Derivatives of 1,2,4-triazole and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel derivatives of 1,2,4-triazole of the general formula (I): wherein A and b can be taken separately or in common being when they are taken separately then A means (C1-C6)-alkyl or phenyl, and B means (C1-C6)-alkyl; A and B taken in common mean (C2-C5)-alkanediyl, and they form with C-atoms 3-6-membered cycle optionally substituted with (C1-C4)-alkylene, oxo, ethylenedioxy group, (C1-C4)-alkyl, 1-2 halogen atoms, (C1-C3)-alkoxy-(C1-C3)-alkoxy or hydroxy group; each R1 means independently hydrogen atom, -OH, halogen atom, (C3-C6)-cycloalkyl, (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms; or two R1 groups near adjacent carbon atoms form 6-membered aryl cycle; R2 and R3 can be taken in common or separately, and when they are taken in common then they represent (C3-C8)-alkanediyl that forms condensed 5-10-membered nonaromatic cycle; when R2 and R3 are taken separately then R2 means (C1-C6)-alkyl possibly substituted with 1-3 halogen atoms or cyclopropyl, and R3 means cyclopropyl possibly substituted with (C1-C4)-alkyl, naphthyl, phenyl possibly substituted with halogen atom, -OH, (C1-C6)-alkyl wherein indicated (C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, -O-(C1-C6)-alkyl wherein indicated -O-(C1-C6)-alkyl is optionally substituted with 1-3 halogen atoms, phenyl or benzyloxy group, dihydrobenzofuranyl, benzothiadiazolyl or benzoimidazolyl possibly substituted with (C1-C6)-alkyl, their pharmaceutically acceptable salts or solvates, and pharmaceutical composition based on thereof. Proposed compounds are inhibitor of 11β-hydroxysteroid dehydrogenase I, and can be used in medicine in treatment of diabetes mellitus, obesity and dyslipidemia.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 17 tbl, 4 ex

 

The technical field

This invention relates to inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type I (11β-HSD-1 or HSD-1) and methods of treatment using such compounds. The compounds are useful for the treatment of diabetes, such as insulin-independent diabetes mellitus type 2 (NIDDM), insulin resistance, obesity, lipid disorders and other diseases and conditions.

BACKGROUND of the INVENTION

Diabetes is caused by many factors and the most simply characterized by elevated levels of plasma glucose (hyperglycemia) on an empty stomach. Usually there are two forms of diabetes: diabetes type 1 diabetes or insulin-dependent diabetes (IDDM), in which patients produced a small amount of insulin is either not produced insulin - the hormone that regulates glucose consumption, and diabetes mellitus type 2 or non-insulin dependent diabetes mellitus (NIDDM), in which insulin patients produced and even appears hyperinsulinemia (i.e. the levels of insulin in the plasma is equal to and even are elevated compared to subjects not suffering from diabetes), and at the same time there is hyperglycemia. Diabetes type 1 diabetes is usually treated with exogenous insulin by injection. However, in patients with diabetes mellitus type 2 is often avivausa "insulin resistance", so the action of insulin in stimulating glucose metabolism and lipids in the main sensitive to insulin tissues, namely muscle tissues, liver tissues, and adipose tissues, weakening. In patients who are insulinorezistentne, but do not have diabetes, there are elevated levels of insulin to compensate for their insulin resistance, therefore, the levels of glucose in the plasma is increased. In patients with NIDDM levels of insulin in the plasma, even when they are raised, are insufficient to overcome the pronounced insulin resistance, which leads to hyperglycemia.

Insulin resistance is primarily due to a violation of receptor binding, which is not yet fully understood. Insulin resistance leads to insufficient activation of absorption of glucose, reduced oxidation of glucose and glycogen accumulation in muscle, inadequate insulin repression of lipolysis in adipose tissue and inadequate production and secretion of glucose by the liver.

Prolonged or uncontrolled hyperglycemia, which occurs in patients with diabetes, is associated with increased morbidity and premature mortality. Abnormal glucose homeostasis is also associated both directly and indirectly, obesity, hypertension, and disorders in ibidem, urine and apolipoprotein metabolism. Patients with diabetes type 2 are patients with increased risk of cardiovascular complications such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity and hypertension is extremely important for clinical monitoring and treatment of diabetes.

A large number of patients with insulin resistance, which, however, is not observed for the development of diabetes mellitus type 2, also have the risk of developing symptoms, called "syndrome X" or "metabolic syndrome". Syndrome X is characterized by insulin resistance in combination with morbid obesity, hyperinsulinemia, high blood pressure, low HDL and high levels of VLDL. These patients, regardless of the presence or absence of development of overt diabetes, are patients with an increased risk of development of cardiovascular complications listed above.

Treatment of diabetes type 2 usually includes physical activity and diet. Increased levels of insulin in plasma by introduction of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide that stimulating the comfort of the secretion of pancreatic β cells more insulin, and/or by injection of insulin when sulfonylureas or meglitinide ineffective, may cause the concentration of insulin become high enough to stimulate insulin resistant fabric. However, in this case can be obtained dangerously low levels of glucose in the plasma and ultimately may have an increased level of insulin resistance.

Biguanides increase sensitivity to insulin, leading to some correction of hyperglycemia. However, many biguanides, such as phenformin and Metformin cause lactic acidosis, nausea, and diarrhea.

Glitazone (i.e., 5-benzylethanolamine-2,4-diones) are a newer class of compounds that can alleviate hyperglycemia, and other symptoms of type 2 diabetes. Data pharmaceutical essentially increase insulin sensitivity in muscle, liver and adipose tissue, leading to partial or complete correction of elevated levels of glucose in the plasma is essentially without causing hyperglycemia. Glitazone that are currently available, are agonists of receptor-activated proliferation peroxisome (PPAR) gamma subtype. It is believed that PPAR-γ agonism responsible for the increased sensitivity to insulin, which is observed when using the years of glitazones. Newer PPAR agonists that are designed for the treatment of type 2 diabetes and/or dyslipidemia, are agonists of one or more PPAR alpha, gamma and Delta subtypes.

Currently, there remains a need for new methods of treatment of diabetes and related conditions. This invention meets these and other needs.

BRIEF description of the INVENTION

This invention relates to the compound represented by formula I

or its pharmaceutically acceptable salt or solvate, where:

A and b can be taken separately or together,

when taken separately,

Rather it represents a halogen, With1-6-alkyl, OC1-6-alkyl or phenyl, and these alkyl, phenyl or alkyl part OS1-6-alkyl are optionally substituted by 1-3 halogen groups; and

B represents H, halogen, C1-6-alkyl, -OS1-6-alkyl, -SC1-6-alkyl, C2-6alkenyl, phenyl or naphthyl, and these alkyl, alkenyl, phenyl, naphthyl and alkyl parts-OS1-6-alkyl, and-SC1-6-alkyl are optionally substituted by 1-3 groups selected from halogen, HE, CH3Oh, CF3and OCF3;

when taken together,

A and b together represent a (a)1-4-alkylene, optionally substituted by 1-3 halogen gr is pami and 1-2 R agroups, where Rarepresents a C1-3-alkyl, OC1-3-alkyl, C6-10-arils1-6-alkylene or phenyl, optionally substituted by 1-3 halogen groups, or (b) (C2-5-alcander, so that they form with the carbon atom to which is attached, 3-6-membered cycle, and this cycle optionally contains 1 double bond or 1-2 heteroatoms selected from O, S and N, and the specified 3-6-membered cycle is optionally substituted C1-4-alkylene, oxo, Ethylenedioxy or Propylenediamine and optionally additionally substituted by 1-4 groups selected from halogen, C1-4-alkyl, halogen-C1-4-alkyl, C1-3-acyl, C1-3-acyloxy,1-3-alkoxy, C1-6-alkyl-OC(O)-, C2-4-alkenyl,With2-4-quinil,1-3-alkoxy-C1-3-alkyl, C1-3-alkoxy-C1-3alkoxy, phenyl, CN, OH, D, NH2, Otheraand N(Ra)2where Ratakes the values defined above;

each R1represents H or is independently selected from the group comprising HE, halogen, C1-10-alkyl, C1-6-alkoxy and C6-10-aryl, and specified With1-10-alkyl, C6-10the aryl and the alkyl part C1-6-alkoxy are optionally substituted by 1-3 Halogens, HE OS1-3-alkyl, phenyl or naftilos groups, and these phenyl and NAF is Il are optionally substituted by 1-3 substituents, independently selected from halogen, och3,OCF3CH3, CF3and phenyl, where the specified phenyl optionally substituted by 1-3 halogen groups,

or two R1groups together represent condensed With5-6is an alkyl or aryl cycle, which may be optionally substituted by 1-2 HE or Ragroups, where Ratakes on the values defined above;

R2and R3taken together or separately;

when taken together, R2and R3represent (a)3-8alcander forming a condensed 5-to 10-membered nonaromatic cycle, optionally containing 1-2 double bonds and optionally containing 1-2 heteroatoms selected from O, S and N; or (b) condensed 6-10-membered aromatic monocyclic or bicyclic group, and these alcander and aromatic monocyclic or bicyclic group is optionally substituted by 1 to 6 halogen atoms and 1-4 groups selected from HE, C1-3-alkyl, OC1-3-alkyl, halogen-C1-3of alkyl, halogen-C1-3-alkoxy and phenyl, and said phenyl is optionally substituted by 1-4 groups independently selected from halogen, C1-3-alkyl, OC1-3-alkyl, and specified With1-3-alkyl and C1-3is an alkyl part of the OS1-3-alkyl are optional for exename 1-3 halogen groups;

when taken separately,

R2selected from the group comprising (a)1-14-alkyl, optionally substituted by 1-6 halogen groups and 1 to 3 substituents selected from HE, OS1-3-alkyl and phenyl, with the specified phenyl is optionally substituted by 1-4 groups independently selected from halogen, och3, OCF3CH3and CF3and specified With1-3is an alkyl part of the OS1-3-alkyl is optionally substituted by 1-3 halogen groups; (b) phenyl or pyridyl, optionally substituted by 1-3 Halogens, HE or Ragroups, where Ratakes the values defined above; (C)2-10alkenyl, optionally substituted by 1-3 substituents, independently selected from halogen, HE and OS1-3-alkyl, and specified With1-3is an alkyl part of the OS1-3-alkyl is optionally substituted by 1-3 halogen groups; (d) CH2CO2N; (e) CH2CO2-C1-6-alkyl; (f) CH2C(O)otherawhere Ratakes the values defined above; (g) NH2, Otheraand N(Ra)2,where Ratakes the values defined above;

and R3selected from the group comprising From1-14-alkyl, C2-10alkenyl, SC1-6-alkyl, C6-10-aryl, heterocyclyl and heteroaryl, and these alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and alkyl is art SC 1-6-alkyl are optionally substituted by (a) R; (b) 1-6 halogen groups, and (C) 1-3 groups selected from HE, NH2, NHC1-4-alkyl, N(C1-4-alkyl)2With1-4-alkyl, OC1-4-alkyl, CN, C1-4-alkyl-S(O)x-where x is equal to 0, 1 or 2, C1-4-alkyl-SO2NH-, H2NSO2-C1-4-alkyl-NHSO2-and (C1-4-alkyl)2NSO2-,with the specified1-4-alkyl and C1-4-alkyl portion of these groups are optionally substituted with phenyl and 1-3 halogen groups, and

R is selected from heterocyclyl, heteroaryl and aryl, with the specified group is optionally substituted by 1-4 groups selected from halogen, C1-4-alkyl, C1-4-alkyl-S(O)x-where x takes the values defined above, With1-4-alkyl-SO2NH-, H2NSO2-C1-4-alkyl-NHSO2-, (C1-4-alkyl)2NSO2-, CN, OH, OC1-4-alkyl, and specified With1-4-alkyl and C1-4-alkyl portion of these groups are optionally substituted by 1-5 halogen, and 1 group selected from HE and OS1-3-alkyl.

DETAILED description of the INVENTION

This invention relates to the compound represented by the formula I:

or its pharmaceutically acceptable salt or MES, where:

A and b can be taken is separately or together;

when taken separately,

Rather it represents a halogen, With1-6-alkyl, OC1-6-alkyl or phenyl, and these alkyl, phenyl and alkyl part OS1-6-alkyl are optionally substituted by 1-3 halogen groups; and

In represents H, halogen, C1-6-alkyl, -OS1-6-alkyl, -SC1-6-alkyl, C2-6alkenyl, phenyl or naphthyl, and these alkyl, alkenyl, phenyl, naphthyl and alkyl parts-OS1-6-alkyl, and-SC1-6-alkyl are optionally substituted by 1-3 groups selected from halogen, HE, CH3Oh, CF3and OCF3; and

when taken together,

A and b together represent a (a)1-4-alkylene, optionally substituted by 1-3 halogen groups and 1-2 Ragroups, where Rarepresents a C1-3-alkyl, OC1-3-alkyl, C6-10-ar-C1-6-alkylene or phenyl, optionally substituted by 1-3 halogen groups, or (b) (C2-5-alcander, so that together with the carbon atom to which are attached, they form a 3-6-membered cycle, and this cycle optionally contains 1 double bond or 1-2 heteroatoms selected from O, S and N, and the specified 3-6-membered cycle is optionally substituted C1-4-alkylene, oxo, Ethylenedioxy or Propylenediamine and optionally additionally substituted by 1-4 groups selected from halogen, the 1-4-alkyl, halogen-C1-4-alkyl, C1-3-acyl, C1-3-acyloxy,1-3-alkoxy, C1-6-alkyl-OC(O)-, C2-4-alkenyl,With2-4-quinil,1-3-alkoxy-C1-3-alkyl, C1-3-alkoxy-C1-3-alkoxy, phenyl, CN, OH, D, NH2, Otheraand N(Ra)2where Ratakes the values defined above;

each R1represents H or is independently selected from the group comprising HE, halogen, C1-10-alkyl, C1-6-alkoxy and C6-10-aryl, and specified With1-10-alkyl, C6-10the aryl and the alkyl part C1-6-alkoxy are optionally substituted by 1-3 Halogens, HE OS1-3-alkyl, phenyl or raftiline groups, and these phenyl and naphthyl are optionally substituted by 1-3 substituents, independently selected from halogen, och3,OCF3CH3, CF3and phenyl, where the specified phenyl is optionally substituted by 1-3 halogen groups,

or two R1groups together form a condensed5-6is an alkyl or aryl cycle, which may be optionally substituted by 1-2 HE or Ragroups, where Ratakes the values defined above;

R2and R3taken together or separately;

when taken together, R2and R3represent (a)3-8-Ala is hiil, forming a condensed 5-to 10-membered nonaromatic cycle, optionally containing 1-2 double bonds and optionally containing 1-2 heteroatoms selected from O, S and N; or (b) condensed 6-10-membered aromatic monocyclic or bicyclic group, and these alcander and aromatic monocyclic or bicyclic group is optionally substituted by 1 to 6 halogen atoms and 1-4 groups selected from HE, C1-3-alkyl, OC1-3-alkyl, halogen-C1-3-alkyl, halogen-C1-3-alkoxy and phenyl, and said phenyl is optionally substituted by 1-4 groups independently selected from halogen, C1-3-alkyl, OC1-3-alkyl, and specified With1-3-alkyl and C1-3is an alkyl part of the OS1-3-alkyl are optionally substituted by 1-3 halogen groups;

when taken separately,

R2selected from the group including: (a)1-14-alkyl, optionally substituted by 1-6 halogen groups and 1 to 3 substituents selected from HE, OS1-3-alkyl and phenyl, with the specified phenyl optionally substituted by 1-4 groups independently selected from halogen, och3, OCF3CH3and CF3and specified With1-3is an alkyl part of the OS1-3-alkyl is optionally substituted by 1-3 halogen groups; (b) phenyl or pyridyl, optionally Zam is placed 1-3 Halogens, HE or Ragroups, where Ratakes the values defined above; (C)2-10alkenyl, optionally substituted by 1-3 substituents, independently selected from halogen, HE and OS1-3-alkyl, and specified With1-3is an alkyl part of the OS1-3-alkyl optionally substituted by 1-3 halogen groups; (d) CH2CO2N; (e) CH2CO2With1-6-alkyl; (f) CH2C(O)otherawhere Ratakes the values defined above; (g) NH2, Otheraand N(Ra)2,where Ratakes the values defined above;

and R3selected from the group comprising From1-14-alkyl, C2-10alkenyl, SC1-6-alkyl, C6-10-aryl, heterocyclyl and heteroaryl, and these alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and the alkyl portion SC1-6-alkyl are optionally substituted by (a) R; (b) 1-6 halogen groups, and (C) 1-3 groups selected from HE, NH2, NHC1-4-alkyl, N(C1-4-alkyl)2With1-4-alkyl, OC1-4-alkyl, CN, C1-4-alkyl-S(O)x-where x is equal to 0, 1 or 2, C1-4-alkyl-SO2NH-, H2NSO2-C1-4-alkyl-NHSO2and (C1-4-alkyl)2NSO2-,with the specified1-4-alkyl and C1-4-alkyl portion of these groups optionally substituted with phenyl and 1-3 halogen groups, and

R is selected from heteros is Lila, heteroaryl and aryl, with the specified group optionally substituted by 1-4 groups selected from halogen, C1-4-alkyl, C1-4-alkyl-S(O)x-where x takes the values defined above, With1-4-alkyl-SO2NH-, H2NSO2-C1-4-alkyl-NHSO2-, (C1-4-alkyl)2NSO2-, CN, OH, OC1-4-alkyl, and specified With1-4-alkyl and C1-4-alkyl portion of these groups optionally substituted by 1-5 halogen groups and 1 group selected from HE and OS1-3-alkyl.

In this specification, the following definitions apply :

The term "Ac" means acetyl, which is a group CH3C(O)-.

The term "alkyl", and the prefix "ALK" in other groups, such as alkoxy and alkanoyl, means carbon chains which may be linear or branched, or combinations thereof, if the carbon chain is not defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec - and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl etc. When the specified number of carbon atoms, for example, With3-C10the term "alkyl" also includes cycloalkyl group and combination of linear or branched alkyl chains with cycloalkene structures. When the number of carbon atoms is not specified, it is understood1-6.

The term "alkenyl" means carbon is ETUI, which contain at least one carbon-carbon double bond and which may be linear or branched, or combinations thereof, if the carbon chain is not defined otherwise. Examples alkenyl include vinyl, allyl, Isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl etc. When the specified number of carbon atoms allows, for example, for C5-C10the term "alkenyl" also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When the number of carbon atoms is not specified, it is understood2-6.

The term "quinil" means carbon chains which contain at least one carbon-carbon triple bond and which may be linear or branched or a combination thereof. Examples of quinil include ethinyl, propargyl, 3-methyl-1-pentenyl, 2-heptenyl etc.

The term "alcander" refers to carbon chains, which are bifunctional, such as-CH2-, -(CH2)2-, -(CH2)3- etc. Alkadiene groups are linear or branched, unless otherwise specified. For comparison, the alkyl groups are mono-functional.

The term "alkylene" in this description refers to the carbon atom or carbon chain, which(th) attached(a) through double with the IDE.

The term "cycloalkyl" refers to the group of alkyl means saturated carbocycle that contains the specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. Cycloalkyl group is usually monocyclic, unless otherwise specified. Cycloalkyl groups are saturated, unless otherwise specified.

The term "aryl" means an aromatic mono - or polycyclic system containing ring carbon atoms. The preferred Allami are aromatic monocyclic or bicyclic 6-10-membered cyclic system. Phenyl and naphthyl are preferred Allami. The most preferred aryl is phenyl.

The terms "heterocycle" and "heterocyclyl" refer to saturated or unsaturated non-aromatic cycles or cyclic systems containing at least one heteroatom selected from O, S and N, and optionally containing a sulfur atom in the oxidized form, SO and SO2. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dition, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrrolin, pyrrolidin, tetrahydropyran, dihydropyran, oxathiolan, ditiolan, 1,3-dioxane, 1,3-dition, Ossetian, thiomorpholine etc.

The term "heteroaryl" means the fragrance is ical or partially aromatic heterocycle, which contains a loop at one heteroatom selected from O, S and N (including SO). Thus, heteroaryl include heteroaryl, condensed with other types of cycles, such as arily, cycloalkyl and heterocycles, which are non-aromatic. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolin, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazole, benzoxazole, benzothiazole, benzothiadiazole, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazoles, isoindolyl, dihydrobenzofuranyl, indolinyl, hemolysins, cinnoline, phthalazine, hintline, naphthyridine, carbazolyl, benzodioxolyl, honokalani, purinol, furutani, isobenzofuranyl, benzimidazolyl, benzofuranyl, benzothiazol (including S-oxide), hinely, indolyl, ethanolic, dibenzofurans, naphthyridin etc. Heterocyclyl and heteroaryl groups include cycles and cyclic system containing from 3 to 15 atoms, forming 1-3 cycle.

The term "halogen" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluoride are usually preferred. Fluorine is most preferred when the halogen substituted alkyl or alkoxygroup (for example, CF3O and CF3CH2O).

The term "farmacevtichnaasociaciya" means a drug, comprising active(s) ingredient(s) and the media, as well as any product which results, directly or indirectly, combination, complexation or aggregation of any two or more ingredients, or the reaction of dissociation or reaction of another type of one or more ingredients. Accordingly, the pharmaceutical compositions of this invention include compositions obtained by mixing the compound or compounds of the present invention and a pharmaceutically acceptable carrier.

The compounds of formula I can contain one or more asymmetric centers and therefore may exist in the form of racemates or racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers. All of these isomeric forms are included within the scope of this invention.

Some compounds described in this invention contain olefinic double connection. In the scope of the present invention included in both E and Z geometric isomers in pure form and in the form of a mixture.

Some compounds described in this invention can exist as tautomers, who have a different point of addition of hydrogen, which is accompanied by displacement of one or more double bonds. For example, a ketone and its enol form are the Xia keto-enol-tautomers. The invention includes both the individual tautomers, and mixtures thereof.

If necessary, the racemic mixture of compounds of formula I can be separated with the separation of individual enantiomers. The separation may be carried out by methods well known in the art, such as a combination of racemic mixtures of compounds of the formula I with enantiomerically pure compound of education diastereomeric mixture, which is then subjected to separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The reaction mix is often the reaction of obtaining salts using enantiomerically pure acids or bases. Diastereomeric derivative then can be turned into essentially pure enantiomers removal of attached chiral residue from diastereomeric connection.

Racemic mixture of compounds of formula I can also be separated directly by chromatographic methods using chiral stationary phases, and these methods are well known in the art.

Alternatively, the enantiomers of the compounds of General formula I can be obtained by stereoselective synthesis using optically pure starting compounds or reagents.

One aspect of the present invention, which OS is the particular interest, refers to the compound of formula I, where a and b are taken together to represent a2-5-alcander, so that together with the carbon atom to which are attached, they form a 3-6-membered cycle, and this cycle optionally contains 1 double bond or 1-2 heteroatoms selected from O, S and N, and the specified 3-6-membered cycle is optionally substituted C1-4-alkylene, oxo, Ethylenedioxy or Propylenediamine and additionally optionally substituted by 1-4 groups selected from halogen, C1-4-alkyl, halogen-C1-4-alkyl, C1-3-acyl, C1-3-acyloxy,1-3-alkoxy, C1-6-alkyl-OC(O)-, C2-4-alkenyl,2-4-quinil,1-3-alkoxy-C1-3-alkyl, C1-3-alkoxy-C1-3-alkoxy, phenyl, CN, OH, D, NH2, Otheraand N(Ra)2where Rarepresents a C1-3-alkyl, OC1-3-alkyl, C6-10-ar-C1-6-alkylene or phenyl, optionally substituted by 1-3 halogen atoms. In this aspect of the invention includes all the other variables that are initially determined according to the formula I.

Another aspect of the present invention, which is of even more interest is the connection described above, where a and b are taken together to represent a2-4-membered landiolol group, so that together with the carbon atom that is attached to the, they form a 3-5 membered cycle, optionally substituted by 1-2 groups selected from halogen, C1-4-alkyl, halogen-C1-4-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-3-alkoxy-C1-3-alkoxy and phenyl. In this aspect includes all the other variables that are initially determined in accordance with formula I.

More precisely, the aspect of the invention that is of interest relates to the compound described above, where a and b are taken together to represent a2-4landiolol group, so that together with the carbon atom to which are attached, they form a 3-5 membered cycle, and this cycle is unsubstituted or substituted by 1-2 halogen groups. In this aspect included all variables that are defined in accordance with formula I.

More precisely, an aspect of the present invention, which is of interest relates to the compound described above, where 1-2 halogen group are fluorine atoms. In this aspect included all variables that are defined in accordance with formula I.

In another aspect of the present invention that is of interest, it is disclosed the compound of formula I, where two groups R1are H and one of R1selected from the group comprising HE, halogen, C1-10-alkyl, C1-6-arcoxia 6-10-aryl, and specified With1-10-alkyl, C6-10the aryl and the alkyl part C1-6-alkoxy are optionally substituted by 1-3 Halogens, HE OS1-3alkyl, phenyl or naftilos groups, and the phenyl and naphthyl are optionally substituted by 1-3 substituents selected from halogen, och3, OCF3CH3, CF3and phenyl, where the specified phenyl optionally substituted by 1-3 halogen groups. In this aspect includes all the other variables that are initially determined according to the formula I.

More precisely, an aspect of the present invention, which is of interest relates to a compound of formula I, where one group R1represents N and the other two groups R1selected from the group comprising HE, halogen, C1-10-alkyl and C1-6-alkoxy, with the specified1-10-alkyl and the alkyl part C1-6-alkoxy are optionally substituted by 1-3 halogen groups. In this aspect includes all the other variables that are initially determined according to the formula I.

More precisely, an aspect of the present invention, which is of interest relates to a compound of formula I, where two groups R1represent halogen or methyl. This aspect includes all the other variables that are initially determined according to the formula I.

In another aspect of the present invention disclosed a compound of formula I, where R2taken separately from R3and selected from the group comprising (a)1-14-alkyl, optionally substituted by 1-6 halogen groups and 1 to 3 substituents selected from HE, OS1-3-alkyl and phenyl, with the specified phenyl is optionally substituted by 1-4 groups independently selected from halogen, och3, OCF3CH3and CF3and specified With1-3-the alkyl part of the OS1-3-alkyl is optionally substituted by 1-3 halogen groups; (b) phenyl or pyridyl, optionally substituted by 1-3 halogen, HE or Ragroups; (C)2-10alkenyl, optionally substituted by 1-3 substituents, independently selected from halogen, HE and OS1-3the alkyl and specified With1-3is an alkyl part of the OS1-3-alkyl is optionally substituted by 1-3 halogen groups; (d) CH2CO2H; (e) CH2CO2C1-6-alkyl; (f) CH2C(O)otheraand (g) NH2, Otheraand N(Ra)2and

Rarepresents a C1-3-alkyl, OC1-3-alkyl, C6-10-aryl-C1-6-alkylene or phenyl, optionally substituted by 1-3 halogen groups. This aspect of the invention includes all the other variables that are initially determined in accordance with formula I.

More precisely, the data aspect of the present invention disclosed a compound of formula I, where R2taken separately from R3and is a1-14-alkyl, optionally substituted by 1-6 halogen groups and 1 to 3 substituents selected from HE, OS1-3-alkyl and phenyl, with the specified phenyl is optionally substituted by 1-4 groups independently selected from halogen, och3, OCF3CH3and CF3and the alkyl part OS1-3-alkyl is optionally substituted by 1-3 halogen groups. This aspect includes all the other variables that are initially determined in accordance with formula I.

More precisely, an aspect of the present invention, which is of particular interest relates to a compound of formula I, where R2taken separately from R3and represents a methyl or cyclopropyl. This aspect includes all the other variables that are initially determined in accordance with formula I.

In another aspect of the present invention, the connection that is of interest, determined in accordance with formula I, where R3taken separately from R2and selected from the group comprising From1-14-alkyl, C2-10alkenyl, SC1-6-alkyl, C6-10-aryl, heterocyclyl and eretail, and the specified alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and the alkyl portion SC1-6-alkyl are optionally substituted by (a) R; (b) 1-6 halogen g is uppada and (C) 1-3 groups selected from HE, NH2, NHC1-4-alkyl, N(C1-4-alkyl)2C1-4-alkyl, OC1-4-alkyl, CN, C1-4-alkyl-S(O)x-where x is equal to 0, 1 or 2, C1-4-alkyl-SO2NH-, H2NSO2-C1-4-alkyl-NHSO2and (C1-4-alkyl)2NSO2-,with the specified1-4-alkyl and C1-4-alkyl portion of these groups are optionally substituted with phenyl and 1-3 halogen groups, and R is selected from heterocyclyl, heteroaryl and aryl, with the specified group is optionally substituted by 1-4 groups selected from halogen, C1-4-alkyl, C1-4-alkyl-S(O)x-where x takes the values defined above, With1-4-alkyl-SO2NH-, H2NSO2-C1-4-alkyl-NHSO2-, (C1-4-alkyl)2NSO2-, CN, OH, OC1-4-alkyl, and specified With1-4-alkyl and C1-4-alkylene part of these groups are optionally substituted by 1-5 halogen atoms and 1 group selected from HE and OS1-3-alkyl. This aspect includes all the other variables that are initially determined according to the formula I.

More precisely, the connection that is of interest, determined in accordance with formula I, where R3taken separately from R2and selected from the group comprising From1-14-alkyl, C6-10-aryl, heterocyclyl and heteroaryl, being the m these groups are optionally substituted by (a) R; (b) 1-6 halogen groups, and (C) 1-3 groups selected from HE, NH2, NHC1-4-alkyl, N(C1-4-alkyl)2With1-4-alkyl, OC1-4-alkyl, CN, C1-4-alkyl-S(O)x-where x is equal to 0, 1 or 2, C1-4-alkyl-SO2NH-, H2NSO2-C1-4-alkyl-NHSO2-, (C1-4-alkyl)2NSO2-and specified With1-4-alkyl and C1-4-alkyl portion of these groups are optionally substituted with phenyl and 1-3 halogen atoms. This aspect of the invention includes all the other variables that are initially determined according to the formula I.

More precisely, the connection that is of interest, determined in accordance with formula I, where R3taken separately and are selected from the group comprising cyclopropyl, optionally substituted stands or phenyl; phenyl, optionally substituted with halogen, HE, co3or OCF3; heteroaryl selected from benzimidazolyl, indolyl, benzofuranyl and dihydrobenzofuranyl, and mentioned heteroaryl groups are optionally substituted by (a) R; (b) 1-6 halogen groups, or (C) 1-3 groups selected from OH, NH2, NHC1-4-alkyl, N(C1-4-alkyl)2With1-4-alkyl, OC1-4-alkyl, CN, C1-4-alkyl-S(O)x-where x is equal to 0, 1 or 2, C1-4-alkyl-SO2NH-, H2NSO2-C1-4-alkyl-NHS 2-, (C1-4-alkyl)2NSO2-and specified With1-4-alkyl and C1-4-alkyl portion of these groups are optionally substituted with phenyl and 1-3 halogen groups, and R is selected from heterocyclyl, heteroaryl and aryl, with the specified group is optionally substituted by 1-4 groups selected from halogen, C1-4-alkyl, HE OS1-4-alkyl, and specified With1-4-alkyl and C1-4-alkyl portion of these groups are optionally substituted by 1-5 halogen groups and 1 group selected from HE and OS1-3-alkyl. This aspect of the invention includes all the other variables that are initially determined according to the formula I.

In another aspect of the present invention, which is of interest described compound of formula I, where R2and R3taken together and are (a)3-8-alcander forming a condensed 5-to 10-membered nonaromatic cycle, optionally containing 1 double bond, and optionally containing 1 heteroatom selected from O, S and N; or (b) condensed 6-10-membered aromatic monocyclic or bicyclic group,

moreover, these alcander and aromatic monocyclic or bicyclic group is optionally substituted with 1-3 halogen atoms and 1-2 groups selected from HE, C1-3-alkyl,OC 1-3-alkyl, halogen-C1-3-alkyl, halogen-C1-3-alkoxy and phenyl, and specified phenyl is optionally substituted with 1-2 groups independently selected from halogen, C1-3-alkyl, OC1-3-alkyl, and specified With1-3-alkyl and C1-3is an alkyl part of the OS1-3-alkyl are optionally substituted by 1-3 halogen groups. This aspect of the invention includes all the other variables that are initially determined in accordance with formula I.

More precisely, an aspect of the present invention, which is of interest relates to a compound of formula I, where R is selected from heterocyclyl, heteroaryl and aryl, with the specified group is optionally substituted by 1-4 halogen groups and 1-2 groups selected from C1-4-alkyl, C1-4-alkyl-S(O)x-where x is equal to 0, 1 or 2, C1-4-alkyl-SO2NH-, H2NSO2-C1-4-alkyl-NHSO2-, (C1-4-alkyl)2NSO2-,CN, OH and OS1-4-alkyl, and specified With1-4-alkyl and C1-4-alkyl portion of these groups are optionally substituted by 1-3 halogen groups and 1 group selected from HE and OS1-3-alkyl. This aspect includes all the other variables that are initially determined in accordance with formula I.

Compounds that are included in the scope of this izopet the tion, include the compounds described in the examples. Illustrative, but not limiting, examples of compounds of this invention are inhibitors of 11β-HSD-1, representing compounds of the following structural formulas

and their pharmaceutically acceptable salt and solvate.

Another aspect of this invention relates to a pharmaceutical composition comprising a compound according to formula I or its salt or hydrate in combination with a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating hyperglycemia, diabetes or insulin resistance in a patient is a mammal in need of such treatment, which includes an introduction to the specified patient an effective amount of a compound according to formula I or its salts or MES.

In another aspect of the present invention disclosed a method of treating non-insulin dependent diabetes mellitus in a patient is a mammal in need of such treatment, which includes an introduction to the specified patient compounds according to formula I in an amount effective for the treatment of diabetes.

In another aspect of the present invention describes a method of treating obesity in a patient is a mammal in need of such treatment, which includes the maintenance of the specified patient compounds according to formula I in a quantity which is effective for the treatment of obesity.

In another aspect of the present invention describes a method of treating syndrome X in a patient is a mammal in need of such treatment, which includes an introduction to the specified patient compounds according to formula I in an amount which is effective for the treatment of syndrome X.

In another aspect of the present invention describes a method of treating a lipid disorder selected from the group including dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high content of LDL, the patient is a mammal in need of such treatment, which includes an introduction to the specified patient compounds according to formula I in an amount effective for the treatment of this lipid disorder.

In another aspect of the present invention describes a method of treating atherosclerosis in a patient is a mammal in need of such treatment, which includes an introduction to the specified patient compounds according to formula I in an amount effective to treat atherosclerosis.

In another aspect of the present invention disclosed a method of treatment of a condition selected from the group comprising (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertro is glyceridae, (9) hypercholesterolemia, (10) low levels of HDL, (11) high levels of LDL, (12) atherosclerosis and its consequences, (13) vascular restenosis, (14) pancreatitis, (15) the deposition of adipose tissue in the area of the peritoneum, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) syndrome X, and other conditions and disorders, a component of which is insulin resistance, the patient is a mammal in need of such treatment, which includes the introduction of patient a compound according to formula I in an amount effective for the treatment of this condition.

In another aspect of the present invention disclosed a method of treatment of a condition selected from the group comprising (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low levels of HDL, (11) high levels of LDL, (12) atherosclerosis and its consequences, (13) vascular restenosis, (14) pancreatitis, (15) the deposition of adipose tissue in the area of the peritoneum, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) syndrome X, and other conditions and disorders, a component of which is insulin resistance, the patient is a mammal in need of such treatment shall, which includes an introduction to the patient an effective amount of a compound according to formula I and a compound selected from the group including:

(a) DP-IV inhibitors;

(b) insulin sensitizers selected from the group including (i) PPAR agonists and (ii) biguanides;

(c) insulin and imitators of insulin;

(d) sulfonylureas and other tools that enhance insulin secretion;

(e) inhibitors α-glucosidase;

(f) antagonists glucagonoma receptor;

(g) GLP-1, replicas of GLP-1 and agonists of the GLP-1 receptor;

(h) GIP, replicas of GIP and GIP agonists of the receptor;

(i) PACAP, replicas of RASER and agonists RACER receptor 3;

(j) means of reducing cholesterol and selected from the group including (i) inhibitors of HMG-CoA reductase, (ii) substances that increase the excretion, (iii) nicotinebuy alcohol, nicotinic acid and their salts, (iv) PPARα agonists, (v) dual PPAR α/γ agonists, (vi) inhibitors of cholesterol absorption, (vii) inhibitors of acyl-COA:cholesterol acyltransferase and (viii) anti-oxidants;

(k) PPAR δ agonists;

(l) compounds for the treatment of obesity;

(m) the inhibitor of the Transporter ileal bile acids;

(n) anti-inflammatory agents other than glucocorticoids;

(a) inhibitors of protein-tyrosine phosphatase-1B (PTP-1B),

moreover, these compounds are introduced to the patient in amounts effective for treatment at asanoha state.

In another aspect of the present invention disclosed a method of treatment of a condition selected from the group including hypercholesterolemia, atherosclerosis, low levels of HDL, high levels of LDL, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a patient is a mammal in need of such treatment, which comprises administration to the patient a therapeutically effective amount of a compound according to formula I and an inhibitor of HMG-CoA reductase.

More precisely, in another aspect of the present invention disclosed a method of treatment of a condition selected from the group including hypercholesterolemia, atherosclerosis, low levels of HDL, high levels of LDL, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a patient is a mammal in need of such treatment, where the inhibitor of HMG-CoA reductase inhibitor is a statin.

More precisely, in another aspect of the invention described is a method of treatment of a condition selected from the group including hypercholesterolemia, atherosclerosis, low levels of HDL, high levels of LDL, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a patient is a mammal in need of such treatment, where the inhibitor of HMG-CoA reductase inhibitor is a statin selected from the group including lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, is devastating, ZD-4522 and mevastatin.

In another aspect of the present invention disclosed a method of treating atherosclerosis in a patient - the person in need of such treatment, where the inhibitor of HMG-CoA reductase inhibitor is a statin, which additionally includes the introduction of an inhibitor of cholesterol absorption.

More precisely, in another aspect of the present invention disclosed a method of treating atherosclerosis in a patient - the person in need of such treatment, where the inhibitor of HMG-CoA reductase inhibitor is a statin and an inhibitor of cholesterol absorption is ezetimib.

In another aspect of the present invention are disclosed pharmaceutical composition, which includes

(1) the compound according to formula I,

(2) a compound selected from the group including

(a) DP-IV inhibitors;

(b) insulin sensitizers selected from the group including (i) PPAR agonists and (ii) biguanides;

(c) insulin and imitators of insulin;

(d) sulfonylureas and other tools that enhance insulin secretion;

(e) inhibitors α-glucosidase;

(f) antagonists glucagonoma receptor;

(g) GLP-1, replicas of GLP-1 and agonists of the GLP-1 receptor;

(h) GIP, replicas of GIP and GIP agonists of the receptor;

(i) PACAP, replicas of RASER and agonists RACER receptor 3;

(j) means of reducing cholesterol and selected from the group including (i) inhibitors of HMG-CoA reductase, (i) substances, enhancing excretion, (iii) nicotinebuy alcohol, nicotinic acid and their salts, (iv) PPARα agonists, (v) dual PPAR α/γ agonists, (vi) inhibitors of cholesterol absorption, (vii) inhibitors of acyl-COA:cholesterol acyltransferase and (viii) anti-oxidants;

(k) PPAR δ agonists;

(l) compounds for the treatment of obesity;

(m) the inhibitor of the Transporter ileal bile acids;

(n) anti-inflammatory agents other than glucocorticoids;

(a) inhibitors of protein-tyrosine phosphatase-1B (PTP-1B);

and

(3) a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum salts, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc and the like, Especially preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Salt in solid form can have multiple crystal structures, and can also exist in the form of hydrates and polyhydrated.

Salts derived from pharmaceutically acceptable organic bases include salts of primary is s, secondary and tertiary amines, substituted amines, including those existing in nature substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamin, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polianinova resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine and the like

When the compound of the present invention is basic, salts may be derived from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, benzosulfimide, benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, isetionate, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate acid and the like, Especially preferred pharmaceutically acceptable acids include citric, Hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. In most cases, the connection on the frame of the invention are basic, because triazole cycle is the key. Derivatives of triazole of the present invention can also be received and processed in the form of not pharmaceutically acceptable salts (for example, trifenatate salts) in the synthesis process them before applying to obtain pharmaceuticals.

It will be understood that reference to compounds of formula I in this invention include pharmaceutically acceptable salts, and pharmaceutically unacceptable salts, when used as precursors to the free compounds or their pharmaceutically acceptable salts or other synthetic manipulations.

The solvate and, in particular, hydrates of compounds of formula I included in the scope of this invention.

Metabolites of the compounds of this invention are therapeutically active and which are defined by formula I, are also included in the scope of this invention. Prodrugs are compounds that are converted to a therapeutically active compound when administered to a patient or after administration to the patient. Compounds which by themselves do not have the structures claimed in the present invention, but which are converted to active compounds defined by formula I, during or after administration to a mammal patient, are prodrugs and compounds of this image is the shadow, as are their active metabolites, which are defined by formula I.

Compounds described in this invention are selective inhibitors of 11β-HSD1 enzyme. Therefore, the present invention relates to the use of an inhibitor of 11β-HSD1 for inhibiting the reductase activity of 11β-gyroklystrons dehydrogenase, which is responsible for conversion of cortisone to cortisol. Excess cortisol is associated with several disorders, including NIDDM, obesity, dyslipidemia, insulin resistance and hypertension. Introduction connections reduces the levels of cortisol and other 11β-hydroxysteroids in target tissues, thus reducing the effects of excess amounts of cortisol and other 11β-hydroxysteroids. Inhibition of 11β-HSD1 may be used for the treatment and control of diseases, held in pathologically high levels of cortisol and other 11β-hydroxysteroids, such as NIDDM, obesity, hypertension and dyslipidemia.

This invention includes the use of 11β-HSD1 inhibitor for the treatment, control, relief, prevention, delay attack or reduce the risk of development of diseases and conditions that are described above and are excessive or uncontrolled amounts of cortisol and/or other corticosteroids, the patient is a mammal,in particular humans, the introduction of an effective amount of the compounds of formula I or its pharmaceutically acceptable salt or MES. Inhibition of 11β-HSD1 enzyme limits the conversion of cortisone, which in the normal state is inert, cortisol, which can cause symptoms or contribute to the symptoms of these diseases and conditions, if present in excessive amounts.

NIDDM and hypertension

The compounds of this invention are selective inhibitors of 11β-HSD1 and not act on 11β-HSD2. While inhibition of 11β-HSD1 is useful to reduce levels of cortisol and treatment of conditions associated with him, inhibition of 11β-HSD2 is associated with serious side effects such as hypertension.

Cortisol is an important and well-known anti-inflammatory hormone that also acts as an antagonist of insulin action in the liver, so that the sensitivity to insulin is reduced, resulting in increased gluconeogenesis and increased levels of glucose in the liver. For patients with already impaired glucose tolerance characterized by a high probability of developing diabetes type 2 in the presence of pathologically high levels of cortisol.

High levels of cortisol in the tissues where mineralocorticoid the command receptor, often leads to hypertension. Inhibition of 11β-HSD1 shifts the ratio of cortisol and cortisone in specific tissues in the direction of cortisone.

The introduction of a therapeutically effective amount of 11β-HSD1 inhibitor is effective for the treatment, control and symptom relief NIDDM, and the regular introduction of a therapeutically effective amount of 11β-HSD1 inhibitor inhibits or prevents the attack NIDDM, especially in humans.

Obesity, metabolic syndrome, dyslipidemia

Excessive levels of cortisol were associated with obesity, possibly due to increased hepatic gluconeogenesis. Morbid obesity is closely associated with intolerance to glucose, hyperinsulinemia, hypertriglyceridemia, and other factors of syndrome X, such as high blood pressure, high concentrations of VLDL and low content of HDL (Montague et al., Diabetes, 2000, 49: 883-888). Thus, the introduction of an effective amount of 11β-HSD1 inhibitor useful for the treatment or control of obesity. Prolonged treatment 11β-HSD1 inhibitor is also useful to delay or prevent early obesity, especially if the patient uses the inhibitor 11β-HSD1 in conjunction with a controlled diet and exercise.

By reducing insulin resistance and maintain glucose plasma level is normal the concentrations of the compounds of this invention can be used for the treatment and prevention of conditions that accompany diabetes type II diabetes and insulin resistance, including metabolic syndrome (syndrome X), obesity, reactive hypoglycemia, and diabetic dyslipidemia.

Atherosclerosis

As described above, the inhibition activity 11β-HSD1 and decrease the amount of cortisol favorable for treatment and control of hypertension. Because hypertension and dyslipidemia contribute to the development of atherosclerosis, the introduction of a therapeutically effective amount of an inhibitor of 11β-HSD1 of the present invention may be particularly useful for the treatment, control, delay the development or prevention of atherosclerosis.

Other applications

When used for treatment of compounds of this invention can be treated to control, prevent diseases, disorders or conditions listed below, or you can slow down their development: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low levels of HDL, (11) high levels of LDL, (12) atherosclerosis and its consequences, (13) vascular restenosis, (14) pancreatitis, (15) for morbid obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nefropatia, (19) neuropathy, (20) sin is rum's and other disorders, component of which is insulin resistance.

The above diseases and conditions can be treated using compounds of the formula I or the compound may be administered to prevent or reduce the risk of development of diseases and conditions described above. Because of competitive inhibition of 11β-HSD2 may have harmful side effects or may actually increase the amount of cortisol in the target tissue where it is desirable to reduce the content of cortisol, selective inhibitors of 11β-HSD1 with a small inhibition of 11β-HSD2 or without such inhibition is desired.

Inhibitors of 11β-HSD1 formula (I usually have the value of the inhibition constants IC50less than about 500 nm, preferably less than about 100 nm. Usually the ratio of the value of the IC5011β-HSD2 to the value of the IC5011β-HSD1 is at least about two or more, preferably about ten or more. Even more preferred are compounds with a ratio IC50for 11β-HDS1 and IC50for 11β-HDS2 equal to about 100 or more. For example, for compounds with IC50that compound is shown the inhibition constant 11β-HSD2 more than about 500 nm, more preferably 1000 nm.

The compounds of formula I can be used in combination with one or more other l the drug means to treat, prevention, suppression or facilitation of the flow of the diseases or conditions for which the applicable compounds of formula I or other drugs. Usually a combination of drugs is more reliable or more efficient than using a single drug or combination is more reliable or more efficient than would be expected on the basis of the summation of the properties of the individual drugs. This(s) other(s) of drug(s) tool(s) may be introduced by the ways and amounts that are usually applied, simultaneously or sequentially with the compound of the formula I. When a compound of formula I is used simultaneously with one or more other drugs, preferred is a complex preparation containing such(s) other(s) of drug(s) tool(a) and the compound of formula I. However, the combination therapy also includes therapeutic treatment in which a compound of formula I and one or more other drugs are entered by different overlapping regimens. This implies that when used in combination with other active ingredients a compound of this invention or other active ingredient or both drugs can be used effectively in lower doses than when each application separately. Accordingly, the pharmaceutical compositions of this invention include compositions which in addition to the compound of the formula I contain one or more other active ingredients.

Examples of other active ingredients that may be administered in combination with the compound of the formula I and can be entered separately or together in the same pharmaceutical compositions, include, but without limitation only by them:

(a) inhibitors dipeptidylpeptidase IV (DP-IV);

(b) insulin sensitizers including (i) PPAR γ agonists, such as glitazone (for example, troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone and the like) and other PPAR ligands, including dual agonists of PPAR α/γsuch as KRP-297, and PPARα agonists such as gemfibrozil, clofibrate, fenofibrate and bezafibrat, and (ii) biguanides, such as Metformin and phenformin;

(c) insulin and imitators of insulin;

(d) sulfonylureas and other tools that enhance insulin secretion, such as tolbutamide and glipizide, meglitinide and similar funds;

(e) inhibitors α-glucosidase (such as acarbose);

(f) antagonists glucagonoma receptor, such as the means described in WO 98/04528, WO 99/01423, WO 00/39088 and WO 00/69810;

(g) GLP-1, replicas of GLP-1 and agonists of the GLP-1 receptor, such as the means described in WO 00/42026 and WO 00/59887;

(h) GIP, replicas GIP, such as tools, described in WO 0/58360, and agonists GIP receptor;

(i) PACAP, replicas of RASER and agonists RACER receptor 3, such as the means described in WO 01/23420;

(j) means of reducing the cholesterol content, such as (i) inhibitors of HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, mevastatin, pitavastatin, rosuvastatin and other statins), (ii) substances that increase the excretion (cholestyramine, colestipol and dialkylaminoalkyl derivatives of cross-linked dextran), (iii) nicotinebuy alcohol, nicotinic acid and their salts, (iv) inhibitors of cholesterol absorption, such as, for example, ezetimibe and beta-sitosterol, (v) inhibitors of acyl-COA:cholesterol acyltransferase such as, for example, avasimibe, (vi) anti-oxidants such as probucol;

(k) PPAR δ agonists, such as tools, described in WO 97/28149;

(l) compounds for the treatment of obesity, such as fenfluramine, dexfenfluramin, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors, SW receptor inverse agonists and antagonists and β3adrenergic receptor agonists;

(m) the inhibitor of the Transporter ileal bile acids;

(n) means intended for use in inflammatory conditions and other than glucocorticoids, such as aspirin, non-steroidal anti-inflammatory drugs, azulfidine and selective inhibitors of qi is lookcheap 2;

(a) inhibitors of protein-tyrosine phosphatase-1B (PTP-1B).

The above combinations include a compound of formula I or its pharmaceutically acceptable salt, hydrate or MES, not only with one or more other active compounds. Examples, not limited to the above list include combinations of compounds of the formula I with two or more active compounds selected from biguanides, sulfonylureas, inhibitors of HMG-CoA reductase inhibitors, PPAR agonists, inhibitors of PTP-1B inhibitors of DP-IV and compounds for the treatment of obesity.

For providing a mammal, especially human, an effective dose of a compound of this invention can use any suitable method of administration. For example, can be used for oral, rectal, local, parenteral, ocular, pulmonary, nasal routes of administration. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. Preferably, the compound of formula is administered orally.

The effective dose of the active ingredient varies depending on the specific applicable connection, the method of administration, the condition to be treated, and the severity of the condition. Such doses can easily be determined by a qualified technician.

In the treatment or prevention of zabolevanii States, described in this invention, which shows the compounds of formula I, satisfactory results are obtained with the introduction of the compounds of this invention at a daily dosage of from about 0.1 to about 100 milligrams per kilogram (mg/kg) of body weight, preferably in the form of a single daily dose or in doses divided about to receive from two to six times a day. Thus, the total daily dose is in the range from about 0.1 mg to about 1000 mg, preferably from about 1 mg to about 50 mg For a typical adult patient weighing 70 kg, the total daily dose will be in the range from about 7 mg to about 350 mg of the dosage can be adjusted for optimal therapeutic result.

Another aspect of this invention relates to a pharmaceutical composition that includes a compound of formula I or its pharmaceutically acceptable salt, hydrate or MES in combination with a pharmaceutically acceptable carrier.

The compositions include compositions suitable for oral, rectal, local, parenteral (including subcutaneous, intramuscular or intravenous), ocular (ophthalmic), percutaneous, pulmonary (nasal or translocally inhalation), or nasal administration, although the most suitable way in I the th case will depend on the nature and severity of the condition, subject to treatment, and active ingredient. They can traditionally be supplied in standard dosage form and may be obtained by any of the means well known in the pharmaceutical field.

The compound of the formula I can be combined with a pharmaceutical carrier according to conventional pharmaceutical methods of making mixtures. The media take a variety of forms. In particular, carriers for liquid compositions for oral administration include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes and other components used in the preparation of liquid suspensions, elixirs and solutions for oral administration. For preparing solid dosage forms for oral administration, for example, powders, hard and soft capsules and tablets, using such media as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricating agents, binders, dezintegriruetsja agents etc. are Solid preparations for oral administration preferred over the liquid preparations for oral administration.

Solid dosage forms for oral administration may also contain a binder, such as tragakant, Arabian gum, corn starch or gelatin; excipients, that is their as calcium phosphate; disintegrity agent such as corn starch, potato starch, alginic acid; a lubricating substance, such as magnesium stearate; and a sweetening substance, such as sucrose, lactose or saccharin. Capsules may also contain a liquid carrier such as fatty oil.

Can be and other substances to act as coatings or to modify the physical form of the standard dose. For example, tablets may be coated with shellac, sugar or both.

Tablets can be covered by standard aqueous or nonaqueous techniques. Usually the percentage of active ingredient, of course, can vary from about 2 percent to about 60 percent (wt./wt.). Thus, the tablets contain the compound of formula I or its salt or hydrate in amount in the range of from about 0.1 mg to about 1.5 g, preferably in the range of from about 1.0 mg to about 500 mg, and most preferably in the range from about 10 mg to about 100 mg

Liquid preparations for oral administration such as syrups or elixirs may contain the active ingredient, sucrose as a sweetening substance, methyl - and propylparaben as preservatives, a dye and flavoring such as cherry or orange flavoring.

Drugs the ATA for parenteral administration, usually in the form of a solution or suspension, usually get water, and they do not include a surfactant, such as hydroxypropylcellulose. Dispersion can be obtained in glycerol, liquid polyethylene glycols and their mixtures in oils. Usually drugs in diluted form also contains a preservative.

Pharmaceutical dosage forms for injection, including aqueous solutions and dispersions and powders to get quick solutions or dispersions for injection are sterile and must be sufficiently liquid to the possibility of introducing them with a syringe; they must be stable under conditions of manufacture and storage and are usually canned. Therefore, the carrier comprises a solvent or dispersion medium containing, for example, water, ethanol, polyhydric alcohol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures and vegetable oil.

BIOLOGICAL TESTING: DETERMINATION of the INHIBITION CONSTANT Ki

In vitro enzymatic activity of the tested compounds evaluated through experience scintillation proximity (Scintillation Proximity Assay - SPA). Briefly, the substrate titiraupenga cortisone, NADPH cofactor and titrated connection incubated with 11β-HSD1 enzyme at 37°to create conditions protein the I transformation of cortisol. After incubation, the drug SPA granules coated with protein A, pre-mixed with anticortisol monoclonal antibody and the nonspecific 11β-HSD inhibitor, added to each cell. The mixture is shaken at 15°and then read using a liquid scintillation counter, suitable for use in 96-well plates. Determine the percentage of inhibition compared with eingeborenen control hole and build graphics IC50. A similar test is carried out using 11β-HSD2, where tretirovanie cortisol and use NAD as substrate and cofactor, respectively. For the start of the experiment 40 μl of substrate (25 nm3N-cortisone + 1.25 mm NADPH in 50 mm HEPES buffer, pH 7.4) is added to the prepared wells of 96-hole tablet. The solid compound was dissolved in DMSO with a concentration of 10 mm with a 50-fold dilution in DMSO. The diluted solution is then titrated up to 4 times 7 times. 1 µl of each titrated connections then double-add to the substrate. To start the reaction, 10 μl of 11β-HSD1 microsomes from SNO of transfectants added to each well at appropriate concentration to achieve approximately 10% conversion of the original substance. For the final calculation of percentage inhibition add a number of holes, which represent the minimum and maximum experience: one series of holes contains Strat without connection or enzyme (background signal), another series of holes contains the substrate and the enzyme without any connection (maximum signal). Tablets for a short period rotate at a low speed in a centrifuge to combine reagents, sealed with tape, gently mixed and incubated at 37°C for 2 hours. After incubation for 45 μl SPA granules, previously suspended with anticortisol monoclonal antibody and the nonspecific 11β-HSD inhibitor, added to each well. The tablets again, sealed and gently shaken for more than 1.5 hours at 15°C. the tablet Data is read using a liquid scintillation counter, such as Topcount. To control for inhibition of binding of antibodies against cortisol with cortisol substrate with 1.25 nm [3]H cortisol added to these single wells. 1 μl of 200 μm compound is added in each of these holes with 10 μl of buffer instead of enzyme. Any calculated inhibition due to the fact that the compound interferes with the binding of cortisol to the antibody on the SPA beads.

BIOLOGICAL TESTING: DETERMINATION of inhibition of IN VIVO

In General terms, the test compound dosage orally administered to a mammal and leave it for some time, usually from 1 to 24 hours. Tretirovanie cor is ison injected and a few minutes later produce blood. From the separated plasma is extracted with steroids and analyzed by HPLC. The relative levels of3N-cortisone and product recovery,3H-cortisol, define for a group that accepts connections and the control group, receiving the dosing medium. From the obtained values, calculate the absolute conversion, as well as the percentage of inhibition.

More precisely, the compounds are prepared for oral administration by dissolving them in the media (5% (vol./about.) hydroxypropyl-beta-cyclodextrin in N2About or equivalent) at the desired concentration to obtain the dose is usually 10 milligrams per kilogram. In the morning on an empty stomach solution injected ICR mice (Charles River) through the probe power at a dose of 0.5 ml per animal with three animals in the experimental group.

After the desired time, usually 1 hour or 4 hours, 0.2 ml of 3 μm3N-cortisone in dPBS administered by injection into the tail vein. The animal is transported into the cell for 2 minutes and then painlessly put to death in the cell with CO2. After the expiry of the mouse is removed and the blood is collected by cardiac puncture. The blood is placed in the tube to separate the serum and incubated at room temperature for at least 30 minutes for proper coagulation. After an incubation period, the blood is separated into serum by centrifugation at 3000 g (4°C) for 10 minutes.

For an is Lisa steroids in the serum of their first extracted with an organic solvent. 0.2 Ml of serum transferred into a clean tube of microcentrifuge. To do this, add 1.0 ml of ethyl acetate, followed by vigorous shaking for 1 minute. A quick spin in the centrifuge leads to the formation of a layer of water of whey proteins and organic supernatant becomes clear. of 0.85 ml of the upper organic phase transferred to a clean tube of microcentrifuge and dried. The dried sample is again suspended in 0,250 ml DMSO with a high concentration of cortisone and cortisol for analysis by HPLC.

0,200 ml of sample injected to the chromatographic column Metachem Inertsil C-18, balanced 30% methanol. The separation of the target steroid is carried out with a small linear gradient to 50% methanol; simultaneous control using UV at 254 nm chilled standard solutions in the newly suspended solution serves as an internal standard. Tritium signal obtained using radiochromatographic detector, which loads the data into the program for analysis. Percent conversion3N-cortisone in3H-cortisol is calculated as the ratio of AUC for cortisol to the combined AUC for cortisol and cortisol.

The following examples illustrate the invention and are not intended to limit its scope.

EXAMPLE 1

The General scheme

table width="90%" border="1" cellpadding="0" cellspacing="0" frams="all"> SubstanceNumberConcentrationMmol.. In DMF714 μl0,14 M in DMF0,1TFFH in DMF200 ál0.5 M in DMF0,1The triethylamine in DMF400 ál0.5 M in DMF0,2Hydrazine in DMF240 ál0.5 M in DMF0,12Simple iminoethyl in DMF600 ál0.25 M in DMF0,15

Described below is the synthesis of one-dimensional single array of pure compounds is performed on the system brand Myriad Core System. All reactors before applying dried in a stream of nitrogen at 120°C for 12 hours. The solvent is dried over sieves for at least 12 hours before use. Reagents and ancillary compound (carboxylic acid and 8-methoxy-2,3,4,5,6,7-hexahydroazepin (simple iminoethyl A)) is dissolved in a suitable solvent immediately before use.

Synthesis

Carboxylic acid shown in the table below as a starting substance, add in the dry reactor Myriad volume of 10 ml with glass porous partition in nitrogen atmosphere (714 ml, 0.1 mmol, 0,14 M in N,N-dimethylformamide (DMF)). Hexaphosphate the EO-N,N,N',N'-tetramethylrhodamine (TFFH) (200 μl, 0.1 mmol, 0.5 M in DMF), followed by triethylamine (400 μl, 0.2 mmol, 0.5 M in DMF) and hydrazine (240 μl, 0.12 mmol, 0.5 M in DMF) is added to the reactor in a nitrogen atmosphere. The reaction mixture was incubated for 1 hour at 25°With mixing gas (1-second pulse every 5 minutes). 8-Methoxy-2,3,4,5,6,7-hexahydroazepin (simple iminoethyl And 600 μl, 0.15 mmol, 0.25 M in DMF) is added to the reactor in a nitrogen atmosphere. The reaction mixture was kept for 12 hours at 120°C with stirring gas (1-second pulse every 5 minutes) and then cooled to room temperature. After cooling, the crude reaction mixture was analyzed LC-MS (method 1). The crude reaction mixture was purified preparative HPLC with mass spectrometric detection (method 2). The purity of the collected fractions analyze LC-MS (method 1); fraction, which, as the analysis shows, have a purity of more than 90%, unite in suspended EPA vials with a volume of 40 ml and lyophilized.

Conditions of HPLC

Analytical LC method 1:
Column:MetaChem Polaris C-18A, 30 mm × 4.6 mm, 5.0 µm.
Eluent A:0,1% triperoxonane acid (TFUC) in the water.
Eluent:0.1% TFUK in acetonitrile.
Gradient:from 5% to 95%for 3.3 minutes and back to 5% b for 0.3 minutes.
Volume flow:2.5 ml/min
The temperature of the column:50°C.
Volume of sample:5 ál of undiluted crude reaction mixture or purified fraction.
Detection:UV at 220 and 254 nm.

MS: API-ES ionization mode, scan area mass (100-600 atomic units of mass)

ELSD: detector light scattering.
Preparative LC method 2:
Column:MetaChem Polaris C-18A, 100 mm × 21,2 mm 10,0 mm.
Eluent A:0.1% TFUK in the water.
Eluent:0.1 TFUK in acetonitrile.
Trim before injection:1.0 minute.
Delay after injection:1.0 minute.
Gradient:from 10% to 100% for 6.0 minutes, hold at 100% for an additional 2.0 minutes, and back from 100% to 10% b for 1.5 minutes.
Volume flow:20 ml/min
The temperature of the column:the room temperature.
Volume of sample:1.5 ml of the undiluted crude reaction mixture.
Detection:MS: API-S mode ionization, scan area mass (100-600 atomic units of mass), collecting fractions begins with the detection of M+1.

The parameters of the lyophilization

Set the initial freezing temperature: 1 hour at -70°

The set temperature of the drying phase capacitor: -50°

Table drying phases
The shelf temperature (°)Duration (min)Installed vacuum (mtorr)
-6024025
-4024025
548025
20100025

The starting material of example 1-1 is

ConnectionStructureNameRetention time (min)MS ESI (m/z)
1-13-[1-(4-chlorophenyl)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin triptorelin1,77329,87

EXAMPLE 2

Method 2A

The General scheme

Obtaining 3-(1,1-diphenyl the filing)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2-1)

2,2-Diphenylbutane acid (to 39.6 mg, 0,166 mmol) dissolved in DMF (0.33 ml). To the solution add hexaphosphate fluoro-N,N,N',N'-tetramethylrhodamine (TFFH, 43,6 mg) and anhydrous triethylamine (46,4 μl) and the solution cooled to 0°C. After 10 minutes, add hydrazine monohydrate (6,5 mm). The resulting reaction mixture was stirred at room temperature for 30 minutes, after which HPLC/MS shows complete conversion of 2,2-diphenylbutyric. Add 8-methoxy-2,3,4,5,6,7-hexahydroazepin (38 ml, 0,249 mmol) and the solution stirred at 120°With during the night. The mixture is heated to room temperature, the product was then purified preparative HPLC and isolated in the form of a salt triperoxonane acid. Salt is added to a saturated solution of sodium bicarbonate and extracted with ethyl acetate to obtain the free base. The extract is dried over magnesium sulfate, filtered and evaporated to obtain the pure triazole (2-1) as a white solid; MS ESI (m/z) 346,3.

Connection 2-2 - 2-23 get essentially in accordance with the same method using an appropriate carboxylic acid (IV). The formation of the product is controlled HPLC/MS.

IV for:Starting material R-COOHIV for:Starting material R-SON
2-22-3
2-42-5
2-62-7
2-82-9
2-102-11
2-122-13
2-142-15
2-162-17
2-182-19
2-202-21
2-22 2-23

ConnectionStructureNameRetention time (min)MS ESI (m/z)
2-23-(1,1-diphenylpropyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,77346,3
2-53-(1-methyl-1-phenylpropyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,24at 284.3
2-63-(8-phenyl-1,4-dioxaspiro[4,5]Dec-8-yl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,22368,2
2-73-[1-(4-cyclohexylphenol)-1-methylethyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin3,16352,3
2-33-[1-(1-naphthyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotinof 2.51332,3
2-83-(1-vinylcyclopropyl)-56,7,8,9,10-hexahydro[1,2,4]triazolo[4,3- a]Asotin1,91268,2
2-92-[1-(2-propenyl)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,15314,2
2-103-(1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotinto 2.29296,3
2-123-(1-methyl-1-phenylethyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin1,97270,3
2-133-(1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,13of 282.3
2-143[1-(4-were)cyclopropyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotinof 2.21282,2
2-113-[1-(3-were)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,53310,2
2-153-[1-(4-chlorophenyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin 2,47316,2
2-163-[1-(4-were)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,53310,2
2-173-[1-(4-forfinal)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,45314,2
2-183-(2-methyl-1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,27296,2
2-193-(1-phenyl-2-vinylcyclopropyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,25294,2
2-203-[1-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)cyclopentyl]phenol1,91312,2
2-213-[1-(4-chlorophenyl)-1-methylethyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,09304,2
2-223-[1-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)-1-methylethyl]phenol1,63 of 286.2
2-233-[1-(4-chlorophenyl)cyclopropyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,25302,2
2-43-[1-(2,4-dichlorophenyl)cyclopropyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,32336,2

Method 2B

The General scheme

Obtain 3-[1-(2-forfinal)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2-24)

Stage 1

Potassium hydroxide (1.78 g) was dissolved in dimethyl sulfoxide (5.8 ml) [1]. (2-Forfinal)acetonitrile (0.97 g, 7.2 mmol) and 1,3-dibromopropane (0.95 ml, 9.3 mmol) dissolved in ethyl ether (2 ml)and the resulting mixture is added dropwise with vigorous stirring to a solution of potassium hydroxide at room temperature. The mixture is stirred at room temperature for one hour, then the reaction quenched by addition of water (3.8 ml), cooled by ice. The mixture is filtered through a loose layer of celite, which is washed with ether (20 ml). The filtrate is transferred into a separating funnel and the aqueous layer was extracted with ether (3×10 ml). The organic layers are combined, dried over magnesium sulfate, filtered and evaporated to a light yellow is about oil (1.0 g). Pure 1-(2-forfinal)cyclobutanecarbonitrile (0.45 g) obtained after chromatography on silica gel.

Stage 2

1-(2-Forfinal)cyclobutanecarbonitrile (0.21 g, 1.15 mmol) and potassium hydroxide (0,194 g) dissolved in ethylene glycol (2 ml). The resulting mixture is refluxed for 3 hours at 198°C, then poured into water (5 ml) and extracted with ether (2×5 ml). The aqueous solution is acidified with HCl and extracted with ether (3×5 ml). The extracts are combined, dried over magnesium sulfate, filtered and evaporated to obtain the crude carboxylic acid.

Stage 3

1-(2-forfinal)cyclobutanecarbonyl acid (51.3 mg, 0,264 mmol) dissolved in DMF (0,52 ml). To the resulting solution at room temperature add hexaphosphate fluoro-N,N,N',N'-tetramethylrhodamine (TFFH, 74,6 mg, 0,282 mmol) and anhydrous triethylamine (71,0 μl, 0,509 mmol). After 5 minutes add anhydrous hydrazine (10 μl, 0,319 mmol). The mixture is stirred at room temperature for 30 minutes, after which HPLC-MS indicates the formation of 1-(2-forfinal)cyclobutanecarbonitrile with a good yield.

8-Methoxy-2,3,4,5,6,7-hexahydroazepin (47 μl, 0,412 mmol) are added to a solution of 1-(2-forfinal)cyclobutanecarbonitrile and the reaction mixture stirred at 120°With during the night. The solution Oh adut, concentrated and the product purified preparative HPLC to obtain it in the form of a salt triperoxonane acid. Salt is added to saturated sodium hydrogen carbonate solution and extracted with ethyl acetate to obtain the free base. The extract is dried over magnesium sulfate, filtered and evaporated to obtain the pure triazole (2-24) in the form of solids.

Connection 2-25 - 2-32 get, essentially, in accordance with the same method using the appropriate phenylacetonitrile. The formation of the product is controlled by HPLC/MS.

IV for:The original substanceIV for:The original substance
2-242-25
2-262-26
2-282-29
2-302-31
2-32

ConnectionStructureNameRetention time (min)MS ESI (m/z)
2-243-[1-(2-forfinal)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,10to 300.2
2-253-[1-(3-forfinal)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,24to 300.2
2-263-[1-(2-were)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,32296,2
2-272-[1-(4-forfinal)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotinof 2.26to 300.2
2-283-[1-(4-were)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,44296,2
2-293-[1-(3-were)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]and is ozin 2,45296,2
2-303-{1-[4-(trifluoromethyl)phenyl]cyclobutyl}-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,62350,3
2-313-{1-[2-(trifluoromethyl)phenyl]cyclobutyl}-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotinto 2.29350,3
2-323-[1-(4-bromophenyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,50360,2

Method 2C

The General scheme

Obtain 3-[1-(3,4-differenl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2-33)

Stage 1

(3,4-Differenl)acetonitrile converted into 1-(3,4-differenl)cyclobutanecarbonitrile in accordance with the method described in method 2B, stage 1.

Stage 2

1-(3,4-Differenl)cyclobutanecarbonitrile (384,5 mg, 1,99 mmol) dissolved in toluene (30 ml) and cooled to -78°C. To the resulting solution was added dropwise hydride diisobutylaluminum (DIBAL-H (1.0 M solution in hexano) (3.98 ml, 3,98 mmol). The mixture was stirred at -78°in those which begins 30 minutes, then add 5% sulfuric acid (2 ml). The reaction mixture is heated to room temperature, stirred for 20 minutes and filtered through a loose layer of celite. Celite is washed with ethyl acetate, the entire filtrate is transferred into a separating funnel and washed with water. The organic layer is dried over sodium sulfate and evaporated to obtain the desired aldehyde.

1-(3,4-Differenl)cyclobutanecarbonitrile (240,0 mg, 1,22 mmol) dissolved in a mixture of tert-butanol/tetrahydrofuran/2-methylbut-2-ene (3.0 ml/1.0 ml/1.0 ml) and vigorously stirred at room temperature. The sodium chlorite (243,4 mg, 2,69 mmol) and sodium dihydrophosphate (370,4 mg, 2.68 mmol) dissolved in water (1.2 ml) and added dropwise to the previous solution. The mixture is stirred for one hour, after which time TLC shows that the reaction is complete. Volatile solvents are removed in vacuo and the product diluted with water and washed with hexane (3 ml). The aqueous solution acidified with 6 N aqueous hydrochloric acid to pH 2. The solution is extracted with ethyl acetate (3×20 ml), the combined organic layers are washed with salt solution (5 ml), dried over magnesium sulfate, filtered and evaporated to obtain the desired carboxylic acid (125 mg).

Stage 3

1-(3,4-Differenl)cyclobutanecarbonyl acid is subjected to transformation of 3-[1-(3,4-differenl)cyclobutyl]-5,67,8,9,10-hexahydro[1,2,4]triazolo[4,3- a]Asotin (2-33) in accordance with the method described in method 2, step 3; MS ESI (m/z) 318,2.

Connections 2-34 - 2-38 get essentially in accordance with the same method, using the appropriate disubstituted phenylacetonitrile. The formation of the product is controlled HPLC/MS.

IV for:The original substanceIV for:The original substance
2-332-34
2-352-36
2-372-38

ConnectionStructureNameRetention time (min)MS ESI (m/z)
2-343-[1-(2,4-differenl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,16318,2
2-35/img> 2-[1-(2,4-dichlorophenyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotinof 2.51350,1
2-363-[1-(3,4-dichlorophenyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,65350,1
2-373-[1-(2-chloro-4-forfinal)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotinto 2.29334,2
2-383-{1-[2-chloro-6-(trifluoromethyl)phenyl]cyclobutyl}-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,56384,2

Method 2D

The General scheme

Obtaining 3-(1-(4-chlorophenyl)cyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2-39)

Methyl 1-(4-chlorophenyl)cyclohexanecarboxylate (277 mg) and hydrazinehydrate (0,30 ml) dissolved in ethylene glycol (5 ml), heated to 150°C and maintained at this temperature for 15 hours. The solution is cooled and water is added (5 ml). The formed precipitate is filtered off and dried in vacuum, obtaining acylhydrazides (108 ml) as a white solid.

Anhydrous toluene is added to a mixture of 1-(-chlorophenyl)cyclohexanecarbonitrile (62 mg) and 8-methoxy-2,3,4,5,6,7-hexahydroazepin (40,1 mg). The reactor is heated to 120°C and maintained at this temperature overnight, then cooled to room temperature and the solvent is evaporated. The crude product is purified column chromatography, obtaining 3-(1-(4-chlorophenyl)cyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin (2-39) in the form of a white solid.

Method preparative LC for example 2:
Column:YMC-PACK ODS, 100 mm × 20 mm, 5.0 µm.
Eluent A:0.05% TFUK in the water.
Eluent:0.05% TFUK in acetonitrile.
Trim before injection:1.0 minute.
Delay after injection:1.0 minute.
Gradient:from 10% to 100% in the interval from 1 to 16 minutes back up to 50%; in the range from 16 to 21 minutes again to 100% and a delay of 100% B for 2 minutes; and from 100% to 10% within 1 minute.
Volume flow:20 ml/min
The temperature of the column:the room temperature.
Volume of sample:5,0 ml
Detector:Photodiode matrix.
Analytical LC method for example 2:
Column:Waters XTerra C-18, 5 μm, 4.6 mm x 50 mm
Eluent A:0,60% TFUK in the water.
Eluent:0,50% TFUK in acetonitrile.
Gradient:from 10% to 90% B over 4.5 min, delay for 0.5 minutes, and back to 10% B for 0.5 minutes.
The temperature of the column:30°C.
Volume of sample:10 ál of undiluted crude reaction mixture.
Detection:DAD: 190 - 600 nm.
MS: API-ES positive mode ionization,
Variable scan interval weight:
LC1-Xlo=50-500 atomic mass
LC1-Low=150-750 atomic mass
L1-Med=300-1000 atomic mass
LC1-High=500-2, 000 atomic mass

Example 3

Method 3A

Obtaining 1-(4-chlorophenyl)cyclobutanecarbonitrile

1-(4-Chlorophenyl)cyclobutanecarbonyl acid (10.0 g) dissolved in dichloromethane (150 ml) and cooled to -10°in a bath with a mixture of ice/salt solution. To the resulting solution was added pyridine (3,84 ml) and then lanehead (8,9 ml in 25 ml dichloromethane). The mixture is stirred at room temperature for one hour, after which TLC is providing, that the reaction is complete. The solution is transferred into a separating funnel containing ice (150 ml). After vigorous shaking, the organic layer removed, dried over magnesium sulfate, filtered and evaporated to obtain carbonitride.

Anhydrous hydrazine (2,02 ml) dissolved in acetonitrile (100 ml) and cooled to 0°C. Add triethylamine (12,8 ml) and then 1-(4-chlorophenyl)cyclobutanecarbonitrile (10 g) in acetonitrile (25 ml). The solution was stirred at room temperature for one hour, after which the acetonitrile is removed by evaporation. The product is obtained after chromatography on silica gel.

Method 3B

Obtaining 1-(4-chlorophenyl)cyclopropanecarbonitrile

1-(4-Chlorophenyl)cyclopropanecarboxylate receive in accordance with the methods 3A, using 1-(4-chlorophenyl)cyclopropanecarbonyl acid.

Method 3C

Obtaining 1-(4-forfinal)cyclobutanecarbonitrile

Stage 1

Potassium hydroxide (8.2 g, 146,1 mmol) dissolved in dimethyl sulfoxide (100 ml) [1]. (4-Forfinal)acetonitrile (6,87 g, 50.8 mmol) and 1,3-dibromopropane (of 56.4 mmol) dissolved in ethyl ether (10 ml) and the resulting mixture with vigorous stirring, added dropwise to a solution of potassium hydroxide at room temperature. The mixture is displaced is more within two hours, then the reaction quenched by adding water (100 ml), cooled by ice. The mixture is filtered through a loose layer of celite, which is washed with ether (10 ml). The filtrate is transferred into a separating funnel and the aqueous layer was extracted with ether (3×100 ml). The organic layers are combined, dried over magnesium sulfate, filtered and evaporated, receiving the product (cent to 8.85 g) as a pale yellow oil.

Stage 2

The crude 1-(4-forfinal)cyclobutanecarbonitrile (cent to 8.85 g, and 50.5 mmol) dissolved in anhydrous toluene (100 ml) and cooled to -78°C. To the resulting solution was added dropwise hydride diisobutylaluminum (DIBAL-H (1.0 M solution in hexano, to 60.6 ml). Reaction control TLC (hexane: ethyl acetate 9:1). The mixture was stirred at -78°C for one hour, then add 5% sulfuric acid (20 ml). The reaction mixture is heated to room temperature, stirred for 20 minutes and filtered through a loose layer of celite. Celite is washed with ethyl acetate, the entire filtrate is transferred into a separating funnel and washed with water. The organic layer is dried over sodium sulfate, filtered and evaporated to dryness, obtaining the target aldehyde.

1-(4-Differenl)cyclobutanecarbonitrile (8.8 g, 49.4 mmol) dissolved in tert-butanol (90 ml), tetrahydrofuran (30 ml) and 2-methylbut-2-ene (30 ml) and vigorously stirred at room temperature. The sodium chlorite (9,8 g, to 108.7 mmol) and digidrive is at sodium (15.0 g, to 108.7 mmol) dissolved in water (54 ml) and added dropwise to the previous solution. The mixture is stirred for one hour, after which time TLC shows that the reaction is complete. Volatile solvents are removed in vacuo, the product is diluted with water and then washed with hexane (3 ml). The aqueous solution acidified with 6 N aqueous hydrochloric acid to pH 2. The solution is extracted with ethyl acetate (3×150 ml), the combined organic layers are washed with salt solution (20 ml), dried over magnesium sulfate, filtered and evaporated, obtaining 1-(4-forfinal)cyclobutanecarbonyl acid (8.0 g).

The obtained carboxylic acid is subjected to transformation of 1-(4-forfinal)cyclobutanecarboxylic in accordance with the method described in method 3A.

Method 3D

Obtaining 1-(4-forfinal)cyclopropanecarbonitrile

1-(4-Forfinal)acetonitrile (3.77 g of 27.9 mmol), 1-bromo-2-chlorate (5.0 g, is 34.9 mmol) and chloride of benzyltriethylammonium (TEVAS, uniforms, 127.6 mg, 0,56 mmol) is added to the flask and vigorously stirred [2]. To the resulting solution was added dropwise potassium hydroxide (50% in water, 195 mmol). The mixture was stirred at 40°C for 5 hours and overnight at room temperature, the reaction mixture is diluted with water and extracted with dichloromethane. The organic layer is separated, washed with 1 N aqueous hydrochloric KIS is Auteuil, with water and dried over magnesium sulfate. The resulting solution is filtered and the dichloromethane is evaporated, obtaining the crude product (4.5 g).

1-(4-Forfinal)cyclopropanecarbonyl acid is obtained from crude 1-(4-forfinal)cyclopropanecarbonitrile in accordance with the method described in method 3, step 2. The obtained carboxylic acid is subjected to transformation of 1-(4-forfinal)cyclopropanecarboxylate in accordance with method 3A.

Methodology 3E

The General scheme

Obtaining 3,4-dicyclopropyl-5-(1-phenylcyclohexyl)-4H-1,2,4-triazole (3-1)

Methyltrichlorosilane (89,1 μl) are added to N-cyclopropanecarboxamide (to 98.6 mg, 0,788 mmol). The resulting mixture was stirred for 30 minutes at 60°C, after which the NMR clearly shows the transformation into methyl N-cyclopropanecarboxamide.

Toluene (2 ml), triethylamine (223 μl) and 1-phenylcyclohexanecarboxylic (90 mg) is added to methyl N-cyclopropanecarboxamide and stirred at 60°C for 3 hours, then at 110°C for 1 hour. The mixture is cooled and evaporated, the residue is purified preparative HPLC, receiving the product as a salt triperoxonane acid. Salt is added to saturated sodium hydrogen carbonate solution and extracted with ethyl acetate, receiving its the same basis. The organic extract is dried over magnesium sulfate, filtered and evaporated to obtain 3,4-dicyclopropyl-5-(1-phenylcyclohexyl)-4H-1,2,4-triazole (3-1); MS ESI (m/z) 280,2.

Another connection example 3 receive essentially in accordance with the same method, using the appropriate carboxamide and acylhydrazides. As a solvent upon receipt 3-2 using acetonitrile. Connection 3-19 produce as a by-product in the synthesis of 3-18. Methylamide receive from their respective methyl esters and methylamine using well known techniques. Other amides standard obtained from commercially available carboxylic acids and amines using 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as a reagent and methods described in the literature. Getting acylhydrazides described in methods 3A, 3B, 3C and 3D.

IV for:Source carboxamidAcylhydrazidesIV for:Source carboxamidAcylhydrazides
XnXn
3-1 H13-2Cl1
3-3Cl13-4Cl1
3-5Cl13-6Cl1
3-7F13-8F1
3-9F03-10F0
3-11Cl03-12Cl0
3-13F03-14Cl1
3-15Cl 13-16Cl1
3-17Cl13-18Cl1
3-20Cl13-21Cl1
3-22Cl13-24Cl1
3-25Cl13-26Cl1
3-27Cl03-30F1
3-31Cl13-32Cl1
3-33 Cl13-34Cl1
3-35Cl13-36Cl1
3-37Cl13-38Cl1
3-39Cl13-40Cl1

ConnectionStructureNameRetention time (min)MS ESI (m/z)
3-13,4-dicyclopropyl-5-(1-phenylcyclohexyl)-4H-1,2,4-triazole2,17280,2
3-23-[1-(4-chlorophenyl)cyclobutyl]-4,5-dicyclopropyl-4H-1,2,4-triazole2,52314,2
3-33-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-5-Fe is Il-4H-1,2,4-triazole 2,75324,2
3-43-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-5-[4-(triptoreline)phenyl]-4H-1,2,4-triazole3,33408,1
3-53-[1-(4-chlorophenyl)cyclobutyl]-4-cyclopropyl-5-(1-methylcyclopropyl)-4H-1,2,4-triazole2,59328,3
3-63-[1-(4-chlorophenyl)cyclobutyl]-4-(2,2,2-triptorelin)-5-[4-(triptoreline)phenyl]-4H-1,2,4-triazole3,85476,0
3-74-cyclopropyl-3-[1-(4-forfinal)cyclobutyl]-5-(1-methylcyclopropyl)-4H-1,2,4-triazole2,34312,3
3-83-[1-(4-forfinal)cyclobutyl]-4-methyl-5-[4-(triptoreline)phenyl]-4H-1,2,4-triazole3.04 from392,1
3-93,4-dicyclopropyl-5-[1-(4-forfinal)cyclopropyl]-4H-1,2,4-triazole2,07284,2
3-104-cyclopropyl-3-[1-(4-forfinal)cyclopropyl]-5-(1-methylcyclopropyl)-4H-1,2,4-triazole 2,28298,2
3-113-[1-(4-chlorophenyl)cyclopropyl]-4-cyclopropyl-5-(1-methylcyclopropyl)-4H-1,2,4-triazole2,47314,1
3-123-[1-(4-chlorophenyl)cyclopropyl]-4-methyl-5-[4-(triptoreline)phenyl]-4H-1,2,4-triazole3,16394,1
3-133-[1-(4-forfinal)cyclopropyl]-4-methyl-5-[4-(triptoreline)phenyl]-4H-1,2,4-triazole2,49378,1
3-144-{5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole-3-yl}phenol2,41340,1
3-152-{5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole-3-yl}phenol2,48340,1
3-163-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-5-(2-naphthyl)-4H-1,2,4-triazole3,12374,1
3-173-(2-chlorophenyl)-5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole2,94358,0
3-18 6-{5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole-3-yl}-1H-benzimidazole2,01364,1
3-196-{5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole-3-yl}-1-methyl-1H-benzimidazole2,37378,1
3-203-[1-(4-chlorophenyl)cyclobutyl]-5-(2,3-dihydro-1-benzofuran-5-yl)-4-methyl-4H-1,2,4-triazole2,55366,1
3-213-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-5-[2-(triptoreline)phenyl]-4H-1,2,4-triazole3,11408,1
3-223-[1-(4-chlorophenyl)cyclobutyl]-5-(2-forfinal)-4-methyl-4H-1,2,4-triazole2,66342,1
3-243-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-5-(2-were)-4H-1,2,4-triazole2,84338,1
3-253-[1-(4-chlorophenyl)cyclobutyl]-5-(2-methoxyphenyl)-4-methyl-4H-1,2,4-triazole2,70354,1
3-265-{5-[1-(4-chlorophenyl)the CEC shall Outil]-4-methyl-4H-1,2,4-triazole-3-yl}-1,2,3-benzothiadiazole 2,82382,1
3-273-[1-(4-chlorophenyl)cyclopropyl]-4,5-dicyclopropyl-4H-1,2,4-triazole2,33300,1
3-303,4-dicyclopropyl-5-[1-(4-forfinal)cyclobutyl]-4H-1,2,4-triazole2,17298,2
3-313-[1-(4-chlorophenyl)cyclobutyl]-5-(3-fluoro-4-methoxyphenyl)-4-methyl-4H-1,2,4-triazole2,80372,1
3-324-{5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole-3-yl}-2-terfenolof 2.51358,1
3-333-[1-(4-chlorophenyl)cyclobutyl]-4-cyclopropyl-5-phenyl-4H-1,2,4-triazole2,92350,2
3-343-[4-(benzyloxy)phenyl]-5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole3,32430,1
3-353-(1,1'-biphenyl-4-yl)-5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole3,30400,1
3-36 3-(3-chlorophenyl)-5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole3,09358,1
3-373-(4-chlorophenyl)-5-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-4H-1,2,4-triazole3.04 from358,1
3-383-[1-(4-chlorophenyl)cyclobutyl]-5-(3-forfinal)-4-methyl-4H-1,2,4-triazole2,78342,1
3-393-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-5-[4-(trifluoromethyl)phenyl-4H-1,2,4-triazole3,30392,1
3-403-[1-(4-chlorophenyl)cyclobutyl]-5-(2,4-dichlorophenyl)-4-methyl-4H-1,2,4-triazole3,40392,1

Method preparative HPLC to example 3:

Use the procedure described in example 2.

Method analytical LC for example 3:

Using methods identical to those described in example 2.

Example 4

Method 4A

Obtain 3-[1-(4-chlorophenyl)-(Z)-3-(methoxyethoxy)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (4-1) and 3-[1-(4-chlorophenyl)-(E)-3-(methoxyethoxy)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (4-2)

Potassium hydroxide (to 2.57 g) dissolved in dimethyl sulfoxide (8.0 ml). (4-Chlorophenyl)acetonitrile (1,58 g, 10.4 mmol) and 1,3 dichloro-2-(methoxyethoxy)propane (1,993 g) dissolved in diethyl ether (3 ml) and the resulting mixture is added dropwise to a solution of potassium hydroxide with vigorous stirring at room temperature. The mixture is stirred at room temperature for one hour, then the reaction quenched by addition of water (5.5 ml), cooled by ice. The mixture is filtered through a loose layer of celite, which is washed with ether (30 ml). The filtrate is transferred into a separating funnel and the aqueous layer was extracted with ether (3×15 ml). The organic layers are combined, dried over magnesium sulfate, filtered and evaporated. The product was then purified by chromatography on silica gel, obtaining 1-(4-chlorophenyl)-3-(methoxyethoxy)cyclobutanecarbonitrile (1.28 g) as a mixture of isomers (˜2:1).

Nitrile (1.28 g) and potassium hydroxide (2.2 g) is dissolved in ethylene glycol (13 ml). The mixture was incubated for six hours at 198°C, then cooled to room temperature, poured into water (15 ml) and washed with ether (2×20 ml). The aqueous solution is carefully acidified with aqueous hydrochloric acid and extracted with ether (2×20 ml). The organic layers are combined, dried over magnesium sulfate, filtered and evaporated, receiving the product as a brown oil (0,9068 g).

1-(4-Chlorophenyl)3-(methoxyethoxy)cyclobutanecarbonyl acid (0,9068 g) and pyridine (0,40 ml) dissolved in dichloromethane (12 ml) and cooled to -10° C. Lanehead (1.0 ml) dissolved in dichloromethane (2 ml) and added dropwise to the reaction mixture. After 30 minutes, the reaction mixture was transferred into a separating funnel containing ice (10 ml). After vigorous shaking dichloromethane layer is removed, dried over magnesium sulfate, filtered and evaporated.

The crude floramite dissolved in acetonitrile (3 ml) and added under stirring to a solution of anhydrous hydrazine (140 μl), triethylamine (1.0 ml) and acetonitrile (15 ml) at 0°C. After 10 minutes, the reaction is complete by HPLC/MS and dried in vacuum.

Part of the crude 1-(4-chlorophenyl)-3-(methoxyethoxy)cyclobutanecarbonitrile (456,1 mg) was dissolved in anhydrous toluene (7 ml) and mixed with 8-methoxy-2,3,4,5,6,7-hexahydroazepin (228 μl). The solution is heated to 120°C and maintained at this temperature for 3 hours, then slowly cooled to room temperature. The product is partially purified by chromatography on silica gel (100% ethyl acetate → 5% methanol in ethyl acetate → 10% methanol in ethyl acetate)to give a mixture of 4-1 and 4-2 in the ratio of 62:38, respectively. Isomers shared by preparative HPLC and isolated in the form of their salts triperoxonane acid. Each salt separately added to saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The purified free base of 3-[1-(4-chlorophenyl)-CIS-3-methoxyethoxy)cyclobutyl] -r-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin (4-1) and 3-[1-(4-chlorophenyl)-TRANS-3-(methoxyethoxy)cyclobutyl]-r-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin (4-2), dried over magnesium sulfate, filtered and concentrated. Isomers, 4-1 and 4-2, more effectively shared by chiral preparative HPLC (ChiralPak OD (Daicel Chemical Industries), column 2 cm × 25 cm, 20% isopropanol/heptane, 6 ml/min); MS ESI (m/z) 376,2.

Method 4B

Obtaining 3-(4-chlorophenyl)-CIS-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)CYCLOBUTANE-r-ol (4-3)

3-[1-(4-Chlorophenyl)-CIS-3-(methoxyethoxy)cyclobutyl]-r-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin (4-1) (53 mg) was dissolved in dichloromethane (1 ml) and stirred at room temperature. To the resulting solution was added triperoxonane acid (0.2 ml) and the solution stirred overnight at room temperature. Volatile solvents are removed in vacuo, and the residue purified by chromatography on silica gel, receiving 3-(4-chlorophenyl)-CIS-3-(5,6,7,8,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)CYCLOBUTANE-r-ol (4-3) in the form of a white solid.

3-(4-Chlorophenyl)-TRANS-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)CYCLOBUTANE-r-ol (4-4) receive essentially in accordance with the same method, using epimerase the original substance (4-2).

IV for:The original substanceIV for:The original substance
4-34-4

ConnectionStructureNameRetention time (min)MS ESI (m/z)
4-33-(4-chlorophenyl)-CIS-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)CYCLOBUTANE-r-ol1,95332,2
4-43-(4-chlorophenyl)-TRANS-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)CYCLOBUTANE-r-ol1,97332,2

Methodology 4S

Obtaining 3-(4-chlorophenyl)-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)cyclobutanone (4-5)

The mixture of alcohols (4-3 and 4-4) (114,1 mg) dissolved in dichloromethane (5 ml) and cooled to 0°C. To the resulting solution add perruthenate of tetrapropylammonium (TRAR, 12,1 mg) and 4-methylmorpholine N-oxide (60,4 mg) and the reaction mixture was stirred at room temperature for the of three hours. Then the crude reaction mixture was loaded directly on a column of silica gel and purified (100% dichloromethane → 5% methanol in methylene chloride; → 10% methanol in dichloromethane)to give 3-(4-chlorophenyl)-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)cyclobutanone (4-5); MS ESI (m/z) 330,1.

Methodology 4D

Obtain 3-[1-(4-chlorophenyl)-3-methylenecyclobutane]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (4-6)

3-(4-Chlorophenyl)-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)cyclobutanone (4-5) (52 mg) was dissolved in freshly tetrahydrofuran (2 ml). To the resulting solution was added bromide methyltriphenylphosphonium (281 mg) and then bis(trimethylsilyl)amide and potassium (KHMDS, 0.5 M in toluene, 1.25 ml). The reaction mixture is stirred for 24 hours at room temperature, after which the crude product is added to saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is collected, dried over magnesium sulfate, filtered and concentrated. The product was then purified column chromatography on silica gel, receiving 3-[1-(4-chlorophenyl)-3-methylenecyclobutane]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin (4-6); MS ES (m/z) 328,2.

Methodology 4E

Obtain 3-[1-(4-chlorophenyl)-3,3-diverticulitis]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (4-7)

3-(4-Chlorophenyl)-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)cyclobutanone (4-5) (11.4 mg) dissolved in dichloromethane (1 ml). To the resulting solution was added TRIFLUORIDE (diethylamino)sulfur (DAST, 73 μl) and the solution stirred at room temperature for 24 hours. The solution was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (100% dichloromethane → 1% methanol in methylene chloride; → 5% methanol in dichloromethane)to give 3-[1-(4-chlorophenyl)-3,3-diverticulitis]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin (4-7); MS ESI (m/z): 352,1.

Methodology 4F

Obtain 3-[1-(4-chlorophenyl)-TRANS-3-forceclosure]-r-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (4-8)

3-(4-Chlorophenyl)-CIS-3-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin-3-yl)CYCLOBUTANE-r-ol (4-3) (21,3 mg) was dissolved in anhydrous dichloromethane (1.5 ml) and cooled to 0°C. To the resulting solution was added TRIFLUORIDE (diethylamino)sulfur (DAST, 80 μl). The solution is heated to room temperature and stirred over night. The product was poured into saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, introit and concentrate. The residue is purified by chromatography on silica gel (100% dichloromethane → 1% methanol in methylene chloride; → 5% methanol in dichloromethane)to give 3-[1-(4-chlorophenyl)-TRANS-3-forceclosure]-r-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin (4-8).

3-[1-(4-Chlorophenyl)-TRANS-3-forceclosure]-r-(5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin (4-9) receive essentially in accordance with the same method, using epimerase the original substance (4-4).

IV for:The original substanceIV for:The original substance
4-84-9

334,1
ConnectionStructureNameRetention time (min)MS ESI (m/z)
4-83-[1-(4-chlorophenyl)-TRANS-3-forceclosure]-r-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,47334,1
4-93-[1-(4-chlorophenyl)-CIS-3-forceclosure]-r-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin2,39

Methodology 4G

Obtaining 3-(3-methyl-1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (4-10)

2-Phenylacetamides (1.01 g) are added to a solution of anhydrous toluene (11 ml) and 8-methoxy-2,3,4,5,6,7-hexahydroazepin (0,96 ml). The mixture was kept at 60°C for 3 hours, then at 110°With during the night. The solution is cooled to room temperature and concentrate. The residue is purified by chromatography on silica gel, receiving 3-benzyl-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin in the form of a white solid.

3-Benzyl-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]Asotin (287,6 mg) and 1-bromo-3-chloro-2-methylpropan (140 μl) dissolved in anhydrous tetrahydrofuran, freed from oxygen, and the solution is cooled to -40°C in argon atmosphere. To the resulting solution was added dropwise bis(trimethylsilyl)amide and potassium (KHMDS, 0.5 M in toluene, 2.5 ml). After 30 minutes, add a second aliquot of KHMDS (2.5 ml). After another 30 minutes again added KHMDS (2,15 ml) and the solution is allowed the opportunity to slowly warm to room temperature. After one hour, the reaction is quenched with water and the reaction mixture is added to the salt solution. The mixture is extracted with ethyl acetate, the organic layer dried with magnesium sulfate, filtered, evaporated and purified by chromatography on silica gel, receiving 3-[1-(4-chlorophenyl)-(Z)-3-(meth is kimitake)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3- a]Asotin (4-10) in the form of a mixture of isomers (˜1,2:1); MS ESI (m/z): 296,2.

Methodology 4H

Obtaining 1-(4-chlorophenyl)-TRANS-3-forceclosure-r-carbohydrazide

(4-Chlorophenyl)acetonitrile (14,04 g) dissolved in freshly tetrahydrofuran (250 ml) and stirred at -78°in argon atmosphere [1]. To the resulting solution was added dropwise motility (LiBr complex, 1.5 M in diethyl ether, 62 ml, 1 EQ.) so that the reaction temperature remained below -66°C. the Solution is stirred for one hour at -78°With the color of the solution changed from yellow to deep red. To the solution is added dropwise epibromohydrin and the solution is stirred for additional 90 minutes. To the solution add iodide Metalmania (3.0 M in diethyl ether, 31 ml), and the solution that is light brown with a slow warming to room temperature, stirred over night. The reaction is quenched with water (75 ml) and acidified to pH 2 with 5 N aqueous hydrochloric acid (˜30 ml). The salt solution added to until the layers are not separated. The organic layer is collected, the aqueous layer was re-extracted with diethyl ether (2×50 ml). The organic layers are combined, dried with magnesium sulfate, filtered and concentrated.

The crude 1-(4-chlorophenyl)-3-hydroxycyclopent-1-carbon is home to the thrill (a mixture of CIS:TRANSisomers with a ratio of about 4.2:1) dissolved in dichloromethane (150 ml) and stirred at 0°C. To the solution was added pyridine (11.3 ml) and then benzoyl chloride (10,8 ml), the solution is heated to room temperature and stirred for 2.5 hours. Then add an additional amount of pyridine (2 ml) and benzoyl chloride (2 ml) and the reaction mixture is stirred at 30°With during the night. The reaction solution was added to saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated ammonium chloride, dried over magnesium chloride, filtered and concentrated, obtaining the oil is reddish in color. Two isomers separated by chromatography on silica gel (25% dichloromethane/hexane → 33% dichloromethane/hexane → 50% dichloromethane/hexane → 100% dichloromethane)to give the target 3-(4-chlorophenyl)-CIS-3-cyanocobalamine (18,63 g).

3-(4-Chlorophenyl)-CIS-3-cyanocobalamine (6.42 per g) dissolved in methanol/tetrahydrofuran (10 ml/20 ml) and stirred at room temperature. The lithium hydroxide monohydrate (1.1 g) dissolved in water (10 ml) and added to a solution of benzoate. After 10 minutes, add solid ammonium chloride (˜2 g), and volatile solvents evaporated. The remaining aqueous mixture is extracted with diethyl ether, the organic layer is dried with magnesium sulfate, filtered and concentrated, obtaining the target cyclobutanol.

A portion of 1-(4-chlorophenyl)-CIS-3-hydroxycyclopent-r-carbonitrile (1.13 g) was dissolved in anhydrous dichloromethane and stirred at 0°C. To the solution was added TRIFLUORIDE (diethylamino)sulfur (DAST, 1,43 g), the solution is heated to 40°C and maintained at this temperature for 10 hours. Add an additional amount of DAST (0.5 ml) and the reaction solution stirred at 40°With during the night. The solution is cooled, add saturated aqueous sodium hydrogen carbonate solution and extracted twice with dichloromethane. The organic extracts are combined, dried with magnesium sulfate, filtered and concentrated. The crude residue carefully chromatographic on silica gel (10% ethyl acetate/hexane → 20% ethyl acetate/hexane → 25% ethyl acetate/hexane)to give 1-(4-chlorophenyl)-TRANS-3-forceclosure-r-carbonitril (1,024 g).

1-(4-Chlorophenyl)-TRANS-3-forceclosure-r-carbonitril (1.65 g) was dissolved in anhydrous toluene (30 ml) and cooled to -78°C. a Solution of hydride diisobutylaluminum (DIBAL, 1 M in hexano, and 9.4 ml) was added dropwise within 10 minutes and the resulting solution was stirred for 30 minutes. The reaction is quenched by adding 5% sulfuric acid (2.5 ml), and the mixture is heated to room temperature. After 1 hour, the mixture is filtered celestially layer celite. Celite is washed with ethyl acetate and the entire filtrate was poured into water (20 ml). The layers separated, and the aqueous solution extracted with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated.

The crude aldehyde was dissolved in a mixture of tert-butanol/tetrahydrofuran/2-methylbut-2-ene (15 ml/5 ml/5 ml) and the resulting solution was stirred at room temperature. Sodium chloride (1.56 g) and sodium dihydrophosphate (2,39 g) dissolved in water (7 ml) and added dropwise to the solution with vigorous stirring. After 80 minutes, the volatile solvents are removed in vacuo and the mixture acidified to pH 2 aqueous 1 N hydrochloric acid. The product is extracted with ethyl acetate (3×30 ml). The extracts are combined, dried over magnesium sulfate, filtered and evaporated, receiving the target carboxylic acid.

1-(4-Chlorophenyl)-TRANS-3-forceclosure-r-carboxylic acid (of 5.68 g) was dissolved in a mixture of dichloromethane/methanol (40 ml/10 ml). To the resulting solution was added (trimethylsilyl)diazomethane (15 ml, 2.0 M in hexano) to obtain nonvanishing yellow staining. The solution was stirred at room temperature for 1 hour, after which time TLC shows that the reaction is complete. For damping (trimethylsilyl)diazomethane add acetic acid (2 ml) and the solution concentrated, obtaining 1-(4-chlorophenyl)-TRANS-3-forceclosure-r-CT is oxalat.

The crude methyl ester (5.8 g) was dissolved in toluene (15 ml). Add anhydrous hydrazine (3.1 ml, 98,8 mmol) and the reaction mixture is refluxed for two days. The solution is cooled to room temperature and the toluene removed in vacuo, the product was then purified by chromatography on silica gel (100% ethyl acetate)to give 1-(4-chlorophenyl)-TRANS-3-forceclosure-r-carbohydrate in the form of a white solid (4,82 g).

Methodology 4I

The General scheme

Obtain 3-[1-(4-chlorophenyl)-TRANS-3-forceclosure]-4,5-dicyclopropyl-r-4H-1,2,3-triazole (4-11)

Methyl triftorbyenzola (84,1 μl) are added to N-cyclopropanecarboxamide (93,0 mg). The mixture is heated to 65°C, kept at this temperature for 2 minutes, then cooled to room temperature. Toluene (1 ml), triethylamine (207 μl) and 1-(4-chlorophenyl)-TRANS-3-forceclosure-r-carbohydrazide (108 mg) is added to methyl N-cyclopropanecarboxamide and the resulting mixture was stirred at 60°during the night and when 115°C for 2 hours. The solution is cooled, then concentrated and the residue purified by chromatography on silica gel (100% ethyl acetate → 1% methanol in ethyl acetate → 3% methanol in ethyl acetate → 5% methanol in ethyl acetate) obtaining purified 3-[1-(4-chlorophenyl)- TRANS-3-forceclosure]-4,5-dicyclopropyl-r-4H-1,2,4-triazole (4-11).

Connection 4-12 - 4-15 get, essentially, in accordance with the same method, using the appropriate carboxamide in as the starting material and 1-(4-chlorophenyl)-TRANS-3-forceclosure-r-carbohydrazide.

IV for:The original substanceIV for:The original substance

4-114-12
4-134-14
4-15

ConnectionStructureNameRetention time (min)MS ESI (m/z)Method
4-113-[1-(4-chlorophenyl)-TRANS-3-forceclosure]-4,5-dicyclopropyl-r-4H-1,2,4-triazole2,45332,15I
4-12 3-[1-(4-chlorophenyl)-TRANS-3-forceclosure]-4-cyclopropyl-5-(1-methylcyclopropyl)-r-4H-1,2,4-triazole2,60346,15I
4-133-[1-(4-chlorophenyl)-TRANS-3-forceclosure]-4-methyl-5-[4-(triptoreline)phenyl]-r-4H-1,2,4-triazoleto 3.58426,05I
4-143-[1-(4-chlorophenyl)-TRANS-3-forceclosure]-4-methyl-5-[2-(triptoreline)phenyl]-r-4H-1,2,4-triazole3,32to 426.25I
4-153-(2-chlorophenyl)-5-[1-(4-chlorophenyl)-TRANS-3-forceclosure]-4-methyl-r-4H-1,2,4-triazole3,14376,15I

Method preparative HPLC to example 4:

Use the method of preparative HPLC as described in example 2.

Analytical LC method identical to the method described in example 2.

Links

1. Jeffery, J.E.; Kerrigan, F.; Miller, T.K.; Smith, G.J; Tometzki, G.B.; J. Chem. Soc., Perkin Trans 1, 1996, (21), 2583-2589.

2. Fedorynski, M.; Jonczyk, A. Org. Prep. Proced Int., 1995, 27 (3), 355-359.

3. Suzuki, H.; Tsutsui, H; Kano, A.; Katoh, S.; Morita, T.; Matsuda, K.; Iibuchi, N.; Ogawa, M. Heterocycles, 1997, 45 (9), 1657-61.

At that time, as in the description presents the preferred is sustained fashion to the embodiment of the present invention, understood that many alternative embodiments are also included in the scope defined by the claims. Therefore, the invention is defined broader than private embodiment disclosed in the description.

1. Derivatives of 1,2,4-triazole represented by formula I

or their pharmaceutically acceptable salt or solvate,

where

A and b can be taken separately or together, and

when a and b are taken separately And represents a C1-6alkyl or phenyl and represents a C1-6alkyl, and

when a and b taken together, they represent a2-5alcander, so that they form with the carbon atom to which is attached, 3-6-membered cycle, optionally substituted C1-4-alkylene, oxo, Ethylenedioxy,1-4the alkyl, 1-2 halogen, C1-3-alkoxy-C1-3-alkoxy or HE;

each R1represents H, C3-6cycloalkyl, HE, halogen, C1-6-alkyl, optionally substituted by 1-3 Halogens,

or two R1the group, standing at adjacent carbon atoms, form a 6-membered aryl cycle;

R2and R3can be taken together or separately, and

when R2and R3taken together, they represent a3-8-alcander forming condensed to 10-membered nonaromatic cycle, and

when R2and R3taken separately, R2represents a C1-6-alkyl, optionally substituted by 1-3 Halogens, or cyclopropyl, and R3is cyclopropyl, optionally substituted C1-4the alkyl, naphthyl, phenyl, optionally substituted with halogen, HE, C1-6the alkyl, where the specified C1-6alkyl optionally substituted by 1-3 Halogens, OC1-6the alkyl, where the specified OC1-6alkyl optionally substituted by 1-3 Halogens, phenyl or benzyloxycarbonyl, dihydrobenzofuranyl, benzothiazolyl or benzimidazolyl, optionally substituted C1-6the alkyl.

2. The compound according to claim 1, where a and b taken together with the carbon atom to which they are attached, form a 3-6-membered cycle, optionally substituted as indicated in claim 1.

3. The compound according to claim 2, where 3-6-membered cycle is 3-5-membered cycle, optionally substituted by 1-2 halogen or C1-3alkoxy-C1-3alkoxy.

4. The compound according to claim 3, 3-5-membered cycle, optionally substituted with 1-2 Halogens.

5. The compound according to claim 4, where halogen represents fluorine atoms.

6. The compound according to claim 1, where the two R1groups are H and one of R1the group is a HE, halogen, C1-6alkyl, optionally substituted with 1-3 Halogens.

7. The compound according to claim 1, where one of R1the group is with the battle N, and the other two R1groups represent IT, halogen, C1-6alkyl, optionally substituted with 1-3 Halogens.

8. The connection according to claim 7, where the two R1groups are halogen or methyl.

9. The compound according to claim 1, where R2represents a C1-6alkyl, optionally substituted with 1-3 Halogens.

10. The compound according to claims 1 and 9, where R2represents methyl or cyclopropyl.

11. The compound according to claim 1, where R3represents naphthyl or phenyl, optionally substituted with halogen, HE1-4the alkyl or OC1-4the alkyl, the latter two radicals optionally substituted by 1-3 Halogens, or phenyl and 1-3 Halogens, respectively.

12. The compound according to claims 1 and 11, where R3is cyclopropyl, optionally substituted stands, phenyl, optionally substituted with halogen, HE, co3and OCF3, benzimidazolyl and dihydrobenzofuranyl.

13. The compound according to claim 1, where R2and R3taken together and are (a)3-8alcander forming a condensed 5-to 10-membered nonaromatic cycle.

14. A compound selected from the group including

or its pharmaceutically acceptable salt or MES.

15. The connection 14

or its pharmaceutically when mlama salt or MES.

16. The connection 14 structural formula

or its pharmaceutically acceptable salt or MES.

17. The connection 14 structural formula

or its pharmaceutically acceptable salt or MES.

18. The connection 14 structural formula

or its pharmaceutically acceptable salt or MES.

19. Pharmaceutical composition having inhibitory activity against 11β-hydroxysteroid dehydrogenase 1, containing a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, medicine, oncology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): or their pharmaceutically acceptable salts possessing the inhibitory effect on activity of tyrosine kinase. Proposed compounds can be used in treatment of proliferative disease, such as tumor. In the formula (I) each R1 and R2 means independently of one another hydrogen atom, methyl, ethyl, isopropyl, hydroxyethyl, piperidine-1-ylmethylcarbonyl, pyrrolidine-1-ylmethylcarbonyl, morpholine-4-ylmethylcarbonyl, 4-methylpiperazine-1-ylmethylcarbonyl, N,N-dimethylaminomethylcarbonyl, 4-ethylpiperazine-1-ylmethylcarbonyl, piperidine-1-ylethylcarbonyl, N,N-diethylaminoethylcarbonyl, N,N-dimethylaminopropylcarbonyl, 2-pyridylcarbonyl, tetrahydropyrane-4-yl, morpholine-4-ylethyl, N,N-diethylaminoethyl, tert.-butyl; or R1 and R2 in common with nitrogen atom to which they are bound form 4-ethylpiperazine-1-yl, pyrrolidine-1-yl, 4-methylpiperazine-1-yl, piperidine-1-yl, morpholine-4-yl, 3,5-dimethylpiperazine-1-yl; R3 is chosen from 3-chloro-4-fluorophenyl, phenyl, 4-benzyloxyphenyl, 3-hydroxy-4-methylphenyl, 3-hydroxy-4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,5-dichlorophenyl, 3-methoxyphenyl, benzo[1,3]dioxol-5-yl, 6-methoxypyridine-3-yl, 2-methoxypyridine-4-yl, pyridine-2(1H)-one-5-yl, pyridine-2(1H)-one-4-yl, 3-methoxyphenyl, 3-methylphenyl, pyridine-2(1H)_one-4-yl; G means -CH2-; Q means -NH-; X absents or means -CH(CH3)-, -CH2- under condition that if X absents then R3 is bound by ring carbon atom. Also, invention relates to variants of methods for synthesis of compounds of the formula (I), preparing a pharmaceutical composition and using compounds proposed.

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

13 cl, 147 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): that are antagonists of CRF receptors and wherein Ar means optionally substituted phenyl or monocyclic 6-membered heteroaryl comprising one heteroatom chosen from nitrogen, oxygen or sulfur atoms; R1-R4 have values given in the invention claim, or to their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of indicated compounds and to pharmaceutical compositions containing these compounds that are useful for administration to a patient suffering from diseases that are relived in therapy using antagonists of CRF receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 tbl, 17 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of 1-[(indole-3-yl)carbonyl]piperazine of the formula (I): wherein R means substitute chosen from hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkyloxy-group (optionally substituted with halogen atom), halogen atom, -OH, -NH2, -CN and -NO2; R1 means (C5-C8)-cycloalkyl or (C5-C8)-cycloalkenyl; R2 means H, methyl or ethyl; radicals R3, R'3, R4, R'4, R5, R'5 and R'6 means independently hydrogen atom or (C1-C4)-alkyl optionally substituted with halogen atom or -OH; R6 means hydrogen atom or (C1-C4)-alkyl optionally substituted with (C1-C4)-alkoxy-group or halogen atom; or R6 in common with R7 forms 5-6-membered saturated heterocyclic ring; R7 means H, (C1-C4)-alkyl optionally substituted with -OH, halogen atom or (C1-C4)-alkoxy- group, or (C3-C5)-cycloalkyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) possess agonistic activity with respect to CB1 receptors. Also, invention describes pharmaceutical composition possessing agonistic activity with respect to CB1 receptors and using compound of the formula (I) for preparing a drug used in pain treatment.

EFFECT: valuable medicinal and pharmacological properties of compounds and pharmaceutical composition.

9 cl, 1 tbl, 21 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

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of triazolo[4,5-d]pyrimidine of the general formula (I): wherein R1 means (C3-C5)-alkyl that can be substituted with halogen atom; R2 means phenyl that can be substituted with fluorine atom; R3 and R4 are similar and mean hydroxy-group; R means XOH wherein X means -CH2, -OCH2CH2 or a bond, or their pharmaceutically acceptable salt or solvate of solvate of such salt under condition that when X means -CH2 or a bond then R1 doesn't mean propyl group; when X means -CH2 and R1 means -CH2CHCF3, butyl or pentyl groups then phenyl group at R2 must be substituted with fluorine atom; when X means -OCH2CH2 and R1 means propyl then phenyl group at R2 must be substituted with fluorine atom. Also, invention describes a pharmaceutical composition based on these compounds, method for their synthesis and novel intermediate compounds of the formula (II) , (V) and R-(R*,R*)-2,3-dihydroxybutanedioate (1:1) of compound of the formula (III): . Also, invention relates to a method for treatment of diseases mediated by P2T-receptors, such as myocardium infarction, prophylaxis or propagation of tumors and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved method of synthesis.

15 cl, 9 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel hydrogenated azepino[4,3-b]indoles of the general formula (1): , their racemates, optical isomers, geometric isomers and their pharmaceutically acceptable salts and/or hydrates. In the general formula (1) a dotted line with accompanying unbroken line represents a simple or double bond; R1 and R2 represent independently of one another substitutes of amino-group chosen from hydrogen atom, possibly substituted (C1-C8)-alkyl possibly substituted with aryl, 5-6-membered azaheterocyclyl, (C1-C8)-alkoxycarbonyl, possibly substituted phenyl, possibly substituted carbonylamino- or thiocarbonylamino-group, substituted acyl, (C1-C8)-alkylsulfonyl, possibly substituted arylsulfonyl and wherein substitutes in indicated R1 and R2 are chosen independently from (C1-C8)-alkyl, halogen atoms, nitro-, carboxy-, alkoxy-group, aryl; Rin represents one or some similar or different substitutes of cyclic system chosen from hydrogen atom, (C1-C8)-alkyl, (C6-C10)-aryl, halogen atom, 5-6-membered azaheterocyclyl. Also, invention relates to methods for synthesis of these compounds, their using and pharmaceutical composition and libraries of compounds. Synthesized compounds possess neuroprotective, cognitive-stimulating and anti-histaminic properties and can be used in treatment of different neurological disorders, allergic and autoimmune diseases, for example, for memory improvement.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition, improved method of synthesis.

25 cl, 2 tbl, 12 ex

FIELD: medicine, pharmaceuticals.

SUBSTANCE: invention relates to compound of general formula I having structure of triazole[4,5-d]pyrimidine derivatives, or pharmaceutically acceptable salts, or prodrugs thereof. Disclosed is method for application of said compound or pharmaceutically acceptable salt thereof to produce pharmaceutical for treatment and prophylaxis of conditions ameliorated with blockage of adenosine A2A receptors. Also disclosed are pharmaceutical composition including compound of formula I, or pharmaceutically acceptable salt, or prodrug thereof in combination with pharmaceutically acceptable carrier or excipient. Said pharmaceutical compositions may be administered to subject by peroral, rectal, parantheral, transdermal, subdermal, etc. methods. Pharmaceutical of present invention are useful in treatment of Parkinson's disease, depression, cognitive or mental disturbances, acute or chronic pain, narcolepsy, etc.

EFFECT: composition of improved neuroprotective characteristics.

50 cl, 3 tbl

FIELD: organic chemistry, medicine, pharmacy, biochemistry.

SUBSTANCE: invention relates to a method for treatment of states caused by activity of p38 kinase. Method involves administration to a patient needed in this treatment of at least one compound of the formula (I): or its pharmaceutically acceptable salt or solvate wherein R3 means hydrogen atom, methyl, perfluoromethyl, methoxy-group, halogen atom, cyano-group or NH2-group; X is chosen from -O-, -OC(=O)-, -S-, -S-, -S(=O)-, -SO2-, -C(=O)-, -CO2-, -NR10-, -NR10C(=O)-, -NR10C(=O)NR11-, -NR10CO2-, -NR10SO2-, -NR10SO2NR11-, -SO2NR10-, -C(=O)NR10, halogen atom, nitro- and cyano-group, or X is absent; Z is chosen from oxygen (O), sulfur (S), nitrogen (N) atoms, and -CR20 being wherein Z means -CR20 optionally substituted bicyclic aryl or heteroaryl with R4 or R5; R1 means hydrogen atom, -CH3, -OH, -OCH3, -SH, -SCH3, -OC()=O)R21, -S(=O)R22, -SO2NR23R25, -CO2R21, -C(=O)NR24R25, -NH2, -NR24R25, -NR21SO2NR24R25, -NR21SO2R22, -NR24C(=O)R25, -NR24CO2R25, -NR21C(=O)NR24R25, halogen atom, nitro- or cyano-group; R2 is chosen from the following group: (a) hydrogen atom under condition that R2 doesn't mean hydrogen atom if X means -S(=O)-, -SO2-, -NR10CO2- or -NR10SO2-; (b) alkyl, alkenyl and alkynyl comprising up to four R26 groups or pentafluoroalkyl as substitutes; (c) aryl and heteroaryl comprising up to three groups R27 as substitutes, and (d) heterocyclo-group or heteroalkyl optionally comprising keto-group (=O), up to three groups R27 as substitutes, and/or comprising carbon-carbon bridge comprising 3-4 carbon atoms, or (e) R2 is absent if X means halogen atom, nitro- or cyano-group; R4 means substituted aryl, aryl comprising NOSE-alkyl, substituted heteroaryl or optionally substituted bicyclic 7-11-membered saturated or unsaturated carbocyclic or heterocyclic fragment as a substitute, and R5 means hydrogen atom, alkyl or substituted alkyl with exception of cases when Z means O or S and then R5 is absent, or R4 and R5 in common with Z form optionally substituted bicyclic 7-11-membered aryl or heteroaryl; R6 means hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group, substituted heterocyclo-group, -NR7R8, -OR7 or halogen atom; R10 and R11 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo-group and substituted heterocyclo-group; R7, R8, R21, R24 and R25 are chosen independently from the following group: hydrogen atom, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group and substituted heterocyclo-group; R20 means hydrogen, lower alkyl or substituted alkyl, or R20 can absent if carbon atom to which is bound and in common with R4 and R5 represents part of bicyclic aryl or heteroaryl; R22 means alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo-group or substituted heterocyclo-group; R26 is chosen from the following group: halogen atom, trifluoromethyl, halogenalkoxy-group, keto (=O)-, nitro-, cyano-group, -SR28, -OR28, -NR28R29, -NR28SO2, -NR28SO2R29, -SO2R28, -SO2NR28R29, -CO2R28, -C(=O)R28, -C(=O)NR28R29, -OC(=O)R28, -C(=O)NR28R29, -NR28C(=O)R29, -NR28CO2R29,=N-OH, =N-O-alkyl; aryl optionally comprising as a substitute from one to three R27 groups; cycloalkyl optionally comprising a substituted keto-group (=O), from one to three R27 groups, or carbon-carbon-containing bridge comprising of 3-4 carbon atoms; and heterocyclo-group comprising optionally as a substitute keto-group (=O), from one to three R27 groups or comprising carbon-carbon bridge comprising 3-4 carbon atoms, and wherein each R28 and R29 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl and (C3-C7)-heterocycle, or they can form in common (C3-C7)-heterocycle; and each R28 and R29, in turn, can comprise optionally up to two substitutes representing alkyl, alkenyl groups, halogen atoms, halogenalkyl groups, halogenalkoxy-, cyano-, nitro-, amino-, hydroxy-, alkoxy-, alkylthio-groups, phenyl, benzyl, phenyloxy- and benzyloxy-groups; and R27 is chosen from the following group: alkyl, R32 and (C1-C4)-alkyl comprising as substitutes from one to three R32groups and wherein each R32 group is chosen independently from the following group: halogen atom, halogenalkyl, halogenalkoxy-, nitro-, cyano-groups, -SR30, -OR30, -NR30R31, -NR30SO2, -NR30SO2R31, -SO2R30, -SO2NR30R31, -CO2R30, -C(=O)R30, -C(=O)NR30R31, --OC(=O)R30, -OC(=O)NR30R31, -NR30C(=O)R31, -NR30CO2R31 and from 3-7-membered carbocyclic or heterocyclic ring comprising optionally as a substitute alkyl, halogen atom, hydroxy-, alkoxy-group, halogenalkyl, halogenalkoxy-, nitro-, amino- or cyano-group, and wherein each R30 and R31 is chosen independently from the following group: hydrogen atom, alkyl, alkenyl, aryl, aralkyl, (C3-C7)-cycloalkyl, and heterocycle, or they in common can form (C3-C7)-heterocycle. Also, invention describes pyrrolotriazine compounds, a pharmaceutical composition based on thereof and a method for treatment of inflammatory diseases using above proposed compounds and pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 14 tbl, 152 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel compound of the general formula (I): wherein R means hydrogen atom (H), -OH, carbamoyl group; n = 1 or 2, or to its pharmaceutically acceptable salt. Compounds of the formula (I) are potential inhibitors of cellular adhesion mediated by integrins that allows its using as components of pharmaceutical composition used in treatment or prophylaxis of inflammatory, autoimmune or allergic state or rejection mediated by LFA-1.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

19 cl, 2 sch, 3 dwg, 3 tbl, 7 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention relates to a novel crystalline form of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidine-1-yl}-3-oxopropionitrile. This form shows characteristic peaks in powder roentgenogram obtained by using Cu as radiation source and expressed as degrees two-theta at about 5.7; 16.1; 20.2 and 20.5. Also, invention relates to a method for preparing this form and its using in preparing medicinal agents in treatment or prophylaxis of diseases mediate by protein-tyrosine-kinases, such as JAK3. Method for preparing this form involves interaction of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropionitrile with citric acid.

EFFECT: improved preparing method, valuable properties of compound.

5 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical agent.

6 cl, 67 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carboxylic acid represented by the general formula (I): , their pharmaceutically acceptable salts or esters wherein values Y, L, X, T, Z, M, R1, W and are given in the invention claim. Proposed compounds possess insulin-sensitizing effect and they are double agonists with respect to PPARα and γ, and triple agonists with respect to PPARα, β(δ) and γ. Except for, the invention relates to a medicinal agent and pharmaceutical compositions based on the claimed derivatives of carboxylic acid, to methods for prophylaxis or treatment of diseases, and to using derivatives carboxylic acid for preparing a medicinal agent.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

56 cl, 2 tbl, 609 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means lower alkyl, -(CH2)n-O-lower alkyl, -(C3-C6)-cycloalkyl or -(CH2)n-NR'2 wherein R' means hydrogen atom, lower alkyl or -(CH2)n-O-lower alkyl independently of one another for R'2; or R'2 in common with nitrogen atom can form pyrrolidine ring, and wherein n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition possessing antagonistic activity with respect to A2 receptors and containing one or some compounds of the general formula (I) and its pharmaceutically acceptable excipients. Invention provides synthesis of compound of the general formula (I) possessing antagonistic activity with respect to A2 receptors.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

11 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazoles of the general formula (I): , wherein R1 represents hydrogen atom (H), direct or branched (C1-C4)-alkyl or COO-(C1-C4)-alkyl or phenyl optionally substituted with one or some substitutes chosen from halogen atom; R2 represents H, direct or branched (C1-C4)-alkyl, COO-(C1-C4)-alkyl. Method for synthesis involves addition to aqueous solution of 4-R1-5-R2-1-hydrazino-1,3-thiazole hydrochloride of the formula (II): , wherein R1 and R2 have above given values of N-cyanoguanidine of the formula (III): in the mole ratio (II) : (III) = (1.10-1.20):100. Prepared mixture is heated at temperature 80-95°C followed by its neutralization, filtering off and recrystallization. Method provides preparing 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazole from inexpensive and available raw and without using complex technological procedures. Synthesized compounds can be used in synthesis of medicinal and biologically active substances.

EFFECT: improved method of synthesis.

10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 3-oxo-1-cyclobutene of the general formula (I): and their salts, solvates, hydrates and N-oxides wherein R1 represents group of the formula: Ar1L2Ar2Alk wherein Ar1 represents aromatic or heteroaromatic group; L2 represents a covalent bond or -O-, -NH- or -CONH-; Ar2 represents arylene or heteroarylene group; Alk represents chain -CH2CH(R) or -CH(CH2R)- wherein R represents -CO2H or -COOAlk7 wherein Alk7 represents (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-heterocycloalkyl group and others; X represents group -N(R2)- wherein R2 represents hydrogen atom or (C1-C6)-alkyl group; V represents oxygen atom; Rx, Ry and Rz represent atom or group -L1(Alk1)n(R3)v wherein L1 represents covalent bond or -O-, -S-, -Se-, -S(O)-, -NH- or -N(CH3)-; Alk1 represents aliphatic group; R3 represents hydrogen, halogen atom, group -OR3a, -SR3a and others wherein R3a represents hydrogen atom, (C1-C6)-alkyl and others; n = 0 or 1; v = 1, 2 or 3 under condition that if n = 0 and L1 represents covalent bond then v = 1; or Rz represents atom or group given above, and Rx and Ry taken together form spiro-bound cycloaliphatic or heterocycloaliphatic group. Compounds of the formula (I) possess inhibitory activity with respect to α4-integrin and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 216 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

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