WO2023226940A1 - 吲哚并七元酰肟类似物的用途及其药物组合 - Google Patents

吲哚并七元酰肟类似物的用途及其药物组合 Download PDF

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Publication number
WO2023226940A1
WO2023226940A1 PCT/CN2023/095586 CN2023095586W WO2023226940A1 WO 2023226940 A1 WO2023226940 A1 WO 2023226940A1 CN 2023095586 W CN2023095586 W CN 2023095586W WO 2023226940 A1 WO2023226940 A1 WO 2023226940A1
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Prior art keywords
formula
compound
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
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PCT/CN2023/095586
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English (en)
French (fr)
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陈凯
于鼎
王训强
杨安琪
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正大天晴药业集团股份有限公司
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Publication of WO2023226940A1 publication Critical patent/WO2023226940A1/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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems

Definitions

  • the present application belongs to the field of medical technology and relates to the use of indolo seven-membered oxime analogs and their pharmaceutical combinations. Specifically, it relates to the use of compounds of formula (I), pharmaceutical combinations of compounds of formula (I) and their uses.
  • PARP is a type of poly ADP-ribose polymerase, which is a family of enzymes that can be used to catalyze the addition of ADP-ribose residues to various target proteins. To date, a total of 18 subtypes have been identified and characterized. Although there are many types of enzymes in the PARP family, PARP-1 is responsible for more than 90% of ADP-ribosylation in cells, so PARP inhibitor research mainly focuses on PARP-1 inhibitors.
  • PARP-1 is closely related to DNA repair and genome functional maintenance.
  • DNA is damaged, usually a single strand break (SSB, Single strand break)
  • SSB Single strand break
  • PARP-1 first binds to the break of DNA and is then activated.
  • NAD+ Coenzyme II
  • the enzyme begins to recruit NAD+ (Coenzyme II ) is used to synthesize poly(ADP) ribose.
  • NAD+ Coenzyme II
  • it also becomes a signal for other repair enzymes such as DNA ligase and DNA polymerase beta to work.
  • BER Base excision repair
  • HR Homologous recombination
  • NHEJ Non-Homologous End Joining
  • BRCA1 and BRCA2 play an important role in homologous recombination (Nature, 2005, 913-917). Studies have found that BRCA1/2 mutations are found in ovarian cancer, breast cancer, and prostate cancer. For tumors lacking BRCA1/2, PARP inhibitors are a good choice.
  • Prostate cancer is the second most common cancer and the fifth leading cause of cancer-related death among men worldwide, and the incidence of prostate cancer in Asia is lower than that in developed countries such as Europe and the United States.
  • endocrine therapy is mainly used for newly diagnosed prostate cancer patients, including castration (surgical castration or medical castration) and anti-androgen therapy.
  • castration surgical castration or medical castration
  • anti-androgen therapy is mainly used for newly diagnosed prostate cancer patients, including castration (surgical castration or medical castration) and anti-androgen therapy.
  • mCRPC metastatic castration-resistant prostate cancer
  • the application provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof for use in treating prostate cancer in a patient:
  • the present application provides a pharmaceutical composition for treating prostate cancer in a patient, the pharmaceutical composition comprising a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present application provides a method for treating prostate cancer in a patient, comprising administering to the patient an effective amount of a compound of formula (I) as described above, an isomer thereof, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof.
  • the present application provides the use of a compound of formula (I) as described above, an isomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating prostate cancer in a patient.
  • the present application provides the use of a compound of formula (I) as described above, an isomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in a medicament for treating prostate cancer in a patient.
  • the above-mentioned compound of formula (I) is a compound of formula (II), and the compound of formula (II) is:
  • the above-mentioned compound of formula (I), isomers or pharmaceutically acceptable salts thereof is a compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of the compound of formula (II) is a hydrochloride salt, such as the monohydrochloride salt of the compound of formula (II).
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof is used as a single active agent.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof may be a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof .
  • the administration period of the compound of formula (II) or its pharmaceutically acceptable salt to treat prostate cancer in patients is 2 to 6 weeks. In some embodiments of the present application, the administration period for treating prostate cancer in a patient is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or a range formed by any of the above values. In some embodiments of the present application, the dosing period for treating prostate cancer in a patient is 4 weeks.
  • the amount of the above-mentioned compound of formula (II) 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, For example, it can be determined based on the subject/patient's routine blood test results, which include platelet count, neutrophil count, or hemoglobin concentration, etc.
  • the compound of Formula (II), or a pharmaceutically acceptable salt thereof is administered at a daily dose of 25 mg to 500 mg.
  • the daily dose administered to the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof may be selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg , 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg or 500mg, or a range composed of any of the foregoing values as endpoints or any value therein, such as 25mg to 500mg, 25mg to 400mg, 25mg to 300mg, 50mg to 300mg, 75mg to 300mg, 100mg to 300mg, 150mg to 300mg, 200mg to 300mg, etc.
  • the daily dosage of the compound of formula (II) or a pharmaceutically acceptable salt thereof may be selected from the group consisting of 100 mg to 300 mg, 150 mg to 300 mg, and 200 mg to 300 mg.
  • the daily dose administered to the compound of Formula (II) above or a pharmaceutically acceptable salt thereof may be selected from the group consisting of 100 mg, 150 mg, 200 mg, or 300 mg.
  • the daily dosage of the compound of formula (II) above or a pharmaceutically acceptable salt thereof is 25 mg to 500 mg.
  • the daily dosage of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof may be selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg , 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg or 500mg, or a range composed of any of the foregoing values as endpoints or any value therein, such as 25mg to 500mg, 25mg to 400mg, 25mg to 300mg, 50mg to 300mg, 75mg to 300mg, 100mg to 300mg, 150mg to 300mg, 200mg to 300mg, etc.
  • the daily dosage of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof may be selected from the group consisting of 100 mg to 300 mg, 150 mg to 300 mg, and 200 mg to 300 mg. In some specific embodiments, the daily dosage of the compound of Formula (II) above or a pharmaceutically acceptable salt thereof may be selected from 100 mg, 150 mg, 200 mg, or 300 mg.
  • each dose of the compound of formula (II) above or a pharmaceutically acceptable salt thereof is 25 mg to 500 mg.
  • each dose of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof can be selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg , 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg or 500mg, or a range composed of any of the foregoing values as endpoints or any value therein, such as 25mg to 500mg, 25mg to 400mg, 25mg to 300mg, 50mg to 300mg, 75mg to 300mg, 100mg to 300mg, 150mg to 300mg, 200mg to 300mg, etc.
  • each dose of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof can be selected from the group consisting of 100 mg to 300 mg, 150 mg to 300 mg, and 200 mg to 300 mg. In some specific embodiments, each dose of the compound of formula (II) above or a pharmaceutically acceptable salt thereof can be selected from 100 mg, 150 mg, 200 mg, or 300 mg.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof can be administered once or multiple times a day. In some embodiments, the compound of formula (II) above, or a pharmaceutically acceptable salt thereof, is administered once or twice daily.
  • the compound of formula (II) above or a pharmaceutically acceptable salt thereof may also be administered in a single dose form. In one embodiment, it is administered in a single dose once or twice daily.
  • the oral solid formulation is administered as a single dose once or twice daily. In a specific embodiment, the oral solid formulation is administered as a single dose once daily.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof in the present application can also be administered in multiple doses.
  • multiple doses are administered once or twice daily.
  • the oral solid formulation is administered in multiple doses once or twice daily.
  • the oral solid formulation is administered once daily in multiple doses.
  • the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, preferably, it is a multi-dose pharmaceutical composition.
  • the provided pharmaceutical composition contains 25 mg to 500 mg of the compound of formula (II) above or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition provided contains 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg or 500 mg, or a range of any of the foregoing values as endpoints or any value thereof, or a pharmaceutically acceptable salt thereof, such as 25 mg to 500 mg, 25 mg to 400 mg, 25 mg to 300 mg, 50 mg to 300 mg , 75mg to 300mg, 100mg to 300mg, 150mg to 300mg, 200mg to 300mg.
  • the provided pharmaceutical composition contains 100 mg, 150 mg, 200 mg or 300 mg of the compound of formula (II) above or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the compound of formula (II) above or a pharmaceutically acceptable salt thereof is a daily dosage. In some embodiments of the present application, the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is a once-daily dose.
  • the above-mentioned pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises a daily dose of the compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof includes each dose of the compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the compound of formula (II) above or a pharmaceutically acceptable salt thereof is administered once a day.
  • the pharmaceutical composition of the compound of formula (II) above or a pharmaceutically acceptable salt thereof is suitable for daily administration. In some embodiments of the present application, the pharmaceutical composition of the compound of formula (II) above or a pharmaceutically acceptable salt thereof is suitable for once-daily administration.
  • the pharmaceutical composition of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof is a once-daily dose, and each dose is a single dose or multiple doses respectively.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is a single-dose or multi-dose pharmaceutical composition, suitable for administration once a day.
  • the pharmaceutical composition of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof is a once-daily dose, and each dose is multiple doses, which consists of a single dose of 25 mg and/or 100 mg. It consists of a compound of formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments of the present application, the pharmaceutical composition consists of a single dose of 100 mg of a compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition suitable for administration once a day, and the multi-dose pharmaceutical composition is composed of A single-dose pharmaceutical composition consisting of 25 mg and/or 100 mg of a compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the multi-dose pharmaceutical composition consists of a single-dose pharmaceutical composition comprising 100 mg of a compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is packaged in a kit, which further contains the compound of formula (II) or a pharmaceutically acceptable salt thereof. Illustration of receiving salt for the treatment of prostate cancer in a patient.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is packaged in a kit, which further contains the compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • Accepted salts are used to treat prostate cancer in patients, the instructions include a treatment cycle of 28 days, and continuous administration of the compound of formula (II) above or a pharmaceutically acceptable compound thereof on days 1 to 28 of each cycle Pharmaceutical compositions of salts.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is packaged in a kit, which further contains the compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • Accepted salts are used to treat prostate cancer in patients, the instructions include a 28-day treatment cycle, and continuous once-daily administration of the compound of formula (II) above or a pharmaceutically acceptable compound thereof on days 1 to 28 of each cycle.
  • Pharmaceutical compositions of accepted salts are used to treat prostate cancer in patients, the instructions include a 28-day treatment cycle, and continuous once-daily administration of the compound of formula (II) above or a pharmaceutically acceptable compound thereof on days 1 to 28 of each cycle.
  • the pharmaceutical composition of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof is packaged in a kit, and the kit contains 1 day, 2 days, 3 days, 4 days , 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st
  • the pharmaceutical composition of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof is packaged in a kit, and the kit contains 1 day, 2 days, 3 days, 4 days , 5-day, 6-day, 7-day, 14-day, 21-day, or 28-day dosage, or the dosage of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof or a drug thereof within a range consisting of any of the foregoing values as endpoints combination.
  • the pharmaceutical composition of the above-mentioned compound of formula (II) or a pharmaceutically acceptable salt thereof is packaged in a kit containing a daily dose of 25 mg to 500 mg of the above-mentioned formula (II).
  • the kit contains a daily dose selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg , 450mg, 475mg or 500mg, or a range composed of any of the foregoing values as endpoints or any value therein, such as 25mg to 500mg, 25mg to 400mg, 25mg to 300mg, 50mg to 300mg, 75mg to 300mg, 100mg to 300mg, 150mg to 300mg , 200 mg to 300 mg, etc.
  • a daily dose selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg , 450mg,
  • the kit contains a daily dose selected from 100 mg to 300 mg, 150 mg to 300 mg, 200 mg to 300 mg of the above compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some specific embodiments, the kit contains a daily dose selected from 100 mg, 150 mg, 200 mg, 300 mg of the above compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the pharmaceutical composition of the compound of formula (II) above or a pharmaceutically acceptable salt thereof is a daily dose, which is administered as follows: Drug: The pharmaceutical composition of the compound of formula (II) or its pharmaceutically acceptable salt is administered once or twice daily. In some protocols of the present application, the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments of the present application, the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is orally administered once a day on an empty stomach.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises a daily dose of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition is administered once a day on an empty stomach.
  • 28 days constitute a treatment cycle
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is continuously administered on days 1-28 of each cycle.
  • 28 days constitute a treatment cycle
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered once daily continuously on days 1-28 of each cycle.
  • 28 days constitute a treatment cycle
  • the total dosage of the pharmaceutical composition of the above-mentioned compound of formula (II) or its pharmaceutically acceptable salt administered in each treatment cycle is 700 to 14000 mg (based on the active ingredient).
  • Compound of formula (II) itself the total dosage of the pharmaceutical composition of the above-mentioned compound of formula (II) or its pharmaceutically acceptable salt is selected from 2800 to 8400 mg (based on the active ingredient compound of formula (II) itself).
  • the total dosage of the pharmaceutical composition of the compound of formula (II) or its pharmaceutically acceptable salt is selected from the range formed by 2800 mg, 4200 mg, 5600 mg, 7000 mg, 8400 mg or any two of the above values. (Based on the active ingredient formula (II) compound itself). In some aspects of the present application, the total dosage of the pharmaceutical composition of the above-mentioned compound of formula (II) or its pharmaceutically acceptable salt is preferably 5600 to 8400 mg (based on the active ingredient compound of formula (II) itself).
  • the above treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof can be formulated into a preparation form suitable for oral administration to humans, such as, but not limited to, tablets, pills , capsules, powders or granules, etc.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is an oral tablet.
  • the single dose strength of the oral tablet of the compound of formula (II) or a pharmaceutically acceptable salt thereof is 25 mg or 100 mg.
  • the present application provides a pharmaceutical combination comprising a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, abiraterone acetate and prednisone or prednisolone,
  • the present application provides a pharmaceutical combination for treating prostate cancer in a patient, which includes a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, abiraterone acetate and prednisone or prednisone. Nylon.
  • the pharmaceutical combination is packaged in the same kit, which further contains a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, abiraterone acetate Instructions for use with prednisone or prednisolone to treat or prevent prostate cancer.
  • the pharmaceutical combination includes: a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical combination of abiraterone acetate and prednisone or prednisolone things.
  • the pharmaceutical combination includes: a pharmaceutical composition of a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of abiraterone acetate and prednisone or pharmaceutical compositions of prednisolone.
  • the pharmaceutical combination is packaged in the same kit, which further includes a pharmaceutical composition of a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, Instructions for the combined use of pharmaceutical compositions of abiraterone acetate and prednisone or prednisolone to treat prostate cancer in a patient.
  • the pharmaceutical combination is packaged in the same kit, which further includes a pharmaceutical composition of a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, Instructions for using a pharmaceutical composition of abiraterone acetate in combination with a pharmaceutical composition of prednisone or prednisolone to treat prostate cancer in a patient.
  • the present application provides a method for treating prostate cancer in a patient, comprising administering to the patient an effective amount of a pharmaceutical combination as described above.
  • the present application provides the use of a pharmaceutical combination as described above in the preparation of a medicament for treating prostate cancer in a patient.
  • the present application provides the use of a pharmaceutical combination as described above in a medicament for treating prostate cancer in a patient.
  • the pharmaceutical combination, the compound of formula (I) is a compound of formula (II), and the compound of formula (II) is:
  • the pharmaceutical combination, the compound of formula (I), its isomer or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of the compound of formula (II).
  • the pharmaceutical combination, the pharmaceutically acceptable salt of the compound of formula (II) is a hydrochloride, for example Monohydrochloride salt of the compound of formula (II).
  • the pharmaceutical combination contains 25 mg to 500 mg, 25 mg to 400 mg, 25 mg to 300 mg, 50 mg to 300 mg, 75 mg to 300 mg, 100 mg to 300 mg, 150 mg to 300 mg or 200 mg to 300 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains 100 mg to 300 mg, 150 mg to 300 mg, or 200 mg to 300 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, or its Pharmaceutical compositions.
  • the pharmaceutical combination contains 200 to 300 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg or 500 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg or 300 mg of the compound of formula (II) or a pharmaceutically acceptable compound thereof. Acceptable salts, or pharmaceutical compositions thereof.
  • the pharmaceutical combination contains 100 mg, 150 mg, 200 mg or 300 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the pharmaceutical combination contains 200 mg or 300 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof in a single dose or multiple dose form. In some embodiments of the present application, in the pharmaceutical combination, the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is in a multi-dose form.
  • the pharmaceutical combination contains a daily dose of the compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination contains the compound of formula (II) or a pharmaceutically acceptable salt thereof per dose. In some embodiments of the present application, in the pharmaceutical combination, the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered once daily.
  • the pharmaceutical combination contains a compound of formula (II) or a pharmaceutically acceptable salt thereof in a once-daily dose.
  • the content of the compound of formula (II) or a pharmaceutically acceptable salt thereof is one dose per day, and each dose is a single dose or multiple doses, usually multiple doses. dose.
  • the pharmaceutical combination contains a pharmaceutical composition containing a single dose of 25 mg and/or 100 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (II).
  • the pharmaceutical combination is in the form of a single-administration preparation, and the pharmaceutical combination contains 25 mg and/or 100 mg of a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical combination thereof calculated as a compound of formula (II). things.
  • the pharmaceutical combination contains a pharmaceutical composition in which a single dose of the compound of formula (II) or a pharmaceutically acceptable salt thereof is 100 mg calculated as the compound of formula (II).
  • the pharmaceutical combination is in the form of a single administration preparation, and the pharmaceutical combination contains 100 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, calculated as the compound of formula (II).
  • the pharmaceutical composition containing the compound of formula (II) or a pharmaceutically acceptable salt thereof is packaged in a kit, and the kit also contains the compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • kit also contains the compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the daily dose of abiraterone acetate is selected from 250 mg to 1500 mg, 250 mg to 1250 mg, 250 mg to 1000 mg, or 500 mg to 1000 mg. In some embodiments of the present application, the daily dose of abiraterone acetate is selected from 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg or 1500 mg. In some embodiments of the present application, the daily dose of abiraterone acetate is selected from 500 mg, 750 mg, or 1000 mg. In some embodiments of the present application, the daily dose of abiraterone acetate is selected from 1000 mg.
  • each dose of abiraterone acetate is selected from 250 mg to 1500 mg, 250 mg to 1250 mg, 250 mg to 1000 mg, or 500 mg to 1000 mg. In some embodiments of the present application, each dose of abiraterone acetate is selected from 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg or 1500 mg. In some embodiments of the present application, each dose of abiraterone acetate is selected from 500 mg, 750 mg, or 1000 mg. In some embodiments of the present application, each dose of abiraterone acetate is selected from 1000 mg.
  • the pharmaceutical composition of abiraterone acetate is a daily dose.
  • the pharmaceutical composition of abiraterone acetate includes a daily dose of abiraterone acetate.
  • the pharmaceutical composition of abiraterone acetate is a once-daily dose.
  • the pharmaceutical composition of abiraterone acetate includes each dose of abiraterone acetate and is administered once a day.
  • the pharmaceutical combination contains 250 mg to 1500 mg, 250 mg to 1250 mg, 250 mg to 1000 mg, or 500 mg to 1000 mg of abiraterone acetate or a pharmaceutical composition thereof (calculated as abiraterone acetate).
  • the pharmaceutical combination contains 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg or 1500 mg of abiraterone acetate or a pharmaceutical composition thereof (calculated as abiraterone acetate).
  • the pharmaceutical combination contains 500 mg, 750 mg or 1000 mg of abiraterone acetate or a pharmaceutical composition thereof (calculated as abiraterone acetate).
  • the pharmaceutical combination contains 1000 mg of abiraterone acetate or a pharmaceutical composition thereof (calculated as abiraterone acetate).
  • the pharmaceutical composition of abiraterone acetate is in a single dose or multiple dose form.
  • the pharmaceutical composition of abiraterone acetate is in a multi-dose form.
  • the pharmaceutical composition contains a single dose of 250 mg of abiraterone acetate.
  • the pharmaceutical combination is in the form of a single administration formulation, the pharmaceutical combination containing 250 mg of abiraterone acetate or a pharmaceutical composition thereof.
  • the multi-dose pharmaceutical composition of abiraterone acetate consists of a single-dose pharmaceutical composition containing 250 mg or 500 mg of abiraterone acetate.
  • the multi-dose pharmaceutical composition of abiraterone acetate consists of a single-dose pharmaceutical composition containing 250 mg of abiraterone acetate.
  • the pharmaceutical composition of abiraterone acetate is packaged in a kit, and the kit further contains instructions for using abiraterone acetate to treat prostate cancer in patients.
  • the instructions may be instructions in the drug instructions of commercially available abiraterone acetate tablets.
  • the description is abiraterone acetate tablets produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (such as ) in the drug package insert.
  • the daily dose of prednisone or prednisolone is selected from 5 mg to 40 mg, 5 mg to 35 mg, 5 mg to 20 mg, or 10 mg to 20 mg. In some embodiments of the present application, the daily dose of prednisone or prednisolone is selected from 5 mg to 20 mg or 10 mg to 20 mg. In some embodiments of the present application, the daily dose of prednisone or prednisolone is selected from 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments of the present application, the daily dose of prednisone or prednisolone is selected from 10 mg or 20 mg.
  • each dose of prednisone or prednisolone is selected from 5 mg to 40 mg, 5 mg to 35 mg, 5 mg to 20 mg, or 10 mg to 20 mg. In some embodiments of the present application, each dose of prednisone or prednisolone is selected from 5 mg to 20 mg or 10 mg to 20 mg. In some embodiments of the present application, each dose of prednisone or prednisolone is selected from 5 mg, 10 mg, 15 mg, or 20 mg. In some embodiments of the present application, each dose of prednisone or prednisolone is selected from 5 mg or 10 mg.
  • the pharmaceutical composition of prednisone or prednisolone is a daily dose.
  • the pharmaceutical composition of prednisone or prednisolone includes a daily dose of prednisone or prednisolone.
  • the pharmaceutical composition of prednisone or prednisolone is a twice daily dose.
  • the pharmaceutical composition of prednisone or prednisolone includes each dose of prednisone or prednisolone administered twice daily.
  • the pharmaceutical combination contains 5 mg to 40 mg, 5 mg to 35 mg, 5 mg to 20 mg or 10 mg to 20 mg of prednisone or prednisolone or a pharmaceutical composition thereof (prednisone or prednisolone). Nylon meter).
  • the pharmaceutical combination contains 5 mg to 20 mg or 10 mg to 20 mg of prednisone or prednisolone or a pharmaceutical composition thereof (calculated as prednisone or prednisolone).
  • the pharmaceutical combination contains 5 mg, 10 mg, 15 mg or 20 mg of prednisone or prednisolone or a pharmaceutical composition thereof (calculated as prednisone or prednisolone).
  • the pharmaceutical combination contains 10 mg or 20 mg of prednisone or prednisolone or a pharmaceutical composition thereof (calculated as prednisone or prednisolone).
  • the pharmaceutical combination, the pharmaceutical composition of prednisone or prednisolone is in a single dose or multiple dose form.
  • the pharmaceutical combination, the pharmaceutical composition of prednisone or prednisolone is in a multiple dose form.
  • the multi-dose pharmaceutical composition of prednisone or prednisolone consists of a single-dose pharmaceutical composition containing 5 mg of prednisone or prednisolone.
  • the pharmaceutical composition contains a single dose of 5 mg of prednisone or prednisolone.
  • the pharmaceutical combination is in the form of a single administration preparation, the pharmaceutical combination containing 5 mg of prednisone or prednisolone or a pharmaceutical composition thereof (calculated as prednisone or prednisolone).
  • the pharmaceutical composition containing prednisone or prednisolone is packaged in a kit, and the kit also contains prednisone or prednisolone. Illustration of Dragon's use to treat patients with prostate cancer.
  • the instructions may be instructions in the drug instructions of commercially available prednisone tablets or prednisolone tablets.
  • the pharmaceutical combination contains 25 mg to 500 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, 250 mg to 1500 mg of abiraterone acetate, and 5mg to 40mg of prednisone or prednisolone.
  • the pharmaceutical combination contains 100 mg to 300 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, 250 mg to 1000 mg of abiraterone acetate, and 5mg to 20mg of prednisone or prednisolone.
  • the pharmaceutical combination contains: a daily dose of 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg or 300 mg of the compound of formula (II) calculated as the compound of formula (II) or a pharmaceutically acceptable salt thereof and a daily dose of abiraterone acetate of 500 mg, 750 mg or 1000 mg, and a daily dose of prednisone or prednisolone of 5 mg, 10 mg, 15 mg or 20 mg.
  • the pharmaceutical combination contains: a daily dose of 100 mg, 150 mg, 200 mg or 300 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, 1000 mg A daily dose of abiraterone acetate, and a daily dose of 10 mg or 20 mg of prednisone or prednisolone.
  • the pharmaceutical combination contains: a daily dose of 200 mg or 300 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, a daily dose of 1000 mg calculated as the compound of formula (II) of abiraterone acetate, and a daily dose of 10 mg of prednisone or prednisolone.
  • the pharmaceutical combination contains: a daily dose of 300 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof, and a daily dose of 1000 mg of acetic acid.
  • a treatment cycle is every 28 days.
  • the pharmaceutical combination contains: a pharmaceutical composition of a compound of formula (II) or a pharmaceutically acceptable salt thereof in a single dose of 25 mg and/or 100 mg calculated as the compound of formula (II), A pharmaceutical composition of abiraterone acetate in a single dose of 250 mg, and a pharmaceutical combination of prednisone or prednisolone in a single dose of 5 mg, respectively, based on prednisone or prednisolone. things.
  • the pharmaceutical combination is in the form of a single administration preparation, and the pharmaceutical combination contains: 25 mg and/or 100 mg based on the compound of formula (II) A compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, 250 mg of abiraterone acetate or a pharmaceutical composition thereof, calculated as abiraterone acetate, and prednisone or prednisolone respectively Counted as 5 mg of prednisone or prednisolone or pharmaceutical compositions thereof.
  • the pharmaceutical combination contains: a single dose of 100 mg of a pharmaceutical composition of a compound of formula (II) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II), a pharmaceutical composition of abirate acetate
  • the pharmaceutical combination is in the form of a single-administration preparation, and the pharmaceutical combination contains: 25 mg or 100 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof calculated as the compound of formula (II). , 250 mg of abiraterone acetate or a pharmaceutical composition thereof, and 5 mg of prednisone or prednisolone or a pharmaceutical composition thereof, respectively, calculated as prednisone or prednisolone.
  • the pharmaceutical combination is a formulation suitable for administration within a single treatment cycle (eg, a treatment cycle of 28 days), the formulation comprising: a total dose of a compound of formula ⁇ (II)
  • the pharmaceutical combination is a formulation suitable for administration within a single treatment cycle (eg, a treatment cycle of 28 days), the formulation comprising: a total dose of a compound of formula (II) of 5600 mg or 8400 mg of a pharmaceutical composition containing a compound of formula (II) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing abiraterone acetate with a total dose of 28000 mg based on abiraterone acetate, and prednisolone acetate respectively.
  • the pharmaceutical combination is a formulation suitable for administration within a single treatment cycle (eg, a treatment cycle of 28 days), the formulation comprising: a total dose of a compound of formula (II) of 8400 mg of a pharmaceutical composition containing a compound of formula (II) or a pharmaceutically acceptable salt thereof, a total dose of 28000 mg of abiraterone acetate-containing pharmaceutical composition, and respectively prednisone or The total dose of prednisolone is 280 mg of a pharmaceutical composition containing prednisone or prednisolone.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof, abiraterone acetate, and prednisone or prednisolone can be in a pharmaceutical combination respectively. drug form or together in the form of a pharmaceutical composition.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof, abiraterone acetate, and prednisone or prednisolone are a fixed combination or a non- Fixed combination.
  • the present application also provides a kit, which contains (a) a first pharmaceutical composition, which contains the compound of formula (II) described in the present application or a pharmaceutically acceptable salt thereof; (b) a second pharmaceutical composition. a pharmaceutical composition containing abiraterone acetate; and (c) a third pharmaceutical composition containing prednisone or prednisolone.
  • the present application also provides a kit of pharmaceutical compositions for treating prostate cancer in patients, which contains (a) a first pharmaceutical composition containing the compound of formula (II) described in the present application or its a pharmaceutically acceptable salt; (b) a second pharmaceutical composition containing abiraterone acetate; and (c) a third pharmaceutical composition containing prednisone or prednisolone.
  • this application also provides a pharmaceutical combination for treating prostate cancer in patients, which contains: a pharmaceutical composition of a compound of formula (II) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of abiraterone acetate, and Pharmaceutical compositions of prednisone or prednisolone.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation, which contains 25 mg or 100 mg of the compound of formula (I).
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation, which contains 100 mg of the compound of formula (I).
  • the present application also provides a method of treating prostate cancer in a patient, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, abiraterone acetate, and prednisolone. pine or prednisolone, for example, to an individual in need thereof a therapeutically effective amount of a pharmaceutical combination described herein above.
  • the present application also provides a combination therapy for treating an individual suffering from prostate cancer, the method comprising separately administering to the individual a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof and the administration of a therapeutically effective amount of abiraterone acetate alone, and the administration of a therapeutically effective amount of prednisone or prednisolone alone.
  • the present application also provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in combination with abiraterone acetate and prednisone or prednisolone in the preparation of a medicament for treating prostate cancer in patients , for example, the use of the above-mentioned drug combination in the present application in preparing drugs for treating prostate cancer in patients.
  • the pharmaceutical combination is any of the pharmaceutical combinations described above in the present application.
  • this application also provides the use of the compound of formula (II) or a pharmaceutically acceptable salt thereof in combination with abiraterone acetate and prednisone or prednisolone for treating prostate cancer in patients, such as the above-mentioned Use of the drug combination to treat prostate cancer in a patient.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof, abiraterone acetate and prednisone or prednisolone in the kit, method, combination therapy or use, the compound of formula (II) or a pharmaceutically acceptable salt thereof, abiraterone acetate and prednisone or prednisolone
  • prednisolone are the same as those of the compound of formula (II) or its pharmaceutically acceptable salt, abiraterone acetate and prednisone or prednisolone in the pharmaceutical combination described above, such as content, dosage, and form of existence , packaging form, etc.
  • each of the compound of formula (II) or a pharmaceutically acceptable salt thereof, abiraterone acetate and prednisone or prednisolone in the form of pharmaceutical compositions, they can be administered simultaneously, separately, concurrently, sequentially or at intervals.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof, abiraterone acetate and prednisone or prednisolone respectively with the same or different treatment cycles.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof, abiraterone acetate and prednisone or prednisone Dragons have the same treatment cycle, such as every 1 week, every 2 weeks, every 3 weeks or every 4 weeks. Preferably, every 4 weeks is a treatment cycle.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is present in a daily dose by Administration:
  • the compound of formula (II) or its pharmaceutically acceptable salt is administered once daily.
  • the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is a daily dose, wherein the compound of formula (II) ) compound or a pharmaceutically acceptable salt thereof is administered in a single dose or a multiple dose manner, usually in a multiple dose manner; further, wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered in a multiple dose manner each time Dosage once daily.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered by: a daily dose of 100 mg; or, every The daily dose is 150 mg; alternatively, the daily dose is 200 mg; or the daily dose is 300 mg.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered by: a daily dose of 200 mg; or, every The daily dose is 300mg.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered by: a daily dose of 300 mg.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is administered in multiple doses, the multiple doses A pharmaceutical composition consisting of a single dose of 25 mg and/or 100 mg of a compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered as a continuous daily administration.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is administered in multiple doses, the multiple doses A pharmaceutical composition consisting of a single dose of 100 mg of a compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered as a continuous daily administration.
  • the amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is a dose per treatment cycle, which Administration is by daily administration of a compound of formula (II) or its Pharmaceutically acceptable salt.
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof is prepared in a single aliquot or multiple aliquots (for example, 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more). equal parts) for packaging.
  • the content of abiraterone acetate in the pharmaceutical combination is a daily dose, which is administered in the following manner: abiraterone acetate daily Administer once.
  • the content of abiraterone acetate in the pharmaceutical combination is a daily dose, wherein abiraterone acetate is administered in a single dose or in multiple doses.
  • the drug is usually administered in multiple doses; further, abiraterone acetate is administered once a day in multiple doses.
  • the abiraterone acetate in the method, combination therapy or use, is administered by: a daily dose of 250 mg; alternatively, a daily dose of 500 mg; alternatively, daily The dose is 750mg; or the daily dose is 1000mg.
  • the abiraterone acetate in the method, combination therapy or use, is administered as follows: a daily dose of 500 mg; alternatively, a daily dose of 1000 mg.
  • the abiraterone acetate in the method, combination therapy or use, is administered in a daily dose of 1000 mg.
  • the abiraterone acetate in the pharmaceutical combination is administered in multiple doses, the multiple doses consist of a single dose of 250 mg of abiraterone acetate.
  • the pharmaceutical composition of Dragon consists of.
  • the abiraterone acetate is administered as a continuous daily administration.
  • the amount of abiraterone acetate in the pharmaceutical combination is a dose per treatment cycle, which is administered by: daily administration of acetate Abiraterone.
  • abiraterone acetate is packaged in single equal portions or multiple equal portions (eg, 2 equal portions, 4 equal portions, 7 equal portions, 14 equal portions, 28 equal portions or more).
  • the amount of prednisone or prednisolone in the pharmaceutical combination is a daily dose, which is administered by: Prednisolone pine or prednisolone administered twice daily.
  • the amount of prednisone or prednisolone in the pharmaceutical combination is a daily dose, wherein the prednisone or prednisolone It is administered in a single dose or multiple doses, usually in a single dose; further, wherein the prednisone or prednisolone is administered twice a day in a single dose.
  • the prednisone or prednisolone is administered by: a daily dose of 10 mg; alternatively, a daily dose of 20 mg.
  • the prednisone or prednisolone is administered in a daily dose of 10 mg.
  • the prednisone or prednisolone in the pharmaceutical combination is administered in multiple doses, the multiple doses starting from a single dose of 5 mg A pharmaceutical composition consisting of prednisone or prednisolone.
  • the prednisone or prednisolone is administered as a continuous daily administration.
  • the amount of prednisone or prednisolone in the pharmaceutical combination is a dose per treatment cycle, which is administered as follows : Administer prednisone or prednisolone daily. Wherein, prednisone or prednisolone is packaged in single aliquots or multiple aliquots (such as 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more) .
  • 28 days is a treatment cycle
  • administration is once a day
  • administration is continuous for 28 days
  • each treatment cycle is administered containing the formula (II ) compound or a pharmaceutically acceptable salt thereof
  • the total dosage of the pharmaceutical composition is 2800 to 8400 mg.
  • the total dosage of the pharmaceutical composition containing the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from the group consisting of 2800 mg, 4200 mg, 5600 mg, 7000 mg or 8400 mg or any two of the above values. scope.
  • the total dosage of the pharmaceutical composition containing the compound of formula (II) or a pharmaceutically acceptable salt thereof is preferably 5600 mg or 8400 mg.
  • the total dosage of the pharmaceutical composition containing the compound of formula (II) or a pharmaceutically acceptable salt thereof is preferably 8400 mg.
  • a 28-day treatment cycle is administered once a day for 28 consecutive days, and a drug containing abiraterone acetate is administered for each treatment cycle.
  • the total dosage of the pharmaceutical composition is 7000 to 28000 mg. in part In embodiments, the total dosage of the pharmaceutical composition containing abiraterone acetate is selected from the range of 7000 mg, 14000 mg, 21000 mg or 28000 mg or any two of the above values. In some embodiments, the total dosage of the pharmaceutical composition containing abiraterone acetate is preferably 21000 mg or 28000 mg. In some embodiments, the total dosage of the pharmaceutical composition containing abiraterone acetate is preferably 28,000 mg.
  • a 28-day treatment cycle is administered twice a day for 28 consecutive days, and each treatment cycle is administered with prednisone or prednisone.
  • the total dosage of the pharmaceutical composition of nisolone is 140 to 560 mg. In some embodiments, the total dosage of the pharmaceutical composition containing prednisone or prednisolone is selected from 140 mg, 280 mg or 560 mg or the range formed by any two of the above values. In some embodiments, the total dosage of the pharmaceutical composition containing prednisone or prednisolone is preferably 280 mg or 560 mg. In some embodiments, the total dosage of the pharmaceutical composition containing prednisone or prednisolone is preferably 280 mg.
  • 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered daily 1 time, continuous administration for 28 days, the total dosage of the pharmaceutical composition containing the compound of formula (II) or its pharmaceutically acceptable salt administered in each treatment cycle is 5600 mg or 8400 mg; abiraterone acetate is administered daily for 1 times, for 28 consecutive days, and the total dose of the pharmaceutical composition containing abiraterone acetate in each treatment cycle is 28,000 mg; prednisone or prednisolone is administered twice a day, for 28 consecutive days, each The total dose of the pharmaceutical composition containing prednisone or prednisolone administered during the treatment cycle is 280 mg.
  • the above treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.
  • the prednisone in the pharmaceutical combination, can also be replaced by prednisone acetate.
  • the prednisolone in the pharmaceutical combination, can also be replaced by prednisolone acetate.
  • the prostate cancer is selected from prostate adenocarcinoma.
  • the prostate adenocarcinoma is selected from the group consisting of acinar adenocarcinoma, atrophic adenocarcinoma, microcystic adenocarcinoma, foamy adenocarcinoma, mucinous (colloid) adenocarcinoma, signet ring adenocarcinoma Adenocarcinoma, pleomorphic giant cell adenocarcinoma, and sarcomatoid carcinoma.
  • the prostate glandular tumor is selected from alveolar adenocarcinoma.
  • the prostate cancer is selected from castration-resistant prostate cancer.
  • the prostate cancer is selected from metastatic castration-resistant prostate cancer.
  • the prostate cancer is selected from metastatic castration-resistant prostate cancer with homologous recombination repair (HRR) gene mutations.
  • HRR homologous recombination repair
  • the prostate cancer is selected from metastatic castration-resistant prostate adenocarcinoma.
  • the metastatic castration-resistant prostate cancer is metastatic disease confirmed by imaging (such as bone scan and CT/MRI) or has metastatic lesions confirmed by imaging (such as bone scan and CT/MRI).
  • the metastatic castration-resistant prostate cancer is prostate cancer that progresses despite receiving castration therapy.
  • the disease progression refers to at least two consecutive increases in PSA values separated by at least one week, and/or disease progression as assessed by RECIST 1.1, and/or bone disease progression as assessed by PCWG3.
  • the disease progression refers to at least two consecutive increases in PSA values separated by at least one week, the last of which is at least 1.0 ng/mL, and/or disease progression as assessed by RECIST 1.1, and /or Bone disease progression as assessed by PCWG3, which includes ⁇ 2 new bone lesions found on bone scan and ⁇ 2 new bone lesions found on bone scan at least 8 weeks later than the last new bone lesions assessed lesions, and ⁇ 2 new bone lesions last time persist this time.
  • the castration treatment includes surgical treatment, radiotherapy castration treatment and medical castration treatment;
  • the surgical treatment refers to bilateral orchiectomy treatment;
  • the medical castration treatment includes docetaxel, cabazide Enzalutamide, revealutamide, ceproterbol acetate, finasteride, abiraterone acetate, dexamethasone, flutamide, nilutamide, bicalutamide, diethylstilbestrol , megestrol acetate, fosbestrol, estramustine phosphate, triptorelin, leuprorelin, goserelin, histaminerelin, buserelin, abrex, degarelix or any combination of one or more of Cetrorelix.
  • the medical castration treatment includes triptorelin, Treatment with any combination of one or more of leuprolide, goserelin, abrumab, degarelix, or cetrorelix. In some embodiments of the present application, the medical castration treatment includes triptorelin, leuprolide or goserelin treatment. In some embodiments of the present application, the medical castration treatment includes abrake, degarelix, or cetrorelix treatment. In some embodiments of the present application, the medical castration treatment includes flutamide, nilutamide, or bicalutamide treatment. In some embodiments of the present application, the medical castration treatment includes degarelix or/and goserelin treatment.
  • the medical castration treatment includes bicalutamide or/and goserelin treatment. In some embodiments of the present application, the medical castration treatment includes bicalutamide or/and triptorelin treatment. In some embodiments of the present application, the medical castration treatment includes any combination of one or more drugs selected from bicalutamide, leuprolide or goserelin. In some embodiments of the present application, the medical castration treatment includes abiraterone acetate or/and enzalutamide treatment. In some embodiments of the present application, the medical castration treatment includes abiraterone acetate or/and bicalutamide treatment.
  • the metastatic castration-resistant prostate cancer is prostate cancer that has progressed after prior treatment with enzalutamide and/or abiraterone acetate.
  • the patient with metastatic castration-resistant prostate cancer has a serum testosterone level ⁇ 1.73 nmol/L (50 ng/dL).
  • the metastatic castration-resistant prostate cancer is a patient treated without surgical castration, and the patient continues to use androgen deprivation therapy (ADT), and the androgen deprivation therapy (ADT ) includes triptorelin, leuprolide or goserelin treatment.
  • ADT androgen deprivation therapy
  • the metastatic castration-resistant prostate cancer is a patient treated without surgical castration, and the patient continues to use androgen deprivation therapy (ADT), and the androgen deprivation therapy (ADT ) includes treatment with abrumab, degarelix, or cetrorelix.
  • ADT androgen deprivation therapy
  • the metastatic castration-resistant prostate cancer is a patient treated with surgical castration.
  • the metastatic castration-resistant prostate cancer is in a patient who has terminated all previous cancer treatments (except androgen deprivation therapy (ADT) and bone loss preventive therapy).
  • ADT androgen deprivation therapy
  • the active components in the pharmaceutical combination of the present application may be each independently formulated, or part or all of them may be formulated together with pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical combinations of the present application may also contain additional therapeutic agents.
  • the additional therapeutic agent may be a therapeutic agent known in the art for cancer, preferably for prostate cancer.
  • the compound of formula (II) of the present application can be administered in the form of its free base, or in the form of its pharmaceutically acceptable salts, hydrates and prodrugs, and the prodrug is converted into the compound of formula (II) in the body form.
  • pharmaceutically acceptable salts of compounds of formula (II) are within the scope of the present application and can be produced from various organic and inorganic acids according to methods well known in the art.
  • the molar ratio of the compound of formula (II) to the acid ion forming the pharmaceutically acceptable salt may be 1:1.
  • the pharmaceutically acceptable salt of the compound of formula (II) can be the hydrochloride salt of the compound of formula (II) (for example, the monohydrochloride salt of the compound of formula (II)), and the monohydrochloride structure of the compound of formula (II) As shown in the compound of formula (II-1),
  • the pharmaceutically acceptable salt of the compound of formula (II) exists in the form of a compound of formula (II-1).
  • the compound of formula (II-1) is in crystalline form.
  • the compound of formula (II-1) is in an amorphous form.
  • the compound of formula (II) or the compound of formula (II-1) or the crystal of the compound of formula (II-1) used in the present application can be prepared by methods in the prior art, for example, by referring to the method of WO2022022664.
  • compositions of compounds of formula (II) or pharmaceutically acceptable salts thereof are provided.
  • the single dose of the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is 25 mg or 100 mg based on the compound of formula (II).
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation, which contains 25 mg or 100 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof. Acceptable salt.
  • the single dose of the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is 100 mg based on the compound of formula (II).
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation, which contains 100 mg of the compound of formula (II) or a pharmaceutically acceptable salt thereof. of salt.
  • the method of administration can be comprehensively determined based on the activity, toxicity and patient tolerance of the drug.
  • the pharmaceutical composition containing the compound of formula (II) or a pharmaceutically acceptable salt thereof also contains pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc.
  • the pharmaceutical compositions include, but are not limited to, formulations suitable for oral, parenteral, and topical administration.
  • the pharmaceutical composition is a formulation suitable for oral administration.
  • the pharmaceutical composition is a solid formulation suitable for oral administration.
  • the pharmaceutical compositions include, but are not limited to, tablets and capsules.
  • the pharmaceutical composition is a solid pharmaceutical composition.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition containing the compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is a tablet containing the compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or The core of the sugar coating.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • Abiraterone acetate 17-(3-pyridyl)androst-5,16-diene-3 ⁇ -acetate, which has the following formula (III) compound: Structural formula:
  • the pharmaceutical composition of abiraterone acetate further contains pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, water for injection, etc.
  • the pharmaceutical composition is a solid pharmaceutical composition.
  • the pharmaceutical composition is a tablet.
  • the single dose of the pharmaceutical composition of abiraterone acetate is 250 mg.
  • Abiraterone acetate tablets used in this application can be obtained commercially, such as abiraterone acetate tablets produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (eg ).
  • Prednisone is 17 ⁇ ,21-dihydroxypregnant-1,4-diene-3,11,20-trione, which has the following compound formula (IV): Structural formula:
  • prednisone acetate 17 ⁇ ,21-dihydroxypregnant-1,4-diene-3,11,20-trione 21-acetate, which has the following formula (V) compound The structural formula shown:
  • compositions of prednisone or prednisone acetate are provided.
  • the pharmaceutical composition of prednisone or prednisone acetate further contains pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, water for injection, etc.
  • the pharmaceutical composition is a solid pharmaceutical composition.
  • the pharmaceutical composition is a tablet.
  • the single dose of the pharmaceutical composition of prednisone or prednisone acetate is 5 mg.
  • prednisone tablets or prednisone acetate tablets used in this application are commercially available.
  • prednisolone 11 ⁇ ,17 ⁇ ,21-trihydroxypregnant-1,4-diene-3,20-dione, which has the following compound formula (VI): Structural formula:
  • prednisolone acetate 11 ⁇ ,17 ⁇ ,21-trihydroxypregnant-1,4-diene-3,20-dione 21-acetate, which has the following compound formula (VII) The structural formula shown:
  • compositions of prednisolone or prednisolone acetate are provided.
  • the pharmaceutical composition of prednisolone or prednisolone acetate further contains pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, water for injection, etc.
  • the pharmaceutical composition is a solid pharmaceutical composition.
  • the pharmaceutical composition is a tablet.
  • the single dose of the pharmaceutical composition of prednisolone or prednisolone acetate is 5 mg.
  • prednisolone tablets or prednisolone acetate tablets used in this application are commercially available.
  • the active ingredients in the pharmaceutical combinations of the present application may be administered individually, or part or all thereof, together, by any suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous way).
  • the active ingredients in the pharmaceutical combination of the present application may be administered orally independently, or part or all thereof may be administered orally together.
  • the active ingredients in the pharmaceutical combination of the present application may be each independently, or part or all of them together may be in suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral administration Dosage forms of sustained-release pharmaceutical preparations.
  • the compound of formula (II) of the present application or its pharmaceutically acceptable salt has the following effects whether used as a single active agent or in combination as a drug:
  • “clinical benefit” includes but is not limited to: the progression-free survival (PFS) of clinical patients is prolonged. , the overall survival (OS) is prolonged, the objective response rate (ORR) is improved, the disease control rate (DCR) is improved, the number and/or degree of adverse reactions are reduced, the distant metastasis rate and the local control rate are reduced, etc.
  • PFS progression-free survival
  • OS overall survival
  • ORR objective response rate
  • DCR disease control rate
  • the compound of formula (II) of the present application or its pharmaceutically acceptable salt, whether used as a single active agent or in combination with drugs, also has the following effects: a better PSA remission rate (PSA decreases by more than 50% of the baseline value and Percentage of subjects maintained for more than 4 weeks), prolongation of radiographic progression-free survival (rPFS), prolongation of time to PSA progression (time from first dose to confirmation of PSA progression), lymph node, soft tissue lesions, and Bone lesions take longer to progress.
  • PSA PSA decreases by more than 50% of the baseline value and Percentage of subjects maintained for more than 4 weeks
  • rPFS radiographic progression-free survival
  • time to PSA progression time from first dose to confirmation of PSA progression
  • lymph node lymph node
  • soft tissue lesions and Bone lesions take longer to progress.
  • pharmaceutical combination refers to two or more active ingredients administered simultaneously or sequentially (in the form of the respective active ingredients themselves, or as their respective pharmaceutically acceptable salts or esters and other derivatives, administered as prodrugs or compositions).
  • drug combination and “drug combination” are used interchangeably.
  • “combination” or “used in combination” means that two or more active substances may be administered to an individual simultaneously as a single entity or dosage form, or separately as separate entities or dosage forms simultaneously, concurrently, or in any Administer to individuals sequentially.
  • fixed combination means that the active ingredients, for example a compound of formula (II), abiraterone acetate and prednisone or prednisolone, are administered simultaneously to a patient in a single entity or dosage form.
  • non-fixed combination means that the active ingredients, for example a compound of formula (II), abiraterone acetate and prednisone or prednisolone, are administered in separate entities simultaneously, simultaneously or without time limits. Administer to patient in sequence.
  • patient or “individual/subject” refers to a mammal, such as a primate (human, macaque, chimpanzee, etc.), rodent (mouse, rat, rabbit, etc.), feline, canine Animals, etc., preferably humans.
  • a primate human, macaque, chimpanzee, etc.
  • rodent mouse, rat, rabbit, etc.
  • feline canine Animals, etc., preferably humans.
  • the patient and the individual are patients who have failed or are lacking standard treatments.
  • pharmaceutically acceptable refers to a carrier, excipient or excipient used in the preparation of a pharmaceutical composition that is generally safe, non-toxic and not bioavailable. Scientifically or otherwise undesirable, including acceptable use in human medicines.
  • terapéuticaally effective amount means an amount of a compound sufficient to effect treatment of a disease when administered to a human for the treatment of the disease.
  • treating means administering a compound or formulation described herein to ameliorate, alleviate, or eliminate a disease or one or more symptoms associated with said disease, and includes: (i) inhibiting a disease or disease state, i.e. To arrest or retard the progression of a disease or disease state; (ii) To alleviate a disease or disease state, i.e. to cause the disease or disease state to subside.
  • prevent means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such disease or condition is present in a mammal.
  • a mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • administration refers to the physical introduction of a composition containing a therapeutic agent to an individual using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral administration.
  • daily dose refers to the daily dose administered to a patient.
  • per dose refers to each dose administered to a patient.
  • single-dose pharmaceutical composition or "unit preparation” refers to the smallest packaging unit of a medicine containing a certain amount of active ingredients. For example, if a box of medicine contains seven capsules, then each capsule is a single-dose pharmaceutical composition or unit preparation; For example, if a box of medicine contains seven tablets, each tablet is a single-dose pharmaceutical composition or unit preparation.
  • single dose or "unit dose” refers to a single dose of a pharmaceutical composition or the amount of active ingredient contained in a unit preparation.
  • multiple dose pharmaceutical composition consists of a plurality of single dose pharmaceutical compositions or unit preparations.
  • multiple doses consists of a plurality of "single doses” or "unit doses”.
  • “combination” or “used in combination” means that two or more active substances may be administered to an individual simultaneously, each as a single formulation, in parallel, or each as a single formulation, sequentially in any order.
  • pharmaceutical combination means that two or more active substances may be administered together in a mixture, simultaneously as a single preparation, or sequentially in any order as a single preparation subjects.
  • composition refers to a mixture of one or more active ingredients of the present application or a pharmaceutical combination thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to an individual of a compound of the present application or a pharmaceutical combination thereof.
  • day When referring to a dosing regimen, the terms "day”, “daily” and the like refer to the time within a calendar day starting at midnight and ending at the next midnight.
  • metalstatic cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.
  • PSA prostate-specific antigen
  • rPFS radio-proliferative progression-free survival
  • 12-month rPFS rate refers to the percentage of subjects with rPFS of 12 months or more.
  • survival time refers to the time from first drug enrollment to death from all causes. For subjects who were still alive at the last follow-up, their OS was calculated based on the time of the last follow-up and the data was censored. For subjects who were lost to follow-up, their OS was calculated as the last confirmed survival time before being lost to follow-up as data censoring.
  • ORR objective response rate
  • DCR disease control rate
  • Disease response refers to subjects whose best response is CR or PR, defined as the time from the date of first documented tumor response to the date of first documented disease progression or death from any cause ( whichever occurs first).
  • CBR clinical benefit rate
  • PSA remission rate refers to the percentage of subjects whose PSA decreases by more than 50% of the baseline value and maintains it for more than 4 weeks.
  • time to PSA progression refers to the time from the first dose to confirmation of PSA progression.
  • PSA progression defined by PCWG3 standards is: for subjects who have a decrease of ⁇ 50% in PSA at 12 weeks of treatment, the PSA increases by more than 25% of the lowest value and the absolute value increases by ⁇ 2ng/mL compared with the lowest value, and after ⁇ 3 Confirmed by the second PSA test after 12 weeks of treatment; for subjects with PSA non-response at 12 weeks of treatment, the PSA rise exceeds 25% of the baseline and the absolute value increases ⁇ 2ng/mL compared with the baseline value, and the second PSA test after ⁇ 3 weeks Confirmed by a PSA test.
  • time to first symptomatic skeletal event is defined as the time from a random date to the first occurrence of SSE.
  • SSE includes the use of external beam radiation therapy (EBRT) to prevent or Relief of skeletal symptoms, development of new symptomatic pathological fractures (vertebral or non-vertebral), development of spinal cord compression, or tumor-related orthopedic surgical intervention, whichever occurs first.
  • EBRT external beam radiation therapy
  • Bone-related events include asymptomatic fractures identified by imaging and are usually assessed using SSE to consider clinical significance.
  • Cohort 1 is the compound of formula (II-1) alone treatment cohort
  • cohort 2 is the compound of formula (II-1), abiraterone acetate, and prednisolone acetate.
  • Nisone combination treatment cohort Both Cohort 1 and Cohort 2 enrolled subjects with metastatic castration-resistant prostate cancer and evaluated the compound of formula (II-1) alone, as well as the combination of compound of formula (II-1), abiraterone acetate, and prednisone acetate. Preliminary efficacy and safety of treatment.
  • Metastatic lesions confirmed by imaging studies (such as bone scan and CT/MRI);
  • At least 4 weeks must have passed from the use of 5-alpha reductase inhibitors (such as dutasteride, finasteride), estrogen and cyproterone to enrollment;
  • 5-alpha reductase inhibitors such as dutasteride, finasteride
  • estrogen and cyproterone to enrollment;
  • Tablets of compound of formula (II-1) specifications: 25 mg or 100 mg.
  • Tablets of compound of formula (II-1) 100 mg, 150 mg, 200 mg or 300 mg (based on compound of formula (II)), taken orally on an empty stomach, once a day, for 28 consecutive days as a treatment cycle.
  • Abiraterone acetate tablets 1000 mg (based on abiraterone acetate), administered orally on an empty stomach, once a day, for 28 consecutive days as a treatment cycle.
  • Prednisone acetate tablets 5 mg (calculated as prednisone acetate), administered orally after meals, twice a day, for 28 consecutive days as a treatment cycle. 1.4 Evaluation criteria
  • ⁇ Evaluation criteria Evaluate patient clinical benefit according to the recommendations of Prostate Cancer Clinical Trials Working Group 3 (PCWG3): evaluate lymph node and soft tissue disease progression according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1); according to PCWG3 "2+2" principle Evaluate Bone disease progression; PSA progression is evaluated according to the PCWG3 definition; when PSA progression occurs, imaging evaluation (lymph nodes, soft tissue lesions, and bone lesions) and clinical symptoms must be combined to comprehensively evaluate the patient's clinical benefit.
  • PCWG3 Prostate Cancer Clinical Trials Working Group 3
  • ⁇ Evaluation indicators include but are not limited to imaging progression-free survival (rPFS), 12-month rPFS rate, survival (OS), objective response rate (ORR), disease control rate (DCR), disease response time (DOR), Clinical benefit rate (CBR), PSA response rate, time to PSA progression, and time to first symptomatic bone-related event.
  • rPFS progression-free survival
  • OS survival
  • ORR objective response rate
  • DCR disease control rate
  • DOR disease response time
  • CBR Clinical benefit rate
  • PSA response rate time to PSA progression, and time to first symptomatic bone-related event.
  • NCI-CTC AE 5.0 standard is used to judge the severity of adverse events.
  • ⁇ Evaluation indicators include but are not limited to the time of occurrence, severity, correlation with study treatment, duration, measures taken and outcomes of adverse events.
  • Table 1 Enrolled patient information
  • N represents the number of participants; NED represents no evaluable lesions.

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Abstract

本申请属于医药技术领域，涉及吲哚并七元酰肟类似物的用途及其药物组合，具体涉及式(I)化合物的用途、式(I)化合物的药物组合及其用途。

Description

吲哚并七元酰肟类似物的用途及其药物组合
相关申请的交叉引用
本申请要求于2022年05月23日向中华人民共和国国家知识产权局提交的第202210562579.5号中国发明专利申请的权益和优先权，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请属于医药技术领域，涉及吲哚并七元酰肟类似物的用途及其药物组合，具体涉及式(I)化合物的用途、式(I)化合物的药物组合及其用途。
背景技术
PARP(ploy(ADP-ribose)polymerase)是一类聚ADP-核糖聚合酶，它是一个酶家族，可以用于催化ADP-核糖残基加到各种靶蛋白上。截至目前，已鉴定和表征了共18个亚型。尽管PARP家族的酶种类众多，但PARP-1负责了细胞内90％以上的ADP-核糖基化，所以PARP抑制剂研究主要集中在PARP-1抑制剂上。
在人类的生活环境中，人类的DNA总是会受到自然环境的影响(如氧化应激、放化疗等)产生损伤。而PARP-1与DNA修复和基因组的功能维护有着密切的联系。当DNA损伤后，一般为单链断裂(SSB,Single strand break)，PARP-1首先结合到DNA的断裂处，然后被激活，随着PARP1酶的结构发生变化，该酶开始招募NAD+(辅酶II)用来合成聚(ADP)核糖，在此同时，这也成为了DNA连接酶、DNA聚合酶β等其他修复酶发挥作用的信号。PARP-1结合和激活的这一过程称之为碱基切除修复(BER，Base excision repair)，有助于DNA扩增修复过程。当PARP-1被PARP抑制剂所抑制之后，DNA无法通过SSB对断裂的DNA进行修复，此时会激活双链断裂(DSB,Double strand break)，而机体对DSB的修复主要通过两种方式：同源重组(HR)和非同源的DNA末端链接(NHEJ,Non-Homologous End Joining)，其中同源重组是DSB修复的主要方式，且修复可靠性高。而BRCA1和BRCA2在同源重组中发挥着重要的作用(Nature,2005,913-917)。研究发现，在卵巢癌、乳腺癌、前列腺癌中，都发现BRCA1/2的突变，对于缺乏BRCA1/2的肿瘤，PARP抑制剂是很好的选择。
前列腺癌是全球范围内男性中第二大常见癌症和第五大癌症相关死亡原因，亚洲前列腺癌的发病率低于欧美等发达国家。前列腺癌初诊时绝大多数是激素敏感型前列腺癌，因此对于初诊的前列腺癌患者主要采用内分泌治疗包括去势(手术去势或药物去势)及抗雄激素治疗，但在经过上述传统内分泌治疗后患者终将进展为转移性去势抵抗性前列腺癌(metastatic castration-resistant prostate cancer,mCRPC)，是最致命的前列腺癌表型。研究显示mCRPC阶段患者5年生存率不到30％，虽然在临床研究显示患者中位总生存已经接近3年，然而真实世界研究中患者中位生存仍往往不足2年。在临床实践中mCPRC一线治疗进展后，仅有不到一半患者能接受到二线治疗，可能是影响真实世界中患者生存的关键。因此，进一步提升mCRPC一线治疗的临床获益是mCRPC患者治疗亟待解决的问题。
发明内容
一方面，本申请提供用于治疗患者的前列腺癌的式(I)化合物、其异构体或其药学上可接受的盐：
另一方面，本申请提供用于治疗患者的前列腺癌的药物组合物，所述药物组合物包含式(I)化合物、其异构体或其药学上可接受的盐。
另一方面，本申请提供用于治疗患者的前列腺癌的方法，其包括向所述患者给予有效量的如上所述的式(I)化合物、其异构体或其药学上可接受的盐，或其药物组合物。
另一方面，本申请提供如上所述的式(I)化合物、其异构体或其药学上可接受的盐，或其药物组合物在制备用于治疗患者的前列腺癌的药物中的用途。
另一方面，本申请提供如上所述的式(I)化合物、其异构体或其药学上可接受的盐，或其药物组合物在治疗患者的前列腺癌的药物中的用途。
在本申请的一些实施方案中，上述式(I)化合物为式(II)化合物，所述式(II)化合物为：
在本申请的一些实施方案中，上述式(I)化合物、其异构体或其药学上可接受的盐为式(II)化合物或其药学上可接受的盐。
在本申请的一些实施方案中，所述式(II)化合物药学上可接受的盐是盐酸盐，例如式(II)化合物的单盐酸盐。
在本申请的一些实施方案中，所述式(II)化合物或其药学上可接受的盐是作为单一活性剂使用。
在本申请的一些实施方案中，所述式(II)化合物或其药学上可接受的盐可以是包含治疗有效量的所述式(II)化合物或其药学上可接受的盐的药物组合物。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐治疗患者的前列腺癌的给药周期是2～6周。在本申请的一些实施方案中，所述治疗患者的前列腺癌的给药周期是2周、3周、4周、5周、6周或上述任意值形成的范围。在本申请的一些实施方案中，所述治疗患者的前列腺癌的给药周期是4周。
在本申请的一些实施方案中，上述式(II)化合物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确定，例如可以根据受试者/患者血常规化验结果确定，所述血常规化验结果包括血小板计数、中性粒细胞计数、或血红蛋白浓度等。在部分实施方案中，给予式(II)化合物或其药学上可接受的盐的日剂量为25mg至500mg。在部分实施方案中，给予上述式(II)化合物或其药学上可接受的盐的日剂量可选自25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg，或者任意前述值作为端点构成的范围或其中的任意值，例如25mg至500mg、25mg至400mg、25mg至300mg、50mg至300mg、75mg至300mg、100mg至300mg、150mg至300mg、200mg至300mg等。在部分特定实施方案中，给予上述式(II)化合物或其药学上可接受的盐的日剂量可选自100mg至300mg、150mg至300mg、200mg至300mg。在部分特定实施方案中，给予上述式(II)化合物或其药学上可接受的盐的日剂量可选自100mg、150mg、200mg、或300mg。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的每日剂量为25mg至500mg。在部分实施方案中，上述式(II)化合物或其药学上可接受的盐的每日剂量可选自25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg，或者任意前述值作为端点构成的范围或其中的任意值，例如25mg至500mg、25mg至400mg、25mg至300mg、50mg至300mg、75mg至300mg、100mg至300mg、150mg至300mg、200mg至300mg等。在部分特定实施方案中，上述式(II)化合物或其药学上可接受的盐的每日剂量可选自100mg至300mg、150mg至300mg、200mg至300mg。在部分特定实施方案中，上述式(II)化合物或其药学上可接受的盐的每日剂量可选自100mg、150mg、200mg、或300mg。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的每次剂量为25mg至500mg。在部分实施方案中，上述式(II)化合物或其药学上可接受的盐的每次剂量可选自25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg，或者任意前述值作为端点构成的范围或其中的任意值，例如25mg至500mg、25mg至400mg、25mg至300mg、50mg至300mg、75mg至300mg、100mg至300mg、150mg至 300mg、200mg至300mg等。在部分特定实施方案中，上述式(II)化合物或其药学上可接受的盐的每次剂量可选自100mg至300mg、150mg至300mg、200mg至300mg。在部分特定实施方案中，上述式(II)化合物或其药学上可接受的盐的每次剂量可选自100mg、150mg、200mg、或300mg。
给予本申请上述式(II)化合物或其药学上可接受的盐可以每日施用一次或多次。在部分实施方案中，每天一次或两次给予上述式(II)化合物或其药学上可接受的盐。给予上述式(II)化合物或其药学上可接受的盐也可以单剂量形式给药。在一个实施方案中，以单剂量每天给药一次或两次。在一个实施方案中，以单剂量的口服固体制剂每天给药一次或两次。在一个具体的实施方案中，以单剂量的口服固体制剂每天给药一次。
给予本申请上述式(II)化合物或其药学上可接受的盐还可以多剂量形式给药。在一个实施方案中，以多剂量每天给药一次或两次。在一个实施方案中，以多剂量的口服固体制剂每天给药一次或两次。在一个具体的实施方案中，以多剂量的口服固体制剂每天给药一次。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐以药物组合物的形式提供，优选地，其为多剂量药物组合物。在部分实施方案中，所述提供的药物组合物含有25mg至500mg的上述式(II)化合物或其药学上可接受的盐。在部分实施方案中，所述提供的药物组合物含有25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg、或者任意前述值作为端点构成的范围或其中的任意值的上述式(II)化合物或其药学上可接受的盐，例如25mg至500mg、25mg至400mg、25mg至300mg、50mg至300mg、75mg至300mg、100mg至300mg、150mg至300mg、200mg至300mg。在部分实施方案中，所述提供的药物组合物含有100mg、150mg、200mg或300mg的上述式(II)化合物或其药学上可接受的盐。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物为每日剂量。在本申请的部分方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物为每日一次剂量。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物包含每日剂量的式(II)化合物或其药学上可接受的盐。在本申请的部分实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物包含每次剂量的式(II)化合物或其药学上可接受的盐。在本申请的部分实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物每天给药一次。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物适于每日给药。在本申请的部分实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物适于每日给药一次。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物为每日一次剂量，每次剂量分别为单剂量或多剂量。
在本申请的一些方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物为单剂量或多剂量药物组合物，适于每天给药一次。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物为每日一次剂量，每次剂量为多剂量，其由单剂量为25mg和/或100mg的式(II)化合物或其药学上可接受的盐组成。在本申请的一些实施方案中，所述药物组合物由单剂量为100mg的式(II)化合物或其药学上可接受的盐组成。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物为多剂量药物组合物，适于每天给药一次，所述多剂量药物组合物由包含25mg和/或100mg的式(II)化合物或其药学上可接受的盐的单剂量药物组合物组成。在本申请的一些实施方案中，所述多剂量药物组合物由包含100mg的式(II)化合物或其药学上可接受的盐的单剂量药物组合物组成。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物包装于一个试剂盒中，所述试剂盒还含有式(II)化合物或其药学上可接受的盐用于治疗患者的前列腺癌的说明。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物包装于一个试剂盒中，所述试剂盒还含有式(II)化合物或其药学上可接受的盐用于治疗患者的前列腺癌的说明，所述说明包括28天为一个治疗周期，在每个周期的第1-28天连续施用上述式(II)化合物或其药学上可接受 的盐的药物组合物。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物包装于一个试剂盒中，所述试剂盒还含有式(II)化合物或其药学上可接受的盐用于治疗患者的前列腺癌的说明，所述说明包括28天为一个治疗周期，在每个周期的第1-28天连续每日一次施用上述式(II)化合物或其药学上可接受的盐的药物组合物。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物包装于一个试剂盒中，所述试剂盒包含1日、2日、3日、4日、5日、6日、7日、8日、9日、10日、11日、12日、13日、14日、15日、16日、17日、18日、19日、20日、21日、22日、23日、24日、25日、26日、27日或28日剂量，或者任意前述值作为端点构成的范围的剂量的上述式(II)化合物或其药学上可接受的盐或其药物组合物。在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物包装于一个试剂盒中，所述试剂盒包含1日、2日、3日、4日、5日、6日、7日、14日、21日、或28日剂量，或者任意前述值作为端点构成的范围的剂量的上述式(II)化合物或其药学上可接受的盐或其药物组合物。
在本申请的一些实施方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物包装于一个试剂盒中，所述试剂盒包含每日剂量为25mg至500mg的上述式(II)化合物或其药学上可接受的盐或其药物组合物。在部分实施方案中，所述试剂盒包含每日剂量可选自25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg，或者任意前述值作为端点构成的范围或其中的任意值，例如25mg至500mg、25mg至400mg、25mg至300mg、50mg至300mg、75mg至300mg、100mg至300mg、150mg至300mg、200mg至300mg等的上述式(II)化合物或其药学上可接受的盐或其药物组合物。在部分特定实施方案中，所述试剂盒包含每日剂量可选自100mg至300mg、150mg至300mg、200mg至300mg的上述式(II)化合物或其药学上可接受的盐或其药物组合物。在部分特定实施方案中，所述试剂盒包含每日剂量可选自100mg、150mg、200mg、300mg的上述式(II)化合物或其药学上可接受的盐或其药物组合物。
在本申请的一些实施方案中，所述治疗患者的前列腺癌的方法或用途中，上述式(II)化合物或其药学上可接受的盐的药物组合物为每日剂量，其通过如下方式给药：式(II)化合物或其药学上可接受的盐的药物组合物每日给药1次或2次。在本申请的部分方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物每日给药1次。在本申请的部分方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物每日空腹口服给药1次。
在本申请的一些实施方案中，所述治疗患者的前列腺癌的方法或用途中，上述式(II)化合物或其药学上可接受的盐的药物组合物包含每日剂量的式(II)化合物或其药学上可接受的盐，所述药物组合物每日空腹给药1次。
在本申请的一些实施方案中，28天为一个治疗周期，在每个周期的第1-28天连续施用上述式(II)化合物或其药学上可接受的盐的药物组合物。
在本申请的一些实施方案中，28天为一个治疗周期，在每个周期的第1-28天连续每日一次施用上述式(II)化合物或其药学上可接受的盐的药物组合物。
在本申请的一些实施方案中，28天为一个治疗周期，每个治疗周期施用上述式(II)化合物或其药学上可接受的盐的药物组合物的总剂量为700～14000mg(以活性成分式(II)化合物本身计)。在本申请的部分方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物的总剂量选自2800～8400mg(以活性成分式(II)化合物本身计)。在本申请的部分方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物的总剂量选自2800mg、4200mg、5600mg、7000mg、8400mg或上述任意两个值所形成的范围(以活性成分式(II)化合物本身计)。在本申请的部分方案中，上述式(II)化合物或其药学上可接受的盐的药物组合物的总剂量优选为5600～8400mg(以活性成分式(II)化合物本身计)。
在本申请的一些实施方案中，只要疾病仍处于控制之下和给药方案具有临床耐受性，就重复上述治疗周期。
在本申请的一些实施方案中，式(II)化合物或其药学上可接受的盐的药物组合物可以被配制为适合于向人口服给药的制剂形式，例如包括但不限于片剂、丸剂、胶囊剂、粉剂或颗粒剂等。
在本申请的一些实施方案中，式(II)化合物或其药学上可接受的盐的药物组合物为口服片剂。
在本申请的一些实施方案中，式(II)化合物或其药学上可接受的盐的口服片剂的单剂量规格为25mg或100mg。
另一方面，本申请提供了一种药物组合，其包含式(I)化合物、其异构体或其药学上可接受的盐，醋酸阿比特龙和泼尼松或泼尼松龙，
另一方面，本申请提供了用于治疗患者的前列腺癌的药物组合，其包含式(I)化合物、其异构体或其药学上可接受的盐，醋酸阿比特龙和泼尼松或泼尼松龙。
在本申请的一些实施方案中，所述药物组合包装于同一试剂盒中，所述试剂盒还包含将式(I)化合物、其异构体或其药学上可接受的盐，醋酸阿比特龙和泼尼松或泼尼松龙联合使用以治疗或预防前列腺癌的说明。
在本申请的一些实施方案中，所述药物组合包括：式(I)化合物、其异构体或其药学上可接受的盐，醋酸阿比特龙和泼尼松或泼尼松龙的药物组合物。
在本申请的一些实施方案中，所述药物组合包括：式(I)化合物、其异构体或其药学上可接受的盐的药物组合物，醋酸阿比特龙的药物组合物和泼尼松或泼尼松龙的药物组合物。
在本申请的一些实施方案中，所述药物组合包装于同一试剂盒中，所述试剂盒还包含将式(I)化合物、其异构体或其药学上可接受的盐的药物组合物，醋酸阿比特龙和泼尼松或泼尼松龙的药物组合物联合使用以治疗患者的前列腺癌的说明。
在本申请的一些实施方案中，所述药物组合包装于同一试剂盒中，所述试剂盒还包含将式(I)化合物、其异构体或其药学上可接受的盐的药物组合物，醋酸阿比特龙的药物组合物和泼尼松或泼尼松龙的药物组合物联合使用以治疗患者的前列腺癌的说明。
另一方面，本申请提供用于治疗患者的前列腺癌的方法，其包括向所述患者给予有效量的如上所述的药物组合。
另一方面，本申请提供如上所述的药物组合在制备用于治疗患者的前列腺癌的药物中的用途。
另一方面，本申请提供如上所述的药物组合在治疗患者的前列腺癌的药物中的用途。
在本申请的一些实施方案中，所述药物组合，所述式(I)化合物为式(II)化合物，所述式(II)化合物为：
在本申请的一些实施方案中，所述药物组合，所述式(I)化合物、其异构体或其药学上可接受的盐为式(II)化合物药学上可接受的盐。
在本申请的一些实施方案中，所述药物组合，所述式(II)化合物药学上可接受的盐是盐酸盐，例如 式(II)化合物的单盐酸盐。
在本申请的一些实施方案中，所述药物组合含有以式(II)化合物计为25mg～500mg、25mg～400mg、25mg～300mg、50mg～300mg、75mg～300mg、100mg～300mg、150mg～300mg或200mg～300mg的式(II)化合物或其药学上可接受的盐，或其药物组合物。
在本申请的一些实施方案中，所述药物组合含有以式(II)化合物计为100mg～300mg、150mg～300mg或200mg～300mg的式(II)化合物或其药学上可接受的盐，或其药物组合物。
在本申请的一些实施方案中，所述药物组合含有以式(II)化合物计为200～300mg的式(II)化合物或其药学上可接受的盐，或其药物组合物。
在本申请的一些实施方案中，所述药物组合含有以式(II)化合物计为25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg的式(II)化合物或其药学上可接受的盐，或其药物组合物。
在本申请的一些实施方案中，所述药物组合含有以式(II)化合物计为100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg或300mg的式(II)化合物或其药学上可接受的盐，或其药物组合物。
在本申请的一些实施方案中，所述药物组合含有以式(II)化合物计为100mg、150mg、200mg或300mg的式(II)化合物或其药学上可接受的盐，或其药物组合物。
在本申请的一些实施方案中，所述药物组合含有以式(II)化合物计为200mg或300mg的式(II)化合物或其药学上可接受的盐，或其药物组合物。
在本申请的一些实施方案中，所述药物组合中，式(II)化合物或其药学上可接受的盐的药物组合物为单剂量或多剂量形式。在本申请的一些实施方案中，所述药物组合中，式(II)化合物或其药学上可接受的盐的药物组合物为多剂量形式。
在本申请的一些实施方案中，所述药物组合中，式(II)化合物或其药学上可接受的盐的含量为每日剂量。
在本申请的一些实施方案中，所述药物组合中，式(II)化合物或其药学上可接受的盐的含量为每次剂量。在本申请的一些实施方案中，所述药物组合中，式(II)化合物或其药学上可接受的盐每日给药一次。
在本申请的一些实施方案中，所述药物组合中，式(II)化合物或其药学上可接受的盐的含量为每日一次剂量。
在本申请的一些实施方案中，所述药物组合中，式(II)化合物或其药学上可接受的盐的含量为每日一次剂量，且每次剂量为单剂量或多剂量、通常为多剂量。
在本申请的一些实施方案中，所述药物组合含有单剂量以式(II)化合物计为25mg和/或100mg的式(II)化合物或其药学上可接受的盐的药物组合物。或者，所述药物组合处于单次给予制剂的形式，所述药物组合含有以式(II)化合物计为25mg和/或100mg的式(II)化合物或其药学上可接受的盐或其药物组合物。
在本申请的一些实施方案中，所述药物组合含有单剂量以式(II)化合物计为100mg的式(II)化合物或其药学上可接受的盐的药物组合物。或者，所述药物组合处于单次给予制剂的形式，所述药物组合含有以式(II)化合物计为100mg的式(II)化合物或其药学上可接受的盐或其药物组合物。
在本申请的一些实施方案中，所述药物组合中，其含有的式(II)化合物或其药学上可接受的盐的药物组合物包装于一个试剂盒中，所述试剂盒还含有式(II)化合物或其药学上可接受的盐用于治疗患者的前列腺癌的说明。
在本申请的一些实施方案中，醋酸阿比特龙的每日剂量选自250mg～1500mg、250mg～1250mg、250mg～1000mg或500mg～1000mg。在本申请的一些实施方案中，醋酸阿比特龙的每日剂量选自250mg、500mg、750mg、1000mg、1250mg或1500mg。在本申请的一些实施方案中，醋酸阿比特龙的每日剂量选自500mg、750mg或1000mg。在本申请的一些实施方案中，醋酸阿比特龙的每日剂量选自1000mg。
在本申请的一些实施方案中，醋酸阿比特龙的每次剂量选自250mg～1500mg、250mg～1250mg、250mg～1000mg或500mg～1000mg。在本申请的一些实施方案中，醋酸阿比特龙的每次剂量选自250mg、500mg、750mg、1000mg、1250mg或1500mg。在本申请的一些实施方案中，醋酸阿比特龙的每次剂量选自500mg、750mg或1000mg。在本申请的一些实施方案中，醋酸阿比特龙的每次剂量选自1000mg。
在本申请的一些实施方案中，所述药物组合中，醋酸阿比特龙的药物组合物为每日剂量。
在本申请的一些实施方案中，所述药物组合中，醋酸阿比特龙的药物组合物包含每日剂量的醋酸阿比特龙。
在本申请的一些实施方案中，所述药物组合中，醋酸阿比特龙的药物组合物为每日一次剂量。
在本申请的一些实施方案中，所述药物组合中，醋酸阿比特龙的药物组合物包含每次剂量的醋酸阿比特龙，每日给药一次。
在本申请的一些实施方案中，所述药物组合含有250mg～1500mg、250mg～1250mg、250mg～1000mg或500mg～1000mg的醋酸阿比特龙或其药物组合物(以醋酸阿比特龙计)。
在本申请的一些实施方案中，所述药物组合含有250mg、500mg、750mg、1000mg、1250mg或1500mg的醋酸阿比特龙或其药物组合物(以醋酸阿比特龙计)。
在本申请的一些实施方案中，所述药物组合含有500mg、750mg或1000mg的醋酸阿比特龙或其药物组合物(以醋酸阿比特龙计)。
在本申请的一些实施方案中，所述药物组合含有1000mg的醋酸阿比特龙或其药物组合物(以醋酸阿比特龙计)。
在本申请的一些实施方案中，所述药物组合中，醋酸阿比特龙的药物组合物为单剂量或多剂量形式。
在本申请的一些实施方案中，所述药物组合中，醋酸阿比特龙的药物组合物为多剂量形式。
在本申请的一些实施方案中，所述药物组合含有单剂量250mg的醋酸阿比特龙的药物组合物。或者，所述药物组合处于单次给予制剂的形式，所述药物组合含有250mg的醋酸阿比特龙或其药物组合物。
在本申请的一些实施方案中，所述醋酸阿比特龙的多剂量药物组合物由含有250mg或500mg醋酸阿比特龙的单剂量药物组合物组成。
在本申请的一些实施方案中，所述醋酸阿比特龙的多剂量药物组合物由含有250mg醋酸阿比特龙的单剂量药物组合物组成。
在本申请的一些实施方案中，所述药物组合中，醋酸阿比特龙的药物组合物包装于一个试剂盒中，所述试剂盒还含有醋酸阿比特龙用于治疗患者的前列腺癌的说明。在本申请的一些实施方案中，所述说明可以为市售的醋酸阿比特龙片的药品说明书中的说明。在本申请的一些实施方案中，所述说明为正大天晴药业集团股份有限公司生产的醋酸阿比特龙片(例如)的药品说明书中的说明。
在本申请的一些实施方案中，泼尼松或泼尼松龙的每日剂量选自5mg～40mg、5mg～35mg、5mg～20mg或10mg～20mg。在本申请的一些实施方案中，泼尼松或泼尼松龙的每日剂量选自5mg～20mg或10mg～20mg。在本申请的一些实施方案中，泼尼松或泼尼松龙的每日剂量选自5mg、10mg、15mg或20mg。在本申请的一些实施方案中，泼尼松或泼尼松龙的每日剂量选自10mg或20mg。
在本申请的一些实施方案中，泼尼松或泼尼松龙的每次剂量选自5mg～40mg、5mg～35mg、5mg～20mg或10mg～20mg。在本申请的一些实施方案中，泼尼松或泼尼松龙的每次剂量选自5mg～20mg或10mg～20mg。在本申请的一些实施方案中，泼尼松或泼尼松龙的每次剂量选自5mg、10mg、15mg或20mg。在本申请的一些实施方案中，泼尼松或泼尼松龙的每次剂量选自5mg或10mg。
在本申请的一些实施方案中，所述药物组合中，所述泼尼松或泼尼松龙的药物组合物为每日剂量。
在本申请的一些实施方案中，所述药物组合中，所述泼尼松或泼尼松龙的药物组合物包含每日剂量的泼尼松或泼尼松龙。
在本申请的一些实施方案中，所述药物组合中，所述泼尼松或泼尼松龙的药物组合物为每日两次剂量。
在本申请的一些实施方案中，所述药物组合中，所述泼尼松或泼尼松龙的药物组合物包含每次剂量的泼尼松或泼尼松龙，每日给药两次。
在本申请的一些实施方案中，所述药物组合含有5mg～40mg、5mg～35mg、5mg～20mg或10mg～20mg的泼尼松或泼尼松龙或其药物组合物(以泼尼松或泼尼松龙计)。
在本申请的一些实施方案中，所述药物组合含有5mg～20mg或10mg～20mg的泼尼松或泼尼松龙或其药物组合物(以泼尼松或泼尼松龙计)。
在本申请的一些实施方案中，所述药物组合含有5mg、10mg、15mg或20mg的泼尼松或泼尼松龙或其药物组合物(以泼尼松或泼尼松龙计)。
在本申请的一些实施方案中，所述药物组合含有10mg或20mg的泼尼松或泼尼松龙或其药物组合物(以泼尼松或泼尼松龙计)。
在本申请的一些实施方案中，所述药物组合，所述泼尼松或泼尼松龙的药物组合物为单剂量或多剂量形式。
在本申请的一些实施方案中，所述药物组合，所述泼尼松或泼尼松龙的药物组合物为多剂量形式。
在本申请的一些实施方案中，所述泼尼松或泼尼松龙的多剂量药物组合物由含有5mg泼尼松或泼尼松龙的单剂量药物组合物组成。
在本申请的一些实施方案中，所述药物组合含有单剂量5mg的泼尼松或泼尼松龙的药物组合物。或者，所述药物组合处于单次给予制剂的形式，所述药物组合含有5mg的泼尼松或泼尼松龙或其药物组合物(以泼尼松或泼尼松龙计)。
在本申请的一些实施方案中，所述药物组合中，其含有的泼尼松或泼尼松龙的药物组合物包装于一个试剂盒中，所述试剂盒还含有泼尼松或泼尼松龙用于治疗患者的前列腺癌的说明。在本申请的一些实施方案中，所述说明可以为市售的泼尼松片或泼尼松龙片的药品说明书中的说明。
在本申请的一些实施方案中，所述药物组合含有以式(II)化合物计为25mg～500mg的式(II)化合物或其药学上可接受的盐、250mg～1500mg的醋酸阿比特龙，以及5mg～40mg的泼尼松或泼尼松龙。
在本申请的一些实施方案中，所述药物组合含有以式(II)化合物计为100mg～300mg的式(II)化合物或其药学上可接受的盐、250mg～1000mg的醋酸阿比特龙，以及5mg～20mg的泼尼松或泼尼松龙。
在本申请的一些实施方案中，所述药物组合含有：以式(II)化合物计为100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg或300mg的每日剂量的式(II)化合物或其药学上可接受的盐和500mg、750mg或1000mg的每日剂量的醋酸阿比特龙，以及5mg、10mg、15mg或20mg的每日剂量的泼尼松或泼尼松龙。
在本申请的一些实施方案中，所述药物组合含有：以式(II)化合物计为100mg、150mg、200mg或300mg的每日剂量的式(II)化合物或其药学上可接受的盐、1000mg的每日剂量的醋酸阿比特龙，以及10mg或20mg的每日剂量的泼尼松或泼尼松龙。
在本申请的一些实施方案中，所述药物组合含有：以式(II)化合物计为200mg或300mg的每日剂量的式(II)化合物或其药学上可接受的盐、1000mg的每日剂量的醋酸阿比特龙，以及10mg的每日剂量的泼尼松或泼尼松龙。
在本申请的一些实施方案中，所述药物组合含有：以式(II)化合物计为300mg的每日剂量的式(II)化合物或其药学上可接受的盐、1000mg的每日剂量的醋酸阿比特龙，以及10mg的每日剂量的泼尼松或泼尼松龙。
在本申请的一些实施方案中，每28天为一个治疗周期。
在本申请的一些实施方案中，所述药物组合含有：以式(II)化合物计的单剂量为25mg和/或100mg的式(II)化合物或其药学上可接受的盐的药物组合物、以醋酸阿比特龙计的单剂量为250mg的醋酸阿比特龙的药物组合物，以及分别以泼尼松或泼尼松龙计的单剂量为5mg的泼尼松或泼尼松龙的药物组合物。或者，所述药物组合处于单次给予制剂的形式，所述药物组合含有：以式(II)化合物计为25mg和/或100mg 的式(II)化合物或其药学上可接受的盐或其药物组合物、以醋酸阿比特龙计为250mg的醋酸阿比特龙或其药物组合物，以及分别以泼尼松或泼尼松龙计为5mg的泼尼松或泼尼松龙或其药物组合物。
在本申请的一些实施方案中，所述药物组合含有：以式(II)化合物计的单剂量为100mg的式(II)化合物或其药学上可接受的盐的药物组合物、以醋酸阿比特龙计的单剂量为250mg的醋酸阿比特龙的药物组合物，以及分别以泼尼松或泼尼松龙计的单剂量为5mg的泼尼松或泼尼松龙的药物组合物。或者，所述药物组合处于单次给予制剂的形式，所述药物组合含有：以式(II)化合物计为25mg或100mg的式(II)化合物或其药学上可接受的盐或其药物组合物、以醋酸阿比特龙计为250mg的醋酸阿比特龙或其药物组合物，以及分别以泼尼松或泼尼松龙计为5mg的泼尼松或泼尼松龙或其药物组合物。
在本申请的一些实施方案中，所述药物组合为适用于在单个治疗周期(例如28天的一个治疗周期)内施用的制剂，所述制剂包括：以式～(II)化合物计的总剂量为2800～8400mg(例如2800mg、4200mg、5600mg、7000mg或8400mg)的含有式(II)化合物或其药学上可接受的盐的药物组合物、以醋酸阿比特龙计的总剂量为7000～28000mg的含有醋酸阿比特龙的药物组合物，以及分别以泼尼松或泼尼松龙计的总剂量为140～560mg的含有泼尼松或泼尼松龙的药物组合物。
在本申请的一些实施方案中，所述药物组合为适用于在单个治疗周期(例如28天的一个治疗周期)内施用的制剂，所述制剂包括：以式(II)化合物计的总剂量为5600mg或8400mg的含有式(II)化合物或其药学上可接受的盐的药物组合物、以醋酸阿比特龙计的总剂量为28000mg的含有醋酸阿比特龙的药物组合物，以及分别以泼尼松或泼尼松龙计的总剂量为280～560mg的含有泼尼松或泼尼松龙的药物组合物。
在本申请的一些实施方案中，所述药物组合为适用于在单个治疗周期(例如28天的一个治疗周期)内施用的制剂，所述制剂包括：以式(II)化合物计的总剂量为8400mg的含有式(II)化合物或其药学上可接受的盐的药物组合物、以醋酸阿比特龙计的总剂量为28000mg的含有醋酸阿比特龙的药物组合物，以及分别以泼尼松或泼尼松龙计的总剂量为280mg的含有泼尼松或泼尼松龙的药物组合物。
在本申请的一些实施方案中，所述药物组合中，所述式(II)化合物或其药学上可接受的盐、醋酸阿比特龙，以及泼尼松或泼尼松龙可以分别呈药物组合物形式或者一起呈药物组合物形式。
在本申请的一些实施方案中，所述药物组合中，所述式(II)化合物或其药学上可接受的盐、醋酸阿比特龙，以及泼尼松或泼尼松龙为固定组合或非固定组合。
另一方面，本申请还提供一种试剂盒，其中含有(a)第一药物组合物，其含有本申请所述的式(II)化合物或其药学上可接受的盐；(b)第二药物组合物，其含有醋酸阿比特龙；以及(c)第三药物组合物，其含有泼尼松或泼尼松龙。
另一方面，本申请还提供一种用于治疗患者的前列腺癌的药物组合物的试剂盒，其中含有(a)第一药物组合物，其含有本申请所述的式(II)化合物或其药学上可接受的盐；(b)第二药物组合物，其含有醋酸阿比特龙；以及和(c)第三药物组合物，其含有泼尼松或泼尼松龙。或者，本申请还提供一种用于治疗患者的前列腺癌的药物组合，其含有：式(II)化合物或其药学上可接受的盐的药物组合物、醋酸阿比特龙的药物组合物、以及泼尼松或泼尼松龙的药物组合物。
在本申请的一些实施方案中，所述药物组合中，所述式(II)化合物或其药学上可接受的盐被制备成单位制剂，其中含有以式(I)化合物计为25mg或100mg的式(II)化合物或其药学上可接受的盐；所述醋酸阿比特龙被制备成单位制剂，其中含有250mg的醋酸阿比特龙；所述泼尼松或泼尼松龙被制备成单位制剂，其中含有5mg的泼尼松或泼尼松龙。
在本申请的一些实施方案中，所述药物组合中，所述式(II)化合物或其药学上可接受的盐被制备成单位制剂，其中含有以式(I)化合物计为100mg的式(II)化合物或其药学上可接受的盐；所述醋酸阿比特龙被制备成单位制剂，其中含有250mg的醋酸阿比特龙；所述泼尼松或泼尼松龙被制备成单位制剂，其中含有5mg的泼尼松或泼尼松龙。
另一方面，本申请还提供了治疗患者的前列腺癌的方法，其包括向有需要的个体施用治疗有效量的式(II)化合物或其药学上可接受的盐、醋酸阿比特龙和泼尼松或泼尼松龙，例如向有需要的个体施用治疗有效量的本申请的上文所述的药物组合。
另一方面，本申请还提供了一种用于治疗患有前列腺癌个体的联合疗法，所述方法包括向所述个体单独施用治疗有效量的式(II)化合物或其药学上可接受的盐和单独施用治疗有效量的醋酸阿比特龙，以及单独施用治疗有效量的泼尼松或泼尼松龙。
另一方面，本申请还提供了式(II)化合物或其药学上可接受的盐联合醋酸阿比特龙和泼尼松或泼尼松龙在制备用于治疗患者的前列腺癌的药物中的用途，例如本申请上述药物组合在制备用于治疗患者的前列腺癌的药物中的用途。在本申请的一些实施方案中，所述药物组合为本申请的上文所述的任一药物组合。
另一方面，本申请还提供了式(II)化合物或其药学上可接受的盐联合醋酸阿比特龙和泼尼松或泼尼松龙用于治疗患者的前列腺癌的用途，例如本申请上述药物组合用于治疗患者的前列腺癌的用途。
在本申请的一些实施方案中，在所述试剂盒、方法、联合疗法或用途中，所述式(II)化合物或其药学上可接受的盐、醋酸阿比特龙和泼尼松或泼尼松龙的各定义，同上文所述的药物组合中式(II)化合物或其药学上可接受的盐、醋酸阿比特龙和泼尼松或泼尼松龙所定义，例如含量、剂量、存在形式、包装形式等等。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述式(II)化合物或其药学上可接受的盐、醋酸阿比特龙和泼尼松或泼尼松龙各自呈药物组合物形式，可同时、分开、并行、顺序或间隔给药。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述式(II)化合物或其药学上可接受的盐、醋酸阿比特龙和泼尼松或泼尼松龙分别具有相同或者不同的治疗周期。在本申请的一些具体的实施方案中，在所述方法、联合疗法或用途中，所述式(II)化合物或其药学上可接受的盐、醋酸阿比特龙和泼尼松或泼尼松龙具有相同的治疗周期，例如每1周、每2周、每3周或每4周为一个治疗周期。优选的，每4周为一个治疗周期。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的式(II)化合物或其药学上可接受的盐的含量为每日剂量，其通过如下方式给药：式(II)化合物或其药学上可接受的盐每日给药1次。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的式(II)化合物或其药学上可接受的盐的含量为每日剂量，其中式(II)化合物或其药学上可接受的盐以单剂量或多剂量方式给药，通常以多剂量方式给药；进一步地，其中式(II)化合物或其药学上可接受的盐以多剂量方式每日给药1次。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述式(II)化合物或其药学上可接受的盐通过如下方式给药：每日剂量为100mg；或者，每日剂量为150mg；或者，每日剂量为200mg；或者每日剂量为300mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述式(II)化合物或其药学上可接受的盐通过如下方式给药：每日剂量为200mg；或者，每日剂量为300mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述式(II)化合物或其药学上可接受的盐通过如下方式给药：每日剂量为300mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的式(II)化合物或其药学上可接受的盐以多剂量方式给药，所述多剂量由单剂量为25mg和/或100mg的式(II)化合物或其药学上可接受的盐的药物组合物组成。在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述式(II)化合物或其药学上可接受的盐以连续每日给药的方式给药。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的式(II)化合物或其药学上可接受的盐以多剂量方式给药，所述多剂量由单剂量为100mg的式(II)化合物或其药学上可接受的盐的药物组合物组成。在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述式(II)化合物或其药学上可接受的盐以连续每日给药的方式给药。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的式(II)化合物或其药学上可接受的盐的含量为每个治疗周期的剂量，其通过如下方式给药：每天施用式(II)化合物或其 药学上可接受的盐。其中，式(II)化合物或其药学上可接受的盐以单等份或多个等份(例如2等份、4、等份、7个等份、14等份、28等份或更多等份)进行包装。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的醋酸阿比特龙的含量为每日剂量，其通过如下方式给药：醋酸阿比特龙每日给药1次。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的醋酸阿比特龙的含量为每日剂量，其中醋酸阿比特龙以单剂量或多剂量方式给药，通常以多剂量方式给药；进一步地，其中醋酸阿比特龙以多剂量方式每日给药1次。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述醋酸阿比特龙通过如下方式给药：每日剂量为250mg；或者，每日剂量为500mg；或者，每日剂量为750mg；或者每日剂量为1000mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述醋酸阿比特龙通过如下方式给药：每日剂量为500mg；或者，每日剂量为1000mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述醋酸阿比特龙通过如下方式给药：每日剂量为1000mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的醋酸阿比特龙以多剂量方式给药，所述多剂量由单剂量为250mg的醋酸阿比特龙的药物组合物组成。在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述醋酸阿比特龙以连续每日给药的方式给药。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的醋酸阿比特龙的含量为每个治疗周期的剂量，其通过如下方式给药：每天施用醋酸阿比特龙。其中，醋酸阿比特龙以单等份或多个等份(例如2等份、4、等份、7个等份、14等份、28等份或更多等份)进行包装。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的泼尼松或泼尼松龙的含量为每日剂量，其通过如下方式给药：泼尼松或泼尼松龙每日给药2次。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的泼尼松或泼尼松龙的含量为每日剂量，其中泼尼松或泼尼松龙以单剂量或多剂量方式给药，通常以单剂量方式给药；进一步地，其中泼尼松或泼尼松龙以每次单剂量方式每日给药2次。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述泼尼松或泼尼松龙通过如下方式给药：每日剂量为10mg；或者，每日剂量为20mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述泼尼松或泼尼松龙通过如下方式给药：每日剂量为10mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的泼尼松或泼尼松龙以多剂量方式给药，所述多剂量由单剂量为5mg的泼尼松或泼尼松龙的药物组合物组成。在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述泼尼松或泼尼松龙以连续每日给药的方式给药。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，所述药物组合中的泼尼松或泼尼松龙的含量为每个治疗周期的剂量，其通过如下方式给药：每天施用泼尼松或泼尼松龙。其中，泼尼松或泼尼松龙以单等份或多个等份(例如2等份、4、等份、7个等份、14等份、28等份或更多等份)进行包装。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有所述式(II)化合物或其药学上可接受的盐的药物组合物的总剂量为2800～8400mg。在部分的实施方案中，所述含有式(II)化合物或其药学上可接受的盐的药物组合物的总剂量选自2800mg、4200mg、5600mg、7000mg或8400mg或上述任意两个值所形成的范围。在部分的实施方案中，所述含有式(II)化合物或其药学上可接受的盐的药物组合物的总剂量优选为5600mg或8400mg。在部分的实施方案中，所述含有式(II)化合物或其药学上可接受的盐的药物组合物的总剂量优选为8400mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有醋酸阿比特龙的药物组合物的总剂量为7000～28000mg。在部分的 实施方案中，所述含有醋酸阿比特龙的药物组合物的总剂量选自7000mg、14000mg、21000mg或28000mg或上述任意两个值所形成的范围。在部分的实施方案中，所述含有醋酸阿比特龙的药物组合物的总剂量优选为21000mg或28000mg。在部分的实施方案中，所述含有醋酸阿比特龙的药物组合物的总剂量优选为28000mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期，每天给药2次，连续给药28天，每个治疗周期施用含有泼尼松或泼尼松龙的药物组合物的总剂量为140～560mg。在部分的实施方案中，所述含有泼尼松或泼尼松龙的药物组合物的总剂量选自140mg、280mg或560mg或上述任意两个值所形成的范围。在部分的实施方案中，所述含有泼尼松或泼尼松龙的药物组合物的总剂量优选为280mg或560mg。在部分的实施方案中，所述含有泼尼松或泼尼松龙的药物组合物的总剂量优选为280mg。
在本申请的一些实施方案中，在所述方法、联合疗法或用途中，28天为一个治疗周期；含有所述式(II)化合物或其药学上可接受的盐的药物组合物每天给药1次，连续给药28天，每个治疗周期施用含有所述式(II)化合物或其药学上可接受的盐的药物组合物的总剂量为5600mg或8400mg；醋酸阿比特龙每天给药1次，连续给药28天，每个治疗周期施用含有醋酸阿比特龙的药物组合物的总剂量为28000mg；泼尼松或泼尼松龙每天给药2次，连续给药28天，每个治疗周期施用含有泼尼松或泼尼松龙的药物组合物的总剂量为280mg。
本申请的实施方案中，只要疾病仍处于控制之下和给药方案具有临床耐受性，就重复上述治疗周期。
在本申请的一些实施方案中，所述药物组合中，所述泼尼松还可替换为醋酸泼尼松。
在本申请的一些实施方案中，所述药物组合中，所述泼尼松龙还可替换为醋酸泼尼松龙。
在本申请的一些实施方案中，所述前列腺癌选自前列腺腺癌。
在本申请的一些实施方案中，所述前列腺腺癌选自腺泡性腺癌、萎缩型腺癌、微囊型腺癌、泡沫样腺型腺癌、黏液(胶样)腺癌、印戒型腺癌、多形性巨细胞腺癌和肉瘤样癌。
在本申请的一些实施方案中，所述前列腺腺性肿瘤选自腺泡性腺癌。
在本申请的一些实施方案中，所述前列腺癌选自去势抵抗性前列腺癌。
在本申请的一些实施方案中，所述前列腺癌选自转移性去势抵抗性前列腺癌。
在本申请的一些实施方案中，所述前列腺癌选自同源重组修复(HRR)基因突变的转移性去势抵抗性前列腺癌。
在本申请的一些实施方案中，所述前列腺癌选自转移性去势抵抗性前列腺腺癌。
本申请中，所述转移性去势抵抗性前列腺癌为影像学(如骨扫描和CT/MRI)证实的转移性疾病或具有影像学(如骨扫描和CT/MRI)证实的转移病灶。
在本申请的一些实施方案中，所述转移性去势抵抗性前列腺癌为在接受去势治疗的条件下发生疾病进展的前列腺癌。
本申请中，所述疾病进展是指至少两次连续PSA值升高且间隔至少一周、和/或经RECIST 1.1评估的疾病进展，和/或经PCWG3评估的骨骼疾病进展。
在本申请的一些实施方案中，所述疾病进展是指至少两次连续PSA值升高且间隔至少一周，且最后一次至少为1.0ng/mL、和/或经RECIST 1.1评估的疾病进展，和/或经PCWG3评估的骨骼疾病进展，所述骨骼疾病进展包括骨扫描发现有≥2处新发病灶，至少8周后再次骨扫描又发现≥2处上次评估新发骨病灶以外的新发病灶，且上次新发骨病灶有≥2处在此次持续存在。
本申请中，所述去势治疗包括手术治疗、放疗去势治疗和药物去势治疗；所述手术治疗是指双侧睾丸切除术治疗；所述药物去势治疗包括多西他赛、卡巴他赛、恩杂鲁胺、瑞维鲁胺、醋酸赛普罗特博、非那雄胺、醋酸阿比特龙、地塞米松、氟他米特、尼鲁米特、比卡鲁胺、乙基己烯雌酚、醋酸甲地孕酮、磷雌酚、磷酸雌莫司汀、曲普瑞林、亮丙瑞林、戈舍瑞林、组胺瑞林、布舍瑞林、阿布瑞克、地加瑞克或西曲瑞克中的一种或多种药物任意组合治疗。在本申请的一些实施方案中，所述药物去势治疗包括曲普瑞林、 亮丙瑞林、戈舍瑞林、阿布瑞克、地加瑞克或西曲瑞克中的一种或多种药物任意组合治疗。在本申请的一些实施方案中，所述药物去势治疗包括曲普瑞林、亮丙瑞林或戈舍瑞林治疗。在本申请的一些实施方案中，所述药物去势治疗包括阿布瑞克、地加瑞克或西曲瑞克治疗。在本申请的一些实施方案中，所述药物去势治疗包括氟他米特、尼鲁米特或比卡鲁胺治疗。在本申请的一些实施方案中，所述药物去势治疗包括地加瑞克或/和戈舍瑞林治疗。在本申请的一些实施方案中，所述药物去势治疗包括比卡鲁胺或/和戈舍瑞林治疗。在本申请的一些实施方案中，所述药物去势治疗包括比卡鲁胺或/和曲普瑞林治疗。在本申请的一些实施方案中，所述药物去势治疗包括比卡鲁胺、亮丙瑞林或戈舍瑞林中的一种或多种药物任意组合治疗。在本申请的一些实施方案中，所述药物去势治疗包括醋酸阿比特龙或/和恩杂鲁胺治疗。在本申请的一些实施方案中，所述药物去势治疗包括醋酸阿比特龙或/和比卡鲁胺治疗。
在本申请的一些实施方案中，所述转移性去势抵抗性前列腺癌为既往接受恩杂鲁胺和/或醋酸阿比特龙治疗后出现进展的前列腺癌。
在本申请的一些实施方案中，所述转移性去势抵抗性前列腺癌患者的血清睾酮水平≤1.73nmol/L(50ng/dL)。
在本申请的一些实施方案中，所述转移性去势抵抗性前列腺癌为未经手术去势治疗的患者，所述患者持续使用雄激素剥夺疗法(ADT)，所述雄激素剥夺疗法(ADT)包括曲普瑞林、亮丙瑞林或戈舍瑞林治疗。
在本申请的一些实施方案中，所述转移性去势抵抗性前列腺癌为未经手术去势治疗的患者，所述患者持续使用雄激素剥夺疗法(ADT)，所述雄激素剥夺疗法(ADT)包括阿布瑞克、地加瑞克或西曲瑞克治疗。
在本申请的一些实施方案中，所述转移性去势抵抗性前列腺癌为手术去势治疗的患者。
在本申请的一些实施方案中，所述转移性去势抵抗性前列腺癌为终止所有既往癌症治疗(雄激素剥夺疗法(ADT)和骨质流失预防性治疗除外)的患者。
本申请的药物组合中的活性组分可以各自独立地，或者其中的部分或全部地共同与药学上可接受的载体和/或赋形剂配制。本申请的药物组合还可以包含另外的治疗剂。本申请的一些实施方案，所述另外的治疗剂可以是本领域已知的用于癌症的治疗剂，优选用于前列腺癌的治疗剂。
式(II)化合物或其药学上可接受的盐
本申请的式(II)化合物可以以其游离碱形式给药，也可以以其药学上可接受的盐、水合物和前药的形式给药，该前药在体内转换成式(II)化合物形式。例如，式(II)化合物的药学上可接受的盐在本申请的范围内，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。
关于本申请所述的式(II)化合物的药学上可接受的盐，式(II)化合物与形成可药用盐的酸根离子的摩尔比可为1:1。
式(II)化合物的药学上可接受的盐可以是式(II)化合物的盐酸盐(例如式(II)化合物的单盐酸盐)，所述式(II)化合物的单盐酸盐结构如式(II-1)化合物所示，
本申请中涉及的式(II)化合物或其药学上可接受的盐的剂量或质量，除非另有说明，均基于式(II)化合物计算。
在本申请的一些实施方案中，所述式(II)化合物的药学上可接受的盐以式(II-1)化合物的形式存在。
在本申请的一些实施方案中，所述式(II-1)化合物是结晶形式。
在本申请的一些实施方案中，所述式(II-1)化合物是无定型形式。
本申请所用的式(II)化合物或式(II-1)化合物或式(II-1)化合物的结晶可以通过现有技术的方法制备，例如参照WO2022022664的方法进行制备。
式(II)化合物或其药学上可接受的盐的药物组合物
在本申请的一些实施方案中，所述式(II)化合物或其药学上可接受的盐的药物组合物的单剂量以式(II)化合物计为25mg或100mg。或者，所述式(II)化合物或其药学上可接受的盐的药物组合物被制备成单位制剂，其中含有以式(II)化合物计为25mg或100mg的式(II)化合物或其药学上可接受的盐。
在本申请的一些实施方案中，所述式(II)化合物或其药学上可接受的盐的药物组合物的单剂量以式(II)化合物计为100mg。或者，所述式(II)化合物或其药学上可接受的盐的药物组合物被制备成单位制剂，其中含有以式(II)化合物计为100mg的式(II)化合物或其药学上可接受的盐。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在本申请的一些实施方案中，所述含有式(II)化合物或其药学上可接受的盐的药物组合物还含有药学上可接受的辅料。药学上可接受的辅料包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。在本申请的一些实施方案中，所述药物组合物包括但不限于适合口服、肠道外、局部给药的制剂。在一些实施方案中，所述药物组合物为适合口服的制剂。在一些实施方案中，所述药物组合物为适合口服的固体制剂。在一些实施方案中，所述药物组合物包括但不限于片剂、胶囊。
在本申请的一些实施方案中，所述药物组合物为固体药物组合物。
在本申请的一些实施方案中，所述式(II)化合物或其药学上可接受的盐的药物组合物为含有式(II)化合物或其药学上可接受的盐的固体药物组合物。
在本申请的一些实施方案中，所述式(II)化合物或其药学上可接受的盐的药物组合物为含有式(II)化合物或其药学上可接受的盐的片剂。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
醋酸阿比特龙
如本申请所用，醋酸阿比特龙(Abiraterone)化学名为17-(3-吡啶基)雄甾-5,16-二烯-3β-乙酸酯，其具有如下式(III)化合物所示的结构式：
醋酸阿比特龙的药物组合物
在本申请的一些实施方案中，所述醋酸阿比特龙的药物组合物还含有药学上可接受的辅料。优选地，所述药学上可接受的辅料包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂、注射用水等。
在本申请的一些实施方案中，所述药物组合物为固体药物组合物。
在本申请的一些实施方案中，所述药物组合物为片剂。
在本申请的一些实施方案中，所述醋酸阿比特龙的药物组合物的单剂量为250mg。
本申请所用的醋酸阿比特龙片可以通过市售获得，例如正大天晴药业集团股份有限公司生产的醋酸阿比特龙片(例如)。
泼尼松或醋酸泼尼松
如本申请所用，泼尼松(Prednisone)化学名为17α,21-二羟基孕甾-1,4-二烯-3,11,20-三酮，其具有如下式(IV)化合物所示的结构式：
如本申请所用，醋酸泼尼松化学名为17α,21-二羟基孕甾-1,4-二烯-3,11,20-三酮21-醋酸酯，其具有如下式(V)化合物所示的结构式：
泼尼松或醋酸泼尼松的药物组合物
在本申请的一些实施方案中，所述泼尼松或醋酸泼尼松的药物组合物还含有药学上可接受的辅料。优选地，所述药学上可接受的辅料包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂、注射用水等。
在本申请的一些实施方案中，所述药物组合物为固体药物组合物。
在本申请的一些实施方案中，所述药物组合物为片剂。
在本申请的一些实施方案中，所述泼尼松或醋酸泼尼松的药物组合物的单剂量为5mg。
本申请所用的泼尼松片或醋酸泼尼松片可以通过市售获得。
泼尼松龙或醋酸泼尼松龙
如本申请所用，泼尼松龙(prednisolone)化学名为11β,17α,21-三羟基孕甾-1,4-二烯-3,20-二酮，其具有如下式(VI)化合物所示的结构式：
如本申请所用，醋酸泼尼松龙化学名为11β,17α,21-三羟基孕甾-1,4-二烯-3,20-二酮21-醋酸酯，其具有如下式(VII)化合物所示的结构式：
泼尼松龙或醋酸泼尼松龙的药物组合物
在本申请的一些实施方案中，所述泼尼松龙或醋酸泼尼松龙的药物组合物还含有药学上可接受的辅料。优选地，所述药学上可接受的辅料包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂、注射用水等。
在本申请的一些实施方案中，所述药物组合物为固体药物组合物。
在本申请的一些实施方案中，所述药物组合物为片剂。
在本申请的一些实施方案中，所述泼尼松龙或醋酸泼尼松龙的药物组合物的单剂量为5mg。
本申请所用的泼尼松龙片或醋酸泼尼松龙片可以通过市售获得。
施用方式
下述内容并非限制本申请的药物组合的施用方式。
本申请的药物组合中的活性成分可以各自独立地，或者其中的部分或全部共同地以适合的各种途径施用，包括但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。在本申请的一些实施方案中，本申请的药物组合中的活性成分可以各自独立地，或者其中的部分或全部共同地口服施用。
本申请的药物组合中的活性成分可以各自独立地，或者其中的部分或全部共同地是适合的剂型，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
技术效果
本申请的式(II)化合物或其药学上可接受的盐无论作为单一活性剂使用，还是作为药物组合使用，均具有如下效果：
(1)在减少肿瘤的生长或甚至消除肿瘤方面产生较好的疗效；
(2)提供在患者中具有良好耐受的治疗，不良反应和/或并发症少；
(3)提供在所治疗患者之中的较好的疾病控制率；
(4)提供在所治疗的患者中较长的生存期(例如中位生存期、无进展生存期或总生存期)；
(5)提供相比于标准的化疗而言，所治疗患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(6)提供较长时间的疾病缓解持续时间(DOR)。
本申请的式(II)化合物或其药学上可接受的盐无论作为单一活性剂使用，还是作为药物组合使用，“临床有收益”包括但不限于：临床患者无进展生存期(PFS)得到延长、总生存期(OS)得到延长、客观缓解率(ORR)得到提高、疾病控制率(DCR)得到提高、不良反应数量减少和/或程度降低、远处转移率以及局部控制率下降等。
本申请的式(II)化合物或其药学上可接受的盐无论作为单一活性剂使用，还是作为药物组合使用，还具有如下效果：具有较好的PSA缓解率(PSA下降超过基线值50％并维持4周以上的受试者所占百分比例)、影像学无进展生存期(rPFS)延长、至PSA进展时间延长(从首次给药开始至确认出现PSA进展的时间)、淋巴结、软组织病灶和骨病灶进展时间延长。
定义和说明
如文本所用，术语“药物组合”是指同时或先后施用的两种以上的活性成分(以各自的活性成分本身的形式施用，或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。在本文中，术语“药物组合”和“药物联合”可互换使用。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以单一实体或剂型同时施用于个体，或是分开以各自的实体或剂型同时地、并行地或以任何顺序依次地施用于个体。
术语“固定组合”意指活性成分，例如式(II)化合物、醋酸阿比特龙和泼尼松或泼尼松龙，以单一实体或剂型同时施用于患者。
术语“非固定组合”或“成套药盒”意指活性成分，例如式(II)化合物、醋酸阿比特龙和泼尼松或泼尼松龙，以分开的实体没有时间限制地同时、同步或依序施用于患者。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising以及其等同物应理解为开放的、非排他性的意义，即“包括但不限于”，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
术语“患者”或“个体/受试者”是指哺乳动物，例如灵长类动物(人、猕猴、黑猩猩等)、啮齿动物(小鼠、大鼠、兔等)、猫科动物、犬科动物等，优选人。在本申请的一些实施方案中，所述患者和所述个体为经标准治疗失败或缺乏标准治疗的患者。
术语“药学上可接受的”或“可药用的”是指用于制备药物组合物的载体、赋形剂或辅料，该载体、赋形剂或辅料通常是安全、无毒的并且不在生物学上或其它方面不合乎需要，而且包括其对于人类药物的使用是可接受的。
术语“治疗有效量”意指化合物被施用于人来治疗疾病时，足以实现对该疾病的治疗的量。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善、减轻或消除疾病或与所述疾病相关的一个或多个症状，且包括：(i)抑制疾病或疾病状态，即遏制或迟滞其发展；(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
备选方案(例如，“或”)的应用应当被理解为是指备选方案中的任一个、两个或它们的任意组合。本文中使用的不定冠词“一个”或“一种”应当理解为表示任何列举或枚举的组分中的“一个或多个/一种或多种”。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
术语“施用”和“给药”表示使用本领域技术人员已知的多种方法和递送系统中的任一种向个体物理引入包含治疗剂的组合物。在某些实施方案中，施用为口服施用。
术语“每日剂量”是指每日施用于患者的剂量。
术语“每次剂量”是指每次施用于患者的剂量。
术语“单剂量药物组合物”或“单位制剂”是指含有一定量活性成分的药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量药物组合物或单位制剂；例如一盒药有七片药品，则每片药为单剂量药物组合物或单位制剂。
术语“单剂量”或“单位剂量”是指单剂量药物组合物或单位制剂中活性成分的含量。
术语“多剂量药物组合物”由多个单剂量药物组合物或单位制剂组成。
术语“多剂量”由多个“单剂量”或“单位剂量”组成。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、并行地或各自作为单一制剂以任何顺序依次地施用于个体。
如本文所用，“药物组合”、“联用”或“联合使用”意指两种或更多种活性物质可以在混合物中一起、作为单一制剂同时地或作为单一制剂以任何顺序依次地施用于受试者。
术语“药物组合物”是指一种或多种本申请的活性成分或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对个体施用本申请的化合物或其药物组合。
涉及给药方案时，术语“天(日)”、“每天(每日)”等指一个日历日内的时间，开始于午夜且终止于下一个午夜。
术语“转移性”癌症是指从身体的一部分(例如肺部)扩散到身体的另一部分的癌症。
在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。类似地，除非上下文另有明确指示，词语“或”意在包括“和”，反之亦然。
除非另有说明，在本文中，代表成分的量或理化性质或者反应条件等的参数值应当被理解为在所有情况下均由术语“约”修饰。当用术语“约”描述本申请时，术语“约”表示存在的误差值，例如表示在某一特定值的±5％、例如±1％或±0.1％的范围内变化。
在本文中，“PSA”是指前列腺特异抗原。
在本文中，“影像学无进展生存期(rPFS)”指从入组开始至出现疾病影像学进展或复发或各种原因导致的死亡(以先出现的为准)之间的时间。影像学证实的疾病进展包括：RECIST 1.1评价的软组织和淋巴结疾病进展，以及PCWG3评价的骨转移病灶进展。
在本文中，“12个月rPFS率”指rPFS达到12个月及以上的受试者所占百分比例。
在本文中，“生存期(OS)”指从首次用药入组至全因死亡的时间。末次随访时仍存活的受试者，其OS以末次随访时间计为数据删失。失访的受试者，其OS以失访前末次证实存活的时间计为数据删失。
在本文中，“客观缓解率(ORR)”指指研究者依据RECIST 1.1确定的完全缓解(CR)或部分缓解(PR)受试者所占百分比例。
在本文中，“疾病控制率(DCR)”指指研究者依据RECIST 1.1确定的CR、PR或距首次给药大于等于6周后出现疾病稳定(SD)的受试者所占的百分比例。
在本文中，“疾病缓解时间(DOR)”指对于最佳缓解为CR或PR的受试者，定义为从首次记录肿瘤缓解的日期到首次记录疾病进展的日期或因任何原因死亡的日期(以先出现的为准)之间的时间。
在本文中，“临床获益率(CBR)”指按照RECIST 1.1标准评定最佳总体疗效(BOR)为CR、PR和持续≥24周的SD受试者所占的比例。
在本文中，“PSA缓解率”指PSA下降超过基线值50％并维持4周以上的受试者所占百分比例。
在本文中，“至PSA进展时间”指从首次给药开始至确认出现PSA进展的时间。PCWG3标准定义的PSA进展为：对于治疗12周时PSA有下降≥50％的受试者，PSA升高超过最低值25％且绝对值相较于最低值增加≥2ng/mL，并经≥3周后第二次PSA检测确证；对于治疗12周时PSA无应答的受试者，PSA升高超过基线25％且绝对值相较基线值增加≥2ng/mL，并经≥3周后第二次PSA检测确证。
在本文中，“至首发症状性骨相关事件时间(Symptomatic Skeletal Event,SSE)”定义为随机日期至首次发生SSE的时间，SSE包括使用外照射放射治疗(External Beam Radiation therapy,EBRT)来预防或缓解骨骼症状、出现新发症状性病理性骨折(椎骨或非椎骨)、出现脊髓压迫、肿瘤相关骨科手术干预，以先发生者为准。骨相关事件包括通过影像学识别的无症状性骨折,为考虑临床意义，研究通常采用SSE进行评估。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本文中对这些出版物的任何引用并不构成关于该出版物成为本领域 的公知常识的一部分的认可。
实施例
下面的具体实施例的目的是使本领域的技术人员能更清楚地理解和实施本申请。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。
实验例1临床试验
本研究共分为2个队列，分为队列1和队列2，其中队列1为式(II-1)化合物单独治疗队列，队列2为式(II-1)化合物、醋酸阿比特龙、醋酸泼尼松联合治疗队列。队列1和队列2均入组转移性去势抵抗性前列腺癌受试者，评估式(II-1)化合物单独治疗，以及式(II-1)化合物、醋酸阿比特龙、醋酸泼尼松联合治疗的初步疗效和安全性。
1.1主要入选标准：
1)年龄18岁或以上，85岁及以下男性患者；
2)组织学或细胞学证实的前列腺腺癌；
3)具有影像学(如骨扫描和CT/MRI)证实的转移性病灶；
4)筛选访视时血清睾酮水平≤1.73nmol/L(50ng/dL)。未进行双侧睾丸切除术的患者在整个研究期间需要继续使用ADT[促性腺激素释放激素类似物(LHRHa，激动剂/拮抗剂)]治疗；
5)在连续ADT的前提下，出现确定的疾病进展，定义为满足以下一条或多条标准：
(1)至少两次连续PSA值升高且间隔至少1周；如果确定PSA升高是唯一的进展证据，最后一个结果必须至少为1.0ng/mL。；
(2)经RECIST 1.1评估的疾病进展，无论是否存在PSA进展；
(3)经PCWG3评估的骨骼疾病进展，即骨扫描发现有≥2个新发病灶，至少8周后再次评估又发现≥2个上次评估的新骨病灶以外的新发病灶，无论是否存在PSA进展；
6)患者必须终止所有既往癌症治疗(ADT和骨质流失预防性治疗除外)，且在首次用药之前既往治疗或外科手术的所有急性毒性效应均已恢复至≤1级或基线(根据不良事件通用术语标准第5.0版[CTCAE v 5.0])，脱发和周围神经病除外，且自最后1次既往全身性或放射治疗的洗脱期如下：
(1)从使用5-α还原酶抑制剂(例如度他雄胺、非那雄胺)、雌激素和环丙孕酮至入组必须已经过至少4周；
(2)从大手术或放射治疗至入组必须已经过至少4周；
7)具有充足的器官功能；
8)东部肿瘤协作组(ECOG)体能状态(PS)为0至1，预计生存期≥6个月。
1.2试验药
式(II-1)化合物片剂：规格25mg或100mg。
醋酸阿比特龙片：规格250mg。
醋酸泼尼松片：规格5mg。
1.3给药方案
式(II-1)化合物片剂：100mg、150mg、200mg或300mg(以式(II)化合物计)，空腹口服，每日一次，连续服用28天为一个治疗周期。
醋酸阿比特龙片：1000mg(以醋酸阿比特龙计)，空腹口服给药，每日一次，连续服用28天为一个治疗周期。
醋酸泼尼松片：5mg(以醋酸泼尼松计)，餐后口服给药，每日两次，连续服用28天为一个治疗周期。1.4评价标准
1)有效性评价
◆评价标准：根据前列腺癌临床试验工作组3(PCWG3)的建议评估患者临床获益：按照实体瘤疗效评价标准1.1版(RECIST 1.1)评估淋巴结和软组织疾病进展；按照PCWG3“2+2”原则评估 骨骼疾病进展；按照PCWG3定义评估PSA进展；当出现PSA进展后还需结合影像学评估(淋巴结、软组织病灶和骨病灶)以及临床症状综合评估患者临床获益。
◆评价指标包括但不限于影像学无进展生存期(rPFS)、12个月rPFS率、生存期(OS)、客观缓解率(ORR)、疾病控制率(DCR)、疾病缓解时间(DOR)、临床获益率(CBR)、PSA缓解率、至PSA进展时间、至首发症状性骨相关事件时间。
2)安全性评价标准：
◆评价标准：采用NCI－CTC AE 5.0标准判断不良事件严重程度。
◆评价指标包括但不限于不良事件的发生时间、严重程度、与研究治疗的相关性、持续时间、采取的措施和转归等。
1.5部分试验数据
表1入组患者信息
表2部分试验数据

注：N表示入组人数；NED代表无可评估病灶。
本领域技术人员将认识到，本申请的范围并不限于上文描述的各种具体实施方式和实施例，而是能够在不脱离本申请的精神和构思的情况下，进行各种修改、替换、或重新组合，这都落入了本申请的保护范围内。

Claims (15)

  1. 用于治疗患者的前列腺癌的式(I)化合物、其异构体或其药学上可接受的盐，
  2. 用于治疗患者的前列腺癌的药物组合物，所述药物组合物包含式(I)化合物、其异构体或其药学上可接受的盐，
  3. 根据权利要求2所述的药物组合物，其还包含醋酸阿比特龙和泼尼松或泼尼松龙。
  4. 一种药物组合，其包含式(I)化合物、其异构体或其药学上可接受的盐，醋酸阿比特龙和泼尼松或泼尼松龙，
  5. 用于治疗患者的前列腺癌的权利要求3所述的药物组合。
  6. 权利要求1所述的式(I)化合物、其异构体或其药学上可接受的盐，或者权利要求2或3所述的药物组合物，或者权利要求4或5所述的药物组合，其中，式(I)化合物、其异构体或其药学上可接受的盐为式(II)化合物或其药学上可接受的盐，所述式(II)化合物为：
  7. 根据权利要求6所述的式(I)化合物、其异构体或其药学上可接受的盐、或者药物组合物、或者药物组合，其中，式(II)化合物或其药学上可接受的盐的每日剂量为25mg至500mg；
    或者，式(II)化合物或其药学上可接受的盐的每日剂量选自25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg，或者任意前述值作为端点构成的范围或其中的任意值；
    或者，式(II)化合物或其药学上可接受的盐的每日剂量选自100mg、150mg、200mg、或300mg。
  8. 根据权利要求6所述的式(I)化合物、其异构体或其药学上可接受的盐、或者药物组合物、或者药物组合，其中，28天为一个治疗周期，每个治疗周期施用式(II)化合物或其药学上可接受的盐的药物组合物的总剂量为700～14000mg、2800～8400mg或5600～8400mg；
    或者，28天为一个治疗周期，每个治疗周期施用式(II)化合物或其药学上可接受的盐的药物组合物的总剂量选自2800mg、4200mg、5600mg、7000mg、8400mg或上述任意两个值所形成的范围。
  9. 根据权利要求6所述的式(I)化合物、其异构体或其药学上可接受的盐、或者药物组合物、或者药物 组合，其中醋酸阿比特龙的每日剂量选自250mg～1500mg、250mg～1250mg、250mg～1000mg或500mg～1000mg；
    或者，醋酸阿比特龙的每日剂量选自250mg、500mg、750mg、1000mg、1250mg或1500mg；
    或者，醋酸阿比特龙的每日剂量选自500mg、750mg或1000mg。
  10. 根据权利要求6所述的式(I)化合物、其异构体或其药学上可接受的盐、或者药物组合物、或者药物组合，其中泼尼松或泼尼松龙的每日剂量选自5mg～40mg、5mg～35mg、5mg～20mg或10mg～20mg；
    或者，泼尼松或泼尼松龙的每日剂量选自5mg～20mg或10mg～20mg；
    或者，泼尼松或泼尼松龙的每日剂量选自5mg、10mg、15mg或20mg。
  11. 根据权利要求6所述的式(I)化合物、其异构体或其药学上可接受的盐、或者药物组合物、或者药物组合，其中，28天为一个治疗周期，所述药物组合包括：以式(II)化合物计的总剂量为2800～8400mg的含有式(II)化合物或其药学上可接受的盐的药物组合物、以醋酸阿比特龙计的总剂量为7000～28000mg的含有醋酸阿比特龙的药物组合物，以及分别以泼尼松或泼尼松龙计的总剂量为140～560mg的含有泼尼松或泼尼松龙的药物组合物。
  12. 根据权利要求6所述的式(I)化合物、其异构体或其药学上可接受的盐、或者药物组合物、或者药物组合，其中，式(II)化合物或其药学上可接受的盐可以每日施用一次或多次；或者以单剂量每天给药一次或两次；或者以单剂量的口服固体制剂每天给药一次；或者多剂量每天给药一次或两次；或者以多剂量的口服固体制剂每天给药一次。
  13. 根据权利要求6所述的式(I)化合物、其异构体或其药学上可接受的盐、或者药物组合物、或者药物组合，其中，式(II)化合物或其药学上可接受的盐的药物组合物为每日一次剂量，每次剂量为多剂量，其由单剂量为25mg和/或100mg的式(II)化合物或其药学上可接受的盐组成；或者由单剂量为100mg的式(II)化合物或其药学上可接受的盐组成。
  14. 根据权利要求6所述的式(I)化合物、其异构体或其药学上可接受的盐、或者药物组合物、或者药物组合，其中，前列腺癌选自前列腺腺癌。
  15. 根据权利要求6所述的式(I)化合物、其异构体或其药学上可接受的盐、或者药物组合物、或者药物组合，其中，前列腺癌选自去势抵抗性前列腺癌；
    或者，前列腺癌选自转移性去势抵抗性前列腺癌。
PCT/CN2023/095586 2022-05-23 2023-05-22 吲哚并七元酰肟类似物的用途及其药物组合 WO2023226940A1 (zh)

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