WO2021073535A1 - Méthode de prévention ou de traitement de maladies associées à l'administration d'un inhibiteur du vegfr et/ou du vegf - Google Patents

Méthode de prévention ou de traitement de maladies associées à l'administration d'un inhibiteur du vegfr et/ou du vegf Download PDF

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WO2021073535A1
WO2021073535A1 PCT/CN2020/120916 CN2020120916W WO2021073535A1 WO 2021073535 A1 WO2021073535 A1 WO 2021073535A1 CN 2020120916 W CN2020120916 W CN 2020120916W WO 2021073535 A1 WO2021073535 A1 WO 2021073535A1
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inhibitor
vegfr
vegf
administration
inhibitors
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PCT/CN2020/120916
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English (en)
Chinese (zh)
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张诗宜
吴兆宇
陈乐颖
陈玉云
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上海岸阔医药科技有限公司
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Priority to CN202080072302.3A priority Critical patent/CN114585356A/zh
Publication of WO2021073535A1 publication Critical patent/WO2021073535A1/fr

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • This application relates to the field of disease treatment, for example, a method for preventing or treating diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors.
  • Vascular endothelial growth factor receptor Vascular endothelial growth factor receptor, VEGFR
  • VEGFR Vascular endothelial growth factor receptor
  • VEGF therapy for example, administration of VEGFR inhibitors and/or VEGF inhibitors
  • this type of treatment often causes serious side effects, especially on the skin, facial features, and gastrointestinal tract. Severe side effects caused by therapies that inhibit VEGFR and/or VEGF can impair the patient’s quality of life, reduce the patient’s medication compliance and tolerance, and lead to the withdrawal or insufficient dose of VEGFR/VEGF inhibitors, which will adversely affect the therapeutic effect. Influence, and even lead to accelerated disease progression, shortening the patient's survival period.
  • This application provides a method for preventing or treating diseases related to the administration of VEGFR inhibitors and/or VEGF inhibitors.
  • the present application relates to the use of compounds represented by formula I to prevent or treat diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors in subjects, which can effectively control the VEGFR inhibitors and/or Side effects caused by VEGF inhibitors, such as skin tissue diseases or disorders, five sense organs diseases or disorders, and/or gastrointestinal diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors,
  • R 1, R 2 and R 3 each is independently -NO 2 or -OH, R 1, R 2, and R 3 is at least one -NO 2, and R 1, R 2 and R 3 are not simultaneously It is -NO 2 .
  • the compounds described in this application have not been used to treat the above-mentioned diseases.
  • the compounds described in the present application have the effect of preventing or treating the side effects of tumor therapy, for example, preventing or treating diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors, for example, preventing or treating and administering VEGFR inhibitors and/or VEGF inhibitors related skin tissue diseases or disorders, five sense organ diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors, and/or VEGFR inhibitors and/or VEGF inhibitors related The role of gastrointestinal diseases or disorders.
  • the application provides the use of the compound represented by formula I in the preparation of a medicine, and the compound can be used to prevent or treat a disease or condition related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor in a subject,
  • R 1, R 2 and R 3 each is independently -NO 2 or -OH, R 1, R 2, and R 3 is at least one -NO 2, and R 1, R 2 and R 3 are not simultaneously It is -NO 2 .
  • At least two of R 1 , R 2 and R 3 of the compound of formula I are -NO 2 .
  • the compound is selected from 1,2-dinitroglycerol or 1,3-dinitroglycerol.
  • the disease or condition can be caused by the administration of a VEGFR inhibitor and/or a VEGF inhibitor.
  • at least one of the VEGFR inhibitors directly acts on the VEGFR protein and/or the nucleic acid encoding the VEGFR protein.
  • at least one of the VEGF inhibitors directly acts on the VEGF protein and/or the nucleic acid encoding the VEGF protein.
  • the VEGFR inhibitor and/or the VEGF inhibitor are used to treat tumors.
  • the affected area of the disease or condition is different from the affected area of the tumor.
  • the VEGFR inhibitor includes a small molecule VEGFR inhibitor, a protein macromolecule that specifically binds to VEGFR, RNAi that inhibits VEGFR protein expression, and/or an antisense oligonucleotide that inhibits VEGFR protein expression.
  • the VEGF inhibitor includes a VEGF capture agent and/or an agent that reduces VEGF expression.
  • the VEGFR inhibitor inhibits VEGFR1, VEGFR2, and/or VEGFR3.
  • the VEGFR inhibitor and/or VEGF inhibitor includes ramucirumumab, bevacizumab, regorafenib, punatinib, cabozantinib, levatinib , Sorafenib, pazopanib, apatinib, axitinib, nintedanib, vandetanib, sunitinib, midosturin, tivozani, fruquintinib , Cediranib, Brinib, Donafinib, Sofantinib, Anlotinib, Famitinib, Tesevatinib, Vorolanib, Motesanib, Linifanib, Semaxanib, Dovetinib, Orantinib, Varta Nidine, Tilatinib, Glesatinib, Deritinib, Ilorasertib, Rebastinib, Golvatinib, Fore
  • the VEGFR inhibitor and/or VEGF inhibitor are administered in combination with one or more other therapies, for example, the one or more other therapies include one or more other anti-tumor therapies .
  • the disease or condition is caused by the inhibition of VEGFR and/or VEGF.
  • the disease or disorder includes a skin tissue disease or disorder related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor, a disease or disorder of the five sense organs, and/or a gastrointestinal disease or disorder; further, it includes Epithelial tissue diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors in the skin tissue, facial features, and/or gastrointestinal tract; further, including the diseases or disorders related to endothelial cell pathology, and/or The disease or disorder related to epithelial cytopathy, and wherein the endothelial cytopathy and/or epithelial cytopathy is associated with the administration of a VEGFR inhibitor and/or VEGF inhibitor; further, the endothelial cells include blood vessels Endothelial cells, the epithelial cells include skin epithelial cells, oral epithelial cells, nasal cavity epithelial cells, gastric epithelial cells and/or intestinal epithelial cells.
  • the diseases or conditions associated with the administration of VEGFR inhibitors and/or VEGF inhibitors include skin rashes associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and the administration of VEGFR inhibitors and/or Hand-foot syndrome associated with VEGF inhibitors, itching associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, erythema associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR inhibitors and/or VEGF inhibitors Related dry skin, hair loss associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, paronychia associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and related administration of VEGFR inhibitors and/or VEGF inhibitors Pigmentation disorders, oral ulcers associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, dry mouth associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, noses associated
  • the disease or condition associated with the administration of a VEGFR inhibitor and/or a VEGF inhibitor includes hand-foot syndrome associated with the administration of a VEGFR inhibitor and/or a VEGF inhibitor.
  • the severity of the disease or condition related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor is based on NCI-CTCAE V5.0 at level 1 or above, level 2 or above, Level 3 or above, Level 4 or above, and/or Level 5.
  • the compound is capable of directly or indirectly producing NO.
  • the drug is prepared to be suitable for local administration, for example, the administration site of the local administration is not the site of cancer occurrence or the site of potential metastasis of cancer.
  • the medicament is prepared for topical administration.
  • the drug is prepared as an ointment.
  • the drug also includes one or more other active ingredients.
  • the drug does not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor.
  • the subject includes a cancer patient. In certain embodiments, the subject has been, is, and/or will be administered the VEGFR inhibitor and/or the VEGF inhibitor.
  • the subject has or is susceptible to the disease or condition associated with the administration of a VEGFR inhibitor and/or VEGF inhibitor.
  • the severity of the disease or condition increases after the administration of the VEGFR inhibitor and/or VEGF inhibitor.
  • the subject prior to the administration of the VEGFR inhibitor and/or VEGF inhibitor, the subject did not suffer from the disease or condition.
  • the VEGFR inhibitor and/or VEGF inhibitor does not contain the compound.
  • the present application provides a pharmaceutical combination or kit.
  • the pharmaceutical combination or kit may include: 1) a VEGFR inhibitor and/or a VEGF inhibitor; and 2) a compound represented by formula I, the compound of formula I,
  • R 1, R 2 and R 3 each is independently -NO 2 or -OH, R 1, R 2, and R 3 is at least one -NO 2, and R 1, R 2 and R 3 are not simultaneously It is -NO 2 . In certain embodiments, at least two of R 1 , R 2 and R 3 of the compound of formula I are -NO 2 . In certain embodiments, the compound is selected from 1,2-dinitroglycerol or 1,3-dinitroglycerol. In some embodiments, the VEGFR inhibitor and/or VEGF inhibitor and the compound are not mixed with each other. In certain embodiments, the VEGFR inhibitor and/or VEGF inhibitor and the compound are each independently present in separate containers.
  • the compound is prepared for topical administration. In some embodiments, the compound is prepared as an ointment. In some embodiments, the compound in 2) can prevent or treat diseases or disorders caused by the VEGFR inhibitor and/or VEGF inhibitor in 1). In some embodiments, the compound in 2) does not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor in 1). In certain embodiments, the compound of 2) is administered before, at the same time or after the administration of the VEGFR inhibitor and/or VEGF inhibitor of 1).
  • the present application provides a method, which includes the following steps: 1) Monitoring one or more skin tissues, facial features, and/or stomach of a subject to which a VEGFR inhibitor and/or a VEGF inhibitor is administered Intestinal characteristics; 2) When the monitoring shows that the subject has skin tissue diseases or disorders, five organ diseases or disorders, and/or gastrointestinal diseases related to the administration of the VEGFR inhibitor and/or VEGF inhibitor, or In the case of a disease, the subject is administered a compound represented by formula I,
  • R 1, R 2 and R 3 each is independently -NO 2 or -OH, R 1, R 2, and R 3 is at least one -NO 2, and R 1, R 2 and R 3 are not simultaneously It is -NO 2 .
  • At least two of R 1 , R 2 and R 3 of the compound of formula I are -NO 2 .
  • the compound is selected from 1,2-dinitroglycerol or 1,3-dinitroglycerol.
  • the method further includes continuing to monitor the skin tissue disease or disorder, the five sense organs disease or disorder, and/or the gastrointestinal disease or disorder, and optionally reducing or discontinuing the VEGFR inhibitor and / Or VEGF inhibitor.
  • the severity of the disease or condition increases after the administration of the VEGFR inhibitor and/or VEGF inhibitor.
  • the subject prior to the administration of the VEGFR inhibitor and/or VEGF inhibitor, did not suffer from the disease or condition.
  • the VEGFR inhibitor and/or VEGF inhibitor does not contain the compound.
  • the disease or disorder is an epithelial tissue disease or disorder.
  • the VEGFR inhibitor and/or VEGF inhibitor are administered to treat cancer.
  • the affected area of the disease or condition is different from the affected area of cancer.
  • the compound is administered topically to the subject.
  • the compound is administered locally to a site in the subject that is substantially free of cancer cells. In certain embodiments, the compound is administered to a non-cancer site in the subject.
  • R 1, R 2 and R 3 each is independently -NO 2 or -OH, R 1, R 2, and R 3 is at least one -NO 2, and R 1, R 2 and R 3 are not simultaneously As -NO 2 , the drug can be used to prevent or treat cytopathies associated with administration of VEGFR inhibitors and/or VEGF inhibitors in subjects.
  • the cytopathy includes cell death.
  • the cells include endothelial cells and/or epithelial cells, for example, the endothelial cells include vascular endothelial cells, and the epithelial cells include skin epithelial cells, oral cavity epithelial cells, nasal cavity epithelial cells, and gastric epithelial cells And/or intestinal epithelial cells.
  • At least two of R 1 , R 2 and R 3 of the compound of formula I are -NO 2 .
  • the compound is selected from 1,2-dinitroglycerol or 1,3-dinitroglycerol.
  • the present application provides a method for preventing or treating a disease or condition, comprising administering the compound to a subject, wherein the subject has been, is, and/or will be administered a VEGFR inhibitor and And/or VEGF inhibitors and susceptible to or suffering from diseases or disorders related to administration of VEGFR inhibitors and/or VEGF inhibitors.
  • the present application provides a method of preventing or treating a disease or disorder, comprising administering the compound to a subject susceptible to or suffering from the disease or disorder, wherein the subject has been, is currently And/or will be administered a VEGFR inhibitor and/or VEGF inhibitor in the future.
  • the present application provides a method of preventing or treating a disease or condition, comprising administering the compound to a subject susceptible to or suffering from the disease or condition, wherein the disease or condition is hand-foot synthesis Levy.
  • the subject has been, is, and/or will be administered a VEGFR inhibitor and/or a VEGF inhibitor.
  • the present application provides a method of preventing or treating a disease or condition, comprising administering the compound to a subject susceptible to or suffering from the disease or condition, wherein the disease or condition is the same as administering the compound Epithelial cell diseases related to VEGFR inhibitors and/or VEGF inhibitors.
  • Figures 1A-1E show exemplary results of cell proliferation toxicity measured after administering the compounds described in this application to HUVEC cells.
  • Figures 2A-2C show exemplary results of cell proliferation toxicity measured after administration of the compound described in this application to HaCaT cells.
  • Figures 3A-3C show exemplary results of cell proliferation toxicity determined after administration of the compounds described in this application to HOK cells.
  • Figures 4A-4C show exemplary results of cell proliferation toxicity determined after administration of the compound described in this application to GES-1 cells.
  • Figures 5A-5C show exemplary results of cell proliferation toxicity measured after administration of the compound described in this application to FHs 74 Int cells.
  • Figure 6 shows the relative levels of nitric oxide in the cells at each time point after HUVEC cells were treated with 100 ⁇ M of the compounds described in the application (1,2-dinitroglycerin, 1,3-dinitroglycerin).
  • Figure 7 shows the relative content of nitric oxide in the cells of GES-1 cells treated with 100 ⁇ M of the compounds described in this application (1,2-dinitroglycerin, 1,3-dinitroglycerin) for 24 hours.
  • Figure 8 shows the relative content of nitric oxide in HaCaT cells after treating HaCaT cells with 100 ⁇ M of the compounds (1,2-dinitroglycerol, 1,3-dinitroglycerol) described in this application for 24 hours.
  • Fig. 9 shows an enlarged view of the left paw, a front view of the left and right paws, and an enlarged view of the right paw of a rat model in which VEGFR and/or VEGF are inhibited leading to hand-foot syndrome.
  • Figure 10 shows an enlarged view of the left paw, a front view of the left and right paws, and an enlarged view of the right paw of a typical rat in the administration group of Examples 41-48 and 51-52 of the present application (left paw application).
  • Fig. 11 shows an enlarged view of the left paw, a front view of the left and right paws, and an enlarged view of the right paw of a typical rat (applicable on the right paw) in the administration group of Examples 49-50 of this application.
  • Figure 12 shows an enlarged view of the left paw, a front view of the left and right paws, and an enlarged view of the right paw of a typical rat in the administration group of Examples 53-56 of the present application (left paw application).
  • Figure 13 shows an enlarged view of the left paw, a front view of the left and right paws, and an enlarged view of the right paw of a typical rat (applied on the right paw) in the administration group of Examples 57-58 of the present application.
  • VEGFR inhibitor VEGFR inhibitor, VEGF inhibitor
  • VEGFR Vascular Endothelial Growth Factor Receptor, which belongs to the Receptor tyrosine kinases (RTKs) family. According to reports, it includes three main subtypes, namely VEGFR1, VEGFR2 and VEGFR3. Among them, VEGFR1 and VEGFR2 are mainly distributed on the surface of tumor vascular endothelium to mediate the formation of tumor blood vessels, and VEGFR3 is mainly distributed on the surface of lymphatic endothelium to mediate the formation of tumor lymphatic vessels. It is reported that VEGFR2 is the main VEGF signal transduction receptor in the process of angiogenesis and mitosis.
  • RTKs Receptor tyrosine kinases
  • the VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor (PGF). It is reported that VEGF-A binds to VEGFR-1 and VEGFR-2, which can regulate almost all cellular responses to VEGF. The activation of VEGFR-2 on endothelial cells leads to cell proliferation, migration, increased survival rate and increased vascular permeability (see Waldner, Maximilian J. et al., The Journal of Experimental Medicine 207.13, 2010). The expression of VEGFR or the increase of its kinase activity is associated with a series of human cancers.
  • VEGF usually refers to Vascular Endothelial Growth Factor. According to reports, it is considered to be a key endothelial cell-specific growth factor required for pathological angiogenesis signaling pathways, VEGF receptors. Inhibition of the tyrosine kinase signaling pathway blocks the formation of new blood vessels in tumor growth, leading to the stagnation or regression of angiogenic tumors (see Gerald McMahon, The Oncologist 2000, 5:3-10).
  • the term "VEGFR inhibitor” generally refers to any substance or agent known in the art or discovered in the future that can cause a decrease in the expression, quantity, or activity of VEGFR, including any substance or agent that is administered to a subject At this time, any substance that results in the inhibition of the biological activity related to the activity of VEGFR in the subject (including the inhibition of downstream biological effects produced by the binding of any VEGFR to its natural ligand).
  • the VEGFR inhibitor may include any agent capable of blocking the activity of VEGFR or any downstream biological effects during the treatment of cancer.
  • the VEGFR inhibitor can be used to treat tumors.
  • the VEGFR inhibitor can directly inhibit one or more functions of VEGFR.
  • the VEGFR inhibitor can bind to a nucleic acid sequence encoding VEGFR.
  • the VEGFR inhibitor can reduce the transcription level of the VEGFR protein.
  • the term "VEGF inhibitor” generally refers to any substance or agent known in the art or discovered in the future that can cause a decrease in the expression, quantity or activity of VEGF, including any substance or agent that is administered to a subject Time, any substance that results in the inhibition of the biological activity associated with VEGF activity in the subject.
  • the VEGF inhibitor may include any agent capable of blocking the activity of VEGF or any downstream biological effects thereof.
  • the VEGF inhibitor may include any agent capable of blocking the activity of VEGF or any of its downstream biological effects during the treatment of cancer.
  • the VEGF inhibitor can be used to treat tumors.
  • the VEGF inhibitor can directly inhibit one or more functions of VEGF.
  • the VEGF inhibitor can bind to a nucleic acid sequence encoding VEGF.
  • the VEGF inhibitor can reduce the transcription level of VEGF protein.
  • the term "disease or disorder related to the administration of a VEGFR inhibitor and/or VEGF inhibitor” generally refers to a disease or disorder that is related to the administration of a VEGFR inhibitor and/or VEGF inhibitor to a subject.
  • the disease or disorder may be a disease or disorder caused by administering the VEGFR inhibitor and/or the VEGF inhibitor to a subject.
  • the disease or disorder may include a skin tissue disease or disorder related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor, a five sensory disease or disorder related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor, and/or VEGFR inhibitor and/or VEGF inhibitor related gastrointestinal diseases or disorders.
  • the disease or disorder may include skin rashes associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, hand-foot syndrome associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR inhibitors and/or Itching associated with VEGF inhibitors, erythema associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, dry skin associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and the administration of VEGFR inhibitors and/or VEGF inhibitors Hair loss, paronychia associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, pigmentation disorders associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and associated with the administration of VEGFR inhibitors and/or VEGF inhibitors Oral ulcers, dry mouth associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, epistaxis associated with the administration of VEGFR inhibitors and/or VEGF inhibitors
  • tumor usually refers to a new organism formed by the proliferation of local tissue cells under the action of various tumor-causing factors. Because this new organism is mostly a mass-occupying bulge, it is also called a tumor. biological. According to the cell characteristics of new organisms and the degree of harm to the body, tumors are divided into benign tumors and malignant tumors. Cancer is the general term for malignant tumors.
  • the tumor can be selected from the following group: epithelial malignant tumor (epithelial-derived cancer), lung cancer (for example, non-small cell lung cancer), breast cancer, skin cancer, bladder cancer, colon cancer, intestinal cancer, prostate cancer, Pancreatic cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, head and neck cancer, stomach cancer and laryngeal cancer.
  • epithelial malignant tumor epithelial-derived cancer
  • lung cancer for example, non-small cell lung cancer
  • breast cancer for example, skin cancer, bladder cancer, colon cancer, intestinal cancer, prostate cancer, Pancreatic cancer, uterine cancer, cervical cancer, ovarian cancer, esophageal cancer, head and neck cancer, stomach cancer and laryngeal cancer.
  • the tumor may be liver cancer, kidney cancer, colorectal cancer, gastric cancer, esophageal cancer, or thyroid cancer.
  • VEGFR inhibitors and/or VEGF inhibitors can be used to determine or screen VEGFR inhibitors and/or VEGF inhibitors, for example, by detecting changes in VEGFR and/or VEGF expression levels or activities after administration of candidate substances/agents.
  • the expression level of VEGFR and/or VEGF can also be detected by methods known in the art, such as immunohistochemistry, PCR, RT-PCR, in situ hybridization, Southern blot, Western blot, Northern blot, spectrophotometry and ELISA Wait.
  • VEGFR inhibitors can directly act on the VEGFR protein and/or the nucleic acid encoding the VEGFR protein.
  • VEGF inhibitors can directly act on the VEGF protein and/or the nucleic acid encoding the VEGF protein.
  • the VEGFR inhibitor may include a small molecule VEGFR inhibitor, a protein macromolecule that specifically binds to VEGFR, RNAi that inhibits VEGFR protein expression, and/or an antisense oligonucleotide that inhibits VEGFR protein expression.
  • small molecule VEGFR inhibitor may include a small molecule VEGFR inhibitor that binds reversibly or irreversibly to VEGFR or a small molecule VEGFR inhibitor that specifically binds to a mutant VEGFR.
  • the small molecule VEGFR inhibitor may include regorafenib, prnatinib, cabozantinib, levatinib, sorafenib, pazopanib, apatinib, axitinib , Nintedanib, vandetanib, sunitinib, midosturin, tivozanib, fruquintinib, cediranib, brinib, donafenib, sofantinib , Anlotinib, Famitinib, Tesevatinib, Vorolanib, Motecanib, Linifanib, Semaxanib, Dovetinib, Orantinib, Vatanitine, Tilatinib, Glesatinib, Deritinib, Ilorasertib, Rebastinib, Golvatinib, Foretinib, ningetinib, Tafetinib, Alt
  • the protein macromolecule that specifically binds to VEGFR may be an antibody, antibody variant, fusion protein, derivative or fragment thereof against VEGFR.
  • it may be an antibody or an antigen-binding fragment thereof that specifically binds to VEGFR.
  • the antibody generally refers to a polypeptide molecule that can specifically recognize and/or neutralize a specific antigen.
  • an antibody may comprise an immunoglobulin consisting of at least two heavy (H) chains and two light (L) chains connected to each other by disulfide bonds, and includes any molecule comprising an antigen binding portion thereof.
  • the term "antibody” may include monoclonal antibodies, antibody fragments or antibody derivatives, including but not limited to human antibodies (fully human antibodies), humanized antibodies, chimeric antibodies, single chain antibodies (eg, scFv), and Antigen-binding antibody fragments (e.g., Fab, Fab' and (Fab) 2 fragments).
  • the chimeric antibody may be a part of the heavy chain or light chain amino acid sequence homologous to the corresponding amino acid sequence in the antibody from one species, or belong to a specific category, while the remaining segments of the chain are similar to another species.
  • the humanized antibody may refer to a chimeric antibody that contains less sequences derived from non-human immunoglobulins, thereby reducing the immunogenicity of the heterogeneous antibody when introduced into humans, while maintaining the complete antigenicity of the antibody Binding affinity and specificity.
  • the fully human antibody may refer to an amino acid sequence corresponding to an antibody produced by human or human immune cells, or derived from a non-human source such as a transgenic non-human animal using a human antibody library, or other human-encoded antibodies.
  • the antibody of the sequence of the source antibody may refer to an amino acid sequence corresponding to an antibody produced by human or human immune cells, or derived from a non-human source such as a transgenic non-human animal using a human antibody library, or other human-encoded antibodies.
  • the antigen-binding fragment antibody may be one or more fragments that perform the function of specifically binding antigen.
  • the antigen-binding function of an antibody can be achieved by a full-length fragment of the antibody.
  • the antigen-binding function of an antibody can also be achieved by the following: a heavy chain including Fv, ScFv, dsFv, Fab, Fab' or F(ab') 2 fragments, or including Fv, ScFv, dsFv, Fab, Fab' or The light chain of a fragment of F(ab') 2.
  • Fab fragments namely monovalent fragments composed of VL, VH, CL and CH domains;
  • F(ab') 2 fragments containing two Fab fragments connected by disulfide bonds at the hinge region Bivalent fragments;
  • Fd fragments composed of VH and CH domains containing two Fab fragments connected by disulfide bonds at the hinge region Bivalent fragments;
  • Fd fragments composed of VH and CH domains containing two Fab fragments connected by disulfide bonds at the hinge region Bivalent fragments
  • Fd fragments composed of VH and CH domains
  • Fv fragments composed of VL and VH domains of a single arm of an antibody
  • dAb fragments composed of VH domains (Ward et al.
  • the "antigen binding portion” may also include an immunoglobulin fusion protein, the fusion protein comprising a binding domain selected from: (1) a binding domain polypeptide fused to an immunoglobulin hinge region polypeptide; (2) and The immunoglobulin heavy chain CH2 constant region fused to the hinge region; and (3) the immunoglobulin heavy chain CH3 constant region fused to the CH2 constant region.
  • the protein macromolecule that specifically binds to VEGFR may be ramucirumumab, an antigen-binding fragment thereof, or a functional variant thereof.
  • the term "specifically binds" generally means that in a complex mixture, the VEGFR inhibitor can specifically recognize and bind to VEGFR, but does not substantially recognize or bind to other components in the complex mixture.
  • the affinity of the inhibitor to VEGFR may be at least 2-fold (e.g., at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold or at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, or 8-fold affinity with other non-specific binding components. , 9 times, 10 times or more).
  • the value of the equilibrium dissociation constant of the binding of the VEGFR inhibitor and VEGFR is less than or equal to 10 -6 M (for example, it can be less than or equal to 10 -7 M, less than or equal to 10 -8 M, less than or equal to 10 -6 M). Equal to 10 -9 M, less than or equal to 10 -10 M or less).
  • VEGF capture agent generally refers to an agent capable of capturing VEGF by binding to it.
  • the VEGF capture agent may be selected from the group consisting of bevacizumab and aflibercept.
  • the term "agent for reducing the expression of VEGF” generally refers to a substance that can directly or indirectly reduce the expression of VEGF in a subject.
  • the agent for reducing VEGF expression can be selected from the group consisting of Temsirolimus and Thalidomide.
  • RNAi generally refers to RNA interference (RNA interference), which is usually an exogenous or endogenous double-stranded RNA molecule or small RNA, which is generally inhibited by targeting mRNA and specifically degrading it. Expression or translation of target genes.
  • RNAi includes two types of small RNA: microRNA (miRNA) and small interfering RNA (siRNA). These small RNAs can bind to other mRNA molecules to increase or decrease their activity, such as preventing mRNA from being translated into protein.
  • the RNAi pathway cleaves long double-stranded RNA (dsRNA) into siRNA double-stranded fragments of about 20-23 nucleotides in length through the RNaseIII enzyme (eg, Dicer, DCL, or Drosha).
  • dsRNA double-stranded RNA
  • RISC RNA-induced silencing complex
  • RNAi that inhibits the expression of VEGFR protein can inhibit the expression or translation of VEGFR by targeting the mRNA encoding VEGFR, thereby specifically degrading the mRNA.
  • RNAi that inhibits the expression of VEGF protein can inhibit the expression or translation of VEGF by targeting the mRNA encoding VEGF, thereby specifically degrading the mRNA.
  • oligonucleotide generally refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or any of its mimetics or structurally modified nucleic acids.
  • the oligonucleotide may include oligonucleotides composed of naturally-occurring nucleobases, sugars, and covalent nucleoside (backbone) linkages, as well as non-naturally-occurring oligonucleotides with similar functions. Modified or substituted oligonucleotides are generally superior to the natural form because they have, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases.
  • antisense oligonucleotide generally refers to a single-stranded oligonucleotide having a nucleobase sequence that allows at least partial hybridization with a corresponding region or fragment of a target nucleic acid.
  • the antisense oligonucleotide may comprise about 8 to about 50 nucleobases.
  • the VEGFR inhibitor can inhibit VEGFR1, VEGFR2 and/or VEGFR3.
  • the VEGFR inhibitor can inhibit one, two or three of VEGFR1, VEGFR2, and VEGFR3.
  • the VEGFR inhibitor and/or VEGF inhibitor may include ramucirumumab, bevacizumab, regorafenib, punatinib, cabozantinib, levatinib Ni, sorafenib, pazopanib, apatinib, axitinib, nintedanib, vandetanib, sunitinib, midoturin, tivozani, fruquinit Ni, Cediranib, Brinib, Donafinib, Sofantinib, Anlotinib, Famitinib, Tesevatinib, Vorolanib, Motesanib, Linifanib, Semaxanib, Dovetinib, Orantinib, Watt Tanidine, Tilatinib, Glesatinib, Delitinib, Ilorasertib, Rebastinib, Golvatinib, Foretinib,
  • the "pharmaceutically acceptable salt” generally refers to a pharmaceutically acceptable salt of the compound.
  • the pharmaceutically acceptable salt may be selected from the group consisting of sorafenib tosylate, sunitinib malate, pazopanib hydrochloride and Dovitinib (TKI258) lactic acid salt.
  • the VEGFR inhibitor and/or VEGF inhibitor can be administered in combination with one or more other therapies.
  • the one or more other therapies may include one or more other anti-tumor therapies.
  • the other anti-tumor therapies may include cytotoxic anti-cancer agents, immunotherapeutic anti-cancer agents, and/or hormone therapy anti-cancer agents.
  • the other anti-tumor therapies may also include radiotherapy or surgical treatment.
  • the other anti-tumor therapy may be part of a single agent that is mixed with the VEGFR inhibitor and/or VEGF inhibitor into a single composition.
  • the other anti-tumor therapy may be a separate agent, which is administered separately from the VEGFR inhibitor and/or VEGF inhibitor.
  • the VEGFR inhibitor and/or VEGF inhibitor may be about 1-99% relative to the total dose.
  • % (E.g., about 5-95%, about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 99%) is present and/or administered.
  • Cytotoxic anticancer agents used in the treatment of cancer may include alkylating agents such as nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, Isothiocyanate, Busulfan, Nimustine Hydrochloride, Mitropium Bromide, Melphalan, dacarbazine, Ramustine, Imiphene Sodium Phosphate, Ethylene Triamine, Carmustine , Lomustine, Streptozotocin, Pipobroman, ethoglucid, Carboplatin, Cisplatin, Miplatin, Nedaplatin, Tenetamide, Omustine, Diclopyridine, flupistein, prednisodine, pumitepa, bendamustine hydrochloride (Ribomustin), temozolomide, diclofenac, trovafloxacin, zennotastin, si
  • the immunotherapeutic anticancer agents used in the treatment of cancer can include bubicinanib, crestine, etofuran, lentinan, ubiquitin, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony Stimulant factors, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium, everolimus, levamisole, polysaccharide K, procodazole and/or immune checkpoint inhibitors (e.g., CTLA4 inhibitors, TIM-3 inhibitors, PD-1 inhibitors (e.g., Nivolumab, Pembrolizumab, Pidilizumab, AMP514 (Amplimmune), AMP-224, and in the PCT patent application WO2006/121168, WO2009/114335, WO2009/101611, U.S.
  • Patent US8609089 U.S. Patent Application US2010/028330, US2012/0114649 other PD-1 inhibitors
  • PD-L1 inhibitors for example, YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, MDX-1105, and other PD-L1 inhibitors disclosed in PCT Patent Application WO2010/077634 and US Patent 7,943,743)).
  • Hormone therapy anti-cancer agents used in the treatment of cancer may include fustatin, diethylstilbestrol, xylin, medroxyprogesterone acetate, megestrol acetate, cyproterone acetate, cyproterone acetate, Danazol, allylestrol, progesterone, mepartricin (mepartricin), raloxifene or meloxifene, levofloxacin, anti-estrogens (e.g., tamoxifen citrate, progesterone) Remifene citrate, etc.), contraceptives, prostacycloalkane, testosterone lactone, aminosuccinimide, LH-RH agonist (for example, goserelin acetate, buserelin, leuprolide Lin, etc.), droxifene, epiandrostanol, ethinyl estradiol sulfonate, furbendazole hydrochloride,
  • VEGFR inhibitors Diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors
  • the diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors may have a statistically significant correlation with the inhibition of VEGFR and/or VEGF.
  • the disease or condition associated with the administration of a VEGFR inhibitor and/or a VEGF inhibitor may be caused by the inhibition of VEGFR and/or VEGF.
  • the diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors may include skin tissue diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors, five organ diseases or disorders, and/or gastrointestinal Tract disease or condition.
  • the skin tissue disease or disorder, the five sense organ disease or disorder, and/or the gastrointestinal disease or disorder related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor may include the skin tissue, five sense organs, and/or gastrointestinal tract.
  • the disease or condition related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor may include side effects or adverse reactions caused by the administration of a VEGFR inhibitor and/or a VEGF inhibitor.
  • the disease or condition related to the administration of the VEGFR inhibitor and/or VEGF inhibitor may be a new indication, which may be different from any other disease or condition in the past.
  • diagnosis, treatment, and/or symptoms of the diseases or conditions related to the administration of VEGFR inhibitors and/or VEGF inhibitors are unique.
  • erythromycin ointment can treat skin rashes, but has no therapeutic effect on skin rashes associated with administration of VEGFR inhibitors and/or VEGF inhibitors.
  • the term "skin tissue disease or disorder” generally refers to pathological changes in the morphology, structure and/or function of the skin (including hair and nails).
  • the skin tissue disease or condition may include, but is not limited to, skin rash, hand-foot syndrome, pruritus, erythema, dry skin, hair loss, paronychia, pigmentation disorders, and the like.
  • rash generally refers to skin changes that affect the color, appearance, or texture of the skin.
  • the rash can be limited to only a part of the body or affect the entire skin.
  • the rash also includes urticaria.
  • HFS Hand Foot Syndrome
  • PPE Palmar Plantar Erythrodysesthesia
  • HFSR Hand-foot skin reaction
  • the pathological manifestations of HFS mainly include, for example, vacuolar degeneration of basal keratinocytes, peripheral lymphocyte infiltration of skin blood vessels, keratinocyte apoptosis and skin edema.
  • HFS may include palms, plantar numbness, or erythema caused by chemotherapy. Tumor patients may experience symptoms during the course of receiving chemotherapy or molecular targeted therapy (such as VEGFR inhibitors and/or VEGF inhibitors).
  • Hand-foot syndrome currently has a variety of classification methods. Among them, the National Cancer Institute (NCI) classification standard is more commonly used. This classification divides the hand-foot syndrome into three levels: Level 1: mild skin changes or dermatitis with sensation Abnormalities (such as fingerprint disappearance, pigmentation, erythema, peeling, paresthesia, dullness, skin numbness, etc.), but do not affect daily activities; level 2 is the same as level 1 for skin changes, accompanied by pain, and mildly affects daily activities, skin The surface is complete; Grade 3 is ulcerative dermatitis or skin changes with severe pain, which seriously affects daily life and has obvious tissue destruction (such as desquamation, blisters, bleeding, edema, etc.).
  • Level 4 refers to dullness, paresthesia, or tingling sensation in hands and feet
  • Level 2 refers to discomfort, painless swelling or erythema during holding and walking.
  • Grade 3 is painful erythema and edema of the palms and soles, erythema and swelling around the nail
  • Grade 4 is peeling, ulceration, ulceration and severe pain.
  • erythema generally refers to local or systemic red macules caused by the localized or systemic expansion of the capillary network of the dermal papillary layer.
  • paronychia usually refers to the infectious lesions of the soft tissue around the nail (toe), which is usually caused by bacteria invading into the subcutaneous and multiplying through the tiny damage of the paranail skin.
  • the clinical manifestation is swelling and swelling of the affected area. Pain, with inflammatory exudation and granulation tissue hyperplasia.
  • pigmentation disorder generally refers to a condition in which the skin is lighter or darker than normal, causing spots or discoloration. Hypopigmentation is due to the body's inability to produce enough pigment, and hyperpigmentation is due to the body producing too much pigment.
  • the term "disease or disorder of the five sense organs” usually refers to pathological changes in the morphology, structure and/or function of the ears, eyebrows, eyes, nose, mouth and other organs.
  • the five sense organ diseases or conditions may include, but are not limited to, oral Mucositis, dry mouth, epistaxis, nasopharyngitis and/or cheilitis.
  • nasopharyngitis generally refers to the inflammatory response of the nasopharyngeal mucosa, submucosa and lymphatic tissues, and can be divided into acute nasopharyngitis and chronic nasopharyngitis.
  • Symptoms include, but are not limited to, dry nasopharyngeal discomfort, thick secretions that are not easy to cough up, and often accompanied by nausea. In severe cases, there are local or systemic symptoms such as hoarseness, sore throat, headache, dizziness, fatigue, indigestion, and low fever.
  • Nasopharyngeal examination revealed chronic congestion, hyperplasia, and hypertrophy of the mucosa, covered with secretions or dry scabs.
  • cheilitis generally refers to an inflammatory disease or condition that occurs in the lips.
  • it may include inflammation of the perioral skin, vermilion border, and/or lip mucosa, and the like.
  • acute cheilitis and chronic cheilitis.
  • erosive cheilitis eczema cheilitis
  • desquamative cheilitis eczema cheilitis
  • etiology and pathology it can be divided into chronic non-specific cheilitis and glandular cheilitis. Cheilitis, benign lymphoproliferative cheilitis, granulomatous cheilitis, May-Raw syndrome, actinic cheilitis and allergic cheilitis, etc.
  • gastrointestinal disease or disorder generally refers to pathological changes in the morphology, structure, and/or function of stomach or intestinal tissue (for example, digestive tract tissue from the stomach pylorus to the anus).
  • the gastrointestinal disease or disorder may include, but is not limited to, diarrhea, vomitting, nausea, anorexia, constipation, and/or abdominal pain, etc.
  • the VEGFR inhibitor and/or the VEGF inhibitor can be used to treat tumors.
  • the affected area of the disease or condition is different from the affected area of the tumor.
  • the skin tissue disease or disorder, the five sense organ disease or disorder, and/or the gastrointestinal disease or disorder related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor may include the skin tissue, five sense organs, and/or Diseases or disorders of epithelial tissue in the gastrointestinal tract that are associated with the administration of VEGFR inhibitors and/or VEGF inhibitors.
  • epithelial tissue disease or disorder generally refers to a disease or disorder caused by epithelial cell and/or endothelial cell pathology.
  • the epithelial tissue disease or disorder may include skin rash, acne, itchy skin, hair loss, hair changes, erythema, skin exfoliation, herpes pus, hirsutism, hyperpigmentation, nail disease ( nail disorders), paronychia and nail cracks, dry skin, hypersensitivity, mucositis, nasopharyngitis, epistaxis, dry mouth, cheilitis, oral ulcers and/or gastrointestinal mucosal damage.
  • the epithelial tissue disease or disorder may also include skin epithelial cell diseases or disorders (e.g., rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, day Cell sores, pigmentation, melasma, vitiligo, urticaria, tinea corporis, itchy skin, hair loss, hair changes, erythema, paronychia and nail cracks, dry skin, hypersensitivity and psoriasis), oral epithelial cell diseases or Symptoms (for example, pemphigus, cold sores, herpetic stomatitis, granulomatous cheilitis, oral ulcers, pemphigoid, Sjoglin’s syndrome, Behcet’s syndrome and oral sarcoidosis, etc.), Nasal cavity epithelial cell disease or disorder (nasal epithelial disease,
  • the epithelial tissue disease or disorder related to the administration of a VEGFR inhibitor and/or VEGF inhibitor may include the disease or disorder related to endothelial cell pathology, and/or the disease or disorder related to epithelial cell pathology A disease or condition, wherein the endothelial cell pathology and/or epithelial cell pathology is related to the inhibition of the VEGFR and/or VEGF.
  • the endothelial cells may include vascular endothelial cells.
  • the pathology of vascular endothelial cells may include endothelial dysfunction.
  • the vascular endothelial cell pathology may include degenerative vascular diseases (e.g., atherosclerosis, medial arteriosclerosis, and arteriolar sclerosis (e.g., hyaline degenerative arteriosclerosis and proliferative arteriosclerosis)), inflammatory Vascular diseases (e.g., infectious arteritis, syphilitic arteritis, giant cell arteritis, thromboangiitis obliterans, and rheumatic arteritis), functional vascular diseases (e.g., Raynaud’s disease, cyanosis of hands and feet, and erythematous limbs) Pain) and/or congenital vascular disease (for example, congenital arteriovenous fistula).
  • degenerative vascular diseases e.g., athe
  • the epithelial cells may include skin epithelial cells, oral cavity epithelial cells, nasal cavity epithelial cells, gastric epithelial cells and/or intestinal epithelial cells.
  • the epithelial cell lesions may include skin epithelial cell lesions (e.g., skin rash, acne, rosacea, atopic dermatitis, contact dermatitis, seborrheic dermatitis, lupus, scleroderma, gastric sores, pigmentation, Black spot, vitiligo, urticaria, tinea corporis, itchy skin, hair loss, hair changes, erythema, paronychia and nail cracks, dry skin, hypersensitivity and psoriasis), oral epithelial cell lesions (for example, pemphigus, Herpes labialis, herpetic stomatitis, granulomatous cheilitis, oral ulcers, pemphigoid, Sjo
  • epithelial tissue includes one or more layers of cells covering the free and closed surfaces of the entire body, including skin, mucus, cavities, serous and glandular spaces. All epithelial layers contain two special domains: the apical domain facing the mucosal (or cavity) space and the basolateral membrane facing the serosal (or deep) space. Therefore, the important function of epithelial tissue is to provide appropriate barrier function to separate and control many physiological processes between these two spaces.
  • Epithelial tissue includes epithelial cells and endothelial cells.
  • VEGFR and/or VEGF can cause damage to endothelial cells and endothelial tissues, thereby causing diseases or disorders of skin tissues, oral cavity tissues, nasal cavity tissues and/or gastrointestinal tissues.
  • the course of the disease usually starts from the damage/pathological changes of endothelial cells and endothelial tissues, and epithelial cells also have pathological manifestations, and they will eventually be inhibited by the administration of VEGFR inhibitors and/or VEGF.
  • Drug-related endothelial cell lesions, and/or epithelial cell lesions related to the administration of VEGFR inhibitors and/or VEGF inhibitors are manifested in the patient.
  • cytopathic generally refers to abnormal growth or mutation of cells.
  • epithelial cytopathy generally refers to the abnormal growth or mutation of epithelial qualified cells.
  • the diseases or conditions associated with the administration of VEGFR inhibitors and/or VEGF inhibitors may include skin rashes associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and the administration of VEGFR inhibitors and/or Hand-foot syndrome associated with VEGF inhibitors, itching associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, erythema associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR inhibitors and/or VEGF inhibitors Related dry skin, hair loss associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, paronychia associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and related administration of VEGFR inhibitors and/or VEGF inhibitors Pigmentation disorders, oral ulcers associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, dry mouth associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, noses associated with
  • the diseases or conditions associated with the administration of a VEGFR inhibitor and/or a VEGF inhibitor include hand-foot syndrome associated with the administration of a VEGFR inhibitor and/or a VEGF inhibitor.
  • the severity of the disease or condition related to the administration of VEGFR inhibitors and/or VEGF inhibitors is based on NCI-CTCAE V5.0 of grade 1 or above, grade 2 or above, grade 3 or above , Level 4 or above, and/or Level 5.
  • the disease or condition may include skin rash, hand-foot syndrome, pruritus, erythema, dry skin, hair loss, paronychia, pigmentation disorders, oral ulcers, dry mouth, epistaxis, nasopharyngitis, lip Inflammation, esophageal mucositis, gastric mucositis, gastric ulcer, diarrhea, vomiting, nausea, anorexia, constipation and/or abdominal pain.
  • the disease or condition includes hand-foot syndrome.
  • the application provides the use of the compound represented by formula I in the preparation of a medicament for the prevention or treatment of a disease or condition related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor in a subject,
  • R 1 , R 2 and R 3 are each independently -NO 2 or -OH;
  • At least one of R 1 , R 2 and R 3 is -NO 2 ;
  • R 1 , R 2 and R 3 are not -NO 2 at the same time.
  • At least two of R 1 , R 2 and R 3 of Formula I are -NO 2 .
  • the compound may be selected from the group consisting of 1,2-dinitroglycerin and 1,3-dinitroglycerin.
  • the compound described in this application may be different from nitroglycerin.
  • the difference can be embodied in the difference in physicochemical properties and biological activities of the compound of the present application and nitroglycerin in in vivo or in vitro tests.
  • the pharmacokinetic characteristics of the subject are different.
  • the time for the compound of the present application and nitroglycerin to reach a steady-state plasma concentration is different.
  • the compound of the present application and nitroglycerin have different doses when they reach a steady state in plasma.
  • the biological activity of the compound of the present application is different from that of nitroglycerin, for example, the half maximum effective concentration that causes vasodilation reaction is different.
  • the compounds described in this application can release nitric oxide.
  • the compounds described in this application can directly contribute, produce and/or release nitric oxide.
  • the compounds described in this application can contribute, produce, and/or release nitric oxide by stimulating other substances.
  • the compounds described in the present application can be used as reactants in chemical reactions or enzyme-catalyzed reactions to contribute, produce and/or release nitric oxide through these reactions.
  • the compound may be produced NO +, NO -, N 2 O, NO, N 2 O 3, NO 2, NO 3 - and NO 2 - in at least one.
  • the compound can directly or indirectly produce NO.
  • the compounds described in this application can be used to prevent or treat the diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors.
  • the application also provides the use of the compound for the preparation of a medicament for the prevention or treatment of cytopathic diseases associated with the administration of a VEGFR inhibitor and/or a VEGF inhibitor in a subject.
  • the compound can be used to prepare a medicine, and the medicine can be used to prevent or treat the disease or condition related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor.
  • the compound can be used to prevent or treat the skin rash associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, the hand-foot syndrome associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and the administration of VEGFR inhibitors and/or VEGF inhibitors.
  • the compound can be used to prevent or treat skin rash, hand-foot syndrome, itching, erythema, dry skin, hair loss, paronychia, pigmentation disorders, oral ulcers, dry mouth, epistaxis, nasopharyngitis, cheilitis , Esophageal mucositis, gastric mucositis, gastric ulcer, diarrhea, vomiting, nausea, anorexia, constipation and/or abdominal pain.
  • the compound can be used to prevent or treat the hand-foot syndrome.
  • the medicament is prepared for topical administration.
  • the administration site of the local administration may not be the site of cancer occurrence or the site of potential metastasis of cancer.
  • the administration part may not be the primary site of cancer.
  • the administration portion may not be a metastatic site of cancer.
  • the metastasis site may include the site of cancer metastasis caused by lymphatic metastasis, vascular metastasis, and/or implanted metastasis.
  • the metastasis site may include bone, brain, liver, stomach, and/or lung.
  • the administration part may not be the recurrence site of cancer.
  • the concentration of the compound may be about 0.00001% (w/w) to about 50% (w/w), for example, it may be about 0.00001% (w/w) to about 10% (w/w), about 0.00001% (w/w) to about 9.5% (w/w), about 0.00001% (w/w) to about 9% (w/w), about 0.00001% (w/w) To about 8.5% (w/w), about 0.00001% (w/w) to about 8% (w/w), about 0.00001% (w/w) to about 7.5% (w/w), about 0.00001% ( w/w) to about 7% (w/w), about 0.00001% (w/w) to about 6.5% (w/w), about 0.00001% (w/w) to about 6% (w/w), About 0.00001% (w/w) to about 5.5% (w/w), about 0.00001% (w/w) to about 5% (w/w), about 0.00001% (w/w), about 5% (
  • the concentration of the compound may be about 0.00001% (w/w) to about 1% (w/w), about 0.00001% (w/w) to about 0.9% (w/w) ), about 0.00001% (w/w) to about 0.6% (w/w), about 0.05% (w/w) to about 0.5% (w/w), about 0.05% (w/w) to about 0.4% (w/w), about 0.05% (w/w) to about 0.3% (w/w), about 0.05% (w/w) to about 0.2% (w/w), about 0.1% (w/w) To about 0.2% (w/w) or less.
  • the concentration of the compound may be about 0.2% (w/w).
  • the concentration of the compound may be about 0.1% (w/w).
  • the drug containing the compound may not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor.
  • administration of the drug containing the compound does not substantially necessitate an increase in the dose of the VEGFR inhibitor and/or VEGF inhibitor administered to achieve substantially the same therapeutic effect.
  • the medicament is prepared for topical administration.
  • the medicament is formulated to be suitable for topical skin application.
  • the medicine may be an ointment, lotion or cream.
  • the medicine may also include one or more other active ingredients.
  • the active ingredient may refer to a monomer compound having medical utility or physiological activity.
  • the other active ingredients may be selected from the group consisting of anti-inflammatory agents, analgesics, local anesthetics, antibiotics, antihistamines, preservatives, immunosuppressants, and anti-bleeding agents.
  • the drug may also include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be selected from the group consisting of fillers, binders, disintegrants, buffers, preservatives, lubricants, flavoring agents, thickeners, colorants and emulsifiers.
  • the present application provides compounds for the prevention or treatment of diseases or disorders related to the inhibition of VEGFR and/or VEGF (for example, epithelial tissue diseases related to the inhibition of VEGFR and/or VEGF).
  • diseases or disorders related to the inhibition of VEGFR and/or VEGF for example, epithelial tissue diseases related to the inhibition of VEGFR and/or VEGF.
  • the present application provides a method for preventing or treating the diseases or disorders related to the inhibition of VEGFR and/or VEGF in a subject.
  • the method includes administering to the subject a prophylactic or therapeutically effective amount of a compound described herein.
  • prevention can be used interchangeably with “preventive treatment”.
  • prevention generally refers to preventing the onset, recurrence or spread of a disease or one or more of its symptoms by taking certain measures in advance.
  • treatment generally refers to the elimination or amelioration of a disease, or the alleviation of one or more symptoms associated with the disease.
  • the term "subject” generally refers to a human or non-human animal (including mammals, rodents, and avians, etc.) that needs to receive the diagnosis, prognosis, improvement, prevention, and/or treatment of a disease.
  • the subject may be a livestock animal (e.g., cow, pig, sheep, chicken, rabbit, or horse), or a rodent (e.g., rat and mouse), or a primate (e.g., large Orangutans and monkeys), or domestic animals (for example, dogs and cats).
  • the subjects may be those subjects in need of compound treatment or prevention.
  • the subject may include cancer patients.
  • the subject may have been administered the VEGFR inhibitor and/or the VEGF inhibitor at one time, during and/or in the future.
  • the VEGFR inhibitor and/or VEGF inhibitor may be the VEGFR inhibitor and/or VEGF inhibitor described in the application.
  • the severity of the disease or condition may increase after the administration of the VEGFR inhibitor and/or VEGF inhibitor.
  • the severity of the disease or condition can be increased by about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35 % Or more, about 40% or more, about 45% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or Above, about 200% or more or more.
  • the subject before the administration of the VEGFR inhibitor and/or VEGF inhibitor, the subject may not have the disease or condition.
  • the term "the subject does not suffer from the disease or condition” generally means that the subject has no previous medical history related to the administration of the VEGFR inhibitor and/or VEGF inhibitor related disease or condition .
  • the subject before the administration of the VEGFR inhibitor and/or VEGF inhibitor, the subject has not suffered from this application for more than 1 day, more than 1 week, more than 1 month, more than 1 year, more than 10 years or since the birth of the subject
  • the diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors before the administration of the VEGFR inhibitor and/or VEGF inhibitor, the subject may not have the disease or condition.
  • the VEGFR inhibitor and/or VEGF inhibitor does not include the compound.
  • the VEGFR inhibitor and/or VEGF inhibitor does not contain 1,2-dinitroglycerol and/or 1,3-dinitroglycerol.
  • the term "effective amount” generally refers to the amount of a drug that can alleviate or eliminate the disease or symptom of the subject, or prevent or prevent the occurrence of the disease or symptom prophylactically. Generally, it can be based on the subject’s weight, age, sex, diet, excretion rate, past medical history, current treatment, administration time, dosage form, administration method, administration route, drug combination, and the subject’s health. Conditions and potential for cross-infection, allergies, hypersensitivity and side effects, and/or the degree of development of epithelial (or endothelial) tissue diseases, etc. determine the specific effective amount. A person skilled in the art (for example, a doctor or a veterinarian) can proportionally reduce or increase the dosage according to these or other conditions or requirements.
  • the compound is administered at a concentration of about 0.00001% (w/w) to about 50% (w/w), for example, about 0.00001% (w/w) to about 10% (w/w) /w), about 0.00001% (w/w) to about 9.5% (w/w), about 0.00001% (w/w) to about 9% (w/w), about 0.00001% (w/w) to about 8.5% (w/w), about 0.00001% (w/w) to about 8% (w/w), about 0.00001% (w/w) to about 7.5% (w/w), about 0.00001% (w/w) w) to about 7% (w/w), about 0.00001% (w/w) to about 6.5% (w/w), about 0.00001% (w/w) to about 6% (w/w), about 0.00001 %(W/w) to about 5.5%(w/w), about 0.00001%(w/w) to about 5%(w/w), about 0.00001%(w/
  • the concentration of the compound may be about 0.00001% (w/w) to about 1% (w/w), about 0.00001% (w/w) to about 0.9% (w/w) ), about 0.00001% (w/w) to about 0.6% (w/w), about 0.05% (w/w) to about 0.5% (w/w), about 0.05% (w/w) to about 0.4% (w/w), about 0.05% (w/w) to about 0.3% (w/w), about 0.05% (w/w) to about 0.2% (w/w), about 0.1% (w/w) To about 0.2% (w/w) or less.
  • the concentration of the compound may be about 0.2% (w/w).
  • the concentration of the compound may be about 0.1% (w/w).
  • the subject may include human or non-human animals.
  • the non-human animal may be selected from the group consisting of monkeys, chickens, geese, cats, dogs, mice, and rats.
  • non-human animals may also include any animal species other than humans, such as livestock animals, or rodents, or primates, or domestic animals, or poultry animals.
  • the person can be Caucasian, African, Asian, Semitic, or other races, or a hybrid of various races.
  • the person may be an old person, an adult, a teenager, a child, or an infant.
  • the effective amount in humans can be estimated based on the effective amount in experimental animals.
  • Freireich et al. described the interrelationship of animal and human doses (based on milligrams per square meter of body surface) (Freiheim et al., Cancer Chemother. Rep. 50, 219 (1966)).
  • the body surface area can be approximately determined from the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970).
  • the inhibition of the VEGFR and/or VEGF may be caused by administering the VEGFR inhibitor and/or VEGF inhibitor to the subject.
  • the compound can be administered before, at the same time as, or after the administration of the VEGFR inhibitor and/or VEGF inhibitor to the subject.
  • the VEGFR inhibitor and/or VEGF inhibitor described in the present application are administered simultaneously with the compound, the compound is administered at about 0.00001-10% (e.g., about 0.005-10%, about 0.01-10%, About 0.05-10%, about 0.1-10%, about 0.2-10%, about 0.3-10%, about 0.4-10%, about 0.5-10%, about 0.6-10%, about 0.7-10%, about 0.8 -10%, about 0.9-10%, about 0.95-10%, about 1-10%, about 2-10%, about 3-10%, about 5-10%, about 6-10%, about 8-10 % Or less).
  • the compound and the VEGFR inhibitor and/or VEGF inhibitor are administered at intervals
  • the compound may be administered at intervals before or after administration of the VEGFR inhibitor and/or VEGF inhibitor.
  • the interval time can be 1 minute, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18. Hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer.
  • the administration of the compound is topical administration.
  • the compound is contained in an ointment for administration.
  • the compound is co-administered with one or more other active ingredients.
  • the administration of the compound does not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor.
  • the present application provides a pharmaceutical combination or kit.
  • the pharmaceutical combination or kit may include: 1) a VEGFR inhibitor and/or a VEGF inhibitor; and 2) the compound described in the present application. See the description above for the compounds described in this application.
  • the VEGFR inhibitor and/or VEGF inhibitor and the compound are not mixed with each other.
  • the VEGFR inhibitor and/or VEGF inhibitor and the compound are each independently present in separate containers.
  • the drug combination may include two or more drugs packaged separately from each other, wherein at least one of the drugs includes the VEGFR inhibitor and/or VEGF inhibitor described in the present application, and at least one of them additionally The drug contains the compound described in this application.
  • the compound in 2) can prevent or treat a disease or disorder related to the administration of the VEGFR inhibitor and/or VEGF inhibitor in 1) (for example, the present application The diseases or disorders related to the administration of VEGFR inhibitors and/or VEGF inhibitors).
  • the compound in 2) does not substantially affect the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor in 1).
  • the compound of 2) is administered before, at the same time or after the administration of the VEGFR inhibitor and/or VEGF inhibitor of 1).
  • the "substantially not affecting” may refer to the use of the drug combination or kit in 2) compared with the therapeutic effect of the VEGFR inhibitor and/or VEGF inhibitor alone.
  • the therapeutic effects of the compound and the VEGFR inhibitor and/or VEGF inhibitor in 1) are equivalent, or no significant disadvantage is caused.
  • the degree of tumor volume reduction caused by the VEGFR inhibitor and/or VEGF inhibitor is the same, or the degree of reduction is not less than about 5%, not less than about 4%, not less than about 3%, and 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.
  • the application also provides a method comprising administering a compound to a subject, wherein the subject has been, is and/or will be administered a VEGFR inhibitor and/or a VEGF inhibitor and has or is susceptible to VEGFR inhibitor and/or VEGF inhibitor related diseases or conditions.
  • the application also provides a method for preventing or treating a disease or disorder, comprising administering a compound to a subject susceptible to or suffering from the disease or disorder, wherein the subject has, is, and/or will VEGFR inhibitor and/or VEGF inhibitor are administered.
  • the subject may already have a disease or disorder related to the administration of a VEGFR inhibitor and/or a VEGF inhibitor, or the subject may have a greater probability of suffering from the administration of a VEGFR inhibitor. And/or VEGF inhibitor-related diseases or conditions.
  • the term "susceptible to suffering” generally means that the subject has a greater probability of suffering from the diseases or conditions related to the administration of VEGFR inhibitors and/or VEGF inhibitors.
  • the greater probability may mean that compared with a healthy subject, the probability that a subject suffers from the disease or condition associated with the administration of a VEGFR inhibitor and/or a VEGF inhibitor is increased by approximately at least 10% , At least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200% or more.
  • the application also provides a method for preventing or treating a disease or condition, comprising administering the compound to a subject who is susceptible to or suffering from the disease or condition, wherein the disease or condition is hand-foot syndrome.
  • the subject may have been administered a VEGFR inhibitor and/or a VEGF inhibitor in the past, is currently, and/or in the future.
  • the disease or condition may be hand-foot syndrome.
  • the disease or condition may be a disease or condition associated with the administration of a VEGFR inhibitor and/or a VEGF inhibitor.
  • the disease or condition may be hand-foot syndrome associated with the administration of a VEGFR inhibitor and/or a VEGF inhibitor.
  • the application also provides a method of preventing or treating a disease or condition, comprising administering the compound to a subject susceptible to or suffering from the disease or condition, wherein the disease or condition is related to the administration of a VEGFR inhibitor and / Or VEGF inhibitor-related epithelial cell disease.
  • the application also provides a method, which includes the following steps: 1) monitoring one or more skin tissue, facial features and/or gastrointestinal characteristics of a subject to which a VEGFR inhibitor and/or a VEGF inhibitor is administered; 2) When the monitoring shows that the subject has a skin tissue disease or disorder, a five sense organ disease or disorder, and/or a gastrointestinal disease or disorder related to the administration of the VEGFR inhibitor and/or VEGF inhibitor, The subject administers the compound described in the application
  • the term "skin tissue characteristics" generally refers to characteristics that can reflect skin tissue diseases or disorders.
  • the characteristics may include characteristics that can reflect skin tissue diseases or disorders associated with the administration of the VEGFR inhibitor and/or VEGF inhibitor.
  • the characteristics may include the ability to reflect skin rashes associated with administration of VEGFR inhibitors and/or VEGF inhibitors, hand-foot syndrome associated with administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR inhibitors and/or VEGF.
  • the characteristics may include the area and extent of erythema, the area and extent of purpura, the number and extent of papules, the number and extent of pustules, the number and extent of nodules, the extent and extent of skin swelling, the extent and extent of skin ulcers, the extent of skin dryness, and the extent of chapped skin.
  • the term "features of the five sense organs” generally refers to features that can reflect the five sense organs diseases or disorders.
  • the characteristics may include characteristics capable of reflecting the five sense organ diseases or disorders associated with the administration of the VEGFR inhibitor and/or VEGF inhibitor.
  • the characteristics may include the ability to reflect oral ulcers associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, dry mouth associated with the administration of VEGFR inhibitors and/or VEGF inhibitors, and the administration of VEGFR inhibitors and/or VEGF.
  • the characteristics may include the degree of oral mucosal hyperemia, the degree of oral mucosal edema, the degree of oral mucosal herpes, the degree of oral mucosal ulcers, the degree of oral submucosal peri-glandular defects, the degree of atrophy of salivary glands such as tongue/sublingual glands/parotid glands, mouth Degree of dryness, degree of tooth decay, degree of tongue swelling, degree of tooth marks around the tongue, frequency of nosebleeds, amount of nosebleeds, degree of oropharyngeal and nasopharyngeal mucosal edema, degree of oropharyngeal and nasopharyngeal mucosal herpes, oropharyngeal and
  • the term "gastrointestinal characteristics" generally refers to characteristics that can reflect gastrointestinal diseases or disorders.
  • the characteristics may include characteristics capable of reflecting gastrointestinal diseases or disorders associated with administration of the VEGFR inhibitor and/or VEGF inhibitor.
  • the characteristics may include the ability to reflect esophageal mucositis associated with the administration of a VEGFR inhibitor and/or VEGF inhibitor, gastric mucositis associated with the administration of a VEGFR inhibitor and/or VEGF inhibitor, and the administration of a VEGFR inhibitor and/ Or gastric ulcers related to VEGF inhibitors, diarrhea related to administration of VEGFR inhibitors and/or VEGF inhibitors, vomiting related to administration of VEGFR inhibitors and/or VEGF inhibitors, and administration of VEGFR inhibitors and/or VEGF inhibitors Related nausea, anorexia related to administration of VEGFR inhibitor and/or VEGF inhibitor, constipation related to administration of VEGFR inhibitor and/or VEGF inhibitor, and/or, related to administration of VEG
  • the characteristics may include the degree of appetite loss, the degree of gastric belching, the degree of dysphagia, the degree of post-sternal burning sensation, the degree of post-sternal pain, the time and degree of upper abdominal pain (when fasting or full), the degree of bloating, diarrhea Degree, frequency of bowel movements, time of bowel movements, abdominal pain before stool, tenesmus, stool abnormalities (such as black bloody stools, bloody stools, mucous stools, mucus pus and bloody stools, loose watery stools, egg-flower soup-like stools, etc.), frequency of vomiting, and vomiting , Hematemesis, nausea, malnutrition, and trace element deficiency.
  • the method may also include continuing to monitor the skin tissue disease or disorder, the five sense organs disease or disorder, and/or the gastrointestinal disease or disorder, and optionally reducing or discontinuing the VEGFR inhibitor and/ Or VEGF inhibitor.
  • the continued monitoring may refer to about at least 1 day, at least 1 week, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 3 weeks after administration of the VEGFR inhibitor and/or VEGF inhibitor. Monitor for months or longer.
  • the reduction or discontinuation can point to the subject administering the dose of the VEGFR inhibitor and/or VEGF inhibitor to be lower than the dose of the VEGFR inhibitor and/or VEGF inhibitor in step 1) of the method.
  • the reduction is about at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% or 100%.
  • the severity of the disease or condition related to the administration of the VEGFR inhibitor and/or VEGF inhibitor may increase after the administration of the VEGFR inhibitor and/or VEGF inhibitor.
  • the severity can be an increase of at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more. many.
  • the subject before the administration of the VEGFR inhibitor and/or VEGF inhibitor, the subject may not have the disease or condition.
  • the VEGFR inhibitor and/or VEGF inhibitor may not include the compound.
  • the VEGFR inhibitor and/or VEGF inhibitor may not contain nitroglycerin.
  • the disease or disorder may be an epithelial tissue disease or disorder.
  • the administration of the VEGFR inhibitor and/or VEGF inhibitor can be used to treat cancer.
  • the affected area of the disease or condition may be different from the affected area of cancer.
  • the compound may be administered topically to the subject.
  • the compound can be administered locally to a site in the subject that is substantially free of cancer cells.
  • a site substantially free of cancer cells generally refers to a tissue, organ or site where the content of cancer cells in a subject is so low that it is considered substantially free of cancer cells.
  • the "substantially free” may mean that the number of cancer cells accounts for less than 0.01% of the total number of cells in the site, for example, less than 0.005%, less than 0.001%, less than 0.0001%, less than 0.00001% or less.
  • the compound can be administered to a non-cancer site in the subject.
  • non-cancer site generally refers to a site in a subject that is not a cancerous lesion and a non-cancer metastasis area.
  • the cancer lesion may be the primary site of cancer.
  • the cancer metastasis area may be an area where a tumor of the same type as the primary site tumor is located.
  • the cancer metastasis area may be formed by lymphatic metastasis, vascular metastasis, or implanted metastasis.
  • ** means P ⁇ 0.01; * means P ⁇ 0.05; *** means P ⁇ 0.001, using t-test statistical test.
  • Example 1-34 The compounds described in this application (1,2-dinitroglycerol, 1,3-dinitroglycerol) alleviate the immortalization of VEGF/VEGFR inhibitors on human umbilical vein endothelial cells (HUVEC) and humans The cytotoxic effect of epidermal cells (HaCaT), human oral mucosal epithelial keratinocytes (HOK), gastric epithelial cells (GES-1), and human small intestinal epithelial cells (FHs 74Int)
  • Examples 1-10 use human umbilical vein endothelial cells (HUVEC), the results correspond to Table 1, and Examples 11-16 use human immortalized epithelial cells (HaCaT), the results correspond to the table 2; Examples 17-22 use human oral mucosal epithelial keratinocytes (HOK), the results correspond to Table 3; Examples 23-28 use gastric epithelial cells (GES-1), the results correspond to Table 4; Examples 29-34 use human Small intestinal epithelial cells (FHs 74Int), the results correspond to Table 5.
  • HaCaT human immortalized epithelial cells
  • HaCaT human immortalized epithelial cells
  • HOK human oral mucosal epithelial keratinocytes
  • Examples 23-28 use gastric epithelial cells (GES-1), the results correspond to Table 4;
  • Examples 29-34 use human Small intestinal epithelial cells (FHs 74Int), the results correspond to Table 5.
  • each well contains basal medium, and the final liquid volume in each well is about 100 ⁇ L.
  • the specific grouping situation is as follows:
  • VEGF/VEGFR inhibitor group add VEGF/VEGFR inhibitor solution (the final concentration is shown in Table 1 to Table 5, and the solvent of the VEGF/VEGFR inhibitor solution is DMSO);
  • VEGF/VEGFR inhibitor + the compound group described in the application add the VEGF/VEGFR inhibitor solution and the compound solution described in the application (the final concentration of the VEGF/VEGFR inhibitor and the compound described in the application is shown in Table 1 to Table 5.
  • the solvent of the compound solution described in the present application is selected as ethanol or sterile water, and the slight difference in the total volume of each group is supplemented by adding the selected corresponding solvent);
  • VEGF/VEGFR inhibitor solvent group add an equal volume of DMSO corresponding to the VEGF/VEGFR inhibitor solution contained in the VEGF/VEGFR inhibitor solution in group 2);
  • the compound solvent control group of the present application add the same volume and the same type of solvent (for example, ethanol or sterile water) contained in the compound of the present application corresponding to the group 3).
  • solvent for example, ethanol or sterile water
  • the VEGF/VEGFR inhibitor solvent group does not participate in data processing, and is only used as a reference for evaluating experimental system errors.
  • the data of the compound solvent control group described in this application is corrected to eliminate the influence of the solvent on the results.
  • the Cell Counting Kit-8 (CCK-8) Detection Kit (C0037, Shanghai Biyuntian Biotechnology Co., Ltd., Beyotime Biotechnology) was used to determine the survival rate of the cells to calculate the effect of VEGF/VEGFR inhibitors on the cells. Proliferation toxicity and the mitigation effect of the compounds described in this application on proliferation toxicity. Use GraphPad Prism 6.0 software, t test to perform statistical analysis and drawing of the results.
  • Tables 1 to 5 list the combinations of various VEGF/VEGFR inhibitors and the compounds described in this application, as well as the corresponding experimental results (wherein, the data in the cell viability column indicates that compared with the VEGF/VEGFR inhibitor group, Corresponding VEGF/VEGFR inhibitor + the percentage of surviving cells increased by the compound group described in this application).
  • Figure 1 shows the experimental results on HUVEC cells
  • Figure 2 shows the experimental results on HaCaT cells
  • Figure 3 shows the experimental results on HOK cells
  • Figure 4 shows the experimental results on GES-1 cells
  • Figure 5 shows the experimental results on FHs 74Int cells. Experimental results.
  • the abscissas are the control group and different experimental groups
  • the control group is the blank control group
  • the experimental groups are the VEGF/VEGFR inhibitor group (shown as “V2 10 ⁇ M” on the abscissa in Figure 1), VEGF/VEGFR inhibition Agent + 1,2-dinitroglycerin group (shown as "V2+1,2-dinitroglycerin” in the abscissa of Figure 1) and VEGF/VEGFR inhibitor + 1,3-dinitroglycerin group ( As shown in Figure 1 on the abscissa "V2+1,3-Dinitroglycerol"); the ordinate shows the survival rate of cells (the cell survival rate of the blank control group is 100% calculated in other experimental groups or solvent control groups Percentage of cell survival).
  • Figures 1A-1E all show exemplary results of cell proliferation and toxicity measured by the CCK-8 method 24 hours after administering VEGF/VEGFR inhibitors and the compounds described in this application to HUVEC cells;
  • Figures 2A-2C all show the effects on HaCaT Exemplary results of cell proliferation toxicity measured by the CCK-8 method 24 hours after the cells were administered the VEGF/VEGFR inhibitor and the compound described in the present application;
  • Figures 3A-3C all show the administration of the VEGF/VEGFR inhibitor and the present invention to HOK cells 24 hours after the application of the compound, exemplary results of cell proliferation toxicity determined by the CCK-8 method;
  • Figures 4A-4C all show the 24 hours of administration of the VEGF/VEGFR inhibitor and the compound of the application to GES-1 cells After that, the exemplary results of cell proliferation toxicity determined by the CCK-8 method;
  • Figures 5A-5C all show that 24 hours after the administration of the VEGF/VEGFR inhibitor and the compound described in the present application to
  • *** means P ⁇ 0.001, which is significantly different from the corresponding VEGF/VEGFR inhibitor alone administration group; ** means P ⁇ 0.01, which has a significant difference compared with the corresponding VEGF/VEGFR inhibitor alone administration group Significant difference; * means P ⁇ 0.05, which is significantly different from the corresponding VEGF/VEGFR inhibitor alone administration group; t-test statistical test is used.
  • VEGF/VEGFR inhibitors have proliferative toxicity to human umbilical vein endothelial cells (HUVEC), while the compounds described in this application have proliferative toxicity to VEGF/VEGFR inhibitors. There is an obvious relief effect.
  • VEGF/VEGFR inhibitors have proliferative toxicity to skin cells (HaCaT), while the compounds described in this application can significantly alleviate the proliferative toxicity caused by VEGF/VEGFR inhibitors. effect.
  • VEGF/VEGFR inhibitors have proliferative toxicity to human oral mucosal epithelial keratinocytes (HOK), while the compounds described in this application have proliferative toxicity to VEGF/VEGFR inhibitors. There is an obvious relief effect.
  • VEGF/VEGFR inhibitors have proliferative toxicity to human gastric epithelial cells (GES-1), while the compounds described in this application have proliferative toxicity to VEGF/VEGFR inhibitors. There is an obvious relief effect.
  • VEGF/VEGFR inhibitors have proliferative toxicity to human small intestinal epithelial cells (FHs 74Int), while the compounds described in this application have proliferative toxicity to VEGF/VEGFR inhibitors. Obvious relief effect.
  • Example 35-40 Determination of the effect of the compound described in this application on the level of nitric oxide in cells
  • Figure 6 shows the relative nitric oxide in HUVEC cells after 6 hours, 12 hours, 24 hours, and 48 hours after administration of the compounds (1,2-dinitroglycerol, 1,3-dinitroglycerol) described in the present application.
  • Content Figures 7-8 respectively show the relative content of nitric oxide in GES-1 cells and HaCaT cells after 24 hours of treatment with the compounds described in this application.
  • the control group is a basic medium, reflecting the physiological level.
  • *** means P ⁇ 0.001, which is significantly different from the corresponding control group
  • ** means P ⁇ 0.01, which is significantly different from the corresponding control group
  • * means P ⁇ 0.05, which is significantly different from the corresponding control group Compared with significant difference; use t-test statistical test.
  • Examples 41-50 The compounds described in this application can prevent/treat hand-foot syndrome caused by small molecule VEGFR/VEGF inhibitors in vivo
  • a rat animal model was constructed, and 8-week female SD rats were given the small molecule VEGFR/VEGF inhibitors shown in Table 7 by daily gavage. After several days, the paws of the rats showed symptoms of hand-foot syndrome ( As shown in Figure 9). Similar to humans, rats will develop hand-foot syndrome symptoms after taking the VEGFR/VEGF inhibitor, and the symptoms are very similar. Therefore, the rat is a good animal model for simulating the side effects (such as hand-foot syndrome) caused by VEGFR/VEGF inhibitors.
  • the rats (approximately 200 g) were reared and adapted for one week, they were divided into groups, 10 rats in each group, and an oral administration test was performed.
  • Dissolve various small molecule VEGFR/VEGF inhibitors in a mixed solution of castor oil: ethanol 1:1, dilute the VEGFR/VEGF inhibitor drug solution with PBS to the required concentration before gavage (dilute with PBS solution) About 3 times), the amount of gavage each time does not exceed 2 mL, and the dosage is shown in Table 7.
  • the rate of formation of anticancer drugs is not fixed: the completion rate of hand-foot syndrome models in each group is 30%-70%, that is, about 3-7 out of 10 mice have hand-foot syndrome models, which is larger in different drug groups. In the process of realizing the hand and foot model, some rats died or the model was unsuccessful.
  • the control rate refers to the proportion of rats whose paws on the coated side were lighter than those on the uncoated side of the rats in which the experimental group had established a hand-foot syndrome model.
  • Figure 10 shows that after a typical rat in the administration group of Examples 41-48 has been applied with the left paw (the compound ointment described in this application), the hand-foot syndrome of the left paw has been significantly alleviated;
  • Figure 11 shows After a typical rat in the administration group of Examples 49-50 was coated with the right paw (the compound ointment described in this application), the hand-foot syndrome of the right paw was also significantly relieved.
  • Examples 51-52 The compounds described in this application can prevent/treat hand-foot syndrome caused by protein macromolecule VEGFR/VEGF inhibitors in vivo
  • Dilute ramucirumab or Bevacizumab with saline to the desired concentration.
  • rats approximately 200 g
  • they were divided into groups, each with 10 rats, and the injection administration test was performed.
  • the diluted ramucirumab was infused intravenously for 60 minutes at a dose of 40 mg/kg, once a week, with paclitaxel (10 mg/kg).
  • the rate of formation of anticancer drugs is not fixed: the completion rate of hand-foot syndrome models in each group is 10%-30%, that is, about 1-3 out of 10 mice have hand-foot syndrome models, and different drug groups are larger. In the process of realizing the hand and foot model, some rats died or the model was unsuccessful.
  • the control rate refers to the proportion of rats whose paws on the coated side were lighter than those on the uncoated side of the rats in which the experimental group had established a hand-foot syndrome model.
  • Figure 10 shows the left paw, front and right paws of a typical rat in the administration group of Examples 51-52 after the left paw is coated (the compound ointment described in this application).
  • Examples 53-58 Experiments to verify the treatment of small molecule VEGFR/VEGF inhibitors to produce hand-foot syndrome in a rat animal model
  • the rats were divided into groups of 10, and an intragastric administration test was performed.
  • Dissolve the VEGFR/VEGF inhibitor in a mixed solution of castor oil: ethanol 1:1, dilute with PBS to the desired concentration before gavage (diluted with PBS solution about 3 times), the gavage volume does not exceed 2 mL, and administer The dosage is shown in Table 9.
  • the intragastric administration of VEGFR/VEGF inhibitors was continued every day until the rats developed hand-foot syndrome, at which time treatment experiments were started on the rats. During the treatment experiment, continuous low-frequency intragastric administration of VEGFR/VEGF inhibitors (the frequency of intragastric administration is as described in Table 9).
  • the left paw (palm and paw gap) of the rat was coated with the compound described in this application Ointment (about 0.05g), the right paw was used as a blank control without applying the medicine. After applying the medicine, it was fixed in a fixed cylinder for 4 hours. After 4 hours, the rats were released, and the residual medicine was wiped off the application site with clean water, and the rats were returned to the cage.
  • the frequency of intragastric administration of VEGFR/VEGF inhibitors is shown in Table 9, but the compound ointment described in this application is only applied once a day. After 5-6 days of application, the number of rats whose side paws with the drug had returned to normal or was significantly lighter than those on the side paws without the drug was counted as the number of rats with effective treatment of hand-foot syndrome.
  • the rate of formation of anticancer drugs is not fixed: the completion rate of hand-foot syndrome models in each group is 40%-70%, that is, about 4-7 out of 10 mice have hand-foot syndrome models, which is larger in different drug groups. In the process of realizing the hand and foot model, some rats died or the model was unsuccessful.
  • the control rate refers to the proportion of rats whose paws on the coated side were lighter than those on the uncoated side of the rats in which the experimental group had established a hand-foot syndrome model.
  • Figure 12 shows the conditions of the left paw, front and right paws of a typical rat in the administration group of Examples 53-56 after the left paw (the compound ointment described in this application) is applied.
  • Figure 13 shows the conditions of the left and right paws of a typical rat in the administration group of Examples 57-58 after being coated with the right paw (the compound ointment described in this application).

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Abstract

L'invention concerne une nouvelle utilisation d'un composé nitro dans la préparation de médicaments. Les médicaments sont utilisés pour prévenir ou traiter des maladies ou des troubles associés à l'administration d'un inhibiteur du VEGFR et/ou d'un inhibiteur du VEGF. L'invention concerne également une combinaison pharmaceutique ou un kit comprenant le composé et destiné à prévenir ou traiter des maladies associées à l'administration de l'inhibiteur du VEGFR et/ou de l'inhibiteur du VEGF. L'invention concerne en outre une méthode de prévention ou de traitement d'une maladie ou d'un trouble, comprenant le suivi de caractéristiques d'un ou plusieurs éléments parmi les tissus cutanés, les traits du visage et/ou les caractéristiques gastro-intestinales d'un sujet auquel l'inhibiteur du VEGFR et/ou l'inhibiteur du VEGF est/sont administré/s, et l'administration du composé au sujet lorsque l'on s'aperçoit qu'une maladie ou un trouble apparaît.
PCT/CN2020/120916 2019-10-16 2020-10-14 Méthode de prévention ou de traitement de maladies associées à l'administration d'un inhibiteur du vegfr et/ou du vegf WO2021073535A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006054110A2 (fr) * 2004-11-22 2006-05-26 Stanford Rook Limited Agent immunotherapeutique
EP2805730A1 (fr) * 2013-05-21 2014-11-26 Bergen Teknologioverforing AS Donneurs d'oxyde nitrique pour le traitement du syndrome de fatigue chronique
WO2014197847A1 (fr) * 2013-06-07 2014-12-11 The Regents Of The University Of California Procédés et systèmes de traitement de plaies
WO2019201195A1 (fr) * 2018-04-16 2019-10-24 上海岸阔医药科技有限公司 Méthode pour prévenir ou traiter les effets secondaires d'une cancérothérapie

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Publication number Priority date Publication date Assignee Title
WO2006054110A2 (fr) * 2004-11-22 2006-05-26 Stanford Rook Limited Agent immunotherapeutique
EP2805730A1 (fr) * 2013-05-21 2014-11-26 Bergen Teknologioverforing AS Donneurs d'oxyde nitrique pour le traitement du syndrome de fatigue chronique
WO2014197847A1 (fr) * 2013-06-07 2014-12-11 The Regents Of The University Of California Procédés et systèmes de traitement de plaies
WO2019201195A1 (fr) * 2018-04-16 2019-10-24 上海岸阔医药科技有限公司 Méthode pour prévenir ou traiter les effets secondaires d'une cancérothérapie

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