Pharmaceutical composition containing PD-L1 small-molecule inhibitor and application thereof

Abstract

The invention discloses a pharmaceutical composition containing a PD-L1 small-molecule inhibitor and application of the pharmaceutical composition. The medicine composition comprises a PD-L1 small-molecule inhibitor and chemotherapy medicine molecules, or the PD-L1 small-molecule inhibitor and a COX-2 inhibitor. The medicine composition can be used for treating tumors.

Description

[0001] This application claims the priority of Chinese patent application No. 202310785638X filed on June 29, 2023 and Chinese patent application No. 2023117625926 filed on December 20, 2023. This application cites the full text of the above Chinese patent application. Technical Field

[0002] The present invention relates to a drug combination containing a PD-L1 small molecule inhibitor and application thereof. Background Art

[0003] Malignant tumors are major diseases that endanger people's lives and health. With the rapid development of tumor biology and related disciplines in recent years, specific anti-tumor drugs and immunotherapy anti-tumor drugs targeting abnormal signaling system targets in tumor cells have become the focus of new drug research and development. At the same time, the combination of multiple anti-tumor drugs for the treatment of tumor diseases is also a hot topic in scientific research.

[0004] Programmed cell death-1 (PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells and macrophages. It functions as an intrinsic negative feedback system, thereby preventing T cell activation, which in turn reduces autoimmunity and promotes self-tolerance. In addition, PD-1 is also known to play an important role in suppressing antigen-specific T cell responses in diseases such as cancer and viral infections.

[0005] The structure of PD-1 consists of an extracellular immunoglobulin variable region-like domain followed by a transmembrane region and an intracellular domain. The intracellular domain contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switching motif, indicating that PD-1 negatively regulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1 and PD-L2, and they differ in their expression patterns. PD-L1 protein is upregulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells after T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on almost all tumor cells, and this expression is further increased after IFN-γ treatment. A large number of studies have confirmed that PD-L1 on the surface of tumor cells in the tumor microenvironment is increased, and at the same time it binds to PD-1 on activated T cells, transmitting negative regulatory signals, leading to apoptosis or immune anergy of tumor antigen-specific T cells, thereby inhibiting the immune response and promoting the escape of tumor cells.

[0006] Although there are no PD-L1 small molecule inhibitors on the market yet, some PD-L1 small molecule inhibitors are already in the clinical research stage. Among them, WO2019128918A1 discloses the structure and preparation method of a PD-L1 small molecule inhibitor. In vitro studies and pharmacokinetic studies have shown that it has good tumor inhibitory activity. Its specific structure is shown in Formula I;

[0007] Summary of the invention

[0008] The technical problem to be solved by the present invention is to overcome the limited types of anti-tumor drugs in the prior art and provide a drug combination containing a PD-L1 small molecule inhibitor and its application. Compared with the use of a PD-L1 small molecule inhibitor or other small molecule drugs (such as a targeted small molecule inhibitor or a chemotherapeutic drug molecule) alone, the drug combination of the present invention has a synergistic effect and further has a better effect in treating cancer and prolonging survival.

[0009] The present invention provides a drug combination A, which includes a PD-L1 small molecule inhibitor and a chemotherapy drug molecule.

[0010] In some embodiments, the drug combination A has a synergistic effect.

[0011] In the drug combination A, the PD-L1 small molecule inhibitor is preferably a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0012]

[0013] In the drug combination A, the chemotherapy drug molecule is preferably one or more of capecitabine, paclitaxel, oxaliplatin and temozolomide, preferably capecitabine or paclitaxel.

[0014] In some embodiments, the chemotherapeutic drug molecule is temozolomide.

[0015] In the drug combination A, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule may be (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1.

[0016] In some embodiments, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is 6:1, 9.5:1 or 16:1.

[0017] In some embodiments, the pharmaceutical combination A comprises the compound as shown in Formula I as described above and capecitabine. The mass ratio of the compound as shown in Formula I to the capecitabine is preferably (0.2-2):1, such as 0.45:1, 0.58:1 or 1.2:1.

[0018] In some embodiments, the drug combination A comprises the compound as shown in Formula I described above and paclitaxel. The mass ratio of the compound as shown in Formula I to the paclitaxel is preferably (6-16):1, such as 10:1 or 11:1.

[0019] In some embodiments, the pharmaceutical combination A comprises the compound as shown in Formula I and temozolomide. The mass ratio of the compound as shown in Formula I to the temozolomide is preferably (6-16):1, such as 6:1, 9.5:1 or 16:1.

[0020] The active ingredients of the drug combination A are preferably the PD-L1 small molecule inhibitors as described above and the chemotherapeutic drug molecules as described above.

[0021] In some embodiments, the active ingredients of the pharmaceutical combination A are the compound shown as formula I as described above and capecitabine.

[0022] In some embodiments, the active ingredients of the drug combination A are the compound shown as formula I as described above and paclitaxel.

[0023] In some embodiments, the active ingredients of the pharmaceutical combination A are the compound shown as formula I as described above and temozolomide.

[0024] In the drug combination A, the PD-L1 small molecule inhibitor is preferably administered via the gastrointestinal tract (e.g., orally, sublingually, or rectally), injected (e.g., subcutaneously, intradermally, intravenously, intraperitoneally, or intramuscularly), administered to the respiratory tract, or topically (e.g., to the mucosa or skin), more preferably administered via the gastrointestinal tract, such as orally.

[0025] In the drug combination A, the chemotherapy drug molecules are preferably administered via the gastrointestinal tract (e.g., orally, sublingually, or rectally), injected (e.g., subcutaneously, intradermally, intravenously, intraperitoneally, or intramuscularly), administered to the respiratory tract, or topically (e.g., to the mucosa or skin), preferably administered via the gastrointestinal tract or injected, such as orally or intravenously.

[0026] In the drug combination A, the PD-L1 small molecule inhibitor is preferably administered orally; and the chemotherapy drug is preferably administered orally.

[0027] In the drug combination A, the PD-L1 small molecule inhibitor is preferably administered orally; and the chemotherapy drug molecule is preferably administered by intravenous injection.

[0028] The present invention provides a pharmaceutical composition B, which includes a PD-L1 small molecule inhibitor, a chemotherapy drug molecule and a pharmaceutical excipient.

[0029] In some embodiments, the pharmaceutical composition B has a synergistic effect.

[0030] In the pharmaceutical composition B, the types of the PD-L1 small molecule inhibitor and the chemotherapy drug molecules are preferably as described above.

[0031] In the pharmaceutical composition B, the content of the PD-L1 small molecule inhibitor is preferably 30-500 mg, more preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg.

[0032] In the pharmaceutical composition B, the content of the chemotherapy drug molecule is preferably 10-650 mg, more preferably 30-550 mg, such as 30 mg, 60 mg, 100 mg, 150 mg or 500 mg.

[0033] In some embodiments, the content of the chemotherapeutic drug molecule is 20 mg.

[0034] In the pharmaceutical composition B, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule may be (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1.

[0035] In some embodiments, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is 6:1, 9.5:1 or 16:1.

[0036] In some embodiments, the active ingredients of the pharmaceutical composition B are the PD-L1 small molecule inhibitor as described above and the chemotherapy drug molecules as described above, preferably the compound as shown in formula I and capecitabine, or the compound as shown in formula I and paclitaxel.

[0037] In some embodiments, the active ingredients of the pharmaceutical composition B are the compound as shown in Formula I and temozolomide.

[0038] In some embodiments, when the pharmaceutical composition B includes the compound as shown in formula I, capecitabine and pharmaceutical excipients, the mass ratio of the compound as shown in formula I to the capecitabine is preferably (0.2-2):1, for example 0.45:1, 0.58:1 or 1.2:1.

[0039] In some embodiments, when the pharmaceutical composition B comprises the compound of formula I, paclitaxel and pharmaceutical excipients, the mass ratio of the compound of formula I to paclitaxel is preferably (6-16):1, such as 10:1 or 11:1.

[0040] In some embodiments, when the pharmaceutical composition B comprises the compound as shown in formula I, temozolomide and pharmaceutical excipients, the mass ratio of the compound as shown in formula I to the temozolomide is preferably (6-16):1, for example 6:1, 9.5:1 or 16:1.

[0041] The pharmaceutical composition B is preferably composed of the PD-L1 small molecule inhibitor, the chemotherapy drug molecule and pharmaceutical excipients.

[0042] The pharmaceutical composition B may be a separate pharmaceutical composition.

[0043] The pharmaceutical composition B can be prepared into various suitable dosage forms according to different administration methods, including gastrointestinal dosage forms (such as oral dosage forms) and parenteral dosage forms (such as injection dosage forms, respiratory tract dosage forms, mucosal dosage forms or cavity dosage forms), preferably capsules, tablets, pills, granules, powders or oral liquids.

[0044] The pharmaceutical composition B is preferably in the form of an oral dosage form or an injection dosage form.

[0045] The present invention provides a pharmaceutical composition C, comprising:

[0046] A first pharmaceutical composition C-1, which includes a PD-L1 small molecule inhibitor and a pharmaceutical excipient; and,

[0047] The second pharmaceutical composition C-2 comprises a chemotherapeutic drug molecule and a pharmaceutical excipient.

[0048] In some embodiments, the pharmaceutical composition C has a synergistic effect.

[0049] The first pharmaceutical composition C-1 may be a separate pharmaceutical composition; the second pharmaceutical composition C-2 may be a separate pharmaceutical composition.

[0050] In the pharmaceutical composition C, the PD-L1 small molecule inhibitor and the chemotherapy drug molecule are as described above.

[0051] In the pharmaceutical composition C, the content of the PD-L1 small molecule inhibitor is preferably 30-500 mg, more preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg.

[0052] In the pharmaceutical composition C, the content of the chemotherapy drug molecule is preferably 10-650 mg, more preferably 30-550 mg, such as 30 mg, 60 mg, 100 mg, 150 mg or 500 mg.

[0053] In some embodiments, the content of the chemotherapy drug molecule in the pharmaceutical composition C is 20 mg.

[0054] In the pharmaceutical composition C, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule is (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1.

[0055] In some embodiments, in the pharmaceutical composition C, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapy drug molecule is 6:1, 9.5:1 or 16:1.

[0056] In some embodiments, the pharmaceutical composition C consists of a first pharmaceutical composition C-1 and a second pharmaceutical composition C-2; the first pharmaceutical composition C-1 consists of the PD-L1 small molecule inhibitor as described above and pharmaceutical excipients, preferably consists of the compound shown in Formula I as described above and pharmaceutical excipients; the second pharmaceutical composition C-2 consists of the chemotherapy drug molecules as described above and pharmaceutical excipients, preferably consists of capecitabine or paclitaxel, and pharmaceutical excipients.

[0057] In some embodiments, the pharmaceutical composition C consists of a first pharmaceutical composition C-1 and a second pharmaceutical composition C-2; the first pharmaceutical composition C-1 consists of a compound as shown in Formula I as described above and pharmaceutical excipients; and the second pharmaceutical composition C-2 consists of temozolomide and pharmaceutical excipients.

[0058] In some embodiments, when the first pharmaceutical composition C-1 includes the compound as shown in Formula I and a pharmaceutical excipient as described above, and the second pharmaceutical composition C-2 includes capecitabine and a pharmaceutical excipient, the mass ratio of the compound as shown in Formula I to the capecitabine is preferably (0.2-2):1, for example 0.45:1, 0.58:1 or 1.2:1.

[0059] In some embodiments, when the first pharmaceutical composition C-1 includes the compound as shown in Formula I and a pharmaceutical excipient as described above, and the second pharmaceutical composition C-2 includes paclitaxel and a pharmaceutical excipient, the mass ratio of the compound as shown in Formula I to the paclitaxel is preferably (6-16):1, for example 10:1 or 11:1.

[0060] In some embodiments, when the first pharmaceutical composition C-1 includes the compound as shown in Formula I and pharmaceutical excipients as described above, and the second pharmaceutical composition C-2 includes temozolomide and pharmaceutical excipients, the mass ratio of the compound as shown in Formula I to the temozolomide is preferably (6-16):1, for example 6:1, 9.5:1 or 16:1.

[0061] The first pharmaceutical composition C-1 is preferably presented in an oral dosage form.

[0062] The second pharmaceutical composition C-2 is preferably presented in the form of an oral dosage form or an injection dosage form.

[0063] The present invention provides a combination medicine kit D, which comprises:

[0064] A first container comprising the first pharmaceutical composition C-1 as described above; and,

[0065] The second container comprises the second pharmaceutical composition C-2 as described above.

[0066] The present invention also provides the use of the above-mentioned drug combination A, drug composition B or drug composition C in the preparation of drugs for treating tumors.

[0067] The present invention also provides an application of the PD-L1 small molecule inhibitor in combination with the chemotherapy drug molecule in the preparation of a drug for treating tumors.

[0068] The present invention also provides an application of the PD-L1 small molecule inhibitor in the preparation of a drug for treating tumors, wherein the PD-L1 small molecule is used in combination with the chemotherapy drug molecule.

[0069] The present invention also provides an application of the chemotherapy drug molecule in the preparation of a drug for treating tumors, wherein the chemotherapy drug molecule is used in combination with the PD-L1 small molecule inhibitor.

[0070] The present invention also provides a method for treating tumors, comprising administering a therapeutically effective amount of the above-mentioned pharmaceutical combination A, pharmaceutical composition B or pharmaceutical composition C to a subject (eg, a human) in need thereof.

[0071] In the above-mentioned pharmaceutical combination A, pharmaceutical composition B, pharmaceutical composition C, their uses and their methods of treatment:

[0072] In some embodiments, the tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumors, adrenal tumors, renal cell carcinoma and neuroblastoma, preferably breast cancer, gastric cancer or nasopharyngeal cancer.

[0073] In some embodiments, the tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumors, adrenal tumors, renal cell carcinoma, neuroblastoma and glioma, preferably glioma.

[0074] In some embodiments, the PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule can be administered simultaneously or separately.

[0075] The “simultaneous administration” means that the PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule are contained in a separate pharmaceutical composition and administered simultaneously; or, “a separate pharmaceutical composition containing the PD-L1 small molecule inhibitor” and a “separate pharmaceutical composition containing the chemotherapeutic drug molecule” are administered simultaneously.

[0076] The "separate administration" means that the "separate pharmaceutical composition comprising the PD-L1 small molecule inhibitor" and the "separate pharmaceutical composition comprising the chemotherapeutic drug molecule" are administered separately at different times, for example: one of the "separate pharmaceutical composition comprising the PD-L1 small molecule inhibitor" and the "separate pharmaceutical composition comprising the chemotherapeutic drug molecule" is administered first, and the other is administered subsequently. The separate administration may be close in time or far in time.

[0077] Whether administered simultaneously or separately, the administration regimens (including administration routes, administration doses, administration intervals, etc.) of the PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule may be the same or different, and may be adjusted as needed by those skilled in the art to provide the optimal therapeutic effect.

[0078] In some embodiments, the total daily dosage of the PD-L1 small molecule inhibitor ranges from 30-2400 mg; preferably 500-2000 mg; for example 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg.

[0079] In some embodiments, the administration frequency of the PD-L1 small molecule inhibitor is twice a day, once a day, or once every two days, preferably twice a day.

[0080] In some embodiments, the total daily dose of the PD-L1 small molecule inhibitor is 500-2000 mg, for example 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg; the frequency of administration is twice a day, once a day or once every two days, preferably twice a day (BID).

[0081] In some embodiments, the total daily dose of the PD-L1 small molecule inhibitor is 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg; the administration frequency is twice a day.

[0082] In some embodiments, the PD-L1 small molecule inhibitor is administered orally according to the above-mentioned total dosage and frequency.

[0083] In some embodiments, the PD-L1 small molecule inhibitor is administered orally at a total daily dose of 1000-1900 mg twice a day.

[0084] In some embodiments, the chemotherapeutic drug molecule is administered at a dosage based on the subject's body surface area.

[0085] In some embodiments, when the chemotherapy drug molecule is capecitabine, the total daily dose range is 1000-3000 mg / m 2 , preferably 1000 mg / m 2 , 1250mg / m 2 , 1500mg / m 2 , 1750mg / m 2 , 2000mg / m 2 , 2250mg / m 2 , 2500mg / m 2 , 2750mg / m 2 or 3000 mg / m 2 , for example 2000mg / m 2 or 2500 mg / m 2 ; The frequency of administration is once a day or twice a day, preferably twice a day.

[0086] In some embodiments, when the chemotherapy drug molecule is capecitabine, capecitabine is orally administered at a total daily dose of 1000-3000 mg / m 2 , applied twice daily.

[0087] In some embodiments, when the chemotherapy drug molecule is paclitaxel, the total daily dose range is 50-200 mg / m 2 , preferably 50 mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 125mg / m 2 , 135mg / m 2 , 145mg / m 2 , 155mg / m 2 , 165mg / m 2 , 175mg / m 2 , 185mg / m 2 , 195mg / m 2 or 200 mg / m 2 , for example 80 mg / m 2 , 135mg / m 2 or 175 mg / m 2 ; The frequency of administration is once every two weeks, once every three weeks or once every four weeks; preferably once every three weeks.

[0088] In some embodiments, when the chemotherapy drug molecule is paclitaxel, paclitaxel is intravenously injected at a total daily dose of 50-200 mg / m 2 , applied once every three weeks.

[0089] In some embodiments, when the chemotherapy drug molecule is temozolomide, the total daily dose range is 100-250 mg / m 2 , preferably 100 mg / m 2 , 125mg / m 2 , 150mg / m 2 , 175mg / m 2 , 200mg / m 2 , 225mg / m 2 or 250 mg / m 2 , for example 150 mg / m 2 or 200 mg / m 2 ; The frequency of administration is once a day for 5 days, followed by a 23-day break before entering the next cycle.

[0090] In some embodiments, when the chemotherapy drug molecule is temozolomide, temozolomide is orally administered at a total daily dose of 100-250 mg / m 2 The dosage frequency is once a day for 5 days, followed by a 23-day medication break before entering the next cycle.

[0091] In some embodiments, the PD-L1 small molecule inhibitor is administered orally twice daily at a total daily dose of 1000-1900 mg, and the chemotherapeutic drug molecule is administered at a daily dose of 1000-3000 mg / m 2 The total dose is administered orally twice daily.

[0092] In some embodiments, the PD-L1 small molecule inhibitor is administered orally twice daily at a total daily dose of 1000-1900 mg, and the chemotherapeutic drug molecule is administered at a daily dose of 50-200 mg / m 2 The total dose is administered once every three weeks via intravenous injection.

[0093] In some embodiments, the PD-L1 small molecule inhibitor is administered orally twice daily at a total daily dose of 1000-1900 mg, and the chemotherapeutic drug molecule is administered at a daily dose of 100-250 mg / m 2 The total dosage is once a day for 5 days, followed by a 23-day break before entering the next cycle.

[0094] The present invention provides a drug combination E, which comprises a PD-L1 small molecule inhibitor and a COX-2 inhibitor.

[0095] In some embodiments, the pharmaceutical combination E has a synergistic effect.

[0096] In the drug combination E, the PD-L1 small molecule inhibitor is preferably a compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0097]

[0098] In the drug combination E, the COX-2 inhibitor is preferably nimesulide, meloxicam, celecoxib or rofecoxib, more preferably celecoxib.

[0099] In the drug combination E, the mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is preferably (0.1-10):1, more preferably (2-10):1, such as 6:1 or 7.5:1.

[0100] In some embodiments, the active ingredients of the drug combination E are the PD-L1 small molecule inhibitor as described above and the COX-2 inhibitor as described above, preferably the compound as shown in Formula I as described above and celecoxib.

[0101] In the drug combination E, the PD-L1 small molecule inhibitor is preferably administered via the gastrointestinal tract (e.g., orally, sublingually, or rectally), injected (e.g., subcutaneously, intradermally, intravenously, intraperitoneally, or intramuscularly), administered to the respiratory tract, or topically (e.g., mucosa or skin), more preferably administered via the gastrointestinal tract, such as orally.

[0102] In the pharmaceutical combination E, the COX-2 inhibitor is preferably administered via the gastrointestinal tract (e.g., orally, sublingually or rectally), injected (e.g., subcutaneously, intradermally, intravenously, intraperitoneally or intramuscularly), administered to the respiratory tract or topically (e.g., to the mucosa or skin), more preferably administered via the gastrointestinal tract, such as orally.

[0103] In the pharmaceutical combination E, the PD-L1 small molecule inhibitor is preferably administered orally; and the COX-2 inhibitor is preferably administered orally.

[0104] The present invention provides a pharmaceutical composition F, which comprises a PD-L1 small molecule inhibitor, a COX-2 inhibitor and pharmaceutical excipients.

[0105] In some embodiments, the pharmaceutical composition F has a synergistic effect.

[0106] In the pharmaceutical composition F, the PD-L1 small molecule inhibitor and COX-2 inhibitor can be as described above.

[0107] In the pharmaceutical composition F, the content of the PD-L1 small molecule inhibitor is preferably 30-500 mg, more preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg.

[0108] In the pharmaceutical composition F, the content of the COX-2 inhibitor is preferably 50-250 mg, more preferably 100-200 mg, such as 100 mg or 200 mg.

[0109] In the pharmaceutical composition F, the mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is preferably (0.1-10):1, more preferably (2-10):1, such as 6:1 or 7.5:1.

[0110] In some embodiments, the active ingredients of the pharmaceutical composition F are the PD-L1 small molecule inhibitor as described above and the COX-2 inhibitor as described above, preferably the compound as shown in Formula I as described above and celecoxib.

[0111] In some embodiments, the pharmaceutical composition F consists of the PD-L1 small molecule inhibitor described above, the COX-2 inhibitor described above, and pharmaceutical excipients.

[0112] The pharmaceutical composition F can be a separate pharmaceutical composition.

[0113] The pharmaceutical composition F can be prepared into various suitable dosage forms according to different administration methods, including gastrointestinal dosage forms (such as oral dosage forms) and parenteral dosage forms (such as injection dosage forms, respiratory tract dosage forms, mucosal dosage forms or cavity dosage forms), preferably capsules, tablets, pills, granules, powders or oral liquids.

[0114] The present invention also provides a pharmaceutical composition G, comprising:

[0115] A first pharmaceutical composition G-1, which includes a PD-L1 small molecule inhibitor and a pharmaceutical excipient; and,

[0116] The second pharmaceutical composition G-2 comprises a COX-2 inhibitor and pharmaceutically acceptable excipients.

[0117] In some embodiments, the pharmaceutical composition G has a synergistic effect.

[0118] In the pharmaceutical composition G, the PD-L1 small molecule inhibitor and COX-2 inhibitor can be as described above.

[0119] In some embodiments, the pharmaceutical composition G is composed of a first pharmaceutical composition G-1 and a second pharmaceutical composition G-2; the first pharmaceutical composition G-1 is composed of the PD-L1 small molecule inhibitor as described above and pharmaceutical excipients, preferably composed of the compound shown in Formula I as described above and pharmaceutical excipients; the second pharmaceutical composition G-2 is composed of the COX-2 inhibitor as described above and pharmaceutical excipients, preferably composed of celecoxib and pharmaceutical excipients.

[0120] The first pharmaceutical composition G-1 is a separate pharmaceutical composition; the second pharmaceutical composition G-2 is a separate pharmaceutical composition.

[0121] In the pharmaceutical composition G, the content of the PD-L1 small molecule inhibitor is preferably 30-500 mg, more preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg.

[0122] In the pharmaceutical composition G, the content of the COX-2 inhibitor is preferably 50-250 mg, more preferably 100-200 mg, such as 100 mg or 200 mg.

[0123] In the pharmaceutical composition G, the mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is preferably (0.1-10):1, more preferably (2-10):1, such as 6:1 or 7.5:1.

[0124] In the pharmaceutical composition G, the first pharmaceutical composition G-1 is preferably presented in the form of an oral dosage form.

[0125] In the pharmaceutical composition G, the second pharmaceutical composition G-2 is preferably presented in the form of an oral dosage form.

[0126] In the pharmaceutical composition G, preferably, the first pharmaceutical composition G-1 is presented in the form of an oral dosage form; and the second pharmaceutical composition G-2 is presented in the form of an oral dosage form.

[0127] The present invention provides a combination medicine kit H, which comprises:

[0128] A first container comprising the first pharmaceutical composition G-1 as described above; and,

[0129] The second container comprises the second pharmaceutical composition G-2 as described above.

[0130] The present invention also provides the use of the above-mentioned drug combination E, drug composition F or drug composition G in the preparation of drugs for treating tumors.

[0131] The present invention provides an application of the PD-L1 small molecule inhibitor in combination with the COX-2 inhibitor in the preparation of a drug for treating tumors.

[0132] The present invention provides an application of the PD-L1 small molecule inhibitor in the preparation of a drug for treating tumors, wherein the PD-L1 small molecule inhibitor is used in combination with the COX-2 inhibitor.

[0133] The present invention provides an application of the COX-2 inhibitor in the preparation of a drug for treating tumors, wherein the COX-2 inhibitor is used in combination with the PD-L1 small molecule inhibitor.

[0134] The present invention provides a method for treating tumors, comprising administering a therapeutically effective amount of the pharmaceutical combination E, pharmaceutical composition F or pharmaceutical composition G as described above to a subject (eg, a human) in need thereof.

[0135] In the above-mentioned pharmaceutical combination E, pharmaceutical composition F, pharmaceutical composition G, their use and their method of treatment:

[0136] In some embodiments, the tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumors, adrenal tumors, renal cell carcinoma and neuroblastoma, preferably breast cancer, gastric cancer or nasopharyngeal cancer.

[0137] In some embodiments, the tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumors, adrenal tumors, renal cell carcinoma, neuroblastoma and glioma, preferably glioma.

[0138] In some embodiments, the PD-L1 small molecule inhibitor and the COX-2 inhibitor can be administered simultaneously or separately.

[0139] The “simultaneous administration” means that the PD-L1 small molecule inhibitor and the COX-2 inhibitor are contained in a separate pharmaceutical composition and administered simultaneously; or, “a separate pharmaceutical composition of the PD-L1 small molecule inhibitor” and “a separate pharmaceutical composition of the COX-2 inhibitor” are administered simultaneously.

[0140] The "separate administration" means that the "separate pharmaceutical composition of the PD-L1 small molecule inhibitor" and the "separate pharmaceutical composition of the COX-2 inhibitor" are administered separately at different times, for example, one of the "separate pharmaceutical composition of the PD-L1 small molecule inhibitor" and the "separate pharmaceutical composition of the COX-2 inhibitor" is administered first, and the other is administered subsequently. The separate administration may be close in time or far in time.

[0141] Whether administered simultaneously or separately, the administration regimens (including administration routes, administration doses, administration intervals, etc.) of the "separate pharmaceutical composition of the PD-L1 small molecule inhibitor" and the "separate pharmaceutical composition of the COX-2 inhibitor" may be the same or different, and may be adjusted as needed by those skilled in the art to provide the optimal therapeutic effect.

[0142] In some embodiments, the PD-L1 small molecule inhibitor can be administered via the gastrointestinal tract (e.g., orally, sublingually, or rectally), by injection (e.g., subcutaneously, intradermally, intravenously, intraperitoneally, or intramuscularly), by respiratory tract administration, or topically (e.g., by mucosa or skin), preferably via the gastrointestinal tract, such as orally.

[0143] In some embodiments, the COX-2 inhibitor can be administered gastrointestinal tract (e.g., orally, sublingually, or rectally), injected (e.g., subcutaneously, intradermally, intravenously, intraperitoneally, or intramuscularly), respiratory tract, or topically (e.g., mucosa or skin), preferably gastrointestinal tract, such as orally.

[0144] In some embodiments, the PD-L1 small molecule inhibitor is administered orally; and, the COX-2 inhibitor is administered orally.

[0145] In some embodiments, the total daily dosage of the PD-L1 small molecule inhibitor can range from 30-2400 mg; more preferably 500-2000 mg; for example 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg.

[0146] In some embodiments, the administration frequency of the PD-L1 small molecule inhibitor is twice a day, once a day, or once every two days, preferably twice a day.

[0147] In some embodiments, the total daily dose of the PD-L1 small molecule inhibitor is 500-2000 mg, for example 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg; the frequency of administration is twice a day, once a day or once every two days, preferably twice a day (BID).

[0148] In some embodiments, the total daily dose of the PD-L1 small molecule inhibitor is 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg, and the administration frequency is twice a day.

[0149] In some embodiments, the PD-L1 small molecule inhibitor is administered orally according to the above-mentioned total dosage and frequency.

[0150] In some embodiments, the PD-L1 small molecule inhibitor is administered orally at a total daily dose of 1000-1900 mg twice a day.

[0151] In some embodiments, the total daily dosage of the COX-2 inhibitor is in the range of 50-250 mg, preferably 100-200 mg, such as 100 mg or 200 mg.

[0152] In some embodiments, the COX-2 inhibitor is administered once daily or twice daily.

[0153] In some embodiments, the total daily dose of the COX-2 inhibitor is 100 mg, 120 mg, 140 mg, 160 mg, 180 mg or 200 mg, and the administration frequency is once a day or twice a day.

[0154] In some embodiments, the COX-2 inhibitor is administered orally at the total dosage and frequency described above.

[0155] In some embodiments, the PD-L1 small molecule inhibitor is orally administered twice daily at a total daily dose of 1000-1900 mg, and the COX-2 inhibitor is orally administered once or twice daily at a total daily dose of 100-200 mg.

[0156] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.

[0157] The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions; it is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0158] The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that initiates a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

[0159] The term "therapeutically effective amount" refers to the amount of a compound administered to a subject that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the subject, etc., but can be adjusted by those skilled in the art as appropriate.

[0160] The term "subject" refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0161] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0162] The reagents and raw materials used in the present invention are commercially available.

[0163] The positive and progressive effect of the present invention is that in the treatment of tumor diseases, the PD-L1 small molecule inhibitor is combined with different small molecule drugs (such as COX-2 inhibitors, chemotherapy drug molecules, etc.) to have a synergistic effect, showing better anti-tumor activity or longer survival than using small molecule drugs alone. BRIEF DESCRIPTION OF THE DRAWINGS

[0164] Figure 1 This is a graph showing the growth curve of tumor volume in each group of mice in Example 1.

[0165] Figure 2 It is a curve chart of the tumor inhibition rate of each group of mice in Example 1.

[0166] Figure 3 This is a curve diagram of the weight changes of mice in each group in Example 1.

[0167] Figure 4 1 is a curve diagram of the relative change rate of body weight of each group of mice in Example 1.

[0168] Figure 5 This is a graph showing the growth curve of tumor volume in each group of mice in Example 2.

[0169] Figure 6 This is a curve chart of the tumor inhibition rate of each group of mice in Example 2.

[0170] Figure 7 This is a curve diagram of the weight changes of mice in each group in Example 2.

[0171] Figure 8 This is a curve diagram of the relative change rate of body weight of each group of mice in Example 2.

[0172] Fig. 9 This is a survival curve diagram of each group of mice in Example 3.

[0173] Fig.10This is a curve diagram of the weight changes of mice in each group in Example 3.

[0174] Fig.11 This is a curve diagram of the relative change rate of body weight of each group of mice in Example 3.

[0175] Fig.12 This is a curve diagram of the weight changes of mice in each group in Example 4.

[0176] Fig.13 This is a curve diagram of the relative change rate of body weight of each group of mice in Example 4.

[0177] Fig.14 This is a curve diagram of the fluorescence signal intensity of each group of mice in Example 4.

[0178] Fig.15 This is a curve chart of the tumor inhibition rate of each group of mice in Example 4.

[0179] Fig.16 It is the survival curve diagram of each group of mice in Example 4. DETAILED DESCRIPTION

[0180] po: “orally” or “by mouth”; ip: intraperitoneally; iv: intravenously; BID: twice daily; QD: once daily; Q2D: once every two days; BIW: twice a week; QW: once a week.

[0181] Example 1 Pharmacodynamic study of the test drug on mouse breast cancer 4T1 hPD-L1 model

[0182] 1. Experimental Materials

[0183] Experimental animals: 100 BALB / c mice, female, 6-8 weeks old, weighing 18-21 g, purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. (SCXK (Shanghai) 2020-0009; certificate number: 20220009001922).

[0184] Drug: Compound of formula I Production unit: Kanglong Chemical (Tianjin) Pharmaceutical Preparation Technology Co., Ltd., batch number: TJ-MAX-10181-A-2; Capecitabine, production unit: Shanghai Yuanye Biotechnology Co., Ltd., batch number: J10J12L137020.

[0185] 2. Experimental steps and methods

[0186] 2.1 Cell culture

[0187] Murine 4T1 hPD-L1 cells adhered to the wall and grew in vitro. The culture conditions were RPMI-1640 medium with 10% heat-inactivated fetal bovine serum and 4μg / mL Blasticidin (Biyuntian / ST018-1mL), 37℃5% CO2. The cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were collected, counted, and inoculated subcutaneously on the right dorsal side of BALB / c mice.

[0188] 2.2 Tumor cell inoculation and group administration

[0189] 100 μL 1×10 6 4T1 hPD-L1 cell suspension was inoculated subcutaneously on the right dorsal flank of BALB / c mice. On the 6th day after inoculation, appropriate animals were selected according to tumor volume and animal weight, and divided into 4 groups by stratified randomization, with 10 animals in each group, and drug administration began on the day of grouping.

[0190] Table 1 Animal experimental groups and dosing regimen

[0191]

[0192] 2.3 Preparation of test drugs

[0193] Table 2 Preparation method of the tested drugs

[0194]

[0195] 2.4 Experimental indicators

[0196] The experimental indicators examine whether tumor growth can be inhibited, delayed or cured. Tumors are measured with a digital vernier caliper three times a week. The tumor volume is calculated as: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound is expressed by TGI, TGI (%) = [1-(TV i -TV0) / (TV Vi -TV V0 )]×100% (TV0 is the average volume of the treatment group on day 0, TV V0 is the average volume of the control group on day 0; TV i is the mean volume of the treatment group on day i, TV Vi is the average volume of the control group on day i).

[0197] 2.5 End of the experiment

[0198] If the animal's health condition continues to deteriorate, or the tumor volume exceeds 2,000mm 3 If the animal is seriously ill or in pain, it must be euthanized. If the animal has any of the following conditions, notify the veterinarian and euthanize it:

[0199] (1) Obvious weight loss, with a weight loss of more than 20%;

[0200] (2) Not able to freely access food and water;

[0201] (3) The average tumor volume of the control group reached 2000mm 3 , the experiment terminated.

[0202] 2.6 Data Analysis

[0203] GraphPad Prism 8.0 software was used for graphing. Two-way ANOVA was used to analyze the changes in mouse tumor volume. The Dunnett method was used to compare the tumor volume with the vehicle control group. P < 0.05 was considered to be significantly different.

[0204] 3. Experimental results

[0205] 3.1 Tumor volume

[0206] Table 3: Tumor volume, tumor inhibition effect and statistical analysis results of each treatment group in the pharmacodynamic experiment of the test drug on the mouse breast cancer 4T1 hPD-L1 model Figure 1 and Figure 2 .

[0207] Table 3 Tumor volume (mm 3 )(Mean)

[0208]

[0209] The average tumor volume of the compound of formula I (Group 2) on day 21 after po administration was 1103.30 mm 3 , compared with the control group (Group 1, tumor volume on day 21 was 1807.62 mm 3 ) were significantly different (TGI% = 41.88%).

[0210] Capecitabine (Group 3) The mean tumor volume on day 21 after po administration was 862.73 mm 3 , compared with the control group (Group 1, tumor volume on day 21 was 1807.62 mm 3 ) were significantly different (TGI% = 56.16%).

[0211] The average tumor volume of the group treated with the compound of formula I and Capecitabine (Group 4) was 484.07 mm on the 21st day after administration. 3 , compared with the control group (Group 1, tumor volume on day 21 was 1807.62 mm 3Compared with the group treated with the compound of formula I alone (Group 2) and the group treated with Capecitabine alone (Group 3), the combined group had a significantly improved tumor inhibition effect and had a synergistic effect.

[0212] 3.2 Mouse body weight

[0213] Table 4 Body weight changes of treated mice (Mean)

[0214]

[0215]

[0216] The results of the weight and relative weight changes of mice in each treatment group are shown in Table 4. Figure 3 and Figure 4 During this experiment, mice in all treatment groups did not show significant weight loss or other abnormal symptoms, indicating that the mice tolerated all treatments well.

[0217] Example 2 Pharmacodynamic study of the test drug on mouse breast cancer 4T1 hPD-L1 model

[0218] 1. Experimental Materials

[0219] Experimental animals: 100 BALB / c mice, female, 6-8 weeks old, weighing 18-21 g, purchased from

[0220] Shanghai Jihui Experimental Animal Breeding Co., Ltd. (SCXK(Shanghai)2020-0009; Certificate No.: 20220009001922).

[0221] Drug: Compound of formula I, produced by Kanglong Chemical (Tianjin) Pharmaceutical Preparation Technology Co., Ltd., batch number: TJ-MAX-10181-A-2; Celecoxib, produced by Shanghai Yuanye Biotechnology Co., Ltd., batch number: D11A6S2152.

[0222] 2. Experimental steps and methods

[0223] 2.1 Cell culture

[0224] Murine 4T1 hPD-L1 cells adhered to the wall and grew in vitro. The culture conditions were RPMI-1640 medium with 10% heat-inactivated fetal bovine serum and 4μg / mL Blasticidin (Biyuntian / ST018-1mL), 37℃5% CO2. The cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were collected, counted, and inoculated subcutaneously on the right dorsal side of BALB / c mice.

[0225] 2.2 Tumor cell inoculation and group administration

[0226] 100 μL 1×10 6 4T1 hPD-L1 cell suspension was inoculated subcutaneously on the right dorsal flank of BALB / c mice. On the seventh day after inoculation, the mice were divided into 4 groups by stratified randomization according to tumor volume and animal weight, with 10 mice in each group, and drug administration began on the day of grouping.

[0227] Table 5 Animal experiment groups and dosing regimen

[0228]

[0229] 2.3 Preparation of test drugs

[0230] Table 6 Preparation method of the tested drugs

[0231]

[0232]

[0233] 2.4 Experimental indicators

[0234] The experimental indicators examine whether tumor growth can be inhibited, delayed or cured. Tumors are measured with a digital vernier caliper three times a week. The tumor volume is calculated as: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound is expressed by TGI, TGI (%) = [1-(TV i -TV0) / (TV Vi -TV V0 )]×100% (TV0 is the average volume of the treatment group on day 0, TV V0 is the average volume of the control group on day 0; TV i is the mean volume of the treatment group on day i, TV Vi is the average volume of the control group on day i).

[0235] 2.5 End of the experiment

[0236] If the animal's health condition continues to deteriorate, or the tumor volume exceeds 2,000mm 3 If the animal is seriously ill or in pain, it must be euthanized. If the animal has any of the following conditions, notify the veterinarian and euthanize it:

[0237] (1) Obvious weight loss, with a weight loss of more than 20%;

[0238] (2) Not able to freely access food and water;

[0239] (3) The average tumor volume of the control group reached 2000mm 3 , the experiment terminated.

[0240] 2.6 Data Analysis

[0241] GraphPad Prism 8.0 software was used for graphing. Two-way ANOVA was used to analyze the changes in mouse tumor volume. The Dunnett method was used to compare the tumor volume with the vehicle control group. P < 0.05 was considered to be significantly different.

[0242] 3. Experimental results

[0243] 3.1 Tumor volume

[0244] The tumor volume, tumor inhibition effect and statistical analysis results of each treatment group in the pharmacodynamic experiment of the test drug on the mouse breast cancer 4T1 hPD-L1 model are shown in Table 7. Figure 5 and Figure 6 .

[0245] Table 7 Tumor volume (mm 3 )(Mean)

[0246]

[0247] The average tumor volume of the compound of formula I (Group 2) on day 21 after po administration was 921.91 mm 3 , compared with the control group (group 1, tumor volume on day 21 was 1290.12 mm 3 ) were significantly different (TGI% = 32.78%).

[0248] The mean tumor volume of Celecoxib (Group 3) on day 21 after po administration was 341.70 mm 3 , compared with the control group (group 1, tumor volume on day 21 was 1290.12 mm 3 ) were significantly different (TGI%=83.90%).

[0249] The average tumor volume of the group treated with the compound of formula I and Celecoxib (Group 4) was 140.02 mm on the 21st day after administration. 3 , compared with the control group (group 1, tumor volume on day 21 was 1290.12 mm 3 ) compared with the group treated with the compound of formula I alone (Group 2) and the group treated with Celecoxib alone, the tumor inhibition effect of the combined drug group was significantly improved.

[0250] 3.2 Mouse body weight

[0251] Table 8 Body weight changes of treated mice (Mean)

[0252]

[0253] The results of the weight and relative weight changes of mice in each treatment group are shown in Table 8. Figure 7 and Figure 8 During this experiment, mice in all treatment groups did not show significant weight loss or other abnormal symptoms, indicating that the mice tolerated all treatments well.

[0254] Example 3 Study on the Growth and Metastasis of Orthotopic Transplanted Tumors and Prolongation of Survival of Mice by Test Drugs in BALB / c Mouse Breast Cancer Cell 4T1 Model

[0255] 1. Experimental Materials

[0256] Experimental animals: 50 BALB / c mice, female, 6-8 weeks old, weighing 18-20 g. Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd. Tongxiang Branch (SCKX (Zhe) 2021-0006); Certificate No.: 20220728Abzz0600000694.

[0257] Drug: Compound of formula I, produced by Kanglong Chemical (Tianjin) Pharmaceutical Preparation Technology Co., Ltd., batch number: TJ-MAX-10181-A-2; Paclitaxel (paclitaxel) (6 mg / mL), produced by Corden Pharma Latina S.PA, batch number: 2D07013.

[0258] 2. Experimental steps and methods

[0259] 2.1 Cell culture

[0260] Mouse 4T1 cells adhered to the wall and grew in vitro. The culture conditions were RPMI-1640 medium with 10% heat-inactivated fetal bovine serum and cultured at 37°C and 5% CO2. The cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated into the fourth fat pad on the left side of the abdomen of BALB / c mice.

[0261] 2.2 Tumor cell inoculation and group administration

[0262] 50μL 1×10 5 4T1 cell suspension was inoculated into the fourth fat pad on the left side of the abdomen of BALB / c mice. The mice were randomly divided into groups according to the order of tumor inoculation and animal weight on the second day after inoculation, and drug administration began on the same day of grouping. On the 13th day after inoculation, the orthotopic tumors were surgically removed (dosing was suspended on the day of surgery).

[0263] Table 9 Animal experiment groups and dosing regimen

[0264]

[0265] 2.3 Preparation of test drugs

[0266] Table 10 Preparation method of the tested drugs

[0267]

[0268]

[0269] 2.4 Experimental indicators

[0270] The experimental indicators examine whether tumor growth can be inhibited, delayed or cured. Tumors are measured with a digital vernier caliper three times a week. The tumor volume is calculated as: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound is expressed by TGI, TGI (%) = [1-(TV i -TV0) / (TV Vi -TV V0 )]×100% (TV0 is the average volume of the treatment group on day 0, TV V0 is the average volume of the control group on day 0; TV i is the mean volume of the treatment group on day i, TV Vi is the average volume of the control group on day i);

[0271] 2.5 End of the experiment

[0272] If the animal's health condition continues to deteriorate, or the tumor volume exceeds 2,000mm 3 If the animal is seriously ill or in pain, it must be euthanized. If the animal has any of the following conditions, notify the veterinarian and euthanize it:

[0273] (1) Obvious weight loss, with a weight loss of more than 20%;

[0274] (2) Not able to freely access food and water;

[0275] (3) The average tumor volume of the control group reached 2000mm 3 , the experiment terminated.

[0276] 2.6 Data Analysis

[0277] GraphPad Prism 8.0 software was used for graphing. Two-way ANOVA was used to analyze the changes in mouse tumor volume. The Dunnett method was used to compare the tumor volume with the vehicle control group. P < 0.05 was considered to be significantly different.

[0278] 3. Experimental results

[0279] 3.1 Survival Curve

[0280] After each group of mice was inoculated with 4T1 cells and treated accordingly, the survival rate of mice in the treatment group of the combination of Formula I compound and Paclitaxel (Group 4) was 50% on the 38th day compared with the vehicle control group (Group 1), the group of Formula I compound alone (Group 3), and the group of Paclitaxel alone (Group 2). The survival rate of mice in the combination group was 0% on the 38th day, and the survival rate of mice in the group of Formula I compound alone (Group 3) was 0% on the 38th day, and the survival rate of mice in the group of Paclitaxel alone (Group 2) was 10% on the 38th day. The combination group significantly improved the survival rate of mice. Fig. 9 .

[0281] 3.2 Mouse body weight

[0282] After 12 days of administration, the weight of mice in each treatment group remained stable with no obvious adverse reactions; the weight of mice returned to normal in a short time after tumor resection. Fig.10 and Fig.11 .

[0283] Example 4 Pharmacodynamics and survival study of the test drug on the mouse glioma cell GL-261-luc brain orthotopic transplanted tumor model

[0284] 1. Experimental Materials

[0285] Experimental animals: 57 C57 BL / 6 mice, female, 6-8 weeks old, weighing 16-20 g, were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0286] Drug: Compound of formula I Production unit: Kanglong Chemical (Tianjin) Pharmaceutical Preparation Technology Co., Ltd., batch number: TJ-MAX-10181-A-2; TMZ (temozolomide), production unit: Shanghai Aladdin Biochemical Technology Co., Ltd., batch number: J2227749.

[0287] 2. Experimental steps and methods

[0288] 2.1 Cell culture

[0289] Mouse GL-261-luc cells were grown in vitro in DMEM medium with 10% heat-inactivated fetal bovine serum and 0.6 mg / mL G418 (mother solution concentration: 100 mg / mL) at 37°C and 5% CO2. Cells were passaged 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated into the right caudate nucleus of C57 BL / 6 mice.

[0290] 2.2 Tumor cell inoculation and group administration

[0291] GL-261-luc was collected when it was fully grown in the logarithmic growth phase to ensure that the vitality was above 90%; mice were anesthetized by intraperitoneal injection of 41.6 mg / kg of Zotal by weight, and 1×10 5 / 2μL / mouse of cells were inoculated in situ into the right caudate nucleus of each mouse, the skin was sutured with 4 / 0 sutures, and the mice were returned to the cages after they woke up; 4 days after cell inoculation, the mice were imaged and grouped using IVIS LuminaXR mouse animal imager; the fluorescence signal intensity was divided into 4 groups using a stratified randomization method, with 9 mice in each group, and medication was started on the day of grouping. The mice were weighed and their growth was observed every day, and the mice were imaged twice a week.

[0292] Table 11 Animal experiment groups and dosing regimen

[0293]

[0294] 2.3 Preparation of test drugs

[0295] Table 12 Preparation method of the tested drugs

[0296]

[0297]

[0298] 2.4 Experimental indicators

[0299] The experimental indicators examine whether tumor growth can be inhibited, delayed or cured. According to the experimental design, mice were imaged by the small animal imaging instrument IVIS Lumina XR to monitor tumor growth. The anti-tumor efficacy of the compound is expressed by TGI, TGI (%) = [1-(TFtreatment-Dn-TFtreatment-D0) / (TFcontrol-Dn-TFcontrol-D0)] × 100% (TFtreatment-D0 is the fluorescence signal intensity of the treatment group on day 0, TFcontrol-D0 is the fluorescence signal intensity of the control group on day 0; TFtreatment-Dn is the fluorescence signal intensity of the treatment group on day n, and TFcontrol-Dn is the fluorescence signal intensity of the control group on day n). The formula for calculating the extended life span (ILS): ILS = (MSTTreatment-MSTControl) / MSTControl x 100% (MSTTreatment is the median survival time in days of the treatment group, and MSTControl is the median survival time in days of the control group).

[0300] 2.5 Data Analysis

[0301] Tumor size was analyzed based on the fluorescence signal intensity using the statistical software GraphPad Prism. Two-way ANOVA was used to compare whether there was a significant difference in fluorescence signal intensity between the control group and each treatment group. p<0.05 was considered a significant difference, and p<0.01 was considered an extremely significant difference.

[0302] 3. Experimental results

[0303] 3.1 Mouse weight

[0304] In the pharmacodynamics experiment of the test drug on the mouse glioma GL-261-luc brain orthotopic transplanted tumor model, the results of the weight change and relative weight change of tumor-bearing mice in each group are shown in Table 13, Fig.12 and Fig.13 .

[0305] Table 13 Body weight changes of treated mice (Mean)

[0306]

[0307]

[0308] The experimental results showed that by the 14th day of administration, in the vehicle control group (Group 1), 2 mice had a weight loss of more than 10%, of which 1 mouse had a weight loss of more than 15%; in the TMZ group (temozolomide) (Group 2), 2 mice had a weight loss of more than 10%; in the Formula I compound group (Group 3), 2 mice had a weight loss of more than 10%; in the Formula I compound combined with TMZ (temozolomide) group (Group 4), there was no significant weight loss in mice.

[0309] 3.2 Fluorescence signal intensity and tumor inhibition rate

[0310] In the pharmacodynamics experiment of the test drug acting on the mouse glioma GL-261-luc model, the changes in the fluorescence signal intensity of each group of tumor-bearing mice and the tumor inhibition rate of each group of tumor-bearing mice based on the fluorescence signal intensity are shown in Table 14. Fig.14 and Fig.15 .

[0311] Table 14 Fluorescence signal intensity and tumor inhibition rate of mice in each group

[0312]

[0313] The experimental results showed that, by the 14th day of administration, compared with the vehicle control group (Group 1), the tumor inhibition rate of the TMZ group (Temozolomide) (Group 2) was 35.51%; the tumor inhibition rate of the Formula I compound group (Group 3) was 40.52%; the tumor inhibition rate of the Formula I compound and TMZ (Temozolomide) combined group (Group 4) was 63.61%. Compared with the TMZ (Temozolomide) alone group (Group 2) and the Formula I compound (Group 3) alone group, the combined group had a significantly improved tumor inhibition effect.

[0314] 3.3 Survival curve

[0315] After each group of mice was inoculated with GL-261-luc cells and received corresponding treatment, the experiment ended when all mice in each group died. The survival curves of each group of mice are shown in Fig.16 .

[0316] The experimental results showed that by the end of the experiment, compared with the vehicle control group (Group 1), the TMZ group (Temozolomide) (Group 2), the Formula I compound group (Group 3) and the Formula I compound and TMZ (Temozolomide) combination group (Group 4) extended life span rates (ILS) of 25%, 20% and 40%, respectively. The combination group significantly increased the median survival time and life span extension rate of mice.

Claims

1. A drug combination A, characterized in that: The drug combination A includes a PD-L1 small molecule inhibitor and a chemotherapy drug molecule.

2. The pharmaceutical combination A according to claim 1, characterized in that: The drug combination A satisfies one or more of the following conditions: (1) The drug combination A has a synergistic effect; (2) The PD-L1 small molecule inhibitor is a compound as shown in Formula I or a pharmaceutically acceptable salt thereof; (3) The chemotherapy drug molecule is one or more of capecitabine, paclitaxel, oxaliplatin and temozolomide, preferably capecitabine, paclitaxel or temozolomide; (4) The mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1; (5) The active ingredients of the drug combination A are the PD-L1 small molecule inhibitor and the chemotherapy drug molecule; (6) The PD-L1 small molecule inhibitor is administered via the gastrointestinal tract, injection, respiratory tract or local administration, such as oral administration; (7) The chemotherapeutic drug molecules are administered via the gastrointestinal tract, injection, respiratory tract or local administration, such as oral administration or intravenous injection.

3. The pharmaceutical combination A according to claim 2, characterized in that: The drug combination A comprises the compound as shown in formula I and capecitabine, and the mass ratio of the compound as shown in formula I to the capecitabine is preferably (0.2-2):1, such as 0.45:1, 0.58:1 or 1.2:1; Or, the drug combination A comprises the compound as shown in formula I and paclitaxel, and the mass ratio of the compound as shown in formula I to the paclitaxel is preferably (6-16):1, such as 10:1 or 11:1; Alternatively, the drug combination A comprises the compound as shown in formula I and temozolomide, and the mass ratio of the compound as shown in formula I to the temozolomide is preferably (6-16):1, for example 6:1, 9.5:1 or 16:

1.

4. A pharmaceutical composition B, characterized in that: The pharmaceutical composition B includes a PD-L1 small molecule inhibitor, a chemotherapy drug molecule and pharmaceutical excipients.

5. The pharmaceutical composition B according to claim 4, characterized in that The pharmaceutical composition B satisfies one or more of the following conditions: (1) The pharmaceutical composition B has a synergistic effect; (2) The PD-L1 small molecule inhibitor and the chemotherapy drug molecule are as described in claim 2; (3) The content of the PD-L1 small molecule inhibitor is 30-500 mg, preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg; (4) The content of the chemotherapy drug molecule is 10-650 mg, preferably 30-550 mg, such as 20 mg, 30 mg, 60 mg, 100 mg, 150 mg or 500 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1; Preferably, when the pharmaceutical composition B comprises the compound of formula I as claimed in claim 2, capecitabine and pharmaceutical excipients, the mass ratio of the compound of formula I to the capecitabine is preferably (0.2-2):1, such as 0.45:1, 0.58:1 or 1.2:1; when the pharmaceutical composition B comprises the compound of formula I as claimed in claim 2, paclitaxel and pharmaceutical excipients, the mass ratio of the compound of formula I to the paclitaxel is preferably (6-16):1, such as 10:1 or 11:1; when the pharmaceutical composition B comprises the compound of formula I as claimed in claim 2, temozolomide and pharmaceutical excipients, the mass ratio of the compound of formula I to the temozolomide is preferably (6-16):1, such as 6:1, 9.5:1 or 16:1; (6) The active ingredients of the pharmaceutical composition B are the PD-L1 small molecule inhibitor and the chemotherapy drug molecule; (7) The dosage forms of the pharmaceutical composition B include gastrointestinal dosage forms and parenteral dosage forms, preferably capsules, tablets, pills, granules, powders or oral liquids.

6. A pharmaceutical composition C, characterized in that: The pharmaceutical composition C comprises: A first pharmaceutical composition C-1, which includes a PD-L1 small molecule inhibitor and a pharmaceutical excipient; and, The second pharmaceutical composition C-2 comprises a chemotherapeutic drug molecule and a pharmaceutical excipient.

7. The pharmaceutical composition C according to claim 6, characterized in that The pharmaceutical composition C satisfies one or more of the following conditions: (1) The pharmaceutical composition C has a synergistic effect; (2) The PD-L1 small molecule inhibitor and the chemotherapy drug molecule are as described in claim 2; (3) The content of the PD-L1 small molecule inhibitor is 30-500 mg, preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg; (4) The content of the chemotherapy drug molecule is 10-650 mg, preferably 30-550 mg, such as 20 mg, 30 mg, 60 mg, 100 mg, 150 mg or 500 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is (0.04-50):1, preferably (0.2-16):1, more preferably (0.2-2):1 or (6-16):1, for example 0.45:1, 0.58:1, 1.2:1, 10:1 or 11:1; Preferably, when the first pharmaceutical composition C-1 comprises the compound of formula I as claimed in claim 2 and a pharmaceutical excipient, and the second pharmaceutical composition C-2 comprises capecitabine and a pharmaceutical excipient, the mass ratio of the compound of formula I to the capecitabine is preferably (0.2-2):1, for example, 0.45:1, 0.58:1 or 1.2:1; when the first pharmaceutical composition C-1 comprises the compound of formula I as claimed in claim 2 and a pharmaceutical excipient, and the second pharmaceutical composition C-2 comprises paclitaxel and a pharmaceutical excipient, the mass ratio of the compound of formula I to the paclitaxel is preferably (6-16):1, for example, 10:1 or 11:1; when the first pharmaceutical composition C-1 comprises the compound of formula I as described above and a pharmaceutical excipient, and the second pharmaceutical composition C-2 comprises temozolomide and a pharmaceutical excipient, the mass ratio of the compound of formula I to the temozolomide is preferably (6-16):1, for example, 6:1, 9.5:1 or 16:1; (6) The pharmaceutical composition C consists of a first pharmaceutical composition C-1 and a second pharmaceutical composition C-2; the first pharmaceutical composition C-1 consists of the PD-L1 small molecule inhibitor and pharmaceutical excipients; the second pharmaceutical composition C-2 consists of the chemotherapeutic drug molecule and pharmaceutical excipients; (7) The first pharmaceutical composition C-1 is presented in an oral dosage form; (8) The second pharmaceutical composition C-2 is presented in the form of an oral dosage form or an injection dosage form.

8. A combination medicine box D, characterized in that: The combination kit D comprises: A first container comprising the first pharmaceutical composition C-1 according to claim 6 or 7; and, A second container comprising the second pharmaceutical composition C-2 according to claim 6 or 7.

9. A pharmaceutical combination E, characterized in that: The drug combination E includes a PD-L1 small molecule inhibitor and a COX-2 inhibitor.

10. The pharmaceutical combination E according to claim 9, characterized in that: The drug combination E satisfies one or more of the following conditions: (1) The drug combination E has a synergistic effect; (2) The PD-L1 small molecule inhibitor is a compound as shown in Formula I or a pharmaceutically acceptable salt thereof; (3) The COX-2 inhibitor is nimesulide, meloxicam, celecoxib or rofecoxib, preferably celecoxib; (4) The mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is (0.1-10):1, more preferably (2-10):1, for example 6:1 or 7.5:1; (5) The active ingredients of the drug combination E are the PD-L1 small molecule inhibitor and the COX-2 inhibitor; (6) The PD-L1 small molecule inhibitor is administered via the gastrointestinal tract, injection, respiratory tract or local administration, such as oral administration; (7) The COX-2 inhibitor is administered via the gastrointestinal tract, injection, respiratory tract or topical administration, for example, orally.

11. A pharmaceutical composition F, characterized in that: The pharmaceutical composition F comprises a PD-L1 small molecule inhibitor, a COX-2 inhibitor and pharmaceutical excipients.

12. The pharmaceutical composition F according to claim 11, characterized in that The pharmaceutical composition F satisfies one or more of the following conditions: (1) The pharmaceutical composition F has a synergistic effect; (2) The PD-L1 small molecule inhibitor and the COX-2 inhibitor are as described in claim 10; (3) The content of the PD-L1 small molecule inhibitor is 30-500 mg, preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg; (4) the content of the COX-2 inhibitor is 50-250 mg, preferably 100-200 mg, for example 100 mg or 200 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is (0.1-10):1, preferably (2-10):1, for example 6:1 or 7.5:1; (6) The active ingredients of the pharmaceutical composition F are the PD-L1 small molecule inhibitor and the COX-2 inhibitor; (7) The dosage forms of the pharmaceutical composition F include gastrointestinal dosage forms and parenteral dosage forms, preferably capsules, tablets, pills, granules, powders or oral liquids.

13. A pharmaceutical composition G, characterized in that: The pharmaceutical composition G comprises: A first pharmaceutical composition G-1, which includes a PD-L1 small molecule inhibitor and a pharmaceutical excipient; and, The second pharmaceutical composition G-2 comprises a COX-2 inhibitor and pharmaceutically acceptable excipients.

14. The pharmaceutical composition G according to claim 13, characterized in that The pharmaceutical composition G satisfies one or more of the following conditions: (1) The pharmaceutical composition G has a synergistic effect; (2) The PD-L1 small molecule inhibitor and COX-2 inhibitor are as described in claim 10; (3) The content of the PD-L1 small molecule inhibitor is 30-500 mg, preferably 40-400 mg, such as 50 mg, 150 mg or 300 mg; (4) the content of the COX-2 inhibitor is 50-250 mg, preferably 100-200 mg, for example 100 mg or 200 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is (0.1-10):1, preferably (2-10):1, for example 6:1 or 7.5:1; (6) The pharmaceutical composition G consists of a first pharmaceutical composition G-1 and a second pharmaceutical composition G-2; the first pharmaceutical composition G-1 consists of the PD-L1 small molecule inhibitor and pharmaceutical excipients, and the second pharmaceutical composition G-2 consists of the COX-2 inhibitor and pharmaceutical excipients; (7) The first pharmaceutical composition G-1 is presented in an oral dosage form; (8) The second pharmaceutical composition G-2 is presented in an oral dosage form.

15. A combination medicine box H, characterized in that: The combined medicine kit H comprises: A first container comprising the first pharmaceutical composition G-1 according to claim 13 or 14; and, A second container comprising the second pharmaceutical composition G-2 according to claim 13 or 14.

16. A use of the pharmaceutical combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, the pharmaceutical composition C according to claim 6 or 7, the pharmaceutical combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 in the preparation of a medicament for treating a tumor; the tumor is preferably one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumors, adrenal tumors, renal cell carcinoma, neuroblastoma and glioma, more preferably breast cancer, gastric cancer, nasopharyngeal cancer or glioma.

17. A method for treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, the pharmaceutical composition C according to claim 6 or 7, the pharmaceutical combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14.

18. The method for treating tumors according to claim 17, characterized in that: The method for treating tumors satisfies one or more of the following conditions: (1) The tumor is one or more of gastric cancer, nasopharyngeal cancer, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumor, adrenal tumor, renal cell carcinoma, neuroblastoma and brain glioma, preferably breast cancer, gastric cancer, nasopharyngeal cancer or brain glioma; (2) The total daily dosage of the PD-L1 small molecule inhibitor is in the range of 30-2400 mg; preferably 500-2000 mg; for example 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg or 1900 mg; (3) The administration frequency of the PD-L1 small molecule inhibitor is twice a day, once a day, or once every two days, preferably twice a day; (4) When a therapeutically effective amount of the pharmaceutical combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, or the pharmaceutical composition C according to claim 6 or 7 is administered to a subject in need thereof, when the chemotherapy drug molecule is capecitabine, the total daily dose range is 1000-3000 mg / m 2 , preferably 1000 mg / m 2 , 1250mg / m 2 , 1500mg / m 2 , 1750mg / m 2 , 2000mg / m 2 , 2250mg / m 2 , 2500mg / m 2 , 2750mg / m 2 or 3000 mg / m 2 , for example 2000mg / m 2 or 2500 mg / m 2 ; The frequency of administration is once a day or twice a day, preferably twice a day; (5) When a therapeutically effective amount of the drug combination A according to any one of claims 1 to 3, the drug composition B according to claim 4 or 5, or the drug composition C according to claim 6 or 7 is administered to a subject in need thereof, when the chemotherapy drug molecule is paclitaxel, the total daily dose range is 50-200 mg / m 2 , preferably 50 mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 125mg / m 2 , 135mg / m 2 , 145mg / m 2 , 155mg / m 2 , 165mg / m 2 , 175mg / m 2 , 185mg / m 2 , 195mg / m 2 or 200 mg / m 2 , for example 80 mg / m 2 , 135mg / m 2 or 175 mg / m 2 ; The frequency of administration is once every two weeks, once every three weeks or once every four weeks; preferably once every three weeks; (6) When a therapeutically effective amount of the pharmaceutical combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, or the pharmaceutical composition C according to claim 6 or 7 is administered to a subject in need thereof, when the chemotherapy drug molecule is temozolomide, the total daily dose range is 100-250 mg / m 2 , preferably 100 mg / m 2 , 125mg / m 2 , 150mg / m 2 , 175mg / m 2 , 200mg / m 2 , 225mg / m 2 or 250 mg / m 2 , for example 150 mg / m 2 or 200 mg / m 2 ; The frequency of administration is once a day for 5 days, and then the next cycle begins after 23 days of drug withdrawal; (7) When a therapeutically effective amount of the pharmaceutical combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 is administered to a subject in need thereof, the total daily dose of the COX-2 inhibitor is in the range of 50-250 mg, preferably 100-200 mg, for example 100 mg or 200 mg; (8) When a therapeutically effective amount of the pharmaceutical combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 is administered to a subject in need thereof, the COX-2 inhibitor is administered once a day or twice a day.

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