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Novel oxadiazole derivatives and thiadiazole derivatives having neovascularization inhibitory activity

An angiogenesis and oxadiazole technology, applied in the direction of organic active ingredients, cardiovascular system diseases, medical preparations containing active ingredients, etc., to achieve excellent angiogenesis inhibitory effect

Inactive Publication Date: 2013-07-31
SANTEN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis of compounds having a 4-pyridylalkyloxy group or 4-pyridylalkylthio group and their angiogenesis inhibitory activity are not described at all.

Method used

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  • Novel oxadiazole derivatives and thiadiazole derivatives having neovascularization inhibitory activity
  • Novel oxadiazole derivatives and thiadiazole derivatives having neovascularization inhibitory activity
  • Novel oxadiazole derivatives and thiadiazole derivatives having neovascularization inhibitory activity

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0252] Methyl 2-(pyridin-4-yl)methoxybenzoate (reference compound 1-1)

[0253] Add potassium carbonate ( 19 g, 140 mmol), warmed up to room temperature and stirred overnight. The reaction solution was poured into ice water, and extracted with ethyl acetate (150 mL, twice). The ethyl acetate layer was washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) and dried to obtain 12 g (75%) of the title reference compound as a colorless solid.

[0254]

[0255] 1 H-NMR (300MHz, CDCl 3 )

[0256]δ3.93(s, 3H), 5.19(s, 2H), 6.97(d, J=8.3Hz, 1H), 7.04(t, J=7.5Hz, 1H), 7.43-7.50(m, 3H), 7.87 (dd, J=7.9, 1.8Hz, 1H), 8.63 (d, J=6.1Hz, 2H)

[0257] Hereinafter, using a compound selected from known compounds, 4-chloromethylquinoline (CAS#5632-17-7; WO2006 / 093253) and 2-acetamido-4-methylsulfonyloxymethylpyri...

reference example 2

[0287] 2-(pyridin-4-yl)methoxybenzohydrazide (reference compound 2-1)

[0288] Add hydrazine monohydrate (4.6 g, 92 mmol ), heated to reflux for 7 hours. The reaction solution was concentrated, the obtained residue was suspended with methanol, and the solid was collected by filtration. The solid was dried under reduced pressure to afford 3.7 g (63%) of the title reference compound as a colorless solid.

[0289]

[0290] 1 H-NMR (300MHz, CDCl 3 )

[0291] δ4.17(brs, 2H), 5.27(s, 2H), 6.91(d, J=8.4Hz, 1H), 7.14(t, J=7.7Hz, 1H), 7.33(d, J=5.9Hz, 2H ), 7.43(m, 1H), 8.22(dd, J=7.7, 1.7Hz, 1H), 8.67(d, J=5.9Hz, 2H), 8.78(brs, 1H)

[0292] Hereinafter, reference compounds 2-2 to 8 were obtained according to the preparation method of reference compound 2-1 using compounds selected from reference compounds 1-2, 1-4-7, known compounds, and commercially available compounds.

[0293] 2-(quinolin-4-yl)methoxybenzohydrazide (reference compound 2-2)

[0294]

[0295] 1 H-NMR (...

reference example 3

[0322] 2-(2-Acetamidopyridin-4-yl)methoxybenzoic acid (reference compound 3-1)

[0323] Under ice-cooling, in tetrahydrofuran solution (10 mL) of methyl 2-(2-acetylaminopyridin-4-yl) methoxybenzoate (1.1 g, 3.7 mmol, reference compound 1-3), add 1M hydroxide Aqueous sodium solution (8.0 mL, 8.0 mmol), warmed up to room temperature and stirred overnight. Under ice-cooling, 1M hydrochloric acid (8.0 mL, 8.0 mmol) was added to the reaction solution, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 510 mg (48%) of the title reference compound as a colorless solid.

[0324]

[0325] 1 H-NMR (300MHz, DMSO-d 6 )

[0326] δ2.09(s, 3H), 5.25(s, 2H), 7.04(m, 1H), 7.15(d, J=8.4Hz, 1H), 7.25(d, J=6.6Hz, 1H), 7.47(m , 1H), 7.68(dd, J=7.5, 1.8Hz, 1H), 8.15(s, 1H), 8.29(d, J=5.1Hz, 1H), 10.49(s, 1H), 12.69(brs, 1H)

[0327] Hereinafter, reference compound 3-2 was obtained according to the preparation method of reference compound 3-1 us...

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Abstract

The present invention relates to novel oxadiazole derivatives and thiadiazole derivatives having neovascularization inhibitory activity. These compounds are useful as therapeutic agents for diseases associated with neovascularization, particularly, as therapeutic agents for cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, diabetic macular edema, plaque psoriasis, atherosclerosis, and the like.

Description

[0001] The application date is January 29, 2008, the application number is 200880003414.2 (the international application number is PCT / JP2008 / 051312), and the invention name is "Novel oxadiazole derivatives and thiadiazole derivatives with angiogenesis inhibitory activity" The divisional application of the application for "things". technical field [0002] The present invention relates to a novel compound having an oxadiazole ring or a thiadiazole ring or a salt thereof, which are useful as medicines. The above compounds are useful as therapeutic agents for diseases related to angiogenesis, especially cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoid choroidal vasculopathy, diabetic macular edema , psoriasis vulgaris, atherosclerosis and other therapeutic agents useful. Background technique [0003] The so-called angiogenesis is a phenomenon in which the original blood vessels f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D417/12C07D413/12A61K31/4709A61K31/4439A61P35/00A61P29/00A61P19/02A61P27/02A61P9/10A61P9/00A61P17/06
CPCC07D417/14C07D285/135C07D413/14C07D417/12C07D413/12A61P17/06A61P19/02A61P27/02A61P29/00A61P35/00A61P35/02A61P43/00A61P7/02A61P9/00A61P9/10A61P3/10A61K31/4439
Inventor 本田崇宏藤泽幸史青野浩之伴正和
Owner SANTEN PHARMA CO LTD
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