WO2007122970A1

WO2007122970A1 - Ligand capable of binding to nuclear receptor

Info

Publication number: WO2007122970A1
Application number: PCT/JP2007/056780
Authority: WO
Inventors: Takuma Shiraki
Original assignee: Osaka University
Priority date: 2006-04-20
Filing date: 2007-03-29
Publication date: 2007-11-01

Abstract

Disclosed is a peroxisome proliferator-activated receptor gamma (PPARϜ) agonist which comprises a compound represented by the general formula (I) or a salt thereof or a prodrug of the compound or the salt: (I) wherein the ring A represents a heterocyclic ring; R1 represents a hydrogen atom or a carboxyalkyl group which may be esterified; R2 represents -COR5 (wherein R5 represents a C6-14 aryl group which may have a substituent or a heterocyclic group which may have a substituent) or -NO2; R3 represents a hydrogen atom, a halogen atom or a carboxyl group which may be esterified; and R4 represents a hydrogen atom or a C1-6 alkyl group.

Description

Specification

Ligands that bind to nuclear receptors

Technical field

[0001] The present invention relates to a human peroxisome proliferator-activated 匕 receptor gamma (hereinafter abbreviated as PPARγ) agonist.

Background art

[0002] PPAR y is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily, and is highly expressed in adipose tissue, immune cells, adrenal gland, spleen and the like. PPARRT has been reported to be deeply involved in adipocyte differentiation (see Non-Patent Document 1), and research on PPAR y is accelerating as a factor linking type 2 diabetes and obesity. Recently, PPAR y is also expressed in vascular smooth muscle and endothelial cells, and PPAR y agonists are thought to act on PPAR y in blood vessels in an anti-arteriosclerotic manner. It has also been shown that PPAR y agonists may be used clinically in addition to treating type II diabetes. For example, thiazolidinediones that are ligands of PPAR y described later have a blood lipid lowering action (see, for example, Patent Document 1). More recent studies have reported that PPAR y affects monocyte mobilization and foam cell force cholesterol excretion, which are important events in the development of atherosclerosis (2). reference). Furthermore, troglitazone, a PPAR y agonist, has been reported to suppress vascular smooth muscle cell proliferation and intimal thickening (see Non-Patent Document 3). From these facts, PPAR y agonists are considered to be clinically usable as therapeutic agents for suppressing arteriosclerosis and vascular stenosis.

[0003] In recent years, II type diabetes is effective thiazolidinediones force SPPAR gamma ligands (non-patent document 4, 5 reference) finds that at the same time 15 Dokishi one delta ¹² ^'14 prostaglandin j (15d PGj) Has been reported as a ligand for endogenous PPARγ (see Non-Patent Document 6).

twenty two

See). However, induction of unsaturated fatty acids such as endogenous PPARγ ligand, 15d-PGj

2

The body is metabolically and chemically unstable and cannot be used as a medicine.

For this reason, various new thiazolidine derivatives have been reported as ligands for PPARγ. Examples of such thiazolidine derivatives include 4 alkoxybenzylthiazolyl. Thiazolidinediones such as gin 2, 4 dione derivatives (for example, see Patent Documents 1 to 9), monocyclic benzamide derivatives (for example, see Patent Documents 10 to 12), indole derivatives (for example, see Patent Documents 13 and 14) Benzoisoxazole derivatives (see, for example, Patent Document 15) or benzofuran derivatives (see, for example, Patent Document 16). However, these compounds have been reported to have side effects such as compounds and heart failure that cause liver damage. These compounds are also different from the compounds of the present invention.

On the other hand, the present inventor pays attention to a nuclear receptor, examines a method for identifying a compound that modulates the nuclear receptor, and includes a step of determining a compound that covalently binds to cysteine in the nuclear receptor. A method for identifying a compound that modulates a nuclear compound has been clarified (see Patent Document 17). However, a PPAR y agonist that is still fully satisfactory has not been obtained.

Patent Document 1: JP-A-7-173158

Patent Document 2: Japanese Patent Laid-Open No. 55-22636

Patent Document 3: Japanese Patent Application Laid-Open No. 60-51189

Patent Document 4: Japanese Patent Laid-Open No. 61-85372

Patent Document 5: Japanese Patent Laid-Open No. 61-286376

Patent Document 6: Japanese Patent Laid-Open No. 1 131169

Patent Document 7: JP-A-2-83384

Patent Document 8: Japanese Patent Laid-Open No. 5-213913

Patent Document 9: Japanese Patent Laid-Open No. 4-210977

Patent Document 10: JP-T 6-502146

Patent Document 11: JP-A-8-333355

Patent Document 12: JP-A-9-48771

Patent Document 13: JP-A-9 169746

Patent Document 14: JP-A-9 176162

Patent Document 15: Japanese Patent Application Laid-Open No. 2004-67697

Patent Document 16: Japanese Patent Laid-Open No. 10-237049

Patent Document 17: Japanese Patent Laid-Open No. 2006-30037

Non-Patent Document 1: Tontonoz, BP, et al., Cell, 1994, 7th 9 卷, P. 1147-1156

Non-Patent Document 2: Chinetti, G. et al., Circulation, 2000, No. 101, P. 2411-2417

Non-patent document 3: Law, R. et al., The 'Journal' of 'Tari-Cal' Invest., 1996, No. 98, P. 1897-1905

Non-Patent Document 4: Lehmann, J. M. et al., The 'Journal', Biol. Chem., 1995, No. 270, P. 12953—

12956

Non-Patent Document 5: Forman, B. M. et al., Cell, 1995, 83rd, P. 803-812

Non-Patent Document 6: Kliewer, SA et al., Cell, 1995, 83rd, P. 813-819

Disclosure of the invention

Problems to be solved by the invention

[0005] An object of the present invention is to provide a novel PPAR y agonist having a novel structure.

Means for solving the problem

[0006] PPAR y has a wide variety of endogenous ligands with large ligand-binding pockets, making it difficult to design new ligands. Therefore, the present inventor performed nuclear screening from various compounds by in silico screening based on computer-based simulation according to the method for identifying a compound that modulates a nuclear receptor described in JP-A-2006-30037. Compounds that covalently bound to cysteine in the internal receptor were selected. Specifically, first, compounds having α, / 3-unsaturated ketones were extracted by motif search (database: Namiki Shoji Co., Ltd.). Among the extracted compounds having β-unsaturated ketone, compounds having β-unsaturated ketone on the straight chain were selected. Next, cluster classification based on similar structural formulas was performed, and drug-protein docking simulation programs (DOCK and GOLD) were used to search for topologically and highly complementary drugs in the form of nuclear receptors. When the transcriptional activity of the gene in the nuclear receptor was measured for the selected compound, it had a structure common to compounds that promote the transcriptional activity of the gene. I found out. Based on this knowledge, the present inventor has advanced further research and completed the present invention.

That is, the present invention

[1] General formula (I)

[Chemical 1]

(In the formula, A ring represents a heterocyclic ring, R ¹ represents a hydrogen atom or an optionally substituted carboxyalkyl group, R ² represents — COR ⁵ (wherein R ⁵ has a substituent) C carry

6-14 represents a heterocyclic group which may have a substituent or a substituent. ) Or — indicates NO, R ³ is water

2

R ⁴ represents a hydrogen atom or a C alkyl group. Or a salt thereof or a pro thereof

1-6

PPAR y agonist, characterized in that it contains a drug,

[2] The agent according to [1], wherein the A ring is a furan ring or a pyrazole ring.

[3] The compound has the general formula (II)

[Chemical 2]

(In the formula, R ¹ ′ represents an optionally esterified carboxyalkyl group, R ³ ′ represents a hydrogen atom or a halogen atom, R ⁵ has a substituent, and may be a C aryl group. Or place

6-14

It may be substituted with a heterocyclic group. The agent according to [1], which is a compound represented by

[4] The agent according to the above [3], wherein the aryl group represented by R ⁵ is a phenyl group,

[5] The agent according to [3], wherein the heterocyclic group represented by R ⁵ is a 2-chenyl group

The agent according to the above [3],

[7] The compound has the general formula (III) [Chemical 4]

(Wherein R ³ represents a carboxyl group which may be esterified, and R ⁴ represents a hydrogen atom or a C alkyl group), the agent according to the above [1],

1-6

[8] the compound is

[Chemical 5]

The agent according to [7] above, and

[9] The agent according to any one of the above [1] to [8], which is a preventive or therapeutic agent for an insulin-resistant disease state,

[10] The pathologic force of insulin resistance Type 1 diabetes, obesity, hyperlipidemia or arteriosclerosis The agent according to the above [9],

About.

The present invention also relates to an insulin-resistant pathological condition characterized by administering a PPARγ agonist containing a compound represented by the general formula (I), a salt thereof, or a prodrug thereof to mammals including humans. The present invention relates to a method for preventing or treating. Furthermore, the present invention relates to the use of a compound represented by the general formula (I) or a salt thereof or a prodrug thereof for producing a prophylactic or therapeutic agent for an insulin resistant disease state.

The invention's effect [0009] The PPAR y agonist according to the present invention can be covalently bound to PPAR y to increase the transcriptional activity of the gene in the nuclear receptor. The PPAR y agonist according to the present invention can be used as an agent for preventing or treating an insulin-resistant pathological condition such as type II diabetes, obesity, hyperlipidemia or arteriosclerosis. Furthermore, since the PPAR y agonist according to the present invention is useful as a preventive or therapeutic agent for type II diabetes, obesity or hyperlipidemia, a plurality of diseases such as type II diabetes, obesity or hyperlipidemia are simultaneously observed. Conditions that develop, i.e. metabolic syndrome and lifestyle-related diseases can also be prevented, treated or ameliorated.

Brief Description of Drawings

[0010] FIG. 1 shows the results of SDS-PAGE of PPAR y LBD labeled with rhodamine maleimide. (Example 1)

FIG. 2 is a graph showing the luciferase activity of a ligand in cultured COS-7 cells. (Example 2)

BEST MODE FOR CARRYING OUT THE INVENTION

In the compound represented by the general formula (I), the heterocyclic ring represented by the A ring includes, for example, an oxygen atom, a nitrogen atom, and 1 to 5 heteroatoms selected from Z or a sulfur atom. Including 3- to 6-membered heterocycles which may be partially or fully saturated. Specific examples of the heterocyclic ring include aziridine, azetidine, imidazole, imidazoline, imidazolidine, thiazole, isothiazole, thiazoline, thiazolidine, oxazole, isoxazole, oxazolidine, isoxazolidine, pyran, pyrazine, Pyrazole, pyrazoline, virazolidine, piperazine, piperidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, furan, furazane, triazine, morpholine, thiomorpholine, thiopyran or thiophene ring are preferred. Among them, the heterocyclic ring represented by the A ring is particularly preferably a furan ring or a pyrazole ring, which is preferably a 5-membered heterocyclic ring containing one oxygen atom or a 5-membered heterocyclic ring containing 1 or 2 nitrogen atoms.

[0012] The carboxyalkyl group represented by R ¹ is preferably a C carboxyalkyl group.

2-6

Specifically, for example, carboxymethyl, carboxyethyl, carboxypropyl, strong carboxybutyl, carboxypentyl and the like are preferable, and carboxyethyl is particularly preferable. The carboxyl group in the carboxyalkyl group may be esterified, or the “optionally esterified carboxyl group” may be represented by the formula —COOR (where R is a hydrogen atom or substituted, And a group represented by (representing a hydrocarbon group). Of these, carboxy, lower alkoxy carboyl, aryloxy carbo yl, aralkyl carboxy carbo and the like are preferable. Examples of the “lower alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec butoxycarbonyl, tert butoxycarbonyl, pentyloxycarbonyl, isopentyloxy And C alkoxycarbons such as carbo- yl and neopentyloxy carbo yl.

1-6

The Examples of “aryloxyballs” include C-aryloxyballs such as phenoxycarbon, 1-naphthoxyball, 2-naphthoxycarbol, etc.

7-12

I can get lost. Examples of the “aralkyloxycarbol” include C aralkyloxycarbol such as benzyloxycarbol, phenoxycarboxyl and the like (preferably

7-15

And C aryl-C alkoxy carbonyl).

6-10 1-6

[0014] In COR ^{5 represented} by R ² , the C aryl group represented by R ⁵ is a phenol group.

6-14

, A naphthyl group, an anthracenyl group, etc., and a phenyl group is preferred. The C carry

Examples of the substituent that the 6-14 group may have include, for example, a C alkyl group and a C alkoxy group.

1-6 1-6

Or a halogen atom etc. are mentioned. “C alkyl group” includes straight or branched C

1-6 1-6 kill groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec butyl, tert-butyl, n pentyl, isopentyl, 2-methylbutyl, neopentyl, 1 ethylpropyl , N-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3 dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2— Examples thereof include dimethylbutyl, 1,3 dimethylbutyl, 2,3 dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl. "C alkoxy group" includes straight or branched C alkoxy groups

1-6 1-6

Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec butoxy, tert butoxy, n-pentyloxy and the like. Examples of the halogen atom include a chlorine atom, a fluorine atom, and a bromine atom. In COR ^{5 represented} by R ² , the heterocyclic group represented by R ⁵ is, for example, a heterocyclic ring containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom, and Z or a sulfur atom. Group. Specific examples of the heterocyclic group include 1 pyrrolyl, 2 pyrrolyl, 3-pyrrolyl, pyrrolidyl, 1 imidazolyl, 2 imidazolyl, 4 imidazolyl, 1-pyrazolyl, 3 pyrazolyl, 4 pyrazolyl, virazolinyl, 2 thiazolyl, 4 Thiazolyl, 5 thiazolyl, 3 isothiazolyl, 4 isothiazolyl, 5 isothiazolyl, 2 oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4 isoxazolyl, 5 isoxazolyl, piperidino, 2 piperidyl, 4 piperidyl, 4 pyridyl, 4 3 pyridyl, 4 pyridyl, pyrajur, 2 pyrimidyl, 4 pyrimidyl, 5 pyrimidyl, 3 pyridazil, 4 pyridazil, 2 morpholinyl, 3 morpholinyl, 2 furyl, 3 furyl, vial, 2 or 3 chails Is preferred. Among these, as the heterocyclic group represented by R ⁵ , a 5-membered heterocyclic group containing one sulfur atom is preferred, and a 2-chenyl group or a 3-chyl group is more preferred, and a 2-chyl group is more preferred. . Examples of the substituent that the heterocyclic group may have may include the same group as the substituent that the C aryl group represented by R ⁵ may have.

6-14

[0016] The halogen atom represented by R ^3, for example, a chlorine atom, a fluorine atom, and bromine atom.

Esterification represented by R ³ may be the same as the carboxyl group in the carboxyalkyl group represented by R ¹ above as “esterified! /, May! /, Carboxyl group”. Groups.

[0017] The C alkyl group represented by R ⁴ includes the C aryl group represented by R ⁵ described above.

1-6 6-14

The same group as the C alkyl group as an optional substituent may be mentioned.

1-6 2-4 Alkyl group, n-propyl is most preferred!

[0018] As the salt of the compound represented by the general formula (I), a pharmaceutically acceptable salt is preferable. For example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, an organic salt. Examples include salts with acids, salts with basic or acidic amino acids, and the like. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Suitable examples of salts with organic bases For example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, Ν'-dibenzylethylene And salts with diamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, succinic acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfone. And salts with acid, ρ-toluenesulfonic acid and the like. Preferable examples of the salt with basic amino acid include salts with arginine, lysine, orthine and the like, and preferable examples of the salt with acidic amino acid include, for example, aspartic acid, glutamic acid and the like. Salt.

[0019] The prodrug of the compound represented by the general formula (I) includes a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid, or the like in a living body. As a prodrug of the compound represented by the general formula (I), for example, when the compound represented by the general formula (I) has a carboxyl group, the compound in which the carboxyl group is esterified or amidated, for example, Examples of the compound represented by the general formula (I) include, but are not limited to, compounds in which the carboxyl group of the compound represented by the general formula (I) is ethyl ester, phenyl ester, carboxymethyl ester, or methylamidated. . These compounds can be produced by known methods. The prodrug of the compound represented by the general formula (I) has a general formula under physiological conditions as described in Yodogawa Shoten, 1990, “Drug Development”, Vol. 7, “Molecular Design”, pages 163-198. It may be changed to the compound represented by (I). Salts or prodrugs of the compounds represented by the general formula (I) include hydrates and non-hydrates.

[0020] When the compound represented by the general formula (I) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, these are also represented by the general formula (I). As a compound.

[0021] The compound represented by the general formula (I) includes the general formula (II)

[Chemical 6]

(Wherein R ¹ ′ represents an optionally esterified carboxyalkyl group, R ³ ′ represents a hydrogen atom or a halogen atom, and R ⁵ has the same meaning as described above), or a general formula (III )

[Chemical 7]

(Wherein R ³ ″ represents an optionally carboxyl group, and R ⁴ has the same meaning as described above).

The carboxyalkyl group which may be esterified represented by R ¹ ′ in the general formula (Π) has the same meaning as the carboxyalkyl group represented by R ¹ above. As the optionally esterified carboxyalkyl group represented by R ¹ ′, carboxyethyl is preferable. The halogen atom represented by R ³ ′ has the same meaning as the halogen atom represented by R ³ .

Examples of the compound represented by the general formula (Π) include the following compounds (1) to (12) (hereinafter referred to as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, respectively). Compound 8, Compound 9, Compound 10, Compound 11 or Compound 12)):

(1) Compound 1

[Chemical 8]

(2) Compound 2

[Chemical 13]

(10) Compound 10 [Chemical 17]

Is

(12) Compound 12

[Chemical 19]

Etc. are preferable.

In the general formula (III), esterification represented by R ³ ″ may be used, and the carboxyl group may be

The esterification represented by R ³ may have the same meaning as L and a carboxyleno group. R ³ "may be esterified, but the carboxyl group is preferably carboxy! /.

[0025] Examples of the compound represented by the general formula (III) include:

[Chemical 20]

(Hereinafter referred to as Compound 13) and the like are preferred.

[0026] The compounds 1 to 13 are known compounds, and the compound represented by the general formula (I) can be easily produced based on a known method or a method known per se.

The optical isomers of the above compounds can be produced by a method known per se. For example, optically active synthetic intermediates are used, or the final racemate is optically resolved according to a conventional method. Can be obtained. Examples of the optical resolution method include methods known per se, such as fractional recrystallization method, chiral column method, diastereomer method and the like.

[0027] The compound represented by the general formula (I) or a salt or prodrug thereof used in the PPAR y agonist according to the present invention (hereinafter sometimes simply referred to as the compound of the general formula (I)) .) Can be covalently bound to cysteine present in the nuclear receptor. Confirmation of the covalent bond with cysteine can be carried out, for example, by the method described in JP-A-2006-30037.

[0028] The PPARγ agonist according to the present invention can be covalently bound to a receptor that activates proliferation of peroxisomes in a cell to activate (activate) the receptor. When PPARγ is activated (activated) by a ligand, glucose uptake can be activated in, for example, skeletal muscle, fat or liver. Therefore, it is possible to prevent or treat a state in which glucose uptake is suppressed, for example, an insulin resistant disease state. Insulin resistance includes a state in which the action of insulin that promotes glucose uptake from blood in skeletal muscle, fat, liver, or the like is reduced or suppressed in these tissues. Examples of insulin resistance pathologies include type II diabetes (insulin-independent diabetes), obesity, hyperlipidemia, arteriosclerosis and the like. Insulin-resistant conditions include type II diabetes

In addition, a state in which a plurality of diseases such as obesity or hyperlipidemia develop simultaneously, that is, metabolic syndrome and lifestyle-related diseases are also included.

Therefore, the PPARγ agonist according to the present invention can be used for the prevention or treatment of type II diabetes (insulin-independent diabetes), obesity, hyperlipidemia or arteriosclerosis. The prevention or treatment includes prevention, treatment or improvement of metabolic syndrome and lifestyle-related diseases.

In the present invention, type II diabetes includes abnormal glucose tolerance as a symptom before onset of type II diabetes. Prevention or treatment of type 2 diabetes includes lowering blood glucose levels. In addition, for the prevention or treatment of type 2 diabetes, glucose tolerance Includes delay or prevention of progression to disease, and also includes delay or prevention of progression from insulin-independent π-type diabetes to insulin-dependent type I diabetes, and diabetics associated with diabetes This includes delaying or preventing the progression of complications such as diabetic retinopathy, diabetic nephropathy or diabetic neuropathy.

[0030] In the present invention, obesity includes visceral fat accumulation type obesity. Obesity is a condition in which fat is excessively accumulated in the body, exhibits insulin resistance, and can induce type II diabetes and hypertension. For this reason, prevention or treatment of obesity includes prevention or prevention of type II diabetes and hypertension.

In the present invention, for prevention or treatment of hyperlipidemia, blood total cholesterol, LDL (low density lipoprotein) cholesterol, neutral fat (TG), free fatty acid value or remnant-like lipoprotein cholesterol ( RLP-cholesterol) or the like shows a high value, or prevention, treatment or improvement of a state where blood HDL cholesterol shows a low value. Further, the prevention of hyperlipidemia includes suppressing or preventing arteriosclerosis in the heart and brain caused by hyperlipidemia.

[0032] Arteriosclerosis is accompanied by stenosis or occlusion in the lumen of the arterial wall, accompanied by decreased blood flow, for example, transient ischemic attack, cerebral infarction, myocardial infarction, angina, etc. obtain. Atherosclerosis includes atherosclerosis. Prevention or treatment of arteriosclerosis includes, for example, suppressing or preventing cerebral artery disease such as cerebral infarction, coronary artery disease such as angina pectoris, and myocardial infarction.

[0033] The PPAR y agonist according to the present invention is used not only for humans but also for mammals other than humans (for example, monkeys, horses, horses, pigs, hidges, dogs, cats, rats, mice, chimpanzees, etc.). Is also applicable. The PPAR y agonists according to the present invention include human PPAR y agonists, and human PPAR y agonists are preferred when the PPAR y agonist is applied to humans.

[0034] The PPARγ agonist according to the present invention can be used for oral administration or parenteral administration by mixing the compound of general formula (I) as it is or by adding a pharmacologically acceptable carrier to the compound of general formula (I). The dosage form can be used. Examples of the dosage form for oral administration include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), syrups, and emulsions. Or suspension agents etc. It is. Examples of dosage forms for parenteral administration include injections, infusions, drops, suppositories, and the like. These preparations include, for example, butyric acid polymers, glycolic acid polymers, butyric acid-glycolic acid copolymers, mixtures of butyric acid polymers and glycolic acid polymers, or bases such as polyglycerol fatty acid esters. Combinations can be made into sustained-release preparations.

[0035] The content of the compound of the general formula (I) in the preparation in the PPAR y agonist according to the present invention is preferably selected as appropriate according to the form of the preparation, but is usually about 1! 99% by mass is preferred.

[0036] The PPAR y agonist according to the present invention can be produced by using the compound of the general formula (I) as a raw material, for example, the method described in the 14th revised Japanese Pharmacopoeia, General Rules for Preparations or generally used in this field. It can be carried out according to known production methods or according to known production methods. In addition, when the PPAR y agonist is produced in the above-mentioned dosage form, it is preferable to produce it by appropriately adding an appropriate amount of additives usually used in pharmaceutical preparations. Examples of the additive include excipients (eg, lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate, etc.), binders (eg, Gum arabic, carmelol or salts thereof, gelatin, carboxymethylcellulose, hydroxypropylcellulose, popidone, etc.), disintegrant (eg carmellose, starch, calcium carbonate, crystalline cellulose, low substituted hydroxypropylcellulose, etc.), lubricant ( For example, magnesium silicate, stearic acid, magnesium stearate, calcium stearate, talc, plasma paraffin, macrogol, etc.), surfactant (eg, sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester) Steal, polyoxyl stearate 40, polyoxyethylene coin castor oil, etc.), suspension or thickener (eg, gum arabic, sodium alginate, sodium carboxymethyl cellulose, methinoresanolose, popidone, hydroxypropyl methylcellulose) , Bentonite, etc.), emulsifiers (eg, gum arabic, cholesterol, stearic acid, povidone, polysorbate 80, etc.), solvents (eg, saline, normal water, purified water, sterilized purified water, water for injection, etc.) Vegetable oils such as olive oil and sesame oil; organic solvents such as isopropanol, glycerin and ethanol), coloring agents (eg titanium oxide), preservatives (eg For example, benzoic acid, benzalkonium chloride, benzethonium chloride, chlorobutanol, parabens, benzyl alcohol, etc.), fragrances (eg, methyl salicylate, wikial oil, thymol, menthol, etc.), flavoring agents (eg, fructose) , Simple syrup, glucose, D-sorbitol, sucrose and other sweeteners; hydrochloric acid, tartaric acid, etc.), stabilizers (eg, ascorbic acid, sodium thiosulfate, tocopherol, sodium bisulfite, etc .; antioxidants; edetic acid Chelating agents such as sodium), buffering agents (eg, phosphate buffer, sodium acetate buffer, etc.), analgesic glazes (eg, lidocaine, pro-hydrochloride, benzyl alcohol, etc.) or suppository bases (eg, Examples thereof include cocoa butter and macrogol.

[0037] When the PPARγ agonist according to the present invention is produced into, for example, a tablet, for example, the above-mentioned excipient, binder, disintegrant, lubricant and the like are added to the compound of the general formula (I). In the case of producing a pill or granule, for example, the compound of general formula (I) can be produced by containing the above-mentioned excipient, binder, disintegrant and the like. In the case of producing powders and capsules, for example, the above-mentioned excipients and the like are added to the compound of general formula (I), and in the case of producing syrups, for example, the compound of general formula (I) is used. In the case of producing an emulsion or a suspension by using a corrigent, a fragrance, a solvent and the like, for example, a suspending agent, a surfactant or an emulsifier and a solvent are added to the compound of the general formula (I) as an injection. For example, a solvent and a soothing agent are added to the compound of general formula (I), and a suppository base is added to the compound of general formula (I), for example. It can be made to contain. The tablet or capsule may be coated with an enteric coating agent such as methacrylic acid copolymer, hydroxypropylmethylcellulose acetate succinate or hydroxypropylmethylcellulose phthalate. As the capsule, an enteric capsule may be used.

[0038] The PPARy agonist according to the present invention can be used safely with stability and low toxicity. The daily dose varies depending on the patient's condition, body weight, type of compound, route of administration, etc.For example, in the case of oral administration to patients with type II diabetes, adult (body weight approximately 60 kg) The amount is about 1 μg to 500 mg, preferably about 10 μg to 50 mg as an active ingredient (a compound represented by the general formula (I) or a salt thereof or a prodrug thereof). It is preferable to administer in 3 divided doses.

[0039] The PPAR y agonist according to the present invention may be used as long as it does not inhibit the action of the present invention, For example, it can be used in combination with anti-obesity agents, anti-diabetic agents, anti-hyperlipidemic agents, antihypertensive agents and the like.

[0040] Examples of the anti-obesity agent include leptin, dextroamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, mazindol, phentermine and the like.

[0041] Antidiabetic drugs include insulin, sulfonylurea (eg, tolptamide, darribenclamide, daripizide, etc.), biguanide (eg, metformin, etc.), meglitide (eg, repaglinide, etc.), α-darcosidase Inhibitors (for example, miglitonole, akanolevose, etc.), nateglinide, troglitazone, rosiglitazone, pioglitazone and the like can be mentioned.

[0042] Antihyperlipidemic agents include, for example, cholestyramine, colestipol, clofibrate, gemfib mouth gil, fenofibrate, tesaglitazar, atorvastatin, flupastatin, oral pastatin, pravastatin, simpastatin, cerivastatin, and assipimottas , Probucol or dextrothyroxine.

[0043] Examples of antihypertensive agents include 13 blockers such as alprenolol, atenolol, timolol, pindolol or propranolol; angiotensin converting enzyme such as benazepril, captopril, enalabril, fuocinopril, lisinopril, quinapril or ramipril. Inhibitors:-fedipine, ferrodipine,-cardipine, isradipine,-calcium channel blockers such as modipine, diltiazem or veranomil; and 1 blocker such as doxazosin, urapidil, prazosin or terazosin.

[0044] The present invention also provides the use of a compound represented by the general formula (I) or a salt thereof or a prodrug thereof for producing an agent for preventing or treating an insulin-resistant pathological condition. Preferably, the use of the compound represented by the general formula (I) or a salt thereof or a prodrug thereof for producing a therapeutic agent for type 2 diabetes, obesity, hyperlipidemia or arteriosclerosis. The compound represented by formula (I) and preferred forms thereof are the same as described above. The compound represented by the general formula (I) or a salt thereof, a prodrug thereof or a production method thereof is the same as described above.

[0045] The present invention further relates to a method for preventing or treating an insulin-resistant pathological condition wherein a compound represented by the general formula (I) or a salt thereof or a prodrug thereof is administered to mammals including humans. There is also. The compound represented by formula (I) and preferred forms thereof are the same as described above. The compound represented by the general formula (I) or a salt thereof, a prodrug thereof or a production method thereof is the same as described above.

[0046] The prevention or treatment method of the present invention includes mammals including humans, that is, mammals other than humans, such as monkeys, mice, horses, pigs, hidges, nu, cats, rats. It can also be applied to mice, chimpanzees, etc. That is, an insulin-resistant pathological condition is prevented or treated by administering a compound represented by the general formula (I) or a salt thereof or a prodrug thereof to these mammals. The prevention or treatment method of the present invention is preferably applied to a patient exhibiting an insulin-resistant pathological condition that is preferably applied to a human. In addition, among insulin-resistant pathologies, it is preferably applied to patients with type II diabetes, obesity, hyperlipidemia, or arteriosclerosis. When the prevention or treatment method of the present invention is applied to humans, it is preferable to administer human PPARy agonists.

[0047] The method of administering the compound represented by the general formula (I) or a salt thereof or a prodrug thereof to a human or the like is not particularly limited, and may be administered by an appropriate administration route according to the formulation form. it can. In addition, the compound represented by the general formula (I) or a salt thereof or a prodrug thereof and other drugs such as the above-mentioned anti-obesity agent, anti-diabetic drug, A hyperlipidemia agent, an antihypertensive agent or the like can also be used in combination.

[0048] ¾fine 1

The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

Example 1

[0049] Measurement of ligand transcriptional activity using rhodamine maleimide in recombinant nuclear receptor ligand binding domain (PPAR y LBD)

(1) Expression and purification of recombinant ppAR y LBD in E. coli

Novagen's pET28b NdelZBamHI site contains DNA with human PPARy (SEQ ID NO: 1) and BD (aa. 195-477) N-end and C-end restriction enzyme sites (Ndel and BamHI) added. Cloning was performed, and the nucleotide sequence was confirmed by sequencing. E. coli BL 21 (DE3) was transformed into 1 L LB (Luria-Bertani) medium (1% by mass Bacto Tripton 0.5 Incubate at 37 ° C until the absorbance (OD600nm) reaches 0.8 with 1% by weight Yeast Extract, 1% by weight NaCl), then cool to 18 ° C and ImM IPTG (Isopropyl-1-thio-β — D-galatatopyranoside) was added and cultured for 18 hours. E. coli was collected by centrifugation, suspended in 20 mM Hepes (pH 7.4), 200 mM NaCl, 25 mM imidazole solution, and stored at −20 ° C.

[0050] The cells were sonicated and the insoluble protein was removed by centrifugation. After that, the cells were subjected to affinity chromatography using a nickel ram (eluent: 20 mM Tris (pH7.4), 250 mM NaCl, 250 mM imidazole). PPAR y LBD was purified. Further, the buffer eluate was replaced with 20 mM Tris (pH 7.4) and 150 mM NaCl at the same time as purification by Superdex 200 gel filtration chromatography. The obtained PPAR y LBD was concentrated by ultrafiltration until the concentration of PPAR y LBD was about 5 mgZmL to obtain a PPAR y LBD solution.

[0051] (2) Measurement of ligand transcriptional activity using rhodamine maleimide

After mixing 0.1 M PPAR y LBD solution with 10 μΜ of ligand (Compound 12) in dimethylsulfoxide (DMSO) and incubating for 30 minutes at room temperature, sodium dodecyl sulfate (SDS) was added. 0.5 WZV%, rhodamine maleimide (Molecular Probe) was added to 200 M and TCEP (tris [2-carboxyethyl] phosphine) was added to ImM, and the mixture was incubated at room temperature for 30 minutes. After performing SDS-PAGE (polyacrylamide gel electrophoresis), the amount of PPAR y LBD labeled with rhodamine maleimide was measured with a fluorescence imager (FMBIO II manufactured by Hitachi, Ltd.).

As a control, DMSO was used instead of the ligand in DMSO. Also, as a positive control, do not bind to PPAR y instead of compound 12! 12 BRL49653 (mouth ciglitazone; J. Biol. Chem., 2005, Vol. 280 (14), 14145-14153) and MCC555 (J. Chem., 19 98, Vol. 273 (49), 32679-32684), and 15d—PGj covalently bound to PPAR γ and

2

GW9662 (2-black mouth 5-nitro 1-phenol benzamide; PPAR y antagonist; Biochemistry; 2002; 41 (21); 6640-6650) was used.

[0052] The results are shown in FIG. FIG. 1 shows that the signal of PPARγ LBD labeled with rhodamine maleimide is weak, indicating that the ligand is covalently bound. BRL49653 When MCC555 and PPAR y LBD solution were incubated, the signal of P PAR γ LBD was as strong as that of the control, indicating that PPAR y LBD was not covalently bound to BRL49653 or MCC555. On the other hand, 15d-PGi or GW9662 and PPAR y

2

When the LBD solution is incubated, the PPAR y LBD signal is very weak compared to the control. 15d-PGj or GW9662 is covalently bound to PPAR y LBD and the ligand.

2

Showed that. When Compound 12 and the PPAR y LBD solution were incubated, the signal of PPAR y LBD was almost the same as that of 15d-PGj. This is a compound

2

This shows that 12 is covalently bound to PPAR γ LBD of the same degree as 15d-PGi.

2

Example 2

[0053] Luciferase activity in cultured COS-7 cells

The transcriptional activity of compounds 1-13 was evaluated for luciferase activity in cultured COS-7 cells. That is, COS-7 cells were cultured in a culture solution [Dulbecco's modified Eagle medium (DMEM) containing 10% FCS (child fetus serum)]. COS-7 cells cultivated the day before transfection are seeded in 24-well plates at 5 x 10 ⁴ cells, and the next day, UA S -tk-Luc, pEYFP-Cl, pCMX-gal- PPAR γ The plasmid (shiraki, T. et al., J. Biol. Chem., 280: 14145-14153, 2005) was transferred, and after 6 hours, the culture medium was changed and the ligand (compounds 1-13) dissolved in DMSO was exchanged. ) Was added to a final concentration of 10M. Cells were collected 24 hours after the transfusion, and the enzyme activity of the expressed luciferase was measured using a kit with luciferin as a substrate (Pitsukagene; manufactured by Toyo Ink Co., Ltd.) with an excitation wavelength of 485 nm and a fluorescence wavelength of 530 nm. Evaluation was made by measuring fluorescence. Luciferase activity was measured by photon counting and expressed as the value divided by the fluorescence intensity of YFP. As a control, DMSO was used in place of the ligand in DMSO, and 15d-PGj was used as a positive control.

2

Fig. 2 shows the luciferase activity of the ligand (compounds 1 to 13). Both compounds show that luciferase activity has higher transcriptional activity than the control.

Industrial applicability

[0054] The PPARγ agonist of the present invention is useful as an agent for preventing or treating an insulin-resistant pathological condition.

Claims

The scope of the claims

Formula (I)

[Chemical 1]

(In the formula, Α ring represents a heterocyclic ring, R ¹ represents a hydrogen atom or a carboxyalkyl group which may be esterified, R ² represents — COR ⁵ (wherein R ⁵ has a substituent) C carry

6-14 represents a heterocyclic group which may have a substituent or a substituent. ) Or — NO, R ³ is water

2

1-6

A peroxisome proliferator-activated receptor gamma (P PAR γ) agonist characterized by containing a drug.

[2] The agent according to claim 1, wherein the ring is a furan ring or a pyrazole ring.

[3] The compound is represented by the general formula (Π)

[Chemical 2]

(Wherein R ¹ ′ represents an optionally esterified carboxyalkyl group, R ³ represents a hydrogen atom or a halogen atom, R ⁵ has a substituent, may be a C aryl group or Place

6-14

It may have a substituent and represents a heterocyclic group. 2. The agent according to claim 1, which is a compound represented by

[4] The agent according to claim 3, wherein the aryl group represented by R ⁵ is a phenol group.

[5] The agent according to claim 3, wherein the heterocyclic group represented by R ⁵ is a 2-chenyl group.

[6] The compound is [Chemical 3]

The agent according to claim 3, which is The compound has the general formula (III)

[Chemical 4]

The agent according to claim 1, which is a compound represented by the formula (wherein R represents a carboxyl group which may be esterified, and R represents a hydrogen atom or a C alkyl group).

1-6

[8] The compound is

[Chemical 5]

The agent according to claim 7, which is

[9] The agent according to any one of claims 1 to 8, which is a preventive or therapeutic agent for an insulin-resistant disease state.

[10] The agent according to item 9 of the scope of claim, which is type 1 diabetes, obesity, hyperlipidemia or arteriosclerosis.

[11] General formula (I) for producing a prophylactic or therapeutic agent for an insulin-resistant condition

[Chemical 6]

Or a salt thereof or a prodrug thereof c

[12] General formula (I) for mammals including humans [Chemical 7]

A method for preventing or treating an insulin-resistant pathological condition, which comprises administering a compound represented by the formula: