WO2024088392A1 - 用于***的药物组合、药物组合物及其用途 - Google Patents

用于***的药物组合、药物组合物及其用途 Download PDF

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WO2024088392A1
WO2024088392A1 PCT/CN2023/127188 CN2023127188W WO2024088392A1 WO 2024088392 A1 WO2024088392 A1 WO 2024088392A1 CN 2023127188 W CN2023127188 W CN 2023127188W WO 2024088392 A1 WO2024088392 A1 WO 2024088392A1
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combination
pharmaceutical composition
pharmaceutically acceptable
compound
pharmaceutical
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PCT/CN2023/127188
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English (en)
French (fr)
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杨晨
周峰
薛黎婷
杨桂梅
郭瑶
竹霁
杨文清
朱利丽
唐任宏
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南京再明医药有限公司
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Publication of WO2024088392A1 publication Critical patent/WO2024088392A1/zh

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  • the present disclosure belongs to the field of medicine, and relates to a drug combination comprising a selective estrogen receptor downregulator (SERD) and a mammalian target of rapamycin (mTOR) inhibitor, a combination product or a pharmaceutical composition comprising the drug combination, and use of the drug combination, the combination product or the pharmaceutical composition for treating tumors.
  • SESD selective estrogen receptor downregulator
  • mTOR mammalian target of rapamycin
  • Estrogen and estrogen receptor ⁇ are important drivers of breast cancer development. More than two-thirds of breast cancer patients express ER transcription factors, and in most ER-positive patients, ER remains a key driver even in tumors that progress after early endocrine therapy. Therefore, ER is a major target for breast cancer treatment (Pharmacology & Therapeutics 186 (2016) 1–24). The goal of endocrine therapy is to reduce ER activity.
  • SERMs selective estrogen receptor modulators
  • tamoxifen which is an allosteric modulator of ER and inhibits its transcriptional activity after binding to ER
  • AIs aromatase inhibitors
  • fulvestrant selective estrogen receptor downregulators
  • ER estrogen receptor
  • TAM postoperative endocrine therapy
  • Fulvestrant is the first and only clinically approved SERD drug for the treatment of postmenopausal patients with ER-positive, metastatic breast cancer after progression on tamoxifen or aromatase inhibitors. Data from multiple studies have shown that ER degradation is not completely achieved in patients treated with fulvestrant. In addition, the obvious reactions such as pain, swelling, and redness at the injection site caused by intramuscular injection, as well as its slow absorption and limited in vivo exposure limit its clinical application. Therefore, patients with ER-positive breast cancer are in urgent need of new treatment options.
  • Mammalian target of rapamycin is a key serine-threonine kinase that is expressed in some human tumors.
  • Everolimus (chemical name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12- ⁇ (1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl ⁇ -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxo-4-aza-tricyclo[30.3.1.04,9]-triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentanone, structural formula: ) as a selective inhibitor of mTOR and can be used to treat cancer patients.
  • the present disclosure provides a drug combination comprising at least one selective estrogen receptor downregulator (SERD) and at least one mTOR inhibitor, wherein the SERD is selected from a compound of formula (K) or a pharmaceutically acceptable salt thereof:
  • SESD selective estrogen receptor downregulator
  • R 1 , R 2 , R 3 , and 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 cycloalkyl;
  • X 1 , X 2 , X 3 , and X 4 are independently selected from CR 6 or N;
  • R6 is selected from H, F, Cl, Br, I, OH, CN, C1 - C10 alkyl, C3- C10 cycloalkyl, 3-10 membered heterocyclyl, C1 - C10 alkoxy, C3 - C10 cycloalkyloxy or 3-10 membered heterocyclyloxy;
  • R 5 is selected from C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted by Ra ;
  • Ra is selected from F, Cl, Br, I, OH, CN, C1 - C6 alkyl, C1 - C6 alkoxy or C3 - C6 cycloalkyl.
  • R 1 , R 2 , R 3 , and R 4 in the compound of 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 of formula (K) are independently selected from H, F, or methyl.
  • R 1 and R 2 in the compound of formula (K) are independently selected from H, F or methyl.
  • R 3 and R 4 in the compound of formula (K) are independently selected from H or methyl.
  • R 3 and R 4 in the compound of formula (K) are independently selected from H.
  • R 6 in the compound of formula (K) is selected from H or F.
  • R 5 in the compound of formula (K) is selected from CH 2 CF 3 .
  • the compound of formula (K) or a pharmaceutically acceptable salt thereof is selected from a compound of 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 of formula (K) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound of formula (K) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound of formula (K) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • the mTOR inhibitor is selected from Sirolimus, Temsirolimus, Everolimus, Zotarolimus, Umirolimus, Novolimus, Dactolisib, Onatasertib, or Bimiralisib.
  • the mTOR inhibitor is selected from Everolimus.
  • the present disclosure provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and Everolimus.
  • the pharmaceutical combination is a fixed combination.
  • the fixed combination is in the form of a solid pharmaceutical composition.
  • the solid pharmaceutical composition is selected from a tablet or a capsule.
  • the pharmaceutical combination is a non-fixed combination.
  • the compound of formula (K) or a pharmaceutically acceptable salt thereof such as a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • the mTOR inhibitor such as Everolimus
  • the solid pharmaceutical composition is selected from a tablet or a capsule.
  • the present disclosure also provides a pharmaceutical composition, which comprises any of the above-mentioned drug combinations and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises:
  • the present disclosure provides a combination product, which comprises a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one compound of the above formula (K) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and the second pharmaceutical composition comprises at least one mTOR inhibitor and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a medicine box, which comprises:
  • a second container which contains the pharmaceutical composition II as described above.
  • the compound of formula (K) or a pharmaceutically acceptable salt thereof in the first pharmaceutical composition is Selected from the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the mTOR inhibitor in the pharmaceutical composition II is selected from Everolimus.
  • the present disclosure provides a pharmaceutical kit comprising 1) a first container comprising a pharmaceutical composition I containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; and 2) a second container comprising a pharmaceutical composition II containing Everolimus and a pharmaceutically acceptable excipient.
  • the present disclosure relates to use of any of the above-mentioned drug combinations, pharmaceutical compositions, combination products or drug kits in the preparation of anti-tumor drugs.
  • the present disclosure relates to use of any of the above-mentioned drug combinations, pharmaceutical compositions, combination products or drug kits in anti-tumor treatment.
  • the present disclosure relates to any one of the above-mentioned pharmaceutical combinations, pharmaceutical compositions, combination products or pharmaceutical kits for anti-tumor use.
  • the present disclosure relates to an anti-tumor method, which comprises administering a therapeutically effective amount of any one of the above-mentioned pharmaceutical combinations, pharmaceutical compositions, combination products or pharmaceutical kits to a patient in need thereof.
  • the present disclosure also relates to the use of the compound of formula (K) or a pharmaceutically acceptable salt thereof in combination with at least one mTOR inhibitor in the preparation of an anti-tumor drug.
  • the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one mTOR inhibitor in the preparation of an anti-tumor drug.
  • the mTOR inhibitor is Everolimus.
  • the tumor is breast cancer.
  • the tumor is ER-positive breast cancer.
  • the tumor is ER-positive breast cancer with brain metastasis.
  • the tumor is ER-positive, HER-2-negative locally advanced or metastatic breast cancer.
  • the compound of formula (K) or the compound of formula (I) in the pharmaceutical combination, use or treatment method can be administered at a frequency of 3 times a day (t.i.d), 2 times a day (b.i.d) or once a day (q.d); the daily dosage is 0.01 to 100 mg/kg body weight, or 0.05 to 50 mg/kg body weight, or 0.1 to 30 mg/kg body weight.
  • the mTOR inhibitor or Everolimus in the pharmaceutical combination, use or treatment method can be administered 3 times a day (t.i.d), 2 times a day (b.i.d), once a day (q.d), once a week (q1w), once every 2 weeks (q2w), once every 3 weeks (q3w) or once every 4 weeks (q4w); the daily dosage is 0.01 to 100 mg/kg body weight, or 0.05 to 50 mg/kg body weight, or 0.1 to 30 mg/kg body weight.
  • the combination of the SERD compound disclosed herein and the mTOR inhibitor (such as Everolimus) produces better therapeutic effects in reducing tumor growth or even eliminating tumors, showing excellent anti-tumor efficacy. Tumor synergy effect.
  • tautomer refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates.
  • the present disclosure includes all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures.
  • asymmetric carbon atoms asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also included within the definition of the compounds of the present invention.
  • the compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.
  • an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 , etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.
  • any variable eg, Ra , Rb
  • its definition is independent at each occurrence. For example, if a group is substituted with 2 Rb , each Rb has an independent option.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 , which may be linear or branched.
  • C1 - C10 alkyl is understood to mean a linear 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-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 1 -C 1 -C 1 -C 1 -C 1
  • C 1 -C 3 alkyl may be understood to mean a straight or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include a range such as “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl”, and the “C 1 -C 6 alkyl” may further include a "C 1 -C 3 alkyl”.
  • alkoxy refers to a group resulting from the loss of a hydrogen atom from a hydroxyl group of a straight or branched alcohol, and may be understood as an “alkyloxy” or “alkyl-O-".
  • C 1 -C 10 alkoxy may be understood as a “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”;
  • C 1 -C 6 alkoxy may be understood as a "C 1 -C 6 alkyloxy” or "C 1 -C 6 alkyl-O-".
  • the "C 1 -C 10 alkoxy” may include a “C 1 -C 6 alkoxy” and a “C 1 -C 3 alkoxy", and the "C 1 -C 6 alkoxy” may further include a "C 1 -C 3 alkoxy”.
  • cycloalkyl refers to a fully saturated carbocyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3, 4, 5, 6, 7, 8, 9 or 10-membered ring.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, fused, spirocyclic or bridged ring group having 3, 4, 5, 6, 7, 8, 9 or 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]decyl, etc.
  • C 3 -C 10 cycloalkyl may include "C 3 -C 6 cycloalkyl".
  • C 3 -C 6 cycloalkyl may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Ji et al.
  • C 3 -C 10 cycloalkyloxy may be understood as “C 3 -C 10 cycloalkyl-O-", and preferably, the "C 3 -C 10 cycloalkyloxy” may include "C 3 -C 6 cycloalkyloxy”.
  • heterocyclyl refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spiro or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing atomic groups) in the ring atoms
  • 3-10 membered heterocyclyl refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned in the ring atoms.
  • the heterocyclic group may include but is not limited to: specific examples of 4-membered heterocyclic groups include but are not limited to azetidinyl or oxetanyl; specific examples of 5-membered heterocyclic groups include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups include but are not limited to diazepany
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrole-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-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 heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.
  • drug 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 drug combination may be administered simultaneously, and in some embodiments of the present disclosure, the active ingredients or pharmaceutically acceptable salts thereof in the drug combination may also be administered separately or sequentially.
  • pharmaceutically acceptable salt refers to salts of pharmaceutically acceptable acids or bases, including salts of inorganic acids and bases, organic acids and bases, for example, succinate.
  • composition refers to a mixture of one or more active ingredients of the present disclosure and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure or a pharmaceutical combination thereof to a subject.
  • treatment means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
  • the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” varies 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 their own knowledge and the present disclosure.
  • the terms “subject” or “patient” are used interchangeably.
  • 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 mTOR inhibitors include, but are not limited to, oral, parenteral, intravenous, transdermal, sublingual, intramuscular, and subcutaneous administration. In some specific embodiments, SERD and mTOR inhibitors are administered orally.
  • fixed combination means that the active ingredients (e.g., SERD or mTOR inhibitor) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.
  • the active ingredients are present in the same pharmaceutical formulation, in some embodiments, for example, in the same tablet or the same capsule or the same medicine bag.
  • non-fixed combination refers to two or more active ingredients as independent entities (e.g., pharmaceutical compositions, pharmaceutical preparations) that are administered to a subject simultaneously, concurrently or sequentially and without specific time limits, wherein the active ingredients administered to the subject reach a therapeutically effective level.
  • the individual active ingredients can be packaged, sold or administered as completely independent pharmaceutical compositions.
  • the "non-fixed combination” also includes the combined use of "fixed combinations” or “fixed combinations” with any one or more independent entities of the active ingredients.
  • the SERD and mTOR inhibitor may be in separate or single formulations.
  • the SERD and mTOR inhibitor may be administered simultaneously, separately or sequentially.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do 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, etc.
  • the compounds disclosed herein can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments disclosed in WO2021228210A1, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into compounds of the present disclosure 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., respectively.
  • Certain isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to 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 disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, wherein the deuterium substitution may be partial or full, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they 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.
  • suitable pharmaceutically acceptable excipients for example, they 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.
  • Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions 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 invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure 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 mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • FIG1 is a graph showing the in vitro anti-proliferative synergistic effect of the compound of formula (I) in combination with Everolimus on human breast cancer MCF-7 cells.
  • FIG. 2 is a graph showing the anti-tumor growth effect of the compound of formula (I) in combination with Everolimus in a human breast cancer MCF-7 subcutaneous xenograft mouse model.
  • Test Example 1 Inhibitory effect of the compound of formula (I) combined with everolimus on proliferation of human breast cancer MCF-7 cells
  • Human breast cancer MCF-7 cells were purchased from ATCC, and the culture conditions were DMEM (Gibco) + 10% FBS (Gibco) + 0.01 mg/ml human insulin (Shanghai Yisheng) + 1% non-essential amino acids (Gibco).
  • Everolimus was purchased from MCE (HY-10218).
  • Test Example 2 Combined pharmacodynamic study of human breast cancer MCF-7 xenograft subcutaneous tumor mouse model
  • Human breast cancer MCF-7 cells ATCC HTB-22
  • EMEM culture medium ATCC, Cat No.: 30-2003
  • Fetal bovine serum Gibco; Cat No.: 10091-148
  • Bispecific antibody Gibco, Cat No.: 15140-122
  • Pancreatin-EDTA Gibco, Cat No.: 25200-072
  • mice Female, 6-8 weeks old, weighing approximately 18-22 grams, were purchased from Beijing Weitongda Biotechnology Co., Ltd. The mice were housed in an SPF-grade environment with separate ventilation in each cage, and all animals had free access to standard certified commercial laboratory diets and free drinking water.
  • Cell culture Human breast cancer MCF-7 cell line was cultured in vitro. The culture conditions were 10% fetal bovine serum, 1% double antibody, 10 ⁇ g/ml recombinant human insulin in EMEM (cell culture medium) at 37°C and 5% CO 2 incubator. 0.25% trypsin-EDTA digestion solution was used for routine digestion and passage once or twice a week. When the cell confluence was 80%-90% and the number reached the requirement, the cells were collected and counted.
  • the dosage of the compound of formula (I) (succinate form, dosage based on free base) was 1 mg/kg, administered orally (PO), once a day (QD), for a total of 33 times (until Day 32).
  • the dosage of everolimus in the single-drug group was 2.5 mg/kg, administered orally (PO), once a day (QD), for a total of 28 times (until Day 27).
  • the compound of formula (I) in the combination group was administered 33 times (until Day 32), and everolimus was administered 28 times (until Day 27).
  • the diameter of the tumor was measured with a vernier caliper twice a week.
  • the body weight of the mice was measured twice a week.
  • TGI (%) [(1-(average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the beginning of drug administration)/(average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the beginning of treatment)] ⁇ 100%.
  • Relative tumor volume RTV Vt / V0 , where V0 is the tumor volume measured at the time of group drug administration (i.e. Day 0), and Vt is the tumor volume at a certain measurement. In this experiment, the tumor size of each group was statistically analyzed using the RTV value.
  • the test results showed that on the 32nd day (Day 32) after the start of administration, the single-drug groups (2.5 mg/kg of Everolimus was administered to tumor-bearing mice by oral gavage (PO) once a day until Day 27, and 1 mg/kg of the compound of formula (I) was administered to tumor-bearing mice by oral gavage once a day until Day 32) showed a significant inhibitory effect on tumor growth (P ⁇ 0.0001); the combination group (2.5 mg/kg of Everolimus and 1 mg/kg of the compound of formula (I)) showed a significantly enhanced tumor inhibition effect compared with the vehicle control group and the single-drug group (P ⁇ 0.0001).
  • the single-drug groups 2.5 mg/kg of Everolimus was administered to tumor-bearing mice by oral gavage (PO) once a day until Day 27, and 1 mg/kg of the compound of formula (I) was administered to tumor-bearing mice by oral gavage once a day until Day 32
  • the Jin Zhengjun method is used to determine whether the two drugs have a synergistic effect, also known as the probability addition method.

Abstract

包含选择性***受体下调剂(SERD)和哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂的药物组合，包含所述药物组合的组合产品或药物组合物，以及所述药物组合、组合产品或药物组合物用于制备治疗诸如乳腺癌的肿瘤的药物中的用途，其中所述SERD选自式(K)化合物或其药学上可接受的盐。

Description

用于***的药物组合、药物组合物及其用途
相关申请的交叉引用
本公开要求2022年10月28日向中国国家知识产权局提交的，专利申请号为202211331159.2，发明名称为“用于***的药物组合、药物组合物及其用途”的中国专利申请的优先权和权益。上述在先申请的全文通过援引整体并入本文中。
技术领域
本公开属于医药领域，涉及包含选择性***受体下调剂(SERD)和哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂的药物组合，包含所述药物组合的组合产品或药物组合物，以及所述药物组合、组合产品或药物组合物用于***的用途。
背景技术
***及***α受体(ERα)是乳腺癌发生发展的重要驱动因子。在乳腺癌患者中有超过2/3的患者表达ER转录因子，并且在大多数ER阳性患者中，即使经过早期的内分泌治疗后进展的肿瘤中，ER仍是一个关键的驱动因子，因此ER是乳腺癌治疗的一个主要靶点(Pharmacology&Therapeutics 186(2018)1–24)。内分泌治疗目的是降低ER活性，主要有三类，包括选择性***受体调节剂(SERMs)，比如他莫昔芬(tamoxifen)，是ER的别构调节剂，同ER结合后抑制其转录活性；芳香化酶抑制剂(aromatase inhibitors,AIs),通过抑制雄激素转化为***，减低体内***水平；以及选择性***受体下调剂，比如氟维司群(fulvestrant)，不仅作为ER的拮抗剂抑制其活性，还具有诱导ER蛋白降解的作用。虽然内分泌治疗是***受体阳性乳腺癌患者的首选，但是约有30％的病人在治疗后会发生复发，并且几乎所有的转移性乳腺癌患者都会产生耐药而发生进展。
临床上，约70-80％的乳腺癌检测***受体(ER)呈阳性，这类乳腺癌细胞的增殖严重依赖ER，且50％的乳腺癌死亡病例均为该类分型。早期ER阳性乳腺癌预后较好，5年生存率超过90％。术后内分泌治疗(TAM或AI药物)的病人10年内约30％出现复发，但仍然可以接受标准的内分泌治疗。
氟维司群是首个也是唯一经临床批准用于他莫昔芬或芳香化酶抑制剂进展后治疗ER阳性、转移性乳腺癌的绝经后患者的SERD类药物。多项研究数据显示经氟维司群治疗的患者体内并未能完全实现ER的降解，此外肌肉注射方式造成的注射部位疼痛、肿胀、发红等明显反应，且吸收缓慢、体内暴露量受限等特点限制了其临床应用，因此ER阳性乳腺癌患者亟需新的治疗选择。
哺乳动物雷帕霉素靶蛋白(mTOR)是一种关键丝氨酸-苏氨酸激酶，在一些人体肿瘤中 活性上调。依维莫司(Everolimus，化学名为(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-二羟基-12-{(1R)-2-[(1S,3R,4R)-4-(2-羟基乙氧基)-3-甲氧基环己基]-1-甲基乙基}-19,30-二甲氧基-15,17,21,23,29,35-六甲基-11,36-二氧-4-氮杂-三环[30.3.1.04,9]-三十六碳-16,24,26,28-四烯-2,3,10,14,20-戊酮，结构式为)作为mTOR选择性抑制剂，可用于癌症患者的治疗。
发明内容
一方面，本公开提供一种药物组合，所述药物组合包含至少一种选择性***受体下调剂(SERD)和至少一种mTOR抑制剂，其中所述SERD选自式(K)化合物或其药学上可接受的盐：
其中，
R1、R2、R3、R4独立地选自H、F、Cl、Br、I、CN、C1-C6烷基、C1-C6烷氧基或C3-C6环烷基；
X1、X2、X3、X4独立地选自CR6或N；
R6选自H、F、Cl、Br、I、OH、CN、C1-C10烷基、C3-C10环烷基、3-10元杂环基、C1-C10烷氧基、C3-C10环烷基氧基或3-10元杂环基氧基；
R5选自C1-C6烷基，所述C1-C6烷基任选被Ra取代；
Ra选自F、Cl、Br、I、OH、CN、C1-C6烷基、C1-C6烷氧基或C3-C6环烷基。
在一些实施方案中，式(K)化合物中的R1、R2、R3、R4独立选自H、F、Cl、Br、I、CN或C1-C6烷基。
在一些实施方案中，式(K)化合物中的R1、R2、R3、R4独立选自H、F或甲基。
在一些实施方案中，式(K)化合物中的R1、R2独立选自H、F或甲基。
在一些实施方案中，式(K)化合物中的R3、R4独立选自H或甲基。
在一些实施方案中，式(K)化合物中的R3、R4独立选自H。
在一些实施方案中，式(K)化合物中的结构单元选自
在一些实施方案中，式(K)化合物中的R6选自H或F。
在一些实施方案中，式(K)化合物中的结构单元选自
在一些实施方案中，式(K)化合物中的R5选自CH2CF3。
在一些实施方案中，所述式(K)的化合物或其药学上可接受的盐选自式(K-1)化合物或其药学上可接受的盐：
其中，R1、R2、R3、R4、R5、X1、X2、X3、X4如上文定义。
在一些实施方案中，所述式(K)的化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
在一些实施方案中，所述式(K)的化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
在一些实施方案中，所述式(K)化合物或其药学上可接受的盐选自式(I)化合物或其药学上可接受的盐：
在一些实施方案中，所述mTOR抑制剂选自Sirolimus、Temsirolimus、Everolimus、Zotarolimus、Umirolimus、Novolimus、Dactolisib、Onatasertib或Bimiralisib。
在一些实施方案中，所述mTOR抑制剂选自Everolimus。
在一些实施方案中，本公开提供一种药物组合，所述药物组合包含式(I)化合物或其药学上可接受的盐和Everolimus。
在一些实施方案中，所述药物组合是固定组合。在一些实施方案中，所述固定组合呈固体药物组合物的形式。在一些实施方案中，所述固体药物组合物选自片剂或胶囊。
在一些实施方案中，所述药物组合是非固定组合。在一些实施方案中，所述非固定组合中的式(K)化合物或其药学上可接受的盐(如式(I)化合物或其药学上可接受的盐)和mTOR抑制剂(如Everolimus)各自呈固体药物组合物形式。在一些实施方案中，所述固体药物组合物选自片剂或胶囊。
另一方面，本公开还提供了一种药物组合物，所述药物组合物包含上述任一药物组合，和至少一种药学上可接受的辅料。
在一些实施方案中，所述药物组合物包含：
1)式(I)化合物或其药学上可接受的盐；
2)Everolimus；和，
3)至少一种药学上可接受的辅料。
另一方面，本公开提供了一种组合产品，所述组合产品包含第I药物组合物和第II药物组合物，所述第I药物组合物包含至少一种上述式(K)化合物或其药学上可接受的盐和药学上可接受的辅料，所述第II药物组合物包含至少一种上述mTOR抑制剂和药学上可接受的辅料。
本公开还提供了一种药盒，其包含：
1)第一容器，所述第一容器包含如上所述的第I药物组合物；和，
2)第二容器，所述第二容器包含如上所述的第II药物组合物。
本公开的一个实施方案中，所述第I药物组合物中的式(K)化合物或其药学上可接受的盐 选自式(I)化合物或其药学上可接受的盐。
本公开的一个实施方案中，所述第II药物组合物中的mTOR抑制剂选自Everolimus。
在一些实施方案中，本公开提供了一种药盒，其包含1)第一容器，所述第一容器包含含有式(I)化合物或其药学上可接受的盐和药学上可接受的辅料的第I药物组合物；和2)第二容器，所述第二容器包含含有Everolimus和药学上可接受的辅料的第II药物组合物。
另一方面，本公开涉及上述任一药物组合、药物组合物、组合产品或药盒在制备用于抗肿瘤药物中的用途。
另一方面，本公开涉及上述任一药物组合、药物组合物、组合产品或药盒在抗肿瘤中的用途。
另一方面，本公开涉及用于抗肿瘤的上述任一药物组合、药物组合物、组合产品或药盒。
另一方面，本公开涉及抗肿瘤的方法，该方法包括向有需要的患者施用治疗有效量的上述任一药物组合、药物组合物、组合产品或药盒。
另一方面，本公开还涉及式(K)化合物或其药学上可接受的盐联合至少一种mTOR抑制剂在制备用于抗肿瘤药物中的用途。
进一步，本公开涉及式(I)化合物或其药学上可接受的盐联合至少一种mTOR抑制剂在制备用于抗肿瘤药物中的用途。
本公开的一个实施方案中，所述mTOR抑制剂为Everolimus。
本公开的一个实施方案中，所述肿瘤为乳腺癌。
本公开的一个实施方案中，所述肿瘤为ER阳性乳腺癌。
本公开的一个实施方案中，所述肿瘤为脑转移的ER阳性乳腺癌。
本公开的一个实施方案中，所述肿瘤为ER阳性，HER-2阴性局部晚期或转移性乳腺癌。
在一些实施方案中，所述药物组合、用途或治疗方法中式(K)化合物或式(I)化合物可以每日3次(t.i.d)、每日2次(b.i.d)或每日1次(q.d)的频率施用；每天给药的剂量为0.01到100mg/kg体重，或0.05到50mg/kg体重，或0.1到30mg/kg体重。
在一些实施方案中，所述药物组合、用途或治疗方法中mTOR抑制剂或Everolimus可以每日3次(t.i.d)、每日2次(b.i.d)、每日1次(q.d)、每周1次(q1w)、每2周1次(q2w)、每3周1次(q3w)或每4周一次(q4w)的频率施用；每天给药的剂量为0.01到100mg/kg体重，或0.05到50mg/kg体重，或0.1到30mg/kg体重。
技术效果
相对于单独给予该组合中的任一药物，本公开SERD化合物与mTOR抑制剂(如Everolimus)的联用在减少肿瘤的生长或甚至消除肿瘤方面产生更好的疗效，表现出优异的抗 肿瘤协同效果。
术语定义和说明
除非另有说明，本公开说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本公开说明书记载的范围内。
本文中表示连接位点。
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔实键和楔虚键表示一个立体中心的绝对构型，用直实键和直虚键表示一个立体中心的相对构型(如脂环化合物的顺反构型)。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本公开化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本公开包含化合物的所有互变异构形式。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。
本公开的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本公开的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本公开化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本公开化合物的定义范围之内。本公开的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，是指乙基可以是未被取代的(CH2CH3)、单取代的(CH2CH2F、CH2CH2Cl等)、多取代的(CHFCH2F、CH2CHF2、CHFCH2Cl、CH2CHCl2等)或完全被取代的(CF2CF3、CF2CCl3、CCl2CCl3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
当任何变量(例如Ra、Rb)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个Rb所取代，则每个Rb都有独立的选项。
术语“卤代”或“卤素”是指氟、氯、溴和碘。
术语“烷基”是指通式为CnH2n+1的烃基，该烷基可以是直链或支链的。术语“C1-C10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；术语“C1-C6烷基”可理解为表示具有1至6个碳原子的烷基，具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C1-C3烷基”可理解为表示具有1至3个碳原子的直链或支链饱和烷基。所述“C1-C10烷基”可以包含“C1-C6烷基”或“C1-C3烷基”等范围，所述“C1-C6烷基”可以进一步包含“C1-C3烷基”。
术语“烷氧基”是指直链或支链醇类失去羟基上的氢原子产生的基团，可理解为“烷基氧基”或“烷基-O-”。术语“C1-C10烷氧基”可理解为“C1-C10烷基氧基”或“C1-C10烷基-O-”；术语“C1-C6烷氧基”可理解为“C1-C6烷基氧基”或“C1-C6烷基-O-”。所述“C1-C10烷氧基”可以包含“C1-C6烷氧基”和“C1-C3烷氧基”等范围，所述“C1-C6烷氧基”可以进一步包含“C1-C3烷氧基”。
术语“环烷基”是指完全饱和的且以单环、稠环、桥环或螺环等形式存在的碳环基团。除非另有指示，该碳环通常为3、4、5、6、7、8、9或10元环。术语“C3-C10环烷基”可理解为表示饱和的单环、并环、螺环或桥环基，其具有3、4、5、6、7、8、9或10个碳原子。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C3-C10环烷基”可以包含“C3-C6环烷基”，术语“C3-C6环烷基”可理解为表示饱和的单环或双环烃环，其具有3～6个碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己 基等。
术语“C3-C10环烷基氧基”可理解为“C3-C10环烷基-O-”，优选地，“C3-C10环烷基氧基”可以包含“C3-C6环烷基氧基”。
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)单环、稠环、螺环或桥环基团，其环原子中含有1、2、3、4或5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O)2-、-S(＝O)-、-P(＝O)2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“3-10元杂环基”是指环原子数目为3、4、5、6、7、8、9或10的杂环基，且其环原子中含有1、2、3、4或5个独立选自上文所述的杂原子或杂原子团。特别地，所述杂环基可以包括但不限于：4元杂环基的具体实例包括但不限于氮杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基；7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。本公开中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。
术语“3-10元杂环基氧基”是指“3-10元杂环基-O-”。
术语“药物组合”是指两种或两种以上的活性成分或其药学上可接受的盐的组合。在本公开的一些实施方案中，所述药物组合中的活性成分或其药学上可接受的盐可以同时施用，在本公开的一些实施方案中，所述药物组合中的活性成分或其药学上可接受的盐也可以分别或序贯施用。
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐，包括无机酸和碱、有机酸和碱的盐，例如琥珀酸盐。
术语“药物组合物”是指一种或多种本公开的活性成分与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对主体给予本公开的化合物或其药物组合。
术语“治疗”意为将本公开所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
在本文中，术语“受试者”或“患者”可互换使用。在一些实施方案中，术语“受试者”或“患者”是哺乳动物。在部分实施方案中，所述受试者或患者是小鼠。在部分实施方案中，所述受试者或患者是人。
术语“施用”表示，使用本领域技术人员已知的多种方法和递送***中的任一种，向主体物理引入包含治疗剂的组合物。SERD和mTOR抑制剂的施用途径包括但不限于口服、肠胃外、静脉内、透皮、舌下、肌内和皮下给药。在一些特定的实施方案中，SERD和mTOR抑制剂通过口服给药。
术语“固定组合”指活性组分(例如SERD或mTOR抑制剂)以固定的总剂量或剂量比例，或以单一实体、药物组合物或制剂的形式同时给予受试者。换言之，活性组分存在于同一药物制剂中，在部分实施方案中，例如存在于同一片剂或同一胶囊或同一药袋中。
术语“非固定组合”指两种或两种以上的活性组分作为独立的实体(例如药物组合物、药物制剂)同时、并行或依序且无具体时间限制地给予受试者，其中给予受试者的所述活性组分达到治疗有效量水平。在非固定组合中，所述各个活性组分可以作为完全独立的药物组合物进行包装、销售或给药。所述“非固定组合”也包括“固定组合”之间、或“固定组合”与任一种或多种活性组分的独立实体的联合使用。
本公开的药物组合或药物组合物中，SERD和mTOR抑制剂可以在分开的或单一的制剂中。当SERD和mTOR抑制剂在分开的制剂中时，SERD和mTOR抑制剂可以同时、分别或序贯施用。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”、“含有(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括WO2021228210A1公开的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式。
本公开还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
某些同位素标记的本公开化合物(例如用3H及14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。
此外，用较重同位素(诸如氘(即2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
附图的简要说明
图1为式(I)化合物和Everolimus联用对人乳腺癌MCF-7细胞的体外抗增殖协同效果图。
图2为式(I)化合物和Everolimus联用在人乳腺癌MCF-7异种皮下移植瘤小鼠模型上抗肿瘤生长效果图。
实施例
下面通过实施例对本公开进行详细描述，但并不意味着对本公开进行任何限制。本文已经详细地描述了本公开，其中也公开了其具体实施例，对本领域的技术人员而言，在不脱离本公开精神和范围的情况下针对本公开具体实施例进行各种改变和改进将是显而易见的。本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。
实施例1：式(I)化合物琥珀酸盐的制备
将5.0g游离态式(I)化合物(制备方法参考WO2021228210A1实施例3)、100ml异丙醚装入250ml单口瓶中，室温搅拌至固体完全溶清。加入1.21g琥珀酸，室温搅拌过夜，抽滤，室温真空干燥3h，得5.4g式(I)化合物琥珀酸盐固体。
测试例1式(I)化合物与依维莫司联用对人乳腺癌MCF-7细胞的增殖抑制作用
细胞及化合物信息：人乳腺癌MCF-7细胞购自ATCC，培养条件为DMEM(Gibco)+10％FBS(Gibco)+0.01mg/ml人胰岛素(上海翌圣)+1％非必需氨基酸(Gibco)。依维莫司购自MCE(HY-10218)。
实验方法：培养人乳腺癌MCF-7细胞，细胞融合率达到70％以上时，消化细胞，调整密度为500/20μL/孔种在384孔细胞培养板中(Corning)培养过夜。使用Echo650(Beckman)转移120nL的2倍梯度稀释式(I)化合物(琥珀酸盐的形式)至细胞板中,同时转移60nL 2倍梯度稀释依维莫司至细胞板中，补加40μL培养基，化合物处理7天后，加入CellTiter-Glo(Promega)检测细胞活力，细胞孔作为100％活力对照，培养基孔作为0％活力对照，使用Combenefit进行联用分析(数值大于10表明取得了较好的联用协同效果)。
结果：式(I)化合物(0.5～512nM)联合依维莫司(2～2048nM)对人乳腺癌MCF-7细胞的增殖抑制有协同作用效果，其中在2～16nM式(I)化合物联合16～64nM依维莫司联用范围内表现出强协同作用，结果见图1。
测试例2：人乳腺癌MCF-7异种皮下移植瘤小鼠模型联用药效学研究
实验材料：
人乳腺癌MCF-7细胞：ATCC HTB-22
17β-***片：Innovative Research of America,Cat No.:SE-121,60-day release,0.72mg/pellet
EMEM培养液：ATCC,Cat No.:30-2003
胎牛血清：Gibco；Cat No.:10091-148
双抗：Gibco,Cat No.:15140-122
0.25％胰酶-EDTA：Gibco,Cat No.:25200-072
PBS：Hyclone Cytiva,Cat.No.:SH30256.01
基质胶:Corning,Cat.No.:356234
依维莫司(Everolimus)：MCE，Cat No.:159351-69-6
实验方法：
动物信息：NPG小鼠，雌性，6-8周，体重约18-22克，动物购自北京维通达生物技术有限公司，将小鼠饲养在SPF级的环境中，每个笼位单独送排风，所有动物都可以自由获取标准认证的商业实验室饮食和自由饮水。
细胞培养：人乳腺癌MCF-7细胞株体外培养，培养条件为EMEM(细胞培养液)中加入10％胎牛血清，1％双抗，10μg/ml重组人胰岛素37℃，5％CO2孵箱。一周一到两次用0.25％胰酶-EDTA消化液进行常规消化处理传代。当细胞汇合度为80％-90％，数量达到要求时，收取细胞，计数。
细胞接种：于细胞接种前一天皮下接种17β-***贴片。细胞接种当天，将0.1ml/(含1×107个)MCF-7细胞悬液(PBS：基质胶，体积比为1:1)皮下接种于每只小鼠的右后背，在接种细胞后第23天，肿瘤平均体积达到约166mm3时开始分组给药，依据肿瘤体积随机分组给药，分组当天为Day 0。
给药：式(I)化合物(琥珀酸盐形式，剂量以游离碱计)的给药剂量为1mg/kg，口服给药(PO)，每天一次给药(QD)，共给药33次(至Day 32)。单药组依维莫司(Everolimus)的给药剂量为2.5mg/kg，口服给药(PO)，每天一次给药(QD)，共给药28次(至Day 27)。每组8只小鼠。同样地，联用组中式(I)化合物共给药33次(至Day 32)，依维莫司共给药28次(至Day 27)。
肿瘤测量和实验指标：
每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b2，a和b分别表示肿瘤的长径和短径。每周两次测量小鼠体重。
化合物的抑瘤疗效用肿瘤生长抑制率TGI(％)来评价。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100％。相对肿瘤体积RTV＝Vt/V0，其中V0是分组给药时(即Day 0)测量所得肿瘤体积，Vt为某一次测量时的肿瘤体积。本实验中各组肿瘤大小以RTV值进行统计学分析。
实验结果：
见表1和图2。溶剂组有1只小鼠因为***贴片的副作用，在接种***贴片后的第35天(分组给药后第11天)死亡，Everolimus(2.5mg/kg)组有1只小鼠体重下降超过20％，后又自行恢复体重，而式(I)化合物(1mg/kg)单药组及其与Everolimus(2.5mg/kg)联用组的体重在实验过程中相对平稳。
试验结果表明，开始给药后第32天(Day 32)，单药组(一天一次灌胃(PO)给予荷瘤小鼠2.5mg/kg的Everolimus至Day 27，和一天一次灌胃给予荷瘤小鼠1mg/kg的式(I)化合物至Day 32)均显示明显的抑制肿瘤生长的作用(P<0.0001)；联用组(2.5mg/kg的Everolimus和1mg/kg式(I)化合物)，其相对于溶媒对照组和单药组均显示出显著增强的抑瘤效果(P<0.0001)。
采用金正均法判定两药物是否具有协同作用，也称概率相加法，具体公式：q＝Eab/(Ea+Eb-Ea×Eb)，其中Ea、Eb是单药的药效，Eab为联用药效。若q值在0.85-1.15间为两药合用单纯相加，若q>1.15为有协同作用，若q<0.85表示两药合用有拮抗作用。以TGI(％)作为药效值代入金正均法公式，得出q＝1.43，联用组具备协同作用。
表1 MCF-7皮下瘤模型肿瘤体积

Claims (14)

  1. 一种药物组合，所述药物组合包含至少一种选择性***受体下调剂(SERD)和至少一种mTOR抑制剂，其中所述SERD选自式(K)化合物或其药学上可接受的盐：
    其中，
    R1、R2、R3、R4独立地选自H、F、Cl、Br、I、CN、C1-C6烷基、C1-C6烷氧基或C3-C6环烷基；
    X1、X2、X3、X4独立地选自CR6或N；
    R6选自H、F、Cl、Br、I、OH、CN、C1-C10烷基、C3-C10环烷基、3-10元杂环基、C1-C10烷氧基、C3-C10环烷基氧基或3-10元杂环基氧基；
    R5选自C1-C6烷基，所述C1-C6烷基任选被Ra取代；
    Ra选自F、Cl、Br、I、OH、CN、C1-C6烷基、C1-C6烷氧基或C3-C6环烷基。
  2. 根据权利要求1所述的药物组合，其中所述式(K)化合物或其药学可接受的盐选自以下化合物或其药学可接受的盐：

  3. 根据权利要求1或2所述的药物组合，其中所述mTOR抑制剂选自Sirolimus、Temsirolimus、Everolimus、Zotarolimus、Umirolimus、Novolimus、Dactolisib、Onatasertib或Bimiralisib。
  4. 根据权利要求1至3中任一项所述的药物组合，其中所述式(K)化合物或其药学上可接受的盐选自式(I)化合物或其药学上可接受的盐：
  5. 根据权利要求1至4中任一项所述的药物组合，其中所述mTOR抑制剂选自Everolimus。
  6. 一种组合产品，所述组合产品包含第I药物组合物和第II药物组合物，其中所述第I药物组合物包含如权利要求1、2和4中任一项所述的式(K)化合物或其药学可接受的盐和药学上可接受的辅料，以及所述第II药物组合物包含至少一种mTOR抑制剂和药学上可接受的辅料。
  7. 根据权利要求6所述的组合产品，其中所述mTOR抑制剂选自Sirolimus、Temsirolimus、Everolimus、Zotarolimus、Umirolimus、Novolimus、Dactolisib、Onatasertib或Bimiralisib。
  8. 根据权利要求6所述的组合产品，其中所述mTOR抑制剂选自Everolimus。
  9. 一种药物组合物，所述药物组合物包含权利要求1至5中任一项所述的药物组合，以及药学上可接受的辅料。
  10. 权利要求1至5中任一项所述的药物组合、权利要求6至8中任一项所述的组合产品或权利要求9所述的药物组合物在制备抗肿瘤药物中的用途。
  11. 一种抗肿瘤的方法，所述方法包括向有需要的患者施用治疗有效量的如权利要求1至5中任一项所述的药物组合、权利要求6至8中任一项所述的组合产品或权利要求9所述的药物组合物。
  12. 用于***的权利要求1至5中任一项所述的药物组合、权利要求6至8中任一项所述的组合产品或权利要求9所述的药物组合物。
  13. 如权利要求10所述的用途、权利要求11所述的方法、或权利要求12所述的药物组合、组合产品或药物组合物，其中所述肿瘤为乳腺癌；或者，所述肿瘤为ER阳性乳腺癌；或者，所述肿瘤为ER阳性脑转移乳腺癌；或者，所述肿瘤为ER阳性，HER-2阴性局部晚期或转移性乳腺癌。
  14. 如权利要求1至5中任一项所述的药物组合、权利要求11或13所述的方法、或权利要求12或13所述的药物组合、组合产品或药物组合物，其中所述式(K)化合物以每日3次(t.i.d)、每日2次(b.i.d)或每日1次(q.d)的频率施用，和/或每天给药的剂量为0.01到100mg/kg体重，或0.05到50mg/kg体重，或0.1到30mg/kg体重；以及
    所述mTOR抑制剂以每日3次(t.i.d)、每日2次(b.i.d)、每日1次(q.d)、每周1次(q1w)、每2周1次(q2w)、每3周1次(q3w)或每4周一次(q4w)的频率施用，和/或每天给药的剂量为0.01到100mg/kg体重，或0.05到50mg/kg体重，或0.1到30mg/kg体重。
PCT/CN2023/127188 2022-10-28 2023-10-27 用于***的药物组合、药物组合物及其用途 WO2024088392A1 (zh)

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