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CN-121991070-A - Purinone derivative, preparation method and medical application thereof

CN121991070ACN 121991070 ACN121991070 ACN 121991070ACN-121991070-A

Abstract

The invention belongs to the field of medicines, and discloses a purinone derivative, a preparation method and medical application thereof. The purinone derivative has a structure shown in a general formula I: the purinone derivative has strong inhibition effect on proliferation of tumor cells such as liver cancer, lung cancer, colon cancer, pancreatic cancer, prostatic cancer, breast cancer and the like, and can be applied to preparation of medicines for treating and/or preventing malignant tumors.

Inventors

  • LING YONG
  • ZHANG CHI
  • WANG LEI
  • JI DONGLIANG
  • LUO NINGNING
  • LIU DONGWEI
  • ZHU LINA
  • SHEN ZIMING
  • Xiong Minxuan
  • LU HAO

Assignees

  • 南通大学
  • 南通大学启东海洋研究院

Dates

Publication Date
20260508
Application Date
20260108

Claims (10)

  1. 1. A purinone derivative, wherein the purinone derivative has a structure represented by formula I: , Wherein R 1 is selected from one of methoxy substituted phenyl, naphthyl, biphenyl and methoxy fluoro disubstituted phenyl, R 2 is selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, dimethylamino substituted phenyl, ethoxy substituted phenyl, isopropoxy substituted phenyl, methylaminophenyl, ethyl substituted phenyl, ethylamino phenyl, diethylamino substituted phenyl, 、 、 、 One of methoxy fluoro disubstituted phenyl, ethoxy fluoro disubstituted phenyl and isopropoxy fluoro disubstituted phenyl.
  2. 2. The purinone derivative according to claim 1, wherein R 1 is selected from one of phenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 1-naphthyl, 4-biphenyl, 2-naphthyl and 3-biphenyl, R 2 is selected from phenyl, 3-methoxyphenyl, 3-methylphenyl, 3- (N, N-dimethylamino) -phenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3-ethoxyphenyl, 3-isopropoxyphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-methylaminophenyl, 3-ethylaminophenyl, 、 、 、 One of 2-fluoro-5-ethoxyphenyl, 3-fluoro-5-isopropoxyphenyl, 2-fluoro-5-isopropoxyphenyl and 3- (N, N-diethylamino) -phenyl.
  3. 3. The purinone derivative according to claim 1, wherein said purinone derivative is any one of the following compounds: 9- (3-fluoro-4-methoxybenzyl) -6- (3-methoxyphenyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -2-methyl-6- (m-tolyl) -7, 9-dihydro-8H-purin-8-one; 6- (3-dimethylaminophenyl) -9- (3-fluoro-4-methoxybenzyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 6- (3-dimethylaminophenyl) -2-methyl-9- (naphthalen-2-ylmethyl) -7, 9-dihydro-8H-purin-8-one 9- (4- (Difluoromethoxy) benzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 6- (3-dimethylaminophenyl) -2-methyl-9- (naphthalen-1-ylmethyl) -7, 9-dihydro-8H-purin-8-one; 9- ([ 1,1' -biphenyl ] -3-ylmethyl) -6- (3-dimethylaminophenyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 6- (4-fluoro-3-methylphenyl) -9- (3-fluoro-4-methoxybenzyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -6- (3-fluoro-5-methoxyphenyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 6- (4-fluoro-3-methoxyphenyl) -9- (3-fluoro-4-methoxybenzyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -6- (3-fluoro-5-methoxyphenyl) -2-methyl-7, 9-dihydro-8H-purin-8-one 6- (3-Ethoxyphenyl) -9- (3-fluoro-4-methoxybenzyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -6- (3-isopropoxyphenyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 6- (3-ethylphenyl) -9- (3-fluoro-4-methoxybenzyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -6- (3-isopropylphenyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -2-methyl-6- (3- (piperazin-1-yl) phenyl) -7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -2-methyl-6- (3- (pyrrolidin-1-yl) phenyl) -7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -2-methyl-6- (3- (piperidin-1-yl) phenyl) -7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -2-methyl-6- (3-morpholinophenyl) -7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -2-methyl-6- (3- (methylamino) phenyl) -7, 9-dihydro-8H-purin-8-one; 6- (3- (diethylamino) phenyl) -9- (3-fluoro-4-methoxybenzyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 6- (3- (ethylamino) phenyl) -9- (3-fluoro-4-methoxybenzyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 6- (3-ethoxy-5-fluorophenyl) -9- (3-fluoro-4-methoxybenzyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -6- (3-fluoro-5-isopropoxyphenyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -6- (2-fluoro-5-isopropoxyphenyl) -2-methyl-7, 9-dihydro-8H-purin-8-one; 6- (5-ethoxy-2-fluorophenyl) -9- (3-fluoro-4-methoxybenzyl) -2-methyl-7, 9-dihydro-8H-purin-8-one.
  4. 4. A process for the preparation of a purinone derivative according to claim 1, wherein the synthetic route of the process is represented by the formula: , The preparation method comprises the following steps: s1, carrying out substitution reaction on R 1 -CH 2 NH 2 and a compound 1 under the condition of organic alkali to obtain a compound 2; Wherein R 1 is selected from one of methoxy substituted phenyl, naphthyl, biphenyl and methoxy fluoro disubstituted phenyl; S2, carrying out Dieckmann condensation reaction on the compound 2 and excessive carbonyldiimidazole to obtain a compound 3; S3, carrying out Suzuki coupling reaction on the compound 3 and R 2 boric acid under the catalysis of sodium carbonate, pd (OAc) 2 and triphenylphosphine trimetaphosphate sodium salt to obtain a purinone derivative; wherein R 2 is selected from the group consisting of phenyl, methoxy substituted phenyl, methyl substituted phenyl, dimethylamino substituted phenyl, ethoxy substituted phenyl, isopropoxy substituted phenyl, methylaminophenyl, ethyl substituted phenyl, ethylaminophenyl, diethylamino substituted phenyl, 、 、 、 One of methoxy fluoro disubstituted phenyl, ethoxy fluoro disubstituted phenyl and isopropoxy fluoro disubstituted phenyl.
  5. 5. The process according to claim 4, wherein the organic base is triethylamine or N, N-diisopropylethylamine.
  6. 6. The process according to claim 4, wherein in step S1, the ratio of the amounts of the substances of the compound 1 and R 1 -CH 2 NH 2 is 3:3.3, the solvent is N-butanol, and the reaction condition is N 2 protection, 120 ℃ for 2 days.
  7. 7. The process according to claim 4, wherein the ratio of the amounts of the substances of the compound 2 and carbonyldiimidazole in the step S2 is 2.59 (12-13), and the Dieckmann condensation reaction is carried out under the conditions of N 2 protection and 30 ℃ for 12 hours.
  8. 8. The process according to claim 4, wherein the ratio of the amounts of the substances of the compound 3 and the boric acid R 2 in step S3 is 1:1.2.
  9. 9. The process of claim 4, wherein the Suzuki coupling reaction is carried out at 100℃for about 3 hours under N 2 .
  10. 10. Use of the purinone derivative or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient in the manufacture of a medicament for the treatment and/or prophylaxis of a malignant tumor, which is one of prostate cancer, colon cancer, breast cancer, liver cancer, lung cancer and pancreatic cancer.

Description

Purinone derivative, preparation method and medical application thereof Technical Field The invention belongs to the field of medicines, and particularly relates to a purinone derivative, a preparation method and medical application thereof. Background Tumors are one of the diseases with highest global mortality, and complex pathogenesis (such as genetic heterogeneity, multi-drug resistance and remote metastasis capability) of the tumors lead to the difficulty in radical treatment of the existing treatment means. Therefore, the development of highly specific molecular targets and the development of targeted drugs have become the core direction in the field of tumor research. S-phase kinase-associated protein 2 (SKP 2) is used as a key substrate recognition subunit of SKP1-CUL1-ROC1-F-box (SCF) E3 ubiquitin ligase complex to regulate and control cell cycle progression through mediating ubiquitination modification. Studies prove that SKP2 can specifically bind to phosphorylated tumor suppressor factors p27 and p21, promote the degradation of proteasome thereof through K48-linked polyubiquitination marks, and finally relieve cell cycle arrest and promote tumor cell proliferation. In various malignant tumors such as lung cancer, breast cancer, colon cancer and the like, SKP2 presents high-frequency over-expression characteristics, and the expression level of the SKP2 is obviously inversely related to tumor stage, lymph node metastasis and patient prognosis. The gene knockout mouse model further verifies that SKP2 deletion can obviously inhibit tumorigenesis and development, and the core position of the gene knockout mouse model serving as an oncogenic driving factor is clear. Based on the mechanism, the targeted inhibition of SKP2 function has become an important break through for breaking through the traditional treatment bottleneck and developing a novel anticancer strategy. Disclosure of Invention The invention aims to provide a purinone derivative, a preparation method and medical application thereof, wherein the purinone derivative can directly target Skp2, induce tumor cell cycle arrest, promote apoptosis of mitochondrial pathways and the like to play an anti-tumor role. In a first aspect of the present invention, there is provided a purinone derivative having the structure of formula I: Wherein R 1 is selected from one of methoxy substituted phenyl, naphthyl, biphenyl and methoxy fluoro disubstituted phenyl, R 2 is selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, dimethylamino substituted phenyl, ethoxy substituted phenyl, isopropoxy substituted phenyl, methylaminophenyl, ethyl substituted phenyl, ethylamino phenyl, diethylamino substituted phenyl, 、、、One of methoxy fluoro disubstituted phenyl, ethoxy fluoro disubstituted phenyl and isopropoxy fluoro disubstituted phenyl. Further, R 1 is selected from one of phenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 1-naphthyl, 4-biphenyl, 2-naphthyl, 3-biphenyl, R 2 is selected from phenyl, 3-methoxyphenyl, 3-methylphenyl, 3- (N, N-dimethylamino) -phenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3-ethoxyphenyl, 3-isopropoxyphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-methylaminophenyl, 3-ethylaminophenyl,、、、One of 2-fluoro-5-ethoxyphenyl, 3-fluoro-5-isopropoxyphenyl, 2-fluoro-5-isopropoxyphenyl and 3- (N, N-diethylamino) -phenyl. The preferred compound code of the structural general formula I and the corresponding structure are shown in the table 1: TABLE 1 partial compound code of general formula I and corresponding structure In a second aspect of the present invention, there is provided a process for preparing the purinone derivative, wherein the synthetic route is as follows: The preparation method comprises the following steps: s1, carrying out substitution reaction on R 1-CH2NH2 and a compound 1 under the condition of organic alkali to obtain a compound 2; Wherein R 1 is selected from one of methoxy substituted phenyl, naphthyl, biphenyl and methoxy fluoro disubstituted phenyl; s2, carrying out Dieckmann condensation reaction on the compound 2 and excessive Carbonyl Diimidazole (CDI) to obtain a compound 3; S3, carrying out Suzuki coupling reaction on the compound 3 and R 2 boric acid under the catalysis of sodium carbonate, pd (OAc) 2 and triphenylphosphine trimetaphosphate sodium salt to obtain a purinone derivative; R 2 is selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, dimethylamino substituted phenyl, ethoxy substituted phenyl, isopropoxy substituted phenyl, methylaminophenyl, ethyl substituted phenyl, ethylaminophenyl, diethylamino substituted phenyl, 、、、One of methoxy fluoro disubstituted phenyl, ethoxy fluoro disubstituted phenyl and isopropoxy fluoro disubstituted phenyl. Further, the organic base is triethylamine or N, N-diisopropylethylamine. Further, in the step S1, the ratio of the amount of the compound 1 to the amount of the