane and methanol /40:1/. The products obtained recrystallization eight times from a mixture of ethanol and isopropyl simple ether /1: 4/, to obtain R-/+/-3-/deformity/- 1-/4-methoxyphenyl/-5-[4-/methylsulfinyl/phenyl]pyrazole /0.71 g/.

The temperature of the melting point: 113-114oC

[]2D0= +69,4o= to 1.00, CHCl3/

IR /Nujol/: 1615, 1590, 1520 cm-1< / BR>
NMR /CDCl3, /: 2,74 /3H, singlet/, 3,83 /3H, singlet/, 6,5-7,7 /10H, multiplet/

The mass spectrum of the /m/z/: 363 //M+1/+/

Example 33

was olovely-D-/-/-diethyl tartrate.

S-/-/-3-/deformity/-1-/4-methoxyphenyl/-5-[4-/methylsulfinyl/ phenyl] pyrazole

The temperature of the melting point: 112-114oC

[]2D0= -70,9o= 1,02, CHCl3/

IR /Nujol/: 1610, 1590, 1515 cm-1< / BR>
NMR /CDCl3, /: 2,75 /3H, singlet/, 3,83 /3H, singlet/, 6,5-7,7 /10H, multiplet/

The mass spectrum of the /m/z/: 363 //M+1/+/I

Derivatives of pyrazole of the General formula I

< / BR>
in which R1is phenyl, substituted cyclo(lower) alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy) carbonyl group, carbamoyl, optionally substituted lower alkyl;

R3is phenyl, substituted lower akitio, lower alkylsulfonyl or lower alkylsulfonyl, provided that when R1represents phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts.

2. Derivatives of pyrazole on p. 1, where R1

3. Derivatives of pyrazole on p. 1, where R1represents phenyl, substituted lower alkanoyl, and R2is halo(lower)alkyl.

4. Derivatives of pyrazole on p. 1, representing 1-(4-acetylphenyl)-3-deformity-5-[(4-methylsulphonyl)phenyl]-pyrazole.

Priority points:

05.02.92 - priority R1equal to phenyl, substituted lower alkoxy, R2- halogen, halo(lower)alkyl, carboxy, R3the phenyl, substituted lower alkylthio, lower alkylsulfonyl or lower alkylsulfonyl;

28.09.92 - priority R1equal to phenyl, substituted hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, phenoxy, or carbamoyl, optionally substituted lower alkyl, R2- halogen, halo(lower)alkyl, carboxy, cyano, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted lower alkyl, and R3the phenyl, substituted lower alkylthio, lower alkylsulfonyl or lower alkylsulfonyl

 

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< / BR>
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