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Activating agent for peroxisome proliferator activated receptor delta

A compound and alkoxy technology, applied in the field of activators, can solve problems such as undocumented efficacy

Active Publication Date: 2009-06-24
NIPPON CHEMIPHAR CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] However, it is described in the above-mentioned Non-Patent Document 3 that the PPARδ activity of the phenylpropionic acid type is about 30 times weaker than that of the phenoxyacetic acid type.
[0016] In addition, in the above-mentioned patent document 1 and non-patent document 3, for the phenylglycine type, there is no description of specific drug effects

Method used

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  • Activating agent for peroxisome proliferator activated receptor delta
  • Activating agent for peroxisome proliferator activated receptor delta
  • Activating agent for peroxisome proliferator activated receptor delta

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0250] 3-[4-[3-[4-Hexyl-2-(4-methylphenyl)thiazol-5-yl]propanoyl]-2-methylphenyl]propanoic acid

[0251] (1) 4-hexyl-2-(4-methylphenyl)thiazole-5-carbaldehyde

[0252] Dissolve [4-hexyl-2-(4-methylphenyl)thiazol-5-yl]methanol (500 mg, 1.727 mmol) in anhydrous dichloromethane (6 ml), add molecular sieves (3A powder, 890 mg) and Corey reagent (crorochrome) piridium) (745mg, 3.455mmol). After stirring at room temperature for 30 minutes, diethyl ether (20 mL) and silica gel (Wako-gel, C-300HG, 2 g) were added and stirred at room temperature for further 10 minutes. The reaction mixture was filtered through a glass filter, and the residue was washed with diethyl ether to obtain a filtrate, from which the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain the title compound (346 mg, yield 70%) as white crystals from the hexane:ethyl acetate (8:1, v / v) fraction.

[0253] 1 H NMR (CDCl 3 , 400MHz)...

Embodiment 2

[0340] 3-[4-[3-[3-isopropyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl]propionyl]-2-methylphenyl] propionic acid

[0341] (1) 3-isopropyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde

[0342] Using [3-isopropyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl]methanol, the title compound was obtained in the same manner as in Example 1(1).

[0343] light yellow crystal

[0344] Yield 57%

[0345] 1 H NMR (CDCl 3 , 400MHz): δ=

[0346] 1.39(6H,d,J=7Hz),

[0347] 3.6—3.8(1H,m),

[0348] 7.37(1H,s),

[0349] 7.6.8 (2H, d, J = 8Hz),

[0350] 7.77 (2H, d, J = 8Hz),

[0351] 10.11(1H, s).

[0352] (2) 3-[4-[3-[3-isopropyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl]acryloyl]-2-methylphenyl]acrylic acid methyl ester

[0353] The title compound was obtained in the same manner as in Example 1(5).

[0354] yellow crystal

[0355] Yield 67%

[0356] 1 H NMR (CDCl 3 , 400MHz): δ=

[0357] 1.32(6H,d,J=7Hz),

[0358] 2.54(3H,s),

[0359] 3.3—3.5(1H,m),

[0360] 3.8...

Embodiment 3

[0402] 3-[4-[3-(5-Isopropyl-2-phenyl-4-oxazolyl)propionyl]-2-methylphenyl]propanoic acid

[0403] (1) 5-isopropyl-2-(2,4-dichlorophenyl)oxazole-4-carbaldehyde

[0404] Using 5-isopropyl-2-(2,4-dichlorophenyl)oxazole-4-methanol, the title compound was obtained in the same manner as in Example 1(1).

[0405] light yellow crystal

[0406] 1 H NMR (CDCl 3 , 400MHz): δ=

[0407] 1.39(6H,d,J=7Hz),

[0408] 3.72 (1H, dq, J=7, 7Hz),

[0409] 7.37 (1H, dd, J=2, 8Hz),

[0410] 7.5.5 (1H, d, J = 2Hz),

[0411] 7.99 (1H, d, J = 8Hz),

[0412] 10.06(1H, s).

[0413] (2) 3-[4-[3-[5-isopropyl-2-(2,4-dichlorophenyl)-4-oxazolyl]acryloyl]-2-methylphenyl]methacrylate ester

[0414] Use the above-mentioned 5-isopropyl-2-(2,4-dichlorophenyl) oxazole-4-formaldehyde and 3-(4-acetyl-2-methylphenyl) methyl acrylate, adopt and The title compound was obtained in the same manner as in Example 1(5).

[0415] light yellow crystal

[0416] 1 H NMR (CDCl 3 , 400MHz): δ=

[0417] 1.39(6H,d,...

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Abstract

A compound represented by the general formula (II) below or a salt thereof is used as an activating agent for PPAR d. (II) (In the formula, G represents O, CH2 or the like; A represents a thiazole, oxazole or thiophene which may have a substituent selected from an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, a halogen atom, an alkyl group having 1-8 carbon atoms and substituted by a halogen atom and the like; B represents an alkylene chain having 1-8 carbon atoms, and when the alkylene chain has two or more carbon atoms, it may have a double bond; and R<1a> and R<2a> respectively represent a hydrogen atom, an alkyl group having 1-8 carbon atoms, an alkoxy group having 1-8 carbon atoms, a halogen atom, an alkyl group having 1-8 carbon atoms and substituted by a halogen atom or the like.

Description

technical field [0001] The present invention relates to an activator of peroxisome proliferator-activated receptor (PPAR). Background technique [0002] It is known that there are three subtypes of peroxisome proliferator-activated receptors (PPARs), which are called PPARα, PPARγ, and PPARδ. (Proc. Natl. Acad. Sci. USA, 91, p7335-7359, 1994: hereinafter referred to as Non-Patent Document 1.) [0003] Furthermore, various compounds have so far reported transcriptional activation actions of each subtype of PPAR, hypoglycemic and lipid metabolism-improving actions, and the like. For example, GW-590735 (GSK), KRP-101 (キョ-リン) and NS-220 (Roche-Japan Shinyaku) have been reported as selective α agonists having lipid metabolism improving effects. (J Pharmacol Exp Ther 309(3): 970, Jun 2001: hereinafter referred to as Non-Patent Document 2) [0004] In addition, a variety of drugs showing dual agonist (dualagonist) activity of PPARγ and PPARα are known, and KRP-297 (Kyorin) repres...

Claims

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Application Information

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IPC IPC(8): C07D263/32A61K31/381A61K31/421A61K31/426A61P1/04A61P1/12A61P1/16A61P1/18A61P3/06A61P3/10A61P7/02A61P9/00A61P9/04A61P9/10A61P9/12A61P11/06A61P17/00A61P17/06A61P17/10A61P17/14A61P19/02A61P25/00A61P25/28A61P29/00A61P43/00C07D277/20C07D277/30C07D333/22
CPCC07D263/32C07D277/22C07D277/20C07D277/30C07D333/22A61P1/00A61P1/04A61P1/12A61P1/16A61P1/18A61P11/00A61P11/06A61P17/00A61P17/06A61P17/10A61P17/14A61P19/02A61P25/00A61P25/28A61P29/00A61P3/00A61P3/04A61P35/00A61P3/06A61P43/00A61P5/38A61P7/00A61P7/02A61P9/00A61P9/02A61P9/04A61P9/10A61P9/12A61P3/10A61K31/381A61K31/421A61K31/426
Inventor 佐久间诏悟望月信孝潮田胜俊高桥理惠山川富雄增井诚一郎
Owner NIPPON CHEMIPHAR CO LTD
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