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1-{3-[p-bis-(2-chloroethyl)amino]amphetamine}formyl-5-fluorouracil and its preparation and application

A technology based on fluorouracil and amphetamine, applied in the field of chlorambucil derivatives, can solve the problems of easy drug resistance and inability to completely kill tumor cells, achieve good anticancer activity, improve curative effect, and reduce toxicity side effects

Active Publication Date: 2022-02-18
NANJING YOUYI MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, tumors are different from general diseases. Its growth and survival are not only dependent on the conduction of a receptor or a signaling pathway. drug resistance

Method used

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  • 1-{3-[p-bis-(2-chloroethyl)amino]amphetamine}formyl-5-fluorouracil and its preparation and application
  • 1-{3-[p-bis-(2-chloroethyl)amino]amphetamine}formyl-5-fluorouracil and its preparation and application
  • 1-{3-[p-bis-(2-chloroethyl)amino]amphetamine}formyl-5-fluorouracil and its preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1. Synthesis of 1-{3-[p-bis-(2-chloroethyl)amino]amphetamino}formyl-5-fluorouracil (YY-001)

[0106] (1) Synthesis of 3-[to-bis-(2-chloroethyl)amino]phenylpropyl isocyanate

[0107] The reaction formula is as follows:

[0108]

[0109] Experimental steps:

[0110] In a 100mL round bottom flask, add 1.0g chlorambucil (3.287mmol) and 10ml dry toluene, stir to dissolve, add 0.4g powdered 4A molecular sieve, and then add 1.403g (5.10mmol) to the solution Diphenylphosphoryl azide (DPPA) and 0.515g (5.10mmol) of triethylamine were stirred at room temperature until the reaction was complete (about 30 minutes), and about 10ml of saturated NaHCO was added to the reaction solution 3 aqueous solution, stirred for 2-3 minutes, added ethyl acetate (30ml×3) for extraction three times, combined the organic phases, and washed with anhydrous NaSO 4 Drying, column separation, using 200-300 mesh silica gel as the stationary phase, and dichloromethane and petroleum ether mixt...

Embodiment 2

[0119] Example 2. Synthesis of 1-{3-[p-bis-(2-chloroethyl)amino]amphetamino}formyl-5-fluorouracil (YY-001)

[0120] (1) Synthesis of 3-[to-bis-(2-chloroethyl)amino]phenylpropyl isocyanate

[0121] The reaction formula is as follows:

[0122]

[0123] Into a 100mL round bottom flask, add 1.0g chlorambucil (3.287mmol) and 5ml acetone, stir to dissolve it, add 0.365g (3.616mmol) triethylamine, cool to 0 to -5°C in an ice-salt bath, A solution of 0.392 g (3.616 mmol) of ethyl chloroformate in acetone (2 ml) was slowly added dropwise to the solution, and after the drop was completed, stirring was continued at 0 to -5° C. for 30 minutes. Then, 0.427 g (6.574 mmol) of an aqueous solution (1.5 ml) of sodium azide was slowly added dropwise to the solution, and stirring was continued at 0 to -5°C for 30 minutes. Add 30ml of ice water to the solution, pour the mixture into a separatory funnel, add 50ml of toluene to the separatory funnel in four times to extract the reaction product...

Embodiment 3

[0126] Example 3. Synthesis of 1-{3-[p-bis-(2-chloroethyl)amino]amphetamino}formyl-5-fluorouracil (YY-001)

[0127] (1) Synthesis of 3-[to-bis-(2-chloroethyl)amino]phenylpropyl isocyanate

[0128] The reaction formula is as follows:

[0129]

[0130] In a 100ml flask, add 1.0g (3.287mmol) chlorambucil, 30ml chloroform and 2-3 drops of DMF, stir, 0.782g (6.616mmol) thionyl chloride (MW: 119), stir at room temperature under nitrogen protection After 4 hours, the reaction was carried out at reflux for 1 hour, and the solvent and excess thionyl chloride were removed under reduced pressure to obtain 4-[bis(2-chloroethyl)amino]benzenebutyryl chloride (A).

[0131] Add 0.321 g (4.950 mmol) of sodium azide and 10 ml of anhydrous tetrahydrofuran into a 100 ml flask, heat and stir until reflux. Dissolve the 4-[bis(2-chloroethyl)amino]benzenebutyryl chloride obtained above in 10ml of tetrahydrofuran and add it to the constant pressure dropping funnel. After reflux occurs, start to d...

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Abstract

The invention discloses an antitumor drug compound having a structure of formula I: 1-{3-[p-bis-(2-chloroethyl)amino]amphetamino}formyl-5-fluorouracil and a preparation method thereof. The drug compound molecule of the present invention contains both the dichloroethylamine alkylation group that cross-links DNA bases and the 5-fluorouracil precursor structure that inhibits deoxythymidylate synthase, and acts on cancer cells by two mechanisms, Thereby a synergistic effect is produced, the cancer cells can be more effectively inhibited and killed, the curative effect can be improved and the toxic and side effects can be reduced. The compound of the present invention has good anticancer activity and can be used to prepare medicines for treating hematological cancer, solid tumor cancer, sarcoma, skin cancer or glioma.

Description

technical field [0001] The present invention relates to a derivative of chlorambucil, in particular to a compound 1-{3-[p-bis-(2-chloroethyl)amino]amphetamine}formyl-5-fluorouracil Its preparation method and application as antitumor drug. Background technique [0002] Tumor is a kind of disease that seriously endangers human life and health. Under the action of carcinogenic factors, a certain cell in a local tissue loses its normal regulation of its growth at the gene level, resulting in abnormal clonal proliferation. It manifests as excessive cell proliferation and abnormal differentiation. At present, cancer has become the first cause of death for human beings and poses the most serious threat to human survival. [0003] Drug therapy plays an important role in the treatment of tumors, and there are many kinds of anticancer drugs with different mechanisms of action. The mechanism of action of most anti-tumor drugs is mainly to prevent the synthesis of deoxyribonucleic ac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/553A61K31/513A61P35/00A61P35/02
CPCC07D239/553
Inventor 张跃华赵梦尧
Owner NANJING YOUYI MEDICAL TECH CO LTD
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