Derivatives aminopyrazole or their salts with organic or mineral acids or with organic or inorganic bases, and a pharmaceutical composition having inhibitory activity against the neurotensin

 

(57) Abstract:

Use: chemical-pharmacological industry to obtain a composition having inhibitory activity against the neurotensin. The essence of the invention: derivatives of aminopyrazoles General formula I, in which Pyr denotes a group of formula (IIor IIIwhere RIis phenyl, substituted defined substituents, RIa- benzyl group, possibly substituted by Hal, RIY-H, Hal, (C1-C6)-alkyl, Rvis a phenyl group substituted by certain substituents, or Rv-naphthyl, pyridine or substituted (C1-C4) alkyl of styryl, or RIVand Rvtaken together, mean group - 2Ph-(CH2)iwhere the phenyl group substitutes the pyrazole at the 5-position, and (CH2)iwhere i = 1 to 3, substitutes the pyrazole at position 4, R - H1(C1-C4) alkyl, Z is OH1(C1- C6) alkoxy, amino, X and XI-H or one H and the other (C1-C6) alkyl, (C3- C6) cycloalkyl (C1-C4) alkyl, phenyl, amino(C1-C4)alkyl, hydroxy(C1-C4)alkyl, carboxy(C1-C4)alkyl, acetamido (C1-C4) alkylthiomethyl, guanidino (C1 7) cycloalkyl, phenyl (C1-C4), alkyl, possibly substituted by Hal, HE, heteroaryl (C1-C4) alkyl, where heteroaryl - imidazolyl or indolyl, or X is N and XIand R taken together form with the nitrogen atoms of the cycle of formula II, where m = 1 - 2, or the cycle of indolinyl, or 4,5,6,7-tetrahydro-[2,3-c] thienopyridine, or X and XIeach means (C1-C4) alkyl (C3-C6) cycloalkyl, or phenyl, or X and XItogether with the carbon atom to which they are attached, form a (C3- C12) cycloalkylcarbonyl group, optionally substituted (C1- C3) alkyl, adamantylidene, khinuklidinilbenzilata, 4-piperidinylidene group, possibly N-substituted benzyl, tetrahydronaphthalene, 4-tetrahydropyrimidine, 2,3 dihydro (4H)-4-benzothiazolinone, or 2,3 dihydro(4H)-4-benzoperylene group, or a group of formula a and b, or their salts with acids or bases, as well as the pharmaceutical composition on the basis of these compounds. 2 S. and 1 C.p. f-crystals, 16 PL. The structure of the compounds and groups:

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The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in fromcompany the UB>16) amide group, which show anti-inflammatory activity and activity in relation to cardiovascular system.

The applicant has developed a new class of derivatives of pyrazole, which have a broader spectrum of biological activity.

In particular, the invention relates to new derivatives of aminopyrazole General formula I:

Derivatives aminopyrazoles General formula I

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in which Pyr denotes a group of the formula (IIor III:

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where RIrepresents a group

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where RIB, RIIand RIIIis each independently from each other hydrogen atom, halogen atom, (C1-C4) alkyl straight or branched chain, (C1-C4) alkoxygroup, triptorelin group, cryptomaterial, the nitro-group or amino group, or RIrepresents a group selected from a range containing (C3-C6) cycloalkyl, tetrahydronaphthyl, pyridyl, naphthyl, optionally substituted by halogen, chinolin or ethanolic, optionally substituted with halogen, 2-benzothiazolyl, benzothiadiazole and phthalazinedione group

RIais benzia, the alkyl (C1-C6)

Rvmean group

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where R5, RI5and RI5Iis each independently from each other hydrogen atom, halogen atom, (C1-C4), alkyl straight or branched chain, hydroxyl, (C1-C4) alkoxy, phenyl, or Rymeans naftalina or pyridyloxy or substituted (C1-C4) alkyl stielow group, or RIVand RVtaken together mean a group

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where the phenyl group substitutes the pyrazole at position 5 and the group (CH2)iwhere i is an integer from 1 to 3, substitutes the pyrazole at position 4, R is hydrogen, (C1-C4) alkyl straight or branched chain, Z is a hydroxyl group, (C1-C6) alkoxy group, amino group, X and XIare both hydrogen or one is hydrogen and the other (C1-C6) alkyl straight or branched chain, (C3-C6) cycloalkyl (C1-C4) alkyl, amino (C1-C4) alkyl, hydroxy (C1-C4) alkyl, carboxy (C1-C4) alkyl, acetamido (C1-C4) alkylthiomethyl, guanidino (C1-C4) alkylthiomethyl what cycloalkyl, phenyl (C1-C4) alkyl, optionally substituted with halogen, or hydroxyl, heteroaryl (C1-C4) alkyl, where heteroaryl means imidazolyl or indolyl, or X is hydrogen and XIand R taken together form with the nitrogen atom to which R is bound, the loop formula

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where m is an integer 1 or 2, or the cycle of indolinyl or 4,5,6,7-tetrahydro-(2,3-C)-thienopyridine, or X and XIeach means (C1-C4) alkyl, (C3-C6cycloalkyl or phenyl, or X and XItogether with the carbon atom to which they are bound form a (C3-C12) cycloalkylcarbonyl group, optionally substituted C1-C3) alkyl, adamantylidene group, khinuklidinilbenzilata group, 4-piperidinylidene group optionally N-substituted benzyl group, tetrahydronaphthalene group, 4-tetrahydropyrimidine group, 2,3 dihydro (4H)-4-benzothiazolinone group 2,3 dihydro(4H)-4-benzoperylene group or a group of the formula and

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where n is 1 or 2, or a group of formula b

b

or their salts with organic or mineral acids or with organic or inorganic bases.

Possible salts of the products of formula (is that provide the division or the appropriate crystallization of compounds with formula (I) or (I'), such as picric acid or oxalic acid, and salts that are pharmaceutically acceptable, such as hydrochloride, bromohydrin, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, methylsulfonate, maleate, fumarate, 2-naphthalenesulfonate.

Possible salts of the products of formula (I) also include salts with cations, such as salts of alkaline or alkaline-earth metals, such as salts of sodium, potassium, calcium, and sodium salt is preferred when the product of formula (I) contains a carboxylic acid group.

The method of obtaining compounds of formula (I) is that the functional derivative pyrazolylborate acid of formula (II) or formula (II')

II

II'

in which RI, RIV, RVand RIaare such; as defined above, is treated with amino, protected if necessary, the protective groups customary for peptide synthesis formula:

V

in which R, X, X' and Z are as defined above, or, if necessary, protected.

As a functional derivative pyrazolylborate acid of formula (III) or (II') you can use the acid chloride, the anhydride, a mixed ang in activated, for example, using N,N-dicyclohexylcarbodiimide or using hexaphosphate benzotriazolyl-N-oxytrol-(dimethylamino)-phosphonium (BOP).

Thus obtained compound (I) can then if necessary be subjected to unprotect order to obtain the corresponding free acids.

Esters, precursors of carboxylic acids (II) and (II'),

defined above, are synthesized using the method described in Chem. Pharm, Bull, 1984, 32, 4, 1577.

If the amino acid contains as a substituent a hydroxyl group, the latter may be protected by commonly used O-protecting group, followed by removal of protection in accordance with conventional methods.

When the product of formula (I) has a primary function and is obtained in free base form, it is transferred to the salt by treatment with the chosen acid in an organic solvent. In the treatment of the free base, dissolved, for example, in alcohol, such as isopropanol, a solution of the chosen acid in the same solvent to obtain the corresponding salt, which is allocated in accordance with conventional methods. So, get for example, hydrochloride, bramhi the sulfonate.

When the compound of formula (I) has a primary function and is in the form of one of its salts, such as hydrochloride or oxalate, the free base can be obtained by neutralizing the specified salts with mineral or organic bases, such as sodium hydroxide or triethylamine, or with an alkaline carbonate or bicarbonate, such as a carbonate or bicarbonate of sodium or potassium.

When the product of formula (I) contains an acid group, the resulting compound can be converted into a salt of the metal, in particular alkali, such as sodium, or

alkaline-earth, such as a salt of calcium, in accordance with the classical methods.

New derivatives of aminopyrazole are active in relation to the Central nervous system and, in particular, in relation to the systems of regulation of neuropeptides, displacing, for example, tritium-labeled or izlesene neurotensin of its receptor in the membrane of the brain of the Guinea pig in accordance with the method described S/oul J. Z. u comp. Biochemical and Biophysical Research communication, 1984, 120, 3, 821-819.

Compounds of the present invention are of low toxicity; in particular, the low toxicwaste number of compounds with formula (I) or (I') or one of their pharmaceutically acceptable salts.

Thus the compounds claimed in the invention can be the first potential drugs which are able to bind with receptor neurotensin and which may be useful in pathological conditions, as well as dysfunction of dopaminergic systems, such as antipsychotic drugs, as well as disorders of the cardiovascular or gastrointestinal systems.

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

In the pharmaceutical compositions of the present invention for oral, sublingual, intramuscular, intravenous, transdermal or rectal introduction of active ingredients can be administered in the form of single forms of administration, mixed with classical pharmaceutical carriers. The appropriate unit forms of introduction include forms for oral route such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, forms, sublingual and oral administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectally 1 and 1000 mg per day, preferably between 2 and 500 mg.

Each unit dose can contain from 1 to 250 mg of active ingredient, preferably from 2 to 125 mg, in combination with a pharmaceutical carrier. This unit dose can be administered 1-4 times per day.

When preparing a solid composition in the form of tablets, the active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic. Can be applied to tablets a coating of sucrose or other suitable substances, or they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined amount of the active component.

The drug in gelatin capsules get by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.

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

Powders or granules, dispersible is AMI or suspendresume agents, such as polyvinylpyrrolidone and the like, as well as with sweeteners or taste correctors.

For rectal use of candles, which are prepared by using a binder, melting at rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral use aqueous suspensions, isotonic saline solutions or sterile solutions suitable for injection, which contain agents for dispersing and/or wetting agents, and pharmacologically compatible, for example, propylene glycol or butyleneglycol.

The active ingredient may also be present in the composition in the form of microcapsules, if necessary with one or more carriers or additives.

As an example, shows the composition of the tablets, mg:

connection 13 250

hydroxypropylcellulose 6

lactose 62

microcrystalline cellulose 60

carboximetilkrahmal 12

polyoxyethyleneglycol 600 10

Floor, mg:

bndraget L 100 1

dibutyl phthalate 1

isopropyl alcohol (evaporated) 28

The following examples illustrate the image, not limiting it.

The melting temperature (TPL) the Oia. In subsequent tables, we used the following abbreviations:

CH cyclohexane

CH2Cl2dichloromethane

EtOH ethanol

Et2O diethyl ether

Hx hexane

RP pentane

and-RG2O diisopropyl ether

and-Rgon isopropanol

AcOEt ethyl acetate

MeOH methanol

Cxmeans the configuration of the asymmetric carbon

In NMR spectra the following abbreviations are used:

M multiplet

C singlet

PC advanced singlet

D. doublet

Nar aromatic H

about ortho

m meta

The production of intermediate compounds for the synthesis of

A. Obtaining derivatives of hydrazine (RINH NH2).

A large number of derivatives of hydrazine are commercial products. Others were obtained in accordance with known methods by diazotization of the corresponding aromatic amine with subsequent restoration of diazonium salts. So, as an example, you can specify:

5,6,7,8-tetrahydro-1-afterheating in accordance with R,Fusco, Gazz, Chim. Ital, 1974, 104, 813-817;

8-hydrazinophenyl in accordance with A. Albert and others J. Chem. Soc. 1967, 1533-1541;

5-hydrazinophenyl and 5-hydrazinonicotinamide in accordance with M. G. Ferlin, Il Farmaco, P CLASS="ptx2">

The following table a shows as an example (non-limiting) characteristics of the acids with the General formula (II).

C. Obtaining amino acids.

Non-commercial products are obtained in accordance with the Strecker synthesis (Ann. 75, 27, 1850) or in accordance with the synthesis N. T. Bucherer, J. Pract, Chem. 1934, 141,5, followed by hydrolysis to obtain amino acids; for example, -aminoadamantana-2-carboxylic acid is obtained in accordance with N. T. Nasanta. and other J. Med.Chem. B 16 (7), 823.

Alpha aminocyclohexanecarboxylic acid obtained according to J. W. Tsaang and other J. Med.Chem. 1984, 27, 1663.

Cyclopentylamine R and S are obtained by splitting benzyloxycarbonylglycine.

1) preparation of racemic benzyloxycarbonylglycine.

This connection receive according to the following scheme I:

Scheme I

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2) Hydrochloride cyclopentylamine R, s

Dissolve 80% NaOH (1.8 g) in anhydrous THF (50 ml). Added dropwise, with stirring, a mixture of Cyclopentanone (4,2 g) and isocyanatoacetate (5 g) in THF (50 ml). Upon completion of addition, leave for 2 hours Cooled to 5oC and slowly added 10% aqueous solution of acetic acid (50 ml). THF is evaporated under vacuumm. The residue is extracted with pentane, filtered and washed in pentane.

Solid (7.6 g) was dissolved in acetic acid (100 ml). 10% palladium on coal (3 g) and stirred at atmospheric pressure and room temperature under hydrogen for 24 h (absorb 1 liter of hydrogen). Filter on celite, washed several times with acetic acid. Is evaporated under vacuum. The residue is extracted 5,5 N. chlorotalonil acid (70 ml). Heated to education phlegmy for 4 h, Concentrate to dryness, form several times azeotropic mixture with toluene and dried under vacuum. Get the target product.

m 7.2 g

NMR D2O: 8H during 1,6/M, CH2cycle); 1H at of 2.20 (M, CH loop); 1H at of 3.80 (D, J 7 SNCO2H); 3 H at 8,60 (MS, NH3+.

3) Acylation using chloroformiate of benzil.

Dissolve the hydrochloride cyclopentylamine R, S (7.2 g) in 2 BC, the sodium hydroxide solution (65 ml). Add drop by drop chloroformiate of benzyl (8.5 g) in THF (30 ml), cooling to 5oC. Leave with stirring overnight at room temperature. Cool in ice. Acidified using concentrated HCl to pH 2 (T 5oC). Extract in chloroform, dried and evaporated. The residue is extracted with pentane. Get the urbanistically.

Dissolve benzyloxycarbonylation (5,54 g) in absolute ethanol (65 ml). Added 1,2-diphenyl-1-ethanol-2-amine (1 R, 2S) ( - ) obtained in accordance with J. Weijlasd and other J. Am.Chem.Soc. 1951, 73, 1216. Heated to dissolution. Left to precipitate overnight and filtered. Obtain 2.8 g of salt (TPL175oC). Royal solutions remain.

The obtained salt is extracted with water (20 ml) HCl (30 ml) and ether (100 ml). Mix to dissolve. The organic phase is decanted, dried, and evaporated. Get benzyloxycarbonylation, which was immediately treated with concentrated HCl (15 ml), Asón (15 ml Heated to education phlegmy within 3 hours is Evaporated to dryness. The residue is extracted with dry ether, filtered and dried. Receive hydrochloride (S)-cyclopentylamine.

[]2D5+10,4o(With 0.5 HCl 1N)

m 0.6 grams

The mother solution is evaporated to dryness and absorb water (50 ml), HCl (60 ml), Et2O (300 ml). Mix and dissolve all. The ether phase is decanted, dried and evaporated. Remove benzyloxycarbonylglycine (4.3 g), enter it in absolute methanol (50 ml), 1,2-diphenyl-1-ethanol-2-amine (1S, 2R) (+) (3,30 g). Heat to dissolve, leave alone overnight, filter and ether (200 ml). Mix. The ether phase is dried, evaporated, then the residue is treated with concentrated HCl (10 ml), acetic acid (100 ml). Heat the mixture for 3 h until the formation of phlegmy, concentrate under vacuum, extracted with anhydrous ether to obtain the hydrochloride of (R) cyclopentylamine.

m 1,2,

[]2D5situated 10.5 (0,85 HCl 1N)

Optical purity of R-cyclopentylamine.

Dissolve 0.10 g obtained above hydrochloride in absolute methanol. Cooled to a temperature of -40oC, add 0.5 ml of thionyl chloride and leave the mixture for 24 h at room temperature. Concentrate under vacuum, extract the residue with anhydrous chloroform (20 ml), added triethylamine (0.2 ml) and (S)-perimeterisation (0,074 ml). Leave for 24 hours, then evaporate the chloroform. The remainder chromatographic on silica gel, eluant: ethyl acetate. After concentration of the pure fractions get 0.1 g methyl ether complex.

An NMR spectrum in l3shows about 3.8 h/million the presence of two signals for-CO2CH3. Integration shows that the weakest signal is 4% and the most intense signal 96%

Thus, the enantiomeric excess is equal to 92%

Example 1. Methyl ester 2-{[1-phenyl-5-(4-pyridyl)-3-pyrazolyl] -carbylamine}-4 - methylpentanoic acid (S).

(I): R H n 0; X' is H; X is CH2-CH-(CH3)2; Z OCH3; R1C6H5; RIVH;

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Dissolve 0.35 g of 1-phenyl-5-(4-pyridyl)-pyrazole-3-carboxylic acid in 5 ml of dimethylformamide in the presence of 0.45 ml diisopropylethylamine (DIPEA) and 0.59 g of hexaflurophosphate benzotriazolyl-N-exitridmasteroffline (BOP). Then add to 0.23 g (1 equivalent) of the hydrochloride of the methyl ether complex (S)-leucine dissolved in 0.4 ml of DIPEA, and the reaction mixture is left overnight at room temperature. The solvents are concentrated under vacuum, the residual oily liquid extracted with dichloromethane, and this solution is washed with water, then with sodium bicarbonate solution and again with water. The organic phase is dried over sodium sulfate, then concentrated under vacuum. The remainder chromatographic on silica gel, eluent-ethyl acetate.

m 0,18,

An NMR spectrum of the proton of compound I: 3H when 8,82 (M, Nar on and CONH); 5H when to 7.50 (M, Nar Phe); 3H at 7,27 (Nar MP and H4of pyrazole); 1H at 4,60 (M, N, alpha Leu); 3H at of 3.77 (S, CO2CH3); 1H at 2,00 (M, N gamma Lu the Mino}-3-phenylpropane acid (S).

(I): R is H; n is 0; X' is H; X is CH2-C6H5; Z IS OH; RIC6H5; RIVH

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Obtain the acid chloride of 5-(2-naphthyl)1-phenylpyrazol-3-carboxylic acid.

Dissolve 5 g of 5-(2-naphthyl)1-phenylpyrazol-3-carboxylic acid in 56 ml of toluene and added dropwise 3.5 ml of sulphonylchloride to this solution. The mixture is heated at 90oC for 2.5 h, then concentrated under vacuum. The residual oily liquid extracted twice with toluene and concentrated under vacuum.

m 5,

Getting connection 2.

To 60 ml of 2 n sodium hydroxide solution was added 4.9 g (S)-phenylalanine, and then was added dropwise a solution of 4 g of the carboxylic acid obtained above, dissolved in 65 ml of tetrahydrofuran. The reaction mixture is left overnight at room temperature, then concentrated under vacuum. The residue is extracted with water and the pH adjusted to 1 by adding chlorotalonil acid. The solution is extracted with dichloromethane and the organic phase is washed with water and saturated sodium chloride solution, dried on sodium sulfate, filtered and concentrated under vacuum. The residue is recrystallized from pentane.

m 2 g

TPL226oC.

Example 3 6H5; Z-N-(C2H5)2; RIC6H5; RIVH;

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Dissolve 2 g of the product obtained in accordance with example 2, 0.88 g of dicyclohexylcarbodiimide (DCDI) and 1.14 g of 1-hydroxybenzotriazole (HOBT) in 68 ml of tetrahydrofuran and stirred the mixture for 3/4 h at room temperature. Then add 0.4 g of diethylamine and the reaction mixture is stored at room temperature for 24 h

Dicyclohexylcarbodimide separated by filtration, and uterine fluid is concentrated under vacuum. The remainder chromatographic on silica gel, eluent - ethyl acetate. The fractions of pure product are concentrated under vacuum and the residue is recrystallized from pentane.

m, 1,46,

TPL70oC.

Example 4. 2{[1-Phenyl-4,5-dihydrobenzo-(g)-3-indazole]-carbylamine}-4 - methylpentanoic acid (S)

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A) Sodium salt of beta-Methocarbamol-alpha-tetralone.

This intermediate compound is obtained in accordance with the method described by D. Ramech et al. Indian Journal of Chemistry, 1989, 28V, 76-78.

B) Ethyl ester of 1-phenyl-4,5-dihydrobenzo-(g)-indazol-3-carboxylic acid.

Dissolve of 8.04 g of sodium salt obtained above in 100 ml of uksosn the Cooled mixture was poured to ice water, the precipitate was separated by filtration, washed with water, then with pentane.

m, 10,5

C) 1-Phenyl-4,5-dihydrobenzo-(g)-indazol-3-carboxylic acid.

Dissolve 9.5 g obtained above product in 100 ml of methanol and 100 ml of water. Added to 4.2 g of potassium hydroxide and heated the reaction mixture to form phlegmy for 5 hours the Mixture was poured to ice water, then washed with ethyl acetate. The aqueous phase is acidified to pH 2 by adding chlorotalonil acid, the precipitate was separated by filtration, washed with water, then with pentane.

m, 7,3

D) the acid chloride of 1-phenyl-4,5-dihydrobenzo-(g)-indazol-3-carboxylic acid.

Dissolve 2.8 g acid obtained above in 100 ml of toluene, then added 2.2 ml of sulphonylchloride and heated at 100oC for 5 hours the Solution is concentrated under vacuum, add 20 ml of toluene and concentrated under vacuum. Twice repeat the same operation.

E) Compound 4

Dissolving 0.88 g S-leucine in a solution of 1.33 g of sodium hydroxide in 20 ml of water. This solution is cooled, then add to it 0,99 g the above carboxylic acid, dissolved in 16 ml of tetrahydrofuran, and the reaction mixture is stored under stirring teenern 2 by adding chlorotalonil acid, then extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated under vacuum. The residue is recrystallized from isopropyl ether.

m 1,

TPL100oC.

Example 5. 2{[1-Benzyl-3-(2-naphthyl)-5-pyrazolyl]-carbylamine}-3 - phenylpropane acid (S)

(I') R H; n is 0; X' is H; X is CH2H; Z IS OH; RIa-CH2-C6H5; RIVH;

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A) Reaction of 2-naphthylmethylphosphonate with the hydrochloride of benzylpiperazine leads to a mixture of the following esters: melody ester of 1-benzyl-5-(naphthyl)-pyrazole-3-carboxylic acid and methyl ester of 1-benzyl-3-(2-naphthyl)-pyrazole-5-carboxylic acid.

Chromatography on silica gel allows you to separate the two isomers. Methyl ester of 1-benzyl-5-(2-naphthyl)-pyrazole-3-carboxylic acid eluted first with a mixture of ethyl acetate/hexane 50/50 (V/V). Methyl ester of 1-benzyl-3-(2-naphthyl)-pyrazole-5-carboxylic acid eluted in the second fraction.

B) 1-Benzyl-3-(2-naphthyl)-pyrazole-5-carboxylic acid

Acid obtained by saponification of the above complex ether.

(C) the acid chloride of 1-benzyl-3-(2-naphthyl)-pyrazole-5-carboxylic acid.

Chloran>/P>E) Connection 5

Dissolved 0.28 g of phenylalanine (S) in a chilled solution of sodium hydroxide. Then add a solution of 0.3 g obtained above carboxylic acid in 5 ml of THF, and the reaction mixture is stored at room temperature for 24 hours of THF concentrated under vacuum, the residue is extracted with water, neutralized by adding concentrated chlorotalonil acid. Extracted with ethyl acetate, dried on sodium sulfate and concentrated under vacuum. The residue is recrystallized from cyclohexane.

m 1,

TPL100oC.

Example 6.

Methyl ester 2{[1-(4'-methoxycinnamyl)-5-(4-pyridyl)-3-pyrazolyl]-carbylamine}- 4-methylpentanoic acid (S)

(I) R is H; n is 0; X' is H; X is CH2-CH-(CH3)2; Z OCH3< / BR>
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A) Methyl ester 1-(4'-methoxycinnamyl)-5-(4-pyridyl)-pyrazole-3-carboxylic acid.

Dissolved 4.6 g of ester methyl 5-(4-pyridyl)-(1H)-pyrazole-3-carboxylic acid in 60 ml of dimethylformamide, then add to 0.63 g of 80% oil suspension of sodium hydride and the reaction mixture is heated at 40oC for 1 h Then cooled mixture is added a solution of 5.2 g of 4'-metoclopramide 1-cinnamyl dissolved the dimethylformamide under vacuum, extract the residue with water, extracted with ethyl acetate, the organic phase is dried on sodium sulfate, filtered and concentrated under vacuum. The residual oily liquid chromatographic on silica gel, eluent ethyl acetate/cyclohexane 50/50 (V/V). The fractions of pure product are concentrated under vacuum.

m 2.6,

TPL118oC.

B) Compound 6

Dissolve 0.4 g of the above acid in 12 ml of dimethylformamide in the presence of 0.63 ml of DIPEA and of 0.53 g of BOP. Then added to 0.22 g of the hydrochloride of the methyl ether complex (S)-leucine dissolved in 0.63 ml of DIPEA, and the reaction mixture is left overnight at room temperature. Dimethylformamide concentrated under vacuum and the residue extracted with water. Extracted with ethyl acetate, the organic phase is dried on sodium sulfate, filtered and concentrated under vacuum. The residue is compacted in diisopropyl ether.

m 0,15 g

TPL172oC.

Example 7. Sodium salt of 2{[1-(4'-methoxycinnamyl)-5-(4-pyridyl)-3-pyrazolyl]-carbylamine} -3-phenylpropane acid (S)

(I): R is H; n is O; X' is H; X is CH2-C6H5; Z O-Na+;

< / BR>
Proceeding as in example 6, but replacing the hydrochloride of methyl konektory hydrolyzing to the sodium salt using 0.9 equivalent of sodium hydroxide in 10 ml 96oof ethanol. The mixture is left overnight at room temperature, concentrated under vacuum and the residue is washed in ether. After filtration receive connection 7.

TPL137oC.

Example 8. 2{[1-(5-Ethanolic)-5-(2,6-acid)-3-pyrazolyl]-carbylamine} 2-adamantanecarbonyl acid

< / BR>
Dissolve 0.75 g of 2-amino-2-adamantanecarboxylic acid in 20 ml of pyridine. Added 1.4 g of acid chloride of 1-(5-ethanolic)-5-(2,5-acid)-3-pyrazolylborate acid, dissolved in 20 ml of dichloromethane, and the reaction mixture is stored overnight at room temperature. Concentrate under vacuum, remove the remainder of the buffer solution with a pH of 2, mix, filter the precipitate and rinse diisopropyl ether.

m, 0,4

TPLabove 260oC.

Example 9. 2{[1-(5-Chinolin)-5-(2,6-acid)-3-pyrazolyl]- carbylamine}2-adamantanecarbonyl acid

< / BR>
Dissolve to 0.23 g of 2-amino-2-adamantanecarboxylic acid, 0.5 g of acid chloride of 1-(5-chinolin)-5-(2,6-acid)-3-pyrazolylborate acid and 0.7 g of potassium hydroxide in 25 ml of dichloromethane in the presence of 0.1 g of Aliquat 336< / BR>
The reaction mixture was stirred over night at room temperature.

TPLabove 260oC.

Example 10. 2{[1-(4-Chloro-1-naphthyl)-5-(2,6-dihydroxyphenyl)-3-pyrazolyl]- carbylamine}hexanoic acid (S)

(I): R is H; n is O; X' H; X (CH2)3-CH3; X IS OH;

< / BR>
Dissolve 0.3 g of 3-[1-(4-chloro-1-naphthyl)-5-(2,6-acid) pyrazolyl]-2 - carbonyldiimidazole acid 6.7 ml of dichloromethane and cooled to a temperature of -70oC. is Added drop by drop to 5.7 ml tribromide boron, dissolved in 20 ml of dichloromethane, and the reaction mixture is stored for 2 h at -70oC. Allow to return to room temperature, then added, cooling, 12 ml of water. Add concentrated NaOH to pH 14. Wash the aqueous phase is in the air, bring it to pH 2, extracted with ethyl acetate, dried on sodium sulfate, filtered and evaporated. Crystallized residue from diisopropyl ether.

m, 0,13

TPLabove 260oC.

Example 11. 2{[1-(1-Naphthyl)-5-(2,6-acid)-3-pyrazolyl]carbylamine} 2-adamantanecarbonyl acid

< / BR>
Cooled to 0oWith 0,107 g of sodium hydroxide by 1.36 ml of water and 0.51 ml of tetrahydrofuran. Add one portion of 0.52 g of 2-amino-2-adamantanecarboxylic acid, then drop by drop of 0.53 g of acid chloride of 1-(1-naphthyl)-5-(2,6-acid)-3-pyrazolyl the same amount of the same carboxylic acid in 3 ml of tetrahydrofuran; at the same time gain of 1.32 ml of 2 n sodium hydroxide. The reaction mixture is left for 4 days at room temperature; add sequentially the icy water, concentrate chlorodrol acid to pH 1 and the precipitate is filtered off. The crystals are washed in diisopropyl ether.

m 0,48 g

TPLabove 260oC.

Example 12. 2{[1-(1-Naphthyl)-5-(2,6-acid)-3-pyrazolyl]-carbylamine} -2-adamantanecarboxylic

< / BR>
Dissolve 0.5 g of the compound obtained in example 11, 34,6 ml of anhydrous tetrahydrofuran and 4 ml of dimethylformamide. Add 3.5 ml of water and 0,208 g of cesium carbonate and the reaction mixture is stored at room temperature for 1 h, Concentrate under vacuum and azeotroping with toluene. The residue is extracted with 5 ml of tetrahydrofuran. Add 0.6 ml under the conditions and leave the reaction mixture for 1 h at room temperature. Concentrate under vacuum, extract the residue with water, mix and separate the precipitate by filtration. The precipitate is washed with water and pentane.

m, 0,39

TPL242-244oC.

Example 13. 2{[1-(7-Chloro-4-chinolin)-5-(2,6-acid)-3-pyrazolyl] -carbylamine}-2-adamantanecarbonyl acid


< / BR>
melting point which is equal to 249oC.

Dissolve 0.1 g of this intermediate compound in 5 ml of dichloromethane, was added 5 ml triperoxonane acid and leave the mixture for half an hour at room temperature. Concentrate under vacuum to obtain the expected compound.

m 0,080,

TPLabove 260oC.

Repeating any of the embodiments described in examples 1 to 13, received compounds listed in the following table. 1-15. In these tables, R3when it is used is a Deputy

< / BR>
Described below biological and pharmacological tests illustrate the activity of new compounds.

1. The results of biochemical compounds

Compounds according to the invention were tested on the preparations of the brain membranes of adult Guinea pigs. Binding was carried out at 20oIn the presence of 50 PM (125 1)-Tyr-neurotensin. Full binding was measured by the method of J. Z. Sasoul and others (mentioned above). In table 1 (Appendix) summarizes the results of biochemical tests. It follows that several compounds have nanobalance all connections obtained in the examples are inhibitors of neurotensin at more or less high concentrations.

2. Effects on the cardiovascular system

According to R. Quirion, etc. Can. F. Physical. Pharmacol, 1978, 56, (3), 671 the neurotensin has positive inotropic and chronotropic effect on the spontaneous contraction of isolated right atrium of the Guinea pig. This action is called direct stimulation at the level of neurotensin receptors in this tissue (R. Quirion and other Br.Journ, Pharmacol, 1980, 68, 83-91). One of the compounds of the invention (the compound of example 13) was studied in accordance with this test. Cause inhibition of the positive inotropic and chronotropic effect induced by neurotensin concentration 110-8M on the spontaneous contractions of the isolated right atrium of the Guinea pig when Cl504,2 n M and 1.6 n M, respectively.

3. Effects on the Central nervous system

As it was proven for cholecystokinin, P. Wouus and other Life Sci, 1986, 39, 2199-2208 unilateral and inside striatum injection of neurotensin (10 PG to 1 ml) female mice LED1) Charles River France), in the creation, causes rotational movement in the opposite direction from the site of injection.

Seina, causes reduced rotational motions induced by neurotensin, a reduction of 80% rotational motions is achieved at a dose of 80 mg/kg (oral), which proves that it is derived is an antagonist of the neurotensin on the level of the Central nervous system.

4. Effects on the gastrointestinal system

The neurotensin at a concentration of 310-8M leads to the excitation of spontaneous contractions of the isolated rat fundus. Under these conditions, the compound of example 137 at a concentration of 310-6M inhibited by 46% reduction induced by neurotensin.

In addition, it is important to emphasize that the pyrazole derivatives, as claimed in the invention, are the first ones molecules ligand neurotensin receptor. TTT TTT TTT TTT TTT TTT

Derivatives aminopyrazoles General formula I

< / BR>
where Pyr group of the General formula I' or I"

< / BR>
< / BR>
where R1a group of General formula

< / BR>
where is each independently from each other hydrogen, halogen, C1WITH4-alkyl straight or branched chain, WITH1- C4-alkoxygroup, triptorelin group, triptoreline-, nitro - or amino group, or R1group selected from the series, halogen, chinolin or ethanolic, optionally substituted with halogen, 2-benzothiazolyl, benzothiadiazole and phthalazinedione group;

R1abenzyl group, optionally substituted with halogen;

RIVhydrogen or halogen, C1WITH6-alkyl;

RVa group of General formula

< / BR>
where is each independently from each other hydrogen, halogen, C1WITH4-alkyl straight or branched chain, hydroxyl, C1- C4-alkoxy, phenyl

or RVnaftalina, or perederina, or substituted C1-C4the alkyl stiralnaya group,

or RIVand RVtaken together, the group

where the phenyl group substitutes the pyrazole at position 5 and the group (CH2)iwhere i 1 3 integer from 1 to 3, substitutes the pyrazole at position 4;

R is hydrogen, C1C4-alkyl straight or branched chain;

Z is a hydroxyl group, a C1C6-alkoxygroup, the amino group;

X and X' are both hydrogen or one of them is hydrogen and the other WITH1- C6-alkyl straight or branched chain, C3C6- cycloalkyl-C1C4-alkyl, amino-C1C4-alkyl, hydroxy-C1C4-alkyl, carboxy-C1C4-alkyl, acetone is Il, WITH3- C7-cycloalkyl, phenyl-C1C4-alkyl optionally substituted with halogen, or hydroxyl, heteroaryl-C1C4-alkyl, where heteroaryl means imidazolyl or indolyl, or X is hydrogen, and X' and R taken together form with the nitrogen atom to which R is bound, the loop formula

< / BR>
where m is 1 or 2, or the cycle of indolinyl or 4,5,6,7-tetrahydro-(2,3-C)-thienopyridine, or X and X' each WITH a1- C4-alkyl, C3C6-cycloalkyl or phenyl, or X and X' together with the carbon atom to which they are bound, form a3- C12-cycloalkylcarbonyl group, optionally substituted C1- C3-alkyl, adamantylidene group, khinuklidinilbenzilata group, 4-piperidinylidene group optionally N-substituted benzyl group, tetrahydronaphthalene group, 4-tetrahydropyrimidine group, dihydro-2,3(4H)-4-benzothiazolinone group, dihydro-2,3(4H)-4-benzoperylene group or a group of the formula

< / BR>
where n is 1 or 2, or a group of the formula

< / BR>
or their salts with organic or mineral acids or with organic or inorganic bases.

2. Pharmaceutical composition having inhibitory activity in OTO it contains as active principle a compound of General formula I in an effective amount.

3. The composition according to p. 2, characterized in that it contains the active principle in the amount of 0.25 250,0 mg

 

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orwhere R1means-Cho or - CN, namely, that on-halogenoalkane derivative of the formula:

where R has the above meanings, is subjected to the interaction with R3SH, where R3- benzyl, environment aprotic organic solvent, with the formation of the compounds of formula

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Ror< / BR>
R6is hydrogen, C1-C4-alkyl, halogen, actigraphy, trifluoromethyl, cyano, C1-4-alkyloxy-FROM1-4-alkylthiophene,1-4-alkylthio (alkylsulfonyl)1-4-alkylsulfonyl,1-4-allyloxycarbonyl,1-4-alkylcarboxylic or aryl;

R7and R8each independently is hydrogen or C1-4-alkyl;

R9is hydrogen, halogen, amino, C1-4-alkyl, trifluoromethyl or aryl;

R10is hydrogen, halogen, amino or nitro-group;

R11is hydrogen, C1-4-alkyl, C1-4-alkyloxyalkyl, WITH1-4the alkyl or aryl-C1-4-alkyl;

n is an integer from 1 to 4 inclusive;

R1and R2each independently is hydrogen, C1-4-alkyl or halogen;

R3is hydrogen, halogen, cyano-C1-4-alkyloxy, aryl or-СОOR4and R4is hydrogen, C1-4-alkyl, aryl-C1-4-alkyl, C3-6-cycloalkyl-C1-4-alkyl, C3-5-alkenyl,3-5-quinil or1-4-alkyloxy-C1-4-alkyl, or R3is a radical of the formula

or< / BR>
R12and R13each independently is hydrogen, C1-4the alkyl, aryl or aryl-C1-4-alkyl;

each aryl is phenyl, optionally substituted by one or two substituents, each independently selected from halogen, C1-4-alkyl, trifloromethyl,1-4-alkyloxy or actigraphy
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