WO2018024236A1 - 一种jak1选择性抑制剂的新晶型及其制备方法和用途 - Google Patents

一种jak1选择性抑制剂的新晶型及其制备方法和用途 Download PDF

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WO2018024236A1
WO2018024236A1 PCT/CN2017/095867 CN2017095867W WO2018024236A1 WO 2018024236 A1 WO2018024236 A1 WO 2018024236A1 CN 2017095867 W CN2017095867 W CN 2017095867W WO 2018024236 A1 WO2018024236 A1 WO 2018024236A1
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filgotinib
crystalline form
crystal form
ray powder
crystal
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PCT/CN2017/095867
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English (en)
French (fr)
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陈敏华
张炎锋
杨存波
刘凯
张晓宇
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苏州科睿思制药有限公司
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Priority to CN201780045279.7A priority Critical patent/CN109476662A/zh
Priority to US16/322,610 priority patent/US10633376B2/en
Priority to EP17836417.0A priority patent/EP3495364A4/en
Publication of WO2018024236A1 publication Critical patent/WO2018024236A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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 the crystalline form of Filgotinib and its preparation and use.
  • Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of the joints and other parts of the body and can cause permanent joint damage and deformity. If the disease is left untreated, substantial disability and pain can result from loss of joint function, which ultimately leads to a shortened life expectancy.
  • This condition is a chronic condition that requires long-term therapy and repeated ingestion of the drug, while long-term treatment may be a heavy burden for the patient as well as the physician because the patient may be intolerant to the drug or become intolerant to the drug.
  • higher doses or higher dosing frequencies may result in uncomfortable side effects and/or lower patient compliance.
  • rheumatoid arthritis The higher incidence of rheumatoid arthritis (about 0.8% of adults worldwide) indicates a greater social impact.
  • the goal of rheumatoid arthritis therapy is not only to slow down the disease, but to relieve pain in order to prevent joint damage and improve the quality of life of humans.
  • Crohn’s disease is an inflammatory bowel disease that causes inflammation of the digestive tract, abdominal pain, severe diarrhea, intestinal obstruction, ulcers, fistulas, anal fissures, etc., and is prone to recurrent attacks.
  • people with Crohn's disease are at risk of malnutrition because their gut cannot absorb the nutrients their body needs from their diet.
  • Inflammation caused by Crohn's disease may involve different areas of the human digestive tract, usually deep into the layers of the intestinal tissue, causing both pain and weakness, and even life-threatening complications.
  • the recurrence rate of this disease is related to the extent of the lesion, the enhancement of the invasion of the disease, the prolongation of the disease course, the increase of the age, and the mortality rate. Therefore, there is a need to develop therapeutic agents that have a beneficial effect on this disease.
  • JAK refers to the Janus kinase (JAKs) family, a cytoplasmic tyrosine kinase that transduces cytokine signaling from membrane receptors to STAT transcription factors, and is widely involved in many important biology such as inflammation, autoimmunity, and immune regulation. process.
  • the Janus kinase family includes the following four JAK family members: JAK1, JAK2, JAK3, and TYK2. Among them, inhibition of JAK1 is essential for the inflammatory treatment process, while inhibition of JAK2, JAK3 and TYK2 is not necessary for the treatment of inflammation, and its inhibition process may cause some adverse reactions, such as inhibition of JAK2 associated with anemia, inhibition of JAK3 and immune function. Repressed related. JAK1 is a target for immune-inflammatory diseases, and its inhibitors are beneficial for the treatment of diseases such as rheumatoid arthritis and Crohn's disease.
  • Filgotinib (GLPG0634) is a selective inhibitor of JAK1, which IC for JAK1, JAK2, JAK3 and TYK2 50 were 10nM, 28nM, 810nM, and 116nM.
  • IC 50 half maximal inhibitory concentration refers to the measured semi-inhibitory concentration, which can indicate the half amount of a certain drug or substance (inhibitor) in inhibiting certain biological programs. The lower the value, the stronger the inhibition ability of the drug. . Therefore, Filgotinib exhibits higher selectivity for inhibition of JAK1.
  • Filgotinib N-[5-[4-[(1,1-dioxo-1-thiomorpholin-4-yl)methyl]phenyl][1,2,4]triazole [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 is as follows:
  • the prior art crystal forms have the disadvantages of complicated preparation methods, poor crystallinity, low solubility, low yield, poor stability, difficulty in drying, and easy solvent residue.
  • the inventors have found through experimental comprehensive analysis that the mode 4 of the above-mentioned patent document CN105960407A has superior properties compared with other prior art crystal forms, has good stability, is not easy to change at room temperature, has good crystallinity, is easy to dry, and is not easy to produce a solvent.
  • Residue but the inventors found through experiments that the solubility is low, the wettability is high, the mechanical stability is poor under a certain mechanical force, and the preparation method is complicated, and the thermal cycle between the environment and 50 ° C is required. The reaction is not conducive to the opening and amplification of the later process. Therefore, it is necessary to perform polymorphic screening so that the developed crystal form can overcome the deficiencies of the prior art and is more suitable for industrial production.
  • the invention overcomes the above disadvantages of the prior art, and the obtained new crystal form has the advantages of simple preparation method, high solubility, good crystallinity, high purity, low wettability and good stability, especially mechanical, compared with the patent document CN105960407A mode 4. Good stability and other advantages, suitable for the production of industrial pharmaceutical preparations and the use of later drugs, with significant economic value.
  • the main object of the present invention is to provide a novel crystal form of Filgotinib as shown below, a preparation method and use thereof.
  • the X-ray powder diffraction pattern of Form CS1 is shown in FIG.
  • the present invention provides a crystal form CS1 of Filgotinib (hereinafter referred to as "crystal form CS1").
  • the crystal form CS1 is an anhydride.
  • the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at diffraction angle 2 ⁇ values of 10.3° ⁇ 0.2°, 13.7° ⁇ 0.2°, and 16.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 18.0° ⁇ 0.2°, 21.7° ⁇ 0.2°, and 24.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 8.6° ⁇ 0.2° and 19.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has a diffraction angle 2 ⁇ of 10.3° ⁇ 0.2°, 13.7° ⁇ 0.2°, 16.1° ⁇ 0.2°, 18.0° ⁇ 0.2°, 21.7°. There are characteristic peaks at ⁇ 0.2°, 24.7° ⁇ 0.2°, 8.6° ⁇ 0.2°, and 19.4° ⁇ 0.2°.
  • the present invention also provides a method for preparing the crystalline form CS1, which comprises adding a base to a halogenated aromatic hydrocarbon system using Filgotinib hydrochloride, stirring and crystallization at a certain temperature, and separating the obtained. a halogenated aromatic hydrocarbon solvate, heated to remove solvent under nitrogen to obtain the crystalline form CS1;
  • the halogenated aromatic hydrocarbon is a mixture of one or more of an aromatic ring in which an aromatic hydrocarbon is substituted;
  • Preferred is one of chlorobenzene, bromobenzene or a mixture thereof;
  • the halogenated aromatic hydrocarbon is chlorobenzene
  • the base used is an inorganic base
  • it is a mixture of one or more of sodium hydroxide, potassium hydroxide, and calcium hydroxide;
  • the base is sodium hydroxide
  • the crystallization temperature is 25-0 ° C
  • the crystallization temperature is 5 ° C;
  • the temperature of the solvent removal is 150-195 ° C;
  • the present invention provides a crystal form CS2 of Filgotinib (hereinafter referred to as "crystal form CS2").
  • the crystal form CS2 is an anhydrate.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, and 8.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 24.7° ⁇ 0.2°, 17.2° ⁇ 0.2°, and 27.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristic peaks at one or two or three of the diffraction angle 2 ⁇ values of 7.2° ⁇ 0.2°, 11.0° ⁇ 0.2°, and 19.0° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ of 17.5° ⁇ 0.2°, 18.1° ⁇ 0.2°, 8.0° ⁇ 0.2°, 24.7° ⁇ 0.2°, 17.2°. There are characteristic peaks at ⁇ 0.2°, 27.4° ⁇ 0.2°, 7.2° ⁇ 0.2°, 11.0° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS2 is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form CS2, which comprises adding a base to a carboxylic acid system using Filgotinib hydrochloride, stirring and crystallization at a certain temperature, and separating the carboxylic acid. a solvate, heated under nitrogen to obtain a crystalline form CS2;
  • the carboxylic acid is a C 1 -C 3 carboxylic acid or a mixture thereof;
  • the carboxylic acid is acetic acid
  • the base used is an inorganic base
  • it is a mixture of one or more of sodium hydroxide, potassium hydroxide, and calcium hydroxide;
  • the base is sodium hydroxide
  • the crystallization temperature is 25-0 ° C
  • the crystallization temperature is 5 ° C;
  • the temperature of the solvent removal is 150-195 ° C;
  • the present invention provides a crystal form CS3 of Filgotinib (hereinafter referred to as "crystal form CS3").
  • the crystalline form CS3 is a combination of Filgotinib and acetic acid (hereinafter referred to as "acetate conjugate”), including but not limited to solvates or salts.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at diffraction angle 2 ⁇ values of 11.8 ° ⁇ 0.2 °, 14.1 ° ⁇ 0.2 °, 17.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CS3 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 18.4° ⁇ 0.2°, 20.5° ⁇ 0.2°, and 22.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at one or two or three of the diffraction angle 2 ⁇ values of 25.7° ⁇ 0.2°, 11.5° ⁇ 0.2°, and 23.6° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystalline form CS3 has a diffraction angle 2 ⁇ of 11.8° ⁇ 0.2°, 14.1° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.4° ⁇ 0.2°, 20.5°. There are characteristic peaks at ⁇ 0.2°, 22.9° ⁇ 0.2°, 25.7° ⁇ 0.2°, 11.5° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS3 is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form CS3, which comprises adding a base in an acetic acid solvent using Filgotinib hydrochloride, stirring and crystallization at a certain temperature, and separating the crystal form CS3. ;
  • the base used is an inorganic base
  • it is a mixture of one or more of sodium hydroxide, potassium hydroxide, and calcium hydroxide;
  • the base is sodium hydroxide
  • the crystallization temperature is 25-0 ° C
  • the crystallization temperature is 5 °C.
  • the crystalline forms CS1, CS2 and CS3 of Filgotinib of the invention have the following beneficial properties:
  • crystal form CS1 at 25 ° C / 60% RH, 40 ° C / 75% RH placed for 3 weeks crystal form remains unchanged; crystal form CS2 at 25 ° C / 60% RH, 40 ° C / 75% RH The crystal form remained unchanged at 60 ° C / 75% RH for 3 weeks;
  • the crystal form CS1 of the present invention is higher than CN105960407A mode 4.
  • the "room temperature” means 10 to 30 °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.
  • the "drying” can be carried out at room temperature or higher. 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.
  • the solvent removal process includes, but is not limited to, heating with DSC, vacuum drying, etc., and other methods.
  • the DSC heating rate includes, but is not limited to, 20 ° C / min.
  • 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.
  • the relative intensity of the X-ray diffraction pattern may also vary with the experimental conditions, so the peak intensity is smooth. Order 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.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of the crystalline form CS1, crystalline form CS2 and crystalline form CS3 of the present invention, and at least one A pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides the use of one or more of the crystalline form CS1, crystalline form CS2 and form CS3 of Filgotinib in the preparation of a pharmaceutical formulation of a JAK inhibitor, particularly a pharmaceutical formulation of a JAK1 inhibitor.
  • the present invention provides the use of the crystalline form CS1, crystalline form CS2, crystalline form CS3 of Filgotinib, or any mixture thereof, in the preparation of a pharmaceutical preparation for treating rheumatoid arthritis and Crohn's disease.
  • the crystalline form CS1 of the present invention remains unchanged at 25 ° C / 60% RH, 40 ° C / 75% RH for 3 weeks; the crystalline form CS2 is at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 The crystal form remained unchanged at °C/75% RH for 3 weeks, and the stability was good.
  • the crystal form CS2 has a weight gain of 0.198% at 80% relative humidity, and has almost no hygroscopicity.
  • the crystal form CS2 and the crystal form CS3 of the present invention do not change in crystal form during polishing, and have good mechanical stability.
  • Solubility of crystalline form CS1 and crystalline form CS2 of the present invention in SGF simulated artificial gastric juice
  • pH 5.0 FeSSIF artificial intestinal juice in fed state
  • pH 6.5 FaSSIF artificial intestinal fluid in fasting state
  • pure water in a saturated solution Higher.
  • Figure 1 is an XRPD pattern of the crystalline form CS1.
  • Figure 2 is a DSC map of the crystalline form CS1.
  • Figure 3 is a TGA map of the crystalline form CS1.
  • Figure 4 is an XRPD pattern of the crystalline form CS2.
  • Figure 5 is a DSC chart of the crystalline form CS2.
  • Figure 6 is a TGA map of the crystalline form CS2.
  • Figure 7 is a DVS map of the crystalline form CS2.
  • Figure 8 is a comparison of XRPD before and after DVS of crystalline CS2 (top: XRPD pattern after DVS, bottom: XRPD pattern before DVS).
  • Figure 9 is a nuclear magnetic resonance spectrum of crystalline form CS3.
  • Figure 10 is a DSC diagram of the crystalline form CS3.
  • Figure 11 is a TGA diagram of the crystalline form CS3.
  • Figure 12 is an XRPD pattern of the crystalline form CS3.
  • Figure 13 is a nuclear magnetic resonance spectrum of a chlorobenzene solvate.
  • Figure 14 is a DSC chart of a chlorobenzene solvate.
  • Figure 15 is a TGA diagram of a chlorobenzene solvate.
  • Figure 16 is an XRPD pattern of a chlorobenzene solvate.
  • Figure 17 is a DVS map of Mode 4 of the patent CN105960407A.
  • Figure 18 is a comparison of XRPD of CS1 before and after 3 weeks in a 25 ° C / 60% RH, 40 ° C / 75% RH environment.
  • Figure 19 is a comparison of XRPD of CS2 before and after 3 weeks in a 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH environment.
  • Figure 20 is a comparison of XRPD before and after CS2 grinding.
  • Figure 21 is a comparison of XRPD before and after CS3 grinding.
  • Figure 22 is a comparison of XRPD before and after grinding of the patent CN105960407A mode 4.
  • 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 scanning calorimetry (DSC) map of the present invention was acquired on a TA Q200.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • the scanning rate of the apparatus when the portion of the embodiment of the invention is heated by DSC is 20 ° C / min.
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken 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.
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software
  • the analysis software is DVS-Intrinsic Analysis software.
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the reagents used were all commercially available and the purity was analytically pure.
  • the DSC of this crystal form is shown in Figure 2.
  • the first endothermic peak begins to appear near 199 ° C.
  • An exothermic peak appears after the first endothermic peak, and a second endothermic peak begins to appear near 218 ° C.
  • the TGA of this crystal form is as shown in Fig. 3, and the weight loss is about 0.1% when heated to around 225 °C.
  • the obtained crystalline solid was the crystalline form CS2 of the present invention, and its X-ray powder diffraction pattern is shown in Fig. 4, and the data is shown in Table 3.
  • the DSC of this crystal form is as shown in Fig. 5, and an endothermic peak starts to appear near 218 °C.
  • the crystal The type of TGA is as shown in Fig. 6, and the weight loss is about 0.8% when heated to around 225 °C.
  • the obtained crystalline solid was the crystalline form CS2 of the present invention, and its X-ray powder diffraction data is shown in Table 5.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • pattern 4 About 10 mg of the crystalline form CS2 obtained by the present invention and the patent CN105960407A mode 4 (hereinafter referred to as "patent mode 4") were tested for wettability by a dynamic moisture adsorption (DVS) instrument. Cycle once at 0-95%-0 relative humidity and record the mass change at each humidity. The results are shown in Table 6.
  • the DVS of the crystalline form CS2 is shown in Fig. 7.
  • the XRPD pattern before and after the DVS is as shown in Fig. 8. It can be seen that the crystal form of the crystalline form CS2 before and after the DVS does not change; the DVS of the patent mode 4 is as Figure 17 shows.
  • the crystalline form CS2 of the present invention has almost no hygroscopicity, and the wettability of the crystalline form CS2 at 80% relative humidity is lower than that of the patent mode 4.
  • the size of the drug's wettability is closely related to the selection of appropriate packaging and storage conditions, and even the selection of the appropriate formulation process and dosage form. Improper selection of packaging and storage conditions can cause changes in the appearance of drugs with greater hygroscopicity, such as agglomeration, deliquescence, discoloration, etc.
  • the low-wetting drug requirements for packaging and storage conditions are not critical, it is conducive to long-term storage of drugs, which will greatly reduce the cost of material packaging and storage and quality control.
  • the low wettability crystal form does not require special drying conditions in the preparation process, which simplifies the preparation and post-treatment process of the drug, is easy for industrial production, and significantly reduces the research and development cost of the drug.
  • the crystalline form CS1 prepared by the present invention is allowed to stand under the conditions of 25 ° C / 60% relative humidity (RH), 40 ° C / 75% relative humidity (RH) for 3 weeks; the crystalline form CS2 is at 25 ° C / 60% relative humidity ( RH), 40 ° C / 75% relative humidity (RH), 60 ° C / 75% relative humidity (RH) were placed for 3 weeks, and the XRPD was measured.
  • the experimental results are shown in Tables 7 and 8.
  • the XRPD comparison charts of the crystal forms CS1 and CS2 placed under the above conditions for about 3 weeks are shown in Figs. 18 and 19, respectively.
  • the results show that the crystalline form CS1 remains unchanged at 25 °C / 60% RH, 40 °C / 75% RH for 3 weeks; the crystalline form CS2 is at 25 °C / 60% RH, 40 °C / 75% RH, 60 The crystal form remained unchanged at °C/75% RH for 3 weeks.
  • the crystal form CS1 and the crystal form CS2 provided by the invention have good stability.
  • the crystal form CS1, the crystal form CS2 patent CN105960407A mode 4 (hereinafter referred to as "patent mode 4") obtained by the present invention are respectively used for SGF (simulated artificial gastric juice), pH 5.0 FeSSIF (artificial intestinal juice under fed state), pH 6.5 FaSSIF (artificial intestinal fluid in fasting state) and pure water are formulated into a saturated solution.
  • SGF simulated artificial gastric juice
  • pH 5.0 FeSSIF artificial intestinal juice under fed state
  • pH 6.5 FaSSIF artificial intestinal fluid in fasting state
  • pure water are formulated into a saturated solution.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours, and 24 hours.
  • HPLC high performance liquid chromatography
  • the above solubility test results show that the solubility of the crystalline form CS1 and the crystalline form CS2 of the present invention in comparison with the patent mode 4 after being placed in the above saturated solution for 1 hour, 4 hours and 24 hours is higher than the solubility of the patent mode 4, solubility.
  • the improvement of the formulation process reduces the difficulty of the development of the formulation process, and the crystal form of sufficiently high solubility can be developed by the conventional formulation process, and for the crystal form with low solubility, in order to achieve the desired bioavailability, more complicated Formulation process.
  • the increase in the solubility of the crystalline forms CS1 and CS2 enables us to reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.

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Abstract

一种JAK1选择性抑制剂的新晶型及其制备方法和预防和/或治疗与JAK家族激酶相关疾病中的用途。所述新晶型具有制备工艺简单，溶解度高，稳定性好，引湿性低与机械稳定性好等有利性质。

Description

一种JAK1选择性抑制剂的新晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及Filgotinib的晶型及其制备方法和用途。
背景技术
风湿性关节炎是一种自身免疫性疾病，会引起关节和身体其他部位的慢性炎症，并且会导致永久性的关节破坏和畸形。若该疾病不经治疗，可由于关节功能的损失而导致实质性残疾和疼痛，最终导致预期寿命缩短。目前，风湿性关节炎的疗法远不能令人满意，仍需要鉴别可用于其治疗的新药物。此病症为慢性病症，其需要长期疗法和反复摄入药物，而长期治疗可能对于患者以及医师是沉重负担，因为患者可能对药物不耐受或变得对药物不耐受。此外，较高剂量或较高给药频率可能导致不适的副作用和/或较低患者顺应性。风湿性关节炎较高的发病率(在世界范围内约0.8％的成人患病)表明了其较大的社会影响。风湿性关节炎疗法的目标并非仅为减缓疾病，而是使疼痛获得缓解以便阻止关节损坏，并改善人类生活质量。
克罗恩病(Crohn’s disease)是一种炎症性肠道疾病，会引起消化道发炎、腹痛、严重腹泻、肠道阻塞、溃疡、瘘管、肛门裂缝等病症，且易反复发作。此外，患有克罗恩病的人有营养不良的风险，因其肠道不能从饮食中吸收其身体所需营养。由克罗恩病引起的炎症可能涉及人的消化道的不同区域，通常会深入到肠道组织层中，让人既痛苦又虚弱，甚至导致危及生命的并发症。本病的复发率与病变范围、病症侵袭的增强、病程的延长、年龄的增长等因素有关，同时死亡率也随之增高。因此，需要开发对此病具有有益作用的治疗剂。
“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，其广泛参与炎症、自身免疫及免疫调节等多个重要生物学过程。Janus激酶家族包括如下四种JAK家族成员：JAK1、JAK2、JAK3和TYK2。其中，抑制JAK1对炎症治疗过程至关重要，而抑制JAK2、JAK3和TYK2对炎症治疗并不是必须的，其抑制过程反而会引起一些不良反应，比如抑制JAK2与产生贫血相关，抑制JAK3和免疫功能受抑制相关。JAK1作为免疫-炎症疾病的靶标，其抑制剂对治疗风湿性关节炎、克罗恩病等免疫炎症障碍疾病是有益的。
Filgotinib(GLPG0634)是一种JAK1的选择性抑制剂，其对JAK1、JAK2、JAK3和TYK2的IC50分别为10nM、28nM、810nM、和116nM。其中，IC50(half maximal inhibitory concentration)是指被测量的半抑制浓度，能指示某一药物或者物质(抑制剂)在抑制某些生物程序的半量，该数值越低，药物的抑制能力越强。因此，Filgotinib对抑制JAK1表现出较高的选择性。吉利德科技公司(Gilead)的临床试验已证明Filgotinib不会引起贫血和低密度脂蛋白(LDL)的异常增加，且该游离形式被登记用于临床，结果表明Filgotinib在治疗风湿性关节炎和克罗恩病等方面具有非常好的应用前景。
Filgotinib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；化学结构式如下所示：
Figure PCTCN2017095867-appb-000001
专利文献WO2010149769A1(其通过引用的方式并入到本申请作为参考)中公开了Filgotinib游离形式的确认、制备和用途，然而，该专利未披露Filgotinib游离形式的最终形态信息，经专利CN105111206A证明，其形态为无定形态。游离形式的现有技术分析结果如下：
Figure PCTCN2017095867-appb-000002
Figure PCTCN2017095867-appb-000003
综上，现有技术晶型存在制备方法复杂，结晶度差，溶解度低，收率低，稳定性较差，难于干燥，易产生溶剂残留等缺点。本发明人经实验综合分析发现，上述专利文献CN105960407A的模式4较其他现有技术晶型具有较优性质，稳定性较好，在室温下不易转变，结晶度较好，易于干燥，不易产生溶剂残留，但本发明人经实验发现，其溶解度较低，引湿性较高，在一定机械力的作用下机械稳定性较差，且其制备方法复杂，需在环境与50℃之间的热循环反应，不利于后期工艺的开放与放大。因此，有必要进行多晶型筛选，使开发的晶型能够克服现有技术的不足，更加适用于工业化生产。
本发明克服了以上现有技术的缺点，所得新晶型与专利文献CN105960407A模式4相比，具有制备方法简单，溶解度高，结晶度好，纯度高，引湿性低，稳定性好，特别是机械稳定性好等优势，适于工业化药物制剂生产及后期药品运用，具有重大的经济价值。
发明内容
本发明的主要目的是提供如下所示的Filgotinib的新晶型及其制备方法和用途。
Figure PCTCN2017095867-appb-000004
非限制性地，在本发明的一个具体实施方案中，晶型CS1的X射线粉末衍射谱图如图1所示。
根据本发明的目的，本发明提供Filgotinib的晶型CS1(以下称作“晶型CS1”)。所述晶型CS1为无水物。
使用Cu-Kα辐射，所述晶型CS1的X射线粉末衍射在衍射角2θ值为10.3°±0.2°、13.7°±0.2°、16.1°±0.2°处有特征峰。
进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为18.0°±0.2°、21.7°±0.2°、24.7°±0.2°中的一处或两处或三处有特征峰。
更进一步的，所述晶型CS1的X射线粉末衍射在衍射角2θ值为8.6°±0.2°、19.4°±0.2°中的一处或两处有特征峰。
在一个优选的实施方案中，所述晶型CS1的X射线粉末衍射在衍射角2θ值为10.3°±0.2°、13.7°±0.2°、16.1°±0.2°、18.0°±0.2°、21.7°±0.2°、24.7°±0.2°、8.6°±0.2°、19.4°±0.2°处有特征峰。
根据本发明的目的，本发明还提供所述晶型CS1的制备方法，所述制备方法包括使用Filgotinib盐酸盐在卤代芳香烃体系中加入碱，于一定温度下搅拌反应析晶，分离得卤代芳香烃溶剂合物，氮气保护下加热脱溶剂得到所述晶型CS1；
其中：
所述卤代芳香烃为芳香烃类的芳香环被取代的中的一种或多种的混合物；
优选为氯苯、溴苯中的一种或它们的混合物；
更优选地，所述卤代芳香烃为氯苯；
所用碱为无机碱；
优选为氢氧化钠、氢氧化钾、氢氧化钙中的一种或多种的混合物；
更优选地，所述碱为氢氧化钠；
所述析晶温度为25-0℃，
优选为10-0℃；
更优选地，析晶温度为5℃；
所述脱溶剂的温度为150-195℃；
优选为190℃。
根据本发明的目的，本发明提供Filgotinib的晶型CS2(以下称作“晶型CS2”)。所述晶型CS2为无水物。
使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在衍射角2θ值为17.5°±0.2°、18.1°±0.2°、8.0°±0.2°处有特征峰。
进一步的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为24.7°±0.2°、17.2°±0.2°、27.4°±0.2°中的一处或两处或三处有特征峰。
更进一步的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为7.2°±0.2°、11.0°±0.2°、19.0°±0.2°中的一处或两处或三处有特征峰。
在一个优选的实施方案中，所述晶型CS2的X射线粉末衍射在衍射角2θ值为17.5°±0.2°、18.1°±0.2°、8.0°±0.2°、24.7°±0.2°、17.2°±0.2°、27.4°±0.2°、7.2°±0.2°、11.0°±0.2°、19.0°±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CS2的X射线粉末衍射谱图如图4所示。
根据本发明的目的，本发明还提供所述晶型CS2的制备方法，所述制备方法包括使用Filgotinib盐酸盐在羧酸体系中加入碱，于一定温度下搅拌反应析晶，分离得羧酸溶剂合物，氮气保护下加热得晶型CS2；
其中：
所述羧酸为C1～C3羧酸或者它们的混合物；
优选地，所述羧酸为乙酸；
所用碱为无机碱；
优选为氢氧化钠、氢氧化钾、氢氧化钙中的一种或多种的混合物；
更优选地，所述碱为氢氧化钠；
所述析晶温度为25-0℃，
优选为10-0℃；
更优选地，析晶温度为5℃；
所述脱溶剂的温度为150-195℃；
优选为190℃。
根据本发明的目的，本发明提供Filgotinib的晶型CS3(以下称作“晶型CS3”)。所述晶型CS3为Filgotinib与乙酸的结合物(以下称为“乙酸结合物”)，该结合物包括但不限于溶剂合物或盐。
使用Cu-Kα辐射，所述晶型CS3的X射线粉末衍射在衍射角2θ值为11.8°±0.2°、14.1°±0.2°、17.8°±0.2°处有特征峰。
进一步的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为18.4°±0.2°、20.5°±0.2°、22.9°±0.2°中的一处或两处或三处有特征峰。
更进一步的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为25.7°±0.2°、11.5°±0.2°、23.6°±0.2°中的一处或两处或三处有特征峰。
在一个优选的实施方案中，所述晶型CS3的X射线粉末衍射在衍射角2θ值为11.8°±0.2°、14.1°±0.2°、17.8°±0.2°、18.4°±0.2°、20.5°±0.2°、22.9°±0.2°、25.7°±0.2°、11.5°±0.2°、23.6°±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CS3的X射线粉末衍射谱图如图12所示。
根据本发明的目的，本发明还提供所述晶型CS3的制备方法，所述制备方法包括使用Filgotinib盐酸盐在乙酸溶剂中加入碱，于一定温度下搅拌反应析晶，分离得到晶型CS3；
其中：
所用碱为无机碱；
优选为氢氧化钠、氢氧化钾、氢氧化钙中的一种或多种的混合物；
更优选地，所述碱为氢氧化钠；
所述析晶温度为25-0℃，
优选为10-0℃；
更优选地，析晶温度为5℃。
本发明的Filgotinib的晶型CS1、CS2和CS3具有以下有益性质：
①结晶度好；
②稳定性好，晶型CS1在25℃/60％RH，40℃/75％RH条件下放置3周晶型保持不变；晶型CS2在25℃/60％RH，40℃/75％RH，60℃/75％RH条件下放置3周晶型保持不变；
③引湿性低，本发明的晶型CS2在80％相对湿度的增重为0.198％，几乎 无引湿性；
④机械稳定性好，晶型CS2与晶型CS3在研磨前后，晶型无变化；
⑤收率高，晶型CS1与晶型CS2的收率为100％；
⑥不使用高沸点溶剂，晶体已干燥，且不易产生溶剂残留；
⑦溶解度高，在SGF(模拟人工胃液)、pH5.0FeSSIF(进食状态下人工肠液)、pH6.5FaSSIF(空腹状态下人工肠液)和纯水配制成饱和溶液中，本发明的晶型CS1、晶型CS2均比CN105960407A模式4高。
所述“室温”指10～30℃。
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。
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。
所述脱溶剂方法包含但不限于用DSC加热，真空干燥等，还包括其它方法。所述DSC加热速率包括但不限于20℃/min。
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CS1、晶型CS2或晶型CS3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。
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CS1、晶型CS2和晶型CS3中的一种或多种，以及至少一种 药学上可接受的载体、稀释剂或赋形剂。
进一步地，本发明提供的Filgotinib的晶型CS1、晶型CS2和晶型CS3的一种或多种混合在制备JAK抑制剂药物制剂中的用途，尤其是JAK1抑制剂药物制剂中的用途。
更进一步地，本发明提供的Filgotinib的晶型CS1、晶型CS2、晶型CS3，或它们的任意混合在制备治疗风湿性关节炎、克罗恩病药物制剂中的用途。
本发明的晶型CS1在25℃/60％RH，40℃/75％RH条件下放置3周晶型保持不变；晶型CS2在25℃/60％RH，40℃/75％RH，60℃/75％RH条件下放置3周晶型保持不变，稳定性好。晶型CS2在80％相对湿度的增重为0.198％，几乎无引湿性。本发明的晶型CS2与晶型CS3在研磨时晶型不发生变化，机械稳定性好。在SGF(模拟人工胃液)、pH5.0FeSSIF(进食状态下人工肠液)、pH6.5FaSSIF(空腹状态下人工肠液)和纯水配制成饱和溶液中，本发明的晶型CS1和晶型CS2的溶解度较高。
附图说明
图1为晶型CS1的XRPD图谱。
图2为晶型CS1的DSC图谱。
图3为晶型CS1的TGA图谱。
图4为晶型CS2的XRPD图谱。
图5为晶型CS2的DSC图谱。
图6为晶型CS2的TGA图谱。
图7为晶型CS2的DVS图谱。
图8为晶型CS2的DVS前后的XRPD对比图(上：DVS后的XRPD图，下：DVS前的XRPD图)。
图9为晶型CS3的核磁共振氢谱。
图10为晶型CS3的DSC图。
图11为晶型CS3的TGA图。
图12为晶型CS3的XRPD图。
图13为氯苯溶剂合物的核磁共振氢谱。
图14为氯苯溶剂合物的DSC图。
图15为氯苯溶剂合物的TGA图。
图16为氯苯溶剂合物的XRPD图。
图17为专利CN105960407A模式4的DVS图谱。
图18为CS1在25℃/60％RH、40℃/75％RH环境放置3周前后的XRPD对比图。
图19为CS2在25℃/60％RH、40℃/75％RH、60℃/75％RH环境放置3周前后的XRPD对比图。
图20为CS2研磨前后的XRPD对比图。
图21为CS3研磨前后的XRPD对比图。
图22为专利CN105960407A模式4研磨前后的XRPD对比图。
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：Cu,Kα
Figure PCTCN2017095867-appb-000005
1.540598；
Figure PCTCN2017095867-appb-000006
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q200上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
特别声明，本发明实施例部分用DSC加热时仪器的扫描速率为20℃/min。
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
核磁共振氢谱数据(1H NMR)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。
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software，分析软件是DVS-Intrinsic Analysis software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：氮气，200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
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。
所使用的试剂均为商购，纯度为分析纯。
实施例1 CS1晶型的制备方法
500.2mg Filgotinib盐酸盐加入5.0mL氯苯中，室温下搅拌10min，逐滴加入0.55mL，2mol/L的氢氧化钠水溶液，5℃下搅拌反应32小时，过滤，用3.0mL的纯水洗涤，室温下真空干燥得白色粉末。液态核磁(图13)，DSC(图14)，TGA(图15)，XRPD图(图16)测试证明该白色粉末是氯苯溶剂合物，氯苯溶剂合物的核磁数据如下：1H NMR(400MHz,DMSO)δ11.00(s,1H),8.00(d,J＝8.3Hz,2H),7.74–7.65(m,2H),7.53(d,J＝8.3Hz,2H),7.46–7.32(m,2.5H),7.30(dd,J＝6.7,1.9Hz,1H),3.78(s,2H),3.14(d,J＝5.1Hz,4H),2.94(d,J＝5.8Hz,4H),0.81(d,J＝6.2Hz,4H).
取上述制备的17.56mg氯苯溶剂合物，用DSC加热至190℃(加热速率20℃/分钟)得白色固体，收率为100％。
经检测，所得结晶固体为本发明所述之晶型CS1，其X射线粉末衍射数据如表1所示。
表1
衍射角2θ d值 相对强度％
4.85 18.22 1.43
7.23 12.23 11.53
7.98 11.07 4.24
8.55 10.34 93.17
10.34 8.56 40.74
10.98 8.06 11.21
11.63 7.61 5.97
11.89 7.44 11.10
12.35 7.17 1.19
13.09 6.76 41.40
13.66 6.48 9.47
14.52 6.10 2.84
14.93 5.93 1.48
15.59 5.68 7.04
15.88 5.58 17.13
16.13 5.50 37.58
16.36 5.42 37.55
17.30 5.12 25.53
17.57 5.05 16.34
17.98 4.93 16.39
19.43 4.57 100.00
19.69 4.51 90.76
20.12 4.41 65.47
20.43 4.35 27.35
21.70 4.10 8.27
22.10 4.02 7.94
23.01 3.87 16.09
23.85 3.73 6.65
24.73 3.60 8.37
25.36 3.51 5.69
25.93 3.44 3.58
26.35 3.38 2.82
26.92 3.31 2.68
27.43 3.25 8.87
28.01 3.19 5.87
28.72 3.11 2.16
29.52 3.03 7.06
31.42 2.85 5.72
33.15 2.70 1.82
36.24 2.48 1.41
该晶型的DSC如图2所示，在199℃附近开始出现第一个吸热峰，第一个吸热峰后出现一个放热峰，在218℃附近开始出现第二个吸热峰。该晶型的TGA如图3所示，加热至225℃附近失重约为0.1％。
实施例2 CS3晶型的制备方法
499.7mg的Filgotinib盐酸盐加入5.0mL乙酸中，室温下搅拌10min，逐滴加入5.55mL，2.0mol/L的氢氧化钠水溶液，5℃下搅拌反应32小时，过滤，用3.0mL的纯水洗涤，室温下真空干燥得白色粉末。称量计算其收率为84％。液态核磁(图9)，DSC(图10)，TGA(图11)测试证明该白色粉末为本发明所述晶型CS3。晶型CS3为乙酸结合物，该乙酸结合物的核磁数据如下：1H NMR(400MHz,DMSO)δ12.07–11.67(m,1H),δ11.00(s,1H),8.00(d,J＝8.2Hz,2H),7.80–7.64(m,2H),7.53(d,J＝8.2Hz,2H),7.30(dd,J＝6.7,1.8Hz,1H),3.78(s,2H),3.14(d,J＝5.1Hz,4H),2.93(s,4H),2.02(s,1H),1.91(s,3H),0.81(d,J＝6.2Hz,4H)；其XRPD图如图12所示，数据如表2所示。
表2
衍射角2θ d值 相对强度％
4.87 18.16 0.88
5.86 15.08 2.10
11.45 7.73 25.18
11.84 7.47 100.00
12.19 7.26 3.39
14.09 6.28 20.07
16.24 5.46 4.58
16.43 5.40 7.63
16.82 5.27 2.88
17.50 5.07 15.53
17.84 4.97 34.07
18.43 4.81 23.85
18.67 4.75 34.24
18.84 4.71 25.04
19.07 4.66 5.39
19.91 4.46 5.50
20.51 4.33 17.94
21.11 4.21 6.14
21.58 4.12 2.31
21.88 4.06 2.69
22.17 4.01 3.93
22.85 3.89 19.52
23.55 3.78 17.00
23.82 3.74 8.29
24.57 3.62 6.95
24.86 3.58 6.20
25.13 3.54 3.53
25.66 3.47 14.62
26.60 3.35 9.45
26.86 3.32 4.40
27.73 3.22 3.98
28.10 3.18 5.25
29.17 3.06 3.06
29.52 3.03 2.80
30.01 2.98 0.88
30.71 2.91 2.77
30.94 2.89 2.76
31.71 2.82 1.45
32.76 2.73 0.78
33.33 2.69 3.58
33.84 2.65 1.93
34.30 2.61 2.54
34.86 2.57 1.71
35.73 2.51 0.52
38.00 2.37 2.14
实施例3 CS2晶型的制备方法
取13.44mg上述实施例2得到的乙酸结合物，用DSC加热至190℃(加热速率20℃/分钟)得白色固体，收率为100％。
经检测，所得结晶固体为本发明所述之晶型CS2，其X射线粉末衍射图如图4所示，数据如表3所示。
表3
衍射角2θ d值 相对强度％
7.21 12.27 93.05
7.96 11.11 44.90
10.96 8.07 100.00
14.49 6.11 23.84
16.41 5.40 17.71
16.85 5.26 18.87
17.22 5.15 52.97
17.55 5.05 75.03
18.10 4.90 63.73
18.99 4.67 99.04
19.74 4.50 44.06
20.02 4.44 23.83
21.16 4.20 33.08
22.10 4.02 11.72
22.74 3.91 6.59
24.07 3.70 40.39
24.70 3.61 62.60
25.45 3.50 10.82
25.84 3.45 24.65
27.43 3.25 54.09
29.42 3.04 11.84
31.72 2.82 6.40
33.32 2.69 3.60
36.89 2.44 2.41
该晶型的DSC如图5所示，加热至218℃附近开始出现一个吸热峰。该晶 型的TGA如图6所示，加热至225℃附近失重约为0.8％。
实施例4 CS2晶型的制备方法
取11.99mg上述实施例2得到的乙酸结合物，用DSC加热至190℃(加热速率20℃/分钟)得白色固体，收率为100％。
经检测，所得结晶固体为本发明所述之晶型CS2，其X射线粉末衍射数据如表4所示。
表4
衍射角2θ d值 相对强度％
4.66 18.95 3.42
7.20 12.27 77.66
7.96 11.10 42.37
10.96 8.07 73.49
14.48 6.12 19.49
16.42 5.40 15.30
16.84 5.27 17.15
17.22 5.15 53.82
17.55 5.05 66.01
18.11 4.90 68.63
18.99 4.67 100.00
19.74 4.50 45.19
20.03 4.43 22.38
21.16 4.20 34.08
22.09 4.02 9.57
22.75 3.91 7.19
24.08 3.70 43.90
24.70 3.60 68.98
25.43 3.50 10.22
25.84 3.45 25.34
26.98 3.31 8.31
27.43 3.25 58.41
28.01 3.19 5.37
29.40 3.04 13.88
31.70 2.82 4.55
36.88 2.44 2.93
实施例5 CS2晶型的制备方法
取11.02mg上述实施例2得到的乙酸结合物，用DSC加热至190℃(加热速率20℃/分钟)得白色固体，收率为100％。
经检测，所得结晶固体为本发明所述的晶型CS2，其X射线粉末衍射数据如表5所示。
表5
衍射角2θ d值 相对强度％
7.20 12.28 76.37
7.96 11.11 45.46
10.96 8.07 81.95
14.49 6.11 23.88
16.40 5.41 20.81
16.83 5.27 16.35
17.21 5.15 48.61
17.54 5.06 64.96
18.09 4.90 65.77
18.98 4.68 100.00
19.73 4.50 44.51
20.02 4.44 21.98
21.16 4.20 40.14
22.73 3.91 8.18
24.08 3.70 38.80
24.70 3.60 68.19
25.82 3.45 24.73
27.44 3.25 49.23
29.42 3.04 9.45
31.84 2.81 4.07
实施例6 晶型CS2与专利CN105960407A模式4的引湿性研究
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
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。
取本发明制得的晶型CS2与专利CN105960407A模式4(以下简称“专利模式4”)各约10mg采用动态水分吸附(DVS)仪测试其引湿性。在0-95％-0相对湿度下循环一次，记录每个湿度下的质量变化。结果如表6所示，晶型CS2的DVS如图7所示，DVS前后的XRPD图如图8所示，可以看出DVS前后晶型CS2的晶型并无变化；专利模式4的DVS如图17所示。
表6
Figure PCTCN2017095867-appb-000007
结果表明，本发明的晶型CS2几乎无引湿性，且晶型CS2在80％相对湿度下引湿性比专利模式4低。药物引湿性的大小与选择合适的包装和储藏条件，乃至选择合适的制剂工艺和剂型都有着密切的关系。包装和贮存条件的选择不当会引起引湿性较大的药物的外观变化，如结团、潮解、变色等，从而发生内 在质量的变化，而低引湿性药物对包装和贮存条件要求不苛刻，则有利于药品的长期贮存，将大大降低物料包装和贮存以及质量控制成本。同时，低引湿性的晶型在制备过程中无需特殊的干燥条件，简化了药物的制备与后处理工艺，易于工业化生产，显著降低了药物的研发成本。
实施例7 晶型CS1、晶型CS2的稳定性研究
将本发明制备得到的晶型CS1在25℃/60％相对湿度(RH)、40℃/75％相对湿度(RH)的条件下放置3星期；晶型CS2在25℃/60％相对湿度(RH)、40℃/75％相对湿度(RH)、60℃/75％相对湿度(RH)的条件下放置3星期，测定其XRPD，实验结果见表7、8所示。晶型CS1与CS2放置在上述条件下3星期前后的XRPD对比图分别如图18、图19所示。
表7
Figure PCTCN2017095867-appb-000008
表8
Figure PCTCN2017095867-appb-000009
结果表明，晶型CS1在25℃/60％RH，40℃/75％RH条件下放置3周晶型保持不变；晶型CS2在25℃/60％RH，40℃/75％RH，60℃/75％RH条件下放置3周晶型保持不变。本发明所提供晶型CS1与晶型CS2具有良好的稳定性。
实施例8 晶型CS1、晶型CS2与专利CN105960407A模式4的溶解度对比研 究
将本发明制得的晶型CS1、晶型CS2专利CN105960407A模式4(以下简称“专利模式4”)分别用SGF(模拟人工胃液)、pH5.0 FeSSIF(进食状态下人工肠液)、pH6.5 FaSSIF(空腹状态下人工肠液)和纯水配制成饱和溶液。在1个小时，4个小时和24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9～12所示。
表9 各晶型在SGF中的溶解度
Figure PCTCN2017095867-appb-000010
表10 各晶型在FaSSIF中的溶解度
Figure PCTCN2017095867-appb-000011
表11 各晶型在FeSSIF中的溶解度
Figure PCTCN2017095867-appb-000012
表12 各晶型在H2O中的溶解度
Figure PCTCN2017095867-appb-000013
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CS1、晶型CS2与专利模式4相比，其溶解度均高于专利模式4溶解度，溶解度的提高降低了制剂工艺开发的的难度，足够高的溶解度的晶型将可以采用传统的制剂工艺进行开发，而对于溶解度低的晶型，为了达到理想的生物利用度，可能需要采用更加复杂的制剂工艺。同时晶型CS1与CS2溶解度的升高能够使我们在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
实施例9 晶型CS2、晶型CS3与专利CN105960407A模式4的机械稳定性研 究
采用XRPD测试晶型CS2、晶型CS3与专利CN105960407A模式4研磨前后的图谱，结果如图20、21、22所示。
结果表明，晶型CS2、晶型CS3比专利CN105960407A模式4具有更好的机械稳定性。更好的机械稳定性表现在一定机械力的作用下，仍可保持稳定的物理化学性质。具有较好的机械稳定性的晶型药物不用担心在后续的处理及制剂工艺过程中因为机械力而导致的晶型变化，在制剂过程中更加稳定，可显著降低药物的开发成本，提升药物质量，具有很强的经济价值。

Claims (21)

  1. Filgotinib的新晶型CS1，其特征在于，使用Cu-Kα辐射，所述晶型CS1的X射线粉末衍射图在衍射角2θ值为10.3°±0.2°、13.7°±0.2°、16.1°±0.2°处有特征峰。
  2. 根据权利要求1所述的Filgotinib的晶型CS1，其特征还在于，所述晶型CS1的X射线粉末衍射图在衍射角2θ值为18.0°±0.2°、21.7°±0.2°、24.7°±0.2°中的一处或多处有特征峰。
  3. 根据权利要求1所述的Filgotinib的晶型CS1，其特征还在于，所述晶型CS1的X射线粉末衍射图在衍射角2θ值为8.6°±0.2°、19.4°±0.2°中的一处或两处有特征峰。
  4. 权利要求1～3中任一项所述Filgotinib的晶型CS1的制备方法，其特征在于，所述制备方法包括：
    使用Filgotinib盐酸盐在卤代芳香烃类溶剂体系中加入碱，于一定温度下搅拌反应析晶，分离，干燥而获得Filgotinib的卤代芳香烃溶剂合物，该溶剂合物加热至脱溶剂得所述晶型CS1。
  5. 根据权利要求4所述的Filgotinib的晶型CS1的制备方法，其特征在于，所述卤代芳香烃类溶剂为卤代芳香烃类中的一种或多种的混合物；所用碱为无机碱；所述析晶温度为25-0℃；所述脱溶剂的温度为150-195℃。
  6. 根据权利要求4或5所述的Filgotinib的晶型CS1的制备方法，其特征还在于，所述卤代芳香烃类溶剂包括氯苯、溴苯中的一种或它们的混合物；所用碱包括氢氧化钠、氢氧化钾、氢氧化钙中的一种或多种混合物；所述析晶温度为10-0℃；所述加热脱溶剂温度为190℃。
  7. Filgotinib的新晶型CS2，其特征在于，使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射图在衍射角2θ值为17.5°±0.2°、18.1°±0.2°、8.0°±0.2°处有特征峰。
  8. 根据权利要求7所述的Filgotinib的晶型CS2，其特征还在于，所述晶型CS2的X射线粉末衍射图在衍射角2θ值为24.7°±0.2°、17.2°±0.2°、27.4°±0.2°中的一处或多处有特征峰。
  9. 根据权利要求7所述的Filgotinib的晶型CS2，其特征还在于，所述晶型CS2的X射线粉末衍射图在衍射角2θ为7.2°±0.2°、11.0°±0.2°、19.0°±0.2°中的一处或多处有特征峰。
  10. 权利要求7～9中任一项所述Filgotinib的晶型CS2的制备方法，其特征在于，所述制备方法包括：
    使用Filgotinib盐酸盐在羧酸溶剂体系中加入碱，于一定温度下搅拌反应析晶，分离，干燥而获得羧酸溶剂合物，羧酸溶剂合物加热脱溶剂得所述晶型CS2。
  11. 根据权利要求10所述的Filgotinib的晶型CS2的制备方法，其特征在于，所述羧酸为C1～C3羧酸或者它们的混合物；所用碱为无机碱；所述析晶温度为25-0℃；所述脱溶剂的温度为150-195℃。
  12. 根据权利要求10或11所述的Filgotinib的晶型CS2的制备方法，其特征还在于，所述羧酸为乙酸；所用碱包括氢氧化钠、氢氧化钾、氢氧化钙中的一种或多种的混合物；所述析晶温度为10-0℃；所述脱溶剂温度为190℃。
  13. Filgotinib的新晶型CS3，其特征在于，使用Cu-Kα辐射，所述晶型CS3的X射线粉末衍射图在衍射角2θ值为11.8°±0.2°、14.1°±0.2°、17.8°±0.2°处有特征峰。
  14. 根据权利要求13所述的Filgotinib的晶型CS3，其特征在于，所述晶型CS3的X射线粉末衍射图在衍射角2θ值为18.4°±0.2°、20.5°±0.2°、22.9°±0.2°中的一处或多处有特征峰。
  15. 根据权利要求13所述的Filgotinib的晶型CS3，其特征在于，所述晶型CS3的X射线粉末衍射图在衍射角2θ值为25.7°±0.2°、11.5°±0.2°、23.6°±0.2°中的一处或多处有特征峰。
  16. 权利要求13～15中任一项所述Filgotinib的晶型CS3的制备方法，其特征在于，所述制备方法包括：
    使用Filgotinib盐酸盐在乙酸溶剂中加入碱，于一定温度下搅拌反应析晶，分离，干燥而获得上所述的晶型CS3。
  17. 根据权利要求16所述的Filgotinib的晶型CS3的制备方法，其特征在于，所用碱为无机碱；所述析晶温度为25-0℃。
  18. 根据权利要求16或17所述的Filgotinib的晶型CS3的制备方法，其特征还在于，所用碱包括氢氧化钠、氢氧化钾、氢氧化钙中的一种或多种的混合物；所述析晶温度为10-0℃。
  19. 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的晶型CS1、权利要求7～9中任一项所述Filgotinib的晶型CS2、权利要求13～15中任一项所述Filgotinib的晶型CS3，以及至少一种药学上可接受的载体或赋形剂。
  20. 权利要求1～3中任一项所述Filgotinib的晶型CS1、权利要求7～9中任一项所述Filgotinib的晶型CS2、权利要求13～15中任一项所述Filgotinib的晶型CS3在制备具有抑制一种或多种JAK药物中的用途。
  21. 权利要求1～3中任一项所述Filgotinib的晶型CS1、权利要求7～9中任一项所述Filgotinib的晶型CS2、权利要求13～15中任一项所述Filgotinib的晶型CS3，或者权利要求19所述的药物组合物在生产用于制备治疗风湿性关节炎、克罗恩病药物制剂中的用途。
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