JP2003523336A - Aryloxyacetic acid for diabetes and lipid disorders - Google Patents

Abstract

  (57) [Summary] Aryloxyacetic acids are potent agonists of PPARα and / or γ, and thus non-insulin dependent diabetes mellitus (NIDDM), hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia It is useful in the treatment, control or prophylaxis of atherosclerosis, atherosclerosis, obesity, vascular restenosis, inflammation and other PPARα and / or γ mediated diseases, disorders and conditions.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention is particularly useful as a therapeutic compound in the treatment of type 2 diabetes mellitus (often referred to as non-insulin dependent diabetes mellitus (NIDDM)), conditions often associated with the disease and lipid disorders. Aryloxyacetic acid, and pharmaceutically acceptable salts and prodrugs thereof.

BACKGROUND OF THE INVENTION Diabetes mellitus is a disease that is induced by multiple causes and is characterized by high plasma glucose levels after fasting or after glucose administration during an oral glucose tolerance test, ie, hyperglycemia. If hyperglycemia persists or is uncontrolled, morbidity and mortality are high. In many cases, abnormal glucose homeostasis alters the metabolism of lipids, lipoproteins and apolipoproteins, either directly or indirectly, and results in other metabolic and hemodynamic disorders. Therefore, patients with type 2 diabetes are at particularly high risk of developing major and microvascular complications including coronary heart disease, stroke, peripheral vascular disease, hypertension, renal damage, neuropathy and retinal damage. Therefore, therapeutic control of glucose homeostasis, lipid metabolism and hypertension is clinically important in the clinical management and treatment of diabetes.

It is generally accepted that there are two types of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little to no insulin, the hormone that regulates glucose utilization. In type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), patients often have serum insulin levels that are similar to or higher than those in non-diabetics. However, these patients are resistant to insulin-stimulating effects on glucose and lipid metabolism in the major insulin-sensitive tissues, muscle, liver and adipose tissue, with high plasma insulin levels but marked insulin resistance. Is not enough to solve.

Insulin resistance is primarily due to a decreased number of insulin receptors, but not fully elucidated, due to post-insulin receptor binding defects. When resistance to this insulin responsiveness occurs, insulin activation of glucose uptake, oxidation and storage in muscle becomes insufficient, and insulin suppression of lipolysis in adipose tissue and glucose production and secretion in liver becomes insufficient. .

Although current treatments for type 2 diabetes have remained virtually unchanged over the years,
It is acknowledged that there are limits. Although exercise and dietary caloric restriction dramatically improve diabetic status, compliance with this treatment is very poor. This is because an inactive lifestyle is established and foods, especially foods rich in saturated fat, are excessively consumed. Insulin by administering sulfonylureas (eg, tolbutamide and glipizide) that stimulate pancreatic β-cells to secrete more insulin and / or by injecting insulin after not responding to sulfonylureas Elevating plasma levels of insulin causes the insulin concentration to be high enough to stimulate hyperinsulin resistant tissues. However, the two treatments described above can result in very low plasma glucose levels and increased insulin resistance due to high plasma insulin levels. Biguanides increase insulin sensitivity and slightly improve hyperlipidemia. However, the two biguanides phenformin and metformin can induce lactic acidosis and nausea / diarrhea, respectively.

Glitazones (ie 5-benzylthiazolidine-2,4-dione) are:
It is a recently published compound with potential new modes of action in ameliorating many of the symptoms of type 2 diabetes. These compounds substantially increase insulin sensitivity of muscle, liver and adipose tissue in several animal models of type 2 diabetes, thus partially or completely improving high glucose plasma levels without the development of hypoglycemia. To be done.

[0007] For disorders of lipid metabolism, ie dyslipidemia, one or more lipids (ie cholesterol and triglycerides) and / or apolipoproteins (ie
Apolipoproteins A, B, C and E) and / or lipoproteins (ie lipids and apolipoproteins that circulate lipids in the blood (eg LDL, V
Included are various conditions characterized by abnormal concentrations of macromolecular complexes (LDL and IDL). Cholesterol is mainly contained in low density lipoprotein (LDL), and this component is commonly referred to as "bad" cholesterol, as elevated LDL-cholesterol has been found to be closely linked to the risk of coronary heart disease. Are known. A small component of cholesterol is contained in high density lipoproteins, commonly known as "good" cholesterol. In fact, it is known that the main function of HDL is to accept the cholesterol deposited in the arterial wall, return it to the liver, and destroy it via the intestine. It is desirable to reduce high LDL cholesterol levels, but it is also desirable to increase HDL cholesterol levels. Coronary heart disease (CHD) usually associated with elevated HDL levels
Is known to reduce the risk of. For example, Gordon et al., Am. J.
Med. 62: 707-714 (1977), Stampfer et al., N. et al. En
ground J.M. Med. , 325: 373-381 (1991) and Kann.
el et al., Ann. Internal. Med. , 90: 85-91 (1979).
Please refer to. One example of an HDL-elevating agent is nicotinic acid, whose use is limited because of the undesirable side effects such as flushing that occur at doses that raise HDL.

Dyslipidemia was originally classified by Fredrickson according to a combination of the above changes. The Fredrickson classification has six phenotypes (ie, I,
IIa, IIb, III, IV and V), the most common being isolated hypercholesterolemia (ie type IIa), usually with elevated levels of total cholesterol and LDL cholestenol. The initial treatment for hypercholesterolemia is often to change to a diet low in fat and cholesterol and to exercise appropriately, and then to perform drug treatment when the LDL lowering target is not achieved by diet and exercise alone. To do.

The second common form of dyslipidemia is mixed hyperlipidemia, or Fredric
Type IIb and Type III of kson classification. This dyslipidemia often affects patients with type 2 diabetes, obesity and metabolic syndrome. In this dyslipidemia, LDL
-Cholesterol is moderately high and dense LDL-small cholesterol particles, V
DL and / or IDL (ie triglyceride rich lipoproteins) and total triglycerides are significantly higher. In addition, HDL concentrations are often low.

Peroxisome proliferators are the ability of peroxisomes to metabolize fatty acids by increasing the expression of β-oxidation cycle enzymes as well as dramatically increasing the size and number of liver and kidney peroxisomes when administered to rodents. Are structurally distinct compounds that elicit an increase in This group of compounds includes, but is not limited to, lipid modulating drugs, herbicides and phthalate plasticizer fibrates. Peroxisome proliferation is caused by dietary or physiological factors such as high fat diet and cold climate adaptation.

Three subtypes of the peroxisome proliferator-activated receptor (PPAR) have been discovered and published. These are peroxisome proliferator-activated receptor α (PPA
Rα), peroxisome proliferator-activated receptor γ (PPARγ) and peroxisome proliferator-activated receptor δ (PPARδ). PP, a member of the nuclear hormone receptor superfamily, activated by peroxisome proliferators
Since ARα was identified, analysis of the mechanism by which the peroxisome proliferating agent exerts its pleiotropic effect was advanced. PPARα is activated by numerous medium and long chain fatty acids and is involved in stimulating β-oxidation of fatty acids. PPARα has also been implicated in the activity of fibrates and fatty acids in rodents and humans. Fibric acid derivatives (eg, clofibrate, fenofibrate, benzofibrate, ciprofibrate, beclofibrate and etofibrate) and gemfibrozil, which are PPARα ligands and / or activators, respectively, substantially reduce plasma triglycerides. And, in some cases, increase HDL. L
The effect on DL cholesterol is variable and is compound and / or dyslipidemic phenotype dependent. For this reason, compounds of this type are mainly associated with hypertriglyceridemia (
That is, it has been used to treat Fredrickson's classifications IV and V) and / or mixed hyperlipidemia.

The PPARγ receptor subtype is involved in activating the adipocyte differentiation program and not in stimulating peroxisome proliferation in the liver. PPARγ: PPA
Two protein isoforms, Rγ1 and PPARγ2, are known and P
PARγ2 differs only in that it contains an additional 28 amino acids located at the amino terminus. The human isotype DNA sequence is described in Elbrecht et al., BBRC, 2
24: 431-437 (1996). In mice, PPARγ
2 is specifically expressed in adipocytes. Tontonoz et al., Cell, 7
9: 1147-1156 (1994) demonstrate that one physiological role of PPARγ2 is to induce adipocyte differentiation. Like other members of the nuclear hormone receptor superfamily, PPARγ2 regulates gene expression through interactions with other proteins and binding to hormone response regions, such as in the 5'flanking region of response genes. To do. An example of a PPARγ2 responsive gene is the tissue-specific adipocyte p2 gene. Peroxisome proliferators including fibrates and fatty acids activate the transcriptional activity of PPARs, but prostaglandin J2
Only the derivative has high affinity and binds to thiazolidinedione antidiabetic agent P
The PARγ subtype has been identified as a potential natural ligand.

Human nuclear receptor gene PPARδ (hPPARδ) is a human osteosarcoma cell cDNA
Cloned from the library and Schmidt et al., Molecular
Endocrinology, 6: 1634-1641 (1992). PPARδ is also referred to in the literature as PPARβ and NUC1, both of which names refer to the same receptor and are referred to as NUC1 in Schmidt et al.

WO 96/01430 describes the human PPAR subtype hNUClB. The amino acid sequence of hNUC1B differs from human PPARδ (designated herein as hNUC1) by one amino acid, alanine at position 292. Based on the in vivo experiments described here, the inventors suggest that the hNUClB protein suppresses hPPARδ and thyroid hormone receptor protein activity.

WO 97/28149 describes that agonists of PPARδ are useful in increasing HDL plasma levels.
International Patent Application Publication Nos. 97/27857, 97/28115, 97/28137 and 97/27847.
The pamphlet discloses a compound which is useful as an antidiabetic, antiobesity, antiatherosclerotic and antihyperlipidemic agent and can exert its effect through the activation of PPAR.

Normally, glitazones are receptors that control certain transcriptional elements associated with the biological moieties shown above, the peroxisome proliferator-activated receptor (PPAR).
) It is thought that the effect is exerted by binding to the family.
Hulin et al., Current Pharm. Design, 2: 85-102
(1996).

A number of glitazones, which are PPAR agonists, are approved for the treatment of diabetes. These include troglitazone, rosiglitazone and pioglitazone, all of which are predominantly or exclusively PPARγ agonists. Many of the new PPAR agonists currently in development or in clinical stage are 2
It has heavy PPARα and γ activity. They are expected to improve insulin sensitivity and lipid profile in NIDDM patients.

Although glitazones are effective in treating NIDDM, the use of the compounds has caused some serious side effects. The most serious side effect is hepatotoxicity, which is responsible for many deaths. The most serious problem arose when using troglitazone. Because of the problems that occur when using glitazones, many laboratory researchers are investigating PPAR agonists that do not contain the 1,3-thiazolidinedione moiety, rather than glitazones.

Compounds that are agonists of the PPAR subtype, but not glitazone, are expected to be useful in the treatment of diabetes and related conditions. PPARα agonists must improve the lipid profile and restore dyslipidemia by lowering high LDL and high triglyceride levels and / or by raising HDL levels. PPARγ agonists should improve insulin sensitivity and reduce insulin injections in NIDDM patients. P
The role of PARδ is poorly understood.

SUMMARY OF THE INVENTION The compounds described herein are novel PPAR agonists that do not contain a 1,3-thiazolidinedione moiety and are therefore not glitazones. This class of compounds includes compounds that are primarily PPARα agonists and compounds that are mixed PPARα / γ agonists. These compounds are applicable to diabetes, hyperlipidemia, mixed or diabetic dyslipidemia, and (isolated hypercholesterolemia with elevated LDL-C and / or non-HDL-C and / or hyperapoB lipoproteinemia. Other lipid disorders, including proteinemia, hypertriglyceridemia and / or increased triglyceride-rich lipoprotein or low HDL cholesterol levels, atherosclerosis, obesity,
It is useful in treating, controlling and / or preventing vascular restenosis, inflammatory conditions, hyperproliferative conditions and other PPARα and / or γ mediated diseases, disorders and conditions.

The present invention provides compounds having the structure of formula I, including pharmaceutically acceptable salts and prodrugs.

[0022]

[Chemical 4]

[0023]   In compounds having formula I:   R¹And R^TwoAre independently H, F, C_1-5Alkyl, C_2-5Arche
Nil and C_2-5Selected from the group consisting of alkynyl, said alkyl, alkenyl
R and alkynyl may be straight or branched and optionally 1 to 3 halo.
Optionally substituted with a gen atom, or R¹And R^TwoTogether C_3-6 May form a cycloalkyl;   R^ThreeAnd R^FourAre each independently C_1-5Alkyl, C_2-5Alkenyl, C _2-5 Alkynyl and chlorine (however, R^ThreeAnd R^FourBoth are not chlorine)
Wherein the alkyl, alkenyl and alkynyl are straight chain or
It may be branched and optionally substituted with 1 to 5 fluorine atoms;   X is N or CR;   Y is O, S or NR;   Z is O or S;   Each R is H, C_1-5Alkyl, C_2-5Alkenyl and C_2-5Alkynyl?
And the alkyl, alkenyl and alkynyl are straight chain or
May be branched, optionally 1 to 5 fluorine atoms and / or 1 -O.
C_1-3It may be substituted with alkyl, and the aforementioned -OC_1-3Alkyl is sometimes
More optionally substituted with 1 to 7 fluorine atoms;   R⁵Is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C _6-10 Aryl, -OC_1-6Alkyl, -OC_2-6Alkenyl, -OC_{Two -6} Alkynyl, -OC_6-10Aryl, C_3-6Cycloalkyl, 5-6 member
Heterocyclyl, 5- or 6-membered heteroaryl, -OC_3-6Cycloalkyl, -O
5- or 6-membered heterocyclyl, -O 5- or 6-membered heteroaryl, and in the middle of the chain or in the chain
C at the end of_6-10Aryl, C_3-6Cycloalkyl, 5-6 membered heterocyclyl
And a C containing group selected from 5- and 6-membered heteroaryl_1-4From alkyl
Selected from the group consisting of alkyl, alkenyl, alkynyl, -Oalkyl,-
Each of O alkenyl and -O alkynyl may be linear or branched, where
1 to 5 fluorine atoms and / or 1 -OCH_ThreeOr -OCF_ThreeBasis
Optionally substituted with the above-mentioned aryl, cycloalkyl, heteroaryl,
Telocyclyl, -Oaryl, -Ocycloalkyl, -Oheteroaryl and-
Each O heterocyclyl optionally comprises 1 to 7 halogen atoms and / or 1
-OCH_ThreeOr -OCF_ThreeIt may be substituted with a group.

The compounds of the present invention are effective in lowering glucose, lipids and insulin in diabetic animals. The compound of the present invention is used for the treatment, control and / or prevention of non-insulin dependent diabetes mellitus (NIDDM) in human, and hyperlipidemia, dyslipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, atherogenicity. Atherosclerosis, restenosis, inflammatory conditions, hyperproliferative conditions and other PPARα
And / or is expected to be effective in treating, controlling and / or preventing conditions associated with NIDDM, including γ-mediated diseases, disorders and conditions.

DETAILED DESCRIPTION OF THE INVENTION The present invention has numerous embodiments. Some subgroups of compounds having different heterocyclic rings include: compounds of formula I where X is N and Y is O; compounds of formula I where X is N and Y is S A compound having the formula I in which X is N and Y is NR; a compound having the formula I in which X is CR and Y is O; a compound having the formula I in which X is CR and Y is S A compound having the formula I, wherein X is CR and Y is NR.

[0026]   In another subgroup of compounds having formula I above, various heterocycles are fused to an aromatic ring.
R in a compound having formula I (i.e., X and Y are different)⁵Is H, C_1-5 Alkyl, C_2-5Alkenyl, C_2-5Alkynyl, -OC_1-5Alkyl,
-OC_2-5Alkenyl, -OC_2-5From the group consisting of alkynyl and phenyl
Included are selected compounds. In these compounds, alkyl, alkenyl
, Alkynyl, -Oalkyl, -Oalkenyl and -Oalkynyl are optionally
It may be substituted with 1 to 5 fluorine atoms, and phenyl is 1 to 5 in some cases.
It may be substituted with a halogen atom. In a preferred subgroup, R⁵Is H, C _1-5 Alkyl, C_2-5Alkenyl, C_2-5Alkynyl, -OC_1-5Al
Kill, -OC_2-5Alkenyl and -OC_2-5Selected from the group consisting of alkynyl
And the alkyl, alkenyl, alkynyl, -Oalkyl, -Oalkenyl.
And -O alkynyl may be optionally substituted with 1 to 5 fluorine atoms.
.

In preferred compounds, R ¹ and R ² are each H or C _1-3 alkyl, and the total number of carbon atoms in R ¹ and R ² is 0-5.

In a preferred embodiment, R ³ and R ⁴ are each independently C _1-5 alkyl. In another preferred embodiment, one of R ³ and R ⁴ is C _2-5 alkyl and the other is C _1-5 alkyl. In another preferred embodiment,
Both R ³ and R ⁴ are C _2-5 alkyl. In other preferred compounds, one of R ³ and R ⁴ is Cl or C _1-5 alkyl and the other is C _2-5 alkyl. Generally, the alkyl group is straight or branched. In the most preferred compounds R ³ and R ⁴ are linear when alkyl.

In a preferred compound, R ⁵ is selected from the group consisting of C _1-5 alkyl and —OC _1-5 alkyl, said alkyl and —O alkyl optionally substituted with 1 to 5 fluorine atoms. Good.

[0030]   In a preferred embodiment Z is O.

In a preferred embodiment, X is N and Y is O, so the compound is benzisoxazole.

In a highly preferred embodiment of the above group of compounds R ⁵ is C _1-3 alkyl, —OC _1-3 alkyl, CF ₃ , C ₂ F ₅ , —OCF ₃ or —OC ₂ F ₅ . , R ³ and R ⁴ are each n-propyl.

[0033]   Specific examples of the compound of the present invention are shown in Examples 1 to 29.

The present invention further includes pharmaceutical compositions comprising the above compounds and a pharmaceutically acceptable carrier.

The compounds described above are useful in methods of treating, controlling and preventing the diseases listed below or other diseases not listed. (1) A method of treating, controlling or preventing diabetes, especially non-insulin dependent diabetes mellitus in a mammal patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula I to said patient; A method of treating, controlling or preventing hyperglycemia in a patient in need thereof, comprising administering to said mammal patient a therapeutically effective amount of a compound of formula I; A method of treating, controlling or preventing lipid disorders, hyperlipidemia or low HDL in said patient, comprising administering an effective amount of a compound of formula I; (4) A therapeutically effective amount for a mammalian patient in need thereof. A method for treating, controlling or preventing obesity in a patient, comprising: administering a compound having the formula I: (5) Mammalian patient in need thereof A method of treating, controlling or preventing hypercholesterolemia in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula I; (6) A therapeutically effective amount of a formula for a mammalian patient in need thereof. A method of treating, controlling or preventing hypertriglyceridemia in a patient comprising administering a compound having formula I; (7) administering a therapeutically effective amount of a compound of formula I to a mammalian patient in need thereof. A method of treating, controlling or preventing dyslipidemia including low HDL cholesterol in said patient, comprising: (8) administering a therapeutically effective amount of a compound of formula I to a mammalian patient in need thereof. A method for treating, controlling or preventing atherosclerosis in said patient. Thus, it is understood that the sequelae of atherosclerosis (angina, claudication, heart attack, stroke, etc.) are treated.

[0036]   Definition   "Ac" is CH_ThreeC (O) -acetyl.

“Alkyl” and the English prefix “alk” such as alkoxy or alkanoyl
Other groups having a mean carbon chains which are linear or branched or combinations thereof unless the carbon chain is defined otherwise. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

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

“Alkynyl” means carbon chains which are linear or branched or combinations thereof, containing at least one carbon-carbon triple bond. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means a mono- or bicyclic saturated carbocycle having 3 to 10 carbon atoms. The term also includes a monocyclic ring fused to an aryl group at a non-aromatic moiety. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

“Aryl” (and “arylene”) means a mono- or bicyclic aromatic ring in which the ring members are exclusively carbon atoms. The term also includes one in which an aryl group is fused at the aromatic moiety to a monocyclic cycloalkyl or monocyclic heterocyclic group. The preferred aryl is phenyl. "Heterocycle" and "heterocyclic" are fully or partially saturated monocycles containing at least one heteroatom selected from N, S and O, each ring having 3 to 10 atoms. Means a formula, bicyclic or tricyclic ring. Examples of aryl include phenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl. Examples of aryl fused to a heterocyclic group include 2,3-dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl and the like. Examples of heterocycles include tetrahydrofuran, piperazine and morpholine.

“Heteroaryl” (and heteroarylene) means N, O and S (SO and S
O ₂ contains at least one ring heteroatom selected from the containing), each ring 5
Means a monocyclic, bicyclic or tricyclic aromatic ring having from 6 atoms. Examples of heteroaryl are pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,
Imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), furo ( 2,3-b) Pyridyl, quinolyl, indolyl, isoquinolyl, dibenzofuran and the like are included.

[0043]   "Halogen" includes fluorine, chlorine, bromine and iodine.

The term “composition” as a pharmaceutical composition refers to a product consisting of an active ingredient and an inactive ingredient which constitutes a carrier, a mixture, a complex or an agglomeration of two or more ingredients, a dissociation of one or more ingredients or It is understood to include products that result directly or indirectly from other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present invention includes a composition prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier.

[0045]   Optical isomer-Diastereomer-Geometric isomer-Tautomer   The compounds of formula I may contain one or more asymmetric centers and are thus racemic, racemic
Mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers.
O may exist as isomers. The present invention is directed to all isomeric forms of the compounds of formula I
Including state.

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

Some of the compounds described herein may exist with different points of attachment of hydrogen called tautomers. An example thereof may be a ketone and its enol form referred to as keto-enol tautomers. Each tautomer and mixtures thereof are also included in compounds having Formula I.

The compounds of formula I may be separated into enantiomeric diastereoisomeric pairs, for example by fractional crystallization from a suitable solvent such as methanol, ethyl acetate or mixtures thereof. The enantiomeric pairs thus obtained may be separated into individual stereoisomers by conventional means, for example using an optically active acid or base as a resolving agent.

Alternatively, enantiomers of compounds having general formula I or Ia can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

[0050]   salt   The term "pharmaceutically acceptable salt" refers to inorganic or organic bases and inorganic or organic bases.
Salts prepared from pharmaceutically acceptable non-toxic bases or acids, including organic acids.
You Salts derived from inorganic bases include aluminum, ammonium, calcium
, Copper, ferrous iron, ferric iron, lithium, magnesium, ferrous manganese, ferric manganese
, Potassium, sodium, zinc salts and the like. Ammonium, calcium, mac
Gnesium, potassium and sodium salts are particularly preferred. No more than one salt in solid form
It may exist in the crystal structure above and may also exist in the form of a hydrate. Pharmaceutically acceptable
Salts derived from organic non-toxic bases include primary, secondary or tertiary amines,
Substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ions
Exchange resins (eg arginine, betaine, caffeine, choline, N, N'-di)
Benzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-E
Tylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidi
, Hydrabamin, isopropylamine, lysine, methylglucamine, morpholi
, Piperazine, piperidine, polyamine resin, procaine, purine, theobro
Min, triethylamine, trimethylamine, tripropylamine, tromethamine
Etc.) are included.

When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. The acid includes acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid,
Gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucus acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid , P-toluenesulfonic acid and the like. Particularly preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid.

It is to be understood that any reference herein to compounds having Formula I includes pharmaceutically acceptable salts thereof.

[0053]   Metabolite-Prodrug   Metabolites of therapeutically active compounds of the invention are also included in the scope of the compounds of the invention. patient
A compound that is converted to a compound of the present invention when administered to or after administration to a patient
Prodrugs are also included within the scope of active compounds of this invention. Of the carboxylic acid of the present invention
Prodrugs include esters of carboxylic acid groups, which may be linear or branched.
Le (eg C_1-6Ester) or a substance that can be easily hydrolyzed after administration to a patient
Non-limiting examples of the ester having a functional group.

[0054]   Prodrugs of this class of compounds are of formula Ia:

[0055]

[Chemical 5] Wherein R ⁶ is readily administered to a mammalian patient under physiological conditions during or after administration to produce a compound of formula I, or a carboxylate anion thereof (in solution) or a pharmaceutically acceptable salt thereof. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Y, Z and R are as described above for the compound of formula I).
Can be represented as a compound having

[0056]   Examples of prodrugs having formula Ia include R⁶Is -OR⁷, -OCH_TwoOR⁷,
-OCH (CH_Three) OR⁷, -OCH_TwoOC (O) R⁷, -OCH (CH_Three) O
C (O) R⁷, -OCH_TwoOC (O) OR⁷, -OCH (CH_Three) OC (O) O
R⁷, -NR⁸R⁸And -ONR⁸R⁸Each R selected from the group consisting of⁷Is independent
Then-CO_TwoH, -CONH_Two, -NH_Two, -OH, -OAc, NHAc and F
C optionally substituted with one or two groups selected from the group consisting of phenyl _1-6 Each R selected from alkyl⁸Independently H and R⁷A compound selected from
Things are included. Formula Ia (wherein R⁶Has the chemical structure described above)
Things are also represented as prodrugs. However, a compound or salt having formula I
Another drug that exhibits medicinal activity, whether active as a prodrug that produces
Compounds of formula Ia, whether or not they have steps, are included in the invention. Live
Regardless of the mechanism that causes sex, the compounds are included in the present invention.

All discussions regarding usefulness, pharmaceutical compositions, combination therapies, administrations, doses, etc. have been made with respect to compounds of Formula I. Descriptions of utility, etc. also apply to compounds having formula Ia.

[0058]   Usefulness   The compounds of the present invention are useful for various peroxisome proliferator-activated receptor subtypes,
And is a potent agonist of PPARα and / or PPARγ. Compound of the present invention
Is a selective agonist of one receptor subtype (eg, PPARγ or P
PARα agonist) or of two or more receptor subtypes of Agonis
(Eg dual PPARα / γ agonists). The compound of the present invention is a disease
, Is useful in treating, controlling or preventing a disorder or condition, and
Treatment is for each PPAR subtype (α or γ) or combination of PPAR subtypes (
For example, mediated by activation of α / γ). Accordingly, one aspect of the present invention is
Treatment, control or prevention of the above mentioned diseases, disorders or conditions in dairy animals
A method is provided that comprises a therapeutically effective amount of a compound of formula I for said mammal.
Administering the thing. The compound of the present invention has a therapeutic, control or preventive odor.
Useful diseases, disorders or conditions include (1) diabetes, especially non-insulin dependent sugars.
Urine disease (NIDDM), (2) hyperlipidemia, (3) impaired glucose tolerance, (4) insulin resistance
Anti-resistance, (5) obesity, (6) lipid disorder, (7) dyslipidemia, (8) hyperlipidemia, (9
) Hypertriglyceridemia, (10) Hypercholesterolemia, (11) Low HDL level
Bell, (12) high LDL levels, (13) atherosclerosis and its aftereffects
Disease, (14) vascular restenosis, (15) irritable bowel syndrome, (16) Crohn's disease and ulcer
Inflammatory bowel diseases including ulcerative colitis, (17) other inflammatory conditions, (18) pancreatitis, (1
9) Abdominal obesity, (20) Neurodegenerative disease, (21) Retinal disorder, (22) Abnormal growth
Conditions, (23) adipocyte tumors, (24) adipocyte carcinomas such as liposarcoma, (25)
Other cancers including prostate and gastric cancer, breast cancer, bladder cancer and colon cancer, (26) angiogenesis
, (27) Alzheimer's disease, (28) psoriasis, (29) hypertension, (30) syndrome
X, (31) Hyperovarian hyperandrogenism (polycystic ovary syndrome), and insulin
Other disorders include, but are not limited to, phosphorus resistance.

Another aspect of the invention is hypercholesterolemia, atherosclerosis, low HD
Provided is a method for treating, controlling or preventing L level, high LDL level, hyperlipidemia, hypertriglyceridemia and / or dyslipidemia, which method provides a therapeutically effective amount for a mammal in need thereof. Administering a PPARα and / or PPARγ agonist or a PPARα / γ dual agonist. The PPAR agonist may be used alone and is advantageously a cholesterol biosynthesis inhibitor, in particular an HMG-C such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin or ZD-4522.
It can be administered with an oA reductase inhibitor. PPAR agonists are advantageously other lipid lowering substances such as cholesterol absorption inhibitors (eg stanol esters,
Sterol glycosides such as chiqueside, azetidinones such as ezetimibe)
, ACAT inhibitors (eg Abashimibe), niacin, bile acid sequestrants, microsomal triglyceride transport inhibitors and bile acid reuptake inhibitors. The above-mentioned combination treatment includes hypercholesterolemia, atherosclerosis, hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL and low HDL.
It may also be effective for the treatment, control or prevention of one or more related symptoms selected from the group consisting of:

Another aspect of the present invention provides a method for treating inflammatory conditions including inflammatory bowel disease, Crohn's disease and ulcerative colitis, which comprises administering an effective amount of a PPAR agonist. Can be a PPARα agonist, a PPARγ agonist or a PPARα / γ dual agonist. Other inflammatory diseases treatable with the present invention include gout, rheumatoid arthritis, osteoarthritis, multiple sclerosis, asthma, ARDS,
Includes psoriasis, vasculitis, ischemia / reperfusion injury, frostbite and related disorders.

[0061]   Administration and dose range   To administer an effective amount of the compound of the present invention to mammals (especially humans) is optional.
Any suitable route of administration may be used. For example, oral, rectal, topical, parenteral, ocular
, Lung, nasal route, etc. may be used. Dosage forms include tablets, troches, dispersions, suspensions
, Solutions, capsules, creams, ointments, aerosols and the like. Preferred
In other words, the compound having formula I is administered orally.

The effective amount of the active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated and the severity of the condition being treated. The dose can be easily determined by those skilled in the art.

When treating or preventing diabetes and / or hyperlipidemia or hypertriglyceridemia or other diseases to which the compound of formula I is indicated, the compound of the present invention is added in an amount of about 0.1 mg / kg of animal body weight or less. Satisfactory results are usually obtained when administered at a daily dose of about 100 mg. The above-mentioned daily dose may be preferably administered once a day or divided into 2 to 6 times a day, or may be administered in a sustained release form. For many large mammals, the total daily dose will be from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. For a 70 kg adult, the total daily dose is usually about 7.
mg to about 350 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.

[0064]   Pharmaceutical composition   Another aspect of the invention comprises a compound having Formula I and a pharmaceutically acceptable carrier
A pharmaceutical composition is provided. The pharmaceutical composition of the present invention comprises a compound having formula I as an active ingredient.
Or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable
It includes a possible carrier and optionally other therapeutic ingredients. The term "may be pharmaceutically acceptable
Are salts that are pharmaceutically acceptable, including inorganic bases or acids and organic bases or acids.
It refers to the salts formed from possible non-toxic bases or acids.

The compositions include compositions suitable for oral, rectal, topical, parenteral (eg subcutaneous, intramuscular and intravenous), ocular, pulmonary (nasal or buccal inhalation), nasal administration. However, the most suitable route of administration in each case depends on the type and severity of the condition to be treated and the type of active ingredient. The compositions are conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

In practical use, the compounds of Formula I can be used as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take various forms depending on the preparation suitable for administration (eg, oral or parenteral including intravenous). When preparing a composition for oral administration, in the case of suspensions, oral liquid preparations such as elixirs and solutions, water, glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc. Starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrators in the case of oral solid preparations such as various pharmaceutical media, powders, hard capsules, soft capsules and tablets Carriers such as agents may be used. A solid oral preparation is preferred to a liquid preparation.

In terms of ease of administration, tablets and capsules represent the most advantageous oral dosage forms, of which solid pharmaceutical carriers are of course used. If desired, tablets may be coated by standard aqueous or non-aqueous methods. At least 0.1% of the composition and formulation
It contains the active ingredients of. The amount of active ingredient in the composition can of course be varied and can advantageously range from about 2% to about 60% by weight of the unit. The amount of active compound in therapeutically useful compositions is such that an effective dosage will be obtained. The active ingredient may be administered intranasally as, for example, liquid drops or spray.

Tablets, pills, capsules and the like include binders (eg tragacanth gum, gum acacia, corn starch or gelatin), excipients (eg dicalcium phosphate), disintegrants (eg corn starch, potato starch, alginic acid). ), Lubricants such as magnesium stearate and sweeteners such as sucrose, lactose or saccharin. When the unit dosage form is a capsule, it can contain, in addition to the substances mentioned above, a liquid carrier such as fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac and / or sugar or both. Syrups or elixirs are in addition to the active ingredient,
Sucrose as a sweetener, methylparaben and propylparaben as preservatives,
Dyestuffs and flavoring agents may be included, such as cherry or orange flavors.

The compounds of formula I can also be administered parenterally. Solutions or suspensions containing the active ingredients may suitably be prepared in water mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can be prepared in said mixture in glycerol, liquid polyethylene glycol and oil. Under normal storage and use conditions,
The formulation contains a preservative to prevent the growth of microorganisms.

Pharmaceutical formulations adapted for injection include sterile aqueous solutions or dispersions as well as sterile powders for the extemporaneous preparation of sterile injectable solutions or suspensions. In all cases, the formulation must be sterile and must be fluid to the extent that easy syringability exists.
The formulation 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 and includes, for example, water, ethanol, polyols (eg glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

[0072]   Combination treatment   The compounds of formula I are for the treatment of the diseases or conditions for which compounds of formula I are useful.
Used in combination with other drugs that may also be useful in treatment, prevention, improvement or recovery.
Can be used. The other drugs mentioned above are the routes and routes commonly used for these drugs.
The compound of formula I may be administered simultaneously or sequentially in a dose. Compounds having formula I
When used with one or more other drugs, the other drugs and Formula I
A unit dosage form pharmaceutical composition containing a compound is preferred. However, combination treatment
Includes a compound having Formula I and one or more other drugs on different overlapping schedules.
Treatment given is also included. When used in combination with one or more other active ingredients
Light compounds and other active ingredients used at lower doses than when used alone
Can be done. Therefore, in the pharmaceutical composition of the present invention, one compound in addition to the compound of formula I
Those containing the above-mentioned other active ingredients are included.

Examples of other active ingredients which may be administered in combination with a compound of formula I and which may be administered separately or in the same pharmaceutical composition include: (a) (i) glitazones (eg troglitazone, pioglitazone, Englitazone, MCC-555, rosiglitazone, etc.) and International Patent Application Publication No. 97/2785
No. 7 pamphlet, No. 97/28115 pamphlet, No. 97/2813
Nos. 7 and 97/27847, PPARγ agonists such as compounds, (ii) biguanides such as metformin and phenformin, (iii) protein tyrosine phosphatase-1B (PTP-
1B) Insulin sensitizers including inhibitors and (iv) dipeptidyl peptidase IV (DP-IV) inhibitors, (b) insulin or insulin mimetics, (c) sulfonylureas or related substances such as tolbutamide or glipizide (D) α-glucosidase inhibitors such as acarbose, (e) (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins. ), (Ii) sequestering agents (dialkylaminoalkyl derivatives of cholestyramine, cholestipol and cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or its salts, (iv) fenofibric acid derivatives (gemfibrozil, cloffi). Brate, fenofibrate and benzafibrate), PPARα agonists, (v) KRP-
PPARα / γ dual agonists such as 297, (vi) cholesterol absorption inhibitors such as β-sitosterol, (vii) acyl CoA: cholesterol acyltransferase inhibitors such as avasimibe, and (viii) antioxidants such as probucol Cholesterol-lowering substances such as agents, (f) PPARδ agonists as described in WO 97/28149, (g) Fenfluramine, Dexafenfluramine, Fentyramine, Surbitramine, Orlistat, Antiobesity agents such as neuropeptide Y5 inhibitors and β3 adrenergic receptor agonists, (h) ileal bile acid transporter inhibitors, and (i) agents used during inflammatory conditions, eg aspirin, nonsteroidal Anti-inflammatory agent, Glucocor Includes, but is not limited to, ticoids, azulfidine and cyclooxygenase-2 selective inhibitors.

The above formulations include a combination of a compound of this invention and one or more other active compounds. Without limitation, the compounds of formula I and biguanides, sulfonylureas, HMG-
CoA reductase inhibitor, other PPAR agonist, PTP-1B inhibitor, D
Exemplified are combinations of two or more compounds selected from P-IV inhibitors and antiobesity compounds.

[0075]   Biological assay   A) PPAR binding assay   In order to produce recombinant human PPARγ, PPARδ and PPARα, human
PPARγ_Two, Human PPARδ and human PPARα in E. coli
It was expressed as a combined protein. PPARγ_TwoFull length human cDNA of pGEX
-2T expression vector (Pharmacia) was subcloned. PPARδ
And the full-length human cDNAs for PPARα are the pGEX-KT expression vector (Phar
subcloned into M. Proliferate and induce E. coli containing each plasmid
And collected by centrifugation. Break the resuspended pellet with a French press and
The debris was removed by centrifugation at 12,000 xg. Recombinant human PPAR receptor
Purified by affinity chromatography using lutathion sepharose
did. After applying to the column and washing once, the receptor was eluted with glutathione. Receptor
10% glycerol was added to stabilize the aliquot and the aliquot kept at -80 ° C.
Existed. For binding to PPARγ, an aliquot of the receptor was added to Berge
r et al. (“Novel Peroxisome Proliferator-Activated Receptor (PPARγ) and PPA
Rδ ligands produce different biological effects (Novel peroxisome proliferator-a
ctivated receptor (PPARγ) and PPARδ ligands produce distinct biologica
effects), J. Biol. Chem. , 274: 6718-6725 (19
99)) with 0.1% non-fat dry milk and 10 nM
[^ThreeH_Two] AD5075, (21 Ci / mmol), ± T containing test compound
EGM (10 mM Tris (pH 7.2), 1 mM EDTA, 10% glyceride
Roll, 7 μl / 100 ml β-mercaptoethanol, 10 mM molybde
Acid sodium, 1 mM dithiothreitol, 5 μg / ml aprotinin, 2 μg
/ Ml leupeptin, 2 μg / ml benzamidine and 0.5 mM PMS
Incubated in F). Assay in a final volume of 150 μl at 4 ° C
Incubated for about 16 hours. Unbound ligand on ice in 100 μl dextra
And removed by incubation with charcoal / gelatin coated charcoal for about 10 minutes. 4 ° C
After centrifuging at 3000 rpm for 10 minutes in 50 ml of supernatant fraction,
Counted at opcount.

For binding to PPARδ, an aliquot of the receptor was added to Berger et al.
"A novel peroxisome proliferator-activated receptor (PPARγ) and PPARδ ligand produce different biological effects (Novel peroxisome proliferator-activat
ed receptor (PPARγ) and PPARδ ligands produce distinct biological effe
cts) ", J. Biol. Chem. , 274: 6718-6725 (1999).
) Containing 0.1% non-fat dry milk and 2.5 nM [ ³ H ₂ ] compound A, (17 Ci / mmol), ± test compound containing 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) was incubated. The compound A is 3-chloro-4- (3- (7-propyl-3-trifluoromethyl-6-benzo- [4] described in Example 20 of WO 97/28137 pamphlet. , 5] -isoxazoloxy) propylthio) phenylacetic acid. The assay was incubated at 4 ° C. in a final volume of 150 μl for approximately 16 hours. Unbound ligand was removed by incubation with 100 μl dextran / gelatin coated charcoal on ice for about 10 minutes. After centrifugation at 3000 rpm for 10 minutes at 4 ° C, the supernatant fraction 50
μl was counted on the Topcount.

For binding to PPARα, an aliquot of the receptor was added with 0.1% nonfat dry milk and 5.0 nM [ ³ H ₂ ] Compound B, (34 Ci / mmol), ±.
TEGM containing test compound (10 mM Tris (pH 7.2), 1 mM E)
Incubated in DTA, 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). Compound B is described in Example 62 of International Patent Application Publication No. 97/28137 pamphlet (3
-(4- (3-phenyl-7-propyl-6-benzo- [4,5] -isoxazoleoxy) butyloxy) phenylacetic acid. Assay 1 at 4 ° C
Incubated in a final volume of 50 μl for about 16 hours. Unbound ligand on ice 1
It was removed by incubating with 00 μl of dextran / gelatin coated charcoal for about 10 minutes. After centrifugation at 3000 rpm for 10 minutes at 4 ° C., 50 μl of the supernatant fraction was counted on a Topcount.

B) Gal-4 hPPAR transactivation assay By inserting the yeast GAL4 transcription factor DBD adjacent to the ligand binding domain (LBD) of hPPARγ, hPPARδ and hPPARα, respectively, the chimeric receptor expression construct pcDNA3-hPPARγ / GAL4. , PcDNA3-
hPPARδ / GAL4 and pcDNA3-hPPARα / GAL4 were constructed.
The reporter construct pUAS (5X) -tk-luc was created by inserting 5 copies of the GAL4 responsive element upstream of the hepatitis virus minimal thymidine kinase promoter and luciferase reporter gene. pCMV-lacZ contains the galactosidase Z gene under the control of the cytomegalovirus promoter. COS-1 cells were treated with 10% charcoal in a 96-well cell culture plate at 37 ° C. in a humidified atmosphere of 10% CO ₂ (Gemini Bio-Products, Calabasas, Calif.), Non-essential amino acids, 100. High glucose Dulbecco's modified Eagle medium (DMEM) containing units / ml penicillin G and 100 mg / ml streptomycin sulfate.
Were seeded at 12 × 10 ³ cells / well. 24 hours later, Lipofectami
The cells were transfected with ne (GIBCO BRL, Gaithersburg, MD) according to the manufacturer's instructions. Briefly, the transfection mix per well was 0.48 μl of Lipofectami.
ne, 0.00075 μg pcDNA3-PPAR / GAL4 expression vector,
0.045 μg of pUAS (5X) -tk-luc reporter vector and 0.
PCMV as an internal control for transfection efficiency of 0002 μg
-Included lacZ. The cells were incubated for 5 hours in the transfection mixture at 37 ° C. under an atmosphere of 10% CO ₂ . The cells were then treated with 5% charcoal fetal bovine activity, nonessential amino acids, 100 units / ml penicillin G.
And incubated in fresh high glucose DMEM containing 100 mg / ml streptomycin sulfate ± increasing concentration of test compound for approximately 48 hours. Compounds were solubilized in DMSO, so control cells were incubated with an equal concentration of DMSO. The final DMSO concentration was below 0.1%, which was found not to affect transactivating activity. Report cell lysate by Reporter Lysis
Made using Buffer (Promega, Madison, Wis.) According to the manufacturer's instructions. Luciferase activity in cell extracts was determined by Lucif
erase Assay Buffer (P, located in Madison, Wisconsin
ML3000 luminometer (Dynatech Laboratories, Chantilly, VA). β-
Galactidase activity was measured using β-D-galactopyranoside (Calbiochem, San Diego, Calif.).

C) In vivo study Male db / db mice (10-11 week old C57B1 / KFJ, Jackson Labs, Bar Harbor, ME) were housed in 5 cages and ground Purin.
a. Diet for rodents and water were made available freely. Animals and diets were weighed every 2 days and vehicle (0.5% carboxymethylcellulose) ± designated dose of test compound was administered daily through a gastric tube. The drug suspension was prepared daily. During the test period 3
Plasma glucose and triglyceride concentrations were measured from blood collected from the tail at ~ 5 day intervals. Glucose and triglyceride measurements were 1: 6 (v / v
) Boehringer Mannheim using diluted heparinized plasma
Performed on a Hitachi 911 automated analyzer (Boehringer Mannheim, Indianapolis, IN). Lean animals were heterozygous mice of the same age that were maintained as well.

EXAMPLES The following examples, including the method for preparing the compounds of the present invention, are merely illustrative of the present invention and are not to be construed as limiting the present invention in any way.

Intermediate 1

[0082]

[Chemical 6]

Step 1: Preparation of 1,3-diallyloxybenzene

[0084]

[Chemical 7]

K ₂ CO ₃ (4,463 g) was added to a solution of resorcinol (1,200 g, 10.9 mmol) in DMF (10.89 L). Allyl bromide (3,8
11 ml) was added slowly maintaining the temperature below 30 ° C. The reaction mixture was stirred overnight at ambient temperature, poured into water (94L), and extracted with _{Et 2 O (3 × 20L)} . The combined organic layers were washed with water (3 x 15 L) and brine (10 L), Mg
Dried SO _4, filtered through _Na 2 SO _4, and evaporated in vacuo. The residue was dried under high vacuum to give the crude product as a red-yellow oil. This was used in the next step without further purification.

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.5 (d, 4H), 5.2
7 (m, 2H), 5.42 (m, 2H), 6.05 (m, 2H), 6.5 (m,
3H), 7.16 (m, 1H).

Step 2: Preparation of 2,4-diallyl resorcinol

[0088]

[Chemical 8]

[0089]   22L capacity 4-neck flask equipped with stirrer, thermocouple, distillation condenser and nitrogen inlet
The crude starting material (2,278 g) was added to 1,2-dichlorobenzene (11.
4 L). After distilling off a part of the solvent (1.7 L) at 187 ° C., distillation
The condenser was replaced with a reflux condenser. The reaction was refluxed at 187 ° C overnight.
Ice water (4 L) and NaOH (320 g) were added sequentially. Mix the mixture with hexane (1
2 L) and the layers were separated. The organic layer was extracted twice with 2N NaOH aqueous solution (4 L).
I put it out. The combined aqueous layers were acidified with concentrated HCl (ice was added to bring the temperature below 30 ° C.
Maintained) then Et_TwoExtract 3 times with O (4 L). The combined organic layers are MgSO _Four Dried with Na_TwoSO_FourThrough and the solvent was distilled off under vacuum. 10%   Chromatography eluting with EtOAc / hexane (silica gel 12k
g, packed in hexane) to give the desired product.

¹ H NMR (CDCl ₃ , 400 MHz) δ 3.31 (m, 2H), 3.
48 (m, 2H), 5.2 (m, 4H), 6.0 (m, 2H), 6.40 (d,
1H), 6.85 (d, 1H).

Step 3: Preparation of 2,4-dipropylresorcinol

[0092]

[Chemical 9]

The starting material (1237.2 g, 6.5 mmol) was divided between two runs. To each solution of bisallyl starting material (618.6 g) in ethyl acetate (2,780 ml) was added 10% Pd / C (46 g). Hydrogenation was carried out at room temperature under a 40 psi hydrogen atmosphere for 1.5 hours. The reaction was filtered through Supercel and the solvent evaporated under vacuum. The crude products from the two runs were combined and this was slurried in hexanes, filtered and dried to give the product.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.00 (m, overlapping signal, 6H), 1.6 (m, overlapping signal, 4H), 2.48 (t, 2H), 2.6
0 (t, 2H), 4.56 (s, 1H), 4.70 (s, 1H), 6.31 (d
, 1H), 6.80 (d, 1H).

Step 4: Preparation of 2,4-dihydroxy-3,5-dipropyl-1 ', 1', 1'-trifluoroacetophenone

[0096]

[Chemical 10]

AlCl ₃ (1,763 g) was added to a solution of the starting material (785.7 g, 4.04 mmol) in CH ₂ Cl ₂ (20,600 ml). Trifluoroacetic anhydride (814 ml) was added slowly at 0 ° C. The reaction mixture was stirred at room temperature overnight, poured into ice water and extracted 3 times with CH ₂ Cl ₂ . Combine the combined organic layers with saturated NaHC
O ₃ and brine, dried over MgSO _4, filtered through _Na 2 SO _4, and evaporated in vacuo. Chromatography (10 kg silica gel, packed in hexane) eluting with 5% EtOAc / hexane gave the desired product as a yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.00 (m, overlapping signal, 6H), 1.60 (m, overlapping signal, 4H), 2.55 (t, J = 7.4H).
z, 2H), 2.66 (t, J = 7.4Hz, 2H), 5.65 (s, 1H),
7.45 (s, 1H); MS (ESI) 291 (M + 1).

Step 5: Preparation of 2,4-dihydroxy-3,5-dipropyl-1 ', 1', 1'-trifluoroacetophenone oxime

[0100]

[Chemical 11]

To a mixture of NaOAc (2,677 g, 32.5 mol) and hydroxylamine hydrochloride (2,000 g, 28.8 mol) in methanol (1 L) was added methanol (
26 L) was added a solution containing the starting material phenol (1,139.8 g, 3.93 mol). The yellow suspension was refluxed for 18 hours. TLC showed a significant amount of starting material remained. Furthermore, hydroxylamine hydrochloride (1,000
g), NaOAc (1,338 g) and methanol (4 L) were added. The reaction mixture was refluxed overnight. TLC showed the starting material was completely consumed. The reaction was poured into ice water (32 L) and extracted twice with EtOAc (16 L). The combined organic layers were washed with brine, dried and evaporated under vacuum. 15% EtO
Chromatography (10 kg silica gel) with Ac / Hexane as eluent gave the desired product as a yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.98 (m, overlapping signal, 6H), 1.60 (m, overlapping signal, 4H), 2.50 (t, 2H), 2.
68 (t, 2H), 5.00 (s, wide, 1H), 5.80 (s, wide, 1H)
, 6.92 (s, 1H).

Step 6: Preparation of 5,7-dipropyl-6-hydroxy-3-trifluoromethyl- 1,2-benzisoxazole

[0104]

[Chemical 12]

A solution of the starting material oxime (600 g) in Ac ₂ O (3 L) was stirred overnight at room temperature. The solvent was removed under vacuum. The residue was azeotroped 4 times with toluene,
Crude 2,4-dihydroxy-3,5-dipropyl-1 ′, 1 ′, 1′-trifluoroacetophenone O-acetyloxime was obtained. This crude product was converted into pyridine (
6 L) and Et ₃ N (684 ml). The reactants are refluxed for 3 hours (1
(12 ° C) and allowed to cool overnight. The solvent was distilled off under vacuum. The residue was azeotroped twice with toluene then partitioned between EtOAc and 1N HCl. The organic layer was washed with 1N HCl and brine, dried, filtered and concentrated under vacuum to give a black oil which was purified by flash chromatography (10 kg silica gel) eluting with 5% EtOAc / hexane. Then the desired product was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.00 (m, overlapping signal, 6H), 1.70 (m, overlapping signal, 4H), 2.68 (t, 2H), 2.
90 (t, 2H), 5.21 (s, 1H), 7.33 (s, 1H); MS (ESI) 288.3 (M + 1).

Intermediate 2

[0108]

[Chemical 13]

[0109]   Prepared in the same manner as Intermediate 1 using 6-propylresorcinol.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.03 (t, 3H), 1.
71 (m, 2H), 2.72 (t, 2H), 5.5 (s, wide, 1H), 7.0
6 (s, 1H), 7.51 (s, 1H).

Intermediate 3

[0112]

[Chemical 14]

A solution of intermediate 2 (0.22 g, 0.89 mmol) and sulfuryl chloride (0.096 ml, 1.2 mmol) in CH ₂ Cl ₂ (5 ml) was added to Et ₂ O (0.
． 5 ml) was added. The reaction was stirred overnight at room temperature and partitioned between water and Et 2 _O. The organic layer was washed with saturated aqueous NaHCO ₃ solution and brine, dried over MgSO ₄ , filtered and concentrated under vacuum to give 7-chloro-6-hydroxy-5-propyl-3-trifluoromethyl-1,2-. Benzisoxazole was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.01 (t, 3H), 1.
71 (m, 2H), 2.77 (t, 2H), 6.15 (s, 1H), 7.44 (
s, 1H).

Example 1

[0116]

[Chemical 15]

Preparation of methyl 2-[(5,7-dipropyl-3-trifluoromethyl-1,2- benzisoxazol-6-yl) oxy] -2-methylpropionate

[0118]

[Chemical 16]

Starting material phenol (20 g, 69.7 mmol) in DMF (200 ml)
Methyl α-bromoisobutyrate (126.7 g, 0.7 mol) and cesium carbonate (228 g, 0.7 mol) were added to the solution containing and the mixture was stirred at 60 ° C. for 7 days. The reaction was worked up by partitioning between ether and water. Extract the aqueous layer with ether,
The organic layer was washed successively with water and brine, dried over Mg ₂ SO ₄ , filtered and evaporated under vacuum. Purification by chromatography gave the desired product.

¹ H NMR (CDCl ₃ ) δ 1.00 (m, 6H), 1.53 (s, 6H
), 1.69 (m, 2H), 1.76 (m, 2H), 2.62 (t, 2H), 2
． 85 (m, 2H), 3.89 (s, 3H), 7.39 (s, 1H).

Example 2

[0122]

[Chemical 17]

Preparation of 2-[(5,7-dipropyl-3-trifluoromethyl-1,2- benzisoxazol-6-yl) oxy] -2-methylpropionic acid

[0124]

[Chemical 18]

The starting methyl ester (8 g, 20.7) in methanol (50 ml).
1.0 N aqueous sodium hydroxide solution (60 ml) was added to the solution containing (mmol). Sufficient THF (100 ml) was added and the mixture returned to a clear solution. The mixture was heated at 80 ° C. for 2 hours. TLC showed the reaction was complete. The reaction was partitioned between 1N HCl and ether. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated under vacuum. The solid residue was recrystallized from pentane to give the desired product as colorless crystals.

¹ H NMR (CDCl ₃ ) δ 1.01 (m, 6H), 1.59 (s, 6H)
), 1.70 (m, 2H), 1.78 (m, 2H), 2.68 (t, 2H), 2
． 92 (m, 2H), 7.43 (s, 1H).

Example 3

[0128]

[Chemical 19]

[0129]   It was produced in the same manner as in Example 2 using Intermediate 3.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.03 (t, 3H), 1.
68 (s, 6H), 1.72 (m, 2H), 2.75 (t, 2H), 7.52 (
s, 1H).

Example 4

[0132]

[Chemical 20]

Preparation of ethyl 2-[(5,7-dipropyl-3-trifluoromethyl-1,2- benzisoxazol-6-yl) oxy] butyrate

[0134]

[Chemical 21]

A solution of intermediate 1 (150 mg, 0.52 mmol) and ethyl 2-bromobutyrate (152 mg, 0.78 mmol) in DMF (5 ml) was added to a solution of cesium carbonate (
254 mg, 0.78 mmol) was added. The mixture was stirred at room temperature for 6 hours then partitioned between ether and water. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated under vacuum. Purification by flash chromatography gave the desired product.

¹ H NMR (CDCl ₃ ) δ 1.01 (m, 6H), 1.08 (t, 3H
), 1.24 (t, 3H), 1.69 (m, 2H), 1.78 (m, 2H), 2
． 04 (m, 2H), 2.72 (m, 1H), 2.82 (m, 1H), 2.97.
(M, 2H), 4.19 (m, 2H), 4.54 (m, 1H), 7.41 (s,
1H).

Example 5

[0138]

[Chemical formula 22]

[0139] Step 1: 2 - [(5,7-dipropyl-3-trifluoromethyl-1,2 - benzisoxazol-6-yl) oxy] Manufacture of 2-ethyl-valerate ethyl

[0140]

[Chemical formula 23]

1.5M LDA (0.27 ml) and HMPA (0.069 ml) in a solution of the title compound of Example 5 (80 mg) in THF (5 ml) at −78 ° C.
Were sequentially added. After 5 minutes at −78 ° C., iodopropane (98 μl) was introduced.
The mixture was stirred at −78 ° C. for 1 hour and then slowly warmed to room temperature over 2 hours. Workup with water and purification by chromatography gave the desired product as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 0.87 (t, 3H), 0.95 (t, 3H
), 1.01 (m, overlapping signal, 6H), 1.25 (m, 1H), 1.50-
1.80 (m, overlapping signal, 5H), 1.82-2.10 (m, overlapping signal, 4H), 2.68 (m, 2H), 2.91 (m, 2H), 4.18 ( q, 2H
), 7.38 (s, 1H).

Step 2: Preparation of 2-[(5,7-dipropyl-3-trifluoromethyl- 1,2-benzisoxazol-6-yl) oxy] -2-ethylvaleric acid.

[0144]

[Chemical formula 24]

The ethyl ester (1) obtained in step 1 in DMSO (5 ml) at room temperature (
To a solution containing 30 mg) was added t-BuOK (0.5 g). The reaction was stirred at room temperature overnight and was partitioned between 1.0N HCl aqueous solution and EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by preparative HPLC gave the desired product.

¹ H NMR (CDCl ₃ ) δ 0.87 (t, 3H), 0.95 (t, 3H
), 1.01 (m, 6H), 1.25 (m, 1H), 1.56-1.77 (m,
5H), 1.82-2.10 (m, 4H), 2.69 (m, 2H), 2.91 (
m, 2H), 7.42 (s, 1H).

Example 6

[0148]

[Chemical 25]

[0149] 2 - [(5,7-dipropyl-3-trifluoromethyl-1,2-Benzoiso oxazol-6-yl) oxy] -2-methylpropionic acid 2- (Asechirua) ethyl manufacture of

[0150]

[Chemical formula 26]

The title compound of Example 1 (500 mg, 1.3 ml) in dichloromethane (10 ml).
4 mmol) in a solution containing N-2-hydroxyethylacetamide (166 mg
, 1.50 mmol), 1N DCC (1.5 ml) and DMAP (16 mg,
0.13 mmol) was added. The reaction was stirred at room temperature overnight. The precipitate was filtered off. The filtrate and washings were combined and the solvent was evaporated under vacuum. Purification by flash chromatography gave the desired product.

¹ H NMR (CDCl ₃ ) δ 1.00 (m, 6H), 1.54 (s, 6H
), 1.59-1.81 (m, 4H), 2.02 (s, 3H), 2.62 (t,
2H), 2.87 (m, 2H), 3.65 (m, 2H), 4.34 (t, 3H)
5.79 (s, wide, 1H), 7.40 (s, 1H).

Example 7

[0154]

[Chemical 27]

Preparation of 2-[(5,7-dipropyl-3-trifluoromethyl-1,2- benzisoxazol-6-yl) oxy] -2-methylpropionamide

[0156]

[Chemical 28]

2.0 M AlCl ₃ (0.8 ml) was added dropwise to a suspension of NH ₄ Cl (86 mg) in toluene (10 ml) at room temperature. The reaction was stirred for 3 hours.
The resulting clear solution was 2-((5,7-dipropyl-3-) in toluene (5 ml).
Trifluoromethyl-1,2-benzisoxazol-6-yl) oxy]-
Transferred to a solution containing methyl 2-methylpropionate (200 mg). 8 reactants
Stirred at 0 ° C. overnight, cooled to room temperature, then partitioned between EtOAc and 1.0 N aq HCl. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography gave the desired product.

¹ H NMR (CDCl ₃ ) δ 1.00 (m, 6H), 1.51 (s, 6H
), 1.65 (m, 2H), 1.75 (m, 2H), 2.70 (t, 2H), 2
． 94 (m, 2H), 5.72 (s, wide, 1H), 6.87 (s, wide, 1H
), 7.43 (s, 1H).

Example 8

[0160]

[Chemical 29]

[0161] Step 1: [(5,7-dipropyl-3-trifluoromethyl-1,2-Baie emission zone isoxazol-6-yl) oxy] Production of methyl acetate

[0162]

[Chemical 30]

Methyl bromoacetate (0.4) and cesium carbonate (0.85) were added to a solution of starting material phenol (0.5 g) in DMF (10 ml) and the mixture was stirred at room temperature for 4 hours. The reaction was worked up by partitioning between EtOAc and water. The organic layer was washed successively with water and brine, dried over Mg ₂ SO ₄ , filtered and evaporated under vacuum. Purification by chromatography gave the desired product.

¹ H NMR (CDCl ₃ ) δ 1.02 (m, 6H), 1.72 (m, 2H)
), 1.80 (m, 2H), 2.74 (t, 2H), 2.97 (m, 2H), 3
． 89 (s, 3H), 4.51 (s, 2H), 7.45 (s, 1H).

[0165] Step 2: 1 - [(5,7-dipropyl-3-trifluoromethyl-1,2 - benzisoxazol-6-yl) oxy] Production of cyclopentanecarboxylic acid methylation

[0166]

[Chemical 31]

To a solution of the starting material ester (100 mg) obtained in step 1 in THF (4.0 ml) at −78 ° C. was added 1.0 M LiHMDS (0.31 m).
1) and HMPA (0.054 ml) were added. After 15 minutes at -78 ° C, 1,4
-Introduced diiodobutane (96 mg). The reaction was warmed to room temperature over 3 hours then cooled to -78 ° C and an additional 2.1 equivalents of LiHMDS and HMPA were added. The reaction was slowly warmed to room temperature and stirred overnight. The mixture is then Et
Partitioned between OAc and water. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography gave the desired product.

¹ H NMR (CDCl ₃ ) δ 0.99 (m, 6H), 1.72 (m, 8H
), 2.08 (m, 2H), 2.32 (m, 2H), 2.63 (t, 2H), 2
． 84 (t, 2H), 3.81 (s, 3H), 7.39 (s, 1H).

[0169] Step 3: 1 - [(5,7-dipropyl-3-trifluoromethyl-1,2 - benzisoxazol-6-yl) oxy] Manufacture of cyclopentanecarboxylic acid

[0170]

[Chemical 32]

To a solution of the starting methyl ester (30 mg) obtained in step 2 in methanol (2 ml) was added 1.0 N aqueous sodium hydroxide solution (2 ml). Sufficient THF (6 ml) was added and the mixture returned to a clear solution. The mixture was heated at 60 ° C. for 5 hours then partitioned between 1N HCl and ether.
The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated under vacuum. Purification by chromatography gave the desired product.

¹ H NMR (CDCl ₃ ) δ 0.99 (m, 6H), 1.72 (m, 8H
), 2.10 (m, 2H), 2.35 (m, 2H), 2.62 (t, 2H), 2
． 84 (t, 2H), 7.41 (s, 1H).

The compounds of the Examples shown in Table I below were prepared using the same or similar protocols as described in Examples 1-8 above.

[0174]

[Table 3]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/423 A61K 31/423 31/4418 31/4418 45/00 45/00 A61P 1/00 A61P 1 / 00 1/04 1/04 1/18 1/18 3/04 3/04 3/06 3/06 3/10 3/10 5/48 5/48 9/00 9/00 9/10 9/10 101 101 9/12 9/12 15/08 15/08 17/06 17/06 25/08 25/08 25/28 25/28 27/02 27/02 29/00 29/00 35/00 35/00 43 / 00 111 43/00 111 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE , TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, S L, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72 ) Inventor Shiyu, Revo USA, New Jersey 07065-0907, Lowway East Lincarn Avenueu 126 (72) Inventor John Jones, A. Bryan United States, New Jersey 07065-0907, Lowway, East Lincarn Avenue 126 F Term (reference) 4C056 AA01 AB01 AC01 AD03 AE03 FA03 FA04 FA07 FA08 FB01 FC01 4C084 AA02 AA03 AA07 AA19 AA24 BA44 MA13 MA17 MA22 MA23 MA28 MA31 MA35 MA36 MA37 MA43 MA52 MA56 MA58 MA59 MA60 MA63 MA66 NA14 ZA152 ZA162 ZA332 ZA362 ZA422 ZA452 ZA662 ZA682 ZA702 ZA812 ZA892 ZB112 ZB212 ZB262 ZC202 ZC332 ZC352 ZC412 4C086 AA01 AA02 AA03 BA17 BC05 BC13 BC17 BC68 MA01 MA02 MA03 MA04 MA13 MA17 MA22 MA23 MA28 MA31 MA35 MA36 MA37 MA41 MA43 MA52 MA56 MA58 MA59 MA60 MA63 MA66 NA14 ZA15 ZA16 ZA33 ZA36 ZA40 ZC41 Z41 B31 Z41 B31 Z41 B33 Z11 B41 Z26 B11 Z33 B11 Z35 B11 AA01 AA02 AA03 DB03 DB56 MA01 MA02 MA03 MA04 MA14 MA33 MA37 MA42 MA43 MA48 MA51 MA55 MA56 MA57 MA61 MA63 MA72 MA76 MA78 MA79 MA80 MA83 MA86 NA14 ZA15 ZA16 ZA33 ZA 36 ZA40 ZA42 ZA45 ZA66 ZA68 ZA81 ZA89 ZB11 ZB21 ZB26 ZC20 ZC33 ZC35 ZC41

Claims (35)

[Claims] 1. Formula I:     [Chemical 1] (In the formula,   R¹And R^TwoAre independently H, F, C_1-5Alkyl, C_2-5Arche
Nil and C_2-5Selected from the group consisting of alkynyl, said alkyl, alkenyl
R and alkynyl may be straight or branched and optionally 1 to 3 halo.
Optionally substituted with a gen atom, or R¹And R^TwoTogether C_3-6 May form a cycloalkyl;   R^ThreeAnd R^FourAre each independently C_1-5Alkyl, C_2-5Alkenyl, C _2-5 Alkynyl and chlorine (however, R^ThreeAnd R^FourBoth are not chlorine)
Wherein the alkyl, alkenyl and alkynyl are straight chain or
It may be branched and optionally substituted with 1 to 5 fluorine atoms;   X is N or CR;   Y is O, S or NR;   Z is O or S;   Each R is independently H, C_1-5Alkyl, C_2-5Alkenyl and C_2-5Al
Selected from the group consisting of quinyl, wherein said alkyl, alkenyl and alkynyl are direct
May be chain or branched, optionally 1 to 5 fluorine atoms and / or 1
-OC_1-3It may be substituted with alkyl, and the aforementioned -OC_1-3Alkyl
Is optionally substituted with 1 to 7 fluorine atoms;   R⁵Is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C _6-10 Aryl, -OC_1-6Alkyl, -OC_2-6Alkenyl, -OC_{Two -6} Alkynyl, -OC_6-10Aryl, C_3-6Cycloalkyl, 5-6 member
Heterocyclyl, 5- or 6-membered heteroaryl, -OC_3-6Cycloalkyl, -O
5- or 6-membered heterocyclyl, -O 5- or 6-membered heteroaryl, and in the middle of the chain or in the chain
C at the end of_6-10Aryl, C_3-6Cycloalkyl, 5-6 membered heterocyclyl
And a C containing group selected from 5- and 6-membered heteroaryl_1-4From alkyl
Selected from the group consisting of alkyl, alkenyl, alkynyl, -Oalkyl,-
Each of O alkenyl and -O alkynyl may be linear or branched, where
1 to 5 fluorine atoms and / or 1 -OCH_ThreeOr -OCF_ThreeBasis
Optionally substituted with the above-mentioned aryl, cycloalkyl, heteroaryl,
Telocyclyl, -Oaryl, -Ocycloalkyl, -Oheteroaryl and-
Each O heterocyclyl optionally comprises 1 to 7 halogen atoms and / or 1
-OCH_ThreeOr -OCF_ThreeIt may be substituted with a group) And a pharmaceutically acceptable salt or prodrug thereof. 2. The formula I according to claim 1, wherein X is N and Y is O.
A compound having: 3. The formula I according to claim 1, wherein X is N and Y is S.
A compound having: 4. A compound having the formula I as claimed in claim 1, wherein X is N and Y is NR. 5. A compound of formula I according to claim 1 wherein X is CR and Y is O. 6. A compound of formula I as claimed in claim 1 wherein X is CR and Y is S. 7. A compound having the formula I according to claim 1 wherein X is CR and Y is NR. 8. R ⁵ is _{H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, -OC 1-5 alkyl, -OC 2-5 alkenyl, -OC 2-5} alkynyl and phenyl Selected from the group consisting of, said alkyl, alkenyl,
Alkynyl, -Oalkyl, -Oalkenyl and -Oalkynyl are optionally 1
~ 5 fluorine atoms may be substituted, and the phenyl is optionally 1-5.
A compound having the formula I according to claim 1 optionally substituted with one halogen atom. 9. R ¹ and R ² are each H or C _1-3 alkyl, the total number of carbon atoms in R ¹ and R ² is 0-5, and R ³ and R ⁴ are each independently be a _{C 1-5} alkyl; ^{R 5} is selected from the group consisting of _{C 1-5} alkyl and _{-OC 1-5} alkyl, said alkyl and -O alkyl with 1-5 fluorine atoms optionally Optionally substituted; Z is O
The compound according to the item. 10. R ⁵ is C _1-3 alkyl, —OC _1-3 alkyl, CF ₃ , C ₂ F ₅ , —OCF ₃ or —OC ₂ F ₅ ; R ³ and R ⁴ are each n.
-The compound of claim 9 which is propyl. 11. Formula Ia:     [Chemical 2] (In the formula,   R¹And R^TwoAre independently H, F, C_1-5Alkyl, C_2-5Arche
Nil and C_2-5Selected from the group consisting of alkynyl, said alkyl, alkenyl
R and alkynyl may be straight or branched and optionally 1 to 3 halo.
Optionally substituted with a gen atom, or R¹And R^TwoTogether C_3-6 May form a cycloalkyl;   R^ThreeAnd R^FourAre each independently C_1-5Alkyl, C_2-5Alkenyl, C _2-5 Alkynyl and chlorine (however, R^ThreeAnd R^FourBoth are not chlorine)
Wherein the alkyl, alkenyl and alkynyl are straight chain or
It may be branched and optionally substituted with 1 to 5 fluorine atoms;   X is N or CR;   Y is O, S or NR;   Z is O or S;   Each R is independently H, C_1-5Alkyl, C_2-5Alkenyl and C_2-5Al
Selected from the group consisting of quinyl, wherein said alkyl, alkenyl and alkynyl are direct
May be chain or branched, optionally 1 to 5 fluorine atoms and / or 1
-OC_1-3It may be substituted with alkyl, and the aforementioned -OC_1-3Alkyl
Is optionally substituted with 1 to 7 fluorine atoms;   R⁵Is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C _6-10 Aryl, -OC_1-6Alkyl, -OC_2-6Alkenyl, -OC_{Two -6} Alkynyl, -OC_6-10Aryl, C_3-6Cycloalkyl, 5-6 member
Heterocyclyl, 5- or 6-membered heteroaryl, -OC_3-6Cycloalkyl, -O
5- or 6-membered heterocyclyl, -O 5- or 6-membered heteroaryl, and in the middle of the chain or in the chain
C at the end of_6-10Aryl, C_3-6Cycloalkyl, 5-6 membered heterocyclyl
And a C containing group selected from 5- and 6-membered heteroaryl_1-4From alkyl
Selected from the group consisting of alkyl, alkenyl, alkynyl, -Oalkyl,-
Each of O alkenyl and -O alkynyl optionally has 1 to 5 fluorine atoms and
/ Or one -OCH_ThreeOr -OCF_ThreeIt may be substituted with a group, and
Reel, cycloalkyl, heteroaryl, heterocyclyl, -Oaryl,-
Each of O cycloalkyl, -O heteroaryl and -O heterocyclyl is optionally
1 to 7 halogen atoms and / or 1 -OCH_ThreeOr -OCF_ThreeBasis
May be substituted with;   R⁶Is a compound having formula I, or its carboxylate anion (in solution)
Or during administration or administration to a mammalian patient to produce a pharmaceutically acceptable salt thereof.
It is a group that is easily removed under physiological conditions after application.) And a pharmaceutically acceptable salt thereof. 12. Formula Ia:     [Chemical 3] (In the formula,   R¹And R^TwoAre independently H, F, C_1-5Alkyl, C_2-5Arche
Nil and C_2-5Selected from the group consisting of alkynyl, said alkyl, alkenyl
R and alkynyl may be straight or branched and optionally 1 to 3 halo.
Optionally substituted with a gen atom, or R¹And R^TwoTogether C_3-6 May form a cycloalkyl;   R^ThreeAnd R^FourAre each independently C_1-5Alkyl, C_2-5Alkenyl, C _2-5 Alkynyl and chlorine (however, R^ThreeAnd R^FourBoth are not chlorine)
Wherein the alkyl, alkenyl and alkynyl are straight chain or
It may be branched and optionally substituted with 1 to 5 fluorine atoms;   X is N or CR;   Y is O, S or NR;   Z is O or S;   Each R is independently H, C_1-5Alkyl, C_2-5Alkenyl and C_2-5Al
Selected from the group consisting of quinyl, wherein said alkyl, alkenyl and alkynyl are direct
May be chain or branched, optionally 1 to 5 fluorine atoms and / or 1
-OC_1-3It may be substituted with alkyl, and the aforementioned -OC_1-3Alkyl
Is optionally substituted with 1 to 7 fluorine atoms;   R⁵Is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C _6-10 Aryl, -OC_1-6Alkyl, -OC_2-6Alkenyl, -OC_{Two -6} Alkynyl, -OC_6-10Aryl, C_3-6Cycloalkyl, 5-6 member
Heterocyclyl, 5- or 6-membered heteroaryl, -OC_3-6Cycloalkyl, -O
5- or 6-membered heterocyclyl, -O 5- or 6-membered heteroaryl, and in the middle of the chain or in the chain
C at the end of_6-10Aryl, C_3-6Cycloalkyl, 5-6 membered heterocyclyl
And a C containing group selected from 5- and 6-membered heteroaryl_1-4From alkyl
Selected from the group consisting of alkyl, alkenyl, alkynyl, -Oalkyl,-
Each of O alkenyl and -O alkynyl optionally has 1 to 5 fluorine atoms and
/ Or one -OCH_ThreeOr -OCF_ThreeIt may be substituted with a group, and
Reel, cycloalkyl, heteroaryl, heterocyclyl, -Oaryl,-
Each of O cycloalkyl, -O heteroaryl and -O heterocyclyl is optionally
1 to 7 halogen atoms and / or 1 -OCH_ThreeOr -OCF_ThreeBasis
May be substituted with;   R⁶Is -OR⁷, -OCH_TwoOR⁷, -OCH (CH_Three) OR⁷, -OCH_Two OC (O) R⁷, -OCH (CH_Three) OC (O) R⁷, -OCH_TwoOC (O) O
R⁷, -OCH (CH_Three) OC (O) OR⁷, -NR⁸R⁸And -ONR⁸R⁸ Is selected from the group consisting of;   Each R⁷Independently -CO_TwoH, -CONH_Two, -NH_Two, -OH, -OAc,
May be substituted with 1 or 2 groups selected from NHAc and phenyl
C_1-6Selected from alkyl;   Each R⁸Are independently H and R⁷Selected from) And a pharmaceutically acceptable salt thereof. 13. The following Examples 1 to 29 [Table 1] [Table 2] A compound represented by the structure: 14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 15. A pharmaceutical composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier. 16. Insulin independence in a mammalian patient in need of treatment (
A method for the treatment, control or prevention of type 2 diabetes mellitus, said method comprising administering to said patient a therapeutically effective amount of a compound according to claim 1. 17. A method of treating, controlling or preventing hyperglycemia in a mammalian patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of claim 1. The method comprising. 18. A method of treating, controlling or preventing lipid disorders, hyperlipidemia or low HDL in a mammalian patient in need thereof, wherein a therapeutically effective amount of said patient is claimed. The method comprising administering a compound of claim 1. 19. A method of treating, controlling or preventing obesity in a mammal patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a compound of claim 1. Method. 20. A method of treating, controlling or preventing hypercholesterolemia in a mammalian patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of claim 1. The method comprising: 21. A method of treating, controlling or preventing hypertriglyceridemia in a mammal patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of claim 1. The method comprising: 22. A method of treating, controlling or preventing dyslipidemia and / or low HDL cholesterol in a mammalian patient in need thereof, wherein a therapeutically effective amount of said patient is claimed. The method comprising administering a compound of claim 1. 23. A method of treating, controlling or preventing atherosclerosis in a mammalian patient in need thereof, wherein a therapeutically effective amount of the compound of claim 1 is effective against said patient. The above method comprising administering an amount. 24. (1) Non-insulin dependent diabetes mellitus (NIDDM), (2)
Hyperlipidemia, (3) impaired glucose tolerance, (4) insulin resistance, (5) obesity, (6) lipid disorder, (7) dyslipidemia, (8) hyperlipidemia, (9) high Triglycerideemia, (
10) hypercholesterolemia, (11) low HDL level, (12) high LDL level, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (
15) Irritable bowel syndrome, (16) Inflammatory bowel diseases including Crohn's disease and ulcerative colitis, (17) Other inflammatory conditions, (18) Pancreatitis, (19) Abdominal obesity, (20) Neurodegenerative disease , (21) retinal disorder, (22) abnormal growth state, (23) adipocyte tumor,
(24) adipocyte carcinomas such as liposarcoma, (25) other cancers including prostate and gastric cancer, breast cancer, bladder cancer and colon cancer, (26) angiogenesis, (27) Alzheimer's disease, (28) psoriasis One or more selected from the group consisting of: (29) hypertension, (30) syndrome X, (31) hyperovarian hyperandrogenism (polycystic ovary syndrome), and other disorders in which insulin resistance is a factor. A method of treating, controlling or preventing the disease, disorder or condition of claim 1, said method comprising administering an effective amount of a compound of claim 1. 25. (1) Diabetes, especially non-insulin dependent diabetes mellitus (NIDD)
M), (2) hyperlipidemia, (3) impaired glucose tolerance, (4) insulin resistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia Disease, (9) hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDL level, (12)
High LDL level, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (15) irritable bowel syndrome, (16) inflammatory bowel disease including Crohn's disease and ulcerative colitis, ( 17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity,
(20) Neurodegenerative disease, (21) Retinal disorder, (22) Hyperproliferative state, (23) Adipocyte tumor, (24) Adipocyte carcinoma such as liposarcoma, (25) Prostate cancer and gastric cancer, breast cancer, bladder Other cancers, including cancer and colon cancer, (26) angiogenesis, (27) Alzheimer's disease, (28) psoriasis, (29) hypertension, (30) Syndrome X, (31) ovarian hyperandrogenism (multi) Cystic ovary syndrome), and a method of treating, controlling or preventing one or more diseases, disorders or conditions selected from the group consisting of insulinopathy and other disorders. The compound according to item 1 and an effective amount of (a) (i) glitazone (eg, troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, etc.) and International Patent Application No. 97/27857. Pamphlets, 97/28115 pamphlets, 97/28137 pamphlets and 97/28847 papars, such as compounds described in the pamphlet, (ii) metformin and biguanides such as phenformin, ( iii) Protein tyrosine phosphatase-1B (PTP-1B
) Insulin sensitizers including inhibitors and (iv) dipeptidyl peptidase IV (DP-IV) inhibitors, (b) insulin or insulin mimetics, (c) sulfonylureas or related substances such as tolbutamide or glipizide, (D) α-glucosidase inhibitors such as acarbose, (e) (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins). , (Ii) sequestering agents (dialkylaminoalkyl derivatives of cholestyramine, colestipol and cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or its salts, (iv) fenofibric acid derivatives (gemfibrozil, clofibrez. , Fenofibrate and benzafibrate), and (v) KRP-
PPARα / γ dual agonists such as 297, (vi) cholesterol absorption inhibitors such as β-sitosterol, (vii) acyl CoA: cholesterol acyltransferase inhibitors such as avasimibe, and (viii) antioxidants such as probucol Cholesterol-lowering substances such as agents, (f) PPARδ agonists as described in WO 97/28149, (g) Fenfluramine, Dexafenfluramine, Fentyramine, Surbitramine, Orlistat, Neuro Anti-obesity agents such as peptide Y5 inhibitors and β3 adrenergic receptor agonists, (h) ileal bile acid transporter inhibitors, and (i) agents used during inflammatory conditions, eg aspirin, non-steroidal anti-inflammatory Agent, glucocortico Said method comprising administering one or more other compounds selected from the group consisting of id, azulfidine and cyclooxygenase-2 selective inhibitors. 26. Hypercholesterolemia, atherosclerosis, low HD
A method for treating, controlling or preventing one or more conditions selected from L level, high LDL level, hyperlipidemia, hypertriglyceridemia and dyslipidemia, for a mammalian patient in need thereof. 13. A method as described above comprising administering a therapeutically effective amount of the compound of claim 1. 27. The method of claim 26, wherein the compound of claim 1 is administered with an HMG-CoA reductase inhibitor. 28. The method of claim 27, wherein the HMG-CoA reductase inhibitor is a statin. 29. The method of claim 28, wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin. 30. A method for the treatment, control or prevention of one or more conditions selected from inflammatory conditions, inflammatory bowel disease, Crohn's disease and ulcerative colitis, for treating a mammalian patient in need thereof. A method comprising administering an effective amount of the compound of claim 1. 31. The method of claim 30, wherein the compound of claim 1 is administered with an HMG-CoA reductase inhibitor. 32. The method of claim 31, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin. 33. A method for the treatment, prevention or control of atherosclerosis in a mammal patient in need thereof, which comprises an effective amount of the compound according to claim 1 and an effective amount of HMG-CoA reductase inhibition. The above method comprising administering an agent. 34. (1) The compound according to claim 1, (2) HMG-
A pharmaceutical composition for treating, preventing or controlling atherosclerosis, which comprises a CoA reductase inhibitor and (3) a pharmaceutically acceptable carrier. 35. (1) The compound according to claim 1, (2) (a) (i) glitazone (eg, troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, etc.) and international patents Application Publication No. 97/2785
No. 7 pamphlet, No. 97/28115 pamphlet, No. 97/2813
Nos. 7 and 97/27847, PPARγ agonists such as compounds, (ii) biguanides such as metformin and phenformin, (iii) protein tyrosine phosphatase-1B (PTP-
1B) Insulin sensitizers including inhibitors and (iv) dipeptidyl peptidase IV (DP-IV) inhibitors, (b) insulin or insulin mimetics, (c) sulfonylureas or related substances such as tolbutamide or glipizide (D) α-glucosidase inhibitors such as acarbose, (e) (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins. ), (Ii) sequestering agents (dialkylaminoalkyl derivatives of cholestyramine, cholestipol and cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or its salts, (iv) fenofibric acid derivatives (gemfibrozil, cloffi). Brate, fenofibrate and benzafibrate), PPARα agonists, (v) KRP-
PPARα / γ dual agonists such as 297, (vi) cholesterol absorption inhibitors such as β-sitosterol (vii) acyl CoA: cholesterol acyltransferase inhibitors such as avasimibe, and antioxidants such as (viii) probucol Cholesterol-lowering substances such as: (f) PPARδ agonists as described in WO 97/28149, (g) Fenfluramine, Dexafenfluramine, Fentyramine, Surbitramine, Orlistat, Neuro Anti-obesity agents such as peptide Y5 inhibitors and β3 adrenergic receptor agonists, (h) ileal bile acid transporter inhibitors, and (i) agents used during inflammatory conditions such as aspirin, non-steroidal anti-inflammatory Agent, glucocorti A pharmaceutical composition comprising one or more compounds selected from the group consisting of cooids, azulfidine and a cyclooxygenase-2 selective inhibitor, and (3) a pharmaceutically acceptable carrier.