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Biguanide derivatives, pharmaceutical composition, preparation method and application

A biguanide derivative and composition technology, applied in the field of medicine, can solve the problem of high anti-tumor activity, achieve the effect of inhibiting proliferation and migration, and have a good application prospect

Active Publication Date: 2018-12-28
HUNAN NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Guanidine has good pharmacological effects of hypoglycemic, anticancer, and antibacterial, but the concentration required for antitumor activity is relatively high, so it is necessary to further improve the activity efficacy

Method used

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  • Biguanide derivatives, pharmaceutical composition, preparation method and application
  • Biguanide derivatives, pharmaceutical composition, preparation method and application
  • Biguanide derivatives, pharmaceutical composition, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: the preparation of intermediate 1-phenyl-1H-pyrazole-3-alcohol

[0036]

[0037] Put 2.16g (0.02mol) of phenylhydrazine and 2.00g (0.02mol) of ethyl acrylate in ethyl acetate and react at room temperature for 4‐10 hours to obtain 1‐phenyl‐4,5‐dihydro‐1H‐pyridine 2.71g of azole-3-ol, the yield is 83.6%; 2.40g of 1-phenyl-1H-pyrazole-3-ol was obtained by oxidation reaction, and the yield was 88.5%.

Embodiment 2

[0038] Embodiment 2: the preparation of intermediate 1-(4-chlorophenyl)-1H-pyrazole-4-alcohol

[0039]

[0040] 4‐2‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolyl)‐1H‐pyrazole 3.88g (0.02mol) and 1‐bromo‐ 3.83g (0.02mol) of 4-chlorobenzene was dissolved in 50mL of methanol and 51.5mL of NaOH (1mol / L) and stirred at room temperature for 2 days. After purification by silica gel column chromatography, a white solid 1-benzyl-4-2(4,4, 5,5‐tetramethyl‐1,3,2‐dioxaborolyl)‐1H‐pyrazole 2.55g, yield 41.9%.

[0041] Dissolve 1‐benzyl‐4‐2 (4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolyl)‐1H‐pyrazole 3.04g (0.01mol) In 50mL tetrahydrofuran, and cooled to 0 ° C. Add 6mL NaOH solution (2mol / L) and 1.22mL30%H 2 o2 solution (0.012 mol), and the reaction was stirred at room temperature for 40 minutes. The reaction was adjusted to pH=2 with HCl (2mol / L), extracted with organic phase, concentrated and purified to obtain 1-(4-chlorophenyl)-1H-pyrazole-4-alcohol 1.48g, yield 76.2 %.

Embodiment 3

[0042] Embodiment 3: Preparation of intermediate 3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-alcohol

[0043]

[0044] 3-(4-fluorophenyl)-3-oxopropionaldehyde 3.32g (0.02mol) and 0.92g (0.02mol) methylhydrazine were placed in ethyl acetate and reacted at room temperature for 4-10 hours to obtain 3 -(4-fluorophenyl)-1-methyl-4,5-dihydro-1H-pyrazole-5-ol 2.80g, yield 72.1%. 1.93 g of 3-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-ol was obtained by oxidation reaction, with a yield of 69.0%.

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Abstract

The invention belongs to the field of medicine and particularly relates to biguanide derivatives, pharmaceutical composition, a preparation method and an application. The biguanide derivatives are compounds with the structure shown in the description, or pharmaceutically acceptable salts, solvates, isomers, esters and predrugs of the compounds. The compounds can remarkably inhibit proliferation and migration of tumor cells, IC50 is greatly lower than that of metformin and phenformin before derivatization, the compound 11 has the highest activity, and activity of the compounds in UMUC3, T24 andA2780 cells is more than 300-800 times that of metformin, and the compounds have good application prospect in antitumor drugs.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a biguanide derivative, a pharmaceutical composition, a preparation method and an application. Background technique [0002] Biguanides are commonly used clinically to treat diabetes. Among them, metformin is a metabolic drug that has been used as a first-line treatment for type 2 diabetes for many years. Its effectiveness in treating diabetes is mainly due to its inhibition of liver function. Gluconeogenesis. In addition to its glucose-lowering effects, metformin has other pleiotropic health-promoting effects, including reductions in cancer risk and tumorigenesis. In recent years, its anti-tumor effect has also attracted widespread attention. Its mechanism of action is well understood and studied. Recent data have shown that metformin increases the AMP / ATP ratio through multiple, mutually independent mechanisms, leading to AMPK activation and mTORC1 inhibition. It has bee...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/20C07D231/22A61K31/415A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D231/20C07D231/22
Inventor 杨小平周思纯徐思梦王志仁邓俊贺彩梅肖迪胡鑫吴景涛
Owner HUNAN NORMAL UNIVERSITY
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