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WO2025113607A1 - Médicaments pour une utilisation combinée dans le traitement d'une tumeur - Google Patents

Médicaments pour une utilisation combinée dans le traitement d'une tumeur Download PDF

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Publication number
WO2025113607A1
WO2025113607A1 PCT/CN2024/135495 CN2024135495W WO2025113607A1 WO 2025113607 A1 WO2025113607 A1 WO 2025113607A1 CN 2024135495 W CN2024135495 W CN 2024135495W WO 2025113607 A1 WO2025113607 A1 WO 2025113607A1
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Prior art keywords
tumor
cancer
compound
formula
expression
Prior art date
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PCT/CN2024/135495
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English (en)
Chinese (zh)
Inventor
淡墨
张汉承
刘喜宝
吴珍珍
蔡聪聪
李艳玲
张晓琳
刘咏梅
赵杰
张丹丹
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Hangzhou Innogate Pharma Co Ltd
Original Assignee
Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Hangzhou Innogate Pharma Co Ltd
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Publication date
Application filed by Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd, CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd, Hangzhou Innogate Pharma Co Ltd filed Critical Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
Priority to CN202480002813.6A priority Critical patent/CN120417928A/zh
Publication of WO2025113607A1 publication Critical patent/WO2025113607A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application belongs to the field of medicine, and specifically relates to a drug for treating tumors by combining a CDK inhibitor with a FGFR4 selective inhibitor and its application.
  • CDKs Cyclin-Dependent Kinases
  • CDK1, CDK2, CDK4, CDK6, etc. are related to the cell cycle
  • CDK7-9, CDK11-13, CDK19, etc. are related to transcriptional regulation.
  • the dysregulation of CDKs and cyclins leads to abnormal cell proliferation and the occurrence of cancer, such as breast cancer, liver cancer, lung cancer, ovarian cancer, kidney cancer, melanoma and colorectal cancer.
  • Targeting CDKs is an effective strategy for the development of blood and solid tumor drugs.
  • CDK4/6 regulates the cell cycle from G1 phase to S phase by phosphorylating its substrate retinoblastoma (Rb) protein, resulting in the dissociation of the transcription factor E2F bound by Rb protein. Therefore, CDK4/6 inhibitors usually inhibit the proliferation of Rb-positive (Rb + ) cells.
  • Palbociclib is the world's first approved CDK4/6 inhibitor. Its current approved indication is breast cancer. It is used to treat locally advanced or metastatic breast cancer that is hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative. It is used in combination with aromatase inhibitors as the initial endocrine therapy for postmenopausal women.
  • the compound of formula (I) is a CDK inhibitor under study, and its structure is shown in formula (I).
  • PCT application WO2021139817A1 discloses the compound and its preparation method. The results of in vitro enzymatic tests show that the compound of formula (I) has inhibitory effects on multiple CDK subtypes, such as CDK2, 4, 6, and 9.
  • Fibroblast growth factor receptor is a receptor tyrosine kinase, and its family members include FGFR1, 2, 3, and 4. When each member is continuously activated, it can induce tumor cell proliferation, invasion, and migration, promote tumor angiogenesis, and promote the occurrence and development of tumors.
  • FGFRs are highly expressed and abnormally activated in a variety of tumors, among which FGFR4 is most highly expressed in human hepatocytes, and a variety of FGFR4 mutations have been found in liver cancer patients.
  • FGF401 is a FGFR4 selective inhibitor that has entered the clinical stage. Its structure is shown in formula (II).
  • PCT patent application WO2015059668A1 discloses the compound and its preparation method.
  • Chinese patent application CN116761807A further discloses the isomers of the compound of formula (III-A), namely, the compound of formula (III-B) and the compound of formula (III-C), as well as the crystal forms, preparation methods and biological activities of the compounds.
  • the present application provides a drug combination for combined tumor treatment, its pharmaceutical use, and a method for treating tumors.
  • the drug combination uses a CDK inhibitor and an FGFR4 selective inhibitor in combination, which can further enhance the effect of drug treatment of tumors compared to single drugs, exhibits synergistic effects, and is safe and tolerable, providing a new approach to provide more effective tumor treatment.
  • the present application provides a drug or a drug combination or a pharmaceutical composition comprising a CDK inhibitor and a FGFR4 selective inhibitor.
  • the present application provides use of a combination of a CDK inhibitor and a FGFR4 selective inhibitor in the preparation of a medicament for treating tumors.
  • the CDK inhibitor and the FGFR4 selective inhibitor may be simultaneously contained in a clinically acceptable pharmaceutical preparation (single preparation), or may be prepared into clinically acceptable dosage forms, and packaged in combination into the drug or drug combination. That is to say, the drug or drug combination described in the present application not only comprises a compound pharmaceutical preparation (single preparation), but also comprises a combination medicine package or a kit product.
  • the CDK inhibitor and the FGFR4 selective inhibitor are simultaneously contained in one preparation unit to make a clinically acceptable dosage form.
  • the CDK inhibitor and the FGFR4 selective inhibitor are prepared into clinically acceptable pharmaceutical preparations, that is, the CDK inhibitor and the FGFR4 selective inhibitor are respectively contained in different preparation units and presented in the form of a combination package.
  • the preparation forms of the CDK inhibitor and the FGFR4 selective inhibitor may be the same or different.
  • the drug or drug preparation described in the present application is selected from an oral preparation, an injection preparation, a topical preparation or an in vitro preparation.
  • the present application provides the use of a CDK inhibitor in the preparation of a drug for improving the effect of a FGFR4 selective inhibitor in treating tumors.
  • the present application provides the use of a FGFR4 selective inhibitor in the preparation of a drug for improving the effect of a CDK inhibitor in treating tumors.
  • the present application provides a method for treating tumors, comprising administering a therapeutically effective amount of a CDK inhibitor and a FGFR4 selective inhibitor to a patient or subject in need of treatment.
  • the present application provides a method for improving the effect of FGFR4 selective inhibitors in treating tumors, which comprises administering a therapeutically effective amount of a CDK inhibitor to a patient or subject in need of treatment.
  • the present application provides a method for improving the effect of CDK inhibitors in treating tumors, comprising administering a therapeutically effective amount of a FGFR4 selective inhibitor to a patient or subject in need of treatment.
  • the CDK inhibitor and the FGFR4 selective inhibitor can be administered simultaneously or in parallel, or can be administered separately. That is, the CDK inhibitor and the FGFR4 selective inhibitor can be contained in the same compound preparation unit and are administered simultaneously. Alternatively, the CDK inhibitor and the FGFR4 selective inhibitor are respectively contained in different preparation units, administered simultaneously or in parallel, or sequentially administered at different times in one day at clinically accepted time intervals, or at clinically accepted time intervals, respectively administered according to the respective dosing frequency and cycle of the CDK inhibitor and the FGFR4 selective inhibitor.
  • the CDK inhibitor and the FGFR4 selective inhibitor are not particularly limited in the order of administration, and can be used as the first treatment or the second treatment according to clinical needs.
  • the simultaneous administration or parallel administration refers to the first treatment and the second treatment starting at the same time, or, when the second treatment delivery starts, the delivery of the first treatment is still in progress.
  • the administration can be oral administration, injection administration, local administration or in vitro administration.
  • the CDK inhibitor and/or FGFR4 selective inhibitor is an oral preparation, an injection preparation, a local preparation or an in vitro preparation.
  • the method further comprises determining whether the patient or subject suffers from the malignant neoplastic disease, or receiving information that the patient or subject suffers from the malignant neoplastic disease, before administering the drug or the drug combination.
  • the malignant neoplastic disease is characterized by: (1) at least one biomarker selected from the following: overexpression of fibroblast growth factor 19 (FGF19), amplified FGF19, overexpression of fibroblast growth factor receptor 4 (FGFR4); and/or, (2) at least one biomarker selected from the following: positive expression of hormone receptor (HR), positive or negative expression of retinoblastoma protein (Rb).
  • the method further includes identifying that the patient or subject is responsive to administration of the drug or the drug combination after determining whether the patient or subject has the malignant neoplastic disease or receiving information that the patient or subject has the malignant neoplastic disease.
  • the method comprises:
  • FGF19 fibroblast growth factor 19
  • FGFR4 fibroblast growth factor receptor 4
  • HR hormone receptor
  • Rb retinoblastoma protein
  • the present application provides a drug comprising a CDK inhibitor for improving the effect of a FGFR4 selective inhibitor in treating tumors.
  • the present application provides a drug comprising a FGFR4 selective inhibitor for improving the effect of CDK inhibitors in treating tumors.
  • the present application provides a drug or drug combination or a pharmaceutical composition comprising a CDK inhibitor and a FGFR4 selective inhibitor, which is used to treat tumors.
  • the tumor described in the present application is selected from solid tumors or hematologic tumors.
  • the solid tumor is selected from fibrosarcoma, salivary gland cancer, liver cancer, colorectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, brain tumor, lung cancer, melanoma.
  • the hematologic tumor is selected from acute myeloid leukemia.
  • the tumor is a solid tumor.
  • the tumor is liver cancer.
  • the tumor or neoplastic disease is characterized by having: (1) at least one biomarker selected from the following: overexpression of fibroblast growth factor 19 (FGF19), amplified FGF19, overexpression of fibroblast growth factor receptor 4 (FGFR4); and/or, (2) at least one biomarker selected from the following: positive expression of hormone receptor (HR), positive or negative expression of retinoblastoma protein (Rb).
  • the tumor or neoplastic disease is an Rb-positive tumor or an Rb-negative tumor, preferably an Rb-positive solid tumor or an Rb-negative solid tumor, more preferably an Rb-positive liver cancer or an Rb-negative liver cancer.
  • the tumor or neoplastic disease is selected from an Rb-negative solid tumor.
  • the tumor or neoplastic disease is an Rb-negative liver cancer.
  • the CDK inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, G1T-38, G1T-28, AT-7519, FLX-925, avocidib, a compound of formula (I), or a pharmaceutically acceptable form of the foregoing compound.
  • the CDK inhibitor is a compound of formula (I) or a pharmaceutically acceptable form thereof, wherein the structure of the compound of formula (I) is as follows:
  • the FGFR4 selective inhibitor is selected from Futibatinib, Erdafitinib, Lenvatinib, Rogaratinib, IONIS-FGFR4Rx, EVER-4010001, Irpagratinib, Fisogatinib, Roblitinib, Aldafermin, Gunagratinib, JAB-6343, HS-236, HS-10340, H3B-6527, BPI-43487, ZSP-1241, U3-1784, ICP-105, SY-4798, INCB-62079, ASP-5878, LY-2874455, PRN-1371, SC-0011, ODM-203, FGF401, compound of formula (III-A), compound of formula (III-B), compound of formula (III-C), etc.
  • the FGFR4 selective inhibitor is selected from FGF401, a compound of formula (III-A), a compound of formula (III-B), a compound of formula (III-C), or a pharmaceutically acceptable form of the foregoing compounds.
  • the structure of the FGF401 compound is shown in the following formula (II):
  • the FGFR4 selective inhibitor is preferably a compound of formula (III-B) or a pharmaceutically acceptable form thereof.
  • the CDK inhibitor is a compound of formula (I) or a pharmaceutically acceptable form thereof
  • the FGFR4 selective inhibitor is a compound of formula (III-B) or a pharmaceutically acceptable form thereof.
  • the CDK inhibitor and FGFR4 selective inhibitor described in the present application can be combined in any clinically acceptable dose.
  • the CDK inhibitor is a compound of formula (I) or a pharmaceutically acceptable form thereof
  • the FGFR4 selective inhibitor is FGF401 or a pharmaceutically acceptable form thereof
  • the dosage ratio of the two is selected from (1-10): (1-10), preferably (3-8): (2-5), more preferably (4-6): (2-4), and more preferably 5:3, based on the free form of the compound.
  • the CDK inhibitor is a compound of formula (I) or a pharmaceutically acceptable form thereof
  • the FGFR4 selective inhibitor is a compound of formula (III-B) or a pharmaceutically acceptable form thereof
  • the dosage ratio of the two, calculated as the free form of the compound is selected from (1-150): (1-10), preferably (20-125): (2-8), more preferably (30-110): (2-8), more preferably (50-90): (3-7), more preferably (60-80): (4-6), and more preferably 70:5 or 14:1.
  • the compound of formula (I) is selected from the free form of the compound of formula (I) or a pharmaceutically acceptable salt thereof, such as sulfate, methanesulfonate, tartrate, benzenesulfonate, hydrochloride, p-toluenesulfonate, fumarate, citrate and malate.
  • the pharmaceutically acceptable salt is selected from benzenesulfonate, hydrochloride, p-toluenesulfonate, fumarate, citrate and malate.
  • the pharmaceutically acceptable salt is hydrochloride or benzenesulfonate.
  • the compound of formula (III-A), (III-B), (III-C) is selected from the free form of the compound of formula (III-A), (III-B), (III-C) or a pharmaceutically acceptable salt thereof, for example, including salts with acidic groups (e.g., potassium salts, sodium salts, magnesium salts, calcium salts) or salts with basic groups (e.g., sulfates, hydrochlorides, phosphates, nitrates, carbonates).
  • acidic groups e.g., potassium salts, sodium salts, magnesium salts, calcium salts
  • basic groups e.g., sulfates, hydrochlorides, phosphates, nitrates, carbonates.
  • the drug, drug combination, pharmaceutical composition or pharmaceutical preparation described in the present application further comprises a pharmaceutically acceptable adjuvant or excipient.
  • the drug, drug combination, pharmaceutical composition or pharmaceutical preparation can be a single-dose preparation or a divided-dose preparation.
  • the combined use of a CDK inhibitor and a FGFR4 selective inhibitor in the present application can significantly inhibit tumor (especially liver cancer) growth, achieve a synergistic effect, and produce unexpected technical effects.
  • pharmaceutically acceptable is used herein to refer to those compounds, substances, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications within the scope of reasonable medical judgment and in accordance with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable form of a compound in this application is selected from: solvates, hydrates, pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic derivatives, cocrystals, polymorphs, prodrugs and metabolites of the compound; preferably pharmaceutically acceptable salts, stereoisomers, tautomers; more preferably pharmaceutically acceptable salts.
  • the term “pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to salts that are suitable for contact with mammalian tissues, especially human tissues, without excessive toxicity, irritation, allergic reaction, etc., and commensurate with a reasonable benefit/risk ratio within the scope of reasonable medical judgment, such as amines, carboxylic acids and other types of medically acceptable salts of compounds are well known in the art.
  • the salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base or free acid with a suitable reagent.
  • "pharmaceutically acceptable salts” refer to salts formed by the compounds of the present invention and pharmaceutically acceptable inorganic acids and organic acids, wherein preferred inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1,5), oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-tolu
  • isotopic derivative means that the compounds disclosed herein may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes may be radioactive or non-radioactive isotopes.
  • Isotopes commonly used as isotope labels are: hydrogen isotopes: 2 H and 3 H; carbon isotopes: 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotope 35 S.
  • isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues.
  • 3 H and 13 C are more widely used because they are easy to label and convenient to detect.
  • Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques in the same way as non-isotope-labeled compounds.
  • solvate refers to a physical association of a compound disclosed herein with one or more solvent molecules (whether organic or inorganic).
  • the physical association includes hydrogen bonding.
  • the solvent molecules in the solvate may exist in a regular arrangement and/or a disordered arrangement.
  • the solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules.
  • the solvate may be a solvate of the disclosed compound or a pharmaceutically acceptable salt thereof.
  • “Solvate” encompasses solution phases and separable solvates.
  • Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates.
  • the solvent is water
  • the solvate is a "hydrate”.
  • Pharmaceutically acceptable solvates and hydrates are complexes that may include, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It is to be understood that the term "compound” used herein includes the compound and the solvate of the compound and mixtures thereof. Solvation methods are well known in the art.
  • stereoisomer refers to compounds with the same chemical structure but different arrangements of atoms or groups in space.
  • Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization, based on the differences in the physicochemical properties of the components.
  • tautomer refers to structural isomers with different energies that can be mutually converted through a low energy barrier.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • the structural formulas described in the present disclosure include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformers. Therefore, single stereochemical isomers of the compounds disclosed herein or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present disclosure.
  • Enantiomers or “enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any ratio may be referred to as a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture, where appropriate.
  • Diastereomers or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry may be assigned according to the Cahn Ingold Prelog R S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon may be assigned by R or S.
  • Resolved compounds whose absolute configuration is unknown may be assigned as (+) or (-) according to the direction (right-handed or left-handed) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be assigned as (R) or (S) according to the absolute stereochemistry at each asymmetric atom.
  • the chemical entities, pharmaceutical compositions and methods disclosed herein are intended to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures.
  • Optically active (R) and (S) isomers can be prepared, for example, using chiral synthons or chiral reagents or resolved using conventional techniques.
  • Isomers/enantiomers may be substantially free of the corresponding enantiomer in some embodiments, and may also be referred to as "optically enriched”, “enantiomerically enriched”, “enantiomerically pure” and “non-racemic” (used interchangeably herein). These terms refer to compositions in which the amount of one enantiomer is greater than the amount of the enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight).
  • an enantiomerically enriched preparation of the S enantiomer refers to a compound preparation having greater than about 50% by weight, such as at least about 75% by weight, and for example at least about 80% by weight of the S enantiomer relative to the total weight of the preparation (e.g., the total weight of the S and R isomers).
  • the enrichment may be significantly greater than about 80% by weight to provide a "substantially enantiomerically enriched", “substantially enantiomerically pure” or “substantially non-racemic” preparation, which refers to a composition preparation having at least about 85% by weight of one enantiomer relative to the total weight of the preparation, such as at least about 90% by weight, and further for example at least about 95% by weight.
  • the compounds provided herein are composed of at least about 90% by weight of one enantiomer.
  • the compound is made up of at least about 95%, about 98%, or about 99% by weight of one enantiomer.
  • the compound is a racemic mixture of (S) and (R) isomers.
  • provided herein is a mixture of compounds, wherein each compound of the mixture exists primarily as (S) or (R) isomers.
  • the compound mixture has an (S) enantiomeric excess greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, or greater than about 99%.
  • the compound mixture has an (S) enantiomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5% or greater.
  • the compound mixture has an (S) enantiomeric excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or greater than about 99.5%.
  • polymorph refers to different arrangements of chemical drug molecules, generally manifested as the existence form of drug raw materials in the solid state.
  • a drug can exist in multiple crystalline material states, and different crystalline forms of the same drug may have different dissolution and absorption in the body, which will affect the dissolution and release of the formulation.
  • polymorph or “polymorph” as used herein is also intended to include all crystalline and amorphous forms of the compound or its pharmaceutically acceptable salt, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, non-solvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is mentioned.
  • the term "metabolite” refers to a product obtained by metabolism of a specific compound or a pharmaceutically acceptable salt thereof in vivo.
  • the metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described in the present disclosure. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
  • the present disclosure includes metabolites of the compound, including metabolites produced by contacting the compound disclosed herein with a mammal for a period of time.
  • prodrug refers to a drug that is converted into the parent drug in vivo.
  • Prodrugs are generally useful and can improve some determined, undesirable physical or biological properties. Physical properties are usually related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they can be bioavailable by oral administration, while the parent cannot. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug.
  • prodrug can be any compound herein, which is administered as an ester ("prodrug") to facilitate transmission across the cell membrane (where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial), which is then metabolically hydrolyzed to a carboxylic acid, the active entity.
  • prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to show the active part.
  • “combination” administration or “combined” administration refers to administering two (or more) different treatments to a patient or subject during the period when the patient or subject is suffering from a disease, for example, administering two or more drugs to the patient or subject after the patient or subject is diagnosed with a disease and before the disease is cured or eliminated or the treatment is stopped for other reasons.
  • the second treatment delivery begins the delivery of the first treatment is still in progress, so there is overlap in terms of administration. This situation is sometimes referred to as “simultaneous" or “concurrent delivery” herein.
  • the delivery of one treatment has ended before the delivery of another treatment begins. In some embodiments of either of the two, the treatment is more effective due to combined administration.
  • the same effect is observed with less second treatment, or the same dose can alleviate symptoms to a greater extent, or similar situations observed with the first treatment.
  • the delivery causes symptoms or other parameters associated with the disease to be alleviated more.
  • the effects of the two (or more) treatments may be partially additive, fully additive, or greater than additive, ie, synergistic.
  • the delivery may be such that the effect of the first treatment delivered is still detectable when the second treatment is delivered.
  • single formulation refers to a single carrier or vehicle formulated to deliver effective amounts of both therapeutic agents to a patient or subject.
  • a single vehicle is designed to deliver effective amounts of each of the agents and any pharmaceutically acceptable carriers or excipients.
  • the vehicle is a tablet, capsule, pill, or patch.
  • pharmaceutically acceptable excipient or “pharmaceutical excipient” can be selected from carriers, binders, suspending agents, glidants, flavoring agents, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, stabilizers, penetration enhancers, defoaming agents, antioxidants, preservatives, solvents or a combination thereof commonly used in the art.
  • dose range refers to the upper and lower limits of acceptable variation in the amount of a specified pharmaceutical agent. Generally, a dosage of any amount of the pharmaceutical agent within the specified range can be administered to a patient or subject being treated.
  • treat means to alleviate, reduce or relieve at least one symptom of a subject's disease.
  • the term “treat” may mean to prevent, delay the onset of disease (i.e., the period before the clinical manifestation of the disease or symptoms of the disease) and/or reduce the risk of the occurrence or worsening of disease symptoms.
  • therapeutic benefit refers to the eradication or improvement of the underlying disorder being treated.
  • the eradication or improvement of one or more physiological symptoms associated with the underlying disorder also achieves a therapeutic benefit, so that an improvement is observed in the patient or subject, although the patient or subject may still be troubled by the underlying disorder.
  • preventive benefits the pharmaceutical composition can be administered to a patient or subject at risk of developing a specific disease, or to a patient or subject who reports one or more physiological symptoms of the disease, even though the disease may not have been diagnosed.
  • these terms also refer to partially or completely inhibiting or alleviating the condition suffered by an individual. In one embodiment, these terms refer to actions taken to reduce the severity of the condition or to delay or slow the progression of the condition when the patient or subject is suffering from the condition or is diagnosed with the condition. Treatment does not need to result in a complete cure of the condition; this term includes partial inhibition or alleviation of the condition. Treatment is intended to include prevention or prevention.
  • subject or “patient” is intended to include animals that are capable of suffering from or suffering from a malignant neoplastic disease.
  • subjects or patients include mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human, such as a human that suffers from, is at risk of suffering from, or is potentially capable of suffering from a malignant neoplastic disease.
  • enhanced effect refers to the effect of two agents administered together that provides a greater or improved result than when a single agent is administered alone without co-administering the other agent.
  • Administration of the agents together can provide an enhanced effect when they are administered simultaneously or sequentially. Sequential administration of agents includes administration separated by seconds, minutes, hours, or days.
  • Administration of agents together can provide an enhanced effect when the agents are administered as part of a single formulation or when administered in separate formulations.
  • amplified means that an extra copy of a gene or chromosome segment that confers a growth or survival advantage is produced in a cancer cell.
  • FISH fluorescence in situ hybridization
  • a high-resolution array-based test to measure the copy number of a gene or chromosome segment, the high-resolution array-based test being based on: array comparative genomic hybridization (or aCGH), SNP array technology, and a high-resolution microarray including copy number probes and SNPs, and whole genome (WGS) or whole exome DNA sequencing (WES) using next generation sequencing (NGS) technology.
  • GGS whole genome
  • WES whole exome DNA sequencing
  • FGFR4 protein refers to any form of FGFR4 protein, including wild type and all variant forms (including but not limited to mutant forms and splice variants).
  • FGFR4 protein is the product of FGFR4 gene, so FGFR4 protein includes any protein encoded by any form of FGFR4 gene including any aberration (such as point mutation, indel, translocation fusion and focal amplification).
  • overexpression means that the output of gene product in sample is higher than the output observed in control sample group (such as, normal tissue). If gene product is not produced in control sample usually, then overexpression includes expression. The output of gene product can use the routine techniques of this area, such as immunohistochemistry to measure.
  • FGF19 gene product overexpression is FGF19 protein expression ⁇ 1%.
  • therapeutic effect refers to a beneficial local or systemic effect caused in an animal, such as a mammal (e.g., a human), by administering a compound or composition disclosed herein.
  • therapeutically effective amount refers to the amount of a compound or composition disclosed herein that effectively treats a disease or condition at a reasonable benefit/risk ratio.
  • the therapeutically effective amount of the compound or composition will vary depending on the subject and disease or condition being treated, the subject's weight and age, the severity of the disease or condition, the mode of administration, etc., and the therapeutically effective amount is easily determined by those skilled in the art.
  • combination therapy refers to a dosing regimen that requires administration of at least two different compounds to a patient or subject.
  • the at least two different compounds may be administered simultaneously or in parallel, or sequentially at different times of the day at clinically accepted time intervals, or at clinically accepted time intervals, at the respective dosing frequencies and cycles of the CDK inhibitor and the FGFR4 selective inhibitor.
  • the dosing regimens of the at least two compounds may, but need not, overlap.
  • co-administration means exposing a subject to two or more treatment regimens (e.g., two or more compounds) at the same time.
  • two or more compounds can be administered simultaneously; in some embodiments, two or more compounds can be administered sequentially (according to a completely non-overlapping dosing regimen); in some embodiments, two or more compounds can be administered in a partially overlapping dosing regimen.
  • the "administration" of a combination therapy may involve administering one or more compounds to a subject who has already received other compounds (one or more).
  • the combination therapy does not require that each compound be administered together in a single composition (or even not necessarily administered simultaneously), but in some embodiments, two or more compounds can be administered together in a single composition.
  • the compounds to be co-administered are separate dosage forms, but are packaged together (e.g., in a blister pack or other medicine box) to facilitate their co-administration.
  • a and B can produce a synergistic effect in treating the disease, that is, the combined therapeutic effect of A and B is better than the individual therapeutic effect of A or B, or the combined side effects/adverse reactions of A and B are lower than the individual side effects/adverse reactions of A or B, including but not limited to, A can enhance the therapeutic effect of an equal dose of B, so that the combined therapeutic effect of A and B can be better than the sum of the individual therapeutic effects of A and B; A can reduce the dose of B while producing equivalent therapeutic effects, thereby reducing the side effects/adverse reactions that may be caused by using a high dose of B; A can directly reduce or avoid the side effects/adverse reactions that may be caused by B; etc.
  • each numerical value given here not only includes the actual given value (given value), and it is also meant to include the approximate value of such given value reasonably inferred by a person of ordinary skill in the art, including the equivalent and approximate value of such given value produced due to experimental and/or measurement conditions.
  • the given value is obtained by rounding off based on the measured value obtained by experiment or measurement or the calculated data based on the measured value.
  • the approximate value is preferably ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 8%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, 2%, ⁇ 1% on the basis of the given value.
  • the compound of formula (I) of the present application can be prepared by referring to the method disclosed in patent application WO2021139817A1.
  • the compound of formula (II) of the present application can be prepared by referring to the method disclosed in patent application WO2015059668A1.
  • the compound of formula (III-B) of the present application can be prepared by referring to the method disclosed in patent application CN116761807A.
  • Example 1 Study on the efficacy of the compound of formula (I) and FGF401 combined with Nu/Nu mice on human liver cancer Huh-7 cell xenograft tumors
  • the compound of formula (I) was prepared according to the method described in patent application WO2021139817A1 and provided by Shijiazhuang Zhongqi Pharmaceutical Technology Co., Ltd.
  • FGF401 was prepared according to the method described in patent application WO2015059668A1 and provided by Shijiazhuang Zhongqi Pharmaceutical Technology Co., Ltd.
  • Solvent Aqueous solution of 0.4% Tween 80 and 0.5% methylcellulose.
  • FGF401 solution Weigh a certain amount of FGF401, add solvent, add magnetic beads, vortex, and sonicate until a uniform suspension is obtained with a concentration of 1.5 mg/mL.
  • Huh-7 cells human hepatoma cells
  • Huh-7 cells were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • mice Nu/Nu mice, SPF grade, 90 females, 6-8 weeks old/18-20 g, provided by Beijing Weitonglihua Experimental Animal Technology Co., Ltd.
  • a sterile syringe was used to extract Huh-7 cell suspension and inoculated into the subcutaneous tissue on the right back of Nu/Nu mice.
  • the inoculation volume was 0.1 mL/mouse, containing approximately 5 ⁇ 10 6 tumor cells, to prepare a Nu/Nu mouse Huh-7 transplant tumor model.
  • mice with good tumor growth were selected and the animals were evenly divided into 4 groups (G1-G4) according to the tumor volume. Each group was given the drug by gavage once a day with a volume of 10 mL/kg for 6 consecutive days.
  • the administration follows the following principles: when the animal body weight drops below 85% ( ⁇ 85%) of the group body weight, the administration is suspended; when it rises back to 90% ( ⁇ 90%), the administration is resumed.
  • Animals of appropriate weight were selected for the experiment. After the start of drug administration, the animals were weighed once a day at a fixed time for weight monitoring, and the weight statistics were consistent with the tumor volume statistics.
  • the time of death shall be recorded; for dying animals, the frequency of observation shall be increased to determine the time of death.
  • the long and short diameters of the tumors were measured twice a week.
  • RTV xnd average relative tumor volume on day n
  • the tumor observation indexes of each group are shown in Table 2.
  • Table 2 on the 6th day (D6) of administration, the tumor growth inhibition rate (TGI%) of the FGF401 15 mg/kg, the compound of formula (I) 25 mg/kg, and the combined administration of FGF401 15 mg/kg and the compound of formula (I) 25 mg/kg were 106.2%, 102.0%, and 163.7%, respectively; the relative tumor volume proliferation rate (T/C%) was 54.2%, 56.2%, and 30.1%, respectively.
  • Table 2 compared with the solvent group, FGF401 and the compound of formula (I) alone and in combination significantly inhibited tumor growth (G2, G3P ⁇ 0.05; G4P ⁇ 0.001). Calculated by the tumor volume on the 6th day of administration, the tumor inhibition effect of combined administration was significantly better than that of the two alone, and the drug efficacy had an additive effect (0.85 ⁇ Q ⁇ 1.15).
  • Human liver cancer Huh-7 cells are Rb + cell lines.
  • the above experimental results indicate that the compound of formula (I) alone or in combination with the FGFR4 selective inhibitor (FGF401) has a significant growth inhibitory effect on Rb+ tumors.
  • This experiment used a Nu/Nu mouse human liver cancer cell (Hep3b) transplanted tumor model to verify the anti-tumor effect of the compound of formula (I) alone and in combination with the compound of formula (III-B).
  • the compound of formula (I) was prepared according to the method described in patent WO2021139817A1 and provided by Shijiazhuang Zhongqi Pharmaceutical Technology Co., Ltd.
  • the compound of formula (III-B) was prepared according to the method of CN116761807A and provided by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.
  • the solvent is an aqueous solution containing 5% anhydrous ethanol, 0.4% Tween 80 and 0.5% methylcellulose.
  • Hep3b cells human hepatoma cells
  • mice SPF grade, female, 80 mice, 18-20 g, were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.
  • Hep3b cells were revived and passaged in vitro to the required cell number, counted under a microscope, and diluted with MEM serum-free medium and Matrigel (BD, Catalog No.: 354262) (1:1) to adjust the tumor cell number to about 5 ⁇ 10 7 cells/mL.
  • the cell suspension was placed in an ice bath.
  • Hep3b cell suspension was drawn with a sterile syringe and subcutaneously inoculated into the subcutaneous tissue of the axilla of the forelimb of Nu/Nu mice.
  • the inoculation volume was 0.1 mL/mouse, containing approximately 5 ⁇ 10 6 tumor cells, to prepare the Nu/Nu mouse Hep3b transplant tumor model.
  • mice with good tumor growth were selected and divided into groups according to the tumor volume, with 6 mice in each group.
  • the drug was administered by gavage once a day with a volume of 10 mL/kg for 17 days.
  • Body weight All animals were weighed once before the experiment, and animals with appropriate weight were selected for the experiment. After the start of drug administration, the animals were weighed once a day at a fixed time.
  • the long and short diameters of the tumors were measured twice a week.
  • TV0d tumor volume on day 0
  • RTVxnd average relative tumor volume on day n
  • TVXn Average tumor volume on day n in the treatment group
  • TVX0 Average tumor volume on day 0 of the drug-treated group
  • TVM0 Average tumor volume on day 0 in the vehicle group
  • the animals were killed by dislocation, and the tumors were removed and weighed.
  • Tumor weight inhibition rate % (1 - tumor weight of drug administration group / tumor weight of solvent group) ⁇ 100%
  • SPSS19.0 statistical software was used for data processing.
  • the RepeatedMeasure procedure was used to analyze the changes in tumor volume between groups over time.
  • the Multivariate procedure was used to compare the differences in tumor volume between groups at each measurement.
  • the differences in tumor weight between groups were analyzed using the LSD method of One-wayANOVA.
  • the results of tumor volume showed that compared with the solvent control group, the combined administration of the compound of formula (III-B) (5 mg/kg) and the compound of formula (I) (70 mg/kg) significantly inhibited tumor growth (P ⁇ 0.001); the group of single administration of the compound of formula (III-B) 5 mg/kg and the group of single administration of the compound of formula (I) 70 mg/kg or 105 mg/kg had different degrees of tumor growth inhibition, but there was no statistical difference compared with the solvent control group.
  • the tumor inhibition effect of combined administration was significantly better than that of the two alone, and the drug effect had a synergistic effect (Q>1.15). See Table 4 for details.
  • the medium and high dose groups (70 mg/kg or 105 mg/kg) of the compound of formula (I) can inhibit tumor growth in a dose-dependent manner, but there is no statistical difference between the two groups and the solvent control group.
  • the combined administration of the compound of formula (III-B) (5 mg/kg) and the compound of formula (I) (70 mg/kg) can significantly inhibit tumor growth (P ⁇ 0.001), showing a synergistic effect (Q>1.15).
  • the tumor weight and inhibition rate of each group are shown in Table 5.
  • the human liver cancer Hep3b cells are Rb -cell strains.
  • the above experimental results show that although the compound of formula (I) or the compound of formula (III-B) alone did not significantly inhibit the growth of human liver cancer Hep3b, the combined use of these two active ingredients had a tumor growth inhibition rate of up to 90%, producing a significant synergistic effect.

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Abstract

L'invention concerne une combinaison pharmaceutique comprenant un inhibiteur de CDK et un inhibiteur sélectif de FGFR4, son utilisation dans la préparation d'un médicament destiné au traitement d'une tumeur, et une méthode de traitement d'une tumeur. L'inhibiteur de CDK est de préférence un composé représenté par la formule (I) ou une forme pharmaceutiquement acceptable de celui-ci. Des études ont montré que le composé représenté par la formule (I) ou la forme pharmaceutiquement acceptable de celui-ci et l'inhibiteur sélectif de FGFR4 peuvent traiter efficacement des tumeurs lorsqu'ils sont utilisés en combinaison, avec un effet synergique significatif.
PCT/CN2024/135495 2023-11-30 2024-11-29 Médicaments pour une utilisation combinée dans le traitement d'une tumeur Pending WO2025113607A1 (fr)

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CN109803684A (zh) * 2016-08-23 2019-05-24 卫材 R&D 管理有限公司 用于治疗肝细胞癌的组合疗法
CN110022900A (zh) * 2016-09-08 2019-07-16 蓝图药品公司 成纤维细胞生长因子受体4抑制剂与细胞周期蛋白依赖性激酶抑制剂的组合
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WO2021139817A1 (fr) * 2020-01-10 2021-07-15 杭州英创医药科技有限公司 Composé polycyclique agissant en tant qu'inhibiteur de kinases
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CN110022900A (zh) * 2016-09-08 2019-07-16 蓝图药品公司 成纤维细胞生长因子受体4抑制剂与细胞周期蛋白依赖性激酶抑制剂的组合
WO2021139817A1 (fr) * 2020-01-10 2021-07-15 杭州英创医药科技有限公司 Composé polycyclique agissant en tant qu'inhibiteur de kinases
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