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US-12622912-B2 - Application of pyrido[1,2-a]pyrimidinone analog

US12622912B2US 12622912 B2US12622912 B2US 12622912B2US-12622912-B2

Abstract

An application of a pyrido[1,2-a]pyrimidinone analog or a pharmaceutically acceptable salt thereof in the preparation of a drug, the drug being used to treat and/or prevent one or more among PIK3CA-mutated breast cancer, PIK3CA-mutated ovarian cancer, PIK3CA-mutated endometrial cancer, PIK3CA-mutated cervical cancer, and PIK3CA-mutated bladder cancer.

Inventors

  • Yongguo Li
  • Wei Wei
  • Aiyun SONG
  • Wei Ye

Assignees

  • Guangzhou Joyo Pharmatech Co., Ltd
  • SHANGHAI JIA TAN PHARMATECH CO., LTD.

Dates

Publication Date
20260512
Application Date
20220117
Priority Date
20210118

Claims (15)

  1. 1 . A method for treating PIK3CA-mutated cancer, comprising administering to a patient a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof, wherein the structure of the compound I is as follows: wherein the PIK3CA-mutated cancer is PIK3CA-mutated endometrial cancer, PIK3CA-mutated cervical cancer, or PIK3CA-mutated ovarian clear cell carcinoma.
  2. 2 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the PIK3CA-mutated cancer is PIK3CA-mutated ovarian clear cell carcinoma.
  3. 3 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the PIK3CA-mutated cancer is PIK3CA-mutated endometrial cancer.
  4. 4 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the PIK3CA-mutated cancer is PIK3CA-mutated cervical cancer.
  5. 5 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein, the method further includes a step of detecting whether the patient carries PIK3CA gene mutation.
  6. 6 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the administration dosage of the compound I or the pharmaceutically acceptable salt thereof is 0.1 mg per dose, 0.2 mg per dose, 0.3 mg per dose, 0.4 mg per dose, 0.5 mg per dose, 0.6 mg per dose, 0.7 mg per dose, 0.8 mg per dose, 0.9 mg per dose, 1.0 mg per dose, 1.1 mg per dose, 1.2 mg per dose, 1.3 mg per dose, 1.4 mg per dose, 1.5 mg per dose, 1.6 mg per dose, 1.7 mg per dose, 1.8 mg per dose, 1.9 mg per dose or 2.0 mg per dose.
  7. 7 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the PIK3CA-mutated ovarian clear cell carcinoma is PIK3CA-mutated ovarian clear cell carcinoma with metastasis.
  8. 8 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the PIK3CA-mutated ovarian clear cell carcinoma is ovarian clear cell carcinoma that is ineffective to first-line or second-line treatment.
  9. 9 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the PIK3CA-mutated cervical cancer is PIK3CA-mutated cervical squamous cell carcinoma.
  10. 10 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the PIK3CA-mutated cervical cancer is PIK3CA-mutated cervical cancer with metastasis.
  11. 11 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the PIK3CA-mutated cervical cancer is cervical cancer that is ineffective to first-line treatment, second-line treatment or third-line treatment.
  12. 12 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the compound I or the pharmaceutically acceptable salt thereof is presented in an oral dosage form.
  13. 13 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the compound I or the pharmaceutically acceptable salt thereof is presented in a tablet form.
  14. 14 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the administration dosage of the compound I or the pharmaceutically acceptable salt thereof is 0.1-2.0 mg per dose.
  15. 15 . The method for treating PIK3CA-mutated cancer according to claim 1 , wherein the administration frequency of the compound I or the pharmaceutically acceptable salt thereof is once a day or twice a day.

Description

The present application is a National Stage of International Application No. PCT/CN2022/072322, filed on Jan. 17, 2022, which claims priority of the Chinese Patent Application No. CN2021100617618 filed on Jan. 18, 2021, the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present disclosure relates to the technical field of biomedicine, in particular, the present disclosure relates to the application of pyrido[1,2-a]pyrimidinone analog. BACKGROUND Malignant tumors are a type of disease that seriously threatens human life and health at present, whose morbidity and mortality are increasing year by year. Human mortality due to cancer ranks second only to cardiovascular and cerebrovascular diseases. The essence of carcinogenesis is that the molecular signals that regulate the physiological functions of cells are abnormal in the transduction process, which leads to the disorder of normal physiological functions of cells and infinite proliferation. Cell signal transduction is closely related to tumor occurrence, development, recurrence and metastasis. Traditional cytotoxic drugs for tumor treatment generally have disadvantages such as low selectivity, strong side effects and poor drug resistance, which promotes the transfer of the research direction of anti-tumor drugs to small molecule targeting drugs. PI3K-AKT-mTOR is an important pathway of cell cycle regulation, which is crucial to cell growth, division, survival and reproduction. Its transitional activation is involved in the occurrence, development, survival and migration of various tumors. PI3K (phosphatidylinositol 3-kinase), AKT and mTOR (mammalian target of rapamycin) are the key molecules of this pathway, so they become the targets of anti-tumor therapy. PI3K-specific or mTOR-specific inhibitors are already on the market, and the dual inhibitors of these two molecules can theoretically have better anti-tumor efficacy. PF-05212384 (PKI-587) is a PI3K and mTOR dual-target inhibitor developed by Pfizer, which is currently in Phase II clinical trials. Everolimus is an oral mTOR single-target inhibitor developed by Novartis, with a trade name of Afinitor, which was approved for marketing by the FDA in March 2009. Internationally, Everolimus is approved for multiple indications: advanced renal cell carcinoma (RCC), tuberous sclerosis-associated subependymal giant cell astrocytoma (TSC-SEGA) and renal angiomyolipoma (TSC-AML), advanced pancreatic neuroendocrine tumors (pNET), postmenopausal estrogen receptor positive/HER-2 negative advanced breast cancer (BC) and other tumors. CONTENT OF THE PRESENT INVENTION The purpose of the present disclosure is to provide an application of pyrido[1,2-a]pyrimidinone analog. Such compound or a pharmaceutically acceptable salt thereof has good antitumor activity against PIK3CA-mutated cancers, such as one or more of PIK3CA-mutated breast cancer, PIK3CA-mutated ovarian cancer, PIK3CA-mutated endometrial cancer, PIK3CA-mutated cervical cancer, and PIK3CA-mutated bladder cancer. The present disclosure provides a use of compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament, the structure of the compound I is as follows: the medicament is used for treating and/or preventing PIK3CA-mutated cancer. Wherein, the PIK3CA-mutated cancer can be PIK3CA-mutated breast cancer. The PIK3CA-mutated cancer can be PIK3CA-mutated ovarian cancer. The PIK3CA-mutated cancer can be PIK3CA-mutated endometrial cancer. The PIK3CA-mutated cancer can be PIK3CA-mutated cervical cancer. The PIK3CA-mutated cancer can be PIK3CA-mutated bladder cancer. In the present disclosure, the medicament is presented in an oral dosage form. In the present disclosure, the medicament is presented in a tablet form. The PIK3CA-mutated ovarian cancer can be PIK3CA-mutated ovarian clear cell carcinoma, for example, PIK3CA-mutated left ovarian clear cell carcinoma. The PIK3CA-mutated ovarian cancer can be PIK3CA-mutated ovarian cancer with metastasis, and the metastasis can be liver metastasis. The PIK3CA-mutated ovarian cancer can be ovarian cancer that is ineffective to the first-line or second-line treatment. The PIK3CA-mutated cervical cancer can be PIK3CA-mutated cervical squamous cell carcinoma. The PIK3CA-mutated cervical cancer can be PIK3CA-mutated cervical cancer with metastasis, and the metastasis can be lymph and/or lung. The lymph can be left supraclavicular lymph and/or retroperitoneal lymph. The PIK3CA-mutated cervical cancer can be cervical cancer that is ineffective to the first-line, second-line treatment or the third-line treatment. The present disclosure further provides the compound I or the pharmaceutically acceptable salt thereof for use in treating and/or preventing PIK3CA-mutated cancer, the structure of the compound I is as follows: Herein, the PIK3CA-mutated cancer is as described in any of the above embodiments. The present disclosure provides a method for treating and/o