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CN-121991068-A - 6-Phenyl-purine derivative, preparation method and medical application thereof

CN121991068ACN 121991068 ACN121991068 ACN 121991068ACN-121991068-A

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a 6-phenyl-purine derivative, a preparation method and medical application thereof. The structural formula of the 6-phenyl-purine derivative is shown as the following formula: The preparation method of the 6-phenyl-purine derivative comprises the steps of carrying out substitution reaction on S1.R 1 -CH 2 NH 2 and a compound 1 under the catalysis of organic base to obtain a compound 2, carrying out Dieckmann condensation reaction on the compound 2 and excessive CDI to obtain a compound 3, and carrying out Suzuki coupling reaction on the compound 3 and phenylboronic acid under the catalysis of sodium carbonate, pd (OAc) 2 and TPPTS to obtain the 6-phenyl-purine derivative with the structure shown in the general formula I. The 6-phenyl-purine derivative has anti-tumor activity and can be applied to the preparation of anti-tumor drugs.

Inventors

  • LING YONG
  • Xiong Minxuan
  • WANG LEI
  • XU KE
  • ZHAO XUEHAO
  • Ji Liujie
  • QIAN XIAOYANG
  • LU HAO
  • LIU DONGWEI
  • SHEN ZIMING

Assignees

  • 南通大学
  • 南通大学启东海洋研究院

Dates

Publication Date
20260508
Application Date
20251229

Claims (10)

  1. 1. A 6-phenyl-purine derivative, wherein the 6-phenyl-purine derivative has a structure according to formula I: Wherein R 1 is selected from phenyl, pyridinyl, methoxy-substituted phenyl, amino-substituted phenyl, fluoro-substituted phenyl, trimethoxy-substituted phenyl, tert-butyl-substituted phenyl, difluoromethoxy-substituted phenyl, trifluoromethyl-substituted phenyl, dimethoxy-substituted phenyl, isopropoxy-substituted phenyl, dimethyl-substituted phenyl, cyano-substituted phenyl, methyl-substituted phenyl, biphenyl, methylamino-substituted phenyl, methoxyfluoro-bis-substituted phenyl, methoxy-substituted pyridinyl, R 2 is selected from one of H, amino, cyclopropyl, isopropyl and methyl.
  2. 2. The 6-phenyl-purine derivative according to claim 1, wherein, R 1 is selected from phenyl, 3-pyridyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-aminophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4, 5-trimethoxyphenyl, 4-t-butylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethylphenyl, 3, 4-dimethoxyphenyl, 4-isopropoxyphenyl, 3, 4-dimethylphenyl, 4-cyanophenyl, 3-methoxyphenyl, 4-methylphenyl, 4-methylaminophenyl, 3-fluoro-4-methoxyphenyl, 2, 4-dimethoxyphenyl, 3, 5-dimethoxyphenyl, 2-methoxy-5-pyridyl, R 2 is selected from one of H, amino, cyclopropyl, isopropyl and methyl.
  3. 3. The 6-phenyl-purine derivative according to claim 1, wherein, The 6-phenyl-purine derivative is any one of the following compounds: 9-benzyl-2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (4-methoxybenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (2-methoxybenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (4-aminobenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluorobenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (4-fluorobenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 2-methyl-6-phenyl-9- (3, 4, 5-trimethoxybenzyl) -7, 9-dihydro-8H-purin-8-one; 9- (4-tert-butylbenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (4-difluoromethoxybenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 2-methyl-6-phenyl-9- (4-trifluoromethylbenzyl) -7, 9-dihydro-8H-purin-8-one; 9- (3, 4-dimethoxybenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (4-isopropoxybenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (3, 4-dimethylbenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 4- ((2-methyl-8-oxo-6-phenyl-7, 8-dihydro-9H-purin-9-yl) methyl) benzonitrile; 9- (3-methoxybenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 2-methyl-9- (4-methylbenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 2-amino-9-benzyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- ([ 1,1' -biphenyl ] -4-ylmethyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- ([ 1,1' -biphenyl ] -3-ylmethyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 2-methyl-6-phenyl-9- (pyridin-3-ylmethyl) -7, 9-dihydro-8H-purin-8-one; 9- ((6-methoxypyridin-3-yl) methyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (3-fluoro-4-methoxybenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (2, 4-dimethoxybenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; 9- (3, 5-dimethoxybenzyl) -2-methyl-6-phenyl-7, 9-dihydro-8H-purin-8-one; Tert-butyl (4- ((2-methyl-8-oxo-6-phenyl-7, 8-dihydro-9H-purin-9-yl) methyl) benzyl) carbamate; 9- (4-methoxybenzyl) -6-phenyl-7, 9-dihydro-8H-purin-8-one; n- (4- ((2-methyl-8-oxo-6-phenyl-7, 8-dihydro-9H-purin-9-yl) methyl) benzyl) pivalamide; 2-chloro-N- (4- [ (2-methyl-8-oxo-6-phenyl-7, 8-dihydro-9H-purin-9-yl) methyl ] benzyl) acetamide; Tert-butyl (4- ((2-methyl-8-oxo-6-phenyl-7, 8-dihydro-9H-purin-9-yl) methyl) phenyl) carbamate; 2-cyclopropyl-9- (4-methoxybenzyl) -6-phenyl-7, 9-dihydro-8H-purin-8-one; 2-isopropyl-9- (4-methoxybenzyl) -6-phenyl-7, 9-dihydro-8H-purin-8-one.
  4. 4. A process for the preparation of a 6-phenyl-purine derivative according to claim 1, wherein the synthetic route of the preparation process is as follows: The preparation method comprises the following steps: S1.R 1 -CH 2 NH 2 and a compound 1 are subjected to substitution reaction under the catalysis of organic base to obtain a compound 2; 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 phenylboronic acid under the catalysis of sodium carbonate, pd (OAc) 2 and triphenylphosphine tri-m-sodium sulfonate to obtain the 6-phenyl-purine derivative with the structure shown in the general formula I.
  5. 5. The process according to claim 4, wherein in step S1, the organic base is triethylamine or N, N-diisopropylethylamine, and the ratio of the amount of R 1 -CH 2 NH 2 to the amount of the compound 1 is 3.3:3.
  6. 6. The process according to claim 4, wherein in the step S1, the substitution reaction is carried out at 120℃for 2 days using n-butanol as a solvent.
  7. 7. The process according to claim 4, wherein in step S2, the ratio of the amounts of the substances of the compound 2 and CDI is 2.59:12.97, the Dieckmann condensation reaction is carried out under the protection of nitrogen, the reaction temperature is 30 ℃, and the reaction time is 12 hours.
  8. 8. The preparation method according to claim 4, wherein in the step S3, the ratio of the amount of the compound 3 to the amount of the phenylboronic acid is 1:1.2, the Suzuki coupling reaction is performed under the protection of nitrogen, the reaction temperature is 100 ℃, and the reaction time is 3 hours.
  9. 9. The use of a 6-phenyl-purine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient in the manufacture of a medicament for the treatment and/or prophylaxis of a malignant tumor, said malignant tumor being one of lung cancer, breast cancer, prostate cancer, colon cancer and liver cancer.
  10. 10. An antitumor drug characterized in that the active ingredient of the antitumor drug is the 6-phenyl-purine derivative or a pharmaceutically acceptable salt thereof according to claim 1, and the antitumor drug is used for treating and/or preventing malignant tumor, wherein the malignant tumor is one of lung cancer, breast cancer, prostate cancer, colon cancer and liver cancer.

Description

6-Phenyl-purine derivative, preparation method and medical application thereof Technical Field The invention belongs to the technical field of medicine preparation, and particularly relates to a 6-phenyl-purine derivative, a preparation method and medical application thereof. Background In the field of tumor therapy, the contradiction between clinical demand and drug delivery is increasingly prominent-although chemotherapy, targeted drugs and immunotherapy have formed a multi-dimensional therapeutic system, adaptive evolution of tumor cells (e.g. drug-resistant mutations, phenotypic switching) still results in treatment failure in about 60% of patients. Therefore, the development of novel drugs with high-efficiency anti-tumor activity, low toxic and side effects and strong targeting becomes an urgent need of the pharmaceutical industry. Purine is a basic building block for DNA, RNA synthesis, and also the core structure of a variety of key coenzymes (e.g., ATP, nad+) and signaling molecules (e.g., cAMP). Cell proliferation, particularly rapid, unlimited proliferation of tumor cells, is highly dependent on purine nucleotide synthesis and utilization. Compounds of the purine-like structure, because of their unique chemical structure and biological activity, present significant advantages in the treatment of cancer. Such compounds, through mimetic purine analogs, are capable of integrating into DNA or RNA, interfering with DNA synthesis and repair of cancer cells, thereby inhibiting proliferation of cancer cells. Meanwhile, the purine skeleton structure modification has the characteristic of simulating an ATP structure, can competitively inhibit protein kinase which plays a key role in tumorigenesis, and blocks the catalytic activity of the protein kinase for transferring a phosphate group to a substrate protein, so that signal channels (such as BCR-ABL, PI3K/Akt/mTOR and JAK/STAT channels) for driving tumor growth, survival and transfer are interrupted. Disclosure of Invention The invention aims to provide a 6-phenyl-purine derivative, a preparation method and medical application thereof. In a first aspect, the present invention provides a 6-phenyl-purine derivative having the structure of formula I: Wherein R 1 is selected from phenyl, pyridinyl, methoxy-substituted phenyl, amino-substituted phenyl, fluoro-substituted phenyl, trimethoxy-substituted phenyl, tert-butyl-substituted phenyl, difluoromethoxy-substituted phenyl, trifluoromethyl-substituted phenyl, dimethoxy-substituted phenyl, isopropoxy-substituted phenyl, dimethyl-substituted phenyl, cyano-substituted phenyl, methyl-substituted phenyl, biphenyl, methylamino-substituted phenyl, methoxyfluoro-bis-substituted phenyl, methoxy-substituted pyridinyl, R 2 is selected from one of H, amino, hydrogen, cyclopropyl, isopropyl and methyl. Further, R 1 is selected from the group consisting of phenyl, 3-pyridyl, 4-methoxyphenyl, 2-methoxyphenyl, 4-aminophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4, 5-trimethoxyphenyl, 4-t-butylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethylphenyl, 3, 4-dimethoxyphenyl, 4-isopropoxyphenyl, 3, 4-dimethylphenyl, 4-cyanophenyl, 3-methoxyphenyl, 4-methylphenyl, 4-methylaminophenyl, 3-fluoro-4-methoxyphenyl, 2, 4-dimethoxyphenyl, 3, 5-dimethoxyphenyl, 2-methoxy-5-pyridyl,R 2 is selected from one of H, amino, cyclopropyl, isopropyl and methyl. 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, the present invention provides a method for preparing the 6-phenyl-purine derivative, wherein the synthetic route of the preparation method is as follows: The preparation method comprises the following steps: S1.R 1-CH2NH2 and a compound 1 are subjected to substitution reaction under the catalysis of organic base to obtain a compound 2; 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 phenylboronic acid under the catalysis of sodium carbonate, pd (OAc) 2 and triphenylphosphine trimetaphosphate salt (TPPTS) to obtain the 6-phenyl-purine derivative with the structure shown in the general formula I. Further, the organic base is Triethylamine (TEA) or N, N-Diisopropylethylamine (DIPEA). Further, in step S1, the organic base is triethylamine or N, N-diisopropylethylamine, and the ratio of the amount of R 1-CH2NH2 to the amount of the compound 1 is 3.3:3. Further, in the step S1, the reaction condition of the substitution reaction is that n-butanol is taken as a solvent, and the reaction is carried out for 2 days at the temperature of 120 ℃. Further, in the step S2, the ratio of the amount of the compound 2 to the amount of the CDI substance is 2.59:12.97, the Dieckmann condensation reaction is carried out under the protection of nitrogen,