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Water-soluble aza-alpha-naphthoflavone compound and preparation method and medical application thereof

A water-soluble, naphthoflavone technology, applied in pharmaceutical formulations, organic chemistry, anti-tumor drugs, etc., can solve the problems of decreased selectivity, decreased inhibitory activity, etc., and achieves the effects of simple operation, easy availability of raw materials, and good water solubility.

Active Publication Date: 2018-09-21
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, compared with α-naphthoflavones, the selectivity of these compounds to CYP1B1 enzymes decreased significantly, IC 50 The ratio (CYP1A1 / 1B1 and CYP1A2 / 1B1) was lower than that of α-naphthoflavone; at the same time, after the introduction of hydroxyalkyl ether amino acid ester into the C ring of α-naphthoflavone, the inhibitory activity on enzymes also decreased significantly, and the IC of the inhibitory enzyme 50 Values ​​above 10nM

Method used

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  • Water-soluble aza-alpha-naphthoflavone compound and preparation method and medical application thereof
  • Water-soluble aza-alpha-naphthoflavone compound and preparation method and medical application thereof
  • Water-soluble aza-alpha-naphthoflavone compound and preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] This example relates to a 6,7,10-trimethoxy-2-(2'-pyridyl)naphtho[1,2-b]pyran-4-one (Ⅲ-1 ) preparation method, such as figure 1 shown, including the following steps:

[0045]

[0046] Step 1, dissolve 2-acetyl-4,5,8-trimethoxy-1-naphthol in anhydrous N,N'-dimethylformamide, add 3.0 equivalents of 2-pyridinecarboxylic acid, add 3.0 times the equivalent of 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and catalytic amount of 4-dimethylaminopyridine (DMAP ), after stirring at room temperature for 12h, adding saturated ammonium chloride solution to quench the reaction, CH 2 Cl 2 Extract and combine the organic layers. The organic layer was washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and silica gel column chromatography to obtain 4,5,8-trimethoxy-2-acetyl-1-naphthol-2'-pyridinecarboxylic acid The ester is a yellow solid, and the yield is 92%.

[0047] Step 2: Dissolve 4,5,8...

Embodiment 2

[0050] This example relates to a 6,7,10-trimethoxy-2-(3'-fluoro-2'-pyridyl)naphtho[1,2-b]pyran-4- The preparation method of ketone (Ⅲ-2), such as figure 1 shown, including the following steps:

[0051]

[0052] The steps of this example are the same as the steps of Example 1, in Step 1, 2-pyridinecarboxylic acid is replaced by 6-fluoro-2-pyridinecarboxylic acid. The product is yellow powder, and the total yield is 20%. 1 H NMR (400MHz, DMSO-d 6 ):δ8.43(d,J=7.7Hz,1H),8.32–8.25(m,1H),7.48(d,J=7.6Hz,1H),7.36–7.24(m,3H),7.17(s, 1H), 4.14(s,3H), 3.95(s,3H), 3.86(s,3H).

Embodiment 3

[0054] This example relates to a 6,7,10-trimethoxy-2-(3'-chloro-2'-pyridyl)naphtho[1,2-b]pyran-4- The preparation method of ketone (Ⅲ-3), such as figure 1 shown, including the following steps:

[0055]

[0056] The steps of this example are the same as the steps of Example 1, in Step 1, 2-pyridinecarboxylic acid is replaced by 6-chloro-2-pyridinecarboxylic acid. The product was light yellow powder, and the total yield was 26%. 1 H NMR (400MHz, DMSO-d 6 ):δ8.26(d,J=7.0Hz,2H),7.74(d,J=7.0Hz,1H),7.27(s,3H),7.16(s,1H),4.09(s,3H),3.91 (s,1H),3.82(s,1H).

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Abstract

The invention discloses a water-soluble aza-alpha-naphthoflavone compound and a preparation method and medical application thereof. The structural formula of the aza-alpha-naphthoflavone compound is shown in formula (I) as shown in specification, wherein Ar stands for nitrogen-containing heterocyclic aromatic, and comprises substituent-containing pyridine, pyridazine, quinoline, thiazole, benzimidazole, benzo [d] pyrazole, pyrrolo [2,3-b] pyridine and physically acceptable salts thereof. The invention further relates to a preparation method and medical application of the water-soluble aza-alpha-naphthoflavone compound. The water-soluble aza-alpha-naphthoflavone compound can inhibit activity of human body CYP1B1 enzyme, and the inhibition activity of parts of compounds is far higher than alpha- naphthoflavone; and the water-soluble aza-alpha-naphthoflavone compound can be used for preventing tumors and overcoming drug resistance of malignant tumors caused by CYP1B1 enzyme.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a water-soluble aza-alpha-naphthalene flavone derivative, a preparation method and a medical application thereof. Background technique [0002] CYP1B1 enzymes are a subtype of the CYP1 family that are mainly expressed outside the liver. It can metabolize estradiol to 4-hydroxyestradiol, and this metabolite plays a key role in the occurrence and development of estradiol-induced breast cancer (Cavalierie et al, Proc.Natl.Acad.Sci.USA, 1997, 94:10937-10942). In addition, CYP1B1 enzyme is involved in the metabolic activation of polycyclic aromatic hydrocarbon pro-carcinogens such as benzopyrene, and is a factor in inducing tumors. A large number of recent studies have confirmed that CYP1B1 enzymes are highly expressed in tumor tissues such as breast cancer, ovarian cancer, prostate cancer, liver cancer, lung cancer, and kidney cancer, while the expression level in cor...

Claims

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Application Information

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IPC IPC(8): C07D405/04C07D471/04C07D417/04A61K31/4433A61K31/404A61K31/4709A61K31/4184A61K31/416A61K31/437A61K31/501A61K31/427A61P35/00
CPCA61P35/00C07D405/04C07D417/04C07D471/04
Inventor 李绍顺董金云崔家华孟青青
Owner SHANGHAI JIAO TONG UNIV
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