WO2022258001A1 - 治疗化疗相关的胃肠道副作用的化合物和方法 - Google Patents

治疗化疗相关的胃肠道副作用的化合物和方法 Download PDF

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WO2022258001A1
WO2022258001A1 PCT/CN2022/097792 CN2022097792W WO2022258001A1 WO 2022258001 A1 WO2022258001 A1 WO 2022258001A1 CN 2022097792 W CN2022097792 W CN 2022097792W WO 2022258001 A1 WO2022258001 A1 WO 2022258001A1
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cdk
use according
hours
administration
inhibitors
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PCT/CN2022/097792
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English (en)
French (fr)
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项瑾男
李文晰
杨立楠
张诗宜
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上海岸阔医药科技有限公司
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Priority to JP2023575784A priority Critical patent/JP2024520796A/ja
Priority to US18/568,448 priority patent/US20240293413A1/en
Priority to CN202280041119.6A priority patent/CN117529322A/zh
Priority to EP22819598.8A priority patent/EP4353236A1/en
Priority to KR1020247000565A priority patent/KR20240021213A/ko
Publication of WO2022258001A1 publication Critical patent/WO2022258001A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present application relates to the field of biomedicine, in particular to a method for using CDK inhibitors to treat chemotherapy-related gastrointestinal side effects.
  • Tumor chemotherapy is one of the most commonly used means to treat tumors clinically. It mainly uses chemical drugs (chemotherapeutics) to prevent the proliferation, invasion, and metastasis of cancer cells until it finally kills cancer cells.
  • chemotherapeutics chemical drugs
  • the administration of chemotherapeutic agents can not only kill rapidly growing and detached tumor cells, but may also kill normal cells and immune cells together, thus causing serious side effects, including nausea, vomiting, anemia, inflammation and infection, etc. These side effects will lead to the withdrawal of chemotherapeutic agents or the reduction of the dose, which will greatly affect the patient's tumor treatment effect, and will impair the patient's quality of life, and in severe cases, endanger the patient's life.
  • the application provides a method for preventing, alleviating and/or treating chemotherapy-related gastrointestinal side effects (for example, diarrhea or constipation) in a subject, the method comprising administering to the subject a cyclin-dependent kinase (CDK) Inhibitors.
  • CDK cyclin-dependent kinase
  • the medicine of the present application can effectively alleviate the gastrointestinal side effects related to chemotherapy.
  • the present application provides the use of a cyclin-dependent kinase (CDK) inhibitor in the preparation of a medicament for preventing, alleviating and/or treating chemotherapy-related gastrointestinal side effects in a subject.
  • CDK cyclin-dependent kinase
  • the CDK inhibitors include agents that reduce the expression of a CDK, and/or agents that reduce the activity of a CDK.
  • 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.
  • the CDK inhibitors include CDK1 inhibitors, CDK2 inhibitors, CDK3 inhibitors, CDK4 inhibitors, CDK5 inhibitors, CDK6 inhibitors, CDK7 inhibitors, CDK8 inhibitors, and/or CDK9 inhibitors .
  • the CDK inhibitor comprises a CDK2 inhibitor.
  • the CDK inhibitor comprises a CDK4 inhibitor.
  • the CDK inhibitor comprises a CDK6 inhibitor.
  • the CDK inhibitor comprises a CDK9 inhibitor.
  • the CDK inhibitors include CDK4/6 inhibitors.
  • the CDK inhibitors include CDK2/4/6 inhibitors.
  • the CDK inhibitors include CDK4/6/9 inhibitors.
  • the CDK inhibitor comprises a CDK inhibitor exposed locally in the gut.
  • the CDK inhibitors include small molecule compounds, proteins and/or nucleic acid molecules.
  • the CDK inhibitors include small-molecule CDK inhibitors, protein macromolecules that specifically bind to CDKs, RNAi that inhibits CDK protein expression, and/or antisense oligonucleotides that inhibit CDK protein expression.
  • the small molecule CDK inhibitors include small molecule CDK inhibitors that reversibly bind to CDKs, small molecule CDK inhibitors that irreversibly bind to CDKs, and/or small molecule CDK inhibitors that specifically bind mutant CDKs agent.
  • the small molecule CDK inhibitor has a molecular weight of less than or equal to 2000 daltons, less than or equal to 1500 daltons, less than or equal to 1200 daltons, less than or equal to 1000 daltons, less than or equal to 900 daltons, less than or equal to 800 daltons, less than or equal to 700 daltons, less than or equal to 600 daltons, less than or equal to 500 daltons, less than or equal to 400 daltons, less than or equal to 300 daltons Molecular weight less than or equal to 200 Daltons and/or less than or equal to 100 Daltons.
  • the CDK inhibitor comprises one or more compounds selected from the group consisting of 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, Riviciclib , roniciclib, Milciclib, Seliciclib, Roscovitine, Indisulam, Alvocidib, NUV-422, BEY-1107, GLR-2007, FN-1501, BCD-115, TP-1287, BAY-1251152, Atuveciclib, SEL-120, HX-301 , Voruciclib, Fadraciclib, A
  • the chemotherapy comprises administering a chemotherapeutic agent.
  • the chemotherapeutic agent is a cytotoxic agent.
  • the chemotherapeutic agent is selected from one or more of the following group: DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topological Isomerase inhibitors and/or telomerase synthesis inhibitors.
  • the chemotherapeutic agent is selected from the group consisting of fluorouracil, oxaliplatin, tetrahydrofolate, irinotecan, topotecan, docetaxel, gemcitabine, etoposide, carboplatin, methyl aminopterin, doxorubicin, cytarabine, vinorelbine, and capecitabine, and combinations of the above.
  • the chemotherapeutic agent does not include a tumor targeting drug. In certain embodiments, the chemotherapeutic agent does not include a tyrosine kinase inhibitor. In certain embodiments, the chemotherapeutic agent does not include an antineoplastic drug targeting EGFR. In certain embodiments, the chemotherapeutic agent does not include an antineoplastic drug targeting PI3K. In certain embodiments, the chemotherapeutic agent does not include an antineoplastic drug targeting FGFR4. In certain embodiments, the chemotherapeutic agent does not include afatinib, idelaris, fexotinib, imatinib, and osimertinib.
  • the chemotherapeutic agent is administered continuously and/or discontinuously.
  • the chemotherapeutic agent does not include a chemotherapeutic agent administered continuously for 7 days or more.
  • the chemotherapy is used in combination with one or more other therapies.
  • the gastrointestinal side effects associated with chemotherapy include gastrointestinal side effects caused by chemotherapy.
  • chemotherapy-related gastrointestinal side effects include gastrointestinal adverse events that occur or are exacerbated after administration of a chemotherapeutic agent.
  • the gastrointestinal adverse event occurs after about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours after administration of the chemotherapeutic agent without prophylaxis or treatment.
  • the gastrointestinal adverse event occurs after about 6 hours, after about 7 hours, after about 8 hours, after about 9 hours, after about 10 hours, after about 11 hours, after about 12 hours, after about 1 day, after about 2 days, after about 4 days, Appear or worsen after about 7 days, about 2 weeks, about 3 weeks, about 1 month, about 2 months or more.
  • the gastrointestinal side effects include gastric mucosal injury diseases and/or intestinal mucosal injury diseases. In certain embodiments, the gastrointestinal side effect is not a side effect caused by myelosuppression.
  • the gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, loss of appetite, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulcer, intestinal necrosis.
  • the gastrointestinal side effects include diarrhea, constipation.
  • the severity of the gastrointestinal side effects is grade 1 or above, grade 2 or above, grade 3 or above, or grade 4 according to NCI-CTCAE V5.0 or above, or level 5.
  • the subject comprises a cancer patient.
  • the drug does not substantially affect the therapeutic effect of the chemotherapy.
  • the drug 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 before the chemotherapy is administered. 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 Applied earlier.
  • the drug is administered about 0.5-12 hours prior to the administration of chemotherapy.
  • the medicament is formulated for oral administration, intravenous injection, subcutaneous injection, intraperitoneal injection and/or intramuscular injection.
  • the medicament is formulated for administration by injection. In certain embodiments, the medicament is prepared as an injection.
  • the medicament is formulated for oral administration.
  • the medicament is prepared as a tablet and/or capsule.
  • the medicament also includes one or more other active ingredients.
  • the CDK inhibitor independently improves or alleviates the gastrointestinal side effects.
  • the present application provides a use of a cyclin-dependent kinase (CDK) inhibitor in the preparation of a medicament for preventing or treating chemotherapy-related diarrhea in a subject.
  • CDK cyclin-dependent kinase
  • the present application provides a use of a cyclin-dependent kinase (CDK) inhibitor in the preparation of a medicament for preventing or treating chemotherapy-related constipation in a subject.
  • CDK cyclin-dependent kinase
  • the present application provides a method for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy, the method comprising administering the CDK inhibitor described in the present application to a subject in need.
  • the present application provides the CDK inhibitor, which is used for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy.
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related diarrhea, the method comprising administering the CDK inhibitor described in the present application to a subject in need.
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related constipation, the method comprising administering the CDK inhibitor described in the present application to a subject in need.
  • the present application provides a drug combination, which includes the CDK inhibitor and the drug for chemotherapy.
  • the present application provides a kit comprising the CDK inhibitor and the chemotherapeutic agent.
  • Fig. 1 shows the pictures of diarrhea of typical mice in the chemotherapeutic agent group in Example 1-229.
  • Fig. 2 shows some diarrhea grade results of the control group, chemotherapeutic agent group, and CDK inhibitor group in Examples 1-229.
  • Fig. 3 shows some diarrhea grade results of the control group, chemotherapeutic agent group, and CDK inhibitor group in Examples 230-271.
  • Figure 4 shows the photos of the quantity and shape of feces in the control group, chemotherapeutic agent group, and CDK inhibitor group in Examples 272-342.
  • Fig. 5 shows the partial stool reduction rate results of the control group, chemotherapeutic agent group, and CDK inhibitor group in Examples 272-342.
  • Fig. 6 shows some diarrhea grade results of the control group, chemotherapeutic agent group, oral CDK inhibitor group and intravenous CDK inhibitor group in Examples 343-381.
  • Fig. 7 shows some results of diarrhea grades in the control group, chemotherapeutic agent group, oral CDK inhibitor group and other administration modes of CDK inhibitor groups in Examples 382-405.
  • Fig. 8 shows the partial stool reduction rate results of the control group, chemotherapeutic agent group, oral CDK inhibitor group and other CDK inhibitor administration groups in Examples 406-443.
  • Fig. 9 shows some diarrhea grade results of the control group, chemotherapeutic agent group, and CDK inhibitor group in Examples 444-469.
  • Fig. 10 shows the partial stool reduction rate results of the control group, chemotherapeutic agent group, and CDK inhibitor group in Examples 470-481.
  • CDK inhibitor generally refers to any known or future discovery in the art that can block, reduce or inhibit CDK (cyclin-dependent kinase, cyclin-dependent kinase) activity or any function Molecules, including but not limited to small molecule compounds, polynucleotides (eg, DNA or RNA), and/or polypeptides (eg, antibodies or antigen-binding portions thereof).
  • a CDK inhibitor may act directly on a CDK, for example by binding a CDK, or may act indirectly, for example by interfering with the interaction between a CDK and its ligand, inhibiting the activity of a cyclin or by inhibiting the activity of a substrate.
  • CDK is a class of kinases in the protein kinase family that can be used to regulate the cell cycle and is also involved in the regulation of transcription, mRNA processing and differentiation of neural cells.
  • the CDKs described in the present application may refer to complete CDKs or kinase domain fragments, and also encompass CDKs from various vertebrates (such as humans, monkeys, mice, dogs, rabbits, etc.). According to the different cyclins combined, CDK can be divided into different types.
  • 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 .
  • CDK1 which primarily regulates the transition from G2 to M phase
  • the CDK inhibitors of the present application may include selective CDK inhibitors and broad-spectrum CDK inhibitors.
  • CDK2 inhibitor generally refers to an inhibitor acting on CDK2 in the CDK family. Among all members of the CDK family, it mainly has an inhibitory effect on CDK2, and the possibility of inhibiting other CDK family members other than CDK2 is not ruled out, and the possibility of its inhibitory effect on other molecules outside the CDK family is not ruled out.
  • Exemplary CDK2 inhibitors may 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.
  • CDK4 inhibitor generally refers to an inhibitor acting on CDK4 in the CDK family. Among all members of the CDK family, it mainly has an inhibitory effect on CDK4, and the possibility of inhibiting other CDK family members other than CDK4 is not ruled out, and the possibility of its inhibitory effect on other molecules outside the CDK family is not ruled out.
  • Exemplary CDK4 inhibitors may 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.
  • CDK6 inhibitor generally refers to an inhibitor acting on CDK6 in the CDK family. Among all members of the CDK family, it mainly has an inhibitory effect on CDK6, and the possibility of inhibiting other CDK family members other than CDK6 is not ruled out, and the possibility of its inhibitory effect on other molecules outside the CDK family is not ruled out.
  • 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.
  • CDK9 inhibitor generally refers to an inhibitor acting on CDK9 in the CDK family. Among all members of the CDK family, it mainly has an inhibitory effect on CDK9, and the possibility of inhibiting other CDK family members other than CDK9 is not ruled out, and the possibility of its inhibitory effect on other molecules outside the CDK family is not ruled out.
  • 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.
  • CDK2/4/6 inhibitor generally refers to an inhibitor that acts on all CDK2, CDK4 and CDK6 in the CDK family.
  • CDK family mainly has inhibitory effects on CDK2, CDK4, and CDK6, and the possibility of inhibiting other CDK family members other than CDK2, CDK4, and CDK6 is not ruled out, nor is it ruled out that it has inhibitory effects on CDK family members outside the CDK family.
  • Other molecules may have inhibitory effects. It is not required that a CDK2/4/6 inhibitor has the same or similar effect on CDK2, CDK4 and CDK6.
  • Exemplary CDK2/4/6 inhibitors may include, but are not limited to, AT7519HCl, Riviciclib hydrochloride (P276-00), Flavopiridol HCl, AT7519, JNJ-7706621 and/or Flavopiridol (L86-8275).
  • CDK4/6 inhibitor generally refers to an inhibitor that acts on both CDK4 and CDK6 in the CDK family.
  • CDK4/6 inhibitor generally refers to an inhibitor that acts on both CDK4 and CDK6 in the CDK family.
  • CDK4 and CDK6 mainly has inhibitory effects on CDK4 and CDK6, and the possibility of inhibiting other CDK family members other than CDK4 and CDK6 is not ruled out, nor is it ruled out that it has inhibitory effects on other molecules outside the CDK family possible effect. It is not required that a CDK4/6 inhibitor has the same or similar effect on CDK4 and CDK6.
  • Exemplary CDK4/6 inhibitors may include, but are not limited to, Ribociclib succinate, Ribociclib hydrochloride, Palbociclib, Trilaciclib, G1T38, Abemaciclib, ON123300, AT7519HCl, Ribociclib (LEE011), Abemaciclib mesylate (LY2835219), Riviciclib (O hydrochloride)2 Palbociclib (PD0332991) Isethionate, Flavopiridol HCl, AT7519, JNJ-7706621, Flavopiridol (L86-8275), and/or Palbociclib (PD-0332991) HCl.
  • CDK4/6/9 inhibitor generally refers to an inhibitor that acts on all CDK4, CDK6 and CDK9 in the CDK family. Among all members of the CDK family, it mainly has inhibitory effects on CDK4, CDK6, and CDK9, and the possibility of inhibiting other CDK family members other than CDK4, CDK6, and CDK9 is not ruled out, nor is it ruled out that it has inhibitory effects on CDK family members outside the CDK family. Other molecules may have inhibitory effects. It is not required that CDK4/6/9 inhibitors have the same or similar effects on CDK4, CDK6 and CDK9. Exemplary CDK4/6/9 inhibitors may include, but are not limited to, G1T38, AT7519HCl, Riviciclib hydrochloride (P276-00), AT7519, and/or Flavopiridol (L86-8275).
  • chemotherapeutic agents generally refers to a therapy for the treatment of tumors using chemotherapeutic agents that cause the death of cancer cells or interfere with the division, repair, growth and/or function of cancer cells.
  • Agents used in chemotherapy are chemotherapeutic agents.
  • the chemotherapeutic agents include chemical or biological substances capable of causing cancer cell death or interfering with the growth, division, repair and/or function of cancer cells.
  • the chemotherapy may include cytotoxic, cytostatic and antineoplastic agents that kill, inhibit the growth or metastasis of tumor cells or disrupt the cell cycle of rapidly proliferating cells.
  • Chemotherapeutic agents include natural compounds found in plants and animals, or man-made chemicals.
  • the chemotherapy or chemotherapeutic agent has low selectivity to tumor cells and normal cells, so it can also interfere with the growth, division, repair and/or or function, leading to the death of normal cells.
  • the chemotherapeutics described in the present application may not include tumor-targeted drugs, that is, the chemotherapeutics described in the present application may not include proteins that can specifically recognize tumor cells, tumor tissues, tumor organs, or tumor cells (for example, tumor-associated antigen or tumor-specific antigen). Due to genetic mutations or other factors, certain kinases or phosphokinases are activated, leading to the proliferation of cancer cells.
  • the chemotherapeutic agents described herein also do not include those kinase inhibitors that inhibit abnormally activated kinases to prevent the division of cancer cells. Chemotherapeutic agents described herein also do not include antibodies and/or angiogenesis inhibitors.
  • examples of chemotherapeutic agents may include, but are not limited to, alkylating agents such as nitrogen mustards, ethyleneimine 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.
  • alkylating agents such as nitrogen mustards, ethyleneimine 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 may include,
  • Chemotherapy agents may 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 adesleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, CPT-11, 10-Hydroxy-7-ethyl-camptothecin (SN38), floxuridine, fludarabine, hydroxyurea, ifosfamide, idarubicin
  • cytotoxic agent generally refers to an agent that inhibits a biological process of a cell or reduces the viability or proliferative potential of a cell. Cytotoxic agents can act in a variety of ways, such as, but not limited to, by inducing DNA damage, inducing cell cycle arrest, inhibiting DNA synthesis, inhibiting transcription, inhibiting translation or protein synthesis, inhibiting cell division, or inducing apoptosis.
  • the term "substantially does not affect” generally means that compared with the therapeutic effect of using the chemotherapy alone, the therapeutic effect of the combination of the drug described in the present application and the chemotherapy is equivalent, or does not cause significant disadvantages .
  • the degree of tumor volume reduction caused by the combination of the drug and the chemotherapy is the same, or the degree of reduction is not less than About 5%, not less than about 4%, not less than about 3%, not less than about 2%, not less than about 1%, not less than about 0.5%, not less than about 0.1%, not less than about 0.01%, not less than about 0.001 % or less.
  • continuous administration generally means repeated administration of the same drug every day. Repeated daily administration can be once a day, twice a day, three times a day or more. For example, continuous administration may be administered once a day for at least two days or more.
  • the continuous administration period of 2 days may refer to the administration once a day (twice, 3 times or more), and the administration lasts for 2 days.
  • continuous administration for 3 days may refer to administration once a day (twice, 3 times or more), and continuous administration for 3 days.
  • continuous administration for 5 days may be administered once a day (twice, 3 times or more) for 5 consecutive days.
  • continuous administration for 7 days may refer to administration once a day (twice, 3 times or more), and continuous administration for 7 days.
  • the continuous administration period of 10 days may refer to the administration once a day (twice, three times or more), and the administration lasts for 10 days.
  • continuous administration for 14 days may refer to administration once a day (twice, three times or more) for 14 consecutive days.
  • continuous administration for more than 7 days may refer to administration once a day (twice, 3 times or more), and continuous administration for more than 7 days.
  • discontinuous administration generally refers to the administration mode in which the same drug is not administered every day within the administration cycle, and may also be referred to as intermittent administration and/or pulse administration. Discontinuous administration can be regular or irregular. In the case of non-continuous administration, if the administration cycle is longer than 7 days, for any continuous period of time, if the administration is administered every day and lasts for 7 days or more, it also belongs to the category of "continuous administration for 7 days or within 7 days". above" situation.
  • gastrointestinal adverse event generally refers to a harmful, undesired, gastrointestinal-related A response, effect, action, effect, result or influence of or manifested in the gastrointestinal region. Also known as adverse gastrointestinal effects, adverse gastrointestinal effects, or adverse gastrointestinal consequences. Gastrointestinal adverse events include adverse events in various parts of the digestive system, such as the digestive tract and glands.
  • gastrointestinal adverse events may include, but are not limited to, abdominal distension, abdominal pain, anal fissure, 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 hemorrhage, colonic obstruction, colonic perforation, colonic stenosis, colonic ulcer, constipation, dental caries, diarrhea, dry mouth, duodenal fistula, duodenal hemorrhage, duodenum Intestinal obstruction, duodenal perforation, duodenal stricture, duodenal ulcer, dyspepsia, dysphagia, enterocolitis, intestinal fistula, esophageal fistula, esophageal hemorrhage, esophageal necrosis
  • gastrointestinal side effect generally refers to the harmful and adverse effects caused by prophylactic or therapeutic drugs related to or manifested in the gastrointestinal tract area. Adverse effects are often undesired, but undesired effects are not necessarily adverse. Adverse effects of preventive or therapeutic medicines may be harmful, uncomfortable or dangerous. Gastrointestinal side effects include side effects of various parts of the digestive system such as the digestive tract and glands. Chemotherapy-related gastrointestinal side effects may refer to any abnormal clinical manifestations of the gastrointestinal tract that are temporally associated with the use of a chemotherapeutic agent, and which may not be causally related to the administration of the chemotherapeutic agent.
  • gastric mucosal injury disease generally refers to a disease or condition whose symptoms are gastric mucosal injury, and gastric mucosal injury may include abnormal color of gastric mucosa, bleeding points, congestion and erosion.
  • intestinal mucosal injury disease generally refers to a disease or condition whose symptoms are intestinal mucosal injury, and intestinal mucosal injury may include abnormal color of intestinal mucosa, bleeding points, congestion and erosion.
  • the term "diarrhea” generally refers to a disease or condition characterized by increased frequency of bowel movements and/or loose or watery bowel movements.
  • the diarrhea may appear or worsen after the administration of the chemotherapeutic agent.
  • constipation generally refers to a disease or condition characterized by irregular, infrequent or difficult bowel movements. In the present application, said constipation may occur or worsen after said administration of chemotherapy.
  • the term "without prevention or treatment” generally refers to the situation where prevention or treatment of gastrointestinal adverse events is not implemented, and measures are not taken to weaken or eliminate gastrointestinal adverse events.
  • Measures to reduce or eliminate gastrointestinal adverse events may be, for example, administering drugs or other means to prevent or treat gastrointestinal adverse events, stopping administration of drugs or other means that cause gastrointestinal adverse events, said measures include Administering the CDK inhibitor described herein or the drug.
  • the gastrointestinal adverse events will occur after 1 hour, 2 hours, or 3 hours after the administration of the chemotherapy.
  • NCI-CTCAE generally refers to the standardized definition of adverse events published by the National Cancer Institute (NCI) - the Common Terminology Criteria for Adverse Events (CTCAE) to describe severe organ toxicity in cancer treatment patients degree. The standard can be continuously updated as the scientific basis advances.
  • the evaluation of diarrhea can refer to the evaluation criteria of "NCI-CTCAE” in some cases.
  • NCI-CTCAE may include any version of "NCI-CTCAE”.
  • constipation and diarrhea are defined as 5 grades, as shown in Table 1 and Table 2.
  • CTCAE level standard Level 1 Episodic or intermittent symptoms; occasional use of stool softeners, laxatives, dietary modification, or enemas level 2 Persistent symptoms with long-term use of laxatives or enemas; limit instrumental ADL level 3 Constipation with manual evacuation instructions; limiting self-care Level 4 Life-threatening consequences; indicates urgent intervention level 5 die
  • local intestinal exposure when the term "local intestinal exposure” is used to describe a compound, it usually means that the compound is given a certain method of administration or delivery, so that the compound acts preferentially in the intestinal lumen without sufficient exposure to the systemic circulation . May also be referred to as “gut-restricted” or “gut-restricted compound”.
  • Localized intestinal exposure can reduce the systemic exposure of the compound or its derivatives and reduce its effects on cells, tissues and organs/organ systems unrelated to the desired disease treatment, thereby improving the safety of the molecule.
  • Local intestinal exposure can be achieved by adjusting the type of compound, route of administration, dosage form, mode of administration, dose of administration, use of equipment and other auxiliary means to make the compound reach the local intestinal tract or target the intestinal tract.
  • Compounds exposed locally to the gut have one or more of the following properties: (1) (due to mode of administration, etc.) gut targeting exposure, and (2) systemic drug concentrations below the effective concentration ( IC50).
  • IC50 systemic drug concentrations below the effective concentration
  • it can be administered orally or administered manually, such as through catheterization.
  • the term "independently improving or alleviating” generally means that the gastrointestinal side effects can be improved or alleviated only by using the drug or pharmaceutical composition of the present application without resorting to other drugs or treatments.
  • cancer generally refers to any medical condition mediated by the growth, proliferation or metastasis of tumor or malignant cells and giving rise to solid tumors and non-solid tumors (eg, leukemia).
  • Cancers described in this application may include, but are not limited to, epithelial malignancies (cancers of epithelial origin), lung cancer (e.g., non-small cell lung cancer), breast cancer, skin cancer, bladder cancer, colon cancer, bowel ( GI) cancer, prostate cancer, pancreatic cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, head and neck cancer, stomach cancer and laryngeal cancer.
  • the present application provides a use of a CDK inhibitor in the preparation of a medicament for preventing or treating chemotherapy-related gastrointestinal side effects in a subject.
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related gastrointestinal side effects in a subject, comprising administering the CDK inhibitor to the subject in need.
  • the CDK inhibitor can block its kinase activity by directly binding to the CDK kinase domain; or occupy the ligand binding site or a part of the CDK ligand, or occupy the CDK binding site or a part of cyclin , so that the biological activity of CDK is reduced or blocked.
  • CDK inhibitors may be non-specific inhibitors of CDK, that is, such inhibitors inhibit other targets besides CDK.
  • CDK inhibitors act directly on CDK protein or nucleic acid encoding CDK protein.
  • the CDK inhibitor acts directly on the CDK protein.
  • the term "acts directly on” when used to describe the inhibitor and the target protein, it usually means that the inhibitor and the target protein can be directly bound without other molecules (including covalent binding and non-covalent binding). price combination).
  • the CDK inhibitor can be a small molecule EGFR inhibitor, a protein macromolecule that specifically binds to EGFR, RNAi that inhibits the expression of EGFR protein, or an antisense oligonucleotide.
  • the CDK inhibitor can be a small molecule CDK inhibitor.
  • CDK inhibitors may be ATP competitive inhibitors, allosteric site inhibitors, covalent inhibitors and non-ATP competitive polypeptide mimetics.
  • the CDK inhibitor can be a CDK that inhibits one or more of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CLK, Cdc, CDK8, CDK10, CDK12, CDK13, CDK19 and CDK11 Inhibitors.
  • the CDK inhibitor can be a CDK4/6 inhibitor capable of inhibiting both CDK6 and CDK4.
  • the CDK inhibitor can be a CDK2/4/6 inhibitor capable of simultaneously inhibiting CDK2, CDK4 and CDK6.
  • the CDK inhibitor can be a CDK4/6/9 inhibitor capable of simultaneously inhibiting CDK9, CDK4 and CDK6.
  • exemplary CDK inhibitors can 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, zotiraciclib, XZP-3287, Rigosertib, KRX-0601, Riviciclib, roniciclib, Milciclib, Seliciclib, Roscovitine, Indisulam, Alvocidib , NUV-422, BEY-1107, GLR-2007, FN-1501, BCD-115, TP-1287, BAY-1251152, Atuveciclib, SEL-120, HX-301, Voruciclib, Fadraciclib, AGM-130
  • CDK inhibitors can be identified or screened by methods known in the art, for example, by detecting changes in CDK expression levels or kinase activity following administration of a test compound.
  • the expression level or kinase activity of CDK can be detected by methods known in the art, for example, immunohistochemical methods, PCR, RT-PCR, in situ hybridization, Southern blot, Western blot, Northern blot, spectrophotometry and ELISA.
  • the chemotherapeutic agent used in the chemotherapy can be selected from any compound or agent used for cancer treatment in the classes known to those skilled in the art.
  • chemotherapeutic agents may include DNA synthesis inhibitors, RNA synthesis inhibitors, protein synthesis inhibitors, cell division inhibitors, DNA base analogs, topoisomerase inhibitors, and/or telomerase synthesis inhibitors .
  • chemotherapeutic agents may be toxic to cells.
  • chemotherapeutic agents can inhibit cell growth.
  • the chemotherapeutic agent administered may be a DNA damaging chemotherapeutic agent.
  • chemotherapeutic agents are protein synthesis inhibitors, DNA-damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binders, thiolate alkylating agents, guanine alkylating agents Tubulin-binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazophosphorine compounds, integrin inhibitors such as cilengitide, camptothecin, or homocamptothecin , antifolates, folate antimetabolites, telomerase inhibitors and/or telomere DNA binding compounds.
  • the alkylating agents may include alkyl sulfonates such as busulfan, improsulfan, and pipoxulfan; aziridines such as benzodizepa, carboquinone, meturedepa, and uridine; Alternate; ethyleneimines and methylmelamines such as hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as phenylbutyric acid Nitrogen mustard, naphthalene nitrogen mustard, cyclophosphamide, estramustine, dichloromethyldiethylamine, methoxymustine hydrochloride, melphalan, new nitrogen mustard (novembichine), phenesterine, prednimustine, koji lofosfamide and uracil mustard; and nitrosoureas such as carmustine, chlorurecin, formustine, lomustine, nimustine,
  • chemotherapeutic agents may include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin, and streptozotocin.
  • Chemotherapeutic antimetabolites may include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate , azathioprine, acyclovir, adenine ⁇ -1-D-arabinoside, methotrexate, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine, diazo Serine, 6-azauracil, 2'-azido-2'-deoxynucleoside, 5-bromodeoxycytidine, cytosine ⁇ -1-D-arabinoside, diazooxynorleucine, dideoxy nucleosides, 5-
  • protein synthesis inhibitors may include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, idamicin A, emetine, erythromycin, Ethionine, Fluoride, 5-Fluorotryptophan, Fusidic Acid, Guanylmethylene Diphosphonate and Guanylimidyl Diphosphonate, Kanamycin, Kasugamycin, Yellow Mycin and O-methylthreonine.
  • protein synthesis inhibitors include modeccin, neomycin, norvaline, micycline, paromomycine, puromycin, ricin, shiga toxin, pyrooxytetracycline, sparsomycin, spectinomycin, streptomycin tetracyclines, thiostreptons, and trimethoprim.
  • DNA synthesis inhibitors may include alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards; intercalating agents such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, diiodide Propidium-interleaving; topoisomerase inhibitors such as irinotecan, teniposide, coumarin, nalidixic acid, novobiocin, and oxolinic acid; cell division inhibitors including colcemid, mitol Anthraquinones, colchicine, vinblastine, and vincristine; and other agents such as distamycin and netlastine.
  • alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards
  • intercalating agents such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, diiodide Propidium-interleaving
  • the chemotherapeutic agent may be a DNA complex binding agent such as camptothecin or etoposide; a thiolate alkylating agent such as nitrosourea, BCNU, CCNU, ACNU or fotesmustine; a guanine alkylating agent, Examples include temozolomide, tubulin-binding agents such as vinblastine, vincristine, vinorelbine, vinflunine, nodocin 52, halichondrin such as halichondrin B, dolastatin such as dolastatin 10, and dolastatin Toxin 15, hemiasterlins (eg, hemiasterlin A and hemiasterlin B), colchicine, combrestatins, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, asculonide; DNA polymerization Enzyme inhibitors such as cytarabine; anticancer enzymes such as as as
  • the CDK inhibitor can be used to treat one or more chemotherapy-related gastrointestinal side effects mentioned above.
  • the CDK inhibitors can be used for the treatment of gastrointestinal side effects associated with the administration of the following chemotherapeutic 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.
  • chemotherapeutic agents fluorouracil, oxaliplatin, irinotecan (CPT-11), docetaxel (DTX), gemcitabine (GEM ), paclitaxel, carboplatin, doxorubicin (Dox), methotrexate (MTX), cytara
  • the CDK inhibitor can be used for the treatment of gastrointestinal side effects associated with the administration of the following chemotherapeutic agents: fluorouracil, oxaliplatin (Oxaliplatin), topotecan, irinotecan, tetrahydrofolic acid, docetaxel, gemcitabine, carboplatin, cisplatin, etoposide, methotrexate, doxorubicin, cytarabine, vinorelbine, and capecitabine, and any combination of the above.
  • fluorouracil oxaliplatin
  • topotecan irinotecan
  • tetrahydrofolic acid docetaxel
  • gemcitabine gemcitabine
  • carboplatin cisplatin
  • etoposide methotrexate
  • doxorubicin doxorubicin
  • cytarabine vinorelbine
  • capecitabine capecitabine
  • the CDK inhibitors can be used for the treatment of gastrointestinal side effects associated with the administration of the following chemotherapeutic agents: fluorouracil, oxaliplatin (Oxaliplatin), irinotecan, docetaxel, gemcitabine, carboplatin, methotrexate Glycine, doxorubicin, cytarabine, vinorelbine and capecitabine, and any combination of the above.
  • the chemotherapeutic agents may not include tumor targeting drugs.
  • the chemotherapeutic agent may not include those kinase inhibitors that inhibit abnormally activated kinases to prevent the division of cancer cells.
  • the chemotherapeutic agents may not include antibodies and/or angiogenesis inhibitors.
  • the chemotherapy can be administered continuously.
  • the chemotherapy can be administered for 2, 3, 4, 5, 6, 7, 8, 9 or more consecutive days.
  • the chemotherapy is administered continuously for no more than 7 days, for example, the chemotherapy can be administered for 2 days, 3 days, 4 days, 5 days or 6 days in a row.
  • the administration frequency of the chemotherapy can be once a day, twice a day, three times a day or others.
  • the chemotherapy may be administered discontinuously.
  • the administration frequency of the chemotherapy may be once every two days, once every three days, twice every three days or others.
  • the administration frequency of the chemotherapeutic agent may be once a day, and the administration time may last no more than 7 days and/or no more than 7 days.
  • the administration period of the chemotherapeutic agent may be 3 days, 5 days, 7 days, 2 weeks, 20 days, 1 month, 2 months or longer.
  • one or more different chemotherapeutic agents may be used.
  • two or more different chemotherapeutic agents can be used in combination.
  • the CDK inhibitor may be used in combination with one or more other cancer treatments.
  • the other cancer therapy may be a method conventionally used in the art to treat cancer, such as a cytotoxic anticancer agent, an immunotherapeutic anticancer agent or a hormonal therapy anticancer agent.
  • drugs for cancer treatment may also be used in combination with radiation therapy or surgery.
  • the CDK inhibitor and other anticancer agents may be administered to the subject simultaneously, or separately at intervals.
  • the CDK inhibitor can prevent, relieve and/or treat gastrointestinal side effects associated with the administration of chemotherapy in a subject.
  • chemotherapy-related gastrointestinal side effects may refer to the gastrointestinal side effects caused by the administration of the chemotherapy, and the gastrointestinal side effects are generated or aggravated after the administration of the chemotherapeutic agent.
  • the gastrointestinal side effects will occur after 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours after the administration of the chemotherapeutic agent , 8 hours later, 9 hours later, 10 hours later, 11 hours later, 12 hours later, 1 day later, 2 days later, 4 days later, 7 days later, 2 weeks later, 3 weeks later, 1 month later, 2 months later Appear or worsen after a long time.
  • the subject before administering the chemotherapeutic agent to the subject, the subject does not experience the gastrointestinal side effects; after administering the chemotherapeutic agent to the subject, the subject produce the gastrointestinal side effects.
  • the subject before administering the chemotherapeutic agent to the subject, the subject has developed the gastrointestinal side effect; after administering the chemotherapeutic agent to the subject, the subject The degree of the gastrointestinal side effects was exacerbated.
  • the gastrointestinal side effect symptoms of the subject can be increased by at least about 10%, for example, increased by 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 higher.
  • the degree of the gastrointestinal side effect e.g., diarrhea or constipation
  • the degree of the gastrointestinal side effect increases from Grade 1 to Grade 2 , from level 1 to level 3, from level 1 to level 4, from level 1 to level 5, from level 2 to level 3, from level 2 to level 4 , from level 2 to level 5, from level 3 to level 4, from level 3 to level 5 or from level 4 to level 5.
  • the subject's constipation score increases from grade 0 to grade 1, from grade 0 to grade 2, from grade 0 level to level 3, level 1 to level 2, level 1 to level 3 or level 2 to level 3.
  • the gastrointestinal side effects include gastric mucosal injury diseases and/or intestinal mucosal injury diseases.
  • the gastrointestinal side effects include diarrhea, abdominal pain, nausea, vomiting, mucositis, loss of appetite, gastric ulcer, gastritis, constipation, enteritis, intestinal perforation, intestinal bleeding, ulceration and/or intestinal necrosis.
  • the gastrointestinal side effects include abnormal excretion.
  • the gastrointestinal side effects include diarrhea and/or constipation.
  • the chemotherapy-related gastrointestinal side effects include chemotherapy-related gastric mucosal injury diseases and/or chemotherapy-related intestinal mucosal injury diseases.
  • the gastrointestinal side effects associated with chemotherapy include diarrhea associated with chemotherapy, abdominal pain associated with chemotherapy, nausea associated with chemotherapy, vomiting associated with chemotherapy, mucositis associated with chemotherapy, and Chemotherapy-related anorexia, chemotherapy-related gastric ulcer, chemotherapy-related gastritis, chemotherapy-related constipation, chemotherapy-related enteritis, chemotherapy-related intestinal perforation, chemotherapy-related intestinal bleeding, chemotherapy-related ulcer and/or bowel necrosis associated with chemotherapy.
  • the chemotherapy-related gastrointestinal side effects include chemotherapy-related excretion abnormalities.
  • the chemotherapy-related gastrointestinal side effects include chemotherapy-related diarrhea and/or chemotherapy-related constipation.
  • the severity of chemotherapy-related gastrointestinal side effects of the subject was alleviated.
  • the alleviation may generally mean that the onset or development of gastrointestinal side effects in the subject is delayed.
  • the symptoms of gastrointestinal side effects of the subject can be alleviated.
  • the subject's gastrointestinal side effects can be alleviated 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 lightened.
  • the symptoms of gastrointestinal side effects for example, diarrhea and/or constipation
  • the symptoms of gastrointestinal side effects for example, diarrhea and/or constipation
  • the symptoms of gastrointestinal side effects can be reduced from grade 5 to grade 4, from grade 5 from level 3 to level 2, from level 5 to level 2, from level 5 to level 1, from level 4 to level 3, from level 4 to level 2, from level 4 downgrade from level 1 to level 1, from level 3 to level 2, from level 3 to level 1 or from level 2 to level 1.
  • the subject's diarrhea score can be reduced from grade 3 to grade 2, from grade 3 to grade 1, from grade 3 to grade 0 level, from level 2 to level 1, from level 2 to level 0, or from level 1 to level 0.
  • the gastrointestinal side effects of the subject can be eliminated.
  • the gastrointestinal side effects recur or aggravate again.
  • prevention generally refers to preventing the onset, recurrence or spread of a disease or one or more symptoms thereof. "Prevention” may be used interchangeably with “prophylactic treatment” in this application.
  • prophylaxis generally refers to providing, prior to the onset of symptoms, with or without other agents described herein, to a patient suffering from a disease or condition described herein. treatment with the above-mentioned drugs.
  • patients with a family history of a particular disease may be candidates for prophylactic regimens.
  • patients with a history of recurrent symptoms are also potential candidates for prophylaxis.
  • treating generally refers to eliminating or ameliorating a disease, or one or more symptoms associated with a disease.
  • treatment generally refers to the elimination or remission of a disease by administering one or more therapeutic agents to a patient suffering from the disease.
  • treatment may be the administration of a drug in the presence or absence of other therapeutic agents after the onset of symptoms of a particular disease.
  • subject generally refers to a human or non-human animal (including a mammal) in need of diagnosis, prognosis, improvement, prevention, mitigation and/or treatment of a disease, particularly a CDK inhibitor treatment or prevention of those subjects.
  • the subject can include a cancer patient.
  • the cancer patient may have been, is and/or will be administered chemotherapy.
  • the subject can be a human or a non-human mammal.
  • Non-human mammals can include any mammalian species other than humans, such as livestock animals (e.g., cows, pigs, sheep, chickens, rabbits, or horses), or rodents (e.g., rats and mice), or Primates (eg, gorillas and monkeys), or domestic animals (eg, dogs and cats).
  • livestock animals e.g., cows, pigs, sheep, chickens, rabbits, or horses
  • rodents e.g., rats and mice
  • Primates eg, gorillas and monkeys
  • domestic animals eg, dogs and cats.
  • an effective amount used in the present application generally refers to the amount of the drug that can alleviate or eliminate the disease or symptom of the subject, or can prophylactically inhibit or prevent the occurrence of the disease or symptom.
  • An effective amount may be that amount of a drug that alleviates to a certain extent one or more diseases or symptoms in a subject; may partially or completely restore one or more physiological or biochemical parameters related to the cause of the disease or symptoms to the normal amount of the drug; and/or the amount of the drug that can reduce the likelihood of the disease or symptoms occurring.
  • the drug or the CDK inhibitor may be administered to prevent, relieve and/or Treatment of occurrence or aggravation of gastrointestinal side effects.
  • administering the drug or the CDK inhibitor 0.5-12 hours before administering chemotherapy can prevent, relieve and/or treat the occurrence or aggravation of gastrointestinal side effects.
  • the site of administration of the CDK inhibitor may or may not be the site of occurrence of cancer or the site of potential metastasis of cancer.
  • the CDK inhibitors described in the present application can be administered by administration methods known in the art, such as injection administration (for example, subcutaneous, intraperitoneal, intra-articular, intraarterial, intrathecal, intrasternal, intrathecal, intralesional, intracranial, intramuscular, intradermal, and intravenous bolus or infusion) or non-injection administration (eg, oral, nasal, sublingual, vaginal, rectal, or topical administration).
  • injection administration for example, subcutaneous, intraperitoneal, intra-articular, intraarterial, intrathecal, intrasternal, intrathecal, intralesional, intracranial, intramuscular, intradermal, and intravenous bolus or infusion
  • non-injection administration eg, oral, nasal, sublingual, vaginal, rectal, or topical administration.
  • the CDK inhibitors of the present application can be administered in the form of pharmaceutical combinations or kits.
  • the CDK inhibitors described herein can be administered by the same route of administration as chemotherapy or by
  • the drug and/or the CDK inhibitor can be prepared for oral administration.
  • the CDK inhibitor may act preferentially in the intestinal lumen, or may preferentially reach the intestinal lumen without being exposed to the systemic circulation.
  • the CDK inhibitor can be prepared into a dosage form suitable for delivery to the intestinal cavity or to exert an effect in the intestinal cavity (for example, the effect of preventing, alleviating and/or treating side effects of the gastrointestinal tract), and the CDK inhibitor can be used
  • the administration route or mode of delivery into the intestinal lumen or exerting effect in the intestinal lumen can also use auxiliary means such as instruments to enable the delivery of the CDK inhibitor into the intestinal lumen or exerting an effect in the intestinal lumen.
  • the systemic drug concentration of the CDK inhibitor is lower than the effective concentration (IC50).
  • the drug and/or the CDK inhibitor can be prepared for gastrointestinal administration, for example, powder, tablet, granule, capsule, solution, emulsion and/or mixed Suspension.
  • the drug and/or the CDK inhibitor can be prepared in a dosage form suitable for cavity administration, for example, a suppository and/or a drop pill.
  • the drug and/or the CDK inhibitor may be prepared in a dosage form suitable for delivery to the gastrointestinal tract by artificially assisted means, for example, by intubation.
  • the drug and/or the CDK inhibitor are prepared in a dosage form suitable for gastrointestinal exposure.
  • a dosage form suitable for gastrointestinal exposure may be a dosage form suitable for delivery to the gastrointestinal tract, a dosage form suitable for gastrointestinal administration, a dosage form suitable for oral administration, a dosage form suitable for oral administration and/or A dosage form suitable for delivery to the gastrointestinal tract by artificially assisted means.
  • the dosage of the CDK inhibitor can be about 0.01-1000 mg/kg, for example, about 0.01-800 mg/kg, about 0.01-900 mg/kg, about 0.01-800 mg/kg, about 0.01 -700mg/kg, about 0.01-600mg/kg, about 0.01-500mg/kg, about 0.01-400mg/kg, about 0.01-300mg/kg, about 0.01-200mg/kg, about 0.01-100mg/kg, about 0.1- 1000mg/kg, about 1-1000mg/kg, about 10-1000mg/kg, about 50-1000mg/kg, about 100-1000mg/kg, about 0.1-800mg/kg, about 1-600mg/kg, about 10-500mg /kg, about 10-400 mg/kg, about 15-300 mg/kg, about 50-250 mg/kg, or about 50-200 mg/kg.
  • the dosage of the CDK inhibitor when administered orally can be about 0.01-1000 mg/kg, for example, about 0.01-800 mg/kg, about 0.01-900 mg/kg, about 0.01-800 mg/kg, about 0.01-700mg/kg, about 0.01-600mg/kg, about 0.01-500mg/kg, about 0.01-400mg/kg, about 0.01-300mg/kg, about 0.01-200mg/kg, about 0.01-100mg/kg, about 0.1-1000mg/kg, about 1-1000mg/kg, about 10-1000mg/kg, about 50-1000mg/kg, about 100-1000mg/kg, about 0.1-800mg/kg, about 1-600mg/kg, about 10 - 500 mg/kg, about 10-400 mg/kg, about 15-300 mg/kg, about 50-250 mg/kg or about 50-200 mg/kg.
  • a given dose may be given at multiple intervals, such as once a day, two or more times a day, once a week, once every two weeks, once every three weeks, once a month, or once every two or more months .
  • the dosage administered may vary over the course of the treatment.
  • the initial dose administered may be higher than the subsequent doses administered.
  • the dose administered is adjusted during the course of treatment based on the response of the subject.
  • the CDK inhibitor of the present application can be administered at a maintenance dose as needed. Subsequently, the dose or frequency of administration, or both, can be reduced to a level at which the improved state is maintained when symptoms are alleviated to the desired level.
  • the dosing can be spaced according to the condition of the subject.
  • the CDK inhibitor can be administered about 0.5 h to about 24 h before the administration of the chemotherapeutic agent, and can be administered orally, and the dosage can be about 30-200 mg/kg, and the administration cycle can be 1 week-24 h. 1 time in 2 weeks.
  • the CDK inhibitor can be administered about 0.5h to about 24h before the administration of the chemotherapeutic agent, and can be administered orally, and the dosage can be about 50-200mg/kg, and the administration cycle can be 1-2 hours. 1 time a week.
  • the CDK inhibitor can be administered about 0.5h to about 24h before the administration of the chemotherapeutic agent, it can be administered orally, and the dosage can be about 30-200mg/kg, and the administration cycle can be 7 days. once every 8 days, once every 9 days, or once every 10 days.
  • the CDK inhibitor can be administered about 0.5h to about 12h before the administration of the chemotherapeutic agent, and can be administered orally, and the dosage can be about 50-200mg/kg, and the administration cycle can be 7 days. once every 8 days, once every 9 days, or once every 10 days.
  • the CDK inhibitor can be administered about 0.5h to about 12h before the administration of the chemotherapeutic agent, and can be administered orally, and the dosage can be about 50-100mg/kg, and the administration cycle can be 7 days. once every 8 days, once every 9 days, or once every 10 days.
  • the CDK inhibitor can be administered about 0.5h to about 12h before the administration of the chemotherapeutic agent, and can be administered orally, and the dosage can be about 100-200mg/kg, and the administration cycle can be 7 days. once every 8 days, once every 9 days, or once every 10 days.
  • the CDK inhibitor can be administered about 0.5 h to about 24 h before the administration of the chemotherapeutic agent, and can be administered by injection, and the dosage can be about 30-200 mg/kg, and the administration cycle can be 1 week-24 h. 1 time in 2 weeks.
  • the CDK inhibitor can be administered about 0.5h to about 12h before the administration of the chemotherapeutic agent, and can be administered by injection, and the dosage can be about 50-200mg/kg, and the administration cycle can be 7 days. once every 8 days, once every 9 days, or once every 10 days.
  • palbociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the administration of chemotherapeutic agents.
  • the palbociclib can be administered about 0.5 h to about 12 h before the administration of the chemotherapeutic agent, the palbociclib can be administered orally, and the dosage can be about 10-200 mg/kg.
  • the chemotherapeutic agent can be administered orally or by injection.
  • palbociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the administration of fluorouracil (5-Fu).
  • the palbociclib can be administered about 0.5 h to about 12 h before the administration of fluorouracil (5-Fu), the palbociclib can be administered orally, and the dosage can be about 125 mg/kg to about 150 mg/kg.
  • fluorouracil (5-Fu) can be administered orally or by injection.
  • palbociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the administration of oxaliplatin.
  • the palbociclib can be administered about 0.5h to about 12h (for example, about 6h) before the administration of the oxaliplatin, the palbociclib can be administered orally, and the dosage can be about 125mg/kg-about 150mg /kg.
  • oxaliplatin can be administered as an injection.
  • palbociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the administration of irinotecan.
  • the palbociclib can be administered about 0.5 h to about 24 h before the administration of irinotecan, the palbociclib can be administered orally, and the dosage can be about 50 mg/kg to about 200 mg/kg.
  • irinotecan can be administered as an injection.
  • palbociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the administration of gemcitabine.
  • the palbociclib can be administered about 0.5 h to about 12 h before the administration of gemcitabine, the palbociclib can be administered orally, and the dosage can be about 50 mg/kg to about 200 mg/kg.
  • gemcitabine can be administered as an injection.
  • palbociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the administration of docetaxel.
  • the palbociclib can be administered about 0.5h to about 12h before the administration of docetaxel, the palbociclib can be administered orally, and the dosage can be about 150mg/kg to about 200mg/kg.
  • docetaxel can be administered as an injection.
  • palbociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the combination of gemcitabine and paclitaxel.
  • the palbociclib can be administered about 0.5 h to about 12 h before the combination of gemcitabine and paclitaxel, the palbociclib can be administered orally, and the dosage can be about 150 mg/kg to about 200 mg/kg.
  • gemcitabine and paclitaxel can be given as injections.
  • palbociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with capecitabine.
  • the palbociclib can be administered about 0.5h to about 12h before the administration of capecitabine, the palbociclib can be administered orally, and the dosage can be about 150mg/kg to about 200mg/kg.
  • capecitabine can be administered as an injection.
  • palbociclib may be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the combination of etoposide and carboplatin.
  • the palbociclib can be administered about 0.5 h to about 12 h before the combination of etoposide and carboplatin, the palbociclib can be administered orally, and the dosage can be about 150 mg/kg to about 200 mg/kg.
  • etoposide and carboplatin can be administered by injection.
  • ribociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with chemotherapy.
  • the ribociclib can be administered about 0.5 to about 24 hours before the administration of the chemotherapeutic agent, the ribociclib can be administered orally, and the dosage can be about 20 mg/kg to about 200 mg/kg.
  • the chemotherapeutic agent may be administered by injection or orally.
  • ribociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with fluorouracil (5-FU).
  • the ribociclib can be administered about 0.5 h to about 12 h before the administration of fluorouracil (5-FU), the ribociclib can be administered orally, and the dosage can be about 150 mg/kg to about 200 mg/kg.
  • fluorouracil (5-FU) can be administered by injection.
  • ribociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with irinotecan.
  • the ribociclib can be administered about 0.5 h to about 24 h before the administration of irinotecan, the ribociclib can be administered orally, and the dosage can be about 100 mg/kg to about 200 mg/kg.
  • irinotecan can be administered orally.
  • ribociclib may be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the combination of etoposide and carboplatin.
  • the ribociclib can be administered about 0.5 h to about 12 h before the administration of etoposide and carboplatin, the ribociclib can be administered orally, and the dosage can be about 50 mg/kg to about 200 mg/kg.
  • etoposide and carboplatin can be administered by injection.
  • ribociclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the administration of docetaxel (DTX).
  • DTX docetaxel
  • the ribociclib can be administered about 0.5 h to about 24 h before the administration of docetaxel (DTX), the ribociclib can be administered orally, and the dosage can be about 100 mg/kg to about 200 mg/kg.
  • docetaxel (DTX) can be administered by injection.
  • abemaciclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the administration of the chemotherapeutic agent.
  • the abemaciclib can be administered about 0.5 h to about 12 h before the administration of the chemotherapeutic agent, the abemaciclib can be administered orally, and the dosage can be about 150 mg/kg to about 200 mg/kg.
  • the chemotherapeutic agent may be administered by injection or orally.
  • abemaciclib can be used to treat fluorouracil (5-Fu)-related gastrointestinal side effects (eg, diarrhea or constipation).
  • the abemaciclib can be administered about 0.5 h to about 12 h before the administration of fluorouracil (5-Fu), the abemaciclib can be administered orally, and the dosage can be about 150 mg/kg to about 200 mg/kg.
  • capecitabine can be administered as an injection.
  • abemaciclib can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with irinotecan.
  • the abemaciclib can be administered about 0.5 h to about 24 h before the administration of irinotecan, the abemaciclib can be administered orally, and the dosage can be about 10 mg/kg to about 200 mg/kg.
  • irinotecan can be administered as an injection.
  • abemaciclib may be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with gemcitabine (GEM).
  • the abemaciclib can be administered about 0.5 h to about 24 h before the administration of gemcitabine (GEM), the abemaciclib can be administered orally, and the dosage can be about 150 mg/kg to about 200 mg/kg.
  • gemcitabine (GEM) can be administered by injection.
  • G1T28 can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with the administration of the chemotherapeutic agent.
  • the G1T28 can be administered about 0.5 h to about 24 h before the administration of the chemotherapeutic agent, the G1T28 can be administered orally, and the dosage can be about 150 mg/kg to about 200 mg/kg.
  • the chemotherapeutic agent may be administered by injection or orally.
  • G1T28 can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with fluorouracil (5-Fu).
  • the G1T28 can be administered about 0.5 h to about 24 h before the administration of fluorouracil (5-Fu), the G1T28 can be administered orally, and the dosage can be about 100 mg/kg to about 200 mg/kg.
  • fluorouracil (5-Fu) can be administered by injection.
  • G1T28 can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with topotecan.
  • the G1T28 can be administered about 0.5 h to about 12 h before the administration of topotecan, the G1T28 can be administered orally, and the dosage can be about 100 mg/kg to about 200 mg/kg.
  • topotecan can be administered as an injection.
  • G1T28 can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with oxaliplatin.
  • the G1T28 can be administered about 0.5 h to about 24 h before the administration of oxaliplatin, the G1T28 can be administered orally, and the dosage can be about 100 mg/kg to about 200 mg/kg.
  • oxaliplatin can be administered as an injection.
  • G1T28 can be used to treat gastrointestinal side effects (eg, diarrhea or constipation) associated with gemcitabine (GEM).
  • the G1T28 can be administered about 0.5 h to about 24 h before the administration of gemcitabine (GEM), the G1T28 can be administered orally, and the dosage can be about 100 mg/kg to about 200 mg/kg.
  • gemcitabine (GEM) can be administered by injection.
  • the medicament may further include one or more pharmaceutically acceptable carriers (carriers).
  • Pharmaceutically acceptable carriers may include, but are not limited to, for example, pharmaceutically acceptable liquid, gel or solid carriers, aqueous media, non-aqueous media, antimicrobial substances, isotonic substances, buffers, antioxidants , anesthetic, suspending agent/dispersing agent, chelating agent, emulsifier, diluent, adjuvant, excipient, non-toxic auxiliary substance, filler, binder, disintegrant, buffer, preservative, lubricant, flavor Agents, thickeners, colorants, emulsifiers, other components known in the art or multiple combinations of the above.
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related gastrointestinal side effects by the CDK inhibitor.
  • the present application provides the use of the CDK inhibitor in the preparation of drugs for preventing, alleviating and/or treating gastrointestinal side effects associated with chemotherapy.
  • the present application provides the CDK inhibitor, which is used for preventing or treating gastrointestinal side effects associated with chemotherapy.
  • the chemotherapy does not include chemotherapy administered continuously for 7 days or more.
  • the chemotherapy does not include tumor-targeted therapy.
  • the chemotherapy is administered orally.
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related diarrhea by the CDK inhibitor.
  • the present application provides the use of the CDK inhibitor in the preparation of a medicament for preventing, alleviating and/or treating diarrhea associated with chemotherapy.
  • the present application provides the CDK inhibitor, which is used for preventing or treating diarrhea associated with chemotherapy.
  • the chemotherapy does not include chemotherapy administered continuously for 7 days or more.
  • the chemotherapy does not include tumor-targeted therapy.
  • the chemotherapy is administered orally.
  • the present application provides a method for preventing, alleviating and/or treating chemotherapy-related constipation by the CDK inhibitor.
  • the present application provides the use of the CDK inhibitor in the preparation of a medicament for preventing, alleviating and/or treating chemotherapy-related constipation.
  • the present application provides the CDK inhibitor, which is used for preventing or treating constipation associated with chemotherapy.
  • the chemotherapy does not include chemotherapy administered continuously for 7 days or more.
  • the chemotherapy does not include tumor-targeted therapy.
  • the chemotherapy is administered orally.
  • Example 1-229 The effect of oral CDK inhibitors on relief of diarrhea caused by chemotherapy agents
  • mice had symptoms of diarrhea in varying degrees (as shown in Figure 1), which was similar to that seen in humans. Therefore, the model of diarrhea caused by chemotherapeutic agents in mice is a good model for simulating the diarrhea caused by chemotherapeutic agents in humans.
  • mice After one week of adaptive feeding of Balb/c mice, they were divided into groups, and the experiment was divided into control group, chemotherapeutic agent group, and CDK inhibitor group, with 10 mice in each group, and the administration experiment was carried out, the administration dose, method and time And the frequency is shown in Table 3.
  • Control group intragastric administration of the solvent identical to that of the CDK inhibitor group (time as shown in Table 3), followed by injection/gastric administration of the same solvent (administration method as shown in Table 3) with the chemotherapeutic agent group;
  • the chemotherapeutic agent group Intragastric administration of the same solvent as the CDK inhibitor group (time as shown in Table 3), followed by intragastric injection/administration of chemotherapeutic agents (type, administration method and dosage as shown in Table 3);
  • CDK inhibitor group intragastric administration of CDK Inhibitors (times are shown in Table 3), and then chemotherapeutic agents (methods and doses are shown in Table 3).
  • Diarrhea scoring refers to the Akinobu Kurita method (Cancer Chemother Pharmacol 2000; 46:211-20.), grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, loose stool and Mild perianal infection; 3 points: severe diarrhea, watery stools accompanied by severe perianal coloring (see Figure 1).
  • the reduction in the level of diarrhea in the mice in the CDK inhibitor group compared with the mean level of the mice in the chemotherapy group was regarded as effective relief.
  • Figure 1 shows typical pictures of different grades of diarrhea in mice in the chemotherapeutic agent group in Table 3, and Figure 2 shows the results of partial diarrhea grades in the control group, chemotherapeutic agent group, and CDK inhibitor group in Table 3.
  • Example 230-271 The effect of oral CDK inhibitors on the alleviation of diarrhea caused by chemotherapy agents
  • mice were divided into groups, and the experiment was divided into control group, chemotherapeutic agent group, and CDK inhibitor group, with 10 mice in each group, and the administration experiment was carried out, the administration dose, method, time and frequency As shown in Table 4.
  • Control group intragastric administration of the same solvent as the CDK inhibitor group (time as shown in Table 4), followed by injection or/gastric administration of the same solvent as the chemotherapeutic agent group (administration method as shown in Table 4);
  • chemotherapeutic agent group Oral administration of the same solvent as that of the CDK inhibitor group (time as shown in Table 4), followed by intragastric injection/administration of chemotherapeutic agents (type, administration method and dosage as shown in Table 4);
  • CDK inhibitor group intragastric administration of CDK inhibition (time as shown in Table 4), and then chemotherapeutic agents (as shown in Table 4 for the manner and dosage).
  • Diarrhea scoring refers to Akinobu Kurita method (Cancer Chemother Pharmacol2000; 46:211-20.), grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, loose stool and mild Degree of perianal infection; 3 points: severe diarrhea, watery stools accompanied by severe perianal coloring (see Figure 1).
  • the reduction in the level of diarrhea in the mice in the CDK inhibitor group compared with the mean level of the mice in the chemotherapy group was regarded as effective relief.
  • Figure 3 shows some results of diarrhea grades in the control group, chemotherapeutic agent group, and CDK inhibitor group in Table 4.
  • Example 272-342 The effect of oral CDK inhibitors on relief of constipation caused by chemotherapeutic agents
  • mice A mouse animal model was constructed, and the constipation model induced by the chemotherapeutic agent in Balb/c mice was established according to the administration mode and frequency of the chemotherapeutic agent shown in Table 5. After a few days of administration, the mice showed a decrease in the amount of stool (as shown in Figure 4), which was consistent with the symptoms of constipation caused by chemotherapeutic agents in humans. Therefore, the mouse chemotherapeutic-induced constipation model is a good model for chemotherapeutic-induced constipation.
  • mice After one week of adaptive feeding of Balb/c mice, they were divided into groups, and the experiment was divided into control group, chemotherapeutic agent, and CDK inhibitor group, with 10 mice in each group, and the administration experiment was carried out.
  • the dosage, method, time and frequency of administration were as follows: Table 5 shows.
  • Control group intragastric administration of the same solvent as the CDK inhibitor group (time as shown in Table 5), followed by injection or intragastric administration of the same solvent (administration method as shown in Table 5) with the chemotherapeutic agent group; chemotherapeutic agent group: intragastric administration Stomach and CDK inhibitor group same solvent (time as shown in Table 3), then inject or gavage chemotherapeutic agent (type, administration method and dosage as shown in Table 5); CDK inhibitor group: gavage CDK inhibitor (time as shown in Table 5), and then give chemotherapeutic agent (mode and dosage as shown in Table 5).
  • mice Observe and record the amount of defecation of the mice within 3 hours every day. At the end of the experiment, count how many mice in the CDK inhibitor group had a lower stool reduction rate than the chemotherapy agent group.
  • Figure 4 shows the typical pictures of the amount of feces in the control group, chemotherapeutic agent group, and CDK inhibitor group in Table 5 within 3 hours
  • Figure 5 shows the partial stool reduction rate in the control group, chemotherapeutic agent group, and CDK inhibitor group in Table 5 result.
  • Example 343-381 Both oral CDK inhibitors and intravenous CDK inhibitors can alleviate the diarrhea caused by chemotherapy agents
  • mice After one week of adaptive feeding of Balb/c mice, they were divided into groups, and the experiment was divided into control group, chemotherapeutic agent group, oral CDK inhibitor group, and intravenous CDK inhibitor group, with 10 mice in each group, and the administration experiment was carried out.
  • the dose, method, time and frequency of the drug are shown in Table 6.
  • Control group inject/gavage the same solvent (time as shown in table 6) with CDK inhibitor group, then inject/gavage the same solvent (administration method as shown in table 6) with chemotherapeutic agent group afterwards; chemotherapeutic agent group Injection/gavage of the same solvent as the CDK inhibitor group (time as shown in Table 6), followed by injection/gavage of chemotherapeutic agents (type, administration and dosage as shown in Table 6); oral CDK inhibitor group: Intragastric administration of CDK inhibitors (times shown in Table 6), followed by chemotherapeutics (method and dosage shown in Table 6); intravenous CDK inhibitor group: tail vein injection of CDK inhibitors (times shown in Table 6) Afterwards, chemotherapeutic agents were given (the manner and dosage are shown in Table 6).
  • Diarrhea scoring refers to the Akinobu Kurita method (Cancer Chemother Pharmacol2000; 46:211-20.): grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, loose stool and mild Degree of perianal infection; 3 points: severe diarrhea, watery stools accompanied by severe perianal coloring (see Figure 1). Oral CDK inhibitor group/intravenous injection CDK inhibitor group mice diarrhea grade decreased compared with chemotherapy agent group mice diarrhea grade mean reduction was considered as effective remission.
  • Figure 6 shows the results of typical diarrhea grades in the control group, chemotherapeutic agent group, oral CDK inhibitor group and intravenous CDK inhibitor group in Table 6. It can be seen from Table 6 and Figure 6 that oral administration and injection administration of palbociclib, abeciclib, trilaciclib, ribociclib, SHR-6390, Dinaciclib, KR-0601, and Riviciclib can effectively alleviate the pain caused by etoposide. , etoposide combined with cisplatin, carboplatin, gemcitabine, gemcitabine and carboplatin, topotecan caused diarrhea, and the effect of oral administration is the most significant.
  • Example 382-405 The CDK inhibitor CDK inhibitors of various administration modes can alleviate the diarrhea caused by chemotherapy agents
  • mice were divided into groups, and the experiment was divided into control group, chemotherapeutic agent group, and CDK inhibitor group (including oral CDK inhibitor group, intraperitoneal injection of CDK inhibitor group, and intramuscular injection of CDK inhibitor group).
  • group local administration CDK inhibitor group
  • 10 rats in each group the administration experiment was carried out, and the administration dose, mode, time and frequency are shown in Table 7.
  • Control group give the solvent identical to CDK inhibitor group (time, mode are as shown in Table 7), then inject/gavage the same solvent (administration mode as shown in Table 7) with chemotherapeutic agent group afterwards;
  • Chemotherapy agent group Give the same solvent as the CDK inhibitor group (time and method are shown in Table 7), and then inject/gavage chemotherapeutic agent (type, administration method and dosage as shown in Table 7); oral CDK inhibitor group: gavage CDK inhibitor (time as shown in Table 7), then give chemotherapeutic agent (method and dose as shown in Table 7); intraperitoneal injection of CDK inhibitor group: intraperitoneal injection of CDK inhibitor (time as shown in Table 7), and then give Chemotherapeutic agent (method and dose as shown in Table 7); intramuscular injection of CDK inhibitor group: intramuscular injection of CDK inhibitor (time as shown in Table 7), and then chemotherapy (method and dosage as shown in Table 7); local To the CDK inhibitor group: the mouse abdomen was shaved (approximately 2cm*2
  • Diarrhea scoring refers to the Akinobu Kurita method (Cancer Chemother Pharmacol2000; 46:211-20.): grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, loose stool and mild Degree of perianal infection; 3 points: severe diarrhea, watery stools accompanied by severe perianal coloring (see Figure 1).
  • the reduction in the level of diarrhea in the mice in the CDK inhibitor group compared with the mean level of the mice in the chemotherapy group was regarded as effective relief.
  • Figure 7 shows the comparison of diarrhea grade results in the control group, chemotherapeutic agent group, oral CDK inhibitor and other administration methods of CDK inhibitor in Table 7.
  • CDK inhibitors in various administration modes can alleviate the constipation caused by chemotherapeutic agents
  • mice were divided into groups, and the experiment was divided into control group, chemotherapeutic agent, and CDK inhibitor group (including oral CDK inhibitor group, intravenous CDK inhibitor group, and intraperitoneal injection of CDK inhibitor group). , intramuscular injection CDK inhibitor group, local administration CDK inhibitor group), 10 rats in each group, the administration experiment was carried out, and the administration dosage, mode, time and frequency are shown in Table 8.
  • Control group give the solvent identical to CDK inhibitor group (time, mode are as shown in Table 8), then inject/gavage the same solvent (administration mode as shown in Table 8) with chemotherapeutic agent group afterwards;
  • Chemotherapy agent group Give the same solvent as the CDK inhibitor group (time and method are shown in Table 8), and then inject/gavage chemotherapeutic agent (type, administration method and dosage as shown in Table 8); oral CDK inhibitor group: gavage CDK inhibitor (time as shown in Table 8), then give chemotherapeutic agent (method and dose as shown in Table 8); intravenous CDK inhibitor group: tail vein injection of CDK inhibitor (time as shown in Table 8), after that Give chemotherapeutic agent (method and dose as shown in Table 8); intraperitoneal injection of CDK inhibitor group: intraperitoneal injection of CDK inhibitor (time as shown in Table 8), and then give chemotherapeutic agent (method and dosage as shown in Table 8); Intramuscular injection of CDK inhibitor group: intramuscular injection of CDK inhibitor (time as shown in
  • mice Observe and record the amount of defecation of the mice within 3 hours every day. At the end of the experiment, count how many mice in the CDK inhibitor group had a lower stool reduction rate than the chemotherapy agent group.
  • Figure 8 shows the comparison of the stool reduction rate results of the control group, chemotherapy agent group, oral CDK inhibitors and other administration methods of CDK inhibitors in Table 8.
  • Example 444-469 Oral CDK inhibitors are effective in alleviating diarrhea caused by continuous administration of chemotherapeutic agents
  • mice were divided into groups, and the experiment was divided into control group, chemotherapeutic agent group, and CDK inhibitor group, with 10 mice in each group, and the administration experiment was carried out, the administration dose, method, time and frequency As shown in Table 9.
  • Control group intragastric administration of the same solvent as the CDK inhibitor group (time as shown in Table 9), followed by injection or intragastric administration of the same solvent (administration method as shown in Table 9) with the chemotherapeutic agent group; chemotherapeutic agent group: intragastric administration Stomach and CDK inhibitor group same solvent (time as shown in Table 9), then inject or gavage chemotherapeutic agent (type, administration mode, dosage and duration as shown in Table 9); CDK inhibitor group: gavage CDK inhibitors (times are shown in Table 9), and then chemotherapeutic agents (types, administration methods, doses and durations are shown in Table 9).
  • Diarrhea scoring refers to Akinobu Kurita method (Cancer Chemother Pharmacol2000; 46:211-20.), grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, loose stool and mild Degree of perianal infection; 3 points: severe diarrhea, watery stools accompanied by severe perianal coloring (see Figure 1).
  • the reduction in the level of diarrhea in the mice in the CDK inhibitor group compared with the mean level of the mice in the chemotherapy group was regarded as effective relief.
  • Figure 9 shows the comparison of partial diarrhea grade results in the control group, chemotherapeutic agent group, and CDK inhibitor group in Table 9.
  • mice were divided into groups, and the experiment was divided into control group, chemotherapeutic agent group, and CDK inhibitor group, with 10 mice in each group, and the administration experiment was carried out, the administration dose, method, time and frequency As shown in Table 10.
  • Control group intragastric administration of the same solvent (as shown in Table 10) with the CDK inhibitor group, followed by injection or intragastric administration of the same solvent (as shown in Table 10) with the chemotherapeutic agent group;
  • chemotherapeutic agent group intragastric administration Stomach and CDK inhibitor group same solvent (time as shown in Table 10), inject or gavage chemotherapeutic agent (kind, administration mode, dosage and duration as shown in Table 10) afterwards;
  • CDK inhibitor group gavage CDK inhibitors (times are shown in Table 10), and then chemotherapeutic agents (types, administration methods, doses and durations are shown in Table 10).
  • mice Observe and record the amount of defecation of the mice within 3 hours every day. At the end of the experiment, count how many mice in the CDK inhibitor group had a lower stool reduction rate than the chemotherapy agent group.
  • Figure 10 shows the results of partial stool reduction rates in the control group, chemotherapeutic agent group, and CDK inhibitor group in Table 10.
  • Example 482-485 The effect of oral CDK inhibitors on alleviating diarrhea caused by other antitumor drugs
  • mice After one week of adaptive feeding of Balb/c mice, they were divided into groups, and the experiment was divided into control group, antineoplastic drug group, and CDK inhibitor group, with 10 mice in each group, and the administration experiment was carried out.
  • the dosage, method, time and The frequencies are shown in Table 11.
  • Control group intragastric administration of the same solvent as the CDK inhibitor group (time as shown in Table 11), followed by injection or intragastric administration of the same solvent as the antineoplastic drug group (administration methods are as shown in Table 11); antineoplastic drug group : intragastric administration of the same solvent as that of the CDK inhibitor group (time as shown in Table 11), followed by injection or intragastric administration of antineoplastic drugs (type, administration, dosage and duration as shown in Table 11); CDK inhibitor group : intragastric administration of CDK inhibitors (time as shown in Table 11), followed by antineoplastic drugs (type, administration, dosage and duration as shown in Table 11).
  • Diarrhea scoring refers to the Akinobu Kurita method (Cancer Chemother Pharmacol2000; 46:211-20.): grade 0: normal stool; grade 1: mild diarrhea, slightly wet and soft stool; grade 2: moderate diarrhea, loose stool and mild Degree of perianal infection; 3 points: severe diarrhea, watery stools accompanied by severe perianal coloring (see Figure 1).
  • the reduction in the level of diarrhea in mice in the CDK inhibitor group compared with the average level of diarrhea in the antineoplastic drug group was regarded as effective relief.
  • mice in the CDK inhibitor group have a lower diarrhea grade than that in the antineoplastic drug group.
  • Table 11 lists animal experiment combinations of various antineoplastic drugs and CDK inhibitors, and corresponding experimental results.
  • (relative remission rate % CDK inhibitor group diarrhea effectively alleviates mouse number/CDK inhibitor group mouse total number*100%.
  • Chemotherapeutic agent group diarrhea model establishment rate is at 50%-80%, namely in experimental process 10 About 5-8 of the mice had diarrhea, and some mice died or did not have diarrhea.)
  • Example 486-487 The effect of oral CDK inhibitor on the relief of constipation caused by other antitumor drugs
  • mice After one week of adaptive feeding of Balb/c mice, they were divided into groups, and the experiment was divided into control group, antineoplastic drug group, and CDK inhibitor group, with 10 mice in each group, and the administration experiment was carried out.
  • the dosage, method, time and The frequencies are shown in Table 12.
  • Control group intragastric administration of the same solvent as the CDK inhibitor group (time as shown in Table 12), followed by injection or intragastric administration of the same solvent as the antineoplastic drug group (administration methods are as shown in Table 12); antineoplastic drug group : intragastric administration of the same solvent as the CDK inhibitor group (time as shown in Table 12), followed by injection or intragastric administration of antineoplastic drugs (type, administration, dosage and duration as shown in Table 12); CDK inhibitor group : intragastric administration of CDK inhibitors (time as shown in Table 12), followed by antineoplastic drugs (type, administration, dosage and duration as shown in Table 12).
  • mice Observe and record the amount of defecation of the mice within 3 hours every day. At the end of the experiment, count how many mice in the CDK inhibitor group had a lower stool reduction rate than that in the antineoplastic drug group.

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Abstract

一种治疗化疗相关的胃肠道副作用的方法，具体涉及CDK抑制剂在制备药物中的用途，所述药物用于预防、缓解和/或治疗受试者中与化疗相关的胃肠道副作用，所述CDK抑制剂包括CDK1抑制剂、CDK2抑制剂、CDK3抑制剂、CDK4抑制剂、CDK5抑制剂、CDK6抑制剂、CDK7抑制剂、CDK8抑制剂和/或CDK9抑制剂，所述的化疗剂可选择氟尿嘧啶、奥沙利铂、拓扑替康、伊立替康、四氢叶酸、多西紫杉醇等，所述的胃肠道副作用包括腹泻、便秘等。

Description

治疗化疗相关的胃肠道副作用的化合物和方法 技术领域
本申请涉及生物医药领域，具体的涉及一种使用CDK抑制剂治疗化疗相关的胃肠道副作用的方法。
背景技术
肿瘤化疗是临床上治疗肿瘤最常用的手段之一，主要利用化学药物(化疗剂)阻止癌细胞的增殖、浸润、转移，直至最终杀灭癌细胞。然而，化疗剂给药不仅能够杀死快速生长和分离的肿瘤细胞，也可能将正常细胞和免疫细胞一同杀灭，因此会引起严重的副作用，包括恶心、呕吐、贫血、炎症感染等。这些副作用会导致化疗剂停药或者剂量减少，极大影响患者的肿瘤治疗效果，并且会损害患者的生活质量，严重者危及患者生命。
现有技术中尚没有成功的治疗方案来控制化疗剂给药相关的副作用。因此，目前迫切需要能够成功控制该等副作用的治疗方案。
发明内容
本申请提供了预防、缓解和/或治疗受试者中与化疗相关的胃肠道副作用(例如，腹泻或便秘)的方法，所述方法包括向受试者施用周期蛋白依赖性激酶(CDK)抑制剂。本申请的药物能够有效缓解化疗相关的胃肠道副作用。
一方面，本申请提供了周期蛋白依赖性激酶(CDK)抑制剂在制备药物中的用途，所述药物用于预防、缓解和/或治疗受试者中与化疗相关的胃肠道副作用。
在某些实施方式中，所述CDK抑制剂包括减少CDK表达的试剂，和/或降低CDK活性的试剂。
在某些实施方式中，所述CDK抑制剂直接作用于CDK蛋白、编码CDK蛋白的核酸、细胞周期蛋白和/或编码细胞周期蛋白的核酸。
在某些实施方式中，所述CDK抑制剂包括CDK1抑制剂、CDK2抑制剂、CDK3抑制剂、CDK4抑制剂、CDK5抑制剂、CDK6抑制剂、CDK7抑制剂、CDK8抑制剂和/或CDK9抑制剂。
在某些实施方式中，所述CDK抑制剂包括CDK2抑制剂。
在某些实施方式中，所述CDK抑制剂包括CDK4抑制剂。
在某些实施方式中，所述CDK抑制剂包括CDK6抑制剂。
在某些实施方式中，所述CDK抑制剂包括CDK9抑制剂。
在某些实施方式中，所述CDK抑制剂包括CDK4/6抑制剂。
在某些实施方式中，所述CDK抑制剂包括CDK2/4/6抑制剂。
在某些实施方式中，所述CDK抑制剂包括CDK4/6/9抑制剂。
在某些实施方式中，所述CDK抑制剂包括肠道局部暴露的CDK抑制剂。
在某些实施方式中，所述CDK抑制剂包括小分子化合物、蛋白质和/或核酸分子。
在某些实施方式中，所述CDK抑制剂包括小分子CDK抑制剂、特异性结合CDK的蛋白大分子、抑制CDK蛋白表达的RNAi和/或抑制CDK蛋白表达的反义寡核苷酸。
在某些实施方式中，所述小分子CDK抑制剂包括与CDK可逆结合的小分子CDK抑制剂、与CDK不可逆结合的小分子CDK抑制剂和/或特异性结合突变型CDK的小分子CDK抑制剂。
在某些实施方式中，所述小分子CDK抑制剂具有小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿和/或小于或等于100道尔顿的分子量。
在某些实施方式中，所述CDK抑制剂包含选自下组中的一种或多种化合物：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、Riviciclib、roniciclib、Milciclib、Seliciclib、Roscovitine、Indisulam、Alvocidib、NUV-422、BEY-1107、GLR-2007、FN-1501、BCD-115、TP-1287、BAY-1251152、Atuveciclib、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和G1T38。
在某些实施方式中，所述化疗包括施用化疗剂。在某些实施方式中，所述化疗剂为细胞毒性剂。
在某些实施方式中，所述化疗剂选自下组中的一种或多种：DNA合成抑制剂、RNA合成抑制剂、蛋白质合成抑制剂、细胞分裂抑制剂、DNA碱基类似物、拓扑异构酶抑制剂和/或端粒酶合成抑制剂。
在某些实施方式中，所述化疗剂选自氟尿嘧啶、奥沙利铂(Oxaliplatin)、四氢叶酸、伊立替康、拓朴替康、多西紫杉醇、吉西他滨、依托泊苷、卡铂、甲氨蝶呤、阿霉素、阿糖胞苷、长春瑞滨和卡培他滨，以及上述的组合。
在某些实施方式中，所述化疗剂不包括肿瘤靶向药物。在某些实施方式中，所述化疗剂不包括酪氨酸激酶抑制剂。在某些实施方式中，所述化疗剂不包括靶向EGFR的抗肿瘤药物。在某些实施方式中，所述化疗剂不包括靶向PI3K的抗肿瘤药物。在某些实施方式中，所述化疗剂不包括靶向FGFR4的抗肿瘤药物。在某些实施方式中，所述化疗剂不包括阿法替尼、艾代拉里斯、非索替尼、伊马替尼和奥希替尼。
在某些实施方式中，所述化疗剂为连续给药和/或非连续给药。
在某些实施方式中，所述化疗剂不包括连续给药时间为7天或7天以上的化疗剂。
在某些实施方式中，所述化疗与一种或多种其他疗法联用。
在某些实施方式中，所述与化疗相关的胃肠道副作用包括由化疗引起的胃肠道副作用。
在某些实施方式中，与化疗相关的胃肠道副作用包括施用化疗剂后出现或加重的胃肠道不良事件。
在某些实施方式中，所述胃肠道不良事件在无预防或治疗实施的情况下会在化疗剂施用约1小时后、约2小时后、约3小时后、约4小时后、约5小时后、约6小时后、约7小时后、约8小时后、约9小时后、约10小时后、约11小时后、约12小时后、约1天后、约2天后、约4天后、约7天后、约2周后、约3周后、约1个月后、约2个月后或更久后出现或加重。
在某些实施方式中，所述胃肠道副作用包括胃黏膜损伤疾病和/或肠道黏膜损伤疾病。在某些实施方式中，所述胃肠道副作用不是骨髓抑制引起的副作用。
在某些实施方式中，所述胃肠道副作用包括腹泻、腹痛、恶心、呕吐、黏膜炎、食欲减退、胃溃疡、胃炎、便秘、肠炎、肠穿孔、肠出血、溃疡、肠坏死。
在某些实施方式中，所述胃肠道副作用包括腹泻、便秘。
在某些实施方式中，所述胃肠道副作用的严重程度为依据NCI-CTCAE V5.0中的第1级或其以上、第2级或其以上、第3级或其以上、第4级或其以上，或者第5级。
在某些实施方式中，所述受试者包括癌症患者。
在某些实施方式中，所述药物基本上不影响所述化疗的治疗效果。
在某些实施方式中，所述药物在所述化疗施用前约0.5小时、约1小时、约2小时、约3小时、约4小时、约5小时、约6小时、约7小时、约8小时、约9小时、约10小时、约11小时、约12小时、约13小时、约14小时、约15小时、约16小时、约17小时、约18小时、约19小时、约20小时或更久前施用。
在某些实施方式中，所述药物在所述化疗施用前约0.5-12小时施用。
在某些实施方式中，所述药物被制备为适用于口服给药、静脉注射、皮下注射、腹腔注射和/或肌肉注射。
在某些实施方式中，所述药物被制备为适用于注射给药。在某些实施方式中，所述药物被制备为注射液。
在某些实施方式中，所述药物被制备为适用于口服给药。在某些实施方式中，所述药物被制备为片剂和/或胶囊。
在某些实施方式中，所述药物中还包括一种或多种其他活性成分。
在某些实施方式中，所述CDK抑制剂可独立改善或减轻所述胃肠道副作用。
另一方面，本申请提供了周期蛋白依赖性激酶(CDK)抑制剂在制备药物中的用途，所述药物用于预防或者治疗受试者中与化疗相关的腹泻。
另一方面，本申请提供了周期蛋白依赖性激酶(CDK)抑制剂在制备药物中的用途，所述药物用于预防或者治疗受试者中与化疗相关的便秘。
另一方面，本申请提供了一种预防、缓解和/或治疗与化疗相关的胃肠道副作用的方法，所述方法包括向有需要的受试者施用本申请所述的CDK抑制剂。
另一方面，本申请提供了所述CDK抑制剂，所述CDK抑制剂用于预防、缓解和/或治疗与化疗相关的胃肠道副作用。
另一方面，本申请提供了一种预防、缓解和/或治疗与化疗相关的腹泻的方法，所述方法包括向有需要的受试者施用本申请所述的CDK抑制剂。
另一方面，本申请提供了一种预防、缓解和/或治疗与化疗相关的便秘的方法，所述方法包括向有需要的受试者施用本申请所述的CDK抑制剂。
另一方面，本申请提供了药物组合，其包括所述的CDK抑制剂和用于所述化疗的药物。
另一方面，本申请提供了试剂盒，其包括所述的CDK抑制剂和所述化疗剂。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下：
图1显示了实施例1-229中化疗剂组典型小鼠的腹泻照片。
图2显示了实施例1-229中的对照组、化疗剂组、CDK抑制剂组的部分腹泻等级结果。
图3显示了实施例230-271中的对照组、化疗剂组、CDK抑制剂组的部分腹泻等级结果。
图4显示了实施例272-342中的对照组、化疗剂组、CDK抑制剂组粪便数量及形状照片。
图5显示了实施例272-342中的对照组、化疗剂组、CDK抑制剂组的部分大便减少率结果。
图6显示了实施例343-381中的对照组、化疗剂组、口服CDK抑制剂组及静脉注射CDK抑制剂组的部分腹泻等级结果。
图7显示了实施例382-405中的对照组、化疗剂组、口服CDK抑制剂组及CDK抑制剂其他给药方式组的部分腹泻等级结果。
图8显示了实施例406-443中的对照组、化疗剂组、口服CDK抑制剂组及CDK抑制剂其他给药方式组的部分大便减少率结果。
图9显示了实施例444-469中的对照组、化疗剂组、CDK抑制剂组的部分腹泻等级结果。
图10显示了实施例470-481中的对照组、化疗剂组、CDK抑制剂组的部分大便减少率结果。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，本领域技术人员可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中，术语“CDK抑制剂”通常是指本领域中已知的或将来发现的任何能够阻断、降低或抑制CDK(周期蛋白依赖性激酶，cyclin-dependent kinase)活性或功能的任何分子，包括但不限于小分子化合物、多核苷酸(例如DNA或RNA)，和/或多肽(例如，抗体或其抗原结合部分)。CDK抑制剂可以直接作用于CDK，例如通过结合CDK，或者可以间接作用，例如通过干扰CDK与其配体之间的相互作用，抑制细胞周期蛋白(cyclin)或通过抑制底物的活性。CDK是蛋白质激酶家族中的一类激酶，可用于调节细胞周期，还参与调节转录，mRNA加工和神经细胞的分化。本申请所述的CDK可以指完整的CDK或激酶结构域片段，还涵盖来自各种脊椎动物(例如人类、猴、鼠、狗、兔等)的CDK。根据结合的cyclin的不同，CDK可分为不同的类型。在本申请中，所述CDK抑制剂可抑制CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8、CDK9、CDK10、CLK、Cdc、CDK11、CDK12、CDK13和CDK19中的一种或多种。例如，有四种CDK明显参与细胞增殖：CDK1，其主要调节从G2到M期的转变，CDK2、CDK4和CDK6，其调节从G1期到S期的转变。本申请的CDK抑制剂可包括选择性CDK抑制剂和广谱性CDK抑制剂。
在本申请中，术语“CDK2抑制剂”通常是指对CDK家族中的CDK2起作用的抑制剂。在CDK家族的所有成员中，其主要针对CDK2有抑制作用，不排除对于CDK2之外的其他CDK家族成员有抑制作用的可能，也不排除其对于CDK家族外的其他分子有抑制作用的可能。示例性的CDK2抑制剂可包括但不限于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和/或LDC000067。
在本申请中，术语“CDK4抑制剂”通常是指对CDK家族中的CDK4起作用的抑制剂。在CDK家族的所有成员中，其主要针对CDK4有抑制作用，不排除对于CDK4之外的其他CDK家族成员有抑制作用的可能，也不排除其对于CDK家族外的其他分子有抑制作用的可能。示例性的CDK4抑制剂可包括但不限于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和/或LEE011。
在本申请中，术语“CDK6抑制剂”通常是指对CDK家族中的CDK6起作用的抑制剂。在CDK家族的所有成员中，其主要针对CDK6有抑制作用，不排除对于CDK6之外的其他CDK家族成员有抑制作用的可能，也不排除其对于CDK家族外的其他分子有抑制作用的可能。示例性的CDK6抑制剂可包括但不限于LY2835219、Palbociclib(PD-0332991)HCl、Palbociclib(PD0332991)Isethionate、Flavopiridol(Alvocidib)、Flavopiridol(Alvocidib)HCl、AT7519、JNJ-7706621、P276-00和/或LEE011。
在本申请中，术语“CDK9抑制剂”通常是指对CDK家族中的CDK9起作用的抑制剂。在CDK家族的所有成员中，其主要针对CDK9有抑制作用，不排除对于CDK9之外的其他CDK家族成员有抑制作用的可能，也不排除其对于CDK家族外的其他分子有抑制作用的可能。示例性的CDK9抑制剂可包括但不限于LY2835219、Palbociclib(PD-0332991)HCl、Palbociclib(PD0332991)Isethionate、Flavopiridol(Alvocidib)、Flavopiridol(Alvocidib)HCl、AT7519、JNJ-7706621、P276-00和/或LEE011。
在本申请中，术语“CDK2/4/6抑制剂”通常是指对CDK家族中的CDK2、CDK4和CDK6均起作用的抑制剂。在CDK家族的所有成员中，其主要针对CDK2、CDK4和CDK6有抑制作用，不排除对于CDK2、CDK4和CDK6之外的其他CDK家族成员有抑制作用的可能，也不排除其对于CDK家族外的其他分子有抑制作用的可能。不要求CDK2/4/6抑制剂对CDK2、CDK4和CDK6具有相同或相近的作用。示例性的CDK2/4/6抑制剂可包括但不限于AT7519HCl、Riviciclib hydrochloride(P276-00)、Flavopiridol HCl、AT7519、JNJ-7706621和/或Flavopiridol(L86-8275)。
在本申请中，术语“CDK4/6抑制剂”通常是指对CDK家族中的CDK4和CDK6均起作用的抑制剂。在CDK家族的所有成员中，其主要针对CDK4和CDK6有抑制作用，不排除对于CDK4和CDK6之外的其他CDK家族成员有抑制作用的可能，也不排除其对于CDK家族外的其他分子有抑制作用的可能。不要求CDK4/6抑制剂对CDK4和CDK6具有相同或相近的作用。示例性的CDK4/6抑制剂可包括但不限于Ribociclib succinate、Ribociclib hydrochloride、Palbociclib、Trilaciclib、G1T38、Abemaciclib、ON123300、AT7519HCl、Ribociclib(LEE011)、Abemaciclib mesylate(LY2835219)、Riviciclib hydrochloride(P276-00)、Palbociclib(PD0332991)Isethionate、Flavopiridol HCl、AT7519、JNJ-7706621、Flavopiridol(L86-8275)和/或Palbociclib(PD-0332991)HCl。
在本申请中，术语“CDK4/6/9抑制剂”通常是指对CDK家族中的CDK4、CDK6和CDK9均起作用的抑制剂。在CDK家族的所有成员中，其主要针对CDK4、CDK6和CDK9有抑制作用，不排除对于CDK4、CDK6和CDK9之外的其他CDK家族成员有抑制作用的可能，也不排除其对于CDK家族外的其他分子有抑制作用的可能。不要求CDK4/6/9抑制剂对CDK4、CDK6和CDK9具有相同或相近的作用。示例性的CDK4/6/9抑制剂可包括但 不限于G1T38、AT7519HCl、Riviciclib hydrochloride(P276-00)、AT7519和/或Flavopiridol(L86-8275)。
在本申请中，术语“化疗”通常是指使用化疗剂治疗肿瘤的一种疗法，其可导致癌细胞死亡，或者干扰癌细胞的分裂、修复、生长和/或功能。在化疗中使用的药剂为化疗剂。所述化疗剂包括能够引起癌细胞死亡或干扰癌细胞的生长、分裂、修复和/或功能的化学或生物学物质。例如，所述化疗可以包括杀死、抑制肿瘤细胞的生长或抑制肿瘤细胞的转移或破坏快速增殖细胞的细胞周期的细胞毒性剂、细胞抑制剂和抗肿瘤剂。化疗剂包括动植物中发现的天然化合物，或人造的化学物质。在本申请中，所述化疗或化疗剂对肿瘤细胞和正常细胞的选择性较低，因此还可以干扰正常细胞(例如骨髓细胞、头发毛囊细胞或消化道细胞)的生长、分裂、修复和/或功能，导致正常细胞的死亡。本申请所述的化疗剂可以不包括肿瘤靶向药物，即，本申请所述的化疗剂不包括可以特异性识别肿瘤细胞、肿瘤组织、肿瘤器官、或肿瘤细胞特异性表达的蛋白(例如，肿瘤相关抗原或肿瘤特异性抗原)的物质。由于基因突变或其他因素，使得某些激酶或磷酸激酶激活，导致癌症细胞的繁殖。本申请所述的化疗剂也不包括那些抑制异常激活的激酶来阻止癌症细胞的分裂的激酶抑制剂。本申请所述的化疗剂也不包括抗体和/或血管再生抑制剂。
在本申请中，化疗剂的实例可包括但不限于烷基化剂，例如氮芥、亚乙基亚胺化合物、烷基磺酸盐以及具有烷基化作用的其他化合物，例如亚硝基脲、顺铂以及达卡巴嗪；抗代谢物，例如叶酸、嘌呤或嘧啶拮抗剂；有丝分裂抑制剂，例如长春花生物碱和鬼臼毒素的衍生物；细胞毒性抗生素和喜树碱衍生物。化疗剂还可包括氨磷汀顺铂、达卡巴嗪(DTIC)、更生霉素、链霉素、环磷酰胺、卡莫司汀(BCNU)、洛莫司汀(CCNU)、多柔比星、多柔比星脂质体、吉西他滨、红霉素、柔红霉素脂质体丙卡巴肼、丝裂霉素、阿糖胞苷、依托泊苷、甲氨喋呤、5-氟尿嘧啶(5-FU)、长春碱、长春新碱、博来霉素、紫杉醇、多西他赛阿地白介素、门冬酰胺酶、白消安、卡铂、克拉屈滨、喜树碱、CPT-11、10-羟基-7-乙基-喜树碱(SN38)、氟尿苷、氟达拉滨、羟基脲、异环磷酰胺、伊达比星、美司钠、干扰素α、干扰素β、伊立替康、米托蒽醌、拓扑替康、利普安、甲地孕酮、美法仑、巯基嘌呤、普卡霉素、米托坦、培加帕酶、培门冬酶、喷司他丁、哌泊溴烷、普卡霉素、链佐星、他莫昔芬、替尼泊苷、睾丸酯、硫鸟嘌呤、塞替派、尿嘧啶氮芥、长春瑞滨、苯丁酸氮芥芳香酶抑制剂及其组合。
在本申请中，术语“细胞毒性剂”通常是指抑制细胞的生物学过程或降低细胞的活力或增殖潜力的试剂。细胞毒性剂可以以多种方式起作用，例如，但不限于，通过诱导DNA损伤、诱导细胞周期阻滞、抑制DNA合成、抑制转录、抑制翻译或蛋白合成、抑制细胞分裂或诱导细胞凋亡。
在本申请中，术语“基本上不影响”通常是指与单独使用所述化疗的治疗效果相比，使用本申请所述药物和所述化疗的组合的治疗效果相当，或者不产生显著的劣势。例如，对任意的受试者，与单独使用所述化疗的治疗效果相比，使用所述药物和所述化疗的组合所导致的肿瘤体积减少的程度是相同的，或者，减少的程度不小于约5％、不小于约4％、不小于约 3％、不小于约2％、不小于约1％、不小于约0.5％、不小于约0.1％、不小于约0.01％、不小于约0.001％或更小。
在本申请中，术语“连续给药”通常是指每天重复施用同一药物。每天重复施用可以是每天1次、每天2次、每天3次或更多。例如，连续给药可以是给药一天1次，至少给药2天以上。例如，连续给药时间为2天可以是指给药一天1次(2次、3次或更多)，持续给药2天。例如，连续给药时间为3天可以是指给药一天1次(2次、3次或更多)，持续给药3天。例如，连续给药时间为5天可以是给药一天1次(2次、3次或更多)，持续给药5天。例如，连续给药时间为7天可以是指给药一天1次(2次、3次或更多)，持续给药7天。例如，连续给药时间为10天可以是指给药一天1次(2次、3次或更多)，持续给药10天。例如，连续给药时间为14天可以是指给药一天1次(2次、3次或更多)，持续给药14天。例如，连续给药时间为7天以上可以是指给药一天1次(2次、3次或更多)，持续给药7天以上。
在本申请中，术语“非连续给药”通常是指给药周期内，同一药物不是每天施用的给药方式，也可以称为间歇给药和/或脉冲式给药。非连续给药可以是规律性的或非规律性的。在非连续给药时，如果给药周期大于7天，对于任意连续的一段时间，如果每天给药且持续给药7天或7天以上，也属于“连续给药时间为7天或7天内以上”的情形。
在本申请中，术语“胃肠道不良事件”通常是指一种有害的，人们所不希望出现的，由于某种药物或其他诸如化疗或手术之类的医疗所造成的与胃肠道相关的或体现在胃肠道区域的反应、效应、作用、效果、结果或影响。也可称为胃肠道不良作用、胃肠道不良影响或胃肠道不良后果。胃肠道不良事件包括消化系统各部分(如消化道及腺体)的不良事件。例如，胃肠道不良事件可包括但不限于，腹胀、腹痛、肛裂、肛瘘、肛门出血、肛门粘膜炎、肛门坏死、肛门疼痛、肛门狭窄、肛门溃疡、腹水、打嗝、盲肠出血、唇炎、乳糜性腹水、结肠炎、结肠瘘、结肠出血、结肠梗阻、结肠穿孔、结肠狭窄、结肠溃疡、便秘、龋齿、腹泻、口干、十二指肠瘘、十二指肠出血、十二指肠阻塞、十二指肠穿孔、十二指肠狭窄、十二指肠溃疡、消化不良、吞咽困难、小肠结肠炎、肠瘘、食管瘘、食道出血、食道坏死、食道阻塞、食道疼痛、食管穿孔、食管狭窄、食道溃疡、食管静脉曲张破裂出血、食管炎、粪便失禁、肠胃胀气、胃瘘、胃出血、胃坏死、胃穿孔、胃狭窄、胃溃疡、胃炎、胃食管反流病、胃肠道疾病-其他，请注明、胃肠道瘘、胃肠道疼痛、胃轻瘫、牙龈疼痛、痔疮出血、痔疮、回肠瘘、回肠出血、回肠梗阻、回肠穿孔、回肠狭窄、回肠溃疡、伊柳斯、腹腔内出血、空肠瘘、空肠出血、空肠阻塞、空肠穿孔、空肠狭窄、空肠溃疡、唇痛、下消化道出血、吸收不良、口腔粘膜炎、恶心、胃梗阻、口腔瘘、口腔感觉不良、口腔出血、口腔疼痛、胰管狭窄、胰瘘、胰腺出血、胰腺坏死、胰腺炎、牙周疾病、腹膜坏死、直肠炎、直肠裂、直肠瘘、直肠出血、直肠粘膜炎、直肠坏死、直肠梗阻、直肠疼痛、直肠穿孔、直肠狭窄、直肠溃疡、腹膜后出血、唾液管炎症、唾液腺瘘、小肠粘膜炎、小肠梗阻、小肠穿孔、 小肠狭窄、小肠溃疡、腹痛、牙齿发育障碍、牙齿变色、牙疼、盲肠炎、上消化道出血、内脏动脉缺血、呕吐。
在本申请中，术语“胃肠道副作用”通常是指预防药或治疗药引起的胃肠道相关或体现在胃肠道区域的有害和不良影响。不良影响常常是不希望的，但不希望的影响不一定是不良的。预防药或治疗药的不良影响可能是有害的、不适的或危险的。胃肠道副作用包括消化系统各部分(如消化道及腺体)的副作用。与化疗相关的胃肠道副作用可以指与使用化疗剂有时间关联的胃肠道的任何异常临床表现，这些异常表现和化疗剂的施用可以不存在因果关系。
在本申请中，术语“胃黏膜损伤疾病”通常是指症状为胃黏膜损伤的疾病或病症，胃黏膜损伤可包括胃黏膜色泽异常、出血点、充血及糜烂。
在本申请中，术语“肠道黏膜损伤疾病”通常是指症状为肠道黏膜损伤的疾病或病症，肠道黏膜损伤可包括肠道黏膜色泽异常、出血点、充血及糜烂。
在本申请中，术语“腹泻”通常是指一种以肠蠕动频率增加和/或松弛或水样的肠蠕动位特征的疾病或病症。在本申请中，所述腹泻可以在所述化疗剂施用之后出现或加重。在某些情况下，也可以参考动物实验腹泻评级：如Akinobu Kurita方法(Cancer Chemother Pharmacol 2000；46:211-20.)对腹泻的严重程度进行评分，其中，0级：大便正常；1级：轻度腹泻，大便可见轻微湿软；2级：中度腹泻，稀便并且有轻度肛周沾染；3级：重度腹泻，稀水样便并伴有重度肛周着色。
在本申请中，术语“便秘”通常是指一种以肠的不规则排泄、不频繁排泄或排泄困难为特征的疾病或病症。在本申请中，所述便秘可以在所述化疗施用之后出现或加重。
在本申请中，术语“无预防或治疗实施的情况下”通常是指不实施预防或治疗胃肠道不良事件的情况，不采取措施使胃肠道不良事件减弱或消失。使胃肠道不良事件减弱或消失的措施可以是，例如，施用药物或其他手段以预防或治疗胃肠道不良事件，停止引起胃肠道不良事件的药物或其他手段的施用，所述措施包括施用本申请所述CDK抑制剂或所述药物。在本申请中，施用本申请所述化疗后，如果不采取措施使胃肠道不良事件减弱或消失，则胃肠道不良事件会在所述化疗施用1小时后、2小时后、3小时后、4小时后、5小时后、6小时后、7小时后、8小时后、9小时后、10小时后、11小时后、12小时后、1天后、2天后、4天后、7天后、2周后、3周后、1个月后、2个月后或更久后出现或加重。如果施用本申请所述CDK抑制剂或所述药物，胃肠道不良事件可以减弱或消失。
在本申请中，术语“NCI-CTCAE”通常是指美国国家癌症研究所(NCI)发布的不良事件的标准化定义——不良事件常用术语标准(CTCAE)，用以描述癌症治疗患者的器官毒性严重程度。随着科学依据的进步，该标准可以不断更新。在本申请中，腹泻的评价在某些情况下可以参考“NCI-CTCAE”的评价标准。“NCI-CTCAE”可以包括任何一种版本的“NCI-CTCAE”。在第5版的CTCAE中，便秘和腹泻分别被定义为5个等级(grade)，如表1和表2所示。
表1 CTCAE V5.0中对便秘的等级标准定义
CTCAE等级 标准
第1级 偶发性或间歇性症状；偶尔使用大便软化剂，泻药，饮食调节或灌肠
第2级 长期服用泻药或灌肠的持续症状；限制工具性ADL
第3级 带有手动疏散指示的便秘；限制自我护理
第4级 威胁生命的后果；表示紧急干预
第5级 死亡
表2 CTCAE V5.0中对腹泻的等级标准定义
Figure PCTCN2022097792-appb-000001
在本申请中，术语“肠道局部暴露”用于形容化合物时，通常是指所述化合物通过一定的给药或递送方法，使该化合物优先作用于肠腔内，而没有充分暴露在体循环中。也可称为“肠道限制”或“肠道限制化合物”。肠道局部暴露可以减少化合物或其衍生物的系统性暴露，降低其对与所需疾病治疗无关的细胞、组织和器官/器官系统的影响，从而提高分子的安全性。可以通过调节化合物种类、给药途径、给药剂型、给药方式、给药剂量、使用器械等辅助手段的方式使化合物到达肠道局部或靶向肠道，从而实现肠道局部暴露。肠道局部暴露的化合物具有如下一种或多种特性：(1)(由于给药方式等)是肠道靶向的(gut targeting exposure)，和(2)系统药物浓度低于起效浓度(IC50)。例如，可以通过口服给药或通过人工途径，例如插管等方式给药。
在本申请中，术语“独立改善或减轻”通常是指不借助与其他药物或疗法，仅使用本申请的药物或药物组合物即可改善或减轻所述胃肠道副作用。
本申请中，术语“癌症”通常是指任何由肿瘤或恶性细胞生长、增殖或转移所介导，并引发实体瘤和非实体瘤(例如，白血病)的医学状况。本申请中所述的癌症可以包括，但不限于，上皮的恶性肿瘤(上皮来源的癌)，肺癌(例如，非小细胞肺癌)、乳腺癌、皮肤癌、膀胱癌、结肠癌、肠道(GI)癌、前列腺癌、胰腺癌、子宫癌、宫颈癌、卵巢癌、食管癌、头颈部癌、胃癌和喉癌。
发明详述
一方面，本申请提供一种CDK抑制剂在制备药物中的用途，所述药物用于预防或者治疗受试者中与化疗相关的胃肠道副作用。另一方面，本申请提供一种预防、缓解和/或治疗受试者中与化疗相关的胃肠道副作用的方法，包括向有需要的受试者施用所述的CDK抑制剂。
CDK抑制剂
在本申请中，CDK抑制剂可以通过与CDK激酶结构域直接结合阻断其激酶活性；或者 占据了CDK配体的配体结合位点或其一部分，或者占据cyclin的CDK结合位点或其一部分，从而使得CDK的生物活性降低或被阻断。
在本申请中，CDK抑制剂可以是CDK的非特异性抑制剂，即，该等抑制剂除了抑制CDK之外，还抑制其它的靶点。
在本申请中，CDK抑制剂直接作用于CDK蛋白或者编码CDK蛋白的核酸。在一些实施方式中，CDK抑制剂直接作用于CDK蛋白。在本申请中当使用术语“直接作用于”来形容抑制剂与靶蛋白时，通常是指抑制剂与靶蛋白之间能够直接的、不需要通过其它分子的结合(包括共价结合和非共价结合)。在一些实施方式中，CDK抑制剂可以是小分子EGFR抑制剂、特异性结合EGFR的蛋白大分子，抑制EGFR蛋白表达的RNAi或者反义寡核苷酸。在一些实施方式中，CDK抑制剂可以是小分子CDK抑制剂。
在本申请中，CDK抑制剂可以是ATP竞争性抑制剂、变构位点抑制剂、共价抑制剂和非ATP竞争的多肽模拟物。
例如，CDK抑制剂可以是抑制选自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK9、CLK、Cdc、CDK8、CDK10、CDK12、CDK13、CDK19和CDK11中的一种或多种的CDK抑制剂。例如，CDK抑制剂可以是同时能够抑制CDK6和CDK4的CDK4/6抑制剂。例如，CDK抑制剂可以是同时能够抑制CDK2、CDK4和CDK6的CDK2/4/6抑制剂。例如，CDK抑制剂可以是同时能够抑制CDK9、CDK4和CDK6的CDK4/6/9抑制剂。
例如，示例性的CDK抑制剂可以包括但不限于，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、Riviciclib、roniciclib、Milciclib、Seliciclib、Roscovitine、Indisulam、Alvocidib、NUV-422、BEY-1107、GLR-2007、FN-1501、BCD-115、TP-1287、BAY-1251152、Atuveciclib、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和G1T38，以及它们的其他盐、盐型、晶型、溶剂化物和前药。
可以通过本领域公知的方法来确定或筛选CDK抑制剂，例如通过检测施用受试化合物之后CDK表达水平或激酶活性的变化。检测CDK的表达水平或激酶活性可以通过本领域公知的方法，例如，免疫组织化学方法、PCR、RT-PCR、原位杂交、Southern blot，Western blot，Northern blot、分光光度法和ELISA等。
化疗
在本申请中，所述化疗中使用的化疗剂可以选自本领域技术人员已知的类别中的任意一种用于癌症治疗的化合物或药剂。从作用机制上，化疗剂可包括DNA合成抑制剂、RNA合成抑制剂、蛋白质合成抑制剂、细胞分裂抑制剂、DNA碱基类似物、拓扑异构酶抑制剂和/或端粒酶合成抑制剂。
在本申请中，化疗剂对细胞可以是有毒性的。在本申请中，化疗剂可以抑制细胞生长。 在本申请中，所施用的化疗剂可以是DNA损伤的化疗剂。在本申请，化疗剂是蛋白质合成抑制剂、DNA-损伤化疗剂、烷化剂、拓扑异构酶抑制剂、RNA合成抑制剂、DNA复合结合剂、硫醇盐烷化剂、鸟嘌呤烷化剂、微管蛋白结合剂、DNA聚合酶抑制剂、抗癌酶、RAC1抑制剂、胸苷酸合成酶抑制剂、oxazophosphorine化合物、整联蛋白抑制剂如西仑吉肽、喜树碱或高喜树碱、抗叶酸剂、叶酸抗代谢物、端粒酶抑制剂和/或端粒DNA结合化合物。
例如，所述烷化剂可以包括烷基磺酸盐如白消安、英丙舒凡和哌泊舒凡；氮丙啶类如benzodizepa、卡波醌、美妥替哌(meturedepa)和乌瑞替派；乙烯亚胺类和甲基三聚氰胺类如六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基三聚氰胺；氮芥类如苯丁酸氮芥、萘氮芥、环磷酰胺、雌莫司汀、二氯甲基二乙胺、盐酸甲氧氮芥、美法仑、新氮芥(novembichine)、phenesterine、泼尼莫司汀、曲洛磷胺和尿嘧啶芥末；和亚硝基脲类，如卡莫司汀、氯脲霉素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀。其他化疗剂可包括柔红霉素、多柔比星、伊达比星、表柔比星、丝裂霉素和链脲佐菌素。化疗抗代谢药可包括吉西他滨、巯基嘌呤、硫鸟嘌呤、克拉屈滨、磷酸氟达拉滨、氟尿嘧啶(5-FU)、氟尿苷、阿糖胞苷、喷司他丁、甲氨蝶呤、硫唑嘌呤、阿昔洛韦、腺嘌呤β-1-D-阿拉伯糖苷、氨甲蝶呤、氨蝶呤、2-氨基嘌呤、阿非迪霉素、8-氮杂鸟嘌呤、重氮丝氨酸、6-氮尿嘧啶、2'-叠氮基-2'-脱氧核苷、5-溴脱氧胞苷、胞嘧啶β-1-D-阿拉伯糖苷、重氮氧正亮氨酸、双脱氧核苷、5-氟脱氧胞苷、5-氟脱氧尿苷和羟基脲。
例如，蛋白质合成抑制剂可以包括相思豆毒素、金精三羧酸、氯霉素、大肠杆菌素E3、环己酰亚胺、白喉毒素、伊短菌素A、吐根碱、红霉素、乙硫氨酸、氟化物、5-氟色氨酸、夫西地酸、鸟苷酰亚甲基二膦酸盐和鸟苷酰亚氨基二磷酸盐、卡那霉素、春日霉素、黄色霉素和O-甲基苏氨酸。其他蛋白质合成抑制剂包括modeccin、新霉素、正缬氨酸、密旋霉素、paromomycine、嘌呤霉素、蓖麻毒素、志贺毒素、焦土霉素、稀疏霉素、壮观霉素、链霉素、四环素、硫链丝菌素和甲氧苄啶。
例如，DNA合成抑制剂可包括烷化剂如硫酸二甲酯、氮芥和硫芥；嵌入剂如吖啶染料、放线菌素、蒽类、苯并芘、溴化乙锭、二碘化丙锭-交织；拓扑异构酶抑制剂如伊立替康、替尼泊苷、香豆霉素、萘啶酸、新生霉素和恶喹酸；细胞分裂抑制剂，包括秋水仙胺、米托蒽醌、秋水仙素、长春花碱和长春新碱；和其他药剂，如偏端霉素和纺锤菌素。
在本申请中，化疗剂可以是DNA复合结合剂，例如喜树碱或依托泊苷；硫醇盐烷化剂，例如亚硝基脲、BCNU、CCNU、ACNU或fotesmustine；鸟嘌呤烷化剂，例如替莫唑胺，微管蛋白结合剂如长春花碱、长春新碱、长春瑞滨、长春氟宁、念珠藻素52、软海绵素如软海绵素B、海兔毒素如海兔毒素10和海兔毒素15、hemiasterlins(如hemiasterlin A和hemiasterlin B)、秋水仙碱、combrestatins、2-甲氧基雌二醇、E7010、紫杉醇、多西他赛、埃坡霉素、圆皮海绵内酯；DNA聚合酶抑制剂，例如阿糖胞苷；抗癌酶，例如天冬酰胺酶；RAC1抑制剂，例如6-硫鸟嘌呤；胸苷酸合成酶抑制剂，例如卡培他滨或5-FU；oxazophosphorine化合物，例如癌得星；整联蛋白抑制剂，例如西仑吉肽；抗叶酸剂，例如普拉曲沙；叶酸抗代谢物， 例如培美曲塞；或喜树碱或高喜树碱，例如二氟替康。
在本申请中，所述CDK抑制剂可用于治疗上述一种或多种化疗相关的胃肠道副作用。在本申请中，所述CDK抑制剂可用于治疗施用以下化疗剂相关的胃肠道副作用：氟尿嘧啶、奥沙利铂、伊立替康(CPT-11)、多西紫杉醇(DTX)、吉西他滨(GEM)、紫杉醇、卡铂、阿霉素(Dox)、甲氨蝶呤(MTX)、阿糖胞苷(Ara-C)、长春瑞滨(NVB)、拓扑替康(TP)、依托泊苷和顺铂，以及上述的任意组合。
在本申请中，所述CDK抑制剂可用于治疗施用以下化疗剂相关的胃肠道副作用：氟尿嘧啶、奥沙利铂(Oxaliplatin)、拓扑替康、伊立替康、四氢叶酸、多西紫杉醇、吉西他滨、卡铂、顺铂、依托泊苷、甲氨蝶呤、阿霉素、阿糖胞苷、长春瑞滨和capecitabine卡培他滨，以及上述的任意组合。
在本申请中，所述CDK抑制剂可用于治疗施用以下化疗剂相关的胃肠道副作用：氟尿嘧啶、奥沙利铂(Oxaliplatin)、伊立替康、多西紫杉醇、吉西他滨、卡铂、甲氨蝶呤、阿霉素、阿糖胞苷、长春瑞滨和capecitabine，以及上述的任意组合。
在本申请中，所述的化疗剂可以不包括肿瘤靶向药物。在本申请中，所述的化疗剂可以不包括那些抑制异常激活的激酶来阻止癌症细胞的分裂的激酶抑制剂。在本申请中，所述的化疗剂可以不包括抗体和/或血管再生抑制剂。
在本申请中，所述化疗可以是连续给药的。例如，所述化疗可以连续给药2天、3天、4天、5天、6天、7天、8天、9天或更多天。在某些实施方式中，所述化疗的连续给药天数不超过7天，例如，所述化疗可以连续给药2天、3天、4天、5天或6天。在本申请中，所述化疗的给药频率可以是一天1次、一天2次、一天3次或其他。
在本申请中，所述化疗可以是非连续给药的。在本申请中，所述化疗的给药频率可以为两天1次、三天1次、三天2次或其他。
在本申请中，所述化疗剂的给药频率可以为一天1次，给药时间可以持续不为7天和/或不超过7天。
在本申请中，所述化疗剂的给药周期可以为3天、5天、7天、2周、20天、1个月、2个月或更长时间。
在本申请中，可以使用一种或多种不同的化疗剂。在本申请中，两种或两种以上不同的化疗剂可以联用。在一些实施方式中，所述CDK抑制剂可以与一种或多种其他癌症治疗法联用。所述其他癌症治疗法可以是本领域中常规用于治疗癌症的方法，例如细胞毒抗癌剂、免疫治疗抗癌剂或激素治疗抗癌剂。根据本申请，用于癌症治疗的药物也可以与放射治疗或手术组合使用。在一些实施方式中，在将CDK抑制剂和其他抗癌剂组合使用的情况下，它们可以同时施用于受试者，或者以一定间隔分开施用。
胃肠道副作用
在本申请中，所述CDK抑制剂可以预防、缓解和/或治疗受试者中与施用化疗相关的胃肠道副作用。在本申请中，化疗相关的胃肠道副作用可以指所述胃肠道副作用由施用所述化 疗引起，所述胃肠道副作用在施用所述化疗剂之后产生或加重。在没有预防或治疗实施的情况下，所述胃肠道副作用会在所述化疗剂施用1小时后、2小时后、3小时后、4小时后、5小时后、6小时后、7小时后、8小时后、9小时后、10小时后、11小时后、12小时后、1天后、2天后、4天后、7天后、2周后、3周后、1个月后、2个月后或更久后出现或加重。
在某些实施方式中，在向受试者施用所述化疗剂之前，所述受试者不产生所述胃肠道副作用；在向受试者施用所述化疗剂之后，所述受试者产生所述胃肠道副作用。
在某些实施方式中，在向受试者施用所述化疗剂之前，所述受试者已产生所述胃肠道副作用；在向受试者施用所述化疗剂之后，所述受试者的所述胃肠道副作用的程度加重。
在本申请中，施用所述化疗剂后，受试者的胃肠道副作用症状可以加重至少约10％，例如，加重约15％、约20％、约25％、约30％、约35％、约40％、约45％、约50％、约55％、约60％、约65％、约70％、约75％、约80％、约85％、约90％、约95％、约99％或更高。
例如，根据NCI-CTCAE的标准，在向受试者施用所述化疗剂之后，所述受试者的所述胃肠道副作用(例如，腹泻或便秘)程度从第1级升为第2级、从第1级升为第3级、从第1级升为第4级、从第1级升为第5级、从第2级升为第3级、从第2级升为第4级、从第2级升为第5级、从第3级升为第4级、从第3级升为第5级或从第4级升为第5级。例如，根据Akinobu Kurita方法，在向受试者施用所述化疗剂之后，所述受试者的便秘评分从第0级升为第1级、从第0级升为第2级、从第0级升为第3级、从第1级升为第2级、从第1级升为第3级或从第2级升为第3级。
在某些实施方式中，所述胃肠道副作用包括胃黏膜损伤疾病和/或肠道黏膜损伤疾病。
在某些实施方式中，所述胃肠道副作用包括腹泻、腹痛、恶心、呕吐、黏膜炎、食欲减退、胃溃疡、胃炎、便秘、肠炎、肠穿孔、肠出血、溃疡和/或肠坏死。在某些实施方式中，所述胃肠道副作用包括排泄异常。在某些实施方式中，所述胃肠道副作用包括腹泻和/或便秘。
在某些实施方式中，所述与化疗相关的胃肠道副作用包括与化疗相关的胃黏膜损伤疾病和/或与化疗相关的肠道黏膜损伤疾病。
在某些实施方式中，所述与化疗相关的胃肠道副作用包括与化疗相关的腹泻、与化疗相关的腹痛、与化疗相关的恶心、与化疗相关的呕吐、与化疗相关的黏膜炎、与化疗相关的食欲减退、与化疗相关的胃溃疡、与化疗相关的胃炎、与化疗相关的便秘、与化疗相关的肠炎、与化疗相关的肠穿孔、与化疗相关的肠出血、与化疗相关的溃疡和/或与化疗相关的肠坏死。在某些实施方式中，所述与化疗相关的胃肠道副作用包括与化疗相关的排泄异常。在某些实施方式中，所述与化疗相关的胃肠道副作用包括与化疗相关的腹泻和/或与化疗相关的便秘。
在本申请中，在施用了本申请的CDK抑制剂后，受试者的与化疗相关的胃肠道副作用的严重程度得到了缓解。在本申请中，所述缓解通常可以指所述受试者的胃肠道副作用的发作或发展被推迟。在本申请中，施用所述CDK抑制剂后，受试者的胃肠道副作用症状可以减轻。在本申请中，施用所述CDK抑制剂后，受试者的胃肠道副作用症状可以减轻至少约10％，例如，减轻约15％、约20％、约25％、约30％、约35％、约40％、约45％、约50％、约55％、 约60％、约65％、约70％、约75％、约80％、约85％、约90％、约95％、约99％或减轻更多。
例如，根据NCI-CTCAE的标准，施用所述CDK抑制剂后，受试者的胃肠道副作用(例如，腹泻和/或便秘)的症状可以从第5级降为第4级、从第5级降为第3级、从第5级降为第2级、从第5级降为第1级、从第4级降为第3级、从第4级降为第2级、从第4级降为第1级、从第3级降为第2级、从第3级降为第1级或从第2级降为第1级。
或者，根据Akinobu Kurita方法，施用所述CDK抑制剂后，受试者的腹泻评分可以从第3级降为第2级、从第3级降为第1级、从第3级降为第0级、从第2级降为第1级、从第2级降为第0级或从第1级降为第0级。
在本申请中，施用所述CDK抑制剂后，受试者的胃肠道副作用症状可以消除。但不排除停用所示CDK抑制剂后，胃肠道副作用再次复发或加重的情况。
治病方法
本申请中使用的术语“预防”通常是指预防疾病或其一种或多种症状的发作，复发或扩散。在本申请中“预防”可以与“预防性治疗”互换使用。在某些实施方案中，“预防”通常是指在症状发作之前，在有或没有本申请所述的其他药物的情况下，向患有本申请所述的疾病或病症的患者提供本申请所述的药物的治疗。在某些实施方案中，具有特定疾病家族史的患者可以作为预防方案的候选者。在某些实施方案中，有复发症状史的患者也是潜在的预防对象。
本申请中使用的术语“治疗”通常是指消除或改善疾病，或与疾病相关的一种或多种症状。在一些实施方式中，治疗通常是指通过向患有这种疾病的患者施用一种或多种治疗剂而使得疾病消除或缓解。在一些实施方式中，“治疗”可以是在特定疾病的症状发作后，在其他治疗剂存在或不存在的情况下施用药物。
本申请中使用的术语“受试者”通常是指需要诊断、预后、改善、预防、缓解和/或治疗疾病的人或非人动物(包括哺乳动物)，特别是需要CDK抑制剂治疗或预防的那些受试者。在一些实施方式中，所述受试者可以包括癌症患者。例如，所述癌症患者可以曾经、正在和/或将来被施用化疗。
在一些实施方式中，所述受试者可以是人或非人哺乳动物。非人哺乳动物可以包括任何除人之外的哺乳动物物种，例如家畜动物(例如，牛、猪、羊、鸡、兔或马)，或啮齿类动物(例如，大鼠和小鼠)，或灵长类动物(例如，大猩猩和猴子)，或家养动物(例如，狗和猫)。“受试者”可以是雄性或者雌性，也可以是不同年龄阶段。
本申请中使用的术语“有效量”通常是指可以缓解或者消除受试者的疾病或症状，或者可以预防性地抑制或防止疾病或症状发生的药物的量。有效量可以是将受试者的一种或多种疾病或症状缓解到一定程度的药物的量；可以将那些跟疾病或症状成因相关的一种或多种生理或生物化学参数部分或完全恢复到正常的药物的量；和/或可以降低疾病或症状发生的可能性的药物的量。
在本申请中，在施用化疗前，例如，施用化疗0.5小时、1小时、2小时、3小时、4小 时、5小时、6小时、7小时、8小时、9小时、10小时、11小时、12小时、13小时、14小时、15小时、16小时、17小时、18小时、19小时、20小时或更久前，可以施用所述药物或所述CDK抑制剂，可以预防、缓解和/或治疗胃肠道副作用的产生或加重。例如，在施用化疗之前0.5-12小时，施用所述药物或所述CDK抑制剂，可以预防、缓解和/或治疗胃肠道副作用的产生或加重。
在本申请中，所述CDK抑制剂的给药部位可以为或不为癌症的发生部位或癌症的潜在转移部位。
本申请所述的CDK抑制剂可以通过本领域已知的给药方式给药，例如注射给药(例如，皮下、腹腔、关节内、动脉内、鞘内、胸骨内、鞘内、病灶内、颅内、肌肉、皮内以及静脉推注或者滴注)或非注射给药(例如，口服、鼻腔、舌下、阴道、直肠或外用给药)。本申请的CDK抑制剂可以以药物组合或试剂盒的形式施用。在一些实施方案中，本申请所述的CDK抑制剂可以与化疗以相同的给药途径给药或者以不同的给药途径给药。
在本申请中，所述药物和/或所述CDK抑制剂可以被制备为适用于口服给药。在本申请中，所述CDK抑制剂可以优先作用于肠腔内，或可以优先到达肠腔内，而没有暴露于体循环中。可以将所述CDK抑制剂制备为适于递送至肠腔内或在肠腔内发挥效果(例如，预防、缓解和/或治疗胃肠道副作用的效果)的剂型，可以采用适于CDK抑制剂递送至肠腔内或在肠腔内发挥效果的给药途径或方式，还可以使用器械等辅助手段使得所述CDK抑制剂递送至肠腔内或在肠腔内发挥效果。在本申请中，所述CDK抑制剂的系统药物浓度低于起效浓度(IC50)。
在本申请中，所述药物和/或所述CDK抑制剂可以被制备为适用于经胃肠道给药，例如，散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂和/或混悬剂。在本申请中，所述药物和/或所述CDK抑制剂可以被制备为适用于腔道给药的剂型，例如，栓剂和/或滴丸剂。在本申请中，所述药物和/或所述CDK抑制剂可以被制备为适用于通过人工辅助手段递送至胃肠道的剂型，例如，通过插管。
在本申请中，所述药物和/或所述CDK抑制剂被制备为适用于胃肠道暴露的剂型。适用于胃肠道暴露的剂型可以为适用于递送至胃肠道的剂型、适用于经胃肠道给药的剂型、适用于腔道给药的剂型、适用于口服给药的剂型和/或适用于通过人工辅助手段递送至胃肠道的剂型。
在本申请中，所述CDK抑制剂的给药剂量可以为约0.01-1000mg/kg，例如，可以为约0.01-800mg/kg、约0.01-900mg/kg、约0.01-800mg/kg、约0.01-700mg/kg、约0.01-600mg/kg、约0.01-500mg/kg、约0.01-400mg/kg、约0.01-300mg/kg、约0.01-200mg/kg、约0.01-100mg/kg、约0.1-1000mg/kg、约1-1000mg/kg、约10-1000mg/kg、约50-1000mg/kg、约100-1000mg/kg、约0.1-800mg/kg、约1-600mg/kg、约10-500mg/kg、约10-400mg/kg、约15-300mg/kg、约50-250mg/kg或约50-200mg/kg。
例如，所述CDK抑制剂在口服给药时的给药剂量可以为约0.01-1000mg/kg，例如，可以 为约0.01-800mg/kg、约0.01-900mg/kg、约0.01-800mg/kg、约0.01-700mg/kg、约0.01-600mg/kg、约0.01-500mg/kg、约0.01-400mg/kg、约0.01-300mg/kg、约0.01-200mg/kg、约0.01-100mg/kg、约0.1-1000mg/kg、约1-1000mg/kg、约10-1000mg/kg、约50-1000mg/kg、约100-1000mg/kg、约0.1-800mg/kg、约1-600mg/kg、约10-500mg/kg、约10-400mg/kg、约15-300mg/kg、约50-250mg/kg或约50-200mg/kg。
某一特定剂量可分为多次间隔给药，例如每天一次、每天两次或更多、每周一次、每两周一次、每三周一次、每月一次或每两月或更多月一次。在一些实施方式中，给药剂量可随治疗进程变化。例如，在一些实施方式中，初始给药剂量可比后续给药剂量高。在一些实施方式中，给药剂量在治疗进程中根据给药对象的反应进行调整。在改善受试者状况时，可以根据需要以维持剂量施用本申请CDK抑制剂。随后，施用的剂量或频率或两者可以降低到当症状缓解到所需水平时保持改善状态的水平。在一些实施方式中，可以根据受试者的疾病状况间隔给药。
例如，所述CDK抑制剂可以在所述化疗剂施用前约0.5h-约24h施用，可以为口服给药，且给药剂量可以为约30-200mg/kg，给药周期可以为1周-2周1次。
例如，所述CDK抑制剂可以在所述化疗剂施用前约0.5h-约24h施用，可以为口服给药，且给药剂量可以为约50-200mg/kg，给药周期可以为1-2周1次。
例如，所述CDK抑制剂可以在所述化疗剂施用前施用约0.5h-约24h，可以为口服给药，且给药剂量可以为约30-200mg/kg，给药周期可以为7天1次、8天1次、9天1次或10天1次。
例如，所述CDK抑制剂可以在所述化疗剂施用前约0.5h-约12h施用，可以为口服给药，且给药剂量可以为约50-200mg/kg，给药周期可以为7天1次、8天1次、9天1次或10天1次。
例如，所述CDK抑制剂可以在所述化疗剂施用前约0.5h-约12h施用，可以为口服给药，且给药剂量可以为约50-100mg/kg，给药周期可以为7天1次、8天1次、9天1次或10天1次。
例如，所述CDK抑制剂可以在所述化疗剂施用前约0.5h-约12h施用，可以为口服给药，且给药剂量可以为约100-200mg/kg，给药周期可以为7天1次、8天1次、9天1次或10天1次。
例如，所述CDK抑制剂可以在所述化疗剂施用前约0.5h-约24h施用，可以为注射给药，且给药剂量可以为约30-200mg/kg，给药周期可以为1周-2周1次。
例如，所述CDK抑制剂可以在所述化疗剂施用前约0.5h-约12h施用，可以为注射给药，且给药剂量可以为约50-200mg/kg，给药周期可以为7天1次、8天1次、9天1次或10天1次。
在本申请中，palbociclib可以用于治疗与施用化疗剂相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述palbociclib可以在所述化疗剂施用前约0.5h-约12h施用，所述palbociclib 可以为口服给药，且给药剂量可以为约10-200mg/kg。所述化疗剂可以为口服给药或注射给药。
在本申请中，palbociclib可以用于治疗与施用氟尿嘧啶(5-Fu)相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述palbociclib可以在氟尿嘧啶(5-Fu)施用前约0.5h-约12h施用，所述palbociclib可以为口服给药，且给药剂量可以为约125mg/kg-约150mg/kg。例如，氟尿嘧啶(5-Fu)可以为口服给药或注射给药。
在本申请中，palbociclib可以用于治疗与施用奥沙利铂相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述palbociclib可以在所述奥沙利铂施用前约0.5h-约12h施用(例如约6h)，所述palbociclib可以为口服给药，且给药剂量可以为约125mg/kg-约150mg/kg。例如，奥沙利铂可以为注射给药。
在本申请中，palbociclib可以用于治疗与施用伊立替康相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述palbociclib可以在伊立替康施用前约0.5h-约24h施用，所述palbociclib可以为口服给药，且给药剂量可以为约50mg/kg-约200mg/kg。例如，伊立替康可以为注射给药。
在本申请中，palbociclib可以用于治疗与施用吉西他滨相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述palbociclib可以在吉西他滨施用前约0.5h-约12h施用，所述palbociclib可以为口服给药，且给药剂量可以为约50mg/kg-约200mg/kg。例如，吉西他滨可以为注射给药。
在本申请中，palbociclib可以用于治疗与施用多西紫杉醇相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述palbociclib可以在所述多西紫杉醇施用前约0.5h-约12h施用，所述palbociclib可以为口服给药，且给药剂量可以为约150mg/kg-约200mg/kg。例如，多西紫杉醇可以为注射给药。
在本申请中，palbociclib可以用于治疗与吉西他滨和紫杉醇联用相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述palbociclib可以在吉西他滨和紫杉醇联用前约0.5h-约12h施用，所述palbociclib可以为口服给药，且给药剂量可以为约150mg/kg-约200mg/kg。例如，吉西他滨和紫杉醇可以为注射给药。
在本申请中，palbociclib可以用于治疗与卡培他滨相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述palbociclib可以在施用卡培他滨前约0.5h-约12h施用，所述palbociclib可以为口服给药，且给药剂量可以为约150mg/kg-约200mg/kg。例如，卡培他滨可以为注射给药。
在本申请中，palbociclib可以用于治疗与依托泊苷和卡铂联用相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述palbociclib可以在依托泊苷和卡铂联用前约0.5h-约12h施用，所述palbociclib可以为口服给药，且给药剂量可以为约150mg/kg-约200mg/kg。例如，依托泊苷和卡铂可以为注射给药。
在本申请中，ribociclib可以用于治疗与化疗相关的胃肠道副作用(例如，腹泻或便秘)。 例如，所述ribociclib可以在施用所述化疗剂前约0.5-约24h施用，所述ribociclib可以为口服给药，且给药剂量可以为约20mg/kg-约200mg/kg。例如，所述化疗剂可以为注射给药或口服给药。
在本申请中，ribociclib可以用于治疗与氟尿嘧啶(5-FU)相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述ribociclib可以在施用氟尿嘧啶(5-FU)前约0.5h-约12h施用，所述ribociclib可以为口服给药，且给药剂量可以为约150mg/kg-约200mg/kg。例如，氟尿嘧啶(5-FU)可以为注射给药。
在本申请中，ribociclib可以用于治疗与伊立替康相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述ribociclib可以在施用伊立替康前约0.5h-约24h施用，所述ribociclib可以为口服给药，且给药剂量可以为约100mg/kg-约200mg/kg。例如，伊立替康可以为口服给药。
在本申请中，ribociclib可以用于治疗与依托泊苷和卡铂联用相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述ribociclib可以在施用依托泊苷和卡铂前约0.5h-约12h施用，所述ribociclib可以为口服给药，且给药剂量可以为约50mg/kg-约200mg/kg。例如，依托泊苷和卡铂可以为注射给药。
在本申请中，ribociclib可以用于治疗与施用多西紫杉醇(DTX)相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述ribociclib可以在施用多西紫杉醇(DTX)前约0.5h-约24h施用，所述ribociclib可以为口服给药，且给药剂量可以为约100mg/kg-约200mg/kg。例如，多西紫杉醇(DTX)可以为注射给药。
在本申请中，abemaciclib可以用于治疗与施用所述化疗剂相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述abemaciclib可以在施用所述化疗剂前约0.5h-约12h前施用，所述abemaciclib可以为口服给药，且给药剂量可以为约150mg/kg-约200mg/kg。例如，所述化疗剂可以为注射给药或口服给药。
在本申请中，abemaciclib可以用于治疗与氟尿嘧啶(5-Fu)相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述abemaciclib可以在施用氟尿嘧啶(5-Fu)前约0.5h-约12h施用，所述abemaciclib可以为口服给药，且给药剂量可以为约150mg/kg-约200mg/kg。例如，卡培他滨可以为注射给药。
在本申请中，abemaciclib可以用于治疗与伊立替康相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述abemaciclib可以在施用伊立替康前约0.5h-约24h施用，所述abemaciclib可以为口服给药，且给药剂量可以为约10mg/kg-约200mg/kg。例如，伊立替康可以为注射给药。
在本申请中，abemaciclib可以用于治疗与吉西他滨(GEM)相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述abemaciclib可以在施用吉西他滨(GEM)前约0.5h-约24h施用，所述abemaciclib可以为口服给药，且给药剂量可以为约150mg/kg-约200mg/kg。例如，吉西他滨(GEM)可以为注射给药。
在本申请中，G1T28可以用于治疗与施用所述化疗剂相关的胃肠道副作用(例如，腹泻 或便秘)。例如，所述G1T28可以在施用所述化疗剂前约0.5h-约24h施用，所述G1T28可以为口服给药，且给药剂量可以为约150mg/kg-约200mg/kg。例如，所述化疗剂可以为注射给药或口服给药。
在本申请中，G1T28可以用于治疗与氟尿嘧啶(5-Fu)相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述G1T28可以在施用氟尿嘧啶(5-Fu)前约0.5h-约24h施用，所述G1T28可以为口服给药，且给药剂量可以为约100mg/kg-约200mg/kg。例如，氟尿嘧啶(5-Fu)可以为注射给药。
在本申请中，G1T28可以用于治疗与拓扑替康相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述G1T28可以在施用拓扑替康前约0.5h-约12h施用，所述G1T28可以为口服给药，且给药剂量可以为约100mg/kg-约200mg/kg。例如，拓扑替康可以为注射给药。在本申请中，G1T28可以用于治疗与奥沙利铂相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述G1T28可以在施用奥沙利铂前约0.5h-约24h施用，所述G1T28可以为口服给药，且给药剂量可以为约100mg/kg-约200mg/kg。例如，奥沙利铂可以为注射给药。
在本申请中，G1T28可以用于治疗与吉西他滨(GEM)相关的胃肠道副作用(例如，腹泻或便秘)。例如，所述G1T28可以在施用吉西他滨(GEM)前约0.5h-约24h施用，所述G1T28可以为口服给药，且给药剂量可以为约100mg/kg-约200mg/kg。例如，吉西他滨(GEM)可以为注射给药。
在本申请中，所述药物还可包括一种或多种药学上可接受的载剂(carrier)。药学上可接受的载剂可以包括但不限于，例如，药学可接受的液体、凝胶或固体载剂、水相介质、非水相介质、抗微生物物质、等渗物质、缓冲液、抗氧化剂、麻醉剂、悬浮剂/分散剂、螯合剂、乳化剂、稀释剂、佐剂、辅料、无毒辅助物质、填充剂、粘合剂、崩解剂、缓冲液、防腐剂、润滑剂、搅味剂、增稠剂、着色剂、乳化剂、其他本领域公知的组分或以上的多种组合。
另一方面，本申请提供了所述CDK抑制剂预防、缓解和/或治疗与化疗相关的胃肠道副作用的方法。另一方面，本申请提供了所述CDK抑制剂在制备预防、缓解和/或治疗在制备与化疗相关的胃肠道副作用的药物中的用途。另一方面，本申请提供了所述CDK抑制剂，其用于防或治疗在制备与化疗相关的胃肠道副作用。在某些实施方式中，所述化疗不包括连续给药时间为7天或7天以上的化疗。在某些实施方式中，所述化疗不包括肿瘤靶向疗法。在某些实施方式中，所述化疗为口服给药。
另一方面，本申请提供了所述CDK抑制剂预防、缓解和/或治疗与化疗相关的腹泻的方法。另一方面，本申请提供了所述CDK抑制剂在制备预防、缓解和/或治疗在制备与化疗相关的腹泻的药物中的用途。另一方面，本申请提供了所述CDK抑制剂，其用于防或治疗在制备与化疗相关的腹泻。在某些实施方式中，所述化疗不包括连续给药时间为7天或7天以上的化疗。在某些实施方式中，所述化疗不包括肿瘤靶向疗法。在某些实施方式中，所述化疗为口服给药。
另一方面，本申请提供了所述CDK抑制剂预防、缓解和/或治疗与化疗相关的便秘的方 法。另一方面，本申请提供了所述CDK抑制剂在制备预防、缓解和/或治疗在制备与化疗相关的便秘的药物中的用途。另一方面，本申请提供了所述CDK抑制剂，其用于防或治疗在制备与化疗相关的便秘。在某些实施方式中，所述化疗不包括连续给药时间为7天或7天以上的化疗。在某些实施方式中，所述化疗不包括肿瘤靶向疗法。在某些实施方式中，所述化疗为口服给药。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请发明的各个技术方案，而不用于限制本申请发明的范围。
实施例
实施例1-229口服CDK抑制剂对化疗剂导致腹泻的缓解效果
构建小鼠动物模型，按照表3所示化疗剂的给药方式及频率建立Balb/c小鼠化疗剂导致的腹泻模型。给药几天后，小鼠出现不同程度的腹泻症状(如图1所示)，与在人体上相接近。因此，小鼠化疗剂导致的腹泻模型是很好的模拟人体上化疗剂导致腹泻的模型。
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、化疗剂化疗剂组、CDK抑制剂组，每组10只，进行给药实验，给药剂量、方式、时间及频率如表3所示。对照组：灌胃与CDK抑制剂组相同的溶剂(时间如表3所示)，之后注射/灌胃与化疗剂化疗剂组相同的溶剂(给药方式如表3所示)；化疗剂组：灌胃与CDK抑制剂组相同的溶剂(时间如表3所示)，之后注射/灌胃化疗剂(种类、给药方式及剂量如表3所示)；CDK抑制剂组：灌胃CDK抑制剂(时间如表3所示)，之后给化疗剂(方式及剂量如表3所示)。
腹泻观察
腹泻评分参考Akinobu Kurita方法(Cancer Chemother Pharmacol 2000；46:211-20.)，0级：大便正常；1级：轻度腹泻，大便可见轻微湿软；2级：中度腹泻，稀便并且有轻度肛周沾染；3分：重度腹泻，稀水样便并伴有重度肛周着色(见图1)。CDK抑制剂组小鼠腹泻等级与化疗剂组小鼠腹泻等级平均值相比降低视为有效缓解。
每天观察并记录小鼠的腹泻等级。实验终点时，统计CDK抑制剂组有多少小鼠的腹泻等级比化疗剂组的腹泻等级低。表3列出来各种化疗剂和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝CDK抑制剂组腹泻有效缓解的小鼠只数/CDK抑制剂组小鼠总数*100％。化疗剂组腹泻模型建成率在50％-70％，即在实验过程中10只鼠里面约5-7只出现腹泻，有个别小鼠死亡或者不出现腹泻等情况。)
表3：实施例1-229的实验条件及实验结果
Figure PCTCN2022097792-appb-000002
Figure PCTCN2022097792-appb-000003
Figure PCTCN2022097792-appb-000004
Figure PCTCN2022097792-appb-000005
Figure PCTCN2022097792-appb-000006
Figure PCTCN2022097792-appb-000007
Figure PCTCN2022097792-appb-000008
Figure PCTCN2022097792-appb-000009
Figure PCTCN2022097792-appb-000010
Figure PCTCN2022097792-appb-000011
Figure PCTCN2022097792-appb-000012
图1显示了表3中化疗剂组小鼠腹泻的不同等级典型图片，图2显示了表3中对照组、化疗剂组、CDK抑制剂组的部分腹泻等级结果。
从表3及图2的结果可以看出，CDK抑制剂组相对于化疗剂组腹泻等级有不同程度的缓解，因此，提前口服CDK抑制剂能够有效的缓解化疗剂导致的腹泻。
实施例230-271口服CDK抑制剂对化疗剂导致腹泻的缓解效果
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、化疗剂组、CDK抑制剂组，每组10只，进行给药实验，给药剂量、方式、时间及频率如表4所示。对照组：灌胃与CDK抑制剂组相同的溶剂(时间如表4所示)，之后注射或/灌胃与化疗剂组相同的溶剂(给药方式如表4所示)；化疗剂组：灌胃与CDK抑制剂组相同的溶剂(时间如表4所示)，之后注射/灌胃化疗剂(种类、给药方式及剂量如表4所示)；CDK抑制剂组：灌胃CDK抑制剂(时间如表4所示)，之后给化疗剂(方式及剂量如表4所示)。
腹泻观察
腹泻评分参考Akinobu Kurita方法(Cancer Chemother Pharmacol2000；46:211-20.)，0级：大便正常；1级：轻度腹泻，大便可见轻微湿软；2级：中度腹泻，稀便并且有轻度肛周沾染；3分：重度腹泻，稀水样便并伴有重度肛周着色(见图1)。CDK抑制剂组小鼠腹泻等级与化疗剂组小鼠腹泻等级平均值相比降低视为有效缓解。
每天观察并记录小鼠的腹泻等级。实验终点时，统计CDK抑制剂组有多少小鼠的腹泻等级比化疗剂组的腹泻等级低。表4列出来各种化疗剂和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝CDK抑制剂组腹泻有效缓解的小鼠只数/CDK抑制剂组小鼠总数*100％。化疗剂组腹泻模型建成率在50％-70％，即在实验过程中10只鼠里面约5-7只出现腹泻，有个别小鼠死亡或者不出现腹泻等情况。)
表4：实施例230-271的实验条件及实验结果
Figure PCTCN2022097792-appb-000013
Figure PCTCN2022097792-appb-000014
Figure PCTCN2022097792-appb-000015
图3显示了表4中对照组、化疗剂组、CDK抑制剂组的部分腹泻等级结果。
从表4及图3的结果可以看出，CDK抑制剂组相对于化疗剂组腹泻等级有不同程度的缓解，因此，提前口服CDK抑制剂能够有效的缓解化疗剂导致的腹泻。
实施例272-342口服CDK抑制剂对化疗剂导致便秘的缓解效果
构建小鼠动物模型，按照表5所示化疗剂的给药方式及频率建立Balb/c小鼠化疗剂导致的便秘模型。给药几天后，小鼠出现大便量减少(如图4所示)，与人体上化疗剂导致的便秘症状一致。因此，小鼠化疗剂导致的便秘模型是很好的模型化疗剂导致便秘的模型。
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、化疗剂、CDK抑制剂组，每组10只，进行给药实验，给药剂量、方式、时间及频率如表5所示。对照组：灌胃与CDK抑制剂组相同的溶剂(时间如表5所示)，之后注射或灌胃与化疗剂组相同的溶剂(给药方式如表5所示)；化疗剂组：灌胃与CDK抑制剂组相同的溶剂(时间如表3所示)，之后注射或灌胃化疗剂(种类、给药方式及剂量如表5所示)；CDK抑制剂组：灌胃CDK抑制剂(时间如表5所示)，之后给化疗剂(方式及剂量如表5所示)。
便秘观察
收集3小时内小鼠的排便，观察形状，用电子天平称其重量。计算大便减少率，参考Ji Eun Kim方法(Lab Anim Res.2016 Dec；32(4):231–240.)。大便减少率(％)＝(对照组-化疗剂或CDK抑制剂组)/对照组*100％
CDK抑制剂组小鼠大便减少率与化疗剂组相比降低视为有效缓解。
每天观察并记录3小时内小鼠的排便量。实验终点时，统计CDK抑制剂组有多少小鼠的大便减少率比化疗剂组的低。表5列出来各种化疗剂和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝CDK抑制剂组有效缓解的小鼠只数/CDK抑制剂组小鼠总数 *100％。化疗剂组便秘模型建成率在30％-60％，即在实验过程中10只鼠里面约3-6只出现大便量减少，有个别小鼠死亡或者大便量不变或增加等情况。)
表5：实施例272-342的实验条件及实验结果
Figure PCTCN2022097792-appb-000016
Figure PCTCN2022097792-appb-000017
Figure PCTCN2022097792-appb-000018
Figure PCTCN2022097792-appb-000019
图4显示了表5中对照组、化疗剂组、CDK抑制剂组3小时内粪便量的典型图片，图5 显示了表5中对照组、化疗剂组、CDK抑制剂组的部分大便减少率结果。
从表5及图4-5的结果可以看出，CDK抑制剂组相对于化疗剂组大便减少率有不同程度的降低，因此，提前口服CDK抑制剂能够有效的缓解化疗剂导致的便秘。
实施例343-381口服CDK抑制剂与静脉注射CDK抑制剂均能缓解化疗剂导致腹泻
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、化疗剂组、口服CDK抑制剂组、静脉注射CDK抑制剂组，每组10只，进行给药实验，给药剂量、方式、时间及频率如表6所示。对照组：注射/灌胃与CDK抑制剂组相同的溶剂(时间如表6所示)，之后注射/灌胃与化疗剂组相同的溶剂(给药方式如表6所示)；化疗剂组：注射/灌胃与CDK抑制剂组相同的溶剂(时间如表6所示)，之后注射/灌胃化疗剂(种类、给药方式及剂量如表6所示)；口服CDK抑制剂组：灌胃CDK抑制剂(时间如表6所示)，之后给化疗剂(方式及剂量如表6所示)；静脉注射CDK抑制剂组：尾静脉注射CDK抑制剂(时间如表6所示)之后给化疗剂(方式及剂量如表6所示)。
腹泻观察
腹泻评分参考Akinobu Kurita方法(Cancer Chemother Pharmacol2000；46:211-20.)：0级：大便正常；1级：轻度腹泻，大便可见轻微湿软；2级：中度腹泻，稀便并且有轻度肛周沾染；3分：重度腹泻，稀水样便并伴有重度肛周着色(见图1)。口服CDK抑制剂组/静脉注射CDK抑制剂组小鼠腹泻等级与化疗剂组小鼠腹泻等级平均值相比降低视为有效缓解。
每天观察并记录小鼠的腹泻等级。实验终点时，统计口服CDK抑制剂组/静脉注射CDK抑制剂组有多少小鼠的腹泻等级比化疗剂组的腹泻等级低。表6列出来各种化疗剂和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝口服或静脉注射CDK抑制剂组腹泻有效缓解的小鼠只数/口服或静脉注射CDK抑制剂组小鼠总数*100％。化疗剂组腹泻模型建成率在50％-70％，即在实验过程中10只鼠里面约5-7只出现腹泻，有个别小鼠死亡或者不出现腹泻等情况。)
表6：实施例343-381的实验条件及实验结果
Figure PCTCN2022097792-appb-000020
Figure PCTCN2022097792-appb-000021
Figure PCTCN2022097792-appb-000022
Figure PCTCN2022097792-appb-000023
图6显示了表6中对照组、化疗剂组、口服CDK抑制剂与静脉注射CDK抑制剂组的典型腹泻等级结果。从表6及图6可以看出，哌柏西利、阿贝西利、trilaciclib、瑞博西尼、SHR-6390、Dinaciclib、KR-0601、Riviciclib口服给药和注射给药均能够有效缓解依托泊苷、依托泊苷联合顺铂、卡铂、吉西他滨、吉西他滨和卡铂、拓朴替康导致的腹泻，且口服给药的效果最显著。
实施例382-405多种给药方式的CDK抑制剂CDK抑制剂均能缓解化疗剂导致腹泻
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、化疗剂组、CDK抑制剂组(包括口服CDK抑制剂组、腹腔注射CDK抑制剂组、肌肉注射CDK抑制剂组、局部给药CDK抑制剂组)，每组10只，进行给药实验，给药剂量、方式、时间及频率如表7所示。对照组：给与CDK抑制剂组相同的溶剂(时间、方式如表7所示)，之后注射/灌胃与化疗剂组相同的溶剂(给药方式如表7所示)；化疗剂组：给与CDK抑制剂组相同的溶剂(时间、方式如表7所示)，之后注射/灌胃化疗剂(种类、给药方式及剂量如表7所示)；口服CDK抑制剂组：灌胃CDK抑制剂(时间如表7所示)，之后给化疗剂(方式及剂量如表7所示)；腹腔注射CDK抑制剂组：腹腔注射CDK抑制剂(时间如表7所示)，之后给化疗剂(方式及剂量如表7所示)；肌肉注射CDK抑制剂组：肌肉注射CDK抑制剂(时间如表7所示)，之后给化疗剂(方式及剂量如表7所示)；局部给CDK抑制剂组：小鼠腹部剃毛(约2cm*2cm)，涂抹CDK抑制剂(时间如表7所示)，之后给化疗剂(方式及剂量如表7所示)。
腹泻观察
腹泻评分参考Akinobu Kurita方法(Cancer Chemother Pharmacol2000；46:211-20.)：0级：大便正常；1级：轻度腹泻，大便可见轻微湿软；2级：中度腹泻，稀便并且有轻度肛周沾染；3分：重度腹泻，稀水样便并伴有重度肛周着色(见图1)。CDK抑制剂组小鼠腹泻等级与化疗剂组小鼠腹泻等级平均值相比降低视为有效缓解。
每天观察并记录小鼠的腹泻等级。实验终点时，统计CDK抑制剂组有多少小鼠的腹泻等级比化疗剂组的腹泻等级低。表7列出来各种化疗剂和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝CDK抑制剂组腹泻有效缓解的小鼠只数/CDK抑制剂组小鼠总数*100％。化疗剂组腹泻模型建成率在50％-70％，即在实验过程中10只鼠里面约5-7只出现腹泻，有个别小鼠死亡或者不出现腹泻等情况。)
表7：实施例382-405的实验条件及实验结果
Figure PCTCN2022097792-appb-000024
Figure PCTCN2022097792-appb-000025
图7显示了表7中对照组、化疗剂组、口服CDK抑制剂与CDK抑制剂其他给药方式的腹泻等级结果对比。
从表7及图7的结果可以看出，哌柏西利、阿贝西利、Trilaciclib、瑞博西尼、SHR-6390在一定条件下口服给药、注射给药和局部给药均能够缓解多西紫杉醇、卡铂、吉西他滨、吉西他滨联合卡铂导致的腹泻，且口服给药的效果最显著。
实施例406-443多种给药方式的CDK抑制剂均能够缓解化疗剂导致便秘
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、化疗剂、CDK抑制剂组(包括口服CDK抑制剂组、静脉注射CDK抑制剂组、腹腔注射CDK抑制剂组、肌肉注射CDK抑制剂组、局部给药CDK抑制剂组)，每组10只，进行给药实验，给药剂量、方式、时间及频率如表8所示。对照组：给与CDK抑制剂组相同的溶剂(时间、方式如表8所示)，之后注射/灌胃与化疗剂组相同的溶剂(给药方式如表8所示)；化疗剂组：给与CDK抑制剂组相同的溶剂(时间、方式如表8所示)，之后注射/灌胃化疗剂(种类、给药方式及剂量如表 8所示)；口服CDK抑制剂组：灌胃CDK抑制剂(时间如表8所示)，之后给化疗剂(方式及剂量如表8所示)；静脉注射CDK抑制剂组：尾静脉注射CDK抑制剂(时间如表8所示)，之后给化疗剂(方式及剂量如表8所示)；腹腔注射CDK抑制剂组：腹腔注射CDK抑制剂(时间如表8所示)，之后给化疗剂(方式及剂量如表8所示)；肌肉注射CDK抑制剂组：肌肉注射CDK抑制剂(时间如表8所示)，之后给化疗剂(方式及剂量如表8所示)；局部给CDK抑制剂组：小鼠腹部剃毛(约2cm*2cm)，涂抹CDK抑制剂(时间如表8所示)，之后给化疗剂(方式及剂量如表8所示)。
便秘观察
收集3小时内小鼠的排便，观察形状，用电子天平称其重量。计算大便减少率，参考Ji Eun Kim方法(Lab Anim Res.2016 Dec；32(4):231–240.)。大便减少率(％)＝(对照组-化疗剂或CDK抑制剂组)/对照组*100％
CDK抑制剂组小鼠大便减少率与化疗剂组相比降低视为有效缓解。
每天观察并记录3小时内小鼠的排便量。实验终点时，统计CDK抑制剂组有多少小鼠的大便减少率比化疗剂组的低。表8列出来各种化疗剂和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝CDK抑制剂组有效缓解的小鼠只数/CDK抑制剂组小鼠总数*100％。化疗剂组便秘模型建成率在30％-60％，即在实验过程中10只鼠里面约3-6只出现大便量减少，有个别小鼠死亡或者大便量不变或增加等情况。)
表8实施例406-443的实验条件及实验结果
Figure PCTCN2022097792-appb-000026
Figure PCTCN2022097792-appb-000027
Figure PCTCN2022097792-appb-000028
图8显示了表8中对照组、化疗剂组、口服CDK抑制剂与CDK抑制剂其他给药方式的大便减少率结果对比。
从表8及图8的结果可以看出，哌柏西利、阿贝西利、Trilaciclib、瑞博西尼、SHR-6390、Doniciclib、Seliciclib在一定条件下口服给药、腹腔注射、肌肉注射、局部给药均能够显著改善阿霉素、依托泊苷、依托泊苷联合顺铂、卡铂、吉西他滨、吉西他滨联合卡铂导致的便秘，且口服给药的缓解效果最显著。
实施例444-469口服CDK抑制剂对化疗剂连续给药导致腹泻的缓解效果
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、化疗剂组、CDK抑制剂组，每组10只，进行给药实验，给药剂量、方式、时间及频率如表9所示。对照组：灌胃与CDK抑制剂组相同的溶剂(时间如表9所示)，之后注射或灌胃与化疗剂组相同的溶剂(给 药方式如表9所示)；化疗剂组：灌胃与CDK抑制剂组相同的溶剂(时间如表9所示)，之后注射或灌胃化疗剂(种类、给药方式、剂量及持续时间如表9所示)；CDK抑制剂组：灌胃CDK抑制剂(时间如表9所示)，之后给化疗剂(种类、给药方式、剂量及持续时间如表9所示)。
腹泻观察
腹泻评分参考Akinobu Kurita方法(Cancer Chemother Pharmacol2000；46:211-20.)，0级：大便正常；1级：轻度腹泻，大便可见轻微湿软；2级：中度腹泻，稀便并且有轻度肛周沾染；3分：重度腹泻，稀水样便并伴有重度肛周着色(见图1)。CDK抑制剂组小鼠腹泻等级与化疗剂组小鼠腹泻等级平均值相比降低视为有效缓解。
每天观察并记录小鼠的腹泻等级。实验终点时，统计CDK抑制剂组有多少小鼠的腹泻等级比化疗剂组的腹泻等级低。表9列出来各种化疗剂和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝CDK抑制剂组腹泻有效缓解的小鼠只数/CDK抑制剂组小鼠总数*100％。化疗剂组腹泻模型建成率在50％-80％，即在实验过程中10只鼠里面约5-8只出现腹泻，有个别小鼠死亡或者不出现腹泻等情况。)
表9实施例444-469的实验条件和实验结果
Figure PCTCN2022097792-appb-000029
Figure PCTCN2022097792-appb-000030
图9显示了表9中对照组、化疗剂组、CDK抑制剂组的部分腹泻等级结果对比。
从表9及图9可以看出：哌柏西利、阿贝西利、Trilaciclib、瑞博西尼剂对于氟尿嘧啶连续给药少于7天的腹泻有明显缓解，但对于氟尿嘧啶和卡培他滨连续给药7天及以上的腹泻缓解作用不明显。
实施例470-481口服CDK抑制剂对化疗剂连续给药导致便秘的缓解效果
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、化疗剂组、CDK抑制剂组，每组10只，进行给药实验，给药剂量、方式、时间及频率如表10所示。对照组：灌胃与CDK抑制剂组相同的溶剂(时间如表10所示)，之后注射或灌胃与化疗剂组相同的溶剂(给药方式如表10所示)；化疗剂组：灌胃与CDK抑制剂组相同的溶剂(时间如表10所示)，之后注射或灌胃化疗剂(种类、给药方式、剂量及持续时间如表10所示)；CDK抑制剂组：灌胃CDK抑制剂(时间如表10所示)，之后给化疗剂(种类、给药方式、剂量及持续时间如 表10所示)。
便秘观察
收集3小时内小鼠的排便，观察形状，用电子天平称其重量。计算大便减少率，参考Ji Eun Kim方法(Lab Anim Res.2016 Dec；32(4):231–240.)。大便减少率(％)＝(对照组-化疗剂或CDK抑制剂组)/对照组*100％
CDK抑制剂组小鼠大便减少率与化疗剂组相比降低视为有效缓解。
每天观察并记录3小时内小鼠的排便量。实验终点时，统计CDK抑制剂组有多少小鼠的大便减少率比化疗剂组的低。表10列出来各种化疗剂和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝CDK抑制剂组有效缓解的小鼠只数/CDK抑制剂组小鼠总数*100％。化疗剂组便秘模型建成率在30％-60％，即在实验过程中10只鼠里面约3-6只出现大便量减少，有个别小鼠死亡或者大便量不变或增加等情况。)
表10实施例470-481的实验条件和实验结果
Figure PCTCN2022097792-appb-000031
图10显示了表10中对照组、化疗剂组、CDK抑制剂组的部分大便减少率结果。
从表10及图10可以看出：哌柏西利在一定条件下口服给药对于氟尿嘧啶连续给药少于7天的便秘有明显缓解作用，对于氟尿嘧啶连续给药7天及以上的便秘缓解作用不明显。
实施例482-485口服CDK抑制剂对其他抗肿瘤药物导致腹泻的缓解效果
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、抗肿瘤药组、CDK抑制剂组，每组10只，进行给药实验，给药剂量、方式、时间及频率如表11所示。对照组：灌胃与CDK抑制剂组相同的溶剂(时间如表11所示)，之后注射或灌胃与抗肿瘤药组相同的溶剂(给药方式如表11所示)；抗肿瘤药组：灌胃与CDK抑制剂组相同的溶剂(时间如表11所示)，之后注射或灌胃抗肿瘤药(种类、给药方式、剂量及持续时间如表11所示)；CDK抑制剂组：灌胃CDK抑制剂(时间如表11所示)，之后给抗肿瘤药(种类、给药方式、剂量及持续时间如表11所示)。
腹泻观察
腹泻评分参考Akinobu Kurita方法(Cancer Chemother Pharmacol2000；46:211-20.)：0级：大便正常；1级：轻度腹泻，大便可见轻微湿软；2级：中度腹泻，稀便并且有轻度肛周沾染；3分：重度腹泻，稀水样便并伴有重度肛周着色(见图1)。CDK抑制剂组小鼠腹泻等级与抗肿瘤药组小鼠腹泻等级平均值相比降低视为有效缓解。
每天观察并记录小鼠的腹泻等级。实验终点时，统计CDK抑制剂组有多少小鼠的腹泻等级比抗肿瘤药组的腹泻等级低。表11列出来各种抗肿瘤药和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝CDK抑制剂组腹泻有效缓解的小鼠只数/CDK抑制剂组小鼠总数*100％。化疗剂组腹泻模型建成率在50％-80％，即在实验过程中10只鼠里面约5-8只出现腹泻，有个别小鼠死亡或者不出现腹泻等情况。)
表11实施例482-485的实验条件和实验结果
Figure PCTCN2022097792-appb-000032
Figure PCTCN2022097792-appb-000033
从表11的实验结果可以看出，CDK抑制剂对于连续用药的靶向抗肿瘤药导致的腹泻没有缓解效果。
实施例486-487口服CDK抑制剂对其他抗肿瘤药物导致便秘的缓解效果
Balb/c小鼠适应性饲养一周后，对其进行分组，实验分为对照组、抗肿瘤药组、CDK抑制剂组，每组10只，进行给药实验，给药剂量、方式、时间及频率如表12所示。对照组：灌胃与CDK抑制剂组相同的溶剂(时间如表12所示)，之后注射或灌胃与抗肿瘤药组相同的溶剂(给药方式如表12所示)；抗肿瘤药组：灌胃与CDK抑制剂组相同的溶剂(时间如表12所示)，之后注射或灌胃抗肿瘤药(种类、给药方式、剂量及持续时间如表12所示)；CDK抑制剂组：灌胃CDK抑制剂(时间如表12所示)，之后给抗肿瘤药(种类、给药方式、剂量及持续时间如表12所示)。
便秘观察
收集3小时内小鼠的排便，观察形状，用电子天平称其重量。计算大便减少率，参考Ji Eun Kim方法(Lab Anim Res.2016 Dec；32(4):231–240.)。大便减少率(％)＝(对照组-抗肿瘤药或CDK抑制剂组)/对照组*100％
CDK抑制剂组小鼠大便减少率与抗肿瘤药组相比降低视为有效缓解。
每天观察并记录3小时内小鼠的排便量。实验终点时，统计CDK抑制剂组有多少小鼠的大便减少率比抗肿瘤药组的低。表12列出来各种抗肿瘤药和CDK抑制剂的动物实验组合，以及相应的实验结果。(相对缓解率％＝CDK抑制剂组有效缓解的小鼠只数/CDK抑制剂组小鼠总数*100％。化疗剂组便秘模型建成率在30％-50％，即在实验过程中10只鼠里面约3-5只出现大便量减少，有个别小鼠死亡或者大便量不变或增加等情况。)
表12实施例486-487的实验条件和实验结果
Figure PCTCN2022097792-appb-000034
Figure PCTCN2022097792-appb-000035
从表12的实验结果可以看出，CDK抑制剂对于连续用药的靶向抗肿瘤药导致的便秘没有缓解效果。
前述详细说明是以解释和举例的方式提供的，并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的，且保留在所附的权利要求和其等同方式的范围内。

Claims (43)

  1. 周期蛋白依赖性激酶(CDK)抑制剂在制备药物中的用途，所述药物用于预防、缓解和/或治疗受试者中与化疗相关的胃肠道副作用。
  2. 根据权利要求1所述的用途，其中所述CDK抑制剂包括减少CDK表达的试剂，和/或降低CDK活性的试剂。
  3. 根据权利要求1-2中任一项所述的用途，其中所述CDK抑制剂直接作用于CDK蛋白、编码CDK蛋白的核酸、细胞周期蛋白和/或编码细胞周期蛋白的核酸。
  4. 根据权利要求1-3中任一项所述的用途，其中所述CDK抑制剂包括CDK1抑制剂、CDK2抑制剂、CDK3抑制剂、CDK4抑制剂、CDK5抑制剂、CDK6抑制剂、CDK7抑制剂、CDK8抑制剂和/或CDK9抑制剂。
  5. 根据权利要求1-4中任一项所述的用途，其中所述CDK抑制剂包括CDK2抑制剂。
  6. 根据权利要求1-5中任一项所述的用途，其中所述CDK抑制剂包括CDK4抑制剂。
  7. 根据权利要求1-6中任一项所述的用途，其中所述CDK抑制剂包括CDK6抑制剂。
  8. 根据权利要求1-7中任一项所述的用途，其中所述CDK抑制剂包括CDK9抑制剂。
  9. 根据权利要求1-8中任一项所述的用途，其中所述CDK抑制剂包括CDK4/6抑制剂。
  10. 根据权利要求1-9中任一项所述的用途，其中所述CDK抑制剂包括CDK2/4/6抑制剂。
  11. 根据权利要求1-10中任一项所述的用途，其中所述CDK抑制剂包括CDK4/6/9抑制剂。
  12. 根据权利要求1-11中任一项所述的用途，其中所述CDK抑制剂包括肠道局部暴露的CDK抑制剂。
  13. 根据权利要求1-12中任一项所述的用途，其中所述CDK抑制剂包括小分子化合物、蛋白质和/或核酸分子。
  14. 根据权利要求13所述的用途，其中所述小分子CDK抑制剂包括与CDK可逆结合的小分子CDK抑制剂、与CDK不可逆结合的小分子CDK抑制剂和/或特异性结合突变型CDK的小分子CDK抑制剂。
  15. 根据权利要求13-14中任一项所述的用途，其中所述小分子CDK抑制剂具有小于或等于2000道尔顿、小于或等于1500道尔顿、小于或等于1200道尔顿、小于或等于1000道尔顿、小于或等于900道尔顿、小于或等于800道尔顿、小于或等于700道尔顿、小于或等于600道尔顿、小于或等于500道尔顿、小于或等于400道尔顿、小于或等于300道尔顿、小于或等于200道尔顿和/或小于或等于100道尔顿的分子量。
  16. 根据权利要求1-15中任一项所述的用途，其中所述CDK抑制剂包含选自下组中的一种或多种化合物：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、Riviciclib、roniciclib、Milciclib、Seliciclib、Roscovitine、Indisulam、Alvocidib、NUV-422、BEY-1107、GLR-2007、FN-1501、BCD-115、TP-1287、BAY-1251152、Atuveciclib、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和G1T38。
  17. 根据权利要求1-16中任一项所述的用途，其中所述化疗包括施用化疗剂。
  18. 根据权利要求17所述的用途，其中所述化疗剂为细胞毒性剂。
  19. 根据权利要求17-18中任一项所述的用途，其中所述化疗剂选自下组中的一种或多种：
    DNA合成抑制剂、RNA合成抑制剂、蛋白质合成抑制剂、细胞分裂抑制剂、DNA碱基类似物、拓扑异构酶抑制剂和/或端粒酶合成抑制剂。
  20. 根据权利要求17-19中任一项所述的用途，其中所述化疗剂选自氟尿嘧啶、奥沙利铂(Oxaliplatin)、拓扑替康、伊立替康、四氢叶酸、多西紫杉醇、吉西他滨、卡铂、顺铂、依托泊苷、甲氨蝶呤、阿霉素、阿糖胞苷、长春瑞滨和卡培他滨，以及上述的组合。
  21. 根据权利要求17-20中任一项所述的用途，其中所述化疗剂为连续给药和/或非连续给药。
  22. 根据权利要求17-21中任一项所述的用途，其中所述化疗剂不包括连续给药时间为7天或7天以上的化疗剂。
  23. 根据权利要求1-22中任一项所述的用途，其中所述化疗与一种或多种其他疗法联用。
  24. 根据权利要求1-23中任一项所述的用途，其中所述与化疗相关的胃肠道副作用包括由化疗引起的胃肠道副作用。
  25. 根据权利要求1-24中任一项所述的用途，其中与化疗相关的胃肠道副作用包括施用化疗剂后出现或加重的胃肠道不良事件。
  26. 根据权利要求17-25中任一项所述的用途，其中所述胃肠道不良事件，在无预防或治疗实施的情况下会在所述化疗剂施用约1小时后、约2小时后、约3小时后、约4小时后、约5小时后、约6小时后、约7小时后、约8小时后、约9小时后、约10小时后、约11小时后、约12小时后、约1天后、约2天后、约4天后、约7天后、约2周后、约3周后、约1个月后、约2个月后或更久后出现或加重。
  27. 根据权利要求1-26中任一项所述的用途，其中所述胃肠道副作用包括胃黏膜损伤疾病和/或肠道黏膜损伤疾病。
  28. 根据权利要求1-27中任一项所述的用途，其中所述胃肠道副作用包括腹泻、腹痛、恶心、呕吐、黏膜炎、食欲减退、胃溃疡、胃炎、便秘、肠炎、肠穿孔、肠出血、溃疡和/或肠坏死。
  29. 根据权利要求1-28中任一项所述的用途，其中所述胃肠道副作用包括腹泻和/或便秘。
  30. 根据权利要求1-29中任一项所述的用途，其中所述胃肠道副作用的严重程度为依据NCI-CTCAE中的第1级或其以上、第2级或其以上、第3级或其以上、第4级或其以上，或者第5级。
  31. 根据权利要求1-30中任一项所述的用途，其中所述受试者包括癌症患者。
  32. 根据权利要求1-31中任一项所述的用途，其中所述药物基本上不影响所述化疗的治疗效果。
  33. 根据权利要求1-32中任一项所述的用途，其中所述药物在所述化疗施用前约0.5小时、约1小时、约2小时、约3小时、约4小时、约5小时、约6小时、约7小时、约8小时、约9小时、约10小时、约11小时、约12小时、约13小时、约14小时、约15小时、约 16小时、约17小时、约18小时、约19小时、约20小时或更久前施用。
  34. 根据权利要求1-33中任一项所述的用途，其中所述药物在所述化疗施用前约0.5-12小时施用。
  35. 根据权利要求1-34中任一项所述的用途，其中所述药物被制备为适用于口服给药、静脉注射、皮下注射、腹腔注射和/或肌肉注射。
  36. 根据权利要求1-35中任一项所述的用途，其中所述药物被制备为适用于口服给药。
  37. 根据权利要求1-36中任一项所述的用途，其中所述药物被制备为片剂和/或胶囊。
  38. 根据权利要求1-37中任一项所述的用途，其中所述药物中还包括一种或多种其他活性成分。
  39. 根据权利要求1-38所述的用途，所述CDK抑制剂能够独立改善或减轻所述胃肠道副作用。
  40. 一种预防、缓解和/或治疗受试者中与化疗相关的胃肠道副作用的方法，包括向有需要的受试者施用权利要求1-39中任一项的用途中所述的CDK抑制剂。
  41. 权利要求1-39中任一项所述的用途中所述的CDK抑制剂，其用于预防、缓解和/或治疗受试者中与化疗相关的胃肠道副作用。
  42. 药物组合，其包括权利要求1-39中任一项的用途中所述的CDK抑制剂和化疗剂。
  43. 试剂盒，其包括权利要求1-39中任一项的用途中所述的CDK抑制剂和化疗剂。
PCT/CN2022/097792 2021-06-10 2022-06-09 治疗化疗相关的胃肠道副作用的化合物和方法 WO2022258001A1 (zh)

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