WO2018019244A1 - Salts of 2,6-dimethylpyrimidone derivative and uses of the salts - Google Patents

Salts of 2,6-dimethylpyrimidone derivative and uses of the salts Download PDF

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WO2018019244A1
WO2018019244A1 PCT/CN2017/094409 CN2017094409W WO2018019244A1 WO 2018019244 A1 WO2018019244 A1 WO 2018019244A1 CN 2017094409 W CN2017094409 W CN 2017094409W WO 2018019244 A1 WO2018019244 A1 WO 2018019244A1
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salt
crystal form
acid addition
benzenesulfonate
ray powder
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PCT/CN2017/094409
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French (fr)
Chinese (zh)
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林润锋
陈亮
王晓军
张英俊
张健存
曹生田
康宁
聂飚
许娟
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广东东阳光药业有限公司
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Priority to CN201780029840.2A priority Critical patent/CN109311820B/en
Publication of WO2018019244A1 publication Critical patent/WO2018019244A1/en

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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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical

Definitions

  • the invention belongs to the field of medicine, relates to a salt of a 2,6-dimethylpyrimidinone derivative and a use thereof, in particular to 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethyl
  • the salt or the pharmaceutical composition is for use in the treatment and prevention of tissue or organ fibrotic diseases.
  • the salt of the compound of the present invention may be in a crystalline form, a partially crystalline form, a polymorphic form or an amorphous form.
  • Fibrosis refers to the process of excessively forming fibrous connective tissue in an organ or tissue for repair or reaction processes.
  • Organ tissue fibrosis is called fibrosis, and severe cases cause structural damage and organ sclerosis.
  • Tissue fibrosis occurs not only in organs such as the lungs, liver, heart, and kidneys. Tissue fibrosis can affect almost all organs and systems in the human body. About one-third of the world's people die from tissue fibrosis and organ failure.
  • the patents WO 2014012360 and CN 103570630 disclose nitrogen heterocyclic derivatives having anti-fibrotic effects, wherein the compound 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine- 4(3H)-ketone (a compound of formula (I)) is effective for preventing or treating tissue fibrotic lesions in humans or animals.
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, in drug development, the polymorphic problem of the drug should be fully considered.
  • Amorphous is a form of material polymorphism and is an amorphous state.
  • the various physical and chemical properties and clinical efficacy characteristics of amorphous drugs are often different from the general crystalline drugs. Therefore, in the study of polymorphism of solid drugs, the in-depth discussion of amorphous substances is also of great significance.
  • the compound 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (the compound of the formula (I)) is a pale yellow oil.
  • the present invention has studied the salt form of the compound of the formula (I) and the salt form thereof, and further proposed a pharmaceutically acceptable acid of the compound of the formula (I). Addition salts and compositions thereof.
  • the salt or the pharmaceutical composition of the invention has better biological activity, less toxic side effects and better stability, thereby having better drug-forming properties.
  • the present invention relates to an acid addition salt of a compound of the formula (I) and a pharmaceutical composition thereof, and a salt of the compound or the pharmaceutical composition for preparing a medicament for treating or preventing a tissue fibrotic disease Use in.
  • the acid addition salt of the present invention may be in a crystalline form, a partially crystalline form, a polymorphic form or an amorphous form; in another aspect, the acid addition salt of the present invention may also be in the form of a solvate, such as a hydrated form.
  • the invention provides a pharmaceutically acceptable acid addition salt of a compound of formula (I),
  • the acid addition salts of the present invention are inorganic or organic acid salts.
  • the inorganic acid salt of the present invention is a hydrochloride, a sulfate, a hydrogen sulfate, a nitrate, a hydrobromide, a hydroiodide, a carbonate, a hydrogencarbonate, a sulfurous acid.
  • Salt bisulfite, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, heavy sulfate, thiocyanate, phosphate, pyrophosphate, Metaphosphate or any combination thereof.
  • the organic acid salt of the present invention is a formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate , mesylate, ethanesulfonate, propane sulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, malate, propiolate, 2 -butynoate, 2-hydroxy-ethanesulfonate, vinyl acetate, tartrate, L-tartrate, fumarate, isethionate, maleate, lactate , lactobionate, pamoate, salicylate, galactose salt, glucoheptonate, mandelate, 1,2-ethanedisulfonate, naphthalene sulfonate (including --naphthalene sulfonate and ⁇ -naphthalene sulfonic acid), ox
  • the acid addition salt of the present invention wherein the salt is a hydrobromide salt form I of the compound of formula (I), characterized in that the hydrobromide crystal
  • the X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.07 ⁇ 0.2 °, 8.86 ⁇ 0.2 °, 13.92 ⁇ 0.2 °, 24.73 ⁇ 0.2 °, 25.68 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a hydrobromide salt form I of the compound of formula (I), characterized in that the hydrobromide crystal
  • the X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.07 ⁇ 0.2 °, 8.86 ⁇ 0.2 °, 13.92 ⁇ 0.2 °, 15.28 ⁇ 0.2 °, 18.04 ⁇ 0.2 °, 19.60 ⁇ 0.2 °, 22.25 ⁇ 0.2 °, 22.62 ⁇ 0.2 °, 24.73 ⁇ 0.2 °, 25.68 ⁇ 0.2 °, 26.72 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a hydrobromide salt form I of the compound of formula (I), characterized in that the hydrobromide crystal
  • the X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.07 ⁇ 0.2 °, 8.86 ⁇ 0.2 °, 9.41 ⁇ 0.2 °, 12.13 ⁇ 0.2 °, 13.92 ⁇ 0.2 °, 15.28 ⁇ 0.2 °, 15.69 ⁇ 0.2 °, 16.36 ⁇ 0.2°, 16.59 ⁇ 0.2°, 17.17 ⁇ 0.2°, 18.04 ⁇ 0.2°, 18.75 ⁇ 0.2°, 19.60 ⁇ 0.2°, 21.18 ⁇ 0.2°, 22.25 ⁇ 0.2°, 22.62 ⁇ 0.2°, 23.37 ⁇ 0.2 °, 24.73 ⁇ 0.2°, 25.68 ⁇ 0.2°, 26.72 ⁇ 0.2°, 27.43 ⁇ 0.2°, 28.10 ⁇ 0.2°, 29.63 ⁇ 0.2°, 30.62 ⁇ 0.2°, 32.
  • the acid addition salt of the present invention wherein the salt is a hydrobromide salt form I of the compound of formula (I), characterized in that the hydrobromide crystal Type I has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a hydrobromide salt crystal form II of the compound of formula (I), characterized in that the hydrobromide salt crystal
  • the X-ray powder diffraction pattern of Form II has diffraction peaks at the following 2 theta angles: 3.64 ⁇ 0.2 °, 10.80 ⁇ 0.2 °, 21.70 ⁇ 0.2 °, 25.38 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a hydrobromide crystal form of the compound of formula (I) II, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt crystal form II has diffraction peaks at the following 2 ⁇ angles: 3.64 ⁇ 0.2°, 10.80 ⁇ 0.2°, 17.14 ⁇ 0.2°, 18.07 ⁇ 0.2°, 21.70 ⁇ 0.2 °, 22.30 ⁇ 0.2 °, 25.38 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a hydrobromide salt crystal form II of the compound of formula (I), characterized in that the hydrobromide salt crystal
  • the X-ray powder diffraction pattern of Type II has diffraction peaks at the following 2 theta angles: 3.64 ⁇ 0.2 °, 7.20 ⁇ 0.2 °, 10.80 ⁇ 0.2 °, 11.39 ⁇ 0.2 °, 12.36 ⁇ 0.2 °, 14.52 ⁇ 0.2 °, 17.14 ⁇ 0.2 °, 18.07 ⁇ 0.2°, 19.39 ⁇ 0.2°, 21.70 ⁇ 0.2°, 22.30 ⁇ 0.2°, 23.18 ⁇ 0.2°, 23.89 ⁇ 0.2°, 25.38 ⁇ 0.2°, 26.26 ⁇ 0.2°, 29.15 ⁇ 0.2°, 32.76 ⁇ 0.2 °, 36.92 ⁇ 0.2 °, 38.93 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a hydrobromide salt crystal form II of the compound of formula (I), characterized in that the hydrobromide salt crystal Type II has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.79 ⁇ 0.2 °, 13.08 ⁇ 0.2 °, 17.00 ⁇ 0.2 °, 20.52 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.79 ⁇ 0.2 °, 10.22 ⁇ 0.2 °, 13.08 ⁇ 0.2 °, 13.59 ⁇ 0.2 °, 17.00 ⁇ 0.2 °, 20.52 ⁇ 0.2 °, 20.67 ⁇ 0.2 °, 22.74 ⁇ 0.2 °, 23.06 ⁇ 0.2 °, 25.55 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.79 ⁇ 0.2 °, 8.09 ⁇ 0.2 °, 8.83 ⁇ 0.2 °, 9.54 ⁇ 0.2 °, 10.22 ⁇ 0.2 °, 11.26 ⁇ 0.2 °, 13.08 ⁇ 0.2 °, 13.59 ⁇ 0.2°, 14.35 ⁇ 0.2°, 16.13 ⁇ 0.2°, 17.00 ⁇ 0.2°, 17.80 ⁇ 0.2°, 18.50 ⁇ 0.2°, 19.20 ⁇ 0.2°, 20.52 ⁇ 0.2°, 20.67 ⁇ 0.2°, 20.90 ⁇ 0.2 °, 21.87 ⁇ 0.2°, 22.17 ⁇ 0.2°, 22.74 ⁇ 0.2°, 23.06 ⁇ 0.2°, 23.58 ⁇ 0.2°, 23.91 ⁇ 0.2°
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal Type I has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the differential scanning calorimetry of Form I contains an endothermic peak at 180.99 °C ⁇ 3 °C.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal Type I has a differential scanning calorimetry diagram substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the X-ray powder diffraction pattern of Form II has diffraction peaks at the following 2 theta angles: 9.49 ⁇ 0.2 °, 16.48 ⁇ 0.2 °, 17.20 ⁇ 0.2 °, 18.37 ⁇ 0.2 °, 19.21 ⁇ 0.2 °, 32.91 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the X-ray powder diffraction pattern of Type II has diffraction peaks at the following 2 theta angles: 7.23 ⁇ 0.2 °, 9.29 ⁇ 0.2 °, 9.49 ⁇ 0.2 °, 16.48 ⁇ 0.2 °, 17.20 ⁇ 0.2 °, 18.37 ⁇ 0.2 °, 19.21 ⁇ 0.2 °, 19.82 ⁇ 0.2 °, 28.79 ⁇ 0.2 °, 29.52 ⁇ 0.2 °, 32.91 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the X-ray powder diffraction pattern of Type II has diffraction peaks at the following 2 theta angles: 5.32 ⁇ 0.2 °, 5.73 ⁇ 0.2 °, 7.23 ⁇ 0.2 °, 8.91 ⁇ 0.2 °, 9.29 ⁇ 0.2 °, 9.49 ⁇ 0.2 °, 9.88 ⁇ 0.2 °, 13.26 ⁇ 0.2°, 13.57 ⁇ 0.2°, 14.88 ⁇ 0.2°, 15.51 ⁇ 0.2°, 15.80 ⁇ 0.2°, 16.48 ⁇ 0.2°, 17.20 ⁇ 0.2°, 17.82 ⁇ 0.2°, 18.37 ⁇ 0.2°, 19.21 ⁇ 0.2 °, 19.82 ⁇ 0.2 °, 20.77 ⁇ 0.2°, 21.28 ⁇ 0.2°, 21.68 ⁇ 0.2°, 22.29 ⁇ 0.2°, 23.47 ⁇ 0.2°,
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal Type II has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the differential scanning calorimetry of Form II contains an endothermic peak at 159.45 °C ⁇ 3 °C.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal Type II has a differential scanning calorimetry diagram substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the X-ray powder diffraction pattern of Form III has diffraction peaks at the following 2 theta angles: 3.73 ⁇ 0.2 °, 7.40 ⁇ 0.2 °, 11.12 ⁇ 0.2 °, 14.85 ⁇ 0.2 °, 19.05 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the X-ray powder diffraction pattern of Type III has diffraction peaks at the following 2 theta angles: 3.73 ⁇ 0.2 °, 7.40 ⁇ 0.2 °, 11.12 ⁇ 0.2 °, 14.85 ⁇ 0.2 °, 16.63 ⁇ 0.2 °, 19.05 ⁇ 0.2 °, 20.24 ⁇ 0.2 °, 20.75 ⁇ 0.2 °, 22.44 ⁇ 0.2 °, 25.95 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the X-ray powder diffraction pattern of Type III has diffraction peaks at the following 2 theta angles: 3.73 ⁇ 0.2 °, 7.40 ⁇ 0.2 °, 8.10 ⁇ 0.2 °, 9.14 ⁇ 0.2 °, 9.79 ⁇ 0.2 °, 11.12 ⁇ 0.2 °, 12.02 ⁇ 0.2 °, 14.53 ⁇ 0.2°, 14.85 ⁇ 0.2°, 15.70 ⁇ 0.2°, 16.63 ⁇ 0.2°, 17.11 ⁇ 0.2°, 17.87 ⁇ 0.2°, 19.05 ⁇ 0.2°, 20.24 ⁇ 0.2°, 20.75 ⁇ 0.2°, 21.45 ⁇ 0.2 °, 21.87 ⁇ 0.2°, 22.44 ⁇ 0.2°, 23.36 ⁇ 0.2°, 25.95 ⁇ 0.2°, 26.36 ⁇ 0.2°, 29.24 ⁇ 0.2°
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal Type III has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the differential scanning calorimetry of Form III contains an endothermic peak at 96.67 °C ⁇ 3 °C.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal
  • the differential scanning calorimetry of Form III contains an endothermic peak at 140.76 °C ⁇ 3 °C.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the besylate salt
  • the differential scanning calorimetry of Form III contains an endothermic peak at 96.67 °C ⁇ 3 °C and 140.76 °C ⁇ 3 °C.
  • the acid addition salt of the present invention wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal Type III has a differential scanning calorimetry diagram substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is amorphous to the besylate salt of the compound of formula (I), characterized in that the besylate salt is amorphous
  • the besylate salt is amorphous
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the X-ray powder diffraction pattern of the sulfonate crystal form I has diffraction peaks at the following 2 theta angles: 8.96 ⁇ 0.2 °, 9.97 ⁇ 0.2 °, 12.67 ⁇ 0.2 °, 17.91 ⁇ 0.2 °, 26.77 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the X-ray powder diffraction pattern of the sulfonate crystal form I has diffraction peaks at the following 2 theta angles: 8.96 ⁇ 0.2 °, 9.97 ⁇ 0.2 °, 12.67 ° ⁇ 0.2, 13.45 ⁇ 0.2 °, 17.91 ⁇ 0.2 °, 20.08 ⁇ 0.2 ° , 22.22 ⁇ 0.2 °, 26.77 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal of the compound of formula (I) Form I, characterized in that the X-ray powder diffraction pattern of the ⁇ -naphthalenesulfonate crystal form I has diffraction peaks at the following 2 ⁇ angles: 4.50 ⁇ 0.2°, 6.35 ⁇ 0.2°, 7.06 ⁇ 0.2°, 8.43 ⁇ 0.2°, 8.96 ⁇ 0.2°, 9.97 ⁇ 0.2°, 11.92 ⁇ 0.2°, 12.67 ⁇ 0.2°, 13.45 ⁇ 0.2°, 13.78 ⁇ 0.2°, 14.16 ⁇ 0.2°, 14.75 ⁇ 0.2°, 15.80 ⁇ 0.2°, 16.12 ⁇ 0.2°, 16.74 ⁇ 0.2°, 16.91 ⁇ 0.2°, 17.91 ⁇ 0.2°, 18.64 ⁇ 0.2°, 19.05 ⁇ 0.2°, 19.52 ⁇ 0.2°, 20.08 ⁇ 0.2°, 20.65 ⁇ 0.2°, 22.22 ⁇ 0.2°, 22.51 ⁇ 0.2°, 22.75 ⁇ 0.2°, 23.17
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the sulfonate crystal form I has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the differential scanning calorimetry of the sulfonate Form I contains an endothermic peak at 163.92 °C ⁇ 3 °C.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the differential scanning calorimetry of the sulfonate Form I contains an endothermic peak at 220.42 °C ⁇ 3 °C.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the ⁇ - The differential scanning calorimetry of naphthalenesulfonate Form I comprises an endothermic peak at 163.92 °C ⁇ 3 °C and 220.42 °C ⁇ 3 °C.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the sulfonate crystal form I has a differential scanning calorimetry diagram substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the X-ray powder diffraction pattern of the sulfonate crystal form II has diffraction peaks at the following 2 theta angles: 6.43 ⁇ 0.2 °, 13.60 ⁇ 0.2 °, 19.41 ⁇ 0.2 °, 19.62 ⁇ 0.2 °, 21.50 ⁇ 0.2 °, 22.45 ⁇ 0.2 ° .
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the X-ray powder diffraction pattern of the sulfonate crystal form II has diffraction peaks at the following 2 theta angles: 6.43 ⁇ 0.2 °, 13.60 ⁇ 0.2 °, 16.75 ⁇ 0.2 °, 16.95 ⁇ 0.2 °, 19.41 ⁇ 0.2 °, 19.62 ⁇ 0.2 ° , 19.97 ⁇ 0.2 °, 20.65 ⁇ 0.2 °, 21.50 ⁇ 0.2 °, 21.82 ⁇ 0.2 °, 22.45 ⁇ 0.2 °, 25.97 ⁇ 0.2 °.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the X-ray powder diffraction pattern of the sulfonate type II has diffraction peaks at the following 2 theta angles: 6.43 ⁇ 0.2 °, 8.10 ⁇ 0.2 °, 9.15 ⁇ 0.2 °, 9.73 ⁇ 0.2 °, 10.57 ⁇ 0.2 °, 12.64 ⁇ 0.2 °, 12.90 ⁇ 0.2°, 13.60 ⁇ 0.2°, 16.04 ⁇ 0.2°, 16.26 ⁇ 0.2°, 16.75 ⁇ 0.2°, 16.95 ⁇ 0.2°, 17.43 ⁇ 0.2°, 17.90 ⁇ 0.2°, 18.37 ⁇ 0.2°, 19.41 ⁇ 0.2°, 19.62 ⁇ 0.2°, 19.97 ⁇ 0.2°, 20.65 ⁇ 0.2°, 21.50 ⁇ 0.2°, 21.82 ⁇ 0.2°, 22.07 ⁇ 0.2°, 22.45 ⁇ 0.2
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the ⁇ -naphthalene The sulfonate Form II has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the differential scanning calorimetry of the sulfonate Form II contains an endothermic peak at 221.99 °C ⁇ 3 °C.
  • the acid addition salt of the present invention wherein the salt is a ⁇ -naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the ⁇ -naphthalene
  • the sulfonate Form II has a differential scanning calorimetry diagram substantially as shown in FIG.
  • the present invention also provides a pharmaceutical composition comprising any one of the acid addition salts of the compound of formula (I) or a combination thereof;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or a combination thereof.
  • the acid addition salt in the pharmaceutical composition of the present invention may be in any one of the crystalline forms of the salt, and may be any crystal form, amorphous or any of the salts. combination.
  • the pharmaceutical composition of the present invention comprises any one of the acid addition salts of the compound of formula (I), or any of the crystal forms or amorphous forms, or the salts, Any combination of crystal form and amorphous form.
  • the invention relates to an acid addition salt of a compound of formula (I) or the use of said pharmaceutical composition for the preparation of a medicament, wherein said medicament is for preventing, treating or ameliorating tissue of a human or animal Or organ fibrosis.
  • the use comprises administering to a human or animal an acid addition salt of the invention or an effective therapeutic dose of the pharmaceutical composition.
  • the tissue or organ fibrotic disease of the present invention is renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, cutaneous fibrosis, surgery Post-adhesion, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibroma, pulmonary fibrosis, diabetic nephropathy, Alzheimer's disease or Vascular fibrosis disease.
  • the pulmonary fibrosis of the invention comprises idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • post-operative adhesion as described herein refers to scar healing.
  • the invention further relates to an acid addition salt of the compound of the formula (I) or the use of the pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of diabetic nephropathy or Alzheimer's disease in a patient disease.
  • One aspect of the invention relates to a method of preventing, treating or ameliorating a fibrotic disease of a tissue or organ of a patient comprising administering to the patient an acid addition salt of the invention or a pharmaceutically acceptable effective amount of said pharmaceutical composition .
  • Another aspect of the invention relates to an acid addition salt of the compound of formula (I) or a pharmaceutical composition for preventing, treating or ameliorating a tissue or organ fibrotic disease in a human or animal.
  • the invention relates to an acid addition salt of a compound of formula (I) and a process for the preparation thereof.
  • the crystal form of the acid addition salt of the present invention can be produced by a conventional preparation method, and some of the crystal forms of the present invention can also be produced by a crystal transformation method.
  • the amorphous form of the present invention can be prepared by a spray drying method.
  • the amorphous yield of the spray drying preparation according to the present invention is affected by factors such as the temperature of the air inlet of the instrument, the temperature of the air outlet, the pressure of the system during the spraying process, and the temperature of the air inlet, the temperature of the air outlet, the pressure of the system during the spraying process, and the like.
  • the model number, the solvent used, and other factors are relevant.
  • the solvent used in the salt, crystal form or amorphous preparation method of the present invention is not particularly limited, and any solvent which can dissolve the starting material to a certain extent and does not affect its properties is included in the present invention.
  • any solvent which can dissolve the starting material to a certain extent and does not affect its properties is included in the present invention.
  • many variations, equivalents, or equivalents to the solvents, solvent combinations, and solvent combinations described herein are considered to be within the scope of the invention.
  • the present invention provides preferred solvents for use in the various reaction steps.
  • the preparation of the salts of the present invention will be described in detail in the Examples section. Meanwhile, the present invention provides activity testing experiments (such as pharmacokinetic experiments), solubility experiments, stability experiments, and wettability experiments of the salts. It can be seen from the experimental results that the crystalline salt of the present invention has good biological activity (for example, good pharmacokinetic properties), and has good solubility and high stability, and is suitable for pharmaceutical use.
  • the salt of the invention is not easily affected by high humidity and deliquesces, and facilitates long-term storage placement of the drug.
  • the salt of the present invention or a pharmaceutical composition thereof has a small toxic side effect.
  • the inventors have found in experiments that the salt or a pharmaceutical composition thereof according to the present invention has a small toxic side effect in dogs, and the side effects include side effects such as vomiting.
  • “Pharmaceutically acceptable acid addition salt” means a salt of a compound of formula (I) of the present invention with a pharmaceutically acceptable non-toxic acid, including but not limited to the various organic acid salts described herein. And inorganic acid salts.
  • the "acid addition salt of the compound of the formula (I)” means a salt formed by reacting a compound of the formula (I) (free base) with various suitable organic or inorganic acids, including but not limited to the present invention. Hydrochloride, hydrobromide, sulfate, maleate, benzenesulfonate, p-toluenesulfonate, beta-naphthalenesulfonate, oxalate, methanesulfonate, and the like.
  • the "acid addition salt of the compound of the formula (I)” includes an amorphous form or a crystalline form of the salt, including a solvate form thereof (for example, a hydrate form), and a polycrystal of the salt.
  • Type form for example, the besylate salt of the compound of formula (I) includes amorphous forms of such salts, various crystalline forms, various solvates, various hydrates, and polymorphic forms of such salts.
  • Form or "crystalline form” refers to a solid having a highly regular chemical structure, including, but not limited to, one-component or multi-component crystals, and/or polymorphs, solvates, hydrates, A clathrate, a eutectic, a salt, a solvate of a salt, or a hydrate of a salt.
  • the crystalline form of the material can be obtained by a number of methods known in the art.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, for example, in a nanopore or capillary, crystallization on a surface or template, for example, on a polymer, Crystallization, solvent removal, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding, and solvent drip grinding in the presence of additives such as co-crystallized antimolecules.
  • Amorphous or “amorphous form” refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and is characterized by having a diffuse X-ray powder diffraction pattern without sharp peaks.
  • Amorphous is a special physical form of solid matter, and its local ordered structural features suggest that it is inextricably linked with crystalline materials.
  • the amorphous form of the material can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, solid dispersion techniques, and the like.
  • Solvent means a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
  • Solvents useful in the practice of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol.
  • Antisolvent refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent.
  • the anti-solvent may include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in a solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a liquid different from the solvent.
  • Solidvate means a compound having a solvent on a surface, in a crystal lattice or on a surface, and in a crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, Dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethyl Amide, formamide, formic acid, heptane, hexane, isopropanol, A Alcohol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof and the like.
  • a specific example of a solvate is a hydrate in which the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water.
  • the hydrate may or may not have a solvent other than water on the surface of the substance, in the crystal lattice or on the surface and in the crystal lattice.
  • Crystalline or amorphous can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA). ), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolved calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect crystal form changes, crystallinity, crystal state and other information, and is a common means of identifying crystal forms.
  • the peak position of the XRPD pattern depends primarily on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry.
  • the crystalline form of the invention is characterized by an XRPD pattern having certain peak positions substantially as shown in the XRPD pattern provided in the figures of the present invention.
  • the 2 ⁇ measure of the XRPD pattern may have experimental errors.
  • the 2 ⁇ measure of the XRPD pattern may be slightly different between different instruments and different samples, so the value of 2 ⁇ cannot be considered absolute. According to the condition of the instrument used in this test, the diffraction peak has an error tolerance of ⁇ 0.2°.
  • Differential Scanning Calorimetry is a technique in which the energy difference between a sample and an inert reference (usually ⁇ -Al 2 O 3 ) is measured as a function of temperature by continuous heating or cooling under program control.
  • the melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details.
  • the crystalline form of the present invention is characterized by a DSC pattern having a characteristic peak position substantially as shown in the DSC chart provided in the figures of the present invention.
  • the DSC spectrum can have experimental errors.
  • the peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the condition of the instrument used in this test, the melting peak has an error tolerance of ⁇ 3°.
  • DSC Differential Scanning Calorimetry
  • Solids with the same chemical composition often form homoisomers with different crystal structures, or variants, under different thermodynamic conditions. This phenomenon is called homopoly or homogeneous multiphase. When temperature and pressure conditions change, mutual transformation occurs between the variants. This phenomenon is called crystal transformation. Due to the crystal transformation, the mechanical, electrical, magnetic and other properties of the crystal will change greatly. When the temperature of the crystal transition is within the measurable range, this transition process can be observed on a differential scanning calorimetry (DSC) map, characterized in that the DSC map has an exothermic peak reflecting this transition process, and There are two or more endothermic peaks, which are characteristic endothermic peaks of different crystal forms before and after the transition.
  • DSC differential scanning calorimetry
  • Thermogravimetric analysis is a technique for determining the mass of a substance as a function of temperature under program control. It is suitable for checking the loss of solvent in a crystal or the process of sublimation and decomposition of a sample. It is speculated that crystal water or crystal solvent is contained in the crystal. Case.
  • the quality of the TGA curve shows changes depending on many factors such as sample preparation and instrumentation; the quality of the TGA test varies slightly between different instruments and between samples.
  • the amorphous feature of the present invention is characterized in that the weight loss range of the TGA test is from 1.75% to 4.10%. According to the condition of the instrument used in this test, the quality variation has a margin of error of ⁇ 0.1%.
  • Raman spectroscopy (Roman) is a spectroscopic technique used to study the vibration modes, rotation modes, and other low-frequency modes in a system. Different spatial structures of the same molecule (different crystal forms or amorphous) have different Raman activities, so Raman spectroscopy can be used to determine and identify crystal forms or amorphous forms.
  • the peak position of the Raman spectrum is mainly related to the structure of the material, and is relatively insensitive to experimental details, and the peak intensity depends on factors such as sample preparation and instrumentation.
  • the crystalline form or amorphous form of the present invention is characterized by a Raman spectrum having a characteristic peak position substantially as shown in the Raman spectrum provided in the drawings of the present invention. At the same time, the Raman spectrum can have experimental errors.
  • the peak position and peak value of the Raman spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or peak intensity of the Raman spectrum cannot be regarded as absolute. of. According to the condition of the instrument used in this test, the absorption peak has an error tolerance of ⁇ 2 cm -1 .
  • the bond length and bond angle of some chemical bonds will be different, resulting in different vibration-rotation transition levels, and some of the main characteristics of the corresponding infrared spectrum such as absorption band frequency and peak shape.
  • peak position, peak intensity, etc. There are also differences in peak position, peak intensity, etc., so infrared spectroscopy can be used for drug polymorphism research.
  • the crystalline form or amorphous form of the present invention is characterized by a Fourier infrared (FT-IR) spectrogram having a characteristic peak position, substantially as shown by the Fourier infrared spectrum provided in the drawings of the present invention.
  • Fourier infrared spectroscopy can have experimental errors.
  • the peak position and peak value of Fourier infrared spectrum may be slightly different between different instruments and different samples, so the peak position or peak intensity of the Fourier infrared spectrum The value cannot be considered absolute. According to the condition of the instrument used in this test, the absorption peak has an error tolerance of ⁇ 2 cm -1 .
  • the 2 ⁇ values in the X-ray powder diffraction pattern are all in degrees (°).
  • substantially as shown means at least 50%, or at least 60%, or at least 70%, or at least 80%, or in an X-ray powder diffraction pattern or DSC pattern or Raman spectrum or infrared spectrum, or At least 90%, or at least 95%, or at least 99% of the peaks are shown in the figure.
  • peak refers to a feature that can be identified by those skilled in the art that does not belong to background noise.
  • the present invention relates to various new crystal forms of the acid addition salt of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one They exist in a substantially pure crystalline form.
  • the present invention also relates to the amorphous form of various acid addition salts of the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one
  • the amorphous form can be prepared by spray drying.
  • substantially pure means that one crystal form is substantially free of another one or more crystalline forms, ie, the crystalline form is at least 80% pure, or at least 85%, or at least 90%, or at least 93%, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or other crystalline forms in the crystalline form, The percentage of other crystalline forms in the total or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, Or less than 0.1%, or less than 0.01%.
  • substantially free means that the percentage of one or more other crystalline forms in the total or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • the “relative intensity” (or “relative peak height” in the XRPD pattern refers to the intensity of the other peaks when the intensity of the first strong peak among all the diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%.
  • the ratio of the intensity of a strong peak is 100%.
  • Room temperature in the present invention means that the temperature is from about 10 ° C to about 40 ° C.
  • room temperature refers to a temperature of from about 20 ° C to about 30 ° C; in other embodiments, “room temperature” refers to 20 ° C, 22.5 ° C, 25 ° C, 27.5 ° C, and the like.
  • compositions, formulation, administration and use of an acid addition salt of a compound of the invention are provided.
  • the pharmaceutical composition of the present invention is characterized by comprising an acid addition salt of a compound of the formula (I) and a pharmaceutically acceptable carrier, adjuvant, or excipient.
  • the amount of the acid addition salt of the compound in the pharmaceutical composition of the present invention is effective to detectably reduce or alleviate the disease of tissue or organ fibrosis in a patient.
  • compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form.
  • a pharmaceutically acceptable carrier including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
  • Substances which may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum proteins; buffer substances such as phosphate; glycine; sorbic acid; Potassium acid; a partial glyceride mixture of saturated vegetable fatty acids; water; salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa butter and suppository
  • the pharmaceutical composition of the present invention may be a capsule, a tablet, a pill, a powder, a granule and an aqueous suspension or solution; it may be administered by the following routes: oral administration, injection administration, spray inhalation, topical administration. , for rectal administration, nasal administration, buccal administration, vaginal administration or administration via an implantable kit.
  • Oral administration can be carried out in the form of tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs, and the like; topical administration can be carried out by the following forms: ointments, gels , containing drug tape, etc.
  • composition of the present invention can be administered parenterally in the form of a sterile injectable solution or suspension, or parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose, polyvinylpyrrolidone.
  • Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. These preparations contain preservatives to prevent microbial growth under normal conditions of storage and use.
  • the pharmaceutical forms suitable for injection include: sterile aqueous solutions or dispersions and sterile powders (for the preparation of sterile injectable solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate the discharge of fluid from the syringe. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating effects of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, an alcohol such as glycerol, propylene glycol, and liquid polyethylene glycol, suitable mixtures thereof, and vegetable oils.
  • the compound of the present invention or a salt thereof or the pharmaceutical composition of the present invention can be administered in a localized manner without being administered in a systemic manner.
  • the compound is usually injected directly into the organ in the form of a diluted formulation or a sustained release formulation.
  • pharmaceutical compositions containing a compound of the invention or a salt thereof can be used in a targeted drug delivery system, for example, in the weight of a lipid coated with an organ-specific antibody. The liposomes will target the organ and be selectively taken up by the organ.
  • compositions containing a compound of the invention may be provided in the form of a rapid release formulation, a time release formulation or a ready release formulation.
  • the compound of the present invention or a salt thereof may be in the form of an aerosol, an aerosol or a powder.
  • the pharmaceutical composition of the compound of the present invention or a salt thereof can be conveniently delivered in the form of an aerosol spray which can be contained in a pressure vessel or atomizer using a suitable propellant such as dichlorodifluoromethane, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit can be determined by a valve to deliver a metered amount.
  • gelatin for use in an inhaler or insufflator can be prepared to contain a powder mix of the compound with a suitable powder base such as lactose or starch.
  • the compound of the present invention or a salt thereof can also be prepared as a rectal composition such as an enema, a rectal gel, a rectal foam, a rectal aerosol, a suppository, a gel suppository or a retention enma, which contains Conventional suppository bases such as cocoa butter or other glycerides and synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low melting wax such as, but not limited to, a fatty acid glyceride, optionally mixed with cocoa butter, is first melted.
  • the compounds of the invention or salts thereof may also be combined with other agents for treating fibrosis.
  • agents for treating fibrosis Specifically included, but not limited to, Ivacaftor, Rofluent, Pirfenidone, Nidanib, Megruth, Losartan, Interferon, Arafat-Chainase, Veldona, ataluren, Corticosteroids, Methotrexate, tacrolimus, etc.
  • the pharmaceutical compositions may be prepared in a conventional manner using one or more physiologically acceptable carriers including excipients and adjuvants which may aid in the preparation of the active compound or a salt thereof in a pharmaceutically acceptable formulation.
  • the route of administration chosen determines the appropriate dosage form. Any of the well-known techniques, carriers and excipients can be suitably employed in accordance with the understanding in the prior art.
  • the pharmaceutical composition containing the compound of the present invention or a salt thereof can be produced according to a conventional method, for example, by a conventional mixing, dissolving, granulating, tableting, grinding, emulsifying, encapsulating, encapsulating or pressing process.
  • a pharmaceutical composition comprising a compound of the present invention or a salt thereof can be administered in a therapeutically effective amount of a pharmaceutical composition in a conventional form and route known in the art including, but not limited to, intravenous, oral, rectal, aerosol. , parenteral route, transocular, transpulmonary, transdermal, transvaginal, transaural, nasal and topical administration.
  • the pharmaceutical composition will comprise, as an active ingredient, at least one pharmaceutically acceptable carrier, diluent or excipient and a compound of the invention in the form of a free acid, a free base or a pharmaceutically acceptable salt.
  • the pharmaceutical compositions may also include other medical or pharmaceutically active agents, carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure or buffers.
  • the pharmaceutical compositions may also contain other therapeutically valuable substances.
  • a method of preparing a composition comprising a compound of the invention or a salt thereof comprises preparing the compound together with one or more inert pharmaceutically acceptable excipients or carriers in solid, semi-solid or liquid form.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, solutions containing liposomes, micelles or nanoparticles comprising the compounds disclosed herein.
  • Semi-solid compositions include, but are not limited to, gels, suspensions, and creams.
  • compositions may be in the form of a liquid solution or suspension, in a solid form or in an emulsion form suitable for dissolution or suspension in a liquid prior to use.
  • compositions may also contain minor amounts of non-toxic adjuvants such as wetting or emulsifying agents, pH buffering agents and the like.
  • the compound of the present invention or a salt thereof is preferably prepared in a dosage unit form in a formulation to reduce the uniformity of administration and dosage.
  • dosage unit type refers to the physically discrete unit of the drug required for the patient to receive appropriate treatment.
  • the particular effective dosage level will depend on a number of factors, including the severity of the condition or condition being treated, the activity of the particular compound or salt thereof, the particular composition employed, the age, weight, and health of the patient for any particular patient or organism. Condition, sex and eating habits, time of administration, route of administration and rate of excretion of the particular compound employed, duration of treatment, use of the drug in combination or in combination with a compound having a specific effect, and other factors well known in the pharmaceutical arts.
  • the effective dose of the active ingredient employed may vary depending on the compound or salt thereof employed, the mode of administration, and the severity of the condition to be treated. However, usually, when the compound of the present invention or a salt thereof is administered at a dose of about 0.25 to 1000 mg/kg of animal body weight per day, a satisfactory effect can be obtained, preferably administered in 2-4 divided doses per day, or Sustained release form of administration. For most large mammals, the total daily dose is from about 1 to 100 mg/kg, preferably from about 2 to 80 mg/kg of active compound. Dosage forms for internal administration comprise from about 0.25 to about 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide an optimal therapeutic response. In addition, several separate doses may be administered per day, or the dose may be proportionally reduced, depending on the condition being treated.
  • the compound or the salt and the pharmaceutical composition of the invention can be effectively used for preventing, treating, treating or alleviating fibrotic diseases of tissues or organs of patients, in particular, effective treatment of renal interstitial fibrosis, glomerular sclerosis, liver Fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, cutaneous fibrosis, postoperative adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibers Disease, cirrhosis, muscle tumor, neurofibromatosis, pulmonary interstitial fibrosis, diabetic nephropathy, Alzheimer's disease or vascular fibrosis.
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of the hydrobromide salt form I of the compound of formula (I).
  • Figure 2 is an X-ray powder diffraction (XRPD) pattern of the hydrobromide salt form II of the compound of formula (I).
  • Figure 3 is an X-ray powder diffraction (XRPD) pattern of the benzenesulfonate salt form I of the compound of formula (I).
  • FIG. 4 is a differential scanning calorimetry (DSC) chart of the besylate salt form I of the compound of formula (I).
  • Figure 5 is an X-ray powder diffraction (XRPD) pattern of the benzenesulfonate salt form II of the compound of formula (I).
  • FIG. 6 is a differential scanning calorimetry (DSC) chart of the besylate salt form II of the compound of formula (I).
  • Figure 7 is an X-ray powder diffraction (XRPD) pattern of the besylate salt form III of the compound of formula (I).
  • Figure 8 is a differential scanning calorimetry (DSC) chart of the besylate salt form III of the compound of formula (I).
  • Figure 9 is an amorphous X-ray powder diffraction (XRPD) pattern of the besylate salt of the compound of formula (I).
  • Figure 10 is an X-ray powder diffraction (XRPD) pattern of the ⁇ -naphthalenesulfonate crystal form I of the compound of the formula (I).
  • Figure 11 is a differential scanning calorimetry (DSC) chart of Form I of the ⁇ -naphthalenesulfonate salt of the compound of Formula (I).
  • Figure 12 is an X-ray powder diffraction (XRPD) pattern of the ⁇ -naphthalenesulfonate crystal form II of the compound of the formula (I).
  • Figure 13 is a differential scanning calorimetry (DSC) chart of the ⁇ -naphthalenesulfonate Form II of the compound of Formula (I).
  • the X-ray powder diffraction analysis method used in the present invention is an Empyrean diffractometer, and an X-ray powder diffraction pattern is obtained using Cu-K ⁇ radiation (45 kV, 40 mA).
  • the powdered sample was prepared as a thin layer on a single crystal silicon sample holder and placed on a rotating sample stage for analysis in the range of 3 to 40 degrees in steps of 0.0168°. Data is collected using Data Collector software, HighScore Plus software processes the data, and Data Viewer software reads the data.
  • the differential scanning calorimetry (DSC) analysis method used in the present invention is to perform differential scanning calorimetry using a TA Q2000 module with a thermal analysis controller. Data was collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of the sample was accurately weighed into a special aluminum crucible with a lid, and sample analysis was performed from room temperature to about 300 ° C using a linear heating device at 10 ° C/min. During use, the DSC chamber was purged with dry nitrogen.
  • the Fourier Infrared (FT-IR) analysis method used in the present invention is: using the German Bruker TENSOR27 infrared spectrometer test, OPUS software for data analysis. KBr tableting, scanning times: 16 times, wave number range: 4000 ⁇ 600cm -1 , resolution: 2cm -1 .
  • the compound of the formula (I) according to the present invention (compound 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one), different
  • the crystal forms of the salt are separately filled into capsules for oral administration.
  • the salt of the present invention has no obvious change in appearance and purity, and has good stability effect and is suitable for pharmaceutical use.

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Abstract

The present invention relates to salts of 2,6-dimethylpyrimidone derivative and uses of the salts. The present invention also relates to a pharmaceutical composition comprising the salts or a combination thereof, and uses of the salts or the pharmaceutical composition in preparing a medicament for treating and preventing tissue or organ fibrosis.

Description

2,6-二甲基嘧啶酮衍生物的盐及其用途Salt of 2,6-dimethylpyrimidinone derivative and use thereof 技术领域Technical field
本发明属于药物领域，涉及2,6-二甲基嘧啶酮衍生物的盐及其用途，具体涉及3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(式(I)所示化合物)的盐及其用途，进一步涉及包含所述的盐的药物组合物。所述的盐或所述药物组合物用于治疗和预防组织或器官纤维化疾病。本发明化合物的盐可以为晶型、部分晶型、多晶型或无定形形式。The invention belongs to the field of medicine, relates to a salt of a 2,6-dimethylpyrimidinone derivative and a use thereof, in particular to 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethyl A salt of a pyrimidine-4(3H)-one (a compound of the formula (I)) and use thereof, further relates to a pharmaceutical composition comprising the salt. The salt or the pharmaceutical composition is for use in the treatment and prevention of tissue or organ fibrotic diseases. The salt of the compound of the present invention may be in a crystalline form, a partially crystalline form, a polymorphic form or an amorphous form.
背景技术Background technique
纤维化(Fibrosis)是指在一个器官或组织为修复或反应过程而过度地形成纤维***的过程。器官组织纤维化轻者称为纤维化，重者引起组织结构破坏而发生器官硬化。组织纤维化不仅发生在肺、肝、心脏、肾脏等器官，组织纤维化可累及人体几乎所有的器官和***，全球约有1/3的人死于组织纤维化以及由其产生的器官衰竭。Fibrosis refers to the process of excessively forming fibrous connective tissue in an organ or tissue for repair or reaction processes. Organ tissue fibrosis is called fibrosis, and severe cases cause structural damage and organ sclerosis. Tissue fibrosis occurs not only in organs such as the lungs, liver, heart, and kidneys. Tissue fibrosis can affect almost all organs and systems in the human body. About one-third of the world's people die from tissue fibrosis and organ failure.
专利WO 2014012360和CN 103570630公开了具有抗纤维化作用的氮杂环衍生物，其中，化合物3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(式(I)所示化合物)能有效的阻止或治疗人体或动物的组织纤维化病变。The patents WO 2014012360 and CN 103570630 disclose nitrogen heterocyclic derivatives having anti-fibrotic effects, wherein the compound 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidine- 4(3H)-ketone (a compound of formula (I)) is effective for preventing or treating tissue fibrotic lesions in humans or animals.
Figure PCTCN2017094409-appb-000001
Figure PCTCN2017094409-appb-000001
药物多晶型是药物研发中的常见现象，是影响药物质量的重要因素。同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同，也会对药物的稳定性、生物利用度及疗效等产生不同的影响。因此，在药物研发中，应全面考虑药物的多晶型问题。Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, in drug development, the polymorphic problem of the drug should be fully considered.
无定形是物质多晶型现象中的一种形式，是一种非晶型状态。无定形药物的各种理化性质及临床药效特征常有别于一般的晶型药物。因此，在固体药物的多晶型研究中，对无定形物质的深入探讨同样有着重要意义。Amorphous is a form of material polymorphism and is an amorphous state. The various physical and chemical properties and clinical efficacy characteristics of amorphous drugs are often different from the general crystalline drugs. Therefore, in the study of polymorphism of solid drugs, the in-depth discussion of amorphous substances is also of great significance.
发明内容Summary of the invention
化合物3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(式(I)所示化合物)为淡黄色油状物，为了改善化合物的稳定性和生物利用度，本发明对式(I)所示化合物的盐、及其盐的晶型进行了研究，进而提出了式(I)所示化合物的药学上可接受的酸加成盐及其组合物。本发明所述的盐或药物组合物具有较好的生物活性、较小的毒副作用和较好的稳定性，从而具有更优良的成药性。The compound 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (the compound of the formula (I)) is a pale yellow oil. To improve the stability and bioavailability of the compound, the present invention has studied the salt form of the compound of the formula (I) and the salt form thereof, and further proposed a pharmaceutically acceptable acid of the compound of the formula (I). Addition salts and compositions thereof. The salt or the pharmaceutical composition of the invention has better biological activity, less toxic side effects and better stability, thereby having better drug-forming properties.
具体而言，本发明涉及式(I)所示化合物的酸加成盐及其药物组合物，以及所述化合物的盐或所述药物组合物在制备用于治疗或预防组织纤维化疾病的药物中的用途。本发明的酸加成盐可以为晶型、部分晶型、多晶型或无定形形式；另一方面，本发明的酸加成盐还可以为溶剂化物形式，例如水合物形式。In particular, the present invention relates to an acid addition salt of a compound of the formula (I) and a pharmaceutical composition thereof, and a salt of the compound or the pharmaceutical composition for preparing a medicament for treating or preventing a tissue fibrotic disease Use in. The acid addition salt of the present invention may be in a crystalline form, a partially crystalline form, a polymorphic form or an amorphous form; in another aspect, the acid addition salt of the present invention may also be in the form of a solvate, such as a hydrated form.
一方面，本发明提供了一种式(I)所示化合物的药学上可接受的酸加成盐，In one aspect, the invention provides a pharmaceutically acceptable acid addition salt of a compound of formula (I),
Figure PCTCN2017094409-appb-000002
Figure PCTCN2017094409-appb-000002
在一些实施例中，本发明所述的酸加成盐为无机酸盐或有机酸盐。 In some embodiments, the acid addition salts of the present invention are inorganic or organic acid salts.
在另一些实施例中，本发明所述的无机酸盐为盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、氢溴酸盐、氢碘酸盐、碳酸盐、碳酸氢盐、亚硫酸盐、亚硫酸氢盐、焦硫酸盐、磷酸一氢盐、磷酸二氢盐、高氯酸盐、过硫酸盐、半硫酸盐、重硫酸盐、硫氰酸盐、磷酸盐、焦磷酸盐、偏磷酸盐或它们的任意组合。In other embodiments, the inorganic acid salt of the present invention is a hydrochloride, a sulfate, a hydrogen sulfate, a nitrate, a hydrobromide, a hydroiodide, a carbonate, a hydrogencarbonate, a sulfurous acid. Salt, bisulfite, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, heavy sulfate, thiocyanate, phosphate, pyrophosphate, Metaphosphate or any combination thereof.
在另一些实施例中，本发明所述的有机酸盐为甲酸盐、乙酸盐、丙酸盐、丁酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、丙酮酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、柠檬酸盐、4-硝基苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、丙炔酸盐、2-丁炔酸盐、2-羟基-乙烷磺酸盐、乙烯基乙酸盐、酒石酸盐、L-酒石酸盐、富马酸盐、羟乙基磺酸盐、马来酸盐、乳酸盐、乳糖酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚糖酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、萘磺酸盐(包括α-萘磺酸盐和β-萘磺酸)、草酸盐、三氟乙酸盐、三氟甲磺酸盐、己二酸盐、辛二酸盐、癸二酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、羟基乙酸盐、藻酸盐、抗坏血酸盐、异抗坏血酸盐、天冬氨酸盐、L-天冬氨酸盐、谷氨酸盐、L-谷氨酸盐、2-苯氧基苯甲酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、乙酰乙酸盐、2-羟基乙磺酸盐、苯磺酸盐、硼酸盐、氯代苯甲酸盐、樟脑酸盐、衣康酸盐、樟脑磺酸盐、左旋樟脑磺酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、氨基磺酸盐、乳糖醛酸盐、半乳糖醛酸盐、环戊基丙酸盐、十二烷基硫酸盐、丙烯酸盐、环戊烷丙酸盐、甘油磷酸盐、甲氧基苯甲酸盐、二葡萄糖酸盐、葡萄糖酸盐、庚酸盐、己酸盐、2-羟基-乙磺酸盐、三甲基乙酸盐、葡糖醛酸盐、月桂酸盐、邻苯二甲酸盐、苯乙酸盐、月桂基硫酸盐、2-乙酰氧基苯甲酸盐、烟酸盐、肉桂酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、苯二甲酸盐、戊二酸盐、羟基马来酸盐、羟基苯甲酸盐、3-羟基-2-萘甲酸盐、3-苯基丙酸盐、异丁酸盐、新戊酸盐、苦味酸盐、硬脂酸盐、2,2-二氯乙酸盐、酰化氨基酸盐、海藻酸盐、4-乙酰氨基苯磺酸盐、葵酸盐、胆酸盐、辛酸盐、壬酸盐、环拉酸盐、酞酸盐、盐酸半胱氨酸盐、山梨酸盐、帕莫酸盐、粘酸盐、盐酸甘氨酸盐、萘二磺酸盐、二甲苯磺酸盐、二盐酸胱氨酸盐、十一酸盐、聚乙烯磺酸盐、磺基水杨酸盐、苯基丁酸盐、4-羟基丁酸盐、聚乙烯硫酸盐、萘-1-磺酸盐、萘-2-磺酸盐、戊酸盐或它们的任意组合。In other embodiments, the organic acid salt of the present invention is a formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate , mesylate, ethanesulfonate, propane sulfonate, citrate, 4-nitrobenzoate, benzenesulfonate, p-toluenesulfonate, malate, propiolate, 2 -butynoate, 2-hydroxy-ethanesulfonate, vinyl acetate, tartrate, L-tartrate, fumarate, isethionate, maleate, lactate , lactobionate, pamoate, salicylate, galactose salt, glucoheptonate, mandelate, 1,2-ethanedisulfonate, naphthalene sulfonate (including --naphthalene sulfonate and β-naphthalene sulfonic acid), oxalate, trifluoroacetate, triflate, adipate, suberate, sebacate, butyne-1 , 4-diacid salt, hexyne-1,6-diacid salt, glycolic acid salt, alginate, ascorbate, isoascorbate, aspartate, L-aspartate, glutamine Acid salt, L-glutamate, 2-phenoxybenzoate, 2-(4-hydroxybenzoyl)benzoic acid Salt, acetoacetate, 2-hydroxyethanesulfonate, besylate, borate, chlorobenzoate, camphorate, itaconate, camphorsulfonate, levo-camphorsulfonate , methyl benzoate, dinitrobenzoate, sulfamate, lactobionate, galacturonate, cyclopentyl propionate, lauryl sulfate, acrylate, ring Pentane propionate, glycerol phosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, trimethylacetate , glucuronate, laurate, phthalate, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, Palmitate, pamoate, pectate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, 3-hydroxy-2-naphthoate, 3-benzene Propionate, isobutyrate, pivalate, picrate, stearate, 2,2-dichloroacetate, acylated amino acid salt, alginate, 4-acetamidobenzenesulfonic acid Salt, acid salt, cholate, octanoic acid , citrate, cyclamate, citrate, cysteine hydrochloride, sorbate, palmitic acid salt, mucic acid salt, glycine hydrochloride, naphthalene disulfonate, xylene sulfonate, Cysteine dihydrochloride, eleven acid salt, polyvinyl sulfonate, sulfosalicylic acid salt, phenyl butyrate, 4-hydroxybutyrate, polyethylene sulfate, naphthalene-1-sulfonate , naphthalene-2-sulfonate, valerate or any combination thereof.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的氢溴酸盐晶型I，其特征在于，所述氢溴酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.07±0.2°,8.86±0.2°,13.92±0.2°,24.73±0.2°,25.68±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a hydrobromide salt form I of the compound of formula (I), characterized in that the hydrobromide crystal The X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.07 ± 0.2 °, 8.86 ± 0.2 °, 13.92 ± 0.2 °, 24.73 ± 0.2 °, 25.68 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的氢溴酸盐晶型I，其特征在于，所述氢溴酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.07±0.2°,8.86±0.2°,13.92±0.2°,15.28±0.2°,18.04±0.2°,19.60±0.2°,22.25±0.2°,22.62±0.2°,24.73±0.2°,25.68±0.2°,26.72±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a hydrobromide salt form I of the compound of formula (I), characterized in that the hydrobromide crystal The X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.07 ± 0.2 °, 8.86 ± 0.2 °, 13.92 ± 0.2 °, 15.28 ± 0.2 °, 18.04 ± 0.2 °, 19.60 ± 0.2 °, 22.25 ± 0.2 °, 22.62 ± 0.2 °, 24.73 ± 0.2 °, 25.68 ± 0.2 °, 26.72 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的氢溴酸盐晶型I，其特征在于，所述氢溴酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.07±0.2°,8.86±0.2°,9.41±0.2°,12.13±0.2°,13.92±0.2°,15.28±0.2°,15.69±0.2°,16.36±0.2°,16.59±0.2°,17.17±0.2°,18.04±0.2°,18.75±0.2°,19.60±0.2°,21.18±0.2°,22.25±0.2°,22.62±0.2°,23.37±0.2°,24.73±0.2°,25.68±0.2°,26.72±0.2°,27.43±0.2°,28.10±0.2°,29.63±0.2°,30.62±0.2°,32.13±0.2°,34.88±0.2°,36.79±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a hydrobromide salt form I of the compound of formula (I), characterized in that the hydrobromide crystal The X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.07 ± 0.2 °, 8.86 ± 0.2 °, 9.41 ± 0.2 °, 12.13 ± 0.2 °, 13.92 ± 0.2 °, 15.28 ± 0.2 °, 15.69 ± 0.2 °, 16.36±0.2°, 16.59±0.2°, 17.17±0.2°, 18.04±0.2°, 18.75±0.2°, 19.60±0.2°, 21.18±0.2°, 22.25±0.2°, 22.62±0.2°, 23.37±0.2 °, 24.73±0.2°, 25.68±0.2°, 26.72±0.2°, 27.43±0.2°, 28.10±0.2°, 29.63±0.2°, 30.62±0.2°, 32.13±0.2°, 34.88±0.2°, 36.79±0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的氢溴酸盐晶型I，其特征在于，所述氢溴酸盐晶型I具有基本上如图1所示的X射线粉末衍射图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a hydrobromide salt form I of the compound of formula (I), characterized in that the hydrobromide crystal Type I has an X-ray powder diffraction pattern substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的氢溴酸盐晶型II，其特征在于，所述氢溴酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.64±0.2°,10.80±0.2°,21.70±0.2°,25.38±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a hydrobromide salt crystal form II of the compound of formula (I), characterized in that the hydrobromide salt crystal The X-ray powder diffraction pattern of Form II has diffraction peaks at the following 2 theta angles: 3.64 ± 0.2 °, 10.80 ± 0.2 °, 21.70 ± 0.2 °, 25.38 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的氢溴酸盐晶型 II，其特征在于，所述氢溴酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.64±0.2°,10.80±0.2°,17.14±0.2°,18.07±0.2°,21.70±0.2°,22.30±0.2°,25.38±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a hydrobromide crystal form of the compound of formula (I) II, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt crystal form II has diffraction peaks at the following 2θ angles: 3.64±0.2°, 10.80±0.2°, 17.14±0.2°, 18.07±0.2°, 21.70 ± 0.2 °, 22.30 ± 0.2 °, 25.38 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的氢溴酸盐晶型II，其特征在于，所述氢溴酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.64±0.2°,7.20±0.2°,10.80±0.2°,11.39±0.2°,12.36±0.2°,14.52±0.2°,17.14±0.2°,18.07±0.2°,19.39±0.2°,21.70±0.2°,22.30±0.2°,23.18±0.2°,23.89±0.2°,25.38±0.2°,26.26±0.2°,29.15±0.2°,32.76±0.2°,36.92±0.2°,38.93±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a hydrobromide salt crystal form II of the compound of formula (I), characterized in that the hydrobromide salt crystal The X-ray powder diffraction pattern of Type II has diffraction peaks at the following 2 theta angles: 3.64 ± 0.2 °, 7.20 ± 0.2 °, 10.80 ± 0.2 °, 11.39 ± 0.2 °, 12.36 ± 0.2 °, 14.52 ± 0.2 °, 17.14 ± 0.2 °, 18.07±0.2°, 19.39±0.2°, 21.70±0.2°, 22.30±0.2°, 23.18±0.2°, 23.89±0.2°, 25.38±0.2°, 26.26±0.2°, 29.15±0.2°, 32.76±0.2 °, 36.92 ± 0.2 °, 38.93 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的氢溴酸盐晶型II，其特征在于，所述氢溴酸盐晶型II具有基本上如图2所示的X射线粉末衍射图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a hydrobromide salt crystal form II of the compound of formula (I), characterized in that the hydrobromide salt crystal Type II has an X-ray powder diffraction pattern substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.79±0.2°,13.08±0.2°,17.00±0.2°,20.52±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal The X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.79 ± 0.2 °, 13.08 ± 0.2 °, 17.00 ± 0.2 °, 20.52 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.79±0.2°,10.22±0.2°,13.08±0.2°,13.59±0.2°,17.00±0.2°,20.52±0.2°,20.67±0.2°,22.74±0.2°,23.06±0.2°,25.55±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal The X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.79 ± 0.2 °, 10.22 ± 0.2 °, 13.08 ± 0.2 °, 13.59 ± 0.2 °, 17.00 ± 0.2 °, 20.52 ± 0.2 °, 20.67 ± 0.2 °, 22.74 ± 0.2 °, 23.06 ± 0.2 °, 25.55 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.79±0.2°,8.09±0.2°,8.83±0.2°,9.54±0.2°,10.22±0.2°,11.26±0.2°,13.08±0.2°,13.59±0.2°,14.35±0.2°,16.13±0.2°,17.00±0.2°,17.80±0.2°,18.50±0.2°,19.20±0.2°,20.52±0.2°,20.67±0.2°,20.90±0.2°,21.87±0.2°,22.17±0.2°,22.74±0.2°,23.06±0.2°,23.58±0.2°,23.91±0.2°,24.58±0.2°,25.55±0.2°,26.31±0.2°,27.17±0.2°,27.53±0.2°,27.83±0.2°,28.13±0.2°,28.84±0.2°,29.24±0.2°,29.92±0.2°,30.20±0.2°,30.50±0.2°,31.49±0.2°,33.01±0.2°,33.99±0.2°,35.28±0.2°,37.63±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal The X-ray powder diffraction pattern of Form I has diffraction peaks at the following 2 theta angles: 6.79 ± 0.2 °, 8.09 ± 0.2 °, 8.83 ± 0.2 °, 9.54 ± 0.2 °, 10.22 ± 0.2 °, 11.26 ± 0.2 °, 13.08 ± 0.2 °, 13.59±0.2°, 14.35±0.2°, 16.13±0.2°, 17.00±0.2°, 17.80±0.2°, 18.50±0.2°, 19.20±0.2°, 20.52±0.2°, 20.67±0.2°, 20.90±0.2 °, 21.87±0.2°, 22.17±0.2°, 22.74±0.2°, 23.06±0.2°, 23.58±0.2°, 23.91±0.2°, 24.58±0.2°, 25.55±0.2°, 26.31±0.2°, 27.17±0.2 °,27.53±0.2°, 27.83±0.2°, 28.13±0.2°, 28.84±0.2°, 29.24±0.2°, 29.92±0.2°, 30.20±0.2°, 30.50±0.2°, 31.49±0.2°, 33.01±0.2 °, 33.99 ± 0.2 °, 35.28 ± 0.2 °, 37.63 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I具有基本上如图3所示的X射线粉末衍射图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal Type I has an X-ray powder diffraction pattern substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I的差示扫描量热图包含180.99℃±3℃的吸热峰。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal The differential scanning calorimetry of Form I contains an endothermic peak at 180.99 °C ± 3 °C.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I具有基本上如图4所示的差示扫描量热图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form I of the compound of formula (I), characterized in that the benzene sulfonate crystal Type I has a differential scanning calorimetry diagram substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：9.49±0.2°,16.48±0.2°,17.20±0.2°,18.37±0.2°,19.21±0.2°,32.91±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal The X-ray powder diffraction pattern of Form II has diffraction peaks at the following 2 theta angles: 9.49 ± 0.2 °, 16.48 ± 0.2 °, 17.20 ± 0.2 °, 18.37 ± 0.2 °, 19.21 ± 0.2 °, 32.91 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：7.23±0.2°,9.29±0.2°,9.49±0.2°,16.48±0.2°,17.20±0.2°,18.37±0.2°,19.21±0.2°,19.82±0.2°,28.79±0.2°,29.52±0.2°,32.91±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal The X-ray powder diffraction pattern of Type II has diffraction peaks at the following 2 theta angles: 7.23 ± 0.2 °, 9.29 ± 0.2 °, 9.49 ± 0.2 °, 16.48 ± 0.2 °, 17.20 ± 0.2 °, 18.37 ± 0.2 °, 19.21 ± 0.2 °, 19.82 ± 0.2 °, 28.79 ± 0.2 °, 29.52 ± 0.2 °, 32.91 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.32±0.2°,5.73±0.2°,7.23±0.2°,8.91±0.2°,9.29±0.2°,9.49±0.2°,9.88±0.2°,13.26±0.2°,13.57±0.2°,14.88±0.2°,15.51±0.2°,15.80±0.2°,16.48±0.2°,17.20±0.2°,17.82±0.2°,18.37±0.2°,19.21±0.2°,19.82±0.2°, 20.77±0.2°,21.28±0.2°,21.68±0.2°,22.29±0.2°,23.47±0.2°,23.82±0.2°,24.49±0.2°,25.88±0.2°,27.13±0.2°,27.71±0.2°,28.79±0.2°,29.52±0.2°,29.95±0.2°,32.12±0.2°,32.91±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal The X-ray powder diffraction pattern of Type II has diffraction peaks at the following 2 theta angles: 5.32 ± 0.2 °, 5.73 ± 0.2 °, 7.23 ± 0.2 °, 8.91 ± 0.2 °, 9.29 ± 0.2 °, 9.49 ± 0.2 °, 9.88 ± 0.2 °, 13.26±0.2°, 13.57±0.2°, 14.88±0.2°, 15.51±0.2°, 15.80±0.2°, 16.48±0.2°, 17.20±0.2°, 17.82±0.2°, 18.37±0.2°, 19.21±0.2 °, 19.82 ± 0.2 °, 20.77±0.2°, 21.28±0.2°, 21.68±0.2°, 22.29±0.2°, 23.47±0.2°, 23.82±0.2°, 24.49±0.2°, 25.88±0.2°, 27.13±0.2°, 27.71±0.2°, 28.79 ± 0.2 °, 29.52 ± 0.2 °, 29.95 ± 0.2 °, 32.12 ± 0.2 °, 32.91 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II具有基本上如图5所示的X射线粉末衍射图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal Type II has an X-ray powder diffraction pattern substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II的差示扫描量热图包含159.45℃±3℃的吸热峰。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal The differential scanning calorimetry of Form II contains an endothermic peak at 159.45 °C ± 3 °C.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II具有基本上如图6所示的差示扫描量热图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form II of the compound of formula (I), characterized in that the benzene sulfonate crystal Type II has a differential scanning calorimetry diagram substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.73±0.2°,7.40±0.2°,11.12±0.2°,14.85±0.2°,19.05±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal The X-ray powder diffraction pattern of Form III has diffraction peaks at the following 2 theta angles: 3.73 ± 0.2 °, 7.40 ± 0.2 °, 11.12 ± 0.2 °, 14.85 ± 0.2 °, 19.05 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.73±0.2°,7.40±0.2°,11.12±0.2°,14.85±0.2°,16.63±0.2°,19.05±0.2°,20.24±0.2°,20.75±0.2°,22.44±0.2°,25.95±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal The X-ray powder diffraction pattern of Type III has diffraction peaks at the following 2 theta angles: 3.73 ± 0.2 °, 7.40 ± 0.2 °, 11.12 ± 0.2 °, 14.85 ± 0.2 °, 16.63 ± 0.2 °, 19.05 ± 0.2 °, 20.24 ± 0.2 °, 20.75 ± 0.2 °, 22.44 ± 0.2 °, 25.95 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.73±0.2°,7.40±0.2°,8.10±0.2°,9.14±0.2°,9.79±0.2°,11.12±0.2°,12.02±0.2°,14.53±0.2°,14.85±0.2°,15.70±0.2°,16.63±0.2°,17.11±0.2°,17.87±0.2°,19.05±0.2°,20.24±0.2°,20.75±0.2°,21.45±0.2°,21.87±0.2°,22.44±0.2°,23.36±0.2°,25.95±0.2°,26.36±0.2°,29.24±0.2°,37.70±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal The X-ray powder diffraction pattern of Type III has diffraction peaks at the following 2 theta angles: 3.73 ± 0.2 °, 7.40 ± 0.2 °, 8.10 ± 0.2 °, 9.14 ± 0.2 °, 9.79 ± 0.2 °, 11.12 ± 0.2 °, 12.02 ± 0.2 °, 14.53±0.2°, 14.85±0.2°, 15.70±0.2°, 16.63±0.2°, 17.11±0.2°, 17.87±0.2°, 19.05±0.2°, 20.24±0.2°, 20.75±0.2°, 21.45±0.2 °, 21.87±0.2°, 22.44±0.2°, 23.36±0.2°, 25.95±0.2°, 26.36±0.2°, 29.24±0.2°, 37.70±0.2°.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III具有基本上如图7所示的X射线粉末衍射图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal Type III has an X-ray powder diffraction pattern substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的差示扫描量热图包含96.67℃±3℃的吸热峰。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal The differential scanning calorimetry of Form III contains an endothermic peak at 96.67 °C ± 3 °C.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的差示扫描量热图包含140.76℃±3℃的吸热峰。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal The differential scanning calorimetry of Form III contains an endothermic peak at 140.76 °C ± 3 °C.
在另一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的差示扫描量热图包含96.67℃±3℃和140.76℃±3℃的吸热峰。In other embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the besylate salt The differential scanning calorimetry of Form III contains an endothermic peak at 96.67 °C ± 3 °C and 140.76 °C ± 3 °C.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III具有基本上如图8所示的差示扫描量热图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a benzenesulfonate salt form III of the compound of formula (I), characterized in that the benzene sulfonate crystal Type III has a differential scanning calorimetry diagram substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的苯磺酸盐无定形，其特征在于，所述苯磺酸盐无定形具有基本上如图9所示的X射线粉末衍射图。In some embodiments, the acid addition salt of the present invention, wherein the salt is amorphous to the besylate salt of the compound of formula (I), characterized in that the besylate salt is amorphous There is an X-ray powder diffraction pattern substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：8.96±0.2°,9.97±0.2°,12.67±0.2°,17.91±0.2°,26.77±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the β-naphthalene The X-ray powder diffraction pattern of the sulfonate crystal form I has diffraction peaks at the following 2 theta angles: 8.96 ± 0.2 °, 9.97 ± 0.2 °, 12.67 ± 0.2 °, 17.91 ± 0.2 °, 26.77 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：8.96±0.2°,9.97±0.2°,12.67°±0.2,13.45±0.2°,17.91±0.2°,20.08±0.2°,22.22±0.2°,26.77±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the β-naphthalene The X-ray powder diffraction pattern of the sulfonate crystal form I has diffraction peaks at the following 2 theta angles: 8.96 ± 0.2 °, 9.97 ± 0.2 °, 12.67 ° ± 0.2, 13.45 ± 0.2 °, 17.91 ± 0.2 °, 20.08 ± 0.2 ° , 22.22 ± 0.2 °, 26.77 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶 型I，其特征在于，所述β-萘磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.50±0.2°,6.35±0.2°,7.06±0.2°,8.43±0.2°,8.96±0.2°,9.97±0.2°,11.92±0.2°,12.67±0.2°,13.45±0.2°,13.78±0.2°,14.16±0.2°,14.75±0.2°,15.80±0.2°,16.12±0.2°,16.74±0.2°,16.91±0.2°,17.91±0.2°,18.64±0.2°,19.05±0.2°,19.52±0.2°,20.08±0.2°,20.65±0.2°,22.22±0.2°,22.51±0.2°,22.75±0.2°,23.17±0.2°,23.73±0.2°,23.99±0.2°,24.42±0.2°,25.23±0.2°,25.59±0.2°,26.01±0.2°,26.77±0.2°,27.06±0.2°,27.79±0.2°,30.09±0.2°,31.14±0.2°,31.71±0.2°,31.92±0.2°,35.25°±0.2,36.14±0.2°,37.15±0.2°,38.22±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal of the compound of formula (I) Form I, characterized in that the X-ray powder diffraction pattern of the β-naphthalenesulfonate crystal form I has diffraction peaks at the following 2θ angles: 4.50±0.2°, 6.35±0.2°, 7.06±0.2°, 8.43± 0.2°, 8.96±0.2°, 9.97±0.2°, 11.92±0.2°, 12.67±0.2°, 13.45±0.2°, 13.78±0.2°, 14.16±0.2°, 14.75±0.2°, 15.80±0.2°, 16.12± 0.2°, 16.74±0.2°, 16.91±0.2°, 17.91±0.2°, 18.64±0.2°, 19.05±0.2°, 19.52±0.2°, 20.08±0.2°, 20.65±0.2°, 22.22±0.2°, 22.51± 0.2°, 22.75±0.2°, 23.17±0.2°, 23.73±0.2°, 23.99±0.2°, 24.42±0.2°, 25.23±0.2°, 25.59±0.2°, 26.01±0.2°, 26.77±0.2°, 27.06± 0.2°, 27.79±0.2°, 30.09±0.2°, 31.14±0.2°, 31.71±0.2°, 31.92±0.2°, 35.25°±0.2, 36.14±0.2°, 37.15±0.2°, 38.22±0.2°.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I具有基本上如图10所示的X射线粉末衍射图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the β-naphthalene The sulfonate crystal form I has an X-ray powder diffraction pattern substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I的差示扫描量热图包含163.92℃±3℃的吸热峰。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the β-naphthalene The differential scanning calorimetry of the sulfonate Form I contains an endothermic peak at 163.92 °C ± 3 °C.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I的差示扫描量热图包含220.42℃±3℃的吸热峰。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the β-naphthalene The differential scanning calorimetry of the sulfonate Form I contains an endothermic peak at 220.42 °C ± 3 °C.
在另一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I的差示扫描量热图包含163.92℃±3℃和220.42℃±3℃的吸热峰。In another embodiment, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the β- The differential scanning calorimetry of naphthalenesulfonate Form I comprises an endothermic peak at 163.92 °C ± 3 °C and 220.42 °C ± 3 °C.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I具有基本上如图11所示的差示扫描量热图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form I of the compound of formula (I), characterized in that the β-naphthalene The sulfonate crystal form I has a differential scanning calorimetry diagram substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.43±0.2°,13.60±0.2°,19.41±0.2°,19.62±0.2°,21.50±0.2°,22.45±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the β-naphthalene The X-ray powder diffraction pattern of the sulfonate crystal form II has diffraction peaks at the following 2 theta angles: 6.43 ± 0.2 °, 13.60 ± 0.2 °, 19.41 ± 0.2 °, 19.62 ± 0.2 °, 21.50 ± 0.2 °, 22.45 ± 0.2 ° .
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.43±0.2°,13.60±0.2°,16.75±0.2°,16.95±0.2°,19.41±0.2°,19.62±0.2°,19.97±0.2°,20.65±0.2°,21.50±0.2°,21.82±0.2°,22.45±0.2°,25.97±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the β-naphthalene The X-ray powder diffraction pattern of the sulfonate crystal form II has diffraction peaks at the following 2 theta angles: 6.43 ± 0.2 °, 13.60 ± 0.2 °, 16.75 ± 0.2 °, 16.95 ± 0.2 °, 19.41 ± 0.2 °, 19.62 ± 0.2 ° , 19.97 ± 0.2 °, 20.65 ± 0.2 °, 21.50 ± 0.2 °, 21.82 ± 0.2 °, 22.45 ± 0.2 °, 25.97 ± 0.2 °.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.43±0.2°,8.10±0.2°,9.15±0.2°,9.73±0.2°,10.57±0.2°,12.64±0.2°,12.90±0.2°,13.60±0.2°,16.04±0.2°,16.26±0.2°,16.75±0.2°,16.95±0.2°,17.43±0.2°,17.90±0.2°,18.37±0.2°,19.41±0.2°,19.62±0.2°,19.97±0.2°,20.65±0.2°,21.50±0.2°,21.82±0.2°,22.07±0.2°,22.45±0.2°,23.32±0.2°,24.11±0.2°,24.82±0.2°,25.70±0.2°,25.97±0.2°,26.49±0.2°,27.17±0.2°,27.50±0.2°,28.04±0.2°,28.62±0.2°,29.55±0.2°,29.96±0.2°,30.49±0.2°,31.17±0.2°,32.10±0.2°,33.52±0.2°,34.53±0.2°,35.38±0.2°,36.03±0.2°,36.99±0.2°,38.19±0.2°,39.50±0.2°。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the β-naphthalene The X-ray powder diffraction pattern of the sulfonate type II has diffraction peaks at the following 2 theta angles: 6.43 ± 0.2 °, 8.10 ± 0.2 °, 9.15 ± 0.2 °, 9.73 ± 0.2 °, 10.57 ± 0.2 °, 12.64 ± 0.2 °, 12.90±0.2°, 13.60±0.2°, 16.04±0.2°, 16.26±0.2°, 16.75±0.2°, 16.95±0.2°, 17.43±0.2°, 17.90±0.2°, 18.37±0.2°, 19.41±0.2°, 19.62±0.2°, 19.97±0.2°, 20.65±0.2°, 21.50±0.2°, 21.82±0.2°, 22.07±0.2°, 22.45±0.2°, 23.32±0.2°, 24.11±0.2°, 24.82±0.2°, 25.70±0.2°, 25.97±0.2°, 26.49±0.2°, 27.17±0.2°, 27.50±0.2°, 28.04±0.2°, 28.62±0.2°, 29.55±0.2°, 29.96±0.2°, 30.49±0.2°, 31.17±0.2°, 32.10±0.2°, 33.52±0.2°, 34.53±0.2°, 35.38±0.2°, 36.03±0.2°, 36.99±0.2°, 38.19±0.2°, 39.50±0.2°.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II具有基本上如图12所示的X射线粉末衍射图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the β-naphthalene The sulfonate Form II has an X-ray powder diffraction pattern substantially as shown in FIG.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II的差示扫描量热图包含221.99℃±3℃的吸热峰。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the β-naphthalene The differential scanning calorimetry of the sulfonate Form II contains an endothermic peak at 221.99 °C ± 3 °C.
在一些实施例中，本发明所述的酸加成盐，其中，所述的盐为式(I)所示化合物的β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II具有基本上如图13所示的差示扫描量热图。In some embodiments, the acid addition salt of the present invention, wherein the salt is a β-naphthalene sulfonate crystal form II of the compound of formula (I), characterized in that the β-naphthalene The sulfonate Form II has a differential scanning calorimetry diagram substantially as shown in FIG.
一方面，本发明还提供一种药物组合物，其包含式(I)化合物的任意一种酸加成盐或它们的组合； 所述药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。在一些实施例中，本发明所述药物组合物中的酸加成盐可以为所述盐的任意一种结晶形式，具体可以为所述盐的任意一种晶型、无定形或它们的任意组合。在一些实施例中，本发明所述药物组合物包含式(I)所示化合物的任意一种酸加成盐、或本发明所述的任意一种晶型或无定形、或所述盐、晶型和无定形的任意组合。In one aspect, the present invention also provides a pharmaceutical composition comprising any one of the acid addition salts of the compound of formula (I) or a combination thereof; The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or a combination thereof. In some embodiments, the acid addition salt in the pharmaceutical composition of the present invention may be in any one of the crystalline forms of the salt, and may be any crystal form, amorphous or any of the salts. combination. In some embodiments, the pharmaceutical composition of the present invention comprises any one of the acid addition salts of the compound of formula (I), or any of the crystal forms or amorphous forms, or the salts, Any combination of crystal form and amorphous form.
另一方面，本发明还涉及所述式(I)化合物的酸加成盐或所述药物组合物在制备药物中的用途，其中，所述药物用于预防、治疗或减轻人或动物的组织或器官纤维化疾病。进一步地，所述用途包括给予人或动物本发明所述的酸加成盐或所述的药物组合物的有效治疗剂量。In another aspect, the invention relates to an acid addition salt of a compound of formula (I) or the use of said pharmaceutical composition for the preparation of a medicament, wherein said medicament is for preventing, treating or ameliorating tissue of a human or animal Or organ fibrosis. Further, the use comprises administering to a human or animal an acid addition salt of the invention or an effective therapeutic dose of the pharmaceutical composition.
在一些实施方案中，本发明所述的组织或器官纤维化疾病为肾间质纤维化、肾小球硬化、肝纤维化、肺纤维化、腹膜纤维化、心肌纤维化、皮肤纤维化、手术后粘连、良性***肥大症、骨骼肌纤维化、硬皮病、多发性硬化症，胰腺纤维化，肝硬化，肌肉瘤，神经纤维瘤，肺间质纤维化，糖尿病肾病，阿尔茨海默病或血管纤维化疾病。In some embodiments, the tissue or organ fibrotic disease of the present invention is renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, cutaneous fibrosis, surgery Post-adhesion, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myoma, neurofibroma, pulmonary fibrosis, diabetic nephropathy, Alzheimer's disease or Vascular fibrosis disease.
在另一些实施例中，本发明的肺纤维化包括特发性肺纤维化(IPF)。In other embodiments, the pulmonary fibrosis of the invention comprises idiopathic pulmonary fibrosis (IPF).
在另一些实施例中，本发明所述的手术后粘连是指疤痕愈合。In other embodiments, post-operative adhesion as described herein refers to scar healing.
本发明还涉及所述式(I)化合物的酸加成盐或所述药物组合物在制备药物中的用途，其中，所述药物用于预防、治疗或减轻患者的糖尿病肾病或阿尔茨海默病。The invention further relates to an acid addition salt of the compound of the formula (I) or the use of the pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of diabetic nephropathy or Alzheimer's disease in a patient disease.
本发明一方面涉及预防、治疗或减轻患者组织或器官纤维化疾病的方法，包括使用本发明所述的酸加成盐或所述的药物组合物药学上可接受的有效剂量对患者进行给药。One aspect of the invention relates to a method of preventing, treating or ameliorating a fibrotic disease of a tissue or organ of a patient comprising administering to the patient an acid addition salt of the invention or a pharmaceutically acceptable effective amount of said pharmaceutical composition .
本发明另一方面涉及所述式(I)化合物的酸加成盐或所述药物组合物用于预防、治疗或减轻人或动物的组织或器官纤维化疾病。Another aspect of the invention relates to an acid addition salt of the compound of formula (I) or a pharmaceutical composition for preventing, treating or ameliorating a tissue or organ fibrotic disease in a human or animal.
另一方面，本发明还涉及式(I)所示化合物的酸加成盐及其晶型的制备方法。In another aspect, the invention relates to an acid addition salt of a compound of formula (I) and a process for the preparation thereof.
本发明所述的酸加成盐的晶型可以通过常规的制备方法制备得到，其中，本发明中某些晶型还可以通过晶型转变的方法制备得到。The crystal form of the acid addition salt of the present invention can be produced by a conventional preparation method, and some of the crystal forms of the present invention can also be produced by a crystal transformation method.
本发明所述的无定形可以通过喷雾干燥的方法制备得到。本发明所述的喷雾干燥制备无定形的产率受仪器进风口温度、出风口温度、喷雾过程中体系压力等因素的影响，而进风口温度、出风口温度、喷雾过程中体系压力等与仪器的型号、所使用的溶剂等因素相关。The amorphous form of the present invention can be prepared by a spray drying method. The amorphous yield of the spray drying preparation according to the present invention is affected by factors such as the temperature of the air inlet of the instrument, the temperature of the air outlet, the pressure of the system during the spraying process, and the temperature of the air inlet, the temperature of the air outlet, the pressure of the system during the spraying process, and the like. The model number, the solvent used, and other factors are relevant.
本发明所述的盐、晶型或无定形的制备方法中所使用的溶剂没有特别限制，任何在程度上能溶解起始原料并且不影响其性质的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。本发明给出了各反应步骤所使用的较佳的溶剂。The solvent used in the salt, crystal form or amorphous preparation method of the present invention is not particularly limited, and any solvent which can dissolve the starting material to a certain extent and does not affect its properties is included in the present invention. In addition, many variations, equivalents, or equivalents to the solvents, solvent combinations, and solvent combinations described herein are considered to be within the scope of the invention. The present invention provides preferred solvents for use in the various reaction steps.
本发明所述的盐的制备实验将在实施例部分进行了详细描述。同时，本发明提供了所述盐的活性测试实验(如药代动力学实验)、溶解度实验、稳定性实验和引湿性实验等。由实验结果可知，本发明所述的晶盐具有较好的生物活性(例如，较好的药代动力学性质)，且其溶解性好，稳定性高，适合制药用途。The preparation of the salts of the present invention will be described in detail in the Examples section. Meanwhile, the present invention provides activity testing experiments (such as pharmacokinetic experiments), solubility experiments, stability experiments, and wettability experiments of the salts. It can be seen from the experimental results that the crystalline salt of the present invention has good biological activity (for example, good pharmacokinetic properties), and has good solubility and high stability, and is suitable for pharmaceutical use.
其中，关于引湿性特征描述与引湿性增重的界定(中国药典2015年版附录9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％±2％相对湿度)如下表所述：Among them, the definition of wettability and the definition of wet weight gain (Chinese Pharmacopoeia 2015 edition Appendix 9103 guidelines for drug wettability test, experimental conditions: 25 ° C ± 1 ° C, 80% ± 2% relative humidity) are as follows:
引湿性特征描述与引湿性增重的界定Determining the characteristics of wettability and the definition of wettability
Figure PCTCN2017094409-appb-000003
Figure PCTCN2017094409-appb-000003
Figure PCTCN2017094409-appb-000004
Figure PCTCN2017094409-appb-000004
本发明所述的盐不易受高湿度影响而潮解，方便药物的长期贮存放置。The salt of the invention is not easily affected by high humidity and deliquesces, and facilitates long-term storage placement of the drug.
本发明所述的盐或其药物组合物的毒副作用小。发明人在实验中发现，根据本发明所述盐或其药物组合物在犬中的毒副作用小，该毒副作用包括引起呕吐等副作用。The salt of the present invention or a pharmaceutical composition thereof has a small toxic side effect. The inventors have found in experiments that the salt or a pharmaceutical composition thereof according to the present invention has a small toxic side effect in dogs, and the side effects include side effects such as vomiting.
定义和一般术语Definitions and general terms
除非另有说明，本发明使用的所有技术和科学术语与本发明所属领域的普通技术人员所通常理解的具有相同含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。尽管在本发明的实践或者测试中可以使用与本发明所述相似或者相同的任何方法和物质，但是本发明中描述的是优选的方法、设备和物质。Unless otherwise indicated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described in the present invention.
“药学上可接受的酸加成盐”是指本发明式(I)所示化合物与药学上可接受的无毒的酸形成的盐，包括但不限于本发明所述的各种有机酸盐和无机酸盐。"Pharmaceutically acceptable acid addition salt" means a salt of a compound of formula (I) of the present invention with a pharmaceutically acceptable non-toxic acid, including but not limited to the various organic acid salts described herein. And inorganic acid salts.
“式(I)所示化合物的酸加成盐”是指式(I)所示化合物(游离碱)与各种适合的有机酸或无机酸反应形成的盐，包括但不限于本发明所述的盐酸盐、氢溴酸盐、硫酸盐、马来酸盐、苯磺酸盐、对甲苯磺酸盐、β-萘磺酸盐、草酸盐、甲磺酸盐等。其中，所述的“式(I)所示化合物的酸加成盐”包括该盐的无定形形式或结晶形式，包括其溶剂化物形式(例如，水合物形式)，还包括该盐的多晶型形式。例如，式(I)所示化合物的苯磺酸盐包括该类盐的无定形形式、各种结晶形式、各种溶剂化物、各种水合物，还包括该类盐的多晶型形式。The "acid addition salt of the compound of the formula (I)" means a salt formed by reacting a compound of the formula (I) (free base) with various suitable organic or inorganic acids, including but not limited to the present invention. Hydrochloride, hydrobromide, sulfate, maleate, benzenesulfonate, p-toluenesulfonate, beta-naphthalenesulfonate, oxalate, methanesulfonate, and the like. Wherein the "acid addition salt of the compound of the formula (I)" includes an amorphous form or a crystalline form of the salt, including a solvate form thereof (for example, a hydrate form), and a polycrystal of the salt. Type form. For example, the besylate salt of the compound of formula (I) includes amorphous forms of such salts, various crystalline forms, various solvates, various hydrates, and polymorphic forms of such salts.
“晶型”或“结晶形式”是指具有高度规则化学结构的固体，包括，但不限于，单组分或者多组分晶体，和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。物质的结晶形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，熔体结晶、熔体冷却、溶剂结晶、在限定的空间中结晶，例如，在纳米孔或者毛细管中，在表面或者模板上结晶，例如，在聚合物上，在添加剂如共结晶反分子的存在下结晶、去溶剂、脱水、快速蒸发、快速冷却、缓慢冷却、蒸气扩散、升华、反应结晶、反溶剂添加、研磨和溶剂滴研磨等。"Form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, one-component or multi-component crystals, and/or polymorphs, solvates, hydrates, A clathrate, a eutectic, a salt, a solvate of a salt, or a hydrate of a salt. The crystalline form of the material can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, for example, in a nanopore or capillary, crystallization on a surface or template, for example, on a polymer, Crystallization, solvent removal, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding, and solvent drip grinding in the presence of additives such as co-crystallized antimolecules.
“无定形”或“无定形形式”是指物质的质点(分子、原子、离子)在三维空间排列无周期性时形成的物质，其特征是具有漫射的不具尖峰的X射线粉末衍射图。无定形是固体物质的一种特殊的物理形式，其局部有序的结构特征，提示其与晶型物质有着千丝万缕的联系。物质的无定形形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，骤冷法、反溶剂絮凝法、球磨法、喷雾干燥法、冷冻干燥法、湿法制粒法和固体分散体技术等等。"Amorphous" or "amorphous form" refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and is characterized by having a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter, and its local ordered structural features suggest that it is inextricably linked with crystalline materials. The amorphous form of the material can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, solid dispersion techniques, and the like.
“溶剂”是指一种物质(典型地是一种液体)，该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于，水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。"Solvent" means a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol. , ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, Methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof and the like.
“反溶剂”是指促进产物(或产物前体)从溶剂中沉淀的流体。反溶剂可以包括冷气体、或通过化学反应促进沉淀的流体、或降低产物在溶剂中的溶解度的流体；其可以是与溶剂相同的液体但是处于不同温度，或者它可以是与溶剂不同的液体。"Antisolvent" refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent. The anti-solvent may include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in a solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a liquid different from the solvent.
“溶剂化物”是指在表面上、在晶格中或者在表面上和在晶格中具有溶剂的化合物，所述溶剂可以是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲 醇、甲基乙基酮、甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、吡啶、四氢呋喃、甲苯、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、在晶格中或者在表面上和在晶格中的溶剂是水。在物质的表面上、在晶格中或者在表面上和在晶格中，水合物可以具有或者不具有除了水以外的其它溶剂。"Solvate" means a compound having a solvent on a surface, in a crystal lattice or on a surface, and in a crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, Dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethyl Amide, formamide, formic acid, heptane, hexane, isopropanol, A Alcohol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof and the like. A specific example of a solvate is a hydrate in which the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrate may or may not have a solvent other than water on the surface of the substance, in the crystal lattice or on the surface and in the crystal lattice.
晶型或无定形可以通过多种技术手段进行鉴别，例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。Crystalline or amorphous can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA). ), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolved calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施方案中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本试验所用仪器状况，衍射峰存在±0.2°的误差容限。X-ray powder diffraction (XRPD) can detect crystal form changes, crystallinity, crystal state and other information, and is a common means of identifying crystal forms. The peak position of the XRPD pattern depends primarily on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystalline form of the invention is characterized by an XRPD pattern having certain peak positions substantially as shown in the XRPD pattern provided in the figures of the present invention. At the same time, the 2θ measure of the XRPD pattern may have experimental errors. The 2θ measure of the XRPD pattern may be slightly different between different instruments and different samples, so the value of 2θ cannot be considered absolute. According to the condition of the instrument used in this test, the diffraction peak has an error tolerance of ±0.2°.
差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al2O3)之间的能量差随温度变化的一种技术。DSC曲线的熔化峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本试验所用仪器状况，熔化峰存在±3°的误差容限。Differential Scanning Calorimetry (DSC) is a technique in which the energy difference between a sample and an inert reference (usually α-Al 2 O 3 ) is measured as a function of temperature by continuous heating or cooling under program control. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC pattern having a characteristic peak position substantially as shown in the DSC chart provided in the figures of the present invention. At the same time, the DSC spectrum can have experimental errors. The peak position and peak value of the DSC spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the condition of the instrument used in this test, the melting peak has an error tolerance of ±3°.
差示扫描量热(DSC)还可用于检测分析晶型是否有转晶或混晶现象。Differential Scanning Calorimetry (DSC) can also be used to detect the presence or absence of crystallisation or crystal mixing.
化学组成相同的固体，在不同的热力学条件下，常会形成晶体结构不同的同质异构体，或称为变体，这种现象称为同质多晶或同质多相现象。当温度和压力条件变化时，变体之间会发生相互转变，此现象称为晶型转变。由于晶型转变，晶体的力学、电学、磁学等性能会发生巨大的变化。当晶型转变的温度在可测范围内时，在差示扫描量热(DSC)图上可观察到这一转变过程，其特征在于，DSC图具有反映这一转变过程的放热峰，同时具有两个或多个吸热峰，分别为转变前后的不同晶型的特征吸热峰。Solids with the same chemical composition often form homoisomers with different crystal structures, or variants, under different thermodynamic conditions. This phenomenon is called homopoly or homogeneous multiphase. When temperature and pressure conditions change, mutual transformation occurs between the variants. This phenomenon is called crystal transformation. Due to the crystal transformation, the mechanical, electrical, magnetic and other properties of the crystal will change greatly. When the temperature of the crystal transition is within the measurable range, this transition process can be observed on a differential scanning calorimetry (DSC) map, characterized in that the DSC map has an exothermic peak reflecting this transition process, and There are two or more endothermic peaks, which are characteristic endothermic peaks of different crystal forms before and after the transition.
热重分析(TGA)是在程序控制下，测定物质的质量随温度变化的一种技术，适用于检查晶体中溶剂的丧失或样品升华、分解的过程，可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间，TGA检测的质量变化略有差别。本发明所述的无定形的特征在于TGA检测的失重范围为1.75％-4.10％。根据本试验所用的仪器状况，质量变化存在±0.1％的误差容限。Thermogravimetric analysis (TGA) is a technique for determining the mass of a substance as a function of temperature under program control. It is suitable for checking the loss of solvent in a crystal or the process of sublimation and decomposition of a sample. It is speculated that crystal water or crystal solvent is contained in the crystal. Case. The quality of the TGA curve shows changes depending on many factors such as sample preparation and instrumentation; the quality of the TGA test varies slightly between different instruments and between samples. The amorphous feature of the present invention is characterized in that the weight loss range of the TGA test is from 1.75% to 4.10%. According to the condition of the instrument used in this test, the quality variation has a margin of error of ±0.1%.
拉曼光谱(Roman)是用来研究分子的振动模式、旋转模式和在一***里的其他低频模式的一种分光技术。同一分子的不同空间结构(不同晶型或无定形)，具有不同的拉曼活性，因此应用拉曼光谱可以测定和鉴别晶型或无定形。拉曼光谱的峰位置主要与物质的结构相关，对于实验细节相对不敏感，而峰强度取决于样品的制备和仪器等因素。因而，本发明的晶型或无定形的特征在于具有特征峰位置的拉曼光谱图，其基本上如本发明附图中提供的拉曼光谱图所示。同时，拉曼光谱可以有实验误差，不同仪器以及不同样品之间，拉曼光谱的峰位置和峰值可能会略有差别，因此所述拉曼光谱的峰位置或峰强度的数值不能视为绝对的。根据本试验所用仪器状况，吸收峰存在±2cm-1的误差容限。Raman spectroscopy (Roman) is a spectroscopic technique used to study the vibration modes, rotation modes, and other low-frequency modes in a system. Different spatial structures of the same molecule (different crystal forms or amorphous) have different Raman activities, so Raman spectroscopy can be used to determine and identify crystal forms or amorphous forms. The peak position of the Raman spectrum is mainly related to the structure of the material, and is relatively insensitive to experimental details, and the peak intensity depends on factors such as sample preparation and instrumentation. Thus, the crystalline form or amorphous form of the present invention is characterized by a Raman spectrum having a characteristic peak position substantially as shown in the Raman spectrum provided in the drawings of the present invention. At the same time, the Raman spectrum can have experimental errors. The peak position and peak value of the Raman spectrum may be slightly different between different instruments and different samples. Therefore, the peak position or peak intensity of the Raman spectrum cannot be regarded as absolute. of. According to the condition of the instrument used in this test, the absorption peak has an error tolerance of ±2 cm -1 .
在同一分子的不同空间结构中，某些化学键的键长、键角会有所不同，致使其振动-转动跃迁能级不同，与其相应的红外光谱的某些主要特征如吸收带频率、峰形、峰位、峰强度等也会出现差异，因此红外光谱可用于药物多晶型研究。本发明的晶型或无定形的特征在于具有特征峰位置的傅里叶红外 (FT-IR)光谱图，其基本上如本发明附图中提供的傅里叶红外光谱图所示。同时，傅里叶红外光谱可以有实验误差，不同仪器以及不同样品之间，傅里叶红外光谱的峰位置和峰值可能会略有差别，因此所述傅里叶红外光谱的峰位置或峰强度的数值不能视为绝对的。根据本试验所用仪器状况，吸收峰存在±2cm-1的误差容限。In different spatial structures of the same molecule, the bond length and bond angle of some chemical bonds will be different, resulting in different vibration-rotation transition levels, and some of the main characteristics of the corresponding infrared spectrum such as absorption band frequency and peak shape. There are also differences in peak position, peak intensity, etc., so infrared spectroscopy can be used for drug polymorphism research. The crystalline form or amorphous form of the present invention is characterized by a Fourier infrared (FT-IR) spectrogram having a characteristic peak position, substantially as shown by the Fourier infrared spectrum provided in the drawings of the present invention. At the same time, Fourier infrared spectroscopy can have experimental errors. The peak position and peak value of Fourier infrared spectrum may be slightly different between different instruments and different samples, so the peak position or peak intensity of the Fourier infrared spectrum The value cannot be considered absolute. According to the condition of the instrument used in this test, the absorption peak has an error tolerance of ±2 cm -1 .
在本发明的上下文中，X-射线粉末衍射图中的2θ值均以度(°)为单位。In the context of the present invention, the 2θ values in the X-ray powder diffraction pattern are all in degrees (°).
术语“基本上如图所示”是指X-射线粉末衍射图或DSC图或拉曼光谱图或红外光谱图中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在其图中。The term "substantially as shown" means at least 50%, or at least 60%, or at least 70%, or at least 80%, or in an X-ray powder diffraction pattern or DSC pattern or Raman spectrum or infrared spectrum, or At least 90%, or at least 95%, or at least 99% of the peaks are shown in the figure.
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。When referring to a spectrum or/and data appearing in the figures, "peak" refers to a feature that can be identified by those skilled in the art that does not belong to background noise.
本发明涉及所述的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮的酸加成盐的各种新晶型，它们以基本上纯净的结晶形态存在。The present invention relates to various new crystal forms of the acid addition salt of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one They exist in a substantially pure crystalline form.
本发明还涉及所述的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮的各种酸加成盐的无定形，所述无定形可以通过喷雾干燥制备。The present invention also relates to the amorphous form of various acid addition salts of the 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one The amorphous form can be prepared by spray drying.
“基本上纯净的”是指一种晶型基本上不含另外一种或多种晶型，即晶型的纯度至少80％，或至少85％，或至少90％，或至少93％，或至少95％，或至少98％，或至少99％，或至少99.5％，或至少99.6％，或至少99.7％，或至少99.8％，或至少99.9％，或晶型中含有其它晶型，所述其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于3％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。"Substantially pure" means that one crystal form is substantially free of another one or more crystalline forms, ie, the crystalline form is at least 80% pure, or at least 85%, or at least 90%, or at least 93%, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or other crystalline forms in the crystalline form, The percentage of other crystalline forms in the total or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, Or less than 0.1%, or less than 0.01%.
“基本上不含”是指一种或多种其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于4％，或少于3％，或少于2％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。"Substantially free" means that the percentage of one or more other crystalline forms in the total or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
XRPD图中的“相对强度”(或“相对峰高”)是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。The "relative intensity" (or "relative peak height" in the XRPD pattern refers to the intensity of the other peaks when the intensity of the first strong peak among all the diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%. The ratio of the intensity of a strong peak.
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。In the context of the present invention, when used or whenever the words "about" or "about" are used, it means within 10% of a given value or range, suitably within 5%, especially within 1%. . Alternatively, the term "about" or "about" means within the acceptable standard error range of the average for those of ordinary skill in the art. Whenever a number with an N value is disclosed, any has N +/- 1%, N +/- 2%, N +/- 3%, N +/- 5%, N +/- 7%, N +/- 8% or N+ A number within the /-10% value will be explicitly disclosed, where "+/-" means plus or minus.
本发明中“室温”指的是温度由大约10℃到大约40℃。在一些实施例中，“室温”指的是温度由大约20℃到大约30℃；在另外一些实施例中，“室温”指的是20℃，22.5℃，25℃，27.5℃等等。"Room temperature" in the present invention means that the temperature is from about 10 ° C to about 40 ° C. In some embodiments, "room temperature" refers to a temperature of from about 20 ° C to about 30 ° C; in other embodiments, "room temperature" refers to 20 ° C, 22.5 ° C, 25 ° C, 27.5 ° C, and the like.
本发明化合物的酸加成盐的组合物，制剂，给药和用途Composition, formulation, administration and use of an acid addition salt of a compound of the invention
本发明的药物组合物的特点包括式(I)所示化合物的酸加成盐和药学上可接受的载体，辅剂，或赋形剂。本发明的药物组合物中化合物的酸加成盐的量能有效地可探测地治疗或减轻患者组织或器官纤维化的疾病。The pharmaceutical composition of the present invention is characterized by comprising an acid addition salt of a compound of the formula (I) and a pharmaceutically acceptable carrier, adjuvant, or excipient. The amount of the acid addition salt of the compound in the pharmaceutical composition of the present invention is effective to detectably reduce or alleviate the disease of tissue or organ fibrosis in a patient.
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的载体，辅剂，或赋形剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的载体 可应用于药学上可接-受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物或其酸加成盐不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999 , Marcel Dekker, New York, synthesizing the contents of this document, indicating different vectors Formulations for pharmaceutically acceptable compositions are accepted and their known methods of preparation. In addition to any conventional carrier medium incompatible with the compound of the present invention or an acid addition salt thereof, for example, any adverse biological effects produced or any other component of the pharmaceutically acceptable composition in a detrimental manner The resulting interactions, their use, are also contemplated by the present invention.
可作为药学上可接受载体的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。Substances which may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins such as human serum proteins; buffer substances such as phosphate; glycine; sorbic acid; Potassium acid; a partial glyceride mixture of saturated vegetable fatty acids; water; salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid Pyrogen-free water; isotonic salt; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; Clothing; sweeteners; flavoring agents; flavors; preservatives and antioxidants.
本发明的药物组合物可以是胶囊，片剂，丸剂，粉剂，粒剂和水制悬浮液或溶液；可以通入如下途径给药：口服给药，注射给药，喷雾吸入法，局部给药，经直肠给药，经鼻给药，含服给药，***给药或通过植入性药盒给药。The pharmaceutical composition of the present invention may be a capsule, a tablet, a pill, a powder, a granule and an aqueous suspension or solution; it may be administered by the following routes: oral administration, injection administration, spray inhalation, topical administration. , for rectal administration, nasal administration, buccal administration, vaginal administration or administration via an implantable kit.
口服给药可以用如下形式给药：片剂、丸剂、胶囊、可分散的粉末、颗粒或悬浮液、糖浆、和酏剂等；外用方式给药可以通过如下形式给药：软膏剂、凝胶、含药胶布等。Oral administration can be carried out in the form of tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs, and the like; topical administration can be carried out by the following forms: ointments, gels , containing drug tape, etc.
本发明药物组合物可以无菌可注射溶液或悬浮液形式进行非肠胃给药，也可肠胃外或腹腔内给药。也可在适当混合有表面活性剂(如羟丙基纤维素、聚乙烯吡咯烷酮)的水中制备这些活性化合物(作为游离碱或药学上可接受的盐)的溶液或悬浮液。还可在甘油、液体、聚乙二醇及其在油中的混合物中制备分散液。在常规储存和使用条件下，这些制剂中含有防腐剂以防止微生物生长。The pharmaceutical composition of the present invention can be administered parenterally in the form of a sterile injectable solution or suspension, or parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as free base or pharmaceutically acceptable salts) may also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose, polyvinylpyrrolidone. Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. These preparations contain preservatives to prevent microbial growth under normal conditions of storage and use.
适于注射的药物形式包括：无菌水溶液或分散液和无菌粉(用于临时制备无菌注射溶液或分散液)。在所有情况下，这些形式必须是无菌的且必须是流体以易于注射器排出流体。在制造和储存条件下必须是稳定的，且必须能防止微生物(如细菌和真菌)的污染影响。载体可以是溶剂或分散介质，其中含有如水、醇(如甘油、丙二醇和液态聚乙二醇)、它们的适当混合物和植物油。The pharmaceutical forms suitable for injection include: sterile aqueous solutions or dispersions and sterile powders (for the preparation of sterile injectable solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate the discharge of fluid from the syringe. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, an alcohol such as glycerol, propylene glycol, and liquid polyethylene glycol, suitable mixtures thereof, and vegetable oils.
本发明化合物或其盐或本发明的药物组合物可以以局部方式施用，而不以***方式施用。例如通常以稀释制剂或持续释放制剂的形式将化合物直接注射至器官内。此外，含有本发明化合物或其盐的药物组合物可以在靶向药物传递***中使用，例如在用器官特异性抗体包衣的脂质体重递送。所述脂质体将靶向所述器官并被该器官选择性摄取。此外，含有本发明化合物的组合物可以以快速释放制剂、延时释放制剂或即时释放制剂的形式提供。The compound of the present invention or a salt thereof or the pharmaceutical composition of the present invention can be administered in a localized manner without being administered in a systemic manner. For example, the compound is usually injected directly into the organ in the form of a diluted formulation or a sustained release formulation. Furthermore, pharmaceutical compositions containing a compound of the invention or a salt thereof can be used in a targeted drug delivery system, for example, in the weight of a lipid coated with an organ-specific antibody. The liposomes will target the organ and be selectively taken up by the organ. Furthermore, compositions containing a compound of the invention may be provided in the form of a rapid release formulation, a time release formulation or a ready release formulation.
对于吸入施用，本发明的化合物或其盐可以是气溶胶、气雾剂或粉末形式。本发明化合物或其盐的药物组合物可以方便地以气溶胶喷雾剂形式递送，所述气溶胶喷雾剂可以装在压力容器或雾化器中，使用合适的抛射剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。在压力气溶胶的情况下，剂量单位可以通过阀门进行确定以递送计量量。例如，以胶囊剂和药筒为例，用于吸入器或吹药器的明胶可以制备为含有所述化合物与适当粉末基质例如乳糖或淀粉的粉末混合物。For administration by inhalation, the compound of the present invention or a salt thereof may be in the form of an aerosol, an aerosol or a powder. The pharmaceutical composition of the compound of the present invention or a salt thereof can be conveniently delivered in the form of an aerosol spray which can be contained in a pressure vessel or atomizer using a suitable propellant such as dichlorodifluoromethane, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by a valve to deliver a metered amount. For example, in the case of capsules and cartridges, gelatin for use in an inhaler or insufflator can be prepared to contain a powder mix of the compound with a suitable powder base such as lactose or starch.
本发明化合物或其盐还可以制备为直肠组合物例如灌肠剂、直肠凝胶剂、直肠泡沫剂、直肠气溶胶、栓剂、凝胶栓剂(jelly suppository)或保留灌肠剂(retention enma)，其中含有常规的栓剂基质例如可可脂或其他甘油酯以及合成聚合物例如聚乙烯吡咯烷酮、PEG等。在组合物的栓剂形式中，低熔点蜡例如但不限于脂肪酸甘油酯任选与可可脂的混合物首先被熔化。 The compound of the present invention or a salt thereof can also be prepared as a rectal composition such as an enema, a rectal gel, a rectal foam, a rectal aerosol, a suppository, a gel suppository or a retention enma, which contains Conventional suppository bases such as cocoa butter or other glycerides and synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In the suppository form of the composition, a low melting wax such as, but not limited to, a fatty acid glyceride, optionally mixed with cocoa butter, is first melted.
此外，本发明化合物或其盐还可与其他治疗纤维化的药物联用。具体包括，但不限于，Ivacaftor、罗氟斯特、吡非尼酮、尼达尼布、美格鲁特、洛沙坦、干扰素、阿拉法-链道酶、Veldona、ataluren、皮质激素、氨甲喋呤、他克莫司等。Furthermore, the compounds of the invention or salts thereof may also be combined with other agents for treating fibrosis. Specifically included, but not limited to, Ivacaftor, Rofluent, Pirfenidone, Nidanib, Megruth, Losartan, Interferon, Arafat-Chainase, Veldona, ataluren, Corticosteroids, Methotrexate, tacrolimus, etc.
可以根据常规方式用一种或多种生理学可接受的载体制备药物组合物，其中包括可帮助将活性化合物或其盐加工为可药用制剂的赋形剂和辅剂。所选择的施用途径决定适当的剂型。任何熟知的技术、载体和赋形剂都可以根据现有技术中的理解适当的使用。含有本发明化合物或其盐的药物组合物可以根据常规方法制备，例如通过常规的混合、溶解、制粒、制锭、研磨、乳化、包囊、包封或压制过程制备。含有本发明化合物或其盐的药物组合物可以以治疗有效量的药物组合物形式、以本领域已知的常规形式和途径施用，包括但不限于：静脉内、口服、经直肠、气雾剂、非胃肠途径、经眼、经肺、透皮、经***、经耳、经鼻和局部施用。The pharmaceutical compositions may be prepared in a conventional manner using one or more physiologically acceptable carriers including excipients and adjuvants which may aid in the preparation of the active compound or a salt thereof in a pharmaceutically acceptable formulation. The route of administration chosen determines the appropriate dosage form. Any of the well-known techniques, carriers and excipients can be suitably employed in accordance with the understanding in the prior art. The pharmaceutical composition containing the compound of the present invention or a salt thereof can be produced according to a conventional method, for example, by a conventional mixing, dissolving, granulating, tableting, grinding, emulsifying, encapsulating, encapsulating or pressing process. A pharmaceutical composition comprising a compound of the present invention or a salt thereof can be administered in a therapeutically effective amount of a pharmaceutical composition in a conventional form and route known in the art including, but not limited to, intravenous, oral, rectal, aerosol. , parenteral route, transocular, transpulmonary, transdermal, transvaginal, transaural, nasal and topical administration.
药物组合物将包含至少一种可药用载体、稀释剂或赋形剂和游离酸、游离碱或可药用盐形式的本发明的化合物作或其盐为活性成分。此外，药物组合物还可包括其它医学或药学活性剂、载体、辅剂、例如防腐剂、稳定剂、湿润剂或乳化剂、溶解促进剂、调节渗透压的盐或缓冲剂。此外，药物组合物还可含有其它有治疗价值的物质。The pharmaceutical composition will comprise, as an active ingredient, at least one pharmaceutically acceptable carrier, diluent or excipient and a compound of the invention in the form of a free acid, a free base or a pharmaceutically acceptable salt. In addition, the pharmaceutical compositions may also include other medical or pharmaceutically active agents, carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure or buffers. In addition, the pharmaceutical compositions may also contain other therapeutically valuable substances.
含有本发明所述化合物或其盐的组合物的制备方法包括将化合物与一种或多种惰性的可药用赋形剂或载体一起制备为固体、半固体或液体形式。固体组合物包括但不限于散剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。液体组合物包括其中溶解有化合物的溶液剂、含有化合物的乳剂、含有包含本文公开化合物的脂质体、胶团或纳米粒子的溶液剂。半固体组合物包括但不限于凝胶剂、混悬剂和乳膏剂。组合物可以是液体溶液剂或混悬剂形式、适合于在使用前溶解或悬浮在液体中的固体形式或乳剂形式。这些组合物还可以含有少量无毒的辅剂，例如湿润剂或乳化剂、pH缓冲剂等。A method of preparing a composition comprising a compound of the invention or a salt thereof comprises preparing the compound together with one or more inert pharmaceutically acceptable excipients or carriers in solid, semi-solid or liquid form. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, solutions containing liposomes, micelles or nanoparticles comprising the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The composition may be in the form of a liquid solution or suspension, in a solid form or in an emulsion form suitable for dissolution or suspension in a liquid prior to use. These compositions may also contain minor amounts of non-toxic adjuvants such as wetting or emulsifying agents, pH buffering agents and the like.
本发明的化合物或其盐优选地按制剂配方制备成剂量单位型以减轻给药量和剂量的均匀性。术语“剂量单位型”在此处是指患者得到适当治疗所需药物的物理分散单位。然而，应了解本发明的化合物或其盐、或本发明的药物组合物每日总的用法将通过主治医生根据可靠的医学范围判断来确定。具体的有效剂量水平对于任何一个特殊的患者或有机体将取决于许多因素包括被治疗的病症和病症的严重性，具体化合物或其盐的活性，所用的具体组合物，患者的年龄、体重、健康状况、性别和饮食习惯，给药时间，给药途径和所用具体化合物的***速率，治疗的持续时间，药物应用于联合用药或与有特效的化合物联用，以及其他一些药学领域公知的因素。The compound of the present invention or a salt thereof is preferably prepared in a dosage unit form in a formulation to reduce the uniformity of administration and dosage. The term "dosage unit type" as used herein refers to the physically discrete unit of the drug required for the patient to receive appropriate treatment. However, it is to be understood that the total daily usage of the compound of the present invention or a salt thereof, or the pharmaceutical composition of the present invention will be determined by the attending physician based on a reliable medical range judgment. The particular effective dosage level will depend on a number of factors, including the severity of the condition or condition being treated, the activity of the particular compound or salt thereof, the particular composition employed, the age, weight, and health of the patient for any particular patient or organism. Condition, sex and eating habits, time of administration, route of administration and rate of excretion of the particular compound employed, duration of treatment, use of the drug in combination or in combination with a compound having a specific effect, and other factors well known in the pharmaceutical arts.
所用的活性成分的有效剂量可随所用的化合物或其盐、给药的模式和待治疗的疾病的严重程度而变化。然而，通常当本发明的化合物或其盐每天以约0.25-1000mg/kg动物体重的剂量给予时，能得到令人满意的效果，较佳地每天以2-4次分开的剂量给予，或以缓释形式给药。对大部分大型哺乳动物而言，每天的总剂量约为1-100mg/kg，较佳地约为2-80mg/kg的活性化合物。适用于内服的剂量形式，包含与固态或液态药学上可接受的载体密切混合的约0.25-500mg的活性化合物。可调节此剂量方案以提供最佳治疗应答。另外，由于治疗状况的不同，可每天给予若干次分开的剂量，或将剂量按比例减少。The effective dose of the active ingredient employed may vary depending on the compound or salt thereof employed, the mode of administration, and the severity of the condition to be treated. However, usually, when the compound of the present invention or a salt thereof is administered at a dose of about 0.25 to 1000 mg/kg of animal body weight per day, a satisfactory effect can be obtained, preferably administered in 2-4 divided doses per day, or Sustained release form of administration. For most large mammals, the total daily dose is from about 1 to 100 mg/kg, preferably from about 2 to 80 mg/kg of active compound. Dosage forms for internal administration comprise from about 0.25 to about 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide an optimal therapeutic response. In addition, several separate doses may be administered per day, or the dose may be proportionally reduced, depending on the condition being treated.
本发明涉及的化合物或所述的盐、药物组合物能有效用于预防、处理、治疗或减轻患者组织或器官纤维化疾病，特别是能有效治疗肾间质纤维化，肾小球硬化，肝纤维化，肺纤维化，特发性肺纤维化，腹膜纤维化，心肌纤维化，皮肤纤维化，手术后粘连，良性***肥大症，骨骼肌纤维化，硬皮病，多发性硬化症，胰腺纤维化，肝硬化，肌肉瘤，神经纤维瘤，肺间质纤维化，糖尿病肾病，阿尔茨海默病或血管纤维化的疾病。The compound or the salt and the pharmaceutical composition of the invention can be effectively used for preventing, treating, treating or alleviating fibrotic diseases of tissues or organs of patients, in particular, effective treatment of renal interstitial fibrosis, glomerular sclerosis, liver Fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, cutaneous fibrosis, postoperative adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibers Disease, cirrhosis, muscle tumor, neurofibromatosis, pulmonary interstitial fibrosis, diabetic nephropathy, Alzheimer's disease or vascular fibrosis.
附图说明DRAWINGS
图1为式(I)所示化合物的氢溴酸盐晶型I的X射线粉末衍射(XRPD)图。 Figure 1 is an X-ray powder diffraction (XRPD) pattern of the hydrobromide salt form I of the compound of formula (I).
图2为式(I)所示化合物的氢溴酸盐晶型II的X射线粉末衍射(XRPD)图。Figure 2 is an X-ray powder diffraction (XRPD) pattern of the hydrobromide salt form II of the compound of formula (I).
图3为式(I)所示化合物的苯磺酸盐晶型I的X射线粉末衍射(XRPD)图。Figure 3 is an X-ray powder diffraction (XRPD) pattern of the benzenesulfonate salt form I of the compound of formula (I).
图4为式(I)所示化合物的苯磺酸盐晶型I的差示扫描量热(DSC)图。Figure 4 is a differential scanning calorimetry (DSC) chart of the besylate salt form I of the compound of formula (I).
图5为式(I)所示化合物的苯磺酸盐晶型II的X射线粉末衍射(XRPD)图。Figure 5 is an X-ray powder diffraction (XRPD) pattern of the benzenesulfonate salt form II of the compound of formula (I).
图6为式(I)所示化合物的苯磺酸盐晶型II的差示扫描量热(DSC)图。Figure 6 is a differential scanning calorimetry (DSC) chart of the besylate salt form II of the compound of formula (I).
图7为式(I)所示化合物的苯磺酸盐晶型III的X射线粉末衍射(XRPD)图。Figure 7 is an X-ray powder diffraction (XRPD) pattern of the besylate salt form III of the compound of formula (I).
图8为式(I)所示化合物的苯磺酸盐晶型III的差示扫描量热(DSC)图。Figure 8 is a differential scanning calorimetry (DSC) chart of the besylate salt form III of the compound of formula (I).
图9为式(I)所示化合物的苯磺酸盐无定形的X射线粉末衍射(XRPD)图。Figure 9 is an amorphous X-ray powder diffraction (XRPD) pattern of the besylate salt of the compound of formula (I).
图10为式(I)所示化合物的β-萘磺酸盐晶型I的X射线粉末衍射(XRPD)图。Figure 10 is an X-ray powder diffraction (XRPD) pattern of the β-naphthalenesulfonate crystal form I of the compound of the formula (I).
图11为式(I)所示化合物的β-萘磺酸盐晶型I的差示扫描量热(DSC)图。Figure 11 is a differential scanning calorimetry (DSC) chart of Form I of the β-naphthalenesulfonate salt of the compound of Formula (I).
图12为式(I)所示化合物的β-萘磺酸盐晶型II的X射线粉末衍射(XRPD)图。Figure 12 is an X-ray powder diffraction (XRPD) pattern of the β-naphthalenesulfonate crystal form II of the compound of the formula (I).
图13为式(I)所示化合物的β-萘磺酸盐晶型II的差示扫描量热(DSC)图。Figure 13 is a differential scanning calorimetry (DSC) chart of the β-naphthalenesulfonate Form II of the compound of Formula (I).
具体实施方式detailed description
下面通过实施例的方式进一步说明本发明，并不因此将本发明限制在所述的实施例范围之中。The invention is further illustrated by the following examples, which are not intended to limit the invention.
本发明所用X射线粉末衍射分析方法为：Empyrean衍射仪，使用Cu-Kα辐射(45KV,40mA)获得X射线粉末衍射图。在单晶硅样品架上将粉末状样品制备成薄层，放在旋转样品台上，在3°-40°的范围内以0.0168°步长进行分析。使用Data Collector软件收集数据，HighScore Plus软件处理数据，Data Viewer软件读取数据。The X-ray powder diffraction analysis method used in the present invention is an Empyrean diffractometer, and an X-ray powder diffraction pattern is obtained using Cu-Kα radiation (45 kV, 40 mA). The powdered sample was prepared as a thin layer on a single crystal silicon sample holder and placed on a rotating sample stage for analysis in the range of 3 to 40 degrees in steps of 0.0168°. Data is collected using Data Collector software, HighScore Plus software processes the data, and Data Viewer software reads the data.
本发明所用差示扫描量热(DSC)分析方法为：使用带有热分析控制器的TA Q2000模件进行差示扫描量热。收集数据并使用TA Instruments Thermal Solutions软件进行分析。将约1-5mg样品准确地称重到带有盖子的特制铝坩埚中，使用10℃/分钟的线形加热装置，从室温至大约300℃进行样品分析。在使用期间，将DSC小室用干燥氮气吹扫。The differential scanning calorimetry (DSC) analysis method used in the present invention is to perform differential scanning calorimetry using a TA Q2000 module with a thermal analysis controller. Data was collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of the sample was accurately weighed into a special aluminum crucible with a lid, and sample analysis was performed from room temperature to about 300 ° C using a linear heating device at 10 ° C/min. During use, the DSC chamber was purged with dry nitrogen.
本发明所用傅里叶红外(FT-IR)分析方法为：采用德国布鲁克TENSOR27红外光谱仪测试，OPUS软件进行数据分析。KBr压片，扫描次数：16次，波数范围：4000～600cm-1，分辨率：2cm-1。The Fourier Infrared (FT-IR) analysis method used in the present invention is: using the German Bruker TENSOR27 infrared spectrometer test, OPUS software for data analysis. KBr tableting, scanning times: 16 times, wave number range: 4000 ~ 600cm -1 , resolution: 2cm -1 .
本发明的溶解度采用Aglient 1200高效液相色谱仪DAD/VWD检测器测定，色谱柱型号为Agilent XDB-C18(4.6×50mm，5μm)。检测波长为266nm，流速为1.0mL/min，柱温为35℃，流动相A：乙腈-0.01M醋酸铵＝10：90(V：V)分析方法：乙腈-流动相A＝70：30(V：V)，运行时间：10分钟。The solubility of the present invention was measured using an Agilent 1200 high performance liquid chromatograph DAD/VWD detector, and the column type was Agilent XDB-C18 (4.6 x 50 mm, 5 μm). The detection wavelength was 266 nm, the flow rate was 1.0 mL/min, the column temperature was 35 ° C, and the mobile phase A: acetonitrile - 0.01 M ammonium acetate = 10:90 (V: V). Analytical method: acetonitrile - mobile phase A = 70:30 ( V: V), running time: 10 minutes.
具体实施方法Specific implementation method
式(I)所示化合物3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮的具体合成方法参照专利CN 103570630 A中的实施例24。The specific synthesis method of the compound of the formula (I), 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one, is described in the patent CN 103570630 A. Example 24.
实施例Example
实施例1 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 氢溴酸盐晶型IExample 1 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one Hydrobromide salt form I
1. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 氢溴酸盐晶型I的制备1. Preparation of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrobromide salt form I
将3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(0.408g)溶解在乙酸乙酯(5.0mL)中，加入氢溴酸(1.0mL)，室温反应过夜，抽滤，滤饼用乙酸乙酯洗涤，得到白色固体(0.295g,60.18％)。3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (0.408 g) was dissolved in ethyl acetate (5.0 mL) Hydrobromide (1.0 mL), mp.
2. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 氢溴酸盐晶型I的鉴定2. Identification of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrobromide salt form I
通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：6.07°,8.86°,9.41°,12.13°,13.92°,15.28°,15.69°,16.36°,16.59°,17.17°,18.04°,18.75°,19.60°,21.18°,22.25°,22.62°,23.37°,24.73°,25.68°,26.72°,27.43°,28.10°,29.63°,30.62°,32.13°,34.88°和36.79°, 存在±0.2°的误差容限。It was identified by Empyrean X-ray powder diffraction (XRPD) analysis that: using Cu-Kα radiation, the following characteristic peaks expressed by angle 2θ: 6.07°, 8.86°, 9.41°, 12.13°, 13.92°, 15.28°, 15.69°, 16.36 °, 16.59°, 17.17°, 18.04°, 18.75°, 19.60°, 21.18°, 22.25°, 22.62°, 23.37°, 24.73°, 25.68°, 26.72°, 27.43°, 28.10°, 29.63°, 30.62°, 32.13°, 34.88° and 36.79°, There is an error tolerance of ±0.2°.
实施例2 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 氢溴酸盐晶型IIExample 2 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one Hydrobromide salt crystal form II
1. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 氢溴酸盐晶型II的制备1. Preparation of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one Hydrobromide salt form II
将3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(0.418g)溶解在乙醇(8.0mL)中，加入氢溴酸(0.5mL)，室温反应过夜，抽滤，滤饼用水洗涤，得到白色固体(0.356g,70.89％)。Dissolve 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (0.418g) in ethanol (8.0mL), add hydrobromide The acid (0.5 mL) was stirred at rt EtOAc (EtOAc)EtOAc.
2. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 氢溴酸盐晶型II的鉴定2. Identification of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one hydrobromide salt form II
通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：3.64°,7.20°,10.80°,11.39°,12.36°,14.52°,17.14°,18.07°,19.39°,21.70°,22.30°,23.18°,23.89°,25.38°,26.26°,29.15°,32.76°,36.92°和38.93°,存在±0.2°的误差容限。Characterized by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, having the following characteristic peaks expressed by angle 2θ: 3.64°, 7.20°, 10.80°, 11.39°, 12.36°, 14.52°, 17.14°, 18.07 °, 19.39°, 21.70°, 22.30°, 23.18°, 23.89°, 25.38°, 26.26°, 29.15°, 32.76°, 36.92° and 38.93°, there is a tolerance of ±0.2°.
实施例3 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐晶型IIExample 3 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzenesulfonate salt form II
1. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐晶型II的制备1. Preparation of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzenesulfonate salt form II
将3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(4.01g)溶解在丙酮(12mL)中，加入苯磺酸(1.896mmol)，60℃反应3.5小时，然后将反应体系自然冷却至室温并搅拌过夜，析出白色固体，抽滤，滤饼用正庚烷洗涤，室温真空干燥，得到白色固体(2.0g,36％)。3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (4.01 g) was dissolved in acetone (12 mL) and benzenesulfonic acid was added. (1. 896 mmol), the reaction was carried out at 60 ° C for 3.5 hours, then the reaction was cooled to room temperature and stirred overnight, then white solid was crystallised, filtered, filtered, washed with n-heptane. %).
2. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐晶型II的鉴定2. Identification of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzenesulfonate salt form II
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：5.32°,5.73°,7.23°,8.91°,9.29°,9.49°,9.88°,13.26°,13.57°,14.88°,15.51°,15.80°,16.48°,17.20°,17.82°,18.37°,19.21°,19.82°,20.77°,21.28°,21.68°,22.29°,23.47°,23.82°,24.49°,25.88°,27.13°,27.71°,28.79°,29.52°,29.95°,32.12°和32.91°,存在±0.2°的误差容限。(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, having the following characteristic peaks expressed by angle 2θ: 5.32°, 5.73°, 7.23°, 8.91°, 9.29°, 9.49°, 9.88 °, 13.26°, 13.57°, 14.88°, 15.51°, 15.80°, 16.48°, 17.20°, 17.82°, 18.37°, 19.21°, 19.82°, 20.77°, 21.28°, 21.68°, 22.29°, 23.47°, 23.82°, 24.49°, 25.88°, 27.13°, 27.71°, 28.79°, 29.52°, 29.95°, 32.12° and 32.91°, there is a tolerance of ±0.2°.
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，包含159.45℃的吸热峰，存在±3℃的误差容限。(2) It was identified by TA Q2000 differential scanning calorimetry (DSC) analysis: the scanning speed was 10 ° C / min, containing an endothermic peak of 159.45 ° C, and there was an error tolerance of ± 3 ° C.
实施例4 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐晶型IExample 4 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one Toluenesulfonate Form I
1. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐晶型I的制备1. Preparation of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzenesulfonate salt form I
将3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮苯磺酸盐晶型II(0.3g)加入到乙醇(1.0mL)中，加热至80℃反应1.0小时，将反应体系自然冷却至室温，加入正庚烷(5.0mL)，抽滤，滤饼用少量正庚烷洗涤，室温真空干燥，得到白色固体(0.28g,93.33％)。3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzenesulfonate salt form II (0.3 g) was added to ethanol (1.0 In mL), the reaction was heated to 80 ° C for 1.0 hour, the reaction system was naturally cooled to room temperature, n-heptane (5.0 mL) was added, suction filtered, and the filter cake was washed with a small amount of n-heptane and dried under vacuum at room temperature to give a white solid (0.28) g, 93.33%).
2. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐晶型I的鉴定2. Identification of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzenesulfonate salt form I
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：6.79°,8.09°,8.83°,9.54°,10.22°,11.26°,13.08°,13.59°,14.35°,16.13°,17.00°,17.80°,18.50°,19.20°,20.52°,20.67°,20.90°,21.87°,22.17°,22.74°,23.06°,23.58°,23.91°,24.58°,25.55°,26.31°,27.17°,27.53°,27.83°,28.13°,28.84°,29.24°,29.92°,30.20°,30.50°,31.49°,33.01°,33.99°,35.28°和37.63°,存在±0.2°的误差容限。(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, having the following characteristic peaks expressed by angle 2θ: 6.79°, 8.09°, 8.83°, 9.54°, 10.22°, 11.26°, 13.08 °, 13.59, 14.35, 16.13, 17.00, 17.80, 18.50, 19.20, 20.52, 20.67, 20.90, 21.87, 22.17, 22.74, 23.06, 23.58, 23.91, 24.58°, 25.55°, 26.31°, 27.17°, 27.53°, 27.83°, 28.13°, 28.84°, 29.24°, 29.92°, 30.20°, 30.50°, 31.49°, 33.01°, 33.99°, 35.28° and 37.63° There is an error tolerance of ±0.2°.
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，包含180.99℃的吸热峰，存在±3℃的误差容限。(2) It was identified by TA Q2000 differential scanning calorimetry (DSC) analysis: the scanning speed was 10 ° C / min, containing an endothermic peak of 180.99 ° C, and there was an error tolerance of ± 3 ° C.
实施例5 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐晶型IIIExample 5 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one Toluenesulfonate Form III
1. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐晶型III的制备1. Preparation of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzenesulfonate salt form III
将3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(4.01g)溶解在丙酮(12mL)中，加入苯磺酸(1.896mmol)，60℃反应3.5小时，然后将反应自然冷却至室温并加入正庚烷(20mL)，再将反应冷却至-20℃，保温2.0小时，抽滤，滤饼用正庚烷洗涤，室温真空干燥，得到白色固体(3.4g,61％)。3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (4.01 g) was dissolved in acetone (12 mL) and benzenesulfonic acid was added. (1.896 mmol), reacted at 60 ° C for 3.5 hours, then the reaction was naturally cooled to room temperature and n-heptane (20 mL) was added, then the reaction was cooled to -20 ° C, incubated for 2.0 hrs, filtered, and the filter cake was washed with n-heptane Dry at room temperature under vacuum to give a white solid (3.
2. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐晶型III的鉴定2. Identification of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzenesulfonate salt form III
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：3.73°,7.40°,8.10°,9.14°,9.79°,11.12°,12.02°,14.53°,14.85°,15.70°,16.63°,17.11°,17.87°,19.05°,20.24°,20.75°,21.45°,21.87°,22.44°,23.36°,25.95°,26.36°,29.24°和37.70°,存在±0.2°的误差容限。(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, having the following characteristic peaks expressed by angle 2θ: 3.73°, 7.40°, 8.10°, 9.14°, 9.79°, 11.12°, 12.02 °, 14.53°, 14.85°, 15.70°, 16.63°, 17.11°, 17.87°, 19.05°, 20.24°, 20.75°, 21.45°, 21.87°, 22.44°, 23.36°, 25.95°, 26.36°, 29.24° and 37.70°, there is a tolerance of ±0.2°.
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，包含96.67℃和140.76℃的吸热峰，存在±3℃的误差容限。(2) It was identified by TA Q2000 differential scanning calorimetry (DSC) analysis: the scanning speed was 10 ° C / min, including the endothermic peak at 96.67 ° C and 140.76 ° C, and there was an error tolerance of ± 3 ° C.
实施例6 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐无定形Example 6 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one Toluene benzenesulfonate
1. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐无定形的制备1. Preparation of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzsulfonate amorphous
将3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮苯磺酸盐晶型I(1.0g)溶解在丙酮(40mL)中，加热溶解，置于喷雾干燥器进样口，进样喷雾，得到白色固体粉末。3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one benzenesulfonate Form I (1.0 g) was dissolved in acetone (40 mL) In the case, it was dissolved by heating, placed in the spray dryer inlet, and sprayed to obtain a white solid powder.
2. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 苯磺酸盐无定形的鉴定2. Identification of amorphous form of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one besylate
通过Empyrean X射线粉末衍射(XRPD)分析鉴定：其X射线粉末衍射基本上如图9所示。It was identified by Empyrean X-ray powder diffraction (XRPD) analysis that its X-ray powder diffraction is substantially as shown in FIG.
实施例7 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 β-萘磺酸盐晶型IExample 7 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one β-naphthalenesulfonate crystal form I
1. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 β-萘磺酸盐晶型I的制备1. Preparation of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one β-naphthalenesulfonate crystal form I
将3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(0.227g)溶解在乙腈(3.0mL)中，加入自制β-萘磺酸(0.153g)的乙腈(2.0mL)溶液，室温反应过夜，加入甲基叔丁基醚(20mL)后搅拌析晶1.0小时，抽滤，滤饼用甲基叔丁基醚(4.0mL)洗涤，室温真空干燥，得到白色固体粉末(0.15g,43.52％)。3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (0.227 g) was dissolved in acetonitrile (3.0 mL). a solution of naphthalenesulfonic acid (0.153 g) in acetonitrile (2.0 mL), mp. The mixture was washed with EtOAc (EtOAc).
1. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 β-萘磺酸盐晶型I的鉴定1. Identification of crystal form I of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one β-naphthalene sulfonate
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：4.50°,6.35°,7.06°,8.43°,8.96°,9.97°,11.92°,12.67°,13.45°,13.78°,14.16°,14.75°,15.80°,16.12°,16.74°,16.91°,17.91°,18.64°,19.05°,19.52°,20.08°,20.65°,22.22°,22.51°,22.75°,23.17°,23.73°,23.99°,24.42°,25.23°,25.59°,26.01°,26.77°,27.06°,27.79°,30.09°,31.14°,31.71°,31.92°,35.25°,36.14°,37.15°和38.22°,存在±0.2°的误差容限。(1) Identification by Emp y rean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, having the following characteristic peaks expressed by angle 2θ: 4.50°, 6.35°, 7.06°, 8.43°, 8.96°, 9.97° , 11.92°, 12.67°, 13.45°, 13.78°, 14.16°, 14.75°, 15.80°, 16.12°, 16.74°, 16.91°, 17.91°, 18.64°, 19.05°, 19.52°, 20.08°, 20.65°, 22.22 °, 22.51°, 22.75°, 23.17°, 23.73°, 23.99°, 24.42°, 25.23°, 25.59°, 26.01°, 26.77°, 27.06°, 27.79°, 30.09°, 31.14°, 31.71°, 31.92°, 35.25°, 36.14°, 37.15° and 38.22°, there is a tolerance of ±0.2°.
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，包含163.92℃和220.42℃的吸热峰，存在±3℃的误差容限。(2) It was identified by TA Q2000 differential scanning calorimetry (DSC) analysis: the scanning speed was 10 ° C / min, including the endothermic peak of 163.92 ° C and 220.42 ° C, and there was an error tolerance of ± 3 ° C.
实施例8 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 β-萘磺酸盐晶型IIExample 8 3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one β-naphthalenesulfonate salt form II
1. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 β-萘磺酸盐晶型II的制备1. Preparation of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one β-naphthalenesulfonate crystal form II
将3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(0.216g)溶解在甲醇(3.0mL)中，加入自制β-萘磺酸(0.153g)的甲醇(1.0mL)溶液，室温反应1.5小时，加入甲基叔丁基醚(30mL)，搅拌过夜，抽滤，滤饼室温真空干燥，得到白色固体粉末(0.165g,50.31％)。3-(4-(Dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (0.216 g) was dissolved in methanol (3.0 mL). a solution of naphthalenesulfonic acid (0.153 g) in MeOH (1.0 mL), EtOAc (EtOAc) (EtOAc) g, 50.31%).
2. 3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮 β-萘磺酸盐晶型II的鉴定2. Identification of 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one β-naphthalene sulfonate crystal form II
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定：使用Cu-Kα辐射，具有下列以角度2θ表示的特征峰：6.43°,8.10°,9.15°,9.73°,10.57°,12.64°,12.90°,13.60°,16.04°,16.26°,16.75°,16.95°,17.43°,17.90°,18.37°,19.41°,19.62°,19.97°,20.65°,21.50°,21.82°,22.07°,22.45°,23.32°,24.11°,24.82°,25.70°,25.97°,26.49°,27.17°,27.50°,28.04°,28.62°,29.55°,29.96°,30.49°,31.17°,32.10°,33.52°,34.53°,35.38°,36.03°,36.99°,38.19°,39.50°,存在±0.2°的误差容限。(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, having the following characteristic peaks expressed by angle 2θ: 6.43°, 8.10°, 9.15°, 9.73°, 10.57°, 12.64°, 12.90 °, 13.60°, 16.04°, 16.26°, 16.75°, 16.95°, 17.43°, 17.90°, 18.37°, 19.41°, 19.62°, 19.97°, 20.65°, 21.50°, 21.82°, 22.07°, 22.45°, 23.32°, 24.11°, 24.82°, 25.70°, 25.97°, 26.49°, 27.17°, 27.50°, 28.04°, 28.62°, 29.55°, 29.96°, 30.49°, 31.17°, 32.10°, 33.52°, 34.53° , 35.38°, 36.03°, 36.99°, 38.19°, 39.50°, there is an error tolerance of ±0.2°.
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定：扫描速度为10℃/分钟，包含221.99℃的吸热峰，存在±3℃的误差容限。(2) It was identified by TA Q2000 differential scanning calorimetry (DSC) analysis: the scanning speed was 10 ° C / min, containing an endothermic peak of 221.99 ° C, and there was an error tolerance of ± 3 ° C.
实施例9 本发明所述盐的药代动力学实验 Example 9 Pharmacokinetic experiment of the salt of the present invention
本发明所述的式(I)所示化合物(化合物3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮)、不同盐的晶型分别灌装胶囊，用于口服给药。The compound of the formula (I) according to the present invention (compound 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one), different The crystal forms of the salt are separately filled into capsules for oral administration.
取6-10kg雄性Beagle犬随机分组，每组3只，一组口服给予式(I)所示化合物，其它组分别口服给予不同的盐，给药剂量均为5mg/kg。给药后按时间点0.25,0.5,1.0,2.0,4.0,6.0,8.0,12和24h采血。根据样品浓度建立合适范围的标准曲线，使用Agilent 6430型LC-MS/MS，在MRM模式下测定血浆样品中供试样品的浓度，并进行定量分析。根据药物浓度-时间曲线，采用WinNonLin 6.3软件非房室模型法计算药动学参数。实验结果如表1所示。6-10 kg male Beagle dogs were randomly divided into groups of 3, one group was orally administered with the compound of formula (I), and the other groups were orally administered with different salts at a dose of 5 mg/kg. Blood was collected at time points 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12 and 24 h after administration. A suitable range of standard curves was established based on the sample concentration, and the concentration of the test sample in the plasma sample was measured in MRM mode using Agilent Model 6430 LC-MS/MS, and quantitative analysis was performed. According to the drug concentration-time curve, the pharmacokinetic parameters were calculated using the WinNonLin 6.3 software non-compartmental model method. The experimental results are shown in Table 1.
表1本发明所述盐的药代动力学实验数据Table 1 Pharmacokinetic experimental data of the salt of the present invention
Figure PCTCN2017094409-appb-000005
Figure PCTCN2017094409-appb-000005
实验结论：由表1可知，本发明所述的盐具有较好的生物活性。与游离状态的3-(4-(二己氨基)-3-氟苯基)-2,6-二甲基嘧啶-4(3H)-酮(即，式(I)所示化合物)相比，实施例4(苯磺酸盐晶型I)具体较高的暴露量、较长的半衰期。Experimental conclusion: It can be seen from Table 1 that the salt of the present invention has good biological activity. Compared with 3-(4-(dihexylamino)-3-fluorophenyl)-2,6-dimethylpyrimidin-4(3H)-one (ie, the compound of formula (I)) in a free state Example 4 (benzenesulfonate Form I) has a particularly high exposure and a long half-life.
实施例10 本发明所述盐的稳定性实验Example 10 Stability Test of the Salt of the Invention
(1)高温实验：取供试样品适量放入扁形称量瓶中，摊成≤5mm厚的薄层，60℃温度下放置10天，于第5、10天取样，观察样品颜色变化，HPLC检测样品纯度。(1) High temperature experiment : Take the appropriate amount of the test sample into a flat weighing bottle, spread it into a thin layer ≤5mm thick, place it at 60°C for 10 days, sample on the 5th and 10th day, observe the color change of the sample, HPLC Test sample purity.
(2)高湿实验：取一批供试品适量放入扁形称量瓶中，摊成≤5mm厚的薄层，25℃、RH 90％±5％条件下放置10天，于第5、10天取样，观察样品颜色变化，HPLC检测样品纯度。(2) High-humidity experiment : Take a batch of the test sample into a flat weighing bottle and spread it into a thin layer ≤5mm thick, and place it for 10 days at 25°C and RH 90%±5%. Samples were taken for 10 days, the color change of the samples was observed, and the purity of the samples was determined by HPLC.
实验表明，在高温(60℃)、高湿(25℃,RH 90％±5％)条件下，本发明所述的盐的外观和纯度均无明显变化，稳定性效果好，适合制药用途。Experiments show that under the conditions of high temperature (60 ° C), high humidity (25 ° C, RH 90% ± 5%), the salt of the present invention has no obvious change in appearance and purity, and has good stability effect and is suitable for pharmaceutical use.
实施例11 本发明所述盐的引湿性实验Example 11 Experimental study on the wettability of the salt of the present invention
取供试品适量，采用动态水分吸附仪测试其引湿性。实验结果证明，本发明所述的盐不易受高湿度影响而潮解。Take the appropriate amount of the test sample and test its wettability with a dynamic moisture adsorber. The experimental results prove that the salt of the present invention is not easily affected by high humidity and deliquesces.
以上所述内容仅为本发明构思下的基本说明，而依据本发明的技术方案所作的任何等效变换，均应属于本发明的保护范围。The above description is only a basic description of the present invention, and any equivalent transformation made according to the technical solution of the present invention should fall within the protection scope of the present invention.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" and the like means a specific feature described in connection with the embodiment or example. A structure, material or feature is included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms is not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. In addition, various embodiments or examples described in the specification, as well as features of various embodiments or examples, may be combined and combined.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。 Although the embodiments of the present invention have been shown and described, it is understood that the above-described embodiments are illustrative and are not to be construed as limiting the scope of the invention. The embodiments are subject to variations, modifications, substitutions and variations.

Claims (44)

  1. 一种式(I)所示化合物的药学上可接受的酸加成盐，a pharmaceutically acceptable acid addition salt of a compound of formula (I),
    Figure PCTCN2017094409-appb-100001
    Figure PCTCN2017094409-appb-100001
  2. 根据权利要求1所述的酸加成盐，其中，所述的盐为无机酸盐或有机酸盐；The acid addition salt according to claim 1, wherein the salt is a mineral acid salt or an organic acid salt;
    其中，所述的无机酸盐为盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、氢溴酸盐、氢碘酸盐、碳酸盐、碳酸氢盐、亚硫酸盐、亚硫酸氢盐、焦硫酸盐、磷酸一氢盐、磷酸二氢盐、高氯酸盐、过硫酸盐、半硫酸盐、重硫酸盐、硫氰酸盐、磷酸盐、焦磷酸盐、偏磷酸盐或它们的任意组合；Wherein, the inorganic acid salt is a hydrochloride, a sulfate, a hydrogen sulfate, a nitrate, a hydrobromide, a hydroiodide, a carbonate, a hydrogencarbonate, a sulfite, a bisulfite, Pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, heavy sulfate, thiocyanate, phosphate, pyrophosphate, metaphosphate or any of them combination;
    所述的有机酸盐为甲酸盐、乙酸盐、丙酸盐、丁酸盐、苯甲酸盐、丙二酸盐、丁二酸盐、丙酮酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、柠檬酸盐、4-硝基苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、丙炔酸盐、2-丁炔酸盐、2-羟基-乙烷磺酸盐、乙烯基乙酸盐、酒石酸盐、L-酒石酸盐、富马酸盐、马来酸盐、乳酸盐、乳糖酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚糖酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、α-萘磺酸盐、β-萘磺酸盐、草酸盐、三氟乙酸盐、三氟甲磺酸盐、己二酸盐、辛二酸盐、癸二酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、羟基乙酸盐、藻酸盐、抗坏血酸盐、异抗坏血酸盐、天冬氨酸盐、L-天冬氨酸盐、谷氨酸盐、L-谷氨酸盐、2-苯氧基苯甲酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、乙酰乙酸盐、硼酸盐、氯代苯甲酸盐、樟脑酸盐、衣康酸盐、樟脑磺酸盐、左旋樟脑磺酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、氨基磺酸盐、乳糖醛酸盐、半乳糖醛酸盐、环戊基丙酸盐、十二烷基硫酸盐、丙烯酸盐、环戊烷丙酸盐、甘油磷酸盐、甲氧基苯甲酸盐、二葡萄糖酸盐、葡萄糖酸盐、庚酸盐、己酸盐、三甲基乙酸盐、葡糖醛酸盐、月桂酸盐、邻苯二甲酸盐、苯乙酸盐、月桂基硫酸盐、2-乙酰氧基苯甲酸盐、烟酸盐、肉桂酸盐、油酸盐、棕榈酸盐、果胶酸盐、苯二甲酸盐、戊二酸盐、羟基马来酸盐、羟基苯甲酸盐、3-羟基-2-萘甲酸盐、3-苯基丙酸盐、异丁酸盐、新戊酸盐、苦味酸盐、硬脂酸盐、2,2-二氯乙酸盐、酰化氨基酸盐、海藻酸盐、4-乙酰氨基苯磺酸盐、葵酸盐、胆酸盐、辛酸盐、壬酸盐、环拉酸盐、酞酸盐、盐酸半胱氨酸盐、山梨酸盐、帕莫酸盐、盐酸甘氨酸盐、萘二磺酸盐、二甲苯磺酸盐、二盐酸胱氨酸盐、十一酸盐、聚乙烯磺酸盐、磺基水杨酸盐、苯基丁酸盐、4-羟基丁酸盐、聚乙烯硫酸盐、戊酸盐或它们的任意组合。The organic acid salt is formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, methanesulfonate, ethanesulfonic acid Salt, propane sulfonate, citrate, 4-nitrobenzoate, besylate, p-toluenesulfonate, malate, propiolate, 2-butynoate, 2-hydroxyl -ethanesulfonate, vinyl acetate, tartrate, L-tartrate, fumarate, maleate, lactate, lactobionate, pamoate, salicylate, Galactose diphosphate, glucoheptonate, mandelate, 1,2-ethanedisulfonate, α-naphthalenesulfonate, β-naphthalenesulfonate, oxalate, trifluoroacetic acid Salt, triflate, adipate, suberate, sebacate, butyne-1,4-diate, hexyne-1,6-diate, glycolate , alginate, ascorbate, isoascorbate, aspartate, L-aspartate, glutamate, L-glutamate, 2-phenoxybenzoate, 2- (4-hydroxybenzoyl) benzoate, acetoacetate, borate, chlorobenzoate, camphorate, Potassate, camphor sulfonate, levo-camphorsulfonate, methyl benzoate, dinitrobenzoate, sulfamate, lactobionate, galacturonate, cyclopentyl Acid salt, lauryl sulfate, acrylate, cyclopentane propionate, glycerol phosphate, methoxybenzoate, digluconate, gluconate, heptanoate, hexanoate, three Methyl acetate, glucuronate, laurate, phthalate, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate , oleate, palmitate, pectate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, 3-hydroxy-2-naphthoate, 3- Phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2,2-dichloroacetate, acylated amino acid salt, alginate, 4-acetamidobenzene Acid salt, acid salt, cholate, octoate, decanoate, cyclamate, citrate, cysteine hydrochloride, sorbate, palmitic acid salt, glycine hydrochloride, naphthalene Sulfonate Acid salt, cysteine dihydrochloride, eleven acid salt, polyvinyl sulfonate, sulfosalicylic acid salt, phenyl butyrate, 4-hydroxybutyrate, polyethylene sulfate, valerate or Any combination of them.
  3. 根据权利要求1所述的酸加成盐，其中，所述的盐为氢溴酸盐晶型I，其特征在于，所述氢溴酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.07±0.2°,8.86±0.2°,13.92±0.2°,24.73±0.2°,25.68±0.2°。The acid addition salt according to claim 1, wherein the salt is a hydrobromide salt form I, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt form I is at the following 2 theta angle There are diffraction peaks at: 6.07 ± 0.2 °, 8.86 ± 0.2 °, 13.92 ± 0.2 °, 24.73 ± 0.2 °, 25.68 ± 0.2 °.
  4. 根据权利要求1所述的酸加成盐，其中，所述的盐为氢溴酸盐晶型I，其特征在于，所述氢溴酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.07±0.2°,8.86±0.2°,13.92±0.2°,15.28±0.2°,18.04±0.2°,19.60±0.2°,22.25±0.2°,22.62±0.2°,24.73±0.2°,25.68±0.2°,26.72±0.2°。The acid addition salt according to claim 1, wherein the salt is a hydrobromide salt form I, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt form I is at the following 2 theta angle There are diffraction peaks: 6.07±0.2°, 8.86±0.2°, 13.92±0.2°, 15.28±0.2°, 18.04±0.2°, 19.60±0.2°, 22.25±0.2°, 22.62±0.2°, 24.73±0.2°, 25.68 ± 0.2 °, 26.72 ± 0.2 °.
  5. 根据权利要求1所述的酸加成盐，其中，所述的盐为氢溴酸盐晶型I，其特征在于，所述氢溴酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.07±0.2°,8.86±0.2°,9.41±0.2°,12.13±0.2°,13.92±0.2°,15.28±0.2°,15.69±0.2°,16.36±0.2°,16.59±0.2°,17.17±0.2°,18.04±0.2°,18.75±0.2°,19.60±0.2°,21.18±0.2°,22.25±0.2°,22.62±0.2°,23.37±0.2°,24.73±0.2°,25.68±0.2°,26.72±0.2°,27.43±0.2°,28.10±0.2°,29.63±0.2°,30.62±0.2°,32.13±0.2°,34.88±0.2°,36.79±0.2°。The acid addition salt according to claim 1, wherein the salt is a hydrobromide salt form I, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt form I is at the following 2 theta angle There are diffraction peaks at: 6.07±0.2°, 8.86±0.2°, 9.41±0.2°, 12.13±0.2°, 13.92±0.2°, 15.28±0.2°, 15.69±0.2°, 16.36±0.2°, 16.59±0.2°, 17.17±0.2°, 18.04±0.2°, 18.75±0.2°, 19.60±0.2°, 21.18±0.2°, 22.25±0.2°, 22.62±0.2°, 23.37±0.2°, 24.73±0.2°, 25.68±0.2°, 26.72±0.2°, 27.43±0.2°, 28.10±0.2°, 29.63±0.2°, 30.62±0.2°, 32.13±0.2°, 34.88±0.2°, 36.79±0.2°.
  6. 根据权利要求1所述的酸加成盐，其中，所述的盐为氢溴酸盐晶型I，其特征在于，所述氢溴酸盐晶型I具有基本上如图1所示的X射线粉末衍射图。The acid addition salt according to claim 1, wherein the salt is a hydrobromide salt form I, characterized in that the hydrobromide salt form I has an X substantially as shown in FIG. Ray powder diffraction pattern.
  7. 根据权利要求1所述的酸加成盐，其中，所述的盐为氢溴酸盐晶型II，其特征在于，所述氢溴酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.64±0.2°,10.80±0.2°,21.70±0.2°, 25.38±0.2°。The acid addition salt according to claim 1, wherein the salt is a hydrobromide salt crystal form II, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt crystal form II is at the following 2 theta angle Has a diffraction peak: 3.64 ± 0.2 °, 10.80 ± 0.2 °, 21.70 ± 0.2 °, 25.38 ± 0.2 °.
  8. 根据权利要求1所述的酸加成盐，其中，所述的盐为氢溴酸盐晶型II，其特征在于，所述氢溴酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.64±0.2°,10.80±0.2°,17.14±0.2°,18.07±0.2°,21.70±0.2°,22.30±0.2°,25.38±0.2°。The acid addition salt according to claim 1, wherein the salt is a hydrobromide salt crystal form II, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt crystal form II is at the following 2 theta angle There are diffraction peaks: 3.64 ± 0.2 °, 10.80 ± 0.2 °, 17.14 ± 0.2 °, 18.07 ± 0.2 °, 21.70 ± 0.2 °, 22.30 ± 0.2 °, 25.38 ± 0.2 °.
  9. 根据权利要求1所述的酸加成盐，其中，所述的盐为氢溴酸盐晶型II，其特征在于，所述氢溴酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.64±0.2°,7.20±0.2°,10.80±0.2°,11.39±0.2°,12.36±0.2°,14.52±0.2°,17.14±0.2°,18.07±0.2°,19.39±0.2°,21.70±0.2°,22.30±0.2°,23.18±0.2°,23.89±0.2°,25.38±0.2°,26.26±0.2°,29.15±0.2°,32.76±0.2°,36.92±0.2°,38.93±0.2°。The acid addition salt according to claim 1, wherein the salt is a hydrobromide salt crystal form II, characterized in that the X-ray powder diffraction pattern of the hydrobromide salt crystal form II is at the following 2 theta angle There are diffraction peaks: 3.64±0.2°, 7.20±0.2°, 10.80±0.2°, 11.39±0.2°, 12.36±0.2°, 14.52±0.2°, 17.14±0.2°, 18.07±0.2°, 19.39±0.2°, 21.70±0.2°, 22.30±0.2°, 23.18±0.2°, 23.89±0.2°, 25.38±0.2°, 26.26±0.2°, 29.15±0.2°, 32.76±0.2°, 36.92±0.2°, 38.93±0.2°.
  10. 根据权利要求1所述的酸加成盐，其中，所述的盐为氢溴酸盐晶型II，其特征在于，所述氢溴酸盐晶型II具有基本上如图2所示的X射线粉末衍射图。The acid addition salt according to claim 1, wherein the salt is a hydrobromide salt crystal form II, characterized in that the hydrobromide salt crystal form II has an X substantially as shown in FIG. Ray powder diffraction pattern.
  11. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.79±0.2°,13.08±0.2°,17.00±0.2°,20.52±0.2°。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form I, characterized in that the X-ray powder diffraction pattern of the benzenesulfonate crystal form I is at the following 2 theta angle There are diffraction peaks: 6.79 ± 0.2 °, 13.08 ± 0.2 °, 17.00 ± 0.2 °, 20.52 ± 0.2 °.
  12. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.79±0.2°,10.22±0.2°,13.08±0.2°,13.59±0.2°,17.00±0.2°,20.52±0.2°,20.67±0.2°,22.74±0.2°,23.06±0.2°,25.55±0.2°。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form I, characterized in that the X-ray powder diffraction pattern of the benzenesulfonate crystal form I is at the following 2 theta angle There are diffraction peaks: 6.79±0.2°, 10.22±0.2°, 13.08±0.2°, 13.59±0.2°, 17.00±0.2°, 20.52±0.2°, 20.67±0.2°, 22.74±0.2°, 23.06±0.2°, 25.55 ± 0.2 °.
  13. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.79±0.2°,8.09±0.2°,8.83±0.2°,9.54±0.2°,10.22±0.2°,11.26±0.2°,13.08±0.2°,13.59±0.2°,14.35±0.2°,16.13±0.2°,17.00±0.2°,17.80±0.2°,18.50±0.2°,19.20±0.2°,20.52±0.2°,20.67±0.2°,20.90±0.2°,21.87±0.2°,22.17±0.2°,22.74±0.2°,23.06±0.2°,23.58±0.2°,23.91±0.2°,24.58±0.2°,25.55±0.2°,26.31±0.2°,27.17±0.2°,27.53±0.2°,27.83±0.2°,28.13±0.2°,28.84±0.2°,29.24±0.2°,29.92±0.2°,30.20±0.2°,30.50±0.2°,31.49±0.2°,33.01±0.2°,33.99±0.2°,35.28±0.2°,37.63±0.2°。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form I, characterized in that the X-ray powder diffraction pattern of the benzenesulfonate crystal form I is at the following 2 theta angle There are diffraction peaks: 6.79±0.2°, 8.09±0.2°, 8.83±0.2°, 9.54±0.2°, 10.22±0.2°, 11.26±0.2°, 13.08±0.2°, 13.59±0.2°, 14.35±0.2°, 16.13±0.2°, 17.00±0.2°, 17.80±0.2°, 18.50±0.2°, 19.20±0.2°, 20.52±0.2°, 20.67±0.2°, 20.90±0.2°, 21.87±0.2°, 22.17±0.2°, 22.74±0.2°, 23.06±0.2°, 23.58±0.2°, 23.91±0.2°, 24.58±0.2°, 25.55±0.2°, 26.31±0.2°, 27.17±0.2°, 27.53±0.2°, 27.83±0.2°, 28.13±0.2°, 28.84±0.2°, 29.24±0.2°, 29.92±0.2°, 30.20±0.2°, 30.50±0.2°, 31.49±0.2°, 33.01±0.2°, 33.99±0.2°, 35.28±0.2°, 37.63 ± 0.2 °.
  14. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I具有基本上如图3所示的X射线粉末衍射图。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form I, characterized in that the benzene sulfonate crystal form I has an X substantially as shown in FIG. Ray powder diffraction pattern.
  15. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I的差示扫描量热图包含180.99℃±3℃的吸热峰。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form I, characterized in that the differential scanning calorimetry of the benzenesulfonate crystal form I comprises 180.99 ° C An endothermic peak of ±3 °C.
  16. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型I，其特征在于，所述苯磺酸盐晶型I具有基本上如图4所示的差示扫描量热图。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form I, characterized in that the benzene sulfonate crystal form I has a difference substantially as shown in FIG. Show the scanning calorimetry map.
  17. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：9.49±0.2°,16.48±0.2°,17.20±0.2°,18.37±0.2°,19.21±0.2°,32.91±0.2°。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form II, characterized in that the X-ray powder diffraction pattern of the benzenesulfonate salt form II is at the following 2 theta angle There are diffraction peaks: 9.49 ± 0.2 °, 16.48 ± 0.2 °, 17.20 ± 0.2 °, 18.37 ± 0.2 °, 19.21 ± 0.2 °, 32.91 ± 0.2 °.
  18. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：7.23±0.2°,9.29±0.2°,9.49±0.2°,16.48±0.2°,17.20±0.2°,18.37±0.2°,19.21±0.2°,19.82±0.2°,28.79±0.2°,29.52±0.2°,32.91±0.2°。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form II, characterized in that the X-ray powder diffraction pattern of the benzenesulfonate salt form II is at the following 2 theta angle There are diffraction peaks: 7.23 ± 0.2 °, 9.29 ± 0.2 °, 9.49 ± 0.2 °, 16.48 ± 0.2 °, 17.20 ± 0.2 °, 18.37 ± 0.2 °, 19.21 ± 0.2 °, 19.82 ± 0.2 °, 28.79 ± 0.2 °, 29.52 ± 0.2 °, 32.91 ± 0.2 °.
  19. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：5.32±0.2°,5.73±0.2°,7.23±0.2°,8.91±0.2°,9.29±0.2°,9.49±0.2°,9.88±0.2°,13.26±0.2°,13.57±0.2°,14.88±0.2°,15.51±0.2°,15.80±0.2°,16.48±0.2°,17.20±0.2°,17.82±0.2°,18.37±0.2°,19.21±0.2°,19.82±0.2°,20.77±0.2°,21.28±0.2°,21.68±0.2°,22.29±0.2°,23.47±0.2°,23.82±0.2°,24.49±0.2°,25.88±0.2°,27.13±0.2°,27.71±0.2°, 28.79±0.2°,29.52±0.2°,29.95±0.2°,32.12±0.2°,32.91±0.2°。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form II, characterized in that the X-ray powder diffraction pattern of the benzenesulfonate salt form II is at the following 2 theta angle There are diffraction peaks: 5.32 ± 0.2 °, 5.73 ± 0.2 °, 7.23 ± 0.2 °, 8.91 ± 0.2 °, 9.29 ± 0.2 °, 9.49 ± 0.2 °, 9.88 ± 0.2 °, 13.26 ± 0.2 °, 13.57 ± 0.2 °, 14.88±0.2°, 15.51±0.2°, 15.80±0.2°, 16.48±0.2°, 17.20±0.2°, 17.82±0.2°, 18.37±0.2°, 19.21±0.2°, 19.82±0.2°, 20.77±0.2°, 21.28±0.2°, 21.68±0.2°, 22.29±0.2°, 23.47±0.2°, 23.82±0.2°, 24.49±0.2°, 25.88±0.2°, 27.13±0.2°, 27.71±0.2°, 28.79 ± 0.2 °, 29.52 ± 0.2 °, 29.95 ± 0.2 °, 32.12 ± 0.2 °, 32.91 ± 0.2 °.
  20. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II具有基本上如图5所示的X射线粉末衍射图。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form II, characterized in that the benzenesulfonate salt form II has an X substantially as shown in FIG. Ray powder diffraction pattern.
  21. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II的差示扫描量热图包含159.45℃±3℃的吸热峰。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form II, wherein the differential scanning calorimetry of the benzenesulfonate salt form II comprises 159.45 ° C. An endothermic peak of ±3 °C.
  22. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型II，其特征在于，所述苯磺酸盐晶型II具有基本上如图6所示的差示扫描量热图。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form II, characterized in that the benzenesulfonate salt form II has a difference substantially as shown in FIG. Show the scanning calorimetry map.
  23. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.73±0.2°,7.40±0.2°,11.12±0.2°,14.85±0.2°,19.05±0.2°。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form III, characterized in that the X-ray powder diffraction pattern of the benzenesulfonate crystal form III is at the following 2 theta angle There are diffraction peaks: 3.73 ± 0.2 °, 7.40 ± 0.2 °, 11.12 ± 0.2 °, 14.85 ± 0.2 °, 19.05 ± 0.2 °.
  24. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.73±0.2°,7.40±0.2°,11.12±0.2°,14.85±0.2°,16.63±0.2°,19.05±0.2°,20.24±0.2°,20.75±0.2°,22.44±0.2°,25.95±0.2°。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form III, characterized in that the X-ray powder diffraction pattern of the benzenesulfonate crystal form III is at the following 2 theta angle There are diffraction peaks: 3.73±0.2°, 7.40±0.2°, 11.12±0.2°, 14.85±0.2°, 16.63±0.2°, 19.05±0.2°, 20.24±0.2°, 20.75±0.2°, 22.44±0.2°, 25.95 ± 0.2 °.
  25. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的X射线粉末衍射图谱在下列2θ角处具有衍射峰：3.73±0.2°,7.40±0.2°,8.10±0.2°,9.14±0.2°,9.79±0.2°,11.12±0.2°,12.02±0.2°,14.53±0.2°,14.85±0.2°,15.70±0.2°,16.63±0.2°,17.11±0.2°,17.87±0.2°,19.05±0.2°,20.24±0.2°,20.75±0.2°,21.45±0.2°,21.87±0.2°,22.44±0.2°,23.36±0.2°,25.95±0.2°,26.36±0.2°,29.24±0.2°,37.70±0.2°。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form III, characterized in that the X-ray powder diffraction pattern of the benzenesulfonate crystal form III is at the following 2 theta angle There are diffraction peaks: 3.73±0.2°, 7.40±0.2°, 8.10±0.2°, 9.14±0.2°, 9.79±0.2°, 11.12±0.2°, 12.02±0.2°, 14.53±0.2°, 14.85±0.2°, 15.70±0.2°, 16.63±0.2°, 17.11±0.2°, 17.87±0.2°, 19.05±0.2°, 20.24±0.2°, 20.75±0.2°, 21.45±0.2°, 21.87±0.2°, 22.44±0.2°, 23.36 ± 0.2 °, 25.95 ± 0.2 °, 26.36 ± 0.2 °, 29.24 ± 0.2 °, 37.70 ± 0.2 °.
  26. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III具有基本上如图7所示的X射线粉末衍射图。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form III, characterized in that the benzenesulfonate salt form III has an X substantially as shown in FIG. Ray powder diffraction pattern.
  27. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III的差示扫描量热图包含96.67℃±3℃和140.76℃±3℃的吸热峰。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form III, wherein the differential scanning calorimetry of the benzenesulfonate crystal form III comprises 96.67 ° C. Endothermic peak at ±3 ° C and 140.76 ° C ± 3 ° C.
  28. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐晶型III，其特征在于，所述苯磺酸盐晶型III具有基本上如图8所示的差示扫描量热图。The acid addition salt according to claim 1, wherein the salt is a benzenesulfonate crystal form III, characterized in that the benzenesulfonate salt form III has a difference substantially as shown in FIG. Show the scanning calorimetry map.
  29. 根据权利要求1所述的酸加成盐，其中，所述的盐为苯磺酸盐无定形，其特征在于，所述苯磺酸盐无定形具有基本上如图9所示的X射线粉末衍射图。The acid addition salt according to claim 1, wherein said salt is amorphous to besylate salt, characterized in that said besylate salt has an amorphous X-ray powder substantially as shown in Fig. 9. Diffraction pattern.
  30. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：8.96±0.2°,9.97±0.2°,12.67±0.2°,17.91±0.2°,26.77±0.2°。The acid addition salt according to claim 1, wherein the salt is a β-naphthalene sulfonate crystal form I, characterized in that the X-ray powder diffraction pattern of the β-naphthalene sulfonate crystal form I There are diffraction peaks at the following 2 theta angles: 8.96 ± 0.2 °, 9.97 ± 0.2 °, 12.67 ± 0.2 °, 17.91 ± 0.2 °, 26.77 ± 0.2 °.
  31. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：8.96±0.2°,9.97±0.2°,12.67°±0.2,13.45±0.2°,17.91±0.2°,20.08±0.2°,22.22±0.2°,26.77±0.2°。The acid addition salt according to claim 1, wherein the salt is a β-naphthalene sulfonate crystal form I, characterized in that the X-ray powder diffraction pattern of the β-naphthalene sulfonate crystal form I There are diffraction peaks at the following 2 theta angles: 8.96 ± 0.2 °, 9.97 ± 0.2 °, 12.67 ° ± 0.2, 13.45 ± 0.2 °, 17.91 ± 0.2 °, 20.08 ± 0.2 °, 22.22 ± 0.2 °, 26.77 ± 0.2 °.
  32. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I的X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.50±0.2°,6.35±0.2°,7.06±0.2°,8.43±0.2°,8.96±0.2°,9.97±0.2°,11.92±0.2°,12.67±0.2°,13.45±0.2°,13.78±0.2°,14.16±0.2°,14.75±0.2°,15.80±0.2°,16.12±0.2°,16.74±0.2°,16.91±0.2°,17.91±0.2°,18.64±0.2°,19.05±0.2°,19.52±0.2°,20.08±0.2°,20.65±0.2°,22.22±0.2°,22.51±0.2°,22.75±0.2°,23.17±0.2°,23.73±0.2°,23.99±0.2°,24.42±0.2°,25.23±0.2°,25.59±0.2°,26.01±0.2°,26.77±0.2°,27.06±0.2°,27.79±0.2°,30.09±0.2°,31.14±0.2°,31.71±0.2°,31.92±0.2°,35.25°±0.2,36.14±0.2°,37.15±0.2°,38.22±0.2°。The acid addition salt according to claim 1, wherein the salt is a β-naphthalene sulfonate crystal form I, characterized in that the X-ray powder diffraction pattern of the β-naphthalene sulfonate crystal form I There are diffraction peaks at the following 2θ angles: 4.50±0.2°, 6.35±0.2°, 7.06±0.2°, 8.43±0.2°, 8.96±0.2°, 9.97±0.2°, 11.92±0.2°, 12.67±0.2°, 13.45 ±0.2°, 13.78±0.2°, 14.16±0.2°, 14.75±0.2°, 15.80±0.2°, 16.12±0.2°, 16.74±0.2°, 16.91±0.2°, 17.91±0.2°, 18.64±0.2°, 19.05 ±0.2°, 19.52±0.2°, 20.08±0.2°, 20.65±0.2°, 22.22±0.2°, 22.51±0.2°, 22.75±0.2°, 23.17±0.2°, 23.73±0.2°, 23.99±0.2°, 24.42 ±0.2°, 25.23±0.2°, 25.59±0.2°, 26.01±0.2°, 26.77±0.2°, 27.06±0.2°, 27.79±0.2°, 30.09±0.2°, 31.14±0.2°, 31.71±0.2°, 31.92 ±0.2°, 35.25°±0.2, 36.14±0.2°, 37.15±0.2°, 38.22±0.2°.
  33. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型I，其特征在于，所述β- 萘磺酸盐晶型I具有基本上如图10所示的X射线粉末衍射图。The acid addition salt according to claim 1, wherein the salt is a β-naphthalene sulfonate crystal form I, characterized in that the β- Naphthalenesulfonate Form I has an X-ray powder diffraction pattern substantially as shown in FIG.
  34. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I的差示扫描量热图包含163.92℃±3℃和220.42℃±3℃的吸热峰。The acid addition salt according to claim 1, wherein the salt is β-naphthalene sulfonate crystal form I, characterized in that the differential scanning calorimetry of the β-naphthalene sulfonate crystal form I The graph contains endotherms at 163.92 °C ± 3 °C and 220.42 °C ± 3 °C.
  35. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型I，其特征在于，所述β-萘磺酸盐晶型I具有基本上如图11所示的差示扫描量热图。The acid addition salt according to claim 1, wherein the salt is a β-naphthalene sulfonate crystal form I, characterized in that the β-naphthalene sulfonate crystal form I has substantially the same shape as in FIG. The differential scanning calorimetry shown.
  36. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.43±0.2°,13.60±0.2°,19.41±0.2°,19.62±0.2°,21.50±0.2°,22.45±0.2°。The acid addition salt according to claim 1, wherein the salt is β-naphthalenesulfonate crystal form II, characterized in that the X-ray powder diffraction pattern of the β-naphthalenesulfonate crystal form II There are diffraction peaks at the following 2 theta angles: 6.43 ± 0.2 °, 13.60 ± 0.2 °, 19.41 ± 0.2 °, 19.62 ± 0.2 °, 21.50 ± 0.2 °, 22.45 ± 0.2 °.
  37. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.43±0.2°,13.60±0.2°,16.75±0.2°,16.95±0.2°,19.41±0.2°,19.62±0.2°,19.97±0.2°,20.65±0.2°,21.50±0.2°,21.82±0.2°,22.45±0.2°,25.97±0.2°。The acid addition salt according to claim 1, wherein the salt is β-naphthalenesulfonate crystal form II, characterized in that the X-ray powder diffraction pattern of the β-naphthalenesulfonate crystal form II There are diffraction peaks at the following 2 theta angles: 6.43 ± 0.2 °, 13.60 ± 0.2 °, 16.75 ± 0.2 °, 16.95 ± 0.2 °, 19.41 ± 0.2 °, 19.62 ± 0.2 °, 19.97 ± 0.2 °, 20.65 ± 0.2 °, 21.50 ±0.2°, 21.82±0.2°, 22.45±0.2°, 25.97±0.2°.
  38. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐型II的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.43±0.2°,8.10±0.2°,9.15±0.2°,9.73±0.2°,10.57±0.2°,12.64±0.2°,12.90±0.2°,13.60±0.2°,16.04±0.2°,16.26±0.2°,16.75±0.2°,16.95±0.2°,17.43±0.2°,17.90±0.2°,18.37±0.2°,19.41±0.2°,19.62±0.2°,19.97±0.2°,20.65±0.2°,21.50±0.2°,21.82±0.2°,22.07±0.2°,22.45±0.2°,23.32±0.2°,24.11±0.2°,24.82±0.2°,25.70±0.2°,25.97±0.2°,26.49±0.2°,27.17±0.2°,27.50±0.2°,28.04±0.2°,28.62±0.2°,29.55±0.2°,29.96±0.2°,30.49±0.2°,31.17±0.2°,32.10±0.2°,33.52±0.2°,34.53±0.2°,35.38±0.2°,36.03±0.2°,36.99±0.2°,38.19±0.2°,39.50±0.2°。The acid addition salt according to claim 1, wherein the salt is β-naphthalenesulfonate crystal form II, characterized in that the X-ray powder diffraction pattern of the β-naphthalenesulfonate type II is The following 2θ angles have diffraction peaks: 6.43±0.2°, 8.10±0.2°, 9.15±0.2°, 9.73±0.2°, 10.57±0.2°, 12.64±0.2°, 12.90±0.2°, 13.60±0.2°, 16.04± 0.2°, 16.26±0.2°, 16.75±0.2°, 16.95±0.2°, 17.43±0.2°, 17.90±0.2°, 18.37±0.2°, 19.41±0.2°, 19.62±0.2°, 19.97±0.2°, 20.65± 0.2°, 21.50±0.2°, 21.82±0.2°, 22.07±0.2°, 22.45±0.2°, 23.32±0.2°, 24.11±0.2°, 24.82±0.2°, 25.70±0.2°, 25.97±0.2°, 26.49± 0.2°, 27.17±0.2°, 27.50±0.2°, 28.04±0.2°, 28.62±0.2°, 29.55±0.2°, 29.96±0.2°, 30.49±0.2°, 31.17±0.2°, 32.10±0.2°, 33.52± 0.2°, 34.53±0.2°, 35.38±0.2°, 36.03±0.2°, 36.99±0.2°, 38.19±0.2°, 39.50±0.2°.
  39. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II具有基本上如图12所示的X射线粉末衍射图。The acid addition salt according to claim 1, wherein the salt is β-naphthalene sulfonate crystal form II, characterized in that the β-naphthalene sulfonate crystal form II has substantially the same structure as in Fig. 12. The X-ray powder diffraction pattern shown.
  40. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II的差示扫描量热图包含221.99℃±3℃的吸热峰。The acid addition salt according to claim 1, wherein the salt is β-naphthalenesulfonate crystal form II, characterized in that the differential scanning calorimetry of the β-naphthalenesulfonate crystal form II The graph contains an endothermic peak at 221.99 °C ± 3 °C.
  41. 根据权利要求1所述的酸加成盐，其中，所述的盐为β-萘磺酸盐晶型II，其特征在于，所述β-萘磺酸盐晶型II具有基本上如图13所示的差示扫描量热图。The acid addition salt according to claim 1, wherein the salt is β-naphthalene sulfonate crystal form II, characterized in that the β-naphthalene sulfonate crystal form II has substantially the same structure as in FIG. The differential scanning calorimetry shown.
  42. 一种药物组合物，其包含权利要求1-41任意一项所述的酸加成盐或其组合；和药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。A pharmaceutical composition comprising the acid addition salt of any one of claims 1 to 41, or a combination thereof; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or a combination thereof.
  43. 权利要求1-41任意一项所述的酸加成盐或其组合或权利要求42所述的药物组合物在制备药物中的用途，所述药物用于预防、治疗或减轻患者组织或器官纤维化疾病。Use of an acid addition salt or a combination thereof according to any one of claims 1 to 41 or a pharmaceutical composition according to claim 42 for the preparation of a medicament for preventing, treating or ameliorating a tissue or organ fiber of a patient Disease.
  44. 根据权利要求43所述的用途，其中，所述的组织或器官纤维化疾病为肾间质纤维化、肾小球硬化、肝纤维化、肺纤维化、特发性肺纤维化、腹膜纤维化、心肌纤维化、皮肤纤维化、手术后粘连、良性***肥大症、骨骼肌纤维化、硬皮病、多发性硬化症、胰腺纤维化、肝硬化、肌肉瘤、神经纤维瘤、肺间质纤维化、糖尿病肾病、阿尔茨海默病或血管纤维化疾病。 The use according to claim 43, wherein the tissue or organ fibrosis disease is renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, peritoneal fibrosis , myocardial fibrosis, cutaneous fibrosis, postoperative adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, muscle tumor, neurofibroma, pulmonary interstitial fibrosis , diabetic nephropathy, Alzheimer's disease or vascular fibrosis.
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