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CN-121991067-A - 2-Methyl-6-phenyl-8-carbonyl purine compound, and preparation method and medical application thereof

CN121991067ACN 121991067 ACN121991067 ACN 121991067ACN-121991067-A

Abstract

The invention belongs to the field of medicines, and discloses a 2-methyl-6-phenyl-8-carbonyl purine compound, a preparation method and medical application thereof. The 2-methyl-6-phenyl-8-carbonyl purine compound has a structure shown in a general formula I: The 2-methyl-6-phenyl-8-carbonyl purine compound selectively has strong inhibition effect on proliferation of tumor cells such as lung cancer, breast cancer, colon cancer, liver cancer and the like, and can be applied to preparation of medicines for treating and/or preventing malignant tumors.

Inventors

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

Assignees

  • 南通大学
  • 南通大学启东海洋研究院

Dates

Publication Date
20260508
Application Date
20251224

Claims (10)

  1. 1. The 2-methyl-6-phenyl-8-carbonyl purine compound is characterized in that the 2-methyl-6-phenyl-8-carbonyl purine compound has a structure shown in a general formula I: wherein R 1 is selected from One of them.
  2. 2. A process for the preparation of 2-methyl-6-phenyl-8-carbonylpurine compounds according to claim 1, wherein the synthetic route of the process is shown in the following 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 the following; 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 2-methyl-6-phenyl-8-carbonyl purine compound I.
  3. 3. The preparation method according to claim 2, wherein the organic base is triethylamine or N, N-diisopropylethylamine.
  4. 4. The process according to claim 2, wherein in step S1, the ratio of the amounts of the substances of compound 1 to R 1 -CH 2 NH 2 is 3:3.3.
  5. 5. The method according to claim 2, wherein in the step S1, the substitution reaction is performed under the conditions that the solvent is N-butanol, N 2 is used for protection, and the reaction is performed at 120 ℃ for 2 days.
  6. 6. The process according to claim 2, wherein the ratio of the amounts of the substances of compound 2 to CDI in step S2 is 2.59 (12-13).
  7. 7. The preparation method according to claim 2, wherein in the step S2, the Dieckmann condensation reaction is performed under the reaction condition of N 2 protection at 30 ℃ for 12 hours.
  8. 8. The method according to claim 2, wherein the ratio of the amounts of the substances of the compound 3 and phenylboronic acid in step S3 is 1:1.2.
  9. 9. The preparation method according to claim 2, wherein in the step S3, the Suzuki coupling reaction is performed under the conditions of N 2 protection at 100 ℃ for about 3 hours.
  10. 10. The use of a 2-methyl-6-phenyl-8-oxopurine compound 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 malignant tumor, said malignant tumor being one of liver cancer, lung cancer, colon cancer and breast cancer.

Description

2-Methyl-6-phenyl-8-carbonyl purine compound, and preparation method and medical application thereof Technical Field The invention belongs to the field of medicines, and in particular relates to a 2-methyl-6-phenyl-8-carbonyl purine compound, a preparation method and medical application thereof. Background Tumors are one of the etiologies of mortality in humans, and are severely threatening to human health and life. Although there are few clinically available tumor therapeutic drugs, the existing drugs still cannot meet the clinical therapeutic needs due to factors such as complexity, heterogeneity, drug resistance and metastasis of tumor etiology. Therefore, the search for a novel tumor drug with high efficiency, low toxicity and strong targeting has important significance. 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. 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 purine compounds induce cancer cell apoptosis by activating mitochondrial dependent apoptosis channels or up-regulating pro-apoptosis proteins (such as Bax and p 53), so that the anticancer effect of the purine compounds is further enhanced. Disclosure of Invention The invention aims to provide a 2-methyl-6-phenyl-8-carbonyl purine compound, a preparation method and medical application thereof, and the 2-methyl-6-phenyl-8-carbonyl purine compound has a strong inhibition effect on proliferation of various tumor cells such as lung cancer, breast cancer, colon cancer and liver cancer. In a first aspect of the present invention, there is provided a 2-methyl-6-phenyl-8-carbonylpurine compound having the structure of formula I: wherein R 1 is selected from One of them. 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, a preparation method of the 2-methyl-6-phenyl-8-carbonyl purine compound is provided, and the synthetic route of the preparation method is shown in the following formula: 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 the following; 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 sodium tri-m-sulfonate (TPPTS) to obtain the 2-methyl-6-phenyl-8-carbonyl purine compound I. Further, in the step S1, the ratio of the amount of the compound 1 to the amount of the substance of R 1-CH2NH2 is 3:3.3, and the reaction condition of the substitution reaction is N2 protection and 120 ℃ reaction for 2 days. Further, in step S2, the ratio of the amount of the compound 2 to the CDI substance was 2.59 (12-13). Further, in the step S2, the reaction condition of the Dieckmann condensation reaction is N2 protection and 30 ℃ reaction is carried out for 12 hours. Further, in step S3, the ratio of the amounts of the substances of the compound 3 and phenylboronic acid was 0.28:0.34. Further, in the step S3, the condition of the Suzuki coupling reaction is N2 protection, and the reaction is carried out for about 3 hours at 100 ℃. In a third aspect, there is provided an application of the above 2-methyl-6-phenyl-8-carbonylpurine compound or a pharmaceutically acceptable salt thereof as an active ingredient in the preparation of a medicament for treating and/or preventing malignant tumor, wherein the malignant tumor is one of liver cancer, lung cancer, colon cancer and breast cancer. Compared with the prior art, the invention refers to the potential therapeutic value of purine analogues in anti-tumor, selects purine as a large framework core to occupy an active site cavity through an electron isosteichiometrical principle, introduces carbonyl groups on an imidazole ring of the purine to form a urea substrate segment so as to form an 8-carbonyl purine framework, further introduces phenyl groups at a 6 position to improve the lipophilicity, and adjusts substituent groups on a parent nucleus according to the long and narrow characteristics of a target pocket region so as to design and develop a 2-methyl-6-phenyl-8-carbonyl purine compound with stronger anti-tumor activity. Through activity tests of