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Pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives, preparation methods of pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives, and application of pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives in oncotherapy

A technology of pyrimidine mustard and tumor treatment, which is applied in the direction of antineoplastic drugs, drug combinations, and pharmaceutical formulas, etc.

Inactive Publication Date: 2014-03-12
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there has been no report on the research on nitrogen mustard compounds with pyrazolo[1,5-a]pyrimidine compounds as carriers as anti-tumor drugs, which also makes this invention highly innovative

Method used

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  • Pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives, preparation methods of pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives, and application of pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives in oncotherapy
  • Pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives, preparation methods of pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives, and application of pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives in oncotherapy
  • Pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives, preparation methods of pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives, and application of pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives in oncotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0074] Example A. Inhibition of Five Common Tumor Cells

[0075] The assay method for inhibiting cell proliferation adopts the commonly used MTT method. This assay method can be used to determine the ability of different target compounds of the present invention to inhibit the proliferation of five cancer cells. Using methods well known in the art, a similar assay method can be used for any cancer cell . The tumor cells (HepG2, SH-SY5Y, MCF-7, A549, DU145) in the logarithmic growth phase were digested with 0.25% trypsin, and then the cells were cultured (DMEM+10%FBS or PRMI1640+10%FBS) Dilute and suspend into a single cell suspension, adjust the cell density to 2.0×10 4 cells / mL, add 100 μL to each well and inoculate in a 96-well plate. After culturing for 24 hours in an incubator at 37°C, saturated humidity, and 5% carbon dioxide, add 0.1 μM, 1 μM, 5 μM, 10 μM, 20 μM, and 30 μM according to the experimental design. , 50 μM, 100 μM of the compound of formula A-D, each concen...

Embodiment B

[0080] Example B. Acute Toxicity Test

[0081] For the results of Example A, when the substituent R 1 = chloromethyl, and R 2 = nitrogen mustard, R 3 The in vivo toxicity of compounds of formula C = hydrogen was determined. The test subjects were Kunming white mice (18-22g, half male and half male), fasted for 12 hours before the test, without water. The formula C was formulated into injection solutions with different concentrations and irradiated under ultraviolet light for 15 minutes before use. Get 10 small white mice, with 2 as a group (half and half female), divide into 5 groups, select a series of doses with larger dose intervals, inject different concentrations of injections of formula C to each group of mice respectively, and obtain 0% and 100% lethal range. In the formal experiment, 10 animals (half male and half female) were selected in each dose group, randomly assigned in stratification by weight and gender, and administered by tail vein injection after comple...

Embodiment 1

[0087] Prepared according to the following steps is the substituent R of formula A 1 = methyl, R 2 = nitrogen mustard, R 3 = Hydrogen compounds.

[0088]1.1 Synthesis of Ethoxymethylene Malononitrile

[0089] 9.9 g (0.15 mol) of malononitrile, 33.3 g (0.23 mol) of triethyl orthoformate and 38.4 g (0.38 mol) of acetic anhydride were added to a 250 mL one-necked flask. After 6 hours of reflux reaction, cool, add activated carbon, heat to reflux for 30 minutes, heat filter, wash the filter cake with hot ethanol, put the filtrate in the refrigerator overnight, filter with suction, and dry to obtain 15.4 g of a light yellow solid with a yield of 84.3%. The obtained spectrum is consistent with that reported in the literature.

[0090]

[0091] 1.2 Synthesis of 3-amino-4-cyanopyrazole

[0092] 15.0 g (0.12 mol) of ethoxymethylene malononitrile was slowly added to 12 mL (0.25 mol) of 85% hydrazine hydrate at room temperature, heated under reflux in a water bath for 1 h, and 10...

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Abstract

The invention relates to pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives or medical salts thereof, as well as application of the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives or the medical salts thereof. The pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives and the medical salts thereof have the structure shown as the formula I. Pharmacological experiments show that the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives and the medical salts thereof have inhibiting effects on the proliferation of various tumor cells. Moreover, the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives are small in toxicity, have the advantages of selectivity on tumor cells, and are dual-functional anti-tumor drugs. Meanwhile, the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives are easy to synthesize, and the overall yields are high. All the advantages show that the pyrazolo[1,5-alpha] pyrimidine nitrogen mustard derivatives have great potential of being anti-tumor drugs.

Description

technical field [0001] The present invention relates to new pyrazolo[1,5-a]pyrimidine nitrogen mustard derivatives, their preparation method and their application as tumor treatment drugs. Background technique [0002] Nitrogen mustards are cytotoxic drugs and are the earliest non-structural specific anti-tumor bioalkylating agents used in clinical practice. Since its inception, nitrogen mustard drugs have been actively researched and developed, and have played an important role in the treatment of tumors, and have been widely used at home and abroad. However, nitrogen mustard compounds can produce many serious side effects when inhibiting and killing tumor cells, such as nausea, vomiting, bone marrow suppression, and hair loss. Therefore, how to reduce the adverse reactions of nitrogen mustard compounds, improve the treatment efficiency, reduce its toxicity and increase its selectivity has become a research hotspot in the field of medicine, attracting and encouraging count...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCC07D487/04
Inventor 齐传民赵明霞宁红玉常进任红玉李石磊贺勇
Owner BEIJING NORMAL UNIVERSITY
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