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Biguanide derivative, medicinal composition, preparation method of medicinal composition, and application of biguanide derivative or medicinal composition in preparation of antitumor medicines

A technology for biguanide derivatives and drugs, applied in the field of medicine, can solve problems such as unfavorable drug effects, achieve good application prospects, and inhibit proliferation and migration.

Active Publication Date: 2019-10-22
HUNAN NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Biguanide derivatives generally have anticancer properties when one end is substituted by phenyl, and generally only have antibacterial properties if they are substituted or not substituted by other small molecules; when one end is substituted by phenyl, the substituent at the other end It cannot be a substituent of a macromolecule, and generally cannot exceed six carbon atoms; otherwise, it will be detrimental to its medicinal effect

Method used

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  • Biguanide derivative, medicinal composition, preparation method of medicinal composition, and application of biguanide derivative or medicinal composition in preparation of antitumor medicines
  • Biguanide derivative, medicinal composition, preparation method of medicinal composition, and application of biguanide derivative or medicinal composition in preparation of antitumor medicines
  • Biguanide derivative, medicinal composition, preparation method of medicinal composition, and application of biguanide derivative or medicinal composition in preparation of antitumor medicines

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the preparation of intermediate 1-(4-trifluoromethyl) phenyl-3-cyanoguanidine

[0049]

[0050] NaN(CN) 2 (50g, 0.56mol) was dissolved in 430mL water to form a solution, and 4-trifluoromethylaniline solution was added at 80°C (dissolve 45g, 0.3mol 4-trifluoromethylaniline in water and concentrated HCl (132mL / 23.5mL)), maintained at 80°C, and continued to react for about 1 hour. White powdery solids gradually precipitated in the reaction solution. TLC detected the reaction solution until no 4-trifluoromethylaniline was contained, that is, the reaction was over. After filtration and vacuum drying, 1-(4-trifluoromethyl)phenyl-3-cyanoguanidine was obtained with a yield of 95.5%.

[0051] Structural validation:

[0052] 1 H NMR (600MHz, DMSO-d 6)δ9.45(s,1H),7.66(d,J=8.5Hz,2H),7.60(d,J=8.5Hz,2H); LC-MS m / z229.0[M+1] + .

Embodiment 2

[0053] Embodiment 2: Preparation of intermediate 1-(3,4-difluoro)phenyl-3-cyanoguanidine

[0054]

[0055] NaN(CN) 2 (50g, 0.56mol) was dissolved in 430mL water to form a solution, and 3,4-difluoroaniline solution was added at 80°C (dissolve 38.7g, 0.3mol 3,4-difluoroaniline in water and concentrated HCl (132mL / 23.5mL)), maintained at 80°C, and continued to react for about 1 hour. Solids gradually precipitated out of the reaction solution. TLC detected the reaction solution until it contained no 3,4-difluoroaniline, that is, the reaction was over. After filtration and vacuum drying, 1-(3,4-difluoro)phenyl-3-cyanoguanidine was obtained with a yield of 95.2%.

[0056] Structural validation:

[0057] 1 H NMR (600MHz, DMSO-d 6 )δ7.50 (d, J = 7.5Hz, 1H), 7.34 (dd, J = 18.0, 8.9Hz, 1H), 7.09 (d, J = 5.8Hz, 1H); LC-MS m / z 197.0[ M+1] + .

Embodiment 3

[0058] Embodiment 3: Preparation of intermediate 1-(2,4-difluoro)phenyl-3-cyanoguanidine

[0059]

[0060] NaN(CN) 2 (50g, 0.5618mob) was dissolved in 430mL water to form a solution, and 2,4-difluoroaniline solution was added at 80°C (dissolve 38.7g, 0.3mol 2,4-difluoroaniline in water and concentrated HCl ( 132mL / 23.5mL)), maintained at 80°C, and continued to react for about 1 hour. Solids gradually precipitated in the reaction solution. TLC detected the reaction solution until no 2,4-difluoroaniline was contained, that is, the reaction was over. After filtration and vacuum drying, 1-(2,4-difluoro)phenyl-3-cyanoguanidine was obtained with a yield of 94.9%.

[0061] Structural validation:

[0062] 1 H NMR (600MHz, DMSO-d 6 )δ8.87(s,1H),7.59(d,J=6.2Hz,1H),7.35–7.29(m,1H),7.07(d,J=8.6Hz,1H); LC-MS m / z194. 8[M-1] - .

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Abstract

The invention discloses a biguanide derivative, a medicinal composition, a preparation method of the medicinal composition, and an application of the biguanide derivative or the medicinal compositionin the preparation of antitumor medicines. The biguanide derivative is a compound having a structure represented by a formula shown in the description, or a pharmaceutically acceptable salt, an isomer, an ester or a prodrug thereof; and in the formula, R1 and R2 are halogen, or R1 is a halogen-substituted methyl group, and R2 is hydrogen; R3 is an isobutyl group, an ethyl group, a cyclopentyl group or an n-heptyl group, and R4 is hydrogen, a methyl group or an ethyl group. The biguanide derivative can significantly inhibit the proliferation and migration of tumor cells, and the IC50 value of the biguanide derivative is much lower than that of underivated proguanil, and is larger than that of general biguanide derivatives; and the biguanide derivative has greatly higher activity in UMUC3, T24, A2780, A549 and HCT116 cells than the underivated proguanil and existing compounds.

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 its application in the preparation of antitumor drugs. Background technique [0002] Cancer incidence and mortality are rapidly increasing worldwide. According to the GLOBOCAN 2018 cancer incidence and death estimates, there will be about 18.1 million new cancer cases and 9.6 million cancer deaths worldwide in 2018. Among the 18.1 million new cancer cases, Asia accounted for nearly half, and among the 9.6 million cancer deaths, Asia accounted for nearly 70%. The latest statistics show that the incidence rate of bladder cancer ranks among the top among cancer patients in the world, and it is rising year by year, ranking seventh among male tumors in my country. The incidence rate (3.4%) and mortality rate (4.4%) of ovarian cancer in female patients are both in the top ten. Lung cancer is still the ...

Claims

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Application Information

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IPC IPC(8): C07C279/26A61P35/00A61P35/02A61K31/155C07C277/08
CPCA61P35/00A61P35/02C07C279/26C07C2601/08
Inventor 杨小平肖迪王志仁周思纯邓俊胡鑫彭美贺彩梅
Owner HUNAN NORMAL UNIVERSITY