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5-fluorouracil-platinum (IV) complex, intermediate, as well as preparation method and application thereof

A technology of fluorouracil and complexes, applied in the field of anticancer chemical drugs, can solve the problems of restricted application and development of ototoxicity and neurotoxicity, and achieve the effects of obvious cell selectivity, simple operation and good anti-proliferation ability of the compound.

Active Publication Date: 2019-03-08
TIANJIN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the ototoxicity, nephrotoxicity and neurotoxicity of divalent platinum drugs including oxaliplatin including cisplatin seriously limit their clinical application and development.

Method used

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  • 5-fluorouracil-platinum (IV) complex, intermediate, as well as preparation method and application thereof
  • 5-fluorouracil-platinum (IV) complex, intermediate, as well as preparation method and application thereof
  • 5-fluorouracil-platinum (IV) complex, intermediate, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0084] The preparation method of formula (14) compound comprises:

[0085] 5-fluorouracil is reacted with formaldehyde to obtain a compound of formula (17);

[0086] The compound of formula (17) and the compound of formula (18) undergo an esterification reaction in the presence of the second condensing agent and the second acid-binding agent to obtain the compound of formula (14)

[0087]

[0088] Wherein, the second condensing agent is DMAP, and HOBT and EDCI can also be used;

[0089] The second acid binding agent is triethylamine, or adopts pyridine.

[0090] The above-mentioned 5-fluorouracil-platinum (IV) complex can be applied in the preparation of anti-tumor, breast cancer, colon cancer, cervical cancer or lung cancer drugs, and has a synergistic sensitization effect, and the IC50 value is significantly lower than that of cisplatin, oxali Platinum, 5-FU and combined administration have shown to have good anti-proliferation ability on cancer cells, and the lethality...

Embodiment 1

[0093] The structural formula of the 5-fluorouracil-platinum (IV) complex a of the present embodiment is as follows:

[0094]

[0095] The synthesis route of the preparation method of the 5-fluorouracil-platinum (IV) complex described in this example is as follows:

[0096]

[0097]

[0098] 1. Preparation of compound a2

[0099] Accurately weigh 5-fluorouracil (2.20g, 17.0mmol) into a 50mL round-bottomed flask, add 37% formaldehyde solution (2.06g, 37.8mmol), heat and reflux at 60°C for 2 hours, and obtain a transparent solution by rotary evaporation after 2 hours. Viscose a1 (78% yield). Add 20mL of anhydrous acetonitrile to compound a1, add succinic anhydride (2.18g, 21.8mmol), 4-dimethylaminopyridine DMAP (0.12g, 0.96mmol) and triethylamine (1.42mL, 10mmol) successively under stirring , react overnight at 50°C. After the reaction was detected by TCL, the solvent was removed by rotation, purified by a silica gel column, crystallized from absolute ethanol to obta...

Embodiment 2

[0124] The structural formula of the 5-fluorouracil-platinum (IV) complex b of the present embodiment is as follows:

[0125]

[0126] The synthesis route of the preparation method of the 5-fluorouracil-platinum (IV) complex described in this example is as follows:

[0127]

[0128] 1. Preparation of compound b

[0129] Accurately weigh compound a4 (115.0mg, 0.20mmol) and place it in a 10mL round-bottomed flask, add 2mL of ultra-dry DMF to it, add stearic anhydride (165.4mg, 0.30mmol) under magnetic stirring, and protect from light with argon for 60 °C overnight. TCL detection After the reaction was completed, the DMF was removed by rotary evaporation in a water bath at 60°C, the residue was dissolved in 1 mL of methanol, and a silica gel plate was prepared for purification to obtain a light yellow solid. After washing with anhydrous ether to remove residual DMF, the product was vacuum-dried to obtain 50.0 mg of compound b with a yield of 29.7%.

[0130] pass 1 H NMR...

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Abstract

The invention provides a 5-fluorouracil-platinum (IV) complex, an intermediate, and a preparation method. The 5-fluorouracil-platinum (IV) complex is represented by a formula (1) shown in the description, wherein the part shown in the description is selected from cis-platinum, oxaliplatin, carboplatin, eptaplatin, nedaplatin or miriplatin, and is preferably the cis-platinum or the oxaliplatin; R1is -CnH2n-, n is an integer and is larger than or equal to 1, and preferably, -CnH2n- is a straight chain group; and R2 is -CmH2m+1, m is an integer and is larger than or equal to 1, and preferably, -CmH2m+1 is a straight chain group. According to the 5-fluorouracil-platinum (IV) complex provided by the invention, the toxic and side effects of the cis-platinum, the oxaliplatin and 5-fluorouracil can be reduced, and meanwhile, the 5-fluorouracil-platinum (IV) complex has a synergistic sensitization effect when being used in medicines for treating cancers and antitumor drugs.

Description

technical field [0001] The invention belongs to the technical field of anticancer chemical drugs, and in particular relates to 5-fluorouracil-platinum (IV) complexes, intermediates, preparation methods and applications thereof. Background technique [0002] Cancer is a major disease that threatens human life and health worldwide, and is recognized as a "death killer" by the medical profession. There are as many as 3.5 million new cancer cases in my country every year, and about 2.7 million people die of cancer every year. Moreover, with the increasingly serious problems of environmental pollution and population aging, the incidence of cancer continues to rise. Worldwide, colorectal cancer ranks third in incidence (945,000 new cases, or 9.4% of the world total) and fourth in mortality (492,000 deaths, or 7.9% of the total), with both men and women The quantities are similar. Colorectal cancer is the second most prevalent cancer in the world after breast cancer, with 2.4 mi...

Claims

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Application Information

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IPC IPC(8): C07F15/00A61P35/00
CPCA61P35/00C07F15/0093
Inventor 徐靖源张然
Owner TIANJIN MEDICAL UNIV
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