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Isoxazole derivatives as mutant isocitrate dehydrogenase 1 inhibitors

A compound and hydrogen atom technology, applied in the field of isoxazole derivatives as mutant isocitrate dehydrogenase 1 inhibitors, can solve problems such as the influence of tumor properties

Active Publication Date: 2020-06-26
DAIICHI SANKYO CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

From these reports, there is a possibility that the mutant IDH1 protein expressed in tumors may affect tumor properties by producing 2-HG through enzymatic activity different from that of wild-type IDH

Method used

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  • Isoxazole derivatives as mutant isocitrate dehydrogenase 1 inhibitors
  • Isoxazole derivatives as mutant isocitrate dehydrogenase 1 inhibitors
  • Isoxazole derivatives as mutant isocitrate dehydrogenase 1 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0973] [Example 1] (2E)-3-(1-{[5-(3-methyloxetane-3-yl)-3-(2,4,6-trichlorophenyl)-1 ,2- Azol-4-yl]carbonyl}-1H-indol-4-yl)prop-2-enoic acid

[0974] Formula 67

[0975]

[0976] [Step 1] 5-(3-methyloxetan-3-yl)-3-(2,4,6-trichlorophenyl)-1,2- Azole-4-carboxylic acid pentafluorophenyl ester

[0977] Under ice-cooling, to a dichloromethane solution (100 ml) of the compound (10.2 g) obtained in Reference Example X-11 were successively added dropwise N,N-bis(propan-2-yl)amine (7.6 ml) and trifluoro Pentafluorophenyl acetate (7.3ml), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / dichloromethane) to obtain the title compound (11.4 g).

[0978] 1 H-NMR (CDCl 3 ) δ: 1.92 (3H, s), 4.70 (2H, d, J = 6.7 Hz), 5.21 (2H, d, J = 6.7 Hz), 7.46 (2H, s).

[0979] [Step 2] (2E)-3-(1-{[5-(3-methyloxetan-3-yl)-3-(2,4,6-trichloro...

Embodiment 10

[0993] [Example 10] (2E)-3-(3-methyl-1-{[5-(1-methylcyclobutyl)-3-(2,4,6-trichlorophenyl)-1, 2- Azol-4-yl]carbonyl}-1H-indol-4-yl)prop-2-enoic acid

[0994] Formula 68

[0995]

[0996] [Step 1] 5-(1-methylcyclobutyl)-3-(2,4,6-trichlorophenyl)-1,2- Azole-4-carboxylic acid pentafluorophenyl ester

[0997] Using the compound (0.109 g) obtained in Reference Example X-14, the title compound (0.123 g) was obtained by the same method as in Step 1 of Example 1.

[0998] 1 H-NMR (CDCl 3 )δ: 1.72 (3H, s), 1.92-2.01 (1H, m), 2.14-2.30 (3H, m), 2.72-2.82 (2H, m), 7.44 (2H, s).

[0999] MS (m / z): 526 (M+H) + .

[1000] [Step 2] (2E)-3-(3-methyl-1-{[5-(1-methylcyclobutyl)-3-(2,4,6-trichlorophenyl)-1,2 - Azol-4-yl]carbonyl}-1H-indol-4-yl)prop-2-enoic acid tert-butyl ester

[1001] Using the compound obtained in Step 1 above (0.123 g) and the compound obtained in Reference Example E-8 (0.054 g), the title compound (0.103 g) was obtained by the same method as in Step 2 of Exa...

Embodiment 21

[1017] [Example 21] (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2- Azol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoic acid

[1018] Formula 69

[1019]

[1020] [Step 1] (2E)-3-(1-{[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2- Azol-4-yl]carbonyl}-3-methyl-1H-indol-4-yl)prop-2-enoic acid tert-butyl ester

[1021] To a solution of the compound (200 mg) obtained in Reference Example X-20 and N,N-dimethylformamide (10 µl) in dichloromethane (6 ml) was added oxalyl chloride (216 mg), and the mixture was stirred at room temperature for 30 minutes . The reaction solution was concentrated under reduced pressure to obtain acid chloride.

[1022] Under ice-cooling, to the compound obtained in Reference Example E-8 (218 mg), N,N-di(propan-2-yl)ethylamine (0.19 ml) and 4-dimethylaminopyridine (7.0 mg) To a dichloromethane (3 ml) solution was added dropwise a dichloromethane (3 ml) solution of the above acid chloride, and the mixture was stirred...

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Abstract

The present invention finds that the compound of general formula (I) with an isoxazole skeleton has excellent inhibitory activity on mutant IDH1 protein, can inhibit the production of 2-HG through the protein, and can effectively inhibit various tumors expressing the protein proliferation.

Description

technical field [0001] The present invention relates to a compound having excellent inhibitory activity against mutant isocitrate dehydrogenase 1 (hereinafter also referred to as "IDH1") and a pharmaceutically acceptable salt thereof. Background technique [0002] Isocitrate dehydrogenases (IDHs: isocitrate dehydrogenases) are a group of enzymes that convert isocitrate into 2-oxoglutarate (α-ketoglutarate). This group of enzymes can be further subdivided into NAD+-dependent isocitrate dehydrogenases (EC 1.1.1.41) and NADP+-dependent isocitrate dehydrogenases (EC 1.1.1.42). [0003] IDH1 (isocitrate dehydrogenase 1 (NADP+), soluble) protein and IDH2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial) protein are classified as NADP+-dependent isocitrate dehydrogenase (EC 1.1.1.42) enzymes. Mutations in the IDH1 gene or IDH2 gene are found in various cancers. Specific examples include glioma and glioblastoma, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/06A61K31/422A61K31/437A61K31/4439A61K31/454A61K31/496A61K31/5377A61P35/00A61P35/02A61P43/00C07D413/14C07D471/04
CPCC07D413/14A61K31/422A61K31/437A61K31/4439A61K31/454A61K31/496A61K31/5377C07D413/06A61P35/00A61P35/02C07D471/04C07D413/04
Inventor 斋藤昭一伊藤雅夫藤泽哲则齐藤博直清冢洋平渡边秀昭松永大典神子岛佳子铃木彻也小川原阳子北林一生
Owner DAIICHI SANKYO CO LTD
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