WO2018000250A1 - Nouvelle forme cristalline ibrutinib et méthode de préparation de celle-ci - Google Patents

Nouvelle forme cristalline ibrutinib et méthode de préparation de celle-ci Download PDF

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Publication number
WO2018000250A1
WO2018000250A1 PCT/CN2016/087692 CN2016087692W WO2018000250A1 WO 2018000250 A1 WO2018000250 A1 WO 2018000250A1 CN 2016087692 W CN2016087692 W CN 2016087692W WO 2018000250 A1 WO2018000250 A1 WO 2018000250A1
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form iii
solvent
ibrutinib
alkane
crystal form
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PCT/CN2016/087692
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English (en)
Chinese (zh)
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任华森
蔡志刚
杨勤刚
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上海创诺医药集团有限公司
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Priority to PCT/CN2016/087692 priority Critical patent/WO2018000250A1/fr
Publication of WO2018000250A1 publication Critical patent/WO2018000250A1/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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular, the present invention relates to 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d A new crystalline form III of pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, and a process for the preparation and use of the novel crystalline form.
  • Ibrutinib was developed by Pharmacyclics and Johnson & Johnson, under the trade name Imbruvica, and its chemical name is 1-[(3R)-3-[4-amino-3-(4-phenoxybenzene) -1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, the structural formula X is as follows:
  • Ibrutinib is the first innovative drug for oral Bruton's tyrosine kinase (BTK) inhibitor, which is selectively shared with the target protein Btk active site cysteine residue (Cys-481).
  • BTK target protein Btk active site cysteine residue
  • Cys-481 target protein Btk active site cysteine residue
  • Patent No. WO 2013/184572 filed by Pharmacyclics, Inc., 2013, discloses six crystal forms of Ibrutinib, wherein Form D is a methyl isobutyl ketone solvate, Form E is a toluene solvate, and Form F is methanol. Solvates are not suitable for pharmaceutical preparations.
  • the hygroscopicity of the crystal form B is relatively large, and in contrast, the crystal form A is not easily hygroscopic, and the stability and solubility data of the crystal form C are not reported.
  • Method 1 is to suspend the ibrutinib amorphous substance in 10 volumes. In an organic solvent, heat to 50 ° C in a shaker, shake for 1 hour, add 30 times the volume of organic solvent, heat again to 50 ° C for 1 hour, then cool to 0 ° C at a rate of 0.1 ° C / min, filter The obtained solid was Form A, and the filtrate was slowly evaporated through a pinhole to obtain Form A.
  • This method is cumbersome to operate, and because the amount of organic solvent is 40 times, the yield of the product obtained by the first filtration is low, and although the product is also obtained from the filtrate, it takes too long; the second method is to use the ruru The niobium is suspended in 1-10 volumes of organic solvent, and then the reaction flask is sealed, sealed in a curing chamber for 5 days, and filtered to obtain crystal form A. This The method is also too long and requires special equipment; the third method is to dissolve ibrutinib in 10 times volume of methanol, add water under heat, then heat up, then cool to room temperature and continue stirring for 16 hours. Form A, the yield was 80%. The operation of this method is cumbersome, and there are repeated heating and cooling in the operation, and the production process is not well controlled.
  • crystal form A' another crystal form A (hereinafter referred to as crystal form A'), which has been reported to have three preparation methods: method one, dissolving crude ibrutinib in a mixed solution of isopropanol and n-heptane In the above, the crystal form A' is stirred at a rate of 750 rpm at room temperature, so that the high-speed stirring industrialization is difficult to carry out; the second method, the crude ibrutinib is dissolved in a mixed solvent of isopropyl alcohol and n-heptane.
  • WO2015145415A discloses six crystal forms of their self-named Ibrutinib Forms III, IV, V, VI, VII, VIII, IX, wherein only Form VI is an unsolvated crystalline form, and Form VI is a crystalline form.
  • IV is strictly controlled at a temperature of 40 ° C and a relative humidity of 75%, and can be placed for a sufficient period of time to convert the crystal form to VI. This method is easy to obtain a mixed crystal of Form IV and Form VI, especially in industrial large-scale production. The effect will be even worse.
  • Form VII which is an anisole solvate
  • Form VIII which is a chlorobenzene solvate
  • WO2016025720A discloses that acetic acid solvate crystal form I and anisole solvate form J of Ibrutinib are likewise unsuitable for further formulation development.
  • a crystalline form III of a compound of the formula X which is a crystal of high stability
  • the "high stability" means that the crystal form III is exposed to open at 60 ° C for 10 days, or at a relative humidity of 92%, at a normal temperature of 25 ° C for 10 days, or at room temperature. After standing for 10 days under 4500 xl light, the crystal form was stable.
  • the crystalline form III has an optical purity of > 98%, preferably > 99%, optimally > 99.5%.
  • the crystalline form III has a chemical purity of > 95%, preferably > 97%, optimally > 99%.
  • the X-ray powder diffraction pattern of Form III includes 3 or more 2 ⁇ values selected from the group consisting of 5.11° ⁇ 0.2°, 6.47° ⁇ 0.2°, and 11.13° ⁇ 0.2°. 13.42° ⁇ 0.2°, 17.05° ⁇ 0.2°, 19.13° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III comprises 5 or more 2 ⁇ values selected from the group consisting of: 5.11 ° ⁇ 0.2 °, 6.47 ° ⁇ 0.2 °, 6.63 ° ⁇ 0.2 ° 11.13° ⁇ 0.2°, 13.42° ⁇ 0.2°, 17.05° ⁇ 0.2°, 17.92° ⁇ 0.2°, 19.13° ⁇ 0.2°, 20.03° ⁇ 0.2°, 20.61° ⁇ 0.2°, 23.70° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III is substantially characterized as in Figure 1.
  • the differential scanning calorimetry profile of Form III has a characteristic peak in the range of 185 ⁇ 5 °C.
  • the differential scanning calorimetry analysis pattern of Form III is substantially characterized by Figure 2.
  • thermogravimetric analysis pattern of Form III is substantially characterized as in Figure 3.
  • the Form III Infrared Fourier Transform spectrum includes three or more features selected from the group consisting of three peaks: 1681cm -1, 1646cm -1, 1610cm -1, 1518cm -1 , 1487cm -1, 1436cm -1, 1372cm -1, 1235cm -1, 1142cm -1, 1100cm -1 ⁇ 2cm -1.
  • the infrared Fourier transform spectrum of Form III is substantially as shown in FIG.
  • the crude Iribinib I is selected from the group consisting of Ibrutinib Form C, Ibrutinib Amorph, Ibrutinib Form A, or a combination thereof.
  • the organic solvent is selected from the group consisting of an alcohol solvent, an ester solvent, a ketone solvent, an alkane, or a combination thereof, preferably an alcohol solvent. a mixed solvent with an alkane, a mixed solvent of an ester solvent and an alkane, a mixed solvent of a ketone solvent and an alkane, or a combination thereof.
  • the volume ratio of the alcohol to the alkane is 1-10:1.
  • the ester to alkane volume ratio is 1-10:1.
  • the volume ratio of the ketone to the alkane is 1-10:1.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, and Pentanol, or a combination thereof.
  • the ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, methyl acetate, ethyl formate, butyl acetate, or a combination thereof.
  • the ketone solvent is selected from the group consisting of acetone, 2-butanone, methyl isobutyl ketone, cyclohexanone, or a combination thereof.
  • the alkane is selected from the group consisting of n-pentane, n-hexane, cyclohexane, n-heptane, or a combination thereof.
  • a pharmaceutical composition comprising (a) Ibrutinib Form III of the first aspect of the invention, and (b) a pharmaceutically acceptable carrier.
  • a pharmaceutical composition according to the first aspect or the third aspect of the present invention for the preparation of a medicament for preventing and/or treating cancer, or for preparing a tumor for inhibiting Cellular drugs.
  • the tumor comprises a lymphoma.
  • the tumor cells comprise lymphoma cells.
  • Figure 1 shows the X-ray powder diffraction pattern (XRPD) of Ibrutinib Form III of the present invention.
  • Figure 2 shows a differential scanning calorimetry spectrogram (DSC) of Ibrutinib Form III of the present invention.
  • FIG. 3 shows the thermogravimetric analysis spectrum (TGA) of Ibrutinib Form III of the present invention.
  • FIG. 4 shows an infrared Fourier transform spectrum (FT-IR) of Ibrutinib Form III of the present invention.
  • Figure 5 is a graph showing the stability XRPD of Ibrutinib Form III of the present invention (a is the original spectrum, b is a relative humidity of 92%, a normal temperature of 25 ° C for 10 days, and c is 60 ° C for 10 days of spectrum.
  • Figure, d is room temperature, 4500 xl light 10 days spectrum).
  • the inventors have for the first time developed a 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazole [3,4] through extensive and intensive research.
  • the crystal form of -d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one is crystalline form III, which has good thermal stability and non-hygroscopicity, and the preparation process is simple and efficient. It has good repeatability and can realize large-scale industrial production. On the basis of this, the present invention has been completed.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • the term “3 or more”, “5 or more” includes technical solutions having all values.
  • Form III As used herein, "Form III”, "1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] Form III” and “Ibrutinib Form III” of pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one are used interchangeably.
  • the invention also provides a preparation method of the crystal III, comprising the steps of:
  • the crude Iribinib I is selected from the group consisting of Ibrutinib Form C, Ibrutinib Amorph, Ibrutinib Form A, or a combination thereof.
  • the organic solvent is selected from the group consisting of an alcohol solvent, an ester solvent, a ketone solvent, an alkane, or a combination thereof, preferably an alcohol solvent. a mixed solvent with an alkane, a mixed solvent of an ester solvent and an alkane, a mixed solvent of a ketone solvent and an alkane, or a combination thereof.
  • each of the alcohol solvent, the ester solvent, the ketone solvent, and the alkane has a carbon number ranging from 1 to 10.
  • the mother liquor is subjected to one or more recovery and application, and is combined and recycled for recycling.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient in a safe and effective amount, together with a pharmaceutically acceptable carrier.
  • the "active ingredient" as used in the present invention means the ibrutinib form III of the present invention.
  • the "active ingredient" and pharmaceutical composition of the present invention are useful for the preparation of a medicament for preventing and/or treating cancer, or for the preparation of a medicament for inhibiting tumor cells.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose” is a tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • the administration form of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, and representative administration forms include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example,
  • the solid dosage forms can also be prepared with coatings and shell materials, such as casings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • Liquid dosage forms can contain, in addition to the active ingredient, inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, and the like.
  • inert diluents such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, and the like.
  • the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other therapeutic agents, such as chemotherapeutic agents.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the starting material Ibrutinib Form C, Form A was prepared by reference to WO 2013/184572, and Ibrutinib amorphous form was prepared with reference to WO 2008/039218.
  • X-ray powder diffraction instrument Dedye ⁇ Scherrer INEL CPS ⁇ 120X-ray powder diffractometer; radiation source: The intensity ratio ⁇ 1/ ⁇ 2 is 0.5; generator Kv: 40 kv; generator mA: 30 mA; initial 2 ⁇ : 2.000°, scanning range: 2.000 to 50.000°.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric Analysis (TGA) instrument SDT Q600 type from TA Company, USA, in the range of 20-450 ° C, heating rate 10 ° C / min, nitrogen flow rate 100 ml / min.
  • FTIR Infrared spectrophotometry
  • the crystalline form III of the present invention has good thermal stability and low hygroscopicity.
  • Ibrutinib amorphous (5.0 g) was added to 50 ml of n-propanol and heated to reflux to dissolve. Stirring was continued for 30 minutes after being dissolved. The heating was stopped, the temperature was lowered at a rate of about 1 ° C/min, cooled to 50 ° C, solids were precipitated, and the mixture was stirred for 2 hours while being filtered. The filtrate was washed with ethyl acetate, and the cake was vacuum dried at 50 ° C to obtain 3.2 g of product.
  • Ibrutinib Form C (5.0 g) was added to 75 ml of isopropanol and stirred at room temperature overnight. The resulting suspension was filtered and dried in vacuo to a constant weight to afford 3.9 g of white solid.
  • Ibrutinib amorphous (50.0 g) was added to 300 ml of ethyl acetate, heated to 70 ° C to dissolve, and after heating, the heating was stopped, and the mixture was rapidly cooled to 50 °C. Stir for 2 hours with heat and filter. Filter cake It was rinsed with 15 ml of ethyl acetate and dried under vacuum at 50 ° C to give a white solid.
  • Ibrutinib Form A (3.0g) was added to a mixed solvent of 20 ml of isopropanol and 10 ml of n-hexane, and heated to 50 ° C to dissolve. After the solution was dissolved, the heating was stopped, and the mixture was rapidly cooled to 0 to 5 ° C. . Stir for 2 hours with heat and filter. The filter cake was rinsed with a mixed solvent of 2 ml of isopropyl alcohol and 1 ml of n-hexane, and dried under vacuum at 50 ° C to obtain 2.5 g of a white solid.
  • Ibrutinib Form C (5.0 g) was added to 50 ml of 2-butanone, stirred and dissolved, heated to 70 ° C, and kept under stirring for 2 hours. The obtained suspension was filtered while hot, and the cake was filtered with 3 ml of 2-butyl The ketone was rinsed and dried under vacuum at 50 ° C to constant weight to give 2.5 g of a white solid.
  • the mother liquor in the above examples can be combined and recycled.
  • the Iridinib Form III prepared in Example 1-5 was divided into the same three groups and placed at 60 ° C for 10 days; at a relative humidity of 92% at 25 ° C for 10 days; room temperature After 10 days of light exposure to 4500 xl, the XRPD control maps of the above three groups are shown in Fig. 5.
  • the crystalline form III crystal form obtained by the present invention is very stable.
  • Form III is not only simple in preparation process, but also has extremely high stability and very beneficial low hygroscopicity.

Abstract

L'invention concerne une nouvelle forme cristalline d'ibrutinib et son procédé de préparation. Spécifiquement, l'invention concerne une forme cristalline III d'ibrutinib et son procédé de préparation. La forme cristalline III de l'ibrutinib préparée par le procédé de préparation fourni par la présente invention a une bonne stabilité thermique, et est stockée de manière stable sous des conditions standards, et par conséquent, est appropriée pour une application industrielle.
PCT/CN2016/087692 2016-06-29 2016-06-29 Nouvelle forme cristalline ibrutinib et méthode de préparation de celle-ci WO2018000250A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10183024B2 (en) 2016-12-02 2019-01-22 Apotex Inc. Crystalline forms of ibrutinib
WO2019070698A1 (fr) 2017-10-02 2019-04-11 Johnson Matthey Public Limited Company Nouvelles formes d'ibrutinib
WO2019195827A1 (fr) 2018-04-06 2019-10-10 Johnson Matthey Public Limited Company Nouvelle forme d'ibrutinib
CN111138436A (zh) * 2018-11-04 2020-05-12 鲁南制药集团股份有限公司 伊布替尼晶型a单晶及其制备方法
US10688050B1 (en) 2018-12-21 2020-06-23 Synthon B.V. Pharmaceutical composition comprising ibrutinib
EP3669867A1 (fr) 2018-12-21 2020-06-24 Synthon B.V. Composition pharmaceutique comprenant de l'ibrutinib

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CN103121999A (zh) * 2012-08-29 2013-05-29 苏州迪飞医药科技有限公司 一种酪氨酸激酶抑制剂pci-32765的合成方法
CN103626774A (zh) * 2013-11-20 2014-03-12 苏州明锐医药科技有限公司 伊鲁替尼的制备方法
CN106117214A (zh) * 2016-06-29 2016-11-16 上海创诺医药集团有限公司 依鲁替尼新晶型及其制备方法

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CN102887900A (zh) * 2006-09-22 2013-01-23 药品循环公司 布鲁顿酪氨酸激酶的抑制剂
CN103121999A (zh) * 2012-08-29 2013-05-29 苏州迪飞医药科技有限公司 一种酪氨酸激酶抑制剂pci-32765的合成方法
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10183024B2 (en) 2016-12-02 2019-01-22 Apotex Inc. Crystalline forms of ibrutinib
WO2019070698A1 (fr) 2017-10-02 2019-04-11 Johnson Matthey Public Limited Company Nouvelles formes d'ibrutinib
WO2019195827A1 (fr) 2018-04-06 2019-10-10 Johnson Matthey Public Limited Company Nouvelle forme d'ibrutinib
CN111138436A (zh) * 2018-11-04 2020-05-12 鲁南制药集团股份有限公司 伊布替尼晶型a单晶及其制备方法
US10688050B1 (en) 2018-12-21 2020-06-23 Synthon B.V. Pharmaceutical composition comprising ibrutinib
EP3669867A1 (fr) 2018-12-21 2020-06-24 Synthon B.V. Composition pharmaceutique comprenant de l'ibrutinib
WO2020127912A1 (fr) 2018-12-21 2020-06-25 Synthon B.V. Composition pharmaceutique comprenant de l'ibrutinib

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