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CN-122010953-A - Pyrazolo [1, 5-alpha ] pyrimidine compound, and synthetic method and application thereof

CN122010953ACN 122010953 ACN122010953 ACN 122010953ACN-122010953-A

Abstract

The invention discloses pyrazolo [1, 5-alpha ] pyrimidine compounds, a synthesis method and application thereof, wherein the pyrazolo [1, 5-alpha ] pyrimidine compounds have the following structural general formula: The invention also specifically discloses a synthesis method of the pyrazolo [1, 5-alpha ] pyrimidine compound and application of the pyrazolo [1, 5-alpha ] pyrimidine compound in preparation of medicines for preventing or/and treating liver cancer. The synthesized pyrazolopyrimidine compound disclosed by the invention has a good inhibition effect on liver cancer HepG2 cells, and the antitumor activity in the liver cancer HepG2 cells is better than that of a positive control drug CX-4945 and a compound I-1, especially the compounds I-2 and I-5 show excellent proliferation inhibition performance on the liver cancer HepG2 cells.

Inventors

  • WU DOUCAN
  • WANG MENGLIN
  • Ma Guanshuo
  • QIAN HUIQIN
  • WANG YUE
  • ZHAO YUAN
  • WU JIE
  • YANG JINGYI
  • WU MENGHAN

Assignees

  • 豫北医学院

Dates

Publication Date
20260512
Application Date
20260212

Claims (7)

  1. 1. Pyrazolo [1, 5-alpha ] pyrimidine compounds are characterized by the following structural general formula: wherein R is 4-NO 2 -Ph-、3-NO 2 -Ph-、2-NO 2 -Ph-, 3-F-Ph-, or 4-F-Ph-.
  2. 2. Pyrazolo [1,5- α ] pyrimidine compound according to claim 1, characterized in that it comprises in particular a compound of the following structure: 、 、 、 、 ; IC50 values of the corresponding compounds for inhibiting proliferation activity of liver cancer HepG2 cells were 40.60. Mu.M, 32.36. Mu.M, 40.24. Mu.M, 38.37. Mu.M, 36.77. Mu.M, 39.25. Mu.M, respectively.
  3. 3. A synthesis method of a pyrazolo [1, 5-alpha ] pyrimidine compound is characterized by comprising the specific synthesis process of reacting a compound 4, namely 5, 7-dichloropyrazolo [1, 5-alpha ] pyrimidine-3-carbonitrile, with cyclopropylamine to obtain a compound 5, namely 5-chloro-7-cyclopropylaminopyrazolo [1, 5-alpha ] pyrimidine-3-carbonitrile, and reacting the compound 5 with a substituted aniline compound to obtain a target compound I, namely pyrazolo [1, 5-alpha ] pyrimidine compound, wherein the substituted aniline compound is o-nitroaniline, m-nitroaniline, p-nitroaniline, m-fluoroaniline or p-fluoroaniline, and the corresponding synthesis route is as follows: 。
  4. 4. The synthesis method of pyrazolo [1, 5-alpha ] pyrimidine compound according to claim 1 is characterized in that the specific synthesis process of the compound 5 comprises the steps of adding compound 4 and absolute ethyl alcohol into a reaction container, heating and stirring at 40-60 ℃ for dissolution, adding cyclopropylamine for reaction, changing the reaction liquid from light yellow turbidity into milky suspension, analyzing the reaction process by thin layer chromatography, and stopping heating and cooling to room temperature after the reaction is completed to obtain the compound 5, wherein the developing agent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:2.
  5. 5. The synthesis method of the pyrazolo [1, 5-alpha ] pyrimidine compound is characterized in that the specific synthesis process of the compound I comprises the steps of adding a compound 5 and a substituted aniline compound, cesium carbonate, palladium dichloride, sodium acetate and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine into a tube sealing, adding 1, 4-dioxane, sealing, heating to 110-130 ℃, stopping heating after the reaction is finished, standing and cooling to room temperature, adding dichloromethane and water, standing and layering, washing a lower organic phase with water, concentrating an organic phase, and separating by column chromatography to obtain the compound I.
  6. 6. Use of pyrazolo [1, 5-alpha ] pyrimidine compounds according to claim 1 or 2 in the preparation of medicaments for the prophylaxis or/and treatment of liver cancer.
  7. 7. Use of pyrazolo [1, 5-alpha ] pyrimidine compound according to claim 1 or 2 in the preparation of a medicament for inhibiting liver cancer HepG2 cell proliferation.

Description

Pyrazolo [1, 5-alpha ] pyrimidine compound, and synthetic method and application thereof Technical Field The invention belongs to the technical field of medicine synthesis, and particularly relates to pyrazolo [1, 5-alpha ] pyrimidine compounds, and a synthesis method and application thereof. Background Pyrazolo [1,5-a ] pyrimidine compounds are reported in various documents, and have biological activities （Turowec J P,Duncan J S,French A C,et al. Protein kinase CK2 is a constitutively active enzyme that promotes cell survival: strategies to identify CK2 substrates and manipulate its activity in mammalian cells.Methods Enzymol, 2010, 484:471-493）. such as antitumor, antiviral, antibacterial, anti-inflammatory, central nervous system medicines, cardiovascular and the like, namely （Turowec J P,Duncan J S,French A C,et al. Protein kinase CK2 is a constitutively active enzyme that promotes cell survival: strategies to identify CK2 substrates and manipulate its activity in mammalian cells.Methods Enzymol, 2010, 484:471-493）. casein kinase 2 (CK 2) is a ubiquitous and highly specific protein serine or threonine kinase, generally exists in tetramer complexes consisting of alpha subunits and beta subunits, and has biological targeting effect. Inhibition of CK2 is thought to affect multiple pathways simultaneously, participate in regulating the growth, proliferation and differentiation processes of cells, play an important role in survival and apoptosis of cells, and can promote alteration of survival （Pack M,Wrublewsky S,Montenarh M,et al.SGC-CK2-1 Is an Efficient Inducer of Insulin Production and Secretion in Pancreatic β-Cells.Pharmaceutics, 2021, 14）.CK2 functions of cells by regulating apoptosis signaling pathways in relation to various human diseases including cancer, （Haddach M,Tran J A,Pierre F,et al.Pyrazolopyrimidines and Related Heterocycles as CK2 Inhibitors.US20110152240(2024-05-29)）. such as SGC-CK2-1（Carrow Wells, David H, Drewry,Julie E, Pickett, Alison D, et. al. SGC-CK2-1: the first selective chemical probe for the pleiotropic kinase CK2. ChemRxiv. 2020, 1）,SGC-CK2-1 useful for treating cancer, infectious diseases, inflammatory conditions, neurodegenerative diseases, pain and immune disorders is a highly potent, ATP-competitive CK2 chemical probe selective for CK2 isoforms, ck2α and CK2α'（Trembley J H, Unger G M, Tobolt D K, et al. Systemic administration of antisense oligonucleotides simultaneously targeting CK2α and α' subunits reduces orthotopic xenograft prostate tumors in mice. Molecular & Cellular Biochemistry, 2011, 356(1-2):21-35.）, with IC50 values of 36nM and 16nM, respectively. The same article also reports the analogue N- {5- [ (3-cyano-7-cyclopropylaminopyrazol [1,5, -a ] pyrimidin-5-) amino ] -2-methylphenyl } -acetamide (compound I-1) of CK2-1 with IC50 values of 3.2nM and 1.8nM, respectively. However, there is no description about the inhibition of liver cancer HepG2 cell proliferation activity by pyrazolo [1,5-a ] pyrimidine compounds. Disclosure of Invention The invention aims to provide pyrazolo [1, 5-alpha ] pyrimidine compounds and a synthesis method thereof, and the pyrazolo [1, 5-alpha ] pyrimidine compounds synthesized by the method have better liver cancer HepG2 cell proliferation inhibition activity and can be further used for preparing medicines for preventing or/and treating liver cancer. The invention adopts the following technical scheme to realize the aim, and the pyrazolo [1, 5-alpha ] pyrimidine compounds have the structural general formula: wherein R is 4-NO 2-Ph-、3-NO2-Ph-、2-NO2 -Ph-, 3-F-Ph-, or 4-F-Ph-. The pyrazolo [1, 5-alpha ] pyrimidine compound disclosed by the invention specifically comprises a compound with the following structure: 、、、、; IC50 values of the corresponding compounds for inhibiting proliferation activity of liver cancer HepG2 cells were 40.60. Mu.M, 32.36. Mu.M, 40.24. Mu.M, 38.37. Mu.M, 36.77. Mu.M, 39.25. Mu.M, respectively. The invention relates to a synthesis method of pyrazolo [1, 5-alpha ] pyrimidine compounds, which comprises the specific synthesis process of reacting a compound 4, namely 5, 7-dichloro pyrazolo [1,5-a ] pyrimidine-3-carbonitrile, with cyclopropylamine to obtain a compound 5, namely 5-chloro-7-cyclopropylaminopyrazolo [1,5-a ] pyrimidine-3-carbonitrile, and reacting the compound 5 with a substituted aniline compound to obtain a target compound I, namely pyrazolo [1, 5-alpha ] pyrimidine compound, wherein the substituted aniline compound is o-nitroaniline, m-nitroaniline, p-nitroaniline, m-fluoroaniline or p-fluoroaniline, and the corresponding synthesis route is as follows: 。 Further, the specific synthesis process of the compound 5 comprises the steps of adding the compound 4 and absolute ethyl alcohol into a reaction container, heating and stirring at 40-60 ℃ for dissolution, adding cyclopropylamine for reaction, changing the reaction liquid from light yellow turbidity into milky suspension, analyzing the reaction pro