WO2024027790A1 - 吡咯并嘧啶化合物治疗急性移植物抗宿主病的用途 - Google Patents

吡咯并嘧啶化合物治疗急性移植物抗宿主病的用途 Download PDF

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WO2024027790A1
WO2024027790A1 PCT/CN2023/110930 CN2023110930W WO2024027790A1 WO 2024027790 A1 WO2024027790 A1 WO 2024027790A1 CN 2023110930 W CN2023110930 W CN 2023110930W WO 2024027790 A1 WO2024027790 A1 WO 2024027790A1
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compound
formula
stereoisomer
dose
pharmaceutically acceptable
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PCT/CN2023/110930
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English (en)
French (fr)
Inventor
屠礼凡
张喜全
王训强
于鼎
李超逸
Original Assignee
正大天晴药业集团股份有限公司
首药控股(北京)股份有限公司
连云港润众制药有限公司
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Publication of WO2024027790A1 publication Critical patent/WO2024027790A1/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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This application belongs to the field of medicinal chemistry and relates to the use of pyrrolopyrimidine compounds in the treatment of acute graft-versus-host disease. Specifically, it relates to the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts in the treatment of acute graft-versus-host disease. the use of.
  • Janus kinase is a type of non-receptor tyrosine kinase (PTK) that exists in cells and transmits cytokine stimulation signals through the JAK-STAT pathway.
  • the JAK-STAT pathway conducts extracellular chemical signals through the cell membrane to the gene promoter located on the DNA in the nucleus, ultimately affecting changes in DNA transcription and activity levels in the cell.
  • the JAK-STAT pathway consists of three main components: 1) receptor; 2) Janus kinase (JAK) and 3) signal transducer and activator of transcription (STAT).
  • the receptor can be activated by interferons, interleukins, growth factors or other chemical messengers, and the activation leads to autophosphorylation of JAK; then the STAT protein binds to the phosphorylated receptor, causing STAT to be phosphorylated by JAK; and then the STAT protein is phosphorylated Dissociates from the receptor, dimerizes, and translocates into the nucleus to bind to specific DNA sites and alter transcription (Scott, M.J., C.J. Godshall et al. (2002). "Jaks, STATs, Cytokines, and Sepsis" Clin Diagn Lab Immunol 9(6):1153-9).
  • Allogeneic Hematopoietic Stem Cell Transplantation is now widely used in the treatment of hematological and non-hematological diseases, and is even the only way to cure some diseases.
  • Graft Versus Host Disease (GVHD) is a major complication of allogeneic stem cell transplantation. It is caused by a series of "cytokine storms" initiated by the recipient after T lymphocytes in the allogeneic donor graft. Stimulation greatly enhances the immune response to the recipient's antigens, and launches cytotoxic attacks targeting the recipient's target cells, of which the skin, liver and intestines are the main targets.
  • Acute graft-versus-host disease also known as fulminant graft-versus-host disease, usually presents within the first 100 days after allogeneic hematopoietic stem cell transplantation and is generally characterized by damage to the skin, liver, Selective damage to the mucosa and gastrointestinal tract.
  • B-cell targeting drugs including SYK inhibitors (fostamatinib-Sarantopoulos et al., Biology of Blood and Marrow Transplantation, 21 (2015) S11-S18) and BTK inhibitors (ibrutinib-Nakasone et al., Int. J. Hematol.— March 27, 2015) was shown to selectively reduce the function and frequency of abnormal GVHD B cell populations in vitro.
  • the application provides a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating graft versus host disease in a patient:
  • the present application provides a pharmaceutical composition for treating graft versus host disease in a patient, the pharmaceutical composition comprising a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present application provides a method for treating graft versus host disease in a patient, comprising administering to the patient an effective amount of a compound of Formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable version thereof salts, or pharmaceutical compositions thereof.
  • the present application provides the use of a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating graft versus host disease in a patient.
  • the present application provides the use of a compound of Formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of graft versus host disease in a patient.
  • the graft-versus-host disease is selected from acute graft-versus-host disease.
  • the application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating acute graft versus host disease in a patient:
  • the present application provides a pharmaceutical composition for treating acute graft-versus-host disease in a patient, the pharmaceutical composition comprising a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present application provides a method for treating acute graft-versus-host disease in a patient, comprising administering to the patient an effective amount of a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable compound thereof. Acceptable salts, or pharmaceutical compositions thereof.
  • the present application provides a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating acute graft-versus-host disease in a patient. use.
  • the present application provides the use of a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of acute graft versus host disease in a patient.
  • the compound of formula I described in the present application is used as a single active agent.
  • the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt described in this application may comprise a therapeutically effective amount of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.
  • pharmaceutical compositions of acceptable salts may comprise a therapeutically effective amount of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.
  • compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients.
  • they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • 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.
  • Suitable excipients include but are not limited to: binders, diluents, wetting agents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the pharmaceutical composition is a preparation suitable for oral administration, including tablets, Capsules, powders, granules, dropping pills, pastes, powders, etc., preferably tablets and capsules.
  • the oral preparation can be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art.
  • Pharmaceutically acceptable carriers include diluents, binders, wetting agents, disintegrating agents, lubricants, etc.
  • Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin or mixtures thereof, etc.; binders include hypromellose, carboxymethylcellulose, sodium carboxymethylcellulose , ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, starch, sucrose, glucose, gelatin or mixtures thereof, etc.; wetting agents include stearic acid Magnesium, talc, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talc or mixtures thereof, etc.; disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl Cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropylmethylcellulose or crospo
  • the compound of formula I described in the present application is a compound of formula II
  • the compound of formula I and the compound of formula II of the present application can be prepared by referring to the preparation methods in WO2016095805 or WO2017215627.
  • AGVHD Acute graft-versus-host disease
  • acute graft-versus-host disease refers to complications caused by allogeneic stem cell transplantation.
  • the patient has received allogeneic hematopoietic stem cell transplantation in the past; in some schemes, the allogeneic hematopoietic stem cell transplantation includes but is not limited to bone marrow, peripheral blood stem cells and umbilical cord blood. Inertness and reduced intensity conditioning transplantation.
  • the acute graft-versus-host disease is divided into classic acute graft-versus-host disease. Primary disease, delayed acute graft-versus-host disease, persistent acute graft-versus-host disease and recurrent acute graft-versus-host disease.
  • the classic acute graft-versus-host disease often occurs within 100 days after transplantation or after donor leukocyte transfusion.
  • the persistent acute graft-versus-host disease occurs 100 days after transplantation or after donor leukocyte infusion.
  • the acute graft-versus-host disease can be graded according to the Acute GVHD International Consortium (MAGIC) grading standard, including grades I, II, III, and IV.
  • MAGIC Acute GVHD International Consortium
  • the acute graft-versus-host disease is graded according to the aGVHD International Consortium (MAGIC) grading standard, and grade I, II, III or IV is selected; in some scenarios, it is preferably graded from II, III or IV. .
  • MAGIC aGVHD International Consortium
  • the organs involved in the acute graft-versus-host disease include but are not limited to mucous membranes, skin, oral cavity, eyes, gastrointestinal tract, liver, lungs, joints/fascia, and reproductive tract.
  • the acute graft-versus-host disease described in this application is grade I, II, III or IV acute graft-versus-host disease.
  • the acute graft-versus-host disease is grade II-IV acute graft-versus-host disease.
  • the acute graft-versus-host disease is grade II-III acute graft-versus-host disease.
  • the acute graft-versus-host disease is glucocorticoid-resistant grade II-IV acute graft-versus-host disease.
  • the acute graft-versus-host disease is glucocorticoid-resistant grade II-III acute graft-versus-host disease.
  • the acute graft-versus-host disease is resistant to glucocorticoid treatment.
  • the acute graft-versus-host disease is resistant to glucocorticoid treatment, and the resistance includes disease progression, no improvement, or incomplete remission.
  • the acute graft-versus-host disease is resistant to glucocorticoid treatment, and the resistance includes: 1) aGVHD progression after the 3rd day of starting glucocorticoid treatment; and/or, 2 ) No improvement in aGVHD after day 5 of initiating glucocorticoid therapy; and/or, 3) Incomplete resolution of aGVHD after day 14 of initiating glucocorticoid therapy.
  • the acute graft-versus-host disease is resistant to glucocorticoid treatment, Including treatment with methylprednisolone ⁇ 1 mg/kg/day or other glucocorticoids at equivalent doses, and 1) aGVHD progresses after the 3rd day of starting glucocorticoid treatment; and/or, 2) after starting glucocorticoid treatment No improvement in aGVHD after day 5 of corticosteroid therapy; and/or, 3) Incomplete resolution of aGVHD after day 14 of initiation of corticosteroid therapy.
  • the glucocorticoid is selected from the group consisting of prednisone, methylprednisone, prednisone acetate, prednisolone, methylprednisolone, prednisolone acetate, prednisone Methylprednisolone sodium succinate, methylprednisolone sodium succinate, betamethasone, beclomethasone propionate, hydrocortisone, dexamethasone, pulse high-dose glucocorticoid.
  • the acute graft-versus-host disease is acute graft-versus-host disease that cannot tolerate hormonal drug treatment.
  • the acute graft-versus-host disease is glucocorticoid-resistant acute graft-versus-host disease.
  • the acute graft-versus-host disease is acute graft-versus-host disease that has not been previously treated with hormonal drugs.
  • the acute graft-versus-host disease is acute graft-versus-host disease that has not been previously treated with extracorporeal photopheresis therapy.
  • the acute graft versus host disease is steroid-refractory acute graft versus host disease.
  • the acute graft-versus-host disease is an acute graft-versus-host disease that has been previously treated with extracorporeal photopheresis therapy.
  • extracorporeal light separation and replacement therapy mainly includes ultraviolet irradiation, and the ultraviolet irradiation includes but is not limited to ultraviolet UVA, ultraviolet UVB, ultraviolet UVC and ultraviolet UVD, preferably ultraviolet UVA.
  • the acute graft-versus-host disease is acute graft-versus-host disease that has been previously treated with drugs.
  • the drugs used for drug treatment include but are not limited to hormonal drugs, calcineurin inhibitors, mammalian targeted rapamycin (M-Tor) inhibitors and immunosuppressants. one or more types.
  • the hormonal drugs are adrenocortical hormone drugs, including but not limited to adrenocorticotropic hormone, glucocorticoids, mineralocorticoids, preferably glucocorticoids, and the hormonal drugs include but are not limited to prednisone A.
  • the calcineurin inhibitor includes but is not limited to tacrolimus or cyclosporine.
  • the mammalian target of rapamycin (M-Tor) inhibitor includes, but is not limited to, sirolimus, or tacrolimus.
  • the immunosuppressants include immune antibody drugs, wherein the immune antibody drugs include but do not Limited to anti-T cell monoclonal antibodies (anti-CD3 monoclonal antibodies), anti-interleukin-2 receptor antibodies, anti-TNF antibodies, etc.
  • the immunosuppressants include but are not limited to daclizumab, basiliximab anti-, alemtuzumab, or rituximab.
  • the drugs also include, but are not limited to, ganciclovir sodium, imatinib, mycophenolate sodium, mycophenolate mofetil (mycophenolate mofetil), azathioprine, psoralen, methamine Pterin, hydroxychloroquine, amphenazine, cyclophosphamide, thalidomide, or alefacept.
  • the acute graft-versus-host disease is glucocorticoid-resistant acute graft-versus-host disease
  • the glucocorticoid resistance includes resistance to glucocorticoid therapy alone; or glucocorticoid resistance. Resistance to co-treatment with hormones and one or more other drugs.
  • the acute graft-versus-host disease is acute graft-versus-host disease that is resistant to glucocorticoid therapy alone.
  • the glucocorticoid is methylprednisolone or prednisone.
  • the acute graft-versus-host disease is an acute graft-versus-host disease that is resistant to the combined treatment of glucocorticoids and calcineurin inhibitors.
  • the glucocorticoid is methylprednisolone or prednisone.
  • the calmodulin inhibitor is tacrolimus or cyclosporine.
  • the acute graft-versus-host disease is acute graft-versus-host disease that is resistant to the combined treatment of glucocorticoids, calcineurin inhibitors, and mycophenolate mofetil.
  • the glucocorticoid is methylprednisolone or prednisone.
  • the calmodulin inhibitor is tacrolimus or cyclosporine.
  • the acute graft-versus-host disease is an acute graft-versus-host disease that is resistant to the combined treatment of glucocorticoids, calcineurin inhibitors, mycophenolate mofetil, and methotrexate. sick.
  • the glucocorticoid is methylprednisolone or prednisone.
  • the calmodulin inhibitor is tacrolimus or cyclosporine.
  • the acute graft-versus-host disease is acute graft-versus-host disease that is resistant to co-treatment of glucocorticoids and CD25 monoclonal antibodies.
  • the glucocorticoid is methylprednisolone or prednisone.
  • the calmodulin inhibitor is tacrolimus or cyclosporine.
  • the CD25 monoclonal antibody is basiliximab.
  • the resistance to glucocorticoid treatment includes taking high-dose systemic Glucocorticoid resistance
  • the high-dose systemic glucocorticoid refers to taking methylprednisolone 1-2mg/kg/day or an equal dose of prednisone 1.25-2.5mg/kg/day; the Prednisolone or prednisone is given alone or in combination with a calcineurin inhibitor (CNI).
  • CNI calcineurin inhibitor
  • acute graft-versus-host disease occurs with neutrophil count (ANC) >1 ⁇ 10 9 /L and platelets (PLT) ⁇ 20 ⁇ 10 9 /L within 48 hours before the start of treatment.
  • neutrophil count >1 ⁇ 10 9 /L
  • PHT platelets
  • a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for acute graft-versus-host disease that has failed previous drug therapy.
  • a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hormonal drug-resistant acute graft versus host disease.
  • a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of glucocorticoid-resistant acute graft versus host disease.
  • a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of glucocorticoid-resistant grade II-IV acute graft-versus-host disease uses in.
  • a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of prednisone, methylprednisone, prednisone acetate, prednisolone, Use in the treatment of acute graft-versus-host disease that is resistant to methylprednisolone, prednisolone acetate, prednisolone sodium succinate, or methylprednisolone sodium succinate.
  • a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of methylprednisone or methylprednisolone-resistant acute graft resistance there is provided a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of methylprednisone or methylprednisolone-resistant acute graft resistance.
  • a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of methylprednisone or methylprednisolone-resistant grade II-IV Use in drugs to treat acute graft-versus-host disease.
  • the dosage cycle for treating acute graft-versus-host disease in patients is 2 to 6 weeks.
  • the administration period for treating acute graft-versus-host disease in a patient is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or a range formed by any of the above values.
  • the administration period for treating acute graft-versus-host disease in the patient is 4 weeks.
  • the amount of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt 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 patient's age and health status.
  • the tester/patient's routine blood test results are determined, including platelet count, neutrophil count, or hemoglobin concentration, etc.
  • a daily dose of 1 mg to 50 mg of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered.
  • the daily dose administered to the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt may be selected from the group consisting of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg, or a range composed of any of the aforementioned values as endpoints or any value therein, such as 1 mg to 50 mg, 5 mg to 50 mg, 5 mg to 40 mg, 5 mg to 30 mg, 5 mg to 25 mg, 5 mg to 20 mg, 10 mg to 20 mg, etc.
  • the daily dose administered to a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can be selected from the group consisting of 5 mg to 30 mg, 5 mg to 25 mg, 5 mg to 20 mg, and 10 mg to 20 mg.
  • the daily dose administered to a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be selected from the group consisting of 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg , 22mg, 25mg, 28mg, 30mg, 32mg, 35mg, 38mg, 40mg, 42mg, 45mg, 48mg or 50mg, or a range of any of the foregoing values as endpoints or any value therein, such as 5mg to 30mg, 5mg to 25mg, 5mg to 20mg, 10mg to 20mg, etc.
  • a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered once or multiple times daily. In some embodiments, a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered once or twice daily.
  • the compounds of the present application, their stereoisomers, or their pharmaceutically acceptable salts 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 twice daily.
  • the compounds of the present application, their stereoisomers, or their pharmaceutically acceptable salts may also be administered in multiple dosage forms.
  • multiple doses are administered once or twice daily.
  • the oral solid formulation is administered in multiple doses once or twice daily.
  • the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is provided in the form of a pharmaceutical composition, preferably, it is a single-dose pharmaceutical composition.
  • the pharmaceutical composition contains 1 mg to 50 mg of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg or 50 mg, or any of the ranges formed by the aforementioned values as endpoints or any value therein, the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, such as 5 mg to 30 mg, 5 mg to 25 mg, 5 mg to 20mg, 10mg to 20mg, etc.
  • the pharmaceutical composition contains 5 mg, 10 mg, 15 mg, or 20 mg of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 10 mg or 15 mg of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 10 mg of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is a daily dose. In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is twice daily dosage. In some aspects of the application, each of the two doses is the same.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice daily, and each dose is a single dose or multiple doses.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is twice daily, and each dose is multiple doses, which consists of a single dose. It is composed of 5 mg, 10 mg, 15 mg and/or 20 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt. In some aspects of the present application, the pharmaceutical composition consists of a single dose of 5 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is twice daily, and each dose is multiple doses, which consists of a single dose.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is twice daily, and each dose is a single dose.
  • the single dose It is 5 mg, 10 mg, 15 mg and/or 20 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt. In some embodiments of the present application, the single dose is 20 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is packaged in a kit, and the kit also contains the compound of formula I, its pharmaceutical composition Instructions for the use of stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of acute graft-versus-host disease.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is daily Dosage, which is administered in the following manner: a pharmaceutical composition of a compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once or twice a day; in some protocols of this application, formula The pharmaceutical composition of compound I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day, and the dosage is the same each time; in some protocols of this application, the compound of formula I, its stereoisomer The pharmaceutical composition of the body, or its pharmaceutically acceptable salt, is administered twice a day, with the same dose each time, and the interval between each administration is 12 hours.
  • 28 days constitute a treatment cycle
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is continuously administered on days 1 to 28 of each cycle.
  • 28 days is a treatment cycle, and the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice daily continuously on days 1-28 of each cycle.
  • Pharmaceutical compositions are provided.
  • 28 days is a treatment cycle, and the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice daily continuously on days 1-28 of each cycle.
  • the dosage of the pharmaceutical composition is the same for each administration.
  • 28 days is a treatment cycle, and the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice daily continuously on days 1-28 of each cycle.
  • the pharmaceutical composition has the same dose for each administration, and each dose is multiple doses. It consists of a single dose of 5 mg of the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof, and each dose is 5 mg. 10mg, 15mg or 20mg; or 10mg or 15mg per dose; or 10mg per dose.
  • the total dosage of the pharmaceutical composition of the compound, its stereoisomer, or its pharmaceutically acceptable salt is 140 to 840 mg (based on the active ingredient formula (I) compound itself). In some aspects of the present application, the total dosage of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is selected from 140 mg, 280 mg, 420 mg, 560 mg, 700 mg, 840 mg or the above. The range formed by any two values (based on the active ingredient compound of formula (I) itself).
  • the total dosage of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is preferably 280 to 840 mg (based on the active ingredient compound of formula (I) itself. count). In some aspects of the present application, the total dosage of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is preferably 560 mg or 840 mg (based on the active ingredient compound of formula (I) itself. count). In some aspects of the present application, the total dosage of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is preferably 560 mg (based on the active ingredient compound of formula (I) itself) .
  • the above treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.
  • the compounds of the present application, their stereoisomers, or their pharmaceutically acceptable salts can be administered through a variety of routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, arterial Intradermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafatal, intraarticular, or intrathecal.
  • routes including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, arterial Intradermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafatal, intraarticular, or intrathecal.
  • the drug is administered orally.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt can be formulated into a preparation form suitable for oral administration to humans, for example, including but Not limited to tablets, pills, capsules, powders or granules, etc.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is an oral tablet.
  • the single dose specification of the oral tablet of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is 5 mg or 20 mg.
  • the single dose specification of the oral tablet of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is 5 mg.
  • the dosing regimens described herein are also applicable to graft versus host disease.
  • the compound of formula I of the present application, its stereoisomer, or its pharmaceutically acceptable salt or its pharmaceutical composition has good therapeutic effect, which is reflected in including but not limited to better objective response rate (such as 28-day objective response rate), complete response rate (e.g., 28-day complete response rate), overall survival, longer duration of disease response (DOR), higher event-free survival rate, lower non-relapse death and recurrence of original disease/ Progress events.
  • objective response rate such as 28-day objective response rate
  • complete response rate e.g., 28-day complete response rate
  • overall survival longer duration of disease response (DOR)
  • DOR duration of disease response
  • higher event-free survival rate lower non-relapse death and recurrence of original disease/ Progress events.
  • 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 tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts includes salts of alkali ions with free acids or salts of acid ions with free bases.
  • the pharmaceutically acceptable salts described in this application are selected from maleate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, malonate, butyrate. Diacidate, fumarate, malate, mandelate, tartrate, citrate, ascorbate, palmitate, benzoate, phenylacetate, cinnamate, salicylate, Mesylate, benzenesulfonate or toluenesulfonate.
  • the amount of a compound of formula I eg an administration amount, dosage, content in a pharmaceutical composition, is calculated in its free base form.
  • a compound in a pharmaceutical combination of the present application is defined as having, for example, at least one basic center, Then it can form an acid addition salt. If desired, the corresponding acid addition salts with additionally present basic centers can also be formed.
  • Compounds having at least one acidic group eg COOH
  • Stereoisomers of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • patient refers to mammals such as humans, dogs, cattle, horses, pigs, sheep, goats, cats, mice, rabbits, rats and transgenic non-human animals. In some embodiments, the patient is human.
  • composition refers to a mixture of one or more compounds of the present application or a pharmaceutical combination thereof or a salt thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate the administration of a compound of the present application or a pharmaceutical combination thereof to a subject.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect, including partial or complete stabilization or cure of a disease and/or effects resulting from a disease.
  • treatment encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
  • an effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) reduces, 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 one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine. For example, if there are seven capsules in a box of medicine, each capsule is a single dose; or each bottle of injection is a single dose.
  • multiple doses consists of a plurality of single doses.
  • 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.
  • day When referring to a dosing regimen, the terms “day”, “daily”, etc. refer to the time within a calendar day. time, starting at midnight and ending at the next midnight.
  • acute graft-versus-host disease is graded according to the aGVHD International Consortium (MAGIC) grading scale.
  • MAGIC aGVHD International Consortium
  • Harris 2016 efficacy evaluation criteria were used to evaluate disease status or effectiveness.
  • the prescription composition of 5 mg and 20 mg tablet solid pharmaceutical compositions is shown in Table 1:
  • API suspension add hydroxypropyl cellulose to the prescribed amount of purified water and dissolve it to prepare a 4% (w/w) hydroxypropyl cellulose solution; dissolve sodium lauryl sulfate; add the compound of formula II and stir to disperse , to obtain the raw material drug suspension;
  • Fluidized bed granulation and drying Spray the API suspension onto Mixture A to perform fluidized granulation.
  • Granulation parameters inlet air temperature 55 ⁇ 80°C, atomization pressure 600 ⁇ 1000mbar, material temperature 25 ⁇ 35°C; dry after spraying, drying ends when the material temperature is higher than 45°C; use crushing and granulating machine for granulation , the aperture of the whole particle screen is ⁇ 0.6 ⁇ 1.2mm, and the dry particles after whole particle are obtained;
  • This study is used to evaluate the safety and preliminary efficacy of compounds of Formula II in the treatment of subjects with acute graft-versus-host disease who are resistant to glucocorticoids.
  • Dosing method Oral administration on an empty stomach, twice a day, 10 mg or 15 mg each time, for 28 consecutive days as a treatment cycle.
  • Drug Tablets of a compound of formula I, with a specification of 5 mg or 20 mg.
  • the compound of formula I exhibits its stereoisomer compound of formula II.
  • Aged 12-75 years old (including 12 and 75 years old), gender is not limited;
  • Resistance to glucocorticoid therapy* is defined as taking high-dose systemic glucocorticoids (methylprednisolone 1-2 mg/kg/day or an equivalent dose of prednisone 1.25-2.5 mg/kg/day), Taken alone or in combination with a calcineurin inhibitor (CNI);
  • CNI calcineurin inhibitor
  • aGVHD progresses after the 3rd day of glucocorticoid treatment; (2) aGVHD does not improve after the 5th day of glucocorticoid treatment; (3) aGVHD does not completely resolve after the 14th day of glucocorticoid treatment ;
  • neutrophil count >1 ⁇ 10 9 /L
  • PHT platelets
  • graft failure evaluations For the study, investigators will conduct graft failure evaluations. Consider graft failure defined as whole blood or bone marrow donor chimerism ⁇ 5%, which decreases to ⁇ 5% in subsequent testing, so chimerism testing needs to be performed on time.
  • the investigator should promptly take any measures to deal with it, including rapidly reducing immunosuppression, administering DLI, using stem cells and/or chemotherapy, or any other measures taken.
  • Chimerism testing Donor chimerism testing after hematopoietic stem cell transplantation involves identifying the genetic characteristics of the recipient and donor before transplantation and then assessing the ratio of donor-to-recipient cells in the recipient's blood or bone marrow. Chimerism testing, using peripheral blood mononuclear cells or bone marrow, is performed during the screening period, days 14, 28, 42, and 56, and at subsequent visits. If the chimerism test is done within 28 days before the first dose, it will be used as a screening period test and will not be repeated.
  • the investigator will evaluate whether the subject's primary malignant hematological disease has recurred/progressed according to the visit plan, and record whether any therapy has been taken to treat the hematological disease, including discontinuation of immunosuppressive therapy, chemotherapy, and/or or lymphocyte infusion.
  • Evaluation indicators can be selected from:
  • ORR Objective response rate: the percentage of subjects with complete response (CR) or very good partial response (VGPR) or partial response (PR).
  • Complete remission rate (CR): the percentage of subjects with complete remission (CR).
  • OS Overall survival
  • Duration of disease response For subjects in complete response (CR) or very good partial response (VGPR) or partial response (PR) on day 28, defined as the time from the date of first documented response to the first documented disease progression Date or date of initiation of any new systemic therapy for aGVHD.
  • Event-free survival defined as the date of first dose to the date of recurrence/progression of hematological disease, transplant failure, or death from any cause.
  • Non-relapse mortality defined as the date of first medication to the date of death from non-hematological disease recurrence/progression.
  • MR Malignancy Relapse/Progression
  • Hormones in Table 2 represent glucocorticoids; CNI represents calcineurin inhibitors, which mainly include tacrolimus and/or cyclosporine; MMF represents mycophenolate mofetil; MTX represents methotrexate; CD25 Monoclonal antibodies include basiliximab; "hormone ⁇ CNI" indicates the use of hormones alone or the combination of hormones and CNI.

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Abstract

提供了一种吡咯并嘧啶化合物的治疗急性移植物抗宿主病的用途，具体涉及式I化合物、其立体异构体、或其药学上可接受的盐治疗急性移植物抗宿主病的用途。

Description

吡咯并嘧啶化合物治疗急性移植物抗宿主病的用途
相关申请的交叉引用
本申请要求于2022年08月04日向中国国家知识产权局提交的第202210932006.7号中国专利申请的优先权和权益，所述申请公开的内容通过援引整体并入本文中。
技术领域
本申请属于医药化学领域，涉及吡咯并嘧啶化合物的治疗急性移植物抗宿主病的用途，具体涉及式I化合物、其立体异构体、或其药学上可接受的盐治疗急性移植物抗宿主病的用途。
背景技术
两面神激酶(Janus kinase，JAK)是一类非受体型酪氨酸激酶(PTK)，其存在于细胞内，通过JAK-STAT通路传导细胞因子刺激信号。JAK-STAT通路将细胞外的化学信号经细胞膜传导入位于细胞核内DNA上的基因启动子上，最终影响细胞中DNA转录与活性水平发生改变。JAK-STAT通路由三个主要部分组成：1)受体；2)两面神激酶(JAK)和3)信号转导和转录激活蛋白(STAT)。所述受体可由干扰素、白细胞介素、生长因子或其它化学信使激活，激活导致JAK自身磷酸化；接下来STAT蛋白与磷酸化受体结合，使得STAT被JAK磷酸化；然后磷酸化STAT蛋白从受体上分离、二聚并易位到细胞核中，以结合到特异性DNA位点并改变转录(Scott,M.J.,C.J.Godshall et al.(2002).“Jaks,STATs,Cytokines,and Sepsis”Clin Diagn Lab Immunol 9(6):1153-9)。
异基因造血干细胞移植(allogeneic Hematopoietic Stem Cell Transplantation,allo-HSCT)现已广泛用于血液系统与非血液系统疾病治疗，甚至是治愈某些疾病的唯一方法。移植物抗宿主病(Graft Versus Host Disease,GVHD)是异基因干细胞移植的主要并发症，是由于移植后异基因供者移植物中的T淋巴细胞，经受者发动的一系列“细胞因子风暴”刺激，大大增强了其对受者抗原的免疫反应，以受者靶细胞为目标发动细胞毒攻击，其中皮肤、肝及肠道是主要的靶目标。
急性移植物抗宿主病(aGVHD)也被称为暴发性移植物抗宿主病，通常在同种异体造血干细胞移植后的前100天内出现症状，其一般特征在于对皮肤、肝脏、 粘膜和胃肠道的选择性损伤。
人类和动物模型已经证明异常的B-淋巴细胞信号传导和存活在GVHD的发病机制中是重要的。B细胞靶向药物，包括SYK抑制剂(fostamatinib-Sarantopoulos等人，Biology of Blood and Marrow Transplantation,21(2015)S11-S18)和BTK抑制剂(ibrutinib-Nakasone等人，Int.J.Hematol.—2015年3月27日)显示出可以选择性地降低体外异常GVHD B细胞群的功能和频率。
发明内容
一方面，本申请提供用于治疗患者的移植物抗宿主病的式I化合物、其立体异构体、或其药学上可接受的盐：
一方面，本申请提供用于治疗患者的移植物抗宿主病的药物组合物，所述药物组合物包含式I化合物、其立体异构体、或其药学上可接受的盐。
一方面，本申请提供用于治疗患者的移植物抗宿主病的方法，其包括向所述患者给予有效量的如上所述的式I化合物、其立体异构体、或其药学上可接受的盐，或其药物组合物。
一方面，本申请提供如上所述的式I化合物、其立体异构体、或其药学上可接受的盐，或其药物组合物在制备治疗患者的移植物抗宿主病的药物中的用途。
一方面，本申请提供如上所述的式I化合物、其立体异构体、或其药学上可接受的盐，或其药物组合物在治疗患者的移植物抗宿主病中的用途。
在本申请的部分方案中，所述移植物抗宿主病选自急性移植物抗宿主病。
另一方面，本申请提供用于治疗患者的急性移植物抗宿主病的式I化合物、其立体异构体、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急性移植物抗宿主病的药物组合物，所述药物组合物包含式I化合物、其立体异构体、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急性移植物抗宿主病的方法，其包括向所述患者给予有效量的如上所述的式I化合物、其立体异构体、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、其立体异构体、或其药学上可接受的盐，或其药物组合物在制备治疗患者的急性移植物抗宿主病的药物中的用途。
另一方面，本申请提供如上所述的式I化合物、其立体异构体、或其药学上可接受的盐，或其药物组合物在治疗患者的急性移植物抗宿主病中的用途。
在本申请的部分方案中，本申请所述式I化合物、其立体异构体、或其药学上可接受的盐是作为单一活性剂使用。
在本申请的部分方案中，本申请所述式I化合物、其立体异构体、或其药学上可接受的盐可以是包含治疗有效量的式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。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。适合的辅料包括但不限于：黏合剂、稀释剂、润湿剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
在本申请的部分方案中，所述的药物组合物是适于口服的制剂，包括片剂、 胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂。所述的口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂等。稀释剂包括微晶纤维素、甘露醇、乳糖、蔗糖、淀粉、预胶化淀粉、糊精或其混合物等；黏合剂包括羟丙甲纤维素、羧甲基纤维素、羧甲基纤维素钠、乙基纤维素、甲基纤维素、羟丙基纤维素、低取代羟丙基纤维素、明胶、聚乙烯吡咯烷酮、淀粉、蔗糖、葡萄糖、明胶或其混合物等；润湿剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉或其混合物等；崩解剂包括羧甲基淀粉钠、干淀粉、微晶纤维素、羟乙基甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、低取代羟丙甲基纤维素或交联聚维酮或其混合物等；润滑剂包括硬脂酸镁、胶体二氧化硅、滑石粉、聚乙二醇、硬脂酸、硬脂富马酸钠或其混合物等。药用辅料还包括着色剂、甜味剂、包衣剂等。
式I化合物
在本申请的部分方案中，本申请所述的式I化合物是式II化合物
本申请的式I化合物和式II化合物可以参照WO2016095805或WO2017215627中的制备方法制备得到。
急性移植物抗宿主病(aGVHD)
本申请的部分方案中，急性移植物抗宿主病是指由异基因干细胞移植引起的并发症。
本申请的部分方案中，所述患者既往接受过异基因造血干细胞移植；在部分方案中，所述异基因造血干细胞移植包括但不限于骨髓、外周血干细胞和脐带血，非清髓性、清隋性和降低强度调节移植。
本申请的部分方案中，所述急性移植物抗宿主病分为经典的急性移植物抗宿 主病、迟发性急性移植物抗宿主病、持续型急性移植物抗宿主病和复发型急性移植物抗宿主病。
在本申请的部分方案中，所述经典的急性移植物抗宿主病常发生于移植后100天内或供者白细胞输注后。
在本申请的部分方案中，所述持续型急性移植物抗宿主病发生于移植后100天或供者白细胞输注后。
在本申请的部分方案中，所述急性移植物抗宿主病可按照急性GVHD国际联盟(MAGIC)分级标准进行分级，包括I、II、III、IV度。
在本申请的部分方案中，所述急性移植物抗宿主病根据aGVHD国际联盟(MAGIC)分级标准分级，选择I、II、III或IV度；在部分方案中，优选自II、III或IV度。
在本申请的部分方案中，所述急性移植物抗宿主病累及器官包括但不限于粘膜、皮肤、口腔、眼、胃肠道、肝脏、肺、关节/筋膜、生殖道。
在本申请的部分方案中，本申请所述的急性移植物抗宿主病为I度、II度、III度或IV度急性移植物抗宿主病。在一些实施方案中，所述的急性移植物抗宿主病为II度-IV度急性移植物抗宿主病。在一些实施方案中，所述的急性移植物抗宿主病为II度-III度急性移植物抗宿主病。在一些实施方案中，所述的急性移植物抗宿主病为糖皮质激素耐药的II度-IV度急性移植物抗宿主病。在一些实施方案中，所述的急性移植物抗宿主病为糖皮质激素耐药的II度-III度急性移植物抗宿主病。
在本申请的部分方案中，所述急性移植物抗宿主病经糖皮质激素治疗耐药。
在本申请的部分方案中，所述急性移植物抗宿主病经糖皮质激素治疗耐药，所述耐药包括疾病进展、没有改善或未完全缓解。
在本申请的部分方案中，所述急性移植物抗宿主病经糖皮质激素治疗耐药，所述耐药包括：1)在开始使用糖皮质激素治疗第3天后aGVHD进展；和/或，2)在开始使用糖皮质激素治疗第5天后aGVHD没有改善；和/或，3)在开始使用糖皮质激素治疗第14天后aGVHD未完全缓解。
在本申请的部分方案中，所述急性移植物抗宿主病经糖皮质激素治疗耐药， 包括经甲基泼尼松龙≥1mg/kg/天或同等剂量其他类型糖皮质激素治疗，且1)在开始使用糖皮质激素治疗第3天后aGVHD进展；和/或，2)在开始使用糖皮质激素治疗第5天后aGVHD没有改善；和/或，3)在开始使用糖皮质激素治疗第14天后aGVHD未完全缓解。
在本申请的部分方案中，所述糖皮质激素选自泼尼松、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、脉冲高剂量糖皮质激。
在本申请的部分方案中，所述的急性移植物抗宿主病为无法耐受激素类药物治疗的急性移植物抗宿主病。在一些实施方案中，所述急性移植物抗宿主病为糖皮质激素耐药的急性移植物抗宿主病。在一些实施方案中，所述的急性移植物抗宿主病为在先未接受过激素类药物治疗的急性移植物抗宿主病。在一些实施方案中，所述的急性移植物抗宿主病为在先未接受过体外光分离置换疗法的急性移植物抗宿主病。在一些实施方案中，所述的急性移植物抗宿主病为激素抵抗型(steroid-refractory)急性移植物抗宿主病。
在本申请的部分方案中，所述的急性移植物抗宿主病为在先接受过体外光分离置换疗法的急性移植物抗宿主病。其中，体外光分离置换疗法主要包括紫外线照射，所述的紫外线照射包括但不限于紫外线UVA、紫外线UVB、紫外线UVC和紫外线UVD，优选为紫外线UVA。
在本申请的部分方案中，所述的急性移植物抗宿主病为在先接受过药物治疗的急性移植物抗宿主病。在本申请的部分方案中，所述的药物治疗的药物包括但不限于激素类药物、钙调神经蛋白抑制剂、哺乳动物雷帕霉素靶向(M-Tor)抑制剂和免疫抑制剂中的一种或几种。所述的激素类药物为肾上腺皮质激素类药物，包括但不限于促肾上腺皮质激素、糖皮质激素、盐皮质激素，优选为糖皮质激素，所述的激素类药物包括但不限于泼尼松甲基泼尼松、泼尼松龙、甲基泼尼松龙、甲泼尼龙琥珀酸钠、倍他米松、丙酸倍氯米松、得宝松、氢化可的松、地塞米松、或脉冲高剂量糖皮质激素。所述的钙调神经蛋白抑制剂包括但不限于他克莫司、或环孢素。所述哺乳动物雷帕霉素靶向(M-Tor)抑制剂包括但不限于西罗莫司、或他克莫司。所述的免疫抑制剂包括免疫抗体药物，其中免疫抗体药物包括但不 限于抗T细胞单克隆抗体(抗CD3单抗)、抗白细胞介素-2受体的抗体、抗TNF抗体等，所述的免疫抑制剂包括但不限于达利珠单抗、巴利昔单抗、阿仑单抗、或利妥昔单抗。所述的药物还包括但不限于更昔洛韦钠、伊马替尼、麦考酚钠、麦考酚酸酯(吗替麦考酚酯)、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、或阿法赛特(alefacept)。
在本申请的部分方案中，所述的急性移植物抗宿主病为糖皮质激素耐药的急性移植物抗宿主病，所述糖皮质激素耐药包括糖皮质激素单独治疗耐药；或糖皮质激素和其他药物中的一种或多种共同治疗耐药。
在本申请的部分方案中，所述的急性移植物抗宿主病为糖皮质激素单独治疗耐药的急性移植物抗宿主病。在本申请的部分方案中，所述的糖皮质激素为甲基泼尼松龙或泼尼松。
在本申请的部分方案中，所述的急性移植物抗宿主病为糖皮质激素和钙调神经蛋白抑制剂共同治疗耐药的急性移植物抗宿主病。在本申请的部分方案中，所述的糖皮质激素为甲基泼尼松龙或泼尼松。在本申请的部分方案中，所述钙调神经蛋白抑制剂为他克莫司或环孢素。
在本申请的部分方案中，所述的急性移植物抗宿主病为糖皮质激素、钙调神经蛋白抑制剂和吗替麦考酚酯共同治疗耐药的急性移植物抗宿主病。在本申请的部分方案中，所述的糖皮质激素为甲基泼尼松龙或泼尼松。在本申请的部分方案中，所述钙调神经蛋白抑制剂为他克莫司或环孢素。
在本申请的部分方案中，所述的急性移植物抗宿主病为糖皮质激素、钙调神经蛋白抑制剂、吗替麦考酚酯和甲氨蝶呤共同治疗耐药的急性移植物抗宿主病。在本申请的部分方案中，所述的糖皮质激素为甲基泼尼松龙或泼尼松。在本申请的部分方案中，所述钙调神经蛋白抑制剂为他克莫司或环孢素。
在本申请的部分方案中，所述的急性移植物抗宿主病为糖皮质激素和CD25单抗共同治疗耐药的急性移植物抗宿主病。在本申请的部分方案中，所述的糖皮质激素为甲基泼尼松龙或泼尼松。在本申请的部分方案中，所述钙调神经蛋白抑制剂为他克莫司或环孢素。在本申请的部分方案中，所述CD25单抗为巴利昔单抗。
在本申请的部分方案中，所述经糖皮质激素治疗耐药包括服用高剂量全身性 糖皮质激素耐药，所述高剂量全身性糖皮质激素是指服用甲基泼尼松龙1-2mg/kg/日或等剂量的泼尼松1.25-2.5mg/kg/日；所述甲基泼尼松龙或泼尼松单独服用或与钙调神经磷酸酶抑制剂(CNI)结合使用。
在本申请的部分方案中，急性移植物抗宿主病在治疗开始前48小时内，中性粒细胞计数(ANC)>1×109/L，血小板(PLT)≥20×109/L。
在本申请的部分方案中，提供了式I化合物、其立体异构体、或其药学上可接受的盐在制备用于在先接受药物治疗失败的急性移植物抗宿主病的药物中的用途。在一些实施方案中，提供了式I化合物、其立体异构体、或其药学上可接受的盐在制备用于治疗激素类药物耐药的急性移植物抗宿主病的药物中的用途。在一些实施方案中，提供了式I化合物、其立体异构体、或其药学上可接受的盐在制备用于治疗激素类药物耐药的II度-IV度急性移植物抗宿主病的药物中的用途。在一些实施方案中，提供了式I化合物、其立体异构体、或其药学上可接受的盐在制备用于治疗糖皮质激素耐药的急性移植物抗宿主病的药物中的用途。在一些实施方案中，提供了式I化合物、其立体异构体、或其药学上可接受的盐在制备用于治疗糖皮质激素耐药的II度-IV度急性移植物抗宿主病的药物中的用途。
在一些实施方案中，提供了式I化合物、其立体异构体、或其药学上可接受的盐在制备用于治疗泼尼松、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、或甲基泼尼松龙琥珀酸钠耐药的急性移植物抗宿主病的药物中的用途。在一些实施方案中，提供了式I化合物、其立体异构体、或其药学上可接受的盐在制备用于治疗泼尼松、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、或甲基泼尼松龙琥珀酸钠耐药的II度-IV度急性移植物抗宿主病的药物中的用途。在一些实施方案中，提供了式I化合物、其立体异构体、或其药学上可接受的盐在制备用于治疗甲基泼尼松或甲基泼尼松龙耐药的急性移植物抗宿主病的药物中的用途。在一些实施方案中，提供了式I化合物、其立体异构体、或其药学上可接受的盐在制备用于治疗甲基泼尼松或甲基泼尼松龙耐药的II度-IV度急性移植物抗宿主病的药物中的用途。
给药方案
在本申请的部分方案中，所述治疗患者的急性移植物抗宿主病的给药周期是 2～6周。在本申请的一些方案中，所述治疗患者的急性移植物抗宿主病的给药周期是2周、3周、4周、5周、6周或上述任意值形成的范围。在本申请的一些方案中，所述治疗患者的急性移植物抗宿主病的给药周期是4周。
本申请的化合物、其立体异构体、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，给予本申请的化合物、其立体异构体、或其药学上可接受的盐的日剂量为1mg至50mg。在部分实施方案中，给予本申请的化合物、其立体异构体、或其药学上可接受的盐的日剂量可选自1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg，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1mg至50mg、5mg至50mg、5mg至40mg、5mg至30mg、5mg至25mg、5mg至20mg、10mg至20mg等。在部分特定实施方案中，给予本申请的化合物、其立体异构体、或其药学上可接受的盐的日剂量可选自5mg至30mg、5mg至25mg、5mg至20mg、10mg至20mg。在部分特定实施方案中，给予本申请的化合物、其立体异构体、或其药学上可接受的盐的日剂量可选自1mg、2mg、5mg、8mg、10mg、12mg、15mg、18mg、20mg、22mg、25mg、28mg、30mg、32mg、35mg、38mg、40mg、42mg、45mg、48mg或50mg，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5mg至30mg、5mg至25mg、5mg至20mg、10mg至20mg等。
给予本申请的化合物、其立体异构体、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本申请的化合物、其立体异构体、或其药学上可接受的盐。给予本申请的化合物、其立体异构体、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两次。
给予本申请的化合物、其立体异构体、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两次。
在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐以药物组合物的形式提供，优选地，其为单剂量药物组合物。在部分实施方案中，所述药物组合物含有1mg至50mg的本申请的化合物、其立体异构体、或其药学上可接受的盐。在部分实施方案中，所述药物组合物含有1mg、2mg、5mg、8mg、10mg、12mg、15mg、18mg、20mg、22mg、25mg、28mg、30mg、32mg、35mg、38mg、40mg、42mg、45mg、48mg或50mg、或者任意前述值作为端点构成的范围或其中的任意值的本申请的化合物、其立体异构体、或其药学上可接受的盐，例如5mg至30mg、5mg至25mg、5mg至20mg、10mg至20mg等。在部分实施方案中，所述药物组合物含有5mg、10mg、15mg或20mg的本申请的化合物、其立体异构体、或其药学上可接受的盐。在部分实施方案中，所述药物组合物含有10mg或15mg的本申请的化合物、其立体异构体、或其药学上可接受的盐。在部分实施方案中，所述药物组合物含有10mg的本申请的化合物、其立体异构体、或其药学上可接受的盐。
在本申请的部分方案中，所述式I化合物、其立体异构体、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，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物为每日两次剂量。在本申请的部分方案中，所述两次剂量的每次剂量相同。
在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物为每日两次剂量，每次剂量分别为单剂量或多剂量。
在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物为每日两次剂量，每次剂量为多剂量，其由单剂量为5mg、10mg、15mg和/或20mg的式I化合物、其立体异构体、或其药学上可接受的盐组成。在本申请的部分方案中，所述药物组合物由单剂量为5mg的式I化合物、其立体异构体、或其药学上可接受的盐组成。
在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物为每日两次剂量，每次剂量为多剂量，其由单剂量为5mg的式I化合物、其立体异构体、或其药学上可接受的盐组成，每次剂量为5mg、10mg、15mg或20mg；或每次剂量为10mg或15mg；或每次剂量为10mg。
在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物为每日两次剂量，每次剂量为单剂量，所述单剂量为5mg、10mg、15mg和/或20mg的式I化合物、其立体异构体、或其药学上可接受的盐。在本申请的部分方案中，所述单剂量为20mg的式I化合物、其立体异构体、或其药学上可接受的盐。
在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物包装于一试剂盒中，所述试剂盒还含有式I化合物、其立体异构体、或其药学上可接受的盐用于治疗急性移植物抗宿主病的说明。
在本申请的部分方案中，所述治疗急性移植物抗宿主病的方法或用途中，所述式I化合物、其立体异构体、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I化合物、其立体异构体、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，式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物每日给药2次，且每次剂量相同；在本申请的部分方案中，式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物每日给药2次，且每次剂量相同，并且每次给药间隔为12小时。
在本申请的部分方案中，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、其立体异构体、或其药学上可接受的盐的药物组合物。
在本申请的部分方案中，28天为一个治疗周期，在每个周期的第1-28天连续每日两次施用式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物。
在本申请的部分方案中，28天为一个治疗周期，在每个周期的第1-28天连续每日两次施用式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物，每次施用剂量相同。
在本申请的部分方案中，28天为一个治疗周期，在每个周期的第1-28天连续每日两次施用式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物，每次施用剂量相同，每次剂量为多剂量，其由单剂量为5mg的式I化合物、其立体异构体、或其药学上可接受的盐组成，每次剂量为5mg、10mg、15mg或20mg；或每次剂量为10mg或15mg；或每次剂量为10mg。
在本申请的部分方案中，28天为一个治疗周期，每个治疗周期施用式I化 合物、其立体异构体、或其药学上可接受的盐的药物组合物的总剂量为140～840mg(以活性成分式(I)化合物本身计)。在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物的总剂量选自140mg、280mg、420mg、560mg、700mg、840mg或上述任意两个值所形成的范围(以活性成分式(I)化合物本身计)。在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物的总剂量优选为280～840mg(以活性成分式(I)化合物本身计)。在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物的总剂量优选为560mg或840mg(以活性成分式(I)化合物本身计)。在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物的总剂量优选为560mg(以活性成分式(I)化合物本身计)。
在本申请的部分方案中，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。
本申请的化合物、其立体异构体、或其药学上可接受的盐可通过多种途径给药，所述途径包括但不限于以下途径：口服、胃肠外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内或鞘内。在一个特定的方案中，通过口服给药。
在本申请的部分方案中，所述式I化合物、其立体异构体、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。
在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物为口服片剂。
在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的口服片剂的单剂量规格为5mg或20mg。
在本申请的部分方案中，所述式I化合物、其立体异构体、或其药学上可接受的盐的口服片剂的单剂量规格为5mg。
本申请所述的给药方案也适用于移植物抗宿主病。
技术效果
本申请的式I化合物、其立体异构体、或其药学上可接受的盐或其药物组合物具有良好的治疗效果，体现在包括但不限于更好的客观缓解率(例如28天客观缓解率)、完全缓解率(例如28天完全缓解率)、总生存期、更长时间的疾病缓解持续时间(DOR)、更高的无事件生存率、更低的非复发死亡和原疾病复发/进展事件。本申请的式I化合物、其立体异构体、或其药学上可接受的盐或其药物组合物在具有良好的治疗效果时，也具有良好的安全性，包括但不限于较低的不良反应发生率。
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。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”，包括碱根离子与自由酸形成的盐或酸根离子与自由碱形成的盐。本申请所述的药学上可接受的盐选自马来酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、乙酸盐、乳酸盐、丙二酸盐、丁二酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、柠檬酸盐、抗坏血酸盐、棕榈酸盐、苯甲酸盐、苯乙酸盐、肉桂酸盐、水杨酸盐、甲磺酸盐、苯磺酸盐或甲基苯磺酸盐。
如本申请所用，式I化合物的量，例如给药量、剂量、药物组合物中的含量，以其游离碱形式计算。
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。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
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。
术语“药物组合物”是指一种或多种本申请的化合物或其药物组合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受试者给予本申请的化合物或其药物组合。
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“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“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。
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。
如本申请所用，所述急性移植物抗宿主病根据aGVHD国际联盟(MAGIC)分级标准分级。
如本申请所用，采用Harris 2016疗效评价标准评价疾病状态或有效性。
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。
制备例1：制备5mg和20mg规格片剂固体药物组合物
5mg和20mg规格片剂固体药物组合物处方组成如表1所示：
表1 5mg和20mg规格片剂处方组成
制备流程：
1)将甘露醇、微晶纤维素、交联羧甲基纤维素钠混合，所得混合物A留用；
原料药混悬液配制：将羟丙基纤维素加入处方量纯化水中溶解，配制成4％(w/w)羟丙基纤维素溶液；溶解十二烷基硫酸钠；加式II化合物搅拌分散，得原料药混悬液；
2)流化床制粒、干燥：将原料药混悬液喷雾到混合物A上，进行流化制粒。制粒参数：进风温度55～80℃，雾化压力600～1000mbar，物料温度25～35℃；喷液结束后烘干，物料温度高于45℃时干燥结束；采用粉碎整粒机整粒，整粒筛网孔径Φ0.6～1.2mm，获得整粒后的干颗粒；
3)将整粒后的干颗粒、硬脂酸镁依次投入料斗混合机中，充分混合，所得 固体药物组合物进行压片。
实施例1 急性移植物抗宿主病临床方案
本研究用于评价式II化合物治疗糖皮质激素耐药的急性移植物抗宿主病受试者的安全性和初步有效性。
1.1给药方案
给药方法：空腹口服给药，每天两次，每次10mg或15mg，连续给药28天为一个治疗周期。
药物：式I化合物的片剂，规格为5mg或20mg，所述式I化合物表现为其立体异构体式II化合物
1.2入组标准
1)年龄12-75周岁(包括12和75周岁)，性别不限；
2)既往接受过异基因造血干细胞移植(包括骨髓、外周血干细胞和脐带血，非清髓性，清髓性和降低强度调节移植均可)；
3)根根据MAGIC指南临床诊断为II度至IV度aGVHD；
经糖皮质激素治疗耐药*，定义为服用高剂量全身性糖皮质激素(甲基泼尼松龙1-2mg/kg/日或等剂量的泼尼松1.25-2.5mg/kg/日)，单独服用或与钙调神经磷酸酶抑制剂(CNI)结合使用；
*满足以下条件之一可定义为经常规糖皮质激素治疗耐药：甲基泼尼松龙≥1mg/kg/天或同等剂量其他类型糖皮质激素治疗。(1)在开始使用糖皮质激素治疗第3天后aGVHD进展；(2)在开始使用糖皮质激素治疗第5天后aGVHD没有改善；(3)在开始使用糖皮质激素治疗第14天后aGVHD未完全缓解；
4)研究治疗开始前48h内，中性粒细胞计数(ANC)>1×109/L，血小板(PLT)≥20×109/L；
5)受试者自愿加入本研究，签署知情同意书，依从性好。
1.3评价方法
aGVHD评价
研究期间，研究者将根据Harris 2016疗效评价标准进行aGVHD治疗反应评分。
研究期间需要监测aGVHD的变化情况，包括激素、CNI使用情况，式I化合物的片剂的剂量调整情况等。
cGVHD评价
研究期间，研究者将在第1天至第56天每28天一次根据NIH关于cGVHD的共识指南评估cGVHD，后续周期每次访视时评价一次，并做好相应记录。
移植失败评价
研究期间，研究者将进行移植失败评价。考虑移植失败定义为全血或骨髓供体嵌合≥5％，在后续检测中降低到<5％，因此需要按时进行嵌合检测。
如果受试者发生移植失败，研究者应及时采取任何措施来处理，包括快速降低免疫抑制，进行DLI给药，使用干细胞和/或化疗，或采取的任何其他措施。
嵌合检测：造血干细胞移植后供体嵌合检测涉及到鉴定受体和供体移植前遗传特征，然后评估受体血液或骨髓中供体到受体细胞的比例。嵌合检测使用的是外周血单核细胞或骨髓，在筛选期、第14天、第28天、第42天和第56天及后续访视进行。如果在首次用药前28天内做过嵌合检测，将做为筛选期检测，不再重复进行。
原发恶性血液系统疾病复发/进展评价
研究期间，研究者将根据访视计划对受试者原发恶性血液系统疾病是否复发/进展做出评估，并记录是否已采取任何疗法来治疗血液病，包括终止免疫抑制疗法，化疗，和/或淋巴细胞输注。
1.4评价指标
评价指标可选自：
客观缓解率(ORR)：完全缓解(CR)或非常好的部分缓解(VGPR)或部分缓解(PR)受试者所占百分比例。
完全缓解率(CR)：完全缓解(CR)受试者所占百分比例。
总生存期(OS)：指从首次用药开始至各种原因导致的死亡之间时间。
疾病缓解时间(DOR)：对于第28天完全缓解(CR)或非常好的部分缓解(VGPR)或部分缓解(PR)的受试者，定义为从首次记录缓解的日期到首次记录疾病进展的日期或开始任何新针对aGVHD系统性治疗的日期。
无事件生存率(EFS)：定义为首次用药日期到血液系统疾病复发/进展，移植失败或任何原因导致的死亡的日期。
非复发死亡(Non-relapse mortality，NRM)：定义为首次用药日期到非血液系统疾病复发/进展死亡的日期。
原疾病复发/进展(Incidence of Malignancy Relapse/Progression，MR)：定义为首次用药日期到血液系统疾病复发进展日期。
1.5效果数据
1.5.1有效性
可评价的12例受试者空腹口服给予式II化合物片剂，每天两次，每次10mg，28天为一个给药周期。12例受试者D28的ORR为83.3％(10/12)，其中8例CR，2例VGPR(非常好的部分缓解)。安全性方面，式II化合物片剂耐受性和安全性均良好，总体不良事件可控。总之，式II化合物片剂治疗糖皮质激素耐药的急性移植物抗宿主病有显著的临床获益。代表性病例如下表2所示：
表2评估患者有效性


注：表2中激素表示糖皮质激素；CNI表示钙调神经蛋白抑制剂，主要包括他克
莫司和/或环孢素；MMF表示吗替麦考酚酯；MTX表示甲氨蝶呤；CD25单抗包括巴利昔单抗；“激素±CNI”表示激素单独用药或激素和CNI共同用药。
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. 用于治疗患者的移植物抗宿主病的式I化合物、其立体异构体、或其药学上可接受的盐：
  2. 用于治疗患者的移植物抗宿主病的药物组合物，所述药物组合物包含权利要求1所述的式I化合物、其立体异构体、或其药学上可接受的盐。
  3. 权利要求1所述的式I化合物、其立体异构体、或其药学上可接受的盐，或权利要求2所述的药物组合物在制备治疗患者的移植物抗宿主病的药物中的用途。
  4. 权利要求1所述的式I化合物、其立体异构体、或其药学上可接受的盐，或权利要求2所述的药物组合物，或权利要求3所述的用途，其中移植物抗宿主病选自急性移植物抗宿主病。
  5. 权利要求3或4所述的用途，所述急性移植物抗宿主病为I度、II度、III度或IV度急性移植物抗宿主病。
  6. 权利要求3-5任一项所述的用途，所述急性移植物抗宿主病经糖皮质激素治疗耐药。
  7. 权利要求6所述的用途，所述糖皮质激素选自泼尼松、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、脉冲高剂量糖皮质激。
  8. 权利要求3-7任一项所述的用途，其中式I化合物、其立体异构体、或其药学上可接受的盐的日剂量为1mg至50mg；或者，式I化合物、其立体异构 体、或其药学上可接受的盐的日剂量为1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg，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1mg至50mg、5mg至50mg、5mg至40mg、5mg至30mg、5mg至25mg、5mg至20mg、10mg至20mg；或者，式I化合物、其立体异构体、或其药学上可接受的盐的日剂量为5mg至30mg、5mg至25mg、5mg至20mg、10mg至20mg。
  9. 权利要求3-7任一项所述的用途，其中式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物为每日剂量；或者，所述式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物为每日两次剂量。
  10. 权利要求3-7任一项所述的用途，式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物以多剂量形式给药；或者，以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两次。
  11. 权利要求3-7任一项所述的用途，式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物为每日两次剂量，每次剂量为多剂量，其由单剂量为5mg的式I化合物、其立体异构体、或其药学上可接受的盐组成，每次剂量为5mg、10mg、15mg或20mg；或每次剂量为10mg或15mg；或每次剂量为10mg。
  12. 权利要求3-11任一项所述的用途，其中28天为一个治疗周期，在每个周期的第1-28天连续每日两次施用式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物。
  13. 权利要求3-12任一项所述的用途，28天为一个治疗周期，在每个周期的第1-28天连续每日两次施用式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物，每次施用剂量相同，每次剂量为多剂量，其由单剂量为5mg的式I化合物、其立体异构体、或其药学上可接受的盐组成，每次剂量为5mg、10mg、15mg或20mg；或每次剂量为10mg或15mg；或每次剂量为10mg。
  14. 权利要求3-13任一项所述的用途，其中式I化合物、其立体异构体、或其药学上可接受的盐的药物组合物的总剂量为140～840mg；或者总剂量为280～840mg；或者总剂量为560mg或840mg；或者总剂量为560mg。
  15. 权利要求3-14任一项所述的用途，其中式I化合物、其立体异构体、或其药 学上可接受的盐的口服片剂的单剂量规格为5mg或20mg；或者单剂量规格为5mg。
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WO2016095805A1 (zh) * 2014-12-16 2016-06-23 北京赛林泰医药技术有限公司 吡咯并嘧啶化合物
WO2021180093A1 (zh) * 2020-03-09 2021-09-16 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物的治疗噬血细胞综合征的用途
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