WO2024114740A1 - 喹诺林化合物治疗甲状腺癌的用途 - Google Patents

喹诺林化合物治疗甲状腺癌的用途 Download PDF

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Publication number
WO2024114740A1
WO2024114740A1 PCT/CN2023/135494 CN2023135494W WO2024114740A1 WO 2024114740 A1 WO2024114740 A1 WO 2024114740A1 CN 2023135494 W CN2023135494 W CN 2023135494W WO 2024114740 A1 WO2024114740 A1 WO 2024114740A1
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Prior art keywords
iodine
thyroid cancer
pharmaceutically acceptable
compound
formula
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PCT/CN2023/135494
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English (en)
French (fr)
Inventor
王怡然
张喜全
王训强
于鼎
陈勇强
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正大天晴药业集团股份有限公司
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Publication of WO2024114740A1 publication Critical patent/WO2024114740A1/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
    • A61K31/33—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

Definitions

  • the present disclosure belongs to the field of medical technology, and relates to the use of quinoline compounds in treating thyroid cancer, and specifically to the use and method of N-(4-((7-((1-(cyclopentylamino)cyclopropane)methoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in treating differentiated thyroid cancer.
  • Thyroid cancer is a malignant tumor that originates from the thyroid follicular epithelium or parafollicular epithelial cells. In recent years, the incidence of thyroid cancer has continued to grow rapidly worldwide. In 2020, the number of new cases of thyroid cancer worldwide was approximately 580,000, and the incidence rate ranked 11th among all cancers. It is estimated that around 2030, thyroid cancer will become the fourth most common cancer in terms of incidence.
  • Differentiated thyoid cancer accounts for up to 95% of thyroid cancer.
  • Most DTC patients have a good prognosis and can survive for a long time after surgery, radioiodine therapy and thyroid-stimulating hormone (TSH) suppression therapy.
  • TSH thyroid-stimulating hormone
  • RAIR-DTC iodine-refractory differentiated thyroid cancer
  • the survival of RAIR-DTC patients is significantly shortened, with an average survival of only 3 to 5 years and a 10-year survival rate of only about 10%. How to conduct follow-up treatment for RAIR-DTC patients has become a hot topic and difficulty in clinical attention.
  • WO2012034055 discloses N-(4-((7-((1-(cyclopentylamino)cyclopropanyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as the compound of formula (I)) as a c-Met kinase inhibitor and its use in inhibiting tyrosine kinase activity.
  • the compound of formula (I) is a new class of compounds with excellent pharmacological properties, which can inhibit the activity of multiple protein tyrosine kinases, such as c-Met, VEGFr, EGFr, c-kit, PDGF, FGF, SRC, Ron, Tie2, etc.
  • multiple protein tyrosine kinases such as c-Met, VEGFr, EGFr, c-kit, PDGF, FGF, SRC, Ron, Tie2, etc.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating differentiated thyroid cancer.
  • the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating differentiated thyroid cancer.
  • the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in treating differentiated thyroid cancer.
  • the present disclosure provides a method for treating differentiated thyroid cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating differentiated thyroid cancer.
  • the pharmaceutical composition further contains a pharmaceutically acceptable excipient.
  • the present disclosure provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating differentiated thyroid cancer.
  • the pharmaceutical composition is a pharmaceutical composition in a single-dose form, or a pharmaceutical composition in a multi-dose form.
  • the pharmaceutical composition further contains a pharmaceutically acceptable excipient.
  • the present disclosure provides use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in treating differentiated thyroid cancer.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for treating differentiated thyroid cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • the present disclosure provides a kit for treating differentiated thyroid cancer, the kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and b) instructions for use in treating differentiated thyroid cancer.
  • the kit may contain a single dose or multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the differentiated thyroid cancer is selected from papillary thyroid carcinoma, follicular thyroid carcinoma, and oncocytic carcinoma.
  • the differentiated thyroid cancer is selected from papillary thyroid carcinoma.
  • the differentiated thyroid cancer is selected from metastatic differentiated thyroid cancer.
  • the differentiated thyroid cancer is selected from recurrent metastatic differentiated thyroid cancer.
  • the differentiated thyroid cancer is selected from iodine-refractory differentiated thyroid cancer.
  • the differentiated thyroid cancer is selected from iodine-refractory metastatic differentiated thyroid cancer.
  • the differentiated thyroid cancer is selected from iodine-refractory recurrent metastatic differentiated thyroid cancer.
  • the patient with differentiated thyroid cancer meets all of the following conditions:
  • the local treatment comprises surgical resection, external beam radiation, or ablative therapy.
  • the patient with differentiated thyroid cancer has previously been treated with at least one tyrosine kinase inhibitor (TKI).
  • TKI tyrosine kinase inhibitor
  • the patient with differentiated thyroid cancer has previously been treated with at least one tyrosine kinase inhibitor and has failed treatment.
  • the patient with differentiated thyroid cancer has had disease progression (treatment failure) after previous treatment with at least one tyrosine kinase inhibitor.
  • the patient with differentiated thyroid cancer has been previously treated with one or two tyrosine kinase inhibitors.
  • the patient with differentiated thyroid cancer has previously been treated with one or two tyrosine kinase inhibitors and has failed treatment.
  • the patient with differentiated thyroid cancer has had disease progression (treatment failure) after prior treatment with one or two tyrosine kinase inhibitors.
  • the differentiated thyroid cancer is selected from iodine-refractory differentiated thyroid cancer that has previously failed treatment with one or two tyrosine kinase inhibitors.
  • the differentiated thyroid cancer is selected from iodine-refractory differentiated thyroid cancer that has experienced disease progression (treatment failure) after previous treatment with one or two tyrosine kinase inhibitors.
  • the patient with differentiated thyroid cancer is selected from patients with iodine-refractory differentiated thyroid cancer who have failed previous treatment with one or two tyrosine kinase inhibitors.
  • the patient with differentiated thyroid cancer is selected from patients with iodine-refractory differentiated thyroid cancer who have experienced disease progression (treatment failure) after previous treatment with one or two tyrosine kinase inhibitors.
  • the patient with differentiated thyroid cancer is selected from patients with papillary thyroid cancer who have previously failed treatment with one or two tyrosine kinase inhibitors.
  • the patient with differentiated thyroid cancer is selected from patients with papillary thyroid cancer who have experienced disease progression (treatment failure) after previous treatment with one or two tyrosine kinase inhibitors.
  • the tyrosine kinase inhibitors include but are not limited to Surufatinib, Donafenib, Sorafenib, Lenvatinib, Vandetanib, Cabozantinib, Sunitinib, Pazopanib, Motesanib, Dovitinib, Apatinib, Axitinib, Anlotinib, or Pralsetinib.
  • the tyrosine kinase inhibitor is selected from VEGFR targeted inhibitors.
  • the VEGFR targeted inhibitor includes but is not limited to Sorafenib, Lenvatinib, Vandetanib, Cabozantinib, Sunitinib, Pazopanib, Motesanib, Dovitinib, Apatinib, Axitinib, Anlotinib or Pralsetinib.
  • the VEGFR targeted inhibitor is selected from sorafenib, lenvatinib, apatinib, anlotinib, or pratinib.
  • the patient with iodine-refractory differentiated thyroid cancer includes but is not limited to one of the following:
  • radioactive iodine e.g. 131 I
  • a cumulative dose of ⁇ 600 mCi or 22 GBq but the disease has not been relieved.
  • the patient with iodine-refractory differentiated thyroid cancer meets one of the following conditions in the thyroid stimulating hormone stimulation state (>30 mIU/L) without the interference of exogenous iodine load:
  • Some metastatic lesions take up iodine, while others do not, and can be shown by other imaging examinations such as 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/CT, CT or MRI;
  • 18 F-FDG 18 F-fluorodeoxyglucose
  • the iodine-uptake metastatic lesions maintained their iodine uptake capacity after multiple 131 I treatments, they still showed disease progression within 1 year, including gradual growth of lesions, the appearance of new lesions, and a continuous increase in serum thyroglobulin (Tg).
  • the patient with iodine-refractory differentiated thyroid cancer meets one of the following conditions:
  • the lesion does not take up iodine on whole-body imaging after 131I treatment and cannot benefit from subsequent 131I treatment (if there is too much residual thyroid, it may affect the iodine uptake of the metastatic lesion, which can be evaluated during the second treatment after ablation of the thyroid gland);
  • the patient with differentiated thyroid cancer is being treated with a thyroid stimulating hormone inhibitor.
  • the patient with differentiated thyroid cancer has thyroid stimulating hormone ⁇ 0.5 mIU/L.
  • the patient with differentiated thyroid cancer has a thyroid stimulating hormone level of ⁇ 0.5 mIU/L while on thyroid stimulating hormone inhibitor therapy.
  • the thyroid stimulating hormone inhibitor is selected from levothyroxine or a salt thereof (eg, levothyroxine sodium), or desiccated thyroid.
  • the thyroid stimulating hormone inhibitor is selected from levothyroxine sodium tablets or dried thyroid tablets.
  • the patient with differentiated thyroid cancer is iodine-refractory and has disease progression after previously receiving at least one (eg, one or two) VEGFR targeted therapies.
  • the patient with differentiated thyroid cancer is iodine-refractory and has disease progression after previously receiving at least 1 (e.g., 1 or 2) VEGFR targeted therapies, and has a thyroid stimulating hormone ⁇ 0.5 mIU/L under thyroid stimulating hormone inhibitor treatment.
  • the patient with differentiated thyroid cancer meets all of the following conditions:
  • DTC Differentiated thyroid cancer
  • VEGFR targeted therapies including surufatinib, sorafenib, lenvatinib, apatinib, anlotinib or pratinib;
  • Patients who are refractory to iodine treatment can be defined as iodine refractory if they meet any of the following conditions:
  • the lesion does not take up iodine on whole-body imaging after 131I treatment and cannot benefit from subsequent 131I treatment (must be confirmed by an endocrinologist or nuclear medicine physician. If there is too much residual thyroid, it may affect the iodine uptake of the metastatic lesion, which can be evaluated during the second treatment after ablation of the thyroid gland);
  • the patient with differentiated thyroid cancer meets all of the following conditions:
  • DTC Differentiated thyroid cancer
  • VEGFR targeted therapies including sorafenib, lenvatinib, apatinib, anlotinib, or pratinib;
  • Patients who are refractory to iodine treatment can be defined as iodine refractory if they meet any of the following conditions:
  • the lesion does not take up iodine on whole-body imaging after 131I treatment and cannot benefit from subsequent 131I treatment (must be confirmed by an endocrinologist or nuclear medicine physician. If there is too much residual thyroid, it may affect the iodine uptake of the metastatic lesion, which can be evaluated during the second treatment after ablation of the thyroid gland);
  • the differentiated thyroid cancer does not include a thyroid cancer known to be RET fusion-positive.
  • the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 2-6 weeks. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or the range formed by any of the above values. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 3 weeks or 4 weeks.
  • the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt may be more than 1 cycle, including 1, 2, 3, 4, 5, 6 or more cycles. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt may preferably be 1-6 administration cycles.
  • the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt can be 3 times a day, 2 times a day, 1 time a day, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 3 times a week, 2 times a week, 1 time a week, 1 time every two weeks, or 1 time every three weeks.
  • the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is 3 times a day, 2 times a day, or 1 time a day.
  • the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 time a day.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, or a range formed by any of the above values.
  • the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 20-180 mg. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 20-40 mg, 20-60 mg, 20-90 mg, 20-120 mg, 20-150 mg, 40-60 mg, 40-90 mg, 40-120 mg, 40-150 mg, 40-180 mg, 60-90 mg, 60-120 mg, 60-150 mg, 60-180 mg, 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 60-90 mg, 60-120 mg, 60-150 mg, 60-180 mg, 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg.
  • the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 60 mg, 90 mg, 120 mg, 150 mg or 180 mg. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 60 mg, 90 mg or 120 mg. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt may be 90 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered in a single dose or multiple doses. In some embodiments, it is administered in multiple doses.
  • the pharmaceutical composition is a pharmaceutical composition with a single dose of 30-60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a pharmaceutical composition with a single dose of 30 mg or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is a multiple-dose pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple doses may consist of a single dose of 30 mg or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is a pharmaceutical composition of multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be 60 mg, 90 mg, 120 mg, 150 mg, or 180 mg. In some embodiments, the multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be 60 mg, 90 mg, or 120 mg. In some embodiments, the multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof is 90 mg.
  • the multiple doses of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof may consist of a single dose of 30 mg or 60 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered for one or more dosing cycles.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered for one or more dosing cycles, and the frequency of administration may be 3 times a day, 2 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, once a week, once every two weeks, or once every three weeks, preferably 3 times a day, 2 times a day or once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject for one or more dosing cycles, and the administration is continued every day (e.g., 3 times a day, 2 times a day or once a day).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered to the subject continuously every day (e.g., 3 times a day, 2 times a day or once a day).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: with a 28-day administration cycle, a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, administered once a day.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: one or more administration cycles are administered with 28 days as one administration cycle, and the daily dose is 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, administered once a day.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 60 mg, 90 mg, 120 mg, 150 mg or 180 mg.
  • the daily dose can be adjusted after administration (including but not limited to increasing or decreasing the daily dose).
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg.
  • the daily dose may be adjusted after administration (including but not limited to upward or downward adjustment of the daily dose).
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg, optionally, the daily dose is adjusted upward after administration. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg, optionally, the daily dose is adjusted upward after administration to a daily dose selected from 120 mg, 150 mg or 180 mg.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg, optionally, the daily dose is adjusted upward after administration. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg, optionally, the daily dose is adjusted upward after administration to 120 mg.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg, optionally, the daily dose is adjusted downward after administration. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg, optionally, After administration, the daily dose was adjusted down to 60 mg or less.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg, optionally, the daily dose is adjusted downward after administration. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg, optionally, the daily dose is adjusted downward after administration to 60 mg.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition can be administered by various routes, including but not limited to oral administration.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition can be taken orally on an empty stomach (e.g., in the morning on an empty stomach).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered by the following method: oral administration on an empty stomach in the morning, once a day, for one or more dosing cycles (for example, 28 days can be one dosing cycle). In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered by the following method: oral administration on an empty stomach in the morning, once a day, for one or more dosing cycles, wherein 28 days is one dosing cycle.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: oral administration on an empty stomach every day (e.g., once a day), with a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, for one or more consecutive administration cycles (e.g., 28 days as one administration cycle).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: with a dosing cycle of 28 days, it is orally administered once a day on an empty stomach, with a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, for 28 consecutive days (i.e., one dosing cycle).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: with a dosing cycle of 28 days, orally administered once a day on an empty stomach, with each dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, for 28 consecutive days (i.e., one dosing cycle).
  • the above-described dosing cycle is repeated as long as the disease remains under control and the regimen is clinically tolerated.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared in a single or multiple dose form suitable for each administration of 60 mg-180 mg, or 60 mg-150 mg, or 60 mg-120 mg, or 90 mg-180 mg, or 90 mg-150 mg, or 90 mg-120 mg, or 120 mg-150 mg, or 120 mg-180 mg, or 150 mg-180 mg, or 60 mg, or 90 mg, or 120 mg, or 150 mg, or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared in a single or multiple dose form suitable for once a day and administering 60mg-180mg, or 60mg-150mg, or 60mg-120mg, or 90mg-180mg, or 90mg-150mg, or 90mg-120mg, or 120mg-150mg, or 120mg-180mg, or 150mg-180mg, or 60mg, or 90mg, or 120mg, or 150mg, or 180mg of the compound of formula (I) or its pharmaceutically acceptable salt to the patient each time.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared in a single or multiple dose form suitable for administering 60 mg-180 mg, or 60 mg-150 mg, or 60 mg-120 mg, or 90 mg-180 mg, or 90 mg-150 mg, or 90 mg-120 mg, or 120 mg-150 mg, or 120 mg-180 mg, or 150 mg-180 mg, or 60 mg, or 90 mg, or 120 mg, or 150 mg, or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt once a day for 28 consecutive days.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof disclosed herein are used as a single active agent.
  • the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt or its pharmaceutical composition can be used in combination with other active agents.
  • the other active agents include but are not limited to thyroid stimulating hormone inhibitors (such as levothyroxine sodium tablets or dried thyroid tablets).
  • the disclosed compound of formula (I) can be administered in the form of its free base or in the form of its pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt of the compound of formula (I) is within the scope of the present disclosure, and can be produced from different organic acids and inorganic acids according to methods known in the art, such as the inorganic acid can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and the organic acid can be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthylsulfuric acid.
  • the compound of formula (I) is administered in the form of its free base.
  • the "compound of formula (I) or its pharmaceutically acceptable salt” described in the present disclosure may be in the “compound of formula (I) or its pharmaceutically acceptable salt”
  • the invention further provides a pharmaceutical composition of a salt thereof.
  • the method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be suitable for oral administration.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.
  • the solid pharmaceutical composition is a capsule.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule formulation with strengths of 30 mg and 60 mg.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule preparation, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule preparation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, corn starch, carboxymethylcellulose calcium, hypromellose and magnesium stearate.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule preparation, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, sodium starch glycolate and magnesium stearate.
  • the strength of the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is 30-60 mg (calculated as the compound of formula (I)). In some embodiments, the strength of the pharmaceutical composition may be 30 mg or 60 mg (calculated as the compound of formula (I)).
  • the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition disclosed herein has good safety and anti-tumor activity, shows good inhibitory activity against differentiated thyroid cancer cells, and shows good tumor inhibition activity in a nude mouse subcutaneous transplant tumor model of differentiated thyroid cancer cells.
  • the disclosed treatment regimen using the compound of formula (I) or its pharmaceutically acceptable salt has good efficacy and good safety in the treatment of iodine-refractory differentiated thyroid cancer.
  • the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition has excellent effect in at least one aspect of survival efficacy evaluation, such as overall survival (OS), median survival; tumor response efficacy evaluation such as disease-free survival (DFS), median DFS, progression-free survival (PFS), 6-month PFS rate, time to disease progression (TTP), objective response rate (ORR), disease control rate (DCR), duration of remission (DOR); and tolerance or safety evaluation such as adverse event incidence, etc.
  • OS overall survival
  • tumor response efficacy evaluation such as disease-free survival (DFS), median DFS, progression-free survival (PFS), 6-month PFS rate, time to disease progression (TTP), objective response rate (ORR), disease control rate (DCR), duration of remission (DOR); and tolerance or safety evaluation such as adverse event incidence, etc.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof has a good objective response rate and/or disease control rate in the treatment of iodine-refractory differentiated thyroid cancer.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt includes salts formed by alkali ions and free acids (free acid) or salts formed by acid ions and free bases (free alkali).
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect, including partial or complete stabilization or cure of a disease and/or effects resulting from a disease.
  • treatment encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its development; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or symptoms.
  • an effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder.
  • the amount of active substance e.g., a compound of the present disclosure
  • a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the subject (e.g., a mammal) to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • administering means physically introducing a composition comprising an active compound into a host or patient or subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral.
  • differentiated thyroid cancer does not include anaplastic thyroid cancer or medullary thyroid cancer.
  • daily dose refers to the dose administered to a patient for one day.
  • patient or “subject” or “subject” are used interchangeably herein to refer to mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the patient, subject, or subject is a human.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; for example, if a box of medicine contains seven tablets, each tablet is a single dose.
  • multiple doses consists of a plurality of single doses.
  • composition refers to a mixture of one or more active ingredients of the present disclosure and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to a subject.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into a solid preparation (e.g., granules, tablets, pills, capsules, etc.), or formulated into a liquid preparation (e.g., injection).
  • suitable pharmaceutically acceptable excipients for example, it can be formulated into a solid preparation (e.g., granules, tablets, pills, capsules, etc.), or formulated into a liquid preparation (e.g., injection).
  • the pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain the core of a capsule, tablet or dragee.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • day When referring to a dosing regimen, the terms "day,” “daily,” and the like refer to the times within a calendar day, beginning at midnight and ending at the following midnight.
  • IHH-4 cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 6 ⁇ 10 4 cells/mL, and inoculated on 96-well plates (100 ⁇ L/well), cultured overnight in a cell culture incubator, and the compound was added using a nanoliter pipette to make the final concentration of the compound 10000nM-4.57nM, 2 replicates, and a control was set at the same time.
  • IHH-4 cells were subcutaneously inoculated in the right axilla of SPF female nude mice (source: Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.), 5 ⁇ 10 6 cells/mouse. When the average tumor volume reached about 150 mm 3 , the animals were divided into groups.
  • the day of grouping was day 0. From day 0 onwards, drugs were administered by gavage once a day. Tumor volume was measured 2-3 times a week, and the mice were weighed and the data were recorded. The general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.
  • the detection indicators and calculation formula are as follows:
  • Tumor volume, TV (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ); where a is the long diameter of the tumor, and b is the short diameter of the tumor.
  • T/C (%) TRTV / CRTV ⁇ 100%, wherein TRTV is the RTV of the treatment group; CRTV is the RTV of the vehicle control group.
  • TGI (%) (1-TW/TW 0 ) ⁇ 100%; wherein, TW is the tumor weight of the treatment group, and TW 0 is the tumor weight of the vehicle control group.
  • Body weight change rate, WCR (%) (Wt t - Wt 0 )/Wt 0 ⁇ 100%; wherein Wt 0 is the body weight of mice on day 0, and Wt t is the body weight of mice at each measurement.
  • FTC-133 cells were subcutaneously inoculated in the right axilla of SPF male nude mice (source: Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.), 1 ⁇ 10 7 cells/mouse. When the average tumor volume reached about 150 mm 3 , the animals were divided into groups.
  • the day of grouping was day 0. Starting from day 0, the compound of formula (I) was administered by gavage once a day. The tumor volume was measured 2-3 times a week, and the mice were weighed and the data were recorded. The general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.
  • the detection indicators and calculation formula are as follows:
  • Tumor volume, TV (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ); where a is the long diameter of the tumor, and b is the short diameter of the tumor.
  • T/C (%) TRTV / CRTV ⁇ 100%, wherein TRTV is the RTV of the treatment group; CRTV is the RTV of the vehicle control group.
  • TGI (%) (1-TW/TW 0 ) ⁇ 100%; wherein, TW is the tumor weight of the treatment group, and TW 0 is the tumor weight of the vehicle control group.
  • Body weight change rate, WCR (%) (Wt t - Wt 0 )/Wt 0 ⁇ 100%; wherein Wt 0 is the body weight of mice on day 0, and Wt t is the body weight of mice at each measurement.
  • Patients who are iodine-refractory can be defined as iodine-refractory if they meet any of the following conditions:
  • the lesion does not take up iodine on whole-body imaging after 131I treatment and cannot benefit from subsequent 131I treatment (must be confirmed by an endocrinologist or nuclear medicine physician. If there is too much residual thyroid, it may affect the iodine uptake of the metastatic lesion, which can be evaluated during the second treatment after ablation of the thyroid gland);
  • HBsAg-positive patients must meet the requirement of HBV DNA quantitative ⁇ 1 ⁇ 10 4 IU/mL (or 5 ⁇ 10 4 copies/mL) or have received anti-HBV treatment for at least 1 week before the start of the study and the viral index has decreased by more than 10 times, and the patients are willing to receive anti-HBV treatment throughout the entire study period; patients with positive hepatitis C antibodies and positive HCV RNA quantitative must have completed antiviral treatment at least 1 month before the start of the study;
  • Test drug capsules of compound of formula (I), specifications: 30 mg or 60 mg.
  • Dosage method Oral administration on an empty stomach in the morning, once a day, for 28 consecutive days as a dosing cycle, until the study termination criteria are met.
  • the dose may be increased to 120 mg
  • the dose can be lowered to 60 mg.
  • Effectiveness evaluation RECIST 1.1 standard was used for evaluation.
  • AEs adverse events
  • SAEs serious adverse events
  • TEAEs treatment-emergent adverse events
  • Objective response rate refers to the percentage of subjects with complete response (CR) or partial response (PR) determined by the investigator according to RECIST 1.1;
  • PFS Progression-free survival
  • 6-month PFS rate the proportion of subjects who had no disease progression and no death from the first dose to the 6th month;
  • DCR Disease control rate: refers to the percentage of subjects with CR, PR, or disease stability (SD) greater than or equal to 12 months as determined by the investigator according to RECIST 1.1;
  • Duration of response For subjects with CR or PR, the time from the first tumor assessment as CR or PR to disease progression (PD) or death before PD; if the subject with CR or PR does not experience PD or death before PD, the date of the last imaging assessment is used as the cutoff date.
  • OS Overall survival
  • the best efficacy was partial remission (PR) in 1 patient, stable disease (SD) in 6 patients, and the disease control rate (DCR) was 100% (7/7).
  • Table 1 shows the test results of representative cases.
  • NA means not evaluated;

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Abstract

本申请涉及喹诺林化合物（I）治疗甲状腺癌的用途，具体涉及N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺治疗分化型甲状腺癌的用途和方法。

Description

喹诺林化合物治疗甲状腺癌的用途
相关申请的引用
本申请要求于2022年12月01日向中华人民共和国国家知识产权局提交的第202211533759.7号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本公开属于医药技术领域，涉及喹诺林化合物治疗甲状腺癌的用途，具体涉及N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺治疗分化型甲状腺癌的用途和方法。
背景技术
甲状腺癌是一种起源于甲状腺滤泡上皮或滤泡旁上皮细胞的恶性肿瘤，近年来，全球范围内甲状腺癌的发病率持续快速增长，2020年全球新发甲状腺癌病例数约为58万例，发病率在所有癌症中列第11位，预计2030年前后甲状腺癌将成为发病率位列第四的常见癌症。
分化型甲状腺癌(differentiated thyoid cancer，DTC)在甲状腺癌中的比例高达95％。多数DTC患者经过手术、放射性碘治疗和促甲状腺激素(thyroid-stimulating hormone，TSH)抑制治疗后预后良好，可长期生存，但仍有少数患者在病程中因肿瘤细胞出现失分化，失去摄碘能力而发展为碘难治性DTC(radioiodine refractory differentiated thyroid cancer，RAIR-DTC)。RAIR-DTC患者的生存期明显缩短，平均生存期仅3～5年，10年生存率仅为10％左右。对RAIR-DTC患者如何进行后续治疗已成为临床关注的热点和难点。
WO2012034055公开了作为c-Met激酶抑制剂的N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺(下称式(I)化合物)及其抑制酪氨酸激酶活性的用途。式(I)化合物是一类新的具有优良药理学性质的化合物，该化合物可抑制多种蛋白酪氨酸激酶的活性，例如c-Met、VEGFr、EGFr、c-kit、PDGF、FGF、SRC、Ron、Tie2等。
发明内容
一方面，本公开提供用于治疗分化型甲状腺癌的式(I)化合物或其药学上可接受的盐，
另一方面，本公开提供式(I)化合物或其药学上可接受的盐在制备用于治疗分化型甲状腺癌的药物中的用途。
另一方面，本公开提供式(I)化合物或其药学上可接受的盐在治疗分化型甲状腺癌中的用途。
另一方面，本公开提供治疗分化型甲状腺癌的方法，所述方法包括向有需要的患者给予治疗有效量的式(I)化合物或其药学上可接受的盐。
再一方面，本公开提供用于治疗分化型甲状腺癌的包含式(I)化合物或其药学上可接受的盐的药物组合物。在一些实施方案中，所述药物组合物还含有药学上可接受的辅料。
再一方面，本公开提供包含式(I)化合物或其药学上可接受的盐的药物组合物在制备用于治疗分化型甲状腺癌的药物中的用途。在一些实施方案中，所述药物组合物为单剂量形式的药物组合物，或者多剂量形式的药物组合物。在一些实施方案中，所述药物组合物还含有药学上可接受的辅料。
再一方面，本公开提供包含式(I)化合物或其药学上可接受的盐的药物组合物在治疗分化型甲状腺癌中的用途。在一些实施方案中，所述药物组合物还含有药学上可接受的辅料。
再一方面，本公开提供治疗分化型甲状腺癌的方法，所述方法包括向有需要的患者给予治疗有效量的包含式(I)化合物或其药学上可接受的盐的药物组合物。在一些实施方案中，所述药物组合物还含有药学上可接受的辅料。
又一方面，本公开提供一种用于治疗分化型甲状腺癌的试剂盒，所述试剂盒包含：a)式(I)化合物或其药学上可接受的盐，或者包含式(I)化合物或其药学上可接受的盐的药物组合物；以及b)治疗分化型甲状腺癌的使用说明。
在一些实施方案中，所述试剂盒可包含单剂量或多剂量的式(I)化合物或其药学上可接受的盐，或者包含式(I)化合物或其药学上可接受的盐的药物组合物。
分化型甲状腺癌
在一些实施方案中，所述分化型甲状腺癌选自甲状腺乳头状癌、甲状腺滤泡癌和嗜酸细胞癌。
在一些实施方案中，所述分化型甲状腺癌选自甲状腺乳头状癌。
在一些实施方案中，所述分化型甲状腺癌选自转移性分化型甲状腺癌。
在一些实施方案中，所述分化型甲状腺癌选自复发转移性分化型甲状腺癌。
在一些实施方案中，所述分化型甲状腺癌选自碘难治性分化型甲状腺癌。
在一些实施方案中，所述分化型甲状腺癌选自碘难治性转移性分化型甲状腺癌。
在一些实施方案中，所述分化型甲状腺癌选自碘难治性复发转移性分化型甲状腺癌。
在一些实施方案中，所述分化型甲状腺癌的患者满足以下所有条件：
1)病情进展迅速；
2)临床症状明显，甚至危及患者生命(但预期生存时间大于3个月)；
3)无法采取适宜的局部治疗方案。
在一些实施方案中，所述局部治疗包括手术切除、外照射或消融治疗。
在一些实施方案中，所述分化型甲状腺癌的患者既往接受过至少一种酪氨酸激酶抑制剂(TKI)治疗。
在一些实施方案中，所述分化型甲状腺癌的患者既往接受过至少一种酪氨酸激酶抑制剂治疗且治疗失败。
在一些实施方案中，所述分化型甲状腺癌的患者既往接受过至少一种酪氨酸激酶抑制剂治疗后出现疾病进展(治疗失败)。
在一些实施方案中，所述分化型甲状腺癌的患者既往接受过一种或两种酪氨酸激酶抑制剂治疗。
在一些实施方案中，所述分化型甲状腺癌的患者既往接受过一种或两种酪氨酸激酶抑制剂治疗且治疗失败。
在一些实施方案中，所述分化型甲状腺癌的患者既往接受过一种或两种酪氨酸激酶抑制剂治疗后出现疾病进展(治疗失败)。
在一些实施方案中，所述分化型甲状腺癌选自既往经一种或两种酪氨酸激酶抑制剂治疗失败的碘难治性分化型甲状腺癌。
在一些实施方案中，所述分化型甲状腺癌选自既往经一种或两种酪氨酸激酶抑制剂治疗后出现疾病进展(治疗失败)的碘难治性分化型甲状腺癌。
在一些实施方案中，所述分化型甲状腺癌的患者选自既往经一种或两种酪氨酸激酶抑制剂治疗失败的碘难治性分化型甲状腺癌患者。
在一些实施方案中，所述分化型甲状腺癌的患者选自既往经一种或两种酪氨酸激酶抑制剂治疗后出现疾病进展(治疗失败)的碘难治性分化型甲状腺癌患者。
在一些实施方案中，所述分化型甲状腺癌的患者选自既往经一种或两种酪氨酸激酶抑制剂治疗失败的甲状腺乳头状癌患者。
在一些实施方案中，所述分化型甲状腺癌的患者选自既往经一种或两种酪氨酸激酶抑制剂治疗后出现疾病进展(治疗失败)的甲状腺乳头状癌患者。
在一些实施方案中，所述酪氨酸激酶抑制剂包括但不限于索凡替尼(Surufatinib)、甲苯磺酸多纳非尼(Donafenib)、索拉非尼(Sorafenib)、仑伐替尼(Lenvatinib)、凡德他尼(Vandetanib)、卡博替尼(Cabozantinib)、舒尼替尼(Sunitinib)、帕唑帕尼(Pazopanib)、莫特塞尼(Motesanib)、多韦替尼(Dovitinib)、 阿帕替尼(Apatinib)、阿西替尼(Axitinib)、安罗替尼(Anlotinib)或普拉替尼(Pralsetinib)。
在一些实施方案中，所述酪氨酸激酶抑制剂选自VEGFR靶向抑制剂。
在一些实施方案中，所述VEGFR靶向抑制剂包括但不限于索拉非尼(Sorafenib)、仑伐替尼(Lenvatinib)、凡德他尼(Vandetanib)、卡博替尼(Cabozantinib)、舒尼替尼(Sunitinib)、帕唑帕尼(Pazopanib)、莫特塞尼(Motesanib)、多韦替尼(Dovitinib)、阿帕替尼(Apatinib)、阿西替尼(Axitinib)、安罗替尼(Anlotinib)或普拉替尼(Pralsetinib)。
在一些实施方案中，所述VEGFR靶向抑制剂选自索拉非尼、仑伐替尼、阿帕替尼、安罗替尼或普拉替尼。
在一些实施方案中，所述碘难治性分化型甲状腺癌的患者包括但不限于以下情形之一：
a)病灶不摄碘；
b)病灶经放射性碘(例如131I)治疗后丧失摄碘能力；
c)存在部分病灶不摄碘；
d)病灶摄碘，但疾病进展(例如在12个月内出现疾病进展)；
e)经放射性碘(例如131I)治疗，且累积用量≥600mCi或22GBq，但疾病无缓解。
在一些实施方案中，所述碘难治性分化型甲状腺癌的患者在无外源性碘负荷干扰的情况下，促甲状腺激素刺激状态(>30mIU/L)时，满足下列情形之一：
a)转移灶在清甲成功后的首次131I治疗后全身显像中即表现为不摄碘，致其无法从后续的131I治疗中获益；
b)原本摄碘的功能性转移灶在经131I治疗后逐渐丧失摄碘能力；
c)部分转移灶摄碘，部分转移灶不摄碘，且可被18F-脱氧葡萄糖(18F-fluorodeoxyglucose,18F-FDG)PET/CT、CT或MRI等其他影像学检查手段所显示；
d)摄碘转移灶在经过多次131I治疗后虽然保持摄碘能力，但仍在1年内出现病情进展，包括病灶逐渐增长、出现新发病灶和血清甲状腺球蛋白(thyroglobulin,Tg)持续上升等。
在一些实施方案中，所述碘难治性分化型甲状腺癌的患者满足下列情形之一：
a)病灶在131I治疗后全身显像上表现为不摄碘，且无法从后续的131I治疗中获益(如残留甲状腺太多，可能会影响转移灶摄碘，可清甲后再次治疗时进行评估)；
b)原本摄碘的病灶经131I治疗后逐渐丧失摄碘能力；
c)同一患者体内部分病灶摄碘，而部分病灶不摄碘，且生化无缓解；
d)病灶摄碘，但在12个月内出现疾病进展；
e)131I累积用量≥600mCi或22GBq，但疾病无缓解。
在一些实施方案中，所述分化型甲状腺癌的患者接受促甲状腺激素抑制剂的治疗。
在一些实施方案中，所述分化型甲状腺癌的患者的促甲状腺激素≤0.5mIU/L。
在一些实施方案中，所述分化型甲状腺癌的患者在促甲状腺激素抑制剂治疗下促甲状腺激素≤0.5mIU/L。
在一些实施方案中，所述促甲状腺激素抑制剂选自左甲状腺素或其盐(例如左甲状腺素钠)、或者干甲状腺。
在一些实施方案中，所述促甲状腺激素抑制剂选自左甲状腺素钠片或者干甲状腺片。
在一些实施方案中，所述分化型甲状腺癌的患者为碘难治性患者，且既往接受过至少1种(例如1种或2种)VEGFR靶向治疗后出现疾病进展。
在一些实施方案中，所述分化型甲状腺癌的患者为碘难治性患者，且既往接受过至少1种(例如1种或2种)VEGFR靶向治疗后出现疾病进展，以及在促甲状腺激素抑制剂治疗下促甲状腺激素≤0.5mIU/L。
在一些实施方案中，所述分化型甲状腺癌的患者满足以下所有条件：
1)经病理组织学或者细胞学检查确诊的分化型甲状腺癌(DTC)；
2)根据RECIST 1.1，至少具有一个可测量病灶；
3)既往接受过至少1种(但不超过2种)VEGFR靶向治疗后出现疾病进展，所述VEGFR靶向治疗包括索凡替尼、索拉非尼、仑伐替尼、阿帕替尼、安罗替尼或普拉替尼；
4)碘难治患者，满足下列情形之一可界定为碘难治：
a)病灶在131I治疗后全身显像上表现为不摄碘，且无法从后续的131I治疗中获益(必须由内分泌科或核医学医师确认，如残留甲状腺太多，可能会影响转移灶摄碘，可清甲后再次治疗时进行评估)；
b)原本摄碘的病灶经131I治疗后逐渐丧失摄碘能力；
c)同一患者体内部分病灶摄碘，而部分病灶不摄碘，且生化无缓解；
d)病灶摄碘，但在12个月内出现疾病进展(经影像学确认)；
e)131I累积用量≥600mCi或22GBq，但疾病无缓解(经影像学确认)；
5)知情前14个月内有影像学进展的证据；
6)促甲状腺激素抑制剂治疗下促甲状腺激素≤0.5mIU/L。
在一些实施方案中，所述分化型甲状腺癌的患者满足以下所有条件：
1)经病理组织学或者细胞学检查确诊的分化型甲状腺癌(DTC)；
2)根据RECIST 1.1，至少具有一个可测量病灶；
3)既往接受过至少1种(但不超过2种)VEGFR靶向治疗后出现疾病进展，所述VEGFR靶向治疗包括索拉非尼、仑伐替尼、阿帕替尼、安罗替尼或普拉替尼；
4)碘难治患者，满足下列情形之一可界定为碘难治：
a)病灶在131I治疗后全身显像上表现为不摄碘，且无法从后续的131I治疗中获益(必须由内分泌科或核医学医师确认，如残留甲状腺太多，可能会影响转移灶摄碘，可清甲后再次治疗时进行评估)；
b)原本摄碘的病灶经131I治疗后逐渐丧失摄碘能力；
c)同一患者体内部分病灶摄碘，而部分病灶不摄碘，且生化无缓解；
d)病灶摄碘，但在12个月内出现疾病进展(经影像学确认)；
e)131I累积用量≥600mCi或22GBq，但疾病无缓解(经影像学确认)；
5)知情前14个月内有影像学进展的证据；
6)促甲状腺激素抑制剂治疗下促甲状腺激素≤0.5mIU/L。
在一些实施方案中，所述分化型甲状腺癌不包括已知伴随RET融合阳性的甲状腺癌。
给药方案
在一些实施方案中，给予式(I)化合物或其药学上可接受的盐的给药周期是2-6周。在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期是2周、3周、4周、5周、6周或上述任意值形成的范围。在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期是3周或4周。
在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期可为1个周期以上，包括1、2、3、4、5、6个或更多个周期。在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期可优选为1-6个给药周期。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的给药频率可以是每天3次、每天2次、每天1次、每两天1次、每三天1次、每四天1次、每五天1次、每六天1次、每一周3次、每一周2次、每一周1次、每两周1次、或每三周1次。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的给药频率是每天3次、每天2次或每天1次。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的给药频率是每天1次。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量为20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、或上述任意值形成的范围。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量选自20-180mg。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的每日剂量选自20-40mg、20-60mg、20-90mg、20-120mg、20-150mg、40-60mg、40-90mg、40-120mg、40-150mg、40-180mg、60-90mg、60-120mg、60-150mg、60-180mg、90-120mg、90-150mg、90-180mg、120-150mg、120-180mg或150-180mg。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的每日剂量选自60-90mg、60-120mg、60-150mg、60-180mg、90-120mg、90-150mg、90-180mg、120-150mg、120-180mg或150-180mg。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量选自60mg、90mg、120mg、150mg或180mg。在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量选自60mg、90mg或120mg。在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg。
在一些实施方案中，式(I)化合物或其药学上可接受的盐以式(I)化合物或其药学上可接受的盐的药物组合物形式给药。
在一些实施方案中，式(I)化合物或其药学上可接受的盐或其药物组合物以单剂量或多剂量形式给药。在一些实施方案中，以多剂量形式给药。
在一些实施方案中，所述药物组合物为单剂量为30-60mg的式(I)化合物或其药学上可接受的盐的药物组合物。在一些实施方案中，所述药物组合物为单剂量为30mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物。
在一些实施方案中，所述药物组合物为式(I)化合物或其药学上可接受的盐的多剂量药物组合物，所述多剂量可由单剂量为30mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物组成。
在一些实施方案中，所述药物组合物为多剂量的式(I)化合物或其药学上可接受的盐的药物组合物，其中所述多剂量的式(I)化合物或其药学上可接受的盐可为60mg、90mg、120mg、150mg或180mg。在一些实施方案中，所述多剂量的式(I)化合物或其药学上可接受的盐可为60mg、90mg或120mg。在一些实施方案中，所述多剂量的式(I)化合物或其药学上可接受的盐为90mg。
在一些实施方案中，所述多剂量的式(I)化合物或其药学上可接受的盐的药物组合物可由单剂量为30mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物组成。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：以每日剂量为60mg、90mg、120mg、150mg或者180mg的式(I)化合物或其药学上可接受的盐进行给药，给药一个或多个给药周期。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：以每日剂量为60mg、90mg、120mg、150mg或者180mg的式(I)化合物或其药学上可接受的盐进行给药，给药一个或多个给药周期，给药频率可为每天3次、每天2次、每天1次、每两天1次、每三天1次、每四天1次、每五天1次、每六天1次、每一周3次、每一周2次、每一周1次、每两周1次、或每三周1次，优选每天3次、每天2次或每天1次。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：给予受试者每日剂量为60mg、90mg、120mg、150mg或者180mg的式(I)化合物或其药学上可接受的盐，给药一个或多个给药周期，连续每天给药(例如，每天3次、每天2次或每天1次)。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：给予受试者每日剂量为60mg、90mg、120mg、150mg或者180mg的式(I)化合物或其药学上可接受的盐，连续每天给药(例如，每天3次、每天2次或每天1次)。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：以28天为一个给药周期，每日剂量为60mg、90mg、120mg、150mg或者180mg，每天给药一次。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：以28天为一个给药周期，给药一个或多个给药周期，每日剂量为60mg、90mg、120mg、150mg或者180mg，每天给药一次。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量选自60mg、90mg、120mg、150mg或者180mg，任选地，可在给药后调整每日剂量(包括但不限于上调或下调每日剂量)。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg，任选地，可在给药后调整每日剂量(包括但不限于上调或下调每日剂量)。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg，任选地，给药后上调每日剂量。在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg，任选地，给药后上调每日剂量为选自120mg、150mg或者180mg的每日剂量。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg，任选地，给药后上调每日剂量。在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg，任选地，给药后上调每日剂量为120mg。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg，任选地，给药后下调每日剂量。在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg，任选地， 给药后下调每日剂量为60mg或以下。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg，任选地，给药后下调每日剂量。在一些实施方案中，式(I)化合物或其药学上可接受的盐的每日剂量可为90mg，任选地，给药后下调每日剂量为60mg。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物可通过多种途径给药，所述途径包括但不限于口服给药。在一些实施方案中，式(I)化合物或其药学上可接受的盐或其药物组合物可空腹口服(例如早上空腹口服)。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：早上空腹口服给药，每日一次，连续服药一个或多个给药周期(例如，28天可为一个给药周期)。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：早上空腹口服给药，每日一次，连续服药一个或多个给药周期，其中28天为一个给药周期。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：每天空腹口服给药(例如每天1次)，每日给药剂量为60mg、90mg、120mg、150mg或者180mg，连续给药一个或多个给药周期(例如，以28天为一个给药周期)。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：以28天为一个给药周期，每天空腹口服给药一次，每日给药剂量为60mg、90mg、120mg、150mg或者180mg，连续给药28天(即一个给药周期)。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：以28天为一个给药周期，每天空腹口服给药一次，每次给药剂量为60mg、90mg、120mg、150mg或者180mg，连续给药28天(即一个给药周期)。
本公开的实施方案中，只要疾病仍处于控制之下和方案具有临床耐受性，就重复上述给药周期。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物被制备为适合每次给予60mg-180mg、或者60mg-150mg、或者60mg-120mg、或者90mg-180mg、或者90mg-150mg、或者90mg-120mg、或者120mg-150mg、或者120mg-180mg、或者150mg-180mg、或者60mg、或者90mg、或者120mg、或者150mg、或者180mg的式(I)化合物或其药学上可接受的盐的单剂量或多剂量形式。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物被制备为适合每天1次并且每次向患者给予60mg-180mg、或者60mg-150mg、或者60mg-120mg、或者90mg-180mg、或者90mg-150mg、或者90mg-120mg、或者120mg-150mg、或者120mg-180mg、或者150mg-180mg、或者60mg、或者90mg、或者120mg、或者150mg、或者180mg的式(I)化合物或其药学上可接受的盐的单剂量或多剂量形式。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物被制备为适合连续28天、每天1次并且每次向患者给予60mg-180mg、或者60mg-150mg、或者60mg-120mg、或者90mg-180mg、或者90mg-150mg、或者90mg-120mg、或者120mg-150mg、或者120mg-180mg、或者150mg-180mg、或者60mg、或者90mg、或者120mg、或者150mg、或者180mg的式(I)化合物或其药学上可接受的盐的单剂量或多剂量形式。
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐是作为单一活性剂使用。
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐或其药物组合物可与其他活性剂联合使用。在一些实施方案中，所述其他活性剂包括但不限于促甲状腺激素抑制剂(如左甲状腺素钠片或者干甲状腺片)。
式(I)化合物或其药学上可接受的盐
本公开式(I)化合物可以以其游离碱形式给药，也可以以其药学上可接受的盐的形式给药。例如，式(I)化合物的药学上可接受的盐在本公开的范围内，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，例如无机酸可选自盐酸、氢溴酸、硫酸、硝酸或磷酸，有机酸可选自琥珀酸、马来酸、醋酸、富马酸、柠檬酸、酒石酸、苯甲酸、对甲苯磺酸、甲磺酸或萘硫酸。
在一些实施方案中，式(I)化合物以其游离碱形式给药。
药物组合物
本公开所述的“式(I)化合物或其药学上可接受的盐”可处于“式(I)化合物或其药学上可接受的 盐的药物组合物”的形式。
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。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物还含有药学上可接受的辅料。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物可适于口服给药。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物为固体药物组合物。在一些实施方案中，所述固体药物组合物为胶囊。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物为胶囊制剂，规格为30mg和60mg。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物为胶囊制剂，所述胶囊制剂包含式(I)化合物或其药学上可接受的盐、以及药学上可接受的辅料。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物为胶囊制剂，所述胶囊制剂包含式(I)化合物或其药学上可接受的盐、玉米淀粉、羧甲基纤维素钙、羟丙甲纤维素和硬脂酸镁。
在另一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物为胶囊制剂，所述胶囊制剂包含式(I)化合物或其药学上可接受的盐、乳糖、微晶纤维素、羧甲淀粉钠和硬脂酸镁。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物的规格为30-60mg(以式(I)化合物计)。在一些实施方案中，所述药物组合物的规格可为30mg或60mg(以式(I)化合物计)。
技术效果
本公开的式(I)化合物或其药物上可接受的盐、或其药物组合物具有良好的安全性以及抗肿瘤活性，对分化型甲状腺癌细胞表现出良好的抑制活性，并在分化型甲状腺癌细胞裸小鼠皮下移植瘤模型中表现出良好的抑瘤活性。
本公开的使用式(I)化合物或其药物上可接受的盐的治疗方案在治疗碘难治性分化型甲状腺癌中具有较好的疗效，安全性良好。其中，式(I)化合物或其药物上可接受的盐、或其药物组合物至少在生存疗效评价，例如总生存期(OS)、中位生存期；在肿瘤反应疗效评价例如无病生存期(DFS)、中位DFS、无进展生存期(PFS)、6个月PFS率、疾病进展时间(TTP)、客观缓解率(ORR)、疾病控制率(DCR)、缓解持续时间(DOR)；以及耐受性或安全性评价如不良事件发生率等中的至少一个方面具有优异的效果。
在本公开的一些实施方案中，式(I)化合物或其药物上可接受的盐或其药物组合物在治疗碘难治性分化型甲状腺癌中具有良好的客观缓解率和/或疾病控制率。
定义和说明
除非另有说明，本公开中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本公开中出现商品名时，意在指代其对应的商品或其活性成分。本公开中，除非另有说明，这里提供的涉及式(I)化合物或其药学上可接受的盐的剂量及其范围，均是基于式(I)化合物游离碱的分子量计算的。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
除非另外特别说明，否则单数术语涵盖复数术语，并且复数术语涵盖单数术语。除非另外特别说明，否则词语“一个”或“一种”意指“至少一个”或“至少一种”。除非另外说明，否则“或”的使用意指“和/或”。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”包括碱根离子与自由酸(free acid)形成的盐或酸根离子与自由碱(free alkali)形成的盐。
术语“治疗”一般是指获得需要的药理和/或生理效应，包括部分或完全稳定或治愈疾病和/或由于疾病产生的影响。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，或(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状的本公开化合物的用量。构成“治疗有效量”的活性物质(例如本公开化合物)的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的受试者(例如哺乳动物)的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“施用”或“给药”或“给予”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体或患者或受试者物理引入包含活性化合物的组合物。在某些实施方案中，口服施用。
本领域技术人员应当理解，术语“分化型甲状腺癌”不包括未分化型甲状腺癌或髓样甲状腺癌。
术语“每日剂量”是指施用给患者一日的剂量。
术语“患者”或“受试者”或“主体”在本文中可互换使用，指哺乳动物，如人、狗、牛、马、猪、绵羊、山羊、猫、小鼠、兔、大鼠和转基因非人动物。在部分实施方案中，所述患者或受试者或主体是人。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量；例如一盒药有七片药品，则每片药为单剂量。
术语“多剂量”由多个单剂量组成。
术语“药物组合物”是指一种或多种本公开的活性成分与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本公开的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本公开的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态制剂(例如，颗粒剂、片剂、丸剂、胶囊剂等)，或者配制成液态制剂(例如，注射液)。
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了胶囊、片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
涉及给药方案时，术语“天(日)”、“每天(每日)”等指一个日历日内的时间，开始于午夜且终止于下一个午夜。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
下面的具体实施例的目的是使本领域的技术人员能更清楚地理解和实施本公开。它们不应该被认为是对本公开范围的限制，而只是本公开的示例性说明和典型代表。
实施例1体外细胞增殖抑制活性
1.1 IHH-4细胞(乳头状甲状腺癌细胞)增殖抑制活性测定
取处于生长状态良好的IHH-4细胞，收集至离心管，调整细胞密度至6×104个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养过夜，使用纳升加样仪进行化合物加样，使化合物终浓度为10000nM-4.57nM，2个复孔，同时设置对照。细胞培养箱中继续培养72小时后，加入检测试剂CCK-8(厂家同仁化学，10μL/孔)，细胞培养箱中孵育4小时后，Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC50。
1.2 FTC-133细胞(人滤泡性甲状腺癌细胞)增殖抑制活性测定
取处于生长状态良好的FTC-133细胞，收集至离心管，调整细胞密度至4×104个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养过夜，使用纳升加样仪进行化合物加样，使化合物终浓度为10000nM-4.57nM，2个复孔，同时设置对照。细胞培养箱中继续培养72小时后，加入检测试剂CCK-8(厂家同仁化学，10μL/孔)，细胞培养箱中孵育4小时后，Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC50。
实施例2体内药效评价
1.1 IHH-4人乳头状甲状腺癌细胞裸小鼠皮下移植瘤模型中的药效学评价
在SPF级雌性裸小鼠(来源：江苏华创信诺医药科技有限公司)右侧腋窝皮下接种IHH-4细胞，5×106个/只。待肿瘤平均体积达150mm3左右时，将动物分组。
分组当天为第0天，从第0天开始，每天灌胃给药一次。每周测2-3次瘤体积，同时称小鼠体重，记录数据；每日观察与记录小鼠一般表现。实验结束后剥取肿瘤并称重、拍照。
检测指标及计算公式如下：
肿瘤体积，TV(mm3)＝1/2×(a×b2)；其中，a为肿瘤长径，b为肿瘤短径。
相对肿瘤体积，RTV＝TVt/TV0；其中，TV0为第0天肿瘤体积，TVt为每一次测量时的肿瘤体积。
相对肿瘤增殖率，T/C(％)＝TRTV/CRTV×100％；其中，TRTV为治疗组RTV；CRTV为溶媒对照组RTV。
肿瘤生长抑制率，TGI(％)＝(1-TW/TW0)×100％；其中，TW为治疗组瘤重，TW0为溶媒对照组瘤重。
体重变化率，WCR(％)＝(Wtt-Wt0)/Wt0×100％；其中，Wt0为第0天小鼠体重，Wtt为每一次测量时的小鼠体重。
1.2 FTC-133人滤泡性甲状腺癌裸小鼠皮下移植瘤模型中的药效学评价
在SPF级雄性裸小鼠(来源：江苏华创信诺医药科技有限公司)右侧腋窝皮下接种FTC-133细胞，1×107个/只。待肿瘤平均体积达150mm3左右时，将动物分组。
分组当天为第0天，从第0天开始，每天灌胃给药一次式(I)化合物。每周测2-3次瘤体积，同时称小鼠体重，记录数据；每日观察与记录小鼠一般表现。实验结束后剥取肿瘤并称重、拍照。
检测指标及计算公式如下：
肿瘤体积，TV(mm3)＝1/2×(a×b2)；其中，a为肿瘤长径，b为肿瘤短径。
相对肿瘤体积，RTV＝TVt/TV0；其中，TV0为第0天肿瘤体积，TVt为每一次测量时的肿瘤体积。
相对肿瘤增殖率，T/C(％)＝TRTV/CRTV×100％；其中，TRTV为治疗组RTV；CRTV为溶媒对照组RTV。
肿瘤生长抑制率，TGI(％)＝(1-TW/TW0)×100％；其中，TW为治疗组瘤重，TW0为溶媒对照组瘤重。
体重变化率，WCR(％)＝(Wtt-Wt0)/Wt0×100％；其中，Wt0为第0天小鼠体重，Wtt为每一次测量时的小鼠体重。
实施例3临床试验
1.1主要入选标准
(1)性别不限，年龄为18～80周岁；
(2)经病理组织学或者细胞学检查确诊的分化型甲状腺癌；
(3)根据RECIST 1.1标准，至少具有一个可测量病灶
(4)既往接受过至少1种(但不超过2种)VEGFR靶向治疗后出现疾病进展；
(5)碘难治患者，满足下列情形之一可界定为碘难治；
a)病灶在131I治疗后全身显像上表现为不摄碘，且无法从后续的131I治疗中获益(必须由内分泌科或核医学医师确认，如残留甲状腺太多，可能会影响转移灶摄碘，可清甲后再次治疗时进行评估)；
b)原本摄碘的病灶经131I治疗后逐渐丧失摄碘能力；
c)同一患者体内部分病灶摄碘，而部分病灶不摄碘，且生化无缓解；
d)病灶摄碘，但在12个月内出现疾病进展(经影像学确认)；
e)131I累积用量≥600mCi或22GBq，但疾病无缓解(经影像学确认)。
(6)知情前14个月内有影像学进展的证据；
(7)促甲状腺激素抑制剂治疗下促甲状腺激素≤0.5mIU/L；
(8)ECOG PS评分为0～1分；
(9)预计生存期≥12周；
(10)主要器官功能正常；
(11)HBsAg阳性患者须满足HBV DNA定量<1×104IU/mL(或5×104copy/mL)或在研究开始前至少接受1周抗HBV治疗且病毒指数降低10倍以上，同时患者愿意在整个研究期间全程接受抗HBV治疗；丙肝抗体阳性且HCV RNA定量阳性患者须在开始研究前至少1个月完成抗病毒治疗；
(12)育龄女性患者在研究入组前的7天内血清HCG检查必须为阴性，且必须为非哺乳期；患者应同意在研究期间和研究期结束后6个月内必须采用避孕措施；
1.2给药方案
试验药物：式(I)化合物胶囊，规格：30mg或60mg。
给药方法：早上空腹口服给药，每日一次，连续服药28天为一个给药周期，直至研究终止标准。
给药剂量：90mg。
1.3剂量调整
若研究者判定受试者因剂量暴露不足而存在疾病进展的风险时，可将剂量上调为120mg；
若研究者判定受试者存在安全性风险，但疗效仍获益时，可将剂量下调为60mg。
1.4评价标准
安全性评价：采用NCI CTCAE 5.0标准评价不良事件性质和严重程度；
有效性评价：采用RECIST 1.1标准评价。
1.5安全性评估
不良反应发生率：所有不良事件(AE)、严重不良事件(SAE)和治疗相关不良事件(TEAEs)的发生情况。
1.6疗效评估
客观缓解率(ORR)：指研究者依据RECIST 1.1确定的完全缓解(CR)或部分缓解(PR)受试者所占百分比例；
无进展生存期(PFS)：指从首次给药开始至出现疾病进展或任何原因引起的死亡的时间(以先出现的为准)；
6个月PFS率：从首次给药开始至第6个月时未发生疾病进展且未死亡的受试者比例；
疾病控制率(DCR)：指研究者依据RECIST 1.1确定的CR、PR或大于等于12个月的疾病稳定(SD)的受试者所占的百分比例；
缓解持续时间(DOR)：对于CR或PR的受试者中，肿瘤首次评估为CR或PR至疾病进展(PD)或PD前死亡之间的时间；若CR或PR的受试者没有出现PD或PD前死亡，以最后一次影像学评估日期作为截止日期。
总生存期(OS)：指从首次给药开始至因任何原因引起死亡的时间。
1.7试验结果
在可评估的7例患者中，最佳疗效部分缓解(PR)为1例，6例为疾病稳定(SD)，疾病控制率(DCR)为100％(7/7)。
本申请的式(I)化合物表现出临床获益。
表1为代表性病例试验结果。
表1
注：“NA”表示未评估；“*”代表肿瘤体积缩小百分比，即肿瘤体积缩小百分比(％)＝(检测时肿瘤直径-基线肿瘤直径)/基线肿瘤直径×100％；C2表示给药2个给药周期，以此类推。
本领域技术人员将认识到，本申请的范围并不限于上文描述的各种具体实施方式和实施例，而是能够 在不脱离本申请的精神和构思的情况下，进行各种修改、替换、或重新组合，这都落入了本申请的保护范围内。

Claims (15)

  1. 用于治疗分化型甲状腺癌的式(I)化合物或其药学上可接受的盐，
  2. 如权利要求1所述的式(I)化合物或其药学上可接受的盐，其中所述式(I)化合物或其药学上可接受的盐以式(I)化合物或其药学上可接受的药物组合物的形式存在；任选地，所述药物组合物还含有药学上可接受的辅料。
  3. 如权利要求1或2所述的式(I)化合物或其药学上可接受的盐，其中，所述分化型甲状腺癌选自甲状腺乳头状癌、甲状腺滤泡癌和嗜酸细胞癌；
    或者，所述分化型甲状腺癌选自甲状腺乳头状癌；
    或者，所述分化型甲状腺癌选自转移性分化型甲状腺癌；
    或者，所述分化型甲状腺癌选自复发转移性分化型甲状腺癌；
    或者，所述分化型甲状腺癌选自碘难治性分化型甲状腺癌；
    或者，所述分化型甲状腺癌选自碘难治性转移性分化型甲状腺癌；
    或者，所述分化型甲状腺癌选自碘难治性复发转移性分化型甲状腺癌；
    或者，所述分化型甲状腺癌选自既往经一种或两种酪氨酸激酶抑制剂治疗失败的碘难治性分化型甲状腺癌；
    任选地，所述酪氨酸激酶抑制剂选自VEGFR靶向抑制剂。
  4. 如权利要求1-3中任一项所述的式(I)化合物或其药学上可接受的盐，其中，所述分化型甲状腺癌的患者满足以下所有条件：
    1)病情进展迅速；
    2)临床症状明显，甚至危及患者生命(但预期生存时间大于3个月)；
    3)无法采取适宜的局部治疗方案；
    任选地，所述局部治疗包括手术切除、外照射或消融治疗。
  5. 如权利要求1-4中任一项所述的式(I)化合物或其药学上可接受的盐，其中，所述分化型甲状腺癌的患者既往接受过至少一种酪氨酸激酶抑制剂治疗；
    或者，所述分化型甲状腺癌的患者既往接受过至少一种酪氨酸激酶抑制剂治疗后出现疾病进展；
    或者，所述分化型甲状腺癌的患者既往接受过一种或两种酪氨酸激酶抑制剂治疗；
    或者，所述分化型甲状腺癌的患者既往接受过一种或两种酪氨酸激酶抑制剂治疗后出现疾病进展；
    或者，所述分化型甲状腺癌的患者选自既往经一种或两种酪氨酸激酶抑制剂治疗后出现疾病进展的碘难治性分化型甲状腺癌患者；
    任选地，所述酪氨酸激酶抑制剂选自VEGFR靶向抑制剂。
  6. 如权利要求1-5中任一项所述的式(I)化合物或其药学上可接受的盐，其中，所述分化型甲状腺癌选自碘难治性分化型甲状腺癌，所述碘难治性分化型甲状腺癌的患者包括以下情形之一：
    a)病灶不摄碘；
    b)病灶经放射性碘治疗后丧失摄碘能力，优选地，所述放射性碘为131I；
    c)存在部分病灶不摄碘；
    d)病灶摄碘，但疾病进展，任选地，在12个月内出现疾病进展；
    e)经放射性碘治疗，且累积用量≥600mCi或22GBq，但疾病无缓解，优选地，所述放射性碘为131I；或者，所述碘难治性分化型甲状腺癌的患者在无外源性碘负荷干扰的情况下，促甲状腺激素刺激状态(>30mIU/L)时，满足下列情形之一：
    a)转移灶在清甲成功后的首次131I治疗后全身显像中即表现为不摄碘，致其无法从后续的131I治疗中获益；
    b)原本摄碘的功能性转移灶在经131I治疗后逐渐丧失摄碘能力；
    c)部分转移灶摄碘，部分转移灶不摄碘，且可被18F-脱氧葡萄糖(18F-fluorodeoxyglucose,18F-FDG)PET/CT、CT或MRI等其他影像学检查手段所显示；
    d)摄碘转移灶在经过多次131I治疗后虽然保持摄碘能力，但仍在1年内出现病情进展，包括病灶逐渐增长、出现新发病灶和血清甲状腺球蛋白(thyroglobulin,Tg)持续上升等；
    或者，所述碘难治性分化型甲状腺癌的患者满足下列情形之一：
    a)病灶在131I治疗后全身显像上表现为不摄碘，且无法从后续的131I治疗中获益；
    b)原本摄碘的病灶经131I治疗后逐渐丧失摄碘能力；
    c)同一患者体内部分病灶摄碘，而部分病灶不摄碘，且生化无缓解；
    d)病灶摄碘，但在12个月内出现疾病进展；
    e)131I累积用量≥600mCi或22GBq，但疾病无缓解。
  7. 如权利要求1-6中任一项所述的式(I)化合物或其药学上可接受的盐，其中，所述分化型甲状腺癌的患者接受促甲状腺激素抑制剂的治疗；
    或者，所述分化型甲状腺癌的患者的促甲状腺激素≤0.5mIU/L；
    或者，所述分化型甲状腺癌的患者在促甲状腺激素抑制剂治疗下促甲状腺激素≤0.5mIU/L；
    任选地，所述促甲状腺激素抑制剂选自左甲状腺素或其盐、或者干甲状腺，优选地，所述左甲状腺素的盐为左甲状腺素钠。
  8. 如权利要求1-7中任一项所述的式(I)化合物或其药学上可接受的盐，其中，所述分化型甲状腺癌的患者为碘难治性患者，且既往接受过至少1种VEGFR靶向治疗后出现疾病进展；
    或者，所述分化型甲状腺癌的患者为碘难治性患者，且既往接受过至少1种VEGFR靶向治疗后出现疾病进展，以及在促甲状腺激素抑制剂治疗下促甲状腺激素≤0.5mIU/L。
  9. 如权利要求1-8中任一项所述的式(I)化合物或其药学上可接受的盐，其中，所述分化型甲状腺癌的患者满足以下所有条件：
    1)经病理组织学或者细胞学检查确诊的分化型甲状腺癌(DTC)；
    2)根据RECIST 1.1，至少具有一个可测量病灶；
    3)既往接受过至少1种VEGFR靶向治疗后出现疾病进展，所述VEGFR靶向治疗包括索拉非尼、仑伐替尼、阿帕替尼、安罗替尼或普拉替尼，任选地，所述VEGFR靶向治疗不超过2种；
    4)碘难治患者，满足下列情形之一可界定为碘难治：
    a)病灶在131I治疗后全身显像上表现为不摄碘，且无法从后续的131I治疗中获益；
    b)原本摄碘的病灶经131I治疗后逐渐丧失摄碘能力；
    c)同一患者体内部分病灶摄碘，而部分病灶不摄碘，且生化无缓解；
    d)病灶摄碘，但在12个月内出现疾病进展(经影像学确认)；
    e)131I累积用量≥600mCi或22GBq，但疾病无缓解(经影像学确认)；
    5)知情前14个月内有影像学进展的证据；
    6)促甲状腺激素抑制剂治疗下促甲状腺激素≤0.5mIU/L；
    或者，
    所述分化型甲状腺癌的患者满足以下所有条件：
    1)经病理组织学或者细胞学检查确诊的分化型甲状腺癌(DTC)；
    2)根据RECIST 1.1，至少具有一个可测量病灶；
    3)既往接受过至少1种VEGFR靶向治疗后出现疾病进展，所述VEGFR靶向治疗包括索凡替尼、索拉非尼、仑伐替尼、阿帕替尼、安罗替尼或普拉替尼，任选地，所述VEGFR靶向治疗不超过2种；
    4)碘难治患者，满足下列情形之一可界定为碘难治：
    a)病灶在131I治疗后全身显像上表现为不摄碘，且无法从后续的131I治疗中获益；
    b)原本摄碘的病灶经131I治疗后逐渐丧失摄碘能力；
    c)同一患者体内部分病灶摄碘，而部分病灶不摄碘，且生化无缓解；
    d)病灶摄碘，但在12个月内出现疾病进展(经影像学确认)；
    e)131I累积用量≥600mCi或22GBq，但疾病无缓解(经影像学确认)；
    5)知情前14个月内有影像学进展的证据；
    6)促甲状腺激素抑制剂治疗下促甲状腺激素≤0.5mIU/L。
  10. 如权利要求1-9中任一项所述的式(I)化合物或其药学上可接受的盐，其中，式(I)化合物或其药学上可接受的盐的每日剂量为20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、或上述任意值形成的范围；
    或者，式(I)化合物或其药学上可接受的盐的每日剂量选自20-180mg；
    或者，式(I)化合物或其药学上可接受的盐的每日剂量选自20-40mg、20-60mg、20-90mg、20-120mg、20-150mg、40-60mg、40-90mg、40-120mg、40-150mg、40-180mg、60-90mg、60-120mg、60-150mg、60-180mg、90-120mg、90-150mg、90-180mg、120-150mg、120-180mg或150-180mg。
  11. 如权利要求1-10中任一项所述的式(I)化合物或其药学上可接受的盐，其中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：给予受试者每日剂量为60mg、90mg、120mg、 150mg或者180mg的(I)化合物或其药学上可接受的盐，给予一个或多个给药周期，连续每天给药3次、2次或1次；
    或者，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：给予受试者每日剂量为60mg、90mg、120mg、150mg或者180mg的(I)化合物或其药学上可接受的盐，连续每天给药；
    或者，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：以28天为一个治疗周期，每日剂量为60mg、90mg、120mg、150mg或者180mg，每天给药一次；
    或者，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：以28天为一个治疗周期，每天空腹口服给药一次，每次给药剂量为60mg、90mg、120mg、150mg或者180mg，连续给药28天。
  12. 如权利要求2-11中任一项所述的式(I)化合物或其药学上可接受的盐，其中，式(I)化合物或其药学上可接受的盐的药物组合物为固体药物组合物；任选地，所述固体药物组合物为胶囊。
  13. 一种用于治疗分化型甲状腺癌的试剂盒，所述试剂盒包含：
    a)式(I)化合物或其药学上可接受的盐，
    以及b)治疗分化型甲状腺癌的使用说明。
  14. 式(I)化合物或其药学上可接受的盐在制备用于治疗分化型甲状腺癌的药物中的用途，
  15. 一种治疗分化型甲状腺癌的方法，所述方法包括向有需要的患者给予治疗有效量的式(I)化合物或其药学上可接受的盐，
PCT/CN2023/135494 2022-12-01 2023-11-30 喹诺林化合物治疗甲状腺癌的用途 WO2024114740A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120123126A1 (en) * 2010-09-12 2012-05-17 Guoqing Paul Chen Compounds As c-Met Kinase Inhibitors
US20170224692A1 (en) * 2014-07-25 2017-08-10 Novartis Ag Combination Therapy

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120123126A1 (en) * 2010-09-12 2012-05-17 Guoqing Paul Chen Compounds As c-Met Kinase Inhibitors
US20170224692A1 (en) * 2014-07-25 2017-08-10 Novartis Ag Combination Therapy

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