UA80459C2 - Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 - Google Patents

Abstract

Triazole derivatives of structural formula (I) are selective inhibitors of the 11 -hydroxysteroid dehydrogenase-1. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dyslipidemia, hyperlipidemia, hypertension, Metabolic Syndrome, and other symptoms associated with NIDDM.

Description

Description of the invention

The present invention relates to triazole derivatives as inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase 29 14th type (118-GSD-1 or GOSD-1) and methods of treating certain conditions using them. The compounds of this invention are used for the treatment of diabetes, for example, non-insulin-dependent diabetes of the 2nd type (INZCD), insulin resistance, obesity, disorders of fat metabolism, hypertension and other diseases and conditions.

The cause of diabetes is a set of factors, and the most simplified diabetes is characterized by an increased content of glucose in the fasting blood plasma (hyperglycemia). There are two most studied forms of diabetes: type 1 diabetes 70 or insulin-dependent diabetes mellitus (IIDDM), in which patients produce little or no insulin, the hormone that regulates glucose uptake, and type 2 diabetes, or non-insulin-dependent diabetes 2- type 1 (INZCD), in which patients produce insulin and even exhibit hyperinsulinemia (insulin levels in the blood plasma are the same, or even increased, compared to people without diabetes), while they exhibit hyperglycemia. Type 1 diabetes is usually treated with insulin injections. However, with 72 type 2 diabetes, often develops "insulin resistance", that the stimulating effect of insulin on glucose and lipid metabolism in the main insulin-sensitive tissues, namely, muscle, liver and adipose tissue, is reduced. Insulin-resistant patients who are not diabetic , have elevated insulin levels that compensate for their insulin resistance, so that serum glucose levels are not elevated.In patients with ILD, plasma insulin levels, even if elevated, are insufficient to overcome marked insulin resistance, leading to hyperglycemia.

Insulin resistance mainly occurs due to a defect in binding to the receptor, which is still not completely clear. Insulin resistance leads to insufficient activation of glucose absorption, reduced glucose oxidation and glycogen deposition in muscles, inadequate insulin suppression of lipolysis in adipose tissue, and inadequate glucose production and secretion by the liver. with

Chronic or uncontrolled hyperglycemia observed in diabetics is associated with increased Ge) morbidity and premature mortality. Abnormal glucose homeostasis is also directly and indirectly associated with obesity, hypertension, and changes in lipid, lipoprotein, and apolipoprotein metabolism. Type 2 diabetes is accompanied by an increased risk of developing cardiovascular complications, such as atherosclerosis, coronary artery disease, heart attack, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity and hypertension is fundamentally important in the clinical management and treatment of diabetes. WITH

Many patients who have insulin resistance but do not have overt type 2 diabetes are also at risk for symptoms called "syndrome X" or "metabolic syndrome." Syndrome X and metabolic syndrome are characterized by insulin resistance, along with abdominal obesity, with hyperinsulinemia, high blood pressure, low HDL (high-density lipoprotein) and high LDL (very low-density lipoprotein). Such patients, regardless of whether they have severe diabetes or not, are prone to high risk of developing cardiovascular complications, listed "above. Z

Treatment of type 2 diabetes usually includes exercise and diet. Elevation of plasma insulin levels with sulfonylureas (eg, tolbutamide and glipizide) or meglitinide, which stimulates B cells

From the pancreas to secrete more insulin, and/or by injecting insulin when sulfonylureas or meglitinide are ineffective, can create a high enough concentration of insulin to stimulate insulin-resistant tissues. However, the result may be a dangerously low glucose level, 49 and ultimately an increased level of insulin resistance. because Biguanides increase insulin sensitivity, leading to some correction of hyperglycemia. However, many av | which biguanides, for example, phenformin and metformin, cause lactic acidosis, nausea and diarrhea. iz Glitazones (namely, 5-benzylthiazolidine-2,4-diones) form a new class" 1 of compounds with the ability to improve hyperglycemia and other symptoms of type 2 diabetes. These agents significantly increase insulin sensitivity (9) 50 muscles, liver and adipose tissue, leading to partial or complete correction of elevated plasma glucose levels, mostly without causing hypoglycemia. The recently marketed glitazones are peroxisome proliferator-activated receptor-gamma subtype (RAPP) agonists. It is believed that agonism

RAPP-gamma is mainly responsible for the increased insulin sensitivity observed with glitazones. New RAPP agonists created for the treatment of type 2 diabetes and/or dyslipidemia are agonists of 99 one or more RAPP subtypes alpha, gamma, and delta. A review of insulin-sensitizing agents and others

HF) mechanisms of treatment of type 2 diabetes, see M. Tadauuop and 5.A. tii, "Ipzcyip zepziyzayop ip (She 7 igeaitepi oi Toure 2 aiare(ev), Ekhregi Orip. Ipmesiid. Ogydv. 12: 307-324 (2003)).

There is a constant need for new treatments for diabetes and related conditions such as metabolic syndrome. This invention solves this and other problems. because the present invention relates to bicyclo|2.2.21-oct-1-yl-1,2,4-triazoles of the structural formula I: b5

; | These derivatives of bicyclo|2.2.2|1-octyltriazole are effective as inhibitors of 11B-hydroxysteroid dehydrogenase type 1 (118-GSDI1). Thus, they are effective in treatment, control and prevention of disorders that respond to inhibition of 118-GSDI, such as hyperglycemia, insulin resistance, type 2 diabetes, lipid disorders, obesity, atherosclerosis and metabolic syndrome.

The present invention also relates to pharmaceutical compositions containing compounds of the present invention and a pharmaceutically acceptable carrier.

The present invention also relates to methods of treating or controlling hyperglycemia, insulin resistance, type 2 diabetes, obesity, lipid disorders, atherosclerosis, and metabolic syndrome by administering compounds and pharmaceutical compositions of the present invention.

The present invention relates to bicyclo|2.2.21-oct-1-yl-1,2,4-triazole derivatives used as inhibitors of 118-GSD1. The compounds of this invention are described by the structural formula I: o (22) i m-m

Z I U cy and -x z

M Fo d2 d) shi or their rarmaceutically acceptable salt; where s because their f y

And each p independently represents 0, 1 or 2; and? each n independently represents 0, 1 or 2;

X is chosen from the group consisting of a single bond, O, 5(O)5, MA, 6 b b b so o v Azh hi o o o A r M M M i che

M r y rai - M rai r:d y t" ! r: M - in! o o I v o, o A iChe)

Ve ve in o

M o o I r Z o 8) name) o o . for BE" is selected from the group consisting of arylcarbonyl, (CHNo)p-aryl, and (CHNo)p-heteroaryl; wherein aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from B;

IN? selected from the group consisting of hydrogen,

S. valkilu,

Co valkenyl, and (CHo)n-C3 cycloalkyl, and wherein the alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from 28 and oxo; each B" is independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo,

Su zalkilu, i

S. zalkoxi;

VZ is selected from the group consisting of hydrogen,

Su zralkilu,

Co 1 arkenyl, (CH No)p-C3 vcycloalkyl, 2000. (CH No)raryl, (CH No)p-heteroaryl, and (CH No)d-heterocyclyl; wherein aryl, heteroaryl and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from VU; and alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to five c 29 groups independently selected from KZ and oxo; Huh) 2? and 28, each independently selected from the group consisting of hydrogen, form, b» 1-alkyl, (sno)aryl, u (CHNo)p-heteroaryl, (CHNo)d-heterocyclyl, C(CHno)p-C3 .7cycloalkyl, and "c) halogen,

ОВ", so (sno 7", cyano, (СНозСОоВ, "

MO», - with (СНо)zamv 78025, "» (сно 7, " (СНоднВ(О) р, (СНоз5О2ОВ, 7 7 со (СноазаМмае СОМ з), (Snow 7), ши (СНодимвс(ОВ), их ( SnozamA so, hundred 20 (snom 7",

SE", iChe) SNoSE",

OS",

OSNO", and

OSNSE"; where aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, and de C 1-4 hydroxy; and where is any carbon atom of the methylene group (CH) in KE? and KZ is unsubstituted or substituted by one or two groups independently selected from halogen, hydroxy, and C-alkyl; or two substituents that 60 are on the same carbon atom of the methylene group (CH 5), taken together with the carbon atom to which they are attached, form a cyclopropyl group; each 2? independently selected from the group consisting of

S. valkyl, (СНо)p-aryl, for (СНодп-heteroaryl, i

(СНо)п-C3.7cycloalkyl; where alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C 1 -dalkoxy, C 1 -dalalkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted

From one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C. dalalkyl and C. lalkoxy; or two KZ groups together with the atom to which they are attached to form a 5-8-membered mono- or bicyclic ring system, which optionally contains an additional heteroatom selected from 0, 5 and MC. far away and each B" is hydrogen or 5.

In one embodiment of the compounds of this invention K? is cyclopropyl, C.salkyl or C.salkenyl and R" is phenyl or naphthyl wherein the phenyl or naphthyl is unsubstituted or substituted with one to three substituents independently selected from KZ. In a class of this embodiment, 2? is selected from the group that consists of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C-alkyl, C-alkyl, C-alkylthio, and C-alkylsulfonyl. In a subclass of this class, B? is methyl and B" is hydrogen. 19 In the second embodiment of the compounds of this invention

X is a single bond;

B is phenyl or naphthyl, wherein the phenyl and naphthyl are unsubstituted or substituted with one to three substituents independently selected from K?;

IN? is cyclopropyl, C. zalkyl or C. zalkenyl; and

VZ is S. valkyl, unsubstituted or substituted with one or three substituents independently selected from KZ and oxo.

In the class of this second incarnation of KE? selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C. alkyl, Si. zalkoxy, C 1 alkylthio and C 1 alkylsulfonyl. In a subclass of this class B? is methyl. CM |B is hydrogen. at

In another class of this embodiment, KZ is selected from the group consisting of halogen, hydroxy, oxo, C. daloxy,

C..alkylthio, C..alkylsulfinyl, C.alkylsulfonyl, and phenyl is unsubstituted or substituted by one to three groups independently selected from halogen and trifluoromethyl. In a subclass of this class, K2 is methyl and B" is hydrogen. b"

In the third grade of this incarnation of KE? is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, Sisalkyl, Cisalkoxy, Sisalkylthio and Csalkylsulfonyl; and BZ is selected from the group consisting of halogen, hydroxy, oxo, C-1-alkylthio, C-1-alkylsulfonyl, and phenyl is unsubstituted or substituted with one to three groups independently selected from halogen and trifluoromethyl. In a subclass of this class, 2 is methyl and E7 is hydrogen. -

In the third embodiment of the compounds of this invention, p

X is a single bond;

B is phenyl or naphthyl, wherein the phenyl and naphthyl are unsubstituted or substituted with one to three substituents independently selected from K?; "

IN? is cyclopropyl, C. zalkyl or C. zalkenyl; and 70 BZ is phenyl or heteroaryl, wherein the phenyl and heteroaryl are unsubstituted or substituted from one to 8 with three substituents independently selected from KU. In the class of this embodiment, 2 is methyl and 27 is hydrogen.

In another class of this embodiment, BZ is phenyl, unsubstituted or substituted with one to three substituents 5 independently selected from R", In a subclass of this class B? is selected from the group consisting of halogen, hydroxy, (ee) trifluoromethyl, trifluoromethoxy, C-alkyl, C-alkyl, C-alkylthio and C-alkylsulfonyl. In the subclass of this about class B? is methyl and B" is hydrogen.

In the third class of this embodiment, C is oxadiazolyl, unsubstituted or substituted with one to two pi substituents independently selected from B". 4! 20 In a subclass of this class, Vo is phenyl, unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy and C 1-4 methoxy. In a subclass of this

Fo class B? is methyl and B" is hydrogen.

The following definitions apply in this description. "Alkyl," as well as other groups prefixed with "alk," such as alkoxy and alkanoyl, refers to carbon chains that may be straight or branched, and combinations thereof, unless the carbon chain is

GF) is defined differently. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. In the case where a certain number of carbon atoms allows, for example, from C zio, the term "alkyl" also includes cycloalkyl groups, and combinations of linear or branched alkyl chains condensed with cycloalkyl structures; when the number of carbon atoms is not determined, C..6 is meant. "Alkenyl" refers to carbon chains that contain at least one carbon-carbon double bond, which may be linear or branched, or combinations thereof, unless the carbon chain is otherwise specified. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. In the case when a certain number of carbon atoms allows, for example, from Svlo, the term "alkenyl" also includes cycloalkenyl groups, and combinations of linear,

branched and cyclic structures. When the number of carbon atoms is not determined, it means CO. "Alkynyl" refers to carbon chains that contain at least one carbon-carbon triple bond, and which may be linear or branched, or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. "Cycloalkyl" is a subtype of alkyl and refers to a saturated carbocyclic ring having a certain number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. A cycloalkyl group is generally monocyclic unless otherwise specified. Cycloalkyl groups are saturated unless otherwise specified. 70 The term "Alkoxy" refers to straight or branched chain alkoxides with a specific number of carbon atoms (e.g., C 1 -Alkoxy) or with any number of carbon atoms within a given range |ie, methoxy (Meo-), ethoxy, isopropoxy, etc. d.).

The term "alkylthio" refers to straight or branched chain alkyl sulfides with a specific number of carbon atoms (e.g., C. valkylthio), or with any number of carbon atoms within a given range |hobto, methylthio (Meb-), ethylthio, isopropylthio, and etc.).

The term "alkylamino" refers to straight or branched chain alkyl amines with a specific number of carbon atoms (eg, C. alkylamino) or with any number of carbon atoms within a given interval |hobto, methylamino, ethylamino, isopropylamino, t-butylamino, etc. .d.1.

The term "alkylsulfonyl" refers to a straight or branched chain of alkylsulfones with a certain number of 20 carbon atoms (eg, C. alkylsulfonyl) or with any number of carbon atoms within a given interval, (ie, . methylsulfonyl (Me5o»5-), ethylsulfonyl, isopropylsulfonyl, etc.

The term "alkylsulfinyl" refers to straight or branched chain alkylsulfoxides with a specific number of carbon atoms (eg, C.alkylsulfinyl), or with any number of carbon atoms within a given range (ie, methylsulfinyl (MesOO-), ethylsulfinyl, isopropylsulfinyl, and etc. 1. sch

The term "alkyloxycarbonyl" refers to a straight or branched ester of the carboxylic acid derivatives of this invention with a certain number of carbon atoms (for example, C. alkyloxycarbonyl) or with any number of i) carbon atoms within the given interval (i.e., methyloxycarbonyl (MeOsSoO-) ethyloxycarbonyl or butyloxycarbonyl. "Aryl" refers to a mono- or polycyclic aromatic ring system containing carbon, hydrogen, and ring atoms. Preferred aryls are monocyclic or bicyclic 6- to 10-membered aromatic ring systems.

Preferred aryls are phenyl and naphthyl. The most preferred aryl is phenyl. o "Heterocycle" and "heterocyclyl" refer to saturated or unsaturated non-aromatic rings or ring "g" systems containing at least one heteroatom selected from 0, 5 and M, additionally containing oxidized forms of sulfur, namely 5O and 5O5. Examples heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, o-morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane , 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine and the like. "Heteroaryl" refers to an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, 5, and M. Heteroaryls therefore include heteroaryls fused to other types of rings, such as aryls, cycloalkyls, and heterocycles, which are not aromatic. "

Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, nta» with oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, . benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, and? indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl and similar heterocycles

Go! heteroaryl groups include rings and ring systems containing 3-15 atoms, forming 1-3 rings. "Halogen" refers to fluorine, chlorine, bromine and iodine. Basically, chlorine and fluorine are predominant. Fluorine is most preferred when the halogens are substituted by an alkyl or alkoxy group (for example, SEzZO and SRZSN»O). The term "composition", for example, a pharmaceutical composition, covers a product containing an active ingredient(s) and an inert ingredient(s) forming a carrier, as well as any product obtained directly or indirectly by combination, complexation or the aggregation of any two or more ingredients,

Ge or dissociation of one or more ingredients, or other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of this invention include any composition formed by mixing a compound of this invention and a pharmaceutically acceptable carrier.

It should be understood that the terms "administration" and "purpose" of the compound mean the use of the compound of this invention or prodrugs of the compound of this invention for individual consumption. Structural compounds

F) formulas I may contain one or more asymmetric centers and, therefore, may exist in the form of racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures, and individual diastereomers. It is intended that the present invention encompasses all given isomeric forms of the compounds of structural formula I. Some of the compounds described herein contain olefinic double bonds and, unless otherwise specified, are intended to contain the geometric isomers EE and 7.

Some of the compounds described herein may exist as tautomers, such as ketoenol tautomers.

Individual tautomers, as well as their mixtures, are covered by compounds of the structural formula |.

Compounds of the structural formula | can be separated into individual diastereoisomers, for example, by fractional crystallization from an appropriate solvent, for example, methanol or ethyl acetate, or a mixture thereof, or by chiral chromatography using an optically active stationary (stationary) phase.

Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

Alternatively, any stereoisomer of the general structural formula !/ can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.

In another aspect of the present invention, the pharmaceutical composition specifically contains a compound according to the structural formula !| or a pharmaceutically acceptable salt, or their solvates, in combination with a 7/0 pharmaceutically acceptable carrier. The term "solvate" refers to a hydrate, alcoholate, or other crystallization solvate.

Another aspect of the present invention is directed to a method of treating hyperglycemia, diabetes, or insulin resistance in mammals in need of such treatment, which comprises administering to said patient an effective amount of a compound of structural formula I, or a pharmaceutically acceptable salt or 1/5 bolwatt thereof.

Another aspect of this invention describes a method of treating non-insulin-dependent diabetes mellitus (type 2) in mammals in need of such treatment, which includes administering to the patient an effective amount of an antidiabetic compound corresponding to structural formula I.

In the next aspect of the present invention, a method of treating obesity in mammals in need of such treatment is described, which includes administering to the specified patient a compound corresponding to the structural formula I in an amount effective for the treatment of obesity.

In another aspect of this invention, a method of treating metabolic syndrome in mammals in need of such treatment is described, which includes administering to the specified patient a compound corresponding to the structural formula I in an amount effective for the treatment of metabolic syndrome. high school

In a further aspect of the present invention, there is described a method of treating a disorder of lipid metabolism selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL in a mammalian patient in need of such treatment, comprising administering to said patient compounds corresponding to the structural formula I; in an amount effective for the treatment of the specified disorder of fat metabolism. Another aspect of the present invention describes a method of treating atherosclerosis in a mammalian patient in need of such treatment, which includes administering to said patient a compound according to structural formula I in an amount effective for the treatment of atherosclerosis. "Mr

Another aspect of this invention concerns the use of compounds of the structural formula | for the treatment of hyperglycemia, insulin resistance, type 2 diabetes, lipid disorders, obesity, atherosclerosis, and metabolic syndrome. co

In addition, an additional aspect of this invention provides the use of compounds of the structural formula | in the manufacture of medicaments for use in the treatment of a condition selected from the group consisting of hyperglycemia, insulin resistance, type 2 diabetes, lipid metabolism disorders, obesity, atherosclerosis and metabolic syndrome. "

The compounds of this invention can be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salt;" basic compounds covered by the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention, which are mainly obtained by the interaction of a free base with a suitable organic or inorganic acid. Representative salts of the main compounds of this invention include, but are not limited to: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edsylate, estolate, esylate, fumarate , gluceptate, gluconate, o glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, i5» isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, ammonium salt of M-methylglucamine, oleate, oxalate, pamoate (embonate), o palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,

He tannate, tartrate, theoclate, tosylate, triethyl iodide and valerate. In addition, when the compounds of the present invention bear an acidic moiety, pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases containing aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese , divalent manganese, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from organic nontoxic bases (F) include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins such as arginine, betaine, caffeine, choline, M,M-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, M-ethylmorpholine, M-ethylpiperidine, glucamine, glucosamine, vo histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

Also, in the case of the carboxylic acid (-COOH) or alcohol group represented in the compounds of this invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl alcohol derivatives, such as acetate or maleate, can be used. 65 Included are those esters and acyl groups known in the art to modify solubility or hydrolysis characteristics when used as sustained release formulations or prodrugs.

It is to be understood that references used herein to compounds of structural formula I are intended to also include pharmaceutically acceptable salts as well as salts which are not pharmaceutically acceptable when used as precursors of the free compounds or pharmaceutically acceptable salts thereof or in other processes of binding.

Solvates, and in particular hydrates of compounds of structural formula I are also included in the present invention.

The compounds described herein are selective inhibitors of the enzyme 118-GSD1. Thus, the present invention relates to the use of 118-GSDI inhibitors to inhibit the reductase activity of 11B-hydroxysteroid dehydrogenase, which is responsible for the conversion of cortisone into cortisol. Excess cortisol 70 is associated with a variety of disorders, including IBD, obesity, dyslipidemia, insulin resistance, and hypertension. Administration of the compounds of this invention reduces the level of cortisol and other 11B-hydroxysteroids in target tissues, thus reducing the effects of excessive amounts of cortisol and other 11B-hydroxysteroids. Inhibition of 118-HSDI can be used in the treatment and control of diseases caused by abnormally high levels of cortisol and other 11B-hydroxysteroids, such as INZCD, obesity, 7/5 Pipertension and dyslipidemia. Inhibition of 118-GSD activity in the brain, such as lowering cortisol levels, may also be useful in treating or reducing anxiety, depression, and cognitive impairment.

The present invention also includes the use of an 118-HSDI inhibitor for treating, controlling, ameliorating, preventing, delaying the onset of, or reducing the risk of the diseases and conditions described herein caused by excess or uncontrolled amounts of cortisol and/or other corticosteroids in a mammalian patient, particularly in humans, by introducing an effective amount of a compound of the structural formula I! or a pharmaceutically acceptable salt or solvate thereof. Inhibition of the enzyme 118-GSDI limits the conversion of cortisone, which is normally inert, to cortisol, which can cause or contribute to the symptoms of such diseases and conditions if present in excessive amounts.

INZCD and hypertension: sch

The compounds of the present invention are selective inhibitors of 118-HSDI1 compared to 118-HSDI2. While inhibition of 118-GSD1 is used to reduce cortisol levels and treat conditions related to it, i) inhibition of 118-GSD2 is associated with serious side effects such as hypertension.

Cortisol is an important and well-studied anti-inflammatory hormone that also acts as an antagonist of insulin action in the liver, such that insulin sensitivity is reduced, leading to reduced gluconeogenesis and increased hepatic glucose levels. Patients who already have developed glucose tolerance are more likely to develop type 2 diabetes in the presence of abnormally high cortisol levels. at

A high level of cortisol in tissues where there is a mineralocorticoid receptor often leads to hypertension. Inhibition of 118-GSD1 shifts the ratio of cortisol to cortisone in certain tissues in favor of cortisone. at

Administration of a therapeutically effective amount of an 118-HSDI inhibitor is effective in treating, controlling, and ameliorating the symptoms of INSDI, and regular administration of a therapeutically effective amount of an 118-HSDI inhibitor delays or prevents the occurrence of INSID, particularly in humans.

Obesity, metabolic syndrome, dyslipidemia:

Excessive cortisol levels are associated with obesity, probably due to increased hepatic gluconeogenesis. "

Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia with c, and other factors of the metabolic syndrome, such as high blood pressure, elevated LDL, and decreased LDL. |Mopiadze et al., YuOiaresfez, 2000, 49: 883-888.I. Thus, the introduction of effective ;" amount of 118-HSDI inhibitor is used in the treatment or control of obesity. Long-term treatment with an 118-HSDI1 inhibitor is also used to delay or prevent the onset of obesity, especially if the patient uses the 118-HSDI1 inhibitor in combination with a controlled diet and exercise.

Go! The compounds of this invention can be used in the treatment and prevention of conditions accompanying type 2 diabetes and insulin resistance, including metabolic syndrome or X syndrome, obesity, reactive hypoglycemia and diabetic dyslipidemia, due to the reduction of insulin resistance and the preservation of the plasma glucose level in normal concentrations.

Atherosclerosis: o As described above, inhibition of 118-GSDI1 activity and reduction of cortisol is useful in the treatment of or

Ge) control of hypertension. Because hypertension and dyslipidemia contribute to the development of atherosclerosis, administration of a therapeutically effective amount of the 118-GSDI inhibitor of the present invention may also be particularly useful in the treatment, control, delay, or prevention of atherosclerosis.

Other application options:

The following diseases, disorders and conditions can be treated, controlled, prevented or removed (F, caused by treatment with the compounds of this invention: ka (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, ( 5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, 65 (8) hypertriglyceridemia, (9) hypercholesterolemia,

(10) low level of LDL, (11) high level of LDL, (12) atherosclerosis and its consequences, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, 70 (18) nephropathy, (19) neuropathy, (20) metabolic syndrome, (21) hypertension and other disorders in which insulin resistance is a component.

The above diseases and conditions can be treated using compounds of structural formula I, or /5 The compounds can be administered to prevent or reduce the risk of developing the diseases and conditions described herein. Because competitive inhibition of 118-GSD2 may have dangerous side effects or may actually increase cortisol in a target tissue where cortisol reduction is desired, selective 118-GSD1 inhibitors with little inhibition of 118-GSD2 or its absence

Inhibitors of 118-GSDI of the structural formula I generally have an inhibition constant of IS 5o less than approximately 500NM, and preferably less than approximately 00NM. Basically, the value of IC 50 for the compound 118-GSD?2 compared to 118-GSD1 is at least two or more, and preferably about ten or more. Even more preferred are compounds with an IC50 value for 118-HSD2, as compared to 118-HSDI, of about 100 or greater. For example, the compounds of this invention ideally exhibit an inhibition constant of IS 50 when acting against 118-HSD2 greater than about 1000 nm, and preferably greater than 500 nm. with

Any suitable route of administration may be used to provide a mammal, particularly a human, with an effective dose of a compound of this invention. For example, oral, rectal, local, parenteral, i) ocular, inhalation, intranasal and the like. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compound of structural formula I is administered orally. Gee! The effective dosage of the active ingredient varies depending on the individual compound used, the mode of administration, the condition being treated, and the severity of the condition. Such a dosage can be easily established by one skilled in the art. "Mr

In the treatment or prevention of the diseases and conditions described herein for which the compounds of structural formula I are intended, satisfactory results have been obtained when the compounds of this invention are administered in a daily dose of from about 0.1 to about 100 milligrams per kilogram (mcg). of body weight, which is preferably administered in the form of a single daily dose or in the form of separate doses, approximately, from two to six times a day. The total daily dose thus ranges from about 0.1 mg to about 100 mg, preferably from about 1 mg to about 5 mg. In the case of a standard adult weighing 7Okg, the total daily dose will vary from approximately 7mg to approximately 35Omg. This dosage can be changed to ensure optimal therapeutic effect. in c Another aspect of this invention relates to a pharmaceutical composition that contains a compound of structural . formula I, or a pharmaceutically acceptable salt or its solvate, in combination with a pharmaceutically acceptable carrier. and?" These compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), transdermal, inhalational (nasal or buccal inhalation), or intranasal administration, although the most suitable route of administration in in any given case will depend on the nature and severity of the condition being treated and the active ingredient. They can be conveniently presented in the form of a standard dosage form and prepared using any of the methods well known in pharmacy. their Compound of the structural formula | can be combined with a pharmaceutically acceptable carrier, according to traditional methods of preparation of pharmaceutical preparations. Media can have a wide variety of forms. 1 For example, carriers for oral liquid compositions include, for example, water, glycols, oils, alcohols,

These are flavoring agents, preservatives, dyes and other components used in the production of oral liquid suspensions, elixirs and solutions. Carriers such as starch, sugar and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like are used in the preparation of solid dosage forms, for example, powders, hard and soft capsules and tablets. Solid preparations for oral use are preferable compared to liquid ones.

F) Oral solid dosage forms may also contain a binding agent such as gum tragacanth, cacao, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin. Capsules may also contain a liquid carrier such as a fatty oil.

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

Tablets can be coated using standard aqueous or non-aqueous techniques. A typical 65 percent active compound content in these compositions may, of course, vary from about 2 percent to about bOm/wt percent on a basis. Thus, tablets contain a compound of the structural formula or its salt or hydrates in an amount ranging from approximately 0.1 mg to approximately 1.5 g, preferably from approximately 1.0 mg to approximately 50 mg, and more preferably from about 1 Ω to about 10 Ω.

Liquid forms for oral use such as syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetener, methyl or propylarabens as preservatives, color and flavoring, such as cherry or orange flavor.

Parenteral forms usually exist as a solution or suspension, usually prepared in water and optionally contain a surfactant such as hydroxypropyl cellulose. Dispersions can be prepared on glycerin, liquid polyethylene glycols and their mixtures in oils. Usually the drugs are diluted 7/0. forms also contain preservatives.

Pharmaceutical dosed injection forms, including aqueous solutions and dispersions and powders for extemporaneous preparation of injection solutions or dispersions, are also sterile and must be liquid to such an extent that they can be easily filled with a syringe; they must be stable under production and storage conditions, and traditionally contain preservatives. The carrier thus includes a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerin, propylene glycol, and liquid polyethylene glycol), their respective mixtures, and oils.

Analyzes: measurement of inhibition constants:

Enzyme activity for the test compounds was evaluated with the help of Zsipijayop Rgohityu Avzzau (5RA). Briefly, the tritium-labeled cortisone substrate, the NADPH cofactor, and the titrated compound of structural formula I! incubated with 20. 118-GSDI1 at 372C for conversion to cortisol. After incubation with the preparation of protein A, coated ZRA granules pre-mixed with anti-cortisol monoclonal antibodies and a non-specific inhibitor of 118-HOSD, for example, 18B-glycerytic acid, were added to each well. The mixture was shaken at 1590 and then analyzed using a liquid scintillation counter suitable for 96 wells. The percentage of inhibition was calculated relative to the uninhibited control well, and ISvo curves were constructed. Ha

This analysis was applied in a similar way in relation to 118-GSD2, while tritium-labeled cortisol and o

NAD was used as substrate and cofactor, respectively. To start the analysis, add 4 µl of substrate (258 M ZN-cortisone 41.25 mM NADPH in 50 mM HERE5 buffer, pH 7.4) to certain wells in a 9b-well tablet.

The compounds were dissolved in T10MM DMSO followed by a 50-fold dilution with DMSO. The diluted material was then titrated 4 times, seven times. 1 µl of each titrated compound was then added in double amount to the F3 substrate. To initiate the interaction, 1 μl of 118-HSD1 microsomes from CHO-transfectants were added to each well at the appropriate concentration to obtain approximately 1095 transformations of the original material. For the final calculation of the percentage of inhibition, a series of wells representing the minimum and maximum in the assay were added: one set containing substrate without compound or enzyme (background) and another set containing substrate and enzyme without any compound (maximum signal). Tablets were briefly centrifuged at low speed in a centrifuge to combine the reagents, closed with an adhesive strip, carefully mixed, and incubated at 372 (ee) for 2 hours. After incubation, 45 μl of ZRA granules pre-suspended with anti-cortisol monoclonal antibodies and the compound of formula I were added to each well. The tablets were re-closed and gently shaken for more than 1.5 hours. at 152C. Data were collected from a liquid scintillation counter for a “tablet, such as Torsocpi. To control the inhibition of binding of anticortisol antibodies to cortisol, a substrate bound to 1.25 NM |IZ|IN-cortisol was added to certain standard wells. 1 µl of 200 µM compound was added to each of these wells together with 1 µl of buffer instead of enzyme. Any calculated inhibition was observed "" due to the compound interfering with the binding of cortisol to antibodies to ZRA granules. " Assays: Measurement of IP mimo inhibition:

In general terms, the test compound was administered orally to a mammal and waited for the time interval described, usually between 1 and 24 hours. Tritium-labeled cortisone was administered intravenously, followed by blood collection after a few minutes. Steroids were extracted from the separated serum and analyzed by HPLC. The relative levels of ZN-cortisone and its reduction product, ZN-cortisol, were determined for the compound and vehicle control groups. Based on these values, the absolute conversion and the percentage of inhibition were calculated. More specifically, the compounds were prepared for oral administration by dissolving them in a carrier (595 ml of 20 tihydroxypropyl-beta-cyclodextrin vol./vol. NHO, or equivalent) at the required concentration to obtain a dosage of, of course, 1Omg per kg. After an overnight fast, the solutions were administered to ISK mice (obtained from Spagiez and Kimeg) by oral gavage, 0.5 ml per dose per animal, with three animals per test group.

After the required time, usually after 4 or 1 hour, 0.2 ml was injected into the tail vein

ZMkM of N-cortisone in aRV5. The animal was put down and after two minutes was killed in a CO chamber. After death, the mouse was removed and blood was collected by cardiac puncture. The blood was left in a test tube for serum separation for at least

GF) on ЗОхв. at room temperature to achieve adequate coagulation. After the incubation period, blood was separated to obtain serum by centrifugation at 3000X, 42C for 10 minutes.

For the analysis of steroids in the serum, they were first extracted with an organic solvent. About 0.2 ml of serum was transferred to a clean microcentrifuge tube. To this amount was added 1.0 ml of ethyl acetate, followed by vigorous shaking for 60 minutes. Rapid centrifugation in a microcentrifuge results in the formation of a precipitate of aqueous whey proteins and a clarified organic supernatant. 0.85 ml of the upper organic phase was transferred to a clean microcentrifuge tube and dried. The dried sample was resuspended in 0.250 ml

DMSO containing a high concentration of cortisone and cortisol for analysis by HPLC.

A sample with a volume of 0.200 ml was introduced into a chromatographic column C-18 Meiaspet Ipegivzia, balanced with 3090 bo of methanol. A slow linear gradient to 5095 methanol resolved the target steroids; simultaneous monitoring by UV at 254 nm of cooled standards in resuspended solution acted as an internal standard.

The tritium signal was recorded by a radiochromatographic detector and analyzed using appropriate software. The percentage of conversion of ZN-cortisone to ZN-cortisol was calculated as the ratio of AOC for cortisol to the total AOC for cortisone and cortisol.

Preparation of compounds of this invention:

The compounds of this invention of the structural formula I! can be obtained according to the methods of the following schemes and examples, using the appropriate materials, and further presented by the following individual examples.

The compounds exemplified are not, however, the only class of compounds contemplated as compounds of the present invention. The following examples illustrate in detail the preparation of the compounds of this invention. Those skilled in the art will readily appreciate that known variations of the conditions and processes of the following preparative techniques may be used in the preparation of these compounds. The presented compounds are isolated mainly in neutral form, but the triazole fragment can be further converted into a pharmaceutically acceptable salt by dissolution in an organic solvent followed by the addition of an appropriate acid and subsequent evaporation, precipitation or 75 Crystallization. All temperatures are in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured using ion electrospray mass spectroscopy (EMSP).

The phrase "standard peptide synthesis conditions" refers to the coupling of a carboxylic acid to an amine using an acid-activating agent such as EOS, OSS and BOR in an inert solvent such as dichloromethane in the presence of a catalyst such as NOVT. The use of protective groups for amine and carbonyl

Acids are designed to facilitate the necessary interaction and minimize unwanted reactions, which is well known.

The conditions necessary for the removal of protecting groups can be found in standard books such as (Ogeepe, T., and

UUTsiv, R. b. M., Rgoiesiime Ogoshrz ip Ogdapis Zupipeviv, dopp UMieu 5 Bopv, Ips., Mem/ Hogk, MU, 19911. Срб2 and BOS are protective groups commonly used in organic synthesis, and the conditions for their removal are known to a specialist in this field. with

Abbreviations used in the description of the preparation of the compounds of this invention: o

F zo yu " o zv so " and Z s :" 5 so 2 i. sp s z o yu bo vv

TEREN M,M,M',M'-tetramethylformamide hexafluorophosphate

Schemes of reactions 1-5 illustrate the methods used in the synthesis of compounds of the structural formula I of this invention.

All substituents are as defined above unless otherwise noted.

Reaction scheme 1 illustrates a key stage in the synthesis of new compounds of structural formula I of this invention. As shown in reaction scheme 1, the secondary amide (1-1) (M-Me or M-EiY is preferred) can be methylated at 70 by heating with pure methyl triflate to give the imino ester (1-2). Alternatively, other methylating reagents can be used, such as methyl iodide or methyl sulfate without impurities or in a non-nucleophilic organic solvent. As shown in Scheme 1, bicyclo|2.2.2|octane-1-carboxylic acid (1-3) is converted into acylhydrazide (1-4). using a terene coupling reagent and hydrazine, in the presence of a tertiary amine base such as triethylamine. Alternatively, for this transformation, along with hydrazine, other binding reagents, which are usually used for the preparation of amides, can be used. Alternatively, bicyclo|2.2.2|octane-1-carbon ether can be heated with hydrazine to give acyl hydrazides (1-4).

The acylhydrazide (1-4) and iminoester (1-2) thus obtained can be heated together in an inert high-boiling organic solvent such as toluene in the presence of a tertiary amine base such as triethylamine to give bicyclo|2.2.2 |)octyltriazoles (1-5) of structural formula I.

Scheme 1 o to /Me sch no meoti x, o

Mon

H all where

I'm not -

Iii n 12 F yu

Z TEREN, hydrazik KI z d SON 7 a СсОоМмаМН. at

With d)

From 14 cm-M shi che - . - It was provided by Ge 1109C, Agreed. Alternatively, the reaction can be carried out in the reverse direction, as shown in reaction scheme 2. In this method, the secondary amide (2-1) is obtained from bicyclo(2.2.2)octane- 1-carboxylic acid, using the standard peptide synthesis reaction. This compound is methylated to form the iminoester (2-2) and subjected to

Ge) interaction with acylhydrazide, as shown in scheme 1, with the formation of bicyclo(|2.2.2)octyltriazoles (2-3) of the structural formula |.

F) name) 60 b5

Scheme 2 of the OMe

In soMmnA: 0 Meoti vi pe chechitinlgia.-l. IN

B In S

70 and "d2 21 n o m-M

V UM, V and mA ia)

EM, toluene, 1107C, General it's not me with

Reaction scheme C demonstrates an alternative approach to the compounds of the present invention of structural formula I, in which the key step is a palladium-catalyzed Suzuki synthesis reaction between bicyclo|2.2.2octylbromotriazole (o) (3-1) and arylboronic acid to give triazoles (3-2 ) of structural formula I. Tetrakis(triphenylphosphine)palladium(0) is preferably used as a catalyst in a DMF solvent with cesium carbonate, but other catalysts and conditions known to those skilled in the art may be used. о з Scheme 3 ой «

М-М "m o 1 z" e-70- ХМ vi A В(ОН» t-73-i a: SHE

RFRRNV, then in C8voCOz, DMF « 3-1 3-2 With c Reaction scheme 4 demonstrates yet another synthetic approach to obtaining compounds of the structural formula |. :z" Using this technique, 4-(bicyclo|2.2.2)octyl)oxadiazoles (4-1) are condensed with methylamine during dehydration, either in pure form in a melt with methylammonium trifluoroacetate, or in a buffered solution

Meon. These reactions are best carried out at elevated temperatures in a reactor under high pressure to prevent the loss of methylamine. o Scheme i -M with 50 sh-M «tFOo- M in 4 MemMn.a di and x. vd (Che) in? / ZU - in frames M o (o) 15 s. e n im - or i mMemna tFo Z o 41 2m memn.ImMeon -- ime) 15076 bo Reaction scheme 5 demonstrates yet another synthetic approach to obtaining compounds of the structural formula |.

Using this technique, bicyclo|2.2.2|octylcarboxamides (5-1) are converted to iminochlorides (5-2) using a reagent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride, optionally in the presence of DMF. The imino chloride (5-2) is condensed with an aryltetrazole at a high boiling point in an inert organic solvent such as toluene to give the triazole (5-3).

Scheme 5 toluene, DMF F Mne g 1

MM

Mom in T-K, and! hand

N. M

OZ school

Preparation of 12.2.2|bicyclooctyl intermediates: o

The methods used in the preparation of (2.2.2|bicyclooctyl intermediates for use in the preparation of the compounds of this invention are presented below.

Schemes for the preparation of intermediate compounds 1-4 describe the preparation of oxadiazoles, which are important intermediates in the synthesis of compounds of structural formula I. They can be converted into compounds of structural formula /Ф3 using, for example, the reactions described in reaction scheme 4.

Scheme for the preparation of intermediate compounds 1 demonstrates a preferred method for the preparation of oxadiazoles by dehydration of diacylhydrazides using a dehydrating reagent such as thionyl chloride. Alternatively, other dehydrating reagents such as phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride may be used. Diacylhydrazides can be prepared preferably from a hydrazide and an activated acid, such as acid chloride, in the presence of a tertiary amine base. Alternatively, reactions 09 of standard peptide synthesis can be used to obtain diacylhydrazide from hydrazide and carboxylic acid.

The scheme for the preparation of intermediate compounds 2 demonstrates a suitable reagent for the dehydration of diacylhydrazides to oxadiazoles, namely, 2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazole-3-inium chloride. This reagent in a non-polar solvent (preferably methylene chloride) together with a tertiary amine base (preferably triethylamine) affords the target oxadiazole intermediates most efficiently. t c The scheme for the preparation of intermediate compounds Z shows the preferred reagent for the one-reactor transformation (from h» hydrazide and carboxylic acid) and the dehydration of diacylhydrazides to oxadiazoles: " 2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazole-Z -inium chloride. This reagent in a nonpolar solvent (preferably methylene chloride) together with a tertiary amine base (preferably triethylamine) gives the necessary oxadiazole intermediates in the most efficient manner. (ee) The scheme for the preparation of intermediate compounds 4 demonstrates an efficient method for the preparation of oxadiazoles from secondary o amides and hydrazides. The secondary amide (preferably M-Me or M-EU)Y can be methylated by heating with neat methyl triflate to give the iminoether. Alternatively, other methylating reagents such as methyl iodide or methyl sulfate can be used without impurities or in a non-nucleophilic organic solvent. Heating with 20 of the iminoether formed in this way in a high-boiling inert organic solvent in the presence of hydrazide allows obtaining oxa diazoles as shown in the diagram. 3e) ime) 60 b5

Scheler scheme of intermediate compounds 1 and 2 b-lifluorobenzoyl chloride not Scheler

MiMNe EM, SNhS about E

Н 1. ОС, ru, СНСЯ, not SHASHKI, etc

M 2, toluene, boiling with N o E reverse cooling

M-M Yi shchi

X s / e-7-9--

E sch (5)

Scheme of preparation of intermediate compounds 2 and si o

OMe s 7 He memeA 9 yu ns that | Me - non pp pln y o "no a EM, SNoSI so

SI

М-М « и ве- 7-Х ) Z s o ;" "ОоМе со 45 Scheme of obtaining intermediate compounds Зо з SI s g e ОМе memeХ

Fo soMmyMN I. /lme s (son a 2000

EBM, DREAM about OME

MAM t U bo o 65

The scheme for obtaining intermediate compounds 4 is

No - OA me SNOTI, 85C mon lady medicine. lots of Pina

N

CE"

No xx

Mm'-Me "t inn Chechnya from Kr

AND

20 N EM, toluene m-M SE, sc 25 / x o ne o (22) 30 Intermediate scheme 5 demonstrates the preferred method for the synthesis of bicyclo|2.2.2|octane-1-carboxylic acid. i am

The scheme of obtaining intermediate compounds 5 « «c) zv 1. (СОС, СНСШ сой и « 40 2. M. ZMa shi id 2» rya

EVY5H, 4 (lymethylamino)pyridine with benzene, light («c) » 3. aq. МАОН, МеОН i-th Schemes for the preparation of intermediate compounds b and 7 demonstrate the preferred methods of obtaining iChe) bicyclo|2.2.2|octane-1-carboxylic acids with a heteroaryl group in the KU position, as represented by the structural formula I. Oxadiazoles in the КZ position can be obtained by condensation of bicyclo(|2.2.2)octane-1-carboxylic acid with amidoxime, as shown in intermediate scheme 6, a suitable reagent for the synthesis of SOY. Alternatively, other reagents suitable for dehydration or peptide synthesis reactions may be used. Intermediate scheme 7 illustrates a preferred method of synthesis of intermediates of compounds of structural formula I, which carry a thiazole group in the KZ-position. yuyu rupu ts 60 b5

Scheme of obtaining intermediate compounds b

Mmesss son i o rani ti prati ram M - ky at 70 2 boiling with reverse in and in MN "refrigerator, tolUusl with o SON 2

Z. aq. CON

MES

The scheme of obtaining intermediate compounds 7 1. RuVhor meoho--473--son ZAHY meso--1-sokn, 2. MN sia ' Z ! o (8) g zve or Lavesson's reagent (22) 79 a. water, KON Me SM U tn oyu . there is eOH, Manso", molecular filters " "c) 2. aq. MAON, Meon

E s d) and id;

3 - 3 Schemes for the production of intermediate compounds 8-14 show the preferred methods of production of intermediates :z» bicyclo|2.2.2|octane-1-carboxylic acids in the synthesis of compounds of the structural formula | with various alkyl or alkenyl or substituted alkyl groups in the KZ position. The key reaction is the Wittig reaction carried out with bicyclo|2.2.2)octane-1-carboxaldehyde, as shown in intermediate scheme 8. The double bond in

Ho) the product of this reaction can be hydrogenated to obtain an alkyl group of different length and character (which will become

With the B substituent in structural formula I), depending on the Wittig reagent, as shown in intermediate scheme 9. o Alternatively, the double bond can be used to introduce other functional groups, such as hydroxy or fluoro groups, as shown in intermediate scheme 10. Aldehyde itself can be used for step 50 to obtain a difluoromethyl group in the KZ position, as shown in intermediate scheme 11. Alkene, reaction product

Wittig, can undergo a variety of other transformations, such as cyclopropanation, as shown in intermediate Scheme 12. Alternatively, the Wittig reagent can contain a remote functional group, such as a ketal, as shown in intermediate Scheme 13. This functional group can undergo characteristic functional transformations groups after sequentially carrying out the reaction and Wittig and reduction, for example, hydrolysis

ketal to a ketone, as shown in intermediate scheme 13, or reduction of a ketal to an alcohol, as shown in intermediate scheme 14. Thus, compounds of structural formula I with a variety of different

VZ substitutes. Individual examples are presented to reflect the basic principles and are not intended to limit the volume of short-circuit substitutes. 60 b5

Scheme for obtaining intermediate compounds 8 8; reaction

MebS Wittig mmeb»o

But ---- Z

Ku n

Scheme for obtaining intermediate compounds 9 sh 1. No, 1095 ROS

Me o u Es no; tyna... year in 2. water KON, MEON, 20 V to

The scheme for obtaining intermediate compounds 10 sch 25 o mes 1. 8-VVM, pF ? -02- 2. Mao, SOYU F 30 on

IS

" 1. OA5T, SN.S, noya at 35 2. water. KOH, MeOH E so

The scheme of obtaining intermediate compounds | | « 40 - - E

I» meogo--47--, RAVT, SNs meozh-473--4 o E (ee) i-o Scheme for obtaining intermediate compounds 12 s»

Fo 1. Bo, SNA, 000 Mmeoyu-41 u lonoy-4U--

X 2. aq. KON, MEON (F) ko bo 65

The scheme for obtaining intermediate compounds 13 g o; and ! oxalyl chloride o o;

HU ov Memn", SNosh, and nin ni YAK

Si tF o a. ment sch | at

The scheme for the preparation of intermediate compounds 14 (22) from M E 1. TON, acetone, boiling (о с х о 9, with a reflux condenser "t tenet chno l znyliyin fr. o В SY 72. Mavn,, Meon o vi 8 ) 4 d) shi 7 Zh SN" with Vo

The main chemical transformations of the functional group used in the preparation of compounds of this invention are presented below in the preparation of individual compounds of this invention. o These functional group transformations in their diversity are generally well understood by specialists in this field. ((c) ch" p. 50 3e)

F) name) 60 b5 no

M-M no-7 -IO-E in NOMN" NS

M MabAs, Meon

SNU n. AMmOon -M not from RRiz, SS

M mesn

AND

СН с о (о) ю «И (ав) с « - с з со 45 (ав)

Sg» p 50 (Che)

F co

SM

M-M

M sna m-m OH ns U and alkyl iodide

M С8в»бО»з и sna dMSO

M O-alkyl

K- noru Di iy sn. sch o) m-M OMe usu, VViz, SN»SI; about | drinking

СН» ОМе « o d) che i z i СН on z

ZMe

M-M so not-7 There is | TISRVA shchi M SstSh 2 СН» и s 50 s c

M-Mm (O)vsn tvo IY o A with CH 7 r:i or? b5

M-M

Nis I and TSRVA

And Mi SNS

And ra gi

Snae mem t r

M noe-/ IY and their sh - " S Z cho

Mmm? ! 2095 NMO 7-5 i KB - o l sna sch

MN. at

MAM

МФ з СН ой "I

Tk o vo -)-Yi, sho; DIVM, Benzop co

IM B5! about her

SN. 4 - with mm

SN about

Ge) o - h no and In p-VShi, TF sa 70 ? M methyl benzoate with sn. m Go) o ns z o z M bo Sn. 65 -2A-

Ome

N mm; 1st at RSHCHON"

Wed: M ammonium formate

SNU

SEZ

OMa Z e m-m (S AH on M ss

I ptn ant inst latogenasnn i rr p SNU EM, tolusl/dMFA 1002s

SEZ sch o cm OMe he ZhD M-M F

Their

N and "

SN | "c) d) I 5 t shi s A-K9AH M-va Mabei;" y M rogo and DMF, 1500 v o M-m s 50 Z M 3e) V sh-M yav av ly t ko de

The following examples provide illustration of the invention and are not intended to limit the scope of this invention in any way.

Example 1 t x M-M

ХХ ХУ СНУ ОН 3-Methoxy-4-I(4-methyd-5-(4-pentylbicyclo|2.2.2|oct-1-yl)-4H-1,2,4-triazol-3-ylphenol (1 -E) !!! 15 Sosna Sm Mam Ye name and In - Z

Man DMA Evizh NO

Vpon n po SNz toluene toluvl Vp 1 Osn" 20 "A 1-6 12 4.

ІсСОСОСИ си шип латив винни ннининнв ни ннининнв ный и 25 с т снси СА-9 о boiling with толудл о return refrigerator "

Me - o i Ne RYS Lk a d) meOon Her 1 n 1 OVp « "E

Stage A: c) c To a solution of 4-benzyloxy-2-hydroxybenzonitrile (1-A, MUO 00/698411 "c) (7.95 g, 35.3 mmol) and iodomethane (5.4 mL, 87.2 mmol) stirred with a magnetic stirrer DMF (90 ml), cooled to -5 C, was added immediately to the entire amount of sodium hydride (6095 dispersion, 2.17 g, 54.2 mmol). The mixture was stirred for 30 minutes, warmed to room temperature and further stirred for 2 hours.

Most of the DMF was distilled off in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and a saturated solution of salt and av| dried (Ma950,4). The residue after removal of the solvent was triturated with hexane and chromatographed on silica gel with hexane-CHNOCl (2:3) to obtain 4-benzyloxy-2-methoxybenzonitrile (1-8). MS: t/2 240 (Mat); "H NMR (500 MHz, SOSIv): δ 7.47 (d, 1H, 9U-8.4Hz), 7.36-7.45 (m, 5H), 6.58 (dd, 1H, 9U-2, 3, 8.4 Hz), 6.57 1 (d, 1H, 9-2.9HuCs), 5.10 (s, 2H), 3.88 (s, ЗН) m.ch. s Stage B:

A vigorously stirred suspension of 4-benzyloxy-2-methoxybenzonitrile (1-8) (1.20 g, 5.0 mmol), sodium azide (732 mg, 11.3 mmol), and triethylamine hydrochloride (1.54 g, 11.3 mmol) in toluene (bml) was heated at 1102°C for 48 hours. The brown suspension was cooled, water (15 ml) was added, and the mixture was stirred continuously

REFERENCE The organic layer was separated and extracted with water (bml). The pH of the combined aqueous extracts was adjusted to (F; approximately 1) with concentrated HCl. The initially precipitated resin solidified at

GI mixing during ZOkhv.

The solid part was washed with water and dried Kk! by obtaining 5-I4-(benzyloxy)-2-methoxyphenyl|-2H-tetrazole (1-C). "H NMR (500MHz, SOSIv): 5 12.9 (width, 1H), 7.37 (d, 1H, 9-8.7Hz), 7.34-7.48 (m, 5H), 6 .78 (dd, 1H, 9-23, 8.7Gu), 6.70 (d, 1H, 9U-2.3Hz), 5.15 (s, 2H), 4.05 (s, ЗН) m. h

Stage C:

Oxalyl chloride (3.49 ml, dOmmol) was added dropwise to the solution

M-methyl-4-pentylbicyclo|2.2.2)octane-1-carboxamide (1-0) (952 mg, 4.0 mmol) in dry СНоСи» at room temperature. After the reduction of intense gas evolution, the solution was stirred at room temperature for 2 hours. CHC was carefully removed in vacuo at room temperature and then at 502C. The pure residue in the form of syrup was dissolved in toluene (ml) and 5-14-(benzyloxy)-2-methoxyphenyl)|-2H-tetrazole (1-C) (1.13g, 4.00mmol) was added. The mixture was heated at 1202 for 9 hours. The mixture was cooled and the precipitated solid was filtered, washed with toluene and dried to obtain the triazole hydrochloride salt. The salt was distributed between СНоСи» and 1095 aqueous K»СО»z. The aqueous phase was extracted twice with СНоСи». The combined extracts of СНоСІ» were dried (MaSO)) and evaporated in vacuo. The residue was chromatographed on silica gel with 596 Meon/cSnos» to obtain // 3-I4-(benzyloxy)-2-methoxyphenyl|-4-methyl-5-(4-pentylbicyclo|2.2.2|oct-1-yl)-4H -1,2,4-triazole (1-). MS: t/2 474 (Ma); "H NMR (500MHz, SOSIv): δ 7.33-7.47 (m, 6H), 6.65 (dd, 1H, 4-2.3, 8.5Hz), 6.60 (d, 1H, 9U-2.3HZ), 5.10 (s, 2H), 3.75 (s, ЗН), 3.48 (s, ЗН), 2.08 (m, 6Н), 1.51 (m, 6Н ), 1.00-1.35 (m, 8H), 0.89 70. (t, ZN, 9-7.2) m.h.

Stage 0:

A solution of 3-I4-(benzyloxy)-2-methoxyphenyl)|-4-methyl-5-(4-pentylbicyclo|2.2.2|-oct-1-yl)-4H-1,2,4-triazole (1- E) (272 mg, 0.572 mmol) in Meon (8 ml) was hydrogenated for 19 hours. with 1095 Ra/s catalyst (27mg) at room temperature and atmospheric pressure. The catalyst was filtered and washed with MeonN. The meon was removed at 75°C in vacuo to give 3-methoxy-4-(4-methyl-5-(4-pentylbicyclo(2.2.2|oct-1-yl)-4H-1,2,4-triazol-3-ylphenol) ( 1-). MS: t/2 384 (May1); "H NMR (500 MHz, DMSO-iv): 5 9.94 (s, 1H), 7.09 (d, 1H, 9-83), 6, 53 (d, 1H,

U-1.6Hutz), 6.46 (dd, 1H, 9-22, 8.2Gsh), 3.72 (s, ЗН), 3.40 (s, ЗН), 1.95 (m, 6Н) , 1.44 (m, 6H), 1.07-1.33 (m, 8H), 0.86 (t, ZN, 9-72).

Example 2

Y and oh sch z" ne- A? sleep on

With (22)

3-Chloro-4-(4-methyl-5-(4-pentylbicyclo|2.2.2|oct-1-yl)-4H-1,2,4-triazol-3-yl phenol (2-0) that) (SOS actions to her stump write (av)

Н СНноо со 2А 2-в

СНзМН; НС ч я - (ROM СНСІ s ;» " s (SOS МН ss -

Со 2-0 о 2-5 2» і і I slo 70 toluene, boiling with M s reverse H refrigerator Me і 2E

F) name) -th VVgz p---4 in 60

Ii Snosi 2-E Me 2-4

Step A: bB Oxalyl chloride (505 µl, 5.79 mmol) was added dropwise to a mixture of 4-pentylbicyclo(2.2.2)octane-1-carboxylic acid (2-A) in methylene chloride (1 Oml). The solution was stirred at room temperature for and then,

concentrated in a vacuum to obtain 4-pentylbicyclo|2.2.2|octane-1-carbonyl chloride (2-8). "H NMR (5O00 MHz,

SOSI"): 5 0.90 (t, ZN); 1.21 (m, 8H); 1.45 (m, 6H); 1.88 (m, 6H) m.h.

Stage B:

M,M-diisopropylethylamine (1.44 mL, 11.1 mmol) was added to a mixture of 4-pentylbicyclo|2.2.2)octane-1-carboxylic acid (2-A) (1.09 g, 445 mmol) and methylamine hydrochloride (1.5 g, 22.3 mmol) in methylene chloride (1 Oml) and the mixture was stirred at room temperature for 18 hours. After dilution with methylene chloride, the mixture was washed with water, brine, dried (Ma5O)) and concentrated in vacuo to give

M-methyl-4-pentylbicyclo(|2.2.2|octane-1-carboxamide (2-C). "H NMR (500 MHz, SOSI): δ 0.91 (t, ЗН); 1.22 (m, 70 8H); 1.43 (m, 6H); 1.77 (m, 6H); 2.82 (d, ЗН)m.h.

Stage C:

Oxalyl chloride (846 bml, 9.7 mmol) was added dropwise to the solution

M-methyl-4-pentylbicyclo|2.2.2|octane-1-carboxamide (2-C) (230 mg, 0.97 mmol) in methylene chloride (2.00 ml) and the mixture was stirred at room temperature for 4 hours. The solvent and excess reagent were removed in vacuo to give Momethyl-4-pentylbicyclo|2.2.2)octane-1-carboximidoyl chloride (2-0). Toluene (1.5 mL) was added followed by 5-(2-chloro-4-methoxyphenyl)-1H-tetrazole (2-E) (204 mg, 0.97 mmol) and the mixture was heated under reflux for 18 h. The reaction mixture was cooled to room temperature and the precipitate was filtered, washed with cold toluene, hexane, dissolved in methylene chloride, dried (Mazo y) and concentrated in vacuo Kk! by obtaining 3-(2-chloro-4-methoxyphenyl)-4-methyl-5-(4-pentylbicyclo|2.2.2|oct-1-yl)-4H-1,2,4-triazole (2-B). Mass spectrum: 402 (MaYa1); "H NMR (500MHz, SOSIV): 85 0.94 (t, ЗН), 1.27 (m, 8Н), 1.56 (m, 6Н), 2.13 (m, 6Н), 3.56 ( c, ZN), 3.89 (c, ZN), 6.95 (dd, 1H), 7.07 (d, 1H), 7.43 (d, 1H).

Stage 0:

Boron tribromide (135 μl, 1.4 mmol) was added dropwise to a solution with 3-(2-chloro-4-methoxyphenyl)-4-methyl-5-(4-pentylbicyclo|2.2.2)oct-1-yl)-4H- 1,2,4-triazole (2-E) (287 g, (3 0.714 mmol) in methylene chloride (ml) at 02C. The mixture was stirred at room temperature for 2.5 hours.

The solution was washed with water, 10906 MnSO 2 , dried (M950,) and concentrated in vacuo and the residue was purified by column chromatography (silica gel, 590 MeonN/methylene chloride) Kk) to give F

C-chloro-4-(4-methyl-5-(4-pentylbicyclo|2.2.2)oct-1-yl)-4H-1,2,4-triazol-3-yl)phenol (2-5). Mass spectrum: 388 (MaYa1); "H NMR (500MHz, SOSIV): 5 0.93 (t, ЗН), 1.26 (m, 8Н), 1.56 (m, 6Н), 2.13 (m, 6Н), 3.58 ( s, ZN), 6.69. M (dd, 1H), 6.92 (d, 1H), 7.09 (d, 1H) m.h. "II

Example C

SE" to her

M d)

M- ns "

M - s On I:z» st, 5-(4-71-Methyl-5-(2-trifluoromethyl)phenyl|-1-H-1,2,4-triazol-3-ylIbicyclo-(2.2.2oct -1-yl)pentan-2-ol (3-Y) (ee) («c) sh» c 50 3e)

F) name) 60 b5

8

Not / M 7 con --- - - - 0 0 -І2----2--

RO/S Meon/nyo 36

SI t o SE" ge ve si o o sh-

ОН schu, still, 0 to y nn --zEe-O53- Ф 3-9 ze oyu "I 97 SE" 5 arc r-t5on so poten tent t poten nnnnntttetyu tini x acetone/water

М - М boiling with a reverse « нлникМ - with 40 kJe cold;» (ee) (av) i» sl 50 (Che) (F) ko bo b5

Ge; SE" oh mavn, asked x M metanop

KG Fr

СНзМнь 1509 S s o on Sta kh F 3o M y u ch y mM o z g)

Stage A: (2-(2-Methyl-1,3-dioxolan-2-yl)ethyltriphenyl)phosphonium bromide (3-A, Zupipevziv: 532 (1986)) (5.99g, « 12.7mmol) was stirred in dry THF (200ml). Potassium bis(trimethylsilyl)amide (20.4 ml, 2 M solution in toluene, 10.2 mmol) was added. The reaction mixture was left to stir for 30 minutes. Then the reaction mixture was cooled to -782C. Using a cannula, methyl-4-formylbicyclo(|2.2.2)octane-1-carboxylate was added at -7182C. The reaction mixture was left to warm to room temperature overnight. The volume was reduced by evaporation of THF under vacuum. 100 ml of water was added. 100 ml of diethyl ether was layered on the mixture. The ether was extracted and dried (Mo5O,). Product (methyl-4-I(1E)-3-(2-methyl-1,3-dioxolan-2-yl)prop-1-enyl|bicyclo|2.2.2)octane-1-carboxylate (3-8) ) was purified by flash chromatography on silica gel with a mixture of 10/90 ethyl acetate-hexane. o Stage B: (Methyl-4-K1E)-3-(2-methyl-1,3-dioxolan-2-yl)prop-1-enyl|bicycloi|2.2.21-ve octane-1-carboxylate (3- B) (1.1 g) was stirred in ethanol (75 ml). 1095 Ra per sl 20 coal (150 mg) was added at the tip of the spatula. Hydrogen was injected from a cylinder and the mixture was stirred in a hydrogen atmosphere for 10 minutes. The palladium on charcoal was filtered and the ethanol was removed in vacuo to give 4-I3-(2-methyl-1,3-dioxolane-2-

Me, 43 yl)propyl|bicyclo|2.2.2)octane-1-carboxylate (3-C).

Stage C:

Methyl 4-I3-(2-methyl-1,3-dioxolan-2-yl)propyl|bicyclo|2.2.2|octane-1-carboxylate (3-C) (1.0 g, 3.3 mmol) was stirred in a solution of 90956 methanol and 1095 water (5 Oml). An excess of potassium hydroxide (2.0 g) was added. The mixture was refluxed overnight. 1 N hydrochloric acid (100 ml) was added to the cooled mixture, and then it was washed twice with ethyl acetate (100 ml). The combined organic layers were dried (MaSO). Ethyl acetate was removed in vacuo to give pure 4-N3-(2-methyl-1,3-dioxolan-2-yl)propyl|bicyclo|2.2.2)octane-1-carboxylic acid (3-0). 60 Stage Y: 4-I3-2-Methyl-1,3-dioxolan-2-yl)propyl|bicyclo(2.2.2)octane-1-carboxylic acid (3-0) (0.200g, 0.708mmol) was combined with 2-(trifluoromethyl)benzoic acid hydrazide (3-E) (0.173g, 0.847mmol) and azeotropically distilled twice from toluene. Then, the mixture was stirred in dry methylene chloride (1 Oml). 2-Chloro-1,3-dimethylimidazolinium chloride (3-PE) (0.718g, 4.25mmol) was added, followed by the addition of 1.184ml of triethylamine. 65 The reaction mixture was left to stir for 2 hours. The reaction mixture was diluted with methylene chloride and washed with water. The obtained oxadiazole,

2-(A4-Y3-(-2-methyl-1,3-dioxolan-2-yl)propyl|bicyclo|2.2.2oct-1-yl)-5-(2-(trifluoromethyl)phenyl|)-1, 3,4-oxadiazole (3-0) was purified by flash chromatography on silica gel with a mixture of 50/50 ethyl acetate-hexane.

Stage E: 2-(A4-Y3--2-Methyl-1,3-dioxolan-2-yl)propyl|bicyclo|2.2.2oct-1-yl)-5-(2-trifluoromethyl)phenyl/d- 1,3,4-oxadiazole (3-5) (0.158 g) was mixed in a mixture of 9095 acetone/1095 water (200 ml). p-toluenesulfonic acid (1mg) was added to the solution. The reaction mixture was refluxed for one hour.

The volume was reduced by vacuum evaporation of acetone. Ethyl acetate (25 ml) and saturated sodium bicarbonate solution (25 ml) were then layered on the mixture. The ethyl acetate layer was extracted and dried (MaSO). The solvent /o was removed under vacuum Kk! by obtaining pure 5-(4-15-(2-(trifluoromethyl)phenyl)|-1,3,4-oxadiazol-2-yl)bicyclo|2.2.2oct-1-yl)pentan-2-one(3-H ).

KE stage: 5-(4-45-12-"Trifluoromethyl)phenyld|-1,3,4-oxadiazol-2-yl)bicyclo|2.2.2)oct-1-yl)pentan-2-one (3- H) (0.072g) was stirred in methanol (2ml) at 02. Sodium borohydride (20mg) was added. The reaction mixture was left for 7/5 stirring at room temperature. The mixture was then layered with ethyl acetate (15 ml) and water (15 ml). The ethyl acetate layer was extracted and dried (Ma950;). The solvent was removed in vacuo to give pure 5-(4-15-(2-(trifluoromethyl)phenyl/|-1,3,4-oxadiazol-2-yl)y bicyclo|2.2.2)oct-1-yl)pentane -2-olu (3-1).

Stage 0: 5-(4-45-I2-("Trifluoromethyl)phenyld|-1,3,4-oxadiazol-2-yl)bicyclo|2.2.2)oct-1-yl)pentan-2-ol (3 -I) (5Omg)

It was placed in a sealed flask in a solution of 2M methylamine (2.5 ml). TFO salt was added with a small measuring spoon and the flask was hermetically closed. The sealed flask was heated to 1502 for 3 days. The reaction mixture was diluted with ethyl acetate (15 ml), washed with water (15 ml) and dried (Mo950O/). Ethyl acetate was removed in vacuo. Product, 5-(4-71-methyl-5-(2-(trifluoromethyl)phenyl|-1-H-1,2,4-triazol-3-yl)bicyclo|2.2.2)oct-1-yl) pentan-2-ol (3-)), Ha was purified by preparative reversed-phase HPLC on a C-18 column with silica gel using a gradient o acetonitrile-water buffered with 0.195 trifluoroacetic acid. The effluent containing the pure triazole was made more basic with 1095 MansSo', evaporated in vacuo to remove most of the acetonitrile, and extracted with methylene chloride. The organic extract was dried (Mo2O) and evaporated, and the residue was dried in vacuo to give the desired compound. MS (ECI 7)-422.5 (M--1); "H NMR (5O00MHz, SOSIv): δ 1.21 (2Н, m), ФЙ 1.23 (ЗН, d, 9У-6.5Hz), 1.29 (2Н, m), 1.57 (6Н, m), 2.13 (6Н, m), 3.47 (ЗН, с), 3.85 (IN, m), 7.51 (1Н, m), ю 7.70 (2Н, m), 7 .85 (1N, m) m.-h.

Example 4 "I

E. o

CE d)

Mm

Ch x Yi shi s Ko. M

And" | On (ee) ("c) sh" p 50 3e)

F) name) 60 b5

It contains carbonyldiimidazole; / o t Pure shk What

A A Sean 4-8 y con gz meon/nyo n -- y t now

M 4-0 M

Sg! / fo

M on mM M-"M Ez mukh s -3 o ge) 4E zo Memnz'tFO F

IS) gm memno/meon M M gas « 15096 OZ

M-o ii o | d)

Stage A: "

To a suspension of 4-(methoxycarbonyl)bicyclo(2.2.2)octane-1-carboxylic acid (4-A) (0.906g, 4.27mmol) in dichloromethane (20ml) was added 1,1'-carbonyldiimidazole (1.04g, b6 .41 mmol). The reaction mixture turned into a clear solution with constant gas release. After stirring the mixture at room temperature for 1 hour. 4-fluorobenzamidoxime (1.98 g, 12.8 mmol) was added. Stirring was continued throughout the night. Then the mixture was concentrated and the residue was refluxed in toluene for 1 h. The mixture was concentrated and the residue was purified by column chromatography using hexane/ethyl acetate (7/1) as an eluent to give methyl-4-I3-(4-fluorophenyl) -1,2,4-oxadiazol-5-yl|bicyclo(|2.2.2|octane-1-carboxylate (4-8) in the form of a white solid. IN NMR (50 MHz, SOCI5): 5 1, 96-1.99 (m, 6H), 2.08-2.14 (m, 6H), 3.71 (s, o ZN), 7.16-7.20 (m, 2H), 8.08 -8.10 (m, 2H) m.h., ESI-MS: t/2 (MAN) 349.2.

Step B: The ether (4-8) (1.01g, 3.0bmmol) was treated with KOH (0.52g, 9.18mmol) in methanol/water (95/5, 20ml). After sl 50 of heating it at 602C for 12 hours. the reaction mixture was concentrated, diluted with water, extracted twice with ethyl acetate. An aqueous solution of other NS was added to the aqueous layer! and a white solid precipitate fell out. Precipitate

Me; 4-I3-(4-fluorophenyl)-i,2,4-oxadiazol-5-yl|bicyclo|2.2.2)octane-1-carboxylic acid (4-C) was collected and further dried by co-distillation with toluene. ESI-MS: n/2 (MAN) 317.2.

Stage C:

A mixture of (4-C) acid (138.9 mg, 0.439 mmol) and 2-(trifluoromethyl)benzoic acid hydrazide (4-0) (89.7 mg,

GF! 0.439 mmol) was first distilled three times with toluene. Dichloromethane (7ml) was added to the mixture as a solvent. 2-chloro-1,3-dimethylimidazolinium chloride (74 mg, 4.3 mmol) was added to the resulting suspension, followed by the addition of triethylamine (1.2 ml, 8.78 mmol). The mixture was left to stir at room temperature in a nitrogen atmosphere for 48 hours. to confirm the completion of the interaction. Then the reaction mixture was diluted with 60% dichloromethane, washed with water, 1N HCl, a saturated aqueous solution of sodium bicarbonate, and finally, a saturated salt solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.

The residue was purified by column chromatography using hexane/ethyl acetate (3/1) as an eluent to give 3-(4-fluorophenyl)-5-(4-15-(2-(trifluoromethyl)phenyl)-1,3,4-oxadiazole -2-yl)bicyclo|2.2.2|oct-1-yl)-1,2,4-oxadiazole (4-E) as a white solid. "H NMR (500MHz, SOSIA): δ 2.25 (s, 12H), 7.21 (t, 9-8.7Hz, 2H),

7.74-7.76 (m, 2H), 7.91 (m, 1H), 8.11-8.15 (m, ZN) m.h., ESI-MS: t/2 (MAN) 485 ,2.

Stage 0:

A mixture of the above-mentioned 1,2,4-oxadiazole (4-E) (115.2 mg, 0.238 mmol) and methylamine and trifluoroacetate salts

ACIDS (1.73g, 11.9mmol) in a 2M solution of methylamine in methanol (4ml) were heated at 15092 in a sealed test tube for 48h. Then the mixture was concentrated and the residue was transferred to dichloromethane, washed with a saturated solution of sodium bicarbonate. The organic phase was concentrated and the residue was purified using reversed-phase HPLC with TFO-buffered acetonitrile/water (40-80905) as eluent. Fractions containing the product were combined, neutralized with a saturated aqueous sodium bicarbonate solution and lyophilized from a 7/0 acetonitrile/water mixture to give 3-(4-fluorophenyl)-5-(4-14-methyl-5-(2- (trifluoromethyl)phenyl|-4H-1,2,4-triazol-3-yl)-bicyclo|2.2.2)oct-1-yl)-1,2,4-0xadiazole (4-E). "H NMR (SOSIv): 5 2.25-2.35 (m, 12Н), 3.53 (s, ЗН), 7.21 (t, 9-8.7Hz, 2Н), 7.54 (m , 1H), 7.73 (m, 2H), 7.88 (m, 1H), 8.13 (m, 2H), ESI-MS: t/2 (M.H) 498.2.

Example 5 and SEZ and one

Sn on c 4-(D-Methyl-5-(4-phenylbicyclo|2.2.2|oct-1-yl)-4H-1,2,4-triazol-3-ylI-3--trifluoromethyl)phenol (5 -E) (5)

MN" Fr. AN o yu o Stz (u2Mm(СсОоСс « 4 Y. I pniv van y av) on (r) EVM (ge)

А Ов СНС» « ю 5-В 2 с -си. with g" o shk.

M rol (ee) («c) и E OV BM with snsi,

Me) EU 5-0

F) name) 60 b5

ОВп о Мемн- СгзЗЗСООН pe ше гм МеМнНо/МеОН - With and! 0 Me me BOS at 1095 Ra/С in the atmosphere of No

M yd h EUAs/Meon'

IOM Oz 5th school

HE about her

Yi Yu xx "

M-MoO0btav "c) d) 5

Preparation of 4-phenylbicyclo(|2.2.2)octane-1-carboxylic acid (5-A). Literary source: |Spartap, M. V., Oipeezmagap, Z., and Toupe, K. .), 3). Oh Speth, 35: - . 20 BOSH 5., and K. 9., U. Ogu. Sp 35: 917-923 (1970) with c Stage A:

To a solution stirred on a magnetic stirrer of 4-phenylbicyclo|2.2.2|octane-1-carboxylic acid (5-A) :z" (700 mg, 0.3 mmol) in methylene chloride (iml) at room temperature was added 2M oxalyl chloride in methylene chloride (0.61 ml, 1.22 mmol). Two drops of catalytic DMF were added to catalyze the reaction. The reaction mixture was stirred for 30 min, and the solvent and reagent were removed in vacuo. Methylene chloride (ml) was added directly to the residue, followed by the addition of 4-(benzyloxy)-2-"-trifluoromethyl)benzoic acid hydrazide (5-8) (141mg, 00.4bmmol) and triethylamine (0.07ml, 0.4bmmol) The reaction mixture was stirred at room temperature overnight to obtain intermediate 5-C, i. carbohydrazide, which was not isolated. 20 To the crude product was then added (5-C) 2-chloro-1,3-dimethylimidazolinium chloride (257 mg, 1.52 mmol), triethylamine (0.42 mL, C, 04 mmol) and methylene chloride (2 mL ).The reaction mixture was stirred at room temperature

Ge) temperature for 4 hours. Then the reaction mixture was diluted with methylene chloride (30ml) and washed with water (30ml) twice and saturated salt solution (30ml) once. The combined aqueous layers were extracted with methylene chloride (25 ml) once. The combined organic layers were dried (Mo 5 O)) and the solvent was removed in vacuo. The residue was chromatographed on silica gel with 1095 ethyl acetate in hexane as eluent to give 2-I4-(benzyloxy)-2-(trifluoromethyl)phenyl)|-5-(4-phenylbicyclo|2.2.2|-oct-1-yl)- 1,3,4-oxadiazole (5-0). MS: t/: (F) 505 (M--1). co Stage B:

Methylamine trifluoroacetate salt (38Omg, 2.61 mmol) and 2-I4-(benzyloxy)-2-(trifluoromethyl)phenyl)|-5-(4-phenylbicyclo|2.2.2|oct-1-yl)-1,3 ,4-oxadiazole (5-0) was suspended in a 2M solution of methylamine in methanol (1.3ml, 2.61mmol) and heated at 150922 overnight.

After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (25ml) and saturated aqueous sodium bicarbonate solution (30ml). The layers were separated and the aqueous layer was extracted twice with ethyl acetate (25 mL). The combined organic layers were washed with saturated salt solution, dried (Mo5O)), and the solvent was removed. in a vacuum The residue was dissolved in methanol (dml) and purified by reverse phase chromatography using a gradient elution from 1095 acetonitrile (0.196 TFO)/water (0.195 TFO) to 10090 acetonitrile (0.195 TFO) over 100 min. (2O0ml/min.). Fractions containing the product were distributed between a saturated aqueous solution of sodium bicarbonate (25ml) and methylene chloride (1Bml). The layers were separated and the aqueous layer was extracted with methylene chloride (15 mL) three times, dried (MgSO), and the solvent was removed in vacuo to give 3-I4-(benzyloxy)-2-"-trifluoromethyl)phenyl/|-4-methyl-5- (4-phenylbicyclo|2.2.2)oct-1-yl)-4H-1,2,4-triazole (5-E).

MS: t/:2 518 (M.n1).

Stage C: 3-I4-(Benzyloxy)-2-trifluoromethyl)phenyl|-4-methyl-5-(4-phenylbicycloyl|2.2.2|-oct-1-yl)-4H-1,2,4- triazole 70. F5-E) (27 mg, 0.05 mmol) was dissolved in ethyl acetate/methanol (1:11, 4 ml), to which 1090 palladium on carbon (4 mg) was added. Then the reaction mixture was placed in a hydrogen atmosphere and stirred for 10 minutes. at room temperature and pressure. After appropriate removal of the hydrogen atmosphere, the palladium was filtered through a filter and washed with methanol (4 Oml). The filtrate was collected and the solvent was removed in vacuo to give 4-(4-methyl-5-(4-phenylbicyclo|2.2.2)oct-1-yl)-4H-1,2,4-triazol-3-yl|-3 --trifluoromethyl)phenol (5-B). MS: t/72 428 75. (May); "H NMR (BO0MHZc, SOSIv): 5 1.92 (6Н, m), 2.11 (ВН, m), 3.41 (ЗН, с), 7.17 (2Н, m), 7.24 ( 1Н, m), 7.31 (2Н, m), 7.38 (ЗН, m)m-h.

Example 6 I Fo gas

H-- - a- sch

M

(8) (22) 3-4--2--Ethylsulfonyl)ethyl|bicyclo|2.2.2oct-1-yl)-4-methyl-5-I(2--trifluoromethyl)phenyl|-4H-1,2 ,4-triazole (6-6) y " "c) d) " - c ;" (ee) ((c) sh" p. 50 3e)

F) ime) 60 b5 ohm rme

GENEALOGY" Om and

MaOMe, meon v-2 8-1 10 pn nni, PO nn pan furor 15 5 O 002. Memn, 6-3, A - Me 20 64, nen

MNMe 1. (SOS) school 2 25

Otsi Z ' o 65 | In Yaku t 30 St

From " "c) 35 o'clock d) o kerosene

M-« | t - СНз з» 6-6

Stage A: so 15 Diethyl(ethylsulfonmethane)phosphonate (1.12g, 4.bmmol) |Roroii, I. S. et al., U. Ogd. Spet., 34: 1128-30 (1969)) and 4-carbomethoxybicyclo|2.2.2)octane-1-carboxaldehyde (6-1) (0.82g, 4.2mmol) |(Adsosk, MU., Kok, O .V., ("in U. Oga. Spet., 50: 1079-1087 (1985)) was dissolved in 1 ml of absolute methanol. The mixture was placed in an atmosphere of nitrogen, cooled in an ice bath and treated with a 0.5M solution of sodium methoxide in methanol (8.8 mL, 4.4 mmol). The reaction mixture was heated under reflux for 4 h, then cooled to 20 °C at room temperature, concentrated under reduced pressure, then treated with 2 mL of water and allowed to settle in the refrigerator overnight. The mixture was filtered and the solid was washed with a small amount of cold 11 MeOH/water. The resulting white precipitate was collected and dried in vacuo to give unsaturated sulfone 6-2. MS (ECI"): t/2 287 (Mt).

Stage B:

Sulfone 6-2 (88Omg, C3.0vmmol) was dissolved in a mixture of ethyl acetate/methanol 1:2 (30ml), placed in an atmosphere (F) of nitrogen, then treated with 1095 Ra/C (800mg). The reaction mixture was placed in a hydrogen atmosphere and vigorously stirred for 09 min. The resulting solution was filtered through celite, washed with methanol and ethyl acetate, and evaporated to give 4-(2-(-ethylsulfonyl)ethyl-bicyclo(|2.2.2|)octane-1-carboxylate (6-3) as a white solid. 60th

Stage C:

Ester 6-3 (880 mg, Zmmol) was dissolved in a solution of 1095 water/methanol (100 ml) and treated with 1 g of potassium hydroxide.

The reaction mixture was heated at 602 for 1 hour, then at 459C overnight. The mixture was concentrated in a vacuum, then the pH was adjusted to 2 using 1M HCl and extracted with three portions of de / Methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to obtain 4-(2-(-ethylsulfonyl)ethylibicyclo-(2.2.2)octane-1-carboxylic acid (6-4).

Stage 0:

Carboxylic acid 6-4 (810mg, 2.9b6mmol) was dissolved in 12ml of anhydrous methylene chloride in a nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 4.4ml, 8.8mmol) and sequentially with 5 drops of DMF. The reaction mixture was stirred at room temperature in a nitrogen atmosphere for 9 minutes, then evaporated and placed in a vacuum for 20 minutes. Acid chloride was dissolved in anhydrous methylene chloride (12 mL), cooled in an ice bath, and then treated dropwise with methylamine solution (2 M in THF, 8.9 U mL, 17.8 mmol). After the addition of the amine was complete, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 30 min. The mixture was diluted with 200 ml of methylene chloride and washed with aqueous In 7/0. NS, a saturated aqueous solution of sodium bicarbonate and a saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to chromatography on silica gel, eluting with a gradient from (0) to 3.590 methanol in methylene chloride to obtain 4-(2--ethylsulfonyl)ethyl|-Momethylbicyclo|(2.2.21-octane-1-carboxamide 6-5) in the form of a white powder. MS (ESI 7): t/2 288 (M.-1).

Stage E:

Methylamide 6-5 (220 mg, 0.77 mmol) was dissolved in anhydrous methylene chloride (2 mL) and treated with oxalyl chloride (2 M in methylene chloride, 0.77 mL, 1.54 mmol) and DMF (2 drops). The reaction mixture was stirred at room temperature for 1 hour, then the solvent was removed by evaporation under reduced pressure.

The residue was re-dissolved in anhydrous toluene (2 ml) and treated with 5-(2-«(trifluoromethyl)phenyl|-1H-tetrazole (214 mg, Tmmol). The mixture was heated under reflux for 18 hours. The reaction mixture was cooled to room temperature and the cream-colored precipitate was filtered and washed to give 100 mg of crude product, as the HCl salt. The mixture was taken up in methylene chloride/1N HCl and the aqueous layer was washed with two additional portions of methylene chloride. The organic layers were combined and evaporated, and the residue was flash chromatographed on silica gel. The gradient was eluted in the interval from 0 to 595 su methanol/methylene chloride. The corresponding fractions were combined and evaporated to obtain 3-4-(2--ethylsulfonyl)ethyl|bicyclo-I(2.2.2)oct-1-yl.)-4-methyl -5-(2-(trifluoromethyl)phenyl|-4H-1,2,4-triazole and9) (6-6) in the form of a white powder. MC (ECI): 456.2 (M--1); "H NMR (500MHz, SOSIv): 5 1.46 (ZH, t, 9U-7.3Hz), 1.63 (6Н, m), 1.78 (2Н, m), 2.19 (6Н, m ), 2.96 (2H, m), 3.05 (2H, sq., 9U-7.2Hz), 3.50 (ZH, s), 7.56 (W, m), 7.72 (2H , m), 7.87 (1Н, m)m-h (22)

Example 7

E as -

NS MAM 2 and Y M co and others

I

7 СН 7 с З ; » 3-4-(3--Ethylsulfonyl)propyl|bicyclo|2.2.2|oct-1-yl)-4-methyl-5-12-(trifluoromethyl)phenyl)|-4H-1,2,4-triazole (7-5) (ee) («c) sh» p. 50 3e)

Ф) име) 60 b5 и ОМе n ОМе ВпОЛИ 7 РРЯАВг О о и о о 0 0 О------ vp

KNMOB, pF, 7-8 7A benzoic acid

Ome

Nh, 1095 ROS 3-9 VN pF ------ o niv)

her

OMe Messiah OMe sch o Sn o o no pyridine M5O to GE F yu

ОМе h

EVMa pSRVA at 5 -----ya -3 o'clock with DMA / S Sho di sNs, so 459

SAME « - with z

Ge) about them with 50

Gee)

F) t bo b5 o OM water This is on 00 d) water. BUT! (8) "in 7 N

Toxalyl chloride l-o MNMe

R ch- / 2u MemnNh o 7» 1) oxalyl chloride o M shch t- pliialaolaaaaaalai t anna ech olinttiny.- lian

NS, 52 YM school 5; 2) M. and Z

IOM sv M i Z h F zo M Not those 7-4 yu " "c)

Step A: (Benzyloxycarbonylmethyl)utriphenylphosphonium bromide (4.6bg, 9.4mmol) was azeotroped twice from toluene, and then suspended in 30ml dry THF. Potassium hexamethyldisilazide (0.5M in toluene, 16.vml, 8.4mmol) was added dropwise at room temperature and the yellow solution was left to stir for an hour, after which time it became milky white. A solution of 4-carbomethoxy-bicyclo(|2.2.2)octane-1-carboxaldehyde (7-АХ) (0.50g, 2.55mmol) was prepared | Aisosk, MU., Kok, 5. V., y). Oh Spet., 50: 1079-1087 (1985)| and benzoic acid Che) with (0.015 g, 0.1 mmol) in 2 ml of dry THF and added dropwise with a syringe at room temperature. The mixture was heated. to 902C and left for stirring at the temperature of phlegm formation, after that the mixture was diluted with 200 ml of ethyl acetate and successively washed with portions of 5 ml of InHC (twice), a saturated aqueous solution of sodium bicarbonate and a saturated salt solution. The organic layer was dried using magnesium sulfate, and The solvent was removed under reduced pressure. bicyclo|2.2.2)octane-1-carboxylate (7-8) in the form of a colorless oil. "H NMR (500 MHz, SOSIa): 5 7.4 (BN, m), 6.94 (1IN, d, 9- 17Hz), 5.77 (1H, d, 9-17Hz), 5.21 t. (2H, s), 3.69 (ZH, s), 1.86 (6H, m), 1.63 (6H , m) m.h. sl 50 Stage B:

The 7-B diester (0.625 g, 1.90 mmol) was dissolved in a 1:11 ethyl acetate/methanol (30 ml) mixture, placed in a nitrogen atmosphere, then treated with 1095 Ra/C (500 mg) and 0.1 ml of acetic acid. The reaction mixture was placed in a hydrogen atmosphere and vigorously stirred for 2 hours. The resulting solution was filtered through celite and the solvent was removed under reduced pressure. The residue was distributed between 200 ml of ethyl acetate and 200 ml of Mahon's solution. Water

The layer was separated and neutralized, then extracted three times with 50 ml of methylene chloride. The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure to give 3-Id-(methoxycarbonyl)bicyclo|(2.2.2oct-1-yl|Ipropanoic acid (7-C). "H NMR (500MHz, SOSI»v): 5 3.62 (ZN, s), where 2.20 (2H, width t, 9U-9Hz), 1.75 (6H, m), 1.47 (2H, width t, U-9Hz), 1.38 (BN, m) m.h.

Stage C: 6o Carboxylic acid 7-C (400Omg, 1.67mmol) was dissolved in tetrahydrofuran (bml) and borane (1M solution in TG/F, 2.17ml, 1.3Sq.) was added dropwise at room temperature. After 2 hours the reaction mixture was added to 50 ml

After that, it was extracted three times with 500 ml of methylene chloride. The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure to give crude methyl 4-(3-hydroxypropyl)/2.2.2|octane-1-carboxylate (7-O0), which was used without purification at the next stage. "H NMR (500MHz, СО5300): δ 3.66 (ZH, s), 3.62 (2Н, t, 9-6.5Hz), 1.78 (6Н, m), 1.50 (2Н, m ), 1.41 (2H,

m), 1.17 (2Н, m) m.h.

Stage 0:

Hydroxyether 7-0 (430mg, 1.9mmol) was dissolved in 2.5ml of anhydrous methylene chloride under a nitrogen atmosphere, treated with pyridine (0.5ml) and methanesulfonyl chloride (0.368ml, 4.8mmol) and stirred for 4h. at room temperature. The mixture was diluted with 100 ml of ethyl acetate and washed with aqueous 1N HCl, saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and evaporated. Crude methyl-4-13-(methylsulfonyl)oxy|propyl)bicyclo-|2.2.2|octane-1-carboxylate (7-E) obtained in this way was used without purification in the next reaction. "H NMR (500 MHz, SOSIv): 5 70... 422 (2H, t, 9-7.5 Hz), 3.68 (ZN, s), 3.04 (ZN, s), 1.82 (BN , m), 1.70 (2Н, m), 1.44 (6Н, m), 1.24 (2Н, m) m.h.

Stage E:

Mesylate 7-E (3.30g, 10.b9mmol) was dissolved in DMF (20ml) and treated with sodium ethanethiolate (1.82g, 21.7mmol). The solution was stirred at 459C for 1 hour, then the mixture was diluted with 100 ml of ethyl acetate and washed twice with aqueous 1N CARRIER, then with a saturated aqueous solution of sodium bicarbonate and a saturated solution of 75% salt. The organic layer was dried over anhydrous sodium sulfate and evaporated to give methyl 4-I(3-(ethylthio)propyl|bicyclo|2.2.2)octane-1-carboxylate (7-E) as a crude oil, which was used in the next step without cleaning. "H NMR (500 MHz, SOSIv): 5 3.68 Mm.h. (ZH, s), 2.56 (2H, sq.,

U-7Hz), 2.51 (2H, t, 9-7.5Hz), 1.80 (6H, m), 1.52 (2H, m), 1.42 (6H, m), 1.28 (2H, t, 9-7 Hz), 1.02 (2H, m).

KE stage:

Sulfide 7-E (3.0g, 11mmol) was dissolved in methylene chloride (50ml) and treated with m-chloroperbenzoic acid (7595, 6.2g). The solution was stirred at room temperature for 2 hours, then the mixture was diluted with 100 ml of methylene chloride and washed with a saturated aqueous solution of sodium bicarbonate, then twice with a saturated aqueous solution of sodium bisulfite, then twice with a saturated aqueous solution of sodium bicarbonate and a saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to give methyl-4-13-ethylsulfonyl)propyl|bicyclo|2.2.2)octane-1-carboxylate (7-0) in the form of a crude oil, which was used in the next step without cleaning. "H NMR (500 MHz, SOSIv): 5 3.68 m.h. (ZH, s), 2.56 (2H, sq.,

U-7Hz), 2.51 (2H, t, 9-7.5Hz), 1.80 (6H, m), 1.52 (2H, m), 1.42 (6H, m), 1.28 (2H, t, 9-7 Hz), 1.02 (2H, m) m.h.

Stage 0:

Sulfone 7-0 (3.1 g, 1 tommol) was dissolved in 9:11 MeOH/water (50 mL) and treated with potassium hydroxide (KH). The solution was stirred at room temperature during the night, then another NCI was added to the mixture and extracted four times with 50 ml of methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to obtain 4-133-ethylsulfonyl)propyl|bicyclo(|2.2.2)octane-1-carboxylic acid (7-H), which was used in the next step without purification. "IN NMR (500MHz, SOSI"): 5 3.03 (2H, sq., U-7Hz), 2.94 (2H, dd, 9U-7.5Hz), 184 F (8H, m), 1, 45 (8H, m), 1.30 (2H, m) m.ch so

Stage H:

7-H carboxylic acid (3.0 g, 11 mmol) was dissolved in bbml of anhydrous methylene chloride in a nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 16b, 2 ml, 32.4 mmol) and then with 5 drops of DMF. The solution was stirred at room temperature in a nitrogen atmosphere for 9 minutes, then evaporated and placed in a 70 degree vacuum for 20 minutes. The acid chloride was dissolved in anhydrous methylene chloride (12 mL), cooled to room temperature in an ice bath, and then treated dropwise with a methylamine solution (2 M in THF, 27 mL, 54 mmol). After addition of methylamine, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 30 minutes. The mixture was diluted with 200 ml of methylene chloride and washed with aqueous 1N HCl, saturated aqueous sodium bicarbonate solution, and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to chromatography on silica gel, eluting with a gradient from 0 to 00 00 methanol in ethyl acetate to obtain 4-(3-ethylsulfonyl)propyl|-M-methylbicyclo|2.2.2|octane-1-carboxamide 7-I as a white powder. MS o (ESIZ-302 (Ma1); "YAN NMR (5000 MHz, SOSIia): 5 5.56 (1H, width s), 3.02 (2H, sq., U-7Hz), 2.94 (2H . )m.h.

Stage I: ini Methylamide 7-I (0.470g, 1.5bmmol) was dissolved in anhydrous methylene chloride (bml) and treated

He) with oxalyl chloride (2M in methylene chloride, 1.5 bml, 3.12 mmol) and DMF (2 drops). The solution was stirred at room temperature for 1 hour, then the solvent was removed by evaporation under reduced pressure. The residue was re-dissolved in anhydrous toluene (7 ml) and treated with 5-(2-"-(trifluoromethyl)phenyl|-1H-tetrazole (368 mg, 5B 1.72 mmol). The mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered off and washed to give 300mg of crude product as (F, HCl salts. The salt was taken up in methylene chloride/1N HCl and the aqueous layer was washed with two additional portions of methylene chloride. The organic layers were combined and evaporated, and the residue subjected to flash chromatography on silica gel. Elution was carried out with a gradient in the interval from 0 to 595 methanol/methylene chloride. The corresponding fractions were combined and evaporated to obtain 3-4-I(3-ethylsulfonyl)propyl|bicyclo|2.2.2oct-1-yl )-4-methyl-5-I2-(trifluoromethyl)phenyl|-4H-1,2,4-triazole (7--) in the form of a white powder. MS (ECI")-470.4 (Ma-1), "H NMR (500 MHz, SOSIv): 5 7.87 (1H, m), 7.72 (2H, m), 7.56 (IN, m), 3.49 (ZH, s), 3.05 ( 2H, sq., 9U-7.2Hz), 2.96 (2H, m), 2.18 (6H, m), 1.86 (2H, m), 1.62 (6H, m), 1.46 (ZN, t, 9-7.9HuC), 1.36 (2H, m) m.-h. 65 Example 8

Z x s Y " de / | ; hi SE" !

Stz 4-Methyl-3-(2-(trifluoromethyl)phenyl1|-5-(4--2-Trifluoromethyl)sulfonyl|-ethyl)bicyclo|2.2.2)oct-1-yl)-4H-1,2, 4- triazole (8-5) deE (1) 9-BEVM, tgF sno (g) MaOH, EYUN, ov 2 SNaRR avg no; issues and questions

KNMOB, tgF (3) SNUZOSI,

SNeSi", pyridine, 25 bOMe, SOZHMe, SOMe, at 8:

Her 8-8 8-A 8-year: A with 505SNU (22) 30 502SEz ZO SE; Yuyu (1 wife, SNeoN «

SEZVOZ neo Pho

NN nina 35 yen (ee)

You. mi (2) DMF cache

DMFA, 140 C sne sooMNeN

SOoMe (3) SNaMNY, 11F, With their 50 SS with 8E 8-E ;" I (1) (SISO)", DMFA KhM

SsNsi, iy chi: o MSE 2 (2 M. -b mm z

M Okh 1 Kh i s m SRz

Ca 8-a toluene, boiling with (F, reflux co Stage A:

To a stirred solution of methyltriphenylphosphonium bromide (9.1g, 12.6mmol) in THF (50ml) at 02 60 was added dropwise potassium hexamethyldisilazide (0.5M in toluene, 48.bml) over a period of 2 h. The resulting mixture was left to warm to room temperature for 1 hour, then cooled again to 02C and treated with methyl-4-formylbicyclo|2.2.2|octane-1-carboxylate 8-A | Spartap, M. V. et al., U. Ogud Spet., 1970, 35, 917) (2.5g, 12.mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted

EUAs (35Oml). The organic phase was washed with an aqueous carrier (1N), saturated aqueous sodium bicarbonate solution and 65% saturated salt solution, then dried (Ma»25O)) and concentrated in vacuo. The resulting solid was purified by flash chromatography on silica gel, eluting with a gradient of 0-495 EAbs/hexane. The resulting methyl-4-vinylbicyclo|2.2.2|octane-1-carboxylate (8-B) was isolated as a clear, colorless oil.

Stage B:

To a stirred solution of olefin 8-8 (1.6 g, 8.3 mmol) in THF (20 mL) was added dropwise 9-VVM (0.5 M in

THF, 49 ml). The solution was left to stir at room temperature for 18 hours, then successively treated with ethanol (14.5 ml), aqueous Mahon (5n, 5 ml) and hydrogen peroxide (3095 aqueous solution, 9.7 ml). The pH of the reaction mixture was adjusted to a value of 2 with an aqueous solution of NOCI (1n) and extracted with СНоСи three times. The organic layers were combined, washed with a saturated salt solution, dried (Ma»5O)) and scraped. The obtained alcohol 8-C was purified by chromatography on silica gel, eluting with a gradient of 30-5090 EtOAc/hexane and isolated as a 7/0 transparent, colorless oil.

Stage C:

A solution of 8-C alcohol (1.5g, 7.1mmol) in CHNSiO (7.5ml), pyridine (1.5ml) was cooled to 09C and treated with methanesulfonyl chloride (1.65ml, 21.3mmol) dropwise over 12h. The reaction mixture was left to warm to room temperature, then stirred for 10 minutes. E(Ac (ZOO ml) was added and the organic 75 phase was washed with an aqueous solution of NH (Tn) three times, with a saturated aqueous solution of sodium bicarbonate twice and with a saturated salt solution. The organic layer was dried (Ma»5O);) and scraped to obtain methyl-4 -2-(methylsulfonyl)oxy|ethyl)bicyclo|2.2.2|octane-1-carboxylate 8-0 as a white solid. "YAN NMR (BO0MHZ, SOSIv): 5 1.52 (6H, m), 1.66 (2H, t, 9U-7.1Hz), 1.84 (6H, m), 3.04 (ZH, s ), 3.69 (ZH, s), 4.29 (2H, t, 9-7.2 Hz) m.h.

Stage 0:

A solution of 8-0 (0.25g, O0.8bmmol), potassium trifluoromethanesulfinate (0.3g, 1.72mmol) and tetrabutylammonium iodide (0.15g, O4mmol) in DMF (Bbml) was heated at 14092 for bh. in a nitrogen atmosphere. The solution was then cooled to room temperature and diluted with EtOAc (100 ml) and washed twice with an aqueous solution of HCl (In) and saturated salt solution. The organic layer was dried (Ma»5O)), scraped and subjected to SM flash chromatography on silica gel, eluting by a 5-2095 EtOAc/hexane gradient. The resulting trifluoromethylsulfone 8-E was isolated as a white solid. IN YAM (50OoMGhz, SOSIv): 5 1.50 (6H, m), 1.78 (2H, m), 1.82 (EN, m), 3.17 (2H, m), 3.67 (ZN , c)m.h.

Stage E:

Methyl ether 8-E (0.035 g, 0.11 mmol) was converted to methyl amide 8-E using the methods described in example 6 at the stages of SIU. yu

M-methyl-4-2-trifluoromethyl)sulfonyl|ethyl)bicyclo|2.2.2)octane-1-carboxamide was isolated as a white solid; MS (ESI")-328.2 (М'Н1). Z

KE stage: I av

Methylamide 8-E (0.030 g, 0.092 mmol) was converted into triazole 8-5, according to the method of example 6, stage E -Ctrifluoromethyl)sulfonyl|ethyl)bicyclo|2.2.2|oct-1-yl)-4H-1,2,4-triazole (8-C) was isolated as a white powder; MS (ESI")-496.4. (M'-1).

Examples 9-102

Following methods similar to those described above, the following compounds of formula II were also obtained: (ee) ((c) sh" p. 50 3e)

F) ime) 60 b5 m-M "v

M dg (1) 70 " and 5 J pukh

SNI g ze V» s full vv | in and

SI

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MeO aa ; in h 47 that MeV Z

MeOo5 iz RaASO si y

But in (and; name) EYU b5 -AZ-

And Med OMe ee |»

Me 7 aa SYAZ 387 | on Me sch 25 26 ra and SV 400 about us dovo

M

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gzS

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Mao 37 Tu SN KU. OSN 474 what about oxen in | runes

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By whom; in NU with" actions by her

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AND

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Mesch 51 van SNOSIZ yad 382 o z Me b

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СН 389 со 45 здя (ав) oz int and 1

Me iChe) yari uyu 55 o ES with 58 pan SN 3 378 bo - b5 -4v-

SI and ev U

Ma

Y Nnyut SiZ Soh e 354 pni

And nas t st -GU on 361

MeOo 62 | he in he 356

Me 53 H 7 СН su on 340 s o ab || Well, you

F zo | MeO yu 65 r. SN nd 338 h o

Slave (ge) on | KU | same « 20 ' MeO -v p 67 No. SV Sun 326th" at p

Sg» si NIS. and, Sy -3 331 p

Me and (F) y Me and b5 -A7-

Me 72 Nab. SN and OMe

Si 73 No. and, SN is OMe

Me and OMe 556 ik 75 EE SNZ S on 365 ya ts o

Ma at 77 l dream

The star is 78 years old

И |: с со 79 Nast vy SNI VU on "aura in not 5 z" what se |U o E MeO s 50 s Me

With CH -3 294

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F. and "is 1e5 because 65

EC

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WITH

Me s DI sv 1: "U ; " lit iy y u 1 y 900 lo t " s o " me I pk V ee; (ee) ("in gas ne re: SNZ 470 1 s ke!

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An example of a pharmaceutical composition

As a separate embodiment of the oral composition of the compounds of this invention, 5 mg of any of the compounds of examples 1-8 is formulated with a sufficient amount of finely divided lactose to obtain a total amount equal to 580 to 590 mg to fill an O-size hard gelatin capsule.

Despite the fact that this invention is described and illustrated, with reference to its individual embodiments, Fr

Those skilled in the art will appreciate that changes, modifications, and substitutions may be made therein without departing from the spirit and scope of the present invention. For example, an effective dosage that differs from those established above may be used due to variations in the response of an individual being treated for a particular condition. Moreover, the pharmacological response observed may vary according to and depends on the selected active compound, or on the pharmaceutical carriers, if present, as well as on the type of composition and the mode of administration, and such expected variations or differences in results are expected accordingly. to the objects and practical aspects of the embodiment of this invention. Therefore, it is necessary to limit this invention only to the scope of the following formula. of the invention and interpret such claims as broadly as possible. » p

Claims (26)

The formula of the invention is the same 1. Compound of structural formula I: (ав) in ЧК» A--IM with sia 70 Koch ! - P Che) is that F or its pharmaceutically acceptable salt, where: each p is independently 0, 1 or 2, HF) each p is independently 0, 1 or 2; He X is chosen from the group consisting of a single bond, О, 5(О)р, Ме, 60 б5 -БО0- ge Ge IN o | Y Y M ICH Z re re tr Y t 7 yah sa Y y (8) y o ' o o o, ve Kba ' YE Y Y a mya she she she zh sh y . oh oh! o and B" are selected from the group consisting of arylcarbonyl, (CH5)claim 1-aryl and (CH), -heteroaryl; wherein the aryl and heteroaryl are unsubstituted or substituted and have from one to three substituents independently selected from K? ; B? is selected from the group consisting of hydrogen, C 4 alkyl, Co valkenyl, and (CHO)p-C 3 cycloalkyl, wherein the alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted and have from one to three substituents independently selected from B and oxo; each K7 is independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo, C 1 alkyl, and S. dalcox; BZ is selected from the group consisting of hydrogen, C 29 C loalkyl, He) Co 1 arkenyl, (CNo)p-C3 cycloalkyl, (CNo)p-aryl, (CNo)p-heteroaryl, o (CNo)d-heterocyclyl ; wherein aryl, heteroaryl and heterocyclyl are unsubstituted or substituted and have from one to three substituents independently selected from 5; alkyl, alkenyl and cycloalkyl are unsubstituted or substituted and have from one to five t groups independently selected from P and oxo; (ав) B3 and E8 are independently selected from the group consisting of hydrogen, formyl, C1 alkyl, (СНо)p-aryl, (СНо)p-heteroaryl, (СНо)d-heterocyclyl, (СНо)п-С3 7cycloalkyl, halogen, z c OB", z" (CHonMA 7", " cyano, (CHnoSOV", MO", co (snom 80, o (snovOo (В 7), iz (СНожВ(О)рА, (СНоз5О2ОВ, s 50 7 7 (SnoazaMmAe SOM z", (4e) (Snou 7", (Snoazamv Us(Ov, (SnozamA so, 59 (snom 7", GF) SR, СНоСЕ», о ОСЕ, OSНеСЕ» 60 OSNoСЕ"); wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted and have one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, and C 1-4 alkoxy; and wherein any methylene carbon atom (CH 2 ) in KE? and KZ is unsubstituted or substituted and has from one to two groups, independently selected from halogen, hydroxy and C. dalkyl; or two substituents located on the same carbon atom of the methylene group (СНо), taken together with by the carbon atom to which they are attached, form a cyclopropyl group; each 2? independently selected from the group consisting of C. alkyl, (CHNa)p-aryl, (CHNo)d-heteroaryl and (CHNo)p-C3.7cycloalkyl; where alkyl and cycloalkyl are unsubstituted or substituted and have from one to five substituents independently selected from halogen, oxo, C-.alkoxy, C.-alkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted and 70 has from one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C. dalalkyl and C. lalkoxy; or two KU-groups, together with the atom to which they are connected, form a 5- to 8-membered mono- or bicyclic system, which optionally contains an additional heteroatom selected from 0, 5 and M C. dalkilu; and each K" is hydrogen or K.E. 2. Compound according to claim 1, where K? is cyclopropyl, C 4 alkyl or C 4 alkyl or C 4 alkyl and KE" is phenyl or 72 naphthyl, in which the phenyl and naphthyl are unsubstituted or substituted and have from one to three substituents independently selected from VU. 3. The compound according to claim 2, where KU- is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C. alkyl, Si. zalkoxy, S. zalkylthio and S. zalkylsulfonyl. 4. The compound according to item C, where 2 represents methyl and 2" represents hydrogen. 5. Compound according to claim 1, where X is a single bond; B" represents phenyl or naphthyl, where phenyl and naphthyl are unsubstituted or substituted and have from one to three substituents independently selected from ω; Ha B? is cyclopropyl, C. alkyl or C 0 -alkenyl; and o BZ is unsubstituted or substituted C 4 is alkyl and has one to three substituents independently selected from B and oxo. b. Compound for claim 5, where is BC? is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C..alkyl, C.4.alkoxy, C.alkylthio and C-alkylsulfonyl. b 7. The compound according to claim 6, where B2 represents methyl and P" represents hydrogen. IS o) 8. The compound according to claim 5, where eff is selected from the group consisting of halogen, hydroxy, oxo, C 4.alkoxy, " C. dalkylthio, C. dalkylsulfinyl, C. ylalkylsulfonyl, and phenyl is unsubstituted or substituted with one to three groups independently selected from halogen and trifluoromethyl. at 9. The compound according to claim 8, where 2 represents methyl and 2" represents hydrogen. 10. Compound according to claim 5, where K? selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C-alkyl, C-alkyl, C-alkylthio and C-alkylsulfonyl; and BZ is selected from the group consisting of halogen, hydroxy, oxo, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulfonyl, and phenyl is unsubstituted or substituted with one to three groups independently selected from halogen and trifluoromethyl. 11. Compound according to claim 10, where B? represents methyl and 2" represents hydrogen. o) p 12. The compound according to claim 1, where "» X represents a single bond; "B" represents phenyl or naphthyl, in which the phenyl and naphthyl are unsubstituted or substituted and have from one to three substituents independently selected from vo; o 75 B? is cyclopropyl, C. alkyl or C. alkenyl; and BZ is phenyl or heteroaryl, where the phenyl and heteroaryl are unsubstituted or substituted and have from one to about three substituents independently selected from KU. 13. Compound according to claim 12, where B? represents methyl and 2" represents hydrogen. sl 50 14. The compound according to claim 12, where WZ is phenyl which is unsubstituted or substituted and has from one to three substituents independently selected from WZ. with 15. Compound according to claim 14, where is KE? selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C. alkyl, Si. zalkoxy, S. zalkylthio and S. zalkylsulfonyl. 16. The compound according to claim 15, where B? is methyl and 2" is hydrogen. 17. The compound according to claim 12, where BZ is oxadiazolyl, which is unsubstituted or substituted and has from one to (F) two substituents independently selected from 2. Io) 18. The compound according to claim 17, where ER is phenyl, which is unsubstituted or substituted and has from one to three substituents independently selected from halogen, hydroxy, C..alkyl, trifluoromethyl, trifluoromethoxy and Si. , alkoxy. 60 19. The compound according to claim 18, where B? is methyl and 2" is hydrogen. 20. A compound selected from the group consisting of: b5 IS ! OO | SEZ I MI M A- 1 z Oh Z Her i u | | r sn, si! m--M "-230 " I don't sleep SEZ, M--m -5 more | -- snu o o sez , Hv M--m cm not og B : still she snu o | F Я o SEZ yu in m-m - rach DE - ns M | I am about it with (ge) Ov m--m Her « -72U5 : 7 I | as. with | he "» snu " oo in M m-M " (o) k is U Okh stu o that Zo i SNU sia 70 s , m-M rily he zh on 55 This iF) sEz , t M--m - on | I sleep 65 SI, MAM nu-0 --53rd in | te M y on | Yan SNU SEZ; ICH A h-- m le an SNU Me Sai and I uh tn, muz " , - hi SE ne and Me sho ! х | sch tt, Y. o- - I from -- | M Ge) with SEz or its pharmaceutically acceptable salt. 21. The compound according to claim 20, which is "I E , I | SEZ o a M MAM G» c) i U-4 5th | | With IM-- M (8) pcs « sc, more , - or its pharmaceutically acceptable salt. p 22. The compound according to claim 20, which is I" ! SE LLC from owl m--M not M | i (av) | -sh i» sn; c 20 or its pharmaceutically acceptable salt. 23. The compound according to claim 20, which is (Che) SI , MAM -695 MI t. GF) an SNU ko p. - and or its pharmaceutically acceptable salt. in 24. The compound according to claim 20, which is Me and ! "SHY x tt, mule" Y she: 65 - - with no m -B4- or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition containing a compound according to claim 1 in combination with a pharmaceutically acceptable carrier. 26. Use of a compound according to claim 1 in the preparation of a medicinal product used in the treatment of a condition selected from the group consisting of hyperglycemia, insulin resistance, type 2 diabetes, lipid metabolism disorders, obesity, atherosclerosis and metabolic syndrome. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 15, 25.09.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. c) 6) (o) IS) « «c) d) - with . and? (ee) («c) sh» c 50 3e) ime) 60 b5