New pyrazole derivatives, method for their production and containing pharmaceutical compositions

 

(57) Abstract:

The invention relates to pyrazole derivative of the formula I, where1means the group - NRR1R2or group-OR2, g2- g6the same or different and independently of one another denote hydrogen, halogen, C1-4alkyl, C1-4alkoxyl, trifluoromethyl, or C1-4allylthiourea; w2-w6the same or different and independently of one another denote hydrogen, halogen, C1-4alkyl, C1-4alkoxy or trifluoromethyl, provided that at least one of the substituents g2-g6and one of the substituents w2-w6different from hydrogen; R1means hydrogen or C1-4alkyl; R2- nah3-15-carbocyclic radical, unsubstituted or mono - or multiply substituted WITH1-4by alkyl; R3is hydrogen or the group CH2-R6; R4and R5each independently of one another denote hydrogen or C1-4alkyl; or R4means hydrogen and R5and w6together form an ethylene radical; R6means hydrogen, or when the deputies of the g2g3, g4, g5and/or g6different from1-4of alkyl, R6means water which I derivatives of pyrazole of the formula I and pharmaceutical composition containing them. The technical result is to provide new compounds which are antagonists of receptors SV2and pharmaceutical compositions, having affinity to the receptors SV2. They can be used to treat autoimmune diseases. 3 S. and 14 C.p. f-crystals, 2 tab.

The invention relates to new derivatives of pyrazole and its possible salts, method of production thereof and containing pharmaceutical compositions.

Particularly the present invention relates to new derivatives of pyrazole with high affinity to the peripheral receptor for cannabinoids, called receptors CB2and suitable therapeutic areas containing receptors CB2.

9-THC is the main active component of Cannabis Sativa (Tuner, 1985; Marijuana, 1984; ed. Harvey, DY, IRL Press, Oxford).

Characterization of receptors cannabinoids possible due to the inclusion of synthetic ligands, such as agonists WIN-55212-2 (J. Pharmacol. Exp. Ther. , 264, 1352-1363 (1993)) or CP-55940 (J. Pharmacol. Exp. Ther., 247, 1046-1051 (1988)).

Numerous articles describe not only the psychotropic effects of cannabinoids, but also the impact of these on the last related to immune function (Hollister L. E., Psychoact. Drugs, 24, 159-164 (1992)). Bolsheretsky responses of T-lymphocytes and B-lymphocytes, induced by mitogens (Luo Y. D. and other Int. J. Immunopharmacol., 14, 49-56 (1992); N. Schwartz. and others, J. Neuroimmunol., 55, 107-115 (1994)), the inhibition activity of cytotoxic T-cells (Klein and others, J. Toxicol. Environ. Health, 32, 465-477 (1991)), inhibition of bactericidal activity of macrophages and synthesis of TNF (tumor necrosis factor) (Arata S. and other Life Sci. , 49, 473-479 (1991); Fisher-Stenger and others, J. Pharm. Exp. Ther., 267, 1558-2565 (1993)), inhibition of cytolytic activity and the production of TNF some lymphocytes (Kusher and other Cell. Immun., 154, 99-108 (1994)). On the contrary, some studies have observed the effects of amplification: the biologic activity of interleukin-1 by histiocytes mouse or differentiated macrophage cell lines (due to higher levels of TNF (Zhu and others, J, Pharm. Exp. Ther., 270, 1334-1339 (1994); Shivers S. C. and other Life Sci., 54, 1281-1289 (1994)).

Effects of cannabinoids occur due to the interaction with specific high affinity receptors that are present on the Central (Devane and other, Molecular Pharmacology, 34, 605-613 (1988)) and peripheral level (Nye and others The Journal of Pharmacology and Experimental Theraupetics, 234, 784-791 (1985); Kaminski and other Molecular Pharmacology, 42, 736-742 (1992); Munro and others, Nature, 365, 61-65 (1993)).

Central effects are dependent on the first type of receptor for cannabinoids (CB1), which is located in the head m G, called CB2that is only present in the periphery and in particular in cells of immune origin. The presence of receptors cannabinoids ST2in lymphoid cells may explain the immunomodulation carried out by agonists of receptors cannabinoids, as indicated above.

Numerous derivatives of pyrazole described in the literature: more specifically, in the application for the European patent 268554 and in the description of the invention it is lined accepted the application for patent in Germany 3910248 claimed pyrazoles with herbicide properties; in the application for the European patent 430186 and in the patent application of Japan 3031840 describes compounds suitable for pictures; and in the application for the European patent 418845 the subject invention are pyrazoles, which has anti-inflammatory, analgesic and antithrombotic activity.

Also described derivatives pyrazolecarboxylate, especially in applications for European patents 0289879 and 0492125: these compounds possess insecticidal properties.

In addition, the application for the European patent 0477049 describes derivatives of pyrazole-3-carboxamide of the formula (I);

< / BR>
in which, for example,

RImeans variously substituted and is oxyl, alkoxy with 1-6 carbon atoms, amino group;

RIVmeans hydrogen, halogen or alkyl with 1-6 carbon atoms;

RVmeans variously substituted phenyl group;

n means 0, 1, 2, or 3.

These compounds affect the Central nervous system and in particular by the interaction of neurotensin receptor.

In addition, applications for European patents 576357 and 658546 describes pyrazole derivatives having affinity to receptors cannabinoids. Moreover, in the application for the European patent 656354 describes N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide or SR 141716 and its pharmaceutically acceptable salts, which have high affinity to the Central receptors cannabinoids.

Currently received new pyrazole derivatives, which have an increased affinity for the receptor CB2man and specificity to the above receptor and which are potent immunomodulatory.

In the present description, the term "high affinity for the human receptor CB1>> understand the affinity characterized by a constant affinity is typically below 100 nm, 2 usually at least ten times less constant affinity receptor CB1.

According to one aspect of the present invention, the subject invention are the compounds of formula (I):

< / BR>
in which X1means the group-NR1R2or group-OR2;

g2, g3, g4, g5, g6and w2, w3, w4, w5, w6are the same or different and each, independently of one another, mean hydrogen, halogen atom, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, trifluoromethyl, nitro-group, alkylthiols with 1-4 carbon atoms; provided that at least one of the substituents g2, g3, g4, g5, g6and at least one of the substituents w2, w3, w4, w5, w6different from hydrogen;

R1means hydrogen or alkyl with 1-4 carbon atoms;

R2means a non-aromatic carbocyclic radical with 3 to 15 carbon atoms, unsubstituted or mono - or multiply substituted by the Deputy, selected among halogen atom, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms;

R3means hydrogen or a group-CH2-R or trifluoromethyl;

or R4means hydrogen and R5and w6together form an ethylene or trimethylenebis radical;

R6means hydrogen or, when the deputies of the g2, g3, g4, g5and/or g6are other than alkyl with 1-4 carbon atoms, R6denotes hydrogen, alkyl with 1-4 carbon atoms, fluorine, hydroxyl, alkoxy with 1-5 carbon atoms, alkylthiols with 1-5 carbon atoms, hydroxyalkoxy with 1-5 carbon atoms, cyano, alkylsulfonyl with 1-5 carbon atoms, alkylsulfonyl of 1 to 5 carbon atoms;

as well as their possible salts.

When the compound of formula (I) according to the invention includes one or more asymmetric carbon atoms, the various optical isomers as well as racemates, form part of the invention.

Possible salts of compounds of formula (I) include salts attaching a pharmaceutically acceptable acids, such as hydrochloride, hydrobromide, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, methyl sulfate, malate, oxalate, fumarate, naphthalenesulfonate, gluconate, piconet, citrate, ideational, p-toluensulfonate, mesitylenesulfonic or bansilalpet.

Non-aromatic carbocyclic radicals with from 3 to 15 atom is unsaturated, in the case of terpene radicals. These radicals are unsubstituted or singly or multiply substituted by a group selected among alkyl with 1-4 carbon atoms, alkoxyl with 1-4 carbon atoms or halogen, provided that in the case of terpenes or terpene radicals, as, for example, bornyl, mental or pentenyl, alkyl groups of terpenes are not considered as substitutes.

Monocyclic radicals include cycloalkyl, as, for example, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, which is unsubstituted or substituted one or more times by alkyl with 1-4 carbon atoms, alkoxyl with 1-4 carbon atoms or halogen, such as, for example, 2-methylcyclohex-1-yl, 2,6 - dimethylcyclohex-1-yl, 2,2,6,6-tetramethylchroman-1-yl.

Di - or tricyclic, condensed, bridged or smirnovii, in the case of a terpene, radicals include, for example, bicyclo[2.2.1]heptyl or norbornyl, bornyl, isobornyl, lordamantr, substituted, bicyclo[3.2.1]octyl, bicyclo[2.2.2] octyl, tricyclo[5.2.1.02,6] decyl, Spiro[5,5]-undecyl, bicyclo[2.2.2]Oct-2-EN-5-yl, tricyclo[2.2.1.02,6]-hept-3-yl, and the above-mentioned radicals are unsubstituted or substituted one or more times by alkyl with 1-4 atoms Phil.

In the present description, the alkyl or CNS groups are linear or branched. Under the halogen atom understand the chlorine atom, bromine, fluorine or iodine.

According to the present invention, preferred compounds of formula (I), in which

X1means the group-NR1R2;

g2, g3, g4, g5, g6and w2, w3, w4, w5, w6are the same or different and each, independently of one another, mean hydrogen, halogen atom, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, trifluoromethyl, nitro-group, alkylthiols with 1-4 carbon atoms; provided that at least one of the substituents g2, g3, g4, g5, g6and at least one of the substituents w2, w3, w4, w5, w6are other than hydrogen;

R1means hydrogen or alkyl with 1-4 carbon atoms;

R2means a non-aromatic carbocyclic radical with 3 to 15 carbon atoms, unsubstituted or singly or multiply substituted by the Deputy, selected among halogen atom, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms;

R3means the location, alkyl with 1-4 carbon atoms or trifluoromethyl;

R6means hydrogen, methyl or ethyl;

as well as their possible salts.

Of the compounds of formula (I) in which X1means the group-NR1R2preferred are those in which R1means hydrogen.

Of the compounds of formula (I) in which X1means the group-NR1R2or group-OR2preferred are those in which R2means 1,3 .3m-trimethylbicyclo[2.2.1]hept-2-yl or bicyclo [3.2.1] Oct-3-yl.

Of the compounds of formula (I) preferred are those in which R3means hydrogen or a group-CH2-R6in which R6means hydrogen.

Of the compounds of formula (I) preferred are those in which the or each of R3and R5means hydrogen, or R4means hydrogen, a R5means alkyl with 1-4 carbon atoms.

Of the compounds of formula (I) preferred are those in which g2, g5and g6mean hydrogen and g3and g4have the values specified above for compounds of formula (I).

Of the compounds of formula (I) preferred are those in which w5mi carbon trifluoromethyl or alkylthiols with 1-4 carbon atoms, or each of w2and g3mean hydrogen or one of them denotes hydrogen and the other denotes a halogen atom, alkyl with 1-4 carbon atoms or trifluoromethyl.

One group of preferred compounds according to the present invention is the group of compounds of formula (Ia):

< / BR>
in which R1, R2have the meanings specified for compounds of formula (I);

R3ameans hydrogen or a group-CH2-R6a;

R6ameans hydrogen or, provided that the substituents g3aand

g4aare other than alkyl with 1-4 carbon atoms,

R6ameans hydrogen, methyl or ethyl;

g3ameans hydrogen, halogen atom, alkyl with 1-4 carbon atoms or trifluoromethyl;

g4ameans halogen atom, alkyl with 1-4 carbon atoms or trifluoromethyl;

w4ameans halogen atom, alkyl with 1-4 carbon atoms or trifluoromethyl;

each of w2aand w3ameans hydrogen or one of them denotes hydrogen and the other denotes a halogen atom, alkyl with 1-4 carbon atoms or trifluoromethyl;

as well as their possible salts.

Of these compounds, especially pre is installed for compounds of formula (I);

R3ahas the value specified for compounds of the formula (Ia);

g'3ameans hydrogen, chlorine atom, fluorine atom, methyl or trifluoromethyl;

g'4ameans chlorine atom, fluorine atom, methyl or trifluoromethyl;

w'4ameans chlorine atom, fluorine atom, methyl or trifluoromethyl;

each of w'2aand w'3ameans hydrogen or one of them denotes hydrogen and the other denotes a chlorine atom, fluorine atom, methyl or trifluoromethyl;

and their possible salts.

Even more preferred compounds are the compounds of formula (I'a), in which:

R1means hydrogen;

R2means 1.3.3-trimethylbicyclo[2.2.1] hept-1-yl or bicyclo[3.2.1] Oct-3-yl;

R3ahas the value specified for compounds of the formula (Ia);

w'2aw'3aw'4a, g'3aand g'4ahave the meanings specified for compounds of the formula (I a);

as well as their possible salts.

Highly preferred are the compounds of formula (I a) where;

g'3ameans hydrogen, chlorine atom, fluorine atom or methyl;

g'4ameans chlorine atom, fluorine atom or methyl;

w'4ameans chlorine atom, fluorine atom or methyl;

each of w'2ais Teal;

R1, R2and R3have the meanings specified for compounds of the formula (I a);

as well as their possible salts.

Another group of preferred compounds according to the invention is that group of compounds of formula (Ib):

< / BR>
in which

R1, R2have the meanings specified for compounds of the formula (I);

R3a, w2a, w3a, w4a, g3aand g4ahave the meanings specified for compounds of the formula (Ia);

R5bmeans alkyl with 1-4 carbon atoms;

as well as their possible salts.

Of these compounds, especially preferred are the compounds of formula (I b):

< / BR>
in which

R1, R2have the meanings specified for compounds of the formula (I);

R3ahas the value specified for compounds of the formula (Ia);

w'2aw'3aw'4a, g'3aand g'4ahave the meanings specified for compounds of the formula (Ia);

R'5bmeans methyl;

as well as their possible salts.

Even more preferred compounds are the compounds of formula (I b) in which

R1means hydrogen;

R2means 1,3 .3m-trimethylbicyclo[2.2.1] hept-2-yl or bicyclo[3.2.1] Oct-3-yl;

R3a w'4a, g'3aand g'4ahave the meanings specified for compounds of the formula (I a);

as well as their salts.

In highly preferred are the compounds of formula (I b), in which:

g'3ameans hydrogen, chlorine atom, fluorine atom or methyl;

g'4ameans chlorine atom, fluorine atom or methyl;

w'4ameans chlorine atom, fluorine atom or methyl;

each of w'2aand w'3ameans hydrogen or one of them denotes hydrogen and the other denotes a chlorine atom, the fluorine atom or methyl;

R1, R2, R2and R'5bhave the meanings specified for compounds of the formula (I b);

as well as their possible salts.

Another group of preferred compounds according to the invention is that group of compounds of formula (Ic):

< / BR>
where:

R2is the name under which the value specified for the compounds of formula (I);

R3a, w2a, w3a, w4a, g3aand g4ahave the meanings specified for compounds of the formula (Ia);

as well as their possible salts.

According to another aspect of the present invention, it relates to a method for producing compounds of formula (I) and their salts, characterized in that:

1) functional coverage is>
, g2, g3, g4, g5, g6, R3, R4and R5have the meanings specified for compounds of the formula (I), is treated with a compound of formula (XXIV):

H-X1(XXIV),

in which X1has the value specified for compounds of the formula (I);

2) and, if necessary, the thus obtained compound is transformed into one of its salts.

One of the ways to obtain according to the invention (method A) suitable for the synthesis of compounds of formula (I) in which X1means the group - NR1R2.

This method differs in that:

1) the functional derivative of pyrazole-3-carboxylic acid of the above formula (II) is treated with an amine of formula (III):

HNR1R2(III)

in which R1and R2have the meanings specified for compounds of the formula (I);

2) and, if necessary, the thus obtained compound is transformed into one of its salts.

As a functional derivative of the acid of formula (II), it is possible to use the acid chloride acid; an anhydride; a mixed anhydride; compound alkilany ether with 1 to 4 carbon atoms in the alkyl part, in which alkyl is linear or branched; aktivirovannoi, for example, using N,N-dicyclohexylcarbodiimide or benzotriazol-1 - yloxytris(dimethylamino)phosphodiesterase (THIEF).

Thus, in method A, according to the invention, the acid chloride pyrazole-3-carboxylic acid, obtained by reacting thionyl chloride with the acid of formula (II), you can enter into interaction with the amine of the formula HNR1R2in an inert solvent such as a chlorinated solvent (e.g. dichloromethane, dichloroethane, chloroform), a simple ether (e.g. tetrahydrofuran, dioxane) or an amide (for example N, N-dimethylformamide) in an inert atmosphere at a temperature of from 0oC to room temperature in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.

One variant of the method And is getting mixed anhydride of the acid of formula (II) by reaction ethylchloride acid of formula (II) in the presence of a base, such as triethylamine, and in the introduction of his interaction with the amine HNR1R2in a solvent such as dichloromethane, in an inert atmosphere, at room temperature and in the presence of a base such as triethylamine.

Another way to get (method B) is.

This method differs in that:

1) the functional derivative of pyrazole-3-carboxylic acid of formula (II) is treated with alcohol of formula (XIV):

HO-R2(XIV)

in which R2has the value specified for compounds of the formula (I);

2) and, if necessary, thus mess up the connection to turn into one of its salts.

As a functional derivative of the acid of formula (II), it is possible to use the acid chloride acid; an anhydride; a mixed anhydride, or the free acid, in turn, activated, for example, using N,N-dicyclohexylcarbodiimide or benzotriazol - 1-yloxytris(dimethylamino)phosphodiesterase (THIEF).

Thus, in method B, according to the invention, the acid chloride pyrazole-3-carboxylic acid, obtained by reacting thionyl chloride with the acid of formula (II), you can enter into interaction with alcohol of the formula HO-R2or in an inert solvent such as a chlorinated solvent (e.g. dichloromethane, dichloroethane, chloroform), a simple ether (e.g. tetrahydrofuran, dioxane) or an amide (for example N, N - dimethylformamide), in an inert atmosphere at a temperature of from 0oC to room temperature, PI temperature, in the presence of 4-dimethylaminopyridine.

One variant of the method B is to obtain a mixed acid anhydride of the formula (II) by reaction ethylchloride acid of formula (II), in the presence of a base, such as triethylamine, and in the introduction of his interaction with alcohol HO-R2in a solvent such as dichloromethane, in an inert atmosphere, at room temperature and in the presence of a base such as triethylamine.

During any of the stages of obtaining compounds of formula (I), and predominantly in the production of intermediate compounds of formula (II) may be necessary and/or desirable to protect reactive functional or sensitive groups, such as amino, hydroxyl or carboxyl present in any of the input in the interaction of molecules. This ban can be implemented using a conventional protective group such as the groups described in "Protective groups in organic chemistry," J. F. W. McOmie, ed. Plenum Press, 1973, and in "Protective groups in organic synthesis" T. W. Greene and P. G. M. Wutts, ed. John Wiley et Sons, 1991. Removing the protective groups can be carried out in an appropriate later stage, using the known specialisterne compound of formula (I) was isolated in the usual way.

Depending on the nature of the substituents, the compound of formula (I), if necessary, can be translated into salt. Salt is obtained by treatment with the chosen acid in an organic solvent. By treating the free base, dissolved, for example, in a simple ether, such as diethyl ether, or alcohol such as propan-2-ol, or in acetone or dichloromethane, with a solution of the chosen acid in the same solvent to obtain the corresponding salt, which distinguish by classical methods.

Thus get, for example, hydrochloride, hydrobromide, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, oxalate, maleate, fumarate, naphthalenesulfonate, bansilalpet.

The compounds of formula (II) are obtained by different techniques.

The compounds of formula (II) in which R3=R'3and means hydrogen or a group CH2-R6where R6means hydrogen or alkyl with 1 to 4 carbon atoms, receive according to Scheme 1 (see the end of the description).

The first stage consists in obtaining a salt of an alkali metal derivative of acetophenone of the formula (IV) in which R'3means hydrogen or a group CH2-R6where R6means water the crystals (I) the value to which you then add equimolar amount of diethyloxalate (stage b1) to obtain the salt complex keeeper formula (V).

In the particular case where R'3=H, alkali metal is preferably sodium (M= Na) and salt complex keeeper (formula (V), Alk=CH3) get the method described in Bull. Soc.Chim.Fr., 14, 1098 (1947), using sodium methylate in methanol to implementation stage In the stage also can be affected tert. -butyl potassium in ethanol on a derivative of formula (IV), then add diethyloxalate, as described above. The reaction is carried out at the boiling point under reflux of the solvent. Thus obtained compound of the formula (V) in which M=K and Alk = CH2CH3.

In the particular case where R'3=CH3, the alkali metal is preferably lithium (M=Li) and salt complex keeeper (formula (V), Alk=CH2CH3) get the method described in J. Heterocyclic Chem., 26, 1389-1392 (1989), using lithium salt hexamethyldisilazane in an inert solvent, such as diethyl ether or cyclohexane, to the implementation stage

In phase thus obtained compound of the formula (V) and excess of hydrazine (hydrazinoacetate or an aqueous solution hydrauuc pyrazole-3-carboxylates of the formula (VI).

In phase thus obtained compound of the formula (VI) is treated with a strong base such as sodium hydride or sodium amide, in a solvent to produce anion, which is injected into the interaction with the compound of the formula (VII) in which Hal denotes halogen, preferably chlorine, bromine or iodine, R4means hydrogen and w2, w3, w4, w5, w6and R5have the meanings specified for compounds of the formula (I), to obtain the compounds of formula (IX). The reaction is carried out preferably in toluene at a temperature from room temperature up to the boiling temperature under reflux of the solvent to obtain the predominant target of the compounds of formula (IX). When the reaction is carried out in N, N-dimethylformamide at a temperature from 0oC to room, watching the predominant formation of the geometric isomer of the formula (XI):

< / BR>
Alternatively, according to the stage of the compound of formula (V) with excess hydrazine derivative of the formula (VIII) in which R4, R5, w2, w3, w4, w5, w6have the meanings specified for compounds of the formula (I), is refluxed in acetic acid; by precipitation in a mixture of water with ice get connection faraut target compounds of formula (II). The hydrolysis is carried out using, for example, alkali metal hydroxide such as potassium hydroxide, sodium hydroxide or lithium hydroxide, in an inert solvent, such as water, methanol, ethanol, dioxane or a mixture of these solvents, at temperatures from 0oC to the boiling temperature under reflux of the solvent.

The compounds of formula (IX) in which R4means hydrogen, preferably get through the stages outlined above then

The compounds of formula (IX) in which R4and R5different from hydrogen, preferably get through the stage described above.

The compounds of formula (IX) in which R'3means CH2-(C1-C4)-alkyl, preferably receive, or when R4and R5different from hydrogen, of the compounds of formula (IX), or when R4=H, compounds of formula (VI), according to Scheme 2 (see the end of the description).

Stage is to obtain 4-brometalia-3 - carboxylate of the formula (X) by exposure to N-bromosuccinimide on the compound of the formula (VI) or formula (IX) wherein R'3means methyl. The reaction is carried out in an inert solvent like carbon tetrachloride, in the presence of dibenzoylperoxide and temperatureprofile carry out the bromination according to the stage of connection, pyrazol nitrogen is protected with a (Y=N-protective group). As the N-protective group used the well-known specialist classical N-protective group, such as tert.- butoxycarbonyl.

Stage consists in obtaining the compounds of formula (VI) or (IX) in which R'3means the group-CH2-(C1-C4)-alkyl, by influencing organoborate (Alk')2CuLi, in which Alk' is alkyl with 1-4 carbon atoms. The reaction is carried out according to the method described in the application for the European patent 0658546.

If necessary, when used as a compound of the formula (VI), protected by pyrazol nitrogen, after stage N-protective group is removed well-known specialist of ways.

The compounds of formula (II) in which R4means hydrogen and R3=R3and means the group-CH2-R6where R6different from hydrogen or different from the alkyl with 1-4 carbon atoms, receive according to Scheme 3 (see end of description).

In stage, the nitrogen atom of the compounds of formula (VI) (R'3=CH3protect using the N-protective group such as tert.-butoxycarbonyl (Boc), according to well-known specialist methods.

Stage is to obtain 4-promotility (XVI) is treated with a compound of the formula R6-A, in which R6having specified for formula (I) is different from hydrogen or different from the alkyl with 1-4 carbon atoms and A denotes hydrogen or a cation, such as a cation of an alkaline or alkaline earth metal or Quaternary ammonium group, such as tetraethylammonium group.

To obtain the compounds of formula (XVIII) in which R6means alkoxy with 1-5 carbon atoms or hydroxyalkoxy with 1-5 carbon atoms, as a reagent of formula (XVII) use alcohol with 1-5 carbon atoms or diatomic alcohol with 1-5 carbon atoms in the presence of nucleophilic base, such as a metal hydride, such as sodium hydride or potassium. Depending on the values of R6in stage technique, you can obtain a mixture of esters, which amyraut in stages to obtain the acid of formula (II).

To obtain the compounds of formula (XVIII) in which R6means alkylthiols with 1-5 carbon atoms, as a reagent of formula (XVII) use dispert with 1-5 carbon atoms in the presence of nucleophilic base, such as a metal hydride like sodium hydride or potassium.

In the desirable case, obtained in stage ester of the formula (XVIII), Kok hydrogen peroxide or m-chlormadinone acid, can be converted into a compound of formula (XVIII), where R6means alkylsulfonyl of 1 to 5 carbon atoms or alkylsulphonyl with 1-5 carbon atoms.

To obtain the compounds of formula (XVIII) in which R6means cyano, as a reagent of formula (XVII) can be used cyanide Quaternary ammonium compounds, for example, tetraethylammonium cyanide or metal cyanide such as sodium cyanide; in this latter case, the nucleophilic substitution reaction according to stage is carried out in the presence of a phase transfer catalyst.

To obtain the compounds of formula (XVIII) in which R6means fluorine, as a reagent of formula (XVII) can be used fluorinating agent; as a fluorinating agent, you can use a metal fluoride, such as potassium fluoride, used in the presence of a complexing agent, as Kryptofix.

To obtain the compounds of formula (XVIII) in which R6means hydroxyl, as a reagent of formula (XVII) using a hydroxide of alkali or alkaline earth metal, such as sodium hydroxide or potassium.

In stage removes the N-protective group known specialist ways.

In stage thus poluchennoe to produce anion, which is injected into the interaction with the compound of the formula (VII) in which Hal denotes halogen, preferably chlorine, bromine or iodine; R4means hydrogen and w2, w3, w4, w5, w6and R5have the meanings specified for compounds of the formula (I), to obtain the compounds of formula (XX). The reaction is carried out preferably in toluene at a temperature from room temperature up to the boiling temperature under reflux of the solvent in order to obtain the majority of the target compounds of formula (XX). When the reaction is carried out in N,N-dimethylformamide at a temperature from 0oC to room, watching the predominant formation of the geometric isomer of the formula (XXIII):

< / BR>
In stage by hydrolysis in alkaline medium compounds of formula (XX), then acidification get the target compounds of formula (II). The hydrolysis is carried out using, for example, alkali metal hydroxide such as potassium hydroxide, sodium hydroxide or lithium hydroxide, in an inert solvent, such as water, methanol, ethanol, dioxane or a mixture of these solvents, at temperatures from 0oC to the boiling temperature under reflux of the solvent.

The compounds of formula (II) in which R3=R34and R5different from hydrogen, receive according to Scheme 4, where Alk denotes methyl or ethyl (see the end of the description).

Stage is to obtain 4-brometalia-3 - carboxylate of the formula (XXI) according to the method described above under Scheme 2.

In the stage of the compound of formula (XXI) is treated with a compound of the formula R6-A (XVII), as described above, and according to the methods described under Scheme 3.

In stage by hydrolysis in alkaline medium compounds of the formula (XXII), then acidification get the target compounds of formula (II). The hydrolysis is performed according to the methods described under Scheme 1.

Under Scheme 1 or stage in Scheme 3, the reaction of compounds of formula (VI) or the compounds of formula (XIX) with a halogenated derivative of formula (VII) can be obtained mixture in variable proportions of the compounds of formula (IX) or the compound of formula (XX) with their corresponding isomers of the formula (XI) or (XXIII):

< / BR>
< / BR>
Both isomers of formulas (IX) and (XI) or both isomers of the formulae (XX) and (XXIII) can be separated by chromatography on silica gel according to the classical methods. Both isomers of formulas (IX) and (XI) or formula (XX) and (XXIII) oharakterizovat their NMR spectrum, especially by studying the effect Overcautiously using the mixture of isomers with the aim of obtaining a mixture of acids of the formula (II) with its isomer of formula (XII):

< / BR>
In this case, to obtain a mixture of the two isomers of the formula (II) and (XII) using the method according to the invention described above to obtain a mixture of compounds of formula (I) in which R4means hydrogen, with its isomer of formula (XIII):

< / BR>
Then both isomers are divided according to the classical methods such as, for example, chromatography on silica gel or crystallization, and finally get the compound of formula (I) according to the invention.

According to another aspect of the present invention, the subject invention are compounds represent by-products of the method of obtaining compounds of formula (I), formula (XIII):

< / BR>
in which X1, g2, g3, g4, g5, g6, w2, w3, w4, w5, w6, R3and R5have the meanings specified for compounds of the formula (I);

as well as their possible salts.

According to the next aspect of the present invention, it relates to a process for the preparation of intermediate compounds of formula (II) and compounds of formula (XII), suitable for producing compounds of formula (I) in which R4means hydrogen, and compounds of the formula (XIII). This method differs in that:

1) link Azania for compounds of formula (I) and Alk denotes methyl or ethyl,

treated with a strong base in the solvent, and then the thus obtained anion enter into interaction with the compound of the formula (VII):

< / BR>
in which w2, w3, w4, w5, w6and R5have the meanings specified for compounds of the formula (I), and Hal means a halogen atom, to obtain:

or, when the reaction is performed in toluene at a temperature from room temperature up to the boiling temperature under reflux of the solvent, the compounds of formula (XXVI):

< / BR>
or, when the reaction is carried out in N,N-dimethylformamide at a temperature from 0oC to room, the compounds of formula (XXVII):

< / BR>
2) hydrolyzing in an alkaline environment or the compound of formula (XXVI) or a compound of formula (XXVII) to obtain, respectively,

any of the compounds of formula II: R4=H):

< / BR>
any of the compounds of formula (XII):

< / BR>
According to the next aspect of the present invention, it relates to a method for producing compounds of the formula (XIII) and their salts, characterized in that:

1) the functional derivative of the acid of formula (XII):

< / BR>
in which g2, g3, g4, g5, g6, w2, w3, w4, w5, w6, R3and R5matter, decree 1 has the value specified for compounds of the formula (I), to obtain the compounds of formula (XIII):

< / BR>
2) and, if necessary, the thus obtained compound is transformed into one of its salts.

Benzylchloride formula (VII) are known or they are obtained by known methods.

As a rule, the compounds of formula (VII) in which Hal denotes bromine atom, can be obtained by exposure to N-bromosuccinimide to the appropriate methylbenzene derivatives in the presence of dibenzoylperoxide. Benzylbromide can also be obtained from the corresponding benzyl alcohol by the impact of bromovalerate in the form of a solution in water or in acetic acid. You can also use impact tribromide phosphorus to the corresponding benzyl alcohol to obtain the compounds of formula (VII) in which Hal denotes bromine atom.

The compounds of formula (VII) in which Hal denotes an iodine atom, can be obtained by exposure of sodium iodide in the compound of formula (VII) in which Hal denotes a chlorine atom, in a solvent such as acetone or butane-2-on.

The compounds of formula (VII) in which Hal denotes a chlorine atom, can be obtained through action of thionyl chloride on the corresponding benzo is Laura, preferably can be obtained by a method described in J. Fluorine Chem., 32(4), 361-366 (1986).

The compounds of formula (VII) in which R5means trifluoromethyl, can also be obtained from the relevant - (trifluoromethyl)benzyl alcohols according to the above methods. - (Trifluoromethyl) benzyl alcohols can be obtained according to the method described in Tetrahedron, 45 (5), 1423 (1989), or according to the method described in J. Org.Chem., 56(1) 2 (1991).

The compounds of formula (VIII) are known or they are obtained by known methods, such as described in J. Org.Chem., 53, 1768-1774 (1988) or in J. Am.Chem. Soc., 80, 6562-6568 (1958).

Amines of the formula HNR1R2or are commercially available or described in the literature, or they are obtained by known methods according to the following methods:

endo - and Exo-bicyclo[3.2.1]octane-2-ylamine receive according to H. Maskill, etc., J. Chem.Soc., Perkin II, 119 (1984):

< / BR>
bicyclo[2.2.2] Octan-2-ylamine receive according to R. Seka and others, Ber., 1379 (1942):

< / BR>
endo - and Exo-bicyclo[3.2.1]Octan-3-ylamine receive according to H. Maskill, etc., J. Chem.Soc., Perkin II, 1369 (1984):

< / BR>
endo-tricyclo[5.2.1.02,6]decane-8-ylamine receive according to G. Buchbauer and other Arch. Pharm., 323, 367 (1990):

< / BR>
endo - and Exo-, 1R - and 1S - 1,3 .3m-trimethylbicyclo[2.2.1]- heptane-2-ylamine get suchaut according to Smith and others, J. Org.Chem., 17, 294 (1952):

< / BR>
2,6-dimethylcyclohexylamine receive according Cornubert and other Bull. Soc. Chim. Fr., 12, 367 (1945):

< / BR>
2-methoxycyclohexyl receive according to Noyce and others, J. Am.Chem.Soc., 76, 768 (1954):

< / BR>
4-ethylcyclohexylamine receive according to A. Shirachata and others, Biochem. Pharmacol., 41, 205 (1991):

< / BR>
bicyclo[2.2.2]Oct-2-EN-5-amine receive according to H. L. Goering and others, J. Am. Chem.Soc., 83, 1391 (1961):

< / BR>
N-ethyl-1-adamantylamine receive according to V. L. Narayanan and others, J. Med. Chem., 15, 443 (1972):

< / BR>
tricyclo [2.2.1.02,6] heptane-3-ylamine receive according to G. Muller and others, Chem. Ber., 98, 1097 (1965):

< / BR>
N-methyl-Exo-bicyclo[2.2.1]heptane-2-ylamine receive according to W. G. Kabalka and others, Synth.Commun., 20, 231 (1991):

< / BR>
2,2,6,6-tetramethylcyclopentadiene receive according to J. Chem. Soc., WITH, 1845 (1970):

< / BR>
The alcohols of the formula HO-R2or are commercially available or described in the literature, or they are obtained by known methods. For example, to obtain the alcohol of formula (XIV) can be done in the recovery of the corresponding ketones. The recovery is carried out using a reducing agent such as sodium borohydride in a solvent such as methanol or sociallyengaged in a solvent such as tetrahydrofuran or diethyl ether, at a temperature of from room temperature to a temperature ciproglen Compterendu hebdomadaire des seances de 1'Academic des Sciences, 156, 1201.

The use of compounds of the formula (III) in the form of individual enantiomers in stage 1) method A, or the use of compounds of the formula (XIV) in the form of individual enantiomers in stage 1) method B, and the use of compounds of the formula (VII) or formula (VIII) in the form of individual enantiomers in stages of Scheme 1 or stage Circuit 3 for obtaining compounds of formula (II) allow one to obtain the compounds of formula (I) in the form of individual enantiomers.

The splitting of racemic mixtures of compounds of the formula (III), (VII), (VIII) or (XIV) perform well-known specialist methods.

The compounds of formula (I) have high affinity in vitro receptor CB2in the experimental conditions described Bouaboula and others, Eur.J.Biochem., 214, 173-180 (1993).

In particular, the compounds according to the present invention and their possible salts are strong and selective ligands of receptors CB2Ki-value which is usually from 0.1 to 100 nm. They typically 10-1000 times more active against the receptors CB2than to receptors CB1and effective when ingested.

The compounds of formula (I) according to the invention are antagonists of receptors CB2. spruce trees. It is known that agonists of receptors cannabinoids (9-THC, WIN 55212-2, or CP-55940) is able to inhibit the activity of adenylate cyclase induced by Forskolin, as described in M. Rinaldi-Carmona and others, Journal of Pharmacology and Experimental Therapeutics, 278, 871-878 (1996). In the case of this model, the compounds of formula (I) according to the invention is able to completely block the effects of agonists of receptors cannabinoids.

On the other hand, it is known that in nanomolar concentrations of agonists of receptors cannabinoids (WIN 55212-2 or CP-55940) can increase DNA synthesis in the case of B-cells, costimulatory antibodies against immunoglobulin: an increase of approximately 40% inclusion thymidine (J. M. Decorcq and others, FEBS Letters, 369, 177-182 (1995)). When using the compounds of formula (I) according to the invention or one of their possible salts in wide concentration ranges from 10-10mol to 10-5mol, we find that they block the increase in DNA synthesis in the case of B-cells stimulated as described above, induced by agonists of receptors cannabinoids (WIN 55212-2 or CP-55940).

In addition, agonists of receptors cannabinoids (C3-55940, or WIN 55212-2) induce the activation of protein kinases, mitogen-activated (MARKs: "mitogen-ActiView specifically block the activation of MAPKs, induced by agonists of receptors cannabinoids (CP-55940, or WIN 55212-2).

Compounds according to the invention or their possible salts have affinity in vivo to receptors cannabinoids CB2present in the spleen of the mouse when they are administered intravenously, intraperitoneally or orally. Their activity revealed by experiments on the binding ex vivo [3H]-CP-55940. Experiments are performed in experimental conditions described by M. Rinaldi-Carmona and other Life Sciences, 56, 1941-1947 (1995).

Compounds according to the present invention have toxicity, acceptable for their use as pharmaceuticals.

Due to its excellent properties, especially its high affinity and selectivity to the peripheral receptors CB2the compounds of formula (I) as such or in the form of pharmaceutically acceptable salts can be used as active principles of drugs.

Diseases for which treatment can be used the compounds of formula (I) and, if necessary, their pharmaceutically acceptable salts, are pathologies involving cells of the immune system or immune system disorders, as napoleonska disease, gastro-intestinal tract, such as Crohn's disease. In particular, one can mention the following autoimmune diseases: systemic lupus erythematosus, connective tissue disease, Sjogren syndrome, ankylosing spondylitis, reactive arthritis, rheumatoid arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anemia, multiple sclerosis, psoriasis. Curable allergic diseases can be, for example, such as an allergic reaction of immediate type or asthma. Similarly, compounds and their possible pharmaceutically acceptable salts can be used for the treatment of vasculitis, parasitic infections, viral infections, bacterial infections, amyloidosis, diseases affecting lymphohematopoietic system.

Thus, according to another aspect of the present invention, it relates to a method of treatment of the above diseases, which consists in the introduction to a patient in need, an effective amount of the compounds of formula (I) or one of its pharmaceutically acceptable salts.

According to the next aspect of the present invention, it also relates to the use of compounds of formula (I) DL is naidov CB2especially related to immune system disorders and diseases involving the immune system.

Moreover, the compounds of formula (I) or formula (XIII) according to the invention, as such or in radiolabelled form, can be used as pharmacological agents for human or animal for the identification and marking of peripheral receptors CB2cannabinoids. It is another aspect of the present invention.

Compounds according to the present invention is generally introduced in the form of a single dose. The above single dose preferably included in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.

Thus, according to further aspect of the present invention, it relates to pharmaceutical compositions comprising as an active start compound of formula (I) or one of its pharmaceutically acceptable salts.

Compounds of the above formula (I) and their pharmaceutically acceptable salts can be used in daily doses of from 0.01 to 100 mg per kilogram of body weight curable mammal, died from 0.5 to 4000 mg per day, in particular from 2.5 to 1000 mg, depending on age treatable entity or type of treatment: prophylaxis or treatment.

In the pharmaceutical compositions of the present invention for the introduction of oral, sublingual, by inhalation, subcutaneous, intramuscular, intravenous, transdermal, local or rectal acting early can be entered in a unitary forms of administration, mixed with classical pharmaceutical carriers, to animals and people. The corresponding unitary form of introduction include oral forms such as tablets, gelatin capsules with the medicine, powders, granules and oral solutions or suspensions; sublingual and buccal forms of administration; aerosols; implants; subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

When preparing a solid composition in tablet form, by acting early, micronized or not, you can add a wetting agent, such as sodium lauryl sulfate, all mixed with a pharmaceutical excipient, such as silicon dioxide, gelatin, starch, lactose, magnesium stearate, talc, gum Arabic or similar components. Tablets may be coated with sucrose, once had a prolonged or delayed activity and continuously release a specified number of the current beginning.

The drug is in the form of gelatin capsules with the medicine are obtained by mixing the applicable beginning with a diluent such as a glycol or ester of glycerol, and introducing the resulting mixture into soft or hard gelatin capsules.

The drug is in the form of a syrup or elixir may contain the active principle together with a sweetener, preferably low-calorie vehicle, methyl paraben and propyl paraben as an antiseptic, as well as giving a taste agent and an appropriate dye.

Dispersible in water powders or granules can contain the active principle in a mixture with dispersing agents, wetting or suspendresume agents, as polyvinylpyrrolidone, just as with sweetening means or corrective taste substances.

For rectal use of suppositories which are prepared with binders, melting at rectal temperature, as, for example, cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular injection using aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain dispersing agents and/or pharmacologically acceptable is, the La preparing an aqueous solution for intravenous injection, you can use a co-solvent: alcohol, such as ethanol; glycols such as polyethylene glycol or propylene glycol; and hydrophilic surface-active agent, such as, TWIN80. For cooking oil solution for injection intramuscularly can be solubilisate effective beginning with the triglyceride or a complex ester of glycerin.

For local introduction you can use creams, ointments, gels.

For percutaneous introduction you can use the patches in multimineralnoe or tank form, in which the active principle may be in the form of alcohol solution. For administration by inhalation using an aerosol containing, for example, sarbatorile or oleic acid, as well as Trichlorofluoromethane, DICHLOROFLUOROMETHANE, dichlorotetrafluoroethane or any other biologically acceptable propellant; you can also use the system containing the active principle individually or in combination with excipients, in the form of powder.

The active principle can also be used for preparation of the formulation in the form of microcapsules or microspheres, in the case of neobhodimosti may be in the form of a complex with a cyclodextrin, as, for example, -,- or - cyclodextrin, 2-hydroxypropyl- - cyclodextrin or methyl- - cyclodextrin.

Form of slow release, suitable for continuous processing, it is possible to use implants. They can prepare in the form of an oil suspension or in the form of a suspension of microspheres in an isotonic environment.

In each case the dose of active principle of formula (I) is in quantities adapted to the envisaged daily doses. Usually each single dose appropriately selected, depending on the dosage and the envisaged type of administration, such as tablets, gelatin capsules with the medicine and other similar forms, sachets, ampoules, syrups and the like form, the drops, so that this single dose contains 0.5 to 1000 mg of active early, preferably 2.5 to 250 mg, for administration 1-4 times per day.

The following examples illustrate the invention, but without limiting the scope of protection.

The melting point or decomposition products, so pl. determine the capillary device Tottoli.

1H-NMR spectra shoot at 200 MHz in hexacyanometallate.

Used for preparative vysokomepie 50 mm and a maximum height of layer 35-40 see

Used terms are as follows:

- stationary phase: Kromasil C 18 - 100 angstroms, 10 μm

- mobile phase: eluting the tool And water eluting tool B: methanol/water (90/10 by volume);

- consumption: 114 ml/min; the position of the pumps 8 mm;

the gradient elution:

Time (min)% A %B

0 - 10 90

5 - 10 90

80 - 4 96

- UV detection at =230 nm; the length of the cell...0; absorption = 0.5 to AUFS.

Used for analytical high performance liquid chromatography (HPLC) instrument is an HPLC analyzer company Hewlett Packard. Used terms are as follows:

- column: stationary phase: Kromasil (wouterse) C 18 - 100 angstroms, 10 µm;

- mobile phase: eluting the tool And water eluting tool B: methanol

the gradient elution:

Time (min)% A %B

0 - 20 80

5 - 20 80

50 - 7 93

- flow rate: 1 ml/min

- UV detection at =230 nm; absorption = 8;

- volume of added sample: 30 ál.

In Preparative examples and Examples use the following abbreviations:

Me, OMe: methyl, methoxy

Et, OEt ethyl, ethoxy

EtOH: ethanol

MeOH: methanol

ether: diethyl ether

saafir: diisopropyl ether

DMF: what>/BR>THF: tetrahydrofuran

AcOEt: ethyl acetate

K2CO3: potassium carbonate

Na2CO3: sodium carbonate

KHCO3: potassium bicarbonate

NaHCO3: sodium bicarbonate

NaCl: sodium chloride

Na2SO4: sodium sulphate

MgSO4: magnesium sulfate

NaOH: sodium hydroxide

KOH: potassium hydroxide

AcOH: acetic acid

H2SO4: sulfuric acid

HCl: hydrochloric acid

HBr: Hydrobromic acid

hydrochloric ether: saturated solution of hydrogen chloride in ether

BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium-hexachloro

DBU: 1,8-diazabicyclo [5.4.0]undec-7-ene

NH4Cl: ammonium chloride

so pl.: melting point

so Kip.: boiling point

TC: room temperature

silicon dioxide H: silica gel 6OH, issued for the sale by the company Merck (Darmstadt)

HPLC: high performance liquid chromatography

TR: retention time

NMR: nuclear magnetic resonance

: chemical shift, expressed in ppm (M. D.)

s: s (singlet); se: ush.with (broadened singlet); sd: DS (double singlet); d: d (doublet); dd: double doublet); t: t (triplet); qd KD (quadruplet); sept: septuplet; mt: mu is(4-were)pyrazole-3-carboxylic acid

A) Sodium salt of methyl-4-(4-were)-2-oxo-4 - oxidant-3-enoate

6.24 g of Sodium are dissolved in 150 ml of methanol. After cooling to room temperature, add 36,4 ml 4'-methylacetophenone, then a solution of 37 ml diethyloxalate in 50 ml of methanol. Then add 100 ml of methanol to dilute the reaction mixture and stirred for 2 hours at room temperature. Add 500 ml of diethyl ether and stirred for 30 minutes at room temperature. Suck the precipitation, washed his diethyl ether and dried. Get 57.4 g of the target product.

B) Methyl ester of 5-(4-were)pyrazole-3-carboxylic acid

In a bath with ice cooled mixture of 30 g of the obtained in the previous stage of the compound in 100 ml of acetic acid and added dropwise 7,94 ml of a 55% aqueous solution of hydrazine in water. Then the reaction mixture is refluxed for 5 hours and stirred overnight at room temperature. The precipitation is sucked off, washed with water and thus receive the first portion of the product. The filtrate is poured into a mixture of ice water, the precipitation is sucked off, washed with water, dried and receive the second portion of the product. The first and second portions of the product about the ether is 1-(3,4 - dichlorobenzyl)-5-(4 - were) pyrazole-3-carboxylic acid

To a suspension of 5 g obtained in the preceding stage connection in 50 ml of toluene at room temperature and added in several portions 2,03 g of sodium hydride as a 60% dispersion in oil, then the reaction mixture is heated at 65oC for 1 hour. After cooling to room temperature was added dropwise of 5.82 g of 3,4 - dichlorobenzamide, then refluxed for 20 hours. The reaction mixture is cooled to room temperature and added dropwise 100 ml of a 50% aqueous solution of ammonium chloride in water. After decanting, the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane/ethyl acetate (75:25 by volume). Get 5,28 g of the target product, so pl. = 98,6oC.

G) 1-(3,4-Dichlorobenzyl)-5-(4-were)pyrazole-3 - carboxylic acid

To a solution of 5.2 g obtained in the previous stage of the compound in 100 ml of ethanol at room temperature, add a solution of 1.16 g of KOH in 20 ml of water, then refluxed for 5 hours. The reaction mixture was stirred at room temperature over night, add 200 ml of aqueous 1 n hydrochloric ASS="ptx2">

NMR-spectrum (M. D.): 2,4 (s, 3H), and 5.5 (s, 2H); 6,9 (s, 1H); 7,0 (DD, 1H); and 7.3 (d, 1H); 7,35 system (AA'-BB', 4H); the 7.65 (d, 1H); 1,30 (ush.s, 1H).

See Overhauser effect (N. O. E.) between the benzyl protons (R4= R5=H) and protons (g2=g6=H.

Preparative example 1.2

1-(3-Chloro-4-methylbenzyl)-5-(4-were)pyrazole-3-carboxylic acid

A) Methyl ester of 1-(3-chloro-4-methylbenzyl)-5-(4-were) pyrazole-3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1.1, starting from 5 g of compound obtained in stage B of Preparative example 1.1, 2,03 g of sodium hydride as a 60% dispersion in oil, 100 ml of toluene and 4,22 g of 3-chloro-3-methylbenzylamine. Obtain 1.52 g of the target product.

B) 1-(3-Chloro-4-methylbenzyl)-5-(4-were)pyrazole-3 - carboxylic acid

To a solution of 1.52 g obtained in the preceding stage connection in 50 ml of ethanol at room temperature is added a solution of 0.36 g of KOH in 10 ml of water, then refluxed overnight. The reaction mixture was concentrated in vacuo, the residue is treated with water, the aqueous phase washed with ether, the aqueous phase is acidified to pH 2 by addition of 6 n hydrochloric acid, the precipitation is sucked off the/P> NMR-spectrum (M. D.): 2,1-2,45 (2s, 6H); to 5.4 (s, 2H); 6,7-7,5 (m, 8H); 12,85 (ush.s, 1H).

Preparative example 1.3

1-(3-Fluoro-4-methylbenzyl)-5-(4-were)pyrazole-3 - carboxylic acid and 1-(3-fluoro-4-methylbenzyl)-3-(4-were) pyrazole-5-carboxylic acid

A) Methyl ester of 1-(3-fluoro-4-methylbenzyl)-5-(4 - were)pyrazole-3-carboxylic acid and methyl ester 1- (3-fluoro-4-methylbenzyl)-3-(4-were)pyrazole-5-carboxylic acid

To a suspension of 2.5 g obtained in stage B of Preparative example 1.1 compound in 100 ml of toluene at room temperature and added in several portions of 1.01 g of sodium hydride as a 60% dispersion in oil, then the reaction mixture is heated for 1 hour at 65oC. After cooling to room temperature, was added dropwise at 2.45 g of 3-fluoro-4-methylbenzylamine (Preparative example 3.1), then refluxed for 48 hours. After cooling to room temperature was added dropwise 50 ml of a 50% aqueous solution of ammonium chloride in water. After decanting, the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira a mixture of ethyl acetate with cyclohexane (50:50 by volume). Get 1,29-(3-fluoro-4-methylbenzyl)-3-(4-were) pyrazole-5-carboxylic acid

To a solution of 1.2 g of the mixture of compounds obtained in the preceding stage in 50 ml of ethanol at room temperature is added a solution of 0.3 g of KOH in 10 ml of water, then refluxed for 5 hours and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue is treated with water, the aqueous phase washed with ethyl acetate, the aqueous phase is acidified to pH 2 by addition of 6 n hydrochloric acid, the precipitated precipitate is sucked off, washed with water and dried in vacuum. Obtain 0.95 g of the mixture of target products.

Preparative example 1.4

1-(3,4-Dichlorobenzyl)-5-(4-methoxyphenyl)pyrazole-3-carboxylic acid

A) Sodium salt of methyl-4-(4-methoxyphenyl)-2-oxo-4 - oxidant-3-enoate

of 3.9 g of sodium are dissolved in 100 ml of methanol. After cooling to room temperature, add 24.4 g of 4'-methoxyacetophenone, then a solution of 23 ml of diethyloxalate in 50 ml of methanol and stirred for 2 hours at room temperature. Add 500 ml of diethyl ether and stirred for 30 minutes at room temperature. The precipitation is sucked off, washed his diethyl ether and dried. Gain of 33.4 g of the target product.

B) Methyl ester of 5-(4-methoxybenzene in 100 ml of acetic acid and added dropwise 2.2 ml of hydrazinoacetate. Then the reaction mixture is refluxed for 5 hours and stirred overnight at room temperature. The reaction mixture was poured into a mixture of ice water, the precipitation is sucked off and washed with water. The residue is treated with dichloromethane, filtered off the insoluble portion, the filtrate is dried over magnesium sulfate and the solvent is evaporated in vacuum. Obtain 7.1 g of the target product.

C) Methyl ester of 1-(3,4-dichlorobenzyl)-5-(4-methoxyphenyl) pyrazole-3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1.1, from 3.5 g obtained in the preceding stage connection of 1.32 g of sodium hydride as a 60% dispersion in oil, 150 ml of toluene and of 3.77 g of 3,4-dichlorobenzamide. Product chromatografic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (60:40 by volume). Obtain 2.4 g of the target product; so pl. = 95,5oC.

NMR-spectrum (M. D.): 3,8 (2s, 6H); the 5.45 (s, 2H); 6,8-7,1 (m, 4H); to 7.25 (d, 1H); 7.35 (d, 2H); at 7.55 (d, 1H)

G) 1-(3,4-dichlorobenzyl)-5-(4-methoxyphenyl)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.2, from 2.4 g obtained in the previous stage is connected>1-(3-Chloro-4-methylbenzyl)-5-(4-methoxyphenyl)pyrazole-3 - carboxylic acid and 1-(3-chloro-4-methylbenzyl)-3-(4-methoxyphenyl) pyrazole-5-carboxylic acid

A) Methyl ester of 1-(3-chloro-4-methylbenzyl)-5-(4 - methoxyphenyl)pyrazole-3-carboxylic acid and methyl ester

1-(3-chloro-4-methylbenzyl)-3-(4-methoxyphenyl)pyrazole-5-carboxylic acid

The mixture of these two compounds get through the procedure described in stage a of Preparative example 1.3, from 3.5 g obtained in stage B of Preparative example 1.4 connection of 1.32 g of sodium hydride as a 60% dispersion in oil, 100 ml of toluene and 2.75 g of 3-chloro-4-methylbenzylamine. Gain of 1.93 g of a mixture of target products.

B) 1-(3-Chloro-4-methylbenzyl)-5-(4-methoxyphenyl) pyrazole-3-carboxylic acid and 1-(3-chloro-4-methylbenzyl)-3-(4 - methoxyphenyl)pyrazole-5-carboxylic acid

The mixture of these two compounds get through the procedure described in stage B of Preparative example 1.3, from 1.9 grams of the mixture of compounds obtained in the previous stage, 50 ml of ethanol, 0.43 g of KOH and 10 ml of water. Obtain 1.73 g of the mixture of target products.

Preparative example 1.6

1-(3-Chloro-4-methylbenzyl)-5-(4-forfinal)pyrazole-3-carboxylic acid

A) Sodium salt of methyl-4-(4-forfinal)-3-oxo-4 - oxidant-3-enoate

diethyloxalate in 50 ml of methanol. Get 42,68 g of the target product.

B) Methyl ester of 5-(4-forfinal)pyrazole-3-carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.1, from 15 g obtained in the preceding stage connection, 100 ml of acetic acid and of 3.73 ml of a 55% aqueous solution of hydrazine in water. After stirring over night at room temperature the reaction mixture was poured into a mixture of ice water, the precipitation is sucked off, washed with water and dried. Get a 10.74 g of the target product.

C) Methyl ester of 1-(3-chloro-4-methylbenzyl)-5-(4-forfinal) pyrazole-3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1.1, from 3.5 g obtained in the preceding stage connection, 1.4 g of sodium hydride as a 60% dispersion in oil, 100 ml of toluene and 4.45 g of 3-chloro-4-methylbenzylidene (Preparative example 3.2) in 50 ml of toluene. Chromatographic on the silicon dioxide, elwira mixture of cyclohexane with ethyl acetate (70:30 by volume). Gain of 1.57 g of the target product; so pl. = 110oC.

G) 1-(3-Chloro-4-methylbenzyl)-5-(4-forfinal)pyrazole-3 - carboxylic acidoC.

Preparative example 1.7

1-(2,4-Dichlorobenzyl)-5-(4-methoxyphenyl)pyrazole-3 - carboxylic acid

A) Sodium salt of methyl-4-(4-chlorophenyl)-2-oxo-4 - oxidant-3-enoate

This connection get the procedure described in stage a of Preparative example 1.1, from 12,66 g of sodium in 270 ml of methanol and 68.4 ml of 4'-chloroacetophenone and 71,8 ml diethyloxalate in 110 ml of methanol. Obtain 97 g of the target product.

B) Methyl ester of 5-(4-chlorophenyl)pyrazole-3-carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.4 on the basis of 15 g obtained in the preceding stage connection, 65 ml of acetic acid, 3,05 ml hydrazinoacetate. The precipitate proscout in a mixture of 100 ml of dichloromethane with 50 ml of ethyl acetate, suck it up and dried. Get 8,13 g of the target product; so pl. = 215oC.

C) Methyl ester of 1-(2,4-dichlorobenzyl)-5-(4-chlorophenyl) pyrazole-3-carboxylic acid

To a suspension of 1.02 g of sodium hydride (60% in oil) in 100 ml of toluene at room temperature was added dropwise a solution 5,07 g obtained in the previous stage of the compound in 100 ml of toluene, and then heated at 65ooC.

G) 1-(2,4-Dichlorobenzyl)-5-(4-chlorophenyl)pyrazole-3 - carboxylic acid

This connection receive according to the method described in stage g of Preparative example 1.1, from 3.6 g obtained in the preceding stage connection, 60 ml of methanol, 1.27 g of KOH and 6 ml of water. Get to 3.52 g of the target product; so pl. = 185oC.

Preparative example 1.8

1-(3-Chloro-4-methylbenzyl)-5-(3,4-dimetilfenil)pyrazole-3 - carboxylic acid

A) Sodium salt of methyl-4-(3,4-dimetilfenil)-2-oxo-4 - oxidant-3-enoate

This connection get the procedure described in stage a of Preparative example 1.1, based on a 3.9 g of sodium in 100 ml of methanol, 25 g of 3',4'-dimethylacetophenone and 23 ml of diethyloxalate in 50 ml of methanol. Get 39,42 g of the target product.

B) Methyl ester of 5-(3,4-dimetilfenil)pyrazole-3-carbon is from 10 g obtained in the preceding stage connection in 150 ml of acetic acid and 2.2 ml of a 55% aqueous solution of hydrazine in water. Get 9 g of the target product.

C) Methyl ester of 1-(3-chloro-4-methylbenzyl)-5-(3,4 - dimetilfenil)pyrazole-3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1.1, from 1.52 g of sodium hydride as a 60% dispersion in oil, 4 g obtained in the preceding stage connection, 70 ml of toluene and 5.8 g of 3-chloro-4-methylbenzylidene (Preparative example 3.2). The resulting product was then purified by powdering in hexane, then suction and washing with hexane. Get 2,84 g of the target product; so pl. = 88oC.

NMR-spectrum (M. D.) is 2.0 to 2.35 (m, 9H); 3,95 (C, ZN); 5,3 (s, 2H); compared to 6.6-7.4 (m, 7H).

G) 1-(3-Chloro-4-methylbenzyl)-5-(3,4-dimetilfenil)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.2, from 1.8 g obtained in the preceding stage connection in 30 ml of ethanol and 0,392 g of KOH in 30 ml of water. Obtain 1.6 g of the target product; so pl. = 163oC.

Preparative example 1.9

1-(3-Chloro-4 - terbisil)-5-(3,4-dimetilfenil)pyrazole-3 - carboxylic acid

A) Methyl ester of 1-(3-chloro-4-terbisil)-5-(3,4-dimetilfenil) pyrazole-3-carboxylic acid

This connection receive according to the method described in stage Prepare g of sodium hydride as a 60% dispersion in oil, and 2.5 g of 3 - chloro-4-ftorangidridy (Preparative example 3.3). The product was then purified by powdering in ethyl acetate, then the suction and drying. Obtain 3.6 g of the target product.

B) 1-(3-Chloro-4-terbisil)-5-(3,4-dimetilfenil)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.2, from 1.6 g obtained in the preceding stage connection in 25 ml of ethanol and 0,481 g of KOH in 10 ml of water. Obtain 1.22 g of the target product.

NMR-spectrum (M. D.): 2,2 (2s, 6H); to 5.35 (s, 2H); compared to 6.6-7.4 (m, 7H).

Preparative example 1.10

1-(4-Methylbenzyl)-5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

A) Sodium salt of methyl-4-(4-chloro-3-were)-2-oxo-4 - oxidant-3-enoate

This connection get the procedure described in stage a of Preparative example 1.1, from 7.6 g of sodium in 100 ml of methanol, at 55.6 g of 4'-chloro-3'-methylacetophenone and 45 ml diethyloxalate in 100 ml of methanol. Get to 85.8 g of the target product.

B) Methyl ester of 5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative examples 1 to 4, on the basis of the data obtained in the previous stage of the compound in 150 ml of acetic acid and 2.9 ml of hydrazinoacetate. After stirring over night at quaday. After drying obtain 13 g of the target product.

C) Methyl ester of 1- (4-methylbenzyl)-5-(4-chloro-3-were) pyrazole-3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1-1, starting from 5 g obtained in the preceding stage connection in 50 ml of toluene, and 1.8 g of sodium hydride as a 60% dispersion in oil, and 4,07 g of 4-methylbenzylamine. Obtain 4.6 g of the target product; so pl. = 98oC.

NMR-spectrum (M. D.): 2,0-2,4 (2s, 6H); and 3.8 (s, 3H); to 5.4 (s, 2H); 6,7-to 7.6 (m, 8H).

G) 1-(4-Methylbenzyl)-5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.2, from 4 g obtained in the previous stage of the compound in 100 ml of ethanol and 0.95 g of KOH in 20 ml of water. Obtain 3.4 g of the target product; so pl. = 180oC.

NMR-spectrum (M. D.): of 2.25 (s, 3H); to 2.35 (s, 3H); to 5.4 (s, 2H); 6,7-to 7.15 (m, 5H); to 7.25 (DD, 1H); 7,4-7,6 (m, 2H).

Following the techniques described in stage (based on the compound obtained in stage B of Preparative example 1.10 and related benzylchloride), then in stage g of Preparative example 1.10, get esters, then acid, described in table 1. Preparative example 1.11: Z= OMe; NMR spectrum-chlorophenyl) pyrazole-3 - carboxylic acid

A) Methyl ester of 1-[1-(2,4-dichlorophenyl)ethyl]-5-(4 - chlorophenyl)pyrazole-3-carboxylic acid

To a suspension of 1.5 g of compound obtained in stage B of Preparative example 1.7, 50 ml of toluene at room temperature and portions add 0.3 g of sodium hydride as a 60% dispersion in oil, then heated at 65oC for 30 minutes. After cooling to room temperature, added dropwise to 1.77 g of 1-(1-bromacil)-2,4-dichlorobenzene (Preparative example 3.4), then refluxed for 5 days. After cooling to room temperature the reaction mixture is poured into 100 ml of a 50% aqueous solution of ammonium chloride cooled to 0oC water. Extracted with ethyl acetate, the organic phase is washed with water, saturated sodium chloride solution, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira mixture of toluene with ethyl acetate (95:5 by volume). Get 1,02 g of the target product.

B) 1-[1-(2,4-Dichlorophenyl)ethyl]-5-(4-chlorophenyl)pyrazole-3 - carboxylic acid

To a solution of 1.02 g obtained in the previous stage of the compound in 20 ml of methanol at room temperature is added a solution of 0.35 g of KOH in 5 ml of water, then boil with reverse, chilling the second acid, suck the precipitation, washed with water and dried in vacuum. Obtain 0.74 g of the target product; so pl. = 80oC.

Preparative example 1.15

1-(3,4-Dichlorobenzyl)-5-(2,6-acid)pyrazole-3 - carboxylic acid

A) Potassium salt of ethyl-4-(2,6-acid)-2 - oxo-4-oxidant-3-enoate

A mixture of 18 g of 2',6'-dimethoxyacetophenone in 54 ml of ethanol is heated to 50oC for 5 minutes, add a solution of 13.4 g of potassium tert-butylate in 72 ml of ethanol. The reaction mixture is heated to boiling point under reflux for 10 minutes added 16.3 ml diethyloxalate and continue to boil under reflux for 1 hour. Distilled 40 ml of ethanol, and then stirred for 2.5 hours while the temperature drops to room temperature, the precipitation is sucked off, washed it with ethanol and dried in vacuum at 60oC. Obtain 31 g of the target product.

B) Methyl ester of 5-(2,6-acid)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.4 on the basis of 4 g obtained in the preceding stage connection, 50 ml of acetic acid and 0.7 ml of hydrazinoacetate. After stirring overnight at room for the ABC washed with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent was partially removed under vacuum. The precipitation is sucked off and dried. Get 2,53 g of the target product.

C) 1-(3,4-Dichlorobenzyl)-5-(2,6-acid)pyrazole - 3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1.1, from 2.5 g obtained in the preceding stage connection, 50 ml of toluene, 0.88 g of sodium hydride as a 60% dispersion in oil, and 2.16 g of 3,4-dichlorobenzamide. After boiling under reflux overnight, the reaction mixture was cooled to room temperature, was added dropwise 50 ml of a 50% aqueous solution of ammonium chloride in water, the precipitation is sucked off and dried. Obtain 1.1 g of the target product.

NMR-spectrum (M. D. ): a 3.5 (s, 6H); 4,8 (very broadened signal, 1H); of 4.95 (s, 2H); and 6.25 (s, 1H); and 6.6 (d, 2H); 6,85 (DD, 1H); to 6.95 (d, 1H); and 7.3 (t, 1H), and 7.4 (d, 1H).

Preparative example 1.16

1-(4-Terbisil)-5-(3,4-dimetilfenil)pyrazole-3-carboxylic acid

A) Methyl ester of 1-(4-terbisil)-5-(3,4-dimetilfenil)- pyrazole-3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1.1, from 2.3 g of the compound obtained in stage B of Preparative example 1.8, 50 mproduct; so pl. = 93oC.

NMR-spectrum (M. D.): 2,25 (2s, 6H); and 3.8 (s, 3H); to 5.4 (s, 2H); 6,85 (s, 1H); the 6.9 and 7.3 (m, 7H).

B) 1-(4-Terbisil)-5-(3,4-dimetilfenil)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.14, based on 1 g of the obtained in the preceding stage connection, 15 ml of methanol, 0,406 g of KOH and 15 ml of water. Get 0,94 g of the target product; so pl. = 141oC.

NMR-spectrum (M. D.): 2 (2s, 6H); 3,4 (ush.s, 1H); to 5.35 (s, 2H); 6.75 in (s, 1H); of 6.8 to 7.3 (m, 7H).

Preparative example 1.17

1-(2,4-Dichlorobenzyl)-5-(4-were)pyrazole-3-carboxylic acid

A) Methyl ester of 1-(2,4-dichlorobenzyl)-5-(4-were - pyrazole-3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1.1, from 2.5 g of compound obtained in stage B of Preparative example 1.1, 1 g of sodium hydride as a 60% dispersion in oil, 50 ml of toluene and 2.3 g of 2,4-dichlorobenzaldehyde. Get 2,53 g of the target product; so pl. = 105oC.

B) 1-(2,4-Dichlorobenzyl)-5-(4-were)pyrazole-3 - carboxylic acid

To a suspension of 1.5 g obtained in the preceding stage connection in 15 ml of methanol at room temperature is added a solution of 0.5 g of KOH in 15 ml of water, then boil the mixture of 1 N. hydrochloric acid with ice, the precipitated precipitate is sucked off, washed with water and dried in vacuum. Obtain 1.4 g of the target product.

NMR-spectrum (M. D.): 2,3 (s, 3H); of 5.45 (s, 2H); and 6.6 to 7.7 (m, 8H); 12,85 (ush.s, 1H).

Preparative example 1.18

1-(4-active compounds)-5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

A) Methyl ester of 1-(4-active compounds)-5-(4-chloro-3-were) pyrazole-3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1.1, from 2.5 g of the compound obtained in stage B of Preparative example 1.10, 50 ml of toluene, 0.88 g of sodium hydride as a 60% dispersion in oil, and 2 g of 4-ethylbenzylamine (Preparative example 3.5). After hydrolysis with 50% aqueous solution of ammonium chloride, then decanting, the organic phase is concentrated in vacuo. The residue is extracted with ethyl acetate, the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Get 2,63 g of the target product.

B) 1-(4-active compounds)-5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

This credituse connection stage in 20 ml of methanol and 0.57 g of KOH in 20 ml of water. Obtain 2.2 g of the target product.

NMR-spectrum (M. D.): 1.1 (t, 3H); 2,3 (s, 3H); 2,5 (multiplet, 2H); to 5.4 (s, 2H); of 6.7 to 7.7 (m, 8H); 12,9 (ush.s, 1H).

Preparative example 1.19

1-(3,4-Dichlorobenzyl)-5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

To a suspension of 2.5 g of compound obtained in stage B of Preparative example 1.10, 25 ml of toluene at room temperature and added in several portions 0.88 g of sodium hydride as a 60% dispersion in oil, then the reaction mixture is heated at 65oC for 1 hour. After cooling to room temperature was added dropwise a solution of 2.4 g of 3,4-dichlorobenzaldehyde in 25 ml of toluene, and then refluxed overnight. The reaction mixture is cooled to room temperature, the precipitation is sucked off and dried. Receive 2 g of the target product, used without further purification.

Preparative example 1.20

1-(2,4-Dichlorobenzyl)-5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

A) Methyl ester of 1-(2,4-dichlorobenzyl)-5-(4-chloro-3-were) pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Preparative example 1.18, based on 2.5 g of the compound obtained in stage B of Preparative example 1.10, 25 ml indicate 0,86 g of the target product.

B) 1-(2,4-Dichlorobenzyl)-5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.17, based on 0.5 g obtained in the preceding stage connection in 15 ml of methanol and 0,205 g of KOH in 15 ml of water. Obtain 0.31 g of the target product.

NMR-spectrum (M. D.): of 2.25 (s, 3H); to 5.4 (s, 2H); of 6.6 to 7.6 (m, 7H); 3,3 (DOH:1H).

See Overhauser effect (N. O. E.) between the benzyl protons (R4= R5=H) and protons (g2=g6=N.

Preparative example 1.21

1-(4-Methylbenzyl)-5-(3,4-dichlorophenyl)pyrazole-3-carboxylic acid

A) Sodium salt of methyl-4-(3,4-dichlorophenyl)-2-oxo-4 - oxidant-3-enoate

15,17 g of sodium are dissolved in 500 ml of methanol. After cooling to room temperature, add 124,97 g 3', 4'-dichloroacetophenone, then the solution is 91 ml diethyloxalate in 400 ml of methanol and stirred for two hours at room temperature. Add 1 l of diethyl ether and stirred for 30 minutes at room temperature. The precipitation is sucked off, washed his diethyl ether and dried. Get 140,77 g of the target product.

B) Methyl ester of 5-(3,4-dichlorophenyl)pyrazole-3-carboxylic acid

This connection produces is soedineniya in 150 ml of acetic acid and 6 ml of a 55% aqueous solution of hydrazine. After stirring over night at room temperature the reaction mixture was poured into ice water, the precipitated precipitate is sucked off and washed with water. After drying gain of 12.9 g of the target product.

C) Methyl ester of 1-(4-methylbenzyl)-5-(3,4-dichlorophenyl) pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Preparative example 1.18, based on 2.5 g obtained in the previous stage of the connection, in 25 ml of toluene, 0.88 g of sodium hydride as a 60% dispersion in oil and 1.9 g of methylbenzylamine in 25 ml of toluene. Gain of 0.82 g of the target product.

G) 1-(4-Methylbenzyl)-5-(3,4-dichlorophenyl)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.17, on the basis of 0.7 g obtained in the preceding stage connection in 15 ml of methanol and 0,252 g of KOH in 15 ml of water. Obtain 0.65 g of the target product.

NMR-spectrum (M. D.): 2,2 (s, 3H); to 5.35 (s, 2H); 6,7-7,2 (m, 5H); to 7.4 (DD, 1H); 7,6-7,8 (m, 2H); 12,85 (ush.s, 1H).

Preparative example 1.22

1-(3-Chloro-4-methylbenzyl)-5-(3,4-dichlorophenyl)pyrazole - 3-carboxylic acid

A) Methyl ester of 1-(3-chloro-4-methylbenzyl)-5-(3,4-dichlorophenyl) pyrazole-3-carboxylic acid

This connection get operativnogo example 1.21, in 350 ml of toluene, to 2.18 g of sodium hydride as a 60% dispersion in oil, and 21,96 g of 3-chloro-4-methylbenzylidene (Preparative example 3.2). After crystallization from hexane get 21,79 g of the target product.

B) 1-(3-Chloro-4-methylbenzyl)-5-(3,4-dichlorophenyl)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.17, based on 21,79 g obtained in the preceding stage connection in 59 ml of methanol and 8,93 g of KOH in 50 ml of water. Get 17,43 g of the target product, used without further purification.

Preparative example 1.23

1-(2,4-Dichlorobenzyl)-5-(4-methylthiophenyl)pyrazole-3 - carboxylic acid

A) 4'-Methylthiazolidine

At a temperature of from 0oC to 10oC, and 11.8 ml of acetylchloride was added dropwise to a suspension of 20.4 g of aluminium chloride in 85 ml of chloroform. Then, at a temperature of 0-5oC, was added dropwise 15 ml of thioanisole and stirred for 1.5 hours at room temperature. The reaction mixture was cooled to 0oC and hydrolyzing by adding 100 ml of water. Extracted with chloroform, the organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated in vacuum. After crystallization from ethanol and recrystallization from heptane obtain 10.7 g of Sodium are dissolved in 35 ml of methanol and this solution is quickly added to a suspension of 10.7 g obtained in the preceding stage connection and 9.8 ml of diethyloxalate 80 ml) cooled to 0oC methanol. Stirred for 30 minutes at room temperature, refluxed for 1 hour, then stirred for two hours at room temperature. The reaction mixture is poured into 400 ml of diethyl ether, stirred for 15 minutes, the precipitation is sucked off, washed his diethyl ether and dried. Obtain 12.8 g of the target product.

C) Methyl ester of 5-(4-methylthiophenyl)pyrazole-3-carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.1, from 15 g obtained in the preceding stage connection in 140 ml of acetic acid and 7 ml of a 55% aqueous solution of hydrazine. After stirring over night at room temperature the reaction mixture was poured into a mixture of ice water, the precipitated precipitate is sucked off and washed with water. After drying in vacuum over KOH receive 12,96 g of the target product.

D) Methyl ester of 1-(2,4-dichlorobenzyl)-5-(4-methylthiophenyl) pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Preparative example 1.18, starting from 5 g obtained in the previous stage of the compound in 100 ml of toluene, 1,063 g of sodium hydride as a 60% dispersion in which thiophenyl)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.14, on the basis of 1.52 g obtained in the preceding stage connection in 30 ml of methanol and 0.7 g of KOH in 25 ml of water. After drying in vacuo get 1.4 g of the target product.

NMR-spectrum (M. D.): a 2.5 (s, 3H); to 5.4 (s, 2H); of 6.6 to 7.6 (m, 8H); 12,8 (ush.s, 1H).

Preparative example 1.24

1-(2,4-Dichlorobenzyl)-5-(4-tryptophanyl)pyrazole-3 - carboxylic acid

A) Sodium salt of methyl-4-(4-triptoreline)-2-oxo-4 - oxidant-3-enoate

This connection get the procedure described in stage a of Preparative example 1.4, based on 4'-triftoratsetofenona.

B) Methyl ester of 5-(4-triptoreline)pyrazole-3-carboxylic acid

This connection receive according to the method described in stage In Preparative example 1.23, based on 6,37 g obtained in the preceding stage connection in 50 ml of acetic acid and 3 ml of a 55% aqueous solution of hydrazine. Get 5,43 g of the target product.

C) Methyl ester of 1-(2,4-dichlorobenzyl)-5-(4 - tryptophanyl)pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Preparative example 1.18, based on 2.5 g obtained in the preceding stage connection in 150 ml of toproduct.

G) 1-(2,4-Dichlorobenzyl)-5-(4-tryptophanyl)pyrazole-3 - carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.14, based on 1.6 g obtained in the preceding stage connection in 30 ml of methanol and 0.63 g of KOH in 30 ml of water. Obtain 1.5 g of the target product.

NMR-spectrum (M. D.): the 5.45 (s, 2H); 6,85 (d, 1H); to 6.95 (s, 1H); and 7.3 (DD, 1H); 7.5 (d, 1H); 7,55-7,8 system (AA'- BB', 4H); 12,9 (ush.s, 1H).

Preparative example 1.25 1-[1-(3,4-Dichlorophenyl)ethyl] -5- (4-were)pyrazole-3-carboxylic acid

A) Methyl Efir-[1-(3,4-dichlorophenyl)ethyl]-5-(4-were) pyrazole-3-carboxylic acid

To a suspension of 2.5 g of compound obtained in stage B of Preparative example 1.1, in 25 ml of toluene at room temperature and portions add 1 g of sodium hydride as a 60% dispersion in oil, then heated at 65oC for 1 hour. After this was added dropwise a solution of 3 g of 1-(1-bromacil)-3,4 - dichlorobenzene (Preparative example 3.6) in 25 ml of toluene, then refluxed overnight. Cooled to 0oC and added dropwise 100 ml of a 50% aqueous solution of ammonium chloride. After decanting, the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent vapour:25 by volume). Obtain 1.6 g of the target product.

B) 1-[1-(3,4-Dichlorophenyl)ethyl]-5-(4-were)pyrazole-3 - carboxylic acid

To a suspension of 1.4 g obtained in the preceding stage connection in 15 ml of methanol at room temperature is added a solution of 0.5 g of KOH in 15 ml of water, then refluxed for two hours. After removing the vacuum of methanol, the reaction mixture was poured into a mixture of 1 N. hydrochloric acid with ice, the precipitated precipitate is sucked off, washed with water and dried in vacuum over KOH. Earn 1.25 g of the target product.

NMR-spectrum (M. D.): 1,85 (d, 3H) and 2.4 (s, 3H); 5,7 (CH, 1H); 6,85 (s, 1H); 7,05 (DD. 1H); to 7.2-7.45 (m, 5H); the 7.65 (d, 1H); 12,95 (ush.s, 1H).

Preparative example 1.26

1-[1-(4-Were)ethyl] -5-(4-chloro-3-were)pyrazole - 3-carboxylic acid

A) Methyl ester of 1-[1-(4-were)ethyl] -5-(4-chloro-3 - were)pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Preparative example 1.25, based on 2.5 g of the compound obtained in stage B of Preparative example 1.10, 25 ml of toluene, 0.88 g of sodium hydride as a 60% dispersion in oil and 2.3 g of 1- (1-bromacil)-4-methylbenzene (Preparative example 3.7) in 25 ml of toluene. After adding an aqueous solution of chloride IMMonitor washed with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (75:25 by volume). Obtain 0.7 g of the target product.

B) 1-[1-(4-Were)ethyl]-5-(4-chloro-3-were) pyrazole-3-carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.25, on the basis of 0.7 g obtained in the preceding stage connection in 15 ml of methanol and a solution of 0.28 g of KOH in 15 ml of water. Get to 0.63 g of the target product, used without further purification.

Preparative example 1.27

1-[1-(3,4-Dichlorophenyl)ethyl]-5-(4-chloro-3-were) pyrazole-3-carboxylic acid

A) Methyl ester of 1-[1-(3,4-dichlorophenyl)ethyl] -5-(4-chloro-3 - were)pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Preparative example 1.25, on the basis of 3.0 g of the compound obtained in stage B of Preparative example 1.10, 25 ml of toluene, 1 g of sodium hydride as a 60% dispersion in oil and 3 g of 1-(1-bromacil)-3,4-dichlorobenzene (Preparative example 3.6) in 25 ml of toluene. After adding an aqueous solution of ammonium chloride and decanting, the organic phase is concentrated in vacuo, the residue is treated and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Obtain 1.4 g of the target product.

B) 1-[1-(3,4-Dichlorophenyl)ethyl] -5-(4-chloro-3-were) pyrazole-3-carboxylic acid

This connection get the procedure described in stage B of Preparative example 1.25, based on 1 g of the obtained in the previous stage of the compound in 20 ml of methanol and a solution of 0.40 g of KOH in 20 ml of water. Obtain 0.96 g of the target product.

NMR-spectrum (M. D.): 1,8 (d, 3H); to 2.35 (s, 3H); 5,7 (CH, 1H); of 6.7 to 7.7 (m, 7H); 12,9 (ush.with 1H).

See Overhauser effect (N. O. E.) between the benzyl proton (R4=H) and protons (g2=g6=H.

Preparative example 1.28

1-[1-(4-Were)propyl] -5-(4-chloro-3-were) pyrazole-3-carboxylic acid

A) N,N'- Dipropylacetate

58 g of Propionic aldehyde cooled to 0oC add 10 ml of water, then added dropwise to 19.9 ml of hydrazinoacetate, keeping the temperature below 10oC. then added in several portions of 67.5 g of KOH in tablets and the reaction mixture is left to stand overnight at room temperature. After decanting, the organic phase is distilled under reduced pressure. Get 24,37 g of the target product; so bales. = 48 the wrath of bromide in diethyl ether is heated to the boiling temperature under reflux, in nitrogen atmosphere, and then was added dropwise a solution of 10 g obtained in the preceding stage connection in 40 ml of anhydrous diethyl ether and stirred overnight at room temperature. After cooling the reaction mixture to 5oC add aqueous saturated solution of ammonium chloride, decanted, extracted with diethyl ether, the combined organic phases are dried over magnesium sulfate and the solvent is evaporated in vacuum. Get 6 g of the target product; so bales. = 102-103oC at 20 PA; nD20= 1,5180.

C) [1-(4-Were)propyl]hydrazinoacetate

To a solution 4,78 g of oxalic acid in 20 ml ethanol and 20 ml of diethyl ether is added a solution of 6 g obtained in the preceding stage connection in 5 ml of diethyl ether and incubated over night at 0 - 5oC. the Resulting crystalline product is sucked off and washed his diethyl ether. Obtain 1.84 g of the target product.

D) Methyl ester of 1-[1-(4-were)propyl] -5-(4-chloro-3 - were)pyrazole-3-carboxylic acid

To a solution of 2 g of compound obtained in stage a of Preparative example 1.10, 100 ml of water and 100 ml of ethanol at room temperature is added a solution of 1.84 g obtained in the preceding stage connection is diethyl ether, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. The residue is treated with hexane, filtered off the insoluble part and the filtrate concentrated in vacuo. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Obtain 1.12 g of the target product.

D) 1-[1-(4-Were)propyl] -5-(4-chloro-3-were) pyrazole-3-carboxylic acid

To a solution of 1.1 g obtained in the preceding stage connection in 40 ml ethanol at room temperature, add a solution of 0.47 g of KOH in 10 ml of water, then refluxed for three hours. Concentrated in vacuo, the residue is treated with 50 ml of water, acidified to pH 2 by addition of 6 n hydrochloric acid, the precipitation is sucked off, washed with water and dried. Get 0,89 g of the target product.

Preparative example 1.29

1-[1-Methyl-1-(4-were)ethyl] -5-(4-chloro-3-were) pyrazole-3-carboxylic acid

A) N,N'-Diisopropylethylamine

This connection get the procedure described in stage a of Preparative example 1.28, based on 92 g of acetone, 20 ml of water, 39.7 hydrazinoacetate and 135 g of KOH. Get 66 g of the target product; so bales is RA n-talismani bromide in diethyl ether is heated to the boiling temperature under reflux, in nitrogen atmosphere, and then was added dropwise a solution 8,46 g obtained in the preceding stage connection in 200 ml of anhydrous diethyl ether and continue boiling under reflux for 5 days. After cooling to 5oC add aqueous saturated solution of ammonium chloride, decanted, extracted with diethyl ether, the combined organic phases are dried over sodium sulfate and the solvent is evaporated in vacuum. The residue is distilled under reduced pressure. Get 6,45 g of the target product; so bales. =95oC when 266,6 PA.

C) [1-Methyl-1-(4-were)ethyl]hydrazinoacetate

To a solution of 5,12 g of oxalic acid in 24 ml of ethanol and 24 ml of diethyl ether is added a solution of 6.45 g obtained in the preceding stage connection in 5 ml of diethyl ether and incubated over night at room temperature. The resulting crystalline product is sucked off and washed it with hexane. Get to 2.57 g of the target product.

D) Methyl ester of 1-[1-methyl-1-(4-were)ethyl]-5-(4 - chloro-3-were)pyrazole-3-carboxylic acid

To a solution of 2.66 g of the compound obtained in stage a of Preparative example 1.10, 600 ml of water and 1 l of ethanol at room temperature, add a solution of 2.54 g obtained as m left to stand for 24 hours. The precipitation is sucked off, washed it with hexane and dried. Gain of 3.46 g of the target product.

D) 1-[1-Methyl-1-(4-were)ethyl]-5-(4-chloro-3 - were)pyrazole-3-carboxylic acid

To a solution of 3.3 g obtained in the preceding stage connection in 80 ml of ethanol at room temperature is added a solution of 1.44 g of KOH in 20 ml of water, then refluxed for three hours. Filtered off the insoluble part and the filtrate was concentrated in vacuo to a volume of 20 ml. Add 30 ml of ice water, acidified to pH 3.5 by addition of 1 N. hydrochloric acid, decanted, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. Get 3,15 g of the target product.

Preparative example 1.30

1-(2,4-Dichlorobenzyl)-5-(4-chlorophenyl)-4-methylpyrazole-3 - carboxylic acid

A) a Lithium salt of ethyl-4-(4-chlorophenyl)-3-methyl-4-oxido-2 - exabot-3-enoate

In nitrogen atmosphere, 154 ml of 1 M solution of lithium salt hexamethyldisilazane in tetrahydrofuran is added to 120 ml) cooled to 0oC cyclohexane. Then at a temperature of 0oC for 30 minutes was added dropwise a solution of 21.6 g of 4'-chloropropiophenone in 60 ml of cyclohexane and stirred for 3 hours at room temperature.aces at room temperature. The precipitation is sucked off, washed it with cyclohexane and dried. Get 31,3 g of the target product.

B) Ethyl ester of 5-(4-chlorophenyl)-4-methylpyrazole-3-carboxylic acid

To a solution of 15 g obtained in the previous stage of the compound in 100 ml of acetic acid at room temperature was added dropwise 2,04 ml hydrazinoacetate, then refluxed for 5 hours and stirred overnight at room temperature. The reaction mixture was poured into a mixture of ice water, the precipitated precipitate is sucked off, washed with water, then hexane and dried. Get 11,47 g of the target product.

B) Ethyl ester of 1-(2,4-dichlorobenzyl)-5-(4-chlorophenyl)-4 - methylpyrazole-3-carboxylic acid

To a solution of 2.17 g obtained in the preceding stage connection in 25 ml of toluene at room temperature and added in several portions to 0.72 g of sodium hydride as a 60% dispersion in oil, then heated at 65oC for 1 hour. After cooling to room temperature was added dropwise a solution of 2.28 g of 2,4-dichlorobenzaldehyde in 25 ml of toluene, and then refluxed for 20 hours. After cooling to room temperature, add aqueous saturated solution of ammonium chloride,the solvent is evaporated in vacuum. The residue is extracted with ethyl acetate, the organic phase is washed with saturated sodium hydrogen carbonate solution, the buffer solution with pH 2 water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (75: 25 by volume). Obtain 1.10 g of the target product; so pl. = 82oC.

NMR-spectrum (M. D.): 1,2 (t, 3H); 2,0 (s, 3H); 4,2 (KD, 2H); 5,3 (s, 2H); 6,7 (d, 1H); 7,15-to 7.6 (m, 6H).

See Overhauser effect (N. O. E.) between the benzyl protons (R4= R5=H) and protons (g2=g6=N.

G) 1-(2,4-Dichlorobenzyl)-5-(4-chlorophenyl)-4-methylpyrazole - 3-carboxylic acid

To a solution of 0.8 g obtained in the preceding stage connection in 50 ml of ethanol at room temperature add a solution 0,166 g of KOH in 10 ml of water, then refluxed for four hours. Concentrated in vacuo, the residue is treated with water, filtered off the insoluble portion, the filtrate is acidified to pH 2 by adding 6 N. hydrochloric acid, the precipitated precipitate is sucked off, washed with water and dried. Obtain 0.73 g of the target product.

Preparative example 1.31

1-(3,4-Dichlorobenzyl)-5-(4-chlorophenyl)-4-methylpyrazole

This connection receive according to the method described in stage In Preparative example 1.30, on the basis of 2.17 g of the compound obtained in stage B of Preparative example 1.30, in 25 ml of toluene, to 0.72 g of sodium hydride as a 60% dispersion in oil, and to 2.99 g of 3,4-dichlorobenzaldehyde in 25 ml of toluene. Get to 1.87 g of the target product; so pl. = 117,5oC.

NMR-spectrum (M. D.): a 1.25 (t, 3H); is 2.05 (s, 3H); 4.25 in (KD, 2H); 5,3 (s, 2H); 6.8 cm (DD, 1H); to 7.15 (s, 1H); and 7.3 (d, 2H); 7,4-7,6 (m, 3H).

See Overhauser effect (N. O. E.) between the benzyl protons (R4= R5=H) and protons (g2=g6=H.

B) 1-(3,4-Dichlorobenzyl)-5-(4-chlorophenyl)-4-methylpyrazole-3 - carboxylic acid

This connection receive according to the method described in stage g of Preparative example 1.30, on the basis of 1.5 g obtained in the preceding stage connection in 50 ml of ethanol and 0.3 g of KOH in 10 ml of water. Obtain 1.31 g of the target product.

Preparative example 1.32

1-(3-Chloro-4-methylbenzyl)-5-(4-chlorophenyl)-4-methylpyrazole - 3-carboxylic acid

To a solution of 2.17 g of the compound obtained in stage B of Preparative example 1.30, 100 ml of toluene at room temperature and added in several portions to 0.72 g of sodium hydride as a 60% dispersion in oil, then heated at 65oC for 1 h the military refrigerator for 20 hours. After cooling to room temperature, add aqueous saturated solution of ammonium chloride, decanted, the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent is evaporated in vacuum. The residue is extracted with ethyl acetate, the organic phase is washed with saturated sodium hydrogen carbonate solution, the buffer solution with pH 2 water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The residue is treated with a mixture of cyclohexane with ethyl acetate (75:25 by volume), the precipitate is sucked off and get to 1.38 g of crude product. 0.35 g thus obtained product is dissolved in ethyl acetate, add cyclohexane until the precipitation and the precipitate is sucked off. Obtain 0.17 g of purified target product; so pl. = 162oC.

NMR-spectrum (M. D.): 1,95-2,6 (m, 6H); and 5.2 (s, 2H); and 6.6 to 7.7 (m, 7H); 12,85 (ush.s, 1H).

See Overhauser effect (N. O. E.) between the benzyl protons (R4= R5=H) and protons (g2=g6=H.

Preparative example 1.33

1-(4-Methylbenzyl)-5-(4-chloro-3-were)-4-methylpyrazole - 3-carboxylic acid

A) 4'-Chloro-3'-methylpropiophenone

To a mixture of 18 ml of toluene and an increase of 22.7 g of aluminium chloride are added dropwise 16 g propionitrile, then naked is up in a mixture of 100 ml of concentrated hydrochloric acid and ice, extracted with diethyl ether, the organic phase is washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and the solvent is evaporated in vacuum. The residue is distilled under reduced pressure. Obtain 1.27 g of the target product, which crystallizes; so bales. = 95oC at 5 PA.

B) Lithium salt of ethyl-4-(4-chloro-3 - were)-3-methyl-4 - oxido-2-exabot-3-enoate

This connection get the procedure described in stage a of Preparative example 1.30, on the basis of 50 ml of 1 M solution of lithium salt hexamethyldisilazane in tetrahydrofuran, 40 ml of cyclohexane, 10 g obtained in the preceding stage connection in 70 ml of cyclohexane and 9.8 g of diethyloxalate. After stirring over night at room temperature the reaction mixture was concentrated in vacuo, the residue treated with diethyl ether and the solvent is evaporated in vacuum. The residue is treated with heptane and the precipitation is sucked off. Receive 15 g of the target product.

C) Ethyl ester 5-(4-chloro-3-were)-4-methylpyrazole - 3-carboxylic acid

A solution of 15 g obtained in the preceding stage connection in 150 ml of acetic acid cooled to 5oC, was added dropwise 2.5 ml of hydrazinoacetate, then boiled with milk products is ü poured into a mixture of ice water, extracted with ethyl acetate, the organic phase is washed three times with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The residue is treated with diisopropyl ether, the precipitated precipitate is sucked off. Washed it diisopropyl ether and dried. Get 7,88 g of the target product.

D) Ethyl ester 1-(4-methylbenzyl)-5-(4-chloro-3-were) -4-methylpyrazole-3-carboxylic acid

To a suspension of 5 g obtained in the preceding stage connection in 70 ml of toluene at room temperature and added in several portions of 0.98 g of sodium hydride as a 60% dispersion in oil, then heated at 65oC for 1 hour. After cooling to room temperature was added dropwise 3.7 g of 4-methylbenzylamine, then refluxed overnight. After cooling to room temperature, add 50% aqueous solution of ammonium chloride, decanted and the organic phase concentrated in vacuo. The residue is extracted with ethyl acetate, the organic phase is washed twice with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with utilized the pyrazole-3-carboxylic acid

To a solution of 2 g of the obtained in the previous stage of the compound in 20 ml of ethanol at room temperature add a solution 0,439 g of KOH in 20 ml of water, then refluxed for three hours. After cooling to room temperature the reaction mixture was poured into a mixture of 1 N. hydrochloric acid with ice, the precipitated precipitate is sucked off, washed with water and dried in vacuum. Obtain 1.8 g of the target product.

NMR-spectrum (M. D.): 2-2,4 (m, 9H); and 5.2 (s, 2H); 6,7-to 7.6 (m, 7H); 12,65 (ush.s, 1H)

Preparative example 1.34

1-(3,4-Dichlorobenzyl)-5-(4-chloro-3-were)-4 - methylpyrazole-3-carboxylic acid

A) Ethyl ester of 1-(3,4-dichlorobenzyl)-5-(4-chloro-3 - were)-4 - methylpyrazole-3-carboxylic acid

This connection receive according to the method described in stage g of Preparative example 1.33, based on 2.5 g of the compound obtained in stage In Preparative example 1.33, 50 ml of toluene, 0.8 g of sodium hydride as a 60% dispersion in oil, and 2.4 g of 3,4-dichlorobenzamide. After hydrolysis by adding water to a 50% aqueous solution of ammonium chloride the organic phase is decanted, filtered off the insoluble part and the filtrate concentrated in vacuo. The residue is extracted with ethyl acetate, the organic phase is washed Residue chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Get 3 g of the target product.

B) 1-(3,4-Dichlorobenzyl)-5-(4-chloro-3-were)-4 - methylpyrazole-3-carboxylic acid

This connection receive according to the method described in stage D of Preparative example 1.33, based on 3 g obtained in the previous stage of the compound in 20 ml of ethanol and 0.56 g of KOH in 20 ml of water. Obtain 2.7 g of the target product.

NMR-spectrum (M. D.): 2 (s, 3H); 2,3 (m, 3H); and 5.2 (s, 2H); 6,7-to 7.6 (m, 6H); 12,65 (ush.s, 1H).

Preparative example 1.35

1-(4-Chloro-3-methylbenzyl)-5-(4-chlorophenyl)-4-(ethoxymethyl) pyrazole-3-carboxylic acid

A) Ethyl ester of 1-(tert.-butoxycarbonyl)-5-(4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid

To a solution of 6 g of compound obtained in stage B of Preparative example 1.30, 150 ml of dioxane is added to 4.62 ml of triethylamine, to 6.57 g of di-tert.BUTYLCARBAMATE and 1.18 g of sodium hydride as a 60% dispersion in oil, then stirred for 72 hours at room temperature. Filtered off the insoluble part and the filtrate concentrated in vacuo. The residue is treated with cyclohexane, the precipitation is sucked off, washed it with cyclohexane and dried. Get 6,23 g of the target product.

B) Ethyl e is built in the previous stage of the compound in 150 ml of tetrachlorophenol add 3,18 g of N-bromosuccinimide and 0.02 g of dibenzoylperoxide, then refluxed overnight. Filtered off the insoluble part and the filtrate concentrated in vacuo. The residue is treated with cyclohexane, decanted and the solvent is evaporated in vacuum. Get 8,72 g of the desired product in the form of butter.

C) Ethyl ester 5-(4-chlorophenyl)-4-(ethoxymethyl)pyrazole-3 - carboxylic acid

To 100 ml of ethanol is added to 0.23 g of sodium, and then, after dilution, was added dropwise 4.5 g obtained in the preceding stage connection and refluxed over night. The reaction mixture was concentrated in vacuo and the residue chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (60: 40 by volume). Gain of 2.26 g of the target product.

D) Ethyl ester of 1-(3-chloro-4-methylbenzyl)-5-(4-chlorophenyl) -4-(ethoxymethyl)pyrazole-3-carboxylic acid

To a solution of 1.65 g obtained in the preceding stage connection in 50 ml of toluene at room temperature and added in several portions 0,254 g of sodium hydride as a 60% dispersion in oil, then heated at 65oC for 1 hour. After cooling to room temperature was added dropwise 1.7 g of 3-chloro-4-methylbenzylidene, then refluxed for 20 hours. After ohlord is OK extracted with ethyl acetate, the organic phase is washed with a saturated solution of ammonium chloride, a buffer solution with pH 2 water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (75:25 by volume). Get 0,90 g of the product, which again chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Obtain 0.24 g of the target product.

D) 1-(4-Chloro-3-methylbenzyl)-5-(4-chlorophenyl)-4- (ethoxymethyl)pyrazole-3-carboxylic acid

To a solution of 0.23 g obtained in the previous stage of the compound in 10 ml of ethanol at room temperature add a solution 0,088 g of KOH in 10 ml of water, then refluxed for three hours. Concentrated in vacuo until a volume of 10 ml, add 10 ml of water, acidified to pH of 2.5 by adding 1 N. hydrochloric acid, the precipitated precipitate is sucked off and dried. Obtain 0.21 g of the target product.

Preparative example 1.36

1-(5-Clorinda-1-yl)-5-(4-chlorophenyl)pyrazole-3-carboxylic acid

To a suspension of 2.5 g of compound obtained in stage B of Preparative example 1.7, 20 ml of toluene are added in several portions 0.88 g of sodium hydride as a 60% dispersion solution of 2.3 g of 1-bromo-5-floridana (Preparative example 3.8) in 10 ml of toluene and refluxed over night. The reaction mixture is cooled to 5oC, was added dropwise 20 ml of aqueous 50% solution of ammonium chloride, decanted and the organic phase concentrated in vacuo. The residue is extracted with ethyl acetate, the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. Obtain 1.04 g of the target product, used without further purification.

Preparative example 1.37

1-(4-Methoxybenzyl)-5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

A) Methyl ester of 1-(4-methoxybenzyl)-5-(4-chloro-3-were) pyrazole-3-carboxylic acid

To a suspension of 2.5 g of compound obtained in stage B of Preparative example 1.10, 25 ml of toluene at room temperature and added in several portions of 0.53 g of sodium hydride as a 60% dispersion in oil, then heated at 65oC for 1 hour. After cooling to room temperature was added dropwise a solution of 1.7 g of 4-methoxybenzylamine in 25 ml of toluene, and then refluxed for 20 hours. After cooling to room temperature, add 20 ml of aqueous 50% solution of ammonium chloride, decanted and the organic phase is evaporated in vacuum. The residue is extracted with ethyl acetate, organisat in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80: 20 by volume). Gain of 1.03 g of the target product, used without further purification.

B) 1-(4-Methoxybenzyl)-5-(4-chloro-3-were)pyrazole-3 - carboxylic acid

To a solution of 1.03 g obtained in the previous stage of the compound in 20 ml of methanol at room temperature, add a solution of 0.23 g of KOH in 20 ml of water, then refluxed for three hours. After cooling to room temperature the reaction mixture was poured into a mixture of 1 N. hydrochloric acid with ice, extragere diethyl ether, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. Obtain 0.8 g of the target product, used without further purification.

Preparative example 1.38

1-(2,4-Dichlorobenzyl)-3-(4-chlorophenyl)pyrazole-5-carboxylic acid

A) Methyl ester of 1-(2,4-dichlorobenzyl)-3-(4-chlorophenyl) pyrazole-5-carboxylic acid

To a solution of 0.8 g of the compound obtained in stage B of Preparative example 1.7, in 15 ml of dimethylformamide at room temperature and added in several portions 0.16 g of sodium hydride as a 60% dispersion in oil, and stirred for 30 minutes at room those whom methylformamide, then stirred for 16 hours at room temperature. The reaction mixture was poured into ice water, the aqueous phase washed with dichloromethane, the precipitate is sucked off white, washed with water and dried. Get 0,86 g of the target product; so pl. = 120oC.

B) 1-(2,4-Dichlorobenzyl)-3-(4-chlorophenyl)pyrazole-5 - carboxylic acid

To a solution of 0.85 g obtained in the preceding stage connection in 15 ml of methanol is added a solution of 0.3 g of KOH in 5 ml of water, then refluxed for three hours. The reaction mixture was poured into 100 ml ice water, the precipitated precipitate is sucked off, washed with water and dried in vacuum. Get 0,79 g of the target product; so pl. = 218oC.

Preparative example 2.1

(1S)-endo-Amino-1,3 .3m-trimethylbicyclo[2.2.1]heptahydrate

A) (1S)-1,3 .3m-Trimethylbicyclo[2.2.1]heptane-2-he-oxime

To a solution of 38.1 g of (1S)-(+)-fenchone in 120 ml of methanol at room temperature is added a solution of 23 g of hydroxylaminopurine and 41 g of sodium acetate in 200 ml of water, then refluxed for 48 hours. After cooling to room temperature, the precipitation is sucked off, washed with water and dried in vacuum. Get 41 g calitri room temperature and a pressure of 6 bar within 48 hours hydronaut a mixture of 8 g obtained in the preceding stage connection and 0.8 g of platinum oxide in 700 ml of ethanol and 20 ml of chloroform. The catalyst is filtered off on celiteand the filtrate concentrated in vacuo. The residue is treated with diethyl ether and the precipitated precipitate is sucked off. Get 2,61 g of the target product.

2D0= -4,6(c = 1; ethanol)

Preparative example 2.2

(1S)-endo, Exo-Amino-1,3 .3m-Trimethylbicyclo[2.2.1]heptane

A solution of the compound obtained in stage a of Preparative example 2.1, in 70 ml of acetic acid is cooled to 10oC, add 25 g of Raney Nickel and leave the mixture to stand to raise the temperature to room. The mixture is then hydronaut for 24 hours at room temperature and atmospheric pressure. The catalyst is filtered off on celiteto the filtrate is added a mixture of 100 ml of ice water, adjusted pH to 7 by adding concentrated sodium hydroxide solution, extracted with diethyl ether, the organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum. Get 7,37 g of the desired product as oil (endo, Exo-mix).

Preparative example 2.3

(1R)-endo, ecao-Amino-1,3 .3m-trimethylbicyclo[2.2.1] heptane and (1R)-2-imino-1,3 .3m-trimethylbicyclo[2.2.1]heptane

A) (1R)-1,3 .3m-Trimethylbicyclo[2.2.1]heptane-2-he-ofenjoy.

B) (1R)-endo, Exo-Amino-1,3 .3m-trimethylbicyclo[2.2.1] heptane and

(1R)-2-imino-1,3 .3m-trimethylbicyclo[2.2.1]heptane

A solution of 14 g obtained in the previous stage of the compound in 100 ml of acetic acid is cooled to 10oC add 35 g of Raney Nickel and leave the mixture to stand to raise the temperature to room. The mixture is then hydronaut for 24 hours at room temperature and atmospheric pressure. The catalyst is filtered off on celiteadd to the filtrate a mixture of 100 ml of ice water, adjusted pH to 7 by adding concentrated sodium hydroxide solution, extracted with diethyl ether, the organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum. Get 10,77 g of a mixture of target products.

Preparative example 2.4

Akzo(Propylamino)bicyclo[2.2.1]heptahydrate

A) Akzo(Propionamido)bicyclo[2.2.1]heptane

In a bath with ice cooled solution of 15 g Akzo - aminomorpholine and 20.5 ml of triethylamine in 80 ml of dichloromethane, was added dropwise a solution of 11.2 ml propionitrile in 80 ml dichloromethane and stirred overnight at room temperature. After filtering the reaction mixture, the filtrate was washed with aqueous saturated solution guide who Receive 23 g of the target product.

B) Akzo(Propylamino)bicyclo[2.2.1]heptahydrate

To a suspension of 7.6 g of sociallyengaged in 100 ml of tetrahydrofuran was added dropwise a solution of 23 g obtained in the previous stage of the compound in 100 ml of tetrahydrofuran, then refluxed for two hours and stirred overnight at room temperature. The reaction mixture was hydrolized by adding 10 ml of water, then 5 ml of 15% sodium hydroxide solution and 14 ml of water. After stirring for 15 minutes inorganic salts filtered off and the filtrate was concentrated in vacuo. The oil obtained is treated with diisopropyl ether, add up to pH 1 a saturated solution of hydrogen chloride in diethyl ether and precipitated precipitate is sucked off. The residue is treated with ethyl acetate, extracted with water, the aqueous phase is alkalinized to pH 12 by adding 5 n sodium hydroxide solution, extracted with ethyl acetate, the organic phase is washed with water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The resulting product is treated with diisopropyl ether, add up to pH 1 a saturated solution of hydrogen chloride in diethyl ether and precipitated precipitate is sucked off. Get 14 g of the target product; so pl. = 230oC (inania get method described H. Maskill, etc., J. Chem. Soc., Perkin Trans.II, 1369-1376 (1984).

Preparative example 2.6

(1R)-endo-Amino-1,3 .3m-trimethylbicyclo[2.2.1] heptahydrate

In the Parr apparatus at room temperature and a pressure of 8 bar, hydronaut mixture of 15.5 g of compound obtained in stage a of Preparative example 2.3, and 2 g of platinum oxide in 500 ml of ethanol and 14 ml of chloroform. The catalyst is filtered off on celiteand the filtrate concentrated in vacuo. The precipitate is treated with a saturated solution of hydrogen chloride in diethyl ether and the solvent is evaporated in vacuum. The residue is treated with hexane, filtered off the insoluble part and the solvent is removed in vacuum. Get 5,64 g of oil, which crystallizes over time. The resulting crystals are sucked off, treat them hexane, again sucked off and washed them. Gain of 0.85 g of the target product;2D0= +1(C = 1; ethanol).

Preparative example 2.7

2,2,6,6-Tetramethylcyclopentadiene

A) 2,2,6,6-Tetramethylcyclopentadiene

To a solution of 3.4 g 2.2.6.6-tetramethylcyclopentadiene in 20 ml of methanol at room temperature is added a solution of 2.3 g of hydroxylaminopurine and 3.6 g of sodium acetate in 20 ml of water, sitedoc sucked off, washed with water and dried in vacuum. Obtain 1.2 g of the target product.

B) 2,2,6,6-Tetramethylcyclopentadiene

Cooled to 10oC, in nitrogen atmosphere, a solution of 1 g obtained in the preceding stage connection in 30 ml of acetic acid, add 2.5 g of Raney Nickel and leave the temperature to rise to room. The thus obtained mixture hydronaut at room temperature and atmospheric pressure for 24 hours. The catalyst is filtered off on celiteto the filtrate add a mixture of ice water, adjusted pH to 7 by adding concentrated sodium hydroxide solution, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. Get to 0.63 g of the target product.

Preparative example 3.1.

3-Fluoro-4-methylbenzylamine

A) Ethyl ester of 3-fluoro-4-methylbenzoic acid

In a bath with ice cooled and 150 ml of ethanol is added slowly to 10 ml of thionyl chloride, then add 10 g of 3-fluoro-4-methylbenzoic acid and stirred while raising the temperature to room. The reaction mixture is refluxed for two hours, then concentrated in vacuo. g sociallyengaged in 100 ml of tetrahydrofuran is cooled to 0oC, was added dropwise a solution 10,45 g obtained in the preceding stage connection in 50 ml of tetrahydrofuran and stirred until then, until the temperature rises to room temperature. Then the reaction mixture is refluxed for three hours, add 1.5 g of sociallyengaged and continue boiling under reflux for 48 hours. After cooling to room temperature the reaction mixture was hydrolized by adding aqueous saturated solution of ammonium chloride, then decanted and the organic phase is stored. The aqueous phase is extracted with tetrahydrofuran, and then the combined organic phases are dried over magnesium sulfate and the solvent is evaporated in vacuum. Get 7.78 g of target compound in the form of butter.

C) 3-Fluoro-4-methylbenzylamine

A mixture of 7.8 g obtained in the preceding stage connection in 112 ml of 47% aqueous solution of bromoiodide heated at 100oC for two hours. After cooling to room temperature the reaction mixture was extracted with diethyl ether, the organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum. Get of 11.15 g of the desired product in the form of oil, which is used without further purification.

Preparative example 3.3

3-Chloro-4-florantyrone

To a mixture of 5 g of 3-chloro-4-Tortolla in 100 ml of carbon tetrachloride is added 0.05 g of dibenzoylperoxide, then of 6.1 g of N-bromosuccinimide and refluxed for 12 hours. Filtered off the insoluble part and washed it with carbon tetrachloride. The filtrate is washed with water, saturated sodium chloride solution, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. Obtain 7.5 g of the desired product in the form of oil, which is used without further purification.

Preparative example 3.4

1-(1-Bromacil)-2,4-dichlorobenzene

15 ml of a 33% aqueous solution of bromovalerate in acetic acid is cooled to 0oC, was added dropwise 2 ml of 2,4-dichloro-1-(1-hydroxyethyl)benzene and stirred for 30 minutes at 0oC, then 3 hours at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate, the organic phase is washed with aqueous saturated solution hydrocarb in vacuum. Obtain 3.4 g of the target product.

Preparative example 3.5

4-Ethylbenzylamine 15 ml of a 33% aqueous solution of bromovalerate in acetic acid is cooled to 0oC, was added dropwise 5 g of 4-ethylbenzylamine alcohol and stirred for 30 minutes at 0oC, then overnight at room temperature. The reaction mixture is poured into 200 ml ice water, extracted with ethyl acetate, the organic phase is washed with aqueous saturated sodium hydrogen carbonate solution, saturated sodium chloride solution, dried over sodium sulfate and the solvent is evaporated in vacuum. Obtain 5.6 g of the target product.

Preparative example 3.6

1-(1-Bromacil)-3,4-dichlorobenzene

This connection receive according to the method described in Preparative example 3.4 based on 25 ml of a 33% aqueous solution of bromovalerate in acetic acid and 5 g of 3,4-dichloro-1-(1-hydroxyethyl)benzene. Obtain 6.4 g of the target product.

Preparative example 3.7

1-(1-Bromacil)-4-methylbenzoyl

This connection receive according to the method described in Preparative example 3.4 based on 30 ml of 33% aqueous solution of bromovalerate in acetic acid and 7 ml of 1-(1-hydroxyethyl)-4-methylbenzene. Get 9 g of the target product.

Preparative example 3.8

1-BYuT to 0-5oC, add 2.5 ml of concentrated sodium hydroxide solution, then portions of 0.88 g of sodium borohydride and stirred over night at room temperature. The reaction mixture was poured into 100 ml of water, acidified to pH 2 by adding concentrated hydrochloric acid, extracted with ethyl acetate, the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Obtain 2.1 g of the target product.

B) 1-Bromo-5-chlorinda

12 ml of a 33% aqueous solution of bromovalerate in acetic acid is cooled to 0oC, was added dropwise to 2 g obtained in the preceding stage connection, stirred for 30 minutes at 0oC, then 3 hours at room temperature. The reaction mixture is poured into 200 ml ice water, extracted with ethyl acetate, the organic phase is washed with a saturated solution of sodium bicarbonate, saturated sodium chloride solution, dried over sodium sulfate and the solvent is evaporated in vacuum. Obtain 2.8 g of the target product.

Example 1

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] - 1-(3,4-dichlorobenzyl)-5-(4-meth is the notes

To a solution of 5.1 g obtained in Preparative example 1.1 connection in 50 ml of toluene at room temperature type of 1.52 ml of thionyl chloride and then refluxed for four hours and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue treated with diethyl ether and the solvent is evaporated in vacuum. Get to 5.17 g of the desired product in the form of butter.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo - yl]-1-(3,4-dichlorobenzyl)-5-(4-were)pyrazole-3 - carboxamide

To a solution of 0.38 g obtained in Preparative example 2.1 connections and 0,554 ml of triethylamine in 50 ml dichloromethane at room temperature add 0,759 g obtained in the preceding stage connection and stirred over night at room temperature. The reaction mixture was concentrated in vacuo, the residue is extracted with ethyl acetate, the organic phase is washed with saturated sodium hydrogen carbonate solution, the buffer solution with pH 2 water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The residue is treated with hexane, the precipitated precipitate is sucked off and dried. Get to 0.67 g of the target product; so pl. = 137oC,2D0= +1
To a solution of 0.5 g obtained in Preparative example 2.2 connection and 0,364 ml of triethylamine in 50 ml dichloromethane at room temperature was added 1 g of compound obtained in stage a of Example 1, and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue is extracted with ethyl acetate, the organic phase is washed with aqueous saturated sodium hydrogen carbonate solution, the buffer solution with pH 2 water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (75:25 by volume). There are two isomers:

the least polar compound of Example 1;

the most polar, the target connection: obtain 0.08 g, so pl. 101oC.

NMR-spectrum (M. D.): 0,6-2 (m, 16H); 2,3 (s, 3H); of 3.45 (d, 1H); to 5.4 (s, 2H); at 6.8 (s, 1H); 6,9 (DD, 1H); and 7.1 to 7.4 (m, 6H); 7.5 (d, 1H).

Example 3 and Example 4

N-[(1R)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl]-1- (3,4-dichlorobenzyl)-5-(4-were)pyrazole-3-carboxamide (Example C) and N-[(1R)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-Akzo-yl] -1-(3,4 - dichlorobenzyl)-5-(4-were)pyrazole-3-carboxamide (Example 4)

To a solution of 0.5 g of the mixture of compounds obtained in Preparative example 2.3, and 0,364 g triethyleneamine over night at room temperature. The reaction mixture was concentrated in vacuo, the residue is extracted with ethyl acetate, the organic phase is washed with aqueous saturated sodium hydrogen carbonate solution, the buffer solution with pH 2 water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (75:25 by volume). There are different connections:

the least polar compound of Example 3: obtain 0.07 g; so pl. = 130oC;

NMR-spectrum (M. D.): 0,6-1,9 (m, 16H); 2,3 (s, 3H); the 3.65 (d, 1H); to 5.4 (s, 2H); 6,85 (s, 1H); 6,9 (DD, 1H); 7,0 (d, 1H); 7,15 to 7.4 (m, 5H); 7.5 (d, 1H);

connection Example 4: get 0,09 g; so pl. = 121oC;

NMR-spectrum (M. D.): 0,6-2 (m, 16H); 2,3 (s, 3H); 3,4 (d, 1H); to 5.4 (s, 2H); at 6.8 (s, 1H); 6,9 (DD, 1H); and 7.1 to 7.4 (m, 5H); 7.5 (d, 1H).

and the most polar compound: N - [(1R)-1,3 .3m-trimethylbicyclo [2.2.1] hept-2-ilidene] -1-(3,4-dichlorobenzyl)-5-(4-were)pyrazole - 3-carboxamide; get 0,54 g

Example 5

N-[Bicyclo[2.2.1] hept-Akzo-yl] -N-propyl-1-(3,4 - dichlorobenzyl)-5-(4-were)pyrazole-3-carboxamide

To a solution of 0,266 g obtained in Preparative example 2.4 connections and of 0.48 ml of triethylamine in 50 ml dichloromethane at room temperature is added 0.66 g of the compound obtained in stage a of Example 1, and var is irout with ethyl acetate, the organic phase is washed with aqueous saturated sodium hydrogen carbonate solution, the buffer solution with pH 2 water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (70:30 by volume). Obtain 0.5 g of the target product; so pl.=108oC.

Example 6

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1-(3-fluoro-4-methylbenzyl)-5-(4-were)pyrazole-3 - carboxamide

A) the acid chloride of 1-(3-fluoro-4-methylbenzyl)-5-(4 - were)pyrazole-3-carboxylic acid and the acid chloride of 1-(3-fluoro - 4-methylbenzyl)-3-(4-were)pyrazole-5-carboxylic acid

To a solution of 0.9 g of the mixture of compounds obtained in Preparative example 1.3, 50 ml of toluene at room temperature, add 0.3 ml of thionyl chloride and then refluxed for 5 hours and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue treated with diethyl ether and the solvent is evaporated in vacuum. Receive 1 g of a mixture of target products.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl]-1- (3-fluoro-4-methylbenzyl)-5-(4-were)pyrazole-3-carboxamide

To a solution of 0.33 g obtained in Rushing to 0.63 g of a mixture of compounds, obtained in the previous stage, and stirred for 48 hours at room temperature. The reaction mixture was concentrated in vacuo, the residue elute with ethyl acetate, the organic phase is washed with aqueous saturated sodium hydrogen carbonate solution, the buffer solution with pH, water, dried over magnesium sulfate and the solvent is evaporated in vacuum. There are two connections:

the least polar compound of Example 6: get 0.5 g; so pl. = 53oC,2D0= -3,3(C = 1; ethanol).

the most polar: N-[(1S)-1,3 .3m-trimethylbicyclo-[2.2.1] hept-endo-yl]-1-(3-fluoro-4-methylbenzyl)-3-(4-methyl-phenyl) pyrazole-5-carboxamide.

Example 7

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1-(3 - chloro-4-methylbenzyl)-5-(4-methoxyphenyl)pyrazole-3-carboxamide

A) the acid chloride of 1-(3-chloro-4-methylbenzyl)-5-(4 - methoxyphenyl)pyrazole-3-carboxylic acid and the acid chloride of 1- (3-chloro-4-methylbenzyl)-3-(4-methoxyphenyl)pyrazole-5-carboxylic acid

The mixture of these two compounds get through the procedure described in stage a of Example 6, from 1.7 g of the mixture of compounds obtained in Preparative example 1.5, 0.54 ml of thionyl chloride and 50 ml of toluene. Get 1,77 g of a mixture of target products.

B) N-[(1S)-1,3 .3m-Trimethylsilyl according to the method described in stage B of Example 6, on the basis of the mean HDI of 0.531 g obtained in Preparative example 2.1 connection 0,775 ml of triethylamine, 100 ml of dichloromethane and 1 g of a mixture of compounds obtained in the previous stage. Chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (75:25 by volume). There are two connections:

the least polar compound of Example 7: get 0,77 g; so pl. = 116oC;2D0= -1,1(C = 1; ethanol);

the most polar: N - [(1S)-1,3 .3m-trimethylbicyclo-[2.2.1] hept-endo-yl]-1-(3-chloro-4-methylbenzyl)-3-(4-methoxyphenyl) pyrazole-5-carboxamide.

Example 8

N-(adamant-2-yl)-1-(2,4-dichlorobenzyl)-5-(4 - chlorophenyl)pyrazole-3-carboxamide

A) the acid chloride of 1-(2,4-dichlorobenzyl)-5-(4-chlorophenyl) pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 1, from 3.27 to g obtained in Preparative example 1.7 connections, 2.2 ml of thionyl chloride and 60 ml of toluene. Obtain 3.25 g of the desired product which is used without further purification.

B) N-(adamant-2-yl)-1-(2,4-dichlorobenzyl)-5-(4-chlorophenyl) pyrazole-3-carboxamide

A solution of 0.39 g of 2-aminoadamantane and of 0.58 ml of triethylamine in 15 ml of dichloromethane is cooled to 0oC, tell the hours at room temperature. The reaction mixture is poured into 50 ml ice water, after decanting, the organic phase is washed with water, saturated sodium chloride solution, dried over magnesium sulfate and the solvent is evaporated in vacuum. After crystallization, then recrystallization from a mixture of dichloromethane with diisopropyl ether get 0,42 g of the target product; so pl. = 154oC.

Example 9

N-[endo-Bicyclo[3.2.1] Oct-3-yl] -1-(2,4-dichlorobenzyl)-5- (4-chlorophenyl)pyrazole-3-carboxamide

This connection get the procedure described in stage B of Example 8, on the basis of 0.17 g obtained in Preparative example 2.5 connection, 0.3 ml of triethylamine in 10 ml dichloromethane and 0.41 g of compound obtained in stage a of Example 8 in 10 ml of dichloromethane. The resulting product was then purified by chromatography on silica, elwira gradient mixtures of toluene with ethyl acetate (97:3 to 95:5 by volume). Gain of 0.43 g of the target product; so pl.=130oC.

Example 10

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] - 1-[(1R,S)-1-(2,4-dichlorophenyl)ethyl]-5-(4-chlorophenyl) pyrazole-3-carboxamide

A) the acid chloride of 1-[1-(2,4-dichlorophenyl)ethyl]-5-(4-chlorophenyl) pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 1, based on 0,68 what about the product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- [(1R,S)-1-(2,4-dichlorophenyl)ethyl]-5-(4-chlorophenyl)pyrazole-3 - carboxamide

This connection get the procedure described in stage B of Example 8, on the basis of 0.34 g obtained in Preparative example 2.1 connections and 0.5 ml of triethylamine in 15 ml of dichloromethane and 0.72 g obtained in the preceding stage connection in 15 ml of dichloromethane. The resulting product was then purified by chromatography on silica, elwira mixture of toluene with ethyl acetate (96:4 by volume). Obtain 0.84 g of the target product; so pl. = 70oC.

Example 11

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1-(3,4 - dichlorobenzyl-5-(2,6-acid)pyrazole-3-carboxamide

A) the acid chloride of 1-(3,4-dichlorobenzyl-5-(2,6-acid) pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 1, from 1.1 g obtained in Preparative example 1.15 connection, 0.6 ml of thionyl chloride and 25 ml of toluene. Receive 1 g of the target compound.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- (3,4-dichlorobenzyl-5-(2,6-acid)pyrazole-3-carboxamid

This connection get the procedure described in stage B of Example 1, based on 0,303 g obtained in Preparative example 2.1 corbetena. Purify by crystallization from a mixture of cyclohexane to ethyl acetate (7: 25 by volume). Gain of 0.53 g of the target product.

2D0= +1,2(C = 1; ethanol).

Following the techniques described in the previous examples, based on the acid chlorides of the corresponding acids, which in turn is obtained from the described in the Preparative examples, acids, and obtained in Preparative example 2.1 connection, get the connection according to the invention listed in Table 2.

(a) This compound is prepared as in the techniques described in stages a, then B of Example 1. The product was then purified by chromatography on silica, elwira with a mixture of cyclohexane with ethyl acetate (75:25 by volume).

(b) This compound is prepared as in the techniques described in stages a, then B of Example 8. The product was then purified by chromatography on silica, elwira mixture of toluene-ethyl acetate (90:10 by volume).

(C) This compound is prepared as in the techniques described in stages a, then B of Example 1. The product was then purified by chromatography on silica, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume).

(d) This compound is prepared as in the techniques described in stages a, then B will Accept, described in stages a, then B of Example 1. The product was then purified by crystallization from diisopropyl ether.

(f) This compound is prepared as in the techniques described in stages a, then B of Example 32, using obtained in Preparative example 2.1 connection. The product was then purified by chromatography on silica, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume).

(g) This compound is prepared as in the techniques described in stages a, then B of Example 32, using obtained in Preparative example 2.1 connection. After drying over sodium sulfate the solvent was partially removed, the precipitation is sucked off, washed his diethyl ether and dried.

Example 32

N-[(1R)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- (4-methylbenzyl-5-(4-chloro-3-were)pyrazole-3-carboxamide

A) the acid chloride of 1-(4-methylbenzyl-5-(4-chloro-3-were - pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 1, from 2.8 g obtained in Preparative example 1.10 connection, 1.7 ml of thionyl chloride and 50 ml of toluene. Obtain 2.9 g of the target compound.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- (4-methylbenzyl-5-(4-chloro-3-were)piraso ml of dichloromethane at room temperature was added dropwise a solution of 1.6 g obtained in the previous stage of the compound in 20 ml dichloromethane and stirred overnight at room temperature. Concentrated in vacuo, the residue is treated with ethyl acetate, filtered off the insoluble portion, the filtrate was washed with aqueous saturated sodium hydrogen carbonate solution, the buffer solution with pH 2, aqueous saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (75:25 by volume). Obtain 1.08 g of the target product; so pl. = 108oC.

2D0= +0,3C = 1; ethanol).

Example 33

N-[(1R)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-Akzo-yl]-1- (4-methylbenzyl)-5-(4-chloro-3-were)pyrazole - 3-carboxamide

To a solution of 0.4 g of the mixture of compounds obtained in Preparative example 2.3, in 10 ml of dichloromethane added 0.6 ml of triethylamine, and then was added dropwise a solution of 0.66 g obtained in stage a of Example 32 compound in 10 ml dichloromethane and stirred overnight at room temperature. Concentrated in vacuo, the residue is extracted with ethyl acetate, filtered off the insoluble portion, the filtrate is washed two times with aqueous saturated sodium hydrogen carbonate solution, twice with buffer solution with pH 2, twice aqueous saturated solution of sodium chloride, with elwira with a mixture of cyclohexane with ethyl acetate (80: 20 by volume). Get a mixture containing 58% of the compound of Example 33 (form Exo) and 41.6 % of the compound of Example 32 (form endo) (determined by analytical HPLC). Both isomers separated by preparative HPLC: cleaned sample mass of 0.31 g dissolved in 13 ml original eluting funds (A/B=10%/90%) add 9 ml of methanol and 4 ml of acetonitrile. After lyophilization get:

connection Example 33: mass= 0,084 g; purity 100% (analytical HPLC) retention time = 41 minutes;2D0= +0,3(C = 1; ethanol).

NMR-spectrum (M. D.): 0,8-1,15 (3s, 9H); 1.2 to 2 (m, 7H); 2,2-of 2.25 (m, 6H); 3,5 (d, 1H); to 5.4 (s, 2H); of 6.8 to 7.7 (m, 9H);

connection Example 32: mass = 0,056 g; purity 98% (analytical HPLC) retention time = 43.9 minutes.

Example 34

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-Akzo-yl]-1- (4-methylbenzyl)-5-(4-chloro-3-were)pyrazole-3-carboxamide

To a solution of 0,853 g obtained in Preparative example 2.2 compound in 20 ml of dichloromethane added 1.5 ml of triethylamine, and then was added dropwise a solution of 1.6 g obtained in stage a of Example 32 compound in 20 ml dichloromethane and stirred overnight at room temperature. Concentrated in vacuo, the residue is extracted with ethyl acetate, filtered off the insoluble part, with a pH of 2, twice aqueous saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Get a mixture containing 58% of the compound of Example 34 (form Exo) and 37% of the compound of Example 18 (form endo) (determined by analytical HPLC). Both isomers separated by preparative HPLC: cleaned sample weight 0,23 g dissolved in 13 ml original eluting funds (A/B=10%/90%), add 3 ml of methanol and 9 ml of acetonitrile. After lyophilization get:

the compound of Example 34: weight=0.16 g; purity 99.6% of (analytical HPLC) retention time = 34.7 minutes; so pl. = 49oC;2D0= -6,8(C = 1; ethanol).

NMR-spectrum (M. D.): 0,8-1,15 (3s, 9H); 1.2 to 2 (m, 7H); of 2.1-2.4 (m, 6H); 3,5 (d, 1H); 5.4 (s, 2H); of 6.8 to 7.6 (m, 9H);

connection Example 18: mass = of 0.066 g; purity 94.7% of (analytical HPLC) retention time = 37,2 minutes.

Example 35

N-(2,2,6,6-Tetramethylchroman-1-yl)-1-(4-methylbenzyl)-5- (4-chloro-3-were)pyrazole-3-carboxamide

To a solution of 0.25 g) obtained in Preparative example 2.7 compound in 15 ml of dichloromethane added 0.4 ml of triethylamine, and then added dropwise restates temperature. Concentrated in vacuo, the residue is extracted with ethyl acetate, the filtrate is washed two times with aqueous saturated sodium hydrogen carbonate solution, twice with buffer solution with pH 2, twice aqueous saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Obtain 0.1 g of the target product.

Example 36

N-[Bicyclo[2.2.1] hept-Akzo-yl] -1-(3-chloro-4-methylbenzyl)-5- (3,4-dichlorophenyl)pyrazole-3-carboxamide

A) the acid chloride of 1-(3-chloro-4-methylbenzyl)-5-(3,4 - dichlorophenyl)-pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 1 from 10 g obtained in Preparative example 1.22 connection, 5.5 ml of thionyl chloride and 125 ml of toluene. Get 9,41 g of the target product.

B) N-[Bicyclo[2.2.1] hept-Akzo-yl] -1-(3-chloro-4-methylbenzyl) -5-(3,4-dichlorophenyl)pyrazole-3-carboxamide

To a solution of 0,411 g Akzo-aminomorpholine and 1 ml of triethylamine in 15 ml of dichloromethane at room temperature is added a solution of 1.5 g obtained in the preceding stage connection in 15 ml dichloromethane and stirred overnight at room temperature. Recast, the organic phase is washed with saturated sodium hydrogen carbonate solution, the buffer solution with pH 2 water, dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Obtain 0.5 g of the target product; so pl. = 145,6oC.

Example 37

N-[Bicyclo[2.2.1] hept-Akzo-yl] -N-propyl-1-(3-chloro-4 - methylbenzyl)-5-(3,4-dichlorophenyl)pyrazole-3-carboxamide

This connection get the procedure described in stage B of Example 36, from 0,695 g obtained in Preparative example 2.4 connection, 1 ml of triethylamine in 15 ml of dichloromethane and 1.5 g of compound obtained in stage a of Example 36, in 15 ml of dichloromethane. Get 0,417 g of the target product.

Example 38

N-(2-Methylcyclohex-1-yl)-1-(3-chloro-4-methylbenzyl)-5- (3,4-dichlorophenyl)pyrazole-3-carboxamide

This connection get the procedure described in stage B of Example 36, on the basis of 1 ml of 2-methylcyclohexylamine, 1 ml of triethylamine in 15 ml of dichloromethane and 1.5 g of compound obtained in stage a of Example 36, in 15 ml of dichloromethane. Connection purify by chromatography on silica, elwira mixture with dichloromethane-methanol (98:2 by volume). Obtain 0.27 g of the target is lorgeril)pyrazole-3-carboxamide

This connection get the procedure described in stage B of Example 36, from 0,605 g 2,6-dimethylcyclohexylamine, 1 ml of triethylamine in 15 ml of dichloromethane and 1.5 g of compound obtained in stage a of Example 36, in 15 ml of dichloromethane. Obtain 0.6 g of the target product; so pl. = 59,9oC.

Example 40

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- [(1R,S)-1-(3,4-dichlorophenyl)ethyl]-5-(4-were)pyrazole-3 - carboxamide

A) the acid chloride of 1-[1-(3,4-dichlorophenyl)ethyl]-5-(4 - were)pyrazole-3-carboxylic acid

To a suspension of 1.2 g obtained in Preparative example 1.25 compound in 50 ml of toluene at room temperature, add 0.7 ml of thionyl chloride and then refluxed for two hours. After cooling to room temperature the reaction mixture was concentrated in vacuo, the residue treated with toluene and the solvent is evaporated in vacuum. Obtain 1.3 g of the target product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo - yl] -1-[(1R,S)-1-(3,4-dichlorophenyl)ethyl]-5-(4-were) pyrazole-3-carboxamide

To a solution of 0,341 g obtained in Preparative example 2.1 compound in 15 ml of dichloromethane added 0.6 ml of triethylamine, and then was added dropwise a solution of 0.7 g obtained in the previous SV vacuum, the residue is extracted with ethyl acetate, filtered off the insoluble portion, the filtrate was washed with aqueous saturated sodium hydrogen carbonate solution, the buffer solution with pH 2, aqueous saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80:20 by volume). Gain of 0.54 g of the target product; so pl. = 112oC.

NMR-spectrum (M. D. ): 0,6-1,9 (m, 19H); 2,3 (s, 3H); 3,6 (multiplet, 1H); 5,55 (CH, 1H); of 6.6 to 7.6 (m, 9H).

Example 41

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- [(1R,S)-1-(4-were)ethyl]-5-(4-chloro-3-were) pyrazole-3-carboxamide

A) the acid chloride of 1-[1-(4-were)ethyl]-5-(4-chloro-3 - were)pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 40, from 0,61 g obtained in Preparative example 1.26 compound in 30 ml of toluene and 0.4 ml of thionyl chloride. Obtain 0.7 g of the target product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo-yl]-1- [(1R,S)-1-(4-were)ethyl]-5-(4-chloro-3-were)pyrazole - 3-carboxamide

This connection get the procedure described in stage B of Example 40, on the basis of 0.36 g obtained in Preparative p the organisations in 15 ml of dichloromethane. Connection purify by chromatography on silica, elwira with a mixture of cyclohexane with ethyl acetate (75:25 by volume). Obtain 0.13 g of the target product; so pl. = 65oC.

NMR-spectrum (M. D.): 0,8-2,05 (m, 19H); 2,2-2,5 (m, 6H); 3.75 to (d, 1H; 5,65 (CH, 1H); of 6.8 to 7.7 (m, 9H).

Example 42

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- [(1R,S)-1-(3,4-dichlorophenyl)ethyl]-5-(4-chloro-3-were) pyrazole-3-carboxamide

A) the acid chloride of 1-[1-(3,4-dichlorophenyl)ethyl] -5-(4-chloro-3 - were)pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 40, from 0.9 g obtained in Preparative example 1.27 compound in 20 ml of toluene and 0.5 ml of thionyl chloride. Obtain 0.95 g of the target product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- [(1R,S)-1-(3,4-dichlorophenyl)ethyl]-5-(4-chloro-3-were) pyrazole-3-carboxamide

This connection get the procedure described in stage B of Example 40, from 0,455 g obtained in Preparative example 2.1 compound in 15 ml of dichloromethane, 0.8 g of triethylamine and a solution of 0.95 g obtained in the preceding stage connection in 15 ml of dichloromethane. After drying the organic phase over sodium sulfate the solvent was partially removed in vacuo and the resulting crystals is,7 (multiplet, 1H); 5,7 (CH, 1H); of 6.7 to 7.7 (m, 8H).

Example 43

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- [(1R,S)-1-(4-were)propyl]-5-(4-chloro-3-were) pyrazole-3-carboxamide

A) the acid chloride of 1-[1-(4-were)propyl] -5-(4-chloro-3 - were)pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 40, from 0.87 g obtained in Preparative example 1.28 compound in 50 ml of toluene and 0.26 ml of thionyl chloride. Get 0,89 g of the target product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo-yl]-1- [(1R,S)-1-(4-were)propyl]-5-(4-chloro-3-were) pyrazole-3-carboxamide

To a solution of 0.51 g obtained in the preceding stage connection and 0.25 g) obtained in Preparative example 2.1 connection in 50 ml of dichloromethane add 0,363 ml of triethylamine and stirred for 72 hours at room temperature. Concentrated in vacuo, the residue is extracted with ethyl acetate, filtered off the insoluble portion, the filtrate was washed with aqueous saturated sodium hydrogen carbonate solution, the buffer solution with pH 2, saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethylacetate, 1H); 4,95 (DD, 1H); compared to 6.6-7.4 (m, 9H).

Example 44

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1-[1-methyl-1-(4-were)ethyl]-5-(4-chloro-3-were) pyrazole-3-carboxamide

A) the acid chloride of 1-[1-methyl-1-(4-were)ethyl]-5-(4-chloro-3 - were)pyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 40, from 1.5 g obtained in Preparative example 1.29 compound in 100 ml of toluene and 0.44 ml of thionyl chloride. Obtain 1.55 g of the target compound.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- [1-methyl-1-(4-were)ethyl]-5-(4-chloro-3-were) pyrazole-3-carboxamide

To a solution of 0.59 g obtained in the preceding stage connection and 0.29 grams obtained in Preparative example 2.1 connection in 50 ml of dichloromethane add 0,424 ml of triethylamine and stirred overnight at room temperature. Concentrated in vacuo, the residue is extracted with ethyl acetate, filtered off the insoluble portion, the filtrate was washed with aqueous saturated sodium hydrogen carbonate solution, the buffer solution with pH 2, saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira a mixture dichlormid>
(C = 0,64; dichloromethane).

Example 45

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- (2,4-dichlorobenzyl)-5-(4-chlorophenyl)-4-methylpyrazole-3-carboxamide

A) the acid chloride of 1-(2,4-dichlorobenzyl)-5-(4-chlorophenyl)-4 - methylpyrazole-3-carboxylic acid

To a solution of 0.71 g obtained in Preparative example 1.30 compound in 50 ml of toluene at room temperature add 0,191 ml of thionyl chloride and then refluxed overnight. Concentrated in vacuo, the residue treated with toluene and the solvent is evaporated in vacuum. Get to 0.72 g of the desired product in the form of oil, which solidified.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1-(2,4-dichlorobenzyl)-5-(4-chlorophenyl)-4-methylpyrazole-3-carboxamide

This connection get the procedure described in stage B of Example 43, on the basis of 0,315 g obtained in Preparative example 2.1 connection, and 0.46 ml of triethylamine and 0,653 g obtained in the preceding stage connection in 50 ml of dichloromethane. Gain of 0.68 g of the target product; so pl. = 125oC;2D0= -0,3(C = 1; ethanol).

Example 46

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo-yl]-1-(3, 4-dichlorobenzyl)-5-(4-chlorophenyl)-4-methylpyrazole-3-carboxamide

A) HT according to the method described in stage a of Example 45, based on 1 g of the obtained in Preparative example 1.31 compound in 50 ml of toluene and 0.28 ml of thionyl chloride. Gain of 1.03 g of the desired product in the form of oil, which solidified.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1-(3,4-dichlorobenzyl)-5-(4-chlorophenyl)-4-methylpyrazole-3 - carboxamide

This connection get the procedure described in stage B of Example 43, on the basis of 0,315 g obtained in Preparative example 2.1 connection, and 0.46 ml of triethylamine and 0,687 g obtained in the preceding stage connection in 50 ml of dichloromethane. Obtain 0.72 g of the target product; so pl. = 69oC;2D0= -1,8(C = 1; ethanol).

Example 47

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo-yl]-1-(3 - chloro-4-methylbenzyl)-5-(4-chlorophenyl)-4-methylpyrazole-3-carboxamide

A) the acid chloride of 1-(3-chloro-4-methylbenzyl)-5-(4-chlorophenyl)- 4-methylpyrazole-3-carboxylic acid

This connection get the procedure described in stage a of Example 45, based on 1 g of the crude compound obtained in Preparative example 1.32, 50 ml of toluene and of 0.29 ml of thionyl chloride. Gain of 1.05 g of the target product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo-yl]-1- (3-chloro-4-methylbenzyl)-5-(4-chlorophenyl)-4-metalpar the scientists in Preparative example 2.1 connection of 0.24 ml of triethylamine and 0.6 g obtained in the preceding stage connection in 50 ml of dichloromethane. Gain of 0.43 g of the target product; so pl. = 58oC;2D0= -1,7(C = 1; ethanol).

Example 48

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl]- 1-(4-methylbenzyl)-5-(4-chloro-3-were)-4-methylpyrazole-3 - carboxamide

A) the acid chloride of 1-(4-methylbenzyl)-5-(4-chloro-3-were) -4-methylpyrazole-3-carboxylic acid

To a suspension of 1.5 g obtained in Preparative example 1.33 compound in 40 ml of toluene was added 1 ml of thionyl chloride and refluxed for two hours. The reaction mixture was concentrated in vacuo, the residue treated with toluene and the solvent is evaporated in vacuum. Obtain 1.5 g of the target product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1-(4-methylbenzyl)-5-(4-chloro-3-were)-4-methylpyrazole-3 - carboxamide

This connection get the procedure described in stage B of Example 43, based on 0,42 g obtained in Preparative example 2.1 connection, 0.7 ml of triethylamine and 0.8 g obtained in the preceding stage connection in 40 ml of dichloromethane. Gain of 0.62 g of the target product; so pl. = 58oC;2D0= -2,4(C = 1; ethanol).


A) the acid chloride of 1-(3,4-dichlorobenzyl)-5-(4-chloro-3 - were)-4-methylpyrazole-3-carboxylic acid

To a suspension of 2.7 g obtained in Preparative example 1.34 compound in 50 ml of toluene, add 1.5 ml of thionyl chloride and refluxed for two hours. The reaction mixture was concentrated in vacuo, the residue treated with toluene and the solvent is evaporated in vacuum. Obtain 2.8 g of the target product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo-yl] -1-(3,4-dichlorobenzyl)-5-(4-chloro-3-were)-4-methylpyrazole - 3-carboxamide

This connection get the procedure described in stage B of Example 43, on the basis of 0,683 g obtained in Preparative example 2.1 connections, 1.2 ml of triethylamine and 1.5 g obtained in the preceding stage connection in 40 ml of dichloromethane. Gain of 1.03 g of the target product; so pl. = 69oC;2D0= of-2.1(C = 1; ethanol).

Example 50

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo-yl]-1-(3 - chloro-4-methylbenzyl)-5-(4-chlorophenyl)-4-(ethoxymethyl)pyrazole-3 - carboxamide

A) the acid chloride of 1-(3-chloro-4-methylbenzyl)-5-(4-chlorophenyl)- 4-(ethoxymethyl)pyrazole-3-carboxylic acid

To a solution of 0.2 g obtained in Preparative example 1.35 compound in 30 ml of toluene doba is the STATCOM is treated with toluene and the solvent is evaporated in vacuum. Obtain 0.21 g of the desired product in the form of butter.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo - yl]-1-(3-chloro-4-methylbenzyl)-5-(4-chlorophenyl)-4-(ethoxymethyl) pyrazole-3-carboxamide

This connection get the procedure described in stage B of Example 40, from 0,086 g obtained in Preparative example 2.1 compound in 25 ml of dichloromethane, with 0.125 ml of triethylamine and 0.2 g obtained in the preceding stage connection in 25 ml of dichloromethane. Obtain 0.15 g of the target product; so pl. = 50-51oC;2D0= -2,8(C = 1; ethanol).

Example 51

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl]-1-(5-Clorinda-1-yl)-5-(4-chlorophenyl) pyrazole-3-carboxamide

A) the acid chloride of 1-(5-Clorinda-1-yl)-5-(4-chlorophenyl) pyrazole-3-carboxylic acid

To a suspension of 1 g obtained in Preparative example 1.36 compound in 20 ml of toluene, add 0.6 ml of thionyl chloride and refluxed for two hours. After cooling to room temperature the reaction mixture was concentrated in vacuo, the residue treated with toluene and the solvent is evaporated in vacuum. Receive 1 g of the target product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo-yl]-1- (5-Clorinda-1-yl)-5-(4-chlorophenyl)pyrazole-3-carboxamide
at room temperature was added dropwise a solution of 1 g obtained in the preceding stage connection in 15 ml dichloromethane and stirred overnight at room temperature. Concentrated in vacuo, the residue is treated with ethyl acetate, filtered off the insoluble portion, the filtrate was washed with aqueous saturated sodium hydrogen carbonate solution, the buffer solution with pH 2, aqueous saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate (80: 20 by volume). Obtain 0.71 g of the target product; so pl. = 86oC;2D0= +0,5(c=1; ethanol).

NMR-spectrum (M. D. ): 0,4-1,8 (m, 16H); 2,5 (multiplet, 2H); 2.95 and (multiplet, 2H); 3,5 (d, 1H); 5,8 (t, 1H); and 6.6 to 7.7 (m, 9H).

See Overhauser effect (N. O. E.) between protons in position 1 indan-1-ilen group and the proton g2=g6=H.

Example 52

[(1R)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1-(3,4 - dichlorobenzyl)-5-(4-were)pyrazole-3-carboxylate

Within 72 hours at room temperature stirred mixture of 1.5 g of compound obtained in stage a of Example 1, 0.73 g of (1R)-endo-(+)penjelajah alcohol, 50 ml of pyridine and 0.02 g of 4-dimethylaminopyridine. The reaction mixture was concentrated in vacuo, the residue chromatographic on the silicon dioxide, elwira dichloromethane. Get to 0.23 g of the target p is a 3-Trimethylbicyclo[2.2.1] hept-endo-yl] -1- (3-chloro-4-methylbenzyl)-5-(3,4-dichlorophenyl)pyrazole-3 - carboxylate

To a solution of 2.6 g of the compound obtained in stage a of Example 36, 50 ml of pyridine added 0.87 g of (1R)-endo-(+)penjelajah alcohol and 0.02 g of 4-dimethylaminopyridine, then stirred at room temperature for 48 hours. Concentrated in vacuo, the residue treated with diethyl ether, the precipitated precipitate is filtered off and dried. Sediment chromatographic on the silicon dioxide, elwira with a mixture of cyclohexane with ethyl acetate and dichloromethane (85:15:3 by volume). Obtain 0.40 g of the target product; so pl. = 161oC;

2D0= +3,9(C = 1; dichloromethane).

Example 54

N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1] hept-endo-yl] -1-(2, 4-dichlorobenzyl)-3-(4-chlorophenyl)pyrazole-5-carboxamide

A) the acid chloride of 1-(2,4-dichlorobenzyl)-3-(4-chlorophenyl) pyrazole-5-carboxylic acid

To a suspension of 0.79 g obtained in Preparative example 1.38 compound in 20 ml of toluene added 0.54 ml of thionyl chloride and refluxed for three hours. Concentrated in vacuo, the residue is treated with 20 ml of toluene and the solvent is evaporated in vacuum. Obtain 0.9 g of the target product.

B) N-[(1S)-1,3 .3m-Trimethylbicyclo[2.2.1]hept-endo-yl]-1- (2,4-dichlorobenzyl)-3-(4-chlorophenyl)pyrazole-5-carboxamide
oC, was added dropwise a solution of 0.45 g obtained in the preceding stage connection in 15 ml dichloromethane and stirred for 16 hours at room temperature. The reaction mixture was poured into 100 ml ice water, extracted with dichloromethane, the organic phase is washed with water, saturated sodium chloride solution, dried over sodium sulfate and the solvent is evaporated in vacuum. After crystallization from a mixture of dichloromethane with diisopropyl ether gain of 0.37 g of the target product; so pl. = 171oC;

2D0= -3,2(C = 0,5; ethanol).

Example 55

Gelatin capsule (medicine)

The compound of Example 18 to 1 mg

Modified corn starch - 47 mg

Monohydrate lactose EFK - 150 mg

Magnesium stearate 2 mg

One white opaque gelatin capsule, size 3 - Filling: 200 mg

Example 56

Gelatin capsule (medicine)

The compound of Example 18 to 30 mg

Modified corn starch 30 mg

Magnesium stearate 2 mg

Monohydrate lactose EFK - Sufficient

One white opaque gelatin capsule, size 3 - Filling: 200 mg

Example 57

Tablet:

The compound of Example 18, 10 mg

the - ,5 mg

Monohydrate lactose 200 mesh - Sufficient

Purified water, a Sufficient quantity of

On one end deleau tablet: 150 mg

Example 58

Gelatin capsule (medicine)

The compound of Example 48 30 mg

The hypromellose 6mPas - 7.5 mg

Monohydrate lactose 200 mesh - Sufficient

Magnesium stearate 2.5 mg

Purified water, a Sufficient quantity of

One gelatin capsule, size 1 - Filling: 250 mg

Example 59

Tablet:

The compound of Example 48 40 mg

Corn starch 50 mg

Polyvinylpyrrolidone, CSO - 9 mg

Sodium salt of carboxymethyl amylum - 9 mg

Magnesium stearate 3 mg

Monohydrate lactose 200 mesh - Sufficient

Ha one end deleau tablet: - 300 MGM

1. Derivatives of pyrazole of the formula I

< / BR>
where X1means the group-NR1R2or group-OR2;

g2, g3, g4, g5, g6are the same or different and each, independently of one another, mean hydrogen, halogen atom, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, trifluoromethyl or alkylthiols with 1 to 4 carbon atoms; w2T friend, denotes hydrogen, halogen atom, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, or trifluoromethyl, provided that at least one of the substituents g2, g3, g4, g5, g6and at least one of the substituents w2, w3, w4, w5, w6different from hydrogen;

R1means hydrogen or alkyl with 1 to 4 carbon atoms;

R2means a non-aromatic carbocyclic radical of 3 to 15 carbon atoms, unsubstituted or mono - or multiply substituted by alkyl with 1 to 4 carbon atoms;

R3means hydrogen or a group-CH2-R6;

R4and R5each, independently of one another, mean hydrogen or alkyl with 1 to 4 carbon atoms;

or R4means hydrogen and R5and w6together form an ethylene radical;

R6means hydrogen or, when the deputies of the g2, g3, g4, g5and/or g6differ from alkyl with 1 to 4 carbon atoms, R6denotes hydrogen, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 5 carbon atoms,

and their salts.

2. The compound of formula I under item 1, where X1means the group-NR1R2in which R1means in the group-OR2in which R2means 1,3 .3m-trimethylbicyclo [2.2.1]hept-2-yl or bicyclo[3.2.1]Oct-3-yl, and the salts thereof.

4. The compound of formula I under item 1, where R3means hydrogen or a group-CH2-R6in which R6means hydrogen, and its salts.

5. The compound of formula I under item 1, or where each of R4and R5means hydrogen, or R4means hydrogen, and R5means alkyl with 1 to 4 carbon atoms, and salts thereof.

6. The compound of formula I under item 1, where each of g2, g5and g6means hydrogen, and g3and g4have the values specified above for compounds of formula I in paragraph 1, and its salts.

7. The compound of formula I under item 1, where each of w5and w6means hydrogen, w4means halogen atom, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or trifluoromethyl, or each of w2and w3mean hydrogen or one of them denotes hydrogen and the other denotes a halogen atom or alkyl with 1 to 4 carbon atoms, and salts thereof.

8. Connection on p. 1 of formula Ia

< / BR>
where R1, R2have the meanings specified for compounds of the formula I in p. 1;

R3ameans hydrogen or a group-CH2-R6a;

RAAMI carbon R6ameans hydrogen, methyl or ethyl;

g3ameans hydrogen, halogen atom, alkyl with 1 to 4 carbon atoms or trifluoromethyl;

g4ameans halogen atom, alkyl with 1 to 4 carbon atoms or trifluoromethyl;

w4ameans halogen atom, alkyl with 1 to 4 carbon atoms or trifluoromethyl;

each of w2aand w3Ameans hydrogen or one of them denotes hydrogen and the other denotes a halogen atom or alkyl with 1 to 4 carbon atoms,

and its salts.

9. Connection on p. 1 of formula Ib

< / BR>
where R1, R2have the meanings specified for compounds of the formula I in p. 1;

R3a, w2a, w3a, g3aand g4ahave the meanings specified for compounds of the formula Ia in paragraph 8;

R5bmeans alkyl with 1 to 4 carbon atoms,

and its salts.

10. Connection on p. 1 of formula Ic

< / BR>
where R2has the value specified for compounds of formula I in p. 1;

R3a, w2a, w3a, w4a, g3aand g4ahave the meanings specified for compounds of the formula Ia in paragraph 8,

and its salts.

11. The method of obtaining derivatives of pyrazole of the formula I on p. 1 and their salts, characterized in that:

1) the functional derivative of pyrazole-3-carb 4
, g5, g6, R3, R4and R5have the meanings specified for compounds of the formula I in paragraph 1, is treated with a compound of formula XXIV

H-X1< / BR>
where X1has the value specified for compounds of formula I in p. 1;

2) and, if necessary, the thus obtained compound is transformed into one of its salts.

12. The method according to p. 11, obtain the compounds of formula I, where X1means the group-NR1R2and their salts, characterized in that:

1) the functional derivative of pyrazole-3-carboxylic acid of the formula II under item 11 is treated with an amine of the formula III

HNR1R2< / BR>
where R1and R2have the meanings specified for compounds of the formula I in p. 1;

2) and, if necessary, the thus obtained compound is transformed into one of its salts.

13. The method according to p. 11 obtain the compounds of formula I, where X1means the group-OR2and their salts, characterized in that:

1) the functional derivative of pyrazole-3-carboxylic acid of the formula II according to p. 11 treated with alcohol of formula XIV

HO-R2< / BR>
where R2has the value specified for compounds of formula I in p. 1;

2) and, if necessary, the thus obtained compounds SW, containing the active principle and a pharmaceutically acceptable excipients, characterized in that the active principle is a connection on PP.1 - 10 or one of its pharmaceutically acceptable salts contained in an effective amount.

15. The pharmaceutical composition according to p. 14, containing 0.5 to 1000 mg of active beginning.

16. The pharmaceutical composition according to p. 15, containing 2.5 to 250 mg of active beginning.

17. Compounds according to any one of paragraphs.1 - 10, or their pharmaceutically acceptable salts, characterized in that these compounds are antagonists of receptors SV2.

 

Same patents:

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

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to new substituted pyrazolylborate, and to their use as herbicide compositions

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to medicine, specifically to medicines, exhibiting anti-allergic, anti-asthma and anti-inflammatory effect

The invention relates to medicine and relates to methods of inducing T-cell tolerance to tissue or organ transplant

The invention relates to medicine, namely to immunology, and can be used in immunotherapy for the correction of immune homeostasis, the violation of which is associated with exposure to antigen

The invention relates to the field of medical biotechnology

The invention relates to the field of medicine and veterinary medicine, in particular to immunology, and relates to methods of correcting the immune system of a living organism
The invention relates to medicine and relates to immunomodulatory agent that can be used to treat a variety of diseases involving disorders of modulating the activity of the immune system

The invention relates to medicine, in particular to combustology, and can be used for prevention of early sepsis in children tyazheloobozhzhennykh

The invention relates to medicine, in particular to immunology and neurology, and for the treatment of autoimmune diseases

The invention relates to products derived from histamine and, in particular, the condensation products of histamine or methylsiloxanes histamine and amino acids, the method of their preparation and use as active principle in areas such as therapy and cosmetology, as well as the factor (agent), improving the stability of compositions used in therapy, cosmetology, agriculture and food industry (region)
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