WO2018000250A1 - 依鲁替尼新晶型及其制备方法 - Google Patents

依鲁替尼新晶型及其制备方法 Download PDF

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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)
French (fr)
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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/zh
Publication of WO2018000250A1 publication Critical patent/WO2018000250A1/zh

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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

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  • 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

本发明提供一种依鲁替尼新晶型及其制备方法。具体地，本发明提供了依鲁替尼晶型III及其制备方法。本发明所提供的制备方法制得的依鲁替尼晶型III具有良好的热稳定性，常规条件下储存稳定，适合工业化应用。

Description

依鲁替尼新晶型及其制备方法 技术领域
本发明涉及药物化学领域，具体地，本发明涉及1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮的新晶型III，以及新晶型的制备方法和用途。
背景技术
依鲁替尼(Ibrutinib)由美国Pharmacyclics公司和强生公司联合研制，商品名为Imbruvica，其化学名称为：1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮，结构式X如下所示：
Figure PCTCN2016087692-appb-000001
依鲁替尼是一种口服的布鲁顿酪氨酸激酶(BTK)抑制剂的首创新药,该药通过与靶蛋白Btk活性位点半胱氨酸残基(Cys-481)选择性地共价结合,不可逆性地抑制BTK,从而有效地阻止肿瘤从B细胞迁移到适应于肿瘤生长环境的淋巴组织。2013年11月，美国食品药品管理局(FDA)批准其上市，用于治疗一种罕见的侵袭性血癌—套细胞淋巴瘤(MCL)，2014年7月FDA批准其用于慢性淋巴细胞性白血病(CLL)的治疗。
2013年美国Pharmacyclics公司申请的专利WO2013/184572公开了依鲁替尼的六种晶型，其中晶型D为甲基异丁基酮溶剂化物，晶型E为甲苯溶剂化物，晶型F为甲醇溶剂化物，均不适合于药用制剂。其余三种晶型中，根据WO2013/184572报道了晶型B吸湿性比较大，相比之下晶型A不容易吸湿，没有报道晶型C的稳定性和溶解性数据。
根据WO2013/184572公开的内容，六种晶型中，只有晶型A适合药用制剂，其报道的晶型A有三种制备方法：方法一是将依鲁替尼无定形物悬浮于10倍体积的有机溶剂中，在振荡器中加热至50℃，振荡1小时，再加入30倍体积的有机溶剂，再次加热至50℃振荡1小时，然后以0.1℃/min的速率冷却至0℃，过滤，得到的固体为晶型A，滤液通过针孔缓慢蒸发也得到晶型A。此种方法操作繁琐，而且因为有机溶剂用量为40倍，所以第一次过滤得到的产品收率低，而虽然从滤液中也可获得产品，但耗时太长；方法二是将依鲁替尼无定形物悬浮于1-10倍体积的有机溶剂中，然后密封反应瓶，在熟化室中密封5天，过滤得到晶型A。此 种方法同样耗时过长，并需要特殊设备；方法三是将依鲁替尼加热溶解于10倍体积的甲醇中，保温下加入水，再升温，然后冷却至室温并继续搅拌16小时，得到晶型A，收率为80％。此种方法的操作繁琐，操作中有反复的升温和降温，生产过程不好控制。
苏州晶云CN104327085A公开了另外一种晶型A(下面称为晶型A′)，其报道的制备方法有三种：方法一，将依鲁替尼粗品溶解在异丙醇和正庚烷的混合溶液中，在室温下以每分钟750转的速度搅拌得到晶型A′，如此高转速的搅拌工业化实施很困难；方法二，将依鲁替尼粗品溶解在异丙醇和正庚烷的混合溶剂中，并以0.1℃/min的降温速度从50℃降到5℃得到晶型A，这样精密的降温速度很难控制；方法三，将依鲁替尼粗品溶解在丙酮中，再缓慢加入正庚烷，并在每分钟1000转的转速下搅拌1天得到晶型A，这个方法比方法一要求的转速更高，工业化更难实现。发明人在重复这些方法时，发现重现性差，稍微控制不好就会得到WO2013/184572公开的晶型A。
WO2015145415A公开了其自命名的依鲁替尼晶型III、IV、V、VI、VII、VIII、IX共6种晶型，其中只有晶型VI是非溶剂化物晶型，而晶型VI由晶型IV在严格控制在温度40℃、相对湿度75％的环境下，放置足够长的时间可转化晶型为VI，此方法容易得到晶型IV和晶型VI的混晶，尤其工业化大生产中转晶效果会更差。WO2015145415A报道的相对稳定的晶型有两种，一种是晶型VII，为苯甲醚溶剂化物，另一种是晶型VIII，为氯苯溶剂化物，均不适合于药用制剂。
WO2016025720A公开了依鲁替尼的乙酸溶剂化物晶型G和苯甲醚溶剂化物晶型J，同样均不适合进一步的制剂开发。
因此，本领域亟需开发制备方法简单，热稳定性好，适合制剂开发的依鲁替尼新晶型。
发明内容
本发明的目的在于提供一种1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮的晶型III，以及新晶型的制备方法和用途。
本发明第一方面，提供一种结构如式X所示的化合物的晶型III，所述晶型为高稳定性的晶体，
Figure PCTCN2016087692-appb-000002
在另一优选例中，所述的“高稳定性”指将所述晶型III在60℃下敞口放置10天，或在相对湿度92％、常温25℃下放置10天，或在室温4500xl光照下放置10天后，晶型稳定。
在另一优选例中，所述晶型III的光学纯度≥98％，较佳地≥99％，最佳地≥99.5％。
在另一优选例中，所述晶型III的化学纯度≥95％，较佳地≥97％，最佳地≥99％。
在另一优选例中，所述晶型III的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：5.11°±0.2°、6.47°±0.2°、11.13°±0.2°、13.42°±0.2°、17.05°±0.2°、19.13°±0.2°。
在另一优选例中，所述晶型III的X射线粉末衍射图谱包括5个或5个以上选自下组的2θ值：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°。
在另一优选例中，所述晶型III的X射线粉末衍射图谱基本如图1所表征。
在另一优选例中，所述晶型III的差示扫描量热法分析图谱在185±5℃范围内具有特征峰。
在另一优选例中，所述晶型III的差示扫描量热法分析图谱基本如图2所表征。
在另一优选例中，所述晶型III的热重分析图谱基本如图3所表征。
在另一优选例中，所述晶型III的红外傅里叶变换光谱包括3个或3个以上选自下组的特征吸收峰：1681cm-1、1646cm-1、1610cm-1、1518cm-1、1487cm-1、1436cm-1、1372cm-1、1235cm-1、1142cm-1、1100cm-1±2cm-1。
在另一优选例中，所述晶型III的红外傅里叶变换光谱基本上如图4所示。
本发明第二方面，提供一种制备如本发明第一方面所述的依鲁替尼晶型III的方法，包括步骤：
(i)将依鲁替尼粗品I溶解于有机溶剂中，其中，依鲁替尼粗品I与有机溶剂的重量体积比为1：1-1：30g/ml；
(ii)-10℃至90℃下析晶，从而得到所述的晶型III；
其中，所述的依鲁替尼粗品I选自下组：依鲁替尼晶型C、依鲁替尼无定形物、依鲁替尼晶型A、或其组合。
在另一优选例中，所述步骤(i)中，所述的有机溶剂选自下组：醇类溶剂、酯类溶剂、酮类溶剂、烷烃、或其组合，较佳地为醇类溶剂与烷烃的混合溶剂、酯类溶剂与烷烃的混合溶剂、酮类溶剂与烷烃的混合溶剂、或其组合。
在另一优选例中，所述醇类溶剂与烷烃的混合溶剂中，所述醇类与烷烃的体积比为1-10：1。
在另一优选例中，所述酯类溶剂与烷烃的混合溶剂中，所述酯类与烷烃体积比为1-10：1。
在另一优选例中，所述酮类溶剂与烷烃的混合溶剂中，所述酮类与烷烃的体积比为1-10：1。
在另一优选例中，所述步骤(i)中，所述醇类溶剂选自下组：甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、正戊醇、或其组合。
在另一优选例中，所述步骤(i)中，所述酯类溶剂选自下组：乙酸乙酯、乙酸异丙酯、乙酸甲酯、甲酸乙酯、乙酸丁酯、或其组合。
在另一优选例中，所述步骤(i)中，所述酮类溶剂选自下组：丙酮、2-丁酮、甲基异丁基酮、环己酮、或其组合。
在另一优选例中，所述步骤(i)中，所述烷烃选自下组：正戊烷、正己烷、环己烷、正庚烷、或其组合。
本发明第三方面，提供一种医药组合物，所述的组合物包含(a)本发明第一方面所述的依鲁替尼晶型III，以及(b)药学上可接受的载体。
本发明第四方面，提供一种如本发明第一方面所述晶型III或第三方面所述医药组合物的用途，用于制备预防和/或治疗癌症的药物、或用于制备抑制肿瘤细胞的药物。
在另一优选例中，所述肿瘤包括淋巴瘤。
在另一优选例中，所述肿瘤细胞包括淋巴瘤细胞。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一赘述。
附图说明
图1显示了本发明的依鲁替尼晶型III的X-射线粉末衍射谱图(XRPD)。
图2显示了本发明的依鲁替尼晶型III的差示扫描量热分析谱图(DSC)。
图3显示了本发明的依鲁替尼晶型III的热失重分析谱图(TGA)。
图4显示了本发明的依鲁替尼晶型III的红外傅里叶变换光谱图(FT-IR)。
图5显示了本发明的依鲁替尼晶型III稳定性XRPD对比图(a为原始谱图，b为相对湿度92％、常温25℃放置10天谱图，c为60℃放置10天谱图，d为室温、4500xl光照10天谱图)。
具体实施方式
本发明人通过广泛而深入的研究，首次研发出一种1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮的晶型即晶型III，其具备良好的热稳定性和非吸湿性，且制备工艺简单高效，重复性好，可实现规模化工业生产。在此基础上，完成了本发明。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。术语“3个或3个以上”、“5个或5个以上”包括具有全部数值的技术方案。
多晶型物
如本发明所用，“晶型III”、“1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮的晶型III”、“依鲁替尼晶型III”可互换使用。
制备方法
本发明还提供所述晶体III的制备方法，包括步骤：
(i)将依鲁替尼粗品I溶解于有机溶剂中，重量体积比为1：1-1：30g/ml；
(ii)-10℃至90℃下析晶，从而得到所述的晶型III；
其中，所述的依鲁替尼粗品I选自下组：依鲁替尼晶型C、依鲁替尼无定形物、依鲁替尼晶型A、或其组合。
在另一优选例中，所述步骤(i)中，所述的有机溶剂选自下组：醇类溶剂、酯类溶剂、酮类溶剂、烷烃、或其组合，较佳地为醇类溶剂与烷烃的混合溶剂、酯类溶剂与烷烃的混合溶剂、酮类溶剂与烷烃的混合溶剂、或其组合。
如本文所用，所述各醇类溶剂、酯类溶剂、酮类溶剂、烷烃的碳原子数范围为1-10。
此外，本发明的制备方法中，对母液进行一次或多次回收套用，合并回收循环利用。
药物组合物
本发明还提供了一种药物组合物，所述药物组合物包含安全有效量范围内的活性成分，以及药学上可接受的载体。
本发明所述的“活性成分”是指本发明所述的依鲁替尼晶型III。
本发明所述的“活性成分”和药物组合物用于制备预防和/或治疗癌症的药物、或用于制备抑制肿瘤细胞的药物。
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2016087692-appb-000003
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制。本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合 物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他治疗药物(如化疗药)联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
原料和通用方法
实施例中所用原料依鲁替尼晶型C、晶型A参考WO2013/184572制备，依鲁替尼无定形物参考WO2008/039218制备。
XRD图谱测定方法
X-射线粉末衍射仪器：Dedye～Scherrer INEL CPS～120X-射线粉末衍射仪；辐射源：
Figure PCTCN2016087692-appb-000004
强度比α1/α2为0.5；发生器(Generator)kv：40kv；发生器(Generator)mA：30mA；起始的2θ：2.000°，扫描范围:2.0000～50.000°。
DSC图谱测定方法
差示扫描量热法(DSC)仪器：美国TA公司的Q2000型，20～450℃范围内，加热速率10℃/min，氮气流速50ml/min。
TGA图谱测定方法
热重分析(TGA)仪器：美国TA公司的SDT Q600型，20～450℃范围内，加热速率10℃/min，氮气流速100ml/min。
FTIR图谱测定方法
红外分光光度法(FTIR)仪器：PE Spectrum Two，测试温度23℃，相对湿度54％，采用溴化钾压片法。
本发明的主要优点在于：
(1)本发明的晶型III具有良好的热稳定性和低吸湿性。
(2)本发明的晶型III的制备方法简单，适合大规模工业化生产。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1 依鲁替尼晶型III的制备
将依鲁替尼无定形物(5.0g)加入50ml正丙醇中，加热至回流使溶解。待溶清后继续搅拌30分钟。停止加热，以约1℃/分钟的速度降温，冷却到50℃，有固体析出，保温搅拌2小时，过滤，滤液用乙酸乙酯淋洗，滤饼于50℃真空干燥得3.2g产品。
结果：所得固体的粉末X射线衍射图如图1所表征，差热扫描谱图如图2所示，热重分析如图3所示，红外傅里叶变换光谱如图4所示。
实施例2 依鲁替尼晶型III的制备
将依鲁替尼晶型C(5.0g)加入75ml异丙醇中，室温搅拌过夜，将得到的混悬物过滤，50℃真空干燥至恒重，得到3.9g白色固体。
结果：所得固体的粉末X射线衍射图同实施例1所得晶型相同。
实施例3 依鲁替尼晶型III制备
将依鲁替尼无定形物(50.0g)加入300ml乙酸乙酯中，加热至70℃使溶解，待溶清后，停止加热，将混合物迅速降温到50℃。保温搅拌2小时，过滤。滤饼 用15ml乙酸乙酯淋洗，50℃下真空干燥得26.2g白色固体。
结果：所得固体的粉末X射线衍射图同实施例1所得晶型相同。
实施例4 依鲁替尼晶型III制备
将依鲁替尼晶型A(3.0g)加入20ml异丙醇与10ml正己烷的混合溶剂中，加热至50℃使溶解，待溶清后，停止加热，将混合物迅速降温到0～5℃。保温搅拌2小时，过滤。滤饼用2ml异丙醇与1ml正己烷的混合溶剂淋洗，50℃下真空干燥得2.5g白色固体。
结果：所得固体的粉末X射线衍射图同实施例1所得晶型相同。
实施例5 依鲁替尼晶型III制备
将依鲁替尼晶型C(5.0g)加入50ml 2-丁酮中，搅拌溶解，加热到70℃，保温搅拌2小时，将得到的混悬物趁热过滤，滤饼用3ml 2-丁酮淋洗，50℃真空干燥至恒重，得到2.5g白色固体。
结果：所得固体的粉末X射线衍射图同实施例1所得晶型相同。
上述实施例中的母液可以进行合并回收套用。
实施例6 稳定性试验
取实施例1-5所制得的依鲁替尼晶型III，分为相同三组，分别在60℃下敞口放置10天；在相对湿度为92％常温25℃下放置10天；室温下4500xl光照10天后，上述三组的XRPD对照图谱如图5所示。
从图5中可以看出，本发明得到的晶型III晶型稳定性很好。
实施例7 吸湿性试验
分别称取实施例1-5所制得的依鲁替尼晶型III各0.5克平铺于称量瓶中，称重，将称量好的称量瓶开口放置于湿度为80％的干燥器(用饱和氯化铵溶液控制)中部，并盖上干燥器密封盖；放置24小时，取出再次称量称量瓶的重量，并以此计算增重百分率约为0.5％。
本发明的上述实施例表明，晶型III不仅制备工艺简单，而且具有极高的稳定性和非常有益的低吸湿性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本 领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种结构如式X所示的化合物的晶型III，其特征在于，所述晶型为高稳定性的晶体，
    Figure PCTCN2016087692-appb-100001
  2. 如权利要求1所述的晶型III，其特征在于，所述晶型III具有选自下组的一个或多个特征：
    (1)所述晶型III的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：5.11°±0.2°、6.47°±0.2°、11.13°±0.2°、13.42°±0.2°、17.05°±0.2°、19.13°±0.2°；
    (2)所述晶型III的X射线粉末衍射图谱包括5个或5个以上选自下组的2θ值：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°；
    (3)所述晶型III的X射线粉末衍射图谱基本如图1所表征；和/或
    (4)所述晶型III的热重分析图谱基本如图3所表征。
  3. 如权利要求1所述的晶型III，其特征在于，所述晶型III的差示扫描量热法分析图谱在185±5℃范围内具有特征峰；和/或
    所述晶型III的差示扫描量热法分析图谱基本如图2所表征。
  4. 如权利要求1所述的晶型III，其特征在于，所述晶型III的红外傅里叶变换光谱包括3个或3个以上选自下组的特征吸收峰：1681cm-1、1646cm-1、1610cm-1、1518cm-1、1487cm-1、1436cm-1、1372cm-1、1235cm-1、1142cm-1、1100cm-1±2cm-1；和/或
    所述晶型III的红外傅里叶变换光谱基本上如图4所示。
  5. 一种制备如权利要求1所述的依鲁替尼晶型III的方法，包括步骤：
    (i)将依鲁替尼粗品I溶解于有机溶剂中，其中，依鲁替尼粗品I与有机溶剂的重量体积比为1：1-1：30g/ml；
    (ii)-10℃至90℃下析晶，从而得到所述的晶型III；
    其中，所述的依鲁替尼粗品I选自下组：依鲁替尼晶型C、依鲁替尼无定形物、依鲁替尼晶型A、或其组合。
  6. 如权利要求5所述的方法，其特征在于，所述步骤(i)中，所述的有机溶剂选自下组：醇类溶剂、酯类溶剂、酮类溶剂、烷烃、或其组合，较佳地为醇类溶 剂与烷烃的混合溶剂、酯类溶剂与烷烃的混合溶剂、酮类溶剂与烷烃的混合溶剂、或其组合。
  7. 如权利要求6所述的方法，其特征在于，所述醇类溶剂与烷烃的混合溶剂中，所述醇类与烷烃的体积比为1-10：1；和/或
    所述酯类溶剂与烷烃的混合溶剂中，所述酯类与烷烃体积比为1-10：1；和/或
    所述酮类溶剂与烷烃的混合溶剂中，所述酮类与烷烃的体积比为1-10：1。
  8. 如权利要求5所述的方法，其特征在于，所述步骤(i)中，所述醇类溶剂选自下组：甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、正戊醇、或其组合。
  9. 如权利要求5所述的方法，其特征在于，所述步骤(i)中，所述酯类溶剂选自下组：乙酸乙酯、乙酸异丙酯、乙酸甲酯、甲酸乙酯、乙酸丁酯、或其组合。
  10. 一种医药组合物，其特征在于，所述的组合物包含(a)权利要求1所述的依鲁替尼晶型III，以及(b)药学上可接受的载体。
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US10183024B2 (en) 2016-12-02 2019-01-22 Apotex Inc. Crystalline forms of ibrutinib
WO2019070698A1 (en) 2017-10-02 2019-04-11 Johnson Matthey Public Limited Company NEW FORMS OF IBRUTINIB
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EP3669867A1 (en) 2018-12-21 2020-06-24 Synthon B.V. Pharmaceutical composition comprising ibrutinib
WO2020127912A1 (en) 2018-12-21 2020-06-25 Synthon B.V. Pharmaceutical composition comprising ibrutinib

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