WO2022144042A1 - Forme cristalline de tas-116, son procédé de préparation, sa composition pharmaceutique et son utilisation - Google Patents

Forme cristalline de tas-116, son procédé de préparation, sa composition pharmaceutique et son utilisation 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)
Chinese (zh)
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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.

Abstract

La divulgation concerne une forme cristalline de TAS-116, son procédé de préparation, sa composition pharmaceutique et son utilisation.
PCT/CN2022/078224 2020-12-31 2022-02-28 Forme cristalline de tas-116, son procédé de préparation, sa composition pharmaceutique et son utilisation WO2022144042A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103313970A (zh) * 2011-01-07 2013-09-18 大鹏药品工业株式会社 新型二环式化合物或其盐
CN104710420A (zh) * 2009-07-10 2015-06-17 大鹏药品工业株式会社 氮杂二环式化合物或其盐、含有其的医药、组合物及应用
CN107531707A (zh) * 2015-05-12 2018-01-02 大鹏药品工业株式会社 氮杂二环式化合物的结晶
US20180243306A1 (en) * 2017-02-26 2018-08-30 Institute For Cancer Research D/B/A The Research Institute Of Fox Chase Cancer Center Dual Inhibition Of CDK And HSP90 Destabilize HIF1alpha And Synergistically Induces Cancer Cell Death

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104710420A (zh) * 2009-07-10 2015-06-17 大鹏药品工业株式会社 氮杂二环式化合物或其盐、含有其的医药、组合物及应用
CN103313970A (zh) * 2011-01-07 2013-09-18 大鹏药品工业株式会社 新型二环式化合物或其盐
CN107531707A (zh) * 2015-05-12 2018-01-02 大鹏药品工业株式会社 氮杂二环式化合物的结晶
US20180243306A1 (en) * 2017-02-26 2018-08-30 Institute For Cancer Research D/B/A The Research Institute Of Fox Chase Cancer Center Dual Inhibition Of CDK And HSP90 Destabilize HIF1alpha And Synergistically Induces Cancer Cell Death

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
S. OHKUBO, Y. KODAMA, H. MURAOKA, H. HITOTSUMACHI, C. YOSHIMURA, M. KITADE, A. HASHIMOTO, K. ITO, A. GOMORI, K. TAKAHASHI, Y. SHIB: "TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90 and , Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models", MOLECULAR CANCER THERAPEUTICS, vol. 14, no. 1, 1 January 2015 (2015-01-01), US , pages 14 - 22, XP055506314, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-14-0219 *
UNO TAKAO, KAWAI YUICHI, YAMASHITA SATOSHI, OSHIUMI HIROMI, YOSHIMURA CHIHOKO, MIZUTANI TAKASHI, SUZUKI TATSUYA, CHONG KHOON TEE, : "Discovery of 3-Ethyl-4-(3-isopropyl-4-(4-(1-methyl-1 H -pyrazol-4-yl)-1 H -imidazol-1-yl)-1 H -pyrazolo[3,4- b ]pyridin-1-yl)benzamide (TAS-116) as a Potent, Selective, and Orally Available HSP90 Inhibitor", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 2, 24 January 2019 (2019-01-24), US , pages 531 - 551, XP055774258, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b01085 *

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