Pharmaceutical combinations and uses thereof for tumor treatment

Abstract

The present invention discloses a pharmaceutical combination and its use for treating tumors. The pharmaceutical combination of the present invention comprises a compound of Formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor and / or a PD-L1 inhibitor. When used in combination, the components of this pharmaceutical combination can significantly enhance the tumor growth inhibition rate of each individual drug, and no acute side effects were observed in mice after administration, demonstrating good safety and efficacy of this combined therapy. JPEG2023509158000012.jpg4172

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 201911417368.7, filed on December 31, 2019. This application cites the above Chinese patent application in its entirety.

[0002] Technical Field The present invention relates to pharmaceutical combinations and uses thereof in tumor treatment. [Background technology]

[0003] Precision tumor treatment is the inevitable mainstream and future direction of oncology drug development. Polyadenosine diphosphate ribonucleotide cleavage (PARP) has become a hot drug target in recent years, embodying the concept of precision tumor treatment. Its inhibitors inhibit PARP1 / 2, a key enzyme in the DNA base excision repair (BER) pathway, and exert a synergistic lethal effect on DNA homologous recombination deficiency (HRD), which includes BRCA1 / 2, PTEN, and EWS-FLI. Because HRD occurs exclusively in tumor cells, while HR function is intact in normal cells, PARP inhibitors are highly selective for HR pathway-deficient tumors. In 2014, the PARP inhibitor olaparib was simultaneously approved for commercial use in Europe and the United States for the treatment of advanced ovarian cancer, establishing for the first time in clinical trials the potential of PARP inhibitors as antitumor targets and their synergistic lethality. Currently, four PARP inhibitors are listed worldwide, and olaparib entered the Chinese market in 2018. There are currently no new drugs listed as original Chinese PARP inhibitors, and the few PARP inhibitors that are in the early clinical stage.

[0004] Mefuparib hydrochloride (its structural formula is [ka] It has a novel structure, and its parent 2-arylfuran nucleus is widely present in active natural products, making it one of the dominant structures in medicinal chemistry and offering promising prospects for new drugs. This PARP inhibitor has advantages such as good water solubility (>35 mg / ml, more than 350 times higher than olaparib), simple synthesis, simple formulation, good stability, excellent pharmacokinetic properties, high tissue distribution, and easy penetration of the blood-brain barrier. These characteristics provide an important basis for the treatment of various malignancies with mefparib.

[0005] Tumor immunotherapy activates the human immune system and strengthens anti-tumor immunity to suppress and kill tumor cells. Tumor immunotherapy is currently one of the most promising research directions in the field of tumor treatment. PD-1 (programmed death-1) is derived from apoptotic T cell hybridomas and is named the programmed death PD-1 receptor because of its association with apoptosis. PD-1 is an important immunosuppressive molecule and a member of the CD28 superfamily. PD-1 is primarily expressed on activated T cells and B cells. It is a surface receptor on activated T cells. PD-1 has two ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC). Tumors in the tumor microenvironment express high levels of PD-1 molecules on infiltrating T cells, and tumor cells express high levels of PD-1 ligands PD-L1 and PD-L2, causing persistent activation of PD-1 pathways within the tumor microenvironment. After PD-L1 binds to PD-1, T cell function is suppressed and the immune system is unable to signal to attack the tumor. PD-1 inhibitors, including PD-1 and PD-L1 antibodies, are a new class of drugs for tumor immunotherapy. Unlike surgery, radiation therapy, and targeted drugs, PD-1 inhibitors themselves cannot directly kill cancer cells, but rather work by activating the patient's own immune system.

[0006] Currently, five PD-1 inhibitors are available in China, the United States, Europe, and other countries, including dozens of other countries. These include two PD-1 antibodies and three PD-L1 antibodies: Opdivo (Nivolumab), Keytruda (Pembrolizumab), Tecentriq (Atezolizumab), Imfinzi (Durvalumab), and Bavencio (Avelumab). Opdivo and Keytruda are already listed in China. Three other PD-1 inhibitors from domestic pharmaceutical companies are listed: Junshi Biosciences' Toripalimab, Innoventbiogics' Sintilimab, and Hengrui Pharmaceuticals' Camrelizumab.

[0007] At the 2017 San Antonio Breast Cancer Society Conference, researchers presented important study results. The MEDIOLA phase II trial evaluated the combination of the PD-1 antibody imfinzi (durvalumab) with the PARP inhibitor olaparib (Lynparza) in patients with BRCA-mutated, HER2-amplified, late-stage breast cancer. Data showed an 80% disease control rate at 12 weeks, a 63% response rate at 28 weeks, a 9.2-month median 28-week DoR, and a 8.2-month median 28-week PFS. The response rate was 59.9% and median PFS was 7.0 months, significantly better than patients receiving conventional olaparib monotherapy. The most common level 3 adverse events associated with olaparib were anemia (12%) and neutrophil deficiency (6%); the most common level 3 adverse event associated with durvalumab was pancreatitis (6%).

[0008] At the 2018 American Society of Gynecologic Oncology (SGO) meeting, results from the TOPACIO study (combining the PARP inhibitor niraparib with the PD-1 inhibitor Keytruda) were reported, demonstrating the durability of the PARP inhibitor and PD-1 inhibitor combination in patients with platinum-resistant / refractory ovarian cancer and triple-negative breast cancer. In patients with secondary platinum-resistant or primary-resistant ovarian cancer or triple-negative breast cancer, the total ORR (including CR and PR) was 25%, and the DCR (CR + PR + SD) was 68%. In patients with primary platinum-resistant disease, the ORR was 24%. Patients' treatment response was independent of marker status. In patients with BRCA wild-type disease, the ORR was 26% (9 / 34). In patients with HRD-negative disease, the ORR was 29% (7 / 24). Data regarding the duration of treatment response are still immature; 60% (9 / 15) of responding patients remain on treatment, and more than half of patients whose disease improved received treatment for 6 months or more. Regarding adverse events, 32 were grade 3 or higher adverse events out of a total of 58 (55%). The most common grade 3 or higher adverse events were anemia (18%), thrombocytopenia (15%), and fatigue (4%). The majority of adverse events were caused by the PARP inhibitor, with 15% (8) of patients experiencing immune-related adverse events.

[0009] Overall, while the combination of PARP inhibitors and PD-1 antibodies for cancer treatment has demonstrated remarkable clinical efficacy, it also carries a significant risk of side effects, which current clinical data suggest are primarily caused by PARP. Therefore, the combination of PARP inhibitors and PD-1 antibodies has broad market potential for cancer treatment, and better clinical efficacy and fewer side effects are the inevitable trend in clinical development. Summary of the Invention [Means for solving the problem]

[0010] The present invention provides a pharmaceutical combination for tumor treatment and its use that is different from the prior art. By combining the components of the pharmaceutical combination of the present invention, the inhibitory rate of each drug on tumor growth can be significantly increased, and no acute side effects were observed in mice after administration, demonstrating the good safety and efficacy of this combination therapy.

[0011] 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 a "PD-1 inhibitor and / or a PD-L1 inhibitor."

[0012] [ka]

[0013] In one embodiment, the pharmaceutically acceptable salt of the compound of Formula A is mefuparib hydrochloride.

[0014] In some embodiments, the PD-1 inhibitor may be one or more of a PD-1 antibody, a PD-1 polypeptide, and a PD-1 small molecule inhibitor, and may further be one or more of toripalimab, sintilimab, camrelizumab, pembrolizumab, and nivolumab, or may further be toripalimab.

[0015] In some embodiments, the PD-L1 inhibitor may be one or more of a PD-1 antibody, a PD-1 polypeptide, and a PD-1 small molecule inhibitor, and may further be one or more of atezolizumab (trade name Tecentriq), durvalumab (trade name Imfinzi), and avelumab (trade name Bavencio).

[0016] In one embodiment, the "PD-1 inhibitor and / or PD-L1 inhibitor" and the compound of Formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof may be administered simultaneously or separately. The separate administration may be sequential.

[0017] The simultaneous administration may be the simultaneous administration of "the PD-1 inhibitor and / or PD-L1 inhibitor" and "the compound of Formula A, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof" as contained in a single drug combination, or the simultaneous administration of a single pharmaceutical composition containing "the PD-1 inhibitor and / or PD-L1 inhibitor" and a single pharmaceutical composition containing "the compound of Formula A, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof."

[0018] The separate administration may refer to the separate administration of a single pharmaceutical composition comprising "the PD-1 inhibitor and / or PD-L1 inhibitor" and a single pharmaceutical composition comprising "the compound of Formula A, a pharmaceutically acceptable salt, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" at different times. The separate administration may be close in time or separate in time.

[0019] The sequential administration may involve administering one of a single pharmaceutical composition containing "the PD-1 inhibitor and / or PD-L1 inhibitor" and a single pharmaceutical composition containing "the compound of Formula A, a pharmaceutically acceptable salt, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" first and then administering the other. The separate administrations may be close in time or separate in time.

[0020] Whether administered simultaneously or separately, the administration methods (including administration route, dosage, and administration interval) of the "PD-1 inhibitor and / or PD-L1 inhibitor" and the "compound of Formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" may be the same or different, and can be adjusted as necessary by those skilled in the art to obtain an optimal therapeutic effect.

[0021] In one embodiment, the pharmaceutical combination is mefparib hydrochloride and triplimab.

[0022] The present invention further comprises: A compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; the "PD-1 inhibitor and / or PD-L1 inhibitor"; and medicinal adjuvants; The present invention provides a pharmaceutical composition X comprising:

[0023] The pharmaceutical composition can be prepared into various suitable dosage forms depending on the administration method, including gastrointestinal dosage forms (e.g., oral agents (tablets, pills, capsules, powders, granules)), gas dosage forms (inhalants), and non-gastrointestinal dosage forms (e.g., injection forms, ointments, emulsions).

[0024] In one embodiment, the pharmaceutical composition X is in the form of an injection or oral dosage form, which may be a tablet.

[0025] The present invention further provides pharmaceutical composition Y, which comprises pharmaceutical composition I and pharmaceutical composition II.

[0026] The pharmaceutical composition I comprises a compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant.

[0027] The pharmaceutical composition II comprises the "PD-1 inhibitor and / or PD-L1 inhibitor" and an adjuvant.

[0028] In one embodiment, said pharmaceutical composition I is in an oral dosage form, further in a tablet dosage form.

[0029] In one embodiment, said pharmaceutical composition II is in an injectable form.

[0030] In one embodiment, said Drug Formulation I is in tablet dosage form and said Drug Formulation II is in injectable dosage form.

[0031] The present invention further comprises: a first container containing said pharmaceutical composition I; a second container containing said pharmaceutical composition II; A drug kit comprising:

[0032] The present invention further provides the use of substance M for use in the preparation of a medicament for the prevention and / or treatment of tumors, wherein said substance M is said pharmaceutical combination, said pharmaceutical composition X, or said medicinal composition Y.

[0033] The type of tumor may be a solid tumor and / or a hematological tumor, and the solid tumor may be one or more of 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, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma.

[0034] In the above-mentioned use, the administration methods (including administration route, dosage, and administration interval) of the compound represented by Formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and the "PD-1 inhibitor and / or PD-L1 inhibitor" may be the same or different. Those skilled in the art can adjust these as necessary to achieve the optimal therapeutic effect.

[0035] The dosage of the "compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" and the "PD-1 inhibitor and / or PD-L1 inhibitor" may be administered based on the body weight of a subject.

[0036] In one embodiment, the "compound of Formula A, a pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof" and the "PD-1 inhibitor and / or PD-L1 inhibitor" may be administered simultaneously or separately.

[0037] In one embodiment, the dosage of the "compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" is 100 to 1000 mg / dose.

[0038] In one embodiment, the administration frequency of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is 0.5 to 2 times per day.

[0039] In one embodiment, the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is administered orally.

[0040] In one embodiment, the dose of the "PD-1 inhibitor and / or PD-L1 inhibitor" is 50 to 500 mg per administration.

[0041] In one embodiment, the "PD-1 inhibitor and / or PD-L1 inhibitor" is administered once every 7 to 31 days.

[0042] In one embodiment, the "PD-1 inhibitor and / or PD-L1 inhibitor" is administered orally or by injection.

[0043] In one embodiment, the oral administration dose of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is 100 to 1000 mg / kg, and the administration frequency is 0.5 to 2 times per day.

[0044] In addition, in the injection administration of the "PD-1 inhibitor and / or PD-L1 inhibitor," the dosage is 50 to 500 mg / kg, and the administration frequency is once every 7 to 31 days.

[0045] The present invention further provides use of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a tumor, wherein the "compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" is used in combination with the "PD-1 inhibitor and / or PD-L1 inhibitor."

[0046] [ka]

[0047] Here, the "compound represented by Formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" and the "PD-1 inhibitor and / or PD-L1 inhibitor" may be administered simultaneously or separately, or may be administered separately. The aforementioned separate administration may also be sequential administration.

[0048] Here, the compound represented by the formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof may be administered orally.

[0049] Here, the dose of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof may be 100 to 1000 mg / kg.

[0050] Here, the administration frequency of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof may be 0.5 to 2 times per day.

[0051] Here, the "PD-1 inhibitor and / or PD-L1 inhibitor" may be administered orally or by injection.

[0052] Here, the dose of the "PD-1 inhibitor and / or PD-L1 inhibitor" may be 50 to 500 mg / dose.

[0053] Here, the administration frequency of the "PD-1 inhibitor and / or PD-L1 inhibitor" may be once every 7 to 31 days.

[0054] The tumor may be one or more of a solid tumor and / or a blood tumor, including 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, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma.

[0055] In one embodiment, in oral administration of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, the dosage is 100 to 1000 mg / time, and the administration frequency is 0.5 to 2 times / day.

[0056] In addition, when the "PD-1 inhibitor and / or PD-L1 inhibitor" is administered by injection, the dosage is 50 to 500 mg per injection, and the administration frequency is once every 7 to 31 days.

[0057] The present invention further provides use of the "PD-1 inhibitor and / or PD-L1 inhibitor" in the manufacture of a medicament for treating a tumor, wherein the "PD-1 inhibitor and / or PD-L1 inhibitor" is used in combination with the "compound represented by Formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof."

[0058] [ka]

[0059] Here, the "compound represented by Formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" and the "PD-1 inhibitor and / or PD-L1 inhibitor" may be administered simultaneously or separately, or may be administered separately. The separate administration may be sequential administration.

[0060] Here, the "PD-1 inhibitor and / or PD-L1 inhibitor" may be administered orally or by injection.

[0061] Here, the dose of the "PD-1 inhibitor and / or PD-L1 inhibitor" may be 50 to 500 mg / dose.

[0062] Here, the administration frequency of the "PD-1 inhibitor and / or PD-L1 inhibitor" may be once every 7 to 31 days.

[0063] Here, the compound represented by the formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof can be administered orally.

[0064] Here, the dose of the compound represented by formula A may be 100 to 1000 mg / dose.

[0065] Here, the administration frequency of the compound represented by formula A may be 0.5 to 2 times per day.

[0066] The tumor may be one or more of a solid tumor and / or a blood tumor, including 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, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma.

[0067] In one embodiment, the compound represented by formula A is orally administered at a dosage of 100 to 1000 mg / time, and at an administration frequency of 0.5 to 2 times / day.

[0068] In addition, when the "PD-1 inhibitor and / or PD-L1 inhibitor" is administered by injection, the dosage is 50 to 500 mg per injection, and the administration frequency is once every 7 to 31 days.

[0069] The present invention further provides a method for treating or preventing tumors, comprising the step of administering to a subject an effective amount of substance M, wherein said substance M is said pharmaceutical combination, said pharmaceutical composition X or said pharmaceutical composition Y.

[0070] In the method, the tumor may be a solid tumor and / or a hematological tumor, and the solid tumor may be one or more of 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, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma.

[0071] In the above-mentioned method, the administration methods (including the administration route, dosage, administration frequency, etc.) of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and the "PD-1 inhibitor and / or PD-L1 inhibitor" are all as described above.

[0072] The term "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. PD-1, collectively known as programmed cell death protein 1, is an important immunosuppressive molecule.

[0073] The term "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.

[0074] The term "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.

[0075] The term "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 for PD-L1 is programmed cell death protein 1 ligand 1.

[0076] The term "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.

[0077] The term "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. A "small molecule compound" refers to a compound with a molecular weight of less than 1000.

[0078] The term "pharmaceutically acceptable salt" refers to a salt of a compound prepared with a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. The term "pharmaceutically acceptable salt" includes, but is not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, and diethanolamine salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, phosphorous acid, sulfuric acid, and hydrogen sulfate. The pharmaceutically acceptable organic acids include, but are not limited to, acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, antibutenedioic acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthalenecarboxylic acid)), amino acids (e.g., glutamic acid, arginine), and the like. When a compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.Specifically, reference can be made to Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camile G. Wermuth, ed., Wiley-VCH, 2002).

[0079] The term "solvate" refers to a substance formed by crystallization of a compound with a solvent (including, but not limited to, water, methanol, ethanol, etc.) Solvates are divided into stoichiometric and non-stoichiometric solvates.

[0080] The term "solvate of a pharmaceutically acceptable salt" refers to a substance formed when a compound is combined with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, a solvent (including, but not limited to, water, methanol, ethanol, etc.), where the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent may be stoichiometric or non-stoichiometric. Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.

[0081] The term "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 varies depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by a person skilled in the art according to the situation.

[0082] The above preferred conditions can be arbitrarily combined without violating common knowledge in this field, that is, preferred embodiments of the present invention can be obtained.

[0083] All reagents and materials used in the present invention are commercially available. [Effects of the Invention]

[0084] The positive effect of the present invention is that the tumor growth inhibition rate of the pharmaceutical composition of the present invention can reach 60%, and no acute side effects were observed in the subjects during the trial. [Brief explanation of the drawings]

[0085] [Figure 1] This is the rate of change in body weight of the experimental animals after the start of treatment. [Figure 2] 1 shows tumor growth curves in experimental animals after the start of treatment. [Figure 3] This shows the tumor volume of individual experimental animals after administration (PG-D24), where "-" indicates the median value. [Figure 4] hCD 45 FACS detection in peripheral blood of experimental animals 3 weeks after PBMC inoculation, where "-" indicates the median value. DETAILED DESCRIPTION OF THE INVENTION

[0086] The present invention will be further described below in the form of examples, but the present invention is not limited to the scope of the above examples. Experimental methods for which specific conditions are not described in the following examples are selected according to conventional methods and conditions or product instructions.

[0087] 1. Test reagents Test substance 1: Takuei (toriparimab PD-1 monoclonal antibody) injection. Test sample 2: Mefparib hydrochloride.

[0088] 2. Preparation of test samples 2.1. Solvent selection: Tuoyi PD-1 monoclonal antibody injection solution: PBS; mefpiperidine hydrochloride: normal saline. 2.2, Preparation method: [Table 1]

[0089] 3. Experimental materials and equipment [Table 2]

[0090] [Table 3]

[0091] 4. Laboratory animals and breeding management 4.1 Experimental animals Species and Attributes Section: Mus Musculus, NCG (NOD-Prkdc em26Cd52 Il2rg em26Cd22 / Nju); Gender: Female; Weight: 18-22g; Quantity: 55; Experimental Animal Provider: Jiangsu Jisu Yaokang Bioscience and Technology Co., Ltd.

[0092] 4.2. Breeding management Breeding management: Experimental animals were kept in an SPF-level temperature and humidity balanced laminar flow clean room, using independent ventilation cages (IVC), with one cage for every five animals. Temperature / humidity: Control within the range of (23±3)℃ / 40~70%. Cages were made of polycarbonate and measured 370mm x 155mm x 135mm. The soft corncob autoclaved cleaning mat was replaced twice a week. Each cage had a cage tag indicating the number of animals, sex, caretaker, reception time, group, and start time of the experiment. Feed and drinking water: SPF-grade mouse feed, sterilized by cobalt-60 irradiation. Drinking water was purified by ultrafiltration and sterilized by high pressure. Animals were allowed free access to sterile food and water. Animal number: Pierced ears.

[0093] 5. Experimental method 5.1, Cell culture MDA-MB-436 tumor cells (YK-CL-075) were purchased from ATCC. They were cultured in Leibovitz's L-15 medium containing 10% inactivated fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin in a 5% CO2 incubator at 37°C. Cells were passaged every 3–4 days after cell growth. Tumor cells in the logarithmic growth phase were used for inoculation of in vivo tumors. PBMC (human peripheral blood mononuclear cells): Derived from ALLCELLS (Donor #: A 0075).

[0094] 5.2 Tumor cell inoculation and grouping MDA-MB-436 tumor cells were resuspended in PBS and Matrigel at a volume ratio of 1:1 at a concentration of 1 × 10 8 The tumor volume was approximately 1000 mm. 3 When the tumors reached a size of 93 mm, they were removed under sterile conditions and cut into small pieces, each measuring approximately 2 mm x 2 mm x 2 mm, and inoculated subcutaneously into the right rib cage of the experimental animals. After two weeks, PBMC cells were resuspended in PBS and inoculated into the mice at a cell inoculation dose of 2 x 106 cells / mouse. The tumors in the experimental animals were 93 mm 3 When the mice grew to about 100 mg / kg, they were divided into groups and administered the drug (the day was recorded as PG-D0). There were a total of 4 groups, each with 10 mice. The specific administration methods are shown in Table 4.

[0095] 5.3 Measurement of mouse body weight and experimental parameters Tumor volume was measured twice a week using a vernier caliper. The long and short diameters of the tumor were measured, and the volume was calculated using the formula: volume = 0.5 × long diameter × short diameter. 2 is.

[0096] The T / C value was calculated from the tumor volume, where T is the mean relative tumor volume (RTV) for each subject treatment group, and C is the mean relative tumor volume (RTV) for the control group. RTV is the ratio of tumor volume after administration to tumor volume before administration. Tumor growth inhibition rate (TGI, %) = (1 - T / C) × 100%.

[0097] Three weeks after PBMC inoculation, peripheral blood was collected from the mice and analyzed for human CD45 + The percentage of cells (hCD45 cells) was measured by flow cytometry (FACS).

[0098] After the experiment was completed, the tumors were removed, weighed, arranged neatly, and photographed.

[0099] 6. Dosage form [Table 4]

[0100] 7, Statistical analysis Using IBM SPSS Statistics 22.0 statistical software, intergroup statistical analysis was performed using mixed linear model analysis for tumor volume and one-way ANOVA analysis for tumor weight, with p<0.05 considered to be significant.

[0101] Example 1 Test Results 1. Reactions and weight changes after administration to experimental animals During the experimental period, no obvious acute side effects were observed in the mice of each group after administration. During the middle and later stages of the experiment, the mice in each group lost weight (see Figure 1). The above experiment confirmed that the combination of mefparib hydrochloride and Tuoyi PD-1 monoclonal antibody injection was safe.

[0102] 2. Tumor growth inhibition results The changes in tumor volume in the experimental animals after treatment are shown in Table 5, Figures 2 and 3. [Table 5]

[0103] Conclusions: At 24 days post-grouping (PG-D24), the tumor growth inhibition rates were 54%, 29%, and 60%, respectively, in the mefparib hydrochloride group, the Tuoyi PD-1 monoclonal antibody injection group, and the mefparib hydrochloride + Tuoyi PD-1 monoclonal antibody injection group. The tumor volumes in each treatment group were significantly smaller than those in the control group (p<0.05). The tumor volumes in the mefparib hydrochloride + Tuoyi PD-1 monoclonal antibody injection group were significantly smaller than those in the Tuoyi PD-1 monoclonal antibody injection group (p<0.05). This indicates that the combination therapy provides significantly better therapeutic efficacy than PD-1 monotherapy and a better therapeutic trend than mefparib hydrochloride.

[0104] 3. Peripheral blood FACS test Three weeks after PBMC inoculation, FACS detection of hCD45 in mouse peripheral blood was performed (see Figure 4).

[0105] Figure 4 shows that the FACS test results for hCD45 cells in mouse peripheral blood were positive, indicating successful modeling of the humanized immune reconstitution model. The median number of hCD45 cells was higher in the mefparib hydrochloride group, the Tuoyi PD-1 monoclonal antibody injection group, and the mefparib hydrochloride + Tuoyi PD-1 monoclonal antibody injection group than in the control group. The median number in the mefparib hydrochloride + Tuoyi PD-1 monoclonal antibody injection group was higher than that in the mefparib hydrochloride group and the Tuoyi PD-1 monoclonal antibody injection group.

[0106] In conclusion, in the PBMC-humanized MDA-MB-436 subcutaneous tumor model, the combined administration of Tuoyi PD-1 monoclonal antibody injection and mefparib hydrochloride produced a statistically significant antitumor effect, effectively inhibiting tumor growth. The tumor inhibition rate was significantly higher than that of Tuoyi PD-1 monoclonal antibody injection, and the proportion of hCD45 cells in the peripheral blood of mice was correspondingly higher.

[0107] Although specific embodiments of the present invention have been described above, it should be understood by those skilled in the art that these are merely examples and that various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is limited by the appended claims. (Addendum) The present disclosure includes the following aspects. Item 1: A pharmaceutical combination comprising a compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate including a pharmaceutically acceptable salt thereof, and a "PD-1 inhibitor and / or PD-L1 inhibitor." [ka] Item 2: The pharmaceutically acceptable salt of the compound of formula A is mefparib hydrochloride, and / or the PD-1 inhibitor is one or more of a PD-1 antibody, a PD-1 polypeptide, and a PD-1 small molecule inhibitor, and may further be one or more of toripalimab, sintilimab, camrelizumab, pembrolizumab, and nivolumab, and may further be toripalimab or may further be Takumi; and / or the PD-L1 inhibitor is one or more of a PD-L1 antibody, a PD-L1 polypeptide, and a PD-L1 small molecule inhibitor, and may further be one or more of atezolizumab, durvalumab, and avelumab; and / or administering the "PD-1 inhibitor and / or PD-L1 inhibitor" and the "compound of formula A, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof" simultaneously, separately, or sequentially; and / or the "PD-1 inhibitor and / or PD-L1 inhibitor" is administered orally or by injection; and / or the pharmaceutical combination according to item 1, wherein the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is administered orally. Item 3: 2. The pharmaceutical combination according to item 1, wherein the pharmaceutical combination is mefparib hydrochloride and toripalimab. Item 4: A compound represented by formula A according to any one of items 1 to 3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; The "PD-1 inhibitor and / or PD-L1 inhibitor" according to any one of items 1 to 3; and medicinal adjuvants; Pharmaceutical composition X comprising: Item 5: 5. Pharmaceutical composition X according to item 4, characterized in that the pharmaceutical composition X is in an injection dosage form or an oral dosage form. Item 6: Pharmaceutical composition Y, comprising pharmaceutical composition I and pharmaceutical composition II, The pharmaceutical composition I comprises a compound represented by formula A according to any one of items 1 to 3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant; The pharmaceutical composition II comprises a "PD-1 inhibitor and and / or PD-L1 inhibitors," and pharmaceutical adjuvants, Pharmaceutical composition Y characterized by: Item 7: The pharmaceutical composition I is in oral dosage form, and further in tablet dosage form; And / or the pharmaceutical composition II is in the form of an injection dosage form; Item 7. Pharmaceutical composition Y according to item 6, characterized in that Item 8: a first container containing the pharmaceutical composition I according to item 6 or 7; and a second container containing the pharmaceutical composition II according to item 6 or 7; 12. A pharmaceutical kit comprising: Item 9: 1. Use of a substance M in the manufacture of a medicament for preventing and / or treating a tumor, comprising The substance M is the pharmaceutical combination according to any one of items 1 to 3, the pharmaceutical composition X according to item 4 or 5, or the pharmaceutical composition Y according to item 6 or 7. Item 10: The tumor is a solid tumor and / or a blood tumor, specifically one or more of 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, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma; and / or the "compound of formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" and the "PD-1 inhibitor and / or PD-L1 inhibitor" are administered simultaneously or separately, or sequentially; and / or the dose of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is 100 to 1000 mg / dose; and / or the administration frequency of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is 0.5 to 2 times per day; and / or the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is orally administered; and / or the dose of the "PD-1 inhibitor and / or PD-L1 inhibitor" is 50 to 500 mg / dose; and / or the administration frequency of the "PD-1 inhibitor and / or PD-L1 inhibitor" is once every 7 to 31 days; and / or the "PD-1 inhibitor and / or PD-L1 inhibitor" is administered orally or by injection; 10. The use according to item 9, characterized in that Item 11: The compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is orally administered in an amount of 100 to 1000 mg / dose, and the administration frequency is 0.5 to 2 times / day; Item 11. The use according to Item 10, wherein the "PD-1 inhibitor and / or PD-L1 inhibitor" is administered by injection at a dose of 50 to 500 mg once every 7 to 31 days. Item 12: Use of the "compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" according to any one of items 1 to 3 in the preparation of a medicament for treating a tumor, The "compound represented by formula A or a pharmaceutically acceptable salt thereof" is used in combination with the "PD-1 inhibitor and / or PD-L1 inhibitor" described in any one of items 1 to 3, Preferably, the tumor is a solid tumor and / or a blood tumor, in particular lung cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, one or more of bone cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma; 10. The use characterized by: Item 13: Use of the "PD-1 inhibitor and / or PD-L1 inhibitor" according to any one of items 1 to 3 in the preparation of a medicament for treating a tumor, The "PD-1 inhibitor and / or PD-L1 inhibitor" is used in combination with the "compound of Formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" described in any one of Items 1 to 3; Preferably, the tumor is a solid tumor and / or a hematological tumor, in particular one or more of 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, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma and multiple myeloma; 10. The use characterized by: Item 14: administering to the subject an effective amount of substance M; the substance M is the pharmaceutical combination according to any one of items 1 to 3, the pharmaceutical composition X according to item 4 or 5, or the pharmaceutical composition Y according to item 6 or 7; Preferably, the administration route, dosage and frequency of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and the "PD-1 inhibitor and / or PD-L1 inhibitor" are as described in item 10 or 11. A method for treating or preventing tumors.

Claims

1. A compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; a PD-1 inhibitor, toripalimab; 10. A pharmaceutical combination comprising: 【Chemistry 1】

2. The pharmaceutically acceptable salt of the compound of formula A is mefparib hydrochloride, Or, the PD-1 inhibitor is toripalimab injection; Alternatively, the PD-1 inhibitor and the "compound of formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" are administered simultaneously or separately, Alternatively, the PD-1 inhibitor is administered orally or by injection; Alternatively, the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is administered orally. The pharmaceutical combination according to claim 1 .

3. 2. The pharmaceutical combination of claim 1, wherein the pharmaceutical combination is mefparib hydrochloride and toripalimab.

4. A compound of formula A according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; The PD-1 inhibitor of claim 1; and medicinal adjuvants; Pharmaceutical composition X comprising:

5. The pharmaceutical composition X according to claim 4, wherein the pharmaceutical composition X is in an injection or oral dosage form.

6. Pharmaceutical composition Y, comprising pharmaceutical composition I and pharmaceutical composition II, The pharmaceutical composition I comprises a compound represented by formula A according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant; The pharmaceutical composition II comprises the PD-1 inhibitor of claim 1 and a pharmaceutical adjuvant; Pharmaceutical composition Y characterized by the following:

7. The pharmaceutical composition I is in an oral dosage form, And / or the pharmaceutical composition II is in the form of an injection dosage form; Pharmaceutical composition Y according to claim 6.

8. a first container containing the pharmaceutical composition of claim 6 or 7; and a second container containing the Phase II pharmaceutical composition of claim 6 or 7; 12. A pharmaceutical kit comprising:

9. 1. Use of a substance M in the manufacture of a medicament for preventing and / or treating a tumor, comprising: The use, wherein the substance M is a pharmaceutical combination according to claim 1, a pharmaceutical composition X according to claim 4, or a pharmaceutical composition Y according to claim 6.

10. the tumor is one or more of 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, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma, and multiple myeloma; Alternatively, the "compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" and the PD-1 inhibitor are administered simultaneously or separately, or the dose of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is 100 to 1000 mg / dose; or the administration frequency of the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is 0.5 to 2 times per day; Alternatively, the compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is orally administered, Or, the dose of the PD-1 inhibitor is 50 to 500 mg / dose, or the administration frequency of the PD-1 inhibitor is once every 7 to 31 days; Alternatively, the PD-1 inhibitor is administered orally or by injection.

10. The use according to claim 9.

11. The compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is orally administered at a dose of 100 to 1000 mg / time, and at a frequency of 0.5 to 2 times / day; and the dose of the PD-1 inhibitor administered by injection is 50 to 500 mg / injection, and is administered once every 7 to 31 days.

11. Use according to claim 10.

12. Use of the "compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" according to claim 1 in the preparation of a medicament for treating a tumor, The use of the "compound represented by formula A or a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" in combination with the PD-1 inhibitor according to claim 1.

13. The use according to claim 12, characterized in that the tumor is one or more of lung cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, gastric cancer, skin cancer, bone cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma and multiple myeloma.

14. 10. Use of the PD-1 inhibitor of claim 1 in the preparation of a medicament for treating a tumor, comprising: The PD-1 inhibitor is used in combination with the "compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof" according to claim 1.

10. The use characterized by:

15. The use according to claim 14, characterized in that the tumor is one or more of lung cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, gastric cancer, skin cancer, bone cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck cancer, leukemia, lymphoma, myeloma and multiple myeloma.

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