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WO2018157803A1 - Formes cristallines de vénétoclax et leur procédé de préparation - Google Patents

Formes cristallines de vénétoclax et leur procédé de préparation Download PDF

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WO2018157803A1
WO2018157803A1 PCT/CN2018/077484 CN2018077484W WO2018157803A1 WO 2018157803 A1 WO2018157803 A1 WO 2018157803A1 CN 2018077484 W CN2018077484 W CN 2018077484W WO 2018157803 A1 WO2018157803 A1 WO 2018157803A1
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crystal form
compound
ray powder
powder diffraction
crystal
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PCT/CN2018/077484
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English (en)
Chinese (zh)
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陈敏华
张炎锋
王金秋
刘凯
张晓宇
王鹏
李丕旭
刘远华
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苏州科睿思制药有限公司
苏州鹏旭医药科技有限公司
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Publication of WO2018157803A1 publication Critical patent/WO2018157803A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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 chemical medicine, in particular to a crystal form of vintomone and a preparation method thereof.
  • Bcl-2 The dynamic balance of apoptosis and proliferation is the most basic biological process for multicellular organisms to maintain their structural stability and balance of internal environment functions and growth.
  • Veneta also known as Venetoclax, ABT199, is a selective, potent, orally administered small molecule Bcl-2 inhibitor.
  • ABT199 a selective, potent, orally administered small molecule Bcl-2 inhibitor.
  • the FDA approved its marketing under the trade name Venclexta for the treatment of chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • Venetatal is 4-(4- ⁇ [2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl ⁇ piperazine-1 -yl)-N-( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ sulfonyl)-2-(1H-pyrrolo[2, 3-b]pyridin-5-yloxy)benzamide (hereinafter referred to as "compound (I)”), and has a structural formula of the formula I.
  • a preparation method of the compound (I) is disclosed in Example 5 of CN103153993A, in which the solid of the compound (I) obtained is amorphous.
  • CN103328474A discloses a crystalline form of compound (I) comprising 2 anhydrates A and B, 2 hydrates C and D and various solvates E, F, G, H, I, J, anhydrous in the patent Both the substance and the hydrate need to be obtained by drying the solvate, which determines that the preparation process requires a synthetic solvate intermediate, the preparation method is complicated, the operation is cumbersome, and it is not suitable for industrial large-scale production.
  • anhydrate B in CN103328474A is more stable than other crystal forms, but has problems such as high wettability and low solubility. Therefore, a novel anhydrate and hydrate form of the compound (I) can be provided, and these anhydrates and hydrates can be directly crystallized from a solvent, and have good stability, high solubility, low wettability, and uniform particle size distribution. It will be of great significance for the further development of the drug.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art, and to provide an anhydrous form, a hydrate, a solvate form of the compound (I), a preparation method thereof and use thereof.
  • the present invention provides the crystal form CS1 of the compound (I) (hereinafter referred to as "crystal form CS1").
  • the crystal form CS1 is a hydrate.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at a diffraction angle 2 ⁇ of 4.8° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ of 8.7° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 19.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at a diffraction angle 2 ⁇ of 8.7° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 19.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 11.2° ⁇ 0.2°, and 17.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 has a characteristic peak at a diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 11.2° ⁇ 0.2°, and 17.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has one or more of the diffraction angle 2 ⁇ of 9.7° ⁇ 0.2°, 14.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 22.8° ⁇ 0.2°. Characteristic peaks. Preferably, the X-ray powder diffraction of the crystalline form CS1 has a characteristic peak at a diffraction angle 2 ⁇ of 9.7° ⁇ 0.2°, 14.9° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 22.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS1 is 4.8° ⁇ 0.2°, 17.0° ⁇ 0.2°, 19.0° ⁇ 0.2°, 8.7° ⁇ 0.2°, 13.9° ⁇ at the diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of Form CS1 is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form CS1, which comprises obtaining a target solvent set by steam distillation using a tetrahydrofuran solution of the compound (I), and obtaining the crystal by crystallization at a certain temperature.
  • the target solvent is a C 3 -C 8 ester solvent;
  • the ester solvent is ethyl formate, ethyl acetate, isopropyl acetate or a mixed solvent thereof, more preferably isopropyl acetate;
  • the crystallization temperature is 20-40 ° C, more preferably room temperature;
  • the crystallization time is 6-24 hours, more preferably 12 hours.
  • the present invention provides the crystal form CS2 of the compound (I) (hereinafter referred to as "crystal form CS2").
  • the crystalline form CS2 is a 1,4-dioxane solvate.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at a diffraction angle 2 ⁇ of 5.4° ⁇ 0.2°, 8.0° ⁇ 0.2°, and 18.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ of 14.5° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 20.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at a diffraction angle 2 ⁇ of 14.5° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 20.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at one or two of the diffraction angle 2 ⁇ of 15.9° ⁇ 0.2° and 18.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic peak at a diffraction angle 2 ⁇ of 15.9° ⁇ 0.2° and 18.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 is 5.4° ⁇ 0.2°, 8.0° ⁇ 0.2°, 18.7° ⁇ 0.2°, 14.5° ⁇ 0.2°, 19.6° ⁇ at the diffraction angle 2 ⁇ . There are characteristic peaks at 0.2°, 20.0° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 18.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS2 is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form CS2, which comprises obtaining a target solvent sleeve steam displacement using a tetrahydrofuran solution of the compound (I), and obtaining the crystal by crystallization at a certain temperature.
  • the target solvent is 1,4-dioxane
  • the crystallization temperature is 20-40 ° C, more preferably room temperature;
  • the crystallization time is 6-24 hours, more preferably 12 hours.
  • the present invention provides a crystal form CS3 of the compound (I) of the formula (hereinafter referred to as "crystal form CS3").
  • the crystal form CS3 is an anhydride.
  • the X-ray powder diffraction of the crystal form CS3 has a characteristic peak at a diffraction angle 2 ⁇ of 10.4° ⁇ 0.2°, 15.2° ⁇ 0.2°, and 21.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ of 5.2° ⁇ 0.2°, 19.7° ⁇ 0.2°, and 29.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has a characteristic peak at a diffraction angle 2 ⁇ of 5.2° ⁇ 0.2°, 19.7° ⁇ 0.2°, and 29.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS3 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 20.9° ⁇ 0.2°, 24.3° ⁇ 0.2°, and 26.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has a characteristic peak at a diffraction angle 2 ⁇ of 20.9° ⁇ 0.2°, 24.3° ⁇ 0.2°, and 26.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 is 10.4° ⁇ 0.2°, 15.2° ⁇ 0.2°, 21.7° ⁇ 0.2°, 5.2° ⁇ 0.2°, 19.7° ⁇ at the diffraction angle 2 ⁇ . There are characteristic peaks at 0.2°, 29.4° ⁇ 0.2°, 20.9° ⁇ 0.2°, 24.3° ⁇ 0.2°, and 26.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS3 is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form CS3, which comprises: stirring and crystallization using a solution of the compound (I) in tetrahydrofuran at a certain temperature, and filtering the filter cake to be added to the tetrahydrofuran solvent again after filtration. Medium, dissolved by heating, then concentrated, and obtained by crystallization at a certain temperature;
  • the crystallization temperature is 20-40 ° C, more preferably room temperature;
  • the crystallization time is from 3 to 24 hours, more preferably from 3 hours.
  • the "room temperature” means 20-30 °C.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "sleeve steaming" is accomplished by conventional methods in the art by first evaporating the original solvent and then adding another solvent.
  • the present invention provides the crystal forms CS4, CS5, CS6 of the compound (I).
  • the crystal forms CS4, CS5, and CS6 are MIBK (methyl isobutyl ketone) solvates.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of crystalline form CS1, CS3 or a mixture thereof and a pharmaceutically acceptable pharmaceutical excipient.
  • the present invention provides the use of the crystalline form CS1, CS3 or a mixture thereof or the pharmaceutical composition for the preparation of a medicament for the treatment of chronic lymphocytic leukemia.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that 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. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • 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.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline forms CS1 and CS3 of the present invention are 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 Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • the crystal forms CS1 and CS3 provided by the present invention have the following advantages compared with the prior art:
  • the crystal form provided by the invention has good physical and chemical stability, thereby ensuring consistent and controllable quality standards of the sample, and meeting the stringent requirements for the crystal form in the pharmaceutical application and preparation process.
  • the crystalline form CS1 of the present invention is kept at 25 ° C / 60% RH, 40 ° C / 75% RH and 60 ° C / 75% RH for at least 3 weeks, and the crystalline form CS3 is at 25 ° C / 60% RH, 40 ° C /75%RH and 60 °C / 75% RH for at least 2 weeks; the crystal form CS1 and CS3 have little change in purity before and after placement, and have good physical and chemical stability, which is conducive to sample preservation and formulation stability. .
  • the crystal form provided by the present invention has good mechanical stability, and the crystal form remains unchanged after grinding. Good mechanical stability can reduce the risk of crystal transformation during grinding or tableting during preparation.
  • the crystal forms CS1 and CS3 of the invention have high grinding stability, and the grinding and pulverizing of the raw material medicine are often required in the processing of the preparation, and the high grinding stability can reduce the crystallinity change and the crystal transformation of the raw material medicine during the processing of the preparation. risk.
  • the crystal form provided by the invention has good solubility, can reduce the dosage of the drug, thereby reducing the side effects of the drug and improving the safety of the drug, and can achieve the desired therapeutic blood concentration without a high dose after oral administration. Conducive to the absorption of drugs in the human body, so as to achieve the desired bioavailability and efficacy of the drug, in line with medicinal requirements;
  • the crystal form provided by the invention has low wettability and can overcome the disadvantages caused by high wettability, such as the weight change of the water absorption due to the weight change of the raw material, which is favorable for long-term storage of the medicine and reduction of material storage and Quality control costs.
  • the crystal form CS3 provided by the present invention has a weight gain of 1.12% under 80% relative humidity, and has lower wettability than the prior art.
  • the low wettability of the crystalline form CS3 of the present invention can well resist 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 advantageous for preparation of the preparation. Accurate quantification and later transport and storage;
  • the crystal form CS3 particles of the present invention are normally distributed and have a narrow particle size distribution. Its uniform particle size helps to simplify the post-treatment process of the formulation process, such as reducing the grinding of the crystal, saving cost, reducing the crystallinity change and the risk of crystal transformation in the grinding, and improving the quality control. Its narrow particle size distribution can improve the uniformity of the drug substance components in the preparation, and make the difference between different batches of preparations smaller, such as more uniform dissolution; its smaller crystal grain size can increase the drug ratio.
  • the surface area increases the dissolution rate of the drug, which is beneficial to the absorption of the drug, thereby improving the bioavailability;
  • novel solvate provided by the present invention can be used in process development intermediates, and the purification effect is remarkable, which is very important for drug development.
  • Figure 1 is an XRPD pattern of the compound (I) crystal form CS1
  • Figure 2 is a 1 H NMR chart of the compound (I) crystal form CS1
  • Figure 3 is a DSC chart of the compound (I) crystal form CS1
  • Figure 4 is a TGA diagram of the compound (I) crystal form CS1
  • Figure 5 is an XRPD pattern of the compound (I) crystal form CS2
  • Figure 6 is a 1 H NMR chart of the compound (I) crystal form CS2
  • Figure 7 is a DSC chart of the compound (I) crystal form CS2
  • Figure 8 is a TGA diagram of the compound (I) crystal form CS2
  • Figure 9 is an XRPD pattern of the compound (I) crystal form CS3
  • Figure 10 is a 1 H NMR chart of the compound (I) crystal form CS3
  • Figure 11 is a DSC chart of the compound (I) crystal form CS3
  • Figure 12 is a TGA diagram of the compound (I) crystal form CS3
  • Figure 13 is an XRPD pattern of the compound (I) crystal form CS4
  • Figure 14 is a 1 H NMR chart of the compound (I) crystal form CS4
  • Figure 15 is a DSC chart of the compound (I) crystal form CS4
  • Figure 16 is a TGA diagram of the compound (I) crystal form CS4
  • Figure 17 is an XRPD pattern of the compound (I) crystal form CS5
  • Figure 18 is a 1 H NMR chart of the compound (I) crystal form CS5
  • Figure 19 is a DSC chart of the compound (I) crystal form CS5
  • Figure 20 is a TGA diagram of the compound (I) crystal form CS5
  • Figure 21 is an XRPD pattern of the compound (I) crystal form CS6
  • Figure 22 is a 1 H NMR chart of the compound (I) crystal form CS6
  • Figure 23 is a DSC chart of the compound (I) crystal form CS6
  • Figure 24 is a TGA diagram of the compound (I) crystal form CS6
  • Figure 25 is an XRPD overlay of the compound (I) crystal form CS1 before and after the polishing treatment (the upper graph is an XRPD pattern of the starting crystal form CS1, and the lower graph is an XRPD pattern of the crystal form CS1 after grinding)
  • Figure 26 is an XRPD overlay of the compound (I) crystal form CS3 before and after the grinding treatment (the upper graph is an XRPD pattern of the starting crystal form CS3, and the lower graph is an XRPD pattern of the crystal form CS3 after grinding)
  • Figure 27 is an XRPD overlay of the anhydrate A before and after the treatment of the compound (I) CN103328474A (the upper panel is an XRPD pattern of the anhydride A in the starting CN103328474A, and the lower panel is the XRPD of the anhydride A in the ground CN103328474A after grinding.
  • Figure
  • Figure 28 is an XRPD overlay of the compound (I) crystal form CS1 placed at 25 ° C / 60% RH for 3 weeks (the upper image shows the XRPD pattern of the crystalline form CS1 before placement, and the lower figure shows the crystal form CS1 after placement) XRPD diagram)
  • Figure 29 is an XRPD overlay of the compound (I) crystal form CS1 placed at 40 ° C / 75% RH for 3 weeks (the upper image shows the XRPD pattern of the crystalline form CS1 before placement, and the lower figure shows the crystal form CS1 after placement) XRPD diagram)
  • Figure 30 is an XRPD overlay of the compound (I) crystal form CS1 placed at 60 ° C / 75% RH for 3 weeks (the upper graph is the XRPD pattern of the crystalline form CS1 before placement, and the lower figure is the deposited form CS1 XRPD diagram)
  • Figure 31 is an XRPD overlay of the compound (I) crystal form CS3 placed at 25 ° C / 60% RH for 2 weeks (the upper image shows the XRPD pattern of the crystalline form CS3 before placement, and the lower figure shows the crystal form CS3 after placement) XRPD diagram)
  • Figure 32 is an XRPD overlay of Compound (I) Form CS3 placed at 40 °C / 75% RH for 2 weeks (the above figure is the XRPD pattern of the crystalline form CS3 before placement, and the lower figure is the placed form of CS3).
  • XRPD diagram
  • Fig. 33 is an XRPD stack of the compound (I) crystal form CS3 placed at 60 ° C / 75% RH for 2 weeks (the upper graph is the XRPD pattern of the crystal form CS3 before placement, and the lower graph is the crystal form CS3 after the placement) XRPD diagram)
  • Figure 34 is a DVS diagram of the compound (I) crystal form CS3
  • Figure 35 is a DVS diagram of an anhydride B in the compound (I) CN103328474A
  • Figure 36 is a PSD diagram of the compound (I) crystal form CS3
  • Figure 37 is a PSD diagram of anhydrate B in compound (I) CN103328474A
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • H NMR data (1 HNMR) collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • a compound of formula II ABT28 (5.0 g, 1.0 eq.), a compound of formula III ABT09 (3.6 g, 1.3 eq.), carbodiimide (2.2 g, 1.3 eq.) and dimethylaminopyridine (1.07 g, 1.0 eq.) were added.
  • the mixture was stirred at room temperature for 5 minutes in 150 mL of dichloromethane, and then triethylamine (1.8 g, 2.0 eq.) was added, and the mixture was stirred at room temperature for 12 hours to give Compound (I).
  • the reaction solution was washed with water several times, and the washed compound (I) dichloromethane solution was evaporated over tetrahydrofuran to obtain a tetrahydrofuran solution of the compound (I).
  • the tetrahydrofuran solution of the compound (I) obtained in Example 1 was subjected to a sleeve distillation with an isopropyl acetate solvent to obtain a corresponding clear solution.
  • the target clear solution was stirred and spontaneously devitrified at room temperature. After stirring for 12 hours, it was filtered, and the obtained solid was dried in a forced air oven at 50 ° C for 12 hours, and then the sample was subjected to a crystal form test.
  • the obtained crystalline solid is the crystalline form CS1 of the present invention, and the X-ray powder diffraction data thereof are shown in Fig. 1 and Table 1.
  • the DSC of this crystal form showed an endothermic peak near 128 ° C, which is the dehydration of the crystal form CS1 near this temperature.
  • the TGA of this crystal form as shown in Fig. 4, had a mass loss gradient of about 4.6% when heated to about 150 °C.
  • the tetrahydrofuran solution of the compound (I) obtained in Example 1 was subjected to a sleeve distillation with a 1,4-dioxane solvent to obtain a corresponding clear solution.
  • the target clear solution was spontaneously decanted for 12 hours at room temperature.
  • the obtained solid was subjected to a crystal form test after drying in a forced air oven at 50 ° C for 12 hours.
  • the obtained crystalline solid is the crystalline form CS2 of the present invention, and its X-ray powder diffraction data is shown in FIG. 5 and Table 2.
  • the nuclear magnetic resonance spectrum is shown in Fig. 6.
  • the DSC of this crystal form is shown in Fig. 7.
  • the TGA of this crystal form has a mass loss gradient of about 4.4% when heated to about 160 °C. From the TGA calculation, about 0.5 mole of 1,4-dioxane is contained per mole of the crystalline form CS2.
  • the tetrahydrofuran solution of the compound (I) prepared in Example 1 was spontaneously crystallized at room temperature for 3 hours. Then, a filter cake was obtained by filtration, the filter cake was added to a solvent of tetrahydrofuran, dissolved by heating, and then the solution was concentrated to 350 mL, and spontaneously crystallized for 3 hours at room temperature, finally filtered, and the obtained cake was dried at 50 °C. The crystal form of the dry product is tested. Upon examination, the obtained crystalline solid is the crystalline form CS3 of the present invention, and its X-ray powder diffraction data is shown in FIG. 9 and Table 3.
  • the DSC of this crystal form is as shown in Fig. 11, and the endothermic peak at around 139 ° C is the melting endothermic peak of the crystal form.
  • the TGA of this crystal form as shown in Fig. 12, had a mass loss gradient of about 0.6% when heated to about 150 °C.
  • the DSC of this crystal form as shown in Fig. 15, showed an endothermic peak near 125 ° C, which is the solvent removal of the methyl isobutyl ketone solvate near this temperature.
  • the TGA of this crystal form is as shown in Fig. 16, and when it is heated to about 150 ° C, it has a mass loss of about 3.9%.
  • the DSC of this crystal form shows an endothermic peak near 140 ° C as shown in Fig. 19, which is the solvent removal of the methyl isobutyl ketone solvate near this temperature.
  • the TGA of this crystal form had a mass loss gradient of about 10.5% when heated to about 150 °C. Calculated from TGA, about 1.0 mole of methyl isobutyl ketone per mole of CS5.
  • the DSC of this crystal form has two endothermic peaks, and an endothermic peak begins to appear near 114 ° C.
  • This endothermic peak is the solvent removal of the methyl isobutyl ketone solvate near this temperature.
  • the TGA of this crystal form had a mass loss gradient of about 10.4% when heated to about 150 °C. Calculated from TGA, about 1.0 mole of methyl isobutyl ketone per mole of CS6.
  • Example 8 Study on Mechanical Stability of Crystal Forms CS1 and CS3
  • Forms CS1 and CS3 and CN103328474A without crystal type A were placed in a mortar and manually ground for 5 minutes.
  • the XRPD pattern of the crystal form before and after the test was tested.
  • the test results are shown in Fig. 25 (XRPD stack before and after crystal form CS1), 26 (XRPD stack before and after crystal form CS3), and 27 (CN103328474A without crystal type A) XRPD overlay before and after).
  • the crystalline drug with better mechanical stability has low requirements on the crystallization equipment, requires no special post-treatment conditions, is more stable in the preparation process, can significantly reduce the development cost of the drug, enhance the quality of the drug, and has strong economic value.
  • Example 9 Physical and chemical stability of crystalline forms CS1 and CS3
  • the CS1 prepared by the present invention was placed under the conditions of 25 ° C / 60% RH, 40 ° C / 75% RH and 60 ° C / 75% RH for 3 weeks, and the stability of CS1 was examined.
  • the test results are shown in Table 7, XRPD characterization. As shown in Figures 28, 29, and 30.
  • the CS3 prepared by the present invention was placed under the conditions of 25 ° C / 60% RH, 40 ° C / 75% RH and 60 ° C / 75% RH for 2 weeks, and the stability of CS3 was examined.
  • the test results are shown in Table 8, XRPD characterization. As shown in Figures 31, 32, and 33.
  • test results show that the crystalline form CS1 and the crystalline form CS3 of the invention have good physical and chemical stability, and good physical and chemical stability can ensure that the chemical degradation of the drug is maintained at a low level, and the raw material drug itself and the raw material drug are in the preparation. Stability and quality indicators. Better physical stability can reduce the risk of drug dissolution rate and bio-profit change due to crystal form changes, which is of great significance to ensure drug efficacy and safety and prevent adverse drug reactions.
  • the crystalline forms CS1, CS3 and CN103328474A anhydrate B of the present invention were prepared into a saturated solution by using FaSSIF, FeSSIF and water, respectively, and the samples in the saturated solution were respectively tested by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours.
  • the content ( ⁇ g/mL) is shown in Table 9.
  • Example 11 Study on the wettability of crystalline form CS3
  • CN103328474A anhydrate B belongs to the hygroscopicity, and the crystalline form CS3 of the present invention is slightly wetted, and it can be seen that the crystalline form CS3 is compared with the CN103328474A anhydrate B. It has lower moisture absorption and is suitable for later product development and storage.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • Example 12 Study on particle properties of crystalline form CS3
  • the PSD test was performed on the crystalline form CS3 of the present invention and CN10328474A anhydrate B, respectively.
  • the PSD data of the crystalline form CS3 and the CN103328474A anhydrous B of the present invention are shown in Table 11, and the PSD diagram is shown in Figs.
  • Mv represents the average particle size by volume
  • D10 indicates that the particle size distribution (volume distribution) accounts for 10% of the particle size of the anhydrate
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
  • D90 indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
  • the crystal form CS3 of the present invention has an average particle diameter of about 6 ⁇ m and is normally distributed, and has a uniform particle dispersion property and a narrow particle size distribution.
  • CN103328474A anhydrate B has different particle sizes, large differences, no normal distribution, and poor particle uniformity.
  • a narrower particle size distribution improves the uniformity of the drug substance components in the formulation, while making the difference between different batches of the formulation smaller, such as more uniform dissolution; smaller crystal size can increase the specific surface area of the drug, and increase The dissolution rate of the drug is beneficial to the absorption of the drug, thereby improving the bioavailability.
  • Large clusters of crystals are often susceptible to entrapment of residual solvents or other impurities.
  • the bulk crystal powder cannot be uniformly dispersed, and it is difficult to mix uniformly with the auxiliary material, which is disadvantageous for the preparation of the preparation.

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Abstract

La présente invention concerne des formes cristallines de vénétoclax et un procédé de préparation correspondant, la formule structurale de ces formes cristallines de vénétoclax étant représentée par la formule (I), et de telles formes cristallines pouvant être directement obtenues à partir de la cristallisation dans un solvant.
PCT/CN2018/077484 2017-02-28 2018-02-28 Formes cristallines de vénétoclax et leur procédé de préparation WO2018157803A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020127503A1 (fr) 2018-12-18 2020-06-25 Argenx Bvba Cd70 et venetoclax, inhibiteur de bcl-2, polythérapie pour le traitement de la leucémie myéloïde aiguë
WO2021028678A1 (fr) * 2019-08-14 2021-02-18 Johnson Matthey Public Limited Company Polymorphe de vénétoclax et son procédé de préparation
WO2021207581A1 (fr) * 2020-04-10 2021-10-14 Abbvie Inc. Formes cristallines d'un agent induisant l'apoptose
WO2022043538A1 (fr) 2020-08-29 2022-03-03 argenx BV Méthode de traitement de patients ayant une sensibilité réduite à un inhibiteur de bcl-2

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WO2011150016A1 (fr) * 2010-05-26 2011-12-01 Abbott Laboratories Agents inducteurs d'apoptose pour le traitement du cancer et de maladies immunitaires et auto-immunes
WO2012058392A1 (fr) * 2010-10-29 2012-05-03 Abbott Laboratories Dispersions solides contenant un agent induisant l'apoptose
CN103328474A (zh) * 2010-11-23 2013-09-25 Abbvie公司 细胞凋亡诱导剂的盐和晶形
CN107089981A (zh) * 2017-04-24 2017-08-25 杭州科耀医药科技有限公司 一种BCL‑2抑制剂Venetoclax的合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011150016A1 (fr) * 2010-05-26 2011-12-01 Abbott Laboratories Agents inducteurs d'apoptose pour le traitement du cancer et de maladies immunitaires et auto-immunes
WO2012058392A1 (fr) * 2010-10-29 2012-05-03 Abbott Laboratories Dispersions solides contenant un agent induisant l'apoptose
CN103328474A (zh) * 2010-11-23 2013-09-25 Abbvie公司 细胞凋亡诱导剂的盐和晶形
CN107089981A (zh) * 2017-04-24 2017-08-25 杭州科耀医药科技有限公司 一种BCL‑2抑制剂Venetoclax的合成方法

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020127503A1 (fr) 2018-12-18 2020-06-25 Argenx Bvba Cd70 et venetoclax, inhibiteur de bcl-2, polythérapie pour le traitement de la leucémie myéloïde aiguë
EP4218761A1 (fr) 2018-12-18 2023-08-02 Argenx BVBA Cd70 et venetoclax, inhibiteur de bcl-2, polythérapie pour le traitement de la leucémie myéloïde aiguë
WO2021028678A1 (fr) * 2019-08-14 2021-02-18 Johnson Matthey Public Limited Company Polymorphe de vénétoclax et son procédé de préparation
CN114174295A (zh) * 2019-08-14 2022-03-11 庄信万丰股份有限公司 维奈托克的多晶型体和用于制备该多晶型体的方法
WO2021207581A1 (fr) * 2020-04-10 2021-10-14 Abbvie Inc. Formes cristallines d'un agent induisant l'apoptose
WO2022043538A1 (fr) 2020-08-29 2022-03-03 argenx BV Méthode de traitement de patients ayant une sensibilité réduite à un inhibiteur de bcl-2

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