WO2015081566A1 - Forme cristallines de trametinib et de son solvate, procede de preparation correspondant, composition pharmaceutique en comportant et son utilisation - Google Patents

Forme cristallines de trametinib et de son solvate, procede de preparation correspondant, composition pharmaceutique en comportant et son utilisation Download PDF

Info

Publication number
WO2015081566A1
WO2015081566A1 PCT/CN2013/088797 CN2013088797W WO2015081566A1 WO 2015081566 A1 WO2015081566 A1 WO 2015081566A1 CN 2013088797 W CN2013088797 W CN 2013088797W WO 2015081566 A1 WO2015081566 A1 WO 2015081566A1
Authority
WO
WIPO (PCT)
Prior art keywords
trimetinib
cancer
crystal form
preparation
solvate
Prior art date
Application number
PCT/CN2013/088797
Other languages
English (en)
Chinese (zh)
Inventor
胡晨阳
盛晓霞
盛晓红
Original Assignee
杭州普晒医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州普晒医药科技有限公司 filed Critical 杭州普晒医药科技有限公司
Priority to PCT/CN2013/088797 priority Critical patent/WO2015081566A1/fr
Priority to CN201380069544.7A priority patent/CN104918937B/zh
Publication of WO2015081566A1 publication Critical patent/WO2015081566A1/fr

Links

Classifications

    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • the invention relates to the field of medicinal chemical crystallization technology.
  • it relates to crystalline forms of trimetinib and its solvates and methods for their preparation, and to pharmaceutical compositions and uses of such crystalline forms.
  • trimetinib N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6 ,8-Dimercapto-2,4,7-trioxo-pyrido[4,3-D]pyrimidin-1(2H)-yl]phenyl]acetamide
  • English name is TRAMETINIB, aka GSK1120212, GSK 212 or JTP 74057, the structure is as follows:
  • Trimetinib is a novel targeting drug for melanoma cancer developed by GlaxoSmithKline. It is a potent and selective MEK1/MEK2 inhibitor that effectively prevents cancer cell proliferation and induces apoptosis and prolongs patient life. .
  • Phase III clinical trials have shown that the efficacy of trimetinib is significantly better than traditional chemotherapy for the treatment of advanced or positive metastatic melanoma with BRAF V600E/K mutation.
  • trimetinib and other anticancer drugs is under further study and the results are very promising.
  • trimetinib is an oral coated tablet, and the active ingredient is trimetinib disulfoxide solvate (also known as GSK 1120212B), each tablet containing 0.5 mg, 1 mg or 2 mg of trimetinib.
  • the standard content of disulfoxide is 11.3% (theoretical value) and the low content is about 9.5%.
  • trimetini preparation also has an oral liquid dosage form. Its 1 H-NMR. Although the text of this document describes the disulfoxide solvate, ethanol solvate, etc. of trimetinib, only the -NMR data are disclosed, and no specific description of the preparation methods of these solvates is given.
  • Patent document WO2012088033A2 discloses a pharmaceutical composition of trimetinib sulfoxide solvate, a method for the treatment thereof and a method of preparing the composition, but this document also does not disclose any characterization data of the solvate.
  • trimetinib disulfoxide solvate can be prepared according to various conventional methods in the art, and the solvate has the following defects: low solubility in water; dimercaptosulfoxide has a high boiling point and saturation The vapor pressure is low, it is difficult to remove, and the solvent residual amount is large, and it is easy to form an extremely fine particle form.
  • a certain ethanol solvate can be prepared according to various conventional methods in the art, but the solvate has the following defects: unstable at room temperature, and crystal transformation occurs when left at room temperature for 2 months; It can be found from the XRPD pattern that the ethanol solvate has a low crystallinity.
  • trimetinib and its solvates and/or crystal forms with more improved properties to meet the stringent requirements of different pharmaceutical preparations for the active form.
  • the present invention provides crystal forms of trimetinib and its solvates and processes for their preparation, as well as pharmaceutical compositions and uses comprising the crystalline forms.
  • the novel crystalline form of the invention has one or more improved properties compared to the trimetinib disulfoxide solvate, ethanol solvate prepared according to conventional methods, in particular the new crystalline form has a higher Crystallinity, higher solubility in water, better stability, higher active ingredient content, better flowability and better processability, and the crystal form can be at room temperature or low temperature It is more convenient to prepare, which is more conducive to the industrialization of products.
  • crystal form E is a compound formed by trimetinib and ethanol in a 1:1 molar ratio, and its structural formula is as follows: .
  • the trimetini ethoxide solvate crystal form E is characterized in that, using Cu- ⁇ radiation, the X-ray powder diffraction pattern expressed in terms of 2 ⁇ angle has a characteristic peak at the following position: 5.4 ⁇ 0.2. , 10.5 ⁇ 0.2. 12.2 ⁇ 0.2. 12.8 ⁇ 0.2. 18.3 ⁇ 0.2. And 21.1 ⁇ 0.2. Further, the X-ray powder diffraction pattern expressed in terms of 2 ⁇ angle has a characteristic peak at the following position: 5.4 ⁇ 0.2. , 9.2 ⁇ 0.2. , 10.5 ⁇ 0.2.
  • the X-ray powder diffraction pattern expressed in 2 ⁇ angle has characteristic peaks and their relative intensities in the following positions:
  • Form E has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier transform infrared spectroscopy of Form E has characteristic peaks at wave numbers of 693, 777, 812, 1228, 1438, 1548, 1610, 1631, 1676, 2631, 3321 and 3497 cm.
  • the polarized light microscopy (PLM) pattern of Form E is shown as a fine crystal.
  • thermogravimetric analysis (TGA) pattern of Form E showed a weight loss of 6.3% before 200 ° C, which is equivalent to an ethanol molecule.
  • the differential thermal analysis (DSC) pattern of Form E shows a broad endothermic peak at 100 to 200 °C.
  • the isothermal adsorption curve of Form E showed a weight change of 1.07% in the range of 20% to 80% relative humidity.
  • the crystal form E was allowed to stand at room temperature and 44% relative humidity for 3 months, and the XRPD detection crystal form was unchanged, and was more stable than the ethanol solvate prepared according to the conventional method (under the same conditions, 2 months of crystal transformation). .
  • Form E has a higher crystallinity than the ethanol solvate prepared according to the conventional method.
  • the Form E was stirred in water for 1 hour and the solubility was 1.31 g/mL, and the stirring time was 0.50 g/mL for 4 hours, which was significantly better than the disulfoxide solvate prepared according to the conventional method (1 hour and 4 hours).
  • the solubility in hours was 0.51 g/mL and 0.35 g/mL, respectively.
  • the crystal form E is more stable than the ethanol solvate prepared according to the conventional method; by the XRPD pattern comparison, the crystal form E has higher crystallinity, has better fluidity and processability;
  • the above 2 and 3 indicate that the crystal form E of the present invention is better able to counteract the problem of crystal form instability during the preparation of the pharmaceutical preparation and/or storage, and the unworkability of the preparation caused by external factors such as environmental moisture, and is more advantageous. Accurate quantification and subsequent transport and storage in the preparation of unit preparations;
  • Form E Compared to the trimetinidil sulfoxide solvate prepared according to the conventional method, Form E has a higher effective component content, lower solvent toxicity, and is more acceptable in pharmaceutical applications.
  • the preparation method of the trimetine ethanol solvate crystal form E adopts any one of the following methods: (1) the trimetinib amorphous substance is placed in a sealed container filled with ethanol vapor at room temperature to obtain the crystal form E;
  • the resting time is 1 to 3 days, preferably 1 to 1.5 days;
  • the organic solvent is selected from the group consisting of a mixed solvent of ethanol and isopropyl acetate in an ethanol or volume ratio of 1:1 to 5:1;
  • the weight to volume ratio of the trimetinib to the organic solvent is 1 to 20 mg: 1 ml, preferably 5-10 mg: 1 ml;
  • B is 1:1 ⁇ 2:1; preferably, the crystallization time is 1 ⁇ 3 days;
  • the amount of trimetinib is 0.5 to 1 times its solubility in dimercaptosulfoxide at room temperature;
  • the volume ratio of the dimercaptosulfoxide to ethanol is from 0.1:1 to 0.2:1;
  • the crystallization time is 10 to 16 hours.
  • a second aspect of the present invention provides a trimetinib n-propanol solvate and a crystalline form thereof, and a process for the preparation thereof.
  • trimetinib n-propanol solvate is a compound formed by trimetinib and n-propanol at a molar ratio of 1:1, and the structural formula is as follows
  • crystal form N a crystal of the trimetini n-propanol solvate characterized by using Cu- ⁇ radiation, an X-ray powder diffraction pattern expressed at a 2 ⁇ angle in the following position Has a characteristic peak: 10 ⁇ 5 ⁇ 0 ⁇ 2. , 12 ⁇ 1 ⁇ 0 ⁇ 2. , 12 ⁇ 8 ⁇ 0 ⁇ 2. , 13 ⁇ 9 ⁇ 0 ⁇ 2. , 18 ⁇ 3 ⁇ 0 ⁇ 2.
  • the X-ray powder diffraction pattern expressed in terms of 2 ⁇ angle has characteristic peaks at the following positions: 9.1 ⁇ 0.2 °, 10.5 ⁇ 0.2 °, 12.1 ⁇ 0.2 °, 12.8 ⁇ 0.2 °, 13.9 ⁇ 0.2 °, 18.3 ⁇ 0.2 °, 19.8 ⁇ 0.2 °, 20.6 ⁇ 0. 2. 20.9 ⁇ 0 ⁇ 2. 21.9 ⁇ 0. 2. 22.6 ⁇ 0.2. And 24.3 ⁇ 0 ⁇ 2. Further, the X-ray powder diffraction pattern expressed in terms of 2 ⁇ angle has characteristic peaks and their relative intensities at the following positions:
  • a typical example of the crystalline form has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier transform infrared spectrum of the crystalline germanium is 693, 777, 1229, 1350, 1367,
  • the polarized light microscopy (PLM) pattern of the Form N is shown as a fine crystal.
  • thermogravimetric analysis (TGA) pattern of the Form N showed: 8.5% weight loss before 200 ° C, containing about one n-propanol molecule.
  • the differential thermal analysis (DSC) pattern of the crystalline form N shows a broad endothermic peak at 100 to 200 °C.
  • the isothermal adsorption curve of the Form N showed a weight change of 1.1% in the range of 20% to 80% relative humidity.
  • the crystal form N was allowed to stand at room temperature and 44% relative humidity for 3 months, and the crystal form was not changed by XRPD. It is more stable than the ethanol solvate prepared under the conventional method (under the same conditions, 2 months of crystal transformation).
  • Form N has a higher degree of crystallinity than the ethanol solvate prepared according to a conventional method.
  • the Form N was stirred in water for 1 hour and the solubility was ll g/mL, and the stirring time was 1.2 g/mL for 4 hours, which was significantly better than the disulfoxide solvate prepared according to the conventional method (1 hour and 4 hours).
  • the solubility in hours was 0.51 g/mL and 0.35 g/mL, respectively.
  • the crystal form N is more stable than the ethanol solvate prepared according to the conventional method, and the crystal form N has higher crystallinity by comparison with the XRPD pattern;
  • the above 2 and 3 indicate that the crystal form N of the present invention is better able to counteract the problem of crystal form instability during the preparation of the pharmaceutical preparation and/or storage, and the unworkability of the preparation caused by external factors of environmental moisture, and is more advantageous for the unit. Accurate quantification and subsequent transport and storage in preparation of the preparation;
  • the crystalline form N has a higher effective component content than the trimetinib disulfoxide solvate prepared according to a conventional method.
  • the preparation method of the trimetinidol n-propanol solvate crystal form N adopts the following method: the trimetinib amorphous substance is placed in n-propanol to form a solid suspension, and the crystal is stirred at room temperature for 3 to 16 After the hour, the precipitated crystals were separated and dried to obtain the crystal form N.
  • the weight-to-volume ratio of the trimetinib amorphous substance to n-propanol is 5 to 40 mg: 1 ml, preferably 5 to 20 mg: 1 ml;
  • the crystallization time is 3 to 8 hours.
  • a third aspect of the present invention is to provide an anhydride anhydrate of trimetinib and a crystal form thereof, and a process for the preparation thereof.
  • the trimetine anhydrate has the structural formula shown below:
  • crystal form A a crystal of the trimetine anhydrate characterized in that, using Cu- ⁇ radiation, an X-ray powder diffraction pattern expressed at a 2 ⁇ angle has characteristics at the following positions Peaks: 3.8 ⁇ 0.2°, 9.2 ⁇ 0.2°, 14.7 ⁇ 0.2°, 18.5 ⁇ 0.2°, 19.5 ⁇ 0.2°, and 22.1 ⁇ 0.2°; further, The X-ray powder diffraction pattern expressed at an angle of 2 ⁇ has a characteristic peak at the following position: 3.8 ⁇ 0.2. 9.2 ⁇ 0.2.
  • the X-ray powder diffraction pattern expressed in 2 ⁇ angle has characteristic peaks and their relative intensities at the following positions:
  • a typical example of the crystalline form has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier transform infrared spectrum of the Form A has characteristic peaks at wave numbers of 694, 779, 1241, 1302, 1420, 1478, 1550, 1645, 1718, 2363, 2927, 3024 and 3305 cm.
  • the polarized light microscopy (PLM) pattern of the crystal form A is shown as a very fine crystal.
  • thermogravimetric analysis (TGA) spectrum of the crystal form A shows that the weight loss at 30 ° C to 150 ° C is about 0.84%, which is lower than the specific gravity of the hemihydrate water molecule ( 1.44% ), and the crystal is determined by the slow weight loss phenomenon.
  • Type does not contain water or other organic solvents.
  • the differential thermal analysis (DSC) pattern of Form A shows: a small endothermic peak before 50 ° C (Table The surface solvent peak) has a hot melt peak of 289.5 °C.
  • the isothermal adsorption curve of Form A showed a weight change of 4.5% in the range of 20% to 80% relative humidity.
  • Form A is stable at room temperature; this indicates that Form A of the present invention is better able to resist crystal instability in the process of pharmaceutical preparation and/or storage, and is caused by external factors of environmental moisture.
  • the preparation of the preparation is not problematic, and is more conducive to accurate quantification and post-transportation and storage in the preparation of the unit preparation;
  • the crystalline form A has a higher effective component content and no toxic solvent, and is more acceptable in pharmaceutical applications;
  • Form 3 can be used to prepare other solvates, such as the preparation of Formmetine Ethanol Solvate Form E of the present invention.
  • a preparation method of the trimetine anhydrate form A comprises the following steps: forming a solid suspension of the trimmetini amorph in an organic solvent, and stirring and crystallization at room temperature for 1 to 7 days. Then, the precipitated crystals are separated and dried to obtain the crystal form A, and the organic solvent is selected from the group consisting of butanol, ethyl acetate, isopropyl acetate, acetonitrile, toluene or a mixed solvent of two solvents in any ratio thereof;
  • the weight ratio of the trimetinib amorphous substance to the organic solvent is 5-20 mg: 1 ml, preferably 5-10 mg: l ml;
  • the crystallization time is 1 to 3 days.
  • a fourth aspect of the present invention is to provide a trimetinib amorphous form and a process for the preparation thereof.
  • trimetinib amorphous substance has the structural formula shown below.
  • XRPD X-ray powder diffraction
  • DSC Differential Thermal Analysis
  • a preparation method of the trimetinib amorphous substance comprises the following steps:
  • trimetinib tetrahydrofuran solvate and crystal thereof trimetinib trifluoroethanol solvate and crystal thereof, trimetinib acetone solvate and crystal thereof, and trimetinilide are also prepared.
  • trimetinib tetrahydrofuran solvate and crystal thereof trimetinib trifluoroethanol solvate and crystal thereof, trimetinib acetone solvate and crystal thereof, and trimetinilide are also prepared.
  • Tert-butyl ether solvate and its crystals trimetinib tetrahydrofuran solvate and crystal thereof, trimetinib trifluoroethanol solvate and crystal thereof, trimetinib acetone solvate and crystal thereof, and trimetinilide are also prepared.
  • Tert-butyl ether solvate and its crystals are also prepared.
  • a preparation method of the trimetinib tetrahydrofuran solvate crystal comprises the steps of: subjecting a solution of trimetinib tetrahydrofuran to natural volatile crystallization, and evaporating the solvent to obtain a crystal of trimetinib tetrahydrofuran solvate.
  • trimetinib trifluoroethanol solvate crystal adopts any one of the following methods:
  • trimetinib amorphous substance is statically placed in a closed container filled with trifluoroethanol vapor to obtain a crystal of trimetinib trifluoroethanol solvate;
  • trimetine acetone solvate crystal adopts any one of the following methods:
  • trimetinib amorphous form is statically placed in a closed vessel filled with acetone vapor to obtain a crystal of trimetinib acetate;
  • the preparation method of the trimetinimidyl tert-butyl ether solvate crystal comprises the following steps: In a solution of trimetine in a supersaturated trichloromethane, decyl tert-butyl ether is added with stirring, and the crystals are stirred and then the precipitated crystals are separated and dried to obtain a solvent of trimetinidol tert-butyl ether. Crystals.
  • the present invention provides a crystal form of trimetinib and its solvate, including its ethanol solvate crystal form
  • crystalline form N anhydrate crystal form A, tetrahydrofuran solvate crystal, trifluoroethanol solvate crystal, acetone solvate crystal and mercapto tert-butyl ether solvate crystal, solving the prior art Insufficient crystal form.
  • the crystalline form has one or more advantageous properties such as: higher solubility, less solvent residue, higher purity, more convenient preparation, better thermodynamic stability, good particle morphology , low hygroscopicity, better fluidity, better apparent density, better storage stability, suitable for formulation applications.
  • the crystal form has a good crystalline state, improved solubility in water, good stability, low moisture absorption, higher active ingredient content, lower solvent toxicity, and is more acceptable in pharmaceutical applications.
  • the preparation method of the related crystal form of trimetinib of the invention, the process tube, the conventional operation, is carried out under the condition of room temperature or low temperature, does not require high-temperature crystallization, and is more favorable for industrialization of the product.
  • the crystalline form of the present invention is pure, unitary, and substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Less than 5% by weight of other crystal forms, more than less than 1% by weight of other crystal forms.
  • crystal or “crystal form” means confirmed by the X-ray diffraction pattern characterization shown.
  • the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • X-ray diffraction patterns typically vary with the conditions of the instrument.
  • the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2 is usually allowed.
  • trimetine ethanol solvate crystal form E trimetinib n-propanol solvate crystal form N, trimetinib tetrahydrofuran solvate crystal, trimetinib trifluoroethanol solvate crystal, trimmetine Preparation of starting materials for nicotone solvate crystals and trimetinidol tert-butyl ether solvate crystals
  • Patent Document WO2005121142 A1 Example 4-149
  • the text describes that the ethanol solvate and the dimethyl sulfoxide solvate can be obtained by conventional methods, no confirmation characterization data and specific preparation are disclosed. method.
  • the present inventors have prepared the determined ethanol solvate and dimercapto sulfoxide solvate according to the conventional methods mentioned in the literature, such as the volatile crystallization method, the cooling crystallization method, and the distillation crystallization method, specifically in Comparative Example 1.
  • the inventors herein refer to these specific crystal forms as known crystal forms.
  • the "room temperature” means 10-30 °C.
  • anhydrous means that the sample contains no more than 1.5% by weight or not more than 1.0% by weight of water as measured by TGA.
  • the “stirring” may be carried out by any conventional stirring method known in the art, for example, stirring, including magnetic stirring, mechanical stirring, and stirring at a speed of 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation” can be carried out by any conventional separation method known in the art including filtration, centrifugation, and concentration under reduced pressure.
  • the filtration is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the specific procedure for centrifugation in the laboratory is: Place the suspension or emulsion sample in a 2 mL centrifuge tube and centrifuge at 6000 rpm until the solids all settle to the bottom of the tube.
  • the specific operation of concentration under reduced pressure is: placing the container containing the solution in a rotary evaporator at a temperature of from room temperature to the boiling point of the solvent (preferably 30 to 50 ° C), less than atmospheric pressure (preferably, the pressure is less than 0.08 MPa). ), at a rotation speed of 10 to 180 rpm (preferably 50 to 100 rpm), the solvent is removed.
  • the "drying” can be carried out by conventional techniques in the art, such as drying at room temperature, blast drying or reduced pressure drying, in a fume hood, a blast oven or a vacuum oven; the pressure can be reduced or not, preferably the pressure is less than 0.09 MPa.
  • the drying temperature is 20 to 40 ° C, and the drying time is 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours.
  • the "pore volatilization” means that the reaction flask containing the solution is volatilized and crystallized at room temperature through a single small hole having a diameter of 2 mm.
  • the "ultrasonic" operation is to place a container containing the solution or suspension in an ultrasonic cleaner and ultrasonically for 1 to 30 minutes at an ultrasonic working power of 20 Khz to 40 Khz. Generally use 40 Khz ultrasonic power super Sound for 5 minutes. Ultrasound has higher energy, which is conducive to the dissolution of the sample, shortens the crystallization time, hinders the agglomeration of the crystal, and changes the habit.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the crystalline form or amorphous form of trimetinib and a solvate thereof of the present invention or a crystalline form or amorphous form of trimetinib and a solvate thereof obtained by the preparation method of the present invention, and at least one pharmaceutically acceptable carrier, wherein the crystalline form comprises an ethanol solvate crystal form of trimetinib E, n-propanol solvate Form N, anhydrate Form A, tetrahydrofuran solvate crystals, trifluoroethanol solvate crystals, acetone solvate crystals, and decyl tert-butyl ether solvate crystals.
  • the pharmaceutical composition may further comprise other pharmaceutically acceptable salts, solvates or crystalline forms of trimetinib.
  • the pharmaceutical composition may also comprise one or more other pharmaceutically acceptable pharmaceutically
  • Pharmaceutically acceptable carriers in the pharmaceutical compositions include, but are not limited to, binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxy Ethyl cellulose, polyethylene glycol, copolyvidone, etc.; diluents, such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, tricalcium phosphate, mannitol, Sorbitol, sugar, etc.; disintegrating agents, such as starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; Lubricants, such as stearic acid, magnesium stearate, stearic acid, sodium benzoate, sodium acetate, etc.; glidants, such as colloidal silica; etc.; complex
  • the pharmaceutical composition may be in the form of a tablet (including a plain tablet, a film coated tablet, a sugar coated tablet, an enteric coated tablet, etc.), a pill, a powder, a granule, a capsule, a syrup, an emulsion, a suspension, an injection. , solutions, suppositories, tinctures, tinctures, aerosols, eye drops, lyophilizates, and the like.
  • the route of administration includes systemic administration or topical administration, oral administration or parenteral administration, preferably oral administration which enables good absorption of the drug and long-term maintenance of blood concentration.
  • the crystalline form or amorphous form of trimetinib and its solvate of the invention is admixed with one or more pharmaceutically acceptable carriers, optionally with one or more
  • the other pharmaceutically active ingredients are mixed.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • the present invention provides the use of a crystalline form or an amorphous form of trimetinib and a solvate thereof of the present invention for the preparation of a medicament for treating and/or preventing a hyperproliferative disease, the crystal form comprising Qumei Ethanol solvate crystal form ⁇ , n-propanol solvate crystal form ⁇ , anhydrate form ⁇ , tetrahydrofuran solvate crystal, trifluoroethanol solvate crystal, acetone solvate crystal and decyl tert-butyl ether solvent Crystalline
  • the hyperproliferative disease may involve, for example, a tumor, specifically a brain tumor (a glioma with malignant astroglioma and oligodendroglioma, etc.), esophagus Cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, primary and metastatic squam
  • the crystalline form or amorphous form of trimetinib and its solvates of the present invention may be involved in the treatment of chronic pain, in particular neuropathic pain, sudden pain, chronic alcoholism, vitamin deficiency, uremia and symptoms. Pain associated with hypogonadism. In addition, it may involve neutrophil-mediated diseases or symptoms, specifically ischemia-reperfusion injury, chronic pulmonary obstruction, acute respiratory disease syndrome, bloated fibrosis, sudden pulmonary fibrosis, sepsis , endotoxemia, emphysema and asbestosis lungs. In addition, transplant rejection can be involved. In addition, arthritis may be involved, specifically rheumatoid arthritis and osteoarthritis.
  • asthma can be involved.
  • it may involve viral diseases, specifically herpesvirus HSV-1 infection, human cytomegalovirus HCMV infection, human immunodeficiency virus HIV infection.
  • diseases caused by cartilage degeneration or damage may be involved, specifically osteoarthritis, rheumatoid arthritis, isolated osteochondritis, and diseases requiring cartilage formation.
  • the present invention provides a method of treating and/or preventing a hyperproliferative disease, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of one or more of the trimetine forms of the present invention.
  • a pharmaceutical composition of the invention having an amorphous form; the crystalline form comprising an ethanol solvate crystal form E of trimetinib, a n-propanol solvate crystal form N, an anhydrate form A, a tetrahydrofuran solvate crystal, a trifluoroethanol solvate crystal, an acetone solvate crystal, and a decyl tert-butyl ether solvate crystal; the hyperproliferative disease selected from the group consisting of brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, lung cancer , kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, melanoma, neuroblastoma or sarcoma, preferably colon cancer, pancreatic cancer, kidney cancer, lung cancer, breast cancer or melanoma cancer; said patient is Refers to mammals including humans; adult doses are 0.01 mg to 1 g, and oral or injectables
  • Figure 6 isotherm adsorption curve of crystal form E of trimetini ethoxide solvate of the present invention
  • Figure 10 is a DSC pattern of the crystal form N of trimetinidol n-propanol solvate of the present invention
  • Figure 12 isotherm adsorption curve of crystal form N of trimetinidol n-propanol solvate of the present invention
  • Figure 18 isotherm adsorption curve of crystal form A of trimetine anhydrate in the present invention
  • Figure 19 XRPD pattern of the trimetinib amorphous form of the present invention
  • the XRD powder diffraction (XRPD) instrument used was a Bruker D8 Advance Diffractometer equipped with a ⁇ -2 ⁇ goniometer, a Mo monochromator, and a Lynxeye detector.
  • the acquisition software is Diffrac Plus XRPD Commander and the analysis software is MDI Jade 5.0.
  • the instrument is calibrated with the standard (usually corundum) supplied with the instrument before use.
  • Detection method The sample is placed on a non-reflecting plate, tested at room temperature, using a Ka X-ray with a copper target wavelength of 1.54 nm, scanning at 40 kV and 40 mA operating conditions, 2 ⁇ scanning angle range 3 ⁇ 40°, step 0.02° long and 0.2 second/step. Samples were not ground prior to testing unless otherwise stated.
  • the polarized light microscope (PLM) image was taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on the stage of the XP-500E polarized light microscope, select the appropriate magnification Multiply observe the morphology of the sample and take a picture.
  • PLM polarized light microscope
  • the differential thermal analysis (DSC) data was taken from the TA Instruments Q200 MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually, samples of 1 ⁇ 10 mg are placed in an uncoated (unless otherwise specified) aluminum crucible, and the sample is raised from room temperature to a temperature of 10 °C/min under the protection of 40 mL/min dry N 2 . At 310 ° C, the TA software records the change in heat during the temperature rise of the sample. In the present application, the melting point is reported as the starting temperature.
  • Thermogravimetric analysis (TGA) data is taken from TA Instruments Q500 TGA, instrument control software is Thermal Advantage, and analysis software is Universal Analysis. Normally 5 to 15 mg of sample is placed in platinum crucible, using segmented high-resolution detection. The sample was raised from room temperature to 400 ° C under the protection of 40 mL/min dry N 2 at a heating rate of 10 ° C/min, while the TA software recorded the change in weight of the sample during the temperature increase.
  • the isothermal adsorption curve data was taken from the TA Instruments Q5000 TGA, and the instrument control software was Thermal Advantage, the analysis software is Universal Analysis. A sample of 1 to 10 mg is usually placed in a platinum crucible, and the TA software records the change in weight of the sample during a change in relative humidity from 0% to 80% to 0%. Depending on the specifics of the sample, different adsorption and desorption steps are also applied to the sample. The isothermal adsorption curve can be obtained by the analysis software.
  • Nuclear magnetic resonance spectroscopy (1H NMR) data was taken from Bruker Ascend Tm 500. Usually full-frequency excitation is used, with a spectral width of 30 PPM, single pulse, 30. Angle excitation, scanning 16 times, digital orthogonal detection, temperature control 298 K.
  • Infrared spectroscopy (IR) data was taken from Bruker Tensor 27, and instrument control software and data analysis software were OPUS.
  • the ATR device is usually used to collect the infrared absorption spectrum in the range of ⁇ - ⁇ - 1 .
  • the scanning time of the sample and the blank background is 16 seconds.
  • the resolution of the instrument A cm-high performance liquid chromatography (HPLC) data is collected from Waters. 2695/2487, Instrument Control Software and Analysis Software is Empower.
  • HPLC cm-high performance liquid chromatography
  • the X-ray powder diffraction pattern XRPD of the trimetinib amorphous form is shown in Fig. 19.
  • Example 2 1.57 g of a 28% sodium decyl alcohol decyl alcohol solution was added to 40 mL of N-[3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)- under a nitrogen atmosphere. 6,8-dimercapto-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino] A solution of phenyl]-acetamide (5.0 g) in tetrahydrofuran was stirred at room temperature for 4 hours.
  • trimetinib amorphous substance was added, 15.0 mL of ethanol was added, and 40 Khz was ultrasonicated for 5 minutes to obtain a solution, and the pores were volatilized and crystallized to obtain an ethanol solvate prepared according to a conventional method.
  • trimetinib amorphous substance At room temperature, take 20.0 mg of trimetinib amorphous substance, add lO.O mL of ethanol, heat to 75 ° C to dissolve, 15 ° C per hour to room temperature, crystallize, filter, filter cake 30 ° C vacuum drying 16 In an hour, an ethanol solvate prepared according to a conventional method was obtained.
  • trimetinib amorphous substance was added, and 10 mL of ethanol was added thereto, and the mixture was heated to 50 ° C for distillation crystallization, and the solvent was distilled to dry to obtain an ethanol solvate prepared according to a conventional method.
  • Comparative Examples 2 to 3 had the same or similar XRPD (not shown) as Comparative Example 1. It is stated that the samples of Comparative Example 2 to 3 and the sample of Comparative Example 1 are the same substance.
  • trimetinib amorphous substance was added, 2.5 mL of dimercaptosulfoxide was added, and the mixture was heated to 80 ° C to dissolve. After 2 hours, the solid was precipitated, stirred for 3 hours, cooled to room temperature and stirred overnight. After filtration, the filter cake was dried under vacuum at 30 ° C for 16 hours to obtain a dimethyl sulfoxide solvate prepared according to a conventional method.
  • the DSC spectrum is shown in Fig. 21. It has an endothermic peak at 160 to 190 ° C and a melting point of 183.8 ° C.
  • the solubility of the disulfoxide solvate prepared according to the conventional method at room temperature in water for 1 hour and 4 hours was 0.51 g/mL and 0.35 g/mL, respectively.
  • trimetinib amorphous At room temperature, take 20.0 mg of trimetinib amorphous, add lO.O mL of dimercaptosulfoxide, and heat up to
  • the mixture was subjected to distillation under reduced pressure at 80 ° C, and the solvent was distilled to dryness to obtain a dimercapto sulfoxide solvent prepared according to a conventional method.
  • Comparative Example 5 had the same or similar XRPD graphic and DSC graphic (not shown) as Comparative Example 4.
  • the sample of Comparative Example 5 and the sample of Comparative Example 4 are the same substance.
  • the X-ray powder diffraction pattern XRPD is shown in Figure 13.
  • the PLM graphics are shown in Figure 14.
  • the TGA map is shown in Figure 15.
  • the DSC spectrum is shown in Figure 16.
  • trimetinib amorphous substance Take 50.0 mg of trimetinib amorphous substance, add 100.0 mL of acetonitrile, sonicate for 40 minutes at 40 Khz to obtain a suspension, stir at room temperature for 7 days, centrifuge at 30 ° C for 20 hours under vacuum to obtain trimetinib. Water crystal form eight. The yield was 42.5 mg; the yield was 85.0%.
  • Example 5 Take 50.0 mg of trimetinib amorphous substance, add 2.5 mL of a mixed solvent of butanol and terpene 1:1, sonicate at 40 Khz for 5 minutes, stir at room temperature for 1 day, centrifuge at 30 ° C and vacuum dry 18 In hours, the crystal form A of trimetine anhydrate was obtained. The yield was 45.6 mg; the yield was 91.2%.
  • the samples prepared in Examples 4 to 5 had the same or similar XRPD patterns, PLM patterns, TGA patterns, DSC patterns, and IR patterns (not shown) as in Example 3.
  • the samples of Examples 4 to 5 and the samples of Example 3 were the same.
  • trimetinib amorphous substance Take 10.0 mg of trimetinib amorphous substance, add 1.0 mL of ethanol, sonicate for 40 minutes at 40 Khz to obtain a suspension, stir at room temperature for 3 days, centrifuge at 30 ° C for 16 hours under vacuum to obtain trimetinib ethanol solvate.
  • Form 5 The yield was 9.2 mg; the yield was 85.6%.
  • X-ray powder diffraction pattern XRPD is shown in Figure 1.
  • the PLM graphics are shown in Figure 2.
  • the TGA map is shown in Figure 3.
  • the solubility of trimetine ethanol solvate Form E at room temperature in water for 1 hour and 4 hours was 1.31 g/mL and 0.50 g/mL, respectively.
  • trimetine anhydrate Form A Take 10.0 mg of trimetine anhydrate Form A, add 2.0 mL of 1:1 ethanol/isopropyl acetate solution, sonicate for 40 minutes at 40 Khz, stir at room temperature for 1 day, centrifuge, 30 Drying in vacuo at °C for 16 hours gave the crystal form E of trimetine ethanol solvate. The yield was 9.4 mg; the yield was about 87.5%.
  • trimetinib amorphous substance Take 20.0 mg of trimetinib amorphous substance, add 1.0 mL volume ratio of 5:1 ethanol/isopropyl acetate solution, sonicate for 40 minutes at 40 Khz, stir at room temperature for 5 days, centrifuge, vacuum at 30 °C After drying for 16 hours, the crystal form E of trimetinib ethanol solvate was obtained. The yield was 17.8 mg; the yield was about 82.8%.
  • trimetine anhydrate crystal form A Take 10.0 mg of trimetine anhydrate crystal form A, add 10 mL of ethanol/acetic acid isopropyl ester solution in a volume ratio of 2:1, stir at room temperature for 5 days, centrifuge, and vacuum dry at 30 ° C for 16 hours to obtain Qumei. Tinifol solvate Form E.
  • the yield was 8.8 mg; the yield was 81.9%.
  • Example 11 50.0 mg of the trimetinib amorphous substance prepared in Example 1 was placed in an open reaction flask, 10 mL of ethanol was added, and the open reaction flask was placed in a sealed glass bottle filled with ethanol vapor, and allowed to stand at room temperature. After 3 days, the crystal form E of trimetine ethanol solvate was obtained. The yield was 54.0 mg; the yield was about 100.0%.
  • Example 11
  • trimetine anhydrate crystal form A Take 15.0 mg of trimetine anhydrate crystal form A, add 0.5 mL of dimethyl sulfoxide, sonicate for 40 minutes at 40 Khz to obtain a yellow solution, slowly add 2.5 mL of ethanol, stir and crystallize at room temperature for 16 hours, centrifuge, 30 Drying under vacuum at °C for 16 hours gave the crystal form E of trimetine ethanol solvate.
  • the yield was 13.5 mg; the yield was 83.7%.
  • trimetinib amorphous substance Take 10.0 mg of trimetinib amorphous substance, add 1 mL of dimethyl sulfoxide, sonicate for 40 minutes at 40 Khz to obtain a yellow solution, slowly add 2 mL of ethanol, stir and crystallize at 10 ° C for 24 hours, centrifuge, 30 ° C Vacuum drying for 16 hours gave the crystal form E of trimetinib ethanol solvate. The yield was 8.9 mg; the yield was 82.8%.
  • trimetine anhydrate crystal form A Take 10.0 mg of trimetine anhydrate crystal form A, add 0.5 mL of dimethyl sulfoxide, sonicate for 40 minutes at 40 Khz to obtain a yellow solution, slowly add 5 mL of ethanol, stir and crystallize at 10 ° C for 10 hours, centrifuge It was dried under vacuum at 30 ° C for 16 hours to obtain crystal form E of trimetine ethanol solvate.
  • the yield was 9.4 mg; the yield was 87.5%.
  • the samples prepared in Examples 7 to 13 had the same or similar XRPD patterns, PLM patterns, TGA patterns, DSC patterns, and IR patterns (not shown) as in Example 6.
  • the samples of Examples 7 to 13 and the samples of Example 6 are the same.
  • the preparation of the crystal form E of trimetinib ethanol solvate in Examples 6 to 13 was significantly different from the conventional method of preparing the ethanol solvate in Comparative Examples 1 to 3, for example, using 40 Khz sonication or longer. Stirring time or co-crystallization with a mixed solvent containing ethanol or the like.
  • trimetinib amorphous substance prepared in Example 1 10.0 mg was added, 2.0 mL of n-propanol was added, and 40 Khz was sonicated for 5 minutes to obtain a suspension, stirred at room temperature for 3 hours, centrifuged, and vacuum dried at 30 ° C for 16 hours to obtain a koji.
  • Metinib n-propanol solvate crystal form N The yield was 8.7 mg; the yield was 79.2%.
  • the PLM graphics are shown in Figure 8.
  • the TGA map is shown in Figure 9.
  • the DSC spectrum is shown in Figure 10.
  • the n-propanol solvate crystal form N had a solubility of 1.1 g/mL in water for 1 hour and a solubility of 1.2 g/mL at 4 hours.
  • trimetinib amorphous substance Take 20.0 mg of trimetinib amorphous substance, add 1 mL of n-propanol, sonicate for 40 minutes at 40 Khz, stir at room temperature for 8 hours, centrifuge, and vacuum dry at 30 ° C for 16 hours to obtain trimetinib. Alcohol solvate crystal form N. The yield was 18.2 mg; the yield was 82.8%.
  • trimetinib amorphous substance Take 40.0 mg of trimetinib amorphous substance, add 1 mL of n-propanol, sonicate for 40 minutes at 40 Khz, stir at room temperature for 16 hours, centrifuge, and vacuum dry at 30 ° C for 16 hours to obtain trimetinib. Alcohol solvate crystal form N. The yield was 30.8 mg; the yield was 70.1%.
  • the samples prepared in Examples 15 to 16 had the same or similar XRPD patterns, PLM patterns, TGA patterns, DSC patterns, and IR patterns (not shown) as in Example 14. The samples of Examples 15 to 16 and the samples of Example 14 are the same.
  • trimetinib amorphous substance 10 mg was added, 5 mL of tetrahydrofuran was added, and 40 Khz was sonicated for 5 minutes to obtain a solution, which was filtered, and the pores were volatilized at room temperature, and the solvent was evaporated to dryness to obtain crystals of trimetinib tetrahydrofuran solvate.
  • the yield was 9.2 mg; the yield was 82.3%.
  • the ometinidin amorphous material prepared in Example 1 was placed in a sealed glass bottle filled with trifluoroethanol vapor, and allowed to stand at room temperature for 1 day to obtain a crystal of trimetinib trifluoroethanol solvate.
  • the yield was 11.6 mg; the yield was about 100.0%.
  • trimetinib amorphous substance Take 30.0 mg of trimetinib amorphous substance, add 3 mL of trifluoroethanol, sonicate for 40 minutes at 40 Khz to obtain a saturated solution, and quickly filter. The filtrate is slowly added to 30 mL of water while stirring at room temperature, and a white solid is precipitated and stirred for 1 hour. After centrifugation, vacuum drying at 30 ° C for 16 hours gave crystals of trimetinib trifluoroethanol solvate. The yield was 18.5 mg; the yield was 53.0%.
  • the omethatinib prepared in Example 1 was amorphous, placed in a sealed glass vial filled with acetone vapor, and allowed to stand at room temperature for 3 days to obtain a crystal of trimetinib acetate.
  • the yield was 10.9 mg; the yield was about 100.0%.
  • trimetinib amorphous substance Take 30.0 mg of trimetinib amorphous substance, add 1 mL of trifluoroethanol, sonicate for 40 minutes at 40 Khz to obtain a saturated solution, and quickly filter. The filtrate is slowly added with 5 mL of acetone while stirring at room temperature, and stirred for 5 days to precipitate a white solid. After centrifugation, vacuum drying at 30 ° C for 16 hours gave crystals of trimetinib acetal solvate. The yield was 9.7 mg; the yield was 29.5%.
  • trimetinib amorphous substance Take 30.0 mg of trimetinib amorphous substance, add 1 mL of trichloromethane, sonicate for 40 minutes at 40 Khz to obtain a saturated solution, and quickly filter. The filtrate is slowly added with 10 mL of decyl tert-butyl ether at room temperature. After stirring at ° C for 1 day, a white solid was precipitated, centrifuged, and dried under vacuum at 30 ° C for 16 hours to obtain crystals of the trimetinimidyl tert-butyl ether solvate. The yield was 8.0 mg; the yield was 23.3%.
  • trimetinidil sulfoxide solvate prepared according to the conventional method 5.0 mg were taken.
  • Form N 5 mg sample per 100 mL of water was stirred at 25 ° C, and the solubility test was performed by HPLC for 1 hour and 4 hours. The solubility results are shown in Table 1 in g/mL.
  • Trimetrinol Ethanol Solvate Form E 0.54 1.07 2.15 Sodium lauryl sulfate 0.017 0.034 0.068 Colloidal silica 0.01 0.02 0.04 Mannitol 95.47 101.51 106.95 Microcrystalline cellulose 36.25 38.75 41.25 Hydroxypropyl cellulose 7.25 7.75 8.25 Crosslinking Carboxymethyl cellulose sodium 4.35 4.65 4.95 Magnesium stearate 1.09 1.16 1.24 Coating material Opadry YS-1-14762-A 0 0 4.95 Coating material Opadry YS-1-12525-A 4.35 0 0 Coating material Opadry OY- S-28876 0 4.65 0 Tablet Weight 149.33 159.59 169.85 Procedure:
  • trimetine ethanol solvate crystal form E and mannitol is equal in the three-dimensional mixer
  • the addition method is uniformly mixed, and sodium lauryl sulfate, colloidal silica, microcrystalline cellulose, hydroxypropylcellulose and croscarmellose sodium are added and sieved.
  • step 2 The mixture in step 2 is pressed into a tablet core of each dose on a rotary tablet press. A total of 1000 tablets were pressed. 4)
  • the film core is continuously coated with an aqueous solution of the coating material until an increase of about 3% of the target weight is achieved.
  • Opadry YS-1-14762-A pink
  • Opadry YS-1-12525-A yellow
  • Opadry OY-S- 28876 white

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes cristallines de trametinib et de son solvate, un procédé de préparation correspondant, des compositions pharmaceutiques comportant la forme cristalline et son utilisation dans la préparation de médicaments associés. Par rapport à l'art antérieur, les formes cristallines du tramétinib et du solvate selon la présente invention possède un bon état cristallin, une bonne stabilité cristalline, une faible absorption d'humidité, une solubilité améliorée dans l'eau, une quantité supérieure de composants actifs, une toxicité de solvants inférieure, et est plus avantageux pour satisfaire des exigences pour la préparation pharmaceutique. Les formes cristallines peuvent être préparées à la température ambiante ou à faible température, et sont avantageuses pour la production industrielle de produits.
PCT/CN2013/088797 2013-12-06 2013-12-06 Forme cristallines de trametinib et de son solvate, procede de preparation correspondant, composition pharmaceutique en comportant et son utilisation WO2015081566A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2013/088797 WO2015081566A1 (fr) 2013-12-06 2013-12-06 Forme cristallines de trametinib et de son solvate, procede de preparation correspondant, composition pharmaceutique en comportant et son utilisation
CN201380069544.7A CN104918937B (zh) 2013-12-06 2013-12-06 曲美替尼及其溶剂化物的晶型、其制备方法、含有它们的药物组合物及其用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2013/088797 WO2015081566A1 (fr) 2013-12-06 2013-12-06 Forme cristallines de trametinib et de son solvate, procede de preparation correspondant, composition pharmaceutique en comportant et son utilisation

Publications (1)

Publication Number Publication Date
WO2015081566A1 true WO2015081566A1 (fr) 2015-06-11

Family

ID=53272785

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2013/088797 WO2015081566A1 (fr) 2013-12-06 2013-12-06 Forme cristallines de trametinib et de son solvate, procede de preparation correspondant, composition pharmaceutique en comportant et son utilisation

Country Status (2)

Country Link
CN (1) CN104918937B (fr)
WO (1) WO2015081566A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016169532A1 (fr) * 2015-04-24 2016-10-27 Zentiva, K.S. Formes cristallines de tramétinib
WO2020125747A1 (fr) * 2018-12-21 2020-06-25 基石药业（苏州）有限公司 Forme cristalline et forme amorphe d'inhibiteur de mek et leurs applications
WO2020161654A1 (fr) * 2019-02-06 2020-08-13 Aurobindo Pharma Limited Procédé de préparation d'un solvate d'acide acétique du tramétinib
WO2021082683A1 (fr) * 2019-10-28 2021-05-06 北京亿药科技有限公司 Utilisation de trametinib dans la préparation d'un médicament pour prévenir et/ou traiter une hépatite non alcoolique et/ou une stéatose hépatique non alcoolique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017173800A1 (fr) * 2016-04-06 2017-10-12 福州大学 Application utilisant un inhibiteur de la voie de signalisation mapk pour préparer un produit pharmaceutique destiné à retarder la dégénérescence des neurones dopaminergiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101006086A (zh) * 2004-06-11 2007-07-25 日本烟草产业株式会社 用于治疗癌症的5－氨基－2,4,7－三氧代－3,4,7,8－四氢－2H－吡啶并[2,3－d]嘧啶衍生物和相关化合物
WO2012088033A2 (fr) * 2010-12-20 2012-06-28 Glaxosmithkline Llc Nouvelle composition pharmaceutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101006086A (zh) * 2004-06-11 2007-07-25 日本烟草产业株式会社 用于治疗癌症的5－氨基－2,4,7－三氧代－3,4,7,8－四氢－2H－吡啶并[2,3－d]嘧啶衍生物和相关化合物
WO2012088033A2 (fr) * 2010-12-20 2012-06-28 Glaxosmithkline Llc Nouvelle composition pharmaceutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ABE, H. ET AL.: "Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate", ACS MEDICINAL CHEMISTRY LETTERS, vol. 2, no. 4, 28 February 2011 (2011-02-28), pages 320 - 324 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016169532A1 (fr) * 2015-04-24 2016-10-27 Zentiva, K.S. Formes cristallines de tramétinib
WO2020125747A1 (fr) * 2018-12-21 2020-06-25 基石药业（苏州）有限公司 Forme cristalline et forme amorphe d'inhibiteur de mek et leurs applications
CN112912380A (zh) * 2018-12-21 2021-06-04 基石药业（苏州）有限公司 一种mek抑制剂的晶型、无定形及其应用
CN112912380B (zh) * 2018-12-21 2023-08-11 基石药业（苏州）有限公司 一种mek抑制剂的晶型、无定形及其应用
WO2020161654A1 (fr) * 2019-02-06 2020-08-13 Aurobindo Pharma Limited Procédé de préparation d'un solvate d'acide acétique du tramétinib
WO2021082683A1 (fr) * 2019-10-28 2021-05-06 北京亿药科技有限公司 Utilisation de trametinib dans la préparation d'un médicament pour prévenir et/ou traiter une hépatite non alcoolique et/ou une stéatose hépatique non alcoolique

Also Published As

Publication number Publication date
CN104918937B (zh) 2016-09-14
CN104918937A (zh) 2015-09-16

Similar Documents

Publication Publication Date Title
JP4414237B2 (ja) ケチアピンヘミフマレートの結晶形
WO2018184185A1 (fr) Cristal de sel d'addition d'ozanimod, procédé de préparation, composition pharmaceutique, et utilisations
TWI849043B (zh) B-raf激酶二聚體抑制劑之穩定固體分散體、製備方法及其用途
WO2015081566A1 (fr) Forme cristallines de trametinib et de son solvate, procede de preparation correspondant, composition pharmaceutique en comportant et son utilisation
WO2015014315A1 (fr) Forme cristalline d'inhibiteur et son procédé de préparation et son utilisation
WO2015139591A1 (fr) Forme cristalline du sel de sodium du dolutégravir et procédé pour sa préparation
WO2018049632A1 (fr) Forme cristalline d'ozanimod, procédé de préparation et composition pharmaceutique associés
WO2015054804A1 (fr) Forme solide d'enzalutamide, procédé de préparation et utilisation associée
WO2014198178A1 (fr) Cristal de macitentan, son procédé de préparation, composition pharmaceutique et utilisation associée
US11639341B2 (en) Crystal form of tipifarnib and method of treatment thereof
WO2019062854A1 (fr) Co-cristaux de ribociclib et de co-cristaux de mono-succinate de ribociclib, leur procédé de préparation, leurs compositions et leurs utilisations
JP2020500912A (ja) ブロモドメインタンパク質阻害薬の結晶形及びその製造方法並びに用途
TW202308991A (zh) 三苯化合物之固體形式
JP2023062091A (ja) Ｓ１ｐ１受容体アゴニストの付加塩およびその結晶形態、ならびに薬学的組成物
TW201925190A (zh) 嘧啶基胺基─吡唑化合物之多晶型物及固體形式及製備方法
TW202404604A (zh) [(1S)-1-[(2S,4R,5R)-5-(5-胺基-2-酮基-噻唑并[4,5-d]嘧啶-3-基)-4-羥基-四氫呋喃-2-基]丙基]乙酸酯之新穎固態形式
TWI662031B (zh) １－｛２－氟－４－［５－（４－異丁基苯基）－１，２，４－噁二唑－３－基］－苄基｝－３－吖丁啶羧酸的晶型
CN111868054A (zh) 呋喹替尼的共晶、其制备方法、组合物和用途
WO2015003571A1 (fr) Nouvelle forme cristalline de mésylate de dabrafenib et procédé de préparation de celle-ci
WO2018165979A1 (fr) Forme cristalline du 2-(6-méthyl-pyridin-2-yl)-3-yl-[6-amido-quinoléin-4-yl]-5,6-dihydro-4h-pyrrolo[1,2-b]pyrazole, son procédé de préparation et composition pharmaceutique associée
WO2019028689A1 (fr) Forme cristalline d'odm-201, son procédé de préparation et composition pharmaceutique correspondante
CN113444073A (zh) 吗啉基喹唑啉类化合物的晶型ⅲ、其制备方法及应用
CN112778290B (zh) 一种s1p1受体激动剂的加成盐及其晶型和药物组合物
US9181243B2 (en) Solvate form M of trametinib dimethyl sulfoxide and methods of making and using thereof
CN105367492B (zh) 他喹莫德的晶型及其制备方法、其药物组合物和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13898669

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13898669

Country of ref document: EP

Kind code of ref document: A1