WO2023083283A1 - Combinaison de médicaments pour le traitement d'une tumeur, et une application de celle-ci - Google Patents

Combinaison de médicaments pour le traitement d'une tumeur, et une application de celle-ci Download PDF

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WO2023083283A1
WO2023083283A1 PCT/CN2022/131280 CN2022131280W WO2023083283A1 WO 2023083283 A1 WO2023083283 A1 WO 2023083283A1 CN 2022131280 W CN2022131280 W CN 2022131280W WO 2023083283 A1 WO2023083283 A1 WO 2023083283A1
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compound
pharmaceutically acceptable
formula
acceptable salt
pharmaceutical composition
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PCT/CN2022/131280
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English (en)
Chinese (zh)
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薛黎婷
古鹏
陈平
杨桂梅
杨文清
周峰
唐任宏
任晋生
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先声药业有限公司
江苏先声药业有限公司
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Priority to CN202280069694.7A priority Critical patent/CN118119620A/zh
Publication of WO2023083283A1 publication Critical patent/WO2023083283A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the disclosure belongs to the field of medicine, and relates to a drug combination of a compound represented by formula (K) as a selective estrogen receptor down-regulator (SERD) and a CDK4/6 inhibitor, a combination product or a drug combination comprising the drug combination substances, and their use in the treatment of tumors.
  • K a compound represented by formula (K) as a selective estrogen receptor down-regulator (SERD) and a CDK4/6 inhibitor
  • Estrogen (E2) and estrogen alpha receptor (ER ⁇ ) are important drivers of breast cancer development. More than 2/3 of breast cancer patients express ER transcription factors, and in most ER-positive patients, ER is still a key driver even in tumors that progress after early endocrine therapy, so ER is A major target for breast cancer therapy (Pharmacology & Therapeutics 186 (2016) 1–24).
  • the purpose of endocrine therapy is to reduce the activity of ER.
  • SERMs selective estrogen receptor modulators
  • tamoxifen tamoxifen
  • Aromatase inhibitors by inhibiting the conversion of androgen into estrogen, reduce the level of estrogen in the body; and selective estrogen receptor down-regulators, such as fulvestrant (fulvestrant), not only as ER Antagonists inhibit its activity and also induce ER protein degradation.
  • fulvestrant fulvestrant
  • Fulvestrant is the first and only SERD drug clinically approved for the treatment of postmenopausal patients with ER-positive, metastatic breast cancer after progression on tamoxifen or an aromatase inhibitor.
  • a number of research data show that patients treated with fulvestrant have not completely degraded ER in vivo.
  • intramuscular injection caused obvious reactions such as pain, swelling, and redness at the injection site, and the absorption was slow and the exposure in vivo was limited. And other characteristics limit its clinical application, so patients with ER-positive breast cancer urgently need new treatment options.
  • Cyclin-dependent kinases 4 and 6 mediate the cell cycle transition from G0/G1 to S phase and promote cell proliferation.
  • Palbociclib (Palbociclib, chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyrido[2 ,3-d]pyrimidin-7(8H)-one) as a CDK4/6 selective inhibitor, can be used for the treatment of cancer patients.
  • the present disclosure provides a pharmaceutical combination comprising at least one selective estrogen receptor down-regulator (SERD) and at least one CDK4/6 inhibitor, the SERD being selected from formula (K)
  • SESD selective estrogen receptor down-regulator
  • CDK4/6 inhibitor the SERD being selected from formula (K)
  • K The indicated compound or its pharmaceutically acceptable salt:
  • R 1 , R 2 , R 3 , R 4 are independently selected from H, F, Cl, Br, I, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkane base;
  • X 1 , X 2 , X 3 , X 4 are independently selected from CR 6 or N;
  • R 6 is selected from H, F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 1 -C 10 alkoxy Base, C 3 -C 10 cycloalkyloxy or 3-10 membered heterocyclyloxy;
  • R 5 is independently selected from C 1 -C 6 alkyl, the C 1 -C 6 alkyl is optionally substituted by R a ;
  • R a is selected from F, Cl, Br, I, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl.
  • the present disclosure provides a combination product, the combination product comprises the first pharmaceutical composition and the second pharmaceutical composition, and the first pharmaceutical composition comprises at least one compound represented by formula (K) or Its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, the pharmaceutical composition II includes at least one CDK4/6 inhibitor and pharmaceutically acceptable excipients.
  • the present disclosure also provides a kit comprising:
  • a first container comprising the first pharmaceutical composition as described above;
  • a second container comprising the pharmaceutical composition II as described above.
  • the present disclosure also provides a pharmaceutical composition, which comprises any of the above pharmaceutical combinations and at least one pharmaceutically acceptable excipient.
  • the present disclosure relates to the use of any of the above-mentioned pharmaceutical combinations, combination products or pharmaceutical compositions in the preparation of antitumor drugs.
  • the present disclosure relates to the use of any of the above-mentioned pharmaceutical combinations, combination products or pharmaceutical compositions in anti-tumor.
  • the present disclosure relates to any of the above-mentioned pharmaceutical combinations, combination products or pharmaceutical compositions for anti-tumor.
  • the present disclosure relates to an anti-tumor method, the method comprising administering a therapeutically effective amount of any of the above-mentioned pharmaceutical combinations, combination products or pharmaceutical compositions to a patient in need.
  • the present disclosure also relates to the use of a compound represented by formula (K) or a pharmaceutically acceptable salt thereof in combination with a CDK4/6 inhibitor in the preparation of an antitumor drug.
  • Figure 1 is the NOESY spectrum of the compound of formula (I).
  • Fig. 2 is the survival curve of the human ER-positive breast cancer MCF-7 brain orthotopic model mouse of the compound of formula (I).
  • Fig. 3 is a diagram of the body weight change of the human ER-positive breast cancer MCF-7 brain orthotopic model mouse with the compound of formula (I).
  • Fig. 4 is a graph showing the synergistic anti-proliferation effect of the compound of formula (I) combined with palbociclib on human breast cancer MCF-7 cells in vitro.
  • Fig. 5 is a diagram showing the anti-tumor growth effect of the compound of formula (I) and palbociclib in combination on human ER-positive breast cancer MCF-7 xenograft xenograft mouse model.
  • Fig. 6 is a diagram of body weight change of mice with subcutaneous xenograft tumor of human ER-positive breast cancer MCF-7 treated with compound of formula (I) and palbociclib.
  • pharmaceutical combination refers to a combination of two or more active ingredients or pharmaceutically acceptable salts thereof.
  • the active ingredients or pharmaceutically acceptable salts thereof in the pharmaceutical combination can be administered simultaneously, and in some embodiments, the active ingredients or pharmaceutically acceptable salts thereof in the pharmaceutical combination can also be administered administered separately or sequentially.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable non-toxic acid or base salt, including salts of inorganic acids and bases, organic acids and bases, such as succinate.
  • pharmaceutical composition refers to a mixture of one or more active ingredients of the present disclosure and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound of the present disclosure, or a pharmaceutical combination thereof, to a subject.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • Compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates.
  • the present disclosure encompasses all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of compounds of the present disclosure.
  • asymmetric carbon atoms there may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Compounds of the disclosure are within the definition.
  • the asymmetric atom-containing compounds of the present disclosure can be isolated in optically pure form or in racemic form, the optically active form can be resolved from a racemic mixture, or by using a chiral starting material or a chiral reagent synthesis.
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by substituents, as long as the valence of the specified atom is normal and the compound after substitution is stable.
  • ethyl is “optionally” substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted ( CH2CH2F , CH2CH2Cl , etc.), polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc.) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • any variable eg R a , R b
  • its definition is independent at each occurrence. For example, if a group is substituted by 2 R b , each R b has independent options.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group may be straight or branched.
  • C 1 -C 10 alkyl is understood to mean a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl" can be understood as an
  • C 1 -C 3 alkyl is understood to mean a linear or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl”, and the “C 1 -C 6 alkyl” may further include “ C 1 -C 3 alkyl”.
  • alkoxy refers to the group produced by the loss of the hydrogen atom on the hydroxyl group of straight-chain or branched alcohols, which can be understood as “alkyloxy” or “alkyl-O-".
  • C 1 -C 10 alkoxy can be understood as “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”; the term “C 1 -C 6 alkoxy” It can be understood as “C 1 -C 6 alkyloxy” or "C 1 -C 6 alkyl-O-".
  • the "C 1 -C 10 alkoxy” may include “C 1 -C 6 alkoxy” and “C 1 -C 3 alkoxy” and other ranges, and the "C 1 -C 6 alkoxy”"C 1 -C 3 alkoxy” may be further included.
  • cycloalkyl refers to a fully saturated carbocyclic ring in the form of a monocyclic ring, a fused ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, fused, spiro or bridged ring having 3 to 10 carbon atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decanyl, etc.
  • C 3 -C 10 cycloalkyl may include “C 3 -C 6 cycloalkyl”, and the term “C 3 -C 6 cycloalkyl” can be understood as representing a saturated monocyclic or bicyclic hydrocarbon ring, which has 3-6 carbon atoms, specific examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
  • C 3 -C 10 cycloalkyloxy can be understood as “C 3 -C 10 cycloalkyl-O-", preferably, "C 3 -C 10 cycloalkyloxy” can include "C 3 -C 6 cycloalkyloxy”.
  • heterocyclyl refers to a fully saturated or partially saturated (not aromatic heteroaromatic as a whole) monocyclic, fused, spiro or bridged ring group containing 1-5 ring atoms
  • 3-10 membered heterocyclic group refers to a heterocyclic group with 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1-5 ring atoms independently selected from the above The heteroatom or heteroatom group.
  • the heterocyclic group may include but not limited to: specific examples of 4-membered heterocyclic groups include but not limited to azetidinyl or oxetanyl; specific examples of 5-membered heterocyclic groups include but not limited to Not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrole
  • Specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydro Pyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl include, but are not limited to, diazepan
  • the heterocyclic group can also be a bicyclic group, wherein, specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; 5,6-membered bicyclic group Specific examples include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • some bicyclic heterocyclyl groups in this disclosure partially contain a benzene ring or a heteroaryl ring, the heterocyclyl groups as a whole are nonaromatic.
  • treating means administering a compound or formulation described herein to prevent, improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying The amount of a compound of the disclosure for the onset of one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the disclosure that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. Based on its own knowledge and this disclosure.
  • the term “subject” or “patient” is used interchangeably herein.
  • the term “subject” or “patient” is a mammal.
  • the subject or patient is a mouse.
  • the subject or patient 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 of SERD and CDK4/6 inhibitors include, but are not limited to, oral, parenteral, intravenous, transdermal, sublingual, intramuscular, and subcutaneous administration.
  • the SERD and CDK4/6 inhibitors are administered orally.
  • the SERD and CDK4/6 inhibitors may be in separate or single formulations.
  • the SERD and CDK4/6 inhibitors can be administered simultaneously, separately or sequentially.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • Certain isotopically labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (ie3H ) and carbon-14 (ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • deuterium substitution may be partial or complete, partial deuterium substitution meaning at least one hydrogen is replaced by at least one deuterium.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administering a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • the disclosure provides a pharmaceutical combination comprising at least one selective estrogen receptor down-regulator (SERD) and at least one CDK4/6 inhibitor, the SERD being selected from compounds represented by formula (K) or a pharmaceutically acceptable salt thereof:
  • SESD selective estrogen receptor down-regulator
  • R 1 , R 2 , R 3 , R 4 are independently selected from H, F, Cl, Br, I, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkane base;
  • X 1 , X 2 , X 3 , X 4 are independently selected from CR 6 or N;
  • R 6 is selected from H, F, Cl, Br, I, OH, CN, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclyl, C 1 -C 10 alkoxy Base, C 3 -C 10 cycloalkyloxy or 3-10 membered heterocyclyloxy;
  • R 5 is independently selected from C 1 -C 6 alkyl, the C 1 -C 6 alkyl is optionally substituted by R a ;
  • R a is selected from F, Cl, Br, I, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl.
  • R 1 , R 2 , R 3 , and R 4 in the compound represented by formula (K) are independently selected from H, F, Cl, Br, I, CN, or C 1 -C 6 alkyl.
  • R 1 , R 2 , R 3 , and R 4 in the compound represented by formula (K) are independently selected from H, F, or methyl.
  • R 1 and R 2 in the compound represented by formula (K) are independently selected from H, F or methyl.
  • R 3 and R 4 in the compound represented by formula (K) are independently selected from H or methyl.
  • R 3 and R 4 in the compound represented by formula (K) are independently selected from H.
  • R 5 in the compound represented by formula (K) is selected from CH 2 CF 3 .
  • the compound represented by the formula (K) or a pharmaceutically acceptable salt thereof is selected from the compound represented by the formula (K-1) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 , and X 4 are as defined above.
  • the compound represented by the formula (K) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound represented by the formula (K) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound represented by formula (K) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • the CDK4/6 inhibitor is selected from the group consisting of abemaciclib, ribociclib, palbociclib, alvociclib, lerociclib, trilaciclib, voruciclib, AT-7519, FLX-925, INOC-005, BPI-1178, PD-0183812, NSC-625987, CGP-82996, PD-171851, SHR-6390, BPI-16350, and pharmaceutically acceptable salts of the above compounds.
  • the CDK4/6 inhibitor is selected from palbociclib or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical combination which comprises the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and palbociclib or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a combination product, the combination product comprises the first pharmaceutical composition and the second pharmaceutical composition, the first pharmaceutical composition comprises at least one compound represented by formula (K) or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, the pharmaceutical composition II comprises at least one CDK4/6 inhibitor and pharmaceutically acceptable excipients.
  • the compound represented by formula (K) or a pharmaceutically acceptable salt thereof in the first pharmaceutical composition is selected from the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor in the pharmaceutical composition II is selected from palbociclib or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a combination product, the combination product comprises the first pharmaceutical composition and the second pharmaceutical composition, the first pharmaceutical composition comprises the compound represented by formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, the pharmaceutical composition II comprises palbociclib or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.
  • the present disclosure also provides a kit comprising:
  • a first container comprising the first pharmaceutical composition as described above;
  • a second container comprising the pharmaceutical composition II as described above.
  • the present disclosure also provides a pharmaceutical composition, which comprises any of the above-mentioned pharmaceutical combinations and at least one pharmaceutically acceptable auxiliary material.
  • the pharmaceutical composition comprises:
  • the present disclosure relates to the use of any of the above-mentioned pharmaceutical combinations, combination products or pharmaceutical compositions in the preparation of antitumor drugs.
  • the present disclosure relates to the use of any of the above-mentioned pharmaceutical combinations, combination products or pharmaceutical compositions in anti-tumor.
  • the present disclosure relates to any of the above-mentioned pharmaceutical combinations, combination products or pharmaceutical compositions for anti-tumor.
  • the present disclosure relates to an anti-tumor method, the method comprising administering a therapeutically effective amount of any of the above-mentioned pharmaceutical combinations, combination products or pharmaceutical compositions to a patient in need.
  • the present disclosure also relates to the use of a compound represented by formula (K) or a pharmaceutically acceptable salt thereof in combination with a CDK4/6 inhibitor in the preparation of an antitumor drug.
  • the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in combination with a CDK4/6 inhibitor in the preparation of an antitumor drug; in one embodiment of the present disclosure, the CDK4/6 The inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.
  • the tumor is breast cancer.
  • the tumor is ER positive breast cancer.
  • the tumor is ER positive brain metastatic breast cancer.
  • the tumor is ER positive, HER-2 negative locally advanced or metastatic breast cancer.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 1 mg to 1000 mg (calculated as free base).
  • the palbociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 50 mg to 500 mg (calculated as free base).
  • the SERD compound herein has good antitumor activity in vivo and in vitro and druggability. In vivo experiments found that the SERD compound herein can significantly inhibit the tumor growth of ER-positive breast cancer mouse model, and significantly improve the survival period of ER-positive breast cancer brain orthotopic model mice. In addition, the SERD compound herein has one or more of the following technical benefits: high bioavailability, strong ER degradation ability, oral administration, and high ability to pass through the blood-brain barrier. Therefore, the SERD compounds herein have the potential to effectively treat ER-positive breast cancer (especially ER-positive breast cancer with brain metastases).
  • the combination of the SERD compound herein and CDK4/6 inhibitors (such as palbociclib) produces better efficacy in reducing the growth of tumors or even eliminating tumors, showing excellent antitumor synergistic effect.
  • the compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed herein, the embodiments formed by combining them with other chemical synthesis methods, and the methods described by those skilled in the art.
  • Known equivalents, preferred embodiments include, but are not limited to, the examples of this disclosure.
  • ratios indicated for mixed solvents are volume mixing ratios.
  • % means weight percent wt%.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • Step 1 Synthesis of tert-butyl(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate
  • Step 3 Synthesis of (R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propane-2-amine
  • Step 4 (1S,3R)-1-(5-Bromopyridin-2-yl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- Synthesis of Tetrahydro-1H-pyrido[3,4-b]indole
  • Step 5 N-(1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl Synthesis of )-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-amine
  • reaction solution was stirred at 80°C for 4 hours. After the LCMS detection reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 3 ⁇ m silica, 30 mm diameter, 75 mm length); (using water (containing 0.225% formic acid) and a mixture of decreasing polarity of acetonitrile as eluent) to obtain compound N-(1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((1S,3R)-3 -Methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridine- 3-Amine (22.23 mg).
  • Example 3-1 N-(S)(1-(3-fluoropropyl)pyrrolidin-3-yl)-6-((1S,3R)-3-methyl-2-(2,2, 2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-amine (compound of formula (I)) Synthetic method 1
  • Embodiment 3-2 the synthetic method 2 of formula (I) compound
  • Step 3 N-((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)-6-(((1S,3R)-3-methyl-2-(2,2,2 Synthesis of -trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyridin-3-amine
  • the NOESY spectrum (Fig. 1) shows that the methyl hydrogen on the 3-position of the compound of formula (I) and the hydrogen on the 1-position have a significant NOE effect, which proves that both are on the same side, and the pyridyl group on the 1-position and the hydrogen on the 3-position
  • the relative configuration of the methyl group on the 6-membered piperidine ring is trans, and the absolute configuration of the carbon atom at the 3-position is known as R, so the absolute configuration of the carbon atom at the 1-position is S.
  • Embodiment 3-3 the preparation of formula (I) compound succinate
  • Step 1 Synthesis of (S)-tert-butyl(1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate
  • Step 3 (1S,3R)-1-(4-Bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, Synthesis of 4,9-tetrahydro-1H-pyrido[3,4-b]indole
  • Step 4 (S)-N-(3,5-difluoro-4-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3, Synthesis of 4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)pyrrolidin-3-amine
  • reaction solution was stirred and reacted at 80° C. for 4 hours.
  • the filter cake is rinsed with tetrahydrofuran, the filtrate is concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (Phenomenex Gemini C18 column, 7 ⁇ m silica, 50 mm diameter, 250 mm length, using Water (containing 0.225% formic acid) and a mixture of decreasing polarity of acetonitrile as eluent) to obtain compound (S)-N-(3,5-difluoro-4-((1S,3R)-3-methyl -2-(2,2,2-Trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1 -(3-fluoropropyl)pyrrolidin-3-amine (4.69 mg).
  • Step 1 Synthesis of tert-butyl(trans-4-fluoro-1-(3-fluoropropyl)pyrrolidin-3-yl)carbamate
  • Step 3 trans-N-(3,5-difluoro-4-((1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4 , Synthesis of 9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-4-fluoro-1-(3-fluoropropyl)pyrrolidin-3-amine
  • Step 1 Synthesis of tert-butyl N-[trans-1-(3-fluoropropyl)-4-methyl-pyrrolidin-3-yl]carbamate
  • Step 3 trans-N-[3,5-difluoro-4-[(1S,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4 ,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]-1-(3-fluoropropyl)-4-methyl-pyrrolidin-3-amine synthesis
  • Test Example 1 Detection of SERD compounds on the degradation of estrogen receptors in MCF7 cells
  • the purpose of this experiment is to determine the degradative activity of the SERD compound in this paper on the endogenously expressed estrogen receptor in MCF7 cells, and evaluate the activity of the compound according to the DC 50 and the maximum degradation efficiency.
  • MCF7 cells (ATCC, HTB-22) were cultured with DMEM (Gibco, 11995-065) complete medium containing 10% fetal bovine serum. On the first day of the experiment, MCF7 cells were seeded in a 384-well plate at a density of 3000 cells/well using complete medium, and cultured in a 5% CO 2 cell incubator at 37°C. The compound to be tested was dissolved in DMSO with a storage concentration of 10 mM, diluted with Echo 550 (Labcyte Inc.) and added to the cell culture plate.
  • DMEM Gibco, 11995-065
  • the initial concentration of each compound was 100 nM, 3-fold serial dilution, 9 concentration points, and the settings contained A blank control of 0.5% DMSO was used, and a double-well control was set at each concentration point. Incubate in a 37°C, 5% CO 2 cell incubator for 24 hours. Add paraformaldehyde to the cell culture medium in each cell culture well, and the final concentration of paraformaldehyde is about 3.7% to fix the cells.
  • the wells treated with 0.1 ⁇ M fulvestrant were used as the 100% degradation control, and the degradation rate at each concentration point was calculated.
  • XlLfit was used to analyze and process the data, and the degradation activity DC 50 and the maximum degradation rate Imax of each compound were calculated. See Table 1 for data analysis.
  • Test Example 2 Detection of the inhibitory effect of SERD compounds on the proliferation of MCF7 cells
  • the purpose of this experiment is to determine the inhibitory effect of the SERD compounds herein on the proliferation of MCF7 cells in vitro, and to evaluate the activity of the compounds according to the IC 50 and the maximum inhibitory efficiency.
  • MCF7 cells (ATCC, HTB-22) were cultured with DMEM (Gibco, 11995-065) complete medium containing 10% fetal bovine serum. On the first day of the experiment, MCF7 cells were seeded in a 384-well plate at a density of 500 cells/well using complete medium, and cultured overnight at 37°C in a 5% CO 2 cell incubator. The next day, add the compound to be tested for drug treatment, and use Echo550 (Labcyte Inc.) to dilute the compound solution with a storage concentration of 10 mM and transfer it to each cell culture well.
  • DMEM Gibco, 11995-065
  • Echo550 Echo550
  • the initial concentration of each compound in the cell is 100 nM , 3-fold serial dilution, 9 concentration points, a blank control containing 0.3% DMSO was set, and double-well controls were set at each concentration point.
  • join in Luminescent Cell Viability Assay Promega, G7573
  • use XLfit to calculate the inhibitory activity IC 50 of each compound according to the concentration and luminescence signal value of the compound .
  • Data analysis see Table 2
  • Test Example 3 Inhibition of SERD Compounds on CYP2C9 and CYP2D6 Enzyme Activities
  • the inhibition of the SERD compounds herein on CYP2C9 and CYP2D6 enzyme activities was determined by the following test method.
  • Substrate working solutions 120 ⁇ M diclofenac, 400 ⁇ M dextromethorphan, and 200 ⁇ M midazolam were prepared at 200 ⁇ concentrations in water, acetonitrile or acetonitrile/methanol.
  • IC 50 values of SERD compounds against CYP2C9 and CYP2D6 were calculated by Excel XLfit 5.3.1.3.
  • Drug-drug interaction refers to the physical or chemical changes produced by two or more drugs, and the changes in drug efficacy caused by these changes. Understanding drug interactions can provide patients with better pharmaceutical services, promote rational drug use, and maximize the avoidance of adverse reactions. Drug interactions are mainly metabolic interactions, which are mainly related to CYP450 enzymes involved in drug metabolism. The experimental results in Table 3 show that the SERD compounds herein have weak inhibitory ability to CYP450, which indicates that the SERD compounds herein have a low potential risk of DDI.
  • Human plasma protein binding is a key factor controlling the amount of free (unbound) drug available for binding to the target and plays an important role in the observed in vivo efficacy of the drug.
  • compounds with high free fractions low levels of plasma protein binding may exhibit enhanced efficacy for compounds with similar potency and exposure levels.
  • the protein binding rate of the SERD compound in the plasma of five species was determined by the following test method.
  • Concentration is the preparation of the buffer solution of 100mM sodium phosphate and 150mM NaCl: prepare the alkaline solution that concentration is 14.2g/L Na HPO 4 and 8.77g/L NaCl with ultrapure water, prepare concentration with ultrapure water An acidic solution of 12.0g/L NaH 2 PO 4 and 8.77g/L NaCl. Titrate the alkaline solution with an acidic solution to pH 7.4 to prepare a buffer solution with a concentration of 100mM sodium phosphate and 150mM NaCl.
  • Preparation of the dialysis membrane Soak the dialysis membrane in ultrapure water for 60 minutes to separate the membrane into two pieces, then soak it in 20% ethanol for 20 minutes, and finally soak it in the buffer used for dialysis for 20 minutes.
  • Preparation of plasma Thaw the frozen plasma quickly at room temperature, then centrifuge the plasma at 4°C and 3,220g for 10 minutes to remove clots, and collect the supernatant into a new centrifuge tube. The pH of the plasma was measured and recorded, using plasma with a pH of 7-8.
  • Equilibrium dialysis step assemble the dialysis device according to the operating instructions. 120 ⁇ L of plasma samples containing 1 ⁇ M compound were added to one side of the dialysis membrane, and an equal volume of dialysate (phosphate buffered saline) was added to the other side. The experiment has two samples. Seal the dialysis plate, put it into the incubation device, and incubate at 37° C., 5% CO 2 and about 100 rpm for 6 hours. After incubation, remove the sealant and pipette 50 ⁇ l from the buffer and plasma side of each well into a different well of a new plate.
  • dialysate phosphate buffered saline
  • the peak areas of the compounds on the buffer side and the plasma side were determined.
  • the formula for calculating the plasma protein binding rate of a compound is as follows:
  • Free rate% (the ratio of the peak area of the compound to the peak area of the internal standard on the buffer side /the ratio of the peak area of the compound to the peak area of the internal standard on the plasma side ) ⁇ 100
  • Test Example 5 Apparent Solubility of SERD Compounds in Phosphate Buffer at pH 7.4
  • the compounds to be tested were prepared according to the methods described.
  • the control drug progesterone was purchased from Sigma.
  • Phosphate buffer with a pH value of 7.4 was prepared by our laboratory.
  • Acetonitrile and methanol were purchased from Fisher.
  • Other reagents were purchased from the market.
  • the hERG potassium channel is critical for the heart's normal electrical activity. Cardiac arrhythmias can be induced by blockade of hERG channels with various drugs. This side effect is a common cause of drug failure in preclinical safety trials, so minimization of hERG channel-blocking activity may be a desirable property of a drug candidate.
  • HEK293 cell line stably expressing hERG ion channel (product number: K1236) was purchased from Invitrogen.
  • the cell line was cultured in 85% DMEM, 10% dialyzed fetal bovine serum, 0.1mM non-essential amino acid solution, 100U/mL penicillin-streptomycin solution, 25mM HEPES, 5 ⁇ g/mL blasticidin and 400 ⁇ g/mL genetic in the culture medium of mycomycin.
  • trypsin is used for digestion and passage, and the passage is carried out three times a week.
  • the cells were cultured in a 6 cm dish at a density of 5 ⁇ 10 5 , induced by adding 1 ⁇ g/mL doxycycline for 48 hours, and then the cells were digested and seeded on glass slides for subsequent manual patch clamp experiments.
  • the compound to be tested was dissolved in DMSO and prepared into a stock solution with a final concentration of 10 mM.
  • the hERG current test method is as follows: apply a depolarization command voltage for 4.8 seconds to depolarize the membrane potential from -80mV to +30mV, and then apply a repolarization voltage for 5.2 seconds to reduce the membrane potential to -50mV to remove channel loss. live, so that the hERG tail current can be observed.
  • the peak value of the tail current is the magnitude of the hERG current.
  • the hERG current used to detect the test compound was continuously recorded for 120 seconds before administration to evaluate the stability of the hERG current produced by the test cells. Only stable cells within the acceptance range of the evaluation criteria can enter the subsequent compound detection.
  • the data is output by PatchMaster software and analyzed according to the following steps:
  • the percent current inhibition is calculated by the following formula.
  • the dose-response curve was fitted by Graphpad Prism 8.0 software and the IC50 value was calculated.
  • CD-1 mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • DMSO dimethyl sulfoxide
  • HP- ⁇ -CD hydroxypropyl- ⁇ -cyclodextrin
  • tetraethylene glycol Tetraethylene Glycol
  • Captisol SBE- ⁇ -CD, sulfobutyl- ⁇ -cyclodextrin
  • Merck USA.
  • mice Six female CD-1 mice (20-30g, 4-6 weeks) were randomly divided into 2 groups with 3 mice in each group.
  • the 1st group tail vein injection administration test compound, dosage is 1mg/kg
  • vehicle is the aqueous solution (95%, v/v) of DMSO (5%, v/v) and 10% HP- ⁇ -CD
  • the 2nd group is oral
  • the test compound was administered at a dose of 10 mg/kg in a vehicle of tetraethylene glycol (40%, v/v) and 7.5% aqueous solution of sulfobutyl- ⁇ -cyclodextrin (60%, v/v). Animals were fed and watered normally before the experiment.
  • Venous blood was collected from mice in each group before administration and at 0.083 (intravenous injection group only), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
  • the collected whole blood samples were placed in K 2 EDTA anticoagulant tubes, centrifuged for 5 minutes (12,000 rpm, 4° C.) and plasma was collected for testing.
  • Test Example 8 SERD Compounds Permeability of Blood Brain Barrier (BBB) in Rats
  • Drugs can pass through the blood-brain barrier of animals and have sufficient exposure in the brain is the key to the effectiveness of drugs on brain metastases. Therefore, by measuring drug concentrations in plasma and brain tissue after administration to animals, the effect of drugs in the brain Distribution, and then judge whether the drug can inhibit tumor growth in the brain orthotopic model.
  • SD female rats were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • MC methylcellulose
  • acetonitrile was purchased from Merck (USA).
  • PBS phosphate buffered saline
  • rat plasma sample Take 10 ⁇ L of rat plasma sample, add 150 ⁇ L of acetonitrile solvent (including internal standard compound) to precipitate protein, vortex for 5 min, centrifuge (14,000 rpm) for 5 min, and dilute the supernatant with water containing 0.1% (v/v) FA for 2 times, quantitative detection was performed on LC-MS/MS system (AB Sciex Triple Quad 6500+).
  • acetonitrile solvent including internal standard compound
  • Rat brain tissue samples were first homogenized with 4 times the mass volume of PBS homogenate. Take 20 ⁇ L of brain tissue homogenate sample, add 20 ⁇ L of blank mouse plasma to dilute and mix, then add 600 ⁇ L of acetonitrile solvent (including internal standard compound) to precipitate protein, vortex for 5 min, centrifuge (14,000 rpm) for 5 min, supernatant with Diluted 2 times with 0.1% (v/v) FA in water, and carried out quantitative detection on LC-MS/MS system (AB Sciex Triple Quad 6500+).
  • the compound of formula (I) of the present disclosure exhibits excellent blood-brain barrier penetration ability and high drug exposure in rat brain tissue.
  • the BBB test results are as follows:
  • Test Example 9 Growth inhibition experiment of SERD compound on MCF-7 mouse subcutaneous tumor model
  • Human breast cancer MCF-7 cells ATCC, HTB-22
  • EMEM medium ATCC, Cat No.: 30-2003
  • Fetal bovine serum Gbico; Cat No.:1099-141C
  • Pen Strep (Pen Strep): Gibco, Cat No.: 15240-122
  • D-PBS phosphate buffered saline without calcium and magnesium ions
  • mice Female, 6-7 weeks old, weighing about 19-28 grams, were purchased from Beijing Weitongda Biotechnology Co., Ltd., and the mice were raised in an SPF-grade environment, and each cage was sent separately All animals had free access to a standard certified commercial laboratory diet and water ad libitum.
  • Cell culture In vitro culture of human breast cancer MCF-7 cell line, the culture conditions are 10% fetal bovine serum, 1% Pen Strep, 10 ⁇ g/ml recombinant human insulin in EMEM (cell culture medium), 37°C, 5% CO 2 incubator. Routine digestion with 0.25% trypsin-EDTA digestion solution once a week for passage. When the cell saturation is 80%-90% and the number reaches the requirement, collect the cells and count them.
  • the dosage of the compound of formula (I) is 1, 3, or 10 mg/kg, administered orally (PO), and administered once a day (QD) for 3 weeks. There were 8 mice in the vehicle group and 6 mice in the administration group.
  • Tumor diameters were measured twice a week with vernier calipers.
  • Mouse body weights were measured twice a week.
  • TGI (%) [(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment of the solvent control group-at the beginning of treatment of the solvent control group Average tumor volume)] ⁇ 100%.
  • the compound of formula (I) has a significant inhibitory effect on tumor growth (P ⁇ 0.01) at 1 mg/kg, 3 mg/kg, or 10 mg/kg orally administered once a day (P ⁇ 0.01), and has It has a good dose-response relationship, and has the effect of shrinking tumors at the doses of 3mg/kg and 10mg/kg.
  • Oral administration of the compound of formula (I) once a day at 10 mg/kg has a significant inhibitory effect on tumor growth (P ⁇ 0.01), and has the effect of shrinking tumors.
  • the compound of formula (I) did not significantly affect the body weight of the mice at the doses tried.
  • Test Example 10 Inhibitory experiment of the compound of formula (I) on the growth of mouse MCF-7 brain orthotopic tumor model
  • Human breast cancer MCF-7 cells ATCC, HTB-22
  • EMEM medium ATCC, Cat No.: 30-2003
  • Fetal bovine serum Gibco, Cat.No.:1099-141C
  • Pen Strep (Pen Strep): Gibco, Cat No.: 15240-122
  • Micro injection pump KDS, Cat No.: Legato130
  • mice Female, 6-8 weeks old, weighing about 17-29 grams, were purchased from Beijing Weitongda Biotechnology Co., Ltd., and the mice were raised in an SPF-grade environment, and each cage was sent separately All animals had free access to a standard certified commercial laboratory diet and water ad libitum.
  • Cell culture In vitro culture of human breast cancer MCF-7 cell line, the culture conditions are 10% fetal bovine serum, 1% Pen Strep, 10 ⁇ g/ml recombinant human insulin in EMEM (cell culture medium), 37°C, 5% CO 2 incubator. Routine digestion with 0.25% trypsin-EDTA digestion solution was performed twice a week for subculture. When the cell saturation is 80%-90% and the number reaches the requirement, collect the cells and count them.
  • Fulvestrant (Fulvestrant, AstraZeneca) dosage is 250mg/kg, subcutaneous injection (SC), administration (QW) once a week, the dosage of formula (I) compound is 30mg/kg , administered orally (PO), administered once a day (QD).
  • SC subcutaneous injection
  • QW administration
  • PO administration
  • QD administration
  • mice There were 11 mice in the vehicle group and 8 mice in the administration group. All groups continued administration until the mice died, were euthanized due to poor condition or the experiment ended.
  • mice The body weight of the mice was measured twice a week, and the survival status of the mice was observed.
  • Test Example 11 The effect of the compound of formula (I) combined with palbociclib on the cell cycle of human breast cancer MCF-7
  • human breast cancer MCF-7 cells were purchased from ATCC, and the culture conditions were DMEM (purchased from Gibco) + 10% FBS (purchased from Gibco) + 0.01 mg/ml human insulin (purchased from Yisheng) + 1% non-essential Amino acids (purchased from Gibco).
  • Palbociclib was purchased from MCE.
  • the compound of formula (I) can cause cell cycle arrest and arrest cells in G1 phase. After combined with palbociclib, it can significantly increase the proportion of G1 phase arrest and reduce the proportion of S phase cells. The results are shown in Table 10.
  • Test Example 12 Inhibitory effect of the compound of formula (I) combined with palbociclib on the proliferation of human breast cancer MCF-7 cells
  • human breast cancer MCF-7 was purchased from ATCC, and the culture conditions were DMEM (Gibco) + 10% FBS (Gibco) + 0.01 mg/ml human insulin (Yisheng) + 1% non-essential amino acids (Gibco).
  • Palbociclib was purchased from MCE.
  • Use Echo650 (Beckman) to transfer 120nL of 2-fold serial dilution of the compound of formula (I) (in the form of succinate) to the cell plate, and transfer 120nL of 2-fold serial dilution of palbociclib to the cell plate at the same time, add 40 ⁇ L of medium, After 7 days of compound treatment, CellTiter-Glo (Promega) was added to detect cell viability, cell wells were used as 100% viability control, medium wells were used as 0% viability control, combined analysis was carried out using Combinefit (a value greater than 10 indicated that a better combination was obtained) with synergistic effects).
  • results The compound of formula (I) combined with palbociclib has a synergistic effect on the proliferation inhibition of human breast cancer MCF-7 cells, and the results are shown in FIG. 4 .
  • Test Example 13 Combination pharmacodynamic study of human breast cancer MCF-7 xenograft subcutaneous xenograft mouse model
  • Human breast cancer MCF-7 cells ECACC, 86012803
  • EMEM medium ATCC, Cat No.: 30-2003
  • Fetal bovine serum ExCell; Cat No.: FND500
  • Double antibody Gibco, Cat No.: 15240-062
  • mice Female, 6-8 weeks old, weighing about 18-22 grams, were purchased from Shanghai Lingchang Biotechnology Co., Ltd., and the mice were raised in an SPF-grade environment. Each cage Separate exhaust ventilation was provided and all animals had free access to a standard certified commercial laboratory diet and water ad libitum.
  • Cell culture human breast cancer MCF-7 cell line was cultured in vitro, and the culture conditions were 10% fetal bovine serum and 1% double antibody in EMEM (cell culture medium), 37° C., 5% CO 2 incubator. Routine digestion with 0.25% trypsin-EDTA digestion solution was performed twice a week for subculture. When the cell saturation is 80%-90% and the number reaches the requirement, collect the cells and count them.
  • the dosage of the compound of formula (I) (in the form of succinate, the dose is calculated as free base) is 1 mg/kg, administered orally (PO), once a day (QD) ⁇ 25 times.
  • the dosage of palbociclib is 40 mg/kg, administered orally (PO), administered once a day (QW) x 25 times. 8 mice per group.
  • Tumor diameters were measured twice a week with vernier calipers.
  • Mouse body weights were measured twice a week.
  • TGI (%) [(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment of the solvent control group-at the beginning of treatment of the solvent control group Average tumor volume)] ⁇ 100%.
  • the vehicle group has 1 mouse body weight to drop more than 10%
  • palbociclib (40mg/kg) group has 4 mice body weight to drop more than 10%
  • palbociclib (40mg/kg) and formula (I) compound (1mg/kg) kg) combination group there was one mouse whose body weight decreased by more than 10%. It can be seen that in this model, 40mg/kg of palbociclib has a certain effect on animal body weight. There was no morbidity or mortality in this model.
  • test results showed that on the 24th day after the start of administration (Day 24), palbociclib administered orally once a day to tumor-bearing mice at 40 mg/kg showed a certain effect of inhibiting tumor growth (P ⁇ 0.0001); 1mg/kg of the compound of formula (I) in tumor-bearing mice showed a significant effect of inhibiting tumor growth (P ⁇ 0.0001); Compared with the vehicle control group and the corresponding single drug group, it showed a significantly enhanced tumor inhibitory effect.

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Abstract

L'invention concerne une combinaison de médicaments comprenant un composé représenté par la formule (K) en tant que répresseur sélectif du récepteur des œstrogènes (SERD) ou un sel pharmaceutiquement acceptable de celui-ci et un inhibiteur de CDK4/6, un produit combiné ou une composition pharmaceutique contenant la combinaison de médicaments, ainsi qu'une application de celle-ci.
PCT/CN2022/131280 2021-11-12 2022-11-11 Combinaison de médicaments pour le traitement d'une tumeur, et une application de celle-ci WO2023083283A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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