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WO2017162139A1 - 用于治疗或预防jak相关疾病药物的盐酸盐晶型及其制备方法 - Google Patents

用于治疗或预防jak相关疾病药物的盐酸盐晶型及其制备方法 Download PDF

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WO2017162139A1
WO2017162139A1 PCT/CN2017/077492 CN2017077492W WO2017162139A1 WO 2017162139 A1 WO2017162139 A1 WO 2017162139A1 CN 2017077492 W CN2017077492 W CN 2017077492W WO 2017162139 A1 WO2017162139 A1 WO 2017162139A1
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WO
WIPO (PCT)
Prior art keywords
filgotinib
crystal form
hydrochloride salt
crystal
filgotinib hydrochloride
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PCT/CN2017/077492
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English (en)
French (fr)
Inventor
陈敏华
张炎锋
刘凯
张晓宇
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Crystal Pharmatech Co Ltd
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Crystal Pharmatech Co Ltd
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Priority to EP17769416.3A priority Critical patent/EP3434675A4/en
Priority to CN201780013652.0A priority patent/CN109071531A/zh
Priority to CA3018610A priority patent/CA3018610A1/en
Priority to KR1020187030279A priority patent/KR20180120273A/ko
Priority to US16/087,252 priority patent/US20190100519A1/en
Priority to AU2017239301A priority patent/AU2017239301A1/en
Application filed by Crystal Pharmatech Co Ltd filed Critical Crystal Pharmatech Co Ltd
Priority to MX2018011422A priority patent/MX2018011422A/es
Priority to JP2018549510A priority patent/JP2019509306A/ja
Publication of WO2017162139A1 publication Critical patent/WO2017162139A1/zh
Priority to IL261862A priority patent/IL261862A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of pharmaceutical crystal technology.
  • it relates to a novel hydrochloride salt form for use in the treatment or prevention of a medicament for JAK-related diseases, and a preparation method and use thereof.
  • Polymorphism or polymorphism is a peculiar property of certain molecular and molecular compositions.
  • the same molecules may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties such as solubility and stability. , thermal properties, mechanical properties, purification capabilities, X-ray diffraction patterns, infrared absorption spectra, Raman spectroscopy and solid state nuclear magnetic.
  • One or more analytical assays can be used to distinguish between different crystal forms of the same molecule or combination of molecules.
  • New crystalline forms of pharmaceutically active ingredients have been found to produce more processing advantages or to provide materials with better physicochemical properties, such as better bioavailability, storage stability, and ease of use. Processed, easy to purify or as an intermediate crystal form that facilitates conversion to other crystal forms. New crystalline forms of certain pharmaceutically useful compounds can also help improve the performance of the drug. It expands the formulation of raw materials that can be used in the formulation, such as improved dissolution, improved shelf life, easier processing, and the like.
  • JAK1 is essential for the inhibition of inflammatory processes, inhibition of JAK2, JAK3 and TYK2 is not necessary to inhibit inflammation, but is associated with some adverse reactions, such as inhibition of JAK2 and anemia, inhibition of JAK3 and immunosuppression.
  • Filgotinib (GLPG0634) is a selective JAK1 inhibitor with IC 50 of 10 nM, 28 nM, 810 nM, and 116 nM for JAK1, JAK2, JAK3, and TYK2, respectively. Clinical trials have shown that it does not cause an abnormal increase in anemia and LDL.
  • the chemical name of the compound is: N-[5-[4-[(1,1-dioxo-1-thiomorpholin-4-yl)methyl]phenyl][1,2,4] Zizo[1,5-a]pyridin-2-yl]cyclopropanamide; chemical formula: C 21 H 23 N 5 O 3 S; molecular weight: 425.5; chemical structural formula as shown in formula (I).
  • Filgotinib is a 1:1 hydrochloride salt, and the crystalline form of the salt (including 1:1:0 anhydrate, 1) is disclosed in the patent document WO2015117981A1, which is hereby incorporated by reference. : 1:3 trihydrate, 1:1:1 methanolate and 1:1:1.5 formate).
  • the developable value of the solvate is inferior to the anhydrate and the hydrate, the solvate is unstable, the solvent may be removed in a long-term place, and the safety of the solvate is low; and the inventors of the present invention found that the patent The 1:1:3 trihydrate is not stable at low water activity.
  • the present invention provides a novel crystalline form of Filgotinib hydrochloride as shown in formula (II), a preparation method thereof and use thereof.
  • Form A of Filgotinib hydrochloride
  • the X-ray powder diffraction of the Form A has a characteristic peak at a diffraction angle 2 ⁇ of 7.3 ° ⁇ 0.2 °, 14.7 ° ⁇ 0.2 °, and 29.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystalline form A is in the form of
  • the angle of incidence 2 ⁇ is 7.3° ⁇ 0.2°, 12.4° ⁇ 0.2°, 14.7° ⁇ 0.2°, 17.4° ⁇ 0.2°, 20.6° ⁇ 0.2°, and 29.6° ⁇ 0.2°.
  • the X-ray powder diffraction of Form A is 7.3 ° ⁇ 0.2 °, 8.9 ° ⁇ 0.2 °, 12.4 ° ⁇ 0.2 °, 14.7 ° ⁇ 0.2 °, 16.8 ° at a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of Form A is shown in FIG.
  • Form A of the present invention is a hydrate; further, it has a mass loss gradient of about 9% to 13% when heated to about 192 °C.
  • the present invention also provides a preparation method of the crystal form A, which comprises adding hydrochloric acid to an alkyl nitrile system using a Filgotinib free base, stirring the reaction at a certain temperature, separating, and drying. Get, or use the known Filgotinib. HCl.
  • the crystal form of 3H2O is obtained by suspension and crystallization at a certain temperature in an alkylnitrile system, separating and drying;
  • the alkyl nitrile is a C 2 -C 3 alkyl nitrile or a mixture thereof;
  • the alkyl nitrile is selected from one of acetonitrile, propionitrile or a mixture thereof;
  • the alkyl nitrile is acetonitrile
  • the molar ratio of Filgotinib free base to hydrochloric acid is 1:1.0-1:1.5, preferably 1:1.0;
  • the Filgotinib free base or known Filgotinib. HCl Preferably, the Filgotinib free base or known Filgotinib. HCl.
  • the amount of the 3H2O crystal form is 20-70 times, more preferably 40-50 times, the solubility in the solvent system at the reaction or operating temperature;
  • reaction temperature or operating temperature is 10-40 ° C, more preferably room temperature;
  • the crystallization time is from 36 to 72 hours, more preferably 48 hours.
  • the Filgotinib hydrochloride salt Form A of the present invention has the following beneficial properties:
  • the present invention also provides Form B of Filgotinib hydrochloride (hereinafter referred to as "Form B").
  • the X-ray powder diffraction pattern of Form B is at a diffraction angle 2 ⁇ There are characteristic peaks at 7.1 ° ⁇ 0.2 °, 13.2 ° ⁇ 0.2 °, and 14.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the Form B is 7.1 ° ⁇ 0.2 °, 13.2 ° ⁇ 0.2 °, 14.2 ° ⁇ 0.2 °, 18.8 ° ⁇ 0.2 ° at the diffraction angle 2 ⁇ . , 20.6 ° ⁇ 0.2 °, 28.7 ° ⁇ 0.2 ° at the characteristic peak.
  • the X-ray powder diffraction pattern of Form B is 7.1 ° ⁇ 0.2 °, 13.2 ° ⁇ 0.2 °, 14.2 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 16.7 at diffraction angle 2 ⁇ . ° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, 22.0° ⁇ 0.2°, and 28.7° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of Form B of Filgotinib hydrochloride is shown in FIG.
  • Form B of the present invention is a hydrate; it has a mass loss gradient of about 11% to 14% when heated to 200 °C.
  • the present invention also provides a preparation method of the crystal form B, which comprises adding hydrochloric acid to a ketone solvent system using a Filgotinib free base, stirring the reaction at a certain temperature, separating, and drying. Get, or use the known Filgotinib. HCl.
  • the 3H 2 O crystal form is obtained by suspension and crystallization at a certain temperature in a ketone solvent system, separating and drying;
  • the ketone solvent is acetone
  • the molar ratio of the Filgotinib free base to hydrochloric acid is 1:1.0-1:1.5, preferably 1:1.0;
  • the Filgotinib free base or known Filgotinib. HCl Preferably, the Filgotinib free base or known Filgotinib. HCl.
  • the amount of the 3H 2 O crystal form is 20-60 times, more preferably 40-50 times, the solubility in the solvent system at the reaction or operating temperature;
  • the reaction or operating temperature is 10-40 ° C, more preferably room temperature;
  • the crystallization time is 24-72 hours, more preferably 48 hours.
  • the Filgotinib hydrochloride salt Form B of the present invention has the following beneficial properties:
  • the crystalline form B has the advantage of having a higher solubility.
  • the present invention provides a crystalline form C of Filgotinib hydrochloride (hereinafter referred to as "Form C").
  • the X-ray powder diffraction pattern of the Form C is at a diffraction angle 2 ⁇ There are characteristic peaks at 7.0 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2 °, and 20.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form C is at a diffraction angle 2 ⁇ of 7.0° ⁇ 0.2°, 14.0° ⁇ 0.2°, 16.7° ⁇ 0.2°, 18.7° ⁇ 0.2°. , 20.5 ° ⁇ 0.2 °, 28.3 ° ⁇ 0.2 ° at the characteristic peak.
  • the X-ray powder diffraction pattern of Form C is at a diffraction angle 2 ⁇ of 7.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 14.0° ⁇ 0.2°, 14.8° ⁇ 0.2°, 15.8. ° ⁇ 0.2°, 16.7° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.5° ⁇ 0.2°, and 28.3° ⁇ 0.2° have characteristic peaks.
  • the Form C using Cu-K ⁇ radiation, has an X-ray powder diffraction pattern represented by a 2 ⁇ angle having a map substantially as shown in FIG.
  • the crystalline form C of the present invention is a hydrate; it has a mass loss gradient of about 10.0% to 13% when heated to 180 °C.
  • the present invention also provides a process for preparing the crystalline form C, which comprises adding hydrochloric acid to a ketone solvent system having a carbon number of 4 or more using a Filgotinib free base, and stirring the reaction at a certain temperature. Crystallization, separation, drying, or using known Filgotinib. HCl.
  • the 3H2O crystal form is obtained by suspending and stirring at a certain temperature in a ketone solvent system having a carbon number of 4 or more, separating and drying;
  • the ketone solvent having a carbon number of 4 or more is a C 4 -C 7 alkyl ketone or a mixture thereof;
  • the ketone solvent having a carbon number of 4 or more is selected from one of methyl ethyl ketone and methyl isobutyl ketone or a mixture thereof;
  • the ketone solvent having a carbon number of 4 or more is methyl ethyl ketone
  • the molar ratio of the Filgotinib free base to hydrochloric acid is 1:1.0-1:1.5, preferably 1:1.0;
  • the reaction or operating temperature is 10-40 ° C, more preferably room temperature;
  • the crystallization time is 24-72 hours, more preferably 48 hours.
  • the Filgotinib hydrochloride Form C of the present invention has the following beneficial properties:
  • the crystalline form C has the advantage that it has a higher solubility.
  • Form D of Filgotinib hydrochloride
  • the X-ray powder diffraction pattern of the crystal form D has a characteristic peak at a diffraction angle 2 ⁇ of 7.0° ⁇ 0.2°, 10.7° ⁇ 0.2°, and 17.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form D is at a diffraction angle 2 ⁇ of 7.0° ⁇ 0.2°, 8.0° ⁇ 0.2°, 8.7° ⁇ 0.2°, 10.7° ⁇ 0.2°. , 16.2 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 ° at the characteristic peak.
  • the X-ray powder diffraction pattern of Form D is at a diffraction angle 2 ⁇ of 7.0° ⁇ 0.2°, 8.0° ⁇ 0.2°, 8.7° ⁇ 0.2°, 10.7° ⁇ 0.2°, 16.2. ° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.4° ⁇ 0.2°, 22.1° ⁇ 0.2°, and characteristic peaks at 25.3° ⁇ 0.2°.
  • the Form D using Cu-K ⁇ radiation, has an X-ray powder diffraction pattern represented by an angle of 2 ⁇ having a map substantially as shown in FIG.
  • the crystalline form D of the present invention is a hydrate; it has a mass loss gradient of about 11.0% to 14% when heated to 180 °C.
  • the present invention also provides a preparation method of the crystal form D, which comprises adding hydrochloric acid to an alcohol solvent system using a Filgotinib free base, stirring the reaction at a certain temperature, separating, and drying. Get, or use the known Filgotinib. HCl.
  • the 3H2O crystal form is obtained by suspension and crystallization at a certain temperature in an alcohol solvent system, separating and drying;
  • the alcohol solvent is a C 2 -C 5 alcohol or a mixture thereof;
  • the alcohol solvent is selected from the group consisting of one or more of ethanol, propanol, and isopropanol;
  • the alcohol solvent is isopropanol
  • the molar ratio of the Filgotinib free base to hydrochloric acid is 1:1.0-1:1.5, preferably 1:1.0;
  • the Filgotinib free base or known Filgotinib. HCl Preferably, the Filgotinib free base or known Filgotinib. HCl.
  • the amount of the 3H 2 O crystal form is 20-70 times, more preferably 40-50 times, the solubility in the solvent system at the reaction or operating temperature;
  • the reaction or operating temperature is 10-40 ° C, more preferably room temperature;
  • the agitation time is from 24-72 hours, more preferably 48 hours.
  • the Filgotinib hydrochloride salt form D of the present invention has the following beneficial properties:
  • the solvent used in the preparation is low in toxicity.
  • the present invention solves the problems of prior art crystal forms by providing a new Form A, Form B, Form C or Form D of Filgotinib hydrochloride having a beneficial property selected from the following: Better stability, higher solubility, better flow.
  • the "known crystal form of Filgotinib hydrochloride” includes Filgotinib disclosed in the prior art document WO2015117981A1: HCl:H 2 O is 1:1:0 crystal-free, 1:1:3 trihydrate crystal , Filgotinib: HCl: MeOH is a 1:1:1 methanolic crystal and Filgotinib:HCl:HCO 2 H is a 1:1:1.5 formic acid crystal.
  • Filgotinib.HCl.3H 2 O crystal form or “prior art Filgotinib.HCl.3H 2 O crystal form” as used in the present invention specifically refers to documents 3.2.3.2 and 3.2.3.3 of WO2015117981A1. Sections and other related content, and the crystal forms confirmed by Table IX, Figure 5 and Figure 11.
  • the "room temperature” means 15 to 25 °C.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the “separation” is accomplished using conventional methods in the art, such as centrifugation or filtration.
  • the “centrifugation” operation was performed by placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until the solids all settled to the bottom of the centrifuge tube.
  • Drying can be carried out at room temperature or higher unless otherwise specified. Drying temperatures range from room temperature to about 60 ° C, or to 40 ° C, or to 50 ° C. The drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.
  • the novel crystalline form of the invention is pure, unitary, and substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Polymorphic forms of the drug can be obtained by methods including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, solvent loss, rapid volatilization, rapid temperature drop, slow temperature drop, vapor diffusion, and sublimation. Sometimes, different methods may also achieve the same crystallization. Polymorphs can be detected, discovered, and classified by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), optical microscopy, hygroscopicity, and the like.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • optical microscopy hygroscopicity, and the like.
  • the crystal form adopted by the crystal form of the present invention is a crystal slurry method, for example, a saturated solution of a sample (in the presence of insoluble solids) is stirred and crystallized in a solvent system, and the crystallization time is usually 24-72 hours.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of Form A, Form B, Form C or Form D of the present invention, And at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition may also comprise other crystalline forms or amorphous forms of pharmaceutically acceptable Filgotinib or a salt thereof, including but not limited to, for example, the known crystalline forms disclosed in WO2015117981A1.
  • Form A, Form B, Form C or Form D of the present invention may be administered as a separate active agent, or they may be administered in combination with other active agents, including having the same or similar therapeutic activity and for The combination of classes is determined to be other compounds that are safe and effective.
  • co-administration of the two (or more) active agents allows for a significant reduction in the dosage of each active agent used, thereby reducing the side effects seen, including but not limited to Those disclosed in the specification of the prior art document WO2010149769A1.
  • the above pharmaceutical composition can be formulated into a certain dosage form and administered by a suitable route.
  • a suitable route for example, oral, Parenteral (including subcutaneous, intramuscular, intravenous or intradermal), rectal, transdermal, nasal, vaginal and other routes.
  • Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, which may be suitable for rapid release, delayed release or Regulating release;
  • dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions; formulations suitable for rectal administration include suppositories or enemas; formulations suitable for transdermal administration include ointments, creams Agents, patches; dosage forms suitable for nasal administration include aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, suppositories, gels, pastes or sprays
  • the crystalline form of the present invention has unexpectedly low hygroscopicity and stability in water or aqueous ethanol solution, it is especially suitable for preparation into tablets, suspensions, capsules, disintegrating tablets, immediate release, and slow release. Release and controlled release tablets; further preferred are tablets, suspensions and capsules.
  • a pharmaceutically acceptable excipient in the above pharmaceutical composition, in the case of a solid oral dosage form including but not limited to: a diluent such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, Calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, poly Ethylene glycol or the like; a disintegrating agent such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; a lubricant such as stearic acid , magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; glidants, such as colloidal silica; complex forming agents, such as
  • the coating is applied to the tablet, for example to provide a shellac barrier coating, a sugar coating or a polymeric coating, a polymer in the coating layer such as hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl Cellulose, methacrylic polymer, hydroxypropyl cellulose or starch may also include anti-adherents such as silica, talc, opacifiers such as titanium dioxide, colorants such as iron oxide-based colorants.
  • suitable excipients include water, oils, alcohols, glycols, flavoring agents, preservatives, stabilizers, coloring agents, and the like; aqueous or nonaqueous sterile suspensions may be employed Containing suspending agents and thickeners; excipients suitable for aqueous suspensions include synthetic or natural gums such as gum arabic, arborvitae, alginate, dextran, sodium carboxymethylcellulose, methylcellulose , polyvinylpyrrolidone or gelatin.
  • the excipient of the aqueous or non-aqueous sterile injectable solution is usually sterile water, physiological saline or aqueous dextrose, may contain buffers, antioxidants, bacteriostatic agents and enable The pharmaceutical composition is isotonic with a blood solute.
  • Each excipient must be acceptable, compatible with the other ingredients in the formulation, and not deleterious to the patient.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art in the art. Ready.
  • Form A, Form B, Form C or Form D of the Filgotinib hydrochloride salt of the present invention is mixed with one or more pharmaceutically acceptable excipients, optionally with One or more other pharmaceutically active ingredients are mixed.
  • tablets, capsules, granules can be prepared by a process such as mixing, granulating, tableting or filling capsules; powders are prepared by mixing finely divided pharmaceutically active ingredients and excipients; solution and syrup
  • the agent can be prepared by dissolving the pharmaceutically active ingredient in a suitably flavored water or aqueous solution; the suspension can be prepared by dispersing the pharmaceutically active ingredient in a pharmaceutically acceptable carrier.
  • wet granulation process for solid preparations which is exemplified by wet granulation of tablets by mixing dry solids such as active ingredients, fillers, binders, etc., with a wetting agent such as water or alcohol Wet, the wetted solid is made into agglomerates or granules, and wet granulation is continued until the desired uniform particle size is obtained, followed by drying of the granulated product. The resulting dried granules are then mixed with a disintegrant, a lubricant, an anti-adhesive, etc., and compressed in a tablet machine; alternatively, coated with a suitable coating powder.
  • a wet granulation process for solid preparations which is exemplified by wet granulation of tablets by mixing dry solids such as active ingredients, fillers, binders, etc., with a wetting agent such as water or alcohol Wet, the wetted solid is made into agglomerates or granules, and wet granulation is
  • oral suspensions are also specifically mentioned, an advantage of this form of administration is that the patient does not have to swallow a solid form, especially for elderly people, children or patients with oral or throat damage who may have difficulty swallowing solid forms.
  • Suspensions are two-phase systems formed by dispersing solid particles in a liquid. Crystals that retain their original solid form in the aqueous or aqueous carrier of the suspension are expected to be more advantageous in maintaining the stability of the properties of the drug product.
  • Other components in the oral suspensions may include buffers, surfactants, viscosity modifiers, preservatives, antioxidants, colorants, flavoring agents, taste masking agents, and the like.
  • Form A, Form B, Form C or Form D of Filgotinib hydrochloride provided by the present invention has advantageous properties suitable for the above dosage forms.
  • the present invention provides the use of one or more of Form A, Form B, Form C or Form D of Filgotinib hydrochloride in the manufacture of a medicament having the effect of inhibiting JAK, particularly JAK1.
  • JAK refers to the Janus kinase (JAKs) family, which is a cytoplasmic tyrosine kinase that transduces cytokine signaling from a membrane receptor to a STAT transcription factor, and includes the following four JAK family members: JAK1 JAK2, JAK3 and TYK2.
  • the invention provides a method of treating and/or preventing a disease associated with one or more JAKs, in particular JAK1, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of Filgotinib hydrochloride One or more of Form A, Form B, Form C or Form D, or one or more of Form A, Form B, Form C or Form D Pharmaceutical composition.
  • JAKs in particular JAK1
  • Such patients include, but are not limited to, mammals, such as humans.
  • the diseases associated with one or more of the JAKs include, but are not limited to, inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired cartilage turnover, congenital cartilage malformations, and/or with IL6 Excessive secretion of related diseases.
  • the "inflammation” means a group of disorders including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, allergic airway diseases (eg asthma, rhinitis), inflammatory bowel Disease (eg, Crohn's disease, colitis), endotoxin-driven disease states (eg, complications after bypass surgery or chronic endotoxin status due to, for example, chronic heart failure) and related diseases involving cartilage, such as joint diseases.
  • the "inflammation” is selected from the group consisting of rheumatoid arthritis, osteoarthritis, allergic airway diseases (such as asthma), and inflammatory bowel disease.
  • the "autoimmune disease” means a group of diseases including obstructive airway diseases such as COPD, asthma (eg endogenous asthma, exogenous asthma, dust asthma, infant asthma), especially chronic or long-term formation.
  • Asthma eg advanced asthma and airway hyperresponsiveness
  • bronchitis including bronchial asthma
  • systemic lupus erythematosus SLE
  • multiple sclerosis type I diabetes and its associated complications
  • atopic eczema atopic Dermatitis
  • contact dermatitis also includes eczema dermatitis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis.
  • the "autoimmune disease” is selected from the group consisting of COPD, asthma, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease.
  • the "proliferative diseases” include, for example, cancer (for example, uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (such as polycythemia vera, primary thrombocytosis and myelofibrosis), leukemia (for example, acute myeloid leukemia). And acute lymphocytic leukemia), multiple myeloma, psoriasis, restenosis, sclerosing dermatitis or fibrosis.
  • the "proliferative disease” is selected from the group consisting of cancer, leukemia, multiple myeloma, and psoriasis.
  • the “cancer” includes malignant or benign growth of cells in the skin or body organs including, but not limited to, the breast, prostate, lung, kidney, pancreas, stomach or intestine. Cancer is prone to invade adjacent tissues and spread (metastasize) to distant organs such as bone, liver, lungs or brain.
  • the cancer of the present invention includes metastatic tumor cell types such as, but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma, as well as tissue cancer types such as, but not limited to, colorectal cancer, prostate cancer , small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer, and uterine leiomyosarcoma.
  • metastatic tumor cell types such as, but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • tissue cancer types such as, but not limited to, colorectal cancer, prostate cancer , small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer,
  • leukemia includes tumor diseases of blood and hematopoietic organs. Leukemia especially refers to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • the "transplant rejection” includes cells, tissues or solid organs such as islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, cardiopulmonary, kidney, liver, intestine, pancreas, trachea or esophagus. Acute or chronic rejection of allografts or xenografts, or graft versus host disease.
  • Figure 1 is an X-ray powder diffraction pattern of Form A obtained in Example 1 of the present invention.
  • Example 2 is an X-ray powder diffraction pattern of Form A obtained in Example 2 of the present invention.
  • Figure 3 is a DSC chart of Form A obtained in Example 2 of the present invention.
  • Example 4 is a TGA pattern of Form A obtained in Example 2 of the present invention.
  • Figure 5 is a hydrogen form of the crystal form A obtained in Example 2 of the present invention.
  • Figure 6 is a graph showing the one-cycle stability XRPD of Form A of the present invention.
  • Figure 7 is a comparison of the two-cycle stability XRPD of Form A of the present invention.
  • Figure 8 is an X-ray powder diffraction pattern of Form B obtained in Example 3 of the present invention.
  • Figure 9 is a hydrogen nuclear magnetic resonance spectrum of Form B obtained in Example 3 of the present invention.
  • Figure 10 is an X-ray powder diffraction pattern of Form B obtained in Example 4 of the present invention.
  • Figure 11 is an X-ray powder diffraction pattern of Form C obtained in Example 5 of the present invention.
  • Figure 12 is an X-ray powder diffraction pattern of Form C obtained in Example 6 of the present invention.
  • Figure 13 is an X-ray powder diffraction pattern of Form D obtained in Example 7 of the present invention.
  • Figure 14 is an X-ray powder diffraction pattern of Form D obtained in Example 8 of the present invention.
  • Figure 15 is a TGA chart of Form B obtained in Example 3 of the present invention.
  • Figure 16 is a TGA chart of Form C obtained in Example 5 of the present invention.
  • Figure 17 is a TGA chart of Form C obtained in Example 7 of the present invention.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential thermal analysis (DSC) data was taken from the TA Instruments Q200MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually, 1 to 10 mg of the sample is placed in an aluminum crucible (unless otherwise specified), and the sample is raised from room temperature to 250 ° C under the protection of 50 mL/min dry N 2 at a heating rate of 10 ° C/min. At the same time, the TA software records the change in heat of the sample during the heating process. In the present application, the melting point is reported as the starting temperature.
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500TGA, the instrument control software was Thermal AdVantage, and the analysis software was Universal Analysis. Usually, 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 300 ° C under the protection of 50 mL/min dry N 2 at a heating rate of 10 ° C/min using a segmented high-resolution detection method. At the same time, the TA software records the change in weight of the sample during the heating process.
  • H NMR data (1 HNMR) collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • Filgotinib free base used in the following examples and known Filgotinib. HCl.
  • the 3H 2 O crystal forms were all prepared according to the method described in WO2010149769A1.
  • the obtained crystalline solid is the crystalline form A of the present invention, and its X-ray powder diffraction data is shown in Table 1, Table 1.
  • the solid obtained in this example was crystalline form A, and its X-ray powder diffraction data is shown in Fig. 2 and Table 2, and its nuclear magnetic resonance spectrum is shown in Fig. 5.
  • the DSC of this crystal form is shown in Figure 3. It has two endothermic peaks, and the first endothermic peak begins to appear near 48 ° C. The endothermic peak is that crystal water will be lost near this temperature, at 195 ° C. A second endothermic peak begins to appear, which is the melting endotherm.
  • the TGA of this crystalline form had a mass loss gradient of about 10.0% when heated to 192 °C.
  • Fig. 6 is a comparison chart of XRPD stability for one week. From top to bottom, the crystal form A reference XRPD pattern, 25 ° C / 60% RH, 40 ° C / 75% RH , 60 ° C / 75% RH, 80 ° C XRPD chart;
  • Figure 7 is a two-week stability XRPD comparison chart, from top to bottom for the crystal form A reference XRPD chart, 5 ° C, 25 ° C / 60% RH, 40 XRPD pattern of °C/75% RH, 60 ° C / 75% RH, 80 ° C.
  • the solid obtained in this example was crystalline form B, and its X-ray powder diffraction data is shown in Fig. 8, and Table 4, and the nuclear magnetic resonance spectrum of the crystal form is shown in Fig. 9.
  • the solid obtained in this example was Form B, and the X-ray powder diffraction data thereof is shown in FIG. 10 and Table 5.
  • TGA of this crystalline form is shown in Figure 16, which, when heated to 180 ° C, has a mass loss gradient of about 11.6%.
  • the above solubility test results show that the crystalline form A, the crystalline form B, the crystalline form C, and the crystalline form D of the present invention are dissolved in the above saturated solution for 1 hour, 4 hours and 24 hours, compared with the reference crystalline form.
  • the resolution is higher than the solubility of the reference crystal form. Higher solubility helps to enhance the absorption and utilization of drugs in the body and improve the efficacy.
  • the crystal form A, the crystal form B, the crystal form C, the crystal form D of the present invention were measured using a Microtrac S3500 laser particle size analyzer (Microtrac S3500 equipped with a SDC (Sample Delivery Controller) injection system) and Filgotinib in the patent document WO2015117981 A1. Particle size distribution of hydrochloride trihydrate crystals (reference crystal form).
  • This test uses a wet method and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are shown in Table 12:
  • the flow rate is 60% of 60% of 65 ml/sec.
  • the prepared crystal form A (Example 2), Form B (Example 4), Form C (Example 5), Form D (Example 8) and the reference crystal form were measured for particle size distribution, and the results were measured. As shown in Table 13.
  • D10 indicates the particle size distribution (volume distribution) accounts for 10% of the particle size
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
  • D90 indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
  • the volume average particle diameter of the reference crystal form is 7.24 ⁇ m
  • the volume average particle diameter of the crystal form A of the present invention is 24.64 ⁇ m
  • the volume average particle diameter of the crystal form B is 44.66 ⁇ m
  • the volume average particle diameter of the crystal form C is 29.92 ⁇ m
  • the volume average particle diameter of the crystal form D is 41.24 ⁇ m, which is larger than the reference crystal form.
  • the larger the particle size of the drug the easier it is to filter and separate, saving time; at the same time, the larger the particle size of the drug has a certain effect on increasing the stability of the drug; the larger the particle size of the drug, the better the fluidity, which is beneficial for subsequent treatment.

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Abstract

用于治疗或预防JAK相关疾病的药物（Filgotinib）盐酸盐的晶型、其制备方法、药物组合物、制剂以及它们在预防和／或治疗与JAK家族激酶相关疾病中的用途被公开。相对于已知晶型，所述晶型具有在低水活度条件下更加稳定、制备工艺简单和／或溶解度更高等制剂学上更有利的性质。

Description

用于治疗或预防JAK相关疾病药物的盐酸盐晶型及其制备方法 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及用于治疗或预防JAK相关疾病药物的盐酸盐新晶型及其制备方法和用途。
背景技术
多晶型或者多晶现象是某些分子和分子组合物的特有性质，相同的分子可能因不同的排列形式而形成不同晶体，而这些晶体具有不同的晶体结构和物理性质，如溶解度、稳定性、热性质、机械性质、纯化能力、X射线衍射图谱、红外吸收图谱、拉曼光谱和固态核磁等。一种或多种分析检测方式可用于区分同一分子或分子组合物的不同晶型。
发现药物活性成分新的晶型(包括无水物、水合物、溶剂化物等)可能会产生更具加工优势或提供具有更好理化特性的物质，比如更好的生物利用度、储存稳定、易加工处理、易提纯或作为促进转化为其他晶型的中间体晶型。某些药学上有用的化合物的新晶型也可以帮助改善药物的性能。它扩大了制剂学上可选用的原料型态，例如改善溶出度、改善储藏期限、更容易加工等。
研究表明，JAK1对抑制炎症过程至关重要，抑制JAK2、JAK3和TYK2并不是抑制炎症必须的，反而与一些不良反应相关，比如抑制JAK2和贫血相关，抑制JAK3和免疫抑制有关。而Filgotinib(GLPG0634)是一种选择性JAK1抑制剂，其对JAK1、JAK2、JAK3和TYK2的IC50分别为10nM、28nM、810nM、和116nM，临床试验证明其不会引起贫血和LDL的异常增加；该化合物的化学名称为：N-[5-[4-[(1,1-二氧代-1-硫吗啉-4-基)甲基]苯基][1,2,4]三唑并[1,5-a]吡啶-2-基]环丙酰胺；化学式为：C21H23N5O3S；分子量为：425.5；化学结构式如式(I)所示。
Figure PCTCN2017077492-appb-000001
专利文献WO2010149769A1(其通过引用的方式并入到本申请中作为参考)中公开了Filgotinib的确认、制备和用途，然而，该专利文献并未披露任何其所制备获得的Filgotinib化合物或其盐的最终形态信息。
专利文献WO2015117981A1(其通过引用的方式并入到本申请中)中公开了Filgotinib：HCl为1:1的盐酸盐，以及该盐的结晶形式(包括1：1：0的无水物，1:1:3的三水合物、1:1:1的甲醇合物以及1:1:1.5的甲酸合物)。然而，溶剂合物的可开发价值不及无水物和水合物，溶剂合物不稳定，长期放置可能会脱溶剂，而且溶剂合物的安全性低；并且，本发明的发明人发现，该专利1:1:3的三水合物在低水活度下并不稳定。
因此，仍有需要开发Filgotinib的新的晶型，寻找具有更高的溶解度、更好的流动性和/或在低水活度的含水体系中具有更好的热力学稳定性等优势的晶型，以适于工业化药物制剂生产及后期药品运用中对于晶体性质或药品性质的严苛要求。
发明内容
针对现有技术的不足，本发明提供了如式(II)所示的Filgotinib盐酸盐新晶型及其制备方法和用途。
Figure PCTCN2017077492-appb-000002
根据本发明的目的，本发明提供Filgotinib盐酸盐的晶型A(以下称作“晶型A”)。
使用Cu-Kα辐射，所述晶型A的X-射线粉末衍射在衍射角2θ为7.3°±0.2°,14.7°±0.2°,29.6°±0.2°处有特征峰。
在本发明的一个优选实施方案中，所述晶型A的X-射线粉末衍射在衍 射角2θ为7.3°±0.2°,12.4°±0.2°,14.7°±0.2°,17.4°±0.2°,20.6°±0.2°,29.6°±0.2°处有特征峰。
在进一步优选的实施方案中，所述晶型A的X-射线粉末衍射在衍射角2θ为7.3°±0.2°,8.9°±0.2°,12.4°±0.2°,14.7°±0.2°,16.8°±0.2°,17.4°±0.2°,20.6°±0.2°,22.6°±0.2°,29.6°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型A的X-射线粉末衍射谱图如图2所示。
非限制性地，本发明所述晶型A为水合物；进一步地，其加热至约192℃时，具有约9％～13％的质量损失梯度。
根据本发明的目的，本发明还提供所述晶型A的制备方法，所述制备方法包括使用Filgotinib游离碱在烷基腈体系中加入盐酸，于一定温度下搅拌反应析晶，分离，干燥而获得，或者使用已知Filgotinib﹒HCl﹒3H2O晶型在烷基腈体系中，于一定温度下悬浮搅拌析晶，分离，干燥而获得；
其中：
所述烷基腈为C2～C3烷基腈或者它们的混合物；
优选地，所述烷基腈选自乙腈、丙腈中的一种或它们的混合物；
更优选地，所述烷基腈为乙腈；
当使用Filgotinib游离碱为原料时，Filgotinib游离碱与盐酸的摩尔比为1：1.0-1：1.5，优选为1：1.0；
优选地，所述Filgotinib游离碱或已知Filgotinib﹒HCl﹒3H2O晶型的用量为反应或操作温度下其在所述溶剂体系中的溶解度的20-70倍，更优选为40-50倍；
优选地，所述反应温度或操作温度为10-40℃，更优选为室温；
优选地，所述析晶时间为36-72小时，更优选为48小时。
本发明的Filgotinib盐酸盐晶型A具有以下有益性质：
①稳定性好；
②制备工艺简单，可重复放大；
③结晶度好；
此外，与现有技术的Filgotinib﹒HCl﹒3H2O及其他溶剂合物晶型相比，所述晶型A的优势在于其在低水活度(低湿度下)环境中比已知的这些晶型更加稳定。
根据本发明的目的，本发明还提供Filgotinib盐酸盐的晶型B(以下称作“晶型B”)。
使用Cu-Kα辐射，所述晶型B的X-射线粉末衍射图在衍射角2θ为 7.1°±0.2°、13.2°±0.2°、14.2°±0.2°处有特征峰。
在本发明的一个优选实施方案中，所述晶型B的X-射线粉末衍射图在衍射角2θ为7.1°±0.2°,13.2°±0.2°,14.2°±0.2°,18.8°±0.2°,20.6°±0.2°,28.7°±0.2°处有特征峰。
在进一步的优选实施方案中，所述晶型B的X-射线粉末衍射图在衍射角2θ为7.1°±0.2°,13.2°±0.2°,14.2°±0.2°,15.9°±0.2°,16.7°±0.2°,18.8°±0.2°,20.6°±0.2°,22.0°±0.2°,28.7°±0.2°处具有特征峰。
非限制性的，在本发明的一个具体实施方案中，Filgotinib盐酸盐的晶型B的X-射线粉末衍射图如图8所示。
非限制性地，本发明所述晶型B为水合物；其加热至200℃时，具有约11％～14％的质量损失梯度。
根据本发明的目的，本发明还提供所述晶型B的制备方法，所述制备方法包括使用Filgotinib游离碱在酮类溶剂体系中加入盐酸，于一定温度下搅拌反应析晶，分离，干燥而获得，或者使用已知Filgotinib﹒HCl﹒3H2O晶型在酮类溶剂体系中，于一定温度下悬浮搅拌析晶，分离，干燥而获得；
其中：
优选地，所述酮类溶剂为丙酮；
当使用Filgotinib游离碱为原料时，所述Filgotinib游离碱与盐酸的摩尔比为1：1.0-1：1.5，优选为1：1.0；
优选地，所述Filgotinib游离碱或已知Filgotinib﹒HCl﹒3H2O晶型的用量为反应或操作温度下其在所述溶剂体系中的溶解度的20-60倍，更优选为40-50倍；
优选地，所述反应或操作温度为10-40℃，更优选为室温；
优选地，所述析晶时间为24-72小时，更优选为48小时。
本发明的Filgotinib盐酸盐晶型B具有以下有益性质：
①溶解度高；
②结晶度好；
③能重复放大，适合工艺开发；
尤其是，与现有技术的Filgotinib﹒HCl﹒3H2O及其他溶剂合物晶型相比，所述晶型B的优势在于其具备更高的溶解度。
根据本发明的目的，本发明提供Filgotinib盐酸盐的晶型C(以下称作“晶型C”)。
使用Cu-Kα辐射，所述晶型C的X-射线粉末衍射图在衍射角2θ为 7.0°±0.2°,14.0°±0.2°,20.5°±0.2°处有特征峰。
在本发明的一个优选实施方案中，所述晶型C的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,14.0°±0.2°,16.7°±0.2°,18.7°±0.2°,20.5°±0.2°,28.3°±0.2°处有特征峰。
在进一步的优选实施方案中，所述晶型C的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,13.0°±0.2°,14.0°±0.2°,14.8°±0.2°,15.8°±0.2°,16.7°±0.2°,18.7°±0.2°,20.5°±0.2°,28.3°±0.2°处具有特征峰。
非限制性地，所述晶型C，使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图具有基本上如图11所示的图谱。
非限制性地，本发明所述晶型C为水合物；其加热至180℃时，具有约10.0％～13％的质量损失梯度。
根据本发明的目的，本发明还提供所述晶型C的制备方法，所述制备方法包括使用Filgotinib游离碱在碳原子数大于等于4的酮类溶剂体系中加入盐酸，于一定温度下搅拌反应析晶，分离，干燥而获得，或者使用已知Filgotinib﹒HCl﹒3H2O晶型在碳原子数大于等于4的酮类溶剂体系中，于一定温度下悬浮搅拌析晶，分离，干燥而获得；
其中：
优选地，所述碳原子数大于等于4的酮类溶剂为C4～C7烷基酮或者它们的混合物；
优选地，所述碳原子数大于等于4的酮类溶剂选自甲基乙基酮、甲基异丁基酮中的一种或它们的混合物；
更优选地，所述碳原子数大于等于4的酮类溶剂为甲基乙基酮；
当使用Filgotinib游离碱为原料时，所述Filgotinib游离碱与盐酸的摩尔比为1：1.0-1：1.5，优选为1：1.0；
优选地，所述反应或操作温度为10-40℃，更优选为室温；
优选地，所述析晶时间为24-72小时，更优选为48小时。
本发明的Filgotinib盐酸盐晶型C具有以下有益性质：
①溶解度大；
②易重复；
③制备简单；
尤其是，与现有技术的Filgotinib﹒HCl﹒3H2O及其他溶剂合物晶型相比，所述晶型C的优势在于其具备更高的溶解度。
根据本发明的目的，本发明提供Filgotinib盐酸盐的晶型D(以下称作“晶型D”)。
使用Cu-Kα辐射，所述晶型D的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,10.7°±0.2°,17.1°±0.2°处有特征峰。
在本发明的一个优选实施方案中，所述晶型D的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,8.0°±0.2°,8.7°±0.2°,10.7°±0.2°,16.2°±0.2°,17.1°±0.2°处有特征峰。
在进一步的优选实施方案中，所述晶型D的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,8.0°±0.2°,8.7°±0.2°,10.7°±0.2°,16.2°±0.2°,17.1°±0.2°,18.4°±0.2°,22.1°±0.2°,25.3°±0.2°处具有特征峰。
非限制性地，所述晶型D，使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图具有基本上如图13所示的图谱。
非限制性地，本发明所述晶型D为水合物；其加热至180℃时，具有约11.0％～14％的质量损失梯度。
根据本发明的目的，本发明还提供所述晶型D的制备方法，所述制备方法包括使用Filgotinib游离碱在醇类溶剂体系中加入盐酸，于一定温度下搅拌反应析晶，分离，干燥而获得，或者使用已知Filgotinib﹒HCl﹒3H2O晶型在醇类溶剂体系中，于一定温度下悬浮搅拌析晶，分离，干燥而获得；
其中：
所述醇类溶剂为C2～C5醇或者它们的混合物；
优选地，所述醇类溶剂选自乙醇、丙醇、异丙醇中的一种或多种的混合物；
更优选地，所述醇类溶剂为异丙醇；
当使用Filgotinib游离碱为原料时，所述Filgotinib游离碱与盐酸的摩尔比为1：1.0-1：1.5，优选为1：1.0；
优选地，所述Filgotinib游离碱或已知Filgotinib﹒HCl﹒3H2O晶型的用量为反应或操作温度下其在所述溶剂体系中的溶解度的20-70倍，更优选为40-50倍；
优选地，所述反应或操作温度为10-40℃，更优选为室温；
优选地，所述搅拌时间为24-72小时，更优选为48小时。
本发明的Filgotinib盐酸盐晶型D具有以下有益性质：
①溶解度高；
②制备简单；
③制备所用溶剂毒性低。
尤其是，与现有技术的Filgotinib﹒HCl﹒3H2O及其他溶剂合物晶型相比，所述晶型D的优势在于其具备更高的溶解度。
本发明通过提供Filgotinib盐酸盐新的晶型A、晶型B、晶型C或晶型D，解决了现有技术晶型存在的问题，该新的晶型具有选自以下的有利性质：更好的稳定性、更高的溶解度、更好的流动性。
在本发明的晶型A、晶型B、晶型C或晶型D的制备方法中：
所述“Filgotinib盐酸盐的已知晶型”包括现有技术文献WO2015117981A1中公开的Filgotinib:HCl:H2O为1:1:0的无水晶型、1:1:3的三水合物结晶、Filgotinib:HCl:MeOH为1:1:1的甲醇合物结晶以及Filgotinib:HCl:HCO2H为1:1:1.5的甲酸合物结晶。
除非另有说明，本发明中所述“已知Filgotinib﹒HCl﹒3H2O晶型”或“现有技术的Filgotinib﹒HCl﹒3H2O晶型”特指WO2015117981A1文献3.2.3.2和3.2.3.3节等相关内容，并经由表IX，图5和图11确认的晶型。
所述“室温”指15～25℃。
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，优选300～900转/分钟。
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
除非特别说明，所述“干燥”可以在室温或更高的温度下进行。干燥温度室温～约60℃，或者到40℃，或者到50℃。干燥时间可以为2～48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本 领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。在极端的情况下，溶解度或溶出速度的不同可以造成药物低效，甚至毒性。
在一些实施方案中，本发明的新晶型，包括晶型A、晶型B、晶型C或晶型D是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
药物的多晶型可通过包括但不限于如下的方法获得：熔融重结晶、熔融冷却、溶剂重结晶、失溶剂、快速挥发、快速降温、慢速降温、蒸汽扩散和升华。有时，不同的方法也可能获得相同的结晶。多晶型可以通过X射线粉末衍射(XRPD)、差示扫描量热分析(DSC)、热重分析(TGA)、光学显微镜技术、吸湿性等来检测、发现和归类。而本发明晶型采用的结晶方式为晶浆法，晶浆例如是将样品的饱和溶液(有不溶解固体存在)在溶剂体系中搅拌析晶，通常析晶时间是24-72小时。
此外，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明晶型A、晶型B、晶型C或晶型D中的一种或多种，以及至少一种药学上可接受的赋形剂。此外，所述药物组合物还可以包含其它可药用的Filgotinib或其盐的晶型或无定型物，这些晶型包括但不限于例如WO2015117981A1中所披露的已知晶型。任选地，本发明的晶型A、晶型B、晶型C或晶型D可以作为单独的活性剂施用，或者它们可以与其它活性剂组合施用，包括具有相同或相似治疗活性并且对于此类组合施用确定为安全且有效的其它化合物。在特别的实施方案中，两种(或多种)活性剂的共同施用使得可以显著降低所用的每种活性剂的剂量，从而降低所见的副作用，这种药物联合使用的方案包括但不限于现有技术文献WO2010149769A1说明书中所披露的那些。
上述药物组合物可制成一定的剂型，通过适合的途径给药。例如口服、 肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、阴道等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂，根据需要，可适于药物活性成分的快速释放、延迟释放或调节释放；适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液；适合直肠给药的剂型包括栓剂或灌肠剂；适合透皮给药的剂型包括软膏、霜剂、贴剂；适合经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂；适合阴道给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。优选地，由于本发明的晶型具有出人意料的低吸湿性和在水中或乙醇水溶液中的稳定性，因此，尤其适合制备成片剂、混悬剂、胶囊剂、崩解片、即释、缓释和控释片剂；进一步优选为片剂、混悬剂和胶囊剂。
上述药物组合物中药学上可接受的赋形剂，在固体口服剂型的情况下，包括但不限于：稀释剂，例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、磷酸三钙、甘露醇、山梨醇、糖等；粘合剂，例如阿拉伯胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇等；崩解剂，例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。可用的其他药学上可接受的赋形剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。任选地，对片剂涂覆包衣层，例如提供虫胶隔离包衣、糖衣或聚合物包衣，包衣层中的聚合物例如羟丙基甲基纤维素、聚乙烯醇、乙基纤维素、甲基丙烯酸类聚合物、羟丙基纤维素或淀粉，还可以包括抗粘着剂如二氧化硅、滑石粉，乳浊剂如二氧化钛，着色剂如氧化铁类着色剂。在液体口服剂型的情况下，合适的赋形剂包括水、油类、醇类、二醇类、调味剂、防腐剂、稳定剂、着色剂等；水或非水的无菌混悬剂可含有悬浮剂和增稠剂；适用于水性混悬剂的赋形剂包括合成胶或天然胶例如阿拉伯树胶、苍耳树胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。在胃肠外给药剂型的情况下，水或非水的无菌注射溶液的赋形剂通常为无菌水、生理盐水或葡萄糖水溶液，可以含有缓冲剂、抗氧化剂、抑菌剂和能够使该药物组合物与血液等渗的溶质。每一种赋形剂必须是可接受的，能与配方中的其他成分兼容并且对于患者无害。
所述药物组合物可以使用现有技术中本领域技术人员公知的方法来制 备。制备药物组合物时，将本发明Filgotinib盐酸盐的晶型A、晶型B、晶型C或晶型D与一种或多种药学上可接受的赋形剂相混合，任选地与一种或多种其他的药物活性成分相混合。例如，片剂、胶囊剂、颗粒剂可以通过混合、制粒、压片或填充胶囊等工艺来制备；粉剂通过将研细到合适大小的药物活性成分及赋形剂混合来制备；溶液和糖浆剂可通过将药物活性成分溶解于适当调味的水或水性溶液中来制备；混悬剂可通过将药物活性成分分散于药学上可接受的载体中来制备。
特别提及的是固体制剂的湿法制粒工艺，以片剂的湿法制粒为例，制备工艺是：混合活性成分、填充剂、粘合剂等干固体，用润湿剂例如水或醇润湿，将该润湿的固体制成凝聚物或颗粒剂，继续湿法制粒，直到获得所要求的均匀粒径，随后干燥该颗粒产物。然后将得到的干燥颗粒与崩解剂、润滑剂、抗粘着剂等混合，在制片机中压片；可选地，用适当的包衣粉进行包衣。
此外，还特别提及的是口服混悬剂，这种给药形式的一个优点是患者可以不必吞咽固体形式，尤其对于吞咽固体形式可能有困难的老年人、儿童或口腔、咽喉损伤的患者。混悬剂是将固体颗粒分散在液体中形成的两相系统，在混悬剂的水或水性载体中仍保持其原有的固体形式的晶体预期将更有利于保持药物产品性质的稳定。口服混悬剂中的其他组分可包括缓冲剂、表面活性剂、粘度调节剂、防腐剂、抗氧化剂、着色剂、调味剂、味道掩盖剂等。
本发明提供的Filgotinib盐酸盐的晶型A、晶型B、晶型C或晶型D具有适用于上述剂型的有利性质。
此外，本发明提供Filgotinib盐酸盐的晶型A、晶型B、晶型C或晶型D中的一种或多种在制备具有抑制JAK，尤其是抑制JAK1作用的药物中的用途。
本发明中，术语“JAK”是指Janus激酶(JAKs)家族，其是从膜受体向STAT转录因子转导细胞因子信号的细胞质酪氨酸激酶，其包括如下四种JAK家族成员：JAK1、JAK2、JAK3和TYK2。
此外，本发明提供一种治疗和/或预防与一种或多种JAK，尤其是JAK1相关的疾病的方法，所述方法包括给与需要的患者治疗和/或预防有效量的Filgotinib盐酸盐的晶型A、晶型B、晶型C或晶型D中的一种或多种，或所述包含晶型A、晶型B、晶型C或晶型D中的一种或多种的药物组合物。所述患者包括但不限于哺乳动物，所述哺乳动物例如人。
所述与一种或多种一种或多种JAK相关的疾病包括但不限于炎症、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨更新受损的疾病、先天软骨畸形和/或与IL6分泌过多相关的疾病。
其中，所述“炎症”表示一组病症，其包括类风湿性关节炎、骨关节炎、幼年特发性关节炎、银屑病、过敏性气道疾病(例如哮喘、鼻炎)、炎性肠病(例如克隆病、结肠炎)、内毒素驱动的疾病状态(例如心脏搭桥手术后的并发症或由于例如慢性心力衰竭引起的慢性内毒素状态)以及涉及软骨的相关疾病，例如关节疾病。优选地，所述“炎症”选自类风湿性关节炎、骨关节炎、过敏性气道疾病(例如哮喘)和炎性肠病。
所述“自身免疫疾病”表示一组疾病，其包括阻塞性气道疾病，例如COPD、哮喘(例如内源性哮喘、外源性哮喘、粉尘性哮喘、婴儿哮喘)，特别是慢性或长期形成的哮喘(例如晚期哮喘和气道高反应性)、支气管炎(包括支气管哮喘)、系统性红斑狼疮(SLE)、多发性硬化、I型糖尿病及其相关的并发症、特应性湿疹(特应性皮炎)、接触性皮炎，还包括湿疹性皮炎、炎性肠病(例如克隆病和溃疡性结肠炎)、动脉粥样硬化和肌萎缩性侧索硬化。优选地，所述“自身免疫疾病”选自COPD、哮喘、系统性红斑狼疮、I型糖尿病和炎性肠病。
所述“增殖性疾病”包括例如癌症(例如子宫平滑肌肉瘤或前列腺癌)、骨髓增殖性障碍(例如真性红细胞增多症、原发性的血小板增多和骨髓纤维化)、白血病(例如急性髓性白血病和急性淋巴细胞白血病)、多发性骨髓瘤、银屑病、再狭窄、硬化性皮炎或纤维化等病症。优选地，所述“增殖性疾病”选自癌症、白血病、多发性骨髓瘤和银屑病。
所述“癌症”包括皮肤或机体器官中细胞的恶性或良性生长，所述器官包括但不限于乳房、前列腺、肺、肾、胰、胃或肠。癌症易于侵入相邻的组织并且扩散(转移)到较远的器官，例如骨、肝、肺或脑。本发明所述的癌症包括转移肿瘤细胞型，例如但不限于黑素瘤、淋巴瘤、白血病、纤维肉瘤、横纹肌肉瘤和肥大细胞瘤，以及组织癌类型，例如但不限于结肠直肠癌、前列腺癌、小细胞肺癌和非小细胞肺癌、乳癌、胰腺癌、膀胱癌、肾癌、胃癌、胶质母细胞瘤、原发性肝癌、卵巢癌、前列腺癌和子宫平滑肌肉瘤。
所述“白血病”包括血液和造血器官的肿瘤疾病。白血病尤其是指急性髓性白血病(AML)和急性淋巴细胞白血病(ALL)。
所述“移植排斥”包括例如胰岛、干细胞、骨髓、皮肤、肌肉、角膜组织、神经元组织、心脏、肺、心肺联合、肾、肝、肠、胰、气管或食道的细胞、组织或实体器官的同种异体移植物或异种移植物的急性或慢性排斥，或者移植物抗宿主病。
附图说明
图1为本发明实施例1所得晶型A的X射线粉末衍射图。
图2为本发明实施例2所得晶型A的X射线粉末衍射图。
图3为本发明实施例2所得晶型A的DSC图谱。
图4为本发明实施例2所得晶型A的TGA图谱。
图5为本发明实施例2所得晶型A氢核磁共振图谱。
图6为本发明晶型A的一周稳定性XRPD对比图。
图7为本发明晶型A的二周稳定性XRPD对比图。
图8为本发明实施例3所得晶型B的X射线粉末衍射图。
图9为本发明实施例3所得晶型B氢核磁共振图谱。
图10为本发明实施例4所得晶型B的X射线粉末衍射图。
图11为本发明实施例5所得晶型C的X射线粉末衍射图。
图12为本发明实施例6所得晶型C的X射线粉末衍射图。
图13为本发明实施例7所得晶型D的X射线粉末衍射图。
图14为本发明实施例8所得晶型D的X射线粉末衍射图。
图15为本发明实施例3所得晶型B的TGA图谱。
图16为本发明实施例5所得晶型C的TGA图谱。
图17为本发明实施例7所得晶型C的TGA图谱。
具体实施方式
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：CuKa
Kα1
Figure PCTCN2017077492-appb-000003
1.540598；Kα2
Figure PCTCN2017077492-appb-000004
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
发散狭缝：自动
扫描模式：连续
扫描范围：自3.0至40.0度
取样步长：0.013度
差热分析(DSC)数据采自于TA Instruments Q200MDSC，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取1～10毫克的样品放置于加盖(除非特别说明)的铝坩埚内，以10℃/min的升温速度在50mL/min干燥N2的保护下将样品从室温升至250℃，同时TA软件记录样品在升温过程中的热量变化。在本申请中，熔点是按起始温度来报告的。
热重分析(TGA)数据采自于TA Instruments Q500TGA，仪器控制软件是Thermal AdVantage，分析软件是Universal Analysis。通常取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在50mL/min干燥N2的保护下将样品从室温升至300℃，同时TA软件记录样品在升温过程中的重量变化。
核磁共振氢谱数据(1HNMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所使用的Filgotinib游离碱及已知Filgotinib﹒HCl﹒3H2O晶型均根据WO2010149769A1文献所记载的方法制备。
实施例1
将19.9mg Filgotinib游离碱加入1.0mL乙腈溶剂中，室温下悬浮搅拌，加入4微升盐酸(12moL/L)，室温下悬浮搅拌析晶48小时，离心，室温下真空干燥，得白色的盐酸盐固体结晶。
经检测，所得结晶固体为本发明所述之晶型A，其X射线粉末衍射数据如图1，表1所示。
表1
衍射角2θ d值 相对强度％
4.6 19.07 0.73
7.31 12.09 100.00
8.92 9.92 11.00
12.39 7.14 11.83
13.13 6.74 3.95
14.69 6.03 37.61
15.14 5.85 11.61
16.70 5.31 1.98
17.47 5.08 5.78
18.42 4.82 0.73
20.63 4.30 17.09
22.60 3.93 3.48
23.60 3.77 1.27
24.99 3.56 0.31
25.99 3.43 2.57
27.36 3.26 1.65
28.45 3.14 2.82
29.68 3.01 10.68
31.37 2.85 1.35
32.32 2.77 2.39
33.92 2.64 1.91
实施例2
100.0mg Filgotinib游离碱加入5.0mL乙腈溶剂中，室温下悬浮搅拌，加入20微升盐酸(12moL/L)，室温下悬浮搅拌析晶48小时，离心，真空干燥，得白色的盐酸盐固体结晶。
经检测，本实施例得到固体为晶型A，其X射线粉末衍射数据如图2，表2所示，其核磁共振氢谱如图5所示。
表2
衍射角2θ d值 相对强度％
7.31 12.09 100.00
8.90 9.93 6.21
11.64 7.60 2.0
12.33 7.18 12.42
13.38 6.62 1.16
14.70 6.03 52.86
15.05 5.89 13.01
16.75 5.29 5.24
17.40 5.09 10.38
18.37 4.83 1.55
18.75 4.73 1.72
19.28 4.60 1.92
19.82 4.48 2.43
20.66 4.30 13.64
21.42 4.15 2.07
22.13 4.02 2.32
22.66 3.92 8.76
23.38 3.81 1.77
24.70 3.60 3.36
25.98 3.43 2.34
26.55 3.36 1.26
28.35 3.15 3.12
29.70 3.01 17.45
30.44 2.94 1.40
31.43 2.85 2.03
32.32 2.77 4.45
33.25 2.69 2.79
33.83 2.65 2.11
36.32 2.47 0.66
37.76 2.38 0.99
该晶型的DSC如图3所示，其有两个吸热峰，在48℃附近开始出现第一个吸热峰，该吸热峰是在该温度附近结晶水会失去，在195℃处开始出现第二个吸热峰，该吸热峰是熔化吸热。
该晶型的TGA如附图4所示，将其加热至192℃时，具有约10.0％的质量损失梯度。
晶型A的稳定性试验
取5份(每份质量10.0mg)实施例2中制备得到的晶型A样品分别置于5℃、25℃/60％RH、40℃/75％RH和60℃/75％RH、80℃的恒温恒湿箱中敞口放置两周，分别在一周、两周时取样测XRPD。
测定结果如图6，图7所示，其中，图6为一周稳定性XRPD对比图，从上至下依次为晶型A参比XRPD图，25℃/60％RH，40℃/75％RH，60℃/75％RH，80℃的XRPD图；图7为两周稳定性XRPD对比图，从上至下依次为晶型A参比XRPD图，5℃，25℃/60％RH，40℃/75％RH，60℃/75％RH，80℃的XRPD图。
结果表明，晶型A在5℃，25℃/60％RH，40℃/75％RH，60℃/75％RH，80℃条件下，两周晶型保持不变，故而其具有良好的稳定性。
现有Filgotinib﹒HCl﹒3H2O晶型的不同水活度搅拌试验
以WO2015117981A1中的现有技术的Filgotinib﹒HCl﹒3H2O晶型为起始原料，将其加入水活度为0.15的H2O/EtOH，水活度为0.2、0.4的H2O/MeOH，水活度为0.2、0.4的H2O/ACN体系中进行搅拌，48小时后离心，用XRPD表征，该晶型转变为本发明的晶型A，结果如下表3所示：
表3
溶剂 水活度 起始晶型 最终晶型
H2O/EtOH 2:98 0.15 现有Filgotinib﹒HCl﹒3H2O结晶 晶型A
H2O/MeOH 7:93 0.2 现有Filgotinib﹒HCl﹒3H2O结晶 晶型A
H2O/MeOH 16:84 0.4 现有Filgotinib﹒HCl﹒3H2O结晶 晶型A
H2O/ACN 1:99 0.2 现有Filgotinib﹒HCl﹒3H2O结晶 晶型A
H2O/ACN 2:98 0.4 现有Filgotinib﹒HCl﹒3H2O结晶 晶型A
该试验说明，在低水活度(低湿度)环境中，低于40％相对湿度下，晶型A比现有技术的Filgotinib﹒HCl﹒3H2O晶型稳定。
实施例3
20.0mg Filgotinib游离碱加入到0.8mL丙酮溶剂中，室温下悬浮搅拌，加入4微升盐酸(12moL/L)，室温下搅拌反应48小时，离心，真空干燥，得白色的盐酸盐固体结晶。
经检测，本实施例得到固体为晶型B，其X射线粉末衍射数据如图8，表4所示，该晶型的核磁共振氢谱如图9所示。
表4
衍射角2θ d值 相对强度％
7.10 12.45 100.00
8.85 9.99 24.69
9.29 9.52 5.14
12.50 7.08 14.90
13.21 6.70 60.08
14.22 6.23 42.62
14.72 6.02 15.33
15.95 5.56 18.79
16.71 5.31 34.68
18.75 4.73 49.61
19.60 4.53 22.51
20.21 4.39 32.80
20.60 4.31 61.13
21.18 4.20 11.98
21.94 4.05 21.58
23.32 3.81 6.00
23.85 3.73 12.10
24.40 3.65 8.32
25.18 3.54 6.07
25.73 3.46 9.89
26.70 3.34 19.11
27.62 3.23 7.19
28.66 3.11 24.98
29.40 3.04 14.22
30.97 2.89 3.39
32.73 2.74 6.61
33.80 2.65 3.15
该晶型的TGA如附图15所示，将其加热至200℃时，具有约12.7％的质量损失梯度。
实施例4
80.0mg Filgotinib游离碱加入到4.0mL丙酮溶剂中，加入16微升盐酸(12moL/L)，室温下搅拌反应48小时，离心，真空干燥，得白色的盐酸盐固体结晶。
经检测，本实施例得到固体为晶型B，其X射线粉末衍射数据如图10，表5所示。
表5
衍射角2θ d值 相对强度％
4.70 18.80 3.20
7.10 12.45 100.00
8.85 10.00 7.83
13.22 6.69 28.28
14.22 6.23 34.43
14.74 6.01 11.14
15.96 5.55 12.86
16.73 5.30 13.47
18.82 4.72 20.04
19.61 4.53 7.53
20.21 4.39 16.54
20.62 4.31 17.46
22.04 4.03 10.94
23.86 3.73 5.78
25.66 3.47 4.34
26.73 3.33 4.84
27.65 3.23 3.77
28.65 3.12 25.00
29.50 3.03 3.94
30.72 2.91 1.03
32.72 2.74 3.63
实施例5
30.0mg Filgotinib游离碱加入到1.2mL甲基乙基酮溶剂中，室温下悬浮搅拌，加入6微升盐酸(12moL/L)，室温下悬浮搅拌48小时，离心，真空干燥，得白色的盐酸盐固体结晶。
经检测，本实施例得到固体为晶型C，其X射线粉末衍射数据如图11，表6所示。
表6
衍射角2θ d值 相对强度％
6.99 12.65 100.00
8.80 10.05 8.38
12.98 6.82 26.23
14.03 6.31 35.93
14.76 6.00 12.12
15.83 5.60 15.54
16.71 5.31 17.46
18.66 4.76 25.03
19.59 4.53 10.16
19.92 4.46 13.69
20.46 4.34 25.28
21.11 4.21 4.18
22.09 4.02 8.55
23.79 3.74 9.46
24.50 3.63 3.99
26.52 3.36 4.83
27.25 3.27 4.81
28.34 3.15 22.82
29.15 3.06 6.13
30.58 2.92 4.37
32.24 2.78 2.64
该晶型的TGA如附图16所示，将其加热至180℃时，具有约11.6％的质量损失梯度。
实施例6
1.9mg现有技术的Filgotinib﹒HCl﹒3H2O晶体加入1.5mL甲基乙基酮溶剂中，室温下悬浮搅拌48小时，离心，真空干燥，得白色的盐酸盐固体结晶。
经检测，本实施例得到固体为晶型C，其X射线粉末衍射数据如图12，表7所示。
表7
衍射角2θ d值 相对强度％
7.02 12.59 100.00
8.71 10.15 1.90
13.01 6.80 7.12
14.08 6.29 34.65
14.77 6.00 6.33
15.86 5.59 8.66
16.72 5.30 5.58
18.71 4.74 4.76
19.95 4.45 6.31
20.46 4.34 8.26
21.17 4.20 3.77
22.00 4.04 4.27
23.81 3.74 5.87
25.29 3.52 2.31
26.52 3.36 2.07
28.34 3.15 29.76
29.11 3.07 4.76
30.64 2.92 2.97
32.28 2.77 2.54
35.91 2.50 1.70
36.45 2.47 1.38
实施例7
30.0mg Filgotinib游离碱加入到1.2mL异丙醇溶剂中，室温下悬浮搅拌，加入6微升盐酸(12moL/L)，室温下悬浮搅拌48小时，离心，真空干燥，得白色的盐酸盐固体结晶。
经检测，本实施例得到固体为晶型D，其X射线粉末衍射数据如图13，表8所示。
表8
衍射角2θ d值 相对强度％
3.20 27.58 78.86
5.78 15.28 57.75
7.03 12.58 97.14
8.03 11.02 58.71
8.61 10.27 83.79
10.73 8.25 89.61
12.81 6.91 20.19
13.86 6.39 29.33
14.52 6.10 34.78
16.20 5.47 47.57
16.75 5.29 45.23
17.17 5.16 82.11
18.38 4.83 100.00
18.67 4.75 84.07
19.09 4.65 33.26
19.69 4.51 66.57
20.34 4.37 44.63
20.69 4.29 37.02
22.12 4.02 62.79
24.81 3.59 58.50
25.27 3.53 87.94
27.33 3.26 71.64
28.07 3.18 24.97
30.62 2.92 18.03
32.37 2.77 16.25
34.74 2.58 7.39
该晶型的TGA如附图17所示，将其加热至180℃时，具有约12.8％的质量损失梯度。
实施例8
80.0mg Filgotinib游离碱加入到4.0mL异丙醇溶剂中，室温下悬浮搅拌，加入16微升盐酸(12moL/L)，室温下悬浮搅拌48小时，离心，真空干燥，得白色的盐酸盐固体结晶。
经检测，本实施例得到固体为晶型D，其X射线粉末衍射数据如图14，表9所示。
表9
衍射角2θ d值 相对强度％
5.84 15.13 20.65
7.05 12.55 100.00
8.03 11.02 35.43
8.58 10.30 67.20
10.73 8.25 85.74
14.46 6.13 31.04
16.21 5.47 33.68
17.11 5.18 87.90
18.13 4.89 54.39
18.37 4.83 96.42
18.65 4.76 86.86
19.67 4.51 49.84
19.96 4.45 37.49
20.51 4.33 27.67
22.12 4.02 62.41
24.74 3.60 35.60
25.25 3.53 70.70
27.30 3.27 75.94
28.11 3.17 23.84
28.53 3.13 12.63
30.67 2.92 12.58
32.20 2.78 18.34
实施例9溶解度试验
将制备得到的晶型A(实施例2)、晶型B(实施例4)、晶型C(实施例5)、晶型D(实施例8)与专利文献WO2015117981 A1中的Filgotinib盐酸盐三水合物结晶(参比晶型)分别用模拟人工胃液(SGF)和纯水配制成饱和溶液。在1个小时，4个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表10至表11所示。
表10
Figure PCTCN2017077492-appb-000005
表11
Figure PCTCN2017077492-appb-000006
上述溶解度实验结果表明，在上述饱和溶液中放置1小时，4小时和24个小时后本发明的晶型A、晶型B、晶型C、晶型D与参比晶型相比，其溶 解度均高于参比晶型的溶解度。更高的溶解度有助于提升药物在生物体内的吸收利用，提高药效。
实施例10粒度对比试验
利用Microtrac公司的S3500型激光粒度分析仪(Microtrac S3500配备SDC(Sample Delivery Controller)进样系统)测量本发明晶型A、晶型B、晶型C、晶型D与专利文献WO2015117981 A1中的Filgotinib盐酸盐三水合物结晶(参比晶型)的粒径分布。
本测试采用湿法，测试分散介质为Isopar G。激光粒度分析仪的方法参数如表12所示：
表12
Figure PCTCN2017077492-appb-000007
*：流速60％为65毫升/秒的60％。
制备得到的晶型A(实施例2)、晶型B(实施例4)、晶型C(实施例5)、晶型D(实施例8)与参比晶型进行粒径分布测量，结果如表13所示。
表13
晶型 MV(μm) D10(μm) D50(μm) D90(μm)
参比晶型 7.24 2.95 6.29 12.35
晶型A 24.64 1.72 8.93 62.08
晶型B 44.66 2.53 20.30 110.4
晶型C 29.92 1.87 13.57 66.16
晶型D 41.24 5.77 25.92 82.42
注：
MV：按照体积计算的平均粒径
D10：表示粒径分布中(体积分布)占10％所对应的粒径
D50：表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径
D90：表示粒径分布中(体积分布)占90％所对应的粒径
参比晶型的体积平均粒径为7.24微米，本发明晶型A的体积平均粒径为24.64微米，晶型B的体积平均粒径为44.66微米，晶型C的体积平均粒径为29.92微米，晶型D的体积平均粒径为41.24微米，均比参比晶型大。一般来说，药物粒径越大越容易过滤分离，节省时间；同时药物粒径变大对增加药物稳定性也有一定的作用；药物的粒径越大，流动性越好，有利于后续处理。
本领域技术人员可以理解，在本说明书的教导之下，可以对本发明做出一些修改或变化。这些修改和变化也应当在本发明权利要求所限定的范围之内。

Claims (28)

  1. 结构式如下所示的Filgotinib盐酸盐晶型B，
    Figure PCTCN2017077492-appb-100001
    其特征在于，使用Cu-Kα辐射，所述晶型B的X-射线粉末衍射图在衍射角2θ为7.1°±0.2°,13.2°±0.2°,14.2°±0.2°处有特征峰。
  2. 根据权利要求2所述的Filgotinib盐酸盐晶型B，其特征在于，所述晶型B的X-射线粉末衍射图在衍射角2θ为7.1°±0.2°,13.2°±0.2°,14.2°±0.2°,18.8°±0.2°,20.6°±0.2°,28.7°±0.2°处有特征峰。
  3. 根据权利要求3所述的Filgotinib盐酸盐晶型B，其特征在于，所述晶型B的X-射线粉末衍射图在衍射角2θ为7.1°±0.2°,13.2°±0.2°,14.2°±0.2°,15.9°±0.2°,16.7°±0.2°,18.8°±0.2°,20.6°±0.2°,22.0°±0.2°,28.7°±0.2°处有特征峰。
  4. 权利要求1～3中任一项所述Filgotinib盐酸盐晶型B的制备方法，其特征在于，所述制备方法包括：
    使用Filgotinib游离碱在丙酮溶剂中加入盐酸，于一定温度下搅拌反应析晶，分离，干燥而获得所述晶型B；
    或者使用已知Filgotinib﹒HCl﹒3H2O晶型在丙酮溶剂中，于一定温度下悬浮搅拌析晶，分离，干燥而获得所述晶型B。
  5. 结构式如下所示的Filgotinib盐酸盐晶型A，
    Figure PCTCN2017077492-appb-100002
    其特征在于，使用Cu-Kα辐射，所述晶型A的X-射线粉末衍射图在衍射角2θ为7.3°±0.2°,14.7°±0.2°,29.6°±0.2°处有特征峰。
  6. 根据权利要求5所述的Filgotinib盐酸盐晶型A，其特征在于，所述晶型A的X-射线粉末衍射图在衍射角2θ为7.3°±0.2°,12.4°±0.2°,14.7°±0.2°,17.4°±0.2°,20.6°±0.2°,29.6°±0.2°处有特征峰。
  7. 根据权利要求6所述的Filgotinib盐酸盐晶型A，其特征在于，所述晶型A的X-射线粉末衍射图在衍射角2θ为7.3°±0.2°,8.9°±0.2°,12.4°±0.2°,14.7°±0.2°,16.8°±0.2°,17.4°±0.2°,20.6°±0.2°,22.6°±0.2°,29.6°±0.2°处有特征峰。
  8. 权利要求5～7中任一项所述Filgotinib盐酸盐晶型A的制备方法，其特征在于，所述制备方法包括：
    使用Filgotinib游离碱在烷基腈溶剂体系中加入盐酸，于一定温度下搅拌反应析晶，分离，干燥而获得所述晶型A；
    或者使用已知Filgotinib﹒HCl﹒3H2O晶型在烷基腈溶剂体系中，于一定温度下悬浮搅拌析晶，分离，干燥而获得所述晶型A。
  9. 根据权利要求8所述的Filgotinib盐酸盐晶型A的制备方法，其特征在于，所述烷基腈为C2～C3烷基腈或者它们的混合物，优选为乙腈、丙腈中的一种或它们的混合物。
  10. 根据权利要求9所述的Filgotinib盐酸盐晶型A的制备方法，其特征在于，所述烷基腈为乙腈。
  11. 结构式如下所示的Filgotinib盐酸盐晶型C，
    Figure PCTCN2017077492-appb-100003
    其特征在于，使用Cu-Kα辐射，所述晶型C的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,14.0°±0.2°,20.5°±0.2°处有特征峰。
  12. 根据权利要求11所述的Filgotinib盐酸盐晶型C，其特征在于，所述晶型C的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,14.0°±0.2°,16.7°±0.2°,18.7°±0.2°,20.5°±0.2°,28.3°±0.2°处有特征峰。
  13. 根据权利要求12所述的Filgotinib盐酸盐晶型C，其特征在于，所述晶型C的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,13.0°±0.2°,14.0°±0.2°,14.8°±0.2°,15.8°±0.2°,16.7°±0.2°,18.7°±0.2°,20.5°±0.2°,28.3°±0.2°处有特征峰。
  14. 权利要求11～13中任一项所述Filgotinib盐酸盐晶型C的制备方法，其特征在于，所述制备方法包括：
    使用Filgotinib游离碱在碳原子数大于等于4的酮类溶剂体系中加入盐酸，于一定温度下搅拌反应析晶，分离，干燥而获得所述晶型C；
    或者使用已知Filgotinib﹒HCl﹒3H2O晶型在碳原子数大于等于4酮类溶剂体系中，于一定温度下悬浮搅拌析晶，分离，干燥而获得所述晶型C。
  15. 根据权利要求14所述的Filgotinib盐酸盐晶型C的制备方法，其特征在于，所述碳原子数大于等于4的酮类溶剂为C4～C7烷基酮或者它们的混合物，优选甲基乙基酮、甲基异丁基酮中的一种或它们的混合物。
  16. 根据权利要求15所述的Filgotinib盐酸盐晶型C的制备方法，其特征在于，所述碳原子数大于等于4的酮类溶剂为甲基乙基酮。
  17. 结构式如下所示的Filgotinib盐酸盐晶型D，
    Figure PCTCN2017077492-appb-100004
    其特征在于，使用Cu-Kα辐射，所述晶型D的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,10.7°±0.2°,17.1°±0.2°处有特征峰。
  18. 根据权利要求17所述的Filgotinib盐酸盐晶型D，其特征在于，所述晶型D的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,8.0°±0.2°,8.7°±0.2°,10.7°±0.2°,16.2°±0.2°,17.1°±0.2°处有特征峰。
  19. 根据权利要求18所述的Filgotinib盐酸盐晶型D，其特征在于，所述晶型D的X-射线粉末衍射图在衍射角2θ为7.0°±0.2°,8.0°±0.2°,8.7°±0.2°,10.7°±0.2°,16.2°±0.2°,17.1°±0.2°,18.4°±0.2°,22.1°±0.2°,25.3°±0.2°处有特征峰。
  20. 权利要求17～19中任一项所述Filgotinib盐酸盐晶型D的制备方法，其特征在于，所述制备方法包括：
    使用Filgotinib游离碱在醇类溶剂体系中加入盐酸，于一定温度下搅拌反应析晶，分离，干燥而获得所述晶型D；
    或者使用已知Filgotinib﹒HCl﹒3H2O晶型在醇类溶剂体系中，于一定温度下悬浮搅拌析晶，分离，干燥而获得所述晶型D。
  21. 根据权利要求20所述的Filgotinib盐酸盐晶型D的制备方法，其特征在于，所述醇类溶剂为C2～C5醇或者它们的混合物，优选乙醇、丙醇、异丙醇中的一种或多种的混合物。
  22. 根据权利要求21所述的Filgotinib盐酸盐晶型D的制备方法，其特征在于，所述醇类溶剂为异丙醇。
  23. 一种药物组合物，所述药物组合物包含治疗和/或预防有效量的一种或多种权利要求1～3中任一项所述Filgotinib盐酸盐晶型A、权利要求7～9 中任一项所述Filgotinib盐酸盐晶型B、权利要求11～13中任一项所述Filgotinib盐酸盐晶型C或权利要求17～19中任一项所述Filgotinib盐酸盐晶型D，以及至少一种药学上可接受的载体或赋形剂。
  24. 一种药物制剂，其包含一种或多种治疗和/或预防有效量的权利要求1～3中任一项所述Filgotinib盐酸盐晶型A、权利要求7～9中任一项所述Filgotinib盐酸盐晶型B、权利要求11～13中任一项所述Filgotinib盐酸盐晶型C或权利要求17～19中任一项所述Filgotinib盐酸盐晶型D。
  25. 根据权利要求24的药物制剂，该制剂为片剂、胶囊剂、混悬剂、崩解片、即释、缓释和控释片剂。
  26. 权利要求1～3中任一项所述Filgotinib盐酸盐晶型A、权利要求7～9中任一项所述Filgotinib盐酸盐晶型B、权利要求11～13中任一项所述Filgotinib盐酸盐晶型C或权利要求17～19中任一项所述Filgotinib盐酸盐晶型D在制备具有抑制一种或多种JAK。
  27. 权利要求1～3中任一项所述Filgotinib盐酸盐晶型A、权利要求7～9中任一项所述Filgotinib盐酸盐晶型B、权利要求11～13中任一项所述Filgotinib盐酸盐晶型C或权利要求17～19中任一项所述Filgotinib盐酸盐晶型D在制备用于治疗和/或预防下列疾病的药物中的用途：炎症、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨更新受损的疾病、先天软骨畸形和/或与IL6分泌过多相关的疾病。
  28. 一种治疗或预防与一种或多种JAK相关的疾病的方法，其特征在于，所述方法包括给与需要的患者治疗和/或预防有效量的权利要求1～3中任一项所述Filgotinib盐酸盐晶型A、权利要求7～9中任一项所述Filgotinib盐酸盐晶型B、权利要求11～13中任一项所述Filgotinib盐酸盐晶型C或权利要求17～19中任一项所述Filgotinib盐酸盐晶型D，或者权利要求23所述的药物组合物，或者权利要求24～25中任一项所述的药物制剂。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020177705A1 (zh) * 2019-03-05 2020-09-10 苏州科睿思制药有限公司 Filgotinib的马来酸盐晶型CSI及其制备方法和用途
US10815227B2 (en) 2018-08-27 2020-10-27 Cadila Healthcare Limited Processes for the preparation of filgotinib
CN114042073A (zh) * 2021-11-01 2022-02-15 浙江大学 非洛替尼在抑制胰腺癌细胞和肿瘤组织增殖中的应用
US12502394B2 (en) 2017-03-14 2025-12-23 Alfasigma S.P.A. Pharmaceutical compositions comprising a JAK inhibitor

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010149769A1 (en) 2009-06-26 2010-12-29 Galapagos Nv 5-phenyl-[1,2,4 ]triazolo[1,5-a]pyridin-2-yl carboxamides as jak inhibitors
WO2015011798A1 (ja) 2013-07-24 2015-01-29 三菱電機株式会社 界磁巻線方式回転電機の診断装置および界磁巻線方式回転電機の診断方法
WO2015117980A1 (en) * 2014-02-07 2015-08-13 Galapagos Nv Pharmaceutical compositions for the treatment of inflammatory disorders
WO2015117981A1 (en) 2014-02-07 2015-08-13 Galapagos Nv Novel salts and pharmaceutical compositions thereof for the treatment of inflammatory disorders
CN105669669A (zh) * 2016-03-04 2016-06-15 上海宣创生物科技有限公司 一种环丙烷甲酰胺衍生物的a晶型、b晶型、d晶型、g晶型和m晶型及其制备方法
WO2017012773A1 (en) * 2015-07-23 2017-01-26 Ratiopharm Gmbh Solid forms of filgotinib free base

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010149769A1 (en) 2009-06-26 2010-12-29 Galapagos Nv 5-phenyl-[1,2,4 ]triazolo[1,5-a]pyridin-2-yl carboxamides as jak inhibitors
WO2015011798A1 (ja) 2013-07-24 2015-01-29 三菱電機株式会社 界磁巻線方式回転電機の診断装置および界磁巻線方式回転電機の診断方法
WO2015117980A1 (en) * 2014-02-07 2015-08-13 Galapagos Nv Pharmaceutical compositions for the treatment of inflammatory disorders
WO2015117981A1 (en) 2014-02-07 2015-08-13 Galapagos Nv Novel salts and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2017012773A1 (en) * 2015-07-23 2017-01-26 Ratiopharm Gmbh Solid forms of filgotinib free base
CN105669669A (zh) * 2016-03-04 2016-06-15 上海宣创生物科技有限公司 一种环丙烷甲酰胺衍生物的a晶型、b晶型、d晶型、g晶型和m晶型及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3434675A4

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12502394B2 (en) 2017-03-14 2025-12-23 Alfasigma S.P.A. Pharmaceutical compositions comprising a JAK inhibitor
US10815227B2 (en) 2018-08-27 2020-10-27 Cadila Healthcare Limited Processes for the preparation of filgotinib
WO2020177705A1 (zh) * 2019-03-05 2020-09-10 苏州科睿思制药有限公司 Filgotinib的马来酸盐晶型CSI及其制备方法和用途
CN114042073A (zh) * 2021-11-01 2022-02-15 浙江大学 非洛替尼在抑制胰腺癌细胞和肿瘤组织增殖中的应用

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