WO2020057539A1 - 用于治疗小细胞肺癌的喹啉衍生物 - Google Patents
用于治疗小细胞肺癌的喹啉衍生物 Download PDFInfo
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- WO2020057539A1 WO2020057539A1 PCT/CN2019/106406 CN2019106406W WO2020057539A1 WO 2020057539 A1 WO2020057539 A1 WO 2020057539A1 CN 2019106406 W CN2019106406 W CN 2019106406W WO 2020057539 A1 WO2020057539 A1 WO 2020057539A1
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- WIPO (PCT)
- Prior art keywords
- acid
- lung cancer
- small cell
- cell lung
- compound
- Prior art date
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- 208000000587 small cell lung carcinoma Diseases 0.000 title claims abstract description 133
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Classifications
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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
- A61K9/4866—Organic macromolecular 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- 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 invention belongs to the field of medicine, in particular, the invention relates to the use of a quinoline derivative in the treatment of small cell lung cancer, a method for treating the same, a pharmaceutical composition and a kit.
- Lung cancer is a malignant tumor with high incidence and death worldwide. In recent years, the incidence and mortality of lung cancer in China has increased rapidly. SCLC accounts for 15% -20% of all lung cancer cases. It is very different from non-small cell lung cancer in terms of tissue origin, biological characteristics, response to treatment and prognosis, so it is considered a systemic disease, and SCLC has the characteristics of high malignancy, strong invasiveness, and easy to transfer. SCLC is highly invasive and has a poor prognosis. The 5-year survival rate is less than 5%. The average survival time of patients without treatment is only 2-4 months.
- Chemotherapy and radiotherapy are the main treatments of SCLC. Although the main treatment of SCLC is very sensitive to the initial treatment, most patients with SCLC relapse and metastasize soon after treatment. Because of rapid progress, prone to drug resistance, and poor prognosis, only a small number of patients have the opportunity to receive third-line treatment. Studies have reported that only 20% of SCLC have received third-line treatment. There is no standard treatment for chemotherapy. The development of chemotherapy resistance makes relapsed SCLC treatment more difficult, especially for relapsed refractory SCLC. Therefore, there is an urgent need to find new treatments to treat relapsed SCLC.
- the present application provides a method of treating small cell lung cancer, the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
- the present application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the treatment of small cell lung cancer or the preparation of a medicament for the treatment of small cell lung cancer.
- the present application provides a pharmaceutical composition for treating small cell lung cancer, the pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
- the present application provides a kit for treating small cell lung cancer, comprising (a) a pharmaceutical composition of at least one unit dose of Compound I or a pharmaceutically acceptable salt thereof, and (b) Instructions for treating small cell lung cancer.
- the small cell lung cancer is relapsed small cell lung cancer, including, but not limited to, small cell lung cancer that relapses and / or progresses due to failure of treatment with a chemotherapeutic drug and / or a targeted drug.
- the small cell lung cancer is advanced small cell lung cancer.
- the small cell lung cancer is small cell lung cancer that has failed treatment with at least two chemotherapy regimens.
- the small cell lung cancer is small cell lung cancer that has failed second-line chemotherapy and / or more than second-line chemotherapy.
- the small cell lung cancer is metastatic small cell lung cancer; wherein the metastatic lesions include, but are not limited to, lymph nodes, pleura, bone, brain, pericardium, adrenal gland, and liver.
- the application provides a method of treating small cell lung cancer, the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
- the present application provides a method of treating at least two chemotherapy regimens for small cell lung cancer, which method comprises administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
- the present application provides a method of treating small cell lung cancer in which second-line chemotherapy and / or above-line chemotherapy fails, which method comprises administering to a patient in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable amount thereof Of salt.
- the present application provides a method of treating refractory relapsed small cell lung cancer, the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
- the "refractory relapsed small cell lung cancer” refers to small cell lung cancer that has not been relieved by chemotherapy, and small cell lung cancer that is effective but has progressed within 3 months after the end of chemotherapy.
- the chemotherapy includes first-line chemotherapy and second-line chemotherapy; including but not limited to one or more of podophyllum, alkylating agents, camptothecins, taxanes, antimetabolites, antibiotics and antitumor drugs; can Listed examples include, but are not limited to, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, mitoplatin, loplatin, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, changchun One or more of Ruibin, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin.
- the small cell lung cancer is extensive stage small cell lung cancer.
- the small cell lung cancer is metastatic small cell lung cancer, wherein the metastatic lesions include, but are not limited to, lymph nodes, pleura, bone, pericardium, adrenal gland, liver, and brain. In some embodiments, the small cell lung cancer is brain metastatic small cell lung cancer.
- the small cell lung cancer is a refractory relapsed small cell lung cancer that has previously received second-line chemotherapy.
- the second-line chemotherapy includes, but is not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, loplatin, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, One or more of gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin.
- the small cell lung cancer is a refractory small cell lung cancer that has previously been treated with one or more of irinotecan, platinum, paclitaxel, and docetaxel.
- the small cell lung cancer is previously treated with irinotecan and platinum (e.g., including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, lopin) Of refractory recurrent small cell lung cancer.
- platinum e.g., including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, lopin
- platinum e.g., including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, lopin
- the application provides a method of treating brain metastatic small cell lung cancer, the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
- Compound I can be administered in its free base form, or in the form of its salts, hydrates, and prodrugs, which prodrugs are converted into the free base form of Compound I in vivo.
- a pharmaceutically acceptable salt of Compound I is within the scope of the present invention, and the salt can be produced from different organic and inorganic acids according to methods known in the art.
- the compound I is administered as the hydrochloride salt. In some embodiments, administration is in the form of Compound I monohydrochloride. In some embodiments, administration is in the form of Compound I dihydrochloride. In some embodiments, administration is in the form of a crystal of Compound I hydrochloride. In a particular embodiment, administration is in the form of a crystal of Compound I dihydrochloride. In some embodiments, administration is in the form of Compound I maleate.
- Compound I or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafat, intra-articular, intraperitoneal and intrathecal. In some specific embodiments, it is administered orally.
- the amount of Compound I or a pharmaceutically acceptable salt administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
- the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 30 mg.
- the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 6 mg to 20 mg.
- the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 20 mg.
- the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is 8 mg to 16 mg.
- the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 14 mg.
- the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 14 mg.
- Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the oral solid formulation is administered once daily.
- the method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the patient.
- Compound I or a pharmaceutically acceptable salt thereof is administered in a spaced manner.
- the interval administration includes an administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per 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 period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated multiple times.
- the ratio in days between the administration period and the withdrawal period is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, and even more preferably 2: 0.5 to 1.
- the administration is discontinued for 2 weeks for 2 weeks. In some embodiments, the dose is administered once a day for 14 days and then discontinued for 14 days.
- the administration is discontinued for 2 weeks for 1 week. In some embodiments, the dose is administered once a day for 14 days and then discontinued for 7 days.
- the dosing is discontinued for 5 days for 2 days. In some embodiments, the dose is administered once a day for 5 days and then discontinued for 2 days.
- the drug is administered orally at a dose of 12 mg once a day for 2 weeks and then stopped for 1 week.
- the drug is administered orally at a dose of 10 mg once a day for two consecutive weeks and one week off.
- the drug is administered orally at a dose of 8 mg once a day for 2 weeks and then stopped for 1 week.
- Compound I or a pharmaceutically acceptable salt thereof is administered alone as a sole active ingredient to a small cell lung cancer patient. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a small cell lung cancer patient simultaneously or sequentially with other antitumor drugs.
- other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllum anticancer drugs, hormone antitumor drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of fluoropyrimidine derivatives, anthracyclines, taxanes, tyrosine kinase inhibitors (e.g., EGFR inhibitors, VEGFR inhibitors), mitomycin, trastuzumab .
- antifolate antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllum anticancer drugs, hormone antitumor drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of fluoropyrimidine derivatives, anthracyclines, taxanes, tyrosine kinase inhibitors (e.g., EGFR inhibitors, VEGFR inhibitors), mitomycin
- the present application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the treatment of small cell lung cancer or the preparation of a medicament for the treatment of small cell lung cancer.
- the present application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the treatment of small cell lung cancer in which at least two chemotherapy regimens have failed treatment or the preparation of a small Use in medicine for cell lung cancer.
- the present application provides the use of compound I or a pharmaceutically acceptable salt thereof for the treatment of small cell lung cancer in which second-line chemotherapy and / or above-line chemotherapy fails, or for the preparation of second-line chemotherapy and / or above-line chemotherapy Use of Medicines for Chemotherapy Failure in Small Cell Lung Cancer
- the present application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the treatment of refractory relapsed small cell lung cancer or the preparation of a medicament for the treatment of refractory relapsed small cell lung cancer. use.
- the "refractory relapsed small cell lung cancer” refers to small cell lung cancer that has not been relieved by chemotherapy, and small cell lung cancer that is effective but has progressed within 3 months after the end of chemotherapy.
- the chemotherapy includes first-line chemotherapy and second-line chemotherapy; including but not limited to one or more of podophyllum, alkylating agents, camptothecins, taxanes, antimetabolites, antibiotics and antitumor drugs; can Listed examples include, but are not limited to, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, mitoplatin, loplatin, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, changchun One or more of Ruibin, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin.
- the small cell lung cancer is extensive stage small cell lung cancer.
- the small cell lung cancer is metastatic small cell lung cancer, wherein the metastatic lesions include, but are not limited to, lymph nodes, pleura, bone, pericardium, adrenal gland, liver, and brain. In some embodiments, the small cell lung cancer is brain metastatic small cell lung cancer.
- the small cell lung cancer is a refractory relapsed small cell lung cancer that has previously received second-line chemotherapy.
- the second-line chemotherapy includes, but is not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, loplatin, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, One or more of gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin.
- the small cell lung cancer is a refractory small cell lung cancer that has previously been treated with one or more of irinotecan, platinum, paclitaxel, and docetaxel.
- the small cell lung cancer is previously treated with irinotecan and platinum (e.g., including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, lopin) Of refractory recurrent small cell lung cancer.
- platinum e.g., including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, lopin
- platinum e.g., including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, lopin
- the present application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the treatment of brain metastatic small cell lung cancer or the preparation of a medicament for the treatment of brain metastatic small cell lung cancer.
- Compound I may be in its free base form, or in the form of its salts, hydrates, and prodrugs, which prodrugs are converted into the free base form of Compound I in vivo.
- the pharmaceutically acceptable salts of Compound I are within the scope of the present invention, and salts can be produced from different organic and inorganic acids according to methods well known in the art.
- Compound I or a pharmaceutically acceptable salt thereof is the hydrochloride form of Compound I. In some embodiments, it is in the form of Compound I monohydrochloride. In some embodiments, it is in the form of Compound I dihydrochloride. In some embodiments, it is a crystalline form of Compound I hydrochloride. In a particular embodiment, it is a crystalline form of the dihydrochloride salt of Compound I. In some embodiments, it is in the form of Compound I maleate.
- Compound I or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafat, intra-articular, intraperitoneal and intrathecal. In some specific embodiments, it is administered orally.
- the amount of Compound I or a pharmaceutically acceptable salt thereof can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
- the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 30 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 6 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 14 mg.
- the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 14 mg.
- Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the oral solid formulation is administered once daily.
- the method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the patient.
- Compound I or a pharmaceutically acceptable salt thereof is administered in a spaced manner.
- the interval administration includes an administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per 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 period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated multiple times.
- the ratio in days between the administration period and the withdrawal period is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, and even more preferably 2: 0.5 to 1.
- the administration is discontinued for 2 weeks for 2 weeks. In some embodiments, the dose is administered once a day for 14 days and then discontinued for 14 days.
- the administration is discontinued for 2 weeks for 1 week. In some embodiments, the dose is administered once a day for 14 days and then discontinued for 7 days.
- the dosing is discontinued for 5 days for 2 days. In some embodiments, the dose is administered once a day for 5 days and then discontinued for 2 days.
- the drug is administered orally at a dose of 12 mg once a day for 2 weeks and then stopped for 1 week.
- the drug is administered orally at a dose of 10 mg once a day for two consecutive weeks and one week off.
- the drug is administered orally at a dose of 8 mg once a day for 2 weeks and then stopped for 1 week.
- Compound I or a pharmaceutically acceptable salt thereof is administered alone as a sole active ingredient to a small cell lung cancer patient. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a small cell lung cancer patient simultaneously or sequentially with other antitumor drugs.
- other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllum anticancer drugs, hormone antitumor drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of fluoropyrimidine derivatives, anthracyclines, taxanes, tyrosine kinase inhibitors (e.g., EGFR inhibitors, VEGFR inhibitors), mitomycin, trastuzumab .
- antifolate antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllum anticancer drugs, hormone antitumor drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of fluoropyrimidine derivatives, anthracyclines, taxanes, tyrosine kinase inhibitors (e.g., EGFR inhibitors, VEGFR inhibitors), mitomycin
- the present application provides a pharmaceutical composition for treating small cell lung cancer, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
- the present application provides a pharmaceutical composition for the treatment of small cell lung cancer that has failed treatment with at least two chemotherapy regimens, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable salt. a.
- the present application provides a pharmaceutical composition for treating small cell lung cancer in which second-line chemotherapy and / or above-line chemotherapy fails, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Acceptable carrier.
- the present application provides a pharmaceutical composition for the treatment of refractory relapsed small cell lung cancer, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
- the "refractory relapsed small cell lung cancer” refers to small cell lung cancer that has not been relieved by chemotherapy, and small cell lung cancer that is effective but has progressed within 3 months after the end of chemotherapy.
- the chemotherapy includes first-line chemotherapy and second-line chemotherapy; including but not limited to one or more of podophyllum, alkylating agents, camptothecins, taxanes, antimetabolites, antibiotics and antitumor drugs; can Listed examples include, but are not limited to, cisplatin, etoposide, carboplatin, nedaplatin, oxaliplatin, mitoplatin, loplatin, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, changchun One or more of Ruibin, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin.
- the small cell lung cancer is extensive stage small cell lung cancer.
- the small cell lung cancer is metastatic small cell lung cancer, wherein the metastatic lesions include, but are not limited to, lymph nodes, pleura, bone, pericardium, adrenal gland, liver, and brain. In some embodiments, the small cell lung cancer is brain metastatic small cell lung cancer.
- the small cell lung cancer is a refractory relapsed small cell lung cancer that has previously received second-line chemotherapy.
- the small cell lung cancer is a refractory small cell lung cancer that has previously been treated with one or more of irinotecan, platinum, paclitaxel, and docetaxel.
- the small cell lung cancer is previously treated with irinotecan and platinum (e.g., including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, lopin) Of refractory recurrent small cell lung cancer.
- platinum e.g., including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, lopin
- platinum e.g., including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, lopin
- a pharmaceutical composition for treating brain metastatic small cell lung cancer which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
- Compound I can be in its free base form, or in the form of salts, hydrates and prodrugs, which prodrugs are converted into the free base form of Compound I in vivo.
- the pharmaceutically acceptable salts of Compound I are within the scope of the present invention, and salts can be produced from different organic and inorganic acids according to methods well known in the art.
- Compound I or a pharmaceutically acceptable salt thereof is the hydrochloride form of Compound I. In some embodiments, it is in the form of Compound I monohydrochloride. In some embodiments, it is in the form of Compound I dihydrochloride. In some embodiments, it is a crystalline form of Compound I hydrochloride. In a particular embodiment, it is a crystalline form of the dihydrochloride salt of Compound I. In some embodiments, it is in the form of Compound I maleate.
- the pharmaceutical composition may be suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal , Intraocular, topical, subcutaneous, intrafat, intra-articular, intraperitoneal and intrathecal formulations.
- the amount of the pharmaceutical composition administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
- the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 30 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 6 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is from 8 mg to 20 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 16 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is from 8 mg to 14 mg.
- the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 14 mg.
- the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, and the like, preferably tablets and capsules.
- the tablet can be an ordinary tablet, a dispersible tablet, an effervescent tablet, a sustained-release tablet, a controlled-release tablet, or an enteric tablet
- the capsule can be an ordinary capsule, a sustained-release capsule, a controlled-release capsule, or an enteric capsule.
- the oral preparation may be prepared by a conventional method using a pharmaceutically acceptable carrier known in the art.
- the pharmaceutically acceptable carrier includes a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, and the like.
- Fillers 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, polymer Retinone, microcrystalline cellulose, etc .
- disintegrants include croscarmellose sodium, crospovidone, surfactants, low-substituted hydroxypropyl cellulose, etc .
- lubricants include magnesium stearate, talc Powder, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talc, etc.
- Pharmaceutical excipients also include colorants, sweeteners, and the like.
- the pharmaceutical composition is a solid formulation suitable for oral administration.
- the composition may be in the form of a tablet or capsule, for example.
- the pharmaceutical composition is a capsule.
- pharmaceutically acceptable carriers for oral solid preparations include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate.
- Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the oral solid formulation is administered once daily.
- the method of administration can be comprehensively determined according to the activity, toxicity, and tolerance of the patient.
- Compound I or a pharmaceutically acceptable salt thereof is administered in a spaced manner.
- the interval administration includes an administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per 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 period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated multiple times.
- the ratio in days between the administration period and the withdrawal period is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, and even more preferably 2: 0.5 to 1.
- the administration is discontinued for 2 weeks for 2 weeks. In some embodiments, the dose is administered once a day for 14 days and then discontinued for 14 days.
- the administration is discontinued for 2 weeks for 1 week. In some embodiments, the dose is administered once a day for 14 days and then discontinued for 7 days.
- the dosing is discontinued for 5 days for 2 days. In some embodiments, the dose is administered once a day for 5 days and then discontinued for 2 days.
- the drug is administered orally at a dose of 12 mg once a day for 2 weeks and then stopped for 1 week.
- the drug is administered orally at a dose of 10 mg once a day for two consecutive weeks and one week off.
- the drug is administered orally at a dose of 8 mg once a day for 2 weeks and then stopped for 1 week.
- a pharmaceutical composition is formulated for treating refractory relapsed small cell lung cancer in a unit dosage form.
- the pharmaceutical composition in the unit dosage form contains 2 mg to 30 mg of Compound I or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition in a unit dosage form contains 6 mg to 20 mg of Compound I or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition in the unit dosage form contains 8 mg to 20 mg of Compound I or a pharmaceutically acceptable salt thereof, preferably 8 mg to 16 mg of Compound I or a pharmaceutically acceptable salt thereof, 8 mg to 14 mg of Compound I or a pharmaceutically acceptable salt thereof is more preferable.
- the pharmaceutical composition in the unit dosage form contains 8 mg of Compound I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in the unit dosage form contains 10 mg of Compound I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 12 mg of Compound I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the unit dosage form pharmaceutical composition contains 14 mg of Compound I or a pharmaceutically acceptable salt thereof.
- Compound I or a pharmaceutically acceptable salt thereof is administered alone as the sole active ingredient to a patient with relapsed small cell lung cancer. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a relapsed small cell lung cancer patient simultaneously or sequentially with other antitumor drugs.
- other antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllum anticancer drugs, hormone antitumor drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of fluoropyrimidine derivatives, anthracyclines, taxanes, tyrosine kinase inhibitors (e.g., EGFR inhibitors, VEGFR inhibitors), mitomycin, trastuzumab .
- antifolate antitumor drugs include, but are not limited to, antifolate antitumor drugs, podophyllum anticancer drugs, hormone antitumor drugs, alkylating agent antitumor drugs, camptothecin antitumor drugs, One or more of fluoropyrimidine derivatives, anthracyclines, taxanes, tyrosine kinase inhibitors (e.g., EGFR inhibitors, VEGFR inhibitors), mitomycin
- the present application provides a kit comprising (a) a pharmaceutical composition of at least one unit dose of Compound I or a pharmaceutically acceptable salt thereof, and (b) instructions for treating small cell lung cancer.
- the application provides a kit comprising (a) a pharmaceutical composition of at least one unit dose of Compound I or a pharmaceutically acceptable salt thereof, and (b) for treating at least two types of chemotherapy Protocols for Protocols for Failure to Treat Small Cell Lung Cancer.
- the application provides a kit comprising (a) a pharmaceutical composition of at least one unit dose of Compound I or a pharmaceutically acceptable salt thereof, and (b) for treating second-line chemotherapy and / Or instructions for small cell lung cancer that have failed second-line chemotherapy.
- the present application provides a kit comprising (a) a pharmaceutical composition of at least one unit dose of Compound I or a pharmaceutically acceptable salt thereof, and (b) for treating refractory relapse Instructions for small cell lung cancer.
- kits comprising (a) at least one unit dose of a suitable formulation for oral administration of Compound I or a pharmaceutically acceptable salt thereof, and (b) administered at intervals for treating difficult problems Instructions for the treatment of relapsed small cell lung cancer.
- a kit is provided that comprises (a) at least one unit dose of a tablet or capsule of Compound I or a pharmaceutically acceptable salt thereof and (b) is administered at intervals Instructions for treating refractory small cell lung cancer.
- radiotherapy and chemotherapy can also be received in an alternating, sequential or synchronous manner.
- unit dose or unit dose refers to a pharmaceutical composition, such as each tablet or capsule, packaged in a single package for convenience.
- a pharmaceutical composition in a unit dosage form means each tablet or capsule.
- the crystal form of the hydrochloride salt of the compound I includes, but is not limited to, A, B, and C type crystals disclosed in Chinese patent application CN102344438A, wherein the A and B type crystals are crystals substantially free of crystal water and other solvents.
- Type C crystals are crystals containing two crystal waters.
- the crystalline form of the dihydrochloride salt of Compound I is Form A crystal.
- Patient means a mammal, preferably a human.
- “Pharmaceutically acceptable” means its use in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically or otherwise undesirable, and includes that it is acceptable for human pharmaceutical use Accepted.
- “Pharmaceutically acceptable salt” includes, but is not limited to, acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; the organic acids such as acetic acid , Trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, 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-toluenesulf
- terapéuticaally effective amount is meant an amount of a compound that, when administered to a human for treating a disease, is sufficient to effect treatment of the disease.
- Treatment means any administration of a therapeutically effective amount of a compound, and includes:
- “Failure to treat” refers to intolerable toxic or side effects, disease progression during treatment, or relapse after treatment is completed.
- Extensive phase means that the lesion extends beyond one side of the thorax and includes malignant and effusion or blood metastases.
- EGFR inhibitor refers to an epidermal growth factor receptor inhibitor.
- VEGFR inhibitor refers to a vascular endothelial growth factor receptor inhibitor.
- CR refers to complete remission, that is, all target lesions disappear, and the short diameter of all pathological lymph nodes (including target and non-target nodules) must be reduced to ⁇ 10mm.
- PR means partial remission, the sum of the diameters of the target lesions is reduced by at least 30% from the baseline level.
- PD refers to disease progression, taking the minimum value of the sum of the diameters of all target lesions measured throughout the study as a reference, with a relative increase in diameter of at least 20% (if the baseline measurement is the smallest, the baseline value is used as a reference); and The relative value of the sum of the diameters must be increased by at least 5mm, and the occurrence of one or more new lesions is also considered to be disease progression.
- SD means that the disease is stable, and the reduction of the target lesion does not reach the level of PR, and the increase does not reach the level of PD, somewhere in between.
- PFS progression-free survival, the time from randomization to objective tumor progression or patient death.
- DCR refers to the rate of disease control, including the complete response, partial response, and stable disease, and the percentage of patients who have maintained the disease for more than 4 weeks among the evaluable patients.
- OS overall survival refers to the time from enrollment to death for any reason. In terms of days, lost follow-up subjects usually calculated the last follow-up time as death.
- FES refers to the full analysis data set. According to the intention to analyze (ITT) principle, the efficacy analysis is performed on all cases where the drug is used at least once.
- RECIST 1.1 refers to the standard 1.1 for evaluating the efficacy of solid tumors.
- CI refers to the confidence interval, the estimated interval of the overall parameter constructed by the sample statistics.
- Compound I or a pharmaceutically acceptable salt thereof in the present application has an unexpected therapeutic effect on small cell lung cancer, especially refractory recurrent small cell lung cancer, and can significantly prolong patients with refractory relapsed small cell lung cancer.
- the survival time is also very significant for brain metastatic small cell lung cancer.
- Example 24 in WO2008112407 1-[[[[4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl was prepared. [Oxy] methyl] cyclopropylamine, and then referring to the preparation method of "Example of Salt Form" in the specification of WO2008112407, the title compound was prepared. Or it can be prepared by referring to the method disclosed in Chinese patent application CN102344438A.
- Capsules of dihydrochloride of compound I with other contents can be prepared by referring to the above manner in corresponding proportions and prescriptions.
- a multicenter, randomized, double-blind, placebo-controlled phase II clinical study was performed in patients with measurable lesions who had previously received standard treatment and relapsed.
- 120 patients were enrolled and randomized to receive 12 mg / 0 mg of the compound I dihydrochloride capsule once a day.
- Oral administration was discontinued for 2 weeks for 1 week, that is, 3 weeks (21 days) was a treatment cycle.
- These patients were aged 18-75 years old, using the dihydrochloride capsules of Compound I and placebo, and had previously used other targeted drugs (such as sunitin, bevacizumab, endo), etc. Patients targeted were excluded.
- Efficacy evaluation criteria are determined to be disease progression (PD) or clinically considered disease progression, use of other anti-tumor drug treatments (such as chemotherapy, targeted therapy or biologic therapy), accidental pregnancy, death, etc.
- the test was discontinued (finally).
- Patients with disease control (CR + PR + SD) who can tolerate adverse reactions continue to take the drug.
- the investigator believes that the patient is not suitable for continued medication or is evaluated as PD according to the RECIST 1.1 criteria, the medication is terminated.
- the investigator decides whether to adjust the dose, and the adjustable dose is 8mg / 0mg or 10mg / 0mg.
- the primary efficacy indicators were progression-free survival (PFS), and the secondary efficacy indicators were overall survival (OS), objective response rate (ORR) (CR + PR), and disease control rate (DCR) (CR + PR + SD). ), Quality of life score, safety.
- Objective efficacy indicators were evaluated according to the efficacy evaluation criteria for solid tumors (RECIST 1.1).
- the product limit method was used, and 50% (median) PFS and PFS at different times after the start of treatment were calculated according to the actual situation of the data, and Log-Rank test was used to compare the two groups.
- the product limit method was used for OS, and 50% (median) OS was calculated according to the actual situation of the data, and Log-Rank test was used to compare the two groups.
- the statistical data set uses a Full Analysis Data Set (FAS). The research results are summarized in the following table.
- TC regimen paclitaxel + carboplatin
- TC regimen paclitaxel + carboplatin
- the efficacy evaluation was PD.
- an IP regimen 120 mg of irinotecan, d1 of 80 mg, d8; 100 mg of cisplatin
- CT showed stable intrapulmonary and craniocerebral lesions, increased intrahepatic metastases, and the effect was evaluated as PD; target lesions (64mm): left inner lobe nodules and right posterior lobe nodules; non Target lesion: Multiple metastatic tumors in the brain.
- target lesions 63mm; non-target lesions: non-CR / non-PD.
- target lesions 65mm; non-target lesions: non-CR / non-PD.
- target lesions 66mm; non-target lesions: non-CR / non-PD.
- target lesions 72mm; non-target lesions: non-CR / non-PD.
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Abstract
Description
Claims (20)
- 根据权利要求1所述的用途,其特征在于,所述小细胞肺癌为至少两种化疗方案治疗失败的小细胞肺癌。
- 根据权利要求1或2所述的用途,其特征在于,所述小细胞肺癌为二线化疗和/或二线以上化疗失败的小细胞肺癌。
- 根据权利要求2或3所述的用途,其特征在于,所述化疗为顺铂、依托泊苷、卡铂、奈达铂、奥沙利铂、米铂、洛铂、伊立替康、拓扑替康、紫杉醇、多西他赛、替莫唑胺、长春瑞滨、吉西他滨、环磷酰胺、阿霉素、长春新碱、苯达莫司汀、表阿霉素、甲氨蝶呤、氨柔比星中的一种或多种。
- 根据权利要求1-4任一项所述的用途,其特征在于,所述小细胞肺癌为难治性复发的小细胞肺癌。
- 根据权利要求1-5任一项所述的用途,其特征在于,所述的小细胞肺癌为广泛期小细胞肺癌。
- 根据权利要求1-6任一项所述的用途,其特征在于,所述的小细胞肺癌为脑转移的小细胞肺癌。
- 根据权利要求1-7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,更优选为二盐酸盐。
- 根据权利要求9所述的方法,其特征在于,所述小细胞肺癌为至少两种化疗方案治疗失败的小细胞肺癌。
- 根据权利要求9或10所述的方法,其特征在于,所述小细胞肺癌为二线化疗和/或二线以上化疗失败的小细胞肺癌和/或难治性复发的小细胞肺癌。
- 根据权利要求10或11所述的方法,其特征在于,所述化疗为顺铂、依托泊苷、卡铂、奈达铂、奥沙利铂、米铂、洛铂、伊立替康、拓扑替康、紫杉醇、多西他赛、替莫唑胺、长春瑞滨、吉西他滨、环磷酰胺、阿霉素、长春新碱、苯达莫司汀、表阿霉素、甲氨蝶呤、氨柔比星中的一种或多种。
- 根据权利要求9-12任一项所述的方法,其特征在于,所述小细胞肺癌为广泛期小细胞肺癌和/或脑转移的小细胞肺癌。
- 根据权利要求9-13任一项所述的方法,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,更优选为二盐酸盐。
- 根据权利要求9-14任一项所述的方法,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。
- 根据权利要求9-15任一项所述的方法,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。
- 根据权利要求17所述的药物组合物,其特征在于,所述小细胞肺癌为至少两种化疗方案治疗失败的小细胞肺癌。
- 根据权利要求17或18所述的药物组合物,其特征在于,所述小细胞肺癌为二线化疗和/或二线以上化疗失败的小细胞肺癌和/或难治性复发的小细胞肺癌。
- 一种试剂盒,所述试剂盒包含(a)至少一个单位剂量的权利要求17-19中任一项所述的药物组合物和(b)用于治疗小细胞肺癌的说明书、尤其是以间隔给药的方式用于治疗小细胞肺癌的说明书;所述药物组合物优选为适于口服的制剂,更优选为片剂或胶囊。
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CN202311015952.6A CN117085017A (zh) | 2018-09-18 | 2019-09-18 | 用于治疗小细胞肺癌的喹啉衍生物 |
SG11202102682SA SG11202102682SA (en) | 2018-09-18 | 2019-09-18 | Quinoline derivative used for treating small cell lung cancer |
AU2019344764A AU2019344764A1 (en) | 2018-09-18 | 2019-09-18 | Quinoline derivative used for treating small cell lung cancer |
CN201980052510.4A CN112533600B (zh) | 2018-09-18 | 2019-09-18 | 用于治疗小细胞肺癌的喹啉衍生物 |
US17/276,972 US20220031689A1 (en) | 2018-09-18 | 2019-09-18 | Quinoline derivative used for treating small cell lung cancer |
EP19861634.4A EP3854396A4 (en) | 2018-09-18 | 2019-09-18 | Quinoline derivative used for treating small cell lung cancer |
CA3112946A CA3112946A1 (en) | 2018-09-18 | 2019-09-18 | Quinoline derivative used for treating small cell lung cancer |
CN202311015937.1A CN117085016A (zh) | 2018-09-18 | 2019-09-18 | 用于治疗小细胞肺癌的喹啉衍生物 |
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US20220031689A1 (en) | 2022-02-03 |
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SG11202102682SA (en) | 2021-04-29 |
EP3854396A1 (en) | 2021-07-28 |
CN117085016A (zh) | 2023-11-21 |
AU2019344764A1 (en) | 2021-05-20 |
CN112533600B (zh) | 2023-07-14 |
CN117085017A (zh) | 2023-11-21 |
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EP3854396A4 (en) | 2022-06-29 |
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