Incretin secretagogues, methods for preparing and applying them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula 1, or their pharmaceutically acceptable salts showing the properties of incretin secretagogues, preferentially the properties of a bile acid receptor TGR5 agonist. The compounds are applicable for treating metabolic diseases associated with glucose metabolism, such as diabetes, obesity, metabolic syndrome, etc. In formula 1 R1, R2 and R3 independently represent a cyclic system substitute specified in: hydrogen, C1-C3alkyl, halogen, a trifluoromethyl group, C1-C3alkoxy, a cyano group, a trifluoromethoxy group; an amino group substituted by C1-C3alkyl; or two radicals R3, found at carbon neighbours in a benzene ring, together with the benzene ring bound therewith form 3,4-methylene dioxyphenyl; R4 represents hydrogen, C1-C5alkyl, a carboxyl group, C1-C3alkoxycarbonyl or an amide group CONHR5; R5 is an optionally substituted by C1-C3alkyl, C5-C6cycloalkyl optionally substituted by phenyl, benzyl, pyridyl; X and Y represent two hydrogen atoms or an oxygen atom, provided Y=O, then X=2H, provided Y=2H, then X=O or X=Y=2H; the sign (N) shows the possibility of bioisosteric substitution of the benzene ring by the pyridine, pyrimidine, pyridazine, triazine or pyrazine ones.

EFFECT: preparing the pharmaceutical composition and the combined drugs with the use of the compounds of formula 1 or the based pharmaceutical composition and a protein kinase DPP-IV inhibitor specified in Vildagliptin or Sitagliptin, and/or an endogenous bile acid or mied bile acid secretagogues.

53 cl, 7 dwg, 8 ex

 

The invention relates to new physiologically active substances, new stimulators of secretion ingreenwich hormones, active ingredients for pharmaceutical compositions, to pharmaceutical compositions and pharmaceutical combination means containing a non-steroidal agonist receptors bile acids TGR5 or one of the endogenous bile acids, which stimulate the secretion of ingreenwich hormones, as well as one of the known inhibitors of DPPIV protease, and by the combined method of treatment of metabolic, cardiovascular and neurodegenerative diseases, such as diabetes, obesity, metabolic syndrome, etc.

Diabetes in combination with overweight (obese or obesity) is an annual cause of death of more than 280 thousand people in the United States. Recently, a new medical research, the term "Diabesity" (in the Russian version - ' Diabetesthe"), meaning a combination of two interrelated pathologies: diabetes and obesity. Currently diabetesthe is regarded as one of the most serious health problems of humanity became, in fact, the first non-infectious epidemic [Schmidt MI, Duncan BB. Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med. 2003; 41: 1120-1130],[DangMN, Hashem BE-S. The epidemiology of obesity. Gastroenterol Clin North Am. 2010; 39: 1-7].

A wide spread of diabetes in combination with obesity acquired and began to rapidly spread treatise in the past century. The main causes of this epidemic is considered a sedentary lifestyle, and poor diet [Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414: 782-787], and genetic predisposition [Ling C, Groop L. Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 2009; 58: 2718-2725]. Diabetesthe is also an integral component of the metabolic syndrome. The prevalence of diabetes occurs at an accelerating rate. In 2010, diabetes was observed in 6.4% of the world's population in 2030 is projected 7.7% of patients in the world [Farag Y, M. Gaballa Diabesity: an overview of a rising epidemic. Nephrol Dial Transplant 2011; 26:28-35].

Currently, such a simple healing diabetesthe as special diets, do not lead to the problem 98% of lost weight acquire it in excess of 5 years. A noticeable effect have various surgical operations in the fight against diabetology (bariatric surgery), but they are associated with a higher number of side effects associated with hormonal homeostasis [G Tharakan, Tan T, Bloom S. Emerging therapies in the treatment of 'diabesity': beyond GLP-1. Trend Pharm Sci. 2011; 32:8-15].

Numerous efforts of pharmaceutical companies to create highly effective means of treatment of diabetes (diabetesthe) so far not led to notable successes. Despite the fact that currently, more than 130 new drug candidates are tested various the I, the application allowed no more than ten drugs. Clinical trials a large number of candidates were suspended because of their serious side effects. For example, the most promising anti-diabetic medication Avandia" (Rosiglitazone agonist of PPARgamma receptors), as it turned out, increases the risk of heart attack and cardiac arrest [Thomson Reuters Drug News (formerly DailyDrugNews.com) September 28, 2010].

The main causes of permanent failures researchers are lack of understanding of the complex picture of the disease, in particular, the presence of numerous signaling mechanisms. The impact of only one effector target leads to "escape" the pathological process due to activation of other mechanisms.

Therefore, the main direction in the development of anti-diabetic medication at the present time is the search for pharmacological agents that stimulate important processes to be able to pause the development of the pathology (e.g., secretion ingreenwich proteins GLP1, YYP, GIP), in particular, non-steroidal agonists of bile acids (LC), which specifically bind to receptors LCD, stimulating the secretion ingreenwich hormones (GLP1, YYP, GIP).

Most preferred are agonists of receptors LCD TGR5.

TGR5 receptors (also known as GPBAR1, M-BAR, AXOR 109 and GPCR19) are GPCR receptors, is provided with Gs-proteins [Tiwari, A.; Maiti, P. Drug Disc. Today 2009, 14, 523]. They are expressed mainly in the gastrointestinal tract, gall bladder, spleen, lung and placenta [Maruyama, T.; Miyamoto, Y.; Nakamura, T.; Tamai, Y.; Okada, H.; Sugiyama, E.; Nakamura, T.; Itadani, H.; Tanaka, K. Biochem. Biophys. Res. Commun. 2002, 298, 714]. Linking LCD with TGR5 receptors activates adenylate the cyclase, which increases intracellular concentration of camp and subsequent activation of the signalling cascade MAR-kinase. On the other hand, stimulation of TGR5 receptor regulates a number of metabolic processes [Groen, A. J. J. Hepatol. 2006, 45, 337]. In particular, it is shown that the effect of agonists at these receptors enteroendocrine cells STC-1 significantly increases the secretion of the peptide GLP-1 [Katasuma, S.; Hirasawa, A.; Tsujimoto, G. Biochem. Biophys. Res. Commun. 2005. 329, 386]. The peptide GLP-1 improves glucose homeostasis in several ways, including stimulation of insulin secretion and suppression of secretion of glucagon, which is very important in the treatment of diseases such as diabetes, diabetesthe and obesity. However, since endogenous LCD due to its steroid interact simultaneously with neskolkimi receptors [Makishima, M.; Okamoto, A.Y.; Repa, J.J.; Tu, H.; Learned, R.; Luk, A.; Hull, M.V.; Lustig, K.D.; Mangelsdorf, D.J.; Shanz, B. Science 1999, 284, 1362], the search for selective TGR5 agonist receptors should be conducted among small molecules, non-steroidal nature.

The authors of this invention was carried out synthesis vary the x heterocyclic compounds and screening of these substances in experiments with cell line SOME 293 expressionin human receptor TGR5 (hTGR5). Agonisticheskoe activity of compounds was evaluated by increasing the intracellular concentration of camp. The result was revealed a series of new substances with pronounced agonistic activity against receptors hTGR5.

Found new derivative tetrahydrobenzo[f][1,4]oxazepine in the form of bases and pharmaceutically acceptable salts and hydrates with the properties of the secretion stimulator ingreenwich hormones, which is a non-steroidal agonists of receptors bile acids TGR5.

Moreover, it was shown that the physiological effects of new compounds can be significantly enhanced while using inhibitors of DPPIV protease. In all likelihood, the multidirectional effects of non-steroidal agonists of receptors bile acids TGR5 and proteinase inhibitors is combined simultaneous impact of two metabolic process. First, this effect is to stimulate the secretion of incretins the action on the receptors of bile acids (LC) TGR5 in L-cells of the synthetic non-steroidal agonists or their natural ligands of bile acids (LC). Secondly, the effect is the inhibition of enzymes that break down entretenue peptides, in particular peptidases DPP-IV.

It was found that a special attention has also m the hundred and the introduction of a combined therapeutic effect.

With their use have been established pharmaceutical compositions and pharmaceutical combination products containing non-steroidal agonist receptors bile acids TGR5 and/or one of the endogenous bile acids or a mixture of endogenous bile acids, which stimulate the secretion of ingreenwich hormones, as well as one of the known inhibitors of DPPIV protease. However, the imposition of TGR5 agonists is oral, and the introduction of endogenous bile acids is carried out rectally in the form of a suppository or gel.

As inhibitors of DPPIV protease can be used Vildagliptin, Saxagliptin, Sitagliptin, Teneligliptin, Linagliptin, Dutogliptin, Alogliptin, Gemigliptin, Carmegliptin etc.

The invention provides for increasing the effectiveness of therapy due to the synergistic action of the components, while simultaneous treatment of diabetes and obesity, other metabolic diseases and cardiovascular and renal complications. The invention provides a high efficiency of treatment and facilitates the healing process in a wide range of patients.

To date in the scientific literature (patents, articles, abstracts, etc.) did not describe the combined application of receptor agonists LCD TGR5 and DPPIV inhibitors. There is no description of the use of rectal introduction of endogenous LCD in the form of appropriate dosage forms for Leche is of metabolic diseases.

Below are definitions of terms used in the description of this invention.

"Agonist" refers to compounds which binds with the receptors of a particular type, actively promote the transfer of these receptors to their inherent specific signal and thereby cause a biological response of a cell.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom. Azaheterocycle can have one or more "cyclic system substituents".

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance is synthetic or other (biotechnology, plant, animal, microbial or other origin, possessing pharmacological activity and which is the active beginning of the pharmaceutical composition used for the production and manufacture of the medicinal product (tools).

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl batch is of Italy"), including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic orwhereandindependently from each other represent "amino substituents", which is defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, orandtogether with the N atom to which they are bound, form throughand4-7 membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, ethyl, propyl, cyclopropyl the sludge, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic orannelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Alkylamino" meansorthe group in which alkyl is defined in this section. The preferred alkylaminocarbonyl are methylamino, ethylamino, n-propylamino, out-propylamino and n-butylamine.

"Alkyloxy" meansthe group in which alkyl is defined in this section.

The preferred alkyloxyaryl are metiloksi, ethyloxy, n-propyloxy, out-propyloxy and n-Butylochka.

"Allyloxycarbonyl" means-group in which alkyl is defined in this section.

"Amino group" meansgroup, substituted or nezamedin the Yu is not necessarily the same substituents of the amino group" andwhose value is defined in this section, for example, amino (H2N-), methylamino, diethylamino, pyrrolidino, morpholino, benzylamino or phenethylamine.

"Aminocarbonyl" meansgroup, substituted or unsubstituted not necessarily the same substituents carbamaepine"andincluding hydrogen, alkenyl, alkyl, aryl, heteroaryl, heterocyclyl, the value of which is determined in this section.

"Antagonists" refers to ligands that bind to receptors of a particular type and do not cause active cellular response. Antagonists inhibit the binding of agonists to receptors and thereby block the transmission of specific receptor signal.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preimushestvenno from 6 to 10 carbon atoms. Aryl can contain one or more "cyclic system substituents"which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle.

"Arylsulfonyl" means aryl-SO2-the group in which a is aryl op is Adelino in this section.

Bioisostere connection. The compound received by the exchange of an atom or group of atoms to other similar atoms or groups of atoms. In order bioisosteric substitution is the creation of new compounds with biological properties similar to the original connection. Bioisostere substitution may be physico-chemical or topological.

"Halogen" means fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine.

"Heteroaryl" (hetaryl) means an aromatic monocyclic or polycyclic system containing from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms replaced by a heteroatom or heteroatoms, such as nitrogen, sulfur or oxygen. The prefix "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system, nitrogen atom, oxygen atom or sulfur atom, respectively. The nitrogen atom located in heteroaryl, can be oxidized to N-oxide. Heteroaryl may have one or more "cyclic system substituents"which may be the same or different. Representatives of heteroaryl are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isooxazolyl, isothiazolin, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furutani, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, honokalani, phthalazine, imidazo[,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, chinoline, imidazolyl, cyanopyridyl, hintline, thienopyrimidines, pyrrolopyridine, imidazopyridine, ethenolysis, benzoxazinones, 1,2,4-triazinyl, thienopyrrole, properaly and other

"Heterocyclyl" means a non-aromatic monocyclic or polycyclic system containing from 3 to 13 carbon atoms, mainly from 5 to 13 carbon atoms, in which one or more carbon atoms replaced by a heteroatom, such as nitrogen, oxygen, sulfur, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. The prefix "Aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Heterocyclyl may have one or more "cyclic system substituents"which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives of heterocyclyl are 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 2-pyrazoline, dihydrofurane, dihydrothiophene etc.

"Heterocyclyl" means an aromatic or neuromate the definition saturated monocyclic or polycyclic system, comprising from 3 to 10 carbon atoms, mainly from 5 to 6 carbon atoms, in which one or more carbon atoms replaced by a heteroatom, such as nitrogen, oxygen, sulfur. The prefix "Aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of nitrogen atom, oxygen atom or sulfur atom, respectively. Heterocyclyl may have one or more "cyclic system substituents"which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives heterocyclyl are piperidinyl, pyrrolidinyl, piperazinil, morpholinyl, thiomorpholine, thiazolidine, 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrothiophene and other

"Hydrate" means a stoichiometric or non-stoichiometric composition of the compound or its salt with water.

Bile acids (endogenous bile acids LCD). The main types of bile acids present in the human body, are the so-called primary bile acids (primarily secreted by the liver): cholic acid (3α, 7α, 12α-trioxi-5β-Galanova acid) and chenodeoxycholic acid (3α, 7α-deoxy-5β-Galanova acid)and secondary (formed from the primary bile acids in the large intestine under the action of intestinal microflora): desoxycholate KIS the PTA (3α, 12α-deoxy-5β-Galanova acid, lithocholic (3α-maniaxe-5β-Galanova acid), allagollewa and ursodeoxycholic acid. From the secondary in enterohepatic circulation in affecting the physiology of the amount involved only desoxycholic acid that is absorbed into the blood and secretiruema then the liver in the composition of bile. Allagollewa, ursodeoxycholic and lithocholic acid are stereoisomers holeva and deoxycholic acids. All bilious acids of the person have in their molecules 24 carbon atoms. Bile acids designed to stimulate ingreenwich hormones.

"Deputy" means a chemical moiety that is attached to scaffold (fragment), for example, Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system, the values of which are defined in this section.

"Deputy amino group" means the Deputy attached to the amino group. Deputy amino group represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, annul the computerized heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonylmethyl, alcoxycarboxylates, heteroarylboronic.

"Deputy carbamoyl" means the Deputy attached to aminocarbonyl group, the value of which is defined in this section. Deputy carbamoyl represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic orannelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic. Preferred substituents carbamaepine" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic orannelirovannymi ariete ticleni, annelirovannymi arylheteroacetic.

"Deputy cyclic system" means the Deputy attached to aromatic or non-aromatic cyclic system, including hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, aryloxyalkyl, arelaxation, alkyloxyalkyl, aryloxyalkyl, geterotsiklicheskikh, arylalkylamines, geterotsiklicheskikh, alkylsulfonyl, arylsulfonyl, heterocyclization, alkylsulfonyl, arylsulfonyl, heterocyclization, alkylthio, aaltio, heterocyclic, alkylsulfonates, arylsulfonyl, geterotsiklicheskikh, alkylsulfonates, arylsulfonyl geterotsiklicheskikh, alkylthiomethyl, alltoall, geterotsiklicheskikh, arylalkylamines, geterotsiklicheskie, arylalkylamines, geterotsiklicheskikh, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, amidino,orwhereandrepresent independently from each other "Vice-amino group", mn is the significance of which is defined in this section, for example, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroalkyl, or Deputywherecan be acyl or aroyl anddefined above, or "Deputy cyclic systems areorwhereandtogether with the nitrogen atom to which they are bound, form throughand4-7 membered heterocyclyl or heterocyclyl.

"Carboxyl" means the group-CO2N.

"Medicine combined medicine - drug" of several medicinal substances for use in the form of tablets, capsules, injections, ointments, rectal suspensions and gels, etc. of the finished form, intended for restoring, correcting or modifying physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others. Medicinal substance in one set can be presented in various forms, designed to be inserted into the animal or human body various JV the ways, for example, oral and rectal.

"Ligands" (from the Latin ligo - link) is a chemical (small molecule, an inorganic ion, a peptide, a protein, etc.) capable of interacting with receptors that transform this interaction in specific signal.

"Neurodegenerative disease (NT)" means the specific condition and a disease characterized by damage to the primary and death of populations of nerve cells in certain regions of the Central nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's disease and Parkinson's disease; disease (horay) Huntington's, multiple sclerosis, cerebellar degeneration; amyotrophic lateral sclerosis; dementia with calves Levi; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis ("mad cow disease", Creutzfeld-Jakob Disease); AIDS-associated dementia; multi-infarct dementia; frontotemporal dementia; leucoencephalopathy (illness vanishing white matter); chronic neurodegenerative disease; stroke; ischemic and reperfusion of hypoxic brain damage; epilepsy; cerebral ischemia; glaucoma; traumatic brain injury; down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; depression. In addition, neurodegen erative diseases include pathological conditions and disorders, when developing hypoxia, substance abuse, addictive, when exposed to neurotoxins, infectious and oncological diseases of the brain and neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

"Optionally substituted radical" means a radical without substituents or with one or more substituents.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms.

"Receptors" (from Latin recipere to receive, to learn) are biological macromolecules that are located on the plasma membrane of cells or intracellular able to interact specifically with a limited set of physiologically active substances (ligands) and transform the signal about this interaction in a specific cellular response.

"TGR5 receptors the receptors (also known as GPBAR1, M-BAR, AXOR 109 and GPCR19) are GPCR receptors related to Gs-proteins. They are expressed mainly in the gastrointestinal tract, gall bladder, spleen, lung and placenta.

"Cycloalkyl" means a non-aromatic mono - or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more substituents, cyclizes the th system", which may be the same or different. Representatives cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl, etc. Cycloalkyl can be annylirovan with aromatic cycle or a heterocycle. Preferred "cyclic system substituents" are alkyl, Alcoxy, hydroxy orthe value which is defined in this section.

"Pharmaceutical composition" means a composition comprising a compound of formula 1 and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum is tion, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, aginova acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal entered the I active principle, single or in combination with other active early, can be introduced animals and people in the standard form of introduction in the form of a mixture with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration. Pharmaceutical compositions typically obtained using standard procedures involving mixing the active compound with a liquid or finely powdered solid carrier. For the manufacture of suppositories, in addition to the active components, is also used cocoa butter, alloys with paraffin wax and hydrogenated fats, hydrogenated vegetable and animal fats, tallow, lanai, alloys hydrogenated fats with wax, solid paraffin and other bases permitted for medical use.

"Pharmaceutically acceptable excipients". Under the pharmaceutically acceptable excipients are meant to be applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers.

"Pharmaceutically acceptable salt" refers to the relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates. palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like (for a Detailed description of the properties of these salts is given in S.M. Berge et al. "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts. Suitable inorganic bases that had the t to be the salts of metals, are the hydroxide. carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The purpose of the present invention is to provide new derivatives of 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, which TGR5 agonists of receptors.

This goal is achieved derivatives of compounds of General formula 1 or their pharmaceutically acceptable salts,

where:

R1, R2 and R3 independently from each other represent is a Deputy cyclic system, selected from: hydrogen, C1-C3of alkyl, halogen, triptorelin group1-C3alkoxy, ceanography, cryptometer; amino, substituted C1-C4by alkyl;

or two radicals R3, located at adjacent carbon atoms in a benzene ring together with the benzene ring to which they are bound, form a 3,4-methylenedioxyphenyl;

R4 represents hydrogen, C1-C5alkyl, carboxyl group, With1-C3alkoxycarbonyl or amide group CONHR5;

R5 is an optionally substituted C1-C3the alkyl, C5-C6cycloalkyl, optionally substituted phenyl, benzyl, pyridium;

X and Y represent two hydrogen atoms or an oxygen atom

moreover, if Y=O, then X=2N,

if Y=2H, X=O or

X=Y=2H;

N - indicates the possibility of bioisosteric substitution of the benzene ring on azaheterocyclic: pyridine, pyrimidine, pyridazine, triazine or pyrazinone.

Preferred are derivatives of compounds of General formula 1.1 and 1.2 or their pharmaceutically acceptable salt,

where: R1, R2, R3, R4 and N have the above values.

More preferred are derivatives of compounds of General formula 1.3 and 1.4 or their pharmaceutically acceptable salt,

where R1, R2, R3, R5 and N have the above values.

Most preferred are compounds represented by the formulas 01-101:

4-(3-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (01),

4-(3-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine(02),

4-(4-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (03),

4-(2-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (04),

4-[2-(pyridin-4-yl)benzoyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (05),

4-[2-(pyridin-2-yl)benzoyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (06),

4-(4-phenyldiamine)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (07),

4-[(4-vinylpyridin-3-yl)methyl]-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f] [1,4]oxazepine (08),

4-[2-(pyridin-4-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (09),

4-[2-(pyridin-2-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (10),

4-(4-phenyldiamine)-7-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (11),

4-[2-(pyridin-4-yl)benzoyl]-7-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (12),

4-[2-(pyridin-2-yl)benzoyl]-7-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (13),

4-(3-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclopentylamine (14),

4-(3-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid t is clohexane (15),

4-(4-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (16),

4-(2-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (17),

4-[2-(pyridin-4-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (18),

4-[2-(pyridin-2-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (19),

4-(2-phenylbenzyl)-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (20),

4-[2-(pyridin-4-yl)benzyl]-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (21),

4-[2-(pyridin-2-yl)benzyl]-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (22),

4-[2-(3,4-methylenedioxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (23),

4-[2-(pyridin-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (24),

4-[2-(pyridin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (25),

4-[2-(pyridin-3-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (26),

4-[2-(3,4-methylenedioxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (27),

4-[2-(pyridin-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[][1,4]oxazepine-5-carboxylic acid (28),

4-[2-(pyridin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (29),

4-[2-(pyridin-3-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (30),

4-[2-(3,4-methylenedioxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid ethyl ester (31),

4-[2-(pyridin-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid ethyl ester (32),

4-[2-(pyridin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid ethyl ester (33),

4-[2-(pyridin-3-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid ethyl ester (34),

4-[2-(4-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (35),

4-[2-(3-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (36),

4-[2-(2-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (37),

4-[2-(4-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (38),

4-[2-(3-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (39),

4-[2-(2-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (40),

4-[2-(4-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (41),

4-[2-(3-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (42),

4-[2-(2-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (43),

4-[2-(4-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (44),

4-[2-(3-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (45),

4-[2-(2-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (46),

4-[2-(4-were)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (47),

4-[2-(3-were)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (48),

4-[2-(2-were)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (49),

4-[2-(4-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (50),

4-[2-(3-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (51),

4-[2-(2-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[G][1,4]oxazepine-5-carboxylic acid tert-butylamide (52),

4-[2-(pyrimidine-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (53),

4-[2-(pyrimidine-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f[1,4]oxazepan-5-carboxylic acid tert-butylamide (54),

4-[2-(pyrimidine-5-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (55),

4-[2-(pyrazin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (56),

4-[2-(pyrazin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclopentylamine (57),

4-[2-(pyrazin-2-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclopentylamine (58),

4-[2-(pyrazin-2-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (59),

4-[2-(pyrimidine-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid(60),

4-[2-(pyrimidine-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (61),

4-[2-(pyrimidine-5-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (62),

4-[2-(4-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (63),

4-[2-(3-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid(64),

4-[2-(2-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (65),

4-[2-(4-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (66),

4-[2-(3-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (67),

4-[2-(2-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (68),

<> 4-[2-(4-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (69).

4-[2-(3-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (70),

4-[2-(2-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (71),

4-[2-(4-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (72),

4-[2-(3-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (73),

4-[2-(2-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5 - carboxylic acid (74),

4-[2-(4-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5 - carboxylic acid (75),

4-[2-(3-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5 - carboxylic acid(76),

4-[2-(2-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5 - carboxylic acid(77),

4-(2-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5 - carboxylic acid(78),

4-(2-phenylbenzyl)-7-triptoreline-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (79),

4-(2-phenylbenzyl)-7-tertbutyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (80),

4-(3-phenylbenzyl)-3-oxo-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclopentylamine (81),

4-(3-phenylbenzyl)-3-oxo-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclohexylamine (82),

p> 4-(2-phenylbenzyl)-3-oxo-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (83),

4-[2-(pyridin-4-yl)benzyl]-3-oxo-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (84),

4-[2-(pyridin-2-yl)benzyl]-3-oxo-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (85),

4-(2-phenylbenzyl)-3-oxo-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (86),

4-[2-(pyridin-4-yl)benzyl]-3-oxo-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (87),

4-[2-(pyridin-2-yl)benzyl]-3-oxo-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (88),

4-[2-(3,4-methylenedioxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (89),

4-[2-(pyridin-4-yl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (90),

4-[2-(pyridin-2-yl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (91),

4-[2-(pyridin-3-yl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (92),

4-[2-(4-methoxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (93),

4-[2-(3-methoxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-karbonovoi acid tert-butylamide (94),

4-[2-(2-methoxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (95),

4-[2-(4-were)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (96),

4-[2-(3-were)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (97),

4-[2-(2-were)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (98),

4-[2-(4-forfinal)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (99),

4-[2-(3-forfinal)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (100),

4-[2-(2-forfinal)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (101).

The subject of this invention is a method of obtaining derivatives of 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine General formula 1.3, in which the recovery of the corresponding ortho-cyanoacetate General formula A1 over Raney Nickel, followed by cyclization and recovery of lithium aluminum hydride in connection with the General formula A2 and acylation last appropriate billnum allelochemical,

where R1, R2, R3, X and N have the above values.

The subject of this invention is a method for manufacturing adnych compounds of General formula 1.4, which consists in the interaction of the appropriate allegedely General formula B1 with isonitriles and the appropriate amine, and recovering the resulting compound of General formula B2 complex brandibelle in tetrahydrofuran,

where R1, R2, R3, R5 and N have the above values.

The object of the present invention is an active component that has the property of secretion stimulator ingreenwich hormones (agonist receptors bile acids TGR5), which is a derivative of the compounds of General formula 1.

The subject of this invention is a pharmaceutical composition for the prevention and treatment of metabolic diseases and associated cardiovascular and neurodegenerative diseases, containing an effective quantity of the active component.

The subject of this invention is a pharmaceutical composition for the prevention and treatment of metabolic diseases and associated cardiovascular and neurodegenerative diseases, containing an effective amount of an active component and a proteinase inhibitor DPP-IV,

and any of the above pharmaceutical compositions in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing.

The DPPIV protease inhibitors is a promising pre is Arata, not allowing pathological process to destroy protein GLP1. However, this does not increase the number of GLP1 in the body, but only to its conservation. The most preferred inhibitors of DPPIV protease are known drugs: Vildagliptin, Saxagliptin, Sitagliptin, Teneligliptin, Linagliptin, Dutogliptin, Alogliptin, Gemigliptin, Carmegliptin, etc. of the Joint application of two raznonapravlennyh agents, the General application of which leads to synergetic results in the induction of the necessary hormones and their preservation.

The pharmaceutical composition may include pharmaceutically acceptable excipients. Under the pharmaceutically acceptable excipients are meant to be applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers. The pharmaceutical composition along with the active component of the present invention may include other active ingredients provided that they do not cause unwanted effects, such as allergic reactions.

If you want to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed to produce different forms, however, they can contain conventional pharmaceutical carriers, for example, oral formulations such as tablets, gelatin capsules, pills, solutions or suspensions); form is for injection (such as solutions or suspensions for injection or dry powder for injection, which requires only the addition of water for injection before use); local forms such as ointments or solutions).

The media used in the pharmaceutical compositions of the present invention, are media that are used in the pharmaceutical industry to obtain common forms, including oral forms are used binders, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, colorless agents, korrigentami taste; in forms for injection are used antiseptic agents, solubilization, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents.

A new pharmaceutical composition can be obtained by mixing with an inert filler and/or solvent of the active component representing at least one of the compounds of General formulas 1, 1.1, 1.2, 1.3, 1.4 or its pharmaceutically acceptable salt and/or hydrate.

The subject of this invention is a pharmaceutical combination for the prevention and treatment of metabolic diseases and associated cardiovascular and neurodegenerative diseases, containing an effective kolichestvennymi protease DPP-IV and secretion stimulator ingreenwich hormones (agonists of receptors bile acids TGR5) - endogenous bile acid, or a mixture of endogenous bile acids, the latter in the form of rectal suspension or gel.

The distinctive feature of this drug combined tool is the use of natural agonists of receptors bile acids TGR5-endogenous bile acids or a mixture of endogenous bile acids stimulate secretion ingreenwich hormones. This is based on the ability of bile acids to induce the synthesis of incretins. The effect is achieved through activation of receptors LCD (mainly TGR5), present in the membranes of L-cells. Bile acids include the following LCD: Holevo, desoxycholate, chenodesoxycholic, glycocholate, glycometabolism, glyconanoparticles, human beings need it, taurodeoxycholate, taurochenodeoxycholate acids and their conjugates with other endogenous compounds (amino acids, taurine) or their prodrugs or transport complexes. Most preferred is the use of human beings need it and glycobiotechnology LCD, and their prodrugs, and transport systems.

The subject of this invention is a method for the prevention and treatment of metabolic diseases and associated cardiovascular and neurodegenerative diseases introduction in the effective number of the new active ingredient or n is howling pharmaceutical compositions.

The subject of this invention is a method for the prevention and treatment of metabolic diseases and associated cardiovascular and neurodegenerative diseases the introduction of an effective amount of dosage of the combined funds, the inhibitor of the protease DPP-IV administered orally or injected and endogenous bile acid, or a mixture of endogenous bile acids is administered rectally.

Because of the nature of the metabolic landscape of endogenous LCD with a dose do not reach their receptors in sufficient quantities and do not produce a useful effect. The basis for this conclusion is the fact that the content of regulatory peptides in the mucosa of the gastrointestinal tract increases significantly in its caudal part.

Using a combination of several raznonapravlennyh agents (TGR5 agonists, inhibitors of DPPIV) is suitable for treating a number of diseases, namely diabetes, diabetesthe, obesity, loss of insulin sensitivity, metabolic syndrome, impaired glucose metabolism, coronary syndrome, ventricular dysfunction, myocardial condition, nervous system diseases, neurodegenerative diseases (e.g. Alzheimer's disease), stroke, kidney damage, hypervolemia, ischemia, bowel disease, osteo is atii and other diseases of musculoskeletal system.

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally, topically or rectally). The clinical dosage of the active ingredient (substance), pharmaceutical composition or drug combination tool, comprising pharmaceutically effective amount of the active component, patients may be adjusted depending on therapeutic efficacy and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosage, each the unit dosage of the drug should contain 10 ~ 500 mg, preferably 50 ~ 300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably from one to six times).

The invention is illustrated by drawings.

Figure 1. The distribution of the secreted peptide PYY in different parts of the gastrointestinal tract, showing the mean is inoe increase its content in the anterograde direction.

Figure 2. The effect of rectal introduction of LCD GDC on the level of glucose in the blood diabetonic mice db/db mice.

Figure 3. The effect of rectal introduction of LCD GDC on weight diabetonic mice db/db mice (P<0.05).

The following examples illustrate, but not limit the invention.

The structure of the obtained compounds was confirmed by the data of chemical, chromatographic and spectral analysis.

Example 1. A common way of obtaining some of the compounds represented by General formula 1, the B2 structure.

where the radicals R, R1 and R5 have the values given above.

The corresponding alegitimate General formula B1 (1.0 equivalent) and the appropriate primary bearily amine (1.0 equivalent) was dissolved in methanol and stirred at room temperature for 10 minutes. Then added a suitable isonitrile (1.2 equivalent) and the resulting mixture was heated at 50°C With stirring for 1-5 hours. After the reaction mixture was cooled to room temperature, and the precipitation was filtered and washed with methanol. The resulting material was recrystallized from ether or purified chromatographically on silica gel, using as eluent methylene chloride with a suitable gradient of methanol.

Structures of the compounds are confirmed by the data of LC-MS analysis. This method b is whether the compounds obtained 81-87,89-101:

81: Molecular weight (MB) 508.55, signal LC MS m/z 509 (M+1);

82: 522.57 MB; LC-MS m/z 523 (M+1); 83: 496.53 MB; LC-MS m/z 497 (M+1);

84: 447.51 MB; LC-MS m/z 448 (M+1); 85: 447.51 MB; LC-MS m/z 448 (M+1);

86: 458.56 MB; LC-MS m/z 459 (M+1); 87: 459.55 MB; LC-MS m/z 460 (M+1);

89: 472.55 MB; LC-MS m/z 473 (M+1); 90: 429.52 MB; LC-MS m/z 430 (M+1);

91: 429.52 MB; LC-MS m/z 430 (M+1); 92: 429.52 MB; LC-MS m/z 430 (M+1);

93: 458.56 MB; LC-MS m/z 459 (M+1); 94: 458.56 MB; LC-MS m/z 459 (M+1);

95: 458.56 MB; LC-MS m/z 459 (M+1); 96: 448.56 MB; LC-MS m/z 449 (M+1);

97: 448.56 MB; LC-MS m/z 449 (M+1); 98: 448.56 MB; LC-MS m/z 449 (M+1);

99: 446.53 MB; LC-MS m/z 447 (M+1); 100: 446.53 MB; LC-MS m/z 447 (M+1);

101: 446.53 MB; LC-MS m/z 447 (M+1);

as well as connections

168: 4-(3-phenylbenzyl)-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid cyclopentylamine, 441.53 MB; LC-MS m/z 442 (M+1);

169: 4-(3-phenylbenzyl)-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid cyclohexylamine, 455.56 MB; LC-MS m/z 456 (M+1);

170: 4-(2-phenylbenzyl)-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 429.52 MB; LC-MS m/z 430 (M+1);

171: 4-[2-(4-pyridyl)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 430.51 MB; LC-MS m/z 431 (M+1);

172: 4-[2-(2-Piri DIL)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido [3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 430.51 MB; LC-MS m/z 431 (M+1);

173: 4-[2-(3,4-methylenedioxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 473.53 MB; LC-MS m/z 474 (M+1);

174: 4-[2-(3-pyridyl)benzyl)]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f]1,4]oxazepine-5-carboxylic acid tert-butylamide, 430.51 MB; LC-MS m/z 431 (M+1);

175: 4-[2-(4-methoxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 459.55 MB; LC-MS m/z 460 (M+1);

176: 4-[2-(3-methoxyphenyl)benzoyl]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 459.55 MB; LC-MS m/z 460 (M+1);

177: 4-[2-(2-methoxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido [3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 459.55 MB; LC-MS m/z 460 (M+1);

178: 4-[2-(4-were)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 443.55 MB; LC-MS m/z 444 (M+1);

179: 4-[2-(3-were)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 443.55 MB; LC-MS m/z 444 (M+1);

180: 4-[2-(2-were)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 443.55 MB; LC-MS m/z 444 (M+1);

181: 4-[2-(4-forfinal)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 447.51 MB; LC-MS m/z 448 (M+1);

182: 4-[2-(3-forfinal)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido [3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 447.51 MB; LC-MS m/z 448 (M+1);

183: 4-[2-(2-forfinal)benzyl]-3-oxo-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 447.51 MB; LC-MS m/z 448 (M+1);

244: 6-(3-phenylbenzyl)-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid cyclopentylamine, 442.52 MB; LC-MS m/z 443 (M1);

245: 6-(3-phenylbenzyl)-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid cyclohexylamine, 456.55 MB; LC-MS m/z 457 (M+1);

246: 6-(2-phenylbenzyl)-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 430.51 MB; LC-MS m/z 431 (M+1);

247: 6-[2-(4-pyridyl)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, MB 431.50; LC-MS m/z 432 (M+1);

248: 6-[2-(2-pyridyl)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, MB 431.50; LC-MS m/z 432 (M+1);

249: 6-[2-(3,4-methylenedioxyphenyl)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 474.52 MB; LC-MS m/z 475 (M+1);

250: 6-[2-(3-pyridyl)benzyl)]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, MB 431.50; LC-MS m/z 432 (M+1);

251: 6-[2-(4-methoxyphenyl)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 460.54 MB; LC-MS m/z 461 (M+1);

252: 6-[2-(3-methoxyphenyl)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 460.54 MB; LC-MS m/z 461 (M+1);

253: 6-[2-(2-methoxyphenyl)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 460.54 MB; LC-MS m/z 461 (M+1);

254: 6-[2-(4-were)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 444.54 MB; LC-MS m/z 445 (M+1);

255: 6-[2-(3-methyl phenyl)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido [5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 444.54 MB; LC-MS m/z 445 (M+1);

256: 6-[2-(2-were)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 444.54 MB; LC-MS m/z 445 (M+1);

257: 6-[2-(4-forfinal)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, MB 448.50; LC-MS m/z 449 (M+1);

258: 6-[2-(3-forfinal)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, MB 448.50; LC-MS m/z 449 (M+1);

259: 6-[2-(2-forfinal)benzyl]-3-oxo-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, MB 448.50; LC-MS m/z 449 (M+1).

Example 2. A common method of obtaining compounds of General formula 1.2 and 1.4

A solution of 1.0 mmol of compounds of General formula structure B2 in 3 ml of anhydrous tetrahydrofuran was treated with 2.0 ml of 2.0 M solution (4.0 mmol) of the complex of borane-dimethyl sulfide in tetrahydrofuran. The mixture was stirred at room temperature for 10-12 hours, then the solvent was evaporated, and the residue was dissolved in a saturated solution of Hcl in methanol. The resulting solution was heated at boiling for 30 minutes, after cooling, neutralize 10% aqueous potash, and was extracted with CH2Cl2(3×50 ml). The combined organic extract after drying over magnesium sulfate then concentrated under vacuum. OS is atok was purified preparative TLC (on silica gel, eluent CH2Cl2) or HPLC. Structures of the compounds are confirmed by the data of LC-MS analysis.

In this method were obtained connections: 14, 15, 17-19, 24-26, 50-52.

14: 494.56 MB; LC-MS m/z 495 (M+1); 15: 508.59 MB; LC-MS m/z 509 (M+1);

17: 482.55 MB; LC-MS m/z 483 (M+1); 18: 433.53 MB; LC-MS m/z 434 (M+1);

19: 433.53 MB; LC-MS m/z 434 (M+1); 24: 415.54 MB; LC-MS m/z 416 (M+1);

25: 415.54 MB; LC-MS m/z 416 (M+1); 26: 415.54 MB; LC-MS m/z 416 (M+1);

50: 450.53 MB; LC-MS m/z 451 (M+1); 51: 450.53 MB; LC-MS m/z 451 (M+1);

52: 450.53 MB; LC-MS m/z 451 (M+1);

as well as connections

102: 4-[2-(4-dimethylaminophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid, 402.49 MB; LC-MS m/z 403 (M+1);

103: 4-[2-(4-diethylaminophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid, 430.55 MB; LC-MS m/z 431 (M+1);

104: 4-(2-phenylbenzyl)-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid phenylamide, 464.56 MB; LC-MS m/z 465 (M+1);

105: 4-(2-phenylbenzyl]-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid m-pyridinylamino, 465.56 MB; LC-MS m/z 466 (M+1);

106: 4-[2-(4-cyanophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, 340.42 MB; LC-MS m/z 341 (M+1);

107: 4-(2-phenylbenzyl]-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid benzylamine, 478.59 MB; LC-MS m/z 479 (M+1);

113: 4-[(4-vinylpyridin-3-yl)methyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine, 317.39 MB; LC-MS m/z 318 (M+1);

114: 4-[2-(4-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine, 317.39 MB; LC-MS m/z 318 (M+1);

115: 4-[2-(2-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4f][1,4]oxazepine, 317.39 MB; LC-MS m/z 318 (M+1);

118: 4-(3-phenylbenzyl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid cyclopentylamine, MB 427.55; LC-MS m/z 429 (M+1);

119: 4-(3-phenylbenzyl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid cyclohexylamine, 441.58 MB; LC-MS m/z 443 (M+1);

120: 4-(4-phenylbenzyl)-2,3,4,5-tetrahydropyrido[3,4-f] [1,4]oxazepine-5-carboxylic acid, 360.42 MB; LC-MS m/z 361 (M+1);

121: 4-(2-phenylbenzyl)-2,3,4,5-tetrahydropyrido[3,4-f] [1,4]oxazepine-5-carboxylic acid tert-butylamide, 415.54 MB; LC-MS m/z 417 (M+1);

122: 4-[2-(4-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 416.53 MB; LC-MS m/z 418 (M+1);

123: 4-[2-(2-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 416.53 MB; LC-MS m/z 418 (M+1);

125: 4-[2-(3-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 416.53 MB; LC-MS m/z 418 (M+1);

127: 4-[2-(4-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid, 361.40 MB; LC-MS m/z 362 (M+1);

128: 4-[2-(2-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid, 361.40 MB; LC-MS m/z 362 (M+1);

129: 4-[2-(3-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid, 361.40 MB; LC-MS m/z 362 (M+1);

131: 4-[2-(4-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid ethyl ester, 389.46 MB; LC-MS m/z 390 (M+1);

132: 4-[2-(2-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido what about[3,4-f][1,4]oxazepine-5-carboxylic acid ethyl ester, 389.46 MB; LC-MS m/z 390 (M+1);

133: 4-[2-(3-pyridyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid ethyl ester, 389.46 MB; LC-MS m/z 390 (M+1);

134: 4-[2-(4-methoxyphenyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 445.57 MB; LC-MS m/z 447 (M+1);

135: 4-[2-(3-methoxyphenyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 445.57 MB; LC-MS m/z 447 (M+1);

136: 4-[2-(2-methoxyphenyl)benzyl]-2,3,4,5-tetrahydropyrido [3,4-f] [1,4]oxazepine-5-carboxylic acid tert-butylamide, 445.57 MB; LC-MS m/z 447 (M+1);

137: 4-[2-(4-were)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 429.57 MB; LC-MS m/z 431 (M+1);

138: 4-[2-(3-were)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 429.57 MB; LC-MS m/z 431 (M+1);

139: 4-[2-(2-were)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 429.57 MB; LC-MS m/z 431 (M+1);

140: 4-[2-(4-forfinal)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 433.53 MB; LC-MS m/z 435 (M+1);

141: 4-[2-(3-forfinal)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 433.53 MB; LC-MS m/z 435 (M+1);

142: 4-[2-(2-forfinal)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 433.53 MB; LC-MS m/z 435 (M+1);

143: 4-[2-(4-chlorophenyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]about steps-5-carboxylic acid tert-butylamide, MB 449.98; LC-MS m/z 451 (M+1);

144: 4-[2-(3-chlorophenyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 449.98 MB; LC-MS m/z 451 (M+1);

145: 4-[2-(2-chlorophenyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 449.98 MB; LC-MS m/z 451 (M+1);

146: 4-[2-(pyrimidine-4-yl)benzyl]-2,3,4,5-tetrahydropyrido [3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 417.52 MB; LC-MS m/z 419 (M+1);

147: 4-[2-(pyrimidine-2-yl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 417.52 MB; LC-MS m/z 419 (M+1);

148: 4-[2-(pyrimidine-5-yl)benzyl]-2,3,4,5-tetrahydropyrido [3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 417.52 MB; LC-MS m/z 419 (M+1);

149: 4-[2-(pyrazin-2-yl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 417.52 MB; LC-MS m/z 419 (M+1);

150: 4-[2-(pyrazin-2-yl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid cyclopentylamine, 429.53 MB; LC-MS m/z 431 (M+1);

166: 4-[2-(2-chlorophenyl)benzyl]-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid, 394.86 MB; LC-MS m/z 396 (M+1);

167: 4-(2-phenylbenzyl)-2,3,4,5-tetrahydropyrido[3,4-f][1,4]oxazepine-5-carboxylic acid, 360.42 MB; LC-MS m/z 361 (M+1);

184: 6-(3-phenylbenzyl)-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine, 317.39 MB; LC-MS m/z 318 (M+1);

189: 6-[(4-vinylpyridin-3-yl)methyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine, 318.38 MB; LC-MS m/z 319 (M+1);

190: 6-[2-(4-pyridyl)benzyl]-5,6,7,8-tetrahydro is pyrimido[5,4-f][1,4]oxazepine, 318.38 MB; LC-MS m/z 319 (M+1);

191: 6-[2-(2-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine, 318.38 MB; LC-MS m/z 319 (M+1);

194: 6-(3-phenylbenzyl)-5,6,7,8-tetrahydropyrimido[5,4-f] [1,4]oxazepine-5-carboxylic acid cyclopentylamine, 428.54 MB; LC-MS m/z 430 (M+1);

195: 6-(3-phenylbenzyl)-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid cyclohexylamine, MB 442.57; LC-MS m/z 444 (M+1);

196: 6-(4-phenylbenzyl)-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid, 361.40 MB; LC-MS m/z 362 (M+l);

197: 6-(2-phenylbenzyl)-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 416.53 MB; LC-MS m/z 418 (M+1);

198: 6-[2-(4-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 417.52 MB; LC-MS m/z 419 (M+1);

199: 6-[2-(2-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 417.52 MB; LC-MS m/z 419 (M+1);

201: 6-[2-(3-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 417.52 MB; LC-MS m/z 419 (M+1);

203: 6-[2-(4-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid, 362.39 MB; LC-MS m/z 363 (M+1);

204: 6-[2-(2-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid, 362.39 MB; LC-MS m/z 363 (M+1);

205: 6-[2-(3-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid, 362.39 MB; LC-MS m/z 363 (M+1);

207: 6-[2-(4-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]who xazepam-5-carboxylic acid ethyl ester, 390.45 MB; LC-MS m/z 391 (M+1);

208: 6-[2-(2-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid ethyl ester, 390.45 MB; LC-MS m/z 391 (M+1);

209: 6-[2-(3-pyridyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid ethyl ester, 390.45 MB; LC-MS m/z 391 (M+1);

210: 6-[2-(4-methoxyphenyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 446.55 MB; LC-MS m/z 448 (M+1);

211: 6-[2-(3-methoxyphenyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 446.55 MB; LC-MS m/z 448 (M+1);

212: 6-[2-(2-methoxyphenyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 446.55 MB; LC-MS m/z 448 (M+1);

213: 6-[2-(4-were)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 430.55 MB; LC-MS m/z 432 (M+1);

214: 6-[2-(3-were)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 430.55 MB; LC-MS m/z 432 (M+1);

215: 6-[2-(2-were)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 430.55 MB; LC-MS m/z 432 (M+1);

216: 6-[2-(4-forfinal)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 434.52 MB; LC-MS m/z 436 (M+1);

217: 6-[2-(3-forfinal)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 434.52 MB; LC-MS m/z 436 (M+1);

218: 6-[2-(2-forfinal)benzyl]-5,6,7,8-then it is carbonated is loperimide[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 434.52 MB; LC-MS m/z 436 (M+1);

219: 6-[2-(4-chlorophenyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 450.97 MB; LC-MS m/z 452 (M+1);

220: 6-[2-(3-chlorophenyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 450.97 MB; LC-MS m/z 452 (M+1);

221: 6-[2-(2-chlorophenyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f] [1,4]oxazepine-5-carboxylic acid tert-butylamide, 450.97 MB; LC-MS m/z 452 (M+1);

222: 6-[2-(pyrimidine-4-yl)benzyl]-5,6,7,8-tetrahydropyrimido [5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 418.50 MB; LC-MS m/z 420 (M+1);

223: 6-[2-(pyrimidine-2-yl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 418.50 MB; LC-MS m/z 420 (M+1);

224: 6-[2-(pyrimidine-5-yl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 418.50 MB; LC-MS m/z 420 (M+1);

225: 6-[2-(pyrazin-2-yl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid tert-butylamide, 418.50 MB; LC-MS m/z 420 (M+1);

226: 6-[2-(pyrazin-2-yl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid cyclopentylamine, 430.51 MB; LC-MS m/z 432 (M+1);

242: 6-[2-(2-chlorophenyl)benzyl]-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine-5-carboxylic acid, 395.85 MB; LC-MS m/z 397 (M+1);

243: 6-(2-phenylbenzyl)-5,6,7,8-tetrahydropyrimido[5,4-f] [1,4]oxazepine-5-carboxylic acid, 361.40 MB; LC-MS m/z 362 (M+1).

Example 3. The definition of agonistic activity of compounds in respect to the tion to the receptor TGR5

Screening for substances represented by the General formula I, carried out in experiments with cell line SOME 293, in which were expressed human receptor TGR5 (hTGR5). Agonistic activity of compounds was evaluated by increasing the intracellular concentration of camp. For the most active compounds of the concentration dependency was determined values IS (the concentration of the substance in mcmash that causes 50% of maximal effect). Table 1 presents data for some compounds of the formula 1, and And means that IS<1.0 mmol; 1.0 µmol<IS<10 µmol, AS>10 µmol.

Table 1
Atomistic active connections
SubstanceActivitySubstanceActivity
1481
15And90
18In96In
50And97

Example 4. Study of the effect of rectal injection of bile acids (LC)

Investigated the effects of rectal introduction glycometabolic acid (GDC) on the level of glucose in the blood diabetonic mice db/db mice. Sugar levels in male db/db mice (39.5 g) was measured for 24 hours before and at the time of rectal injection, and then through 1, 2, 3, 4, 5, 6 and 24 hours after that. Mice received rectal four compositions: 1) gel containing no active ingredients (vehicle only); 2) gel that does not contain active components, however, followed by oral administration of DPP4 inhibitor Sitagliptin (vehicle+Sitagliptin); 3) gel containing 5 mmol GDC and followed by oral administration of DPP4 inhibitor Sitagliptin (GDC 5 mmol + Sitagliptin); 4) gel containing 5 mmol GDC and followed by oral administration of DPP4 inhibitor Sitagliptin (GDC 50 mmol + Sitagliptin). Inhibitor Sitagliptin was administered orally at a dose of 30 mg/kg 15 minutes before rectal administration of compositions. The gel was obtained on the basis of an aqueous solution of methylcellulose (1%) and Tween-80 (2%). Introduction LCD GDC at both doses significantly and statistically significantly lowers the concentration of glucose in plasma diabetonic mice db/db mice (24% at 50 µm and 20% at 5 mmol). Use only the DPP4 inhibitor Sitagliptin reduces the sugar content in the plasma only 5-1%.

The results clearly show the positive effect of the proposed method of treatment of metabolic diseases.

Example 5. Study of the effect of rectal introduction of LCD on weight change when diabetesthe

Investigated the effects of rectal introduction glycometabolic acid (GDC) on weight diabetonic mice db/db mice. Mice received rectal four compositions: 1) gel containing no active ingredients (vehicle only); 2) gel that does not contain active components, however, followed by oral administration of DPP4 inhibitor Sitagliptin (vehicle + Sitagliptin); 3) gel containing 5 mmol GDC and followed by oral administration of DPP4 inhibitor Sitagliptin (GDC 5 mmol + Sitagliptin); 4) gel containing 5 mmol GDC and followed by oral administration of DPP4 inhibitor Sitagliptin (GDC 50 mmol + Sitagliptin). Inhibitor Sitagliptin was administered orally at a dose of 30 mg/kg 15 minutes before rectal administration of compositions. The gel was obtained on the basis of an aqueous solution of methylcellulose (1%) and Tween-80 (2%). Mice were weighed two days before the experiment, at the time of introduction and two days after administration of the compositions. Introduction LCD GDC at both doses significantly and statistically significantly lowers the weight of the experimental animals.

The results clearly show an effective reduction of weight of the subjects.

Example 5. Metabolic model using DIO-mice.

DIO-m is Shi (Diet Induced Obesity mice mice with obesity induced by diet) are widely used for modeling of the metabolic syndrome in humans, which is characterized by abdominal obesity, high triglycerides, impaired homeostasis of glucose and hyperinsulinemia [Hariri N, Thibault L. High-fat diet-induced obesity in animal models. Nutr Res Rev. 2010; 23(2): 270-99]. To create a DIO model used mice C57B L/6J fed a diet high in fat (high fat diet HFD; food includes 58% of lard. Diet D12492, Research Diet, New Brunswick, NJ; D. West et al. 1992). HFD-diet and water were provided to the animals ad libitum for 28 days before the start of the experiment. Received DIO-model was used to study the pharmacological action of the compounds of General formula I on the secretion of the peptide GLP-1 and glucose metabolism.

Example 6. The study of pharmacological activity of the compounds of General formula I on the secretion incrediboi peptide GLP-1

The investigated compound 4-(3-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclohexylamine (15) of General formula I (dose of 30 mg/kg) in aqueous solution of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%) was administered orally DIO-mice C57B L/6J (6 mice at the time point) for 15 min before oral administration of dextrose (2 g/kg in saline). Blood samples were collected from the tail vein of the animals after 5, 10, 15 and 30 minutes after administration of sa is Ara. As a control were injected aqueous solution of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%). The experiment was repeated for compounds 18, 50 and 96 General formula 1.

Content incrediboi peptide GLP-1 in plasma were determined by standard ELISA method. Figure 4 shows the stimulation of secretion of GLP-1 after 15 and 30 minutes after the introduction of sugar (or after 30 and 45 minutes after administration of the compound). Introduction compounds of General formula I (30 mg/kg) in all cases substantially and statistically significantly stimulates the secretion of the hormone GLP-1.

Example 7. The study of the joint action of the compounds of General formula I and the DPP4 inhibitor Sitagliptin

As follows from the data shown in figure 4, the content of the peptide GLP-1 in plasma significantly decreases due to its degradation by the action of proteases, mainly proteases DPP4 (in all cases the concentration of GLP-1 decreases after 30 minutes compared to 15 minutes).

In this regard, it was studied the effect of proteinase inhibitor DPP4 stability in plasma peptide GLP-1 secretion was induced by the action of TGR5 agonist receptors in the presence of glucose. Inhibitor Sitagliptin was administered orally at a dose of 30 mg/kg for 25 minutes until the introduction of the sugar. As follows from the data shown in figure 5, the proteinase inhibitor DPP4 supports a high concentration of GLP-1 in plasma, which increases the effectiveness of TGR5 agonists.

the results clearly show the positive effect of the proposed method of treatment of metabolic diseases.

Example 8. The study of pharmacological activity of the compounds of General formula I on glucose metabolism (test glucose tolerance GTT)

The investigated compound 4-(3-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclohexylamine (15) of General formula I (doses from 5 to 100 mg/kg) in aqueous solution of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%) was administered orally DIO-mice C57B L/6J (6 mice at the time point) for 15 min before oral administration of dextrose (2 g/kg in saline). Blood samples were collected from the tail vein of animals through 0, 5, 10, 20, 30, 60 and 120 minutes after administration of sugar. As a control were injected aqueous solution of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%). The experiment was repeated for compounds 18, 50 and 96 General formula 1.

The data presented in Fig.6 and 7, indicate statistically significant decrease of glucose in plasma DIO-mice under the action of agonists TGR5 receptor.

The results clearly indicate the availability of the proposed approach for the treatment of metabolic diseases.

1. The compound of General formula 1 or its pharmaceutically acceptable salt

where R1, R2 and R3 independently from each other represent a Deputy cyclic system selected from: hydrogen, C1-C3alkyl is, halogen, triptorelin group, C1-C3alkoxy, ceanography, cryptometer; amino, substituted C1-C3by alkyl;
or two radicals R3, located at adjacent carbon atoms in a benzene ring together with the benzene ring to which they are bound, form a 3,4-methylenedioxyphenyl,
R4 represents hydrogen, C1-C5alkyl, carboxyl group, C1-C3alkoxycarbonyl or amide group CONHR5;
R5 is an optionally substituted C1-C3the alkyl, C5-C6cycloalkyl, optionally substituted phenyl, benzyl, pyridium;
X and Y represent two hydrogen atoms or an oxygen atom,
moreover, if Y=O, then X=2N,
if Y=2H, X=O or
X=Y=2H;
sign (N) indicates the possibility of bioisosteric substitution of the benzene ring to the pyridine, pyrimidine, pyridazine, triazine or pyrazinone.

2. The compound according to claim 1 of General formula 1.1 and 1.2 or its pharmaceutically acceptable salt

where R1, R2, R3, R4 and N have the above values.

3. The compound according to claim 2 represented by the General formula 1.3 and 1.4 or its pharmaceutically acceptable salt

where R1, R2, R3, R5 and N have the above values.

4. The compound according to claim 1, selected from the group represented by the formula 01-101:
4-(3-fenil nil)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (01),
4-(3-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (02),
4-(4-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (03),
4-(2-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (04),
4-[2-(pyridin-4-yl)benzoyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (05),
4-[2-(pyridin-2-yl)benzoyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (06),
4-(4-phenyldiamine)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (07),
4-[(4-vinylpyridin-3-yl)methyl]-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (08),
4-[2-(pyridin-4-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (09),
4-[2-(pyridin-2-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (10),
4-(4-phenyldiamine)-7-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (11),
4-[2-(pyridin-4-yl)benzoyl]-7-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (12),
4-[2-(pyridin-2-yl)benzoyl]-7-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (13),
4-(3-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclopentylamine (14),
4-(3-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclohexylamine (15),
4-(4-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (16),
4-(2-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (17),
4-[2-(pyridine-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (18),
4-[2-(pyridin-2-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (19),
4-(2-phenylbenzyl)-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (20),
4-[2-(pyridin-4-yl)benzyl]-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (21),
4-[2-(pyridin-2-yl)benzyl]-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (22),
4-[2-(3,4-methylenedioxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (23),
4-[2-(pyridin-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (24),
4-[2-(pyridin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (25),
4-[2-(pyridin-3-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (26),
4-[2-(3,4-methylenedioxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (27),
4-[2-(pyridin-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (28),
4-[2-(pyridin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (29),
4-[2-(pyridin-3-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (30),
4-[2-(3,4-methylenedioxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid ethyl ester (31),
4-[2-(Piri is in-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid ethyl ester (32),
4-[2-(pyridin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid ethyl ester (33),
4- [2-(pyridin-3-yl)benzyl]-2,3,4,5-tetrahydrobenzo [f] [1,4]oxazepine-5-carboxylic acid ethyl ester (34),
4-[2-(4-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (35),
4-[2-(3-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (36),
4-[2-(2-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (37),
4-[2-(4-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (38),
4-[2-(3-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (39),
4-[2-(2-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (40),
4-[2-(4-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (41),
4-[2-(3-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (42),
4-[2-(2-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (43),
4-[2-(4-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (44),
4-[2-(3-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (45),br/> 4-[2-(2-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (46),
4-[2-(4-were)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (47),
4-[2-(3-were)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (48),
4-[2-(2-were)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (49),
4-[2-(4-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (50),
4-[2-(3-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (51),
4-[2-(2-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (52),
4-[2-(pyrimidine-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (53),
4-[2-(pyrimidine-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (54),
4-[2-(pyrimidine-5-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (55),
4-[2-(pyrazin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (56),
4-[2-(pyrazin-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclopentylamine (57),
4-[2-(pyrazin-2-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxaze the ine-5-carboxylic acid cyclopentylamine (58),
4-[2-(pyrazin-2-yl)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (59),
4-[2-(pyrimidine-4-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (60),
4-[2-(pyrimidine-2-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (61),
4-[2-(pyrimidine-5-yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (62),
4-[2-(4-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (63),
4-[2-(3-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (64),
4-[2-(2-methoxyphenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (65),
4-[2-(4-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (66),
4-[2-(3-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (67),
4-[2-(2-were)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (68),
4-[2-(4-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (69),
4-[2-(3-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (70),
4-[2-(2-forfinal)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (71),

4.[2-(4-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (72),
4-[2-(3-chlorophenyl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (73),
4-[2-(2-harfe who yl)benzyl]-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (74),
4-[2-(4-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (75),
4-[2-(3-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (76),
4-[2-(2-forfinal)benzyl]-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (77),
4-(2-phenylbenzyl)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (78),
4-(2-phenylbenzyl)-7-triptoreline-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (79),
4-(2-phenylbenzyl)-7-tertbutyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid (80),
4-(3-phenylbenzyl)-3-oxo-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclopentylamine (81),
4-(3-phenylbenzyl)-3-oxo-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid cyclohexylamine (82),
4-(2-phenylbenzyl)-3-oxo-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (83),
4-[2-(pyridin-4-yl)benzyl]-3-oxo-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (84),
4-[2-(pyridin-2-yl)benzyl]-3-oxo-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (85),
4-(2-phenylbenzyl)-3-oxo-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (86),
4-[2-(pyridin-4-yl)benzyl]-3-oxo-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carbon is howling acid tert-butylamide (87),
4-[2-(pyridin-2-yl)benzyl]-3-oxo-7-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (88),
4-[2-(3,4-methylenedioxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (89),
4-[2-(pyridin-4-yl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (90),
4-[2-(pyridin-2-yl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (91),
4-[2-(pyridin-3-yl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (92),
4-[2-(4-methoxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (93),
4-[2-(3-methoxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (94),
4-[2-(2-methoxyphenyl)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (95),
4-[2-(4-were)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (96),
4-[2-(3-were)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (97),
4-[2-(2-were)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (98),
4-[2-(4-forfinal)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (99),
4-[2-(-forfinal)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (100),
4-[2-(2-forfinal)benzyl]-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-5-carboxylic acid tert-butylamide (101).

5. The method of obtaining compounds of General formula 1.3 according to claim 3, which consists in recovering the corresponding ortho-cyanoacetate General formula A1 over Raney Nickel, followed by cyclization and recovery of lithium aluminum hydride in connection with the General formula A2 and acylation last appropriate billnum allelochemical

where R1, R2, R3, X and N have the above values.

6. The method of obtaining compounds of General formula 1.4 according to claim 3, which consists in the interaction of the appropriate allegedely General formula B1 with isonitriles and the appropriate amine, and recovering the resulting compound of General formula B2 complex, borane-dimethyl sulfide in tetrahydrofuran

where R1, R2, R3, R5 and N have the above values.

7. Active component that has the property of secretion stimulator ingreenwich hormones, it is preferable properties of agonist receptors bile acids TGR5, representing a compound of General formula 1 according to any one of claims 1 to 4.

8. Pharmaceutical composition for the prevention and treatment of metabolic diseases associated with glucose metabolism, containing an effective amount of an active component according to claim 7.

10. The pharmaceutical composition according to any one of p and 9 in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing.

11. Drug combo tool for the prevention and treatment of metabolic diseases associated with glucose metabolism, containing an effective amount of an active component according to claim 7, or pharmaceutical composition according to any one of p-10 and secretion stimulator is an endogenous bile acid, or a mixture of endogenous bile acids in the form of rectal suspension or gel.

12. Method for the prevention and treatment of metabolic diseases associated with glucose metabolism, the introduction of an effective quantity of the active component according to claim 7, or pharmaceutical composition according to any one of p-10.

13. Method for the prevention and treatment of metabolic diseases associated with glucose metabolism, the introduction of an effective amount of dosage of the combined funds under paragraph 11, the inhibitor of the protease DPP-IV administered orally or by injection, and endogenous bile acid, or a mixture of endoge the different bile acids is administered rectally.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described are novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side with considerable absorption in the region up to 410-420 nm, having general formulae (a)-(k) (structural formula and values of radicals are given in the description), composition which is stabilised with respect to UV radiation and containing novel UV-absorbers, and use of the novel compounds as UV light stabilisers for organic materials.

EFFECT: obtaining novel benzotriazole UV-absorbers, having absorption spectrum shifted towards the long-wave side.

13 cl, 23 ex, 2 tbl

Polycyclic compound // 2451685

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a new polycyclic compound with general formula (I-1) and (1-3) or a pharmaceutically acceptable salt thereof where X1- -CR1 =CR2 - where R1 and R2 independently stand for hydrogen or C1-6 alkyl while Het stands for a radical of the following formulae: that may be substituted 1-3 times additionally described is a pharmaceutical composition containing such compound and intended for prevention or treatment of diseases caused by β-amyloid.

EFFECT: production of a pharmaceutical composition prevention or treatment of diseases caused by β-amyloid.

7 cl, 392 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (R)-N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide substantially free from (S)-N-(3-amino-propyl)-N[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methypropyl]-4-methyl-benzamide, or its pharmaceutically acceptable salt which shows the properties of Eg5 inhibitor.

EFFECT: invention also refers to a pharmaceutical composition containing said compound and its pharmaceutically acceptable salt.

4 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), and a salt or hydrate thereof:

,

in which R1 denotes a hydrogen atom; R2 denotes a hydrogen atom; R3 and R4 independently denote a hydrogen atom; R5 denotes a hydrogen atom or a fluorine atom; R6 and R7, together with carbon atoms to which they are bonded, form a 5- or 6-member cyclic structure, where the cyclic structure is a partial structure which, together with a pyrrolidine ring, forms a condensed cyclic (bicyclic) structure, the 5- or 6-member cyclic structure can contain an oxygen atom as a ring atom, R5 can be a methylene group which, together with R6, forms a 3-member condensed cyclic structure; and Q is a partial structure of formula (II):

,

in which R8 denotes a 1,2-cis-2-halogencyclopropyl group, a cyclopropyl group or a 6-amino-3,5-difluoropyridin-2-yl group; R9 denotes a hydrogen atom; R10 denotes a hydrogen atom; R11 denotes a hydrogen atom; XI denotes a fluorine or hydrogen atom; A1 denotes a nitrogen or partial structure of formula (III):

,

in which X2 is a methyl group, an ethyl group, a methoxy group or a chlorine atom, or X2 and R8, together with their coupling part of the parent skeleton, form a cyclic structure, such that Q denotes a partial structure of formula , in which Y0 denotes a methyl group or a pre-methyl group, and X1, R9, R10, R11 assume values given above. The invention also describes a medicinal agent based on said compound, having antibacterial activity, an antibacterial agent and a therapeutic agent for treating infections.

EFFECT: novel compounds are obtained and described, which have strong antibacterial activity not only on gram-negative bacteria, but gram-positive cocci as well, which have low sensitivity to quinolone antibacterial agents, and which demonstrate high safety and excellent pharmacokinetic properties.

18 cl, 61 ex

FIELD: pharmachology.

SUBSTANCE: invention describes new compounds with general formula (I-c) Where R1 is a radical (d-1) or (d-2) (radical values are given in the invention formula) and pharmaceutical composition containing them. The described compounds are the hepatitis C inhibitors and can be used in medicine.

EFFECT: enhanced hepatitis C inhibition.

5 cl, 1 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula l where R1 represents CH2CI, CH2F or-C1-2alkyl-R3R4; R3 represents -O-; R4 represents phenyl, where said R4 group is optionally substituted by 0-5 groups J where J represents halogen; R2 represents C6-10aryl; or a group: where Y represents CH, AA2 represents C1-C7alkyl, R8 and R9 represents hydrogen or halogen; or a group: where Y represents CH, AA2 represents C1-C7alkyl, and R6 represents hydrogen, P4 represents -(T)p-R, where T represents -C(O)O-group, R represents C1-C12alkyl, and p is equal to 1; or a group: where A2 represents O, R7 and R8 together with atom whereto attached form a (10-14)members tricyclic unsaturated ring, e.g. carbazole; or a group: where AA2 represents C1-C7alkyl, and R15 represents 2-tert-butylphenyl. The declared compounds are caspase inhibitor prodrugs which under certain conditions can be transformed into biologically active compounds, particularly caspase inhibitors. Also, said invention refers to methods of producing said compounds and to a pharmaceutical composition exhibiting caspase inhibitory action on the basis of the said compounds.

EFFECT: what is produced are new compounds and based pharmaceutical composition which can find application in medicine for treating the diseases associated with inflammatory or degenerative conditions.

13 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted 4-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6,7-dicarbonitriles of general formula: where R=H (a); CH3 (b); OCH3 (c); CI (d) which can be used as biologically active substances, fluorescent materials and for synthesis of phthalocyanines. The method involves synthesis of substituted 4-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6,7-dicarbonitriles through a reaction which takes place in two steps, where at the first step 4-bromo-5-nitrophthalonitrile reacts with sodium salts of substituted 3-phenylpropanoates in molar ratio 1:2, respectively, at temperature 19…25°C for 12-20 hours in dimethyl formamide (DMF) solution, after which the reaction mass is diluted with tenfold excess water with T=0…25°C. The released resinous residue is extracted with dichloromethane, thoroughly washed with water and chromatographed on silica gel. The eluent (solvent) is evaporated. The residue of the intermediate product is filtered and re-crystallised from alcohol. At the second step of the method, tin dichloride solution in concentrated hydrochloric acid is mixed with the solution of the obtained intermediate product in ethyl alcohol in molar ratio 3.5-4.5:1, respectively, at temperature 30...50°C and reaction time of 1-2 hours, after which the reaction mixture is diluted with tenfold excess water with T=0…25°C, and the precipitate is filtered and re-crystallised from alcohol.

EFFECT: obtaining novel heterocyclic dicyano-derivatives of benzoxazines.

1 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

,

where R1 is selected from formulae

, and ,

n equals 0; R6 and R7 are independently selected from hydrogen, C1-C6alkyl, cyanoC1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; or R6 and R7 together with a carbon atom to which they are bonded form a 6-member heterocycloalkyl with one nitrogen atom; wherein any alkyl in R6 and R7 can optionally contain a methylene group substituted with an O atom; wherein any aryl in R6 and R7 or formed by a combination of R6 and R7 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, -XC(O)OR10; where X denotes a bond; R10 is independently selected from C1-C6alkyl; R8 is selected from C5-C9heteroarylC0-C4alkyl containing 2-3 heteroatoms independently selected from N, O and S; wherein any heteroaryl in R8 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, C3-C6cycloalkyl; R2 denotes hydrogen; R3 and R4 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; wherein any alkyl in R3 and R4 can optionally contain a methylene group substituted with a S(O)2 group; R5 is selected from C5-C6heterocycloalkyl with 1-2 heteroatoms selected from N and O, and NR12R13; where R12 and R13 are independently selected from C1-C6alkyl; as well as pharmaceutically acceptable salts and isomers thereof. The invention also relates to use of compounds of formula (I) in preparing a medicinal agent, and to a pharmaceutical composition having cathepsin S inhibiting properties, which contains a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically acceptable filler.

EFFECT: obtaining compounds which can be used as cathepsin S inhibitors.

10 cl, 12 dwg, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oxazolidinone derivatives covered by general graphic formula (I) and to their pharmaceutically acceptable salts. In formula (I) R1, R2, R3 and R4 are independently chosen from a group including -H and halogen; A is chosen from a group including R5 and R6 are independently chosen from a group including -H, -F, -CI, -Br, -OH, alkyl(C1-C6), haloalkyl(C1-C6), alkoxygroup(C1-C6); R7 is chosen from a group including -H, alkyl(C1-C6); either R7 and R5 or R6 taken together form a cycle of 2 carbon atoms and include 1 group chosen from O which in turn can be substituted by one substitute chosen from alkyl(C1-C6); R12 is chosen from a group including -H, -COR14, -CSR14, -COOR14; R14 is chosen from a group including alkyl (C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), R16, R17 and R18 represent -H; R21 is chosen from a group including -H, alkyl(C1-C6); X is chosen from a group including O, S, and Y is chosen from a group including O, S, SO, SO2, and NR12; and optional substitutes of alkyl(C1-C6) groups can represent one or two groups chosen from the following: -OR21, -CN.

EFFECT: invention refers to methods for preparing the compounds of the invention, to application of oxazolidinone derivatives for preparing a drug for treating bacterial infections and to a pharmaceutical composition for treating bacterial infections, including a therapeutically effective amount of the compound of the invention.

36 cl, 10 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4.5-c][1.5]naphthyridine-4-amine. The method involves the following: 2-methyl-1-(2-methypropyl)-5-oxido-1H-imidazo[4.5-c][1.5]naphthyridine is obtained in a carrier which contains lower alcohol; the 2-methyl-1-(2-methypropyl)-5-oxido-1H-imidazo[4.5-c][1.5]naphthyridine in the carrier is combined with a reagent which contains ammonia or ammonium and arylsulfonyl halide to form a mixture; and components of the mixture can react in a period of time sufficient for formation of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4.5-c][1.5]naphthyridine-4-amine.

EFFECT: obtaining a new compound.

67 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to ligand with a wide range of simultaneous receptor activity towards adrenergic α1A, α1B , α1D, α1A, α2A, β2, dopamine D1, D21, D2S, D3, serotonin 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, 5- HT7, sigma α1, α2 receptors, to calcium and sodium channels, monoamine transporters [norepinephrine (NET) and dopamine (DAT)], which is 3-methyl-9-benzyl-1,2,3,4-tetrahydrocarbonyl naphthalene-1,5-disulphonate of formula 1:

. The invention also relates to a pharmaceutical composition, which has a medicinal origin, which is a ligand of formula 1 with the given range of simultaneous receptor activity for preventing and/or treating diseases of the central nervous system, pathogenesis of which is related to GPCR receptors, ion channels and monoamine transporters, method of preparing said composition, and to medicinal agents.

EFFECT: range of simultaneous activity towards said receptors increases capacity and effectiveness of using the said ligand.

10 cl, 10 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 3-[(3,5-dinitrophenyl)carboxamido]1,4,6-trimethyl-5-chloropyrazolo[3,4-b]pyridine, which exhibits antidote activity towards 2,4- dichlorophenoxyacetic acid on sunflower.

EFFECT: wide range of biologically active substances, obtained synthetically.

1 cl, 3 ex, 1 tbl

The invention relates to compounds of the formula a-b-D-E-F-G, where the values of the radicals presented in the description in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates
The invention relates to the production of highly pure substances that are used as reagents, in particular to an improved process for the preparation of 1,10-phenanthroline

FIELD: organic chemistry, technology of organic compounds.

SUBSTANCE: invention relates to heterocyclic o-dicarbonitriles. Invention describes heterocyclic o-dicarbonitriles of the general formula: wherein R1 means the following substances: wherein R2 means the following substances: . Heterocyclic o-dicarbonitriles can be used for preparing hexazocyclanes-fluorophores as a donor-fragment used for preparing hexazocyclanes-bifluorophores and hexazocyclanes-trifluorophores. Invention provides preparing new compounds possessing useful properties.

EFFECT: valuable properties of compounds.

4 tbl, 4 ex

The invention relates to new derivatives dibenzoxazepine or dibenzodiazepine formula I, where R1and R2independently of one another denote hydrogen, unsubstituted (NISS
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