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WO2024140537A1 - Utilisation d'un inhibiteur de cdk - Google Patents

Utilisation d'un inhibiteur de cdk Download PDF

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Publication number
WO2024140537A1
WO2024140537A1 PCT/CN2023/141461 CN2023141461W WO2024140537A1 WO 2024140537 A1 WO2024140537 A1 WO 2024140537A1 CN 2023141461 W CN2023141461 W CN 2023141461W WO 2024140537 A1 WO2024140537 A1 WO 2024140537A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
tumor
breast cancer
pharmaceutically acceptable
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/141461
Other languages
English (en)
Chinese (zh)
Inventor
张晓琳
淡墨
张汉承
杨华
蔡聪聪
刘咏梅
赵方亮
王敏
耿佳
王以美
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Hangzhou Innogate Pharma Co Ltd
Original Assignee
Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Hangzhou Innogate Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd, CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd, Hangzhou Innogate Pharma Co Ltd filed Critical Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
Publication of WO2024140537A1 publication Critical patent/WO2024140537A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present application belongs to the field of medicine, and specifically relates to the anti-tumor use of a CDK inhibitor.
  • CDKs Cyclin-dependent kinases
  • Cyclin D-CDK4/6 and Cyclin E-CDK2 work together to drive the G1/S phase transition, while Cyclin A-CDK2 is crucial for the S/G2 phase transition.
  • CDKs bind to corresponding Cyclins to form heterodimer complexes to regulate the cell cycle.
  • growth factors, mitotic signals, etc. lead to the release of Cyclin D, which binds to CDK4/6 to form a Cyclin D-CDK4/6 complex, triggering phosphorylation of its substrate retinoblastoma (Rb) protein at sites such as Ser807/811, dissociation of transcription factor E2F, and upregulation of transcription of E2F-responsive genes (including Cyclin A, Cyclin E, etc.).
  • Rb retinoblastoma
  • CDK2 is activated after binding to Cyclin E, completing further phosphorylation of pRb protein (T821), driving cells through the G1/S checkpoint and entering the S phase.
  • CDK2 binds to Cyclin A, phosphorylates E2F, and drives cells from the S phase into the G2 phase.
  • endocrine therapy is often used as an early treatment option.
  • Commonly used endocrine therapy drugs include anastrozole, letrozole, exemestane, tamoxifen, toremifene, fulvestrant, megestrol acetate, fluoxymesterone, ethinyl estradiol, etc.; early medium- and high-risk patients can receive chemotherapy at the same time.
  • the current first-line standard therapy is a combination of CDK4/6 inhibitors and endocrine therapy.
  • the present application provides the anti-tumor use of the above CDK inhibitor compound A.
  • the inventors of the present application unexpectedly discovered in their research that the compound A has a good therapeutic effect on tumors, especially CDK4/6 inhibitor-resistant tumors, and can be used to prepare related drugs.
  • the present application provides a use of compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof, in the preparation of a drug for treating a tumor, wherein the structure of compound A is shown in the following formula (I):
  • the present application provides a method for treating a tumor in an individual, comprising administering to the individual a therapeutically effective amount of the above-mentioned compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound A or a pharmaceutically acceptable salt thereof.
  • the individual is a subject or patient in need of treatment.
  • the present application provides the above-mentioned compound A or its pharmaceutically acceptable salt, or a pharmaceutical composition or drug comprising the compound A or its pharmaceutically acceptable salt, for use in treating tumors.
  • the present application provides an anti-tumor drug composition, which comprises the above-mentioned compound A or a pharmaceutically acceptable salt thereof, and other clinically/pharmaceutically acceptable drugs.
  • the present application provides the use of the above-mentioned compound A or a pharmaceutically acceptable salt thereof in combination with other clinically/pharmaceutically acceptable drugs for preparing anti-tumor drugs.
  • the present application provides a method for treating tumors in an individual, comprising administering to the individual a therapeutically effective amount of the above-mentioned compound A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound A or a pharmaceutically acceptable salt thereof, and other clinically/pharmaceutically acceptable drugs.
  • the tumor described in the first to sixth aspects above is selected from a sensitive tumor or a drug-resistant tumor.
  • the tumor described in the first to sixth aspects above is a drug-resistant tumor.
  • the drug-resistant tumor is selected from a primary drug-resistant tumor or a secondary drug-resistant tumor.
  • the sensitive tumor or drug-resistant tumor is selected from breast cancer, liver cancer, melanoma or acute myeloid leukemia.
  • the breast cancer is selected from HR+/HER2- breast cancer, triple negative breast cancer, HR-/HER2+ breast cancer.
  • the acute myeloid leukemia is myelomonocytic leukemia.
  • the tumor is melanoma.
  • the drug-resistant tumor is a CDK4/6 inhibitor-resistant tumor.
  • the CDK4/6 inhibitor-resistant tumor is selected from a CDK4/6 inhibitor primary tumor. Drug-resistant tumors or CDK4/6 inhibitor-acquired drug-resistant tumors.
  • the CDK4/6 inhibitor is selected from Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib, preferably Palbociclib.
  • the CDK4/6 inhibitor-resistant tumor is selected from breast cancer or liver cancer.
  • the CDK4/6 inhibitor-resistant tumor is selected from breast cancer or liver cancer resistant to Palbociclib, such as breast cancer or liver cancer that is primary resistant to Palbociclib, breast cancer or liver cancer that is acquired resistant to Palbociclib.
  • the breast cancer that is primary resistant to Palbociclib and the breast cancer that is acquired resistant to Palbociclib are selected from HR+/HER2- breast cancer, triple negative breast cancer, or HR-/HER2+ breast cancer that is primary resistant to Palbociclib or acquired resistant to Palbociclib.
  • Palbociclib-resistant human breast cancer xMCF-7/Palbo-R cells are CDK4/6i acquired resistance breast cancer cell lines induced by long-term palbociclib in vitro, and have similar CCNE amplification, The expression of Rb protein was decreased.
  • RTV xnd average relative tumor volume on day n
  • Tumor weight inhibition rate (1-tumor weight of drug group/tumor weight of solvent group) ⁇ 100%
  • Example 4 In vivo efficacy test of compound A in mice transplanted with human breast cancer palbociclib-resistant MDA-MB-468 cells
  • MDA-MB-468 cells are triple-negative breast cancer cells, and Rb expression is negative (Rb-), so they may be insensitive to CDK4/6 inhibitors (intrinsic resistance/primary resistance).
  • CDK4/6 inhibitors intrasic resistance/primary resistance.
  • This study used a NOD SCID mouse human breast cancer MDA-MB-468 cell xenograft tumor model to compare the in vivo anti-tumor effects of compound A and palbociclib on Rb-breast cancer, and to examine the dose-effect relationship of the anti-tumor effect of compound A.
  • MDA-MB-468 cells Resuscitate and passage (11th generation) MDA-MB-468 cells to the required cell number, dilute the cells with serum-free medium and matrigel (1:1), count with a cell counter, adjust the number of tumor cells to about 1 ⁇ 10 8 cells/mL, and place the cell suspension in an ice bath.
  • the inoculation volume is 0.1 mL/mouse, containing about 1 ⁇ 10 7 tumor cells, to prepare a NOD SCID mouse MDA-MB-468 transplant tumor model.
  • When the tumor volume grows to about 105 mm 3 select mice with good tumor growth and divide the animals into balanced groups according to the tumor volume. Grouping and administration methods are shown in Table 4. Observation and evaluation indicators are the same as in Example 3.
  • Example 5 In vivo efficacy test of compound A in mice transplanted with human breast cancer MCF-7 cells
  • Human breast cancer MCF-7 cells were cultured in vitro in monolayers, and the culture conditions were 2mM glutamine + 1% non-essential amino acids (NEAA) + 10% fetal bovine serum, 1% penicillin/streptomycin/amphotericin B in EMEM (EBSS) medium, and cultured in a 37°C 5% CO 2 incubator. The cells were routinely digested and passaged twice a week with trypsin-EDTA. When the cell saturation was 80%-90% and the number reached the requirement, the cells were collected, counted, and inoculated.
  • NEAA non-essential amino acids
  • EBSS EMEM
  • estrogen tablets (0.36 mg) were inoculated on the left back of each mouse, and 0.2 mL (1x10 7 ) MCF-7 cells (with matrix gel, volume ratio of 1:1) were subcutaneously inoculated on the right back of each mouse.
  • group administration began. Grouping and administration methods are shown in Table 5. Observation and evaluation indicators are the same as in Example 3.
  • the compound A 30 mg/kg group achieved better therapeutic effects at a molar concentration of less than half that of palbociclib (55 mg/kg). This suggests that for breast cancer sensitive to CDK4/6 inhibitors, the tumor inhibition effect of compound A is significantly better than that of palbociclib.
  • Example 6 In vivo efficacy test of compound A in mice with human myelomonocytic leukemia MV-4-11 cell transplant tumors
  • mice Resuscitate and passage MV-4-11 cells to the required cell number, dilute the cells with serum-free medium, count with a cell counter, adjust the number of tumor cells to about 1 ⁇ 10 8 /mL, and place the cell suspension in an ice bath.
  • mice were intraperitoneally injected with cyclophosphamide one day before inoculation, with a dose of 100 mg/kg and a dosing volume of 10 mL/kg.
  • a sterile syringe was used to extract the MV-4-11 cell suspension and inoculate it into the subcutaneous tissue of the axilla of the right forelimb of NOD/SCID mice.
  • the inoculation volume was 0.1 mL/mouse, containing about 1 ⁇ 10 7 tumor cells, to prepare a NOD/SCID mouse MV-4-11 transplant tumor model.
  • mice with good tumor growth were selected, and the animals were evenly divided into groups for dosing according to the tumor volume. Grouping and dosing methods are shown in Table 7. Observation and evaluation indicators are the same as in Example 3.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un composé A inhibiteur de CDK dans la préparation d'un médicament antitumoral, en particulier l'utilisation dans la préparation d'un médicament pour le traitement de tumeurs résistantes aux inhibiteurs de CDK4/6. L'invention concerne en outre un procédé de préparation correspondant. La structure du composé A est représentée par la formule (I) suivante. Les résultats d'essai montrent que le composé A possède une bonne activité antitumorale dans différentes cellules tumorales humaines, telles qu'une souche de cancer du sein résistant au palbociclib (comprenant une résistance au médicament primaire et une résistance au médicament acquise), une souche de cancer du sein sensible au palbociclib, un cancer du foie, un mélanome et une leucémie myéloïde aiguë, et un modèle de transplantation de tumeur in vivo chez la souris.
PCT/CN2023/141461 2022-12-26 2023-12-25 Utilisation d'un inhibiteur de cdk Ceased WO2024140537A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211681854.1 2022-12-26
CN202211681854 2022-12-26

Publications (1)

Publication Number Publication Date
WO2024140537A1 true WO2024140537A1 (fr) 2024-07-04

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PCT/CN2023/141461 Ceased WO2024140537A1 (fr) 2022-12-26 2023-12-25 Utilisation d'un inhibiteur de cdk

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CN (1) CN118252835A (fr)
TW (1) TW202430185A (fr)
WO (1) WO2024140537A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118806774A (zh) * 2024-08-16 2024-10-22 深圳市第二人民医院(深圳市转化医学研究院) 阿司匹林与阿贝西利联合或协同在乳腺癌治疗中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016030439A1 (fr) * 2014-08-28 2016-03-03 Ratiopharm Gmbh Procédé de production de palbociclib et compositions pharmaceutiques comprenant celui-ci
CN108699055A (zh) * 2015-12-13 2018-10-23 杭州英创医药科技有限公司 用作抗癌药物的杂环化合物
CN110734454A (zh) * 2016-12-12 2020-01-31 石药集团中奇制药技术（石家庄）有限公司 一类含有三环杂芳基的化合物
WO2021139817A1 (fr) * 2020-01-10 2021-07-15 杭州英创医药科技有限公司 Composé polycyclique agissant en tant qu'inhibiteur de kinases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016030439A1 (fr) * 2014-08-28 2016-03-03 Ratiopharm Gmbh Procédé de production de palbociclib et compositions pharmaceutiques comprenant celui-ci
CN108699055A (zh) * 2015-12-13 2018-10-23 杭州英创医药科技有限公司 用作抗癌药物的杂环化合物
CN110734454A (zh) * 2016-12-12 2020-01-31 石药集团中奇制药技术（石家庄）有限公司 一类含有三环杂芳基的化合物
WO2021139817A1 (fr) * 2020-01-10 2021-07-15 杭州英创医药科技有限公司 Composé polycyclique agissant en tant qu'inhibiteur de kinases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118806774A (zh) * 2024-08-16 2024-10-22 深圳市第二人民医院(深圳市转化医学研究院) 阿司匹林与阿贝西利联合或协同在乳腺癌治疗中的应用

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Publication number Publication date
CN118252835A (zh) 2024-06-28
TW202430185A (zh) 2024-08-01

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