WO2021180093A1 - 吡咯并嘧啶化合物的治疗噬血细胞综合征的用途 - Google Patents

吡咯并嘧啶化合物的治疗噬血细胞综合征的用途 Download PDF

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Publication number
WO2021180093A1
WO2021180093A1 PCT/CN2021/079820 CN2021079820W WO2021180093A1 WO 2021180093 A1 WO2021180093 A1 WO 2021180093A1 CN 2021079820 W CN2021079820 W CN 2021079820W WO 2021180093 A1 WO2021180093 A1 WO 2021180093A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
acceptable salt
stereoisomer
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PCT/CN2021/079820
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English (en)
French (fr)
Inventor
梁洪铭
张喜全
王训强
于鼎
王栋
葛琪
王昭
王旖旎
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
Shouyao Holdings Beijing Co Ltd
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
Shouyao Holdings Beijing Co Ltd
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Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd, Lianyungang Runzhong Pharmaceutical Co Ltd, Shouyao Holdings Beijing Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to EP21767840.8A priority Critical patent/EP4119562A4/en
Priority to CN202510484092.3A priority patent/CN120267676A/zh
Priority to CN202411581903.3A priority patent/CN119367372A/zh
Priority to US17/910,331 priority patent/US12447154B2/en
Priority to CN202180008532.8A priority patent/CN114981272B/zh
Publication of WO2021180093A1 publication Critical patent/WO2021180093A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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 to treat hemophagocytic syndrome.
  • Janus Kinase is a type of non-receptor tyrosine kinase (PTK), which exists in cells and transmits cytokine stimulation signals through the JAK-STAT pathway.
  • the JAK-STAT pathway transmits chemical signals from outside the cell through the cell membrane to the gene promoter located on the DNA in the nucleus, and ultimately affects the changes in the level of DNA transcription and activity in the cell.
  • the JAK-STAT pathway is composed of three main parts: 1) receptor; 2) Janus Kinase (JAK) and 3) Signal Transduction and Activator of Transcription (STAT).
  • the receptor can be activated by interferon, interleukin, growth factor or other chemical messengers, and activation leads to the autophosphorylation of JAK; then the STAT protein binds to the phosphorylated receptor, so that STAT is phosphorylated by JAK; then the STAT protein is phosphorylated Isolate from the receptor, dimerize and translocate into the nucleus to bind to specific DNA sites and change transcription (Scott, MJ, CJ Godshall et al. (2002). "Jaks, STATs, Cytokines, and Sepsis" Clin Diagn Lab Immunol 9(6):1153-9).
  • JAK1 JAK2, JAK3 and TYK2 (Tyrosine Kinase 2).
  • JAK1 JAK2, JAK3 and TYK2
  • JH conserved JAK homology
  • Hemophagocyic lymphohistiocytosis also known as hemophagocytic lymphohistiocytosis, is a group of CD8 + T lymphocytes and monocyte-macrophage cell system that overproliferate and produce a large number of inflammatory factors, causing multiple
  • the clinical syndrome of fulminant inflammation of the organ system is clinically characterized by persistent fever, hepatosplenomegaly, and bleeding.
  • the disease has a rapid onset, a dangerous condition, rapid progress, and an extremely high case fatality rate.
  • HLH is a disease in which the balance between regulatory T cells and CD8+ T cells is unbalanced, and the homeostasis of IL-2 network is disturbed.
  • HLH In the process of HLH, CD8+ T cells are over-activated and successfully compete with regulatory T cells for IL-2, which leads to the decline of regulatory T cells.
  • HLH is characterized by acute clinical signs and symptoms of immune activation, including hepatomegaly, jaundice, lymphadenopathy, rash, seizures, and focal neurological deficits. Laboratory examinations show that serum levels of various inflammatory cytokines are elevated. High, including interferon- ⁇ (IFN- ⁇ ), tumor necrosis factor ⁇ (TNF- ⁇ ), interleukin 6 (IL-6), interleukin 10 (IL-10) and macrophage colony stimulating factor (M-CSF) .
  • IFN- ⁇ interferon- ⁇
  • TNF- ⁇ tumor necrosis factor ⁇
  • IL-6 interleukin 6
  • IL-10 interleukin 10
  • M-CSF macrophage colony stimulating factor
  • the application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of hemophagocytic syndrome:
  • the present application provides a pharmaceutical composition for the treatment of hemophagocytic syndrome, 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 hemophagocytic syndrome in a patient, which comprises administering to the patient an effective amount of a compound of formula I, its stereoisomer, or a pharmaceutically acceptable Salt, or a pharmaceutical composition thereof.
  • the present application provides the use of the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of hemophagocytic syndrome.
  • the application provides the use of the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of hemophagocytic syndrome as described above.
  • This application provides a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof for the treatment of hemophagocytic syndrome:
  • the present application provides a pharmaceutical composition for the treatment of hemophagocytic syndrome, 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 hemophagocytic syndrome in a patient, which comprises administering to the patient an effective amount of a compound of formula I, its stereoisomer, or a pharmaceutically acceptable A salt, or a pharmaceutical composition comprising a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the application provides the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof, or includes the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof
  • the pharmaceutical composition is used in the preparation of a medicament for the treatment of hemophagocytic syndrome in patients.
  • the application provides the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof, or includes the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof Of the pharmaceutical composition in the treatment of patients with hemophagocytic syndrome.
  • the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is used as a single active agent.
  • the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof may contain a therapeutically effective amount of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.
  • Pharmaceutical composition of the above acceptable salt may contain a therapeutically effective amount of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, 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.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, 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, dripping pills, pastes, powders, etc., preferably tablets and capsules.
  • the oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art.
  • Pharmaceutically acceptable carriers include diluents, binders, wetting agents, disintegrants, lubricants and the like.
  • Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin or mixtures thereof, etc.; binders include hypromellose, carboxymethyl cellulose, sodium carboxymethyl cellulose , Ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, starch, sucrose, glucose, gelatin or mixtures thereof; wetting agents include stearic acid Magnesium, talcum powder, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talc powder or mixtures thereof, etc.; disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl Cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl
  • 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.
  • the hemophagocytic syndrome includes primary hemophagocytic syndrome and secondary hemophagocytic syndrome.
  • the primary hemophagocytic syndrome includes familial HLH, immunodeficiency syndrome-related HLH, or Epstein-Barr virus (EBV) driven HLH and other HLH caused by abnormalities in related genes;
  • the secondary hemophagocytic syndrome Including infection-related HLH, malignant tumor-related HLH, macrophage activation syndrome (MAS), or other types of HLH.
  • the familial HLH (also called FHL) includes FHL-1, FHL-2, FHL-3, FHL-4 or FHL-5.
  • the immunodeficiency syndrome-related HLH includes Griscelli syndrome 2 (GS-2), Chediak-Higashi syndrome 1 (CHS-1) or Hermansky-Pudlak syndrome II (HPS-II) .
  • the infections in the HLH related to infections include viral, bacterial, fungal, and protozoal infections.
  • the malignant tumor in the malignant tumor-related HLH includes hematological tumors or solid tumors; preferably, the hematological tumors include lymphoma, acute leukemia, multiple myeloma, and myelodysplasia Syndrome, etc.; preferably, the solid tumors include embryonic cell tumors, thymoma, gastric cancer and the like.
  • the macrophage activation syndrome includes systemic or organ-specific autoimmune diseases.
  • the other types of HLH include HLH induced by pregnancy, drugs, organ and hematopoietic stem cell transplantation, and rare metabolic diseases.
  • the diagnostic criteria for hemophagocytic syndrome can refer to the principles commonly used in the art, such as the “Chinese Expert Consensus on the Diagnosis and Treatment of Hemophagocytic Syndrome (2016)" or the HLH-2004 diagnostic criteria.
  • the hemophagocytic syndrome includes gene mutation hemophagocytic syndrome, and the mutant genes include, but are not limited to, JAK2/STAT, PRF1, UNC13D, STX11, STXBP2, Rab27a, LYST, SH2D1A, BIRC4 , ITK, AP3 ⁇ 1, MAGT1, CD27.
  • the administration period of the hemophagocytic syndrome of the treatment patient is 2-6 weeks.
  • the administration cycle of the hemophagocytic syndrome of the treated patient is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or a range formed by any of the above values.
  • the administration cycle for the treatment of lymphoma of the patient is 4 weeks.
  • the amount of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient, for example, it can be determined according to the The tester/patient's routine blood test results are confirmed, and the routine blood test results include platelet count, neutrophil count, or hemoglobin concentration.
  • the daily dose administered to the compound of the present application, its stereoisomers, or a pharmaceutically acceptable salt thereof is 1 mg to 100 mg.
  • the daily dose administered to the compound of the present application, its stereoisomers, or pharmaceutically acceptable salts thereof may be selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, or 100mg, or any of the foregoing values as a range constituted by endpoints or any value therein, such as 1mg to 90mg, 5mg to 80mg, 10mg To 70mg, 15mg to 60mg, 20mg to 50mg, 20mg to 40mg, 30mg to 40mg, etc.
  • the daily dose administered to the compound of the present application, its stereoisomers, or a pharmaceutically acceptable salt thereof may be selected from 1 mg to 50 mg, 5 mg to 50 mg, 5 mg to 45 mg, 5 mg to 40 mg, 10 mg To 35mg, 10mg to 30mg, 20mg to 40mg, 30mg to 40mg.
  • the daily dose administered to the compound of the application, its stereoisomers, or pharmaceutically acceptable salts thereof may be selected from 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 any of the foregoing values as a range constituted by endpoints or any value therein, such as 2mg to 50mg, 10mg to 40mg, 5mg To 30mg, 5mg to 20mg, 20mg to 40mg, 30mg to 40mg, etc.
  • Administration of the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, the compound of the application, its stereoisomer, or a pharmaceutically acceptable salt thereof is administered once or twice a day. Administration of the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof can also be administered in a single dosage form. In one embodiment, it is administered once or twice a day in a single dose. In one embodiment, a single oral solid formulation is administered once or twice a day. In a specific embodiment, a single oral solid formulation is administered twice a day.
  • Administration of the compound of the present application, its stereoisomers, or a pharmaceutically acceptable salt thereof can also be administered in the form of multiple doses.
  • multiple doses are administered once or twice a day.
  • multiple doses of oral solid formulations are administered once or twice a day.
  • multiple doses of oral solid formulations are administered twice a day.
  • the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof 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 the compound of the present application, its stereoisomers, 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 foregoing values as the endpoints or any value in the range of the compound of the present application, its stereoisomers, or a pharmaceutically acceptable salt thereof, for example, 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30mg, 5mg to 20mg, 20mg to 40mg, 30mg to 40mg, etc.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is a daily dose. In some of the schemes of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof is twice a day. In some of the schemes of the present application, each dose of the two doses is the same.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is dosed twice a day, and each dose is a single dose or multiple doses, respectively.
  • the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is twice a day, and each dose is a multiple dose, which consists of a single dose It is composed of 5 mg, 10 mg, 15 mg and/or 20 mg of a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition consists of a single dose of 5 mg of the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is twice a day, and each dose is a single dose, and the single dose It is 5 mg, 10 mg, 15 mg and/or 20 mg of a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof.
  • the single dose is 20 mg of the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof is packaged in a kit, and the kit further contains the compound of formula I, its Description of the use of stereoisomers, or pharmaceutically acceptable salts thereof, for the treatment of hemophagocytic syndrome.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is daily
  • the dosage is administered in the following manner: the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered once or twice a day; in some of the schemes of this application, the formula The pharmaceutical composition of compound I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day, and the dose is the same each time; in some of the schemes of this application, the compound of formula I, its stereoisomer
  • the pharmaceutical composition of the body, or a pharmaceutically acceptable salt thereof is administered twice a day, and the dose is the same each time, and the interval between each administration is 12 hours.
  • 28 days is a treatment cycle
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is continuously administered from day 1 to day 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 a day on the 1-28th day of each cycle.
  • Pharmaceutical composition
  • the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is 140-840 mg ( Calculated as the active ingredient of the compound of formula (I) itself).
  • the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof 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 dose of the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is preferably 560 to 840 mg (based on the active ingredient of the compound of formula (I) itself count).
  • the compounds of the present application, their stereoisomers, or their pharmaceutically acceptable salts can be administered by various routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, arterial Intradermal, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vagina, intraocular, topical administration, subcutaneous, intrafatty, intraarticular, or intrathecal. In a specific regimen, it is administered orally.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof can be formulated into a preparation form suitable for oral administration to humans, for example, including but It is not limited to tablets, pills, capsules, powders or granules.
  • the pharmaceutical composition of the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is an oral tablet.
  • the oral tablet of the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof has a single-dose specification of 5 mg or 20 mg.
  • the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts or pharmaceutical compositions thereof of the present application have good therapeutic effects, including but not limited to better disease control rate and longer survival period (Such as median survival, progression-free survival or overall survival), longer duration of disease remission (DOR).
  • the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts or pharmaceutical compositions thereof of the present application also have good safety when they have good therapeutic effects, including but not limited to low adverse reactions Incidence rate.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt includes a salt formed by a base ion and a free acid or a salt formed by an acid radical and a free base.
  • the pharmaceutically acceptable salt described in this application is selected from the group consisting of maleate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, malonate, butyl Diacid salt, fumarate, malate, mandelate, tartrate, citrate, ascorbate, palmitate, benzoate, phenylacetate, cinnamate, salicylate, Methanesulfonate, benzenesulfonate or toluenesulfonate.
  • the amount of the compound of formula I is calculated in its free base form.
  • the compound in the pharmaceutical combination of the present application has, for example, at least one basic center, it can form an acid addition salt. If necessary, it is also possible to form a corresponding acid addition salt having a basic center additionally present.
  • Compounds having at least one acidic group for example COOH
  • the compounds of the application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compound containing asymmetric carbon atoms of the present application can be isolated in an optically pure form or a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • patient refers to mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the patient is a human.
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their pharmaceutical combinations or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the application or its pharmaceutical combination to a subject.
  • treatment generally refers to obtaining the desired pharmacological and/or physiological effects, including partial or complete stabilization or cure of diseases and/or effects due to diseases.
  • Treatment encompasses any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, that is, preventing its development; or (b) alleviating the symptoms of the disease, that is, causing the disease or symptoms to degenerate.
  • an effective amount means the amount of the compound of the present application that (i) treats a specific disease, condition, or disorder, or (ii) reduces, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder.
  • the amount of the compound of the present application that constitutes a "therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine.
  • a box of medicines has seven capsules, and each capsule is a single dose; or each bottle of injection is a single dose.
  • multi-dose consists of multiple 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.
  • the administration is oral administration.
  • daily dose refers to the daily dose administered to a patient.
  • day (day) When referring to a dosing regimen, the terms “day (day)”, “every day (daily)”, etc. refer to the time within a calendar day, starting at midnight and ending at the next midnight.
  • the prescription composition of the solid pharmaceutical composition of 5mg and 20mg tablets is shown in Table 1:
  • Table 1 The prescription composition of 5mg and 20mg tablets
  • Preparation of bulk drug suspension add hydroxypropyl cellulose to purified water in the prescribed amount to dissolve it to prepare a 4% (w/w) hydroxypropyl cellulose solution; dissolve sodium lauryl sulfate; add formula II compound to stir and disperse , Get the API suspension;
  • Fluidized bed granulation and drying spray the bulk drug suspension onto the mixture A for fluidized granulation.
  • Granulation parameters inlet air temperature 55 ⁇ 80°C, atomization pressure 600 ⁇ 1000mbar, material temperature 25 ⁇ 35°C; drying after spraying, drying ends when the material temperature is higher than 45°C; granulating by crushing and sizing machine , The aperture of the whole-size screen is ⁇ 0.6 ⁇ 1.2mm to obtain the dry particles after the whole-size;
  • Administration method take it once every morning on an empty stomach, and then take it again after 12 hours. Continuous administration for 28 days constitutes a treatment cycle.
  • contraceptive measures such as intrauterine device [IUD], contraceptives or condoms
  • IUD intrauterine device
  • condoms serum pregnancy within 7 days before the study entry drug The test is negative and must be a non-lactating patient
  • men should agree to use contraceptive measures during the study period and at least 6 months after the end of the study period;
  • the efficacy was evaluated according to the standards of "Chinese Expert Consensus on Diagnosis and Treatment of Hemophagocytic Syndrome (2016)”. During induction therapy, it is recommended to evaluate the efficacy every 2 weeks.
  • the main indicators of efficacy evaluation include sCD25, ferritin, blood cell count, triacylglycerol, hemophagocytosis, and level of consciousness (for those with CNS-HLH).
  • Partial response ⁇ 2 symptoms/laboratory indicators improved by more than 25%, and individual indicators need to meet the following standards: 1sCD25 level decreased by more than 1/3; 2ferritin and triglycerides decreased by more than 25%; 3 Without blood transfusion: Those with neutrophils ⁇ 0.5x10 9 /L need to increase by 100% and >0.5x10 9 /L; for those with neutrophils 0.5 ⁇ 2.0x10 9 /L, they need to increase by 100% and return to normal; 4If ALT>400U/L, it needs to drop by more than 50%.

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Abstract

吡咯并嘧啶化合物治疗噬血细胞综合征的用途，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及其药物组合物治疗噬血细胞综合征的用途。

Description

吡咯并嘧啶化合物的治疗噬血细胞综合征的用途
相关申请的交叉引用
本申请要求于2020年03月09日向中国国家知识产权局提交的第202010157375.4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引用整体并入本文中。
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噬血细胞综合征的用途。
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)。
JAK家族在涉及免疫应答的细胞增殖和功能性细胞因子依赖性调节中产生作用。目前，有四种已知的哺乳动物JAK家族成员：JAK1、JAK2、JAK3和TYK2(Tyrosine kinase 2)。JAK蛋白的大小范围在120-140kDa，其包含7个保守的JAK同源性(JH)结构域；其中之一为功能性催化激酶结构域，而另一个为假性激酶(pseudokinase)结构域，其有效地发挥调节功能和/或作为STAT的停靠位点起作用(Scott,Godshall et al.2002，supra)。
噬血细胞综合征(hemophagocyic lymphohistiocytosis，HLH)，又称为噬血细胞性淋巴组织细胞增多症，是一组以CD8 +T淋巴细胞及单核-巨噬细胞系统过度增生并产生大量炎症因子，引起多器官系统暴发性炎症反应的临床综合征，临床上以持续发热、肝脾肿大、出血为特征。该病起病急、病情凶险、进展迅速、病死率极高。HLH是一种调节性T细胞与CD8+T细胞平衡失衡，以及IL-2网络稳态紊乱的疾病。在HLH的过程中，CD8+T细胞被过度激活并成功地与调节性T细胞竞争IL-2，从而导致调节性T细胞功能减退。HLH特征是免疫激活的急性临床体征和症状，包括肝肿大，黄疸，淋巴结肿大，皮疹，癫痫发作和局灶性神经功能缺损，实验室检查中显示，多种炎症细胞因子的血清水平升高，包括 干扰素-γ(IFN-γ)，肿瘤坏死因子α(TNF-α)，白介素6(IL-6)，白介素10(IL-10)和巨噬细胞集落刺激因子(M-CSF)。
发明概述
一方面，本申请提供用于治疗噬血细胞综合征的式I化合物、其立体异构体、或其药学上可接受的盐：
Figure PCTCN2021079820-appb-000001
另一方面，本申请提供用于治疗噬血细胞综合征的药物组合物，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噬血细胞综合征的方法，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用于治疗噬血细胞综合征的药物中的用途。
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噬血细胞综合征中的用途。
发明详述
本申请提供用于治疗噬血细胞综合征的式I化合物、其立体异构体、或其药学上可接受的盐：
Figure PCTCN2021079820-appb-000002
另一方面，本申请提供用于治疗噬血细胞综合征的药物组合物，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噬血细胞综合征的方法，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，或者包含式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。
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，或者包含式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制备用于治疗患者的噬血细胞综合征的药物中的用途。
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，或者包含式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治疗患者的噬血细胞综合征中的用途。
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
Figure PCTCN2021079820-appb-000003
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。
噬血细胞综合征
在本申请的部分方案中，所述噬血细胞综合征包括原发性噬血细胞综合征和继发性噬血细胞综合征。其中，所述原发性噬血细胞综合征包括家族性HLH、免疫缺陷综合征相关HLH或EB病毒(EBV)驱动HLH及其他因相关基因异常所引起的HLH；所述继发性噬血细胞综合征包括感染相关HLH、恶性肿瘤相关HLH、巨噬细胞活化综合征(MAS)、或其他类型的HLH。
在本申请的部分方案中，所述家族性HLH(也叫FHL)包括FHL-1、FHL-2、FHL-3、FHL-4或FHL-5。
在本申请的部分方案中，所述免疫缺陷综合征相关HLH包括Griscelli综合征2(GS-2)、Chediak-Higashi综合征1(CHS-1)或Hermansky-Pudlak综合征Ⅱ(HPS-Ⅱ)。
在本申请的部分方案中，所述EBV驱动HLH包括X连锁淋巴组织增生综合征(XLP)，优选地，其包括XLP-1和XLP-2(即X连锁凋亡抑制因子(XIAP)缺陷)；所述EBV驱动HLH还包括其他EBV驱动HLH，优选地，其包括IL-2诱导的T细胞激酶缺乏(IL-2-inducible T-cell kinase deficiency,ITK)、CD27缺乏以及镁离子转运基因(magnesium transporter gene,MAGT1)的突变。
在本申请的部分方案中，所述感染相关HLH中所述感染包括病毒、细菌、真菌以及原虫感染等。
在本申请的部分方案中，所述恶性肿瘤相关HLH中所述恶性肿瘤包括血液系统肿瘤或实体肿瘤；优选地，所述血液系统肿瘤包括淋巴瘤、急性白血病、多发性骨髓瘤、骨髓增生异常综合征等；优选地，所述实体肿瘤包括胚胎细胞肿瘤、胸腺瘤、胃癌等。
在本申请的部分方案中，所述巨噬细胞活化综合征(MAS)包括系统性或器官特异性自身免疫性疾病。
在本申请的部分方案中，所述其他类型的HLH包括由妊娠、药物、器官及造血干细胞移植、罕见的代谢性疾病诱发的HLH。
本申请中，所述噬血细胞综合征诊断标准可参考本领域通用的原则，例如《噬血细胞综合征诊治中国专家共识(2018)》或HLH-2004诊断标准。
本申请中，所述的噬血细胞综合征包括基因突变的噬血细胞综合征，所述的突变型基因包括但不限于如JAK2/STAT、PRF1、UNC13D、STX11、STXBP2、Rab27a、LYST、SH2D1A、BIRC4、ITK、AP3β1、MAGT1、CD27。
给药方案
在本申请的部分方案中，所述治疗患者的噬血细胞综合征的给药周期是2～6周。在本申请的一些方案中，所述治疗患者的噬血细胞综合征的给药周期是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，所述治疗患者的淋巴瘤的给药周期是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100mg。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、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、或100mg，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90mg、5mg至80mg、10mg至70mg、15mg至60mg、20mg至50mg、20mg至40mg、30mg至40mg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1mg至50mg、5mg至50mg、5mg至45mg、5mg至40mg、10mg至35mg、10mg至30mg、20mg至40mg、30mg至40mg。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2mg至50mg、10mg至40mg、5mg至30mg、5mg至20mg、20mg至40mg、30mg至40mg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2mg至50mg、10mg至40mg、5mg至30mg、5mg至20mg、20mg至40mg、30mg至40mg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噬血噬血细胞综合征的说明。
在本申请的部分方案中，所述治疗噬血噬血细胞综合征的方法或用途中，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，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560～840mg(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。
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疾病控制率、更长的生存期(例如中位生存期、无进展生存期或总生存期)、更长时间的疾病缓解持续时间(DOR)。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。
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
Figure PCTCN2021079820-appb-000004
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 噬血细胞综合征临床方案
1.1给药方案
给药方法：每天早晨空腹口服一次，12小时后再口服一次，连续给药28天为一个治疗周期。
药物：式I化合物的片剂，5mg或20mg，所述式I化合物表现为其立体异构体式II化合物
Figure PCTCN2021079820-appb-000005
1.2入组标准
1)年龄≥18周岁；ECOG体力状况：0～3分；预计生存期超过3个月；
2)根据HLH-2004标准，明确诊断为HLH的初发或首次复发患者；
3)使用过其它HLH治疗药物者，需停药2周以上。接受过大手术者需手术4周以后；
4)实验室检查需满足：血常规检查：血红蛋白(Hb)≥60g/L；绝对中性粒细胞计数(ANC)≥0.5×10 9/L；血小板(PLT)≥30×10 9/L；肝功能：血清总胆红素(TBIL)<171μmol/L；肾功能：血清肌酐(Cr)≤1.5×ULN；凝血功能：活化部分凝血活酶时间(APTT)、国际标准化比值(INR)≤1.5×ULN；
5)女性患者应同意在研究期间和研究结束后至少6个月内必须采用避孕措施(如宫内节育器[IUD]，避孕药或避孕套)；在研究入组用药前的7天内血清妊娠试验阴性，且必须为非哺乳期患者；男性应同意在研究期间和研究期结束后至少6个月内必须采用避孕措施；
6)患者自愿加入本研究，签署知情同意书，依从性好。
1.3评价方法
参考《噬血细胞综合征诊治中国专家共识(2018)》标准评价疗效。诱导治疗期间，建议每2周评估一次疗效。
疗效评价的主要指标包括sCD25、铁蛋白、血细胞计数、三酰甘油、噬血现象、意识水平(有CNS-HLH者)。
a)完全应答(complete response):上述所有指标均恢复正常范围。
b)部分应答(partial response):≥2项症状/实验室指标改善25％以上，个别指标需达到以下标准:①sCD25水平下降1/3以上；②铁蛋白和甘油三酯下降25％以上；③不输血情况下:中性粒细胞<0.5x10 9/L者,需上升100％并>0.5x10 9/L；中性粒细胞0.5～2.0x10 9/L者,需增加100％并恢复正常；④ALT>400U/L者,需下降50％以上。
1.4治疗效果
病例1
45岁女性患者，诊断为噬血细胞综合征，按照1.1所述给药方案给予式II化合物的片剂20mg/次。定点行血检检测血药浓度，动态监测血象、生化、凝血等指标，继续密切动态监测患者病情及生命体征变化。病例1在用药一个周期后，疾病保持稳定，患者耐受性尚可。
病例2
44岁女性患者，诊断为噬血细胞综合征，按照1.1所述给药方案给予式II化合物的片剂15mg/次。定点行血检检测血药浓度，动态监测血象、生化、凝血等指标，继续密切动态监测患者病情及生命体征变化。
病例2在用药一个周期后，疾病保持稳定，其sCD25水平下降1/3以上，铁蛋白下降25％以上，疾病出现部分应答，患者耐受性尚可。

Claims (15)

  1. 用于治疗噬血细胞综合征的式I化合物、其立体异构体、或其药学上可接受的盐，或者包含式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，
    Figure PCTCN2021079820-appb-100001
  2. 如权利要求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者所述的药物组合物，其中，所述噬血细胞综合征选自原发性噬血细胞综合征和继发性噬血细胞综合征。
  3. 如权利要求2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者所述的药物组合物，其中，所述原发性噬血细胞综合征选自家族性HLH、免疫缺陷综合征相关HLH或EB病毒驱动HLH及其他因相关基因异常所引起的HLH，所述相关基因选自JAK2/STAT、PRF1、UNC13D、STX11、STXBP2、Rab27a、LYST、SH2D1A、BIRC4、ITK、AP3β1、MAGT1、CD27。
  4. 如权利要求2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者所述的药物组合物，其中，所述继发性噬血细胞综合征选自感染相关HLH、恶性肿瘤相关HLH、巨噬细胞活化综合征、或由妊娠、药物、器官及造血干细胞移植、罕见的代谢性疾病诱发的HLH。
  5. 如权利要求1-4中任一项所述的式I化合物、其立体异构体、或其药学上可接受的盐或者所述的药物组合物，其中，所述噬血细胞综合征为基因突变的噬血细胞综合征，所述的突变型基因选自JAK2/STAT、PRF1、UNC13D、STX11、STXBP2、Rab27a、LYST、SH2D1A、BIRC4、ITK、AP3β1、MAGT1、CD27。
  6. 如权利要求1-5中任一项所述的式I化合物、其立体异构体、或其药学上可接受的盐或者所述的药物组合物，其中所述式I化合物为：
    Figure PCTCN2021079820-appb-100002
  7. 式I化合物、其立体异构体、或其药学上可接受的盐或者包含式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治疗噬血细胞综合征中的用途：
    Figure PCTCN2021079820-appb-100003
  8. 如权利要求7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或者包含式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日剂量为1mg至100mg；优选日剂量为1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、或100mg，或者任意前述值作为端点构成的范围，或者1mg至90mg、5mg至80mg、10mg至70mg、15mg至60mg、20mg至50mg、30mg至40mg。
  9. 如权利要求7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或者包含式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施用一次或多次；优选每天一次或两次。
  10. 如权利要求7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或者包含式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单剂量每天给药一次或两次；优选以单剂量的口服固体制剂每天给药一次或两次；更优选以单剂量的口服固体制剂每天给药两次。
  11. 如权利要求7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或者包含式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每天给药一次或两次；优选以多剂量的口服固体制剂每天给药一次或两次；更优选以多剂量的口服 固体制剂每天给药两次。
  12. 如权利要求7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或者包含式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；优选由单剂量为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。
  13. 如权利要求7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或者包含式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；优选单剂量为20mg的式I化合物、其立体异构体、或其药学上可接受的盐。
  14. 如权利要求7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。
  15. 如权利要求7所述的用途，其中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；优选总剂量选自140mg、280mg、420mg、560mg、700mg、840mg或上述任意两个值所形成的范围；更优选总剂量为560～840mg。
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