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Benzisoselenazolone difluorocytidine compound as well as preparation method and application thereof

A technology of benzisoselazolone difluorocytidine and benzisoselazole, which is applied in the field of benzisoselazolone difluorocytidine compounds and their preparation, and can solve the problems of reducing toxicity and the like

Inactive Publication Date: 2010-12-22
曾慧慧
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The toxicity of 2'-deoxy-2', 2'-difluorocytidine may be related to this mechanism of action, because diphosphate not only inhibits the DNA synthesis of tumor cells, but also affects the DNA synthesis of rapidly proliferating normal cells
Therefore, merely enhancing or improving the inhibitory activity of 2'-deoxy-2',2'-difluorocytidine on ribonucleotide reductase cannot reduce its toxicity
Moreover, there is no report that 2'-deoxy-2', 2'-difluorocytidine modification significantly reduces toxicity

Method used

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  • Benzisoselenazolone difluorocytidine compound as well as preparation method and application thereof
  • Benzisoselenazolone difluorocytidine compound as well as preparation method and application thereof
  • Benzisoselenazolone difluorocytidine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1 Preparation of Compound 1-4

[0076] The synthetic route of compound 1-4 is as follows figure 2 Shown, wherein, R1 is selected from-H,-Cl,-F,-CH3, preparation process is:

[0077] 1) Take 4mmol 2-R14-nitrobenzoic acid (R1 is selected from -H, -Cl, -F, -CH3) and place it in 25ml of thionyl chloride to reflux for 3h, spin dry the excess thionyl chloride, and the remaining oily Liquid; add an appropriate amount of dichloromethane, dissolve, and spin dry to obtain a light yellow solid, that is, 2-R1-4-nitrophenylformyl chloride (R1 is selected from -H, -Cl, -F, -CH3), and It was dissolved in 20ml of dichloromethane and set aside;

[0078] 2) Weigh 0.132g (0.4mmol) tetrabutylamine bromide (TBAP) and dissolve it in 10ml of dichloromethane, and slowly add 5ml of 20% NaOH solution dropwise, cool to -10°C, stir; then slowly Add dropwise the 2-R1-4-nitrophenylformyl chloride dichloromethane solution prepared in step 1), keep the reaction system at -10°C, and conti...

Embodiment 2

[0082] Example 2 Preparation of Compound 5-6

[0083] The synthetic route of compound 5-6 is as follows image 3 As shown, the preparation conditions of compound 5 are the same as in Example 1, and compound 5 is placed in a hydrogenator, and then a catalytic amount of Ni is added to react for 20 minutes to obtain compound 6.

Embodiment 3

[0084] Example 3 Preparation of Compound 7-10

[0085] The synthetic route of compound 7-10 is as follows Figure 4 Shown, wherein, R1' is selected from -H, -Cl, -F, -CH3, 2-R1-5-nitrophenyl acid chloride (R1 is selected from -H, -Cl, -F, -CH3), 2 , 2'-diR1-5,5'-dinitrobenzoic anhydride, N-(5-nitro-2-R1phenylyl)-2'-deoxy-2',2'-difluorocytidine , N-(5-amino-2-R1 phenylacyl)-2'-deoxy-2', 2'-difluorocytidine and the preparation conditions of compound 7-10 are the same as in Example 1.

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PUM

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Abstract

The invention discloses a novel antitumor medicament, in particular a benzisoselenazolone difluorocytidine compound or a pharmaceutically acceptable salt or ester thereof as well as a preparation method and application thereof, wherein a benzisoselenazolone structure can identify selenocysteine residues in the activity center of thioredoxin reductase to generate the action of reversibly competitive inhibition and reserves the activity structure of 2'-deoxidization-2'2'-difluorocytidine. Therefore, the benzisoselenazolone difluorocytidine compound in the invention can selectively kill tumor cells, inhibit the growth of the tumor cells, and has the characteristics of high efficiency and low toxicity.

Description

technical field [0001] The invention relates to a class of novel antitumor drugs, in particular to a benzisoselazolone-difluorocytidine compound, a preparation method thereof and an application thereof. Background technique [0002] Nucleosides and their analogs have a wide range of biological activities. Among them, 2'-deoxy-2', 2'-difluorocytidine (Gemcitabine) and other cytidine nucleoside analogs have strong anti-tumor activity. Currently the drug of choice for the clinical prevention and treatment of pancreatic cancer. However, these drugs are highly toxic and have a strong myelosuppressive effect, which affects their wide clinical application. [0003] Ribonucleotide reductase (RR), as an indispensable enzyme for cell DNA synthesis, is closely related to normal and abnormal cell division. Studies have shown that the abnormality of RR is closely related to the formation and metastasis of tumor cells, and it is highly expressed in many tumor patients. The thioredoxin ...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00A61K31/7068A61P35/00A61P35/02
Inventor 曾慧慧李叶桓
Owner 曾慧慧
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