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Hypoxia-activated prodrug of lenvatinib and application of hypoxia activated prodrug

A technology of lenvatinib and oxygen activation, applied in the field of hypoxia-activated prodrugs, can solve problems such as limited tumor effect, and achieve the effects of reduced toxic side effects, low inhibitory activity, and reduced possibility

Inactive Publication Date: 2017-12-26
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional antineoplastic drugs have good lethality against tumors near blood vessels, but have limited effect on tumors in hypoxic areas

Method used

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  • Hypoxia-activated prodrug of lenvatinib and application of hypoxia activated prodrug
  • Hypoxia-activated prodrug of lenvatinib and application of hypoxia activated prodrug
  • Hypoxia-activated prodrug of lenvatinib and application of hypoxia activated prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment 1: the synthesis of target compound:

[0020] Synthesis of compound 1

[0021]

[0022] 0.412g (1.00mmol) O-desmethyllenvatinib (3), 0.28g (3.00mmol) 2-methyl-2(5-nitrofuran)ethanol were dissolved in dry dichloromethane (50mL). Cool to 0°C, add 0.752 mL of tributylphosphine (3.06 mmol) dropwise, and stir at room temperature for 48 hours. The solvent was recovered under reduced pressure, and the title compound (0.035 g) was obtained by silica gel column chromatography. 1 H NMR(DMSO-d6,δ,ppm,300MHz):8.66(d,2H),8.28(d,1H),7.96(d,1H),7.86(s,1H),7.73(s,1H),7.51 (s,1H), 7.48(d,1H), 7.42(d,1H), 7.24(dd,1H), 7.19(d,1H), 6.71(d,1H), 6.53(t,1H), 2.66( s, 1H), 1.77 (s, 6H), 0.66 (q, 2H), 0.41 (s, 2H).

[0023] Synthesis of compound 2:

[0024]

[0025] Referring to the method of target compound 1, it was synthesized with 2-methyl-2(5-nitrothiophene)ethanol instead of 2-methyl-2(5-nitrofuran). 1 H NMR(DMSO-d6,δ,ppm,300MHz):8.62(d,2H),8.23(d,1H),7.92(d,1H),7.8...

Embodiment 2

[0026] Example 2: Inhibitory activity screening of target compounds on tyrosine kinases in vitro

[0027] A series of gradient concentrations of the test compound were incubated with a specific concentration of enzyme solution at room temperature for 5 minutes, and then an appropriate amount of enzyme reaction substrate and ATP was added to start the enzyme reaction process. After 30 minutes, an appropriate amount was added to the enzyme reaction system. After incubation for 1 h, measure the enzyme activity at a specific compound concentration on a multifunctional microplate reader, and calculate the inhibitory activity of different concentrations of compounds on the enzyme activity, and then according to the four-parameter equation, for different The inhibitory activity of the enzyme activity at the concentration of the compound was fitted, and the IC50 value was calculated.

[0028] Table 1 Inhibitory activity of target compounds on tyrosine kinases in vitro (IC50, nM)

[0...

Embodiment 3

[0031] Example 3: Stability investigation of target compound in liver homogenate

[0032] Preparation of NADPH start-up system: Precisely weigh NADPNa 2 , G-6-P-Na, G-6-PDH and MgCl 2 Appropriate amount, add water to dissolve and make to volume, the system contains 2mmol L -1 NADPNa 2 , 40 mmol L -1 G-6-P-Na, 4U L -1 G-6-PDH, 40 mmol L - 1 MgCl 2 , stored at -20°C.

[0033] Sample preparation: First, add an appropriate amount of sample methanol solution to the EP tube, evaporate the solvent in a water bath, add Tris buffer solution, rat liver homogenate, and vortex to mix. Pre-incubate at 37°C for 5 minutes in a constant temperature shaking water tank. Add 200 μL of NADPH priming system and vortex to mix well to initiate the reaction. The final volume of the reaction is 400 μL, containing 1.0 mmol L -1 1NADPNa 2 , 20 mmol L -1 G-6-P-Na, 2U L -1 G-6-PDH, 20 mmol L -1 MgCl 2 , the concentration of liver homogenate protein is 2.0mg mL -1 , with a final substrate...

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PUM

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Abstract

The invention provides a hypoxia-activated prodrug of lenvatinib and application of the hypoxia activated prodrug. A structure of the hypoxia-activated prodrug accords with a general formula (I), wherein the formula (I) is shown in the description, wherein R is -O- and -S-. The drug provided by the invention is stable under normal conditions and has a relatively weak drug function. The hypoxia-activated prodrug is not stable under a hypoxia condition and can generate molecules with the stronger drug function. The drug provided by the invention has good drug function and safety and can be used for preparing drugs for treating tumors.

Description

technical field [0001] The invention belongs to the field of pharmacy and provides a hypoxia-activated prodrug of lenvatinib and an application thereof. Background technique [0002] Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activity of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4 ). Lenvatinib also inhibits the fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet-derived growth factor receptor alpha (PDGFRα), KIT, and RET9. (Int J Cancer.2008, 122, 664-671) is suitable for the treatment of patients with local recurrence or metastasis, progressive, radioactive iodine-refractory differentiated thyroid cancer and liver cancer. The most common side effects of lenvatinib are high blood pressure, fatigue, diarrhea, joint and muscle pain (arthralgia / myalgia), decreased appetite, vomiting, excess protein in the urine (proteinuria), swelling and pain in the palms, sole...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D409/12A61K31/4709A61P35/00
CPCC07D405/12C07D409/12
Inventor 李飞陈冬寅杨磊罗宏华蒋南
Owner NANJING MEDICAL UNIV
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