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CA-3186568-C - SALT OF DIHYDROPYRIDO[2,3-D]PYRIMIDINONE DERIVATIVE, PREPARATION METHOD THEREFOR, AND USE THEREOF

CA3186568CCA 3186568 CCA3186568 CCA 3186568CCA-3186568-C

Abstract

The present application discloses a salt of a dihydropyrido[2,3-d]pyrimidinone derivative, a preparation method therefor and the use thereof. The salt is selected from fumarate, methanesulfonate, isethionate, -naphthalenesulfonate, p-toluenesulfonate, 1,2-ethanedisulfonate, oxalate, maleate, citrate, succinate, L-(+)-tartrate, hippurate, L-ascorbate, L-malate, benzoate, gentisate, a hydrochloride, a sulfate or a phosphate. The salt of the dihydropyrido[2,3-d]pyrimidinone derivative of the present application can be used in the treatment of breast cancer, prostate cancer, or ovarian cancer.

Inventors

  • CHANGYOU MA
  • He Tian
  • Jianliang Zhao
  • Donghui Chen
  • Jian Wu
  • Dan Xu
  • Chunxia Zhu
  • Zhoushan Tian

Assignees

  • NANJING CHIA TAI TIANQING PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260505
Application Date
20210722
Priority Date
20200722

Claims (19)

  1. 18 Claims 1. A pharmaceutically acceptable salt of a compound represented by formula 1, the salt selected from a salt of organic acid or a salt of inorganic acid, wherein the salt of organic acid is selected from a fumarate, a mesylate, an 5 isethionate, an α-naphthalenesulfonate, a p-toluenesulfonate, a 1,2-ethanedisulphonate, an oxalate, a maleate, a citrate, a succinate, an L-(+)-tartrate, a hippurate, an L-ascorbate, an L-malate, a benzoate, or a gentisate, and the salt of inorganic acid is selected from a hydrochloride, a sulfate or a phosphate, .
  2. 2. The salt according to claim 1, wherein the salt is selected from a fumarate and a hydrochloride. 10
  3. 3. The salt according to claim 1, wherein a ratio of the compound represented by formula 1 to organic acid is 1: 1.
  4. 4. The salt according to claim 1, wherein a ratio of the compound represented by formula 1 to hydrogen chloride is 1: 1 or 1: 2.
  5. 5. The salt according to claim 1, wherein a ratio of the compound represented by formula 1 to hydrogen chloride is 1: 2. 15
  6. 6. The salt according to claim 1, wherein the salt is a fumarate, and a molar ratio of the compound represented by formula 1 to fumaric acid is 1: 1.
  7. 7. A preparation method of the pharmaceutically acceptable salt of the compound represented by formula 1 according to any one of claims 1 to 6, comprising a step of salification reation of the compound represented by formula 1 with the corresponding acid. 20
  8. 8. The method according to claim 7, wherein a solvent for salification reaction is selected from a mixed solvent of an alcohol solvent and an alkane solvent, a mixed solvent of a ketone solvent and an alkane solvent, a mixed solvent of an ester solvent and an alkane solvent, a mixed solvent of a benzene solvent and an alkane solvent, and a mixed solvent of a halogenated hydrocarbon solvent and an alkane solvent.
  9. 9. A pharmaceutical composition comprising the salt according to any one of claims 1 to 6, and one or more 25 pharmaceutically acceptable carriers.
  10. 10. The pharmaceutically acceptable salt of the compound represented by formula 1 according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 for use as a medicament.
  11. 11. Use of the salt according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 in CA3,186,568 MTPICA220605 19 the prevention and/or treatment of an AKT protein kinase-mediated disease or disease state.
  12. 12. Use of the salt according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and/or treating an AKT protein kinase-mediated disease or disease state.
  13. 13. The use according to claim 11 or 12, wherein the AKT protein kinase-mediated disease or disease state is 5 cancer.
  14. 14. The use according to claim 13, wherein the cancer is breast cancer, prostate cancer or ovarian cancer.
  15. 15. The use according to claim 14, wherein the cancer is prostate cancer.
  16. 16. Use of the salt according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 for prevention and/or treatment of an AKT protein kinase-mediated disease or disease state. 10
  17. 17. The use according to claim 16, wherein the AKT protein kinase-mediated disease or disease state is cancer.
  18. 18. The use according to claim 17, wherein the cancer is breast cancer, prostate cancer or ovarian cancer.
  19. 19. The use according to claim 17, wherein the cancer is prostate cancer. CA 3186568

Description

1 Description SALT OF DIHYDROPYRIDO[2,3 D ]PYRIMIDINONE DERIVATIVE, PREPARATION METHOD THEREFOR, AND USE THEREOF The present application claims priority to Chinese Patent Application No. 202010711260.5 entitled " S alt of 5 dihydropyrido[2,3 d]pyrimidinone deri vative, preparation method therefor, and use thereof and filed with the China Patent Office on July 22, 2020 TECHNICAL FIELD The present application belongs to the field of medici nal chemistry, and specifically relates to a salt of a 10 dihydropyrido[2,3 d ]pyrimidinone derivative, a preparation method and medical use BACKGROUND The PI3K/AKT/mTOR pathway consisting of phosphoinositide 3 kinase (PI3K) and its downstream protein AKT (also known as protein kinase B PKB), and mammalian target of Rapam ycin (mTOR) as a very important 15 intracellular signal transduction pathway, the pathway exerts an extremely im portant biological function in the process of cell growth, survival, proliferation, apoptosis, angiogenesis, autophagy, etc . Abnormal activation of the pathway will cause a series of diseases such as cancer, neuropathy, autoimmune disease, and hemolymphatic system disease. AKT is a type of serine/threonine kinase and affects the survival, growth, metabolism, proliferation, migration, and 20 differentiat ion of cell through numerous downstream effectors. Overactivation of AKT has been observed in more than 50% o f human tumors, especially in prostate cancer, pancreatic cancer, bladder cancer, ovarian cancer, and breast cancer. Overactivation of AKT may lead to the formation, metastasis, and drug resistance of tumor. AKT has three isoforms: AKT1, AKT2, and AKT3. As a typical protein kinase, each isoform consists of an amino terminal pleckstrin homology (PH) domain, a middle ATP binding kinase domain, and a ca rboxy l terminal 25 regulatory domain. A bout 80% amino acid sequence s of the three isoforms are homologous, and o nly the amino acid sequences in a binding domain between the PH domain and the kinase domain changes greatly The current drugs targeting the PI3K/ AKT/mTOR signaling pathway mainly include PI3K inhibitors and mTOR inhibitors, while AKT is at the core of the signal transduction pathway. Inhibition of the AKT activity can not only avoid the severe side effects caused by inhibition of upstream PI3K, but also avoid the negative feedback 30 mechanism caused by inhibition of downstream mTOR from affecting the effica cy of a drug. For example, CN101631778A discloses a class of cyclopenta[D]pyrimidine derivatives, CN101578273A discloses a class of hydroxylated an d methoxylated cyclopenta[D]pyrimidine derivatives, CN101511842A discloses a class of dihydrofuropyrimidine derivatives, CN101970415A discloses a class of 5H cyclopenta[d]pyrimidine derivatives, and these compounds inhibit AKT1 with IC 50 less than 10 µM. H owever, development of effective and selective 35 CA 3186568 CA3,186,568 MTPICA220605 2 AKT inhibitors is still an important direction for current development of tumor-targeting drugs. SUMMARY OF THE INVENTION In one aspect, the present application provides a pharmaceutically acceptable salt of a compound represented by 5 formula 1, which is selected from a salt of organic acid or a salt of inorganic acid. The salt of organic acid is selected from a fumarate, a mesylate, an isethionate, an α-naphthalenesulfonate, a p-toluenesulfonate, a 1,2-ethanedisulphonate, an oxalate, a maleate, a citrate, a succinate, an L-(+)-tartrate, a hippurate, an L-ascorbate, an L-malate, a benzoate, or a gentisate, and the salt of inorganic acid is selected from a hydrochloride, a sulfate, and a phosphate, and the compound represented by formula 1 has the following structure: 10 . In some embodiments, the salt of organic acid is a fumarate. In some embodiments, the salt of inorganic acid is a hydrochloride. In some embodiments, in the salt of organic acid, a molar ratio of the compound represented by formula 1 to organic acid is 1: 1. 15 In some embodiments, in the hydrochloride, a molar ratio of the compound represented by formula 1 to hydrogen chloride is 1: 1 or 1: 2. In some embodiments, in the hydrochloride, a molar ratio of the compound represented by formula 1 to hydrogen chloride is 1: 2. In some embodiments, in the sulfate, a molar ratio of the compound represented by formula 1 to sulfuric acid is 1: 20 1. In some embodiments, in the phosphate, a molar ratio of the compound represented by formula 1 to phosphoric acid is 1: 1. It can be understood that the salt of the present application results from a salification reaction of the compound represented by formula 1 with a corresponding acid. In the reaction, the compound represented by formula 1 is 25 converted into cations that bind to acid radicals of the corresponding acid to form the salt. Therefore, in the present application, a molar ratio of the compound represented by formula 1 to an acid can be understood as a molar ratio of cations of the compound represented by formula 1 to aci