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Novel ligands of nuclear receptors PPAR's

A technology of nuclear receptors and ligands, applied in medical preparations containing active ingredients, receptors/cell surface antigens/cell surface determinants, pharmaceutical formulations, etc.

Inactive Publication Date: 2002-05-08
财团法人产业创造研究所 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the possibility that the same compound acts as a ligand for both RXR and PPAR receptors is neither mentioned nor reported

Method used

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  • Novel ligands of nuclear receptors PPAR's
  • Novel ligands of nuclear receptors PPAR's
  • Novel ligands of nuclear receptors PPAR's

Examples

Experimental program
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Effect test

preparation example 1

[0102] Dehydro ascofuranone

[0103] The synthesis of dehydro ascofuranone by removing two hydrogen atoms from the tetrahydrofuran ring of ascofuranone is as follows. Under water bath cooling, add AgNO to 0.16g (4.0mmol) sodium hydroxide in 0.7ml deionized water solution in batches 3 (0.34g, 2.00mmol) in deionized water (0.7ml). A solution of ascofuranone (0.2 g, 0.476 mmol) in dioxane (1.4 ml) was added to the resulting aqueous suspension of silver nitrate. The reaction mixture was stirred at room temperature for 3 hours, then diluted with water / dioxane mixed solvent (1:1), filtered through celite, the filtrate was acidified with 6N HCl, and then extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine, and then subjected to MgSO 4 Dry and concentrate under reduced pressure. The residue was purified by silica gel II column chromatography and eluted with dichloromethane / acetone (60:1) to obtain 0.047 g of dehydro ascofuranone (yield 24%)....

preparation example 2

[0107] A. 4-O-Ethoxycarbonylmethyl-2-O-methyl ascochlorin (1): compound 27

[0108]Sodium hydroxide (60%, 23.1 mg, 0.578 mmol) was washed with pentane and then suspended in DMF (1 ml). To this suspension was added dropwise a solution of 2-O-methyl ascochlorin (0.220g, 0.525mmol) in DMF (2ml), the mixed solution was stirred at room temperature for 30 minutes, and then mixed with ethyl bromoacetate ( 0.0641ml, 0.578mmol) was stirred at 50°C for 4 hours. The reaction solution was dissolved in a saturated aqueous ammonium chloride solution, extracted with ether, and the organic layer was successively washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (15g SiO 2 , Hexane / ethyl acetate), 0.204 g (77%) (1) (colorless gum) was obtained.

[0109] IR (thin film): 1765, 1713, 1694. NMR (CDCl 3 , 500MHz):...

preparation example 3

[0115] 4-O-(4-carboxybutyryl) ascochlorin (4): compound 29

[0116] To ascochlorin (0.150 g, 0.358 mmol) in anhydrous pyridine (1.5 ml) was added 4-dimethylaminopyridine (4.4 mg, 0.036 mmol) and glutaraldehyde (0.049 g, 0.430 mmol). The reaction solution was stirred at 50°C overnight, then adjusted to pH 2 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After filtering the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (13g SiO 2 , Hexane / ethyl acetate) to obtain 0.081 g (42%) (4) as colorless crystals.

[0117] mp 120-123°C.IR (KBr disk): ~ 3000, 1771, 1711, 1649. NMR (CDCl 3 , 500MHz): 0.70 (3H, s), 0.81 (3H, d, J = 7.0 Hz), 0.83 (3H, d, J = 7.0 Hz), 1.59-1.66 (1H, m), 1.88 (3H, s) , 1.89-1.96 (2H, m), 2.12 (2H, qui, J=7.2Hz), 2.34-2.45 (3H, m), 2.55 (2H, t, J=7.2Hz), 2.65 (3H, s), 2.76...

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Abstract

Ligands of nuclear receptors PPAR's (peroxisome proliferator-activated receptors) which are compounds selected from the group consisting of ascofuranone; and ascofuranone homologs and ascochlorin homologs having at least an orcyl aldehyde moiety wherein the hydrogen atom(s) of the hydroxyl group(s) at the 2-position and / or the 4-position of the orcyl aldehyde moiety are substituted by C1-15 alkyl, C1-15 alkenyl, CH2COOH, CH2COO(C1-15 alkyl), C(C=O)(C1-15 alkyl), C(=O)(CH2)1-15COOH, nicotinoyl, isonicotinoyl, etc. These ligands are usable in preventing and / or treating diabetes; hypertension or cerebrovascular disorders; arteriosclerosis; complications of diabetes; chronic inflammation; cachexia; digestive cancers, etc.

Description

Technical field [0001] The present invention relates to the treatment and / or prevention of nuclear receptor PPAR ligands and PPAR ligand-dependent regulation of gene expression. Background technique [0002] The present invention finds industrial applications in the field of medical products, covering candidate compounds of medical products for the treatment of animal metabolic diseases, chronic inflammation and malignant tumors including humans. Steroids, retinoids, active vitamin D3 and thyroid hormones show significant physiological activity in animals at very small doses. They are collectively called fat-soluble hormones because they are soluble in organic solvents but not in water. With the progress of the research on the mechanism of fat-soluble hormones showing specific activity at very small doses, their mechanism of action shows similarity. These fat-soluble hormones directly control the expression of genetic information by binding to receptors in t...

Claims

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Application Information

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IPC IPC(8): A61K31/12A61K31/122A61K31/192A61K31/216A61K31/341A61K31/455A61P3/10A61P9/10A61P9/12A61P35/00A61P37/00A61P37/06C07C59/92C07C67/38C07C403/20C07C403/24C07D213/65C07D213/68C07D213/79C07D213/80C07D307/32C07D307/33C07D307/58C07D405/12C07K14/705
CPCC07D307/33C07C403/14C07D307/58C07D307/32C07D405/12C07C2101/14C07D213/79C07D213/65C07D213/68A61P3/10A61P9/10A61P9/12A61P35/00A61P37/00A61P37/06C07C2601/14
Inventor 田村学造安藤邦雄马替纯二
Owner 财团法人产业创造研究所
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