Search

CN-121991069-A - Pyrimidoimidazolone derivative, preparation method and medical application thereof

CN121991069ACN 121991069 ACN121991069 ACN 121991069ACN-121991069-A

Abstract

The invention belongs to the field of medicines, and discloses a pyrimidoimidazolone derivative, a preparation method and medical application thereof. The pyrimidoimidazolone derivative has a structure shown in a general formula I: The preparation method comprises the steps of carrying out substitution reaction on 1- (4-methoxyphenyl) -1-R 2 -methylamine and a compound 1 under the catalysis of organic base to obtain a compound 2, carrying out Dieckmann reaction on the compound 2 and excessive CDI to obtain a compound 3, and carrying out Suzuki coupling reaction on the compound 3 and different substituted aryl boric acid or morpholine under the catalysis of sodium carbonate, pd (OAc) 2 and TPPTS to obtain the pyrimidoimidazole derivative. The pyrimidoimidazolone derivative has strong inhibition effect on proliferation of tumor cells such as lung cancer, prostatic cancer, colon cancer, breast cancer, liver cancer and the like, and can be applied to preparation of medicines for treating and/or preventing malignant tumors.

Inventors

  • LING YONG
  • QIAN XIAOYANG
  • Ji Liujie
  • WANG LEI
  • XU KE
  • JI DONGLIANG
  • LUO NINGNING
  • LIU DONGWEI
  • SHEN ZIMING
  • Xiong Minxuan
  • ZHAO XUEHAO

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 pyrimidoimidazolone derivative, characterized in that it has the structure represented by general formula I: Wherein R 1 is selected from the group consisting of phenyl, pyridyl, thienyl, pyrazolyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, amino-substituted phenyl, nitro-substituted phenyl, hydroxy-substituted phenyl, dimethylamino-substituted phenyl, trifluoromethoxy-substituted phenyl, methoxy-fluoro-disubstituted phenyl, diethylamino-substituted phenyl, R 2 is selected from H or methyl.
  2. 2. The pyrimidoimidazolone derivative according to claim 1, wherein R 1 is selected from the group consisting of 4-methoxyphenyl, 3-fluorophenyl, 4-nitrophenyl, 3-methylphenyl, 2-methoxyphenyl, 3-aminophenyl, 3-hydroxyphenyl, 3- (N, N-dimethylamino) phenyl, 3- (N, N-diethylamino) phenyl, 3-trifluoromethoxyphenyl, 3-methoxy-4-fluorophenyl, 3-fluoro-4-methoxyphenyl, R 2 is selected from H or methyl.
  3. 3. A process for the preparation of a pyrimidoimidazolone derivative as claimed in claim 1, wherein the synthetic route of the process is represented by the following formula: The preparation method comprises the following steps: s1.1- (4-methoxyphenyl) -1-R 2 -methylamine and a compound 1 undergo a substitution reaction under the catalysis of organic base to obtain a compound 2, wherein R 2 is selected from H or methyl; 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 different substituted aryl boric acid or morpholine under the catalysis of sodium carbonate, pd (OAc) 2 and triphenylphosphine trimetaphosphate salt to obtain a pyrimidoimidazole derivative I; The differently substituted arylboronic acids are selected from one of 4-methoxyphenylboronic acid, 3-fluorophenylboronic acid, 4-nitrobenzeneboronic acid, 3-methylphenylboronic acid, 2-methoxyphenylboronic acid, 3-aminophenylboronic acid, 3-hydroxyphenylboronic acid, 3- (N, N-dimethylamino) phenylboronic acid, 3-trifluoromethoxyphenylboronic acid, 3- (N, N-diethylamino) phenylboronic acid, 3-methoxy-4-fluorophenylboronic acid, 3-fluoro-4-methoxyphenylboronic acid, 4-phenoxyphenylboronic acid, pyridine-4-boronic acid, 2-thiopheneboronic acid, 3-thiopheneboronic acid, (1H-pyrazol-4-yl) boronic acid and 1H-pyrazole-3-boronic acid.
  4. 4. A process according to claim 3, wherein the organic base is triethylamine or N, N-diisopropylethylamine.
  5. 5. The process according to claim 3, wherein in step S1, the ratio of the amounts of the substances of compound 1 to 1- (4-methoxyphenyl) -1-R 2 -methylamine is 3:3.3.
  6. 6. The process according to claim 3, wherein the substitution reaction is carried out at 120℃for 2 days under the conditions of N 2 protection in step S1.
  7. 7. A process according to claim 3, wherein in step S2 the ratio of the amounts of the substances of compound 2 and CDI is 2.59 (12-13), and the Dieckmann reaction is carried out under the conditions of N 2 protection and 30 ℃ for 12 hours.
  8. 8. The process according to claim 3, wherein in step S3, the ratio of the amounts of the compound 3 and the differently substituted arylboronic acid is 0.28:0.34, and the Suzuki coupling reaction is carried out under the conditions of N 2 protection at 100℃for about 3 hours.
  9. 9. The use of a pyrimidoimidazolone derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 as an active ingredient in the manufacture of a medicament for the treatment and/or prevention of a malignant tumor, which is one of lung cancer, prostate cancer, colon cancer, breast cancer and liver cancer.
  10. 10. An antitumor drug characterized in that the active ingredient of the antitumor drug is the pyrimidoimidazolone 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, prostate cancer, colon cancer, breast cancer and liver cancer.

Description

Pyrimidoimidazolone derivative, preparation method and medical application thereof Technical Field The invention belongs to the field of medicines, and particularly relates to a pyrimidoimidazolone derivative, a preparation method and medical application thereof. Background Tumor treatment has entered the accurate medical era, but three major core challenges are still faced in clinical practice, namely, treatment response difference caused by tumor heterogeneity, multi-drug resistance caused by long-term treatment, and toxic damage of drugs to normal tissues. These problems make it difficult to balance the efficacy and safety of existing treatment protocols, and there is a need to explore therapeutic strategies that better meet clinical needs. The pyrimidine imidazole ketone compound has unique chemical structure and biological activity, and the nitrogen atom in the skeleton and ATP binding pocket key amino acid of various kinases (such as EGFR, VEGFR, CDK and the like) form a hydrogen bond network, so that the pyrimidine imidazole ketone compound is an ideal kinase inhibitor skeleton and has outstanding potential in the treatment of cancers and inflammatory diseases. The structure of the compound is similar to purine skeletons, can be integrated into DNA or RNA, and interferes with DNA synthesis and repair of cancer cells, so that the compound has the proliferation inhibiting property of the cancer cells, and meanwhile, hydrophobic or electronic effect groups are introduced into specific positions, so that the interaction with a target protein hydrophobic pocket can be enhanced, and the activity and selectivity are improved. In addition, they are able to target a variety of critical signaling pathways associated with cancer, such as PI3K/AKT/mTOR and RAS/MAPK pathways, inhibiting tumor growth and metastasis. Meanwhile, the compounds can induce cancer cell apoptosis to play an anticancer effect by activating mitochondrial dependent apoptosis channels or up-regulating pro-apoptosis proteins (such as Bax and p 53). The pyrimidine-imidazole ketone skeleton has a unique heterocyclic structure with strong modifiable property, and can play an anti-tumor role through a plurality of key links (kinase signals, DNA functions, cell cycle and the like) which interfere with proliferation, survival and diffusion of tumor cells. Through the research of the structure-activity relationship of the system, the invention carries out rational drug design aiming at specific structural modification, and is hopeful to develop a novel anti-tumor drug with high efficiency and low toxicity from the framework. Disclosure of Invention The invention aims to provide a pyrimidoimidazolone derivative, a preparation method and medical application thereof. In a first aspect of the present invention there is provided a pyrimidoimidazolone derivative having the structure of formula I: Wherein R 1 is selected from the group consisting of phenyl, pyridyl, thienyl, pyrazolyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, amino-substituted phenyl, nitro-substituted phenyl, hydroxy-substituted phenyl, dimethylamino-substituted phenyl, trifluoromethoxy-substituted phenyl, methoxy-fluoro-disubstituted phenyl, diethylamino-substituted phenyl, R 2 is selected from H or methyl. Further, R 1 is selected from the group consisting of phenyl, 4-methoxyphenyl, 3-fluorophenyl, 4-nitrophenyl, 3-methylphenyl, 2-methoxyphenyl, 3-aminophenyl, 3-hydroxyphenyl, 3-diethylaminophenyl, 3-trifluoromethoxyphenyl, 3-methoxy-4-fluorophenyl, 3-fluoro-4-methoxyphenyl, 2-methoxyphenyl, 3-aminophenyl, 3-diethylaminophenyl, 3-trifluoromethoxyphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-aminophenyl, and combinations thereof,R 2 is selected from H or 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 of the present invention, there is provided a process for the preparation of a compound of formula I, the synthetic route of which is shown in the following formula: The preparation method comprises the following steps: S1.1- (4-methoxyphenyl) -1-R 2 -methylamine and a compound 1 undergo substitution reaction under the catalysis of organic base to obtain a compound 2; s2, carrying out Dieckmann standing 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 different substituted aryl boric acid or morpholine under the catalysis of sodium carbonate, pd (OAc) 2 and triphenylphosphine sodium tri-m-sulfonate (TPPTS) to obtain the pyrimidoimidazolone derivative I. Further, the differently substituted arylboronic acids are selected from one of 4-methoxyphenylboronic acid, 3-fluorophenylboronic acid, 4-nitrobenzeneboronic acid, 3-methylphenylboronic