WO2023138574A1 - Composition médicamenteuse d'oxyde de spiro aryl phosphine et d'anticorps anti-vegf - Google Patents

Composition médicamenteuse d'oxyde de spiro aryl phosphine et d'anticorps anti-vegf Download PDF

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WO2023138574A1
WO2023138574A1 PCT/CN2023/072599 CN2023072599W WO2023138574A1 WO 2023138574 A1 WO2023138574 A1 WO 2023138574A1 CN 2023072599 W CN2023072599 W CN 2023072599W WO 2023138574 A1 WO2023138574 A1 WO 2023138574A1
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lung cancer
formula
compound
vegf
pharmaceutical composition
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PCT/CN2023/072599
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English (en)
Chinese (zh)
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郑善松
郑庆梅
董欣
王新美
陈冬妹
段会成
马翠翠
张臣伟
赵树雍
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齐鲁制药有限公司
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry and relates to a combined pharmaceutical composition for treating tumors. Specifically, the present invention relates to the drug combination of spirocyclic aryl phosphorus oxide and antibody and its use in the preparation of antitumor drugs.
  • Anaplastic lymphoma kinase is a receptor tyrosine kinase (RTK) and a member of the insulin receptor (IR) superfamily.
  • ALK was first discovered in 60-80% of anaplastic large cell lymphoma (ALCLS) cell lines in the form of fusion protein NPM (nucleophosmin)-ALK. NPM-ALK was caused by t(2;5) chromosome translocation.
  • ALK fusion proteins have been identified in various human cancers such as breast cancer, colorectal cancer, inflammatory myofibroblastic tumor (IMT), diffuse large B-cell lymphoma (DLBCL), and most notably in non-small cell lung cancer (NSCLC). Therefore, the kinase activity associated with ALK fusion proteins is considered to play a very important role in the survival and proliferation of human cancer cells.
  • IMT inflammatory myofibroblastic tumor
  • DLBCL diffuse large B-cell lymphoma
  • NSCLC non-small cell lung cancer
  • the ALK gene provides a signaling instruction for receptor tyrosine kinases to transmit signals from the cell surface into the cell. This process begins when a kinase is stimulated at the cell surface and then attaches to a similar kinase (dimerization). After dimerization, the kinase is tagged with a phosphate group, a process called phosphorylation. Phosphorylation-activated kinase, an activated kinase is another protein capable of transferring a phosphate group into the cell, activating a series of proteins that continue through the signaling pathway. These signaling pathways are important for many cellular processes, such as cell growth and division (proliferation) or maturation (differentiation).
  • ALK is rearranged such that the tyrosine kinase domain of ALK is fused to the 5′-terminal domain of another protein, such as echinoderm microtubule-associated protein-like 4 (EML4) in NSCLC or nucleophosphoprotein (NPM) in anaplastic large cell lymphoma.
  • EML4 echinoderm microtubule-associated protein-like 4
  • NPM nucleophosphoprotein
  • the 5'-end of the fusion protein usually contains a coiled-coil or leucine zipper domain, which oligomerizes the fusion protein and leads to ligand-dependent activation of the ALK tyrosine kinase. This in turn constitutively activates downstream signaling pathways such as Ras/MAPK, PI3K/AKT, and JAK/STAT.
  • ALK-driven lung cancers respond and regress following treatment with ALK small-molecule tyrosine kinase inhibitors. This finding demonstrates "oncogene dependency," whereby cancer cells become dependent on oncogenic driver genes and are thus highly sensitive to suppressing oncogenes.
  • Crizotinib is the first ALK inhibitor approved by the FDA for the treatment of ALK-positive lung cancer. Although patients initially responded very well to crizotinib therapy, most patients relapsed during the first year of treatment due to the development of drug resistance. In April 2014, the FDA approved Ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), including patients who are effective and resistant to crizotinib. However, drug resistance always occurs with the prolongation of treatment time, so that the drug loses its effectiveness.
  • ALK anaplastic lymphoma kinase
  • NSCLC metastatic non-small cell lung cancer
  • Spirocyclic aryl phosphine oxide chemical name: (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, is a novel ALK/ROS1 inhibitor for the treatment of ALK/ROS1 positive non-small cell lung cancer. It has the following structural formula:
  • the compound of formula I inhibits the phosphorylation of ALK by inhibiting the activation of ALK kinase, thereby preventing the phosphorylation of downstream signaling molecules, Such as ERK, STAT5 and AKT.
  • the compound of formula I inhibits the activation of ROS1 by inhibiting the phosphorylation of ROS1 fusion kinase, thereby preventing the phosphorylation of downstream signaling molecules such as ERK or AKT.
  • patent WO2016/000581 discloses spirocyclic aryl phosphorus oxides as ALK inhibitors
  • patent CN106928275 discloses the preparation method and intermediates of spirocyclic aryl phosphorus oxides
  • patent CN110407877 discloses polymorphic forms of spirocyclic aryl phosphorus oxides.
  • VEGF vascular endothelial growth factor
  • Angiogenesis is an extremely complex process that requires the participation of vasculature, circulating endothelial cells, and pro-angiogenic mediators including VEGF.
  • VEGF/VEGFR is an important signal transduction pathway.
  • VEGF combines with VEGFR-1 and VEGFR-2 expressed in tissue epithelial cells to activate intracellular signal transduction pathways, leading to vascular endothelial cell proliferation and neovascularization.
  • the expression of VEGF is related to the progression, stage, ascites formation, shortened disease-free survival time and poor prognosis of malignant tumors. Immunohistochemical examination found that VEGF was expressed in the tumor and its metastatic tissues, and could be detected in malignant ascites and serum.
  • the expression of VEGF and VEGFR detected in tumor patients is an independent prognostic factor.
  • Bevacizumab (AVASTIN ® ) is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody that can bind to VEGF-A, inhibit its binding to VEGF receptor-2 (VEGFR-2), and then inhibit the biological effects of VEGF, including affecting the permeability and proliferation of blood vessels, as well as the migration and survival of endothelial cells, so as to inhibit tumor angiogenesis, growth and metastasis.
  • IgG1 humanized immunoglobulin G1
  • bevacizumab Compared with single administration, the combination of bevacizumab and chemotherapy drugs can improve the anti-tumor efficacy, which may benefit from the fact that bevacizumab can reduce the pressure of intratumoral tissue space, thereby enhancing the penetration of chemotherapy drugs inside the tumor.
  • bevacizumab has been widely used in the treatment of colorectal cancer, lung cancer, ovarian cancer, cervical cancer, glioblastoma and other tumors worldwide.
  • the purpose of the present invention is to provide a combination pharmaceutical composition, which comprises ALK inhibitor and anti-VEGF antibody.
  • the combined pharmaceutical composition of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as an ALK inhibitor, and an anti-VEGF antibody.
  • the anti-VEGF antibody in the above combined pharmaceutical composition is bevacizumab.
  • the bevacizumab in the above-mentioned combination pharmaceutical composition may be AVASTIN ® , Agoda ® .
  • the above-mentioned combined pharmaceutical composition is a non-fixed combination.
  • the anti-VEGF antibody and the compound of Formula I, or a pharmaceutically acceptable salt thereof, in the non-fixed combination are each in the form of a pharmaceutical composition.
  • a kit of a combined pharmaceutical composition for treating lung tumors which contains (a) a first pharmaceutical composition comprising an anti-VEGF antibody; and (b) a second pharmaceutical composition comprising a compound of formula I as an active ingredient.
  • the present invention also provides an application of a combined pharmaceutical composition in the preparation of a drug for treating and/or preventing lung cancer, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an ALK inhibitor, and an anti-VEGF antibody.
  • the anti-VEGF antibody in the above use is bevacizumab.
  • bevacizumab (bevacizumab) in the above-mentioned application can be
  • the anti-VEGF antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above application are each in the form of a pharmaceutical composition.
  • the lung cancer in the above application is positive for ALK and/or ROS1 fusion gene.
  • the lung cancer mentioned in the above application is early-middle stage, locally advanced, advanced metastatic non-small cell lung cancer.
  • the lung cancer in the above application is early-middle stage, locally advanced, advanced metastatic non-small cell lung cancer that is positive for ALK and/or ROS1 fusion gene.
  • the lung cancer in the above application is non-small cell lung cancer that has not been treated with ALK and/or ROS1 inhibitors or failed to be treated with ALK and/or ROS1 inhibitors.
  • the non-small cell lung cancer in the above application is adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma or large cell carcinoma.
  • the anti-VEGF antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above application are each in the form of a pharmaceutical composition, and can be administered simultaneously, sequentially or at intervals.
  • the invention also provides a method for treating a subject suffering from cancer or tumor comprising administering to said subject a therapeutically effective amount of an ALK inhibitor and a therapeutically effective amount of an anti-VEGF antibody.
  • the ALK inhibitor in the above treatment method is a spirocyclic aryl phosphorus oxide represented by formula I.
  • the anti-VEGF antibody in the above method of treatment is bevacizumab.
  • bevacizumab (bevacizumab) in the above-mentioned treatment method can be any known treatment method.
  • the anti-VEGF antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above treatment methods are each in the form of a pharmaceutical composition.
  • the lung cancer in the above treatment method is positive for ALK and/or ROS1 fusion gene.
  • the lung cancer mentioned in the above treatment method is early-middle stage, locally advanced, advanced metastatic non-small cell lung cancer.
  • the lung cancer described in the above treatment method is ALK and/or ROS1 fusion gene-positive early-middle stage, locally advanced, advanced metastatic non-small cell lung cancer.
  • the lung cancer in the above treatment method is non-small cell lung cancer that has not been treated with an ALK/ROS1 inhibitor or failed to be treated with an ALK/ROS1 inhibitor.
  • the non-small cell lung cancer in the above treatment method is adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma or large cell carcinoma.
  • the anti-VEGF antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above treatment method are each in the form of a pharmaceutical composition, and can be administered simultaneously, sequentially or at intervals.
  • the present invention also provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof for treating lung cancer, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is used in combination with an anti-VEGF antibody.
  • the present invention also provides the use of an anti-VEGF antibody for treating lung cancer.
  • the anti-VEGF antibody is used in combination with the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the anti-VEGF antibody for the above uses is selected from bevacizumab.
  • the bevacizumab used above can be any bevacizumab used above.
  • the present invention also provides a pharmaceutical pack comprising a single packaged pharmaceutical composition in separate containers, comprising a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof in one container, and comprising a pharmaceutical composition comprising an anti-VEGF antibody in a second container.
  • compositions of compounds of formula I can be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like. Oral administration is preferred, eg as a tablet.
  • the dosage of the pharmaceutical composition of the compound of formula I is 60 mg/time to 180 mg/time, or the dosage is 90 mg/time to 180 mg/time.
  • the pharmaceutical composition of the compound of formula I is administered about 60 mg-180 mg; or 90 mg-180 mg each time.
  • the pharmaceutical composition of the compound of formula I is about 60 mg to 180 mg; or 90 mg to 180 mg.
  • the compound of formula I is a spirocyclic aryl phosphorus oxide with a chemical name of (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, which is a newly developed highly selective anaplastic lymphoma kinase (ALK) inhibitor, which has the following structural formula:
  • patent WO2016/000581 discloses spirocyclic aryl phosphorus oxides as ALK inhibitors
  • patent CN106928275 discloses the preparation method and intermediates of spirocyclic aryl phosphorus oxides
  • patent CN110407877 discloses polymorphic forms of spirocyclic aryl phosphorus oxides.
  • bevacizumab is an anti-VEGF antibody, and its sequence and structure can be found in document WO1998/045331.
  • NMPA National Medical Products Administration
  • NSCLC non-small cell lung cancer
  • bevacizumab is an anti-VEGF antibody, and its sequence and structure can be found in document WO1998/045331.
  • NMPA National Medical Products Administration
  • NSCLC metastatic or recurrent non-small cell lung cancer
  • NSCLC metastatic colorectal cancer
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • antibody refers to a binding protein having at least one antigen binding domain.
  • Antibodies and fragments thereof of the present invention may be whole antibodies or any fragments thereof. Accordingly, the antibodies and fragments of the invention include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein can be of the IgG1, IgG2, IgG3 or IgG4 isotype.
  • humanized antibody refers to an antibody in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may contain substitutions in the framework regions such that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.
  • mAb refers to an antibody molecule of single molecular composition. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope, or, in the case of bispecific monoclonal antibodies, dual binding specificities for two different epitopes. A mAb is an example of an isolated antibody. mAbs can be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.
  • VEGF refers to the 165 amino acid human vascular endothelial growth factor and related 121, 145, 189, and 206 amino acid human vascular endothelial growth factors, e.g., as described by Leung et al. Science, 246:1306 (1989), and Houck et al., Mol. Its naturally occurring allelic and processed forms.
  • VEGF-A is part of a gene family that includes VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and P1GF.
  • VEGF-A mainly binds to two high-affinity receptor tyrosine kinases VEGFR-1 (F1t-1) and VEGFR-2 (F1k-1/KDR), which is the main transmitter of VEGF-A mitotic signal in vascular endothelial cells. Additionally, neuropilin-1 has been identified as a receptor for the heparin-binding isoform of VEGF-A and may play a role in vascular development.
  • the term "VEGF” or "VEGF-A” also refers to VEGFs from non-human species such as mice, rats or primates. Sometimes, VEGF from a particular species is indicated by a term, such as hVEGF for human VEGF or mVEGF for murine VEGF.
  • VEGF refers to human VEGF.
  • the term "VEGF” is also used to refer to truncated forms or fragments of polypeptides comprising amino acids 8-109 or 1-109 of the 165 amino acid human vascular endothelial growth factor. References to any of said forms of VEGF can be identified in the present invention, for example, by "VEGF(8-109)", “VEGF(1-109)” or “VEGF165". Amino acid positions for "truncated" native VEGF are numbered as indicated in the native VEGF sequence.
  • anti-VEGF antibody refers to an antibody that binds VEGF with sufficient affinity and specificity.
  • the antibody selected typically has a binding affinity for VEGF, eg, the antibody can bind hVEGF with a Kd value from 1 pM to 100 nM.
  • antibody affinity can be determined by surface plasmon resonance-based assays such as the BIAcore assay described in PCT Publication WO2005/012359; by enzyme-linked immunosorbent assays (ELISA); and competition assays such as RIA's.
  • the anti-VEGF antibodies of the invention can be used as therapeutic agents in targeting and interfering with diseases or disorders in which VEGF activity is implicated.
  • the antibodies can be tested for other biological activities, eg, to assess their efficacy as therapeutic agents.
  • Such assays are known in the art and depend on the target antigen and the intended application of the antibody. Examples include HUVEC inhibition assays; Tumor cell growth inhibition assays (eg, described in WO89/06692); antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) assays (eg, patent US 5,500,362); and agonist activity or hematopoietic assays (see WO95/27062).
  • Anti-VEGF antibodies generally do not bind other VEGF homologues, such as VEGF-B or VEGF-C, nor do they bind other growth factors, such as P1GF, PDGF, or bFGF.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a disease in a patient, including: (a) preventing the disease or symptom in a patient susceptible to the disease or symptom but not yet diagnosed with the disease; (b) inhibiting the symptom of the disease, i.e. preventing its development; or (c) relieving the symptom of the disease, i.e. causing regression of the disease or symptom.
  • the term "subject” refers to mammals, such as rodents, felines, canines, and primates.
  • the subject of the invention is a human.
  • administering means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration for anti-VEGF antibodies include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, eg, by injection or infusion.
  • parenteral administration refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation.
  • the anti-VEGF antibody is administered non-parenterally, and in certain embodiments, orally.
  • non-parenteral routes include topical, epidermal or mucosal routes of administration, eg, intranasal, vaginal, rectal, sublingual or topical. Administration can also be performed, eg, once, multiple times, and/or over one or more extended periods of time.
  • subject includes any human or non-human animal.
  • non-human animal includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
  • the subject is a human.
  • subject and patient are used interchangeably in certain contexts herein.
  • a “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is any amount of the drug which, when used alone or in combination with another therapeutic agent, protects a subject from disease onset or promotes regression of disease as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or prevention of impairment or disability resulting from disease affliction.
  • the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predicting efficacy in humans, or by measuring the activity of the agent in in vitro assays.
  • a therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of drug that inhibits the onset or recurrence of cancer when administered alone or in combination with an antineoplastic agent to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of cancer recurrence.
  • the prophylactically effective amount completely prevents the occurrence or recurrence of cancer.
  • “Inhibiting" the occurrence or recurrence of cancer means reducing the likelihood of the occurrence or recurrence of cancer, or preventing the occurrence or recurrence of cancer altogether.
  • recurrent cancer is cancer that regenerates at the original site or at a distant site after a response to initial treatment (eg, surgery).
  • a "locally recurrent” cancer is one that, after treatment, arises in the same location as a previously treated cancer.
  • metalstatic cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.
  • fixed combination means that the active ingredients (eg, anti-VEGF antibody or compound of formula I) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.
  • active ingredients eg, anti-VEGF antibody or compound of formula I
  • non-fixed combination means that two or more active components are administered to a subject simultaneously, concurrently or sequentially as independent entities (eg, pharmaceutical composition, preparation) without specific time limit, wherein the active components administered to the subject reach a therapeutically effective level.
  • examples of non-fixed combinations are cocktail therapy, eg administration of 3 or more active ingredients.
  • the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions.
  • the "non-fixed combination” also includes the combined use of "fixed combinations" or independent entities of any one or more active components.
  • pharmaceutical composition refers to one or more active ingredients of the present application (such as anti-VEGF antibody or compound of formula I) or its drug A mixture of drug combination and pharmaceutically acceptable excipients.
  • active ingredients of the present application such as anti-VEGF antibody or compound of formula I
  • pharmaceutical composition is to facilitate administration of a compound of the present application, or a pharmaceutical combination thereof, to a subject.
  • the term "synergistic effect” means that two or more ingredients (eg, anti-VEGF antibody or compound of formula I) produce an effect (eg, inhibition of lung cancer growth) that is greater than the simple additive effect of the ingredients administered alone.
  • the components in the combined drug combination of the present invention can be formulated separately.
  • the components in the combination pharmaceutical composition of the present invention can be formulated into a pharmaceutical composition suitable for single or multiple administration.
  • the components in the combined pharmaceutical composition of the present invention can be administered alone, or part or all of them can be administered together.
  • the components in the combined pharmaceutical composition of the present invention may be administered substantially differently, or part or all of them may be administered substantially simultaneously.
  • the components in the combined pharmaceutical composition of the present invention can be administered independently, or part or all of them together, in various suitable routes, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes).
  • the components of the combined pharmaceutical composition of the present invention can be administered independently, or part or all of them can be administered together orally or by injection, such as intravenous injection or intraperitoneal injection.
  • the components in the combined pharmaceutical composition of the present invention can be each independently, or some or all of them can be suitable dosage forms together, including, but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and dosage forms of sustained release preparations for oral or parenteral administration.
  • suitable dosage forms including, but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and dosage forms of sustained release preparations for oral or parenteral administration.
  • the components in the combined pharmaceutical composition of the present invention may be each independently, or part or all of them together contain pharmaceutically acceptable carriers and/or excipients.
  • the combination pharmaceutical compositions of the present invention may also contain additional therapeutic agents.
  • the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a lung cancer therapeutic agent.
  • the curative effect of the compound of formula I and anti-VEGF antibody alone or in combination on lung tumors was also investigated.
  • the compound of formula I had an obvious synergistic effect with the anti-VEGF antibody, breaking the established immune tolerance of the body to tumor cells.
  • Figure 1 shows the human lung cancer LU-01-1443 xenograft model tumor-bearing mice administered formula I compound, bevacizumab And formula I compound and bevacizumab Weight change after joint;
  • Figure 2 shows the human lung cancer LU-01-1443 xenograft model tumor-bearing mice administered formula I compound, bevacizumab And formula I compound and bevacizumab Relative body weight change after combination;
  • Figure 3 shows the human lung cancer LU-01-1443 xenograft model tumor-bearing mice administered formula I compound, bevacizumab And formula I compound and bevacizumab Tumor growth curve after combination;
  • Figure 4 shows the human lung cancer LU-01-1443 xenograft model tumor-bearing mice administered formula I compound, bevacizumab And formula I compound and bevacizumab Relative tumor growth curves after combination.
  • Example 1 In vivo efficacy of spirocyclic aryl phosphine oxides in combination with bevacizumab
  • the purpose of this experiment is to evaluate the in vivo efficacy of the compound of formula I combined with bevacizumab on the subcutaneous xenograft tumor BALB/c nude mouse model of human lung cancer LU-01-1443.
  • N the number of mice in each group; b. When the body weight dropped by more than 15%, the mice were stopped for observation and treatment until their body weight recovered to more than 10%; c.
  • the vehicle was a mixed solution of 5% absolute ethanol and polyoxyethylene 40 hydrogenated castor oil (1:1) + 95% sterile water for injection.
  • the establishment of the human lung cancer LU-01-1443 model was initially derived from surgically resected clinical samples, which were defined as the P0 generation after implantation into mice. Implantation of tumor tissue from generation P0 into the next generation is referred to as generation P1. Continue to implant in nude mice by analogy. Among them, FP3 tumors were resuscitated through P2 generation. The next generation generated by the FP3 generation is defined as FP4, and so on. The model used in this experiment is the FP5 generation.
  • the LU-01-1443 model is EML4-ALK Fusion, VEGFA/B/C secreted.
  • LU-01-1443 tumor tissue pieces of 20-30 mm 3 were subcutaneously inoculated in the right forelimb axilla of each mouse. On day 13 after inoculation, when the average tumor volume of the enrolled animals reached 115 mm 3 , group administration began.
  • the experimental grouping and dosing regimen are shown in Table 2.
  • the health status and death of the animals were monitored every day. Routine inspections included observing the effects of tumor growth and drug treatment on the daily behavior of the animals, such as behavioral activities, food and water intake (visual inspection only), changes in body weight (body weight was measured once a day), appearance signs or other abnormal conditions. Animal deaths and side effects within groups were recorded based on the number of animals in each group.
  • the experimental index is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured twice a week with vernier calipers.
  • TGI (%) reflects tumor growth inhibition rate.
  • TGI (%) [1-(average tumor volume at the end of administration of a treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment of the vehicle control group-average tumor volume at the beginning of treatment of the vehicle control group)] ⁇ 100%.
  • the human lung cancer LU-01-1443 xenograft tumor female BALB/c nude mouse model was given the compound of formula I and bevacizumab And formula I compound and bevacizumab
  • the changes in tumor volume in each group after combined treatment are shown in Table 4.
  • the human lung cancer LU-01-1443 xenograft tumor female BALB/c nude mouse model was given the compound of formula I and bevacizumab And formula I compound and bevacizumab
  • the tumor growth curves and relative tumor growth curves of each group after combined treatment are shown in Fig. 3 and Fig. 4 .
  • T/C and TGI tumor growth inhibition
  • c.p value is analyzed by T-test according to the relative tumor volume of each mouse in different groups and the vehicle group as the control;
  • the dp value is according to the relative tumor volume of each mouse in different groups with formula I compound group as contrast, and formula I compound+bevacizumab Groups were compared using T-test;
  • the ep value is according to the relative tumor volume of each mouse in different groups with bevacizumab group as contrast, and formula I compound+bevacizumab Groups were compared using T-test.
  • the p value is analyzed by T-test according to the tumor weight of each mouse in different groups and the vehicle group as a control;
  • the cp value is based on the tumor weight of each mouse in different groups with formula I compound group as contrast, and formula I compound+bevacizumab Groups were compared using T-test;
  • the dp value was compared with bevacizumab according to the tumor weight of each mouse in different groups Group is control, with formula I compound+bevacizumab Groups were compared using T-test.
  • the tumor volume of the tumor-bearing mice in the vehicle control group reached 2,623 mm 3 .
  • Test drug formula I compound and bevacizumab Figure 1 and Figure 2 show the effects on body weight changes in tumor-bearing mice.
  • vehicle group formula I compound single drug group
  • bevacizumab Single drug group compound of formula I + bevacizumab
  • body weight of the animals in the combined group remained stable.

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Abstract

Est divulguée dans la présente invention une composition médicamenteuse d'un inhibiteur d'ALK et d'un anticorps, la composition médicamenteuse comprenant un oxyde de spiro aryl phosphine et un anticorps anti-VEGF, et l'inhibiteur d'ALK étant un composé de formule (I) ou un sel pharmaceutiquement acceptable de ce dernier. La composition médicamenteuse divulguée par la présente invention est utilisée pour traiter le cancer du poumon et présente une activité antitumorale élevée.
PCT/CN2023/072599 2022-01-18 2023-01-17 Composition médicamenteuse d'oxyde de spiro aryl phosphine et d'anticorps anti-vegf WO2023138574A1 (fr)

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