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2-furanyl-quinoline-4-formamide compound and application thereof

A technology of carboxamides and compounds, which is applied in the field of 2-furan-quinoline-4-carboxamide compounds, can solve the problems of tumors, decreased activity and the like

Active Publication Date: 2021-02-05
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above two reasons will make some dioxygenases dependent on α-KG include prolyl hydroxylase (prolyl hydroxylase, PHD), DNA hydroxylase Tet family and histone lysine demethylase (histone lysine demethylases, KDMs) activity decreased, eventually leading to tumorigenesis

Method used

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  • 2-furanyl-quinoline-4-formamide compound and application thereof
  • 2-furanyl-quinoline-4-formamide compound and application thereof
  • 2-furanyl-quinoline-4-formamide compound and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0018] Example 1: Preparation of 2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (3a)

[0019]

[0020] 0.3g (2.0mmol) isatin (1a), 0.7g mass concentration is 33% KOH aqueous solution and 0.25g (2.0mmol) 5-methyl-2-acetylfuran (2a) are dissolved in 10mL ethanol, heating React at 80°C for 24 hours. After the reaction, concentrate under reduced pressure to remove the solvent to obtain a residue, add 10wt% acetic acid aqueous solution, adjust the pH to about 5, cool and crystallize, filter to obtain a solid crude product, wash with appropriate amount of ethanol and petroleum ether, and dry to obtain 0.31g of 3a compound (ie 2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid), yield 60.4%, melting point: >250°C. 1 H NMR (500MHz, DMSO-d 6 )δ8.64-8.58(m,1H),8.14(s,1H),8.02(d,J=8.5Hz,1H),7.80-7.72(m,1H),7.62-7.54(m,1H),7.31 (d,J=3.3Hz,1H),6.39-6.34(m,1H),2.44(s,3H).

Embodiment 2

[0021] Example 2: Preparation of 6-fluoro-2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (3b)

[0022]

[0023] The preparation method of Example 2 was repeated in Example 1, except that "isatin (1a) was replaced by 5-fluoroisatin (1b) in an equivalent molar amount", and the rest of the operating steps were the same as in Example 1. Compound 3b was finally obtained with a yield of 87.5% and melting point: >250°C.

Embodiment 3

[0024] Example 3: Preparation of 8-fluoro-2-(5-methylfuran-2-yl)quinoline-4-carboxylic acid (3c)

[0025]

[0026] The preparation method of Example 3 was repeated in Example 1, except that "isatin (1a) was replaced by 7-fluoroisatin (1c) in an equivalent molar amount", and the rest of the operation steps were the same as in Example 1. Compound 3c was finally obtained with a yield of 62.4% and a melting point of >250°C.

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Abstract

The invention discloses a 2-furanyl-quinoline-4-formamide compound and application thereof, and the structural formula of the 2-furanyl-quinoline-4-formamide compound is shown as a formula (4) in thespecification, wherein R1 is selected from H, halogen or C1-C3 alkyl, R2 is selected from H or C1-C3 alkyl, and R3 is selected from C1-C3 alkyl, C3-C5 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halogen. The 2-furanyl-quinoline-4-formamide compound designed and synthesized by the invention is a novel IDH1 / R132H inhibitor, and is suitable for drug development taking IDH1 / R132H as a target point, and the obtained drug can be used for treating malignant tumors such as glioma, acute myeloid leukemia, soft osteosarcoma, bile duct cancer, acute lymphatic leukemia and the like.

Description

technical field [0001] The invention relates to 2-furan-quinoline-4-carboxamide compounds and applications thereof. Background technique [0002] Isocitrate dehydrogenase-1 (IDH1) is the key rate-limiting enzyme of the tricarboxylic acid cycle (TCA). It mainly exists in the cytoplasm and peroxisomes, and can use nicotinamide adenine dinucleotide phosphate (NADP) as an electron acceptor to oxidatively decarboxylate isocitrate into α-ketoglutarate (α-ketoglutarate, α -KG), and produce reduced nicotinamide adenine dinucleotide phosphate (NADPH), both products are involved in energy metabolism, amino acid and vitamin synthesis, etc., therefore, the activity regulation of this enzyme will directly affect IDH1 or IDH1 substrate Different biological pathways involved in regulation exert different biological functions. Recent studies have found that IDH1 has high mutations in a variety of malignant tumors, including glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinom...

Claims

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Application Information

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IPC IPC(8): C07D405/04A61P35/02A61P35/00
CPCC07D405/04A61P35/02A61P35/00
Inventor 叶青曾源煦许萌
Owner ZHEJIANG UNIV OF TECH
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