WO2011043453A1 - Activateur pour récepteur activé par les proliférateurs de peroxysomes - Google Patents

Activateur pour récepteur activé par les proliférateurs de peroxysomes Download PDF

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WO2011043453A1
WO2011043453A1 PCT/JP2010/067715 JP2010067715W WO2011043453A1 WO 2011043453 A1 WO2011043453 A1 WO 2011043453A1 JP 2010067715 W JP2010067715 W JP 2010067715W WO 2011043453 A1 WO2011043453 A1 WO 2011043453A1
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carbon atoms
group
alkyl group
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acceptable salt
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佐久間詔悟
小林邦夫
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日本ケミファ株式会社
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Definitions

  • the present invention relates to an activator of peroxisome proliferator activated receptor (PPAR).
  • PPAR peroxisome proliferator activated receptor
  • PPARs Peroxisome proliferator activated receptors
  • Patent Document 1 Patents relating to compounds represented by the following general formula in which the thiazole ring of GW-501516 is replaced with a benzothiophene ring or a benzofuran ring have also been filed.
  • Patent Document 2 Patents relating to compounds represented by the following general formula in which the thiazole ring of GW-501516 is replaced with a benzothiophene ring or a benzofuran ring have also been filed.
  • Patent Document 3 Patent Document 3 and the compounds described in Patent Documents 4 to 10 have been found to have a PPAR transcriptional activation action, and have been applied for a patent.
  • the compounds of the present invention represented by the general formula (I) to be described later have benzothiophene monooxide and benzothiophene dioxide at positions corresponding to the thiazole ring and benzothiophene ring in the compounds described in Patent Documents 1 to 10 above.
  • the compound described in Patent Document 2 is different from the compound described in Patent Document 2 in that the alkylene chain in the linker portion connecting the benzothiophene ring and phenoxyacetic acid is interrupted by a sulfur atom or an oxygen atom (X 2 ).
  • the present compounds have the difference that they do not have such interruptions. Further, the difference between the compound of the present invention and GW-501516 is that GW-501516 is located at a position corresponding to a condensed ring such as benzothiophene monooxide, benzothiophene dioxide, etc. Is a single ring (thiazole ring). Further, in Patent Document 3, A is a monocycle such as pyrazole, thiophene, furan, and pyrrole, and the compounds described in Patent Documents 4 to 10 are also monocyclic in the portion corresponding to A in Patent Document 3.
  • the compound of the present invention has a difference that it is a condensed ring such as benzothiophene monooxide and benzothiophene dioxide. Therefore, the compound of the present invention and the compounds described in the above-mentioned known literature have a clear structural difference.
  • An object of the present invention is to provide a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof having an activating action for a peroxisome proliferator-activated receptor.
  • R 1 and R 3 may be the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, an alkylamino group having 1 to 8 carbon atoms, or a dialkylamino group having 2 to 12 carbon atoms).
  • R 4 , R 5 , R 6 and R 7 may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom;
  • X represents CR 8 or a nitrogen atom;
  • R 8 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms)
  • R 4 , R 5 , R 6 and R 7 may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom
  • X represents CR 8 or a nitrogen atom;
  • R 8 is a hydrogen atom, an alkyl group having
  • the present invention also relates to an activator for peroxisome proliferator-activated receptor ⁇ containing as an active ingredient a compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof. Furthermore, the present invention relates to a therapeutic and / or prophylactic agent for PPAR-mediated diseases containing the compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9, and R 10 alkyl group having 1 to 8 carbon atoms is methyl.
  • Examples of the alkenyl group having 2 to 8 carbon atoms of R 1 , R 2 and R 3 include a vinyl group and an allyl group.
  • Examples of the alkynyl group having 2 to 8 carbon atoms of R 1 and R 3 include a propargyl group.
  • Examples of the 3- to 7-membered cycloalkyl group represented by R 1 and R 3 include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.
  • Examples of the alkoxy group having 1 to 8 carbon atoms of R 1 and R 3 include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, i-butoxy group, t-butoxy group, pentyloxy group or hexyloxy group Etc.
  • Examples of the halogen atom for R 1 and R 3 include a fluorine atom, a chlorine atom, or a bromine atom.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted with halogen atoms of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 include 1 to 3 And a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or a t-butyl group substituted by a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom, preferably a trifluoromethyl group, a chloro group A methyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-fluoroethyl group, and the like can be given.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted with the alkoxy group having 1 to 8 carbon atoms of R 1 , R 2 and R 3 include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, i- Methyl group, ethyl group, propyl group, isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group or hexyl group substituted with butoxy group, t-butoxy group, pentyloxy group or hexyloxy group Etc., and preferably an ethoxyethyl group.
  • Examples of the alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom of R 1 and R 3 include a methoxy group, an ethoxy group, and a propoxy group substituted with a halogen atom such as 1 to 3 fluorine atoms, chlorine atoms or bromine atoms.
  • a halogen atom such as 1 to 3 fluorine atoms, chlorine atoms or bromine atoms.
  • Examples of the aryl group having 6 to 10 carbon atoms of R 1 , R 2 and R 3 include a phenyl group, etc.
  • Examples of the acyl group having 2 to 8 carbon atoms of R 1 , R 2 and R 3 include an acetyl group. It is done.
  • Examples of the alkyl group having 1 to 8 carbon atoms which is substituted with a 3- to 7-membered cycloalkyl group represented by R 1 , R 2 and R 3 include a methyl group substituted with a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, Examples thereof include an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, a pentyl group, and a hexyl group.
  • R 1 , R 2 , R 3 , R 8 , R 9 and R 10 aralkyl groups include a benzyl group or a phenethyl group Etc.
  • Examples of the 5- or 6-membered heterocyclic group for R 1 and R 3 include a pyridyl group.
  • Examples of the alkyl group having 1 to 8 carbon atoms substituted by a 5- or 6-membered heterocyclic group of R 1 and R 3 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group substituted with a pyridyl group or the like Group, i-butyl group, t-butyl group, pentyl group or hexyl group.
  • Examples of the alkylamino group having 1 to 8 carbon atoms of R 1 and R 3 include a methylamino group and an ethylamino group.
  • Examples of the dialkylamino group having 2 to 12 carbon atoms of R 1 and R 3 include a dimethylamino group and a diethylamino group.
  • R 1 (excluding a hydrogen atom) may have 1 to 3 substituents which may be the same or different, and R 3 (excluding a hydrogen atom) may be present. One or two of the same or different substituents may be present.
  • R 1 is a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group having 1 to 8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or a carbon number
  • a compound of the above general formula (I) or a pharmaceutically acceptable salt thereof which is an alkyl group having 1 to 8 carbon atoms substituted with an alkoxy group or an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom
  • R 1 is a C 1-8 alkyl group substituted with a halogen atom.
  • R 2 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a 3 to 7-membered cycloalkyl group, or a halogen atom.
  • the above general formula (I) or the above (1) or (2) is an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms substituted with an alkoxy group having 1 to 8 carbon atoms.
  • a compound or a pharmacologically acceptable salt thereof is (4) A compound of the above general formula (I), the above (1) or (2) or a pharmaceutically acceptable salt thereof, wherein R 2 is an alkyl group having 3 to 8 carbon atoms.
  • R 3 is a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group having 1 to 8 carbon atoms, a 3 to 7-membered cycloalkyl group, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or a carbon number
  • R 3 is an alkyl group having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or a compound or pharmacology thereof described in the above general formula (I) or (1) to (4) above Acceptable salt.
  • R 6 and R 7 may be the same or different and each is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, the compound of the above general formula (I) or the above (1) to (7), or a pharmacological compound thereof Acceptable salt.
  • the pharmacologically acceptable salt of the compound represented by the general formula (I) include alkali metal salts such as sodium, potassium and lithium.
  • the compound of the present invention may contain optically active substances, cis and trans geometric isomers, etc., and any of them is included in the present invention.
  • Synthesis method 1 (In the general formula (I), when R 4 and R 5 are hydrogen atoms, Z is an oxygen atom, m is 2 and p is 2)
  • the compound of the general formula (q) is esterified to obtain the compound of the general formula (r), and then this is treated with an oxidizing agent such as m-chloroperbenzoic acid to obtain the compound of the general formula (s). Can do.
  • the compound of the general formula (t) can be obtained by subjecting the compound of the general formula (s) to a hydrolysis reaction.
  • the compound of the present invention represented by the above general formula (I) can be produced by referring to the synthesis methods described later, the synthesis examples described later, and the synthesis methods described in Patent Documents 1 to 10. . Next, examples of the compound of the present invention are shown below. Representative compound example 1
  • the PPAR activation effect of the compound of the present invention was measured as follows.
  • the receptor expression plasmid, luciferase expression plasmid and ⁇ -galactosidase expression plasmid were introduced into CV-1 cells. After transfection using a transfection reagent, the cells were cultured in the presence of the test compound. Solubilized cells were used for measuring luciferase activity and ⁇ -GAL activity. The luciferase activity was corrected by ⁇ -GAL activity, and relative ligand activity was calculated with the luciferase activity value of cells treated with GW-590735, Rosiglizone, GW-501516 as 100%. (Example 5) As is clear from Table 9, the compound of the present invention showed an excellent PPAR ⁇ activation action.
  • the compound represented by the general formula (I) of the present invention has an excellent PPAR ⁇ activation action, diseases mediated by PPAR, ie, hyperlipidemia, dyslipidemia, hypercholesterolemia, High TG, low HDL, high LDL and / or non-HDL, high VLDL, lipoprotein abnormality, low apolipoprotein AI, atherosclerosis, arteriosclerosis, coronary Diseases, cerebrovascular disorders, peripheral vascular disorders, metabolic syndrome, syndrome X, obesity including visceral fat obesity, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, heart failure, Myocardial infarction, cardiomyopathy, hypertension, fatty liver, nonalcoholic steatohepatitis, thrombus, Alzheimer's disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne , Skin aging, abnormal hair growth, inflammation
  • the compound of the present invention can be administered to humans by an appropriate administration method such as general oral administration or parenteral administration.
  • an appropriate administration method such as general oral administration or parenteral administration.
  • it can be produced into a dosage form such as a tablet, granule, powder, capsule, suspension, injection, suppository and the like by a conventional method in the technical field of formulation.
  • usual excipients, disintegrants, binders, lubricants, dyes, diluents and the like are used.
  • lactose lactose, D-mannitol, crystalline cellulose, glucose and the like are used, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca) and the like, as the lubricant, magnesium stearate,
  • binders include talc and the like, hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like.
  • the compound of the present invention which is an active ingredient in injections, is about 0.1 mg to 100 mg per day, and 1 mg to 2000 mg per day by oral administration, but may be increased or decreased depending on age, symptoms, etc. .
  • this invention is not limited to these.
  • reaction solution was poured into a saturated aqueous ammonium chloride solution, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (15.0 g, yield 40%) was obtained as a pale yellow oil from a hexane: ethyl acetate (10: 1, v / v) fraction. .
  • This reaction solution was added dropwise to 75% sulfuric acid (1.5 mL) heated to 120 ° C. over 5 minutes, and heated at the same temperature for 1 hour. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (20 mg, yield 20%) was obtained as yellow crystals from a hexane: ethyl acetate (5: 1, v / v) fraction.
  • reaction solution was acidified with ice water and 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and the title compound (370 mg) was obtained as pale yellow crystals from a chloroform: methanol (100: 1 to 5: 1, v / v) fraction. Got as.
  • IR (KBr, cm ⁇ 1 ): 2975, 2929, 1702, 1436, 1328, 1303, 1259, 1234, 1213, 1162, 1153, 1116, 1083, 883, 869, 815, 721, 418.
  • PPAR activation effect of the test compound was measured as follows.
  • Receptor expression plasmid pSG5-GAL4-hPPAR ⁇ or ⁇ or ⁇ LBD
  • luciferase expression plasmid pUC8-MH100 ⁇ 4-TK-Luc
  • ⁇ -galactosidase ATCC (American type culture collection)
  • pCMX- ⁇ -GAL pCMX- ⁇ -GAL
  • PPAR activity relative value of test compound 10 ⁇ 7 M with reference to 100% of control drug ⁇ : GW-590735 10 ⁇ 6 M ⁇ : Rosiglitazole 10 ⁇ 6 M ⁇ : GW-501516
  • Examples 1 and 4 are 10 ⁇ 6 M
  • Examples 2 and 3 are 10 ⁇ 7 M
  • the compound of the present invention showed an excellent PPAR ⁇ activation action.
  • PPAR activity (EC 50 ( ⁇ M): The relative value of the test compound when the control drug was 100% was calculated, and the concentration of the test compound at which the relative value was 50% was calculated as EC 50 ( ⁇ M).
  • ⁇ GW-590735 10 ⁇ 6 M
  • GW-501516 10 ⁇ 7 M As is clear from Table 10, the compound of the present invention described in Example 2 has high PPAR ⁇ selectivity.

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Abstract

Cette invention concerne un composé représenté par la formule générale (I) ou un sel pharmacologiquement acceptable de celui-ci ; et un activateur pour récepteur activé par les proliférateurs de peroxysomes(PPAR), qui contient ledit composé ou sel à titre de principe actif. (Dans la formule, R1 et R3 représentent chacun un atome d'hydrogène, un atome d'halogène, un groupe alkyle ayant de 1 à 8 atomes de carbone, un groupe alkyle qui est substitué par un atome d'halogène et ayant de 1 à 8 atomes de carbone, ou autre ; R2 représente un atome d'hydrogène, un groupe alkyle ayant de 1 à 8 atomes de carbone, ou autre ; R4, R5, R6 et R7 représentent chacun un atome d'hydrogène, un groupe alkyle ayant de 1 à 8 atomes de carbone, ou autre ; X représente un atome d'azote ou autre ; Y représente un atome d'oxygène ou autre ; Z représente un atome d'oxygène, un atome de soufre, une main de liaison ou autre ; p vaut 1 ou 2 ; m représente un nombre entier de 1 à 4 ; et n représente un nombre entier de 0 à 4).
PCT/JP2010/067715 2009-10-08 2010-10-08 Activateur pour récepteur activé par les proliférateurs de peroxysomes WO2011043453A1 (fr)

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JP2009234600A JP2013006769A (ja) 2009-10-08 2009-10-08 ペルオキシソーム増殖剤活性化受容体の活性化剤
JP2009-234600 2009-10-08

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WO2011043453A1 true WO2011043453A1 (fr) 2011-04-14

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