WO2022144042A1 - Tas-116的晶型及其制备方法、药物组合物和用途 - Google Patents

Tas-116的晶型及其制备方法、药物组合物和用途 Download PDF

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WO2022144042A1
WO2022144042A1 PCT/CN2022/078224 CN2022078224W WO2022144042A1 WO 2022144042 A1 WO2022144042 A1 WO 2022144042A1 CN 2022078224 W CN2022078224 W CN 2022078224W WO 2022144042 A1 WO2022144042 A1 WO 2022144042A1
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crystal form
form iii
cancer
tas
crystal
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PCT/CN2022/078224
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English (en)
French (fr)
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盛晓红
盛晓霞
吴涛
吕康乐
余鹏
胡晨阳
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杭州领业医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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 disclosure relates to the field of medicinal chemistry.
  • the present disclosure relates to crystalline forms of TAS-116 and methods for their preparation, pharmaceutical compositions and uses.
  • TAS-116 is a selective heat shock protein 90 (HSP90) inhibitor for the treatment of gastrointestinal cancers such as colon cancer and gastric stromal tumor.
  • HSP90 selective heat shock protein 90
  • TAS-116 3-ethyl-4- ⁇ 3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)- 1H-pyrazolo[3,4-b]pyridin-1-yl ⁇ benzamide, also known as THS-1593, molecular formula is C 25 H 26 N 8 O, molecular weight is 454.53, and its chemical structure is as follows:
  • Patent CN102471335B discloses the general structure of compounds including TAS-116.
  • Patent CN104710420B discloses the specific structure of TAS-116, and discloses a preparation method of free state of TAS-116, mentioning that TAS-116 is a white solid.
  • Patent CN107531707B discloses type I crystals (hereinafter referred to as “crystal form I”) and type II crystals (hereinafter referred to as “crystal form II”) of TAS-116, wherein crystal form I only has an XRPD spectrum, and the oral administration of crystal form I Absorption problems exist; Form II is anhydrous, and the patent also informs that Form II is a better form than Form I.
  • the inventor found that the sample of TAS-116 prepared according to Example 102 in the patent CN104710420B was the crystal form II, and the DMSO (dimethyl sulfoxide) residue of the obtained sample was very high. more residue. The inventors found that the crystal form II sample appeared in the crystal form I after being retained in the solvent of Example 102 for more than 2 hours, indicating that the stability of the crystal form II was problematic.
  • TAS-116 crystal form I prepared according to CN107531707B is unstable, and is prone to crystal form transformation when placed at room temperature (20-30° C.), and transforms into crystal form II.
  • Form I requires more severe storage conditions to be stable, indicating that its medicinal value is not high.
  • the inventors also found in the research process that the stability of TAS-116 crystal form II prepared according to the CN107531707B patent has great limitations. Crystallization also occurred in the environment, and the crystal form I appeared in different degrees.
  • the purpose of the present disclosure is to provide a TAS-116 crystal form with better physicochemical properties, as well as a preparation method, pharmaceutical composition and use thereof.
  • the TAS-116 crystal form of the present disclosure has better crystal form stability.
  • the crystalline form also possesses better fluidity, formulation processability and bioavailability.
  • a first aspect of the present disclosure provides TAS-116 crystalline form, hereinafter referred to as Form III.
  • the crystal form III of the present disclosure is an anhydrate, and its structural formula is shown in formula (I):
  • the X-ray powder diffraction pattern of the crystal form III has characteristic peaks at 2 ⁇ values of 6.39° ⁇ 0.2°, 10.40° ⁇ 0.2°, 12.94° ⁇ 0.2° and 19.48° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of said Form III has at least 2 ⁇ values of 3.20° ⁇ 0.2°, 6.39° ⁇ 0.2°, 10.40° ⁇ 0.2°, 11.41 There is a characteristic peak at one of ° ⁇ 0.2°, 12.94° ⁇ 0.2° and 19.48° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of said Form III has at least 2 ⁇ values of 3.20° ⁇ 0.2°, 6.39° ⁇ 0.2°, 10.40° ⁇ 0.2°, 11.41
  • One of ° ⁇ 0.2°, 12.94° ⁇ 0.2°, 17.58° ⁇ 0.2°, 18.26° ⁇ 0.2°, 19.48° ⁇ 0.2°, 21.71° ⁇ 0.2°, 22.69° ⁇ 0.2° and 23.65° ⁇ 0.2° has characteristic peaks.
  • the X-ray powder diffraction pattern of Form III has 2 ⁇ values of 3.20° ⁇ 0.2°, 6.39° ⁇ 0.2°, 10.40° ⁇ 0.2°, 11.41° There are characteristic peaks at ⁇ 0.2°, 12.94° ⁇ 0.2° and 19.48° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III has 2 ⁇ values of 3.20° ⁇ 0.2°, 6.39° ⁇ 0.2°, 10.40° ⁇ 0.2°, 11.41° There are characteristic peaks at ⁇ 0.2°, 12.94° ⁇ 0.2°, 17.58° ⁇ 0.2°, 18.26° ⁇ 0.2°, 19.48° ⁇ 0.2°, 21.71° ⁇ 0.2°, 22.69° ⁇ 0.2° and 23.65° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III has characteristic peaks at the following diffraction angles with 2 ⁇ values and relative intensities as shown in the table below:
  • the X-ray powder diffraction (XRPD) pattern of the Form III is substantially as shown in FIG. 4 .
  • the differential scanning calorimetry (DSC) pattern of the Form III is shown in FIG. 5 .
  • the crystal form III has a melting point onset value of 269°C and a peak value of 270°C.
  • thermogravimetric analysis (TGA) pattern of the Form III is shown in FIG. 6 .
  • the crystal form III is anhydrous, with only 0.9% weight loss before 105°C.
  • the Fourier transform infrared spectrum of the Form III is shown in FIG. 7 .
  • the Fourier transform infrared spectrum of the crystal form III is at wavenumbers of 1650cm- 1 ⁇ 2cm- 1 , 1569cm- 1 ⁇ 2cm- 1 , 1504cm -1 ⁇ 2cm -1 , 1424cm -1 ⁇ 2cm -1 , 1272cm -1 ⁇ 1 2cm -1 , 1030cm -1 ⁇ 2cm -1 , 823cm -1 ⁇ 2cm -1 , 812cm -1 ⁇ 2cm -1 , 748cm -1 ⁇ 2cm -1 , 711cm -1 ⁇ 2cm -1 , 668cm -1 ⁇ 2cm - There are characteristic peaks at 1 and 653 cm -1 ⁇ 2 cm -1 .
  • the DVS isotherm of Form III is shown in FIG. 8 .
  • the crystal form III has only a 0.3% weight change in the humidity range of 0%RH-80%RH.
  • a polarized light microscope (PLM) image of the Form III is shown in FIG. 9 .
  • the crystal form III is a fine granular crystal.
  • the second aspect of the present disclosure provides a preparation method of TAS-116 crystal form III, including any one of the following methods:
  • the solvent 1 is selected from cyclic ethers. In certain embodiments, the solvent 1 is 1,4-dioxane.
  • the mass volume ratio of the compound TAS-116 solid to solvent 1 is 10 to 200:1 (mg:mL). In certain embodiments, the mass volume ratio of the compound TAS-116 solid to solvent 1 is 30 to 100:1 (mg:mL).
  • the stirring time is from 10 hours to 168 hours. In certain embodiments, the stirring time is from 16 hours to 72 hours.
  • the stirring is performed at room temperature.
  • the resulting solid is reheated at a temperature of 60°C to 150°C after drying. In certain embodiments, the resulting solid is reheated at a temperature of 80°C to 130°C after drying. In certain embodiments, the heating time is 5 minutes to 16 hours.
  • the solvent 2 is selected from halogenated alkanes, alcohols, ketones, furans, cyclic ethers, nitriles or mixed solvents thereof. In certain embodiments, the solvent 2 is tetrahydrofuran and chloroform. In certain embodiments, the volume ratio of the two solvents in the mixed solvent is 1:4 to 4:1.
  • the mass volume ratio of solute to solvent 2 in the solution is 5 to 100:1 (mg:mL). In certain embodiments, the mass volume ratio of solute to solvent 2 in the solution is 40 to 100:1 (mg:mL).
  • the temperature at which the solution is formed is 60°C to 80°C.
  • the temperature is lowered to 10°C to 50°C. In certain embodiments, the temperature is lowered to 10°C to 40°C.
  • Form III seeds of TAS-116 are added during the cooling process.
  • the seed crystals are added in an amount ranging from 10% to 30% TAS-116 solids.
  • the cooling may be concurrent with stirring or cooling followed by stirring.
  • the stirring time is from 2 hours to 24 hours.
  • the TAS-116 crystal form III of the present disclosure has the following advantages:
  • the TAS-116 crystalline form III of the present disclosure has better stability. Compared with the known TAS-116 crystal form I, it has better crystal form stability under thermal conditions; compared with the known TAS-116 crystal form II, it has better crystal form stability under water conditions
  • the range of water conditions includes but is not limited to aqueous solutions, aqueous media, body fluids and humidity environments, etc.; Form I cannot tolerate heat (40°C), and Form II cannot tolerate water, and neither can maintain the original There are crystalline forms.
  • the TAS-116 Form III of the present disclosure has a faster dissolution rate than the known TAS-116 Form I and Form II.
  • the TAS-116 Form III of the present disclosure has a higher solubility than the known TAS-116 Form I and Form II.
  • the TAS-116 crystalline form III of the present disclosure has a moisture absorption of 0.3% in a 0% to 80% RH environment, and is not easily hygroscopic.
  • the TAS-116 crystal form III of the present disclosure is a uniform and fine powder, which has better solubility and dissolution rate, which is beneficial to improve the bioavailability of the drug; has better particle size distribution, and is easier to achieve mixing uniformity and content uniformity; It has lower hygroscopicity and is more stable in humidity environment.
  • overnight means 10 hours to 16 hours.
  • Root temperature refers to a temperature of 10 to 30°C.
  • stirring conventional methods in the art can be used, for example, stirring methods include magnetic stirring and mechanical stirring, and the stirring speed is 50 to 1800 rpm. In certain embodiments, the stirring speed is 300 to 900 rpm.
  • Isolation can be performed by conventional methods in the art, such as centrifugation or filtration.
  • filtration under reduced pressure typically suction filtration, is performed at room temperature at less than atmospheric pressure. In certain embodiments, the pressure is less than 0.09 MPa.
  • Drying can be accomplished by using conventional techniques in the art, such as drying at room temperature, air drying or drying under reduced pressure; it can be under reduced pressure or normal pressure, preferably the pressure is less than 0.09 MPa.
  • the drying apparatus and method are not limited, and can be a fume hood, a forced air oven, a spray dryer, a fluidized bed drying or a vacuum oven; it can be carried out under reduced or no reduced pressure, preferably the pressure is less than 0.09Mpa.
  • the starting material TAS-116 can be prepared by referring to the method described in Example 102 in the patent document CN104710420B, or it can be purchased from the market, which is incorporated into the present disclosure by reference in its entirety.
  • crystalline form means as evidenced by the characterization of the X-ray powder diffraction pattern shown. It is well known to those skilled in the art that the experimental errors therein depend upon instrumental conditions, sample preparation and sample purity. Spectra generally vary with instrument conditions. The relative intensities of peaks may vary with experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor; experimental errors in peak angles should also be taken into account, usually allowing an error of ⁇ 0.2°; the influence of factors such as sample height can cause The peak angle is shifted as a whole, and a certain shift is usually allowed.
  • any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present disclosure belongs to the scope of the present disclosure.
  • the "single crystal form” refers to a single crystal form detected by X-ray powder diffraction.
  • novel crystalline form of TAS-116 of the present disclosure is pure, single, and substantially not mixed with any other crystalline form or amorphous state.
  • substantially absent when used to refer to a new crystal form means that the new crystal form contains less than 20% by weight of other crystal forms or amorphous states, more particularly less than 10% by weight, especially It means less than 5% by weight, especially less than 1% by weight.
  • the third aspect of the present disclosure provides a pharmaceutical composition
  • the pharmaceutical composition comprises a therapeutically effective amount of the TAS-116 crystal form III or the TAS-116 crystal form III prepared by the method of the present disclosure, and at least one pharmaceutically acceptable carrier.
  • compositions provided by the present disclosure can be administered by a number of routes including, but not limited to: oral (enteral) administration, parenteral (injection) administration, rectal administration, topical administration, transdermal administration, intradermal administration administration, intrathecal, subcutaneous (SC), intramuscular (IM), sublingual/buccal, ocular, otic, vaginal and intranasal or inhalation, usually, an effective amount of
  • the present disclosure provides solid forms of TAS116.
  • the solid form of TAS116 actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. amount.
  • Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. More usually, however, the compositions are provided in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc., either conventional immediate release formulations or Dispersible, chewable, orally dissolving formulations, or sustained-release formulations, may be enteric-coated tablets.
  • a typical regimen is one to five oral doses per day, especially one to four oral doses.
  • each dose provides about 0.01 to about 20 mg/kg of the solid form of TAS-116 provided by the present disclosure, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 0.2 to about 5 mg /kg, which depends on the particular condition being treated, the age and weight of the particular patient, and the particular patient's response to drug therapy, the exact dose is to be determined under the guidance of a physician and in accordance with standard medical principles.
  • a specific unit dose can be, for example, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 200 mg, and the like.
  • the pharmaceutically acceptable carriers or adjuvants in the pharmaceutical composition are well known to those skilled in the art, and can have various well-known forms, such as, but not limited to, diluents, such as starch, modified starch, lactose, powder, etc.
  • cellulose microcrystalline cellulose, calcium hydrogen phosphate anhydrous, tricalcium phosphate, mannitol, sorbitol, sugar, etc.
  • binders such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose Vinegar, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, etc.
  • disintegrants such as starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, crospovidone, crospovidone Sodium bicarboxymethylcellulose, colloidal silicon dioxide, etc.
  • lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.
  • glidants such as colloidal silicon dioxide, etc.
  • Complex formers such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxy
  • compositions that can be used include, but are not limited to, film formers, plasticizers, colorants, flavors, viscosity modifiers, preservatives, antioxidants, and the like.
  • commonly used carriers include lactose and corn starch, and lubricants such as magnesium stearate may also be added;
  • useful carriers/diluents include lactose, high and low molecular weight polyethylene glycols and dry corn starch; in the case of gelatin capsules, powdered carriers or adjuvants such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like; when administered orally as a suspension,
  • the active ingredient is mixed with emulsifying and suspending agents; if desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • Each carrier or adjuvant must be acceptable, compatible with the other ingredients in the formulation and not injurious to the patient.
  • the fourth aspect of the present disclosure provides the TAS-116 crystal form III, the TAS-116 crystal form III obtained by the preparation method of the present disclosure, or the pharmaceutical composition in the preparation of a drug for the treatment of cancer use in.
  • the cancer includes, but is not limited to, the following specific diseases and conditions, such as head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder-cholangiocarcinoma, biliary tract cancer, pancreas cancer Cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone-soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain cancer Tumors, mesothelioma, etc.
  • specific diseases and conditions such as head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder-cholangiocarcinoma, biliary tract cancer, pancreas cancer Cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone-soft tissue
  • a fifth aspect of the present disclosure provides a method of treating cancer, the method comprising administering to a patient in need of the method a therapeutically effective amount of the TAS-116 Form III or a pharmaceutical composition thereof.
  • the patient includes, but is not limited to, a mammal.
  • the sixth aspect of the present disclosure provides the combined use of the TAS-116 crystal form III or its pharmaceutical composition with other drugs.
  • the other drug is a monoclonal antibody drug.
  • the other drugs are PD-1 and PD-L1 inhibitors.
  • the other drug is nivolumab, AB122, and the like.
  • Figure 1 is the XRPD pattern (crystal form II) of the TAS-116 compound prepared according to the method described in Example 102 in the patent document CN104710420B.
  • Fig. 2 is the XRPD pattern of the TAS-116 compound crystal form I (type I crystal) prepared according to the method described in the comparative example 1 in the patent document CN107531707B.
  • Figure 3 is the XRPD pattern of the TAS-116 compound crystal form II (type II crystal) prepared according to the method described in Example 1 in the patent document CN107531707B.
  • FIG. 4 is the XRPD pattern of TAS-116 crystal form III prepared in Example 1 of the present disclosure.
  • FIG. 5 is the DSC spectrum of TAS-116 crystal form III prepared in Example 1 of the present disclosure.
  • FIG. 7 is the IR spectrum of TAS-116 crystal form III prepared in Example 1 of the present disclosure.
  • FIG. 8 is the DVS spectrum of TAS-116 crystal form III prepared in Example 1 of the present disclosure.
  • Example 9 is a PLM image of the TAS-116 crystal form III prepared in Example 1 of the present disclosure.
  • FIG. 10 is the XRPD pattern of TAS-116 crystal form I under thermal conditions in Experiment 1 of Experimental Example 1.
  • FIG. 10 is the XRPD pattern of TAS-116 crystal form I under thermal conditions in Experiment 1 of Experimental Example 1.
  • FIG. 11 is the XRPD pattern of TAS-116 crystal form II in water condition in Experiment 1, Experiment 1.
  • FIG. 11 is the XRPD pattern of TAS-116 crystal form II in water condition in Experiment 1, Experiment 1.
  • FIG. 12 is the XRPD pattern of TAS-116 crystal form II and crystal form III under thermal conditions in Experiment 1 of Experimental Example 1.
  • FIG. 12 is the XRPD pattern of TAS-116 crystal form II and crystal form III under thermal conditions in Experiment 1 of Experimental Example 1.
  • FIG. 13 is the XRPD pattern of TAS-116 crystal form I and crystal form III in water condition in Experiment 1, Experiment 1.
  • FIG. 13 is the XRPD pattern of TAS-116 crystal form I and crystal form III in water condition in Experiment 1, Experiment 1.
  • FIG. 14 is an XRPD comparison diagram of the crystal form stability test of TAS-116 crystal form III in Experiment 1, Experiment 2.
  • FIG. 14 is an XRPD comparison diagram of the crystal form stability test of TAS-116 crystal form III in Experiment 1, Experiment 2.
  • FIG. 15 is an XRPD comparison diagram of the 63-day stability test of the crystal form of TAS-116 crystal form III in Experiment 1, Experiment 2.
  • FIG. 15 is an XRPD comparison diagram of the 63-day stability test of the crystal form of TAS-116 crystal form III in Experiment 1, Experiment 2.
  • FIG. 15 is an XRPD comparison diagram of the 63-day stability test of the crystal form of TAS-116 crystal form III in Experiment 1, Experiment 2.
  • FIG. 16 is a particle size distribution (PSD) diagram of TAS-116 crystal form III in Experimental Example 2.
  • PSD particle size distribution
  • Figure 17 is the solubility curve of crystal form I, crystal form II and crystal form III in the buffer solution of pH 6.8 in Experiment 1 of Experimental Example 3.
  • X-ray powder diffraction (XRPD): The instrument is a Bruker D8 Advance diffractometer. Samples were tested at room temperature. The detection conditions are as follows, angle range: 3 to 40° 2 ⁇ , step size: 0.02° 2 ⁇ , speed: 0.2 sec/step.
  • PLM images were taken from an XP to 500E polarized light microscope. Take a small amount of powder sample and place it on a glass slide, add a small amount of mineral oil dropwise to disperse the sample, cover it with a cover glass, place it on the stage for observation and take pictures.
  • Thermogravimetric analysis (TGA) data were obtained from TA Instruments Q500 TGA.
  • the detection method is as follows: take the sample and raise the sample to 400 °C at a heating rate of 10 °C/min under the protection of 40 mL/min of dry N2 .
  • Dynamic moisture sorption (DVS) analysis data and isothermal adsorption analysis data were obtained from SMS Intrinsic PLUS.
  • the detection method is as follows: take a sample and detect the weight change during the change of relative humidity from 0% to 80% to 0%.
  • Infrared spectroscopy (IR) data were collected from Bruker Tensor 27 using ATR equipment to collect infrared absorption spectra in the range of 600 to 4000 cm ⁇ 1 .
  • HPLC purity data were obtained from a Uitimate 3000 high performance liquid chromatograph.
  • the chromatographic column is C18 (4.6*150mm, 5 ⁇ m), the detection wavelength is 254nm, the detection column temperature is 30°C, the flow rate is 1mL/min, and the injection volume is 5 ⁇ L.
  • the examples are all operated at room temperature, and the solvent ratios are all volume ratios.
  • TAS-116 was prepared as a free white solid.
  • the free state sample of TAS-116 was prepared according to the method described in Comparative Example 1 in the patent document CN107531707B.
  • the free state sample of TAS-116 was prepared according to the method described in Example 1 in the patent document CN107531707B.
  • TAS-116 About 500 mg of TAS-116 was taken, 10 mL of 1,4-dioxane was added to form a suspension, stirred at room temperature overnight, centrifuged, and vacuum dried at room temperature overnight to obtain a solid, and then heated at 120 ° C for 5 minutes to obtain about 401 mg of white solid.
  • the DSC spectrum is shown in Figure 5, the melting point onset value is 269 °C, and the peak value is 270 °C;
  • TGA spectrum is shown in Figure 6; it is anhydrous, with only 0.9% weight loss before 105 °C;
  • the DVS diagram is shown in Fig. 8, with only 0.3% weight change in the humidity range of 0%RH-80%RH;
  • the PLM diagram is shown in Figure 9.
  • the fine granular crystals have a crystal size far less than 50 microns, and the fine particles are more conducive to improving the solubility and dissolution rate.
  • TAS-116 About 1000 mg of TAS-116 was taken, 5 mL of 1,4-dioxane was added to form a suspension, stirred at room temperature for 72 hours, centrifuged, and vacuum dried at room temperature overnight to obtain a solid, and then heated at 150 °C for 5 minutes to obtain about 850 mg of white solid.
  • TAS-116 Take about 200 mg of TAS-116, add 20 mL of 1,4-dioxane to form a solution, which becomes a suspension after 0.5 hours, stir at room temperature for 10 hours, centrifuge, and vacuum dry at room temperature overnight to obtain a solid, which is then heated at 60°C for 16 hours About 100 mg of white solid were obtained afterward.
  • TAS-116 prepared in Preparation Example 1, add 1.0 mL of chloroform, form a solution at 60 °C, cool down to 30 °C to 40 °C to obtain a saturated solution, add 5 mg of the crystal form III seed crystal prepared in Example 1, and stir for 2 hours, Continue to cool down to 0°C, centrifuge, and vacuum dry at room temperature overnight to obtain about 47 mg of white solid.
  • TAS-116 prepared in Preparation Example 1, add 1.0 mL of chloroform and 0.25 mL of tetrahydrofuran, form a solution at 60°C, cool down to room temperature to obtain a saturated solution, add 15 mg of the crystal form III seed crystal prepared in Example 1, and stir for 24 hours, Centrifugation and vacuum drying overnight at room temperature yielded about 44 mg of a white solid.
  • the solids obtained in Examples 2 to 5 are TAS-116 crystal form III, which has the same characteristic pattern as the crystal form III prepared in Example 1, and is not repeated in this disclosure.
  • the disclosed crystal form I, crystal form II samples and crystal form III samples of the present disclosure were taken to investigate the crystal form changes after heating and under water conditions.
  • Thermal conditions including but not limited to blast drying method above 30°C, vacuum drying method, acceleration (40°C/75%RH) influencing factors, heating method in solvent above 30°C, etc.
  • the thermal conditions of the present disclosure refer to a 40°C blast drying method.
  • Aqueous conditions including but not limited to samples in aqueous solutions, aqueous media, body fluids, and humidity.
  • the water conditions of the present disclosure are stirring in an aqueous solution at room temperature for 16 hours.
  • Table 1 shows that the crystal form I cannot withstand heat, and the crystal form II cannot withstand water, and the original crystal form cannot be maintained under these two conditions.
  • the crystal form III of the present disclosure has good thermal and water crystal form stability.
  • crystal form III sample of the present disclosure was weighed and placed in the open under long-term (25°C/60%RH), accelerated (40°C/75%RH), and high temperature (40°C) conditions, and XRPD was regularly detected.
  • Crystal form III sample of the present disclosure was weighed and placed openly under long-term (25°C/60%RH), accelerated (40°C/75%RH), high temperature (40°C) and high humidity (97%RH) conditions , take the initial 0 days, long-term (25°C/60%RH) 63 days, accelerated (40°C/75%RH) 63 days, high temperature (40°C) 63 days and high humidity (97%RH) 63 days Samples of Form III were tested for purity by HPLC.
  • HPLC detection method is shown in Table 2 below.
  • the purity test results of crystal form III are shown in Table 3 below.
  • the purity test results in Table 3 show that the crystal form III of the present disclosure has good chemical stability.
  • the mixed samples of the raw and auxiliary materials of the three crystal forms were tableted with a single punch tablet machine (pressure 2MPa, time 2min).
  • Dissolution medium pH 6.8 phosphate buffer.
  • Dissolution tests were performed on the tablets containing Form I, Form II and Form III, respectively.
  • Dissolution method temperature 37°C, rotating speed 50rpm, medium volume 900mL, slurry method.
  • Dissolution Apparatus Agilent 708-DS, Sampler: Agilent 850-DS
  • the dissolution rate of crystal form III was higher than that of crystal form I and crystal form II; after 2 h, the dissolution rate of crystal form III reached 49%, while the dissolution rates of crystal forms I and II were only 29% and 33%.
  • the tablet dissolution curves of crystal form I, crystal form II and crystal form III are shown in Figure 18, and the specific dissolution test results of crystal form I, crystal form II and crystal form III are shown in Table 8 below.

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Abstract

公开了TAS-116的晶型，及其制备方法、药物组合物和用途。

Description

TAS-116的晶型及其制备方法、药物组合物和用途
相关申请的引用
本公开要求于2020年12月31日向中华人民共和国国家知识产权局提交的第202011630937.9号中国发明专利申请以及于2021年12月31日向中华人民共和国国家知识产权局提交的第202111665564.3号中国发明专利申请的全部权益，并通过引用的方式将其全部内容并入本公开。
领域
本公开涉及药物化学领域。具体而言，本公开涉及TAS-116的晶型及其制备方法、药物组合物和用途。
背景
TAS-116是一种选择性热激蛋白90(HSP90)抑制剂，用于治疗结肠癌、胃间质瘤等胃肠道癌症。目前，TAS-116正在胃肠道癌症患者中开展临床研究。
TAS-116化学名称为3-乙基-4-{3-异丙基-4-(4-(1-甲基-1H-吡唑-4-基)-1H-咪唑-1-基)-1H-吡唑并[3,4-b]吡啶-1-基}苯甲酰胺，又名THS-1593，分子式为C 25H 26N 8O，分子量为454.53，其化学结构式如下所示：
Figure PCTCN2022078224-appb-000001
专利CN102471335B公开了包括TAS-116化合物的通式结构。
专利CN104710420B公开TAS-116的具体结构，并公开了一种TAS-116游离态的制备方法，提及TAS-116为白色固体。
专利CN107531707B公开了TAS-116的I型结晶(以下简称为“晶型I”)和II型结晶(以下简称为“晶型II”)，其中晶型I仅有XRPD图谱，晶型I的口服吸收性存在问题；晶型II为无水物，专利还告知，晶型II是优于晶型I的晶型。
本发明人在研究过程中发现，根据专利CN104710420B中实施例102制备获得的TAS-116的样品是晶型II，且获得的样品的DMSO(二甲亚砜)残留很高，采用***清洗依旧有较多残留。本发明人发现，晶型II样品在实施例102溶剂中保留超过2小时后出现了晶型I，说明晶型II的稳定性存在问题。
本发明人在研究过程中还发现，根据CN107531707B制备的TAS-116晶型I不稳定，在室温下(20-30℃)放置容易发生晶型转变，转变成晶型II。晶型I需要更苛刻的储存条件才能稳定，说明其可药用的价值不高。
本发明人在研究过程中还发现，根据CN107531707B专利中制备的TAS-116晶型II的稳定性有较大的局限性，除了上述CN104710420B中实施例102溶剂中不稳定之外，在多种其他环境下也有发生转晶，出现不同程度的晶型I。
鉴于现有技术尚存不足，特别是稳定性不足的问题，本领域需要开发更稳定的、具有更多优势性能的TAS-116的固体形态。
概述
针对现有技术的不足，本公开的目的是提供理化性质更优的TAS-116晶型，及其制备方法、药物组合物和用途。与已知的TAS-116化合物相比，本公开的TAS-116晶型具有更好的晶型稳定性。除此之外，还发现具有其他意想不到的效果，主要表现在更好的溶解度和溶出速度，更好的颗粒形貌，更高的结晶度、更优良的吸湿性等方面，进一步认为本公开的晶型还拥有更好的流动性、制剂可加工性和生物利用度。
根据本公开的目的，本公开的第一方面提供了TAS-116晶型，在下文中称为晶型III。
本公开的晶型III为无水物，其结构式如式(I)所示：
Figure PCTCN2022078224-appb-000002
使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱在2θ值为6.39°±0.2°、10.40°±0.2°、12.94°±0.2°和19.48°±0.2°处具有特征峰。
在某些实施方案中，使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱至少在2θ值为3.20°±0.2°、6.39°±0.2°、10.40°±0.2°、11.41°±0.2°、12.94°±0.2°和19.48°±0.2°处中的一处具有特征峰。
在某些实施方案中，使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱至少在2θ值为3.20°±0.2°、6.39°±0.2°、10.40°±0.2°、11.41°±0.2°、12.94°±0.2°、17.58°±0.2°、18.26°±0.2°、19.48°±0.2°、21.71°±0.2°、22.69°±0.2°和23.65°±0.2°处中的一处具有特征峰。
在某些实施方案中，使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱在2θ值为3.20°±0.2°、6.39°±0.2°、10.40°±0.2°、11.41°±0.2°、12.94°±0.2°和19.48°±0.2°处具有特征峰。
在某些实施方案中，使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱在2θ值为3.20°±0.2°、6.39°±0.2°、10.40°±0.2°、11.41°±0.2°、12.94°±0.2°、17.58°±0.2°、18.26°±0.2°、19.48°±0.2°、21.71°±0.2°、22.69°±0.2°和23.65°±0.2°处具有特征峰。
在某些实施方案中，使用Cu-Kα辐射，所述晶型III的X-射线粉末衍射图谱在以下衍射角处具有特征峰，其2θ值和相对强度如下表所示：
Figure PCTCN2022078224-appb-000003
在某些实施方案中，所述晶型III的X-射线粉末衍射(XRPD)图谱基本上如图4所示。
在某些实施方案中，所述晶型III的差示扫描量热(DSC)图谱如图5所示。所述晶型III熔点onset值为269℃，峰值为270℃。
在某些实施方案中，所述晶型III的热重分析(TGA)图谱如图6所示。所述晶型III为无水物，105℃之前仅有0.9％的失重。
在某些实施方案中，所述晶型III的傅里叶红外光谱如图7所示。所述晶型III的傅里叶红外光谱在波数为1650cm -1±2cm -1、1569cm -1±2cm -1、1504cm -1±2cm -1、1424cm -1±2cm -1、1272cm -1±2cm -1、1030cm -1±2cm -1、823cm -1±2cm -1、812cm -1±2cm -1、748cm -1±2cm -1、711cm -1±2cm - 1、668cm -1±2cm -1和653cm -1±2cm -1处具有特征峰。
在某些实施方案中，所述晶型III的DVS等温曲线如图8所示。所述晶型III在0％RH-80％RH湿度范围内仅0.3％的重量变化。
在某些实施方案中，所述晶型III的偏振光显微镜(PLM)图如图9所示。所述晶型III为细小颗粒状晶体。
根据本公开的目的，本公开的第二方面提供了TAS-116晶型III的制备方法，包括以下方法中任意一种：
(1)将化合物TAS-116固体在溶剂1中形成悬浊液，搅拌，分离出固体，干燥，得到所述的晶型III。
在某些实施方案中，所述溶剂1选自环醚类。在某些实施方案中，所述溶剂1为1,4-二氧六环。
在某些实施方案中，所述化合物TAS-116固体与溶剂1的质量体积比为10至200:1(mg:mL)。在某些实施方案中，所述化合物TAS-116固体与溶剂1的质量体积比为30至100:1(mg:mL)。
在某些实施方案中，所述搅拌时间为10小时至168小时。在某些实施方案中，所述搅拌时间为16小时至72小时。
在某些实施方案中，所述搅拌在室温进行。
在某些实施方案中，干燥后将所得固体再在60℃至150℃温度下加热。在某些实施方案中，干燥后将所得固体再在80℃至130℃温度下加热。在某些实施方案中，加热时间为5分钟至16小时。
(2)将化合物TAS-116固体在溶剂2中形成溶液，降温，分离固体，干燥，得到晶型III。
在某些实施方案中，所述溶剂2选自卤代烷烃类、醇类、酮类、呋喃类、环醚类、腈类或其混合溶剂。在某些实施方案中，所述溶剂2为四氢呋喃和氯仿。在某些实施方案中，所述混合溶剂中两种溶剂的体积比为1:4至4:1。
在某些实施方案中，所述溶液中溶质与溶剂2的质量体积比为5至100:1(mg:mL)。在某些实施方案中，所述溶液中溶质与溶剂2的质量体积比为40至100:1(mg:mL)。
在某些实施方案中，所述形成溶液的温度为60℃至80℃。
在某些实施方案中，降温至10℃至50℃。在某些实施方案中，降温至10℃至40℃。
在某些实施方案中，在降温过程中添加TAS-116的晶型III晶种。
在某些实施方案中，所述晶种添加量为TAS-116固体10％至30％。
在某些实施方案中，所述降温可同时搅拌或降温后搅拌。在某些实施方案中，搅拌时间为2小时至24小时。
本公开的TAS-116晶型III相比于已知晶型具有以下优势：
在某些实施方案中，本公开的TAS-116晶型III具有更好的稳定性。与已知的TAS-116晶型I相比，具有更好的热条件下的晶型稳定性；与已知的TAS-116晶型II相比，具有更好的水条件下的晶型稳定性，水条件范围包括但不限于水溶液、含水介质、体液和湿度环境等；晶型I不能耐受热(40℃)，晶型II不能耐受水，在这两个条件下均不能维持原有晶型。而热条件和水在制备API的过程中和干燥阶段、制剂操作过程中，药品货架期期间，体内崩解和溶出期间均非常常见，因此TAS-116的晶型1和晶型II难免会在上述过程中出现晶型不稳定的情况。
众所周知晶型的转变将会对药物的溶解、溶出、生物利用度、稳定性、安全性、合规性等造成不良影响，因此需要避免使用晶型I和晶型II，而晶型III更具药用价值。
在某些实施方案中，本公开的TAS-116晶型III与已知的TAS-116晶型I和晶型II相比，具有更快的溶出速度。
在某些实施方案中，本公开的TAS-116晶型III与已知的TAS-116晶型I和晶型II相比，具有更高的溶解度。
在某些实施方案中，本公开的TAS-116晶型III在0％至80％RH环境下吸湿为0.3％，不易吸湿。
本公开的TAS-116晶型III为均匀细小粉末，具有更好的溶解度和溶出速度，有利于提高药物的生物利用度；具有更好的粒度分布，更易于实现混合均一性和含量均一性；具有更低的吸湿性，在湿度环境下更稳定。
本公开的TAS-116晶型III的制备方法中：
除非特殊注明，“过夜”是指10小时至16小时。
“室温”是指10至30℃的温度。
“搅拌”，可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50至1800转/分。在某些实施方案中，搅拌速度为300至900转/分。
“分离”可以采用本领域的常规方法，例如离心或过滤。在某些实施方案中，减压过滤，一般是在室温下以小于大气压的压力进行抽滤。在某些实施方案中，压力小于0.09MPa。
“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥；可以减压或常压，优选压力小于0.09MPa。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；可以在减压或不减压下进行，优选为压力小于0.09Mpa。起始原料TAS-116可参照专利文献CN104710420B中实施例102所描述的方法制备得到，亦可由市售购买得到，该文献通过引用其全文的方式并入到本公开中。
本公开中，“晶型”是指被所示X-射线粉末衍射图表征所证实的。本领域技术人员公知，其中的实验误差取决于仪器条件、样品准备和样品纯度。图谱通常会随着仪器条件而有所改变。峰的相对强度可能随实验 条件而变化，所以峰强度的顺序不能作为唯一或决定性因素；峰角度的实验误差也应该被考虑进去，通常允许±0.2°的误差；样品高度等因素的影响会造成峰角度整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本公开X射线粉末衍射图谱相同或相似特征峰的晶型均属于本公开的范畴。所述“单一晶型”是指经X-射线粉末衍射检测为单一晶型。
本公开的TAS-116的新晶型是纯的、单一的，基本没有混合任何其他晶型或非晶态。本公开中“基本没有”当用来指新晶型时，指这个新晶型中含有的其他晶型或非晶态少于20％(重量)，更指少于10％(重量)，尤其指少于5％(重量)，特别是指少于1％(重量)。
根据本公开的目的，本公开的第三方面提供了药物组合物，所述药物组合物包含治疗有效量的所述TAS-116晶型III或者由本公开方法制备得到的TAS-116晶型III，以及至少一种药学上可接受的载体。
本公开提供的药物组合物可以通过许多途径给药，包括但不限于：口服(肠内)给药、肠胃外(注射)给药、直肠给药、局部给药、透皮给药、皮内给药、鞘内给药、皮下(SC)给药、肌内(IM)给药、舌下/经颊，眼部、耳部、***和鼻内或吸入给药，通常，给予有效量的本公开所提供的TAS116的固体形式。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度等等，可以由医生确定实际上给予的TAS116的固体形式的量。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常是以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等，可以是常规的速释制剂，也可以是可分散的、可咀嚼的、口腔溶解的制剂，也可以是缓释制剂，可以是肠溶片。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是一个至四个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本公开提供的TAS-116的固体形式，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约0.2至大约5mg/kg，这依赖于具体治疗的病症、特定患者的年龄和体重以及特定患者对药物治疗的反应，准确的剂量要在医师指导下根据标准的医疗原则来确定。具体单位剂量可以是例如20mg、40mg、60mg、80mg、100mg、120mg、140mg、160mg、200mg等。
所述药物组合物中药学上可接受的载体或助剂是本领域技术人员熟知的，可具有各种公知的形式，例如包括但不限于：稀释剂，例如淀粉、改性淀粉、乳糖、粉状纤维素、微晶纤维素、无水磷酸氢钙、磷酸三钙、甘露醇、山梨醇、糖等；粘合剂，例如***胶、瓜尔胶、明 胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇、共聚维酮等；崩解剂，例如淀粉、羧甲基淀粉钠、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。可用的其他药学上可接受的载体或助剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。口服片剂的情况中，通常使用的载体包括乳糖和玉米淀粉，还可以加入润滑剂如硬脂酸镁；口服胶囊剂的情况中，有用的载体/稀释剂包括乳糖、高和低分子量聚乙二醇和干玉米淀粉；明胶胶囊剂的情况下，粉末载体或助剂例如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸与类似物；当以混悬液口服给药时，所述活性成分与乳化剂和悬浮剂混合；如果需要，可以加入某些甜味剂和/或调味剂和/或着色剂。每一个载体或助剂必须是可接受的，能与配方中的其他成分兼容并且对于病患无害。
根据本公开的目的，本公开的第四方面提供了所述TAS-116晶型III、由本公开制备方法得到的TAS-116晶型III，或所述药物组合物在制备用于治疗癌症的药物中的用途。
在某些实施方案中，所述的癌症包括但不限于以下具体疾病和病症，如头颈部癌、食管癌、胃癌、结肠癌、直肠癌、肝脏癌、胆囊-胆管癌、胆道癌、胰腺癌、肺癌、乳腺癌、卵巢癌、子***、子宫体癌、肾癌、膀胱癌、***癌、睾丸肿瘤、骨-软组织肉瘤、白血病、恶性淋巴瘤、多发性骨髓瘤、皮肤癌、脑肿瘤、间皮瘤等。
根据本公开的目的，本公开的第五方面提供了治疗癌症的方法，所述方法包括给予需要所述方法的患者治疗有效量的所述TAS-116晶型III或其药物组合物。
在某些实施方案中，所述患者包括但不限于哺乳动物。
根据本公开的目的，本公开的第六方面提供了所述TAS-116晶型III或其药物组合物与其他药物的联合应用。
在某些实施方案中，所述其他药物为单克隆抗体药物。在某些实施方案中，所述其他药物为PD-1和PD-L1抑制剂。在某些实施方案中，所述其他药物为nivolumab、AB122等。
附图简要说明
图1为按照专利文献CN104710420B中实施例102所描述的方法制备的TAS-116化合物的XRPD图谱(晶型II)。
图2为按照专利文献CN107531707B中比较例1所描述的方法制备的TAS-116化合物晶型I(I型结晶)的XRPD图谱。
图3为按照专利文献CN107531707B中实施例1所描述的方法制备的TAS-116化合物晶型II(II型结晶)的XRPD图谱。
图4为本公开实施例1制得的TAS-116晶型III的XRPD图谱。
图5为本公开实施例1制得的TAS-116晶型III的DSC图谱。
图6为本公开实施例1制得的TAS-116晶型III的TGA图谱。
图7为本公开实施例1制得的TAS-116晶型III的IR图谱。
图8为本公开实施例1制得的TAS-116晶型III的DVS图谱。
图9为本公开实施例1制得的TAS-116晶型III的PLM图。
图10为实验例1实验一中TAS-116晶型I热条件下的XRPD图。
图11为实验例1实验一中TAS-116晶型II水条件下的XRPD图。
图12为实验例1实验一中TAS-116晶型II和晶型III热条件下的XRPD图。
图13为是实验例1实验一中TAS-116晶型I和晶型III水条件下的XRPD图。
图14为实验例1实验二中TAS-116晶型III的晶型稳定性实验的XRPD对比图。
图15为实验例1实验二中TAS-116晶型III的晶型63天稳定性实验的XRPD对比图。
图16为实验例2中TAS-116晶型III的粒径分布(PSD)图。
图17为实验例3实验一中晶型I、晶型II和晶型III在pH 6.8的缓冲液中的溶解度曲线。
图18为实验例4中TAS-116晶型I、晶型II和晶型III的片剂溶出度曲线。
详述
下列实施例进一步解释说明本公开，但是，它们并不构成对本公开范围的限制或限定。本说明书中所引用的所有专利文件及非专利出版物均通过引用以其全文并入本文中。
检测仪器及方法：
X-射线粉末衍射(XRPD)：仪器为Bruker D8 Advance diffractometer。样品在室温下测试。检测条件如下，角度范围：3至40°2θ，步长：0.02°2θ，速度：0.2秒/步。
偏振光显微镜(PLM)图采自于XP至500E偏振光显微镜。取少量粉末样品置于载玻片上，滴加少量矿物油分散样品，盖上盖玻片，放置在载物台上进行观测并拍照。
热重分析(TGA)数据采自于TA Instruments Q500 TGA。检测方法为：取样品以10℃/min的升温速度在40mL/min干燥N 2的保护下将样品升至400℃。
动态水分吸附(DVS)分析数据和等温吸附分析数据采自于SMS Intrinsic PLUS。检测方法为：取样品，检测相对湿度从0％到80％到0％变化过程中的重量变化。
红外光谱分析(IR)数据采自于Bruker Tensor 27，采用ATR设备，在600至4000cm -1范围内，采集红外吸收光谱。
HPLC纯度数据采自于Uitimate 3000高效液相色谱仪。色谱柱为C18(4.6*150mm，5μm)，检测波长为254nm，检测柱温30℃，流速为1mL/min，进样量5μL。
除非特殊注明，实施例均在室温下操作，溶剂比均为体积比。
实施例中所用的各种试剂如无特别说明均为市售购买。
制备例1  TAS-116游离态的制备
根据专利文献CN104710420B中实施例102(P77)所描述的方法制备得到TAS-116游离态白色固体。
经检测，其XRPD图谱如图1所示，表明，根据专利文献CN104710420B中实施例102所描述的方法制备得到的TAS-116为晶型II。
制备例2  TAS-116晶型I制备
根据专利文献CN107531707B中比较例1所描述的方法制备得到TAS-116游离态样品。
经检测，其XRPD图谱如图2所示，表明，根据专利文献CN107531707B中比较例1所描述的方法制备得到TAS-116游离态样品为晶型I。
制备例3  TAS-116晶型II制备
根据专利文献CN107531707B中实施例1所描述的方法制备得到TAS-116游离态样品。
经检测，其XRPD图谱如图3所示，表明，根据专利文献CN107531707B中实施例1所描述的方法制备得到TAS-116游离态样品为晶型II。
实施例1  TAS-116晶型III的制备
取约500mg TAS-116，加入10mL1,4-二氧六环，形成悬浮液，常温下搅拌过夜，离心，室温下真空干燥过夜得到固体，再在120℃加热5分钟后得到约401mg白色固体。
经检测，所得固体为TAS-116晶型III，其
XRPD图谱如图4所示；
DSC图谱如图5所示，熔点onset值为269℃，峰值为270℃；
TGA图谱如图6所示；为无水物，105℃之前仅有0.9％的失重；
IR图谱如图7所示；
DVS图如图8所示，在0％RH-80％RH湿度范围内仅0.3％的重量变化；
PLM图如图9所示，细小颗粒状晶体，晶体粒径均远小于50微米，细小颗粒更有利于提高溶解度和溶解速度。
实施例2  TAS-116晶型III的制备
取约1000mgTAS-116，加入5mL1,4-二氧六环，形成悬浮液，常温下搅拌72小时，离心，室温下真空干燥过夜得到固体，再在150℃加热5分钟后得到约850mg白色固体。
实施例3  TAS-116晶型III的制备
取约200mgTAS-116，加入20mL1,4-二氧六环，形成溶液，0.5小时后变成悬浮液，常温下搅拌10小时，离心，室温下真空干燥过夜得到固体，再在60℃加热16小时后得到约100mg白色固体。
实施例4  TAS-116晶型III的制备
取约50mg制备例1制备的TAS-116，加入1.0mL氯仿，60℃形成溶液，降温至30℃至40℃获得饱和溶液，加入5mg实施例1制备的晶型III晶种，搅拌2小时，继续降温至0℃，离心，室温下真空干燥过夜得到约47mg白色固体。
实施例5  TAS-116晶型III的制备
取约50mg制备例1制备的TAS-116，加入1.0mL氯仿和0.25mL四氢呋喃，60℃形成溶液，降温至室温获得饱和溶液，加入15mg实施例1制备的晶型III晶种，搅拌24小时，离心，室温下真空干燥过夜得到约44mg白色固体。
经检测，实施例2至5所得固体为TAS-116晶型III，其具有与实施例1制备的晶型III相同的表征图谱，不在本公开中重复示出。
实验例1稳定性对比实验
实验一
取已公开的晶型I、晶型II样品和本公开的晶型III样品，考察在受热后和水条件下的晶型变化情况。
热条件：包括但不限于高于30℃的鼓风干燥方式、真空干燥方式，加速(40℃/75％RH)影响因素，高于30℃的溶剂中加热方式等。本公开的热条件是指40℃鼓风干燥方式。
水条件：包括但不限于样品处于水溶液、含水介质、体液和湿度等环境中。本公开的水条件是室温下的水溶液中搅拌16小时。
实验结果见下表1。表1显示：晶型I不能耐受热，晶型II不能耐受水，在这两个条件下均不能维持原有晶型。而本公开的晶型III却有良好的热和水的晶型稳定性。
表1
Figure PCTCN2022078224-appb-000004
Figure PCTCN2022078224-appb-000005
实验二
称取适量本公开的晶型III样品，敞口放置在长期(25℃/60％RH)、加速(40℃/75％RH)、高温(40℃)条件下，定期检测XRPD。
实验结果显示，晶型III在长期、加速和高温条件下15天未转晶，其XRPD对比图如图14所示。
进一步地，晶型III敞口在长期(25℃/60％RH)、高温(40℃)条件下63天晶型未变，其XRPD对比图如图15所示。
实验三
称取适量本公开的晶型III样品，敞口放置在长期(25℃/60％RH)、加速(40℃/75％RH)、高温(40℃)和高湿(97％RH)条件下，分别取起始0天、长期(25℃/60％RH)63天、加速(40℃/75％RH)63天、高温(40℃)63天和高湿(97％RH)63天的晶型III样品进行HPLC纯度检测。
HPLC检测方法见下表2。
表2
类目 参数
仪器 Uitimate3000高效液相色谱仪
色谱柱类型 C18,4.6×150mm,5um
紫外波长 UVat254nm
流速 1.0mL/min
柱温 30℃
进样量 5.0uL
稀释剂 甲醇
流动相A 水(0.05％FA)
流动相B 甲醇(0.05％FA)
流动相比例 A:B＝45:55
晶型III的纯度检测结果见下表3。表3纯度检测结果表明，本公开晶型III具有良好的化学稳定性。
表3
Figure PCTCN2022078224-appb-000006
实验例2粒度分布
分别取适量本公开的晶型III样品，用正庚烷分散后，进行激光粒度仪检测。粒度分布(PSD)在Microtrac S3500型激光粒度分析仪上采集。方法参数如下表4：
表4
参数 数值
调零时间 30s
检测时间 30s
分散剂流速 55％
分散剂 正庚烷
激光源波长 780nm
实验结果见下表5以及图16。图16显示晶型III的PSD呈正态分布。
表5
晶型 D (10)(μm) D (50)(μm) D (90)(μm)
晶型III 5.42 10.75 25.47
实验例3溶解度实验
实验一  pH6.8下溶解度
取晶型I、晶型II和晶型III各约10mg于瓶中，分别加入15mL的pH 6.8的缓冲液形成混悬液，然后将所有样品在25℃±2℃条件下振荡，分别在振荡5min、30min、45min、60min时取pH 6.8缓冲液中各个晶型样品1mL过滤，用HPLC检测样品溶解度。HPLC检测方法同表2。
pH＝6.8的缓冲液：配制0.2mol/L磷酸二氢钾100mL，用0.2mol/L氢氧化钠调节pH至6.8。
晶型I、晶型II和晶型III在pH 6.8的缓冲液中的溶解度检测结果如下表6所示，溶解度曲线如图17所示。
表6
Figure PCTCN2022078224-appb-000007
实验二水中溶解度
取晶型III约4mg的样品于瓶中，加入15mL水形成混悬液，然后在25℃±2℃条件下振荡，分别在振荡60min时取样品1mL过滤，用HPLC(方法同表6)检测样品溶解度，所述溶解度5.83μg/mL。
实验例4片剂溶出度
片剂制作及溶出实验过程：
分别取适量处方量的晶型I、晶型II和晶型III样品按下表7中原辅料的称样量混合均匀。
表7片剂处方表
Figure PCTCN2022078224-appb-000008
分别将三个晶型的原辅料混合样品用单冲压片机压片(压力2MPa，时间2min)。
溶出介质：pH 6.8磷酸盐缓冲液。
分别对含晶型I、晶型II和晶型III的片剂，进行溶出度检测。
溶出方法：温度37℃，转速50rpm，介质体积900mL，浆法。(溶出仪：安捷伦708-DS，取样器：安捷伦850-DS)
分别在5min、10min、15min、20min、30min、45min、1h、1.5h和2h九个时间点取样检测。
实验结果：
相同时间内，晶型III的溶出度比晶型I和晶型II均更高；2h后，晶型III溶出度达到49％，而晶型I、II溶出度仅为29％和33％。晶型I、晶型II和晶型III的片剂溶出度曲线见图18，具体的晶型I、晶型II和晶型III的片剂溶出度检测结果见如下表8。
表8
Figure PCTCN2022078224-appb-000009
以上所述，仅为本公开的具体实施方式，但本公开的保护范围并不局限于此，任何熟悉本领域的技术人员在本公开所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本公开的保护范围之内。因此，本公开的保护范围应该以权利要求书所限定的保护范围为准。

Claims (14)

  1. 式(I)所示的化合物TAS-116的晶型III，
    Figure PCTCN2022078224-appb-100001
    其中，使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱在2θ值为6.39°±0.2°、10.40°±0.2°、12.94°±0.2°和19.48°±0.2°处具有特征峰。
  2. 如权利要求1所述的晶型III，其中，使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱至少在2θ值为3.20°±0.2°、6.39°±0.2°、10.40°±0.2°、11.41°±0.2°、12.94°±0.2°和19.48°±0.2°处中的一处具有特征峰。
  3. 如权利要求1或2所述的晶型III，其中，使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱至少在2θ值为3.20°±0.2°、6.39°±0.2°、10.40°±0.2°、11.41°±0.2°、12.94°±0.2°、17.58°±0.2°、18.26°±0.2°、19.48°±0.2°、21.71°±0.2°、22.69°±0.2°和23.65°±0.2°处中的一处具有特征峰。
  4. 如权利要求1至3中任一权利要求所述的晶型III，其中，使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱在2θ值为3.20°±0.2°、6.39°±0.2°、10.40°±0.2°、11.41°±0.2°、12.94°±0.2°和19.48°±0.2°处具有特征峰。
  5. 如权利要求1至4中任一权利要求所述的晶型III，其中，使用Cu-Kα辐射，所述的晶型III的X-射线粉末衍射图谱在2θ值为3.20°±0.2°、6.39°±0.2°、10.40°±0.2°、11.41°±0.2°、12.94°±0.2°、17.58°±0.2°、18.26°±0.2°、19.48°±0.2°、21.71°±0.2°、22.69°±0.2°和23.65°±0.2°处具有特征峰。
  6. 如权利要求1至5中任一权利要求所述的晶型III，其中，使用Cu-Kα辐射，所述晶型III的X-射线粉末衍射图谱在以下衍射角处具有特征 峰，其2θ值和相对强度如下表所示：
    Figure PCTCN2022078224-appb-100002
  7. 如权利要求1至6中任一权利要求所述的晶型III，其中，所述晶型III的X-射线粉末衍射图谱基本上如图4所示。
  8. 如权利要求1至7中任一权利要求所述的晶型III，其中，所述晶型III的傅里叶红外光谱在波数为1650cm -1±2cm -1、1569cm -1±2cm -1、1504cm -1±2cm -1、1424cm -1±2cm -1、1272cm -1±2cm -1、1030cm -1±2cm -1、823cm -1±2cm -1、812cm -1±2cm -1、748cm -1±2cm -1、711cm -1±2cm -1、668cm -1±2cm -1和653cm -1±2cm -1处具有特征峰。
  9. 制备权利要求1至8中任一权利要求所述的晶型III的方法，其包括：
    将化合物TAS-116固体在溶剂1中形成悬浊液，搅拌，分离固体，干燥，得到所述的晶型III；
    优选地，所述溶剂1选自环醚类；更优选为1,4-二氧六环；
    优选地，所述化合物TAS-116固体与溶剂1的质量体积比为10至200:1；
    优选地，所述搅拌时间为10小时至168小时；更优选16小时至72小时；
    优选地，所述搅拌在室温进行；
    优选地，干燥后将所得固体再在60℃至150℃温度下，更优选80℃至130℃温度下加热，优选地，加热时间为5分钟至16小时。
  10. 制备权利要求1至8中任一权利要求所述的晶型III的方法，其包括：
    将化合物TAS-116固体在溶剂2中形成溶液，降温，分离固体，干燥，得到晶型III；
    优选地，所述溶剂2选自卤代烷烃类、醇类、酮类、呋喃类、环醚类、腈类或其混合溶剂；更优选为四氢呋喃和氯仿；优选地，所述混合溶剂中两种溶剂的体积比为1:4至4:1；
    优选地，所述溶液中溶质与溶剂2的质量体积比为5至100:1；
    优选地，所述形成溶液的温度为60℃至80℃；
    优选地，降温至10℃至50℃，更优选地，降温至10℃至40℃；
    优选地，在降温过程中添加TAS-116的晶型III晶种；
    优选地，所述晶种添加量为TAS-116固体10％至30％；
    优选地，所述搅拌时间为2小时至24小时。
  11. 药物组合物，其包含权利要求1至8中任一权利要求所述的晶型III，或者由权利要求9或10所述的方法制备得到的晶型III，以及至少一种药学上可接受的载体。
  12. 治疗癌症的方法，其包括向需要所述方法的个体给予治疗有销量的权利要求1至8中任一权利要求所述的晶型III、由权利要求9或10所述的方法制备得到的晶型III或权利要求11所述的药物组合物。
  13. 如权利要求12所述的方法，其中所述的癌症选自头颈部癌、食管癌、胃癌、结肠癌、直肠癌、肝脏癌、胆囊-胆管癌、胆道癌、胰腺癌、肺癌、乳腺癌、卵巢癌、子***、子宫体癌、肾癌、膀胱癌、***癌、睾丸肿瘤、骨-软组织肉瘤、白血病、恶性淋巴瘤、多发性骨髓瘤、皮肤癌、脑肿瘤和间皮瘤。
  14. 如权利要求12或13所述的方法，还包括向所述个体给予至少另一种治疗癌症的药物，优选单克隆抗体药物，更优选PD-1和PD-L1抑制剂，甚至更优选nivolumab和AB122。
PCT/CN2022/078224 2020-12-31 2022-02-28 Tas-116的晶型及其制备方法、药物组合物和用途 WO2022144042A1 (zh)

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