WO2020135401A1 - 吡咯并嘧啶化合物的治疗用途及其固体药物组合物 - Google Patents

吡咯并嘧啶化合物的治疗用途及其固体药物组合物 Download PDF

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Publication number
WO2020135401A1
WO2020135401A1 PCT/CN2019/127837 CN2019127837W WO2020135401A1 WO 2020135401 A1 WO2020135401 A1 WO 2020135401A1 CN 2019127837 W CN2019127837 W CN 2019127837W WO 2020135401 A1 WO2020135401 A1 WO 2020135401A1
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WIPO (PCT)
Prior art keywords
sodium
pharmaceutical composition
compound
formula
cellulose
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PCT/CN2019/127837
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English (en)
French (fr)
Inventor
王栋
李清侠
戴峻
李晨
江竹莲
孙艳清
陈晶晶
金玲玲
刘君动
李其德
Original Assignee
正大天晴药业集团股份有限公司
连云港润众制药有限公司
首药控股(北京)有限公司
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Application filed by 正大天晴药业集团股份有限公司, 连云港润众制药有限公司, 首药控股(北京)有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to US17/417,712 priority Critical patent/US20220072002A1/en
Priority to JP2021537128A priority patent/JP2022515272A/ja
Priority to KR1020217023608A priority patent/KR20210132007A/ko
Priority to CN202310447777.1A priority patent/CN116473973A/zh
Priority to CN201980081492.2A priority patent/CN113242859B/zh
Priority to CA3123985A priority patent/CA3123985A1/en
Priority to EP19905962.7A priority patent/EP3904356A4/en
Priority to AU2019413421A priority patent/AU2019413421A1/en
Publication of WO2020135401A1 publication Critical patent/WO2020135401A1/zh

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Classifications

    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

  • the present application belongs to the field of medicinal chemistry, and relates to the therapeutic use of a pyrrolopyrimidine compound and its solid pharmaceutical composition.
  • Januskinase 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 transmits chemical signals from outside the cell through the cell membrane to the gene promoter located on the DNA in the nucleus, which ultimately affects the changes in DNA transcription and activity levels in the cell.
  • the JAK-STAT pathway consists of three main parts: 1) receptors; 2) bifacial kinase (JAK) and 3) signal transduction and transcriptional activation protein (STAT).
  • the receptor can be activated by interferon, interleukin, growth factor, or other chemical messengers, and the activation leads to JAK autophosphorylation; then the STAT protein binds to the phosphorylated receptor, so that the STAT is phosphorylated by JAK; then the STAT protein is phosphorylated Separated from the receptor, dimerized and translocated 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 (Tyrosinekinase2).
  • JAK2 JAK1, JAK2, JAK3, and TYK2 (Tyrosinekinase2).
  • JAK1 JAK2, JAK3, and TYK2
  • JH conserved JAK homology
  • Myeloproliferative neoplasms are clonal hematopoietic stem cell diseases whose cell proliferation is the main feature.
  • the main feature is the excessive proliferation of relatively mature cells of one or more lines of bone marrow.
  • Myeloproliferative tumors mainly include polycythemia (PV), primary thrombocythemia (ET), and primary myelofibrosis (PMF).
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 alkyl acyl or C 1-6 alkylsulfonyl; R 3 and R 4 are each independently It is selected from H, hydroxyl or oxo.
  • the present application provides a pharmaceutical composition for treating myeloproliferative tumors, the pharmaceutical composition comprising a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present application provides a method for treating myeloproliferative tumors, which comprises administering to the subject an effective amount of a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable thereof Salt, or a pharmaceutical composition thereof.
  • the present application provides the use of the compound of formula I as described above, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for the treatment of myeloproliferative tumors.
  • the present application provides the use of the compound of formula I as described above, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment of myeloproliferative tumors.
  • the present application provides a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising a compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof, as well as a diluent, binder, wetting agent, and disintegrant.
  • the present application provides the above-mentioned solid pharmaceutical composition for treating diseases mediated by bifacial kinase.
  • the present application provides the use of the above solid pharmaceutical composition in the preparation of a medicament for treating a disease mediated by bifacial kinase.
  • the present application provides a method of treating a bifacial kinase-mediated disease, the method comprising administering to the subject an effective amount of the above solid pharmaceutical composition.
  • the present application provides the use of the above solid pharmaceutical composition in the treatment of diseases mediated by bifacial kinase.
  • the present application provides compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof for the treatment of myeloproliferative tumors:
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 alkyl acyl or C 1-6 alkylsulfonyl; R 3 and R 4 are each independently It is selected from H, hydroxyl or oxo.
  • the present application provides a pharmaceutical composition for treating myeloproliferative tumors, the pharmaceutical composition comprising a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present application provides a method for treating myeloproliferative tumors, which comprises administering to the subject an effective amount of a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable thereof Salt, or a pharmaceutical composition thereof.
  • the present application provides the use of the compound of formula I as described above, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for the treatment of myeloproliferative tumors.
  • the present application provides the use of the compound of formula I as described above, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment of myeloproliferative tumors.
  • the pharmaceutical composition comprises the compound of formula I as described above, its stereoisomer, or a pharmaceutically acceptable salt thereof.
  • the R 1 and R 2 are each independently selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propionyl, butyl Acyl, valeryl, hexanoyl, methanesulfonyl, ethanesulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, or hexanesulfonyl.
  • the R 1 is selected from H
  • the R 2 is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propionyl, butyl Acyl, valeryl, hexanoyl, methanesulfonyl, ethanesulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, or hexanesulfonyl.
  • the compound of formula I shown has the configuration shown in the following formula:
  • the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is selected from:
  • the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is preferably selected from:
  • the hydrochloride salt of formula I is preferred.
  • the monohydrochloride salt of formula I is preferred.
  • crystallization of the monohydrochloride salt of formula I is preferred.
  • the free base of formula I is preferred. In some embodiments of the present application, crystallization of the free base of formula I is preferred.
  • the compound of formula I is a compound of formula II
  • a compound of formula II, or a pharmaceutically acceptable salt thereof, for use in the treatment of polycythemia vera is provided.
  • a compound of formula II, or a pharmaceutically acceptable salt thereof, for use in the treatment of thrombocytosis is provided.
  • a compound of Formula II, or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis is provided.
  • a pharmaceutical composition for treating polycythemia vera comprising a compound of formula II as described above, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating thrombocytosis comprising a compound of formula II as described above, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating myelofibrosis comprising a compound of formula II as described above, or a pharmaceutically acceptable salt thereof.
  • the present application provides a method for treating polycythemia vera, comprising administering to the subject an effective amount of a compound of formula II as described above, or a pharmaceutically acceptable salt thereof , Or a pharmaceutical composition thereof.
  • the present application provides a method for treating thrombocytosis, which comprises administering to the subject an effective amount of a compound of formula II as described above, or a pharmaceutically acceptable salt thereof, Or its pharmaceutical composition.
  • the present application provides a method for treating myelofibrosis, which comprises administering to the subject an effective amount of a compound of formula II as described above, or a pharmaceutically acceptable salt thereof, Or its pharmaceutical composition.
  • the present application provides the use of the compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating polycythemia vera.
  • the present application provides the use of a compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating thrombocytosis.
  • the present application provides the use of a compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of myelofibrosis.
  • the use of the compound of formula II of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of polycythemia vera is not limited.
  • the use of the compound of formula II of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of thrombocytosis is not limited.
  • the use of the compound of formula II of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of myelofibrosis is not limited.
  • 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 formulations, such as tablets, pills, capsules, powders , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable 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 and the like.
  • Suitable excipients include, but are not limited to: binders, diluents, wetting agents, disintegrating agents, lubricants, glidants, sweeteners, or flavoring agents.
  • the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, 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 and the like.
  • Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, or mixtures thereof; 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, talc, polyethylene glycol, sodium lauryl sulfate, micropowder silica gel, talc or mixtures thereof; disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl Cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropylmethylcellulose or crospovidone
  • the pharmaceutical composition is a single-dose pharmaceutical composition.
  • the pharmaceutical composition contains 1 mg to 50 mg of the compound of the present application, its stereoisomer, 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 range in which the foregoing values are used as endpoints or any value therein, the compound of the present application, its stereoisomer, 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, etc.
  • the present application provides a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising the compound of formula I or compound of formula II, its stereoisomers or pharmaceutically acceptable salts thereof, as well as diluents, binders, wetting agents and disintegrating agents Antidote.
  • the solid pharmaceutical composition includes a compound of Formula I or a compound of Formula II, a diluent, a binder, a wetting agent, and a disintegrant.
  • the solid pharmaceutical composition further comprises a lubricant.
  • the amount of the compound of formula I or the compound of formula II is selected from 1-30% wt, preferably 1-25% wt, 1-20% wt, 2-20% wt, 2-15 %Wt, 2-10%wt, 3-10%wt or 2-8%wt, more preferably 3-8%wt, further preferably 3.5-6%wt; or in some embodiments, the compound of formula I or compound of formula II The amount is selected from 1%wt, 1.2%wt, 1.4%wt, 1.6%wt, 1.8%wt, 2%wt, 2.2%wt, 2.4%wt, 2.6%wt, 2.8%wt, 3%wt, 3.2% wt, 3.4%wt, 3.6%wt, 3.8%wt, 4%wt, 4.2%wt, 4.4%wt, 4.6%wt, 4.8%wt, 5%wt, 5.2%wt, 5.4%w
  • the diluent is selected from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin or mixtures thereof; preferably microcrystalline cellulose, mannitol, lactose , Pregelatinized starch or mixtures thereof; more preferably microcrystalline cellulose, mannitol or mixtures thereof.
  • the amount of the diluent is selected from 50 to 95% wt, preferably 60 to 95% wt, 65 to 95% wt, 70 to 95% wt, 75 to 95% wt, 80 to 95%wt, 80-90%wt or 85-95%wt, more preferably 85-90%wt; or in some embodiments, the amount of the diluent is selected from 55%wt, 60%wt, 65%wt, 70%wt, 75%wt, 80%wt, 85%wt, 90%wt or 95%wt, or any of the foregoing values as a range constituted by the endpoints or any value therein.
  • the binder is selected from hypromellose (HPMC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na), ethyl cellulose ( EC), methyl cellulose (MC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), gelatin, polyvinylpyrrolidone (PVP), partially hydrolyzed starch, starch, pre Gelatinized starch, sucrose, glucose, gelatin, polyethylene glycol (PEG), polyvinyl alcohol or mixtures thereof; preferably hypromellose (HPMC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na), ethyl cellulose (EC), methyl cellulose (MC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpyrrolidone or mixtures thereof ; More preferably hypromellose (HPMC),
  • the amount of the binder is selected from 1.0% to 10% wt, preferably 1.0% to 8.0% wt, 1.0% to 6.0% wt, or 1.0% to 5.0% wt, more preferably 2.0 to 4.0%wt; or in some embodiments, the amount of the binder is selected from 1.0%wt, 1.5%wt, 2.0%wt, 2.5%wt, 3.0%wt, 3.5%wt, 4.0%wt, 4.5%wt, 5.0%wt, 5.5%wt, 6.0%wt, 6.5%wt, 7.0%wt, 7.5%wt, 8.0%wt, 8.5%wt, 9.0%wt, 9.5%wt or 10%wt, or any of the foregoing values as endpoints Constituent range or any value in it.
  • the wetting agent is selected from sodium dodecylbenzenesulfonate, magnesium dodecylbenzenesulfonate, sodium tetradecylbenzenesulfonate, cetylbenzenesulfonic acid Sodium, sodium octadecylbenzenesulfonate, sodium dodecylsulfonate, magnesium dodecylsulfonate, sodium tetradecylsulfonate, sodium cetylsulfonate, sodium octadecylsulfonate , Sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium cetyl sulfate, sodium octadecyl sulfate, sodium lauroyl sarcosinate, sodium lactate, sodium palmitate, lauryl Isopropano
  • the amount of the wetting agent is selected from 0.01 to 5.0%wt, preferably 0.01 to 4.0%wt, 0.01 to 3.0%wt, 0.02 to 2.5%wt, 0.02 to 2.0%wt, more Preferably it is 0.03 to 2.0%wt, further preferably 0.05 to 1.0%wt, still more preferably 0.1 to 0.5%wt; or in some embodiments, the amount of the lubricant is selected from 0.01%wt, 0.02%wt, 0.03%wt, 0.04%wt, 0.05%wt, 0.06%wt, 0.07%wt, 0.08%wt, 0.09%wt, 0.1%wt, 0.2%wt, 0.3%wt, 0.4%wt, 0.5%wt, 0.6%wt, 0.7% wt, 0.8%wt, 0.9%wt, 1.0%wt, 1.1%wt, 1.2%wt, 1.3%wt, 1.4%wt, 1.5%wt, 1.6%wt, 1.7%wt, 0.8%wt, 0.9%w
  • the disintegrant is selected from sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose Calcium, croscarmellose sodium, low-substituted hydroxypropylmethyl cellulose or crospovidone, sodium lauryl sulfate or magnesium dodecyl sulfate or mixtures thereof; preferably sodium carboxymethyl starch, Croscarmellose sodium or mixtures thereof.
  • the amount of the disintegrant is selected from 1.0 to 7.0% wt, preferably 1.0 to 6.5% wt, 1.0 to 6.5% wt, 1.0 to 6.0% wt, 1.5 to 5.5% wt, 1.5 ⁇ 5.0%wt or 1.5 ⁇ 4.5%wt, more preferably 2.0 ⁇ 4.0%wt; or in some embodiments, the amount of the disintegrant is selected from 1.0%wt, 1.5%wt, 2.0%wt, 2.5%wt, 3.0%wt, 3.5%wt, 4.0%wt, 4.5%wt, 5.0%wt, 5.5%wt, 6.0%wt, 6.5%wt, or 7.0%wt, or any of the foregoing values as a range of endpoints or any of them value.
  • the lubricant is selected from magnesium stearate, colloidal silicon dioxide, talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate Or sodium lauryl sulfate or mixtures thereof, preferably magnesium stearate, colloidal silica or mixtures thereof.
  • the amount of the lubricant is selected from 0.1 to 3%wt, preferably 0.2 to 2.5%wt, 0.3 to 2.0%wt or 0.4 to 1.5%wt, more preferably 0.5 to 1%wt; Or in some embodiments, the amount of the lubricant is selected from 0.1%wt, 0.2%wt, 0.3%wt, 0.4%wt, 0.5%wt, 0.6%wt, 0.7%wt, 0.8%wt, 0.9%wt, 1.0%wt, 1.1%wt, 1.2%wt, 1.3%wt, 1.4%wt, 1.5%wt, 1.6%wt, 1.7%wt, 1.8%wt, 1.9%wt, 2.0%wt, 2.1%wt, 2.2% wt, 2.3%wt, 2.4%wt, 2.5%wt, 2.6%wt, 2.7%wt, 2.8%wt, 2.9%wt, or 3.0%wt, or any of the foregoing values as a range of endpoints or any value therein
  • the solid pharmaceutical composition includes 50-95% wt of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or a mixture thereof; preferably 60-60% wt, 65- 95%wt, 70-95%wt, 75-95%wt, 80-95%wt, 80-90%wt or 85-95%wt microcrystalline cellulose, mannitol, lactose, pregelatinized starch or Mixtures; more preferably 85 to 90% wt microcrystalline cellulose, mannitol, lactose, pregelatinized starch or mixtures thereof; further preferably 85 to 90% wt microcrystalline cellulose, mannitol or mixtures thereof.
  • the diluent is selected from a mixture of microcrystalline cellulose and mannitol, wherein the weight ratio of microcrystalline cellulose and mannitol is selected from 1:1 to 5:1, preferably from 1:1 to 4 :1, 1.2:1 to 3.5:1 or 1.2:1 to 3:1, more preferably 1.5:1 to 2.5:1; or the weight ratio of microcrystalline cellulose and mannitol is selected from 1:1, 1.2:1 1.5:1, 1.8:1, 1.9:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, 4:1, 4.2: 1. 4.5:1, 4.8:1 or 5:1.
  • the diluent in the solid pharmaceutical composition is selected from 50 to 70% wt microcrystalline cellulose and 20 to 40% wt mannitol, or preferably 52 to 68%wt microcrystalline cellulose and 22-38%wt mannitol, 54-66%wt microcrystalline cellulose and 24-36%wt mannitol, 54-64%wt microcrystalline cellulose and 24-34%wt mannitol Alcohol, 56-62%wt microcrystalline cellulose and 26-32%wt mannitol, more preferably 56-60%wt microcrystalline cellulose and 26-30%wt mannitol, further preferably 58.3%wt microcrystalline cellulose and 29.4% wt mannitol.
  • the solid pharmaceutical composition includes 1.0% to 10% wt hypromellose (HPMC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC- Na), ethyl cellulose (EC), methyl cellulose (MC), hydroxypropyl cellulose (HPC), L-HPC, polyvinylpyrrolidone or mixtures thereof; preferably 1.0% to 8.0% wt, 1.0% ⁇ 6.0%wt or 1.0% ⁇ 5.0%wt hypromellose (HPMC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na), ethyl cellulose (EC), Methyl cellulose (MC), hydroxypropyl cellulose (HPC), L-HPC, polyvinylpyrrolidone or mixtures thereof; more preferably including 2.0-4.0% wt hypromellose (HPMC), carboxymethyl fiber (CMC), sodium carboxymethyl cellulose (CMC-Na), ethyl cellulose (EC
  • the solid pharmaceutical composition includes 0.01 to 5.0% wt of sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, dodecyl Sodium sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium cetyl sulfate, sodium octadecyl sulfate or sodium lauroyl sarcosinate or mixtures thereof; preferably 0.01 to 4.0% wt, 0.01 ⁇ 3.0%wt, 0.02 ⁇ 2.5%wt, 0.02 ⁇ 2.0%wt sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, twelve Magnesium alkyl sulfate, sodium tetradecyl sulfonate, sodium
  • the solid pharmaceutical composition includes 1.0-7.0% wt of sodium carboxymethyl starch or croscarmellose sodium or a mixture thereof; preferably 1.0-6.5% wt, 1.0- 6.5%wt, 1.0-6.0%wt, 1.5-5.5%wt, 1.5-5.0%wt or 1.5-4.5%wt carboxymethyl starch sodium, croscarmellose sodium or mixtures thereof; more preferably including 2.0 ⁇ 4.0% wt sodium carboxymethyl starch, croscarmellose sodium or mixtures thereof.
  • the solid pharmaceutical composition includes 0.1 to 3% wt magnesium stearate, colloidal silica, or a mixture thereof; preferably 0.2 to 2.5% wt, 0.3 to 2.0% wt, or 0.4 to 1.5%wt magnesium stearate, colloidal silica or mixtures thereof; more preferably 0.5 to 1%wt magnesium stearate, colloidal silica or mixtures thereof.
  • the solid pharmaceutical composition described in the present application includes:
  • microcrystalline cellulose 50-95% wt of microcrystalline cellulose, mannitol, lactose, pregelatinized starch or mixtures thereof;
  • HPMC hypromellose
  • CMC carboxymethyl cellulose
  • CMC-Na sodium carboxymethyl cellulose
  • EC ethyl cellulose
  • MC methyl cellulose
  • HPC hydroxypropyl cellulose
  • L-HPC polyvinylpyrrolidone or mixtures thereof;
  • magnesium stearate optionally 0.1 to 3% wt magnesium stearate, colloidal silica or mixtures thereof; or
  • microcrystalline cellulose 75-95% wt of microcrystalline cellulose, mannitol or a mixture thereof, wherein the weight ratio of microcrystalline cellulose and mannitol in the mixture of microcrystalline cellulose and mannitol is selected from 1.2:1 to 3.5:1;
  • magnesium stearate optionally 0.3-2.0%wt magnesium stearate, colloidal silica or mixtures thereof; or
  • microcrystalline cellulose 85-90%wt of microcrystalline cellulose, mannitol or a mixture thereof, wherein the weight ratio of microcrystalline cellulose and mannitol in the mixture of microcrystalline cellulose and mannitol is selected from 1.5:1 to 2.5:1;
  • magnesium stearate 0.5 to 1% wt magnesium stearate, colloidal silica or mixtures thereof; or
  • magnesium stearate optionally 0.5 to 2% wt magnesium stearate; or
  • magnesium stearate optionally 0.5 to 1% wt magnesium stearate; or
  • the compound of formula I or the compound of formula II exists in the form of a free base or hydrochloride salt. In some typical embodiments of the present application, the compound of formula I or the compound of formula II exists as a free base. In some typical embodiments of the present application, the compound of Formula I or the compound of Formula II exists as a monohydrochloride salt.
  • the solid pharmaceutical composition further includes a coating agent.
  • a coating agent is formed from the aqueous film coating composition, wherein the aqueous film coating composition comprises a film-forming polymer, water and/or alcohol as a carrier, and optionally one or more auxiliary agents , Such as additives known in the field of film coating.
  • the coating agent is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and cellulose acetate phthalate acetate Element, sodium ethyl cellulose sulfate, carboxymethyl cellulose, polyvinylpyrrolidone, zein, and acrylic polymers (eg, methacrylic acid/methacrylate copolymers, such as methacrylic acid/methyl methacrylate copolymer Etc.), and the group consisting of polyvinyl alcohol.
  • the coating agent comprises polyvinyl alcohol.
  • the dissolution rate of the solid pharmaceutical composition within 30 minutes is not less than 60% of the indicated amount. In some embodiments of the present application, the dissolution rate of the solid pharmaceutical composition within 30 minutes is not less than 80% of the indicated amount. In some embodiments of the present application, the solid pharmaceutical composition does not have a dissolution rate within 30 minutes in a pH 1.0 hydrochloric acid solution, a pH 4.5 acetate buffer, a pH 6.8 phosphate buffer, or purified water. Less than 80% of the marked amount, preferably not less than 85% of the marked amount.
  • the dissolution of the solid pharmaceutical composition in purified water within 30 minutes is not less than 80% of the indicated amount, preferably not less than 85% of the indicated amount, further preferably not less than the indicated amount 90%. In some typical embodiments of the present application, the dissolution rate of the solid pharmaceutical composition in purified water within 15 minutes is not less than 85% of the indicated amount.
  • the dosage form of the solid pharmaceutical composition may be selected from powders, granules, tablets, capsules, pills, pellets, dispersions or inhalable powders, preferably tablets or capsules, further Tablets are preferred.
  • the solid pharmaceutical composition is a unit dose pharmaceutical composition, and the amount of the compound of formula I or compound of formula II in each unit dose of the composition is 5 mg to 20 mg. In some embodiments of the present application, the amount of the compound of formula I or compound of formula II in each unit dose of the composition is 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, or 20 mg, or any of the foregoing values as a range of endpoints Or any value in it.
  • the present application provides a method for preparing a solid pharmaceutical composition of a compound of formula I or a compound of formula II.
  • wet granulation can be used to prepare solid particles.
  • other auxiliary materials with good compatibility with the compound of formula I or compound of formula II can be added as needed.
  • wet granulation can be selected in wet granulator (mixed granulation) or fluidized bed (fluidized bed granulation) Carried out in the medium, preferably fluid bed granulation.
  • the compound of formula I or compound of formula II can be added to the premix as a solid additive together with other additives or prepared as a solution (suspension or clear solution) for granulation. It is preferably prepared so that the suspension is introduced into the granules during the granulation stage.
  • a method for preparing a solid pharmaceutical composition of a compound of formula I or a compound of formula II includes the following steps:
  • step 2) Spray the mixed solution obtained in step 1) onto the mixture obtained in step 1), granulate through a fluidized bed, dry, and adjust the granules to obtain dried granules after granulation;
  • the mixed solution in step 1) is a suspension or a clear solution, preferably a suspension;
  • the diluent, binder, wetting agent, disintegrant and lubricant are as described above.
  • the inlet air temperature is selected from 35 to 90°C, preferably from 45 to 85°C, and more preferably from 55 to 80°C.
  • the atomization pressure is selected from 400 to 1200 mbar, preferably 500 to 1100 mbar, more preferably 600 to 1000 mbar.
  • the temperature of the material is selected from 20 to 40°C, preferably 25 to 35°C.
  • the pore size of the whole-mesh sieve is 0.4 to 1.5 mm, preferably 0.5 to 1.4 mm, and more preferably 0.6 to 1.2 mm.
  • the present application provides the use of the solid pharmaceutical composition of the compound of formula I or the compound of formula II in the preparation of a medicament for treating diseases mediated by bifacial kinase.
  • the present application provides a solid pharmaceutical composition of the compound of Formula I or the compound of Formula II for treating a disease mediated by bifacial kinase.
  • the present application provides the use of the solid pharmaceutical composition of the compound of formula I or the compound of formula II in the treatment of diseases mediated by bifacial kinase.
  • the present application provides a method of treating a bifacial kinase-mediated disease, the method comprising administering to a subject a therapeutically effective amount of a solid pharmaceutical composition of the compound of formula I or compound of formula II.
  • the two-sided neurokinase-mediated diseases include but are not limited to tumors.
  • the tumor described herein is lymphoma or leukemia.
  • the lymphomas described in this application include but are not limited to Hodgkins disease (Non-Hodgkins lymphoma), and the non-Hodgkins lymphomas include but are not limited to B-cell lymphomas (B-cell lymphoma) or T-cell lymphoma.
  • the leukemias described in this application include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia.
  • the disease mediated by bifacial neurokinase is myeloproliferative tumor.
  • the myeloproliferative tumor includes polycythemia vera, thrombocythemia, or myelofibrosis.
  • the polycythemia vera includes polycythemia vera which is resistant to and/or intolerant to hydroxyurea and/or interferon.
  • the thrombocytosis includes primary thrombocytosis, primary thrombocytosis that is resistant and/or intolerant to hydroxyurea and/or interferon.
  • the bone marrow fibrosis includes primary myelofibrosis, post-polycythemia myelofibrosis (PPV-MF), post-essential thrombocythemia myelofibrosis, PET-MF).
  • the myeloproliferative tumors and diseases included include low-risk, intermediate-risk, and high-risk myeloproliferative tumors.
  • polycythemia vera can be divided into low-risk and high-risk polycythemia vera
  • thrombocytosis can be divided into very low-risk, low-risk, medium-risk, and high-risk thrombocytosis
  • myelofibrosis can be divided into low-risk and medium-risk And/or high-risk bone marrow fibrosis.
  • the polycythemia vera is moderate-risk and/or high-risk polycythemia
  • the thrombocytosis is moderate-risk and/or high-risk thrombocytosis
  • the bone marrow fibrosis is moderate-risk and/or Or high-risk bone marrow fibrosis
  • the primary thrombocytosis is intermediate-risk and/or high-risk primary thrombocytosis.
  • the primary myelofibrosis, myelofibrosis after polycythemia vera, and myelofibrosis after primary thrombocythemia all belong to corresponding high-risk myelofibrosis.
  • the diagnostic criteria and risk stratification for example, very low-risk, low-risk, medium-risk, and high-risk
  • myeloproliferative tumors can refer to the general principles in the field, and can refer to "NCCN Guidelines” Version 2.2019 Myeloproliferative Neoplasms ", for example, you can refer to Dynamic International Prognostic Scoring System (DIPSS, Dynamic international prognostic scoring system) for evaluation.
  • DIPSS Dynamic International Prognostic Scoring System
  • the WHO 2016 standard and the IWG-MRT standard are used as the diagnostic basis.
  • the myeloproliferative tumors include gene mutant myeloproliferative tumors, and the mutant genes include but are not limited to JAK2 (eg JAK2V617F), MPL, CALR, ASXL1/SRSF2/IDH1/21, JAK2exon12, TP53, SH2B3/IDH2/U2AF1/SF3B1/EZH2/TP53, MPL W515L/K, CALR Type 1/Type 1-like, triple negative (JAK2, MPL, and CALR no mutation), ASXL1, EZH2, IDH1/2, SRSF2 , SF3B1, CALR/ASXL1, TP53, or U2AF1Q157.
  • JAK2 eg JAK2V617F
  • MPL eg JAK2V617F
  • CALR ASXL1/SRSF2/IDH1/21, JAK2exon12
  • TP53 SH2B3/IDH2/U2AF1/SF3B1/EZH2/TP53
  • the compound of formula I or the compound of formula II is administered as a free base. In some embodiments of the present application, the compound of formula I or the compound of formula II is administered in crystalline form as a free base. In some aspects of the present application, the free base crystals of the compound of formula II may be selected from Form A or Form B disclosed in WO2017215630.
  • the compound of formula II is administered in the form of the hydrochloride salt.
  • the hydrochloride salt of the compound of formula II may be selected from the hydrochloride salts disclosed in WO2017101777.
  • the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof can be administered by various routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, arterial Intradermal, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhaled, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular or intrathecal. In a specific regimen, it is administered orally.
  • the amount of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition may be based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age of the subject
  • the health status can be determined, for example, based on the results of routine blood tests of the subject, which include platelet count, neutrophil count, or hemoglobin concentration.
  • the daily dose of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition is 1 mg to 100 mg.
  • the daily dose of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition may be selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg , 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg, or any of the foregoing values as a range of endpoints or any value therein, such as 1 mg to 90mg, 5mg to 80mg, 10mg to 70mg, 15mg to 60mg, 20mg to 50mg, etc.
  • the daily dose of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition may be selected from 1 mg to 50 mg, 5 mg to 50 mg, 5 mg to 45mg, 5mg to 40mg, 10mg to 35mg, 10mg to 30mg.
  • the daily dose of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition may be selected from 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12mg, 15mg, 18mg, 20mg, 22mg, 25mg, 28mg, 30mg, 32mg, 35mg, 38mg, 40mg, 42mg, 45mg, 48mg or 50mg, or any of the foregoing values as a range of endpoints or any value therein, such as 2mg to 50mg, 10mg to 40mg, 5mg to 30mg, 5mg to 20mg, etc.
  • the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition can be administered one or more times per day. In some embodiments, the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition is administered once or twice a day.
  • the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can also be administered in a single dose. In one embodiment, a single dose is administered once or twice a day. In one embodiment, the oral solid formulation is administered in a single dose once or twice a day.
  • the method of administration can be comprehensively determined according to factors such as the activity of the drug, toxicity and the tolerance of the subject.
  • the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof is administered at intervals.
  • the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition can be administered at intervals.
  • the interval administration includes an administration period and a withdrawal period, within which the compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof can be administered once, twice or more times a day, or Its solid pharmaceutical composition.
  • Interval dosing can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health status of the subject, for example, can be determined based on the results of the routine blood test of the subject/subject Test results include platelet count, neutrophil count, or hemoglobin concentration.
  • the compounds described in this application can effectively reduce the spleen of a subject.
  • the compound described in the present application has a good therapeutic effect on myeloproliferative tumors, and has more excellent safety.
  • the solid pharmaceutical composition described in this application has excellent stability and dissolution properties and is suitable for clinical use. Further, the tablet solid pharmaceutical composition of the present application has the property of rapid release, and its dissolution within 30 minutes is not less than 80% of the marked amount.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without Multiple toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • salts formed with alkali ions and free acids or salts formed with free ions including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, Formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-toluene Sulfonates, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, mesylate, p-toluene Sulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.
  • the molar ratio of the free acid to the alkali ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • the molar ratio of the free base to the acid ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1 :3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • a compound of formula I or a compound of formula II of the present application may form an acid addition salt if it has, for example, at least one basic center. If necessary, corresponding acid addition salts with additionally present basic centers can also be formed.
  • Compounds having at least one acidic group eg COOH
  • the compounds 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 containing asymmetric carbon atoms of the present application can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.
  • subject is a mammal. In some embodiments, the subject is a human.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compound of the present application to the subject.
  • treatment means administration of a compound or pharmaceutical composition described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • the term "effective amount” means (i) treatment of a specific disease, condition or disorder, (ii) reduction, improvement or elimination of one or more symptoms of a specific disease, condition or disorder, or (iii) prevention or delay of The amount of the compound of the present application for the onset of one or more symptoms of the specific disease, condition or disorder.
  • the amount of the compound of the present application constituting the "therapeutically effective amount” depends 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 those skilled in the art Determined by its own knowledge and this disclosure.
  • the "pharmaceutically acceptable salts” include, but are not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid; or with organic acids such as formic acid, acetic acid, Acid addition salts of fluoroacetic acid, succinic acid, malic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-methyl or benzenesulfonic acid; or with acidic amino acids
  • acid addition salts formed from aspartic acid or glutamic acid includes but is not limited to the hydrate form.
  • the content of the compound of formula I and the compound of formula II in the pharmaceutical composition is calculated in the form of its free base.
  • the diluent described in this application may also be called a filler, which is mainly divided into water-soluble diluents, water-insoluble diluents, diluents for direct compression, etc., including but not limited to starch, sucrose, dextrin, lactose, Gelatinized starch microcrystalline cellulose, inorganic salts and/or sugar alcohols.
  • the lactose includes but is not limited to anhydrous lactose, lactose monohydrate or a mixture thereof.
  • Adhesives can be divided into adhesives that are viscous when they are made into an aqueous solution or glue, dry adhesives that are also viscous in a dry state, and adhesives that are viscous after being dissolved or wet by a non-aqueous solvent.
  • Binders include but are not limited to starch syrup, cellulose derivatives, povidone, gelatin, polyethylene glycol, sucrose solution and/or sodium alginate solution.
  • the wetting agent in the present application is a liquid and/or surfactant with a small surface tension that is miscible with water.
  • the surfactant includes anionic surfactant, cationic surfactant, zwitterionic surfactant and/or non-ionic Ionic surfactant.
  • the anionic surfactant includes, but is not limited to, alkylbenzene sulfonate, alkyl sulfonate, alkyl sulfonate, alkyl sulfate, fluorine-containing fatty acid salt, polysiloxane and/or fatty alcohol Sulfate.
  • the cationic surfactants include but are not limited to quaternary ammonium compounds, alkyl pyridine salts and/or amine salts.
  • the zwitterionic surfactants include but are not limited to lecithin, amino acid type and/or betaine type, and the nonionic surfactants include but are not limited to alkyl glucoside (APG), fatty acid glyceride, fatty acid sorbitan ( Span), polysorbate (Tween), polyoxyethylene and/or poloxamer.
  • APG alkyl glucoside
  • Span fatty acid sorbitan
  • Teween polysorbate
  • polyoxyethylene and/or poloxamer polyoxyethylene and/or poloxamer.
  • disintegrants described in this application include but are not limited to starch and its derivatives, celluloses, surfactants, effervescent disintegrants, gums, alginates and/or ion exchange resins.
  • the lubricant described in this application broadly includes three kinds of auxiliary materials: lubricant (narrow sense), glidant and anti-sticking agent.
  • Lubricants described herein include but are not limited to stearic acids, colloidal silica, talc, hydrogenated vegetable oils and/or polyethylene glycols.
  • %wt refers to the weight of the ingredient in the total weight of the solid pharmaceutical composition (wherein the weight of the compound of formula I and the compound of formula II is calculated in the form of its free base) percentage.
  • the total weight of the solid pharmaceutical composition does not include the weight of the coating agent.
  • the preparation method of the solid pharmaceutical composition or the corresponding dosage form described in this application can be carried out according to a method known in the art.
  • the specific preparation method may include the steps of crushing, mixing, sieving, granulating, filling, tabletting, etc., selecting the required steps according to the actual situation, and the method or equipment for implementing the specific steps.
  • the crushing step may be performed using a mortar, ball mill, roller press, impact crusher, hammer crusher, and/or jet mill;
  • the mixing step may employ stirring mixing, grinding mixing, and/or sieving mixing;
  • the sieve step may use a shaking sieve and/or a shaking sieve. Or you can refer to "Pharmaceutics" edited by Cui Fude (6th or 7th edition, People's Medical Publishing House).
  • the term "or a mixture thereof” means “a mixture of two or more”, for example, "the diluent is selected from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin or a mixture thereof” ie "The diluent is selected from one or a mixture of two or more of microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin".
  • marked amount in the field of pharmaceutical compositions refers to the content of the main drug specified in the unit dose preparation.
  • 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 prescription composition of 5mg and 20mg tablet solid pharmaceutical composition is shown in Table 1:
  • API suspension add hydroxypropylcellulose to a prescribed amount of purified water and dissolve it into a 4% (w/w) hydroxypropylcellulose solution; dissolve sodium dodecyl sulfate; add the compound of formula II and stir to disperse.
  • Fluidized bed granulation and drying spraying the raw material drug suspension onto the mixture A to perform fluidized granulation.
  • Granulation parameters inlet air temperature 55 ⁇ 80°C, atomization pressure 600 ⁇ 1000mbar, material temperature 25 ⁇ 35°C; drying after spraying, drying when the material temperature is higher than 45°C; granulation using a granulator , The pore size of the whole-grain screen is ⁇ 0.6 ⁇ 1.2mm, and the dry granules after the whole-grain are obtained;
  • prescription A to I solid pharmaceutical compositions are prepared.
  • the prescription A to I solid pharmaceutical compositions are 5 mg tablets, and the specific prescription composition is as follows:
  • the fourth method of dissolution and release in the Chinese Pharmacopoeia 2015 edition of four parts 0931 the dissolution behavior of the above-mentioned prescription solid pharmaceutical composition in four media was investigated.
  • the four media are pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and purified water, and the medium volume is 900 mL.
  • the compound of formula II is used as a reference solution to prepare a solution containing about 5.6 ⁇ g of compound of formula II per 1 mL.
  • the method and conditions are: paddle method, speed: 50rpm, medium temperature: 37°C ⁇ 0.5°C, sampling time point: 5, 10, 15, 20, 30 or 45min.
  • the drug used was the 5 mg tablet of Example 2.
  • Method of administration oral fasting, pre-test once a day. Subsequent dose groups were taken orally every 12 hours, and no food was allowed within 2 hours after administration. 28 days of continuous medication is a treatment cycle.
  • the enrolled subjects are required to administer the medicine for at least 1 cycle to observe the tolerance and the initial efficacy.
  • the study drug will continue to be provided free of charge until the disease progresses or the investigator determines that it is not suitable to continue using the study drug.
  • DIPSS Dynamic International Prognostic Point System
  • PV and ET subjects who are resistant or intolerant to treatment with hydroxyurea and/or interferon;
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • UPN upper limit of normal
  • Female subjects should agree to use contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study period and at least 6 months after the end of the study; serum pregnancy test within 7 days before study enrollment Negative and must be a non-lactating subject; males should agree to use contraception during the study period and at least 6 months after the end of the study period;
  • contraceptive measures such as intrauterine devices, contraceptives or condoms
  • Active systemic infections such as the presence of bacterial, fungal, parasitic or viral infections that require clinical treatment.
  • Active systemic infections such as the presence of bacterial, fungal, parasitic or viral infections that require clinical treatment.
  • Obvious cardiovascular diseases such as heart failure grade 2 or above by the New York Heart Association (NYHA), unstable angina within the past 3 months, myocardial ischemia or myocardial infarction, arrhythmia (female QTc >470ms, male QTc>450ms) and Grade I cardiac insufficiency;
  • the subject's upper limb vein was indwelled with a catheter to collect blood samples, each time about 3 mL of venous blood was collected.
  • the collected blood sample is placed in a pre-treated heparin sodium anticoagulation blood collection tube (at room temperature for no more than 0.5h), centrifuged at 4°C for 10min (2500g), separated the plasma, and stored at -80°C for testing (at Leave at room temperature for no more than 2h).

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Abstract

一种吡咯并嘧啶化合物的治疗用途及其固体药物组合物。具体涉及用于治疗骨髓增殖性肿瘤的吡咯并嘧啶化合物或其药物组合物，吡咯并嘧啶化合物或其药物组合物用于治疗骨髓增殖性肿瘤的方法或用途。

Description

吡咯并嘧啶化合物的治疗用途及其固体药物组合物
相关申请的交叉引用
本申请要求于2018年12月24日向中华人民共和国国家知识产权局提交的第201811581815.8号中国发明专利申请和于2019年07月26日向中华人民共和国国家知识产权局提交的第201910679429.0号中国发明专利的权益和优先权，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本申请属于医药化学领域，涉及吡咯并嘧啶化合物的治疗用途及其固体药物组合物。
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)。
骨髓增殖性肿瘤(myeloproliferative neoplasms,MPN)是细胞增殖为主要特征的克隆性造血干细胞疾病主要特征是骨髓一系或多系相对成熟的细胞过度增殖。骨髓增殖性肿瘤主要包括真性红细胞增多症(polycythemia vera,PV)、原发性血小板增多症(essential thrombocythemia,ET)、原发性骨髓纤维化(primary myelofibrosis,PMF)。
发明概述
本申请提供用于治疗骨髓增殖性肿瘤的式I化合物、其立体异构体、或其药学上可接受的盐：
Figure PCTCN2019127837-appb-000001
其中，所述R 1和R 2各自独立地选自H、C 1～6烷基、C 1～6烷基酰基或C 1～6烷基磺酰基；所述R 3和R 4各自独立地选自H、羟基或氧代。
另一方面，本申请提供用于治疗骨髓增殖性肿瘤的药物组合物，所述药物组合物包括如上所述的式I化合物、其立体异构体、或其药学上可接受的盐。
另一方面，本申请提供用于治疗骨髓增殖性肿瘤的方法，其包括向所述受试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骨髓增殖性肿瘤药物中的用途。
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骨髓增殖性肿瘤中的用途。
又一方面，本申请提供一种固体药物组合物，其包括式I化合物、其立体异构体、或其药学上可接受的盐，以及稀释剂、黏合剂、润湿剂和崩解剂。
又一方面，本申请提供用于治疗两面神激酶介导的疾病的上述固体药物组合物。
又一方面，本申请提供上述固体药物组合物在制备治疗两面神激酶介导的疾病的药物中的用途。
又一方面，本申请提供治疗两面神激酶介导的疾病的方法，所述方法包括给予受试者有效量的上述固体药物组合物。
又一方面，本申请提供上述固体药物组合物在治疗两面神激酶介导的疾病中的用途。
发明详述
本申请提供用于治疗骨髓增殖性肿瘤的式I化合物、其立体异构体、或其药学上可接受 的盐：
Figure PCTCN2019127837-appb-000002
其中，所述R 1和R 2各自独立地选自H、C 1～6烷基、C 1～6烷基酰基或C 1～6烷基磺酰基；所述R 3和R 4各自独立地选自H、羟基或氧代。
另一方面，本申请提供用于治疗骨髓增殖性肿瘤的药物组合物，所述药物组合物包括如上所述的式I化合物、其立体异构体、或其药学上可接受的盐。
另一方面，本申请提供用于治疗骨髓增殖性肿瘤的方法，其包括向所述受试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骨髓增殖性肿瘤药物中的用途。
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骨髓增殖性肿瘤中的用途。
在本申请的部分实施方案中，所述药物组合物包含如上所述的式I化合物、其立体异构体、或其药学上可接受的盐。
在本申请的部分实施方案中，所述R 1和R 2各自独立地选自H、甲基、乙基、丙基、丁基、戊基、己基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、戊磺酰基或己磺酰基。
在本申请的部分实施方案中，所述R 1选自H，所述R 2选自甲基、乙基、丙基、丁基、戊基、己基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、戊磺酰基或己磺酰基。
在本申请的部分实施方案中，所示式I化合物具有如下式所示构型：
Figure PCTCN2019127837-appb-000003
在本申请的部分实施方案中，式I化合物、其立体异构体、或其药学上可接受的盐选自：
Figure PCTCN2019127837-appb-000004
在本申请的部分实施方案中，式I化合物、其立体异构体、或其药学上可接受的盐优选自：
Figure PCTCN2019127837-appb-000005
在本申请的部分实施方案中，优选式I的盐酸盐。在本申请的部分实施方案中，优选式I的一盐酸盐。在本申请的部分实施方案中，优选式I的一盐酸盐的结晶。
在本申请的部分实施方案中，优选式I的自由碱。在本申请的部分实施方案中，优选式I的自由碱的结晶。
在本申请的部分实施方案中，所述式I化合物为式II化合物
Figure PCTCN2019127837-appb-000006
在本申请的部分实施方案中，提供用于治疗真性红细胞增多症的式II化合物、或其药学上可接受的盐。
在本申请的部分实施方案中，提供用于治疗血小板增多症的式II化合物、或其药学上可接受的盐。
在本申请的部分实施方案中，提供用于治疗骨髓纤维化的式II化合物、或其药学上可接受的盐。
在本申请的部分实施方案中，提供用于治疗真性红细胞增多症的药物组合物，所述药物组合物包括如上所述的式II化合物、或其药学上可接受的盐。
在本申请的部分实施方案中，提供用于治疗血小板增多症的药物组合物，所述药物组合物包括如上所述的式II化合物、或其药学上可接受的盐。
在本申请的部分实施方案中，提供用于治疗骨髓纤维化的药物组合物，所述药物组合物包括如上所述的式II化合物、或其药学上可接受的盐。
在本申请的部分实施方案中，本申请提供用于治疗真性红细胞增多症的方法，其包括向所述受试者给予有效量的如上所述的式II化合物、或其药学上可接受的盐、或其药物组合物。
在本申请的部分实施方案中，本申请提供用于治疗血小板增多症的方法，其包括向所述受试者给予有效量的如上所述的式II化合物、或其药学上可接受的盐、或其药物组合物。
在本申请的部分实施方案中，本申请提供用于治疗骨髓纤维化的方法，其包括向所述受试者给予有效量的如上所述的式II化合物、或其药学上可接受的盐、或其药物组合物。
在本申请的部分实施方案中，本申请提供式II化合物、或其药学上可接受的盐、或其药物组合物在制备治疗真性红细胞增多症药物中的用途。
在本申请的部分实施方案中，本申请提供式II化合物、或其药学上可接受的盐、或其药 物组合物在制备治疗血小板增多症药物中的用途。
在本申请的部分实施方案中，本申请提供式II化合物、或其药学上可接受的盐、或其药物组合物在制备治疗骨髓纤维化药物中的用途。
在本申请的部分实施方案中，本申请式II化合物、或其药学上可接受的盐、或其药物组合物在治疗真性红细胞增多症中的用途。
在本申请的部分实施方案中，本申请式II化合物、或其药学上可接受的盐、或其药物组合物在治疗血小板增多症中的用途。
在本申请的部分实施方案中，本申请式II化合物、或其药学上可接受的盐、或其药物组合物在治疗骨髓纤维化中的用途。
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。
在本申请的部分方案中，所述的药物组合物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等。
固体药物组合物
本申请提供一种固体药物组合物，其包括本申请所述式I化合物或式II化合物、其立体异构体或其药学上可接受的盐，以及稀释剂、黏合剂、润湿剂和崩解剂。
在本申请的部分实施方案中，所述固体药物组合物包括式I化合物或式II化合物、稀释剂、黏合剂、润湿剂和崩解剂。
在本申请的一些实施方案中，所述固体药物组合物进一步包含润滑剂。在本申请的部分实施方案中，所述式I化合物或式II化合物的量选自1～30％wt，优选1～25％wt、1～20％wt、2～20％wt、2～15％wt、2～10％wt、3～10％wt或2～8％wt，更优选3～8％wt，进一步优选3.5～6％wt；或者一些实施方案中，式I化合物或式II化合物的量选自1％wt、1.2％wt、1.4％wt、1.6％wt、1.8％wt、2％wt、2.2％wt、2.4％wt、2.6％wt、2.8％wt、3％wt、3.2％wt、3.4％wt、3.6％wt、3.8％wt、4％wt、4.2％wt、4.4％wt、4.6％wt、4.8％wt、5％wt、5.2％wt、5.4％wt、5.6％wt、5.8％wt、6％wt、6.2％wt、6.4％wt、6.6％wt、6.8％wt、7％wt、7.2％wt、7.4％wt、7.6％wt、7.8％wt、8％wt、8.2％wt、8.4％wt、8.6％wt、8.8％wt、9％wt、9.2％wt、9.4％wt、9.6％wt、9.8％wt、10％wt、10.5％wt、11％wt、11.5％wt、12％wt、12.5％wt、13％wt、13.5％wt、14％wt、14.5％wt、15％wt、15.5％wt、16％wt、16.5％wt、17％wt、17.5％wt、18％wt、18.5％wt、19％wt、19.5％wt、20％wt、21％wt、22％wt、23％wt、24％wt、25％wt、26％wt、27％wt、28％wt、29％wt或30％wt，或者任意前述值作为端点构成的范围或其中的任意值。
在本申请的部分实施方案中，所述稀释剂选自微晶纤维素、甘露醇、乳糖、蔗糖、淀粉、预胶化淀粉、糊精或其混合物；优选微晶纤维素、甘露醇、乳糖、预胶化淀粉或其混合物；更优选微晶纤维素、甘露醇或其混合物。
在本申请的部分实施方案中，所述稀释剂的量选自50～95％wt，优选60～95％wt、65～95％wt、70～95％wt、75～95％wt、80～95％wt、80～90％wt或85～95％wt，更优选85～90％wt；或者一些实施方案中，所述稀释剂的量选自55％wt、60％wt、65％wt、70％wt、75％wt、80％wt、85％wt、90％wt或95％wt，或者任意前述值作为端点构成的范围或其中的任意值。
在本申请的部分实施方案中，所述黏合剂选自羟丙甲纤维素(HPMC)、羧甲基纤维素(CMC)、羧甲基纤维素钠(CMC-Na)、乙基纤维素(EC)、甲基纤维素(MC)、羟丙基纤维素(HPC)、低取代羟丙基纤维素(L-HPC)、明胶、聚乙烯吡咯烷酮(PVP)、部分水解的淀粉、淀粉、预胶化淀粉、蔗糖、葡萄糖、明胶、聚乙二醇(PEG)、聚乙烯醇或其混合物； 优选羟丙甲纤维素(HPMC)、羧甲基纤维素(CMC)、羧甲基纤维素钠(CMC-Na)、乙基纤维素(EC)、甲基纤维素(MC)、羟丙基纤维素(HPC)、低取代羟丙基纤维素(L-HPC)、聚乙烯吡咯烷酮或其混合物；更优选羟丙基纤维素、聚乙烯吡咯烷酮或其混合物。
在本申请的部分实施方案中，所述黏合剂的量选自1.0％～10％wt，优选1.0％～8.0％wt、1.0％～6.0％wt或1.0％～5.0％wt，更优选2.0～4.0％wt；或者一些实施方案中，所述黏合剂的量选自1.0％wt、1.5％wt、2.0％wt、2.5％wt、3.0％wt、3.5％wt、4.0％wt、4.5％wt、5.0％wt、5.5％wt、6.0％wt、6.5％wt、7.0％wt、7.5％wt、8.0％wt、8.5％wt、9.0％wt、9.5％wt或10％wt，或者任意前述值作为端点构成的范围或其中的任意值。
在本申请的部分实施方案中，所述润湿剂选自十二烷基苯磺酸钠、十二烷基苯磺酸镁、十四烷基苯磺酸钠、十六烷基苯磺酸钠、十八烷基苯磺酸钠、十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十六烷基磺酸钠、十八烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠、月桂酰肌氨酸钠、乳酸钠、棕榈酸钠、月桂酸异丙醇酰胺、月桂酸二乙醇酰胺、乳酸十四烷基酯、乳酸十六基酯、聚山梨酯20、聚山梨酯40、聚山梨酯60、聚山梨酯65、聚山梨酯80、聚山梨酯85、聚氧乙烯十二烷基醚、聚氧乙烯十六烷基醚、聚氧乙烯山梨醇四油基醚、聚氧乙烯硬脂酸酯、聚氧乙烯蓖麻油或聚氧乙烯氢化蓖麻油或其混合物；优选地，本申请所述润湿剂选自十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠或月桂酰肌氨酸钠或其混合物；更优选地，本申请所述润湿剂选自十二烷基硫酸钠或十二烷基硫酸镁或其混合物。
在本申请的部分实施方案中，所述润湿剂的量选自0.01～5.0％wt，优选0.01～4.0％wt、0.01～3.0％wt、0.02～2.5％wt、0.02～2.0％wt，更优选0.03～2.0％wt，进一步优选0.05～1.0％wt，更进一步优选0.1～0.5％wt；或者一些实施方案中，所述润滑剂的量选自0.01％wt、0.02％wt、0.03％wt、0.04％wt、0.05％wt、0.06％wt、0.07％wt、0.08％wt、0.09％wt、0.1％wt、0.2％wt、0.3％wt、0.4％wt、0.5％wt、0.6％wt、0.7％wt、0.8％wt、0.9％wt、1.0％wt、1.1％wt、1.2％wt、1.3％wt、1.4％wt、1.5％wt、1.6％wt、1.7％wt、1.8％wt、1.9％wt、2.0％wt、2.1％wt、2.2％wt、2.3％wt、2.4％wt、2.5％wt、2.6％wt、2.7％wt、2.8％wt、2.9％wt、3.0％wt、3.2％wt、3.4％wt、3.6％wt、3.8％wt、4.0％wt、4.2％wt、4.4％wt、4.6％wt、4.8％wt或5.0％wt，或者任意前述值作为端点构成的范围或其中的任意值。
在本申请的部分实施方案中，所述崩解剂选自羧甲基淀粉钠、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、十二烷基硫酸钠或十二烷基硫酸镁或其混合物；优选羧甲基淀粉钠、 交联羧甲基纤维素钠或其混合物。
在本申请的部分实施方案中，所述崩解剂的量选自1.0～7.0％wt，优选1.0～6.5％wt、1.0～6.5％wt、1.0～6.0％wt、1.5～5.5％wt、1.5～5.0％wt或1.5～4.5％wt，更优选2.0～4.0％wt；或者一些实施方案中，所述崩解剂的量选自1.0％wt、1.5％wt、2.0％wt、2.5％wt、3.0％wt、3.5％wt、4.0％wt、4.5％wt、5.0％wt、5.5％wt、6.0％wt、6.5％wt、或者7.0％wt，或者任意前述值作为端点构成的范围或其中的任意值。
在本申请的部分实施方案中，所述润滑剂选自硬脂酸镁、胶体二氧化硅、滑石粉、聚乙二醇4000、聚乙二醇6000、硬脂酸、硬脂富马酸钠或十二烷基硫酸钠或其混合物，优选硬脂酸镁、胶体二氧化硅或其混合物。
在本申请的部分实施方案中，所述润滑剂的量选自0.1～3％wt，优选0.2～2.5％wt、0.3～2.0％wt或0.4～1.5％wt，更优选0.5～1％wt；或者一些实施方案中，所述润滑剂的量选自0.1％wt、0.2％wt、0.3％wt、0.4％wt、0.5％wt、0.6％wt、0.7％wt、0.8％wt、0.9％wt、1.0％wt、1.1％wt、1.2％wt、1.3％wt、1.4％wt、1.5％wt、1.6％wt、1.7％wt、1.8％wt、1.9％wt、2.0％wt、2.1％wt、2.2％wt、2.3％wt、2.4％wt、2.5％wt、2.6％wt、2.7％wt、2.8％wt、2.9％wt或3.0％wt，或者任意前述值作为端点构成的范围或其中的任意值。
在本申请的部分实施方案中，所述固体药物组合物包括50～95％wt的微晶纤维素、甘露醇、乳糖、预胶化淀粉或其混合物；优选包括60～95％wt、65～95％wt、70～95％wt、75～95％wt、80～95％wt、80～90％wt或85～95％wt的微晶纤维素、甘露醇、乳糖、预胶化淀粉或其混合物；更优选包括85～90％wt微晶纤维素、甘露醇、乳糖、预胶化淀粉或其混合物；进一步优选包括85～90％wt微晶纤维素、甘露醇或其混合物。在部分优选方案中，所述稀释剂选自微晶纤维素和甘露醇的混合物，其中微晶纤维素和甘露醇的重量比选自1:1～5:1，优选自1:1～4:1、1.2:1～3.5:1或1.2:1～3:1，更优选1.5:1～2.5:1；或者微晶纤维素和甘露醇的重量比选自1:1、1.2:1、1.5:1、1.8:1、1.9:1、2:1、2.2:1、2.5:1、2.8:1、3:1、3.2:1、3.5:1、3.8:1、4:1、4.2:1、4.5:1、4.8:1或5:1。
在本申请的部分实施方案中，基于固体药物组合物的量，所述固体药物组合物中稀释剂选自50～70％wt微晶纤维素和20～40％wt甘露醇，或者优选52～68％wt微晶纤维素和22～38％wt甘露醇、54～66％wt微晶纤维素和24～36％wt甘露醇、54～64％wt微晶纤维素和24～34％wt甘露醇、56～62％wt微晶纤维素和26～32％wt甘露醇，更优选56～60％wt微晶纤维素和26～30％wt甘露醇，进一步优选58.3％wt微晶纤维素和29.4％wt甘露醇。
在本申请的部分实施方案中，所述固体药物组合物包括1.0％～10％wt的羟丙甲纤维素(HPMC)、羧甲基纤维素(CMC)、羧甲基纤维素钠(CMC-Na)、乙基纤维素(EC)、甲基 纤维素(MC)、羟丙基纤维素(HPC)、L-HPC、聚乙烯吡咯烷酮或其混合物；优选包括1.0％～8.0％wt、1.0％～6.0％wt或1.0％～5.0％wt的羟丙甲纤维素(HPMC)、羧甲基纤维素(CMC)、羧甲基纤维素钠(CMC-Na)、乙基纤维素(EC)、甲基纤维素(MC)、羟丙基纤维素(HPC)、L-HPC、聚乙烯吡咯烷酮或其混合物；更优选包括2.0～4.0％wt的羟丙甲纤维素(HPMC)、羧甲基纤维素(CMC)、羧甲基纤维素钠(CMC-Na)、乙基纤维素(EC)、甲基纤维素(MC)、羟丙基纤维素(HPC)、L-HPC或其混合物；进一步优选包括2.0～4.0％wt的羟丙基纤维素、聚乙烯吡咯烷酮或其混合物。
在本申请的部分实施方案中，所述固体药物组合物包括0.01～5.0％wt的十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠或月桂酰肌氨酸钠或其混合物；优选包括0.01～4.0％wt、0.01～3.0％wt、0.02～2.5％wt、0.02～2.0％wt的十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠或月桂酰肌氨酸钠或其混合物；更优选包括0.03～2.0％wt的十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠或月桂酰肌氨酸钠或其混合物；进一步优选包括0.03～2.0％wt的十二烷基硫酸钠或十二烷基硫酸镁或其混合物；进一步优选包括0.1～0.5％wt的十二烷基硫酸钠或十二烷基硫酸镁或其混合物。
在本申请的部分实施方案中，所述固体药物组合物包括1.0～7.0％wt的羧甲基淀粉钠或交联羧甲基纤维素钠或其混合物；优选包括1.0～6.5％wt、1.0～6.5％wt、1.0～6.0％wt、1.5～5.5％wt、1.5～5.0％wt或1.5～4.5％wt的羧甲基淀粉钠、交联羧甲基纤维素钠或其混合物；更优选包括2.0～4.0％wt的羧甲基淀粉钠、交联羧甲基纤维素钠或其混合物。
在本申请的部分实施方案中，所述固体药物组合物包括0.1～3％wt的硬脂酸镁、胶体二氧化硅或其混合物；优选0.2～2.5％wt、0.3～2.0％wt或0.4～1.5％wt的硬脂酸镁、胶体二氧化硅或其混合物；更优选0.5～1％wt的硬脂酸镁、胶体二氧化硅或其混合物。
在本申请的部分实施方案中，本申请所述固体药物组合物包括：
A)1～30％wt的式I化合物或式II化合物；
50～95％wt的微晶纤维素、甘露醇、乳糖、预胶化淀粉或其混合物；
1.0％～10％wt的羟丙甲纤维素(HPMC)、羧甲基纤维素(CMC)、羧甲基纤维素钠(CMC-Na)、乙基纤维素(EC)、甲基纤维素(MC)、羟丙基纤维素(HPC)、L-HPC、聚乙烯吡咯烷酮或其混合物；
0.01～5.0％wt的十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十二烷基硫酸钠、 十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠或月桂酰肌氨酸钠或其混合物；
1.0～7.0％wt的羧甲基淀粉钠或交联羧甲基纤维素钠或其混合物；
任选的0.1～3％wt的硬脂酸镁、胶体二氧化硅或其混合物；或
B)2～10％wt的式I化合物或式II化合物；
75～95％wt的微晶纤维素、甘露醇或其混合物，其中微晶纤维素和甘露醇的混合物中微晶纤维素和甘露醇的重量比选自1.2:1～3.5:1；
1.0～6.0％wt羟丙基纤维素、聚乙烯吡咯烷酮或其混合物；
0.01～3.0％wt的十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠或月桂酰肌氨酸钠或其混合物；
1.0～6.0％wt的羧甲基淀粉钠或交联羧甲基纤维素钠或其混合物；
任选的0.3～2.0％wt的硬脂酸镁、胶体二氧化硅或其混合物；或
C)3～8％wt的式I化合物或式II化合物；
85～90％wt的微晶纤维素、甘露醇或其混合物，其中微晶纤维素和甘露醇的混合物中微晶纤维素和甘露醇的重量比选自1.5:1～2.5:1；
2.0～4.0％wt的羟丙基纤维素、聚乙烯吡咯烷酮或其混合物；
0.03～2.0％wt的十二烷基硫酸钠或十二烷基硫酸镁或其混合物；
2.0～4.0％wt的羧甲基淀粉钠、交联羧甲基纤维素钠或其混合物；
任选的0.5～1％wt的硬脂酸镁、胶体二氧化硅或其混合物；或
D)3.0～5.0％wt的式I化合物或式II化合物；
50～70％wt的微晶纤维素；
20～40％wt的甘露醇；
2.0～6.0％wt的羟丙基纤维素；
0.05～0.2％wt的十二烷基硫酸钠；
2.0～6.0％wt的交联羧甲基纤维素钠；
任选的0.5～2％wt的硬脂酸镁；或
E)3.4～4.6％wt的式I化合物或式II化合物；
55～60％wt的微晶纤维素；
26～32％wt的甘露醇；
2.0～4.0％wt的羟丙基纤维素；
0.1～0.5％wt的十二烷基硫酸钠；
2.0～4.0％wt的交联羧甲基纤维素钠；
任选的0.5～1％wt的硬脂酸镁；或
F)4.2％wt的式I化合物或式II化合物；
58.3％wt的微晶纤维素；
29.4％wt的甘露醇；
4.0％wt的羟丙基纤维素；
0.1％wt的十二烷基硫酸钠；
3.0％wt的交联羧甲基纤维素钠；和
任选的1.0％wt的硬脂酸镁。
在本申请的一些实施方案中，所述式I化合物或式II化合物以游离碱或盐酸盐形式存在。在本申请的一些典型的实施方案中，所述式I化合物或式II化合物以游离碱形式存在。在本申请的一些典型的实施方案中，所述式I化合物或式II化合物以一盐酸盐形式存在。
在本申请的一些实施方案中，所述固体药物组合物进一步包括包衣剂。在部分实施方案中，从水性膜包衣组合物形成包衣剂，其中水性膜包衣组合物包含成膜聚合物、作为载体的水和/或醇以及可选的一种或多种助剂，如膜包衣领域已知的助剂。在部分实施方案中，所述包衣剂选自由羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、醋酸邻苯二甲酸醋酸纤维素、乙基纤维素硫酸钠、羧甲基纤维素、聚乙烯吡咯烷酮、玉米蛋白和丙烯酸聚合物(例如，甲基丙烯酸/甲基丙烯酸酯共聚物，如甲基丙烯酸/甲基丙烯酸甲酯共聚物等)，以及聚乙烯醇组成的组。在一些典型的实施方案中，包衣剂包含聚乙烯醇。
在本申请的一些实施方案中，所述固体药物组合物在30分钟内的溶出度不小于标示量的60％。在本申请的一些实施方案中，所述固体药物组合物在30分钟内的溶出度不小于标示量的80％。在本申请的一些实施方案中，所述固体药物组合物在pH1.0盐酸溶液、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液或纯化水中，在30分钟内的溶出度不小于标示量的80％，优选不小于标示量的85％。在本申请的一些实施方案中，所述固体药物组合物在纯化水中，在30分钟内的溶出度不小于标示量的80％，优选不小于标示量的85％，进一步优选不小于标示量的90％。在本申请的一些典型的实施方案中，所述固体药物组合物在纯化水中，在15分钟内的溶出度不小于标示量的85％。
在本申请的一些实施方案中，所述固体药物组合物的剂型可选自散剂、颗粒剂、片剂、胶囊、丸剂、微丸剂、分散体或可吸入粉末剂，优选片剂或胶囊，进一步优选片剂。
在本申请的一些实施方案中，所述固体药物组合物为单位剂量药物组合物，并且每个单 位剂量的组合物中式I化合物或式II化合物的量为5mg～20mg。在本申请的一些实施方案中，每个单位剂量的组合物中式I化合物或式II化合物的量为5mg、8mg、10mg、12mg、15mg、18mg或20mg，，或者任意前述值作为端点构成的范围或其中的任意值。
另一方面，本申请提供一种式I化合物或式II化合物的固体药物组合物的制备方法。本申请可采用湿法制粒制备固体颗粒。湿法制粒过程中视需要添加与式I化合物或式II化合物相容性良好的其他辅料，其中湿法制粒可选择在湿法制粒机(混合制粒)或者流化床(流化床制粒)中进行，优选流化床制粒。在湿法制粒时，式I化合物或式II化合物可以作为固体添加物与其他添加物一起加入到预混物中或者制备成溶液(混悬液或溶清溶液)供制粒使用。优选制备成混悬液在制粒阶段引入到颗粒中。
在本申请的一些实施方案中，式I化合物或式II化合物的固体药物组合物的制备方法包括以下步骤：
1)将稀释剂、崩解剂混合，所得混合物备用；将式I化合物或式II化合物、黏合剂、润湿剂与水混合，得到混合溶液；
2)将步骤1)所得混合溶液喷雾到步骤1)所得混合物上，并经流化床制粒，烘干，整粒，得到整粒后的干颗粒；
3)任选地，将整粒后的干颗粒、润滑剂混合，压片；
所述步骤1)的混合溶液为混悬液或溶清溶液，优选混悬液；
所述稀释剂、黏合剂、润湿剂、崩解剂和润滑剂如前所述。
在本申请的一些实施方案中，所述步骤2)中，进风温度选自35～90℃，优选45～85℃，更优选55～80℃。在本申请的一些实施方案中，所述步骤2)中，雾化压力选自400～1200mbar，优选500～1100mbar，更优选600～1000mbar。在本申请的一些实施方案中，所述步骤2)中，物料温度选自20～40℃，优选25～35℃。在本申请的一些实施方案中，所述步骤2)中，整粒筛网孔径Φ0.4～1.5mm，优选0.5～1.4mm，更优选0.6～1.2mm。
另一方面，本申请提供所述式I化合物或式II化合物的固体药物组合物在制备治疗两面神激酶介导的疾病的药物中的用途。
另一方面，本申请提供用于治疗两面神激酶介导的疾病的所述式I化合物或式II化合物的固体药物组合物。
另一方面，本申请提供所述式I化合物或式II化合物的固体药物组合物在治疗两面神激酶介导的疾病的用途。
另一方面，本申请提供治疗两面神激酶介导的疾病的方法，所述方法包括给予受试者治疗有效量的所述式I化合物或式II化合物的固体药物组合物。
在本申请的一些实施方案中，所述两面神激酶介导的疾病包括但不限于肿瘤。在一些实施方案中，本申请所述肿瘤为淋巴瘤或白血病。本申请所述的淋巴瘤包括但不限于霍奇金病(Hodgkins disease)或非霍奇金淋巴瘤(Non-Hodgkins lymphoma)，所述非霍奇金淋巴瘤包括但不限于B-细胞淋巴瘤(B-cell lymphoma)或T-细胞淋巴瘤(T-cell lymphoma)。本申请所述的白血病包括但不限于急性淋巴细胞白血病(Acute lymphoblastic leukemia)、慢性淋巴细胞白血病(Chronic lymphocyticleukemia)、急性粒细胞白血病(Acute myeloid leukemia)、慢性粒细胞白血病(Chronic myelocytic leukemia)。
在本申请的一些实施方案中，所述两面神激酶介导的疾病为骨髓增殖性肿瘤。
在本申请的部分实施方案中，所述骨髓增殖性肿瘤包括真性红细胞增多症、血小板增多症、或骨髓纤维化。其中，所述真红细胞增多症包括对羟基脲和/或干扰素耐药和/或不耐受的真性红细胞增多症。所述血小板增多症包括原发性血小板增多症、对羟基脲和/或干扰素耐药和/或不耐受的原发性血小板增多症。所述骨髓纤维化包括原发性骨髓纤维化、真性红细胞增多症后骨髓纤维化(post-polycythemia vera myelofibrosis，PPV-MF)、原发性血小板增多症后骨髓纤维化(post-essential thrombocythemia myelofibrosis，PET-MF)。
在本申请的部分实施方案中，所述骨髓增殖性肿瘤及其包括的疾病包括低危、中危、高危骨髓增殖性肿瘤。例如，真性红细胞增多症可分为低危、高危真性红细胞增多症；血小板增多症可分为极低危、低危、中危、高危血小板增多症；骨髓纤维化可分为低危、中危和/或高危骨髓纤维化。在一些实施方案中，所述真性红细胞增多症为中危和/或高危真性红细胞增多症，所述血小板增多症为中危和/或高危血小板增多症，所述骨髓纤维化为中危和/或高危骨髓纤维化，所述原发性血小板增多症为中危和/或高危原发性血小板增多症。例如，所述原发性骨髓纤维化、真性红细胞增多症后骨髓纤维化、原发性血小板增多症后骨髓纤维化都属于相应的中高危骨髓纤维化。本申请中，所述骨髓增殖性肿瘤的诊断标准和风险分级(risk stratification，例如极低危、低危、中危、高危)可参考本领域通用的原则，可参考“NCCN Guidelines Version 2.2019Myeloproliferative Neoplasms”，例如可参照动态国际预后评分系统(DIPSS，Dynamic international prognostic scoring system)进行评估。在一些实施方案中，采用WHO 2016标准和IWG-MRT标准作为诊断依据标准。
本申请中，所述的骨髓增殖性肿瘤包括基因突变的骨髓增殖性肿瘤，所述的突变型基因包括但不限于JAK2(例如JAK2V617F)、MPL、CALR、ASXL1/SRSF2/IDH1/21、JAK2exon12、TP53、SH2B3/IDH2/U2AF1/SF3B1/EZH2/TP53、MPL W515L/K、CALR Type 1/Type 1-like、三阴性(JAK2、MPL、和CALR无突变)、ASXL1、EZH2、IDH1/2、SRSF2、SF3B1、CALR/ASXL1、TP53、或U2AF1Q157。
在本申请的部分实施方案中，式I化合物或式II化合物以自由碱形式给药。在本申请的部分实施方案中，式I化合物或式II化合物以自由碱的结晶形式给药。在本申请的部分方案中，式II化合物的自由碱结晶可选自WO2017215630公开的晶型A或晶型B。
在本申请的部分实施方案中，式II化合物以盐酸盐形式给药。在本申请的部分实施方案中，式II化合物的盐酸盐可选自WO2017101777公开的盐酸盐。
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。
本申请的化合物、其立体异构体、或其药学上可接受的盐、或其固体药物组合物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、受试者的年龄和健康状态确定，例如可以根据受试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、或其固体药物组合物的日剂量为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、或其固体药物组合物的日剂量可选自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、或其固体药物组合物的日剂量可选自1mg至50mg、5mg至50mg、5mg至45mg、5mg至40mg、10mg至35mg、10mg至30mg。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、或其固体药物组合物的日剂量可选自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、或其固体药物组合物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、或其固体药物组合物。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。
给药的方法可根据药物的活性、毒性以及受试者的耐受性等因素综合确定。在部分实施方案中，以间隔给药的方式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、或其固体药物组合物可以采用间隔给药。所述间隔给药包括给药期和停药期，在给药其内可以每天一次、两次或多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、或其固体药物组合物。间隔给药可以根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、受试者的年龄和健康状态确定，例如可以根据受试者/受试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。
技术效果
本申请所述化合物可有效缩小受试者脾脏。本申请所述化合物对骨髓增殖性肿瘤具有良好的治疗效果，并且具有更优良的安全性。
本申请所述的固体药物组合物具有优良的稳定性和溶出性质，适合临床使用。进一步地，本申请的片剂固体药物组合物具有快速释放的性质，其30分钟内的溶出度不小于标示量的80％。
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。
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，例如包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐，优选盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐、对甲基苯磺酸盐、钠盐、钾盐、铵盐、氨基酸盐等。本申请中，当形成药学上可接受的盐时，所述自由酸与碱根离子的摩尔量之比为约1:0.5～1:5，优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。本申请中，当形成药学上可接受的盐时，所述自由碱与酸根离子的摩尔量之比为约1:0.5～1:5，优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。
如本申请所用，本申请式I化合物或者式II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“受试者”是哺乳动物。在部分实施方案中，所述受试者是人。
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。
术语“治疗”意为将本申请所述化合物或药物组合物进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，(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，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作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。
本申请中，所述“药学上可接受的盐”包括但不限于与无机酸例如盐酸、氢溴酸、硫酸、硝酸或磷酸形成的酸加成盐；或者与有机酸例如甲酸、乙酸、三氟乙酸、琥珀酸、苹果酸、马来酸、富马酸、草酸、酒石酸、柠檬酸、甲磺酸、苯磺酸、对甲或苯磺酸等形成的酸加成盐；或者与酸性氨基酸例如天冬氨酸或谷氨酸形成的酸加成盐。所述溶剂合物包括但不限于水合物形式。
本申请中，所述药物组合物中的式I化合物式II化合物的含量以其游离碱(free base)形式计算。
本申请所述稀释剂亦可称为填充剂，主要分为水溶性稀释剂、水不溶性稀释剂、直接压片用稀释剂等几类，包括但不限于淀粉、蔗糖、糊精、乳糖、预胶化淀粉微晶纤维素、无机盐类和/或糖醇类。所述乳糖包括但不限于无水乳糖、一水乳糖或其混合物。
本申请所述黏合剂按照来源可以分为天然黏合剂和合成黏合剂。黏合剂按照用法可以分为做成水溶液或胶浆才具黏性的黏合剂、干燥状态下也具有黏性的干燥粘合剂和经非水溶剂 溶解或湿润后具有黏性的黏合剂。黏合剂包括但不限于淀粉浆、纤维素衍生物、聚维酮、明胶、聚乙二醇、蔗糖溶液和/或海藻酸钠溶液。
本申请所述润湿剂为表面张力小能与水混溶的液体和/或表面活性剂，所述表面活性剂包括阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂和/或非离子型表面活性剂。所述阴离子表面活性剂包括但不限于烷基苯磺酸盐、烷基磺酸酯盐、烷基磺酸盐、烷基硫酸盐、含氟脂肪酸盐、聚硅氧烷和/或脂肪醇硫酸盐。所述阳离子表面活性剂包括但不限于季铵化物、烷基吡啶盐和/或胺盐。所述两性离子表面活性剂包括但不限于卵磷脂、氨基酸型和/或甜菜碱型，所述非离子表面活性剂包括但不限于烷基葡糖苷(APG)、脂肪酸甘油酯、脂肪酸山梨坦(司盘)、聚山梨酯(吐温)、聚氧乙烯类和/或泊洛沙姆。
本申请所述崩解剂包括但不限于淀粉及其衍生物、纤维素类、表面活性剂、泡腾崩解剂、胶类、海藻酸盐类和/或离子交换树脂类。
本申请所述润滑剂广义上包括三种辅料：润滑剂(狭义)、助流剂和抗黏剂。本申请所述润滑剂包括但不限于硬脂酸类、胶体二氧化硅、滑石粉、氢化植物油和/或聚乙二醇类。
本申请所述某种成分(包括活性物质或辅料)的量“％wt”指该成分的重量占固体药物组合物总重量(其中式I化合物式II化合物的重量以其游离碱形式计)的百分比。所述固体药物组合物的总重量不包括包衣剂的重量。
本申请所述的固体药组合物或相应剂型的制备方法可依据本领域公知的方法进行。具体制备方法可包括粉碎、混合、筛分、制粒、填充、压片等步骤，根据实际情况选择所需步骤，以及实施具体步骤的方法或设备。例如，粉碎步骤可采用研钵、球磨机、滚压机、冲击式粉碎机、锤击式粉碎机和/或气流粉碎机进行；混合步骤可采用搅拌混合、研磨混合和/或过筛混合；过筛步骤可采用摇动筛和/或振荡筛。或可参见崔福德等主编的《药剂学》(第6版或第7版，人民卫生出版社)。
术语“或其混合物”意指“两种以上的混合物”，例如“所述稀释剂选自微晶纤维素、甘露醇、乳糖、蔗糖、淀粉、预胶化淀粉、糊精或其混合物”即“所述稀释剂选自微晶纤维素、甘露醇、乳糖、蔗糖、淀粉、预胶化淀粉、糊精中的一种或两种以上的混合物”。
术语“标示量”在药物组合物领域，指该单位剂量的制剂中规定的主药含量。
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。
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。
实施例1 (3R)-3-{3-氨基-4-{7H-吡咯并[2,3-d]嘧啶-4-基}-1H-吡唑-1-基}-3-环戊基丙腈(II)
Figure PCTCN2019127837-appb-000007
参照WO2016095805或WO2017215627制备得到标题化合物。
实施例2 (3R)-3-{3-氨基-4-{7H-吡咯并[2,3-d]嘧啶-4-基}-1H-吡唑-1-基}-3-环戊基丙腈(II)的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 PCTCN2019127837-appb-000008
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：将羟丙纤维素加入处方量纯化水中溶解，配制成4％(w/w)羟丙纤维素溶液；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3 制备处方A～I固体药物组合物
参考实施例2的方法制备处方A～I固体药物组合物，所述处方A～I固体药物组合物为5mg 规格片剂，其具体处方组成如下所示：
表2处方A～E固体药物组合物处方组成
Figure PCTCN2019127837-appb-000009
表3处方F～I固体药物组合物处方组成
Figure PCTCN2019127837-appb-000010
实施例4 固体药物组合物稳定性实验
依据中国《原料药与药物制剂稳定性试验指导原则》，考察上述处方的固体药物组合物的稳定性。将实施例2所得5mg和20mg片剂固体药物组合物分别置于光照(6000lux)、高温(60℃)和高湿(RH75％)的敞口条件下，取样品适量，加水-乙腈(30:70)制成每1mL中含待测样品约0.5mg的溶液，作为供试品溶液；用十八烷基硅烷键合硅胶为填充剂；以磷酸二氢钾缓冲溶液-乙腈(90:10)为流动相A，乙腈为流动相B，进行线性梯度洗脱；流速为每 分钟1.0mL；检测波长为220nm；柱温为30℃。检测总杂含量，结果如下：
表4稳定性实验
Figure PCTCN2019127837-appb-000011
实施例5 溶出特性实验
依据中国药典2015年版四部0931溶出度与释放度第二法操作，考察上述处方的固体药物组合物在四种介质中的溶出行为。所述四种介质分别是pH1.0盐酸溶液、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液和纯化水，介质体积900mL。取式II化合物对照品制成每1mL中含式II化合物约5.6μg的溶液，作为对照品溶液。方法和条件是：桨法，转速：50rpm，介质温度：37℃±0.5℃，取样时间点：5、10、15、20、30或45min。用十八烷基硅烷键合硅胶为填充剂；以磷酸二氢钾缓冲溶液-乙腈(70:30)为流动相；流速为每分钟0.4mL；检测波长为220nm；柱温为30℃。结果如下：
表5实施例2的5mg规格片剂溶出特性实验
Figure PCTCN2019127837-appb-000012
表6实施例2的20mg规格片剂溶出特性实验
Figure PCTCN2019127837-appb-000013
表7处方A～E溶出特性实验
Figure PCTCN2019127837-appb-000014
表8处方F～I溶出特性实验
Figure PCTCN2019127837-appb-000015
实施例6 (剂量和化合物)
6.1给药方案
所用药物是实施例2的5mg规格片剂。
给药方法：空腹口服，预试验每日一次。后续剂量组每12h口服一次，用药后2小时内不得进食。连续用药28天为一个治疗周期。
要求入组的受试者至少给药1个周期，进行耐受性的观察和初步疗效的观察。对于研究者认为临床受益的受试者，且受试者同意继续使用研究药物，将持续免费提供研究药物直至疾病进展或研究者判定不适合再继续使用研究药物为止。本次研究停止入组后，正在接受治疗的受试者连续用药时间至6个周期时，将关闭本次研究。
6.2入组标准
1)年龄≥18周岁；ECOG体力状况：0～2分；预计生存期超过3个月；
2)根据世界卫生组织(WHO)2016年发布的PMF、PV和ET标准和国际骨髓纤维化研究与治疗工作组(IWG-MRT)建议的PPV-MF和PET-MF标准，受试者的诊断为PMF、PV、ET、PPV-MF或PET-MF；
3)根据动态国际预后积分系统(DIPSS)，必须至少处于中危-1及以上的接受治疗的骨髓纤维化受试者。
4)对接受羟基脲和/或干扰素治疗耐药或者不耐受的PV、ET受试者；
5)主要血液学实验室检查值符合下列标准：
血小板计数(PLT)>100×10 9/L；
中性粒细胞计数(ANC)>1.5×10 9/L；
血红蛋白浓度(Hgb)>75g/L，(四周内未输注过全血或悬浮红细胞等血制品)；
6)受试者脾脏最突出的部位必须离肋骨下缘≥5cm；
7)骨髓原始细胞和外周血原始细胞<20％；
8)主要肝肾功能实验室检查值符合下列标准：
谷丙转氨酶(ALT)、谷草转氨酶(AST)≤2.5×正常上限(ULN)；
血清肌酐≤2.0mg/dL(176.82μmol/L)；
直接胆红素≤2×正常上限(ULN)；
9)主要凝血功能实验室检查值符合下列标准：
凝血酶原时间(PT)或凝血酶时间(TT)对照正常值范围≤3s；
活化部分凝血活酶时间(APTT)对照正常值范围≤10s；
10)使用过其它MPN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；
11)女性受试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，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，且必须为非哺乳期受试者；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；
12)受试者自愿。
6.3排除标准
符合以下任何一项目的受试者将不能入组本研究：
1)5年内患有其它恶性肿瘤者，但已治愈的非黑色素瘤、皮肤癌和原位癌者除外；
2)四周内参加过其他药物临床试验者；
3)具有影响口服药物的因素(比如无法吞咽、胃肠道切除术后、慢性腹泻和肠梗阻等)者；
4)具有精神类药物滥用史且无法戒除或有精神障碍者；
5)HBsAg阳性；HBcAb阳性且HBV-DNA检测≥检测正常值上限；HCV抗体阳性；HIV抗体阳性；
6)有免疫缺陷的受试者(患有获得性、先天性免疫缺陷疾病，或有器官移植史者)；
7)4周内发生过动/静脉血栓事件，如脑血管意外(包括暂时性缺血性发作)、深静脉血栓及肺栓塞者；
8)受试者在筛选评估访视开始前28天内接受长期(≥3天)大剂量(≥10mg相当剂量的强的松)糖皮质激素或其他免疫抑制剂的治疗，或者使用的剂量有增加；
9)全身活动性感染，例如存在需要治疗的、具有临床意义的细菌、真菌、寄生虫或病毒感染。对于需要抗生素治疗急性细菌感染的受试者，应推迟其筛选/入组，直到抗生素治疗结束为止；
10)明显的心血管疾病，例如美国纽约心脏病协会(NYHA)分级为2级及以上的心力衰竭、既往3个月内的不稳定的心绞痛、心肌缺血或心肌梗塞、心律失常(女性QTc>470ms,男性QTc>450ms)及I级心功能不全者；
11)经药物治疗仍无法控制的高血压(收缩压≥150mmHg，舒张压≥100mmHg)受试者；
12)根据研究者的判断，有严重的危害受试者安全或影响受试者完成研究的伴随疾病者。
6.4血样采集方案
受试者上肢静脉留置导管以便收集血液样本，每次采集约3mL静脉血。采集的血样置于事先处理好的肝素钠抗凝的采血管中(在室温条件下放置时间不超过0.5h)，4℃离心10min(2500g)，分离血浆，-80℃保存供测试用(在室温条件下放置时间不超过2h)。
6.5观察项目
连续用药第2周期起：
1)每次访视时进行全面体查：体重、生命体征、各脏器的体检；
2)观察用药期间各种临床表现，症状、体征(包括肝、脾肿大)状况，每3个周期采用骨髓增殖性肿瘤总症状评估量表对受试者进行症状负荷评估；
3)第2周期末、第3周期起每3个周期以及出组时行脾脏核磁检查。
4)第2周期末、第3周期起每3个周期以及出组时行骨髓穿刺涂片和外周血涂片分类计数检查；
5)第2周期末、第3周期起每3个周期以及出组时行骨髓活检病理细胞学分析和网状纤
维(嗜银)染色。
6.6结果和评价
表9受试者的结果和评价
Figure PCTCN2019127837-appb-000016
注：Null指未检测。

Claims (24)

  1. 用于治疗骨髓增殖性肿瘤的式I化合物、其立体异构体、或其药学上可接受的盐、或药物组合物：
    Figure PCTCN2019127837-appb-100001
    其中，所述R 1和R 2各自独立地选自H、C 1～6烷基、C 1～6烷基酰基或C 1～6烷基磺酰基；
    所述R 3和R 4各自独立地选自H、羟基或氧代；
    所述药物组合物包含所述式I化合物、其立体异构体、或其药学上可接受的盐。
  2. 如权利要求1所述的式I化合物，其中所述R 1和R 2各自独立地选自H、甲基、乙基、丙基、丁基、戊基、己基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、戊磺酰基或己磺酰基；优选地，所述R 1选自H，所述R 2选自甲基、乙基、丙基、丁基、戊基、己基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、戊磺酰基或己磺酰基。
  3. 如权利要求1所述的式I化合物，其中所述式I化合物具有如下式所示的构型：
    Figure PCTCN2019127837-appb-100002
  4. 如权利要求1所述的式I化合物，其中所述式I化合物选自：
    Figure PCTCN2019127837-appb-100003
  5. 用于治疗骨髓增殖性肿瘤的方法，其包括向所述受试者给予有效量的式I化合物、其立体异构体、或其药学上可接受的盐、或药物组合物：
    Figure PCTCN2019127837-appb-100004
    其中，所述R 1和R 2各自独立地选自H、C 1～6烷基、C 1～6烷基酰基或C 1～6烷基磺酰基；
    所述R 3和R 4各自独立地选自H、羟基或氧代；
    所述药物组合物包含所述式I化合物、其立体异构体、或其药学上可接受的盐。
  6. 一种固体药物组合物，其包括式I化合物、其立体异构体、或其药学上可接受的盐，以及稀释剂、黏合剂、润湿剂和崩解剂，
    Figure PCTCN2019127837-appb-100005
    其中，所述R 1和R 2各自独立地选自H、C 1～6烷基、C 1～6烷基酰基或C 1～6烷基磺酰基；
    所述R 3和R 4各自独立地选自H、羟基或氧代。
  7. 如权利要求6所述的固体药物组合物，其中所述R 1和R 2各自独立地选自H、甲基、乙基、丙基、丁基、戊基、己基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、戊磺酰基或己磺酰基；优选地，所述R 1选自H，所述R 2选自甲基、乙基、丙基、丁基、戊基、己基、甲酰基、乙酰基、丙酰基、丁酰基、戊酰基、己酰基、甲磺酰基、乙磺酰基、丙磺酰基、丁磺酰基、戊磺酰基或己磺酰基。
  8. 如权利要求6或7所述的固体药物组合物，其中所述式I化合物的量选自1～30％wt，优选1～25％wt、1～20％wt、2～20％wt、2～15％wt、2～10％wt、3～10％wt或2～8％wt，更优选3～8％wt，进一步优选3.5～6％wt。
  9. 如权利要求6-8任一项所述的固体药物组合物，其中所述稀释剂选自微晶纤维素、甘露醇、乳糖、蔗糖、淀粉、预胶化淀粉、糊精或其混合物；优选微晶纤维素、甘露醇、乳糖、预胶化淀粉或其混合物；更优选微晶纤维素、甘露醇或其混合物；和/或
    所述稀释剂的量选自50～95％wt，优选60～95％wt、65～95％wt、70～95％wt、75～95％wt、80～95％wt、80～90％wt或85～95％wt，更优选85～90％wt。
  10. 如权利要求6-9任一项所述的固体药物组合物，其中所述稀释剂选自微晶纤维素和甘露醇的混合物，其中微晶纤维素和甘露醇的重量比选自1:1～5:1，优选自1:1～4:1、1.2:1～3.5:1或1.2:1～3:1，更优选1.5:1～2.5:1。
  11. 如权利要求6-10任一项所述的固体药物组合物，其中所述黏合剂选自羟丙甲纤维素、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、部分水解的淀粉、淀粉、预胶化淀粉、蔗糖、葡萄糖、明胶、聚乙二醇、聚乙烯醇或其混合物；优选羟丙甲纤维素、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、聚乙烯吡咯烷酮或其混合物；更优选羟丙基纤维素、聚乙烯吡咯烷酮或其混合物；和/或
    所述黏合剂的量选自1.0％～10％wt，优选1.0％～8.0％wt、1.0％～6.0％wt或1.0％～5.0％wt，更优选2.0～4.0％wt。
  12. 如权利要求6-11任一项所述的固体药物组合物，其中所述润湿剂选自十二烷基苯磺酸钠、十二烷基苯磺酸镁、十四烷基苯磺酸钠、十六烷基苯磺酸钠、十八烷基苯磺酸钠、十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十六烷基磺酸钠、十八烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠、月桂酰肌氨酸钠、乳酸钠、棕榈酸钠、月桂酸异丙醇酰胺、月桂酸二乙醇酰胺、乳酸十四烷基酯、乳酸十六基酯、聚山梨酯20、聚山梨酯40、聚山梨酯60、聚山梨酯65、聚山梨酯80、聚山梨酯85、聚氧乙烯十二烷基醚、聚氧乙烯十六烷基醚、聚氧乙烯山梨醇四油基醚、聚氧乙烯硬脂酸酯、聚氧乙烯蓖麻油或聚氧乙烯氢化蓖麻油或其混合物；优选十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠或月桂酰肌氨酸钠或其混合物；更优选十二烷基硫酸钠或十二烷基硫酸镁或其混合物；和/或
    所述润湿剂的量选自0.01～5.0％wt，优选0.01～4.0％wt、0.01～3.0％wt、0.02～2.5％wt、0.02～2.0％wt，更优选0.03～2.0％wt，进一步优选0.05～1.0％wt，更进一步优选0.1～0.5％wt。
  13. 如权利要求6-12任一项所述的固体药物组合物，其中所述崩解剂选自羧甲基淀粉钠、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、十二烷基硫酸钠或十二烷基硫酸镁或其混合物；优选羧甲基淀粉钠、交联羧甲基纤维素钠或其混合物；和/或
    所述崩解剂的量选自1.0～7.0％wt，优选1.0～6.5％wt、1.0～6.5％wt、1.0～6.0％wt、1.5～5.5％wt、1.5～5.0％wt或1.5～4.5％wt，更优选2.0～4.0％wt。
  14. 如权利要求6-13任一项所述的固体药物组合物，其中所述润滑剂选自硬脂酸镁、胶体二氧化硅、滑石粉、聚乙二醇4000、聚乙二醇6000、硬脂酸、硬脂富马酸钠或十二烷基硫酸钠或其混合物，优选硬脂酸镁、胶体二氧化硅或其混合物；和/或
    所述润滑剂的量选自0.1～3％wt，优选0.2～2.5％wt、0.3～2.0％wt或0.4～1.5％wt，更优选0.5～1％wt。
  15. 如权利要求6-14任一项所述的固体药物组合物，所述固体药物组合物包括：
    1～30％wt的式I化合物；
    50～95％wt的微晶纤维素、甘露醇、乳糖、预胶化淀粉或其混合物；
    1.0％～10％wt的羟丙甲纤维素、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、L-HPC、聚乙烯吡咯烷酮或其混合物；
    0.01～5.0％wt的十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠或月桂酰肌氨酸钠或其混合物；
    1.0～7.0％wt的羧甲基淀粉钠或交联羧甲基纤维素钠或其混合物；和
    任选的0.1～3％wt的硬脂酸镁、胶体二氧化硅或其混合物。
  16. 如权利要求6-14任一项所述的固体药物组合物，所述固体药物组合物包括：
    2～10％wt的式I化合物；
    75～95％wt的微晶纤维素、甘露醇或其混合物，其中微晶纤维素和甘露醇的混合物中微晶纤维素和甘露醇的重量比选自1.2:1～3.5:1；
    1.0～6.0％wt羟丙基纤维素、聚乙烯吡咯烷酮或其混合物；
    0.01～3.0％wt的十二烷基磺酸钠、十二烷基磺酸镁、十四烷基磺酸钠、十二烷基硫酸钠、十二烷基硫酸镁、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠或月桂酰肌氨酸钠或其混合物；
    1.0～6.0％wt的羧甲基淀粉钠或交联羧甲基纤维素钠或其混合物；和
    任选的0.3～2.0％wt的硬脂酸镁、胶体二氧化硅或其混合物。
  17. 如权利要求6-14任一项所述的固体药物组合物，所述固体药物组合物包括：
    3.4～4.6％wt的式I化合物；
    55～60％wt的微晶纤维素；
    26～32％wt的甘露醇；
    2.0～4.0％wt的羟丙基纤维素；
    0.1～0.5％wt的十二烷基硫酸钠；
    2.0～4.0％wt的交联羧甲基纤维素钠；和
    任选的0.5～1％wt的硬脂酸镁。
  18. 如权利要求6-14任一项所述的固体药物组合物，所述固体药物组合物包括：
    4.2％wt的式I化合物；
    58.3％wt的微晶纤维素；
    29.4％wt的甘露醇；
    4.0％wt的羟丙基纤维素；
    0.1％wt的十二烷基硫酸钠；
    3.0％wt的交联羧甲基纤维素钠；和
    任选的1.0％wt的硬脂酸镁。
  19. 如权利要求6-18任一项所述的固体药物组合物，其中所述式I化合物为式II化合物：
    Figure PCTCN2019127837-appb-100006
  20. 权利要求6-19任一项所述的固体药物组合物的制备方法，包括以下步骤：
    1)将稀释剂、崩解剂混合，所得混合物留用；将式I化合物、黏合剂、润湿剂与水混合，得到混合溶液；
    2)将步骤1)所得混合溶液喷雾到步骤1)所得混合物上，并经流化床制粒，烘干，整粒，得到整粒后的干颗粒；
    3)任选地，将整粒后的干颗粒、润滑剂混合，压片；
    所述步骤1)的混合溶液为混悬液或溶清溶液，优选混悬液。
  21. 如权利要求6-19任一项所述的固体药物组合物在制备治疗两面神激酶介导的疾病的药物中的用途；优选地，所述两面神激酶介导的疾病为骨髓增殖性肿瘤。
  22. 如权利要求1-4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、或药物组合物，如权利要求5所述的方法，如权利要求21所述的用途，其中所述骨髓增殖性肿瘤选自真性红细胞增多症、血小板增多症、或骨髓纤维化。
  23. 如权利要求1-4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、或药物组合物，如权利要求5所述的方法，如权利要求21所述的用途，其中采用的日剂量为1mg至100mg；优选地，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。
  24. 如权利要求1-4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、或药物组合物，如权利要求5所述的方法，如权利要求21所述的用途，其中每日施用一次或多次；任选地，以单剂量形式给药；优选地，以单剂量形式每天给药一次或两次。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022098828A1 (en) * 2020-11-05 2022-05-12 Exelixis, Inc. Pharmaceutical compositions of a kinase inhibitor
WO2023179547A1 (zh) * 2022-03-21 2023-09-28 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物治疗中高危骨髓纤维化的用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024153148A1 (zh) * 2023-01-18 2024-07-25 北京普祺医药科技股份有限公司 一种杂环化合物、药物组合物及其用途

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103585126A (zh) * 2013-11-18 2014-02-19 南京艾德凯腾生物医药有限责任公司 一种托法替尼组合物及制备方法
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
WO2017017542A1 (en) * 2015-07-27 2017-02-02 Unichem Laboratories Limited Tofacitinib orally disintegrating tablets
WO2017101777A1 (zh) 2015-12-15 2017-06-22 北京赛林泰医药技术有限公司 吡咯并嘧啶化合物的盐
CN107334738A (zh) * 2016-04-28 2017-11-10 天津科伦药物研究有限公司 一种含巴瑞克替尼的药物组合物及其制备方法和用途
WO2017215627A1 (zh) 2016-06-16 2017-12-21 正大天晴药业集团股份有限公司 手性吡咯并嘧啶化合物的制备方法
WO2017215628A1 (zh) * 2016-06-16 2017-12-21 北京赛林泰医药技术有限公司 含有取代环戊基的吡咯并嘧啶化合物
WO2017215630A1 (zh) 2016-06-16 2017-12-21 正大天晴药业集团股份有限公司 作为jak抑制剂的吡咯并嘧啶化合物的结晶
WO2018169875A1 (en) * 2017-03-14 2018-09-20 Gilead Sciences, Inc. Pharmaceutical compositions comprising a jak inhibitor

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW201100429A (en) * 2009-05-22 2011-01-01 Incyte Corp N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
ES2595407T3 (es) * 2011-06-14 2016-12-29 Novartis Ag Combinación de panobinostat y ruxolitinib en el tratamiento de cáncer, tal como una neoplasia mieloproliferativa

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103585126A (zh) * 2013-11-18 2014-02-19 南京艾德凯腾生物医药有限责任公司 一种托法替尼组合物及制备方法
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
WO2017017542A1 (en) * 2015-07-27 2017-02-02 Unichem Laboratories Limited Tofacitinib orally disintegrating tablets
WO2017101777A1 (zh) 2015-12-15 2017-06-22 北京赛林泰医药技术有限公司 吡咯并嘧啶化合物的盐
CN107334738A (zh) * 2016-04-28 2017-11-10 天津科伦药物研究有限公司 一种含巴瑞克替尼的药物组合物及其制备方法和用途
WO2017215627A1 (zh) 2016-06-16 2017-12-21 正大天晴药业集团股份有限公司 手性吡咯并嘧啶化合物的制备方法
WO2017215628A1 (zh) * 2016-06-16 2017-12-21 北京赛林泰医药技术有限公司 含有取代环戊基的吡咯并嘧啶化合物
WO2017215630A1 (zh) 2016-06-16 2017-12-21 正大天晴药业集团股份有限公司 作为jak抑制剂的吡咯并嘧啶化合物的结晶
WO2018169875A1 (en) * 2017-03-14 2018-09-20 Gilead Sciences, Inc. Pharmaceutical compositions comprising a jak inhibitor

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Chinese Pharmacopoeia", vol. IV, 2015, PEOPLE'S MEDICAL PUBLISHING HOUSE
SCOTT, M. J.C. J. GODSHALL ET AL.: "Jaks, STATs, Cytokines, and Sepsis", CLIN DIAGN LAB IMMUNOL, vol. 9, no. 6, 2002, pages 1153 - 9
See also references of EP3904356A4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022098828A1 (en) * 2020-11-05 2022-05-12 Exelixis, Inc. Pharmaceutical compositions of a kinase inhibitor
WO2023179547A1 (zh) * 2022-03-21 2023-09-28 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物治疗中高危骨髓纤维化的用途

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