Substituted 1-phenyl-3-carboxamide and their pharmaceutically acceptable salts, method of production thereof, intermediate compounds and pharmaceutical composition based on them having affinity to the human neurotensin receptor

 

(57) Abstract:

The invention relates to substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group bulbasaur rich heterocycle, having from 4 to 7 units, which, in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts. In addition, the proposed intermediate compound 1-phenylpyrazol-3-carboxylic acid of formula (II) and (II') in which R1, R2, R3have values that match the values of R1x, R2xand R3xindicated for formula (Ia), the method of obtaining compounds of formula (Ia), on the basis of these intermediate compounds, and intermediate derivatives of phenylhydrazine to produce compounds of formulas (II) and (II'). The compounds of formula (Ia) have affinity to the human neurotensin receptors and are the basis for pharmaceutical compositions. 6 C. and 2 h.p. f-crystals, 7 PL.

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-NR9(CH2)sCR7R8(CH2)tNR5R6(a)

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The invention relates to new substituted 1-Fennia and containing them as active principles of pharmaceutical compositions.

The first potential synthetic medicines ones type, able to connect with neurotensin receptors described in the European patent 0477049. We are talking about Amidah pyrazole-3-carboxylic acids in which the amino acids are differently substituted, which displace audirovannyj the neurotensin from its receptor, in doses below micromole, according to the experience with brain membrane of the Guinea pig. To this class of substances includes the compound 2-[(1-(7-chloro-4-chinolin)-5-(2,6-acid) pyrazole-3-yl)carbylamine]adamantane-2-carboxylic acid (SR 48692) with high and selective antagonistic activity against neurotensin (D. Gully, and others, Proc. Natl. Acad. Sci. USA, 90, 65-69 (1993)).

A characteristic feature of this class of compounds described in European patent 0477049 is to position 1 pyrazol cycle Deputy, in particular phenyl, naftilos, 4-chinoline group, which is substituted or not substituted. More specifically, the connection SR 48692 in position 1 of the pyrazole contains 7-chloro-4-pinolillo group. Described in the mentioned patent compounds containing 1-naftalina or 4-chloro-1-naftalina group in position 1 pyrazol cycle, have an extremely high affinity of the l, while their affinity for the human receptor is less because their IR50is the magnitude of 10-100 nmol.

Currently, it is found that by replacing the phenyl group in 1-phenylpyrazol-3-carboxamido special groups, you can increase the affinity neurotensin receptors and, especially, to increase the affinity to the human neurotensin receptors.

In addition, the compounds according to the invention in vitro show a broader spectrum of activity than the compounds described in European patent 0477049, as a receptor antagonist of the neurotensin.

Thus, the invention relates, according to one of its objects to new substituted 1-phenylpyrazol-3-carboxamide formula (Ia):

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in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen, NRaRbdenotes a group chosen from:

-NR9(CH2)sCR7R8(CH2)tNR5R6;

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where R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom, to the military in position 4 Deputy R9;

R7denotes hydrogen, (C1-C4)-alkyl or benzyl;

R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalken;

R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6where R'5and R'6represent, independently from each other, (C1-C6)-alkyl;

R10denotes hydrogen, (C1-C4)-alkyl;

s=0-3;

t=0-3, provided that (s+t) in the same group greater than or equal to 1;

the divalent radicals a and E together with the carbon atom and the nitrogen atom to which they are linked, form a saturated a heterocycle having from 4 to 7 units, which, in addition, may be substituted by one or more (C1-C4-alkilani;

R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen, or R2xand R3xtogether form tetramethylene group;

and their pharmaceutically acceptable salts.

Salts of the compounds with the sodium or potassium, with alkaline earth metals, preferably calcium salts, and salts with organic bases, such as diethylamine, trimethylamine, N-methyl-D-glucamine, lysine, arginine, histidine, choline or diethanolamine, or salts with optically pure organic bases, such as methylbenzylamine.

Salts of compounds of formula (I) according to the invention are also salts with inorganic or organic acids which allow appropriate separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, such as mandelic acid or camphorsulfacid, and preferably those which form pharmaceutically acceptable salts such as hydrochloride, acetate, hydrosulfate, dihydrophosphate, methanesulfonate, maleate, fumarate, 2-naphthalenesulfonate, isetionate, bansilalpet, p-toluensulfonate, tartrate, citrate, etandisulfonat.

Preferably the invention relates to compounds of formula (Ia) in which:

T denotes a direct link;

NRaRbmeans:

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One of the preferred compounds for imaging the-ylcarbonyl]adamantane-2-carboxylic acid, her inner salt and its pharmaceutically acceptable salts.

The invention relates, according to another of its objects, the method of production of substituted 1-phenylpyrazol-3-carboxamido formula (I) and their salts, namely, that:

1) the functional derivative of 1-phenylpyrazol-3-carboxylic acid of formula (II) or (II'):

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in which R1, R2, R3have values that match the values of R1x, R2xand R3xspecified for compounds of formula (Ia), R'1means the predecessor of R1selected among carboxyl, (C1-C4)-alkoxycarbonyl, benzyloxycarbonyl, process, amino acid, possibly protected using conventional peptide synthesis of protective groups of the formula (III):

H-NH-AA(OH), (III)

in which the-NH-AA(OH) denotes a group of the formula

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2) if necessary, the thus obtained functional derivative of the acid of formula (I')

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put then the appropriate treatment for the conversion of the substituent R'1, which is a predecessor of R1in the substituent R1;

3) possibly obtained in stage 1 or stage 2) connection remove the protective group to obtain sootvetstvenno formula (I).

As a functional derivative of 1-phenylpyrazol-3-carboxylic acid of formula (II) or (II') you can use the acid chloride, mixed anhydride with chloroformiate of isobutyl or ethyl, (C1-C4)-alkilany ester.

Amino acids of formula (III) can be used either as is, or after pre-sewn carboxyl group using a conventional in peptide synthesis as described, for example, in "Protective groups in organic chemistry", ed. J. F. W. McOmie, Plenum Press, 1973, S. 183, or in "Protective groups in organic synthesis", II-nd edition, J. F. W. Greene and P. G. M. Wuts, John Willey and Sons, 1991, S. 224.

Thus, in stage 1) how can the acid chloride 1-phenylpyrazol-3-carboxylic acid obtained by the reaction of thionyl chloride with the acid of formula (II) or (II'), to enter into interaction with the amino acid of formula (III) in a solvent such as acetonitrile, tetrahydrofuran, dimethylformamide or dichloromethane, in the atmosphere of inert gas at room temperature for from several hours to several days in the presence of a base, such as pyridine, sodium hydroxide or triethylamine.

One variant of implementation stage 1) consists in obtaining haramata acid of formula (II) or (II') in the presence of a base, such as triethylamine, and in the introduction of its interaction with N, O-bestemmelser derived amino acids of the formula (III) obtained by the reaction of bis(trimethylsilyl)ndimethylacetamide or 1,3-bis(trimethylsilyl)urea, or bis(triptoreline)ndimethylacetamide with the amino acid of formula (III), in solvents such as acetonitrile, dichloromethane, in an inert atmosphere for a time from 1 hour to several days at temperatures from room temperature up to the boiling temperature under reflux of the solvent.

Another variant of implementation stage 1) consists in the introduction into the interaction of the mixed anhydride 1-phenylpyrazol-3-carboxylic acid of formula (II) or (II') with the amino acid of formula (III) in a solvent such as dichloromethane, in an inert atmosphere at room temperature for a period of time from 1 day to several days in the presence of a base such as triethylamine.

When the compound of formula (I) contains the main function and is obtained in free base form, the salt formation is carried out by treatment with the chosen acid in an organic or aqueous solvent. By treating the free base, dissolved, for example, in alcohol, such as isopropanol, with razzaboni. So, for example, receive the hydrochloride, hydrobromide, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, methyl sulfate, oxalate, maleate, fumarate, 2-naphthalenesulfonate.

When the compound of formula (I) contains a primary function, and it is isolated in the form of one of its salts, e.g. the hydrochloride or oxalate, the free base can be obtained by neutralizing the above-mentioned salts with inorganic or organic bases, such as sodium hydroxide or triethylamine, or with carbonate or bicarbonate of an alkali metal, such as a carbonate or bicarbonate of sodium or potassium.

When the product of formula (I) are obtained in acid form, it can be converted into a salt of the metal, in particular alkali metal such as sodium salt or alkaline earth metal, such as a salt of calcium, according to conventional methods.

The compounds of formula (Ia) can be subjected to dehydration in the presence of an anhydride, for example acetic anhydride, to obtain the derived oxazolone formula (IC):

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in which R1is in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen and NRa/BR>R2means (C1-C6)-alkyl,

R3denotes hydrogen,

R5and R6denote (C1-C6)-alkyl;

R7and R8represent hydrogen;

s is equal to the number from 0 to 3;

t is equal to the number from 0 to 3 provided that the sum (s+t) is greater than or equal to 1.

On the basis of the compounds of formula (IC), again get the connection formula (Ia) by hydrolysis in an acidic or alkaline medium, for example, in the presence of salts of alkaline metal such as tert-butyl potassium.

Intermediate obtaining compound (IC) may be suitable for cleaning the compounds of formula (la).

1-Phenylpyrazol-3-carboxylic acid of formula (II) or (II'):

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in which R1, R2, R3have values that match the values of R1x, R2x, R3xspecified for compounds of formula (Ia), R'1means the precursor of the radical R1selected among carboxyl, (C1-C4)-alkoxycarbonyl, benzyloxycarbonyl, as well as its functional derivative, selected from mixed anhydride with chloroformiate of isobutyl or ethyl, acid chloride and compound (C1-C4)-Olkiluoto ether, are new compounds and costall(II) and (II'), (C1-C4)-alkalemia esters of the acids of formula (II) and (II'), which can also be precursors of the foregoing acids (in particular, methyl, ethyl and tert-butyl esters and mixed anhydrides of the acid of formula (II) and formula (II') with isobutyl or etelcharge.com represent the most preferred intermediate products.

The method of obtaining compounds of formula (II) or formula (II') through the esters of the formula (IIA) or (II) is represented by the diagram at the end of the description.

In the first stage (a) a strong base, such as a metal alcoholate, enter into interaction with the ketone of formula 1 in which R4has the above value, then (stage b) carry out the reaction with equimolar amounts of diethyloxalate in alkanol, as, for example, methanol or ethanol, according to L. Claisen, Ber. , 42, 59 (1909). After deposition in a simple ether, such as diethyl ether or diisopropyl ether, enolate formula 2 sucked. You can also obtain the lithium enolate according to W. V. Murray and others, J. Heterocyclic Chem., 26, 1389 (1989).

Thus obtained Analyt metal formula 2 and phenylhydrazine derivative of the formula 3 or its salt is then refluxed with acetic acid (one hundred is or (II) under the action of an alkaline agent, such as, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide, then acidification get acid of formula (II) or (II') (stage d).

Among the compounds of formula 3 some are new and constitute the object of the invention.

Thus, the compounds of formula (3'):

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in which R'2and R'3each, independently of one another denote hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl or R'2and R'3together form tetramethylene group;

Ryis in position 4 or in position 5 indicates a group selected among the following groups: carboxyl, (C1-C4-alkoxycarbonyl, benzyloxycarbonyl; provided that R'2and R'3at the same time does not mean hydrogen and R'2is not ethyl when R'3means hydrogen, a Rymeans methoxycarbonyl group in position 4,

as well as their salts are novel compounds and constitute the following object of the invention.

Derivatives of phenylhydrazine of formula 3 can be obtained according to Houben-Weil, 1967, X-2, 169. For example, it is possible to carry out the diazotization of the corresponding phenylamine in the presence of sodium nitrite, and then restore corny Deputy, such as cyano - or nitro-group, you can also replace terfenadine derived by hydrazinehydrate to obtain the corresponding hydrazinophenyl derived. Substituted phenylamine known or get them by known methods. For example, aminosalicylate receive according to Houben-Weil, "Methods of organic chemistry", ed. 1955, volume IX, S. 450.

Derivatives of phenyl substituted by a group R1=YCO2R7receive from the corresponding aniline derivatives or nitrophenyl.

Amino acids of formula (III) are industrial products, or they can be very easily obtained by classical methods. In particular, it is not commercially available amino acids of the formula (III) are obtained according to the Strecker synthesis, Ann., 75, 27 (1850), or according to the synthesis of N.T. Bucherer, etc., J. Pract. Chem., 141, 5 (1934), followed by hydrolysis in order to obtain amino acids; for example, 2-aminoadamantana-2-carboxylic acid and 9-aminobutyl(3.3.1)nonan-9-carboxylic acid is obtained according to N. T. Naqasava etc., J. Med. Chem., 16 (7), 823 (1973).

The compounds of formula (Ia) and their salts have a very high affinity to the human neurotensin receptors in the tests described D. Gully, and others, Proc. Natl. Acad. Sci. USA, 90, 65-69 (1993).

C. harmacol., 60, 349-357 (1994) observe that the connection according to the invention, administered orally, prevents contralateral rotations caused intrastriatal unilateral injection of neurotensin in the case of the mouse.

In addition, acting in accordance with the method described by D. Nisato and others in the Life Sciences, 54, 7, 95-100 (1994), note that the connection according to the invention, administered intravenously inhibited the increase in blood pressure induced by intravenous infusion of neurotensin in the case of the Guinea pig.

Known compounds described in European patent 0477049, these tests show the activity of the compounds according to the invention.

Compounds according to the invention are non-toxic; in particular, their acute toxicity is compatible with their use as a medicine. For therapeutic applications mammal is administered an effective amount of the compounds of formula (I) or one of its pharmaceutically acceptable salts for the treatment neuroengineering pathologies. Thus, the compounds according to the invention can be used to treat neuropsychiatric disorders, in particular those that are associated with dysfunctie is istemi, for example, Parkinson's disease (D. R. Handrich, etc. , Brain Research, 231, 216-221 (1982) and C. B. Nemero, Biological Psychiatry, 15(2), 283-302 (1980)). They can be used for diagnosis and/or treatment of cancerous diseases, such as inoperable human meningiomas (P. Mailleux, Peptides, 11, 1245-1253 (1990)), cancer of the prostate (I. Sehqal and others, Proc. Natl. Acad. Sci., 91, 4673-4677 (1994)), lung cancer in small cells (T. Sethi and others, Cancer Res., 51, 3621-3623 (1991)). They can be used to treat disorders of peristalsis of the gastrointestinal tract, and disorders of the gastrointestinal tract secretory ulcer and/or neoplastic origin (Review A. Shulkes in the book "the Peptides: biochemistry and physiology", ed. J. Waish and G. J. Dockray, 1994). The compounds of formula (I) according to the invention can also be suitable for the treatment of diseases such as syndrome irritable colon, diarrhea, colitis, ulcers, tumors of the gastrointestinal tract, dyspepsia, pancreatitis, esophagitis. They may also be of interest as modulators of eating (VESK Century, Metabolism., 44, 972-975 (1995)). Compounds according to the invention can be used as diuretics, also as in the case of cardio-vascular disorders and in the case of pathologies associated with release of histamine, such as inflammatory prorich violations caused by stress, such as migraines, itching nervous origin and interstitial cystitis (Theoharides T. C., and others, Endocrynol., 136, 5745-5750 (1995)). Compounds according to the invention may also be of interest for use in analgesia, influencing the effects of morphine (M. O. Urban, J. Pharm. Exp. Ther., 265(2), 580-586 (1993)).

Thus, the object of the invention is pharmaceutical compositions containing as active principles of an effective amount of the compounds of formula (I) or their possible pharmaceutically acceptable salts.

In the pharmaceutical compositions according to the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal injection current starters, you can enter to animals or humans in the form of a unit dosage forms in a mixture with classical pharmaceutical carriers. Appropriate dosage forms include forms for oral administration such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, forms for administration by inhalation, forms for sublingual injection or by mouth; forms for subcutaneous, transcutaneous, intramuscular or intravenous administration and forms dlatgs from 0.5 to 1000 mg per day, preferably from 2 to 500 mg.

Each single dose may contain from 0.5 to 250 mg of active early, preferably 1-125 mg, in combination with a pharmaceutical carrier. This single dose can be administered 1-4 times per day.

When preparing a solid composition in the form of tablets, the active principle is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic or the like fillers. Tablets may be coated with sucrose or other appropriate materials or they can be treated so that they have a prolonged or delayed activity and continuously release a specified number of the current beginning.

Dosage form in the form of gelatin capsules is obtained by mixing the applicable beginning with the diluent and introducing the resulting mixture into soft or hard gelatin capsules.

Dosage form in the form of a syrup or elixir may contain the active principle together with a sweetening agent, preferably low-calorie; methyl paraben and propyl paraben as an antiseptic, as well as with the agent, giving the appropriate taste and color.

Dispersible in water is hiroumi agents, such as polyvinylpyrrolidone, etc., as well as sweetening agents or improves the taste of agents.

For rectal use of suppositories, which was produced using the binder, melting at rectal temperature, for example, cocoa butter or polyethylene glycols.

For parenteral administration using aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain dispersing agents and/or wetting, which is pharmacologically acceptable, for example propylene glycol or butyleneglycol.

The active principle may also be included in the dosage form in the form of microcapsules, possibly with one or more carriers or additives.

To improve the solubility of the products according to the invention the compounds of formula (I) and their pharmaceutically acceptable salts can also be in the form of complexes with cyclodextrins.

In the description and in the examples use the following abbreviations:

Meon: methanol

EtOH: ethanol

ether: diethyl ether

ISO-ether: diisopropyl ether

hydrochloric ether: saturated solution of hydrogen chloride in ether

hydrochloric acid ethanol: saturated the MFA: dimethylformamide

DMSO: dimethyl sulfoxide

THF: tetrahydrofuran

HCl: hcl

H2SO4: sulfuric acid

Asón: acetic acid

TFUCK: triperoxonane acid

NaOH: sodium hydroxide

KOH: potassium hydroxide

LiOH: lithium hydroxide

NH4OH: ammonium hydroxide

Na2SO4: sodium sulphate

NaHCO3: sodium bicarbonate

NaHSO3: hydrosulfite sodium

Na2CO3: sodium carbonate

TO2CO3: potassium carbonate

P2O5: phosphoric anhydride

NBS: N-bromosuccinimide

l3: phosphorus oxychloride

NaNO2: sodium nitrite

SOCl2: thionyl chloride

SnCl2: chloride divalent tin

CuCN: cyanide monovalent copper

Me, MeO: methyl, methoxy group

Et: ethyl

iPr: isopropyl

iBu: isobutyl

n-Bu: n-butyl

t-Bu: tert.-butyl

Bz: benzil

so pl.: melting point

TC: room temperature

silicon dioxide N: silica gel 60 N, available on sale from Merck (Darmstadt)

NMR: nuclear magnetic resonance

Except the opposite, NMR spectra are recorded at 200 MHz in deuterated dimethyl sulfoxide. Henichesk is. In the spectra are legend: s - singlet; ush.with a broadened singlet; Rass.with - split singlet; d - doublet; D. D. - double doublet; t - triplet; CD quadruplet; CT quintet; SP - septet, m - array; MT - multiplet.

PREPARATIVE EXAMPLE 1.1

Sodium salt of methyl-4-(2,6-acid)-4-oxido-2-exabot-3-enoate (connection)

A solution of 100 g of 2,6-dimethoxyacetophenone and 7.5 ml of diethyloxalate in 520 ml of anhydrous methanol is added slowly to a solution of sodium methylate obtained from 12.7 g of sodium and 285 ml of anhydrous methanol. Refluxed for 7 hours and left to stand overnight at room temperature. The reaction mixture was poured into 2 l of diisopropyl ether and stirred for 15 minutes. Get the target product by filtration, washing diisopropyl ether and drying in vacuo; weight 120 g; so pl.=178oC.

Potassium salt of ethyl-4-(2,6-acid)-4-oxido-2-exabot-3-enoate (compound a1)

It is heated to a temperature of 50oAnd mixed solution of 18 g of 2,6-dimethoxyacetophenone in 54 ml of ethanol for 6 minutes, add a solution of 13.4 g of 95% tert.-the butyl potassium in 72 ml of ethanol. Heated to the boiling temperature with the inverse of ω for 1 hour. Then 40 ml of distilled ethanol and allowed to cool with stirring for 2.5 hours. The precipitate is filtered off, washed with 40 ml of ethanol and dried in a vacuum at a temperature of 60oC for 17 hours, receiving 31 g of the target product.

NMR: 1,2 (t, 3H); 3,6 (C, 6N); 4 (MT, 2H), and 5.5 (s, 1H); 6,55 (d, 2H); 2 and 7.1 (t, 1H).

PREPARATIVE EXAMPLE 1.2

Sodium salt of ethyl-4-[2-(cyclopropylmethoxy)-6-methoxyphenyl] -4-oxido-2-exabot-3-enoate

A) 2-(Cyclopropylmethoxy)-6-methoxyacetophenone

To a solution of 26 g of 2-hydroxy-6-methoxyacetophenone in 400 ml of propan-2-ol at room temperature add to 32.7 ml of 50% solution of cesium hydroxide in water and stirred for 15 minutes at room temperature. Concentrated in vacuo, the residue is treated propane-2-I, concentrated in vacuo, then add toluene and concentrated in vacuo. The residue is dissolved in 200 ml of DMF, add to 25.3 g cyclopropanemethylamine and heated at 80oC for 2.5 hours. Concentrated in vacuo, the residue is treated with water, 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. Get to 32.7 g of zelenog the ATA

A solution of 32.6 g obtained in the preceding stage connection and 20.1 ml diethyloxalate in 100 ml of ethanol is added slowly to a solution of ateleta sodium derived from 3.4 g of sodium and 60 ml of ethanol. Heated at a temperature of 60oWith overnight, allowed to cool to room temperature and concentrated in vacuo. The residue is treated with pentane deposited precipitate is filtered under vacuum, washed his pentane and dried in vacuum. Get 41,2 g of the target product.

Methods of obtaining hydrazines of formula 3

PREPARATIVE EXAMPLE 2.1

Hydrochloride 3-isopropyl-4-hydrazinobenzene acid

A) 2-Isopropylacetanilide

This connection is described in Bull. Soc. Chim. France, 144 (1949).

Cool ice mixture containing 300 ml of toluene and 31 ml of 2-isopropylaniline, and slowly add 22 ml of acetic anhydride. After stirring for 40 minutes at room temperature, the reaction medium is evaporated, then treat the residue with petroleum ether. The precipitation is filtered off under vacuum. Get 35,9 g of the target product (after crystallization from petroleum ether). So pl.=81oC.

B) 4-Bromo-2-isopropylacetanilide

This connection is described in J. Med. Chem.islote, slowly add a few drops of a solution of 10.1 ml of bromine in 180 ml of acetic acid, then heated to 50oC; after cooling again add a few drops of solution and heated to 50oAnd all this continued until the end just add. The reaction mixture is gradually heated to the boiling temperature under reflux, then leave overnight to reduce the temperature to room. The precipitation is filtered, then added to the diluted solution of NaHSO3. Again filtered off, washed with water, then dried over P2ABOUT5. Get a 27.4 g of the target product. So pl.=134oC.

The compound obtained in stage B can also be obtained according nigeoplachivaemoy method.

B) 4-Bromo-2-isopropylacetanilide

Prepare a mixture containing of 117.6 g of 2-isopropylacetanilide in 330 ml of DMF, and within 25 minutes, add a solution of 117.6 g of N-bromosuccinimide in 330 ml of dimethylformamide. Stirred at room temperature for 5 hours, then poured into 1.5 liters of water, cooling the reaction medium ice. The precipitation is filtered off, washed with water, then dried at a temperature of 50oWith the vacuum. The filtrate is extracted 2 times with dichloromethane, washing the purified fractions obtain 158 g of the target product. So pl.=134oC.

C) 4-Cyano-2-isopropylacetanilide

A mixture containing 26,48 g obtained in the previous stage of the product, 60 ml of dimethylformamide, 1 ml of water and of 10.25 g of cyanide monovalent copper, refluxed for 10 hours. After cooling, it was poured into a solution of 50 g of sodium cyanide in 150 ml of water at a temperature of 40oC. the precipitation is filtered off and washed several times with water. Obtain 16.7 g of the target product. So pl.=134oC.

G) of the Hydrochloride of 4-cyano-2-isopropylaniline

Mix 16,13 g obtained in the preceding stage connection, 65 ml of 100% ethanol and 40 ml of 1 N. hydrochloric acid and stirred at the boil under reflux for 19 hours. After keeping overnight at room temperature, add 10% NaOH solution to reach pH 10. The reaction medium is extracted 2 times with dichloromethane, the organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in ether and add hydrochloric ether. The precipitation is filtered off and washed it ether. Get 15,32 g of the target product, which crystallized from a mixture of diethyl ether with hydrogen chloride. So pl.=188oC.

D) Hydrochloride 4-amino-show 1 g obtained in the preceding stage connection 2.86 g of crushed dioxide potassium, 6 ml of water and 0.5 ml of dimethoxyethane, refluxed for 12 hours. After cooling, add concentrated hydrochloric acid to reach pH 1, then extracted 2 times with dichloromethane; the organic phase is dried over sodium sulfate and concentrated. Obtain 0.96 g of the target product. So pl.=128oC.

E) of the Hydrochloride of 3-isopropyl-4-hydrazinobenzene acid

A mixture containing 0.96 g obtained in the previous stage of the product 22 ml of concentrated hydrochloric acid and 20 ml of acetic acid, cooled to -5oTo add to it a solution of 0.36 g of sodium nitrite in 4 ml of water, then stirred at a temperature of 0oC for 1 hour and 15 minutes. Cooled to -10oWith and add to 3.73 g of the dihydrate salt of divalent tin in 4 ml of concentrated hydrochloric acid. Leave to stand to raise the temperature to 18oWith, then the precipitation is filtered off and washed it with 1 ml of diluted hydrochloric acid. Obtain 0.96 g of the target product (after drying over P2ABOUT5).

PREPARATIVE EXAMPLE 2.1 BIS

Hydrochloride 3-isopropyl-4-hydrazinobenzene acid can also be obtained according to lageopsa the s below 60oWith 200 ml of acetic anhydride is added to 300 ml of 2-isopropylaniline. After stirring for 45 minutes at room temperature add a solution of one equivalent of N-bromosuccinimide in 720 ml of dimethylformamide. After stirring for 2 hours the mixture was poured in (5.7 l / water mixture with ethyl acetate (volume ratio 2: 1), decanted, the organic phase is separated, dried over sodium sulfate and evaporated in vacuum. The remainder is condensed in diisopropyl ether and filtered off, getting 367 g of the target product.

B) 4-Cyano-2-isopropylacetanilide

of 10.25 g obtained at the stage And product and 1.2 equivalent of cyanide monovalent copper in 20 ml of dimethylformamide is refluxed for 6 hours. Then cooled to 20oC, poured into a mixture of 200 ml of ethyl acetate with 200 ml of 20% ammonia solution. The organic phase is washed with 50 ml of 20% ammonia solution, and then 2 times with saturated solution of NaCl. After drying over sodium sulfate evaporated in vacuo, the residue is treated with diisopropyl ether, filtered and dried at a temperature of 40oC in vacuum, obtaining x 6.15 g of the target product.

The compound obtained in stage B, can also batavi And product and 0.6 equivalent of cyanide of zinc in 67 ml of anhydrous dimethylformamide pass by ozonation argon. Heated to 80oWith and add 2 g of tetrakis(triphenylphosphine)palladium(0) in the absence of light. After stirring for three hours at a temperature of 80oWith cooled to room temperature and add 120 ml of 4% ammonia solution and 200 ml of ethyl acetate, the combined organic phases are washed with 4% aqueous ammonia solution, then dried over sodium sulfate, evaporated in vacuo, the residue is treated with diisopropyl ether, filtered off and dried in vacuum, obtaining 15 g of the target nitrile.

In) Hydrochloride 4-amino-3-isopropylbenzoic acid

A mixture of 100 g of the product obtained at stage B, with 500 ml of concentrated hydrochloric acid and 500 ml of acetic acid is refluxed for 10 hours. Concentrated in vacuo, the precipitate is filtered off and dried in vacuum, obtaining to 103.8 g of the target product.

G) of the Hydrochloride of 3-isopropyl-4-hydrazinobenzene acid

To a cooled to -5oWith a mixture of 59 g obtained at the stage In the product together with 1050 ml of acetic acid and 1420 ml of concentrated hydrochloric acid is added slowly a solution of 27.7 g of sodium nitrite in 250 ml of water. After stirring for 1 hour 20 minutes at a temperature of 0oWith the mixture of the centered hydrochloric acid. Increase to room temperature, the precipitate is filtered off, washed it with concentrated hydrochloric acid and dried in vacuum, obtaining 56,36 g of the target product.

PREPARATIVE EXAMPLE 2.2

Hydrochloride 3-isopropyl-4-hydrazinobenzothiazole

A) 4-Amino-3-isopropylbenzenesulfonyl

5.7 ml of Sulfuric acid is added to 10 ml of water and heated to a temperature of 80oWith, then add 13.5 g of 2-isopropylaniline. Water is evaporated by heating in vacuum, and then gradually, over one and a half hours, the temperature was raised to 260oC. After stirring for three hours in vacuum at a temperature of 260oThe mixture is left to stand to return to room temperature and the pressure to atmospheric pressure, then for 30 minutes, heated in the presence of 15 ml of NaOH and 100 ml of water for dilution of the reaction medium. Filtered off the insoluble part is cooled to 5oC, then acidified with concentrated sulfuric acid to pH 1. The precipitation is filtered off, washed with 5 ml of cold water and dried, obtaining 20 g of the target product.

NMR spectrum: 1,1 (d, 6N); 2,95 (MT, 1H); 6,85 (d, 1H); 7,45 (doctor d, 1H); and 7.6 (d, 1H).

B) Hydrochloride of 3-isopropyl-4 - Ki-the RA Paon and 20 ml of water, add 10 ml of ice and 3.2 g of sodium nitrite. This solution is slowly poured into a solution of 30 ml of concentrated hydrochloric acid in 20 ml of water at a temperature of from -5oC to -15oC. Stirred for 1 hour at this temperature, then add 26 grams of chloride dihydrate divalent tin in 40 ml of concentrated hydrochloric acid at a temperature of from 0oWith -5oC. After stirring for 2.5 hours at room temperature, filtered, and then the resulting product is dried under vacuum in the presence of P2O5. Thus obtained 9.7 g of the target product.

NMR spectrum: 1,2 (d, 6N); 3.15 in (MT, 1H); to 6.8 (d, 1H), 7,45 (d, 1H); at 7.55 (s, 1H), 7,9 (ush.s, 1H); 10 (ush.s, 3H).

PREPARATIVE EXAMPLE 2.3

Hydrochloride 4-hydrazino-5,6,7,8-tetrahydronaphthalen-1-carboxylic acid

A) 4-Amino-5,6,7,8-tetrahydronaphthalen-1-carboxylic acid

4-Nitro-5,6,7,8-tetrahydronaphthalen-1-carboxylic acid is described in Chem. Pharm. Bull., 32, 3968 (1984).

Carry out the hydrogenation of 1.48 g of this nitro-derivatives in methanol in the presence of Raney Nickel. After stirring for 4 hours the catalyst is filtered off, the filtrate is evaporated to dryness, the residue is treated with ether and filtered, obtaining 1 g of the target product. So pl.=180TO a solution of 0.73 g of 4-amino-5,6,7,8-tetrahydronaphthalen-1-carboxylic acid in 10 ml of concentrated hydrochloric acid, cooled to -5oC, add a solution of 0.26 g of sodium nitrite in 1 ml of water. After stirring for one and a half hours at a temperature of -5oWhen -5oTo add a solution of 3.4 g of the dihydrate salt of divalent tin in 34 ml of concentrated hydrochloric acid. Stirred for 1 hour at room temperature, washed with concentrated hydrochloric acid, dried in a stream of dried nitrogen, getting to 0.67 g of the target hydrazine.

PREPARATIVE EXAMPLE 2.4

Hydrochloride 4-hydrazino-5,6,7,8-tetrahydronaphthalen-1-sulfonic

A) 4-Amino-5,6,7,8-tetrahydronaphthalen-1-acid

To a solution of 10 g of 5,6,7,8-tetrahydronaphthalene in 100 ml of 1,2-dichlorobenzene add the heated suspension of 20 g of sulfamic acid in 40 ml of N-methylpyrrolidone. Heated for 7 hours under stirring at a temperature of 150oC, filtered off, washed with dichlorobenzene, then with toluene. The precipitate is again suspended in 70 ml of water, neutralized to pH 7 with 5.5 ml of 30% sodium hydroxide solution. Filtered off the insoluble portion, the aqueous phase is extracted with ether. the pH Value of the aqueous phase was adjusted to 5 by addition of hydrochloric acid at the 5oC, the precipitate is filtered off, washed with water and fissility

To a solution of 3 g obtained at the stage And acid in 10 ml of water and 2 ml of 30% sodium hydroxide solution was added 1 g of sodium nitrite. Within 1 hour the solution was poured into 10 ml of concentrated hydrochloric acid, cooled to 5oC. After stirring for three hours at a temperature ofoSlowly add a solution of 7.5 g of the dihydrate salt of divalent tin in 15 ml of concentrated hydrochloric acid, keeping the temperature 5oC. Stirred for fifteen hours at room temperature, filtered and dried in vacuum, obtaining 2.86 g of the target product.

NMR spectrum (D2O-NaOD): 1,6 (MT, 4H); to 2.25 (MT, 2H); 2,9 (MT, 2H); 6.75 in (d, 1H); and 7.6 (d, 1H).

PREPARATIVE EXAMPLE 2.5

Hydrochloride 4-hydrazino-3-methylbenzamide

A) 4-Amino-3-methylbenzamide

This product is produced by catalytic hydrogenation of 3-methyl-4-nitrobenzamide. So pl.=124oC.

B) Hydrochloride of 4-hydrazino-3-methylbenzamide

0.5 g Obtained at the stage And compounds dissolved in 10 ml of 1 N. hydrochloric acid and 5 ml of concentrated hydrochloric acid. Cooled to 0oAnd add a solution of 230 mg of sodium nitrite in 3 ml of water. After incubation for 15 minutes at a temperature of -102O5getting 390 mg of the target product.

PREPARATIVE EXAMPLE 2.6

Hydrochloride of 2,3-dimethyl-4-hydrazinobenzene acid

To a solution of 4.5 g of 4-amino-2,3-dimethylbenzoic acid in 135 ml of concentrated hydrochloric acid, cooled to a temperature of -5oC, slowly add a solution of 1.87 g of nitrite in 7 ml of water. After stirring for two hours at a temperature of -5oS temperature -10oTo add a solution of 25 g of the dihydrate salt of divalent tin in 250 ml of concentrated hydrochloric acid, stirred for 30 minutes at a temperature of -5oWith, then for two hours at room temperature. The precipitate is filtered off, washed with 5 ml of concentrated hydrochloric acid, dried in a current of dry nitrogen, and then in a vacuum, getting 5.5 g of the target product.

NMR spectrum: 2,1 (s, 3H) and 2.4 (s, 3H); to 6.8 (d, 2H); and 7.6 (d, 2H); or 8.2 (s, 1H); 10 (ush.s, 2H).

PREPARATIVE EXAMPLE 2.7

Hydrochloride 4-hydrazino-3-methoxybenzoic acid

To a solution of 5 g of 4-amino-3-methoxybenzoic acid in 50 ml of concentrated hydrochloric acid, cooled to 0oC, slowly add a solution of 2.17 g of nitrification is o
C, for 30 minutes, add a solution of 23.6 g of the dihydrate salt of divalent tin in 20 ml of concentrated hydrochloric acid and 20 ml of water. After stirring for one and a half hours at a temperature of -10oWith the precipitate is filtered off, washed with 50 ml of pentane, receiving, after drying, 6 g of the target product.

The NMR spectrum of 3.8 (s, 3H); 7 (d, 1H); to 7.4 (s, 1H); 7.5 (a D. d, 1H); 8 (ush.s, 1H); 10,6 (ush.s, 2H).

PREPARATIVE EXAMPLE 2.8

Hydrochloride of 2-chloro-4-hydrazinophenyl

At a temperature of -5oWith mixed 5 g of 4-amino-2-chlorobenzonitrile with 40 ml of concentrated hydrochloric acid in 30 ml of tetrahydrofuran, add and 2.26 g of sodium nitrite in 30 ml water and stirred for two hours, then add 30 g of the dihydrate salt of divalent tin in 30 ml of concentrated hydrochloric acid and stirred for 30 minutes at a temperature of -5oC. After returning to room temperature, filtered nerastvorim part, add NaCl and again mix. The desired product crystallizes with NaCl, absorbed by ethanol, whereas NaCI filtered. After evaporation of the solvents gain of 4.25 g of the target product.

PREPARATIVE EXAMPLE 2.9

Hydrochloride 3-cyclopropylacetylene (obtained according to J. Am. Chem. Soc., 90, 3404 (1968)) in 100 ml of dimethylformamide add to 1.67 g of CuCN and boiled for 24 hours under reflux. Poured into 30 ml water, the precipitate is filtered off, washed with water, and then the precipitate is stirred for 30 minutes in a mixture of 59 ml of water and 25 ml of Ethylenediamine. After extraction with 100 ml of ethyl acetate, drying over sodium sulfate and evaporation in vacuo get 2,39 g of the target product.

NMR spectrum: 0,6 (m, 2H); 0,9 (m, 2H); 1,9 (m, 1H); 2,1 (s, 3H); and 7.3 (d, 1H); 7.5 (a D. d, 1H); 7,8 (d, 1H); 9,5 (ush.s, 1H).

B) Hydrochloride 4-amino-3-cyclopropylbenzene

The mixture 2,39 g obtained in stages a product in the form of a solution in 45 ml of ethanol with 36 ml of water and 5 ml of concentrated hydrochloric acid is stirred at the boil under reflux for 12 hours. The ethanol is evaporated in vacuo, the precipitate is filtered off, washed it with 1 ml of water and dried in vacuum, obtaining 1.5 g of the target product.

NMR SPECT: 0,5 (m, 2H); 0,9 (m, 2H); 1,6 (m, 1H); 6,7 (d, 1H); 7,1-7,3 (MT, 2H); 8 (ush.s, 2H).

In) Hydrochloride 4-amino-3-cyclopropylbenzene acid

1.3 g Obtained in stage B of the product in 21 ml of 50% KOH solution was stirred at the boil under reflux for 29 hours. After acidification to relevage product.

NMR spectrum: 0,5 (m, 2H); 0,9 (m, 2H); 1,7 (m, 1H); 5,9 (ush.s, 2H); and 6.6 (d, 1H); to 7.4 (s, 1H); 7.5 (a MT, 1H); 12 (ush.s, 1H).

G) of the Hydrochloride of 3-cyclopropyl-4-hydrazinobenzene acid

To a solution of 0.95 g obtained at the stage In the product in 22 ml of concentrated hydrochloric acid and 21 ml of acetic acid, cooled to a temperature of -5oC, slowly add a solution of 0.38 g of sodium nitrite in 4.5 ml of water and stirred for 1 hour and 15 minutes at a temperature of 0oC. is Cooled to -10oWith and slowly add a solution 3,76 g dihydrate salt of divalent tin in 8 ml of concentrated hydrochloric acid. After stirring for 4 hours at room temperature the precipitate is filtered off, washed with 2 ml of concentrated hydrochloric acid and dried in vacuum, obtaining 1 g of the target product.

NMR spectrum: 0,6 (m, 2H); 1 (m, 2H); 1,9 (m, 1H); and 7.1 (d, 1H); and 7.6 (s, 1H); 7,8 (d, 1H); and 8.4 (s, 1H); 10,7 (ush.s, 2H).

PREPARATIVE EXAMPLE 2.10

Hydrochloride 5-hydrazino-2-chlorbenzoyl acid

To a suspension of 5 g of 5-amino-2-chlorbenzoyl acid in 50 ml of concentrated hydrochloric acid, cooled to a temperature of -2oC, for 30 minutes, add a solution 2,11 g of sodium nitrite in 40 ml of water. Stirred for two hours at orida divalent tin in 20 ml of concentrated hydrochloric acid and 20 ml of water. Stirred for one and a half hours at 0oC, the precipitate is filtered off and dried, receiving 4 g of the target product.

NMR spectrum: 7,6 (ush.s, 2H), and 7.7 (ush.s, 1H); 8.4V (ush.s, 1H); 11.0 in (ush.s, 3H).

PREPARATIVE EXAMPLE 2.11

Hydrochloride 3-hydrazino-4-methylbenzoic acid

To a solution of 5 g of 3-amino-4-methylbenzoic acid in 120 ml of concentrated hydrochloric acid and 40 ml of acetic acid, cooled to a temperature of -5oC, for 30 minutes, add a solution to 2.74 g of sodium nitrite in 28 ml of water and stirred for 1 hour and 20 minutes at 0oC. After cooling to -10oSlowly add a solution of 27.6 g of chloride dihydrate divalent tin in 28 ml of concentrated hydrochloric acid. After stirring for 1 hour at room temperature, filtering off and washing the precipitate with 5 ml of 1 N. hydrochloric acid, drying over phosphorus pentoxide in vacuo get 6,15 g of the target product.

Using the above methods of obtaining, from an appropriately substituted aniline derivatives have the hydrazines described in table 1.

PREPARATIVE EXAMPLE 2.18

Oxalate of N-(4-hydrazino-3-isopropylphenyl)-4-methylbenzenesulfonamide

A) N-(2-Bromo-5-is ml of tetrahydrofuran is cooled to -30oWith add 100 ml of 2 M solution of isopropylacrylamide in ether and stirred for 30 minutes at a temperature of -30oC. Then added 10.3 ml of bromine at a temperature of -30oC, stirred for 15 minutes at this temperature, then allowed to stand until the temperature rises to 20oC. Then add 55 ml of triethylamine and stirred for 1 hour at room temperature. Add water, acidified to pH 3-4 by adding 10% hydrochloric acid, decanted organic phase, the aqueous phase is extracted with ether and the combined organic phases are dried over sodium sulfate. The organic phase is stirred in the presence of animal charcoal, filtered and concentrated in vacuo. The residue is treated with ethanol and vegascasinoonline the product is filtered under vacuum. Obtain 11.6 g of the target product. So pl.=132oC.

NMR spectrum: 1,0 (d, 6N); 2,32 (s, 3H); 3,12 (s, 1H); 7,14 (s, 1H); of 7.36 (d, 2H); the 7.65 (d, 2H); 8,08 (s, 1H); of 10.25 (ush.s, 1H).

B) N-(4-Amino-3-isopropylphenyl)-4-methylbenzenesulfonamide

For 7 hours at room temperature and pressure 1 bar hydronaut mixture of 11.5 g obtained at the previous stage of the connection and 1 g of 5% palladium-on-coal in 200 ml of methanol and 30 ml dimethylphenyl to pH 7 by adding 10% NaOH solution, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. Get 8 g of the target product.

NMR spectrum: 1,01 (d, 6N) and 2.4 (s, 3H); 2,89 (MT, 1H); 4,91 (ush.s, 2H); 6.42 per of 6.68 (m, 3H); to 7.35 (d, 2H); 7,56 (d, 2H); 9,38 (s, 1H).

C) the Oxalate of N-(4-hydrazino-3-isopropylphenyl)-4 - methylbenzenesulfonamide

Stirred at a temperature of 0oWith a mixture of 6.68 g obtained in the previous phase connections and 70 ml of concentrated hydrochloric acid, add a solution of 1.48 g of sodium nitrite in 5 ml of water and stirred for 1 hour at 0oC. Then add a solution 11,35 g dithionite of sodium in 60 ml of water and continue stirring for 1 hour at a temperature of 0oC. then add 120 g of sodium acetate in the form of a powder, 300 ml of water and stirred for 30 minutes atoC. the Reaction mixture was extracted with ethyl acetate, the organic phase is dried over sodium sulfate, filtered, the filtrate is added a solution of 1.98 g of oxalic acid in a minimum amount of ethanol and all concentrated in vacuo. The residue is treated with diisopropyl ether, stirred for 12 hours and the precipitated precipitate is filtered off under vacuum. Get 4,84 g of the target product, which used the La

A mixture of 4.6 g of 1-fluoro-2-methyl-4-nitrobenzene and 3 ml of hydrazine hydrate is added in 45 ml of propan-2-ol is refluxed for two hours. Add 3 ml of hydrazine hydrate is added, continue to boil under reflux for two hours and stirred overnight at room temperature. The precipitation is filtered off under vacuum. Gain of 3.53 g of the target product. So pl.=182oC.

PREPARATIVE EXAMPLE 2.20

The hydrobromide of N-(4-hydrazino-3-isobutylphenyl)-4-methylbenzenesulfonamide

A) N-(2-Bromo-5-isobutyl-4-nitrophenyl)-4 - methylbenzenesulfonamide

This connection receive according to the method described in stage a of Preparative example 2.18, on the basis of 10 g of N-(4-nitrophenyl)-4-methylbenzenesulfonamide in 100 ml of tetrahydrofuran and 42.6 ml of 2 M solution of Isobutyraldehyde in ether, then with 4.4 ml of bromine and 23.4 ml of triethylamine. Obtain 5.9 g of the target product. So pl.=170oC.

NMR spectrum: 0.8 in (d, 6N); 1,7 (MT, 1H); to 2.35 (s, 3H); 2,6 (d, 2H); to 7.2 (s, 1H); and 7.3 (d, 2H); to 7.4 (d, 2H); or 8.2 (s, 1H); of 10.25 (s, 1H).

B) N-(4-Amino-3-isobutylphenyl)-4 - methylbenzenesulfonamide

This connection receive according to the procedure described in stage B of Preparative example 2.18, on the basis of 4.7 g obtained at the previous stage is connected; ,5 (d, 1H); 6,65 (doctor d, 1H); to 7.35 (d, 2H); at 7.55 (d, 2H); and 9.4 (s, 1H).

C) the hydrobromide of N-(4-hydrazino-3-isobutylphenyl)-4-methylbenzenesulfonamide

This connection receive in accordance with the method described at the stage In Preparative example 2.18, based on 2.5 g obtained in the previous phase connection, 35 ml of concentrated hydrochloric acid, 50 ml of acetic acid and of 0.53 g of sodium nitrite, then 4,78 g dithionite of sodium in 50 ml of water, 140 g of sodium acetate and 70 ml of water. After stirring for 30 minutes at 0oS temperature 0oTo add Hydrobromic acid, vegascasinoonline the product is filtered under vacuum and dried. Get 1,9 g of the target product.

NMR spectrum: 0,65 (d, 6N); 1,6 (MT, 1H); 2,05 (d, 2H); 2,2 (s, 3H); 6,05 (ush.s, 1H); 6,4 (ush.s, 1H); 6,6-6,8 (m, 2H); to 7.2 (d, 2H); to 7.4 (d, 2H).

PREPARATIVE EXAMPLE 2.21

Oxalate of N-(4-hydrazino-3-cyclopentenyl)-4-methylbenzenesulfonamide

A) N-(2-Bromo-5-cyclopentyl-4-nitrophenyl)-4-methylbenzenesulfonamide

This connection receive according to the procedure described in stage a of Preparative example 2.18, on the basis of 15 g of N-(4-nitrophenyl)-4-methylbenzenesulfonamide in 100 ml of tetrahydrofuran and 64 ml of 2 M solution of cyclopentylamine in the air, then 6.8 ml of bromine and 35 of 1.5-1.7 (m, 4H); 1,95 (MT, 2H); of 2.36 (s, 3H); 3,2 (CT, 1H); for 7.12 (s, 2H); to 7.4 (d, 2H); 7.7 (d, 2H); 8,08 (s, 1H).

B) N-(4-Amino-3-cyclopentenyl)-4-methylbenzenesulfonamide

This connection receive according to the procedure described in stage B of Preparative example 2.18, on the basis of 6 g obtained at the previous stage of the connection. Gain of 4.25 g of the target product. So pl.=128oC.

NMR-spectrum (DMSO+TFUC): 1,25 (MT, 2H); 1.5 to about 1.75 (m, 4H); 1,95 (MT, 2H), 2,3 (s, 3H); 3,0 (CT, 1H); 7,0 (doctor d, 1H); for 7.12 (d, 1H); to 7.2 (d, 1H); 7,34 (d, 2H); the 7.65 (d, 2H).

C) the Oxalate of N-(4-hydrazino-3-cyclopentenyl)-4-methylbenzenesulfonamide

This connection receive in accordance with the method described at the stage In Preparative example 2.18, according to 3.35 g obtained in the previous phase connection, 20 ml of sulfuric acid, 50 ml of acetic acid, 10 ml of water and 0.69 g of sodium nitrite, and then 5.5 g of dithionite of sodium in 50 ml of water and 200 g of sodium acetate and 300 ml of water. Get 2,42 g of the target product.

PREPARATIVE EXAMPLE 2.22

Hydrochloride 4-hydrazino-2-isopropylbenzoic acid

A) 4-Iodine-3-isopropylacetanilide

This connection receive according to the method described in Bull. Soc. Chim. Jap., 62, 1349 (1989).

To a solution of 5 g 3-isopropylacetanilide in 150 ml of acetic acid at room temperature until tryout in vacuum, the residue is treated with 100 ml of 5% Hydrosulphite solution of sodium, adjusted the pH value to 5-6 by adding 10% sodium carbonate solution, extracted 4 times with 200 ml of chloroform and the organic phase is dried over sodium sulfate. After filtration the filtrate chromatographic per 100 g of aluminum oxide, elwira chloroform. Gain of 5.2 g of the target product.

NMR spectrum: 1,1 (d, 6N); 2,0 (s, 3H); to 3.06 (m, 1H); 7,28 (doctor d, 1H); 7.5 (d, 1H); 7,72 (d, 1H); 10,0 (ush.s, 1H).

B) 4-Iodine-3-isopropylaniline

A mixture of 5.1 g obtained at the previous stage of the compound in 40 ml of 96% ethanol and 25 ml of concentrated sodium hydroxide solution is refluxed for 6 hours. Concentrated in vacuo, extracted with ether, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. Get 5 g of the target product in the form of oil.

NMR spectrum: 1,16 (d, 6N); to 2.94 (m, 1H); 5,2 (ush.s, 2H); 6,2 (doctor d, 1H); and 6.6 (d, 1H); to 7.4 (d, 1H).

B) 4-Amino-2-isopropylbenzoic acid

To a solution of 5 g obtained at the preceding stage connection in 60 ml of dimethylformamide, add 40 ml of water and 11 g of potassium carbonate, then the solution Tegaserod within 10 minutes by ozonation of nitrogen. Then add the ect is placed in an atmosphere of carbon monoxide under a pressure of 1 bar for 10 hours under stirring. The solution is filtered, the filtrate is washed 4 times with 20 ml of water and concentrated in vacuo. The residue is treated with 50 ml of water and 10 ml of saturated solution of sodium chloride, the aqueous phase washed with ether, acidified to pH 3.5-4 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. Receive 2 g of crude product, which was treated with 20 ml of a saturated solution of gaseous hydrogen chloride in methanol and during the night refluxed. Concentrated in vacuo, the residue treated with 20 ml of water, alkalinized to pH 8 by addition of concentrated NaOH solution and extracted with 30 ml dichloromethane. To the organic phase, add 0.8 ml of acetic anhydride, sodium bicarbonate and sodium sulfate and stirred. After filtration, the filtrate was concentrated in vacuo and the residue chromatographic on the silicon dioxide, elwira a mixture of dichloromethane and ether in a volume ratio of 50: 50. Obtain 0.8 g of methyl ester of 4-acetamido-2-isopropylbenzoic acid in the form of oil. A mixture of the obtained product and 3 g of KOH in 10 ml of water and 2 ml of 1,2-dimethoxy the mixture is washed with ether, acidifying the aqueous phase to pH 3-4 by addition of concentrated hydrochloric acid, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. Obtain 0.6 g of the target product.

NMR spectrum: 1,17 (d, 6N); 4,0 (MC, 1H); 5,7 (ush.s, 2H); 6,36 (doctor d, 1H); to 6.80 (d, 1H); and 7.6 (d, 1H); 11,80 (ush.s, 1H).

G) of the Hydrochloride of 4-hydrazino-2-isopropylbenzoic acid

A mixture of 0.5 g obtained at the previous stage of the compound in 7 ml of concentrated hydrochloric acid cooled to 0oC, add a solution of 0.23 g of sodium nitrite in 4 ml of water and stirred for one and a half hours at a temperature of 0oC. is Cooled to -10oAnd add a solution of 2.6 g of the dihydrate salt of divalent tin in 5 ml of concentrated hydrochloric acid and 3 ml of water and stirred for two hours at a temperature of 0oC. the precipitation is sucked off, washed with concentrated hydrochloric acid and dried at 50oWith the vacuum. Obtain 0.36 g of the target product.

NMR spectrum: 1,15 (d, 6N); 3,98 (m, 1H); 6,7 (doctor d, 1H); of 6.96 (d, 1H); 7,8 (d, 1H); 8,2 (ush.s, 1H); 13 (ush.s, 4H).

PREPARATIVE EXAMPLE 2.23

Hydrochloride 1 hydrazino-4-nitro-5,6,7,8 - tetrahydronaphthalene

A) 1-Acetamido-5,6,7,8-tetrapeptide and 18.6 g of acetic anhydride in 230 ml of dichloromethane. Concentrated in vacuo, the residue is treated with ether and the precipitated precipitate is filtered off under vacuum. Get to 26.8 g of the target product. So pl.=158oC.

B) 1-Amino-4-nitro-5,6,7,8-tetrahydronaphthalen

A mixture of 13 g obtained at the preceding stage connection in 72 ml of concentrated sulfuric acid cooled to 0oWith add mixture 4,55 ml of nitric acid (tank weight=1,4) and 22 ml of concentrated sulfuric acid and stirred for 45 minutes at a temperature of 0oC. the Reaction mixture is poured on ice and the precipitated precipitate is filtered off under vacuum. The residue is treated with 145 ml of ethanol, 30 ml of concentrated hydrochloric acid and 30 ml of water, then refluxed for one and a half hours. The reaction mixture is evaporated to a volume of 70 ml, the remaining solution was added 220 ml of water, adjusted pH to 7 by adding concentrated ammonium hydroxide solution, the precipitation is filtered under vacuum and dried. The residue is treated with 210 ml of nitrobenzene, cooled to 0oWith, and within 50 minutes after the resulting solution was bubbled current of gaseous hydrogen chloride. The precipitation is filtered under vacuum and washed with ether. Acidobasic water and the precipitate is filtered off under vacuum. Gain of 5.15 g of the target product (after drying). So pl.=114oC.

In) Hydrochloride 1 hydrazino-4-nitro-5,6,7,8-tetrahydronaphthalene

A mixture of 3.8 g obtained at the preceding stage connection in 70 ml of concentrated hydrochloric acid is cooled to 3oC, add a solution of 1.34 g of sodium nitrite in 2 ml of water and stirred for two hours at a temperature of 3oC. Then add a solution of 18.2 g of the dihydrate salt of divalent tin in 90 ml of concentrated hydrochloric acid and stirred for 30 minutes at a temperature of 3oWith, then leave the temperature to rise to room. The precipitation is filtered under vacuum and dried. Obtain 6.3 g of the target product in a mixture with salts of tin.

NMR-spectrum (DMSO+TFUC): 1,7 (MT, 4H); to 2.55 (MT, 2H); to 2.85 (MT, 2H); to 6.88 (d, 1H), a 7.85 (d, 1H).

PREPARATIVE EXAMPLE 2.24

3-Diethylamino-N-(4-isopropyl-3 - hydrazinophenyl)propionamide

A) Oxalate 3 diethylamino-N-(4-isopropyl-3 - nitrophenyl)propionamide

4 g of 4-Isopropyl-3-nitroaniline (obtained according to J. Orq. Chem., 19, 1067 (1954)) is treated by boiling under reflux for 1 hour together with 8,14 ml of bis(trimethylsilyl)ndimethylacetamide in 20 ml of acetonitrile, then add chlorimipramine. After stirring for 1 hour at room temperature, evaporated to dryness, the residue is extracted with dichloromethane, wash the extract with water, then with 5% sodium hydroxide solution. After drying over sodium sulfate evaporated in vacuo, the resulting oil was dissolved in minimum quantity of ethanol, add 1.2 g of oxalic acid. After stirring for two hours, filtered, receiving 4.5 g of the target oxalate. So pl.=165oC.

B) Oxalate 3 diethylamino-N-(4-isopropyl-3 - AMINOPHENYL)propionamide

A solution of 4.5 g obtained in the previous phase of nitro-derivatives in 100 ml of methanol and 10 ml of dimethylformamide hydronaut for 5 hours in the presence of Raney Nickel. After filtering off the catalyst, the filtrate was concentrated in vacuo, precipitated by adding diisopropyl ether and stirred for 1 hour at room temperature. After filtering off get 3 g of the target aniline oxalate. So pl.=127oC.

C) 3-Diethylamino-N-(4-isopropyl-3 - hydrazinophenyl)propionamide

To a mixture of 2.7 g obtained in the previous phase amine and 30 ml of concentrated hydrochloric acid, cooled to 0oTo add to 0.67 g of sodium nitrite, dissolve Aut 5 g dithionite sodium, dissolved in minimum amount of water, and stirred for further 30 minutes at 0oC. Add 50 g of sodium acetate in the form of a powder and stirred for 30 minutes at 0oC. Add 50 g of water and some impurities extracted with ethyl acetate. The aqueous phase is saturated with sodium chloride, raise pH to 9 with 20% aqueous ammonium hydroxide solution, extracted with dichloromethane, drying the extract over sodium sulfate and evaporated in vacuum. The residue crystallizes from pentane during the night, it sucked, getting 3,26 g target hydrazine. So pl.=77-80oC.

The methodology of the esters of formulas (IIA) and (II)

PREPARATIVE EXAMPLE 3.1

Methyl ester 1-(4-carboxy-2-isopropylphenyl)-5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II a); R'1- 4-CO2H; R2- 2-isopropyl; R3- H; R4- CH3)

A mixture containing 0.96 g of the compound obtained in Preparative example 2.1, and 1.2 g of compound a, obtained in Preparative example 1.1, in 15 ml of acetic acid is refluxed for 5 hours. After aging for three days at room temperature, the reaction mixture was poured into a mixture of ice water. The precipitation from the -230oC.

NMR spectrum: 0,85 (d, 6N); 2,55 (MC, 1H); 3,5 (C, 6N); of 3.75 (s, 3H); 6.5 in (d, 2H); 6.75 in (s, 1H); 7,05 of 7.3 (m, 2H); 7.7 (d, 1H); of 13.05 (ush.s, 1H).

PREPARATIVE EXAMPLE 3.1 BIS

Ethyl ester of 1-(4-carboxy-2-isopropylphenyl)-5-(2,6-acid)pyrazole-3-carboxylic acid

By reacting the compounds obtained according to Preparative example 2.1 or 2.1 bis connection AND1according to the Preparative method of example 3.1, after recrystallization from ethyl acetate to obtain the target ethyl ester. So pl.=231oC.

PREPARATIVE EXAMPLE 3.2

Methyl ester 1-[4-[N-methyl-N-(3-N',N'- dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] -5-(2,6-acid)pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CON(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; R4- CH3)

A) Methyl ester of 1-(4-chloroformyl-2-isopropylphenyl)-5-(2,6-acid)pyrazole-3-carboxylic acid

Prepare a mixture containing 26 g of the compound obtained in Preparative example 3.1, and 170 ml of thionyl chloride, stirred for 1 day at room temperature, then evaporated in vacuo, the residue is treated with dichloromethane, evaporated. The operation was repeated 3 times.

B) Erbanova acid

To 50 ml of dichloromethane added to 9.3 ml of triethylamine and 9.9 ml of N,N,N'-trimethyl-1,3-propandiamine. In nitrogen atmosphere add obtained in the previous phase of the ether in 280 ml of dichloromethane and stirred for three and a half hours at room temperature. After washing with water (2 times), dried over magnesium sulfate and evaporated in vacuum. The residue is treated with ether. After filtering off nerastvorimaya parts and evaporation the residue chromatographic on the silicon dioxide, elwira a mixture of dichloromethane with methanol and water in a volume ratio of 95:5:0.5 to 88:12:0,8. Obtain 24.5 g of the target product.

The NMR spectrum of 0.95 (d, 6N); and 1.7 (m, 2H); 1,9-2,4 (m, 8H); 2,95 (split singlet, 3H); 3,5 (m, 2H); 3,7 (C, 6N); 3,9 (s, N); 6,7 (d, 2H); 6,9 (s, 1H); and 7.1-7.5 (m, 4H).

PREPARATIVE EXAMPLE 3.2 BIS

Ethyl ester 1-[4-[N-methyl-N-(3-N',N'- dimethylaminopropyl)carbarnoyl]-2-isopropylphenyl]-5-(2,6-acid)pyrazole-3-carboxylic acid

A) Ethyl ester of 1-(4-chloroformyl-2-isopropylphenyl)-5-(2,6-acid)pyrazole-3-carboxylic acid

To 50 ml of thionyl chloride, cooled to 5oTo add 26 g of the product obtained in Preparative example 3.1 or 3.1 bis, and stirred for 5 hours at room temperature under borborygmi; operation is repeated 2 times.

You can also obtain the acid chloride of the acid according to the following procedure a'.

A') To a solution of 5 g obtained in Preparative example 3.1 or 3.1 bis product in 50 ml of dichloromethane add 2.5 ml of thionyl chloride and refluxed for three hours, evaporated in vacuo, the residue is treated with dichloromethane and evaporated under vacuum; the operation is repeated 2 times.

B) Ethyl ester of 1-[4-[N-methyl-N-(3-N',N'- dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl]-5-(2,6-acid)pyrazole-3-carboxylic acid

To a solution of 9 ml of triethylamine and 9.5 ml of N,N,N'-trimethyl-1,3-propandiamine in 50 ml of dichloromethane in an atmosphere of dry nitrogen was added a solution of the carboxylic acid obtained in stage A, in 220 ml of dichloromethane and stirred over night. The reaction mixture was washed 2 times with water, the aqueous phase is extracted 2 times with dichloromethane. The combined organic phases are dried over magnesium sulfate and evaporated in vacuum. The residue is stirred with 300 ml of ether, filtered off nerastvorim part, the filtrate discolor with animal charcoal and evaporated, receiving 28.8 g of the desired product in the form of butter.

NMR-spectrum (DMSO+TFUC): 1 (d, 6N); 1,3 (t, 3>The product of stage B can also be obtained according to the following method.

B') To a solution of 1.32 g of N,N,N'-trimethyl-1,3-propandiamine 37.5 ml of 3 n sodium hydroxide solution add a solution of the carboxylic acid obtained in stage A', 37.5 ml of dichloromethane. After stirring for 1 hour, add 25 ml of chloroform and 25 ml of water, decanted, the organic phase is separated, dried over sodium sulfate and evaporated in vacuum, obtaining of 6.1 g of the target product.

PREPARATIVE EXAMPLE 3.3

Methyl ester 1-[4-[N-(2-cyanoethyl)carbarnoyl] -2 - isopropylphenyl]-5-(2,6-acid)pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CONHCH2CH2CN; R2- 2-isopropyl; R3- H; R4- CH3)

0.935 g 3-Aminopropionitrile-profumata mix from 3.7 ml of 1,3 n sodium hydroxide solution, extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. The residue is treated with 6 ml of dichloromethane, add to 0.96 ml of triethylamine, then slowly add a solution of 2.45 g of compound obtained in stage a of Preparative example 3.2, in 30 ml of dichloromethane. Stirred over night at room temperature and under nitrogen atmosphere. Otfit the th, dried over sodium sulfate and the solvent is evaporated in vacuum. Obtain 2.24 g of the target product. So pl.=114-116oC (decomposition).

NMR spectrum: 1 (d, 6N); 2,7 (MT, 1H); and 2.8 (t, 2H); 3,5 (K, 2N); the 3.65 (s, 6N); a 3.9 (s, 3H); 6,7 (d, 2H); 6,9 (s, 1H); 7.3 to 7.4 (m, 2H); of 7.75 (d, 1H); 7,9 (s, 1H); 9 (t, 1H).

Entering into cooperation with the corresponding primary amine with the compound obtained in stage a of Preparative example 3.2, and following the procedure described in Preparative example 3.2, stage B, get esters described in table 2.

PREPARATIVE EXAMPLE 3.12

Methyl ester 5-(2,6-acid)-1-(2-isopropyl-4-sulfophenyl)pyrazole-3-carboxylic acid (formula (II a); R'1- 4-SO3H; R2- 2-isopropyl; R3- H; R4- CH3)

Within 5 hours refluxed mixture of 0.82 g of 3-isopropyl-4 - hydrazinobenzothiazole obtained in Preparative example 2.2, and 1.26 g of compound a, obtained in Preparative example 1.1, in 15 ml of acetic acid. After evaporation the residue is dissolved in dichloromethane, the resulting solution is washed with 1 N. hydrochloric acid and discolor activated carbon, dried, evaporated, the residue after evaporation was stirred at the boiling reverse x is S="ptx2">

NMR spectrum: 1 (d, 6N); 2,6 (MT, 1H); 3,6 (C, 6N); and 3.8 (s, 3H); and 6.6 (d, 2H); at 6.8 (s, 1H); to 7.15 (d, 1H); and 7.3 (t, 1H); to 7.4 (d, 1H); 7.5 (a s, 1H).

PREPARATIVE EXAMPLE 3.13

Methyl ester 5-(2,6-acid)-1-[2-isopropyl-4-(N-methyl-N-(3-N', N'-dimethylaminopropyl)aminosulfonyl) phenyl] pyrazole-3-carboxylic acid (formula (IIA); R1- -4-SO2N(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; R4- CH3)

A) Methyl ester of 5-(2,6-acid)-1-(4 - chlorosulfonyl-2-isopropylphenyl)pyrazole-3-carboxylic acid

1,08 g Obtained in Preparative example 3.12 product and 4 ml of phosphorus oxychloride was stirred at room temperature for 24 hours, then continue mixing at a temperature of 70oC for an additional 24 hours. The reaction medium is evaporated with toluene (2 times) and obtain 1.6 g of the target product.

B) Methyl ester of 5-(2,6-acid)-1-[2 - isopropyl-4-(N-methyl-N-(3-N', N'-dimethylaminopropyl)aminosulfonyl)phenyl]pyrazole-3-carboxylic acid

To a suspension of 1.6 g obtained at the previous stage of the product in 10 ml of toluene and 5 ml of dichloromethane added to 1.8 ml of N,N,N'-trimethyl-1,3-propandiamine, then 2 ml of triethylamine. Stirred for three hours at room the Finance to dryness, the residue is extracted with ether, then with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated in vacuum. Obtain 1.13 g of the target product.

NMR spectrum: 0,85 (d, 6N); to 1.45 (MT, 2H); 2 (C, 6N); 2,6 (C+MT, 4H); to 2.85 (t, 2H); 3,5 (C, 6N); and 3.8 (s, 3H); 6.5 in (d, 2H); at 6.8 (s, 1H); to 7.2 (t, 1H); to 7.4 (d, 1H); 7.5 to about 7.6 (m, 2H).

PREPARATIVE EXAMPLE 3.14

Methyl ester 5-(2,6-acid)-1-(4-carboxy - 5,6,7,8-tetrahedronal-1-yl)pyrazole-3-carboxylic acid (formula (II a); R'1- 4-CO2H; R2, R3- -(CH2)4-; R4- CH3)

Stirred for two hours at boiling under reflux a mixture of 0.67 g of hydrazine obtained in Preparative example 2.3, and of 0.83 g of compound in 6 ml of acetic acid. Extracted with dichloromethane, washed with water the organic phase, dried over magnesium sulfate and evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira a mixture of dichloromethane with methanol in a volume ratio of 100:2, gaining 0.7 g of the target product.

NMR spectrum: 1,4-2 (m, 4H); 2,3-3,1 (m, 4H); 3,4-4 (m, N); and 6.6 (d, 2H); of 6.8 to 7.6 (m, 4H); 12,95 (ush.s, 1H).

PREPARATIVE EXAMPLE 3.15

Methyl ester 5-(2,6-acid)-1-[4-[N-(3-N', N'-dimethylaminopropyl)carbarnoyl] -5,6,7,8-tetrahedronal-1 - yl]pyrazole-3-carbon is/SUB>-; R4- CH3)

Within one and a half hours at a temperature of 40oWith a heated solution of 0.7 g of the product obtained in Preparative example 3.14, 6 ml of thionyl chloride and 30 ml of dichloromethane. Evaporated in vacuo, then the resulting acid chloride acid dissolved again in 5 ml of dichloromethane, cooled to 5oTo add 0,225 ml of N,N-dimethylpropanediamine and 0,225 ml of triethylamine. After stirring for two hours at room temperature the mixture is evaporated in vacuo, the residue is again dissolved in dichloromethane, the resulting solution was washed with water, dried over magnesium sulfate and evaporated in vacuum, obtaining 0,79 g of the target product.

PREPARATIVE EXAMPLE 3.16

Methyl ester 5-(2,6-acid)-1-(4-sulfo-5,6,7,8-tetrahedronal-1-yl)pyrazole-3-carboxylic acid (formula (II a); R'1- 4-SO3H; R2, R3- -(CH2)4-; R4- CH3)

Over 4.5 hours refluxed mixture of 0.5 g of hydrazine obtained in Preparative example 2.4, and 0.62 g of compound in 4 ml of acetic acid. Evaporated in vacuo, the residue is again dissolved in dichloromethane, the resulting solution was washed 2 times with 1 N. hydrochloric acid, dried over magnesium sulfate and evaporated,9 (m, 2H); to 7.35 (t, 1H); at 7.55 (d, 1H).

PREPARATIVE EXAMPLE 3.17

Methyl ester 5-(2,6-acid)-1-[4-N-methyl-N-(2-N',N'-dimethylaminoethyl)aminosulfonyl] -5,6,7,8-tetrahedronal-1-yl] pyrazole-3-carboxylic acid (formula (IIA); R1- 4-SO2N(CH3)(CH2)2N(CH3)2; R2, R3- (CH2)4; R4- CH3)

A mixture containing 1 g of the acid obtained in Preparative example 3.16, and 3 ml l3, stirred for 5 hours at room temperature, then for 3.5 hours at a temperature of 70oC. Evaporated in vacuo, then add toluene and evaporated in vacuum (2 times). Thus obtained in 10 ml of dichloromethane solution sulphonylchloride added to a solution of 1.5 ml N,N, N'-trimethylethylenediamine and 1.5 triethylamine in 10 ml dichloromethane at a temperature of 5oC. Stirred for four days at a temperature of 10oC, filtered and evaporated to dryness. Once dissolved again in dichloromethane, washing with water, extraction of the aqueous phase with dichloromethane the organic phase is dried over magnesium sulfate and evaporated in vacuum, obtaining 1.07 g of the target sulfonamida. So pl.=90oC.

The NMR spectrum is 1.6-1.8 (m, 4H); 2,1 (s, 6N); 2,35 (t, 2H); 2,4-2,6 (m, 2H); 2,9 (s, 3H); 3,1 (MT/BR> Methyl ester 5-(2,6-acid)-1-(4-carbarnoyl-2-were)pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CONH2; R2- 2-CH3; R3- H; R4- CH3)

Suspension 0.39 g of hydrazine obtained in Preparative example 2.5, and 450 mg of the compound in 5 ml of acetic acid is refluxed for 8 hours. To the reaction medium, add 100 ml of water, precipitated precipitate is filtered off, then bring in 10 ml of diisopropyl ether and refluxed for 30 minutes, then filtered. Receive 300 mg of the target product. So pl.=219oC. By filtration of the aqueous phase after 24 hours, receive a second portion in the amount of 70 mg of the desired product in the form of needles.

NMR spectrum: 2,05 (s, 3H); 3,5 (C, 6N); and 3.8 (s, 3H); and 6.6 (d, 2H); at 6.8 (s, 1H); 7 (d, 1H); to 7.2 (t, 1H); 7,4 (ush.s, 1H); and 7.6 (d, 1H), and 7.7 (s, 1H); 7,9 (ush.s, 1H).

PREPARATIVE EXAMPLE 3.19

Methyl ester 5-(2,6-acid)-1-(4-carboxy-2,3-dimetilfenil)pyrazole-3-carboxylic acid (formula (II a); R'1- 4-CO2H; R2- 2-CH3; R3- 3-CH3; R4- CH3)

Under stirring for three hours refluxed mixture of 4.5 g of the product obtained in Preparative example byvaut the precipitation, washed it with 50 ml of water. After stirring in 50 ml of ether, filtering off, drying in vacuum over P2ABOUT5get 5 g of the target product. So pl.=240oC.

PREPARATIVE EXAMPLE 3.20

Methyl ester 5-(2,6-acid)-1-[2,3-dimethyl-4-[N-(2-N',N'-dimethylaminoethyl)carbarnoyl]phenyl]pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CONH(CH2)2N(CH3)3; R2- 2-CH3; R3- 3-CH3; R4- CH3)

After heating for six hours at a temperature of 40oWith a solution of 2 g of the product obtained in Preparative example 3.19, 10 ml of thionyl chloride and 40 ml of dichloromethane, this solution is evaporated in vacuo, the obtained acid chloride acid dissolved again in 10 ml of dichloromethane and the resulting solution was poured into a solution of 0.54 ml of N,N-diethylaminoethylamine in 10 ml of dichloromethane. Add to 0.68 ml of triethylamine and stirred for two hours at room temperature. After evaporation in vacuo, extraction with 100 MP dichloromethane, washing with water, drying over magnesium sulfate and evaporation in vacuo obtain 1.8 g of the target product.

NMR spectrum: 1,9 (s, 3H); 2,2 (C+C, N) and 2.4 (t, 2H); 3,4 (m, 2H); 3,6 (C, 6N); and 3.8 (s, 3H); and 6.6 (d, 2H); at 6.8 (s, 1H(4-carboxy-2-methoxyphenyl)pyrazole-3-carboxylic acid (formula (II); R'1- 4-CO2H; R2- 2-OCH3; R3- H; R4- CH3)

Stirred for 6 hours while boiling under reflux a mixture of 4.8 g of the product obtained in Preparative example 2.7, and 5.6 g of compound in 60 ml of acetic acid. After deposition of 300 ml of ice water, stirring for 30 minutes, filtering off, washing with water and then with pentane and drying the precipitate obtain 6 g of the target product. So pl.=210oC.

PREPARATIVE EXAMPLE 3.22

Methyl ester 5-(2,6-acid)-1-[-4-[N-methyl-N-(2-N',N'-diethylaminoethyl)carbarnoyl] -2-methoxyphenyl] pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CON(CH3)(CH2)2N(C2H5)2; R2- 2-OCH3; R3- H; R4- CH3)

Within 3.5 hours refluxed solution of 2.5 g obtained in Preparative example 3.21 product in 30 ml of dichloromethane and 5 ml of thionyl chloride. After evaporation in vacuum with subsequent two azeotropic authonomy with 20 ml of dichloromethane formed acid chloride acid dissolved again in 40 ml of dichloromethane, are added to a solution containing 1.1 ml of N, N-diethyl-N'-methylethylenediamine and 1 ml of triethylamine in 40 ml of dichloromethane, and stirred silicon, elwira gradient of solvents from a mixture of dichloromethane with methanol in a volume ratio of 90:10 mixture of dichloromethane with methanol and water in a volume ratio of 80:20:0,7 getting 1.73 g of the target product.

NMR spectrum: 07-1,1 (MT, 6N); 2,2-3,7 (MT, 20N); 3,85 (s, 3H); 6,55 (d, 2H); at 6.8 (s, 1H); 6,95 (MT, 2H); 7,3 (MT, 2H).

PREPARATIVE EXAMPLE 3.23

Ethyl ester of 1-(4-carboxy-2-chlorophenyl)-5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R'1- 4-CO2H; R2- 2-Cl; R3- H; R4- CH3)

3-Chloro-4-Gerasimenya acid described in U.S. patent 3959309. This acid number of 5.6 g and 8.75 g of compound1in 100 ml of acetic acid is refluxed for 6 hours. The reaction mixture is poured onto 500 ml of ice water, the precipitation is filtered off, then washed the last of the water, pentane and diisopropyl ether. Then it is dried in vacuum, obtaining 2 g of the target compound.

PREPARATIVE EXAMPLE 3.24

Ethyl ester of 5-(2,6-acid)-1-[4-[N-methyl-N-(2-N',N'-diethylaminoethyl)carbarnoyl]-2-chlorophenyl]pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CON(CH3)(CH2)2N(C2H5)2; R2- 2-Cl; R3- H; R4CH

NMR-spectrum (DMSO+TFUC): or 2.8 (s, 3H); 3-3,7 (m, 17H); and 6.6 (d, 2H), 6,8 (s, 1H); 7,05 (m, 2H); and 7.3 (m, 2H).

PREPARATIVE EXAMPLE 3.25

Ethyl ester of 5-(2,6-acid)-1-[4-(N-(2-morpholinoethyl)carbarnoyl)-2-chlorophenyl] pyrazole-3-carboxylic acid (formula (IIa); ; R2- 2-Cl; R3- H; R4- CH3)

Stirred for four hours while boiling under reflux the solution 2,63 g of the product obtained in Preparative example 3.23, 4.5 ml of thionyl chloride and 30 ml of dichloromethane. After igrid acid dissolved again in 40 ml of dichloromethane, add the resulting solution to a solution of 0.9 ml of 4-(2-amino-ethyl)research and 1 ml of triethylamine in 4 ml of toluene. After stirring for 15 hours at room temperature, evaporation in vacuo, dissolving again the residue in 200 ml of dichloromethane, washing with 100 ml of saturated solution of sodium chloride, drying over sodium sulfate and evaporation in vacuo get 3 g of the target product.

NMR spectrum: 1,3 (t, 3H); 2,3-2,6 (MT, 6N); 3,3 (MT, 2H); 3,5 (MT, 10H); 4,3 (KD, 2H); 6,55 (d, 2H); at 6.8 (s, 1H); and 7.1 to 7.4 (MT, 3H); 6.75 in (D. d, 1H); 6,9 (doctor d, 1H); 8,6 (t, 1H).

PREPARATIVE EXAMPLE 3.26

Methyl ester 5-(2,6-acid)-1-(3-chloro-4-cyanophenyl)pyrazole-3-carboxylic acid (formula (II); R'1- 4-CN; R2- 3-Cl; R3- H; R4- CH3)

On a water bath for two hours, heated mixture of 4.2 g of the compound obtained in Preparative example 2.8, and 6 g of compound a in 10 ml of acetic acid. The reaction mixture was poured into ice water, the precipitate is filtered off, then dried, obtaining of 3.78 g of the target product.

PREPARATIVE EXAMPLE 3.27

Methyl ester 5-(2,6-acid)-1-[4-carboxy-2-cyclopropylethyl] pyrazole-3-carboxylic acid (formula (II a); R'1- 4-CO2H; R2

NMR spectrum: 0,5 (m, 2H); 0,8 (m, 2H); 1,3 (t, 3H); 1,5 (m, 1H); 3,6 (C, 6N); 4,3 (KD, 2H); and 6.6 (d, 2H); 6,9 (s, 1H); and 7.3 (m, 3H); 7.7 (d, 1H); 13 (ush.s, 1H).

PREPARATIVE EXAMPLE 3.28

Methyl ester 5-(2,6-acid)-1-[4-[N-methyl-N-(2-N',N'-diethylaminoethyl)carbarnoyl] -2-cyclopropylethyl]pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CON(CH3)(CH2)2N(C2H5)2; R2- 2-cyclopropyl; R3- H; R4- CH3)

For 5 hours, heated at 100oTo a solution of 1.27 g of the product obtained in Preparative example 3.27, 28 ml of toluene and 2 ml of thionyl chloride. After evaporation in vacuum with subsequent two azeotropic authonomy with 30 ml of toluene is obtained the acid chloride of the acid is again dissolved in 19 ml of dichloromethane, slowly poured into a solution of 0.53 ml of N,N-diethyl-N'-methylethylenediamine and 0.61 ml of triethylamine in 1.9 ml of toluene. After stirring for 12 hours at room temperature, evaporation under vacuum, extraction of the residue with 100 ml of dichloromethane, washing extract">

NMR spectrum: 0,4-1 (m, 10H); 1,2 (t, 3H); 1,4 (MT, 1H); 2.1 to 3 (m, N); 3,5 (m, 8H); 4,3 (KD, 2H); 6.5 in (d, 2H); and 6.6 (s, 1H); 6.8 cm (s, 1H); 6,9-7,2 (MT, 3H).

PREPARATIVE EXAMPLE 3.29

Methyl ester 5-(2,6-acid)-1-[3-carboxy-4-chlorophenyl] pyrazole-3-carboxylic acid (formula (II a); R'1- 3-CO2H; R2- 4-Cl; R3- N; R4- CH3)

Under stirring for 5 hours refluxed mixture of 4 g of the product obtained in Preparative example 2.10, and 4.6 g of compound in 60 ml of acetic acid. Pour 100 ml of ice water, the precipitate is filtered off, washed with 5 ml water, then with 20 ml of ether, dried in vacuum, obtaining 3 g of the target product. So pl.=206oC.

NMR spectrum: 3,55 (C, 6N); 3,85 (s, 3H); 6,7 (d, 2H); 6,9 (s, 1H); 7,35 (doctor d, 1H); to 7.4 (t, 1H); at 7.55 (d, 1H); 7.7 (d, 1H).

PREPARATIVE EXAMPLE 3.30

Methyl ester 5-(2,6-acid)-1-[3-[N-methyl-N-(2-N',N'-dimethylaminoethyl)carbarnoyl] -4-chlorophenyl] pyrazole-3-carboxylic acid (formula (IIA); R1- 3-CON(CH3)(CH2)2N(CH3)2; R2- 4-Cl; R3- N; R4- CH3)

With stirring for 3.5 hours at a temperature of 60oWith a heated solution of 1.5 g obtained in Preparative example 3.29 product in 20 ml dig oraut in 10 ml of dichloromethane and the resulting solution was poured into a solution of 0.5 ml of N,N,N'- trimethylethylenediamine and 0.6 ml of triethylamine in 2.5 ml of toluene, then mix all for 15 hours at room temperature. After evaporation in vacuo, dissolving the residue in 100 ml of dichloromethane, washing with 100 ml of water, drying over sodium sulfate and evaporation in vacuo obtain 0.8 g of the target product.

PREPARATIVE EXAMPLE 3.31

Methyl ester 5-(2,6-acid)-1-[5-carboxy-2-were]pyrazole-3-carboxylic acid (formula (II a); R'1- 5-CO2H; R2- 2-CH3; R3- H; R4- CH3)

When stirring for one and a half hours refluxed mixture 6,15 g of the product obtained in Preparative example 2.11, and 7,76 g of compound a in 100 ml of acetic acid. After concentration in vacuo to a volume of 5 ml, deposition in 20 ml of ice-water, filtering off the precipitate, wash it with 5 ml of water, drying over phosphorus pentoxide in vacuum at 80oC get of 9.55 g of the target product. So pl.=189oC.

The NMR spectrum of 1.20 (t, 3H); 3,55 (C, 6N); 4.26 deaths (KD, 2H); to 6.58 (d, 2H); to 6.80 (s, 1H); 7,20 (m, 1H); of 7.60 (d, 1H); of 7.70 (d, 1H); 7,80 (doctor d, 1H).

PREPARATIVE EXAMPLE 3.32

Methyl ester 5-(2,6-acid)-1-[5-[N-methyl-N-(3-N',N'-dimethylaminopropyl)carbarnoyl] -2-were] pyrazole-3-carboxylic acid (formula (IIA); R/BR> At room temperature for 5 hours and stirred solution of 2 g obtained in Preparative example 3.31 product in 10 ml of thionyl chloride. After evaporation in vacuo, followed by three azeotropic authonomy with 30 ml of dichloromethane is obtained the acid chloride of the acid is again dissolved in 25 ml of dichloromethane, poured into a solution 0,81 ml of N,N,N'-trimethyl-1,3-propandiamine and 0.77 ml of triethylamine in 5 ml dichloromethane and stirred for two hours at room temperature. After washing twice with 20 ml of water, twofold extraction of the aqueous phase with 50 ml of dichloromethane dichloromethane phase is washed twice with 20 ml of 5% sodium hydrogen carbonate solution, then with 20 ml of water, then dried over magnesium sulfate and evaporated in vacuum, obtaining 2.3 g of the target product (oil).

NMR spectrum: 1,9 (m, 2H); 2,1 (s, 3H); 2,6 (s, 3H); 2,8 (C, 6N); 2,9-3,2 (m, 2H); to 3.45 (m, 2H); 3,6 (C, 6N); and 3.8 (s, 3H); and 6.6 (d, 2H); 6,85 (s, 1H); 7,05 (ush.s, 1H); of 7.2 to 7.4 (m, 3H).

Following the above techniques, get esters of the formula (IIA) described in table 3, any of a complex ester of the formula (II), substituted by the radical R'1or by exposure to the corresponding hydrazine connection a or connection AND1.

PREPARATION the Il]carbarnoyl]-2-isopropylphenyl]pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CON(CH3)(CH2)3N(CH3)COO-tert.-butyl; R2- 2-isopropyl; R3- H; R4- CH3)

A) Tert.-butyl ether N-methyl-N-(3-methylaminopropyl)carbamino acid

The solution 4,19 g N,N'-dimethyl-1,3-propandiamine in 80 ml of tetrahydrofuran is cooled to 0oC, add a solution of 2.68 g of di-tert.-BUTYLCARBAMATE in 25 ml of tetrahydrofuran and stirred for 72 hours at room temperature. Nerastvorim part is filtered off and the filtrate was concentrated in vacuo. The residue is extracted with dichloromethane, the organic phase is washed three times with water, dried over magnesium sulfate and the solvent is evaporated in vacuum. Obtain 1.6 g of the desired product as a yellow oil.

B) Methyl ester of 5-(2,6-acid)-1-[4-[N-methyl-N-[3-[N'-methyl-N'-(tert.-butoxycarbonyl)amino]propyl] carbarnoyl]-2-isopropylphenyl]pyrazole-3-carboxylic acid

To a solution of 1.31 g obtained at the previous stage of the connection and 0.9 ml of triethylamine in 4 ml of dichloromethane at room temperature and under nitrogen atmosphere add a solution of 2.6 g of compound obtained in stage a of Preparative example 3.2, and stirred overnight at room temperature. The reaction mixture is washed with two rotavirus on the silicon dioxide, elwira mixture of toluene with ethyl acetate in a volume ratio of 65:35 to 60:40. Obtain 2.85 g of the target product.

NMR-spectrum (DMSO+TFUC): 1,0 (d, 6N); 1,4 (d, N); 1,6-1,9 (m, 2H); 2,7 (MT, 1H); 2,7-3,55 (d+ush.C+m, 10H); the 3.65 (s, 6N); a 3.9 (s, 3H); of 6.65 (d, 2H); 6,9 (s, 1H); 7,3 was 7.45 (m, 4H).

PREPARATIVE EXAMPLE 3.58

Ethyl ester of 5-(2,6-acid)-1-[4-(4- methylphenylsulfonyl)-2-isopropylphenyl]pyrazole-3-carboxylic acid (formula (IIA); ; R2- 2-isopropyl; R3- H; R4- CH3)

Within 1 hour at a temperature of 70oWith heat the mixture 3,44 g of the compound obtained in Preparative example 2.18, and 2.6 g of compound A1in 50 ml of acetic acid. The reaction mixture was poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol in a volume ratio of 100:0.5 to. Obtain 1.26 g of the target product.

NMR spectrum: 0,7 (d, 6N); to 1.22 (t, 3H); 2,2-2,5 (m, 4H); 3.45 points (C, 6N); 4,2 (t, 2H); 6,46 (doctor 2H); 6,69 (s, 1H); 6.75 in-6,9 (m, 2H); 7,0 (d, 1H); 7,15-to 7.3 (m, 3H); 7.5 (d, 2H); to 10.2 (s, 1H).

PREPARATIVE EXAMPLE 3.59

Ethyl ester of 5-(2,6-acid)-1-[4-[4- methylphenylsulfonyl-N-(3-diethylaminopropyl)amino] -2-isopropy is for two hours at a temperature of 80oWith a heated mixture of 0.65 g of the compound obtained in Preparative example 3.58, 0,338 g (3-chlorpropyl)diethylamine and 0.65 g of potassium carbonate in 5 ml of dimethylformamide. The reaction mixture was poured into water, extracted with ethyl acetate, dried with an ethyl acetate layer over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol in a volume ratio of 100:5. Get 0,57 g of the target product.

NMR spectrum: 0,8 (ush. C, 6N); of 0.95 (t, 6N); 1,4 (t, 3H); 1,5 (CT, 2H); 2,3-to 2.65 (m, 10H); 3.5 to 3.8 (m, 8H); 4,35 (KD, 2H); 6,7 (d, 2H); 6.75 in (d, 1H); 6,9 (s, 1H); 7,05 (doctor d, 1H); 7,2-7,6 (m, 6N).

PREPARATIVE EXAMPLE 3.60

Ethyl ester 5-[2-(cyclopropylmethoxy)-6-methoxyphenyl]-1-(4-carboxy-2-isopropylphenyl)pyrazole-3-carboxylic acid (formua (II a); R'1- 4-CO2H; R2- 2-isopropyl; R3- H; )

Within 8 hours at a temperature of 80oWith a heated mixture of 5.26 g of the compound obtained in Preparative example 1.2, and 3.9 g of the compound obtained in Preparative example 2.1, in 50 ml of acetic acid. The reaction mixture was poured into a mixture of ice water, the precipitated precipitate is filtered under vacuum and washed with water, then with pentane. The residue is treated with toluene and the solvent vapour is coprophiliacs)-6-methoxyphenyl] -1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl]-2-isopropylphenyl]pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CON(CH3)(CH2)3N(CH3)2; R2is isopropyl; R3- H; )

This connection receive according to the procedures described in stages a and B of Preparative example 3.2, on the basis of the 5.2 g of the compound obtained in Preparative example 3.60, and 2.4 ml of thionyl chloride, and then 1.39 g of N,N,N'-trimethyl-1,3-propandiamine and 1.5 ml of triethylamine in 10 ml of toluene. Purification is carried out by chromatography on silica, elwira dichloromethane, then with a mixture of dichloromethane with methanol in a volume ratio of 88:2. Obtain 3.8 g of the target product.

PREPARATIVE EXAMPLE 3.62

Methyl ester 5-(2,6-acid)-1-[4-(4-methylphenylsulfonyl)-2-isobutylphenyl]pyrazole-3-carboxylic acid (formula (IIA); R2- 2-isobutyl; R3- H; R4- CH3)

Within 45 minutes refluxed mixture of 1.9 g of the compound obtained in Preparative example 2.20, and 1.6 g of compound in 30 ml of acetic acid. After cooling to room temperature the reaction mixture was poured into water, the precipitated precipitate is filtered under vacuum and dried. Receive 1 g of the target product after recrystallization from propan-2-ol. So pl.=224oC.

NMR spectrum: 0,55 (d, 6N); 1,5 (MT, 1H); 1,9 (on ARTIGNY EXAMPLE 3.63

Methyl ester 5-(2,6-acid)-1-[4-(4-methylphenylsulfonyl)-2-cyclopentylphenol] pyrazole-3-carboxylic acid (formula (IIA); ; R3- H; R4- CH3)

Within 1 hour at a temperature of 80oWith heat the mixture to 2.42 g of the compound obtained in Preparative example 2.21, and of 2.92 g of compound in 50 ml of acetic acid. The reaction mixture was poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol in a volume ratio of 100:1. Obtain 0.95 g of the target product (after powdering in the air). So pl.=200-230oC.

NMR spectrum: 1,0-1,8 (m, 8H); is 2.37 (s, 3H); of 3.1 to 3.7 (m, 7H); is 3.82 (s, 3H); 6,55 (d, 2H); 6,79 (s, 1H); 6,85-7,0 (m, 2H); 7,05 (d, 1H); 7,21-7,42 (m, 3H), 7,58 (d, 2H); or 10.3 (s, 1H).

PREPARATIVE EXAMPLE 3.64

Ethyl ester of 5-(2,6-acid)-1-(4-carboxy-3-isopropylphenyl)pyrazole-3-carboxylic acid (formula (II a); R'1- 4-CO2H; R2- 3-isopropyl; R3- H; R4- CH3)

Within 5 hours refluxed mixture of 0.36 g of compound obtained in Preparative example 2.22, and of 0.48 g of compound A1in 10 ml of acetic acid. The reaction're asked. Obtain 0.52 g of the target product. So pl.=180oC (decomposition).

PREPARATIVE EXAMPLE 3.65

Ethyl ester 1-[4-[N-(2-diethylaminoethyl)carbarnoyl]-3-isopropylphenyl]-5-(2,6-acid)pyrazole-3-carboxylic acid (formula (IIA); R1- 4-CONH(CH2)2N(C2H5)2; R2- 3-isopropyl; R3- H; R4- CH3)

This connection receive according to the procedure described in stages a and B of Preparative example 3.2, from 0.5 g of the compound obtained in Preparative example 3.64, and 5 ml of thionyl chloride in 20 ml of chloroform, and then 0.2 ml of N, N-diethylethylenediamine and 0.8 ml of triethylamine in 20 ml of chloroform. Get 0,37 g of the target product (after crystallization from ethyl acetate). So pl.=130oC (decomposition).

PREPARATIVE EXAMPLE 3.66

Methyl ester 5-(2,6-acid)-1-(4-nitro - 5,6,7,8-tetrahedronal-1-yl)pyrazole-3-carboxylic acid (formula (II a); R'1- 4-NO2; R2, R3- -(CH2)4-; R4- CH3)

Within two hours refluxed mixture of 6.3 g of the compound obtained in Preparative example 2.23, and was 7.45 g of compound in 150 ml of acetic acid. After cooling to room temperature, add 100 ml of water and 30 ml of methanol IPL.=212oC.

NMR spectrum: 1,7 (MT, 4H); to 2.55 (MT, 2H); 2,82 (MT, 2H); 3,65 (C, 6N); 3,85 (s, 3H); of 6.65 (d, 2H); 6,9 (s, 1H); 7,02 (d, 1H); 7,33 (t, 1H); to 7.67 (d, 1H).

PREPARATIVE EXAMPLE 3.67

Methyl ester 5-(2,6-acid)-1-(5-(3-diethylamino)propanolamine)-2-isopropylphenyl)pyrazole-3-carboxylic acid (formula (IIA); R1- 5-NHCO(CH2)2N(C2H5)2; R2- 2-isopropyl; R3- H; R4- CH3)

This compound is obtained from hydrazine obtained in Preparative example 2.24.

NMR-spectrum (DMSO+TFUC): 0,65-of 1.35 (m, N); 2,5 (CT, 1H); and 2.8 (t, 2H); 3.15 in (KD, 4H); to 3.36 (t, 2H); 3,57 (C, 6N); and 3.8 (s, 3H); 6.5 in (d, 2H); is 6.78 (s, 1H); and 7.1 to 7.4 (m, 3H); 7,8 (d, 1H).

The methodology of the acids of formula (II) and (II')

PREPARATIVE EXAMPLE 4.1

1-[4-[N-methyl-N-(3-N',N'-dimethylaminopropyl)carbarnoyl]-2-isopropylphenyl] -5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R1- 4-CON(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- N; R4- CH3)

23 g of the Compound obtained in Preparative example 3.2, in 230 ml of dioxane is mixed with 6.2 g of potassium hydroxide in 6 ml of water. The resulting mixture was refluxed for 3.5 hours. After cooling, the reaction mixture is evaporated again races is zentrierung hydrochloric acid; the aqueous phase is evaporated, then the residue is dissolved in minimum quantity of ethanol and filtered KCl (2 times). After evaporation receive 23,93 g of the target product as a pale yellow foam. So pl.=128oC (decomposition).

The NMR spectrum of 0.95 (d, 6N); 1,95 (MT, 2H); 2,45-3,3 (m, N); 3,35 to 3.8 (m, 8H); and 6.6 (d, 2H); at 6.8 (s, 1H); 7-7,5 (m, 4H).

PREPARATIVE EXAMPLE 4.1 BIS

Potassium salt of 1-[4-[N-methyl-N-(3-N',N'-dimethylaminopropyl)carbarnoyl]-2-isopropylphenyl]-5-(2,6-acid)pyrazole-3-carboxylic acid

To a solution of 26.6 g obtained in Preparative example 3.2 product in 133 ml of ethanol is added a solution 8,07 g KOH in 133 ml of water. The solution is stirred for eight hours, then incubated with stirring for 15 hours and evaporated in vacuum, obtaining the target potassium salt.

PREPARATIVE EXAMPLE 4.2

1-[4-[N-(2-Cyanoethyl)carbarnoyl] -2-isopropylphenyl] -5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R1- 4-CONHCH2CH2CN; R2- 2-isopropyl; R3- H; R4- CH3)

To a solution of 3.04 from g of the compound obtained in Preparative example 3.3, in 30 ml of 1,4-dioxane with a few drops of methanol is added a solution of 0.9 g of KOH in 3 ml of water and stirred for overnight at comatt to pH 2 by adding 10% hydrochloric acid, extracted with dichloromethane, organic

phase is dried over sodium sulfate and evaporated in vacuo of the solvent. Gain of 2.93 g of the target product. So pl.=128oC (decomposition).

NMR spectrum: 1 (d, 6N); to 2.65 (MT, 1H); and 2.8 (t, 2H); 3,5 (t, 2H); 3,6 (C, 6N); and 6.6 (d, 2H); at 6.8 (s, 1H); 7,2-7,4 (m, 2H), and 7.7 (doctor d, 1H); 7,8 (d, 1H).

Based on esters of the formula (IIA) described in table 2 and following the procedure described in Preparative example 4.1 or 4.2, get acid of formula (II) described in table 4.

PREPARATIVE EXAMPLE 4.11

5-(2,6-Acid)-1-[2-isopropyl-4-(N-methyl-N-(3 - N',N'-dimethylaminopropyl)aminosulfonyl)phenyl]pyrazole-3-carboxylic acid (formula (II); R1- 4-SO2N(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; R4- CH3)

Within 6 hours at room temperature stirred mixture containing 1.1 g of ester obtained in Preparative example 3.13, and 280 mg of potassium hydroxide in 10 ml of water. The reaction medium was concentrated in vacuo to a final volume of 5 ml, then stirred in the presence of 100 ml of ether and 3 ml of water. The aqueous phase is neutralized to pH 6 by addition of 1 N. hydrochloric acid, filtered off, then dried over P2O5getting a 6.5 (d, 2H); 6,7 (s, 1H); to 7.2 (t, 1H); to 7.4 (d, 1H); 7.5 (m, 2H).

PREPARATIVE EXAMPLE 4.12

5-(2,6-Acid)-1-[4-[N-[3-(N',N'-dimethylamino) propyl]carbarnoyl] -5,6,7,8-tetrahedronal-1-yl] pyrazole-3-carboxylic acid (formula (II); R1- 4-CONH(CH2)3N(CH3)2; R2, R3- -(CH2)4-; R4- CH3)

Within three hours at a temperature of 40oWith a heated mixture of 0.98 g of the compound obtained in Preparative example 3.15, and 0.16 g of lithium hydroxide in 5 m l of methanol and 1 ml of water, then it is evaporated in vacuo, neutralized to pH 6 with 1 N. hydrochloric acid, then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated in vacuum, obtaining of 0.47 g of the target product.

The NMR spectrum of 1.5-2.1 (m, 6N); 2,3-4 (m, 20N); 6.5 to about 7.6 (m, 6N); 8.4V (t, 1H).

PREPARATIVE EXAMPLE 4.13

Potassium salt of 5-(2,6-acid)-1-[4-[N-methyl-N-(2-N', N'-dimethylaminoethyl)aminosulfonyl] -5,6,7,8-tetrahedronal-1-yl]pyrazole-3-carboxylic acid (formula (II); R1- 4-SO2N(CH3)(CH2)2N(CH3)2; R2, R3- -(CH2)4-; R4- methyl)

For eight hours at room temperature stirred solution of 0.87 g of ester, poluchennogo the t with a mixture of 10 ml of water, 5 ml of ethanol and 100 ml of ether. After decanting, the resulting resin proscout three times in the ether, the product crystallizes. It is filtered off, gaining 0.9 g of the target salt.

PREPARATIVE EXAMPLE 4.14

4-(2,6-Acid)-1-(4-carbarnoyl-2 - were)pyrazole-3-carboxylic acid (formula (II); R1- 4-CONH2; R2- 2-CH3; R3- H; R4- CH3)

At room temperature for two hours stirred solution containing 0.4 g of the compound obtained in Preparative example 3.18, in 5 ml of dioxane and 220 mg KOH in 1 ml of water. The solution is acidified to pH 1 by adding concentrated hydrochloric acid, then concentrated in vacuo. Add 5 ml of water, after which the formed resin is stirred with 50 ml of dichloromethane and filtered loose sediment. Obtain 330 mg of the target product. So pl.=275-276oC.

NMR spectrum: 2,05 (s, 3H); 3,55 (C, 6N); 6,55 (d, 2H); 6,7 (s, 1H); 7 (d, 1H); to 7.2 (t, 1H); 7,4 (ush.s, 1H); at 7.55 (d, 1H), and 7.7 (s, 1H); 7,9 (ush.s, 1H).

PREPARATIVE EXAMPLE 4.15

5-(2,6-Acid)-1-[2,3-dimethyl-4-[N-(2-N', N'-dimethylaminoethyl)carbarnoyl] phenyl]pyrazole-3-carboxylic acid (formula (II); R1- 4-CONH(CH2)2N(CH3)2; R2- 2-CH3; R3- 3-CH3; R4- CH<$ Preparative example 3.20, and 0.32 g of lithium hydroxide in 10 ml of methanol and 2 ml of water. Bring the pH to 6 with 1 N. hydrochloric acid and evaporated in vacuum. After extraction of the residue with 50 ml dichloromethane and evaporation to obtain 1.3 g of the target product.

NMR spectrum: 1,9 (s, 3H); 2,2 (C+C, N); 2,5 (t, 2H); 3,4 (KD, 2H); 3,7 (C, 6N); and 6.6 and 6.7 (m, 3H); 6,9-7,1 (m, 2H); and 7.3 (t, 1H); 8.3 in (t, 1H).

PREPARATIVE EXAMPLE 4.16

5-(2,6-Acid)-1-[4-[N-methyl-N-(2-N',N'-diethylaminoethyl)carbarnoyl]-2-methoxyphenyl]pyrazole-3-carboxylic acid (formula (II); R1- 4-CON(CH3)(CH2)3N(C2H5); R2- 2-OCH3; R3- H; R4- CH3)

For 6 hours with stirring, refluxed mixture of 1.73 g of the product obtained in Preparative example 3.22, 0.3 g of lithium hydroxide in 400 ml of methanol and 6 ml of water, then acidified to pH 2 using concentrated hydrochloric acid. After evaporation in vacuum, stirring for 30 minutes at room temperature residual oil with 400 ml of chloroform, decanting, separation, drying the organic phase over sodium sulfate and evaporation to obtain 1.2 g of the target product.

NMR spectrum: 1,05-1,4 (MT, 6N); 3 (ush.s, 3H); 3,1-3,9 (MT, 13H); and 6.6 (d, 2H); at 6.8 (s, 1H); 7-7,4 (MT, 4H).

pyrazole-3-carboxylic acid (formula (II); R1- 4-CON(CH3)(CH2)2N(C2H5)2; R2- 2-Cl; R3- H; R4- CH3)

For three days at room temperature stirred mixture of 2.6 g of the product obtained in Preparative example 3.24 dissolved in 100 ml of ethanol, and of 0.53 g of KOH in 15 ml of water. After acidification to pH 3 using concentrated hydrochloric acid, evaporation in vacuum, powdering of the residue in 10 ml of water, filtering and drying in vacuum over phosphorus pentoxide obtain 1.55 g of the target product.

PREPARATIVE EXAMPLE 4.18

5-(2,6-Acid)-1-[4-(N-(2-morpholinoethyl)carbarnoyl)-2-chlorophenyl] pyrazole-3-carboxylic acid (formula (II); ; R2- 2-CL; R3- N; R4- CH3)

Within 1 hour with stirring at a temperature of 60oWith a heated solution of 1.5 g of the product obtained in Preparative example 3.25, in 75 ml of ethanol together with a solution of 0.38 g of KOH in 10 ml of water. After acidification to pH 4.5 with concentrated hydrochloric acid and evaporation in vacuo get 4 g of a mixture of desired product and potassium chloride.

NMR-spectrum (DMSO+TFUC): 2,9-4 (MT, N); and 6.5 (d, 2H); at 6.8 (s, 1H); and 7.1 to 7.4 (MT, 2H); 7,8 (doctor d, 1H); 8 (d, 1H); 9,1 (ush.s, 1H).

PREPARATIVE EXAMPLE 4.19

5-(2,6-Dim is - ; R4- CH3)

On a water bath for three hours heated mixture containing 0.5 g) obtained in Preparative example 3.26 product and 60 mg of lithium hydroxide in 5 ml of aqueous methanol. After cooling to reduce the pH to 5 by adding 1 N. hydrochloric acid. The precipitation is filtered off and dried, obtaining 0.36 g of the target compound.

PREPARATIVE EXAMPLE 4.20

5-(2,6-Acid)-1-(4-carbarnoyl-3-chlorophenyl)pyrazole-3-carboxylic acid (formula (II); R1- 4-CONH2; R2- 3-CL; R3- N; R4- CH3)

Within 24 hours at room temperature stirred mixture containing 0.87 g of the compound obtained in Preparative example 4.19, 390 mg of potassium carbonate and 0.4 ml of 30% hydrogen peroxide in 5 ml of dimethylsulfoxide. Acidified to pH 3 by addition of 1 N. hydrochloric acid, then water is added, the precipitation is filtered off and dried, obtaining 0.73 g of the target product.

PREPARATIVE EXAMPLE 4.21

5-(2,6-Acid)-1-[4-[N-methyl-N-(2-N',N'-diethylaminoethyl)carbarnoyl] -2-cyclopropylethyl] pyrazole-3-carboxylic acid (formula (II); R1- 4-CON(CH3)(CH2)2N(C2H5)2; R2- 2-cyclopropyl; R3- H; R4

NMR spectrum: 0,4-1,2 (MT, 14N), and 1.5 (m, 1H); from 2.1 to 3.8 (MT, 13H); and 6.5 (d, 2H), 6,7 (ush.s, 2H); 7 (s, 2H); to 7.2 (t, 1H).

PREPARATIVE EXAMPLE 4.22

5-(2,6-Acid)-1-[3-[N-methyl-N-(2-N', N'- dimethylaminoethyl)carbarnoyl] -4-chlorophenyl]pyrazole-3-carboxylic acid (formula (II); R1- 3-CON(CH3)(CH2)2N(CH3)2; R2- 4-Cl; R3- H; R4- CH3)

Within 6 hours at room temperature stirred solution of 0.8 g of the product obtained in Preparative example 3.30, in 10 ml of dioxane together from 0.22 g of KOH in 2 ml of water. After evaporation in vacuo the residue is dissolved in 5 ml of water, neutralize the resulting solution to pH 5 with concentrated hydrochloric acid, then saturated with sodium chloride. Extracted 2 times with 100 ml dichloromethane, the organic phase is dried over sodium sulfate and evaporated in vacuum, obtaining of 0.43 g of the target product.

NMR spectrum: 1,9-3,15 (m, 13H); 3,6 (Stefanel)-1-[5-[N-methyl-N-(3-N', N'- dimethylaminopropyl)carbarnoyl]-2-were]pyrazole-3-carboxylic acid (formula (II); R1- 5-CON(CH3)(CH2)3N(CH3)2; R2- 2-CH3; R3- H; R4- CH3)

For 15 hours at room temperature stirred solution of 2.28 g of the product obtained in Preparative example 3.32, in 10 ml of dioxane together with a solution of 0.65 g of KOH in 1.5 ml of water, evaporated in vacuo, then the residue is dissolved in 20 ml of water and extracted 3 times with 50 ml ether. After acidification of the aqueous phase to pH 4 by addition of 1 N. hydrochloric acid, azeotropic distillation with ethanol, the residue proscout with 20 ml of ethanol, potassium chloride is filtered off, then the filtrate is evaporated in vacuum. Repeat the operation for the removal of the potassium chloride and the filtrate is evaporated in vacuum, obtaining 2 g of the target product.

NMR spectrum: 1,9 (m, 2H); 2,2 (s, 3H); 2.4 to 3 (m, 11N); 3,5 (MT, 2H); 3,65 (C, 6N); of 6.65 (d, 2H); 6,85 (s, 1H); 7,1 (ush.s, 1H); 7.3 to 7.5 (m, 3H).

Following the above methods, get the acid of formula (II) described in table 5.

PREPARATIVE EXAMPLE 4.40

1-[4-[N-Ethyl-N-(2-N', N'-diethylaminoethyl)carbarnoyl]-2 - isopropylphenyl]-5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R1- 4-CON(C2H5)(CH48 g of compound, obtained in Preparative example 4.32, and 0.28 ml of ethyliodide in 3 ml of tetrahydrofuran cooled to a temperature of 5oWith, then added in several portions 0,063 g of sodium hydride as a 60% dispersion in oil is added and stirred for 24 hours at room temperature. Add to 0.48 ml of a mixture of tetrahydrofuran with water in a volume ratio of 50:50 and the reaction mixture was concentrated in vacuo. The residue is treated with water, the aqueous phase is washed 2 times with pentane, the aqueous phase is acidified to pH 1 by addition of 1 N. hydrochloric acid, extracted with ethyl acetate and then dichloromethane, the organic phase is dried over sodium sulfate and evaporated in vacuo solvents. Obtain 0.14 g of the target product.

NMR-spectrum (DMSO+TFUC): 0,8-1,3 (m, 15 NM); 2,6 (m, 1H); from 3.0 to 3.8 (m, N); and 6.5 (d, 2H); 6.75 in (s, 1H); to 7.2 (m, 4H).

PREPARATIVE EXAMPLE 4.41

Hydrochloride 1-[4-[[3-(diethylamino)pyrrolidin-1-yl] carbonyl] -2-isopropylphenyl] -5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); ; R2- 2-isopropyl; R3- N; R4- CH3)

To a solution of 0.44 g of the compound obtained in Preparative example 3.51, 4 ml of dioxane at room temperature is added a solution of 0.11 g of KOH in 0.5 ml of water and stirred over night at room temperature. The end is to pH 2 by the addition of 1.2 N. hydrochloric acid, add ethanol and concentrated in vacuo. The residue is treated with ethanol, potassium chloride is filtered off and the filtrate was concentrated in vacuo. Obtain 0.39 g of the target product.

NMR-spectrum (DMSO+TFUC): 1,0 (d, 6N); 1,15-1,35 (m, 6N); 2,1-of 2.45 (m, 2H); to 2.65 (MT, 1H); 2,9-4,1 (3 m+, 15 NM); and 6.6 (d, 2H); at 6.8 (s, 1H); 7,2-7,5 (MT, 3H); at 7.55 (s, 1H).

PREPARATIVE EXAMPLE 4.42

1-[4-[N-(Propan-2-yl)carbarnoyl] -2-isopropylphenyl] -5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R1- 4-CONHCH2CH=CH2; R2- 2-isopropyl; R3- H; R4- CH3)

For 7 hours at room temperature stirred mixture 1,72 g of the compound obtained in Preparative example 3.54, and 0.78 g of the hydrate of lithium hydroxide in 10 ml of methanol and 1 ml of water. Concentrated in vacuo, the residue is treated with water, the aqueous phase is washed twice with ether, acidified to pH 2-3 by adding 1,2 N. hydrochloric acid, extracted with dichloromethane, the organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum. Obtain 1.64 g of the target product.

NMR spectrum: 1,0 (d, 6N); 2,7 (CT, 1H); 3,7 (C, 6N); of 3.95 (t, 2H); 5,1-5,3 (m, 2H); 5,8-6,1 (m, 1H); of 6.65 (d, 2H); 6,85 (s, 1H); 7,25 to 7.4 (m, 2H); of 7.75 (d, 1H); 7,9 (s, 1H); 8,8 (t, 1H).

PREPARATIVE EXAMPLE 4.43
1
- 4-CON(CH3)(CH2)3N(CH3)COO-tert.-butyl; R2- 2-isopropyl; R3- H; R4- CH3)

For 3.5 hours at room temperature stirred mixture of 2.85 g of the compound obtained in Preparative example 3.57, and 0.98 g of the hydrate of lithium hydroxide in 20 ml of methanol and 1 ml of water. Concentrated in vacuo, the residue is treated with water, acidified to pH 2 by adding a buffer solution with a pH of 2, the precipitation is filtered under vacuum and washed with water. Get 2,47 g of the target product (after drying over phosphorus pentoxide). So pl.=112-114oC.

PREPARATIVE EXAMPLE 4.44

1-[4-(4-Methylphenylsulfonyl)-2-isopropylphenyl] -5-(2,6-acid]pyrazole-3-carboxylic acid (formula IIA);

;

R2- 2-isopropyl; R3- H; R4- CH3)

Within three hours at a temperature of 60oWith a heated mixture of 1.05 g of the compound obtained in Preparative example 3.58, and 0.33 g of the hydrate of lithium hydroxide in 5 ml of methanol and 0.5 ml of water. The reaction mixture was poured into water, acidified to pH 2-3 by adding 10% hydrochloric acid, the precipitated precipitate is filtered under vacuum and dried. Get to 0.92 g of the target product.

NMR IS N).

PREPARATIVE EXAMPLE 4.45

1-(4-Amino-2-isopropylphenyl)-5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II'); R'1- 4-NH2; R2- 2-isopropyl; R3- H; R4- methyl)

Within 10 minutes refluxed mixture of 0.9 g of the compound obtained in Preparative example 3.58, 11 ml of acetic acid and 25 ml of 70% perchloric acid. The reaction mixture was poured into a mixture of ice water, filtered off the insoluble portion, the pH value of the filtrate was adjusted to 5 by adding 10% sodium hydroxide solution, filtered off, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. The residue is treated with ether and the precipitated precipitate is filtered off under vacuum. Gain of 0.54 g of the target product. So pl.=190oC (decomposition).

NMR spectrum: 0,92 (d, 6N); 2,42 (MT, 1H); the 3.65 (s, 6N); 5,42 (ush.s, 2H); 6,3 (doctor d, 1H); at 6.4 (d, 1H); and 6.6 (d, 2H); to 6.67 (s, 1H); 6,85 (d, 1H); and 7.3 (t, 1H).

PREPARATIVE EXAMPLE 4.46

1-[4-[3-(Diethylamino)propanolamine] -2-isopropylphenyl] -5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R1- 4-NHCO(CH2)2N(C2H5)2; R2- 2-isopropyl; R3- H; R4- methyl)

Within 1 h orida in 2 ml of dichloromethane, then concentrated in vacuo. The thus obtained acid chloride acid is used as is. On the other hand, for 1 hour at a temperature of 70oWith a heated mixture of 0.47 g of the compound obtained in Preparative example 4.45, and 0.95 ml of bis(trimethylsilyl)ndimethylacetamide in 5 ml of acetonitrile. After cooling to room temperature, add videolocity the acid chloride of the acid in solution in dichloromethane, followed by 0.17 ml of triethylamine and everything is stirred for 1 hour at room temperature. Concentrated in vacuo, the residue is treated with water, the pH value of the aqueous solution was adjusted to 5 by adding 10% sodium hydroxide solution, extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. The residue is treated with ether and the precipitated precipitate is filtered off under vacuum. Obtain 0.27 g of the target product.

NMR-spectrum (DMSO+TFUC): 0,91 (d, 6N); 1,2 (MT, 6N); to 2.55 (MT, 1H); and 2.8 (t, 2H); 3.1 and up 3.22 (m, 4H); at 3.35 (t, 2H); 3,6 (C, 6N); to 6.58 (d, 2H); 6.75 in (s, 1H); 7,1-7,3 (m, 2H); 7,4-of 7.55 (m, 2H).

PREPARATIVE EXAMPLE 4.47

1-[4-[(3-Diethylaminopropyl)amino] -2-isopropylphenyl] -5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R1- 4-NH(CH2)3N(CTim refrigerator mixture of 0.55 g of compound, obtained in Preparative example 3.59, 6,5 ml of acetic acid and 14 ml of 70% perchloric acid. The reaction mixture was poured into water, adjusted pH to 5 by adding 10% sodium hydroxide solution, extracted with ethyl acetate, the extract is dried over sodium sulfate and the solvent is evaporated in vacuum. Obtain 0.5 g of the target product.

NMR spectrum: 1,0 (MT, 6N); 1,25 (t, 6N); 1,9 (MT, 2H); to 2.55 (s, 1H); 3,0-3,3 (m, 8H); 3,7 (C, 6N); at 5.9 (s, 1H); 6,3-6,55 (m, 2H); of 6.65 (d, 2H); 6.75 in (s, 1H); 7,0 (d, 1H); and 7.3 (t, 1H).

PREPARATIVE EXAMPLE 4.48

1-[4-[N-Acetyl-N-(3-diethylaminopropyl)amino] -2-isopropylphenyl]-5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R1- 4-N(COCH3)(CH2)3N(C2H5)2; R2- 2-isopropyl; R3- H; R4- methyl)

Within 1 hour at a temperature of 60oWith a heated mixture of 0.38 g of the compound obtained in Preparative example 4.47, and 0.36 ml of bis(trimethylsilyl)ndimethylacetamide in 10 ml of toluene. Add 0,052 ml acetylchloride, then 0.1 ml of triethylamine and stirred for 2 hours at room temperature. Concentrated in vacuo, the residue is treated with saturated solution of sodium chloride, extracted with ethyl acetate, dried over sodium sulfate and the solvent is evaporated in vacuum. Get 0, is); of 6.65 (d, 2H); 6,85 (s, 1H); 7,2-7,6 (m, 4H).

PREPARATIVE EXAMPLE 4.49

Potassium salt of 1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl]-2-isopropylphenyl] -5-[2-(cyclopropylmethoxy)-6-methoxyphenyl] pyrazole-3-carboxylic acid (formula (II); R1- 4-CON(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; )

For 20 hours at room temperature stirred mixture of 3.8 g of the compound obtained in Preparative example 3.61, and 0.92 g of KOH in 76 ml of ethanol and 12 ml of water. Concentrated in vacuo, the residue treated with toluene and the solvent is evaporated in vacuum. Gain of 3.9 g of the target product.

PREPARATIVE EXAMPLE 4.50

1-(2-Methyl-4-nitrophenyl)-5-(2,6-acid)pyrazole-3-carboxylic acid (formula ( II'); R'1- 4-NO2; R2- 2-methyl; R3- H; R4- methyl)

During the night stirred mixture of 3.5 g of the compound obtained in Preparative example 3.56, and 0.44 g of the hydrate of lithium hydroxide in 20 ml of methanol and 4 ml of water. Concentrated in vacuo, the residue is treated with water, acidified to pH 3 by adding 10% hydrochloric acid, the precipitated precipitate is filtered under vacuum and dried. Obtain 3.2 g of the target product.

NMR spectrum: 2,9 (s, 3H); to 3.58 (s, 6L)-5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II'); R'1- 4-NH2; R2- 2-isobutyl; R3- H; R4- methyl)

This connection receive according to the procedure described in Preparative example 4.45, based on 0.5 g of the compound obtained in Preparative example 3.62, 6 ml of acetic acid and 14 ml of 70% perchloric acid. Obtain 0.3 g of the target product.

NMR spectrum: 0,65 (d, 6N); to 1.55 (MT, 1H); 1,9 (d, 2H); 3,5 (C, 6N); of 5.05 (s, 2H); 6,0 was 7.3 (m, 7H).

PREPARATIVE EXAMPLE 4.52

1-[4-[3-(Diethylamino)propanolamine] -2-isobutylphenyl] -5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R1- 4-NHCO(CH2)2N(C2H5)2; R2- 2-isobutyl; R3- H; R4- methyl)

This connection receive according to the procedure described in Preparative example 4.46 based on of 0.133 g of the hydrochloride of 3-diethylaminopropyl acid and 1 ml of thionyl chloride in 1 ml of dichloromethane and 0.29 grams of the compound obtained in Preparative example 4.51, and 4 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile. Obtain 0.15 g of the target product.

NMR spectrum: 0,7 (d, 6N); 1,1 (t, 6N); of 1.65 (MT, 1H); 2.0 (d, 2H); to 2.75 (t, 2H); 3,1 (KD, 4H); 3,3 (t, 2H); 3,6 (C, 6N); and 6.5 (d, 2H); 6,7 (s, 1H); and 7.1 (d, 1H); to 7.2 (t, 1H); 7.3 to 7.5 (m, 2H); to 10.3 (s, 1H); 15 (s, 1H).

PREPARATIVE EXAMPLE 4.53

1-(4-Amino-2-cyclopentyl - methyl)

This connection receive according to the procedure described in Preparative example 4.45, from 0.9 g of the compound obtained in Preparative example 3.63, 11 ml of acetic acid and 27 ml of 70% perchloric acid. Obtain 0.52 g of the target product.

NMR-spectrum (DMSO+TFUC): 1,18-1,9 (m, 8H); 2,6 (MT, 1H); 3,6 (C, 6N); and 6.6 (d, 2H); 6.75 in (s, 1H); and 7.1 to 7.4 (m, 4H).

PREPARATIVE EXAMPLE 4.54

1-[4-[3-(Diethylamino)propanolamine] -2-cyclopentylphenol] -5-(2,6-acid)pyrazole-3-carboxylic acid (formula (II); R1- 4-NHCO(CH2)2N(C2H5); ; R3- H; R4- methyl)

This connection receive according to the procedure described in Preparative example 4.46, according to 0.22 g of the hydrochloride of 3-diethylaminopropyl acid, 2 ml of thionyl chloride in 5 ml of dichloromethane, 0.5 g of the compound obtained in Preparative example 4.53, and 0.73 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile. Obtain 0.32 g of the target product.

NMR-spectrum (DMSO+TFUC): 1,1-1,8 (m, 14N); 2,5 (MT, 1H); of 2.72 (t, 2H); to 3.02 (m, 4H); 3,22 (MT, 2H); to 3.58 (s, 6N); and 6.5 (d, 2H); of 6.65 (s, 1H); 7.03 is (d, 1H); to 7.2 (t, 1H); 7,35 (doctor d, 1H); 7.5 (d, 1H).

PREPARATIVE EXAMPLE 4.55

Potassium salt of 1-[4-[N-(2-Diethylaminoethyl)carbarnoyl]-3-isopropylphenyl]-5-(2,6-acid)pyrazole-3-carboxylic acid (formula is l)

Within two days at room temperature stirred mixture of 0.34 g of the compound obtained in Preparative example 3.65, and 0,073 g KOH in 6 ml of dioxane and 2 ml of water. Concentrated in vacuo, the residue treated with toluene and concentrated in vacuo. Get 0,37 g of the target product. So pl. above 260oC.

PREPARATIVE EXAMPLE 4.56

5-(2,6-Acid)-1-(4-nitro-5,6,7,8-tetrahedronal-1-yl)pyrazole-3-carboxylic acid (formula (II'); R'1- 4-NO2; R2, R3- -(CH2)4-; R4- methyl)

For two hours at a temperature of 70oWith a heated mixture of 4.2 g of the compound obtained in Preparative example 3.66, together with 0.8 g of the hydrate of lithium hydroxide in 95 ml of ethanol and 5 ml of water. After cooling to room temperature, add water, acidified to pH 3 by adding 10% hydrochloric acid, the precipitated precipitate is filtered under vacuum and dried. Gain of 4.16 g of the target product. So pl.=130oC.

NMR spectrum: 1,7 (MT, 4H); to 2.55 (MT, 2H); 2,82 (MT, 2H); 3,65 (C, 6N); of 6.65 (d, 2H); 6,85 (s, 1H); 7,05 (d, 1H);to 7.35 (t, 1H); 7.7 (d, 1H); 12,95 (ush.s, 1H).

PREPARATIVE EXAMPLE 4.57

5-(2,6-Acid)-1-[5-(3-diethylaminopropylamine)-2-isopropylphenyl]pyrazole-3-carboxylic acid (formula (II);This compound is obtained from the complex methyl ester, obtained in Preparative example 3.67. After recrystallization from methanol the melting point is 195-198oC.

NMR-spectrum (DMSO+TFUC): 0,65-of 1.35 (m, N); 2,5 (CT, 1H); 2,82 (t, 2H); 3.15 in (MT, 4H); to 3.36 (t, 2H); 3,6 (C, 6N); 6,55 (d, 2H); 6,76 (s, 1H); 7,15 to 7.4 (m, 3H); 7,8 (d, 1H).

EXAMPLE 1

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CON(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

A) Hydrochloride of the acid chloride of l-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl]-5-(2,6-acid)pyrazole-3-carboxylic acid

In nitrogen atmosphere and at room temperature for 5 hours and stirred 1.07 g of the acid obtained in Preparative example 4.1, 2 ml of thionyl chloride. Is evaporated, then the residue is treated 3 times with dichloromethane, obtaining the target product, which is used as is in the next stage.

The acid chloride of the acid can also be obtained by the following method.

A') of the Hydrochloride of the acid chloride of 1-[4-[N-methyl-N-(3 - dimethylaminopropyl)carbamoylation example 4.1 bis, dissolved in 130 ml of ethanol, add 50 ml of hydrochloric acid ethanol, inorganic substance is filtered off and the filtrate is evaporated in vacuum. The residue is again dissolved in 100 ml of dichloromethane, slowly add 11 ml of thionyl chloride and refluxed for 4 hours. Evaporated in vacuo, the residue is again dissolved in 30 ml of dichloromethane and again evaporated in vacuo, repeating this operation 3 times.

B) Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid

In nitrogen atmosphere for 40 minutes refluxed mixture of 0.37 g of 2-aminoadamantana-2-carboxylic acid (compound B), 5 ml of acetonitrile and 0.82 ml of bis(trimethylsilyl)ndimethylacetamide. After returning to room temperature, add 0.3 ml of triethylamine and obtained at the previous stage, the product is dissolved in 15 ml of acetonitrile. Stirred at room temperature for 1 week, the solvent is removed by concentration of the reaction mixture. By adding ether to cause crystallization. The crystals are stirred in a mixture of 1.5 ml of toluene and 1.5 ml of acetonitrile. Filtered off the insoluble part,anywayt ethanol. Extracted with dichloromethane, the organic phase is washed with a saturated solution of sodium chloride, then chromatographic on the silicon dioxide, elwira a mixture of dichloromethane with methanol and water in a volume ratio of 92:8: 0,7. Obtain 0.18 g of the desired product after powdering in the air. So pl.= 185oC (decomposition).

NMR-spectrum (DMSO+TFUC): 0,95 (d, 6N); 1,6-2,2 (m, 14N); 2,4-3 (m, N), 3,1 (MT, 2H); 3,5 (MT, 2H); 3,65 (C, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1-7.5 (m, 4H).

Alternative stage B can be carried out as follows.

In nitrogen atmosphere for 40 minutes refluxed mixture 8,79 g of compound B, 22 ml of bis(trimethylsilyl)ndimethylacetamide in 120 ml of anhydrous acetonitrile and cooled to room temperature. Then add a solution of the carboxylic acid obtained according to stage And from 23,83 g of the acid obtained in Preparative example 4.1, and 140 ml of thionyl chloride in 300 ml of anhydrous acetonitrile. After stirring for 15 hours at room temperature and evaporation in vacuo the residue is again dissolved in 180 ml of methanol, slowly add 180 ml of water, stirred for one hour, filtered off the insoluble matter and the filtrate after the addition of ethanol is evaporated in a vacuum. After premesis vacuum over phosphorus pentoxide, getting to 29.8 g of the product of example 1. So pl.= 211oC (decomposition) after recrystallization from propan-2-ol).

EXAMPLE 1'

Internal salt of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid

From hydrochloride of the compound obtained in example 1, release inner salt as follows.

0.97 g of the Product of example 1 dissolved in 10 ml of water, increase the pH to 7 by adding 1,3 n sodium hydroxide solution. Filtered, the precipitate washed with water and dried in vacuum over P2O5getting 0,86 g of the inner salt, which is recrystallized from 3 ml of acetonitrile, receiving 0.5 g of the target internal salt.

NMR-spectrum (DMSO+TFUC): 1 (MT, 6N); of 1.4-2.3 (m, 14N); 2,3-3,4 (m, 14N); 3,5 (m, 2H); 3,65 (C, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1-7.5 (m, 4H).

After recrystallization from propan-2-ol T. pl.=238oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,2 (m, 14N); 2,5 (ush.s, 2H); 2,6-3 (m, 10H); 3,1 (MT, 2H); 3,5 (MT, 2H); 3,6 (C, 6N); and 6.6 (d, 2H); 6.75 in (s, 1H); and 7.1-7.5 (m, 4H).

You can also obtain the product of example 1' without isolating the product of example 1 according to the following method.

In nitrogen atmosphere for two hours to chlormethine. After cooling, the thus obtained solution was poured into a solution of the product from stage A' of example 1 in 100 ml dichloromethane and stirred overnight at room temperature. Evaporated in vacuo, the residue is treated by stirring for three hours with 100 ml of methanol and 100 ml of water and increase the pH to 7-7,5, by adding a saturated solution of sodium bicarbonate. After stirring for 1 hour, filtered off, getting 22.1 g of the desired product (purity according to HPLC 98.5 per cent).

Internal salt can also be converted into its hydrochloride (the product of example 1) according to the following method.

6.85 g of the Inner salt in a mixture of 3.5 ml of concentrated hydrochloric acid and 40 ml of water is heated under stirring. After dissolution is cooled under stirring, filtered and dried in vacuum, obtaining 6.5 g of hydrochloride.

Internal salt can be obtained hydrochloride as follows.

When heated 0.3 g of the inner salt is dissolved in 3 ml of methanol and 2 ml of dichloromethane, cooled to room temperature, add 0.5 ml of 1,2 N. hydrochloric acid, concentrated in vacuo to a volume of 0.5 ml, cooled to -20oWith and sucked, getting to 0.2 g of the product of primararily]adamantane-2-carboxylic acid (formula (I); R1- 4-CONHCH2CH2CN; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

For 5 hours at room temperature stirred mixture of 2.6 g of the compound obtained in Preparative example 4.2, and 20 ml of thionyl chloride. Concentrated in vacuo, the residue is treated with dichloromethane and the solvent is evaporated in vacuum. Thus obtained acid chloride acid is used as is. On the other hand, in an atmosphere of nitrogen for 30 minutes, refluxed mixture of 1.09 g of 2-aminoadamantana-2-carboxylic acid and 4.2 ml of bis(trimethylsilyl)ndimethylacetamide in 20 ml of acetonitrile. After cooling slowly add a solution of the carboxylic acid, obtained above, in 40 ml of acetonitrile and stirred over night at room temperature. Concentrated in vacuo, the residue is treated with methanol, add a few drops of water and stirred for 2 hours at room temperature. The precipitate is filtered under vacuum, washed with methanol and dried. Sediment chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol in a volume ratio of 100:3, then a mixture of dichloromethane with methanol and acetic acid in a volume ratio of 100:3:0.5 in. On the of-2.1 (m, N); 2.4 to 2.8 (m, 5H); 3,4 (MT, 2H); 3,5 (C, 6N); and 6.5 (d, 2H); and 6.6 (s, 1H); and 7.1 to 7.4 (m, 2H); 7.5 (d, 1H); 7,8 (s, 1H); 8,9 (t, 1H).

EXAMPLE 3

2-[1-[4-[N-(3-Aminopropyl)carbarnoyl] -2-isopropylphenyl] -5-(2,6-acid)pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-CONH(CH2)3NH2; R2- 2-isopropyl; R3- H; R4- CH3; AA(HE) - 2-carboxyamide-2-yl)

Over night at room temperature and at atmospheric pressure hydronaut a mixture of 0.3 g obtained in example 2 compound in the presence of 0.03 g of Raney Nickelin 10 ml of methanol, and then the catalyst is filtered off, washed with methanol and the filtrate is partially concentrated in vacuo. The formed crystals are filtered and washed with ethanol, receiving the first batch of the desired product. The filtrate is partially concentrated in vacuo and stirred at room temperature. The formed crystals are filtered under vacuum and washed with ethanol, receiving the second batch of the desired product. By combining both parties receive 0,045 g of the target product. So pl.=280oC (decomposition).

NMR spectrum: 1,1 (d, 6N); 1,5-2,2 (m, 14N); 2,4-3 (m, 5H); 3,3 (MT, 2H); 3,6 (C, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); 7,2-7,4 (m, 2H); and 7.6 (d, 1H), and 7.7 (s, 1H).

Primerno-2-carboxylic acid (formula (I); R1- 4-CONH(CH2)2C (NH)NH2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Stage A: In a bath with ice cooled solution of 0.37 g of the compound obtained in example 2 in 10 ml ethanol and 10 ml of anhydrous ether, and then for 50 minutes bubbled through a solution of gaseous hydrogen chloride. Stand for three days at a temperature of +5oWith, then concentrated in vacuo, obtaining hydrochloride intermediate imidate (R1- 4-CONH(CH2)2C(=NH)OC2H5).

Stage B: the Residue is treated with 20 ml of anhydrous ethanol, the resulting solution is cooled in a bath with ice and passed through it for 35 minutes ammonia. Stirred for 30 minutes at room temperature, concentrated in vacuo, the residue is treated with water and allowed to crystallize. After filtration under vacuum, and then drying the crystals will recrystallized from hot ethanol. Obtain 0.3 g of the target product. So pl.=257oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1,1 (d, 6N); 1,5-2,2 (m, 14N); 2.4 to 2.8 (m, 3H); 3,4-3,7 (m+s, 8H); and 6.6 (d, 2H); 6,7 (s, 1H); 7,2-7,4 (m, 2H); 7,6 (doctor d, 1H); 7,8 (ush.s, 1H).

EXAMPLE 5

The dihydrochloride of 2-[5-(2,6-acid)-1-[4-[N-(2-diformyl (I); ; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within 30 minutes, stirred mixture of 0.49 g of the intermediate imidate obtained in example 4, step A, and 5 ml of 1,2-diaminoethane. The reaction medium is evaporated. By adding water falls precipitate, which is filtered off, then washed with water. This product is suspended in ethanol and add hydrochloric ether. After evaporation of the solvent the product proscout in ether, filtered off, washed with ether, then dried at 60oWith over phosphoric anhydride. Obtain 0.3 g of the target product. So pl.=220oC (decomposition).

The NMR spectrum of 1.05 (d, 6N); 1,5-2,2 (m, N); 2,5 (ush.s, 2H); 2,6-2,8 (m, 3H); 3,55 (MT, 2H); 3,65 (C, 6N); and 3.8 (s, 1H); and 6.6 (d, 2H); 6,7 (s, 1H); 7,2-7,4 (doctor d, 1H); 7,8 (d, 1H).

EXAMPLE 6

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-(3-N', N'- dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-CONH(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Get a mixture containing 1.45 g of the compound obtained in Preparative example 4.3, 30 ml of dichloromethane, 0,38 ml isobutylparaben the other hand, mix of 0.57 g of 2-aminoadamantana-2-carboxylic acid in 10 ml of acetonitrile and 2.2 ml of bis(trimethylsilyl)ndimethylacetamide and refluxed under nitrogen atmosphere for 30 minutes. After cooling, add videolocity mixed anhydride and stirred at room temperature for 1 day. The insoluble substance is filtered off and remove; the solvent is evaporated, then add water, stirred for 30 minutes and filtered loose sediment. A second fraction is obtained from the filtrate after the addition of ethanol, extraction with dichloromethane (2 times), drying the extract over sulfate

magnesium and evaporation of solvents. Both combined fractions chromatographic on the silicon dioxide, elwira a mixture of dichloromethane with methanol and water in a volume ratio first 90:10:0,8, then 88:12:1. Receive 40 mg of the target product after powdering in diisopropyl ether and filtering off. So pl.=220oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1,1 (d, 6N); 1,5-2,2 (m, 14N); 2,5 (ush.s, 2H); 2,75 (C+MT, 7H); 3,1 (m, 2H); 3,3 (m, 2H); 3,65 (C, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); 7,2-7,4 (m, 2H); 7,6 (doctor d, 1H); 7,8 (d, 2H).

On the basis of the acids of formula (II) described in table 4, and following the procedure described in example 1, receive connections were radioactive)-4-[4-[N-methyl-N-(3-N', N'-dimethylaminopropyl)aminosulfonyl] -2 - isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-SO2N(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

For 5.5 hours at room temperature and stirred 850 mg) obtained in Preparative example 4.11 acid and 3 ml of thionyl chloride. Add 10 ml of toluene, then the reaction medium is evaporated in vacuum (repeat 2 times). Thus obtain 1 g of the carboxylic acid obtained in Preparative example 4.11. Over 4.5 hours stirred mixture of 0.41 g of 2-amino-adamantane-2-carboxylic acid and 3.5 ml of bis(trimethylsilyl)ndimethylacetamide in 5 ml of acetonitrile. To this reaction medium, add a solution videolooking the carboxylic acid in 5 ml of acetonitrile and 1 ml of triethylamine and stirred for four days at room temperature. Add 3 ml of water, 5 ml of methanol and stirred for 4 hours at room temperature, then filtered and evaporated in vacuum. The remainder proscout in 6 ml of 1 N. hydrochloric acid, then add ethanol and evaporated in vacuum. The residue is stirred in 200 ml of dichloromethane and 5 ml of water, the purified product. It is recrystallized from 5 ml of CH3CN, cooling to -20oWith, and filtered 0.6 g of the target product. So pl.=211oC.

NMR spectrum: 1 (d, 6N); 1,4-2,1 (m, 14N); 2,4-2,5 (MT, 2H); a 2.5 to 2.65 (MT, 1H); 2,6 (s, 3H); to 2.65 (s, 6N); 2,9 (MT, 4H); 3,5 (C, 6N); and 6.5 (d, 2H); 6,7 (s, 1H); 7,15 to 7.4 (m, 3H); 7,45-to 7.6 (m, 2H).

EXAMPLE 15

2-[5-(2,6-Acid)-1-[4- [N-[3-(N',N'- dimethylamino)propyl]carbarnoyl] -5,6,7,8-tetrahedronal-1-yl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CONH(CH2)3N(CH3)3; R2, R3- -(CH2)4-; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within one and a half hours at a temperature of 40oWith a heated solution of 0.47 g of the compound obtained in Preparative example 4.12, 5 ml of thionyl chloride and 30 ml of dichloromethane. Is evaporated in vacuum, obtaining the acid chloride of the acid, which is again dissolved in 5 ml of acetonitrile and added to a solution obtained by boiling under reflux for two hours a mixture of 0.28 g of compound B, to 0.69 ml of bis(trimethylsilyl)ndimethylacetamide and 3 ml of acetonitrile. Type of 0.26 ml of triethylamine and stirred for two hours at room temperature. Evaporated in vacuo, the residue proscout in 2 ml of saturated solution of chloride natrona using a mixture of dichloromethane with methanol and water in a volume ratio of 80:20: 2,5. Evaporated, proscout the residue in ether and filtered off, getting 0.11 g of the target product. So pl.=200oWith (resin).

NMR spectrum: 1,4-2,05 (m, N); 2,1 (s, 6N); 2,2 (t, 3H); 2.4 to 2.8 (m, 6N); 3,2 (KD, 2H); 3,6 (C, 6N); AND 6.6 (2H, d); of 6.65 (s, 1H); 6.8 or 7 (D. d, 2H); 7,2-7,3 (m, 2H); 8,2 (t, 1H).

EXAMPLE 16

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(2-N', N'-dimethylaminoethyl)aminosulfonyl] -5,6,7,8-tetrahedronal-1-yl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-SO2N(CH3)(CH2)2N(CH2)2; R2, R3- -(CH2)4-; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

For 15 hours at room temperature, stirred for 0.5 g of the salt obtained in Preparative example 4.13, 10 ml of thionyl chloride, and then evaporated with toluene, receiving the acid chloride of the acid, which is mixed with solution similarvideo compound B obtained by stirring for 6 hours at room temperature a mixture of 0,279 g of compound B, 2 ml of bis(trimethylsilyl)ndimethylacetamide and 8 ml of acetonitrile. After stirring for 20 days at room temperature, the reaction medium is evaporated in vacuo, then the residue is stirred for 1 hour at room temperature with 5 ml of water and 5 ml IU the N., elwira a mixture of dichloromethane with methanol and acetic acid. The remainder proscout in ether and filtered off, getting 0.31 g of the target product. So pl. above 260oC.

NMR-spectrum (DMSO+TFUC): 1,6-2,3 (m, N); 2,6 (m, 2H); 2,9 (ush.with, N); 3,1 (MT, 2H); 3,4 (MT, 2H); 3,6 (MT, 2H); 3,7 (C, 6N); 6,7 (d, 2H); 6,85 (s, 1H); to 7.15 (d, 1H); TO 7.4 (1H, t); 7.5 (a ush.s, 1H); and 7.6 (d, 1H).

EXAMPLE 17

2-[5-(2,6-Acid)-1-(2-methyl-4-carbamoylmethyl)pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-CONH2; R2- 2-methyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within an hour, refluxed suspension of 220 mg of compound B with 0.4 mg of bis(trimethylsilyl)ndimethylacetamide in 10 ml of acetonitrile. In addition, prepare a solution containing 330 mg of the compound obtained in Preparative example 4.14, and 0.15 ml of triethylamine in 10 ml of acetonitrile, cooled to -5oWith the add of 0.13 ml of isobutylacetate, then stirred for 1 hour at room temperature and the resulting mixed anhydride are added to a solution similarvideo compound B obtained above. Incubated at room temperature for eight days, then filtered off the insoluble matter, the filtrate is evaporated to dryness, after the shat over sodium sulfate and evaporated; add to the residue 5 ml of dichloromethane, precipitated precipitate is filtered off and dissolve it in 1 ml of methanol. The formed crystals are filtered, receiving 100 mg of the target product. So pl.=290oC (decomposition).

NMR spectrum: of 1.4-2.3 (m, 15 NM); to 2.55 (m, 2H); 3,6 (C, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); 7,05 (d, 1H); and 7.3 (t, 1H); 7.4 for (s, 2H); 7,6 (doctor d, 1H); of 7.75 (s, 1H); 7,9 (s, 1H).

EXAMPLE 18

2-[5-(2,6-Acid)-1-[2,3-dimethyl-4-[N-(2-N',N'- dimethylaminoethyl)carbarnoyl] phenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CONH(CH2)2N(CH3)2; R2- 2-methyl; R3- 3-methyl; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within a half hour refluxed solution of 1.3 g of the product obtained in Preparative example 4.15, 10 ml of thionyl chloride and 50 ml of dichloromethane. Is evaporated in vacuum, obtaining the acid chloride of the acid, which is again dissolved in 10 ml of acetonitrile, and the solution added to the solution obtained after boiling under reflux for two hours a mixture of about 0.82 g of compound B, 2 ml of bis(trimethylsilyl)ndimethylacetamide in 10 ml of acetonitrile. Type of 0.77 ml of triethylamine and stirred for 15 hours at room temperature. After evaporation in oduct chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol and water in a volume ratio of 100:10:1. After evaporation of the solvents and powdering of the residue in ether is filtered off, gaining 0.7 g of the target product. So pl.=210oC.

NMR spectrum: 1,6-2,2 (m, N); 2 (s, 3H), of 2.25 (s, 3H); 2,35 (C, 6N); at 2.5-2.7 (m, 2H + 2H); 3,4 (KD, 2H); 3.7 (s, 6N); of 6.65 (d, 2H); at 6.8 (s, 1H); 7,0-7,2 (m, 2H); 7,3 was 7.45 (m, 2H); 8.4V (t, 1H).

EXAMPLE 19

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(2-N', N'-diethylaminoethyl)carbarnoyl] -2-methoxyphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CON(CH3)(CH2)2N(C2H5)2; R2- 2-OCH3; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within 24 hours at room temperature, stirred with 1.2 g of the product obtained in Preparative example 4.16, in 12 ml of thionyl chloride and 12 ml of dichloromethane. After evaporation in vacuum with two subsequent azeotropic distillation with 30 ml of toluene, the obtained acid chloride acid dissolved again in 10 ml of acetonitrile and the resulting solution was added to a solution obtained by boiling under reflux for 1 hour and 15 minutes a mixture of of 0.43 g of compound B, 1.1 ml of bis(trimethylsilyl)ndimethylacetamide and 20 ml of acetonitrile. is up in 4 ml of methanol and 0.5 ml of water; evaporated in vacuo, then chromatographic on silica gel 60 N, elwira using mixtures of dichloromethane with methanol and 20% ammonium hydroxide in the volume ratios of 95:5:0.5 to; then 90:10:0.5 and 85:15:0.5, and receiving 0.3 g of the target product. So pl.=170oC (decomposition).

NMR spectrum: 0,8 (MT, 3H); 1 (MT, 3H); 1.5 to 3.6V (MT, 34N); and 6.5 (d, 2H); of 6.65 (s, 1H); 6,95 (MT, 2H); 7,3 (MT, 3H).

EXAMPLE 20

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(2-N', N'-diethylaminoethyl)carbarnoyl] -2-chlorophenyl] pyrazole-3 - ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CON(CH3)(CH2)2N(C2H5)2; R2- 2-Cl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within 24 hours at room temperature and stirred for 1.3 g of the product obtained in Preparative example 4.17, in 12 ml of dichloromethane and 12 ml of thionyl chloride. After evaporation in vacuum with subsequent two azeotropic distillation with 30 ml of toluene, the obtained acid chloride acid dissolved again in 10 ml of acetonitrile and the resulting solution was added to a solution obtained by boiling under reflux for 1 hour and 15 minutes a mixture of 0,46 g soedineniya B, 1.2 ml of bis(trimethylsilyl)ndimethylacetamide in 20 ml of acetonitrile. Boil with Opla and 2 ml of water, stirred for 30 minutes at room temperature and evaporated in vacuum. The remainder chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol and 20% ammonium hydroxide in a volume ratio of 80:20:0.5, and receiving 0.3 g of the target product. So pl.=160oC (decomposition).

EXAMPLE 21

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-(2 - morpholinoethyl)carbarnoyl] -2-chlorophenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); ; R2- 2-Cl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within 18 hours at room temperature stirred mixture of 1.4 g of the product obtained in Preparative example 4.18, 14 ml of thionyl chloride and 80 ml of dichloromethane. After evaporation in vacuum with subsequent two azeotropic distillation with 30 ml of toluene and dissolved again the obtained carboxylic acid in 20 ml of acetonitrile, the resulting solution was added to a solution obtained by boiling under reflux for 4 hours suspension of 0.53 g of compound B 1.33 ml of bis(trimethylsilyl)ndimethylacetamide and 30 ml of acetonitrile. After boiling for 4 hours under reflux and with stirring, evaporated in vacuo, the residue is stirred with 10 ml of methanol and 1 ml virovanny hydrochloric acid, filtering off, washing with 1 ml of water, 5 ml of pentane and 5 ml of diisopropyl ether to obtain 0.7 g of the target product. So pl.=200oC.

NMR spectrum: 1,5-2,2 (m, N); 2,6 (ush.s, 2H); 2,85 (ush.s, 4H); 3,3-3,8 (MT, 20N); and 6.6 (d, 2H); 6.75 IN (1H, s); and 7.3 (t, 1H); was 7.45 (MT, 2H); 7,8 (doctor d, 1H); to 7.95 (d, 1H); cent to 8.85 (ush.s, 1H).

EXAMPLE 22

2- [5-(2,6-Acid)-1-(3-chloro-4-cyanophenyl)pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CN; R2- 3-Cl; R3- H; R4- CH3; AA(OH) - 2-carboxyamide-2-yl)

For three days at room temperature stirred mixture containing 0.36 g of the compound obtained in Preparative example 4.19, 0,145 ml isobutylphthalate and 0,145 ml of triethylamine in 5 ml dichloromethane. In addition, within 1 hour, refluxed mixture of 0.23 g of compound B and 0.34 ml of bis(triptoreline)ndimethylacetamide in 2 ml of acetonitrile. Mix the thus obtained two solution and stirred at room temperature for 48 hours. After filtering off and washing with methanol, the solvent is evaporated, then the residue chromatographic on the silicon dioxide, elwira a mixture of dichloromethane with methanol and acetic acid in a volume ratio of 100:1:0.5, the receiving 120 mg telazol-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-CONH2; R2- 3-CL; R3- H; R4- CH3; AA(OH) - 2-carboxyamide-2-yl)

Within 24 hours at room temperature stirred mixture containing 0.73 g of the compound obtained in Preparative example 4.20, to 0.263 ml isobutylphthalate and 0.26 ml of triethylamine in 5 ml dichloromethane. In addition, within 1 hour, refluxed mixture containing 0.34 g of compound B and 0.65 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile. Mix the two thus obtained solution and stirred at room temperature for 4 days. After filtering off, washing 1 N. hydrochloric acid, then with ethanol and drying over magnesium sulfate, the residue chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol and acetic acid in a volume ratio of 100:2:1. So pl.=293oC.

EXAMPLE 24

Hydrochloride of 2-[1-[4-[N-methyl-N-(2-N',N'- diethylaminoethyl)carbarnoyl]-2-cyclopropylethyl] -5-(2,6-acid)pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CON(CH3)(CH2)2N(C2H5)2; R2- 2-cyclopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within 24 hours at room teluride. After evaporation in vacuum with two subsequent azeotropic distillation with 30 ml of toluene, the resulting acid chloride acid dissolved again in 5 ml of acetonitrile, the resulting solution was added to a solution obtained by boiling under reflux for 2.5 hours suspension of 0,19 g of compound B in 0.5 ml of bis(trimethylsilyl)ndimethylacetamide and 8.5 ml of acetonitrile, and stirred for 12 hours at room temperature. Evaporated in vacuo, the residue is within 45 minutes mixed with 3.5 ml of methanol and 1 ml of water, then added dropwise 2.5 ml of water and filtered. After evaporation of the filtrate in vacuo and drying the residue for 24 hours at a temperature of 60oWith the vacuum obtain 0.14 g of the target product. So pl.=135oC (decomposition).

NMR-spectrum (DMSO+TFUC): 0,6 (m, 2H); 0,9 (m, 2H); 1,2 (m, 6N); 1,5-2,2 (m, N); 2,6 (m, 2H); 2,9 (ush.s, 3H); 3,2 (m, 6N); 3,6 (C, 6N); 3,7 (m, 2H); and 6.6 (d, 2H); 6.75 in (c, 1H); 6,85 (c, 1H); and 7.1 to 7.4 (m, 3H).

EXAMPLE 25

Hydrochloride of 2-[1-[3-N-methyl-N-(2-N',N'- dimethylaminoethyl)carbarnoyl]-4-chlorophenyl] -5-(2,6-acid)pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 3-CON(CH3)(CH2)2N(CH3)2; R2- 4-Cl; R3- H; R4- CH3; AA(OH) - 2-carboxyamide-2-Eative example 4.22, in 10 ml of dichloromethane and 6 ml of thionyl chloride. After evaporation in vacuum with subsequent two azeotropic distillation with 30 ml of toluene is obtained the acid chloride of the acid is again dissolved in 3 ml of acetonitrile, the resulting solution was added to a solution obtained by boiling under reflux for three hours suspension of 0.17 g of compound B in 0.5 ml of bis(trimethylsilyl)ndimethylacetamide and 10 ml of acetonitrile. Stirred for three hours while boiling under reflux, then for 15 hours at room temperature. Evaporated in vacuo, the residue is stirred for one hour with 12 ml of methanol and 6 ml of water. The methanol is evaporated in vacuo, the residue is extracted with 2 times 50 ml of dichloromethane, the organic phase is dried over sodium sulfate and evaporated in vacuum, obtaining 0.16 g of the target product. So pl.=206oC (decomposition).

NMR spectrum: 1,5-2,3 (m, N); 2,6-3,8 (m, N); 6,7 (d, 2H); at 6.8 (s, 1H); and 7.1 to 7.7 (m, 4H).

EXAMPLE 26

2-[1-[5-[N-methyl-N-(3-N', N'-dimethylaminopropyl)carbarnoyl]-2-were] -5-(2,6-acid)pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 5-CON(CH3)(CH2)3N(CH3)2; R2- 2-CH3; R3- N; R4- CH3; AA(HE) - 2-carbox the operational example 4.23 product in 15 ml of thionyl chloride. After evaporation in vacuo, followed by three azeotropic distillation with 30 ml of dichloromethane formed acid chloride of the acid is again dissolved in 30 ml of acetonitrile, the resulting solution was added to a solution obtained by boiling under reflux for 1 hour the suspension is 0.69 g of compound B 1.75 ml of bis(trimethylsilyl)ndimethylacetamide and 6 ml of acetonitrile. After stirring for 15 hours at room temperature and evaporation in vacuo the resulting residue is dissolved in 13 ml of methanol, slowly add 12 ml of water and stirred for 30 minutes at room temperature. After evaporation in vacuum, powdering of the residue in 5 ml of 1 N. hydrochloric acid, decanting, three extraction of residual resin with 100 ml of dichloromethane, drying of the extracts over magnesium sulfate is evaporated in vacuo, then dissolve the residue in 15 ml of water. Alkalinized with 30% sodium hydroxide solution to pH 8, and then crystallized under the action of ultrasound. After filtering off the crystals recrystallized from toluene and dried in a vacuum at a temperature of 60oWith the receiving of 1.32 g of the target product. So pl.=165oC.

NMR-spectrum (DMSO+TFUC): 1,6-2,2 (m, 14N); 2,2 (s, 3H); 2,5-3,2 (m, 13H); 3,5 (MT, 2H); 3,7 (the main examples and following the above techniques, receive a connection according to the invention, presented in table 7.

EXAMPLE 37

The hydrosulfate 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

To a solution of 0.08 g of sulfuric acid in 5 ml of methanol at room temperature, add 0.5 g of the compound obtained in example 1', the solution is poured into 150 ml of chilled to a temperature of 5oWith ether and the precipitated precipitate is centrifuged. Gain of 0.54 g of the target product. After recrystallization from water so pl.=212oC (decomposition). After recrystallization from isopropyl-2-ol T. pl.=263oC.

NMR-spectrum (DMSO+TFUC): 1,1 (d, 6N); 1,5-2,2 (m, 14N); 2,5 (ush.s, 2H); 2,6-3 (m, 10H); 3,1 (MT, 2H); 3,5 (MT, 2H); 3,65 (C, 6N); and 6.6 (d, 2H); 6.75 in (s, 1H); and 7.1-7.5 (m, 4H).

The product of example 37 can also be obtained by the following method.

To a suspension of 3.4 g of the inner salt obtained in example 1', 34 ml of water while mixing, slowly add 22 ml of concentrated sulfuric acid and heated at a temperature of 40oTo change the appearance of the suspension. For 4 hours, cooled to room temperature under stirring, ocado is at 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2 - isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

A mixture of 0.5 g of the compound obtained in example 1', and 0.16 g of benzosulfimide in 5 ml of methanol was poured into 75 ml of ether, cooled to a temperature of 5oC, and the precipitation is filtered off under vacuum. Obtain 0.06 g of the target product. So pl.=170oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1 (d, 6N); 1,4-2,2 (m, 14N); 2,45 (ush.s, 2H); 2,5-3,2 (m, N); 3,4 (MT, 2H); 3,55 (C, 6N); and 6.5 (d, 2H); of 6.65 (s, 1H); 7-7,4 (m, 7H); 7,5 (MT, 2H).

EXAMPLE 39

Citrate 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

To a solution of 0.3 g of the compound obtained in example 1', 5 ml of ethanol and 3 ml of dichloromethane at room temperature add 0,084 g of citric acid and stirred for two hours at room temperature. Concentrated in vacuo and the residue crystallized from propan-2-ol. Obtain 0.26 g of the target product. So pl.=168oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,3 (m, 14N); 2,5 (ush.s, 2H); 2,6-3,3 (m, N); 3,3-3,8 (C+m, 8H); and 6.6 (d, 2H); 6.75 in (s, 1H); and 7.1-7.5 (m, 4H).

EXAMPLE 40

Maleate 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

When heat is tryout in vacuum. The residue is dissolved in 0.3 ml of ethanol, the solution was poured into 30 ml of ether and the resulting precipitate is filtered under vacuum. Obtain 0.04 g of the target product. So pl.=260oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,55-2,2 (m, 14N); 2,5 (ush.s, 2H): 2,6-3 (m, 10H); 3,5 (MT, 2H); 3,65 (C, 6N); and 6.3 (s, 2H); and 6.6 (d, 2H); 6.75 in (s, 1H); 7,15 was 7.45 (m, 4H).

EXAMPLE 41

Salt (S)-(+)-arginine 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid

0.1 g of the Compound obtained in example 1', and 0.03 g of (S)-(+)-arginine are dissolved when heated in 4 ml of methanol, the solution concentrated to a volume of 1 ml and poured into 10 ml of ether, cooled to 5oC. Get to 0.055 g of the target product (after filtering off under vacuum and drying over phosphorus pentoxide). So pl.=176oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,2 (m, 20N); 2,55 (ush.s, 2H); 2,6-3,55 (m, N); the 3.65 (s, 6N); 3,95 (t, 1H); and 6.6 (d, 2H); 6.75 in (s, 1H); 7,15 to 7.4 (m, 4H).

EXAMPLE 42

Etandisulfonat 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid

A) 1,2-Ethicalfashion

A solution of 3 g d is elute with 200 ml of demineralized water. The eluate is diluted by adding ethanol and concentrated in vacuo. Get at 3.35 g of the desired product in the form of oil, which crystallizes at room temperature.

B) Etandisulfonat 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2 - isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

0.05 g of the Compound obtained in example 1', and 0.04 g of compound obtained in stage a, dissolve when heated in 2 ml of propan-2-ol and concentrated in vacuo. The residue is dissolved in 0.3 ml of water with 8-mew drops of dioxane and left to crystallize at room temperature. Vegascasinoonline the product is filtered under vacuum, washed with water and dried in vacuum at 90oC. Get 0,042 g of the target product. So pl.=266oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,2 (m, 14N); 2,5 (ush.s, 2H); 2,6-3 (m+, 14N); 3,1 (MT, 2H); 3,5 (MT, 2H); 3,65 (C, 6N); and 6.6 (d, 2H); 6.75 in (s, 1H); 7,15 was 7.45 (m, 4H).

EXAMPLE 43

Sodium salt of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid

0,206 g of the Compound obtained in example 1', and was 0.026 g of sodium methylate are dissolved in 1 ml methanphetamine a gelatinous precipitate is filtered under vacuum and dried in a vacuum over phosphoric anhydride. Obtain 0.15 g of the target product. So pl.=191oC.

This connection can also be obtained according to the following method.

To a solution of 0.1 g of the compound obtained in example 1', 5 ml of methanol and 4 ml of dichloromethane added 0.7 ml of a solution of 0.104 g g of sodium hydroxide in 10 ml of methanol and then concentrated in vacuo. The residue is dissolved in 1 ml of propan-2-ol, the solution was poured into 75 ml of ether, cooled to a temperature of 5oC, and the precipitation is filtered off under vacuum. Obtain 0.05 g of the target product.

NMR spectrum: 1 (d, 6N); of 1.4-2.3 (m, 20N); 2,55 (ush.s, 2H); 2,6 (MT, 1H); 2,85 (d, 3H); 3.1 and 3,4 (2 MT, 4H); 3,6 (C, 6N); 6,55 (s, 1H); and 6.6 (s, 2H); to 6.95 (s, 1H); 2 7-7,35 (m, 4H).

Filmed in the presence of DMSO+TFUK NMR spectrum is slightly different: of 1.05 (d, 6N); 1,5-2,3 (m, 14N); 2,5 (ush.s, 2H); 2,6-3 (m, 10H); 3,1 (MT, 2H); 3,5 (MT, 6N); and 6.6 (d, 2H); 6.75 in (s, 1H); and 7.1 to 7.4 (m, 4H).

EXAMPLE 44

Fumarate 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

0.1 g of the Compound obtained in example 1', and 0.017 g of fumaric acid dissolved in 1.5 ml of ethanol with 1.5 ml of dichloromethane and 4 ml of methanol and stirred for 10 minutes at room temperature. Partially conc what womam and washing with ethanol). So pl.=243oC.

NMR-spectrum (DMSO+TFUC): 1 (d, 6N); 1,5-2,3 (m, 14N); 2,5 (ush.s, 2H); 2,6-3 (m, 10H); 3,1 (MT, 2H); 3,4 (MT, 2H); 3,6 (C, 6N); 6,5-6,7 (l+s, 3H); 6.75 in (s, 1H); and 7.1 to 7.4 (m, 5H).

EXAMPLE 45

Salt of N-methyl-(D)-glucamine 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl]-2-isopropylphenyl]pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid

A solution of 0.07 g of the compound obtained in example 1', 5 ml of ethanol with 1 ml of dichloromethane is refluxed add 0.02 g of N-methyl-(D)-glucamine and stirred for half hour at room temperature. Partially concentrated in vacuo, poured into 15 ml of ether and the precipitated precipitate is filtered off under vacuum. Get to 0.032 g of the target product. So pl.=90oWith (resin).

NMR-spectrum (DMSO+TFUC): 1 (d, 6N); 1,5-2,2 (m, 14N); 2,5-2,6 (MT, 5H); 2,6-3,2 (m, 14N); and 3.2 to 3.7 (m, 13H); of 3.85 (MT, 1H); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1 to 7.4 (m, 4H).

EXAMPLE 46

Salt diethanolamine 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl ] -2-isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

0.1 g Obtained in example 1' compounds dissolved in 1.5 ml of ethanol with 1.5 ml of dichloromethane, is added 0.015 g diethanolamine, stirred for 30 minutes at room UltraVivid under vacuum. Obtain 0.03 g of the target product. So pl.=200oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,2 (m, 14N); 2,5 (ush.s, 2H); 2,6-of 3.25 (m, N); 3,3-3,8 (m+, N); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1 to 7.4 (m, 4H).

EXAMPLE 47

(L)(+)-Tartrate 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid

Refluxed the mixture of 0.1 g of the compound obtained in example 1', and of 0.022 g (L)(+)-tartaric acid in 1.5 ml of ethanol with 1.5 ml of dichloromethane, then add 8 ml of ethanol and continue to boil under reflux for 5 minutes. After cooling to room temperature the reaction medium was partially concentrated in vacuo, poured into 10 ml of ether and the precipitated precipitate is filtered off under vacuum. Obtain 0.07 g of the desired product after drying over phosphorus pentoxide. So pl.=154oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,4 (m, 14N); 2,55 (ush.s, 2H); 2,6-3 (m, 10H); 3,1 (MT, 2H); 3,5 (MT, 2H); 3,65 (C, 6N); of 4.35 (s, 2H); and 6.6 (d, 2H); 6.75 in (s, 1H); to 7.15-7.5 (m, 4H).

EXAMPLE 48

Salt of choline 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

In what must register in example 1', and 0.025 ml of a 45% aqueous solution of choline hydroxide in methanol, then concentrated in vacuo. The remainder proscout in 5 ml of ether and the resulting precipitate is filtered under vacuum. Obtain 0.03 g of the target product. So pl.=150oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,4-2,2 (m, 14N); 2,5 (ush.s, 2H); 2.4 to 3 (m, 10H); 3,1 (ush.with, 11N); 3,4 (MT, 2H); 3,5 (MT, 2H); 3,6 (C, 6N); 3,8 (MT, 2H); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1 to 7.4 (m, 4H).

EXAMPLE 49

Isetionate 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

Refluxed the mixture of 0.1 g of the compound obtained in example 1', 3 ml of propan-2-ol add to 0.022 g 83% isetionate acid (obtained by elution of isetionate sodium on the resin Dowex-50WX8 in the N+-form) and left to crystallize overnight. Vegascasinoonline the product is filtered under vacuum. Get to 0.055 g of the target product. So pl.=230oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); of 1.55 (m, 14N); 2,55 (ush.s, 2H); 2,6-3,05 (m, N); 3,1 (m, 2H); 3,5 (MT, 2H); 3,6-3,7 (C+MT, 8H); and 6.6 (d, 2H); 6.75 in (s, 1H); 7,15 was 7.45 (m, 4H).

EXAMPLE 50

Potassium salt of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylpyrimidine solution of 0.15 g of compound, obtained in example 1', and 0.03 g of tert.-of potassium butyl 6.5 ml of propan-2-ol, and then concentrated in vacuo. The residue is dissolved in 0.5 ml of methanol and this solution was poured into 25 ml of diisopropyl ether, cooled to a temperature of -20oC. the precipitation is filtered under vacuum and dried over phosphorus pentoxide at a temperature of 80oC. Obtain 0.09 g of the target product. So pl.=222oC.

This connection can also be obtained by following the below method.

To a solution of 0.1 g of the compound obtained in example 1', 4 ml dichloromethane was added 1 ml of 0,129 g of KOH in 10 ml of methanol, then concentrated in vacuo. The residue is dissolved in 0.5 ml of propan-2-ol, the solution was poured into 75 ml of ether cooled to 5oC, and the precipitation is filtered off under vacuum. Get 0,015 g of the target product.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,3 (m, 14N); 2,5 (ush.s, 2H); 2,6-3 (m, 10H); 3,1 (t, 2H); 3,5 (t, 2H); 3,6 (C, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1-7.5 (m, 4H).

EXAMPLE 51

Dihydrophosphate 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

For 1 hour at room temperature stirred mixture of 0.1 g Conn is irout partially in vacuum, poured into 10 ml of ether, cooled to 5oC, and the precipitation is filtered off under vacuum. Obtain 0.04 g of the desired product after drying at 60oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,2 (m, 14N); 2,5 (ush.s, 2H); 2,6-3,3 (m, N); 3,5 (MT, 2H); 3,6 (C, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1 to 7.4 (m, 4H).

EXAMPLE 52

2-Naphthalenesulfonate 2-[5-(2,6-acid)-1-[4-[N - methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid

A solution of 0.5 g of the compound obtained in example 1', and 0.16 g of 2-naphthalenesulfonate in 5 ml of methanol was poured into 25 ml) cooled to 5oWith ether, the precipitated precipitate is filtered off under vacuum and the filtrate concentrated. The residue is dissolved in 2 ml of methanol, the solution was poured into 50 ml, cooled to 5oWith ether, the precipitated precipitate is filtered under vacuum and obtain 0.2 g of the target product. The first filtrate is poured into 50 ml, cooled to 5oWith ether, filtered off under vacuum, the precipitation and obtain 0.27 g of the second portion of the target product.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,2 (m, 14N); 2,5 (ush.s, 2H); 2,6-3 (m, 10H); 3,1 (MT, 2H); 3,5 (MT, 2H); 3,65 (C, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); a 7.1 to 7.6 (m, 7H); 7.7 (d, 1H); 7,8 and 8.1 (m, 2H); or 8.2 (s, 1H).

An EXAMPLE is Ino] adamantane-2-carboxylic acid (formula (I); R1- 4-CONH(CH2)2N(isopropyl)2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

For 4 hours at room temperature stirred mixture of 0.53 g of the compound obtained in Preparative example 4.30, and 2 ml of thionyl chloride. Concentrated in vacuo, the residue is treated with dichloromethane and evaporated in vacuo, the residue is treated with dichloromethane and the solvent is evaporated in vacuum. The thus obtained acid chloride acid is used as is. On the other hand, for 35 minutes in a nitrogen atmosphere refluxed mixture to 0.19 g of compound B and 0.49 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile. After cooling to room temperature, add the solution videolooking the carboxylic acid in 8 ml of acetonitrile and stirred over night at room temperature. Evaporated in vacuo, the residue is stirred with 8.8 ml of methanol, add to 8.8 ml of water and evaporated in vacuum. The residue is treated with 1.2 G. hydrochloric acid, the precipitated precipitate is filtered off under vacuum. The residue is treated with 10 ml of water, alkalinized to pH 8 by adding 1,3 n sodium hydroxide solution, the precipitate is filtered under vacuum is. the.sq.=196-198oC.

NMR-spectrum (DMSO+TFUC): 1,1 (d, 6N); 1,3 (d, N); 1,6-2,2 (m, N); to 2.55 (m, 2H); to 2.7 (m, 1H); 3,2 (m, 2H); 3.5 to 3.8 (m+s, 10H); and 6.6 (d, 2H); 6.75 in (s, 1H); of 7.2 to 7.4 (MT, 2H); the 7.65 (d, 1H); a 7.85 (s, 1H).

EXAMPLE 54

2-[5-(2,6-Acid)-1-[4-[N, N-bis(2-diethylaminoethyl) carbarnoyl]-2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-CON(CH2CH2N(C2H5)2)2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within 24 hours at room temperature stirred mixture of 0.4 g of the compound obtained in Preparative example 4.34, and 2.5 ml of thionyl chloride. Concentrated in vacuo, the residue treated with toluene and the solvent is evaporated in vacuum. The thus obtained acid chloride acid is used as is. On the other hand, within 45 minutes refluxed mixture of 0.18 g of compound B and 0.5 ml of bis(trimethylsilyl)ndimethylacetamide in 4 ml of acetonitrile. After cooling to room temperature, add the solution videolooking the carboxylic acid in 3 ml of acetonitrile and stirred for 72 hours at room temperature. Add 3 ml of methanol and the reaction mixture was concentrated in vacuo. The OS is by adding concentrated sodium hydroxide solution is decanted and the resulting resinous product. This resinous product chromatographic on silica gel N, elwira a mixture of dichloromethane with methanol and ammonium hydroxide in a volume ratio of 75:25:1,2. Obtain 0.4 g of the target product (after powdering in the air). So pl.=169oC.

EXAMPLE 55

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-(piperid-4-yl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); ; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within 5 days at room temperature, then

for 4 days at a temperature of 50oC and at atmospheric pressure hydronaut a mixture of 0.3 g of the compound obtained in example 12, 0.05 g of 10% palladium-on-coal and 0,033 ml of concentrated hydrochloric acid in 10 ml of methanol and 4 ml of dimethylformamide. The catalyst is filtered off on celiteand the filtrate is evaporated in vacuum. The residue is treated with ether and vegascasinoonline the product is filtered under vacuum. After drying over phosphorus pentoxide at a temperature of 70oWith the vacuum get 0,121 g of the target product. So pl.=252oC.

NMR-spectrum (DMSO+TFUC): 1,1 (d, 6N); 1,5-2,2 (m, N); 2,4-3,5 (3 MT+ush. s, 7H); 3,6 (C, 6N); 3,9-to 4.15 (m, 1H); and 6.6 (d, 2H); 6,7 (s, 1H); 7 is rebamol] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); ; R2- 2-isopropyl; R3- N; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 53, according to 0.48 g of the compound obtained in Preparative example 4.35, and 2 ml of thionyl chloride, and then 0.18 g of compound B and 0.46 g of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile. Obtain 0.2 g of the target product (after crystallization from propan-2-ol). So pl.=212oC (decomposition).

NMR-spectrum (DMSO+TFUC): 0,9 (ush.C, 6N); of 1.05 (m, 3H); 1,3-2,1 (m, 14N); 2,3 (ush. s, 2H); 2,5 (m, 1H); 2,9 (m, 2H); 3,2-3,6 (m+, 11N); at 6.4 (d, 2H); 6,5 (ush.s, 1H); 7-7,3 (m, 2H); was 7.45 (d, 1H); 7,65 (ush.s, 1H).

EXAMPLE 57

2-[5-(2,6-Acid)-1-[4-[N-(2,2,6,6-tetramethylpiperidine-4-yl)carbarnoyl] -2 - isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); ; R2- 2-isopropyl; R3- H; R4- CH3; AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 53, on the basis of of 0.43 g of the compound obtained in Preparative example 4.36, and 2 ml of thionyl chloride, and then 0.15 g of compound B and 0.39 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile. After stirring the reaction mixture overnight at room temperature, the precipitation is filtered off under vacuum and the and then concentrated in vacuo. The residue is treated with 1.2 G. hydrochloric acid and after powdering the precipitate is filtered off under vacuum. The residue is treated with 3 ml of water, alkalinized to pH 9 by adding 1,3 n sodium hydroxide solution, the precipitation is filtered under vacuum and washed with water. Obtain 0.24 g of the target product (after drying over phosphorus pentoxide). So pl.=270-272oC.

NMR-spectrum (DMSO+TFUC): 1,5 (d, 6N); 1,2 (s, 6N); 1,4 (C. 6N); 1,5-2,2 (2 m, N); to 2.65 (MT, 1H); 3,6 (C, 6N); 4,2-4,4 (m, 1H); 6,55 (d, 2H); 6,7 (s, 1H); and 7.1 to 7.4 (m, 2H); and 7.6 (d, 1H); 7,8 (s, 1H).

EXAMPLE 58

2-[5-(2,6-Acid)-1-[4-[[3-(diethylamino)pyrrolidin-1-yl] carbonyl]-2 - isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); ; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 53, on the basis of 0.39 g of the compound obtained in Preparative example 4.41, and 2 ml of thionyl chloride, then with 0.13 g of compound B and 0.34 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile. After stirring the reaction mixture overnight at room temperature, filtered off the insoluble matter and the filtrate concentrated in vacuo. The residue is treated with the nd and the formed crystals are sucked off. The crystals are dissolved in water, the solution is alkalinized to pH 9 by adding 1,3 n sodium hydroxide solution and the precipitated precipitate is filtered off under vacuum. Get after recrystallization from acetonitrile, 0.07 g of the target product. So pl.=175oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1,0 (d, 6N); 1,1-1,3 (m, 6N); 1,5-2,8 (4 m, 17H); 2,8-4,2 (3 m+, 15 NM); and 6.6 (d, 2H); 6,7 (s, 1H); of 7.2 to 7.4 (m, 3H); 7.5 (a ush.s, 1H).

EXAMPLE 59

2-[5-(2,6-Acid)-1-[4-[[-4- (dimethylamino)piperid-1-yl] carbonyl] -2-isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); ; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 53, on the basis of 0.45 g of the compound obtained in Preparative example 4.37, and 2 ml of thionyl chloride, and then 0.17 g of compound B and 0.43 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile. After crystallization when heated from acetone, then methanol obtain 0.26 g of the target product. So pl.=200oC (decomposition).

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,4-2,3 (2 m, N); 2,5 (ush.s, 2H); 2,7 (C+MT, 7H); 2,8-3,8 (2 m+s, 10H); 4,4-4,8 (m, 1H); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1 to 7.4 (m, 4H).

EXAMPLE 60

2-[5-(2,6-Acid)-1-[4-[N-methyl-N-(2 - cyanoethyl)ON(CH3)(CH2)2CN; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 53, based on 3,48 g of the compound obtained in Preparative example 4.38, and 20 ml of thionyl chloride, then 1,43 g of compound B and 3.6 ml of bis(trimethylsilyl)ndimethylacetamide in 25 ml of acetonitrile. After stirring the reaction mixture overnight at room temperature, it was concentrated in vacuo, the residue is treated with 64 ml of methanol, add 64 ml of water and concentrated in vacuo. The residue is treated with 1.2 G. hydrochloric acid, the precipitated precipitate is filtered under vacuum and washed his 1,2 N. hydrochloric acid. The residue is treated with 5 ml of methanol, refluxed, cooled to room temperature and the precipitate is filtered off under vacuum. Get of 3.78 g of the target product (after drying over P2O5). So pl.=249oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,2 (m, N); 2,42 to 3.0 (m, 8H); 3,3-of 3.75 (m, 8H); to 6.58 (d, 2H); 6.73 x (s, 1H); 7,1-7,42 (m, 4H).

EXAMPLE 61

2-[5-(2,6-Acid)-1-[4-[N-methyl-N-(3 - aminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); Ris xiaguan-2-yl)

For 4 hours at room temperature and at atmospheric pressure hydronaut a mixture of 1 g of the compound obtained in example 60, 10 ml of 20% ammonium hydroxide solution and 0.1 g of Raney Nickelin 20 ml of ethanol. The catalyst is filtered off on celite, washed with ethanol, then with methanol and the filtrate is partially concentrated. Vegascasinoonline the product is filtered under vacuum, and the filtrate was concentrated in vacuo. Vegascasinoonline product and the residue after concentration is treated with 1.2 G. hydrochloric acid, the precipitate is filtered under vacuum and washed his 1,2 N. hydrochloric acid. The precipitate is dissolved in water, the aqueous phase is neutralized to pH 7 by adding 1,3 n sodium hydroxide solution, the precipitation is filtered under vacuum, washed with propan-2-I, refluxed, cooled to room temperature and the precipitate is filtered off under vacuum. Gain of 0.54 g of the target product (after drying). So pl.=239-241oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,2 (m, 14N); 2.4 to 3.8 (m, 8H); 3,5 (MT, 2H); to 3.64 (s, 6N); and 6.6 (d, 2H); 6,72 (s, 1H); 7,1 was 7.45 (m, 4H).

EXAMPLE 62

2-[5-(2,6-Acid)-1-[4-[N-methyl-N-(2-carbamoylethyl)carbarnoyl] -2-isopropylphenyl] Piras the
; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

For 3.5 hours at room temperature stirred mixture of 0.2 g of the compound obtained in example 60, 0,12 ml of 30% hydrogen peroxide solution in water and 0.18 ml of 6 n sodium hydroxide solution in 10 ml of 95% ethanol. Then added 0.06 ml of 30% hydrogen peroxide solution and 0.06 ml of 6 n sodium hydroxide solution and continue stirring for one and a half hours at room temperature. The insoluble substance is filtered off, the filtrate water is added, the aqueous phase is washed twice with dichloromethane, acidified to pH 3 by adding 1,2 N. hydrochloric acid, extracted with dichloromethane, the organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on silica gel 60 N, elwira mixture of toluene with methanol in a volume ratio of 90:10. Get 0,018 g of the target product (after powdering in the air). So pl.=164-166oC.

EXAMPLE 63

2-[5-(2,6-Acid)-1-[4-[N-methyl-N-(2-carboxyethyl)-carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 3-CON(CH3)(CH2)2CO2H; R2- 2-isopropyl; R3oWith over 30 minutes, passed through a current of gaseous hydrogen chloride, the reaction mixture was diluted with 17 ml of dichloromethane and stirred for two hours at a temperature of 0oC. Concentrated in vacuo, the obtained intermediate imidate treated with 9 ml of acetone, add 2 ml of 1,2 N. hydrochloric acid and stirred for 5 days at room temperature. Add 6 ml of dimethylformamide and 1 ml of 1,2 N. hydrochloric acid, in the course of three days, refluxed and stirred for 72 hours at room temperature. Concentrated in vacuo, the residue is treated with dichloromethane, the organic phase is extracted with saturated sodium hydrogen carbonate solution, the aqueous phase washed with dichloromethane, acidified to pH 1 by adding concentrated hydrochloric acid, extracted with dichloromethane, the organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum. After powdering in the air, and then drying at 60oWith over phosphoric anhydride obtain 0.03 g of the target product. So pl.=166-168oC.

NMR-spectrum (DMSO+TFUC): 1 (d, 6N); of 1.5-1.9 (m, N); 1,9-2,8 (m, 5H); 2,8-3,0 (MT, 3H); 3,2-3,6 (MT, 2H); 3,65 (C, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); 7,0-7,5 (m, 4H).

EXAMPLE 64

2-[5-(2,6-Dimethoxy formula (I); R1- 4-CONHCH2CH=CH2; R2- 2-isopropyl; R3- H; R4- CH3; AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 53, on the basis of 1.49 g of the compound obtained in Preparative example 4.42, and 25 ml of thionyl chloride, and then 0.65 g of compound B and 1.6 ml of bis(trimethylsilyl)ndimethylacetamide in 10 ml of acetonitrile. After stirring overnight at room temperature, filtered, the insoluble part and the filtrate concentrated in vacuo. The residue is treated with 10 ml of methanol, add 10 ml of water, the solid product is filtered under vacuum and washed it with methanol. The solid product is treated with acetonitrile, is boiled under reflux, allowed to cool to room temperature, the precipitate is filtered under vacuum and dried over phosphoric anhydride. Obtain 1.6 g of the target product. So pl.=304oC.

NMR spectrum: 1,1 (d, 6N); 1,5-2,2 (m, N); 2,5 (ush.s, 2H); 2,65 (CT, 1H); the 3.65 (s, 6N); a 3.9 (t, 2H); 5,0-5,2 (m, 2H); of 5.8-6.0 (m, 1H); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1 to 7.4 (m, 3H); to 7.6 (d, 1H); a 7.85 (s, 1H); 8,7 (t, 1H).

EXAMPLE 65

Iodide 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3 - trimethylammonio)carbarnoyl] -2 - isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic shall within 24 hours at room temperature stirred mixture of 0.1 g of compound, obtained in example 1', and 0.04 g under the conditions in 6 ml of dichloromethane. Concentrated in vacuo, the residue proscout in ether and precipitated precipitate is filtered off under vacuum. Obtain 0.12 g of the target product. So pl.=22oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,5-2,3 (m, 14N); 2,5 (ush.s, 2H); 2,7 (CT, 1H); 2,75-3,7 (m, 22N); and 6.6 (d, 2H); 6,7 (s, 1H); and 7.1-7.5 (m, 4H).

EXAMPLE 66

2-[5-(2,6-Acid)-1-[4-[N-methyl-N-[3-[N'-methyl-N'-(tert. -butoxycarbonyl)amino] propyl] carbarnoyl] -2 - isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CON(CH3)(CH2)3N(CH3)COO-tert. -butyl; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

A solution of 1.17 g of the compound obtained in Preparative example 4.43, and 0.3 ml of triethylamine in 3 ml of dimethylformamide cooled to -10oC. in the nitrogen atmosphere add to 0.21 ml ethylchloride and stirred for 15 minutes at a temperature of -10oC. on the other hand, for 45 minutes at a temperature of 80oWith a heated mixture of 0.77 g of compound B and 2 ml of bis(trimethylsilyl)ndimethylacetamide in 3 ml of dimethylformamide. After cooling to room temperature, this solution is added to the above solution of mixed anhydride and pancentric in vacuum. The residue is treated with 32 ml of methanol, gradually add 32 ml of water and concentrated in vacuo. The residue is treated with water, vegascasinoonline the product is filtered under vacuum, washed with water and dried. The crystals are treated with dichloromethane, filtered off the insoluble part and the filtrate chromatographic on the silicon dioxide, elwira a mixture of dichloromethane with methanol in a volume ratio of 100:0.5 to 100:2,5. After powdering in pentane receive 1 g of the target product. So pl.=118-120oC.

EXAMPLE 67

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-methylaminopropyl)carbarnoyl]-2-isopropylphenyl]pyrazole-3 - ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CON(CH3)(CH2)3NH(CH3); R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Within 20 minutes at room temperature, stirred mixture of 0.6 g of the compound obtained in example 66, and 4.2 ml of concentrated hydrochloric acid in 2.7 ml of methanol and 1.8 ml of water. Add the ethanol and the reaction mixture was concentrated in vacuo. The residue is treated with ethanol and the solvent is evaporated in vacuum. The residue is treated with ether, the precipitation tfilter is 1 g of the target product. So pl.=240oC.

NMR-spectrum (DMSO+TFUC): 1,1 (d, 6N); 1,5-2,4 (m, 14N); 2,6 (d, 3H); 2,7 (MT, 1H); 2,8-3,6 (m+s, 7H); the 3.65 (s, 6N); and 6.6 (d, 2H); 6,7 (s, 1H); 7,1 was 7.45 (m, 4H).

EXAMPLE 68

2-[5-(2,6-Acid)-1-[4-(4-methylphenylsulfonyl)-2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); ; R2- 2-isopropyl; R3- H; R4- CH3; AA(HE) - 2-carboxyamide-2-yl)

Within 1 hour at a temperature of 40oWith a heated mixture of 0.92 g of the compound obtained in Preparative example 4.44, and 7 ml of thionyl chloride in 7 ml of dichloromethane. Concentrated in vacuo and the resulting acid chloride acid is used as is. On the other hand, within 1 hour, refluxed mixture of 0.54 g of compound B and 1.35 ml of bis(trimethylsilyl)ndimethylacetamide in 5 ml of acetonitrile. After cooling to room temperature, this solution is added to visaelectron the acid chloride of the acid, add 0.25 ml of triethylamine and stirred for two hours at room temperature. Concentrated in vacuo, the residue is treated with 10% hydrochloric acid, extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder of the items is,5. Obtain 0.9 g of the target product.

NMR-spectrum (DMSO+TFUC): 0,85 (d, 6N); 1,52 was 2.25 (m, N); of 2.34 (s, 3H); 2,45-to 2.06 (m, 3H); 3,55 (C, 6N); 6,55 (d, 2H), 6,65 (s, 1H); 6,84 (doctor d, 1H); 6,95-7,05 (m, 2H); 7.23 percent and 7.36 (m, 3H); 7,58 (d, 2H).

EXAMPLE 69

2-[5-(2,6-Acid)-1-[4-[3- (diethylamino)propanolamine ] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-NHCO(CH2)2N(C2H5)2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 68, on the basis of 0.27 g of the compound obtained in Preparative example 4.46, 5 ml of thionyl chloride and 5 ml of dichloromethane, on the one hand, and 0,155 g of compound B and 0.39 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile from 0.14 ml of triethylamine, with the other hand. Gain of 0.13 g of the target product. So pl.=180oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,25 (t, 6N); 1,55-2,22 (m, N); 2,5-of 2.72 (m, 3H); to 2.85 (t, 2H); 3,2 (KD, 4H); 3,4 (MT, 2H); 3,68 (C, 6N); and 6.6 (d, 2H); 6,72 (s, 1H); to 7.15 (d, 1H); of 7.25-7.5 (m, 2H); 7,58 (d, 1H).

EXAMPLE 70

2-[5-(2,6-Acid)-1-[4-[N-acetyl-N-(3 - diethylaminopropyl)amino] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-N(COOH)3(SN
This connection receive according to the procedure described in example 68, according to 0.38 g of the compound obtained in Preparative example 4.48, and 3 ml of thionyl chloride in 3 ml of dichloromethane, then 0,164 g of compound B and 0.36 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile with 0.075 ml of triethylamine. Obtain 0.24 g of the target product. So pl.=220oC.

NMR-spectrum (DMSO+TFUC): 1,0 (d, 6N), and 1.5 (t, 6N); 1,45-2,2 (m, 17H); 2,5-of 2.72 (m, 3H); 2,9-3,15 (m, 6N); 3,6 (C, 6N); 3,7 (t, 2H); 6,59 (d, 2H); 6,74 (s, 1H); 7,15-7,42 (m, 5H).

EXAMPLE 71

2-[5-(2,6-Acid)-1-[4-[(3-diethylaminopropyl)amino] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-NH(CH2)3N(C2H5)2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

For 16 hours refluxed mixture of 0.2 g of the compound obtained in example 70, and 1 ml of concentrated hydrochloric acid in 5 ml of water with 5 ml ethanol. Add water to bring the pH to 5 by adding 10% sodium hydroxide solution and the precipitate is filtered off under vacuum. Get 0,145 g of the target product. So pl.=180oC.

NMR-spectrum (DMSO+TFUC): 1,05 (d, 6N); 1,19 (t, 6N); 1,4-2,2 (m, 14N); 2,4-2,63 (m, 3H); 2,98-3,3 (m, 8H); 3,62 (C, 6N); 6,5-6,85 (m, nil-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CON(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3N; ; AA(HE) - 2-carboxyamide-2-yl)

For eight hours at a temperature of 60oWith a heated mixture of a 3.87 g of the compound obtained in Preparative example 4.49, and 2.4 ml of thionyl chloride in 50 ml dichloromethane. Concentrated in vacuo, the residue treated with toluene and the solvent is evaporated in vacuum. The thus obtained acid chloride acid is used as is. On the other hand, for 3 hours at a temperature of 80oWith a heated mixture of 1.27 g of compound B and 2.65 g of bis(trimethylsilyl)ndimethylacetamide in 80 ml of acetonitrile. Then add a solution videolooking the carboxylic acid in 80 ml of acetonitrile and heated at 60oWith over three hours. Filtered off the insoluble part and the filtrate concentrated in vacuo. The residue is treated with 16 ml of methanol, add 16 ml of water and concentrated in vacuo. The residue is treated with water, extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol and water in a volume ratio of 100:5:0.5 in. Obtain 2.1 g target programor] -2 - isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-CON(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; R4- H; AA(HE) - 2-carboxyamide-2-yl)

For 5 hours at a temperature of 60oWith a heated mixture of 1 g of the compound obtained in example 72, and 20 ml of methanol with 20 ml of hydrochloric acid. Concentrated in vacuo, the residue treated with toluene and concentrated in vacuo. The remainder chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol in a volume ratio of 90:10, then a mixture of dichloromethane with methanol and ammonium hydroxide in a volume ratio of 80:20:2. Obtain 0.6 g of the target product. So pl. above 250oC.

EXAMPLE 74

2-[5-(2,6-Acid)-1-[4-[3-(diethylaminopropyl)amino] -2-were]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-NHCON(CH2)2N(C2H5)2; R2- 2-methyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

A) 2-[5-(2,6-Acid)-1-(2-methyl-4 - nitrophenyl)pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

This connection receive according to the procedure described in example 68, on the basis of 3.2 g obtained in Preparative example 4.50 connection and 20 ml of thionyl chloride in 40 ml of dichloromethane, is remesiana over night at room temperature, the reaction medium was concentrated in vacuo. The residue is treated with a mixture of acetone with water, the precipitated precipitate is filtered under vacuum and dried. Sediment chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol and water in a volume ratio of 100:0,3:0,2. Obtain 4.3 g of the target product. So pl.=150oC.

NMR spectrum: 1,6-2,2 (m, N); of 2.25 (s, 3H); 2,62 (MT, 2H); 3,63 (C, 6N); of 6.68 (d, 2H); to 6.88 (s, 1H); 7.03 is-the 7.43 (m, 2H); 7,58 (s, 1H); 8,05 (doctor d, 1H), 8,28 (d, 1H); 12,4 (ush.s, 1H).

B) 2-[5-(2,6-Acid)-1-(4-amino-2 - were)pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

For 4 hours at room temperature and at atmospheric pressure hydronaut mixture of 4.2 g of the compound obtained in the previous phase, in the presence of 0.5 g of Raney Nickelin 40 ml of methanol and 2 ml of dimethylformamide. The catalyst is filtered off and the filtrate was concentrated in vacuo. The residue is treated with ether and filtered under vacuum loose sediment. Get 3,37 g of the target product. So pl.=205oC.

NMR spectrum: 1,42-2,1 (m, 15 NM); 2,52 (MT, 2H); 3,57 (C, 6N); 5,1 (ush.s, 2H); 6,1 (doctor d, 1H); from 6.22 (d, 1H); 6.42 per of 6.68 (m, 4H); 7,17-7,25 (m, 2H).

A) 2-[5-(2,6-Acid)-1-[4-[3-(diethylaminopropyl)amino] -2-were]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

During onshored in 6 ml of dichloromethane, then concentrated in vacuo. The thus obtained acid chloride acid are added to a solution of 0.87 g of the compound obtained in the previous stage, and of) 0.157 ml of triethylamine in 5 ml dichloromethane. Concentrated in vacuo and the residue chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol and water in a volume ratio of 100:5:0.5 in. Obtain 0.5 g of the target product. So pl.=190oC.

NMR spectrum: 1,28 (t, 6N); 1,6-2,2 (m, 15 NM); 2,5-3,2 (m, 10H); 3,6 (C, 6N); 6,63 (d, 2H); 6.75 in (s, 1H), 7,05 (d, 1H); 7,28-of 7.48 (m, 3H); at 7.55 (d, 1H); 10,18 (s, 1H).

EXAMPLE 75

2-[5-(2,6-Acid)-1-[4-[[-3(piperid-1-yl)propanol]amino]-2-were] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); ; R2- 2-methyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 74, step B, from 0.1 g of 3-(piperid-1-yl)propanoic acid and 1 ml of thionyl chloride in 2 ml of dichloromethane, then of 0.337 g of compound obtained in stage B of example 74, and 0.17 ml of triethylamine in 5 ml dichloromethane. Obtain 0.2 g of the target product. So pl.=240oC.

NMR spectrum: 1,22-2,1 (m, N); 2,22-of 2.38 (m, 10H); to 3.58 (c, 6H); and 6.5 (d, 2H); and 6.6 (s, 1H); to 6.9 (d, 1H); 7.18 in with 7.3 (m, 3H); 7,38 (d, 1H); from 10.1 (s, 1H).

EXAMPLE 76

2-[5-(2, what about the acid (formula (I); R1- 4-NHCO(CH2)2N(C2H5)2; R2- 2-isobutyl; R3- H; R4is methyl, AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 68, on the basis of, on the one hand, 0.15 g of the compound obtained in Preparative example 4.52, and 2 ml thionylchloride in 2 ml of dichloromethane and, on the other hand, 0,084 g of compound B and 0.21 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile and 0.79 ml of triethylamine. Get 0,014 g of the target product. So pl.= 180-200oC.

NMR spectrum: 0.75 in (d, 6N); to 1.15 (t, 6N); 1,4-of 2.25 (m, 15 NM); 2,5 (s, 2H); and 2.8 (t, 2H); 3,1 (KD, 4H); 3,3 (t, 2H); 3,55 (C, 6N); and 6.5 (d, 2H); and 6.6 (s, 1H); of 6.8 to 7.6 (m, 5H); or 10.3 (s, 1H).

EXAMPLE 77

2-[5-(2,6-Acid)-1-[4-[3-(diethylamino)propanolamine] -2-cyclopentylphenol] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-NHCO(CH2)2-N(C2H5)2; ; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

This connection receive according to the procedure described in example 68, on the basis of, on the one hand, 0.32 g of the compound obtained in Preparative example 4.54, and 2 ml of thionyl chloride in 5 ml of dichloromethane and, on the other hand, 0.17 g of compound B of 0.42 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of acetonitrile,1-2,55 (m, N); 2,5-2,75 (m, 5H); 3.15 in (MT, 4H); to 3.35 (MT, 2H); 3,62 (C, 6N); 6,55 (d, 2H); of 6.65 (s, 1H); 7.03 is (d, 1H); to 7.25 (t, 1H); 7,35 (doctor d, 1H); at 7.55 (d, 1H).

EXAMPLE 78

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-(2-diethylaminoethyl)carbarnoyl] -3-isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-CONH(CH2)2N(C2H5)2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

Over night at room temperature stirred mixture of 0.36 g of compound obtained in Preparative example 4.55, and 5 ml of thionyl chloride in 15 ml of chloroform. Concentrated in vacuo, the residue treated with toluene and concentrated in vacuo. The thus obtained acid chloride acid is used as is. On the other hand, within 30 minutes, refluxed mixture 0,123 g of compound B and 0,315 ml of bis(trimethylsilyl)ndimethylacetamide in 10 ml of acetonitrile. This solution is added to the solution videolooking the carboxylic acid in 15 ml of acetonitrile and within three hours refluxed. Concentrated in vacuo, the residue is treated with 15 ml of methanol and 5 ml of water and stirred for 2 hours at room temperature. Concentrated in vacuo, the residue is the Aquum. After crystallization from chloroform obtain 0.35 g of the target product. So pl.=210oC (decomposition) (product crystallizes with 1 mol of chloroform).

EXAMPLE 79

Hydrochloride of 2-[5-(2,6-acid)-1-[4-(2-aminoethylamino)-5,6,7,8-tetrahedronal-1-yl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 4-NHCOCH2NH3; R2, R3- -(CH2)4-; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

A) 2-[5-(2,6-Acid)-1-[4-nitro-5,6,7,8 - tetrahedronal-1-yl]-pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

This connection receive in accordance with the method described in example 15, from 4 g of the compound obtained in Preparative example 4.56, and 20 ml of thionyl chloride in 20 ml of dichloromethane, then to 2.74 g of compound B and 6,86 ml of bis(trimethylsilyl)ndimethylacetamide in 20 ml of acetonitrile and 0.8 ml of triethylamine. After concentration in vacuo the residue is treated with ethanol and precipitated precipitate is filtered under vacuum, treated with methanol, filtered under vacuum and washed with ether. Gain of 5.3 g of the target product.

NMR-spectrum (DMSO+TFUC): 1,5-2,25 (m, N); 2,42-to 2.65 (m, 4H); 2,8 (MT, 2H); 3,6 (C, 6N), is 6.61 (d, 2H); 6.75 in (s, 1H); 7,06 (d, 1H); and 7.3 (t, 1H); 7.4 in (c, 1H), 7,65 (d, 1H).

B) 2-[a

At room temperature and at atmospheric pressure hydronaut a mixture of 3 g obtained at the previous stage of the connection and 0.5 g of Raney Nickelin 200 ml of dimethylformamide. The catalyst is filtered off and the filtrate was concentrated in vacuo. The residue is treated with water and the precipitated precipitate is filtered off under vacuum. Obtain 2.16 g of the target product (after drying).

NMR-spectrum (DMSO+TFUC): 1,42-2,2 (m, N); 2,3-2,8 (m, 6H); 3,6 (C, 6N); 6,55 (d, 2H); 6,7 (s, 1H); 6,98 (d, 1H); for 7.12 (d, 1H); to 7.25 (t, 1H).

A) 2-[5-(2,6-Acid)-1-[4-[2-(tert. -butoxycarbonylamino)acetylamino] -5,6,7,8-tetrahedronal-1-yl]pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid

Within 1 hour at a temperature of 60oWith a heated mixture of 0.3 g obtained at the previous stage of the connection and 0,258 ml of bis(trimethylsilyl)ndimethylacetamide in 2 ml of toluene. After cooling to room temperature, add of 0.64 ml of BOC-glycine-N-carboxyanhydride, 0,006 ml of N-methylmorpholine and stirred over night at room temperature. Add buffer solution with pH 4, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with the criminal code): 1,32 (s, N); 1,45-2,12 (m, N); 2,35-2,6 (m, 6N); 3,55 (C, 6N); the 3.65 (s, 2H); 6.5 in (d, 2H); 6,62 (s, 1H); 6,83 (d, 1H); 7,13-to 7.3 (m, 3H).

G) of the Hydrochloride of 2-[5-(2,6-acid)-1-[4-(2- aminoethylamino)-5,6,7,8-tetrahedronal-1-yl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

For 30 minutes at room temperature, stirred mixture of 0.14 g obtained at the previous stage of the connection and 5 ml of concentrated hydrochloric acid in 5 ml of methanol. Add water, filtered off under vacuum, the precipitation and dried. Obtain 0.06 g of the target product. So pl.= 220oC.

NMR spectrum: 1,59-2,5 (m, N); 2,42 is 2.75 (m, 6N); 3,7 (C, 6N); 3,88 (MT, 2H); of 6.68 (d, 2H); 6.75 in (s, 1H); to 6.95 (d, 1H); 7,2-of 7.48 (m, 3H); 8,2 (MT, 1H); 9,85 (s, 1H); 12,4 (ush.s, 1H).

EXAMPLE 80

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[(3-diethylaminopropyl)amino] -5,6,7,8-tetrahedronal-1 - yl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-NHCO(CH2)2N(C2H5); R2, R3- -(CH2)4-; R4- CH3; AA(OH) - 2-carboxyamide-2-yl)

Within 1 hour at a temperature of 40oWith a heated mixture of 0.16 g of the hydrochloride of 3-diethylaminopropyl acid and 2 ml of dichloromethane. Concentrated in vacuo, the residue is treated with dichloromethane and com, and 0,124 ml of triethylamine in 3 ml of dichloromethane. After stirring overnight at room temperature, water is added, extracted with dichloromethane, the organic phase is dried over magnesium sulfate and the solvent is evaporated in vacuum. The remainder chromatographic on silica gel 60 N, elwira a mixture of dichloromethane with methanol in a volume ratio of 100:3. Obtain 0.11 g of the target product.

NMR-spectrum (DMSO+TFUC): 1,21 (t, 6N); 1,41-2,2 (m, N); 2,35-2,7 (m, 6N); 2,84 (t, 2H); 3,01-of 3.12 (m, 4H); at 3.35 (t, 2H); 3,6 (C, 6N); 6,55 (d, 2H); 6,7 (s, 1H); to 6.9 (d, 1H); 7,12-to 7.3 (m, 2H).

EXAMPLE 81

Hydrochloride of 2-[5-(2,6-acid)-1-[4-(2-aminoethylethanolamine)-5,6,7,8-tetrahedronal-1 - yl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid (formula (I); R1- 4-NHSO2(CH2)2NH2; R2, R3- -(CH2)4-; R4is methyl; AA(HE) - 2-carboxyamide-2-yl)

A) Potassium salt of 2-palmitoylethanolamide

This connection and the connection phase B receive according to J. Am. Chem. Soc. , 69, 1393-1401 (1947).

Within 10 minutes, heated to the boiling temperature under reflux a mixture containing 30 g of taurine, 25 g of potassium acetate and 90 ml of acetic acid, then add of 37.8 g of phthalic anhydride. Within 2.5 hours boil m washed with ether and dried in vacuum, getting 59,14 g of the target product.

B) the acid chloride of 2-palmitoylethanolamide

Within 1 hour, refluxed 60 g obtained at the stage And join in 300 ml of toluene in the presence of 30.7 g pentachloride phosphorus. Again add a 30.7 g pentachloride phosphorus and refluxed for 90 minutes. Add 280 g of ice to the reaction medium is stirred, filtered off the insoluble part, then washed with cold water. The residue is dried over phosphorus pentoxide, and then recrystallized from dichloroethane, receiving 32 g of the target product. So pl.=160oC.

A) 2-[5-(2,6-Acid-1-[4-(2 - phthalimidomethyl)-5,6,7,8-tetrahedronal-1-yl]pyrazole-3-yl-carbylamine]adamantane-2-carboxylic acid

Within 1 hour at a temperature of 70oWith the stirred mixture containing 0.5 g of the compound obtained in example 79, step B, of 0.43 ml of bis (trimethylsilyl)ndimethylacetamide and 5 ml of acetonitrile. Stand to return to room temperature, then add 0,63 g obtained in stage B of the connection and 0.30 ml of triethylamine. After stirring for two hours at room temperature, acidified with 10% hydrochloric acid. The precipitate is filtered off, plugged into the comfort of ethanol (100%) and provide animal charcoal in dichloromethane. The resulting product chromatographic on silica gel 60 N, eperua a mixture of dichloromethane with methanol and water in a volume ratio of 100:2:0.2 to getting 0.28 g of the target product.

NMR-spectrum (DMSO+TFUC): 1,45-of 2.15 (m, N); 2,4-2,6 (m, 4H); to 2.75 (MT, 2H); 3,48 (C, 6N); 3.95 to to 4.15 (m, 4H); 6,46 (d, 1H); 6.75 in (s, 1H); to 6.9 (d, 1H); 7,1-7,3 (m, 2H); 7,7-a 7.85 (m, 4H).

G) of the Hydrochloride of 2-[5-(2,6-acid)-1-[4-(2- aminoethylethanolamine)-5,6,7,8-tetrahedronal-1 - yl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

Within two hours refluxed mixture containing 0.24 g obtained in the previous phase connection, 2 ml of 95% ethanol and 23 ml of hydrazine hydrate is added. The reaction medium is diluted with methanol, and then the crystals are filtered, then heated to boiling point in water and the solution is filtered hot. The obtained crystals are dried over phosphoric anhydride. These crystals are dissolved again in methanol, add hydrochloric ether, evaporated to dryness, and then treated with ether and pentane. Filtered, receiving 60 mg of the target product.

NMR-spectrum (DMSO+TFUC): 1,48-to 2.18 (m, N); 2,18-2,62 (m, 4H); 2,7 (MT, 2H); 3,19 (MT, 2H); 3,41 (MT, 2H); 3,62 (C, 6N); to 6.58 (d, 1H); 6,7 (s, 1H); PC 6.82 (d, 1H); was 7.08 (d, 1H); 7,28 (m, 1H); 7,39 (s, 1H).

EXAMPLE 82
1
- 4-CON(CH3)(CH2)3N (CH3)2; R2- 2-isopropyl: R3- H; R4is methyl; AA(OH) - (R)-(-carboxy)cyclohexylmethyl)

Mixing 1.2 g of sodium hydroxide 20.2 ml of water and of 1.62 g (D)-cyclohexylpiperazine. Was added dropwise a solution 1,58 g of the carboxylic acid obtained in example 1, stage A, in 40 ml of anhydrous tetrahydrofuran and stirred for 48 hours at room temperature. Wednesday concentrate, add ice and bring the pH to a value of 7 by adding concentrated hydrochloric acid. Filtered off, washed with water, then with pentane and dried in vacuum. The product is crushed, then stirred in a mixture of water with dichloromethane. Filtered off, then the aqueous phase is extracted with dichloromethane and dried the extract obtained over sodium sulfate. Concentrated, the residue is stirred in pentane and again filtered. Obtain 380 mg of the target product. So pl.=160oC.

EXAMPLE 83

Hydrochloride (S)-2-cyclohexyl-2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl]acetic acid (formula (I); R1- 4-CON(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; R4the t mixture, containing 0,57 g (S)-cyclohexylglycine and 1,49 g of bis(trimethylsilyl)ndimethylacetamide in 39 ml of acetonitrile and added dropwise a solution of 1.93 g obtained in example 1, stage A, chlorine-rangered acid in 39 ml of acetonitrile. After incubation for three hours at a temperature of 60oWith the temperature of the mixture is left to return to room temperature after which the reaction medium is filtered and the filtrate concentrated. To the residue add 8 ml of methanol, 3 ml of water and stirred for 30 minutes. Add 5 ml of water and concentrate. The resulting oil is absorbed in dichloromethane, the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated. The residue is treated with diisopropyl ether and filtered, obtaining 1.12 g of the target compound. So pl.=160oC.

EXAMPLE 84

2-[5-(2,6-Acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] bicyclo[3.3.1] nonan-9-carboxylic acid (formula (I); R1- 4-CON(CH3)(CH2)3N(CH3)2; R2- 2-isopropyl; R3- H; R4is methyl; AA(HE) - 9-carboxybutyl[3.3.1]nonan-9-yl)

585 mg of 9-Amino[3.3.1]bicycleand-9-carboxylic acid is mixed with 1.5 ml of bis(trimethylsilyl)Yo 1 equivalent of carboxylic acid, obtained in example 1, stage A, in 39 ml of acetonitrile and heated at 60oWith over three hours. After incubation for 12 hours at room temperature, filtered, the insoluble part, then concentrate the filtrate and the residue is stirred with 8 ml of methanol and 8 ml of water. Again concentrated, then extracted with dichloromethane, then getting 900 mg of the target product. So pl.=160oC.

EXAMPLE 85

2-[5-(2,6-Acid)-1-[5-[(3-diethylaminopropyl)amino] -2-isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid (formula (I); R1- 5-NHCO(CH2)2N(C2H5)2; R2- 2-isopropyl; R3- H; R4- CH3; AA(HE) - 2-carboxyamide-2-yl)

The acid chloride of the acid is obtained from 0.95 g of the compound obtained in Preparative example 4.57, 5 ml of thionyl chloride and 15 ml of dichloromethane by boiling under reflux for 1 hour, then evaporation. Within 1 hour, refluxed mixture of 0.55 g of compound B, to 1.37 ml of bis(trimethylsilyl)ndimethylacetamide in 5 ml of acetonitrile and the carboxylic acid in the form of a solution in 5 ml of dichloromethane and 0.5 ml of triethylamine. After stirring for two hours at room temperature viparivartate magnesium, is evaporated to dryness and the residue crystallized from acetone, getting 0.55 g of the target product.

NMR-spectrum (DMSO+TFUC): from 0.8 to 1.35 (m, N); 1,5-2,4 (m, 12H); 2,4-2,6 (m, 3H); and 2.8 (t, 2H); 3.15 in (KD, 4H); 3,3 (t, 2H); 3,5 (C, 6N); 6,55 (d, 2H); of 6.65 (s, 1H); 7,15 to 7.4 (m, 3H); of 7.75 (d, 1H).

EXAMPLE 86

Internal salt of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl]-2-isopropylphenyl]pyrazole-3-ylcarbonyl]-adamantane-2-carboxylic acid

The connection can also be obtained from the compound of example 61 according to the following method.

For 30 minutes at a temperature of 100oWith a heated mixture containing 0.2 g of the compound of example 61, 0.33 ml of formic acid and 0.11 ml of formaldehyde. After incubation for two hours at room temperature was added 1 ml of 2 N. hydrochloric acid, then add dichloromethane and methanol to dissolve the formed resin. The solvent is evaporated, the residue is treated with water, then neutralize 1,3-called sodium hydroxide solution until pH 7, the cooling medium ice. The precipitate is filtered off, washed with water, then dried over phosphoric anhydride, receiving of 0.13 g of the target product.

EXAMPLE 87

Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-(3 - dimethylaminopropyl carb is the second method of obtaining the compound of example 1.

A) 2-(Benzyloxycarbonylamino)adamantane-2-carboxylic acid

Within a half hour refluxed 1,015 g of 2-aminoadamantana-2-carboxylic acid and 6 ml of bis(trimethylsilyl)ndimethylacetamide in 10 ml of dichloromethane. Add 0.75 ml of benzyloxycarbonylglycine and within 15 minutes, heated at 50oC. the Reaction medium is cooled to -70oWith, then degraded by adding ice and extracted with ethyl acetate. Wash the extract with water (2 times), saturated sodium chloride solution, dried the organic phase over magnesium sulfate and evaporated in vacuum. The product is crystallized from hexane. Get 1,164,

NMR-spectrum (DMSO+TFUC): 1,5 (d, 2H); 1.8 m (m, 6N); 2 (t, 4H); 2,4-2,5 (m, 2H); 5 (s, 2H); 7,3 (ush.s, 5H).

B) tert. -Butyl ester 2- (benzyloxycarbonyl)aminoadamantana-2-carboxylic acid

1,164 g Obtained in the previous phase compounds dissolved in 15 ml of dichloromethane, was added 100 g hydratase-EN-p-toluenesulfonic acid, the mixture is then cooled to a temperature of -78oAnd add a solution of isobutylene in 15 ml of dichloromethane. Leave to stand to return to room temperature and stirred for 24 hours. Add 50 ál of concentrated sulfuric acid for dissolution of cordoned magnesium sulfate and evaporated in vacuum. The remainder chromatographic on the silicon dioxide, elwira with a mixture of hexane with ethyl acetate in a volume ratio of 80:20, and receive 612 mg of the target compound.

NMR-spectrum (deuterochloroform): 1,4 (C, H); of 1.5-1.9 (m, 8H); 2 (t, 4H); 2,5 (s, 2H) and 4.9 (s, 1H); from 5.1 (s, 2H); of 7.2 to 7.4 (m, 5H).

In) Hydrochloride tert.-butyl ether 2-aminoadamantana-2-carboxylic acid

600 mg Obtained in the previous phase of the product is dissolved in 40 ml of ethanol, add 150 ál of concentrated hydrochloric acid, and then 80 g of palladium-on-charcoal, then Wednesday hydronaut. After 1 hour the catalyst is filtered off and evaporated from the filtrate the solvent is getting 503 mg of the target product.

NMR-spectrum (deuterated methanol): 1,6 (s, N); 1,8-2 (m, 8H); 2-2,2 (m, 4H); 2,4 (s, 2H).

D) Methyl ester of 5-(2,6-acid)-1-[4-[N-methyl-[3-[N'-methyl-N'-(benzyloxycarbonyl)amino] propyl] carbarnoyl]-2-isopropylphenyl]pyrazole-3-carboxylic acid

0.33 g of the Compound obtained in Preparative example 3.57, dissolved in 20 ml of hydrochloric acid methanol. After stirring for 72 hours, the solvent is evaporated. The obtained hydrochloride was dissolved in 5 ml dichloromethane, then add 0.5 ml of triethylamine and 150 μl of benzyloxycarbonylamino. After 1 hour of reaction is with acetone in a volume ratio of 80:20 to 70:30. Obtain 252 mg of the target product.

D) 5-(2,6-Acid)-1-[4-(N-methyl-N-[3-[N'-methyl-N'-(benzyloxycarbonyl)amino]propyl]carbarnoyl]-2-isopropylphenyl]pyrazole-3-carboxylic acid

252 mg Obtained in the previous phase compounds are dissolved in 2.5 ml of dioxane and 90 μl of an aqueous solution of potassium hydroxide (1 g/ml). After stirring for 24 hours the medium is acidified with 1 ml concentrated hydrochloric acid. Extracted with ethyl acetate, the organic phase is dried over magnesium sulfate, then getting 236 mg of the target compound.

E) tert.-Butyl ester of[5-(2,6-acid)-1-[4-[N-methyl-N-[3-[N'-methyl-N'- (benzyloxycarbonyl)amino] propyl]carbarnoyl]-2-isopropylphenyl]pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

Obtained in the previous phase of the acid dissolved in 2 ml of acetonitrile, add 0.5 ml of carbon tetrachloride and 158 mg of triphenylphosphine and stirred for two hours. To the resulting acid chloride acid added 110 mg obtained at the stage In connections and 100 μl of triethylamine. Precipitated trietilenglikole and stirred for further 15 minutes. Add water, then extracted with dichloromethane; the organic phase is dried over magnesium sulfate and concentrated in Vacu is 0:20, getting then 323 mg of the target product.

W) Hydrochloride tert. butyl ester of [5-(2,6 - acid)-1-[4-[N-methyl-N-[3-[N'- methylamino]propyl]carbarnoyl]-2-isopropylphenyl]-pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

Within 24 hours in an atmosphere of hydrogen stirred mixture containing 323 mg obtained in the previous phase connection, 2 mg of palladium-on-coal, and 40 μl of concentrated hydrochloric acid in 15 ml of ethanol. The catalyst is filtered off and the filtrate is evaporated in vacuum. The environment is treated with ether and stirred. Precipitated white precipitate is filtered off, getting 190 mg of the target product.

NMR-spectrum (deuterated methanol): 1,1 (d, 6N), and 1.5 (s, N); 1.7 to 1.9 (m, 8H); about 2.2-2.3 (m, 6N); 2,6 (s, 2H); 2,7-2,9 (K+s, 4H); 3 (s, 3H); 3,1 (t, 2H); 3,7 (C+MT, 8H); and 6.6 (d, 2H); at 6.8 (s, 1H); a 7.2 to 7.6 (m, 5H).

C) the Hydrochloride of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbarnoyl] -2 - isopropylphenyl] pyrazole-3-ylcarbonyl]adamantane-2-carboxylic acid

190 mg) Obtained in the previous phase compounds suspended in 50 μl of acetonitrile, add 0.5 ml of the solution under the conditions in toluene (89 μl under the conditions in 100 ml of toluene) and 7.6 mg of silver carbonate. Filtered off the insoluble part, then dissolve the th acid and stirred over night. After evaporation in vacuum and powdering of the residue in ether to obtain 90 mg of the target product.

EXAMPLE 88

Oxazole compound of example 1':

< / BR>
Over 4.5 hours stirred solution of 0.23 g of compound of example 1' in 2 ml of dichloromethane and 0.5 ml of acetic anhydride. Evaporated in vacuo, the residue proscout in pentane, filtered and dried, obtaining 230 mg of the target oxazolone. So pl.=129oC (decomposition).

IR-spectrum (KBr): 1800 cm-1.

Mass spectrum: M 667,9.

NMR spectrum: 1 (d, 6N); of 1.5-1.9 (m, 8H); 2 (ush.s, 8H); to 2.1-2.5 (m, 6N); 2,65 (CT, 1H); 2.9 and 3 (2s, 3H); 3,1 (MT, 2H); 3,4 (MT, 2H); 3,65 (C, 6N); and 6.6 (d, 2H); 6,9 (s, 1H); and 7.1 to 7.4 (m, 4H).

1. Substituted 1-phenylpyrazol-3-carboxamide formula

< / BR>
in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen;

NRaRbdenotes a group selected from

-NR9(CH2)sCR7R8(CH2)tNR5R6< / BR>
< / BR>
< / BR>
where R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl; or R5and R6together with the nitrogen atom to which they are sogenji 4 Deputy R9;

R7denotes hydrogen, (C1-C4)-alkyl or benzyl;

R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalken;

R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6;

R'5and R'6represent, independently from each other, (C1-C6)-alkyl;

R10denotes hydrogen, (C1-C4)-alkyl;

s= 0-3;

t= 0-3, provided that (s+t) in the same group greater than or equal to 1;

the divalent radicals a and E together with the carbon atom and the nitrogen atom to which they are linked, form a saturated a heterocycle having from 4 to 7 units, which, in addition, may be substituted by one or more (C1-C4-alkilani;

R2xand R3denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl, provided that R2xand R3do not simultaneously denote hydrogen, or R2xand R3together form tetramethylene group;

and their pharmaceutically acceptable salts.

2. Link

< / BR>
< / BR>
< / BR>
3. Connection on p. 1, characterized in that it consists of 2-[5-(2,6-acid)-1-[4-[N-methyl-N-(3-dimethylaminopropyl)carbamoyl] -2-isopropylphenyl] pyrazole-3-ylcarbonyl] adamantane-2-carboxylic acid, its internal salt, and its pharmaceutically acceptable salts.

4. Oxazol formula (IC)

< / BR>
in which R1is in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7)alkylen;

NRaRbrefers to the group-NR9(CH2)sCR7R8(CH)tNR5R6;

R2means (C1-C6)alkyl;

R3denotes hydrogen;

R5and R6denote (C1-C6)alkyl;

R7and R8represent hydrogen;

s = 0-3;

t = 0-3, provided that the sum (s+t) is greater than or equal to 1.

5. The method of obtaining substituted 1-phenylpyrazol-3-carboxamide according to any one of paragraphs. 1-3 and their salts, characterized in that

1) the functional derivative of 1-phenylpyrazol-3-carboxylic acid of formula (II) or (II')

< / BR>
< / BR>
which R1, R2, R3have values that match the values of R1x, R2xand R3that is carboxyl, (C1-C4)-alkoxycarbonyl, benzyloxycarbonyl,

process amino acid, possibly protected using conventional peptide synthesis of protective groups of the formula (III)

H-HN-AA(OH) (III)

in which the-NH-AA(OH) denotes a group of the formula

< / BR>
2) if necessary, the thus obtained functional derivative of the acid of formula (I')

< / BR>
put then the appropriate treatment for the conversion of the substituent R'1, which is a predecessor of R1in the substituent R1;

3) possibly obtained in stage 1 or stage 2) connection remove the protective group to obtain the corresponding free acid of formula (I);

4) and, if necessary, get the salt thus obtained the compounds of formula (I).

6. 1-phenylpyrazol-3-carboxylic acid of formula (II) or (II'):

< / BR>
< / BR>
in which R1, R2, R3have values that match the values of R1x, R2xand R3specified for compounds of the formula (1A) in paragraph (1;

R'1means the precursor of the radical R1selected among carboxyl, (C1-C4)-alkoxycarbonyl, benzyloxycarbonyl,

as well as its functional derivatives, sybrina formula (3')

< / BR>
in which R'2and R'3independently of one another, mean hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl; or R'2and R'3together form tetramethylene group;

Ryis in position 4 or in position 5 indicates a group selected among the following groups: carboxyl, (C1-C4-alkoxycarbonyl, benzyloxycarbonyl, provided that R'2and R'3at the same time do not represent hydrogen and R'2differs from ethyl when R'3denotes hydrogen, and Rymeans methoxycarbonyl group in position 4;

and its salts.

8. Pharmaceutical composition having affinity to the human neurotensin receptor, characterized in that it contains as active beginning of the connection according to any one of paragraphs. 1-3 or one of its pharmaceutically acceptable salts in combination with a pharmaceutically acceptable carrier.

 

Same patents:

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

The invention relates to new derivatives of kalaidjieva, fungicides, method of combating fungal diseases of crops and intermediate compounds for obtaining

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to new derivatives of benzoxazinone General formula (I), where R1means N or carboxyethyl, R2represents hydrogen or alkyl, and R3is a different derivatively of amino acids, dipeptides and hydrazones acid groups, respectively, their conjugates with active substances, such as residues from a number of penicillin

The invention relates to compounds: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl] methyl]-N,3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide and their pharmaceutically acceptable salts, such as lithium, sodium or potassium salt or a salt with a base, which is an organic amine

The invention relates to new derivatives of oxadiazole General formula I, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula II, R1means phenyl radical, which is optionally substituted directly or through alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C1-C4-alkyl, CF3, -NR5R6, NO2, -OR7

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a new method of obtaining isoxazolidinone the compounds of formula (II) in which R represents an optionally substituted aromatic hydrocarbon group or its salt, by reacting the compounds of formula (1) or its salt with the compound of the formula (2) in the presence of an inorganic base in an aqueous solvent with getting aspartates the compounds of formula (3), which interacts with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula (4), to which is added p-toluensulfonate acid to obtain oxazolidinedione derivative of the formula (5)which then restores the tetrahydrofuran in the presence of NaBH4and methanol to obtain oxazolidinones the compounds of formula (6) and its further interaction with methylchloride in the presence of triethylamine to obtain methanesulfonate derivative of the formula (7), which interacts with the compound of the formula (8) in the presence of potassium carbonate to obtain benzylidene derivative of the formula (9), which is further restored in an atmosphere of hydrogen for the floor is warping with obtaining the compounds of formula (11)

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

The invention relates to sulphonilecarbomide acids of the formula

< / BR>
and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

< / BR>
where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;

The invention relates to acylaminocinnamic derivative of the formula (I), where R denotes phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R1is hydrogen, alkyl, R2is hydrogen, alkyl or phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R3is phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, or represents naphthyl, lH-indol-3-yl or 1-alcheringa-3-yl, R4' and R4"is hydrogen, alkyl, and one of the radicals R4' and R4"is hydrogen, and R5- cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its salt

The invention relates to an improved process for the preparation of 8-methyl-8-azabicyclo[3,2,1]Oct-3-silt ester of indole-3-carboxylic acid hydrochloride which is a substance tropisetrona and is used as an antiemetic, effective for vomiting caused by anticancer chemotherapy drugs

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4ebony in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new derivatives of carboxylic acids of General formula I containing heterocyclic ring

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient
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