JP2008501027A - Benzourea with anti-diabetic activity - Google Patents

Abstract

のベンゾ尿素化合物はＰＰＡＲγアゴニスト又は部分アゴニストであり、高血糖症や２型糖尿病に併発することが多い他の症状（例えば異脂肪血症、高脂血症、高コレステロール血症、高トリグリセリド血症、及び肥満症）を含めた２型糖尿病の治療と抑制に有用である。Formula I having an aryl- (CH ₂ ) _x -oxazolidinedione or aryl- (CH ₂ ) _x -thiazolidinedione substituent (wherein x is 0 or 1) on one of the N atoms of the benzourea ring:

The benzourea compound of PPARγ is a PPARγ agonist or partial agonist, and other symptoms that often accompany hyperglycemia and type 2 diabetes (eg dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia) , And obesity) are useful for the treatment and suppression of type 2 diabetes.

Description

  The present invention relates to benzourea and pharmaceutically acceptable salts and prodrugs thereof that are useful as therapeutic compounds, particularly in the treatment of type 2 diabetes and symptoms often associated with this disease (eg obesity and lipid metabolism disorders). .

  Diabetes is a disease caused by multiple causative factors and is characterized by an increase in plasma glucose levels (hyperglycemia) after administration of glucose during a fasted state or oral glucose tolerance test. Two types of diabetes are generally recognized. In type 1 diabetes or insulin dependent diabetes (IDDM), patients produce little or no insulin, a hormone that regulates glucose utilization. In type 2 diabetes or non-insulin dependent diabetes mellitus (NIDDM), insulin is still produced in the body. Patients with type 2 diabetes are often associated with hyperinsulinism (increased plasma insulin levels), but these patients are insulin resistant, ie glucose and lipid metabolism in major insulin sensitive tissues, which are muscle, liver and adipose tissue Resistant to the effects of insulin stimulating Since patients who are insulin resistant but not diabetic compensate for insulin resistance by secreting large amounts of insulin, serum glucose levels do not rise enough to meet the criteria for type 2 diabetes. In patients with type 2 diabetes, plasma insulin levels are elevated but not sufficient to compensate for significantly higher insulin resistance.

  Persistent or uncontrolled hyperglycemia associated with diabetes is linked to increased morbidity and mortality and early onset. In many cases, glucose homeostasis is directly and indirectly linked to obesity, hypertension, lipid, lipoprotein and apolipoprotein metabolism changes and other metabolic and blood flow disorders. Patients with type 2 diabetes are at great risk for macrovascular and microvascular complications such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neurosis, and retinopathy. Therefore, suppression of treatment of glucose homeostasis, lipid metabolism, obesity, and hypertension is extremely important for clinical management and treatment of diabetes.

  Many patients with insulin resistance or type 2 diabetes often have several symptoms called Syndrome X or metabolic syndrome. Patients with this syndrome are characterized by having three or more symptoms selected from the group consisting of the following five symptoms. (1) Abdominal obesity; (2) Hypertriglyceridemia; (3) High density lipoprotein cholesterol (HDL) reduction; (4) Hypertension; and (5) Fasting blood glucose elevation (if the patient is also diabetic Can take the characteristic range of type 2 diabetes). Each of these symptoms is the recently announced Third Report of the National Cholesterol Education, Program Expert Nest and Phenol at Detection, High Amount of ATP, and ATP. NIH Publication No. 01-3670. Patients with metabolic syndrome, regardless of whether or not they have overt diabetes, are at risk of developing the macrovascular and microvascular complications associated with type 2 diabetes (eg, atherosclerosis and coronary heart disease) large.

  Insulin resistance is not primarily due to a decrease in the number of insulin receptors, but to a post-insulin receptor binding defect that has not yet been fully elucidated. As a result of this lack of response to insulin, muscles have inadequate activation of glucose uptake, oxidation and storage by insulin, and lipolysis in adipose tissue and glucose production and secretion in the liver are not sufficiently suppressed by insulin. .

  Several types of treatment are available for type 2 diabetes, each with its own drawbacks and potential risks. Exercise and suppression of calorie intake are often the best frontline treatment for type 2 diabetes, often dramatically improving diabetic symptoms. However, compliance with this treatment is very low, as sedentary lifestyles and excessive consumption of foods with particularly high fat content have become established. A widely used drug treatment is the administration of meglitinides and sulfonylureas (eg tolbutamide and glipizide), which are insulin secretagogues. These drugs increase plasma insulin levels by stimulating pancreatic β cells to promote insulin secretion. If administration of sulfonylurea or meglitinide is not effective, the amount of insulin in the body can be supplemented by insulin injection so that the insulin concentration is sufficiently high to stimulate insulin resistant tissue. However, administration of insulin and / or insulin secretagogues can result in dangerously low plasma glucose levels or increased levels of insulin resistance due to increased plasma insulin levels.

  Biguanides are another class of drugs that are widely used to treat type 2 diabetes. Two biguanides, phenformin and metformin, are best known and improve hyperglycemia to some extent without the risk of developing hypoglycemia. Biguanides can be used in combination with insulin or insulin secretagogues without increasing the risk of hypoglycemia. However, phenformin and metformin can induce lactic acidosis and nausea / diarrhea. Metformin has a lower risk of side effects than phenformin and is widely prescribed for the treatment of type 2 diabetes.

  Glitazone (ie 5-benzylthiazolidine-2,4-dione) is a new class of compounds that can alleviate hyperglycemia and other symptoms of type 2 diabetes. These drugs substantially increase insulin sensitivity in muscle, liver and adipose tissue in several type 2 diabetes animal models, resulting in partial or complete elevation of plasma glucose levels without causing hypoglycemia It is corrected. Currently marketed glitazones (rosiglitazone and pioglitazone) are agonists of the peroxisome proliferator activated receptor (PPAR) γ subtype. PPARγ agonism is generally thought to be involved in the improvement of insulin sensitization observed with glitazones. New PPAR agonists are under development for the treatment of type 2 diabetes and / or dyslipidemia. Many of the new PPAR compounds are one or more agonists of the PPARα, γ and δ subtypes. Compounds that are agonists of both PPARα and PPARγ subtypes (PPARα / γ dual agonists) are promising because they inhibit hyperglycemia and improve lipid metabolism.

  PPAR agonists, particularly glitazones, have previously had the disadvantage of reducing their attractiveness. Certain compounds, particularly troglitazone, have shown hepatotoxicity. Troglitazone has eventually withdrawn from the market due to hepatotoxicity. Another drawback of currently marketed PPAR agonists is that they are less potent with monotherapy of type 2 diabetes, with an average plasma glucose reduction of about 20% and a hemoglobin A1C reduction of about 9.0% to about 8.0%. Only. Currently used compounds do not significantly improve lipid metabolism and may actually have a negative effect on the lipid profile. In view of these drawbacks, the development of better insulin sensitizers for type 2 diabetes that function by a similar mechanism of action is spurred.

  Recently, compounds that are PPARγ antagonists or partial agonists have been reported. WO 01/30343 describes certain compounds that are PPAR partial agonists / antagonists useful for the treatment of obesity and type 2 diabetes. WO 02/08188, WO 2004/020408, WO 2004/020409, and WO 2004/09869 disclose a class of PPAR agonists and partial agonists that are useful in the treatment of type 2 diabetes and are indole derivatives with reduced side effects related to weight and heart weight gain. ing. Benzourea has not yet been disclosed as having antidiabetic activity.

  The class of compounds described herein is a new class of PPARγ agonists and partial agonists. These compounds are potent ligands for the PPARγ nuclear receptor. This class of compounds includes not only many compounds that are PPARγ partial agonists, but also PPARγ full agonists and / or PPARγ antagonists. Some compounds have PPARα activity in addition to PPARγ activity. These compounds are useful for the treatment and suppression of hyperglycemia and insulin resistance. These compounds treat non-insulin dependent diabetes mellitus (NIDDM) in humans and other mammalian patients, particularly hyperglycemia and symptoms associated with NIDDM (eg hyperlipidemia, dyslipidemia, obesity) , Hypercholesterolemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, inflammatory symptoms, and other diseases, disorders and conditions mediated by PPAR).

  The above compounds are mixed or diabetic dyslipidemia, isolated hypercholesterolemia that can be expressed by LDL-C and / or non-HDL-C elevation, high apo B lipoproteinemia, increase in lipoprotein with high triglyceride concentration It appears to be useful for the treatment of one or more lipid metabolism disorders such as hypertriglyceridemia, as well as reduced HDL cholesterol levels. The compounds are also useful for the treatment or amelioration of atherosclerosis, obesity, vascular restenosis, inflammatory symptoms, psoriasis, polycystic ovary syndrome, and other diseases, disorders and conditions mediated by PPAR. Seem.

  The present invention relates to formula I:

［式中、
Ｒ^１は−Ｘ−アリール−Ｙ−Ｚであり、アリールは場合によりＡから独立して選択される１〜３個の基で置換されており；
アリールはフェニル又はナフチルであり；
Ｘ及びＹは各々独立して結合及び−ＣＲ^４Ｒ^５−から選択され；
Ｚは

[Where:
R ¹ is —X-aryl-YZ, where aryl is optionally substituted with 1 to 3 groups independently selected from A;
Aryl is phenyl or naphthyl;
X and Y are each independently selected from a bond and —CR ⁴ R ⁵ —;
Z is

であり、
ＱはＳ及びＯから選択され；
ＡはＣ_１−Ｃ_４アルキル、Ｃ_２−Ｃ_４アルケニル、−ＯＣ_１−Ｃ_４アルキル、及びハロゲンから選択され、前記アルキル、アルケニル、及び−Ｏアルキルは各々場合により１〜５個のハロゲンで置換されており；
Ｒ^２は
（ａ）ベンズイソキサゾリル、
（ｂ）アリール、
（Ｃ）−（ＣＨ_２）アリール、
（ｄ）−（Ｃ＝Ｏ）アリール、及び
（ｅ）ベンゾチアゾリルから選択され、
Ｒ^２は場合によりハロゲン、Ｃ_１−Ｃ_３アルキル、及び−ＯＣ_１−Ｃ_３アルキルから独立して選択される１〜３個の置換基で置換されており、前記Ｃ_１−Ｃ_３アルキル及び−ＯＣ_１−Ｃ_３アルキルは場合により１〜５個のハロゲンで置換されており；
Ｒ^３、Ｒ^４及びＲ^５は水素、ハロゲン、Ｃ_１−Ｃ_３アルキル、及び−ＯＣ_１−Ｃ_３アルキルから各々独立して選択され、前記Ｃ_１−Ｃ_３アルキル及び−ＯＣ_１−Ｃ_３アルキルは場合により１〜５個のハロゲンで置換されており；
Ｒ^６はＨ、Ｃ_１−Ｃ_３アルキル、及びハロゲンから選択され、前記Ｃ_１−Ｃ_３アルキルは場合により１〜３個のＦで置換されており；
ｐは０〜４の整数である］の化合物と医薬的に許容可能なその塩及びプロドラッグに関する。

And
Q is selected from S and O;
A is selected from C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, —OC ₁ -C ₄ alkyl, and halogen, wherein said alkyl, alkenyl, and —O alkyl are each optionally 1 to 5 halogens. Has been replaced;
R ² is (a) benzisoxazolyl,
(B) aryl,
(C) - (CH ₂₎ aryl,
(D)-(C═O) aryl, and (e) benzothiazolyl,
R ² is optionally substituted with 1 to 3 substituents independently selected from halogen, C ₁ -C ₃ alkyl, and —OC ₁ -C ₃ alkyl, and said C ₁ -C ₃ alkyl and If -OC ₁ -C ₃ alkyl by being substituted with 1-5 halogens;
R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, halogen, C ₁ -C ₃ alkyl, and —OC ₁ -C ₃ alkyl, and the C ₁ -C ₃ alkyl and —OC ₁ -C ₃ Alkyl is optionally substituted with 1 to 5 halogens;
R ⁶ is selected from H, C ₁ -C ₃ alkyl, and halogen, wherein said C ₁ -C ₃ alkyl is optionally substituted with 1 to 3 F;
p is an integer from 0 to 4] and pharmaceutically acceptable salts and prodrugs thereof.

  In the above definition and the following definition, the alkyl group may be linear or branched unless otherwise specified.

  The present invention has a number of embodiments as described below. All embodiments also include pharmaceutically acceptable salts of the specified compounds.

Other embodiments include compounds of Formula I, wherein R ¹ is —X-phenyl-YZ.

In other embodiments of the compounds of Formula I, X and Y can each independently be a bond or —CH ₂ —.

In other embodiments of the compounds of formula I, aryl is optionally substituted with 1 to 2 A groups, wherein each A group is halogen, —CF ₃ , —OCF ₃ , —CH ₃ , or —OCH _3. It can be.

In other embodiments of the compounds of formula I, R ³ is —CH ₃ , —OCH ₃ , —OCF ₃ , or —CF ₃ .

In other embodiments, R ⁶ is H, CH ₃ , or CF ₃ .

  In other embodiments, p is 0 or 1.

In other embodiments of the compounds of formula I, optionally substituted by halogen ^{R 2} _{is, -OCH 3, -OCF 3, CH} 3, and independently from CF ₃ substituted with 1 to 2 groups selected 3- Benzisoxazolyl.

In other embodiments of the compounds of formula I, R ² is optionally substituted with 1 to 2 groups independently selected from halogen, —OCH ₃ , —OCF ₃ , CH ₃ , and CF _3. Benzothiazolyl.

In another embodiment of the compound of formula I:
R ¹ is —X-phenyl-YZ, wherein the phenyl is optionally substituted with 1 to 2 groups independently selected from A;
X and Y are each independently selected from a bond and —CH ₂ —;
A is selected from halogen, —CF ₃ , —OCF ₃ , —CH ₃ , and —OCH ₃ ;
R ³ is selected from —CF ₃ , —OCF ₃ , —CH ₃ , and —OCH ₃ ;
R ⁶ is selected from H, —CH ₃ , and —CF ₃ ;
p is 0 or 1.

Compounds of formula I, or any subset of the above embodiments, include compounds wherein Q is O, X is a bond, and Y is —CH ₂ —.

Compounds of formula I, or another subset of any of the above embodiments, include compounds wherein Q is O, X is —CH ₂ —, and Y is a bond.

Compounds of formula I, or another subset of any of the above embodiments, include compounds wherein Q is O and X and Y are each —CH ₂ —.

  Compounds of formula I, or another subset of any of the above embodiments, include compounds wherein Q is O and X and Y are each a bond.

  Compounds of formula I, or any other subset of the above optional embodiments, include compounds wherein Q is S.

  The present invention includes pharmaceutical compositions containing, in addition to the compounds of formula I, pharmaceutically acceptable salts of these compounds, prodrugs of these compounds, and pharmaceutically acceptable carriers.

  The structures of specific compounds are disclosed in the Examples and Table 1. The synthesis of specific compounds is also described in the examples below.

  The compounds of the present invention can be used in pharmaceutical compositions containing this compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compounds according to the invention can also be used in pharmaceutical compositions whose sole active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof.

  Compounds of the present invention and pharmaceutically acceptable salts thereof provide the manufacture of a medicament for the treatment of type 2 diabetes in humans or other mammalian patients and the treatment of other diseases described herein which are treated with said compounds It can be used for the manufacture of pharmaceuticals.

The above compounds can be used in any of the following methods for treating or inhibiting the following diseases and methods for treating other diseases in mammalian patients, particularly humans, by administering to the patient a therapeutically effective amount of a compound of formula I: :
(1) Non-insulin dependent diabetes (type 2 diabetes);
(2) hyperglycemia;
(3) metabolic syndrome;
(4) Obesity;
(5) hypercholesterolemia;
(6) Hypertriglyceridemia; and / or (7) Mixed or diabetic dyslipidemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, etc. More lipid metabolism disorders.

  The compounds of the present invention can also be used in a method for reducing the risk of sequelae associated with metabolic syndrome in human or other mammalian patients in need of treatment, wherein a therapeutically effective amount of a compound of formula I is administered to the patient. To do.

  The compound treats atherosclerosis in a human or other mammalian patient in need of treatment for atherosclerosis or at risk of developing atherosclerosis or atherosclerosis sequelae To reduce the risk of developing atherosclerosis, to delay the onset of atherosclerosis, and / or to reduce the risk of sequelae of atherosclerosis A therapeutically effective amount of the compound of formula I is administered to the patient. Examples of sequelae of atherosclerosis include angina, lameness, heart attack, stroke and the like.

The compound is administered to a patient in need of treatment with a therapeutically effective amount of a compound of formula I, particularly for the following diseases:
(1) Type 2 diabetes, especially hyperglycemia due to type 2 diabetes;
(2) metabolic syndrome;
(3) obesity; and (4) useful for the treatment of hypercholesterolemia.

Definitions “Ac” is acetyl which is CH ₃ C (O) —.

  “Alkyl” means a saturated carbon chain that may be a straight chain, branched chain, or a combination thereof, unless otherwise defined. Other groups beginning with “ar” (eg, alkoxy and alkanoyl) may be linear, branched or combinations thereof unless otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

  “Alkenyl” means a carbon chain that contains at least one carbon-carbon double bond, and which may be linear, branched, or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl and the like.

  “Alkynyl” means a carbon chain that contains at least one carbon-carbon triple bond, and which may be linear, branched, or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

  “Cycloalkyl” means a monocyclic or bicyclic saturated or partially unsaturated carbocyclic ring, each having from 3 to 10 carbon atoms, unless otherwise specified. The term also includes a single ring fused to an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

  A cycloalkylidene group is a divalent cycloalkane group in which two bonds are on the same carbon. For example, the cyclopropyl group of 1,1-dimethylcyclopropane is a cyclopropylidene group.

  "Aryl" (and "arylene") when used to represent a substituent or group in a structure is monocyclic or bicyclic where all rings are aromatic and have only one carbon ring atom Means a compound. The term “aryl” may also refer to an aryl group fused to a cycloalkyl or heterocycle. "Heterocyclyl", "heterocycle", and "heterocyclic" are 3 to 8 membered fully or partially saturated monocyclic rings containing 1 to 4 heteroatoms independently selected from N, S and O Or refers to a bicyclic ring system. Examples of aryl substituents include phenyl and naphthyl. Aryl rings fused to cycloalkyl include indanyl, indenyl, and tetrahydronaphthyl. Examples of aryl fused to a heterocyclic group include 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl and the like. Examples of heterocycles include tetrahydrofuran, piperazine, and morpholine. Preferred aryl groups are phenyl and naphthyl. Generally phenyl is most preferred.

“Heteroaryl” (and heteroarylene) is 5 to 6 containing 1 to 4 heteroatoms selected from N, O and S (including —S (O) — and —S (O) ₂ —). Means a membered monocyclic or bicyclic aromatic ring system. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoisoxazolyl, benzox Examples include zolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), furo (2,3-b) pyridyl, quinolyl, indolyl, isoquinolyl and the like. Preferred heteroaryl groups include pyridyl (2-, 3-, and 4-pyridyl) and quinolyl.

  “Halogen” includes fluorine, chlorine, bromine and iodine.

  “Me” represents methyl.

  The term “composition” in a pharmaceutical composition or the like refers to a preparation containing an active ingredient and an inactive ingredient constituting a carrier, and any combination of two or more ingredients, complexation or aggregation, or dissociation of one or more ingredients. Or any formulation obtained directly or indirectly by one or more other types of reactions or interactions of the components. Accordingly, the pharmaceutical compositions of the present invention include any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

  The substituent “tetrazole” means the 2H-tetrazol-5-yl substituent and its tautomers.

Optical isomers-diastereomers-geometric isomers-tautomers The compounds of formula I may contain one or more asymmetric centers and are therefore racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and Can exist as individual diastereomers. The present invention is meant to encompass all such isomeric forms of the compounds of Formula I.

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

  Some of the compounds described herein exist with different hydrogen bonding points (referred to as tautomers). One example is a ketone and its enol form (referred to as a keto-enol tautomer). The individual tautomers and mixtures thereof are included in the compounds of formula I.

  Compounds of formula I having one or more asymmetric centers can be separated into diastereomers, enantiomers and the like by methods well known in the art.

  Alternatively, enantiomers and other compounds with chiral centers can be synthesized by stereospecific synthesis using optically pure starting materials and / or reagents of known structure.

Salts The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of the salt derived from an inorganic base include aluminum, ammonium, calcium, copper, trivalent iron, divalent iron, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc salt, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. The solid form salt may exist in two or more crystal structures or may be in a hydrate form. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, and tertiary amines, substituted amines (including naturally substituted amines), cyclic amines, and basic ion exchange resins (eg, arginine). , Betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine , Hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine) It is done.

  When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, such as inorganic and organic acids. Such acids include acetic acid, benzene sulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethane sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, Examples include malic acid, mandelic acid, methanesulfonic acid, mucous acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, oxalic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid are particularly preferred.

  It will be appreciated that reference to a compound of formula I herein includes pharmaceutically acceptable salts.

Applications The compounds of the present invention are potent ligands with agonist, partial agonist or antagonist activity against one or more of the various peroxisome proliferator activated receptor subtypes, particularly PPARγ. These compounds may be ligands or agonists, partial agonists or antagonists of the PPARα subtype and PPARγ, resulting in mixed PPARα / γ agonism. Some compounds (which are generally less preferred) may be PPARδ ligands and have PPARδ activity in addition to other PPAR activities. The compounds of the present invention are useful for the treatment or suppression of diseases, disorders or conditions mediated by one or more ligands of individual PPAR subtypes (eg γ or α) or combinations of PPAR subtypes (eg α / γ). is there. One aspect of the present invention provides methods for the treatment and suppression of diseases (eg, type 2 diabetes) that can be modulated by administration of PPAR agonists or partial agonists, particularly PPARγ agonists or partial agonists. One aspect of the present invention provides a method of administering to a mammal a therapeutically effective amount of a compound of formula I as a method of treating and suppressing such disease, disorder or condition in a mammal. The compounds of the present invention are believed to be useful for the treatment or suppression of a number of PPAR-mediated diseases and conditions, including but not limited to (1) diabetes, particularly non-insulin dependent diabetes (NIDDM), (2) high Glycemia, (3) low glucose tolerance, (4) insulin resistance, (5) obesity, (6) lipid metabolism disorder, (7) dyslipidemia, (8) hyperlipidemia, (9) high Triglyceridemia, (10) hypercholesterolemia, (11) low HDL level, (12) high LDL level, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (15) hypersensitivity Bowel syndrome, (16) inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, (17) other inflammatory symptoms, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative diseases, (21) retina Disease, (22) psoriasis, (23) metabolic syndrome, (24 Ovarian High androgens hyperlipoproteinemia (polycystic ovarian syndrome), and include other disorders involving insulin resistance. The compounds of the present invention treat hypertension, tumor symptoms, adipocyte tumors, adipocyte cancer (eg liposarcoma), prostate cancer and other cancers (eg gastric cancer, breast cancer, bladder cancer and colon cancer), angiogenesis, and Alzheimer's disease. It is also useful.

  The present invention can be used to reduce glucose, lipids and insulin in non-diabetic patients with reduced glucose tolerance and / or pre-diabetic conditions.

  The present invention can be used to treat obesity in patients in need of treatment by administering to the patient a therapeutically effective amount of a compound of formula I.

  The present invention can be used to treat or reduce the risk of developing atherosclerosis in a patient in need of treatment by administering to the patient a therapeutically effective amount of a compound of formula I.

  The present invention can be used to treat or alleviate hyperglycemia in diabetic patients in need of treatment by administering to the patient a therapeutically effective amount of a compound of formula I.

  The compounds of the present invention are believed to be useful in the treatment of osteoporosis. The compounds of the present invention can treat osteoporosis or reduce the risk of developing osteoporosis by delaying or halting bone density reduction in patients with or at risk of developing osteoporosis. The compounds of the present invention can also reverse bone loss in patients who have already started to lose bone.

  One aspect of the present invention is the treatment and suppression of mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL value, high LDL value, hyperlipidemia, and / or hypertriglyceridemia As a method, a method of administering a therapeutically effective amount of a compound of formula I to a patient in need of treatment is provided. The compounds may be used alone, but in combination with cholesterol biosynthesis inhibitors, particularly HMG-CoA reductase inhibitors such as lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, or ZD-4522 It is advantageous to administer. Compounds include cholesterol absorption inhibitors (eg, stanol esters, sterol glycosides such as ticueside, and azetidinones such as ezetimibe), ACAT inhibitors (eg, avasimibe), CETP inhibitors, niacin, niacin receptor agonists, bile acid solubilizers, microsomal triglycerides It is also advantageous to use in combination with other lipid lowering agents such as transport inhibitors and bile acid reuptake inhibitors. These combination treatments include one or more selected from the group consisting of hypercholesterolemia, atherosclerosis, hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL, and low HDL It is also considered effective in treating or suppressing related symptoms.

  Another aspect of the present invention provides a method for treating inflammatory conditions such as inflammatory bowel disease, Crohn's disease and ulcerative colitis by administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof. To do. Other inflammatory diseases that can be treated according to the present invention include gout, rheumatoid arthritis, osteoarthritis, multiple sclerosis, asthma, ARDS, psoriasis, vasculitis, ischemia / reperfusion injury, frostbite, and related Disease.

Administration and Dose Range Any route of administration suitable for administering an effective dose of a compound of the invention to a mammal, particularly a human, can be used. For example, routes such as oral, rectal, topical, parenteral, intraocular, pulmonary, intranasal and the like can be used. Examples of the dosage form include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. The compound of formula I is preferably administered orally.

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

  Daily doses of about 0.1 mg to about 100 mg / kg animal body weight when treating or inhibiting diabetes and / or hyperglycemia or hypertriglyceridemia or other diseases that are indications of compounds of formula I Administration of the compounds of the present invention will generally give satisfactory results, and it is preferable to administer the daily dose at once, or in divided doses 2-6 times daily or in sustained release form. For most large mammals, including humans (eg, adults weighing 70 kg), the total daily dose is about 1.0 mg to about 1000 mg, likely about 0.5 mg to about 350 mg, and about 1 mg to about 50 mg. Often. For particularly potent compounds, the adult dose can be reduced to as little as 0.1 mg. Examples of daily doses for an adult weighing 70 kg are 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg / day. The daily dosage regimen can be adjusted within or outside these ranges to obtain the optimal therapeutic response.

  Generally, it is administered orally using a tablet. Examples of tablet doses that can be administered once a day or more than once a day (eg twice a day, three times, or (exceptionally) four times or more) are 0.1 mg, 0.5 mg, 1 mg 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg. Other oral dosage forms (eg capsules or suspensions) can be administered at similar doses.

Pharmaceutical Compositions Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention contain a compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, and further contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or inorganic acids and organic bases or organic acids. When administering a prodrug, the pharmaceutical composition may further comprise a prodrug, or a pharmaceutically acceptable salt thereof.

  Compositions include compositions suitable for oral, rectal, topical, parenteral (eg, subcutaneous, intramuscular and intravenous), intraocular (ophthalmic), pulmonary (nasal or buccal inhalation), or intranasal administration. However, the optimal route for any given case depends on the type and severity of the condition being treated and the type of active ingredient. The composition is convenient as a unit dosage form and can be produced by any method known in the pharmaceutical field. In general, compositions suitable for oral administration are preferred.

  For practical use, the compound of formula I can be admixed as an active ingredient with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral (eg, intravenous). When preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used, such as water, glycols for oral liquid formulations such as suspensions, elixirs and solutions. Oils, alcohols, flavoring agents, preservatives, coloring agents, etc., for example, in the case of oral solid preparations such as powders, hard capsules, soft capsules and tablets, starch, saccharides, microcrystalline cellulose, diluents, Carriers such as granulating agents, lubricants, binders, and disintegrants can be used, and solid oral preparations are preferred over liquid preparations.

  Tablets and capsules are the most advantageous oral unit dosage forms because they are easy to administer, in which case solid pharmaceutical carriers are used. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of active compound in these compositions can of course vary and is conveniently from about 2% to about 60% of the unit weight. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compound can also be administered intranasally, for example as drops or spray.

  Tablets, pills, capsules and the like are further binders (eg gum tragacanth, gum arabic, corn starch or gelatin); excipients (dicalcium phosphate); disintegrants (eg corn starch, potato starch, alginic acid); lubricants (eg stearin) Acid magnesium); and sweeteners (eg sucrose, lactose or saccharin) can be added. When the unit dosage form is a capsule, a liquid carrier such as fatty oil can be added in addition to the above-mentioned materials.

  Various other materials may be used as coatings or to change the physical shape of the dosage unit. For example, tablets can be coated with shellac, sugar or both. Syrups or elixirs may contain sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavor (eg cherry or orange flavor) in addition to the active ingredient.

  The compound of formula I can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water and suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be made in glycerol, liquid polyethylene glycols and mixtures thereof in oil. Under normal conditions of storage and use, these preparations can contain preservatives to prevent microbial growth.

  Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the dosage form must be sterile and must be fluid to the extent that easy syringability exists. Furthermore, it must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Combination Therapy The compounds of formula I can be used in combination with other drugs that are also considered useful in the treatment or amelioration of diseases or conditions for which compounds of formula I are useful. Such other agents can be administered simultaneously or sequentially with the compound of Formula I by the route and amount normally used for such agents. When a compound of formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the 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 on separate overlapping schedules. When used in combination with one or more other active ingredients, it is contemplated that the compounds of the present invention and the other active ingredients can be used at lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.

Examples of other active ingredients that can be co-administered with a compound of formula I as separate or identical pharmaceutical compositions include, but are not limited to:
(A) (i) other PPARγ agonists such as glitazones (eg, troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, valaglitazone, netoglitazone, etc.) and PPARγ agonists and partial agonists that do not have a glitazone structure; Partial agonist;
(B) biguanides such as metformin and phenformin;
(C) a protein tyrosine phosphatase-1B (PTP-1B) inhibitor;
(D) dipeptidyl peptidase IV (DP-IV) inhibitors (eg, MK-0431, LAF-237, BMS-477118, PSN-9301, and GSK-823093);
(E) insulin or insulin mimetics;
(F) sulfonylureas (eg tolbutamide and glipizide) or related substances;
(G) an alpha glucosidase inhibitor (eg acarbose);
(H) substances that improve a patient's lipid profile, such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins) (Ii) bile acid solubilizers (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or salts thereof, (iv) niacin receptor agonists, (v) fenofibulin PPARα agonists such as acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (vi) cholesterol absorption inhibitors (eg ezetimibe), (vii) acyl CoA: Sterol acyl transferase (ACAT) inhibitors (e.g. avasimibe), (viii) CETP inhibitors, and (ix) phenolic anti-oxidants (e.g. probucol);
(I) PPARα / γ dual agonist (eg, KRP-297, muraglitazar, tesaglitazar, LY-818, etc.);
(J) PPARδ agonists (for example those disclosed in WO 97/28149);
(K) anti-obesity compounds (eg, fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y ₅ inhibitor, Mc4r agonist, cannabinoid receptor 1 (CB-1) antagonist / inverse agonist, and β ₃ adrenergic receptor agonists);
(L) ileal bile acid transporter inhibitor;
(M) drugs for inflammatory symptoms (eg, aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azalfidine, and selective cyclooxygenase-2 inhibitors);
(N) a glucagon receptor antagonist;
(O) GLP-1,
(P) GIP-1 and (q) GLP-1 analog (eg exendin).

  The above combination includes not only the combination of the compound of the present invention and one other active compound but also the combination of two or more other active compounds. Non-limiting examples include compounds selected from Formula I and biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors, and anti-obesity compounds 2 The combined use with the active compound of a seed | species or more is mentioned.

  The compound of the present invention (ie, the compound of formula I) is administered to a patient in need of treatment by administering a therapeutically effective amount of the compound of claim 1 in combination with an HMG-CoA reductase inhibitor to hypercholesterolemia, atherosclerosis. It can be used to treat one or more diseases or conditions selected from arteriosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia. A preferred HMG-CoA reductase inhibitor for this combination therapy is a statin. Preferred statins include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522, rivastatin, and rosuvastatin. This combination therapy may be particularly desirable to treat or reduce the risk of developing atherosclerosis.

Biological Assays A) PPAR Binding Assays Recombinant human PPARy, PPAR [delta, and to produce PPARa, human PPARy _2, were expressed in E. coli human PPAR [delta and human PPARa as gst fusion protein. The full length human cDNA for PPARy ₂ was subcloned into the pGEX-2T expression vector (Pharmacia). The full length human cDNAs of PPARδ and PPARα were subcloned into the pGEX-KT expression vector (Pharmacia). Escherichia coli introduced with each plasmid was grown, induced, and collected by centrifugation. The resuspended pellet was crushed with a French press and debris was removed by centrifugation at 12,000 × g. Recombinant human PPAR receptor was purified by affinity chromatography on glutathione sepharose. After applying to the column and washing once, the receptor was eluted with glutathione. Glycerol (10%) was added to stabilize the receptor and aliquots were stored at -80 ° C.

As described in Berger et al. (As described in Novel peroxisome proliferator-activated receptor (PPARγ) and PPARδ ligands product biochemical effects. J. Biol. 67: 99. Chem. 25: 19). TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL / 100 mL β-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg / mL aprotinin, 2 μg / mL leupeptin, 2 μg / mL benzamidine and 0. 5 mM PMSF) 0.1% non-fat dry milk and 10nM ^[3 _H 2] AD5075 ( 1ci / mmol) was added and the receptor aliquots were incubated under ± test compound of? The assay was incubated for ˜16 hours at 4 ° C. to a final volume of 150 μL. Unbound ligand was removed by incubation with 100 μL of dextran / gelatin coated activated carbon on ice for 10 minutes. After centrifugation at 3000 rpm for 10 minutes at 4 ° C., 50 μL of the supernatant fraction was counted by top counting.

In order to bind to PPARδ, it is described in Berger et al. (Novel peroxisome proliferator-activated receptorγ (PPARγ) and PPARδ ligands product distant bioelectrics. 2.1, 1 mM EDTA, 10% glycerol, 7 μL / 100 mL β-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg / mL aprotinin, 2 μg / mL leupeptin, 2 μg / mL benzamide and 0.5 mM PMSF). 1% non-fat dry milk and _{^{2.5nM [3 H 2] L-}} 783483 (17 i / mmol) was added and the receptor aliquots were incubated under ± test compound of? (L-783483 is 3-chloro-4- (3- (7-propyl-3-trifluoromethyl-6-benz- [4,5] -isoxazole, described in Example 20 of WO 97/28137). Oxy) propylthio) phenylacetic acid). The assay was incubated for ˜16 hours at 4 ° C. to a final volume of 150 μL. Unbound ligand was removed by incubation with 100 μL of dextran / gelatin coated activated carbon on ice for 10 minutes. After centrifugation at 3000 rpm for 10 minutes at 4 ° C., 50 μL of the supernatant fraction was counted by top counting.

For binding to PPARα, TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL / 100 mL β-mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 μg / mL aprotinin, 2 μg / mL leupeptin, 2 μg / mL benzamide and 0.5 mM PMSF) with 0.1% nonfat dry milk and 5.0 nM [ ³ H ₂ ] L-797733 (34 Ci / mmol), in which a receptor aliquot is incubated under ± test compound did. (L-777733 is described in Example 62 of WO 97/28137 (3- (4- (3-phenyl-7-propyl-6-benz- [4,5] -isoxazoleoxy) butyloxy)) Phenylacetic acid). The assay was incubated for ˜16 hours at 4 ° C. to a final volume of 150 μL. Unbound ligand was removed by incubation with 100 μL of dextran / gelatin coated activated carbon on ice for 10 minutes. After centrifugation at 3000 rpm for 10 minutes at 4 ° C., 50 μL of the supernatant fraction was counted by top counting.

B) Gal-4hPPAR transactivation assay The chimeric receptor expression construct pcDNA3-hPPARγ / GAL4, pcDNA3- by inserting the yeast GAL4 transcription factor DBD adjacent to the ligand binding domain (LBD) of hPPARγ, hPPARδ, hPPARα, respectively. hPPARδ / GAL4 and pcDNA3-hPPARα / GAL4 were prepared. The reporter construct pUAS (5X) -tk-luc was made by inserting 5 copies of the GAL4 response element upstream of the herpesvirus minimal thymidine kinase promoter and the luciferase reporter gene. pCMV-lacZ contains the galactosidase Z gene under the control of the cytomegalovirus promoter. High glucose Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal calf serum (Gemini Bio-Products, Calabasas, CA) adsorbed on activated carbon, non-essential amino acids, penicillin G100 units / ml and streptomycin sulfate 100 mg / ml In addition to the 96-well cell culture plate, 12 × 10 ³ COS-1 cells / well were seeded at 37 ° C. in a humidified atmosphere of 10% CO ₂ . Transfection was performed 24 hours later using Lipofectamine (GIBCO BRL, Gaithersburg, MD) according to the manufacturer's instructions. In summary, each well from 0.48 μl Lipofectamine, 0.00075 μg pcDNA3-PPAR / GAL4 expression vector, 0.045 μg pUAS (5X) -tk-luc reporter vector and 0.0002 μg pCMV-lacZ as an internal control for transactivation efficiency. The transfection mixture was constructed. The cells were incubated in the transfection mixture for 5 hours at 37 ° C. in an atmosphere of 10% CO ₂ . The cells are then exchanged for high glucose DMEM supplemented with 5% fetal calf serum adsorbed on activated carbon, non-essential amino acids, penicillin G 100 units / ml and streptomycin sulfate 100 mg / ml, and cells are added to ˜48 under increasing concentrations of test compound. Incubated for hours. Since the compounds were solubilized with DMSO, control cells were incubated with an equal concentration of DMSO and the final DMSO concentration was ≦ 0.1%, a concentration known to produce no transactivation activity. Cell lysates were made using reporter lysis buffer (Promega, Madison, WI) according to the manufacturer's instructions. Luciferase activity in the cell extract was measured with an ML3000 luminometer (Dynatech Laboratories, Chantilly, VA) using luciferase assay buffer (Promega, Madison, WI). β-galactosidase activity was measured using β-D-galactopyranoside (Calbiochem, San Diego, Calif.).

  Agonism is determined by comparing maximal transactivation activity to a full PPAR agonist such as rosiglitazone. In general, a compound is said to be a partial agonist if the maximum stimulation of transactivation is less than 50% of the effect observed with a full agonist. A compound is said to be a full agonist if the maximum stimulation of transactivation exceeds 50% of the effect observed with a full agonist. The compounds of the invention generally have EC50 values of 1 nM to 3000 nM.

C) In Vivo Test Male db / db mice (10-11 weeks old C57Bl / KFJ, Jackson Labs, Bar Harbor, ME) are placed in cages and fed freely with powdered Purina rodent diet and water. Animals and their feed are weighed every two days and the vehicle (0.5% carboxymethylcellulose) ± designated dose of test compound is administered daily by gavage. A drug suspension is prepared daily. Blood is drawn from the tail at 3-5 day intervals during the test period and plasma glucose and triglyceride concentrations are measured. Glucose and triglyceride measurements are performed on a Boehringer Mannheim Hitachi 911 automated analyzer (Boehringer Mannheim, Indianapolis, IN) using heparinized plasma diluted 6-fold (v / v) with saline. Lean animals are age-matched heterozygous mice bred similarly.

(Example)
The following schemes and examples are intended to illustrate the present invention and not to limit it. The scope of the invention is defined by the claims.

  The structures in Table 1 further illustrate compounds of the invention that were or can be made using the methods disclosed herein.

The synthesized compounds in Table 1 were analyzed using tandem high pressure liquid chromatography-mass spectrometry (LC-MS) and / or proton NMR. LC-MS samples were analyzed using a combination of Agilent 1100 Series high pressure liquid chromatography and a Waters Micromass ZQ mass spectrometer. The column used was Waters XTerra, flow rate 2.5 mL / min; solvent A: water containing 0.06% trifluoroacetic acid; solvent B: acetonitrile containing 0.05% trifluoroacetic acid, gradient elution program. (10% B → 100% B, 4.5 min) was used to elute the compound. Retention time is given in minutes.
Method A: XTerra MS-C18, 4.5 × 50 mm, 10 → 100% B, 4.5 minutes, flow rate 2.5 ml / min.
Method B: XTerra C18, 3 × 50 mm, 10 → 98%, 3.75 minutes, then 98%, 1 minute, flow rate 1 ml / min.

  General and specific manufacturing procedures for the compounds of the present invention and synthetic intermediates are summarized below. Those skilled in the art of medicine and / or synthetic organic chemistry can readily produce other compounds of the present invention by applying the procedures disclosed herein to specific compounds.

  Experimental procedure:

2-Nitro-4-trifluoromethoxyacetylaniline:
Acetic anhydride (75 mL) was added to a solution of 4-trifluoromethoxyaniline (35 g, 200 mmol) in acetic acid (35 mL) at 0 to 10 ° C. The reaction mixture was stirred at 10-30 ° C. for 30 minutes. H ₂ SO ₄ (96%, 1.5 mL, 26 mmol) was added while cooling in an ice bath followed by HNO ₃ (90%, 9.4 mL, 200 mmol). The mixture was stirred at room temperature for 1 hour and diluted with water (300 ml). The resulting slurry was stirred in an ice bath for 30 minutes and filtered. The solid was washed with water and air dried to give a yellow solid. LC-MS ¹ H NMR (CDCl ₃ , 500 MHz).

2-Nitro-4-trifluoromethoxyaniline:
To a solution of 2-nitro-4-trifluoromethoxyacetylaniline (45 g, 170 mmol) in methanol (200 mL) at 0-10 ° C. was added sodium hydroxide solution (8.5 g NaOH, 45 mmol in 45 mL water). The reaction mixture was stirred at room temperature for 1 hour and diluted with 300 mL of water. The slurry was stirred in an ice bath for 2 hours and filtered. The yellow solid was washed with 50 mL of methanol: water (1: 2) and dried under reduced pressure to give a yellow solid.

1,2-diamino-4-trifluoromethoxybenzene:
10% palladium on carbon (Pd / C, 10% wt / wt, 500 mg) was added to a solution of 2-nitro-4-trifluoromethoxyaniline (40 g, 180 mmol) in methanol (250 ml). The suspension was shaken in a Parr bottle under 45 psi hydrogen for 4 hours and then filtered through celite. The filtrate was concentrated to dryness to give a light gray solid.

5-trifluoromethoxybenzimidazol-2-one:
Urea (32 g, 180 mmol) was added to a tetrahydrofuran (350 ml) solution of 1,2-diamino-4-trifluoromethoxybenzene (35 g, 180 mmol). The solution was refluxed at 70 ° C. overnight, concentrated under reduced pressure to a volume of about 100 mL and diluted with water (500 mL). The suspension was stirred at room temperature overnight and filtered. The solid was washed with water and dried under reduced pressure to obtain a white crystalline solid. LC-MS: m / e (M + 1) = 219. < ¹ > H NMR (DMSO, 500 MHz) [delta] 10.85 (d, J = 8 Hz, 2H), 6.97 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 11 Hz, 2H).

1-Boc-5-trifluoromethoxybenzimidazol-2-one and 1-Boc-6-trifluoromethoxybenzimidazol-2-one:
To a solution of 5-trifluoromethoxybenzimidazol-2-one (35 g, 160 mmol) in DMF (150 mL) was added NaH (95%, 4.9 g, 190 mmol). After the reaction mixture was stirred at room temperature for 2 hours, di-tert-butyl dicarbonate (35 g, 160 mmol) was added. The mixture was stirred at room temperature overnight, diluted with water (400 ml) and extracted with ethyl acetate (2 × 150 ml). The organic extract was washed with water (2 × 100 ml) and brine (100 ml), dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was subjected to silica gel chromatography using hexane / ethyl acetate (3: 1) as the solvent system to give 1-Boc-5-trifluoromethoxybenzimidazol-2-one as the initial eluate. The fractions containing the late eluate were combined and concentrated to dryness to give 1-Boc-5-trifluoromethoxybenzimidazol-2-one. LC-MS (M + 1) = 319. ¹ H NMR (DMSO, 500 MHz) δ 11.21 (brs, 1H), 7.56 (s, 1H), 7.12 (d, J = 7 Hz, 1H), 7.03 (d, J = 7 Hz, 1H) ),) 1.57 (s, 9H).

1-[(6-Chloro) -benzisoxazol-3-yl] -5-trifluoromethoxylbenzimidazol-2-one and 1-[(6-Chloro) -benzisoxazol-3-yl]- 6-trifluoromethoxylbenzimidazol-2-one:
To a solution of 1-Boc-5-trifluoromethoxybenzimidazol-2-one (5 g, 15.7 mmol) in DMF (20 ml), 3,6-dichlorobenzisoxazole (3.0 g, 15.7 mmol) and Cs ₂ CO ₃ (11 g, 31.4 mmol) was added. The suspension was heated to 150 ° C. in an oil bath and stirred overnight. The mixture was then cooled to room temperature, diluted with water (30 ml) and extracted with ethyl acetate (2 × 20 ml). The organic extracts were combined, dried over anhydrous Mg ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography using hexane / ethyl acetate (4: 1) as a solvent system. Fractions containing the initial eluate were combined and concentrated to give 1- [3- (6-chloro) -benzisoxazoyl] -5-trifluoromethoxylbenzimidazol-2-one as a white solid. ¹ H NMR (DMSO, 500 MHz) δ 8.28 (d, J = 9.0 Hz, 1H), 8.12 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.54 (D, J = 8.5, 1H), 7.14 (d, J = 8.5, 1H), 7.13 (s, 1H). Fractions containing the late eluate were combined and concentrated to give 1- [3- (6-chloro) -benzisoxazoyl] -6-trifluoromethoxylbenzimidazol-2-one as a white solid. ¹ H NMR (DMSO, 500 MHz) δ 8.28 (d, J = 9.0 Hz, 1H), 8.12 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.66 (Brs, 1H), 7.54 (d, J = 8.5, 1H), 7.13 (brs, 1H).

1-[(6-Methoxy) -benzisoxazol-3-yl] -6-trifluoromethoxylbenzimidazol-2-one:
A solution of 1- [3- (6-chloro) -benzisoxazoyl] -6-trifluoromethoxylbenzimidazol-2-one (1.2 g, 3.25 mmol) in DMF (5 ml) in methanol solution of NaOMe (30 % Wt / wt, 20 ml). The mixture was heated to 80 ° C. under reduced pressure to remove residual methanol and then stirred at 110 ° C. under nitrogen overnight. The mixture was then cooled to room temperature, diluted with water (50 ml) and adjusted to pH 6 with 10% aqueous HCl. The resulting suspension was stirred in an ice bath for 2 hours and filtered. The solid was washed with water and dried in an oven (90 ° C.) for 2 hours, then at high vacuum for 3 hours at room temperature to give a pale yellow solid. LC-MS m / e: (M + 1) = 366.

1- (6-Chlorobenzisoxazol-3-yl) benzimidazol-2-one and 1- (6-methoxybenzisoxazol-3-yl) benzimidazol-2-one:
To a solution of benzimidazol-2-one (Aldrich, 1.1 g, 7.5 mmol) in DMF (20 ml), 3,6-dichlorobenzisoxazole (1.5 g, 7.5 mmol) and Cs ₂ CO ₃ (4. 8 g, 15 mmol) was added. The suspension was heated to 150 ° C. in an oil bath and stirred overnight. The mixture was then cooled to room temperature, diluted with water (30 ml) and stirred in an ice bath for 2 hours. The mixture was then filtered. The solid was washed with water and dried under high vacuum to give 2.0 g (93%) of 1- (6-chlorobenzisoxazol-3-yl) benzimidazol-2-one as a yellow solid. To a solution of the above product (1.0 g, 3.5 mmol) in DMF (15 ml) was added a methanol solution of NaOMe (30% wt / wt, 10 ml). The mixture was heated to 80 ° C. under reduced pressure to remove residual methanol and then stirred at 110 ° C. under nitrogen overnight. The mixture was then cooled to room temperature, diluted with water (50 ml) and adjusted to pH 6 with 10% aqueous HCl. The resulting suspension was stirred in an ice bath for 2 hours and filtered. The solid was washed with water and dried in an oven (90 ° C.) for 2 hours, then at high vacuum for 3 hours at room temperature to give a pale yellow solid. LC-MS m / e: (M + 1) = 282.

1- (4-Chlorobenzyl) -5-trifluoromethylbenzimidazol-2-one:
To a solution of 1-Boc-5-trifluoromethylbenzimidazol-2-one (100 mg, 0.33 mmol) in DMF (2 ml) was added 4-chlorobenzyl bromide (81 mg, 0.39 mmol) and Cs ₂ CO ₃ (300 mg, 0.92 mmol) was added. The mixture was stirred at room temperature for 2 hours, diluted with water (4 ml) and extracted with ethyl acetate (2 × 3 ml). The organic extracts were combined and concentrated to obtain a solid. The solid was dissolved in TFA (1.5 ml), stirred at room temperature for 2 hours and concentrated to dryness. The residue was purified by silica gel chromatography using hexane / ethyl acetate (4: 1) as solvent system to give a white solid. ¹ H NMR (DMSO, 500 MHz) δ 9.35 (brs, 1H), 7.38 (s, 1H), 7.34 (d, 2H), 7.28 (d, 2H), 7.27 (d, 1H), 6.93 (d, 1H), 5.10 (s, 2H).

1- (4-Chlorobenzoyl) -5-trifluoromethylbenzimidazol-2-one:
4-Chlorobenzoyl chloride (115 mg, 0.66 mmol) was added to a solution of 1-Boc-5-trifluoromethylbenzimidazol-2-one (200 mg, 0.66 mmol) in anhydrous pyridine (4 ml). The mixture was stirred at room temperature overnight and concentrated to dryness. The residue was dissolved in TFA (2 ml) and stirred at room temperature for 2 hours. The mixture was concentrated to dryness and purified by silica gel column chromatography to give a solid. ¹ H NMR (DMSO, 500 MHz) δ 7.92 (d, 1H), 7.81 (d, 2H), 7.56 (d, 2H), 7.66 (brs, 1H), 7.48 (d, 1H), 7.32 (brs, 1H).

1- (4-trifluoromethoxyphenyl) -5-trifluoromethylbenzimidazol-2-one:
To a solution of 1-Boc-5-trifluoromethylbenzimidazol-2-one (870 mg, 2.88 mmol) in methylene chloride (100 ml) was added Cu (OAc) ₂ (521 mg, 2.88 mmol), triethylamine (0.94 ml, 14 mmol). ), And molecular sieves (200 mg) were added. The mixture was stirred overnight at room temperature under open air and filtered. The filtrate was concentrated to dryness. The residue was dissolved in TFA (5 ml), stirred at room temperature for 3 hours and concentrated to dryness. The residue was dissolved in ethyl acetate (5 ml), passed through a silica gel pad and washed with hexane / ethyl acetate (3: 1) (100 ml). The filtrate was concentrated to give a solid. LC-MS m / e (M + 1) = 363.

1-[(6-Chloro) benzothiazol-2-yl] -5-trifluoromethylbenzimidazol-2-one:
To a solution of 1-Boc-5-trifluoromethylbenzimidazol-2-one (500 mg, 1.65 mmol) in DMF (5 ml), 2,6-dichlorobenzothiazole (336 mg, 1.65 mmol) and Cs ₂ CO ₃ (1 .2 g, 3.68 mmol) was added. The mixture was heated to 150 ° C. in an oil bath and stirred overnight. The reaction mixture was then cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (2 × 20 ml). The organic extracts were combined and concentrated to dryness, and purified by silica gel column chromatography using hexane / ethyl acetate (3: 1) as a solvent system to obtain a white powder. LC-MS m / e (M + 1) = 372.

  Experimental procedure:

2- (3-Methylphenyl) propene:
To a room temperature diethyl ether (200 mL) suspension of methyltriphenylphosphonium bromide (33.2 g, 92.9 mmol) was added nBuLi (2.5 M in 37 mL hexane) slowly. The resulting yellow solution was stirred for 30 minutes before 3-methylacetophenone (12 mL, 90 mmol) was added. The reaction mixture was stirred at room temperature overnight. The precipitate was removed by filtration. The solvent was removed under reduced pressure. Purification by flash chromatography gave the 2- (3-methylphenyl) propene product.

2 (R)-(3-methylphenyl) -1,2-propane-diol:
To a suspension of AD-mix-β (7 g) at 0 ° C. H ₂ O / tBuOH (25 mL / 25 mL) was added 2- (3-methylphenyl) propene (0.66 g, 5 mmol). The reaction mixture was stirred at 0 ° C. overnight. Na ₂ SO ₃ (7.5 g) was added. After 1 hour at room temperature, the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by flash chromatography gave 2 (R)-(3-methylphenyl) -1,2-propane-diol. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.30 (overlap signal, 2H), 7.12 (d, J = 7.1 Hz, 1H), 3.82 (d, J = 11.2 Hz), 3. 66 (d, J = 11.2 Hz, 1H), 2.59 (s, 1H), 2.40 (s, 3H), 1.55 (s, 3H).

2 (R)-(3-methylphenyl) lactic acid:
To a solution of 2 (R)-(3-methylphenyl) -1,2-propane-diol (0.7 g) in water (50 mL) was added NaHCO ₃ (0.4 g) and 10% Pt / C (0.7 g). added. Air was bubbled through the reaction mixture at 70 ° C. overnight with a gas dispenser. The reaction mixture was cooled to room temperature and then filtered through celite. The filtrate was acidified to pH 2 with aqueous H ₂ SO ₄ (1.0 N) and then extracted with EtOAc (3 ×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the acid. ¹ H NMR (600 MHz, DMSO) δ (ppm): 7.32 (s, 1H), 7.28 (d, 1H), 7.19 (t, 1H), 7.02 (d, 1H), 2 .25 (s, 3H), 1.59 (s, 3H).

2 (R)-(3-methylphenyl) methyl lactate 2 (R)-(3-methylphenyl) lactic acid (3.64 g, 20.2 mmol) in anhydrous diethyl ether (100 ml) until light yellow or Diazomethane ether solution (freshly prepared according to the procedure of Aldrich Technical Bulletin AL-180) was added until no more bubbles. The solution was then concentrated to dryness to give a white solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.39 (s, 1H), 7.35 (d, 1H), 7.25 (t, 1H), 7.13 (d, 1H), 3.79 (s, 3H), 2.40 (s, 3H), 1.80 (s, 3H).

(R) -5-methyl-5- (3-methylphenyl) oxazolidinedione:
2 (R)-(3-methylphenyl) methyl lactate (3.9 g, 20.1 mmol) in absolute ethanol (50 ml) was added to an ethanol solution of NaOEt (21% wt / wt, 9.8 m1, 30 mmol) and urea ( 1.5 g, 24.2 mmol) was added. The mixture was heated to 95 ° C. and refluxed overnight. The solution was then cooled to room temperature, acidified with 1N HCl, concentrated to a small volume and diluted with water (100 ml). The aqueous mixture was extracted with ethyl acetate (3 × 50 ml). The combined organic extracts were washed with brine, dried over anhydrous Mg ₂ SO ₄ and concentrated to dryness to give an oil that was used in the next step without further purification. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.70 (s, wide, 1 H), 7.4-7.2 (overlap signal, 4 H), 2.40 (s, 3 H), 1.96 (s, 3H).

Of (R) -5-methyl-5- (3-methylphenyl) -N-trityloxazolidinedione (R) -5-methyl-5- (3-methylphenyl) oxazolinedione (4.3 g, 20.9 mmol) Triethylamine (2.1 g, 23 mmol) and trityl chloride (6.4 g, 23 mmol) were added to an anhydrous methylene chloride (50 ml) solution. The mixture was stirred at room temperature under nitrogen for 1 hour, washed with water (20 ml), brine (20 ml), dried over anhydrous Mg ₂ SO ₄ and concentrated to dryness to give a solid. _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.40-7.20 ( multiplex overlap signal, 19H), 2.40 (s, 3H), 1.76 (s, 3H).

(R) -5-Bromomethyl-5- (3-methylphenyl) -N-trityloxazolidinedione:
(R) -5-methyl-5- (3-methylphenyl) -N-trityloxazolidinedione (3.0 g, 6.7 mmol) in carbon tetrachloride (100 ml) was added to N-bromosuccinamide (1.1 g). , 6.7 mmol) and AIBN (catalyst). The mixture was heated to 80 ° C. and refluxed overnight. The solution was then cooled to room temperature, washed with saturated NaHCO ₃ solution (20 ml), water (20 ml), and brine (20 ml) and concentrated to dryness. The residue was purified by silica gel column chromatography using hexane / ethyl acetate (9:10) as a solvent to give a white solid. _{^{1 H NMR (500MHz, CDCl 3}} ) δ7.5-7.2 ( multiplex overlap signal, 19H), 4.56 (s, 2HH), 1.76 (s, 3H).

(5R) -5- (4-Chloro-3-{[3- (6-methoxy-1,2-benzisoxazol-3-yl) -2-oxo-6- (trifluoromethoxy) -2, 3-Dihydro-1H-benzimidazol-1-yl] methyl} phenyl) -5-methyl-1,3-oxazolidine-2,4-dione:
To a solution of 1- [3- (6-methoxy) -benzisoxazoyl] -5-trifluoromethoxylbenzimidazol-2-one (700 mg, 1.92 mmol) in DMF (20 ml) was added (R) -5-methyl- 5- (3-Bromomethyl-4-chlorophenyl) -N-trityloxazolidinedione (1.1 g, 1.93 mmol) and Cs ₂ CO ₃ (1.25 g, 3.8 mmol) were added. The mixture was stirred at room temperature overnight, diluted with water (30 ml) and extracted with ethyl acetate (2 × 30 ml). The combined organic extracts were dried over anhydrous Mg ₂ SO ₄ and concentrated to give 1.5 g (92%) solids. The solid was dissolved in neat trifluoromethanesulfonic acid (5 ml) and stirred at room temperature for 6 hours. The mixture was then concentrated to dryness under reduced pressure and purified by silica gel column chromatography using hexane / ethyl acetate / TFA (3/1 / 0.01) as a solvent system to obtain a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.59 (brs, 1H), 8.14 (d, 1H), 7.95 (d, 1H), 7.62 (s, 1H), 7.56 (s , 2H), 7.03 (m, 3H), 6.91 (s, 1H), 5.34 (s, 2H), 3.98 (s, 3H), 1.84 (s, 3H).

(5R) -5- (3-{[3- (6-Methoxy-1,2-benzisoxazol-3-yl) -2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ] Methyl} phenyl) -5-methyl-1,3-oxazolidine-2,4-dione:
To a solution of 1- [3- (6-methoxy) -benzisoxazoyl] benzimidazol-2-one (266 mg, 0.95 mmol) in DMF (3 ml) was added (R) -5-methyl-5- (3-bromo. methylphenyl) -N- trityl oxazolidinedione (500 mg, 0.95 mmol) and _{Cs 2 CO 3 (620mg, 1.9mmol} ) was added. The mixture was stirred at room temperature overnight, diluted with water (10 ml) and extracted with ethyl acetate (2 × 10 ml). The organic extracts were combined, dried over anhydrous Mg ₂ SO ₄ and concentrated to give a solid. The solid was dissolved in neat trifluoromethanesulfonic acid (5 ml) and stirred at room temperature for 6 hours. The mixture was then concentrated to dryness under reduced pressure and purified by silica gel column chromatography using hexane / ethyl acetate / TFA (3/1 / 0.01) as a solvent system to obtain a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.18 (d, 1H), 7.92 (d, 1H), 7.71 (s, 1H), 7.56 (brs, 1H), 7.43 (brs) , 2H), 7.23 (m, 2H), 7.08 (s, 1H), 7.02 (m, 2H), 5.28 (dd, 2H), 3.98 (s, 3H), 1 .99 (s, 3H).

5- (3-{[2-oxo-3- [4- (trifluoromethoxy) phenyl] -6- (trifluoromethyl) -2,3-dihydro-1H-benzimidazol-1-yl] methyl} benzyl ) -1,3-oxazolidine-2,4-dione:
To a solution of 1- (4-trifluoromethoxyphenyl) -5-trifluoromethylbenzimidazol-2-one (362 mg, 1 mmol) in DMF (4 ml) was added 5- (3-bromomethylbenzyl) -N-trityloxazolidinedione ( 525 mg, 1.0 mmol) and Cs ₂ CO ₃ (620 mg, 1.9 mmol) were added. The mixture was stirred at room temperature overnight, diluted with water (10 ml) and extracted with ethyl acetate (2 × 10 ml). The organic extracts were combined, dried over anhydrous Mg ₂ SO ₄ and concentrated to give a solid. The solid was dissolved in neat trifluoromethanesulfonic acid (2 ml) and stirred at room temperature for 4 hours. The mixture was then concentrated to dryness under reduced pressure and purified by silica gel column chromatography using hexane / ethyl acetate / TFA (3/1 / 0.01) as a solvent system to obtain a white solid. LC-MS m / e: (M + 1) = 565.
(Example)

(5R) -5- (3-{[3- (5-Chloro-1,2-benzisoxazol-3-yl) -2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ] Methyl} phenyl) -5-methyl-1,3-oxazolidine-2,4-dione:
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.39 (s, 1 H), 8.33 (brs, 1 H), 7.92 (d, 1 H), 7.71 (s, 1 H), 7.61 (s , 2H), 7.58 (d, 1H), 7.42 (m, 2H), 7.21 (d, 2H), 7.02 (d, 1H), 5.23 (dd, 2H), 1 .99 (s, 3H).

(5R) -5- (4-Chloro-3-{[3- (6-methoxy-1,2-benzisoxazol-3-yl) -2-oxo-6- (trifluoromethyl) -2, 3-Dihydro-1H-benzimidazol-1-yl] methyl} phenyl) -5-methyl-1,3-oxazolidine-2,4-dione:
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.14 (d, 1H), 8.02 (d, 1H), 7.67 (s, 1H), 7.57 (s, 1H), 7.52 (d , 1H), 7.26 (m, 2H), 7.09 (s, 1H), 7.06 (d, 1H), 5.38 (s, 2H), 3.98 (s, 3H), 1 .83 (s, 3H).

(5S) -5- (4-Chloro-3-{[3- (6-methoxy-1,2-benzisoxazol-3-yl) -2-oxo-2,3-dihydro-1H-benzimidazole -1-yl] methyl} phenyl) -5-methyl-1,3-oxazolidine-2,4-dione:
¹ H NMR (500 MHz, CDCl ₃ ) δ 9.30 (brs, 1H), 8.09 (d, 1H), 7.88 (d, 1H), 7.61 (s, 1H), 7.42 (s , 2H), 7.21 (m, 2H), 7.01 (m, 3H), 5.32 (s, 2H), 3.98 (s, 3H), 1.76 (s, 3H).

(5R) -5- (4-{[3- (6-Methoxy-1,2-benzisoxazol-3-yl) -2-oxo-6- (trifluoromethoxy) -2,3-dihydro- 1H-benzimidazol-1-yl] methyl} phenyl) -5-methyl-1,3-oxazolidine-2,4-dione:
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.19 (d, 1H), 7.98 (d, 1H), 7.65 (d, 2H), 7.52 (d, 2H), 7.13 (d , 1H), 7.11 (s, 1H), 7.02 (d, 1H), 6.83 (s, 1H), 5.20 (s, 2H), 3.98 (s, 3H), 1 .99 (s, 3H).

(5S) -5- (4-{[3- (6-Methoxy-1,2-benzisoxazol-3-yl) -2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ] Methyl} benzyl) -5-methyl-1,3-oxazolidine-2,4-dione:
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.19 (d, 1H), 7.90 (d, 1H), 7.40 (d, 2H), 7.23 (d, 2H), 7.21 (m , 2H), 7.05 (s, 1H), 7.00 (d, 1H), 6.98 (d, 1H), 5.19 (dd, 2H), 3.98 (s, 3H), 3 .18 (dd, 2H), 1.64 (s, 3H).

(5R) -5- (3-{[3- (6-Methoxy-1,2-benzisoxazol-3-yl) -2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ] Methyl} phenyl) -5-methyl-1,3-oxazolidine-2,4-dione:
¹ H NMR (500 MHz, CDCl ₃ ) δ 8.18 (d, 1H), 7.92 (d, 1H), 7.71 (s, 1H), 7.56 (brs, 1H), 7.43 (brs) , 2H), 7.23 (m, 2H), 7.08 (s, 1H), 7.02 (m, 2H), 5.28 (dd, 2H), 3.98 (s, 3H), 1 .99 (s, 3H).

  Examples of other compounds of the present invention are shown in Table 1. These compounds were or can be made using the procedures disclosed herein.

Claims (19)

Formula I:

[Where:
R ¹ is —X-aryl-YZ, wherein said aryl is optionally substituted with 1 to 3 groups independently selected from A;
Aryl is phenyl or naphthyl;
X and Y are each independently selected from the group consisting of a bond and —CR ⁴ R ⁵ —;
Z is

And
Q is selected from the group consisting of S and O;
A is selected from the group consisting of C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, —OC ₁ -C ₄ alkyl, and halogen, wherein said alkyl, alkenyl, and —O alkyl are each optionally 1 to 1 Substituted with 5 halogens;
R ² is (a) benzisoxazolyl,
(B) aryl,
(C) - (CH ₂₎ aryl,
Selected from the group consisting of (d)-(C═O) aryl, and (e) benzothiazolyl,
R ² is optionally substituted with 1 to 3 substituents independently selected from halogen, C ₁ -C ₃ alkyl, and —OC ₁ -C ₃ alkyl, and said C ₁ -C ₃ alkyl and If -OC ₁ -C ₃ alkyl by being substituted with 1-5 halogens;
R ³ is selected from the group consisting of halogen, C ₁ -C ₃ alkyl, and —OC ₁ -C ₃ alkyl, wherein said C ₁ -C ₃ alkyl and —OC ₁ -C ₃ alkyl are optionally 1-5 Substituted with halogens;
R ⁴ and ^{R 5} are hydrogen, _halogen, each independently selected from C 1 -C ₃ alkyl, and the group consisting of _-OC 1 -C ₃ alkyl, wherein _C 1 -C ₃ alkyl and -OC ₁ - C ₃ alkyl is optionally substituted with 1 to 5 halogens;
R ⁶ is selected from the group consisting of H, C ₁ -C ₃ alkyl, and halogen, wherein said C ₁ -C ₃ alkyl is optionally substituted with 1 to 3 F;
p is an integer of 0 to 4, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein R ¹ is -X-phenyl-YZ. _2. A compound according to claim 1 wherein X and Y are each independently selected from a bond and -CH2-. Optionally substituted by halogen _{aryl, -CF 3, -OCF 3, -CH} 3, and claim 1 which are substituted with one to two groups independently selected from the group consisting of -OCH ₃ Compound. R ³ is selected from the group consisting of —CH ₃ , —OCH ₃ , —OCF ₃ , and —CF ₃ ;
R ⁶ is selected from H, CH ₃ , and CF ₃ ;
The compound according to claim 1, wherein p is 0 or 1. R ¹ is —X-phenyl-YZ, and said phenyl is optionally substituted with 1 to 2 groups independently selected from A;
X and Y are each independently selected from a bond and —CH ₂ —;
A is selected from the group consisting of halogen, —CF ₃ , —OCF ₃ , —CH ₃ , and —OCH ₃ ;
R ³ is selected from the group consisting of —CF ₃ , —OCF ₃ , —CH ₃ , and —OCH ₃ ;
R ⁶ is selected from the group consisting of H, —CH ₃ , and —CF ₃ ;
The compound according to claim 1, wherein p is 0 or 1. 7. R ³ is _3- benzisoxazolyl optionally substituted with 1 to 2 groups independently selected from halogen, —OCH ₃ , —OCF ₃ , CH ₃ , and CF _3. Compound described in 1. The compound according to claim 1, wherein Q is O, X is a bond, and Y is —CH ₂ —. The compound according to claim 1, wherein Q is O, X is —CH ₂ —, and Y is a bond. Q is O, X and Y are each -CH ₂ - The compound according to claim 1 in which.   The compound according to claim 1, wherein Q is O, and X and Y are each a bond.   The compound according to claim 1, wherein Q is S. The following structure:

The compound according to claim 1 having a structure selected from the group consisting of: or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.   Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of type 2 diabetes.   (1) Non-insulin dependent diabetes mellitus (NIDDM), (2) Hyperglycemia, (3) Low glucose tolerance, (4) Insulin resistance, (5) Obesity, (6) Lipid metabolism disorder, (7) Different Dyslipidemia, (8) hyperlipidemia, (9) hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDL level, (12) high LDL level, (13) atheromatous Arteriosclerosis and its sequelae, (14) vascular restenosis, (15) irritable bowel syndrome, (16) inflammatory bowel disease, (17) Crohn's disease, (18) ulcerative colitis, (19) abdominal obesity, (20) retinopathy, (21) psoriasis, (22) hypertension, (23) metabolic syndrome, (24) ovarian hyperandrogenemia (polycystic ovary syndrome), and other diseases, disorders with insulin resistance, Or selected from the group consisting of symptoms It said method comprising one or more diseases, a disorder, or condition of the treatment methods, the administration of a compound or a pharmaceutically acceptable salt thereof according to claim 1 of the effective amount.   A method for the treatment of non-insulin dependent (type 2) diabetes in a patient in need of treatment, comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. Including said method.   A method of treating diabetic dyslipidemia in a patient in need of treatment, comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. Method. (1) the compound according to claim 1 or a pharmaceutically acceptable salt thereof;
(2) (a) PPARγ agonist and partial agonist;
(B) biguanide;
(C) a protein tyrosine phosphatase-1B (PTP-1B) inhibitor;
(D) a dipeptidyl peptidase IV (DP-IV) inhibitor;
(E) insulin or insulin mimetics;
(F) sulfonylurea;
(G) an α-glucosidase inhibitor;
(H) (i) an HMG-CoA reductase inhibitor, (ii) a bile acid solubilizer, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) a niacin receptor agonist, (v) a PPARα agonist, (vi) A substance selected from the group consisting of :) a cholesterol absorption inhibitor; (vii) acyl CoA: cholesterol acyltransferase (ACAT) inhibitor; (viii) a CETP inhibitor; and a phenolic antioxidant;
(I) a PPARα / γ dual agonist;
(J) a PPARδ agonist;
(K) an anti-obesity compound;
(L) ileal bile acid transporter inhibitor;
(M) an anti-inflammatory drug;
(N) a glucagon receptor antagonist;
(O) GLP-1;
(P) GIP-1; and (q) one or more compounds selected from the group consisting of GLP-1 analogs;
(3) A pharmaceutical composition containing a pharmaceutically acceptable carrier.