WO2017152707A1 - 吡啶胺基嘧啶衍生物甲磺酸盐的结晶形式及其制备和应用 - Google Patents

吡啶胺基嘧啶衍生物甲磺酸盐的结晶形式及其制备和应用 Download PDF

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WO2017152707A1
WO2017152707A1 PCT/CN2017/000203 CN2017000203W WO2017152707A1 WO 2017152707 A1 WO2017152707 A1 WO 2017152707A1 CN 2017000203 W CN2017000203 W CN 2017000203W WO 2017152707 A1 WO2017152707 A1 WO 2017152707A1
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solvent
crystalline form
formula
methyl
compound
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PCT/CN2017/000203
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English (en)
French (fr)
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罗会兵
张强
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上海艾力斯医药科技有限公司
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Priority to EP17762393.1A priority Critical patent/EP3428159B1/en
Priority to JP2018547272A priority patent/JP6894917B2/ja
Priority to US16/083,210 priority patent/US10550101B2/en
Priority to ES17762393T priority patent/ES2863923T3/es
Priority to CA3016830A priority patent/CA3016830C/en
Priority to KR1020187028799A priority patent/KR102142797B1/ko
Priority to PL17762393T priority patent/PL3428159T3/pl
Publication of WO2017152707A1 publication Critical patent/WO2017152707A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—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
    • 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
    • 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
    • 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 crystalline form of a pyridylaminopyrimidine derivative mesylate salt, and in particular, the present invention relates to N- ⁇ 2- ⁇ [2-(dimethylamino)ethyl](methyl)amino ⁇ - 6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino ⁇ pyridine-3- a crystalline form of the acrylamide methanesulfonate, a process for the preparation thereof, a pharmaceutical composition comprising the crystalline form, and a morphological form of the bacterium, particularly a human mediated by an EGFR-activated or drug-resistant mutant, It is an application in cancer.
  • Epidermal growth factor receptor has been identified as a critical driver of cell growth and proliferation.
  • the epidermal growth factor receptor family consists of EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4.
  • Epidermal growth factor receptors are involved in disease progression in most cancers, such as lung cancer, colon cancer, breast cancer, and the like. Overexpression and mutation of EGFR have been clearly identified as major risk factors for breast cancer with poor prognosis.
  • Patent application CN201410365911.4 discloses a structural compound of the formula (I) which is significantly more inhibitory against EGFR-activated mutations (such as exon 19 deletion activating mutation, or L858R activating mutation) and T790M resistance mutations than in wild
  • the inhibitory activity of EGFR (WT EGFR) is very selective, with low toxic side effects and good safety.
  • the crystal form has a certain influence on the physical properties of the compound.
  • a medicinal compound having various crystal forms due to its different lattice structure, in addition to possibly having different appearances such as color and shape, it may also cause certain physical properties such as Melting point, solubility, density, stability, hygroscopicity, etc., which lead to different dissolution and absorption behaviors in the body, to a certain extent affect the clinical efficacy and safety of pharmaceutical compounds.
  • a particular crystal form can produce a thermodynamic line that is different from an amorphous material or another crystal form.
  • Measuring a thermal property in a laboratory using a technique such as melting point, thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC) can distinguish a particular crystal form from an amorphous or another crystal form.
  • specific crystal forms can produce specific spectral properties, such as powder X-ray diffraction pattern data and infrared spectral data can be used to characterize a particular crystal form.
  • the technical problem to be solved by the present invention is to provide a crystalline form of the mesylate salt of the compound of the formula (I), a process for the preparation thereof, a pharmaceutical composition comprising the crystalline form and the crystalline form in the treatment of a mammal, especially a human, by EGFR-activated or resistant Drug-type mutant-mediated diseases, particularly in cancer.
  • the present invention provides N- ⁇ 2- ⁇ [2-(dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy) of the formula (I).
  • the crystal form I of the present invention has a powder X-ray diffraction pattern with diffraction angles 2 ⁇ of 4.58° ⁇ 0.2°, 14.08° ⁇ 0.2°, 15.00° ⁇ 0.2°, 16.40° ⁇ 0.2°, 17.84° ⁇ 0.2°, 18.30. Characteristic peaks are found at ° ⁇ 0.2°, 20.26° ⁇ 0.2°, 21.10° ⁇ 0.2°, 21.88° ⁇ 0.2°, 22.66° ⁇ 0.2°, 25.58° ⁇ 0.2°, 26.78° ⁇ 0.2°.
  • the crystal form I provided by the present invention has an X-ray powder diffraction pattern (XRPD) as shown in FIG.
  • the crystalline form I provided by the present invention begins to have an endothermic peak upon heating to 212.6 ° C, and its differential scanning thermal analysis spectrum (DSC) is shown in FIG.
  • the crystal form I provided by the present invention has a weight loss of about 1% when heated to 230 ° C, and its thermogravimetric analysis chart (TGA) is shown in FIG. 5 .
  • the present invention provides a process for the preparation of the crystalline form I of the mesylate salt of the compound (I), comprising:
  • the first solvent is water, a ketone, a cyclic ether or a nitrile solvent or a mixed solvent thereof; and the second solvent is water, a ketone, a cyclic ether or a nitrile solvent or a mixed solvent thereof.
  • the first solvent is a mixed solvent of water and a ketone, a cyclic ether or a nitrile solvent; the second solvent is a ketone, a cyclic ether or a nitrile solvent, or a water and a ketone, a cyclic ether or a nitrile solvent.
  • Mixed solvent is water, a ketone, a cyclic ether or a mixed solvent.
  • the ketone solvent includes, but is not limited to, acetone
  • the cyclic ether solvent includes, but is not limited to, tetrahydrofuran or 1,4-dioxane
  • the nitrile solvent includes, but not limited to, acetonitrile
  • the mixed solvent of the ketone, cyclic ether or nitrile solvent and water wherein the volume ratio of the ketone, cyclic ether or nitrile solvent to water is 10:1 to 25:1, further ketone, cyclic ether Or the volume ratio of the nitrile solvent to water is from 15:1 to 19:1.
  • the temperature is raised to 35 to 55 ° C in the step b).
  • the present invention provides a process for the preparation of the crystalline form I of the mesylate salt of the compound (I), comprising:
  • the first solvent is water, a ketone, a cyclic ether or a nitrile solvent or a mixed solvent thereof; and the second solvent is water, a ketone, a cyclic ether or a nitrile solvent or a mixed solvent thereof.
  • the first solvent is a mixed solvent of water and a ketone, a cyclic ether or a nitrile solvent; the second solvent is a ketone, a cyclic ether or a nitrile solvent, or a water and a ketone, a cyclic ether or a nitrile solvent.
  • Mixed solvent is water, a ketone, a cyclic ether or a mixed solvent.
  • the ketone solvent includes, but is not limited to, acetone
  • the cyclic ether solvent includes, but is not limited to, tetrahydrofuran or 1,4-dioxane
  • the nitrile solvent includes, but not limited to, acetonitrile
  • the mixed solvent of the ketone, cyclic ether or nitrile solvent and water wherein the volume ratio of the ketone, cyclic ether or nitrile solvent to water is 10:1 to 25:1, further ketone, cyclic ether Or the volume ratio of the nitrile solvent to water is from 15:1 to 19:1.
  • the temperature is raised to 35 to 55 ° C in the step b).
  • the third solvent is a C 6-7 alkane, ether or ester solvent.
  • the C 6-7 alkane solvent includes, but is not limited to, n-heptane;
  • the ether solvent includes, but is not limited to, methyl tert-butyl ether;
  • the ester solvent includes, but is not limited to, methyl formate, ethyl acetate, acetic acid. Isopropyl ester, propyl acetate or butyl acetate.
  • the present invention provides N- ⁇ 2- ⁇ [2-(dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy) of the formula (I).
  • the crystal form II of the present invention provides a powder X-ray diffraction pattern with diffraction angles 2 ⁇ of 6.94° ⁇ 0.2°, 11.24° ⁇ 0.2°, 11.94° ⁇ 0.2°, 14.72° ⁇ 0.2°, 18.74° ⁇ 0.2°, 19.38. Characteristic peaks are found at ° ⁇ 0.2°, 20.22° ⁇ 0.2°, 22.10° ⁇ 0.2°, 22.92° ⁇ 0.2°, 24.48° ⁇ 0.2°, 25.14° ⁇ 0.2°, 26.42° ⁇ 0.2°.
  • the crystal form II provided by the present invention has an X-ray powder diffraction pattern (XRPD) as shown in FIG. 2 .
  • XRPD X-ray powder diffraction pattern
  • the crystalline form II provided by the present invention starts to have an endothermic peak upon heating to 206.8 ° C, and its differential scanning thermal analysis spectrum (DSC) is shown in FIG. 4 .
  • DSC differential scanning thermal analysis spectrum
  • the crystal form II provided by the present invention has a weight loss of about 0.95% when heated to 220 ° C, and its thermogravimetric analysis chart (TGA) is shown in FIG. 6 .
  • the invention provides a preparation method of the crystal form II of the mesylate salt of the compound (II), which comprises dissolving the crystal form I of the methanesulfonate salt of the compound of the formula (I) in an alcohol solvent under heating, and cooling the solution. Crystallization gave crystal form II.
  • the alcohol solvent includes, but is not limited to, methanol or ethanol.
  • the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1.
  • the present invention provides a pharmaceutical composition comprising crystalline Form I of the methanesulfonate salt of the compound of formula (I).
  • the present invention provides a pharmaceutical composition comprising crystalline Form II of the methanesulfonate salt of the compound of formula (I).
  • the present invention provides a pharmaceutical composition comprising a mixture of crystalline Form I and crystalline Form II of the mesylate salt of the compound of formula (I).
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Form I of the methanesulfonate salt of the compound of formula (I), and a pharmaceutically acceptable carrier, excipient or diluent.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline Form II of the mesylate salt of the compound of formula (I), and a pharmaceutically acceptable carrier, excipient or diluent.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a knot of a mesylate salt of a compound of formula (I) A mixture of crystalline Form I and crystalline Form II, together with a pharmaceutically acceptable carrier, excipient or diluent.
  • the invention also provides the use of a pharmaceutical composition comprising a crystalline form I or crystalline form II or crystalline form I and crystalline form II of a compound of formula (I), wherein the compound of formula (I) is mesylate mixture.
  • the present invention provides crystalline Form I of the mesylate salt of the compound of formula (I) for use as an antitumor drug.
  • the present invention provides a crystalline form II of the mesylate salt of the compound of formula (I) for use as an antitumor drug.
  • the present invention provides a mixture of crystalline Form I and crystalline Form II of the mesylate salt of the compound of formula (I) for use as an antitumor drug.
  • the invention also provides the use of crystalline Form I of the mesylate salt of the compound of formula (I) for the manufacture of a medicament for the treatment of cancer.
  • the invention further provides the use of crystalline Form I of the mesylate salt of the compound of formula (I) for the manufacture of a medicament for the treatment of a disease, in particular a cancer, mediated by an EGFR-activated or drug-resistant mutant in a mammal, in particular a human.
  • the invention also provides the use of crystalline Form II of the mesylate salt of the compound of formula (I) for the manufacture of a medicament for the treatment of cancer.
  • the invention further provides the use of crystalline Form II of the mesylate salt of the compound of formula (I) for the manufacture of a medicament for the treatment of a disease, in particular a cancer, mediated by an EGFR-activated or drug-resistant mutant in a mammal, in particular a human.
  • the invention further provides the use of a mixture of crystalline Form I and crystalline Form II of the mesylate salt of the compound of formula (I) for the manufacture of a medicament for the treatment of cancer.
  • the present invention also provides a mixture of crystalline form I and crystalline form II of the mesylate salt of the compound of formula (I) for the preparation of a medicament for the treatment of diseases, particularly cancer, mediated by EGFR-activated or drug-resistant mutants in mammals, especially humans. Use in.
  • the invention further provides the use of crystalline Form I of the mesylate salt of the compound of formula (I) for the treatment of diseases, in particular cancer, mediated by EGFR-activated or drug-resistant mutants in mammals, especially humans.
  • the invention further provides the use of the crystalline form II of the mesylate salt of the compound of formula (I) for the treatment of diseases, in particular cancer, mediated by EGFR-activated or drug-resistant mutants in mammals, especially humans.
  • the invention further provides a mixture of crystalline form I and crystalline form II of a mesylate salt of a compound of formula (I) for use in the treatment of diseases, particularly cancer, mediated by EGFR-activated or drug-resistant mutants in mammals, especially humans. .
  • the invention also provides a method of treating a disease, in particular a cancer, mediated by an EGFR-activated or drug-resistant mutant in a mammal, in particular a human, comprising administering to the patient a crystal of the mesylate salt of the compound of formula (I) Form I, or a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form I of the compound of formula (I) mesylate and a pharmaceutically acceptable carrier, excipient or diluent.
  • the invention also provides a method of treating a disease, in particular a cancer, mediated by an EGFR-activated or drug-resistant mutant in a mammal, in particular a human, comprising administering to the patient a crystal of the mesylate salt of the compound of formula (I) Form II, or a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form II of the mesylate salt of a compound of formula (I) and a pharmaceutically acceptable carrier, excipient or diluent.
  • the invention also provides a method of treating a disease, in particular a cancer, mediated by an EGFR-activated or drug-resistant mutant in a mammal, in particular a human, comprising administering to the patient a crystal of the mesylate salt of the compound of formula (I) Mixture of Form I and Crystalline Form II, or a pharmaceutical composition comprising a mixture of crystalline Form I and crystalline Form II of a therapeutically effective amount of a mesylate salt of a compound of Formula (I) and a pharmaceutically acceptable carrier, excipient or diluent .
  • the cancers mentioned in the present invention include, but are not limited to, for example, lung cancer, ovarian cancer, cervical cancer, breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, Lymphoma, non-Hodgkin's lymphoma, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML) ), multiple myeloma, mesothelioma, especially for the tumor type of epidermal growth factor receptor 790 threonine mutation to methionine (EGFR T790M).
  • the crystalline form of the mesylate salt of the compound of formula (I) of the present invention can be used as a medicament for the treatment of non-small cell carcinoma (EGFR T790M).
  • the crystalline form I or crystalline form II of the methanesulfonate salt of the compound of the formula (I) of the present invention or a mixture of the crystalline form I and the crystalline form II can be administered to a mammal including a human, and can be administered orally, rectally, parenterally (intravenously, intramuscularly). Internal or subcutaneous), topical administration (powder, ointment or drops), or intratumoral administration.
  • the dose of the mixture of Form I and Crystalline Form II can be administered at a dose of 0.05 to 50 mg/kg body weight/day, for example 0.1 to 45 mg/kg body weight/day, more preferably 0.5 to 35 mg/kg body weight/day.
  • the crystalline form I or crystalline form II of the methanesulfonate salt of the compound of the formula (I) of the present invention or a mixture of the crystalline form I and the crystalline form II may be formulated into a solid dosage form for oral administration, including, but not limited to, capsules, tablets. Agents, pills, powders and granules.
  • the mesylate salt of the compound of the formula (I) of the present invention is mixed as an active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate, or with the following Ingredient mixing: (1) filler or compatibilizer, for example, starch, lactose, sucrose, glucose, mannitol, silicic acid, etc.; (2) binders, such as hydroxymethylcellulose, alginate, gelatin, polyethylene Pyrrolidone, sucrose, gum arabic, etc.; (3) humectants, for example, glycerol, etc.; (4) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and carbonic acid Sodium or the like; (5) a slow solvent such as paraffin or the like; (6) an absorption accelerator such as a quaternary ammonium compound; (7) a wetting agent such as cetyl alcohol
  • the solid dosage forms such as tablets, dragees, capsules, pills, and granules can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • the crystalline form I or crystalline form II of the methanesulfonate salt of the compound of the formula (I) of the present invention or a mixture of the crystalline form I and the crystalline form II may be formulated into a liquid dosage form for oral administration including, but not limited to, pharmaceutically acceptable Emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may comprise inert diluents conventionally employed in the art, such as water and Other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, especially cottonseed oil, peanut oil , corn germ oil, olive oil, castor oil and sesame oil, etc. or a mixture of these substances.
  • the liquid dosage form of the present invention may also contain conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, Flavoring agents and spices.
  • the suspending agent includes, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum methoxide, agar, and the like, or a mixture of these.
  • the crystalline form I or crystalline form II of the methanesulfonate salt of the compound of the formula (I) of the present invention or a mixture of the crystalline form I and the crystalline form II may be formulated into a dosage form for parenteral injection, including, but not limited to, physiologically acceptable.
  • a dosage form for parenteral injection including, but not limited to, physiologically acceptable.
  • Suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may also be formulated into a dosage form for topical administration, including, for example, ointments, powders, suppositories, drops, propellants, and inhalants.
  • the agents, buffers, or propellants that may be needed if necessary are mixed together.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form I or a crystalline form II of the methanesulfonate salt of the compound of the formula (I) or a mixture of crystalline form I and crystalline form II, and a pharmaceutically acceptable carrier, excipient Or thinner.
  • the crystalline form I or the crystalline form II of the methanesulfonate salt of the compound of the formula (I) of the present invention or a mixture of the crystalline form I and the crystalline form II is usually combined with a pharmaceutically acceptable carrier, excipient or Mix the diluent.
  • composition of the present invention can be formulated into a conventional pharmaceutical preparation by a conventional preparation method.
  • a conventional preparation method for example, tablets, pills, capsules, powders, granules, emulsions, flocs, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, propellants, and the like.
  • the crystalline form I or crystalline form II of the mesylate salt of the compound of the formula (I) according to the invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, in a mixture of crystalline form I and crystalline form II. Especially in combination with other anti-tumor drugs.
  • the therapeutic agent includes, but is not limited to, a drug antitumor drug acting on the chemical structure of DNA such as cisplatin, an antitumor drug affecting nucleotide synthesis such as methotrexate (MTX), 5-fluorouracil (5FU), etc.
  • Anti-tumor drugs for nucleic acid transcription such as doxorubicin, epirubicin, aclarithromycin, phosfomycin, etc., antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine, etc., aromatase inhibitors such as Aminoglutide, lantron, letrozole, ruined, etc., cells Signal pathway inhibitors such as the epidermal growth factor receptor inhibitors Imatinib, Gefitinib, Erlotinib and the like.
  • the ingredients to be combined may be administered simultaneously or sequentially, in the form of a single preparation or in the form of no preparation.
  • the combination includes not only combinations of the compounds of the invention and one other active agent, but also combinations of the compounds of the invention and two or more other active agents.
  • the method for determining the absolute bioavailability of the crystalline form of the mesylate salt of the compound of the formula (I) of the present invention is as follows:
  • Intravenous administration healthy SD rats, randomized. The test substance was administered intravenously according to a certain dose of D, and blood was taken from the posterior venous plexus before and 5 minutes, 15 minutes, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, 12h and 24h after administration.
  • concentration of the drug in the plasma was determined by liquid chromatography/tandem mass spectrometry to obtain a drug concentration-time curve.
  • Oral administration healthy SD rats, randomized.
  • the test substance was administered by a certain dose of D, and venous blood was taken from the posterior venous plexus of the rat before and after administration at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 12 and 24 h after administration.
  • the concentration of the drug in the plasma was determined by liquid chromatography/tandem mass spectrometry to obtain a drug concentration-time curve.
  • the crystalline form I or the crystalline form II of the mesylate salt of the compound of the formula (I) provided by the present invention has been tested to have excellent bioavailability in animals.
  • the crystalline form I or the crystalline form II of the mesylate salt of the compound of the formula (I) provided by the present invention has a better solubility in a solvent of a different pH value than the compound of the formula (I).
  • Figure 1 is an XRPD pattern of Form I of the methanesulfonate salt of the compound of formula (I).
  • Figure 2 is an XRPD pattern of Form II of the methanesulfonate salt of the compound of formula (I)
  • Figure 3 is a DSC chart of Form I of the methanesulfonate salt of the compound of formula (I)
  • Figure 4 is a DSC chart of Form II of the methanesulfonate salt of the compound of formula (I)
  • Figure 5 is a TGA diagram of Form I of the methanesulfonate salt of the compound of formula (I)
  • Figure 6 is a TGA diagram of Form II of the methanesulfonate salt of the compound of formula (I)
  • 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 according to the present invention are as follows:
  • Scan range: from 3.0 to 50.0 degrees
  • a differential scanning calorimetry (DSC) map of the invention was acquired on a Perkin Elmer DSC8500.
  • the method parameters of the differential scanning calorimetry described in the present invention are as follows:
  • Temperature control starting temperature is 50 ° C, 50 ° C for 1 min, and ramping to 250 ° C at 10 ° C / min
  • thermogravimetric analysis (TGA) map of the present invention was acquired on NETZSCH TG 209F3.
  • the method parameters of the thermogravimetric analysis according to the present invention are as follows:
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (451.5 g, 0.77 mol) was added to a 10 L autoclave, and an aqueous acetone solution (5.42) was added. L, the volume ratio of the two is 15:1), stirred, replaced with nitrogen, and heated to 35-40 °C. A solution of methanesulfonic acid (74.2 g, 0.76 mol) in acetone (1.35 L) was added dropwise.
  • the X-ray diffraction pattern of the Form I powder obtained in this example has a diffraction angle 2 ⁇ value of 4.58° ⁇ 0.2°, 14.08° ⁇ 0.2°, 15.00° ⁇ 0.2°, 16.40° ⁇ 0.2°, 17.84° ⁇ 0.2°, 18.30° ⁇ 0.2°, 20.26° ⁇ 0.2°, 21.10° ⁇ 0.2°, 21.88° ⁇ 0.2°, 22.66° ⁇ 0.2°, 25.58° ⁇ 0.2°, 26.78° ⁇ 0.2° have characteristic peaks; the XRPD pattern is as follows Figure 1, DSC diagram is shown in Figure 3, and TGA diagram is shown in Figure 5.
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (5 g, 8.8 mmol) was added to a 100 mL reaction flask, and aqueous tetrahydrofuran (42.5 mL) was added. , the volume ratio of the two is 19:1), stirred, replaced with nitrogen, and heated to 40-45 ° C.
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (5 g, 8.8 mmol) was added to a 100 mL reaction flask, and an aqueous solution of acetonitrile (42.5 mL) was added. , the volume ratio of the two is 19:1), stirred, replaced with nitrogen, and heated to 40-45 ° C.
  • Methanesulfonic acid (0.84 g, 8.7 mmol) in acetonitrile (7.5 mL, mp. After the dropwise addition is completed, the temperature is controlled at 40-45 ° C for 15-18 hours. Ethyl acetate (25 mL) was added dropwise, and the mixture was applied dropwise, and then slowly cooled to 20-25 ° C and filtered. Drying at 50 ° C for 40-48 hours gave crystal form I (4.3 g) in a yield of 73.29%.
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (5 g, 8.8 mmol) was added to a 100 mL reaction flask, and aqueous tetrahydrofuran (42.5 mL) was added. , the volume ratio of the two is 19:1), stirred, replaced with nitrogen, and heated to 40-45 ° C.
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (5 g, 8.8 mmol) was added to a 100 mL reaction flask, and aqueous acetone (42.5 mL) was added. , the volume ratio of the two is 19:1), stirred, replaced with nitrogen, and heated to 40-45 ° C.
  • Example 7 N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [ Preparation of Form I of methanesulfonate salt of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (5 g, 8.8 mmol) was added to a 100 mL reaction flask, and aqueous tetrahydrofuran (42.5 mL) was added. , the volume ratio of the two is 19:1), stirred, replaced with nitrogen, and heated to 40-45 ° C.
  • Example 8 N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [ Preparation of Form I of methanesulfonate salt of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (5 g, 8.8 mmol) was added to a 100 mL reaction flask, and aqueous acetone (42.5 mL) was added. , the volume ratio of the two is 19:1), stirred, replaced with nitrogen, and heated to 40-45 ° C.
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (5 g, 8.8 mmol) was added to a 100 mL reaction flask, and aqueous acetone (42.5 mL) was added. , the volume ratio of the two is 19:1), stirred, replaced with nitrogen, and heated to 40-45 ° C.
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (5 g, 8.8 mmol) was added to a 100 mL reaction flask, and an aqueous solution of acetonitrile (42.5 mL) was added. , the volume ratio of the two is 19:1), stirred, replaced with nitrogen, and heated to 40-45 ° C.
  • Methanesulfonic acid (0.84 g, 8.7 mmol) in acetonitrile (7.5 mL, mp. After the dropwise addition is completed, the temperature is controlled at 40-45 ° C for 15-18 hours. Slowly cool to 20-25 ° C and filter. Drying at 50 ° C for 40-48 hours gave Form I (4.0 g) in a yield of 68.18%.
  • N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [4-( 1-Methyl-1H-indol-3-ylpyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide (5 g, 8.8 mmol) was added to a 100 mL reaction flask, and an aqueous solution of acetonitrile (42.5 mL) was added. , the volume ratio of the two is 19:1), stirred, replaced with nitrogen, and heated to 40-45 ° C.
  • Methanesulfonic acid (0.84 g, 8.7 mmol) in acetonitrile (7.5 mL) was added dropwise. After the dropwise addition was completed, the temperature was controlled at 40-45 ° C, methyl formate (355 mL) was added dropwise, and the addition was completed, and the temperature was slowly lowered to 20-25 ° C, and filtered. Drying at 50 ° C for 40-48 hours gave crystal form I (4.5 g), yield 76.70%.
  • Example 12 N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [ Preparation of Form II of Mesylate of 4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide
  • Form I (5 g, 7.5 mmol) obtained according to Example 2 was added to a 100 mL reaction flask, and methanol (50.0 mL) was added thereto, and the mixture was stirred and heated to 50-55 °C. Stir the temperature at 50-55 ° C for 15-18 hours. Slowly cool to 20-25 ° C and filter. Drying at 50 ° C for 40-48 hours gave crystal form II (3.1 g) in a yield of 62.0%.
  • the X-ray diffraction pattern of the Form II powder obtained in this example has a diffraction angle 2 ⁇ of 6.94° ⁇ 0.2°, 11.24° ⁇ 0.2°, 11.94° ⁇ 0.2°, 14.72° ⁇ 0.2°, 18.74° ⁇ 0.2°, 19.38° ⁇ 0.2°, 20.22° ⁇ 0.2°, 22.10° ⁇ 0.2°, 22.92° ⁇ 0.2°, 24.48° ⁇ 0.2°, 25.14° ⁇ 0.2°, 26.42° ⁇ 0.2° have characteristic peaks; the XRPD pattern is as follows Figure 2, DSC diagram is shown in Figure 4, and TGA diagram is shown in Figure 6.
  • Example 13 N- ⁇ 2- ⁇ [2-(Dimethylamino)ethyl](methyl)amino ⁇ -6-(2,2,2-trifluoroethoxy)-5- ⁇ [ Preparation of Form II of Mesylate of 4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl]amino ⁇ pyridin-3-yl ⁇ acrylamide
  • Form I (5 g, 7.5 mmol) obtained according to Example 2 was added to a 100 mL reaction flask, and ethanol (50.0 mL) was added thereto, and the mixture was stirred and heated to 50-55 °C. Stir the temperature at 50-55 ° C for 15-18 hours. Slowly cool to 20-25 ° C and filter. Drying at 50 ° C for 40-48 hours gave crystal form II (3.1 g) in a yield of 62.0%.
  • Test Example 1 Drug absorption test in SD rats (Sprague Dawley rats)
  • Intravenous administration healthy SD rats, 20 males and females, weighing 200-280 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. and randomly divided into five groups.
  • the compound of the formula (I), the mesylate salt form I, the form II, the compound of the formula (I) of Example 1, the control 1 and the control 2 were intravenously administered at the doses listed in the table below, before administration and given At the 5th, 15th, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, 12h and 24h after the drug, 0.2ml of venous blood was taken from the posterior venous plexus of rats, and plasma was separated and determined by liquid chromatography/tandem mass spectrometry. The concentration of the drug in the plasma gives a drug concentration-time curve.
  • Comparative Example 1 the material structure of Comparative Example 1 is as follows, and is prepared according to the method of Example 2 of Patent Application CN201410365911.4.
  • Comparative Example 2 was as follows, and was prepared according to the method of Example 16 of Patent Application CN201410365911.4.
  • T 1/2 elimination half-life
  • C max the highest concentration of drug in plasma
  • AUC 0-t area under the curve
  • Determination method Weigh the appropriate amount of each substance into a brown volumetric flask, add different solvents, sonicate for 20 s, make it evenly dispersed, shake at 25 ° C, 200 rpm for 24 h, take it out, centrifuge at 12000 rpm for 10 min, aspirate the supernatant and use corresponding After the solvent was diluted by a certain multiple, the concentration was measured using HPLC, and the pH was measured. The results are shown in the table.

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Abstract

本发明提供式(I)化合物的甲磺酸盐的结晶形式I、结晶形式II，其制备方法，包含该结晶形式的药物组合物及该结晶形式在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症中的应用。本发明式(I)化合物的甲磺酸盐的结晶形式具有良好的溶解度，在动物体内的生物利用度高。

Description

吡啶胺基嘧啶衍生物甲磺酸盐的结晶形式及其制备和应用 技术领域
本发明涉及吡啶胺基嘧啶衍生物甲磺酸盐的结晶形式，具体的说，本发明涉及N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺甲磺酸盐的结晶形式、其制备方法、包含该结晶形式的药物组合物及该结晶形式在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症中的应用。
背景技术
表皮生长因子受体(EGFR)被确认为是在细胞生长和增值过程中至关重要的驱动因素。表皮生长因子受体家族由EGFR(Erb-B1)、Erb-B2(HER-2/neu)、Erb-B3和Erb-B4组成。表皮生长因子受体与大部分癌症的疾病进程有关，如肺癌、结肠癌、乳腺癌等。EGFR的过度表达和突变已被明确证实是预后不好的乳腺癌的主要危险因素。
目前，研究前沿的已经是不可逆的第三代EGFR抑制剂。专利申请CN201410365911.4公开如下式(I)结构化合物，该化合物对EGFR激活型突变(如19号外显子缺失激活突变、或L858R激活突变)和T790M耐药型突变的抑制活性显著高于对野生型EGFR(WT EGFR)的抑制活性，有很好的选择性，并且毒副作用较低，安全性好。
Figure PCTCN2017000203-appb-000001
晶型对化合物的物理性质有一定影响，对于具有多种晶型的药用化合物，因其晶格结构不同，除可能导致具有不同的外观如颜色、形状外，也会引起某些物理性质如熔点、溶解性、密度、稳定性、吸湿性等不同，进而导致其在体内呈现出不同的溶出和吸收行为，在一定程度上会影响药用化合物的临床疗效和安全性。
特定的晶型可产生与无定型物质或者另一种晶型不同的热力学行 为。在实验室中用诸如熔点仪、热重分析(TGA)或差示扫描量热(DSC)技术测量热性质可将某特定晶型与无定型或者另一晶型区别开来。而且特定的晶型可产生特定的光谱性质，如粉末X衍射图谱数据和红外光谱数据均可用于表征特定的晶型。
发明内容
本发明所要解决的技术问题是提供式(I)化合物甲磺酸盐的结晶形式、其制备方法，包含该结晶形式的药物组合物及该结晶形式在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症中的应用。
本发明提供了式(I)所示N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的结晶形式I，本发明命名为晶型I，
Figure PCTCN2017000203-appb-000002
本发明提供的晶型I，其粉末X衍射图在衍射角2θ值为4.58°±0.2°、14.08°±0.2°、15.00°±0.2°、16.40°±0.2°、17.84°±0.2°、18.30°±0.2°、20.26°±0.2°、21.10°±0.2°、21.88°±0.2°、22.66°±0.2°、25.58°±0.2°、26.78°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型I，其X射线粉末衍射图(XRPD)如图1所示。
更进一步的，本发明提供的晶型I，在加热至212.6℃开始出现吸热峰，其差示扫描热分析谱图(DSC)如图3所示。
更进一步的，本发明提供的晶型I，在加热至230℃时，重量损失约为1％，其热重分析图(TGA)如图5所示。
本发明提供了化合物(I)的甲磺酸盐的晶型I的制备方法，包括：
a)将式(I)化合物悬浮于第一溶剂中，
b)升温至20～70℃，滴加事先溶于第二溶剂中的甲磺酸溶液，
c)析晶、过滤得到晶型I。
更进一步的，所述第一溶剂为水、酮、环醚或腈类溶剂或它们的混合溶剂；第二溶剂为水、酮、环醚或腈类溶剂或它们的混合溶剂。更进一步的所述第一溶剂为水与酮、环醚或腈类溶剂的混合溶剂；所述第二溶剂为酮、环醚或腈类溶剂，或水与酮、环醚或腈类溶剂的混合溶剂。更进一步的所述酮类溶剂包括但不限于丙酮，环醚类溶剂包括但不限于四氢呋喃或1，4-二氧六环，腈类溶剂包括但不限于乙腈。
更进一步的，所述酮、环醚或腈类溶剂与水的混合溶剂，其中酮、环醚或腈类溶剂与水的体积比是10∶1～25∶1，更进一步的酮、环醚或腈类溶剂与水的体积比是15∶1～19∶1。
更进一步的，在b)步骤中升温至35～55℃。
本发明提供了化合物(I)的甲磺酸盐的晶型I的制备方法，包括：
a)将式(I)化合物悬浮于第一溶剂中，
b)升温至20～70℃，滴加事先溶于第二溶剂中的甲磺酸溶液，
c)滴加第三溶剂
d)析晶完过滤得到晶型I。
更进一步的，所述第一溶剂为水、酮、环醚或腈类溶剂或它们的混合溶剂；第二溶剂为水、酮、环醚或腈类溶剂或它们的混合溶剂。更进一步的所述第一溶剂为水与酮、环醚或腈类溶剂的混合溶剂；所述第二溶剂为酮、环醚或腈类溶剂，或水与酮、环醚或腈类溶剂的混合溶剂。更进一步的所述酮类溶剂包括但不限于丙酮，环醚类溶剂包括但不限于四氢呋喃或1，4-二氧六环，腈类溶剂包括但不限于乙腈。
更进一步的，所述酮、环醚或腈类溶剂与水的混合溶剂，其中酮、环醚或腈类溶剂与水的体积比是10∶1～25∶1，更进一步的酮、环醚或腈类溶剂与水的体积比是15∶1～19∶1。
更进一步的，在b)步骤中升温至35～55℃。
更进一步的，所述第三溶剂为C6-7烷烃、醚或酯类溶剂。更进一步的所述C6-7烷烃类溶剂包括但不限于正庚烷；醚类溶剂包括但不限于甲基叔丁基醚；酯类溶剂包括但不限于甲酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丙酯或乙酸丁酯。
本发明提供了式(I)所示N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的结晶形式II，本发明命名为晶型II，
Figure PCTCN2017000203-appb-000003
本发明提供的晶型II，其粉末X衍射图在衍射角2θ值为6.94°±0.2°、11.24°±0.2°、11.94°±0.2°、14.72°±0.2°、18.74°±0.2°、19.38°±0.2°、20.22°±0.2°、22.10°±0.2°、22.92°±0.2°、24.48°±0.2°、25.14°±0.2°、26.42°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型II，其X射线粉末衍射图(XRPD)如图2所示。
更进一步的，本发明提供的晶型II，在加热至206.8℃开始出现吸热峰，其差示扫描热分析谱图(DSC)如图4所示。
更进一步的，本发明提供的晶型II，在加热至220℃时，重量损失约为0.95％，其热重分析图(TGA)如图6所示。
本发明提供了化合物(II)的甲磺酸盐的晶型II的制备方法，包括将式(I)化合物的甲磺酸盐的晶型I在加热条件下溶解于醇类溶剂中，冷却析晶过滤得到晶型II。
更进一步的，所述的醇类溶剂包括但不限于甲醇或乙醇。
本发明提供的式(I)化合物的甲磺酸盐的结晶形式中，式(I)化合物与甲磺酸的摩尔比是1∶1。
本发明提供了药物组合物，包括式(I)化合物甲磺酸盐的结晶形式I。
本发明提供了药物组合物，包括式(I)化合物甲磺酸盐的结晶形式II。
本发明提供了药物组合物，包括式(I)化合物甲磺酸盐的结晶形式I和结晶形式II的混合物。
本发明进一步提供药物组合物，包括式(I)化合物甲磺酸盐的结晶形式I，以及药学上可接受的载体、赋形剂或稀释剂。
本发明进一步提供药物组合物，包括式(I)化合物甲磺酸盐的结晶形式II，以及药学上可接受的载体、赋形剂或稀释剂。
本发明进一步提供药物组合物，包括式(I)化合物甲磺酸盐的结 晶形式I和结晶形式II的混合物，以及药学上可接受的载体、赋形剂或稀释剂。
本发明还提供了药物组合物在制备治疗癌症的药物中的用途，所述药物组合物包括式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物。
本发明提供了用作抗肿瘤药物的式(I)化合物甲磺酸盐的结晶形式I。
本发明提供了用作抗肿瘤药物的式(I)化合物甲磺酸盐的结晶形式II。
本发明提供了用作抗肿瘤药物的式(I)化合物甲磺酸盐的结晶形式I和结晶形式II的混合物。
本发明还提供式(I)化合物甲磺酸盐的结晶形式I在制备治疗癌症的药物中的用途。
本发明还提供式(I)化合物甲磺酸盐的结晶形式I在制备治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症的药物中的用途。
本发明还提供式(I)化合物甲磺酸盐的结晶形式II在制备治疗癌症的药物中的用途。
本发明还提供式(I)化合物甲磺酸盐的结晶形式II在制备治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症的药物中的用途。
本发明还提供式(I)化合物甲磺酸盐的结晶形式I和结晶形式II的混合物在制备治疗癌症的药物中的用途。
本发明还提供式(I)化合物甲磺酸盐的结晶形式I和结晶形式II的混合物在制备治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症的药物中的用途。
本发明还提供式(I)化合物甲磺酸盐的结晶形式I在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症方面的应用。
本发明还提供式(I)化合物甲磺酸盐的结晶形式II在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症方面的应用。
本发明还提供式(I)化合物甲磺酸盐的结晶形式I和结晶形式II的混合物在治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症方面的应用。
本发明还提供一种治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症的方法，所述方法包括对患者施用式(I)化合物甲磺酸盐的结晶形式I、或包括治疗有效量的式(I)化合物甲磺酸盐的结晶形式I和药物可接受载体、赋形剂或稀释剂的药物组合物。
本发明还提供一种治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症的方法，所述方法包括对患者施用式(I)化合物甲磺酸盐的结晶形式II、或包括治疗有效量的式(I)化合物甲磺酸盐的结晶形式II和药物可接受载体、赋形剂或稀释剂的药物组合物。
本发明还提供一种治疗哺乳动物尤其人类由EGFR激活型或耐药型突变体介导的疾病、特别是癌症的方法，所述方法包括对患者施用式(I)化合物甲磺酸盐的结晶形式I和结晶形式II的混合物、或包括治疗有效量的式(I)化合物甲磺酸盐的结晶形式I和结晶形式II的混合物及药物可接受载体、赋形剂或稀释剂的药物组合物。
本发明所提及癌症包括但不限于，例如肺癌、卵巢癌、宫颈癌、乳腺癌、胃癌、结肠直肠癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、肝细胞癌、胃肠道基质瘤(GIST)、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病(AML)、多发性骨髓瘤、间皮瘤，尤其对于表皮生长因子受体790位苏氨酸突变为蛋氨酸(EGFR T790M)的肿瘤类型有更好的应用。举例来说，本发明式(I)化合物的甲磺酸盐的结晶形式可作为和用于治疗非小细胞癌(EGFR T790M)的药物。
本发明式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物可给药于哺乳动物包括人，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药(粉剂、软膏剂或滴剂)、或瘤内给药。
本发明式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶 形式I与结晶形式II的混合物的给药剂量可以大0.05～50mg/kg体重/天，例如0.1～45mg/kg体重/天，更例如0.5～35mg/kg体重/天
本发明式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物可以配制为用于口服给药的固体剂型，包括，但不限于胶囊剂、片剂、丸剂、散剂和颗粒剂等。在这些固体剂型中，本发明式(I)化合物的甲磺酸盐作为活性成分与至少一种常规惰性赋形剂(或载体)混合，例如与柠檬酸钠或磷酸二钙，或与下述成分混合：(1)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等；(2)粘合剂，例如羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶等；(3)保湿剂，例如，甘油等；(4)崩解剂，例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠等；(5)缓溶剂，例如石蜡等；(6)吸收加速剂，例如，季铵化合物等；(7)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯等；(8)吸附剂，例如，高岭土等；和(9)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠等，或其混合物。胶囊剂、片剂和丸剂中也可包含缓冲剂。
所述固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材料例如肠溶衣和其他本领域公知的材料进行包衣或微囊化。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
本发明式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物可以配制为用于口服给药的液体剂型，包括，但不限于药学上可接受的乳液、溶液、悬浮液、糖浆和酊剂等。除了作为活性成分的式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水和其他溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油类，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外，本发明液体剂型也可包含常规助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、 矫味剂和香料等。
所述悬浮剂包括，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇只、微晶纤维素、甲醇铝和琼脂等或这些物质的混合物。
本发明式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物可以配制为用于肠胃外注射的剂型，包括，但不限于生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物或其药学上可接受的盐也可以配制为用于局部给药的剂型，包括如软膏剂、散剂、栓剂、滴剂、喷射剂和吸入剂等。作为活性成分的本发明式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明还提供药物组合物，它含有本发明式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物，以及药学上可接受载体、赋形剂或稀释剂。在制备药物组合物时，通常是将本发明式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物与药学上可接受载体、赋形剂或稀释剂混合。
可以按常规制备方法将所述本发明组合物配制为常规药物制剂。例如片剂、丸剂、胶囊剂、散剂、颗粒剂、乳液剂、混浮剂、分散液、溶液剂、糖浆剂、酏剂、软膏剂、滴剂、栓剂、吸入剂、喷射剂等。
本发明所述的式(I)化合物甲磺酸盐的结晶形式I或结晶形式II或结晶形式I与结晶形式II的混合物可以单独给药，或者与其他药学上可接受的治疗剂联合给药，特别是与其他抗肿瘤药物组合。所述治疗剂包括但不限于：作用于DNA化学结构的药物抗肿瘤药如顺铂，影响核苷酸合成的抗肿瘤药物如甲氨蝶呤(MTX)、5-氟尿嘧啶(5FU)等，影响核酸转录的抗肿瘤药物如阿霉素、表阿霉素、阿克拉霉素、光辉霉素等，作用于微管蛋白合成的抗肿瘤药物如紫杉醇、长春瑞滨等，芳香化酶抑制剂如氨鲁米特、兰特隆、来曲唑、瑞宁德等，细胞 信号通路抑制剂如表皮生长因子受体抑制剂伊马替尼(Imatinib)、吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)等。待组合的各成分可同时或顺序的给予，以单一制剂形式或以不用制剂的形式给予。所述组合不仅包括本发明化合物和一种其他活性剂的组合，而且也包括本发明化合物和两种或更多种其他活性剂的组合。
本发明式(I)化合物的甲磺酸盐的结晶形式灌胃给药的绝对生物利用度的测定方法如下：
静脉给药：健康SD大鼠，随机分组。测试物质按一定剂量D静脉给药，于给药前及给药后5min、15min、0.5h、1.0h、2.0h、4.0h、8.0h、12h和24h经眼球后静脉丛取血，分离制备血浆，采用液相色谱/串联质谱法测定血浆中药物的浓度，得到药物浓度-时间曲线。
灌胃给药：健康SD大鼠，随机分组。测试物质按一定剂量D灌胃给药，于给药前和给药后0.5、1.0、2.0、4.0、6.0、8.0、10、12和24h经大鼠眼球后静脉丛取静脉血，分离制备血浆，采用液相色谱/串联质谱法测定血浆中药物的浓度，得到药物浓度-时间曲线。
经剂量校正，按药时曲线下面积(AUC0-t)计算，得到绝对生物利用度F，计算公式F＝(AUC灌胃×D静脉)/(AUC静脉×D灌胃)×100％。
本发明式(I)化合物的甲磺酸盐的结晶形式溶解度的测定方法如下：
称取各物质适量置于棕色量瓶中，加入不同溶剂，超声20s，使其分散均匀后于25℃，200rpm震摇24h，取出，在12000rpm下离心10min，吸取上清液并用相应溶剂稀释一定倍数后使用HPLC测定浓度，并测定pH值。
本发明的有益效果为：
本发明提供的式(I)化合物甲磺酸盐的结晶形式I或结晶形式II经试验证明在动物体内具有优异的生物利用度。
本发明提供的式(I)化合物甲磺酸盐的结晶形式I或结晶形式II相对于式(I)化合物在不同pH值的溶剂中具有更好的溶解度。
附图说明
附图1是式(I)化合物甲磺酸盐的晶型I的XRPD图
附图2是式(I)化合物甲磺酸盐的晶型II的XRPD图
附图3是式(I)化合物甲磺酸盐的晶型I的DSC图
附图4是式(I)化合物甲磺酸盐的晶型II的DSC图
附图5是式(I)化合物甲磺酸盐的晶型I的TGA图
附图6是式(I)化合物甲磺酸盐的晶型II的TGA图
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于举例说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比分别为重量份和重量百分比。
具体实施方式
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射线粉末衍的方法参数如下：
X射线反射参数：Cu，Kα
Kα1
Figure PCTCN2017000203-appb-000004
：1.540598；Kα1
Figure PCTCN2017000203-appb-000005
：1.544426
Kα2/Kα1强度比例：0.50
电压：45千伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至50.0度
本发明所述的差示扫描量热分析(DSC)图在Perkin Elmer DSC8500上采集。本发明所述的差示扫描量热分析的方法参数如下：
温度控制：起始温度为50℃，50℃维持1min，以10℃/min的速度升温至250℃
保护气体：氮气
本发明所述的热重分析(TGA)图在NETZSCH TG 209F3上采集。本发明所述的热重分析的方法参数如下：
温度控制：30℃维持5min，以10℃/min的速度升温至400℃
保护气体：氮气
I.制备实施例
实施例1：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺
中间体1c：N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-3-硝基吡啶-2，5-二胺，制备方法引用专利申请CN201410365911.4实施例
Figure PCTCN2017000203-appb-000006
中间体2a：3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚，制备方法引用专利申请CN201410365911.4实施例
Figure PCTCN2017000203-appb-000007
化合物(II)：N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-N5-[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]-3-硝基吡啶-2，5-二胺的合成
Figure PCTCN2017000203-appb-000008
在圆底烧瓶中加入3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(73mg，0.3mmol)、N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-3-硝基吡啶-2，5-二胺(100mg，0.3mmol)、三(二亚苄基丙酮)二钯(14mg，0.015mmol)，4，5-双二苯基膦-9，9-二甲基氧杂蒽(14mg，0.03mmol)，磷酸钾(127mg，0.6mmol)和8ml二氧六环，氩气保护下，95℃反应5h。过滤，滤液减压蒸干，硅胶柱层析(二氯甲烷∶甲醇＝20∶1)，得到140mg产物。收率为86％。MS m/z：545[M+1]。
化合物(III)：N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-N5-[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]吡啶-2，3，5-三胺的合成
Figure PCTCN2017000203-appb-000009
在圆底烧瓶中加入N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-N5-[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]-3-硝基吡啶-2，5-二胺(150mg，0.27mmol)、二氧化铂(60mg)和10ml甲醇，通入氢气，室温反应1h。过滤，制备板分离(二氯甲烷∶甲醇＝10∶1)，得到80mg目标化合物。收率为56％。MSm/z：515[M+1]。
化合物(I)：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的合成
Figure PCTCN2017000203-appb-000010
向圆底烧瓶中加入N2-甲基-N2-[2-(二甲胺基)乙基]-6-(2，2，2-三氟乙氧基)-N5-[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]吡啶-2，3，5-三胺(80mg，0.16mmol)和5ml二氯甲烷，冰水浴冷却，加入0.5N丙烯酰氯的二氯甲烷溶液(0.5ml，0.25mmol)。冰水浴下反应1.5小时，反应液用50ml乙酸乙酯稀释，饱和碳酸氢钠溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，制备板分离纯化(二氯甲烷∶甲醇＝10∶1)，得到20mg目标产物。收率为23％。MS m/z：569[M+1]。
1H NMR(400MHz，DMSO-d6)δ10.41(s，1H)，10.27(s，1H)，8.68(s，1H)，8.44(s，1H)，8.28(t，J＝8.5Hz，2H)，8.18(s，1H)，7.52(d，J＝8.0Hz，1H)，7.29-7.14(m，3H)，6.98(s，1H)，6.28(d，J＝17.1Hz，1H)，5.76(d，J＝10.4Hz，1H)，5.00(q，J＝9.0Hz，2H)，3.89(s，3H)，3.61(s，2H)，3.28(s，2H)，2.80(s，3H)，2.73(s，6H)。
其中化合物(II)、(III)、(I)的制备方法参考专利申请CN201410365911.4实施例1。
实施例2：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(451.5g，0.77mol)加至10L反应釜中，加入丙酮水溶液(5.42L，二者体积比15∶1)，搅拌，氮气置换，升温至35-40℃。滴加甲磺酸(74.2g，0.76mol)的丙酮溶液(1.35L)。滴加完毕，控温35-40℃搅拌15-18小时。滴加乙酸乙酯(3.39L)，滴加完毕，缓慢降温至20-25℃，过滤，乙酸乙酯(0.45L)洗滤饼。50℃真空干燥40-48小时，得晶型I(409.9g)，收率80.09％。
1H NMR(400MHz，DMSO-d6)δ9.80(s，1H)，9.23(s，1H)，8.53(s，1H)，8.42(s，1H)，8.30(d，J＝5.4Hz，2H)，8.23(s，1H)，7.52(d，J＝8.2Hz，1H)，7.25(t，J＝7.2Hz，1H)，7.22(d，J＝8.0Hz，1H)，7.15(t，J＝7.4Hz，1H)，6.70(dd，J＝17.0，10.2Hz，1H)，6.34(dd，J＝17.0，1.7Hz，1H)，5.83(dd，J＝10.3，1.6Hz，1H)，5.02(q，J＝9.1Hz，2H)，3.88(s，3H)，3.65(t，J＝6.0Hz，2H)，3.33(t，J＝6.0Hz，2H)，2.86(s，6H)，2.81(s，3H)，2.44(s，3H)。
经检测，本实施例得到晶型I粉末X衍射图在衍射角2θ值为4.58°±0.2°、14.08°±0.2°、15.00°±0.2°、16.40°±0.2°、17.84°±0.2°、18.30°±0.2°、20.26°±0.2°、21.10°±0.2°、21.88°±0.2°、22.66°±0.2°、25.58°±0.2°、26.78°±0.2°处具有特征峰；其XRPD图谱如图1，DSC图如图3，TGA图如图5。
实施例3：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(5g，8.8mmol)加至100mL反应瓶中，加入四氢呋喃水溶液(42.5mL，二者体积比19∶1)，搅拌，氮气置换，升温至40-45℃。滴加甲磺酸(0.84g，8.7mmol)的四氢呋喃水溶液(7.5mL，二者体积比19∶1)。滴加完毕，控温40-45℃搅拌15-18小时。缓慢降温至20-25℃，过滤。50 ℃真空干燥40-48小时，得晶型I(3.4g)，收率57.95％。
实施例4：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(5g，8.8mmol)加至100mL反应瓶中，加入乙腈水溶液(42.5mL，二者体积比19∶1)，搅拌，氮气置换，升温至40-45℃。滴加甲磺酸(0.84g，8.7mmol)的乙腈水溶液(7.5mL，二者体积比19∶1)。滴加完毕，控温40-45℃搅拌15-18小时。滴加乙酸乙酯(25mL)，滴加完毕，缓慢降温至20-25℃，过滤。50℃真空干燥40-48小时，得晶型I(4.3g)，收率73.29％。
实施例5：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(5g，8.8mmol)加至100mL反应瓶中，加入四氢呋喃水溶液(42.5mL，二者体积比19∶1)，搅拌，氮气置换，升温至40-45℃。滴加甲磺酸(0.84g，8.7mmol)的四氢呋喃水溶液(7.5mL，二者体积比19∶1)。滴加完毕，控温40-45℃搅拌15-18小时。滴加乙酸乙酯(25mL)，滴加完毕，缓慢降温至20-25℃，过滤。50℃真空干燥40-48小时，晶型I(4.75g)，收率80.96％。
实施例6：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(5g，8.8mmol)加至100mL反应瓶中，加入丙酮水溶液(42.5mL，二者体积比19∶1)，搅拌，氮气置换，升温至40-45℃。滴加甲磺酸(0.84g，8.7mmol)的四氢呋喃水溶液(7.5mL，二者体积比19∶1)。滴加完毕，控温40-45℃，滴加乙酸乙酯(25mL)，滴加完毕，缓慢降温 至20-25℃，过滤。50℃真空干燥40-48小时，得晶型I(5.1g)，收率86.93％。
实施例7：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(5g，8.8mmol)加至100mL反应瓶中，加入四氢呋喃水溶液(42.5mL，二者体积比19∶1)，搅拌，氮气置换，升温至40-45℃。滴加甲磺酸(0.84g，8.7mmol)的四氢呋喃水溶液(7.5mL，二者体积比19∶1)。滴加完毕，控温40-45℃搅拌15-18小时。滴加乙酸异丙酯(37.5mL)，滴加完毕，缓慢降温至20-25℃，过滤，乙酸异丙酯(5mL)洗滤饼。缓慢降温至20-25℃，过滤。50℃真空干燥40-48小时，得晶型I(4.4g)，收率75.00％。
实施例8：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(5g，8.8mmol)加至100mL反应瓶中，加入丙酮水溶液(42.5mL，二者体积比19∶1)，搅拌，氮气置换，升温至40-45℃。滴加甲磺酸(0.84g，8.7mmol)的四氢呋喃水溶液(7.5mL，二者体积比19∶1)。滴加完毕，控温40-45℃，滴加甲酸乙酯(25mL)，滴加完毕，缓慢降温至20-25℃，过滤。50℃真空干燥40-48小时，得晶型I(5.1g)，收率86.93％。
实施例9：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(5g，8.8mmol)加至100mL反应瓶中，加入丙酮水溶液(42.5mL，二者体积比19∶1)，搅拌，氮气置换，升温至40-45℃。滴加甲磺酸(0.84 g，8.7mmol)的四氢呋喃水溶液(7.5mL，二者体积比19∶1)。滴加完毕，控温40-45℃，滴加正庚烷(25mL)，滴加完毕，缓慢降温至20-25℃，过滤。50℃真空干燥40-48小时，得晶型I(4.8g)，收率81.82％。
实施例10：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(5g，8.8mmol)加至100mL反应瓶中，加入乙腈水溶液(42.5mL，二者体积比19∶1)，搅拌，氮气置换，升温至40-45℃。滴加甲磺酸(0.84g，8.7mmol)的乙腈水溶液(7.5mL，二者体积比19∶1)。滴加完毕，控温40-45℃搅拌15-18小时。缓慢降温至20-25℃，过滤。50℃真空干燥40-48小时，得晶型I(4.0g)，收率68.18％。
实施例11：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型I的制备
将N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺(5g，8.8mmol)加至100mL反应瓶中，加入乙腈水溶液(42.5mL，二者体积比19∶1)，搅拌，氮气置换，升温至40-45℃。滴加甲磺酸(0.84g，8.7mmol)的乙腈溶液(7.5mL)。滴加完毕，控温40-45℃，滴加甲酸甲酯(355mL)，滴加完毕，缓慢降温至20-25℃，过滤。50℃真空干燥40-48小时，得晶型I(4.5g)，收率76.70％。
实施例12：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型II的制备
将按照实施例2所得的晶型I(5g，7.5mmol)加至100mL反应瓶中，加入甲醇(50.0mL)，搅拌，升温至50-55℃。控温50-55℃搅拌15-18小时。缓慢降温至20-25℃，过滤。50℃真空干燥40-48小时，得晶型II(3.1g)，收率62.0％。
1H NMR(400MHz，DMSO-d6)δ9.80(s，1H)，9.23(s，1H)，8.53(s， 1H)，8.42(s，1H)，8.30(d，J＝5.4Hz，2H)，8.23(s，1H)，7.52(d，J＝8.2Hz，1H)，7.25(t，J＝7.2Hz，1H)，7.22(d，J＝8.0Hz，1H)，7.15(t，J＝7.4Hz，1H)，6.70(dd，J＝17.0，10.2Hz，1H)，6.34(dd，J＝17.0，1.7Hz，1H)，5.83(dd，J＝10.3，1.6Hz，1H)，5.02(q，J＝9.1Hz，2H)，3.88(s，3H)，3.65(t，J＝6.0Hz，2H)，3.33(t，J＝6.0Hz，2H)，2.86(s，6H)，2.81(s，3H)，2.44(s，3H)。
经检测，本实施例得到晶型II粉末X衍射图在衍射角2θ值为6.94°±0.2°、11.24°±0.2°、11.94°±0.2°、14.72°±0.2°、18.74°±0.2°、19.38°±0.2°、20.22°±0.2°、22.10°±0.2°、22.92°±0.2°、24.48°±0.2°、25.14°±0.2°、26.42°±0.2°处具有特征峰；其XRPD图谱如图2，DSC图如图4，TGA图如图6。
实施例13：N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的晶型II的制备
将按照实施例2所得的晶型I(5g，7.5mmol)加至100mL反应瓶中，加入乙醇(50.0mL)，搅拌，升温至50-55℃。控温50-55℃搅拌15-18小时。缓慢降温至20-25℃，过滤。50℃真空干燥40-48小时，得晶型II(3.1g)，收率62.0％。
II.活性测试实施例
测试实施例1：SD大鼠(Sprague Dawley大鼠)药物吸收实验
静脉给药：健康SD大鼠，雌雄各半共20只，体重200～280g，由上海西普尔-必凯实验动物有限公司提供，随机分成五组。分别按下表所列剂量静脉给予式(I)化合物甲磺酸盐晶型I、晶型II、实施例1的式(I)化合物、对照例1和对照例2，于给药前及给药后5min、15min、0.5h、1.0h、2.0h、4.0h、8.0h、12h和24h经大鼠眼球后静脉丛取静脉血0.2ml，分离制备血浆，采用液相色谱/串联质谱法测定血浆中药物的浓度，得到药物浓度-时间曲线。
其主要的药物动力学参数如下表1所示：
参数 晶型I 晶型II 实施例1 对照例1 对照例2
剂量D(mg/kg) 2.5 2.5 2.5 3.0 4.0
Cmax(ng/mL) 104.7 125.4 81.3 327.5 630.2
AUC0-t(ng·h/mL) 307.9 362.0 307.3 437.8 810.7
T1/2(h) 4.73 4.83 3.96 2.72 1.71
表1
表1中，对照例1物质结构如下，按专利申请CN201410365911.4实施例2方法制备得到，
Figure PCTCN2017000203-appb-000011
对照例2物质结构如下，按专利申请CN201410365911.4实施例16方法制备得到，
Figure PCTCN2017000203-appb-000012
T1/2：消除半衰期；Cmax：血浆中药物的最高浓度；AUC0-t：药时曲线下面积
灌胃给药：健康SD大鼠，雌雄各半共20只，体重200～280g，由上海西普尔-必凯实验动物有限公司提供，随机分成五组。分别按下表所列剂量灌胃给予式(I)化合物甲磺酸盐晶型I、晶型II、实施例1的式(I)化合物、对照例1和对照例2，于给药前和给药后0.5、1.0、2.0、4.0、6.0、8.0、10、12和24h经大鼠眼球后静脉丛取静脉血0.2ml，分离制备血浆，采用液相色谱/串联质谱法测定血浆中药物的浓度，得到药物浓度-时间曲线。
其主要的药物动力学参数如下表2所示：
参数 晶型I 晶型II 实施例1 对照例1 对照例2
剂量D(mg/kg) 10 10 10 6 10
Cmax(ng/mL) 45.3 36.7 17.6 12.63 28.3
AUC0-t(ng·h/mL) 613.2 566.3 231.7 77.66 172.2
T1/2(h) 7.98 5.79 4.14 8.60 5.76.
F(％) 49.8 39.1 18.85 8.9 8.5
表2，其中对照例1、2的结构与制备方法同表1
经剂量校正后，按AUC0-t计算，得到绝对生物利用度F，计算公式F＝(AUC灌胃×D静脉)/(AUC静脉×D灌胃)×100％，得到的绝对生物利用度F见上表2。
结论：式(I)化合物的甲磺酸盐的晶型I、晶型II灌胃给药的绝对生物利用度明显优于实施例1式(I)化合物、对照例1和对照例2灌胃给药的绝对生物利用度。
测试实施例2：溶解度试验
考察实施例1的式(I)化合物、式(I)化合物的甲磺酸盐的晶型I、式(I)化合物的甲磺酸盐的晶型II在不同pH缓冲液下的溶解度。
测定方法：称取各物质适量置于棕色量瓶中，加入不同溶剂，超声20s，使其分散均匀后于25℃，200rpm震摇24h，取出，在12000rpm下离心10min，吸取上清液并用相应溶剂稀释一定倍数后使用HPLC测定浓度，并测定pH值。结果见表。
Figure PCTCN2017000203-appb-000013
结论：式(I)化合物的甲磺酸盐的晶型I及晶型II在溶剂pH值为1.0、4.5、6.8时的溶解度均明显优于实施例1的式(I)化合物。
在本文中提及的所有文献均通过引用被并入本申请中。此外还应 指明的是，在阅读了本申请的上述公开内容之后，本领域技术人员可以无需背离本发明的精神和范围，对本发明作出各种修饰、改动或修改，但这些变化形式同样都应落于本申请所附权利要求书所记载的范围。

Claims (16)

  1. 式(I)所示N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的结晶形式I，即晶型I，其特征在于粉末X衍射图在衍射角2θ值为4.58°±0.2°、14.08°±0.2°、15.00°±0.2°、16.40°±0.2°、17.84°±0.2°、18.30°±0.2°、20.26°±0.2°、21.10°±0.2°、21.88°±0.2°、22.66°±0.2°、25.58°±0.2°、26.78°±0.2°处具有特征峰，
    Figure PCTCN2017000203-appb-100001
  2. 如权利要求1所述的晶型I，其特征在于，其X射线粉末衍射图基本上与图1一致。
  3. 制备权利要求1或2所述晶型I的方法，包括：
    a)将式(I)化合物悬浮于第一溶剂中，
    b)升温至20～70℃，滴加事先溶于第二溶剂中的甲磺酸溶液，
    c)析晶、过滤得到晶型I。
  4. 制备权利要求1或2所述晶型I的方法，包括：
    a)将式(I)化合物悬浮于第一溶剂中，
    b)升温至20～70℃，滴加事先溶于第二溶剂中的甲磺酸溶液，
    c)滴加第三溶剂
    d)析晶完过滤得到晶型I。
  5. 如权利要求3或4所述的方法，其特征在于所述第一溶剂为水、酮、环醚或腈类溶剂或它们的混合溶剂；第二溶剂为水、酮、环醚或腈类溶剂或它们的混合溶剂。
  6. 如权利要求5所述的方法，其特征在于所述第一溶剂为水与酮、环醚或腈类溶剂的混合溶剂；所述第二溶剂为酮、环醚或腈类溶剂，或水与酮、环醚或腈类溶剂的混合溶剂。
  7. 如权利要求5所述的方法，其特征在于所述酮类溶剂包括丙酮， 环醚类溶剂包括四氢呋喃或1，4-二氧六环，腈类溶剂包括乙腈。
  8. 如权利要求3或4所述的方法，其特征在于b)步骤中升温至35～55℃。
  9. 如权利要求4所述的方法，其特征在于所述第三溶剂为C6-7烷烃、醚或酯类溶剂。
  10. 如权利要求9所述的方法，其特征在于C6-7烷烃类溶剂包括正庚烷；醚类溶剂包括甲基叔丁基醚；酯类溶剂包括甲酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丙酯或乙酸丁酯。
  11. 式(I)所示N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2，2，2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐的结晶形式II，即晶型II，其特征在于粉末X衍射图在衍射角2θ值为6.94°±0.2°、11.24°±0.2°、11.94°±0.2°、14.72°±0.2°、18.74°±0.2°、19.38°±0.2°、20.22°±0.2°、22.10°±0.2°、22.92°±0.2°、24.48°±0.2°、25.14°±0.2°、26.42°±0.2°处具有特征峰，
    Figure PCTCN2017000203-appb-100002
  12. 如权利要求11所述的晶型II，其特征在于，其X射线粉末衍射图基本上与图3一致。
  13. 制备权利要求11或12所述晶型II的方法，包括将式(I)化合物的甲磺酸盐的晶型I在加热条件下溶解于醇类溶剂中，冷却析晶过滤得到晶型II。
  14. 如权利要求13所述的方法，其特征在于所述醇类溶剂包括甲醇或乙醇。
  15. 药物组合物，其特征在于包含权利要求1、2、11或12所述的晶型以及药学上可接受的载体。
  16. 权利要求1、2、11或12所述的晶型在制备治疗癌症的药物中的用途。
PCT/CN2017/000203 2016-03-07 2017-03-01 吡啶胺基嘧啶衍生物甲磺酸盐的结晶形式及其制备和应用 WO2017152707A1 (zh)

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