WO2019052520A1 - 用于治疗神经内分泌肿瘤的喹啉衍生物 - Google Patents

用于治疗神经内分泌肿瘤的喹啉衍生物 Download PDF

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Publication number
WO2019052520A1
WO2019052520A1 PCT/CN2018/105628 CN2018105628W WO2019052520A1 WO 2019052520 A1 WO2019052520 A1 WO 2019052520A1 CN 2018105628 W CN2018105628 W CN 2018105628W WO 2019052520 A1 WO2019052520 A1 WO 2019052520A1
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Prior art keywords
acid
neuroendocrine tumor
administration
compound
tumor
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PCT/CN2018/105628
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English (en)
French (fr)
Inventor
张喜全
王训强
江海
田心
杨玲
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正大天晴药业集团股份有限公司
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Priority to CN201880058533.1A priority Critical patent/CN111065395B/zh
Priority to EP18855594.0A priority patent/EP3682883A4/en
Publication of WO2019052520A1 publication Critical patent/WO2019052520A1/zh

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    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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 neuroendocrine tumors.
  • NETs Neuroendocrine tumors originate from neuroendocrine cells of the systemic diffuse endocrine system. The incidence of NETs has increased from 1.09 per 100,000 in 1973 to 5.25 per 100,000 in 2004, and more than one-third of patients in the new diagnosis have been locally advanced or have metastasized.
  • the most common types of NETs include carcinoid tumors (which originate in the lungs and bronchi, small intestine, appendix, rectum, and thymus) and pancreatic neuroendocrine tumors. Other less common types include types that originate from the parathyroid glands, the thyroid gland, the adrenal glands, and the pituitary gland. According to the origin of primary tumors, the most common neuroendocrine tumor is a gastrointestinal pancreatic neuroendocrine tumor.
  • NETs are loose-haired, and people know less about the pathogenic factors of NETs.
  • NETs may also originate from genetic syndrome, including MEN1 (multiple endocrine neoplasia type 1) and MEN2.
  • MEN1 is associated with mutations in the menin gene and is associated with a variety of tumor types originating from the parathyroid glands, pituitary glands, and pancreas.
  • MEN2 is associated with mutations in the RET gene and is associated with the development of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism.
  • NETs patients vary according to hormone secretion, including intermittent blushing and diarrhea in patients with carcinoid syndrome, hypertension in patients with pheochromocytoma, and insulin-based, glucagon, and gastric-promoting patients in pancreatic neuroendocrine tumors. Symptoms caused by secretion of hormones and other peptides. Patients with hormonal symptoms are considered to be functional tumors, and asymptomatic patients are considered to be nonfunctional tumors.
  • NETs are histologically classified according to tumor differentiation and tumor grade (grade 1-3). Histologically, it can be classified according to the degree of tumor differentiation (differentiated, poorly differentiated) and tumor grade (grade 1-3). "Most NETs can be classified into three categories: well-differentiated, low-grade (G1); well-differentiated, intermediate (G2); poorly differentiated, advanced (G3). Tumor differentiation and tumor grading are often associated with mitotic counts and Ki-67 proliferation index. Many studies have confirmed that high mitotic rate and high Ki-67 index are associated with greater invasiveness and poor prognosis of NETs.
  • somatostatin analogues somatostatin analogues
  • PRRT peptide receptor radionuclides
  • Cytotoxic chemotherapy drugs are also the main treatment for G3 neuroendocrine tumors.
  • the FDA approved the molecularly targeted drugs sunitinib and everolimus for the treatment of pancreatic neuroendocrine tumors.
  • the application provides a method of treating a neuroendocrine tumor, 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 application provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the treatment of a neuroendocrine tumor or in the manufacture of a medicament for the treatment of a neuroendocrine tumor.
  • the application provides a pharmaceutical composition for treating a neuroendocrine tumor, 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 a neuroendocrine tumor comprising (a) at least one unit dose of a pharmaceutical composition of Compound 1, or a pharmaceutically acceptable salt thereof, and (b) for treating a nerve Instructions for endocrine tumors.
  • the application provides a method of treating a neuroendocrine tumor, 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 neuroendocrine tumors include, but are not limited to, carcinoid and pancreatic neuroendocrine tumors.
  • the neuroendocrine tumors include, but are not limited to, gastrointestinal neuroendocrine tumors, pulmonary neuroendocrine tumors, pancreatic neuroendocrine tumors, liver neuroendocrine tumors, prostate neuroendocrine tumors, biliary neuroendocrine tumors, Breast neuroendocrine tumors, ampullary neuroendocrine tumors, thymus neuroendocrine tumors, mediastinal neuroendocrine tumors, retroperitoneal neuroendocrine tumors, thyroid neuroendocrine tumors, adrenal neuroendocrine tumors.
  • the neuroendocrine tumor is a poorly differentiated neuroendocrine tumor. In some typical embodiments, the neuroendocrine tumor is a well-differentiated neuroendocrine tumor.
  • the neuroendocrine tumor is a late-stage and/or metastatic neuroendocrine tumor.
  • the neuroendocrine tumor is a well-differentiated neuroendocrine tumor of advanced and/or metastatic.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails radiotherapy and/or chemotherapy.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails treatment with a molecularly targeted drug, including but not limited to sunitinib or a salt thereof and/or everolimus. In some embodiments, the neuroendocrine tumor is a neuroendocrine tumor that fails to treat sunitinib or a salt thereof and/or everolimus.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails treatment with a somatostatin analogue and/or an interferon-alpha and/or peptide receptor radionuclide.
  • a method of treating a pancreatic neuroendocrine tumor comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the pancreatic neuroendocrine tumor comprises islet cell tumor, insulinoma, amine precursor uptake and decarboxylated cell tumor (APUDomas), vasoactive intestinal peptide tumor (VIP tumor), pancreatic polypeptide tumor, pancreatic hyperglycemia A tumor, gastrinoma.
  • APUDomas amine precursor uptake and decarboxylated cell tumor
  • VIP tumor vasoactive intestinal peptide tumor
  • pancreatic polypeptide tumor pancreatic hyperglycemia A tumor, gastrinoma.
  • the pancreatic neuroendocrine tumor is a poorly differentiated neuroendocrine tumor. In some typical embodiments, the pancreatic neuroendocrine tumor is a well-differentiated neuroendocrine tumor.
  • the pancreatic neuroendocrine tumor is a late-stage and/or metastatic neuroendocrine tumor.
  • the pancreatic neuroendocrine tumor is a well-differentiated neuroendocrine tumor of advanced and/or metastatic.
  • the pancreatic neuroendocrine tumor is a neuroendocrine tumor that fails radiotherapy and/or chemotherapy.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails treatment with a molecularly targeted drug, including but not limited to sunitinib or a salt thereof and/or everolimus.
  • the pancreatic neuroendocrine tumor is a neuroendocrine tumor that fails to treat sunitinib or a salt thereof and/or everolimus.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails treatment with a somatostatin analogue and/or an interferon-alpha and/or peptide receptor radionuclide.
  • 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.
  • the drug is administered once a day for 14 days, then for 14 days; then once a day for 14 days, then for 14 days, 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 present application also provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the treatment of a neuroendocrine tumor or in the manufacture of a medicament for the treatment of a neuroendocrine tumor.
  • the neuroendocrine tumors include, but are not limited to, carcinoid and pancreatic neuroendocrine tumors.
  • the neuroendocrine tumors include, but are not limited to, gastrointestinal neuroendocrine tumors, pulmonary neuroendocrine tumors, pancreatic neuroendocrine tumors, liver neuroendocrine tumors, prostate neuroendocrine tumors, biliary neuroendocrine tumors, Breast neuroendocrine tumors, ampullary neuroendocrine tumors, thymus neuroendocrine tumors, mediastinal neuroendocrine tumors, retroperitoneal neuroendocrine tumors, thyroid neuroendocrine tumors, adrenal neuroendocrine tumors.
  • the neuroendocrine tumor is a poorly differentiated neuroendocrine tumor. In some typical embodiments, the neuroendocrine tumor is a well-differentiated neuroendocrine tumor.
  • the neuroendocrine tumor is a late-stage and/or metastatic neuroendocrine tumor.
  • the neuroendocrine tumor is a well-differentiated neuroendocrine tumor of advanced and/or metastatic.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails radiotherapy and/or chemotherapy.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails treatment with a molecularly targeted drug, including but not limited to sunitinib or a salt thereof and/or everolimus. In some embodiments, the neuroendocrine tumor is a neuroendocrine tumor that fails to treat sunitinib or a salt thereof and/or everolimus.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails treatment with a somatostatin analogue and/or an interferon-alpha and/or peptide receptor radionuclide.
  • the pancreatic neuroendocrine tumor comprises islet cell tumor, insulinoma, amine precursor uptake and decarboxylated cell tumor (APUDomas), vasoactive intestinal peptide tumor (VIP tumor), pancreatic polypeptide tumor, pancreatic hyperglycemia A tumor, gastrinoma.
  • APUDomas amine precursor uptake and decarboxylated cell tumor
  • VIP tumor vasoactive intestinal peptide tumor
  • pancreatic polypeptide tumor pancreatic hyperglycemia A tumor, gastrinoma.
  • the pancreatic neuroendocrine tumor is a poorly differentiated neuroendocrine tumor. In some typical embodiments, the pancreatic neuroendocrine tumor is a well-differentiated neuroendocrine tumor.
  • the pancreatic neuroendocrine tumor is a late-stage and/or metastatic neuroendocrine tumor.
  • the pancreatic neuroendocrine tumor is a well-differentiated neuroendocrine tumor of advanced and/or metastatic.
  • the pancreatic neuroendocrine tumor is a neuroendocrine tumor that fails radiotherapy and/or chemotherapy.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails treatment with a molecularly targeted drug, including but not limited to sunitinib or a salt thereof and/or everolimus.
  • the pancreatic neuroendocrine tumor is a neuroendocrine tumor that fails to treat sunitinib or a salt thereof and/or everolimus.
  • the neuroendocrine tumor is a neuroendocrine tumor that fails treatment with a somatostatin analogue and/or an interferon-alpha and/or peptide receptor radionuclide.
  • 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 provides a pharmaceutical composition for treating a neuroendocrine tumor, the pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • 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 and intrathecal administration; preferably suitable for oral administration, including tablets, capsules, powders, granules, dropping pills, pastes, powders, etc. 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 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 pharmaceutical composition is administered orally at a dose of 12 mg once daily for 2 weeks of continuous administration and 1 week of administration.
  • the pharmaceutical composition is administered orally at a dose of 10 mg once daily for 2 weeks of continuous administration and 1 week of administration.
  • the pharmaceutical composition is administered orally at a dose of 8 mg once daily for 2 weeks of continuous administration and 1 week of administration.
  • kits comprising (a) at least one unit dose of a pharmaceutical composition of Compound 1, or a pharmaceutically acceptable salt thereof, and (b) instructions for treating a neuroendocrine tumor .
  • a kit comprising (a) at least one unit dose of a suitable oral formulation of Compound 1, or a pharmaceutically acceptable salt thereof, and (b) treating the nerve in a separate manner Instructions for endocrine tumors.
  • 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 provided herein 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 with a neuroendocrine tumor simultaneously or sequentially.
  • the second type includes, but is not limited to, a somatostatin analogue, an interferon- ⁇ , a peptide receptor radionuclide, a molecular targeted therapy, a chemotherapeutic drug, etc., such as an anticancer drug (preferably an anti-neuroendocrine tumor agent), Anti-inflammatory agents and/or immunomodulators and/or anti-allergic agents, and second drugs also include drugs for treating symptoms associated with neuroendocrine tumors.
  • a somatostatin analogue such as an interferon- ⁇ , a peptide receptor radionuclide, a molecular targeted therapy, a chemotherapeutic drug, etc.
  • an anticancer drug preferably an anti-neuroendocrine tumor agent
  • Anti-inflammatory agents and/or immunomodulators and/or anti-allergic agents and second drugs also include drugs for treating symptoms associated with neuroendocrine tumors.
  • 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 person.
  • “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 means any administration of a therapeutically effective amount of a compound and includes:
  • PR refers to partial relief, specifically the sum of the target lesion diameters of the tumor is reduced by more than 30% from the baseline level.
  • PD refers to disease progression, specifically the sum of the target lesion diameters of the tumor is increased by more than 20% from the baseline level.
  • SD refers to the stability of the disease, specifically the extent to which the tumor target lesion has not decreased to the PR level, and the degree of increase has not reached the PD level, which is somewhere in between.
  • PFS progression free survival
  • OS refers to the overall lifetime.
  • 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.
  • MRI magnetic resonance imaging
  • pancreatic head mass was performed, specifically: 30Gy/3Gy/10f (3gy per radiation, 30 times for 10 times radiotherapy), and SD after treatment.
  • the EP regimen (gemcitabine + cisplatin) was administered for 2 cycles postoperatively from April to June, during which IV° myelosuppression occurred.
  • Two-year postoperative abdominal MRI showed that the liver metastases were larger than before, and the disease progressed.
  • the sum of the target lesions (liver metastases) was 25 mm.
  • a dose of Compound I dihydrochloride capsule was administered once daily at a dose of 12 mg orally (two consecutive weeks for one treatment cycle).
  • CT scan was performed. After two cycles of treatment, the imaging examination showed that the sum of the diameters of the metastases fell to 21 mm; the sum of the diameters after the four-cycle treatment was reduced to 16 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the six-cycle treatment was reduced to 15mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the eight-cycle treatment was reduced to 15mm, and the therapeutic effect was evaluated as PR; after the eleventh cycle, due to the II° weakness, the dose was adjusted to 10mg.
  • the sum of the diameters after the 12-cycle treatment was reduced to 15 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the 16-cycle treatment was reduced to 15 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the 22-second treatment was reduced to 13 mm, and the therapeutic effect was evaluated.
  • PR The sum of the diameters after the 12-cycle treatment was reduced to 15 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the 16-cycle treatment was reduced to 15 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the 22-second treatment was reduced to 13 mm, and the therapeutic effect was evaluated.
  • PR The sum of the diameters after the 12-cycle treatment was reduced to 15 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the 16-cycle treatment was reduced to 15 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the 22-second treatment was reduced to 13 mm, and the therapeutic effect was evaluated.
  • a 34-year-old male patient with a chest mass puncture pathology suggested: neuroendocrine tumors, considering atypical carcinoid.
  • the pleura did not affect the lung tissue and pericardial fat, and no lymphatic metastasis was found in the lymph nodes.
  • Local chest radiotherapy was performed in the first 1-2 months after surgery, and SD was evaluated after radiotherapy. III° radiation esophagitis occurred during the procedure and chemotherapy was given to the EP regimen (gemcitabine + cisplatin) for 2 cycles. Every 3 months after the end of treatment, the condition was stable and there was no recurrence.
  • CT scan at 23 months postoperatively showed progression of the disease, bilateral pleural, bilateral kidney, left adrenal gland and lymph node metastasis. Temozolomide + capecitabine was given for 2 cycles after 23-25 months, and the effect was SD (large).
  • CT scans were performed regularly. After two cycles of treatment, the imaging examination showed that the sum of the target lesion diameters fell to 151 mm; the sum of the diameters after the four-cycle treatment dropped to 135 mm; The sum of the diameters after the treatment was reduced to 127 mm; the sum of the diameters after the eight-cycle treatment was reduced to 115 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the ten-cycle treatment was reduced to 106 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the thirteen-cycle administration was decreased. To 119 mm, the therapeutic effect was evaluated as PR; the sum of the diameters after the sixteen-cycle administration was reduced to 120 mm.
  • Compound I dihydrochloride capsule was administered once daily at a dose of 12 mg orally (two consecutive weeks for one treatment cycle).
  • the imaging examination showed that the sum of the target lesion diameters was reduced to 24 mm, and the therapeutic effect was evaluated as PR; the target lesion diameter after four cycles of treatment And decreased to 22mm, the therapeutic effect was evaluated as PR; the sum of the target lesion diameters after the six-cycle medication was reduced to 21mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the eight-cycle medication was reduced to 21mm, and the therapeutic effect was evaluated as PR; The sum was reduced to 21mm, the therapeutic effect was evaluated as PR; the sum of the diameters after the seventeenth cycle was reduced to 20mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the twenty-first cycle was reduced to 20mm, and the therapeutic effect was evaluated as PR; twenty-five cycles The sum of the diameters after the treatment was reduced to 19 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the administration of the thirty-first cycle was reduced to 16 mm, and the therapeutic effect was evaluated as PR; the sum of the diameters after the thirty
  • liver metastases liver cells in the epithelial cell nest, combined with medical history and immunohistochemistry, diagnosed as pancreatic neuroendocrine tumors.
  • General anesthesia was performed with laparotomy, pancreatic body and tail combined with spleen resection.
  • Shanlong injection octreotide acetate microspheres
  • traditional Chinese medicine were given. After 6 months, the effect was PD, and then the clinical trial was started.
  • Compound I dihydrochloride capsules were dosed once daily at a dose of 12 mg (continuously used for two weeks for one treatment cycle).
  • the sum of the diameters of the target lesions (right adrenal metastases, liver metastases) was 59 mm.
  • the use of the compound I dihydrochloride capsule treatment after two cycles of imaging examination showed that the sum of the target lesion diameter decreased to 41 mm, the therapeutic effect was evaluated as PR;
  • the sum of the diameters after the four-cycle treatment was reduced to 37 mm, and the therapeutic effect was evaluated as PR;
  • the sum of the diameters after the six-cycle administration was reduced to 35 mm, and the therapeutic effect was evaluated as PR;
  • the sum of the diameters after the eight-cycle administration was reduced to 32 mm, and the therapeutic effect was evaluated as PR;
  • the sum of the diameters after the cycle was reduced to 34 mm, and the therapeutic effect was evaluated as PR;
  • the sum of the diameters after the 17-month cycle was reduced to 32 mm, and the therapeutic effect was evaluated as PR;
  • IP protocol (irinotecan 200 mg d1, 100 mg d8; cisplatin 30 mg d1-3) was given chemotherapy.
  • the CEA value was 824.400 ng/ml, and on August 23, 2017, the CEA value was 5621.000 ng/ml.
  • the EOS regimen (EPI (epimycin) 80 mg d1, LOHP (oxaliplatin) 100 mg d1, and S-1 (Tiggio capsule) 50 mg PO bid d1-14; Q3W) was started on August 25, 2017. Systemic chemotherapy for 2 cycles, the effect was evaluated as PR, and the upper abdominal pain was relieved after chemotherapy.
  • a compound I dihydrochloride capsule of 12 mg (continuous administration for two weeks, ie three weeks for one treatment cycle) was administered orally once a day.
  • the CT scan showed that the sum of the diameters of the metastases fell to 18.1 mm (the retroperitoneal lymph nodes of the hilar and pancreas); after four cycles of administration, 2018, 7
  • the CT scan showed that the sum of the diameters was 18.0 mm (the hepatic and pancreatic head and the retroperitoneal lymph nodes), and the therapeutic effect was evaluated as SD.
  • patients are still taking medication.
  • Chemotherapy was started on April 26, 2017. Specific medications: irinotecan (100 mg d1, d8, d15) and carboplatin (600 mg dl), Q3W. Tolerance was good, so the adjustment was "Irinotecan 270mg d1 + carboplatin 700mg d1" chemotherapy for 3 cycles. On August 1st, 2017, total gastrectomy was performed. Postoperative pathology showed: small-bend ulcer-type poorly differentiated gland neuroendocrine carcinoma (about 20% for adenocarcinoma and 80% for neuroendocrine cancer) (Lauren) Classification: diffuse type).
  • FL0T regimen (Oxaliplatin 150 mg, d1; liposomal paclitaxel) on January 11, 2018, January 24, 2018, February 11, 2018, February 27, 2018, and March 13, 2018 150 mg dl; calcium folinate 300 mg d1; tegafur 3.6 g, CIV 24h)) + Endo (210 mg civ 120h) chemotherapy.
  • the efficacy was evaluated PD.
  • the CAP regimen (cyclophosphamide 800 mg d1; and cisplatin 40 mg d1-3; and liposomal doxorubicin 40 mg d1) was adjusted for chemotherapy.
  • CT scan showed target lesions. The sum of the diameters was 47.8 mm (liver S5 and liver S6). Subsequently, the clinical trial was conducted with "postoperative liver metastasis of gastric neuroendocrine cancer".
  • CT scans showed that the sum of the target lesion diameters was 180 mm (large liver mass).
  • Subsequent clinical trial of compound I dihydrochloride capsules starting from July 6, 2018, once daily oral 12mg (continuous administration for two weeks, one week for three weeks for one treatment cycle) of compound I dihydrochloride The capsule is treated.
  • CT scan showed that the sum of the diameters of the metastases fell to 150 mm (large liver mass), and the efficacy was evaluated SD; as of September 2018, the patients were still taking the drug. During the medication, the patient was generally well tolerated with no adverse events.

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Abstract

具有如下所示的式(I)的用于治疗神经内分泌肿瘤的喹啉衍生物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。还公开了它们在制备用于治疗肿瘤、特别是神经内分泌肿瘤的药物组合物/药剂中的用途。

Description

用于治疗神经内分泌肿瘤的喹啉衍生物 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神经内分泌肿瘤中的用途。
背景技术
神经内分泌肿瘤(Neuroendocrine tumors，NETs)起源于全身弥散性内分泌系统的神经内分泌细胞。NETs的发病率已从1973年的每10万人1.09例升高至2004年的每10万人5.25例，新诊断时超过三分之一的患者已为局部晚期或已转移。NETs的最常见类型包括类癌(carcinoid tumors)(多起源于肺及支气管、小肠、阑尾、直肠和胸腺)和胰腺神经内分泌肿瘤。其它较不常见类型包括起源于甲状旁腺、甲状腺、肾上腺和垂体的类型。根据原发性肿瘤的起源，最常见的神经内分泌肿瘤为胃肠胰神经内分泌肿瘤。
大部分NETs为散发型，人们对于散发型NETs的致病因素还了解较少。NETs还可能起源于遗传综合征，包括MEN1(multiple endocrine neoplasia type 1)和MEN2两种类型。MEN1与menin基因突变相关，与起源于甲状旁腺、垂体和胰腺等的多种肿瘤类型相关。MEN2与RET基因突变相关，与甲状腺髓样癌、嗜铬细胞瘤及甲状旁腺功能亢进等的发展相关。
NETs患者根据激素分泌情况的不同而表现不同，症状包括类癌综合征患者的间歇性脸红和腹泻、嗜铬细胞瘤患者的高血压以及胰腺神经内分泌肿瘤患者基于胰岛素、胰高血糖素、促胃液素及其它多肽类分泌而出现的症状。有激素症状的患者被认为是功能性(functional)肿瘤，无症状的患者被认为是非功能性(nonfunctional)肿瘤。
NETs组织学上是根据肿瘤分化和肿瘤分级(1-3级)分类的。在组织学上，可以按照肿瘤分化程度(分化良好、低分化)和肿瘤分级(1-3级)分类。”大部分NETs可以归为三类：分化良好，低级(G1)；分化良好，中级(G2)；低分化，高级(G3)。肿瘤分化和肿瘤分级常与有丝分裂计数和Ki-67增殖指数相关。很多研究证实了高的有丝分裂率和高的Ki-67指数与NETs更强的侵袭性及差的预后相关。
根治手术是唯一可以治愈NETs的方法。其它对于局部晚期或转移性G1/G2神经内分泌肿瘤的系统治疗包括生长抑素类似物(somatostatin analogues，SSAs)、干扰素-α、肽受体放射性核素(PRRT)联合生长抑素类似物、靶向治疗及化疗药物。细胞毒化疗药物还是G3神经内分泌肿瘤的主要治疗手段。FDA分别批准了分子靶向药物舒尼替尼 (sunitinib)和依维莫司(everolimus)用于胰腺神经内分泌肿瘤的治疗。
发明内容
一方面，本申请提供了一种治疗神经内分泌肿瘤的方法，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。
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 PCTCN2018105628-appb-000001
另一方面，本申请提供了化合物I或其药学上可接受的盐在治疗神经内分泌肿瘤中的用途或制备用于治疗神经内分泌肿瘤的药物中的用途。
再一方面，本申请提供了一种治疗神经内分泌肿瘤的药物组合物，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神经内分泌肿瘤的试剂盒，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)用于治疗神经内分泌肿瘤的说明书。
一方面，本申请提供了一种治疗神经内分泌肿瘤的方法，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。
在一些典型的实施方案中，所述的神经内分泌肿瘤包括但不限于类癌和胰腺神经内分泌肿瘤。
在一些典型的实施方案中，所述的神经内分泌肿瘤包括但不限于胃肠道神经内分泌肿瘤、肺神经内分泌肿瘤、胰腺神经内分泌肿瘤、肝脏神经内分泌肿瘤、前列腺神经内分泌肿瘤、胆管神经内分泌肿瘤、乳腺神经内分泌肿瘤、壶腹神经内分泌肿瘤、胸腺神经内分泌肿瘤、纵膈神经内分泌肿瘤、腹膜后神经内分泌肿瘤、甲状腺神经内分泌肿瘤、肾上腺神经内分泌肿瘤。
在一些典型的实施方案中，所述的神经内分泌肿瘤为低分化的神经内分泌肿瘤。在一些典型的实施方案中，所述的神经内分泌肿瘤为分化良好的神经内分泌肿瘤。
在一些典型的实施方案中，所述的神经内分泌肿瘤为晚期和/或转移性的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为晚期和/或转移性的分化良好的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为放疗和/或化疗失败的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为分子靶向药物(包括但不限于舒尼替尼或其盐和/或依维莫司)治疗失败的神经内分泌肿瘤。在一些实施方案中，所述的神经内分泌肿瘤为舒尼替尼或其盐和/或依维莫司治疗失败的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为生长抑素类似物和/或干扰素-α和/或肽受体放射性核素治疗失败的神经内分泌肿瘤。
在本申请的一些实施方案中，提供了一种治疗胰腺神经内分泌肿瘤的方法，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，所述的胰腺神经内分泌肿瘤包括胰岛细胞瘤、胰岛素瘤、胺前体摄取和脱羧细胞瘤(APUDomas)、血管活性肠肽瘤(VIP瘤)、胰多肽瘤、胰高血糖素瘤、胃泌素瘤。
在一些典型的实施方案中，所述的胰腺神经内分泌肿瘤为低分化的神经内分泌肿瘤。在一些典型的实施方案中，所述的胰腺神经内分泌肿瘤为分化良好的神经内分泌肿瘤。
在一些典型的实施方案中，所述的胰腺神经内分泌肿瘤为晚期和/或转移性的神经内分泌肿瘤。
在一些实施方案中，所述的胰腺神经内分泌肿瘤为晚期和/或转移性的分化良好的神经内分泌肿瘤。
在一些实施方案中，所述的胰腺神经内分泌肿瘤为放疗和/或化疗失败的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为分子靶向药物(包括但不限于舒尼替尼或其盐和/或依维莫司)治疗失败的神经内分泌肿瘤。在一些实施方案中，所述的胰腺神经内分泌肿瘤为舒尼替尼或其盐和/或依维莫司治疗失败的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为生长抑素类似物和/或干扰素-α和/或肽受体放射性核素治疗失败的神经内分泌肿瘤。
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，本申请还提供了化合物I或其药学上可接受的盐在治疗神经内分泌肿瘤中的用途或制备用于治疗神经内分泌肿瘤的药物中的应用。
在一些典型的实施方案中，所述的神经内分泌肿瘤包括但不限于类癌和胰腺神经内分泌肿瘤。
在一些典型的实施方案中，所述的神经内分泌肿瘤包括但不限于胃肠道神经内分泌肿瘤、肺神经内分泌肿瘤、胰腺神经内分泌肿瘤、肝脏神经内分泌肿瘤、前列腺神经内分泌肿瘤、胆管神经内分泌肿瘤、乳腺神经内分泌肿瘤、壶腹神经内分泌肿瘤、胸腺神经内分泌肿瘤、纵膈神经内分泌肿瘤、腹膜后神经内分泌肿瘤、甲状腺神经内分泌肿瘤、肾上腺神经内分泌肿瘤。
在一些典型的实施方案中，所述的神经内分泌肿瘤为低分化的神经内分泌肿瘤。在一些典型的实施方案中，所述的神经内分泌肿瘤为分化良好的神经内分泌肿瘤。
在一些典型的实施方案中，所述的神经内分泌肿瘤为晚期和/或转移性的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为晚期和/或转移性的分化良好的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为放疗和/或化疗失败的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为分子靶向药物(包括但不限于舒尼替尼或其盐和/或依维莫司)治疗失败的神经内分泌肿瘤。在一些实施方案中，所述的神经内分泌肿瘤为舒尼替尼或其盐和/或依维莫司治疗失败的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为生长抑素类似物和/或干扰素-α和/或肽受体放射性核素治疗失败的神经内分泌肿瘤。
在一些实施方案中，所述的胰腺神经内分泌肿瘤包括胰岛细胞瘤、胰岛素瘤、胺前体摄取和脱羧细胞瘤(APUDomas)、血管活性肠肽瘤(VIP瘤)、胰多肽瘤、胰高血糖素瘤、胃泌素瘤。
在一些典型的实施方案中，所述的胰腺神经内分泌肿瘤为低分化的神经内分泌肿瘤。在一些典型的实施方案中，所述的胰腺神经内分泌肿瘤为分化良好的神经内分泌肿瘤。
在一些典型的实施方案中，所述的胰腺神经内分泌肿瘤为晚期和/或转移性的神经内分泌肿瘤。
在一些实施方案中，所述的胰腺神经内分泌肿瘤为晚期和/或转移性的分化良好的神经内分泌肿瘤。
在一些实施方案中，所述的胰腺神经内分泌肿瘤为放疗和/或化疗失败的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为分子靶向药物(包括但不限于舒尼替尼或其盐和/或依维莫司)治疗失败的神经内分泌肿瘤。在一些实施方案中，所述的胰腺神经内分泌肿瘤为舒尼替尼或其盐和/或依维莫司治疗失败的神经内分泌肿瘤。
在一些实施方案中，所述的神经内分泌肿瘤为生长抑素类似物和/或干扰素-α和/或肽受体放射性核素治疗失败的神经内分泌肿瘤。
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神经内分泌肿瘤的药物组合物，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。
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、腹膜内和鞘内给药的制剂；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。
优选地，以间隔给药的方式给予所述药物组合物。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的剂量口服给予所述药物组合物，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的剂量口服给予所述药物组合物，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的剂量口服给予所述药物组合物，连续用药2周，停1周的给药方式给药。
另一方面，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)用于治疗神经内分泌肿瘤的说明书。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神经内分泌肿瘤的说明书。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、应用、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、应用、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神经内分泌肿瘤的患者。所述的第二种包括但不限于生长抑制素类似物、干扰素-α、肽受体放射性核素、分子靶向治疗、化疗药物等，例如抗癌药(优选抗神经内分泌肿瘤剂)、抗炎剂和/或免疫调节剂和/或抗变态反应药，第二种药物还包括用于治疗与神经内分泌瘤有关的症状的药物。
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”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)。
“PR”是指部分缓解，具体指肿瘤的靶病灶直径之和比基线水平减少30％以上。
“PD”是指疾病进展，具体指肿瘤的靶病灶直径之和比基线水平增加20％以上。
“SD”是指疾病稳定，具体指肿瘤靶病灶减小的程度没达到PR水平，增加的程度也没达到PD水平，介于两者之间。
“PFS”是指无进展生存期。
“OS”是指总生存期。
“po”是指口服。
“qd”是指一天一次。
“bid”是指一天两次。
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 PCTCN2018105628-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 PCTCN2018105628-appb-000003
Figure PCTCN2018105628-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
一名69岁男性患者，MRI(核磁共振成像)示：胰头钩突体积增大，类结节样改变，低位胆道梗阻。腹部CT示：胰头钩突区见大约3.2×2.4cm软组织影，肝脏左内叶结节，考虑为血管瘤，肝脏右前叶结节，行“肝脏肿物切除、胆肠吻合、胆囊切除术”，术后病理示：壶腹神经内分泌肿瘤，肝尾叶肿瘤考虑为转移癌。术后一个月行胰头肿物局部放疗，具体为：30Gy/3Gy/10f(每次放射3gy，分10次放疗共30gy)，治疗后评效SD。术后4-6月行EP方案(吉西他滨+顺铂)化疗2周期，期间出现Ⅳ°骨髓抑制。术后两年复查腹部MRI提示肝脏转移瘤较前增大，病情进展，CT扫描中，靶病灶(肝脏转移瘤)直径之和为25mm。入组临床试验，开始每日一次口服12mg(连续用两周停一周为一个治疗周期)剂量的化合物I二盐酸盐胶囊进行治疗。
在其后的化合物I二盐酸盐胶囊治疗过程中，进行CT扫描，治疗二周期后影像学检查示转移灶直径之和降至21mm；四周期用药后直径之和降至16mm，疗效评价为PR；六周期用药后直径之和降至15mm，疗效评价为PR；八周期用药后直径之和降至15mm，疗效评价为PR；第十一周期后因出现II°乏力，于是调整剂量至10mg；十二周期用药后直径之和降至15mm，疗效评价为PR；十六周期用药后直径之和降至15mm，疗效评价为PR；二十二周期用药后直径之和降至13mm，疗效评价为PR。
患者服用化合物I二盐酸盐胶囊期间，总体耐受性良好，主要不良反应为II°乏力、II°PLT降低、I°腹泻、I°手足皮肤反应。
实施例4
一名34岁男性患者，行胸部肿物穿刺病理提示：神经内分泌肿瘤，考虑不典型类癌。行紫杉醇、足叶乙甙和顺铂方案化疗3周期。化疗结束复查CT，评效为SD。随后行右前纵隔肿物切除和部分右肺上叶切除术，术后病理提示：胸腺组织内见神经内分泌癌浸润，可见脉管癌栓，肿瘤大小12×9×5.5cm，肿瘤侵犯脏壁层胸膜，未累及肺组织及心包脂肪，淋巴结未见癌转移。术后第1-2月行局部胸部放疗，放疗后复查评效SD。过程中出现Ⅲ°放射性食管炎，并给予EP方案(吉西他滨+顺铂)化疗2周期。治疗结束后每3月复查，病情稳定，无复发。术后23个月复查CT提示病情进展，双侧胸膜，双肾、左肾上腺和淋巴结多发转移。术后23-25个月，给予替莫唑胺+卡培他滨治疗2周期，评效为SD(大)。期间出现双下肢疼痛，进行性加重。予唑来膦酸治疗4mg每月一次，2周期化疗后复查CT，评效PD，予以善龙(注射用醋酸奥曲肽微球)治疗1周期。术后27个月，复查CT，评效PD，CT扫描中，靶病灶直径之和为179mm。入组临床试验，开始每日一次口服12mg(连续用两周停一周为一个治疗周期)剂量的化合物I二盐酸盐胶囊进行治疗。
在其后的化合物I二盐酸盐胶囊治疗过程中，定期进行CT扫描，治疗二周期后影像学检查显示靶病灶直径之和降至151mm；四周期用药后直径之和降至135mm；六周期用药后直径之和降至127mm；八周期用药后直径之和降至115mm，疗效评价为PR；十周期用药后直径之和降至106mm，疗效评价为PR；十三周期用药后直径之和降至119mm，疗效评价为PR；十六周期用药后直径之和降至120mm。
患者服用化合物I二盐酸盐胶囊期间，总体耐受性良好，主要不良反应为III°ALT升高、II°蛋白尿、I°高甘油三酯血症。
实施例5
一名65岁女性患者，行穿刺活检提示腹膜后神经内分泌肿瘤，随后给予赛升(薄芝糖肽注射液)、胸腺肽进行抗肿瘤治疗，复查疗效提示无效。随后给予苹果酸舒尼替尼治疗后评效为PD。
之后，开始每日一次口服12mg(连续用两周停一周为一个治疗周期)剂量的化合物I二盐酸盐胶囊进行治疗。
在服用化合物I二盐酸盐胶囊前的CT扫描中，靶病灶(腹膜后淋巴结转移，伴肺和肝脏转移)直径之和为35mm。在其后的化合物I二盐酸盐胶囊治疗过程中，定期进行CT扫描，治疗二周期后影像学检查示靶病灶直径之和降至24mm，疗效评价为PR；四周 期用药后靶病灶直径之和降至22mm，疗效评价为PR；六周期用药后靶病灶直径之和降至21mm，疗效评价为PR；八周期用药后直径之和降至21mm，疗效评价为PR；十四周期用药后直径之和降至21mm，疗效评价为PR；十七周期用药后直径之和降至20mm，疗效评价为PR；二十一周期用药后直径之和降至20mm，疗效评价为PR；二十五周期用药后直径之和降至19mm，疗效评价为PR；三十一周期用药后直径之和降至16mm，疗效评价为PR；三十七周期用药后直径之和降至19mm，疗效评价为PR。
患者服用化合物I二盐酸盐胶囊期间，总体耐受性良好，主要不良反应为II°WBC降低、I°甲低、I°中性粒细胞降低、I°腹泻。
实施例6
一名40岁男性患者，病理提示：(肝脏转移癌)肝组织内见上皮细胞巢，结合病史及免疫组化，诊断为胰腺神经内分泌肿瘤。全麻下行剖腹探查、胰体尾联合脾脏切除术，术后一个月给予善龙(注射用醋酸奥曲肽微球)及中药治疗，术后6个月评效为PD，之后入组临床试验，开始每日一次口服12mg(连续用两周停一周为一个治疗周期)剂量的化合物I二盐酸盐胶囊进行治疗。
在服用化合物I二盐酸盐胶囊前的CT扫描中，靶病灶(右侧肾上腺转移瘤、肝转移瘤)直径之和为59mm。在其后的化合物I二盐酸盐胶囊治疗过程进行的CT扫描中，开始使用化合物I二盐酸盐胶囊治疗二周期后影像学检查显示靶病灶直径之和降至41mm，疗效评价为PR；四周期用药后直径之和降至37mm，疗效评价为PR；六周期用药后直径之和降至35mm，疗效评价为PR；八周期用药后直径之和降至32mm，疗效评价为PR；十四周期用药后直径之和降至34mm，疗效评价为PR；十七周期用药后直径之和降至32mm，疗效评价为PR；二十一周期用药后直径之和降至35mm，疗效评价为PR。
患者服用化合物I二盐酸盐胶囊期间，总体耐受性良好，主要不良反应为I°腹泻、I°手足皮肤反应、II°ALT增高、II°胆红素增高、I°蛋白尿。
实施例7
诊断为神经内分泌肿瘤的患者，每日一次口服12mg(连续用两周停一周为一个治疗周期)剂量的化合物I二盐酸盐胶囊进行治疗后，记录给药之前靶病灶的直径之和(单位：毫米mm)用C0 *表示，C2 *、C4 *、C6 *、C8 *、C10 *、C14 *分别表示给药2、4、6、8、10、 14周期后的靶病灶的直径之和，数值的单位：毫米mm，结果如表1。
表1 神经内分泌肿瘤患者治疗结果
Figure PCTCN2018105628-appb-000005
实施例8
60岁男性患者，2016年3月31日行腹腔镜辅助根治性全胃切除术，术后免疫组化显示：HER2(0)，CK(+)，CgA(+)，Syn(+)，Ki-67(+60％)，诊断为胃体小弯侧溃疡型低分化神经内分泌癌(G3，约占90％)，混合低分化腺癌(约占10％)。术后口服替吉奥8周期。2016年12月26日，肿瘤标志物CEA为3004ng/ml。2016年12月29日，增强CT显示：第二肝门胰头占位，怀疑淋巴结转移融合；肝内多发环形强化病灶，怀疑肝转移。2017年01月04日、2017年02月10日分别给予IP方案(伊立替康200mg d1，100mg d8；顺铂30mg d1-3)化疗。2017年02月09日CEA值为824.400ng/ml，2017年08月23日CEA值为5621.000ng/ml。2017年8月25日开始给予EOS方案(EPI(表阿霉素)80mg d1，LOHP(奥沙利铂)100mg d1，和S-1(替吉奥胶囊)50mg PO bid d1-14；Q3W)全身化疗2周期，疗效评估为PR，化疗后上腹痛明显缓解，故继续原方案化疗2周期；于2017年12月13日、2018年01月12日、2018年02月06日给予第5-7周期化疗。2018年4月19日的CT扫描中，靶病灶直径之和为18.2mm(肝门胰头腹膜后淋巴结)，随后入组化合物I二盐酸盐胶囊的临床试验。
2018年4月21日开始，每日一次口服12mg(连续用药两周停一周，即三个星期为一个治疗周期)的化合物I二盐酸盐胶囊进行治疗。服用化合物I二盐酸盐胶囊二周期后，2018年5月29日，CT扫描显示转移灶直径之和降至18.1mm(肝门胰头腹膜后淋巴结)；给药四周期后，2018年7月12日，CT扫描显示直径之和为18.0mm(肝门胰头腹膜后淋巴结)，疗效评价为SD。截至2018年9月，患者仍在用药中。
患者服用化合物I二盐酸盐胶囊期间，总体耐受性良好，主要不良反应为II°高血压、I°尿糖、I°胆红素升高、I°体重降低、I°食欲下降。
实施例9
55岁男性患者，2017年4月15日胃活检，病理显示分化差的癌，免疫组化结果为：CK(+)，CDX2(小灶弱+)，CK7(-)，CK(+)，Syn(+)，CgA(+)，TTP-1(部分+)，CD56(+)，Ki-67(80％)。2017年4月24日诊断为：低分化癌，神经内分泌癌。
2017年4月26日开始化疗，具体用药：伊立替康(100mg d1、d8、d15)和卡铂(600mg dl)，Q3W。耐受性良好，于是调整为“伊立替康270mg d1+卡铂700mg d1”化疗3周期。2017年8月1日行全胃切除术，术后病理显示：胃体小弯侧溃疡型低分化腺神经内分泌癌(腺癌成份约占20％，神经内分泌癌成份约占80％)(Lauren分型：弥漫型)。2017年11月14日开始EP方案(VP-16(依托泊苷)150mg dl，200mg d2-3；DPP(顺铂)40mg d1-3；Q3W)化疗2周期，疗效评价PD。2017年12月29日进行1个周期的PL0T方案(奥沙利铂150mg，d1；脂质体紫杉醇150mg dl；亚叶酸钙300mg d1；替加氟3.6g，CIV(静脉输注)24小时)化疗。2018年01月11日、2018年01月24日、2018年02月11日、2018年02月27日、2018年03月13日行FL0T方案(奥沙利铂150mg，d1；脂质体紫杉醇150mg dl；亚叶酸钙300mg d1；替加氟3.6g，CIV 24h))+恩度(210mg civ 120h)化疗。化疗结束后，疗效评价PD。2018年4月10日调整为CAP方案(环磷酰胺800mg d1；和顺铂40mg d1-3；和脂质体多柔比星40mg d1)化疗，2018年5月30日，CT扫描显示靶病灶直径之和为47.8mm(肝S5和肝S6)。随后以“胃神经内分泌癌术后肝转移”入组临床试验。
2018年6月02日开始每日一次口服12mg(连续用药两周停一周，即三个星期为一个治疗周期)的化合物I二盐酸盐胶囊进行治疗。给药二周期后，2018年7月11日，CT扫描显示转移灶直径之和降至45.9mm(肝S5和肝S6)，疗效评价SD；截至2018年9 月，患者仍在用药中。患者服用化合物I二盐酸盐胶囊期间，总体耐受性良好，主要不良反应为I°高血压、I°尿糖、I°胆红素升高。
实施例10
67岁男性患者，2016年8月18日行剖腹探查术，切除胆囊、远端部分胃、十二指肠及部分胰腺，术后病理：胆总管至十二指肠大乳头处切面见一肿物，大小2.3*0.8*1.5cm，免疫组化：Ki-67(30％)。2016年11月4日，确诊为壶腹神经内分泌瘤，高增殖活性，核分裂像13个/10HPF，肿瘤位于壶腹部，累及胆总管、十二指肠乳头及主腺管，可见脉管内瘤栓，累及胰腺组织，免疫组化：AFP(—)。
2016年11月18日开始口服替吉奥60mg+替莫唑胺200mg化疗9周期，疗效SD。2017年8月8日开始替吉奥单药维持治疗至2018年2月，因胆红素高，曾停服一周期替吉奥，CT提示肿瘤进展。2018年2月7日至2018年5月25日口服依维莫司10mg qd治疗，2018年3月29日疗效评价SD。2018年5月25日，CT及MRI显示肝脏多发转移瘤，疾病进展。
2018年7月2日，CT扫描中，靶病灶直径之和为44mm(肝右叶占位)。随后入组化合物I二盐酸盐胶囊临床试验。2018年7月4日开始每日一次口服12mg(连续用药两周停一周，即三周为一个治疗周期)剂量的化合物I二盐酸盐胶囊进行治疗。服药二周期后，2018年8月15日，CT扫描显示转移灶直径之和降至35mm(肝右叶占位)，疗效评价SD；截至2018年9月，患者仍在用药中。患者服药期间，总体耐受性良好，无不良事件。
实施例11
45岁男性患者，2016年7月13日行“右肝不规则切除+近端胃大部分切除术+脾切除术”，术后病理显示胃体大弯侧仍可见分化较差的神经内分泌肿瘤残存，伴小灶坏死，瘤细胞轻-中度异型，核分裂易见，为神经内分泌肿瘤，G2，神经内分泌肿瘤肝转移。2016年9月6日，接受顺铂40mg+VP-16(依托泊苷)100mg，治疗1周期。2017年4月20日行肝转移瘤射频消融术和穿刺活检术，术后病理显示肝组织内见肿瘤浸润，免疫组化结果显示：Ki-67(+密集区30％)。2017年6月26日肝脏核磁显示病情进展。2017年7月6日至2017年8月23日给予伊立替康280mg+卡培他滨1500mg po+沙利度胺100mg的方 案，进行3周期化疗。2018年6月7日，CT显示：肝右叶转移瘤明显增大，基本占据整个右肝，疾病进展。
2018年7月4日，CT扫描结果显示，靶病灶直径之和为180mm(肝巨大占位)。随后入组化合物I二盐酸盐胶囊的临床试验，2018年7月6日开始，每日一次口服12mg(连续用药两周停一周，即三周为一个治疗周期)的化合物I二盐酸盐胶囊进行治疗。服药两个周期后，2018年8月14日，CT扫描显示转移灶直径之和降至150mm(肝巨大占位)，疗效评价SD；截至2018年9月，患者仍在用药中。服药期间，患者总体耐受性良好，无不良事件。

Claims (10)

  1. 化合物I或其药学上可接受的盐在制备用于治疗神经内分泌肿瘤的药物中的用途，
    Figure PCTCN2018105628-appb-100001
  2. 根据权利要求1所述的用途，其特征在于，所述神经内分泌肿瘤为胃肠道神经内分泌肿瘤、肺神经内分泌肿瘤、胰腺神经内分泌肿瘤、肝脏神经内分泌肿瘤、前列腺神经内分泌肿瘤、胆管神经内分泌肿瘤、乳腺神经内分泌肿瘤、壶腹神经内分泌肿瘤、胸腺神经内分泌肿瘤、纵膈神经内分泌肿瘤、腹膜后神经内分泌肿瘤、甲状腺神经内分泌肿瘤或肾上腺神经内分泌肿瘤；所述胰腺神经内分泌肿瘤优选为胰岛细胞瘤、胰岛素瘤、胺前体摄取和脱羧细胞瘤、血管活性肠肽瘤、胰高血糖素瘤、胰多肽瘤和胃泌素瘤。
  3. 根据权利要求1或2所述的用途，其特征在于，所述神经内分泌肿瘤为低分化的神经内分泌肿瘤或分化良好的神经内分泌肿瘤。
  4. 根据权利要求1-3任一项所述的用途，其特征在于，所述神经内分泌肿瘤为晚期和/或转移性的神经内分泌肿瘤。
  5. 根据权利要求1-4任一项所述的用途，其特征在于，所述的神经内分泌肿瘤为放疗和/或化疗和/或分子靶向药物治疗失败的神经内分泌肿瘤。
  6. 根据权利要求1-5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。
  7. 根据权利要求1-6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；较优选为片剂、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。
  8. 根据权利要求1-7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。
  9. 根据权利要求1-8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。
  10. 一种治疗神经内分泌肿瘤的方法，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 PCTCN2018105628-appb-100002
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