ZA200504441B - Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 - Google Patents

Description

TITLE OF THE INVENTION

TRIAZOLE DERIVATIVES AS INHIBITORS OF 11-BETA-HYDROXYSTEROID

DEHYDROGENASE-1

FIELD OF THE INVENTION

: The present invention relates to triazole derivatives as inhibitors of the enzyme “11-beta-hydroxysteroid dehydrogenase Type I(11B-HSD-1 or HSD-1) and methods of treatment certain conditions using such compounds. The compounds of the present 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 conditions.

BACKGROUND OF THE INVENTION

Diabetes is caused by multiple factors and is most simply characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state. There are two generally recognized forms of diabetes: Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), in which patients produce little or no insulin, the hormone which regulates glucose utilization, and Type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), wherein patients produce insulin and even exhibit hyperinsulinemia (plasma insulin levels that are the same or even elevated in comparison with non-diabetic subjects), while at the same time demonstrating hyperglycemia. Type 1 diabetes is typically treated with exogenous insulin administered via "injection. However, Type 2 diabetics often develop "insulin resistance”, such that the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, namely, muscle, liver and adipose tissues, is diminished. Patients who are insulin resistant but not diabetic have elevated insulin levels that compensate for their insulin resistance, so that serum glucose levels are not elevated. In patients with NIDDM, the plasma insulin levels, even when they are elevated, are insufficient to overcome the pronounced insulin resistance, resulting in hyperglycemia.

Insulin resistance is primarily due to a receptor binding defect that is not yet completely understood. Resistance to insulin results in insufficient activation of glucose uptake, diminished oxidation of glucose and storage of glycogen in muscle, inadequate insulin repression of lipolysis in adipose tissue and inadequate glucose production and secretion by the liver.

Persistent or uncontrolled hyperglycemia that occurs in diabetics is associated with increased morbidity and premature mortality. Abnormal glucose homeostasis is also associated both directly and indirectly with obesity, hypertension and alterations in lipid, lipoprotein and apolipoprotein metabolism. Type 2 diabetics are at increased risk of developing cardiovascular complications, €.8-, 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 critically important in the clinical management and treatment of diabetes mellitus.

Many patients who have insulin resistance but have not developed Type 2 diabetes are also at a risk of developing symptoms referred to as "Syndrome X" or "Metabolic

Syndrome". Syndrome X or Metabolic Syndrome is characterized by insulin resistance, along with abdominal obesity, hyperinsulinemia, high blood pressure, low HDL and high VLDL.

These patients, whether or not they develop overt diabetes mellitus, are at increased risk of developing the cardiovascular complications listed above.

Treatment of Type 2 diabetes typically includes physical exercise and dieting.

Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic B—cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate insulin-resistant tissues. However, dangerously low levels of plasma glucose can result, and an increased level of insulin resistance can ultimately occur.

Biguanides increase insulin sensitivity, resulting in some correction of hyperglycemia. However, many biguanides, e.g., phenformin and metformin, cause lactic acidosis, nausea and diarrhea.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) form a newer class of compounds with the potential for ameliorating hyperglycemia and other symptoms of Type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue, resulting in partial or complete correction of the elevated plasma levels of glucose substantially without causing hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR) gamma subtype. PPAR- gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones. Newer PPAR agonists that are being developed for treatment of Type 2 diabetes and/or dyslipidemia are agonists of one or more of the PPAR alpha, gamma and delta subtypes. For a review of insulin-sensitizing agents and other mechanisms for the treatment of Type 2 diabetes, see M. Tadayyon and S.A. Smith, “Insulin sensitisation in the treatment of Type 2 diabetes,” Expert Opin. Investig. Drugs, 12: 307-324 (2003).

There is a continuing need for new methods of treating diabetes and related conditions, such as Metabolic Syndrome. The present invention meets this and other needs.

SUMMARY OF THE INVENTION

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

R?

Ni rx >—r'

W

2

R* R : ®

These bicyclo[2.2.2]-octyltriazole derivatives are effective as inhibitors of 11B- hydroxysteroid dehydrogenase type 1 (1 1B-HSD1). They are therefore useful for the treatment, control or prevention of disorders responsive to the inhibition of 118-HSD1, such as hyperglycemia, insulin resistance, Type 2 diabetes, lipid disorders, obesity, atherosclerosis, and

Metabolic Syndrome.

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

The present invention also relates to methods for the treatment or control of hyperglycemia, insulin resistance, Type 2 diabetes, obesity, lipid disorders, atherosclerosis, and

Metabolic Syndrome by administering the compounds and pharmaceutical compositions of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with bicyclo[2.2.2]-oct-1-y}-1,2 4-triazole derivatives useful as inhibitors of 11B-HSD1. Compounds of the present invention are described by structural formula I:

R*

N= 1 re—x—\)—L >—R \ 2

R* ? (1 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 the group consisting of a single bond, O, S(O)p, NRS, 0) Re RR R° Re lo)

N N_ _N \ On ] 7 \

R® lo} 0 oo x:

Re R°® o o 7

ANOS AMS Mo T 0 0) :

R1 is selected from the group consisting of arylcarbonyl, (CH2)p-aryl, and (CH2)n-heteroaryl; in which aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R53;

R2is selected from the group consisting of hydrogen,

Cj-g alkyl,

C2-6 alkenyl, and (CH2)n-C3-6 cycloalkyl, in which alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R8 and oxo; each R4 is independently selected from the group consisting of hydrogen, halogen, hydroxy, 0x0,

C1-3 alkyl, and

C1-3 alkoxy;

R3 is selected from the group consisting of hydrogen,

C1-10 alkyl,

C2-10 alkenyl,

(CH2)p-C3-6 cycloalkyl, (CH2)p-aryl, (CH2)n-heteroaryl, and (CH2)n-heterocyclyl; in which aryl, heteroaryl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from RS; and alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to five groups independently selected from R8 and oxo;

RS and RS are each independently selected from the group consisting of hydrogen, formyl,

C1-6 alkyl, (CH2)p-aryl, (CH2)n-heteroaryl, : (CH2)n-heterocyclyl, (CH2)nC3-7 cycloalkyl, halogen,

OR7, (CH2NR7)2, cyano, (CH2)nCO2R7, .

NO2, ~ (CH2)nNR7SO2RS, (CH2)nSO2NR 7), (CH2)nS(O)pRS, (CH2)nSO20R7, (CH2)nNR7C(O)NR7)2, (CH2)nC(O)NRT)2, (CH2)NRSC(O)RS, (CH2)nNROCO2R7,

O(CH2)nC(ONR)2,

CF3,

CH2CF3,

OCF3,

OCHCF2, and

OCH2CF3;

wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to : three substituents independently selected from halogen, hydroxy, C1-4 alkyl, trifluoromethyl, trifluoromethoxy, and C}.4 alkoxy; and wherein any methylene (CH2) carbon atom in RS and

RS is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and Cj-4 alkyl; or two substituents when on the same methylene (CH2) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R6 is independently selected from the group consisting of

Cj-g alkyl, (CH2)n-aryl, (CH2)p-heteroaryl, and (CH2)nC3-7 cycloalkyl; wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C14 alkoxy, C1-4 alkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C1-4 alkyl, and C14 alkoxy; or two RO groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC1-4 alkyl; and each R7 is hydrogen or RS.

In one embodiment of the compounds of the present invention, R2 is cyclopropyl,

C1-3 alkyl, or C2.3 alkenyl and R1 is phenyl or naphthyl in which phenyl and naphthyl are unsubstituted or substituted with one to three substituents independently selected from RS. Ina class of this embodiment, RS is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, Cj-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, and C1-3 alkylsulfonyl. In a subclass of this class, R2 is methyl and R4 is hydrogen.

In a second embodiment of the compounds of the present invention,

X is a single bond;

R1 is phenyl or naphthyl in which phenyl and naphthyl are unsubstituted or substituted with one to three substituents independently selected from R3;

R2 is cyclopropyl, C1-3 alkyl, or C23 alkenyl; and

R3 is C1.6 alkyl unsubstituted or substituted with one to three substituents independently selected from R8 and oxo.

In a class of this second embodiment, RJ is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio,

and C1-3 alkylsulfonyl. In a subclass of this class, R2 is methyl and R4 is hydrogen. In another class of this embodiment, R8 is selected from the group consisting of halogen, hydroxy, oxo, C1- 4 alkoxy, C1-4 alkylthio, C14 alkylsulfinyl, C14 alkylsulfonyl, and phenyl unsubstituted or substituted with one to three groups independently selected from halogen and trifluoromethyl. In a subclass of this class, R2 is methyl and R4 is hydrogen. In a third class of this embodiment, RS is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1- 3 alkyl, C1-3 alkoxy, C1-3 alkylthio, and C}.3 alkylsulfonyl; and R8 is selected from the group consisting of halogen, hydroxy, oxo, C1-4 alkoxy, C14 alkylthio, C1-4 alkylsulfonyl, and phenyl unsubstituted or substituted with one to three groups independently selected from halogen and trifluoromethyl. In a subclass of this class, R2 is methyl and R4 is hydrogen.

In a third embodiment of the compounds of the present invention,

X is a single bond;

R1 is phenyl or naphthyl in which phenyl and naphthyl are unsubstituted or substituted with one to three substituents independently selected from R3;

R2is cyclopropyl, C1-3 alkyl, or C2.3 alkenyl; and :

R3 is phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with : one with one to three substituents independently selected from RS.

In a class of this embodiment, R2 is methyl and R4 is hydrogen.

In another class of this embodiment, R3 is phenyl unsubstituted or substituted with one with one to three substituents independently selected from RS. In a subclass of this class, RS is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-3 alkyl, C1-3 alkoxy, C]-3 alkylthio, and C1-3 alkylsulfonyl. Ina subclass of this subclass, R2 is methyl and R4 is hydrogen.

In a third class of this embodiment, R3 is oxadiazolyl, unsubstituted or substituted with one with one to two substituents independently selected from R3.

In a subclass of this class, RS is phenyl unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C14 alkyl, trifluoromethyl, trifluoromethoxy, and C1.4 alkoxy. In a subclass of this subclass, R2 is methyl and R4 is hydrogen.

As used herein the following definitions are applicable. "Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, means carbon chains which may be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

Where the specified number of carbon atoms permits, e.g., from C3-10, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures, When no number of carbon atoms is specified, C16 is intended. "Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. Where the specified number of carbon atoms permits, e.g., from C5-10, the term alkenyl also includes cycloalkenyl groups, and combinations of linear, branched and cyclic structures. When no pumber of carbon atoms is specified, C2-6 i8 intended. » Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. “Cycloalkyl" is a subset of alkyl and means a saturated carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. A cycloalkyl group generally is monocyclic unless stated otherwise. Cycloalkyl groups are saturated unless otherwise defined.

The term “alkoxy” refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., C1-6 alkoxy), or any number within this range [i.e., methoxy (MeO-), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain alkylsulfides of the number of carbon atoms specified (e.g., C1-6 alkylthio), or any number within this range [i.e., methylthio (MeS-), ethylthio, isopropylthio, etc.].

The term “alkylamino” refers to straight or branched alkylamines of the number of carbon atoms specified (e.g., C1-6 alkylamino), or any number within this range [i.e., methylamino, ethylamino, isopropylamino, t-butylamino, etc.].

The term “alkylsulfonyl” refers to straight or branched chain alkylsulfones of the number of carbon atoms specified (e.g., C1-6 alkylsulfonyl), or any number within this range [i.e., methylsulfonyl (MeSO2-), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkylsulfinyl” refers to straight or branched chain alkylsulfoxides of the number of carbon atoms specified (e.g., C1-6 alkylsulfinyl), or any number within this range [i.e., methylsulfinyl (MeSO-), ethylsulfinyl, isopropylsulfinyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain esters of a carboxylic acid derivative of the present invention of the number of carbon atoms specified (e.g.,

C1-6 alkyloxycarbonyl), or any number within this range [i.e., methyloxycarbonyl (MeOCO-), ethyloxycarbonyl, or butyloxycarbonyl].

"Aryl" means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems.

Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl. “Heterocycle” and "heterocyclyl" refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S and N, further including the oxidized forms of sulfur, namely SO and SO,. 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 that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus includes heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls and heterocycles that are not aromatic.

Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, 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 from 3-15 atoms are included, forming 1-3 rings. "Halogen" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. Fluorine is most preferred when the halogens are substituted on an alkyl or alkoxy group (e.g. CF30 and CF3CH20).

The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation 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 encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The terms “administration of” and “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

Compounds of structural formuld I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of structural formula L

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

Some of the compounds described herein may exist as tautomers such as keto- enol tautomers. The individual tautomers, as well as mixtures thereof, are encompassed within the compounds of structural formula I

Compounds of structural formula I may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

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

In a different aspect of the invention, a pharmaceutical composition is addressed comprising a compound in accordance with structural formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier. By the term “solvate” is meant a hydrate, an alcoholate, or other solvate of crystallization.

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

In another aspect of the invention, a method of treating non-insulin dependent (Type 2) diabetes mellitus in a mammalian patient in need of such treatment is disclosed comprising administering to the patient an anti-diabetic effective amount of a compound in accordance with structural formula L.

In another aspect of the invention, a method of treating obesity in a mammalian patient in need of such treatment is disclosed comprising administering to said patient a compound in accordance with structural formula Iin an amount that is effective to treat obesity.

In another aspect of the invention, a method of treating Metabolic Syndrome in a mammalian patient in need of such treatment is disclosed, comprising administering to said patient a compound in accordance with structural formula I in an amount that is effective to treat

Metabolic Syndrome.

In another aspect of the invention, 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 of such treatment is disclosed, comprising administering to said patient a compound in accordance with structural formula I in an amount that is effective to treat said lipid disorder.

In another aspect of the invention, a method of treating atherosclerosis in a mammalian patient in need of such treatment is disclosed, comprising administering to said patient a compound in accordance with structural formula I in an amount effective to treat atherosclerosis.

Another aspect of the present invention is concerned with the use of the compounds of structural formula I for the treatment hyperglycemia, insulin resistance, Type 2 diabetes, lipid disorders, obesity, atherosclerosis, and Metabolic Syndrome.

Yet a further aspect of the present invention provides for the use of the compounds of structural formula I in the manufacture of a medicament for use in the treatment of a condition selected from the group consisting of hyperglycemia, insulin resistance, Type 2 diabetes, lipid disorders, obesity, atherosclerosis, and Metabolic Syndrome.

The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the 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, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable

S organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (-COOH) or alcohol group being present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetate or maleate, can be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

It will be understood that, as used herein, references to the compounds of structural formula I are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.

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

The compounds described herein are selective inhibitors of the 11p-HSD1 enzyme.

Thus, the present invention relates to the use of thel 1B-HSD1 inhibitors for inhibiting the reductase activity of 11p-hydroxysteroid dehydrogenase, which is responsible for the conversion of cortisone to cortisol. Excess cortisol is associated with numerous disorders, including NIDDM, obesity, dyslipidemia, insulin resistance and hypertension. Administration of the compounds of the present invention decreases the level of cortisol and other 11B-hydroxysteroids in target tissues, thereby reducing the effects of excessive amounts of cortisol and other 11B-hydroxysteroids.

Inhibition of 11p-HSD1 can be used to treat and control diseases mediated by abnormally high levels of cortisol and other 11B-hydroxysteroids, such as NIDDM, obesity, hypertension and dyslipidemia. Inhibition of 11B-HSD1 activity in the brain such as to Jower cortisol levels may also be useful to treat or reduce anxiety, depression, and cognitive impairment.

The present invention includes the use of an 11p-HSD1 inhibitor for the treatment, control, amelioration, prevention, delaying the onset of or reducing the risk of developing the diseases and conditions that are described herein, as mediated by excess or uncontrolled amounts of cortisol and/or other corticosteroids in a mammalian patient, particularly a human, by the administration of an effective amount of a compound of structural formula I or a pharmaceutically acceptable salt or solvate thereof. Inhibition of the 118-HSD1 enzyme limits the conversion of cortisone, which is normally inert, to cortisol, which can cause or contribute to the symptoms of these diseases and conditions if present in excessive amounts.

NIDDM and Hypertension:

The compounds of this invention are selective inhibitors of 118-HSD1 over 11p-

HSD2. While the inhibition of 11-HSD1 is useful for reducing cortisol levels and treating conditions related thereto, inhibition of 11B-HSD?2 is associated with serious side effects, such as hypertension.

Cortisol is an important and well recognized anti-inflammatory hormone, which also acts as an antagonist to the action of insulin in the liver, such that insulin sensitivity is reduced, resulting in increased gluconeogenesis and elevated levels of glucose in the liver.

Patients who already have impaired glucose tolerance have a greater probability of developing

Type 2 diabetes in the presence of abnormally high levels of cortisol.

High levels of cortisol in tissues where the mineralocorticoid receptor is present often lead to hypertension. Inhibition of 11B-HSD1 shifts the ratio of cortisol and cortisone in specific tissues in favor of cortisone.

Administration of a therapeutically effective amount of an 118-HSD1 inhibitor 1s effective in treating, controlling and ameliorating the symptoms of NIDDM, and administration of a therapeutically effective amount of an 118-HSD1 inhibitor on a regular basis delays or prevents the onset of NIDDM, particularly in humans.

Obesity, Metabolic Syndrome, Dyslipidemia:

Excessive levels of cortisol have been associated with obesity, perhaps due to increased hepatic gluconeogenesis. Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of Metabolic Syndrome, such as high blood pressure, elevated VLDL and reduced HDL. Montague et al., Diabetes, 2000, 49: 883-888. Thus, the administration of an effective amount of an 11-HSD1 inhibitor is useful in the treatment or control of obesity. Long-term treatment with an 118-HSD1 inhibitor is also useful in delaying or preventing the onset of obesity, especially if the patient uses an 11p-HSD1 inhibitor in combination with controlled diet and exercise.

By reducing insulin resistance and maintaining serum glucose at normal concentrations, compounds of the present invention also have utility in the treatment and prevention of conditions that accompany Type II diabetes and insulin resistance, including the

Metabolic Syndrome or Syndrome X, obesity, reactive hypoglycemia and diabetic dyslipidemia.

Atherosclerosis:

As described above, inhibition of 11B-HSD1 activity and a reduction in the amount of cortisol are beneficial in treating or controlling hypertension. Since hypertension and dyslipidemia contribute to the development of atherosclerosis, administration of a therapeutically effective amount of an 11p-HSD1 inhibitor of the present invention may be especially beneficial in treating, controlling, delaying the onset of or preventing atherosclerosis.

Other Utilities:

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

The above diseases and conditions can be treated using the compounds of structural formula I, or the compound can be administered to prevent or reduce the risk of developintg the diseases and conditions described herein. Since concurrent inhibition of 11B-

HSD2 may have deleterious side effects or may actually increase the amount of cortisol in the target tissue where reduction of cortisol is desired, selective inhibitors of 118-HSD1 with little or no inhibition of 118-HSD2 are desirable.

The 11p-HSD1 inhibitors of structural formula I generally have an inhibition constant IC50 of less than about 500 nM, and preferably less than about 100 nM. Generally, the

IC50 ratio for 118-HSD2 to 118-HSD1 of a compound is at least about two or more, and preferably about ten or greater. Even more preferred are compounds with an IC5( ratio for 118-

HSD2 to 11p-HSD1 of about 100 or greater. For example, compounds of the present invention ideally demonstrate an inhibition constant IC50 against 11B-HSD?2 greater than about 1000 nM, and preferably greater than 5000 nM.

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

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

When treating or preventing the diseases and conditions described herein, for which compounds of structural formula I are indicated, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about about 0.1 to about 100 milligram per kilogram (mpk) of body weight, preferably given as a single daily dose orin divided doses about two to six times a day. The total daily dosage thus ranges from about 0.1 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. In the case of a typical 70 kg adult human, the total daily dose will range from about 7 mg to about 350 mg. This dosage may be adjusted to provide the optimal therapeutic response.

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

The compositions include compositions 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 nature and severity of the condition being treated and the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

The compound of structural formula I can be combined with the pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Carriers take a wide variety of forms. For example, carriers for oral liquid compositions include, e.g., water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and other components used in the manufacture of oral liquid suspensions, elixirs and solutions. Carriers such as starches, sugars and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating : agents and the like are used to prepare oral solid dosage forms, e.g., powders, hard and soft capsules and tablets. Solid oral preparations are preferred over oral liquids.

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

Various other materials may be present to act as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.

Tablets may be coated by standard agueous OF nonaqueous techniques. The typical percentage of active compound in these compositions may, of course, be varied from about 2 percent to about 60 percent on a w/w basis. Thus, tablets contain a compound of structural formula I or a salt or hydrate thereof in an amount ranging from as low as about 0.1 mg to as high as about 1.5 g, preferably from as low as about 1.0 mg to as high as about 500 mg, and more preferably from as low as about 10 mg to as high as about 100 mg.

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

Parenterals are typically in the form of a solution or suspension, typically prepared with water, and optionally including a surfactant such as hydroxypropylcellulose. Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Typically preparations that are in diluted form also contain a preservative.

The pharmaceutical injectable dosage forms, including aqueous solutions and dispersions and powders for the extemporaneous preparation of injectable solutions or dispersions, are also sterile and must be fluid to the extent that easy syringability exists; they must be stable under the conditions of manufacture and storage and are usually preserved. The carrier thus includes the solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

ASSAYS: MEASUREMENT OF INHIBITION CONSTANTS:

In vitro enzymatic activity was assessed for test compounds via a Scintillation

Proximity Assay (SPA). In short, tritiated-cortisone substrate, NADPH cofactor and titrated compound of structural formula I were incubated with 11B-HSD1 enzyme at 37°C to allow conversion to cortisol to progress. Following this incubation, a preparation of protein A coated

SPA beads, pre-blended with anti-cortisol monoclonal antibody and a non-specific 118-HSD inhibitor, such as 18B-glycyrrhetinic acid, was added to each well. The mixture was shaken at 15°C and was then read on a liquid scintillation counter suitable for 96 well plates. Percent inhibition was calculated relative to a non-inhibited control well and IC50 curves were generated.

This assay was similarly applied to 11B-HSD2, whereby tritiated cortisol and NAD were used as the substrate and cofactor, respectively. To begin the assay, 40 uL of substrate (25 nM 3H-

Cortisone + 1.25 mM NADPH in 50 mM HEPES Buffer, pH 7.4) was added to designated wells on a 96-well plate. The compound was dissolved in DMSO at 10 mM followed by a subsequent 50 fold dilution in DMSO. The diluted material was then titrated 4 fold, seven times. 1 pL of each titrated compound was then added in duplicate to the substrate. To start the reaction, 10 pL of 118-HSD1 microsome from CHO transfectants was added to each well at the appropriate concentration to yield approximately 10% conversion of the starting material. For ultimate calculation of percent inhibition, a series of wells were added that represented the assay minimum and maximum: one set that contained substrate without compound or enzyme (background), and another set that contained substrate and enzyme without any compound (maximum signal). The plates were spun briefly at a low speed in a centrifuge to pool the reagents, sealed with an adhesive strip, mixed gently, and incubated at 37°C for 2 h. After incubation, 45 pL of SPA beads, pre-suspended with anti-cortisol monoclonal antibody and a compound of formula I, were added to each well. The plates were resealed and shaken gently for greater than 1.5 h at 15°C. Data were collected on a plate based liquid scintillation counter such as a Topcount. To control for inhibition of anti-cortisol antibody/cortisol binding, substrate spiked with 1.25 nM [3]H cortisol was added to designated single wells. 1 pL of 200 uM compound was added to each of these wells, along with 10 uL of buffer instead of enzyme. Any calculated inhibiton was due to compound interfering with the cortisol binding to the antibody on the SPA beads.

ASSAYS: MEASUREMENT OF IN VIVO INHIBITION:

In general terms, the test compound was dosed orally to a mammal and a prescribed time interval was allowed to elapse, usually between 1 and 24 h. Tritiated cortisone was injected intravenously, followed several min later by blood collection. Steroids were extracted from the separated serum and analyzed by HPLC. The relative levels of 3H-cortisone and its reduction product, 3H-cortisol, were determined for the compound and vehicle-dosed control groups. The absolute conversion, as well as the percentage of inhibition, was calculated from these values.

More specifically, compounds were prepared for oral dosing by dissolving them in vehicle (5% hydroxypropyl-beta-cyclodextrin v/v HzO, or equivalent) at the desired concentration to allow dosing at typically 10 mg per kg. Following an overnight fasting, the solutions were dosed to ICR mice (obtained from Charles River) by oral gavage, 0.5 mL per dose per animal, with three animals per test group.

After the desired time had passed, routinely either 4 or 16 h, 0.2 mL of 3 pM 3H- cortisone in dPBS was injected by tail vein. The animal was caged for two min followed by euthanasia in a CO, chamber. Upon expiration, the mouse was removed and blood was collected by cardiac puncture. The blood was set aside in a serum separation tube for no less than 30 min at room temperature to allow for adequate coagulation. After the incubation period, blood was separated into serum by centrifugation at 3000Xg, 4°C, for 10 min.

To analyze the steroids in the serum, they were first extracted with organic solvent. A 0.2 mL volume of serum was transferred to a clean microcentrifuge tube. To this a 1.0 mL volume of ethyl acetate was added, followed by vigorous vortexing for 1 min. A quick spin on a microcentrifuge pelleted the aqueous serum proteins and clarified the organic supernatant. 0.85 mL of the upper organic phase was transferred to a fresh microcentrifuge tube and dried. The dried sample was resuspended in 0.250 mL of DMSO containing a high concentration of cortisone and cortisol for analysis by HPLC.

A 0.200 mL sample was injected onto a Metachem Inertsil C-18 chromatography column equilibrated in 30% methanol. A slow linear gradient to 50% methanol separated the target steroids; simultaneous monitoring by UV at 254 nm of the cold standards in the resuspension solution acted as an internal standard. The tritium signal was collected by a radiochromatography detector that uploaded data to software for analysis. The percent conversion of 3H-cortisone to 3H-cortisol was calculated as the ratio of AUC for cortisol over the combined AUC for cortisone and cortisol. :

Preparation of Compounds of the Invention:

The compounds of structural formula I of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The instant compounds are generally isolated in the their neutral form, but the triazole moeity can be further converted into a pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid and subsequent evaporation, precipitation, or crystallization. All temperatures are degrees Celsius unless otherwise noted.

Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESMS).

The phrase "standard peptide coupling reaction conditions” means coupling a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in an inert solvent such as dichloromethane in the presence of a catalyst such as HOBT. The use of protecting groups for the amine and carboxylic acid functionalities to facilitate the desired reaction and minimize undesired reactions is well documented. Conditions required to remove protecting groups are found 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 commonly used 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 Present

Invention: :

EE

Bn leew

Bai |obuylltiem or |urcwbonydimidssole (MeOTf | methyl mifluoromethanesulfonate ome, dichloromethane oMF |NNdimethylformamide

Pr a I

Namco; | sodium hydrogoncarbonste ore lcotumwetme es [Nbomoweommiee on lhe hexafluorophosphate

Poms |uobenyphosptine or lode soos |tionyicloree a |ufometicad hexafluorophosphate

CE mic [tirlserchromatoguphy

Tom [puwleneofonicacid

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

Reaction Scheme 1 illustrates a key step in the synthesis of the novel compounds of structural formula I of the present invention. As shown in reaction Scheme 1, a secondary amide (1-1) (N-Me or N-Et preferred) can be methylated by heating with neat methyl triflate in order to provide an iminoether (1-2). Alternatively other methylating reagents such as methyl iodide or methyl sulfate may be used neat orin a non-nucleophilic organic solvent. As shown in

Scheme 1, a bicyclo[2.2.2]octane-1-carboxylic acid (1-3) is converted to an acyl hydrazide (1-4) by using the coupling reagent TFFH and hydrazine in the presence of a tertiary amine base such as triethylamine. Alternatively, other coupling reagents commonly used for preparing amides may be used for this tranformation along with hydrazine. Alternatively, a bicyclo[2.2.2]octane- 1-carboxylic ester can be heated with hydrazine to prepare acyl hydrazides (1-4). The acyl hydrazide (1-4) and iminoether (1-2) thus produced can be heated together in an inert high boiling organic solvent such as toluene in the presence of a tertiary amine base such as triethylamine to provide bicyclo[2.2.2]octyltriazoles (1-5) of structural formula I

Scheme 1 9 ri" ot aA MeOTt ~.

H 65°C IR? 14 H 1-2 r—\ cos TFFH, hydrazing rE \—conHNH,

EtsN

AE 14

MN

EtsN, toluene 3 / 1 110°C, 3h Y 2 1-5

Alternatively, the reaction can be conducted in the inverse manner as described by reaction Scheme 2. In this procedure a secondary amide (2-1) is prepared from a bicyclo[2.2.2]octane-1-carboxylic acid using a standard peptide coupling reaction. This compound is methylated to form the iminoether (2-2) and reacted with an acyl hydrazide as described for reaction Scheme 1 to provide bicyclo[2.2.2]octyltriazoles (2-3) of structural formula IL

Scheme 2 . OMe court an. #0 \ oT 65°C ne OTF 1Nn2 2-1 H R 2:2 0) ] N—N

A NHNH, r— OL A

Et;N, toluene, 110°C, 3 h 2 2:3

Reaction Scheme 3 describes an alternate approach to compounds of the present invention of structural formula I, in which the key step is the palladium catalyzed Suzuki coupling reaction between a bicyclo[2.2.2]octylbromotriazole (3-1) and an aryl boronic acid to produce triazoles (3-2) of structural formula l. The preferred conditions use tetrakis(triphenylphosphine)palladium(0) as the catalyst in DMF solvent with cesium carbonate, but other catalysts and conditions may be employed, as recognized by those skilled in the art.

Scheme 3

N-N 1 N-N 1 eo A ) | Spr R'BOH: LL Sr

N Ee —— N l, Pd(PPhg),, & 2

R Cs,CO3, DMF 3-1 3-2

Reaction Scheme 4 describes yet another synthetic approach to the formation of compounds of structural formula L Using this procedure, 4-(bicyclo[2.2.2]octyl)oxadiazoles 4 1) are dehydratively condensed with methylamine, either neat in a melt with methylammonium trifluoroacetate or in buffered MeOH solution. These reactions are best performed at high temperatures in a high pressure reactor to prevent the loss of methylamine.

Scheme 4

N NN

— + - 1 oy pn MT re 0) 150°C CH or MeNHz" TFA” 4p 3 4-1 2M MeNH,/MeOH == 150°C

Reaction Scheme 5 describes yet another synthetic approach to the formation of compounds of structural formulal. Using this procedure, bicyclo[2.2.2)octylcarboxamides (5-1) are converted to iminochlorides (5-2), using a reagent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, optionally in the presence of DMF. The iminochloride (5-2) is condensed with an aryl tetrazole in a high boiling inert organic solvent such as toluene to provide the triazole (5-3).

Scheme 5

Cl ri \)—ConHRE ooh, —-\— toluene, DM NR2

Sl 52

N-N -N

N. Pa R? BNE Yn!

N N

.—— 2 5-3

Preparation of [2.2.2]Bicyclooctyl Intermediates:

The procedures used in the preparation of [2.2.2]bicyclooctyl intermediates for use in the preparation of compounds of the present invention are provided below. :

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

Intermediate Scheme 1 shows a preferred method for the preparation of oxadiazoles via the dehydration of diacyl hydrazides using a dehydrating reagent such as thionyl chloride. Alternatively, other dehydrating reagents such as phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride may be employed. The diacyl hydrazides may be prepared preferentially from a hydrazide and an activated acid, such as an acid chloride, in the presence of a tertiary amine base. Altematively, standard peptide coupling reactions may be employed to prepare the diacyl hydrazide from a hydrazide and a carboxylic acid.

Intermediate Scheme 2 shows a useful reagent for the dehydration of diacyl hydrazides to oxadiazoles, namely, 2-chloro-1,3-dimethyl-4,5-dihydro- 1H-imidazol-3-ium chloride. This reagent in a non-polar solvent (methylene chloride is preferred) along with a tertiary amine base (triethylamine is preferred) gives the desired oxadiazole intermediates in an efficient manner.

Intermediate Scheme 3 shows a preferred reagent for the one pot formation (from a hydrazide and a carboxylic acid) and dehydration of diacyl hydrazides to oxadiazoles: 2-chloro- 1,3-dimethyl-4,5-dihydro-1 H-imidazol-3-ium chloride. This reagent in a non-polar solvent

(methylene chloride is preferred) along with a tertiary amine base (triethylamine is preferred) gives the desired oxadiazole intermediates in an efficient manner.

Intermediate Scheme 4 shows an efficient method for the formation of oxadiazoles from secondary amides and hydrazides. The secondary amide (N-Me or N-Et preferred) can be methylated by heating with neat methyl triflate in order to provide an iminoether. Alternatively other methylating reagents such as methyl iodide or methyl sulfate may be used neat orin a non-nucleophilic organic solvent. Heating the iminoether thus formed in a high boiling inert organic solvent in the presence of a hydrazide affords oxadiazoles as shown in the Scheme. :

INTERMEDIATE SCHEME 1: 0)

H.C 2 6-diF-benzoyl chloride ab —¢ \ Pe —_

NHNH, EtzN, CHCl» 0 F.

H 1. SOC, PY, CHCl»

HC N mh TEE,

N 2

H . toluene, reflux oO F

F i 3 o)

F

INTERMEDIATE SCHEME 2: . Cl

OMe cr 9 Hu MeN A

HC NN L © —_—

H 0 EtsN, CHoCly

Cl

N—N igo!

OMe

INTERMEDIATE SCHEME 3: f

Cr

N =

QMe Me LL NMe

Eco H CONHNH, a + EtsN, CHCl

OMe

N—N \

INTERMEDIATE SCHEME 4:

Oo me—" we CH;OTH, 65°C

H

CF3

CONHNH

— A P Me orf of :

H3C Nyt -Me

H Et3N, toluene : CF. :

N—N ’

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

INTERMEDIATE SCHEME 5: 1. (COCl),, CHCl,

Me0,6—\ cos — CoH ¥ 2. | Na SNa (J +-BuSH, DMAP, benzene, light 3. ag. NaOH, MeOH

Intermediate Schemes 6 and 7 show preferred methods for the preparation of bicyclo[2.2.2]octane-1-carboxylic acids with a heteroaryl group at the R3 position as given by structural formula I Oxadiazoles at the R3 position may be prepared by the condensation of a bicyclo[2.2.2]octyl-1-carboxylic acid with an amidoxime as shown in Intermediate Scheme 6. A useful reagent for this coupling is CDL Alternatively, other reagents useful for dehydration or peptide coupling reactions may be employed. Intermediate Scheme 7 illustrates a preferred method for the synthesis of an intermediate of compounds of structural formula I bearing a thiazole group at the R3 position.

INTERMEDIATE SCHEME 6: e0,6— \ co 1. CDI

EE— 7 N 2. reflux, toluene N_ Icom + NH, 3. aq. KOH 0)

N

“OH

INTERMEDIATE SCHEME 7; 1. PyBrop e0,0— \ COs _EtN _ e0,6— \ CoN, 2. NH3 0 1. Lawesson's reagent, — M3,

Lan s reagen Me0,c—E\ con, ETOH, NaHCO, molecular sieves 2. aq. NaOH, MeOH .

FaC N a )¢ | H—coqH

S

Intermediate Schemes 8-14 show preferred methods for the preparation of bicyclo[2.2.2]octane-1-carboxylic acids intermediates in the synthesis of compounds of structural formula I with various alkyl or alkenyl or substituted alkyl groups at the R3 position. A key reaction is the Wittig reaction performed on a bicyclo[2.2.2]octane-1-carboxaldehyde, as shown in Intermediate Scheme 8. The double bond in the product of this reaction may be hydrogenated to generate an alkyl group of varying length and character (which will become the R3 substituent in structural formula I), depending on the Wittig reagent, as shown in Intermediate Scheme 9.

Alternatively, the double bond can be used to introduce other functionality, such as the hydroxy or fluoro group, as shown in Intermediate Scheme 10. The aldehyde itself may be used to provide the difluoromethyl group at position R3, as shown in Intermediate Scheme 11. The alkene product of the Wittig reaction can undergo numerous other transformations, for example, cyclopropanation, as illustrated in Intermediate Scheme 12. Alternatively, the Wittig reagent may contain a remote functional group, for example, a ketal, as illustrated in Intermediate

Scheme 13. This functional group may undergo characteristic functional group transformations after the Wittig/reduction sequence, for example, the hydrolysis of a ketal to a ketone, as illustrated in Intermediate Scheme 13, or the reduction of a ketal to an alcohol as illustrated in

Intermediate Scheme 14. In this manner compounds of structural formula I with a variety of different R3 substituents may be obtained. The specific examples given are intended to convey general principles and are not intended to limit the scope of the R3 substituents.

INTERMEDIATE SCHEME 8:

O Wittig weo.c—\ reaction ~~ MeOzC \

H —

R®

INTERMEDIATE SCHEME 9: 1. Hy, 10% Pd/C woo) EtOAc oo)

R? 2. aq. KOH, MeOH a8

INTERMEDIATE SCHEME 10: : 1.9-BBN, THF

MeO Oa EES MeO Cav 2 \ 2 NaOH, HO, 2 OH 1. DAST, CH.Clp, _ Hoo \ 2. ag. KOH, MeOH F

INTERMEDIATE SCHEME 11:

F

MeO,C \ DAST, CH,Cl weo,6— \ 0) F

INTERMEDIATE SCHEME 12: 1. EtoZn, CHol,, weo,c—~\ _TEA Ho.c—\ )—< 2. aq. KOH, MeOH

INTERMEDIATE SCHEME 13: iS ° oxalyl chlorid

H CH oxalyl chloride

HOC S > \__/ ~~ ° CHCl 0)

So or MeNH,, CHCl,

Cl ® THF > 0) 0)

MeHN

INTERMEDIATE SC 14:

NN < : 0 Pe 1. TsOH, acetone, reflux

R! PN 3 2. NaBH,, MeOH

N-N HO

Ju OS

R'” 0

General functional group chemical transformations used to prepare compounds of the present invention are illustrated below in the preparation of specific compounds of the present invention.

These functional group transformations are of a general variety well understood by those skilled in the art.

H 0

NN ea HONHo HO

N NaOAc, MeOH

CH

H NOH

NN PPhs, CCl

HsC N MeCN

CH

CN

NN

H oo 3 iS

CHs

OH

N—-N me OL \ alkyl iodide

CHa DMSO ’ O-alkyl

N-N ky

SASSI

N

CH,

OMe

N—N we LL BBr,, CH,Cla

CH, OMe

OH

N—N }

CH, OH

SMe

N—N ne OL \ mCPBA

N CH,Cly

CHa

S(0),CH

NN (O)pCH3 eNO,

CHs p=1or2

N—-N N

HC J \ X mCPBA 3 Nl ro

P CH,Cl,

CHa

NNT

BN N

N PP

CHa

Claims (29)

WHAT IS CLAIMED IS:

1. A compound of structural formula I: rR? NR 1 rx >—R N

2 . R* A 0) 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 the group consisting of a single bond, O, S(O)p. NRS, 0 R® rR® R°® Re 0. 0 J A AN N~ Ny 7 hd ~ ANeg~ ASN 8 ZN R 0 0) 0 0 R® Re R® 0) o) ) [ rd oO 0) ; Rl is selected from the group consisting of arylcarbonyl, (CH)n-aryl, and (CH?)n-heteroaryl; in which aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from RS; R2 is selected from the group consisting of hydrogen, C1-g alkyl, C26 alkenyl, and (CH2)n-C3-6 cycloalkyl;

in which alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R8 and oxo; each R4 is independently selected from the group consisting of hydrogen, halogen, hydroxy, 0X0, C1-3 alkyl, and C1-3 alkoxy; R3 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, (CH2)n-C3-6 cycloalkyl, (CH2)p-aryl, and (CH2)p-heteroaryl; (CH2)p-heterocyclyl; in which aryl, heteroaryl and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from RS; and alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to five groups independently selected from R8 and oxo; RS and R8 are independently selected from the group consisting of hydrogen, formyl, C1-6 alkyl, : (CH2)n-aryl, (CH2)p-heteroaryl, (CH2)p-heterocyclyl, (CH2)nC3-7 cycloalkyl, halogen, OR7, (CH2nNR7)2, cyano, (CH2)nCO2RY, NO3, (CH2)nNR7SO2RS,

(CH2nSO2NRT)2, (CH2)nS(O)pRS, (CH2)nSO20R7, (CHDnNRTC(ONRT)2, (CH)nCONRY, (CH2)nNR6C(O)RS, (CH2)nNRSCO2R7, O(CH2)nC(ON®R7)2, CFs, CH2CF3, OCF3, OCHCF2, and OCH2CF3; wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C14 alkyl, trifluoromethyl, trifluoromethoxy, and C14 alkoxy; and wherein any methylene (CH?) carbon atom in RS and R8 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C14 alkyl; or two substituents when on the same methylene (CH?) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

each R6 is independently selected from the group consisting of

C1-g alkyl,

(CH2)n-aryl, : (CH2)n-heteroaryl, and (CH2)nC3-7 cycloalkyl;

wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C14 alkoxy, C14 alkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, Ci4 alkyl, and C14 alkoxy;

or two RO groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC] 4 alkyl; and each R7 is hydrogen or R6.

2. The compound of Claim 1 wherein R2 is cyclopropyl, C1-3 alkyl, or C2-3 alkenyl and R1 is phenyl or naphthyl in which phenyl and naphthyl are unsubstituted or substituted with one to three substituents independently selected from RS.

3. The compound of Claim 2 wherein R3 is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-3 alkyl, Ci-3 alkoxy, C1.3 alkylthio, and Cj.3 alkylsulfonyl.

4. The compound of Claim 3 wherein R2 is methyl and R# is hydrogen.

5. The compound of Claim 1 wherein X is a single bond; R1 is phenyl or naphthyl in which phenyl and naphthyl are unsubstituted or substituted with one to three substituents independently selected from RS; R2is cyclopropyl, C1-3 alkyl, or C2.3 alkenyl; and R3 is C}-¢ alkyl unsubstituted or substituted with one to three substituents independently selected from R8 and oxo. :

6. The compound of Claim 5 wherein RS is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-3 alkyl, C1-3 alkoxy, C}1-3 alkylthio, and Cj-3 alkylsulfonyl.

7. The compound of Claim 6 wherein R2 is methyl and R4 is hydrogen.

8. The compound of Claim 5 wherein R38 is selected from the group consisting of halogen, hydroxy, oxo, C1-4 alkoxy, C1-4 alkylthio, C14 alkylsulfinyl, C14 alkylsulfonyl, and phenyl unsubstituted or substituted with one to three groups independently selected from halogen and trifluoromethyl.

9. The compound of Claim 8 wherein R2 is methyl and R4 is hydrogen.

10. The compound of Claim S wherein R5 is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, and C3 alkylsulfonyl; and R8 is selected from the group consisting of halogen,

hydroxy, oxo, C]1-4 alkoxy, C1-4 alkylthio, C14 alkylsulfonyl, and phenyl unsubstituted or substituted with one to three groups independently selected from halogen and trifluoromethyl.

11. The compound of Claim 10 wherein R2 is methyl and R4 is hydrogen.

12. The compound of Claim 1 wherein X is a single bond; R1 is phenyl or naphthyl in which phenyl and naphthyl are unsubstituted or substituted with one to three substituents independently selected from RI; R2is cyclopropyl, C1-3 alkyl, or C2-3 alkenyl; and R3 is phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with one with one to three substituents independently selected from RS.

13. The compound of Claim 12 wherein R2 is methyl and R4 is hydrogen.

14. The compound of Claim 12 wherein R3 is phenyl unsubstituted or substituted with one with one to three substituents independently selected from RS.

15. The compound of Claim 14 wherein RS is selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, and C1.3 alkylsulfonyl.

16. The compound of Claim 15 wherein R2 is methyl and R4 is hydrogen.

17. The compound of Claim 12 wherein R3 is oxadiazolyl, unsubstituted or substituted with one with one to two substituents independently selected from RS.

18. The compound of Claim 17 wherein RS is phenyl unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-4 alkyl, trifluoromethyl, trifluoromethoxy, and C14 alkoxy.

19. The compound of Claim 18 wherein R2 is methyl and R#4 is hydrogen.

20. A compound selected from the group consisting of:

F. CF S N—N 3 No N CHs Cl rae! \ CHj OH

CF. N-N : aCe ae \ CH Of N—N TFs we 0-0 N CH; CF 20 NN ~~94 HsC N CHg Oo Cl Od! N-N HC—" Rest \ CHj OH

0 CF Oud . | N—N 3 a N CH Cl N—N OH N CH, OH CF N—N 3 OH N CH; cl N-N OH N CHa OH CE N-N ® Oo N CHa OH Me QP \ HaC NN CFs 3 N and

Me \ 2 ~~ il \ CF 0=$ N-N 3 . CFs or a pharmaceutically acceptable salt thereof.

21. The compound of Claim 20 which is

F. CF3 a, N—-N Ng N CH, or a pharmaceutically acceptable salt thereof.

22. The compound of Claim 20 which is CFs o_o oor HaC N CHs or a pharmaceutically acceptable salt thereof.

23. The compound of Claim 20 which is Cl ave IN / HsC ’ \ CH, OH or a pharmaceutically acceptable salt thereof.

24. The compound of Claim 20 which is

Me WP N : / > \ CF. / HaC N-N 2 or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound in accordance with Claim 1 in combination with a pharmaceutically acceptable carrier.

26. Use of a compound in accordance with Claim 1 in the manufacture of a medicament for usé in treating a condition selected from the group consisting of hyperglycemia, insulin resistance, Type 2 diabetes, lipid disorders, obesity, atherosclerosis, and Metabolic Syndrome.

«0

27. The compound of claim 1 or claim 20, substantially as herein described and exemplified.

28. A pharmaceutical composition of claim 25, substantially as herein described and exemplified.

29. Use of claim 26, substantially as herein described and exemplified. -73a- AMENDED SHEET