WO2019242719A1 - 抑制cdk4/6活性化合物的晶型及其应用 - Google Patents

抑制cdk4/6活性化合物的晶型及其应用 Download PDF

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Publication number
WO2019242719A1
WO2019242719A1 PCT/CN2019/092239 CN2019092239W WO2019242719A1 WO 2019242719 A1 WO2019242719 A1 WO 2019242719A1 CN 2019092239 W CN2019092239 W CN 2019092239W WO 2019242719 A1 WO2019242719 A1 WO 2019242719A1
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Prior art keywords
compound
cancer
crystal form
crystalline form
disease
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PCT/CN2019/092239
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English (en)
French (fr)
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王义乾
张春辉
王家炳
丁列明
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贝达药业股份有限公司
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Priority to CA3104365A priority Critical patent/CA3104365A1/en
Priority to IL279579A priority patent/IL279579B2/en
Application filed by 贝达药业股份有限公司 filed Critical 贝达药业股份有限公司
Priority to MX2020013847A priority patent/MX2020013847A/es
Priority to EP19822566.6A priority patent/EP3812386A4/en
Priority to EA202190036A priority patent/EA202190036A1/ru
Priority to CN202111208432.8A priority patent/CN113861191B/zh
Priority to CN201980037275.3A priority patent/CN112424202B/zh
Priority to KR1020217001384A priority patent/KR20210024004A/ko
Priority to JP2020571503A priority patent/JP7430656B2/ja
Priority to SG11202012858QA priority patent/SG11202012858QA/en
Priority to AU2019290722A priority patent/AU2019290722B2/en
Priority to BR112020026052-5A priority patent/BR112020026052A2/pt
Priority to US17/254,097 priority patent/US20210261546A1/en
Publication of WO2019242719A1 publication Critical patent/WO2019242719A1/zh
Priority to PH12020552236A priority patent/PH12020552236A1/en
Priority to ZA2021/00101A priority patent/ZA202100101B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a compound (R) -N- (5-((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (6-fluoro-1 -Methyl-1,2,3,4-tetrahydrobenzo [4,5] imidazo [1,2-a] pyridin-8-yl) pyrimidin-2-amine salt form and its crystalline form;
  • the invention also relates to a method for preparing the compound and crystal form, and related intermediate compounds, pharmaceutical compositions containing the compound, and their use in inhibiting the activity of CDK4 / 6.
  • the invention also relates to a method for treating a disease, disorder or condition associated with the regulation of CDK4 / 6 using at least one of the compounds or crystalline forms and pharmaceutical compositions described above.
  • CDKs Cyclin-dependent kinases
  • CDKs are a class of serine / threonine protein kinases that participate in the regulation of the cell cycle, transcription initiation, and control of certain specific metabolic cascades. Different CDKs and cyclins form CDK-cyclin complexes. If the CDK activity is dysregulated, it will directly or indirectly cause uncontrolled cell proliferation, genomic instability (increased DNA mutation, chromosome deletion, etc.) and chromosomal instability (change in chromosome number). )Wait.
  • CDKs family has identified more than 20 subtypes.
  • CDK1, CDK2, CDK4, and CDK6 are involved in cell cycle regulation;
  • CDK7, CDK8, CDK9, and CDK11 are involved in transcription regulation; and
  • other kinases include CDK3 and CDK5.
  • CDK4 / 6 cyclin-dependent kinases 4 and 6
  • Cancer-related cell cycle mutations mainly exist in the G1 and G1 / S phase transformation.
  • CDK4 / 6 binds to CyclinD A complex with kinase activity is formed and phosphorylation of the tumor suppressor gene Rb product pRb releases the bound transcription factor E2F to initiate transcription of genes related to the S phase, prompting cells to pass the checkpoint and transfer from the G1 phase to the S phase.
  • the specific activation of CDK4 / 6 is closely related to the proliferation of some tumors. About 80% of human tumors have abnormalities in the cyclin D-CDK4 / 6-INK4-Rb pathway. CDK4 / 6 inhibitors block the cell cycle in the G1 phase, thereby inhibiting tumor proliferation.
  • PCT International Application PCT / CN2017 / 117950 describes a class of benzimidazole derivatives that are used as CDK4 / 6 protein kinase inhibitors, and most of these compounds effectively inhibit CDK4 and CDK6. Because there are still unmet needs in the treatment options for kinase-mediated diseases, here we further screen the salt forms and crystal forms of benzimidazole derivatives to meet the medical needs of patients.
  • the object of the present invention is to provide a compound (R) -N- (5-((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro- 4- (6-fluoro-1-methyl-1,2,3,4-tetrahydrobenzo [4,5] imidazo [1,2-a] pyridin-8-yl) pyrimidin-2-amine Salt form and crystal form:
  • an acid and Compound I form the corresponding salts.
  • These salt-type compounds can exist in various physical forms. For example, it can be in solution, suspension or solid form.
  • the salt-type compound is in a solid form. When in solid form, the compound can be an amorphous, crystalline or mixture thereof.
  • the following exemplifies the salt forms formed by Compound I and two acids. They are tartrate compounds and mesylate compounds, respectively.
  • the tartrate refers to L-tartrate.
  • the structures of L-tartrate and mesylate of compound I are shown in the following formula II and III:
  • the present invention also provides various crystal forms of the above-mentioned compound II and compound III. E.g,
  • the invention provides Form A of Compound II.
  • Form A of Compound II can be identified by X-ray powder diffraction.
  • the X-ray powder diffraction spectrum of the Form A of Compound II has characteristic peaks with diffraction angles 2 ⁇ of 4.4 ⁇ 0.2 °, 23.6 ⁇ 0.2 °, and 26.9 ⁇ 0.2 °.
  • the present invention is referred to as Form A.
  • the X-ray powder diffraction pattern of the aforementioned Form A has a diffraction angle 2 ⁇ of 4.4 ⁇ 0.2 °, 8.7 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 18.4 ⁇ 0.2 °, 23.6 ⁇ 0.2 °, and 26.9 ⁇ 0.2 ° Characteristic peak.
  • the X-ray powder diffraction pattern of the above-mentioned Form A has a diffraction angle 2 ⁇ of 4.4 ⁇ 0.2 °, 8.7 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 15.9 ⁇ 0.2 °, 18.4 ⁇ 0.2 °, 23.6 ⁇ 0.2 ° and 26.9 ⁇ 0.2 ° characteristic peaks.
  • Compound II Form A of the present invention can be identified by differential scanning calorimetry.
  • Form A has a differential scanning calorimetry curve as shown in FIG. 11. In the DSC spectrum, the endothermic peak of Form A is approximately 230.1 to 233.1 ° C.
  • DSC 200F3 240-20-0954-L purge gas: nitrogen; flow rate: 60mL / min; heating rate: 10 ° C / min, measurement range: 30 ° C-300 ° C) ) Measure.
  • the Form A of Compound II of the present invention can be calculated using ion chromatography, a conductivity detector, and an external standard method to calculate the main component content, and the L-tartaric acid content is determined to be about 12.01% -13.27%.
  • the crystal form A has a purity of ⁇ 85%.
  • the crystal form A has a purity of ⁇ 95%.
  • the purity of the crystal form A is ⁇ 99%.
  • the purity of the crystal form A is ⁇ 99.5%.
  • the crystal form A is an anhydrous substance.
  • the compound II crystalline form A provided by the present invention has the characteristics of good crystallinity, weak hygroscopicity and good stability, and has acceptable oral bioavailability.
  • the present invention also provides another crystal form of compound II.
  • the present invention is referred to as crystal form B.
  • the X-ray powder diffraction pattern of the crystal form B has an X-ray powder diffraction pattern as shown in FIG. 2.
  • the crystal form B has a purity of ⁇ 85%.
  • the crystal form B has a purity of ⁇ 95%.
  • the purity of the crystal form B is ⁇ 99%.
  • the purity of the crystal form B is ⁇ 99.5%.
  • the crystal form B is an anhydrous substance.
  • the present invention also provides another crystalline form of compound II.
  • the present invention is called crystalline form C.
  • the X-ray powder diffraction pattern of the crystal form C has an X-ray powder diffraction pattern as shown in FIG. 3.
  • the crystal form C has a purity of ⁇ 85%.
  • the crystal form C has a purity of ⁇ 95%.
  • the crystal form C has a purity of ⁇ 99%.
  • the crystal form C has a purity of ⁇ 99.5%.
  • the present invention further provides an amorphous form of Compound II or a solvate thereof, the amorphous form having an X-ray powder diffraction pattern as shown in FIG. 4.
  • the invention further provides a pharmaceutical composition comprising a therapeutically effective amount of Form A, Form B and / or Form C of Compound II.
  • the pharmaceutical composition contains a therapeutically effective amount of Form A, Form B and / or Form C of Compound II, and a pharmaceutically acceptable excipient, adjuvant or carrier.
  • the pharmaceutical composition contains a therapeutically effective amount of Form A of Compound II, and a pharmaceutically acceptable excipient, adjuvant, or carrier.
  • the pharmaceutical composition contains a therapeutically effective amount of Form A, Form B and / or Form C of Compound II, and at least one other active ingredient is used in parallel.
  • the pharmaceutical composition contains a therapeutically effective amount of Form II of Compound II, and at least one other active ingredient is used in parallel.
  • the pharmaceutical composition is an oral preparation.
  • the pharmaceutical composition is a tablet or capsule.
  • the present invention also provides the use of Form A, Form B and / or Form C of the compound II in the manufacture of a medicament for treating a disease, disorder or condition of a patient, wherein the disease, disorder or condition is described by CDK, such as CDK4 and / or CDK6.
  • CDK such as CDK4 and / or CDK6.
  • the present invention also provides a preferred embodiment of the above-mentioned uses of the crystalline form A, the crystalline form B and / or the crystalline form C of the compound II.
  • said disease, disorder or condition is cancer and / or proliferative disease.
  • the disease, disorder or condition is colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, T Cell lymphoma, melanoma, pancreatic cancer, brain cancer or lung cancer.
  • said disease, disorder or condition is breast cancer.
  • the invention also provides a method of treating a patient's disease, disorder, or condition by administering Form II, Form B, and / or Form C of Compound II to a patient.
  • the present invention further provides a preferred embodiment of the method for treating a disease, disorder, or condition of a patient using the Form A, Form B, and / or Form C of the compound II:
  • the disease, disorder or condition is mediated by CDK, such as CDK4 and / or CDK6.
  • CDK such as CDK4 and / or CDK6.
  • said disease, disorder or condition is cancer and / or proliferative disease.
  • the disease, disorder or condition is colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, T Cell lymphoma, melanoma, pancreatic cancer, brain cancer or lung cancer.
  • said disease, disorder or condition is breast cancer.
  • the present invention provides a crystal form of compound III and / or a solvate thereof.
  • the present invention is referred to as crystal form D.
  • the crystal form D has an X-ray powder diffraction pattern as shown in FIG. 5.
  • the crystal form D has a purity of ⁇ 85%.
  • the purity of the crystal form D is ⁇ 95%.
  • the purity of the crystal form D is ⁇ 99%.
  • the purity of the crystal form D is ⁇ 99.5%.
  • the crystal form D is an anhydrous substance.
  • the present invention provides a crystalline form of compound III and / or a solvate thereof.
  • the present invention is referred to as crystalline form E.
  • the crystal form E has an X-ray powder diffraction pattern as shown in FIG. 6.
  • the purity of the crystal form E is ⁇ 85%.
  • the crystal form E has a purity of ⁇ 95%.
  • the purity of the crystal form E is ⁇ 99%.
  • the crystal form E has a purity of ⁇ 99.5%.
  • the crystalline form E is a dihydrate.
  • the present invention provides a crystal form of compound III and / or a solvate thereof.
  • the present invention is referred to as crystal form F.
  • the crystal form F has an X-ray powder diffraction pattern as shown in FIG. 7.
  • the crystal form F has a purity of ⁇ 85%.
  • the crystal form F has a purity of ⁇ 95%.
  • the purity of the crystal form F is ⁇ 99%.
  • the crystal form F has a purity of ⁇ 99.5%.
  • the crystal form F is 1.5 hydrate.
  • the present invention first provides a crystal form of compound III and / or a solvate thereof.
  • the present invention is referred to as crystal form G.
  • This crystal form G has an X-ray powder diffraction pattern approximately as shown in FIG. 8.
  • the crystal form G has a purity of ⁇ 85%.
  • the crystal form G has a purity of 95% or more.
  • the crystal form G has a purity of ⁇ 99%.
  • the crystal form G has a purity of ⁇ 99.5%.
  • the crystalline form G is 2.5 hydrate.
  • the present invention further provides an amorphous form of Compound III and / or a solvate thereof, the amorphous form having an X-ray powder diffraction pattern as shown in FIG. 9.
  • the invention further provides a pharmaceutical composition comprising a therapeutically effective amount of Form D, Form E, Form F and / or Form G of Compound III.
  • the pharmaceutical composition contains a therapeutically effective amount of Form D, Form E, Form F, and Form G of Compound III, and a pharmaceutically acceptable excipient, adjuvant, or carrier.
  • the pharmaceutical composition contains a therapeutically effective amount of Form D, Form E, Form F and Form G of Compound III, and at least one other active ingredient is used in parallel.
  • the pharmaceutical composition is an oral preparation.
  • the pharmaceutical composition is a tablet or capsule.
  • the invention also provides the use of crystalline form D, crystalline form E, crystalline form F and / or crystalline form G of compound III in the manufacture of a medicament for treating a disease, disorder or condition of a patient, wherein the disease, disorder or The condition is mediated by CDK, such as CDK4 and / or CDK6.
  • CDK such as CDK4 and / or CDK6.
  • the present invention also provides a preferred embodiment of the above uses of the crystalline form D, crystalline form E, crystalline form F and / or crystalline form G of compound III:
  • said disease, disorder or condition is cancer and / or proliferative disease.
  • the disease, disorder or condition is colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, T cells Lymphoma, melanoma, pancreatic cancer, brain cancer or lung cancer.
  • said disease, disorder or condition is breast cancer.
  • the invention also provides a method of treating a patient's disease, disorder, or condition by administering Form III, Form E, Form F, and / or Form G of Compound III to a patient.
  • the present invention further provides a preferred embodiment of the method for treating a disease, disorder, or condition of a patient by using the Form D, Form E, Form F, and / or Form G of Compound III as described above:
  • the disease, disorder or condition is mediated by CDK, such as CDK4 and / or CDK6.
  • CDK such as CDK4 and / or CDK6.
  • said disease, disorder or condition is cancer and / or proliferative disease
  • the disease, disorder or condition is colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, T Cell lymphoma, melanoma, pancreatic cancer, brain cancer or lung cancer.
  • said disease, disorder or condition is breast cancer.
  • the crystalline form of the salt of Compound I provided by the present invention is prepared by the following method:
  • the acid added in step 3) is L-tartaric acid, and the crystal form of L-tartrate of compound I is obtained in step 4).
  • the acid added in step 3) is methanesulfonic acid, and the crystal form of the methanesulfonate of compound I obtained in step 4).
  • the method for preparing Form A of Compound II is as follows:
  • the method for preparing Form B of Compound II is as follows:
  • the method for preparing Form C of Compound II is as follows:
  • the method for preparing the amorphous form of Compound II is as follows:
  • the amorphous form of compound II is susceptible to the formation of crystalline form B of compound II under the influence of moisture in a room temperature environment.
  • the invention also exemplifies (R) -N- (5-((4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (6-fluoro L-tartrate salt of 1-methyl-1,2,3,4-tetrahydrobenzo [4,5] imidazo [1,2-a] pyridin-8-yl) pyrimidin-2-amine (compound II)
  • a preparation method comprising the following steps:
  • the method for preparing Form D of Compound III is as follows:
  • Dissolve compound I in methanol at 50-70 ° C dissolve methanesulfonic acid in methanol, add the methanol solution of methanesulfonic acid to the methanol solution of compound I, add isopropyl ether dropwise after stirring, slowly The solid precipitated out, stirred and filtered, and the filter cake was dried at 40-70 ° C to obtain a solid.
  • Isopropyl ether was added dropwise to the mother liquor, and the mixture was filtered, and the filter cake was dried at 40-70 ° C to obtain a solid. The obtained solid was further dried to obtain Form D of Compound III.
  • the method for preparing Form E of Compound III is as follows:
  • the method for preparing Form F of Compound III is as follows:
  • the method for preparing Form III of Compound III is as follows:
  • the method for preparing the amorphous form of Compound III is as follows:
  • the amorphous form of Compound III was unstable when enlarged to 50 mg, and a crystalline state was obtained.
  • substantially pure used in the present invention means that at least 85% by weight, preferably at least 95% by weight, more preferably at least 99% by weight, and most preferably at least 99.5% by weight, the compound represented by the formula I is present in the crystals of the present invention.
  • forms especially in form A, form B and / or form C.
  • new crystal forms can be identified by powder X-ray diffraction spectroscopy.
  • the peak intensity and / or peak condition of powder X-ray diffraction may be different due to different experimental conditions, such as different diffraction test conditions and / or orientation preference.
  • the measured 2 ⁇ value will be about The error.
  • the relative intensity of a peak is more dependent on certain properties of the sample than the position of the peak, such as the size of the crystals in the sample, the orientation of the crystals, and the purity of the material being analyzed, so the peaks shown Deviations in strength are possible in the range of about ⁇ 20% or more.
  • those skilled in the art can also obtain sufficient information to identify the crystal form from the XRD data provided by this patent.
  • “having an X-ray powder diffraction pattern approximately as shown in FIG. 1” or “having an X-ray powder diffraction pattern approximately as shown in FIG. 2” refers to the main The peaks are shown in Fig. 1 or Fig. 2.
  • the main peaks refer to the relative intensities of more than 10%, and preferably more than 30%, compared to the highest peak in Fig. 1 or Fig. 2, whose relative intensity is designated as 100%. Those peaks.
  • “adding methanol / acetone” and the like involved in the preparation method of the crystal form means that in this preparation method, methanol is added first, and then acetone is added.
  • “ethanol / water” means adding ethanol first and then water; and “trifluoroethanol / ethyl acetate” means adding trifluoroethanol first and then ethyl acetate.
  • solvent 1 / solvent 2 means adding solvent 1 first, and then adding solvent 2; and “solvent 2 / solvent 1” means adding solvent 2 first, and then adding solvent 1.
  • the term "therapeutically effective amount” means that when a compound / crystal form is administered to a subject to treat at least one clinical symptom of a disease, or a disease or disorder, it is sufficient to affect the disease, disorder or symptom.
  • the amount of this treatment may vary with the compound, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the patient being treated, and / or the Changes in patient's weight, etc. In any particular case, a suitable amount may be apparent to those skilled in the art, or it may be determined by routine experimentation.
  • “therapeutically effective amount” refers to the total amount of a combination subject effective to treat a disease, disorder, or condition.
  • All dosage forms of the pharmaceutical composition of the present invention can be prepared by conventional methods in the pharmaceutical field.
  • the active ingredient is mixed with one or more excipients and then made into the desired dosage form.
  • “Pharmaceutically acceptable carrier” refers to a conventional pharmaceutical carrier suitable for the desired pharmaceutical formulation, for example: diluents, excipients such as water, various organic solvents, etc .; fillers such as starch, sucrose, etc .; such as Binders of cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; Surfactants such as cetyl alcohol; absorption carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, and polyethylene glycol.
  • diluents, excipients such as water, various organic solvents, etc .
  • fillers such as starch, sucrose, etc .
  • PVP polyvinylpyrrolidone
  • wetting agents such as
  • excipients can be added to the pharmaceutical composition, such as dispersants, stabilizers, thickeners, complexing agents, buffering agents, penetration enhancers, polymers, fragrances, sweeteners and dyes. . It is preferred to use excipients suitable for the desired dosage form and the desired mode of administration.
  • disease refers to any disease, discomfort, disease, symptom, or indication.
  • Figure 1 XRD pattern of Compound II Form A (small test sample, lot number: 1072P04-A14S01).
  • Figure 4 XRD pattern of Compound II amorphous.
  • Figure 9 XRD pattern of Compound III amorphous.
  • Figure 10 XRD comparison spectra of Compound II Form A (small test sample, lot number: 1072P04-A14S01) under different stability conditions. From bottom to top, the meanings of lines 1 to 4 are as follows:
  • Figure 11 DSC pattern of Compound II Form A.
  • the abscissa (X-axis) represents temperature, unit: ° C; the ordinate (Y-axis) represents heat flow, unit: watt / gram.
  • Figure 12 XRD pattern of Compound II Form A (pilot sample, batch number: 20170903).
  • the abscissa (X-axis) represents the diffraction angle 2 ⁇ , and the unit is "°"; the ordinate (Y-axis) represents the diffraction intensity, and the unit is "count” .
  • DMSO dimethyl sulfoxide
  • DSC differential scanning calorimetry
  • DVS dynamic vapor adsorption
  • RH relative humidity
  • TEA triethanolamine
  • Xantphos 4,5-bis (diphenylphosphine) -9,9-dimethylxanthene;
  • XRD X-ray powder diffraction pattern.
  • an aqueous solution of sodium hydroxide (301 g / 1.5 L of water) was added to a tetrahydrofuran (601 g / 2.3 L of THF) solution of 1-A1-03, and the mixture was heated to reflux for 3-4 hours to stop the reaction. The temperature was lowered to 40-50 ° C, and the layers were left to stand.
  • the organic phase (THF) was collected and concentrated to a large amount of solids; the solids were dissolved by adding water (20L), and the aqueous phase was sequentially treated with methyl tert-butyl ether (2L) and ethyl acetate.
  • the concentrate was purified by n-hexane and dichloromethane column chromatography, and n-hexane (1.2 L) was slurried for 1 hour to obtain 334 g of a gray solid. That is 1-01, and the yield is 70.10%.
  • the aqueous phase was extracted with dichloromethane (700 mL).
  • the organic phases were combined and washed with purified water (700 mL x 2).
  • the organic phase was dried by adding anhydrous sodium sulfate (700 g), filtered to remove the desiccant, and the filtrate was concentrated.
  • Methanol (0.5 L) was added, heated to 55-65 ° C. and stirred for 0.5 hours, lowered to room temperature, and filtered.
  • the solid product was filtered and rinsed with 500 mL of ethyl acetate.
  • the solid was dried under vacuum at 45 ° C for 8 hours to obtain 111.79 g of a pale yellow solid 1-03.
  • a small test sample of compound II (batch number: 1072P04-A14S01) and a pilot sample of compound II (batch number: 20170903) were prepared according to the synthetic method of Example 1, and then characterized by XRD.
  • the small test sample (batch number: 1072P04-A14S01) was analyzed by Hangzhou Lingye Pharmaceutical Technology Co., Ltd. using Bruker D8 Advance Diffractometer. The instruments and detection parameters used are shown in Table 1. The data are shown in Table 2.
  • the pilot test sample (batch number: 20170903) was subjected to XRD analysis by the Beijing Physical and Chemical Analysis and Testing Center using a D8-Advance X-ray diffractometer.
  • the reference method is JY / T General rules for X-ray diffraction of target polycrystals.
  • the used instruments and detection parameters are shown in Table 3, and the XRD spectrum analysis data are shown in Table 4.
  • the relevant data may be subjected to appropriate scientific processing, such as baseline correction processing.
  • appropriate scientific processing such as baseline correction processing.
  • the XRD pattern of Compound II Form A provided by the present invention is not limited to the X-ray powder diffraction pattern shown in FIG. 1 or FIG. 12, and the crystals of the X-ray powder diffraction pattern substantially the same as those shown in FIG. 1 or 12 All fall within the scope of the present invention.
  • the X-ray powder diffraction pattern detection apparatus and method of the present invention are shown in Table 1.
  • Compound II Form A, Compound III Form D, and Compound III Form F samples were dried at 80 ° C for 24 hours, 25 ° C, 60% RH for 10 days, 40 ° C, 75% RH for 10 days, and XRD spectra were measured. The figure is shown in Figure 10 and the results are shown in Table 5.
  • Compound II Form B is metastable, with poor crystalline state, and will be transformed into Form A when heated to 180 ° C.
  • the detection equipment and method of the dynamic moisture adsorption meter of the present invention are shown in Table 7, and the measurement results of the dynamic moisture adsorption are shown in Table 8.
  • Compound II Form A and Form B weight changes in the range of 0% RH to 80% RH are about 5.3% and 5.5%
  • Compound III Form D and Form F weight in the range of 0% RH to 80% RH The changes are approximately 17.2% and 16.6%. It can be seen that, compared with the crystal form of compound III, the crystal form of compound II has weak hygroscopicity and is more suitable for the preparation of solid preparations.
  • CDK4 / CycD3, CDK6 / cycD3 the CDK kinase assay was performed.
  • the reaction buffer was prepared as follows: CDK6 kinase base buffer (50 mM HEPES, pH 7.5; 0.015% Brij-35; 10 mM MgCl 2 ; 2 mM DTT); CDK4 kinase base buffer (20 mM HEPES, pH 7.5; 0.01 % Triton X-100; 10 mM MgCl 2 ; 2 mM DTT); Stop buffer (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent # 3; 50 mM EDTA)
  • Inhibition rate (maximum value-converted value) / (maximum value-minimum value) * 100
  • Maximum is the DMSO control value; “Minimum” is the non-kinase control well value.
  • Compound I was used as the test compound, and compared with the positive control drug LY2835219 (Abemaciclib), the inhibitory activity of CDK kinase at the molecular level and the specificity of selection were compared.
  • Y minimum inhibition rate + (maximum inhibition rate-minimum inhibition rate) / (1 + 10 ⁇ ((LogIC 50 -X) * slope)); where Y represents the percentage of inhibition (%); X represents the concentration of the test compound logarithm.
  • Results by screening more CDK kinases, found that compounds I inhibit IC CDK1 / 2/7/9 is greater than 0.4 M 50, thousands of times or even several tens of CDK4 / 6 (see Table 13).
  • the compound I of the present invention shows a strong inhibitory effect on CDK4 / 6, and has very weak inhibitory effect on CDK1 / 2/7/9, indicating that compound I is a CDK4 / 6 with excellent selectivity Kinase inhibitor.
  • the selectivity of Compound I between CDK1 / 2/9 and CDK4 / 6 was significantly higher than that of LY2835219 (Abemaciclib).
  • JeKo-1 cells were cultured in RPMI 1640 medium containing 20% fetal bovine serum. JeKo-1 cells were collected in exponential growth phase and resuspended in PBS to a suitable concentration for inoculation of subcutaneous tumors in NOD / SCID mice. Seventy female mice were subcutaneously inoculated with 5 ⁇ 106 JeKo-1 cells on the right side, and the cells were resuspended in PBS and matrigel (1: 1). When the average tumor volume is 134mm3, random administration will be started according to tumor size. Of these, 48 were divided into experimental groups, and the remaining 22 were grouped into remaining mice. Tumor volume calculation formula is: long diameter x short diameter 2/2.
  • test compound representative compound I (10mg / kg), test drug representative compound I (25mg / kg), test drug representative compound I (50mg / kg), and test drug representative compound I ( 100mg / kg)
  • a total of 6 groups, 8 mice in each group were administered by oral gavage, once a day after grouping, for 19 consecutive days.
  • the therapeutic effect was evaluated based on the relative tumor growth inhibition rate TGI. The results are shown in Table 14.
  • TGI (%) (C-T) / C ⁇ 100% (C and T are the average tumor weight of the solvent control group and the average tumor weight of the treatment group, respectively). The larger the TGI (%) value, the better the efficacy; and vice versa.
  • p value is a comparative analysis of tumor volume in the treatment group and the solvent control group.

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Abstract

本发明涉及结构式(I)所示的(R)-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-氟-1-甲基-1，2，3，4-四氢苯并[4，5]咪唑并[1，2-a]吡啶-8-基)嘧啶-2-胺(化合物I)的盐型或其晶型，本发明还涉及化合物I的盐型和/或其晶型的制备方法，含有所述盐型和/或晶型的药物组合物，以及它们在制备治疗疾病、病症或病状的药物中的应用或用于治疗疾病、病症或病状的治疗方法。

Description

抑制CDK4/6活性化合物的晶型及其应用 技术领域
本发明涉及一种化合物(R)-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-氟-1-甲基-1，2，3，4-四氢苯并[4，5]咪唑并[1，2-a]吡啶-8-基)嘧啶-2-胺的盐型及其晶型；本发明还涉及所述化合物和晶型的制备方法以及相关的中间体化合物，含有所述化合物的药物组合物，以及它们在抑制CDK4/6的活性中的应用。本发明也涉及应用至少上述之一的化合物或晶型及药物组合物治疗与CDK4/6调节相关的疾病、病症或病状的方法。
背景技术
细胞周期蛋白依赖性激酶(Cyclin-dependent kinase，CDKs)，是一类丝氨酸/苏氨酸蛋白激酶，在细胞周期、转录起始和某些特定代谢级联反应控制等过程中都参与调控。不同的CDK和细胞周期素(cyclin)形成CDK-cyclin复合物，若CDK活性失调会直接或间接引起细胞增殖失控、基因组不稳定(DNA突变增加，染色体缺失等)和染色体不稳定(染色体数目变化)等。
CDKs家族目前已经确认了20多个亚型，CDK1、CDK2、CDK4、CDK6等参与细胞周期调控；CDK7、CDK8、CDK9、CDK11等参与转录调节；以及其他激酶包括CDK3、CDK5等。其中CDK4/6(细胞周期蛋白依赖性激酶4和6)是调节细胞周期的关键因子，与癌症有关的细胞周期突变主要存在于G1期和G1/S期转化过程中，CDK4/6与CyclinD结合形成有激酶活性的复合物，通过抑癌基因Rb产物pRb磷酸化，释放结合的转录因子E2F，启动与S期有关的基因转录，促使细胞通过检验点，并从G1期向S期转移。CDK4/6特异性的激活与一些肿瘤的增殖密切相关，大约80％的人类肿瘤中有cyclin D-CDK4/6-INK4-Rb通路的异常。CDK4/6抑制剂将细胞周期阻滞于G1期，从而起到抑制肿瘤增殖的作用。
靶向CDK4/6激酶药物的研发是意义重大的领域，其抗肿瘤靶点的优势在于：(1)大多数增殖的细胞依赖CDK2或者CDK4/6增殖，但CDK4/6的抑制剂不表现出“pan-CDK抑制剂”的细胞毒性，如骨髓抑制和肠道反应；(2)临床前实验表明，如果细胞cyclin D水平升高或者P16INK4a失活，能够增加细胞对药物的敏感性，由于肿瘤细胞相对于正常细 胞存在上述现象，所以一定程度上增加了药物的靶向性。
PCT国际申请PCT/CN2017/117950描述了一类用作CDK4/6蛋白激酶抑制剂的苯并咪唑衍生物，这些化合物中的大部分有效地抑制CDK4和CDK6。因为在激酶介导疾病的治疗选择方面仍有未满足的需求，在此我们进一步筛选苯并咪唑衍生物的盐型及其晶型以满足患者的医疗需求。
发明内容
本发明的目的在于提供一种如下结构式I所示化合物(R)-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-氟-1-甲基-1，2，3，4-四氢苯并[4，5]咪唑并[1，2-a]吡啶-8-基)嘧啶-2-胺的盐型及其晶型：
Figure PCTCN2019092239-appb-000001
结构式I的盐型
在一些实施方案中，一种酸和化合物I形成相应的盐。这些盐型化合物可以以各种物理形式存在。例如，可以是溶液、悬浮液或固体形式。在某些实施方式中，盐型化合物为固体形式。为固体形式时，所述化合物可以是无定形物，结晶物或其混合物。下面示范性列举了化合物I与两种酸所形成的盐型。分别是酒石酸盐化合物和甲磺酸盐化合物。在一些实施方式中，所述酒石酸盐是指L-酒石酸盐。化合物I的L-酒石酸盐和甲磺酸盐的结构如下结构式II和结构式III所示：
化合物I的L-酒石酸盐(结构式II所示化合物，化合物II)
Figure PCTCN2019092239-appb-000002
化合物I的甲磺酸盐(结构式III所示化合物，化合物III)
Figure PCTCN2019092239-appb-000003
本发明还提供了上述化合物II和化合物III的多种晶型。例如，
化合物II的晶型A
本发明提供了化合物II的晶型A。
在一些实施方式中，化合物II的晶型A可以通过X射线粉末衍射进行鉴别。在一些实施方式中，化合物II的晶型A的X射线粉末衍射谱图具有衍射角2θ为4.4±0.2°、23.6±0.2°和26.9±0.2°的特征峰。为方便，本发明称之为晶型A。
在一些实施方式中，上述晶型A的X射线粉末衍射谱图具有衍射角2θ为4.4±0.2°、8.7±0.2°、10.8±0.2°、18.4±0.2°、23.6±0.2°和26.9±0.2°的特征峰。
在一些实施方式中，上述晶型A的X射线粉末衍射谱图具有衍射角2θ为4.4±0.2°、8.7±0.2°、10.8±0.2°、15.9±0.2°、18.4±0.2°、23.6±0.2°和26.9±0.2°的特征峰。
在一些实施方式中，本发明所述化合物II晶型A可用差式扫描量热分析进行鉴定。在一些实施方式中，晶型A具有如图11所示的差式扫描量热分析曲线。在DSC图谱中，晶型A的吸热峰约在230.1～233.1℃。差式扫描量热分析测定是通过NETZSCH公司的DSC 200F3 240-20-0954-L(吹扫气体：氮气；流速：60mL/min；升温速度：10℃/分钟，测定范围：30℃-300℃)测定。
在一些实施方式中，本发明所述化合物II的晶型A可以利用离子色谱法，电导检测器，采用外标法计算主成分含量，测得L-酒石酸含量约为12.01％-13.27％。
在一些实施方式中，本发明所述化合物II的晶型A可以利用 1HNMR进行鉴定， 1HNMR的数据如下： 1HNMR(500MHz，CDCl3)δppm：1.01-1.04(t，3H，CH3，J＝5.3Hz)，1.50-1.52(d，3H，CH3，J＝6.5Hz)，1.93-1.95(m，2H，CH2)，2.03-2.06(m，1H，CH2)，2.16-2.19(m，1H，CH2)，2.50(s，8H，CH2)，2.57(s，2H，CH2)，2.93-3.09(m，2H，CH2)，3.47(s，1H，CH2)，4.02(s，1H，CH)，4.79(s，1H，CH)，7.68-7.70(d，1H，CH，J＝10.5)，7.71-7.73(d，1H，Ar-H，J＝12.5)，8.12(s，1H，Ar-H)，8.20(s，1H，Ar-H)，8.21(s，1H，Ar-H)，8.68-8.69(d，1H，Ar-H，J＝3.5)，10.03(s，1H，N-H)。
作为优选，该晶型A纯度≥85％。
作为优选，该晶型A纯度≥95％。
作为优选，该晶型A纯度≥99％。
作为优选，该晶型A纯度≥99.5％。
作为优选，该晶型A为无水物。
本发明提供的化合物II晶型A具有结晶性好、弱吸湿性、稳定性好的特性，而且具 有可接受的口服生物利用度。
化合物II的晶型B
本发明还提供了化合物II的另一晶型，为方便，本发明称之为晶型B。该晶型B的X射线粉末衍射谱图有约如图2所示的X-射线粉末衍射图。
作为优选，该晶型B纯度≥85％。
作为优选，该晶型B纯度≥95％。
作为优选，该晶型B纯度≥99％。
作为优选，该晶型B纯度≥99.5％。
作为优选，该晶型B为无水物。
化合物II的晶型C
本发明还提供了化合物II的另一晶型，为方便，本发明称之为晶型C。该晶型C的X射线粉末衍射谱图有约如图3所示的X-射线粉末衍射图。
作为优选，该晶型C纯度≥85％。
作为优选，该晶型C纯度≥95％。
作为优选，该晶型C纯度≥99％。
作为优选，该晶型C纯度≥99.5％。
本发明进一步提供了化合物II或其溶剂化物的无定型物，该无定型物具有约如图4所示的X-射线粉末衍射图。
本发明还进一步提供了含有治疗有效量的化合物II的晶型A、晶型B和/或晶型C的药物组合物。
本发明还提供了上述药物组合物的优选实施方式：
作为优选，所述药物组合物含有治疗有效量的化合物II的晶型A、晶型B和/或晶型C，和药学上可接受的辅料、辅助剂或载体。
作为优选，所述药物组合物含有治疗有效量的化合物II的晶型A，和药学上可接受的辅料、辅助剂或载体。
作为优选，所述药物组合物含有治疗有效量的化合物II的晶型A、晶型B和/或晶型C，并联用至少一种其他有效成分。
作为优选，所述药物组合物含有治疗有效量的化合物II的晶型A，并联用至少一种其他有效成分。
作为优选，所述药物组合物为口服制剂。
作为优选，所述药物组合物为片剂或胶囊。
本发明还提供了所述化合物II的晶型A、晶型B和/或晶型C在制备治疗患者的疾病、病症或病状的药物中的用途，其中，所述的疾病、病症或病状由CDK，如CDK4和/或CDK6介导。
本发明还提供了所述化合物II的晶型A、晶型B和/或晶型C上述用途的优选实施方式。
作为优选，所述疾病、病症或病状是癌症和/或增殖性疾病。
作为优选，所述的疾病、病症或病状是结肠癌、直肠癌、套细胞淋巴瘤、多发性骨髓瘤、乳腺癌、前列腺癌、胶质母细胞瘤、鳞状细胞食管癌、脂肪肉瘤、T细胞淋巴瘤、黑素瘤、胰腺癌、脑癌或肺癌。
作为优选，所述疾病、病症或病状是乳腺癌。
本发明还提供了通过对患者施用化合物II的晶型A、晶型B和/或晶型C治疗患者的疾病、病症或病状的方法。
本发明进一步提供了上述利用化合物II的晶型A、晶型B和/或晶型C治疗患者的疾病、病症或病状的方法的优选实施方式：
作为优选，所述的疾病、病症或病状是由CDK，如CDK4和/或CDK6介导。
作为优选，所述的疾病、病症或病状是癌症和/或增殖性疾病。
作为优选，所述的疾病、病症或病状是结肠癌、直肠癌、套细胞淋巴瘤、多发性骨髓瘤、乳腺癌、前列腺癌、胶质母细胞瘤、鳞状细胞食管癌、脂肪肉瘤、T细胞淋巴瘤、黑素瘤、胰腺癌、脑癌或肺癌。
作为优选，所述疾病、病症或病状是乳腺癌。
化合物III的晶型D
本发明提供了化合物III和/或其溶剂化物的一种晶型，为方便，本发明称之为晶型D。该晶型D具有约如图5所示的X-射线粉末衍射图。
作为优选，该晶型D纯度≥85％。
作为优选，该晶型D纯度≥95％。
作为优选，该晶型D纯度≥99％。
作为优选，该晶型D纯度≥99.5％。
作为优选，该晶型D为无水物。
化合物III的晶型E
本发明提供了化合物III和/或其溶剂化物的一种晶型，为方便，本发明称之为晶型E。该晶型E具有约如图6所示的X-射线粉末衍射图。
作为优选，该晶型E纯度≥85％。
作为优选，该晶型E纯度≥95％。
作为优选，该晶型E纯度≥99％。
作为优选，该晶型E纯度≥99.5％。
作为优选，该晶型E为二水合物。
化合物III的晶型F
本发明提供了化合物III和/或其溶剂化物的一种晶型，为方便，本发明称之为晶型F。该晶型F具有约如图7所示的X-射线粉末衍射图。
作为优选，该晶型F纯度≥85％。
作为优选，该晶型F纯度≥95％。
作为优选，该晶型F纯度≥99％。
作为优选，该晶型F纯度≥99.5％。
作为优选，该晶型F为1.5水合物。
化合物III的晶型G
本发明首先提供了化合物III和/或其溶剂化物的一种晶型，为方便，本发明称之为晶型G。该晶型G具有约如图8所示的X-射线粉末衍射图。
作为优选，该晶型G纯度≥85％。
作为优选，该晶型G纯度≥95％。
作为优选，该晶型G纯度≥99％。
作为优选，该晶型G纯度≥99.5％。
作为优选，该晶型G为2.5水合物。
本发明进一步提供了化合物III和/或其溶剂化物的无定型物，该无定型物具有约如图9所示的X-射线粉末衍射图。
本发明还进一步提供了含有治疗有效量的化合物III的晶型D、晶型E、晶型F和/或晶型G的药物组合物。
本发明还提供了上述药物组合物的优选实施方式：
作为优选，所述药物组合物含有治疗有效量的化合物III的晶型D、晶型E、晶型F和晶型G，和药学上可接受的辅料、辅助剂或载体。
作为优选，所述药物组合物含有治疗有效量的化合物III的晶型D、晶型E、晶型F和晶型G，并联用至少一种其他有效成分。
作为优选，所述药物组合物为口服制剂。
作为优选，所述药物组合物为片剂或胶囊。
本发明还提供了化合物III的晶型D、晶型E、晶型F和/或晶型G在制备治疗患者的疾病、病症或病状的药物中的用途，其中，所述的疾病、病症或病状由CDK，如CDK4和/或CDK6介导。
本发明还提供了化合物III的晶型D、晶型E、晶型F和/或晶型G的上述用途的优选实施方式：
作为优选，所述疾病、病症或病状是癌症和/或增殖性疾病。
作为优选，所述疾病、病症或病状是结肠癌、直肠癌、套细胞淋巴瘤、多发性骨髓瘤、乳腺癌、前列腺癌、胶质母细胞瘤、鳞状细胞食管癌、脂肪肉瘤、T细胞淋巴瘤、黑素瘤、胰腺癌、脑癌或肺癌。
作为优选，所述疾病、病症或病状是乳腺癌。
本发明还提供了通过对患者施用化合物III的晶型D、晶型E、晶型F和/或晶型G治疗患者的疾病、病症或病状的方法。
本发明进一步提供了上述利用化合物III的晶型D、晶型E、晶型F和/或晶型G治疗患者的疾病、病症或病状的方法的优选实施方式：
作为优选，所述的疾病、病症或病状是由CDK，如CDK4和/或CDK6介导。
作为优选，所述的疾病、病症或病状是癌症和/或增殖性疾病
作为优选，所述的疾病、病症或病状是结肠癌、直肠癌、套细胞淋巴瘤、多发性骨髓瘤、乳腺癌、前列腺癌、胶质母细胞瘤、鳞状细胞食管癌、脂肪肉瘤、T细胞淋巴瘤、黑素瘤、胰腺癌、脑癌或肺癌。
作为优选，所述疾病、病症或病状是乳腺癌。
在一些实施方式中，本发明提供的化合物I的盐的晶型，所述晶型是由如下方法制备得到：
1)将(R)-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-氟-1-甲基-1，2，3，4-四氢苯并[4，5]咪唑并[1，2-a]吡啶-8-基)嘧啶-2-胺(化合物I)混悬于水和/或水溶性有机溶剂中，得到混悬物；
2)将上述混悬物加热至50℃以上；
3)在保持50℃以上的温度条件下，在上述混悬物中加入相应的酸，进行酸化处理，得到澄清溶液；
4)降至室温后，搅拌过滤，滤饼经干燥后得到化合物I的盐的晶型。
例如，上述步骤3)中加入的酸为L-酒石酸，步骤4)得到的就是化合物I的L-酒石酸盐的晶型。
又例如，上述步骤3)中加入的酸为甲磺酸，步骤4)得到的就是化合物I的甲磺酸盐的晶型。
在一些实施方式中，化合物II的晶型A的制备方法如下：
50-70℃条件下将化合物I在甲醇中形成清液，将L-酒石酸溶解在甲醇中，将L-酒石酸的甲醇溶液滴加至化合物I的甲醇溶液中，搅拌后过滤，滤饼置于40-70℃干燥，即得到化合物II的晶型A。
在一些实施方式中，化合物II的晶型B的制备方法如下：
取化合物II的晶型A，加入水和丙酮溶清，过滤搅拌，转至0-20℃搅拌，析出固体，离心后干燥，得到化合物II的晶型B。
在一些实施方式中，化合物II的晶型C的制备方法如下：
搅拌状态下，取1-03(100g)、无水甲醇(1L)，依次加入到2L反应釜中，加热至65℃，待反应体系澄清0.5小时后滴加L-酒石酸的甲醇溶液(30.09g酒石酸溶于100mL无水甲醇)，控制滴加时间在45至60分钟，滴加完毕，65℃保温反应4小时，继续滴加L-酒石酸的甲醇溶液(7.48g酒石酸溶于100mL无水甲醇)，控制滴加时间在30至45分钟，滴加完毕，65℃保温反应1.5小时，继续滴加L-酒石酸的甲醇溶液(8.55g酒石酸溶于100mL无水甲醇)，控制滴加时间在30至45分钟，滴加完毕，65℃保温反应1.5小时，停止加热，降温至10℃以下，过滤，滤饼用甲醇(100mL×2)淋洗，45℃真空干燥36小时，得淡黄色结晶性粉末109.4g，即为化合物II的L-酒石酸盐，通过X射线粉末衍射进行鉴定，显示该晶型为化合物II的L-酒石酸盐的晶型C。
在一些实施方式中，化合物II的无定形物的制备方法如下：
取化合物II的晶型A，加入三氟乙醇溶清，减压浓缩，得到化合物II的无定型物。
化合物II的无定型物在室温环境中受水分影响容易形成化合物II的晶型B。
本发明还示范性地列举了(R)-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-氟-1-甲基-1，2，3，4-四氢苯并[4，5]咪唑并[1，2-a]吡啶-8-基)嘧啶-2-胺的L-酒石酸盐(化合物II)的制备方法，其包括如下步骤：
Figure PCTCN2019092239-appb-000004
在一些实施方式中，化合物III的晶型D的制备方法如下：
50-70℃条件下将化合物I在甲醇中溶清，将甲磺酸溶解在甲醇中，取甲磺酸的甲醇溶液滴加至化合物I的甲醇溶液中，搅拌后滴加异丙醚，缓慢析出固体，搅拌后过滤，滤饼置于40-70℃干燥得到固体。母液中再滴加异丙醚搅拌后过滤，滤饼置于40-70℃干燥得到固体。将得到的固体继续干燥后得到化合物III的晶型D。
在一些实施方式中，化合物III的晶型E的制备方法如下：
取化合物III的晶型D室温置于52％RH湿度条件下1-4天，得到化合物III的晶型E。
在一些实施方式中，化合物III的晶型F的制备方法如下：
取化合物III的晶型E在室温44％RH湿度放置1-14天，得到化合物III的晶型F。
在一些实施方式中，化合物III的晶型G的制备方法如下：
取化合物III的晶型D，置于室温97％RH条件下敞口放置1-4天，即得到化合物III的晶型G。
在一些实施方式中，化合物III的无定形物的制备方法如下：
取化合物III的晶型D，加入水溶清，减压浓缩干成粘稠状固体，得到化合物III的无定型物。
化合物III的无定型物放大到50mg时不稳定，得到结晶态。
本发明的所有晶型都是基本上纯的。
本发明所用的术语“基本上纯的”是指至少85重量％，优选至少95重量％，更优选至少99重量％，最优选至少99.5重量％的结构式I所示的化合物存在于本发明的晶型中，尤其是在晶型A、晶型B和/或晶型C中。
如本文所述，新晶型可以通过粉末X-射线衍射谱进行鉴定。然而，本领域技术人员知道，粉末X-射线衍射的峰强度和/或峰情况可能会因为实验条件的不同而不同，如不同的衍射测试条件和/或取向优先等。同时由于不同仪器的精准度不同，测得的2θ值会有约
Figure PCTCN2019092239-appb-000005
的误差。然而，已知的是峰的相对强度值比峰的位置更依赖于所测定样品的某些性质，例如样品中晶体的尺寸、结晶的取向作用和被分析的材料的纯度，因此所显示的峰强度偏差在约±20％或更大范围是可能出现的。但是，尽管存在试验误差、仪器误差和取向优先等，本领域技术人员还可以从本专利提供的XRD数据获取足够的鉴别晶型的信息。
本发明中，“具有约如图1所示的X-射线粉末衍射图”或“具有约如图2所示的X-射线粉末衍射图”，是指X-射线粉末衍射图示出的主要的峰如图1或图2所示，其中主要的峰是指与图1或图2中最高的峰(其相对强度指定为100％)相比，相对强度数值超过10％，优选超过30％的那些峰。
本发明中，晶型的制备方法中涉及的“加入甲醇/丙酮”等，是指在该制备方法中，先加入甲醇，再加入丙酮。类似地，“乙醇/水”是指先加入乙醇，再加入水；而“三氟乙醇/乙酸乙酯”，是指先加入三氟乙醇，再加入乙酸乙酯。同理，类似地如“溶剂1/溶剂2”是指先加入溶剂1，再加入溶剂2；而“溶剂2/溶剂1”是指先加入溶剂2，再加入溶剂1。
本发明中，术语“治疗有效量”是指一个化合物/晶型施用于治疗对象时对于治疗一种疾病、或一种疾病或病症的至少一种临床症状时，足以影响对疾病、病症或症状的这种治疗的量。“治疗有效量”可以随着化合物，疾病、病症和/或疾病或病症的症状，疾病、病症和/或疾病或病症的症状的严重程度，被治疗的患者的年龄，和/或被治疗的患者的体重等变化。在任意特定的情况下，一个合适的量对那些本领域的技术人员可以是显而易见的，也可以是用常规实验确定的。在联合治疗的情况下，“治疗有效量”是指有效治疗疾病、病症或病状的联用对象的总量。
本发明的药物组合物的所有剂型都可以通过药学领域的常规方法制备。例如，将活性成分与一种或多种辅料混合，然后制成所需的剂型。
“药学上可接受的载体”是指适合于期望药物制剂的常规的药用载体，例如：诸如水、各种有机溶剂等的稀释剂、赋形剂；诸如淀粉、蔗糖等的填充剂；诸如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮(PVP)的黏合剂；诸如甘油的湿润剂；诸如琼脂、碳酸钙和碳酸氢钠的崩解剂；诸如季铵化合物的吸收促进剂；诸如十六烷醇的表面活性剂；诸如高岭土和膨润土的吸收载体；诸如滑石粉、硬脂酸钙、硬脂酸镁和聚乙二醇等的润滑剂。另外还可以在药物组合物中加入其它药学上可接受的辅料，如分散剂、稳定剂、增稠剂、络合剂、缓冲剂、渗透促进剂、聚合物、芳香剂、甜味剂和染料。优选使用适合期望剂型和期望给药方式的辅料。
术语“疾病”、“病症”或“病状”是指任意的疾病、不适、病、症状或者适应症。
附图说明
图1：化合物II晶型A(小试样品，批号：1072P04-A14S01)的XRD图谱。
图2：化合物II晶型B的XRD图谱。
图3：化合物II晶型C的XRD图谱。
图4：化合物II无定形物的XRD图谱。
图5：化合物III晶型D的XRD图谱。
图6：化合物III晶型E的XRD图谱。
图7：化合物III晶型F的XRD图谱。
图8：化合物III晶型G的XRD图谱。
图9：化合物III无定形物的XRD图谱。
图10：化合物II晶型A(小试样品，批号：1072P04-A14S01)不同稳定性条件下的XRD对比图谱。由下往上，线条①至线条④分别代表的含义如下：
①化合物II晶型A在0天进行XRD测试所得XRD图谱；
②化合物II晶型A在温度为25℃，湿度为60％条件下放置10天后进行XRD测试所得XRD图谱；
③化合物II晶型A在温度为40℃，湿度为75％条件下放置10天后进行XRD测试所得XRD图谱；
④化合物II晶型A在温度为80℃，干燥条件下放置24小时后进行XRD测试所得XRD图谱。
图11：化合物II晶型A的DSC图谱。横坐标(X-轴)表示温度，单位：℃；纵坐标(Y-轴)表示热流，单位：瓦/克。
图12：化合物II晶型A(中试样品，批号：20170903)的XRD图谱。
以上附图1-附图10及附图12中，横坐标(X-轴)均表示衍射角2θ，单位为“°”；纵坐标(Y-轴)均表示衍射强度，单位为“计数”。
具体实施方式
下面通过给出的实施例对本发明作出进一步说明，但所述实施例并不对本发明要求保护的范围构成任何限制。在本发明的具体实施例中，除非特别说明，所述技术或方法为本领域的常规技术或方法等。
缩略语：
Cbz-Cl：氯甲酸苄酯；
DCM：二氯甲烷；
DMF：N，N-二甲基甲酰胺；
DMSO：二甲基亚砜；
DSC：差式扫描量热法；
DVS：动态蒸汽吸附；
EtOH：乙醇；
EtOAc：乙酸乙酯；
KOAc：醋酸钾；
KO-t-Bu：叔丁醇钾；
MeOH：甲醇；
P(Cy) 3：三环己基膦；
Pd(OAc) 2：乙酸钯；
Pd(dppf)Cl 2：[1，1′-双(二苯基膦基)二茂铁]二氯化钯；
RT：室温；
RH：相对湿度；
TGA：热解重量分析；
TEA：三乙醇胺；
THF：四氢呋喃；
Xantphos：4，5-双(二苯基膦)-9，9-二甲基氧杂蒽；
XRD：X-射线粉末衍射图。
实施例1化合物II晶型A的合成
Figure PCTCN2019092239-appb-000006
1-A1-01的合成(步骤一)
在50L反应釜中加入20L二氯甲烷(DCM)、1-A1-S1(300g)、三乙胺(390g)，搅拌状态下，降温至-5℃以下，滴加氯甲酸苄酯/Cbz-Cl(570g)，5小时滴加完毕，自然升至室温，TLC(乙酸乙酯∶正己烷＝1∶3)监控至反应结束。加入水(1.5L)，缓慢滴加浓盐酸(80mL)，控制pH为1-2，静置分液，有机相用15L水洗，无水硫酸钠干燥0.5小时后，过滤除去干燥剂，收集滤液并浓缩，得到730g淡黄色油状液体，即为1-A1-01粗品，收率95.4％
1-A1-02的合成(步骤二)
在20L反应瓶中加入720mL的DCM，N，N-二甲基亚砜(90g)，氮气保护，搅拌状态下，降温-65℃以下，滴加草酰氯(106g)，2小时滴加完毕，保温搅拌20分钟；滴加1-A1-01的二氯甲烷溶液(143g/500mL DCM)，40分钟滴加完毕，保温反应15分钟。控制在该温度下，滴加TEA，2小时滴加完毕后，自然升温至-20℃，体系加入250L水，用盐酸调节体系pH至1-2，静置、分液，有机相用水(1L×2)洗涤、无水硫酸钠干燥，过滤除去干燥剂，收集滤液并浓缩，得到432g黄色油状液体，即为产品1-A1-02的粗品，直接用于下一步反应。
1-A1-03的合成(步骤三)
搅拌状态下，依次将400mL四氢呋喃(THF)、叔丁醇钾(215g)加入1L反应釜中，降温至5-15℃，滴加磷酰基乙酸三乙酯(430g)，50分钟滴加完毕。控制温度在15℃下，滴加1-A1-02的四氢呋喃溶液(431g/100mL THF)，1小时滴加完毕，TLC(乙酸乙酯∶正己烷＝1∶3)监测至反应完全，体系加入饱和氯化钠水溶液(1.5L)，静置、分液，收集四氢呋喃相；水相再用二氯甲烷(2L)萃取，合并有机相后用无水硫酸钠干燥0.5小时，过滤除去干燥剂，收集滤液并浓缩，浓缩物经柱层析纯化后得390g淡黄色油状液体，即为1-A1-03产品。
1-A1-041的合成(步骤四)
在5L反应釜中，将氢氧化钠的水溶液(301g/1.5L水)加至1-A1-03的四氢呋喃(601g/2.3L THF)溶液中，加热回流，反应3-4小时，停止反应。温度降至40-50℃，静置分层，收集有机相(THF)后浓缩至出现大量固体；固体加入水(20L)溶解，水相依次用甲基叔丁基醚(2L)，乙酸乙酯(2L)，甲基叔丁基醚(2L)洗涤；水相用浓盐酸调pH至1-2，用乙酸乙酯(1.5L、3L)萃取两次，合并有机相，用无水硫酸钠干燥0.5小时；过滤除去干燥剂，收集滤液并浓缩至出现大量固体，固体加入异丙醚(3L)打浆2 小时，过滤，收集固体，固体用异丙醚(1L)淋洗。固体在50℃下鼓风干燥3-4小时，得331g浅黄色固体，即为1-A1-041产品，收率52.7％。
1-051的合成(步骤五)
搅拌状态下，依次将1-A1-041(600g)、甲醇(25L)、浓硫酸加入50L反应釜中，加热回流反应3-4小时，反应完毕，降至室温；体系浓缩至无溶剂旋出，浓缩物加二氯甲烷(15L)，用碳酸钾水溶液调节pH＝9-10，搅拌、静置、分液，收集有机相，并用无水硫酸钠干燥0.5小时，过滤除去干燥剂，收集滤液并浓缩，得6.37kg类白色固体，即为1-A1-051产品，收率97.3％。
1-A1的合成(步骤六)
在2L加氢釜中，分别加入1-A1-051(500g)、甲醇(1.8L)、钯碳，体系依次置换3次氮气和3次氢气；体系保持氢气氛围，升温至85℃、压力3.0Mpa下反应3小时，反应完毕。降至室温，过滤除去钯碳，收集有机相，并浓缩至有大量浅黄色固体出现，加入异丙醚(3L)冷冻(-20℃)析晶1小时，过滤收集固体产物，固体用异丙醚(500mL)淋洗，得到234g浅黄色固体，即为1-A1产品，收率90.5％。
1-A2的合成(步骤七)
搅拌状态下，依次将1-A1(200g)、4-溴-2，6-二氟苯胺(410g)、甲苯(1.2L)加入50L反应釜中，体系滴加三氯氧磷(413g)，1小时滴加完毕。冰浴下，滴加三乙胺，1小时滴加完毕。升温至110℃，反应1小时。将体系降温至2-10℃，加入1L水，并用饱和碳酸钾水溶液调pH＝9-10，用乙酸乙酯(1.5L、1L)萃取两次，合并有机相后用2L饱和氯化钠水溶液洗涤，无水硫酸钠干燥0.5小时，过滤除去干燥剂，收集滤液并浓缩至出现固体产物，固体加入异丙醚(1L)打浆10分钟，过滤，收集黄色固体460g，为1-A2产品。
1-A3的合成(步骤八)
搅拌状态下，依次将1-A2(450g)、N，N-二甲基甲酰胺(2L)、碳酸铯(700g)加入反应釜中，加热至110℃保温反应24小时，TLC检测至反应完全，体系加入乙酸乙酯(3L)，过滤除去固体杂质，滤液用饱和氯化钠水溶液(1L×5)洗涤，有机相用无水硫酸钠干燥0.5小时，浓缩至出现大量固体，用甲基叔丁基醚(1L×2)打浆30分钟，过滤得到淡黄色固体产物382g，即为1-A3，收率90.10％。
1-01的合成(步骤九)
搅拌状态下，依次将1-A3(380g)、联硼酸频那醇酯(400g)、醋酸钾(340g)、醋酸钯(6g)、三环己基磷(7g)、1，4-二氧六环加入到反应釜中，氮气保护，升温至90℃反应2小时。TLC监控至反应完全。降至室温，过滤，滤液浓缩至除去大量1，4-二氧六环，浓缩物经正己烷和二氯甲烷柱层析纯化、正己烷(1.2L)打浆1小时，得334g的灰色固体，即为1-01，收率70.10％。
1-02的合成(步骤十)
搅拌状态下，取1-01(128g)、1，4-二氧六环(1L)、1-S3(85g)、碳酸钾(110g)、纯化水依次加入到2L三口瓶中，氮气保护，加入[1，1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(Pd(dppf)Cl 2.DCM)。加热升温至60℃。反应4小时后，反应完全。将反应液冷却至室温，减压浓缩至除去大部分1，4-二氧六环，加入二氯甲烷(1.5L)和纯化水(1.1L)，搅拌，静置分层，分液，水相用二氯甲烷(10L)萃取，合并有机相，用0.5％的稀盐酸洗涤(1L×2)，饱和氯化钠水溶液(1L)洗涤，分液。有机相用无水硫酸钠(500g)干燥，过滤除去干燥剂，滤液减压浓缩。浓缩物加入乙酸乙酯(0.5L)搅拌30分钟析出固体，过滤后，所得固体用乙酸乙酯(0.5L)淋洗，45℃真空干燥3小时，得黄色固体120g。
1-03的合成(步骤十一)
搅拌状态下，取1-02(100g)、1，4-二氧六环(1L)、1-C2(80g)、碳酸铯(163g)依次加入2L三口瓶中，氮气保护，加入醋酸钯(2g)和4，5-双二苯基膦-9，9-二甲基氧杂蒽(Xantphos)(4g)，加热至85℃，直到反应完全。将反应液冷却至室温，过滤得固体产物，固体用乙酸乙酯淋洗后，加入至二氯甲烷(1.5L)和纯化水(1.1L)的混合体系中，搅拌，静置，分层。水相用二氯甲烷(700mL)萃取。合并有机相，用纯化水(700mL×2)洗涤。有机相加入无水硫酸钠(700g)干燥，过滤除去干燥剂，滤液浓缩，加入甲醇(0.5L)，加热至55～65℃搅拌0.5小时，降至室温，过滤。过滤得固体产物，用乙酸乙酯500mL淋洗。固体在45℃真空下干燥8小时，得淡黄色固体1-03共111.79g。
化合物II的合成(步骤十二)
搅拌状态下，取1-03(500g)、无水甲醇(3.8L)，依次加入到10L反应釜中，加热至65℃，待反应体系澄清0.5小时后滴加L-酒石酸的甲醇溶液(150.89g酒石酸溶于500mL无水甲醇)，控制滴加时间在45至60分钟，滴加完毕，65℃保温反应4小时，继续滴加L-酒石酸的甲醇溶液(35.58g酒石酸溶于250mL无水甲醇)，控制滴加时间在30至45分钟，滴加完毕，65℃保温反应1小时，继续滴加L-酒石酸的甲醇溶液(36.55g 酒石酸溶于250mL无水甲醇)，控制滴加时间在30至45分钟，滴加完毕，65℃保温反应1.5小时，停止加热，自然降温至20-30℃，过滤，滤饼用甲醇(400mL×2)淋洗，45℃真空干燥36小时，得淡黄色结晶性粉末530.64g，即为化合物II，通过X射线粉末衍射进行鉴定，显示该晶型为化合物II的晶型A。
实施例2 XRD分析结果
按实施例1的合成方法分别制备得到化合物II的小试样品(批号：1072P04-A14S01)和化合物II的中试样品(批号：20170903)，然后采用XRD对其分别进行表征。
本发明的一个具体方案中，小试样品(批号：1072P04-A14S01)由杭州领业医药科技有限公司使用Bruker D8 Advance Diffractometer进行了XRD分析，使用的仪器和检测参数见表1，XRD谱图解析数据见表2。
表1 小试样品XRD分析仪器和检测方法参数
Figure PCTCN2019092239-appb-000007
表2 小试样品XRD谱图解析数据
峰# 2θ(°) 强度(I％)
1 4.4 100.0
2 8.8 19.3
3 10.9 24.3
4 16.0 25.1
5 18.5 25.4
6 23.7 32.0
7 27.0 44.5
在另一具体实施方案中，中试样品(批号：20170903)由北京市理化分析测试中心使用D8-Advance型X射线衍射仪进行了XRD分析，参考的方法为JY/T 009-1996《转靶多晶体X射线衍射方法通则》。使用的仪器和检测参数见表3，XRD谱图解析数据见表4。
表3 中试样品XRD分析仪器和检测方法参数
Figure PCTCN2019092239-appb-000008
Figure PCTCN2019092239-appb-000009
表4 中试样品XRD谱图解析数据
峰# 2θ(°) 强度(I％)
1 4.4 100.0
2 8.7 20.9
3 10.8 19.8
4 15.9 14.0
5 18.4 17.5
6 23.6 22.6
7 26.9 34.6
本领域技术人员可以理解，XRD谱图的获取过程中，为减少误差可以将相关数据经过适当科学处理，如基线校正处理等。本领域技术人员也可以理解，在不同实验室条件下操作，所得XRD谱图的2θ角或分离度等会存在少许差异。应当理解，本发明提供的化合物II晶型A的XRD谱图不限于图1或图12所示的X射线粉末衍射图谱，与图1或图12所示基本相同的X射线粉末衍射图的晶体都落在本发明的范围内。
实施例3 晶型稳定性的测定
本发明的X-射线粉末衍射图谱检测设备和方法如表1所示。将化合物II晶型A、化合物III晶型D和化合物III晶型F样品在80℃干燥放置24小时、25℃，60％RH放置10天、40℃，75％RH放置10天，检测XRD谱图见图10，结果见表5。
表5 化合物II不同晶型稳定性测试结果
化合物晶型 80℃干燥放置24h 25℃，60％RH放置10天 40℃，75％RH放置10天
化合物II晶型A XRD不变 XRD不变 XRD不变
化合物III晶型D XRD不变 XRD改变 XRD改变
化合物III晶型F XRD改变 XRD改变 XRD改变
化合物II晶型A在不同稳定性条件下的XRD对比如附图10所示，由图可见，化合物II晶型A样品在80℃干燥放置24小时、25℃，60％RH放置10天、40℃，75％RH放置10天，晶型均不变，化合物II晶型A稳定性良好。
此外，化合物II晶型B为亚稳晶型，晶态较差且升温至180℃会转晶为晶型A。
实施例4 晶型长期稳定性测定
将化合物I和化合物II晶型A样品分别在温度25℃±2℃，相对湿度60％±10％条件下放置18个月，并分别于0个月、3个月和18个月时取样进行HPLC测定，检测结果见表6。
表6 化合物I和化合物II晶型A在0月、3月和18月的HPLC检测结果
Figure PCTCN2019092239-appb-000010
由表6数据可知，在18个月后化合物I的最大单杂含量和总杂含量均为化合物II晶型A的3倍以上，化合物II晶型A在放置18个月后未产生含量大于0.1％的杂质，而化合物I产生4个含量大于0.1％的杂质。相较于化合物I，化合物II晶型A的稳定性具有显著提升。
实施例5 动态水分吸附(DVS)测定
本发明的动态水分吸附仪检测设备和方法如表7所示，动态水分吸附测定结果如表8所示。
表7 动态水分吸附仪检测设备和方法数据
Figure PCTCN2019092239-appb-000011
表8 动态水分吸附测定结果
化合物晶型 0％RH至80％RH范围内重量变化
化合物II晶型A 5.3％
化合物II晶型B 5.5％
化合物III晶型D 17.2％
化合物III晶型F 16.6％
化合物II晶型A和晶型B：0％RH至80％RH范围内重量变化约为5.3％和5.5％，而化合物III晶型D和晶型F：0％RH至80％RH范围内重量变化约为17.2％和16.6％。由此 可见，相比化合物III晶型而言，化合物II晶型的吸湿性较弱，更加适合于固体制剂的制备。
实施例6 溶解度测定
对化合物II晶型A、化合物III晶型D和化合物I进行了溶解度测试，室温时在水中溶解度结果见表9。由此可见，化合物II不同晶型对其溶解性改善程度不同，化合物II晶型A表现出优异的溶解性能。
表9 化合物II不同晶型溶解度测定结果
化合物晶型 室温时在水中的溶解度 溶解度分类
化合物II晶型A 100-200mg/mL 易溶
化合物III晶型D 50-100mg/mL 溶解
化合物I ＜1mg/mL 极微溶
注：溶解度分类标准遵循《2015年版中国药典》四部凡例中相关规定。
实施例7 药代动力学测试
SD大鼠12只，分为两组，每组6只，雌雄各半，分别单次灌胃30mg/kg给药化合物II晶型A和化合物I；分别在指定的时间点通过眼底静脉丛采血，分离血浆，放入-80℃冰箱保存。
上述血浆样品，乙腈沉淀蛋白，取上清用水稀释3倍，取5μL至LC-MS/MS检测，试验数据如表10所示：
表10 药代动力学测试结果
化合物 给药方式 剂量(mg/kg) AUC last(h*ng/mL)
化合物I PO 30 27670
化合物II的晶型A PO 30 47032
由以上结果提示，相较于化合物I，化合物II的晶型A在体内吸收更好。
实施例8 化合物I的CDK4/6抑制活性测定
为了证明化合物对CDK激酶(CDK4/CycD3，CDK6/cycD3)表现出亲和力，进行CDK激酶的测定。
反应缓冲液制备如下：CDK6的激酶碱缓冲液(50mM HEPES，pH7.5；0.0015％Brij-35；10mM MgCl 2；2mM DTT)；CDK4的激酶碱基缓冲液(20mM HEPES，pH7.5；0.01％Triton X-100；10mM MgCl 2；2mM DTT)；停止缓冲液(100mM HEPES，pH7.5；0.015％Brij-35；0.2％涂层试剂#3；50mM EDTA)
酶反应方案：
1)采用100％DMSO将化合物稀释到反应最终所需的最高浓度的50倍。将100μL 该化合物的稀释液转移至96孔板的孔中。然后，在下一个孔中，按30μL的上述稀释液用60μL的100％DMSO稀释的比例依次稀释化合物共10个浓度。在相同的96孔板上，将100μL 100％DMSO溶液加入到两个空孔中，作为无化合物对照和无酶对照。这张板记为源板。
2)分别将10μL各浓度化合物从源板中转移到包含90μL激酶缓冲液的新的96孔板中以制备中间板。
3)从96孔板的中间板中对应孔转移5μL化合物溶液到对应的384孔板中。
4)将10μL 2.5×酶溶液加入到384孔实验板的每个孔中。
5)室温孵育10分钟。
6)加入10μl 2.5×底物溶液，该底物溶液通过在激酶基缓冲液中加入荧光素标记肽和ATP制备。酶和底物的反应浓度如下表所示(表11)：
表11 酶和底物的反应浓度
酶 酶(nM) ATP(μM) 肽 肽浓度(μM)
CDK4 10 280 P8 3
CDK6 15 800 P8 3
7)在28℃孵育特定的时间
8)加入25μL终止缓冲液终止反应。
9)收集Caliper上的数据。然后将转换值转换为抑制值。
抑制率＝(最大值-转换值)/(最大值-最小值)*100
“最大值”为DMSO对照值；“最小值”为无激酶对照孔值。
10)使用XLFit优化版本4.3.1中的百分比抑制曲线拟合来获得IC 50值。方程是：Y＝底+(高-底)/(1+(IC 50/X)^斜率)。
结果用IC 50值表示，如表12所示。
表12 CDK4/6抑制活性测定结果
样品 IC 50(CDK4)/nM IC 50(CDK6)/nM
LY2835219 2 22
化合物I 1.9 22
实施例9 在分子水平对CDK激酶其他亚型的抑制活性以及选择性试验
以化合物I为受试化合物，并与阳性对照药LY2835219(Abemaciclib)比较两者在分子水平对CDK激酶的抑制活性以及选择特异性的高低。
本方法的作用机制如式(IV)所示，激酶催化蛋白质底物磷酸化，使反应体系中放射性同位素 33P标记的ATP(γ- 33P-ATP)上的 33P标记到蛋白质底物上，将反应体系点在P81 离子交换滤膜上，用0.75％磷酸缓冲液充分洗涤滤膜，则有放射活性的磷酸化底物留在滤膜上，通过记录底物蛋白质放射性标记的强度反映激酶的活性。
Figure PCTCN2019092239-appb-000012
用Prism4 Software(GraphPad)处理数据，曲线拟合公式为：
Y＝最小抑制率+(最大抑制率-最小抑制率)/(1+10^((LogIC 50-X)*斜率))；其中，Y表示抑制百分数(％)；X表示待测化合物浓度的对数。
结果：通过对多种CDK激酶的筛选，发现化合物I抑制CDK1/2/7/9的IC 50大于0.4μM，是CDK4/6的几十甚至上千倍(见表13)。
表13 CDK激酶抑制活性
Figure PCTCN2019092239-appb-000013
结论：在分子水平上，本发明化合物I对CDK4/6表现出很强的抑制作用，对CDK1/2/7/9抑制作用极弱，表明化合物I是一个具有极优选择性的CDK4/6激酶抑制剂。此外，化合物I在CDK1/2/9和CDK4/6之间的选择性均明显高于LY2835219(Abemaciclib)。
实施例10 JeKo-1异种移植瘤动物模型的肿瘤抑制实验
JeKo-1细胞培养在含20％胎牛血清的RPMI 1640培养液中。收集指数生长期的JeKo-1细胞，PBS重悬至适合浓度用于NOD/SCID小鼠皮下肿瘤接种。70只雌性小鼠右侧皮下接种5×106个JeKo-1细胞，细胞重悬在PBS和matrigel(1∶1)中。待肿瘤平均体积134mm3时，根据肿瘤大小随机分组开始给药。其中48只分入实验组内，其余22只为分组剩余小鼠。肿瘤体积计算公式为：长径×短径2/2。实验分为溶剂对照组、测试药代表性化合物I(10mg/kg)、测试药代表性化合物I(25mg/kg)、测试药代表性化合物I(50mg/kg)、测试药代表性化合物I(100mg/kg)，共6组，每组8只小鼠，均为口服灌胃给药，分组后每天给药一次，连续给药19天。根据相对肿瘤增长抑制率TGI进行疗效评价，结果见表14。
计算公式如下：TGI(％)＝(C-T)/C×100％(C和T分别为溶剂对照组平均肿瘤重量和治疗组平均肿瘤重量)。TGI(％)值越大，说明药效越好；反之亦然。
结果：化合物I显示出良好的抗肿瘤活性。
表14 代表性化合物I对JeKo-1异种移植瘤模型的抑瘤药效评价
组别 剂量(mg/kg) 相对肿瘤增长抑制率TGI(％) p值 a
溶剂对照组 -- -- --
化合物I 10 42.7 0.087
化合物I 25 73.8 0.003
化合物I 50 98.3 0.001
化合物I 100 104.5 0.001
注：a：p值为治疗组与溶剂对照组肿瘤体积的比较分析。

Claims (28)

  1. 一种结构式I所示化合物的盐型或所述盐型的晶型：
    Figure PCTCN2019092239-appb-100001
  2. 权利要求1所述的盐型或所述盐型的晶型，其特征在于，所述盐型为酒石酸盐，并且所述酒石酸盐为L-酒石酸盐。
  3. 权利要求2所述的盐型或所述盐型的晶型，其特征在于，所述酒石酸盐具有如结构式II所示结构：
    Figure PCTCN2019092239-appb-100002
  4. 一种结构式II所示化合物的晶型。
  5. 权利要求4所述的晶型，其特征在于，所述晶型的X射线粉末衍射谱图具有衍射角2θ为4.4±0.2°、23.6±0.2°和26.9±0.2°的特征峰。
  6. 权利要求5所述的晶型，其特征在于，所述晶型的X射线粉末衍射谱图具有衍射角2θ为4.4±0.2°、8.7±0.2°、10.8±0.2°、18.4±0.2°、23.6±0.2°和26.9±0.2°的特征峰。
  7. 权利要求6所述的晶型，其特征在于，所述晶型的X射线粉末衍射谱图具有衍射角2θ为4.4±0.2°、8.7±0.2°、10.8±0.2°、15.9±0.2°、18.4±0.2°、23.6±0.2°和26.9±0.2°的特征峰。
  8. 权利要求4所述的晶型，其特征在于，所述晶型具有约如图1所示的X-射线粉末衍射图。
  9. 权利要求4所述的晶型，其特征在于，所述晶型具有约如图12所示的X-射线粉末衍射图。
  10. 权利要求4所述的晶型，其特征在于，所述晶型通过如下方法制备得到：
    1)将(R)-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-氟-1-甲基-1，2，3，4-四氢苯并[4，5]咪唑并[1，2-a]吡啶-8-基)嘧啶-2-胺(化合物I)混悬于水和/或水溶性有机溶剂中，得到混悬物；
    2)将上述混悬物加热至50℃以上；
    3)在保持50℃以上的温度条件下，在上述混悬物中加入L-酒石酸，进行酸化处理，得到澄清溶液；
    4)降至室温后，搅拌过滤，滤饼经干燥后得到权利要求4所述的晶型。
  11. 权利要求4-10任一项所述的晶型，其特征在于，所述晶型通过如下方法制备得到：
    50-70℃条件下将化合物I在甲醇中形成清液，将L-酒石酸溶解在甲醇中，将L-酒石酸的甲醇溶液滴加至化合物I的甲醇溶液中，搅拌后过滤，滤饼置于40-70℃干燥，即得到权利要求4-10任一项所述的晶型。
  12. 一种结构式I所示化合物的L-酒石酸盐的晶型，其特征在于，所述晶型具有约如图3所示的X-射线粉末衍射图。
  13. 一种结构式III所示化合物或其晶型：
    Figure PCTCN2019092239-appb-100003
  14. 权利要求13所述的晶型，其特征在于，所述晶型通过如下方法制备得到：
    1)将(R)-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-氟-1-甲基-1，2，3，4-四氢苯并[4，5]咪唑并[1，2-a]吡啶-8-基)嘧啶-2-胺(化合物I)混悬于水和/或水溶性有机溶剂中，得到混悬物；
    2)将上述混悬物加热至50℃以上；
    3)在保持50℃以上的温度条件下，在上述混悬物中加入甲磺酸，进行酸化处理，得到澄清溶液；
    4)降至室温后，搅拌过滤，滤饼经干燥后得到权利要求13所述的晶型。
  15. 权利要求13所述的晶型，其特征在于，所述晶型具有约如图5所示的X-射线粉末衍射图。
  16. 权利要求13所述的晶型，其特征在于，所述晶型具有约如图6所示的X-射线粉末衍射图。
  17. 权利要求13所述的晶型，其特征在于，所述晶型具有约如图7所示的X-射线粉末衍射图。
  18. 权利要求13所述的晶型，其特征在于，所述晶型具有约如图8所示的X-射线粉末衍射图。
  19. 一种(R)-N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-氟-1-甲基-1，2，3，4-四氢苯并[4，5]咪唑并[1，2-a]吡啶-8-基)嘧啶-2-胺的L-酒石酸盐(化合物II)的制备方法，其特征在于，包括如下步骤：
    Figure PCTCN2019092239-appb-100004
  20. 一种药物组合物，其特征在于：含有治疗有效量的权利要求4-12任一项所述的晶型，和药学上可接受的辅料、辅助剂和/或载体。
  21. 一种药物组合物，其特征在于：含有治疗有效量的权利要求13-18任一项所述的化合物和/或其晶型，和药学上可接受的辅料、辅助剂和/或载体。
  22. 权利要求1-18任一项所述的盐型和/或晶型或权利要求20-21任一项所述的药物组合物在制备治疗患者的疾病、病症或病状的药物中的用途，其中所述疾病、病症或病状由CDK介导，如CDK4和/或CDK6介导。
  23. 权利要求22所述的用途，其中所述疾病、病症或病状是癌症和/或增殖性疾病。
  24. 权利要求22或23所述的用途，其中所述疾病、病症或病状是乳腺癌、肺癌、黑色素瘤、结肠癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、淋巴瘤、成神经细胞瘤、肝细胞癌、乳头状肾细胞癌和/或头颈部鳞状细胞癌。
  25. 一种治疗由CDK介导，如CDK4和/或CDK6介导的疾病的方法，其特征在于，向治疗对象施用包括权利要求1-18任一项所述的盐型和/或晶型或权利要求20-21任一项所述的药物组合物。
  26. 权利要求25所述的方法，其中所述疾病是癌症和/或增殖性疾病。
  27. 权利要求25或26所述的方法，其特征在于：所述疾病是乳腺癌、肺癌、黑色素瘤、结肠癌、肝癌、胰腺癌、脑癌、肾癌、卵巢癌、胃癌、皮肤癌、骨癌、神经胶质瘤、淋巴瘤、成神经细胞瘤、肝细胞癌、乳头状肾细胞癌和/或头颈部鳞状细胞癌。
  28. 根据权利要求25-27所述的方法，其特征在于，所述治疗对象为人类。
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