HK1087709B - Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 - Google Patents

Description

Triazole derivatives as 11-beta-hydroxysteroid dehydrogenase-1 inhibitors

Technical Field

The present invention relates to triazole derivatives useful as inhibitors of 11-beta-hydroxysteroid dehydrogenase type I (11 beta-HSD-1 or HSD-1) and methods of using the same for the treatment of certain diseases. The compounds of the invention are useful for the treatment of diabetes, such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, lipid disorders, hypertension, and other diseases and disorders.

Background

Diabetes is caused by a number of factors, the most common of which is the elevated concentration of glucose in the plasma (hyperglycemia) in the fasting state. Two forms of diabetes are generally recognized: type 1 diabetes, or Insulin Dependent Diabetes Mellitus (IDDM), which secretes little or no insulin, which is a hormone regulating glucose utilization, and type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which secretes insulin, even exhibits hyperinsulinemia (the same or higher plasma insulin concentration as compared to non-diabetic individuals), and at the same time, exhibits hyperglycemia. Type 1 diabetes is generally treated by the administration of exogenous insulin by injection. However, type 2 diabetes often develops "insulin resistance" such that the effect of insulin in stimulating glucose and lipid metabolism in the major insulin sensitive tissues, i.e., muscle, liver and adipose tissue, is reduced. Insulin resistant patients who are not diabetic have elevated insulin concentrations to compensate for their insulin resistance so that the serum glucose concentration does not rise. In NIDDM patients, even if the plasma insulin concentration is elevated, it is not sufficient to overcome the insulin resistance, resulting in hyperglycemia.

Insulin resistance was originally due to receptor adhesion defects that have not been fully understood to date. Resistance to insulin results in insufficient glucose absorption, reduced oxidation of glucose and glycogen storage in muscle, inadequate insulin inhibition in adipose tissue lipolysis, and inadequate glucose production and secretion from the liver.

Persistent or uncontrolled hyperglycemia that occurs in diabetes is associated with increased morbidity and premature mortality. Abnormal glucose homeostasis is also associated, directly or and indirectly, with obesity, hypertension and alterations in lipid, lipoprotein and apolipoprotein metabolism. Type 2 diabetes increases the risk of developing cardiovascular complications, such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critical in the clinical management and treatment of diabetes.

Many patients with insulin resistance who have not yet developed type 2 diabetes are also at risk of developing what is known as "syndrome X" or "metabolic syndrome". Syndrome X or metabolic syndrome is characterized by insulin resistance with abdominal obesity, hyperinsulinemia, hypertension, low HDL, and high VLDL. Such patients, whether or not developing overt diabetes, are at increased risk of developing the cardiovascular complications mentioned above.

Treatment of type 2 diabetes typically involves physical exercise and diet. Plasma levels of insulin are increased by administration of sulfonylureas (e.g., tolbutamide and glipizide) or meglitinide, which stimulate pancreatic β -cells to secrete more insulin, and/or injection of insulin when sulfonylureas or meglitinide are ineffective, which allows insulin concentrations high enough to stimulate insulin-resistant tissues. However, dangerously, low concentrations of plasma glucose may result, and eventually an increased strength of insulin resistance may occur.

Biguanides increase insulin sensitivity and allow some correction of hyperglycemia. However, many biguanide drugs, such as phenformin and metformin, cause hyperlactate, regurgitation and diarrhea.

Glitazones (glitazones) (i.e. 5-benzylthiazolidine-2, 4-diones) form a new class of compounds with potential for ameliorating hyperglycemia and other symptoms of type 2 diabetes. The above drugs mainly increase insulin sensitivity in muscle, liver and adipose tissue, partially or completely correct the elevated glucose plasma concentration, causing substantially no hypoglycemia. Glitazones are currently marketed as agonists of the peroxisome proliferator-activated receptor (PPAR) gamma subtype. PPAR-gamma agonists are generally thought to be responsible for the increased insulin sensitivity observed with glitazones. Newer PPAR agonists being developed for the treatment of type 2 diabetes and/or dyslipidemia are one or more of the PPAR α, γ and δ subtypes. For a review of Insulin-sensitive drugs and other mechanisms for treating Type 2 diabetes, see m.tadayyon and s.a.smith, "Insulin sensitivity in the treatment of Type 2 diabetes," expert opin. investig. drugs, 12: 307-324(2003).

There remains a need for new methods of treating diabetes and related conditions, such as metabolic syndrome. The present invention fulfills this need, as well as other needs.

Summary of The Invention

The present invention relates to bicyclo [2.2.2] -oct-1-yl-1, 2, 4-triazole compounds of formula I

The above-mentioned bicyclo [2.2.2] -octyltriazole derivative is effective as an inhibitor of 11- β -hydroxysteroid dehydrogenase type I (11 β -HSD-1). They are therefore useful in the treatment, control or prevention of diseases which respond to inhibition of 11 β -HSD-1, such as hyperglycemia, insulin resistance, type 2 diabetes, lipid disorders, obesity, atherosclerosis and metabolic syndrome.

The invention also relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.

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

Detailed Description

The present invention relates to bicyclo [2.2.2] -oct-1-yl-1, 2, 4-triazole derivatives useful as 11 β -HSD-1 inhibitors. The compounds of the invention are represented by structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

Each p is independently 0, 1 or 2;

each n is independently 0, 1 or 2;

x is selected from single bond O, S (O)_p、NR⁶、

R¹Is selected from

An aryl carbonyl group, a carbonyl group,

(CH₂)_n-aryl, and

(CH₂)_n-a heteroaryl group;

wherein aryl and heteroaryl are unsubstituted or substituted with 1-3 substituents independently selected from R⁵Substituted with the substituent(s);

R²is selected from

The presence of hydrogen in the presence of hydrogen,

C_1-8an alkyl group, a carboxyl group,

C_2-6alkenyl, and

(CH₂)_n-C_3-6a cycloalkyl group,

wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from R⁸And oxo;

each R⁴Is independently selected from

The presence of hydrogen in the presence of hydrogen,

the halogen(s) are selected from the group consisting of,

a hydroxyl group(s),

an oxo group, and a pharmaceutically acceptable salt thereof,

C_1-3alkyl, and

C_1-3an alkoxy group;

R³is selected from

The presence of hydrogen in the presence of hydrogen,

C_1-10an alkyl group, a carboxyl group,

C_2-10an alkenyl group, which is a radical of an alkenyl group,

(CH₂)_n-C_3-6a cycloalkyl group,

(CH₂)_n-an aryl group,

(CH₂)_n-heteroaryl, and

(CH₂)_n-a heterocyclic group;

wherein aryl, heteroaryl and heterocyclyl are unsubstituted or substituted with 1-3 substituents independently selected from R⁵Substituted with the substituent(s); alkyl, alkenyl and cycloalkyl unsubstituted or substituted with 1-5 substituents independently selected from R⁸And oxo;

R⁵and R⁸Each independently selected from

The presence of hydrogen in the presence of hydrogen,

the formyl group is a radical of a carboxylic acid,

C_1-6an alkyl group, a carboxyl group,

(CH₂)_n-an aryl group,

(CH₂)_n-a heteroaryl group,

(CH₂)_n-a heterocyclic group,

(CH₂)_nC_3-7a cycloalkyl group,

the halogen(s) are selected from the group consisting of,

OR⁷，

(CH₂)_nN(R⁷)₂，

the cyano group(s),

(CH₂)_nCO₂R⁷，

NO₂，

(CH₂)_nNR⁷SO₂R⁶，

(CH₂)_nSO₂N(R⁷)₂，

(CH₂)_nS(O)_pR⁶，

(CH₂)_nSO₂OR⁷，

(CH₂)_nNR⁷C(O)N(R⁷)₂，

(CH₂)_nC(O)N(R⁷)₂，

(CH₂)_nNR₆C(O)R⁶，

(CH₂)_nNR⁶CO₂R⁷，

O(CH₂)_nC(O)N(R⁷)₂，

CF₃，

CH₂CF₃，

OCF₃，

OCHCF₂and are and

OCH₂CF₃；

wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or 1-3 independently selected from halogen, hydroxy, C_1-4Alkyl, trifluoromethyl, trifluoromethoxy, and C_1-4Substituent substitution of alkoxy; wherein R is⁵And R⁸Any methylene group (CH) of (1)₂) Carbon atoms unsubstituted or substituted by 1-2 members independently selected from halogen, hydroxy, and C_1-4Alkyl groups; or in the same methylene group (CH)₂) Two substituents on a carbon atom together with the carbon atom to which they are attached form a cyclopropyl group;

each R⁶Is independently selected from

C_1-8An alkyl group, a carboxyl group,

(CH₂)_n-an aryl group,

(CH₂)_n-heteroaryl, and

(CH₂)_nC_3-7a cycloalkyl group;

wherein alkyl and cycloalkyl are unsubstituted or substituted by 1 to 5 substituents independently selected from halogen, oxo, C_1-4Alkoxy radical, C_1-4Alkylthio, hydroxyl and amino substituent substitution; aryl and heteroaryl are unsubstituted or substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C_1-4Alkyl, and C_1-4Substituent substitution of alkoxy;

or, two R⁶The radicals together with the atoms to which they are attached form a 5-to 8-membered mono-or bicyclic ring system optionally containing a further ring member selected from O, S and NC_1-4A heteroatom of an alkyl group; and is

Each R⁷Is hydrogen or R⁶。

In one embodiment of the compounds of the invention, R²Is cyclopropyl, C_1-3Alkyl, or C_2-3Alkenyl, and R¹Is phenyl or naphthyl, wherein phenyl and naphthyl are unsubstituted or substituted by 1-3 independently selected from R⁵Is substituted with the substituent(s). In one class of this embodiment, R⁵Selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, and C_1-3An alkylsulfonyl group. In a subclass of this class, R²Is methyl and R⁴Is hydrogen.

In a second embodiment of the compounds of the invention,

x is a single bond;

R¹is phenyl or naphthyl, wherein phenyl and naphthyl are unsubstituted or substituted by 1-3 independently selected from R⁵Substituted with the substituent(s);

R²is cyclopropyl, C_1-3Alkyl, or C_2-3An alkenyl group; and is

R³Is C_1-6Alkyl which is unsubstituted or substituted with 1-3 substituents independently selected from R⁸And oxo.

In one class of the second embodiment, R⁵Selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, and C_1-3An alkylsulfonyl group. In a subclass of this class, R²Is methyl and R⁴Is hydrogen. In another class of this embodiment, R⁸Selected from halogen, hydroxy, oxo, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfonyl, and phenyl, said phenyl being unsubstituted or substituted with 1-3 groups independently selected from halogen and trifluoromethyl. In a subclass of this class, R²Is methyl and R⁴Is hydrogen. In a third class of this embodiment, R⁵Selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, and C_1-3An alkylsulfonyl group; and R is⁸Selected from halogen, hydroxy, oxo, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylsulfonyl, and phenyl, said phenyl being unsubstituted or substituted with 1-3 groups independently selected from halogen and trifluoromethyl. In a subclass of this class, R²Is methyl and R⁴Is hydrogen.

In a third embodiment of the compounds of the invention,

x is a single bond;

R¹is phenyl or naphthyl, wherein phenyl and naphthyl are unsubstituted or substituted by 1-3 independently selected from R⁵Substituted with the substituent(s);

R²is cyclopropyl, C_1-3Alkyl, orC_2-3An alkenyl group; and is

R³Is phenyl or heteroaryl, wherein phenyl and heteroaryl are unsubstituted or substituted with 1-3 substituents independently selected from R⁵Is substituted with the substituent(s).

In one class of this embodiment, R²Is methyl and R⁴Is hydrogen.

In another class of this embodiment, R³Is phenyl, unsubstituted or substituted by 1 to 3 groups independently selected from R⁵Is substituted with the substituent(s). In a subclass of this class, R⁵Selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, and C_1-3An alkylsulfonyl group. Within a subclass of this subclass, R²Is methyl and R⁴Is hydrogen.

In a third class of this embodiment, R³Is oxadiazolyl which is unsubstituted or substituted with 1-2 groups independently selected from R⁵Is substituted with the substituent(s). In a subclass of this class, R⁵Is phenyl, unsubstituted or substituted by 1 to 3 substituents independently selected from halogen, hydroxy, C_1-4Alkyl, trifluoromethyl, trifluoromethoxy, and C_1-4Substituent of alkoxy. Within a subclass of this subclass, R²Is methyl and R⁴Is hydrogen.

The following definitions as used herein apply.

"alkyl", as well as other groups having the prefix "alkane", such as alkoxy and alkanoyl, means straight or branched carbon chains, and combinations thereof, unless the carbon chain is otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. Wherein the number of specific carbon atoms may be, for example, C_3-10The term alkyl also includes cycloalkyl, and combinations of straight or branched alkyl chains and cycloalkyl structures, when there is no specific number of carbon atoms, referring to C_1-6。

"alkenyl" means a carbon chain containing at least one carbon-carbon double bond, and may be straight or branched or combinations thereof, unless the carbon chain is otherwise defined. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. Wherein the specific number of carbon atoms may be, for example, C_5-10The term alkenyl also includes cycloalkenyl groups, as well as combinations of straight, branched, and cyclic structures. When there is no specific number of carbon atoms, it means C_2-6。

"alkynyl" means a carbon chain containing at least one carbon-carbon triple bond, and may be straight or branched or combinations thereof. Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like.

"cycloalkyl" is a subset of alkyl, meaning a saturated carbocyclic ring containing a specific number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cycloalkyl groups are generally monocyclic unless otherwise indicated. Cycloalkyl groups are saturated unless otherwise defined.

The term "alkoxy" refers to straight or branched chain alkoxides of the indicated number of carbon atoms (e.g., C)_1-6Alkoxy), or an alkoxide of any value within this range [ i.e., methoxy (MeO-), ethoxy, isopropoxy, and the like]。

The term "alkylthio" refers to a straight or branched chain alkyl sulfide of the indicated number of carbon atoms (e.g., C)_1-6Alkylthio), or an alkyl sulfide of any value within this range [ i.e., methylthio (MeS-), ethylthio, isopropylthio, and the like]。

The term "alkylamino" refers to straight or branched alkylamines of the indicated number of carbon atoms (e.g., C)_1-6Alkylamino), or an alkylamine within any of these ranges [ i.e., methylamino, ethylamino, isopropylamino, tert-butylamino, and the like]。

The term "alkylsulfonyl" refers to straight or branched chain alkyl sulfones of the indicated number of carbon atoms (e.g., C)_1-6Alkylsulfonyl), or an alkylsulfonyl of any value within this range [ i.e., methylsulfonyl (MeSO)₂-), ethylsulfonyl, isopropylsulfonyl and the like]。

The term "alkylsulfinyl" refers to a straight or branched chain alkyl sulfoxide of the indicated number of carbon atoms (e.g., C)_1-6Alkylsulfinyl), or an alkylsulfoxide of any value within this range [ i.e., methylsulfinyl (MeSO-), ethylsulfinyl, isopropylsulfinyl, and the like]。

The term "alkyloxycarbonyl" refers to a straight or branched chain ester of a carboxylic acid derivative of the present invention of the indicated number of carbon atoms (e.g., C)_1-6Alkyloxycarbonyl), or an ester of any value within this range [ i.e., methyloxycarbonyl (MeOCO-), ethyloxycarbonyl, or butyloxycarbonyl]。

"aryl" means a monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-to 10-membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

"heterocycle" and "heterocyclyl" refer to compounds containing at least one heteroatom selected from O, S and N, and also includes the oxidized forms of sulfur, i.e., SO and SO₂A saturated or unsaturated non-aromatic ring or ring system of (a). Examples of heterocycles include Tetrahydrofuran (THF), dihydrofuran, 1, 4-dioxane, morpholine, 1, 4-dithiane, piperazine, piperidine, 1, 3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1, 3-dioxane, 1, 3-dithiane, oxathiane, thiomorpholine, and the like.

"heteroaryl" means an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N. Thus heteroaryl includes heteroaryl fused with other kinds of rings such as aryl, cycloalkyl and non-aromatic heterocyclic rings. Examples of heteroaryl groups include pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, dihydroindolyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, 2, 3-diazanaphthyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and the like. For heterocyclyl and heteroaryl groups, rings and ring systems containing 3 to 15 atoms are included, forming 1 to 3 rings.

"halogen" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. When halogen is substituted on alkyl or alkoxy, fluorine is most preferred (e.g., CF)₃O and CF₃CH₂O)。

The term "composition", as in a pharmaceutical composition, is intended to encompass a product comprising the active ingredient and the inert ingredient in a carrier, as well as any product which results, directly or indirectly, from combination, complexation or polymerization of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition resulting from mixing a compound of the present invention and a pharmaceutically acceptable carrier.

The terms "administration" and "administering" of a compound shall be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof.

The compounds of formula I may contain 1 or more asymmetric centers and may thus exist as racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to include all such isomeric forms of the compounds of formula I.

Some of the compounds described herein contain olefinic double bonds and are meant to include both E and Z geometric isomers unless otherwise stated.

Some of the compounds described herein may exist in the form of tautomers, such as keto-enol tautomers. Both individual tautomers, as well as mixtures thereof, are included within the scope of the compounds of structural formula I.

The compounds of formula I can be separated into the individual diastereomers by, for example, fractional crystallization from a suitable solvent such as methanol or ethyl acetate or mixtures thereof, or by chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by the X-ray crystallography of the crystalline product or of a crystalline intermediate from which the product is derived, using, if desired, reagents containing asymmetric centers of known absolute configuration.

Alternatively, stereoisomers of compounds of formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.

In various aspects of the invention, a pharmaceutical composition comprises a compound of structural formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The term "solvate" means a hydrate, alcoholate, or other solvate of crystal.

In another aspect of the present invention, there is provided a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need thereof, which comprises administering to said patient an effective amount of a compound of structural formula I, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect of the invention, a method of treating non-insulin dependent (type 2) diabetes in a mammalian patient in need thereof is disclosed which comprises administering to the patient an anti-diabetic effective amount of a compound of formula I.

In another aspect of the present invention, a method of treating obesity in a mammalian patient in need thereof is disclosed comprising administering to the patient a compound of structural formula I in an amount effective to treat obesity.

In another aspect of the invention, a method of treating metabolic syndrome in a mammalian patient in need thereof is disclosed which comprises administering to said patient a compound of structural formula I in an amount effective to treat metabolic syndrome.

In another aspect of the present invention, there is disclosed a method of treating a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL, in a mammalian patient in need thereof, comprising administering to said patient a compound of formula I in an amount effective to treat said lipid disorder.

In another aspect of the invention, a method of treating atherosclerosis in a mammalian patient in need thereof is disclosed which comprises administering to the patient a compound of 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 in the treatment of hyperglycemia, insulin resistance, type 2 diabetes, lipid disorders, obesity, atherosclerosis, and metabolic syndrome.

Another aspect of the present invention provides the use of a compound of structural formula I in the manufacture of a medicament for the treatment of a disease selected from the group consisting of hyperglycemia, insulin resistance, type 2 diabetes, lipid disorders, obesity, atherosclerosis, and metabolic syndrome.

The compounds of the invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" 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 within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention, which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to, the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, spagholicate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, laurylsulfate propionate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, bromomethane, methylnitrate, methylsulfate, mucate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, oleate, dihydrogensulfate, D-camphorsulfonate, D-camphorate, D-isosulfonate, O-butyrylate, D-isovaleronate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, 8-chlorotheyl salt, tosylate, triethiodide, and valerate. Additionally, where the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion exchange resins, such as salts of arginine, betaine, caffeine, choline, 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, trimethylamine, tripropylamine, tromethamine, and the like.

In addition, where a carboxylic acid (-COOH) or alcohol group is present in the compounds of the invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl esters, or esters of acyl derivatives of alcohols, such as acetates or maleates, may be used. Included are those esters and acyl groups known in the art to modify the solubility or hydrolytic properties of formulations useful as sustained release or prodrugs.

It will be understood that the compounds of formula I as used herein are meant to also include pharmaceutically acceptable salts, as well as non-pharmaceutically acceptable salts when they are used as free compounds, as pharmaceutically acceptable salts thereof, or as precursors in other synthetic procedures.

Solvates, particularly hydrates, of the compounds of structural formula I are also included within the scope of the present invention.

The compounds described herein are selective inhibitors of the 11 β -HSD1 enzyme. The invention therefore relates to the use of an inhibitor of 11 β -HSD1 for inhibiting the reductase activity of 11- β -hydroxysteroid dehydrogenase, which dehydrogenase is responsible for the conversion of cortisone to hydrocortisone. Excessive cortisol is associated with a variety of diseases including NIDDM, obesity, dyslipidemia, insulin resistance and hypertension. Administration of the compounds of the invention reduces the concentration of hydrocortisone and other 11-beta-hydroxysteroids in the target tissue, thereby reducing the effect of excess hydrocortisone and other 11-beta-hydroxysteroids. Inhibition of 11 β -HSD1 is useful in the treatment and management of diseases caused by abnormally high concentrations of hydrocortisone and other 11- β -hydroxysteroids, such as NIDDM, obesity, hypertension and dyslipidemia. Inhibition of 11 β -HSD1 activity in the brain, e.g. lower hydrocortisone concentrations, may also be useful for treating or alleviating anxiety, depression, and cognitive disorders.

The invention encompasses the use of 11 β -HSD1 inhibitors for the treatment, control, amelioration, prophylaxis, delaying the onset of or reducing the risk of developing the diseases and conditions described herein, which are caused by excessive or uncontrolled amounts of hydrocortisone and/or other corticosteroids in mammalian patients, particularly humans, by administering an effective amount of a compound of structural formula I or a pharmaceutically acceptable salt or solvate thereof. Inhibition of the 11 β -HSD1 enzyme limits the conversion of cortisone to hydrocortisone, which is generally inert and which, if present in excess, may cause or contribute to the above-mentioned diseases and conditions.

NIDDM and hypertension:

the compounds of the present invention are selective inhibitors of 11 β -HSD1 with greater selectivity than 11 β -HSD 2. Although inhibition of 11 β -HSD1 is useful for reducing the concentration of hydrocortisone and treating symptoms associated therewith, inhibition of 11 β -HSD2 is associated with severe side effects, such as hypertension.

Hydrocortisone is an important and well-known anti-inflammatory hormone and also acts as an antagonist of insulin action in the liver, resulting in decreased insulin sensitivity, resulting in increased gluconeogenesis and increased glucose concentrations in the liver. Patients with impaired glucose tolerance have a greater likelihood of developing type 2 diabetes in the presence of abnormally high concentrations of hydrocortisone.

High concentrations of cortisone in tissues where mineral steroid corticosteroid receptors are present often lead to hypertension. Inhibition of 11 β -HSD1 alters the ratio of hydrocortisone and cortisone in certain tissues in favor of cortisone.

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

Obesity, metabolic syndrome, dyslipidemia:

excessive cortisol concentrations are associated with obesity, perhaps due to increased hepatic gluconeogenesis. Abdominal obesity is closely associated with glucose allergy, hyperinsulinemia, hypertriglyceridemia, and other factors of metabolic syndrome such as hypertension, elevated VLDL, and reduced HDL. Montague et al, Di α betes, 2000, 49: 883-888. However, administration of an effective amount of an inhibitor of 11 β -HSD1 is useful in the treatment or control of obesity. Chronic treatment with 11 β -HSD1 inhibitors may also be useful for delaying or preventing the onset of obesity, particularly when the patient is on a 11 β -HSD1 inhibitor in combination with controlled diet and exercise.

By reducing insulin resistance and maintaining serum glucose at normal concentrations, the compounds of the invention are also useful in the treatment and prevention of symptoms associated with type II diabetes and insulin resistance, including metabolic syndrome or syndrome X, obesity, reactive hypoglycemia, and diabetic dyslipidemia.

Atherosclerosis:

as mentioned above, inhibition of 11 β -HSD1 activity and reduction of the amount of hydrocortisone is beneficial for treating or controlling hypertension. Because hypertension and dyslipidemia contribute to the development of atherosclerosis, administration of a therapeutically effective amount of a 11 β -HSD1 inhibitor of the present invention may be particularly advantageous for treating, controlling, delaying the onset of, or preventing atherosclerosis.

Other applications are as follows:

the following diseases, conditions and symptoms can be treated, controlled, prevented or delayed by the compounds of the present 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 concentrations, (11) high LDL concentrations, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative diseases, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) metabolic syndrome, (21) hypertension and other diseases where insulin resistance is a component.

The above diseases and conditions may be treated with a compound of structural formula I, or the compound may be used to prevent or reduce the risk of developing the diseases and conditions described herein. Since simultaneous inhibition of 11 β -HSD2 may have deleterious side effects, or indeed increases the amount of hydrocortisone in the target tissue, but it is desirable to reduce the amount of hydrocortisone, a selective inhibitor of 11 β -HSD1 is desired, with little or no inhibition of 11 β -HSD 2.

11 β -HSD1 inhibitors of structural formula I typically have an inhibition constant IC of less than about 500nM, preferably less than about 100nM₅₀. Typically, the IC of the compounds on 11 β -HSD2 and 11 β -HSD1₅₀The ratio is at least about 2 or greater, preferably about 10 or greater. More preferred are the ICs of 11 β -HSD2 and 11 β -HSD1₅₀A compound having a ratio of about 100 or greater. For example, the compounds of the invention theoretically have an inhibition constant IC of greater than about 1000nM, preferably greater than 5000nM, for 11 β -HSD2₅₀。

Any suitable route of administration may be employed for providing an effective dose of a compound of the invention to a mammal, especially a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compounds of structural formula I are administered orally.

The effective dosage of the active ingredient will vary depending upon the particular compound administered, the mode of administration, the condition being treated and the severity of the condition. The above dosages can be readily determined by those skilled in the art.

When treating or preventing the diseases and conditions described herein, for compounds of structural formula I, satisfactory results are obtained when the compounds of the present invention are administered in daily doses of from about 0.1 to about 100 milligrams per kilogram (mpk) of body weight, preferably in a single daily dose, or in about 2-6 divided doses a day. However, the total daily dose is from about 0.1mg to about 1000mg, preferably from about 1mg to about 50 mg. In the case of a 70 kg adult human, the total daily dose is from about 7mg to about 350 mg. The dosage can be adjusted to obtain the best therapeutic effect.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of structural formula I, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), transdermal, pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the type and severity of the condition being treated and the active ingredient. They may conveniently be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

The compounds of structural formula I may be combined with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier takes a variety of forms. For example, carriers for oral liquid compositions include, by way of example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and other ingredients used in the preparation 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 oral solid dosage forms such as powders, hard and soft capsules and tablets. Solid oral formulations are preferred over oral liquids.

Oral solid dosage forms may also contain binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. The capsules may also contain a liquid carrier such as a fatty oil.

Various other materials may be used as coatings for the dosage units or to modify their physical form. For example, tablets may be coated with shellac, sugar or both.

Tablets may be coated by standard aqueous or non-aqueous techniques. Of course, the typical percentage of active compound in the above compositions is from about 2% to about 60% W/W. Thus, the tablet contains the compound of formula I or a salt or hydrate thereof in an amount of from about 0.1mg to about 1.5g, preferably from about 1.0mg to about 500mg, more preferably from about 10mg to about 100 mg.

Oral liquid formulations such as syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetening agent, the preservatives methyl and propylparabens, a dye and flavoring such as cherry or orange flavor.

Parenteral drugs are generally prepared in the form of solutions or suspensions, generally in water, optionally including a surfactant such as hydroxypropylcellulose. Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Formulations which are generally in diluted form may contain a preservative.

Pharmaceutical injectable formulations, including aqueous solutions and dispersions and powders for the extemporaneous preparation of solutions or dispersions for injection, are also sterile and must flow to the extent that they can be readily injected; they are stable under the conditions of preparation and storage and are usually preserved. The carrier thus comprises a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

And (3) determination: measurement of inhibition constant:

the enzymatic activity of the test compounds was determined in vitro by Scintillation Proximity Assay (SPA). Briefly, tritiated cortisone substrate, NADPH cofactor and titrated compound of formula I are incubated at 37 ℃ with 11 β -HSD1 enzyme to convert it to hydrocortisone. After incubation, SPA bead-coated protein a was prepared, pre-mixed with monoclonal antibody against hydrocortisone and a non-specific 11 β -HSD inhibitor such as 18 β -glycyrrhizic acid, and added to each well. The mixture was shaken at 15 ℃ and then read by a liquid scintillation counter suitable for 96-well plates. Percent inhibition was calculated relative to uninhibited control wells to obtain IC₅₀Curve line. The assaySimilarly for 11 β -HSD2, tritiated hydrocortisone and NAD were used as substrate and cofactor, respectively. To start the assay, 40. mu.L of matrix (25 nM in 50mM HEPES buffer, pH 7.4)³H-cortisone +1.25mM NADPH) were added to the designated wells of the 96-well plate. Compounds were dissolved in DMSO at 10mM, followed by 50-fold dilution with DMSO. The diluted material was then titrated four-fold, seven times. 1 μ L of each titrated compound was then added in duplicate to the matrix. To start the reaction, 10 μ L of microsome of 11 β -HSD1 from CHO transfectants was added to each well at the appropriate concentration to give approximately 10% conversion of starting material. For the final calculation of the percentage of inhibition, added to a series of wells, representing the measured minimum and maximum values: one containing the matrix but no compound or enzyme (background) and the other containing the matrix and enzyme but no compound (maximum signal). The plates were spun briefly in a centrifuge at low speed to pellet the reagents, sealed with tape, gently stirred, and incubated at 37 ℃ for 2 hours. After incubation, 45 μ L of SPA beads, pre-suspended with anti-hydrocortisone monoclonal antibody and compound of formula I, were added to each well. The dish was resealed and gently shaken at 15 ℃ for more than 1.5 hours. Data on the tray was collected based on liquid scintillation counters such as Topcount. For controlled inhibition of anti-hydrocortisone antibody/hydrocortisone binding, 1.25nM [3 ] was incorporated]A matrix of hydrocortisone was added to the indicated single well. To each well described above, 1. mu.L of 200. mu.M compound, and 10. mu.L of buffer, instead of enzyme, were added. Either calculated inhibition was due to the compound interfering with hydrocortisone binding to the antibody of the SPA beads.

And (3) determination: measurement of in vivo inhibition rate:

in general, the test compound is administered to the mammal orally, with the elapsed time interval of the drug effect typically being 1-24 hours. Tritiated cortisone was injected intravenously and blood was collected after a few minutes. Steroids were extracted from the separated serum and analyzed by HPLC.³The relative concentrations of H-cortisone and its reduced product, 3H-hydrocortisone, were determined as a control group of compounds and vehicle. Absolute conversion, and inhibitionThe percentage of (c) is calculated from the above values.

More specifically, the compounds are prepared in oral dosage form and they are dissolved in the desired concentration in an excipient (5% hydroxypropyl-. beta. -cyclodextrin v/v H)₂O, or equivalent), typically at a dose of 10 mg/kg. After fasting overnight, ICR mice (obtained from Charles River) were given a liquid formulation by oral gavage, 0.5mL per dose per animal, 3 per test group.

After the desired time, typically 4 hours or 16 hours, 0.2mL of 3. mu.M solution was injected via the tail vein³A solution of H-cortisone in dPBS. After the mice were placed in the cages for 2 minutes, CO was added₂And carrying out indoor euthanasia. After cessation of breathing, the mice were removed and blood collected by cardiac puncture. The blood is placed in the serum separation tube at room temperature for not less than 30 minutes to ensure that the blood is fully coagulated. After incubation, the blood was separated into serum by centrifugation at 3000Xg for 10 minutes at 4 ℃.

To analyze the steroids in the serum, they were first extracted with an organic solvent. A volume of 0.2mL of serum was transferred to a clean microcentrifuge tube. To this was added a volume of 1.0mL of ethyl acetate followed by vigorous vortexing for 1 minute. The aqueous serum proteins were pelleted by rapid spinning of microcentrifugation and the organic supernatant was removed. 0.85mL of the upper organic phase was transferred to a fresh microcentrifuge tube and dried. The dried samples were resuspended in 0.250mL of DMSO containing high concentrations of cortisone and hydrocortisone for HPLC analysis.

A0.200 mL sample was applied to a Metachem Inertsil C-18 column equilibrated with 30% methanol. A slow linear gradient up to 50% methanol separates the target steroid; while monitoring at 254nm on a cold scale using UV as an internal standard in the resuspension solution. Tritium data was collected by a radio-chromatographic detector and uploaded to the software for analysis. Calculated as the ratio of AUC for hydrocortisone to the combined AUC for cortisone and hydrocortisone³H-cortisone to³Percent conversion of H-hydrocortisone.

The invention combinesPreparation of the product:

the compounds of formula I of the present invention can be prepared according to the procedures in the schemes and examples below using suitable starting materials, further exemplified by the specific examples below. However, the compounds set forth in the examples are not limited to forming the only one considered to be the present invention. The examples illustrate in additional detail the preparation of the compounds of the present invention. The known modifications of the conditions will be readily understood by those skilled in the art and the following methods of preparation procedures may be used to prepare the above compounds. The prepared compound is typically isolated in a neutral form, but the triazole moiety can be further converted to a pharmaceutically acceptable salt by dissolution in an organic solvent, followed by addition of a suitable acid, followed by evaporation, precipitation or crystallization. All temperatures are degrees celsius unless otherwise noted. Mass Spectra (MS) were measured by electrospray ion mass spectrometry (ESMS).

The term "standard peptide coupling reaction conditions" means the coupling of a carboxylic acid to an amine using an acid activator such as EDC, DCC and BOP in an inert solvent such as dichloromethane and in the presence of a catalyst such as HOBT. The use of amine and carboxylic acid functional protecting groups to facilitate the desired reaction and to reduce undesirable reactions has been disclosed in a number of documents. The conditions required for removal of the protecting Groups are disclosed in standard textbooks such as Greene, T, and Wuts, P.G.M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY, 1991. Cbz and BOC are common protecting groups in organic synthesis and their removal conditions are known to those skilled in the art.

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

AIBN	2, 2' -azobisisobutyronitrile
		BOC	Tert-butoxycarbonyl group
BBr	Boron tribromide
		9-BBN	9-borabicyclo [3.3.1]Nonane
Bn	Benzyl radical
		nBuLi	N-butyl lithium
Cbz	Benzyloxycarbonyl group
		CDI	1, 1' -carbonyldiimidazole
MeOTf	Trifluoromethyl sulfonic acid methyl ester
		CHCl	Methylene dichloride
CHI	Diiodomethane
		(COCl)	Oxalyl chloride
CsCO	Cesium carbonate
		DAST	(diethylamino) sulfur trifluoride
DMAP	4- (dimethylamino) pyridine
		DMF	N, N-dimethylformamide
Et	Ethyl radical
		EtN	Triethylamine
EtOAc	Ethyl acetate
		EtZn	Diethyl zinc
HO	Hydrogen peroxide

Me	Methyl radical
		MeCN	Acetonitrile
MeOH	Methanol
		mCPBA	Meta-chloroperbenzoic acid
MS	Mass spectrometry
		NaBH	Sodium borohydride
NaHCO	Sodium bicarbonate
		NaOAc	Sodium acetate
NBS	N-bromosuccinimide
		Ph	Phenyl radical
PyBROP	Bromo-trispyrrolidinophosphonium hexafluorophosphate
		PPh	Triphenylphosphine
Pyr	Pyridine compound
		SOCl	Thionyl chloride
TFA	Trifluoroacetic acid
		TFFH	N, N, N ', N' -tetramethylformamidinium hexafluorophosphate
THF	Tetrahydrofuran (THF)
		TLC	Thin layer chromatography
TsOH	P-toluenesulfonic acid

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

Reaction scheme 1 illustrates the key steps in the synthesis of the novel compounds of structural formula I of the present invention. As shown in reaction scheme I, a secondary amide: (1-1) (N-Me or N-Et is preferred) the imino ether can be obtained by heating with methyl trifluoromethanesulfonate in pure form by methylation1-2). Alternatively, other methylating agents such as methyl iodide or dimethyl sulfate may be used alone or in non-nucleophilic organic solvents. As shown in scheme 1, bicyclo [2.2.2]Octane-1-carboxylic acid (C:)1-3) Conversion to hydrazide by means of the coupling reagent TFFH and hydrazine in the presence of a tertiary amine base such as triethylamine: (1-4). Alternatively, other coupling reagents commonly used to prepare amides can be used with hydrazine for this conversion. Or, bicyclo [2.2.2]Octane-1-carboxylate esters can be heated with hydrazine to produce hydrazides (Z-H)1-4). Hydrazide prepared in this way (1-4) And imino ethers (b), (c), (d1-2) The bicyclo [2.2.2] s of formula I can be obtained by heating together in an inert high boiling organic solvent such as toluene and in the presence of a tertiary amine base such as triethylamine]Octyl triazole (C)1-5)。

Reaction scheme 1

Alternatively, the reaction can be carried out in an inverted manner as described in scheme 2. In this process, a secondary amide (2-1) From bicyclo [2.2.2] using standard peptide coupling reactions]Octane-1-carboxylic acid. The compound is methylated to form imino ether(s) ((2-2) Reaction with hydrazides as described in scheme 1 to afford bicyclo [2.2.2] of formula I]Octyl triazole (C)2-3)

Reaction scheme 2

Reaction scheme 3 depicts the inventive Compounds to obtain structural formula IA further process in which the key step is a palladium-catalyzed bicyclo [2.2.2]Octyl bromo triazole (C)3-1) And aryl boric acid to obtain triazole (I) with structural formula3-2). The preferred conditions use tetrakis (triphenylphosphine) palladium (O) as the catalyst in a DMF solvent with cesium carbonate, but other catalysts and conditions may be used and are known to those skilled in the art.

Reaction scheme 3

Reaction scheme 4 describes another synthetic method for forming compounds of structural formula I. By this method, 4- (bicyclo [2.2.2]]Octyl) oxadiazole (C)4-1) With methylamine, without solvent, in the molten state with methylammonium trifluoroacetate, or in a buffered MeOH solution. The above reaction is preferably carried out in a high temperature high pressure reactor to prevent loss of methylamine.

Reaction scheme 4

Reaction scheme 5 describes another synthetic method for forming compounds of structural formula I. By this method, bicyclo [2.2.2]Octyl formamide (5-1) Conversion to the imminochloride using a reagent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, optionally in the presence of DMF (5-2). Imide chloride(s) (5-2) Condensing with aryltetrazoles in a high boiling inert organic solvent such as toluene to provide triazoles (b), (c), (d), (5-3)。

Reaction scheme 5

[2.2.2] preparation of the Dicyclooctyl intermediate:

the process for the preparation of the [2.2.2] bicyclooctyl intermediate used for the preparation of the compounds of the present invention is given below.

Intermediate schemes 1-4 describe the preparation of oxadiazole, an important intermediate in the synthesis of compounds of structural formula I. They can be converted to compounds of structural formula I using, for example, the reactions described in scheme 4.

Intermediate scheme 1 is a preferred method for preparing oxadiazoles by dehydration of diacylhydrazides using a dehydrating agent such as thionyl chloride. Alternatively, other dehydrating agents such as phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride may be used. Diacyl hydrazides can preferably be prepared from a hydrazide and an activating acid such as an acid chloride in the presence of a tertiary amine base. Alternatively, standard peptide coupling reactions can be used to prepare diacyl hydrazides from hydrazides and carboxylic acids.

Intermediate scheme 2 is one useful reagent for the dehydration of diacylhydrazides to oxadiazoles, 2-chloro-1, 3-dimethyl-4, 5-dihydro-1H-imidazol-3-ium chloride. This reagent is effective in obtaining the desired oxadiazole intermediate in a non-polar solvent (dichloromethane is preferred) with a tertiary amine base (triethylamine is preferred).

Intermediate scheme 3 is the preferred reagent for one pot formation (from hydrazide and carboxylic acid) and dehydration of diacylhydrazide to oxadiazole: 2-chloro-1, 3-dimethyl-4, 5-dihydro-1H-imidazol-3-ium chloride. This reagent is effective in obtaining the desired oxadiazole intermediate in a non-polar solvent (dichloromethane is preferred) with a tertiary amine base (triethylamine is preferred).

Intermediate scheme 4 is an efficient method for forming oxadiazoles from secondary amides and hydrazides. Secondary amides (N-Me or N-Et preferred) can be methylated by heating with pure methyl trifluoromethanesulfonate to give the imino ethers. Alternatively, other methylating agents such as methyl iodide or dimethyl sulfate may be used alone or in non-nucleophilic organic solvents. Heating the imino ether thus formed in the presence of hydrazide in a high boiling inert organic solvent gives the oxadiazole as shown in the scheme.

Intermediate scheme 1:

intermediate scheme 2:

intermediate scheme 3:

intermediate scheme 4:

intermediate scheme 5 is a preferred method for the synthesis of bicyclo [2.2.2] octane-1-carboxylic acid.

Intermediate scheme 5:

intermediate schemes 6 and 7 are given in R as structure I³Bicyclo [2.2.2] with heteroaryl in position]A preferred process for the preparation of octane-1-carboxylic acid. At R³The oxadiazole in position is shown in intermediate scheme 6 by a bisRing [2.2.2]Octyl-1-carboxylic acid is condensed with amidoxime. A useful reagent for this coupling reaction is CDI. Alternatively, other reagents for dehydration or peptide coupling reactions may be used. Intermediate scheme 7 illustrates the synthesis at R³Preferred synthesis of intermediates of compounds of formula I having a triazolyl group in position.

Intermediate scheme 6:

intermediate scheme 7:

intermediate schemes 8-14 are prepared at R³Bicyclo [2.2.2] in the synthesis of compounds of formula I having different alkyl or alkenyl or substituted alkyl groups in the positions]Preferred processes for the octane-1-carboxylic acid intermediate. The key reaction is via bicyclo [2.2.2]The Wittig reaction of octane-1-carbaldehyde as shown in intermediate scheme 8. The double bond in the reaction product can be hydrogenated to produce alkyl groups of varying length and character (R will become formula I)³Substituents) as shown in intermediate scheme 9. Alternatively, the double bond can be used to introduce other functional groups, such as hydroxyl or fluorine, as shown in intermediate scheme 10. The aldehydes themselves may be used in R³The difluoromethyl group is obtained in position as shown in intermediate scheme 11. The olefin product of the wittig reaction may be subjected to a variety of other transformations, such as cyclopropanation, as shown in intermediate scheme 12. Alternatively, the wittig reagent may contain remote functional groups, such as ketals, as shown in intermediate scheme 13. This functional group can be subjected to a characteristic functional group transformation after wittig/reduction, such as hydrolysis of the ketal to a ketone, as described in intermediate scheme 13, or reduction of the ketal to an alcohol, as described in intermediate scheme 14. In this way, can obtainHaving a plurality of different Rs³Structural formula I compounds of substituents. The specific examples given are intended to convey general principles and are not intended to limit R³The range of substituents.

Intermediate scheme 8:

intermediate scheme 9:

intermediate scheme 10:

intermediate scheme 11:

intermediate scheme 12:

intermediate scheme 13:

intermediate (II)Body scheme 14:

general functional chemical transformations for preparing the compounds of the invention are set forth below in the preparation of specific compounds of the invention.

The above functional group transformations are general variations well known to those skilled in the art.

The following examples are intended to illustrate the invention and should not be construed as limiting 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 and its preparation (1-F)

Step A:

to a magnetically stirred solution of 4-benzyloxy-2-hydroxybenzonitrile (1-A, WO00/69841) (7.95g, 35.3mmol) and iodomethane (5.43mL, 87.2mmol) in DMF (90mL) cooled to-5 ℃ was added sodium hydride (60% dispersion, 2.17g, 54.2mmol) in one portion. The mixture was stirred for 30 minutes, warmed to room temperature and stirred for an additional 2 hours. Most of the DMF was removed under vacuum 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 saturated brine and dried (MgSO)₄). The residue after removal of the solvent under vacuum was triturated with hexane and chromatographed on silica gel using hexane-CH₂Cl₂(2:3) to give 4-benzyloxy-2-methoxybenzonitrile (1-B). MS: m/z 240(M + 1);¹H NMR(500MHz，CDCl₃)：δ7.47(d，1H，J＝8.4Hz)，7.36-7.45(m，5H)，6.58(dd，1H，J＝2.3，8.4Hz)，6.57(d，1H，J＝2.3Hz)，5.10(s，2H)，3.88(s，3H)ppm。

and B:

a vigorously stirred suspension of 4-benzyloxy-2-methoxybenzonitrile (1-B) (1.20g, 5.0mmol), sodium azide (732mg, 11.3mmol), and triethylamine hydrochloride (1.54g, 11.3mmol) in toluene (6mL) was heated at 110 ℃ for 48 h. The brown suspension was cooled, water (15mL) was added and the mixture was stirred for 30 min. The organic layer was removed and extracted with water (5 mL). The combined aqueous extracts were acidified with concentrated HCl to about pH 1. The initially precipitated gum was stirred for 30 minutes to solidify. The solid was filtered, washed with water and dried to give 5- [4- (benzyloxy) -2-methoxyphenyl]-2H-tetrazole (1-C).¹HNMR(500MHz，CDCl₃)：δ 12.9(vbs，1H)，7.37(d，1H，J＝8.7Hz)，7.34-7.48(m，5H)，6.78(dd，1H，J＝2.3，8.7Hz)，6.70(d，1H，J＝2.3Hz)，5.15(s，2H)，4.05(s，3H)ppm。

And C:

oxalyl chloride (3.49ml, 40mmol) was added dropwise to N-methyl-4-pentylbicyclo [2.2.2] at room temperature]Octane-1-carboxamide (1-D) (952mg, 4.0mmol) in anhydrous CH₂Cl₂In solution. After vigorous gas evolution subsided, the solution was stirred at room temperature for 2 hours. Will CH₂Cl₂At room temperature and then carefully removed by vacuum at 50 °. The clear, slurried residue was dissolved in toluene (8mL) and 5- [4- (benzyloxy) -2-methoxyphenyl added]-2H-tetrazole (1-C) (1.13g, 4.0 mmol). The mixture was heated at 120 ℃ for 9 hours. The mixture was cooled and the precipitated solid was filtered off, washed with toluene and dried to give the triazole hydrochloride. The salt is in CH₂Cl₂And 10% of K₂CO₃And (4) distributing the aqueous solution. Using CH as the aqueous phase₂Cl₂The extraction was performed 2 times. Combining the CH₂Cl₂The extract was dried (MgSO₄) And evaporated in vacuo. The residue was chromatographed on silica gel using 5% MeOH/CH₂Cl₂To obtain 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);¹H NMR(500MHz，CDCl₃)：δ 7.33-7.47(m，6H)，6.65(dd，1H，J＝2.3，8.5Hz)，6.60(d，1H，J＝2.3Hz)，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。

step D:

3- [4- (benzyloxy) -2-methoxyphenyl]-4-methyl-5- (4-pentylbicyclo [ 2.2.2)]A solution of oct-1-yl) -4H-1, 2, 4-triazole (1-E) (272mg, 0.572mmol) in MeOH (8mL) was hydrogenated over 10% Pd/C catalyst (27mg) at room temperature and atmospheric pressure for 19H. The catalyst was filtered and washed with MeOH. MeOH was removed in vacuo to yield 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);¹H NMR(500MHz，DMSO-d₆)：δ9.94(s，1H)，7.09(d，1H，J＝8.3)，6.53(d，1H，J＝1.6Hz)，6.46(dd，1H，J＝2.2，8.2Hz)，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)

Step A:

oxalyl chloride (505 μ L, 5.79mmol) was added dropwise to 4-pentylbicyclo [2.2.2]Octane-1-carboxylic acid (2-A) in dichloromethane (10 mL). The solution was stirred at room temperature for 3 hours, then concentrated in vacuo to give 4-pentylbicyclo [2.2.2]Octane-1-carbonyl chloride (2-B).¹H NMR(500MHz，CDCl₃)：δ 0.90(t，3H)；1.21(m，8H)；1.45(m，6H)；1.88(m，6H)ppm。

And B:

n, N-diisopropylethylamine (1.44mL, 11.1mmol) was added to 4-pentylbicyclo [2.2.2]To a mixture of octane-1-carboxylic acid (2-A) (1.09g, 4.45mmol) was added a solution of methylamine hydrochloride (1.5g, 22.3mmol) in dichloromethane (10mL), and the mixture was stirred at room temperature for 18 hours. After dilution with dichloromethane, the mixture was washed with water, brine and dried (MgSO)₄) And vacuum concentrating to obtain N-methyl-4-pentyl-diRing [2.2.2]Octane-1-carboxamide (2-C).¹H NMR(500MHz，CDCl₃)：δ0.91(t，3H)；1.22(m，8H)；1.43(m，6H)；1.77(m，6H)；2.82(d，3H)ppm。

And C:

oxalyl chloride (846. mu.L, 9.7mmol) was added dropwise to N-methyl-4-pentylbicyclo [2.2.2]Octane-1-carboxamide (2-C) (230mg, 0.97mmol) in dichloromethane (2.0mL) and the mixture stirred at room temperature for 4 hours. The solvent and excess reagent were removed under vacuum to give N-methyl-4-pentylbicyclo [2.2.2]Octane-1-carboximidoyl chloride (2-D). Toluene (1.5mL) was added, followed by 5- (2-chloro-4-methoxyphenyl) -1H-tetrazole (2-E) (204mg, 0.97mmol) and the mixture refluxed for 18 hours. The reaction was cooled to room temperature, the precipitate was filtered, washed with cold toluene, hexanes, dissolved in dichloromethane and dried (MgSO)₄) And vacuum concentrating to obtain 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);¹H NMR(500MHz，CDCl₃)：δ0.94(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)。

step D:

boron tribromide (135 μ L, 1.43mmol) was added dropwise to 3- (2-chloro-4-methoxyphenyl) -4-methyl-5- (4-pentylbicyclo [2.2.2] at 0 ℃]Oct-1-yl) -4H-1, 2, 4-triazole (2-F) (287mg, 0.714mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2.5 hours. The solution was washed with water, 10% NaHCO₃Washed and dried (MgSO)₄) And concentrated in vacuo, and the residue purified by column chromatography (silica gel, 5% MeOH in dichloromethane) 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);¹H NMR(500MHz，CDCl₃)：δ0.93(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]Octyl-1-yl) Pen-2-ol (3-J)

Step A:

reacting [2- (2-methyl-1, 3-dioxolan-2-yl) ethyl](triphenyl) phosphonium bromide (3-A, Synthesis: 532(1986)) (5.99g, 12.7mmol) was stirred in anhydrous THF (200 mL). Potassium bis (trimethylsilyl) amide (20.4mL, 2M in toluene, 10.2mmol) was added. The reaction was stirred for 30 minutes. The reaction mixture was then cooled to-78 ℃. 4-formylbicyclo [2.2.2] was added through a cannula at-78 deg.C]Octane-1-carboxylic acid methyl ester. The reaction was allowed to warm to room temperature overnight. The volume was reduced by evaporation of THF in vacuo. 100mL of water was added. The mixture was then partitioned with 100mL of diethyl ether. The ether layer was extracted and dried (MgSO)₄). The product (4- [ (1E) -3- (2-methyl-1, 3-dioxolan-2-yl) prop-1-enyl)]Bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (3-B)) was purified by flash chromatography on silica gel using 10/90 ethyl acetate-hexane mixture.

And B:

methyl 4- [ (1E) -3- (2-methyl-1, 3-dioxolan-2-yl) prop-1-enyl ] bicyclo [2.2.2] octane-1-carboxylate (3-B) (1.1g) was stirred in ethanol (75 mL). A spatula tip of 10% palladium on carbon (150mg) was added. Hydrogen was added and the mixture was stirred under hydrogen atmosphere for 3 hours. The palladium on carbon was filtered and the ethanol removed in vacuo to give methyl 4- [3- (2-methyl-1, 3-dioxolan-2-yl) propyl ] bicyclo [2.2.2] octane-1-carboxylate (3-C).

And C:

4- [3- (2-methyl-1, 3-dioxolan-2-yl) propyl group]Bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (3-C) (1.0g, 3.38mmol) was stirred in a solution of 90% methanol and 10% water (50 mL). Excess potassium hydroxide (2.0g) was added. The mixture was refluxed overnight. The cooled mixture was acidified with 1N hydrochloric acid (100mL) and washed twice with ethyl acetate (100 mL). The combined organic layers were dried (MgSO)₄). The ethyl acetate was removed in vacuo to give pure 4- [3- (2-methyl-1, 3-dioxolan-2-yl) propyl ester]Bicyclo [2.2.2]Octane-1-carboxylic acid (3-D).

Step D:

4- [3- (2-methyl-1, 3-dioxolan-2-yl) propyl ] bicyclo [2.2.2] octane-1-carboxylic acid (3-D) (0.200g, 0.708mmol) and 2- (trifluoromethyl) phenylhydrazide (3-E) (0.173g, 0.847mmol) were mixed and azeotroped twice from toluene. The mixture was then stirred in dry dichloromethane (10 mL). 2-chloro-1, 3-dimethylimidazolium chloride (3-F) (0.718g, 4.25mmol) was added followed by 1.184mL of triethylamine. The reaction was stirred for 2 hours. The reaction was diluted with dichloromethane 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 using 50/50 ethyl acetate-hexane mixture.

Step E:

2- {4- [3- (2-methyl-1, 3-dioxolan-2-yl) propyl]Bicyclo [2.2.2]Oct-1-yl } -5- [2- (trifluoromethyl) phenyl]The (3-G) -1, 3, 4-oxadiazole (0.158G) was stirred in a mixture of 90% acetone/10% water (20 mL). To the solution was added p-toluenesulfonic acid (10 mg). Reaction is addedHeat to reflux for 1 hour. The volume was reduced by evaporating off the acetone in vacuo. The mixture was then partitioned with ethyl acetate (25mL) and saturated sodium bicarbonate solution (25 mL). The ethyl acetate layer was removed and dried (MgSO₄). 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) pentan-2-one (3-H).

Step F:

reacting 5- (4- {5- [2- (trifluoromethyl) phenyl]-1, 3, 4-oxadiazol-2-yl } bicyclo [2.2.2]Oct-1-yl) pentan-2-one (3-H) (0.072g) was stirred in methanol (2mL) at 0 ℃. Sodium borohydride (20mg) was added. The reaction was stirred at room temperature. The mixture was then partitioned between ethyl acetate (15mL) and water (15 mL). The ethyl acetate layer was removed and dried (MgSO₄). 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) pent-2-ol (3-I).

Step G:

reacting 5- (4- {5- [2- (trifluoromethyl) phenyl]-1, 3, 4-oxadiazol-2-yl } bicyclo [2.2.2]Oct-1-yl) pentan-2-ol (3-I) (50mg) was added to a 2M solution of methylamine in methanol (2.5mL) in a sealed vial. A small spatula tip of methylamine TFA salt was added and the vial was sealed. The sealed vial was heated to 150 ℃ for 3 days. The reaction was diluted with ethyl acetate (15mL) and washed with water (15mL) and dried (MgSO)₄). The 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 a 0.1% trifluoroacetic acid buffered acetonitrile-water gradient. The eluent containing pure triazole was eluted with 10% NaHCO₃Become basic, most of the acetonitrile is removed by evaporation in vacuo and extracted with dichloromethane. The organic extracts were dried (MgSO)₄) And evaporated and the residue dried in vacuo to give the desired compound. MS (ESI)⁺)＝422.5(M+1)；¹H NMR(500MHz，CDCl₃)：δ1.21(2H，m)，1.23(3H，d，J＝6.5Hz)，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

Step A:

to 4- (methoxycarbonyl) bicyclo [2.2.2]To a suspension of octane-1-carboxylic acid (4-A) (0.906g, 4.27mmol) in dichloromethane (20mL) was added 1, 1' -carbonyldiimidazole (1.04g, 6.41 mmol). The reaction turned into a clear solution, generating gas immediately. After the mixture was stirred at room temperature for 1 hour, 4-fluorobenzylamine oxime (1.98g, 12.8mmol) was added. Stirring was continued overnight. The mixture was then concentrated and the residue refluxed in toluene for 16 hours. The mixture is concentrated and the residue is purified by column chromatography using hexane/ethyl acetate as eluent (7/1) to give 4- [3- (4-fluorophenyl) -1, 2, 4-oxadiazol-5-yl]Bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (4-B), white solid.¹H NMR(500MHz，CDCl₃)：δ1.96-1.99(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。

And B:

ester (4-B) (1.01g, 3.06mmol) was treated with KOH (0.52g, 9.18mmol) in methanol/water (95/5, 20 mL). After heating at 60 ℃ for 12 hours, the reaction mixture was concentrated, diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified with 1N HCl in water and a white solid precipitated. The solid 4- [3- (4-fluorophenyl) -1, 2, 4-oxadiazol-5-yl ] bicyclo [2.2.2] octane-1-carboxylic acid (4-C) was collected and further co-evaporated with toluene and dried. ESI-MS M/z (M + H) 317.2.

And C:

acid (4-C) (138.9mg, 0.439mmol) and 2- (trifluoromethyl) benzoylhydrazine (4-D) (89) were added.7mg, 0.439mmol) was first coevaporated with toluene three times. Dichloromethane (7mL) was added to the mixture as a solvent. To the resulting suspension was added 2-chloro-1, 3-dimethylimidazolium chloride (743mg, 4.39mmol), followed by triethylamine (1.2mL, 8.78 mmol). The mixture was stirred at room temperature under nitrogen for 48 hours to ensure completion of the reaction. The reaction mixture was then diluted with dichloromethane, washed with water, 1N HCl, saturated aqueous sodium bicarbonate, and finally with 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 ] methyl ester]-1, 3, 4-oxadiazol-2-yl } bicyclo [2.2.2]Oct-1-yl) -1, 2-, 4-oxadiazole (4-E), white solid.¹H NMR(500MHz，CDCl₃)：δ2.25(s，12H)，7.21(t，J＝8.7Hz，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。

Step D:

a mixture of 1, 2, 4-oxadiazole (4-E) (115.2mg, 0.238mmol) above and 2M methylamine in methanol (4mL) of methylamine in trifluoroacetic acid salt of methylamine (1.73g, 11.9mmol) was heated at 150 ℃ in a sealed tube for 48 h. The mixture was then concentrated and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was concentrated and the residue was purified by reverse phase HPLC using TFA-buffered acetonitrile/water (40-80%) as eluent. The fractions containing the product 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).¹H NMR(CDCl₃)：δ2.25-2.35(m，12H)，3.53(s，3H)，7.21(t，J＝8.7Hz，2H)，7.54(m，1H)，7.73(m，2H)，7.88(m，1H)，8.13(m，2H)。ESI-MSm/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) benzene Phenol (5-F)

Preparation of 4-phenylbicyclo [2.2.2] octane-1-carboxylic acid (5-A)

Reference documents:

Chapman，N.B，Sotheeswaran，S.，and Toyne，K.J，J.Org.Chem，35：917-923(1970)

step A:

4-Phenylbicyclo [2.2.2] magnetically stirred at room temperature]To a solution of octane-1-carboxylic acid (5-A) (70mg, 0.30mmol) in dichloromethane (1mL) was added a solution of 2M oxalyl chloride in dichloromethane (0.61mL, 1.22 mmol). Two drops of catalytic DMF were added to catalyze the reaction. The reaction was stirred for 30 minutes and the solvent and reagents were removed in vacuo. To the residue was added dichloromethane (1mL), followed by 4- (benzyloxy) -2- (trifluoromethyl) benzoyl hydrazine (5-B) (141mg, 0.46mmol) and triethylamine (0.07mL, 0.46 mmol). The reaction was stirred at room temperature overnight to afford intermediate 5-C, N' - [4- (benzyloxy) -2- (trifluoromethyl) benzoyl]-4-phenylbicyclo [2.2.2]Octane-1-carbonyl hydrazine without isolation. To the crude product (5-C) was then added 2-chloro-1, 3-dimethylimidazolium chloride (257mg, 1.52mmol), and triethylamine (0.42mL, 3.04mmol) and dichloromethane (2mL) were added. The reaction was stirred at room temperature for 4 hours. The reaction mixture was then diluted with dichloromethane (30mL), washed twice with water (30mL), and washed with brine (30mL)Once. The combined aqueous layers were extracted once with dichloromethane (25 mL). The combined organic layers were dried (MgSO)₄) The solvent was removed in vacuo. The residue was subjected to silica gel chromatography using 10% ethyl acetate in hexane as an eluent to give 2- [4- (benzyloxy) -2- (trifluoromethyl) phenyl group]-5- (4-Phenylbicyclo [2.2.2]Oct-1-yl) -1, 3, 4-oxadiazole (5-D). MS: m/z 505(M + 1).

And B:

trifluoroacetic acid salt of methylamine (380mg, 2.61mmol) 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 2M methylamine in methanol (1.3mL, 2.61mmol) and heated at 150 ℃ overnight. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (25mL) 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 and dried (MgSO)₄) The solvent was removed in vacuo. The residue was then dissolved in methanol (8mL) and purified by reverse phase chromatography eluting with a gradient of 10% acetonitrile (0.1% TFA)/water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 10 minutes (20 mL/min). The product-containing fractions were partitioned between saturated aqueous sodium bicarbonate (25mL) and dichloromethane (15 mL). The layers were separated, the aqueous layer was extracted three times with dichloromethane (15mL), 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/z518(M + 1).

And 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) (27mg, 0.05mmol) was dissolved in ethyl acetate/methanol (1:1, 4mL), to which 10% palladium on carbon (4mg) was added. The reaction was then placed under a hydrogen atmosphere and stirred at room temperature and atmospheric pressure for 3 hours. After appropriate evacuation of hydrogen, the palladium was filtered off with methanol (40mL) through a filter aid. Collecting the filtrate, and removing the solvent in vacuo to obtain 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/z428(M + 1);¹H NMR(500MHz，CDCl₃)：δ1.92(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)

Step A:

diethyl (ethylsulfonylmethane) phosphate (1.12g, 4.6mmol) (Popoff, I.C. et al, J.org.chem.34: 1128-30(1969)) and 4-methoxycarbonylbicyclo [ 2.2.2: -2)]Octane-1-carbaldehyde (6-1) (0.82g, 4.2mmol) (Adcock, w., Kok, g.b.j.org.chem.50: 1079-1087(1985)) was dissolved in 8mL of anhydrous methanol. The mixture was cooled in an ice bath under nitrogen and treated with 0.5M sodium methoxide in methanol (8.8mL, 4.4 mmol). The reaction mixture was kept under reflux for 4 hours, then cooled to room temperature, concentrated under reduced pressure, then treated with 2mL of water and left to stand overnight in a refrigerator. The mixture was filtered and the solid was washed with a small amount of cold 1:1 MeOH/water. Collecting the resulting white solid and drying under vacuum to obtain the unsaturated sulfone6-2。MS(ESI⁺)＝287(M+1)。

And B:

sulfone6-2(880mg, 3.08mmol) was dissolved in a 1:2 mixture of ethyl acetate/methanol (30mL) under nitrogenNext, it was then treated with 10% Pd/C (800 mg). The reaction was placed under nitrogen 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-carboxylic acid methyl ester (6-3) A white solid.

And C:

esters6-3(880mg, 3mmol) was dissolved in 10% water/methanol solution (100mL) and treated with 1g of potassium hydroxide. The reaction was heated at 60 ℃ for 1 hour and then at 45 ℃ overnight. The mixture was concentrated in vacuo, then acidified to pH2 with 1M HCl and extracted three times with dichloromethane. 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 (C:)6-4)

Step D:

carboxylic acids6-4(810mg, 2.96mmol) was dissolved in 12mL of anhydrous dichloromethane under nitrogen, treated with oxalyl chloride (2M in dichloromethane, 4.4mL, 8.8mmol), and then treated with 5 drops of DMF. The reaction was stirred at room temperature under nitrogen for 90 minutes, then evaporated and placed under vacuum for 20 minutes. The acid chloride was dissolved in anhydrous dichloromethane (12mL), cooled in an ice bath, and treated dropwise with a solution of dichloromethane (2M in THF, 8.9mL, 17.8 mmol). After the amine addition, the cooling bath was removed and the reaction was stirred at room temperature for 30 minutes. The mixture was diluted with 200mL of dichloromethane and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue is chromatographed on silica gel with a gradient of 0-3.5% methanol in dichloromethane to give 4- [2- (ethylsulfonyl) ethyl]-N-methylbicyclo [2.2.2]Octane-1-carboxamides (6-5) White powder. MS (ESI)⁺)＝288(M+1)。

Step E:

carboxamides6-5(220mg, 0.77mmol) was dissolved in anhydrous dichloromethane (2mL) and oxalyl chloride (2M dichloromethane)Alkane solution, 0.77mL, 1.54mmol) and DMF (2 drops). The solution was stirred at room temperature for 1 hour, and then the solvent was removed by evaporation under reduced pressure. The residue was dissolved in anhydrous toluene (2mL) and washed with 5- [2- (trifluoromethyl) phenyl]1H-tetrazole (214mg, 1 mmol). The mixture was refluxed for 18 hours. The reaction was cooled to room temperature and the cream colored precipitate was filtered and washed to give 300mg of the HCl salt of the crude product. The salt was dissolved in dichloromethane/1N HCl and the aqueous layer was washed with two more portions of dichloromethane. The organic layers were combined and evaporated and the residue was purified by flash chromatography on silica gel. Elution was performed using a gradient of 0-5% methanol/dichloromethane. 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 (C)6-6) White powder. MS (ESI)⁺)＝456.2(M+1)；¹H NMR(500MHz，CDCl₃)：δ1.46(3H，t，J＝7.3Hz)，1.63(6H，m)，1.78(2H，m)，2.19(6H，m)，2.96(2H，m)，3.05(2H，q，J＝7.2Hz)，3.50(3H，m)，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)

Step A:

(benzyl)Oxycarbonylmethyl) triphenylphosphonium bromide (4.6g, 9.4mmol) was azeotroped twice from toluene and then suspended in 30mL of anhydrous THF. Potassium hexamethyldisilazide (0.5M in toluene, 16.8mL, 8.4mmol) was added dropwise at room temperature, and the yellow solution was stirred for 1 hour, after which it became milky white. Preparation of 4-Methoxycarbonylcyclo [2.2.2]Octane-1-carbaldehyde (7-A) (0.50g, 2.55mmol) (Adcock, w., Kok, g.b.j.org.chem.50: 1079-1087(1985)) and benzoic acid (0.015g, 0.13mmol) in 2mL of anhydrous THF were added dropwise via syringe at room temperature. The mixture was heated to 90 ℃ and stirred at reflux temperature, after which the mixture was diluted with 200mL of ethyl acetate and washed successively with 50mL of 1N HCl (twice), saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel with a gradient of 5% to 10% ethyl acetate in hexane to give 4- [ (1E) -3- (benzyloxy) -3-oxoprop-1-en-1-yl]Bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (7-B), colorless oil.¹H NMR(500MHz，CDCl₃)：δ7.4(5H，m)，6.94(1H，d，J＝17Hz)，5.77(1H，d，J＝17Hz)，5.21(2H，s)，3.69(3H，s)，1.86(6H，m)，1.63(6H，m)ppm。

And B:

diesters of benzoic acid7-B(0.625g, 1.90mmol) was dissolved in a 1:1 mixture of ethyl acetate/methanol (30mL), placed under a nitrogen atmosphere, and then treated with 10% Pd/C (500mg) and 0.1mL of acetic acid. The reaction was placed under 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 200mL of ethyl acetate and 200mL of 1N NaOH solution. The aqueous layer was separated and neutralized and then extracted three times with 50mL of dichloromethane. The combined organic layers were dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 3- [4- (methoxycarbonyl) bicyclo [2.2.2]Oct-1-yl]Propionic acid (b)7-C)。¹H NMR(500MHz，CDCl₃): δ 3.62(3H, s), 2.20(2H, broad t, J ═ 9Hz), 1.75(6H, m), 1.47(2H, broad t, J ═ 9Hz), 1.38(6H, m) ppm.

And C:

carboxylic acids7-C(400mg, 1, 67mmol) was dissolved in tetrahydrofuran (5mL) and borane (1M in THF, 2.17mL, 1.3 equiv) was added dropwise at room temperature. After 2 hours, 50mL of 1N HCl was added to the reaction, followed by three extractions with 50mL of dichloromethane. The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure to give crude 4- (3-hydroxypropyl) bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (7-D) And used in the next step without purification.¹H NMR(500MHz，CD₃OD)：δ3.66(3H，s)，3.62(2H，t，J＝6.5Hz)，1.78(6H，m)，1.50(2H，m)，1.41(2H，m)，1.17(2H，m)ppm。

Step D:

hydroxy esters7-D(430mg, 1.9mmol) was dissolved in 2.5mL of anhydrous dichloromethane under nitrogen, treated with pyridine (0.5mL) and methanesulfonyl chloride (0.368mL, 4.8mmol) and stirred at room temperature for 4 h. The mixture was diluted with 100mL of ethyl acetate and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. Crude 4- {3- [ (methylsulfonyl) oxy ] thus obtained]Propyl } bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (7-E) Used in the next reaction without purification.¹H NMR(500MHz，CDCl₃)：δ4.22(2H，t，J＝7.5Hz)，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。

Step E:

methanesulfonic acid ester7-E(3.30g, 10.9mmol) was dissolved in DMF (20mL) and treated with sodium ethyl mercaptide (1.82g, 21.7 mmol). The solution was stirred at 45 ℃ for 3 hours, then the mixture was diluted with 100mL of ethyl acetate and washed twice with 1N aqueous HCl, then with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 4- [3- (ethylthio) propyl ] ether]Bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (7-F) The crude oil of (2) is used in the next step without purification.¹H NMR(500MHz，CDCl₃)：δ 3.68ppm(3H，s)，2.56(2H，q，J＝7Hz)，2.51(2H，t，J＝7.5Hz)，1.80(6H，m)，1.52(2H，m)，1.42(6H，m)，1.28(2H，t，J＝7Hz)，1.02(2H，m)。

Step F:

sulfide compound7-F(3.0g, 11mmol) was dissolved in dichloromethane (50mL) 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 100mL of dichloromethane, washed with saturated aqueous sodium bicarbonate solution, then twice with saturated aqueous sodium bisulfite solution, then twice with saturated aqueous sodium bicarbonate solution, and then with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 4- [3- (ethylsulfonyl) propyl ester]Bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (7- G) And used in the next step without purification.¹H NMR(500MHz，CDCl₃)：δ 3.68ppm(3H，s)，2.56(2H，q，J＝7Hz)，2.51(2H，t，J＝7.5Hz)，1.80(6H，m)，1.52(2H，m)，1.42(6H，m)，1.28(2H，t，J＝7Hz)，1.02(2H，m)ppm。

Step G:

sulfone7-G(3.1g, 10mmol) was dissolved in 9:1 MeOH/water (50mL) and treated with potassium hydroxide (3 g). The solution was stirred at room temperature overnight, then the mixture was acidified with 1N HCl and extracted four times with 50mL dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated to give 4- [3- (ethylsulfonyl) propyl ester]Bicyclo [2.2.2]Octane-1-carboxylic acid (C:)7-H) The crude oil of (2) was used in the next step without purification.¹H NMR(500MHz，CDCl₃)：δ 3.03(2H，q，J＝7Hz)，2.94(2H，dd，J＝7.5Hz)，1.84(8H，m)，1.45(8H，m)，1.30(2H，m)ppm。

Step H:

formic acid7-H(3.0g, 11mmol) was dissolved in 50mL of anhydrous dichloromethane under nitrogen, treated with oxalyl chloride (2M in dichloromethane, 16.2mL, 32.4mmol), and then treated with 5 dropsAnd (4) DMF treatment. The reaction was stirred at room temperature under nitrogen for 90 minutes, then evaporated and placed in vacuo for 20 minutes. The acid chloride was dissolved in anhydrous dichloromethane (12mL), cooled in an ice bath, and then treated dropwise with methylamine solution (2M in THF, 27mL, 54 mmol). After addition of methylamine, the cooling bath was removed and the reaction was stirred at room temperature for 30 minutes. The mixture was diluted with 200mL of dichloromethane and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on silica gel with a gradient of 0-3% methanol in ethyl acetate to give 4- [3- (ethylsulfonyl) propyl ] acetate]-N-methylbicyclo [2.2.2]Octane-1-carboxamides (7-I) White powder. MS (ESI)⁺)＝302(M+1)。¹H NMR(500MHz，CDCl₃)：δ5.56(1H，br，s)，3.02(2H，q，J＝7Hz)，2.94(2H，dd，J＝7.5Hz)，2.82(3H，d，J＝4Hz)，1.80(8H，m)，1.45(9H，m)，1.28(2H，m)ppm。

Step I:

carboxamides7-I(0.470g, 1.56mmol) was dissolved in dry dichloromethane (5mL) and treated with oxalyl chloride (2M in dichloromethane, 1.56mL, 3.12mmol) and DMF (2 drops). The solution was stirred at room temperature for 1 hour, and then the solvent was removed by evaporation under reduced pressure. The residue was dissolved in dry toluene (7mL) and washed with 5- [2- (trifluoromethyl) phenyl]1H-tetrazole (368mg, 1.72 mmol). The mixture was refluxed for 18 hours. The reaction was cooled to room temperature, the precipitate was filtered and washed to give 300mg of the crude HCl salt. The salt was dissolved in dichloromethane/1N HCl and the aqueous layer was washed with two additional portions of dichloromethane. The organic layers were combined and evaporated and the residue was purified by flash chromatography on silica gel. Elution was performed with a gradient of 0-5% methanol in dichloromethane. 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 (C)7-J) White powder. MS (ESI)⁺)＝470.4(M+1)。¹H NMR(500MHz，CDCl₃)：δ7.87(1H，m)，7.72(2H，m)，7.56(1H，m)，3.49(3H，s)，3.05(2H，q，J＝7.2Hz)，2.96(2H，m)，2.18(6H，m)，1.86(2H，m)，1.62(6H，m)，1.46(3H，t，J＝7.3Hz)，1.36(2H，m)ppm。

Example 8

4-methyl-3- [2- (trifluoromethyl) phenyl]-5- (4- {2- [ (trifluoromethyl) sulfonyl group]Ethyl bicyclo [2.2.2]Pungent food -1-yl) -4H-1, 2, 4-triazole (8-G)

Step A:

to a stirred solution of methyltriphenylphosphonium bromide (9.1g, 12.8mmol) in THF (50ml) was added dropwise potassium hexamethyldisilazide (0.5M in toluene, 48.6ml) at 0 deg.C over a period of 5 minutes. The resulting mixture was allowed to warm to room temperature over 1 hour, then cooled to 0 ℃ and treated with 4-formylbicyclo [2.2.2]]Octane-1-carboxylic acid methyl ester 8-a (Chapman, n.b. et al, j.org.chem., 1970, 35, 917) (2.5g, 12.8 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc (350 mL). The organic phase was washed with aqueous HCl (1N), saturated aqueous sodium bicarbonate and brine, then dried (Na)₂SO₄) And concentrated in vacuo. The resulting solid was purified by flash chromatography on silica eluting with a gradient of 0-4% EtOAc in hexane. Isolation of the resulting 4-vinylbicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (8-B), clear colorless oil.

And B:

to a stirred solution of alkene 8-B (1.6g, 8.3mmol) in THF (20ml) was added 9-BBN (0.5M in THF, 49ml) dropwise. The solution was stirred at room temperature for 18 h, then successively with ethanol (14.5ml), NaOH (5N, 5ml)Aqueous solution and hydrogen peroxide (30% aqueous solution, 9.7 ml). The reaction mixture was acidified with aqueous HCl (1N) to pH2 and CH₂Cl₂Extraction was carried out three times. The organic layers were combined, washed with brine and dried (Na)₂SO₄) And stripped. The resulting alcohol 8-C was purified by silica gel chromatography eluting with a gradient of 30-50% EtOAc in hexane to isolate a clear colorless oil.

And C:

alcohol 8-C (1.5g, 7.1mmol) CH₂Cl₂(7.5ml), pyridine (1.5ml) solution was cooled to 0 ℃ and treated dropwise with methanesulfonyl chloride (1.65ml, 21.3mmol) over 5 minutes. The reaction mixture was warmed to room temperature and then stirred for 3 hours. EtOAc (300mL) was added and the organic phase was washed three times with aqueous HCl (1N), twice with saturated aqueous sodium bicarbonate and then with brine. Organic layer dried (Na)₂SO₄) Stripping to obtain 4- {2- [ (methylsulfonyl) oxy group]Ethyl bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester 8-D, white solid.¹H NMR(500MHz，CDCl₃)：δ1.52(6H，m)，1.66(2H，t，J＝7.1Hz)，1.84(6H，m)，3.04(3H，s)，3.69(3H，s)4.29(2H，t，J＝7.2Hz)ppm。

Step D:

a solution of 8-D (0.25g, 0.86mmol), potassium trifluoromethylsulfinate (0.3g, 1.72mmol) and tetrabutylammonium iodide (0.15g, 0.4mmol) in DMF (5ml) was heated at 140 ℃ under nitrogen for 5 hours. The solution was then cooled to room temperature, diluted with EtOAc (100mL), washed twice with aqueous HCl (1N) and then brine. Organic layer dried (Na)₂SO₄) Stripped, and flash chromatographed on silica gel, eluting with a gradient of 5-20% EtOAc in hexane. The resulting trifluoromethyl sulfone 8-E was isolated as a white solid.¹H NMR(500MHz，CDCl₃)：δ1.50(6H，m)，1.78(2H，m)，1.82(6H，m)，3.17(2H，m)，3.67(3H，s)ppm。

Step E:

methyl ester 8-E (0.0)35g, 0.11mmol) was converted to formamide 8-F using the method described in example 6, steps C and D. Isolation of N-methyl-4- {2- [ (trifluoromethyl) sulfonyl group]Ethyl bicyclo [2.2.2]Octane-1-carboxamide, white solid; MS (ESI)⁺)＝328.2(M+1)。

Step F:

formamide 8-F (0.030G, 0.092mmol) was converted to triazole 8-G using the method described in step E, example 6. Isolation of 4-methyl-3- [2- (trifluoromethyl) phenyl]-5- (4- {2- [ (trifluoromethyl) sulfonyl group]Ethyl bicyclo [2.2.2]Oct-1-yl) -4H-1, 2, 4-triazole (8-G), white powder; MS (ESI)⁺)＝496.4(M+1)。

Examples 9 to 102

The following compounds of formula II may also be prepared according to methods similar to those described above:

examples of pharmaceutical preparations

As a specific embodiment of an oral composition of the compounds of the present invention, 50mg of any of the compounds of examples 1-8 are processed with lactose finely divided enough to make a total of 580-590mg to fill a hard gelatin capsule type O.

While the invention has been described and illustrated with respect to specific embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, for a particular condition, the effective dose can be varied a priori based on the response of the person to be treated, rather than the preferred doses described above. Similarly, the pharmacological effects observed may vary according to or depending upon the particular active compound selected or whether there is a pharmaceutical carrier present, as well as the type of formulation and mode of administration, and the results of such expected variations or differences are predictable according to the objects and practices of the present invention. It is the intention, therefore, to be limited only as indicated by the scope of the claims appended hereto, and that the claims be interpreted as broadly as is reasonable.

Claims (26)

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

Each p is independently 0, 1 or 2;

each n is independently 0, 1 or 2;

x is selected from single bond O, S (O)_p、NR⁶、

And

R¹is selected from

An aryl carbonyl group, a carbonyl group,

(CH₂)_n-aryl, and

(CH₂)_n-a heteroaryl group;

wherein aryl and heteroaryl are unsubstituted or substituted with 1-3 substituents independently selected from R⁵Substituted with the substituent(s);

R²is selected from

The presence of hydrogen in the presence of hydrogen,

C_1-8an alkyl group, a carboxyl group,

C_2-6alkenyl, and

(CH₂)_n-C_3-6a cycloalkyl group,

wherein alkyl, alkenyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from R⁸And oxo;

each R⁴Is independently selected from

The presence of hydrogen in the presence of hydrogen,

the halogen(s) are selected from the group consisting of,

a hydroxyl group(s),

an oxo group, and a pharmaceutically acceptable salt thereof,

C_1-3alkyl, and

C_1-3an alkoxy group;

R³is selected from

The presence of hydrogen in the presence of hydrogen,

C_1-10an alkyl group, a carboxyl group,

C_2-10an alkenyl group, which is a radical of an alkenyl group,

(CH₂)_n-C_3-6a cycloalkyl group,

(CH₂)_n-aryl, and

(CH₂)_n-a heteroaryl group,

(CH₂)_n-a heterocyclic group;

wherein aryl, heteroaryl and heterocyclyl are unsubstituted or substituted with 1-3 substituents independently selected from R⁵Substituted with the substituent(s); alkyl, alkenyl and cycloalkyl unsubstituted or substituted with 1-5 substituents independently selected from R⁸And oxo;

R⁵and R⁸Is independently selected from

The presence of hydrogen in the presence of hydrogen,

the formyl group is a radical of a carboxylic acid,

C_1-6an alkyl group, a carboxyl group,

(CH₂)_n-an aryl group,

(CH₂)_n-a heteroaryl group,

(CH₂)_n-a heterocyclic group,

(CH₂)_nC_3-7a cycloalkyl group,

the halogen(s) are selected from the group consisting of,

OR⁷，

(CH₂)_nN(R⁷)₂，

the cyano group(s),

(CH₂)_nCO₂R⁷，

NO₂，

(CH₂)_nNR⁷SO₂R⁶，

(CH₂)_nSO₂N(R⁷)₂，

(CH₂)_nS(O)_pR⁶，

(CH₂)_nSO₂OR⁷，

(CH₂)_nNR⁷C(O)N(R⁷)₂，

(CH₂)_nC(O)N(R⁷)₂，

(CH₂)_nNR⁶C(O)R⁶，

(CH₂)_nNR⁶CO₂R⁷，

O(CH₂)_nC(O)N(R⁷)₂，

CF₃，

CH₂CF₃，

OCF₃，

OCHCF₂and are and

OCH₂CF₃；

wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or 1-3 independently selected from halogen, hydroxy, C_1-4Alkyl, trifluoromethyl, trifluoromethoxy, and C_1-4Substituent substitution of alkoxy; wherein R is⁵And R⁸Is unsubstituted or substituted with 1-2 substituents independently selected from halogen, hydroxy, and C_1-4Alkyl groups; or two substituents on the same methylene carbon atom together with the carbon atom to which they are attached form cyclopropyl;

each R⁶Is independently selected from

C_1-8An alkyl group, a carboxyl group,

(CH₂)_n-an aryl group,

(CH₂)_n-heteroaryl, and

(CH₂)_nC_3-7a cycloalkyl group;

wherein alkyl and cycloalkyl are unsubstituted or substituted by 1 to 5 substituents independently selected from halogen, oxo, C_1-4Alkoxy radical, C_1-4Alkylthio, hydroxyl and amino substituent substitution; aryl and heteroaryl are unsubstituted or substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C_1-4Alkyl, and C_1-4Substituent substitution of alkoxy;

or, two R⁶The radicals together with the atoms to which they are attached form a 5-to 8-membered mono-or bicyclic ring system optionally containing a further ring member selected from O, S and NC_1-4A heteroatom of an alkyl group; and is

Each R⁷Is hydrogen or R⁶，

Wherein aryl is a monocyclic or bicyclic 6-to 10-membered aromatic ring system, heterocyclyl is a group containing at least one heteroatom selected from O, S and N, and further includesThe oxidized forms of sulfur, i.e. SO and SO₂The heteroaryl group is an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N, and the heterocyclyl and heteroaryl groups contain 3 to 15 atoms forming 1 to 3 rings.

2. The compound of claim 1, wherein R²Is cyclopropyl, C_1-3Alkyl, or C_2-3Alkenyl, and R¹Is phenyl or naphthyl, wherein phenyl and naphthyl are unsubstituted or substituted by 1-3 independently selected from R⁵Is substituted with the substituent(s).

3. The compound of claim 2, wherein R⁵Selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, and C_1-3An alkylsulfonyl group.

4. The compound of claim 3, wherein R²Is methyl and R⁴Is hydrogen.

5. The compound of claim 1, wherein,

x is a single bond;

R¹is phenyl or naphthyl, wherein phenyl and naphthyl are unsubstituted or substituted by 1-3 independently selected from R⁵Is substituted with the substituent(s).

R²Is cyclopropyl, C_1-3Alkyl, or C_2-3An alkenyl group; and is

R³Is C_1-6Alkyl which is unsubstituted or substituted with 1-3 substituents independently selected from R⁸And oxo.

6. The compound of claim 5, wherein R⁵Selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, and C_1-3Alkyl sulfonyl radicalAnd (4) a base.

7. The compound of claim 6, wherein R²Is methyl and R⁴Is hydrogen.

8. The compound of claim 5, wherein R⁸Selected from halogen, hydroxy, oxo, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylsulfinyl radical, C_1-4Alkylsulfonyl, and phenyl, said phenyl being unsubstituted or substituted with 1-3 groups independently selected from halogen and trifluoromethyl.

9. The compound of claim 8, wherein R²Is methyl and R⁴Is hydrogen.

10. The compound of claim 5, wherein R⁵Selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, and C_1-3An alkylsulfonyl group; and R⁸Selected from halogen, hydroxy, oxo, C_1-4Alkoxy radical, C_1-4Alkylthio radical, C_1-4Alkylsulfonyl, and phenyl, said phenyl being unsubstituted or substituted with 1-3 groups independently selected from halogen and trifluoromethyl.

11. The compound of claim 10, wherein R²Is methyl and R⁴Is hydrogen.

12. The compound of claim 1, wherein,

x is a single bond;

R¹is phenyl or naphthyl, wherein phenyl and naphthyl are unsubstituted or substituted by 1-3 independently selected from R⁵Substituted with the substituent(s);

R²is cyclopropyl, C_1-3Alkyl, or C_2-3An alkenyl group; and

R³is phenyl or heteroaryl, wherein phenyl and heteroaryl are unsubstituted or substituted with 1-3 substituents independently selected from R⁵Is substituted with the substituent(s).

13. The compound of claim 12, wherein R²Is methyl and R⁴Is hydrogen.

14. The compound of claim 12, wherein R³Is phenyl, unsubstituted or substituted by 1 to 3 groups independently selected from R⁵Is substituted with the substituent(s).

15. The compound of claim 14, wherein R⁵Selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, and C_1-3An alkylsulfonyl group.

16. The compound of claim 15, wherein R²Is methyl and R⁴Is hydrogen.

17. The compound of claim 12, wherein R³Is oxadiazolyl which is unsubstituted or substituted with 1-2 groups independently selected from R⁵Is substituted with the substituent(s).

18. The compound of claim 17, R⁵Is phenyl, unsubstituted or substituted by 1 to 3 substituents independently selected from halogen, hydroxy, C_1-4Alkyl, trifluoromethyl, trifluoromethoxy, and C_1-4Substituent of alkoxy.

19. The compound of claim 18, wherein R²Is methyl and R⁴Is hydrogen.

20. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20 which is

Or a pharmaceutically acceptable salt thereof.

22. The compound of claim 20 which is

Or a pharmaceutically acceptable salt thereof.

23. The compound of claim 20 which is

Or a pharmaceutically acceptable salt thereof.

24. The compound of claim 20 which is

Or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

26. Use of a compound of claim 1 for the manufacture of a medicament for treating a disease selected from the group consisting of hyperglycemia, insulin resistance, type 2 diabetes, lipid disorders, obesity, atherosclerosis, and metabolic syndrome by inhibiting 11 β -HSD-1.