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3-substituted-1-indanone derivative compound and its preparation method and pharmaceutical use

A compound, indanone technology, applied in the field of small molecule 3-aryl-1-indanone derivatives TNF-α inhibitors, new tumor necrosis factor inhibitors, can solve the problems of induction of immune response, high price, failure, etc.

Active Publication Date: 2020-11-24
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current TNF-α inhibitors are mainly monoclonal antibodies, which: ① are immunogenic and have the risk of inducing an immune response, and are not suitable for sensitive patients; ② need to be injected, expensive, and long-term use It is easy to form antibodies in the body and become ineffective. Therefore, the development of oral small molecule TNF-α inhibitors will have broad prospects for the thorough treatment of ulcerative colitis.

Method used

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  • 3-substituted-1-indanone derivative compound and its preparation method and pharmaceutical use
  • 3-substituted-1-indanone derivative compound and its preparation method and pharmaceutical use
  • 3-substituted-1-indanone derivative compound and its preparation method and pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1: Synthesis of 3-substituted-1-indanone derivatives

[0018]

[0019] Step 1: Take two-neck bottles, N 2 Protect, vacuumize, first add methyl p-methyl sulfone, stir and dissolve with anhydrous THF at -78°C, slowly add LDA (1.2eq) and react for 1h, add 1 (1.5eq), stir overnight, TLC detection (PE: EA=2:1) ​​Whether the raw material has reacted completely; after the reaction is completed, concentrate under reduced pressure, extract with EA, and saturate NH 4 Cl, water, saturated NaCl solution washing, organic layer anhydrous NaSO 4 Dry, concentrate, and purify on a silica gel column (PE:EA=2:1—1:1) to obtain the target compound 2 in the form of white powder;

[0020] Step 2: Take two neck bottles, N 2 Protect, vacuumize, add 2 and aldehyde 3 (1.2eq), stir and dissolve with anhydrous toluene, add piperidine (0.2eq) and acetic acid (0.2eq), reflux and stir for 6h-8h, TLC detection (PE:EA=3 : 1) Whether the raw material has reacted completely; after the react...

Embodiment 2

[0058] In vitro inhibitory activity of 3-substituted-1-indanone derivatives on tumor necrosis factor (TNF-α) released by LPS-stimulated macrophage RAW264.7:

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry and medicine, relates to a novel tumor necrosis factor (TNF-alpha) inhibitor and particularly relates to a small molecule 3-aryl-1-indanone derivative TNF-alpha inhibitor and its medicinal use. The invention provides the 3-substituted-1-indanone derivative compound shown in the following formula (1). An in-vitro experiment result shows that the prepared derivative compound has specific inhibition effects on a tumor necrosis factor (TNF-alpha) produced by LPS-stimulated macrophages RAW 264.7. The derivative can be used for preparation of a small molecule treatment drug for treating ulcerative colitis and as a small molecule TNF-alpha inhibitor and can be used for treating human TNF-alpha increasing-mediated immunoinflammatory diseases such as ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis and psoriasis.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and medicine, and relates to a novel tumor necrosis factor (TNF-α) inhibitor, in particular to a small molecule 3-aryl-1-indanone derivative TNF-α inhibitor and its medicinal use . Background technique [0002] Studies have disclosed that ulcerative colitis (ulcerative colitis, UC) is a chronic non-specific intestinal inflammation, manifested as acute and recurrent bloody mucus diarrhea, which can last for several weeks to several months. According to statistics, the global incidence of ulcerative colitis is about 6.3-24.3 people / 100,000 people / year, and it has risen sharply in recent years. The pathogenesis of UC is not yet clear, but studies have shown that it is related to factors such as heredity, immunity, infection and mental activity. Recurrent episodes of UC can cause DNA damage and microsatellite instability in mucosal cells, leading to the occurrence of colon cancer. Studie...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/755C07C323/22C07D317/54C07D307/46C07D333/16C07D333/56A61P1/04A61P1/00A61P19/08A61P19/02A61P17/06A61P29/00
CPCC07C45/65C07C49/755C07C315/04C07C319/20C07C323/22C07D307/46C07D317/54C07D333/16C07D333/56C07C317/24
Inventor 孙逊唐美麟沈晓燕游艳刘正玉彭鹏
Owner FUDAN UNIV
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