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Venetoclax and dihydroartemisinin compound and preparation method and application thereof

A technology of dihydroartemisinin and compound, applied in the field of medicine, can solve the problem of narrow indication of venetola

Active Publication Date: 2020-10-16
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to its remarkable curative effect and unique mechanism of action, a number of clinical trials of venetora monotherapy or combination therapy have been carried out, showing positive therapeutic effects on a variety of tumors. Narrow, only in Bcl-2 protein-dependent patients / tumor models to show outstanding therapeutic effect, and cancer cells can be resistant to venetoclax through high expression of other anti-apoptotic proteins (such as Mcl-1 or Bcl-xL)

Method used

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  • Venetoclax and dihydroartemisinin compound and preparation method and application thereof
  • Venetoclax and dihydroartemisinin compound and preparation method and application thereof
  • Venetoclax and dihydroartemisinin compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118]Example 1: 4-((2-((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(( 4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzene Formyl)sulfonamido)-2-nitrophenyl)amino)ethyl)amino)-4-oxobutanoic acid-(10α-dihydroartemisinin-10-yl)ester (Ia-1), Its structural formula is as follows:

[0119]

[0120] Step 1) Synthesis of 4-((2-aminoethyl)amino)-3-nitrobenzenesulfonamide (hydrochloride) (1a)

[0121]

[0122] 3-nitro-4-chlorobenzenesulfonamide (2.36g, 0.01mol), 1-Boc-ethylenediamine (2.4g, 0.015mol), DIEA (3.87g, 0.03mol) were dissolved in 10mL of acetonitrile, 80 °C for 18 hours. After the reaction was completed, 10 mL of water was slowly added dropwise, and a yellow solid was precipitated. Filter with suction, and wash the precipitate three times with water / acetonitrile (V:V=1:1). Mix the filter cake with 30 mL of water, stir at 45°C for half an hour, filter with suction, wash the filter cake with water, and dry to obtain a ...

Embodiment 2

[0132] Example 2: Preparation of 4-((3-((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-( (4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl) Benzoyl)sulfonamido)-2-nitrophenyl)amino)propyl)amino)-4-oxobutanoic acid-(10α-dihydroartemisinin-10-yl)ester (Ia-2) , its structural formula is as follows;

[0133]

[0134] Synthetic steps are with embodiment 1;

[0135] M.p.141.7~141.9℃. LC-MS m / z:1217.1[M+Na] + . 1 H-NMR (600MHz, DMSO-d6) δ11.68(s, 1H), 11.37(s, 1H), 8.65(t, J=5.4Hz, 1H), 8.56(d, J=2.0Hz, 1H), 8.04(d,J=2.5Hz,1H),8.01(t,J=5.8Hz,1H),7.83(d,J=7.9Hz,1H),7.58–7.39(m,3H),7.34(d,J =8.4Hz, 2H), 7.05(t, J=10.3Hz, 3H), 6.68(dd, J=9.1, 1.9Hz, 1H), 6.39(dd, J=3.2, 1.8Hz, 1H), 6.18(d ,J=1.8Hz,1H),5.64(artemisinin characteristic peak d,J=9.7Hz,1H),5.50(s,1H),3.43–3.37(m,2H),3.19–3.10(m,2H) ,3.07(s,4H),2.75(s,2H),2.68–2.57(m,2H),2.41(t,J=6.7Hz,2H),2.30–2.24(m,1H),2.21–2.09(m ,6H),2.00–1.93(m,3H),1.78(dd,J=6.9,3.6Hz,1H),1.74–1.66(m,2...

Embodiment 3

[0136]Example 3: Preparation of 4-((4-((4-(N-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-( (4'-Chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl) Benzoyl)sulfonamido)-2-nitrophenyl)amino)butyl)amino)-4-oxobutanoic acid-(10α-dihydroartemisinin-10-yl)ester (Ia-3) , its structural formula is as follows;

[0137]

[0138] Synthetic steps are with embodiment 1;

[0139] M.p.136.8~137.7℃. LC-MS m / z:1229.2[M+Na] + . 1 H-NMR(600MHz,DMSO)δ11.68(s,1H),11.40(s,1H),8.63–8.47(m,2H),8.04(d,J=2.5Hz,1H),7.90(t,J =5.6Hz,1H),7.80(d,J=9.2Hz,1H),7.54–7.47(m,3H),7.34(d,J=8.4Hz,2H),7.09–7.00(m,3H),6.68 (dd, J=9.1, 2.0Hz, 1H), 6.39(dd, J=3.2, 1.8Hz, 1H), 6.19(d, J=1.7Hz, 1H), 5.76(s, 1H), 5.64 (artemisia annua Prime characteristic peak d, J=9.7Hz, 1H), 5.52(s, 1H), 3.38(dd, J=13.1, 6.7Hz, 2H), 3.17–3.02(m, 6H), 2.75(s, 1H), 2.64–2.56(m,2H),2.38(t,J=7.1Hz,2H),2.31–2.11(m,8H),2.04–1.89(m,3H),1.85–1.74(m,1H),1.65– 1.45(m,8H),1.33–1.29(m,4H),1.27(artemisinin ...

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Abstract

The invention belongs to the technical field of medicines, and relates to a Venetoclax and dihydroartemisinin compound, pharmaceutically acceptable salts, hydrates and optical isomers thereof, a pharmaceutical composition taking the compound as an active component, and an application of the compound in preparation of medicines for treating cancers. The structure of the Venetoclax and dihydroartemisinin compound is as shown in a general formula I in the specification, wherein L is as described in the claims and the specification.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and relates to a combination of venetura and dihydroartemisinin, pharmaceutically acceptable salts, hydrates, optical isomers thereof, and a pharmaceutical combination with the combination as an active ingredient and its use in the treatment of cancer. Background technique: [0002] In 2016, the Bcl-2 highly selective inhibitor Venetoclax (ABT-199) was approved by the FDA for the treatment of chronic lymphocytic leukemia with 17p deletion mutations, and since then cancer therapy targeting the apoptosis pathway has been opened. Venetura specifically interferes with the combination of the anti-apoptotic protein Bcl-2 and the pro-apoptotic protein, releasing the pro-apoptotic protein, thereby activating the downstream apoptotic signaling pathway, and finally inducing the apoptosis of cancer cells. Due to its remarkable curative effect and unique mechanism of action, a number of clinical trials of...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61K31/496A61P35/00
CPCA61P35/00C07B2200/07C07D519/00
Inventor 赵临襄刘丹张真玮张静仪牛群景永奎
Owner SHENYANG PHARMA UNIVERSITY
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