3-benzofuranylindol-2-one derivatives substituted in position 3, preparing and using them in therapy

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 3-benzofuranylindol-2-one derivatives substituted in position 3 of formula wherein: R1 means a hydrogen atom; R2, R3, R4 equal or different, found in any accessible position of the phenyl ring, means independently a hydrogen atom or a halogen atom; R5 means (C1-6) alkyl group; n means 1; in the form of the base or acid-additive salt, as well as to a therapeutic agent and a pharmaceutical composition based on the above compounds possessing the ghrelin receptor antagonist activity, and to using this compounds for preparing the therapeutic agent for preventing or treating obesity, diabetes, appetite disorders and overweight.

EFFECT: preparing the therapeutic agent used for preventing or treating obesity, diabetes, appetite disorders and overweight.

8 cl, 1 ex

 

The object of the present invention are derivatives of 3-benzofuranyl-2-it is substituted in the 3 position, their preparation and use in therapy.

Ghrelin is a peptide hormone composed of 28 amino acids, produced mainly in the stomach the result of post-translational process after splitting prograin (Kojima, M. et al.,Nature1999; 402:656-60). Ghrelin is an endogenous ligand pituitary receptor secrets of human growth hormone (GHSR1a).

GHS-R is encoded by two exons: exon 1 encodes the transmembrane region (TM) 1-5, and exon 2 encodes TM 6 and 7 receptor associated with protein G (GPCR).

Both transcripts have been identified in the pituitary gland and in the brain: one encoding GPCR full length (GHS-R1a), and the other encoding the truncated receptor (GHS-R1b), which lacks TM 6 and 7. Only the subtype of GHS-R1a 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 No. 9).

This receptor type protein with seven transmembrane domains of family And associated with the Gq/phospholipase. In some tissues the ghrelin receptor may also be associated with channels Gs/protein kinase A (N. Ueno et al.,Endocrinology, 2004, 145, 4176-4184; Kim, M. S. et al.,Int. J. Obes. Relat. Metab. Disord., 2004, 28:1264-1271). In an interesting way, the ghrelin receptor on lady unusual property to be the main activity, independent of ligand(R. Barazzoni et al.,Am. J. Phisiol.Endocrinol. Metab., 2004, 288:E228-E235).

Low levels of expression of ghrelin have been documented in different tissues, such as intestine, pojedudocna gland, kidneys, immune system, placenta, testicles, Hipotecaria tissue, hypothalamus (Horm. Res.,2003; 59 (3):109-17).

It has been shown that ghrelin is involved in hunger at mealtimes and in the initiation of meals. Circulating levels decrease in food intake and increase before meals, reaching concentrations sufficient to stimulate hunger and food intake. Techniques ghrelin inside stimulate food intake quickly and transient way, mainly by increasing the desire of meals and number of meals. Ghrelin stimulates food intake in a short time more effectively than any other molecule, with the exception of neuropeptide Y, in comparison with which it has approximately the same efficiency (Wren, A. M., et al.,J.Clin. Endocrinol. Metab.,2001; 86:5992-5). However, ghrelin is unique in its ability to exert this effect regardless of whether he entered perifericheskie or centrally.

It is also the only substance of a mammal, which proves its ability to increase appetite and food intake when administered to humans (Druce, M. R., et al., Int. J. Obes., 2005; 29:1130-6; Wynne K. et al., J. Am. Soc. Nephrol.,2005; 16:2111-8).

In addition to its role in the initiation of food intake, ghrelin also satisfies the established criteria hormone associated with obesity, involved in long-term regulation of body weight. Content ghrelin vary depending on energy costs and demonstrate compensatory changes in response to changes in body mass.

Ghrelin crosses the blood-brain barrier and stimulates food intake, acting on some classic centers governing body weight, such as the hypothalamus, the posterior brain and compensatory mesolimbic system.

Continuous infusions of ghrelin increases the body weight due to various pre-determined effects on food intake, energy expenditure and use of resources. Congenital deletion of ghrelin, or a gene of the ghrelin receptor, causes resistance to obesity induced by diet, and pharmacological blocking ghrelin reduces food intake and body weight.

Existing evidence seems to promote the role of ghrelin at the same time in the short-term initiation of meals and long-term energy homeostasis, making it an attractive target as a drug for the treatment of obesity and/or disorders associated with emaciation.

Similarly, ghrelin although the NGO has psychological and pharmacological effects on the endocrine pancreas. Acylated bioactive 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 a local source of ghrelin, which acts on the β-cells of islets. Blocking the function of endogenous ghrelin by antagonist for receptor dramatically reduces concentration of glucose in the fasting reduces the glycemic movement and increases the response to insulin during test glucose tolerance, suggesting inhibitory role of ghrelin in the control of insulin secretion (K. Dezaki et al., 2004,Diabetes, 53:3142-3151).

Deletion of ghrelin in mice (mouse ghrelin -/-) increases insulin secretion glucose β-pancreatic cells by reducing the expression of Ucp2 and improves the sensitivity of peripheral insulin (Sun Y. et al., 2006,CellMetabolism, 3:379-386).

Antagonists of the receptor for ghrelin could thus regulate hunger, food intake and their frequency, as well as, in the long term, weight, in particular weight gain resulting from a diet and therapeutic regimes. In addition, in the framework of anti-diabetic treatment, ghrelin antagonists could be used to maintain the balance between insulin and glucose and to control diabetic hyperphagia. antagonist ghrelin could also be used as anorexically funds and/or funds to combat obesity, 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 denotes a hydrogen atom or a group (C1-6)alkyl, -C(=O)(C1-6)alkyl, -C(=O)aryl;

R2, R3, R4, equal or different from any of the available positions of the phenyl ring, independently represent a hydrogen atom, a halogen atom, CN, OH, (C1-6)alkyl, optionally substituted by a halogen atom or by a group of IT; peralagan(C1-3)alkyl, (C1-6)alkoxy, peralagan(C1-3) alkoxy, aminocarbonyl, (C1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aryl, aryloxy; heteroaryl; aryl, alloctype or heteroaryl optionally can be substituted by a halogen atom, CN, OH or (C1-6)alkyl, peralagan(C1-3)alkyl or (C1-6)alkoxygroup; of course, at least one of the groups R2, R3 and R4 is different from H, and that aryl, aryloxy or heteroaryl group optionally may be substituted by a halogen atom, CN, OH or (C1-6)alkyl, peralagan(C1-3)alkyl or (C1-6)alkoxygroup;

R5 denotes (C1-6)alkyl or (C2-6)alkenylphenol group, and

n denotes 1 or 2.

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

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

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

In the framework of the present invention include:

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

is an alkyl group: a saturated, linear or branched, aliphatic group; as examples (C1-6)alkyl group containing from 1 to 6 carbon atoms, in particular (C1-4)alkyl group, which may be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl;

- Alchemilla group: mono - or polyunsaturated, linear or branched, aliphatic group comprising, for example, one or two unsaturated groups containing 2-6 carbon atoms;

- halogenation group: an alkyl group, one or more hydrogen atoms were substituted by a halogen atom; for example, foralkyl: an alkyl group, one or more hydrogen atoms of which have been replaced by fluorine atom;

- perhalogenated group: an alkyl group, su the hydrogen atoms were substituted by a halogen atom; for example, perfluoroalkyl - alkyl group, all of the hydrogen atoms of which have been replaced by fluorine atom;

- alkoxygroup: radical-O-alkyl in which the alkyl group is as defined above;

- perhalogenated: radical-O-perhalogenated in which perhalogenated group is the same as defined above, as examples, cryptometer;

- aryl group: a cyclic aromatic group containing from 6 to 10 carbon atoms; and as examples of aryl groups can be called phenyl or naftalina group;

- heteroaryl group: a cyclic aromatic group containing from 2 to 10 carbon atoms and containing from 1 to 3 heteroatoms, such as nitrogen, oxygen or sulfur; as examples of heteroaryl groups include the following groups: furanyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, oxadiazolyl, oxazolyl, isoxazolyl, furutani, thiadiazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, as well as the corresponding groups formed as a result of the merger with phenyl group, such as, for example, benzothiophene, benzofuranyl, benzothiazoline group and so on

Among the compounds of formula (I) which are subjects of the invention, the connection group formed by the compounds for which:

R1 denotes at which m is hydrogen or a group (C1-6)alkyl, -C(=O)(C1-6)alkyl, -C(=O)aryl;

R2, R3, R4, equal or different from any of the available positions of the phenyl ring, independently represent 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, this implies that at least one of the groups R2, R3, R4 is different from H;

R5 denotes (C1-6)alkyl group;

n denotes 1 or 2;

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

Among the compounds of formula (I) which are subjects of the invention, the connection group formed by the compounds for which:

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

R2, R3, R4, equal or different from any of the available positions of the phenyl ring, independently represent a hydrogen atom, a halogen atom, in particular chlorine or bromine, or a group (C1-6)alkyl or trifluoromethyl, this implies that at least one of the groups R2, R3, R4 other than H; and/or

R5 denotes (C1-6)alkyl group; and/or

n denotes 1 or 2;

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

Among the compounds of formula (I) which are subjects of the invention, another group of compounds is formed by compounds for which:

R1 denotes and what Ohm hydrogen or a group-C(=O)methyl, -C(=O)phenyl, methyl; and/or

R2, R3, R4, equal or different from any of the available positions of the phenyl ring, independently represent a hydrogen atom, a halogen atom, in particular chlorine or bromine, or a methyl or triptorelin group, this implies that at least one of the groups R2, R3, R4 other than H; and/or

R5 denotes methyl, ethyl or 2-propyl; and/or

n denotes 1 or 2;

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

Among the compounds of formula (I), which are the objects of the invention can, in particular, to call the following connection:

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

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

In what follows, under the protective group Pg mean a group that allows, on the one hand, to protect a reactive functional group such as hydroxyl group or amino group, during a synthesis and, on the other hand, to regenerate the intact reactive group at the end of the synthesis. Examples of protective groups, and how to protect and unprotect is given inProtective Groups in Organic Synthesis,Green et al., 2ndEdition (John Wiley & Sons, Inc., New York).

Under the deleted group, in what follows, we mean a group that can be easily derived from molecules in which the result of the heterolytic rupture due to transition of electron pairs. Thus, this group can be easily replaced by another group during the substitution reaction, for example. Such groups are removed, for example, Halogens or an activated hydroxyl group such as methanesulfonate, benzolsulfonate, p-toluensulfonate, triflate, acetate, etc. Examples tseplyaesh groups, as well as links on their receipt, are given inAdvances in Organic Chemistry,J. March, 3ndEdition, Wiley Interscience, p.310-316.

According to the invention compounds of General formula (I) can be obtained by the method, as below:

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

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

The compound of General formula (I) in which R1=H, can be obtained according to one or other of the following options.

The reaction of the texts of General formula (III):

with a compound of General formula (IV):

in which R2, R3, R4, R5 and n are as defined in General formula (I), and Hal"denotes 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 and R4 are as defined in General formula (I), and Hal'and Hal"identical or different, represent independently 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 room temperature to the boiling temperature of the solvent.

Under room temperature mean temperature being in the range from 5 to 25°C.

The compound of General formula (I) in which R1=H, can also be is Holocene proceeding from compounds of General formula (V):

and compounds of General formula (VII):

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

Intermediate compounds of General formula (V) are known and can be obtained according to the processes represented in the following diagram:

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

On stage circuit 2 receives the connection of the formula (V) from compounds of formula (VIII) by bubbling gaseous ammonia according to the method described in the application FR 2714378.

The same connection can also be obtained by reduction of compound of formula (X) according to methods known to experts in this field, for example, by means of zinc in a solvent such as methanol. The phasic obtaining the compounds of formula (X) described in the application FR 2714378.

Optically pure compound of formula (V) may be synthesized according to stages d and the circuit 2, such as described in the application WO 03/008407.

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

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

The compound of General formula (VII) can be obtained according to the following method, illustrated in scheme 4:

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

in which R5 and n are defined as in General formula (I), with the corresponding halogenated compound, such as Hal"'CH2COOAlk, where Hal"' denotes a halogen atom such as chlorine, and Alk denotes an alkyl group such as ethyl.

Preferably this reaction is carried out in a solvent such as toluene or benzene or dioxane.

According to another variant implementation of the compounds of General formula (I) in which R1 denotes an alkyl group, R2, R3, R4, R5 and n are as defined in General formula (I) can be also obtained according to the following scheme 5:

According to this scheme, the compound of formula (V) enter into reaction with a protecting group PG from obtaining the soybean is inane formula (XIV). As a protective group of the amine can be used, for example, Bensimon ortertBUTYLCARBAMATE. These last administered according to methods known to experts in this field, for example, in the presence of base, such as K2CO3, NaOH, triethylamine, in a solvent such as dioxane, THF or DMSO.

The compound of General formula (XV) can be obtained by reaction of compounds of formula (XIV) with the compound ALK-Hal in which ALK is a saturated aliphatic group, a linear or branched, containing from 1 to 6 carbon atoms, and Hal represents a halogen atom, for example chlorine.

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

Then the obtained product is introduced into reaction with the compound of General formula (VII):

in which R5 and n are as defined in General formula (I). This reaction is usually carried out using a halogenation agent such as gloriously 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.

Optionally, connect the exclusion of the General formula (I) is transformed into one of its acid additive salts.

The method according to the invention may optionally contain a stage consisting in the allocation of the desired product of General formula (I).

In schemes 1, 2, 3, 4 and 5 of the initial compounds and the reagents, when the retrieval method is not described, are available in the trade or described in the literature, or can be obtained according to the methods described in the literature or which are known to experts in this field.

According to another aspect of the object inventions are the compounds of formula (III). These compounds are used as intermediates for the synthesis of compounds of formula (I).

According to another aspect of the object inventions are the compounds of formula (XVI). These compounds are used as intermediates for the synthesis of compounds of formula (I).

The following examples describe the obtaining of some compounds according to the invention. The examples are not limiting and is provided only to illustrate the present invention.

Physico-chemical measurements were carried out as follows: the melting point was measured on the device BUCHI B-540.

Proton nuclear magnetic resonance spectrum (1H NMR) were recorded at a frequency of 500 MHz on a Bruker instrument, equipped with a remote control Avance III. Chemical shifts are given in memorial plaques in relation to the frequency TMS (TMS).

All JV is CTRY were recorded at 40°C.

Abbreviations used to describe signals, the following: s - singlet, with ush - broad singlet, m = multiplet, m ush - broad multiplet, d - doublet, D. ush - broad doublet, t - triplet, q - quadruple.

* = non-integrable due to overlapping with a broad peak belonging to the water.

** = non-integrable due to overlapping with the peak belonging to the NMR solvent.

*** = readable in the first place.

**** = the most abundant diastereoisomer.

***** = the least abundant diastereoisomer.

Conditions of the analysis by gas chromatography-mass spectrometry (LC/UV/MS) (LC/UV/MS) following.

For part liquid chromatography

Method And

Column Kromasil C18 3.5 µm

- Eluent A = N2About+0.01% of TFA

- Eluent = CH3CN.

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

- Flow rate 0.3 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 In

Column Xterra MS C18×50 3.5 µm

- Eluent A = N2About+0.01% of TFA

- 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

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

Products were detected in the UV region at 220 nm.

For mass spectrometric part

The method of ionization: positive the initial electrospray (API-ES polarité +)

- Scan from 100 to 1200.E. m. (uma)

Thin-layer chromatography TLC (SMS) was performed on plates with silica gel Merck. The silica gel column flash chromatography comes to the sale of the company Biotage.

All used solvents were trained "chemically pure" or "chromatographic clean.

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

In the examples of syntheses:

AcOH and AcOEt denote, respectively, acetic acid and ethyl acetate;

MeOH, EtOH, tBuOH denote, respectively, methanol, ethanol andtert-butanol;

THF (THF means tetrahydrofuran;

TPL(Pf) denotes the melting temperature.

Synthesis 1:(4-ethylpiperazin-1-yl)acetic acid

(i) ethyl(4-ethylpiperazin-yl)acetate

Into the flask was loaded 8,9 ml ethylpiperazine in 91,5 ml of toluene. Was added dropwise a solution of 4.1 ml of ethylbromoacetate in 11.6 ml of toluene. Left to react while boiling under reflux at 110°C for one hour, concentrated to small volume and left in the refrigerator for 3 hours. Formed white precipitate, which was filtered and washed with dichloromethane. Evaporated water filtration; received 7 g of the desired product.

TLC: AcOEt 1/MeOH 1, Rf=0.45 and

(ii) (4-ethylpiperazin-1-yl)acetic acid

obavljale 7 g of the product, obtained in the previous phase to 190 ml of 6 N. HCl and left to react by boiling under reflux for 4 hours. Evaporated to dryness, washed with a mixture of AcOEt 1/EtOH 1 and obtained was dried white substance. Received 7 g of the desired product.

TLC: 100% Meon, Rf=0,2

Synthesis of 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, in a stream of nitrogen was loaded 2.25 g of magnesium for Grignard reaction in 15 ml anhydrous THF. Then was added a mixture of 13.6 g of 5-bromobenzophenone in 35 ml of anhydrous THF. Left under stirring for one hour, then was added a solution of 5 g of 4,6-dichloro-1H-indole-2,3-dione in 50 ml of anhydrous THF. It was allowed to mix at room temperature for four and a half hours. Was added water and was extracted with ethyl acetate. Separated the organic phase, which was dried over Na2SO4, filtered and evaporated in vacuum. The product was extracted with ethyl acetate and washed with 1 N. a solution of sodium hydroxide. The organic phase was dried over Na2SO4, filtered and evaporated in vacuum. The solid was extracted simple with ethyl ether and filtered. Received of 4.2 g of the desired product.

TLC: Hexane/EtOAc 6:4, Rf=0,35

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

At stake is, equipped with a magnetic stirrer, in a stream of nitrogen was downloaded 4.1 g of the product obtained in the previous phase, in 40 ml of dichloromethane. At 0°C was added 1.7 ml of pyridine and the mixture of 1.4 ml SOCl2in 30 ml of dichloromethane. Was left to react at room temperature, then was poured into a saturated aqueous solution of NH4Cl. Separated the organic phase, which was dried over Na2SO4,was filtered and evaporated in vacuum.

TLC: Hexane 7/EtOEt 3, Rf=0,65

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

In a stream of nitrogen was mixed with 4.1 g of compound obtained in the preceding stage in 50 ml of dichloromethane and 3.1 g S-phenylglycinol. Was left to react overnight at room temperature. Was filtered, the resulting solid substance, water filtration evaporated to dryness and purified on a column with eluent hexane/AcOEt 8:2.

Was obtained 0.64 g of the less polar product, isomer A (TPL= 135°C), and 1.23 g of the more polar isomer.

(iiii) (+)3-amino-5,6-dichloro-1,3-dihydro-3-(4-chlorophenyl)indol-2-he

The reaction was introduced to 1.21 g of the product obtained in the previous stage, in a mixture of 20 ml of dichloromethane and 15 ml of methanol. Added 1.26 g of Pb(OAc)4and left to react at room temperature for 1 hour. Evaporated to dryness and extracted the product with ethyl acetate, then washed with saturated the aqueous solution of NaHCO 3. The organic phase was dried, filtered and concentrated. Extracted with a mixture of 36 ml of 3 N. hydrochloric acid and 3.7 ml of methanol and left under stirring overnight. Concentrated and diluted with a mixture of water and dichloromethane. The organic phase is washed with a solution of 1 N. hydrochloric acid. The aqueous phase was combined, brought to alkaline pH aqueous solution of NH3and was extracted with dichloromethane. The organic phase was dried, filtered and concentrated to obtain 870 mg of a white solid product.

TPL=215-216°C

LC/MS: (M+N)+= m/z 333 and.E. m.; tbeats=5.3 minutes.

Example 1

(+)N-[4,6-Dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)ndimethylacetamide and its oxalate

Method a:

(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 was loaded 0.87 g of the product obtained in synthesis 2, 30 ml of toluene, of 0.21 ml of pyridine and 0.21 ml of chloroacetanilide. Was left to react at 110°C for 4 hours, then poured the reaction mixture into water and was extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and evaporated in vacuum. Received 900 mg of beige solid that was purified on a column using flash chromatographyusing a mixture of cyclohexane 8/ethyl acetate 2 p is the receiving 630 mg of the desired product.

TLC: Hexane 1/AcOEt 1, Rf=0,5

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

In a flask equipped with a magnetic stirrer, was loaded and 0.61 g of the product obtained in the previous phase, 0.15 ml of N-ethylpiperazine (d 0,899), 0.2 g of potassium carbonate, 0.1 g of sodium iodide in 8 ml of DMF. Was left to react at 60°C for 4 hours, then poured the reaction mixture into water and was extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and evaporated in vacuum. Received 200 mg of oil corresponding to the product specified in the header, in free base form. Received oxalate.

Solution was added oxalic acid in acetone to a solution of the product in acetone. Was filtered and received 120 mg of the product specified in the header, in the form of a solid white color.

TPL=192-196°C; [αD]=+160°, C=0,1166% of the mass. Meon.

1H NMR δ (M. D., DMSO-d6): of 1.16 (t, J=7,1 Hz, 3H), 2,67-2,86 (m ush, 4H), 2,87-3,14 (m ush, 6H), 3,20-of 3.32 (m, 2H), 6,92 (s, 1H), 7,01 (s, 1H), 7,20 (s, 1H), 7,25 (d, J=9.0 Hz, 1H), 7,53 (s, 1H), to 7.64 (d, J=9.0 Hz, 1H), 8,02 (ush, 1H), of 8.92 (s, 1H), 10,07 (s, 1H).

LC/MS: (M+N)+= m/z 487.E. m.; tbeats=4.7 minutes (method A)

Method:

1) In a stream of nitrogen at 40 ml anhydrous dichloromethane, cooled in an ice bath, was added 1.23 g PCl5then slowly added 430 mg of the acid obtained in synthesis 1. The reaction mixture is left to be mixed at 0°C for 10 minutes, then at room temperature for 3 hours.

2) on the other hand, in 40 ml of dichloromethane in a stream of nitrogen suspended 1 g of the product obtained in synthesis 2, then added 1.3 ml of pyridine. Was cooled in an ice bath. Was added dropwise a solution obtained in 1), and stirred at room temperature for one hour.

Poured the reaction mixture into water and was extracted with ethyl acetate. The organic phase was washed with saturated solution of NaHCO3, dried over Na2SO4, filtered and evaporated in vacuum. Received 700 mg solid orange color, was purified by column flash chromatography,elwira a mixture of ethyl acetate 1/methanol 1, to obtain 440 mg of product, which is extracted from simple isopropyl ether to obtain 350 mg of the product specified in the header, in free base form.

TPL=146-148°C; [αD]=+242°, C=0,1052% wt. in the Meon.

1H NMR δ (M. D., DMSO-d6): and 0.98 (t, J=7.2 Hz, 3H), 2,29 (kV, J=7.2 Hz, 2H), 2,37 (m ush, 4H), 2,47-2,60 m, **), 3,03*** (d, J=15 Hz, 1H), 3,09*** (d, J=15 Hz, 1H), 6,92 (d, J=1.7 Hz, 1H), 7,01 (DD, J=2.1 Hz and 0.7 Hz, 1H), 7,20 (d, J=1.7 Hz, 1H), 7,24 (DD, J=8,8 Hz and 2.0 Hz, 1H), 7,50 (d, J=2.0 Hz, 1H), 7,65 (d, J=8,8 Hz, 1H), 8,02 (d, J=2.1 Hz, 1H), 8,64 (s, 1H), 10,71 (s, 1H).

LC/MS: (M+N)+= m/z 487.E. m.; tbeats=4.7 minutes (method)

Compounds according to the invention has an object testin vivo.

Testin vivo

Male rats CD Cr BR (Charles River, Italie) weighing 150-175 g before using them placed at least 7 days in a chamber with controlled temperature (22±1°C) and humidity (55±10%) and light / dark cycle of 12 hours. Feed and water were availablead libitum.Food took over 18 hours before the withdrawal of animals from the experiment. Rats were taken from experiment cervical dislocation, the stomach was surgically removed, cut along the lowest curvature, and placed in Krebs solution (Krebs) (composition (mm): NaCl 118,4; KCl 4,7; CaCl22,5; NaH2PO43,7; MgSO41,2; NaHCO325; glucose of 5.6). The animal care and conclusion from the experiment was carried out according to the international code of ethics Sanofi-Aventis (Sanofi-Aventis)and international laws governing the care and treatment of laboratory animals (E. E. C Directive 86/609, DJL358, 1, 12 december 1987). Strips of gastric bottom about 1 cm (width 5 mm) were cut along the longitudinal axis, hung in 20-ml bath filled with Krebs solution at 37°C, and blew a gaseous mixture of 95% O2-5% CO2. Strips supported under load at rest 1 g and, after washing in medium were added 10 µm choline (a precursor of acetylcholine) and 10 μm indomethacin (inhibitor prostaglandines) 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 tis what oulurovaniemi electric field. Two electrodes of platinum wire was placed on the surface and the bottom of the tub, which was the organ, and electric field stimulation was carried out using the stimulator Power Lab, AD Instruments Pty Ltd. Castle Hill, Australie), connected to a multichannel pulse generator (Ugo Basil, Varese, Italie) (Fukuda et al.,Scand. J. Gastroenterol.12, 1209-1214, 2004). Spermageile stimulation was applied in order to cause maximum reduction (20 Hz, pulse width: 2ms; 5 volts; pulse sequenceevery 2 minutes, 150 mA). Then the current is reduced to obtain the stimulation is less than the maximum (50% reduction in the maximal capacity to contract). Contractions were recorded using a computing machine system of registration and data analysis (Power Lab, Chart 5) associated with isotonic transducer (Ugo Basil, Varese, Italie) via pre-amplifiers (Octal Bridge Amp). After stabilization of the recorded cumulative curves of the concentration-response ghrelin (0.1 nm-1 μm), incubation with and without incubation (contact time: 30 min) molecule antagonists. Spermageile stimulation electric field applied to each strip as a reference (100%) to evaluate the responses on the test connection. The concentration of agonist that causes 50% of maximal effect (ES), was calculated using chetyrehkamernoe the Yu mathematical model of Rachkovskogo and reedy (Ratkovsky et Reedy) (Biometrics, 42, 575-582, 196), with adjustment by the method of nonlinear regression using the Levenberg-Marquard (Levenberg-Marquard) in a software environment Everstat. Values RKV antagonists was calculated by the equation of Cheng-Prusova (Cheng-Prusoff) (Kenakin et al., Competitive Antagonism,Pharmacologic Analysis of Drug-Receptor Interaction, 3eedition, 331-373, Philadelphie, New York; Raven: Lippincott, 1997).

The compounds of formula (I) show antagonistic activity against ghrelin receptorwith CI50that changed in the range of 5.10-8M to 1.10-9M

For example, the compound of example 1 showed CI50=2,2·10-8M

Thus, it appears that the compounds according to the invention have an antagonistic activity against receptor ghrelin.

The compounds of formula (I) possess interesting pharmacological properties, such as bioavailability, toxicology, selectivity, metabolism, interesting and for the development of drugs, in particular drugs for the prevention or treatment of any abnormalities are involved in the ghrelin receptor.

Thus, according to another of its aspects, the object of the invention is a medicinal product which contains the compound of the formula (I) or salt attaching the latter with a pharmaceutically acceptable acid is.

Thus, the compounds according to the invention can be used for human or animal treatment or prevention of various ghrelin-dependent diseases. Therefore, the compounds according to the invention can be used as a means for reducing the appetite for regulation of appetite, food intake and their frequency, as well as, in the long term, weight, particularly weight gain, which is the result of diet or therapeutic regimens. Therefore, the compounds according to the invention is applicable, in particular, for the prevention or treatment of obesity, disorders of appetite, diabetes, overweight and/or their consequences.

According to another of its aspects the present invention relates to pharmaceutical compositions containing as an active beginning of the connection 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 chosen according to the pharmaceutical form and the desired method of administration among the usual excipients which are known to experts in this field.

In the pharmaceutical compositions according to the present invention for p is moralnego, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal introduction of the specified active principle of formula (I) or its salt can be introduced in a standard dosage form, mixed with classical pharmaceutical excipients, to animals and to humans for the treatment or prevention of disorders or diseases mentioned above.

Standard dosage forms include forms for oral administration such as tablets, soft or hard gelatin capsules, powders, granules and solutions or suspensions for oral administration, the forms for sublingual, buccal, intratracheal, intraocular, intranasal, inhalation, forms for topical application, transdermal, subcutaneous, intramuscular or intravenous administration, the forms for rectal administration and implants. For topical application it is possible to use the compounds according to the invention in the form of creams, gels, ointments or lotions.

As an example, a standard dosage form of the compounds according to the invention in the form of tablets may contain the following components:

The connection according to the invention 50.0 mg
Lures223,75 mg
The sodium croscarmellose6.0 mg
Corn starch15,0 mg
The hypromellose2.25 mg
Magnesium stearate3.0 mg

Oral prescription dose beginning of the current day can be from 0.1 to 100 mg/kg at one time or over several sessions. When administered parenterally, it can reach from 0.01 to 10 mg/kg/day.

May be special cases in which use higher or lower dosages; these dosages are not beyond the invention. According to usual practice, the dosage appropriate to each patient is determined by the physician according to the method of administration, the weight and response of the above-mentioned patient.

Possible combinations

The present invention also concerns 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, it is possible, in particular, be called a substance, letting the e-obesity and antidiabetic agents, and rimonabant, Metformin, or sulfonylureas.

According to another of its aspects the present invention also concerns a method of treating the pathologies indicated above, which is the introduction to the patient an effective dose of the compounds according to the invention or one of its pharmaceutically acceptable salts.

According to another of its aspects the present invention also concerns the compounds of formula (I) or one of its pharmaceutically acceptable salts for the treatment of the pathologies indicated above.

1. The compound corresponding to the formula (I):
,
in which R1 denotes a hydrogen atom;
R2, R3, R4, equal or different from any of the available positions of the phenyl ring, independently represent a hydrogen atom or a halogen atom;
R5 denotes (C1-6)alkyl group;
n denotes 1,
in the form of a base or an acid additive salt.

2. Connection on p. 1,
where R5 denotes methyl, ethyl or 2-propyl,
in the form of a base or an acid additive salt.

3. Connection on p. 1, representing Ν-[4,6-dichloro-3-(benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(4-ethylpiperazin-1-yl)acetamide", she
in the form of a base or an acid additive salt.

4. The compound of formula (III):

in which R2, R3 and R4 are defined in paragraph 1 and Hal" about the means halogen atom.

5. The drug, which has antagonistic activity against ghrelin receptor, characterized in that it contains a compound of the formula (I) according to any one of paragraphs. 1-3 or additive salt with a pharmaceutically acceptable acid.

6. Pharmaceutical composition having antagonistic activity against ghrelin receptor, characterized in that it contains a compound of the formula (I) according to any one of paragraphs. 1-3 or its pharmaceutically acceptable salt.

7. The use of compounds according to any one of paragraphs. 1-3 for obtaining a medicinal product intended for the prevention or treatment of obesity, diabetes, disorders of appetite and excessive weight.

8. The compound according to any one of paragraphs. 1-3 for the prevention or treatment of obesity, diabetes, disorders of appetite and excess weight.



 

Same patents:

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

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 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

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 compounds of structural formula (I), which can be used for treating diseases mediated by an androgen receptor. In formula (I), R1 means (C2-6)alkyl, (C1-6)alkyloxy, -S(O)m-(C1-6)alkyl, (C1-6)fluoroalkyl, CN or halogen, R2 and R3 are identical or different and mean a hydrogen atom or (C1-9)alkyl, R4, R5, R6, R7 are identical or different and mean a hydrogen or halogen, X means CH or N, Y means either a nitrogen atom, or a carbon atom substituted by (C1-6)alkyl, (C1-6)alkyloxy, (C1-6)fluoroalkyl, a hydrogen atom or halogen; m is equal to 0, 1 or 2.

EFFECT: invention refers to using the compounds for preparing a therapeutic agent for preventing and/or treating hirsutism, androgenetic alopecia, hypertrichosis, atopic dermatitis, disordered sebaceous gland, such as hyperseborrhea, acne, greasy skin or seborrheic dermatitis.

8 cl, 2 tbl, 26 ex

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