Substituted 3-benzofuranyl-indol-2-one-3-acetamidopiperazines derivatives, preparing and using them in therapy

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 3-benzofuranyl-indol-2-one-3-acetamidopiperazine derivatives of formula

,

wherein: R1 means hydrogen atom; R2, R3, R4 are identical or different, found in any accessible position of phenyl nucleus; they independently mean hydrogen atom and halogen atom; R5 and R6 are identical or different, mean hydrogen atom, (C1-6) alkyl group; R7 means (C1-6) alkyl group; R8 and R9 found in any accessible position of piperazine nucleus, mean hydrogen atom, or (C1-6)alkyl group; at least one of R8 and R9 is differed from H; n means 1; which are present in the form of a base or an acid addition salt, as well as to methods for preparing these compounds, a therapeutic agent or a based pharmaceutical composition for treating obesity, diabetes, appetite disorder and overweight and to therapeutic use of these compounds.

EFFECT: preparing the compounds for treating obesity, diabetes, appetite disorder and overweight and to therapeutic use of these compounds.

10 cl, 3 ex

 

The object of the present invention are substituted derivatives of 3-benzofuranyl-indol-2-one-3-acetamidophenol, obtaining them and their use in therapy.

Ghrelin is a peptide hormone of 28 amino acids, produced mainly in the stomach in posttranslational process after removal of pre-prograin (Kojima, M. et al.,Nature1999; 402:656-60). Ghrelin is the endogenous ligand pituitary receptor stimulators of secretion of growth hormone (GHSR1a).

GHS-R is encoded by two exons: exon 1 encodes the transmembrane domains (TM) 1-5, and exon 2 encodes TM6 and TM7 receptor, conjugated with protein G (GPCR).

Both transcripts have been identified in the pituitary gland and the brain: one that encodes a GPCR full length (GHS-R1a), and another that encodes a truncated receptor (GHS-R1b), which lacks TM6 and TM7. Only the subtype of the GHS-R1a is activated by ghrelin and ghrelin mimetics. GHS-R1b is present in liver and other peripheral tissues, but its function is unknown (Smith R. G. et al.,Trends in Endocrinology and Metabolism, 2005, 16, № 9).

This receptor type protein with seven transmembrane domains, from A family associated with Gq/phospholipase C. ghrelin Receptor may be linked via a Gs/protein kinase A in certain tissues (Ueno, N., et al.Endocrinology, 2004, 145, 4176-4184; Kim, M. S. et al.,Int. J. Obes. Relat. Metab. Disord., 2004, 28:1264-1271). Interestingly, the receptor for ghrelin has an unusual character is the stick he has significant constitutive activity, independent of ligand (Barazzoni, R. et al.,Am. J. Physiol. Endocrinol. Metab., 2004, 288:E228-E235).

Low levels of expression of ghrelin have been confirmed in various tissues, such as intestine, pancreas, kidneys, immune system, placenta, testicles, mucosal tissue, hypothalamus (Horm. Res.2003; 59 (3):109-17).

It has been demonstrated that ghrelin leads to hunger at meal times and at the beginning of the meal. Circulating levels decrease food intake and increase before meals, achieving sufficient concentrations to stimulate hunger and food intake. Introduction ghrelin rapidly stimulates food intake, and non-stationary manner, primarily by increasing the desire for food and number of meals. Ghrelin more effectively stimulates food intake in a short time than any other molecule, with the exception of neuropeptide Y with which it is approximately equipotent (Wren A. M. et al.,J. Clin. Endocrinol. Metab., 2001; 86:5992-5). However, ghrelin is unique in its ability to show this effect regardless of whether it is peripheral or Central.

It is also the only substance in mammals, which has demonstrated its ability to increase appetite and food intake when administered to man (Druce, M. R. et al.,Int. J. Obes., 2005; 29:1 130-6; Wynne K. et al.,J. Am. Soc. Nephrol., 2005; 16:2111-8).

In addition to the VOA role in the initiation of food intake, ghrelin also meets the criteria established by the hormone associated with obesity, involved in long-term regulation of body weight. The level of ghrelin circulates depending on the energy reserves and manifests compensatory changes in response to changes in body mass.

Ghrelin passes through the blood-brain barrier and stimulates food intake by acting on certain classical centers governing body weight, such as the hypothalamus, diamond-shaped brain and compensatory mesolimbic system.

Chronic intake ghrelin increases body weight as a result of various coordinated effects on food intake, energy expenditure and use of resources. Congenital ablation of ghrelin or receptor gene ghrelin provokes resistance to obesity induced by diet, and pharmacological blockade of ghrelin reduces food intake and body weight.

The available evidence shows the role of ghrelin at the same time to encourage food intake in the short term and in the energy homeostasis in the long run, becoming thus an attractive target as a drug for the treatment of obesity and/or disorders that cause weight loss.

Ghrelin also has physiological and pharmacological actions on the endocrine part of the pancreas. Bioactive ACI is new ghrelin is produced in the ε-cell, recently described in the pancreatic islets (Prado, C. L. et al., 2004,Proc. Natl. Acad. Sci.USA, 101:2924-2929), potentially providing a local source of ghrelin, which acts on the β-cells of islets. Blockade of this function of endogenous ghrelin, using the antagonist of these receptors, drastically reduced the concentration of glucose on an empty stomach, softened glycemic circulation and increased response to insulin trials on glucose tolerance, suggesting inhibitory role of ghrelin in the control of insulin secretion (Dezaki, K. et al. 2004, Diabetes, 53:3142-3151).

Deletion of ghrelin in mice (mouse ghrelin -/-) increases glucosidation insulin secretion from β-cells of the pancreas as a result of reduced expression of Ucp2 and improves insulin sensitivity in peripheral tissues (Sun Y. et al., 2006,Cell Metabolism, 3:379-386).

Thus, antagonists of the receptor for ghrelin could regulate hunger, meals and their frequency, as well as, in the long term, weight, in particular the increase in weight due to dietary or therapeutic regimen. In addition, in the framework of the treatment of diabetes ghrelin antagonists could be useful to hold the balance between insulin and glucose and to control diabetic hyperphagia. The ghrelin antagonists could also be used as agents that reduce appetite, and/or as a means from which Irene, or in the treatment of diabetes and its consequences.

The object of the present invention are compounds corresponding to the formula (I):

in which:

R1 means a hydrogen atom or a (C1-6)alkyl, -C(=O)(C1-6)alkyl, -C(=O)aryl group;

R2, R3, R4, equal or different, are located at any available position of the phenyl nucleus, independently mean a hydrogen atom, a halogen atom, CN, OH, (C1-6)alkyl group, optionally substituted by a halogen atom or OH; peralagan(C1-3)alkyl, (C1-6)alkoxy, peralagan(C1-3)alkoxy, aminocarbonyl, (C1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aryl, aryloxy, heteroaryl; and aryl, aryloxy or heteroaryl group can be optionally substituted by a halogen atom, CN, OH or (C1-6)alkyl, peralagan(C1-3)alkyl or (C1-6)alkoxygroup; and it is expected that at least one of R2, R3, R4 is different from H and that aryl, aryloxy or heteroaryl group can be optionally substituted by a halogen atom, CN, OH or (C1-6)alkyl, peralagan(C1-3)alkyl, (C1-6)alkoxygroup;

R5 and R6, identical or different, denote a hydrogen atom, (C1-6)alkyl group, or R5 and R6 together form a cycle C3-C6;

R7 means (C1-6)alkyl which the Rupp or (C 2-6)alkenylphenol group;

R8 and R9, being in any of the available positions piperazinovogo kernel, mean a hydrogen atom, (C1-6)alkyl group or (C2-6)alkenylphenol group, and at least one of R8 and R9 is not H;

or two of R7, R8 and R9 together form a cycle C3-C6;

and R8 and R9 may be in the steam position on the same carbon atom;

n denotes 1 or 2.

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

The compounds of formula (I) can exist in the state bases or acid additive salts. Such salts attach form part of the invention.

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

In the framework of the present invention:

under a halogen atom understood fluorine, chlorine, bromine or iodine;

under alkyl group understand linear or branched saturated aliphatic group. As examples (C1-6)alkyl group, containing the s from 1 to 6 carbon atoms, in particular, (C1-4)alkyl, which may mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl;

under alkenylphenol group understand aliphatic mono - or polyunsaturated group, linear or branched, containing, for example, one or two unsaturation and having from 2 to 6 carbon atoms;

under halogenoalkanes group understand alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom; for example, foralkyl represents an alkyl group in which one or more hydrogen atoms replaced by fluorine atom;

under perhalogenated group understand alkyl group in which all hydrogen atoms have been substituted by a halogen atom, for example, perfluoroalkyl represents an alkyl group in which all hydrogen atoms replaced by fluorine atom;

under alkoxygroup understand-O-alkyl radical where the alkyl group such as defined above;

under perhalogenated understand-O-perhalogenated radical, where perhalogenated group such as defined above, as an example, you can call triptoreline;

under the aryl group understand cyclic aromatic group containing from 6 to 10 carbon atoms. As examples of aryl groups can be called a phenyl or naphthyl;

under heteroaryl gr is POI understand cyclic aromatic group, containing from 2 to 10 carbon atoms and comprising from 1 to 3 heteroatoms, such as nitrogen, oxygen or sulfur. As examples of heteroaryl groups can be called fornillo, pyrrolidino, imidazolidinyl, pyrazolidine, thienyl, oxadiazolyl, oxazolidinyl, isoxazolyl, foratenolol, thiadiazolidine, thiazolidine, isothiazolinone, pyridyloxy, personilnya, pyrimidinyl, pyridazinyl groups, and groups that correspond to the products of the merging with the phenyl group, such as benzothiophen, benzofuran, benzothiazole, etc.,

Of the compounds of formula (I) objects of the invention, one group of compounds is formed by compounds for which:

R1 means a hydrogen atom or a (C1-6)alkyl, -C(=O)(C1-6)alkyl, -C(=O)aryl group;

R2, R3, R4, equal or different, are located at any available position of the phenyl nucleus, independently mean a hydrogen atom, a halogen atom, CN, OH, (C1-6)alkyl, peralagan(C1-3)alkyl, (C1-6)alkoxy, peralagan(C1-3)alkoxy, aminocarbonyl, (C1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aryl, aryloxy, heteroaryl group, with at least one of R2, R3, R4 is different from H;

R5 and R6, identical or different, denote a hydrogen atom, (C1-6)alkyl group, or R5 and R6 together the way the Ute cycle C 3-C6;

R7 means (C1-6)alkyl group;

R8 and R9, being in any of the available positions piperazinovogo kernel, mean a hydrogen atom or a (C1-6)alkyl group, with at least one of R8 and R9 is different from H;

or two of R7, R8 and R9 together form a cycle C3-C6;

n denotes 1 or 2;

in the form of a base or an acid additive salt.

Of the compounds of formula (I) objects of the invention, one group of compounds is formed by compounds for which:

R1 means a hydrogen atom or-C(=O)(C1-6)alkyl, -C(=O)aryl, (C1-6)alkyl group; and/or

R2, R3, R4, equal or different, are located at any available position of the phenyl nucleus, independently mean a hydrogen atom, a halogen atom, in particular chlorine or bromine, or (C1-6)alkyl or triptorelin group, and at least one of R2, R3, R4 is different from H; and/or

R5 and R6, identical or different, denote a hydrogen atom or a (C1-6)alkyl group; and/or

R7 means (C1-6)alkyl group; and/or

R8 and R9, being in positions 2 and 6 piperazinovogo kernel, mean a hydrogen atom or a (C1-6)alkyl group, with at least one of R8 and R9 is different from H; and/or

two of R7, R8 and R9 together form a cycle C3-C6; and/or

n denotes 1 or 2;

in the form of a base or an acid additive salt.

Of the compounds of formula (I) objects of the invention, another group of compounds is formed by compounds for which:

R1 means a hydrogen atom or-C(=O)methyl, -C(=O)phenyl, methyl group; and/or

R2, R3, R4, equal or different, are located at any available position of the phenyl nucleus, independently mean a hydrogen atom, a halogen atom, in particular chlorine or bromine, or methyl, or triptorelin group, and at least one of R2, R3, R4 is different from H; and/or

R5 and R6, identical or different, denote a hydrogen atom or a (C1-6)alkyl group; and/or

R7 denotes a methyl or ethyl group; and/or

R8 and R9, being in positions 2 and 6 piperazinovogo kernel, mean a hydrogen atom or a methyl group, ethyl group, and at least one of R8 and R9 is different from H; and/or

two of R7, R8 and R9 together form a cycle C3-C6; and/or

n denotes 1 or 2;

in the form of a base or an acid additive salt.

Of the compounds of formula (I) objects of the invention include, in particular, the following connections:

compound 1: (+)N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethyl-3,5-dimethylpiperazine-1-yl)ndimethylacetamide;

compound 2: (+)N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)propionamide;

in the form of a base or an acid additive salt.

In d LINEITEM under the protective group Pg understand group which allows, on the one hand, to protect a reactive group such as hydroxy or amino group, at the time of receipt, and on the other hand, you can restore the reactive group of the whole at the receiving end. Examples of protective groups and methods of protection and removal of protection are given in "Protective Groups in Organic Synthesis", Green et al., 2nd Edition (John Wiley & Sons, Inc., New York).

Under the leaving group further understand the group, which can be easily derived from molecules in the gap heterolytic connection with the passing of the electron pair. Thus, this group can easily be replaced by another group, for example, during the substitution reaction. Such leaving groups are, for example, Halogens or an activated hydroxy-group such as methanesulfonate, benzoylphenyl, p-toluensulfonate, triflate, acetate, etc. Examples of leaving groups and references for them are given in "Advances in Organic Chemistry", J. March, 3d Edition, Wiley Interscience, 1985, p.310-316.

According to the invention to obtain compounds of General formula (I) in the following way.

Scheme 1

The compound of formula (I) in which R1 is different from H, and R2, R3, R4, R5, R6, R7, R8, R9 and n are such as defined in the General formula (I) can be obtained by reaction of compounds of formula (I) in which R1 denotes H, with a compound of formula (II):

R1-Hal (II)

in which a is Oh, R1, other than H, is defined as in General formula (I), and Hal means a halogen atom such as chlorine, by methods known to the expert, for example, in the presence of a base such as K2CO3, NaH, t-BuO-K+, in a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), dimethoxyethane, dimethyl sulfoxide (DMSO).

The compound of General formula (I) can be obtained by one of the following options.

The compound of General formula (I) in which R1 denotes H, can be obtained in the following way, based on the compounds of General formula (V):

and compounds of General formula (VII):

in which R2, R3, R4, R5, R6, R7, R8, R9 and n are such as defined in the General formula (I). This reaction is usually carried out using a halogenation agent, such as chlorination agent, for example, chlorides of phosphorus, in particular, PCl5or PCl3or POCl3. The reaction is usually carried out in the presence of pyridine or 4-dimethylaminopyridine, in a solvent such as dichloromethane or DMF.

The compound of General formula (I) in which R1, R5 and R6 denote H, can be obtained in the following manner, by the reaction of compounds of General formula (III):

with a compound of General formula (IV):

in which R2, R3, R4, R7, R8, R9 and n are such as defined, is Elena in the General formula (I), and Hal means a halogen atom, preferably chlorine. This reaction is usually carried out using a base, organic or inorganic, such as K2CO3, Na2CO3, pyridine or 4-dimethylaminopyridine, in the presence of NaI or KI, in an inert solvent, such as DMF, dichloromethane, THF, dimethoxyethane or toluene.

The compound of General formula (III) can be obtained from compounds of General formula (V):

and compounds of General formula (VI):

in which R2, R3, R4 are such as defined in the General formula (I), and Hal' and Hal", the same or different, independently denote a halogen atom, preferably chlorine.

This reaction is usually carried out using pyridine or 4-dimethylaminopyridine in a solvent such as toluene, benzene or dichloromethane, preferably at a temperature in the range from ambient temperature and the boiling point of the solvent.

Under ambient temperature see temperature, comprising from 5 to 25°C.

Intermediate compounds of General formula (V) are known and can be obtained by methods illustrated by the following scheme:

Scheme 2

in which R2, R3 and R4 are such as defined in the General formula (I), and Hal means a halogen atom, for example chlorine.

On etapes in scheme 2 to obtain compound of formula (V), on the basis of the compounds of formula (VIII) by ozonation gaseous ammonia, in accordance with the method described in the application FR 2714378.

The same compound can be obtained by reduction of compound of formula (X) according to methods known to the expert, for example, using zinc in a solvent such as methanol. Obtaining the compounds of formula (X) at this stage, as described in the application FR 2714378.

Optically pure compound of formula (V) can be obtained according to steps d and e in scheme 2, as described in the application WO 03/008407.

Intermediate compounds of General formula (VIII) can be obtained by the method described in the application WO 03/008407 and illustrated by scheme 3.

Scheme 3

in which R2, R3 and R4 are such as defined in the General formula (I), and Hal means a halogen atom, e.g. chlorine.

The compound of General formula (VII) can be obtained by the following methods shown in schemes 4 and 5.

Scheme 4

The compound of General formula (XIII) can be obtained by condensation of compounds of General formula (IV):

in which R7, R8, R9 and n are defined as in General formula (I), with a corresponding halogen compound, such as Hal”'CH2COOAlk, where Hal”' means a halogen atom such as chlorine, and Alk denotes an alkyl group such as ethyl.

This reaction Ave is doctitle is carried out in a solvent, such as toluene, benzene or dioxane.

Scheme 5

The compound of General formula (XIII) can be obtained by condensation of compounds of General formula (XIV):

in which R5, R6, R8, R9 and n are defined as in General formula (I) and Alk denotes an alkyl group, with the compound R7-Hal”', where Hal”' means a halogen atom, for example chlorine, and R7 are defined as in General formula (I). This reaction is preferably conducted in a solvent such as toluene, benzene, dioxane or DMF, in the presence of a base such as triethylamine or potassium carbonate.

According to another variant implementation of the compounds of General formula (I) in which R1 means an alkyl group, and R2, R3, R4, R5, R6, R7, R8, R9 and n are such as defined in the General formula (I) may also be obtained according to the following scheme 6.

Scheme 6

According to this scheme, the compound of formula (V) result in a reaction with a protecting group PG, obtaining the compound of formula (XV). As a protective group PG amine can be used, for example, Bensimon or tert-BUTYLCARBAMATE. These recent being the methods known to the expert, for example, in the presence of a base, such as K2CO3, NaOH, triethylamine, in a solvent such as dioxane, THF or DMSO.

The compound of General formula (XVI) can be obtained p the action of the compounds of formula (XV) with the compound ALK-Hal, where ALK means a saturated aliphatic group, a linear or branched, containing from 1 to 6 carbon atoms, and Hal means a halogen atom, for example chlorine.

The compound of General formula (XVII) are obtained on the basis of the compounds of formula (XVI), by removing the protective group according to well known methods, for example, in an acidic medium by the action of HCl or triperoxonane acid.

Then, the obtained compound of the formula (XVII) result in a reaction with a compound of General formula (VII):

in which R2, R3, R4, R5, R6, R7, R8, R9 and n are such as defined in the General formula (I). This reaction is usually carried out using a halogenation agent, such as a chlorination agent, such as the chlorides of phosphorus, in particular PCl5or PCl3or POCl3. The reaction is usually carried out in the presence of pyridine or 4-dimethylaminopyridine, in a solvent such as dichloromethane or DMF.

The compound of formula (I) is optionally converted into one of its acid additive salts.

The method according to the invention may optionally include the step of separating the desired product of General formula (I).

In schemes 1, 2, 3, 4, 5 and 6 of the initial compounds and the reagents, when the retrieval method is not described, can be purchased on sale or described in the literature or may be obtained by methods described in the literature or WPI is the local specialist.

The following examples describe the obtaining of some compounds according to the invention. These examples are not restrictive and only to illustrate the present invention.

Physico-chemical measurements were carried out as follows:

The melting temperature was measured on the device BUCHI B-540.

Proton nuclear magnetic resonance spectrum (1H-NMR) were removed using a frequency of 500 MHz on a Bruker instrument, equipped with a console Avance III. Chemical shifts are quoted in M. D. relative frequency TMS.

All spectra were recorded at 40°C.

Abbreviations used to characterize the signal as follows: s - singlet, Shir.with broad singlet, m = multiplet, Shir.m - broad multiplet, d - doublet, Shir.Dr. broad doublet, t - triplet, q - quadruple.

*- not integrated due to blending with a broad peak from water

**- not integrated due to overlap with the peak of solvent in NMR

***- based on first-order

****- the most common diastereoisomer

*****the least common diastereoisomer

Conditions of liquid chromatography in combination with mass spectrometry detection (LC/UV/MS) the following:

As for liquid chromatography:

column XTerra MS C18 3.5 µm

- chromatographic system

- eluent A - H2O+0.01% of TFA

- eluent B - CH3 CN.

- gradient from 98% A to 95% B over 10 minutes, then elution with 95% B for 5 minutes.

- flow rate 0.5 ml/min

- injection of 2 µl of a solution with a concentration of 0.1 mg/ml in a mixture of CH3CN:H2O = 9:1.

Products were detected by UV at 220 nm.

As for mass spectrometry:

- mode ionization: cationic electrospray (API-ES polarity+)

- scanning in the range from 100 to 1200 Amu

Thin layer chromatography (TLC) was performed on TLC plates of silica gel from Merck. Silica gel for column flash chromatography manufactured by a company Biotage.

All used solvents have a purity of "pure for analysis" or "clean for HPLC".

Dimension D alpha was conducted on a Perkin Elmer polarimeter model PE341 using a cell with optical path length of 1 inch

In the examples and get:

AcOH and AcOEt mean, respectively, acetic acid and ethyl acetate.

MeOH, EtOH, tBuOH mean, respectively, methanol, ethanol and tert-butanol.

THF means tetrahydrofuran

So pl. means melting point.

Getting 1

2-(4-ethylpiperazin-1-yl)propionic acid

(i) ethyl 2-(4-ethylpiperazin-1-yl)propionate

The flask 9.7 g of ethyl 2-piperazine-1-ylpropionic in 150 ml of DMF and 21.6 g of potassium carbonate. Added dropwise a solution of 3.9 ml of brometane. Leave the reaction mixture at 130°C for three hours, ka is bonat filtered and concentrated to dryness. Extracted with ethyl acetate. Filtered. The solid phase is removed, the liquid phase is evaporated in vacuum. Get the solid product crystallized with ethyl acetate. Filter and get 8,46 g is specified in the header of the product.

TLC: MeOH 100%, Rf=0,55.

(ii) 2-(4-ethylpiperazin-1-yl)propionic acid

8,45 g of the product obtained in the previous step, add 180 ml of 6 N. HCl and the reaction mixture is stored for 4 hours while boiling under reflux. Is evaporated to dryness, washed with a mixture of AcOEt/EtOH 1/1 and dried resulting solid product is white in color. Gain of 5.4 g of the expected product.

TLC: 100% MeOH, Rf=0,2.

Getting 2

(+)3-amino-4,6-dichloro-1,3-dihydro-3-(benzofuran-5-yl)indole-2-he

(i) 3-hydroxy-4,6-dichloro-1,3-dihydro-3-(benzofuran-5-yl)indole-2-he

In a flask equipped with a mechanical stirrer, a flow of nitrogen injected 2.25 g of magnesium for Grignard reagent in 15 ml anhydrous THF. Then add a mixture of 13.6 g of 5-bromobenzophenone in 35 ml of anhydrous THF. Continue to stir for one hour, then add a solution of 5 g of 4,6-dichloro-1H-indole-2,3-dione in 50 ml of anhydrous THF. Leave mixed at ambient temperature for four and a half hours. Add water and extracted with ethyl acetate. Allocate the organic phase, which is dried over Na2SO4, filtered and evaporated in vacuum. Extracted with ethyl acetate and washed with N. solution of soda. The organic phase is dried over Na2SO4, filtered and evaporated in vacuum. The solid phase is introduced into ethyl ether and filtered. Gain of 4.2 g of the expected product.

(ii) 3,4,6-trichloro-1,3-dihydro-3-(benzofuran-5-yl)indole-2-he

In a flask equipped with a magnetic stirrer, in a stream of nitrogen injected 4.1 g of the product from the previous step in 40 ml of dichloromethane. At 0°C add 1.7 ml of pyridine and the mixture of 1.4 ml SOCl2in 30 ml of dichloromethane. The reaction mixture is stored at ambient temperature, then poured into a saturated aqueous solution of NH4Cl. Allocate the organic phase, which is dried over Na2SO4, filtered and evaporated in vacuum.

TLC: hexane/AcOEt 7/3, Rf=0,65.

(iii) of 4,6-dichloro-[[(1S)-2-hydroxy-1-phenylethyl]amino]-1,3-dihydro-3-(benzofuran-5-yl)indole-2-it, isomer A and isomer B

In the stream of nitrogen is mixed with 4.1 g of compound of the previous step in 50 ml of dichloromethane and 3.1 g S-phenylglycinol. Leave the mixture overnight at ambient temperature. Formed solid phase was filtered, the filtration the solution is evaporated to dryness and purified on a column using as eluent hexane/AcOEt 8:2.

Obtained 0.64 g of the less polar product (isomer A, So pl.=135°C) and 1.23 g of the more polar isomer B.

(iv) (+)-3-amino-5,6-dichloro-1,3-dihydro-3-(4-dichlorophenyl)indole-2-he

Dissolve to 1.21 g of the product obtained in the previous step, in a mixture of 0 ml dichloromethane and 15 ml of methanol. Add 1.26 g of Pb(OAc)4and leave the reaction mixture at ambient temperature for 1 hour. Is evaporated to dryness and extracted with ethyl acetate, then washed with saturated aqueous NaHCO3. The organic phase is dried, filtered and concentrated. Remove mixture of 36 ml of 3 N. hydrochloric acid and 3.7 ml of methanol and allowed to mix overnight. Concentrate and dilute with a mixture of water and dichloromethane. The organic phase is washed with a solution of 1 N. hydrochloric acid. The aqueous phase combine, bring to a basic pH value of the aqueous solution of NH3and extracted with dichloromethane. The organic phase is dried, filtered and concentrated to obtain 870 mg of a white solid product.

So pl.: 215-216°C.

LC/MS: (M+H)+- m/z 333'ail; rt=5.3 min.

Example 1

(+)N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethyl-3,5-dimethylpiperazine-1-yl)ndimethylacetamide

(i) 2-chloro-N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]ndimethylacetamide

In a flask equipped with a magnetic stirrer, in a stream of nitrogen injected 0,43 g of the product obtained in the obtaining 2, 15 ml of toluene, of 0.11 ml of pyridine and 0.11 ml of chloroacetanilide. Leave the reaction mixture at 110°C for 4 hours, then poured into water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated in vacuum. Receive 500 mg of tverdokoraya beige purify by column method flash chromatography with a mixture of cyclohexane/ethyl acetate 8:2 to obtain 330 mg of the expected product.

TLC: hexane/AcOEt 1/1, Rf=0.5 in.

(ii) (+)N-[4,6-dichloro-3-(benzofuran-2-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(3,5-dimethyl-4-ethylpiperazin-1-yl)ndimethylacetamide

In a flask equipped with a magnetic stir bar, enter 0.31 g of the product of the previous stage, and 0.08 ml of 2,6-dimethyl-N-ethylpiperazine (d 0,899), 0.1 g of potassium carbonate, 0.05 g of sodium iodide in 5 ml of DMF. Leave the reaction mixture at 60°C for 4 hours, then poured in water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated in vacuum. Get listed in the header of the product.

So pl.=157-160°C; [αD]=+191°, c=0,946 wt.% in MeOH;

LC/MS: (M+H)+- m/z 515'ail; rt=4.9 minutes

Example 2

(+)N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)propionamide

1) In a stream of nitrogen in 12 ml of anhydrous dichloromethane, cooled in an ice bath, add 520 mg PCl5then slowly add 430 mg acid to obtain 1. The reaction mixture was stirred at 0°C for 10 minutes, then 3 hours at ambient temperature.

2) on the other hand, in a stream of nitrogen suspended 300 mg of the product get 2 in 12 ml of dichloromethane, then add 0.3 ml of pyridine. Cooled in an ice bath. Added dropwise a solution, polucheniya stage 1), and stirred at ambient temperature for one hour.

The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase is washed with a saturated solution of NaHCO3, dried over Na2SO4, filtered and evaporated in vacuum. Receive 500 mg of solid product of orange color, purified on a flash chromatography column, using as eluent a mixture of ethyl acetate/methanol 1:1, to obtain specified in the header of the product.

So pl.=137-138°C; [αD]=+217°, c=0,1064 wt.% in MeOH.

NMR: δ (M. D., DMSO-d6): 0,99 (m, 3H), of 1.08 (m, 3H), 2,24 at 2.45 (m, 6H), 2,47 of 2.68 (m**), 3,18-to 3.33 (m*), 6,92 (m, 1H), 7,01 (s, 1H), 7,19 (m, 1H), 7,21-7,28 (m, 1H), 7,50 (Shir.s, 1H), 7,65 (d, J=8,8 Hz, 1H), 8,02 (s, 1H), 8,61 (s, 0,4 H*****), 8,73 (s, 0,6 H****), at 10.64 (s, 0,6 H****), 10,71 (s, 0,4 H*****).

LC/MS: (M+H)+= m/z 501'ail; rt=4.9 minutes

Example 3

(+)N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethyl-3-methylpiperazin-1-yl)ndimethylacetamide

Act, as described for example 1, but using 2-methyl-N-ethylpiperazin instead of 2,6-dimethyl-N-ethylpiperazine receive specified in the header of the connection.

Compounds according to the invention had the object of studyin vivo.

Experiencein vivo

Male rats Crl CD BR (Charles River, Italy) weighing 150-175 g were in the chamber at controlled temperature (22±1°C), humidity (55±10%) and light / dark cycle of 12 h is in for at least 7 days before using them. Food and water were availablead libitum. Nutrition continued for 18 hours prior to sacrifice of the animals. Rats were killed by cervical dislocation, the stomach was removed surgically by cutting along the lowest curvature, and placed in Krebs solution (composition (mm): NaCl 118,4; KCl 4,7; CaCl22,5; NaH2PO43,7; MgSO41,2; NaHCO325; glucose of 5.6). The animal care and euthanasia were conducted according to the international code of ethics, Sanofi-Aventis and international principles governing the care and treatment of animals in the laboratory (E. E. C. Directive 86/609, DJL358, 1, December 12, 1987). Strips about 1 cm (width 5 mm) body of the stomach was cut along the longitudinal axis and suspended in 20 ml bath filled with Krebs solution at 37°C and blew the gas mixture of 95% O2+ 5% CO2. Strips supported under the residual load of 1 g and after washing choline (a precursor of acetylcholine) in the medium was added to 10 μm and 10 μm indomethacin (an inhibitor of prostaglandin synthetase) to reduce spontaneous phase reduction (Depoortere et al.,Eur. J. Pharmacol.515, 1-3, 160-168, 2003; Dass et al.Neurosciences120, 443-453, 2003). Isotonic contractions evoked by stimulation of the electric field. Two electrodes of platinum wire was placed at the surface and bottom of the tank device, and the electric field stimulation was implemented stimulator Power Lab, AD Instruments Pty Ltd. Castle Hill, ABC is the Australia), connected to the generator multiplex pulses (Ugo Basile, Varese, Italy) (Fukuda et al.,Scand. J. Gastroenterol.12, 1209-1214, 2004). Was applied supramaximal stimulation to create the maximum reduction (20 Hz, pulse width: 2ms; 5 volts; I/O sequence every 2 minutes, 150 mA). Then the current is reduced to obtain submaximal stimulation (50% reduction from the maximum sokrushitelny reaction). Reductions were recorded by a computer system for recording and analysis of data (Power Lab, Chart 5), which is connected with isotonic transduction (Ugo Basile, Varese, Italy) through a preamplifier (Octal Bridge Amp). After stabilization were drawn integral curves of the concentration-response ghrelin (0.1 nm - 1 μm), with and without incubation (contact time: 30 min) molecules antagonists. Supramaximal stimulation electric field was used for each strip as a reference (100%) to categorize the responses by the subject matter. The concentration of agonist that produces the effect of 50% of the maximum (EC50), was calculated using a mathematical model with four parameters, according Ratkovsky and Reedy (Biometrics, 42, 575-582, 1986), with adjustment by the method of nonlinear regression, using the algorithm of Levenberg-Marquard in the program Everstat. The pKB values for antagonists were calculated according to the equation of Cheng-Prusoff (Kenakin et al., Competitive Antagonism,Pharmacologie Analysis of Drug-Receptor Interaction3d editin, 331-373, Philadelphie, New York; Raven: Lippincott, 1997).

The compounds of formula (I) have antagonistic activity of the ghrelin receptor with CI50ranging from 5·10-8M to 1·10-9M.

For example, the compound of example 2 showed CI501,2·10-8M.

The compounds of formula (I) have shown interesting pharmacological properties for drug development, in particular pharmaceuticals for the prevention or treatment of any pathology involving the ghrelin receptor.

Thus, according to one other aspect of the object inventions are the drugs, which contain the compound of formula (I) or salt accession to this last pharmaceutically acceptable acid.

Thus, the compounds according to the invention can be administered to humans or animals for the treatment or prevention of various diseases that are dependent on ghrelin. Thus, the compounds according to the invention can be used as anorexically means for the regulation of appetite, food intake and frequency of food intake, and, in the long term for weight regulation, in particular, the weight gain that occurs after discontinuation of the diet or after a therapeutic regime. Thus, the compounds according to the invention is particularly useful for the prevention or treatment of obesity, destroy the TV appetite, diabetes, overweight and/or their consequences.

According to another of its aspects the present invention relates to pharmaceutical compositions containing as active ingredient the compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient.

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

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal introduction of the active substance of the formula (I) above or its salt can be administered in dosage form, mixed with classical pharmaceutical excipients, to animals and to humans for the prophylaxis or treatment of the above disorders or diseases.

The appropriate unit forms of introduction include forms for oral administration such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, forms for su the lingual, buccal, intratracheal, intraocular, intranasal, for administration by inhalation, forms, topical, percutaneous, subcutaneous, intramuscular or intravenous administration, the forms for rectal administration and implants. For topical introduction of the compounds according to the invention can be used in creams, gels, ointments or lotions.

For example, one single way of introduction, the compounds according to the invention in the form of tablets may contain the following components, mg:

The connection according to the invention50,0
Mannitol223,75
Crosscarmellose sodium6,0
Corn starch15,0

The hypromellose2,25
Magnesium stearate3,0

For oral administration the dose of the active substance, imposed for the day, can be from 0.1 to 100 mg/kg, in one or several stages. When administered parenterally, it can reach from 0.01 to 10 mg/kg per day.

Can be Sobieski, when you get higher or lower dosages; these dosages are not beyond the invention. According to usual practice, the dosage appropriate for each patient is determined by the doctor depending on the method of administration, the weight and response of the specified patient.

Possible combinations

The present invention also relates to combinations of one or more compounds according to the invention of General formula (I) with one or more active ingredients.

As the active ingredients that are suitable for these combinations, can be called, in particular, funds from obesity and diabetes, as well as rimonabant, Metformin, or a sulfonylurea.

The present invention according to another of its aspects, also relates to method of treating the above disorders, which includes an introduction to the patient an effective dose of the compounds according to the invention or one of its pharmaceutically acceptable salts.

The present invention according to another of its aspects, also relates to the compound of formula (I) or one of its pharmaceutically acceptable salts for the treatment of the above disorders.

1. The compound corresponding to the formula (I):

in which:
R1 means a hydrogen atom;
R2, R3, R4, equal or different, are located at any available position of the phenyl poison the well, independently mean a hydrogen atom and a halogen atom;
R5 and R6, identical or different, denote a hydrogen atom, (C1-6) alkyl group;
R7 means (C1-6) alkyl group;
R8 and R9, being in any of the available positions piperazinovogo kernel, mean a hydrogen atom or a (C1-6)alkyl group, with at least one of R8 and R9 is different from H;
n means 1;
in the form of a base or an acid additive salt.

2. Connection on p. 1, and in the General formula (I):
R1 means a hydrogen atom;
R2, R3, R4, equal or different, are located at any available position of the phenyl nucleus, independently mean a hydrogen atom or halogen atom, and at least one of R2, R3, R4 is different from H;
R5 and R6, identical or different, denote a hydrogen atom, (C1-6) alkyl group;
R7 means (C1-6) alkyl group;
R8 and R9, which are in positions 2 and 6 piperazinovogo kernel, mean a hydrogen atom or a (C1-6) alkyl group, with at least one of R8 and R9 is different from H;
n means 1;
in the form of a base or an acid additive salt.

3. Connection under item 1 or 2, and in the General formula (I):
R1 means a hydrogen atom;
R2, R3, R4, equal or different, are located at any available position of the phenyl nucleus, independently mean a hydrogen atom or halogen atom, with at IU is e one of R2, R3, R4 is different from H;
R5 and R6, identical or different, denote a hydrogen atom, (C1-6) alkyl group;
R7 denotes a methyl or ethyl group;
R8 and R9, being in positions 2 and 6 piperazinovogo kernel, mean a hydrogen atom or a methyl group, ethyl group, and at least one of R8 and R9 is different from H;
n means 1;
in the form of a base or an acid additive salt.

4. Connection under item 1 or 2, selected from the following compounds:
compound 1: (+)N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl) ndimethylacetamide;
compound 2:(+)N-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)propionamide;
in the form of a base or an acid additive salt.

5. The method of obtaining the compounds of formula (I) according to any one of paragraphs.1-4, includes the following steps:
the interaction of compounds of General formula (V):

in which R2, R3 and R4 are defined in any of paragraphs. 1-4, with the compound of General formula (VI):

in which l' and Hal", the same or different, independently denote a halogen atom;
then the interaction of the compounds of General formula (III)

with a compound of General formula (IV):

in which R2, R3, R4, R7, R8, R9 and n are such as defined in the General formula (I), and Hal is' means a halogen atom.

6. The method of obtaining the compounds of formula (I) according to any one of paragraphs.1-4, including the stage of interaction of the compounds of General formula (V):

in which R2, R3 and R4 are defined in any of paragraphs.1-4,
with a compound of General formula (VII):

in which R5, R6, R7, R8, R9 and n are defined in any of paragraphs.1-4.

7. A drug for the prophylaxis or treatment of obesity, diabetes, disorders of appetite and excess weight, characterized in that it contains a compound of the formula (I) according to any one of paragraphs.1-5 or salt attaching connections to a pharmaceutically acceptable acid.

8. Pharmaceutical composition for prevention or treatment of obesity, diabetes, disorders of appetite and excess weight, characterized in that it contains a compound of the formula (I) according to any one of paragraphs.1-4 or a pharmaceutically acceptable salt.

9. The use of compounds according to any one of paragraphs.1-4 for obtaining a medicinal product intended for the prevention or treatment of obesity, diabetes, disorders of appetite and excessive weight.

10. The compound according to any one of paragraphs.1-4 for the prevention or treatment of obesity, diabetes, disorders of appetite and excess weight.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention refers to pigment dispersion that can find application in electrophoretic displays. The dispersion contains α) a bis-(oxodihydroindolilene)benzodifuranone colouring agent of formula I wherein R1-R10 have values specified in cl.1, β) a special polymer dispersing agent containing modified poly(meth)acrylates, and γ) a solvent applicable for dispersions used in the electrophoretic displays. There are also described new colouring agents of bis-(oxodihydroindolilene)benzodifuranone compounds, dispersing agents and the electrophoretic display comprising these agents.

EFFECT: presented colouring agents have low conductivity and using them as black pigments in the electrophoretic displays enables reducing energy consumption as compared to using state-of-art carbon black.

11 cl, 1 dwg, 1 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to bis-benzimidazole derivatives of formula I and their optional stereoisomers, pharmaceutically acceptable salts and solvates, wherein R and R' are independently specified in -CR1R2R3, phenyl substituted by 1 substitute specified in halogen; and tetrahydrofuranyl, wherein R1 is specified in C1-4alkyl optionally substituted by methoxy, hydroxyl or dimethylamino; C3-6cycloalkyl; phenyl optionally substituted by 1, 2 or 3 substitutes optionally specified in halogen, C1-4alkoxy, trifluoromethoxy, or 2 substitutes on adjoining atoms of the ring form 1,3-dioxolane group; benzyl substituted by halogen or methoxy; pyridinyl; indolyl; pyridinylmethyl or indolylmethyl; R2 is specified in hydrogen, hydroxyl, di-C1-4alkylamino, (C3-6cycloalkyl) (C1-4alkyl)amino, C1-4alkylcarbonylamino, phenylamino, C1-4alkyloxycarbonylamino, (C1-4alkyloxycarbonyl)(C1-4alkyl)amino, C1-4alkylaminocarbonylamino, tetrahydro-2-oxo-1(2H)-pyrimidinyl, pyrrolidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, morpholin-1-yl, 7-azabicyclo[2.2.1]hept-7-yl and imidazol-1-yl; and R3 represents hydrogen or C1-4alkyl or CR2R3 together form carbonyl; or CR1R3 form cyclopropyl group. The invention also refers to a pharmaceutical composition based on a compound of formula I.

EFFECT: there are prepared bis-benzimidazole derivatives possessing the inhibitory activity on hepatitis C virus.

9 cl, 4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I

or to pharmaceutically acceptable salts or solvates or stereoisomers thereof, where R and R* are each independently -CR1R2R3, C1-4alkylamino, benzylamino, C6-10arylamino, heteroC4-7cycloalkyl containing 1 heteroatom selected from O; where R1 is selected from C1-4alkyl; phenyl, optionally substituted with 1, 2 or 3 substitutes independently selected from halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or 2 substitutes at neighbouring ring atoms, which form a 1,3-dixolane group; benzyl, optionally substituted with a halogen or methoxy; phenylsulphonylmethyl; C3-5heteroaryl containing 1 to 2 heteroatoms independently selected from N and O; C3-5heteroarylmethyl containing 1 to 2 heteroatoms selected from N and C3-6cycloalkyl; R2 is selected from hydrogen, hydroxyl, di-C1-4alkylamino, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, C1-4alkylaminocarbonylamino, piperidin-1-yl or imidazol-1-yl; R3 is hydrogen or, alternatively, R2 and R3 together form an oxo group; or R1 and R3 together form cyclopropyl; under the condition that if one of R and R* is -CH(C6H5)N(CH3)2, the other cannot be -CH(C6H5)NHC(=O)OCH3; and if R and R* are identical, R1 is not phenyl, when R2 is hydroxyl, acetylamino, methoxycarbonylamino or tert-butoxycarbonylamino, and R3 is hydrogen; and R1 is not C1-4alkyl, when R2 is C1-4alkyloxycarbonylamino, and R3 is hydrogen. The invention also relates to a pharmaceutical composition based a compound of formula I and use thereof.

EFFECT: obtaining novel compounds which are useful in preventing or treating HCV infection.

9 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new isatin-5-sulphonamide derivatives of general formula or their physiologically acceptable salts, wherein R represents phenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, tetrahydropyranyl, diazine or triazolyl methyl optionally substituted by one C1-6alkyl, which can be additionally substituted by one halogen; R' represents phenyl optionally substituted by one or two halogens, or triazolyl optionally substituted by one C1-6alkyl which can be additionally substituted by one halogen; provided R means phenyl, R' represents optionally substituted triazolyl, pharmaceutical compositions containing the above derivatives, using them as molecular imaging agents, using them in diagnosing or treating diseases or disorders related to apoptosis dysregulation, methods for synthesis of the above derivatives, methods for molecular imaging of caspase activity and apoptosis, and methods for assessing the therapeutic exposure of the analysed compound on caspase activity.

EFFECT: new isatin-5-sulphonamide derivatives are described.

27 cl, 26 dwg, 4 tbl, 11 ex

FIELD: medicine, pharmaceitics.

SUBSTANCE: invention relates to particular derivatives of N-(phenylsulphonyl)benzamide, given in i.1 of the invention formula. The invention also relates to a pharmaceutical composition, possessing an inhibiting activity with respect to anti-apoptotic proteins Bcl-2, containing an effective quantity of one of the said compounds or a therapeutically acceptable salt of such a compound.

EFFECT: N-(phenylsulphonyl)benzamide derivatives as inhibitors of the anti-apoptotic proteins Bcl-2.

2 cl, 2 tbl, 458 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new macrocyclic compounds of formula

or their tautomer, pharmaceutically acceptable salt, solvate or ester, wherein: X represents O or NR; Y represents -O-(CH2)mCOOR or -O-(CH2)mCON(R)2, wherein groups related to a nitrogen atom, can be in a Z- or E-configuration; R1 and R2 independently represent hydrogen or halogen; R3, R4, R5, R6, R7, R8, R9 and R10 independently represent hydrogen, alkyl, OR, -O(CH2)mC(O)(CH2)pN(R)2, -O(CH2)mN(R)C(O)(CH2)pOR, -(CH2)mN3 or -O(CH2)mN3; and each R independently represents R11, hydrogen, alkyl, alkylamino, dialkylamino, alkoxycarbonyl, phenyl or a protective group; or two R on the same nitrogen are taken together with nitrogen for producing a 5-6-merous heterocyclic or heteroaryl ring; wherein the group contains more than one substitute R; wherein R is optionally substituted, and each R can be identical or different, and wherein the protective group is specified in ethoxymethyl, methoxymethyl, tert-butyldimethylsilyl (TBS), phenylmethylsilyl, trimethylsilyl (TMS), 2-trimethylsilyl ethoxymethyl (SEM), 2-trimethylsilylethyl, benzyl and substituted benzyl; R11 represents a group

,

wherein Z represents an inorganic or organic counter-ion specified in a halogen, -O-alkyl, toluene sulphonate, methylsulphonate, sulphonate, phosphate, formiate or carboxylate; n represents 0, 1 or 2; m and p independently represent 0, 1 or 2; and dashed lines mean either a single, or a double bond, wherein the necessary conditions of the valence are observed by additional hydrogen atoms; and wherein in formula I′, when n represents 1, and X represents O, and the double bond is present between the carbon atoms having R9 and R10, then at least one of R5, R6, R7, R8, R9 or R10 are other than hydrogen; and wherein in formula I′, when n represents 1, and X represents O, and the bond between the carbon atoms having R9 and R10, represents the single bond, then at least one of R5, R6, R7 or R8 is other than hydrogen. The invention also refers to pharmaceutical compositions containing these compounds, using them and methods of treating diseases mediated by kinases and a heat-shock protein 90 HSP90.

EFFECT: preparing the new macrocyclic compounds.

28 cl, 5 dwg, 3 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new phenylamide or pyridylamide derivatives of formula

or their acceptable salts, wherein A1 is CR12 or N; A2 is CR13 or N; R1 and R2 are independently specified in hydrogen, C1-7-alkyl, halogen and C1-7-alkoxygroup; R12 and R13 are independently specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, amino group and C1-7-alkylsulphanyl; R3 is specified in hydrogen, C1-7-alkyl, halogen, C1-7-alkoxygroup, cyano group, C3-7-cycloalkyl, five-merous heteroaryl and phenyl; R4 is specified in methyl and ethyl; or R3 and R4 together represent -X-(CR14R15)n- and form a part of the ring, wherein X is specified in -CR16R17-, O, S, C=O; R14 and R15 are independently specified in hydrogen or C1-7-alkyl; R16 and R17 are independently specified in hydrogen, C1-7-alkoxycarbonyl, heterocyclyl substituted by two groups specified in a halogen, or R16 and R17 together with an atom C, which they are attached to, form =CH2 group; or X is specified in a group NR18; R14 and R15 are hydrogen; R18 is specified in hydrogen, C1-7-alkyl, halogen-C1-7-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-7-alkyl, heterocyclyl, heteroaryl-C1-7-alkyl, carboxyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylcarbonyloxy-C1-7-alkyl, phenyl, wherein phenyl is unsubstituted, phenylcarbonyl, wherein phenyl is substituted by C1-7-alkoxycarbonyl, and phenylsulphonyl, wherein phenyl is substituted by carboxyl-C1-7-alkyl, or R18 and R14 together represent -(CH2)3- and form a part of the ring, or R18 together with R14 and R15 represent -CH=CH-CH= and form a part of the ring; and n has the value of 1, 2 or 3; B1 represents N or CR19 and B2 represents N or CR20, provided no more than one of B1 and B2 represents N; and R19 and R20 are independently specified in a group consisting of hydrogen and halogen-C1-7-alkyl; R5 and R6 are independently specified in a group consisting of hydrogen, halogen and cyano group; and one-three, provided R4 represents methyl or ethyl, two of the residues R7, R8, R9, R10 and R11 are specified in C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxygroup, cyano group, C1-7-alkoxycarbonyl, hydroxy-C3-7-alkynyl, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C2-7-alkynyl, C1-7-alkoxycarbonyl-C1-7-alkylaminocarbonyl, carboxyl-C1-7-alkylaminocarbonyl-C1-7-alkyl, carboxyl-C1-7-alkyl-(C1-7-alkylamino)-carbonyl-C1-7-alkyl, phenyl-carbonyl, wherein phenyl is unsubstituted, phenyl-C1-7-alkyl, wherein phenyl is substituted by 1-2 groups specified in a halogen, C1-7-alkoxygroup, carboxyl, phenyl-C2-7-alkynyl, wherein phenyl is substituted by 2 groups specified in halogen, carboxyl or C1-7-alkoxycarbonyl, and pyrrolidine carbonyl-C1-7-alkyl, wherein pyrrolidinyl is substituted by carboxyl, and the other R7, R8, R9, R10 and R11 represent hydrogen; the term 'heteroaryl' means an aromatic 5-merous ring containing one or two atoms specified in nitrogen or oxygen; the term 'heterocyclyl' means a saturated 4-merous ring, which can contain one atom specified in nitrogen or oxygen. Besides, the invention refers to a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new compounds possessing the GPBAR1 agonist activity.

21 cl, 1 tbl, 190 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 and R2 have the following values: (i) R1 and R2 together form =O; (ii) R1 and R2 together with carbon atom, which they are bound with, form duoxacycloalkyl; R1 represents hydrogen or halogen; and R2 represents halogen; (iv) R1 represents C1-6alkyl, where alkyl is optionally substituted with cyano, -RxS(O)qRv or -RxNRyRz; and R2 represents hydrogen; (v) R1 represents -OR12 or -NR13R14; and R2 represents hydrogen, deutero or phenyl, which is optionally substituted with halogen; R3 represents hydrogen, halogen, C1-6alkyl, cyano, halogen C1-6alkyl, C3-10cycloalkyl or C1-6alkoxy; R4 and R5 represent hydrogen; R6 is independently selected from halogen, C1-6alkyl, halogenC1-6alkyl, -RxOR18 and -RxS(O)qRv; R7 independently represents halogen or -RxORw; R12 is selected from hydrogen and C1-6alkyl, R13 represents hydrogen; R14 is selected from hydrogen, C3-10cycloalkyl, -C(O)Rv and -C(O)ORw; R18 represents hydrogen, C1-6alkyl, or pyperidinyl, where R18 is optionally substituted with 1-3 Q1 groups, each Q1 is independenly selected from hydroxyl, C1-6alkoxy, C1-6alkoxycarbonyl, carboxyl and morpholinyl; Rx independently represents C1-6alkylene or simple bond; Rv and Rw represent hydrogen or C1-6alkyl; Ry and Rz represent hydrogen; n has value 0-4; p has value 0-5; and each q independently has value 0, 1 or 2. Invention also relates to compounds of formula (II) , where substituents have values, given in the invention formula, to pharmaceutical composition, possessing inhibiting activity with respect to JAK kinases, containing compounds of formula (I) or (II), methods of treating JAK-modulated disease, and application of compounds of formula (I) or (II).

EFFECT: compounds of formula (I) or (II) as inhibitors of JAK kinases.

32 cl, 6 dwg, 2 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a composition containing copepods fat, and to using this composition for reducing a visceral fat storage. The composition of copepods fat contains wax esters 20-100 wt %, preferentially wax esters 40-85 wt %. The above wax esters consist of monoesters, preferentially mono- or polyunsaturated C16-C22 fatty acids and preferentially monounsaturated C16-C22 fatty alcohols. What is also presented is a preparation containing the above composition.

EFFECT: invention enables preparing the composition used as a drug for preventing or treating abdominal obesity and diabetes mellitus type 2.

22 cl, 3 dwg, 3 tbl

FIELD: veterinary medicine.

SUBSTANCE: preparation for normalisation of lipid peroxidation processes in animals comprises, wt %: 2-ethyl-6-methyl-3-hydroxypyridine succinate 20.0-30.0, ascorbic acid 5.0-7.0, selenium (Se°) 0.3-0.5, polyvinylpyrrolidone 3.0-5.0, water for injection - the rest.

EFFECT: antioxidant effect, prevention of excessive formation of lipid peroxidation products, high efficiency in normalisation of functioning of the system of antioxidant protection of animals and the process of lipid peroxidation, low toxicity and ease of administration.

6 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrazolopyridine derivatives of formula (I) , a based pharmaceutical composition, and using them for treating and/or preventing disorders or conditions related to nictonamide adenine dinucleotide phosphatoxidase (NADPH-oxidase), as well as to a method for preparing them and an intermediate of formula (VIII) . In general formula (I), G1 is specified in H; and optionally substituted heteroaryl-C1-C6-alkyl; G2 is specified in H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-heterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G3 is specified in H; optionally substituted amino; optionally substituted aminoalkyl; optionally substituted aminocarbonyl; optionally substituted alkoxy, optionally substituted alkoxy-C1-C6-alkyl; optionally substituted carbonyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted C1-C6-alkylaryl: optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-hterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G4 is specified in -NR2-C(O)-R1 and -(CHR3)m-(CH2)n-R4, G5 represents H.

EFFECT: preparing the pharmaceutical composition for treating and/or preventing the disorders and conditions related to nictonamide adenine dinucleotide phosphatoxidase.

16 cl, 3 tbl, 87 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical industry, particularly to compositions for treating and/or preventing obesity. The composition contains the peptide compound Pro-Val-Asn-Phe-Lys-Phe-Leu-Ser-His in water containing a salt solution in the physiologically acceptable concentration. A therapeutic agent containing the above composition can be presented in the form of spray/drops applicable for nasal, subglossal or oral administration. A dosage form of the nasal or subglossal spray/drops, as well as oral film provides ease of administration and makes it applicable by the patient in need of treating and/or preventing obesity.

EFFECT: compositions and agents are effective for treating obesity.

45 cl, 4 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent containing activated-potentiated forms of anti-histamine, anti-tumour necrosis factor alpha (anti-TNF - α) and anti-S-100 brain specific antibodies is administered.

EFFECT: treating functional bowel disorders by ensuring the spasmolytic action and normalising the motor-evacuation function of the intestine.

11 cl, 4 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to pyrazolopyridine derivatives of formula (I), a pharmaceutical composition based thereon, use for treating and/or preventing disorders or conditions associated with nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and an intermediate of formula (VIII). In general formula (I) G1 denotes H; G2 is selected from H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted phenyl; optionally substituted C1-C6-alkylaryl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted-C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G3 is selected from -(CH2)n-R1 and -(CH2)p-R5; G4 is selected from H; optionally substituted acyl; optionally substituted acylamino; optionally substituted acyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkynyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkylheterocycloalkyl and optionally substituted heterocycloalkyl-C1-C6-alkyl; G5 dentes H.

EFFECT: high effectiveness of compounds.

15 cl, 2 tbl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I: cis-COOR-XCH-(CH2)a-CH=CH-(CH2)b-CH3, wherein (a) and (b) can take any value from 0 to 14, (X) is specified in: OH, NH2, CH3, F, F3C, HS, O-CH3, PO4(CH2-CH3)2 and CH3COO, and (R) represents sodium (Na) applicable for preventing and/or treating obesity, hypertension and/or cancer. Also, the invention refers to using the compounds of formula I for preparing a pharmaceutical and/or nutrient composition, to the pharmaceutical and/or nutrient composition based on the compounds of formula I, to a cosmetic, non-therapeutic method for improving skin manifestations and to a method for preventing and/or treating the diseases in humans and animals with using the compounds of formula I.

EFFECT: preparing the new compounds.

18 cl, 22 dwg, 5 tbl, 9 ex

FIELD: veterinary medicine.

SUBSTANCE: method of growing quails consists in that the sodium hypochlorite solution obtained in electrochemical method, diluted with distilled water to a concentration of 100-200 mg/l, is used for free watering quails from the first days to 42 days old birds once in 7 days during a day.

EFFECT: invention enables to improve the performance of quail meat productivity, livestock safety, while simultaneous reducing the cost of feed for poultry live weight gain.

6 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: waist circumference (WC), height and weight are measured to calculate a body weight index (BWI), to determine glucose and lipids. The WC more than 80 cm requires prescribing a moderately hypocaloric diet that implies limiting an energy value of food ration by 500-600 kkal a day with the daily food ration composed taking into account as follows: total fat consumption less than 30% of total energy consumption; carbohydrates - up to 50%; protein content in the food ration - 15-20%; dietary fibre - 20-30 mg; fresh fruit and vegetables - 400-500 g; nuts, cereals, beans - 30 g; table salt - less than 5 g; 1000 mg of calcium a day for females taking hormonal contraception or replacement hormonal therapy (RHT), and 1500-2000 mg in females taking no hormonal contraception or RHT, vitamin D - 800 IU, polysaturated fatty acids 0.5-1.0 g, folic acid - 400 mcg, vitamin C - 60 mcg, vitamin E - 30 Units; physical exercises - not less than 40 min a day and not less than 5 times a week; alternating aerobic and anaerobic exercises. If BWI falls within the range of 25 to 29.9 kg/m2, a normal glucose and lipid level, combined oral contraceptives (COC) with natural oeastrogen and dienogest, or the COC with drosperinone are taken. The BWI within the range of 30 kg/m2 and more, the normal glucose and lipid level, pure progestin oral contraceptives (PPOC) are administered. If the BWI exceeds 25 kg/m2, and fasting hyperglycemia, impaired glucose tolerance (IGT) and/or dyslipidemia are observed, pure progestin oral contraceptives (PPOC) are administered. If a postmenopausal female has the BWI less than 30 kg/m2 and suffers climacteric syndrome, a combined replacement hormonal therapy (RHT) containing drospirenone is prescribed. The BWI more than 30 kg/m2 requires administering meldonium into postmenopausal females.

EFFECT: method enables individual prevention of oestrogen-dependent diseases.

6 cl, 14 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an immunomodulatory composition for injection into a mammal. The immunomodulatory composition for injection into a mammal containing a hydrolysate prepared by acid and/or enzymatic hydrolysis of one or more bioresources specified in a group consisting of bivalve molluscs, annelids, leeches, and water taken in certain proportions. A method for preparing the immunomodulatory composition for injection into a mammal. A method of treating a pathological condition in a mammal in need thereof involving the injections of the immunomodulatory composition into the above mammal. Using the composition for normalising metabolism into the mammal in need thereof.

EFFECT: composition enables extending the range of products with immunomodulatory activity for injections.

19 cl, 7 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: present invention refers to compounds having formula III such as below, wherein: Q represents C(Y3) or N; R represents H, -R1, -R1-R2-R3, -R1-R3 or -R2-R3; R1 represents heteroaryl or heterocyclyl each of which is optionally substituted by one or more C1-6alkyls, hydroxyC1-6alkyls, oxogroups or halogenC1-6alkyls; R2 represents -C(=O), -O, -C(R2')2, -C(R2')2C(=O), -C(R2')2C(=O)NR2', C(R2')2 N(R2')C(=O), -C(=NH), -C(R2')2NR2' or -S(=O)2; each R2' independently represents H or C1-6alkyl; R3 represents H or R4; R4 represents C1-6alkyl, C1-6alkoxygroup, aminogroup, C1-6alkylaminogroup, di(C1-6alkyl)aminogroup, heterocyclyl, C1-10alkylheterocycloalkyl, heterocycloalkylC1-10alkyl each of which is optionally substituted by one or more C1-6alkyls, C1-6alkylaminogroups, di(C1-6alkyl)aminogroups, hydroxygroups, hydroxyC1-6alkyls, C1-6alkoxygroups, oxogroups or halogenC1-6alkyls; X represents CH; X' represents CH; and the rest symbols have values as specified in the patent claim. The compounds of formula III inhibit Bruton's tyrosine kinase (Btk). There are also described compositions containing the compounds of formula III, and at least one carrier, thinner or excipient, and a method for producing the compound of formula X in accordance with the following procedure.

EFFECT: compositions are effective for modulating Btk activity and treating diseases related to Btk hyperactivity, and can be used for treating inflammatory and autoimmune diseases related to disturbed B-cell proliferation, such as rheumatoid arthritis.

22 cl, 2 tbl, 260 ex

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