RU2360910C2 - Triazole derivatives as inhibitors of 11-beta-hydroxysteroiddehydrogenase-1 - Google Patents

Abstract

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I

or their pharmaceutically acceptable salts R⁴ is hydrogen; X is selected from group, consisting of single bond, NH- and groups:

, values of R¹-R³ radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

Description

FIELD OF THE INVENTION

This invention relates to derivatives of triazole as inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase type I (11β-GSD-1 or GSD-1) and methods of treating certain conditions using them. The compounds of this invention are useful for the treatment of diabetes, for example, non-insulin-dependent type 2 diabetes (NIDDM), insulin resistance, obesity, impaired fat metabolism, hypertension and other diseases and conditions.

BACKGROUND OF THE INVENTION

The cause of diabetes is many factors and the most simplified diabetes is characterized by an increased fasting plasma glucose (hyperglycemia). There are two most studied forms of diabetes: type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), in which patients produce little or no insulin, a hormone that regulates glucose uptake, and type 2 diabetes or non-insulin-dependent diabetes type (NIDDM), in which patients produce insulin and even manifest hyperinsulinemia (insulin levels in blood plasma are the same or even increased compared to people without diabetes), while they manifest hyperglycemia. Type 1 diabetes is usually treated by injecting insulin. However, with type 2 diabetes, "insulin resistance" often develops, so that the stimulating effect of insulin on glucose and lipid metabolism in the main insulin-sensitive tissues, namely muscles, liver and fatty tissues, is reduced. Non-diabetic insulin-resistant patients have elevated insulin levels that compensate for their insulin resistance, so serum glucose levels are not elevated. In patients with NIDDM, insulin levels in the blood plasma, even if they are elevated, are insufficient to overcome pronounced insulin resistance, leading to hyperglycemia.

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

Chronic or uncontrolled hyperglycemia observed in diabetics is associated with increased 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 associated with 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 crucial in the clinical management and treatment of diabetes.

Many patients who have insulin resistance but do not have severe 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, hyperinsulinemia, high blood pressure, low HDL (high density lipoproteins) and high levels of VLDL (very low density lipoproteins). Such patients, regardless of whether they have severe diabetes or not, are at a high risk of developing the cardiovascular complications described above.

Treatment for type 2 diabetes usually involves exercise and diet. Increased plasma insulin levels by the administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulates pancreatic β-cells to secrete more insulin, and / or by injection of insulin when sulfonylureas or meglitinide become ineffective, can lead to a sufficiently high concentration of insulin for stimulation of insulin resistant tissues. However, dangerously low glucose levels and ultimately elevated levels of insulin resistance can result.

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

Glitazones (namely 5-benzylthiazolidine-2,4-dione) form a new class of compounds with the ability to improve hyperglycemia and other symptoms of type 2 diabetes. These agents significantly increase insulin sensitivity of muscles, liver and adipose tissue, leading to partial or complete correction of elevated plasma glucose levels, mainly without causing hypoglycemia. Recently released glitazones are agonists of receptors activated by the gamma subtype peroxisome proliferator (RAPP). It is believed that the agonism of RAPP-gamma is mainly responsible for the increased sensitivity to insulin that is observed with respect to glitazones. New RAPP agonists designed to treat type 2 diabetes and / or dyslipidemia are agonists of one or more RAPP subtypes of alpha, gamma and delta. For a review of insulin sensitizing agents and other mechanisms for treating type 2 diabetes, see M. Tadayyon and SA Smith, "Insulin sensitisation in the treatment of Type 2 diabetes", Expert Opin. Investig. Drugs , 12: 307-324 (2003).

There is a continuing need for new treatments for diabetes and related conditions, such as metabolic syndrome. This invention solves this and other problems.

SUMMARY OF THE INVENTION

The present invention relates to bicyclo [2.2.2] oct-1-yl-1,2,4-triazoles of structural formula I:

These derivatives of bicyclo [2.2.2] octyltriazole are effective as inhibitors of type 1β-hydroxysteroid dehydrogenase (11β-HSD1). Thus, they are effective in the treatment, control, and prophylaxis of disorders responsive to the inhibition of 11β-HSD1, such as hyperglycemia, insulin resistance, type 2 diabetes, lipid disorders, obesity, atherosclerosis, and metabolic syndrome.

The invention also relates to pharmaceutical compositions comprising the compounds of the 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 the administration of the compounds and pharmaceutical compositions of this invention.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to derivatives of bicyclo [2.2.2] oct-1-yl-1,2,4-triazole used as inhibitors of 11β-HSD1. The compounds of this invention are described by structural formula I:

or a pharmaceutically acceptable salt thereof; Where

each p independently represents 0, 1, or 2;

each n independently represents 0, 1, or 2;

X is selected from the group consisting of a single bond, O, S (O) _p , NR ⁶ ,

R ¹ selected from the group consisting of

arylcarbonyl,

(CH ₂ ) _n -aryl and

(CH ₂ ) _n- heteroaryl;

where aryl and heteroaryl are unsubstituted or substituted by one to three substituents independently selected from R ⁵ ;

R ² selected from the group consisting of

hydrogen

C _1-8 alkyl,

C _2-6 alkenyl and

(CH ₂ ) _n -C _3-6 cycloalkyl,

in which alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R ⁸ and oxo;

each R ^{4 is} independently selected from the group consisting of

hydrogen

halogen

hydroxy

oxo

C _1-3 alkyl and

C _1-3 alkoxy;

R ³ selected from the group consisting of

hydrogen

C _1-10 alkyl,

C _2-10 alkenyl,

(CH ₂ ) _n -C _3-6 cycloalkyl,

(CH ₂ ) _n -aryl,

(CH ₂ ) _n- heteroaryl and

(CH ₂ ) _n -heterocyclyl;

in which aryl, heteroaryl and heterocyclyl are unsubstituted or substituted by one to three substituents independently selected from R ⁵ ; and alkyl, alkenyl and cycloalkyl are unsubstituted or substituted by one to five groups independently selected from R ⁸ and oxo;

R ⁵ and R ⁸ are each independently selected from the group consisting of

hydrogen

formed

C _1-6 alkyl,

(CH ₂ ) _n -aryl,

(CH ₂ ) _n- heteroaryl,

(CH ₂ ) _n -heterocyclyl,

(CH ₂ ) _n -C _3-7 cycloalkyl,

halogen

OR ⁷ ,

(CH ₂ ) _n N (R ⁷ ) ₂ ,

cyano

(CH ₂ ) _n CO ₂ R ⁷ ,

NO ₂

(CH ₂ ) _n NR ⁷ SO ₂ R ⁶ ,

(CH ₂ ) _n SO ₂ N (R ⁷ ) ₂ ,

(CH ₂ ) _n S (O) _p R ⁶ ,

(CH ₂ ) _n SO ₂ OR ⁷ ,

(CH ₂ ) _n NR ⁷ C (O) N (R ⁷ ) ₂ ,

(CH ₂ ) _n C (O) N (R ⁷ ) ₂ ,

(CH ₂ ) _n NR ⁶ C (O) R ⁶ ,

(CH ₂ ) _n NR ⁶ CO ₂ R ⁷ ,

O (CH ₂ ) _n C (O) N (R ⁷ ) ₂ ,

CF ₃

CH ₂ CF ₃ ,

OCF ₃ ,

OCHCF ₂ and

OCH ₂ CF ₃ ;

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 C _1-4 alkoxy; and where any carbon atom of a methylene group (CH ₂ ) in R ⁵ and R ⁸ is unsubstituted or substituted by one to two groups independently selected from halogen, hydroxy and C _1-4 alkyl; or two substituents on the same carbon atom of a methylene group (CH ₂ ) taken together with the carbon atom to which they are attached form a cyclopropyl group;

each R ^{6 is} independently selected from the group consisting of

C _1-8 alkyl,

(CH ₂ ) _n -aryl,

(CH ₂ ) _n- heteroaryl and

(CH ₂ ) _n -C _3-7 cycloalkyl;

where alkyl and cycloalkyl are unsubstituted or substituted by one to five substituents independently selected from halogen, oxo, C _1-4 alkoxy, C _1-4 alkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C _1-4 alkyl and C _1-4 alkoxy;

or two R ⁶ groups together with the atom to which they are attached to form a 5-8 membered mono- or bicyclic ring system, optionally containing an additional heteroatom selected from O, S and NC _1-4 alkyl; and

each R ⁷ is hydrogen or R ⁶ .

In one embodiment of the compounds of this invention, R ² is cyclopropyl, C _1-3 alkyl or C _2-3 alkenyl and R ¹ is phenyl or naphthyl, in which phenyl or naphthyl are unsubstituted or substituted with one to three substituents independently selected from R ⁵ . In the class of this embodiment, R ^{5 is} selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylsulfonyl. In a subclass of this class, R ² is methyl and R ⁴ is hydrogen.

In a second embodiment of the compounds of this invention

X is a single bond;

R ¹ is phenyl or naphthyl, in which phenyl and naphthyl are unsubstituted or substituted by one to three substituents independently selected from R ⁵ ;

R ² is cyclopropyl, C _1-3 alkyl or C _2-3 alkenyl; and

R ³ is C _1-6 alkyl unsubstituted or substituted by one or three substituents independently selected from R ⁸ and oxo.

In the class of this second embodiment, R ^{5 is} selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylsulfonyl. In a subclass of this class, R ² is methyl and R ⁴ is hydrogen.

In another class of this embodiment, R ^{8 is} selected from the group consisting of halogen, hydroxy, oxo, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, and phenyl is unsubstituted or substituted from one up to three groups independently selected from halogen and trifluoromethyl. In a subclass of this class, R ² is methyl and R ⁴ is hydrogen.

In the third class of this embodiment, R ^{5 is} selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylsulfonyl; and R ^{8 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 from one to three groups independently selected from halogen and trifluoromethyl . In a subclass of this class, R ² is methyl and R ⁴ is hydrogen.

In a third embodiment of the compounds of this invention

X is a single bond;

R ¹ is phenyl or naphthyl, in which phenyl and naphthyl are unsubstituted or substituted by one to three substituents independently selected from R ⁵ ;

R ² is cyclopropyl, C _1-3 alkyl or C _2-3 alkenyl; and

R ³ is phenyl or heteroaryl, in which phenyl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R ⁵ .

In the class of this embodiment, R ² is methyl and R ⁴ is hydrogen.

In another class of this embodiment, R ³ is phenyl unsubstituted or substituted with one to three substituents independently selected from R ⁵ . In a subclass of this class, R ^{5 is} selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylsulfonyl. In a subclass of this class, R ² is methyl and R ⁴ is hydrogen.

In the third class of this embodiment, R ³ is oxadiazolyl unsubstituted or substituted by one to two substituents independently selected from R ⁵ .

In a subclass of this class, R ⁵ is phenyl unsubstituted or substituted by one to three substituents independently selected from halogen, hydroxy, C _1-4 alkyl, trifluoromethyl, trifluoromethoxy and C _1-4 alkoxy. In a subclass of this class, R ² is methyl and R ⁴ is hydrogen.

In this description, the following definitions apply.

"Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, mean carbon chains that can be linear or branched, and combinations thereof, unless otherwise specified. 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 _3-10 , the term "alkyl" also includes cycloalkyl groups and combinations of linear or branched alkyl chains fused to cycloalkyl structures; when the number of carbon atoms is not determined, C _{1-6 is} meant.

“Alkenyl” means carbon chains that contain at least one carbon-carbon double bond, which may be linear or branched, or combinations thereof, unless 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 where a certain number of carbon atoms allows, for example, from C _5-10 , the term "alkenyl" also includes cycloalkenyl groups and combinations of linear, branched and cyclic structures. When the number of carbon atoms is not determined, C _{2-6 is} implied.

"Alkynyl" means 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-heptinyl and the like.

"Cycloalkyl" is a subtype of alkyl and means a saturated carbocyclic ring having a certain number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The cycloalkyl group is substantially monocyclic unless otherwise specified. Cycloalkyl groups are saturated, unless otherwise specified.

The term “alkoxy” refers to a straight or branched chain alkoxides with a specific number of carbon atoms (eg, C _1-6 alkoxy) or with any number of carbon atoms within a given range [ie, methoxy (MeO-), ethoxy, isopropoxy, etc. .].

The term “alkylthio” refers to straight or branched chain alkyl sulfides with a specific number of carbon atoms (eg, C _l-6 alkylthio) or with any number of carbon atoms within a given range [ie, methylthio (MeS-), ethylthio, isopropylthio, etc. .].

The term “alkylamino” refers to a straight or branched chain alkylamines with a specific number of carbon atoms (eg, C _1-6 alkylamino) or with any number of carbon atoms within a given range [ie methylamino, ethylamino, isopropylamino, t-butylamino, etc. .].

The term “alkylsulfonyl” refers to straight or branched chain alkyl sulfones with a specific number of carbon atoms (e.g., C _1-6 alkylsulfonyl) or with any number of carbon atoms within a given range [i.e., methylsulfonyl (MeSO ₂ -), ethylsulfonyl, isopropylsulfonyl, etc. d.].

The term “alkylsulfinyl” refers to a straight or branched chain alkyl sulfoxides with a specific number of carbon atoms (for example, C _1-6 alkylsulfinyl) or with any number of carbon atoms within this range [ie methylsulfinyl (MeSO-), ethylsulfinyl, isopropylsulfinyl, etc. .].

The term "alkyloxycarbonyl" refers to straight or branched chain esters of carboxylic acid derivatives of the invention with a number of carbon atoms (e.g., C _l-6 alkyloxycarbonyl), or any number of carbon atoms within this range [i.e. methyloxycarbonyl (MeOCO-), ethyloxycarbonyl, or butyloxycarbonyl ].

“Aryl” means a mono- or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryls are monocyclic or bicyclic 6-10 membered ring aromatic systems. Preferred aryls are phenyl and naphthyl. The most preferred aryl is phenyl.

“Heterocycle” and “heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S and N, further containing oxidized forms of sulfur, namely SO and SO ₂ . Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithian, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydrolanedi, oxidiropan, dihydrolanedi, oxidiropan 1,3-dioxane, 1,3-dithian, oxathian, thiomorpholine and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. 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, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolidazole, benzisoxazolidazole, benzisoxazolidazole, benzisoxazolidazole indazolyl, isoindolyl, dihydrobenzothienyl, indolisinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl and the like. The concept of heterocyclyl and heteroaryl groups includes rings and ring systems containing 3-15 atoms, forming 1-3 rings.

"Halogen" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. Fluorine is most preferred when the halogens are substituted with an alkyl or alkoxy group (e.g. CF ₃ O and CF ₃ CH ₂ O).

The term “composition”, for example a pharmaceutical composition, encompasses a product containing the active ingredient (s) and the inert ingredient (s) forming a carrier, as well as any product that is obtained directly or indirectly, by combination, complexation, or aggregation of any two or more ingredients, or the 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 admixing a compound of this invention and a pharmaceutically acceptable carrier.

It should be understood that the terms “administration” and “administration” of a compound mean the use of a compound of the invention or a prodrug of a compound of the invention for individual consumption. Compounds of structural formula I may contain one or more asymmetric centers and, therefore, can exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The invention is intended to cover all of these isomeric forms of compounds of structural formula I.

Some of the compounds described herein contain olefinic double bonds and, unless otherwise specified, it is implied that they contain geometric isomers E and Z.

Some of the compounds described herein may exist as tautomers, such as ketoenol tautomers. Individual tautomers, as well as mixtures thereof, are encompassed by compounds of structural formula I.

Compounds of structural formula I can be separated into individual diastereoisomers, for example, by fractional crystallization from a suitable 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 that, if necessary, are derivatized with a reagent containing an asymmetric center of known absolute configuration.

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

In another aspect of the invention, the pharmaceutical composition deliberately contains a compound in accordance with structural formula I or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier. By the term “solvate” is meant 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 corresponding to structural formula I or a pharmaceutically acceptable salt or solvates thereof.

In another aspect of the present invention, a method is described for treating non-insulin-dependent diabetes mellitus (type 2) in mammals in need of such treatment, comprising administering to the patient an effective amount of an antidiabetic compound corresponding to structural formula I.

In a further aspect of the present invention, there is described a method of treating obesity in mammals in need of such treatment, comprising administering to said patient a compound corresponding to structural formula I in an amount effective to treat obesity.

In another aspect of the present invention, there is provided a method of treating a metabolic syndrome in mammals in need of such treatment, comprising administering to said patient a compound corresponding to structural formula I in an amount effective to treat metabolic syndrome.

In a further aspect of the present invention, there is provided a method for treating a fat metabolism disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL in a mammal patient in need of such treatment, comprising administering to a specified patient a compound corresponding to structural formula I, in an amount effective for the treatment of said impaired fat metabolism.

In another aspect of the present invention, there is provided a method for treating atherosclerosis in a mammal patient in need of such treatment, comprising administering to said patient a compound corresponding to structural formula I in an amount effective to treat atherosclerosis.

Another aspect of the present invention relates to the use of compounds of structural formula I for the treatment of hyperglycemia, insulin resistance, type 2 diabetes, lipid disorders, obesity, atherosclerosis and metabolic syndrome.

In addition, an additional aspect of the present invention provides the use of compounds of structural formula I in the manufacture of drugs for use in the treatment of a condition selected from the group consisting of hyperglycemia, insulin resistance, type 2 diabetes, impaired fat metabolism, obesity, atherosclerosis and metabolic syndrome.

The compounds of this invention may 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. Salts of basic compounds encompassed by the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention, which are mainly prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the basic 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, edisylate, estolate, esylate, gluceptate, gluconate, glutamate, glycollyl larsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy naphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl bromide, methyl bromide, methyl bromide, methyl nitrate bromide at, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoklate, tosylate, triethylate, triethylate, triethylate, trie. In addition, when the compounds of this invention carry an acidic site, their pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases containing aluminum, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, ferric manganese, divalent manganese, potassium, sodium, zinc and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from organic non-toxic bases include salts of primary, secondary and tertiary amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, triethyltrimethyl trimetil methamine and the like.

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

It should be understood that the references used here to compounds of structural formula I are also intended to include pharmaceutically acceptable salts, as well as salts that are not pharmaceutically acceptable when used as precursors of free compounds or their pharmaceutically acceptable salts or in other synthesis processes.

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

The compounds described herein are selective inhibitors of the 11β-HSD1 enzyme. Thus, the present invention relates to the use of 11β-HSD1 inhibitors for inhibiting the reductase activity of 11β-hydroxysteroid dehydrogenase, which is responsible for the conversion of cortisone to cortisol. Excess cortisol is associated with a variety of disorders, including NIDDM, obesity, dyslipidemia, insulin resistance, and hypertension. Administration of the compounds of this invention reduces the level of cortisol and other 11β-hydroxysteroids in the target tissues, thereby reducing the effects of excess amounts of cortisol and other 11β-hydroxysteroids. Inhibition of 11β-HSD1 can be used in the treatment and control of diseases caused by abnormally high levels of cortisol and other 11β-hydroxysteroids, such as NIDDM, obesity, hypertension, and dyslipidemia. Inhibition of the activity of 11β-HSD in the brain, for example, a decrease in cortisol, may also be useful in treating or reducing anxiety, depression, and cognitive impairment.

The invention also includes the use of an 11β-HSD1 inhibitor for treating, controlling, improving, preventing, delaying the onset or reducing the risk of developing the diseases and conditions described herein due to an excess or uncontrolled amounts of cortisol and / or other corticosteroids in a mammalian patient, especially in human, the introduction of an effective amount of a compound of structural formula I or its pharmaceutically acceptable salt or solvate. Inhibition of the 11β-HSD1 enzyme 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 excess.

NIDDM and hypertension:

The compounds of this invention are selective inhibitors of 11β-HSD1 compared to 11β-HSD2. While inhibition of 11β-HSD1 is used to lower cortisol and treatment of conditions associated with it, inhibition of 11β-HSD2 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 the action of insulin in the liver, so that insulin sensitivity is reduced, leading to decreased gluconeogenesis and increased glucose levels in the liver. Patients who already have developed glucose tolerance are more likely to develop type 2 diabetes in the presence of abnormally high levels of cortisol.

High levels of cortisol in tissues where a mineralocorticoid receptor is present often leads to hypertension. Inhibition of 11β-HSD1 shifts the ratio of cortisol to cortisone in certain tissues in favor of cortisone.

Administration of a therapeutically effective amount of an 11β-HSD1 inhibitor is effective in treating, controlling and improving the symptoms of NIDDM, and regular administration of a therapeutically effective amount of an 11β-GDM1 inhibitor delays or prevents the occurrence of NIDDM, in particular in humans.

Obesity, metabolic syndrome, dyslipidemia :

Excessive levels of cortisol are associated with obesity, probably due to increased hepatic gluconeogenesis. Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia and other metabolic syndrome factors such as high blood pressure, elevated VLDL and low HDL. Montague et al., Diabetes , 2000, 49: 883-888. Thus, the administration of an effective amount of an 11β-HSD1 inhibitor is used in the treatment or control of obesity. Long-term treatment with an 11β-HSD1 inhibitor is also used to delay or prevent the onset of obesity, especially if the patient uses an 11β-HSD1 inhibitor in combination with a controlled diet and exercise.

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 a decrease in insulin resistance and maintaining plasma glucose levels at normal concentrations.

Atherosclerosis:

As described above, inhibition of the activity of 11β-HSD1 and a decrease in the amount of cortisol are useful in treating or controlling hypertension. Due to the fact that hypertension and dyslipidemia contribute to the development of atherosclerosis, the administration of a therapeutically effective amount of the 11β-HSD1 inhibitor of the present invention can also be especially useful in the treatment, control, delaying of onset or prevention of atherosclerosis.

Other applications:

The following diseases, disorders and conditions can be treated, controlled, prevented or delayed by treatment with the compounds of this invention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL, (11) high LDL, (12) atherosclerosis and its consequences, (13) vascular restenosis, (14 ) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease , (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) metabolic syndrome, (21) hypertension and other disorders in which the component is insulin resistance.

The above diseases and conditions can be treated using compounds of structural formula I, or a compound can be administered to prevent or reduce the risk of developing the diseases and conditions described herein. Since competitive inhibition of 11β-HSD2 can have dangerous side effects or can actually increase the amount of cortisol in the target tissue, where a decrease in cortisol is desired, selective 11β-HSD1 inhibitors with little or no 11β-HSD2 inhibition are desirable.

11β-HSD1 inhibitors of structural formula I generally have an IC ₅₀ inhibition constant of less than about 500 nM and preferably less than about 100 nM. Basically, the IC ₅₀ value for the compound 11β-HSD2 in comparison with 11β-HSD1 is at least two or more, and preferably about ten or more. Even more preferred are compounds with an IC ₅₀ value of 11β-HSD2 compared to 11β-HSD1 of about 100 or more. For example, the compounds of this invention ideally demonstrate an IC ₅₀ inhibition constant when acting against 11β-HSD2 of more than about 1000 nM and preferably more than 5000 nM.

Any suitable route of administration can be used to provide a mammal, especially a human, with an effective dose of a compound of this invention. For example, oral, rectal, local, parenteral, 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.

The effective dosage of the active ingredient varies depending on the particular compound used, the mode of administration, the condition being treated and the severity of the condition. Such dosages can be readily established by a person skilled in the art.

In the treatment or prophylaxis of the diseases and conditions described herein, for which the compounds of structural formula I are intended, satisfactory results have been obtained with the administration of the compounds of this invention in a daily dose of from about 0.1 to about 100 milligrams per kilogram (BMS) of body weight, preferably given a single daily dose or in separate doses from about two to six times a day. The total daily dose, therefore, ranges from about 0.1 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. In the case of a standard adult person weighing 70 kg, the total daily dose will vary from about 7 mg to about 350 mg. This dosage can be changed to provide an optimal therapeutic effect.

Another aspect of the present invention relates to a pharmaceutical composition which comprises a compound of structural formula I or a pharmaceutically acceptable salt or solvate thereof in combination with a pharmaceutically acceptable carrier.

These compositions include those suitable for oral, rectal, local, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), transdermal, inhalation (nasal or buccal inhalation) or intranasal administration, although the most appropriate route of administration in any case will depend from the nature and severity of the treated condition and the active ingredient. They can be conveniently presented in unit dosage form and prepared using any methods well known in pharmacy.

A compound of structural formula I may be combined with a pharmaceutically acceptable carrier in accordance with conventional pharmaceutical preparation techniques. Media can have a wide variety of forms. For example, carriers for oral liquid compositions include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants and other components used in the manufacture of oral liquid suspensions, elixirs and solutions. Carriers such as starches, sugars 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 administration are preferred over liquid preparations.

Oral solid dosage forms may also contain a binder, such as gum tragacanth, acacia, 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 modify the physical form of a unit dose. For example, tablets may be coated with shellac, sugar, or both.

Tablets may be coated using standard aqueous or anhydrous techniques. The usual percentage of active compound in these compositions may, of course, vary from about 2 percent to about 60% w / w based. Thus, tablets contain a compound of structural formula I or a salt or hydrate thereof in an amount ranging from about 0.1 mg to about 1.5 g, preferably from about 1.0 mg to about 500 mg, and more preferably from about 10 mg up to about 100 mg.

Liquid forms for oral administration, such as syrups or elixirs, may contain, in addition to the active ingredient, sucrose as a sweetener, methyl or propyl parabens as preservatives, a coloring and flavoring agent, for example a cherry or orange flavor.

Parenteral forms usually exist in the form of a solution or suspension, are usually prepared in water and optionally contain a surfactant, such as hydroxypropyl cellulose. Dispersions can be prepared on glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Diluted preparations usually also contain preservatives.

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

Assays: measurement of inhibition constants:

Using Scintillation Proximity Assay (SPA), enzyme activity for test compounds was evaluated. Briefly, tritium-labeled cortisone substrate, the NADPH cofactor, and the titratable compound of structural formula I were incubated with 11β-HSD1 at 37 ° C to convert to cortisol. After protein incubation with protein A, SPA beads were coated, pre-mixed with an anticortisol monoclonal antibody and a non-specific 11β-HSD inhibitor, for example 18β-glycerol acid, was added to each well. The mixture was shaken at 15 ° C and then analyzed using a liquid scintillation counter suitable for 96 wells. The percent inhibition was calculated relative to the uninhibited control well and IC ₅₀ curves were plotted.

This assay was used similarly for 11β-HSD2, with tritium-labeled cortisol and NAD used as substrate and cofactor, respectively. To start the analysis, 40 μl of substrate (25 nM ³ H-cortisone + 1.25 mM NADPH in 50 mM HEPES buffer, pH 7.4) was added to specific wells in a 96-well plate. The compound was dissolved in 10 mM DMSO followed by 50-fold dilution of 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 substrate. To initiate the interaction, 10 μl of 11β-HSD1 microsomes from CHO transfectants were added to each well in the corresponding concentration to obtain approximately 10% conversion of the starting material. To finally calculate the percentage of inhibition, a series of wells was added that represented the minimum and maximum in the analysis: one set containing a substrate without a compound or an enzyme (background), and another set containing a substrate and an enzyme without any compound (maximum signal). The plates were briefly centrifuged at a low speed in a centrifuge to combine the reagents, covered with an adhesive strip, gently mixed and incubated at 37 ° C for 2 hours. After incubation, 45 μl, SPA granules previously suspended with anticortisol monoclonal antibodies and compound were added to each well. Formulas I. The plates were re-closed and gently shaken for more than 1.5 hours at 15 ° C. Data was collected from a liquid scintillation counter for a tablet, such as Topcount. To control inhibition of the binding of anticortisol antibodies to cortisol, a substrate bound to 1.25 nM ³ H-cortisol was added to certain standard wells. 1 μl of 200 μM compound was added to each of these wells together with 10 μl of buffer, instead of the enzyme. Any calculated inhibition was observed because the compound interfered with the binding of cortisol to antibodies on SPA granules.

Assays: measurement of in vivo inhibition:

In general terms, a test compound was orally administered to a mammal and the end of the described time interval, usually between 1 and 24 hours, was expected. Tritium-labeled cortisone was administered intravenously, followed by blood collection after several minutes. Steroids were extracted from the separated serum and analyzed by HPLC. The relative levels of ³ H-cortisone and its reduction product, ³ H-cortisol, were determined for the compound and the control groups receiving the vehicle. Based on these values, the absolute conversion and percent inhibition were calculated. More specifically, the compounds were prepared for oral administration by dissolving them in a carrier (5% hydroxypropyl beta-cyclodextrin v / v H ₂ O, or equivalent) at the required concentration to obtain a dosage of usually 10 mg per kg. After overnight fasting, the solutions were injected with ICR mice (obtained from Charles River) with an oral probe, 0.5 ml per dose per animal, with three animals in the test group.

After the required time, usually either after 4 or 16 hours, 0.2 ml of 3 μM ³ H-cortisone in dPBS was injected into the tail vein. The animal was precipitated and, after two minutes, killed in a CO ₂ chamber. After death, the mouse was removed and blood was collected by puncture of the heart. Blood was left in the tube to separate the serum for at least 30 minutes at room temperature to achieve adequate coagulation. After the incubation period, the blood was separated to obtain serum by centrifugation at 3000Xg, 4 ° C, for 10 min.

For analysis of steroids in serum, they were first extracted with an organic solvent. 0.2 ml of serum was transferred to a clean microcentrifuge tube. 1.0 ml of ethyl acetate was added to this amount, followed by vigorous shaking for 1 min. Rapid centrifugation in a microcentrifuge leads to the formation of a precipitate of aqueous whey proteins and an enlightened 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 of 0.200 ml was introduced into a C-18 Metachem Inertsil chromatographic column, equilibrated with 30% methanol. A slow linear gradient of up to 50% methanol separated target steroids; simultaneous UV monitoring at 254 nm of cooled standards in a resuspended solution acted as an internal standard. The tritium signal was recorded by a radio-chromatographic detector and analyzed using appropriate software. The percentage conversion of ³ H-cortisone to ³ H-cortisol was calculated as the ratio of AUC for cortisol to total AUC for cortisone and cortisol.

Preparation of compounds of this invention:

Compounds of the present invention of structural formula I can be obtained in accordance with the methods of the following schemes and examples using the appropriate materials, and are further presented by the following particular examples. The compounds illustrated by the examples are not, however, the only class of compounds that is considered to be the compounds of this invention. The examples further illustrate in detail the preparation of the compounds of the present invention. Skilled in this area, experts will easily understand that the known variations in the conditions and processes of the following preparative methods can be used to obtain these compounds. The present compounds are isolated mainly in neutral form, but the triazole moiety can be further converted to a pharmaceutically acceptable salt by dissolution in an organic solvent, followed by the addition of the appropriate acid and subsequent evaporation, precipitation or crystallization. All temperatures are expressed in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured using ion spectroscopy mass spectroscopy (MSIER).

The phrase “standard peptide synthesis conditions” means the binding of a carboxylic acid to an amine using an acid activating agent such as EDC, DCC and BOP in an inert solvent such as dichloromethane in the presence of a catalyst such as HOBT. The use of protective groups for amine and carboxylic acid is intended to facilitate the desired interaction and minimize undesirable reactions, which is well known. The conditions necessary for the removal of protecting groups can be found in standard books such as Greene, T., and Wuts, PGM, Protective Groups in Organic Synthesis , John Wiley & Sons, Inc., New York, NY, 1991. Cbz and BOC are commonly used protecting groups in organic synthesis, and the conditions for their removal are known to those skilled in the art.

Abbreviations used in the description of the preparation of compounds of the present invention:

Aibn 2,2'-azobisisobutyronitrile Boc t-butyloxycarbonyl BBr ₃ boron tribromide 9-BBN 9-borabicyclo [3.3.1] nonane Bn benzyl nBuLi n-butyllithium Cbz benzyloxycarbonyl Cdi 1,1'-carbonyldiimidazole Meotf methyl trifluoromethanesulfonate CH ₂ Cl ₂ dichloromethane CH ₂ I ₂ diiodomethane (COC1) ₂ oxalyl chloride Cs ₂ CO ₃ cesium carbonate DAST (diethylamino) sulfur trifluoride DMAP 4- (dimethylamino) pyridine DMF N, N-dimethylformamide Et ethyl Et ₃ N triethylamine EtOAc ethyl acetate Et ₂ Zn diethylzinc H ₂ O ₂ hydrogen peroxide Me methyl iPr isopropyl Mecn acetonitrile Meon methanol mCPBA meta-chloroperbenzoic acid MS mass spectrum NaBH ₄ sodium borohydride NaHCO ₃ sodium bicarbonate NaOAc sodium acetate Nbs N-bromosuccinimide Ph phenyl Pybrop bromotripyrrolidinophosphonium hexafluorophosphate PPh ₃ triphenylphosphine Pyr pyridine SOCl ₂ thionyl chloride Tfu trifluoroacetic acid Tffh N, N, N ', N'-tetramethylformamide hexafluorophosphate THF tetrahydrofuran TLC thin layer chromatography Tsoh p-toluenesulfonic acid

Reaction Schemes 1-5 illustrate the methods used in the synthesis of compounds of the present invention of structural formula I. All substituents are as defined above, unless otherwise indicated.

Reaction Scheme 1 illustrates a key step in the synthesis of new compounds of structural formula I of the present invention. As shown in Reaction Scheme 1, the secondary amide (1-1) (N-Me or N-Et is preferred) can be heat methylated with pure methyl triflate to give the imino ester (1-2) . Alternatively, other methylating reagents, such as methyl iodide or methyl sulfate without impurities or in a non-nucleophilic organic solvent, can be used. As shown in Scheme 1, bicyclo [2.2.2] octane-1-carboxylic acid (1-3) is converted to acyl hydrazide (1-4) using the TFFH coupling reagent and hydrazine in the presence of a tertiary amine base such as triethylamine. Alternatively, other binding reagents commonly used to prepare amides can be used along with hydrazine for this transformation. Alternatively, bicyclo [2.2.2] octane-1-carboxylic ether can be heated with hydrazine to produce acyl hydrazides (1-4). The acylhydrazide (1-4) and iminoether (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

Alternatively, the reaction can be carried out in the opposite direction, as shown in Reaction Scheme 2. In this procedure, the secondary amide (2-1) is prepared from bicyclo [2.2.2] octane-1-carboxylic acid using a standard peptide synthesis reaction. This compound is methylated to form an iminoether (2-2) and reacted with an acyl hydrazide, as shown in Scheme 1, to form bicyclo [2.2.2] octyl triazoles (2-3) of structural formula I.

Scheme 2

Reaction Scheme 3 shows an alternative approach to the compounds of the present invention of structural formula I, in which the key step is the palladium-catalyzed Suzuki synthesis reaction between bicyclo [2.2.2] octylbromotriazole (3-1) and arylboronic acid to give triazoles (3-2) structural formula I. Under preferred conditions, tetrakis (triphenylphosphine) palladium (0) is used as a catalyst in a solvent of DMF with cesium carbonate, but other catalysts and conditions can be used, as is known to those skilled in the art this area.

Scheme 3

Reaction scheme 4 demonstrates another synthetic approach to the preparation of compounds of structural formula I. Using this procedure, 4- (bicyclo [2.2.2] octyl) oxadiazoles (4-1) are condensed with methylamine in dehydration or in pure form in a melt with methyl ammonium trifluoroacetate, or in a buffered MeOH solution. These reactions are best carried out at elevated temperatures in the reactor under high pressure to prevent loss of methylamine.

Scheme 4

Reaction Scheme 5 demonstrates another synthetic approach to the preparation of compounds of structural formula I. Using this technique, bicyclo [2.2.2] octyl carboxamides (5-1) are converted to iminochlorides (5-2) using a reagent such as oxalyl chloride, thionyl chloride, phosphoroxychloride or phosphoropentachloride, optionally in the presence of DMF. Iminochloride (5-2) is condensed with aryltetrazole in a high boiling inert organic solvent such as toluene to give triazole (5-3) .

Scheme 5

Obtaining [2.2.2] bicyclooctyl intermediates:

The techniques used in the preparation of [2.2.2] bicyclooctyl intermediates for use in the preparation of compounds of the present invention are presented below.

Schemes for the preparation of intermediates 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 I, using, for example, the reactions described in reaction scheme 4.

The preparation of intermediates 1 shows a preferred method for the preparation of oxadiazoles by dehydration of diacyl hydrazides using a dehydrating reagent such as thionyl chloride. Alternatively, other dehydrating reagents such as phosphoroxychloride, phosphorpentachloride or oxalyl chloride may be used. Diacyl hydrazides can be prepared preferably from hydrazide and an activated acid, such as an acid chloride, in the presence of a tertiary amine base. Alternatively, standard peptide synthesis reactions can be used to produce diacyl hydrazide from hydrazide and carboxylic acid.

The preparation of intermediates 2 shows a suitable reagent for the dehydration of diacyl hydrazides to oxadiazoles, namely 2-chloro-1,3-dimethyl-4,5-dihydro-lH-imidazol-3-yn chloride. This reagent in a non-polar solvent (methylene chloride is preferred) together with a tertiary amine base (triethylamine is preferred) gives the desired oxadiazole intermediates in the most efficient manner.

The preparation of intermediates 3 shows the preferred reagent for one-reactor conversion (from hydrazide and carboxylic acid) and the dehydration of diacylhydrazides to oxadiazoles: 2-chloro-1,3-dimethyl-4,5-dihydro-lH-imidazol-3-chloride. This reagent in a non-polar solvent (methylene chloride is preferred) together with a tertiary amine base (triethylamine is preferred) gives the desired oxadiazole intermediates in the most efficient manner.

The scheme for the preparation of intermediate compounds 4 demonstrates an effective method for the preparation of oxadiazoles from secondary amides and hydrazides. The secondary amide (preferably N-Me or N-Et) can be heat methylated with pure methyl triflate to give the imino ester. Alternatively, other methylating reagents, such as methyl iodide or methyl sulfate without impurities or in a non-nucleophilic organic solvent, can be used. Heating the iminoether, thus formed in a high-boiling inert organic solvent in the presence of hydrazide, allows the production of oxadiazoles, as shown in the diagram.

Scheme for the preparation of intermediate compounds 1

Scheme for the preparation of intermediate compounds 2

Scheme for the preparation of intermediates 3

Scheme for the preparation of intermediates 4

Intermediate Scheme 5 shows a preferred method for the synthesis of bicyclo [2.2.2] octane-1-carboxylic acid.

Scheme for the preparation of intermediates 5

Schemes for the preparation of intermediates 6 and 7 demonstrate preferred methods for the preparation of bicyclo [2.2.2] octane-1-carboxylic acids with a heteroaryl group in position R ³ as represented by structural formula I. Oxadiazoles in position R ³ 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 CDI. Alternatively, other reagents suitable for dehydration or peptide synthesis reactions may be used. Intermediate Scheme 7 illustrates a preferred method for synthesizing intermediates of compounds of structural formula I bearing a thiazole group in the R ³ position.

The scheme for the preparation of intermediate compounds 6

Scheme for the preparation of intermediates 7

Schemes for the preparation of intermediates 8-14 show preferred methods for the preparation of intermediates of bicyclo [2.2.2] octane-1-carboxylic acids in the synthesis of compounds of structural formula I with various alkyl or alkenyl or substituted alkyl groups in position R ³ . 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 the product of this reaction can be hydrogenated to give an alkyl group of various lengths and character (which will become R ³ - substituent in structural formula I), depending on the Wittig reagent, as shown in intermediate scheme 9. Alternatively, a double bond can be used to introduce other functional groups, such as hydroxy or fluoro groups, as shown in the gap ary scheme 10. The aldehyde itself may be used to obtain the difluoromethyl group at position R ^3, as shown in Intermediate Scheme 11. The alkene product of the Wittig reaction can undergo numerous other transformations, for example, cyclopropanation, as illustrated in Intermediate Scheme 12. Alternatively, Wittig reagent may contain a distant functional group, for example, ketal, as shown in intermediate scheme 13. This functional group may undergo characteristic transformations of the functional group after after carrying out the Wittig reaction and reduction, for example, hydrolysis of ketal to ketone, as shown in intermediate scheme 13, or reduction of ketal to alcohol, as shown in intermediate scheme 14. Thus, compounds of structural formula I with a variety of different R ³ can be obtained - substituents. Particular examples are presented to reflect the basic principles and do not seek to limit the scope of R ³ substituents.

The scheme for the preparation of intermediate compounds 8

The scheme for obtaining intermediate compounds 9

Scheme for the preparation of intermediate compounds 10

Scheme for the preparation of intermediate compounds 11

The scheme for the preparation of intermediate compounds 12

Scheme for the preparation of intermediate compounds 13

The scheme for the preparation of intermediate compounds 14

The main chemical transformations of the functional group used in the preparation of the compounds of the present invention are presented below in the preparation of the private compounds of the present invention.

These transformations of a functional group in their diversity are generally well understood by specialists in this field.

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

Example 1

3-Methoxy-4- [4-methyl-5- (4-pentylbicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazol-3-yl] phenol (1-F)

Stage A:

To a solution of 4-benzyloxy-2-hydroxybenzonitrile (1-A, WO 00/69841) (7.95 g, 35.3 mmol) and iodomethane (5.43 ml, 87.2 mmol) in DMF (90 ml), cooled to -5 ° C, immediately added the entire amount of sodium hydride (60% 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 brine and dried (MgSO ₄ ). The residue after removal of the solvent in vacuo was triturated with hexane and chromatographed on silica gel with hexane-CH ₂ Cl ₂ (2: 3) to give 4-benzyloxy-2-methoxybenzonitrile (1-B). MS: m / z 240 (M + 1); ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.47 (d, 1H, J = 8.4 Hz), 7.36-7.45 (m, 5H), 6.58 (dd, 1H, J = 2.3, 8.4 Hz), 6.57 (d, 1H, J = 2.3 Hz), 5.10 (s, 2H), 3.88 (s, 3H) ppm.

Stage B:

Vigorously stirred suspension of 4-benzyloxy-2-methoxybenzonitrile (1-B) (1.20 g, 5.0 mmol), sodium azide (732 mg, 11.3 mmol) and triethylamine hydrochloride (1.54 g, 11.3 mmol ) in toluene (6 ml) was heated at 110 ° C for 48 hours. The brown suspension was cooled, water (15 ml) was added and the mixture was stirred for 30 minutes. The organic layer was separated and extracted with water (5 ml). The pH of the combined aqueous extracts was adjusted to about 1 with concentrated HCl. Initially, the precipitated resin solidified with stirring for 30 minutes.

The solid was washed with water and dried to give 5- [4- (benzyloxy) -2-methoxyphenyl] -2H-tetrazole (1-C). ¹ H NMR (500 MHz, CDCl ₃ ): δ 12.9 (br s, 1H), 7.37 (d, 1H, J = 8.7 Hz), 7.34-7.48 (m, 5H ), 6.78 (dd, 1H, J = 2.3, 8.7 Hz), 6.70 (d, 1H, J = 2.3 Hz), 5.15 (s, 2H), 4.05 (s, 3H) ppm

Stage C:

Oxalyl chloride (3.49 ml, 40 mmol) was added dropwise to a solution of N-methyl-4-pentylbicyclo [2.2.2] octane-1-carboxamide (1-D) (952 mg, 4.0 mmol) in dry CH ₂ Cl ₂ at room temperature. After reducing the intense evolution of gas, the solution was stirred at room temperature for 2 hours. CH ₂ Cl _{2 was} carefully removed in vacuo at room temperature and then at 50 ° C. The pure syrup residue was dissolved in toluene (8 ml) and 5- [4- (benzyloxy) -2-methoxyphenyl] -2H-tetrazole (1-C) (1.13 g, 4.0 mmol) was added. The mixture was heated at 120 ° C. for 9 hours. The mixture was cooled and the precipitated solid was filtered, washed with toluene and dried to give a triazole hydrochloride salt. The salt was partitioned between CH ₂ Cl ₂ and 10% aqueous K ₂ CO ₃ . The aqueous phase was extracted twice with CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ extracts were dried (MgSO ₄ ) and evaporated in vacuo. The residue was chromatographed on silica gel with 5% MeOH / CH ₂ Cl ₂ to give 3- [4- (benzyloxy) -2-methoxyphenyl] -4-methyl-5- (4-pentylbicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazole (1-E). MS: m / z 474 (M + 1); ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.33-7.47 (m, 6H), 6.65 (dd, 1H, J = 2.3, 8.5 Hz), 6.60 (d , 1H, J = 2.3 Hz), 5.10 (s, 2H), 3.75 (s, 3H), 3.48 (s, 3H), 2.08 (m, 6H), 1.51 (m, 6H), 1.00-1.35 (m, 8H), 0.89 (t, 3H, J = 7.2) ppm.

Stage D:

Solution of 3- [4- (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 MeOH (8 ml) was hydrogenated for 19 h with 10% Pd / C catalyst (27 mg) at room temperature and atmospheric pressure. The catalyst was filtered and washed with MeOH. MeOH was removed in vacuo to give 3-methoxy-4- [4-methyl-5- (4-pentylbicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazol-3-yl] phenol (1-F). MS: m / z 384 (M + 1); ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 9.94 (s, 1H), 7.09 (d, 1H, J = 8.3), 6.53 (d, 1H, J = 1, 6 Hz), 6.46 (dd, 1H, J = 2.2, 8.2 Hz), 3.72 (s, 3H), 3.40 (s, 3H), 1.95 (m, 6H) 1.44 (m, 6H); 1.07-1.33 (m, 8H); 0.86 (t, 3H, J = 7.2).

Example 2

3-Chloro-4- [4-methyl-5- (4-pentylbicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazol-3-yl] phenol (2-G)

Stage A:

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 (10 ml). The solution was stirred at room temperature for 3 hours and then concentrated in vacuo to give 4-pentylbicyclo [2.2.2] octane-1-carbonyl chloride (2-B). ¹ H NMR (500 MHz, CDCl ₃ ): δ 0.90 (t, 3H); 1.21 (m, 8H); 1.45 (m, 6H); 1.88 (m, 6H) ppm.

Stage B:

N, N-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, 4.45 mmol) and methylamine hydrochloride (1.5 g, 22.3 mmol) in methylene chloride (10 ml) and the mixture was stirred at room temperature for 18 hours. After dilution with methylene chloride, the mixture was washed with water, brine, dried (MgSO ₄ ) and concentrated in vacuo with obtaining N-methyl-4-pentylbicyclo [2.2.2] octane-1-carboxamide (2-C). ¹ H NMR (500 MHz, CDCl ₃ ): δ 0.91 (t, 3H); 1.22 (m, 8H); 1.43 (m, 6H); 1.77 (m, 6H); 2.82 (d, 3H) ppm.

Stage C:

Oxalyl chloride (846 μl, 9.7 mmol) was added dropwise to a solution of N-methyl-4-pentylbicyclo [2.2.2] octane-1-carboxamide (2-C) (230 mg, 0.97 mmol) in methylene chloride (2 , 0 ml) and the mixture was stirred at room temperature for 4 hours. The solvent and excess reagent were removed in vacuo to give N-methyl-4-pentylbicyclo [2.2.2] octane-1-carboxymethyloyl chloride (2-D). Toluene (1.5 ml) was added followed by 5- (2-chloro-4-methoxyphenyl) -lH-tetrazole (2-E) (204 mg, 0.97 mmol) and the mixture was heated under reflux for 18 hours The reaction mixture was cooled to room temperature and the precipitate was filtered, washed with cold toluene, hexane, dissolved in methylene chloride, dried (MgSO ₄ ) and concentrated in vacuo to give 3- (2-chloro-4-methoxyphenyl) -4-methyl-5- (4-pentylbicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazole (2-F). Mass spectrum: 402 (M + 1); ¹ H NMR (500 MHz, CDCl ₃ ): δ 0.94 (t, 3H), 1.27 (m, 8H), 1.56 (m, 6H), 2.13 (m, 6H), 3, 56 (s, 3H), 3.89 (s, 3H), 6.95 (dd, 1H), 7.07 (d, 1H), 7.43 (d, 1H).

Stage D:

Boron tribromide (135 μl, 1.43 mmol) was added dropwise to a solution of 3- (2-chloro-4-methoxyphenyl) -4-methyl-5- (4-pentylbicyclo [2.2.2] oct-1-yl) - 4H-1,2,4-triazole (2-F) (287 mg, 0.714 mmol) in methylene chloride (5 ml) at 0 ° C. The mixture was stirred at room temperature for 2.5 hours. The solution was washed with water, 10% NaHCO ₃ , dried (MgSO ₄ ) and concentrated in vacuo and the residue was purified by column chromatography (silica gel, 5% MeOH / methylene chloride) to give 3-chloro- 4- [4-methyl-5- (4-pentylbicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazol-3-yl] phenol (2-G). Mass spectrum: 388 (M + 1); ¹ H NMR (500 MHz, CDCl ₃ ): δ 0.93 (t, 3H), 1.26 (m, 8H), 1.56 (m, 6H), 2.13 (m, 6H), 3, 58 (s, 3H), 6.69 (dd, 1H), 6.92 (d, 1H), 7.09 (d, 1H) ppm.

Example 3

5- (4- {1-Methyl-5- [2- (trifluoromethyl) phenyl] -1-H-1,2,4-triazol-3-yl} bicyclo [2.2.2] oct-1-yl) pentane -2-ol (3-J)

Stage A:

[2- (2-Methyl-1,3-dioxolan-2-yl) ethyl] (triphenyl) phosphonium bromide (3-A, Synthesis: 532 (1986)) (5.99 g, 12.7 mmol) was stirred in dry THF (200 ml). Potassium bis (trimethylsilyl) amide (20.4 ml, 2M solution in toluene, 10.2 mmol) was added. The reaction was allowed to stir for 30 minutes. Then the reaction mixture was cooled to -78 ° C. Methyl 4-formylbicyclo [2.2.2] octane-1-carboxylate was added via cannula at -78 ° C. The reaction mixture was allowed to warm to room temperature overnight. The volume was reduced by evaporation of THF in vacuo. 100 ml of water was added. 100 ml of diethyl ether was layered onto the mixture. The ether was extracted and dried (MgSO ₄ ). Product (methyl-4 - [(lE) -3- (2-methyl-1,3-dioxolan-2-yl) prop-1-enyl] bicyclo [2.2.2] octane-1-carboxylate (3-B) ) was purified by flash chromatography on silica gel with 10/90 ethyl acetate-hexane.

Stage B:

(Methyl-4 - [(lE) -3- (2-methyl-1,3-dioxolan-2-yl) prop-1-enyl] bicyclo [2.2.2] octane-1-carboxylate (3-B) ( 1.1 g) was stirred in ethanol (75 ml). 10% Pd on charcoal (150 mg) was added on the tip of a spatula. Hydrogen was introduced from the balloon and the mixture was stirred in a hydrogen atmosphere for 3 hours. The palladium on carbon was filtered and ethanol was removed in vacuum to give 4- [3- (2-methyl-1,3-dioxolan-2-yl) propyl] bicyclo [2.2.2] octane-1-carboxylate (3-C).

Stage C:

Methyl 4- [3- (2-methyl-1,3-dioxolan-2-yl) propyl] bicyclo [2.2.2] octane-1-carboxylate (3-C) (1.0 g, 3.38 mmol ) was stirred in a solution of 90% methanol and 10% water (50 ml). An excess of potassium hydroxide (2.0 g) was added. The mixture was refluxed overnight. 1N was added to the cooled mixture. hydrochloric acid (100 ml) and then washed twice with ethyl acetate (100 ml). The combined organic layers were dried (MgSO ₄ ). Ethyl acetate was removed in vacuo to give pure 4- [3- (2-methyl-1,3-dioxolan-2-yl) propyl] bicyclo [2.2.2] octane-1-carboxylic acid (3-D).

Stage D:

4- [3- (2-Methyl-1,3-dioxolan-2-yl) propyl] bicyclo [2.2.2] octane-1-carboxylic acid (3-D) (0.200 g, 0.708 mmol) were combined with hydrazide 2 - (trifluoromethyl) benzoic acid (3-E) (0.173 g, 0.847 mmol) and azeotroped twice from toluene. The mixture was then stirred in dry methylene chloride (10 ml). 2-Chloro-1,3-dimethylimidazolinium chloride (3-F) (0.718 g, 4.25 mmol) was added, followed by 1.184 ml of triethylamine. The reaction mixture was allowed to stir for 2 hours. The reaction mixture was diluted with methylene chloride and washed with water. The resulting oxadiazole, 2- {4- [3- (2-methyl-1,3-dioxolan-2-yl) propyl] bicyclo [2.2.2] oct-1-yl} -5- [2- (trifluoromethyl) phenyl ] -1,3,4-oxadiazole (3-G) was purified by flash chromatography on silica gel with a 50/50 mixture of ethyl acetate-hexane.

Stage E:

2- {4- [3- (2-Methyl-1,3-dioxolan-2-yl) propyl] bicyclo [2.2.2] oct-1-yl} -5- [2- (trifluoromethyl) phenyl] -1 , 3,4-oxadiazole (3-G) (0.158 g) was stirred in a mixture of 90% acetone / 10% water (20 ml). P-Toluenesulfonic acid (10 mg) was added to the solution. The reaction mixture was refluxed for 1 h. The volume was reduced by evaporation of acetone in vacuo. Ethyl acetate (25 ml) and saturated sodium bicarbonate solution (25 ml) were then layered onto the mixture. The ethyl acetate layer was extracted and dried (MgSO ₄ ). The solvent was removed in vacuo to give pure 5- (4- {5- [2- (trifluoromethyl) phenyl] -1,3,4-oxadiazol-2-yl} bicyclo [2.2.2] oct-1-yl) pentane- 2-one (3-H).

Stage F:

5- (4- {5- [2- (Trifluoromethyl) phenyl] -1,3,4-oxadiazol-2-yl} bicyclo [2.2.2] oct-1-yl) pentan-2-one (3-H ) (0.072 g) was stirred in methanol (2 ml) at 0 ° C. Sodium borohydride (20 mg) was added. The reaction mixture was allowed to stir at room temperature. Ethyl acetate (15 ml) and water (15 ml) were then layered onto the mixture. The ethyl acetate layer was extracted and dried (MgSO ₄ ). The solvent was removed in vacuo to give pure 5- (4- {5- [2- (trifluoromethyl) phenyl] -1,3,4-oxadiazol-2-yl} bicyclo [2.2.2] oct-1-yl) pentane- 2-ol (3-I).

Stage G:

5- (4- {5- [2- (Trifluoromethyl) phenyl] -1,3,4-oxadiazol-2-yl} bicyclo [2.2.2] oct-1-yl) pentan-2-ol (3-I ) (50 mg) was placed in a sealed flask in a solution of 2M methylamine (2.5 ml). Salt of TFU was added with a small measuring spoon and the flask was hermetically sealed. The sealed flask was heated to 150 ° C for 3 days. The reaction mixture was diluted with ethyl acetate (15 ml), washed with water (15 ml) and dried (MgSO ₄ ). Ethyl acetate was removed in vacuo. Product, 5- (4- {1-methyl-5- [2- (trifluoromethyl) phenyl] -1-H-1,2,4-triazol-3-yl} bicyclo [2.2.2] oct-1-yl ) pentan-2-ol (3-J), was purified by preparative reverse phase HPLC on a C-18 silica gel column using an acetonitrile-water gradient with 0.1% trifluoroacetic acid buffer. The effluent containing pure triazole was made more basic with 10% NaHCO ₃ , evaporated in vacuo to remove most of the acetonitrile and extracted with methylene chloride. The organic extract was dried (MgSO ₄ ) and evaporated, and the residue was dried in vacuo to obtain the desired compound. MS (ESI ⁺ ) = 422.5 (M + 1); ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.21 (2H, m), 1.23 (3H, d, J = 6.5 Hz), 1.29 (2H, m), 1.57 ( 6H, m), 2.13 (6H, m), 3.47 (3H, s), 3.85 (1H, m), 7.51 (1H, m), 7.70 (2H, m), 7.85 (1H, m) ppm.

Example 4

Stage A:

To a suspension of 4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid (4-A) (0.906 g, 4.27 mmol) in dichloromethane (20 ml) was added 1,1'-carbonyldiimidazole (1.04 g, 6.41 mmol). The reaction mixture turned into a clear solution with constant evolution of gas. After the mixture was stirred at room temperature for 1 h, 4-fluorobenzamidoxime (1.98 g, 12.8 mmol) was added. Stirring was continued overnight. The mixture was then concentrated and the residue was refluxed in toluene for 16 hours. 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- [3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl] bicyclo [2.2.2] octane-1-carboxylate (4-B) as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.96-1.99 (m, 6H), 2.08-2.14 (m, 6H), 3.71 (s, 3H), 7.16 -7.20 (m, 2H), 8.08-8.10 (m, 2H) ppm, ESI-MS: m / z (M + H) 349.2.

Stage B:

Ether (4-B) (1.01 g, 3.06 mmol) was treated with KOH (0.52 g, 9.18 mmol) in methanol / water (95/5, 20 ml). After heating it at 60 ° C for 12 h, the reaction mixture was concentrated, diluted with water, and extracted twice with ethyl acetate. An aqueous solution of 1N was added to the aqueous layer. HCl and a white solid precipitated. The precipitate of 4- [3- (4-fluorophenyl) -1,2,4-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: m / z (M + H) 317.2.

Stage C:

A mixture of acid (4-C) (138.9 mg, 0.439 mmol) and 2- (trifluoromethyl) benzoic acid hydrazide (4-D) (89.7 mg, 0.439 mmol) was first distilled with toluene three times. Dichloromethane (7 ml) was added to the mixture as a solvent. To the resulting suspension was added 2-chloro-1,3-dimethylimidazolinium chloride (743 mg, 4.39 mmol), followed by the addition of triethylamine (1.2 ml, 8.78 mmol). The mixture was allowed to stir at room temperature under nitrogen for 48 hours to confirm completion of the reaction. Then the reaction mixture was diluted with dichloromethane, washed with water, 1N. HCl, saturated aqueous sodium bicarbonate and finally brine. 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 eluent to give 3- (4-fluorophenyl) -5- (4- {5- [2- (trifluoromethyl) phenyl] -1,3,4- oxadiazol-2-yl} bicyclo [2.2.2] oct-1-yl) -1,2,4-oxadiazole (4-E) as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 2.25 (s, 12H), 7.21 (t, J = 8.7 Hz, 2H), 7.74-7.76 (m, 2H), 7.91 (m, 1H), 8.11-8.15 (m, 3H) ppm, ESI-MS: m / z (M + H) 485.2.

Stage D:

A mixture of the above 1,2,4-oxadiazole (4-E) (115.2 mg, 0.238 mmol) and a salt of methylamine and trifluoroacetic acid (1.73 g, 11.9 mmol) in a 2M solution of methylamine in methanol (4 ml ) was heated at 150 ° C in a sealed tube for 48 hours. Then the mixture was concentrated and the residue was taken up in dichloromethane, washed with saturated sodium bicarbonate solution. The organic phase was concentrated and the residue was purified using reverse phase HPLC with a TFU-buffered acetonitrile / water mixture (40-80%) as an eluent. The product containing fractions were combined, neutralized with saturated aqueous sodium bicarbonate and lyophilized from acetonitrile / water to give 3- (4-fluorophenyl) -5- (4- {4-methyl-5- [2- (trifluoromethyl) phenyl] -4H-1,2,4-triazol-3-yl} bicyclo [2.2.2] oct-1-yl) -1,2,4-oxadiazole (4-F). ¹ H NMR (CDCl ₃ ): δ 2.25-2.35 (m, 12H), 3.53 (s, 3H), 7.21 (t, J = 8.7 Hz, 2H), 7.54 (m, 1H), 7.73 (m, 2H), 7.88 (m, 1H), 8.13 (m, 2H), ESI-MS: m / z (M + H) 498.2.

Example 5

4- [4-Methyl-5- (4-phenylbicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazol-3-yl] -3- (trifluoromethyl) phenol (5-F )

Preparation of 4-phenylbicyclo [2.2.2] octane-l-carboxylic acid (5-A). References: Chapman, NB, Sotheeswaran, S., and Toyne, KJ, J. Org. Chem . 35: 917-923 (1970).

Stage A:

To a solution of 4-phenylbicyclo [2.2.2] octane-l-carboxylic acid (5-A) (70 mg, 0.30 mmol) in methylene chloride (1 ml), stirred with magnetic stirrer, was added 2M oxalyl chloride in methylene chloride (0 61 ml, 1.22 mmol). Two drops of catalytic DMF were added to catalyze the interaction. The reaction mixture was stirred for 30 minutes and the solvent and reagent were removed in vacuo. Methylene chloride (1 ml) was added to the residue, followed by 4- (benzyloxy) -2- (trifluoromethyl) benzoic acid hydrazide (5-B) (141 mg, 0.46 mmol) and triethylamine (0.07 ml, 0.46 mmol). The reaction mixture was stirred at room temperature overnight to give 5-C, N ′ - [4- (benzyloxy) -2- (trifluoromethyl) benzoyl] -4-phenylbicyclo [2.2.2] octane-l-carbohydrazide intermediate, which was not allocated. (5-C) 2-chloro-1,3-dimethylimidazolinium chloride (257 mg, 1.52 mmol), further triethylamine (0.42 ml, 3.04 mmol) and methylene chloride (2 ml) were then added to the crude product. The reaction mixture was stirred at room temperature for 4 hours. Then the reaction mixture was diluted with methylene chloride (30 ml) and washed with water (30 ml) twice and brine once (30 ml). The combined aqueous layers were extracted with methylene chloride (25 ml) once. The combined organic layers were dried (MgSO ₄ ) and the solvent was removed in vacuo. The residue was chromatographed on silica gel with 10% ethyl acetate in hexane as an eluent to give 2- [4- (benzyloxy) -2- (trifluoromethyl) phenyl] -5- (4-phenylbicyclo [2.2.2] oct-1-yl) - 1,3,4-oxadiazole (5-D). MS: m / z 505 (M + 1) .

Stage B:

Methylamine trifluoroacetate salt (380 mg, 2.61 mmol) and 2- [4- (benzyloxy) -2- (trifluoromethyl) phenyl] -5- (4-phenylbicyclo [2.2.2] oct-1-yl) -1, 3,4-oxadiazole (5-D) was suspended in a 2M solution of methylamine in methanol (1.3 ml, 2.61 mmol) and heated at 150 ° C. overnight. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (25 ml) and saturated aqueous sodium bicarbonate (30 ml). The layers were separated and the aqueous layer was extracted twice with ethyl acetate (25 ml). The combined organic layers were washed with brine, dried (MgSO ₄ ) and the solvent was removed in vacuo. The residue was dissolved in methanol (8 ml) and purified by reverse phase chromatography using gradient elution from 10% acetonitrile (0.1% TFA) / water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 10 min (20 ml / min). The product containing fractions were partitioned between saturated aqueous sodium bicarbonate (25 ml) and methylene chloride (15 ml). The layers were separated and the aqueous layer was extracted with methylene chloride (15 ml) three times, dried (MgSO ₄ ) and the solvent was removed in vacuo to give 3- [4- (benzyloxy) -2- (trifluoromethyl) phenyl] -4-methyl-5- ( 4-phenylbicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazole (5-E). MS: m / z 518 (M + 1) .

Stage C:

3- [4- (Benzyloxy) -2- (trifluoromethyl) phenyl] -4-methyl-5- (4-phenylbicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazole (5 -E) (27 mg, 0.05 mmol) was dissolved in ethyl acetate / methanol (1: 1, 4 ml), to which 10% palladium-carbon (4 mg) was added. Then the reaction mixture was placed in a hydrogen atmosphere and stirred for 3 hours at room temperature and pressure. After appropriate removal of the hydrogen atmosphere, palladium was filtered through a filter and washed with methanol (40 ml). 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-F). MS: m / z 428 (M + 1); ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.92 (6H, m), 2.11 (6H, m), 3.41 (3H, s), 7.17 (2H, m), 7, 24 (1H, m), 7.31 (2H, m), 7.38 (3H, m) ppm.

Example 6

3- {4- [2- (Ethylsulfonyl) ethyl] bicyclo [2.2.2] oct-1-yl} -4-methyl-5- [2- (trifluoromethyl) phenyl] -4H-1,2,4-triazole (6-6)

Stage A:

Diethyl (ethylsulfonomethane) phosphonate (1.12 g, 4.6 mmol) (Popoff, IC et al., J. Org. Chem., 34: 1128-30 (1969)) and 4-carbomethoxybicyclo [2.2.2] octane -1-carboxaldehyde (6-1) (0.82 g, 4.2 mmol) (Adcock, W., Kok, GB, J. Org. Chem ., 50: 1079-1087 (1985)) was dissolved in 8 ml absolute methanol. The mixture was placed under a nitrogen atmosphere, 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 refluxed for 4 hours, then cooled to 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 1: 1 MeOH / water. The resulting white precipitate was collected and dried in vacuo to give an unsaturated sulfone 6-2 . MS (ESI ⁺ ): m / z 287 (M + 1).

Stage B:

Sulfone 6-2 (880 mg, 3.08 mmol) was dissolved in a 1: 2 ethyl acetate / methanol mixture (30 ml), placed in a nitrogen atmosphere, then treated with 10% Pd / C (800 mg). The reaction mixture was placed in a hydrogen atmosphere and stirred vigorously for 90 minutes. 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.

Stage C:

Ether 6-3 (880 mg, 3 mmol) was dissolved in a solution of 10% water / methanol (100 ml) and treated with 1 g of potassium hydroxide. The reaction mixture was heated at 60 ° C for 1 h, then at 45 ° C overnight. The mixture was concentrated in vacuo, then adjusted to pH 2 with 1M HCl and extracted with three portions of methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to give 4- [2- (ethylsulfonyl) ethyl] bicyclo [2.2.2] octane-1-carboxylic acid (6-4) .

Stage D:

Carboxylic acid 6-4 (810 mg, 2.96 mmol) was dissolved in 12 ml of anhydrous methylene chloride in a nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 4.4 ml, 8.8 mmol) and successively 5 drops of DMF. The reaction mixture was stirred at room temperature in a nitrogen atmosphere for 90 minutes, then evaporated and placed in vacuum for 20 minutes. The acid chloride was dissolved in anhydrous methylene chloride (12 ml), cooled in an ice bath, and then dropwise treated with a solution of methylamine (2M in THF, 8.9 ml, 17.8 mmol). After completion of the amine addition, 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 and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel chromatography, eluting with a gradient from 0 to 3.5% methanol in methylene chloride, to give

4- [2- (ethylsulfonyl) ethyl] -N-methylbicyclo [2.2.2] octane-1-carboxamide 6-5 in the form of a white powder. MS (ESI ⁺ ): m / z 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 (2M in methylene chloride, 0.77 ml, 1.54 mmol) and DMF (2 drops). The reaction mixture was stirred at room temperature for 1 h, then the solvent was removed by evaporation under reduced pressure. The residue was redissolved in anhydrous toluene (2 ml) and treated with 5- [2- (trifluoromethyl) phenyl] -1H-tetrazole (214 mg, 1 mmol). The mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and the cream-colored precipitate was filtered off and washed to obtain 300 mg of the crude product as an HCl salt. The mixture was taken up in methylene chloride / 1N. HCl and the aqueous layer were washed with two additional portions of methylene chloride. The organic layers were combined and evaporated, and the residue was flash chromatographed on silica gel. Elution was carried out in a gradient in the range from 0 to 5% methanol / methylene chloride. The appropriate fractions were combined and evaporated to give 3- {4- [2- (ethylsulfonyl) ethyl] bicyclo [2.2.2] oct-1-yl} -4-methyl-5- [2- (trifluoromethyl) phenyl] -4H- 1,2,4-triazole (6-6) as a white powder. MS (ESI ⁺ ): 456.2 (M + 1); ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.46 (3H, t, J = 7.3 Hz), 1.63 (6H, m), 1.78 (2H, m), 2.19 ( 6H, m), 2.96 (2H, m), 3.05 (2H, q, J = 7.2 Hz), 3.50 (3H, s), 7.56 (1H, m), 7 72 (2H, m); 7.87 (1H, m) ppm.

Example 7

3- {4- [3- (Ethylsulfonyl) propyl] bicyclo [2.2.2] oct-1-yl} -4-methyl-5- [2- (trifluoromethyl) phenyl] -4H-1,2,4-triazole (7-J)

Stage A:

(Benzyloxycarbonylmethyl) triphenylphosphonium bromide (4.6 g, 9.4 mmol) was azeotroped twice from toluene and then suspended in 30 ml of dry THF. Potassium hexamethyldisilazide (0.5 M in toluene, 16.8 ml, 8.4 mmol) was added dropwise at room temperature and the yellow solution was allowed to stir for 1 h, after which it turned milky white. A solution of 4-carbomethoxy-bicyclo [2.2.2] octane-1-carboxaldehyde (7-A) (0.50 g, 2.55 mmol) was prepared (Adcock, W., Kok, GB, J. Org. Chem ., 50: 1079-1087 (1985)) and benzoic acid (0.015 g, 0.13 mmol) in 2 ml of dry THF and was added dropwise with a syringe at room temperature. The mixture was heated to 90 ° C and allowed to mix at reflux temperature, after which the mixture was diluted with 200 ml of ethyl acetate and washed successively with 50 ml of 1N each. HCl (twice), saturated aqueous sodium bicarbonate and brine. The organic layer was dried using magnesium sulfate, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluting with a gradient of 5% to 10% ethyl acetate in hexane to give methyl 4 - [(lE) -3- (benzyloxy) -3-oxoprop-1-en-1-yl] bicyclo [2.2.2 ] octane-1-carboxylate (7-B) as a colorless oil. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.4 (5H, m), 6.94 (1H, d, J = 17 Hz), 5.77 (1H, d, J = 17 Hz), 5 21 (2H, s), 3.69 (3H, s), 1.86 (6H, m), 1.63 (6H, m) ppm.

Stage B:

7-B diester (0.625 g, 1.90 mmol) was dissolved in a 1: 1 mixture of ethyl acetate / methanol (30 ml), placed in a nitrogen atmosphere, then treated with 10% Pd / C (500 mg) and 0.1 ml of acetic acid . The reaction mixture was placed in a hydrogen atmosphere and stirred vigorously for 2 hours. The resulting solution was filtered through celite and the solvent was removed under reduced pressure. The residue was partitioned between 200 ml of ethyl acetate and 200 ml of 1N solution. NaOH. The aqueous 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 obtain 3- [4- (methoxycarbonyl) bicyclo [2.2.2] oct-1-yl] propanoic acid (7-C) . ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.62 (3H, s), 2.20 (2H, brt, J = 9 Hz), 1.75 (6H, m), 1.47 ( 2H, broad t, J = 9 Hz), 1.38 (6H, m) ppm.

Stage C:

7-C carboxylic acid (400 mg, 1.67 mmol) was dissolved in tetrahydrofuran (5 ml) and borane (1M solution in THF, 2.17 ml, 1.3 eq.) Was added dropwise at room temperature. After 2 hours, the reaction mixture was added to 50 ml of 1N. HC1 and 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 obtain crude methyl 4- (3-hydroxypropyl) bicyclo [2.2.2] octane-l-carboxylate (7-D), which was used without purification in the next step. ¹ H NMR (500 MHz, CD ₃ OD): δ 3.66 (3H, s), 3.62 (2H, t, J = 6.5 Hz), 1.78 (6H, m), 1.50 (2H, m), 1.41 (2H, m), 1.17 (2H, m) ppm.

Stage D:

The hydroxyether 7-D (430 mg, 1.9 mmol) was dissolved in 2.5 ml of anhydrous methylene chloride in a nitrogen atmosphere, treated with pyridine (0.5 ml) and methanesulfonyl chloride (0.368 ml, 4.8 mmol) and stirred for 4 hours at room temperature. The mixture was diluted with 100 ml ethyl acetate and washed with aqueous 1N. HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. Crude methyl

4- {3 - [(methylsulfonyl) oxy] propyl} bicyclo [2.2.2] octane-l-carboxylate (7-E) , thus obtained, was used without purification in the following reaction. ¹ H NMR (500 MHz, CDCl ₃ ): δ 4.22 (2H, t, J = 7.5 Hz), 3.68 (3H, s), 3.04 (3H, s), 1.82 ( 6H, m), 1.70 (2H, m), 1.44 (6H, m), 1.24 (2H, m) ppm.

Stage E :

7-E mesylate (3.30 g, 10.9 mmol) was dissolved in DMF (20 ml) and treated with sodium ethanethiolate (1.82 g, 21.7 mmol). The solution was stirred at 45 ° C for 3 hours, then the mixture was diluted with 100 ml of ethyl acetate and washed twice with aqueous 1N. HCl, then saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to give methyl 4- [3- (ethylthio) propyl] bicyclo [2.2.2] octane-l-carboxylate (7-F) as a crude oil, which was used in the next step without cleaning up. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.68 ppm. (3H, s), 2.56 (2H, q, J = 7 Hz), 2.51 (2H, t, J = 7.5 Hz), 1.80 (6H, m), 1.52 ( 2H, m), 1.42 (6H, m), 1.28 (2H, t, J = 7 Hz), 1.02 (2H, m).

Stage F:

Sulfide 7-F (3.0 g, 11 mmol) was dissolved in methylene chloride (50 ml) and treated with m-chloroperbenzoic acid (75%, 6.2 g). The solution was stirred at room temperature for 2 hours, then the mixture was diluted with 100 ml of methylene chloride and washed with saturated aqueous sodium bicarbonate, then twice with saturated aqueous sodium bisulfite, then twice with saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to give methyl 4- [3- (ethylsulfonyl) propyl] bicyclo [2.2.2] octane-l-carboxylate (7-G) as a crude oil, which was used in the next step without cleaning up. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.68 ppm. (3H, s), 2.56 (2H, q, J = 7 Hz), 2.51 (2H, t, J = 7.5 Hz), 1.80 (6H, m), 1.52 ( 2H, m), 1.42 (6H, m), 1.28 (2H, t, J = 7 Hz), 1.02 (2H, m) ppm.

Stage G:

Sulfone 7-G (3.1 g, 10 mmol) was dissolved in 9: 1 MeOH / water (50 ml) and treated with potassium hydroxide (3 g). The solution was stirred at room temperature overnight, then 1N was added to the mixture. HC1 and extracted four times with 50 ml of methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 4- [3- (ethylsulfonyl) propyl] bicyclo [2.2.2] octane-l-carboxylic acid (7-H) , which was used in the next step without purification. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.03 (2H, q, J = 7 Hz), 2.94 (2H, dd, J = 7.5 Hz), 1.84 (8H, m ), 1.45 (8H, m), 1.30 (2H, m) ppm.

Stage H:

7-H carboxylic acid (3.0 g, 11 mmol) was dissolved in 50 ml of anhydrous methylene chloride in a nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 16.2 ml, 32.4 mmol) and then 5 drops of DMF. The solution was stirred at room temperature in a nitrogen atmosphere for 90 minutes, then evaporated and placed in vacuum for 20 minutes. The acid chloride was dissolved in anhydrous methylene chloride (12 ml), cooled in an ice bath, and then dropwise treated with a solution of methylamine (2M in THF, 27 ml, 54 mmol). After methylamine was added, 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 and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel chromatography, eluting with a gradient from 0 to 3% methanol in ethyl acetate, to give 4- [3- (ethylsulfonyl) propyl] -N-methylbicyclo [2.2.2] octane-1-carboxamide 7-I as a white powder. MS (ESI ⁺ ) = 302 (M + 1); ¹ H NMR (500 MHz, CDCl ₃ ): δ 5.56 (1H, br s), 3.02 (2H, q, J = 7 Hz), 2.94 (2H, dd, J = 7, 5 Hz), 2.82 (3H, d, J = 4 Hz), 1.80 (8H, m), 1.45 (9H, m), 1.28 (2H, m) ppm.

Stage I:

Methylamide 7-I (0.470 g, 1.56 mmol) was dissolved in anhydrous methylene chloride (5 ml) and treated with oxalyl chloride (2M in methylene chloride, 1.56 ml, 3.12 mmol) and DMF (2 drops). The solution was stirred at room temperature for 1 h, then the solvent was removed by evaporation under reduced pressure. The residue was redissolved in anhydrous toluene (7 ml) and treated with 5- [2- (trifluoromethyl) phenyl] -lH-tetrazole (368 mg, 1.72 mmol). The mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered and washed to obtain 300 mg of the crude product as an HCl salt. The salt was taken up in methylene chloride / ln. HCl and the aqueous layer were washed with two additional portions of methylene chloride. The organic layers were combined and evaporated and the residue was flash chromatographed on silica gel. Elution was performed with a gradient in the range from 0 to 5% methanol / methylene chloride. The appropriate fractions were combined and evaporated to give 3- {4- [3- (ethylsulfonyl) propyl] bicyclo [2.2.2] oct-1-yl} -4-methyl-5- [2- (trifluoromethyl) phenyl] -4H- 1,2,4-triazole (7-J) as a white powder. MS (ESI ⁺ ) = 470.4 (M + 1), ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.87 (1H, m), 7.72 (2H, m), 7.56 (1H , m), 3.49 (3H, s), 3.05 (2H, q, J = 7.2 Hz), 2.96 (2H, m), 2.18 (6H, m), 1, 86 (2H, m), 1.62 (6H, m), 1.46 (3H, t, J = 7.3 Hz), 1.36 (2H, m) ppm.

Example 8

4-Methyl-3- [2- (trifluoromethyl) phenyl] -5- (4- {2 - [(trifluoromethyl) sulfonyl] ethyl} bicyclo [2.2.2] oct-1-yl) -4H-1,2, 4-triazole (8-G)

Stage A:

Potassium hexamethyldisilazide (0.5 M in toluene, 48.6 ml) was added dropwise to a stirred solution of methyltriphenylphosphonium bromide (9.1 g, 12.8 mmol) in THF (50 ml) at 0 ° C over 5 minutes. The resulting mixture was allowed to warm to room temperature for 1 h, then was again cooled to 0 ° C and treated with methyl 4-formylbicyclo [2.2.2] octane-l-carboxylate 8-A (Chapman, NB et al., J. Org. Chem., 1970, 35, 917) (2.5 g, 12.8 mmol). The reaction mixture was stirred at room temperature for 18 hours, then diluted with EtOAc (350 ml). The organic phase was washed with aqueous HCl (1N), saturated aqueous sodium bicarbonate and brine, then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The resulting solid was purified by flash chromatography on silica gel eluting with a 0-4% EtOAc / hexane gradient. The resulting methyl 4-vinyl bicyclo [2.2.2] octane-l-carboxylate (8-B) was isolated as a clear, colorless oil.

Stage B:

To a stirred solution of 8-B olefin (1.6 g, 8.3 mmol) in THF (20 ml) was added dropwise 9-BBN (0.5 M in THF, 49 ml). The solution was allowed to stir at room temperature for 18 hours, then it was sequentially treated with ethanol (14.5 ml), aqueous NaOH (5N, 5 ml) and hydrogen peroxide (30% aqueous solution, 9.7 ml). The pH of the reaction mixture was adjusted to 2 with aqueous HCl (1N) and extracted three times with CH ₂ C1 ₂ . The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ) and scraped off. The resulting 8-C alcohol was purified by silica gel chromatography, eluting with a gradient of 30-50% EtOAc / hexane, and isolated as a clear, colorless oil.

Stage C:

A solution of 8-C alcohol (1.5 g, 7.1 mmol) in CH ₂ C1 ₂ (7.5 ml), pyridine (1.5 ml) was cooled to 0 ° C and treated with methanesulfonyl chloride (1.65 ml, 21 , 3 mmol), drip, for 5 minutes The reaction mixture was allowed to warm to room temperature, then was stirred for 3 hours. EtOAc (300 ml) was added and the organic phase was washed with an aqueous HCl solution (1N) three times, a saturated aqueous sodium bicarbonate solution two times and brine. The organic layer was dried (Na ₂ SO ₄ ) and scraped off to give methyl 4- {2 - [(methylsulfonyl) oxy] ethyl} bicyclo [2.2.2] octane-l-carboxylate 8-D as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.52 (6H, m), 1.66 (2H, t, J = 7.1 Hz), 1.84 (6H, m), 3.04 ( 3H, s), 3.69 (3H, s), 4.29 (2H, t, J = 7.2 Hz) ppm.

Stage D:

A solution of 8-D (0.25 g, 0.86 mmol), potassium trifluoromethanesulfinate (0.3 g, 1.72 mmol) and tetrabutylammonium iodide (0.15 g, 0.4 mmol) in DMF (5 ml) were heated at 140ºC for 5 hours in a nitrogen atmosphere. The solution was then cooled to room temperature and diluted with EtOAc (100 ml) and washed twice with aqueous HCl (1N) and brine. The organic layer was dried (Na ₂ SO ₄ ), scraped off and flash chromatographed on silica gel, eluting with a 5-20% EtOAc / hexane gradient. The resulting trifluoromethylsulfone 8-E was isolated as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 1.50 (6H, m), 1.78 (2H, m), 1.82 (6H, m), 3.17 (2H, m), 3, 67 (3H, s) ppm.

Stage E:

8-E methyl ester (0.035 g, 0.11 mmol) was converted to 8-F methylamide using the methods described in example 6 in steps C and D.

N-methyl-4- {2 - [(trifluoromethyl) sulfonyl] ethyl} bicyclo [2.2.2] octane-l-carboxamide was isolated as a white solid; MS (ESI ⁺ ) = 328.2 (M + 1).

Stage F:

Methylamide 8-F (0.030 g, 0.092 mmol) was converted to triazole 8-G according to the procedure for Example 6, Step E. 4-Methyl-3- [2- (trifluoromethyl) phenyl] -5- (4- {2 - [( trifluoromethyl) sulfonyl] ethyl} bicyclo [2.2.2] oct-1-yl) -4H-1,2,4-triazole (8-G) 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 prepared:

An example of a pharmaceutical composition

As a private embodiment of the oral composition.

98

CH ₃

470 99

CH ₃

484 one hundred

CH ₃

490 101

CH ₃

508 102

CH ₃

402

Following methods similar to those described above, compounds 103-654 of formula I of the present invention were prepared and tested in accordance with the procedure described above on pages 29-33 of the activity. In particular, an inhibitory concentration (IC ₅₀ ) expressed in nanomoles is provided for all compounds; for some, the percent conversion of ³ H-cortisone to ³ H-cortisol is given.

The tables below show the specific compounds with different group values, which fully confirm the presence of all types of compounds of this invention that have the properties of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1, GSD-1 (hHSDl).

An example of a pharmaceutical composition:

As a particular embodiment of the oral composition of the compounds of this invention, 50 mg of any of the compounds of Examples 1-8 is formed with a sufficient amount of finely divided lactose to give a total amount of 580 to 590 mg to fill a 0-size hard gelatin capsule.

Although the invention has been described and illustrated with reference to its particular embodiments, those skilled in the art will understand that, without departing from the spirit and scope of the invention, changes, modifications and substitutions can be made therein. For example, effective dosages other than those set forth above may be applied due to variations in the response of a person who is being treated for a particular condition. Moreover, the observed pharmacological response may vary in accordance with and depends on the selected active compound or on, if present, pharmaceutical carriers, as well as on the type of composition and mode of administration, and such expected variations or differences in results are expected in accordance with the objects and a practical embodiment of the present invention. Thus, the invention should be limited only to the scope of the following claims and to interpret such claims as broadly as possible.

Claims (26)

1. The compound of structural formula I

or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen;
X is selected from the group consisting of a single bond, NH - and groups:

,

and

,
in which R ⁶ means hydrogen;
R ¹ selected from the group consisting of phenylcarbonyl or aryl, where specified in the definition of R ¹ aryl is:
naphthyl, possibly substituted with OH or C _1-3 alkoxy, phenyl, optionally substituted with one to three substituents independently selected from R ⁵ ,
where R ⁵ independently selected from the group consisting of
formed
C _1-6 alkyl,
C _1-3 alkoxy,
NO ₂
NH ₂
halogen
cyano
CF ₃ -
CH ₂ CF ₃ ,
OCF ₂ H,
OR ⁷ where R ⁷ means hydrogen,
OCF ₃ ,
phenyl
phenyloxy
benzyloxy
C _3-7 cycloalkyl,
CO ₂ R ⁷ where R ⁷ means hydrogen or C _1-6 alkyl,
S (O) _p R ⁶ , where p is 0, 1 or 2, and R ⁶ is C _1-8 alkyl, diC _1-6 alkylamino, or pyrazolyl,
C (O) N (R ⁷ ) ₂ , where R ⁷ are the same and mean hydrogen,
NR ⁶ C (O) R ⁶ , where R ⁶ means hydrogen, R ^{6 '} means hydrogen, C _1-6 alkyl,
NR ⁷ SO ₂ R ⁶ where R ⁷ means hydrogen and R ⁶ means C _1-6 alkyl,
SO ₂ N (R ⁷ ) ₂ , where R ⁷ means hydrogen or C _1-6 alkyl;
or R ^{1 is} selected from heteroaryl, wherein said heteroaryl is benzofuranyl, benzopyrrole, indolyl, quinolinyl, pyrimidinyl, pyridinyl, 1,3-benzodioxolanyl or thiophenyl, pyrazolyl and triazolyl, optionally substituted with one to three substituents independently selected from hydrogen, halogen C _1-3 alkyl, C _3-7 cycloalkyl, phenyl optionally substituted with halogen or C _1-3 alkoxy;
R ² selected from the group consisting of
hydrogen
C _1-8 alkyl,
C _2-6 alkenyl and
C _3-6 cycloalkyl;
R ³ selected from the group consisting of
hydrogen
C _1-10 alkyl
C _2-10 alkenyl,
C _3-6 cycloalkyl and
where specified for R ³ alkyl, alkenyl and cycloalkyl unsubstituted or substituted by one to five groups independently selected from R ⁸ :
oxo
hydrogen
halogen
OR ⁷ where R ⁷ = H or alkyl;
CF ₃ ;
tetrazolyl;
(CH ₂ ) _n CO ₂ R ⁷ where n = 0-2, R ⁷ means hydrogen or C _1-6 alkyl;
(CH ₂ ) _n NR ⁷ SO ₂ R ⁶ , where n = 0-2, R ⁶ is optionally substituted with halogen atoms C _1-6 alkyl, phenyl optionally substituted with halogen atoms; R ⁷ means hydrogen or C _1-6 alkyl;
(CH ₂ ) _n SO ₂ OR ⁷ where R ⁷ -H;
(CH ₂ ) _n S (O) _p R ⁶ where n = 0-2, p = 0, 1 or 2, and R ⁶ represents:
phenyl,
phenyl optionally substituted with halogen,
C _1-6 alkyl;
C _1-6 alkyl, possibly substituted with NH ₂ ,
C _1-6 alkyl optionally substituted with halogen atoms
or
R ³ selected from the group consisting of
phenyl
heteroaryl and heterocyclyl;
where specified for R ³ aryl, heteroaryl and heterocyclyl are unsubstituted or substituted by one to three substituents independently selected from R ⁹ where R ⁹ selected from:
hydrogen;
C _1-6 alkyl;
CF ₃ CH ₂ ;
C _3-7 cycloalkyl;
aryl;
heteroaryl, or heterocyclyl,
halogen;
OR ⁷ where R ⁷ = H or R ⁷ = R ⁶ ;
N (R ⁷ ) ₂ , where R ⁷ means C _1-6 alkyl;
(CH ₂ ) _n NR ⁷ SO ₂ R ⁶ , where n = 0-2, R ⁶ is optionally substituted C _1-6 alkyl, phenyl, R ⁷ is hydrogen or C _1-6 alkyl;
(CH ₂ ) _n S (O) _p R ⁶ , where n = 0-2, p = 0, 1 or 2, R ⁶ is optionally substituted with halogen or carboxy; C _1-6 alkyl optionally substituted with halogen phenyl or pyrimidinyl;
(CH ₂ ) _n C (O) N (R ⁷ ) ₂ ,;
(CH ₂ ) _n NR ⁶ C (O) R ⁶ where R ⁶ is C _1-6 alkyl and R ⁶ (CH ₂ ) _{n is} heteroaryl;
(CH ₂ ) _n CO ₂ R ⁷ where R ⁷ is hydrogen or C _1-6 alkyl;
(CH ₂ ) _n N (R ⁷ ) ₂ ;
(CH ₂ ) _n NR ⁶ CO ₂ R ⁷ ;
and where specified in the definition of R ⁸ and R ⁹ :
aryl (phenyl), heteroaryl, cycloalkyl and heterocyclyl are unsubstituted or substituted by one to three substituents independently selected from R ¹⁰ :
halogen;
hydroxy;
C _1-4 alkyl;
C _1-4 alkoxy;
trifluoromethyl;
trifluoromethoxy and
and where in the definition of R ⁵ , R ⁸ and R ⁹ any methylene carbon atom (CH ₂ ) is unsubstituted or substituted by one or two groups independently selected from R ¹¹ :
halogen;
hydroxy and
C _1-4 alkyl;
or in the definition of R ⁵ , R ⁸ and R ^9, two substituents on the same carbon atom of the methylene group (CH ₂ ) taken together with the carbon atom to which they are attached form a cyclopropyl group;
each R ⁷ is hydrogen or R ⁶ ;
and each R ^{6 is} independently selected from the group consisting of
hydrogen
C _1-8 alkyl,
C _3-7 cycloalkyl;
and where the definitions in R ⁶ alkyl and cycloalkyl are unsubstituted or substituted by one to five substituents independently selected from R ¹²
halogen
oxo
C _1-4 alkoxy,
C _1-4 alkylthio,
hydroxy
amino;
or R ^{6 is} selected from the group consisting of
aryl
heteroaryl;
where the aryl and heteroaryl indicated in the definition of R ^{6 are} unsubstituted or substituted and have from one to three substituents independently selected from R ¹³
halogen
C _1-4 alkyl,
hydroxy
amino,
carboxy
trifluoromethyl,
trifluoromethoxy,
piano, and
C _1-4 alkoxy;
either two R ⁶ groups together with the atom to which they are attached form a 5-8 membered mono- or bicyclic system, optionally containing an additional heteroatom selected from O, S and NC _1-4 alkyl,
each p is independently 0, 1, or 2, unless otherwise indicated;
each n is independently 0, 1, or 2 unless otherwise indicated. 2. The compound according to claim 1, where R ² represents cyclopropyl, C _1-3 alkyl or C _2-3 alkenyl and R ¹ represents phenyl or naphthyl, in which phenyl is unsubstituted or substituted and has from one to three substituents, independently selected from R ⁵ , and naphthyl, optionally substituted with an OH group or a C _1-3 alkoxy group. 3. The compound according to claim 2, where R ^{5 is} selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylsulfonyl. 4. The compound according to claim 3, where R ² represents methyl. 5. The compound according to claim 1, where
X represents a single bond;
R ¹ represents phenyl or naphthyl in which phenyl is unsubstituted or substituted and has one to three substituents independently selected from R ⁵ and naphthyl optionally substituted with an OH group or a C _1-3 alkoxy group.
R ² represents cyclopropyl, C _1-3 alkyl or C _2-3 alkenyl; and
R ³ represents unsubstituted or substituted C _1-6 alkyl and has from one to three substituents independently selected from R ⁸ . 6. The compound according to claim 5, where R ^{5 is} selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylsulfonyl. 7. The compound according to claim 6, where R ² represents methyl. 8. The compound according to claim 5, where R ^{8 is} selected from the group consisting of halogen, hydroxy, oxo, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, and R ¹ - phenyl, unsubstituted or substituted from one to three groups independently selected from halogen and trifluoromethyl. 9. The compound of claim 8, where R ² represents hydrogen. 10. The compound according to claim 5, where R ^{5 is} selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio and C _1-3 alkylsulfonyl; and R ^{8 is} selected from the group consisting of halogen, hydroxy, oxo, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfonyl, and R ^{1 is} phenyl unsubstituted or substituted from one to three groups independently selected from halogen and trifluoromethyl. 11. The compound of claim 10, where R ² represents methyl and R ⁴ represents hydrogen. 12. The compound according to claim 1, where
X represents a single bond;
R ¹ represents phenyl or naphthyl in which phenyl is unsubstituted or substituted and has one to three substituents independently selected from R ⁵ and naphthyl optionally substituted with an OH group or a C _1-3 alkoxy group,
R ² represents cyclopropyl, C _1-3 alkyl or C _2-3 alkenyl; and
R ³ represents phenyl or heteroaryl, where phenyl and heteroaryl are unsubstituted or substituted and have one to three substituents independently selected from R ⁹ . 13. The compound of claim 12, wherein R ² is methyl. 14. The compound of claim 12, wherein R ³ is phenyl, which is optionally substituted with halogen or S (O) ₂ R ⁶ , where R ⁶ is C ₁ -C ₆ alkyl. 15. The compound of claim 14, wherein R ^{9 is} selected from the group consisting of halogen and C _1-3 alkylsulfonyl. 16. The compound of claim 14, wherein R ² is methyl. 17. The compound of claim 12, wherein R ³ is oxadiazolyl, which is unsubstituted. 18. The compound according to 17, where R ⁹ represents phenyl, which is unsubstituted or substituted by halogen. 19. The compound of claim 18, wherein R ² is methyl. 20. A compound selected from the group consisting of

and

or a pharmaceutically acceptable salt thereof. 21. The compound according to claim 20, which is a

or a pharmaceutically acceptable salt thereof. 22. The compound according to claim 20, which is a

or a pharmaceutically acceptable salt thereof. 23. The compound according to claim 20, which is a

or a pharmaceutically acceptable salt thereof. 24. The compound according to claim 20, which is a

or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition exhibiting the properties of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme (GDM-1), containing the compound according to claim 1, in combination with a pharmaceutically acceptable carrier. 26. The use of the compound according to claim 1 for the manufacture of a medicament used in the treatment of a condition selected from the group consisting of hyperglycemia, insulin resistance, type 2 diabetes, impaired fat metabolism, obesity, atherosclerosis, and metabolic syndrome.