Heterocyclic tgr5 bile acid receptor agonists, pharmaceutical composition, methods for preparing and using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula I, or their racemic mixture, or their individual optic isomers, or pharmaceutically acceptable salts possessing the properties of TGR bile acid receptor agonist. The invention also refers to methods for preparing the compounds. In general formula I , X represents amino group R'R"N, wherein the substitutes R' and R" can be optionally identical, or represents hydrogen, C1-C6alkyl, C3-C6cycloalkyl; substituted C1-C6alkyl, wherein the substitute is specified in phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy, phenyloxy, C3-C6cycloalkyl, 5-6-merous heteroaryl with 1 nitrogen atom; aryl specified in phenyl optionally substituted by fluorine, C1-C3alkyl, C1-C3 alkoxy; 5-6-merous heteroaryl with nitrogen atom as heteroatom; C2-C4alkenyl, acyl specified in C1-C6alkylcarbonyl or C3-C6cycloalkylcarbonyl; or substituted oxygroup, which represents hydroxy group, wherein hydrogen is substituted by C1-C6alkyl optionally substituted by hydroxy, di(C1-C3alkyl)amino, phenyl, which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C2-C4alkenyl; and 5-6-merous heterocyclyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom; R1a and R1b represents hydrogen, C1-C3alkyl, or R1a and R1b together form methylene chain -(CH2)n-, wherein n=2-5; R1c and R1d represents hydrogen, C1-C3alkyl; R2 represents acyl group specified in C1-C6alkylcarbonyl, wherein alkyl can be substituted by phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C3-C6cycloalkylcarbonyl; phenylcarbonyl, which can be substituted by halogen, C1-C3alkyl, C1-C3alkoxygroup, oxygroup, C1-C3alkylene dioxygroup; 5-6-merous heteroarylcarbonyl with nitrogen atom, or oxygen atom, or sulphur atom as heteroatom, optionally substituted by carboxy, halogen or C1-C3alkoxycarbonyl, substituted aminocarbonyl group, wherein the substitute can be specified in C1-C6alkyl optionally substituted by C1-C3alkoxycarbonyl, halogen, 5-6-merous heteroaryl together with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom; C3-C6cycloalkyl; phenyl optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3alkoxycarbonyl, C1-C3alkylenedioxygroup; 5-6-merous heteroarym with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom optionally substituted by carboxy, C1-C3alkoxycarbonyl; aminocarbonyl group substituted by C1-C3alkyl; sulphonyl group specified in alkylsuphonyl optionally substituted by hydroxyl group, cyano group, phenyl, which is optionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group; henylsulphonyl oprtionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group, cyano group, C1-C3alkylene dioxygroup, or 5-6-merous heteroarylsulphonyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy group; R3 represents hydrogen.

EFFECT: compounds can be used for preparing the pharmaceutical composition applicable in treating or preventing metabolic diseases, such as diabetes, obesity, diabetic obesity, metabolic syndrome, hypercholesterolemia, dislipidemia.

14 cl, 17 dwg, 8 tbl, 16 ex

 

The invention relates to new physiologically active substances, new the non-steroidal agonist receptor TGR5, active ingredients for pharmaceutical compositions, to pharmaceutical compositions and medicines containing heterocyclic agonist receptors bile acids TGR5, which stimulates the secretion of ingreenwich hormones, the method of treatment of metabolic diseases such as diabetes, obesity, metabolic syndrome and associated cardiovascular and neurodegenerative diseases.

According to the world Health Organization in 2008, 347 million people worldwide were suffering from diabetes [who fact sheet 312, September 2012], while the number of patients has more than doubled compared to 153 million in 1980 [Danaei G, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2-7 million participants. Lancet. 2011; 378(9785): 31-40]. 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, Gaballa M Diabesity: an overview of a rising epidemic. Nephrol Dial Transplant 2011; 26: 28-35.] The danger of diabetes in combination with overweight (obese or obesity), which is an annual cause of death of more than 280 thousand people in the USA. Widely 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]. Widespread diabetesthe acquired and began to spread rapidly 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], a 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.

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 is [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 undergo various tests, admitted of 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) appeared to increase the risk of heart attack and cardiac arrest [Avorn J. Two centuries of assessing drug risks. New Engl J Med. 2012; 193-197]. The main causes of permanent failures researchers are lack of understanding of the complex picture of the disease, particularly the availability of numerous signaling mechanisms. The impact of only one effector target leads to "escape" the pathological process due to activation of other mechanisms. Therefore, one of the main directions in the development of anti-diabetic medication at the present time is the search for pharmacological agents to be able to pause the development of pathology. In particular, the search is conducted stimulators of secretion of the hormone is new proteins, mainly, GLP1, and YYP and GIP. These properties are jelasnya acid (LCD), which are specifically associated with GPCR receptors LCD TGR5.

TGR5 receptors (also known as GPBAR1, M-BAR, AXOR 109, GPR131 and GPCR19) are GPCR-receptor class a, related to Gs-proteins [Tiwari And P. Maiti TGR5: an emerging bile acid GPCR target for the potential treatment of metabolic disorders. Drug Disc Today. 2009; 14: 523]. They are expressed mainly in the gallbladder, gastrointestinal tract, spleen, lung and placenta [Maruyama T, et al. Identification of membrane-type receptor for bile acids (M-BAR). 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 [Pols TWH, et al. The bile acid membrane receptor TGR5: a valuable metabolic target. Dig Dis. 2011; 29: 37]. On the other hand, stimulation of TGR5 receptor regulates a number of metabolic processes [Chen X, et al. TGR5: a novel target for weight maintenance and glucose metabolism. Exp Diabetes Res. 2011; ID 853501]. 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. [Knop FK. Bile-induced secretion of GLP-1: patophysiological Memorandum in type 2 diabetes? Am J Physiol Endocrinol Metab. 2010; E10-E13]. In turn, 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 Les the attachment of such diseases, as diabetes, diabetesthe and obesity.

Because endogenous LCD due to its steroid (hormone) nature is able to interact simultaneously with many biological targets (Fig.1), including FXR nuclear receptors [Prawitt J, et al. Bile acid metabolism and the pathogenesis of type 2 diabetes. Curr Diab Rep.2011; 11: 160], it is necessary to search for selective TGR5 agonist receptors. The most reasonable search among small molecules, non-steroidal nature. The prospects of this approach is confirmed by a series of drug candidates - non-steroidal TGR5 agonists that are currently in various stages of clinical and laboratory research (table 1) [1) http://www.integrity.prous.com. 2) Gioiello A, Rosatelli E, Nuti R, Macchiarulo A, Pellicciari R. Patented TGR5 modulators: a review (2006 - present). Expert Opin Ther Patents. 2012; 1-16]. Known patent of the Russian Federation [RU 2456287, publ. 27.07.12], which describes the secretion stimulants ingreenwich hormones, non-steroidal compounds derivatives of 2,3,4,5-tetrahydrobenzo[f] [1, 4]oxazepine interest in the quality of drug substances to create new drugs for prevention and treatment of metabolic diseases. The disadvantage of this series of compounds is the difficulty of obtaining pure prodrugs, because the receiving occurs in several stages: cyclization and recovery with lithium aluminum hydride to obtain poliuto the aqueous product then the subsequent acylation polesotechnic product billnum allelochemical. This makes it difficult obtaining a drug candidate for clinical studies.

/tr>
Table 1
Non-steroidal agonists of the receptor TGR5 in various stages of clinical and preclinical development as potential antidiabetic agents
ConnectionStructurePhase I trialsDeveloperPatent/article
SB-756050Phase IGlaxoSmithKline (Originator)WO 2007127505
APreclinicaGlaxoSmithKline (Originator)J Med Chem 2009, 52 (24): 7962
GlaxoSm ithKlinePreclinicaGlaxoSmithKline (Originator)Bioorg Med Chem Lett 2010, 20(4): 1363
Kalypsys-35PreclinicaKalypsys (Originator)WO 2008097976
RDX-009The structure is not openPreclinicaArdelyx (Originator)Ardelyx Press Rel.
2011, August 30
XL-475The structure is not openPhase IExelixisExelixis Pharmaceuti cals Web Site 2010, May 25

/tr>
Table 1
RocheTestRoche (Originator)WO 1012117000
IRMTestIRM, LLC (Originator)WO 2012082947
Roche
TestRoche (Originat or)WO 2012007365
RocheTestRoche (Originator)US 2011178089

Table 1
ExelixisTestExelixis Originator)WO 011071565
MSD KKTestMSD KKWO 2010117090
ExelixisTestExelixisWO 2010093845
TakedaTestPfizer Takeda (Originator)JP 2006063064
Kalypsys TestKalypsys (Originator)WO 2010014739

Table 1
KalypsysTestKalypsys 1 (Originator)WO 009026241
NovartisTestNovartis(Originator)WO 2008125627
KalypsysTestKalypsysWO 2008067222
NovartisTestNovartis (Originator)WO 2007110237
TakedaTestTakeda (Originator)JP 2006063064

Takeda
Table 1
TestTakeda (Originator)WO 2004067008 JP 2006056881
RocheTestRpche (Originator)US 2010105906
BanyuTestBanyu (Originator)WO 2010117084

Thus, the search for an effective non-steroidal agonists of the receptor TGR5 is extremely important, relevant and promising task.

With the aim of developing new high-performance anti-diabetic drugs by the authors of the present invention made extensive screening of low molecular weight compounds of different classes were found connection-hits connection-leaders belonging to several families of heterocyclic compounds, we then conducted aimed modification of many of the positions of the detected structures and their testing, established relationship "structure-activity" and selected the most promising series. In the synthesized a series of new derivatives, the cat is who are original and highly effective agonists of the receptor TGR5. Received physiologically active heterocyclic compounds include the new derivative tetrahydrobenzo[f][1,4]oxazepine not previously described in the literature. To date, the ability of these compounds to exhibit agonistic properties in relation to TGR5 receptors was not known.

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, in a loop containing at least one nitrogen atom.

"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" (1-C6)alkyl substituents. Preferred alkyl groups are lower (1-C6)alkyl, or methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl. The alkyl may have substituents.

"Lam is practical" radical means radical, obtained by removing a hydrogen atom from a non-aromatic C-H bond. Aliphatic radical can optionally contain substituents is an aliphatic or aromatic radicals, as defined in this section. Representatives of aliphatic radicals include alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, aralkyl, aralkylamines, uralelectromontrage, aralkyl, aralkyl, aralkylamines, heteroalkyl, heteroalkyl, heteroalicyclic, heteroalicyclic, annelirovannymi aristically, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi heteroarylboronic, annelirovannymi arithmetiles, annelirovannymi heteroalicyclic, annelirovannymi arylheteroacetic, annelirovannymi heterooligomerization.

"Alkenyl" means aliphatic linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and including the carbon-carbon double bond. Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. To alkenylphenol group can be attached one or more aromatic, cyclic or heterocyclic systems.

"Active component" (the drug in the society, 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).

"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.

"Alkyloxy" or "Alkoxy" means Alkyla - group in which alkyl is defined in this section. The preferred alkoxygroup are methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy and tert-butoxy.

"Amino group" means R R"N - group, unsubstituted or optionally substituted by the same substituents R' and R". The amino group may have substituents.

"Alkylthio" means alkyl-S-group in which the alkyl group defined in this section.

"Aminocarbonyl" means C(=O)N R R" group, unsubstituted or optionally substituted by the same substituents carbamaepine R' and R", including hydrogen, methyl, cycloalkyl that with atomo the nitrogen forms a pyrolidine cycle.

"Annelirovannymi cycle" (condensed cycle) means of bi - or polycyclic system, where annelirovannymi cycle and cycle or politics, with whom he "annylirovan have at least two common atom. Annulated can be aromatic, non-aromatic system and the heterocyclic system.

"Aralkyl" means an alkyl group substituted by one or more aryl groups, in which values of aryl and alkyl are defined in this section. Examples Uralkalij groups are optionally substituted benzyl, phenethyl, inproper.

"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.

"Aromatic cycle" (aromatic system) means a planar cyclic system in which all the atoms of the cycle involved in the formation of a unified system of conjugation, including, according to the hückel rule, (4n+2) π-electrons (n is a nonnegative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, etc., In the case of heteroaromatic cycles in the system of pairing involves π-electrons and the p-electrons of heteroatoms, their total number is also ravnets the (4n+2). Examples of such cycles include pyridine, thiophene, pyrrole, furan, thiazole, etc., Aromatic cycle can have one or more "cyclic system substituents" which may be annylirovan with non-aromatic cycle, heteroaromatic or heterocyclic system.

"Acyl group (Acyl) means H-C(=O)-, optionally substituted C1-C5alkyl-C(=O)-, C1-C5alkenyl-C(=O)-, C1-C5cycloalkyl-C(=O)-, (preferably cyclopropyl-C(=O)-, cyclobutyl-C(=O)-); heterocyclyl-C(=O) -, preferably 2-methylfuran), aryl-C(=O)- (aroyl), aralkyl-C(=O) -, preferably 3-phenylpentane-C(=O)-), heteroaryl-C(=O)- (heteroaryl), heteroallyl-C(=O)group, in which C1-C5alkyl, C1-C5alkenyl-, C3-C5cycloalkyl-, heterocyclyl-, aryl-, aralkyl, heteroaryl, heteroaromatic, methoxy group, these groups may have substituents, see "cyclic system substituents", "substituted alkyl", "substituted alkenyl, the substituents of the heterocyclic system" is defined in this section.

"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. Pristavki the "Aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of 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. Preferably pyrrolyl, furanyl, thienyl, pyridinyl, pyrrolidin, imidazolyl, oxazolyl, benzothiadiazole, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, chinoline, imidazolyl, cyanopyridyl, hintline, thienopyrimidines, pyrrolopyridine, imidazopyridine, ethenolysis, benzoxazinones, 1,2,4-triazinyl, thienopyrrole, properaly and other

"Heterocyclyl" means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system containing from 3 to 10 carbon atoms, predominantly from 4 to 6 carbon atoms, in which one or more carbon atoms replaced by a heteroatom, such as nitrogen, oxygen, sulfur, phosphorus. 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 substituents, which may be the same or different. Atoms of nitrogen and sulfur, in heteros who cycline, 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, tetrahydrofuryl, tetrahydrothieno and other

"Replaced alkenyl" is replaced by alkenyl may also have one or more identical or different substituents including halogen, alkenylacyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic etc. Preferred alkenylamine groups are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-enyl, n-pentenyl and n-hexenyl.

"Substituted alkyl" substituted alkyl may have one or more identical or different substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonyl, heteroarylboronic, R R"N-, where R' and R" independently from each other represent "amino substituents", which is defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, hetero is iklil or heteroaryl, or R' and R" together with the N atom to which they are bound, form a through R' and R" 4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl substituents are aryl, heteroaryl, heterocyclyl, hydroxy, C1-C5alkoxy, C1-C5alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or R R N-R R NC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arithmetiles. Namely, the hydroxy-group, substituted florfenicol oxygraph, mono - and dis1-C5alkylamino (dimethylaminopropyl, methylaminopropyl)1-C5allyloxycarbonyl group (ethoxycarbonyl), phenyl, chlorophenyl, forfinal,1-C5alkyl (methyl) substituted phenyl, With3-C5cycloalkyl (cyclopentyl) substituted phenyl, With1-C5alkoxy substituted phenyl (methoxyphenyl), thiophenyl, furanyl, pyrrolidin.

"The Vice-amino - substituents of the amino group, R' and R" represent hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C5cycloalkyl (see Deputy cyclic system), optionally substituted aryl (see Deputy cyclic system), optionally substituted, heteroa the Il (see Deputy cyclic system), optionally substituted heterocyclyl (see Deputy cyclic systems)1-C5alkenyl, acyl, aroyl, heteroaryl, C1-C5alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkoxycarbonyl, aryloxyalkyl, arelaxation, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, optionally substituted aminosulfonyl. R R"N-group may represent nonaromatic azaheterocycle, preferably azetidin, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperazine, homopiperazin. Preferred substituents of the amino groups are hydrogen, C1-C5alkyl, C3-C5cycloalkyl, substituted C1-C5alkyl (the"substituted alkyl"), not necessarily simultaneously substituted by 1-3 radicals substituted phenyl (C1-C5by alkyl, halogen, C1-C5alkoxy group, a C1-C5allyloxycarbonyl), pyridinyl, optionally substituted by titaniam, optionally substituted TuranAlem (see "cyclic system substituents").

"Cyclic system substituents" can represent aryl groups, preferably f the Nile or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle. Preferably the cyclic system substituents are hydrogen, halogen (chlorine, fluorine, bromine), optionally substituted C1-C5alkyl, optionally substituted ciclos3-C5alkyl, C1-C5alkene, the hydroxy-group, With1-C5alkyloxy (methoxy, ethoxy, propoxy, fluids ethylene glycol fluids of methanediol), cyano, C1-C5allyloxycarbonyl (methyl, ethyl), allylthiourea (methylthio) carboxypropyl, aminocarbonyl (see "aminocarbonyl"), phenyl annelirovannymi with a 5-7 membered saturated cycle containing 1-3 heteroatoms (atoms nitrogen, oxygen and sulfur, preferably).

"Deputy heterocyclyl" can be representatives of the aryl groups are preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle. Preferably the cyclic system substituents are hydrogen, halogen (chlorine, fluorine, bromine), optionally substituted C1-C5alkyl, optionally substituted ciclos3-C5alkyl, C1-C5alkene, the hydroxy-group, With1-C5alkyloxy (methoxy, ethoxy, propoxy, W etrange is Olya, fluids of methanediol), cyano, C1-C5allyloxycarbonyl (methyl, ethyl), allylthiourea (methylthio) carboxypropyl, aminocarbonyl (see "aminocarbonyl"), phenyl annelirovannymi with a 5-7 membered saturated cycle containing 1-3 heteroatoms (atoms nitrogen, oxygen and sulfur, preferably).

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

"Substituted medinova group" means R R"N-(C=NR'")- group in which the substituents R', R" and R"' can be represented optionally substituted by alkyl, alkenyl, quinil, cycloalkyl, aryl, hetaryl and heterocyclyl, the value of which is determined in this section. R R"N-fragment amedieval group may represent nonaromatic azaheterocycle, preferably azetidin, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperazine, homopiperazin.

"Replaced aminocarbonyl group" (aminocarbonyl) means R R N-C(=O)- group in which the substituents R' and R" can be represented optionally substituted by alkyl, alkenyl, quinil, cycloalkyl, aryl, hetaryl and gets what reticella, the value which is defined in this section. Preferred aminocarbonyl groups are optionally substituted C1-C5alkyl, C1-C5alkenyl,3-C5cycloalkyl, optionally substituted aryl (see Deputy cyclic system), optionally substituted hetaryl (see Deputy cyclic system), optionally substituted heterocyclyl (see Deputy heterocyclyl) or amino group, R R"n

"Substituted iminodicarboxylate group" (aminothiophenol) means R R N-C(=S)- group in which the substituents R' and R" can be represented optionally substituted by alkyl, alkenyl, quinil, cycloalkyl, aryl, hetaryl and heterocyclyl, the value of which is determined in this section. Preferred aminocarbonyl groups are alkylaminocarbonyl, cycloalkylcarbonyl, allumination, getriebemotoren and benzylaminocarbonyl.

"Substituted oxygraph" means a hydroxy-group in which hydrogen may be substituted With1-C5the alkyl, C1-C5alkenyl,3-C5cycloalkyl, aryl, hetaryl and heterocyclyl, forming ethers, or acyl, forming esters, or aminocarbonyl group, forming carbamates, or oxycarbonyl group, forming carbon is s.

"Substituted oxycarbonyl group" (oxycarbonyl) means R-O-C(=O)- group in which the substituent R can be represented optionally substituted by alkyl, alkenyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the value of which is determined in this section. Preferred oxycarbonyl groups are methoxycarbonyl, etoxycarbonyl, tert-butyloxycarbonyl and benzyloxycarbonyl.

"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-carbonylethyl or R R N-R R NC(=O)-alkyl, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arithmetiles. Preferred substituents carbamaepine" are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonyl, alcoxycarboxylates, heteroarylboronic-carbonylethyl or R R N-R R NC(=O)-alkyl, annelirovannymi aryl is heterocyclyl, annelirovannymi arithmetiles.

"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): desoxycholic acid (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.

"Carboxyl" means the group-CO2N.

"Medicine combined medicine (drug)" - a combination of several drugs for simultaneous use in the form of tablets, capsules, injections, ointments, rectally with whom spense and gels and other 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 in various ways, such as oral and rectal.

"Metabolic disease" is a group of diseases associated with metabolic disorders. These diseases can be caused by genetic predisposition, disruptions in the endocrine and nervous systems, as well as violations in metabolically active organs. Currently, there are a large number of metabolic disorders, however, the present invention focuses primarily on the disease, associated with a signaling cascade receptor TGR5, in particular, such as diabetes, obesity, diabetesthe, metabolic syndrome, hypercholesterolemia, dyslipidemia, and so on

"Lower alkyl" means a linear or branched alkyl with 1-5 carbon atoms (C1-C5alkyl).

"Neurodegenerative disease" means a specific state and a disease characterized by damage to the primary and death of populations nervous the notches in certain areas 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, neurodegenerative diseases include pathological conditions and disorders developing during 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.

"Receptors" (from Latin recipere to receive, to learn) are biological macromolecules that are located on qi is plazmaticheskoi the cell membrane 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.

"Receptor TGR5" receptors (also known as GPBAR1, M-BAR, AXOR 109 and GPCR19) are GPCR receptors related to Gs-proteins. They are expressed mainly in the gallbladder, gastrointestinal tract, spleen, lung, placenta, some parts of the Central nervous system, and immune cells (monocytes and dendritic cells).

"Signaling cascade" (signaling system, a cascade of signal transmission) means a set of interrelated sequential and parallel molecular process regulation of cellular metabolism is the external (primary) signals, carriers in the cell information that fundamentally distinguishes them from other applicants in a cage of chemical compounds that serve to her a source of matter and energy. Molecular mechanisms of transfer (transduction) of external signals into the cell involve not only the transmission of signals, as such, but also the whole complex of events, paired with her, including the strengthening, weakening and suppression (or off) signal.

"Steroids" are a group of natural, semisynthetic and synthetic compounds derived fully or partially hydrogenated 1,2-cyclopenten the phenanthrene, in the molecular skeleton which 17 carbon atoms form a 4 articulated ring. Steroids are widely distributed in nature, they are involved in diverse biological functions. Steroid nature are sex hormones, vitamin D, adrenal hormones, bile acids, hormones metamorphosis and arthropod repellents, plant ticosteroid and so on Steroids with similar structure are very different physiological activity, they are widely used in medicine as anti-inflammatory, heart, birth control and other means. When you want to avoid hormonal effects of steroids, develop the so-called "non-steroidal" medicinal agents.

"Sulfonyl" means R-SO2- the group in which the substituent R can be represented optionally substituted C1-C5the alkyl, C1-C5alkenyl, C1-C5cycloalkyl, optionally substituted aryl (see Deputy cyclic system), optionally substituted hetaryl (see Deputy cyclic system), optionally substituted by heterocyclyl (see Deputy cyclic system) or amino group, R R N, the value of which is determined in this section.

"Tiarella group" (Thioacyl) denotes optionally substituted alkyl-C(=S)-, alkenyl-C(=S)-, the cycle is alkyl-C(=S)-, heterocyclyl-C(=S)-, aryl-C(=S)- aralkyl-C(=S)-, heteroaryl-C(=S)-, heteroallyl-C(=S)-group.

"Cycloalkyl" means a non-aromatic mono - or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more "cyclic system substituents" which may be the same or different. Representatives cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl, etc. Preferred "cyclic system substituents" are alkyl, alkoxy, hydroxy or amino group, the value of which is determined in this section.

"Cycloalkenyl" means a non-aromatic mono - or polycyclic system containing from 3 to 10 carbon atoms and containing one or more double carbon-carbon bond. Representatives cycloalkenyl groups are cyclopentenyl and cyclohexenyl.

"Pharmaceutical composition" means a composition comprising a compound of General formula I 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, blantely, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depend 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, 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, carb is NAT calcium, 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 injection of the active principle, one or in combination with other active beginning can be introduced animals and people in the standard form of administration, mixed 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 powdered solid carrier. For the manufacture of suppositories in addition to the active ingredients used oil ka is AO, 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 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 such salts are described in Berge S. M., 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, this may be sintezirovany 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 which can be obtained metal salts 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 early 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.

"Pharmaceutically acceptable excipients" under the pharmaceutically acceptable excipients refers to the use of Jaimie in the field of pharmaceutical diluents, auxiliary agents and/or carriers.

The purpose of the present invention is to create a new selective non-steroidal heterocyclic TGR5 agonists of receptors.

This goal is achieved heterocyclic agonists of receptors bile acids TGR5 General formula I in the form of free bases, racemic mixtures or individual optical isomers, and also in the form of their pharmaceutically acceptable salts.

The object of the present invention is the use of compounds, which are a derivative of tetrahydrobenzo[f][1,4]oxazepine General formula I in the form of free bases, racemic mixtures or individual optical isomers, and also in the form of their pharmaceutically acceptable salts, pharmaceutical compositions, having the properties of agonist bile acids TGR5

where

X represents the amino group, R R”N, optionally substituted by the same substituents R' and R”, where the substituents of the amino group, R' and R” represent hydrogen, C1-C6alkyl, substituted C1-With6alkyl, where the Deputy is selected from phenyl or phenoxy, each of which in turn may be substituted by halogen, C1-C3the alkyl, C1-C3alkoxy, phenyloxy,3-With6cycloalkyl,3-C6cyclea the kilometres, 5-6-membered heteroaryl with one nitrogen atom; aryl selected from phenyl, possibly substituted by fluorine, With1-C3the alkyl, C1-C3alkoxy; 5-6-membered heteroaryl with a nitrogen atom as a heteroatom; C2-C4alkenyl; acyl selected from C1-C6alkylcarboxylic or3-C6cycloalkylcarbonyl; or substituted oxygraph, which represents a hydroxy-group in which hydrogen is substituted With1-With6the alkyl possibly substituted by hydroxy, di(C1-With3alkyl)amino, phenyl, which in turn may be substituted by halogen, C1-With3the alkyl, C1-With3alkoxy, C2-With4alkenyl; and 5-6-membered heterocyclyl with an atom of oxygen or nitrogen as a heteroatom;

R1a and R1b represent hydrogen, C1-With3alkyl; or R1a and R1b together form a polymethene chain -(CH2)n-, where n=2-5; R1c and R1d represents hydrogen, C1-With3alkyl;

R2 is an acyl group selected from C1-With6alkylsulphonyl, where alkyl may be substituted by phenyl or phenoxy, each of which in turn may be substituted by halogen, C1-With3the alkyl, C1-With3alkoxy, C3-With6cycloalkylcarbonyl; phenylcarbinol that can be replaced is completed by halogen, C1-With3the alkyl, C1-With3alkoxyglycerols; 5-6-membered heteroarylboronic with the nitrogen atom, oxygen or sulphur as heteroatoms, possibly substituted by carboxy or C1-With3alkoxycarbonyl; substituted aminocarbonyl group where the Deputy may be selected from C1-With6of alkyl, possibly substituted C1-With3alkoxycarbonyl; C3-With6cycloalkyl; phenyl, possibly substituted with halogen, C1-With3the alkyl, C1-With3alkoxy, C1-With3alkoxycarbonyl; 5-6-membered heteroaryl with the nitrogen atom or sulfur as heteroatom, possibly substituted by carboxy, C1-With3alkoxycarbonyl; sulfonyloxy group selected from C1-With3alkylsulfonyl, substituted by phenyl, which may samisen C1-3by alkyl, halogen, C1-C3alkoxygroup, cyano; phenylsulfonyl, possibly substituted with halogen, C1-With3by alkyl, halogen, C1-With3alkoxy, or 5-membered heteroarylboronic with the atom of nitrogen, sulfur or oxygen as a heteroatom, possibly substituted with halogen, C1-3the alkyl, C1-C3alkoxygroup;

R3 represents hydrogen.

Preferred is the use of derivatives, tetrahydrobenzo[f][1,4]oxaz the pins of General formula I. 1 and I 2 in the form of free bases, racemic mixtures or individual optical isomers and their pharmaceutically acceptable salts

where

R4a and R4b represent hydrogen or methyl; or R4a and R4b may form together polymethene chain-CH2-CH2-; R4c and R4d represents hydrogen or methyl;

R5 represents an acyl group selected from C1-With6alkylsulphonyl, where alkyl may be substituted by phenyl or phenoxy, each of which in turn may be substituted by halogen, C1-With3the alkyl, C1-With3alkoxy; C3-With6cycloalkylcarbonyl; phenylcarbinol, which may be substituted with halogen, C1-With3the alkyl, C1-With3alkoxyglycerols; 5-6-membered heteroarylboronic with the nitrogen atom, oxygen or sulphur as heteroatoms, possibly substituted by carboxy or1-With3alkoxycarbonyl; substituted aminocarbonyl group where the Deputy may be selected from C1-With6of alkyl, possibly substituted C1-With3alkoxycarbonyl; C3-With6cycloalkyl; phenyl, possibly substituted with halogen, C1-With3the alkyl, C1-With3alkoxy, C1-With3alkoxycarbonyl; 5-6-membered heteroaryl with the nitrogen atom or sulfur as gets is of rotoma, possibly substituted carboxy, C1-With3alkoxycarbonyl; sulfonyloxy group selected from C1-With3alkylsulfonyl, substituted phenyl, possibly substituted C1-With3by alkyl, halogen, C1-With3alkoxygroup, cyano; phenylsulfonyl, possibly substituted with halogen, C1-With3the alkyl, C1-With3alkoxy, or 5-membered heteroarylboronic with the atom of nitrogen, sulfur or oxygen as a heteroatom, possibly substituted with halogen, C1-With3the alkyl, C1-With3alkoxygroup;

R6 represents hydrogen, C1-With6alkyl, substituted C1-With6alkyl, where the Deputy is selected from phenyl or phenoxy, each of which in turn may be substituted by halogen, C1-With3the alkyl, C1-With3alkoxy, phenyloxy,3-With6cycloalkyl,3-With6cycloalkyl, 5-membered heterocyclyl with one nitrogen atom in the cycle; acyl group selected from C1-With3alkylcarboxylic or3-With6cycloalkylcarbonyl;

R7 represents hydrogen, C1-With6alkyl; substituted alkyl, where the Deputy is selected from phenyl or phenoxy, each of which in turn may be substituted by halogen, C1-With3the alkyl, C1-With3alkoxy, phenyloxy,3/sub> -C6cycloalkyl; C2-C4alkenyl; aryl selected from phenyl, possibly substituted with halogen, C1-With3the alkyl, C1-With3alkoxy; 5-6-membered heteroaryl with a nitrogen atom as a heteroatom;

R8 represents C1-With6alkyl, possibly substituted by hydroxy, di(C1-With3alkyl)amino, phenyl, which in turn may be substituted by halogen, C1-With3the alkyl, C1-With3alkoxy; C2-C4alkenyl; 5-6-membered heterocyclyl with an atom of oxygen or nitrogen as a heteroatom.

More preferred is the use of derivatives, tetrahydrobenzo-[f][1,4]oxazepine General formula I. 1.1, I. 1.2, I. 1.3, I. 2.1, I. 2.2 and I. 2.3 in the form of free bases, racemic mixtures or individual optical isomers and their pharmaceutically acceptable salts

where

R4a, R4b, R4c and R4d have the meanings defined above;

R9 represents C1-With3alkyl; C3-With6cycloalkyl;

R10 represents a C1-With3alkyl, optionally substituted by phenyl which may be substituted with halogen; or a 5-6-membered heteroaryl with a nitrogen atom as a heteroatom; C2-With4alkenyl; phenyl, possibly substituted C1-With3by alkyl;

R11 represents sobeys 1-With4alkyl, optionally substituted phenyl, possibly substituted C1-With3the alkyl, C1-With3alkoxygroup, halogen; fenoxaprop, optionally substituted C1-With3alkoxygroup or halogen, With3-With6cycloalkyl or 5-6-membered heteroaryl with the atom of nitrogen, sulfur or oxygen as a heteroatom; C3-With6cycloalkyl; phenyl, optionally substituted C1-With3the alkyl, C1-With3alkoxygroup, actigraphy or halogen; benzo[d][1,3]dioxol; 5-6-membered heteroaryl with the atom of nitrogen, sulfur or oxygen as heteroatoms, optionally substituted with halogen;

R12 represents hydrogen;

R13 represents a C1-With4alkyl, possibly substituted C1-With3alkoxycarbonyl group, or phenyl, optionally substituted with halogen or 5-6-membered heteroaryl with the atom of nitrogen, sulfur or oxygen as a heteroatom; C3-With6cycloalkyl; phenyl, optionally substituted C1-With3the alkyl, C1-With3alkoxygroup, halogen, C1-With3alkoxycarbonyl group; benzo[d][1,3]dioxol; 5-6-membered heteroaryl with the atom of nitrogen, sulfur or oxygen as heteroatoms, optionally substituted by carboxypropyl,1-With3alkoxycarbonyl group, aminocarbonyl group, replaced With1-With3by alkyl; R14 represents a C1-With4alkyl, possibly substituted fluoro-substituted by phenyl; phenyl, optionally substituted C1-With3the alkyl, C1-With3alkoxygroup, halogen, cyano;

R15 represents C1-With6alkyl, optionally substituted by actigraphy, 5-6-membered heterocyclyl with the atom of nitrogen, sulfur or oxygen as a heteroatom, phenyl, optionally substituted C1-With3the alkyl, C1-With3alkoxygroup, halogen; C2-With4alkenyl.

The object of the present invention are derivatives of tetrahydrobenzo[f][1,4]oxazepine:

N-(4-terbisil)-N'-({4-[(3-forfinal)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)ndimethylacetamide (I. 1.1-01);

N-{[4-(cyclopropanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-02);

N-(4-were)-N'-{[4-(2-phenylethanol)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl}ndimethylacetamide (I. 1.1-03);

N-({4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4 - benzoxazepin-7-yl}methyl)-N'-phenylcyclopropanecarboxylic (I. 1.1-05);

N-{[4-(3-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methyl-N'-(4-were)propanamide (I. 1.1-06);

N-{[4-(2-furoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-07);

N-(4-were)-N-({4-[(4-were)acetyl]-2,3,4,5-t is trihydro-1,4-benzoxazepin-7-yl}methyl)ndimethylacetamide (I. 1.1-08);

N-[(4-isobutyryl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-09);

N-[(4-butyryl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl]-2-methyl-N'-(4-were)propanamide (I. 1.1-10);

2-methyl-N-(4-were)-N'-{[4-(2-titilate)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I. 1.1-11);

N-(4-were)-N'-{[4-(2-titilate)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.1-12);

N-{[4-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-phenyl-cyclopropanecarboxamide (I. 1.1-13);

N-{[4-(3-methylbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-phenylcyclopropanecarboxylic (I. 1.1-15);

N-{[4-(2,6-differentail)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-16);

N-{[4-(2,6-differentail)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methyl-N'-(4-were)propanamide (I. 1.1-17);

N-{[4-(3-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-18);

N-{[4-(2-furoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methyl-N'-(4-were)propanamide (I. 1.1-19);

2-methyl-N-(4-were)-N'-{[4-(phenoxyacetyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I. 1.1-20);

N-({4-[(4-methoxyphenoxy)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N'-(phenylcyclopropanecarboxylic (I. 1.1-21);

N-{[4-(cyclopentylacetyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(-were)ndimethylacetamide (I. 1.1-22);

N-{[4-(2-methylbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-23);

N-{[4-(cyclobutanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methyl-N'-(4-were)propanamide (I. 1.1-24);

N-{[4-(2-perbenzoic)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-25);

N-{[4-(cyclopentanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-26);

N-{[4-(cyclohexylcarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-27);

N-{[4-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-phenyl-cyclopropanecarboxamide (I. 1.1-28);

2-methyl-N-(4-were)-N'-[(4-propionyl 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl]propanamide (I. 1.1-29);

2-methyl-N-{[4-(3-methylbutanoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)propanamide (I. 1.1-30);

N-([4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl-N'-(methyl)ndimethylacetamide (I. 1.1-31);

N-([4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)propanamide (I. 1.1-32);

N-([4-propionyl 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl} - N'-(methyl)ndimethylacetamide (I. 1.1-33);

N-([4-benzoyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)ndimethylacetamide (I. 1.1-34);

N-{[4-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-35);

N-{[4-(4-perbenzoic)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylmethyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-36);

N-{[4-(2-perbenzoic)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-37);

N-{[4-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-38);

N-{[4-(4-pyridyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-39);

N-{[4-(thiophene-2-carbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl|methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-40);

N-{[4-(thiophene-3-carbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)propionamide (I. 1.1-41);

N-{[4-(3-pyridyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)propionamide (I. 1.1-42);

N-{[4-phenylacetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)ndimethylacetamide (I. 1.1-43);

N-{[4-(methylamino)acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)ndimethylacetamide (I. 1.1-44);

N-{[4-(dimethylamino)acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)ndimethylacetamide (I. 1.1-45);

N-{[4-(methylamino)acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(2-phenylethyl)ndimethylacetamide (I. 1.1-46);

N-{[4-(dimethylamino)acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(2-phenylethyl)ndimethylacetamide (I. 1.1-47);

N-{[4-(3-pyridyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl-N'-(ethyl)ndimethylacetamide (I. 1.1-48);

N-{[4-(4-pyridyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl-N'-(ethyl)ndimethylacetamide (I. 1.1-49);

N-{[4-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(ethyl)ndimethylacetamide (I. 1.1-50);

N-(1-{4-[(4-the methods of Setenil)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1-{methyl}ethyl)-N'-(4-were)ndimethylacetamide (I. 1.1-51);

N-(1-{4-[4-methoxybenzoyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1-{methyl}ethyl)-N'-(4-were)ndimethylacetamide (I. 1.1-52);

N-(1-{4-[(3-forfinal)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1-{methyl}ethyl)-N'-(4-were)ndimethylacetamide (I. 1.1-53);

N-(1-{[4-(cyclopropanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1-(methyl)ethyl}-N'-(4-were)ndimethylacetamide (I. 1.1-54);

N-[1-(4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-cyclopropyl]-N'-(4-were)ndimethylacetamide (I. 1.1-55);

N-[(4-acetyl-5,5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-56);

N-[1(S)-(4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-ethyl]-N'-(4-were)ndimethylacetamide (I. 1.1-57);

N-[1(R)-(4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-ethyl]-N'-(4-were)ndimethylacetamide (I. 1.1-58);

N-[1(S)-(4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-ethyl]-N'-(4-were)ndimethylacetamide (I. 1.1-57/R);

N-[(4-acetyl-5(S)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-59);

N-[(4-acetyl-5(R)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-60);

N-[(4-acetyl-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-59/60R);

Methyl-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-01);

7-{[(Cyclopropanecarbonyl)(phenyl)-amino]methyl}-N-(4-were)-2,3-dihydro-1,4-benzoxazepin-4(5 is)-carboxamide (I. 1.2-02);

7-{[isobutyl(4-were)amino]methyl}-N-(3-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-04);

7-{[isobutyl(4-were)amino]methyl}-N-(4-were)-2,3-dihydro-1,4 - benzoxazepin-4(5H)-carboxamide (I. 1.2-05);

N-(ISO-butyl)-7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-06);

7-{[(cyclopropanecarbonyl)-(phenyl)amino]methyl}-N-(3-forfinal)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-07);

N-(4-chlorophenyl)-7-{[(cyclopropanecarbonyl)-(phenyl)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-08);

N-(3,4-dimetilfenil)-7-{[isobutyl(4-were)-amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-09);

N-(4-terbisil)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-10);

7-{[acetyl(4-were)amino]methyl}-N-(3-fluoro-4-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-12);

N-(2-forfinal)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-14);

7-{[acetyl(4-were)amino]methyl}-N-(2-ethylphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-16);

7-{[isobutyl(4-were)amino]methyl}-N-(3-methoxyphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-17);

N-(sec-butyl)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-18);

N-(2,5-dime ylphenyl)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-19);

N-(tert-butyl)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-20);

7-{[acetyl(4-were)amino]methyl}-N-cyclopentyl-2,3-dihydro-1,4 - benzoxazepin-4(5H)-carboxamide (I. 1.2-22);

N-(2-chlorophenyl)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-23);

N-(2,4-dimetilfenil)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-24);

N-(2-furylmethyl)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-25);

etil-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-26);

3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4 - benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid dimethylamide (I. 1.2-27);

3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid of methylamide (I. 1.2-28);

3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid N-cyclopentylamine (I. 1.2-29);

3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid (I. 1.2-30);

N-[7-{[acetyl(methyl)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-methyl-carboxamide (I. 1.2-31);

N-[7-{[propioni the(methyl)-amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-methyl-carboxamide (I. 1.2-32);

N-[7-{[acetyl(methyl)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-phenyl-carboxamid (I. 1.2-33);

3-({[7-{[acetyl(methyl)amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid (I. 1.2-34);

Methyl 3-({[7-{[acetyl(methyl)amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-35);

7-N-{[acetyl(methyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(pyridyl-3)-carboxamide (I. 1.2-36);

7-N-{[acetyl(methyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(pyridyl-4)-carboxamide (I. 1.2-37);

7-N-{[acetyl(methyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-benzyl-carboxamid (I. 1.2-38);

7-N-{[acetyl(methyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-were-carboxamid (I. 1.2-39);

7-N-{[acetyl(methyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-forfinal)-carboxamide (I. 1.2-40);

7-N-{[acetyl(ethyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(2-forfinal)-carboxamide (I. 1.2-41);

3-({[7-{[acetyl(ethyl)amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid (I. 1.2-42);

Methyl 3-({[7-{[acetyl(ethyl)amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-43);

3-({[7-{[(2-methylpropionyl)-(ethyl) - amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid (I. 1.2-44);

Methyl 3-({[7-{[(2-methylpropionyl-(ethyl) - amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-45);

N-[7-{[acetyl - (2-phenylethyl)-amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-methyl-carboxamide (I. 1.2-46);

N-[7-{[acetyl - (2-phenylethyl)-amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-tert-butyl-carboxamide (I. 1.2-47);

7-N-{[acetyl(ethyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-benzyl-carboxamid (I. 1.2-48);

7-N-{[acetyl(ethyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(pyridyl-3)-carboxamide (I. 1.2-49);

Methyl 3-({[7-{[acetyl - (2-phenylethyl)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-50);

Methyl 3-({[7-{[acetyl(methyl)amino]-1-(methyl)ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-51);

7-{[N-acetyl(methyl)amino]-1-(methyl)ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-were-carboxamid (I. 1.2-52);

Methyl-3-({[7-{[acetyl(2-phenylethyl)amino]-1(S)-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-53);

Methyl 3-({[7-{[acetyl - (2-phenylethyl)amino]-1(R)-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-54);

Methyl 3-({[7-{[acetyl - (2-phenylethyl)amino]-1-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-53/R);

7-{[N-acetyl(methyl)amino]methyl}-5(R)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-were-carboxamid (I. 1.2-55);

7-{[N-acetyl(methyl)amino]methyl}-5(S)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-shall ethylphenyl)carboxamide (I. 1.2-56);

7-{[N-acetyl(methyl)amino]methyl}-5-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-were-carboxamid (I. 1.2-55/R);

Methyl 3-({[7-{[acetyl(methyl)amino]methyl}-5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-57);

Methyl 3-({[7-{[acetyl(methyl)amino]methyl}-5(R)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-58);

Methyl 3-({[7-{[acetyl(methyl)amino]methyl}-5(S)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-59);

Methyl 3-({[7-{[acetyl(methyl)amino]methyl}-5-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-58/R);

Methyl 3-({[7-{[acetyl(4-were)amino]methyl}-5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-60);

N-({4-[(4-chlorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-were)ndimethylacetamide (I. 1.3-01);

N-({4-[(4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(phenyl)cyclopropanecarboxamide (I. 1.3-02);

N-({4-[(4-isopropylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-were)ndimethylacetamide (I. 1.3-03);

N-(4-terbisil)-N-({4-[(3-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)ndimethylacetamide (I. 1.3-04);

N-(4-were)-N-({4-[(4-propylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)ndimethylacetamide (I. 1.3-05);

N-({4-[(3,5-Demetris xazal-4-yl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-2-methyl-N-(4-were)propanamide (I. 1.3-06);

N-({4-[(3,4-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-terbisil)ndimethylacetamide (I. 1.3-07);

2-methyl-N-(4-were)-N-{[4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I. 1.3-08);

2-methyl-N-(4-were)-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I. 1.3-09);

N-({4-[(3-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-2-methyl-N-(4-were)propanamide (I. 1.3-10);

N-({4-[(2,4-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenyl-cyclopropanecarboxamide (I. 1.3-11);

N-({4-[(2-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-12);

N-({4-[(4-ethylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-13);

N-({4-[(5-fluoro-2-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-14);

N-({4-[(2-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-2-methyl-N-(4-were)propanamide (I. 1.3-15);

N-({4-[(2-chlorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-16);

N-({4-[(2,4-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-terbisil)ndimethylacetamide (I. 1.3-17);

N-({4-[(2,5-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl-N-phenylcyclopropanecarboxylic (I. 1.3-18);

(2-methyl-N-(4-were)-N-{[4-(methylsulphonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I1.3-19);

2-methyl-N-({4-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-were)propanamide (I. 1.3-20);

N-({4-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-21);

(N-(4-were)-N-{[4-(propylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-22);

N-({4-[(3,5-differenl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-23);

N-({4-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-24);

N-{[4-(butylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N-phenylcyclopropanecarboxylic (I. 1.3-25);

N-(4-were)-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-26);

N-methyl-N-{[4-(methylsulphonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-27);

N-methyl-N-{[4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide I. 1.3-28);

N-methyl-N-{[4-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-29);

N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-30);

N-ethyl-N-{[4-(phenylsulfonyl)-2,3,4,5-tetr the hydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-31);

N-ethyl-N-{[4-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-32);

N-ethyl-N-{[4-(4-perpenicular)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-33);

N-ethyl-N-{[4-(2-perpenicular)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-34);

N-ethyl-N-{[4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide(I. 1.3-35);

N-allyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-36);

N-allyl-N-{[4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-37);

N-allyl-N-{[4-(4-methyl-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-38);

N-allyl-N-{[4-(4-fluoro-phenylsulfanyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-39);

N-allyl-N-{[4-(4-methoxy-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-40);

N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-41);

N-ethyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-42);

N-methyl-N-{[4-(4-chlorophenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-43);

N-methyl-N-{[4-(4-perpenicular)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-44);

N-methyl-N-{[4-(2-perpenicular)-2,3,4,5-is tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-45);

N-phenylethyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-46);

N-phenylethyl-N-{[4-(4-chlorophenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-47);

N-phenylethyl-N-{[4-(4-perpenicular)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-48);

N-phenylethyl-N-{[4-(4-methyl-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-49);

N-[2-(pyrid-3-yl)ethyl]-N-{[4-(4-methoxy-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-50);

N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1-methyl(ethyl)}ndimethylacetamide (I. 1.3-51);

N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1(R)-ethyl}ndimethylacetamide (I. 1.3-52);

N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1(S)-ethyl}ndimethylacetamide (I. 1.3-53);

N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1-ethyl}ndimethylacetamide (I. 1.3-52/R);

N-methyl-N-{[4-(2-thienylmethyl)-5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-54);

N-methyl-N-{[4-(2-thienylmethyl)-5(R)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-55);

N-methyl-N-{[4-(2-thienylmethyl)-5(S)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-56);

N-methyl-N-{[4-(2-thienylmethyl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-55/R);

N-methyl--{[4-(4-chloro-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1(R)-ethyl}ndimethylacetamide (I. 1.3-57);

N-methyl-N-{[4-(4-chloro-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1(S)-ethyl}ndimethylacetamide (I. 1.358 for);

N-methyl-N-{[4-(4-chloro-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1-ethyl}ndimethylacetamide (I. 1.3-57/R);

N-methyl-N-{[4-(4-chloro-phenylsulfonyl)-5(S)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-59);

N-methyl-N-{[4-(4-chloro-phenylsulfonyl)-5(R)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-60);

N-methyl-N-{[4-(4-chloro-phenylsulfanyl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-59/60R);

7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-01);

7-{[(4-Chlorobenzyl)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-02);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-03);

7-{[(4-Chlorobenzyl)oxy]methyl}-4-[3-(4-methoxyphenyl)propanol]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-04);

4-(cyclohexylcarbonyl)-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-05);

7-{[(4-Chlorobenzyl)oxy]methyl}-4-[(3-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-06);

7-{[(3-terbisil)oxy]methyl}-4-(3,4,5-trimethoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-07);

7-{[(3-terbisil)oxy]methyl}-4-(phenoxyacetyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-08);

7-{[(4-Chlorobenzyl)oxy]methyl}-4-(4-perbenzoic)2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-09);

4-(3-chlorobenzoyl)-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-10);

4-(5-bromo-2-furoyl)-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-11);

7-{[(4-methylbenzyl)oxy]methyl}-4-(3,4,5-trimethoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-12);

7-{[(4-Chlorobenzyl)oxy]methyl}-4-(2-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-13);

7-[(benzyloxy)methyl]-4-[(3-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-14);

7-{[(3-terbisil)oxy]methyl}-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-15);

7-{[(3-terbisil)oxy]methyl}-4-(3-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-16);

7-[(benzyloxy)methyl]-4-(3-phenylpropenoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-17);

7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenoxy)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-18);

4-(2,3-dimethoxybenzoyl)-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-19);

4-(cyclopentanecarbonyl)-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-20);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-(cyclopentanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-21);

7-{[(4-Chlorobenzyl)oxy]methyl}-4-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-22);

7-(methoxymethyl)-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-23);

7-(ethoxymethyl)-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-t is trihydro-1,4-benzoxazepin (I. 2.1-24);

7-(allyloxymethyl)-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-25);

7-[2-phenylethylene(methyl)]-4-[(4-methoxybenzoyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-26);

7-[2-phenylethylene(methyl)]-4-(pyridyl-4-carbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-27);

7-[2-phenylethylene(methyl)]-4-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-28);

7-[2-phenylethylene(methyl)]-4-(2,3-methylenedioxybenzyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-29);

7-[2-phenylethylene(methyl)]-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-30);

7-(allyloxymethyl)-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-31);

7-[2-phenylethylene(methyl)]-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-32);

7-[2-dimethylamino-acyloxy(methyl)]-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-33);

7-[2-N-pyrrolidino-acyloxy(methyl)]-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-34);

7-[2-dimethylamino-acyloxy(methyl)]-4-(4-pyridylcarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-35);

7-[2-dimethylamino-acyloxy(methyl)]-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-36);

7-[2-N-pyrrolidino-acyloxy(methyl)]-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-37);

7-[2-N-pyrrolidino-acyloxy(methyl)]-4-[(4-chlorophenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-38);

7-[2-dimethyl what Mino-acyloxy(methyl)]-4-[(4-chlorophenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-39);

7-[2-dimethylamino-acyloxy(methyl)]-4-[(4-forfinal)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-40);

7-[2-hydroxyethyloxy(methyl)]-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-41);

7-[2-hydroxyethyloxy(methyl)]-4-[(4-chlorophenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-42);

7-[2-hydroxyethyloxy(methyl)]-4-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-43);

7-[2-hydroxyethyloxy(methyl)]-4-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-44);

7-[2-hydroxyethyloxy(methyl)]-4-benzoyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-45);

7-[2-(2,3-acid), acyloxy(methyl)]-4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-46);

7-[2-(2,3-acid), acyloxy(methyl)]-4-thienylboronic-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-47);

7-[2-(2,3-acid), acyloxy(methyl)]-4-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-48);

7-[2-(2,3-acid), acyloxy (methyl)]-4-(4-chlorbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-49);

7-[2-(2,3-acid), acyloxy(methyl)]-4-cyclohexylcarbonyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-50);

7-{1-[(3-terbisil)oxy]-1-(methyl})ethyl-4-[(4-methoxy-phenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-51);

7-{1(R)-[(3-terbisil)oxy]-1-(methyl})ethyl-4-[(4-methoxy-phenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-52);

7-{1(S)-[(3-terbisil)oxy]-1-(methyl})ethyl-4-[(4-methoxy-phenyl)and ethyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (.2.1-53);

7-{1-[(3-terbisil)oxy]-1-(methyl})ethyl-4-[(4-methoxy-phenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-52/R);

7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-54);

7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-5(R)-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-55);

7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-5(S)-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-56);

7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-55/R);

N-(2-ethoxyphenyl)-7-{[(3-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-01);

Ethyl 3-({[7-{[(3-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)benzoate (I. 2.2-02);

ethyl 3-({[7-{[(2-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)benzoate (I. 2.2-03);

7-{[(2-Chlorobenzyl)oxy]methyl}-N-(2-methoxyphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-04);

7-{[(2-terbisil)oxy]methyl}-N-(2-phenylethyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-05);

7-{[(3-terbisil)oxy]methyl}-N-(3-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-06);

7-{[(3-terbisil)oxy]methyl}-N-phenyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-07);

7-{[(2-Chlorobenzyl)oxy]methyl}-N-(2,5-acid)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-0);

ethyl 3-({[7-{[(4-methylbenzyl)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)benzoate (I. 2.2-09);

N-(3-forfinal)-7-{[(4-methylbenzyl)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-10);

7-{[(3-terbisil)oxy]methyl}-N-(4-forfinal)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-11);

N-(tert-butyl)-7-{[(4-Chlorobenzyl)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-12);

ethyl N-{[7-{[(4-methylbenzyl)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-beta-alaninate (I. 2.2-13);

7-{[(4-Chlorobenzyl)oxy]methyl}-N-phenyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-14);

N-(3,5-acid)-7-{[(4-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-15);

ethyl 2-({[7-{[(4-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)benzoate (I. 2.2-16);

7-[(benzyloxy)methyl]-N-(2-chlorophenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-17);

7-{[(4-terbisil)oxy]methyl}-N-(3-methoxyphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)carboxamide (I. 2.2-18);

7-{[(3-terbisil)oxy]methyl}-N-(3-methoxyphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)carboxamide (I. 2.2-19);

7-{[(2-terbisil)oxy]methyl}-N-(4-forfinal)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-20);

N-cyclopentyl-7-{[(4-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-21);

N-benzyl-7-{[(4-methylbenzyl)oxy]methyl}-2,3-dihydro,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-22);

N-(2,4-differenl)-7-{[(2-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-23);

7-{[(2-terbisil)oxy]methyl}-N-phenyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-24);

7-{[(4-methylbenzyl)oxy]methyl}-N-(4-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-25);

7-{[(3-terbisil)oxy]methyl}-N-(3-forfinal)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-26);

7-{[(4-methylbenzyl)oxy]methyl}-N-(3-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-27);

N-1,3-benzodioxol-5-yl-7-{[(2-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-28);

N-cyclohexyl-7-{[(4-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-29);

7-{[(4-methylbenzyl)oxy]methyl}-N-(2-phenylethyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide I. 2.2-30);

7-[(benzyloxy)methyl]-N-[3-(methylthio)phenyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-31);

N-(2-ethoxyphenyl)-7-methoxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-32);

N-(2-methoxyphenyl)-7-ethoxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-33);

N-(2-ethoxyphenyl)-7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-34);

N-(2-methoxyphenyl)-7-(2-phenylethylene)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-35);

N-(2-ethoxyphenyl)-7-(2-dimethylaminoethoxy)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide(I. 2.2-36);

N-(2-methoxyphenyl)-7-(2-N-pyrrolidinyloxy)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-37);

N-(2-ethoxyphenyl)-7-(2-hydroxyethoxy)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-38);

N-(2-methoxyphenyl)-7-[2-(2,3-acid), acyloxy(methyl)]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-39);

N-(2-methoxyphenyl)-7-[2-(4-chlorophenyl)ethyloxy(methyl)]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-40);

Methyl 3-([7-methoxymethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 2.2-41);

Methyl 3-{[7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbylamine}thiophene-2-carboxylate (I. 2.2-42);

Methyl 3-{[7-(2-phenylethyl-hydroxy(methyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl-amino}thiophene-2-carboxylate (I. 2.2-43);

Methyl 3-{[7-(2-dimethylaminoethyl-hydroxy(methyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl-amino}thiophene-2-carboxylate (I. 2.2-44);

Methyl 3-{[7-(2-N-pyrrolidino-acyloxy(methyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl-amino}thiophene-2-carboxylate (I. 2.2-45);

N-(3-ethoxycarbonylphenyl)-[7-methoxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-46);

N-(3-ethoxycarbonylphenyl)-[7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-47);

N-(3-ethoxycarbonylphenyl)-[7-(2-dimethylaminoethoxy)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-48);

N-(3-methoxycarbonyl the Nile)-[7-(2-N-pyrrolidinyloxy)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-49);

N-(3-ethoxycarbonylphenyl)-[7-(2-phenylethylene)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-50);

N-(2-ethoxyphenyl)-7-{1-[(3-terbisil)oxy]-1-(methyl)ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-51);

N-(2-ethoxyphenyl)-7-{1-[(3-terbisil)oxy]-1(S)-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-52);

N-(2-ethoxyphenyl)-7-{1-[(3-terbisil)oxy]-1(R)-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-53);

N-(2-ethoxyphenyl)-7-{1-[(3-terbisil)oxy]-1-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-52/R);

N-(2-ethoxyphenyl)-7-[(3-terbisil)oxymethyl]-5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-54);

N-(2-ethoxyphenyl)-7-[(3-terbisil)oxymethyl]-5(S)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-55);

N-(2-ethoxyphenyl)-7-[(3-terbisil)oxymethyl]-5(R)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-56);

N-(2-ethoxyphenyl)-7-[(3-terbisil)oxymethyl]-5-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-55/56);

Methyl 3-({7-[1-(3-forbindelse)-1-methylethyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-57);

Methyl 3-({7-[1-(3-forbindelse)-1(S)-ethyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-58);

Methyl 3-({7-[1-(3-forbindelse)-1(R)-ethyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-59);

Methyl 3-({7-[1-(3-terbisil the XI)-1-ethyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-58/R);

Methyl 3-{[7-(3-forbindelse)-methyl]-5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-60);

Methyl 3-{[7-(3-forbindelse)-methyl]-5(S)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-61);

Methyl 3-{[7-(3-forbindelse)-methyl]-5(R)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-62);

Methyl 3-{[7-(3-forbindelse)-methyl]-5-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-61/R);

7-[(benzyloxy)methyl]-4-[(2-terbisil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-01);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(3-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-02);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-03);

7-[(benzyloxy)methyl]-4-(mesitylenesulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-04);

4-{[7-[(benzyloxy)methyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]sulfonyl}benzonitrile (I. 2.3-05);

7-{[(2-terbisil)oxy]methyl}-4-[(3-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-06);

4-[(3-chloro-4-forfinal)sulfonyl]-7-{[(2-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-07);

7-[(benzyloxy)methyl]-4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-08);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-(propylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 23-09);

7-{[(4-terbisil)oxy]methyl}-4-[(4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-10);

7-[(benzyloxy)methyl]-4-[(3-chloro-4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-11);

7-[(benzyloxy)methyl]-4-[(3-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-12);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(2,4-differenl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-13);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-14);

4-[(5-chloro-2-thienyl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-15);

4-[(2,5-acid)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-16);

7-{[(4-Chlorobenzyl)oxy]methyl}-4-(propylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-17);

7-[(benzyloxy)methyl]-4-[(5-bromo-2-thienyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-18);

4-[(5-chloro-2-thienyl)sulfonyl]-7-{[(2-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-19);

7-{[(4-terbisil)oxy]methyl}-4-[(5-fluoro-2-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-20);

4-[(3-chloro-4-methoxyphenyl)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-21);

4-[(3-chloro-4-were)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-22);

7-{[(3-terbisil)oxy]methyl}-4-[(3-methoxyphenyl)sulfon the l]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-23);

4-{[7-{[(3-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]sulfonyl}benzonitrile (.2.3-24);

4-(2,1,3-benzothiadiazole-4-ylsulphonyl)-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-25);

4-[(3,5-differenl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-26);

7-{[(4-Chlorobenzyl)oxy]methyl}-4-[(2,4-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-27);

7-[(benzyloxy)methyl]-4-[(5-chloro-2-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-28);

4-[(4-chlorophenyl)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-29);

7-[(benzyloxy)methyl]-4-[(4-bromophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-30);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(3,5-differenl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-31);

4-[(4-chlorophenyl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-32);

4-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-33);

4-[(3-chloro-4-methoxyphenyl)sulfonyl]-7-{[(2-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-34);

4-(2,3-dihydro-1,4-benzodioxin-6-ylsulphonyl)-7-{[(2-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-35);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(2-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-36);

7-{[(3-forbe the ZIL)oxy]methyl}-4-[(3-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-37);

7-{[(2-Chlorobenzyl)oxy]methyl}-4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-38);

4-(2,1,3-benzothiadiazole-4-ylsulphonyl)-7-[(benzyloxy)methyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-39);

7-{[(2-terbisil)oxy]methyl}-4-[(5-fluoro-2-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-40);

4-[(3-chloro-4-forfinal)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-41);

4-[(3,5-differenl)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-42);

7-[(benzyloxy)methyl]-4-(2,3-dihydro-1,4-benzodioxin-6-yl-sulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-43);

4-[(2,5-dimetilfenil)sulfonyl]-7-{[(2-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-44);

4-[(2,5-differenl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-45);

7-[(benzyloxy)methyl]-4-[(2,4,5-trimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-46);

4-[(2,4-differenl)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-47);

4-[(5-chloro-2-methoxyphenyl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-48);

7-{[(3-terbisil)oxy]methyl}-4-[(4-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-49);

7-{[(4-terbisil)oxy]methyl}-4-[(4-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-50);

7-{[(2-dimethylamino-these who)oxy]methyl}-4-[(4-fluoro-phenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-51);

7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-chloro-phenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-52);

7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-methoxy-phenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-53);

7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(2-fluoro-phenylmethyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-54);

7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(2-thienyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-55);

7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(4-fluoro-phenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-56);

7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(4-chloro-phenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-57);

7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(4-methoxy-phenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.358 for);

7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(2-fluoro-phenylmethyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-59);

7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(2-thienyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-60);

7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-fluoro-phenyl)sulfonyl]-5(R)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-61);

7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-fluoro-phenyl)sulfonyl]-5(S)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-62);

7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-fluoro-phenyl)sulfonyl]-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-61/R).

The subject of this invention are the Xia pharmaceutically acceptable salts of the compounds of General formula I. Part of the compounds of the present invention is a neutral molecules and do not form salts, the other part contains ionogenic groups (secondary, tertiary amines or carboxylic acids) and can form salts, which were obtained by methods known in the art.

The subject of this invention are racemic mixtures and individual optical isomers of compounds of General formula I, as some of the compounds of General formula I has an asymmetric center, and the substance can exist as racemic mixtures and isomeric forms.

The subject of this invention is a method of obtaining derivatives of 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine General formula I. 1.1, I. 1.2 and I. 1.3, based on Cinchona A1 (scheme 1). The acylation of Cinchona A1 suitable allelochemical A2 (acylchlorides, allfreedom, Allbreed in neutral aprotic solvent (dichloromethane, dioxane, chloroform and the like) in the presence of a base (triethylamine, DABCO, pyridine and the like) during cooling leads to a series of substances I. 1.1. The reaction Sinton A1 with triphosgene in neutral aprotic solvent in the presence of strong dinucleophiles base (DIPEA, DABCO and the like) and then adding to the reaction mixture amine A3 in argon atmosphere leads to a series of substances I. 1.2. Impact on synthon A1 sulfochloride A4 inert the m solvent in the presence of a strong base upon cooling leads to a series of substances I. 1.3:

Scheme 1

The subject of this invention is a method of obtaining derivatives of 2,3,4,5-tetrahydrobenzo[1][1,4]oxazepine General formula 1.2.1,1.2.2 and 1.2.3, based on Cinchona B1 (scheme 2). The acylation of Cinchona B1 suitable allelochemical b2 (acylchlorides, allfreedom, Allbreed in neutral aprotic solvent (dichloromethane, dioxane, chloroform and the like) in the presence of a base (triethylamine, DABCO, pyridine and the like) during cooling leads to a series of substances 1.2.1. The reaction Sinton B1 with triphosgene in neutral aprotic solvent in the presence of strong dinucleophiles base (DIPEA, DABCO and the like) and then adding to the reaction mixture amine b3 in argon atmosphere leads to a series of substances 1.2.2. Impact on synthon B1 of sulfochloride b4 in an inert solvent in the presence of a strong base upon cooling leads to a series of substances 1.2.3

The object of the present invention is an active component that has the property of agonist receptors bile acids TGR5 representing derivatives of 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine General formula I.

Non-steroidal agonists of receptors LCD specifically associated with the receptor TGR5 and stimulate the secretion ingreenwich hormones (GLP1, YYP, GIP). Most preferred to depict alauda agonists receptor TGR5.

The subject of this invention is a pharmaceutical composition intended for the prevention and treatment of metabolic diseases and associated cardiovascular and neurodegenerative diseases, containing an effective amount of active component that represents a substituted 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine General formula I, in the form of tablets, capsules or injections, placed in pharmaceutically acceptable packing.

The subject of this invention is a pharmaceutical composition intended for the prevention and treatment of metabolic diseases and associated cardiovascular and neurodegenerative diseases, containing an effective amount of the active ingredient, having the property of agonist receptors bile acids TGR5 and represents a substituted 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine General formula I.

The subject of this invention is a combination drug, prednaznachennye for the prevention and treatment of metabolic diseases and associated cardiovascular and neurodegenerative diseases, containing an effective amount of a TGR5 agonist - derived 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine General formula I and one or more anti-diabetic drugs for simultaneous use is education.

The subject of this invention is a combined pharmaceutical composition intended for the prevention and treatment of metabolic diseases, containing an effective amount of an active component of the TGR5 agonist - derived 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine General formula I and one or more anti-diabetic drugs for simultaneous use in the form of tablets, capsules, injections, ointments, rectal suspensions and gels and other ready-made forms.

The subject of this invention is the above pharmaceutical composition in the form of tablets, capsules, ointments, gels, injections and other ready-made forms, placed in pharmaceutically acceptable packing.

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. 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 manufacture the service of various forms however, they can contain conventional pharmaceutical carriers; for example, oral formulations such as tablets, gelatin capsules, pills, solutions or suspensions); forms 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 formula I. 1.1, I. 1.2, I. 1.3, I. 2.1, I. 2.2 and I. 1.2.3, as well as their free bases, racemic mixtures or individual optical and the of Windows, and their pharmaceutically acceptable salts.

The subject of this invention is a drug.

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, in addition, each 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 subject of this invention is the way in which profilaktiki and treatment of metabolic diseases and associated cardiovascular and neurodegenerative diseases introduction in the effective number of the new active ingredient or new pharmaceutical compositions.

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 combined drug or combination of pharmaceutical compositions.

The invention is illustrated by drawings.

Fig.1 - schematic representation of the functions of the LCD in the regulation of metabolic pathways by receptor TGR5 and FXR.

Fig.2 - scheme of a 384-well plate with substances.

Fig.3 - concentration dependent agonistic activity of the substance I. 1.1-01 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.4 - concentration dependent agonistic activity of the substance I. 1.1-02 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.5 - concentration dependent agonistic activity of the substance I. 1.1-03 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.6 - concentration dependent agonistic activity of the substance I. 1.1-04 in respect of the receptor hTGR5. Each concentration point represents average value for the two repeat the ditch.

Fig.7 - concentration dependence of the activity of substances I. 1.1-05 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.8 - concentration dependence of the activity of substances I. 1.1-06 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.9 - concentration dependence of the activity of substances I. 1.1-07 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.10 - concentration dependence of the activity of substances I. 1.1-08 concerning receptor hTGR.5. Each concentration point represents average value for the two repetitions.

Fig.11 - concentration dependence of the activity of substances I. 1.2-01 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.12 - concentration dependence of the activity of substances I. 1.3-01 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.13 - concentration dependence of the activity of substances I. 1.3-02 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.14 - concentration the ionic dependence of the activity of matter I. 1.3-26 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.15 - concentration dependence of the activity of substances I. 2.1-01 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.16 - concentration dependence of the activity of substances I. 2.1-02 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

Fig.17 - concentration dependence of the activity of substances I. 2.2-01 against receptor hTGR5. Each concentration point represents average value for the two repetitions.

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. General method for the synthesis of synthons A1 (R4=H; scheme 1 and scheme 3)

The synthons A1 was obtained in accordance with scheme 3.

Scheme 3

Connection C2

A solution of compound c1 (150 g, 0.75 mole) and ethanolamine (68.6 g, 1.5 EQ.) in toluene (1 l) was heated to trap Dean-stark 1 hour. Then the toluene was evaporated, added another portion of toluene (0.5 l) and again evaporated. The resulting mass was dissolved in ethyl alcohol was added in portions with stirring NaH 4(42.8 g, 1.5 EQ.). After 1 hour stirring at room temperature the solvent was evaporated, and the resulting viscous mass was dissolved in aqueous ammonia (0.6 l). The solution was separated from the insoluble sludge and left for crystallization. Received 142.8 g of pure compound C2 (exit 77%).

The connection C3

To a suspension S2 (142.8 g, 0.58 mol) in dichloromethane (1 l) was sequentially added triethylamine (116.3 g, 2 EQ.) and boc2O (188.3 g, 1.5 EQ.) and stirred overnight at room temperature. Then the solvent and triethylamine were partially evaporated at 60°C, and to the resulting viscous mass was added hexane (0.5 l). Precipitated solid precipitate was filtered and washed with hexane (2×300 ml). Received 152.4 g of pure product C3 (output - 76%).

Connection C4

DIAD (88.9 g, 0.44 mol) was added in small portions to a solution of C3 (152.4 g, 0.44 mol) and triphenylphosphine (114.7 g, 0.44 mol) in THF (1 l) and stirred overnight at room temperature. Then the solvent was evaporated, and the resulting mass was chromatographically a mixture of ether:hexane (1:3) on silica gel (6 liters). Received 136.7 g of the product c4 (output - 95%).

Connection C5

To a solution of compound C4 (6.3 g, 19 mmol) in 30 ml THF at -70°C was added a 2.5 M solution of BuLi in hexane (sales reagent) and after 1 h exposure DMF (2.2 ml, 28 mmol). The reaction mass was stirred for 2 h at room temperature, was diluted with water and was extracted with chloroform (2 the 100 ml). The organic layer was evaporated (78%) and was applied on a column (height 70 mm and diameter 100 mm) with silica gel 230-400 mesh M has Suirable mixture (328 ml) hexane:ether (70:30), was isolated after evaporation of the rotor and drying in vacuum) 3.5 g (70%) of compound C5.

The synthons A1

A solution of compound C5 (1.2 g, 4.3 mmol), amine R10-NH2 (4.3 mmol) and TsOH (0.05 g) in toluene (20 ml) was boiled for 2 hours with a nozzle Dean-stark then completely evaporated, the residue was dissolved in ethanol (15 ml) was added in two-fold excess of sodium borohydride (sales reagent). After one hour the reaction mass was diluted with 5% aqueous solution (100 ml) of potash, and was extracted with chloroform (2×100 ml). The organic layer was dried with anhydrous sodium sulfate, was completely evaporated and the resulting technical connection C7 was dissolved in 100 ml CH2Cl2 was added triethylamine (0.62 ml, 4.3 mmol) and acylchlorides R9COCl (4.3 mmol).

The reaction mass was passed 3 hours, completely evaporated, dissolved in 50 ml of methanol was added 5 ml conc. of hydrochloric acid. After 12 h, the reaction mass was completely evaporated, diluted with water (100 ml), was extracted SNS (2×50 ml) and was applied to a short column (height 35 mm and diameter 50 mm) with silica gel (230-400 mesh M). Was suirable mixture (150 ml), hexane:CH2Cl2:Meon (5:5:1), was isolated 0.7 g (52%) of compound A1.

Example 2. General method for the synthesis of synthons B1 (R4=H; scheme 2 and scheme 4)

The synthons B1 was obtained in accordance with scheme 4.

CX is 4 mA

Connection d1

Alcohol R15OH (3.67 mol) was dissolved in dichloromethane (50 ml) and successively added triethylamine (1.37 g, 13.6 mmol) and trimethylchlorosilane (1.20 g, 11 mmol), then stirred solution for 30 min at room temperature. Then the reaction mass was added 50 ml of distilled water and was extracted with the separated aqueous layer with dichloromethane (3×20 ml). The combined organic layer was dried and evaporated. The obtained product was dissolved in anhydrous dichloromethane (50 ml), cooled to -50°C. To the cooled solution was sequentially added 5.51 mmol of aldehyde C5, triethylsilane (641 mg, 5.51 mmol) and trimethylsilyl, triplet (408 mg, 1.84 mmol). The mixture was stirred 15 min at the same temperature and then was heated to room temperature. The resulting solution was washed 2 N. NaOH solution (2×30 ml), dried and chromatographically a mixture of hexane/ether. Received net products d1 output 45-70%.

The synthons B1

To connect d1 (0.002 mol) was added 5 ml of HCl in dioxane (3 M), and after 2 hours of stirring at room temperature the reaction mass was evaporated on a rotary evaporator. The obtained solid products B1 used in the following stage without further purification. The outputs of 70-90%.

Example 3. General method for the synthesis of compounds of General formula I. 1.1

The synthesis was carried out according to Scheme 1.

Synthon A1 (0.001 mol) was dissolved in 3 ml of dichloromethane, was added triethylamine (0.002 mol, 0.202 g) and cooled to 0°C. With vigorous stirring gently added 0.0012 mol of acid chloride of a2 and the mixture was heated to room temperature. After three hours the reaction mass was diluted with dichloromethane (30 ml), washed 2 N. hydrochloric acid (2×15 ml), dried over sodium sulfate and chromatographically a mixture of CH2Cl2/EtOH (height of the column of 5 cm, width 1 cm). Received friendly products I. 1.1 with yields of 60-90%.

There were thus obtained the compounds I. 1.1-01 - I. 1.1-59/60R shown in Table 2.

I. 1.1-04472.59 MB; LC-MS m/z 473 (M+1)A

Table 2
I. 1.1-05470.57 MB; LC-MS m/z 471 (M+1l)A
I. 1.1-06472.59 MB; LC-MS m/z 473 (M+1)A
I. 1.1-07 404.47 MB; LC-MS m/z 405 (M+1)A
I. 1.1-08442.56 MB; LC-MS m/z 443 (M+1)A
I. 1.1-09380.49 MB; LC-MS m/z 381 (M+1)In

I. 1.1-14462.53 MB; LC-MS m/z 463 (M+1)

Table 2
I. 1.1-15440.55 MB; LC-MS m/z 441 (m+1)C
I. 1.1-16450.49 MB; LC-MS m/z 451 (m+1)C
I. 1.1-17478.54 MB; LC-MS m/z 479 (m+1)C
I. 1.1-18 444.54 MB; LC-MS m/z 445 (m+1)C
I. 1.1-19432.52 MB; LC-MS m/z 433 (m+1)C

Table 2
I. 1.1-20472.59 MB; LC-MS m/z 473 (M+1)
I. 1.1-21486.57 MB; LC-MS m/z 487 (M+1)
I. 1.1-22420.56 MB; LC-MS m/z 421 (M+1)C
I. 1.1-23428.54 MB; LC-MS m/z 429 (M+1)C
I. 1.1-24420.56 MB; LC-MS m/z 421 (M+1)C

Table 2
I. 1.1-25 MB 432.50; LC-MS m/z 433 (M+1)D
I. 1.1-26406.53 MB; LC-MS m/z 407 (M+1)D
I. 1.1-27420.56 MB; LC-MS m/z 421 (M+1)D
I. 1.1-28440.55 MB; LC-MS m/z 441 (M+1)D
I. 1.1-29394.52 MB; LC-MS m/z 395 (M+1)D
I. 1.1-30422.57 MB; LC-MS m/z 423 (M+1)D

Table 2
I. 1.1-31276.34 MB; LC-MS m/z 277 (M+1)A
I. 1.1-3229.37 MB; LC MS m/z 291 (M+1)A
I. 1.1-33290.37 MB; LC-MS m/z 291 (M+1)In
I. 1.1-34338.41 MB; LC-MS m/z 339 (M+l)A
I. 1.1-35352.44 MB; LC-MS m/z 353 (M+1)A
I. 1.1-36MB 356.40; LC-MS m/z 357 (M+1)A
I. 1.1-37MB 356.40; LC-MS m/z 357 (M+1)A

Table 2
I. 1.1-38368.44 MB; LC-MS m/z 369 (M+1)
I. 1.1-39339.40 MB; LC-MS m/z 340 (M+1)A
I. 1.1-40344.44 MB; LC-MS m/z 345 (M+1)In
I. 1.1-41358.46 MB; LC-MS m/z 359 (M+1)In
I. 1.1-42353.43 MB; LC-MS m/z 354 (M+1)A
I. 1.1-43352.44 MB; LC-MS m/z 353 (M+1)In

Table 2
I. 1.1-44305.38 MB; LC-MS m/z 306 (M+1)In
I. 1.1-45319.41 MB; LC-MS m/z 320 (M+1)In
I. 1.1-46395.51 MB; LC-MS m/z 396 (M+1)In
I. 1.1-47 409.53 MB; LC-MS m/z 410 (M+1)In
I. 1.1-48353.42 MB; LC-MS m/z 354 (M+1)And
I. 1.1-49353.42 MB; LC-MS m/z 354 (M+1)And

Table 2
I. 1.1-50368.44 MB; LC-MS m/z 369 (m+1)D
I. 1.1-51486.62 MB; LC-MS m/z 487 (m+1)A
I. 1.1-52472.59 MB; LC-MS m/z 473 (m+1)A
I. 1.1-53MB 474.58; LC-MS m/z 475 (m+1)A
I. 1.1-54406.53 MB; LC-MS m/z 407 (m+1) A
I. 1.1-55378.48 MB; LC-MS m/z 379 (m+1)A

Table 2
I. 1.1-56380.49 MB; LC-MS m/z 381 (m+1)In
I. 1.1-57366.46 MB; LC-MS m/z 367 (m+1)A
I. 1.1-58366.46 MB; LC-MS m/z 367 (m+1)A
I. 1.1-57/R366.46 MB; LC-MS m/z 367 (m+1)A
I. 1.1-59366.46 MB; LC-MS m/z 367 (m+1)A
I. 1.1-60366.46 MB; LC-MS m/z 367 (m+1)A
I. 1.1-59/60R 366.46 MB; LC-MS m/z 367 (m+1)A

*) And mean activation hTGR5 receptor by more than 75%, more than 50%, With more than 25%, D - 10%.

The structure of a number of compounds 1.1.1 confirmed also by the method of1H NMR (DMSO-d6, 400 MHz):

I. 1.1-02

0.60-0.75 (m, 4H), 1.75 (s, 2H), 1.81-1.98 (m, 1H), 2.30 (s, 3H), 3.17 (s, 2H), 3.57 (s, 2H), 3.79 (m, 1H), 3.99 (m, 1H), 4.06 (d, 1H), 4.50 (s, 1H), 4.70 (m, 3H), 6.86 (t, 1H), 7.00 (d, 2H), 7.16 (d, 2H), 7.20 (s, 1H).

I. 1.1-07

1.80 (s, 2H), 2.24 (s, 3H), 3.18 (s, 3H), 3.57 (s, 1H), 3.75-4.20 (bs, 1H), 4.15 (m, 2H), 4.60-4.93 (bs, 1H), 4.70 (s, 1H), 6.55 (m, 1H), 6.84 (d, 1H), 6.90-7.25 (m, 6H), 7.79 (s, 1H).

I. 1.1-08

1.77 (s, 3H), 2.17-2.34 (m, 6H), 3.17 (s, 3H), 3.58 (s, 3H), 3.60 (d, 2H), 3.78 (m, 2H), 3.90 (m, 1H), 4.07 (m, 1H), 4.50 (d, 2H), 4.74 (s, 2H), 6.76-7.32 (m, 11H).

I. 1.1-09

0.89 (d, 3H), 1.00 (d, 3H), 1.81 (m, 2H), 2.19 (s, 3H), 2.88 (m, 1H), 3.17 (s, 3H), 3.58 (s, 1H), 3.85 (m, 2H), 4.06 (m, 2H), 4.48 (s, 1H), 4.57 (s, 1H), 4.76 (m, 1H), 6.84 (t, 1H), 6.87-7.17 (m, 5H).

I. 1.1-06

0.96 (m, 6H), 2.31 (s, 3H), 2.48 (bs, 1H), 3.19 (m, 4H), 3.57 (s, 1H), 3.76 (m, 4H), 4.01 (bs, 2H), 4.20 (s, 1H), 4.48 (s, 1H), 4.64 (s, 2H), 4.76 (s, 1H), 6.48 (s, 1H), 6.67-7.38 (m, 11H).

I. 1.1-05

0.60 (m, 2H), 0.78 (m, 2H), 1.27 (bs, 1H), 2.76 (s, 1H), 2.93 (s, 1H), 3.17 (m, 4H), 3.08 (d, 2H), 3.72 (m, 3H), 3.59 (m, 2H), 3.85 (m, 2H), 4.05 (m, 2H), 4.49 (d, 2H), 4.62 (s, 2H), 6.75-6.98 (m, 3H), 7.04 (m, 4H), 7.38 (d, 2H), 7.25-7.41 (m, 3H).

Example 4. General method for the synthesis of compounds of General formula I. 1.2

The synthesis was carried out according to Scheme 1.

To 0.063 g (0.000211 mol) of triphosgene dissolved in 1 ml dichloromethane, was added 1 ml of a solution containing the compound A1 (0.00057 mol) and diisopropylethylamine DIPEA (0.00126 mol 0.163 g). Stirred the resulting mass at room temperature in an argon atmosphere for 30 min and then was added amine A3 (0.00057 mol) and DIPEA (0.081 g, 0.00063 mol), dissolved in 1 ml dichloromethane. The mixture after stirring at room temperature (2 h) was diluted in 30 ml of dichloromethane, washed 2 N. HCl solution (20 ml), dried over sodium sulfate and chromatographically a mixture of CH2Cl2/EtOH (height of the column of 4 cm, width 1 cm). Received net products I. 1.2 with the outputs of 30-70%.

There were thus obtained the compounds I. 1.2-01 - I. 1.2-60 presented in Table 3.

I. 1.2-03485.63 MB; LC-MS m/z 486 (M+1)D

Table 3
I. 1.2-04471.60 MB; LC-MS m/z 472 (M+1)In
I. 1.2-05471.61 MB;
LC MS m/z 472 (M+1)
In
I. 1.2-06 409.53 MB; LC-MS m/z 410 (M+1)D
I. 1.2-07459.53 MB; LC-MS m/z 460 (M+1)In

Table 3
I. 1.2-23492.02 MB; LC-MS m/z 493 (M+1)D
I. 1.2-24485.63 MB; LC-MS m/z 486 (M+1)D
I. 1.2-25461.57 MB; LC-MS m/z 462 (M+1)D
I. 1.2-26507.61 MB; LC-MS m/z 508 (M+1l)In
I. 1.2-27506.63 MB; LC-MS m/z 507 (M+1)In

Table 3
I. 1.2-28MB 492.60; LC-MS m/z 493 (M+1)In
I. 1.2-29532.67 MB; LC-MS m/z 533 (M+1)In
I. 1.2-30479.56 MB; LC-MS m/z 480 (M+1)In
I. 1.2-31291.36 MB; LC-MS m/z 292 (M+1)In
I. 1.2-32305.38 MB; LC-MS m/z 306 (M+1)
I. 1.2-33353.42 MB; LC-MS m/z 354 (M+1)And

Table 3
I. 1.2-34403.46 MB; LC-MS m/z 404 (M+1)In
I. 1.2-35417.49 MB; LC-MS m/z 418 (M+1)A
I. 1.2-36354.41 MB; LC-MS m/z 355 (M+1)A
I. 1.2-37354.41 MB; LC-MS m/z 355 (M+1)A
I. 1.2-38367.45 MB; LC-MS m/z 368 (M+1)A
I. 1.2-39367.45 MB; LC-MS m/z 368 (M+1)A

Table 3
I. 1.2-40371.41 MB; LC-MS m/z 372 (M+1)A
I. 1.2-41385.44 MB; LC-MS m/z 386 (M+1)A
I. 1.2-42 417.49 MB; LC-MS m/z 418 (M+1)In
I. 1.2-43431.51 MB; LC-MS m/z 433 (M+1)A
I. 1.2-44445.54 MB; LC-MS m/z 447 (M+1)In
I. 1.2-45459.57 MB; LC-MS m/z 461 (M+1)A

Table 3
I. 1.2-46381.45 MB; LC-MS m/z 382 (M+1)In
I. 1.2-47423.56 MB; LC-MS m/z 424 (M+1)In
I. 1.2-48381.48 MB; LC-MS m/z 382 (M+1)In
I. 1.2-49368.44 MB; LC-MS m/z 369 (M+1) A
I. 1.2-50507.61 MB; LC-MS m/z 509 (M+1)A
I. 1.2-51445.54 MB; LC-MS m/z 447 (M+1)A

Table 3
I. 1.2-52395.51 MB; LC-MS m/z 397 (m+1)
I. 1.2-53431.51 MB; LC-MS m/z 433 (m+1)A
I. 1.2-54431.51 MB; LC-MS m/z 433 (m+1)A
I. 1.2-53/R431.51 MB; LC-MS m/z 433 (m+1)A
I. 1.2-55381.48 MB; LC-MS m/z 382 (m+1)A
I. 1.2-56 381.48 MB; LC-MS m/z 382 (m+1)A

Table 3
I. 1.2-55/R381.48 MB; LC-MS m/z 382 (m+1)A
I. 1.2-57445.54 MB; LC-MS m/z 447 (m+1)A
I. 1.2-58431.51 MB; LC-MS m/z 433 (m+1)A
I. 1.2-59431.51 MB; LC-MS m/z 433 (m+1)A
I. 1.2-58/R431.51 MB; LC-MS m/z 433 (m+1)A
I. 1.2-60521.64 MB; LC-MS m/z 523 (m+1)A

The structure of a number of compounds 1.1.2 confirmed also by the method of1H NMR (DMSO-d6, 400 MHz):

I. 1.2-12

1.75 (s, 3 is), 2.13 (s, 3H), 2.22 (s, 3H), 3.30 (s, 3H), 3.79 (m, 2H), 4.03 (m, 2H), 4.62 (s, 2H), 4.75 (s, 2H), 6.78-7.19 (m, 8H), 7.24 (s, 1H), 7.35 (d, 1H), 8.68 (s, 1H).

I. 1.2-05

0.93 (m, 6H), 2.19 (m, 6H), 2.33 (m, 1H), 3.29 (s, 3H), 3.81 (m, 2H), 4.05 (m, 2H), 4.63 (s, 2H), 4.74 (s, 2H), 6.85-7.03 (m, 8H), 7.17 (s, 1H), 7.32 (m, 2H), 8.47 (s, 1H).

I. 1.2-11

0.93 (m, 6H), 3.29 (s, 3H), 3.38 (m, 1H), 3.18 (s, 3H), 3.82 (m, 2H), 4.04 (m, 2H), 4.56 (s, 2H), 3.71 (s, 2H), 6.85-7.09 (m, 8H), 7.09 (s, 1H), 7.36 (m, 1H), 8.27 (s, 1H).

I. 1.2-09

0.95 (m, 6H), 2.16 (m, 6H), 2.22 (m, 3H), 3.18 (m, 4H), 3.81 (m, 2H), 4.04 (m, 2H), 4.58 (s, 2H), 4.68 (s, 2H), 6.83-7.00 (m, 7H), 7.13 (d, 1H), 7.19 (d, 2H), 8.31 (s, 1H).

I. 1.2-04

0.97 (m, 6H), 2.17 (m, 6H), 2.33 (bs, 1H), 3.34 (m, 2H), 3.80 (m, 2H), 4.06 (m, 2H), 4.61 (s, 1H), 4.73 (s, 2H), 6.72-7.36 (m, 11H), 8.48 (s, 1H).

I. 1.2-08

0.60 (m, 2H), 0.91 (s, 2H), 1.29 (s, 1H), 3.18 (s, 3H), 3.82 (m, 2H), 4.04 (m, 2H), 4.59 (s, 2H), 4.82 (s, 2H), 6.88 (dd, 2H), 7.10-7.28 (m, 7H), 7.48 (d, 2H), 8.61 (s, 1H).

Example 5. General method for the synthesis of compounds of General formula I. 1.3

The synthesis was carried out according to scheme 1.

Connection A1 (0.001 mol) was dissolved in 3 ml of dichloromethane, was added triethylamine (0.002 mol, 0.202 g) and with vigorous stirring gently added 0.0012 mol sulfochloride a4. After 5 hours stirring at room temperature the reaction mass was diluted with dichloromethane (30 ml), washed 2 N. hydrochloric acid (2×15 ml), dried over sodium sulfate and chromatographically a mixture of CH2CL2/EtOH (height of the column of 5 cm, width 1 cm). Received friendly products I. 1.3 outputs 50-65%.

There were thus obtained the compounds I. 1.3-01-I. 1.3-59/60R shown in Table 4.

Table 4
Compounds of General formula 1.1.3 data from LC-MS analysis and activity
The connection numberStructureMB, LC MS data% activation at @10 µM
I. 1.3-01MB 485.01; LC-MS m/z 486 (M+1)A
I. 1.3-02480.56 MB; LC-MS m/z 481 (M+1)A
I. 1.3-03492.64 MB; LC-MS m/z 493 (M+l)A
I. 1.3-04482.58 MB; LC-MS m/z 483 (M+1)In

Table 4
I. 1.3-05492.64 MB; LC-MS m/z 493 (M+1)In
I. 1.3-06 497.62 MB; LC-MS m/z 498 (M+1)In
I. 1.3-07496.61 MB; LC-MS m/z 497 (M+1)In
I. 1.3-08478.62 MB; LC-MS m/z 479 (M+1)In

Table 4
I. 1.3-09484.64 MB; LC-MS m/z 485 (M+1)In
I. 1.3-10496.61 MB; LC-MS m/z 497 (M+1)In
I. 1.3-11490.63 MB; LC-MS m/z 491 (M+1)
I. 1.3-12480.56 MB; LC-MS m/z 481 (M+1)In

Table 4
I. 1.3-13490.63 MB; LC-MS m/z 491 (M+1)In
I. 1.3-14MB 494.59; LC-MS m/z 495 (M+1)
I. 1.3-15496.61 MB; LC-MS m/z 497 (M+1)
I. 1.3-16497.02 MB; LC-MS m/z 498 (M+1)

Table 4
I. 1.3-17496.61 MB; LC-MS m/z 497 (M+1)
I. 1.3-18490.63 MB; LC-MS m/z 491 (M+1)
I. 1.3-19416.54 MB; LC-MS m/z 417 (M+1)C
I. 1.3-20 482.61 MB; LC-MS m/z 483 (M+1)D

Table 4
I. 1.3-21MB 480.59; LC-MS m/z 481 (M+1)D
I. 1.3-22416.54 MB; LC-MS m/z 417 (M+1)D
I. 1.3-23MB 498.55; LC-MS m/z 499 (M+1)D
I. 1.3-24481.58 MB; LC-MS m/z 482 (M+1)D

Table 4
I. 1.3-25442.58 MB; LC-MS m/z 443 (M+1)D
I. 1.3-26456.59 MB; LC-MS m/z 457 (M+1)A
I. 1.3-27 312.39 MB; LC-MS m/z 313 (M+1)
I. 1.3-28374.46 MB; LC-MS m/z 375 (M+1)
I. 1.3-29388.49 MB; LC-MS m/z 389 (M+1)In

Table 4
I. 1.3-30380.49 MB; LC-MS m/z 381 (M+1)In
I. 1.3-31388.49 MB; LC-MS m/z 389 (M+1)In
I. 1.3-32402.52 MB; LC-MS m/z 404 (M+1)In
I. 1.3-33406.48 MB; LC-MS m/z 407 (M+1)In
I. 1.3-34In
I. 1.3-35418.52 MB; LC-MS m/z 420 (M+1)
I. 1.3-36406.53 MB; LC-MS m/z 408 (M+1)

Table 4
I. 1.3-37MB 400.50; LC-MS m/z 402 (M+1)
I. 1.3-38414.53 MB; LC-MS m/z 416 (M+1)
I. 1.3-39MB 418.50; LC-MS m/z 419 (M+1)In
I. 1.3-40430.53 MB; LC-MS m/z 432 (M+1)In
I. 1.3-41408.54 MB; LC-MS m/z 410 (M+1)In
I. 1.3-42422.57 MB; LC-MS m/z 424 (M+1)In

Table 4
I. 1.3-43436.96 MB; LC-MS m/z 438 (m+1)
I. 1.3-44420.51 MB; LC-MS m/z 422 (m+1)
I. 1.3-45420.51 MB; LC-MS m/z 422 (m+1)
I. 1.3-46MB 470.61; LC-MS m/z 472 (m+1)
I. 1.3-47499.03 MB; LC-MS m/z 500 (m+1)In
I. 1.3-48482.58 MB; LC-MS m/z 484 (m+1)B

Table 4
I. 1.3-49478.62 MB; LC-MS m/z 480 (M+1)In
I. 1.3-50494.61 MB; LC-MS m/z 496 (M+1)In
I. 1.3-51408.54 MB; LC-MS m/z 410 (M+1)In
I. 1.3-52394.52 MB; LC-MS m/z 396 (M+1)A
I. 1.3-53394.52 MB; LC-MS m/z 396 (M+1)A
I. 3-52/R394.52 MB; LC-MS m/z 396 (M+1)A

Table 4
I. 1.3-54408.54 MB; LC-MS m/z 410 (M+1)A
I. 1.3-55 394.52 MB; LC-MS m/z 396 (M+1)A
I. 1.3-56394.52 MB; LC-MS m/z 396 (M+1)A
I. 3-55/R394.52 MB; LC-MS m/z 396 (M+1)A
I. 1.3-57422.93 MB; LC-MS m/z 424 (M+1)A
I. 1.358 for422.93 MB; LC-MS m/z 424 (M+1)A
I. 3-57/R422.93 MB; LC-MS m/z 424 (M+1)A

Table 4
I. 1.3-59422.93 MB; LC-MS m/z 424 (M+1)A
I. 1.3-60422.93 MB; LC MS m/z 424 (M+1)A
I. 1.3-59/60p422.93 MB; LC-MS m/z 424 (M+1)A

The structure of a number of compounds 1.1.3 confirmed also by the method of1H NMR (DMSO-d6, 400 MHz):

I. 1.3-05

0.91 (t, 3H), 1.62 (m, 2H), 1.80 (s, 3H), 2.32 (s, 3H), 2.58 (m, 2H), 3.07 (m, 1H), 3.53 (m, 2H), 3.58 (s, 2H), 3.95 (m, 2H), 4.33 (s, 2H), 4.77 (s, 2H), 6.74 (m, 1H), 6.95-7.28 (m, 8H), 7.59 (d, 2H).

I. 1.3-02

1.82 (s, 3H), 2.28 (s, 3H), 3.57 (m, 5H), 4.00 (m, 2H), 4.36 (m, 2H), 4.77 (s, 2H), 6.79 (d, 1H), 6.95-7.19 (m, 7H), 7.48 (m, 1H), 7.88 (m, 1H).

I. 1.3-03

1.43 (m, 8H), 2.33 (s, 3H), 2.95 (m, 1H), 3.17 (s, 3H), 3.52 (m, 2H), 3.59 (s, 1H), 3.99 (m, 2H), 4.38 (s, 2H), 4.79 (s, 2H), 6.65 (d, 1H), 6.96 (d, 1H), 7.03-7.67 (m, 9H).

I. 1.3-06

0.97 (m, 6H), 2.23 (s, 3H), 2.32 (s, 3H), 2.45 (m, 1H), 3.59 (s, 2H), 3.68 (m, 2H), 4.15 (m, 2H), 4.41 (m, 2H), 4.67 (s, 2H), 6.78 (d, 1H), 6.90-7.07 (m, 4H), 7.19 (m, 2H).

I. 1.3-26

0.68 (m, 2H), 0.82 (m, 2H), 1.33 (bs, 1H), 3.57 (m, 2H), 3.94 (m, 2H), 4.37 (s, 2H), 4.83 (s, 2H), 6.71 (d, 1H), 6.92 (d, 1H), 7.08 (s, 1H), 7.21 (m, 4H), 7.26-7.41 (m, 3H), 7.72 (t, 2H).

I. 1.3-04

2.12 (m, 3H), 2.33 (m, 3H), 3.57 (m, 2H), 3.93 (m, 2H), 4.38-4.51 (m, 6H), 6.67 (dd, 1H), 7.03 (m, 1H), 7.10-7.28 (m, 5H), 7.41-7.57 (m, 4H).

Example 6. General method for the synthesis of compounds of General formula I. 2.1

The synthesis was carried out in accordance with scheme 2.

Sinten B1 (0.001 mol) was dissolved in 3 ml of dichloromethane, was added triethylamine (0.002 mol, 0.202 g) and cooled to 0°C. With vigorous stirring gently added 0.0012 mol of acid chloride of b2 and the mixture was heated to room temperature. After three hours reacts the traditional mass was diluted with dichloromethane (30 ml), washed 2 N. hydrochloric acid (2×15 ml), dried over sodium sulfate and chromatographically a mixture of CH2Cl2/EtOH (height of the column of 5 cm, width 1 cm). Received friendly products 1.2.1 with yields of 60-90%.

There were thus obtained the compounds I. 2.1-01-I. 2.1-55/R presented in Table 5.

Table 5
Compounds of General formula 1.2.1 data from LC-MS analysis and activity
The connection numberStructureMB, LC MS data% activation at @10 µM
I. 2.1-01MB 435.50; LC-MS m/z 436 (M+1)A

Table 5
I. 2.1-02451.95 MB; LC-MS m/z 453 (M+1)A
I. 2.1-03413.93 MB; LC-MS m/z 415 (M+1)In
I. 2.1-04465.98 MB; LC-MS m/z 467 (M+1)A
I. 2.1-05397.49 MB; LC-MS m/z 398 (M+1)

Table 5
I. 2.1-06451.95 MB; LC-MS m/z 453 (M+1)
I. 2.1-07MB 481.53; LC-MS m/z 482 (M+1)
I. 2.1-08421.47 MB; LC-MS m/z 422 (M+1)C
I. 2.1-09425.89 MB; LC-MS m/z 426 (M+1)C

Table 5
I. 2.1-10425.89 MB; LC-MS m/z 426 (M+1)
I. 2.1-11460.30 MB; LC-MS m/z 461 (M+1)
I. 2.1-12477.56 MB; LC-MS m/z 478 (M+1)C
I. 2.1-13437.93 MB; LC-MS m/z 439 (M+1)C

Table 5
I. 2.1-14417.51 MB; LC-MS m/z 419 (M+1)D
I. 2.1-15397.47 MB; LC-MS m/z 398 (M+1)D
I. 2.1-16421.47 MB; LC-MS m/z 422 (M+1)D
I. 2.1-17401.51 MB; LC-MS m/z 402 (M+1)D
I. 2.1-18 MB 451.50; LC-MS m/z 452 (M+1)D

Table 5
I. 2.1-19MB 451.50; LC-MS m/z 452 (M+1)D
I. 2.1-20383.47 MB; LC-MS m/z 384 (M+1)D
I. 2.1-21399.92 MB; LC-MS m/z 401 (M+1)D
I. 2.1-22437.93 MB; LC-MS m/z 439 (M+1)D
I. 2.1-23341.41 MB; LC-MS m/z 342 (M+1)In

Table 5
I. 2.1-24355.43 MB; LC-MS m/z 356 (M+1)In
I. 2.1-25367.45 MB; LC-MS m/z 368 (M+1)In
I. 2.1-26417.51 MB; LC-MS m/z 419 (M+1)In
I. 2.1-27388.47 MB; LC-MS m/z 389 (M+1)A
I. 2.1-28403.48 MB; LC-MS m/z 404 (M+1)A
I. 2.1-29431.49 MB; LC-MS m/z 433 (M+1)A

Table 5
I. 2.1-30431.54 MB; LC-MS m/z 433 (M+1)A
I. 2.1-31329.42 MB; LC-MS m/z 330 (M+1)In
I. 2.1-32MB393.51; LC MS m/z 395 (M+1)In
I. 2.1-33360.48 MB; LC-MS m/z 362 (M+1)In
I. 2.1-34386.52 MB; LC-MS m/z 388 (M+1)In
I. 2.1-35355.44 MB; LC-MS m/z 356 (M+1)And

Table 5
I. 2.1-36398.51 MB; LC-MS m/z 400 (M+1)A
I. 2.1-37424.54 MB; LC-MS m/z 426 (M+1)A
I. 2.1-38428.96 MB; LC-MS m/z 430 (M+1)A
I. 2.1-39402.92 MB; LC-MS m/z 404 (M+1)A
I. 2.1-40386.47 MB; LC-MS m/z 387 (M+1)A

Table 5
I. 2.1-41371.44 MB; LC-MS m/z 372 (M+1)In
I. 2.1-42375.86 MB; LC-MS m/z 377 (M+1)In
I. 2.1-43357.41 MB; LC-MS m/z 358 (M+1)In
I. 2.1-44343.38 MB; LC-MS m/z 344 (M+1)In
I. 2.1-45327.38 MB; LC-MS m/z 328 (M+1)In
I. 2.1-46385.46 MB; LC-MS m/z 386 (M+1)In

Table 5
I. 2.1-47453.56 MB; LC-MS m/z 455 (M+1)A
I. 2.1-48463.53 MB; LC-MS m/z 465 (M+1)A
I. 2.1-49481.98 MB; LC-MS m/z 483 (M+1)A
I. 2.1-50453.58 MB; LC-MS m/z 455 (M+1)
I. 2.1-51463.55 MB; LC-MS m/z 465 (M+1)A

Table 5
I. 2.1-52449.53 MB; LC-MS m/z 451 (M+1)A
I. 2.1-53449.53 MB; LC-MS m/z 451 (M+1)A
I. 2.1-52/R 449.53 MB; LC-MS m/z 451 (M+1)A
I. 2.1-54463.55 MB; LC-MS m/z 465 (M+1)A
I. 2.1-55449.53 MB; LC-MS m/z 451 (M+1)A

Table 5
I. 2.1-56449.53 MB; LC-MS m/z 451 (M+1)A
I. 2.1-55/R449.53 MB; LC-MS m/z 451 (M+1)A

The structure of a number of compounds I. 2.1 confirmed also by the method of1H NMR (DMSO-d6, 400 MHz):

I. 2.1-06

3.63-3.72 (m, 5H), 3.87 (m, 2H), 3.99 (m, 1H), 4.07 (m, 1H), 4.45-4.68 (m, 6H), 6.75 (m, 3H), 6.96 (m, 1H), 7.15-7.26 (m, 3H), 7.27-7.48 (m, 4H).

I. 2.1-03

4.03 (bs, 2H), 4.22 (m, 2H), 4.52 (s, 2H), 4.59 (s, 2H), 4.27 (s, 2H), 6.96 (d, 1H), 7.07 (s, 1H), 7.23 (d, 2H), 7.32-7.53 (m, 5H), 7.23 (m, 1H).

I. 2.1-21

1.37-1.75 (m, 8H), 3.00 (m, 1H), 3.84 (m, 2H), 4.07 (m, 2H), 4.55 (m, 5H), 4.17 (s, 1H), 6.93 (m, 1H), 7.16-7.23 (m, 1H), 7.27-7.46 (m, 3H), 7.53 (m, 1H).

I. 2.1-11

4.00 (bs, 2H), 4.21 (m, 2H), 4.48 (s, 2H), 4.56 (s, 2H), 4.60 (bs, 2H), 6.75 (m, 1H), 6.95 (d, 1H), 7.03-7.27 (m, 5H), 7.40 (m, 1H).

I. 2.1-10

3.76 (m, 1H), 4.01 (m, 1H), 4.07 (m, 1H), 4.23 (m, 1H), 4.27-4.76 (m, 5H), 6.77 (s, 1H), 6.96-7.53 (m, 10H).

Example 7. General method for the synthesis of compounds of General formula I. 2.2

The synthesis was carried out in accordance with scheme 2.

To 0.063 g (0.000211 mol) of triphosgene dissolved in 1 ml dichloromethane, was added 1 ml of a solution containing the compound B1 (0.00057 mol) and diisopropylethylamine DIPEA (0.00126 mol, 0.163 g). Stirred the resulting mass at room temperature in an argon atmosphere for 30 min and then was added amine b3 (0.00057 mol) and DIPEA (0.081 g, 0.00063 mol), dissolved in 1 ml dichloromethane. The mixture after stirring at room temperature (2 h) was diluted in 30 ml of dichloromethane, washed with 2 n/ a HCl solution (20 ml), dried over sodium sulfate and chromatographically a mixture of CH2Cl2/EtOH (height of the column of 4 cm, width 1 cm). Received net products I. 2.2 with the outputs of 30-70%.

There were thus obtained the compounds I. 2.2-01-I. 2.2-61/R presented in Table 6.

Table 6
Compounds of General formula I. 2.2 data from LC-MS analysis and activity
The connection numberStructureMB, LC MS data% activation at @10 µM
I. 2.2-01F450.52 MB; LC-MS m/z 451 (M+1)A
I. 2.2-02478.53 MB; LC-MS m/z 479 (M+1)In

Table 6
I. 2.2-03478.53 MB; LC-MS m/z 479 (M+1)In
I. 2.2-04452.94 MB; LC-MS m/z 454 (M+1)In
I. 2.2-05434.52 MB; LC-MS m/z 435 (M+1)In
I. 2.2-06420.49 MB; LC-MS m/z 421 (M+1)

Table 6
I. 2.2-07406.46 MB; LC-MS m/z 407 (M+1)
I. 2.2-08482.97 MB; LC-MS m/z 484 (M+1)
I. 2.2-09474.56 MB; LC-MS m/z 475 (M+1)
I. 2.2-10420.49 MB; LC-MS m/z 421 (M+1)

Table 6
I. 2.2-11424.45 MB; LC-MS m/z 425 (M+1)
I. 2.2-12402.93 MB; LC-MS m/z 403 (M+1)
I. 2.2-13426.52 MB; LC-MS m/z 427 (M+1)
I. 2.2-14422.92 MB; LC-MS m/z 424 (M+1)

Table 6
I. 2.2-15466.51 MB; LC-MS m/z 467 (M+1)
I. 2.2-16478.53 MB; LC-MS m/z 479 (M+1)
I. 2.2-17422.92 MB; LC-MS m/z 424 (M+1)
I. 2.2-18436.49 MB; LC-MS m/z 437 (M+1)

Table 6
I. 2.2-19436.49 MB; LC-MS m/z 437 (M+1)
I. 2.2-20424.45 MB; LC-MS m/z 425 (M+1)
I. 2.2-21398.48 MB; LC-MS m/z 399 (M+1)C
I. 2.2-22416.53 MB; LC-MS m/z 417 (M+l)D
I. 2.2-23442.44 MB; LC-MS m/z 443 (M+l)D

Table 6
I. 2.2-24406.46 MB; LC-MS m/z 407 (M+1)D
I. 2.2-25416.53 MB; LC-MS m/z 417 (M+1)D
I. 2.2-26424.45 MB; LC-MS m/z 425 (M+1)D
I. 2.2-27416.53 MB; LC-MS m/z 417 (M+1)D
I. 2.2-28450.47 MB; LC-MS m/z 451 (M+1)D

Table 6
I. 2.2-29412.51 MB; LC-MS m/z 413 (M+1)D
I. 2.2-30430.55 MB; LC-MS m/z 431 (M+1)D
I. 2.2-31434.56 MB; LC-MS m/z 436 (M+1)D
I. 2.2-32356.43 MB; LC-MS m/z 357 (M+1)In

Table 6
I. 2.2-33356.43 MB; LC-MS m/z 357 (M+1)In
I. 2.2-34382.46 MB; LC-MS m/z 383 (M+1)In
I. 2.2-35432.52 MB; LC-MS m/z 434 (M+1)A
I. 2.2-36 413.52 MB; LC-MS m/z 415 (M+1)A
I. 2.2-37425.53 MB; LC-MS m/z 427 (M+1)A
I. 2.2-38386.45 MB; LC-MS m/z 387 (M+1)A

Table 6
I. 2.2-39492.58 MB; LC-MS m/z 494 (M+1)A
I. 2.2-40480.99 MB; LC-MS m/z 482 (M+1)A
I. 2.2-41376.43 MB; LC-MS m/z 377 (M+1)In
I. 2.2-42402.47 MB; LC-MS m/z 403 (M+1)In
I. 2.2-4366.56 MB; LC MS m/z 468 (M+1)A
I. 2.2-44433.53 MB; LC-MS m/z 435 (M+1)A

Table 6
I. 2.2-45459.57 MB; LC-MS m/z 461 (M+1)A
I. 2.2-46370.41 MB; LC-MS m/z 371 (M+1)In
I. 2.2-47396.45 MB; LC-MS m/z 397 (M+1)In
I. 2.2-48MB 427.50; LC-MS m/z 428 (M+1)A
I. 2.2-49453.54 MB; LC-MS m/z 455 (M+1)A

Table 6
I. 2.2-50 460.53 MB; LC-MS m/z 462 (M+1)A
I. 2.2-51478.57 MB; LC-MS m/z 480 (M+1)A
I. 2.2-52464.54 MB; LC-MS m/z 466 (M+1)A
I. 2.2-53464.54 MB; LC-MS m/z 466 (M+1)A
I. 2.2-
52/R
464.54 MB; LC-MS m/z 466 (M+1)A
I. 2.2-54478.57 MB; LC-MS m/z 480 (M+1)A

Table 6
I. 2.2-55464.54 MB; LC-MS m/z 466 (M+1)A
I. 2.2-56464.54 MB; LC-MS m/z 466 (M+1) A
I. 2.2-55/56464.54 MB; LC-MS m/z 466 (M+1)A
I. 2.2-57498.58 MB; LC-MS m/z 500 (M+1)A
I. 2.2-58484.55 MB; LC-MS m/z 486 (M+1)A
I. 2.2-59484.55 MB; LC-MS m/z 486 (M+1)A

Table 6
I. 2.2-58/R484.55 MB; LC-MS m/z 486 (m+1)A
I. 2.2-60498.58 MB; LC-MS m/z 500 (m+1)A
I. 2.2-61484.55 MB; LC-MS m/z 486 (m+1)A
I. 2.2-62 484.55 MB; LC-MS m/z 486 (m+1)A
I. 2.2-61/R484.55 MB; LC-MS m/z 486 (m+1)A

The structure of a number of compounds 1.2.2 confirmed also by the method of1H NMR (DMSO-d6, 400 MHz):

I. 2.2-04

3.56 (s, 2H), 3.75 (s, 3H), 3.62 (m, 2H), 4.56 (s, 2H), 4.59 (s, 2H), 4.66 (s, 2H), 6.82 (t, 1H), 6.86 (m, 3H), 7.21 (d, 1H), 7.26-7.71 (m, 7H).

I. 2.2-08

3.56 (s, 2H), 3.63 (s, 3H), 3.21 (s, 3H), 3.82 (m, 2H), 4.07 (m, 2H), 4.56 (s, 2H), 4.59 (s, 2H), 4.65 (s, 2H), 6.50 (m, 1H), 6.78 (d, 1H), 6.96 (d, 1H), 7.22 (d, 1H), 7.27-7.59 (m, 7H).

I. 2.2-07

3.57 (s, 2H), 3.76 (m, 2H), 4.07 (m, 2H), 4.47 (s, 2H), 4.51 (s, 2H), 4.68 (s, 2H), 6.96 (m, 2H), 7.05-7.47 (m, 7H), 7.40 (m, 4H), 8.51 (s, 1H).

I. 2.2-02

3.29 (s, 2H), 3.81 (m, 2H), 4.09 (m, 2H), 4.43 (s, 2H), 4.49 (s, 2H), 4.67 (s, 2H), 6.96 (d, 1H), 7.06-7.19 (m, 4H), 7.23-7.41 (m, 3H), 7.51 (d, 1H), 7.67 (d, 1H), 8.07 (s, 1H), 8.27 (s, 1H).

I. 2.2-05

2.66 (t, 2H), 3.17 (m, 2H), 3.69 (m, 2H), 3.96 (m, 2H), 4.46-4.57 (m, 6H), 6.67 (t, 1H), 6.91 (d, 1H), 7.07-7.43 (m, 10 H), 7.48 (t, 1H).

Example 8. General method for the synthesis of compounds of General formula 1.2.3

The synthesis was carried out in accordance with scheme 2.

Connection B1 (0.001 mol) was dissolved in 3 ml of dichloromethane, was added triethylamine (0.002 mol, 0.202 g) and with vigorous stirring gently added 0.0012 mol sulfochloride b4. After 5 hours stirring at room temperature the reaction mass was diluted with dichloromethane (30 ml), washed 2 N. hydrochloric acid (2×15ml), dried over sodium sulfate and chromatographically mixture SNS/EtOH (height of the column of 5 cm, width 1 cm). Received friendly products I. 2.3 outputs 50-65%.

There were thus obtained the compounds I. 2.3-01-I. 2.3-61/R presented in Table 7.

Table 7
Compounds of General formula I. 2.3 data from LC-MS analysis and activity
The connection numberStructureMB, LC MS data% activation at @10 µM
I. 2.3-01441.53 MB; LC-MS m/z 442 (M+1)In
I. 2.3-02473.98 MB; LC-MS m/z 475 (M+1)In
I. 2.3-03MB 461.94; LC-MS m/z 463 (M+1)In

Table 7
I. 2.3-04 451.59 MB; LC-MS m/z 452 (M+1)In
I. 2.3-05434.52 MB; LC-MS m/z 435 (M+1)In
I. 2.3-06MB 457.53; LC-MS m/z 458 (M+1)B
I. 2.3-07479.93 MB; LC-MS m/z 481 (M+1)C

Table 7
I. 2.3-08415.53 MB; LC-MS m/z 416 (M+1)In
I. 2.3-09409.94 MB; LC-MS m/z 411 (M+1)
I. 2.3-10445.49 MB; LC-MS m/z 446 (M+1)In
I. 2.3-11MB 461.94; LC-MS m/z 463 (M+1)In
Table 7
I. 2.3-12439.54 MB; LC-MS m/z 440 (M+1)
I. 2.3-13479.93 MB; LC-MS m/z 481 (M+1)In
I. 2.3-14443.95 MB; LC-MS m/z 445 (M+1)In
I. 2.3-15467.97 MB; LC-MS m/z 469 (M+1)In

Table 7
I. 2.3-16487.55 MB; LC-MS m/z 488 (M+1)In
I. 2.3-17409.94 MB; LC-MS m/z 411 (M+)
I. 2.3-18494.3 MB; LC MS m/z 495 (M+1)C
I. 2.3-19467.97 MB; LC-MS m/z 469 (M+1)B

Table 7
I. 2.3-20459.52 MB; LC-MS m/z 460 (M+1)
I. 2.3-21491.97 MB; LC-MS m/z 493 (M+1)In
I. 2.3-22475.97 MB; LC-MS m/z 477 (M+1)In
I. 2.3-23MB 457.53; LC-MS m/z 458 (M+1)C

Table 7
I. 2.3-24452.51 MB; LC-MS m/z 453 (M+1)
I. 2.3-25 485.56 MB; LC-MS m/z 486 (M+1)
I. 2.3-26463.48 MB; LC-MS m/z 464 (M+1)C
I. 2.3-27472.01 MB; LC-MS m/z 473 (M+1)C

Table 7
I. 2.3-28473.98 MB; LC-MS m/z 475 (M+1)D
I. 2.3-29MB 461.94; LC-MS m/z 463 (M+1)D
I. 2.3-30MB 478.40; LC-MS m/z 479 (M+1)D
I. 2.3-31479.93 MB; LC-MS m/z 481 (M+1)D

Table 7
I. 2.3-32MB 461.94; LC-MS m/z 463 (M+1)D
I. 2.3-33445.52 MB; LC-MS m/z 446 (M+1)D
I. 2.3-34491.97 MB; LC-MS m/z 493 (M+1)D
I. 2.3-35485.54 MB; LC-MS m/z 486 (M+1)D

Table 7
I. 2.3-36MB 461.94; LC-MS m/z 463 (M+1)D
I. 2.3-37441.53 MB; LC-MS m/z 442 (M+1)D
I. 2.3-38MB 449.98; LC-MS m/z 451 (M+1)D
I. 2.3-3946.57 MB; LC MS m/z 468 (M+1)D

Table 7
I. 2.3-40459.52 MB; LC-MS m/z 460 (M+1)D
I. 2.3-41479.93 MB; LC-MS m/z 481 (M+1)D
I. 2.3-42463.48 MB; LC-MS m/z 464 (M+1)D
I. 2.3-43467.55 MB; LC-MS m/z 468 (M+1)D

Table 7
I. 2.3-44455.55 MB; LC-MS m/z 456 (M+1)D
I. 2.3-45463.48 MB; LC-MS m/z 464 (M+1)D
I. 2.3-46 451.59 MB; LC-MS m/z 452 (M+1)D
I. 2.3-47463.48 MB; LC-MS m/z 464 (M+1)D

Table 7
I. 2.3-48491.97 MB; LC-MS m/z 493 (M+1)D
I. 2.3-49441.53 MB; LC-MS m/z 442 (M+1)D
I. 2.3-50441.53 MB; LC-MS m/z 442 (M+1)D
I. 2.3-51MB 408.50; LC-MS m/z 410 (M+1)A

Table 7
I. 2.3-52MB 424.95; LC-MS m/z 426 (M+1)A
I. 2.3-53 420.53 MB; LC-MS m/z 422 (M+1)In
I. 2.3-54422.52 MB; LC-MS m/z 424 (M+1)In
I. 2.3-55396.53 MB; LC-MS m/z 398 (M+1)In
I. 2.3-56434.53 MB; LC-MS m/z 436 (M+1)In
I. 2.3-57450.99 MB; LC-MS m/z 452 (M+1)In

Table 7
I. 2.358 for446.57 MB; LC-MS m/z 448 (M+1)In
I. 2.3-59448.56 MB; LC-MS m/z 450 (M+1)In
I. 2.3-60In
I. 2.3-61MB 408.50; LC-MS m/z 410 (M+1)A
I. 2.3-62MB 408.50; LC-MS m/z 410 (M+1)A
I. 2.3-61/RMB 408.50; LC-MS m/z 410 (M+1)A

The structure of a number of compounds 1.2.3 confirmed also by the method of1H NMR (DMSO-d6, 400 MHz):

I. 2.3-09

0.91 (t, 3H), 1.62 (m, 1H), 2.98 (t, 2H), 3.69 (m, 2H), 4.12 (m, 2H), 4.42 (s, 2H), 4.53 (s, 2H), 4.59 (s, 2H), 7.00 (s, 1H), 7.22 (m, 2H), 7.33 (m, 2H), 7.47 (d, 1H), 7.53 (d, 1H).

I. 2.3-02

3.57 (m, 2H), 3.76 (s, 3H), 4.01 (m, 2H), 4.44 (s, 2H), 4.53 (s, 2H), 4.59 (s, 2H), 6.84 (d, 1H), 7.17 (m, 3H), 7.26-7.49 (m, 6H), 7.57 (d, 1H).

I. 2.3-06

3.63 (m, 2H), 3.74 (s, 3H), 4.01 (m, 2H), 4.43 (s, 2H), 4.48 (s, 2H), 4.58 (s, 2H), 6.83 (d, 1H), 7.07-7.53 (m, 11H).

I. 2.3-05

3.67 (m, 2H), 4.06 (m, 2H), 4.44 (s, 2H), 4.51 (s, 2H), 4.54 (s, 2H), 6.78 (d, 1H), 7.17 (d, 1H), 7.25-7.43 (m, 6H), 7.87-7.98 (m, 4H).

I. 2.3-04

2.25 (s, 3H), 3.51 (m, 2H), 4.12 (m, 2H), 4.41 (s, 2H), 4.46 (s, 2H), 4.51 (s, 2H), 6.98 (d, 1H), 7.06 (s, 2H), 7.13 (s, 1H), 7.21 (d, 1H), 7.26-7.40 (m, 5H).

Example 9. General method for the synthesis of salts of compounds of General formula I

Part of the compounds of the present invention contains an ionic group (secondary and tertiary amines or carboxylic acids) and can image is the close co salt, which is produced by methods known in the art. For this purpose, for example, to a solution of a base in an inert solvent (alcohol, acetone, chloroform, ether, ethyl acetate) solution was added an equivalent amount (sometimes excess) organic or inorganic acid in an inert solvent and was achieved by precipitation of the desired salt. The inorganic acid may be chloroethanol acid, phosphoric acid, sulfuric acid, nitric acid, Hydrobromic acid or iodomethane acid. The organic acid may be methanesulfonate, p-toluensulfonate, acetic acid, triperoxonane acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, almond acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid or vanillic acid, but not limited to.

Compounds according to this invention, containing in its structure a carboxyl group can form salts with suitable therapeutically acceptable inorganic and organic bases. Suitable n is organic bases, which form salts include, for example, hydroxides, carbonates or bicarbonates pharmaceutically acceptable alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium, etc., suitable organic bases include primary, secondary, and tertiary amines, such as methylamine, benzathine (N',N'-dibenziletilendiaminom), choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylpenicillin), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propandiol), procaine, triethylamine, etc.

Table 8 presents examples obtained pharmaceutically acceptable salts and some of their properties.

Tabita 8
I. 2.2-37cMesilate521.60.12And
I. 1.3-50base495.60.00017In
I. 1.3-50dHydrochloride532.10.054In
I. 2.3-51 base408.50.00049And
I. 2.3-51dHydrochloride445.00.55And
I. 1.2-30acid479.60.000026In
I. 1.2-30Na501.50.20And

Example 10. General method for the synthesis of chiral compounds 1.1-57, 1.1-58, 1.2-53, 1.2-54, 1.3-52, 1.3-53, 1.3-57, 1.3-58 and racemic mixtures 1.1-57/R, 1.2-53/R, 1.3-52/R, 1.3-57/R General formula I

Chiral compounds 1.1-57, 1.1-58, 1.2-53, 1.2-54, 1.3-52, 1.3-53, 1.3-57, 1.3-58 and the racemic mixture of 1.1-57/R, 1.2-53/R, 1.3-52/R, 1.3-57/R received in accordance with scheme 1, based on synthons A2-rac, R-A2 and S-A2. Synthesis synthons A2 was carried out in accordance with scheme 5.

Scheme 5

The BOC-protected 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine C8 has azetilirovanie acetylchloride or acetic anhydride in the presence of a catalyst (aluminum chloride, zinc chloride, magnesium bromide, lithium chloride, etc.,), receiving azet the none C9. A series of Iminov C10 was obtained by condensation of ketone C9 with appropriate amines in the presence of dehydrating agents, and the removal of water (for example, TsOH in toluene, the nozzle Dean-stark and so on). A series of racemic amines, c11-rac was obtained by recovering Iminov C10 using the appropriate recovery agents (e.g., NaBH4, LiBH4, Zn/HOAc, H2/Pd, and so on). A series of individual optically active amines R-c11 and S-c11 were obtained by methods known in the art, details of which are described, for example, in ["Stereochemistry of Organic Compounds", Ed. by: E. L. Eliel. Wiley, New York, 1994]. In particular, for the separation of mixtures of amines, c11-rac interaction with a chiral tartaric acid was obtained diastereomer salt, which was separated by chromatography or fractional crystallization.

The acylation of amines c11 appropriate allelochemical R9COX (acylchlorides, allfreedom, Allbreed in neutral aprotic solvent (dichloromethane, dioxane, chloroform and the like) in the presence of a base (triethylamine, DABCO, pyridine and the like) during cooling and subsequent removal of the BOC-protection leads to a series of synthons A2-rac, R-A2 and S-A2. LC-MS characteristics of the final racemates and chiral compounds are presented in tables 1-3

Example 11. General method for the synthesis of chiral compounds 1.1-59, 1.1-60, 1.2-55, 1.2-56, 1.2-58, 1.2-59, 1.3-55, 1.3-56, 1.3-59, 1.3-60, 2.1-55, 2.1-56, 2.2-55, 2.2-56, 2.2-61, 2.2-62, 2.3-61, 2.3-62 and racemic mixtures 1.1-59/60R, 1.2-55/R, 12-58/R, 1.3-55/R, 1.3-59/60R, 2.1-55/R, 2.2-55/R, 2.2-61/R, 2.3-61/R General formula I

Chiral compounds 1.1-59, 1.1-60, 1.2-55, 1.2-56, 1.2-58, 1.2-59, 1.3-55, 1.3-56, 1.3-59, 1.3-60, 2.1-55, 2.1-56, 2.2-55, 2.2-56, 2.2-61, 2.2-62, 2.3-61, 2.3-62 and the racemic mixture of 1.1-59/60R, 1.2-55/R, 1.2-58/R, 1.3-55/R, 1.3-59/60R, 2.1-55/R, 2.2-55/R, 2.2-61/R, 2.3-61/R received in accordance with scheme 1, based on synthons A3-Gus, R-A3 and S-A3, or in accordance with scheme 2, on the basis of synthons B2-rac, R B2, and S-B2. The synthons A3 was obtained in accordance with scheme 6, the synthons B2 in accordance with scheme 7.

Scheme 6

For this 2-hydroxyacetophenone e1 was introduced into the reaction Mitsunobu with N-boc-ethanolamine, subsequent cyclocondensation led to the heterocycle E2, which vosstanavlivali with sodium borohydride in Amin E3, the BOC-protection of the latter led to the product E4. The next sequence of reactions (bromide E4→aldehyde E5→imine E6→amines E7→racemic synthons A3-rac) corresponded to the synthetic path of synthons A1 (scheme 3). A series of individual optically active synthons R-A3 and S-A3 was obtained by methods known in the art, details of which are described, for example, in ["Stereochemistry of Organic Compounds", Ed. by: E. L. Eliel. Wiley, New York, 1994].

Racemic aldehyde E5 (scheme 6) was restored and are condensed with the alcohol R15OH getting esters d2. Removal of the BOC-protection led to racemic SYN is Onam B2-rac, optical splitting which led to chiral series R-B2 and S-B2. LC-MS characteristics of the final racemates and chiral compounds are presented in tables 1-6.

Example 12. The definition of agonistic activity of compounds against the receptor hTGR5

Screening of a library containing more than 10 thousand substances, including compounds of formula I, was performed using the cell line SOME 293, which was stably expressed human receptor TGR5 (hTGR5). Agonistic activity of compounds was evaluated by increasing the intracellular concentration of camp, as it is known from literature that the activation of the receptor hTGR5 by subsequent activation of cellular adenylate cyclase leads to increased intracellular content of camp. As an experimental platform was selected as the test system Lance Ultra camp (Perkin Elmer). Known agonists of the receptor hTGR5 were used as positive control and to determine the absolute value of the maximum signal of the experiment. The substances were tested at a final concentration of 10 µm at one point. Substances showed agonistic activity more than 50% of the maximum signal - 3×SD (minimum signal), were nominated for re-test at a concentration of 10 µm in the replicate to confirm their activity. Data for the most active in the substances presented in tables 3-8. And means activation hTGR5 receptor by more than 75%, more than 50%, With more than 25%, D - 10%. For the most active compounds tested according agonistic activity of substance concentration of substance. From the obtained graphs of dependence was determined values EU50(the concentration of the substance in mcmash that causes 50% of maximal effect).

Cell line: immortalitya lineak 293 stably expressing hTGR5, Millipore, catalogue number HTS238L. Culture medium for cells consisted of DMEM, 10% fetal bovine serum, 1% nonessential amino acids, 2 mm L-glutamine, and 1 μg/ml puromycin/400 µg/ml S/200 mcg/ml of hygromycin B as a selective mixture of antibiotics.

Preparation of cells for the experiment. Cells were thawed in a water bath at 37°C, resuspendable in 5 ml of R-RA Hanks, centrifuged and again resuspendable in 6 ml of Hanks solution. Thus, were shaded cells from serum and culture medium. Repeating the centrifugation step and resuspendable cells in stimulating buffer test systems (SB). The final cell concentration was 2.00 E+05 cells/ml, which gave 1000 cells per well. camp-antibody was added to the cell suspension at a ratio of 1:150.

Preparation of tablets with substances. The substance was initially dissolved in DMSO to the centration of 2.5 mM. Tablets with substances in DMSO stored at -20°C. In Fig.2 presents the scheme of the 384-well plate with substances.

The Protocol of the experiment

1. On the day of the experiment was to prepare a buffer for the experiment (SB): l× HBSS, 5 mM HEPES, 0.1% BSA, pH 7.4. Mixed 45 ml HBSS, 225 μl of 1M HEPES and 600 µl of 7.5% BSA.

2. The suspension of cells, including 4-fold solution of antibodies to the camp, was added to 384-well plates to experiment, 5 μl into the hole using an automated system Biomek 2000 (Beckman Coulter). Was centrifuged at 300 rpm for 1 minute.

3. 2-fold the mixture [SB+substance] was added to the cell suspension using a robotic system Biomek FX 384. For the preparation of 2-fold mixture [SB+substance] SB was transferred into a 384-well plate, 99 μl/well. 1 μl of 200 times the working solution of the compounds in DMSO was transferred on the same 384-well plate. The resulting mixture was thoroughly stirred. 5 μl of 2-fold mixture [SB+substance] was added to the cell suspension at 5 μl per well. Experimental tablet was centrifuged at 300 rpm for 1 minute. Next, the cell suspension was incubated with the substances for 30 minutes at room temperature on a shaker, 300 rpm.

4. The original solution Eu-cAMP tracer was diluted 1:100 in buffer detection signal, receiving a 2x working solution of tracer. Then the solution was added to the experimental tablet, 10 μl, using robotic with the system Biomek 2000. Cell suspension was incubated with a solution to the detection signal 60 minutes on the shaker, 300 rpm.

5. The signal assay measured on the multi-function reader Wallac 1420 Victor3(Perkin Elmer), using a wavelength of 665 nm, the Protocol LANCE High Count_665_OptiPlate.

6. Agonistic activity of the substances was calculated using script to process the data Grand CaLculate_0.1.1. As the minimum signal experiment used the averaged data of the holes 23 of the column experimental tablet containing estimulando cells. As the maximum signal experiment used the averaged data of all the holes 24 of the column experimental tablet containing cells stimulated known steroid agonist hTGR5.

Example 13. The EU definition50for most active substances

Data were analyzed in the program GraphPad Prizm (GraphPad Software, Inc., San Diego, CA). To build concentration dependence was chosen equation

Y=Bottom+(Top-Bottom)1+10(LogEC50-X)-HillSlope

EU50was determined based on the graph, as the concentration of substance that causes 50% of maximal effect.

Example 14. Metabolic model using DIO-mice

DIO-mice (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 15. The study of pharmacological activity of the compounds of General formula I on the secretion incrediboi peptide GLP-1

The analyzed compound N-({4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N'-phenylcyclopropanecarboxylic (1.1.1-05) General formula I (dose of 30 mg/kg) in water RA the creators of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%) was administered orally DIO-mice C57B L/6J (6 mice at the time point) 15 minutes 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 sugar. As a control were injected aqueous solution of carboxymethyl cellulose (0.5%) and Tween-20 (0.25%). The experiment was repeated for compounds I. 1.2-01, I. 1.3-03, I. 2.1-02, I. 2.2-01, I. 2.3-51 General formula I.

Content incrediboi peptide GLP-1 in plasma were determined by standard ELISA method. As a result of stimulation of secretion of GLP-1 after 15 minutes of the experiment for all compounds: I. 1.1-05, I. 1.2-01, I. 1.3-03, I. 2.1-02, I. 2.2-01, I. 2.3-51, content incrediboi peptide GLP-1 in the blood exceeded 6 ng/mmol and 30 minutes after the introduction of sugar for all compounds: I. 1.1-05, I. 1.2-01, I. 1.3-03, I. 2.1-02, I. 2.2-01, I. 2.3-51, content incrediboi peptide GLP-1 in the blood exceeded 5.5 ng/mmol (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 16. The study of pharmacological activity of the compounds of General formula I on glucose metabolism (test glucose tolerance GTT)

The analyzed compound N-({4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N'-phenylcyclopropanecarboxylic (I. 1.1-05) 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) is 15 minutes prior to 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 I. 1.2-01, I. 1.3-03, I. 2.1-02, I. 2.2-01, I. 2.3-51 General formula I.

The data obtained in the result of the experiment, show a statistically significant decrease of glucose in plasma DIO-mice under the influence of TGR5 agonists of receptors:

glucose in plasma within 20 minutes after the start of the experiment (1000 mg/1 LITER; the concentration of glucose in plasma after 60 minutes after the start of the experiment -800 mg/ 1 LITER; the concentration of glucose in plasma after 120 minutes after the start of the experiment -600 mg/ 1L.

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

1. The use of compounds of General formula I, or racemic mixtures or individual optical isomers, or pharmaceutically acceptable salts

where X represents the amino group, R R"N, optionally substituted by the same substituents R' and R", where
the substituents of the amino group, R' and R" represent hydrogen, C1-C6alkyl, C3-C6cycloalkyl; substituted C1-C6alkyl, where the Deputy is selected from phenyl and is, phenoxy, each of which in turn may be substituted by halogen, C1-C3the alkyl, C1-C3alkoxy, phenyloxy,3-C6cycloalkyl, 5-6-membered heteroaryl with 1 nitrogen atom; aryl selected from phenyl, possibly substituted by fluorine, C1-C3the alkyl, C1-C3alkoxy; 5-6-membered heteroaryl, with the nitrogen atom as a heteroatom; C2-C4alkenyl, acyl selected from C1-C6alkylcarboxylic or3-C6cycloalkylcarbonyl;
or replaced oxygraph, which represents a hydroxy-group in which the hydrogen substituted C1-C6the alkyl possibly substituted by hydroxy, di(C1-C3alkyl)amino, phenyl, which in turn may be substituted by halogen, C1-C3the alkyl, C1-C3alkoxy; C2-C4alkenyl; and 5-6-membered heterocyclyl with the nitrogen atom, or sulfur, or oxygen as a heteroatom;
R1a and R1b represents hydrogen, C1-C3alkyl, or
R1a and R1b together form a polymethene chain -(CH2)n-, where n=2-5;
R1c and R1d represents hydrogen, C1-C3alkyl;
R2 is an acyl group selected from C1-C6alkylsulphonyl, where alkyl may be substituted by phenyl or phenoxy, each of the C which in turn may be substituted with halogen, C1-C3the alkyl, C1-C3alkoxy; C3-C6cycloalkylcarbonyl; phenylcarbinol, which may be substituted with halogen, C1-C3the alkyl, C1-C3alkoxygroup, actigraphy,1-C3alkylenedioxy; 5-6-membered heteroarylboronic with the nitrogen atom, oxygen or sulphur as heteroatoms, possibly substituted by carboxy, halogen or1-C3alkoxycarbonyl;
substituted aminocarbonyl group where the Deputy may be selected from C1-C6of alkyl, possibly substituted C1-C3alkoxycarbonyl, halogen, 5-6-membered heteroaryl with the nitrogen atom, oxygen or sulfur as heteroatom; C3-C6cycloalkyl; phenyl, possibly substituted with halogen, C1-C3the alkyl, C1-C3alkoxy, C1-C3alkoxycarbonyl,1-C3alkylenedioxy; 5-6-membered heteroaryl with the nitrogen atom, oxygen or sulphur as heteroatoms, possibly substituted by carboxy, C1-C3alkoxycarbonyl; aminocarbonyl group, substituted C1-C3by alkyl;
sulfonyloxy group selected from alkylsulfonyl, optionally substituted by a hydroxy-group, cyano, phenyl, possibly substituted C1-C3by alkyl, halogen, C1-C alkoxygroup; phenylsulfonyl, possibly substituted C1-C3by alkyl, halogen, C1-C3alkoxygroup, cyano, C1-C3alkylenedioxy or 5-6-membered heteroarylboronic with the atom of nitrogen, sulfur or oxygen as a heteroatom, possibly substituted with halogen, C1-C3the alkyl, C1-C3alkoxygroup;
R3 represents hydrogen,
to obtain a pharmaceutical composition having properties agonist bile acids TGR5.

2. The use of compounds on p. 1, where the compound corresponds to the General formula I. 1 or I 2 or their racemic mixtures or individual optical isomers or pharmaceutically acceptable salts

where
R4a and R4b represents hydrogen or methyl, or
R4a and R4b together form a polymethene chain-CH2-CH2-;
R4c and R4d represents hydrogen or methyl;
R5 represents an acyl group selected from C1-C6alkylsulphonyl, where alkyl may be substituted by phenyl or phenoxy, each of which in turn may be substituted by halogen, C1-C3the alkyl, C1-C3alkoxy; C3-C6cycloalkylcarbonyl; phenylcarbinol, which may be substituted with halogen, C1-C3 the alkyl, C1-C3alkylenedioxy; 5-6-membered heteroarylboronic with the nitrogen atom, oxygen or sulphur as heteroatoms, possibly substituted by carboxy or C1-C3alkoxycarbonyl;
substituted aminocarbonyl group where the Deputy may be selected from C1-C6of alkyl, possibly substituted C1-C3alkoxycarbonyl; C3-C6cycloalkyl; phenyl, possibly substituted with halogen, C1-C3the alkyl, C1-C3alkoxy, C1-C3alkoxycarbonyl; 5-6-membered heteroaryl with the nitrogen atom or sulfur as heteroatom, possibly substituted by carboxy, C1-C3alkoxycarbonyl;
sulfonyloxy group selected from alkylsulfonyl, substituted phenyl, possibly substituted C1-C3by alkyl, halogen, C1-C3alkoxygroup, cyano; phenylsulfonyl, possibly substituted C1-C3by alkyl, halogen, C1-C3alkoxygroup or 5-membered heteroarylboronic with the atom of nitrogen, sulfur or oxygen as a heteroatom, possibly substituted with halogen, C1-C3the alkyl, C1-C3alkoxygroup;
R6 represents hydrogen, C1-C6alkyl, substituted C1-C6alkyl, where the Deputy is selected from phenyl or phenoxy, each the second of which in turn may be substituted with halogen, C1-C3the alkyl, C1-C3alkoxy, phenyloxy,3-C6cycloalkyl; C3-C6cycloalkyl, 5-membered heterocyclyl with one nitrogen atom in the cycle; acyl group selected from C1-C3alkylcarboxylic or3-C6cycloalkylcarbonyl;
R7 represents hydrogen, C1-C6alkyl; substituted alkyl, where the Deputy is selected from phenyl or phenoxy, each of which in turn may be substituted by halogen, C1-C3the alkyl, C1-C3alkoxy, phenoxy,3-C6cycloalkyl; C2-C4alkenyl; aryl selected from phenyl, possibly substituted with halogen, C1-C3the alkyl, C1-C3alkoxy; 5-6-membered heteroaryl, with the nitrogen atom as a heteroatom;
R8 represents a C1-C6alkyl, possibly substituted by hydroxy, di(C1-C3alkyl)amino, phenyl, which in turn may be substituted by halogen, C1-C3the alkyl, C1-C3alkoxy; C2-C4alkenyl; 5-6-membered heterocyclyl with an atom of oxygen or nitrogen as a heteroatom.

3. The use of compounds on p. 1, where the compound corresponds to the General formula I. 1.1, I. 1.2, I. 1.3, I. 2.1, I. 2.2 or I. 2.3, or their racemic mixtures or individual optical isomers, or pharmaceutically acceptable br/>

where R4a, R4b, R4c and R4d have the meanings given in paragraph 2;
R9 represents C1-C3alkyl; C3-C6cycloalkyl;
R10 represents a C1-C3alkyl, optionally substituted by phenyl which may be substituted with halogen; or a 5-6-membered heteroaryl with a nitrogen atom as a heteroatom; C2-C4alkenyl; phenyl, possibly substituted C1-C3by alkyl;
R11 represents a C1-C4alkyl, optionally substituted phenyl, possibly substituted C1-C3the alkyl, C1-C3alkoxygroup, halogen, fenoxaprop, optionally substituted C1-C3alkoxygroup or halogen; C3-C6cycloalkyl or 5-6-membered heteroaryl with the atom of nitrogen, sulfur or oxygen as a heteroatom; C3-C6cycloalkyl; phenyl, optionally substituted C1-C3the alkyl, C1-C3alkoxygroup, actigraphy or halogen; benzo[d][1,3]dioxol; 5-6-membered heteroaryl with the atom of nitrogen, sulfur or oxygen as heteroatoms, optionally substituted with halogen;
R12 represents hydrogen;
R13 represents a C1-C4alkyl, possibly substituted C1-C3alkoxycarbonyl group and a phenyl, optionally substituted with halogen or 5-6-membered heteroaryl with the atom of nitrogen, sulfur or oxygen as a heteroatom; C3-C6cycloalkyl; phenyl, optionally substituted C1-C3the alkyl, C1-C3alkoxygroup, halogen, C1-C3alkoxycarbonyl group; benzo[d][1,3]dioxol; 5-6-membered heteroaryl with the atom of nitrogen, sulfur or oxygen as heteroatoms, optionally substituted by carboxypropyl, C1-C3alkoxycarbonyl group, aminocarbonyl group, substituted C1-C3by alkyl;
R14 represents a C1-C4alkyl, possibly substituted fluoro-substituted by phenyl; phenyl, optionally substituted C1-C3the alkyl, C1-C3alkoxygroup, halogen, cyano;
R15 represents C1-C6alkyl, optionally substituted by actigraphy, 5-6-membered heterocyclyl with the atom of nitrogen, sulfur or oxygen as a heteroatom, phenyl, optionally substituted C1-C3the alkyl, C1-C3alkoxygroup, halogen; C2-C4alkenyl.

4. Compounds representing:
N-(4-terbisil)-N'-({4-[(3-forfinal)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)ndimethylacetamide (I. 1.1-01);
N-{[4-(cyclopropanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide(I. 1.1-02);
N-(4-were)-N'-{[4-(2-phenylethanol)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl}ndimethylacetamide (I. 1.1-03);
N-({4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N'-phenylcyclopropanecarboxylic (I. 1.1-05);
N-{[4-(3-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methyl-N'-(4-were)propanamide (I. 1.1-06);
N-{[4-(2-furoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-07);
N-(4-were)-N-({4-[(4-were)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)ndimethylacetamide (I. 1.1-08);
N-[(4-isobutyryl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-09);
N-[(4-butyryl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl]-2-methyl-N'-(4-were)propanamide (I. 1.1-10);
2-methyl-N-(4-were)-N'-{[4-(2-titilate)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I. 1.1-n);
N-(4-were)-N'-{[4-(2-titilate)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.1-12);
N-{[4-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-phenyl-cyclopropanecarboxamide (I. 1.1-13);
N-{[4-(3-methylbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-phenylcyclopropanecarboxylic (I. 1.1-15);
N-{[4-(2,6-differentail)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-16);
N-{[4-(2,6-differentail)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methyl-N'-(4-were)propane is ID (I. 1.1-17);
N-{[4-(3-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-18);
N-{[4-(2-furoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methyl-N'-(4-were)propanamide (I. 1.1-19);
2-methyl-N-(4-were)-N'-{[4-(phenoxyacetyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I. 1.1-20);
N-({4-[(4-methoxyphenoxy)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N'-phenylcyclopropanecarboxylic (I. 1.1-21);
N-{[4-(cyclopentylacetyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-22);
N-{[4-(2-methylbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-23);
N-{[4-(cyclobutanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methyl-N'-(4-were)propanamide (I. 1.1-24);
N-{[4-(2-perbenzoic)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-25);
N-{[4-(cyclopentanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-26);
N-{[4-(cyclohexylcarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-were)ndimethylacetamide (I. 1.1-27);
N-{[4-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-phenyl-cyclopropanecarboxamide (I. 1.1-28);
2-methyl-N-(4-were)-N'-[(4-propionyl 2,3,4,5-terravita-1,4-benzoxazepin-7-yl)methyl]propanamide (I. 1.1-29);
2-methyl-N-{[4-(3-methylbutanoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'(4-were)propanamide (I. 1.1-30);
N-([4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)ndimethylacetamide (I. 1.1-31);
N-([4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)propanamide (I. 1.1-32);
N-([4-propionyl 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)ndimethylacetamide (LI.1-33);
N-([4-benzoyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)ndimethylacetamide (I. 1.1-34);
N-{[4-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-35);
N-{[4-(4-perbenzoic)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-36);
N-{[4-(2-perbenzoic)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-37);
N-{[4-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-38);
N-{[4-(4-pyridyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-39);
N-{[4-(thiophene-2-carbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)ndimethylacetamide (I. 1.1-40);
N-{[4-(thiophene-3-carbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(4-methyl)propionamide (I. 1.1-41);
N-{[4-(3-pyridyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)propionamide (I. 1.1-42);
N-{[4-phenylacetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)ndimethylacetamide (I. 1.1-43);
N-{[4-(methylamino)acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(methyl)ndimethylacetamide (I. 1.1-44);
N-{[4-(dimethylamino)acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]IU the yl}-N'-(methyl)ndimethylacetamide (I. 1.1-45);
N-{[4-(methylamino)acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(2-phenylethyl)ndimethylacetamide (I. 1.1-46);
N-{[4-(dimethylamino)acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(2-phenylethyl)ndimethylacetamide (I. 1.1-47);
N-{[4-(3-pyridyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(ethyl)ndimethylacetamide (I. 1.1-48);
N-{[4-(4-pyridyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(ethyl)ndimethylacetamide (I. 1.1-49);
N-{[4-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N'-(ethyl)ndimethylacetamide (I. 1.1-50);
N-(1-{4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1-{methyl}ethyl)-N'-(4-were)ndimethylacetamide (I. 1.1-51);
N-(1-{4-[4-methoxybenzoyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1-{methyl}ethyl)-N'-(4-were)ndimethylacetamide (I. 1.1-52);
N-(1-{4-[(3-forfinal)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1-{methyl}ethyl)-N'-(4-were)ndimethylacetamide (I. 1.1-53);
N-(1-{[4-(cyclopropanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1-(methyl)ethyl}-N'-(4-were)ndimethylacetamide (I. 1.1-54);
N-[1-(4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-cyclopropyl]-N'-(4-were)ndimethylacetamide (I. 1.1-55);
N-[(4-acetyl-5,5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-56);
N-[1(S)-(4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-ethyl]-N'-(4-were)ndimethylacetamide (I. 1.1-57);
N-[1(R)-(4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-ethyl]-N'-(4-were)ndimethylacetamide (I. 1.1-58);
N-[1(S)-(4-acetyl-2,3,4,5-tetrahydro-1-benzoxazepin-7-yl)-ethyl]-N'-(4-were)ndimethylacetamide (I. 1.1-57/58p);
N-[(4-acetyl-5(S)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-59);
N-[(4-acetyl-5(R)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-60);
N-[(4-acetyl-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)methyl]-N'-(4-were)ndimethylacetamide (I. 1.1-59/60R);
methyl 3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-01);
7-{[(cyclopropanecarbonyl)(phenyl)-amino]methyl}-N-(4-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-02);
7-{[isobutyl(4-were)amino]methyl}-N-(3-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-04);
7-{[isobutyl(4-were)amino]methyl}-N-(4-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-05);
N-(ISO-butyl)-7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-06);
7-{[(cyclopropanecarbonyl)-(phenyl)amino]methyl}-N-(3-forfinal)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-07);
N-(4-chlorophenyl)-7-{[(cyclopropanecarbonyl)-(phenyl)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-08);
N-(3,4-dimetilfenil)-7-{[isobutyl(4-were)-amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-09);
N-(4-terbisil)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-10);
7-{[acetyl(4-were)amino]methyl}-N-(-fluoro-4-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-12);
N-(2-forfinal)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-14);
7-{[acetyl(4-were)amino]methyl}-N-(2-ethylphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-16);
7-{[isobutyl(4-were)amino]methyl}-N-(3-methoxyphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-17);
N-(sec-butyl)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-18);
N-(2,5-dimetilfenil)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-19);
N-(tert-butyl)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-20);
7-{[acetyl(4-were)amino]methyl}-N-cyclopentyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-22);
N-(2-chlorophenyl)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-23);
N-(2,4-dimetilfenil)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-24);
N-(2-furylmethyl)-7-{[isobutyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 1.2-25);
ethyl 3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-26);
3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid dimethylamide (I. 1.2-7);
3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid of methylamide (I. 1.2-28);
3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid N-cyclopentylamine (I. 1.2-29);
3-({[7-{[acetyl(4-were)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid (I. 1.2-30);
N-[7-{[acetyl(methyl)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-methyl-carboxamide (I. 1.2-31);
N-[7-{[propionyl(methyl)-amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-methyl-carboxamide (I. 1.2-32);
N-[7-{[acetyl(methyl)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-phenyl-carboxamid (I. 1.2-33);
3-({[7-{[acetyl(methyl)amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid (I. 1.2-34);
methyl 3-({[7-{[acetyl(methyl)amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-35);
7-N-{[acetyl(methyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(pyridyl-3)-carboxamide (I. 1.2-36);
7-N-{[acetyl(methyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(pyridyl-4)-carboxamide (I. 1.2-37);
7-N-{[acetyl(methyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-benzyl-carboxamid (I. 1.2-38);
7-N-{[acetyl(methyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-were-carboxamid (I. 1.2-39);
7-N-{[acetyl(methyl)amine is[methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-forfinal)-carboxamide (I. 1.2-40);
7-N-{[acetyl(ethyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(2-forfinal)-carboxamide (I. 1.2-41);
3-({[7-{[acetyl(ethyl)amino]-methyl}-2,3-dihydro-1,4-benzoeiazepine-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid (I. 1.2-42);
methyl 3-({[7-{[acetyl(ethyl)amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-43);
3-({[7-{[(2-methylpropionyl)-(ethyl) - amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylic acid (I. 1.2-44);
methyl 3-({[7-{[(2-methylpropionyl)-(ethyl) - amino]-methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-45);
N-[7-{[acetyl - (2-phenylethyl)-amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-methyl-carboxamide (I. 1.2-46);
N-[7-{[acetyl - (2-phenylethyl)-amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)]-N'-tert-butyl-carboxamide (I. 1.2-47);
7-N-{[acetyl(ethyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-benzyl-carboxamid (I. 1.2-48);
7-N-{[acetyl(ethyl)amino]methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(pyridyl-3)-carboxamide (I. 1.2-49);
methyl 3-({[7-{[acetyl - (2-phenylethyl)amino]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-50);
methyl 3-({[7-{[acetyl(methyl)amino]-1-(methyl)ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-51);
7-{[N-acetyl(methyl)amino]-1-(methyl)ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-were-carboxamid I. 1.2-52);
methyl-3-({[7-{[acetyl(2-phenylethyl)amino]-1(S)-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-53);
methyl 3-({[7-{[acetyl - (2-phenylethyl)amino]-1(R)-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-54);
methyl 3-({[7-{[acetyl - (2-phenylethyl)amino]-1-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-53/R);
7-{[N-acetyl(methyl)amino]methyl}-5(R)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-were-carboxamid (I. 1.2-55);
7-{[N-acetyl(methyl)amino]methyl}-5(S)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)}-N'-(4-were)carboxamide (I. 1.2-56);
7-{[N-acetyl(methyl)amino]methyl}-5-methyl-2,3-dihydro-1,4 - benzoxazepin-4(5H)}-N'-(4-mesylphenyl)-carboxamide (I. 1.2-55/R);
methyl 3-({[7-{[acetyl(methyl)amino]methyl}-5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-57);
methyl 3-({[7-{[acetyl(methyl)amino]methyl}-5(R)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-58);
methyl 3-({[7-{[acetyl(methyl)amino]methyl}-5(S)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-59);
methyl 3-({[7-{[acetyl(methyl)amino]methyl}-5-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 1.2-58/R);
methyl 3-({[7-{[acetyl(4-were)amino]methyl}-5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-CT is oxalat (I. 1.2-60);
N-({4-[(4-chlorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-were)ndimethylacetamide (I. 1.3-01);
N-({4-[(4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(phenyl)cyclopropanecarboxamide (I. 1.3-02);
N-({4-[(4-isopropylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-were)ndimethylacetamide (I. 1.3-03);
N-(4-terbisil)-N-({4-[(3-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)ndimethylacetamide (I. 1.3-04);
N-(4-were)-N-({4-[(4-propylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)ndimethylacetamide (I. 1.3-05);
N-({4-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-2-methyl-N-(4-were)propanamide (I. 1.3-06);
N-({4-[(3,4-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-terbisil)ndimethylacetamide (I. 1.3-07);
2-methyl-N-(4-were)-N-{[4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I. 1.3-08);
2-methyl-N-(4-were)-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I. 1.3-09);
N-({4-[(3-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-2-methyl-N-(4-were)propanamide (I. 1.3-10);
N-({4-[(2,4-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenyl-cyclopropanecarboxamide (I. 1.3-h);
N-({4-[(2-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-2);
N-({4-[(4-ethylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-13);
N-({4-[(5-fluoro-2-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-14);
N-({4-[(2-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-2-methyl-N-(4-were)propanamide (I. 1.3-15);
N-({4-[(2-chlorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-16);
N-({4-[(2,4-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-terbisil)ndimethylacetamide (I. 1.3-17);
N-({4-[(2,5-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-18);
(2-methyl-N-(4-were)-N-{[4-(methylsulphonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}propanamide (I. 1.3-19);
2-methyl-N-({4-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-(4-were)propanamide (I. 1.3-20);
N-({4-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-21);
(N-(4-were)-N-{[4-(propylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-22);
N-({4-[(3,5-differenl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-23);
N-({4-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin the-7-yl}methyl)-N-phenylcyclopropanecarboxylic (I. 1.3-24);
N-{[4-(butylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-N-phenylcyclopropanecarboxylic (I. 1.3-25);
N-(4-were)-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-26);
N-methyl-N-{[4-(methylsulphonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-27);
N-methyl-N-{[4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-28);
N-methyl-N-{[4-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-29);
N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-30);
N-ethyl-N-{[4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-31);
N-ethyl-N-{[4-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-32);
N-ethyl-N-{[4-(4-perpenicular)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-33);
N-ethyl-N-{[4-(2-perpenicular)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-34);
N-ethyl-N-{[4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-35);
N-allyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-36);
N-allyl-N-{[4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-37);
N-allyl-N-{[4-(4-methyl-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-38);
N-all the l-N-{[4-(4-fluoro-phenylsulfanyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-39);
N-allyl-N-{[4-(4-methoxy-phenylsulfonyl)-2,3,4,5-etrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-40);
N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-41);
N-ethyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-42);
N-methyl-N-{[4-(4-chlorophenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-43);
N-methyl-N-{[4-(4-perpenicular)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-44);
N-methyl-N-{[4-(2-perpenicular)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}-2-methylpropanamide (I. 1.3-45);
N-phenylethyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-46);
N-phenylethyl-N-{[4-(4-chlorophenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-47);
N-phenylethyl-N-{[4-(4-perpenicular)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-48);
N-phenylethyl-N-{[4-(4-methyl-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-49);
N-[2-(pyrid-3-yl)ethyl]-N-{[4-(4-methoxy-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-50);
N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1-methyl(ethyl)}ndimethylacetamide (I. 1.3-51);
N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1(R)-ethyl}ndimethylacetamide (I. 1.3-52);
N-methyl-N-{[4(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1(S)-ethyl}ndimethylacetamide (I. 1.3-53);
N-methyl-N-{[4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1-ethyl}ndimethylacetamide (I. 1.3-52/R);
N-methyl-N-{[4-(2-thienylmethyl)-5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-54);
N-methyl-N-{[4-(2-thienylmethyl)-5(R)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-55);
N-methyl-N-{[4-(2-thienylmethyl)-5(S)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-56);
N-methyl-N-{[4-(2-thienylmethyl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-55/R);
N-methyl-N-{[4-(4-chloro-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1(R)-ethyl}ndimethylacetamide (I. 1.3-57);
N-methyl-N-{[4-(4-chloro-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1(S)-ethyl}ndimethylacetamide (I. 1.358 for);
N-methyl-N-{[4-(4-chloro-phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1-ethyl}ndimethylacetamide (I. 1.3-57/R);
N-methyl-N-{[4-(4-chloro-phenylsulfonyl)-5(S)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-59);
N-methyl-N-{[4-(4-chloro-phenylsulfonyl)-5(R)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-60);
N-methyl-N-{[4-(4-chloro-phenylsulfanyl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]methyl}ndimethylacetamide (I. 1.3-59/60R);
7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-01);
7-{[(4-Chlorobenzyl)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-02);
7-{[(2-Chlorobenzyl)oxy]methyl-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-03);
7-{[(4-Chlorobenzyl)oxy]methyl}-4-[3-(4-methoxyphenyl)propanol]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-04);
4-(cyclohexylcarbonyl)-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-05);
7-{[(4-Chlorobenzyl)oxy]methyl}-4-[(3-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-06);
7-{[(3-terbisil)oxy]methyl}-4-(3,4,5-trimethoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-07);
7-{[(3-terbisil)oxy]methyl}-4-(phenoxyacetyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-08);
7-{[(4-Chlorobenzyl)oxy]methyl}-4-(4-perbenzoic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-09);
4-(3-chlorobenzoyl)-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-10);
4-(5-bromo-2-furoyl)-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-11);
7-{[(4-methylbenzyl)oxy]methyl}-4-(3,4,5-trimethoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-12);
7-{[(4-Chlorobenzyl)oxy]methyl}-4-(2-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-13);
7-[(benzyloxy)methyl]-4-[(3-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-14);
7-{[(3-terbisil)oxy]methyl}-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-15);
7-{[(3-terbisil)oxy]methyl}-4-(3-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-16);
7-[(benzyloxy)methyl]-4-(3-phenylpropenoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-17);
7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenoxy)acetyl]-2,3,4,5-Tetra is Idro-1,4-benzoxazepin (I. 2.1-18);
4-(2,3-dimethoxybenzoyl)-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-19);
4-(cyclopentanecarbonyl)-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-20);
7-{[(2-Chlorobenzyl)oxy]methyl}-4-(cyclopentanecarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-21);
7-{[(4-Chlorobenzyl)oxy]methyl}-4-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-22);
7-(methoxymethyl)-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-23);
7-(ethoxymethyl)-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-24);
7-(allyloxymethyl)-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-25);
7-[2-phenylethylene(methyl)]-4-[(4-methoxybenzoyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-26);
7-[2-phenylethylene(methyl)]-4-(pyridyl-4-carbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-27);
7-[2-phenylethylene(methyl)]-4-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-28);
7-[2-phenylethylene(methyl)]-4-(2,3-methylenedioxybenzyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-29);
7-[2-phenylethylene(methyl)]-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-30);
7-(allyloxymethyl)-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-31);
7-[2-phenylethylene(methyl)]-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-32);
7-[2-dimethylamino-acyloxy(methyl)]-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (.2.1-33);
7-[2-N-pyrrolidino-acyloxy(methyl)]-4-(2-thienylboronic)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-34);
7-[2-dimethylamino-acyloxy(methyl)]-4-(4-pyridylcarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-35);
7-[2-dimethylamino-acyloxy(methyl)]-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-36);
7-[2-N-pyrrolidino-acyloxy(methyl)]-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-37);
7-[2-N-pyrrolidino-acyloxy(methyl)]-4-[(4-chlorophenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-38);
7-[2-dimethylamino-acyloxy(methyl)]-4-[(4-chlorophenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-39);
7-[2-dimethylamino-acyloxy(methyl)]-4-[(4-forfinal)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-40);
7-[2-hydroxyethyloxy(methyl)]-4-[(4-methoxyphenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-41);
7-[2-hydroxyethyloxy(methyl)]-4-[(4-chlorophenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-42);
7-[2-hydroxyethyloxy(methyl)]-4-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-43);
7-[2-hydroxyethyloxy(methyl)]-4-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-44);
7-[2-hydroxyethyloxy(methyl)]-4-benzoyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-45);
7-[2-(2,3-acid), acyloxy(methyl)]-4-acetyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-46);
7-[2-(2,3-acid), acyloxy(methyl)]-4-thienylboronic-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-47);
7-[2-2,3-acid), acyloxy(methyl)]-4-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-48);
7-[2-(2,3-acid), acyloxy(methyl)]-4-(4-chlorbenzoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-49);
7-[2-(2,3-acid), acyloxy(methyl)]-4-cyclohexylcarbonyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-50);
7-{1-[(3-terbisil)oxy]-1-(methyl})ethyl-4-[(4-methoxy-phenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-51);
7-{1(R)-[(3-terbisil)oxy]-1-(methyl})ethyl-4-](4-methoxy-phenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-52);
7-{1(S)-[(3-terbisil)oxy]-1-(methyl})ethyl-4-](4-methoxy-phenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-53);
7-{1-[(3-terbisil)oxy]-1-(methyl})ethyl-4-[(4-methoxy-phenyl)acetyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-52/R);
7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-54);
7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl)-5(R)-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-55);
7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-5(S)-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-56);
7-{[(3-terbisil)oxy]methyl}-4-[(4-methoxyphenyl)acetyl]-5-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.1-55/R);
N-(2-ethoxyphenyl)-7-{[(3-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-01);
ethyl 3-({[7-{[(3-terbisil)oxy]methyl}-2,3-dihydro-1,4-basecase-4(5H)-yl]carbonyl}amino)benzoate (I. 2.2-02);
ethyl 3-({[7-{[(2-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}aminobenzoate (I. 2.2-03);
7-{[(2-Chlorobenzyl)oxy]methyl}-N-(2-methoxyphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-04);
7-{[(2-terbisil)oxy]methyl}-N-(2-phenylethyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-05);
7-{[(3-terbisil)oxy]methyl}-N-(3-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-06);
7-{[(3-terbisil)oxy]methyl}-N-phenyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-07);
7-{[(2-Chlorobenzyl)oxy]methyl}-N-(2,5-acid)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-08);
ethyl 3-({[7-{[(4-methylbenzyl)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)benzoate (I. 2.2-09);
N-(3-forfinal)-7-{[(4-methylbenzyl)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-10);
7-{[(3-terbisil)oxy]methyl}-N-(4-forfinal)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-11);
N-(tert-butyl)-7-{[(4-Chlorobenzyl)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-12);
ethyl N-{[7-{[(4-methylbenzyl)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-beta-alaninate (I. 2.2-13);
7-{[(4-Chlorobenzyl)oxy]methyl}-N-phenyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-14);
N-(3,5-acid)-7-{[(4-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-15);
ethyl 2-({[7-{[(4-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)benzoate (I. 2.2-16);
7-[(benzyloxy)methyl]-N-(2-chlorophenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-ka is boxlid (I. 2.2-17);
7-{[(4-terbisil)oxy]methyl}-N-(3-methoxyphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-18);
7-{[(3-terbisil)oxy]methyl}-N-(3-methoxyphenyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-19);
7-{[(2-terbisil)oxy]methyl}-N-(4-forfinal)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-20);
N-cyclopentyl-7-{[(4-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-21);
N-benzyl-7-{[(4-methylbenzyl)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-22);
N-(2,4-differenl)-7-{[(2-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-23);
7-{[(2-terbisil)oxy]methyl}-N-phenyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-24);
7-{[(4-methylbenzyl)oxy]methyl}-N-(4-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-25);
7-{[(3-terbisil)oxy]methyl}-N-(3-forfinal)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-26);
7-{[(4-methylbenzyl)oxy]methyl}-N-(3-were)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-27);
N-1,3-benzodioxol-5-yl-7-{[(2-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-28);
N-cyclohexyl-7-{[(4-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-29);
7-{[(4-methylbenzyl)oxy]methyl}-N-(2-phenylethyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-30);
7-[(benzyloxy)methyl]-N-[3-(methylthio)phenyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-1);
N-(2-ethoxyphenyl)-7-methoxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-32);
N-(2-methoxyphenyl)-7-ethoxymethyl-2,3-dihydro-l,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-33);
N-(2-ethoxyphenyl)-7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-34);
N-(2-methoxyphenyl)-7-(2-phenylethylene)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-35);
N-(2-ethoxyphenyl)-7-(2-dimethylaminoethoxy)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-36);
N-(2-methoxyphenyl)-7-(2-N-pyrrolidinyloxy)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-37);
N-(2-ethoxyphenyl)-7-(2-hydroxyethoxy)methyl-2,3-dihydro-l,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-38);
N-(2-methoxyphenyl)-7-[2-(2,3-acid), acyloxy(methyl))-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-39);
N-(2-methoxyphenyl)-7-[2-(4-chlorophenyl)ethyloxy(methyl)]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-40);
methyl 3-([7-methoxymethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}amino)thiophene-2-carboxylate (I. 2.2-41);
methyl 3-{[7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl-amino}thiophene-2-carboxylate (I. 2.2-42);
methyl 3-{[7-(2-phenylethyl-hydroxy(methyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl-amino}thiophene-2-carboxylate (I. 2.2-43);
methyl 3-{[7-(2-dimethylaminoethyl-hydroxy(methyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl-amino}thiophene-2-carboxylate (I. 2.2-44);
methyl 3-{[7-(2-N-pyrrolic the but-acyloxy(methyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl-amino}thiophene-2-carboxylate (I. 2.2-45);
N-(3-ethoxycarbonylphenyl)-[7-methoxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-46);
N-(3-ethoxycarbonylphenyl)-[7-allyloxymethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-47);
N-(3-ethoxycarbonylphenyl)-[7-(2-dimethylaminoethoxy)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-48);
N-(3-ethoxycarbonylphenyl)-[7-(2-N-pyrrolidinyloxy)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-49);
N-(3-ethoxycarbonylphenyl)-[7-(2-phenylethylene)methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)]-carboxamide (I. 2.2-50);
N-(2-ethoxyphenyl)-7-{1-[(3-terbisil)oxy]-1-(methyl)ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-51);
N-(2-ethoxyphenyl)-7-{1-[(3-terbisil)oxy]-1(S)-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-52);
N-(2-ethoxyphenyl)-7-{1-[(3-terbisil)oxy]-1(R)-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-53);
N-(2-ethoxyphenyl)-7-{1-[(3-terbisil)oxy]-1-ethyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-52/R);
N-(2-ethoxyphenyl)-7-[(3-terbisil)oxymethyl]-5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-54);
N-(2-ethoxyphenyl)-7-[(3-terbisil)oxymethyl]-5(S)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-55);
N-(2-ethoxyphenyl)-7-[(3-terbisil)oxymethyl]-5(R)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxamide (I. 2.2-56);
N-(2-ethoxyphenyl)-7-[(3-terbisil)oxymethyl]-5-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-Carbo who said (I. 2.2-55/56);
methyl 3-({7-[1-(3-forbindelse)-1-methylethyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-57);
methyl 3-({7-[1-(3-forbindelse)-1(S)-ethyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-58);
methyl 3-({7-[1-(3-forbindelse)-1(R)-ethyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-59);
methyl 3-({7-[1-(3-forbindelse)-1-ethyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-58/R);
methyl 3-{[7-(3-forbindelse)-methyl]-5-dimethyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-60);
methyl 3-{[7-(3-forbindelse)-methyl]-5(S)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-61);
methyl 3-{[7-(3-forbindelse)-methyl]-5(R)-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-62);
methyl 3-{[7-(3-forbindelse)-methyl]-5-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl}amino)thiophene-2-carboxylate (I. 2.2-61/R);
7-[(benzyloxy)methyl]-4-[(2-terbisil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-01);
7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(3-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-02);
7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-03);
7-[(benzyloxy)methyl]-4-(mesitylenesulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-04);
4-{[7-[(Benzino the si)methyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]sulfonyl}benzonitrile (I. 2.3-05);
7-{[(2-terbisil)oxy]methyl}-4-[(3-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-06);
4-[(3-chloro-4-forfinal)sulfonyl]-7-{[(2-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-07);
7-[(benzyloxy)methyl]-4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-08);
7-{[(2-Chlorobenzyl)oxy]methyl}-4-(propylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-09);
7-{[(4-terbisil)oxy]methyl}-4-[(4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-10);
7-[(benzyloxy)methyl]-4-[(3-chloro-4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-11);
7-[(benzyloxy)methyl]-4-[(3-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-12);
7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(2,4-differenl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-13);
7-{[(2-Chlorobenzyl)oxy]methyl}-4-(phenylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-14);
4-[(5-chloro-2-thienyl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-15);
4-[(2,5-acid)sulfonyl]-7-{[(4-terbisil)oxy)methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-16);
7-{[(4-Chlorobenzyl)oxy]methyl}-4-(propylsulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-17);
7-[(benzyloxy)methyl]-4-[(5-bromo-2-thienyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-18);
4-[(5-chloro-2-thienyl)sulfonyl-7-{[(2-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-19);
7-{[(4-Torben who yl)oxy]methyl}-4-[(5-fluoro-2-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-20);
4-[(3-chloro-4-methoxyphenyl)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-21);
4-[(3-chloro-4-were)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-22);
7-{[(3-terbisil)oxy]methyl}-4-[(3-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-23);
4-{[7-{[(3-terbisil)oxy]methyl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]sulfonyl}benzonitrile (I. 2.3-24);
4-(2,1,3-benzothiadiazole-4-ylsulphonyl)-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-25);
4-[(3,5-differenl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-26);
7-{[(4-Chlorobenzyl)oxy]methyl}-4-[(2,4-dimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-27);
7-[(benzyloxy)methyl]-4-[(5-chloro-2-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-28);
4-[(4-chlorophenyl)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-29);
7-[(benzyloxy)methyl]-4-[(4-bromophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-30);
7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(3,5-differenl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-31);
4-[(4-chlorophenyl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-32);
4-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-33);
4-[(3-chloro-4-methoxyphenyl)sulfonyl]-7-{[(2-FPO is benzyl)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-34);
4-(2,3-dihydro-1,4-benzodioxin-6-ylsulphonyl)-7-{[(2-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-35);
7-{[(2-Chlorobenzyl)oxy]methyl}-4-[(2-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-36);
7-{[(3-terbisil)oxy]methyl}-4-[(3-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-37);
7-{[(2-Chlorobenzyl)oxy]methyl}-4-(2-thienylmethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-38);
4-(2,1,3-benzothiadiazole-4-ylsulphonyl)-7-[(benzyloxy)methyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-39);
7-{[(2-terbisil)oxy]methyl}-4-[(5-fluoro-2-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-40);
4-[(3-chloro-4-forfinal)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-41);
4-[(3,5-differenl)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-42);
7-[(benzyloxy)methyl]-4-(2,3-dihydro-1,4-benzodioxin-6-yl-sulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-43);
4-[(2,5-dimetilfenil)sulfonyl]-7-{[(2-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-44);
4-[(2,5-differenl)sulfonyl]-7-{[(3-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-45);
7-[(benzyloxy)methyl]-4-[(2,4,5-trimetilfenil)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-46);
4-[(2,4-differenl)sulfonyl]-7-{[(4-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-47);
4-[(5-chloro-2-methoxyphenyl)sulfonyl]-7-{[(-terbisil)oxy]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-48);
7-{[(3-terbisil)oxy]methyl}-4-[(4-were)sulfonyl]-2,3,4,5-terravita-1,4-benzoxazepin (I. 2.3-49);
7-{[(4-terbisil)oxy]methyl}-4-[(4-were)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-50);
7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-51);
7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-chlorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-52);
7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-53);
7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(2-performer)sulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-54);
7- {[(2-dimethylamino-ethyl)oxy]methyl}-4-[(2-thienyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-55);
7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(4-forfinal)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-56);
7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(4-chloro-phenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-57);
7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(4-methoxyphenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.358 for);
7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(2-performer)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-59);
7-{[(2-N-pyrrolidino-ethyl)oxy]methyl}-4-[(2-thienyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-60);
7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-forfinal)sulfonyl]-5(R)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I..3-61);
7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-forfinal)sulfonyl]-5(S)-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-62);
7-{[(2-dimethylamino-ethyl)oxy]methyl}-4-[(4-forfinal)sulfonyl]-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin (I. 2.3-61/R);

5. The method of obtaining compounds of General formula I. 1.1, involves the acylation of Cinchona A1-allelochemical A2 in a neutral solvent in the presence of base

where R4a, R4b, R4c, R4d, R9, R10, R11 have the above values.

6. The method of obtaining compounds of General formula I. 1.2, involves the sequential interaction of Cinchona A1 triphosgene in a neutral solvent in the presence of a strong base and an amine A3 in an inert atmosphere

where R4a, R4b, R4c, R4d, R9, R10, R12, R13 have the above values.

7. The method of obtaining compounds of General formula I. 1.3, which consists in the interaction of Cinchona A1 and sulfochloride A4 in an inert solvent in the presence of a strong base

where R4a, R4b, R4c, R4d, R9, R10 and R14 have the above values.

8. The method of obtaining compounds of General formula I. 2.1, involves the acylation of Cinchona B1-allelochemical b2 in a neutral solvent in the presence of a strong base

where R4a, R4b, R4c, R4d, R11 and R15 have the above values.

9. The method of obtaining compounds of General formula I. 2.2, involves the sequential interaction of Cinchona B1 with triphosgene in the presence of a strong base and an amine b3 in an inert atmosphere

where R4a, R4b, R4c, R4d, R12, R13 and R15 have the above values.

10. The method of obtaining compounds of General formula I. 2.3, which consists in the interaction of Cinchona B1 and sulfochloride b4 in an inert solvent in the presence of base

where R4a, R4b, R4c, R4d, R14, R15 have the meanings given above.

11. Active component that has the property of agonist receptors bile acids TGR5, which are compounds of General formula I according to any one of paragraphs.1-4.

12. Pharmaceutical composition for the prevention and treatment of metabolic diseases such as diabetes, obesity, diabetesthe, metabolic syndrome, hypercholesterolemia, dyslipidemia, containing an effective amount of the active ingredient under item 11.

13. The pharmaceutical composition under item 12 in the form of tablets, capsules, injections, ointments, rectal suspensions and gels, placed in pharmaceutically acceptable packing.

14. Method for the prevention and treatment of metabolic diseases is any, such as diabetes, obesity, diabetesthe, metabolic syndrome, hypercholesterolemia, dyslipidemia, introducing an effective quantity of a new active ingredient under item 11, or the pharmaceutical composition of paragraphs.12, 13.



 

Same patents:

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether oxalate of formula

as water-soluble substance with fungicidal activity. Essence of method consists in interaction of di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether with equimolar quantity of oxalic acid (COOH)2 at room (~20°C) temperature for 15 min.

EFFECT: output constitutes 99%.

2 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

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

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

17 cl, 25 dwg, 20 tbl, 286 ex

Amide derivative // 2536409

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 is a hydrogen atom or a C1-C6-alkyl group, substituted with one or two substitutes selected from C1-C6-alkoxy group, hydroxyl group, which can be substituted with a C1-C6-alkylcarbonyl group (substituted with one or two substitutes γ), and a 4-6-member saturated monocyclic heterocyclic carbonyl group containing a N atom; γ is a hydroxyl group, amino group, di(C1-C6-alkyl)amino group and carbamoyl group; R2 is a H atom or a C1-C6alkyl group, which can be substituted with a hydroxyl group; or R1 and R2, together with the nitrogen atom with which they are bonded, can be combined to form an azetidine group, a pyrrolidine group or morpholine group, which can be substituted with one hydroxyl group or a hydroxy-C1-C6-alkyl group; R3 and R4 is a C1-C6-alkyl group; R5 is a halogen atom or a C1-C6-alkyl group; R6 is a halogen atom; m and n denote an integer from 0 to 1; V and W are CH; X, Y and Z each independently can be CH or N. The invention also relates to a pharmaceutical composition containing a compound of formula (I), use of the compound of formula (I) and a method of treating sugar diabetes a disease associated with diabetes.

EFFECT: compounds of formula (I), having hypoglycemic activity.

21 cl, 6 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula

,

where values A, R1-R6 are given in i.1 of the invention formula. Methods of obtaining the formula (I) compound are described.

EFFECT: compounds demonstrate an inhibiting activity of the cathepsin enzyme, which makes it possible to use them for the preparation of a pharmaceutical composition and for the preparation of a medication.

38 cl, 12 dwg, 495 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinoxaline derivatives of general formula

,

a based pharmaceutical composition, using them as therapeutic agents, as well as to a based therapeutic agent for treating tumour diseases. In general formula I X represents: oxygen or sulphur; R1 represents hydrogen, R2/R3 represents hydrogen, R4 represents: (i) C1-C12-alkyl, (ii) saturated C3-C8-cycloalkyl, optionally substituted by C6-aryl, (iii) unsaturated C3-C8-cycloalkyl, (iv) heterocyclyl substituted by C(O)CF3, (v) C1-C6-alkyl substituted by C6-aryl, the above C6-aryl can be substituted by F, Cl, Br, I, -O-C1-C6-alkyl, C1-C6-alkyl, C6-aryl or hydroxy, (vi) C1-C6-alkyl substituted by C5-heteroaryl, (vii) C1-C8-alkylene, (viii) 1-adamantyl, (ix) C1-C6-alkyl substituted by C6-heterocyclyl containing a nitrogen atom and an oxygen atom, (x) C1-C6-alkyl substituted by C3-C6-cycloalkyl, or (xi) C1-C6-alkyl substituted by C6-heteroaryl; R5 represents hydrogen, R6 represents (i) aryl optionally substituted by C1-C6-alkyl, -O-C1-C6-alkyl, hydroxy, F, Cl, Br, I or amino, or (ii) C5-heteroaryl containing 2 nitrogen atoms optionally substituted by C1-C6-alkyl, R7 and R8 represent hydrogen.

EFFECT: producing the therapeutic agent for treating the tumour diseases.

7 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: described are novel heteroaryl-N-aryl-carbamates of general formula , where: Ar1 is phenyl, probably substituted with C1-C6halogenalkyl or C1-C6halogenalkoxy; Het is triazolyl; Ar2 is phenyl; X1 represents O or S; X2 - O; R4 - H or C1-C6alkyl; n=0, 1 or 2; and R1, R2 and R3 are independently selected from H, CN, C1-C6alkyl, C1-C6halogenalkyl, C3-C6cycloalkyl, C2-C6alkenyl, C2-C6alkinyl, C(=O)O(C1-C6alkyl), phenyl and Het-1, where Het-1 is a 5-membered unsaturated heterocyclic ring, containing one heteroatom, selected from sulphur or hydrogen, or a 6-membered unsaturated heterocyclic ring, containing one nitrogen atom as a heteroatom, and Het-1 can be substituted with F, Cl, C1-C6alkyl, C1-C6halogenalkyl or C1-C6alkoxy, and a method of fighting pest insects Lepidoptera or Homoptera with the application of the said compounds as insecticides and acaricides.

EFFECT: increased efficiency.

5 cl, 2 tbl, 80 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel malonamide derivatives of general formula , to their pharmaceutically acceptable salts of acid bonding and to all forms of their optically pure enantiomers, racemates or diastereomers and diastereomer mixtures, possessing inhibiting activity with respect to γ-secretase, as well as to pharmaceutical preparation, containing one or more than one of claimed compounds, and to application of claimed compounds for manufacturing of drugs. Values of substituents R, R1, R2, R3, as well as X, n are given in invention formula.

EFFECT: obtaining compounds that can be applied in treatment of Alzheimer's disease.

19 cl, 6 dwg, 111 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: compound of formula [I]: is described, where the ring A represents halogen substituted benzene ring; the ring B represents benzene ring substituted with two lower, 1 to 4 carbon atoms, alcoxy-groups; the ring C represents benzene ring or five-member aromatic heterocyclic ring, that may be optionally substituted with substitute as follows: carboxyl group, C1-4-alkyl group, C2-7-alkanoiloxy-C1-6-alkyl group, phenyl-C1-4-alkyl group, phenyl group, optionally substituted with carboxyl group, or oxo-group; R1 represents C1-6-alkyl group, optionally substituted with hydroxyl group, that optionally substituted with C2-20-alkanoil or C1-7-alkyl group; X1a represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X1b represents bound or C1-6-alkylen, optionally substituted with hydroxyl or oxo-group; X2 represents bound, -O- or -S- ; X3 represents bound or group, formed by one hydrogen atom elimination from either straight or branched chain C1-7-alkyl, or C2-6-alkenyl group, that optionally substituted with hydroxyl or oxo-group; and Y represents optionally etherified carboxyl group; or its salt. Benzoxazepin derivatives production method, medicine based on them, and their application are also described.

EFFECT: novel compounds have high lipids-decreasing effect and are helpful as hyperlipidemia prevention and treatment medicine.

20 cl, 168 ex

FIELD: chemistry.

SUBSTANCE: claim describes benzoxazepinone derivatives of formula : wherein R1 represents hydrogen, C1-C6 alkoxy, halogen or NR'R", n is 1 or 2, R', R" independently from each other represents hydrogen or C1-C6 alkyl; R2 represents hydrogen, C1-C6 alkyl -(CH2)m-C3-C7-cycloalkyl, -(CH2)m-phenyl or -(CH2)m-O-C1-C6 alkyl; m is 0.1 or 2; R3 represents C1-C6 alkyl,-(CH2)m-C(O)O-C1-C6 alkyl, C3-C7 cycloalkyl or -(CH2)m-phenyl which is unsubstituted or substituted by one or two substituents, selected from the group consisting of halogen, trifluoromethyl, -NR'R", nitro and -SO2NH2, or represents -C3-C7 -cycloalkyl, unsubstituted or substituted by phenyl, or is -(CR′R″)o-heterocyclyl, selected from the group consisting of tetrahydropyran-4-yl, pyridin-3-yl, indol-3-yl optionally substituted by halogen or C1-C6 alkoxy group, or thiophen-2-yl, furan-2-yl, NH-pyridin-2-yl optionally substituted by nitro group or benzoimidazol-2-yl, 2-oxo-tetrahydrofuran, and benzo[1,3]dioxol-5-yl and represents -tetrahydro-naphthalen-1-yl, -CHR′-naphthalen-2-yl, -fluoren-9-yl, -(CH2)o-S-lower alkyl, -(CH2)o-S-benzyl, -(CH2)o-C(O)NH2, -(CH2)oNR′R″, -CH[C(O)NH2]-(CH2)o-phenyl, -(CH2)o-CF3, or -(CH2)o-CR′R″-CH2-NR′R″; and o is 1 or 2; or their pharmaceutically suitable acid addition salts, excluding: phenetylamide 4-benzyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, butylamide 4-benzyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, phenetylamide 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid, butylamide 4-cyclohexyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]-oxazepine-5-carboxylic acid. The pharmaceutical on basis of the compounds of formula I aimed at the treatment of Alzheimer's disease is described.

EFFECT: production of the new compounds, benzoxazepinone derivatives having useful biological properties.

26 cl, 196 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

The invention relates to new derivatives of acetic acid, the method of production thereof, pharmaceutical preparations containing such compounds and to the use of these compounds in the manufacture of pharmaceutical preparations

The invention relates to a derivative of 4.1-benzoxazepin-2, or their salts, which are useful for inhibiting stvalentines and fungus growth, and to their use

The invention relates to a condensed heterocyclic compounds or their salts and inhibitors of squalene synthetase containing these compounds as an effective component

FIELD: medicine.

SUBSTANCE: invention refers to medicine and can be used for the correction of gynoid obesity. That is ensured by typing an eating disorder to be psychologically corrected. A diet therapy is prescribed with a caloric value determined by reducing a patient's habitual daily average caloric requirement per a percent equal to the patient's body weight index. That is combined with a low-carbohydrate diet with the carbohydrate content reduced to 40-60 g/day for 2 weeks. That is followed by prescribing a low-fat diet with the fat content reduced to 40-60 g/day for 10 weeks with avoiding fast assimilated carbohydrates having a glycaemic index of more than 50. The diet therapy cycle is repeated. That is combined with graduated aerobic physical exercises with no weight and resistance for the muscle groups of the lower body. There are also performed muscle-strengthening load exercises for the muscle group of the upper body promoting muscle fatigue. Between and after the graduated physical exercises, there are performed prolonged aerobic physical loads at least 5 days a week for 40-60 minutes. That is combined with the drug-free procedures aiming at improving the regional blood flow, increasing gluteofemoral and lower extremities muscle tonus. The low-fat diet involves administering health aids from the group of intestinal membrane-bound alpha-glucosidase and pancreatic alpha-amylase inhibitors. The course of the obesity correction involves administering catechin-containing preparations or biologically active additives. From the second month from the beginning of the obesity correction, the patient's face is exposed to full-spectrum natural or artificial light at intensity of not less than 2,000 lux for 1-2 hours a day simultaneously or alternatively with the physical loads.

EFFECT: method provides the effective weight reduction in the patients with gynoid obesity with reducing side effects.

5 cl, 8 tbl, 2 ex

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