WO2007122970A1 - Ligand capable de se lier À un récepteur NUCLÉAIRE - Google Patents

Ligand capable de se lier À un récepteur NUCLÉAIRE Download PDF

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WO2007122970A1
WO2007122970A1 PCT/JP2007/056780 JP2007056780W WO2007122970A1 WO 2007122970 A1 WO2007122970 A1 WO 2007122970A1 JP 2007056780 W JP2007056780 W JP 2007056780W WO 2007122970 A1 WO2007122970 A1 WO 2007122970A1
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group
compound
general formula
agent according
represented
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PCT/JP2007/056780
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Takuma Shiraki
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Osaka University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a human peroxisome proliferator-activated ⁇ receptor gamma (hereinafter abbreviated as PPAR ⁇ ) agonist.
  • PPAR ⁇ human peroxisome proliferator-activated ⁇ receptor gamma
  • 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.
  • 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.
  • 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.
  • the body is metabolically and chemically unstable and cannot be used as a medicine.
  • thiazolidine derivatives have been reported as ligands for PPAR ⁇ .
  • 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
  • benzofuran derivatives see, for example, Patent Document 16.
  • 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.
  • 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).
  • Patent Document 17 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 ⁇ , 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—
  • 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
  • An object of the present invention is to provide a novel PPAR y agonist having a novel structure.
  • 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 ⁇ , / 3-unsaturated ketones were extracted by motif search (database: Namiki Shoji Co., Ltd.). Among the extracted compounds having ⁇ -unsaturated ketone, compounds having ⁇ -unsaturated ketone on the straight chain were selected.
  • 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
  • R 4 represents a hydrogen atom or a C alkyl group. Or a salt thereof or a pro thereof
  • PPAR y agonist characterized in that it contains a drug
  • 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
  • the present invention also relates to an insulin-resistant pathological condition characterized by administering a PPAR ⁇ 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.
  • 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.
  • an insulin-resistant pathological condition such as type II diabetes, obesity, hyperlipidemia or arteriosclerosis.
  • 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.
  • FIG. 1 shows the results of SDS-PAGE of PPAR y LBD labeled with rhodamine maleimide.
  • FIG. 2 is a graph showing the luciferase activity of a ligand in cultured COS-7 cells. (Example 2)
  • 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.
  • heterocyclic ring examples 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.
  • 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.
  • the carboxyalkyl group represented by R 1 is preferably a C carboxyalkyl group.
  • 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).
  • R is a hydrogen atom or substituted
  • a group represented by Representing a hydrocarbon group
  • lower alkoxycarbonyl examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec butoxycarbonyl, tert butoxycarbonyl, pentyloxycarbonyl, isopentyloxy And C alkoxycarbons such as carbo- yl and neopentyloxy carbo yl.
  • aryloxyballs include C-aryloxyballs such as phenoxycarbon, 1-naphthoxyball, 2-naphthoxycarbol, etc.
  • aralkyloxycarbol examples include C aralkyloxycarbol such as benzyloxycarbol, phenoxycarboxyl and the like (preferably
  • COR 5 represented by R 2 the C aryl group represented by R 5 is a phenol group.
  • 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.
  • 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
  • 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.
  • heterocyclic group examples 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
  • 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.
  • 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.
  • 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.
  • the C alkyl group represented by R 4 includes the C aryl group represented by R 5 described above.
  • a pharmaceutically acceptable salt is preferable.
  • 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.
  • 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.
  • salts with organic bases For example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, ⁇ '-dibenzylethylene And salts with diamine and the like.
  • 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, ⁇ -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.
  • 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.
  • 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. .
  • 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.
  • the compound represented by the general formula (I) includes the general formula (II)
  • R 1 ′ represents an optionally esterified carboxyalkyl group
  • R 3 ′ represents a hydrogen atom or a halogen atom
  • R 5 has the same meaning as described above
  • 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 ( ⁇ ) has the same meaning as the carboxyalkyl group represented by R 1 above.
  • 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 ( ⁇ ) 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).
  • Etc. are preferable.
  • esterification represented by R 3 ′′ may be used, and the carboxyl group may be used.
  • 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! /.
  • Examples of the compound represented by the general formula (III) include:
  • Compound 13 (Hereinafter referred to as Compound 13) and the like are preferred.
  • 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.
  • optical isomers of the above compounds can be produced by a method known per se.
  • optically active synthetic intermediates are used, or the final racemate is optically resolved according to a conventional method. Can be obtained.
  • optical resolution method include methods known per se, such as fractional recrystallization method, chiral column method, diastereomer method and the like.
  • 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.
  • the PPAR ⁇ 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.
  • PPAR ⁇ When PPAR ⁇ 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
  • the PPAR ⁇ 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.
  • 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.
  • glucose tolerance Includes delay or prevention of progression to disease, and also includes delay or prevention of progression from insulin-independent ⁇ -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.
  • 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.
  • 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
  • prevention, treatment or improvement of a state where blood HDL cholesterol shows a low value or prevention, treatment or improvement of a state where blood HDL cholesterol shows a low value.
  • the prevention of hyperlipidemia includes suppressing or preventing arteriosclerosis in the heart and brain caused by hyperlipidemia.
  • 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.
  • 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.
  • the PPAR ⁇ 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.
  • 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.
  • dosage forms for parenteral administration include injections, infusions, drops, suppositories, and the like.
  • compositions 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.
  • 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.
  • 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.
  • the additive examples 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 arab
  • the PPAR ⁇ 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).
  • the compound of general formula (I) can be produced by containing the above-mentioned excipient, binder, disintegrant and the like.
  • 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.
  • a suspending agent, a surfactant or an emulsifier and a solvent are added to the compound of the general formula (I) as an injection.
  • a solvent and a soothing agent are added to the compound of general formula (I)
  • 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.
  • 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 ⁇ g to 500 mg, preferably about 10 ⁇ g 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.
  • 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.
  • anti-obesity agent examples include leptin, dextroamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, mazindol, phentermine and the like.
  • Antidiabetic drugs include insulin, sulfonylurea (eg, tolptamide, darribenclamide, daripizide, etc.), biguanide (eg, metformin, etc.), meglitide (eg, repaglinide, etc.), ⁇ -darcosidase Inhibitors (for example, miglitonole, akanolevose, etc.), nateglinide, troglitazone, rosiglitazone, pioglitazone and the like can be mentioned.
  • sulfonylurea eg, tolptamide, darribenclamide, daripizide, etc.
  • biguanide eg, metformin, etc.
  • meglitide eg, repaglinide, etc.
  • ⁇ -darcosidase Inhibitors for example, miglitonole, akanolevose, etc.
  • nateglinide for
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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- ⁇ — 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.
  • 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.
  • ligand Compound 12
  • DMSO dimethylsulfoxide
  • SDS sodium dodecyl sulfate
  • TCEP tris [2-carboxyethyl] phosphine
  • GW9662 (2-black mouth 5-nitro 1-phenol benzamide; PPAR y antagonist; Biochemistry; 2002; 41 (21); 6640-6650) was used.
  • FIG. 1 shows that the signal of PPAR ⁇ 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 ⁇ LBD was as strong as that of the control, indicating that PPAR y LBD was not covalently bound to BRL49653 or MCC555.
  • 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.
  • 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 ⁇ The plasmid (shiraki, T. et al., J. Biol.
  • 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.
  • the PPAR ⁇ agonist of the present invention is useful as an agent for preventing or treating an insulin-resistant pathological condition.

Abstract

L'invention concerne un agoniste gamma du récepteur activé par le proliférateur de peroxysome (PPARγ) qui comprend un composé représenté par la formule générale (I) ou un sel de celui-ci ou un promédicament du composé ou du sel : (I) dans laquelle le cycle A représente un noyau hétérocyclique ; R1 représente un atome d'hydrogène ou un groupe carboxyalkyle qui peut être estérifié ; R2 représente -COR5 (où R5 représente un groupe aryle en C6-14 qui peut avoir un substituant ou un groupe hétérocyclique qui peut avoir un substituant) ou –NO2 ; R3 représente un atome d'hydrogène, un atome d'halogène ou un groupe carboxyle qui peut être estérifié ; R4 représente un atome d'hydrogène ou un groupe alkyle en C1-6.
PCT/JP2007/056780 2006-04-20 2007-03-29 Ligand capable de se lier À un récepteur NUCLÉAIRE WO2007122970A1 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine

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