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Novel hydroxyindole derivative

A hydroxyl and alkyl technology, applied in the field of novel oxindole derivatives, can solve problems such as no discovery

Inactive Publication Date: 2009-09-16
株式会社泰丽巴镠斯
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In addition, it is known that Pim-3 is found in malignant lesions of pancreas and liver cells, but Pim-3 is not found in normal pancreatic tissues, and it has been reported that Pim-3 is found in human pancreatic cancer cells and hepatocellular carcinoma cell lines Acts as a factor for suppressing apoptosis (Non-Patent Document 4, Non-Patent Document 5)

Method used

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  • Novel hydroxyindole derivative
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] (3E)-3-[(5-((E)-(2-indolinone-3-methylidene)methyl)furan-2-yl)methylene]indolin-2-one (1 )

[0154] Oxindole (1 equivalent), diformylfuran (0.5 equivalent) and piperidine (0.2 equivalent) were dissolved in 1 mL of ethanol per 1 μmol, and stirred at room temperature for 12 hours. After the reaction, the precipitate was filtered, washed several times with cold ethanol, and dried to obtain the target compound with a yield of 45%.

[0155] 1 H-NMR (d 6 -DMSO, 400Mz): 13.20(s, 1H), 13.18(s, 1H), 11.01(d, J=7.84Hz, 1H), 10.98(d, J=3.92Hz), 10.43(d, J=7.84Hz , 1H), 10.10(d, J=7.35Hz, 1H), 10.08(s, 1H), 9.96(d, J=3.92Hz, 1H), 9.82(s, 1H), 9.80-9.65(m, 2H) , 9.52(t, J=7.84Hz, 1H-), 9.37(t, J=7.84Hz, 1H), 9.11(t, J=7.84Hz, 1H), MS m / z: 355(M) + .

[0156]

Embodiment 2

[0158] (3E)-1-acetyl-3-[((5E)-((1-acetyl-2-indolone-3-methylidene)methyl)furan-2-yl)methylene]ind Indolin-2-one(2)

[0159] Oxindole (1 equivalent) was dissolved in acetic anhydride and heated to reflux for 3 days. After cooling, the reaction solution was poured into ice water, and the precipitate was filtered, washed with water, and dried to obtain 1-acetyloxindole. By the same method as in Example 1, the target compound was obtained from 1-acetyloxindole and diformylfuran.

[0160] 1 H-NMR (d 6 -DMSO, 400Mz): 11.05(d, J=7.84Hz, 1H), 11.00(d, J=3.92Hz), 10.46(d, J=7.84Hz, 1H), 10.13(d, J=7.35Hz, 1H ), 10.04(s, 1H), 9.94(d, J=3.92Hz, 1H), 9.80(s, 1H), 9.78-9.63(m, 2H), 9.43(t, J=7.84Hz, 1H-), 9.30(t, J=7.84Hz, 1H), 9.08(t, J=7.84Hz, 1H), 2.38(s, 3H), 2.36(s, 3H). MS m / z: 438(M) + .

[0161]

Embodiment 3

[0163] (3E)-3-((5-((E)-(1-acetyl-2-indolone-3-methylidene)methyl)furan-2-yl)methylene)indoline- 2-keto(3)

[0164] Diformylfuran (1 equivalent) was dissolved in ethanol, and a solution of oxindole (0.5 equivalent) and piperidine (0.1 equivalent) dissolved in ethanol was slowly added thereto. After the addition was complete, it was stirred at room temperature for 2 hours. After the reaction, the precipitate was filtered and removed, acetone was added to the filtrate, and it was made acidic with 1N-hydrochloric acid solution, and dried and solidified under reduced pressure to obtain 5-((E)-(indoline-3-methyl (ylidene)methyl)furan-2-carbaldehyde (yield 31%). Then 5-((E)-(indoline-3-methylene)methyl)furan-2-carbaldehyde (1.2 equiv), 1-acetyloxindole (1 equiv) and piperidine (0.1 equiv ) was dissolved in ethanol and stirred at room temperature for 12 hours. After the reaction, the precipitate was filtered, washed with cold ethanol, and dried to obtain the target product.

[01...

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Abstract

A compound or pharmacologically acceptable salt thereof which is represented by the following general formula (I),wherein R1 to R8 each represents hydrogen, halogeno, hydroxy, C1-6 alkyl, C2-8 alkenyl, or C1-6 alkylcarbonyl or may be substituted by -COOR9 (wherein R9 represents hydrogen, C1-6 alkyl, or C2-8 alkenyl); and X represents sulfur, oxygen, or NR10 (wherein R10 represents hydrogen, halogeno, hydroxy, C1-6 alkyl, C2-8 alkenyl, or C1-6 alkoxy).

Description

technical field [0001] The present invention relates to oxindole derivatives and their medical use. Background technique [0002] Kinases are enzymes that transfer (phosphorylate) phosphate groups from molecules with high-energy phosphate bonds such as ATP to substrates or target molecules. Among them, protein kinases, which phosphorylate protein molecules, serve as various signal transduction pathways in cells and regulators of metabolic pathways. However, dysfunction of kinases is often the cause of diseases such as cancer, and it is expected to use drugs for the treatment or prevention of diseases by developing drugs that inhibit the function of specific kinases. [0003] Pim-1, a serine / threonine kinase, was originally identified in T-cell lymphomas caused by murine leukemia virus (MuL V) as a gene frequently activated by insertion of leukemia virus (non-patent Literature 1). In addition, it has been reported that Pim-1 in the cytoplasm functions as a factor for suppr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14A61K31/404A61P3/10A61P9/00A61P9/10A61P25/00A61P27/02A61P29/00A61P31/12A61P35/00A61P37/02A61P43/00
CPCC07D405/14C07D403/14C07D409/14A61P19/02A61P25/00A61P25/28A61P27/02A61P29/00A61P31/12A61P35/00A61P37/02A61P43/00A61P9/00A61P9/10A61P3/10
Inventor 忍典昭邵军小林正孝盛孝男
Owner 株式会社泰丽巴镠斯