Phenyl alkyl piperazines, which modulate tnf activity

FIELD: chemistry.

SUBSTANCE: invention relates to phenyl alkyl piperazines of formula (I) , in which: R1 represents independently on each other hydrogen atom, halogen atom, (C1-C5)alkyl group, (C1-C5)halogenalkyl group, (C1-C2)perfluoroalkyl group, (C1-C5)alkoxyl group or (C1-C2)perfluoroalkoxyl group; R2 stands for (C1-C5)alkyl group or (C1-C5)alkoxyl group, R3 represents (C1-C5)alkyl group; A represents =CH- and =N-; in form of base or additive salt with acid. Invention also relates to pharmaceutical composition for modulation of activity of TNF-alpha, which contains claimed compounds, and to method of their obtaining.

EFFECT: obtained are novel compounds which can be applied in medicine as medications for treating or preventing pain and/or diseases, associated with inflammatory of immune disorders.

24 cl, 3 ex

 

The present invention relates to new phenylalkylamines, modulating the activity of TNF, containing their pharmaceutical compositions and method of production thereof.

TNF-alpha is a cytokine, which is identified as the mediator of the immune system, a mediator of inflammation, a mediator of cell proliferation, fibrosis, and so the mediator in large quantities is in synovial tissue in inflammatory process and performs a major role in the pathogenesis of autoimmune system (Annu. Rep. Med. Chem.,1997,32:241-250).

Presently discovered that phenylalkylamine possess excellent activity against activity modulation of TNF-alpha, more specifically inhibitory activity.

Thus, in accordance with one of its aspects, the present invention relates to phenylalkylamines formula (I):

in which:

and R1 and R2 represent independently from each other hydrogen atom, halogen atom, (C1-C5) alkyl group, (C1-C5)halogenating group, (C1-C2)performanceline group, (C1-C5)CNS group or (C1-C2)performanceline group;

- R3 represents (C1-C5)alkyl group;

- And represents =CH - or =N-.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. Therefore, they can exist in the form of Aisne is tomarow or diastereoisomers. These enantiomers and diastereoisomers, as well as mixtures thereof, including racemic form part of the invention.

The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such additive salt form part of the invention.

These salts can be obtained with pharmaceutically acceptable acids but the salts of other acids that are suitable, for example, for the purification or separation of compounds of formula (I), also form part of the invention.

The compounds of formula (I) can exist in the form of N-oxide derivatives. Thus, the compounds of formula (I) may, in particular, to carry one or two N-oxide group on the piperazine. Although in principle both of the above nitrogen atom may be oxidized, preferred compounds that have only one N-oxide group.

As another object of the present invention include compounds of formula (I)in which:

- R1 denotes (C1-C5)halogenating group, more specifically, (C1-C5)alkyl fluoride group, (C1-C2)performanceline group; and/or

- R2 represents a hydrogen atom or a (C1-C5)alkyl group;

in the form of a base or addition salt with an acid.

In accordance with another feature of the invention, the piperazine is connected with a phenyl group using ethyl group in position 3:

and/or

- R1 about who appoints (C1-C2)performanceline group; and/or

- R2 represents a hydrogen atom or (C1-C3)alkyl group.

As another object of the present invention include compounds of formula (I):

1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

in the form of a base or addition salt with an acid.

As another object of the invention can be called a compound of formula (I)chosen from:

connection n°1: hemipleat 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°1 bis: hemipleat 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine in a mixture with 0.5 moles of free Mamonovo acids;

connection n°2: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methoxy-3-pentylphenol)-ethyl]piperazine;

connection n°3: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methyl-3-propylphenyl)-ethyl]piperazine;

connection n°4: the hydrochloride of 1-(3-forfinal)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°5: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methyl-3-heptylphenol)-ethyl]piperazine;

connection n°6: the hydrochloride of 1-(6-triptoreline-2-yl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°7: the hydrochloride of 1-(3-forfinal)-4-[2-(4-methoxy-3-pentylphenol)-ethyl]piperazine;

connection n°8: the hydrochloride of 1-(3-deformational)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°9: the hydrochloride of 1-(phenyl)-4-[2-4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°10: the hydrochloride of 1-(3-methoxyphenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°11: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methyl-3-(2-methylbutyl)phenyl)-ethyl]piperazine;

connection n°12: the hydrochloride of 1-(3-deformational)-4-[2-(4-methoxy-3-pentylphenol)-ethyl]piperazine;

connection n°13: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methoxy-3-heptylphenol)-ethyl]piperazine;

connection n°14: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methyl-3-hexylphenyl)-ethyl]piperazine;

connection n°15: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methoxy-3-propylphenyl)-ethyl]piperazine;

connection n°16: hydrochloride of 1-(phenyl)-4-[2-(4-methoxy-3-pentylphenol)-ethyl]piperazine;

connection n°17: hydrochloride 1-(4-chlorophenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection nº18: hydrochloride of 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°19: bansilalpet 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°20: 2-naphthalenesulfonate 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°21: p-toolswhat 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°22: Hemi-2,5-naphthalenedisulfonate 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°23: dihydrochloride-(4-forfinal)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°24: 1-(4-methoxyphenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine base;

connection n°25: dihydrochloride of 1-(5-bromopyridin-2-yl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°26: dihydrochloride of 1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-(5-triptorelin-2-yl)-piperazine;

connection n°27: hydrochloride 1-(4-trebutien)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°28: dihydrochloride of 1-(4-ethoxyphenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°29: dihydrochloride of 1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-m-callipering;

connection n°30: dihydrochloride of 1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-pyridine-2-reperusing;

connection n°31: hydrochloride of 1-(6-bromopyridin-2-yl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°32: hydrochloride 1-(2-chlorophenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°33: the hydrochloride of 1-(2-were)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°34: hydrochloride of 1-(3-cryptomailer)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°35: hydrochloride of 1-(5-chloropyridin-2-yl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°36: oxalate of 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°37: fumarate of 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

- with the organisations n°38: succinate 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;

connection n°39: digiport 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine.

In the scope of the present invention mean:

the halogen atom: a fluorine, chlorine, bromine or iodine;

is an alkyl group: a saturated aliphatic group, a linear or branched. For example, (C1-C5)alkyl group containing 1-5 carbon atoms. As example can be mentioned, more specifically, methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, trebutien, pentelow, isopentanol, ... groups;

- halogenoalkanes group: an alkyl group as defined above in which one or more hydrogen atoms substituted by a halogen atom, such as alkyl fluoride group, which may contain one or more fluorine atoms;

- perforaciones group: an alkyl group as defined above, in which all the hydrogen atoms replaced by fluorine atom;

- CNS group: -O-alcinous group in which the alkyl group defined above;

- performanceline group: alkoxygroup, in which all the hydrogen atoms replaced by fluorine atom.

Under the "leaving group" in the further description of the mean group which can be easily derived from molecules heterolytic splitting of care-electron pair. Thus, this group can be easily replaced the s with another group, for example, during a substitution reaction. Such leaving groups are, for example, Halogens or an activated hydroxy-group, such as methanesulfonate, benzolsulfonate, para-toluensulfonate, triflate, acetate, etc. groups. Examples of leaving groups, as well as methods for their preparation are described in Advances in Organic Chemistry, J. March, 3rdEdition, Wiley Interscience, c.310-316.

The compounds of formula (I) can be obtained according to scheme 1:

Scheme 1

Following this scheme, the compounds of formula (I) can be synthesized by condensation of compounds of formula (II):

in which R1 and a are defined above, with a compound of formula (III):

in which R2 and R3 are defined above and Q is a leaving group.

As the leaving group Q can be used, for example, halogen atom or any group capable of condensing with an amine. The condensation reaction carried out in the traditional way of mixing the starting compounds (II) and (III) in an organic solvent such as an alcohol, for example methanol or butanol, optionally in the presence of a base such as a carbonate of an alkali metal, 4-dimethylaminopyridine or triethylamine, at temperatures between room temperature and the reflux temperature of the selected solvent. P is d room temperature mean temperature between 5 and 25°C.

The compound of formula (III) is obtained by transforming the hydroxy-group of compounds of formula (IV) into a leaving group Q according to classical methods known to the expert. For example, the hydroxy-group can be converted into a halogen, such as bromine, in the presence of Hydrobromic acid, tetrabromide carbon or thienylboronic; or such as chlorine in the presence of thionyl chloride. So, you can get a group of mesilate (CH3-SO2-O-) or tosyloxy (tolyl-SO2-O) as the leaving group by reacting the products of formula (IV) with methanesulfonamido or para-tolylaldehyde.

The compound (IV) is obtained by restoring the double bond of the compounds of formula (V). Recovery can be accomplished in accordance with the classical methods known to the expert, for example, in the presence of hydrogen, the catalyst is palladium/charcoal in an organic solvent, such as ethanol, at temperatures between 20 and 40°C.

The compound of formula (V) can be obtained according to the Suzuki reaction (J. Org. Chem., 55 6184-1990). In accordance with this method are subjected to interaction of the compound of formula (VI)in which X denotes a halogen, more specifically, bromine or iodine; or triftormetilfullerenov, with vinylboronic acid or vinylboronate, in the presence of a catalyst such as palladium acetate or tetrakis(triphenylphosphine)pulled the th, in a solvent such as tetrahydrofuran, dioxane or dimethoxyethane.

The compound of formula (VI) can be obtained from the compounds of formula (X) in accordance with the stages outlined in figure 1, under conditions well known to the specialist, or similar conditions, or under conditions, described in detail in the examples.

The compounds of formula (II) may be commercial products or they may be obtained by methods well known to the specialist.

In this scheme, the initial compounds and the reagents, if the retrieval method is not described, are commercially or described in the literature or may be obtained by methods that are described or which are known to the expert.

The method according to the invention may also include the extraction and/or purification obtained in this way, the compounds of formula (I) and/or its eventual transformation into one of its salts and/or its N-oxide.

The desired compound allocate according to conventional methods in the form of a base or its salts. The free base can be converted into one of its salts conventional salt formation in an organic solvent such as an alcohol, preferably ethanol or isopropanol, a simple ether, such as 1,2-dimethoxyethane, ethyl acetate, acetone, or a hydrocarbon, such as hexane.

The compounds of formula (I)bearing an N-oxide group on the ATO is Ah nitrogen, can be obtained by oxidation of the corresponding compounds of formula (I). In this case, the compound of formula (I)obtained above described synthesis, is subjected to oxidation reaction in accordance with conventional ways, for example by reaction with m-chloroperbenzoic acid in a suitable solvent, and isolated in accordance with conventional techniques, well known to the specialist.

The following examples describe the formation of compounds according to the invention. These examples do not limit the invention, but merely illustrate it. The connection number according to the example corresponds to the number listed in the chart below, which characterizes the chemical structure and physical properties of the compounds according to the invention.

Physico-chemical measurements were carried out as follows.

The melting points were measured on a Buchi apparatus W.

The spectra of nuclear magnetic resonance of the proton (NMR-1N) were taken at a frequency of 500 MHz on a Bruker spectrometer equipped with Avance console. Chemical shifts are presented in ppm in relation to the frequency of the TMS.

All spectra were recorded at 40°C.

Abbreviation used in characterizing signals, as follows: s=singlet, width=the broad singlet, m=multiplet, m W=the broad multiplet, d=doublet, t=triplet,=quadruplet.

• =not integrated because John is erference with a broad peak, due to the presence of water.

Method LC/MS:

System ThermoElectron LCQ Deca XP Max, equipped with a mass spectrometer detector with an ion trap and a detector diode matrix.

Used chromatographic system as follows:

Method (A)

- Column Kromasil C18 (of 2.1 × 50 mm, 3.5 µm

- Eluent A=N2About ammonium acetate pH 6.5, 5 mm

- Eluent=CH3CN.

- Gradient from 98% a to 95% b for 12 minutes, then elution with 95% b for 3 minutes

A flow rate of 0.5 ml/min

- Injection of 2 μl of solution with a concentration of 0.1 mg/ml in a mixture of CH3CN:N2O=9:1

Method)

- Column Kromasil C18 (of 2.1 × 50 mm, 3.5 µm

- Eluent A=N2About+0.01% of TFU

- Eluent=CH3CN

- Gradient from 98% a to 95% b for 15 minutes, then elution 95% within 5 minutes

A flow rate of 0.5 ml/min

- Injection of 2 μl of solution with a concentration of 0.1 mg/ml in a mixture of CH3CN:N2O=9:1

Method)

- Column Varian Sunfire C18 (2,0 × 100 mm, 3.5 µm

- Eluent A=N2About+0.01% of TFU

- Eluent=CH3CN

- Gradient from 98% a to 95% b for 15 minutes, then elution 95% within 5 minutes

A flow rate of 0.5 ml/min

- Injection of 2 μl of solution with a concentration of 0.1 mg/ml in a mixture of CH3CN:N2O=9:1

Method D)

- Column Waters Atlantis DB C18 (2,0 × 50 mm), 3.0 mm

- Eluent A=N2About+0.01% of TFU

- Eluent=CH3CN

- Gradient from 98% a to 95% during the 15 minutes, then elution 95% within 5 minutes

A flow rate of 0.5 ml/min

- Injection of 2 μl of solution with a concentration of 0.1 mg/ml in a mixture of CH3CN:N2O=9:1

Method (E)

- Column XTerra C18 (of 2.1 × 50 mm, 3.5 µm n°186000400

- Eluent A=N2About+0.01% of TFU

- Eluent=CH3CN.

- Gradient from 98% a to 95% b for 15 minutes, then elution 98% within 5 minutes

A flow rate of 0.5 ml/min

- Injection of 2 μl of solution with a concentration of 0.1 mg/ml in a mixture of CH3CN:N2O=9:1

Method F)

- Column Ascentis C18 (2 × 50 mm, 3 μm

- Eluent A=N2About+0.01% of TFU

- Eluent=CH3CN

- Gradient from 98% a to 95% b for 10 minutes, then elution 95% within 5 minutes

A flow rate of 0.5 ml/min; 40°C

- Injection of 2 μl of solution with a concentration of 0.1 mg/ml in a mixture of CH3CN:N2O=9:1

Method G)

- Column Ascentis C18 (2 × 50 mm, 3 μm

- Eluent A=N2O+0.05% of TFU

- Eluent=CH3CN+0.035% of TFU

- Gradient from 98% a to 95% b for 12 minutes, then elution with 95% b for 3 minutes

- Flow rate 0.7 ml/min, temperature -40 ° C

- Injection of 2 μl of solution with a concentration of 0.1 mg/ml in a mixture of CH3CN:N2O=9:1

The products detected in UV radiation at a wavelength of 220 nm.

For mass spectrometric analysis:

The method of ionization: positive electrospray (ESI+polarity+)

Scan: 100-1200 Amu

The silica gel on which I flash chromatographic column manufactured by a company Biotage.

SYNTHESIS of 1 4-(2-bromacil)-1-methyl-2-pentylbenzoyl

1A) (3-bromo-4-were)-acetic acid

Mix 13 g (0,061 mol) 3-bromo-4-methylacetophenone, 2.1 g (0,065 mol) of sulfur, 14 ml of the research and a catalytic amount of monohydrate p-toluensulfonate acid. In a stream of nitrogen heated to 130°C. After 7 hours, cooled, add 35 ml of absolute ethanol and stirred overnight at room temperature. Dissolve to 13.9 g obtained thioamide in a solution of 110 ml of ethanol, 70 ml of water and 6 g of NaOH and heated under reflux for 4 hours. The solvent is evaporated and then acidified with dilute hydrochloric acid. Precipitation of white solids. Filter and get 9,16 g of compound specified in the header.

1b) of 2-(3-bromo-4-were)-ethanol

Dissolve the compound obtained in stage 1A)in 170 ml of ethanol. Bubbled gaseous hydrochloric acid for 30 minutes. Heated under reflux for 3 hours. Evaporate the ethanol and treated with diethyl ether. Washed with saturated sodium bicarbonate solution and evaporated in vacuum. Gain of 7.1 g of ester which is dissolved in 70 ml of THF. Added dropwise a solution of 7.6 ml of brandibelle in 110 ml of THF under nitrogen atmosphere and heated under reflux for 3 hours. Cooled to 0°C and carefully add 20 ml of methanol. Heated under reflux for 30 minutes. Evaporated in vacuum. The residue is dissolved in ethyl acetate. Washed with diluted ammonium solution, dried and evaporated in vacuum.

Gain of 5.4 g of the product in the form of oil, corresponding to the connection in the header.

1C) 2[4-methyl-3-(Penta-1-enyl)-phenyl]-ethanol

Mix 2.0 g (0,0093 mol) of the product obtained at the previous stage, 1.12 g (0,01 mol) of Peterborough acid, 2.1 g (0,037 mol) of KOH, 1.5 g (0,0046 mol) of tetrabutylammonium and 50 mg of Pd-tetrakis(triphenylphosphine) in 50 ml of THF. Heated under reflux in a stream of nitrogen for 4 hours. Pour the mixture into water, extracted with ethyl acetate, dry the organic layer and the solvent evaporated. Purify the residue column chromatography on silica gel, elwira a mixture of hexane/ethyl acetate 9/1. Obtain 740 mg of the product specified in the header, in the form of oil.

1d) of 2-(4-methyl-3-pentylphenol)-ethanol

The product obtained in the previous phase, in the amount of 0.74 g (0,0036 mol) solubilizer in 46 ml of ethanol, add 0.12 g of 10% Pd/C and leave the reaction proceed in a stream of hydrogen for 5 hours at a temperature of 40ºC. Filtered and evaporated in vacuum. Obtain 0.65 g of the compound indicated in the title, in the form of oil.

1E) 4-(2-bromacil)-1-methyl-2-pentylbenzoyl

The product obtained in the previous phase, in the amount of 0.65 g (0,0032 mo is), loaded into a flask containing 8 ml of 48% aqueous Hydrobromic acid. Heated at 130°C for 6 hours. Cooled and poured into saturated sodium bicarbonate solution. Extracted with ethyl acetate, dried and evaporated in vacuum. Obtain 0.65 g of the compound indicated in the title, in the form of oil.

SYNTHESIS of 2 4-(2-methanesulfonylaminoethyl)-1-methoxy-2-pentylbenzoyl

2A) (3-bromo-4-methoxyphenyl)-acetic acid

Working according to the procedure described in the synthesis of 1A), but using 3-bromo-4-methoxyacetophenone instead of 3-bromo-4-methylacetophenone and get the connection specified in the header.

2b) 2-(3-bromo-4-methoxyphenyl)ethanol

Working according to the procedure described in the synthesis of 1b), but using compound 2A)obtained in the previous phase, instead of compound 1A) and get the connection specified in the header.

2C) 2-[4-methoxy-3-(Penta-1-enyl)-phenyl]ethanol

Working according to the procedure described in the synthesis of 1C), but using compound 2b)obtained in the previous phase, instead of compound 1b) and get the connection specified in the header.

2d) 2-(4-methoxy-3-pentylphenol)ethanol

Working according to the procedure described in the synthesis of 1d), but using compound 2c)obtained in the previous phase, instead of compound 1c) and get the connection specified in the header.

2e) 4-(2-means homiletical)-1-methoxy-2-pentylbenzoyl

Loaded into the flask 1.2 g (0,0054 mol) of compound 2d)obtained in the previous phase, 20 ml dichloromethane, 0.75 ml (0,0054 mol) of triethylamine and at 0-5°C enter of 0.42 ml (0,0054 mol) of methanesulfonamide.

Stirred for 2 hours at room temperature. Washed with water, dried and evaporated in vacuo of the organic layer. Get the product that is specified in the header, in the form of a yellow oil.

Example 1: compound n°1: 1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-(3-triptoreline)-piperazine and its hemipleat

Loaded into the flask 1.98 g (0,00777 mol) of the compound obtained in synthesis 1, 1.5 g (0,0065 mol) of (3-triptoreline)-1-piperazine, 1.35 g (0,00975 mol) of potassium carbonate and 40 ml of n-butanol. Refluxed for 6 hours. Evaporated n-butanol, treated with ethyl acetate, washed with water, dried the organic layer and evaporate the solvent. Purify the residue column chromatography on silica gel, elwira a mixture of hexane/ethyl acetate 95/5.

Mix a solution of 300 mg of the obtained free base in THF with a solution of 180 mg Mamonovo acid in THF/water 8:2.

Concentrated in vacuo. Add 6 ml of ethanol and receive the precipitate, which is filtered off. Crystallized when heated in ethanol and receive hemipleat whitish: 450 mg TPL=156-157. Subsequent crystallization in ethanol allows to obtain a product with TPL=157-158.

The fact is the melting temperature value=157-158ºC;

M+N+(Method A)=retention time: 10,9 min; m/z=419 (MH+).

NMR1N: δ (ppm, DMSO-d6): 0,88 (m, 3H); 1,27-of 1.39 (m, 4H); 1,45-to 1.59 (m, 2H); of 2.23 (s, 3H); 2.50 each-of 2.58 (m, 2H**); 2,75-2,89 (m, 2H); 2,89-3,50 (m, 10H*); 4,74 (s, 1H); 6,97 (DD, J=7,7 Hz); Jb=1.4 Hz, 1H); 7,02 (d, J=1.4 Hz, 1H); 7,07 (d, J=7.7 Hz, 1H); 7,08-to 7.15 (m, 2H); 7,16-to 7.32 (m, 3H); 7,45 (DD→t, J=8 Hz, 1H); 7,74 (d, J=8 Hz, 1H); 8.17 and (d, J=8 Hz, 1H); 8.30 to (s, 1H).

In accordance with one variant of the present invention receives the connection bis, i.e. a mixture of hemipleat 1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-(3-triptoreline)-piperazine and free Mamonovo acid (molar ratio 1:0.5) is in accordance with the following method.

Mix 600 mg free base obtained in example 1, dissolved in THF, with 540 mg Mamonovo acid dissolved in THF/water 8:2. Evaporated in vacuo, then treated the residue with a mixture of THF and simple isopropyl ether. Heated and filtered. Receive 1 g solid yellow color.

Melting point=158-159°C;

M+N+(method C)=retention time: 10,1 min; m/z 419 (MH+).

Example 2: compound n°2: 1-[2-(4-methoxy-3-pentylphenol)-ethyl]-4-(3-triptoreline)-piperazine and its hydrochloride

Loaded into the flask 0,336 g (0,00112 mol) of the compound obtained in synthesis 2, 20 ml of isopropanol, to 0.47 ml of triethylamine (0,0036 mol) and 0.21 ml (0,00112 mol) of 4-(3-triptoreline)-piperazine. Refluxed in ECENA night. Evaporated the solvent in vacuo and get the oil, which is purified by chromatography, elwira a mixture of hexane/ethyl acetate 8:2. Receive 300 mg of the free base, from which the hydrochloride in isopropanol using a saturated solution of HCl in isopropanol.

Filtered and receive 100 mg of white solid.

Melting point=146-149°C;

M+N+(method C)=retention time: 7,0 min; m/z=435 (MH+).

NMR1N: δ (ppm, DMSO-d6): 0,88 (m, 3H); 1,23-to 1.38 (m, 4H); 1,53 (m, 2H); of 2.51-2.57 m (m, 2H**); 2,95 was 3.05 (m, 2H); 3,11 of 3.28 (m, 4H); 3,30-to 3.41 (m, 2H); 3,60-3,70 (m, 2H*); of 3.77 (s, 3H); 3,93-Android 4.04 (m, 2H); 6,92 (d, J=8 Hz, 1H); 7,05 (d, J=2 Hz, 1H); 7,07 (DD, Ja=8 Hz, Jb=2 Hz, 1H); 7,17 (d Shir., J=7 Hz, 1H); 7.29 trend (with Shir, 1H); 7,31 (d Shir., J=8 Hz, 1H); 7,49 (DD→t, J=8 Hz, 1H); 10,59 (Shir., 1H).

Example 3: compound n°38: 1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-(3-triptoreline)-piperazine and its oxalate

Loaded into the flask 0.24 g (0,89 mol) of the compound obtained in synthesis 1, 0.24 g (0.1 mmol) (3-triptoreline)-1-piperazine and 0.22 g (1.6 mmol) of potassium carbonate and 10 ml of n-butanol. Refluxed for 6 hours. Evaporated n-butanol, treated with ethyl acetate, washed with water, dried the organic layer and evaporate the solvent. Purify the residue column chromatography on silica gel, elwira a mixture of hexane/ethyl acetate 95/5. Obtain 130 mg of the product specified in the header, in the form of oil. The product is dissolved in 2 ml isopr is panola. Add a solution of oxalic acid in isopropanol and get the precipitate of oxalate, which is separated by filtration in the form of a white solid (0.12 g).

Melting point=193-194°C;

M+N+=retention time: 6,7 min; m/z=419 (MH+).

NMR1N: δ (ppm, DMSO-d6): 0,89 (m, 3H); 1,28-of 1.40 (m, 4H); 1,46-to 1.59 (m, 2H); of 2.23 (s, 3H); 2,50-to 2.57 (m **); 2,78-2,89 (m, 2H); 2.91 in-is 3.08 (m, *); 3,39 (Shir., 4H); 6,97 (DD, Ja=7,7 Hz, Jb=1,6 Hz, 1H); 7,02 (Shir., 1H); 7,07 (d, J=7.7 Hz, 1H); for 7.12 (d, J=7,4 Hz, 1H); 7,22 (Shir, 1H); 7,27 (d Shir., J=8,4 Hz, 1H); 7,45 (m, 1H).

Table
No.R2RSolTPL ° CM+H+
14-CH33-n-C3H70,5157-158ºMH+ 419
RT 10,9
Method And
1 bis4-CH33-n-C3 70,5
+0,5 mol free Mamonovo acid
158-159ºMH+ 419
RT is a 10.1
Method In
24-och33-n-C3H7HCl146-149ºMH+ 435
RT 7,0
Method In
34-CH33-CH3HCl198-200ºCMH+ 391
RT 6,6
Method In
44-CH33-n-C3H7HCl215-217ºMH+ 369
RT 7,4
Method In

MH+ 447
RT 7,2
Method
54-CH33-n-C5H11HCl190-192º
64-CH33-n-C3H7HCl161-163ºMH+ 420
RT 7,6
Method In
74-och33-n-C3H7HCl174-177ºMH+ 385
RT 6,7
Method In
84-CH33-n-C3H7HCl182-185ºMH+ 401
RT 10,2
Method D
94-CH33-n-C3H7HCl200-202ºMH+ 351
RT 6,9
Method In
104-CH33-n-C3 7HCl199-201ºMH+ 381
RT 7,1
Method In
114-CH3HCl149ºMH+ 433
RT 10,2
Method In
124-och33-n-C3H7HCl125-128ºMH+ 417
RT 6,9
Method D

15
134-och33-n-C5H11HCl214ºMH+ 463
RT 10,3
Method And
144-CH33-n-C4H9HCl187ºMH+ 433
RT 7,2
Method In
4-och33-CH3HCl184-185ºMH+ 407
RT 6,1
Method
164-och33-n-C3H7HCl171-173ºMH+ 367
RT 6,5
Method In
174-CH33-n-C3H7HCl203ºMH+ 385
RT 10,9
Method And
184-CH33-n-C3H7HCl180-181ºMH+ 386
RT 10,6
Method In
194-CH33-n-C5H11 165ºMH+ 419
RT 7,2
Method In
204-CH33-n-C5H11160-164ºMH+ 419
RT 7,2
Method In

214-CH33-n-C5H11163-165ºMH+ 419
RT 7,1
Method In
224-CH33-n-C5H11283-285ºMH+ 419
RT 7,5
Method In
234-CH33-n-C5H112*HCl>201 MH+ 369
RT 7,3
Method G
244-CH33-n-C5H11-68-70MH+ 381
RT 6,3
Method F
254-CH33-n-C5H112*HCl190-192MH+ 430
RT 6,5
Method F
264-CH33-n-C5H112*HCl>212MH+ 420
RT 7,6
Method G
274-CH33-n-C5H11HCl193-195MH+ 407
RT 8,3
Method G
284-CH33-n-C5H11 2*HCl228-230MH+ 395
RT 7,38
Method G

294-CH33-n-C5H112*HCl226-228MH+ 365
RT 7,1
Method G
304-CH33-n-C5H112*HCl183-185MH+ 352
RT 5,5
Method E
314-CH33-n-C5H11HCl185-187MH+ 430
RT 6,5
Method G
324-CH33-n-C5H11HCl200-202MH+ 385
RT 7,1
Method E
334-CH33-n-C5H11HCl220-222MH+ 365
RT 7,6
Method E
344-CH33-n-C5H11HCl197-200MH+ 435
RT 7,8
Method E
354-CH33-n-C5H11HCl199-201MH+ 386
RT 7,8
Method E
364-CH33-n-C3H7Oxalate193-194MH+ 419
RT 6,7
Method E

374-CH33-n-C3H 7Fumarate140MH+ 419
RT 6,9
Method E
384-CH33-n-C3H7Succinate95-96MH+ 419
RT 6,6
Method E
394-CH33-n-C3H7Digiport91-92MH+ 419
RT 6,7
Method E

Compounds according to the invention possess interesting properties of inhibiting TNF-α.

These properties are proved in the test, which examined the impact of molecules on the synthesis of TNF-α induced in mouse Balb/c mice using lipopolysaccharide (LPS) of Escherichia Coli (055:B5, Sigma, St Luois, Mo).

The compounds were administered orally to groups of five female mice of Balb/c mice (Charls River, France) at the age of 7-8 weeks. One hour later, LPS was injected intravenously (10 μg/mouse). The blood was collected from each animal after 1.5 hours after intravenous injection of LPS. The blood samples were centrifuged, plasma was isolated and frozen at -80°C. the contents of TNF-α was measured using commercial kits (R and D, Abingdon, UK).

In this test, compound 38 showed high activity, as well as inhibit the synthesis of TNF-α even at very low doses, IC50=0.1 mg/kg

These same properties were also demonstrated in the test, studying the effect of compounds on the synthesis of TNF-α induced in rat Sprague-Dawlay using lipopolysaccharide (LPS) of Escherichia Coli (055:B5, Sigma, St Luois, Mo).

The compounds were administered orally to groups of ten rats male Sprague-Dawlay weighing about 200 grams. After 2 hours of LPS was injected intravenously (0.1 mg/kg). The blood was collected from each animal after 1.5 hours after administration of LPS. The blood samples were centrifuged, serum was separated and frozen at-80ºC. The content of TNF-α was measured using commercial kits (RPN 2744 Amersham, UK).

In this test compounds showed high activity, as well as inhibit the synthesis of TNF-α even at very low doses: IC50=0.3-1 mg/kg, in particular, IC50=0.3 mg/kg showed compound 1 and an IC50 of 1 mg/kg showed connections 4 and 8.

Compounds according to the invention were tested in models of inflammation of a joint.

Connection (1 ng/joint in the form of a suspension in 10 μl of solution containing 2% PVP (Polivinilpirolidon)/1% of lotrel F68/0.9% NaCl) according to the invention was injected into the joint hamster by injection 1 hour before the first injection of zymosan® (see below).

The induction of articular inflammation in the knee: easily after the anesthesia using isoflurane suspension zymosan® at a dose of 100 μg in 10 μl of saline was injected into the knee joint of the male hamster. Zymosan® is an extract of yeast, which produces a strong dose-dependent inflammation in subcutaneous injecting. In the conditions of the experiment described here (injection in the knee joint) was called hyperalgesia duration of one week. To extend this period were held 3 consecutive injections of zymosan®. The latent period otdergivanija paws after effects on the skin of the foot in a certain thermal stimulus was measured with the use of device (Plantar Test, Ugo Basile Biological Research Apparatus, Comerio, Italy), including a mini-camera to ensure the exact position of the infrared beam under the rear of the studied paw.

Measurement of secondary hyperalgesia

A timer that measures the duration of the exposure to infrared light that reflects off the back of his paw, was included by the researcher, and off automatically as soon as the animal shook its paw or drawing it. Infrared light is shut off by the researcher after 16 seconds, starting from the moment when the animal was not pulling back his paw in order to avoid burns. The latent period otdergivanija feet was used as an indicator to measure pain. The measurement was performed 4 hours after the first injection zymosan® and measured over the next 3 weeks. In this test, exemplary compounds according to the invention, in frequent is barb connection 1, demonstrated effective reduction of pain for a period of 3 weeks.

Compounds according to the invention was also examined on a model of neuropathic pain: measurement protivoallergennogo effect with the defeat of the intact nerve injury (SNI).

On this model, in vivo in mice, suffering from chronic neuropathic pain, on the hind foot with surgical ligation of the large sciatic nerve was caused by the effect of tactile-allodynia, i.e. pain, usually caused nebulium mechanical stimulus. Then measured the threshold otdergivanija feet (PWT), i.e. the amount of force (in grams)required to make the mouse pulled back his paw.

Tactile allodynia measured on two hind legs, i.e. homolateral and contralateral relative to the lesion caused by a surgical operation, with automatic experience Freya, according to which the skin of the foot hind limbs were subjected Pressor stimulus intensity, increasing to 5 grams, and using a rod with interchangeable needles. The force in grams, which is responsible pet otdergivanija hind legs (the threshold otdergivanija paws PWT)was used as an indicator of the tactile allodynia.

Used animals in the experimental groups, which were introduced compounds according to the invention, and the animals in the control group, each group compiled the Yala from four mice-males SW. In all groups the baseline values PWT (BC) were determined before surgery. For initiation of neuropathic pain are the two main branches of the great sciatic nerve under General anesthesia were tied with a ligature and transversely dissected animals in all groups with subcutaneous outer nerve left intact (damage intact nerve, SNI). In this model of neuropathic pain, i.e. tactile allodynia, fully developed within two days following the cross-dissection of the nerve in the back homolateral paw, i.e. on the side subjected to defeat, and in the control group remained stable during the whole time of the experiment.

After 7 days after surgery just before the introduction of the connection, i.e. at time 0 hour, the animals in all groups was determined values PWT on the back homolateral paw (hit) and on the contralateral paw (not affected). Compounds according to the invention or the media was administered to animals by injection into the tail vein (i.v.). In experimental groups, animals received 0.1 ml/10 g of the solution of the studied compounds in the medium (ethanol/cremophor/phosphate-saline buffer 1:1:18) in the dose of 1 mg/kg In the control group, mice received 0.1 ml/10 g of the carrier. After 1 hour, 2 hours, 4 hours and 6 hours after administration was determined values PWT.

For PR is doing statistical analysis all the data obtained PWT were analysed using univariate analysis, ANOVA and multiple comparisons of Bonferroni. When used dose (1 mg/kg i.v.) a statistically significant decrease in pain (by measuring protivoallergennogo effect) was observed with the compound of example 1 for 1-6 hours.

Thanks to this activity the compounds of formula (I) and their salts can be used for the treatment of diseases associated with immune disorders and disorders of an inflammatory nature, or as an analgesic drug for treatment of pain.

In particular, the compounds of formula (I) can be used to treat atherosclerosis, autoimmune diseases, diseases, leading to demyelination of neurons (such as multiple sclerosis (MS), asthma, pain or inflammation in the joints, specifically pain in the shoulder, knee, fingers, ..., rheumatoid arthritis and associated joint pain, osteoarthritis and related joint pain and other inflammatory joint pain, or other inflammatory pain (e.g., hygroma, tendonitis, ...), fibrotic diseases, idiopathic pulmonary fibrosis, cystic fibrosis glomerulonephritis, rheumatoid spondylitis, gout, bone resorption, resorption of cartilage, osteoporosis, disease Paget, multiple myeloma, uveoretinitis, septic shock, septicemia, endotoxin shock, reaction, graft versus host rejection of the transplant, the REP is some distress syndrome in adults of silicosis, asbestosis, sarcoidosis lungs, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, red, systemic lupus erythematosus, hemodynamic shock, ischemic pathologies (myocardial infarction, myocardial ischemia, coronary vasospasm, angina, heart failure, heart attack), lesions caused post-ischemic reperfusion injury, malaria, Mycobacterium infections, meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpes viruses), opportunistically infections associated with AIDS, tuberculosis, psoriasis, atopic and contact dermatitis, diabetes, cachexia, cancer, damage caused by radiation.

In accordance with one of its aspects, the present invention relates to a compound according to the invention or pharmaceutically acceptable salts of the compounds to treat the aforementioned diseases.

In accordance with another of its aspects, the present invention relates to pharmaceutical compositions containing as active principle a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or one pharmaceutically acceptable salt of this compound, and at least one vspomogatelnaya acceptable substance.

These excipients chosen, depending on the pharmaceutical form and the desired method of administration, from the usual excipients which are known to the expert.

In the pharmaceutical compositions according to the present invention, intended for oral, sublingual, subcutaneous, intramuscular, intravenous, intra-articular, topical, local, intratracheal, nasal, transdermal or rectal routes of administration, the active principle of formula (I)described above, or its salt can be entered in a single way of introduction, mixed with classical pharmaceutical excipients animals and human beings for the prophylaxis or treatment of disorders or diseases mentioned above.

The appropriate unit forms of introduction include forms for oral administration such as tablets, hard or soft gelatin capsules, powders, granules and solutions or suspensions for oral administration, the forms for sublingual, cheek, intra-articular, intratracheal, intraocular, nasal routes of administration, forms for inhalation, forms for topical, transdermal, subcutaneous, intramuscular or intravenous administration, the forms for rectal route of administration or implants. For topical application, the compounds according to the invention can in order to use the creams, gels, lipsticks and lotions.

For example, the singular form of the introduction of the compounds according to the invention in the form of tablets may contain the following components:

The connection according to the invention50.0 mg
Lures223,75 mg
Croscarmellose sodium6.0 mg
Corn starch15,0 mg
The hypromellose2.25 mg
Magnesium stearate3.0 mg

Oral injected dose of active principle per day may range from 0.01 to 100 mg/kg in one or several stages, preferably from 0.02 to 50 mg/kg

For example, the singular form of the introduction of the compounds according to the invention in the form of intra-articular solution or suspension may contain the following components:

The connection according to the invention
Polyvinylpyrrolidone (PVP) R172%
Lotrel F681%
NaCl0,9%

When intra-articular injections injected dose of the active agent may be from 0.01 to 40 mg/kg per joint, preferably the injection is injected with a frequency component of at least one month between injections.

As an additional example, the singular form of the introduction of the compounds according to the invention in the form of intra-articular solution or suspension may contain the following components:

The connection according to the invention48 mg
Polyvinylpyrrolidone (PVP)20 mg
Poloxamer 18810 mg
NaCl9 mg
0.1 N. Paon/HCl 0.1 N.to a pH of 6.8 to 7.4
Water for injections1000 mg

When intra-articular injections injected dose of active principle can vary from 4 ng to 96 mg of a joint, preferably the frequency of injection is at least an interval of one month between injections.

You may experience a special case is, when you need higher or lower doses; these doses are not beyond the scope of the invention. In accordance with the existing practice appropriate dose for each patient is determined by the physician depending on the method of administration, the weight and response of the patient.

In accordance with another of its aspects the present invention relates also to a method of treatment of the above pathologies, which includes an introduction to the patient an effective dose of the compounds according to the invention or one of its pharmaceutically acceptable salts.

In accordance with another of its aspects the present invention relates to a method of treatment of diseases related to immune or inflammatory disorders, as well as for the treatment of pain, in particular atherosclerosis, autoimmune diseases, diseases, leading to demyelination of neurons (such as multiple sclerosis (MS), asthma, rheumatoid arthritis and associated joint pain, osteoarthritis and related joint pain and other inflammatory joint pain, or other inflammatory pain (e.g., hygroma, tendonitis, ...), fibrotic diseases, idiopathic pulmonary fibrosis, cystic fibrosis, glomerulonephritis, rheumatoid spondylitis, gout, bone resorption, resorption of cartilage, osteoporosis, disease Paget, sets the authorized myeloma, uveoretinitis, septic shock, septicemia, endotoxin shock, reaction, graft versus host, transplant rejection, respiratory distress syndrome in adults, silicosis, asbestosis, sarcoidosis lungs, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, red, systemic lupus erythematosus, hemodynamic shock, ischemic pathologies (myocardial infarction, myocardial ischemia, coronary vasospasm, angina, heart failure, heart attack), lesions caused post-ischemic reperfusion injury, malaria, Mycobacterium infections, meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpes viruses), opportunistic infections associated with AIDS, tuberculosis, psoriasis, atopic and contact dermatitis, diabetes, cachexia, cancer, damage caused by radiation, including the introduction of the compounds of formula (I) or one of its pharmaceutically acceptable salts, individually or in combination with other active principles.

In accordance with another of its aspects the present invention relates to a method of treating pain or inflammation in joints, particularly pain in the shoulder, knee or fingers, including the introduction of the compounds of formula (I) or one of its pharmaceutically acceptable salts, individual is om or in combination with other active principles. The invention relates also to method of treatment mentioned above, according to which the introduction of the compounds of formula (I) or one of its pharmaceutically acceptable salts individually or in combination with other active principles is carried out by intra-articular injection.

In accordance with another of its aspects the present invention relates to the use of compounds of formula (I) or one of its pharmaceutically acceptable salts for obtaining a medicinal product intended for the treatment of pain or inflammation in the joints, more specifically to the use of compounds of formula (I) or one of its pharmaceutically acceptable salts, characterized in that the drug is injected into the joint.

According to another of its aspects the invention relates to the compound of formula (I) or one of its pharmaceutically acceptable salts for the treatment of pain or inflammation in the joints, more specifically to the treatment, wherein the drug is injected into the joint.

1. The compounds of formula (I):

in which:
- R1 denotes independently from each other hydrogen atom, halogen atom, (C1-C5)alkyl group, (C1-C5)halogenating group, (C1-C2)performanceline group, (C1-C5)CNS group or (C1-C2)performanceline group;
R2 represents (C1-C5)alkyl group is (C1-C5)CNS group,
- R3 represents (C1-C5)alkyl group;
- A represents =CH - or =N-;
in the form of a base or addition salt with an acid.

2. The compound according to claim 1, in which
- R1 denotes (C1-C5)halogenating group or (C1-C2)performanceline group,
in the form of a base or addition salt with an acid.

3. The compound according to claim 1, in which
- R1 denotes (C1-C5)alkyl fluoride group
in the form of a base or addition salt with an acid.

4. The compound according to any one of claims 1 to 3, in which
- R2 represents (C1-C5)alkyl group
in the form of a base or addition salt with an acid.

5. The compound according to any one of claims 1 to 3, in which the piperazine is connected with a phenyl group using ethyl group in position 3:

in the form of a base or addition salt with an acid.

6. Connection on p. 4, in which the piperazine is connected with a phenyl group using ethyl group in position 3:

in the form of a base or addition salt with an acid.

7. The compound according to any one of items 1-3, in which
- R1 denotes (C1-C2)performanceline group;
in the form of a base or addition salt with an acid.

8. The compound according to claim 4, in which
- R1 denotes (C1-C2)performanceline group;
in the form of a base or addition salt with an acid.

9. The compound according to claim 5, in which
- R1 denotes (C1-C2)performanceline g is the SCP;
in the form of a base or addition salt with an acid.

10. The connection according to claim 6, in which
- R1 denotes (C1-C2)performanceline group;
in the form of a base or addition salt with an acid.

11. The compound according to any one of items 1-3, in which
- R2 represents (C1-C3)alkyl group
in the form of a base or addition salt with an acid.

12. The compound according to claim 4, in which
- R2 represents (C1-C3)alkyl group
in the form of a base or addition salt with an acid.

13. The compound according to claim 5, in which
- R2 represents (C1-C3)alkyl group
in the form of a base or addition salt with an acid.

14. The connection according to claim 6, in which
- R2 represents (C1-C3)alkyl group
in the form of a base or addition salt with an acid.

15. The connection according to claim 7, in which
- R2 represents (C1-C3)alkyl group
in the form of a base or addition salt with an acid.

16. The compound according to any one of paragraphs 8-10, in which
- R2 represents (C1-C3)alkyl group
in the form of a base or addition salt with an acid.

17. Connection in claim 1, characterized in that it is a
1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-(3-triptoreline)-piperazine;
in the form of a base or addition salt with an acid.

18. Connection in claim 1, chosen from:
connection n°1: hemipleat 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
- connect the ment n°1 bis: hemipleat 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine in a mixture with 0.5 moles of free Mamonovo acid;
connection n°2: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methoxy-3-pentylphenol)-ethyl]piperazine;
connection n°3: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methyl-3-propylphenyl)-ethyl]piperazine;
connection n°4: the hydrochloride of 1-(3-forfinal)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°5: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methyl-3-heptylphenol)-ethyl]piperazine;
connection n°6: the hydrochloride of 1-(6-triptoreline-2-yl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°7: the hydrochloride of 1-(3-forfinal)-4-[2-(4-methoxy-3-pentylphenol)-ethyl]piperazine;
connection n°8: the hydrochloride of 1-(3-deformational)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°9: the hydrochloride of 1-(phenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°10: the hydrochloride of 1-(3-methoxyphenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connections n°11: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methyl-3-(2-methylbutyl)phenyl)-ethyl]piperazine;
connection n°12: the hydrochloride of 1-(3-deformational)-4-[2-(4-methoxy-3-pentylphenol)-ethyl]piperazine;
connection n°13: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methoxy-3-heptylphenol)-ethyl]piperazine;
connection n°14: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methyl-3-hexylphenyl)-ethyl]piperazine;
connection n°15: the hydrochloride of 1-(3-triptoreline)-4-[2-(4-methoxy-3-propylphenyl)-ethyl]piperaz is on;
connection n°16: hydrochloride of 1-(phenyl)-4-[2-(4-methoxy-3-pentylphenol)-ethyl]piperazine;
connection n°17: hydrochloride 1-(4-chlorophenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°18: hydrochloride of 1-(6-chloropyridin-2-yl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°19: bansilalpet 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°20: 2-naphthalenesulfonate 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°21: p-toolswhat 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°22: Hemi-2,5-naphthalenedisulfonate 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°23: dihydrochloride of 1-(4-forfinal)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°24: 1-(4-methoxyphenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine base;
connection n°25: dihydrochloride of 1-(5-bromopyridin-2-yl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°26: dihydrochloride of 1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-(5-triptorelin-2-yl)-piperazine;
connection n°27: hydrochloride 1-(4-trebutien)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°28: dihydrochloride of 1-(4-ethoxyphenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°29: dihydrochloride of 1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-m-tolyl piperazine;
connection n°30: dihydrochloride of 1-[2-(4-methyl-3-pentylphenol)-ethyl]-4-pyridine-2-reperusing;
connection n°31: hydrochloride of 1-(6-bromopyridin-2-yl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°32: hydrochloride 1-(2-chlorophenyl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°33: the hydrochloride of 1-(2-were)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°34: hydrochloride of 1-(3-cryptomailer)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°35; hydrochloride of 1-(5-chloropyridin-2-yl)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°36: oxalate of 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°37: fumarate of 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°38: succinate 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine;
connection n°39: digiport 1-(3-triptoreline)-4-[2-(4-methyl-3-pentylphenol)-ethyl]piperazine.

19. A method of obtaining a compound according to any one of the preceding paragraphs, including the state, namely, that condense in an organic solvent such as an alcohol, optionally in the presence of a base, the compound of formula (II):

in which R1 and A are defined in claim 1, with a compound of formula (III):

(III)
in which R2 and R3 are defined in the .1, a Q denotes a leaving group selected from halogen atoms, or activated hydroxyl groups, such as methanesulfonate, benzolsulfonate, para-toluensulfonate, triflate, acetate, optionally converted into one of its salts.

20. Pharmaceutical composition for the modulation of the activity of TNF-alpha, containing as active principle a compound of formula (I) according to any one of claims 1 to 18 or one of its pharmaceutically acceptable salts.

21. Drug to modulate the activity of TNF-alpha, containing as active principle a compound of formula (I) according to claims 1 to 18 or one of its pharmaceutically acceptable salts.

22. The use of the compounds of formula (I) according to any one of claims 1 to 17 or one of its pharmaceutically acceptable salts for obtaining a medicinal product intended for treating or preventing pain and/or diseases associated with inflammation or immune disorders.

23. The use of the compounds of formula (I) or one of its pharmaceutically acceptable salts on p.22 for obtaining a medicinal product intended for the treatment of pain or inflammation in joints.

24. The use of the compounds of formula (I) or one of its pharmaceutically acceptable salts according to item 23, wherein the drug is injected into the joint.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, particularly novel pyridinone derivatives of formula (I) or stereochemically isomeric forms thereof, where R1 is C1-6alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 is a halogen, trifluoromethyl, C1-3alkyl or cyclopropyl; X is a covalent bond, O or O-CH2; Ar is an unsubstituted phenyl or phenyl substituted with n radicals R4, where n equals 1, 2 or 3; where each R4 is a halogen; or pharmaceutically acceptable addition salts or solvates thereof. The invention also relates to a pharmaceutical composition, having the activity of positive allosteric modulators of the metabotropic glutamate receptor subtype 2, based on compounds of formula I and use of compounds of formula I to prepare a medicinal agent for treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved.

EFFECT: novel compounds which can be useful in treating and preventing neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved are obtained and described.

15 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-[2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]methanesulphonamide and N-[6-(1-isopropoxyethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H- quinazolin-3-yl] methanesulphonamide, having antagonistic activity on the AMPA receptor. The invention also relates to a pharmaceutical composition.

EFFECT: use of said compounds to produce drugs for treating AMPA mediated conditions and primarily for treating epilepsy or schizophrenia.

6 cl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 2-nitroheterylthiocyanates, particularly 4-rhodano-5-nitropyrimidine and 2-rhodano-3-nitripyridine derivatives of general formula (I), optionally in crystalline form or in form of pharmaceutically acceptable addition salts thereof with acids or bases, having activity on fungal strains, fungal infection agents, for producing pharmaceutical compositions that are suitable for local application. The compounds are also active on strains that are resistant to existing drugs. In general formula (I) X=N or C-R3, R1 denotes a proton, a saturated or unsaturated linear alkoxy radical having 1-5 carbon atoms; a cycloalkyloxy radical having up to 6 carbon atoms; a saturated linear alkylmercapto radical having 1-3 carbon atoms; an amino radical having 1-10 carbon atoms, selected from a saturated or unsaturated linear mono- or dialkylamino radical or a cycloalkylamino radical, cyclic amino radical. Each of the cyclic groups can be substituted with 1-2 methyl groups, or a benzylamino group; R2 denotes a proton, a saturated or unsaturated linear alkyl radical having 1-5 carbon atoms, or a cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto group; R3 denotes a trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano group or an alkoxycarbonyl substitute having 1-3 carbon atoms in the alkoxy group.

EFFECT: improved properties of compounds.

5 cl, 3 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a non-hydratable crystal form (polymorph A) of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-[4-cyano-2-methyl-6-[(methylamino)-carbonyl]phenyl]-1H-pyrazole-5-carboxamide (compound 1), which is characterised by an X-ray diffraction pattern having reflection angle peaks given in the claim. According to the invention, the method involves heating a hydratable crystal form of compound 1 (polymorph B), having X-ray diffraction characteristics given in the claim, at temperature from about 40°C to the boiling point of the solvent of the mixture, which contains a solvent selected from a group consisting of water, n-heptane, 1-chlorobutane, toluene, 1-butanol and 1-pentanol.

EFFECT: obtaining a stable polymorph A of compound 1, which enables to obtain stable solid insecticide compositions.

15 cl, 2 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 4-(azacycloalkyl)benzene-1,3-diol compounds of general formula (I) given below:

,

where: R1 is: - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom or a trifluoromethyl group, - aralkyl radical, - C1-C5-alkoxy radical, -amine radical, having the structure (a):

,

where R2 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6- cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, and C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical of the structure (b):

,

where p is equal to 1 or 2, - a radical of the structure (c):

,

where R4 is: - carboxymethyl, -COOCH3, or carboxyethyl, -COOEt, radical, - C1-C3-alkyl radica, - hydrogen, and R5 is: - an unsubstituted aryl radical or an aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, fluorine atom or a trifluoromethyl group, - C3-C6-cycloalkyl radical, - pyridyl, and R3 is: - hydrogen, - C1-C5-alkyl radical; or R1 can also be a radical of formula (d):

,

where R6 is: - hydrogen, - C1-C5-alkyl radical, - C3-C6-cycloalkyl radical, - aryl radical, - aryl radical substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy group, a fluorine atom and a trifluoromethyl group, - pyridyl radical, - aralkyl radical, R7 is: - hydrogen, - C1-C5-alkyl radical, and R8 is: - hydrogen, - hydroxyl, - amine radical, - C1-C3-alkoxy radical; Y is hydrogen or fluorine, and m and n are equal to 0, 1 or 2, as well as isomeric and enantiomeric forms of compounds of formula (I). The invention also relates to use of said compounds as a drug for treating pigmentation disorders.

EFFECT: novel compounds, which can be used in pharmacology or cosmetology to treat or prevent pigmentation disorders, are obtained and described.

6 cl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or a pharmaceutically acceptable salt thereof, wherein G1 is phenyl or pyridyl, each of which is optionally additionally substituted by one substitute presented by T; G2 is phenyl, 1,3-thiazolyl or 1,3-oxazolyl, wherein G2 is bound to G1 in the para position in relation to a place of attachment of G1 to group NH in formula (I), wherein G2 means phenyl, G3 is bound to G2 in the para position of G2 in relation to G1, and wherein provided G2 represents 1,3-thiazolyl or 1,3-oxazolyl, G2 is bound to G1 in the position of 5 G2 and G3 is bound to G2 in the position of 2 G2; T in each case is independently specified in a group containing C1-6alkyl and halogen; G3 is presented by formula or by formula ; W1 is -C(R3)(R4)-C(R3)(R4)-, and W2 represents N; or W3 represents O; W4 is -C(R3)(R4) -; each R3 and R4 is hydrogen; each R5 and R6 kis hydrogen; Rc and Rd together with a carbon atom whereto attached, are a 4-5-member cycloalkyl or monocyclic heterocycle of formula ; wherein one hydrogen atoms attached to the carbon atom of the cycloalkyl ring and monocyclic heterocycle is optionally substituted by a radical specified in a group -C(O)O(R8); W5 is -CH2- or -CH2-CH2-; W6 is O or N(RX), wherein Rx is hydrogen, C1-6alkyl or -C(O)O(Rz); RZ in each case is independently C1-6alkyl; R8 is hydrogen; L1 is O; and X is hydrogen, C1-6alkyl, or - (CRgRh)u-C(O)O(R10); or L1 is -CH2- and X is -C(O)OH; R10 is hydrogen; or Q is G4 or Y1-Y3; or Q is described for formula wherein Z is phenyl; G4 is benzothiazole or benzoxazole optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of C1-6alkyl, halogen and -OR1; Y1 in each case is independently -C(O)-, -C(O)O- or -C(O)N(Rw)-, wherein the right side -C(O)O- and -C(O)N(Rw)- of the groups is attached to Y3 or (CRJRk)v, Y3 in each case is independently phenyl, benzyl, piperidinyl or bicyclo[4.2.0]octa-1,3,5-triene, wherein the phenyl and benzyl residues are optionally additionally substituted by 1 or 2 substitutes specified in a group consisting of halogen and haloC1-6alkyl; Rg and Rh in each case is independently hydrogen, or C1-6alkyl; R1 in each case is independently halogenC1-6alkyl; Rw is hydrogen; and u means 1.

EFFECT: compounds being the type 1 diacylglycerol O-acyltransferase (DGAT-1) enzyme inhibitors.

7 cl, 1 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a tosylate salt of trans-N-isobutyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane carboxamide of formula (1):

, which exhibits histamine-3 (H3) receptor antagonist activity.

EFFECT: possibility of use in a method of treating several diseases.

12 cl, 1 tbl, 6 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an agent, which is in form of fluorinated 1,4-naphthoquinone derivatives of general formula (I) which have cytotoxic effect on human cancer cells in a culture. In general formula (I) 1) R1=NHC(CH3)3, R2, R3=F; 2) R1=NHCH2CH2SCH3, R2, R3=F; 3) R1=N(CH2CH2)2, R2, R3=F; 4) R1=N(CH2CH2)2, R2, R3=F; 5) R1=NHCH2CH2CH2CH3, R2, R3=F; 6) R1=NHC6H5R2, R3=F; 7) R1=H(CH3)CH2CH2OH, R2, R3=F; 8) R1, R3=NHCH2CH2CH2CH3, R2=F; 9) R1=N(CH2CH2OH)2, R2, R3=F; 10) R1=NHC6H5, R2=CH3, R3=F; 11) R1=OCH3, R2, R3=F; 12) R1=NH(CH2)2SS(CH2)2NH(2-pentafluoro-1,4-naphthoqunonyl), R2, R3=F; 13) R1=NHC2H5, R2, R3=F; 14) R1=N+C5H5, R2=O; R3=F; 15) R1=NHCH2CH2OH, R2,R3=F; 16)R1, R2=OCH3, R3=F.

EFFECT: proposed compounds can be used in medicine as a base for designing drug formulations of preparations used in malignant growth therapy.

2 dwg, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: compound refers to new biologically active N-2-(2'-methylphenoxy)-ethylmorpholine hydrochloride (I) of formula . The compound is produced from reacted 1-bromine-2-(2'-methylphenoxy)ethane and morpholine. The produced compound represents a white crystalline matter, soluble in hot water, ethanol, chloroform, dimethyl sulphoxide, dimethyl formamide.

EFFECT: there is produced a new long-lasting hypotensive compound.

1 tbl

The invention relates to the field of synthesis of medicinal substances, specifically, to obtain the dihydrochloride of 1-(2,3,4-trimethoxybenzyl)piperazine (I), which is the substance of a drug Trimetazidine

FIELD: medicine.

SUBSTANCE: present group of inventions relates to biotechnology. What is presented is a humanised anti-CD79b antibody and its antigen-binding fragment produced of murine antibody MA79b and CD79b having a substantially analogous binding affinity thereto. A polynucleotide, a vector, a host cell and a method for producing the anti-CD79b antibody according to the invention; immunoconjugates, compositions and methods for cell growth inhibition, a method of treating an individual suffering cancer, a method of treating a proliferative disease and tumour in a mammal, a method for B-cell proliferation inhibition; a method for detecting the presence of CD79b in a sample and method for binding the antibody to the CD79b expressing cell are also disclosed.

EFFECT: given invention can find further application in therapy of the CD79b associated diseases.

86 cl, 20 tbl, 9 ex, 51 dwg

FIELD: medicine.

SUBSTANCE: present invention refers to biotechnology and medicine. What is presented is a method for preventing or treating an inflammatory disease, comprising the stages of producing an NR10 antibody having NR10-neutralising activity, and selecting an antibody inhibiting IL-31-dependent cell line growth, and administering the antibody to a patient with an inflammatory disease that is atopic dermatitis, chronic dermatitis, rheumatism or osteoarthritis.

EFFECT: present invention can find further application in the therapy of the inflammatory diseases.

10 cl, 13 dwg, 10 ex

Anti-mif antibodies // 2509777

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology and immunology. Invention discloses a monoclonal antibody and its antigen-binding parts which specifically bind the C-end or central part of the macrophage migration inhibitory factor (MIF). The anti-MIF antibody and its antigen-binding part further inhibit biological function of the human MIF. The invention also describes an isolated heavy and light chain of immunoglobulins obtained from anti-MIF antibodies, and molecules of nucleic acids which encode such immunoglobulins.

EFFECT: disclosed is a method of identifying anti-MIF antibodies, pharmaceutical compositions containing said antibodies and a method of using said antibodies and compositions for treating diseases associated with MIF.

22 cl, 14 dwg, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a therapeutic agent for treating rheumatoid arthritis administered in a dose of 4 mg/kg for 4 weeks and more that provides an equivalent concentration of the interleukin-6 receptor antibody (IL-6R antibody), containing the interleukin-6 receptor antibody (IL-6R antibody).

EFFECT: invention provides the simultaneous intensification of the therapeutic action on rheumatoid arthritis and reduced hypersensitivity.

46 cl, 4 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: biotechnologies.

SUBSTANCE: peptide of DGSVVVNKVSELPAGHGLNVNTLSYGDLAAD structure is used for suppression of allergic inflammation of respiratory passages, for prophylaxis and treatment of arthritis, as well as for pain relief. A peptide is effective as an adjuvant and for stimulation of IL-12 products in a cell.

EFFECT: peptide allows increasing IL-12 products by 10 times relative to normal levels of IL-12 cellular production.

19 cl, 25 dwg, 10 ex

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