WO2018214925A1 - 用于治疗结直肠癌的喹啉衍生物 - Google Patents

用于治疗结直肠癌的喹啉衍生物 Download PDF

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Publication number
WO2018214925A1
WO2018214925A1 PCT/CN2018/088114 CN2018088114W WO2018214925A1 WO 2018214925 A1 WO2018214925 A1 WO 2018214925A1 CN 2018088114 W CN2018088114 W CN 2018088114W WO 2018214925 A1 WO2018214925 A1 WO 2018214925A1
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Prior art keywords
colorectal cancer
compound
pharmaceutically acceptable
acceptable salt
administration
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PCT/CN2018/088114
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English (en)
French (fr)
Inventor
江海
刘雯雯
于鼎
陈莉
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正大天晴药业集团股份有限公司
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Priority to CN201880033526.6A priority Critical patent/CN110650741A/zh
Publication of WO2018214925A1 publication Critical patent/WO2018214925A1/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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the use of a quinoline derivative for treating colorectal cancer, and belongs to the technical field of medicine.
  • Colorectal cancer is one of the most common malignant tumors in the world. Its incidence varies widely in different parts of the world, with the highest in North America and Oceania, and in Europe and Asia and Africa. In the United States, the incidence and mortality of colorectal cancer ranks among the top in all cancers; in China, the incidence and mortality of colorectal cancer are also increasing. With the changes in people's lifestyles, dietary patterns, and average life expectancy, the incidence of colorectal cancer may increase further.
  • the sites of colorectal cancer include the rectum, sigmoid colon, cecum, ascending colon, descending colon, and transverse colon.
  • Common histological types of colorectal cancer include adenocarcinoma, adenosquamous carcinoma, spindle cell carcinoma, squamous cell carcinoma and undifferentiated carcinoma.
  • Adenocarcinoma is the most common and can be divided into acicular acne-like adenocarcinoma and medullary carcinoma. , micropapillary cancer, mucinous adenocarcinoma, serrated adenocarcinoma, and signet ring cell carcinoma.
  • KRAS gene is the most frequently carcinogenic gene with mutation frequency; its mutation activation is one of the main reasons for the malignant transformation of many tumor cells in human. After mutation of KRAS gene, it inhibits its own GTPase activity, making it difficult to be activated by GAPs, which makes KRAS protein always in an activated state, which eventually leads to abnormal activation of signal transduction pathway and is not affected by EGFR upstream signal command.
  • a targeted drug such as EGFR monoclonal antibody
  • EGFR monoclonal antibody binds to the surface of the cell membrane and block the down-regulation of the signaling pathway.
  • the KRAS gene undergoes autophosphorylation after mutation, and resists the action of EGFR monoclonal antibody. The treatment is invalid. It can be seen that targeted drug therapy is not effective for all EGFR overexpressing colorectal cancer. Studies have shown that patients with wild-type KRAS can benefit from EGFR inhibitors (such as cetuximab or panitumumab), while mutants cannot (see: China Journal, 2013, 48(7): 23 -26).
  • EGFR inhibitors such as cetuximab or panitumumab
  • KRAS mutations reduce the sensitivity of colon cancer patients to radiotherapy, and can increase the sensitivity of radiotherapy by inhibiting the expression of KRAS gene mutations in colon cancer cells.
  • KRAS mutations are closely related to the treatment regimen and efficacy of colorectal cancer.
  • the NCCN Clinical Practice Guidelines for Colorectal Cancer indicate that metastatic colorectal cancer should be tested for KRAS gene status and then guided medication.
  • the present invention provides a method of treating colorectal cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the colorectal cancer is a chemotherapeutic drug And/or colorectal cancer that targets drug therapy failure.
  • the present invention provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating colorectal cancer, wherein the colorectal cancer is a chemotherapeutic drug and/or a targeted drug therapy Failure of colorectal cancer.
  • the present invention provides a pharmaceutical composition for treating colorectal cancer, comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, wherein said colorectal cancer is Chemotherapy drugs and/or targeted drug therapy for colorectal cancer failure.
  • the present invention provides a kit comprising (a) at least one unit dose of a pharmaceutical composition of Compound I or a pharmaceutically acceptable salt thereof, and (b) instructions for treating colorectal cancer, Wherein the colorectal cancer is a colorectal cancer in which a chemotherapy drug and/or a targeted drug treatment fails.
  • the present application provides a method of treating colorectal cancer comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the colorectal cancer is a chemotherapeutic drug and/or Targeted drug therapy for colorectal cancer failure.
  • the chemotherapeutic drugs include, but are not limited to, camptothecin antitumor drugs, platinum complexes or fluoropyrimidine derivatives; and the targeted drugs include, but are not limited to, EGFR inhibitors or VEGFR inhibitors.
  • the invention also provides a method of treating RAS-mutant colorectal cancer, the method comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the colorectal cancer is advanced and/or metastatic colorectal cancer of a RAS mutation.
  • the colorectal cancer is a latent and/or metastatic colorectal cancer of a RAS mutation that is a chemotherapeutic drug and/or a targeted drug therapy failure.
  • a method of treating a RAS-mutant colorectal adenocarcinoma comprising administering to a patient in need of treatment a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the colorectal adenocarcinoma is a late and/or metastatic colorectal adenocarcinoma of a RAS mutation.
  • the colorectal adenocarcinoma is a late-stage and/or metastatic colorectal adenocarcinoma that fails chemotherapy therapy and/or targeted drug therapy.
  • the RAS mutations include, but are not limited to, KRAS and NRAS mutations.
  • the RAS mutation is a KRAS mutation.
  • the KRAS mutation is a mutation at position 2 of the KRAS gene codon.
  • the RAS mutation is an NRAS mutation.
  • the NRAS mutation is a mutation at the 2 and/or 3 position of the NRAS gene codon.
  • Compound I can be administered in the form of its free base or it can be administered in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the invention, and the salt can be produced from different organic and inorganic acids according to methods well known in the art.
  • the administration is in the form of Compound I hydrochloride. In some embodiments, the administration is in the form of Compound I monohydrochloride. In some embodiments, the administration is in the form of Compound I dihydrochloride. In some embodiments, the administration is in the form of a crystal of Compound I hydrochloride. In a particular embodiment, it is administered in the form of a crystal of Compound I dihydrochloride.
  • Compound 1, or a pharmaceutically acceptable salt thereof can be administered by a variety of routes including, but not limited to, those selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intra-, intra-articular, intraperitoneal, and intrathecal. In some specific embodiments, it is administered orally.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 16 mg.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 10 mg to 14 mg. In some specific embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 10 mg. In some specific embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg. In some specific embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 14 mg. In some specific embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is 16 mg.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the oral solid formulation is administered once a day.
  • the method of administration can be comprehensively determined based on the activity, toxicity, and tolerance of the patient.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered in a separate manner.
  • the interval administration includes a administration period and a withdrawal period, and Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times a day during the administration period.
  • Compound I or a pharmaceutically acceptable salt thereof is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated a plurality of times.
  • the ratio of the administration period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, still more preferably 2:0.5 to 1.
  • the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks
  • the two-week interval administration method can be repeated a plurality of times.
  • the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day for 14 days, followed by 7 days of withdrawal; followed by 1 administration per day for 14 days, followed by 7 days of discontinuation, such continuous administration for 2 weeks
  • the interval of administration of the drug for one week can be repeated a plurality of times.
  • the administration is continued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, then for 2 days; then once a day for 5 days, then for 2 days, such continuous administration for 5 days.
  • the two-day interval administration method can be repeated multiple times.
  • Compound 1, or a pharmaceutically acceptable salt thereof is a colorectal cancer patient that is administered the KRAS mutation alone as the sole active ingredient. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a KRAS-mutated colorectal cancer patient simultaneously or sequentially with other anti-tumor drugs.
  • other anti-tumor drugs include, but are not limited to, camptothecin antineoplastic agents, platinum complexes, fluoropyrimidine derivatives, steroid antitumor antibiotics, taxanes, EGFR inhibitors, VEGFR inhibition One or more of a dose, mitomycin, and trastuzumab.
  • the present invention provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating colorectal cancer, wherein the colorectal cancer is a chemotherapeutic drug and/or a targeted drug therapy Failure of colorectal cancer.
  • the chemotherapeutic drugs include, but are not limited to, camptothecin antitumor drugs, platinum complexes or fluoropyrimidine derivatives; and the targeted drugs include, but are not limited to, EGFR inhibitors or VEGFR inhibitors.
  • the invention also provides the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical composition for the treatment of RAS mutations in colorectal cancer.
  • the colorectal cancer is a late and/or metastatic colorectal cancer of a RAS mutation; in some more typical embodiments, the colorectal cancer is a chemotherapeutic drug and/or targeted Drug therapy fails in advanced and/or metastatic colorectal cancer with RAS mutations.
  • the colorectal adenocarcinoma is a late and/or metastatic colorectal adenocarcinoma of a RAS mutation; in some more typical embodiments, the colorectal adenocarcinoma is a chemotherapeutic drug and/ Or advanced and/or metastatic colorectal adenocarcinoma of RAS mutations that target drug therapy failure.
  • the RAS mutations include, but are not limited to, KRAS and NRAS mutations.
  • the RAS mutation is a KRAS mutation.
  • the KRAS mutation is a mutation at position 2 of the KRAS gene codon.
  • the RAS mutation is an NRAS mutation.
  • the NRAS mutation is a mutation at the 2 and/or 3 position of the NRAS gene codon.
  • Compound I may be in its free base form, or it may be in the form of its salts, hydrates and prodrugs which are converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the invention, and salts can be produced from different organic and inorganic acids according to methods well known in the art.
  • Compound 1, or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of Compound I.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof can be determined depending on the severity of the disease, the response of the disease, any treatment-related toxicity, the age of the patient, and the state of health.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is from 8 mg to 20 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 16 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 14 mg.
  • the amount of Compound 1, or a pharmaceutically acceptable salt thereof is 10 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 14 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 16 mg.
  • compositions of Compound 1, or a pharmaceutically acceptable salt thereof, as the sole active ingredient in the manufacture of a pharmaceutical composition for the treatment of KRAS mutations in colorectal cancer are provided.
  • a pharmaceutical composition of Compound I, or a pharmaceutically acceptable salt thereof, and other anti-tumor agents, together as an active ingredient, for the preparation of colorectal cancer for the treatment of KRAS mutations is provided.
  • other anti-tumor drugs include, but are not limited to, camptothecin antineoplastic agents, platinum complexes, fluoropyrimidine derivatives, steroid antitumor antibiotics, taxanes, EGFR inhibitors, VEGFR inhibition One or more of a dose, mitomycin, and trastuzumab.
  • the present invention provides a pharmaceutical composition for treating colorectal cancer, comprising Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, wherein said colorectal cancer is Chemotherapy drugs and/or targeted drug therapy for colorectal cancer failure.
  • the chemotherapeutic drugs include, but are not limited to, camptothecin antitumor drugs, platinum complexes or fluoropyrimidine derivatives; and the targeted drugs include, but are not limited to, EGFR inhibitors or VEGFR inhibitors.
  • the invention also provides a pharmaceutical composition for treating colorectal cancer of a RAS mutation comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the colorectal cancer is a late and/or metastatic colorectal cancer of a RAS mutation; in some more typical embodiments, the colorectal cancer is a chemotherapeutic drug and/or targeted Drug therapy fails in advanced and/or metastatic colorectal cancer with RAS mutations.
  • a pharmaceutical composition for treating a RAS-mutated colorectal adenocarcinoma comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the colorectal adenocarcinoma is a late and/or metastatic colorectal adenocarcinoma of a RAS mutation; in some more typical embodiments, the colorectal adenocarcinoma is a chemotherapeutic drug and/ Or advanced and/or metastatic colorectal adenocarcinoma of RAS mutations that target drug therapy failure.
  • the RAS mutations include, but are not limited to, KRAS and NRAS mutations.
  • the RAS mutation is a KRAS mutation.
  • the KRAS mutation is a mutation at position 2 of the KRAS gene codon.
  • the RAS mutation is an NRAS mutation.
  • the NRAS mutation is a mutation at the 2 and/or 3 position of the NRAS gene codon.
  • Compound I can be in its free base form or in the form of a salt, hydrate and prodrug which is converted in vivo to the free base form of Compound I.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the invention, and salts can be produced from different organic and inorganic acids according to methods well known in the art.
  • Compound 1, or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of Compound I.
  • the amount of Compound I or a pharmaceutically acceptable salt thereof to be administered can be determined depending on the severity of the disease, the response of the disease, any treatment-related toxicity, the age of the patient, and the state of health.
  • the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof is from 2 mg to 20 mg. In some embodiments, the daily dose of Compound 1, or a pharmaceutically acceptable salt thereof, is from 5 mg to 20 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is from 8 mg to 20 mg. In some embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is from 10 mg to 16 mg.
  • the amount of Compound 1, or a pharmaceutically acceptable salt thereof is from 10 mg to 14 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 10 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 12 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 14 mg. In some specific embodiments, the amount of Compound 1, or a pharmaceutically acceptable salt thereof, is 16 mg.
  • the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, pills, pastes, powders, and the like, preferably tablets and capsules.
  • the tablet may be a common tablet, a dispersible tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet or an enteric coated tablet
  • the capsule may be a general capsule, a sustained release capsule, a controlled release capsule or an enteric coated capsule.
  • the oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art.
  • Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • Filling agents include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include hypromellose, poly Retardone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc Powder, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talcum powder, and the like. Pharmaceutical excipients also include coloring agents, sweeteners, and the like.
  • the pharmaceutical composition is a solid preparation suitable for oral administration.
  • the composition may for example be in the form of a tablet or capsule.
  • the pharmaceutical composition is a capsule.
  • the pharmaceutically acceptable carrier of the oral solid formulation comprises mannitol, microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate.
  • a pharmaceutical composition for treating colorectal cancer in a unit dosage form wherein the colorectal cancer is a chemotherapy drug and/or a colorectal cancer that fails to target drug therapy.
  • the pharmaceutical composition in unit dosage form contains from 2 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains from 5 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains from 8 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, preferably from 10 mg to 16 mg of Compound 1, or a pharmaceutically acceptable salt thereof, More preferably, 10 mg to 14 mg of the compound I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 10 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 12 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 14 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 16 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • "pharmaceutical composition in unit dosage form" means tablet or capsule per tablet.
  • the chemotherapeutic drugs include, but are not limited to, camptothecin antitumor drugs, platinum complexes or fluoropyrimidine derivatives; and the targeted drugs include, but are not limited to, EGFR inhibitors or VEGFR inhibitors.
  • the invention also provides a pharmaceutical composition formulated in unit dosage form for the treatment of RAS mutant colorectal cancer.
  • the colorectal cancer is a late and/or metastatic colorectal cancer with a RAS mutation.
  • the colorectal cancer is a latent and/or metastatic colorectal cancer of a RAS mutation that is a chemotherapeutic drug and/or a targeted drug therapy failure.
  • the colorectal cancer is a RAS-mutated colorectal adenocarcinoma; in some typical embodiments, the colorectal adenocarcinoma is a late-stage and/or metastatic colorectal adenocarcinoma of a RAS mutation; In some more typical embodiments, the colorectal adenocarcinoma is a late-stage and/or metastatic colorectal adenocarcinoma of a RAS mutation that is a chemotherapeutic drug and/or a targeted drug therapy failure.
  • the RAS mutations include, but are not limited to, KRAS and NRAS mutations.
  • the RAS mutation is a KRAS mutation.
  • the KRAS mutation is a mutation at position 2 of the KRAS gene codon.
  • the RAS mutation is an NRAS mutation.
  • the NRAS mutation is a mutation at the 2 and/or 3 position of the NRAS gene codon.
  • the above pharmaceutical composition is administered in a separate manner.
  • the interval administration includes a administration period and a withdrawal period, and the above pharmaceutical composition may be administered one or more times a day during the administration period.
  • the pharmaceutical composition is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated several times.
  • the ratio of the administration period to the withdrawal period in terms of days is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, still more preferably 2: 0.5 to 1.
  • the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks
  • the two-week interval administration method can be repeated a plurality of times.
  • the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day for 14 days, followed by 7 days of withdrawal; followed by 1 administration per day for 14 days, followed by 7 days of discontinuation, such continuous administration for 2 weeks
  • the interval of administration of the drug for one week can be repeated a plurality of times.
  • the administration is continued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, then for 2 days; then once a day for 5 days, then for 2 days, such continuous administration for 5 days.
  • the two-day interval administration method can be repeated multiple times.
  • provided pharmaceutical compositions for treating colorectal cancer comprise Compound 1, or a pharmaceutically acceptable salt thereof, as the sole active ingredient.
  • provided pharmaceutical compositions for treating colorectal cancer comprise Compound 1, or a pharmaceutically acceptable salt thereof, further comprising other anti-tumor drugs.
  • other anti-tumor drugs include, but are not limited to, camptothecin antineoplastic agents, platinum complexes, fluoropyrimidine derivatives, steroid antitumor antibiotics, taxanes, EGFR inhibitors, VEGFR inhibition One or more of a dose, mitomycin, and trastuzumab.
  • the present invention provides a kit comprising (a) at least one unit dose of a pharmaceutical composition of Compound 1, or a pharmaceutically acceptable salt thereof, and (b) instructions for treating colorectal cancer
  • the colorectal cancer is a colorectal cancer in which a chemotherapy drug and/or a targeted drug treatment fails.
  • the chemotherapeutic drugs include, but are not limited to, camptothecin antitumor drugs, platinum complexes or fluoropyrimidine derivatives; and the targeted drugs include, but are not limited to, EGFR inhibitors or VEGFR inhibitors.
  • kits comprising (a) at least one unit dose of a formulation suitable for oral administration of Compound I or a pharmaceutically acceptable salt thereof and (b) for treating RAS in a separate manner Instructions for mutated colorectal cancer.
  • a kit is provided comprising (a) at least one unit dose of a tablet or capsule of Compound 1, or a pharmaceutically acceptable salt thereof, and (b) in a manner of interval administration Instructions for the treatment of colorectal cancer with RAS mutations.
  • the colorectal cancer is a latent and/or metastatic colorectal cancer of a RAS mutation that is a chemotherapeutic drug and/or a targeted drug therapy failure.
  • the colorectal cancer is a RAS-mutated colorectal adenocarcinoma; in some typical embodiments, the colorectal adenocarcinoma is a late-stage and/or metastatic colorectal gland of a RAS mutation Cancer; In some more typical embodiments, the colorectal adenocarcinoma is a late-stage and/or metastatic colorectal adenocarcinoma of a RAS mutation that is a chemotherapeutic drug and/or a targeted drug therapy failure.
  • the RAS mutations include, but are not limited to, KRAS and NRAS mutations.
  • the RAS mutation is a KRAS mutation.
  • the KRAS mutation is a mutation in codon 2 of the KRAS gene.
  • the RAS mutation is an NRAS mutation.
  • the NRAS mutation is a mutation at the 2 and/or 3 position of the NRAS gene codon.
  • the pharmaceutical composition in unit dosage form contains from 2 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains from 5 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains from 8 mg to 20 mg of Compound 1, or a pharmaceutically acceptable salt thereof, preferably from 10 mg to 16 mg of Compound 1, or a pharmaceutically acceptable salt thereof, More preferably, 10 mg to 14 mg of the compound I or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 10 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 12 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 14 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In some specific embodiments, the pharmaceutical composition in unit dosage form contains 16 mg of Compound 1, or a pharmaceutically acceptable salt thereof.
  • pharmaceutical composition in unit dosage form means tablet or capsule per tablet.
  • the tablet may be a common tablet, a dispersible tablet, an effervescent tablet, a sustained release tablet, a controlled release tablet or an enteric coated tablet
  • the capsule may be a general capsule, a sustained release capsule, a controlled release capsule or an enteric coated capsule.
  • pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • Filling agents include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include hypromellose, poly Retardone, microcrystalline cellulose, etc.; disintegrants include croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc Powder, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talcum powder, and the like. Pharmaceutical excipients also include coloring agents, sweeteners, and the like.
  • the interval administration includes a administration period and a withdrawal period, and the above pharmaceutical composition may be administered one or more times a day during the administration period.
  • the pharmaceutical composition is administered daily during the administration period, and then the administration is stopped for a certain period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated several times.
  • the ratio of the administration period to the withdrawal period in terms of days is 2: 0.5 to 5, preferably 2: 0.5 to 3, more preferably 2: 0.5 to 2, still more preferably 2: 0.5 to 1.
  • the continuous administration is discontinued for 2 weeks for 2 weeks. In some embodiments, administration once a day for 14 days, followed by 14 days of withdrawal; followed by 1 administration per day for 14 days, followed by 14 days of discontinuation, such continuous administration for 2 weeks
  • the two-week interval administration method can be repeated a plurality of times.
  • the continuous administration is discontinued for 2 weeks for 1 week. In some embodiments, administration once a day for 14 days, followed by 7 days of withdrawal; followed by 1 administration per day for 14 days, followed by 7 days of discontinuation, such continuous administration for 2 weeks
  • the interval of administration of the drug for one week can be repeated a plurality of times.
  • the administration is continued for 5 days for 2 days.
  • the drug is administered once a day for 5 days, then for 2 days; then once a day for 5 days, then for 2 days, such continuous administration for 5 days.
  • the two-day interval administration method can be repeated multiple times.
  • the colorectal adenocarcinoma includes, but is not limited to, sieve-like acne-type adenocarcinoma, medullary carcinoma, micropapillary carcinoma, mucinous adenocarcinoma, serrated adenocarcinoma, and signet ring cell carcinoma.
  • camptothecin antineoplastic agents include, but are not limited to, one or more of camptothecin, hydroxycamptothecin, irinotecan, topotecan; platinum complexes include but not Limited to one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin; fluoropyrimidine derivatives including but not limited to capecitabine, fluorouracil, difurfuryluracil, deoxyfluorouridine, tega One or more of fluorine and carmofur; steroid anti-tumor antibiotics include but not limited to one or more of doxorubicin, epirubicin, daunorubicin, and mitoxantrone Taxanes include, but are not limited to, paclitaxel and/or docetaxel.
  • the EGFR inhibitor is selected from the group consisting of Cetuximab (cetuximab) and/or Panitumumab (panitumumab).
  • the VEGFR inhibitor is selected from the group consisting of Bevacizumab (bevacizumab), Regorafenib (Riefeifenib), Nintedanib (Nidanib), and/or Fruquintinib (furridinib).
  • qd refers to administration once a day unless otherwise stated.
  • the crystalline form of the hydrochloride salt of the compound I includes, but is not limited to, the types A, B, and C crystals disclosed in Chinese Patent Application No. CN102344438A, wherein the A and B type crystals are substantially free of crystal water and other solvents. Crystallization, Form C crystal is a crystal containing two water of crystallization. In some embodiments, the crystalline form of the dihydrochloride salt of Compound I is Form A crystal.
  • Patient means a mammal, preferably a human. In some embodiments, the patient is a patient who fails standard treatment or lacks standard treatment.
  • “Pharmaceutically acceptable” means that it is used in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically or otherwise undesirable, and which includes its use for human pharmaceutical use. Accepted.
  • “Pharmaceutically acceptable salt” includes, but is not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, trifluoroacetic acid, propionic acid , caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenyl
  • “Therapeutically effective amount” means an amount of a compound that is sufficient to effect treatment of a disease when administered to a human.
  • Treatment means any administration of a therapeutically effective amount of a compound and includes:
  • PR refers to partial relief, specifically the sum of the target lesion diameters of the tumor is reduced by more than 30% from the baseline level.
  • PD refers to disease progression, specifically the sum of the target lesion diameters of the tumor is increased by more than 20% from the baseline level.
  • SD refers to the stability of the disease, specifically the extent to which the tumor target lesion has not decreased to the PR level, and the degree of increase has not reached the PD level, which is somewhere in between.
  • Treatment failure refers to intolerance of toxic side effects, progression of disease during treatment, or recurrence after treatment; wherein intolerance includes, but is not limited to, hematological toxicity up to grade IV (platelet decline III and above), non-hematologic toxicity Reach level III or above.
  • EGFR inhibitor refers to an epidermal growth factor receptor inhibitor.
  • VEGFR inhibitor refers to a vascular endothelial growth factor receptor inhibitor.
  • FOLFIRI protocol refers to irinotecan, fluorouracil and calcium tetrahydrofolate solutions.
  • Xelox protocol refers to the capecitabine and oxaliplatin regimens.
  • FOLFOX regimen refers to oxaliplatin, calcium folinate, and fluorouracil.
  • Example 2 contains 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl a capsule of cyclopropylamine dihydrochloride (dihydrochloride salt of Compound I)
  • the dihydrochloride salt of Compound I is pulverized and passed through a 80 mesh sieve; then uniformly mixed with mannitol and hydroxypropylcellulose; then a prescribed amount of microcrystalline cellulose is added, uniformly mixed, and passed through a 0.8 mm sieve; The magnesium stearate is mixed evenly and filled with capsules.
  • the patient was evaluated for SD (small) after 2 cycles of administration, and continued to maintain SD status; the target lesion was lung metastasis, and the non-target lesion was multiple metastasis of left lung, as follows:
  • oral compound I dihydrochloride capsules were treated with 12 mg qd, and the drug was administered continuously for one week in a continuous cycle for 2 weeks.
  • the dose was adjusted to 10 mg qd, and the drug was administered continuously for one week in a continuous cycle for 2 weeks.
  • the target lesion was the soft tissue density nodules in the right axilla, and the non-target lesions were enlarged lymph nodes in the retroperitoneum;
  • the liver has multiple metastatic rectal adenocarcinoma, involving the liver capsule and the portal vein branch vessel wall, but it is not infiltrated.
  • the review showed that the liver had a new metastasis.
  • the FOLFIRI regimen was given chemotherapy for 3 cycles and the efficacy was PD. Radiofrequency ablation of liver metastases was performed in February 2015.
  • oral compound I dihydrochloride capsules were treated with 12 mg qd, and the drug was administered continuously for one week in a continuous cycle for 2 weeks.
  • the long-term diameter of the tumor target lesion remained stable for a long time.
  • the patient's adverse reactions are basically tolerable.
  • stage IV stage IV (cT0NXM1,).
  • oral compound I dihydrochloride capsules were treated with 12 mg qd, and the drug was administered continuously for one week in a continuous cycle for 2 weeks.

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Abstract

一种用于治疗结直肠癌的喹啉衍生物，具体涉及1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺能够有效治疗化疗药物和/或靶向药物治疗失败的结直肠癌，能够稳定或者缓解化疗药物和/或靶向药物治疗失败的结直肠癌患者病情。

Description

用于治疗结直肠癌的喹啉衍生物
相关申请的交叉引用
本申请要求向中华人民共和国国家知识产权局于2017年05月26日提交的第201710382549.5号中国发明专利申请的权益，在此将它们的全部内容以援引的方式整体并入本文中。
技术领域
本发明涉及喹啉衍生物用于治疗结直肠癌的用途，属于医药技术领域。
背景技术
结直肠癌是世界上最常见的恶性肿瘤之一，其发病率在世界不同地区差异很大，以北美洲、大洋洲最高，欧洲居中，亚非地区较低。在美国，结直肠癌的发病率和死亡率居所有肿瘤的前列；在中国，结直肠癌的发病率和死亡率也日益上升。随着人们生活方式、饮食结构的改变，平均寿命的提高，结直肠癌的发病率可能还将进一步上升。
结直肠癌发生部位包括直肠、乙状结肠、盲肠、升结肠、降结肠、横结肠等。常见的结直肠癌组织学类型包括腺癌、腺鳞癌、梭形细胞癌、鳞状细胞癌和未分化癌等；其中腺癌最为常见，可分为筛状粉刺型腺癌、髓样癌、微乳头癌、粘液腺癌、锯齿状腺癌和印戒细胞癌。
近年来，随着新的分子靶向药物的研发和个体化治疗的应用，使结直肠癌患者的存活率有了显著改善，人们逐渐认识到靶向药物治疗与相关基因检测之间的密切联系，因此，对结直肠癌的分子生物学及分子靶向治疗的研究已成为目前肿瘤治疗及预后的热点之一；RAS基因检测与结直肠癌及其靶向治疗的关系也备受关注，且已取得一定的进展。
RAS基因家族与人类肿瘤相关的基因有3种：HRAS、KRAS和NRAS，分别定位于11、12和1号染色体上。其中，KRAS基因是突变频率最高的致癌基因；它的突变激活是人类多种肿瘤细胞恶性转化的主要原因之一。KRAS基因发生突变后，抑制了自身的GTP酶活性，使其不易被GAPs激活，使得KRAS蛋白总是处于活化状态，最终导致信号转导通路异常活化，不受EGFR上游信号指令的影响。这种状态下如果使用靶向药物，例如EGFR单抗，虽然能与细胞膜表面EGFR结合，阻滞了信号通路的下传，但KRAS基因突变后发生自身磷酸化， 抗拒EGFR单抗的作用，从而治疗无效。可见，靶向药物治疗并非对所有EGFR过表达的结直肠癌都有效。有研究显示KRAS野生型的患者能够从EGFR抑制剂(如西妥昔单抗或帕尼单抗)获益，而突变型则不能(参见：《中国医刊》2013，48(7)：23-26)。此外，KRAS突变使结肠癌患者对放疗的敏感性下降，而通过抑制结肠癌细胞KRAS基因突变表达可提高放疗的敏感性。而且，KRAS突变与结直肠癌的治疗方案及疗效息息相关，《NCCN结直肠癌临床实践指南》指出转移性结直肠癌应检测KRAS基因状态，进而指导用药。
因此，进一步寻找结直肠癌的治疗药物是十分必要的。
发明内容
第一方面，本发明提供了一种治疗结直肠癌的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌。
化合物I的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧
基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
Figure PCTCN2018088114-appb-000001
第二方面，本发明提供了化合物I或其药学上可接受的盐在制备用于治疗结直肠癌的药物组合物中的用途，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌。
第三方面，本发明提供了一种治疗结直肠癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌。
第四方面，本发明提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗结直肠癌的说明书，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌。
具体实施方式
第一方面，本申请提供了一种治疗结直肠癌的方法，包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌。
其中，所述的化疗药物包括但不限于喜树碱类抗肿瘤药、铂配合物或氟嘧啶衍生物；所述的靶向药物包括但不限于EGFR抑制剂或VEGFR抑制剂。
本发明还提供了一种治疗RAS突变的结直肠癌的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐。在一些典型的实施方案中，所述结直肠癌为RAS突变的晚期和/或转移性结直肠癌。在一些更为典型的实施方案中，所述结直肠癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠癌。
在本发明的一些实施方案中，提供了一种治疗RAS突变的结直肠腺癌的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐。在一些典型的实施方案中，所述结直肠腺癌为RAS突变的晚期和/或转移性结直肠腺癌。在一些更为典型的实施方案中，所述结直肠腺癌为化疗药物和/或靶向药物治疗失败的晚期和/或转移性结直肠腺癌。
在本发明的一些实施方案中，所述的RAS突变包括但不限于KRAS和NRAS突变。在一些实施方案中，所述的RAS突变为KRAS突变。在一些更为典型的实施例中，所述的KRAS突变为KRAS基因密码子2位的突变。在一些实施方案中，所述的RAS突变为NRAS突变。在一些更为典型的实施例中，所述的NRAS突变为NRAS基因密码子2位和/或3位的突变。
化合物I可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成化合物I的游离碱形式。例如，化合物I的药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
在一些实施方案中，以化合物I盐酸盐的形式给药。在一些实施方案中，以化合物I一盐酸盐的形式给药。在一些实施方案中，以化合物I二盐酸盐的形式给药。在一些实施方案中，以化合物I盐酸盐的晶体形式给药。在特定的实施方案中，以化合物I二盐酸盐的晶体形式给药。
化合物I或其药学上可接受的盐可通过多种途径给药，该途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。
给予化合物I或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为2毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克至16毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克至14毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为12毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为14毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为16毫克。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一些实施方案中，以口服固体制剂每天给药一次。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在一些实施方案中，化合物I或其药学上可接受的盐是作为唯一的活性成分单独给予KRAS突变的结直肠癌患者的。在一些实施方案中，化合物I或其药学上可接受的盐与其他抗肿瘤药物同时或依照次序给予KRAS突变的结直肠癌患者。在一些实施方案中，其他抗肿瘤药物包括但不限于喜树碱类抗肿瘤药、铂配合物、氟嘧啶衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、EGFR抑制剂、VEGFR抑制剂、丝裂霉素、曲妥珠单抗中的一种或几种。
第二方面，本发明提供了化合物I或其药学上可接受的盐在制备用于治疗结直肠癌的药物组合物中的用途，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌。
其中，所述的化疗药物包括但不限于喜树碱类抗肿瘤药、铂配合物或氟嘧啶衍生物；所述的靶向药物包括但不限于EGFR抑制剂或VEGFR抑制剂。
本发明还提供了化合物I或其药学上可接受的盐在制备用于治疗RAS突变的结直肠癌的药物组合物中的用途。在一些典型的实施方案中，所述结直肠癌为RAS突变的晚期和/或转移性结直肠癌；在一些更为典型的实施方案中，所述结直肠癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠癌。
在本发明的一些实施方案中，提供了化合物I或其药学上可接受的盐在制备用于治疗RAS突变的结直肠腺癌的药物组合物中的用途。在一些典型的实施方案中，所述结直肠腺癌为RAS突变的晚期和/或转移性结直肠腺癌；在一些更为典型的实施方案中，所述结直肠腺癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠腺癌。
在本发明的一些实施方案中，所述的RAS突变包括但不限于KRAS和NRAS突变。在一些实施方案中，所述的RAS突变为KRAS突变。在一些更为典型的 实施例中，所述的KRAS突变为KRAS基因密码子2位的突变。在一些实施方案中，所述的RAS突变为NRAS突变。在一些更为典型的实施例中，所述的NRAS突变为NRAS基因密码子2位和/或3位的突变。
化合物I可以是它的游离碱形式，也可以是其盐、水合物和前药的形式，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生盐。
在一些实施方案中，化合物I或其药学上可接受的盐为化合物I的盐酸盐形式。在一些实施方案中，为化合物I一盐酸盐的形式。在一些实施方案中，为化合物I二盐酸盐的形式。在一些实施方案中，为化合物I盐酸盐的晶体形式。在特定的实施方案中，为化合物I二盐酸盐的晶体形式。
化合物I或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为2毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中，化合物I或其药学上可接受的盐的量为8毫克至20毫克。在一些实施方案中，化合物I或其药学上可接受的盐的量为10毫克至16毫克。在一些实施方案中，化合物I或其药学上可接受的盐的量为10毫克至14毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的量为10毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的量为12毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的量为14毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的量为16毫克。
在一些实施方案中，提供了化合物I或其药学上可接受的盐作为唯一活性成份在制备用于治疗KRAS突变的结直肠癌的药物组合物中的用途。在一些实施方案中，提供了化合物I或其药学上可接受的盐和其他抗肿瘤药物共同作为活性成份在制备用于治疗KRAS突变的结直肠癌的药物组合物。在一些实施方案中，其他抗肿瘤药物包括但不限于喜树碱类抗肿瘤药、铂配合物、氟嘧啶衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、EGFR抑制剂、VEGFR抑制剂、丝裂霉素、曲妥珠单抗中的一种或几种。
第三方面，本发明提供了一种治疗结直肠癌的药物组合物，其包含化合物I 或其药学上可接受的盐，以及至少一种药学上可接受的载体，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌。
其中，所述的化疗药物包括但不限于喜树碱类抗肿瘤药、铂配合物或氟嘧啶衍生物；所述的靶向药物包括但不限于EGFR抑制剂或VEGFR抑制剂。
本发明还提供了一种治疗RAS突变的结直肠癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。在一些典型的实施方案中，所述结直肠癌为RAS突变的晚期和/或转移性结直肠癌；在一些更为典型的实施方案中，所述结直肠癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠癌。
在本发明的一些实施方案中，提供了一种治疗RAS突变的结直肠腺癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。在一些典型的实施方案中，所述结直肠腺癌为RAS突变的晚期和/或转移性结直肠腺癌；在一些更为典型的实施方案中，所述结直肠腺癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠腺癌。
在本发明的一些实施方案中，所述的RAS突变包括但不限于KRAS和NRAS突变。在一些实施方案中，所述的RAS突变为KRAS突变。在一些更为典型的实施例中，所述的KRAS突变为KRAS基因密码子2位的突变。在一些实施方案中，所述的RAS突变为NRAS突变。在一些更为典型的实施例中，所述的NRAS突变为NRAS基因密码子2位和/或3位的突变。
化合物I可以是它的游离碱形式，也可以是盐、水合物和前药的形式，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本发明的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生盐。
在一些实施方案中，化合物I或其药学上可接受的盐为化合物I的盐酸盐形式。在一些实施方案中，为化合物I一盐酸盐的形式。在一些实施方案中，为化合物I二盐酸盐的形式。在一些实施方案中，为化合物I盐酸盐的晶体形式。在特定的实施方案中，为化合物I二盐酸盐的晶体形式。
化合物I或其药学上可接受的盐的给药量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为2毫克至20毫克。在一些实施 方案中，给予化合物I或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中，该药物组合物中化合物I或其药学上可接受的盐的量为8毫克至20毫克。在一些实施方案中，化合物I或其药学上可接受的盐的量为10毫克至16毫克。在一些实施方案中，化合物I或其药学上可接受的盐的量为10毫克至14毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的量为10毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的量为12毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的量为14毫克。在一些特定的实施方案中，化合物I或其药学上可接受的盐的量为16毫克。
在本发明的一些实施方案中，所述的药物组合物是适于口服的制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂。其中片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片，胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。所述的口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。填充剂包括淀粉、乳糖、甘露醇、微晶纤维素等；吸收剂包括硫酸钙、磷酸氢钙、碳酸钙等；润湿剂包括水、乙醇等；粘合剂包括羟丙甲纤维素、聚维酮、微晶纤维素等；崩解剂包括交联羧甲基纤维素钠、交联聚维酮、表面活性剂、低取代羟丙基纤维素等；润滑剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉等。药用辅料还包括着色剂、甜味剂等。
在一些实施方案中，该药物组合物是适于口服的固体制剂。该组合物例如可以是片剂或胶囊的形式。在一些特定的实施方案中，该药物组合物是胶囊。在本发明的一些特定实施方案中，口服固体制剂的药学上可接受的载体包括甘露醇、微晶纤维素、羟丙纤维素、硬脂酸镁。
在一些实施方案中，提供了一种治疗结直肠癌的配制成单位剂量形式的药物组合物，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌。在一些实施方案中，该单位剂量形式的药物组合物含有2毫克至20毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有5毫克至20毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有8毫克至20毫克的化合物I或其药学上可接受 的盐，优选10毫克至16毫克的化合物I或其药学上可接受的盐，较优选10毫克至14毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有10毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有12毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有14毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有16毫克的化合物I或其药学上可接受的盐。例如，对于片剂或胶囊而言，“单位剂量形式的药物组合物”意味着每片片剂或每颗胶囊。
其中，所述的化疗药物包括但不限于喜树碱类抗肿瘤药、铂配合物或氟嘧啶衍生物；所述的靶向药物包括但不限于EGFR抑制剂或VEGFR抑制剂。
本发明还提供了一种治疗RAS突变的结直肠癌的配制成单位剂量形式的药物组合物。所述结直肠癌为RAS突变的晚期和/或转移性结直肠癌。在一些更为典型的实施方案中，所述结直肠癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠癌。
在一些实施方案中，所述结直肠癌为RAS突变的结直肠腺癌；在一些典型的实施方案中，所述结直肠腺癌为RAS突变的晚期和/或转移性结直肠腺癌；在一些更为典型的实施中，所述结直肠腺癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠腺癌。
在本发明的一些实施方案中，所述的RAS突变包括但不限于KRAS和NRAS突变。在一些实施方案中，所述的RAS突变为KRAS突变。在一些更为典型的实施例中，所述的KRAS突变为KRAS基因密码子2位的突变。在一些实施方案中，所述的RAS突变为NRAS突变。在一些更为典型的实施例中，所述的NRAS突变为NRAS基因密码子2位和/或3位的突变。
优选地，以间隔给药的方式给予上述药物组合物。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予上述药物组合物。例如在给药期内每天给予药物组合物，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在一些实施方案中，提供的治疗结直肠癌的药物组合物包含化合物I或其药学上可接受的盐作为唯一的活性成分。在一些实施方案中，提供的治疗结直肠癌的药物组合物包含化合物I或其药学上可接受的盐，还进一步包含其他抗肿瘤药物。在一些实施方案中，其他抗肿瘤药物包括但不限于喜树碱类抗肿瘤药、铂配合物、氟嘧啶衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、EGFR抑制剂、VEGFR抑制剂、丝裂霉素、曲妥珠单抗中的一种或几种。
另一方面，本发明还提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗结直肠癌的说明书，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌。
其中，所述的化疗药物包括但不限于喜树碱类抗肿瘤药、铂配合物或氟嘧啶衍生物；所述的靶向药物包括但不限于EGFR抑制剂或VEGFR抑制剂。
本发明还提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的适于口服的制剂和(b)以间隔给药的方式用于治疗RAS突变的结直肠癌的说明书。在一些特定的实施方案中，提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的片剂或胶囊和(b)以间隔给药的方式用于治疗RAS突变的结直肠癌的说明书。在一些更为典型的实施方案中，所述结直肠癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠癌。
在本发明的一些实施方案中，所述结直肠癌为RAS突变的结直肠腺癌；在一些典型的实施方案中，所述结直肠腺癌为RAS突变的晚期和/或转移性结直肠 腺癌；在一些更为典型的实施方案中，所述结直肠腺癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠腺癌。
在本发明的一些实施方案中，所述的RAS突变包括但不限于KRAS和NRAS突变。在一些实施方案中，所述的RAS突变为KRAS突变。在一些更为典型的实施方案中，所述的KRAS突变为KRAS基因密码子2的突变。在一些实施方案中，所述的RAS突变为NRAS突变。在一些更为典型的实施例中，所述的NRAS突变为NRAS基因密码子2位和/或3位的突变。
在一些实施方案中，该单位剂量形式的药物组合物含有2毫克至20毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有5毫克至20毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有8毫克至20毫克的化合物I或其药学上可接受的盐，优选10毫克至16毫克的化合物I或其药学上可接受的盐，较优选10毫克至14毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有10毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有12毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有14毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有16毫克的化合物I或其药学上可接受的盐。例如，对于片剂或胶囊而言，“单位剂量形式的药物组合物”意味着每片片剂或每颗胶囊。
其中片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片，胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。所述的口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。填充剂包括淀粉、乳糖、甘露醇、微晶纤维素等；吸收剂包括硫酸钙、磷酸氢钙、碳酸钙等；润湿剂包括水、乙醇等；粘合剂包括羟丙甲纤维素、聚维酮、微晶纤维素等；崩解剂包括交联羧甲基纤维素钠、交联聚维酮、表面活性剂、低取代羟丙基纤维素等；润滑剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉等。药用辅料还包括着色剂、甜味剂等。
所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予上述药物组合物。例如在给药期内每天给予药物组合物，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
本发明中，所述的结直肠腺癌包括但不限于筛状粉刺型腺癌、髓样癌、微乳头癌、粘液腺癌、锯齿状腺癌和印戒细胞癌。
在本发明的一些实施方案中，喜树碱类抗肿瘤药包括但不限于喜树碱、羟基喜树碱、伊立替康、拓扑替康中的一种或几种；铂配合物包括但不限于顺铂、卡铂、奈达铂、奥沙利铂中的一种或几种；氟嘧啶衍生物包括但不限于卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟中的一种或几种；；蒽醌类抗肿瘤抗生素包括但不限于多柔比星、表柔比星、柔红霉素、米托蒽醌中的一种或几种；紫杉烷类化合物包括但不限于紫杉醇和/或多西他赛。
在本发明的一些实施方案中，所述的EGFR抑制剂选自Cetuximab(西妥昔单抗)和/或Panitumumab(帕尼单抗)。
在本发明的一些实施方案，VEGFR抑制剂选自Bevacizumab(贝伐单抗)、Regorafenib(瑞格非尼)、Nintedanib(尼达尼布)和/或Fruquintinib(呋喹替尼)。
本文中，除非另有说明，这里提供的剂量和范围都是基于化合物I游离碱形式的分子量。
本文中，除非另有说明，qd指每天给药一次。
本文中，所述的化合物I的盐酸盐的晶体形式包括但不限于中国专利申请 CN102344438A公开的A、B和C型结晶，其中A和B型结晶为基本上不含结晶水和其他溶剂的结晶，C型结晶为含两个结晶水的结晶。在一些实施方案中，所述的化合物I的二盐酸盐的晶体形式为A型结晶。
除非另有说明，为本申请的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
“患者”是指哺乳动物，优选人。在一些实施方案中，所述患者为经标准治疗失败或缺乏标准治疗的患者。
“药学上可接受的”是指其用于制备药物组合物，该药物组合物通常是安全、无毒的并且既不在生物学上或其它方面不合乎需要，并且包括其对于人类药物使用是可接受的。
“药学上可接受的盐”包括，但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等等形成的酸加成盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸等形成的酸加成盐。
“治疗有效量”意指化合物被给予人用于治疗疾病时，足以实现对该疾病的治疗的量。
“治疗”意指治疗上有效量的化合物的任何施用，并且包括：
(1)抑制正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即，阻滞所述病理学和/或症状学的进一步发展)，或
(2)改善正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即逆转所述病理学和/或症状学)。
“PR”是指部分缓解，具体指肿瘤的靶病灶直径之和比基线水平减少30％以上。
“PD”是指疾病进展，具体指肿瘤的靶病灶直径之和比基线水平增加20％以上。
“SD”是指疾病稳定，具体指肿瘤靶病灶减小的程度没达到PR水平，增 加的程度也没达到PD水平，介于两者之间。
“治疗失败”是指毒副作用不可耐受、治疗过程中疾病进展或治疗结束后复发；其中不可耐受包括但不限于血液学毒性达IV级(血小板下降III级及以上)、非血液学毒性达到III级或以上。
“晚期”包括“局部晚期”。
“EGFR抑制剂”是指表皮生长因子受体抑制剂。
“VEGFR抑制剂”是指血管内皮生长因子受体抑制剂。“FOLFIRI方案”是指伊立替康、氟尿嘧啶和四氢叶酸钙方案。
“Xelox方案”是指卡培他滨和奥沙利铂方案。
“FOLFOX方案”是指奥沙利铂、亚叶酸钙和氟脲嘧啶。
具体实施方式
实施例1 1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(化合物I的二盐酸盐)
Figure PCTCN2018088114-appb-000002
参照WO2008112407中实施例24的方法制备得到1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，然后参照WO2008112407的说明书中“盐形式的实施例”的制备方法，制备得到标题化合物。或者参照中国专利申请CN102344438A中公开的方法制备得到。
实施例2 含有1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺二盐酸盐(化合物I的二盐酸盐)的胶囊
Figure PCTCN2018088114-appb-000003
Figure PCTCN2018088114-appb-000004
将化合物I的二盐酸盐粉碎，过80目筛；然后与甘露醇、羟丙纤维素混合均匀；接着加入处方量的微晶纤维素，混合均匀，过0.8mm筛网；最后加入处方量的硬脂酸镁混合均匀，并填充胶囊。
对于化合物I的二盐酸盐为其它含量的胶囊，可参照上述相同的比例和处方制备得到。
实施例3 对KRAS突变的结直肠癌的疗效
1)病史
男，61岁，2010年12月行乙状结肠癌根治术，术后病理示：结肠癌(结肠隆起型中分化腺癌，2个，相距1.5cm)。2010年12月底，术后复查CT示：双肺转移。2011年1月至2011年6月，行FOLFOX方案化疗9周期，最佳疗效SD(大)；2011年6月，CT示：肺转移进展。2011年6月至2012年1月予以“伊立替康+卡培他滨”化疗5周期，最佳疗效SD(缩小)。2012年7月至2014年11月口服瑞格非尼治疗24周期，最佳疗效PR；2014年11月，CT示肺转移进展。
2015年1月，接受口服化合物I二盐酸盐胶囊12mg qd治疗，以连续用药2周停药1周为一个周期持续给药。服用化合物I二盐酸盐胶囊前，临床诊断：乙状结肠癌术后多程化疗后、靶向治疗后肺转移进展；临床分期pT4N0M1；IV期。基因检测结果：KRAS突变型，具体为KRAS基因密码子2位突变型。
2)CT结果
患者用药2周期后评效SD(小)，并持续维持SD状态；其中靶病灶为肺转移，非靶病灶为左肺多发转移，具体如下所示：
Figure PCTCN2018088114-appb-000005
Figure PCTCN2018088114-appb-000006
3)耐受性
患者无其他明显不良反应，仍在继续接受治疗。
实施例4 对KRAS突变的结直肠癌的疗效
1)病史
女，50岁，2014年5月经手术，术后病理示：结直肠癌(回盲部中分化腺 癌)。患者行FOLFOX方案化疗9周期后，2015年3月，复查CT示：右侧髂窝内软组织结节(大小约2.4*11.9cm)，考虑转移瘤可能性大。2015年3月至2015年4月，行“伊立替康+替吉奥”化疗1周期，不耐受；2015年5月行“奥沙利铂+替吉奥”化疗2周期，第2周期因口服替吉奥后消化道反应较大，不耐受，仅口服4天。
入组前临床诊断：结直肠癌术后伴盆腔转移癌；临床分期：IV期，TNM分期：pT3NxM1。基因检测：KRAS突变型。
2015年6月，接受口服化合物I二盐酸盐胶囊12mg qd治疗，以连续用药2周停药1周为一个周期持续给药。2016年4月，给药剂量调整为10mg qd，以连续服药2周停药1周为一个周期持续给药。
2)CT结果
患者靶病灶为右侧髂窝软组织密度结节影，非靶病灶为腹膜后可见肿大淋巴结影；
Figure PCTCN2018088114-appb-000007
3)耐受性
患者不良反应基本可耐受，仍在继续接受化合物I二盐酸盐胶囊治疗。
实施例5 对NRAS突变的结直肠癌的疗效
1)病史
男，70岁，2014年5月发现肝多发占位，肠镜示：直肠距肛门12-17cm隆起型肿物。病理：直肠腺癌。基因检测结果示：K-RAS无突变，NRAS中2号密码子突变。2014年6月至8月，患者行“奥沙利铂+卡培他滨”化疗6周期。2014年9月行腹腔镜下乙状结肠切除术+左肝外叶肝转移瘤+右半肝切除，术后病理示：直肠浸润型中分化腺癌，肿瘤侵透肌层累及肠周脂肪，并于肠周脂肪内形成多个癌结节，可见神经侵犯，未见明确脉管瘤栓。肿瘤细胞轻度退变，符合轻度治疗后反应；下切缘、上切缘及环周切缘均未见癌；淋巴结未见转移性癌，伴肠壁脂肪内癌结节形成。肝脏多发转移性直肠腺癌，累及肝被膜及门静脉分支血管壁，但未侵透。2014年11月，复查示：肝脏新出现转移。2014年11月至12月予FOLFIRI方案化疗3周期，疗效PD。2015年2月行肝转移瘤射频消融术。
入组前结合CT临床诊断：直肠癌肝转移术后，多程化疗后，肝转移射频消融术后；临床分期：IV期，TNM分期：pT3N1cM1。
2015年04月，接受口服化合物I二盐酸盐胶囊12mg qd治疗，以连续用药2周停药1周为一个周期持续给药。
2)CT结果
用盐I治疗后患者的肿瘤靶病灶长径长期维持稳定。
Figure PCTCN2018088114-appb-000008
Figure PCTCN2018088114-appb-000009
3)耐受性
患者不良反应基本可耐受。
实施例6 对NRAS突变的结直肠癌的疗效
1)病史：
女，57岁，2014年10月，病理诊断示：乙状结肠腺癌，直肠低级别绒毛管状腺癌。患者于2014年11月行FOLFOX化疗5周期，末次化疗7天后出现左下腹绞痛，伴发热，鲜血便，2015年03月07日急诊全麻下行乙状结肠癌Hartman术，术后病理示：进展期直肠癌，局限溃疡型，乳头状管状腺癌，段端无癌。基因检测结果示：NRAS中3号密码子突变。2015年04月行卡培他滨(希罗达
Figure PCTCN2018088114-appb-000010
)单药化疗5周期，2015年11月复查，疗效评价PD。2015年11月行伊立替康联合去氧氟尿苷化疗1周期，不耐受，停止化疗。2015年12月行Xelox方案，出现频繁恶心，呕吐，不能进食，2016年01月复查CT，疗效评价PD。
入组前结合CT临床诊断示：结肠恶性肿瘤，估息术后，肺继发转移癌；临床分期：IV期(cT0NXM1,)。
2016年01月，接受口服化合物I二盐酸盐胶囊12mg qd治疗，以连续用药2周停药1周为一个周期持续给药。
B)CT结果
Figure PCTCN2018088114-appb-000011
3)耐受性
患者不良反应基本可耐受，仍在继续接受化合物I二盐酸盐胶囊治疗。

Claims (13)

  1. 一种治疗结直肠癌的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌，
    Figure PCTCN2018088114-appb-100001
  2. 一种治疗RAS突变的结直肠癌的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐；优选所述结直肠癌为RAS突变的晚期和/或转移性结直肠癌；更优选所述结直肠癌为化疗药物和/或靶向药物治疗失败的RAS突变的晚期和/或转移性结直肠癌。
  3. 权利要求1或2所述的方法，其特征在于所述的化疗药物选自喜树碱类抗肿瘤药、铂配合物或氟嘧啶衍生物；所述的靶向药物选自EGFR抑制剂或VEGFR抑制剂。
  4. 权利要求1-3任一项所述的方法，其特征在于，所述结直肠癌为结直肠腺癌。
  5. 权利要求4所述的方法，其特征在于，所述结直肠腺癌为筛状粉刺型腺癌、髓样癌、微乳头癌、粘液腺癌、锯齿状腺癌或印戒细胞癌。
  6. 权利要求2-5任一项所述的方法，其特征在于，所述RAS突变为KRAS和NRAS；优选KRAS基因密码子2位的突变；优选NRAS基因密码子2位和/或3位的突变。
  7. 权利要求1-6任一项所述的方法，所述化合物I或其药学上可接受的盐为盐酸盐，优选二盐酸盐。
  8. 权利要求1-7任一项所述的方法，其中，化合物I或其药学上可接受的盐的给药日剂量为如下给药日剂量中的一种：2毫克至20毫克、5毫克至20毫克、8毫克至20毫克、10毫克至16毫克、10毫克至14毫克、10毫克、12毫克、14毫克以及16毫克。
  9. 根据权利要求1-8任一项所述的方法，其特征在于，以间隔给药的方法给予化合物I或其药学上可接受的盐；所述的间隔给药包括给药期和停药期，其中给药期和停药期的以天数计的比值为2:0.5～5，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1；作为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周以及连续给药5天停药2天，上述间隔给药方式可以反复进行多次。
  10. 根据权利要求1-9任一项所述的方法，其特征在于化合物I或其药学上可接受的盐与其他 抗肿瘤药物同时或依照次序给予结直肠癌患者；其他抗肿瘤药物选自喜树碱类抗肿瘤药、铂配合物、氟嘧啶衍生物、蒽醌类抗肿瘤抗生素、紫杉烷类化合物、EGFR抑制剂、VEGFR抑制剂、丝裂霉素、曲妥珠单抗中的一种或几种。
  11. 化合物I或其药学上可接受的盐在制备用于治疗结直肠癌的药物组合物中的用途，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌，
    Figure PCTCN2018088114-appb-100002
  12. 一种治疗结直肠癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体，其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌，
    Figure PCTCN2018088114-appb-100003
  13. 一种试剂盒，其包含(a)至少一个单位剂量的化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗结直肠癌的说明书；其中所述结直肠癌为化疗药物和/或靶向药物治疗失败的结直肠癌，
    Figure PCTCN2018088114-appb-100004
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CN112336726A (zh) * 2019-08-09 2021-02-09 正大天晴药业集团股份有限公司 治疗结直肠癌的联用药物组合物
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WO2021143928A1 (zh) * 2020-01-19 2021-07-22 正大天晴药业集团股份有限公司 用于治疗类风湿性关节炎的喹啉衍生物
WO2021184958A1 (zh) * 2020-03-18 2021-09-23 北京康辰药业股份有限公司 血管生成抑制剂、其制备方法和应用

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