HK1081946B - 11-beta-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia - Google Patents

Description

11-beta-hydroxysteroid dehydrogenase 1 inhibitors for the treatment of diabetes, obesity and dyslipidemia

Technical Field

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

Background

Diabetes is caused by multiple factors, the simplest characterized by elevated plasma glucose concentrations (hyperglycemia) in the fasting state. There are two generally recognized forms of diabetes: type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), in which the patient produces little or no hormone insulin that regulates glucose utilization; and type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), in which the patient produces insulin and even exhibits hyperinsulinemia (plasma insulin concentrations the same as or even higher than in non-diabetic patients), while at the same time exhibiting hyperglycemia. Type 1 diabetes is generally treated by injection of exogenous insulin. However, patients with type 2 diabetes often exhibit "insulin resistance" which diminishes the effect of insulin in stimulating glucose and lipid metabolism in the major insulin sensitive tissues (i.e., muscle, liver and adipose tissue). Patients who are insulin-resistant but not diabetic patients have elevated insulin levels to compensate for their insulin resistance so that serum glucose levels are not elevated. In patients with NIDDM, plasma insulin levels, even when elevated, are insufficient to overcome significant insulin resistance, resulting in hyperglycemia.

Insulin resistance is primarily due to receptor binding defects which are not yet fully understood at present. Tolerance to insulin results in an insufficient activation process for glucose absorption, impaired oxidation of glucose and storage of glycogen in muscle, adequate lipolysis inhibition by insulin in adipose tissue and inadequate production and secretion of glucose by the liver.

Persistent or uncontrolled hyperglycemia that occurs in diabetic patients is associated with increased morbidity and premature death. Abnormal glucose homeostasis is also associated, both directly and indirectly, with obesity, hypertension, and alterations in lipid, lipoprotein and apolipoprotein metabolism. Patients with type 2 diabetes mellitus are at increased risk of cardiovascular complications, such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are of particular importance in the clinical management and treatment of diabetes.

Many patients with insulin resistance who do not develop type 2 diabetes are also at risk of developing symptoms known as "syndrome X" or "metabolic syndrome". Syndrome X is characterized by insulin resistance, as well as abdominal obesity, hyperinsulinemia, hypertension, low HDL, and high VLDL. These patients, whether or not they develop overt diabetes mellitis, are at increased risk for developing the above mentioned cardiovascular complications.

Treatment of type 2 diabetes typically involves physical exercise and special diets. Increasing plasma levels of insulin by administration of sulfonylureas (e.g., tolbutamide and glipizide) or meglitinide, stimulating pancreatic beta-cells to secrete more insulin, and/or injecting insulin when sulfonylureas or meglitinide become ineffective, can result in sufficiently high insulin concentrations, stimulating insulin-resistant tissues. However, dangerously low levels of plasma glucose can occur, and eventually elevated levels of insulin resistance occur.

Biguanides increase insulin sensitivity, resulting in a slight correction of hyperglycemia. However, many biguanides, such as norgyline and metformin, cause lactic acidosis, nausea and diarrhea.

glitazones (i.e., 5-benzylthiazolidine-2, 4-dione) constitute a new class of compounds with the potential to ameliorate the hyperglycemia and other symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue, partially or completely correcting elevated glucose plasma concentrations, while producing substantially no hypoglycemia. Glitazones are now marketed as agonists of the Peroxisome Proliferator Activated Receptor (PPAR) gamma subtype. PPAR-gamma agonists are generally considered to improve insulin sensitivity, which is observed when glitazones are used. New PPAR agonists that are being developed for the treatment of type 2 diabetes and/or dyslipidemia are agonists of one or more of the PPAR α, γ and δ subtypes.

There remains a need for new methods of treating diabetes and related conditions. The present invention fulfills this and other needs.

Summary of The Invention

The present invention relates to compounds represented by formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

a and B may be present individually or in combination;

when it is present alone, it is,

a represents halogen, C_1-6Alkyl, OC_1-6Alkyl or phenyl, said alkyl, phenyl and OC_1-6The alkyl portion of the alkyl group is optionally substituted with 1-3 halo groups;

and B represents H, halogen, C_1-6Alkyl, -OC_1-6Alkyl, -SC_1-6Alkyl radical, C_2-6Alkenyl, phenyl or naphthyl, said alkyl, alkenyl, phenyl, naphthyl and-OC_1-6Alkyl and-SC_1-6The alkyl part of the alkyl group is optionally substituted by 1-3 substituents selected from halogen, OH, CH₃O、CF₃And OCF₃Substituted with a group of (1); and

when brought together in a combined manner, the components,

a and B together represent

(a) Optionally substituted by 1-3 halogen radicals and 1-2R^aRadical substituted C_1-4Alkylene, wherein R^aIs represented by C_1-3Alkyl, OC_1-3Alkyl radical, C_6-10Aryl radical C_1-6Alkylene or phenyl optionally substituted by 1 to 3 halogen groups, or

(b)C_2-5Alkanediyl such that together with the carbon atom to which they are attached they form a 3-6 membered ring, said ring optionally containing 1 double bond or 1-2 heteroatoms selected from O, S and N, said 3-6 membered ring optionally being substituted by C_1-4Alkylene, oxo, ethylenedioxy or propylenedioxy substituted, andfurther optionally substituted by 1-4 substituents selected from halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Acyl radical, C_1-3Acyloxy, C_1-3Alkoxy radical, C_1-6alkyl-OC (O) -, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkoxy, phenyl, CN, OH, D, NH₂、NHR^aAnd N (R)^a)₂Wherein R is^aAs defined above;

each R¹Represents H or is independently selected from the following groups: OH, halogen, C_1-10Alkyl radical, C_1-6Alkoxy and C_6-10Aryl radical, said C_1-10Alkyl radical, C_6-10Aryl and C_1-6The alkyl part of the alkoxy group being optionally substituted by 1 to 3 halogen, OH, OC_1-3Alkyl, phenyl or naphthyl, said phenyl and naphthyl optionally substituted with 1-3 substituents independently selected from halogen, OCH₃、OCF₃、CH₃、CF₃And phenyl, wherein said phenyl is optionally substituted with 1-3 halo groups,

or two R¹Radicals taken together represent condensed C_5-6An alkyl or aryl ring, which may optionally be substituted with 1-2 OH or R^aIs substituted by radicals in which R^aAs defined above;

R²and R³May be combined together or present separately;

when taken together, R²And R³To represent

(a)C_3-8Alkanediyl forming a fused 5-to 10-membered non-aromatic ring, optionally interrupted by 1 to 2 double bonds, and optionally interrupted by 1 to 2 heteroatoms selected from O, S and N; or

(b) A fused 6-to 10-membered aromatic monocyclic or bicyclic group, said alkanediyl and aromatic monocyclic or bicyclic groups optionally being substituted by 1 to 6 halogen atoms, and 1 to 4 OH, C_1-3Alkyl, OC_1-3Alkyl, halo C_1-3Alkyl, aryl, heteroaryl, and heteroaryl,Halogen substituted C_1-3Alkoxy and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, C_1-3Alkyl, OC_1-3Radical substitution of alkyl, said C_1-3Alkyl and OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups;

when it is present alone, it is,

R²selected from the group consisting of:

(a)C_1-14alkyl, optionally substituted by 1-6 halogen groups and 1-3 groups selected from OH, OC_1-3Alkyl and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, OCH₃、OCF₃、CH₃And CF₃Substituted with the group of (1), said OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups;

(b) phenyl and pyridyl, optionally substituted by 1-3 halogens, OH or R^aRadical substitution, R^aThe radicals are as defined above;

(c)C_2-10alkenyl, optionally substituted with 1-3 substituents independently selected from halogen, OH and OC_1-3Substituent of alkyl, the OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halogen atoms;

(d)CH₂CO₂H；

(e)CH₂CO₂C_1-6an alkyl group;

(f)CH₂C(O)NHR^awherein R is^aAs defined above;

(g)NH₂、NHR^aand N (R)^a)₂，

Wherein R is^aAs defined above;

and R³Selected from the following groups: c_1-4Alkyl radical, C_2-10Alkenyl, SC_1-6Alkyl radical, C_6-10Aryl, heterocyclic ringsAlkyl, alkenyl, aryl, heterocyclyl, heteroaryl and SC_1-6The alkyl portion of the alkyl group is optionally substituted with: (a) r; (b)1-6 halogen radicals and (c)1-3 radicals selected from OH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, OC_1-4Alkyl, CN, C_1-4Alkyl S (O)_x- (where x is 0, 1 or 2), C_1-4Alkyl SO₂NH-，H₂NSO₂-，C_1-4Alkyl NHSO₂-and (C)_1-4Alkyl radical)₂NSO₂-, said C_1-4Alkyl and C of said radical_1-4The alkyl moiety being optionally substituted with phenyl and 1-3 halo groups, and

r is selected from the group consisting of heterocyclyl, heteroaryl and aryl, said group being optionally substituted with 1 to 4 groups selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkyl S (O) x- (x is as defined above), C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂-、CN、OH、OC_1-4Alkyl, and said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with 1-5 halogens and 1 halogen selected from OH and OC_1-3Alkyl groups.

Detailed Description

The present invention relates to compounds represented by formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

a and B may be present individually or in combination;

when it is present alone, it is,

a represents halogen, C_1-6Alkyl, OC_1-6Alkyl radicalOr phenyl, said alkyl, phenyl and OC_1-6The alkyl portion of the alkyl group is optionally substituted with 1-3 halo groups; and

b represents H, halogen, C_1-6Alkyl, -OC_1-6Alkyl, -SC_1-6Alkyl radical, C_2-6Alkenyl, phenyl or naphthyl, said alkyl, alkenyl, phenyl, naphthyl and-OC_1-6Alkyl and-SC_1-6The alkyl part of the alkyl group is optionally substituted by 1-3 substituents selected from halogen, OH, CH₃O、CF₃And OCF₃Substituted with a group of (1); and

when brought together in a combined manner, the components,

a and B together represent

(a) Optionally substituted with 1-3 halogen groups and 1-2R^aC of a radical_1-4Alkylene, wherein R^aIs represented by C_1-3Alkyl, OC_1-3Alkyl radical, C_6-10Aryl radical C_1-6Alkylene or phenyl optionally substituted by 1 to 3 halogen groups, or

(b)C_2-5Alkanediyl such that together with the carbon atom to which they are attached they form a 3-6 membered ring, said ring optionally containing 1 double bond or 1-2 heteroatoms selected from O, S and N, said 3-6 membered ring optionally being substituted by C_1-4Alkylene, oxo, ethylenedioxy or propylenedioxy, and further optionally substituted by 1 to 4 substituents selected from halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Acyl radical, C_1-3Acyloxy, C_1-3Alkoxy radical, C_1-6alkyl-OC (O) -, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkoxy, phenyl, CN, OH, D, NH₂、NHR^aAnd N (R)^a)₂Wherein R is^aAs defined above;

each R¹Represents H or is independently selected from the following groups: OH, halogen, C_1-10Alkyl radical, C_1-6Alkoxy and C_6-10Aryl radical, said C_1-10Alkyl radical, C_6-10Aryl and C_1-6The alkyl part of the alkoxy group being optionally substituted by 1 to 3 halogen, OH, OC_1-3Alkyl, phenyl or naphthyl, said phenyl and naphthyl optionally substituted with 1-3 substituents independently selected from halogen, OCH₃、OCF₃、CH₃、CF₃And phenyl, wherein said phenyl is optionally substituted with 1-3 halo groups,

or two R¹Radicals taken together represent condensed C_5-6An alkyl or aryl ring, which may optionally be substituted with 1-2 OH or R^aIs substituted by radicals in which R^aAs defined above;

R²and R³May be present in combination or separately;

when taken together, R²And R³To represent

(a)C_3-8Alkanediyl forming a fused 5-to 10-membered non-aromatic ring, optionally interrupted by 1 to 2 double bonds, and optionally interrupted by 1 to 2 heteroatoms selected from O, S and N; or

(b) A fused 6-to 10-membered aromatic monocyclic or bicyclic group, said alkanediyl and aromatic monocyclic or bicyclic groups optionally being substituted by 1 to 6 halogen atoms, and 1 to 4 OH, C_1-3Alkyl, OC_1-3Alkyl, halo C_1-3Alkyl, halo C_1-3Alkoxy and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, C_1-3Alkyl, OC_1-3Radical substitution of alkyl, said C_1-3Alkyl and OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups;

when the separation is present, the separation is,

R²selected from the group consisting of:

(a)C_1-14alkyl, optionally substituted by 1-6 halogen groups and 1-3 groups selected from OH, OC_1-3Alkyl and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, OCH₃、OCF₃、CH₃And CF₃Is substituted with a group of (a), said OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups;

(b) phenyl and pyridyl, optionally substituted by 1-3 halogens, OH or R^aRadical substitution, R^aThe radicals are as defined above;

(c)C_2-10alkenyl, optionally substituted with 1-3 substituents independently selected from halogen, OH and OC_1-3Substituent of alkyl, the OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halogen atoms;

(d)CH₂CO₂H；

(e)CH₂CO₂C_1-6an alkyl group;

(f)CH₂C(O)NHR^awherein R is^aAs defined above;

(g)NH₂、NHR^aand N (R)^a)₂，

Wherein R is^aAs defined above;

and R³Selected from the following groups: c_1-4Alkyl radical, C_2-10Alkenyl, SC_1-6 alkyl, C_6-10Aryl, heterocyclyl and heteroaryl, said alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and SC_1-6The alkyl portion of the alkyl group is optionally substituted with: (a) r; (b)1-6 halogen radicals and (c)1-3 radicals selected from OH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, OC_1-4Alkyl, CN, C_1-4Alkyl S (O)_x- (where x is 0, 1 or 2), C_1-4Alkyl SO₂NH-，H₂NSO₂-，C_1-4Alkyl NHSO₂-and (C)_1-4Alkyl radical)₂NSO₂-, said C_1-4Alkyl and C of said radical_1-4The alkyl moiety being optionally substituted with phenyl and 1-3 halo groups, and

r is selected from the group consisting of heterocyclyl, heteroaryl and aryl, said group being optionally substituted with 1 to 4 groups selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkyl S (O)_x- (x is as defined above), C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂-、CN、OH、OC_1-4Alkyl, and said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with 1-5 halogens and 1 halogen selected from OH and OC_1-3Alkyl groups.

The following definitions may be used herein.

When "Ac" is acetyl, CH₃C(O)-。

"alkyl" and other groups bearing the prefix "alkyl", such as alkoxy and hydroxyalkyl, refer to carbon chains, which may be linear or branched 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. When a specific number of carbon atoms is specified, e.g. C₃-C₁₀The term alkyl also includes cycloalkyl groups as well as combinations of straight or branched alkyl chains associated with cycloalkyl structures. When the number of carbon atoms is not specifically defined, it represents C_1-6。

"alkenyl" means a carbon chain containing at least one carbon-carbon double bond, which 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, butenyl, 2-methyl-2-butenyl, and the like. When a specific number of carbon atoms is specified, e.g. C₅-C₁₀The term alkenyl also includes cycloalkenyl groups and combinations of straight, branched, and cyclic structures. When a specific number of carbon atoms is not specified, it represents C_2-6。

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

"Alkanediyl" means a difunctional carbon chain, for example-CH₂-、-(CH₂)₂-、-(CH₂)₃-and the like. Alkanediyl groups are straight-chain or branched, unless otherwise indicated. In contrast, alkyl groups are monofunctional.

As used herein, "alkylene" refers to a carbon atom or chain linked by a double bond.

"cycloalkyl" is a subset of alkyl and denotes a saturated carbocyclic ring having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups are typically monocyclic unless otherwise indicated. Cycloalkyl groups are saturated unless otherwise defined.

"aryl" means a mono 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 a saturated or unsaturated non-aromatic ring or a ring containing at least one heteroatom selected from O, S and N (further including oxidized forms of sulfur, SO and SO₂) A ring system of (a). Examples of heterocycles include Tetrahydrofuran (THF), dihydrofuran, 1, 4-dioxane, morpholine, 1, 4-dithiane, piperazine, piperidine, 1, 3-dioxane, 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 heterocyclic ring containing at least one ring heteroatom selected from O, S and N (including SO).

Thus heteroaryl includes heteroaryl fused to other types of rings such as aryl, cycloalkyl and non-aromatic heterocyclic rings. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, dihydroindolyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothiophenyl, indolizinyl, quinolizinyl, cinnolinyl, 2, 3-diazanaphthyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxanyl, quinoxalyl, purinyl, furanyl, isobenzofuranyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-oxide), quinolyl, indolyl, isoquinolyl, dibenzofuranyl, naphthopyridyl (napthylyl), and the like. For heterocyclyl and heteroaryl groups, rings and ring systems containing 3 to 15 atoms are included, forming 1 to 3 rings.

"halo" and "halogen" refer to fluoro, chloro, bromo, and iodo.

Chlorine and fluorine are generally preferred. When halogen is a substituent on an alkyl or alkoxy group, fluorine (e.g., CF) is most preferred₃O and CF₃CH₂O)。

The term "pharmaceutical composition" encompasses a product comprising one or more active ingredients and a 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 decomposition of one or more of the ingredients or from another type of reaction. Thus, the pharmaceutical compositions of the present invention include those prepared by admixing one or more compounds of the present invention and a pharmaceutically acceptable carrier.

The compounds of formula I may contain one or more asymmetric centers and may therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms are included herein.

Some of the compounds described herein contain olefinic double bonds. Pure forms as well as mixtures of E and Z geometric isomers are also included herein.

Some of the compounds described herein may act as tautomers in that they have different hydrogen attachment points accompanied by the movement of one or more double bonds. For example, ketones and their enol forms are keto-enol tautomers.

Included herein are individual tautomers and mixtures thereof.

If desired, racemic mixtures of the compounds of formula I can be separated, thereby isolating the individual enantiomers. Separation may be carried out by methods well known in the art, for example, by combining a racemic mixture of a compound of formula I with an enantiomerically pure compound to form a diastereomeric mixture, which is then separated into the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The binding reaction is usually the salt formation using an enantiomerically pure acid or base.

The diastereomeric derivatives can then be converted into the substantially pure enantiomers by decomposition of the attached chiral residue from the diastereomeric compound.

Racemic mixtures of compounds of formula I can also be separated directly by chromatography using chiral stationary phases, methods well known in the art.

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

A particularly important aspect of the invention relates to compounds of the formula I, in which A and B are taken together and represent C_2-5Alkanediyl, thereby forming together with the carbon atom to which it is attached a 3-6 membered ring, said ring optionally containing 1 double bond or 1-2 heteroatoms selected from O, S and N, said 3-6 membered ring optionally being substituted by C_1-4Alkylene, oxo, ethylenedioxy or propylenedioxy, and further optionally substituted with 1 to 4 groups selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Acyl radical, C_1-3Acyloxy group,C_1-3Alkoxy radical, C_1-6Alkyl OC (O) -, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkoxy, phenyl, CN, OH, D, NH₂、NHR^aAnd N (R)^a)₂Wherein R is^aIs represented by C_1-3Alkyl, OC_1-3Alkyl radical, C_6-10Aryl radical C_1-6Alkylene or phenyl optionally substituted with 1-3 halo groups. In this aspect of the invention, all other variable moieties are defined as in formula I.

Another more important aspect of the present invention are the above compounds, wherein A and B taken together represent C_2-4A member alkanediyl, thereby forming together with the carbon atom to which it is attached a 3-5 membered ring, optionally substituted with 1-3 groups selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkoxy and phenyl. In this aspect of the invention, all other variable moieties are defined as in formula I.

More particularly, an important aspect of the present invention is the above compound, wherein A and B are taken together and represent C_2-4A member of an alkanediyl group, thereby forming together with the carbon atom to which it is attached a 3-5 membered ring, said ring being unsubstituted or substituted by 1-2 halogen groups. In this aspect of the invention, all other variable moieties are defined as in formula I.

More particularly, an important aspect of the present invention relates to the above compounds wherein 1 to 2 halogen groups are fluoro groups. In this aspect of the invention, all other variable moieties are defined as in formula I.

In another important aspect of the invention, compounds of formula I are disclosed wherein two R are¹The radicals being H, an R¹Selected from: OH, halogen, C_1-10Alkyl radical, C_1-6Alkoxy and C_6-10Aryl radical, said C_1-10Alkyl radical, C_6-10Aryl and C_1-6The alkyl part of the alkoxy group being optionally substituted by 1 to 3 halogen, OH, OC_1-3Alkyl, phenyl or naphthyl groups, said phenyl and naphthyl groups being optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, OCH₃、OCF₃、CH₃、CF₃And phenyl, wherein said phenyl is optionally substituted with 1-3 halo groups. In this aspect of the invention, all other variable moieties are defined as in formula I.

More particularly, an important aspect of the present invention relates to compounds of formula I, wherein one R is¹Represents H, two R¹Selected from the following groups: OH, halogen, C_1-10Alkyl and C_1-6Alkoxy radical, said C_1-10Alkyl and C_1-6The alkyl portion of the alkoxy group is optionally substituted with 1-3 halo groups. In this aspect of the invention, all other variable moieties are defined as in formula I.

More particularly, an important aspect of the present invention relates to compounds of formula I, wherein two R are¹The radicals represent halogen or methyl. In this aspect of the invention, all other variable moieties are defined as in formula I.

In another aspect of the invention, compounds of formula I are disclosed wherein R²And R³Apart of R²A group selected from: (a) c_1-14Alkyl, optionally substituted with 1-6 halo groups and 1-3 substituents selected from: OH, OC_1-3Alkyl and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, OCH₃、OCF₃、CH₃And CF₃Substituted with the group of (1), said OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups; (b) phenyl or pyridyl, optionally substituted by 1-3 halogens, OH or R^aSubstituted by groups; (c) c_2-10Alkenyl, optionally substituted with 1-3 substituents independently selected from halogen, OH and OC_1-3Radical substitution of alkyl, OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halogens; (d) CH (CH)₂CO₂H；(e)CH₂CO₂C_1-6An alkyl group; (f) CH (CH)₂C(O)NHR^aAnd (g) NH₂，NHR^aAnd N (R)^a)₂And R^aIs represented by C_1-3Alkyl, OC_1-3Alkyl radical, C_6-10Aryl radical C_1-6Alkylene or phenyl optionally substituted with 1-3 halo groups. In this aspect of the invention, all other variable moieties are defined as in formula I.

More particularly, one aspect of the present invention discloses wherein R²And R³Exist separately, R²Is C_1-14Alkyl, optionally substituted by 1-6 halogen groups and 1-3 groups selected from OH, OC_1-3Alkyl and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, OCH₃、OCF₃、CH₃And CF₃Is substituted by a group of (A), OC_1-3The alkyl portion of the alkyl group is optionally substituted with 1-3 halo groups. In this aspect of the invention, all other variable moieties are defined as in formula I.

More particularly, an important aspect of the present invention relates to compounds of formula I, wherein R²Independently of R³Exist, R²Represents a methyl group or a cyclopropyl group. In this aspect of the invention, all other variable moieties are defined as in formula I.

In a different aspect of the invention, important compounds are defined according to I, wherein R³And R²Apart of R³Selected from the following groups: c_1-14Alkyl radical, C_2-10Alkenyl, SC_1-6Alkyl radical, C_6-10Aryl, heterocyclyl and heteroaryl, said alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and SC_1-6The alkyl portion of the alkyl group is optionally substituted with: (a) r; (b)1-6 halogen radicals and (c)1-3 radicals selected from OH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, OC_1-4Alkyl, CN, C_1-4Alkyl S (O)_x- (where x is 0, 1 or 2), C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-and (C)_1-4Alkyl radical)₂NSO₂-, said C_1-4The alkyl and alkyl portion of said group being optionally substituted with phenyl and 1-3 halo groups, R being selected from heterocyclyl, heteroaryl and aryl, said groups optionally being substituted with 1-4 substituents selected from halo, C_1-4Alkyl radical, C_1-4Alkyl S (O)_x- (wherein x is as defined above), C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂-、CN、OH、OC_1-4Radical substitution of alkyl, said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with 1-5 halogens and 1 halogen selected from OH and OC_1-3Alkyl groups. In this aspect of the invention, all other variable moieties are defined as in formula I.

More particularly, one compound of interest is defined according to formula I, wherein R is³And R²Apart of R³Selected from the following groups: c_1-14Alkyl radical, C_6-10Aryl, heterocyclyl and heteroaryl, said groups being optionally substituted with: (a) r; (b)1-6 halogen radicals and (c)1-3 radicals selected from OH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, OC_1-4Alkyl, CN, C_1-4Alkyl S (O) x- (where x is 0, 1 or 2), C_1-4Alkyl SONH-, H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂The group of (A) and (B), said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with phenyl and 1-3 halo groups. In this aspect of the invention, all other variables are as originally defined with respect to formula I.

More particularly, one compound of interest is defined according to formula I, wherein R is³Independently and selected from the group consisting of: cyclopropyl optionally substituted with methyl or phenyl; optionally substituted by halogen, OH, OCH₃Or OCF₃Substituted phenyl; heteroaryl selected from benzimidazolyl, indolyl, benzofuranyl and dihydrobenzofuranAnd said heteroaryl group is optionally substituted with: (a) r; (b)1-6 halogen radicals or (c)1-3 radicals selected from OH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, OC_1-4Alkyl, CN, C_1-4Alkyl (O)_x(wherein x is 0, 1 or 2), C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂The group of (A) and (B), said C_1-4Alkyl and C of said radical_1-4The alkyl moiety being optionally substituted by phenyl and 1-3 halogen groups, and R is selected from heterocyclyl, heteroaryl and aryl, said groups optionally being substituted by 1-4 groups selected from halogen, C_1-4Alkyl, OH, OC_1-4Alkyl radical, and said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with 1-5 halogen groups and 1 substituent selected from OH and OC_1-3Alkyl groups. In this aspect of the invention, all other variables are as originally defined with respect to formula I.

In a different interesting aspect of the invention, said compound of formula I wherein R²And R³Taken together, represent: (a) c_3-8Alkanediyl forming a fused 5-10 membered non-aromatic ring optionally interrupted by 1 double bond and optionally interrupted by a heteroatom selected from O, S and N; or (b) a fused 6-to 10-membered aromatic monocyclic or bicyclic group, said alkanediyl and aromatic monocyclic or bicyclic groups optionally being substituted by 1 to 3 halogen atoms and 1 to 2 OH, C_1-3Alkyl, OC_1-3Alkyl, halo C_1-3Alkyl, halo C_1-3Alkoxy and phenyl, said phenyl being optionally substituted with 1-2 substituents independently selected from halogen, C_1-3Alkyl, OC_1-3Alkyl radical, and said C_1-3Alkyl and OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups. In this aspect of the invention, all other variable moieties are defined as in formula I.

More particularly, one of interest of the present inventionAspects relate to compounds of formula I wherein R is selected from the group consisting of heterocyclyl, heteroaryl, and aryl, optionally substituted with 1-4 halogen groups and 1-2 groups selected from C_1-4Alkyl radical, C_1-4Alkyl S (O)_x- (where x is 0, 1 or 2), C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂-, CN, OH and OC_1-4Radical substitution of alkyl, said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with 1-3 halogen groups and 1 substituent selected from OH and OC_1-3Alkyl groups. In this aspect of the invention, all other variables are as originally defined with respect to formula I.

Those specific compounds disclosed in the examples are within the scope of the invention. The compounds of the present invention are 11 β -HSD1 inhibitors, illustrative non-limiting examples of which are compounds represented by the following structural formula:

and pharmaceutically acceptable salts and solvates thereof.

In a different aspect of the invention, a pharmaceutical composition is described comprising a compound according to formula I, or a salt or hydrate thereof, in association with a pharmaceutically acceptable carrier.

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 described which comprises administering to said patient an effective amount of a compound of formula I or a salt or solvate thereof.

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

In another aspect of the invention, a method of treating obesity in a mammalian patient in need of such treatment is disclosed which comprises administering to said patient a obesity treating effective amount of a compound of formula I.

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

In another aspect of the invention, there is disclosed a method of treating a lipid disorder selected from the group consisting of dyslipidemia (dyslipemia), hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high density lipoprotein and high low density lipoprotein in a mammalian patient in need of such treatment, which comprises administering to said patient a compound according to formula I in an amount effective to treat said lipid disorder.

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

In another aspect of the invention, a method of treating the following conditions in a mammalian patient in need thereof is disclosed: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low high-density lipoprotein levels, (11) high-low-density lipoprotein levels, (12) atherosclerosis and its sequelae, (13) restenosis of blood vessels, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative diseases, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) syndrome X, and other conditions and disorders in which insulin resistance is a cause, comprising administering to a subject a therapeutically effective amount of a compound defined by formula I.

In another aspect of the invention, a method of treating a condition selected from the group consisting of: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low high-density lipoprotein levels, (11) high-low-density lipoprotein levels, (12) atherosclerosis and its sequelae, (13) restenosis of blood vessels, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative diseases, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) syndrome X, and other conditions and disorders in which insulin resistance is a cause, comprising administering to a patient an effective amount of a compound defined by formula I and a compound selected from the group consisting of: (a) DP-IV inhibitors; (b) an insulin sensitizer selected from the group consisting of (i) a PPAR agonist and (ii) biguanide; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) a-glucosidase inhibitors; (f) a glucagon receptor antagonist; (g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; (h) GIP, GIP mimetics, and GIP receptor agonists; (i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; (j) a cholesterol lowering agent selected from (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinols, nicotinic acid and salts thereof, (iv) PPAR α agonists, (v) PPAR α/γ dual agonists, (vi) cholesterol absorption inhibitors, (vii) fatty acyl CoA: (viii) a cholesterol acyltransferase inhibitor and (viii) an antioxidant; (k) a PPAR α agonist; (1) anti-obesity compounds; (m) ileal bile acid transporter inhibitors; (n) anti-inflammatory agents, excluding glucocorticoids; and (o) protein tyrosine phosphatase-IB (PTP-1B) inhibitors, said plurality of compounds being administered to the patient in an amount effective to treat said condition.

In another aspect of the invention, there is disclosed a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low high density lipoprotein levels, high low density lipoprotein levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia in a mammalian patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of a compound as defined in formula I and an HMG-CoA reductase inhibitor.

More particularly, in another aspect of the invention, a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low high density lipoprotein levels, high low density lipoprotein levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia in a mammalian patient in need of such treatment is disclosed wherein the HMG-CoA reductase inhibitor is a statin.

More particularly, in another aspect of the invention, a method is disclosed for treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low high density lipoprotein levels, high low density lipoprotein levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.

In another aspect of the invention, a method of treating atherosclerosis in a human patient in need of such treatment is disclosed wherein the HMG-CoA reductase inhibitor is a statin, and further comprising administering a cholesterol absorption inhibitor.

More particularly, in another aspect of the invention, a method of treating atherosclerosis in a human patient in need of such treatment is disclosed wherein the HMG-CoA reductase inhibitor is a statin and the cholesterol absorption inhibitor is ezetimibe.

In another aspect of the invention, a pharmaceutical composition is disclosed comprising (1) a compound according to formula I, (2) a compound selected from the group consisting of: (a) DP-IV inhibitors; (b) an insulin sensitizer selected from the group consisting of (i) a PPAR agonist and (ii) biguanide; (c) insulin and insulin mimetics; (d) sulfonylureas and other insulin secretagogues; (e) a-glucosidase inhibitors; (f) a glucagon receptor antagonist; (g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists; (h) GIP, GIP mimetics, and GIP receptor agonists; (i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists; (j) a cholesterol-lowering agent selected from (i) an HMG-CoA reductase inhibitor, (ii) a sequestering agent, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) a PPAR α agonist, (v) a PPAR α/γ dual agonist, (vi) a cholesterol absorption inhibitor, (vii) fatty acyl CoA: (viii) a cholesterol acyltransferase inhibitor and (viii) an antioxidant; (k) a PPAR α agonist; (1) anti-obesity compounds; (m) ileal bile acid transporter inhibitors; (n) anti-inflammatory agents other than glucocorticoids; and (o) protein tyrosine phosphatase-IB (PTP-1B) inhibitors; and (3) a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts in the solid state may exist in more than one crystal structure, and may also exist in the form of hydrates and polyhydrates.

Salts derived from pharmaceutically acceptable organic bases include salts of the following bases: primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and cationic ion exchange resins, such as 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.

When the compounds of the present invention are basic, salts can be prepared from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.

Particularly preferred pharmaceutically acceptable acids include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. In most cases, the compounds of the present invention are basic because the triazole ring is basic. The triazole compounds of the present invention may also be manufactured and handled during synthesis as non-pharmaceutically acceptable salts (e.g., trifluoroacetate salts) before their use in the manufacture of medicaments.

As used herein, reference to a compound of formula I is also meant to include pharmaceutically acceptable salts, as well as non-pharmaceutically acceptable salts which are useful as precursors to the free compound or a pharmaceutically acceptable salt thereof or in other synthetic procedures.

"solvates" and in particular hydrates of the compounds of formula I are also included in the present invention.

Metabolites of the compounds of the invention that are therapeutically active and are also defined by formula I are also included in the invention. Prodrugs are those compounds that are converted to therapeutically active compounds after administration to a patient or after administration to a patient has occurred. The prodrug itself does not have the structure claimed herein, but is converted to the active compound defined by formula I, i.e. the prodrug and the compound of the invention, during or after administration to a mammalian patient, since their active metabolites are defined by formula I.

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 -HDS1 to inhibit the activity of 11 β -hydroxysteroid dehydrogenase reductase, which is responsible for the conversion of cortisone to hydrocortisone. Excessive cortisol is associated with a number of disorders including NIDDM, obesity, dyslipidemia, insulin resistance and hypertension. Administration of the compound reduces the levels of hydrocortisone and other 11 β -hydroxysteroids in the target tissue, thereby reducing the effect of excess hydrocortisone and other 11 β -hydroxysteroids. Inhibition of 11 β -HSD1 is useful for the treatment and control of diseases caused by abnormally high levels of hydrocortisone and other 11 β -hydroxysteroids, such as NIDDM, obesity, hypertension and dyslipidemia.

The invention encompasses the use of 1 β -HSD1 inhibitors for the treatment, control, amelioration, prophylaxis, delay of onset or reduction of risk of the diseases and conditions described herein, e.g. 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 formula I or a pharmaceutically acceptable salt or solvate thereof. Inhibition of the 11 β -HSD1 enzyme limits the conversion of normally inactive cortisone to hydrocortisone, which if present in excess, may cause or exacerbate the symptoms of these diseases and conditions.

NIDDM and hypertension

The compounds of the present invention are selective inhibitors, which are selective for 11 β -HSD1 over 1 β -HSD 2. Inhibition of 11 β -HSD2 is associated with severe side effects, such as hypertension, when inhibition of 11 β -HSD1 is used to reduce cortisol levels and treat related disorders.

Hydrocortisone is an important and well-recognized anti-inflammatory hormone which also acts as an antagonist of hepatic insulin action, thereby reducing insulin sensitivity, resulting in increased gluconeogenesis and elevated hepatic glucose levels. Patients with impaired glucose tolerance have a greater chance of developing type 2 diabetes in the presence of abnormally high levels of hydrocortisone.

In tissues where mineralocorticoid receptors are present, the presence of high levels of hydrocortisone often leads to hypertension. Inhibition of 11 β -HSD1 shifted the ratio of hydrocortisone and cortisone in favor of cortisone in a particular tissue.

Administration of a therapeutically effective amount of an inhibitor of 11 β -HSD1 is effective in treating, managing and ameliorating the symptoms of NIDDM, and periodic administration of a therapeutically effective amount of an inhibitor of 1 β -HSD1 delays or prevents the onset of NIDDM, particularly in humans.

Obesity, metabolic syndrome, dyslipidemia

Excessive levels of cortisol are associated with obesity, probably due to increased hepatic gluconeogenesis. Abdominal obesity is closely related to glucose intolerance, hyperinsulinemia, hypertriglyceridemia and other factors of syndrome X, such as hypertension, elevated very low density lipoproteins and reduced high density lipoproteins.

Montague et al, Diabetes, 2000, 49: 883-888. Thus, administration of an effective amount of an inhibitor of 11 β -HSD1 is useful in the treatment or control of obesity. Long-term treatment with 11 β -HSD1 inhibitors is also useful for delaying or preventing the onset of obesity, particularly if the patient is on 11 β -HSD1 inhibitors in combination with diet control and exercise.

The compounds of the present invention are also useful in the treatment and prevention of type II diabetes and conditions associated with insulin resistance, including metabolic syndrome ("syndrome X"), obesity, reactive hypoglycemia, and dyslipidemia of diabetes by lowering insulin resistance and maintaining serum glucose at normal concentrations.

Atherosclerosis of arteries

As described above, inhibiting 11 β -HSD1 activity and reducing the amount of hydrocortisone is beneficial in treating or controlling hypertension. Because hypertension and dyslipidemia contribute to the development of atherosclerosis, administration of a therapeutically effective amount of an inhibitor of 11 β -HSD1 of the present invention may be particularly beneficial in treating, controlling, delaying the onset of, or preventing atherosclerosis.

Other uses

The following diseases, disorders and conditions can be treated, controlled, prevented or delayed by treatment with 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 high-density lipoprotein levels, (11) high-low-density lipoprotein levels, (12) atherosclerosis and its sequelae, (13) restenosis of blood vessels, (14) pancreatitis, (15) obesity of the abdomen, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) syndrome X and other disorders in which insulin resistance is a cause.

The above-mentioned diseases and conditions may be treated with a compound of formula I, or the compound may be administered for the prevention or reduction of risk of development of the diseases and conditions described herein. Since simultaneous inhibition of 11 β -HSD2 may have deleterious side effects, or may in fact increase the amount of hydrocortisone in target tissues where a reduction of hydrocortisone is desired, it would be desirable to have selective inhibitors of 11 β -HSD1 that have little or no inhibition of 11 β -HSD 2.

The 11 β -HSD1 inhibitors of formula I typically have an inhibition constant IC of less than about 500nM, preferably less than about 100nM₅₀。

Typically, 11 β -HSD2 of the compound is on 11 β -HSD1 IC₅₀The ratio is at least about 2 or greater, preferably about 10 or greater. More preferred compounds have an IC of 1 β -HSD2 for 11 β -HSD1₅₀The ratio is about 100 or greater. For example, for having an IC₅₀The compounds of (1 β -HSD 2) desirably exhibit an inhibition constant IC of greater than about 500nM, preferably greater than 1000nM₅₀。

The compounds of formula I may be used in combination with one or more other drugs to treat, prevent, inhibit or ameliorate a disease or condition for which the compounds of formula I or other compounds are effective.

In general, a combination of drugs is safer or more effective than either the use of a single drug or the expected effect based on the additive properties of multiple drugs alone. Such other drug or drugs may be administered by one route and in the amounts conventionally used, either simultaneously or separately from the compound of formula I. When a compound of formula I is used contemporaneously with one or more other drugs, a combination product containing such one or more other drugs and a compound of formula I is preferred. However, combination therapy also includes therapies in which the compound of formula I and one or more other drugs are administered in different overlapping courses. It is expected that when used in combination with other active ingredients, the compounds of the present invention and other active ingredients, or both, may be effectively used in lower amounts, than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more additional active ingredients in addition to the compound of formula I.

Other active ingredients that may be administered in combination with a compound of formula I and either administered alone or in the same pharmaceutical composition include, but are not limited to: (a) inhibitors of dipeptidyl peptidase IV (DP-IV); (b) insulin sensitizers including (i) PPAR γ agonists such as glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, etc.) and other PPAR ligands, including PPAR α/γ dual agonists such as KPP-297, and PPAR α agonists such as cholesterol lowering drugs, clofibrate, fenofibrate and bezafibrate; and (ii) biguanides, such as metformin and phenformin; (c) insulin or insulin mimetics; (d) sulfonylureas and other insulin secretagogues, such as tolbutamide and glipizide, meglitinide and related substances; (e) alpha-glucosidase inhibitors (e.g., acarbose); (f) glucagon receptor antagonists, such as those disclosed in WO98/04528, WO99/01423, WO00/39088, and WO 00/69810; (g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists, such as those disclosed in WO00/42026 and WO 00/59887; (h) GIP, GIP mimetics such as those disclosed in WO00/58360, and GIP receptor agonists; (i) PACAP, PACAP mimetics and PACAP receptor 3 agonists such as those disclosed in WO 01/23420; (j) cholesterol lowering agents, such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, rosuvastatin and statin), (II) sequestrants (cholestyramine, lipid lowering resin No. II and dialkylaminoalkyl derivatives of cross-linked dextran), (iii) nicotinol, nicotinic acid or salts thereof, (iv) cholesterol absorption inhibitors such as ezetimibe and β -sitosterol, (v) fatty acyl-CoA: (ii) cholesterol acyltransferase inhibitors, such as avasimibe, and (vi) antioxidants, such as bis-thiopropane; (k) PPAR8 agonists such as those disclosed in WO 97/28149; (l) Anti-obesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors, CB1 receptor inverse agonists and antagonists, and β 3 adrenergic receptor agonists; (m) ileal bile acid transporter inhibitors; (n) agents for inflammatory conditions other than glucocorticoids, such as acetylsalicylic acid, non-steroidal anti-inflammatory drugs, sulfasalazine, and cyclooxygenase 2 selective inhibitors, and (o) protein tyrosine phosphatase-1B (PTP-1B) inhibitors.

Such combinations include combinations of a compound of formula I, and pharmaceutically acceptable salts, hydrates, or solvates thereof, and not just combinations with one or more other active compounds. Non-limiting examples include the combination of a compound of formula I with two or more active compounds selected from the group consisting of: biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors, and anti-obesity compounds.

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

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

When treating or preventing the diseases and conditions described herein, which are indicated for compounds of formula I, satisfactory results are obtained when the compounds of the present invention are administered in a daily dose of about 0.1 to 100 milligrams per kilogram (mpk) of body weight, preferably as a single daily dose or in divided doses of about 2 to 6 times daily. The total daily dose is therefore in the range from about 0.1mg to about 1000mg, preferably from about 1mg to about 50 mg. For a typical 70 kg adult human, the total daily dose is in the range of about 7mg to about 350 mg. The dosage may be adjusted to provide the optimum therapeutic response.

Another aspect of the present invention is directed to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in association with 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 oral 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 on the active ingredient. They may conveniently be presented in unit dosage form and prepared by any of the techniques well known in the art of pharmacy.

The compounds of formula I may be combined with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take 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 manufacture of oral liquid suspensions, elixirs, and solutions. Carriers such as starches, sugars and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like are used in the preparation of 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 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 sweetening agents such as sucrose, lactose or saccharin.

The capsules may also contain a liquid carrier, such as a fatty oil.

Various other materials may be present, as coatings, or to improve the appearance of the dosage unit. For example, tablets may be coated with a film gum, sugar, or both.

Tablets may be coated by standard aqueous or non-aqueous techniques.

Of course, the typical percentage of active compound in these compositions may vary from about 2-60% on a w/w basis. Thus, the tablet contains a compound of formula I or a salt or hydrate thereof in an amount ranging from as low as about 0.1mg to as high as about 1.5g, preferably from as low as about 1.0mg to as high as about 500mg, more preferably from as low as about 10mg to 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.

Parenteral administration is generally in the form of a solution or suspension, generally prepared with water, and optionally includes a surfactant, such as hydroxypropylcellulose. Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. The formulations, in generally diluted form, also contain preservatives.

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 liquid for easy injection; they must be stable under the conditions of manufacture and storage, and they are usually preserved. Thus, the carrier includes 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) analysis: determination of inhibition constant

In vitro enzyme activity was determined by Scintillation Proximity Assay (SPA) for evaluation of test compounds. Briefly, tritiated-cortisone enzyme substrate, NADPH co-factor and titrated compound were incubated with 11 β -HSD1 enzyme at 37 degrees celsius for conversion to hydrocortisone. After incubation, the preparation of protein a coated SPA beads was pre-mixed with a monoclonal antibody against hydrocortisone and a non-specific 11 β -HSD inhibitor and then added to each well. The mixture was shaken at 15 degrees celsius and then read in a liquid scintillation counter suitable for 96 well plates.

Percent inhibition was calculated relative to uninhibited control wells to form IC₅₀Curve line. The assay was also applied to 11 β -HSD2, using tritiated hydrocortisone and NAD as enzyme substrate and cofactor, respectively. To start the assay, 40. mu.l of enzyme substrate (25 nM)³H-cortisone +1.25mM NADH in 50mM HEPES buffer, pH7.4) was added to the wells indicated on the 96-well plate. Solid compounds were dissolved in dimethyl sulfoxide at 10mM and then serially diluted 50-fold in DMSO. The diluted material was then titrated 4-fold, 7 times. Then 1. mu.l of each titrated compound was added in duplicate to the enzyme substrate. To start the reaction, 10 μ l of 11 β -HSD1 microsomes from CHO transfectants were added to each well at the appropriate concentration, producing approximately 10% conversion of the starting material. For final calculation of percent inhibition, a series of wells were added, representing assay minimum and maximum values: one group contained the enzyme substrate but no compound or enzyme (background) and the other group contained the enzyme substrate and enzyme but no compound (maximum signal). The plate was spun slightly in a centrifuge at low speed to flatten the reagent, sealed with an adhesive strip, gently mixed, and incubated at 37 ℃ for 2 hours. After incubation, 45. mu.l SPA beads, pre-suspended with anti-hydrocortisone monoclonal antibody and non-specific 11. beta. -HSD inhibitor, were added to each well. The plate was sealed again and shaken gently at 15 ℃ for more than 1.5 hours. Data on the plate is collected based on a liquid scintillation counter, such as Topcount. To control the inhibition of anti-hydrocortisone antibody/hydrocortisone binding, 1.25nM [3 ]]The enzyme substrate for hydrocortisone H was added to the indicated single well. Mu.l of 200. mu.M compound was added to each of these wells followed by 10. mu.l buffer in place of the enzyme, any inhibition assessed being due to the compound interfering with the binding of hydrocortisone to the antibody on SPA beads.

And (3) analysis: in vivo inhibition assays in general, the test compound is administered orally to the mammal over a defined time interval, typically between 1 and 24 hours. Tritiated cortisone was injected intravenously and blood was collected after several minutes.

Steroids were extracted from the separated serum and analyzed by HPLC. Determination of the Compound group and vehicle-dose control group³Relative levels of H-cortisone and 3H-hydrocortisone, the product of its reduction. From these values, the absolute conversion and the percentage inhibition were calculated.

More specifically, the compound was dissolved in the medium at the desired concentration (5% hydroxypropyl-. beta. -cyclodextrin v/v H)₂O, or equivalent) is formulated for oral administration, typically in a dose of 10 milligrams per kilogram. After fasting overnight, the solutions were administered to ICR mice (obtained from Charles River) by oral gavage, 0.5 ml per dose per animal, three animals per test group.

After the desired time has elapsed, typically 1 or 4 hours, 0.2ml of 3 μ M in dPBS is injected from the tail vein³H-cortisone. Animals were closed in cages for 2 minutes and then died in a C02 chamber without pain. After death, mice were removed and blood was collected by cardiac puncture. The blood was kept in serum separation tubes at room temperature for at least 30 minutes to allow sufficient coagulation. After the induction period, the blood was separated into serum by centrifugation at 3000Xg, 4 ℃ for 10 minutes.

To analyze the steroids in the serum, the serum is first extracted with an organic solvent. Serum was transferred in 0.2ml volumes to a clean microcentrifuge tube. To this was added a volume of 1.0ml of ethyl acetate and then vortexed vigorously for 1 minute. Rapidly rotating on a microcentrifuge, agglomerating the aqueous whey protein, and clarifying the organic supernatant. 0.85ml of the upper organic phase was transferred to a new microcentrifuge tube and dried. The oven dried samples were resuspended in 0.250 ml of DMSO containing cortisone at high concentration and then analyzed for hydrocortisone by HPLC.

A0.200 ml sample was injected onto a Metachem Inertsil C-18 chromatography column equilibrated in 30% methanol. Slow linear gradient elution to 50% methanol fractionA off-target steroid; the cold standard in the resuspension solution was also monitored by UV at 254nM, which served as an internal standard. Tritium signals were collected with a radioactive chromatographic detector and the data were loaded into the program for analysis.³H-cortisone to³The conversion of H-hydrocortisone was calculated by dividing the AUC for hydrocortisone by the AUC for cortisone and cortisol combinations.

The examples are merely illustrative and should not be construed as limiting the invention.

Example 1

General procedure

Substance(s)	Measurement of	Concentration of	Mmol
				S.M in DMF.	714μl	0.14M in DMF	0.1
TFFH in DMF	200μl	0.5M in DMF	0.1
				Triethylamine in DMF	400μL	0.5M in DMF	0.2
Hydrazine in DMF	240μl	0.5M in DMF	0.12
				Imino ether A in DMF	600μL	0.25M in DMF	0.15

The synthesis of the following one-dimensional, single pool of pure compounds was performed in the Myriad Core System. All reaction vessels were dried at 120 degrees celsius for 12 hours under a stream of nitrogen prior to use. The solvent is dried over molecular sieves for at least 12 hours before use. The reagents and subgroups (carboxylic acids and 8-methoxy-2, 3, 4, 5, 6, 7-azocin (imino ether A)) were immediately dissolved in a suitable solvent before use.

Synthesis of the carboxylic acids shown in the table below as starting materials were charged under nitrogen to a dry 10ml sintered Myriad reaction vessel (714. mu.l, 0.1mmol, 0.14M in N, N-Dimethylformamide (DMF)). Fluoro-N, N, N ', N' -tetramethylformamidinium hexafluorophosphate (TFFH) (200L, 0.1mmol, 0.5M in DMF), then triethylamine (400. mu.l, 0.2mmol, 0.5M in DMF) and hydrazine (240. mu.l, 0.12mmol, 0.5M in DMF) were added to the reactor under nitrogen.

The reaction was carried out at 25 ℃ for 1 hour; the reaction was gas stirred (1 second pulse every 5 minutes) during the run. 8-methoxy-2, 3, 4, 5, 6, 7-azocin (imino ether A, 600. mu.l, 0.15mmol, 0.25M in DMF) was added to the reaction vessel under nitrogen. The reaction was carried out at 120 ℃ for 12 hours while gas stirring (1 second pulse every 5 minutes) and then cooled to room temperature. After cooling, the crude reaction mixture was analyzed by LC-MS (method 1). The crude reaction was purified by preparative HPLC using mass-directed detection (method 2). The collected fractions were then analyzed for purity by LC-MS (method 1); fractions greater than 90% pure were combined into empty 40mL EPA vials and then lyophilized.

HPLC conditions

Analytical LC method 1:

column: MetaChem Polaris C-18a, 30 mm. times.4.6 mm, 5.0um

Eluent A: 0.1% trifluoroacetic acid (TFA) in water

Eluent B: 0.1% TFA in acetonitrile

Gradient: 5% B to 95% B in 3.3 min, back to 5% B in 0.3 min

Flow rate: 2.5 ml/min.

Column temperature: 50 degree centigrade

Injection amount: 5 μ l of undiluted crude reaction mixture or purified fractions.

And (3) detection: UV at 220 and 254 nm.

MS: API-ES ionization mode, Mass Scan Range (100-600amu)

ELSD: early scatter detector

Preparation of LC method 2:

column: MetaChem Polaris C-18A, 100mm X21.2 mm, 10um

Eluent A: 0.1% TFA in Water

Eluent B: 0.1% TFA in acetonitrile

Pre-injection balancing: 1.0 minute

And (3) maintaining after injection: 1.0 minute

Gradient: 10% B to 100% B in 6.0 min, 2.0 min at 100% B and back to 10% B from 100% B at 1.5 min.

Flow rate: 20 mL/min.

Column temperature: at room temperature

Injection amount: 1.5 ml of undiluted crude reaction mixture

And (3) detection: MS: API-ES ionization mode, Mass Scan Range (100-

Freeze drying parameters

Initial freezing point: 1 hour at-70 deg.C

Condensation point in drying stage: -50 degrees Celsius

Drying stage table:

layer temperature (degree centigrade)	Duration (minutes)	Vacuum point (mTorr)
			-60	240	25
-40	240	25
			5	480	25
20	1000	25

The starting materials for examples 1-1 were

Example 2

Method 2A

General procedure

Preparation of 3- (1, 1-diphenylpropyl) -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (2-1)

2, 2-Diphenylbutyric acid (39.6mg, 0.166mmol) was dissolved in DMF (0.33 ml). fluoro-N, N, N ', N' -tetramethylformamidinium hexafluorophosphate (TFFH, 43.6 mg) and anhydrous triethylamine (46.4. mu.l) were added and the solution cooled to 0 ℃. After 10 min, hydrazine monohydrate (6.5 μ l) was added. After stirring at room temperature for 30 min, HPLC/MS showed complete conversion to 2, 2-diphenylbutyrhydrazide. 8-methoxy-2, 3, 4, 5, 6, 7-hexahydroazocin (38ml, 0.249mmol) was added, and the solution was stirred at 120 ℃ overnight. After warming to room temperature, the product was purified by preparative HPLC and then isolated as the trifluoroacetate salt. The salt was added to a saturated sodium bicarbonate solution and extracted with ethyl acetate to give the free base. The extract was dried over magnesium sulfate, filtered and then concentrated to give the purified triazole (2-1) as a white solid; MSESI (m/z) 346.3.

Compounds 2-2 to 2-23 were prepared in essentially the same way, and the formation of the product using the appropriate carboxylic acid s.m. was monitored by HPLC/MS.

Method 2B

General procedure

Preparation of 3- [1- (2-fluorophenyl) cyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (2-24)

Step I

Potassium hydroxide (1.78g) was dissolved in dimethyl sulfoxide (5.8ml) [1 ]. (2-fluorophenyl) acetonitrile (0.97g, 7.2mmol) and 1, 3-dibromopropane (0.95 ml, 9.3mmol) were dissolved in diethyl ether (2ml), and the mixture was added dropwise to the potassium hydroxide solution while vigorously stirring at room temperature. After stirring at room temperature for 1 hour, the reaction was quenched by the addition of ice-cold water (3.8 ml). The mixture was filtered through a pad of celite, and the pad was washed with diethyl ether (20 ml). The filtrate was added to a separatory funnel, and the aqueous layer was extracted with diethyl ether (3X 10 ml). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give a pale yellow oil (1.0 g). After chromatography on silica gel, pure 1- (2-fluorophenyl) cyclobutanenitrile (0.45g) was obtained.

Step 2

1- (2-fluorophenyl) cyclobutanenitrile (0.21g, 1.15mmol) and potassium hydroxide (0.194g) were dissolved in ethylene glycol (2 mL). After refluxing at 198 ℃ for 3h, the reaction mixture was poured into water (5 ml) and extracted with ether (2 × 5 ml). The aqueous solution was acidified with HCl and extracted with ether (3 × 5 ml). The extracts were combined, dried over magnesium sulfate, filtered and concentrated to give the crude carboxylic acid.

Step 3

1- (2-fluorophenyl) cyclobutanecarboxylic acid (51.3mg, 0.264mmol) was dissolved in DMF (0.52 ml). fluoro-N, N, N ', N' -tetramethylformamidinium hexafluorophosphate (TFFH, 74.6mg, 0.282mmol) and anhydrous triethylamine (71.0. mu.l, 0.509mmol) were added at room temperature. After 5 min, hydrazine (10. mu.l, 0.319mmol) was added. After stirring at room temperature for 30 min, HPLC-MS showed the formation of 1- (2-fluorophenyl) -cyclobutane-carbohydrazide in good yield.

8-methoxy-2, 3, 4, 5, 6, 7-hexahydroazocin (47. mu.l, 0.412mmol) was added to the solution of 1- (2-fluorophenyl) cyclobutanecarbohydrazide and the reaction was stirred at 120 ℃ overnight. After cooling, the solution was concentrated and the product was purified by preparative HPLC as the trifluoroacetate salt. The salt was added to a saturated sodium bicarbonate solution and extracted with ethyl acetate to give the free base. The extract was dried over magnesium sulfate, filtered and evaporated to give pure triazole (2-24) as a solid.

Compounds 2-25 to 2-32 were prepared in essentially the same manner using the appropriate phenylacetonitrile. The formation of the product was monitored by HPLC/MS.

Method 2C

General procedure

Preparation of 3- [1- (3, 4-difluorophenyl) cyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (2-33)

Step 1

(3, 4-difluorophenyl) acetonitrile was converted to 1- (3, 4-difluorophenyl) cyclobutanenitrile according to the procedure described in method 2B, step 1. FIG. 45.4

Step 2

1- (3, 4-difluorophenyl) cyclobutanenitrile (384.5mg, 1.99mmol) was dissolved in toluene (30 mL) and cooled to-78 ℃. Diisobutylaluminum hydride (DIBAL-H) (1.0M solution in hexane) (3.98 mL, 3.98mmol) was added dropwise.

After stirring for 30 minutes at-78 deg.C, 5% sulfuric acid (2mL) was added. The reaction was warmed to room temperature, stirred for 20 minutes and filtered through a pad of celite. The pad was washed with ethyl acetate and all filtrate was added to a separatory funnel and washed with water. The organic layer was dried over sodium sulfate and concentrated to give the desired aldehyde.

1- (3, 4-difluorophenyl) cyclobutanealdehyde (240.0mg, 1.22mmol) was dissolved in tert-butanol/tetrahydrofuran/2-methylbut-2-ene (3.0ml/1.0 ml) and stirred vigorously at room temperature. Sodium chlorite (243.4mg, 2.69mmol) and sodium dihydrogen phosphate (370.4mg, 2.68mmol) were dissolved in water (1.2 ml) and added dropwise to the above solution. After stirring for 1 hour, TLC showed the reaction was complete. The volatile solvent was removed under vacuum and the product was diluted with water and washed with hexane (3 ml).

The aqueous solution was acidified to pH2 with 6N aqueous hydrochloric acid.

After extraction with ethyl acetate (3 × 20ml), the combined organic layers were washed with brine (5 ml), dried over magnesium sulfate, filtered, and concentrated to give the desired carboxylic acid (125 mg).

Step 3

Converting 1- (3, 4-difluorophenyl) cyclobutanecarboxylic acid to 3- [1- (3, 4-difluorophenyl) cyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (2-33) according to the procedure described in method 2B, step 3; MS ESI (m/z) 318.2.

Compounds 2-34 to 2-38 were prepared by essentially the same procedure using the appropriate disubstituted phenylacetonitriles. Product formation was monitored by HPLC/MS.

Method 2D

General procedure

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

Methyl 1- (4-chlorophenyl) cyclohexanecarboxylate (277mg) and hydrazine hydrate (0.30 ml) were dissolved in ethylene glycol (5 ml), followed by heating to 150 ℃ for 15 hours. The solution was cooled and water (5 ml) was added. The resulting precipitate was collected by filtration and dried under vacuum to give the hydrazide (108mg) as a white solid.

Anhydrous toluene was added to a mixture of 1- (4-chlorophenyl) cyclohexane hydrazide (62mg) and 8-methoxy-2, 3, 4, 5, 6, 7-hexahydroazocin (40.1 mg). The reactor was heated to 120 degrees celsius whereupon it was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography to give 3- (1- (4-chlorophenyl) cyclohexyl) -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (2-39) as a white solid.

The preparative LC method used in example 2:

column: YMC-PACK ODS, 100mm X20 mm, 5.0um

Eluent A: 0.05% trifluoroacetic acid in water eluent B: 0.05% trifluoroacetic acid in acetonitrile

Pre-injection balancing: 1.0 minute

Maintenance after injection: 1.0min

Gradient: 10% B to 100% B: return to 50% B between 1 and 16 minutes; return to 100% B between 16 and 21 minutes and hold at 100% B2 minutes; it took 1 minute to return from 100% B to 10% B.

Flow rate: 20 mL/min.

Column temperature: injection amount at room temperature: 5.0ml

And (3) detection: photodiode matrix

Analytical LC method for example 2: column: Waters-XTerra C18, 5um, 4.6X 50mm

Eluent A: 0.60% TFA in water eluent B: 0.50% TFA in acetonitrile

Gradient: from 10% B to 90% B in 4.5 minutes, hold for 0.5 minutes, return to 10% B flow at 0.5 minutes: 2.5 ml/min (into MS 250. mu.l)

Column temperature: injection amount at 30 degrees celsius: 10 μ l of undiluted crude reaction mixture.

And (3) detection: and D, DAD: 190 and 600 nm.

MS: API-ES positive ionization mode, variable mass scan range:

LCl-XLo＝50-500amu

LCl-Low＝150-750amu

LCl-Med＝300-1000amu

LCl-High＝500-2000amu

example 3

Method 3A

Preparation of 1- (4-chlorophenyl) cyclobutanehydrazide

1- (4-chlorophenyl) cyclobutanecarboxylic acid (10.0g) was dissolved in dichloromethane (150ml) and cooled to-10 ℃ in an ice/brine bath. Pyridine (3.84 ml) was added followed by cyanuric fluoride (8.9ml in 25ml dichloromethane). After stirring at room temperature for 1 hour, TLC indicated complete reaction. The solution was added to a separatory funnel containing ice (150 ml). After vigorous shaking, the organic layer was removed, dried over magnesium sulfate, filtered, and concentrated to give carbonyl fluoride.

Hydrazine (2.02 ml) was dissolved in acetonitrile (100ml) and cooled to 0 ℃. Triethylamine (12.8ml) was added followed by 1- (4-chlorophenyl) cyclobutanecarbonyl fluoride (10g) in acetonitrile (25 ml). After stirring at room temperature for 1 hour, acetonitrile was removed by evaporation. The product was obtained after silica gel chromatography.

Method 3B

Preparation of 1- (4-chlorophenyl) cyclopropane hydrazide

Preparation of 1- (4-chlorophenyl) cyclopropanehydrazide as in method 3A, 1- (4-chlorophenyl) cyclopropanecarboxylic acid was used.

Method 3C

Preparation of 1- (4-fluorophenyl) cyclobutanehydrazide

Step 1

Potassium hydroxide (8.2g, 146.1mmol) was dissolved in dimethyl sulfoxide (100mL) [1 ]. (4-fluorophenyl) acetonitrile (6.87g, 50.8mmol) and 1, 3-dibromopropane (5.4 ml, 53.3mmol) were dissolved in diethyl ether (10ml), and the mixture was added dropwise to a vigorously stirred solution of potassium hydroxide at room temperature. After stirring for 2 hours, the reaction was quenched by the addition of ice-cold water (10 ml). The mixture was filtered through a pad of celite, and the pad was washed with ether (100 mL). The filtrate was added to a separatory funnel, and the aqueous layer was extracted with ether (3X 100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to give the product (8.85g) as a pale yellow oil.

Step 2

Crude 1- (4-fluorophenyl) cyclobutanenitrile (8.85g, 50.5mmol) was dissolved in dry toluene (100mL) and then cooled to-78 deg.C. Diisobutylaluminum hydride (DIBAL-H) (1.0M solution in hexane, 60.6 mL) was added dropwise. The reaction was checked by TLC (hexane: ethyl acetate 9: 1). After stirring at-78 ℃ for 1 hour, 5% sulfuric acid (20ml) was added. The reaction was warmed to room temperature, stirred for 20 minutes and filtered through a pad of celite. The pad was washed with ethyl acetate and all filtrate was added to a separatory funnel and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness to give the desired aldehyde.

1- (4-difluorophenyl) cyclobutanealdehyde (8.8g, 49.4mmol) was dissolved in t-butanol (90 mL), tetrahydrofuran (30 mL) and 2-methylbut-2-ene (30 mL) and then stirred vigorously at room temperature. Sodium chlorite (9.8g, 108.7mmol) and sodium dihydrogen phosphate (15.0g, 108.7mmol) were dissolved in water (54 ml) and added dropwise to the above solution. After stirring for 1 hour, TLC showed the reaction was complete. The volatile solvent was removed under vacuum and the product was diluted with water and washed with hexane (3 ml). The aqueous solution was acidified to pH2 with 6N aqueous hydrochloric acid. After extraction with ethyl acetate (3 × 150ml), the combined organic layers were washed with brine (20ml), dried over magnesium sulfate, filtered and concentrated to give 1- (4-fluorophenyl) cyclobutanecarboxylic acid (8.0 g).

This carboxylic acid was converted to 1- (4-fluorophenyl) cyclobutane-carbohydrazide by method 3A.

Method 3D

Preparation of 1- (4-fluorophenyl) cyclopropane hydrazide

1- (4-fluorophenyl) acetonitrile (3.77g, 27.9mmol), 1-bromo-2-chloroethane (5.0g, 34.9mmol) and benzyltriethylammonium chloride (TEACC, 127.6mg 0.56mmol) were added to the flask and stirred vigorously [2 ]. Potassium hydroxide (50% in water, 195mmol) was added dropwise. Stir at 40 ℃ for 5 hours, then at room temperature overnight, the reaction was diluted with water and extracted with dichloromethane. The organic layer was collected, washed with 1N aqueous hydrochloric acid, washed with water, and dried over magnesium sulfate. After filtration and evaporation of the dichloromethane, the crude product (4.5g) was obtained.

1- (4-fluorophenyl) cyclopropanecarboxylic acid was prepared from crude 1- (4-fluorophenyl) cyclopropanecarbonitrile using the procedure described in method 3C, step 2. This carboxylic acid was converted to 1- (4-fluorophenyl) cyclopropanehydrazide using method 3A.

Method 3E

General procedure

Preparation of 3, 4-bicyclopropyl-5- (1-phenylcyclobutyl) -4H-1, 2, 4-triazole (3-1)

Methyl trifluoromethanesulfonate (89.1. mu.l) was added to N-cyclopropylcyclopropaneamide (98.6mg, 0.788 mmol). After stirring for 30 minutes at 60 degrees celsius, NMR showed complete conversion to methyl N-cyclopropylcyclopentimidate.

Toluene (2ml), triethylamine (223. mu.l) and 1-phenylcyclobutylhydrazide (90mg) were added to methyl N-cyclopropylcyclopropaneimidate, which was then stirred at 60 ℃ for 3 hours and 110 ℃ for 1 hour. After cooling, the reaction was concentrated and the residue was purified by preparative HPLC and isolated as trifluoroacetate. The salt was added to a saturated sodium bicarbonate solution and extracted with ethyl acetate to give the free base. The organic extracts were dried over magnesium sulfate, filtered and concentrated to give 3, 4-dicyclopropyl-5- (1-phenylcyclobutyl) -4H-1, 2, 4-triazole (3-1); MS ESI (m/z) 280.2.

Another compound of example 3 was prepared in essentially the same manner with the corresponding carboxamide and hydrazide. Acetonitrile was used as a solvent in the preparation of 3-2. In the synthesis of 3-18, compounds 3-19 were isolated as by-products. Methylamides are prepared from their corresponding methyl and methylamine using well established methods. Other amides can be prepared by published methods from commercially available carboxylic acids and amines using 1- (dimethylaminopropyl) -3-ethylimido acid hydrochloride as the reagent. The hydrazide preparation is described in methods 3A, 3B, 3C, and 3D.

Preparative HPLC method for example 3:

the method described in example 2 was used.

Analytical LC method for example 3:

the same procedure as described in example 2 was used.

Example 4

Method 4A

Preparation of 3- [1- (4-chlorophenyl) - (Z) -3- (methoxymethyloxy) cyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-1) and 3- [1- (4-chlorophenyl) - (E) -3- (methoxymethyloxy) cyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-2)

Potassium hydroxide (2.57g) was dissolved in dimethyl sulfoxide (8.0 ml). (4-chlorophenyl) acetonitrile (1.58g, 10.4mmol) and 1, 3-dichloro-2- (methoxymethoxy) propane (1.993g) were dissolved in diethyl ether (3 ml), and the mixture was added dropwise to a vigorously stirred potassium hydroxide solution at room temperature. After stirring at room temperature for 1 hour, the reaction was quenched by the addition of ice-cold water (5.5ml) the mixture was filtered through a pad of celite and the precipitate was washed with ether (30 ml). The filtrate was added to a separatory funnel, and the aqueous layer was extracted with ether (3X 15 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The product was purified by silica gel chromatography to give 1- (4-chlorophenyl) -3- (methoxymethoxy) cyclobutanenitrile (1.28g) as an isomeric mixture (ca. 2: 1).

The nitrile (1.28g) and potassium hydroxide (2.2g) were dissolved in ethylene glycol (13 ml). After heating at 198 ℃ for 6 h, the reaction mixture was cooled to room temperature, poured into water (15ml) and washed with ether (2X 20 ml). The aqueous solution was carefully acidified with aqueous hydrochloric acid and extracted with ether (2X 20 ml). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give the product as a brown oil (0.9068 g).

1- (4-chlorophenyl) -3- (methoxymethoxy) cyclobutanecarboxylic acid (0.9068g) and pyridine (0.40 ml) were dissolved in dichloromethane (12 ml), followed by cooling to-10 ℃. Cyanuric acid fluoride (1.0ml) was dissolved in dichloromethane (2ml) and added dropwise to the reaction mixture. After 30 minutes, the reaction was added to a separatory funnel containing ice (10 ml). After vigorous shaking, the dichloromethane layer was removed, dried over magnesium sulfate, filtered and concentrated.

The crude acid fluoride was dissolved in acetonitrile (3 ml) and added to a stirred solution of 0 ℃ anhydrous hydrazine (140 μ l), triethylamine (1.0ml) and acetonitrile (15 ml). The reaction was completed by HPLC/MS and dried under vacuum.

A portion of crude 1- (4-chlorophenyl) -3- (methoxymethoxy) cyclobutanecarbohydrazide (456.1mg) was dissolved in anhydrous toluene (7ml), followed by mixing with 8-methoxy-2, 3, 4, 5, 6, 7-hexahydroazocin (228. mu.l). The solution was heated to 120 ℃ for 3 hours and then slowly cooled to room temperature. The product was partially purified by silica gel chromatography (100% ethyl acetate-5% methanol in ethyl acetate-10% methanol in ethyl acetate) to give a mixture of 4-1 and 4-2, respectively, in a ratio of 62: 38. The isomer was isolated as its trifluoroacetate by preparative HPLC. Each salt was added separately to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The purified free bases 3- [1- (4-chlorophenyl) -cis-3- (methoxymethoxy) cyclobutyl ] -r-5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-1) and 3- [1- (4-chlorophenyl) -trans-3- (methoxymethoxy) cyclobutyl ] -r-5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-2) were dried over magnesium sulfate, filtered and then concentrated. Isomers 4-1 and 4-2 were more efficiently separated by chiral preparative HPLC (ChiralPak OD (Daicel chemical Industries)2 cm. times.25 cm column, 20% isopropanol/heptane, 6 ml/min); MS ESI (m/z) 376.2.

Method 4B

Preparation of 3- (4-chlorophenyl) -cis-3- (5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin-3-yl) -cyclobutane-r-ol (4-3)

3- [1- (4-chlorophenyl) -cis-3- (methoxymethoxy) cyclobutyl ] -r-5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-1) (53mg) was dissolved in methylene chloride (1ml), and stirred at room temperature. Trifluoroacetic acid (0.2 ml) was added and the solution was stirred at room temperature overnight. The volatiles were removed under vacuum and the residue was purified by silica gel chromatography to give 3- (4-chlorophenyl) -cis-3- (5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin-3-yl) -cyclobutane-r-ol (4-3) as a white solid.

3- (4-chlorophenyl) -trans-3- (5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin-3-yl) -cyclobutane-r-ol (4-4) was prepared in essentially the same manner using the epimeric starting material (4-2).

Method 4C

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

A mixture of alcohols (4-3 and 4-4) (114.1mg) was dissolved in dichloromethane (5 mL) and cooled to 0 ℃. Tetrapropylammonium perruthenate (TPAP, 12.1mg) and N-oxide of 4-methylmorpholine (60.4mg) were added and the reaction was warmed to room temperature. After 3 hours, the crude reaction was purified directly on a silica gel adsorption column (100% dichloromethane- > 5% methanol in dichloromethane- > 10% methanol in dichloromethane) to give 3- (4-chlorophenyl) -3- (5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin-3-yl) cyclobutanone (4-5); MS ESI (m/z) 330.1.

Method 4D

Preparation of 3- [1- (4-chlorophenyl) -3-methylenecyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-6)

3- (4-chlorophenyl) -3- (5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin-3-yl) cyclobutanone (4-5) (52mg) was dissolved in freshly distilled tetrahydrofuran (2 ml). Methyltriphenylbromide (281mg) was added followed by potassium bis (trimethylsilyl) amide (KHMDS, 0.5M in toluene, 1.25 mL). After stirring at room temperature for 24 hours, the crude product was added to a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated. Purifying the product by silica gel adsorption column chromatography to obtain 3- [1- (4-chlorophenyl) -3-methylene cyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-6); MSESI (m/z) 328.2.

Method 4E

Preparation of 3- [1- (4-chlorophenyl) -3, 3-difluorocyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-7)

3- (4-chlorophenyl) -3- (5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin-3-yl) cyclobutanone (4-5) (11.4mg) was dissolved in methylene chloride (1 ml). (diethylamino) sulfur trifluoride (DAST, 73. mu.l) was added and the solution was stirred at room temperature for 24 hours. The solution was poured into saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane- > 1% methanol in dichloromethane- > 5% methanol in dichloromethane) to give 3- [1- (4-chlorophenyl) -3, 3-difluorocyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-7); MS ESI (m/z): 352.1.

method 4F

Preparation of 3- [1- (4-chlorophenyl) -trans-3-fluorocyclobutyl ] -r-5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-8)

3- (4-chlorophenyl) -cis-3- (5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin-3-yl) -cyclobutane-R-alcohol (4-3) (21.3mg) was dissolved in anhydrous dichloromethane (1.5 ml) and then cooled to 0 ℃. (diethylamino) sulfur trifluoride (DAST, 80. mu.l) was added. The solution was warmed to room temperature and stirred overnight. The product was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane → 1% methanol in dichloromethane → 5% in dichloromethane) to give 3- [1- (4-chlorophenyl) -trans-3-fluorocyclobutyl ] -r-5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-8).

3- [1- (4-chlorophenyl) -trans-3-fluorocyclobutyl ] -R-5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-9) was prepared in substantially the same manner using the stereoisomeric starting material (4-4).

Method 4G

Preparation of 3- (3-methyl-1-phenylcyclobutyl) -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-10)

2-Phenylacethydrazide (1.01g) was added to a solution of anhydrous toluene (11 ml) and 8-methoxy-2, 3, 4, 5, 6, 7-hexahydroazocin (0.96 ml). The mixture was warmed to 60 ℃ for 3 hours and then heated to 110 ℃ overnight. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography to give 3-benzyl-5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin as a white solid.

3-benzyl-5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (287.6mg) and 1-bromo-3-chloro-2-methylpropane (140. mu.l) were dissolved in anhydrous deoxygenated tetrahydrofuran and the solution was cooled to-40 ℃ under an argon atmosphere. Potassium bis (trimethylsilyl) amide (KHMDS, 0.5M in toluene, 2.5mL) was added dropwise. After 30 minutes, a second portion of KHMDS (2.5ml) was added. After an additional 30 minutes, KHMDS (2.15 ml) was added again and the solution was slowly warmed to room temperature. In 1 hour zone, the reaction was quenched with water and added to brine. After extraction with ethyl acetate, the organic layer was dried over magnesium sulfate, filtered, evaporated, and purified by silica gel chromatography to give 3- [1- (4-chlorophenyl) - (Z) -3- (methoxymethoxy) cyclobutyl ] -5, 6, 7, 8, 9, 10-hexahydro [1, 2, 4] triazolo [4, 3-a ] azocin (4-10) as an isomer mixture in a ratio of about 1.2: 1; MS ESI (m/z): 296.2.

method 4H

Preparation of 1- (4-chlorophenyl) -trans-3-fluorocyclobutane-r-carbohydrazide

(4-chlorophenyl) acetonitrile (14.04g) was dissolved in freshly distilled tetrahydrofuran (250ml) and stirred at-78 deg.C under argon [1 ]. Methyllithium (LiBr complex, 1.5M in diethyl ether, 62 mL, 1 eq.) was added dropwise so that the reaction temperature remained below-66 ℃. The solution was stirred at-78 deg.C for 1 hour, the solution turned from yellow to dark red. Epibromohydrin was added dropwise and the solution was stirred for another 90 minutes. Magnesium methyliodide (3.0M in ether, 31 ml) was added and the solution turned light brown when slowly warmed to room temperature and stirred overnight. The reaction was quenched with water (75 ml) and acidified to pH2 (approximately 30ml) with 5N aqueous hydrochloric acid. Brine was added until layers separated. The organic layer was collected and the aqueous layer re-extracted with ether (2X 50 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated.

Crude 1- (4-chlorophenyl) -3-hydroxycyclobutane-1-carbonitrile (cis: trans isomer ratio of about 4.2: 1) was dissolved in dichloromethane (150ml) and stirred at 0 ℃. Pyridine (11.3 ml) was added followed by benzoyl chloride (10.8ml) and the solution warmed to room temperature and stirred for 2.5 hours. Pyridine (2ml) and benzoyl chloride (2ml) were added and the reaction was stirred overnight at 30 ℃. The reaction was added to a saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with saturated ammonium chloride, dried with magnesium chloride, filtered and concentrated to give a reddish oil. The two isomers were separated by silica gel chromatography (25% dichloromethane/hexane → 33% dichloromethane/hexane → 50% dichloromethane/hexane → 100% dichloromethane) to give the desired 3- (4-chlorophenyl) -cis-3-cyanocyclobutylbenzoate (18.63 g).

3- (4-chlorophenyl) -cis-3-cyanocyclobutylbenzoate (6.42g) was dissolved in methanol/tetrahydrofuran (10 ml/20 ml) and stirred at room temperature. Lithium hydroxide monohydrate (1.1g) was dissolved in water (10ml), and added to the benzoate solution. After 10 minutes, solid ammonium chloride (ca. 2g) was added and the volatile solvent was evaporated. The remaining aqueous mixture was extracted with ether and the organic layer was dried over magnesium sulfate, filtered and concentrated to give the desired cyclobutanol.

A portion of 1- (4-chlorophenyl) -cis-3-hydroxycyclobutane-r-carbonitrile (1.13g) was dissolved in anhydrous dichloromethane and stirred at 0 deg.C. (diethylamino) sulfur trifluoride (DAST, 1.43g) was added and the solution was warmed to 40 ℃ for 10 hours. DAST (0.5 mL) was added and the reaction was stirred overnight at 40 ℃. The solution was cooled, added to saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated. The crude residue was carefully chromatographed on silica gel (10% ethyl acetate/hexane → 20% ethyl acetate/hexane → 25% ethyl acetate/hexane) to give 1- (4-chlorophenyl) -trans-3-fluorocyclobutane-r-carbonitrile (1.024 g).

1- (4-chlorophenyl) -trans-3-fluorocyclobutane-r-carbonitrile (1.65g) was dissolved in dry toluene (30 ml) and cooled to-78 ℃. A solution of diisobutylaluminum hydride (DIBAL, 1M in hexane, 9.4 ml) was added over 10 minutes and the solution stirred for 30 minutes. The reaction was quenched by the addition of 5% sulfuric acid (2.5ml) and warmed to room temperature. After 1 hour, the mixture was filtered through a pad of celite. The pad was washed with ethyl acetate and the entire filtrate was poured into water (20 ml). After separation of the layers, the aqueous solution was extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated.

The crude aldehyde was dissolved in t-butanol/tetrahydrofuran/2-methylbut-2-ene (15ml/5 ml) and stirred at room temperature. Sodium chlorite (1.56g) and sodium dihydrogen phosphate (2.39g) were dissolved in water (7ml) and added to the vigorously stirred solution. After 80 minutes, the volatile solvents were removed under vacuum and the mixture was acidified to pH2 with 1N hydrochloric acid. The product was extracted with ethyl acetate (3X 30 ml). The extracts were combined, dried over magnesium sulfate, filtered, and evaporated to give the desired carboxylic acid.

1- (4-chlorophenyl) -trans-3-fluorocyclobutane-r-carboxylic acid (5.68g) was dissolved in methylene chloride/methanol (40ml/10 ml). (trimethylsilyl) diazomethane (15ml, 2.0M in hexanes) was added until a yellow color was obtained. After stirring at room temperature for 1 hour, TLC indicated complete reaction. Quenching (trimethylsilyl) diazomethane was added with acetic acid (2ml) and the solution was concentrated to give 1- (4-chlorophenyl) -trans-3-fluorocyclobutane-R-carboxylic acid methyl ester.

The crude methyl ester (5.8g) was dissolved in toluene (15 ml). Anhydrous hydrazine (3.1 mL, 98.8mmol) was added and the reaction refluxed for 2 days. After cooling to room temperature and removal of the toluene in vacuo, the product is purified by chromatography on silica gel (100% ethyl acetate) to give 1- (4-chlorophenyl) -trans-3-fluorocyclobutane-r-carbohydrazide as a white solid (4.82 g).

Method 4I

General procedure

Preparation of 3- [1- (4-chlorophenyl) -trans-3-fluorocyclobutyl ] -4, 5-bicyclopropyl-r-4H-1, 2, 4-triazole (4-11)

Methyl trifluoromethanesulfonate (84.1. mu.l) was added to N-cyclopropylcyclopropanecarboxamide (93.0 mg). After warming to 65 ℃ for 2 minutes, the reaction was cooled to room temperature. Toluene (1ml), triethylamine (207. mu.l) and 1- (4-chlorophenyl) -trans-3-fluorocyclobutane-r-carbohydrazide (108mg) were added to methyl N-cyclopropylcyclopropanecarbanilide, and stirred at 60 ℃ overnight and 115 ℃ for 2 hours. After cooling, the solution was concentrated, and the residue was purified by silica gel chromatography (100% ethyl acetate → 1% methanol in ethyl acetate → 3% methanol in ethyl acetate → 5% methanol in ethyl acetate) to give purified 3- [1- (4-chlorophenyl) -trans-3-fluorocyclobutyl ] -4, 5-dicyclopropyl-r-4H-1, 2, 4-triazole (4-11).

Compounds 4-12 to 4-15 were prepared in the same manner as the disease using the corresponding carbamide starting material and 1- (4-chlorophenyl) -trans-3-fluorocyclobutane-r-carbohydrazide.

Preparative HPLC method for example 4:

the preparative HPLC method used was the same as described in example 2. Analytical LC methods were the same as described in example 2.

Reference to the literature

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

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

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

While preferred embodiments of the present invention have been described herein, many alternative embodiments are contemplated as falling within the scope of the claims. Accordingly, the present invention is broader than the specific embodiments provided herein.

Claims (28)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

A and B are taken together to represent

(a) Optionally substituted by 1-3 halogen radicals and 1-2R^aRadical substituted C_1-4Alkylene, wherein R^aIs represented by C_1-3Alkyl, OC_1-3Alkyl radical, C_6-10Aryl radical C_1-6Alkylene or phenyl optionally substituted by 1 to 3 halogen groups, or

(b)C_2-5Alkanediyl, whereby they form together with the carbon atom to which they are attached a 3-6 membered ring, said 3-6 membered ring being optionally substituted by C_1-4Alkylene, oxo, ethylenedioxy or propylenedioxy, and further optionally substituted by 1 to 4 substituents selected from halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Acyl radical, C_1-3Acyloxy, C_1-3Alkoxy radical, C_1-6Alkyl OC (O) -, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkoxy, phenyl, CN, OH, D, NH₂、NHR^aAnd N (R)^a)₂Wherein R is^aAs defined above;

each R¹Represents H or is independently selected from the following groups: OH, halogen, C_1-10Alkyl radical, C_1-6Alkoxy and C_6-10Aryl radical, said C_1-10Alkyl radical, C_6-10Aryl and C_1-6The alkyl part of the alkoxy group being optionally substituted by 1 to 3 halogen, OH, OC_1-3Alkyl, phenyl or naphthyl, said phenyl and naphthyl optionally substituted with 1-3 substituents independently selected from halogen, OCH₃、OCF₃、CH₃、CF₃And phenyl, wherein said phenyl is optionally substituted with 1-3 halo groups,

or two R¹Radicals taken together represent condensed C_5-6An alkyl or aryl ring, which may optionally be substituted with 1-2 OH or R^aIs substituted by radicals in which R^aAs defined above;

R²and R³Combined together or separately;

when taken together, R²And R³To represent

(a)C_3-8Alkanediyl forming a fused 5-to 10-membered non-aromatic ring, optionally interrupted by 1 to 2 double bonds, and optionally containing 1 to 2 heteroatoms selected from O, S and N; or

(b) A fused 6-to 10-membered aromatic monocyclic or bicyclic group,

said alkanediyl and aromatic monocyclic or bicyclic groups being optionally substituted by 1 to 6 halogen atoms, and 1 to 4 OH, C_1-3Alkyl, OC_1-3Alkyl, halo C_1-3Alkyl, halo C_1-3Alkoxy and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, C_1-3Alkyl, OC_1-3Radical substitution of alkyl, said C_1-3Alkyl and OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups;

when the separation is present, the separation is,

R²selected from the group consisting of:

(a)C_1-14alkyl, optionally substituted by 1-6 halogen groups and 1-3 groups selected from OH, OC_1-3Alkyl and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, OCH₃、OCF₃、CH₃And CF₃Is substituted with a group of (a), said OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups;

(b) phenyl or pyridyl, optionally substituted by 1-3 halogens, OH or R^aRadical substitution, R^aThe radicals are as defined above;

(c)C_2-10alkenyl, optionally substituted with 1-3 substituents independently selected from halogen, OH and OC_1-3Substituent of alkyl, the OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups;

(d)CH₂CO₂H；

(e)CH₂CO₂C_1-6an alkyl group;

(f)CH₂C(O)NHR^awherein R is^aAs defined above;

(g)NH₂、NHR^aand N (R)^a)₂Wherein R is^aAs defined above;

and R³Selected from the following groups: c_1-14Alkyl radical, C_2-10Alkenyl, SC_1-6Alkyl radical, C_6-10Aryl, heterocyclyl and heteroaryl, said alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and SC_1-6Alkyl of alkylAnd moieties are optionally substituted with: (a) r; (b)1-6 halogen radicals and (c)1-3 radicals selected from OH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, OC_1-4Alkyl, CN, C wherein x is 0, 1 or 2_1-4Alkyl S (O)_x-、C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-and (C)_1-4Alkyl radical)₂NSO₂The group of (A) and (B), said C_1-4Alkyl and C of said radical_1-4The alkyl moiety being optionally substituted by phenyl and 1-3 halogen groups, and

r is selected from the group consisting of heterocyclyl, heteroaryl and aryl, said group being optionally substituted with 1 to 4 groups selected from the group consisting of: halogen, C_1-4Alkyl radical, C_1-4Alkyl S (O)_x-, x is as defined above, C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂-、CN、OH、OC_1-4Alkyl, and said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with 1-5 halogens and 1 halogen selected from OH and OC_1-3Alkyl groups.

2. A compound according to claim 1, wherein A and B taken together represent C_2-5Alkanediyl, thereby forming together with the carbon atom to which it is attached a 3-6 membered ring, said 3-6 membered ring optionally being substituted by C_1-4Alkylene, oxo, ethylenedioxy or propylenedioxy, and further optionally substituted with 1 to 4 groups selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Acyl radical, C_1-3Acyloxy radical, C_1-3Alkoxy radical, C_1-6Alkyl OC (O) -, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkoxy, phenyl, CN, OH, D, NH₂、NHR^aAnd N (R)^a)₂Wherein R is^aIs represented by C_1-3An alkyl group, a carboxyl group,OC_1-3alkyl radical, C_6-10Aryl radical C_1-6Alkylene or phenyl optionally substituted with 1-3 halo groups.

3. A compound according to claim 2, wherein A and B taken together represent C_2-4A member alkanediyl, thereby forming together with the carbon atom to which it is attached a 3-5 membered ring, optionally substituted with 1-2 groups selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkoxy radical C_1-3Alkyl radical, C_1-3Alkoxy radical C_1-3Alkoxy and phenyl.

4. A compound of claim 3, wherein A and B taken together represent C_2-4Alkanediyl, thereby forming, together with the carbon atoms to which it is attached, a 3-5 membered ring, said ring being unsubstituted or substituted by 1-2 halogen groups.

5. The compound of claim 4, wherein said 1-2 halo groups are fluoro groups.

6. The compound of claim 1, wherein two R are¹The radicals being H, an R¹Selected from: OH, halogen, C_1-10Alkyl radical, C_1-6Alkoxy and C_6-10Aryl radical, said C_1-10Alkyl radical, C_6-10Aryl and C_1-6The alkyl part of the alkoxy group being optionally substituted by 1 to 3 halogen, OH, OC_1-3Alkyl, phenyl or naphthyl groups, said phenyl and naphthyl groups being optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, OCH₃、OCF₃、CH₃、CF₃And phenyl, wherein said phenyl is optionally substituted with 1-3 halo groups.

7. The compound of claim 1, wherein one R¹Represents H, two R¹Selected from the following groups: OH, halogen, C_1-10Alkyl and C_1-6An alkoxy group,said C_1-10Alkyl and C_1-6The alkyl portion of the alkoxy group is optionally substituted with 1-3 halo groups.

8. The compound of claim 7, wherein two R' s¹The radicals represent halogen or methyl.

9. The compound of claim 1, wherein R₂And R₃Exist separately, and R²A group selected from: (a) c_1-14Alkyl, optionally substituted with 1-6 halo groups and 1-3 substituents selected from: OH, OC_1-3Alkyl and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, OCH₃、OCF₃、CH₃And CF₃Substituted with the group of (1), said OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups; (b) phenyl or pyridyl, optionally substituted by 1-3 halogens, OH or R^aSubstituted by groups; (c) c_2-10Alkenyl, optionally substituted with 1-3 substituents independently selected from halogen, OH and OC_1-3Substituent of alkyl, the OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halogens; (d) CH (CH)₂CO₂H；(e)CH₂CO₂C_1-6An alkyl group; (f) CH (CH)₂C(O)NHR^aAnd (g) NH₂，NHR^aAnd N (R)^a)₂And are and

R^ais represented by C_1-3Alkyl, OC_1-3Alkyl radical, C_6-10Aryl radical C_1-6Alkylene or phenyl optionally substituted with 1-3 halo groups.

10. The compound of claim 1, wherein R²And R³Exist separately, and R²Is C_1-14Alkyl, optionally substituted by 1-6 halogen groups and 1-3 groups selected from OH, OC_1-3Alkyl and phenyl, said phenyl being optionally substituted with 1-4 substituents independently selected from halogen, OCH₃、OCF₃、CH₃And CF₃Is substituted by a group of (A), OC_1-3The alkyl portion of the alkyl group is optionally substituted with 1-3 halo groups.

11. The compound of claim 9, wherein R²And R³Exist separately, and R²Represents a methyl group or a cyclopropyl group.

12. The compound of claim 1, wherein R³And R²Exist separately, and R³Selected from the following groups: c_1-14Alkyl radical, C_2-10Alkenyl, SC_1-6Alkyl radical, C_6-10Aryl, heterocyclyl and heteroaryl, said alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and SC_1-6The alkyl portion of the alkyl group is optionally substituted with: (a) r; (b)1-6 halogen radicals and (c)1-3 radicals selected from OH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, OC_1-4Alkyl, CN, C wherein x is 0, 1 or 2_1-4Alkyl S (O)_x-、C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-and (C)_1-4Alkyl radical)₂NSO₂-, said C_1-4Alkyl and C of said radical_1-4The alkyl moiety being optionally substituted by phenyl and 1-3 halogen groups, and

r is selected from the group consisting of heterocyclyl, heteroaryl and aryl, said group optionally being substituted with 1-4 substituents selected from the group consisting of halogen, C_1-4Alkyl, wherein x is as previously defined for C_1-4Alkyl S (O)_x-、C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂-、CN、OH、OC_1-4Radical substitution of alkyl, said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with 1-5 halogens and 1 halogen selected from OH and OC_1-3Alkyl groups.

13. The compound of claim 12, wherein R³And R²The components exist separately and are separated from each other,and R is³Selected from the following groups: c_1-14Alkyl radical, C_6-10Aryl, heterocyclyl and heteroaryl, said groups being optionally substituted with: (a) r; (b)1-6 halogen radicals and (c)1-3 radicals selected from OH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, OC_1-4Alkyl, CN, C wherein x is 0, 1 or 2_1-4Alkyl S (O)_x-、C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂The group of (A) and (B), said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with phenyl and 1-3 halo groups.

14. The compound of claim 12, wherein R³Independently exist, and R³Selected from the following groups: cyclopropyl optionally substituted with methyl or phenyl; optionally substituted by halogen, OH, OCH³Or OCF³Substituted phenyl; heteroaryl selected from the group consisting of benzimidazolyl, indolyl, benzofuranyl and dihydrobenzofuranyl, said heteroaryl group optionally substituted with: (a) r; (b)1-6 halogen radicals or (c)1-3 radicals selected from OH, NH₂、NHC_1-4Alkyl, N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, OC_1-4Alkyl, CN, C wherein x is 0, 1 or 2_1-4Alkyl S (O)_x-、C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂The group of (A) and (B), said C_1-4Alkyl and C of said radical_1-4The alkyl moiety being optionally substituted by phenyl and 1-3 halogen groups, and

r is selected from the group consisting of heterocyclyl, heteroaryl and aryl, said group optionally being substituted with 1-4 substituents selected from the group consisting of halogen, C_1-4Alkyl, OH, OC_1-4Alkyl radical, and said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with 1-5 halogen groups and 1 substituent selected from OH and OC_1-3Alkyl groups.

15. The compound of claim 1, wherein R²And R³Taken together, represent: (a) c_3-8Alkanediyl forming a fused 5-to 10-membered non-aromatic ring; or (b) a fused 6-to 10-membered aromatic monocyclic or bicyclic group, said alkanediyl and aromatic monocyclic or bicyclic groups optionally being substituted by 1 to 3 halogen atoms and 1 to 2 OH, C_1-3Alkyl, OC_1-3Alkyl, halo C_1-3Alkyl, halo C_1-3Alkoxy and phenyl, said phenyl being optionally substituted with 1-2 substituents independently selected from halogen, C_1-3Alkyl, OC_1-3Alkyl radical, and said C_1-3Alkyl and OC_1-3C of alkyl_1-3The alkyl moiety is optionally substituted with 1-3 halo groups.

16. The compound of claim 1, wherein R is selected from the group consisting of heterocyclyl, heteroaryl, and aryl, said groups optionally substituted with 1-4 halogen groups and 1-2 groups selected from C_1-4Alkyl, C wherein x is 0, 1 or 2_1-4Alkyl S (O)_x-、C_1-4Alkyl SO₂NH-、H₂NSO₂-、C_1-4Alkyl NHSO₂-、(C_1-4Alkyl radical)₂NSO₂-, CN, OH and OC_1-4Radical substitution of alkyl, said C_1-4Alkyl and C of said radical_1-4The alkyl moiety is optionally substituted with 1-3 halogen groups and 1 substituent selected from OH and OC_1-3Alkyl groups.

17. A compound selected from the group consisting of:

and

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 of the formula:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 17 of the formula:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 17 of the formula:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 17 of the formula:

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

23. The use of a compound according to claim 1 for the preparation of a medicament for the treatment of hyperglycemia, diabetes or insulin resistance.

24. The use of a compound of claim 1 for the preparation of a medicament for the treatment of non-insulin dependent diabetes mellitus.

25. The use of a compound of claim 1 for the manufacture of a medicament for the treatment of obesity.

26. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of syndrome X.

27. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of a lipid disorder selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low and high low density lipoprotein.

28. Use of a compound of claim 1 for the preparation of a medicament for the treatment of atherosclerosis.