WO2019174590A1 - 用于治疗三阴性乳腺癌的喹啉衍生物 - Google Patents

用于治疗三阴性乳腺癌的喹啉衍生物 Download PDF

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Publication number
WO2019174590A1
WO2019174590A1 PCT/CN2019/077946 CN2019077946W WO2019174590A1 WO 2019174590 A1 WO2019174590 A1 WO 2019174590A1 CN 2019077946 W CN2019077946 W CN 2019077946W WO 2019174590 A1 WO2019174590 A1 WO 2019174590A1
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Prior art keywords
acid
breast cancer
negative breast
compound
administration
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PCT/CN2019/077946
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English (en)
French (fr)
Inventor
田心
吕鹏
杨玲
王祥建
张喜全
王善春
王训强
江海
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正大天晴药业集团股份有限公司
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Priority to CN201980016212.XA priority Critical patent/CN111757737B/zh
Priority to US16/980,786 priority patent/US11554115B2/en
Publication of WO2019174590A1 publication Critical patent/WO2019174590A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is in the field of medicine, and the present invention relates to the use of a quinoline derivative for the preparation of a pharmaceutical composition for the treatment of tumors.
  • the invention relates to the use of a quinoline derivative for the treatment of triple negative breast cancer.
  • TNBC Triple-negative breast cancer refers to estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2). -2, HER2) Breast cancer with negative expression.
  • ER estrogen receptor
  • PR progesterone receptor
  • human epidermal growth factor receptor 2 human epidermal growth factor receptor 2
  • HER2 human epidermal growth factor receptor 2
  • TNBC accounts for approximately 15-20% of the 1.7 million breast cancers diagnosed each year worldwide. TNBC has unique pathological and clinical features, with an invasive phenotype and high metastatic rate, and the prognosis is worse than other types.
  • the 5-year survival rate of TNBC is 70%, while the 5-year survival rate of other types of breast cancer is about 80%.
  • TNBC can be divided into 7 subtypes (6 definable subtypes and 1 unstable subtype), including basal-like (BL), mesenchymal (M), mesenchyme Mesenchymal stem-like (MSL), luminal androgen receptor (LAR), immunomodulatory (IM) and unstable (UNS), of which BL is divided into BL1 and BL2.
  • BL basal-like
  • M mesenchymal
  • MSL mesenchyme Mesenchymal stem-like
  • LAR luminal androgen receptor
  • IM immunomodulatory
  • UNS unstable
  • Hormone-targeting drugs such as tamoxifen and aromatase inhibitors, as well as HER2-targeted drugs such as Herceptin, are ineffective in the treatment of TNBC.
  • the standard treatment for TNBC is still chemotherapy, although it is often accompanied by limited efficacy and poor survival outcomes.
  • the lack of treatment options suggests the need and urgency to develop effective therapies for TNBC.
  • the invention provides a method of treating triple negative breast cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the treatment of triple negative breast cancer or in the manufacture of a medicament for the treatment of triple negative breast cancer.
  • the invention provides a pharmaceutical composition for treating triple negative breast cancer, the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the application provides a kit for treating triple negative breast cancer comprising (a) at least one unit dose of a pharmaceutical composition of Compound I or a pharmaceutically acceptable salt thereof and (b) for treatment Instructions for triple negative breast cancer.
  • the invention provides a method of treating triple negative breast cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the triple negative breast cancer is advanced or metastatic triple negative breast cancer.
  • the triple negative breast cancer is a triple negative breast cancer that has failed prior treatment.
  • the triple negative breast cancer is a triple negative breast cancer that fails treatment with radiotherapy and/or chemotherapy.
  • the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with an anthracycline and/or a taxane. In some embodiments, the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with paclitaxel.
  • the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with an antimetabolite. In some embodiments, the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse following prior treatment with gemcitabine and/or capecitabine.
  • the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with a platinum drug. In some embodiments, the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with cisplatin.
  • Compound I can be administered in the form of its free base or it can be administered in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the invention, and the salt can be produced from different organic and inorganic acids according to methods well known in the art.
  • the administration is in the form of Compound I hydrochloride. In some embodiments, the administration is in the form of Compound I monohydrochloride. In some embodiments, the administration is in the form of Compound I dihydrochloride. In some embodiments, the administration is in the form of a crystal of Compound I hydrochloride. In a particular embodiment, it is administered in the form of a crystal of Compound I dihydrochloride. In some embodiments, the administration is in the form of Compound I maleate.
  • Compound 1, or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, those selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrahepatic, intra-articular, intraperitoneal or intrathecal. In a particular embodiment, it is administered orally.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 3 mg to 30 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 16 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 14 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 8 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 10 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In one embodiment, the oral solid preparation is administered once a day.
  • the method of administration can be comprehensively determined based on the activity, toxicity, and tolerance of the patient.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered in a separate manner.
  • the interval administration includes a administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times a day during the administration period.
  • Compound I or a pharmaceutically acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated a plurality of times.
  • the ratio of the administration period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, still more preferably 2:0.5 to 1.
  • the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks
  • the two-week interval administration method can be repeated a plurality of times.
  • the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day for 14 days, followed by 7 days of withdrawal; followed by 1 administration per day for 14 days, followed by 7 days of discontinuation, such continuous administration for 2 weeks
  • the interval of administration of the drug for one week can be repeated a plurality of times.
  • the administration is continued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, then for 2 days; then once a day for 5 days, then for 2 days, such continuous administration for 5 days.
  • the two-day interval administration method can be repeated multiple times.
  • the oral administration is administered once daily at a dose of 12 mg, administered continuously for 2 weeks, and administered for 1 week.
  • the oral administration is administered once daily at a dose of 10 mg, administered continuously for 2 weeks, and administered for 1 week.
  • it is administered orally at a dose of 8 mg once a day for 2 weeks, and for 1 week.
  • the invention also provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the treatment of triple negative breast cancer or in the manufacture of a medicament for the treatment of triple negative breast cancer.
  • the triple negative breast cancer is advanced or metastatic triple negative breast cancer.
  • the triple negative breast cancer is a triple negative breast cancer that has failed prior treatment.
  • the triple negative breast cancer is a triple negative breast cancer that fails treatment with radiotherapy or chemotherapy.
  • the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with an anthracycline and/or a taxane. In some embodiments, the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with paclitaxel.
  • the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with an antimetabolite. In some embodiments, the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse following prior treatment with gemcitabine and/or capecitabine.
  • the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with a platinum drug. In some embodiments, the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with cisplatin.
  • Compound I can be administered in the form of its free base or it can be administered in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the invention, and the salt can be produced from different organic and inorganic acids according to methods well known in the art.
  • the administration is in the form of Compound I hydrochloride. In some embodiments, the administration is in the form of Compound I monohydrochloride. In some embodiments, the administration is in the form of Compound I dihydrochloride. In some embodiments, it is administered in the form of a crystal of Compound I hydrochloride. In a particular embodiment, it is administered in the form of a crystal of Compound I dihydrochloride. In some embodiments, the administration is in the form of Compound I maleate.
  • Compound 1, or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, those selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrahepatic, intra-articular, intraperitoneal or intrathecal. In a particular embodiment, it is administered orally.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 3 mg to 30 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 16 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 14 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 8 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 10 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In one embodiment, the oral solid preparation is administered once a day.
  • the method of administration can be comprehensively determined based on the activity, toxicity, and tolerance of the patient.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered in a separate manner.
  • the interval administration includes a administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times a day during the administration period.
  • Compound I or a pharmaceutically acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated a plurality of times.
  • the ratio of the administration period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, still more preferably 2:0.5 to 1.
  • the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks
  • the two-week interval administration method can be repeated a plurality of times.
  • the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day for 14 days, followed by 7 days of withdrawal; followed by 1 administration per day for 14 days, followed by 7 days of discontinuation, such continuous administration for 2 weeks
  • the interval of administration of the drug for one week can be repeated a plurality of times.
  • the administration is continued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, then for 2 days; then once a day for 5 days, then for 2 days, such continuous administration for 5 days.
  • the two-day interval administration method can be repeated multiple times.
  • the oral administration is administered once daily at a dose of 12 mg, administered continuously for 2 weeks, and administered for 1 week.
  • the oral administration is administered once daily at a dose of 10 mg, administered continuously for 2 weeks, and administered for 1 week.
  • it is administered orally at a dose of 8 mg once a day for 2 weeks, and for 1 week.
  • the invention provides a pharmaceutical composition for treating triple negative breast cancer, the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the triple negative breast cancer is advanced or metastatic triple negative breast cancer.
  • the triple negative breast cancer is a triple negative breast cancer that has failed prior treatment.
  • the triple negative breast cancer is a triple negative breast cancer that fails treatment with radiotherapy or chemotherapy.
  • the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with an anthracycline and/or a taxane. In some embodiments, the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with paclitaxel.
  • the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with an antimetabolite. In some embodiments, the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse following prior treatment with gemcitabine and/or capecitabine.
  • the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with a platinum drug. In some embodiments, the triple negative breast cancer is a triple negative breast cancer that has undergone disease progression or relapse after prior treatment with cisplatin.
  • Compound I can be administered in the form of its free base or it can be administered in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the invention, and the salt can be produced from different organic and inorganic acids according to methods well known in the art.
  • the administration is in the form of Compound I hydrochloride. In some embodiments, it is administered as Compound I monohydrochloride. In some embodiments, the administration is in the form of Compound I dihydrochloride. In some embodiments, the administration is in the form of a crystal of Compound I hydrochloride. In a particular embodiment, it is administered in the form of a crystal of Compound I dihydrochloride. In some embodiments, the administration is in the form of Compound I maleate.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 3 mg to 30 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 16 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 14 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 8 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 10 mg. In a specific embodiment, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg.
  • the pharmaceutical composition may be suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, meridian Formulations for topical administration, subcutaneous, intra-, intra-articular, intraperitoneal or intrathecal administration; preferably suitable for oral administration, including tablets, capsules, powders, granules, dropping pills, pastes, powders, and the like, Preference is given to tablets and capsules.
  • the tablet may be a common tablet, a dispersible tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet or an enteric coated tablet
  • the capsule may be a general capsule, a sustained release capsule, a controlled release capsule or an enteric coated capsule.
  • pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • Filling agents include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include hypromellose, poly Retardone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc Powder, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talcum powder, and the like. Pharmaceutical excipients also include coloring agents, sweeteners, and the like.
  • the pharmaceutical composition is a solid formulation suitable for oral administration.
  • the composition may for example be in the form of a tablet or capsule.
  • the pharmaceutical composition is a capsule.
  • the pharmaceutically acceptable carrier of the oral solid formulation comprises mannitol, microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In one embodiment, the oral solid preparation is administered once a day.
  • the administration method of the above pharmaceutical composition can be comprehensively determined based on the activity, toxicity, and tolerance of the patient.
  • Compound 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is administered in a separate manner.
  • the interval administration includes a administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times a day during the administration period.
  • Compound I or a pharmaceutically acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated a plurality of times.
  • the ratio of the administration period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, still more preferably 2:0.5 to 1.
  • the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks
  • the two-week interval administration method can be repeated a plurality of times.
  • the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day for 14 days, followed by 7 days of withdrawal; followed by 1 administration per day for 14 days, followed by 7 days of discontinuation, such continuous administration for 2 weeks
  • the interval of administration of the drug for one week can be repeated a plurality of times.
  • the administration is continued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, then for 2 days; then once a day for 5 days, then for 2 days, such continuous administration for 5 days.
  • the two-day interval administration method can be repeated multiple times.
  • the oral administration is administered once daily at a dose of 12 mg, administered continuously for 2 weeks, and administered for 1 week.
  • the oral administration is administered once daily at a dose of 10 mg, administered continuously for 2 weeks, and administered for 1 week.
  • it is administered orally at a dose of 8 mg once a day for 2 weeks, and for 1 week.
  • kits comprising (a) at least one unit dose of a pharmaceutical composition of Compound 1, or a pharmaceutically acceptable salt thereof, and (b) for treating triple negative breast cancer Instructions.
  • a kit is provided comprising (a) at least one unit dose of a suitable oral formulation of Compound 1, or a pharmaceutically acceptable salt thereof, and (b) treating three in a separate manner Instructions for negative breast cancer.
  • unit dosage or unit dose refers to a pharmaceutical composition packaged in a single package for convenience of administration. For example, each tablet or capsule.
  • kits Compound 1, or a pharmaceutically acceptable salt thereof, can be administered to a patient as the sole active ingredient; in the methods, uses, pharmaceutical compositions or methods provided
  • the kit may further comprise a second drug, Compound I or a pharmaceutically acceptable salt thereof, and a second drug administered to a patient of triple negative breast cancer simultaneously or sequentially.
  • the second type includes, but is not limited to, a chemotherapeutic drug, including but not limited to an anthracycline, a taxane, a platinum, a capecitabine, a cyclophosphamide, and the like.
  • pre-treatment includes, but is not limited to, one or more of radiotherapy, chemotherapy, and targeted therapy, including but not limited to PARP inhibitors (eg, olaparib ( Olaparib), talaazoparib and immunotherapeutic agents (eg PD-L1 inhibitor atezolizumab).
  • PARP inhibitors eg, olaparib ( Olaparib)
  • talaazoparib e.g. PD-L1 inhibitor atezolizumab
  • the crystalline form of the hydrochloride salt of the compound I includes, but is not limited to, the A, B and C type crystals disclosed in Chinese Patent Application No. CN102344438A, wherein the A and B type crystals are substantially free of crystal water and other solvents. Crystallization, Form C crystal is a crystal containing two water of crystallization. In some embodiments, the crystalline form of the dihydrochloride salt of Compound I is Form A crystal.
  • Patient means a mammal, preferably a human.
  • “Pharmaceutically acceptable” means that it is used in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically or otherwise undesirable, and which includes its use for human pharmaceutical use. Accepted.
  • “Pharmaceutically acceptable salt” includes, but is not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, trifluoroacetic acid, propionic acid , caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenyl
  • terapéuticaally effective amount is meant an amount of a compound that is sufficient to effect control of the disease when administered to a human for the treatment of a disease.
  • Treatment failure includes, but is not limited to, disease progression and/or relapse.
  • Treatment means any administration of a therapeutically effective amount of a compound and includes:
  • ORR refers to the objective response rate, specifically CR (complete remission) + PR (partial remission).
  • CBR refers to the clinical benefit rate, specifically CR+PR+SD.
  • the dihydrochloride salt of Compound I is pulverized and passed through a 80 mesh sieve; then uniformly mixed with mannitol and hydroxypropylcellulose; then a prescribed amount of microcrystalline cellulose is added, uniformly mixed, and passed through a 0.8 mm sieve; The magnesium stearate is mixed evenly and filled with capsules.
  • the dihydrochloride salt of Compound I is effective in the treatment of triple negative breast cancer, and patients have different clinical benefits.
  • a 32-year-old female patient underwent right breast mass surgery and postoperative pathology showed: right breast sarcomatoid carcinoma. 6 cycles of chemotherapy, the best effect of PR, the lower part of the lesion involved the chest wall. After the end of chemotherapy, the reexamination found recurrence (multiple nodules and masses in the front chest wall), disease progression after 2 cycles of chemotherapy, and concurrent radiation therapy. After the right breast tumor resection, pathological consultation: breast tumor recurrence, immunohistochemistry results showed: ER (-), PR (-), HER2 (-).
  • NP regimen chemotherapy vinorelbine + cisplatin
  • Postoperative pathology chest wall, subgingival cancer, diagnosis of breast cancer recurrence and metastasis, immunity Grouping: ER(-), PR(-), HER-2(-).
  • Postoperative adjustment chemotherapy (Gemcitabine + Xeloda) for 4 weeks, review of lung, liver, bone metastasis, treatment with albumin paclitaxel, disease progression, imaging findings liver lesions 2.3cm (long diameter), right adrenal metastases 5.6 Cm (long diameter).
  • 12 mg of the compound I dihydrochloride capsule was received, and the drug was administered once a day, according to the regimen of two weeks of continuous administration and one week of withdrawal, that is, one medication cycle every three weeks. After two cycles of medication, the metastases were significantly reduced.
  • the liver lesions were 1.8 cm (long diameter) and the right adrenal metastases were 4.6 cm (long diameter). The patient continues to take the drug until the disease progresses.

Abstract

本发明提供了一种用于治疗三阴性乳腺癌的喹啉衍生物，及其在制备用于肿瘤治疗的药物组合物的用途。具体而言，本发明涉及喹啉衍生物1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺在治疗三阴性乳腺癌中的用途，(I)。

Description

用于治疗三阴性乳腺癌的喹啉衍生物 技术领域
本发明属于医药领域，本发明涉及喹啉衍生物在制备用于肿瘤治疗的药物组合物的用途。具体而言，本发明涉及喹啉衍生物在治疗三阴性乳腺癌中的用途。
背景技术
三阴性乳腺癌(Triple-negative breast cancer,TNBC)是指雌激素受体(estrogen receptor，ER)、孕激素受体(progesterone receptor，PR)和人表皮生长因子受体2(human epidermal growth factor receptor-2，HER2)表达都为阴性的乳腺癌。TNBC在每年全世界新诊断的170万乳腺癌中约占15-20％。TNBC具有独特的病理学和临床特征，其具有侵袭性表型及高的转移率，预后较其它类型差。TNBC的5年生存率为70％，而其它类型乳腺癌5年生存率约为80％。
TNBC可分为7个亚型(6个可定义亚型和1个不稳定亚型)，具体包括基底细胞样(basal-like，BL)、间充质样(mesenchymal，M)、间充质干细胞样(mesenchymal stem-like，MSL)、腔面雄激素受体表达型(luminal androgen receptor，LAR)、免疫调节型(immunomodulatory，IM)和不稳定型(unstable，UNS)，其中BL又分为BL1和BL2。
激素靶向药物如他莫昔芬和芳香化酶抑制剂以及HER2靶向药物如赫赛汀都对TNBC的治疗无效。TNBC的标准治疗仍为化疗，尽管其经常伴有有限的疗效和差的生存结果。治疗选择的缺乏提示了开发针对TNBC的有效疗法的必要性和急迫性。
发明概述
一方面，本发明提供了一种治疗三阴性乳腺癌的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐。
另一方面，本发明提供了化合物I或其药学上可接受的盐在治疗三阴性乳腺癌中的用途或制备用于治疗三阴性乳腺癌的药物中的用途。
再一方面，本发明提供了一种治疗三阴性乳腺癌的药物组合物，所述药物组合物包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。
再一方面，本申请提供了用于治疗三阴性乳腺癌的试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗三阴性乳腺癌的说明书。
发明内容
一方面，本发明提供了一种治疗三阴性乳腺癌的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐。
在一些实施方案中，所述的三阴性乳腺癌为晚期或转移性三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先治疗失败的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为放疗和/或化疗药物治疗失败的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先接受过蒽环类和/或紫杉烷类药物治疗后疾病进展或者复发的三阴性乳腺癌。在一些实施方案中，所述的三阴性乳腺癌为在先接受过紫杉醇治疗后疾病进展或者复发的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先接受过抗代谢药物治疗后疾病进展或者复发的三阴性乳腺癌。在一些实施方案中，所述的三阴性乳腺癌为在先接受过吉西他滨和/或卡培他滨的治疗后疾病进展或者复发的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先接受过铂类药物治疗后疾病进展或者复发的三阴性乳腺癌。在一些实施方案中，所述的三阴性乳腺癌为在先接受过顺铂治疗后疾病进展或者复发的三阴性乳腺癌。
化合物I的化学名称为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
Figure PCTCN2019077946-appb-000001
化合物I可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
在一些实施方案中，以化合物I盐酸盐的形式给药。在一些实施方案中，以化合物I一盐酸盐的形式给药。在一些实施方案中，以化合物I二盐酸盐的形式给药。在一些实施方案中，以化合物I盐酸盐的晶体形式给药。在特定的实施方案中，以化合物I二盐酸盐的 晶体形式给药。在一些实施方案中，以化合物I马来酸盐的形式给药。
化合物I或其药学上可接受的盐可通过多种途径给药，该途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮下、脂肪内、关节内、腹膜内或鞘内。在一个特定的实施方案中，通过口服给药。
给予化合物I或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至16毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至14毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为12毫克。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一个实施方案中，以口服固体制剂每天给药一次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在某些特定的实施方案中，以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次10mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次8mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
另一方面，本发明还提供了化合物I或其药学上可接受的盐在治疗三阴性乳腺癌中的用途或制备用于治疗三阴性乳腺癌的药物中的用途。
在一些实施方案中，所述的三阴性乳腺癌为晚期或转移性三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先治疗失败的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为放疗或化疗药物治疗失败的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先接受过蒽环类和/或紫杉烷类药物治疗后疾病进展或者复发的三阴性乳腺癌。在一些实施方案中，所述的三阴性乳腺癌为在先接受过紫杉醇治疗后疾病进展或者复发的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先接受过抗代谢药物治疗后疾病进展或者复发的三阴性乳腺癌。在一些实施方案中，所述的三阴性乳腺癌为在先接受过吉西他滨和/或卡培他滨的治疗后疾病进展或者复发的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先接受过铂类药物治疗后疾病进展或者复发的三阴性乳腺癌。在一些实施方案中，所述的三阴性乳腺癌为在先接受过顺铂治疗后疾病进展或者复发的三阴性乳腺癌。
化合物I可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
在一些实施方案中，以化合物I盐酸盐的形式给药。在一些实施方案中，以化合物I一盐酸盐的形式给药。在一些实施方案中，以化合物I二盐酸盐的形式给药。在一些实施方 案中，以化合物I盐酸盐的晶体形式给药。在特定的实施方案中，以化合物I二盐酸盐的晶体形式给药。在一些实施方案中，以化合物I马来酸盐的形式给药。
化合物I或其药学上可接受的盐可通过多种途径给药，该途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮下、脂肪内、关节内、腹膜内或鞘内。在一个特定的实施方案中，通过口服给药。
给予化合物I或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至16毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至14毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为12毫克。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一个实施方案中，以口服固体制剂每天给药一次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如 此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在某些特定的实施方案中，以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次10mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次8mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
再一方面，本发明提供了一种治疗三阴性乳腺癌的药物组合物，所述药物组合物包含化合物I或其药学上可接受的盐以及至少一种药学上可接受的载体。
在一些实施方案中，所述的三阴性乳腺癌为晚期或转移性三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先治疗失败的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为放疗或化疗药物治疗失败的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先接受过蒽环类和/或紫杉烷类药物治疗后疾病进展或者复发的三阴性乳腺癌。在一些实施方案中，所述的三阴性乳腺癌为在先接受过紫杉醇治疗后疾病进展或者复发的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先接受过抗代谢药物治疗后疾病进展或者复发的三阴性乳腺癌。在一些实施方案中，所述的三阴性乳腺癌为在先接受过吉西他滨和/或卡培他滨的治疗后疾病进展或者复发的三阴性乳腺癌。
在一些实施方案中，所述的三阴性乳腺癌为在先接受过铂类药物治疗后疾病进展或者复发的三阴性乳腺癌。在一些实施方案中，所述的三阴性乳腺癌为在先接受过顺铂治疗后疾病进展或者复发的三阴性乳腺癌。
化合物I可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
在一些实施方案中，以化合物I盐酸盐的形式给药。在一些实施方案中，以化合物I一 盐酸盐的形式给药。在一些实施方案中，以化合物I二盐酸盐的形式给药。在一些实施方案中，以化合物I盐酸盐的晶体形式给药。在特定的实施方案中，以化合物I二盐酸盐的晶体形式给药。在一些实施方案中，以化合物I马来酸盐的形式给药。
给予化合物I或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至16毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至14毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为12毫克。
所述的药物组合物可以是适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内或鞘内给药的制剂；优选适于口服的制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂。其中片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片，胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。所述的口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。填充剂包括淀粉、乳糖、甘露醇、微晶纤维素等；吸收剂包括硫酸钙、磷酸氢钙、碳酸钙等；润湿剂包括水、乙醇等；粘合剂包括羟丙甲纤维素、聚维酮、微晶纤维素等；崩解剂包括交联羧甲基纤维素钠、交联聚维酮、表面活性剂、低取代羟丙基纤维素等；润滑剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉等。药用辅料还包括着色剂、甜味剂等。
在一个实施方案中，该药物组合物是适于口服的固体制剂。该组合物例如可以是片剂或胶囊的形式。在一个特定的实施方案中，该药物组合物是胶囊。在本发明的一个特定实施方案中，口服固体制剂的药学上可接受的载体包括甘露醇、微晶纤维素、羟丙纤维素、硬脂酸镁。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一个实施方案中，以口服固体制剂每天给 药一次。
上述药物组合物的给药方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐或所述药物组合物。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在某些特定的实施方案中，以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次10mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
在某些特定的实施方案中，以每日一次8mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
再一方面，本申请还提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗三阴性乳腺癌的说明书。在一些实施方案中，提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的适合口服的制剂和(b)以间隔给药的方式治疗三阴性乳腺癌的说明书。所述的“单位剂量(unit dosage或unit dose)”是指为了服用的方便，包装在单个包装中的药物组合物。例如每片片剂或者胶囊。
本文中，除非另有说明，这里提供的剂量和范围都是基于化合物I的游离碱形式的分 子量。
本文中，所提供的方法、用途、药物组合物或试剂盒中，化合物I或其药学上可接受的盐可以作为唯一的活性成分单独给予患者；在所提供的方法、用途、药物组合物或试剂盒中，还可含有第二种药物，化合物I或其药学上可接受的盐与第二种药物同时或依照次序给予三阴性乳腺癌的患者。所述的第二种包括但不限于化疗药物，所述的化疗药物包括但不限于蒽环类、紫杉烷类、铂类、卡培他滨、环磷酰胺等。
本文中，所述的“在先治疗”包括但不限于放疗、化疗和靶向治疗中的一种或者几种，所述的靶向治疗包括但不限于PARP抑制剂(例如奥拉帕尼(olaparib)、他拉唑帕尼(talazoparib))和免疫治疗剂(例如PD-L1抑制剂阿替珠单抗(atezolizumab))。
本文中，所述的化合物I的盐酸盐的晶体形式包括但不限于中国专利申请CN102344438A公开的A、B和C型结晶，其中A和B型结晶为基本上不含结晶水和其它溶剂的结晶，C型结晶为含两个结晶水的结晶。在一些实施方案中，所述的化合物I的二盐酸盐的晶体形式为A型结晶。
除非另有说明，为本申请的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
“患者”是指哺乳动物，优选人。
“药学上可接受的”是指其用于制备药物组合物，该药物组合物通常是安全、无毒的并且既不在生物学上或其它方面不合乎需要，并且包括其对于人类药物使用是可接受的。
“药学上可接受的盐”包括，但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等等形成的酸加成盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸等形成的酸加成盐。
“治疗有效量”意指化合物被给予人用于治疗疾病时，足以实现对该疾病控制的使用量。
“治疗失败”包括但不限于疾病进展和/或复发。
“治疗”意指治疗上有效量的化合物的任何施用，并且包括：
(1)抑制正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即，阻止所 述病理学和/或症状学的进一步发展)，或
(2)改善正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即逆转所述病理学和/或症状学)。
“ORR”是指客观缓解率，具体为CR(完全缓解)+PR(部分缓解)。
“CBR”是指临床获益率，具体为CR+PR+SD。
具体实施方式
以下以具体的实施例说明本申请的技术方案，但本申请的保护范围不限于所述的实施例范围。
实施例1 1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐
Figure PCTCN2019077946-appb-000002
参照WO2008112407中实施例24的方法制备得到1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，然后参照WO2008112407说明书中“盐形式的实施例”的制备方法，制备得到标题化合物。
或者参照中国专利申请CN102344438A中公开的方法制备得到。
实施例2 1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(化合物Ⅰ的二盐酸盐)的胶囊的制备
Figure PCTCN2019077946-appb-000003
Figure PCTCN2019077946-appb-000004
将化合物Ⅰ的二盐酸盐粉碎，过80目筛；然后与甘露醇、羟丙纤维素混合均匀；接着加入处方量的微晶纤维素，混合均匀，过0.8mm筛网；最后加入处方量的硬脂酸镁混合均匀，并填充胶囊。
对于化合物I的二盐酸盐为其它含量的胶囊，可参照上述相同的比例和处方制备得到。
实施例3 临床试验
在有可测量病灶(根据RECIST 1.1)的≧18岁的女性晚期或转移性三阴性乳腺癌(ER阴性、PR阴性、HER2阴性)患者中开展化合物I的二盐酸盐胶囊的临床试验，患者之前接受过或未接受过化疗，化合物I的二盐酸盐胶囊单用或与化疗联用，以12mg给药，每天服药一次，按照连续服药两周，停药一周的方案服用，即每3个星期为一个服药周期。评价指标包括疗效指标：无进展生存期(PFS)、客观缓解率(ORR)、缓解持续时间(DOR)、疾病稳定(SD)率、临床获益率(CBR)、总生存期(OS)等；安全性指标：不良反应发生率及严重程度；生活质量等。
临床试验结果：
化合物I的二盐酸盐对三阴性乳腺癌的治疗有效，患者出现不同的临床获益。
实施例4
一名32岁女性患者，行右乳肿物手术，术后病理显示：右乳肉瘤样癌。化疗6周期，最佳疗效PR，病变下部累及胸壁。化疗结束后，复查发现再次复发(前胸壁多发结节及肿物)，行2周期化疗后疾病进展，并行放射治疗。后行右乳肿物切除术，病理会诊：乳腺肿瘤复发，免疫组化结果显示：ER(-),PR(-),HER2(-)。
之后接受12mg的化合物I的二盐酸盐胶囊治疗，每天服药一次，按照连续服药两周，停药一周的方案服用，即每3个星期为一个服药周期。服药四个周期后行颈胸脑部影像检查，评估稳定。患者服药十个周期后，经评估为病情稳定，耐受性良好。
实施例5
一名54岁女性，经B超及乳腺肿物穿刺病理确诊为乳腺癌，行左乳改良根治术，术后病理：侵润性导管癌II级，未侵及乳头，免疫组化：ER(-)、PR(-)、HER-2(-)，术后行辅助化疗4个疗程，放疗1个疗程，一年后复查发现后胸壁复发。后给予NP方案化疗(长春瑞滨+顺铂)2个周期，病情进展，再次行胸壁肿物切除+腋窝淋巴结清扫术，术后病理：胸壁、腋下癌，诊断为乳腺癌复发转移，免疫组化：ER(-)、PR(-)、HER-2(-)。术后调整方案化疗(吉西他滨+希罗达)4周，复查出现肺、肝、骨转移，给予白蛋白紫杉醇治疗，疾病进展，影像学提示肝脏病灶2.3cm(长径)，右肾上腺转移瘤5.6cm(长径)。之后接受12mg的化合物I的二盐酸盐胶囊治疗，每天服药一次，按照连续服药两周，停药一周的方案服用，即每3个星期为一个服药周期。两个服药周期后复查，转移灶明显缩小，肝脏病灶1.8cm(长径)，右肾上腺转移瘤4.6cm(长径)。患者继续服药直至疾病进展。

Claims (8)

  1. 化合物I或其药学上可接受的盐在制备用于治疗三阴性乳腺癌的药物中的用途，
    Figure PCTCN2019077946-appb-100001
  2. 根据权利要求1所述的用途，其特征在于，所述的三阴性乳腺癌为晚期或转移性三阴性乳腺癌。
  3. 根据权利要求1-2任一项所述的用途，其特征在于，所述的三阴性乳腺癌为在先治疗失败的三阴性乳腺癌；优选所述的三阴性乳腺癌为放疗和/或化疗药物治疗失败的三阴性乳腺癌。
  4. 根据权利要求1-3中任一项所述的用途，其特征在于，其药学上可接受的盐为化合物I与任意如下酸所形成的盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸；优选为盐酸盐或马来酸盐的形式，更优选为二盐酸盐。
  5. 根据权利要求1-4任一项所述的用途，其特征在于，所述药物为适于口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内或鞘内任一给药方式的制剂；优选适于口服的制剂；进一步优选为片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂或散剂，更优选为片剂或胶囊剂。
  6. 根据权利要求1-5中任一项所述的用途，其特征在于，给予所述化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克，优选为5毫克至20毫克，更优选为8毫克至16毫克，进一步优选为8毫克至14毫克，最优选为8毫克、10毫克或12毫克。
  7. 根据权利要求1-6中任一项所述的用途，其特征在于，所述化合物I或其药学上可接受的盐以给药期和停药期间隔的给药方式；优选的给药期和停药期以天数计的比值为2:0.5～5，更优选2:0.5～3，较优选2:0.5～2，进一步优选2:0.5～1；作为更进一步优选的间隔给药方式，为如下方式中的一种：连续给药2周停药2周、连续给药2周停药1周或连续给药5天停药2天；所述间隔给药方式可以反复进行多次。
  8. 一种治疗三阴性乳腺癌的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐，
    Figure PCTCN2019077946-appb-100002
PCT/CN2019/077946 2018-03-14 2019-03-13 用于治疗三阴性乳腺癌的喹啉衍生物 WO2019174590A1 (zh)

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