WO2002046176A1 - Activateurs de recepteur active par le proliferateur de peroxisome - Google Patents

Activateurs de recepteur active par le proliferateur de peroxisome Download PDF

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Publication number
WO2002046176A1
WO2002046176A1 PCT/JP2001/010577 JP0110577W WO0246176A1 WO 2002046176 A1 WO2002046176 A1 WO 2002046176A1 JP 0110577 W JP0110577 W JP 0110577W WO 0246176 A1 WO0246176 A1 WO 0246176A1
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group
carbon atoms
alkyl
alkyl group
atom
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PCT/JP2001/010577
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English (en)
Japanese (ja)
Inventor
Shinichi Yoshida
Shogo Sakuma
Tsuyoshi Endo
Atsushi Tendo
Toshihiro Takahashi
Kunio Kobayashi
Nobutaka Mochiduki
Tomio Yamakawa
Takashi Kanda
Seiichiro Masui
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Nippon Chemiphar Co., Ltd.
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Priority to AU2002224139A priority Critical patent/AU2002224139A1/en
Priority to JP2002547915A priority patent/JPWO2002046176A1/ja
Publication of WO2002046176A1 publication Critical patent/WO2002046176A1/fr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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 an activator of a peroxisome proliferator-activated receptor. Background technology
  • Peroxisome is a small organ found in the cells of animals and plants.
  • Peroxisome proliferate is a substance that induces the growth of peroxisomes, and is a diverse compound such as antilipidemic drugs (fibrates), herbicides, and plasticizers of fluorate. Flock is known.
  • peroxisome proliferator-responsive receptor peroxisome proliferator-responsive receptor
  • fibrates mentioned above have a ligand effect on PPAR, and a strong serum TG (triglyceride) lowering effect has been recognized in clinical practice.
  • thiazolidinedione compounds which are therapeutic agents for diabetes, are known as ligands for PPARa.
  • a drug having a PP ARd activating effect for example, the following formula:
  • YM—16638 (Yamanouchi Pharmaceutical) and others are known.
  • GW-2433 is described in WO 92 0468 for use as a prophylactic and therapeutic agent for atherosclerosis
  • L-165041 is described in WO 97/281 15 for use as a therapeutic agent for diabetes and as an antiobesity agent
  • YM-16638 is described in WO99 / 04815 as having a serum cholesterol lowering effect and an LDL monocholesterol lowering effect.
  • PPARd ligands have been reported to promote their use as anti-cancer and anti-inflammatory agents (JBC, 272 (6), p 3406-3410, 1997; Cell, 99, 335-345, 1999). I have.
  • thiazole derivative represented by the following general formula (II)
  • bezafibrate having serum lipid improving activity bezafibrate having serum lipid improving activity
  • Both bezafibrate and the compound of the present invention have a chemical structure in which an alkyl group substituted with an amino group and an alkoxy group substituted with a carboxyl group are bonded to a benzene ring, and the alkyl group substituted with the amino group is Zafibrate is an N- (p-chlorobenzoyl) aminoalkyl group, and the compound of the present invention is an N- (nitrogen-containing heterocycle or nitrogen-containing heterocyclecarbonyl) aminoalkyl group, and both are structurally distinct. I do.
  • the above GW-2433 (WO 92/10468) also has a chemical structure in which an alkyl group substituted with an amino group and an alkoxy group substituted with a carboxyl group are bonded to a benzene ring. Since the alkyl group substituted with the group is an N- (phenylcarbamoyl) aminoalkyl group, the structure is clearly different from the compound of the present invention.
  • An object of the present invention is to provide a compound represented by the following general formula (I) having the activity of activating a peroxisome proliferator-activated receptor, a thiazole derivative represented by the following general formula (II) and a salt thereof.
  • a compound represented by the following general formula (I) having the activity of activating a peroxisome proliferator-activated receptor, a thiazole derivative represented by the following general formula (II) and a salt thereof.
  • R 1 and R 2 are each a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or 6 carbon atoms.
  • R 1 and R 2 may together form a benzene ring with the carbon atom to which R 1 and R 2 are attached,
  • X is an oxygen atom, a sulfur atom, —NR.
  • G represents a single bond or a carbonyl group
  • R 3 is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and 3 to 7 carbon atoms
  • n an integer of 0 to 5
  • Z represents an oxygen atom or a sulfur atom
  • p represents an integer from 0 to 5
  • W is a carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a sulfonate group, a phosphonate group, a cyano group, or Represents a tetrazolyl group.
  • the benzene ring formed with carbon atoms is an alkyl group having 1 to 8 carbon atoms, Alkoxy group having 1 to 8 carbon atoms, alkoxycarbonyl group having 2 to 8 carbon atoms, acyl group having 2 to 8 carbon atoms, formyl group, hydroxyl group, halogen atom, nitro group, amino group, alkylamino group (alkyl The group may have a substituent selected from 1 to 8) or a dialkylamino group (the alkyl group has 1 to 8 carbon atoms). )
  • R 6 and R 7 are each a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an aryl group having 6 to 10 carbon atoms. Or R 6 and R 7 may be taken together to form a benzene ring with the carbon atom to which R 6 and R 7 are attached,
  • G 1 represents a single bond or a carbonyl group
  • R 8 is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and 3 to 7 carbon atoms
  • n an integer from 0 to 5
  • Z 1 represents an oxygen atom or a sulfur atom
  • R s and R 1Q each represent an alkyl grave hydrogen atom or a carbon atom number of 1-8, and R represents a hydrogen atom or an alkyl group having a carbon number of 1-6.
  • Ariru groups of R 6 and R 7, Ariru group R 8, ⁇ reel alkyl group, a heterocyclic Ring group, a heterocyclic alkyl group, and R 6 and R 7 gar benzene ring formed together with the carbon atom bonded R 6 and R 7 are taken ⁇ alkyl group having 1 to 8 carbon atoms, charcoal Alkoxy group having 1 to 8 carbon atoms, alkoxycarbonyl group having 2 to 8 carbon atoms, acyl group having 2 to 8 carbon atoms, formyl group, hydroxyl group, halogen atom, nitro group, amino group, alkylamino group (alkyl The group may have a substituent selected from 1 to 8) or a dialkylamino group (the alkyl group has 1 to 8 carbon atoms). )
  • the present invention relates to an activator of PPAR containing a compound represented by the above general formula (I), a compound represented by the above general formula (II) or a salt thereof as an active ingredient.
  • an activator of PPAR containing a compound represented by the above general formula (I), a compound represented by the above general formula (II) or a salt thereof as an active ingredient.
  • Examples of the halogen atom of] 3 ⁇ 4R 2 in the above general formula (I) include a fluorine atom, a chlorine atom and a bromine atom.
  • ⁇ 1 , R ⁇ RRR 4 and; R 5 having 1 to 8 carbon atoms as the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-butyl group, or And a pentyl group.
  • Examples of the alkoxy group having 1 to 8 carbon atoms of 1 and R 2 include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, an i-butyloxy group, a t-butyloxy group, and a pentyloxy group. No.
  • Examples of the alkenyl group having 2 to 8 carbon atoms for R 3 include a vinyl group and an aryl group.
  • alkynyl group having a carbon number 2-8 of R 3 propargyl group and the like, et al is 0
  • Examples of the cycloalkyl group having 3 to 7 carbon atoms for R 3 include a cyclohexyl group and a cyclopentyl group.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted with a cycloalkyl group having 3 to 7 carbon atoms for R 3 include a cyclohexylmethyl group and a cyclopentylmethyl group.
  • Examples of the arylalkyl group of R 3 include a benzyl group and a phenethyl group.
  • heterocyclic group of R 3 examples include a phenyl group, a furyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, an imidazolyl group, a quinolyl group, an indolyl group, and a benzofuranyl group.
  • heterocyclic alkyl group for R 3 (having 1 to 8 carbon atoms in the alkyl portion) those in which the heterocyclic group exemplified as the heterocyclic group for R 3 above is substituted with a methyl group, an ethyl group, or a propyl group are exemplified. No.
  • Examples of the alkoxy group having 1 to 8 carbon atoms include methoxy group, ethoxy group, propyloxy group, An isopropyloxy group, a butyloxy group, an i-butyloxy group, a t-butyloxy group, a pentyloxy group, and the like.
  • Examples of the alkoxycarbonyl group having 2 to 8 carbon atoms include a methoxycarbonyl group
  • Examples of the acryl group having 2 to 8 carbon atoms include an acetyl group and a propionyl group.
  • Examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom.
  • the alkylamino group (the alkyl group has 1 to 8 carbon atoms) includes a methylamino group and an ethylamino group, and the dialkylamino group (the alkyl group has 1 to 8 carbon atoms) has a dimethyl group. And a lumino group and a getylamino group.
  • the same halogen atoms as those exemplified for R 1 and R 2 in the above general formula (I) can be used.
  • the alkyl group having 1 to 8 carbon atoms of R 1D is the same as the alkyl group exemplified for I 1 , R ⁇ RR 4 and R 5 , and the same alkyl group having 1 to 8 carbon atoms of R 6 and R 7 .
  • the alkoxy group include the alkoxy groups exemplified for R 1 and R 2 .
  • R 8 is an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and a cycloalkyl group having 3 to 7 carbon atoms.
  • Examples of the ⁇ alkyl group include those exemplified for R 3 in the above general formula (I).
  • Examples of the aryl groups of RR 7 and R 8 include those exemplified as the aryl groups of 1 , R 2 and R 3 in the general formula (I).
  • the aryl group of H 6 and R 7 , the aryl group of R 8, an arylalkyl group, a heterocyclic group, a heteroalkyl group, and R 6 and H 7 together form R 6 And an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a carbon atom, which may be a substituent that the benzene ring formed with the carbon atom to which R 7 is bonded may have.
  • R 8 is an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms as a substituent.
  • the compound of the present invention includes a thiazole derivative represented by the above general formula (II) wherein Y 1 is —CH 2 — among the thiazole derivatives represented by the above general formula (II) A derivative or a salt thereof, or a thiazole derivative represented by the above general formula (II) wherein H 8 is as described in the above (1) and Y 1 is —CH 2 — or a salt thereof is preferable.
  • R 6 and R 7 are each a hydrogen atom, a nitro group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t- C1-C6 alkyl such as butyl or pentyl, methoxy, ethoxy, proviroxy, isopropyloxy, butyloxy, i-butyloxy, t-butyloxy or pentyloxy, etc. It preferably represents an alkoxy group having 1 to 6 atoms, or: R 6 and R 7 together form a benzene ring with the carbon atom to which 6 and R 7 are bonded.
  • G 1 is a single bond or a carbonyl group.
  • R 8 is an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group or a pentyl group; Has preferably 1 to 6), more preferably a phenylalkyl group such as a benzyl group, a phenethyl group or a 3-phenylpropyl group (the alkyl portion has 1 to 6 carbon atoms).
  • m is preferably an integer of 1 to 4.
  • Y 1 is preferably one CH 2 —.
  • Z 1 is preferably an oxygen atom.
  • R 1 D are the same or different and are preferably an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group or a pentyl group.
  • R 9 and R 1 11 are both include methyl group, Echiru or propyl.
  • R is preferably a hydrogen atom.
  • Alkoxy having 1 to 6 carbon atoms such as an alkyl group having 1 to 6 carbon atoms, such as an alkyl group, a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butyloxy group, an i-butyloxy group, a t-butyloxy group or a pentyloxy group.
  • the compound of the present invention represented by the above general formula (I) and its salt, and the thiazole derivative represented by the above general formula (II) and its salt, are cis and trans geometric isomers and optical isomers. May exist, but these isomers are also included in the present invention.
  • the compounds of the present invention also include pharmaceutically acceptable salts such as alkali metal salts such as sodium salt and potassium salt.
  • Q 1 represents a leaving group such as a bromine atom or a chlorine atom
  • RR 2 , RRR Xs G, n, Y, Z, p and W are the same as described above.
  • the above reaction is represented by the general formula (a )
  • the compound represented by the general formula (b) can be carried out in the presence of a base such as potassium carbonate in a solvent such as acetone or ethyl methyl ketone.
  • the phenol (or thiophenol) derivative represented by the general formula (a) as a raw material can be obtained, for example, by the following method.
  • the compound of the general formula (e) is obtained by converting a heterocyclic compound of the general formula (c) and an amine of the general formula (d) into a solvent such as DMS0 in the presence of a base such as sodium hydride.
  • a base such as sodium hydride.
  • T is a protecting group of a hydroxyl group (or a mercapto group)
  • the compound of the general formula (f) can be obtained by further deprotecting the obtained compound of the general formula (e).
  • Q 3 represents a hydroxyl group, a p-tosyl group, a halogen atom such as a bromine atom or a chlorine atom, or an alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy or butoxy, and 1 , R 2 , R 3 , X, n, Z and T are the same as above.
  • the compound of the general formula (h) is obtained by reacting the carboxylic acid derivative of the general formula (g) with the amine of the general formula (d) in the presence of a base such as sodium methoxide in a solvent such as benzene. (Amidation reaction).
  • T is a protecting group
  • the compound represented by the general formula (i) can be obtained by further deprotecting the compound represented by the general formula (h).
  • R 2fl represents an alkyl group, and! ⁇ 1 , RRRR 5 , X, G, n, Y, and p are the same as described above.
  • the compound represented by the general formula (k) is represented by the general formula (j ) Can be obtained by subjecting the ester to a hydrolysis reaction in a solvent such as ethanol in the presence of a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • the PPAR activating effect of the compound of the present invention was determined by expressing chimeric receptor expression plasmid (GAL4-hPPARd LBD), repo overnight plasmid (UAS X 4-TK-LUC) and 3-galactosidase in CV-1 cells. After transfection of the ( ⁇ -GAL) expression plasmid with the Lipofection reagent DMR IE-C (Lite Technologies), after culturing for 40 hours in the presence of the compound of the present invention or GW-2433 which is a comparative compound, Solubilized cells were determined by measuring luciferase activity and / or GAL activity.
  • the luciferase activity was corrected by one GAL activity.
  • the relative ligand activities for the PPAR and y-activating effects were calculated. (Example 8 described later)
  • the compound of the present invention exhibited an excellent PPAR activating action (PPAR, ⁇ or ( ⁇ activating action)).
  • the compound represented by the general formula (I) of the present invention has an excellent PPAR activating effect, and is therefore a hypoglycemic agent, a lipid-lowering agent, obesity, syndrome X, hypercholesterolemia.
  • Metabolic disorders such as hyperlipoproteinemia, hyperlipidemia, arteriosclerosis, cardiovascular disease, bulimia, ischemic disease, lung cancer, breast cancer, colon cancer, colon cancer, colon cancer, ovarian cancer, etc. Tumors, Alzheimer's disease, inflammatory diseases, osteoporosis (Mano H. et. A 1., (2000) J. Biol.
  • the compound of the present invention can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration.
  • excipients include lactose, D-mannitol, crystalline cellulose, pudose, etc.
  • Disintegrants include starch, carboxymethylcellulose, scalcium (CMC-Ca), etc.
  • lubricants examples include magnesium stearate and talc
  • binder examples include hydroxypropyl cellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP).
  • the dose of the compound of the present invention which is an active ingredient in an injection, is about 0.1 mg / day: L 00 mg / day, and 1 mg / day to 20 mg / day by oral administration, but may vary depending on age, symptoms, etc. can do.
  • the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.
  • the organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate.
  • the extract was washed successively with water (6 mL) and saturated saline (6 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was purified by silica gel column chromatography (black form) to obtain 0.99 g (yield: 50.0%) of the title compound as white crystals.
  • N2 -Promo-2-ethyl propionate (400 mg, 2.05 mmo 1) and potassium carbonate (280 mg, 2.03 mmo 1) were dried with acetone mL) and heated under reflux for 43 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed sequentially with water and saturated saline.
  • This crude product (354 mg) was dissolved in a mixed solvent of THF (2.1 mL) and isopropanol (1.2 mL), 2 M hydrochloric acid aqueous solution (1.2 mL) was added, and the mixture was stirred at 50 ° C for 17 hours. Stirred for 30 minutes. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and washed sequentially with water and saturated saline.
  • reaction solution was washed successively with a mixed solution of water and a 1 M aqueous hydrochloric acid solution, an aqueous sodium hydrogencarbonate solution, and water, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to remove 1.44 g of the solvent.
  • a crude product of N-isobutyl-3- (4-methoxymethoxyphenyl) -12-propenamide was obtained as white crystals.
  • N-isoptyl-N- [3- (4-Methoxy methoxyphenyl) propyl)] Dissolve 1,3-thiazoluyl 2-carboxamide (416 mg) in a mixed solvent of THF (2.5 mL) and isopropanol (1.7 mL), add 2M aqueous hydrochloric acid (1.7 mL), and add The mixture was stirred at ° C for 18 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed sequentially with water and saturated saline.
  • MEK 2-butenonone
  • Test compound [Examples 1-3, 5 and GW-2433 of known PPAR5 agonist (Berger, J. et al., (1999) J. Biol. Chem., 274: 6718) -6725)] was measured as follows.
  • African green monkey kidney fibroblasts (CV-1 cells) were obtained from Medical Cell Resources Senyuichi, Tohoku University Aging Medicine Laboratory. All test compounds were dissolved in dimethyl sulfoxide (DMSO) and used in the test at a final DMSO concentration of 0.1%.
  • DMSO dimethyl sulfoxide
  • test compound final concentration: 1 0 4 M or 1 0 5 obtained by dissolving in 1 0 0% DMS 0 to so that such a M
  • FCS- OP TI-ME FCS- OP TI-ME
  • the medium was removed, washed twice with PBS, and subjected once freezing and thawing, per Uweru, Rushifuweraze activity measurement for solubilization buffer (2 5mM T ris - P 0 4 (p H 7. 8), 1 5 % v / v G lyserol, 2 % CHAP S, 1% L ecithin, 1% BSA, 4mM E GTA (p H 8. 0), with the addition of 8 mM Mg C l 2, 1 mM DTT) 1 00 zl , Left at room temperature for 10 minutes.
  • solubilization buffer 2 5mM T ris - P 0 4 (p H 7. 8), 1 5 % v / v G lyserol, 2 % CHAP S, 1% L ecithin, 1% BSA, 4mM E GTA (p H 8. 0), with the addition of 8 mM Mg C l 2, 1 mM DTT) 1 00
  • Table 10 shows the test results showing the activation of P PAR (E C 50 ⁇ M).
  • Examples 1, 2, 3, and 5 are the following compounds.
  • the compound of the present invention has an excellent PPAR activating action (PPR, ⁇ or (5 activating action)). Revealed

Abstract

L'invention concerne des dérivés du thiazole représentés par la formule (II) ou des sels de ceux-ci, utilisés comme activateurs de récepteur activé par le proliférateur de peroxisome. Dans la formule (II), R6 et R7 représentent chacun nitro, C1-8 alkyle, C6-10 aryle, ou analogue, ou alternativement R6 et R7 peuvent former un noyau benzène avec les atomes de carbone auxquels ils sont liés; G1 représente une liaison unique ou carbonyle; R8 représente C1-8 aryle, C6-10 aryle, arylalkyle (la fraction aryle contenant 6 à 10 atomes de carbone, et la fraction alkyle contenant 1 à 8 atomes de carbone), ou analogue; m est un nombre entier compris entre 0 et 5; Y1 représente -CH2-, carbonyle, ou analogue; Z1 représente oxygène ou soufre; R9 et R10 représentent chacun hydrogène ou C1-8 alkyle; et R représente hydrogène ou C1-6 alkyle.
PCT/JP2001/010577 2000-12-05 2001-12-04 Activateurs de recepteur active par le proliferateur de peroxisome WO2002046176A1 (fr)

Priority Applications (2)

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AU2002224139A AU2002224139A1 (en) 2000-12-05 2001-12-04 Ppar (peroxisome proliferator activated receptor) activators
JP2002547915A JPWO2002046176A1 (ja) 2000-12-05 2001-12-04 ペルオキシソーム増殖剤応答性受容体の活性化剤

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WO2003074495A1 (fr) * 2002-03-01 2003-09-12 Smithkline Beecham Corporation Activateurs de hppars
US6653334B1 (en) * 2002-12-27 2003-11-25 Kowa Co., Ltd. Benzoxazole compound and pharmaceutical composition containing the same
WO2004031129A3 (fr) * 2002-10-03 2004-07-15 New Era Biotech Ltd Nouveaux composes destines au traitement des maladies auto-immunes, des maladies immuno-allergiques et des rejets en cas de greffes d'organes ou de tissus
WO2004071509A1 (fr) * 2003-02-12 2004-08-26 Nippon Chemiphar Co., Ltd. Promoteurs de differenciation d'oligodendrocyte
WO2004093879A1 (fr) * 2003-04-17 2004-11-04 Kalypsys, Inc. Acide (3-{3- (2,4-bis-trifluormethyl-benzyl)-(5-ethyl-pyrimidin-2-yl)-amino!-propoxy}-phenyl)-acetique et composes associes en tant que modulateurs de ppar, et procedes pour traiter des troubles du metabolisme
WO2005023777A1 (fr) * 2003-09-03 2005-03-17 Kowa Co., Ltd. Compose d'activation du recepteur ppar et composition pharmaceutique contenant un tel compose
WO2005097784A1 (fr) * 2004-04-07 2005-10-20 Bayer Healthcare Ag Derives d'acide phenylthioacetique et leur utilisation
WO2006090768A1 (fr) * 2005-02-23 2006-08-31 Kowa Co., Ltd. Procede de production d’un compose activant le ppar optiquement actif et son intermediaire
US7301033B2 (en) 2005-01-27 2007-11-27 Kowa Co., Ltd. PPAR-activating compound
CN100425594C (zh) * 2003-09-03 2008-10-15 兴和株式会社 Ppar活性化化合物及含该化合物的医药组合物
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012027331A1 (fr) 2010-08-27 2012-03-01 Ironwood Pharmaceuticals, Inc. Compositions et procédés pour traiter ou prévenir un syndrome métabolique et des maladies et troubles associés
US8252843B2 (en) 2004-03-26 2012-08-28 Novaremed Limited Compounds for the treatment of AIDS and other viral diseases
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US8802734B2 (en) 2009-09-09 2014-08-12 Novaremed Limited Method of treating or preventing pain
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US8883853B2 (en) 2008-03-06 2014-11-11 Novaremed Limited N-substituted benzenepropanamide or benzenepropenamide derivatives for use in the treatment of pain and inflammation
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
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US7109226B2 (en) 2003-09-03 2006-09-19 Kowa Co., Ltd. PPAR-activating compound and pharmaceutical composition comprising the compound
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WO2005023777A1 (fr) * 2003-09-03 2005-03-17 Kowa Co., Ltd. Compose d'activation du recepteur ppar et composition pharmaceutique contenant un tel compose
US8252843B2 (en) 2004-03-26 2012-08-28 Novaremed Limited Compounds for the treatment of AIDS and other viral diseases
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
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US7301033B2 (en) 2005-01-27 2007-11-27 Kowa Co., Ltd. PPAR-activating compound
US7790903B2 (en) 2005-02-23 2010-09-07 Kowa Co., Ltd. Process for production of optically active PPAR-activating compound and intermediate of the same
WO2006090768A1 (fr) * 2005-02-23 2006-08-31 Kowa Co., Ltd. Procede de production d’un compose activant le ppar optiquement actif et son intermediaire
US8883853B2 (en) 2008-03-06 2014-11-11 Novaremed Limited N-substituted benzenepropanamide or benzenepropenamide derivatives for use in the treatment of pain and inflammation
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
US8802734B2 (en) 2009-09-09 2014-08-12 Novaremed Limited Method of treating or preventing pain
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