Ureido compound or pharmaceutical salt thereof as well as preparation method and application thereof

A compound and medicinal salt technology, applied in the field of medicinal chemistry, can solve the problems of limiting the clinical use of microtubule-targeted drugs, multidrug resistance, etc., and achieve the effect of improving anti-tumor effect and enhancing proliferation inhibitory activity

Active Publication Date: 2022-04-05
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, microtubule-targeted drugs such as paclitaxel and vincristine have been marketed and used for tumor treatment, but long-term use of these drugs can easily lead to the emergence of multidrug resistance, which severely limits the clinical use of microtubule-targeted drugs
Because of its unique mechanism of action, colchicine-binding site inhibitors can overcome the problem of multidrug resistance caused by long-term use of microtubule-targeted drugs, but so far no colchicine-binding site inhibitors have been marketed, so research The development of inhibitors that act on the colchicine binding site has important practical significance

Method used

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  • Ureido compound or pharmaceutical salt thereof as well as preparation method and application thereof
  • Ureido compound or pharmaceutical salt thereof as well as preparation method and application thereof
  • Ureido compound or pharmaceutical salt thereof as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Synthesis of 6-methoxy-N-(2-methoxyphenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (I-1)

[0047]

[0048] Synthesis of N-Benzyl-5-methoxy-2-nitroaniline (III-1)

[0049] Benzylamine (2.07g, 19.28mmol) was dissolved in acetonitrile (40mL), and 3-fluoro-4-nitroanisole (Ⅱ-1) (3.00g, 17.50mmol) and anhydrous potassium carbonate (4.84g , 35.02mmol), reflux and stir at 85°C. After 90 minutes, TLC (developing agent PE:EA=5:1) monitored whether the reaction was complete. After the raw materials were completely reacted, stop heating, cool to room temperature, and filter with suction. The filtrate was washed with water (20mL×3), saturated sodium chloride solution (20mL ×3) Wash and dry overnight with anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated under reduced pressure to obtain 3.92 g of a yellow solid, with a yield of 86.6%. The product was directly sent to the next step without further purification. 1H NMR (300MHz, DMSO-d6) δ8.87(t, ...

Embodiment 2

[0061] Synthesis of 6-methoxy-N-(4-methoxyphenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (I-2)

[0062]

[0063] Synthesis of 4-Benzyl-6-methoxy-N-(4-methoxyphenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (VIII-2)

[0064] Using VI-1 (300mg, 1.18mmol) and 4-methoxyisocyanate (VII-2) (188mg, 1.42mmol) as raw materials, the operation process was the same as that of intermediate VIII-1 to obtain 327mg of white solid with a yield of 68.7%. 1H NMR (300MHz, CDCl3) δ7.36-7.26 (m, 5H), 7.21 (d, J = 7.1Hz, 2H), 7.13 (d, J = 8.2Hz, 1H), 7.06 (s, 1H), 6.83 (d, J=8.9Hz, 2H), 6.31-6.21(m, 2H), 4.54(s, 2H), 3.90(t, J=4.8Hz, 2H), 3.77(s, 3H), 3.70(s, 3H), 3.46(t, J=5.2Hz, 2H).

[0065] Synthesis of 6-methoxy-N-(4-methoxyphenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (I-2)

[0066]Using VIII-2 (300 mg, 0.74 mmol) as the starting material, the operation process was the same as that of the target compound I-1 to obtain 162 mg of white solid with a yield of 69.9%. 1H NMR (300MHz, CDC...

Embodiment 3

[0068] Synthesis of 6-methoxy-N-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (I-3)

[0069]

[0070] 4-Benzyl-6-methoxy-N-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (VIII-3) synthesis

[0071] Using VI-1 (300mg, 1.18mmol) and 4-trifluoromethoxyisocyanate (VII-3) (262mg, 1.29mmol) as raw materials, the operation process was the same as that of intermediate VIII-1 to obtain 399mg of white solid, yield 74.0 %. 1H NMR (300MHz, CDCl3) δ7.45-7.39(m,2H),7.36-7.27(m,3H),7.25-7.22(m,2H),7.20(s,1H),7.17-7.08(m,3H ),6.30-6.24(m,2H),4.54(s,2H),3.91(t,J=5.3Hz,2H),3.71(s,3H),3.47(t,J=5.3Hz,2H).

[0072] Synthesis of 6-methoxy-N-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide (I-3)

[0073] Using VII-3 (350 mg, 0.77 mmol) as the starting material, the operation process was the same as that of the target compound I-1 to obtain 170 mg of a white solid with a yield of 60.3%. 1H NMR (300MHz, CDCl3) δ7.43-7.36(m, 2H...

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a ureido compound or a medicinal salt thereof as well as a preparation method and application thereof. The ureido compound has a structure as shown in a general formula (I). Pharmacological experiment results of the ureido compound provided by the invention show that the compound has a proliferation inhibition activity function on tumor cells, can block a cell cycle in a G2/M phase, and can be used for preparing medicines for treating malignant tumors caused by unbalanced dynamic equilibrium of microtubulin.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a class of microtubule polymerization inhibitors containing a ureido structure, in particular to a ureido compound or a pharmaceutically acceptable salt thereof and a preparation method and use thereof. Background technique [0002] Microtubules exist in almost all eukaryotic cells and are formed by the polymerization of α-tubulin and β-tubulin. Under normal physiological conditions, microtubules are in a state of dynamic equilibrium, and they are involved in the transportation of intracellular substances, cell movement, and maintenance of cell shape. , cell proliferation and many other biological functions. In the process of cell proliferation, microtubules participate in the formation of the spindle body, and are closely related to the distribution of genetic material. [0003] Tumor cells have the ability to proliferate rapidly, and their mitotic processes are frequent and the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/42A61P35/00A61K31/498
Inventor 梁停停冬海洋王建红鲁露张亚宏齐建国
Owner HENAN UNIVERSITY
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