Compounds and methods for treating chemotherapy-associated gastrointestinal side effects - Patents.com

Abstract

A method for treating chemotherapy-associated gastrointestinal side effects, particularly relating to the use of a CDK inhibitor in the preparation of a medicament. The medicament is used to prevent, alleviate and / or treat chemotherapy-associated gastrointestinal side effects in a subject. The CDK inhibitor includes a CDK1 inhibitor, a CDK2 inhibitor, a CDK3 inhibitor, a CDK4 inhibitor, a CDK5 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, a CDK8 inhibitor and / or a CDK9 inhibitor. The chemotherapeutic agent may be selected from fluorouracil, oxaliplatin, topotecan, irinotecan, tetrahydrofolic acid, docetaxel, and the like. The gastrointestinal side effects include diarrhea, constipation, and the like.

Description

[Technical field]

[0001] The present application relates to the biomedical field, and in particular to methods of treating chemotherapy-associated gastrointestinal side effects using CDK inhibitors. [Background technology]

[0002] Tumor chemotherapy is one of the most commonly used means for treating tumors clinically, mainly utilizing chemical drugs (chemotherapeutic agents) to prevent the proliferation, invasion, and metastasis of cancer cells, and ultimately kill cancer cells. However, the administration of chemotherapeutic agents can not only kill rapidly growing and isolated tumor cells, but also kill normal cells and immune cells at the same time, and thus may cause severe side effects, including nausea, vomiting, anemia, inflammation, and infections. Such side effects may lead to the discontinuation or reduction of the dosage of chemotherapeutic agents, greatly affecting the therapeutic effect on the patient's tumor, impairing the quality of life of the patient, and endangering the patient's life in severe cases.

[0003] Successful treatment regimens for controlling the side effects associated with the administration of chemotherapeutic agents are not yet available in the prior art. Therefore, there is an urgent need for treatment regimens that can successfully control these side effects. Summary of the Invention

[0004] The present application provides a method for preventing, alleviating and / or treating chemotherapy-associated gastrointestinal side effects (e.g., diarrhea or constipation) in a subject, the method comprising administering a cyclin-dependent kinase (CDK) inhibitor to the subject. The medicament of the present application can effectively alleviate chemotherapy-associated gastrointestinal side effects.

[0005] In one aspect, the application provides the use of a cyclin-dependent kinase (CDK) inhibitor in the preparation of a medicament used to prevent, reduce and / or treat a gastrointestinal side effect associated with chemotherapy in a subject.

[0006] In some embodiments, a CDK inhibitor comprises an agent that reduces the expression of a CDK and / or an agent that reduces the activity of a CDK.

[0007] In some embodiments, the CDK inhibitor acts directly on a CDK protein, a nucleic acid encoding a CDK protein, a cyclin and / or a nucleic acid encoding a cyclin.

[0008] In some embodiments, the CDK inhibitor comprises a CDK1 inhibitor, a CDK2 inhibitor, a CDK3 inhibitor, a CDK4 inhibitor, a CDK5 inhibitor, a CDK6 inhibitor, a CDK7 inhibitor, a CDK8 inhibitor, and / or a CDK9 inhibitor.

[0009] In some embodiments, the CDK inhibitor comprises a CDK2 inhibitor.

[0010] In some embodiments, the CDK inhibitor comprises a CDK4 inhibitor.

[0011] In some embodiments, the CDK inhibitor comprises a CDK6 inhibitor.

[0012] In some embodiments, the CDK inhibitor comprises a CDK9 inhibitor.

[0013] In some embodiments, the CDK inhibitor comprises a CDK4 / 6 inhibitor.

[0014] In some embodiments, the CDK inhibitor comprises a CDK2 / 4 / 6 inhibitor.

[0015] In some embodiments, the CDK inhibitor comprises a CDK4 / 6 / 9 inhibitor.

[0016] In some embodiments, the CDK inhibitor comprises a CDK inhibitor for local intestinal exposure.

[0017] In some embodiments, the CDK inhibitor comprises a small molecule compound, a protein and / or a nucleic acid molecule.

[0018] In some embodiments, the CDK inhibitor comprises a small molecule CDK inhibitor, a protein macromolecule that specifically binds to a CDK, an RNAi that inhibits expression of a CDK protein, and / or an antisense oligonucleotide that inhibits expression of a CDK protein.

[0019] In some embodiments, small molecule CDK inhibitors include small molecule CDK inhibitors that bind reversibly to a CDK, small molecule CDK inhibitors that bind irreversibly to a CDK, and / or small molecule CDK inhibitors that specifically bind to a mutant CDK.

[0020] In some embodiments, the small molecule CDK inhibitor has a molecular weight that is 2000 daltons or less, 1500 daltons or less, 1200 daltons or less, 1000 daltons or less, 900 daltons or less, 800 daltons or less, 700 daltons or less, 600 daltons or less, 500 daltons or less, 400 daltons or less, 300 daltons or less, 200 daltons or less and / or 100 daltons or less.

[0021] In some embodiments, the CDK inhibitor is selected from the following group: trilaciclib, palbociclib, ribociclib, abemaciclib, FLX-925, SHR-6390, BPI-1178, BPI-16350, FCN 437, G2T28, XZP-3287, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, MM-D37K, zotiraciclib, XZP-3287, rigosertib, KRX-0601, ribiciclib, roniciclib, milciclib, seliciclib, roscovitine, indisulam, alvocidib, NUV-422, BEY-1107, GLR-2007, FN-1501 , BCD-115, TP-1287, BAY-1251152, atabeciclib, SEL-120, HX-301, voruciclib, fadraciclib, AGM-130, PHA-793887, PHA-690509, dinaciclib, RO4584820, R547, AT-7519, RGB-286638, ZK-304709, IIIM-290, PF-07104091 and G1T38.

[0022] In some embodiments, chemotherapy comprises administration of a chemotherapeutic agent, hi some embodiments, the chemotherapeutic agent is a cytotoxic agent.

[0023] In some embodiments, the chemotherapeutic agent is one or more selected from the following group: DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topoisomerase inhibitors, and / or telomerase synthesis inhibitors.

[0024] In some embodiments, the chemotherapeutic agent is selected from fluorouracil, oxaliplatin, tetrahydrofolic acid, irinotecan, topotecan, docetaxel, gemcitabine, etoposide, carboplatin, methotrexate, doxorubicin, cytarabine, vinorelbine, and capecitabine, and combinations thereof.

[0025] In some embodiments, the chemotherapeutic agent does not include a tumor targeted drug. In some embodiments, the chemotherapeutic agent does not include a tyrosine kinase inhibitor. In some embodiments, the chemotherapeutic agent does not include an EGFR targeted anti-tumor drug. In some embodiments, the chemotherapeutic agent does not include a PI3K targeted anti-tumor drug. In some embodiments, the chemotherapeutic agent does not include an FGFR4 targeted anti-tumor drug. In some embodiments, the chemotherapeutic agent does not include afatinib, idelalisib, fisogatinib, imatinib, and osimertinib.

[0026] In some embodiments, the chemotherapeutic agents are administered continuously and / or discontinuously.

[0027] In some embodiments, the chemotherapeutic agents do not include chemotherapeutic agents with a continuous administration time of 7 days or more.

[0028] In some embodiments, chemotherapy is administered in combination with one or more other therapies.

[0029] In some embodiments, chemotherapy-associated gastrointestinal side effects include gastrointestinal side effects caused by chemotherapy.

[0030] In some embodiments, chemotherapy-associated gastrointestinal side effects include gastrointestinal adverse events that occur or worsen following administration of a chemotherapeutic agent.

[0031] In some embodiments, the gastrointestinal adverse event occurs or worsens in the absence of prophylaxis or treatment at about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 1 day, about 2 days, about 4 days, about 7 days, about 2 weeks, about 3 weeks, about 1 month, about 2 months or more after administration of the chemotherapeutic agent.

[0032] In some embodiments, the gastrointestinal side effect comprises a gastric mucosal damaging disease and / or an intestinal mucosal damaging disease. In some embodiments, the gastrointestinal side effect is not a side effect caused by bone marrow suppression.

[0033] In some embodiments, gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, anorexia, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulcers, intestinal necrosis.

[0034] In some embodiments, gastrointestinal side effects include diarrhea, constipation.

[0035] In some embodiments, the severity of the gastrointestinal side effects is Grade 1 or greater, Grade 2 or greater, Grade 3 or greater, Grade 4 or greater, or Grade 5, as assessed according to NCI-CTCAE V5.0.

[0036] In some embodiments, the subject comprises a cancer patient.

[0037] In some embodiments, the medicament does not substantially affect the therapeutic effect of the chemotherapy.

[0038] In some embodiments, the medicament is administered about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours or more prior to administration of the chemotherapy.

[0039] In some embodiments, the medicament is administered about 0.5 to 12 hours prior to administration of the chemotherapy.

[0040] In some embodiments, the medicament is formulated for oral administration, intravenous injection, subcutaneous injection, intraperitoneal injection, and / or intramuscular injection.

[0041] In some embodiments, the medicament is prepared for administration by injection. In some embodiments, the medicament is prepared as an injectable solution.

[0042] In some embodiments, the medicament is formulated for oral administration, hi some embodiments, the medicament is formulated as a tablet and / or capsule.

[0043] In some embodiments, the medicament further comprises one or more other active ingredients.

[0044] In some embodiments, the CDK inhibitor can independently ameliorate or reduce gastrointestinal side effects.

[0045] In another aspect, the application provides the use of a cyclin-dependent kinase (CDK) inhibitor in the preparation of a medicament used to prevent or treat chemotherapy-associated diarrhea in a subject.

[0046] In another aspect, the application provides the use of a cyclin-dependent kinase (CDK) inhibitor in the preparation of a medicament used to prevent or treat chemotherapy-associated constipation in a subject.

[0047] In another aspect, the present application provides a method for preventing, reducing and / or treating gastrointestinal side effects associated with chemotherapy, comprising administering to a subject in need thereof a CDK inhibitor of the present application.

[0048] In another aspect, the present application provides a CDK inhibitor for use in preventing, reducing and / or treating gastrointestinal side effects associated with chemotherapy.

[0049] In another aspect, the present application provides a method of preventing, alleviating and / or treating chemotherapy-associated diarrhea, comprising administering to a subject in need thereof a CDK inhibitor of the present application.

[0050] In another aspect, the present application provides a method of preventing, alleviating and / or treating chemotherapy-associated constipation comprising administering to a subject in need thereof a CDK inhibitor of the present application.

[0051] In another aspect, the present application provides a pharmaceutical composition comprising a CDK inhibitor and a medicament for use in chemotherapy.

[0052] In another aspect, the present application provides a kit comprising a CDK inhibitor and a chemotherapeutic agent.

[0053] Other aspects and advantages of the present application will be readily apparent to those skilled in the art from the following detailed description. In the following detailed description, only exemplary embodiments of the present application are shown and described. As will be understood by those skilled in the art, the disclosure of the present application will enable those skilled in the art to modify the disclosed embodiments without departing from the spirit and scope of the invention contained in the present application. Therefore, the drawings and descriptions in the present application specification are illustrative only and not restrictive.

[0054] Particular features of the invention contained in this application are set forth in the appended claims. The features and advantages of the invention contained in this application can be better understood with reference to the exemplary embodiments detailed below and the accompanying drawings, the brief description of which follows. [Brief description of the drawings]

[0055] [Figure 1] FIG. 1 shows photographs of typical diarrhea in mice in the chemotherapy drug groups of Examples 1 to 229. [Diagram 2] FIG. 2 shows some of the results of diarrhea grading in the control group, the chemotherapy drug group, and the CDK inhibitor groups of Examples 1 to 229. [Diagram 3] FIG. 3 shows some of the results of diarrhea grading in the control group, the chemotherapy agent group, and the CDK inhibitor groups of Examples 230-271. [Figure 4]The figure is a set of photographs showing the number and shape of stools in the control group, the chemotherapy drug group, and the CDK inhibitor groups of Examples 272 to 342. [Diagram 5] FIG. 5 shows the results of the fecal reduction rate for the control group, the chemotherapy drug group, and some of the CDK inhibitor groups of Examples 272-342. [Figure 6] FIG. 6 shows some of the results of diarrhea grading in the control group, the chemotherapy group, and the groups orally administered the CDK inhibitors and the groups intravenously administered the CDK inhibitors of Examples 343 to 381. [Figure 7] FIG. 7 shows some of the results of diarrhea grading in the control group, the chemotherapy group, the groups orally administered the CDK inhibitors of Examples 382 to 405, and the groups administered the CDK inhibitors in other modes. [Figure 8] FIG. 8 shows some of the results of the fecal reduction rate in the control group, the chemotherapy group, the groups orally administered the CDK inhibitors of Examples 406 to 443, and the groups administered the CDK inhibitors via other modes. [Figure 9] FIG. 9 shows some of the results of diarrhea grading in the control group, the chemotherapy agent group, and the CDK inhibitor groups of Examples 444 to 469. [Figure 10] FIG. 10 shows the results of the fecal reduction rate for the control group, the chemotherapy drug group, and some of the CDK inhibitor groups of Examples 470-481. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] The embodiments of the present invention are described below as examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the disclosure of this specification.

[0057] Definition of Terms In this application, the term "CDK inhibitor" generally refers to any molecule known in the art or to be discovered in the future that can block, reduce or inhibit the activity or function of CDK (cyclin-dependent kinase), including, but not limited to, small molecule compounds, polynucleotides (e.g., DNA or RNA), and / or polypeptides (e.g., antibodies or antigen-binding portions thereof). CDK inhibitors can act directly on CDK, e.g., via binding to CDK, or indirectly, e.g., via preventing the interaction between CDK and its ligand, inhibiting cyclins, or inhibiting the activity of substrates. CDKs are a class of kinases of the protein kinase family that can be used to regulate cell cycle and are also involved in regulating transcription, mRNA processing, and differentiation of neuronal cells. CDK in this application may refer to intact CDK or kinase domain fragments, and also encompasses CDKs from various vertebrates (e.g., human, monkey, mouse, dog, rabbit, etc.). According to different binding cyclins, CDKs can be divided into different types. In the present application, the CDK inhibitor can inhibit one or more of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CLK, Cdc, CDK11, CDK12, CDK13 and CDK19. For example, there are four CDKs clearly involved in cell proliferation, namely CDK1, which mainly regulates the transition from G2 to M phase, CDK2, CDK4 and CDK6, which control the transition from G1 to S phase. The CDK inhibitor of the present application can include selective CDK inhibitors and broad-spectrum CDK inhibitors.

[0058] In this application, the term "CDK2 inhibitor" generally refers to an inhibitor that acts on CDK2 of the CDK family. In all members of the CDK family, it mainly has an inhibitory effect on CDK2, but does not exclude the possibility that it has an inhibitory effect on members of the CDK family other than CDK2, and does not exclude the possibility that it has an inhibitory effect on other molecules other than the CDK family. Exemplary CDK2 inhibitors can include, but are not limited to, A-674563, MK-8776 (SCH 900776), dinaciclib (SCH727965), JNJ-7706621, R547, AZD5438, PHA-793887, BMS-265246, SU9516, SNS-032 (BMS-387032), flavopiridol (alvocidib), flavopiridol (alvocidib) HCl, milciclib (PHA-848125), AT7519, P276-00, PHA-767491, roscovitine (seliciclib, CYC202), NU6027, and / or LDC000067.

[0059] In this application, the term "CDK4 inhibitor" generally refers to an inhibitor that acts on CDK4 of the CDK family. In all members of the CDK family, the inhibitor mainly has an inhibitory effect on CDK4. However, it does not exclude the possibility that the inhibitor has an inhibitory effect on members of the CDK family other than CDK4, and does not exclude the possibility that the inhibitor has an inhibitory effect on other molecules other than the CDK family. Exemplary CDK4 inhibitors can include, but are not limited to, R547, LY2835219, palbociclib (PD-0332991) HCl, palbociclib (PD0332991) isethionate, flavopiridol (alvocidib), flavopiridol (alvocidib) HCl, PHA-793887, P276-00, AT7519, milciclib (PHA-848125), SU9516, BMS-265246, JNJ-7706621, SNS-032 (BMS-387032), LDC000067, and / or LEE011.

[0060] In this application, the term "CDK6 inhibitor" generally refers to an inhibitor that acts on CDK6 of the CDK family. In all members of the CDK family, it mainly has an inhibitory effect on CDK6, but does not exclude the possibility of having an inhibitory effect on members of the CDK family other than CDK6, and does not exclude the possibility of having an inhibitory effect on other molecules outside the CDK family. Exemplary CDK6 inhibitors may include, but are not limited to, LY2835219, palbociclib (PD-0332991) HCl, palbociclib (PD0332991) isethionate, flavopiridol (alvocidib), flavopiridol (alvocidib) HCl, AT7519, JNJ-7706621, P276-00 and / or LEE011.

[0061] In this application, the term "CDK9 inhibitor" generally refers to an inhibitor that acts on CDK9 of the CDK family. In all members of the CDK family, it has an inhibitory effect mainly on CDK9, but does not exclude the possibility of having an inhibitory effect on members of the CDK family other than CDK9, and does not exclude the possibility of having an inhibitory effect on other molecules outside the CDK family. Exemplary CDK9 inhibitors may include, but are not limited to, LY2835219, palbociclib (PD-0332991) HCl, palbociclib (PD0332991) isethionate, flavopiridol (alvocidib), flavopiridol (alvocidib) HCl, AT7519, JNJ-7706621, P276-00 and / or LEE011.

[0062] In this application, the term "CDK2 / 4 / 6 inhibitor" generally refers to an inhibitor that acts on all of the CDK family members CDK2, CDK4 and CDK6. In all members of the CDK family, the inhibitor has an inhibitory effect mainly on CDK2, CDK4 and CDK6, but does not exclude the possibility of having an inhibitory effect on members of the CDK family other than CDK2, CDK4 and CDK6, and does not exclude the possibility of having an inhibitory effect on other molecules outside the CDK family. CDK2 / 4 / 6 inhibitors do not need to have the same or similar effects on CDK2, CDK4 and CDK6. Exemplary CDK2 / 4 / 6 inhibitors may include, but are not limited to, AT7519 HCl, ribiciclib hydrochloride (P276-00), flavopiridol HCl, AT7519, JNJ-7706621 and / or flavopiridol (L86-8275).

[0063] In this application, the term "CDK4 / 6 inhibitor" generally refers to an inhibitor that acts on both CDK4 and CDK6 of the CDK family. In all members of the CDK family, it has an inhibitory effect mainly on CDK4 and CDK6, but does not exclude the possibility of having an inhibitory effect on members of the CDK family other than CDK4 and CDK6, and does not exclude the possibility of having an inhibitory effect on other molecules outside the CDK family. CDK4 / 6 inhibitors do not need to have the same or similar effects on CDK4 and CDK6. Exemplary CDK4 / 6 inhibitors may include, but are not limited to, ribociclib succinate, ribociclib hydrochloride, palbociclib, trilaciclib, G1T38, abemaciclib, ON123300, AT7519 HCl, ribociclib (LEE011), abemaciclib mesylate (LY2835219), ribiciclib hydrochloride (P276-00), palbociclib (PD0332991) isethionate, flavopiridol HCl, AT7519, JNJ-7706621, flavopiridol (L86-8275), and / or palbociclib (PD-0332991) HCl.

[0064] In this application, "CDK4 / 6 / 9 inhibitor" generally refers to an inhibitor that acts on all of the CDK family members CDK4, CDK6 and CDK9. In all members of the CDK family, the inhibitor has an inhibitory effect mainly on CDK4, CDK6 and CDK9, but does not exclude the possibility of having an inhibitory effect on members of the CDK family other than CDK4, CDK6 and CDK9, and does not exclude the possibility of having an inhibitory effect on other molecules outside the CDK family. CDK4 / 6 / 9 inhibitors do not need to have the same or similar effects on CDK4, CDK6 and CDK9. Exemplary CDK4 / 6 / 9 inhibitors may include, but are not limited to, G1T38, AT7519 HCl, ribiciclib hydrochloride (P276-00), AT7519 and / or flavopiridol (L86-8275).

[0065] In this application, the term "chemotherapy" generally refers to a therapy that uses chemotherapeutic agents to treat tumors, which may result in the death of cancer cells or may interfere with the division, repair, growth and / or function of cancer cells. The medicines used in chemotherapy are chemotherapeutic agents. Chemotherapeutic agents include chemicals or biological substances that can cause the death of cancer cells or interfere with the growth, division, repair and / or function of cancer cells. For example, chemotherapy may include cytotoxic agents, cell inhibitors and antitumor agents that can kill tumor cells, inhibit the growth or metastasis of tumor cells, or disrupt the cell cycle of rapidly proliferating cells. Chemotherapeutic agents include natural compounds found in animals and plants or man-made chemicals. In this application, chemotherapy or chemotherapeutic agents have low selectivity for tumor cells and normal cells, and therefore may interfere with the growth, division, repair and / or function of normal cells (e.g., bone marrow cells, hair follicle cells or gastrointestinal cells), ultimately resulting in the death of normal cells. The chemotherapeutic agent in the present application may not include tumor targeting agents, i.e., the chemotherapeutic agent in the present application does not include substances that can specifically recognize tumor cells, tumor tissues, tumor organs, or proteins specifically expressed by tumor cells (e.g., tumor-associated antigens or tumor-specific antigens). Due to genetic mutations or other factors, some kinases or phosphate kinases are activated, causing the reproduction of cancer cells. The chemotherapeutic agent in the present application also does not include kinase inhibitors that prevent the division of cancer cells by inhibiting abnormally activated kinases. The chemotherapeutic agent in the present application also does not include antibodies and / or angiogenesis inhibitors.

[0066] In the present application, examples of chemotherapeutic agents may include, but are not limited to, alkylating agents such as mechlorethamine, ethylenimine compounds, alkylsulfonates and other compounds with alkylating effects such as nitrosoureas, cisplatin and dacarbazine; antimetabolites such as folic acid, purine or pyrimidine antagonists; mitotic inhibitors such as vinca alkaloids and podophyllotoxin derivatives; cytotoxic antibiotics and camptothecin derivatives. Chemotherapeutic agents also include amifostine, cisplatin, dacarbazine (DTIC), dactinomycin, streptomycin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin, doxorubicin liposomal, gemcitabine, erythromycin, daunorubicin liposomal, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil (5-FU), vinblastine, vincristine, bleomycin, paclitaxel, docetaxel, aldesleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, CPT-11 , 10-hydroxyl-7-ethyl-camptothecin (SN38), floxuridine, fludarabine, hydroxyurea, ifosfamide, idarubicin, mesna, interferon alpha, interferon beta, irinotecan, mitoxantrone, topotecan, lupulone, megestrol, melphalan, mercaptopurine, plicamycin, mitotane, oncaspase, pegaspargase, pentostatin, pipobroman, plicamycin, streptozocin, tamoxifen, teniposide, testosterone, thioguanine, thiotepa, uramustine, vinorelbine, chlorambucil aromatase inhibitors and combinations thereof.

[0067] In this application, the term "cytotoxic agent" generally refers to an agent for inhibiting a biological process of a cell or for reducing the viability or proliferation ability of a cell. Cytotoxic agents may act in a variety of ways, for example, but not limited to, through inducing DNA damage, inducing cell cycle arrest, inhibiting DNA synthesis, inhibiting transcription, inhibiting translation or protein synthesis, inhibiting cell division, or inducing apoptosis.

[0068] In this application, the term "does not substantially affect" generally refers to the fact that the use of the combination of the medicament and chemotherapy of the present application has the same therapeutic effect or does not cause significant disadvantages compared to the therapeutic effect of using chemotherapy alone.For example, for any subject, the use of the combination of the medicament and chemotherapy causes the same degree of tumor size reduction, or the degree of reduction is about 5% or more, about 4% or more, about 3% or more, about 2% or more, about 1% or more, about 0.5% or more, about 0.1% or more, about 0.01% or more, about 0.001% or more or less than the therapeutic effect of using chemotherapy alone.

[0069] In this application, the term "continuous administration" generally refers to repeated administration of the same medicament every day. Repeated daily administration can be once a day, twice a day, three times a day or more. For example, continuous administration can be once a day for at least more than two days. For example, a continuous administration time of 2 days can mean continuous administration once a day (twice, three or more times) for two days. For example, a continuous administration time of 3 days can mean continuous administration once a day (twice, three or more times) for three days. For example, a continuous administration time of 5 days can mean continuous administration once a day (twice, three or more times) for five days. For example, a continuous administration time of 7 days can mean continuous administration once a day (twice, three or more times) for seven days. For example, a continuous administration time of 10 days can mean continuous administration once a day (twice, three or more times) for ten days. For example, a 14 day continuous dosing period can mean 1 (2, 3 or more) consecutive dosings per day for 14 days. For example, a greater than 7 day continuous dosing period can mean 1 (2, 3 or more) consecutive dosings per day for more than 7 days.

[0070] In this application, the term "discontinuous administration" generally refers to a mode of administration in which the same medicament is not administered every day in a dosing cycle also known as intermittent administration and / or pulse administration. Discontinuous administration may be regular or irregular. In discontinuous administration, if the dosing cycle is longer than 7 days, any continuous period of daily administration, lasting for 7 days or more, also belongs to the case of "continuous administration time of 7 days or more".

[0071] In this application, the term "gastrointestinal adverse events" generally refers to adverse and undesirable reactions, effects, actions, consequences, results, or influences related to or appearing in the gastrointestinal tract caused by a particular medicine or other medical treatment such as chemotherapy or surgery. They are also known as gastrointestinal adverse effects, gastrointestinal side effects, or gastrointestinal adverse results. Gastrointestinal adverse events include adverse events in various parts of the digestive system (e.g., the digestive tract and glands). For example, gastrointestinal adverse events include abdominal distension, abdominal pain, fissures, anal fistula, anal bleeding, anal mucositis, anal necrosis, anal pain, anal stenosis, anal ulcer, ascites, hiccups, cecal bleeding, cheilitis, chylous ascites, colitis, colonic fistula, colonic bleeding, colonic obstruction, colonic perforation, colonic stenosis, colonic ulcer, constipation, dental caries, diarrhea, xerostomia, duodenal fistula, duodenal bleeding, duodenal obstruction, duodenal perforation , duodenal stenosis, duodenal ulcer, dyspepsia, dysphagia, enteritis, intestinal fistula, esophageal fistula, esophageal bleeding, esophageal necrosis, esophageal obstruction, esophageal pain, esophageal perforation, esophageal stenosis, esophageal ulcer, esophageal varices bleeding, esophagitis, fecal incontinence, intestinal gas, gastric fistula, gastric bleeding, gastric necrosis, gastric perforation, gastric stenosis, gastric ulcer, gastritis, gastroesophageal reflux disease, gastrointestinal disease (others to note), gastrointestinal fistula, gastrointestinal pain, gastroparesis, Gingival pain, hemorrhoidal bleeding, hemorrhoids, ileal fistula, ileal bleeding, ileocecal, ileal perforation, ileal stenosis, ileal ulcer, ileum, intraperitoneal bleeding, jejunal fistula, jejunal bleeding, jejunal obstruction, jejunal perforation, jejunal stenosis, jejunal ulcer, lip pain, lower gastrointestinal bleeding, malabsorption, oral mucositis, nausea, gastric obstruction, oral fistula, oral paresthesia, oral bleeding, oral pain, pancreatic duct stenosis, pancreatic fistula, pancreatic bleeding, pancreatic necrosis, pancreatitis, periodontal disease, peritoneum These may include, but are not limited to, necrosis, proctitis, rectal rupture, rectal fistula, rectal bleeding, rectal mucositis, rectal necrosis, rectal obstruction, rectal pain, rectal perforation, rectal stenosis, rectal ulcer retroperitoneal hemorrhage, salivary duct inflammation, salivary gland fistula, small intestinal mucositis, small intestinal obstruction, small intestinal perforation, small intestinal stenosis, small intestinal ulcer, abdominal pain, impaired dental development, dental staining, toothache, appendicitis, upper gastrointestinal bleeding, visceral artery ischemia, and vomiting.

[0072] In this application, the term "gastrointestinal side effects" generally refers to harmful and adverse effects related to or exhibited in the gastrointestinal tract area caused by a prophylactic or therapeutic agent. Adverse effects are always undesirable, but undesirable effects are not necessarily harmful. Adverse effects of a prophylactic or therapeutic agent may be harmful, inappropriate, or dangerous. Gastrointestinal side effects include side effects in various parts of the digestive system (e.g., the digestive tract and glands). Gastrointestinal side effects associated with chemotherapy may refer to abnormal clinical symptoms of the gastrointestinal tract related to the time of use of the chemotherapy agent, although there may be no causal relationship between these abnormal symptoms and the administration of the chemotherapy agent.

[0073] In this application, the term "gastric mucosa damage disease" generally refers to a disease or disorder accompanied by symptoms of gastric mucosa damage, which may include abnormal color of the gastric mucosa, bleeding spots, congestion and erosion.

[0074] In this application, the term "intestinal mucosa damage disease" generally refers to a disease or disorder accompanied by symptoms of intestinal mucosa damage, which may include abnormal color of the intestinal mucosa, bleeding spots, congestion and erosion.

[0075] In this application, the term "diarrhea" generally refers to a disease or disorder characterized by increased peristalsis frequency and / or relaxed or watery peristalsis. In this application, diarrhea may occur or worsen after administration of a chemotherapy agent. In some cases, diarrhea can also be evaluated with reference to animal studies, for example, the severity of diarrhea is scored according to the method of Akinobu Kurita (Cancer Chemother Pharmacol 2000;46:211-20.), where grade 0: normal stool; grade 1: mild diarrhea, slightly moist and soft stool; grade 2: moderate diarrhea, soft stool and mild perianal staining; grade 3: severe diarrhea, watery stool, and severe perianal staining.

[0076] In this application, the term "constipation" generally refers to a disease or disorder characterized by irregular, infrequent, or difficult bowel movements. In this application, constipation may occur or worsen following administration of chemotherapy.

[0077] In this application, the term "in the absence of prevention or treatment" generally refers to a state in which no prevention or treatment is performed against a gastrointestinal adverse event, and no measures are taken to weaken or eliminate the gastrointestinal adverse event. Measures to weaken or eliminate the gastrointestinal adverse event may be, for example, administration of a medicine or other means for preventing or treating the gastrointestinal adverse event, or the cessation of administration of a medicine or other means that causes the gastrointestinal adverse event (including administration of a CDK inhibitor or a medicine of this application). In this application, if no measures are taken to weaken or eliminate the gastrointestinal adverse event after administration of the chemotherapy of this application, the gastrointestinal adverse event will occur or worsen 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 1 day, 2 days, 4 days, 7 days, 2 weeks, 3 weeks, 1 month, 2 months or more after administration of the chemotherapy. When a CDK inhibitor or a medicine of this application is administered, the gastrointestinal adverse event may be weakened or eliminated.

[0078] In this application, the term "NCI-CTCAE" generally refers to the standardized definition of adverse events-Common Terminology Criteria for Adverse Events (CTCAE) issued by the National Cancer Institute (NCI) and is used to describe the severity of organ toxicity in patients treated for cancer. The criteria may be continuously updated as scientific evidence evolves. In this application, diarrhea may be evaluated with reference to the evaluation criteria of "NCI-CTCAE". NCI-CTCAE may include any version of "NCI-CTCAE". In CTCAE V5.0, constipation and diarrhea are each defined into five grades, as shown in Table 1 and Table 2. [Table 1] [Table 2]

[0079] In this application, the term "local intestinal exposure", when used to describe a compound, generally means that the compound acts preferentially in the intestinal lumen by a particular administration or delivery method, rather than being fully exposed to the systemic circulation, also known as "gut-restricted" or "gut-restricted compound". Local intestinal exposure can reduce the systemic exposure of the compound or its derivatives, reduce the effects on cells, tissues and organs / organ systems that are not related to the desired disease treatment, and thus improve the safety of the molecule. Compounds can be delivered locally or targeted to the intestinal tract by adjusting the type of compound, route of administration, dosage form, mode of administration, dosage, and using auxiliary means such as devices, thereby achieving local intestinal exposure. Compounds for local intestinal exposure have one or more of the following characteristics: (1) intestinal targeted exposure (due to the mode of administration, etc.), and (2) systemic drug concentration is lower than the minimum inhibitory concentration (IC50). For example, administration can be oral administration or by artificial route, such as intubation.

[0080] In this application, the term "independently improve or reduce" generally means that a gastrointestinal side effect can be improved or reduced by using only the medicament or pharmaceutical composition of the present application, without the aid of other medicaments or therapies.

[0081] In this application, the term "cancer" generally refers to any medical condition mediated by the growth, proliferation or metastasis of tumor or malignant cells, resulting in solid and non-solid tumors (e.g., leukemia). Cancer in this application may include, but is not limited to, malignant epithelial tumors (epithelial-derived cancers), lung cancer (e.g., non-small cell lung cancer), breast cancer, skin cancer, bladder cancer, colon cancer, gastrointestinal (GI) cancer, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, head and neck cancer, stomach cancer, and laryngeal cancer.

[0082] Detailed Description of the Invention In one aspect, the present application provides the use of a CDK inhibitor in the preparation of a medicament used to prevent or treat a gastrointestinal side effect associated with chemotherapy in a subject. In another aspect, the present application provides a method of preventing, reducing and / or treating a gastrointestinal side effect associated with chemotherapy in a subject, comprising administering a CDK inhibitor to a subject in need thereof.

[0083] CDK inhibitors In this application, a CDK inhibitor can either bind directly to a domain of a CDK kinase to block the activity of the kinase, or occupy the ligand-binding site or a portion thereof of a CDK ligand, or occupy the CDK-binding site or a portion thereof of a cyclin to reduce or block the biological activity of the CDK.

[0084] In the present application, CDK inhibitors may be non-specific inhibitors of CDKs, ie, they also inhibit targets other than CDKs.

[0085] In the present application, the CDK inhibitor acts directly on the CDK protein or on a nucleic acid encoding the CDK protein. In some embodiments, the CDK inhibitor acts directly on the CDK protein. In the present application, when describing an inhibitor and a target protein, the term "acts directly" generally means that the inhibitor can directly bind (including covalently and non-covalently) to the target protein without the aid of other molecules. In some embodiments, the CDK inhibitor can be a small molecule EGFR inhibitor, a protein polymer that specifically binds to EGFR, an RNAi, or an antisense oligonucleotide that inhibits the expression of EGFR protein. In some embodiments, the CDK inhibitor can be a small molecule CDK inhibitor.

[0086] In the present application, CDK inhibitors can be ATP-competitive inhibitors, allosteric site inhibitors, covalent inhibitors and non-ATP-competitive polypeptide mimetics.

[0087] For example, the CDK inhibitor may be a CDK inhibitor that inhibits one or more selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CLK, Cdc, CDK8, CDK10, CDK12, CDK13, CDK19 and CDK11. For example, the CDK inhibitor may be a CDK4 / 6 inhibitor that can simultaneously inhibit CDK6 and CDK4. For example, the CDK inhibitor may be a CDK2 / 4 / 6 inhibitor that can simultaneously inhibit CDK2, CDK4 and CDK6. For example, the CDK inhibitor may be a CDK4 / 6 / 9 inhibitor that can simultaneously inhibit CDK9, CDK4 and CDK6.

[0088] For example, examples of CDK inhibitors include, but are not limited to, trilaciclib, palbociclib, ribociclib, abemaciclib, FLX-925, SHR-6390, BPI-1178, BPI-16350, FCN 437, G2T28, XZP-3287, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, MM-D37K, zotiraclib, XZP-3287, rigosertib, KRX-0601, ribiciclib, roniciclib, milciclib, seliciclib, roscovitine, indisulam, alvocidib, NUV-422, BEY-1107, GLR-2007, FN-1501, BCD-115, TP -1287, BAY-1251152, atubeciclib, SEL-120, HX-301, voruciclib, fadracilib, AGM-130, PHA-793887, PHA-690509, dinaciclib, RO4584820, R547, AT-7519, RGB-286638, ZK-304709, IIIM-290, PF-07104091 and G1T38, as well as other salts, salt forms, crystalline forms, solvates and prodrugs thereof.

[0089] CDK inhibitors can be identified or screened by methods well known in the art, for example, by detecting changes in the expression level of CDK or the activity of the kinase after administration of the compound to be tested. The expression level of CDK or the activity of the kinase can be detected by methods well known in the art, for example, immunohistochemistry, PCR, RT-PCR, in situ hybridization, Southern blot, Western blot, Northern blot, spectrophotometry, and ELISA.

[0090] chemotherapy In the present application, the chemotherapeutic agent used in chemotherapy can be any one compound or medicine used to treat cancer selected from those known to those skilled in the art. In terms of mechanism of action, the chemotherapeutic agent can include DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topoisomerase inhibitors and / or telomerase synthesis inhibitors.

[0091] In the present application, the chemotherapeutic agent may be toxic to cells. In the present application, the chemotherapeutic agent may inhibit cell proliferation. In the present application, the chemotherapeutic agent administered may be a chemotherapeutic agent for DNA damage. In the present application, the chemotherapeutic agent is a protein synthesis inhibitor, a DNA damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binding agent, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binding agent, a DNA polymerase inhibitor, an anticancer enzyme, a RAC1 inhibitor, a thymidylate synthetase inhibitor, an oxazophosphorine compound, an integrin inhibitor (such as cilengitide, camptothecin, homocamptothecin), an antifolate, an antimetabolite, a telomerase inhibitor, and / or a telomeric DNA binding compound.

[0092] For example, alkylating agents may include alkylsulfonates (such as busulfan, improsulfan, and piposulfan), aziridines (such as benzodizepa, carboquone, metholedepa, and uredepa), ethylenimines and methylmelamines (such as altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trimethylolmelamine), mechlorethamines (such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, dichloromethyldiethylamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, and uracil mustard), and nitrosoureas (such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine). Other chemotherapeutic agents may include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin, and streptozotocin. Antimetabolites for chemotherapy can include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine β-1-D-arabinoside, amethopterin, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine, azaserine, 6-azauracil, 2'-azido-2'-deoxynucleosides, 5-bromodeoxycytidine, cytosine β-1-D-arabinoside, diazoxonolol leucine, dideoxynucleosides, 5-fluorodeoxycytidine, 5-fluorodeoxyuridine, and hydroxyurea.

[0093] For example, protein synthesis inhibitors may include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin, ethionine, fluoride, 5-fluorotryptophan, fusidic acid, methylene bisphosphonate and guanylyl iminodiphosphate, kanamycin, kasugamycin, kirromycin and O-methylthreonine. Other protein synthesis inhibitors include modeccin, neomycin, norvaline, pactamycin, paromomycin, puromycin, ricin, shiga toxin, showdomycin, sparsomycin, spectinomycin, streptomycin, tetracycline, thiostreptoton and trimethoprim.

[0094] For example, DNA synthesis inhibitors may include alkylating agents such as dimethyl sulfate, mechlorethamine, and sulfur mustard; intercalating agents such as acridine dyes, actinomycin, anthracene, benzopyrene, ethidium bromide, propidium diiodide-intertwining; topoisomerase inhibitors such as irinotecan, teniposide, coumermycin, nalidixic acid, novobiocin, and oxolinic acid; cell division inhibitors including demecolcine, mitoxantrone, colchicine, vinblastine, and vincristine; and other medications such as distamycin and netropsin.

[0095] In the present application, chemotherapeutic agents include DNA complex binding agents, such as camptothecin or etoposide; thiolate alkylating agents, such as nitrosoureas, BCNU, CCNU, ACNU or fotemustine; guanine alkylating agents, such as temozolomide; tubulin binding agents (such as vinblastine, vincristine, vinorelbine, vinflunine, cryptophycin 52, etc.), halichondrin (such as halichondrin B), aplysiatoxins (such as aplysiatoxin 10 and aplysiatoxin 15), hemiasterins (such as hemiasterin A and hemiasterin B), colchicine, combrestatin, 2 -methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, discodermolide; DNA polymerase inhibitors such as cytarabine; anti-cancer enzymes such as asparaginase; RAC1 inhibitors such as 6-thioguanine; thymidylate synthetase inhibitors such as capecitabine or 5-FU; oxazophosphorine compounds such as endoxan; integrin inhibitors such as cilengitide; antifolates such as pralatrexate; antifolates such as pemetrexed; or camptothecins or homocamptothecins such as diflomotecan.

[0096] In the present application, the CDK inhibitor can be used to treat the gastrointestinal side effects associated with one or more of the above chemotherapy.In the present application, the CDK inhibitor can be used to treat the gastrointestinal side effects associated with the administration of the following chemotherapy agents: fluorouracil, oxaliplatin, irinotecan (CPT-11), docetaxel (DTX), gemcitabine (GEM), paclitaxel, carboplatin, doxorubicin (Dox), methotrexate (MTX), cytarabine (Ara-C), vinorelbine (NVB), topotecan (TP), etoposide and cisplatin, and any combination of the above.

[0097] In the present application, CDK inhibitors can be used to treat gastrointestinal side effects associated with the administration of the following chemotherapeutic agents: fluorouracil, oxaliplatin, topotecan, irinotecan, tetrahydrofolic acid, docetaxel, gemcitabine, carboplatin, cisplatin, etoposide, methotrexate, doxorubicin, cytarabine, vinorelbine and capecitabine, as well as any combination of the above.

[0098] In the present application, CDK inhibitors can be used to treat gastrointestinal side effects associated with the administration of the following chemotherapeutic agents: fluorouracil, oxaliplatin, irinotecan, docetaxel, gemcitabine, carboplatin, methotrexate, doxorubicin, cytarabine, vinorelbine and capecitabine, as well as any combination of the above.

[0099] In the present application, the chemotherapeutic agent may not include a tumor targeting agent. In the present application, the chemotherapeutic agent may not include a kinase inhibitor that prevents cancer cell division by inhibiting an abnormally activated kinase. In the present application, the chemotherapeutic agent may not include an antibody and / or angiogenesis inhibitor.

[0100] In the present application, chemotherapy may be administered continuously. For example, chemotherapy may be administered continuously for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or more. In some embodiments, the number of days for continuous administration of chemotherapy is 7 days or less. For example, chemotherapy may be administered continuously for 2 days, 3 days, 4 days, 5 days or 6 days. In the present application, the administration frequency of chemotherapy may be once a day, twice a day, three times a day, etc.

[0101] In the present application, chemotherapy may be administered discontinuously. In the present application, the administration frequency of chemotherapy may be once every 2 days, once every 3 days, twice every 3 days, etc.

[0102] In the present application, the frequency of administration of the chemotherapeutic agent may be once a day, and may be less than and / or equal to or less than seven days.

[0103] In the present application, the administration cycle of the chemotherapy agent may be 3 days, 5 days, 7 days, 2 weeks, 20 days, 1 month, 2 months or longer.

[0104] In the present application, one or more different chemotherapeutic agents may be used. In the present application, two or more different chemotherapeutic agents may be used in combination. In some embodiments, the CDK inhibitor may be used in combination with one or more other cancer treatments. The other cancer treatments may be common methods used in the art to treat cancer, such as cytotoxic anticancer agents, immunotherapy anticancer agents, or hormonal therapy anticancer agents. According to the present application, the medicaments used to treat cancer may also be used in combination with radiation therapy or surgery. In some embodiments, in the case of a combination of a CDK inhibitor and another anticancer agent, they may be administered to a subject at the same time, or may be administered separately at regular intervals.

[0105] Gastrointestinal side effects In the present application, the CDK inhibitor can prevent, reduce and / or treat gastrointestinal side effects associated with the administration of chemotherapy in a subject. In the present application, gastrointestinal side effects associated with chemotherapy can mean that the gastrointestinal side effects are caused by the administration of chemotherapy and occur or worsen after the administration of the chemotherapeutic agent. In the absence of prevention or treatment, the gastrointestinal side effects occur or worsen 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 1 day, 2 days, 4 days, 7 days, 2 weeks, 3 weeks, 1 month, 2 months or more after the administration of the chemotherapeutic agent.

[0106] In some embodiments, prior to administering the chemotherapeutic agent to the subject, the subject does not experience gastrointestinal side effects, and after administering the chemotherapeutic agent to the subject, the subject experiences gastrointestinal side effects.

[0107] In some embodiments, prior to administering the chemotherapeutic agent to the subject, the subject experiences a gastrointestinal side effect, and after administering the chemotherapeutic agent to the subject, the severity of the gastrointestinal side effect in the subject increases.

[0108] In the present application, following administration of a chemotherapy agent, a subject's gastrointestinal side effect symptoms may worsen by at least about 10%, e.g., about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or more.

[0109] For example, according to the NCI-CTCAE criteria, after administering a chemotherapy agent to a subject, the severity of gastrointestinal side effects (e.g., diarrhea or constipation) in the subject may increase from grade 1 to grade 2, grade 1 to grade 3, grade 1 to grade 4, grade 1 to grade 5, grade 2 to grade 3, grade 2 to grade 4, grade 2 to grade 5, grade 3 to grade 4, grade 3 to grade 5, or grade 4 to grade 5. For example, according to the Akinobu Kurita method, after administering a chemotherapy agent to a subject, the constipation scoring of the subject increases from grade 0 to grade 1, grade 0 to grade 2, grade 0 to grade 3, grade 1 to grade 2, grade 1 to grade 3, or grade 2 to grade 3.

[0110] In some embodiments, the gastrointestinal side effect comprises a gastric mucosa damaging disorder and / or an intestinal mucosa damaging disorder.

[0111] In some embodiments, gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, anorexia, gastric ulcers, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulcers, and / or intestinal necrosis. In some embodiments, gastrointestinal side effects include abnormal bowel movements. In some embodiments, gastrointestinal side effects include diarrhea and / or constipation.

[0112] In some embodiments, chemotherapy-associated gastrointestinal side effects include chemotherapy-associated gastric mucosal damaging disease and / or chemotherapy-associated intestinal mucosal damaging disease.

[0113] In some embodiments, chemotherapy-related gastrointestinal side effects include chemotherapy-related diarrhea, chemotherapy-related abdominal pain, chemotherapy-related nausea, chemotherapy-related vomiting, chemotherapy-related mucositis, chemotherapy-related anorexia, chemotherapy-related gastric ulcers, chemotherapy-related gastritis, chemotherapy-related constipation, chemotherapy-related enteritis, chemotherapy-related intestinal perforation, chemotherapy-related intestinal bleeding, chemotherapy-related ulcers, and / or chemotherapy-related intestinal necrosis. In some embodiments, chemotherapy-related gastrointestinal side effects include chemotherapy-related abnormal bowel movements. In some embodiments, chemotherapy-related gastrointestinal side effects include chemotherapy-related diarrhea and / or chemotherapy-related constipation.

[0114] In the present application, after administration of the CDK inhibitor of the present application, the severity of the gastrointestinal side effects associated with chemotherapy in the subject is reduced. In the present application, alleviation may generally mean that the occurrence or onset of the gastrointestinal side effects in the subject is delayed. In the present application, after administration of the CDK inhibitor, the symptoms of the gastrointestinal side effects in the subject may be improved. In the present application, after administration of the CDK inhibitor, the symptoms of the gastrointestinal side effects in the subject may be improved by at least about 10%, for example, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or more.

[0115] For example, according to NCI-CTCAE criteria, following administration of a CDK inhibitor, symptoms of gastrointestinal side effects (e.g., diarrhea and / or constipation) in a subject may be reduced from grade 5 to grade 4, grade 5 to grade 3, grade 5 to grade 2, grade 5 to grade 1, grade 4 to grade 3, grade 4 to grade 2, grade 4 to grade 1, grade 3 to grade 2, grade 3 to grade 1, or grade 2 to grade 1.

[0116] Alternatively, according to the Akinobu Kurita method, after administration of a CDK inhibitor, the diarrhea scoring in a subject may be reduced from grade 3 to grade 2, grade 3 to grade 1, grade 3 to grade 0, grade 2 to grade 1, grade 2 to grade 0 or grade 1 to grade 0.

[0117] In the present application, after administration of the CDK inhibitor, the symptoms of gastrointestinal side effects in the subject may be resolved. However, this does not exclude cases where the gastrointestinal side effects recur or worsen again after discontinuing administration of the CDK inhibitor.

[0118] Treatment method As used herein, the term "prevention" generally refers to the prevention of the occurrence, recurrence, or spread of a disease or one or more symptoms thereof. In the context of this application, "prevention" may be used interchangeably with "prophylactic treatment." In some embodiments, "prevention" generally refers to treatment in which a patient suffering from a disease or disorder described in this application is provided with a medicament according to this application, with or without administration of other medicaments described in this application, prior to the occurrence of any symptoms. In some embodiments, patients with a family history of a particular disease may be candidates for a prevention program. In some embodiments, patients with a history of recurrent symptoms are also potential candidates for prevention.

[0119] As used herein, the term "treatment" generally refers to eliminating or ameliorating a disease or one or more symptoms associated with a disease. In some embodiments, treatment generally refers to eliminating or ameliorating a disease by administering one or more therapeutic agents to a patient suffering from a disease. In some embodiments, "treatment" can be the administration of a medicament in the presence or absence of other therapeutic agent(s) after the onset of a particular disease symptom.

[0120] As used herein, the term "subject" generally refers to a human or non-human animal (including a mammal) in need of diagnosis, prognosis, amelioration, prevention, mitigation and / or treatment of a disease, particularly a disease requiring treatment or prevention by using a CDK inhibitor. In some embodiments, the subject may include a cancer patient. For example, the cancer patient may have been administered, is being administered, and / or will be administered chemotherapy.

[0121] In some embodiments, the subject may be a human or a non-human mammal. A non-human mammal may include any mammalian species other than humans, such as livestock (e.g., cows, pigs, sheep, chickens, rabbits, or horses), or rodents (e.g., rats and mice), or primates (e.g., gorillas and monkeys), or domestic animals (e.g., dogs and cats). A "subject" may be male or female and may be of different ages.

[0122] As used herein, the term "effective amount" generally refers to an amount of a pharmaceutical agent that can improve or eliminate a disease or condition in a subject, or preventatively inhibit or prevent the occurrence of a disease or condition. An effective amount can be an amount of a pharmaceutical agent that can improve one or more diseases or conditions to some extent in a subject; an amount of a pharmaceutical agent that can partially or completely restore one or more physiological or biochemical parameters related to the cause of the disease or condition to normal; and / or an amount of a pharmaceutical agent that can reduce the likelihood of the occurrence of a disease or condition.

[0123] In the present application, the medicament or CDK inhibitor may be administered prior to administration of chemotherapy, for example, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours or more prior to administration of chemotherapy, to prevent, reduce and / or treat the occurrence or worsening of gastrointestinal side effects. For example, the medicament or CDK inhibitor is administered 0.5 to 12 hours prior to administration of chemotherapy to prevent, reduce and / or treat the occurrence or worsening of gastrointestinal side effects.

[0124] In the present application, the site of administration of the CDK inhibitor may or may not be the site of cancer onset or a potential site of cancer metastasis.

[0125] The CDK inhibitors of the present application may be administered in a manner known in the art, for example, by injection (e.g., subcutaneous, intraperitoneal, intraarticular, intraarterial, intrathecal, intrasternal, intrathecal, intralesional, intracranial, intramuscular, intradermal, and intravenous injection or infusion) or non-injection (e.g., oral, nasal, sublingual, vaginal, rectal, or topical administration). The CDK inhibitors of the present application may be administered in the form of a pharmaceutical combination or kit. In some embodiments, the CDK inhibitors of the present application may be administered by the same route of administration as the chemotherapy or by a different route.

[0126] In the present application, the medicament and / or CDK inhibitor may be prepared for oral administration. In the present application, the CDK inhibitor may act or reach preferentially in the intestinal cavity rather than being exposed to the systemic circulation. The CDK inhibitor may be prepared in a dosage form suitable for delivery to or effect in the intestinal cavity (e.g., effect of preventing, reducing and / or treating gastrointestinal side effects). The CDK inhibitor may be administered by a route or manner suitable for delivering it to the intestinal cavity or suitable for facilitating it to exert its effect in the intestinal cavity, or an auxiliary means such as a device may be used to deliver the CDK inhibitor to or exert its effect in the intestinal cavity. In the present application, the systemic pharmaceutical concentration of the CDK inhibitor is lower than the minimum inhibitory concentration (IC50).

[0127] In the present application, the medicament and / or CDK inhibitor may be prepared for gastrointestinal administration (e.g., powder, tablet, granule, capsule, liquid, emulsion and / or suspension). In the present application, the medicament and / or CDK inhibitor may be prepared in a dosage form suitable for tube administration, such as a suppository and / or drop pill. In the present application, the medicament and / or CDK inhibitor may be prepared in a dosage form suitable for delivery to the gastrointestinal tract by artificial assistance, such as by intubation.

[0128] In the present application, the medicament and / or CDK inhibitor is prepared in a dosage form suitable for gastrointestinal exposure, which may be a dosage form suitable for delivery to the gastrointestinal tract, a dosage form suitable for gastrointestinal administration, a dosage form suitable for tube administration, a dosage form suitable for oral administration and / or a dosage form suitable for delivery to the gastrointestinal tract by artificial means.

[0129] In the present application, the dosage of the CDK inhibitor may be about 0.01 to 1000 mg / kg, for example, about 0.01 to 800 mg / kg, about 0.01 to 900 mg / kg, about 0.01 to 800 mg / kg, about 0.01 to 700 mg / kg, about 0.01 to 600 mg / kg, about 0.01 to 500 mg / kg, about 0.01 to 400 mg / kg, about 0.01 to 300 mg / kg, about 0.01 to 200 mg / kg, about It may be 0.01 to 100 mg / kg, about 0.1 to 1000 mg / kg, about 1 to 1000 mg / kg, about 10 to 1000 mg / kg, about 50 to 1000 mg / kg, about 100 to 1000 mg / kg, about 0.1 to 800 mg / kg, about 1 to 600 mg / kg, about 10 to 500 mg / kg, about 10 to 400 mg / kg, about 15 to 300 mg / kg, about 50 to 250 mg / kg, or about 50 to 200 mg / kg.

[0130] For example, the dosage of the CDK inhibitor in oral administration may be about 0.01 to 1000 mg / kg, for example, about 0.01 to 800 mg / kg, about 0.01 to 900 mg / kg, about 0.01 to 800 mg / kg, about 0.01 to 700 mg / kg, about 0.01 to 600 mg / kg, about 0.01 to 500 mg / kg, about 0.01 to 400 mg / kg, about 0.01 to 300 mg / kg, about 0.01 to 200 mg / kg. , about 0.01 to 100 mg / kg, about 0.1 to 1000 mg / kg, about 1 to 1000 mg / kg, about 10 to 1000 mg / kg, about 50 to 1000 mg / kg, about 100 to 1000 mg / kg, about 0.1 to 800 mg / kg, about 1 to 600 mg / kg, about 10 to 500 mg / kg, about 10 to 400 mg / kg, about 15 to 300 mg / kg, about 50 to 250 mg / kg, or about 50 to 200 mg / kg.

[0131] A particular dosage may be administered multiple times, for example, once a day, more than once a day, once a week, once every two weeks, once every three weeks, once a month, or at intervals of once every two months or more. In some embodiments, the dosage may vary over the course of treatment. For example, in some embodiments, the initial dosage may be higher than subsequent dosages. In some embodiments, the dosage is adjusted over the course of treatment according to the response of the subject to which it is administered. When used to improve the condition of a subject, the CDK inhibitor of the present application may be administered at a maintenance dose as needed. The dosage or frequency of administration, or both, may then be reduced to a level to maintain the improved condition when the symptoms have been improved to a desired level. In some embodiments, the medicament may be administered at intervals depending on the disease condition of the subject.

[0132] For example, the CDK inhibitor may be administered about 0.5 hours to about 24 hours before administration of the chemotherapeutic agent, or may be administered orally, the dosage may be about 30 to 200 mg / kg, and the administration cycle may be once a week to once every two weeks.

[0133] For example, the CDK inhibitor may be administered about 0.5 hours to about 24 hours before administration of the chemotherapeutic agent, or may be administered orally, the dosage may be about 50 to 200 mg / kg, and the administration cycle may be once every 1 to 2 weeks.

[0134] For example, the CDK inhibitor may be administered about 0.5 hours to about 24 hours prior to administration of the chemotherapeutic agent, may be administered orally, the dosage may be about 30 to 200 mg / kg, and the administration cycle may be once every 7 days, once every 8 days, once every 9 days, or once every 10 days.

[0135] For example, the CDK inhibitor may be administered about 0.5 hours to about 12 hours prior to administration of the chemotherapeutic agent, may be administered orally, the dosage may be about 50 to 200 mg / kg, and the administration cycle may be once every 7 days, once every 8 days, once every 9 days, or once every 10 days.

[0136] For example, the CDK inhibitor may be administered about 0.5 hours to about 12 hours prior to administration of the chemotherapeutic agent, may be administered orally, the dosage may be about 50-100 mg / kg, and the administration cycle may be once every 7 days, once every 8 days, once every 9 days, or once every 10 days.

[0137] For example, the CDK inhibitor may be administered about 0.5 hours to about 12 hours prior to administration of the chemotherapeutic agent, may be administered orally, the dosage may be about 100-200 mg / kg, and the administration cycle may be once every 7 days, once every 8 days, once every 9 days, or once every 10 days.

[0138] For example, the CDK inhibitor may be administered about 0.5 hours to about 24 hours before administration of the chemotherapy agent, or may be administered by injection, the dosage may be about 30 to 200 mg / kg, and the administration cycle may be once a week to once every two weeks.

[0139] For example, the CDK inhibitor may be administered about 0.5 hours to about 12 hours prior to administration of the chemotherapeutic agent and may be administered by injection, the dosage may be about 50 to 200 mg / kg, and the administration cycle may be once every 7 days, once every 8 days, once every 9 days, or once every 10 days.

[0140] In the present application, palbociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with administration of a chemotherapy agent. For example, palbociclib can be administered about 0.5 hours to about 12 hours before administration of a chemotherapy agent, and palbociclib can be administered orally, with a dosage of about 10 to 200 mg / kg. The chemotherapy agent can be administered orally or by injection.

[0141] In the present application, palbociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with administration of fluorouracil (5-Fu). For example, palbociclib can be administered about 0.5 hours to about 12 hours before administration of fluorouracil (5-Fu), and palbociclib can be administered orally, with a dosage of about 125 mg / kg to about 150 mg / kg. For example, fluorouracil (5-Fu) can be administered orally or by injection.

[0142] In the present application, palbociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with administration of oxaliplatin. For example, palbociclib can be administered about 0.5 hours to about 12 hours (e.g., about 6 hours) before administration of oxaliplatin, and palbociclib can be administered orally, with a dosage of about 125 mg / kg to about 150 mg / kg. For example, oxaliplatin can be administered by injection.

[0143] In the present application, palbociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with administration of irinotecan. For example, palbociclib can be administered about 0.5 hours to about 24 hours before administration of irinotecan, and palbociclib can be administered orally, with a dosage of about 50 mg / kg to about 200 mg / kg. For example, irinotecan can be administered by injection.

[0144] In the present application, palbociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with the administration of gemcitabine. For example, palbociclib can be administered about 0.5 hours to about 12 hours before the administration of gemcitabine, and palbociclib can be administered orally, with a dosage of about 50 mg / kg to about 200 mg / kg. For example, gemcitabine can be administered by injection.

[0145] In the present application, palbociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with administration of docetaxel. For example, palbociclib can be administered about 0.5 hours to about 12 hours before administration of docetaxel, and palbociclib can be administered orally, with a dosage of about 150 mg / kg to about 200 mg / kg. For example, docetaxel can be administered by injection.

[0146] In the present application, palbociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with the co-administration of gemcitabine and paclitaxel. For example, palbociclib can be administered about 0.5 hours to about 12 hours before the co-administration of gemcitabine and paclitaxel, and palbociclib can be administered orally, with a dosage of about 150 mg / kg to about 200 mg / kg. For example, gemcitabine and paclitaxel can be administered by injection.

[0147] In the present application, palbociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with capecitabine. For example, palbociclib can be administered about 0.5 hours to about 12 hours before the administration of capecitabine, and palbociclib can be administered orally, with a dosage of about 150 mg / kg to about 200 mg / kg. For example, capecitabine can be administered by injection.

[0148] In the present application, palbociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with the co-administration of etoposide and carboplatin. For example, palbociclib can be administered about 0.5 hours to about 12 hours before the co-administration of etoposide and carboplatin, and palbociclib can be administered orally, with a dosage of about 150 mg / kg to about 200 mg / kg. For example, etoposide and carboplatin can be administered by injection.

[0149] In the present application, ribociclib can be used to treat chemotherapy-related gastrointestinal side effects (e.g., diarrhea or constipation). For example, ribociclib can be administered about 0.5 hours to about 24 hours before administration of a chemotherapy agent, and ribociclib can be administered orally, with a dosage of about 20 mg / kg to about 200 mg / kg. For example, the chemotherapy agent can be administered by injection or orally.

[0150] In the present application, ribociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with fluorouracil (5-FU). For example, ribociclib can be administered about 0.5 hours to about 12 hours before administration of fluorouracil (5-FU), and ribociclib can be administered orally, with a dosage of about 150 mg / kg to about 200 mg / kg. For example, fluorouracil (5-FU) can be administered by injection.

[0151] In the present application, ribociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with irinotecan. For example, ribociclib can be administered about 0.5 hours to about 24 hours before administration of irinotecan, and ribociclib can be administered orally, with a dosage of about 100 mg / kg to about 200 mg / kg. For example, irinotecan can be administered orally.

[0152] In the present application, ribociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with the co-administration of etoposide and carboplatin. For example, ribociclib can be administered about 0.5 hours to about 12 hours before the administration of etoposide and carboplatin, and ribociclib can be administered orally, with a dosage of about 50 mg / kg to about 200 mg / kg. For example, etoposide and carboplatin can be administered by injection.

[0153] In the present application, ribociclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with administration of docetaxel (DTX). For example, ribociclib can be administered about 0.5 hours to about 24 hours before administration of docetaxel (DTX), and ribociclib can be administered orally, with a dosage of about 100 mg / kg to about 200 mg / kg. For example, docetaxel (DTX) can be administered by injection.

[0154] In the present application, abemaciclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with administration of a chemotherapeutic agent. For example, abemaciclib can be administered about 0.5 hours to about 12 hours before administration of a chemotherapeutic agent, and abemaciclib can be administered orally, with a dosage of about 150 mg / kg to about 200 mg / kg. For example, the chemotherapeutic agent can be administered by injection or orally.

[0155] In the present application, abemaciclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with fluorouracil (5-Fu). For example, abemaciclib can be administered about 0.5 hours to about 12 hours before administration of fluorouracil (5-Fu), abemaciclib can be administered orally, and the dosage can be about 150 mg / kg to about 200 mg / kg. For example, capecitabine can be administered by injection.

[0156] In the present application, abemaciclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with irinotecan. For example, abemaciclib can be administered about 0.5 hours to about 24 hours before administration of irinotecan, and abemaciclib can be administered orally, with a dosage of about 10 mg / kg to about 200 mg / kg. For example, irinotecan can be administered by injection.

[0157] In the present application, abemaciclib can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with gemcitabine (GEM). For example, abemaciclib can be administered about 0.5 hours to about 24 hours before administration of gemcitabine (GEM), and abemaciclib can be administered orally, with a dosage of about 150 mg / kg to about 200 mg / kg. For example, gemcitabine (GEM) can be administered by injection.

[0158] In the present application, G1T28 can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with administration of a chemotherapeutic agent. For example, G1T28 can be administered about 0.5 hours to about 24 hours before administration of the chemotherapeutic agent, and G1T28 can be administered orally, with a dosage of about 150 mg / kg to about 200 mg / kg. For example, the chemotherapeutic agent can be administered by injection or orally.

[0159] In the present application, G1T28 can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with fluorouracil (5-Fu). For example, G1T28 can be administered about 0.5 hours to about 24 hours before administration of fluorouracil (5-Fu), and G1T28 can be administered orally, with a dosage of about 100 mg / kg to about 200 mg / kg. For example, fluorouracil (5-Fu) can be administered by injection.

[0160] In the present application, G1T28 can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with topotecan. For example, G1T28 can be administered about 0.5 hours to about 12 hours before administration of topotecan, and G1T28 can be administered orally, and the dosage can be about 100 mg / kg to about 200 mg / kg. For example, topotecan can be administered by injection. In the present application, G1T28 can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with oxaliplatin. For example, G1T28 can be administered about 0.5 hours to about 24 hours before administration of oxaliplatin, and G1T28 can be administered orally, and the dosage can be about 100 mg / kg to about 200 mg / kg. For example, oxaliplatin can be administered by injection.

[0161] In the present application, G1T28 can be used to treat gastrointestinal side effects (e.g., diarrhea or constipation) associated with gemcitabine (GEM). For example, G1T28 can be administered about 0.5 hours to about 24 hours before administration of gemcitabine (GEM), and G1T28 can be administered orally, with a dosage of about 100 mg / kg to about 200 mg / kg. For example, gemcitabine (GEM) can be administered by injection.

[0162] In the present application, the medicament may further include one or more pharma- ceutically acceptable carriers. The pharma-ceutically acceptable carriers may include, but are not limited to, for example, pharma-ceutically acceptable liquid, gel or solid carriers, aqueous media, non-aqueous media, antibacterial agents, isotonic agents, buffers, antioxidants, anesthetics, suspending / dispersing agents, chelating agents, emulsifiers, diluents, adjuvants, excipients, non-toxic auxiliary substances, fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickening agents, coloring agents, emulsifiers, other ingredients known in the art, or various combinations of the above.

[0163] In another aspect, the application provides a method of preventing, reducing, and / or treating chemotherapy-associated gastrointestinal side effects using a CDK inhibitor. In another aspect, the application provides a use of a CDK inhibitor in the preparation of a medicament for preventing, reducing, and / or treating chemotherapy-associated gastrointestinal side effects. In another aspect, the application provides a CDK inhibitor for use in preventing or treating chemotherapy-associated gastrointestinal side effects. In some embodiments, the chemotherapy does not include chemotherapy having a continuous administration time of 7 days or more. In some embodiments, the chemotherapy does not include a tumor-targeted therapy. In some embodiments, the chemotherapy is administered orally.

[0164] In another aspect, the application provides a method of preventing, reducing, and / or treating chemotherapy-associated diarrhea with a CDK inhibitor. In another aspect, the application provides a use of a CDK inhibitor in the preparation of a medicament for preventing, reducing, and / or treating chemotherapy-associated diarrhea. In another aspect, the application provides a CDK inhibitor for use in preventing, reducing, and / or treating chemotherapy-associated diarrhea. In some embodiments, the chemotherapy does not include chemotherapy having a continuous administration time of 7 days or more. In some embodiments, the chemotherapy does not include a tumor-targeted therapy. In some embodiments, the chemotherapy is administered orally.

[0165] In another aspect, the application provides a method of preventing, reducing, and / or treating chemotherapy-associated constipation using a CDK inhibitor. In another aspect, the application provides a use of a CDK inhibitor in the preparation of a medicament for preventing, reducing, and / or treating chemotherapy-associated constipation. In another aspect, the application provides a CDK inhibitor for use in preventing, reducing, and / or treating chemotherapy-associated constipation. In some embodiments, the chemotherapy does not include chemotherapy having a continuous administration time of 7 days or more. In some embodiments, the chemotherapy does not include a tumor-targeted therapy. In some embodiments, the chemotherapy is administered orally.

[0166] The following examples are not limited by any theory, but are merely intended to illustrate various technical schemes of the present application, and are not intended to limit the scope of the present application.

[0167] example Example 1-229: Effect of oral administration of CDK inhibitors on chemotherapy-induced diarrhea Construction of mouse animal model: A chemotherapy-induced diarrhea model in Balb / c mice was constructed according to the administration mode and frequency of chemotherapy agents shown in Table 3. After several days of administration, the mice developed various degrees of diarrhea symptoms (as shown in Figure 1), which were similar to the condition in humans. Therefore, the chemotherapy-induced diarrhea model in mice is a very good model for mimicking human diarrhea caused by chemotherapy agents.

[0168] Balb / c mice were fed for one week, then divided into groups. The experiment was divided into a control group, a chemotherapy group, and a CDK inhibitor group, each of which contained 10 mice, and the administration experiment was performed, and the dosage, mode, time, and frequency were shown in Table 3. Control group: The same solvent used in the CDK inhibitor group was administered intragastrically (time shown in Table 3), and then the same solvent used in the chemotherapy group was administered by injection / intragastric administration (administration mode shown in Table 3); Chemotherapy group: The same solvent used in the CDK inhibitor group was administered intragastrically (time shown in Table 3), and then the chemotherapy was administered by injection / intragastric administration (type, administration mode, and dosage shown in Table 3); CDK inhibitor group: The CDK inhibitor was administered intragastrically (mode and dosage shown in Table 3), and then the chemotherapy was administered (time shown in Table 3).

[0169] Observation of diarrhea Scoring of diarrhea can be done by the method of Akinobu Kurita (Cancer Chemother Pharmacol 2000;46:211-20.), with grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, soft stool and mild perianal contamination; grade 3: severe diarrhea, watery stool, and severe perianal staining (see FIG. 1). If the diarrhea grade classification of the mice in the CDK inhibitor group is lowered compared with the average diarrhea grade of the mice in the chemotherapy group, it is considered to be an effective remission.

[0170] The diarrhea grade classification of the mice was observed and recorded daily. At the end of the experiment, the number of mice in the CDK inhibitor group with a lower diarrhea grade classification than those in the chemotherapy group was recorded. Table 3 lists various animal experimental combinations of chemotherapy and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate % = number of mice in the CDK inhibitor group with effectively alleviated diarrhea / total number of mice in the CDK inhibitor group × 100%. The establishment rate of the diarrhea model in the chemotherapy group was 50%-70%, i.e., about 5-7 out of 10 mice developed diarrhea during the experiment, and individual mice died or did not develop diarrhea.) [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15]

[0171] Figure 1 shows typical photographs showing different diarrhea grading classifications of mice in the chemotherapy group in Table 3. Figure 2 shows partial diarrhea grading results of the control group, chemotherapy group, and CDK inhibitor group in Table 3.

[0172] From the results of Table 3 and Figure 2, it can be seen that the diarrhea grade classification is alleviated to different degrees in the CDK inhibitor group compared to the chemotherapy group. Therefore, by orally administering a CDK inhibitor in advance, diarrhea caused by chemotherapy can be effectively alleviated.

[0173] Cases 230-271: Effect of oral administration of CDK inhibitors on chemotherapy-induced diarrhea Balb / c mice were fed for one week, then divided into groups. The experiment was divided into a control group, a chemotherapy group, and a CDK inhibitor group, each of which contained 10 mice, and the administration experiment was performed, and the dosage, mode, time, and frequency were shown in Table 4. Control group: The same solvent used in the CDK inhibitor group was administered intragastrically (time shown in Table 4), and then the same solvent used in the chemotherapy group was administered by injection / intragastric administration (administration mode shown in Table 4); Chemotherapy group: The same solvent used in the CDK inhibitor group was administered intragastrically (time shown in Table 4), and then the chemotherapy was administered by injection / intragastric administration (type, administration mode, and dosage shown in Table 4); CDK inhibitor group: The CDK inhibitor was administered intragastrically (mode and dosage shown in Table 4), and then the chemotherapy was administered (time shown in Table 4).

[0174] Observation of diarrhea Scoring of diarrhea can be done by the method of Akinobu Kurita (Cancer Chemother Pharmacol 2000;46:211-20.), with grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, soft stool and mild perianal contamination; grade 3: severe diarrhea, watery stool, and severe perianal staining (see FIG. 1). If the diarrhea grade classification of the mice in the CDK inhibitor group is lowered compared with the average diarrhea grade of the mice in the chemotherapy group, it is considered to be an effective remission.

[0175] The diarrhea grade classification of the mice was observed and recorded daily. At the end of the experiment, the number of mice in the CDK inhibitor group with a lower diarrhea grade classification than those in the chemotherapy group was recorded. Table 4 lists various animal experimental combinations of chemotherapy and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate % = number of mice in the CDK inhibitor group with effectively alleviated diarrhea / total number of mice in the CDK inhibitor group × 100%. The establishment rate of the diarrhea model in the chemotherapy group was 50%-70%, i.e., about 5-7 out of 10 mice developed diarrhea during the experiment, and individual mice died or did not develop diarrhea.) [Table 4-1] [Table 4-2]

[0176] FIG. 3 shows the partial diarrhea grading results for the control group, chemotherapy drug group, and CDK inhibitor group in Table 4.

[0177] From the results of Table 4 and Figure 3, it can be seen that the diarrhea grade classification is alleviated to different degrees in the CDK inhibitor group compared to the chemotherapy group. Therefore, by orally administering the CDK inhibitor in advance, diarrhea caused by chemotherapy can be effectively alleviated.

[0178] Examples 272-342 Effect of oral administration of CDK inhibitors on chemotherapy-induced constipation Construction of mouse animal model: A chemotherapy-induced constipation model in Balb / c mice was constructed according to the administration mode and frequency of chemotherapy agents shown in Table 5. After several days of administration, the mice showed a decrease in stool volume (shown in FIG. 4), which was consistent with the symptoms of constipation caused by chemotherapy agents in humans. Therefore, the chemotherapy-induced constipation model in mice is a very good model for mimicking constipation caused by chemotherapy agents.

[0179] Balb / c mice were fed for one week, then divided into groups. The experiment was divided into a control group, a chemotherapy group, and a CDK inhibitor group, each of which contained 10 mice, and the administration experiment was performed, and the dosage, mode, time, and frequency were shown in Table 5. Control group: The same solvent used in the CDK inhibitor group was administered intragastrically (time shown in Table 5), and then the same solvent used in the chemotherapy group was administered by injection / intragastric administration (administration mode shown in Table 5); Chemotherapy group: The same solvent used in the CDK inhibitor group was administered intragastrically (time shown in Table 5), and then the chemotherapy was administered by injection / intragastric administration (type, administration mode, and dosage shown in Table 5); CDK inhibitor group: The CDK inhibitor was administered intragastrically (mode and dosage shown in Table 5), and then the chemotherapy was administered (time shown in Table 5).

[0180] Observation of constipation Feces from mice were collected within 3 hours, observed for shape, and weighed on an electronic balance. The feces reduction rate was calculated with reference to the method of Ji Eun Kim (Lab Anim Res. 2016 Dec; 32 (4): 231-240.). Feces reduction rate (%) = (control group - chemotherapy drug group or CDK inhibitor group) / control group x 100%

[0181] In the CDK inhibitor group, a reduction in the fecal matter reduction rate in mice compared to the chemotherapy group was considered to be an effective remission.

[0182] The fecal volume of the mice within 3 hours was observed and recorded daily. At the end of the experiment, the number of mice in the CDK inhibitor group with a lower fecal reduction rate than those in the chemotherapy group was recorded. Table 5 lists various animal experimental combinations of chemotherapy agents and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate% = number of mice in the CDK inhibitor group that were effectively alleviated / total number of mice in the CDK inhibitor group × 100%. The establishment rate of the constipation model in the chemotherapy agent group was 30% to 60%, and about 3 to 6 mice out of 10 mice showed a decrease in fecal volume during the experiment, and individual mice died or had no change or increase in fecal volume). [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0183] Figure 4 is a representative photograph showing the fecal volume within 3 hours for the control group, chemotherapy group, and CDK inhibitor group in Table 5. Figure 5 shows the results of the fecal reduction rate for some of the control group, chemotherapy group, and CDK inhibitor group in Table 5.

[0184] From the results of Table 5 and Figures 4 to 5, it can be seen that the fecal matter reduction rate is reduced to a different extent in the CDK inhibitor group compared to the chemotherapy group. Therefore, by orally administering the CDK inhibitor in advance, constipation caused by chemotherapy can be effectively alleviated.

[0185] Examples 343-381 Both oral administration of CDK inhibitors and intravenous injection of CDK inhibitors can reduce diarrhea caused by chemotherapy agents Balb / c mice were fed for one week and then divided into groups. The experiment was conducted by dividing the mice into a control group, a chemotherapy group, an oral administration group of CDK inhibitors, and an intravenous injection group of CDK inhibitors, each of which contained 10 mice. The dosage, mode, time, and frequency are shown in Table 6. Control group: The same solvent used in the CDK inhibitor group was injected / administered intragastrically (time shown in Table 6), followed by the same solvent used in the chemotherapy group (administration mode shown in Table 6); Chemotherapy group: The same solvent used in the CDK inhibitor group was injected / administered intragastrically (time shown in Table 6), followed by the chemotherapy (type, administration mode and dosage shown in Table 6); Oral administration of CDK inhibitor group: The CDK inhibitor was administered intragastrically (mode and dosage shown in Table 6), followed by the chemotherapy (time shown in Table 6); Intravenous injection of CDK inhibitor group: The CDK inhibitor was injected via the tail vein (time shown in Table 6), followed by the chemotherapy (mode and dosage shown in Table 6).

[0186] Observation of diarrhea Scoring of diarrhea can be done by the method of Akinobu Kurita (Cancer Chemother Pharmacol 2000;46:211-20.), with grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, soft stool and mild perianal contamination; grade 3: severe diarrhea, watery stool, and severe perianal staining (see Figure 1). If the diarrhea grade classification of mice in the oral administration group of CDK inhibitor / intravenous injection group of CDK inhibitor is lower than the average diarrhea grade classification of mice in the chemotherapy group, it is considered to be an effective remission.

[0187] The diarrhea grade classification of the mice was observed and recorded daily. At the end of the experiment, the number of mice with lower diarrhea grade classification in the CDK inhibitor oral administration group / CDK inhibitor intravenous injection group compared to the chemotherapy group was recorded. Table 6 lists various animal experimental combinations of chemotherapy agents and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate % = number of mice in the CDK inhibitor oral administration or intravenous injection group with effectively alleviated diarrhea / total number of mice in the CDK inhibitor oral administration or intravenous injection group × 100%. The establishment rate of the diarrhea model in the chemotherapy agent group was 50%-70%, i.e., about 5-7 mice out of 10 mice developed diarrhea during the experiment, and individual mice died or did not develop diarrhea.) [Table 6-1] [Table 6-2] [Table 6-3]

[0188] Figure 6 shows the typical diarrhea grade classification results of the control group, chemotherapy group, CDK inhibitor oral administration group and CDK inhibitor intravenous injection group in Table 6. From Table 6 and Figure 6, it can be seen that oral administration and injection administration of palbociclib, abemaciclib, trilaciclib, ribociclib, SHR-6390, dinaciclib, KR-0601, and ribiciclib can effectively alleviate the diarrhea caused by etoposide, etoposide combined with cisplatin, carboplatin, gemcitabine, gemcitabine combined with carboplatin, and topotecan, and oral administration has the most significant effect.

[0189] Examples 382-405 Various modes of administration of CDK inhibitors can reduce diarrhea caused by chemotherapy agents Balb / c mice were fed for one week and then divided into groups. The experiment was divided into a control group, a chemotherapy group, and a CDK inhibitor group (including an oral administration group of CDK inhibitors, an intraperitoneal injection group of CDK inhibitors, an intramuscular injection group of CDK inhibitors, and a local administration group of CDK inhibitors), each of which contained 10 mice, and the administration experiment was performed, and the dosage, mode, time, and frequency are shown in Table 7. Control group: The same solvent used in the CDK inhibitor group was administered (time and mode shown in Table 7), and then the same solvent used in the chemotherapy group was administered by injection / intragastric administration (administration mode shown in Table 7); Chemotherapy group: The same solvent used in the CDK inhibitor group was administered (time and mode shown in Table 7), and then the chemotherapy was administered by injection / intragastric administration (type, administration mode, and dosage shown in Table 7); Oral administration group of CDK inhibitor: The CDK inhibitor was administered intragastricly (time shown in Table 7), and then the chemotherapy was administered (mode and dosage). are shown in Table 7); intraperitoneal injection group of CDK inhibitor: the CDK inhibitor was injected intraperitoneally (time is shown in Table 7), followed by administration of the chemotherapy agent (mode and dosage are shown in Table 7); intramuscular injection group of CDK inhibitor: the CDK inhibitor was injected intramuscularly (time is shown in Table 7), followed by administration of the chemotherapy agent (mode and dosage are shown in Table 7); and local administration group of CDK inhibitor: the abdominal hair of the mice was shaved (approximately 2 cm x 2 cm), the CDK inhibitor was applied (time is shown in Table 7), followed by administration of the chemotherapy agent (mode and dosage are shown in Table 7).

[0190] Observation of diarrhea Scoring of diarrhea can be done by the method of Akinobu Kurita (Cancer Chemother Pharmacol 2000;46:211-20.), with grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, soft stool and mild perianal contamination; grade 3: severe diarrhea, watery stool, and severe perianal staining (see FIG. 1). If the diarrhea grade classification of the mice in the CDK inhibitor group is lowered compared with the average diarrhea grade of the mice in the chemotherapy group, it is considered to be an effective remission.

[0191] The diarrhea grade classification of the mice was observed and recorded daily. At the end of the experiment, the number of mice in the CDK inhibitor group with a lower diarrhea grade classification than those in the chemotherapy group was recorded. Table 7 lists various animal experimental combinations of chemotherapy and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate % = number of mice in the CDK inhibitor group with effectively alleviated diarrhea / total number of mice in the CDK inhibitor group × 100%. The establishment rate of the diarrhea model in the chemotherapy group was 50%-70%, i.e., about 5-7 out of 10 mice developed diarrhea during the experiment, and individual mice died or did not develop diarrhea.) [Table 7-1] [Table 7-2]

[0192] FIG. 7 shows a comparison of the diarrhea grading results among the control group, chemotherapy group, oral administration group of CDK inhibitor, and other administration modes of CDK inhibitor group in Table 7.

[0193] The results in Table 7 and Figure 7 show that under certain conditions, oral, injection and topical administration of palbociclib, abemaciclib, trilaciclib, ribociclib and SHR-6390 can alleviate diarrhea caused by docetaxel, carboplatin, gemcitabine and the combination of gemcitabine and carboplatin, with the effect of oral administration being the most significant.

[0194] Examples 406-443 Various modes of administration of CDK inhibitors can reduce constipation caused by chemotherapy agents Balb / c mice were fed for one week, then divided into groups. The experiment was divided into a control group, a chemotherapy group, and a CDK inhibitor group (including an oral administration group of CDK inhibitor, an intravenous injection group of CDK inhibitor, an intraperitoneal injection group of CDK inhibitor, an intramuscular injection group of CDK inhibitor, and a local administration group of CDK inhibitor), each of which contained 10 mice, and the administration experiment was performed, and the dosage, mode, time and frequency are shown in Table 8. Control group: The same vehicle used in the CDK inhibitor group was administered (time and mode shown in Table 8), followed by injection / intragastric administration of the same vehicle used in the chemotherapy group (mode of administration shown in Table 8); Chemotherapy group: The same vehicle used in the CDK inhibitor group was administered (time and mode shown in Table 8), followed by injection / intragastric administration of the chemotherapy (type, mode of administration and dosage shown in Table 8); Oral administration group of CDK inhibitor: The CDK inhibitor was intragastricly administered (time shown in Table 8), followed by administration of the chemotherapy (mode and dosage shown in Table 8); Intravenous injection group of CDK inhibitor: The CDK inhibitor was injected via the tail vein ( CDK inhibitor intraperitoneal injection group: CDK inhibitor was intraperitoneally injected (time shown in Table 8), and then chemotherapy was administered (mode and dosage shown in Table 8); CDK inhibitor intramuscular injection group: CDK inhibitor was intramuscularly injected (time shown in Table 8), and then chemotherapy was administered (mode and dosage shown in Table 8); and CDK inhibitor topical administration group: The abdominal hair of the mice was shaved (approximately 2 cm x 2 cm), CDK inhibitor was applied (time shown in Table 8), and then chemotherapy was administered (mode and dosage shown in Table 8).

[0195] Observation of constipation Feces from mice were collected within 3 hours, observed for shape, and weighed on an electronic balance. The feces reduction rate was calculated with reference to the method of Ji Eun Kim (Lab Anim Res. 2016 Dec; 32 (4): 231-240.). Feces reduction rate (%) = (control group - chemotherapy drug group or CDK inhibitor group) / control group x 100%

[0196] In the CDK inhibitor group, a reduction in the fecal matter reduction rate in mice compared to the chemotherapy group was considered to be an effective remission.

[0197] The fecal volume of the mice within 3 hours was observed and recorded daily. At the end of the experiment, the number of mice in the CDK inhibitor group with a lower fecal reduction rate than those in the chemotherapy group was recorded. Table 8 lists various animal experimental combinations of chemotherapy agents and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate% = number of mice in the CDK inhibitor group that were effectively alleviated / total number of mice in the CDK inhibitor group × 100%. The establishment rate of the constipation model in the chemotherapy agent group was 30% to 60%, and about 3 to 6 mice out of 10 mice showed a decrease in fecal volume during the experiment, and individual mice died or had no change or increase in fecal volume). [Table 8-1] [Table 8-2] [Table 8-3]

[0198] FIG. 8 shows a comparison of the fecal reduction rate results for the control group, chemotherapy group, CDK inhibitor oral administration group, and groups administered the CDK inhibitor in other modes of administration in Table 8.

[0199] From the results in Table 8 and Figure 8, it can be seen that oral administration, intraperitoneal injection, intramuscular injection, and local administration of palbociclib, abemaciclib, trilaciclib, ribociclib, SHR-6390, doniciclib, and seliciclib under certain conditions can all significantly improve constipation caused by doxorubicin, etoposide, the combination of etoposide and cisplatin, carboplatin, gemcitabine, and the combination of gemcitabine and carboplatin, and the alleviating effect of oral administration is most significant.

[0200] Cases 444-469: Effect of oral administration of CDK inhibitors on diarrhea caused by continuous administration of chemotherapy drugs Balb / c mice were fed for one week, then divided into groups. The experiment was divided into a control group, a chemotherapy group, and a CDK inhibitor group, each of which contained 10 mice, and the administration experiment was performed, and the dosage, mode, time, and frequency were shown in Table 9. Control group: The same solvent used in the CDK inhibitor group was administered intragastrically (time was shown in Table 9), and then the same solvent used in the chemotherapy group was administered by injection / intragastric administration (administration mode was shown in Table 9); Chemotherapy group: The same solvent used in the CDK inhibitor group was administered intragastrically (time was shown in Table 9), and then the chemotherapy was administered by injection / intragastric administration (type, administration mode, dosage, and duration were shown in Table 9); CDK inhibitor group: The CDK inhibitor was administered intragastrically (type, administration mode, dosage, and duration were shown in Table 9), and then the chemotherapy was administered (time was shown in Table 9).

[0201] Observation of diarrhea Scoring of diarrhea can be done by the method of Akinobu Kurita (Cancer Chemother Pharmacol 2000;46:211-20.), with grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, soft stool and mild perianal contamination; grade 3: severe diarrhea, watery stool, and severe perianal staining (see FIG. 1). If the diarrhea grade classification of the mice in the CDK inhibitor group is lowered compared with the average diarrhea grade of the mice in the chemotherapy group, it is considered to be an effective remission.

[0202] The diarrhea grade classification of the mice was observed and recorded daily. At the end of the experiment, the number of mice in the CDK inhibitor group with a lower diarrhea grade classification than those in the chemotherapy group was recorded. Table 9 lists various animal experimental combinations of chemotherapy and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate % = number of mice in the CDK inhibitor group with effectively alleviated diarrhea / total number of mice in the CDK inhibitor group × 100%. The establishment rate of the diarrhea model in the chemotherapy group was 50%-80%, i.e., about 5-8 mice out of 10 mice developed diarrhea during the experiment, and individual mice died or did not develop diarrhea.) [Table 9-1] [Table 9-2]

[0203] FIG. 9 shows a comparison of partial results of diarrhea grading in the control group, chemotherapy group, and CDK inhibitor group in Table 9.

[0204] From Table 9 and FIG. 9, it can be seen that palbociclib, abemaciclib, trilaciclib, and ribociclib all have a significant alleviating effect on diarrhea caused by continuous administration of fluorouracil for less than 7 days, but their alleviating effects on diarrhea caused by continuous administration of fluorouracil and capecitabine for 7 days or more are not significant.

[0205] Cases 470-481: Effect of oral administration of CDK inhibitors on constipation caused by continuous administration of chemotherapy drugs Balb / c mice were fed for one week, then divided into groups. The experiment was divided into a control group, a chemotherapy group, and a CDK inhibitor group, each of which contained 10 mice, and the administration experiment was performed, and the dosage, mode, time, and frequency were shown in Table 10. Control group: The same solvent used in the CDK inhibitor group was administered intragastrically (time shown in Table 10), and then the same solvent used in the chemotherapy group was administered by injection / intragastric administration (administration mode shown in Table 10); Chemotherapy group: The same solvent used in the CDK inhibitor group was administered intragastrically (time shown in Table 10), and then the chemotherapy was administered by injection / intragastric administration (type, administration mode, dosage, and duration shown in Table 10); CDK inhibitor group: The CDK inhibitor was administered intragastrically (type, administration mode, dosage, and duration shown in Table 10), and then the chemotherapy was administered (time shown in Table 10).

[0206] Observation of constipation Feces from mice were collected within 3 hours, observed for shape, and weighed on an electronic balance. The feces reduction rate was calculated with reference to the method of Ji Eun Kim (Lab Anim Res. 2016 Dec; 32 (4): 231-240.). Feces reduction rate (%) = (control group - chemotherapy drug group or CDK inhibitor group) / control group x 100%

[0207] In the CDK inhibitor group, a reduction in the fecal matter reduction rate in mice compared to the chemotherapy group was considered to be an effective remission.

[0208] The fecal volume of the mice within 3 hours was observed and recorded daily. At the end of the experiment, the number of mice in the CDK inhibitor group with a lower fecal reduction rate than the mice in the chemotherapy group was recorded. Table 10 lists various animal experimental combinations of chemotherapy agents and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate% = number of mice in the CDK inhibitor group that were effectively alleviated / total number of mice in the CDK inhibitor group × 100%. The establishment rate of the constipation model in the chemotherapy agent group was 30% to 60%, and about 3 to 6 mice out of 10 mice showed a decrease in fecal volume during the experiment, and individual mice died or had no change or increase in fecal volume). [Table 10]

[0209] FIG. 10 shows the results of the stool reduction rate for some of the control group, chemotherapy drug group, and CDK inhibitor group in Table 10.

[0210] From Table 10 and FIG. 10, it can be seen that, when orally administered under certain conditions, palbociclib has a significant effect of reducing constipation caused by continuous administration of fluorouracil for less than 7 days, but has an insignificant effect of reducing diarrhea caused by continuous administration of fluorouracil for 7 days or more.

[0211] Examples 482-485: Effect of oral administration of CDK inhibitors on diarrhea induced by other antitumor drugs Balb / c mice were fed for one week, then divided into groups. The experiment was divided into a control group, an antitumor drug group, and a CDK inhibitor group, each of which contained 10 mice, and the administration experiment was performed, and the dosage, mode, time, and frequency were shown in Table 11. Control group: The same solvent used in the CDK inhibitor group was administered intragastrically (time was shown in Table 11), and then the same solvent used in the antitumor drug group was administered by injection / intragastric administration (administration mode was shown in Table 11); Antineoplastic drug group: The same solvent used in the CDK inhibitor group was administered intragastrically (time was shown in Table 11), and then the antitumor drug was administered by injection / intragastric administration (type, administration mode, dosage, and duration were shown in Table 11); CDK inhibitor group: The CDK inhibitor was administered intragastrically (type, administration mode, dosage, and duration were shown in Table 11), and then the antitumor drug was administered (time was shown in Table 11).

[0212] Observation of diarrhea Scoring of diarrhea can be done by Akinobu Kurita (Cancer Chemother Pharmacol 2000;46:211-20.) method, and it is grade 0: normal stool; grade 1: mild diarrhea, stool is slightly wet and soft; grade 2: moderate diarrhea, soft stool and mild perianal contamination; grade 3: severe diarrhea, watery stool, and severe perianal staining (see FIG. 1). If the diarrhea grade classification of the mice in the CDK inhibitor group is lowered compared with the average diarrhea grade classification of the mice in the antitumor drug group, it is considered as effective remission.

[0213] The diarrhea grade classification of the mice was observed and recorded daily. At the end of the experiment, the number of mice in the CDK inhibitor group with a lower diarrhea grade classification than the mice in the antitumor drug group was recorded. Table 11 lists various animal experimental combinations of antitumor drugs and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate % = number of mice in the CDK inhibitor group with effectively alleviated diarrhea / total number of mice in the CDK inhibitor group × 100%. The establishment rate of the diarrhea model in the chemotherapy drug group was 50%-80%, i.e., about 5-8 mice out of 10 mice developed diarrhea during the experiment, and individual mice died or did not develop diarrhea.) [Table 11]

[0214] The experimental results in Table 11 show that CDK inhibitors have no effect on alleviating diarrhea caused by continuous administration of targeted antitumor drugs.

[0215] Examples 486-487: Effect of oral administration of CDK inhibitors on constipation induced by other antitumor drugs Balb / c mice were fed for one week, then divided into groups. The experiment was divided into a control group, an antitumor drug group, and a CDK inhibitor group, each of which contained 10 mice, and the administration experiment was performed, and the dosage, mode, time, and frequency were shown in Table 12. Control group: The same solvent used in the CDK inhibitor group was administered intragastrically (time was shown in Table 12), and then the same solvent used in the antitumor drug group was administered by injection / intragastric administration (administration mode was shown in Table 12); Antineoplastic drug group: The same solvent used in the CDK inhibitor group was administered intragastrically (time was shown in Table 12), and then the antitumor drug was administered by injection / intragastric administration (type, administration mode, dosage, and duration were shown in Table 12); CDK inhibitor group: The CDK inhibitor was administered intragastrically (type, administration mode, dosage, and duration were shown in Table 12), and then the antitumor drug was administered (time was shown in Table 12).

[0216] Observation of constipation Feces from mice were collected within 3 hours, observed for shape, and weighed on an electronic balance. The feces reduction rate was calculated with reference to the method of Ji Eun Kim (Lab Anim Res. 2016 Dec; 32 (4): 231-240.). Feces reduction rate (%) = (control group - antitumor drug group or CDK inhibitor group) / control group x 100%

[0217] In the CDK inhibitor group, a reduction in the fecal matter in mice was determined to be effective remission when compared to the antitumor drug group.

[0218] The fecal volume of the mice within 3 hours was observed and recorded daily. At the end of the experiment, the number of mice in the CDK inhibitor group with a lower fecal reduction rate than the mice in the antitumor drug group was recorded. Table 12 lists various animal experimental combinations of antitumor drugs and CDK inhibitors, as well as the corresponding experimental results. (Relative remission rate% = number of mice in the CDK inhibitor group that were effectively alleviated / total number of mice in the CDK inhibitor group × 100%. The establishment rate of the constipation model in the chemotherapy drug group was 30% to 50%, and about 3 to 5 mice out of 10 mice showed a decrease in fecal volume during the experiment, and individual mice died or had no change or increase in fecal volume). [Table 12]

[0219] The experimental results in Table 12 show that CDK inhibitors have no effect on alleviating constipation caused by continuous administration of targeted antitumor drugs.

[0220] The foregoing detailed description has been provided by way of illustration and example, and is not intended to limit the scope of the appended claims. Various modifications to the embodiments recited in this application that are now apparent to those skilled in the art are intended to remain within the scope of the appended claims and their equivalents.

Claims

**Claim 1**: A pharmaceutical composition for preventing, reducing and / or treating gastrointestinal side effects associated with chemotherapy, comprising a cyclin-dependent kinase (CDK) inhibitor, wherein the gastrointestinal side effects associated with the chemotherapy include gastrointestinal side effects caused by the chemotherapy. **Claim 2** The pharmaceutical composition according to claim 1, wherein the CDK inhibitor comprises a reagent for reducing the expression of CDK and / or a reagent for reducing the activity of CDK. **Claim 3** The pharmaceutical composition according to claim 1, wherein the CDK inhibitor comprises a CDK inhibitor for local intestinal exposure. **Claim 4** The pharmaceutical composition according to claim 1, wherein the CDK inhibitor comprises a small molecule compound, a protein and / or a nucleic acid molecule. **Claim 5** The pharmaceutical composition according to claim 1, wherein the CDK inhibitor comprises one or more compounds selected from trilaciclib, palbociclib, ribociclib, abemaciclib, FLX-925, SHR-6390, BPI-1178, BPI-16350, FCN 437, G2T28, XZP-3287, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, MM-D37K, zotarolimus, XZP-3287, rigosertib, KRX-0601, libaciclib, lonaciclib, milciclib, sericiclib, roscovitine, indisulam, alvocidib, NUV-422, BEY-1107, GLR-2007, FN-1501, BCD-115, TP-1287, BAY-1251152, atubesiclib, SEL-120, HX-301, volasertib, fadraciclib, AGM-130, PHA-793887, PHA-690509, dinaciclib, RO4584820, R547, AT-7519, RGB-286638, ZK-304709, IIIM-290, PF-07104091 and G1T38. **Claim 6** The pharmaceutical composition according to claim 1, wherein the chemotherapy comprises administration of a chemotherapeutic agent. **Claim 7** The pharmaceutical composition according to claim 6, wherein the chemotherapeutic agent is a cytotoxic agent.

8. The pharmaceutical composition according to claim 6, wherein the chemotherapeutic agent is selected from one or more of a DNA synthesis inhibitor, an RNA synthesis inhibitor, a protein synthesis inhibitor, a cell division inhibitor, a DNA base analog, a topoisomerase inhibitor, and / or a telomerase synthesis inhibitor.

9. The pharmaceutical composition according to claim 6, wherein the chemotherapeutic agent is selected from fluorouracil, oxaliplatin, topotecan, irinotecan, tetrahydrofolic acid, docetaxel, gemcitabine, carboplatin, cisplatin, etoposide, methotrexate, doxorubicin, cytarabine, vinorelbine, capecitabine, and combinations thereof.

10. The pharmaceutical composition according to claim 6, wherein the chemotherapeutic agent is administered continuously and / or discontinuously.

11. The pharmaceutical composition according to claim 6, wherein the chemotherapeutic agent does not include a chemotherapeutic agent having a continuous administration time of 7 days or more.

12. The pharmaceutical composition according to claim 1, wherein the gastrointestinal side effects associated with the chemotherapy include gastrointestinal adverse events that occur or worsen after administration of the chemotherapeutic agent.

13. The pharmaceutical composition according to claim 12, wherein the gastrointestinal adverse events occur or worsen about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 1 day, about 2 days, about 4 days, about 7 days, about 2 weeks, about 3 weeks, about 1 month, about 2 months, or later after administration of the chemotherapeutic agent in the absence of prevention or treatment.

14. The pharmaceutical composition according to claim 1, wherein the gastrointestinal side effects include gastric mucosal injury diseases and / or intestinal mucosal injury diseases.

15. The pharmaceutical composition according to claim 1, wherein the gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, anorexia, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulcer and / or intestinal necrosis.

16. The pharmaceutical composition according to claim 1, wherein the gastrointestinal side effects include diarrhea and / or constipation.

17. The pharmaceutical composition according to claim 1, wherein the subject includes cancer patients.

18. The pharmaceutical composition according to claim 1, which does not substantially affect the therapeutic effect of the chemotherapy.

19. The pharmaceutical composition according to claim 1, which is administered about 0.5 hour before, about 1 hour before, about 2 hours before, about 3 hours before, about 4 hours before, about 5 hours before, about 6 hours before, about 7 hours before, about 8 hours before, about 9 hours before, about 10 hours before, about 11 hours before, about 12 hours before, about 13 hours before, about 14 hours before, about 15 hours before, about 16 hours before, about 17 hours before, about 18 hours before, about 19 hours before, about 20 hours before or before that of the administration of the chemotherapy.

20. The pharmaceutical composition according to claim 1, which is for oral administration, intravenous injection, subcutaneous injection, intraperitoneal injection and / or intramuscular injection.

21. The pharmaceutical composition according to claim 1, which is tablets and / or capsules.

22. The pharmaceutical composition according to claim 1, wherein the CDK inhibitor can independently improve or reduce the gastrointestinal side effects.

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