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Chlorambucil derivative, and preparation method and application thereof

A technology for chlorambucil and derivatives, which is applied in the directions of pharmaceutical formulations, pharmaceutical combinations, and medical preparations containing active ingredients, etc., can solve the problems of large toxic and side effects, limited therapeutic effect, short half-life and the like

Inactive Publication Date: 2015-06-17
NANJING YOUYI MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, topotecan and irinotecan have obvious disadvantages, including short half-life in vivo, severe side effects and limited therapeutic effect.

Method used

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  • Chlorambucil derivative, and preparation method and application thereof
  • Chlorambucil derivative, and preparation method and application thereof
  • Chlorambucil derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0121] Example 1. Synthesis of 4-[bis(2-chloroethyl)amino]benzenebutyrate camptothecin ester (XBB-001, compound of formula II, R=H)

[0122] The reaction formula is as follows:

[0123]

[0124] Experimental steps:

[0125] Into a 100 mL round bottom flask, 0.348 g (1 mmol) of camptothecin and 40 mL of anhydrous DMF were added and heated to dissolve.

[0126] 0.334g (1.1mmol) 4-[p-bis(2-chloroethyl)amino]phenylbutyric acid was added to the solution, then 0.501g (2mmol) 2-chloro-1-methylpyridinium iodide, 0.489 g (4 mmol) 4-dimethylaminopyridine, stirred at room temperature, and reacted overnight until the reaction was complete. 200mL ethyl acetate was added to the reaction solution, stirred for 15 minutes, transferred to a separatory funnel, the mixed solution was washed three times with 100mL salt water, the organic phase was dried with 20g anhydrous magnesium sulfate for 50 minutes, filtered to remove magnesium sulfate, and removed by rotary evaporation Solvent ethyl acetate. The...

Embodiment 24

[0130] Example 2. Synthesis of 7-ethyl-10-hydroxycamptothecin (XBB-002, compound of formula I, R is ethyl)-[bis(2-chloroethyl)amino]phenylbutyric acid

[0131] The reaction formula is as follows:

[0132]

[0133] Experimental steps:

[0134] Add 0.456g (1.5mmol) 4-[p-bis(2-chloroethyl)amino]phenylbutyric acid, 30mL anhydrous toluene, 600μL thionyl chloride and 2 drops of anhydrous DMF into a 100mL round bottom flask, protected by nitrogen After stirring for 6 hours at room temperature, the excess thionyl chloride and anhydrous toluene were removed by rotary evaporation under reduced pressure, and then 10 mL of chloroform was added to dissolve the residue to obtain solution A.

[0135] Weigh 0.392 g (1 mmol) of 7-ethyl-10-hydroxycamptothecin and add it to another 100 mL round bottom flask, add 20 mL of anhydrous DMF, heat and stir to dissolve, and add 250 μL of anhydrous triethylamine. The solution A was slowly added dropwise to the above solution through the dropping funnel. The add...

Embodiment 34

[0140] Example 3. Synthesis of 10-[bis(2-chloroethyl)amino]phenylbutyric acid 10-hydroxycamptothecin (XBB-003, compound of formula I, R=H)

[0141] The reaction formula is as follows:

[0142]

[0143] Experimental steps:

[0144] Add 0.456g (1.5mmol) 4-[p-bis(2-chloroethyl)amino]phenylbutyric acid, 30mL anhydrous toluene, 600μL thionyl chloride and 2 drops of anhydrous DMF into a 100mL round bottom flask, protected by nitrogen After stirring for 6 hours at room temperature, the excess thionyl chloride and anhydrous toluene were removed by rotary evaporation under reduced pressure, and then 10 mL of chloroform was added to dissolve the remainder to obtain solution A.

[0145] Weigh 0.364 g (1 mmol) of 10-hydroxycamptothecin and add it to another 100 mL round bottom flask, add 20 mL of anhydrous DMF, heat and stir to dissolve it, and add 250 μL of anhydrous triethylamine. The solution A was slowly added dropwise to the above solution through the dropping funnel. The addition was compl...

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Abstract

The invention discloses a chlorambucil derivative with a structure as shown in a formula I, II or III and pharmaceutically acceptable salts thereof, wherein the formula is described in the specification. The invention also relates to a preparation method for the chlorambucil derivative, a preparation of the chlorambucil derivative and application of the chlorambucil derivative.

Description

Technical field [0001] The invention relates to a class of chlorambucil derivatives and pharmaceutically acceptable salts thereof, preparation methods, preparations and applications as antitumor drugs. Background technique [0002] At present, targeted therapy has become an important direction of cancer treatment, and one-drug-one-target treatment models are often used, such as irinotecan (CPT-11), which acts on DNA topoisomerase I for the treatment of advanced colorectal cancer. And for the treatment of ovarian cancer and breast cancer, paclitaxel (Taxol) which acts on the microtubules in the cell, etc. However, tumors are different from general diseases. Its growth and survival not only depend on the conduction of a receptor or a signal pathway. This makes the strategy of acting on a target only unable to completely kill tumor cells, and is easy to produce Drug resistance. Therefore, the combination of multiple drugs has become the main method of clinical treatment of cancer....

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/4745A61P35/00A61P35/02
CPCC07D491/22A61P35/00A61P35/02
Inventor 张跃华
Owner NANJING YOUYI MEDICAL TECH CO LTD
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