WO2023083281A1 - 一种喹啉酮衍生物治疗免疫性血小板减少症的用途 - Google Patents

一种喹啉酮衍生物治疗免疫性血小板减少症的用途 Download PDF

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WO2023083281A1
WO2023083281A1 PCT/CN2022/131278 CN2022131278W WO2023083281A1 WO 2023083281 A1 WO2023083281 A1 WO 2023083281A1 CN 2022131278 W CN2022131278 W CN 2022131278W WO 2023083281 A1 WO2023083281 A1 WO 2023083281A1
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Prior art keywords
immune thrombocytopenia
compound
formula
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/131278
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English (en)
French (fr)
Inventor
赵倩
王训强
张喜全
于鼎
Original Assignee
正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to KR1020247018644A priority Critical patent/KR20240108437A/ko
Priority to EP22892074.0A priority patent/EP4431097A1/en
Priority to CN202280074041.8A priority patent/CN118159269A/zh
Priority to CA3236272A priority patent/CA3236272A1/en
Priority to AU2022386485A priority patent/AU2022386485A1/en
Priority to MX2024005200A priority patent/MX2024005200A/es
Publication of WO2023083281A1 publication Critical patent/WO2023083281A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the application belongs to the field of medicinal chemistry, and relates to the use of a quinolinone derivative for treating immune thrombocytopenia, in particular to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for treating immune thrombocytopenia.
  • Immune thrombocytopenia is an acquired autoimmune hemorrhagic disease, the main feature is an isolated decrease in peripheral blood platelet count without clear cause.
  • ITP immune thrombocytopenia
  • the main feature is an isolated decrease in peripheral blood platelet count without clear cause.
  • ITP immune thrombocytopenia
  • the annual incidence of adult immune thrombocytopenia reported abroad is about (2-10)/100,000.
  • Immune thrombocytopenia can occur in any age group, and it is more likely to occur in the elderly over 60 years old and women of childbearing age.
  • the clinical manifestations of patients with immune thrombocytopenia are different. They may be asymptomatic or only present with skin and mucous membrane bleeding.
  • Spleen tyrosine kinase is an intracellular tyrosine protein kinase that belongs to the ZAP70 protein kinase family. Syk participates in the FcR signaling pathway. After FcR binds to its ligand, the receptor ligation will lead to Syk autophosphorylation, so the recruitment of Syk and the activation of downstream signaling cascades will lead to cytoskeleton rearrangement and phagocytosis. Syk plays a role in a variety of immune recognition receptors, and its continuous expression is closely related to the occurrence and development of various hematological malignancies. Therefore, Syk inhibitors can be used in the treatment of allergic diseases, autoimmune diseases and inflammatory diseases as well as some hematological malignancies.
  • WO2018228475 discloses a series of compounds as Syk inhibitors, and specifically discloses a compound of formula I with the following structure:
  • the application provides a compound of formula I or a pharmaceutically acceptable salt thereof for treating or preventing immune thrombocytopenia in a patient:
  • the present application provides a pharmaceutical composition for treating or preventing immune thrombocytopenia in a patient, the pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further comprises pharmaceutically acceptable carriers and/or excipients.
  • compositions described herein comprise a compound of Formula I or a pharmaceutically acceptable salt thereof as the single active agent.
  • the pharmaceutical composition described herein comprises a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition described herein comprises a single dose of 10-200 mg (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition described herein comprises 10-200 mg (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof as a single active agent.
  • the present application provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing immune thrombocytopenia in a patient.
  • the present application provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment or prevention of immune thrombocytopenia in a patient.
  • the present application provides a method for treating or preventing immune thrombocytopenia in a subject, the method comprising administering a therapeutically effective amount or a preventively effective amount of a compound of formula I or a pharmaceutically acceptable amount thereof to a subject in need. Accepted salts, or pharmaceutical compositions thereof.
  • the compound of formula I described herein or a pharmaceutically acceptable salt thereof is used as a single active agent.
  • the compound of formula I described herein or a pharmaceutically acceptable salt thereof is used in a single dose of 10-200 mg (based on the weight of the compound of formula I).
  • the compound of formula I or a pharmaceutically acceptable salt thereof of the present application may be in the form of a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof .
  • the present application provides a kit for treating immune thrombocytopenia in a patient, the kit comprising the compound of formula I described in the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and Instructions for use in the treatment or prevention of immune thrombocytopenia in patients.
  • the compound of formula I described herein or a pharmaceutically acceptable salt thereof may be in the form of a single dose of 10-200 mg (by weight of the compound of formula I).
  • the pharmaceutical composition may be a single-dose pharmaceutical composition comprising 10-200 mg (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of formula I described in the present application can be obtained by referring to the preparation method in WO2018228475 or WO2020119785.
  • a pharmaceutically acceptable salt of a compound of formula I may be a hydrochloride salt of a compound of formula I, such as a monohydrochloride salt of a compound of formula I.
  • the dosage of the compound of formula I or the pharmaceutically acceptable salt thereof involved in this application, unless otherwise specified, is calculated based on the molecular weight of the compound of formula I.
  • the hydrochloride salt of the compound of formula I described in the present application can be obtained by referring to the preparation method in WO2020119785.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains a single dose of 10-200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains a single dose of 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, or 200 mg, or any of the foregoing values as endpoints of a range or any value therein The compound of formula I or a pharmaceutically acceptable salt thereof, such as 50 mg or 200 mg, etc. In some embodiments, the pharmaceutical composition contains a single dose of 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is a single dose pharmaceutical composition. In some embodiments of the present application, the pharmaceutical composition is a pharmaceutical composition with a single dose of 10-200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered every day, and the total dose of each treatment cycle includes 0.7g to 42g, such as 5.6 ⁇ 22.4g.
  • the total dose per treatment cycle of the compound of formula I or a pharmaceutically acceptable salt thereof includes a range selected from 5.6g, 11.2g, 16.8g, 22.4g or any value above.
  • the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof per treatment cycle preferably comprises 11.2-22.4 g.
  • the total dose per treatment cycle of the compound of formula I or a pharmaceutically acceptable salt thereof preferably comprises 11.2 g or 16.8 g.
  • the total dose per treatment cycle of the compound of formula I or a pharmaceutically acceptable salt thereof preferably comprises 16.8 g.
  • the pharmaceutical composition includes, but is not limited to, formulations suitable for oral, parenteral, and topical administration. In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid preparation suitable for oral administration. In some embodiments, the pharmaceutical composition includes, but is not limited to, tablets, capsules.
  • the pharmaceutical composition is a solid pharmaceutical composition.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof may be a solid pharmaceutical composition of the compound of formula I hydrochloride.
  • the pharmaceutical composition described in the application may be a pharmaceutical composition of the monohydrochloride salt of the compound of formula I. In some embodiments, the pharmaceutical composition described in the application may be a solid pharmaceutical composition of the monohydrochloride salt of the compound of formula I.
  • the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is a tablet of the compound of formula I hydrochloride, such as the monohydrochloride of the compound of formula I.
  • composition of the compound of formula I or a pharmaceutically acceptable salt thereof of the present application may also contain pharmaceutically acceptable carriers and/or excipients.
  • pharmaceutically acceptable carriers and/or excipients are well known to those skilled in the art, and include, for example, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • composition of the compound of formula I of the present application or its pharmaceutically acceptable salt can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, sugar-coated pills, pulverizing, emulsifying method, freeze-drying method, etc.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or the core of a capsule or dragee.
  • suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the immune thrombocytopenia is primary immune thrombocytopenia or secondary immune thrombocytopenia.
  • said immune thrombocytopenia is primary immune thrombocytopenia.
  • the immune thrombocytopenia includes: newly diagnosed immune thrombocytopenia, persistent immune thrombocytopenia or chronic immune thrombocytopenia.
  • the immune thrombocytopenia is persistent immune thrombocytopenia or chronic immune thrombocytopenia.
  • the immune thrombocytopenia is chronic immune thrombocytopenia.
  • the immune thrombocytopenia is persistent or chronic primary immune thrombocytopenia.
  • the immune thrombocytopenia is adult persistent or chronic primary immune thrombocytopenia.
  • the immune thrombocytopenia is relapsed and/or refractory primary immune thrombocytopenia.
  • the immune thrombocytopenia is relapsed and/or refractory persistent primary immune thrombocytopenia.
  • the immune thrombocytopenia is relapsed and/or refractory chronic primary immune thrombocytopenia.
  • the immune thrombocytopenia is adult relapsed and/or refractory persistent primary immune thrombocytopenia.
  • the immune thrombocytopenia is adult relapsed and/or refractory chronic primary immune thrombocytopenia.
  • the patient with persistent or chronic immune thrombocytopenia is a patient with sustained decrease in platelets for more than 3 months after diagnosis.
  • the patient with persistent or chronic immune thrombocytopenia is a patient with sustained decrease in platelets for more than 6 months after diagnosis.
  • the WHO bleeding score of the patient with persistent or chronic immune thrombocytopenia is 0-1.
  • the patient with persistent or chronic immune thrombocytopenia has at least two independent platelet counts with an average value less than 30 ⁇ 10 9 /L before treatment, and a single platelet count is not more than 35 ⁇ 10 9 /L.
  • the patient with persistent or chronic immune thrombocytopenia has at least two independent platelet counts with an average value less than 30 ⁇ 10 9 /L before treatment, and a single platelet count is not more than 35 ⁇ 10 9 /L, and no serious bleeding within 4 weeks before treatment.
  • the severe bleeding refers to a WHO bleeding score ⁇ 3 points.
  • the immune thrombocytopenia patient is a patient who has previously received one or more prior treatments for immune thrombocytopenia. In some embodiments, the immune thrombocytopenia patient is a patient who has received one, two, three, four, or five prior treatments for immune thrombocytopenia.
  • the prior immune thrombocytopenia treatment comprises drug treatment, or surgical treatment, or a combination thereof.
  • the drug therapy includes but is not limited to glucocorticoid therapy, immunoglobulin therapy, molecular targeted therapy, thrombocytopenia drug therapy, or other drugs that can be used to treat immune thrombocytopenia treat.
  • the glucocorticoids include but are not limited to prednisone, methylprednisone, prednisone acetate, prednisolone, methylprednisolone, prednisolone acetate, Prednisolone sodium succinate, methylprednisolone sodium succinate, betamethasone, beclomethasone dipropionate, hydrocortisone, or dexamethasone.
  • the glucocorticoids include dexamethasone and prednisone.
  • the glucocorticoid therapy may be pulsed high-dose glucocorticoid therapy.
  • the immunoglobulin includes immunoglobulin for injection.
  • the immunoglobulin may be gamma immunoglobulin.
  • the immunoglobulin for injection is gamma immunoglobulin for injection, such as gamma immunoglobulin for intravenous injection.
  • the drugs for molecular targeted therapy include but are not limited to rituximab, veltuzumab, daclizumab, basiliximab, Alemtuzumab or ocrelizumab.
  • the drug for molecular targeted therapy includes rituximab.
  • the platelet-promoting drugs include but are not limited to avatrombopag, eltrombpag, romiplostim, lusutrombopag ), or recombinant human thrombopoietin (rhTPO).
  • the thrombopoietic drugs include alvatrombopag, eltrombopag, romigrastim, or recombinant human thrombopoietin (rhTPO).
  • the thrombopoietic drugs include Eltrombopag and recombinant human thrombopoietin.
  • the other drugs that can be used to treat immune thrombocytopenia include but are not limited to immunosuppressants.
  • the other drugs that can be used to treat immune thrombocytopenia include but are not limited to immunosuppressants, such as ganciclovir sodium, imatinib, cyclosporine (A), wheat Sodium corfenol, mycophenolate mofetil (mycophenolate mofetil), danazol, azathioprine, psoralen, methotrexate, hydroxychloroquine, triamphenazine, cyclophosphamide, thalidomide Methamide, azithromycin, montelukast, sorafenib, ruxolitinib, decitabine, vincristine, alefacept, all-trans retinoic acid.
  • immunosuppressants such as ganciclovir sodium, imatinib, cyclosporine (A), wheat Sodium corfenol, my
  • the other drugs that can be used to treat immune thrombocytopenia include danazol, azathioprine, cyclosporine (A), vincristine, all-trans retinoic acid or mycophenolate mofetil.
  • the other drugs that can be used to treat immune thrombocytopenia include danazol, azathioprine, cyclosporine (A), all-trans retinoic acid or vincristine.
  • the other drugs that can be used to treat immune thrombocytopenia include all-trans retinoic acid combined with danazol, decitabine, cyclosporine (A), azathioprine, danazol, and/or vincristine treatment.
  • the drugs used in the drug treatment include but are not limited to prednisone, methylprednisone, prednisone acetate, prednisolone, methylprednisolone, prednisolone acetate , prednisolone sodium succinate, methylprednisolone sodium succinate, betamethasone, beclomethasone dipropionate, hydrocortisone, dexamethasone, immunoglobulin for injection (such as gamma immune globulin for injection protein), rituximab, veltuzumab, daclizumab, basiliximab, ocrelizumab, alemtuzumab, avatrumab Avatrombopag, eltrombpag, romiplostim, lusutrombopag, recombinant human thrombopoietin (rhTPO), danazol, azathi
  • the surgical treatment is splenectomy treatment.
  • the patient with immune thrombocytopenia may be a patient with poor efficacy of splenectomy or postoperative recurrence.
  • the immune thrombocytopenia patient may be a patient who has previously failed one or more first-line or multiple-line standard treatments. In some embodiments, the immune thrombocytopenia patient may be a patient who has previously failed one or more first-line, second-line, third-line or fourth-line standard treatments. In some embodiments, the immune thrombocytopenia patient may be a patient who has previously failed one or more first-line, second-line or third-line standard treatments. In some embodiments, the immune thrombocytopenia patient may be a patient who has previously failed one, two, three, four or five first-line standard treatments.
  • the first-line standard treatment includes but is not limited to glucocorticoid treatment and/or injection immunoglobulin treatment.
  • the glucocorticoid therapy is dexamethasone or prednisone therapy.
  • the injectable immunoglobulin therapy is injectable gamma globulin therapy.
  • the second-line standard treatment includes, but is not limited to, platelet-promoting drug treatment and/or molecular targeted therapy and/or surgical treatment.
  • the thrombopoietic drug therapy is Eltrombopag and/or recombinant human thrombopoietin therapy.
  • the molecularly targeted therapy is rituximab therapy.
  • the surgical treatment is splenectomy treatment.
  • the third-line standard treatment includes, but is not limited to, all-trans retinoic acid combined with danazol treatment and/or decitabine treatment.
  • the fourth-line standard treatment includes but is not limited to azathioprine and/or cyclosporine (A) and/or danazol and/or vinblastine treatment.
  • the patient with immune thrombocytopenia may have previously received at least one standard first-line treatment for immune thrombocytopenia (such as glucocorticoid treatment and/or intravenous gamma globulin treatment) Failure, or poor response to splenectomy or postoperative recurrence.
  • at least one standard first-line treatment for immune thrombocytopenia such as glucocorticoid treatment and/or intravenous gamma globulin treatment
  • the patient with immune thrombocytopenia can be an adult patient with persistent or chronic immune thrombocytopenia who has been diagnosed for more than 3 months, and/or has at least one previous first-line standard for immune thrombocytopenia Patients who have failed treatment (such as glucocorticoid therapy and/or intravenous gamma globulin therapy), or who have had poor response to splenectomy or relapsed after surgery.
  • glucocorticoid therapy and/or intravenous gamma globulin therapy or who have had poor response to splenectomy or relapsed after surgery.
  • the treatment failure means that the treatment is ineffective, or the curative effect cannot be maintained, or relapses.
  • the patients with immune thrombocytopenia can be treated with a combination of multiple therapeutic modalities.
  • the patients with immune thrombocytopenia can be combined with first-line standard treatment, and/or second-line standard treatment, and/or third-line standard treatment, and/or fourth-line standard treatment.
  • the patient with immune thrombocytopenia may be a patient who has previously received glucocorticoid therapy and has stopped the drug for at least 3 weeks.
  • the immune thrombocytopenia patient may be a patient who has previously received danazol therapy and has stopped the drug for at least 4 weeks.
  • the patients with immune thrombocytopenia may have received dazathioprine, cyclosporine (A) and/or mycophenolate mofetil in the past, and the drug has been discontinued for at least 4 days. weeks of patients.
  • the immune thrombocytopenia patient may suffer from more than one (eg, one, two or three) immune thrombocytopenias. In some embodiments of the present application, the immune thrombocytopenia optionally includes a combination of any two or more of the above-mentioned types of immune thrombocytopenia. In some embodiments of the present application, the immune thrombocytopenia patient may suffer from two or more types of immune thrombocytopenia. For example, the immune thrombocytopenia patient may suffer from a combination of any two or more selected from the above-mentioned types of immune thrombocytopenia.
  • poor efficacy means that the platelet count after treatment is less than 30 ⁇ 10 9 /L, or the platelet count does not increase to 2 times of the baseline value, or there is bleeding.
  • the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof may be 2-6 weeks. In some embodiments of the present application, the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or the above-mentioned A range of arbitrary values. In some embodiments of the present application, the administration period of the compound of formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof may be 4-5 weeks. In some embodiments, the administration cycle of the compound of formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof may be 1-6 administration cycles, such as 1, 2, 3, 4, 5 or 6 dosing cycles.
  • the administration period of the therapeutic treatment with the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be 2-6 weeks. In some embodiments of the present application, the administration period for therapeutic treatment may be 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or the range formed by any of the above values. In some embodiments of the present application, the administration cycle for therapeutic treatment may be 4-5 weeks.
  • the dosage regimen of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treatment or prevention may be 1 to 3 times a day, Or administered once every two days; preferably once a day.
  • the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be selected from 50-1000 mg.
  • the daily dose of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition can be selected from 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg , 900mg, 1000mg or the range formed by any of the above values.
  • the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 200-800 mg, 200-800 mg, 400-800 mg, 400-600 mg or 600-800mg.
  • the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treatment or prevention may be selected from 50-1000 mg.
  • the daily dose of the compound of formula I or its pharmaceutically acceptable salt or pharmaceutical composition thereof for treatment or prevention can be selected from 100mg, 200mg, 300mg, 400mg, 500mg , 600mg, 700mg, 800mg, 900mg, 1000mg or the range formed by any of the above-mentioned values.
  • the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treatment or prevention can be selected from 200-800 mg, 200-800 mg, 400 - 800mg, 400-600mg or 600-800mg.
  • each dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be selected from 50-1000 mg.
  • each dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be selected from 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg , 800mg, 900mg, 1000mg or the range formed by any of the above values.
  • each dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be selected from 50-800mg, 200-800mg, 200-600mg, 200-400mg , 400-800mg, 400-600mg, or 600-800mg.
  • each dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treatment or prevention may be selected from 50-1000 mg. In some embodiments of the present application, each dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treatment or prevention may be selected from 50 mg, 100 mg, 200 mg, 300 mg, 400 mg , 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg or the range formed by any of the above-mentioned values.
  • each dose of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treatment or prevention may be selected from 50-800 mg, 200-800 mg, 200 - 600 mg, 200-400 mg, 400-800 mg, 400-600 mg, or 600-800 mg.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition.
  • the pharmaceutical composition in the treatment of immune thrombocytopenia in a patient, is administered in a single dose once, twice or three times a day. In some embodiments of the present application, in the treatment of patients with immune thrombocytopenia, the pharmaceutical composition is administered in the form of a single oral solid preparation once, twice or three times a day.
  • the pharmaceutical composition in treating immune thrombocytopenia in a patient, is administered in multiple doses once or twice a day. In some embodiments of the present application, in the treatment of patients with immune thrombocytopenia, the pharmaceutical composition is administered in the form of multiple doses of oral solid preparations once or twice a day. In a specific embodiment, in the treatment of immune thrombocytopenia in a patient, said pharmaceutical composition is administered once daily in the form of multiple doses of oral solid formulations.
  • the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is dosed once a day, and each dose is a single dose or multiple doses, preferably multiple doses, and the multiple doses are The dosage consists of a single dose of 10-200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the multiple doses consist of a single dose of 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, or 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition consists of a single dose of 50 mg or 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • 28 days is a treatment cycle, and the compound of formula I or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered continuously on days 1-28 of each cycle.
  • 28 days is a treatment cycle, and the compound of formula I or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is continuously administered daily on days 1-28 of each cycle.
  • 28 days is a treatment cycle, and the compound of formula I or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is continuously administered once a day on days 1-28 of each cycle.
  • 28 days is a treatment cycle, and the compound of formula I or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered on an empty stomach once a day continuously on days 1-28 of each cycle.
  • 28 days is a treatment cycle, and the compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is continuously administered once a day on days 1-28 of each cycle, said Each dose of the compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is a single dose, and the single dose is 50 mg or 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof can be packaged in a kit, and the kit includes doses for one or more treatment cycles, or one Dosage within a treatment cycle, or a dose of a range consisting of any of the foregoing values as endpoints of the compound of formula I above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is packaged in a kit, and the kit includes 1-28 days (for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, or 28 days), or a dose of one treatment cycle, two treatment cycles, or more than three treatment cycles, or any of the foregoing
  • the dose of the above-mentioned compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof at a dose of a range constituted by values as endpoints.
  • the compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is packaged in a kit, and the kit includes 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 , 22 days, 23 days, 24 days, 25 days, 26 days, 27 days or 28 days doses, or the above-mentioned compound of formula I or its pharmaceutically acceptable salts or medicines thereof in the dose of the range formed by any aforementioned value as the endpoint combination.
  • the compound of formula I above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is packaged in a kit, and the kit includes 1 day, 2 days, 3 days, 4 days, 5 days Daily, 6th, 7th, 14th, 21st, or 28th dose, or the dose of any of the aforementioned values as the range constituted by the endpoint, the above-mentioned compound of formula I or its pharmaceutically acceptable salt or its pharmaceutical composition.
  • 28 days is a treatment cycle
  • the total dose of the compound of formula I or its pharmaceutically acceptable salt or its pharmaceutical composition administered in each treatment cycle is 5.6-22.5 g (in the form of active ingredient formula I compound itself).
  • the total dose of the compound of formula I or its pharmaceutically acceptable salt or its pharmaceutical composition is selected from the range formed by 5.6g, 11.2g, 16.8g, 22.4g or any of the above-mentioned values (Based on active ingredient formula I compound itself).
  • the total dose of the compound of formula I or its pharmaceutically acceptable salt or pharmaceutical composition thereof is preferably 11.2-16.8 g (based on the active ingredient compound of formula I itself).
  • the total dose of the compound of formula I or its pharmaceutically acceptable salt or pharmaceutical composition thereof is preferably 11.2 g or 16.8 g (based on the active ingredient compound of formula I itself).
  • the treatment cycles described above may be repeated as long as the disease remains under control and the dosing regimen is clinically tolerable.
  • the above-mentioned dosage regimen is suitable for the compound of formula I described in this application or its pharmaceutically acceptable salt or its pharmaceutical composition, pharmaceutical combination, kit, or the treatment or prevention of immunity described in this application.
  • the compound of formula I of the present application has good safety in the treatment of immune thrombocytopenia, and can effectively improve the platelet count value of patients with immune thrombocytopenia.
  • the percentage of subjects with at least one platelet count ⁇ 30 ⁇ 10 9 /L and an increase ⁇ 2 times compared with the baseline platelet count within 12 weeks of treatment (during which no emergency treatment was received) was high.
  • the percentage of subjects with at least one platelet count ⁇ 50 x 10 9 /L within 12 weeks of treatment was also higher.
  • administration refers to the physical introduction of a therapeutic agent or a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • administration or “administration” or “administration” are used interchangeably herein.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier and/or excipient refers to those carriers and/or excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound.
  • pharmaceutically acceptable salt includes salts formed between alkali ions and free acids or salts formed between acid ions and free bases.
  • ineffectiveness of treatment refers to treatment until the platelet count ⁇ 30 ⁇ 10 9 /L or an increase of ⁇ 2 times compared with the baseline after 12 weeks of treatment.
  • the curative effect cannot be maintained refers to the platelet count ⁇ 30 ⁇ 10 9 /L or the increase of ⁇ 2 times compared with the baseline for 12 weeks, except for the increase of platelets caused by emergency treatment.
  • the content of the compound of formula I or a pharmaceutically acceptable salt thereof is calculated in the form of free base, such as dosage, dose, and content in the pharmaceutical composition.
  • compounds in the pharmaceutical combinations of the present application may form acid addition salts if they have, for example, at least one basic center.
  • Corresponding acid addition salts can also be formed which, if desired, have an additionally present basic center.
  • Compounds having at least one acidic group eg COOH
  • patient is a mammal such as a human, dog, cow, horse, pig, sheep, goat, cat, mouse, rabbit, rat, and transgenic non-human animals. In some embodiments, the patient is human.
  • subject or “patient” are used interchangeably herein.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound of the present application or a salt thereof to a patient.
  • treatment generally refers to obtaining desired pharmacological and/or physiological effects, including partial or complete stabilization or cure of a disease and/or effects resulting from a disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.
  • prevention means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including: preventing a disease or disease state from occurring in a mammal, especially when the when the mammalian mammal is susceptible to the disease state but has not been diagnosed as having the disease state.
  • an effective amount means an amount of a compound of the present application that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine.
  • a box of medicine has seven capsules, and each capsule is a single dose; or each bottle of injection is a single dose.
  • multiple dose consists of a number of single doses.
  • relapse refers to the reoccurrence of disease after an objective response has been achieved with a treatment regimen.
  • refractory means that a particular disease is resistant or unresponsive to therapy with a particular therapeutic agent.
  • refractory immune thrombocytopenia refers to the ineffectiveness of first-line treatment drugs, platelet-stimulating drugs in second-line treatment, and rituximab, or ineffective splenectomy/postoperative recurrence, and the diagnosis is still confirmed after re-evaluation patients with immune thrombocytopenia.
  • the compound of formula I is prepared based on the method disclosed in WO2018228475.
  • Test drug tablet of the compound of formula I, the specification is 50mg/tablet or 200mg/tablet;
  • Dosing regimen Take it orally once a day on an empty stomach, and take 28 consecutive days as a treatment cycle.
  • the WHO bleeding score is 0 to 1, and the investigator judges that no emergency treatment is expected within 2 weeks after enrollment;
  • ANC neutrophil count
  • Hb hemoglobin
  • TBIL Total bilirubin
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • the prothrombin time (PT) does not exceed ⁇ 3s of the normal value range, and the activated partial thromboplastin time (APTT) does not exceed the normal value range of ⁇ 10s;
  • Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study period and within 90 days after the end of the study; the serum pregnancy test was negative within 7 days before study enrollment, and must Non-lactating subjects; male subjects should agree to use contraceptive measures during the study period and 6 months after the end of the study period.
  • contraceptive measures such as intrauterine devices, contraceptives or condoms
  • Efficacy was evaluated by subjects' platelet count, WHO bleeding score and receiving emergency treatment. To improve the effective rate of platelets as the main efficacy index, the evaluation criteria refer to the "American Hematology Annual Meeting Guidelines for Primary Immune Thrombocytopenia (2019 Edition)” and “Chinese Guidelines for the Diagnosis and Treatment of Adult Primary Immune Thrombocytopenia (2020 Edition) )”.
  • the overall safety of the tablet of the compound of formula I is controllable in adult subjects with persistent or chronic immune thrombocytopenia, with no dose-limiting toxicity (DLT) events, and no grade 3 or above treatment-related adverse events.
  • DLT dose-limiting toxicity
  • the percentage of subjects whose platelet count ⁇ 30 ⁇ 10 9 /L and increased ⁇ 2 times compared with the baseline platelet count within 12 weeks of treatment in the evaluated patients was 50%; platelet count within 12 weeks of treatment
  • the percentage of subjects with at least one episode ⁇ 50 ⁇ 10 9 /L was 33.3%. It was found that the tablet of the compound of formula I of the present application has excellent clinical benefits for the treatment of persistent or chronic immune thrombocytopenia in adults.
  • Table 1 shows the effectiveness in representative cases.

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Abstract

一种喹啉酮衍生物治疗免疫性血小板减少症的用途，具体涉及式(I)化合物或其药学上可接受的盐或其药物组合物治疗免疫性血小板减少症的用途。

Description

一种喹啉酮衍生物治疗免疫性血小板减少症的用途
相关申请的引用
本申请要求于2021年11月12日向中华人民共和国国家知识产权局提交的第202111340688.4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
本申请属于医药化学领域，涉及一种喹啉酮衍生物治疗免疫性血小板减少症的用途，具体涉及式I化合物或其药学上可接受的盐治疗免疫性血小板减少症的用途。
背景技术
原发免疫性血小板减少症(immune thrombocytopenia,ITP)是一种获得性自身免疫性出血性疾病，主要特征为无明确诱因的孤立性外周血血小板计数减少。目前国内尚无基于人群的免疫性血小板减少症流行病学数据，国外报道的成人免疫性血小板减少症年发病率约为(2-10)/10万。免疫性血小板减少症可发生于任何年龄段，好发于60岁以上老年人和育龄期女性。免疫性血小板减少症患者临床表现不一，可无症状，也可仅表现为皮肤黏膜出血，约5％的免疫性血小板减少症患者表现为重要脏器及颅内出血，危及生命；约15％的免疫性血小板减少症患者诊断后5年内因出血事件住院。除出血事件外，绝大多数免疫性血小板减少症患者感到疲乏和健康相关生活质量(HRQoL)下降。
脾酪氨酸激酶(Syk：spleen tyrosine kinase)是一种胞内酪氨酸蛋白激酶，属于ZAP70蛋白激酶家族中的成员。Syk参与FcR信号通路，FcR与其配体结合后，受体连接会导致Syk自身磷酸化，因此Syk募集和下游信号传导级联的激活，将导致细胞骨架重排和吞噬作用。Syk在多种免疫识别受体中发挥作用，其持续表达与多种血液恶性肿瘤的发生、发展有重要关联。因此，Syk抑制剂可用于治疗变态反应性疾病、自身免疫性疾病和炎性疾病以及部分血液恶性肿瘤。
WO2018228475公开了一系列作为Syk抑制剂的化合物，还具体公开了如下结构的式I化合物：
Figure PCTCN2022131278-appb-000001
发明内容
一方面，本申请提供用于治疗或预防患者的免疫性血小板减少症的式I化合物或其药学上可接受的盐：
Figure PCTCN2022131278-appb-000002
另一方面，本申请提供用于治疗或预防患者的免疫性血小板减少症的药物组合物，所述药物组合物包含式I化合物或其药学上可接受的盐。
在一些实施方案中，所述药物组合物还含有药学上可接受的载体和/或赋形剂。
在一些实施方案中，本申请所述药物组合物包含式I化合物或其药学上可接受的盐作为单一活性剂。
在一些实施方案中，本申请所述药物组合物包含治疗有效量或预防有效量的式I化合物或其药学上可接受的盐。
在一些实施方案中，本申请所述药物组合物包含单剂量为10-200mg(以式I化合物重量计)的式I化合物或其药学上可接受的盐。
在一些实施方案中，本申请所述药物组合物包含10-200mg(以式I化合物重量计)的式I化合物或其药学上可接受的盐作为单一活性剂。
另一方面，本申请提供式I化合物或其药学上可接受的盐、或其药物组合物在制备治疗或预防患者的免疫性血小板减少症的药物中的用途。
另一方面，本申请提供式I化合物或其药学上可接受的盐、或其药物组合物在治疗或预防患者的免疫性血小板减少症中的用途。
另一方面，本申请提供治疗或预防受试者的免疫性血小板减少症的方法，所述方法包括向有需要的受试者给予治疗有效量或预防有效量的式I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，本申请所述的式I化合物或其药学上可接受的盐是作为单一活性剂使用。
在一些实施方案中，本申请所述的式I化合物或其药学上可接受的盐以单剂量10-200mg(以式I化合物重量计)使用。
在本申请的一些方案中，本申请的式I化合物或其药学上可接受的盐可处于包含治疗有效量或预防有效量的式I化合物或其药学上可接受的盐的药物组合物的形式。
另一方面，本申请提供用于治疗患者的免疫性血小板减少症的试剂盒，所述试剂盒包含本申请所述的式I化合物或其药学上可接受的盐、或其药物组合物，以及治疗或预防患者的免疫性血小板减少症的使用说明。
在一些实施方案中，本申请所述的式I化合物或其药学上可接受的盐可处于单剂量10-200mg(以式I化合物重量计)的形式。
在一些实施方案中，所述药物组合物可为包含10-200mg(以式I化合物重量计)的式I化合物或其药学上可接受的盐作为活性成分的单剂量药物组合物。
式I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，本申请所述的式I化合物可以参照WO2018228475或WO2020119785中的制备方法得到。
如本申请所用，式I化合物的药学上可接受的盐可以是式I化合物的盐酸盐，例如式I化合物的单盐酸盐。本申请中涉及的式I化合物或其药学上可接受的盐的剂量，除非另有说明，均基于式I化合物的分子量计算。
在本申请的一些实施方案中，本申请所述的式I化合物的盐酸盐可以参照WO2020119785中的制备方法得到。
式I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I化合物或其药学上可接受的盐为包含治疗有效量或预防有效量的式I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，所述药物组合物含有单剂量为10-200mg的式I化合物或其药学上可接受的盐。在一些实施方案中，所述药物组合物含有单剂量为10mg、20mg、40mg、50mg、60mg、80mg、100mg、120mg、150mg、或200mg，或任意前述值作为端点构成的范围或其中的任意值的式I化合物或其药学上可接受的盐，例如50mg或200mg等。在一些实施方案中，所述药物组合物含有单剂量为200mg的式I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，所述药物组合物为单剂量药物组合物。在本申请的一些实施方案中，所述药物组合物为单剂量为10-200mg的式I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，按照2-6周(例如28天)的治疗周期，每天给予式I化合物或其药学上可接受的盐，每治疗周期总剂量包括0.7g～42g，例如5.6～22.4g。在部分实施方案中，所述式I化合物或其药学上可接受的盐的每治疗周期总剂量包括选自5.6g、11.2g、16.8g、22.4g或上述任意值形成的范围。在部分实施方案中，所述式I化合物或其药学上可接受的盐的每治疗周期总剂量优选包括11.2～22.4g。在部 分实施方案中，所述式I化合物或其药学上可接受的盐的每治疗周期总剂量优选包括11.2g或16.8g。在部分实施方案中，所述式I化合物或其药学上可接受的盐的每治疗周期总剂量优选包括16.8g。
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，所述药物组合物为片剂。
在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐的药物组合物可为式I化合物盐酸盐的固体药物组合物。
在一些实施方案中，所述申请所述的药物组合物可为式I化合物的单盐酸盐的药物组合物。在一些实施方案中，所述申请所述的药物组合物可为式I化合物的单盐酸盐的固体药物组合物。
在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐的药物组合物为式I化合物盐酸盐、例如式I化合物的单盐酸盐的片剂。
本申请的式I化合物或其药学上可接受的盐的药物组合物还可以含有药学上可接受的载体和/或赋形剂。药学上可接受的载体和/或赋形剂是本领域技术人员熟知的，例如包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。
本申请的式I化合物或其药学上可接受的盐的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或胶囊或糖衣剂的核心。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。
免疫性血小板减少症
在本申请的一些实施方案中，所述免疫性血小板减少症是原发免疫性血小板减少症或继发性免疫性血小板减少症。优选地，所述免疫性血小板减少症是原发免疫性血小板减少症。
在本申请的一些实施方案中，所述免疫性血小板减少症包括：新诊断的免疫性血小板减少症、持续性免疫性血小板减少症或慢性免疫性血小板减少症。优选地，所述免疫性血小板减少症是持续性免疫性血小板减少症或慢性免疫性血小板减少症。进一步优选地，所述免疫性血小板减少症是慢性免疫性血小板减少症。
在本申请的一些实施方案中，所述免疫性血小板减少症是持续性或慢性原发免疫性血小板减少症。
在本申请的一些实施方案中，所述免疫性血小板减少症是成人持续性或慢性原发免疫性血小板减少症。
在本申请的一些实施方案中，所述免疫性血小板减少症是复发和/或难治性原发免疫性血小板减少症。
在本申请的一些实施方案中，所述免疫性血小板减少症是复发和/或难治性持续性原发免疫性血小板减少症。
在本申请的一些实施方案中，所述免疫性血小板减少症是复发和/或难治性慢性原发免疫性血小板减少症。
在本申请的一些实施方案中，所述免疫性血小板减少症是成人复发和/或难治性持续性原发免疫性血小板减少症。
在本申请的一些实施方案中，所述免疫性血小板减少症是成人复发和/或难治性慢性原发免疫性血小板减少症。
在本申请的一些实施方案中，所述持续性或慢性免疫性血小板减少症患者是确诊后血小板持续减少超过3个月的患者。
在本申请的一些实施方案中，所述持续性或慢性免疫性血小板减少症患者是确诊后血小板持续减少超过6个月的患者。
在本申请的一些实施方案中，所述持续性或慢性免疫性血小板减少症患者WHO出血评分为0～1分。
在本申请的一些实施方案中，所述持续性或慢性免疫性血小板减少症患者在治疗之前至少两次独立血小板计数平均值小于30×10 9/L，并且单次血小板计数不大于35×10 9/L。
在本申请的一些实施方案中，所述持续性或慢性免疫性血小板减少症患者在治疗之前至少两次独立血小板计数平均值小于30×10 9/L，并且单次血小板计数不大于35×10 9/L，且在治疗前4周内无严重出血。在本申请的一些实施方案中，所述严重出血是指WHO出血评分为≥3分。
在本申请的一些实施方案中，所述免疫性血小板减少症患者是既往接受过一种或多种在先免疫性血小板减少症治疗的患者。在一些实施方案中，所述免疫性血小板减少症患者是既往接受过一种、两种、三种、四种或五种在先免疫性血小板减少症治疗的患者。
在本申请的一些实施方案中，所述在先免疫性血小板减少症治疗包括药物治疗、或手术治疗，或其组合。
在本申请的一些实施方案中，所述药物治疗包括但不限于糖皮质激素治疗、免疫球蛋白治疗、分子靶向治疗、促血小板生成药物治疗、或其他可用于治疗免疫性血小板减少症的药物治疗。
在本申请的一些实施方案中，所述糖皮质激素包括但不限于泼尼松、甲泼尼松、醋酸泼尼松、泼尼松龙、甲基泼尼松龙、醋酸泼尼松龙、泼尼松龙琥珀酸钠、甲基泼尼松龙琥珀酸钠、倍他米松、丙酸倍氯米松、氢化可的松或地塞米松。优选地，所述糖皮质激素包括地塞米松和泼尼松。在一些实施方案中，所述糖皮质激素治疗可为脉冲高剂量糖皮质激素治疗。
在本申请的一些实施方案中，所述免疫球蛋白包括注射用免疫球蛋白。在本申请的一些实施方案中，所述免疫球蛋白可为丙种免疫球蛋白。优选地，所述注射用免疫球蛋白为注射用丙种免疫球蛋白，例如静脉注射用丙种免疫球蛋白。
在本申请的一些实施方案中，所述用于分子靶向治疗的药物包括但不限于利妥昔单抗、维妥珠单抗(veltuzumab)、达利珠单抗、巴利昔单抗、阿仑单抗(alemtuzumab)或奥瑞组单抗(ocrelizumab)。优选地，所述用于分子靶向治疗的药物包括利妥昔单抗。
在本申请的一些实施方案中，所述促血小板生成药物包括但不限于阿伐曲泊帕(avatrombopag)、艾曲泊帕(eltrombpag)、罗米司亭(romiplostim)、芦曲泊帕(lusutrombopag)、或重组人血小板生成素(rhTPO)。优选地，所述促血小板生成药物包括阿伐曲泊帕、艾曲泊帕、罗米司亭、或重组人血小板生成素(rhTPO)。进一步优选地，所述促血小板生成药物包括艾曲泊帕和重组人血小板生成素。
在本申请的一些实施方案中，所述其他可用于治疗免疫性血小板减少症的药物包括但不限于免疫抑制剂。在本申请的一些实施方案中，所述其他可用于治疗免疫性血小板减少症的药物包括但不限于免疫抑制剂，例如更昔洛韦钠、伊马替尼、环孢素(A)、麦考酚钠、吗替麦考酚酯(麦考酚酸酯)、达那唑、硫唑嘌呤、补骨脂素、甲氨蝶呤、羟基氯喹、氨苯吩嗪、环磷酰胺、沙利度胺、阿奇霉素、孟鲁司特、索拉非尼、芦可替尼、地西他滨、长春新碱、阿法赛特(alefacept)、全反式维甲酸。优选的，所述其他可用于治疗免疫性血小板减少症的药物包括达那唑、硫唑嘌呤、环孢素(A)、长春新碱、全反式维甲酸或吗替麦考酚酯。进一步优选地，所述其他可用于治疗免疫性血小板减少症的药物包括达那唑、硫唑嘌呤、环孢素(A)、全反式维甲酸或长春新碱。所述其他可用于治疗免疫性血小板减少症的药物治疗包括全反式维甲酸联合达那唑治疗、地西他滨治疗、环孢素(A)治疗、硫唑嘌呤治疗、达那唑治疗、和/或长春新碱治疗。
在本申请的一些实施方案中，所述药物治疗所用药物包括但不限于泼尼松、甲泼尼松、醋酸泼尼松、泼尼松龙、甲基泼尼松龙、醋酸泼尼松龙、泼尼松龙琥珀酸钠、甲基泼尼松龙琥珀酸钠、倍他米松、丙酸倍氯米松、氢化可的松、地塞米松、注射用免疫球蛋白(例如注射用丙种免疫球蛋白)、利妥昔单抗、维 妥珠单抗(veltuzumab)、达利珠单抗、巴利昔单抗、奥瑞组单抗(ocrelizumab)、阿仑单抗(alemtuzumab)、阿伐曲泊帕(avatrombopag)、艾曲泊帕(eltrombpag)、罗米司亭(romiplostim)、芦曲泊帕(lusutrombopag)、重组人血小板生成素(rhTPO)、达那唑、硫唑嘌呤、环孢素(A)、吗替麦考酚酯、长春新碱、全反式维甲酸、或地西他滨，或上述一种或多种药物的组合。
在本申请的一些实施方案中，所述手术治疗为脾切除术治疗。
在本申请的一些实施方案中，所述免疫性血小板减少症患者可为脾切除术疗效欠佳或术后复发的患者。
在本申请的一些实施方案中，所述免疫性血小板减少症患者可为既往接受过一种或多种一线或多线标准治疗失败的患者。在一些实施方案中，所述免疫性血小板减少症患者可为既往接受过一种或多种一线、二线、三线或四线标准治疗失败的患者。在一些实施方案中，所述免疫性血小板减少症患者可为既往接受过一种或多种一线、二线或三线标准治疗失败的患者。在一些实施方案中，所述免疫性血小板减少症患者可为既往接受过一种、两种、三种、四种或五种一线标准治疗失败的患者。
在本申请的一些实施方案中，所述一线标准治疗包括但不限于糖皮质激素治疗和/或注射用免疫球蛋白治疗。在一些实施方案中，所述糖皮质激素治疗为地塞米松或泼尼松治疗。在一些实施方案中，所述注射用免疫球蛋白治疗为注射用丙种球蛋白治疗。
在本申请的一些实施方案中，所述二线标准治疗包括但不限于促血小板生成药物治疗和/或分子靶向治疗和/或手术治疗。在一些实施方案中，所述促血小板生成药物治疗为艾曲泊帕和/或重组人血小板生成素治疗。在一些实施方案中，所述分子靶向治疗为利妥昔单抗治疗。在一些实施方案中，所述手术治疗为脾切除术治疗。
在本申请的一些实施方案中，所述三线标准治疗包括但不限于全反式维甲酸联合达那唑治疗和/或地西他滨治疗。
在本申请的一些实施方案中，所述四线标准治疗包括但不限于硫唑嘌呤和/或环孢素(A)和/或达那唑和/或长春碱类治疗。
在本申请的一些实施方案中，所述免疫性血小板减少症患者可为既往接受过至少1种免疫性血小板减少症一线标准治疗(例如糖皮质激素治疗和/或静脉注射用丙种球蛋白治疗)失败，或脾切除术疗效欠佳或术后复发的患者。
在本申请的一些实施方案中，所述免疫性血小板减少症患者可为诊断超过3个月的成人持续性或慢性免疫性血小板减少患者，和/或既往至少1种免疫性血小板减少症一线标准治疗(例如糖皮质激素治疗和/或静脉注射用丙种球蛋白治疗)失败，或脾切除术疗效欠佳或术后复发的患者。
在本申请的一些实施方案中，所述治疗失败是指治疗无效、或疗效不能维持、或复发。
在一些实施方案中，可通过多种治疗方式合并治疗所述免疫性血小板减少症患者。在本申请的一些实施方案中，所述免疫性血小板减少症患者可合并一线标准治疗、和/或二线标准治疗、和/或三线标准治疗、和/或四线标准治疗。
在本申请的一些实施方案中，所述免疫性血小板减少症患者可为既往接受过糖皮质激素治疗，且已停药至少3周的患者。
在本申请的一些实施方案中，所述免疫性血小板减少症患者可为既往接受过达那唑治疗，且已停药至少4周的患者。
在本申请的一些实施方案中，所述免疫性血小板减少症患者可为既往接受过达硫唑嘌呤、环孢素(A)和/或吗替麦考酚酯治疗，且已停药至少4周的患者。
在本申请的一些实施方案中，所述免疫性血小板减少症患者可患有一种以上(例如，一种、两种或三种)的免疫性血小板减少症。在本申请的一些实施方案中，所述免疫性血小板减少症任选地包括上述类型免疫性血小板减少症的任意两种以上的组合。在本申请的一些实施方案中，所述免疫性血小板减少症患者 可患有两种以上的免疫性血小板减少症。例如，所述免疫性血小板减少症患者可患有选自上述类型免疫性血小板减少症的任意两种以上的组合。
如本申请所用，“疗效欠佳”是指治疗后血小板计数值小于30×10 9/L、或血小板计数增加不到基础值的2倍，或有出血。
给药方案
在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐、或其药物组合物的给药周期可为2-6周。在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐、或其药物组合物的给药周期可为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，所述式I化合物或其药学上可接受的盐、或其药物组合物的给药周期可为4-5周。在一些实施方案中，所述式I化合物或其药学上可接受的盐、或其药物组合物的给药周期可为1-6个给药周期，例如1、2、3、4、5或6个给药周期。
在本申请的一些实施方案中，所述使用式I化合物或其药学上可接受的盐、或其药物组合物进行治疗性处理的给药周期可为2-6周。在本申请的一些实施方案中，所述用于治疗性处理的给药周期可为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，所述用于治疗性处理的给药周期可为4-5周。
在本申请的一些实施方案中，所述用于治疗或预防的式I化合物或其药学上可接受的盐、或其药物组合物的给药方案可为每日1次到每日3次，或每两日给药1次；优选每日1次。
在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐、或其药物组合物的每日剂量可选自50-1000mg。在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐、或其药物组合物的每日剂量可选自100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg或上述任意值形成的范围。在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐、或其药物组合物的每日剂量选自200-800mg、200-800mg、400-800mg、400-600mg或600-800mg。
在本申请的一些实施方案中，所述用于治疗或预防的式I化合物或其药学上可接受的盐、或其药物组合物的每日剂量可选自50-1000mg。在本申请的一些实施方案中，所述用于治疗或预防的式I化合物或其药学上可接受的盐、或其药物组合物的每日剂量可选自100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg或上述任意值形成的范围。在本申请的一些实施方案中，所述用于治疗或预防的式I化合物或其药学上可接受的盐、或其药物组合物的每日剂量可选自200-800mg、200-800mg、400-800mg、400-600mg或600-800mg。
在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐、或其药物组合物的每次剂量可选自50-1000mg。在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐、或其药物组合物的每次剂量可选自50mg、100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg或上述任意值形成的范围。在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐、或其药物组合物的每次剂量可选自50-800mg、200-800mg、200-600mg、200-400mg、400-800mg、400-600mg、或600-800mg。
在本申请的一些实施方案中，所述用于治疗或预防的式I化合物或其药学上可接受的盐、或其药物组合物的每次剂量可选自50-1000mg。在本申请的一些实施方案中，所述用于治疗或预防的式I化合物或其药学上可接受的盐、或其药物组合物的每次剂量可选自50mg、100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg或上述任意值形成的范围。在本申请的一些实施方案中，所述用于治疗或预防的式I化合物或其药学上可接受的盐、或其药物组合物的每次剂量可选自50-800mg、200-800mg、200-600mg、200-400mg、400-800mg、400-600mg、或600-800mg。
在本申请的一些实施方案中，式I化合物或其药学上可接受的盐以药物组合物的形式提供。
在本申请的一些实施方案中，在治疗患者的免疫性血小板减少症中，所述药物组合物以单剂量形式给药，每天给药一次、两次或三次。在本申请的一些实施方案中，在治疗患者的免疫性血小板减少症中，所述药物组合物以单剂量的口服固体制剂形式给药，每天给药一次、两次或三次。
在本申请的一些实施方案中，在治疗患者的免疫性血小板减少症中，所述药物组合物以多剂量形式给药，每天给药一次或两次。在本申请的一些实施方案中，在治疗患者的免疫性血小板减少症中，所述药物组合物以多剂量的口服固体制剂形式给药，每天给药一次或两次。在一个具体的实施方案中，在治疗患者的免疫性血小板减少症中，所述药物组合物以多剂量的口服固体制剂形式每天给药一次。
在本申请的一些实施方案中，所述式I化合物或其药学上可接受的盐的药物组合物为每日一次剂量，每次剂量为单剂量或多剂量，优选为多剂量，所述多剂量由单剂量为10-200mg的式I化合物或其药学上可接受的盐组成。在一些实施方案中，所述多剂量由单剂量为10mg、20mg、40mg、50mg、60mg、80mg、100mg、120mg、150mg、或200mg的式I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50mg或200mg的式I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，在治疗患者的免疫性血小板减少症中，28天为一个治疗周期，每天给药一次，每次给药式I化合物或其药学上可接受的盐200mg、400mg、600mg、800mg或上述任意值形成的范围，每个治疗周期施用式I化合物或其药学上可接受的盐5.6g、11.2g、16.8g、22.4g或上述任意值形成的范围。
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天连续施用式I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，28天为一个治疗周期，在每个周期的第1-28天连续每日施用式I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，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式I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，28天为一个治疗周期，在每个周期的第1-28天连续每日一次空腹施用式I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，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式I化合物或其药学上可接受的盐或其药物组合物，所述式I化合物或其药学上可接受的盐或其药物组合物每次剂量为单剂量，所述单剂量为50mg或200mg的式I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I化合物或其药学上可接受的盐或其药物组合物可包装于试剂盒中，所述试剂盒包含一个或多个治疗周期的剂量，或者一个治疗周期内的剂量，或者任意前述值作为端点构成的范围的剂量的上述式I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I化合物或其药学上可接受的盐或其药物组合物包装于试剂盒中，所述试剂盒包含1-28日(例如，1日、2日、3日、4日、5日、6日、7日、14日、21日、或28日)的剂量，或一个治疗周期、两个治疗周期、或三个治疗周期以上的剂量，或者任意前述值作为端点构成的范围的剂量的上述式I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，所述式I化合物或其药学上可接受的盐或其药物组合物包装于试剂盒中，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I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I化合物或其药学上可接受的盐或其药物组合物包装于试剂盒中，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I化合物或其药学上可接受的盐或其药物组合物。
在本申请的部分实施方案中，28天为一个治疗周期，每个治疗周期施用式I化合物或其药学上可接受的盐或其药物组合物的总剂量为5.6～22.5g(以活性成分式I化合物本身计)。在本申请的部分实施方案中，所述式I化合物或其药学上可接受的盐或其药物组合物的总剂量选自5.6g、11.2g、16.8g、22.4g或上述任意值形成的范围(以活性成分式I化合物本身计)。在本申请的部分实施方案中，所述式I化合物或其药学上可接受的盐或其药物组合物的总剂量优选为11.2～16.8g(以活性成分式I化合物本身计)。在本申请 的部分实施方案中，所述式I化合物或其药学上可接受的盐或其药物组合物的总剂量优选为11.2g或16.8g(以活性成分式I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，可重复上述治疗周期。
如本申请所用，上述给药方案适用于本申请所述的式I化合物或其药学上可接受的盐或其药物组合物、药物组合、试剂盒，或本申请所述的治疗或预防免疫性血小板减少症的用途或方法。
技术效果
本申请的式I化合物在免疫性血小板减少症的治疗过程中具有良好的安全性，并可有效提高免疫性血小板减少症患者的血小板计数值。治疗12周内至少一次血小板计数≥30×10 9/L且较基线血小板计数增加≥2倍(期间未接受过紧急治疗)的受试者百分比较高。治疗12周内至少一次血小板计数≥50×10 9/L的受试者百分比也较高。
定义和说明
除非另有说明，本申请中所用的术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本申请中出现商品名时，意在指代其对应的商品或其活性成分。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，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。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。在本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。
除非另外特别说明，否则单数术语涵盖复数术语，并且复数术语涵盖单数术语。除非另外特别说明，否则词语“一个”或“一种”意指“至少一个”或“至少一种”。除非另外说明，否则“或”的使用意指“和/或”。
术语“施用”或“给予”或“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，向主体物理引入治疗剂或包含治疗剂的组合物。术语“施用”或“给予”或“给药”在本文中可互换使用。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的载体和/或赋形剂”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体和/或赋形剂。
术语“药学上可接受的盐”，包括碱根离子与游离酸形成的盐或酸根离子与游离碱形成的盐。
如本申请所用，“治疗无效”是指治疗至12周血小板计数<30×10 9/L或较基线增加<2倍。
如本申请所用，“疗效不能维持”是指血小板计数<30×10 9/L或较基线增加<2倍持续12周，紧急治疗所致的血小板升高除外。
如本申请所用，以自由碱形式计算式I化合物或其药学上可接受的盐的含量，例如给药量、剂量、药物组合物中的含量。
如本申请所用，本申请药物组合中的化合物如果具有例如至少一个碱性中心，则其可以形成酸加成盐。如果需要的话，还可以形成具有另外存在的碱性中心的相应的酸加成盐。具有至少一个酸性基团(例如COOH)的化合物还可以与碱形成盐。如果化合物例如既包含羧基又包含氨基，则还可以形成相应的内盐。
术语“患者”是哺乳动物，如人、狗、牛、马、猪、绵羊、山羊、猫、小鼠、兔、大鼠和转基因非人动物。在部分实施方案中，所述患者是人。在本文中，术语“受试者”或“患者”可互换使用。
术语“药物组合物”是指一种或多种本申请的化合物或其盐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患者给予本申请的化合物或其盐。
术语“治疗”一般是指获得需要的药理和/或生理效应，包括部分或完全稳定或治愈疾病和/或由于疾病产生的作用。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“预防”意为将本公开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。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，或(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量；或者每瓶注射液为单剂量。术语“多剂量”由多个单剂量组成。
术语“复发”指，已接受某种治疗方案治疗达到客观缓解后，疾病再次发生。
术语“难治性”指，特定的疾病对于使用一种特定治疗剂的疗法有抗性或无反应。例如，难治性免疫性血小板减少症是指对一线治疗药物、二线治疗中的促血小板生成药物及利妥昔单抗治疗均无效，或脾切除无效/术后复发，进行诊断再评估仍确诊为免疫性血小板减少症的患者。
具体实施方式
通过具体的实施例更详细地说明本发明。为说明目的提供以下实施例，它们不应以任何方式限制本发明。
式I化合物基于WO2018228475中公开的方法制备获得。
实施例1免疫性血小板减少症的临床试验
1.1试验药物和给药方案
试验药物：式I化合物的片剂，规格为50mg/片或200mg/片；
给药方案：每日1次空腹口服，连续给药28天为一个治疗周期。
1.2入组标准
1)受试者自愿加入本研究，签署知情同意书，预计生存期大于3个月；
2)年龄18-75周岁(含界值)(签署知情同意书时)，性别不限；体力状况评分(美国东部肿瘤协作组[ECOG]评分)0～2分；
3)筛选前诊断为持续性或慢性免疫性血小板减少症至少3个月(血小板持续减少超过6个月)；
4)既往至少1种免疫性血小板减少症一线标准治疗(糖皮质激素和/或静脉丙种球蛋白)失败(无效或疗效不能维持或复发)，或脾切除术疗效欠佳或术后复发；
5)WHO出血评分0～1分，且经研究者判断预计入组后2周内无需紧急治疗；
6)筛选前2个月内至少2次独立血小板计数(间隔超过24小时)的平均值<30×10 9/L且单次血小板计数不>35×10 9/L；且筛选前4周内无严重出血；
7)主要器官功能良好，符合下列标准：
a.中性粒细胞计数(ANC)>1.5×10 9/L；血红蛋白(Hb)>90g/L；
b.总胆红素(TBIL)、丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)≤正常值上限(ULN)的1.5倍；血肌酐≤1.5×ULN，且肌酐清除率≥50mL/min；
c.血淀粉酶、脂肪酶未超出正常值上限；
d.凝血酶原时间(PT)未超出正常值范围的±3s，活化的部分凝血活酶时间(APTT)未超出正常值范围的±10s；
e.除免疫性血小板减少症外，无其他凝血障碍病史；
8)育龄女性受试者应同意在研究期间和研究结束后90天内必须采用避孕措施(如宫内节育器、避孕药或避孕套)；在研究入组前7天内血清妊娠试验阴性，且必须为非哺乳期受试者；男性受试者应同意在研究期间和研究期结束后6个月必须采用避孕措施。
1.3评价方法及指标
通过受试者的血小板计数、WHO出血评分及接受紧急治疗的情况对疗效进行评价。以提升血小板的有效率作为主要疗效指标，评价标准参考《美国血液学年会原发免疫性血小板减少症指南(2019年版)》和《成人原发免疫性血小板减少症诊断与治疗中国指南(2020年版)》。
1.4实验结果
1.4.1安全性
式I化合物的片剂在成人持续性或慢性免疫性血小板减少症受试者中整体安全性可控，无剂量限制性毒性(DLT)事件，无3级及以上治疗相关不良事件。
1.4.2有效性
共入组6例受试者，400mg组3例(2例剂量上调至600mg)、600mg组3例。
所评估患者治疗12周内血小板计数至少一次≥30×10 9/L且较基线血小板计数增加≥2倍(期间未接受过紧急治疗)的受试者百分比为50％；治疗12周内血小板计数至少一次≥50×10 9/L的受试者百分比为33.3％。结果发现，本申请式I化合物的片剂对治疗成人持续性或慢性免疫性血小板减少症具有优秀的临床效益。
表1为在代表性病例中的有效性。
Figure PCTCN2022131278-appb-000003

Claims (15)

  1. 用于治疗或预防免疫性血小板减少症的式I化合物或其药学上可接受的盐：
    Figure PCTCN2022131278-appb-100001
  2. 如权利要求1所述的式I化合物或其药学上可接受的盐，其中，所述免疫性血小板减少症是原发免疫性血小板减少症或继发性免疫性血小板减少症；优选地，所述免疫性血小板减少症是原发免疫性血小板减少症。
  3. 如权利要求1所述的式I化合物或其药学上可接受的盐，其中，所述免疫性血小板减少症是持续性或慢性免疫性血小板减少症；优选地，所述免疫性血小板减少症是持续性或慢性原发免疫性血小板减少症；更优选地，所述免疫性血小板减少症是成人持续性或慢性原发免疫性血小板减少症。
  4. 如权利要求1所述的式I化合物或其药学上可接受的盐，其中，所述免疫性血小板减少症是复发和/或难治性原发免疫性血小板减少症。
  5. 如权利要求3所述的式I化合物或其药学上可接受的盐，其中，所述持续性或慢性免疫性血小板减少症的患者是确诊后血小板持续减少超过3个月的患者；或者，所述持续性或慢性免疫性血小板减少症的患者是确诊后血小板持续减少超过6个月的患者。
  6. 如权利要求1所述的式I化合物或其药学上可接受的盐，其中，所述免疫性血小板减少症的患者是既往接受过一种或多种在先治疗的患者。
  7. 如权利要求6所述的式I化合物或其药学上可接受的盐，其中，所述在先治疗包括药物治疗、或手术治疗；任选地，所述药物治疗包括糖皮质激素治疗、免疫球蛋白治疗、分子靶向治疗、促血小板生成药物治疗、或免疫抑制剂治疗，所述手术治疗为脾切除术治疗。
  8. 如权利要求7所述的式I化合物或其药学上可接受的盐，其中，所述药物治疗所用药物选自于：泼尼松、甲泼尼松、醋酸泼尼松、泼尼松龙、甲基泼尼松龙、醋酸泼尼松龙、泼尼松龙琥珀酸钠、甲基泼尼松龙琥珀酸钠、倍他米松、丙酸倍氯米松、氢化可的松、地塞米松、注射用免疫球蛋白、利妥昔单抗、维妥珠单抗(veltuzumab)、达利珠单抗、巴利昔单抗、奥瑞组单抗(ocrelizumab)、阿仑单抗(alemtuzumab)、阿伐曲泊帕(avatrombopag)、艾曲泊帕(eltrombpag)、罗米司亭(romiplostim)、芦曲泊帕(lusutrombopag)、重组人血小板生成素(rhTPO)、达那唑、硫唑嘌呤、环孢素(A)、长春新碱、吗替麦考酚酯、全反式维甲酸、或地西他滨，或上述一种或多种药物的组合。
  9. 如权利要求1-8任一项所述的式I化合物或其药学上可接受的盐，其中，所述免疫性血小板减少症的患者是既往接受过一种或多种一线或多线标准治疗失败的患者；任选地，所述免疫性血小板减少症的患者是既往接受过一种或多种一线、二线或三线标准治疗失败的患者；进一步任选地，所述免疫性血小板减少症的患者是既往接受过一种、两种、三种、四种或五种一线标准治疗失败的患者。
  10. 如权利要求1-9任一项所述的式I化合物或其药学上可接受的盐，其中，所述治疗或预防免疫性血小板减少症的一个治疗周期是2-6周。
  11. 如权利要求1-10任一项所述的式I化合物或其药学上可接受的盐，其中，所述治疗或预防免疫性血小板减少症的给药方案是每日1次到每日3次，或每两日给药1次。
  12. 如权利要求1-11任一项所述的式I化合物或其药学上可接受的盐，其中，所述治疗或预防免疫性血小板减少症的每日剂量选自50-1000mg。
  13. 如权利要求1-12任一项所述的式I化合物或其药学上可接受的盐，其中，所述治疗或预防免疫性血小板减少症的每次剂量选自50-1000mg。
  14. 一种用于治疗或预防有需要的受试者的免疫性血小板减少症的药物组合物，所述药物组合物包含如权利要求1-13任一项所述的式I化合物或其药学上可接受的盐；任选地，所述药物组合物含有单剂量为10-200mg的如权利要求1-13任一项所述的式I化合物或其药学上可接受的盐。
  15. 式I化合物或其药学上可接受的盐、或其药物组合物在制备治疗或预防有需要的受试者中的免疫性血小板减少症的药物中的用途。
PCT/CN2022/131278 2021-11-12 2022-11-11 一种喹啉酮衍生物治疗免疫性血小板减少症的用途 WO2023083281A1 (zh)

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EP22892074.0A EP4431097A1 (en) 2021-11-12 2022-11-11 Use of quinolinone derivative in treatment of immune thrombocytopenia
CN202280074041.8A CN118159269A (zh) 2021-11-12 2022-11-11 一种喹啉酮衍生物治疗免疫性血小板减少症的用途
CA3236272A CA3236272A1 (en) 2021-11-12 2022-11-11 Use of quinolinone derivative in treatment of immune thrombocytopenia
AU2022386485A AU2022386485A1 (en) 2021-11-12 2022-11-11 Use of quinolinone derivative in treatment of immune thrombocytopenia
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