WO2021136523A1 - 一种用于治疗肿瘤的药物组合及其应用 - Google Patents

一种用于治疗肿瘤的药物组合及其应用 Download PDF

Info

Publication number
WO2021136523A1
WO2021136523A1 PCT/CN2020/142257 CN2020142257W WO2021136523A1 WO 2021136523 A1 WO2021136523 A1 WO 2021136523A1 CN 2020142257 W CN2020142257 W CN 2020142257W WO 2021136523 A1 WO2021136523 A1 WO 2021136523A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
inhibitor
pharmaceutically acceptable
acceptable salt
solvate
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/CN2020/142257
Other languages
English (en)
French (fr)
Inventor
沈孝坤
栗增
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.)
Fukang Shanghai Health Technology Co Ltd
Original Assignee
Fukang Shanghai Health Technology 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 Fukang Shanghai Health Technology Co Ltd filed Critical Fukang Shanghai Health Technology Co Ltd
Priority to CA3163564A priority Critical patent/CA3163564A1/en
Priority to US17/790,038 priority patent/US20230094843A1/en
Priority to EP20909191.7A priority patent/EP4085908A4/en
Priority to JP2022540813A priority patent/JP7805005B2/ja
Publication of WO2021136523A1 publication Critical patent/WO2021136523A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the invention relates to a drug combination for treating tumors and its application.
  • PARP Polyadenosine diphosphate ribose polymerase
  • BER DNA base excision repair
  • HRD homologous recombination with DNA repair pathway Defects
  • the PARP inhibitor olaparib was approved for the treatment of advanced ovarian cancer in the EU and the United States at the same time, marking the first clinical establishment of the feasibility of PARP inhibitors as anti-tumor targets and co-lethal theory.
  • PARP inhibitors there are 4 PARP inhibitors on the market worldwide, and olaparib entered the Chinese market in 2018.
  • Mefuperil hydrochloride disclosed in patent WO2013117120 (its structural formula is ), the structure is novel, and its nucleus 2-arylfuran is widely present in active natural products, and it is also one of the dominant structures in medicinal chemistry, and has a good prospect of being a medicine.
  • the PARP inhibitor has good water solubility (>35mg/ml, more than 350 times higher than olaparib), simple synthesis process, simple preparation, good stability, excellent pharmacokinetic properties, high tissue distribution, and easy penetration of blood brain Barriers and other advantages. These characteristics provide an important basis for the treatment of a variety of malignant tumors with mefuroperil hydrochloride.
  • Tumor immunotherapy is to mobilize the body's immune system to enhance anti-tumor immunity, thereby inhibiting and killing tumor cells.
  • Tumor immunotherapy is one of the most promising research directions in the current tumor treatment field.
  • PD-1 programmed death-1
  • PD-1 receptor for programmed death Because it is related to apoptosis, it is named as the PD-1 receptor for programmed death, and the PD-1 receptor for programmed death It is an important immunosuppressive molecule and a member of the CD28 superfamily.
  • PD-1 is mainly expressed in activated T cells and B cells, and is a surface receptor of activated T cells.
  • PD-1 has two ligands, namely PD-L1 (B7-H1) and PD-L2 (B7-DC).
  • the tumor microenvironment in the body will induce the infiltrating T cells to highly express PD-1 molecules, and the tumor cells will highly express PD-1 ligands PD-L1 and PD-L2, leading to continuous activation of the PD-1 pathway in the tumor microenvironment.
  • PD-L1 After PD-L1 is connected to PD-1, the function of T cells is inhibited and cannot send a signal to the immune system to attack the tumor.
  • PD-1 inhibitors including PD-1 antibody and PD-L1 antibody, are a new tumor immunotherapy drug. Unlike surgery, radiotherapy and chemotherapy, and targeted drugs, PD-1 inhibitors themselves cannot directly kill cancer cells, but fight cancer by activating the patient's own immune system.
  • PD-1 inhibitors have been marketed in dozens of countries including China, the United States and Europe, including 2 PD-1 antibodies and 3 PD-L1 antibodies, namely Opdivo (Nivolumab), Keytruda (Pembrolizumab), Tecentriq (Atezolizumab), Imfinzi (Durvalumab), Bavencio (Avelumab), of which Opdivo and Keytruda have been listed in China.
  • 3 types of PD-1 from domestic pharmaceutical companies have also been listed, namely Junshi’s Teriplimumab (Tuoyi), Cinda’s Sintilizumab (Daboshu) and Hengrui’s Card. Relizumab (erika).
  • the MEDIOLA Phase II trial is a PD-L1 antibody Imfinzi (Durvalumab) combined with a PARP inhibitor Olaparib (Olaparib, Lynparza).
  • a clinical trial of advanced breast cancer patients with BRCA gene mutations and negative HER2 amplification The data shows that the 12-week disease control rate is 80%, the 28-week effective rate is 63%, the 28-week median DoR is 9.2 months, the 28-week median PFS is 8.2 months, and the 28-week disease control rate Is 50%. It is superior to patients who previously received Olaparib monotherapy, with an effective rate of 59.9% and a median PFS of 7.0 months.
  • the most common grade 3 adverse reactions associated with olaparib are anemia (12%) and neutropenia (6%); the most common grade 3 adverse reactions associated with durvalumab is pancreatitis (6%).
  • the combination of PARP inhibitors and PD-1 antibodies for the treatment of cancer has not only significant therapeutic benefits in the clinic, but still has a greater risk of side effects.
  • the side effects are mainly derived from PARP inhibition.
  • Agent. Therefore, PARP inhibitors combined with PD-1 antibodies have broad market prospects for the treatment of cancer, and better clinical effects and lower side effects are still the inevitable trend of clinical development.
  • the present invention provides a drug combination and application for treating tumors that are different from the prior art.
  • the combined use of the components of the drug combination of the present invention can significantly improve the inhibition rate of each single drug on tumor growth, and the mice after administration have no acute adverse reactions, indicating that this combination therapy has a good effect. Safety and effectiveness.
  • the present invention provides a pharmaceutical combination comprising a compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and "PD-1 inhibition Agent and/or PD-L1 inhibitor";
  • the pharmaceutically acceptable salt of the compound represented by formula A is mefupire hydrochloride.
  • the PD-1 inhibitor may be one or more of PD-1 antibody, PD-1 polypeptide, and PD-1 small molecule inhibitor, and further may be Teripril One or more of anti-, sintilizumab, karelizumab, pembrolizumab and nivolizumab, and further may be teriprizumab.
  • the PD-L1 inhibitor may be one or more of PD-L1 antibody, PD-L1 polypeptide, and PD-L1 small molecule inhibitor, and further may be ater strain monoclonal antibody (Atezolizumab, trade name Tecentriq), durvalumab (Durvalumab, trade name Imfinzi) and alikuumab (Avelumab, trade name Bavencio) one or more Kind.
  • the "PD-1 inhibitor and/or PD-L1 inhibitor” and the compound represented by formula A, its pharmaceutically acceptable salt, and its solvate Or a solvate of a pharmaceutically acceptable salt thereof may be administered simultaneously or separately, and may also be administered separately.
  • the separate application can also be sequential application.
  • the simultaneous administration may be, "the PD-1 inhibitor and/or PD-L1 inhibitor” and "the compound represented by formula A, its pharmaceutically acceptable salt, and its solvate "Solvate of a substance or a pharmaceutically acceptable salt thereof” includes simultaneous administration in a separate drug combination; or, a separate drug composition including "the PD-1 inhibitor and/or PD-L1 inhibitor” and A single pharmaceutical composition comprising "the compound represented by Formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate" is administered simultaneously.
  • Said separate administration may be a separate pharmaceutical composition comprising "the PD-1 inhibitor and/or PD-L1 inhibitor” and a single pharmaceutical composition comprising "the compound represented by formula A, which is pharmaceutically acceptable.
  • the individual pharmaceutical compositions of "accepted salts, solvates thereof, or solvates of pharmaceutically acceptable salts thereof" are administered separately at different times.
  • the separate administration may be close in time or farther in time.
  • the sequential administration may be a separate pharmaceutical composition containing "the PD-1 inhibitor and/or PD-L1 inhibitor" and the "compound of formula A, which is pharmaceutically acceptable.”
  • One of the individual pharmaceutical compositions of "accepted salt, solvate thereof, or solvate of a pharmaceutically acceptable salt thereof" is administered first, and the other is administered subsequently.
  • the separate administration may be close in time or farther in time.
  • the "PD-1 inhibitor and/or PD-L1 inhibitor” and the “compound of formula A, its pharmaceutically acceptable salt, and solvate can be the same or different, and it can be adjusted by those skilled in the art as needed to provide optimal treatment effect.
  • the drug combination is mefuropiril hydrochloride and teriprizumab.
  • the present invention also provides a pharmaceutical composition X, which comprises:
  • the pharmaceutical composition can be made into various suitable dosage forms according to different modes of administration, including dosage forms for administration via the gastrointestinal tract (for example, oral dosage forms (tablets, pills, capsules, powders, granules), gaseous dosage forms (Inhalation)) and parenteral administration dosage forms (e.g. injection dosage forms, ointments, emulsions).
  • dosage forms for administration via the gastrointestinal tract for example, oral dosage forms (tablets, pills, capsules, powders, granules), gaseous dosage forms (Inhalation)
  • parenteral administration dosage forms e.g. injection dosage forms, ointments, emulsions.
  • the pharmaceutical composition X is presented in the form of an injection dosage form or an oral dosage form.
  • the oral dosage form can be a tablet form.
  • the present invention also provides a pharmaceutical composition Y, which includes the first pharmaceutical composition and the second pharmaceutical composition;
  • the first pharmaceutical composition which includes the above-mentioned compound represented by formula A, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, and pharmaceutical excipients ;
  • the second pharmaceutical composition includes the above-mentioned "PD-1 inhibitor and/or PD-L1 inhibitor” and pharmaceutical excipients.
  • the first pharmaceutical composition is presented in the form of oral dosage form, and further presented in the form of tablet form.
  • the second pharmaceutical composition is presented in the form of injection.
  • the first pharmaceutical composition is presented in the form of a tablet
  • the second pharmaceutical composition is presented in the form of an injection.
  • the present invention also provides a medicine kit, which comprises:
  • a first container which contains the first pharmaceutical composition as described above;
  • the second container contains the second pharmaceutical composition as described above.
  • the present invention also provides an application of substance M in the preparation of drugs for the prevention and/or treatment of tumors; wherein, the substance M is the above-mentioned pharmaceutical combination, the above-mentioned pharmaceutical composition X or the above-mentioned pharmaceutical composition Y.
  • the tumor may be a solid tumor and/or hematological tumor.
  • the solid tumor can be lung cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, glioma, glial One or more of blastoma, hepatocellular carcinoma, papillary renal cancer, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma.
  • the compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt, and, "PD-1 inhibitor And/or PD-L1 inhibitor" administration schedule can be the same or different, which can be adjusted by those skilled in the art as needed to provide the optimal therapeutic effect.
  • the "compound of formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate”, and, the "PD-1 inhibitor and The dosage of "PD-L1 inhibitor” can be administered according to the weight of the subject.
  • the "compound of formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate", and, "PD- 1 Inhibitor and/or PD-L1 inhibitor” means simultaneous administration or separate administration.
  • the administration dose of the "compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate” is 100- 1000mg/time.
  • the frequency of administration of the compound represented by Formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate is 0.5-2 times/ day.
  • the compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate is administered orally.
  • the dosage of the "PD-1 inhibitor and/or PD-L1 inhibitor" is 50-500 mg/time.
  • the frequency of administration of the "PD-1 inhibitor and/or PD-L1 inhibitor" is once every 7-31 days.
  • the "PD-1 inhibitor and/or PD-L1 inhibitor” is administered orally or by injection.
  • the compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate is administered orally at a dosage of 100-1000mg/kg, the frequency of administration is 0.5-2 times/day;
  • the "PD-1 inhibitor and/or PD-L1 inhibitor" is administered by injection, the dosage is 50-500 mg/kg, and the frequency of administration is once every 7-31 days.
  • the present invention also provides a compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt in the preparation of a medicament for the treatment of tumors Application, wherein the “compound represented by formula A, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate” is the same as the “PD-1 Inhibitor and/or PD-L1 inhibitor” combined use;
  • the "compound represented by formula A, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate” and the "PD-1 inhibitor and /Or PD-L1 inhibitor” can be administered simultaneously or separately, or separately.
  • the separate application can also be sequential application.
  • the compound represented by formula A can be administered orally.
  • the dosage of the compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate may be 100-1000 mg/kg.
  • the frequency of administration of the compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate can be 0.5-2 times per day.
  • the "PD-1 inhibitor and/or PD-L1 inhibitor” can be administered orally or by injection.
  • the dosage of the "PD-1 inhibitor and/or PD-L1 inhibitor” can be 50-500 mg/time.
  • the frequency of administration of the "PD-1 inhibitor and/or PD-L1 inhibitor" may be once every 7-31 days.
  • the tumor may be a solid tumor and/or hematological tumor.
  • the solid tumor can be lung cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, glioma, glial One or more of blastoma, hepatocellular carcinoma, papillary renal cancer, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma.
  • the compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate is administered orally at a dosage of 100-1000mg/time, the frequency of administration is 0.5-2 times/day;
  • the "PD-1 inhibitor and/or PD-L1 inhibitor" is administered by injection, the dosage is 50-500 mg/time, and the frequency of administration is once every 7-31 days.
  • the present invention also provides an application of the above-mentioned "PD-1 inhibitor and/or PD-L1 inhibitor” in the preparation of a medicament for the treatment of tumors, wherein the "PD-1 inhibitor and/or PD-L1 inhibitor” PD-L1 inhibitor” is used in combination with "a compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate”;
  • the "compound represented by formula A, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate” and the "PD-1 inhibitor and /Or PD-L1 inhibitor” can be administered simultaneously or separately, or separately.
  • the separate application can also be sequential application.
  • the "PD-1 inhibitor and/or PD-L1 inhibitor” can be administered orally or by injection.
  • the dosage of the "PD-1 inhibitor and/or PD-L1 inhibitor” can be 50-500 mg/time.
  • the frequency of administration of the "PD-1 inhibitor and/or PD-L1 inhibitor" may be once every 7-31 days.
  • the compound represented by formula A can be administered orally.
  • the dosage of the compound represented by formula A can be 100-1000 mg/time.
  • the frequency of administration of the compound represented by formula A can be 0.5-2 times/day.
  • the tumor may be a solid tumor and/or hematological tumor.
  • the solid tumor can be lung cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, glioma, glial One or more of blastoma, hepatocellular carcinoma, papillary renal cancer, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma.
  • the compound of formula A is orally administered at a dosage of 100-1000 mg/time, and an administration frequency of 0.5-2 times/day;
  • the "PD-1 inhibitor and/or PD-L1 inhibitor" is administered by injection, the dosage is 50-500 mg/time, and the frequency of administration is once every 7-31 days.
  • the present invention also provides a method for treating or preventing tumors, which comprises administering an effective amount of substance M to a subject, wherein the substance M is the above-mentioned drug combination, the above-mentioned pharmaceutical composition X or the above-mentioned drug Composition Y.
  • the tumor may be a solid tumor and/or hematological tumor.
  • the solid tumor can be lung cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, glioma, glial One or more of blastoma, hepatocellular carcinoma, papillary renal cancer, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma.
  • the compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or the solvate of its pharmaceutically acceptable salt, and, "PD-1 inhibitor And/or PD-L1 inhibitor" administration schedule (including administration route, administration dosage, administration frequency, etc.) are the same as described above.
  • PD-1 antibody refers to an antibody that can bind to PD-1 on the surface of T cells and block the binding of PD-1 to its ligand.
  • the full name of PD-1 is programmed cell death protein 1 (programmed cell death protein 1), which is an important immunosuppressive molecule.
  • PD-1 polypeptide refers to a polypeptide that can bind to PD-1 on the surface of T cells and block the binding of PD-1 to its ligand.
  • PD-1 small molecule inhibitor refers to a small chemical molecule that can bind to PD-1 on the surface of T cells and block the binding of PD-1 to its ligand.
  • PD-L1 antibody refers to an antibody that can bind to PD-L1 on the surface of tumor cells and block the binding of PD-L1 to PD-1 on the surface of T cells.
  • the full name of PD-L1 is programmed cell death protein 1 ligand 1 (programmed cell death protein 1 ligand 1).
  • PD-L1 polypeptide refers to a polypeptide that can bind to PD-L1 on the surface of tumor cells and block the binding of PD-L1 to PD-1 on the surface of T cells.
  • PD-L1 small molecule inhibitor refers to a small molecule compound that can bind to PD-L1 on the surface of tumor cells and block the binding of PD-L1 to PD-1 on the surface of T cells.
  • Small molecular compound refers to a compound with a molecular weight of less than 1,000.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • the pharmaceutically acceptable acids include inorganic acids, and the inorganic acids include but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate Root, phosphorous acid, sulfuric acid, hydrogen sulfate, etc.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
  • solvate refers to a substance formed after a compound crystallizes with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • solvate of a pharmaceutically acceptable salt refers to a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, solvent (including but not limited to: water, methanol, ethanol) Etc.)
  • solvent including but not limited to: water, methanol, ethanol
  • Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.
  • therapeutically effective amount refers to the amount of a compound administered to a patient that is sufficient to effectively treat the disease.
  • the therapeutically effective amount will vary according to the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that the pharmaceutical composition of the present invention can inhibit tumor growth by up to 60%, and in the test phase, the subject has no acute adverse reactions.
  • Figure 1 shows the percentage change in the body weight of experimental animals after the start of treatment.
  • Figure 2 shows the tumor growth curve of experimental animals after the start of treatment.
  • Figure 3 shows the individual tumor volume of experimental animals after administration (PG-D24), where "-" represents the median number.
  • Figure 4 shows the hCD45FACS detection of the peripheral blood of experimental animals 3 weeks after PBMC inoculation, where "-" represents the median.
  • Test drug 1 Tuoyi (Teripril PD-1 monoclonal antibody) injection.
  • Test drug 2 Mefuropiril hydrochloride.
  • Tuoyi PD-1 monoclonal antibody injection PBS
  • Mevoperi hydrochloride physiological saline.
  • FBS Fetal Bovine Serum
  • Leibovitz's L-15 medium 500ml/bottle Gibco Penicillin mixture 100ml/bottle Solarbio Trypsin-EDTA digestion solution (0.25%) 100ml/bottle Solarbio Matrigel 10ml/bottle Corning PBS (phosphate buffered saline) 500ml/bottle Gibco Normal saline (0.9% sodium chloride injection) 500ml/bottle Shijiazhuang Four Medicines Co., Ltd.
  • PE-Cy7 anti-Hu CD45 100Tests Invitrogen
  • Mus Musculus Mus Musculus, NCG (NOD-Prkdc em26Cd52 Il2rg em26Cd22 /Nju); gender: female; weight: 18-22g; number: 55; experimental animal provider: Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
  • Feeding management The experimental animals are kept in an SPF-level constant temperature and humidity laminar flow clean room, using independent ventilated cages with IVC, one cage for every 5 rats.
  • Temperature/Humidity Control in the range of (23 ⁇ 3)°C/40-70%.
  • Cage made of polycarbonate. The volume is 370mm ⁇ 155mm ⁇ 135mm. Soft corncobs are autoclaved and cleaned and replaced twice a week. Each cage has a cage label, indicating the number of animals, gender, strain, reception time, group, and start time of the experiment.
  • Feed and drinking water SPF rodent feed, sterilized by cobalt 60 irradiation.
  • the drinking water is ultra-filtered purified water and is autoclaved. Animals can freely ingest sterile food and drinking water.
  • MDA-MB-436 tumor cells (YK-CL-075) were purchased from ATCC. Use Leibovitz's L-15 medium containing inactivated 10% fetal bovine serum, 100U/ml penicillin and 100 ⁇ g/ml streptomycin to cultivate tumor cells in an incubator at 37°C and 5% CO 2 every 3 to 4 After the cells are overgrown, they are divided into bottles for passage, and tumor cells in the logarithmic growth phase are used for tumor inoculation in vivo.
  • PBMC human peripheral blood mononuclear cells
  • the tumor volume is measured twice a week with a vernier caliper, and the long and short diameters of the tumor are measured.
  • T/C value was calculated based on the tumor volume, where T is the average value of the relative tumor volume (RTV) of each test substance treatment group, and C is the average value of the relative tumor volume (RTV) of the control group.
  • RTV is the ratio of tumor volume after administration to before administration.
  • Tumor growth inhibition rate (TGI, %) (1-T/C) ⁇ 100%.
  • the tumor was stripped and weighed, placed neatly and photographed.
  • the volume of administration with "*" is 10 ⁇ l/g based on the animal's body weight. If there is a 15-20% weight loss, the drug can be stopped until the body weight returns to a normal level;
  • i.p. intraperitoneal injection
  • p.o. oral;
  • qod ⁇ 13 dosing once every other day for a total of 13 times
  • q4d ⁇ 7 dosing once every four days for a total of 7 times.
  • mice in each group did not see obvious acute adverse reactions after the administration.
  • body weight of mice in each group decreased, as shown in Figure 1.
  • the above experiments confirmed that the combined use of Meforpiride hydrochloride + Tuoyi PD-1 monoclonal antibody injection is safe.
  • Tuoyi PD-1 monoclonal antibody injection combined with mefupire hydrochloride produced statistically significant anti-tumor effects , Can effectively inhibit tumor growth, and its tumor inhibition rate is significantly higher than that of Tuoyi PD-1 monoclonal antibody injection, and the proportion of hCD45 cells in peripheral blood of mice is correspondingly increased.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Physiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nutrition Science (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

一种用于治疗肿瘤的药物组合及其应用。药物组合包括如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物、和"PD-1抑制剂和/或PD-L1抑制剂"。该药物组合的各组分联合使用，能够显著性的提高各自单药对肿瘤生长的抑制率，且给药后的小鼠均没有出现急性的不良反应，显示这一联合疗法具有良好的安全性和有效性。

Description

一种用于治疗肿瘤的药物组合及其应用
本申请要求申请日为2019/12/31的中国专利申请201911417368.7的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种用于治疗肿瘤的药物组合及其应用。
背景技术
恶性肿瘤的精准治疗是肿瘤药物发展的必然趋势，也是今后的发展方向。聚腺苷二磷酸核糖聚合酶(PARP)是近年体现肿瘤精准治疗理念的热点药物靶标，其抑制剂通过抑制DNA碱基切除修复(BER)通路关键酶PARP1/2，与DNA同源重组修复通路缺陷(HRD)包括BRCA1/2、PTEN、EWS-FLI等产生协同致死效应。由于HRD仅发生于肿瘤细胞，正常细胞的HR功能正常，因此PARP抑制剂对HR通路缺陷肿瘤具有高度选择性。2014年PARP抑制剂奥拉帕利(olaparib)同时在欧盟和美国被批准上市用于晚期卵巢癌的治疗，标志着PARP抑制剂作为抗肿瘤靶点和协同致死理论的可行性首次在临床确立。目前，全球范围共有4个PARP抑制剂上市，奥拉帕利在2018年进入了中国市场。而中国原创的PARP抑制剂目前无新药上市，少数几个PARP抑制剂处于临床起步阶段。
在专利WO2013117120中公开的盐酸美呋哌瑞(其结构式为
Figure PCTCN2020142257-appb-000001
)，结构新颖，其母核2-芳基呋喃广泛存在于活性天然产物中，也是药物化学优势结构之一，成药前景好。该PARP抑制剂具有水溶性好(>35mg/ml，比奥拉帕尼高350倍以上)、合成工艺简洁、制剂简 单、稳定性好、药代性质优异、组织分布高、易透过血脑屏障等优势。这些特征为盐酸美呋哌瑞治疗多种恶性肿瘤提供了重要基础。
肿瘤免疫治疗是通过调动机体的免疫系统，增强抗肿瘤免疫力，从而抑制和杀伤肿瘤细胞。肿瘤免疫治疗是当前肿瘤治疗领域中最具前景的研究方向之一。PD-1(programmed death-1)是在凋亡的T细胞杂交瘤中得到的，由于其和细胞凋亡相关而被命名为程序性死亡PD-1受体，PD-1程序性死亡受体是一种重要的免疫抑制分子，为CD28超家族成员。PD-1主要在激活的T细胞和B细胞中表达，是激活型T细胞的一种表面受体，PD-1有两个配体，分别是PD-L1(B7-H1)和PD-L2(B7-DC)。机体内的肿瘤微环境会诱导浸润的T细胞高表达PD-1分子，肿瘤细胞会高表达PD-1的配体PD-L1和PD-L2，导致肿瘤微环境中PD-1通路持续激活，PD-L1与PD-1联接后，T细胞功能被抑制，不能向免疫系统发出攻击肿瘤的信号。PD-1抑制剂，包括PD-1抗体和PD-L1抗体，是一种肿瘤免疫治疗新药。不同于手术、放化疗和靶向药，PD-1抑制剂本身并不能直接杀伤癌细胞，而是通过激活病人自身的免疫系统来抗癌。
截止目前，已有5种PD-1抑制剂在中美欧等几十个国家上市，包括2种PD-1抗体和3种PD-L1抗体，分别为Opdivo(Nivolumab)、Keytruda(Pembrolizumab)、Tecentriq(Atezolizumab)、Imfinzi(Durvalumab)、Bavencio(Avelumab)，其中，Opdivo和Keytruda已经先后在中国国内上市。此外，3款来自国内药企的PD-1也已经上市，分别是君实的特瑞普利单抗(拓益)，信达的信迪利单抗(达伯舒)以及恒瑞的卡瑞利珠单抗(艾瑞卡)。
在2017年举办的圣安东尼奥乳腺癌大会上，研究者公布了一个重磅的研究成果：MEDIOLAⅡ期试验是一个PD-L1抗体Imfinzi(Durvalumab)联合PARP抑制剂Olaparib(奥拉帕利，Lynparza)，用于BRCA基因突变的、HER2扩增阴性的晚期乳腺癌患者的临床试验。数据显示，12周的疾病控制率为80％，28周的有效率为63％，28周的中位DoR为9.2个月，28周的中 位PFS为8.2个月，28周的疾病控制率为50％。优于此前接受Olaparib单药治疗的患者，其有效率为59.9％、中位PFS为7.0个月。奥拉帕尼相关的最常见3级不良反应有，贫血(12％)和中性粒细胞减少(6％)；durvalumab相关的最常见的3级不良反应是胰腺炎(6％)。
2018年美国妇科肿瘤学年会(SGO)上，TOPACIO研究(PARP抑制剂Niraparib联合PD-1抑制剂Keytruda)的结果被报道，显示对铂类耐药/难治性卵巢癌和三阴乳腺癌患者，PARP抑制剂联合PD-1抑制剂疗效持久。在铂类继发耐药或原发耐药的卵巢癌患者或三阴性乳腺癌患者中，总的ORR(包括CR和PR)为25％，DCR(CR+PR+SD)为68％；在铂类原发耐药的患者中，ORR为24％。患者的疗效与标志物的状态无关：在BRCA野生型的患者中，ORR为26％(9/34)；在HRD-阴性的患者中，ORR为29％(7/24)。目前疗效持续时间的数据尚未成熟，60％(9/15)有响应的患者仍在接受治疗，超过一半取得疾病控制的患者已经接受了超过6个月的治疗。副作用方面，3级以上不良事件发生32例/共58例(55％)，最常见的3级或以上不良反应是贫血(18％)、血小板减少(15％)和疲劳(4％)。主要的不良反应来自PARP抑制剂。此外，有15％(8名)患者有免疫相关的不良反应。
综上，PARP抑制剂联合PD-1抗体用于治疗癌症，在临床当中既有显著的治疗获益，同时仍存在较大的副作用风险，从现有临床的数据报道，副作用主要来源于PARP抑制剂。所以，PARP抑制剂联合PD-1抗体用于治疗癌症具有广阔的市场前景，而更好的临床效果和更低的副作用仍是临床开发的必然趋势。
发明内容
本发明提供了一种与现有技术不同的用于治疗肿瘤的药物组合及其应用。本发明的药物组合的各组分联合使用，能够显著性的提高各自单药对肿瘤生长的抑制率，且给药后的小鼠均没有出现急性的不良反应，显示这一联 合疗法具有良好的安全性和有效性。
本发明提供了一种药物组合，其包括如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物、和“PD-1抑制剂和/或PD-L1抑制剂”；
Figure PCTCN2020142257-appb-000002
在某一实施方案中，所述的如式A所示的化合物药学上可接受的盐为美呋哌瑞盐酸盐。
在某一实施方案中，所述的PD-1抑制剂可以为PD-1抗体、PD-1多肽和PD-1小分子抑制剂中的一种或多种，进一步可以为特瑞普利单抗、信迪利单抗、卡瑞利珠单抗、帕博利珠单抗和纳武利尤单抗中的一种或多种，进一步还可以为特瑞普利单抗。
在某一实施方案中，所述的PD-L1抑制剂可以为PD-L1抗体、PD-L1多肽和PD-L1小分子抑制剂中的一种或多种，进一步可以为阿特株单抗(Atezolizumab，商品名为特善奇(Tecentriq))、度伐单抗(Durvalumab，商品名为英飞凡(Imfinzi))和阿利库单抗(Avelumab，商品名为Bavencio)中的一种或多种。
在某一实施方案中，所述的“PD-1抑制剂和/或PD-L1抑制剂”和，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物可以同时施用或分别施用，还可以分别施用。所述的分别施用还可以为依次施用。
所述的同时施用可以为，“所述的PD-1抑制剂和/或PD-L1抑制剂”和“所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”包含在单独药物组合中同时施用；或者，包含“所述的PD-1抑制剂和/或PD-L1抑制剂”的单独药物组合物与包含“所述的如 式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”的单独药物组合物同时施用。
所述的分别施用可以为，包含“所述的PD-1抑制剂和/或PD-L1抑制剂”的单独药物组合物与包含“所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”的单独药物组合物在不同时间分开施用。所述的分开施用可在时间上距离接近或时间上距离较远。
所述的依次施用可以为，包含“所述的PD-1抑制剂和/或PD-L1抑制剂”的单独药物组合物和包含所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”的单独药物组合物其中之一首先施用，另一个随后施用。所述的分开施用可在时间上距离接近或时间上距离较远。
无论同时施用还是分别施用，所述的“PD-1抑制剂和/或PD-L1抑制剂”和所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”的施用方案(包括施用途径、施用剂量、施用间隔等)可以相同或不同，其可以由本领域技术人员根据需要进行调整，以提供最优的治疗效果。
在某一实施方案中，所述的药物组合为美呋哌瑞盐酸盐和特瑞普利单抗。
本发明还提供了一种药物组合物X，其包括：
所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
所述的“PD-1抑制剂和/或PD-L1抑制剂”；
和，药用辅料。
所述的药物组合物，根据给药方式不同可制成各种合适的剂型，包括经胃肠道给药剂型(例如口服剂型(片剂、丸剂、胶囊剂、粉剂、颗粒剂)、气态剂型(吸入剂))和非经胃肠道给药剂型(例如注射剂型、膏剂、乳剂)。
在某一实施方案中，所述药物组合物X以注射剂型形式或口服剂型形式呈现。所述的口服剂型可以为片剂型。
本发明还提供了一种药物组合物Y，其包括第I药物组合物和第II药物组合物；
所述的第I药物组合物，其包括上述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，和药用辅料；
所述的第II药物组合物，其包括上述的“PD-1抑制剂和/或PD-L1抑制剂”，和药用辅料。
在某一实施方案中，所述的第I药物组合物以口服剂型形式呈现，进一步为片剂型形式呈现。
在某一实施方案中，所述的第II药物组合物以注射剂型形式呈现。
在某一实施方案中，所述的第I药物组合物以片剂型形式呈现，所述的第II药物组合物以注射剂型形式呈现。
本发明提供还提供了一种药盒，其包含：
第一容器，其包含如上所述的第I药物组合物；和，
第二容器，其包含如上所述的第II药物组合物。
本发明还提供了一种物质M在制备用于预防和/或治疗肿瘤的药物中的应用；其中，所述的物质M为上述的药物组合、上述的药物组合物X或上述的药物组合物Y。
所述的肿瘤可以为实体肿瘤和/或血液肿瘤。所述的实体肿瘤可以为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
所述的应用中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物、和、“PD-1抑制剂和/或PD-L1抑制剂”的施用方案(包括施用途径、施用剂量、施用间隔等)可以相同或 不同，其可以由本领域技术人员根据需要进行调整，以提供最优的治疗效果。
所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”、和、所述的“PD-1抑制剂和/或PD-L1抑制剂”的剂量均可以根据受试者的体重来施用。
在某一实施方案中，所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”、和、“PD-1抑制剂和/或PD-L1抑制剂”为同时施用或分别施用。
在某一实施方案中，所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”的施用剂量为100-1000mg/次。
在某一实施方案中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物施用频率为0.5-2次/天。
在某一实施方案中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物经口服施用。
在某一实施方案中，所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用剂量为50-500mg/次。
在某一实施方案中，所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用频率为每7-31天施用一次。
在某一实施方案中，所述的“PD-1抑制剂和/或PD-L1抑制剂”经口服施用或者注射施用。
在某一实施方案中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物的经口服施用，施用剂量为100-1000mg/kg，施用频率为0.5-2次/天；
和，所述的“PD-1抑制剂和/或PD-L1抑制剂”的经注射施用，施用剂量为50-500mg/kg，施用频率为每7-31天施用一次。
本发明还提供了一种上述的如式A所示的化合物、其药学上可接受的 盐、其溶剂合物或其药学上可接受的盐的溶剂合物在制备用于治疗肿瘤的药物中的应用，其中，所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”与所述的“PD-1抑制剂和/或PD-L1抑制剂”联用；
Figure PCTCN2020142257-appb-000003
其中，所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”和所述的“PD-1抑制剂和/或PD-L1抑制剂”可以同时施用或分别施用，还可以分别施用。所述的分别施用还可以为依次施用。
其中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物可经口服施用。
其中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物的施用剂量可为100-1000mg/kg。
其中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物施用频率可为0.5-2次/天。
其中，所述的“PD-1抑制剂和/或PD-L1抑制剂”可经口服施用或者注射施用。
其中，所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用剂量可为50-500mg/次。
其中，所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用频率可为每7-31天施用一次。
其中，所述的肿瘤可以为实体肿瘤和/或血液肿瘤。所述的实体肿瘤可以为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳 头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
在某一实施方案中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物的经口服施用，施用剂量为100-1000mg/次，施用频率为0.5-2次/天；
和，所述的“PD-1抑制剂和/或PD-L1抑制剂”的经注射施用，施用剂量为50-500mg/次，施用频率为每7-31天施用一次。
本发明还提供了一种上述的“PD-1抑制剂和/或PD-L1抑制剂”在制备用于治疗肿瘤的药物中的应用，其中，所述的“PD-1抑制剂和/或PD-L1抑制剂”与“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”联用；
Figure PCTCN2020142257-appb-000004
其中，所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”和所述的“PD-1抑制剂和/或PD-L1抑制剂”可以同时施用或分别施用，还可以分别施用。所述的分别施用还可以为依次施用。
其中，所述的“PD-1抑制剂和/或PD-L1抑制剂”可经口服施用或者注射施用。
其中，所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用剂量可为50-500mg/次。
其中，所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用频率可为每7-31天施用一次。
其中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物可经口服施用。
其中，所述的如式A所示的化合物的施用剂量可为100-1000mg/次。
其中，所述的如式A所示的化合物施用频率可为0.5-2次/天。
其中，所述的肿瘤可以为实体肿瘤和/或血液肿瘤。所述的实体肿瘤可以为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
在某一实施方案中，所述的如式A所示的化合物的经口服施用，施用剂量为100-1000mg/次，施用频率为0.5-2次/天；
和，所述的“PD-1抑制剂和/或PD-L1抑制剂”的经注射施用，施用剂量为50-500mg/次，施用频率为每7-31天施用一次。
本发明还提供了一种治疗或预防肿瘤的方法，其包括给予受试者使用有效量的物质M，其中，所述的物质M为上述的药物组合、上述的药物组合物X或上述的药物组合物Y。
所述的方法中，所述的肿瘤可以为实体肿瘤和/或血液肿瘤。所述的实体肿瘤可以为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
所述的方法中，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物、和、“PD-1抑制剂和/或PD-L1抑制剂”的施用方案(包括施用途径、施用剂量、施用频率等)均同前所述。
术语“PD-1抗体”是指能与T细胞表面的PD-1相结合，阻断PD-1与其配体结合的抗体。PD-1的全称为程序性细胞死亡蛋白1(programmed cell death protein 1)，是一种重要的免疫抑制分子。
术语“PD-1多肽”是指能与T细胞表面的PD-1相结合，阻断PD-1与其 配体结合的多肽。
术语“PD-1小分子抑制剂”是指能与T细胞表面的PD-1相结合，阻断PD-1与其配体结合的化学小分子。
术语“PD-L1抗体”是指能与肿瘤细胞表面的PD-L1相结合，阻断PD-L1与T细胞表面PD-1结合的抗体。PD-L1的全称为程序性细胞死亡蛋白1配体1(programmed cell death protein 1 ligand 1)。
术语“PD-L1多肽”是指能与肿瘤细胞表面的PD-L1相结合，阻断PD-L1与T细胞表面PD-1结合的多肽。
术语“PD-L1小分子抑制剂”是指能与肿瘤细胞表面的PD-L1相结合，阻断PD-L1与T细胞表面PD-1结合的小分子化合物。“小分子化合物”是指分子量小于1000的化合物。
术语“药学上可接受的盐”是指化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、亚磷酸、硫酸、硫酸氢根等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、 氨基酸(例如谷氨酸、精氨酸)等。当化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂合物”是指化合物与溶剂(包括但不限于：水、甲醇、乙醇等)结晶后形成的物质。溶剂合物分为化学计量类溶剂合物和非化学计量类溶剂合物。
术语“药学上可接受的盐的溶剂合物”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱、溶剂(包括但不限于：水、甲醇、乙醇等)结合形成的物质，其中，药学上可接受的盐与上文术语“药学上可接受的盐”的含义相同，溶剂为化学计量的或非化学计量的。药学上可接受的盐的溶剂合物包括但不限于盐酸盐一水合物。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物、疾病种类、疾病的严重度、患者的年龄等变化，但可由本领域技术人员视情况调整。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的药物组合物对肿瘤生长抑制率可达60％，且试验阶段，受试体无急性的不良反应。
附图说明
图1为治疗开始后的实验动物体重变化百分比。
图2为治疗开始后的实验动物肿瘤生长曲线。
图3为给药后(PG-D24)的实验动物个体肿瘤体积，其中“-”表示中位 数。
图4为PBMC接种3周后实验动物外周血的hCD45FACS检测，其中“-”表示中位数。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
1、供试药物
供试药物1：拓益(特瑞普利PD-1单抗)注射液。
供试药物2：盐酸美呋哌瑞。
2、供试品配制
2.1、溶媒选择：拓益PD-1单抗注射液：PBS；美呋哌瑞盐酸盐：生理盐水。
2.2、配制方法：
表1.受试物的配制及储存
Figure PCTCN2020142257-appb-000005
3、实验材料和仪器设备
表2.实验所用试剂
名称 规格 生产厂家
胎牛血清(FBS) 500ml/瓶 Gibco
Leibovitz's L-15培养基 500ml/瓶 Gibco
青链霉素混合液 100ml/瓶 Solarbio
胰蛋白酶-EDTA消化液(0.25％) 100ml/瓶 Solarbio
Matrigel 10ml/瓶 Corning
PBS(磷酸盐缓冲液) 500ml/瓶 Gibco
生理盐水(0.9％氯化钠注射液) 500ml/瓶 石家庄四药有限公司
PE-Cy7 anti-Hu CD45 100Tests Invitrogen
PE-Cy7 mouse IgG1 κ Iso Control 20Tests Invitrogen
表3.实验所用仪器设备
名称 型号 厂家
CO 2培养箱 3111 Thermo
显微镜 IX53 Olympus
电子天平 EJ-1201C 北京朗科兴业称重设备有限公司
SF2000三按键电子数显卡尺 111N-101B 桂林广陆数字测控有限公司
ACEA NovoCyte流式细胞仪 3130 ACEA
4、实验动物和饲养管理
4.1、实验动物
种属品系：Mus Musculus，NCG(NOD-Prkdc em26Cd52Il2rg em26Cd22/Nju)；性别：雌性；体重：18-22g；数量：55只；实验动物提供商：江苏集萃药康生物科技有限公司。
4.2、饲养管理
饲养管理：实验动物饲养在SPF级恒温恒湿的层流清洁房间内，使用独立通风笼具IVC，每5只鼠一笼。
温度/湿度：控制在(23±3)℃/40-70％范围。
笼具：由聚碳酸酯制成。体积为370mm×155mm×135mm。软制玉米 芯高压消毒清洁垫料，每周更换两次。每只笼具具有笼具标签，标明动物数量、性别、品系、接收时间、组别以及实验开始时间。
饲料和饮水：SPF级鼠料，钴60照射消毒。饮用水为超滤净化水，并经过高压灭菌处理。动物可以自由摄取无菌食物和饮水。
动物编号：耳朵打孔。
5、实验方法
5.1、细胞培养
MDA-MB-436肿瘤细胞(YK-CL-075)购自ATCC。用含有灭活的10％胎牛血清，100U/ml青霉素和100μg/ml链霉素的Leibovitz's L-15培养基在37℃、5％CO 2的培养箱中培养肿瘤细胞，每隔3至4天待细胞长满后分瓶传代，将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
PBMC(人外周血单个核细胞)：来源于ALLCELLS(Donor#：A0075)。
5.2、肿瘤细胞接种与分组
PBS与Matrigel按体积比1：1重悬的MDA-MB-436肿瘤细胞，浓度为1×10 8/ml，接种于小鼠的右侧胁肋部皮下，100μl/只，并在肿瘤体积生长至约1000mm 3左右时，在无菌条件下取瘤，切成小块，每块大小约2mm×2mm×2mm，接种于实验动物的右侧胁肋部皮下，2周后将PBMC细胞用PBS重悬后，接种于小鼠体内，细胞接种量为2×10 6/鼠。在实验动物的肿瘤生长至93mm 3左右时分组给药(当天记为PG-D0)，共4组，每组10只，具体给药方案见表4。
5.3、小鼠体重的测量及实验指标
每周使用游标卡尺对肿瘤体积进行2次测量，测量肿瘤的长径和短径，其体积计算公式为：体积＝0.5×长径×短径 2。
根据肿瘤体积计算T/C值，其中T为各受试物处理组相对肿瘤体积(RTV)的平均值，C为对照组相对肿瘤体积(RTV)的平均值。RTV为给药后与给药前的肿瘤体积比值。肿瘤生长抑制率(TGI，％)＝(1－T/C)×100％。
在PBMC接种3周后，采集小鼠外周血，通过流式细胞术(FACS)检测其中人源CD45 +细胞(hCD45细胞)比例。
实验结束时，剥离肿瘤称重、摆放整齐拍照。
6、给药方案
表4.给药方案表
Figure PCTCN2020142257-appb-000006
注：“*”给药容积依动物体重按10μl/g，如果出现体重下降15-20％时可停药至体重恢复至正常水平；
i.p.：腹腔注射；p.o.：口服；
qod×13：每隔一天给药一次，共给药13次；q4d×7：每四天给药一次，共给药7次。
7、统计学分析
应用IBM SPSS Statistics 22.0统计学软件，应用混合线性模型分析对肿瘤体积进行组间统计学分析，应用One-Way ANOVA分析对肿瘤重量进行组间统计学分析，p<0.05认为有显著性差异。
实施例1试验结果
1、实验动物给药后反应及体重变化
实验期间，各组小鼠在给药后未见明显的急性不良反应。在实验中后期，各组小鼠体重均出现下降，具体地见图1。上述实验证实美呋哌瑞盐酸盐+拓益PD-1单抗注射液联合使用的安全性良好。
2、肿瘤生长抑制结果
治疗后的实验动物肿瘤体积变化见表5、图2和图3。
表5.受试物对MDA-MB-436模型的抑瘤作用(肿瘤体积)
Figure PCTCN2020142257-appb-000007
结论：在分组后24天(PG-D24)，美呋哌瑞盐酸盐组、拓益PD-1单抗注射液组、美呋哌瑞盐酸盐+拓益PD-1单抗注射液组的肿瘤生长抑制率分别为54％、29％、60％，各治疗组的肿瘤体积均显著小于对照组(p<0.05)；美呋哌瑞盐酸盐+拓益PD-1单抗注射液组的肿瘤体积显著小于拓益PD-1单抗注射液组(p<0.05)。表明联合用药产生了显著优于PD-1单药的疗效和优于美呋哌瑞盐酸盐的治疗趋势。
3、外周血FACS检测
PBMC接种3周后，小鼠外周血hCD45的FACS检测见图4。
由图4可知，小鼠外周血中hCD45细胞FACS检测结果阳性，表明人源化免疫重建模型建模成功，并且hCD45细胞百分比中位数在美呋哌瑞盐酸盐组、拓益PD-1单抗注射液组、美呋哌瑞盐酸盐+拓益PD-1单抗注射液组均高于对照组，其中美呋哌瑞盐酸盐+拓益PD-1单抗注射液组中位数高于美呋哌瑞盐酸盐组和拓益PD-1单抗注射液组。
综上所述，在PBMC人源化的MDA-MB-436皮下移植瘤模型中，拓益PD-1单抗注射液联合美呋哌瑞盐酸盐给药产生有统计学意义的抗肿瘤作用，能够有效地抑制肿瘤生长，其肿瘤抑制率显著高于拓益PD-1单抗注射液、 小鼠外周血中hCD45细胞比例也相应增高。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (14)

  1. 一种药物组合，其包括如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物、和、“PD-1抑制剂和/或PD-L1抑制剂”；
    Figure PCTCN2020142257-appb-100001
  2. 如权利要求1所述的药物组合，其特征在于，所述的如式A所示的化合物药学上可接受的盐为美呋哌瑞盐酸盐；
    和/或，所述的PD-1抑制剂为PD-1抗体、PD-1多肽和PD-1小分子抑制剂中的一种或多种，进一步可以为特瑞普利单抗、信迪利单抗、卡瑞利珠单抗、帕博利珠单抗和纳武利尤单抗中的一种或多种，进一步还可以为特瑞普利单抗，更进一步可以为拓益；
    和/或，所述的PD-L1抑制剂为PD-L1抗体、PD-L1多肽和PD-L1小分子抑制剂中的一种或多种，进一步可以为阿特株单抗、度伐单抗和阿利库单抗中的一种或多种；
    和/或，所述的“PD-1抑制剂和/或PD-L1抑制剂”和所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”同时施用或分别施用，进一步为依次施用；
    和/或，所述的“PD-1抑制剂和/或PD-L1抑制剂”经口服施用或者注射施用；
    和/或，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物经口服施用。
  3. 如权利要求1所述的药物组合，其特征在于，所述的药物组合为美呋哌瑞盐酸盐和特瑞普利单抗。
  4. 一种药物组合物X，其特征在于，所述的药物组合物X包括：
    如权利要求1～3任一项所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
    如权利要求1～3任一项所述的“PD-1抑制剂和/或PD-L1抑制剂”；
    和，药用辅料。
  5. 如权利要求4所述的药物组合物X，其特征在于，所述的药物组合物X以注射剂型形式或口服剂型形式呈现。
  6. 一种药物组合物Y，其特征在于，所述的药物组合物Y包括第I药物组合物和第II药物组合物；
    所述的第I药物组合物，其包括如权利要求1～3任一项所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，和药用辅料；
    所述的第II药物组合物，其包括如权利要求1～3任一项所述的“PD-1抑制剂和/或PD-L1抑制剂”，和药用辅料。
  7. 如权利要求6所述的药物组合物Y，其特征在于，所述的第I药物组合物以口服剂型形式呈现，进一步为片剂型形式呈现；
    和/或，所述的第II药物组合物以注射剂型形式呈现。
  8. 一种药盒，其包含：
    第一容器，其包含如权利要求6或7所述的第I药物组合物；和，
    第二容器，其包含如权利要求6或7所述的第II药物组合物。
  9. 一种物质M在制备用于预防和/或治疗肿瘤的药物中的应用，其中，所述的物质M为如权利要求1～3任一项所述的药物组合、如权利要求4或5所述的药物组合物X、或、如权利要求6或7所述的药物组合物Y。
  10. 如权利要求9所述的应用，其特征在于，所述的肿瘤为实体肿瘤和/或血液肿瘤，具体的为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发 性骨髓瘤中的一种或多种；
    和/或，所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”和所述的“PD-1抑制剂和/或PD-L1抑制剂”为同时施用或分别施用，进一步为依次施用；
    和/或，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物的施用剂量为100-1000mg/次；
    和/或，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物施用频率为0.5-2次/天；
    和/或，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物经口服施用；
    和/或，所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用剂量为50-500mg/次；
    和/或，所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用频率为每7-31天施用一次；
    和/或，所述的“PD-1抑制剂和/或PD-L1抑制剂”经口服施用或者注射施用。
  11. 如权利要求10所述的应用，其特征在于，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物经口服施用，施用剂量为100-1000mg/次，施用频率为0.5-2次/天；
    和，所述的“PD-1抑制剂和/或PD-L1抑制剂”的经注射施用，施用剂量为50-500mg/次，施用频率为每7-31天施用一次。
  12. 一种如权利要求1～3任一项所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”在制备用于治疗肿瘤的药物中的应用，其特征在于，所述的“如式A所示的化合物或其药学上可接受的盐”与如权利要求1～3任一项所述的“PD-1抑制剂和/或PD-L1抑制剂”联用；
    优选，所述的肿瘤为实体肿瘤和/或血液肿瘤，具体为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
  13. 一种如权利要求1～3任一项所述的“PD-1抑制剂和/或PD-L1抑制剂”在制备用于治疗肿瘤的药物中的应用，其特征在于，所述的“PD-1抑制剂和/或PD-L1抑制剂”与如权利要求1～3任一项所述的“如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物”联用；
    优选，所述的肿瘤为实体肿瘤和/或血液肿瘤，所述的实体肿瘤为肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、胶质母细胞瘤、肝细胞癌、乳头状肾癌、头颈癌、白血病、淋巴瘤、骨髓瘤和多发性骨髓瘤中的一种或多种。
  14. 一种治疗或预防肿瘤的方法，其包括给予受试者使用有效量的物质M，其中，所述的物质M为如权利要求1～3任一项所述的药物组合、如权利要求4或5所述的药物组合物X、或、如权利要求6或7所述的药物组合物Y；
    优选，所述的如式A所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物、和、所述的“PD-1抑制剂和/或PD-L1抑制剂”的施用途径、施用剂量和施用频率均同权利要求10或11所述。
PCT/CN2020/142257 2019-12-31 2020-12-31 一种用于治疗肿瘤的药物组合及其应用 Ceased WO2021136523A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA3163564A CA3163564A1 (en) 2019-12-31 2020-12-31 A drug combination for treating tumors and its application
US17/790,038 US20230094843A1 (en) 2019-12-31 2020-12-31 Pharmaceutical combination for treating tumors and application thereof
EP20909191.7A EP4085908A4 (en) 2019-12-31 2020-12-31 PHARMACEUTICAL COMBINATION FOR TREATING TUMORS AND ITS APPLICATION
JP2022540813A JP7805005B2 (ja) 2019-12-31 2020-12-31 腫瘍治療の医薬組み合わせとその使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911417368.7 2019-12-31
CN201911417368 2019-12-31

Publications (1)

Publication Number Publication Date
WO2021136523A1 true WO2021136523A1 (zh) 2021-07-08

Family

ID=76686614

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/142257 Ceased WO2021136523A1 (zh) 2019-12-31 2020-12-31 一种用于治疗肿瘤的药物组合及其应用

Country Status (6)

Country Link
US (1) US20230094843A1 (zh)
EP (1) EP4085908A4 (zh)
JP (1) JP7805005B2 (zh)
CN (1) CN113116881B (zh)
CA (1) CA3163564A1 (zh)
WO (1) WO2021136523A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102627620A (zh) * 2012-04-10 2012-08-08 江苏先声药物研究有限公司 一类苯并呋喃衍生物及其医药应用
CN103242273A (zh) * 2012-02-09 2013-08-14 中国科学院上海药物研究所 2-芳基苯并呋喃-7-甲酰胺类化合物、其制备方法及用途
WO2019152989A1 (en) * 2018-02-05 2019-08-08 Tesaro, Inc Pediatric niraparib formulations and pediatric treatment methods
CN110382545A (zh) * 2017-01-09 2019-10-25 泰萨罗公司 用抗pd-1抗体治疗癌症的方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI879716B (zh) * 2017-05-09 2025-04-11 美商提薩羅有限公司 治療癌症的組合療法
KR20200071097A (ko) 2017-10-13 2020-06-18 메르크 파텐트 게엠베하 Parp 억제제 및 pd-1 축 결합 길항제의 조합

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103242273A (zh) * 2012-02-09 2013-08-14 中国科学院上海药物研究所 2-芳基苯并呋喃-7-甲酰胺类化合物、其制备方法及用途
WO2013117120A1 (zh) 2012-02-09 2013-08-15 中国科学院上海药物研究所 2-芳基苯并呋喃-7-甲酰胺类化合物、其制备方法及用途
CN102627620A (zh) * 2012-04-10 2012-08-08 江苏先声药物研究有限公司 一类苯并呋喃衍生物及其医药应用
CN110382545A (zh) * 2017-01-09 2019-10-25 泰萨罗公司 用抗pd-1抗体治疗癌症的方法
WO2019152989A1 (en) * 2018-02-05 2019-08-08 Tesaro, Inc Pediatric niraparib formulations and pediatric treatment methods

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
BERGE ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
See also references of EP4085908A4
SHIPING JIAO, WEIYA XIA, HIROHITO YAMAGUCHI, YONGKUN WEI, MEI-KUANG CHEN, JUNG-MAO HSU, JENNIFER L. HSU, WEN-HSUAN YU, YI DU, HENG: "PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression", CLINICAL CANCER RESEARCH, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 23, no. 14, 15 July 2017 (2017-07-15), US, pages 3711 - 3720, XP055567673, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-16-3215 *

Also Published As

Publication number Publication date
JP2023509158A (ja) 2023-03-07
CN113116881A (zh) 2021-07-16
US20230094843A1 (en) 2023-03-30
EP4085908A4 (en) 2024-01-17
EP4085908A1 (en) 2022-11-09
CA3163564A1 (en) 2021-07-08
JP7805005B2 (ja) 2026-01-23
CN113116881B (zh) 2025-03-07

Similar Documents

Publication Publication Date Title
ES2904880T3 (es) Terapia combinada con inhibidores de Notch y de PD-1 o PD-L1
TWI869398B (zh) 治療癌症之方法
Nakhle et al. Mitochondria transfer from mesenchymal stem cells confers chemoresistance to glioblastoma stem cells through metabolic rewiring
AU2022241509B2 (en) Treatment of HER2 positive cancers
CN114224889B (zh) 西奥罗尼联合免疫检查点抑制剂在抗肿瘤治疗中的应用
JP2021121611A (ja) アピリモドを用いる癌の処置方法
TW201138764A (en) Anticancer combinations of artemisinin-based drugs and other chemotherapeutic agents
UA121392C2 (uk) Комбінація, яка містить глюкокортикоїд і edo-s101
TW201127384A (en) Therapeutic combination comprising a Cdc7 inhibitor and an antineoplastic agent
TW201100081A (en) Treatment of pancreatic cancer
WO2023138630A1 (zh) 治疗肿瘤的药物组合及用途
CN113116895B (zh) 用于治疗神经母细胞瘤的喹啉衍生物
CA3208122A1 (en) Methods of treatment with s1p receptor modulators
WO2021136523A1 (zh) 一种用于治疗肿瘤的药物组合及其应用
WO2025103341A1 (zh) 一种parp7抑制剂联合用药的药物组合及其治疗肿瘤的用途
WO2021143799A1 (zh) 抗pd-1抗体和呋喹替尼联合在制备治疗癌症的药物中的用途
TW202410898A (zh) Fak抑制劑及egfr-tki的藥物組合及用途
CN102327599A (zh) 用于治疗骨髓增生异常综合征的组合物和方法
TWI494113B (zh) 台灣綠蜂膠萃取物用於減緩患者病情發展之用途
TW201306833A (zh) 包含康布列塔司他汀（ｃｏｍｂｒｅｔａｓｔａｔｉｎｓ）族衍生物及西妥昔單抗（ｃｅｔｕｘｉｍａｂ）之組合
JP2023533060A (ja) リンパ系組織の悪性腫瘍
CN121943909A (zh) 西奥罗尼联合免疫检查点抑制剂在抗肿瘤治疗中的应用
CN101653608B (zh) 含有肝细胞生长因子受体抑制剂和组蛋白去乙酰化酶抑制剂的药物组合物及其应用
WO2024140295A1 (zh) 治疗肿瘤的药物组合及用途
WO2024175106A1 (zh) Pd-l1小分子抑制剂与抗体的药物组合及其应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20909191

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022540813

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3163564

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020909191

Country of ref document: EP

Effective date: 20220801