Isoaporphine oxide alkaloid derivative and application thereof

A technology of isoaporphine and derivatives, which is applied in the preparation of anticancer drugs, oxidized isoapofthene alkaloid derivatives and the field of preparation thereof, and can solve the problems of toxicity, side effect, solubility, stability and the like of natural products

Active Publication Date: 2020-10-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Natural products are a treasure trove for the discovery of new anti-tumor drugs. At present, many natural products have been proven to have anti-tumor activity, but natural products often have problems such as toxicity, side effects, solubility, and stability. It is necessary to modify their structures to make them Become an anti-tumor drug that can be used clinically

Method used

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  • Isoaporphine oxide alkaloid derivative and application thereof
  • Isoaporphine oxide alkaloid derivative and application thereof
  • Isoaporphine oxide alkaloid derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: 4-[(2-morpholine) ethoxy]-1-azabenzanthrone (I 1 )Synthesis

[0031] The reaction formula is as follows:

[0032]

[0033] 4-Hydroxy-1-azabenzanthrone (1eq) was dissolved in 5mL of anhydrous DMF, and K 2 CO 3 (1.5eq) and 1,2-dibromoethane (1eq), stirred overnight at 80°C, stopped the reaction, added ethyl acetate and saturated brine to the reaction solution to extract and remove DMF, silica gel column chromatography (eluent was petroleum ether : ethyl acetate P / E=3:1) purification to obtain intermediate 4-(2-bromoethoxy)-1-azabenzanthrone, and then 4-(2-bromoethoxy)-1 -Azabenzanthrone (1eq) was added to the reaction flask, dissolved with 5mL anhydrous DMF, added K 2 CO 3 (1.5eq), CTAB and morpholine (1.2eq), stirred overnight at 60°C, stopped the reaction, extracted and removed DMF, and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate P / E=5:1) to obtain Compound I 1 , yellow solid, yield 67%. Compound I 1 Iden...

Embodiment 2

[0036] Embodiment 2: Compound 4-[(2-isopropylamino)ethoxy]-1-azabenzanthrone (I 2 )Synthesis

[0037] The reaction formula is as follows:

[0038]

[0039] Reference compound I 1 The preparation method, replaces compound morpholine with isopropylamine, and other conditions are unchanged, obtains target compound I 2 , yellow solid, yield 58%. Compound I 2 Identified as 4-[(2-isopropylamino)ethoxy]-1-azabenzanthrone.

[0040] ESI-MS: 333.2.[M+H] + .

[0041] 1 H-NMR (300MHz, CDCl 3 , ppm), δ H8.86(d, J=9Hz, 1H), 8.77(d, J=6Hz, 1H), 8.48(d, J=9Hz, 1H), 8.28(d, J=9Hz, 1H), 7.98(d, J= 6Hz, 1H), 7.87(t, J=7.5Hz, 1H), 7.73(t, J=7.5Hz, 1H), 7.60(d, J=9Hz, 1H), 4.6(s, 1H), 3.96(t ,J=6Hz,2H),3.45(s,3H),1.24(d,J=6Hz,6H).

Embodiment 3

[0042] Embodiment 3: 4-[2-(2-methylpiperidine) ethoxy]-1-azabenzanthrone (I 3 )Synthesis

[0043] The reaction formula is as follows:

[0044]

[0045] Reference compound I 1 The preparation method, replaces compound morpholine with 2-methylpiperidine, other conditions are unchanged, obtains target compound I 3 , yellow solid, yield 80%. Compound I 3 Identified as 4-[2-(2-methylpiperidine)ethoxy]-1-azabenzanthrone.

[0046] ESI-MS: 373.2[M+H] + .

[0047] 1 H-NMR (300MHz, CDCl 3 , ppm), δ H 8.96(d, J=6Hz, 1H), 8.82(d, J=3Hz, 1H), 8.69(d, J=6Hz, 1H), 8.48(d, J=3H, 1H), 8.10(d, J= 3Hz, 1H), 7.84(t, J=4.5Hz, 1H), 7.69(t, J=4.5Hz, 1H), 7.23(d, J=3Hz, 1H), 4.43(t, J=3Hz, 2H) ,3.32(d,J=3Hz,1H),3.06(t,J=3Hz,2H),2.53(t,J=6Hz,J=9Hz,2H),1.72(t,J=6Hz,J=9Hz, 6H), 1.25(d, 3H).

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Abstract

The invention discloses an isoaporphine oxide derivative as shown in a formula I. R is as shown in the formula I. A is selected from-O-or a covalent bond, n is an integer from 0 to 4, and R1 is selected from-NR2R3; R2 is selected from H, and R3 is selected from C1-C3 linear chain or branched chain alkyl; A is selected from-O-, n is equal to 2 or 3, R1 is selected from the isoaporphine oxide alkaloid derivative, and compared with isoaporphine oxide, the inhibitory activity of the isoaporphine oxide alkaloid derivative on lung cancer, liver cancer and breast cancer is obviously improved, and thesolubility is increased. The invention also discloses an application of the isoaporphine oxide derivative in preparation of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, and in particular relates to oxidized isoaporphine alkaloid derivatives, a preparation method thereof and the application of the novel compounds in the preparation of anticancer drugs. Background technique [0002] Cancer is a major disease that affects human health and longevity, and has become one of the most important public health problems in the world. According to the "Global Cancer Report", in 2018, it is estimated that there will be 18.1 million new cancer cases and 9.6 million deaths in the world. The global cancer burden will further increase, and more and more people will pay attention to cancer treatment. Natural products are a treasure trove for the discovery of new anti-tumor drugs. At present, many natural products have been proven to have anti-tumor activity, but natural products often have problems such as toxicity, side effects, solubility, and stabili...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/18C07D401/12A61P35/00
CPCC07D221/18C07D401/12A61P35/00
Inventor 孙建博张佳瑶王豫锦
Owner CHINA PHARM UNIV
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