WO2017144010A1 - (6-(1H-吲唑-6-基)-N-[4-(4-吗啉基)苯基]咪唑并[1，2-a]吡嗪-8-胺)甲磺酸盐的新晶型 - Google Patents

(6-(1H-吲唑-6-基)-N-[4-(4-吗啉基)苯基]咪唑并[1，2-a]吡嗪-8-胺)甲磺酸盐的新晶型 Download PDF

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WO2017144010A1
WO2017144010A1 PCT/CN2017/074729 CN2017074729W WO2017144010A1 WO 2017144010 A1 WO2017144010 A1 WO 2017144010A1 CN 2017074729 W CN2017074729 W CN 2017074729W WO 2017144010 A1 WO2017144010 A1 WO 2017144010A1
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iii
ray powder
powder diffraction
diffraction pattern
present
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PCT/CN2017/074729
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English (en)
French (fr)
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陈敏华
张炎锋
邹坡
张晓宇
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苏州晶云药物科技有限公司
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Priority to CN201780013531.6A priority Critical patent/CN109071547A/zh
Priority to US16/079,764 priority patent/US10472369B2/en
Priority to EP17755839.2A priority patent/EP3421474A4/en
Publication of WO2017144010A1 publication Critical patent/WO2017144010A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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 present invention relates to the field of chemical medicine, in particular to (6-(1H-carbazol-6-yl)-N-[4-(4-morpholinyl)phenyl]imidazo[1,2-a]pyrazine Crystal form of monomethanesulfonate and dimesyl salt of 8-amine (-8-amine) and preparation method thereof.
  • Spleen tyrosine kinase was first cloned from Japanese porcine spleen cDNA by Japanese scholar Taniguchi et al. in 1991.
  • the encoded protein is a non-receptor tyrosine kinase, hence the name spleen tyrosine kinase ( Spleen tyrosine kinase), spleen tyrosine kinase plays an important role in lymphocyte maturation and activation of immune cells.
  • SYK has been found to be abnormally expressed in tumors, and SYK is closely related to many signals related to tumorigenesis, development, and metastasis. It may become a therapeutic target for lymphoma, leukemia and other immune system-related tumors.
  • Entospletinib is an oral drug developed by Gilead. It is a selective spleen tyrosine kinase SYK inhibitor that inhibits the activity of spleen tyrosine kinase, including cancer and inflammation. The disease has a therapeutic effect. Entospletinib is undergoing clinical research in patients with refractory or relapsed chronic lymphocytic leukemia.
  • the chemical name of the drug is: (6-(1H-carbazol-6-yl)-N-[4-(4-morpholinyl)phenyl]imidazo[1,2-a]pyrazine-8- Amine), the structure of which is shown in formula (I):
  • the crystal form is known to be an important factor affecting the quality of the drug. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, the development of new crystal forms that are more suitable for application is of great significance for drug development.
  • the wettability is lower under the following humidity conditions, and its solubility is significantly improved compared to the free base and amorphous monomethanesulfonate, but the existing crystal form 3 is found in high humidity conditions (humidity 80%)
  • the above weight gain is up to 20%, and will be converted to the existing crystal form 7 at 90% humidity, which cannot satisfactorily meet the stringent requirements for crystal properties or drug properties in the production of industrial pharmaceutical preparations and later drug applications.
  • the patent US20150038505A1 reports more than one method for obtaining the existing crystal form 3, these methods are complicated to operate and are not easily available.
  • studies on the particle size distribution of the existing crystal forms 3 and 7 have revealed that the crystal particles are very fine, which would cause difficulty in separation during production.
  • One of the objects of the present invention is to provide various novel crystal forms of the methanesulfonate salt of the compound of the formula (I), specifically the compound of the formula (I), the dimethanesulfonate salt form I, the compound of the formula (I), the dimethanesulfonic acid. Salt crystal form II and the compound of formula (I) monomethanesulfonate crystal form III.
  • Another object of the present invention is to provide a method and use for the preparation of the above novel crystal form.
  • the present invention provides a compound of the formula (I), a form of the dimesylate salt I (hereinafter referred to as the crystalline form I of the present invention), which has an X-ray powder diffraction pattern at a value of 5.9 ° ⁇ 0.2 °, 13.5 ° ⁇ 0.2 ° and 21.8. Characteristic peak at ° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form I of the present invention preferably further has a characteristic peak at one or two or three of 2theta values of 25.9° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 20.4° ⁇ 0.2°. .
  • the X-ray powder diffraction pattern of the crystalline form I of the present invention has a characteristic peak at one or two or three of the 2theta values of 10.6° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 17.7° ⁇ 0.2°. .
  • the X-ray powder diffraction pattern of Form I of the invention is at 5.9 ° ⁇ 0.2 °, 13.5 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, 25.9 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, 20.4 ° ⁇ 0.2 °, 10.6 ° ⁇ 0.2 °, 14.7 ° ⁇ 0.2 ° and 17.7 ° ⁇ 0.2 ° with characteristic peaks.
  • the invention further provides a preparation method of the crystalline form I of the invention, which comprises: a) adding a compound of the formula (I) to a mixed system of a plurality of organic solvents, and stirring at a temperature of 5 to 30 ° C; Filtration through the system of step a) and drying, the resulting solid is Form I of the invention.
  • the mixed system of the plurality of organic solvents is preferably a mixed system of an alcohol organic solvent and an aromatic hydrocarbon organic solvent.
  • the temperature is further preferably from 20 to 30 °C.
  • the compound of the formula (I) provided by the present invention has an X-ray powder diffraction pattern of 25.8° ⁇ 0.2°, 17.2° ⁇ 0.2° and 19.5. Characteristic peak at ° ⁇ 0.2°.
  • the X-ray powder diffraction pattern thereof preferably has a characteristic peak at one or two or three of 2theta values of 26.1 ⁇ 0.2°, 14.7° ⁇ 0.2°, and 21.9° ⁇ 0.2°. .
  • the crystal form II of the present invention has an X-ray powder diffraction pattern preferably also characterized by one or two or three of 2theta values of 7.6 ⁇ 0.2°, 18.2° ⁇ 0.2° and 27.8° ⁇ 0.2°. peak.
  • the X-ray powder diffraction pattern of Form II of the invention has a value of 15.8 ° ⁇ 0.2 °, 17.2 ° ⁇ 0.2 °, 19.5 ° ⁇ 0.2 °, 26.1 ⁇ 0.2 °, 14.7 °. There are characteristic peaks at ⁇ 0.2°, 21.9° ⁇ 0.2°, 7.6 ⁇ 0.2°, 18.2° ⁇ 0.2° and 27.8° ⁇ 0.2°.
  • the present invention still further provides a process for the preparation of the crystalline form II of the present invention, which comprises: a) adding a compound of the formula (I) to a mesylate in one or more aromatic hydrocarbon organic solvents at a temperature of 40 to 80 ° C. Stirring; b) Filtration through the system of step a) and drying, the resulting solid is Form II of the invention.
  • the aromatic hydrocarbon organic solvent is toluene or p-xylene.
  • the stirring is carried out at a temperature of 60 to 70 °C.
  • the crystal form III of the monomethanesulfonate of the compound of the formula (I) provided by the present invention (hereinafter referred to as the crystal form III of the present invention) has an X-ray powder diffraction pattern at a value of 7.4 ° ⁇ 0.2 °, 12.9 ° ⁇ 0.2 ° and There is a characteristic peak at 19.2 ° ⁇ 0.2 °.
  • the crystal form III of the present invention has an X-ray powder diffraction pattern preferably also characterized by one or two or three of 2theta values of 6.5° ⁇ 0.2°, 21.2° ⁇ 0.2° and 24.4° ⁇ 0.2°. peak.
  • the X-ray powder diffraction pattern is more preferably one or two or three in the 2theta value of 17.7 ° ⁇ 0.2 °, 20.7 ° ⁇ 0.2 ° and 26.0 ° ⁇ 0.2 °. Has a characteristic peak.
  • the X-ray powder diffraction pattern of Form III of the invention has a value of 7.4 ° ⁇ 0.2 °, 12.9 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, 6.5 ° ⁇ 0.2 °, 21.2. ° ⁇ 0.2°, 24.4° ⁇ 0.2°, 17.7° ⁇ 0.2°, 20.7° ⁇ 0.2° It has characteristic peaks at both 26.0 ° ⁇ 0.2 °.
  • Another object of the present invention is to provide a process for the preparation of Form III of the present invention, which comprises the optional steps a) or b), and step c) wherein:
  • step c) Filtration through the system of step a) or b) and drying to give a solid which is Form III of the invention.
  • the volume ratio of the ketone solvent to water is from 1:1 to 10:1, preferably from 3:1 to 4:1.
  • the ketone solvent may be, for example, acetone.
  • the molar ratio of methanesulfonic acid to the compound of formula (I) may range from 1.0 to 1.8:1, preferably from 1.1 to 1.2:1.
  • the temperature of the system during the stirring is controlled to be 5 to 50 ° C, preferably 20 to 30 ° C.
  • the volume ratio of the alcohol solvent to water is generally from 99:1 to 1:99, preferably from 85:15 to 95:5.
  • the alcohol solvent may and preferably is isopropanol.
  • the crystalline form I or the crystalline form II or the crystalline form III of the present invention or a mixture thereof can be used for the preparation of an anticancer drug, particularly a drug for treating chronic lymphocytic leukemia and acute myeloid leukemia.
  • Another object of the present invention is to provide a pharmaceutical comprising a therapeutically effective amount of Form I or Form II or Form III of the present invention or a mixture thereof and a pharmaceutically acceptable adjuvant (pharmaceutically acceptable carrier or excipient) combination.
  • a therapeutically effective amount of Form I or Form II or Form III of the present invention or a mixture thereof is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation, or a pharmaceutical composition or The formulations are prepared in a manner well known in the pharmaceutical art.
  • the present invention also provides a method of treating or preventing a disease associated with SYK, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of any one of Form I, Form II, Form III of the present invention or A variety of combinations.
  • the present invention has the following advantages compared with the prior art:
  • the present invention provides a variety of new crystalline forms of Entospletinib mesylate which are more pharmaceutically acceptable than existing crystalline forms and which can be prepared by simpler methods.
  • Example 1 is an XRPD pattern of Formostin dibensulfonate Form I obtained in Example 1;
  • Example 2 is an XRPD pattern of Formosa of Formospletinib dimethanesulfonate obtained in Example 2;
  • Example 3 is a DSC chart of Formos of Entospletinib dimethanesulfonate Form I obtained in Example 2;
  • Figure 4 is a TGA diagram of Form I of Entospletinib dimethanesulfonate obtained in Example 2;
  • Figure 5 is a 1 H NMR chart of the Form I of Entospletinib dimethanesulfonate obtained in Example 2;
  • Figure 6 is an XRPD pattern of the Entospletinib dimethanesulfonate Form II obtained in Example 3;
  • Example 7 is a DSC chart of the Entospletinib dimethanesulfonate Form II obtained in Example 3;
  • Figure 8 is a TGA diagram of Formos II of Entospletinib dimethanesulfonate obtained in Example 3;
  • Figure 9 is a 1 H NMR chart of the Entospletinib dimethanesulfonate Form II obtained in Example 3;
  • Figure 10 is an XRPD pattern of the Entospletinib dimethanesulfonate Form II obtained in Example 4;
  • Figure 11 is an XRPD pattern of the Entospletinib dimethanesulfonate Form II obtained in Example 5;
  • Figure 12 is an XRPD pattern of Formos III of Entospletinib monomethanesulfonate obtained in Example 6;
  • Figure 13 is a DSC chart of Forms III of Entospletinib monomethanesulfonate obtained in Example 6;
  • Figure 14 is a TGA diagram of Forms III of Entospletinib monomethanesulfonate obtained in Example 6;
  • Figure 15 is a 1 H NMR chart of the crystal form III of Entospletinib monomethanesulfonate obtained in Example 6;
  • Figure 16 is an XRPD pattern of Formos III of Entospletinib monomethanesulfonate obtained in Example 7;
  • Figure 17 is a DSC chart of Forms III of Entospletinib monomethanesulfonate obtained in Example 7;
  • Figure 18 is a TGA diagram of Forms III of Entospletinib monomethanesulfonate obtained in Example 7;
  • Figure 19 is an XRPD pattern of Forms III of Entospletinib monomethanesulfonate obtained in Example 8;
  • Figure 20 is a DVS diagram of Forms III of Entospletinib monomethanesulfonate obtained in Example 9;
  • Figure 21 is a comparison diagram of crystal form change of the crystal form III of the present invention before and after the Example 9 DVS experiment;
  • Figure 22 shows an XRPD pattern of the Form II sample before and after placement, wherein the upper image is before placement and the lower image is placed after 90 days;
  • Figure 30 is an XRPD diagram of the crystal form III sample of the present invention stored for 300 days (the top image is the starting diagram, the middle is 25 ° C / 60% RH storage conditions after 300 days of storage, the following figure is 40 ° C / 75% RH storage Tested after 300 days of storage).
  • the present invention provides three novel crystal forms of the methanesulfonate salt of the compound of the formula (I), wherein the crystal form I of the dimesylate salt, i.e., the crystalline form I of the present invention, has an X-ray powder diffraction pattern with a value of 5.9 ° ⁇ 0.2 ° at 2theta.
  • characteristic peaks at 13.5 ° ⁇ 0.2 ° and 21.8 ° ⁇ 0.2 ° preferably It also has characteristic peaks at one or two or three of the 2theta values of 25.9 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 ° and 20.4 ° ⁇ 0.2 °, of which at 25.9 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 ° It is more preferable that the characteristic peaks are all at three places of 20.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I also has a characteristic peak at one or two or three of the 2theta values of 10.6° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 17.7° ⁇ 0.2°, wherein It is more preferable to have a characteristic peak at three points where the 2theta value is 10.6 ° ⁇ 0.2 °, 14.7 ° ⁇ 0.2 °, and 17.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I is at 5.9 ° ⁇ 0.2 °, 13.5 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, 25.9 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, There are characteristic peaks at 20.4 ° ⁇ 0.2 °, 10.6 ° ⁇ 0.2 °, 14.7 ° ⁇ 0.2 ° and 17.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I of the invention is substantially as shown in FIG.
  • the X-ray powder diffraction pattern of Form I of the present invention is substantially as shown in FIG.
  • Form I of the present invention is a hydrate.
  • the crystalline form I of the invention begins to exhibit a first endothermic peak near heating to 87 ° C and a second endothermic near 180 ° C. Peak, its DSC is shown in Figure 3.
  • the crystal form I of the present invention has a mass loss gradient of about 3.5% when heated to 120 ° C when subjected to thermogravimetric analysis, the TGA of which is shown in FIG.
  • the preparation method of the crystalline form I of the present invention comprises: a) adding a compound of the formula (I) to a mixed system of a plurality of organic solvents, stirring at a temperature of 5 to 30 ° C; b) filtering through the step a) The system is dried and the resulting solid (usually light yellow) is Form I of the present invention.
  • the mixed system of the plurality of organic solvents is preferably a mixed system of an alcohol organic solvent and an aromatic hydrocarbon organic solvent, wherein a volume ratio of the alcohol organic solvent to the aromatic hydrocarbon organic solvent is preferably 1:1 to 1: 5, more preferably from 1:2 to 1:3, specifically for example 1:2.
  • the alcohol organic solvent may, for example, be methanol, and the aromatic hydrocarbon organic solvent may, for example, be para-xylene.
  • the temperature is further preferably from 20 to 30 ° C, and most preferably about 25 ° C.
  • the present invention provides a crystal form II of the compound of the formula (I), which is the crystalline form II of the present invention, and has an X-ray powder diffraction pattern having a value of 15.8 ° ⁇ 0.2 °, 17.2 ° ⁇ 0.2 ° and 19.5 ° ⁇ 0.2.
  • Characteristic peaks at ° preferably also at one or two or three of 2theta values of 26.1 ⁇ 0.2 °, 14.7 ° ⁇ 0.2 ° and 21.9 ° ⁇ 0.2 °, with a value of 26.1 ⁇ at 2theta It is more preferable that each of the three points of 0.2°, 14.7° ⁇ 0.2° and 21.9° ⁇ 0.2° has a characteristic peak.
  • the X-ray powder of Form II The final diffraction pattern also has characteristic peaks at one or two or three of the 2theta values of 7.6 ⁇ 0.2°, 18.2 ° ⁇ 0.2 °, and 27.8 ° ⁇ 0.2 °, with a value of 7.6 ⁇ 0.2 °, 18.2 at 2theta. It is more preferable that all of the three points of ° ⁇ 0.2° and 27.8° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of Form II of the invention has a value of 15.8 ° ⁇ 0.2 °, 17.2 ° ⁇ 0.2 °, 19.5 ° ⁇ 0.2 °, 26.1 ⁇ 0.2 °, 14.7 °. There are characteristic peaks at ⁇ 0.2°, 21.9° ⁇ 0.2°, 7.6 ⁇ 0.2°, 18.2° ⁇ 0.2° and 27.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II of the invention is substantially as shown in FIG.
  • the X-ray powder diffraction pattern of Form II of the present invention is substantially as shown in FIG.
  • the X-ray powder diffraction pattern of Form II of the present invention is substantially as shown in FIG.
  • Form II of the invention is also a hydrate.
  • Form II of the present invention begins to exhibit a first endothermic peak near heating to 67 ° C and a second endothermic near 158 ° C. Peak, its DSC is shown in Figure 7.
  • Form II of the present invention when subjected to thermogravimetric analysis, has a mass loss gradient of about 3.3% when heated to 148 ° C, and its TGA is as shown in FIG.
  • the present invention still further provides a process for the preparation of the crystalline form II of the present invention, which comprises: a) adding a compound of the formula (I) to a mesylate in one or more aromatic hydrocarbon organic solvents at a temperature of 40 to 80 ° C. Stirring; b) Filtration through the system of step a) and drying, the resulting solid (usually pale yellow) is Form II.
  • the aromatic hydrocarbon organic solvent is preferably toluene or p-xylene.
  • the stirring is preferably carried out at a temperature of 60 to 70 °C.
  • the compound disulfonate crystal forms I and II of the formula (I) of the invention have good stability and low wettability, and the preparation process is simple, the amplification can be repeated, and the particle size is suitable. Compared with the existing crystal forms 3 and 7, it is more suitable for industrial production and application.
  • the crystalline form III of the monomethanesulfonate of the compound of the formula (I) provided by the present invention that is, the crystalline form III of the present invention, has an X-ray powder diffraction pattern at a value of 7.4 ° ⁇ 0.2 °, 12.9 ° ⁇ 0.2 ° and 19.2 ° ⁇ There is a characteristic peak at 0.2°. Further, the X-ray powder diffraction pattern of the crystalline form III of the present invention preferably further has a characteristic peak at one or two or three of the 2theta values of 6.5° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 24.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form III of the present invention is still more preferably in 2theta
  • the value has a characteristic peak at one or two or three of 17.7 ° ⁇ 0.2 °, 20.7 ° ⁇ 0.2 ° and 26.0 ° ⁇ 0.2 °, wherein the value of 2theta is 17.7 ° ⁇ 0.2 °, 20.7 ° ⁇ 0.2 ° It is most preferable to have characteristic peaks at all three points of 26.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form III of the invention has a value of 7.4 ° ⁇ 0.2 °, 12.9 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, 6.5 ° ⁇ 0.2 °, 21.2. Characteristic peaks are found at ° ⁇ 0.2°, 24.4° ⁇ 0.2°, 17.7° ⁇ 0.2°, 20.7° ⁇ 0.2° and 26.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III of the present invention is substantially as shown in FIG.
  • the X-ray powder diffraction pattern of Form III of the present invention is substantially as shown in FIG.
  • the crystalline form III of the present invention when differential scanning calorimetry is performed, the crystalline form III of the present invention begins to melt when heated to around 293 ° C, and its DSC is as shown in FIG. In another embodiment, the crystalline form III of the present invention begins to melt when heated to near 311 ° C when subjected to differential scanning calorimetry, the DSC of which is shown in FIG.
  • Form III of the present invention has a mass loss gradient of about 0.8% when heated to about 140 ° C when subjected to thermogravimetric analysis, the TGA of which is shown in FIG.
  • Form III of the present invention has a mass loss gradient of about 0.4% when heated to about 167 °C when subjected to thermogravimetric analysis, the TGA of which is shown in FIG.
  • Form III of the invention is an anhydride.
  • Another object of the present invention is to provide a process for the preparation of Form III of the present invention which comprises the optional steps a) or b), and step c) wherein:
  • step c) Filtration through the system of step a) or b) and drying to give a solid which is Form III.
  • the volume ratio of the ketone solvent to water is from 1:1 to 10:1, preferably from 3:1 to 4:1, and the ketone solvent may be, for example, acetone.
  • the molar ratio of methanesulfonic acid to the compound of formula (I) may range from 1.0 to 1.8:1, preferably from 1.1 to 1.2:1.
  • the volume ratio of the alcohol solvent to water is generally from 99:1 to 1:99, preferably from 85:15 to 95:5. Most preferred is 89:11.
  • the alcohol solvent may and preferably is isopropanol.
  • the compound of the formula (I) of the invention has good stability, good crystallinity, low wettability, simple preparation process and repeated amplification. Compared with the existing crystal form 3, the stability under the condition of aqueous system or high humidity has obvious advantages, and in addition, it has obvious advantages in production preparation conditions and repeatability, and is more medicinal than the existing crystal form 3. The required crystal form.
  • Forms I, II, and III of the present invention are pure, unitary, and substantially free of any other crystalline form.
  • substantially free when used in reference to a 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 preferably less than 5% by weight of other crystal forms, more preferably less than 1% by weight of other crystal forms.
  • the compound of the formula (I) and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound of the formula (I) and/or its salt as a raw material is in the form of a solid powder.
  • the "stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is, for example, 50 to 1800 rpm, preferably 300 to 900 rpm.
  • 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 three crystal forms provided by the present invention can be used to prepare a drug having an action of inhibiting SYK.
  • SYK refers to a spleen tyrosine kinase which is a member of the protein tyrosine kinase (PTK) family and is a non-receptor tyrosine kinase mainly present in the spleen and thymus. And the lungs.
  • PTK protein tyrosine kinase
  • the present invention also provides a pharmaceutical combination comprising a therapeutically effective amount of Form I or Form II or Form III of the present invention or a mixture thereof and a pharmaceutically acceptable adjuvant (pharmaceutically acceptable carrier or excipient) Things.
  • a therapeutically effective amount of Form I or Form II or Form III or a mixture thereof is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which is It is prepared in a manner well known in the pharmaceutical art.
  • the pharmaceutical composition is in the form of a pharmaceutical preparation, and the preparation is in the form of a tablet, a capsule, a suspension, a disintegrating tablet, an immediate release, a sustained release or a controlled release tablet.
  • the drug is selected from the group consisting of breast cancer, gastric cancer, lymphoma, rectal cancer, pancreatic cancer, liver cancer, leukemia, malignant epithelial tumor and tumor metastasis, multiple sclerosis, immune disease, allergic disease, arterial porridge Drugs with sclerosing, gastrointestinal dysfunction, idiopathic thrombocytopenic purpura, Wiskott-Aldrich syndrome, and systemic lupus erythematosus with preventive or therapeutic effects.
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used in the present invention refers to a biological response or drug that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent that is reacted.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or exhibiting a disease or condition of the disease, disorder or disorder; and (3) Ameliorating the disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a condition or symptom of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual
  • inhibiting the disease for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • the pharmaceutical composition provided by the present invention may comprise, in addition to the crystalline form of the present invention, other pharmaceutically acceptable 6-(1H-carbazol-6-yl)-N-[4-(4-morpholine).
  • the crystalline form of the invention may be administered as a separate active agent, or it may be administered in combination with other active agents, including other compounds that have the same or similar therapeutic activity and that are determined to be safe and effective for such combination administration.
  • the co-administration of two (or more) active agents results in a significant reduction in the agent of each active agent used
  • the combination of such drugs includes, but is not limited to, those disclosed in the specification of the prior art document US20150038505A1.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art in the art.
  • the crystalline form of the invention is admixed with one or more pharmaceutically acceptable excipients, optionally with one or more additional pharmaceutically active ingredients.
  • 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.
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • 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 Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was collected on a TAQ5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • 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
  • 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 or deuterated water to prepare a solution of 2-10 mg/mL.
  • the particle size distribution results of the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are as follows:
  • the flow rate is 60% of 60% of 65 ml/sec.
  • 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 a particle diameter corresponding to 90% of the particle size distribution (volume distribution).
  • Entospletinib/formula (I) compounds described in the following examples have the same meanings.
  • the Entospletinib disulfonate amorphous or the conventional crystalline form 7 as a raw material can be prepared according to the method described in the related literature.
  • Entospletinib disulfonate (amorphous) was weighed into a 1.5 mL glass vial, and 0.6 mL of a methanol-p-xylene mixed solution (methanol to p-xylene volume ratio of 1:2) was added. The mixture was stirred at room temperature for 2 days and dried by filtration to give a pale yellow solid.
  • the solid obtained in this example was found to be Form I.
  • Entospletinib disulfonate (existing Form 7) was weighed into a 1.5 mL glass bottle, 1.0 mL of toluene was added, and the mixture was stirred at 70 ° C for 2 days, and dried by filtration to give a pale yellow solid.
  • the solid obtained in this example was Form II.
  • Entospletinib disulfonate existing Form 7
  • 22.5 mg of Entospletinib disulfonate existing Form 7
  • 1.0 mL of p-xylene was added, and the mixture was stirred at 70 ° C for 2 days, and dried by filtration to give a pale yellow solid.
  • the solid obtained in this example was Form II.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 4, and its XRPD pattern is shown in FIG.
  • Entospletinib disulfonate (existing Form 7) was weighed into a 3.0 mL glass vial, 1.5 mL of toluene was added, and the mixture was stirred at 70 ° C for 2 days, and dried by filtration to give a pale yellow solid.
  • the solid obtained in this example was Form II.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 5, and the XRPD pattern thereof is shown in Fig. 11.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 6, and the XRPD pattern thereof is shown in Fig. 12.
  • the DSC chart is shown in Fig. 13
  • the TGA chart is shown in Fig. 14
  • the 1 H NMR chart is shown in Fig. 15.
  • Example 6 The crystal form III obtained in Example 6 was weighed and placed in a DVS apparatus, and the wettability was measured.
  • the DVS pattern is as shown in Fig. 20, and the weight gain of 80% relative humidity was 6.48%.
  • the solid was collected for XRPD testing, as shown in Figure 21, and the crystal form did not change.
  • the crystal form III of the invention has a weight gain of 6.48% at 80% relative humidity, while the existing crystal form 3 and the crystal form 7 have a mass increase of nearly 20% at 80% relative humidity, and the wettability of the crystal form III of the present invention is significantly lower.
  • lower moisture permeability can avoid drugs in Deterioration or deliquescence due to absorption of moisture during production and storage is of great significance for drug quality control.
  • Form 3 and Form 7 have a mutual transformation of crystal forms at different humidity levels, which is particularly disadvantageous for production.
  • Form III remains unchanged throughout the process. Therefore, the crystalline form III of the present invention is more in line with pharmaceutical requirements.
  • the crystal form II prepared in Example 3 of the present invention was placed under the condition of 25 ° C and relative humidity of 60% for 90 days, and each sample was taken for 15 days, placed for 30 days, and placed for 90 days, respectively, and the crystal form was mainly investigated.
  • Form I of the present invention was weighed and placed in a DVS apparatus and subjected to a cycle of relative humidity change of 0-95%-0 at 25 ° C.
  • the DVS image is shown in FIG.
  • Form II of the present invention was weighed and placed in a DVS apparatus and subjected to a cycle of relative humidity change of 0-95%-0 at 25 ° C.
  • the DVS image is shown in FIG.
  • the wettability data of the existing crystal form 7, the crystal form I and the form II of the present invention are shown in Table 11.
  • the conventional crystal form 7 is hygroscopic, and has a weight gain of about 10% at 40% RH.
  • the crystalline form I and the crystalline form II of the present invention exhibit a significant wettability advantage.
  • Form II can be stabilized in the humidity range of 0 to 70% RH and does not exhibit significant weight gain.
  • the PLM and PSD tests were performed on the crystal form I, the crystal form II, the conventional form 3, and the conventional form 7 of the present invention, respectively.
  • the PLM diagrams of the crystal form I, the crystal form II, the conventional form 3, and the conventional form 7 of the present invention are shown in Figs. 26, 27, 28, and 29, respectively, and the PSD data is shown in Table 12.
  • the particle size of the crystalline form I and the crystalline form II of the present invention are both larger than the existing crystalline form 3 and the existing crystalline form 7, and the size is suitable, which is advantageous for product separation in the production process. .
  • the crystal form I, the crystal form II of the present invention and the existing crystal form 3 were respectively made into a saturated solution with acetone and tetrahydrofuran, and the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 24 hours. As shown in Table 13.
  • the solubility of Form I and Form II of the present invention is 1.5 to 5 times higher than that of the existing Form 3. Higher solubility can promote the more effective dissolution of the drug substance in the process development, reduce the solvent volume, reduce energy consumption and environmental pressure, and has significant application value.
  • the crystal form III samples of the present invention were respectively placed under the conditions of 25° C. relative humidity 60% and 40° C. relative humidity 75% for 300 days, respectively, and samples were taken once on the 15th day, 30 days, and 300 days, respectively, and the crystal form was mainly investigated.
  • the stability of III the test results show that Form III has good stability
  • the data summary is shown in Table 14
  • the XRPD characterization is shown in Figure 30.

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Abstract

本发明涉及6-(1H-吲唑-6-基)-N-[4-(4-吗啉基)苯基]咪唑并[1，2-A]吡嗪-8-胺甲磺酸盐的新晶型I、晶型II、晶型III及其制备方法和用途。晶型I为二甲磺酸盐，其X射线粉末衍射图在2theta值为5.9°±0.2°，13.5°±0.2°和21.8°±0.2°处具有特征峰。晶型II为二甲磺酸盐，其X射线粉末衍射图在2theta值为15.8°±0.2°，17.2°±0.2°和19.5°±0.2°处具有特征峰。晶型III为单甲磺酸盐，其X射线粉末衍射图在2theta值为7.4°±0.2°，12.9°±0.2°和19.2°±0.2°处具有特征峰。本发明提供的新晶型比现有晶型更符合药用要求，且晶型的制备方法简单，重复性好，对未来该药物的优化和开发具有重要价值。

Description

(6-(1H-吲唑-6-基)-N-[4-(4-吗啉基)苯基]咪唑并[1，2-a]吡嗪-8-胺)甲磺酸盐的新晶型 技术领域
本发明涉及化学医药领域，特别是涉及(6-(1H-吲唑-6-基)-N-[4-(4-吗啉基)苯基]咪唑并[1，2-a]吡嗪-8-胺)的单甲磺酸盐及二甲磺酸盐的晶型及其制备方法。
背景技术
脾酪氨酸激酶(Spleen tyrosine kinase)最早由日本学者Taniguchi等1991年从猪脾cDNA克隆出来，其编码蛋白是一种非受体型酪氨酸激酶，故被命名为脾酪氨酸激酶(Spleen tyrosine kinase)，脾酪氨酸激酶在淋巴细胞的成熟和免疫细胞的激活中起重要作用。近年来发现SYK在肿瘤中也有异常表达，且SYK与许多和肿瘤发生、发展、转移有关的信号有密切关系，其可能成为淋巴瘤、白血病等与免疫系统有关肿瘤的治疗靶点。
Entospletinib是由Gilead公司研发的一种口服药物，是一种选择性脾酪氨酸激酶SYK抑制剂，能够抑制脾酪氨酸激酶(Spleen tyrosine kinase)的活性，对包含癌症、炎症在内的多种疾病具有治疗作用。Entospletinib正在难治或复发慢性淋巴细胞性白血病患者中进行临床研究。该药物的化学名称为：(6-(1H-吲唑-6-基)-N-[4-(4-吗啉基)苯基]咪唑并[1，2-a]吡嗪-8-胺)，其结构如式(I)所示：
Figure PCTCN2017074729-appb-000001
已知晶型是影响药品质量的重要因素。同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同，也会对药物的稳定性、生物利用度及疗效产生不同的影响。因此，研发新的更适合应用的晶型对于药物开发具有非常重要的意义。
如本领域技术人员所知，已知化学物质的新的固体多晶型形式的存在是不可预见的。多晶型的存在或多晶型形式的数量均不可预见。另外，在什么条件下发生结晶并得到特定的形式，以及所述多晶型形式的特性如何，也都是不可预测的。由于每种多晶型的特性(例如溶解度、稳定性)以及因此引起的应用与储存的适用性不同，因此研究药物物质的所有固态形式， 包括所有的多晶型形式，对于提供具有改善的储存稳定性或可预测的溶解度特性的药物是必要的。
关于上述的式(I)化合物，目前仅专利US20150038505A1报道了其二甲磺酸盐的两个水合物即晶型3、晶型7(以下称为现有晶型3和现有晶型7)，根据该专利的报道，这两个晶型中现有晶型7在各种湿度条件下的吸湿性均很高，相对而言，晶型3是更优选的晶型，因为其在70％以下的湿度条件下引湿性是比较低的，而且其溶解度相比游离碱和无定形单甲磺酸盐是有显著提高的，但是该现有晶型3被发现在高湿度条件(湿度80％以上)下增重达到20％，且在90％湿度下会转化为现有晶型7，不能很好满足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。此外，虽然专利US20150038505A1报道了可获得现有晶型3的不止一种方法，但这些方法操作比较复杂，不易获得。而且，对现有晶型3和7的粒径分布进行研究发现，其结晶颗粒非常细小，而这将造成产品生产时分离的困难。
因此，仍有需要开发式(I)化合物或其盐的更适于制成药物制剂且能够通过更加容易重现的方式获得的新晶型。
发明内容
本发明的目的之一是提供式(I)化合物甲磺酸盐的多种新晶型，具体分别为式(I)化合物二甲磺酸盐晶型I、式(I)化合物二甲磺酸盐晶型II以及式(I)化合物单甲磺酸盐晶型III。
本发明的目的之二是提供上述新晶型的制备方法和用途。
本发明所述式(I)化合物如下：
Figure PCTCN2017074729-appb-000002
本发明提供的式(I)化合物二甲磺酸盐晶型I(以下简称本发明晶型I)，其X射线粉末衍射图在2theta值为5.9°±0.2°，13.5°±0.2°和21.8°±0.2°处具有特征峰。
进一步的，本发明晶型I的X射线粉末衍射图还优选在2theta值为25.9°±0.2°，17.1°±0.2°和20.4°±0.2°中的一处或两处或三处具有特征峰。
进一步优选的，本发明晶型I的X射线粉末衍射图还在2theta值为10.6°±0.2°，14.7°±0.2°和17.7°±0.2°中的一处或两处或三处具有特征峰。
根据本发明的一个具体且优选方面，本发明晶型I的X射线粉末衍射图在5.9°±0.2°，13.5°±0.2°，21.8°±0.2°，25.9°±0.2°，17.1°±0.2°，20.4°±0.2°，10.6°±0.2°，14.7°±0.2°和17.7°±0.2°处具有特征峰。
本发明进一步提供本发明晶型I的制备方法，该方法包括：a)将式(I)化合物二甲磺酸盐加入多种有机溶剂的混合体系中，在温度5～30℃下搅拌；b)过滤经过步骤a)的体系并进行干燥，所得固体即为本发明晶型I。
进一步地，所述的多种有机溶剂的混合体系优选为醇类有机溶剂和芳香烃类有机溶剂的混合体系。步骤a)中，所述温度进一步优选为20～30℃。
本发明提供的式(I)化合物二甲磺酸盐晶型II(以下简称本发明晶型II)，其X射线粉末衍射图在2theta值为15.8°±0.2°，17.2°±0.2°和19.5°±0.2°处具有特征峰。
进一步的，本发明晶型II，其X射线粉末衍射图还优选在2theta值为26.1±0.2°，14.7°±0.2°和21.9°±0.2°中的一处或两处或三处具有特征峰。
更进一步地，本发明晶型II，其X射线粉末衍射图还优选在2theta值为7.6±0.2°，18.2°±0.2°和27.8°±0.2°中的一处或两处或三处具有特征峰。
根据本发明的一个具体且优选方面，本发明晶型II的X射线粉末衍射图在2theta值为15.8°±0.2°，17.2°±0.2°，19.5°±0.2°，26.1±0.2°，14.7°±0.2°，21.9°±0.2°，7.6±0.2°、18.2°±0.2°和27.8°±0.2°处均具有特征峰。
本发明还进一步提供本发明晶型II的制备方法，其包括：a)将式(I)化合物二甲磺酸盐加入到一种或多种芳香烃有机溶剂中，在40～80℃温度下搅拌；b)过滤经过步骤a)的体系并干燥，所得固体即为本发明晶型II。
优选地，制备本发明晶型II的步骤a)中，所述芳香烃有机溶剂为甲苯或者对二甲苯。优选地，制备本发明晶型II的步骤a)中，在温度60-70℃下进行所述搅拌。
本发明提供的式(I)化合物单甲磺酸盐的晶型III(以下简称本发明晶型III)，其X射线粉末衍射图在2theta值为7.4°±0.2°，12.9°±0.2°和19.2°±0.2°处具有特征峰。
进一步的，本发明晶型III，其X射线粉末衍射图还优选在2theta值为6.5°±0.2°，21.2°±0.2°和24.4°±0.2°中的一处或两处或三处具有特征峰。
更进一步的，本发明晶型III，其X射线粉末衍射图还更优选在2theta值为17.7°±0.2°，20.7°±0.2°和26.0°±0.2°中的一处或两处或三处具有特征峰。
根据本发明的一个具体且优选方面，本发明晶型III的X射线粉末衍射图在2theta值为7.4°±0.2°，12.9°±0.2°，19.2°±0.2°，6.5°±0.2°，21.2°±0.2°，24.4°±0.2°，17.7°±0.2°，20.7°±0.2° 和26.0°±0.2°处均具有特征峰。
本发明的另一个目的是提供本发明晶型III的制备方法，所述方法包括选择性的步骤a)或b)，以及步骤c)，其中：
a)将式(I)化合物加入酮类和水的混合溶剂中，搅拌下加入甲磺酸，然后继续搅拌；
b)将式(I)化合物的二甲磺酸盐加入到醇类和水的混合溶剂中，搅拌；
c)过滤经过步骤a)或b)的体系并干燥，得到固体，即为本发明晶型III。
进一步地，步骤a)中，所述酮类溶剂和水的体积比为1∶1到10∶1，优选为3∶1到4∶1。所述酮类溶剂可以为例如丙酮。甲磺酸与式(I)化合物的投料摩尔比可以为1.0～1.8∶1，优选为1.1～1.2∶1。
优选地，步骤a)中，控制所述搅拌时体系的温度为5～50℃，优选20～30℃。
进一步地，步骤b)中，所述醇类溶剂和水的体积比一般为99∶1～1∶99，优选为85∶15～95∶5。步骤b)中，醇类溶剂可以且优选为异丙醇。步骤b)中，优选控制所述搅拌时体系的温度为25～60℃，更优选地，控制所述搅拌时体系的温度为45-50℃。
本发明晶型I或晶型II或晶型III或其混合物可用于抗癌药物特别是治疗慢性淋巴细胞白血病和急性髓系白血病药物的制备。
本发明的另一个目的是提供一种包含有效治疗量的本发明晶型I或晶型II或晶型III或其混合物和药用辅料(药学上可接受的载体或赋形剂)的药用组合物。一般是将治疗有效量的本发明晶型I或晶型II或晶型III或其混合物与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
本发明还提供一种治疗或预防与SYK相关的疾病的方法，其包括给予需要的患者治疗和/或预防有效量的本发明晶型I、晶型II、晶型III中的任一种或多种的组合。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明提供了Entospletinib甲磺酸盐的多种新晶型，这些晶型与现有的晶型相比更适于药用而且可通过更加简单的方法重复制备。
附图说明
图1为实施例1所得Entospletinib二甲磺酸盐晶型I的XRPD图；
图2为实施例2所得Entospletinib二甲磺酸盐晶型I的XRPD图；
图3为实施例2所得Entospletinib二甲磺酸盐晶型I的DSC图；
图4为实施例2所得Entospletinib二甲磺酸盐晶型I的TGA图；
图5为实施例2所得Entospletinib二甲磺酸盐晶型I的1H NMR图；
图6为实施例3所得Entospletinib二甲磺酸盐晶型II的XRPD图；
图7为实施例3所得Entospletinib二甲磺酸盐晶型II的DSC图；
图8为实施例3所得Entospletinib二甲磺酸盐晶型II的TGA图；
图9为实施例3所得Entospletinib二甲磺酸盐晶型II的1H NMR图；
图10为实施例4所得Entospletinib二甲磺酸盐晶型II的XRPD图；
图11为实施例5所得Entospletinib二甲磺酸盐晶型II的XRPD图；
图12为实施例6所得Entospletinib单甲磺酸盐晶型III的XRPD图；
图13为实施例6所得Entospletinib单甲磺酸盐晶型III的DSC图；
图14为实施例6所得Entospletinib单甲磺酸盐晶型III的TGA图；
图15为实施例6所得Entospletinib单甲磺酸盐晶型III的1H NMR图；
图16为实施例7所得Entospletinib单甲磺酸盐晶型III的XRPD图；
图17为实施例7所得Entospletinib单甲磺酸盐晶型III的DSC图；
图18为实施例7所得Entospletinib单甲磺酸盐晶型III的TGA图；
图19为实施例8所得Entospletinib单甲磺酸盐晶型III的XRPD图；
图20为实施例9所得Entospletinib单甲磺酸盐晶型III的DVS图；
图21为实施例9DVS实验前后本发明晶型III的晶型变化对比图；
图22显示了放置前后晶型II样品的XRPD图，其中上图为放置前，下图为放置90天后；
图23-25分别为现有晶型7、本发明晶型I、晶型II分别在25℃下经历一个0-95％-0的相对湿度变化的循环图像；
图26-29分别为本发明晶型I、晶型II与现有晶型3、现有晶型7的偏光显微镜(PLM)图；
图30为本发明晶型III样品存储300天前后的XRPD图(上图为起始图，中间为25℃/60％RH存储条件下存储300天后测试，下图为40℃/75％RH存储条件下存储300天后测试)。
具体实施方式
本发明提供式(I)化合物甲磺酸盐的三种新晶型，其中二甲磺酸盐晶型I即本发明晶型I，其X射线粉末衍射图在2theta值为5.9°±0.2°，13.5°±0.2°和21.8°±0.2°处具有特征峰，优选 还在2theta值为25.9°±0.2°，17.1°±0.2°和20.4°±0.2°中的一处或两处或三处具有特征峰，其中以在25.9°±0.2°，17.1°±0.2°和20.4°±0.2°这三处均具有特征峰为更优选。进一步优选的，晶型I的X射线粉末衍射图还在2theta值为10.6°±0.2°，14.7°±0.2°和17.7°±0.2°中的一处或两处或三处具有特征峰，其中以在2theta值为10.6°±0.2°，14.7°±0.2°和17.7°±0.2°这三处均具有特征峰为更优选。根据本发明的一个具体且优选方面，晶型I的X射线粉末衍射图在5.9°±0.2°，13.5°±0.2°，21.8°±0.2°，25.9°±0.2°，17.1°±0.2°，20.4°±0.2°，10.6°±0.2°，14.7°±0.2°和17.7°±0.2°处具有特征峰。在根据本发明的一个具体实施方案中，本发明晶型I的X射线粉末衍射图基本如图1所示。在另一具体实施方案中，本发明晶型I的X射线粉末衍射图基本如图2所示。
优选地，本发明晶型I是水合物。
根据本发明的一个具体方面，当进行差示扫描量热分析时，本发明晶型I在被加热至87℃附近开始出现第一个吸热峰，在180℃附近开始出现第二个吸热峰，其DSC如图3所示。
根据本发明的又一个具体方面，当进行热重分析时，本发明晶型I在被加热至120℃时，具有约3.5％的质量损失梯度，其TGA如图4所示。
根据本发明的还一个具体方面，本发明晶型I的核磁数据如下：1H NMR(400MHz，D2O)δ7.92(s，1H)，7.70(s，1H)，7.44(d，J＝8.4Hz，1H)，7.36(dd，J＝17.4，9.7Hz，4H)，7.26(s，1H)，7.08(d，J＝8.3Hz，1H)，6.98(d，J＝8.3Hz，2H)，4.09(s，4H)，3.33(s，4H)，2.87(s，6H)，核磁谱图如图5所示。
本发明晶型I的制备方法包括：a)将式(I)化合物二甲磺酸盐加入多种有机溶剂的混合体系中，在温度5～30℃下搅拌；b)过滤经过步骤a)的体系并进行干燥，所得固体(通常为浅黄色)即为本发明晶型I。其中，所述的多种有机溶剂的混合体系优选为醇类有机溶剂和芳香烃类有机溶剂的混合体系，其中醇类有机溶剂和芳香烃类有机溶剂的体积比优选为1∶1到1∶5，更优选为1∶2到1∶3，具体例如1∶2。所述醇类有机溶剂可以列举甲醇，所述芳香烃类有机溶剂可以列举对二甲苯。步骤a)中，所述温度进一步优选为20～30℃，最优选为约25℃。
本发明提供的式(I)化合物二甲磺酸盐晶型II即本发明晶型II，其X射线粉末衍射图在2theta值为15.8°±0.2°，17.2°±0.2°和19.5°±0.2°处具有特征峰，优选还在2theta值为26.1±0.2°，14.7°±0.2°和21.9°±0.2°中的一处或两处或三处具有特征峰，其中以在2theta值为26.1±0.2°，14.7°±0.2°和21.9°±0.2°这三处均具有特征峰为更优选。进一步优选地，晶型II的X射线粉 末衍射图还在2theta值为7.6±0.2°，18.2°±0.2°和27.8°±0.2°中的一处或两处或三处具有特征峰，其中以在2theta值为7.6±0.2°、18.2°±0.2°、27.8°±0.2°这三处均具有特征峰为更优选。根据本发明的一个具体且优选方面，本发明晶型II的X射线粉末衍射图在2theta值为15.8°±0.2°，17.2°±0.2°，19.5°±0.2°，26.1±0.2°，14.7°±0.2°，21.9°±0.2°，7.6±0.2°、18.2°±0.2°和27.8°±0.2°处均具有特征峰。在根据本发明的一个具体实施方案中，本发明晶型II的X射线粉末衍射图基本如图6所示。在另一个具体实施方案中，本发明晶型II的X射线粉末衍射图基本如图10所示。在第三个实施方案中，本发明晶型II的X射线粉末衍射图基本如图11所示。
优选地，本发明晶型II也是水合物。
根据本发明的一个具体方面，当进行差示扫描量热分析时，本发明晶型II在被加热至67℃附近开始出现第一个吸热峰，在158℃附近开始出现第二个吸热峰，其DSC如图7所示。
根据本发明的又一个具体方面，当进行热重分析时，本发明晶型II在被加热至148℃时，具有约3.3％的质量损失梯度，其TGA如图8所示。
根据本发明的还一个具体方面，本发明晶型II的核磁数据如下：1H NMR(400MHz，DMSO)δ9.62(s，1H)，8.74(s，1H)，8.18(s，1H)，8.13-8.06(m，2H)，8.02(d，J＝9.0Hz，2H)，7.86(d，J＝8.6Hz，1H)，7.80(s，1H)，7.73(d，J＝8.5Hz，1H)，7.12(d，J＝8.5Hz，2H)，3.83-3.78(m，4H)，3.19(s，4H)，2.32(s，6H)，核磁谱图如图9所示。
本发明还进一步提供本发明晶型II的制备方法，其包括：a)将式(I)化合物二甲磺酸盐加入到一种或多种芳香烃有机溶剂中，在40～80℃温度下搅拌；b)过滤经过步骤a)的体系并干燥，所得固体(通常为浅黄色)即为晶型II。其中芳香烃有机溶剂优选为甲苯或者对二甲苯。优选在温度60-70℃下进行所述搅拌。
本发明的式(I)化合物二甲磺酸盐晶型I和II具有良好的稳定性和较低的引湿性，且制备工艺简单，可重复放大，粒径大小合适。与现有晶型3和7相比，更适于工业化生产和应用。
本发明提供的式(I)化合物单甲磺酸盐的晶型III即本发明晶型III，其X射线粉末衍射图在2theta值为7.4°±0.2°，12.9°±0.2°和19.2°±0.2°处具有特征峰。进一步的，本发明晶型III的X射线粉末衍射图还优选在2theta值为6.5°±0.2°，21.2°±0.2°和24.4°±0.2°中的一处或两处或三处具有特征峰，其中以在2theta值为6.5°±0.2°，21.2°±0.2°和24.4°±0.2°这三处均具有特征峰为更优选。更进一步的，本发明晶型III的X射线粉末衍射图还更优选在2theta 值为17.7°±0.2°，20.7°±0.2°和26.0°±0.2°中的一处或两处或三处具有特征峰，其中以在2theta值为17.7°±0.2°，20.7°±0.2°和26.0°±0.2°这三处均具有特征峰为最优选。
根据本发明的一个具体且优选方面，本发明晶型III的X射线粉末衍射图在2theta值为7.4°±0.2°，12.9°±0.2°，19.2°±0.2°，6.5°±0.2°，21.2°±0.2°，24.4°±0.2°，17.7°±0.2°，20.7°±0.2°和26.0°±0.2°处均具有特征峰。在根据本发明的一个具体实施方案中，本发明晶型III的X射线粉末衍射图基本如图12所示。在根据本发明的又一具体实施方案中，本发明晶型III的X射线粉末衍射图基本如图16所示。
在根据本发明的一个具体实施方式中，当进行差示扫描量热分析时，本发明晶型III在被加热至293℃附近时开始熔化，其DSC如图13所示。在另一个具体实施方式中，当进行差示扫描量热分析时，本发明晶型III在被加热至311℃附近时开始熔化，其DSC如图17所示。
在根据本发明的一个具体实施方式中，当进行热重分析时，本发明晶型III在被加热至约140℃时，具有约0.8％的质量损失梯度，其TGA如图14所示。在另一个具体实施方式中，当进行热重分析时，本发明晶型III在被加热至约167℃时，具有约0.4％的质量损失梯度，其TGA如图18所示。
在根据本发明的一个具体实施方式中，本发明晶型III是无水物。
在根据本发明的一个具体实施方式中，本发明晶型III的核磁数据如下：1H NMR(400MHz，DMSO)δ9.71(s，1H)，8.78(s，1H)，8.18(s，1H)，8.12(dd，J＝5.3，1.1Hz，2H)，8.03(d，J＝8.9Hz，2H)，7.93-7.84(m，2H)，7.73(dd，J＝8.5，1.3Hz，1H)，7.19(d，J＝8.5Hz，2H)，3.89-3.76(m，4H)，3.24(s，4H)，2.37(s，3H)，核磁谱图如图15所示。
本发明的另一个目的是提供本发明晶型III的制备方法，该方法包括选择性的步骤a)或b)，以及步骤c)，其中：
a)将式(I)化合物加入酮类和水的混合溶剂中，搅拌下加入甲磺酸，然后继续搅拌；
b)将式(I)化合物的二甲磺酸盐加入到醇类和水的混合溶剂中，搅拌；
c)过滤经过步骤a)或b)的体系并干燥，得到固体，即为晶型III。
进一步地，步骤a)中，所述酮类溶剂和水的体积比为1∶1到10∶1，优选为3∶1到4∶1，酮类溶剂例如可以是丙酮。甲磺酸与式(I)化合物的投料摩尔比可以为1.0～1.8∶1，优选为1.1～1.2∶1。步骤a)中，优选控制所述搅拌时体系的温度为5～50℃，更优选20～30℃，最优选25℃。
进一步地，步骤b)中，所述醇类溶剂和水的体积比一般为99∶1～1∶99，优选为85∶15～95∶5， 最优选89∶11。步骤b)中，醇类溶剂可以且优选为异丙醇。步骤b)中，优选控制所述搅拌时体系的温度为25～60℃，更优选为45-50℃。
本发明的式(I)化合物单甲磺酸盐晶型III稳定性好，结晶度好，引湿性低，制备工艺简单，可重复放大。与现有晶型3相比，在含水体系或高湿度条件下的稳定性具有明显优势，此外，在生产制备条件和重复性方面也具有明显优势，是比现有晶型3更符合药用要求的晶型。
在一些实施方案中，本发明晶型I、II和III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。
本发明惊奇地发现了具有上述优势的三种晶型，为含式(I)化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
根据本发明，作为原料的所述式(I)化合物和/或其盐是指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的所述式(I)化合物和/或其盐为固体粉末形式。
根据本发明，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，搅拌速度例如为50～1800转/分钟，优选300～900转/分钟。
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。
此外，本发明提供的三种晶型可用于制备具有抑制SYK作用的药物。
本发明中，术语“SYK”是指脾酪氨酸激酶，其是蛋白酪氨酸激酶(PTK)家族中的一员，是一种非受体型酪氨酸激酶，主要存在于脾脏、胸腺和肺部。
进一步地，本发明还提供一种包含有效治疗量的本发明晶型I或晶型II或晶型III或其混合物和药用辅料(药学上可接受的载体或赋形剂)的药用组合物。一般是将治疗有效量的晶型I或晶型II或晶型III或其混合物与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。根据一个具体且优选方面，所述药物组合物为药物制剂形式，且该制剂形式为片剂、胶囊剂、混悬剂、崩解片、即释、缓释或控释片剂。优选地，所述药物为对选自乳腺癌、胃癌、淋巴癌、直肠癌、胰腺癌、肝癌、白血病、恶性上皮肿瘤和肿瘤转移、多发性硬化症、免疫性疾病、过敏性疾病、动脉粥样硬化、胃肠功能紊乱、特发性血小板减少性紫癜、Wiskott-Aldrich综合征和系统性红斑狼疮的疾病有预防或治疗效果的药物。
本发明中所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本发明中所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
此外，本发明提供的药物组合物，除本发明所述晶型外，还可以包含其它可药用的6-(1H-吲唑-6-基)-N-[4-(4-吗啉基)苯基]咪唑并[1，2-a]吡嗪-8-胺或其盐的晶型或无定型物。任选地，本发明的晶型可以作为单独的活性剂施用，或者它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US20150038505A1说明书中所披露的那些。
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，将本发明的晶型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。
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。
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
1H NMR：液态核磁氢谱
PLM：偏光显微镜
PSD：粒度分析
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
Kα1
Figure PCTCN2017074729-appb-000003
1.540598；Kα2
Figure PCTCN2017074729-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)
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 Q2000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
本发明所述的热重分析(TGA)图在TAQ5000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
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：N2，200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
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氘代二甲亚砜或氘代水溶解，配成2-10mg/mL的溶液。
本发明所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。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下：
Figure PCTCN2017074729-appb-000005
Figure PCTCN2017074729-appb-000006
*：流速60％为65毫升/秒的60％。
本发明中所用到的缩写的解释如下：
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。
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所述的Entospletinib/式(I)化合物具有相同的含义。作为原料的Entospletinib二甲磺酸盐无定形或现有晶型7均可根据现有的相关文献所记载的方法来制备。
实施例1 制备本发明晶型I
称取12.2mg的Entospletinib二甲磺酸盐(无定形)放入1.5mL的玻璃瓶中，加入0.6mL的甲醇-对二甲苯混合溶液(甲醇与对二甲苯的体积比为1∶2)，在5℃下搅拌2周，过滤、干燥得到浅黄色固体，经检测，本实施得到的固体为晶型I，本实施例得到的固体的X射线粉末衍射数据如表1所示，其XRPD图如图1所示。
表1
2theta d间隔 强度％
5.96 14.82 75.26
7.71 11.46 52.87
10.67 8.29 36.05
11.41 7.75 22.19
12.94 6.84 26.12
13.51 6.56 98.03
13.96 6.35 40.28
14.82 5.98 38.78
15.42 5.75 33.68
16.46 5.39 30.61
17.13 5.18 53.01
17.73 5.00 48.74
18.75 4.73 23.26
20.55 4.32 42.48
21.80 4.08 58.91
24.06 3.70 37.86
25.89 3.44 53.71
28.42 3.14 13.81
29.29 3.05 11.29
31.53 2.84 2.35
实施例2 制备本发明晶型I
称取14.5mg的Entospletinib二甲磺酸盐(无定形)放入1.5mL的玻璃瓶中，加入0.6mL的甲醇-对二甲苯的混合溶液(甲醇与对二甲苯的体积比为1∶2)中，在室温下搅拌2天，过滤干燥得到浅黄色固体。经检测，本实施例得到的固体为晶型I。本实施例得到的固体的X射线粉末衍射数据如表2所示，其XRPD图如图2所示，DSC图如图3，TGA图如图4，1H NMR图如图5。
表2
2theta d间隔 强度％
5.93 14.91 23.56
10.63 8.32 16.33
13.58 6.52 100.00
14.73 6.01 40.01
15.41 5.75 39.15
16.52 5.37 36.75
17.19 5.16 66.15
17.69 5.01 60.08
18.64 4.76 26.44
20.43 4.35 48.49
21.84 4.07 57.17
23.75 3.75 32.83
25.85 3.45 62.39
28.33 3.15 14.34
29.23 3.06 12.31
实施例3 制备本发明晶型II
称取19.5mg Entospletinib二甲磺酸盐(现有晶型7)放入1.5mL的玻璃瓶中，加入1.0mL的甲苯，在70℃下搅拌2天，过滤干燥得到浅黄色固体。经检测，本实施例得到的固体为晶型II。本实施例得到的固体的X射线粉末衍射数据如表3所示，其XRPD图如图6所示，DSC图如图7，TGA图如图8，1H NMR图如图9。
表3
2theta d间隔 强度％
7.57 11.68 41.95
11.40 7.76 14.94
14.68 6.03 42.48
15.76 5.62 15.46
16.45 5.39 8.72
17.21 5.15 67.93
17.55 5.05 34.15
18.14 4.89 39.11
18.59 4.77 29.71
19.54 4.54 100.00
20.80 4.27 19.33
21.95 4.05 36.17
23.47 3.79 27.56
24.59 3.62 27.51
26.03 3.42 80.76
27.67 3.22 42.48
28.32 3.15 4.94
29.76 3.00 6.06
31.99 2.80 2.14
实施例4 制备本发明晶型II
称取22.5mg Entospletinib二甲磺酸盐(现有晶型7)放入1.5mL的玻璃小瓶中，加入1.0mL的对二甲苯，在70℃下搅拌2天，过滤干燥得到浅黄色固体。经检测，本实施例得到的固体为晶型II。本实施例得到的固体的X射线粉末衍射数据如表4所示，其XRPD图如图10所示。
表4
2theta d间隔 强度％
7.55 11.72 25.40
8.15 10.85 12.30
10.96 8.07 9.72
11.45 7.73 12.91
13.62 6.50 7.57
14.67 6.04 50.93
15.78 5.62 19.59
16.36 5.42 13.42
17.20 5.16 72.10
17.53 5.06 37.35
18.17 4.88 37.10
18.52 4.79 27.37
19.49 4.55 100.00
20.87 4.26 25.70
21.89 4.06 35.62
23.44 3.80 28.07
24.63 3.61 30.14
26.05 3.42 72.29
27.72 3.22 37.09
29.76 3.00 7.93
31.95 2.80 4.33
实施例5 制备本发明晶型II
称取87.5mg的Entospletinib二甲磺酸盐(现有晶型7)放入3.0mL的玻璃小瓶中，加入1.5mL的甲苯，在70℃在搅拌2天，过滤干燥得到浅黄色固体。经检测，本实施例得到的固体为晶型II。本实施例得到的固体的X射线粉末衍射数据如表5所示，其XRPD图如图11所示。
表5
2theta d间隔 强度％
7.61 11.61 38.45
10.97 8.07 10.72
14.68 6.03 34.25
15.81 5.60 15.84
16.38 5.41 14.96
17.21 5.15 55.70
17.57 5.05 34.21
18.17 4.88 49.70
19.53 4.55 100.00
20.80 4.27 18.86
21.98 4.04 32.16
23.45 3.79 17.70
24.59 3.62 19.35
25.28 3.52 9.80
26.02 3.42 45.77
27.64 3.23 18.29
37.05 2.43 5.38
实施例6 制备本发明晶型III
称取30.7mg的式(I)化合物(即Entospletinib)放入1.5mL的玻璃瓶中，加入0.5mL丙酮和水(丙酮与水的体积比为4∶1)的混合溶液中，磁力搅拌下加入5.8μL的甲磺酸99％)，在25℃下反应28小时，过滤干燥得到黄色固体，经检测，本实施例得到的固体为晶型III。
本实施例得到的固体的X射线粉末衍射数据如表6所示，其XRPD图如图12所示。DSC图如图13所示，TGA图如图14所示，1H NMR图如图15所示。
表6
2theta d间隔 强度％
6.44 13.72 18.72
7.38 11.98 100.00
10.54 8.39 3.37
12.94 6.84 52.02
15.16 5.84 5.20
16.20 5.47 3.48
17.69 5.01 33.92
19.24 4.61 43.16
19.93 4.45 12.83
20.70 4.29 18.84
21.23 4.18 47.17
21.92 4.06 7.39
23.48 3.79 6.21
23.88 3.73 7.33
24.37 3.65 43.67
25.95 3.43 13.62
26.50 3.36 5.21
27.08 3.29 12.77
28.64 3.12 9.66
30.83 2.90 1.82
31.41 2.85 5.63
32.80 2.73 1.53
35.23 2.55 1.79
37.60 2.39 0.51
实施例7 制备本发明晶型III
称取100.0mg的式(I)化合物(即Entospletinib)放入5.0mL的玻璃瓶中，加入1.5mL丙酮和水(丙酮与水的体积比为4∶1)的混合溶液，磁力搅拌下加入18.9μL的甲磺酸(99％)，在25℃下反应28小时，过滤干燥得到黄色固体。经检测，本实施例得到的固体为晶型III。本实施例得到的固体的X射线粉末衍射数据如表7所示，其XRPD图如图16所示，DSC图如图17所示，TGA图如图18所示。
表7
2theta d间隔 强度％
6.44 13.72 10.82
7.38 11.98 100.00
10.48 8.44 1.20
12.94 6.84 35.48
16.27 5.45 0.82
17.68 5.02 4.01
19.24 4.61 30.56
19.93 4.46 2.45
20.71 4.29 3.17
21.23 4.18 9.26
24.34 3.66 17.93
25.94 3.44 3.28
27.05 3.30 2.91
28.65 3.12 1.69
30.83 2.90 0.98
31.39 2.85 1.46
实施例8 制备本发明晶型III
称取7.5mg的Entospletinib二甲磺酸盐(现有晶型7)放入1.5mL的玻璃瓶中，加入0.35mL异丙醇与水(异丙醇与水的体积比为89∶11)的混合溶液，在50℃下搅拌6天，过滤干燥得到黄色固体。经检测，本实施例得到的固体为晶型III，X射线粉末衍射数据如表8所示，XRPD图如图19所示。
表8
2theta d间隔 强度％
6.44 13.71 16.35
7.38 11.98 100.00
10.43 8.48 2.65
12.94 6.84 45.05
16.19 5.47 2.78
17.70 5.01 25.34
19.23 4.61 45.36
19.94 4.45 11.16
20.71 4.29 14.57
21.25 4.18 36.56
21.94 4.05 5.49
23.50 3.79 6.51
24.37 3.65 39.45
25.94 3.43 11.72
27.10 3.29 10.04
28.66 3.11 10.76
31.45 2.84 5.63
32.83 2.73 2.17
实施例9 本发明晶型III的引湿性
称取7.34mg的实施例6中得到的晶型III置于DVS仪器中，测试其引湿性，DVS图如图20所示，80％相对湿度的增重为6.48％。收集固体进行XRPD测试，如图21所示，晶型未发生改变。
本发明晶型III在80％相对湿度时增重6.48％，而现有晶型3与晶型7在80％相对湿度时，质量增加接近20％，本发明晶型III的引湿性显著更低，更低的引湿性可以避免药物在 生产与存储过程中因吸收水分而变质或者潮解，对药物质量控制具有重要意义。而且晶型3，晶型7在不同的湿度会有晶型的相互转变，这个对于生产尤为不利。而晶型III在整个过程中晶型保持不变。因此，本发明的晶型III更符合药用要求。
实施例10 本发明晶型III与现有晶型7之间的转化关系
以现有晶型7为起始物质，于室温下在不同水活度的体系中搅拌，6天后取样进行检测，XRPD的结果表明，现有晶型7均转为本发明晶型III，如表9所示。
表9现有晶型7在不同水活度体系中的搅拌实验
溶剂(体积比) 水活度 起始晶型 最终晶型
H2O/IPA＝1∶99 0.12 现有晶型7 本发明晶型III
H2O/IPA＝3∶97 0.3 现有晶型7 本发明晶型III
H2O/IPA＝6∶94 0.5 现有晶型7 本发明晶型III
H2O/IPA＝11∶89 0.7 现有晶型7 本发明晶型III
H2O/IPA＝23∶77 0.9 现有晶型7 本发明晶型III
本实验表明，在有水存在的条件下，现有技术晶型7都会转化为本发明晶型III。无论是在原料药制备生产过程中还是在制剂生产过程中，或者药物储存的过程中，环境或制备条件都无可避免的涉及到水的参与，在含水的环境下转晶将对药物的质量控制带来极大的隐患，因此，开发在含水条件下稳定的晶型十分必要，而本发明晶型III能够在不同水含量条件下稳定存在，具有更大的应用价值。
实施例11 本发明晶型II的稳定性
将本发明实施例3制得的晶型II放置于25℃相对湿度60％的条件下90天，分别于放置前、放置15天、放置30天、放置90天各取样一次，重点考察晶型II的稳定性，试验结果表明晶型II具有良好的稳定性，数据汇总如表10所示，放置90天前后XRPD表征如图22所示。
表10晶型II的稳定性
Figure PCTCN2017074729-appb-000007
实施例12 本发明晶型I和晶型II的引湿性
称取6.5mg现有晶型7，置于DVS仪器中，25℃下经历一个0-95％-0的相对湿度变化的循环，DVS图像如图23所示。
称取9.2mg本发明晶型I，置于DVS仪器中，25℃下经历一个0-95％-0的相对湿度变化的循环，DVS图像如图24所示。
称取3.6mg本发明晶型II，置于DVS仪器中，25℃下经历一个0-95％-0的相对湿度变化的循环，DVS图像如图25所示。
现有晶型7、本发明晶型I和晶型II的引湿性数据见表11。如图23、表11可知，现有晶型7易吸湿，在40％RH时就有10％左右的增重。在0～60％RH的湿度范围内，本发明晶型I与晶型II则表现出明显的引湿性优势。晶型II可以在0～70％RH的湿度范围内稳定，且并未表现出明显的增重。
表11引湿性数据
Figure PCTCN2017074729-appb-000008
实施例13 形态粒径研究
对本发明晶型I、晶型II以及现有晶型3、现有晶型7分别进行PLM、PSD测试。本发明晶型I、晶型II与现有晶型3、现有晶型7的PLM图分别如图26、27、28、29所示，PSD数据如表12所示。
表12 PSD数据
  D(10)/μm D(50)/μm D(90)/μm
现有晶型3 1.67 12.79 76.41
现有晶型7 3.41 9.37 37.69
本发明晶型I 10.23 62.54 240.0
本发明晶型II 4.15 27.48 128.7
由PLM和PSD的数据可知，本发明晶型I与晶型II的粒径均比现有晶型3、现有晶型7都大，且大小合适，在生产过程中，有利于产品的分离。
实施例14 本发明晶型I、晶型II与现有晶型3的溶解度对比
将本发明制晶型I、晶型II与现有晶型3分别用丙酮、四氢呋喃配成饱和溶液，于24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13所示。
表13本发明晶型I、II与现有晶型3的溶解度对比研究
Figure PCTCN2017074729-appb-000009
通过上述对比结果可以看出，在丙酮和四氢呋喃中放置24个小时后，本发明晶型I、晶型II与现有晶型3相比，溶解度提升可达到1.5到5倍。更高的溶解度可以促使原料药在工艺开发中更有效的溶解，减小溶剂倍量，减少能耗与环境压力，具有显著的应用价值。
实施例15 本发明晶型III的稳定性
分别取本发明晶型III样品，分别放置于25℃相对湿度60％、40℃相对湿度75％的条件下300天，分别于第15天、30天、300天各取样一次，重点考察晶型III的稳定性，试验结果表明晶型III具有良好的稳定性，数据汇总如表14所示，XRPD表征如图30所示。
表14晶型III的稳定性
Figure PCTCN2017074729-appb-000010
实施例16 现有晶型3与本发明晶型III之间的转化关系
取现有晶型3样品，放入不同水活度的体系中，并在室温下搅拌，4天后取样检测，XRPD结果如表15所示。结果表明，现有晶型3在含水体系中不如本发明晶型III稳定。
表15现有晶型3在不同水活度体系中的搅拌实验
Figure PCTCN2017074729-appb-000011
Figure PCTCN2017074729-appb-000012
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (30)

  1. 一种式(I)化合物二甲磺酸盐的晶型I，
    Figure PCTCN2017074729-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为5.9°±0.2°，13.5°±0.2°和21.8°±0.2°处具有特征峰。
  2. 如权利要求1所述的晶型I，其特征在于，其X射线粉末衍射图还在2theta值为25.9°±0.2°，17.1°±0.2°和20.4°±0.2°中的一处或两处或三处具有特征峰。
  3. 如权利要求1或2所述的晶型I，其特征在于，其X射线粉末衍射图还在2theta值为10.6°±0.2°，14.7°±0.2°和17.7°±0.2°中的一处或两处或三处具有特征峰。
  4. 如权利要求1所述的晶型I，其特征在于：所述晶型I为水合物。
  5. 一种如权利要求1-4中任一项所述的晶型I的制备方法，其特征在于，所述方法包括：a)将式(I)化合物二甲磺酸盐加入醇类有机溶剂与芳香烃类有机溶剂的混合体系中，在温度5～30℃下搅拌；b)过滤经过步骤a)的体系并进行干燥，所得固体即为晶型I。
  6. 如权利要求5所述的晶型I的制备方法，其特征在于：所述醇类有机溶剂和芳香烃类有机溶剂的体积比为1∶1到1∶5。
  7. 如权利要求5或6所述晶型I的制备方法，其特征在于，所述醇类有机溶剂为甲醇，所述芳香烃类有机溶剂为对二甲苯。
  8. 一种式(I)化合物二甲磺酸盐的晶型II，
    Figure PCTCN2017074729-appb-100002
    其特征在于，其X射线粉末衍射图在2theta值为15.8°±0.2°，17.2°±0.2°和19.5°±0.2°处具有特征峰。
  9. 如权利要求8所述的晶型II，其特征在于，其X射线粉末衍射图还在2theta值为26.1±0.2°，14.7°±0.2°和21.9°±0.2°中的一处或两处或三处具有特征峰。
  10. 如权利要求8或9所述的晶型II，其特征在于，其X射线粉末衍射图还在2theta值为7.6±0.2°，18.2°±0.2°和27.8°±0.2°中的一处或两处或三处具有特征峰。
  11. 如权利要求8-10中任一项所述的晶型II，其特征在于：所述晶型II为水合物。
  12. 一种制备权利要求8-11中任一项所述的晶型II的方法，其特征在于，所述方法包括：a)将式(I)化合物二甲磺酸盐加入到一种或多种芳香烃有机溶剂中，在40～80℃温度下搅拌；b)过滤经过步骤a)的体系并干燥，所得固体即为晶型II。
  13. 如权利要求12所述的方法，其特征在于：所述芳香烃有机溶剂为甲苯或者对二甲苯。
  14. 如权利要求12所述的方法，其特征在于：在温度60-70℃下进行所述搅拌。
  15. 一种式(I)化合物单甲磺酸盐的晶型III，
    Figure PCTCN2017074729-appb-100003
    其特征在于，其X射线粉末衍射图在2theta值为7.4°±0.2°，12.9°±0.2°和19.2°±0.2°处具有特征峰。
  16. 如权利要求15所述的晶型III，其特征在于，其X射线粉末衍射图还在2theta值为6.5°±0.2°，21.2°±0.2°和24.4°±0.2°中的一处或两处或三处具有特征峰。
  17. 如权利要求15或16所述的晶型III，其特征在于，其X射线粉末衍射图还在2theta值为17.7°±0.2°，20.7°±0.2°和26.0°±0.2°中的一处或两处或三处具有特征峰。
  18. 如权利要求15所述的晶型III，其特征在于，所述晶型III为无水物。
  19. 一种如权利要求15-18中任一项所述的晶型III的制备方法，其特征在于，所述方法包括选择性的步骤a)或b)，以及步骤c)，其中：
    a)将式(I)化合物加入酮类和水的混合溶剂中，搅拌下加入甲磺酸，然后继续搅拌；
    b)将式(I)化合物的二甲磺酸盐加入到醇类和水的混合溶剂中，搅拌；
    c)过滤经过步骤a)或b)的体系并干燥，得到固体，即为晶型III。
  20. 如权利要求19所述的晶型III的制备方法，其特征在于，步骤a)中，所述酮类溶剂和水的 体积比为1∶1到10∶1。
  21. 如权利要求19或20所述的晶型III的制备方法，其特征在于：所述酮类溶剂为丙酮。
  22. 如权利要求19所述晶型III的制备方法，其特征在于，步骤a)中，所述甲磺酸与式(I)化合物的投料摩尔比为1.0～1.8∶1。
  23. 如权利要求19所述晶型III的制备方法，其特征在于，步骤a)中，控制所述搅拌时的温度为5～50℃。
  24. 如权利要求19所述晶型III的制备方法，其特征在于，步骤b)中，所述醇类溶剂和水的体积比为99∶1～1∶99。
  25. 如权利要求19所述的晶型III的制备方法，其特征在于：所述醇类溶剂为异丙醇。
  26. 如权利要求19或24或25所述的晶型III的制备方法，其特征在于：步骤b)中，控制所述搅拌时的温度为25～60℃。
  27. 一种药用组合物，所述药用组合物包含治疗和/或预防有效量的选自权利要求1-4中的任一项所述的晶型I、权利要求8-11中任一项所述的晶型II、权利要求15-18中任一项权利要求所述的晶型III中的一种或多种及至少一种药学上可接受的载体或赋形剂。
  28. 如权利要求1-4中的任一项所述的晶型I、权利要求8-11中任一项所述的晶型II、权利要求15-18中任一项权利要求所述的晶型III中的一种或多种的组合在制备具有抑制SYK作用的药物制剂中的用途。
  29. 如权利要求1-4中的任一项所述的晶型I、权利要求8-11中任一项所述的晶型II、权利要求15-18中任一项权利要求所述的晶型III中的一种或多种的组合在制备慢性淋巴细胞白血病和急性髓系白血病药物制剂中的用途。
  30. 一种治疗或预防与SYK相关的疾病的方法，其特征在于，所述方法包括给予需要的患者治疗和/或预防有效量的权利要求1-4中的任一项所述的晶型I、权利要求8-11中任一项所述的晶型II、权利要求15-18中任一项权利要求所述的晶型III。
PCT/CN2017/074729 2016-02-26 2017-02-24 (6-(1H-吲唑-6-基)-N-[4-(4-吗啉基)苯基]咪唑并[1，2-a]吡嗪-8-胺)甲磺酸盐的新晶型 WO2017144010A1 (zh)

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