WO2016146020A1 - 尼达尼布二乙磺酸盐晶体及其制备方法和用途 - Google Patents

尼达尼布二乙磺酸盐晶体及其制备方法和用途 Download PDF

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WO2016146020A1
WO2016146020A1 PCT/CN2016/076110 CN2016076110W WO2016146020A1 WO 2016146020 A1 WO2016146020 A1 WO 2016146020A1 CN 2016076110 W CN2016076110 W CN 2016076110W WO 2016146020 A1 WO2016146020 A1 WO 2016146020A1
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nidanib
crystal
organic solvent
diacetyl
disease
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PCT/CN2016/076110
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English (en)
French (fr)
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王胡博
朱雪焱
郭猛
胡明通
张家松
孙九德
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正大天晴药业集团股份有限公司
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Priority to US15/558,050 priority Critical patent/US10292965B2/en
Priority to JP2017548117A priority patent/JP2018509421A/ja
Priority to EP16764201.6A priority patent/EP3269710B1/en
Priority to CN201680014054.0A priority patent/CN107428686A/zh
Priority to RU2017136104A priority patent/RU2708683C2/ru
Publication of WO2016146020A1 publication Critical patent/WO2016146020A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B28/00—Production of homogeneous polycrystalline material with defined structure
    • C30B28/04—Production of homogeneous polycrystalline material with defined structure from liquids
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
    • C30B29/10—Inorganic compounds or compositions
    • C30B29/46—Sulfur-, selenium- or tellurium-containing compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • This application relates to the field of medical chemistry.
  • the present application relates to nidanib diacetyl sulfonate crystals, crystal compositions, pharmaceutical compositions, and methods of making and using same.
  • Nidanib has inhibitory effects on various kinases, particularly receptor tyrosine kinases such as VEGFR1, VEGFR2, VEGFR3, PDGFR ⁇ , PDGFR ⁇ , FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R, Flt-3 And HGFR, which can be used for the treatment of neoplastic diseases, immune diseases or pathological conditions involving fibrotic components or fibrotic diseases, especially idiopathic pulmonary fibrosis.
  • receptor tyrosine kinases such as VEGFR1, VEGFR2, VEGFR3, PDGFR ⁇ , PDGFR ⁇ , FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R, Flt-3 And HGFR, which can be used for the treatment of neoplastic diseases, immune diseases or pathological conditions involving fibrotic components or fibrotic diseases, especially idiopathic pulmonary fibrosis.
  • WO2012068441 discloses an amorphous form of nidanib diethylene sulfonate of formula (II) and a crystal.
  • nidanib diacetylsulfonate crystals are unstable in storage, are easy to absorb moisture, and have a marked increase in impurity content during storage.
  • the chemical stability, solid state stability and shelf life of the active ingredient are very important factors from the standpoint of obtaining a commercially viable production method or from the production of a pharmaceutical composition containing the active compound. Therefore, it is important to provide a suitable form of a drug having the desired properties for drug production and storage.
  • One aspect of the present application provides a nidanib diacetyl sulfonate type A crystal represented by formula (II),
  • nidanib diacetyl sulfonate Form A crystal comprises 50% or more, preferably 80% or more, more preferably 90% by weight of the crystal composition. Above, it is preferably 95% or more.
  • Another aspect of the present application provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described nidanib diethylsulfonate Form A crystal, or the above crystalline composition.
  • Another aspect of the present application provides the above-described nidanib diacetyl sulfonate type A crystal, wherein the above crystalline composition, or the above pharmaceutical composition is prepared for prevention or treatment selected from a neoplastic disease, an immune disease or Use of a pathological condition of an immunological component and a medicament for a disease or condition of a fibrotic disease, especially in the preparation of a medicament for the treatment of non-small cell lung cancer or idiopathic pulmonary fibrosis.
  • Another aspect of the present application provides a method of preventing or treating a disease or condition selected from a neoplastic disease, an immune disease, or a pathological condition involving an immunological component and a fibrotic disease, comprising administering a treatment to a mammal in need thereof An effective amount of the above-described nidanib diacetyl sulfonate type A crystal, the above crystalline composition, or the above pharmaceutical composition.
  • Another aspect of the present application provides for the prevention or treatment selected from the group consisting of a neoplastic disease and an immune disease
  • a neoplastic disease and an immune disease The above-described nidanib ethanesulfonate type A crystal, a crystalline composition, or the above pharmaceutical composition, which is a disease or a pathological condition involving an immunological component and a disease or condition of a fibrotic disease.
  • Another aspect of the present application provides a method for preparing the above nidanib diacetyl sulfonate type A crystal or the above crystal composition, comprising:
  • Example 1 is an X-ray powder diffraction pattern of a nidanib diethylsulfonate type A crystal obtained in Example 1.
  • Example 2 is a graph showing differential scanning calorimetry (DSC) measurement of Nidanib's diethyl sulfonate type A crystals prepared in Example 1.
  • “Mammal” includes humans and domestic animals such as laboratory mammals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic mammals, such as wild mammals and the like.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes all pharmaceutically acceptable carriers for its use.
  • the pharmaceutical composition facilitates administration of the compound to the organism.
  • carrier is defined as a compound that facilitates the introduction of a compound into a cell or tissue.
  • DMSO dimethyl sulfoxide
  • carrier because it is easy to introduce certain organic compounds into cells or tissues of an organism.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvants, excipients, glidants, sweeteners, diluents, preservatives, dyes approved by the National Drug Administration for human or domestic use.
  • “Therapeutically effective amount” means the amount of a compound of the invention, when administered to a mammal, preferably In humans, it is sufficient to achieve treatment of viral infections in mammals, preferably humans, as defined below.
  • the amount of the compound of the present invention which constitutes a “therapeutically effective amount” varies depending on the compound, the state of the disease and its severity, the mode of administration, and the age of the mammal to be treated, but can be conventionally determined by one of ordinary skill in the art. Knowledge and the content of this disclosure are determined.
  • treatment encompasses the treatment of a viral infection in a mammal, preferably a human, having a viral infection, and includes:
  • One aspect of the present application provides a nidanib diacetyl sulfonate type A crystal represented by formula (II),
  • the X-ray powder diffraction spectrum of the nidanib diacetyl sulfonate type A crystal of the present application has a diffraction peak as shown in the following table.
  • the X-ray powder diffraction spectrum of the nidanib diacetyl sulfonate type A crystal of the present application is shown in FIG.
  • the differential scanning calorimetry (DSC) measurement of the nidanib diacetyl sulfonate Form A crystal of the present application has an absorption peak at about 257 °C.
  • DSC differential scanning calorimetry
  • nidanib diacetyl sulfonate Form A crystal comprises 50% or more, preferably 80% or more, more preferably 90% by weight of the crystal composition. Above, it is preferably 95% or more.
  • compositions comprising a therapeutically effective amount of the above-described nidanib diethylsulfonate Form A crystal, or the above crystalline composition.
  • the pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier.
  • Another aspect of the present application provides the above-described nidanib diacetyl sulfonate type A crystal, wherein the above crystalline composition, or the above pharmaceutical composition is prepared for prevention or treatment selected from a neoplastic disease, an immune disease or Use of a pathological condition of an immunological component and a medicament for a disease or condition of a fibrotic disease, especially in the preparation of a medicament for the treatment of non-small cell lung cancer or idiopathic pulmonary fibrosis.
  • Another aspect of the present application provides a method of preventing or treating a disease or condition selected from a neoplastic disease, an immune disease, or a pathological condition involving an immunological component and a fibrotic disease, comprising administering a treatment to a mammal in need thereof An effective amount of the above-described nidanib diacetyl sulfonate type A crystal, the above crystalline composition, or the above pharmaceutical composition.
  • the mammal is preferably a human.
  • Another aspect of the present application provides the above nidanib diacetyl sulfonate for preventing or treating a disease or condition selected from a neoplastic disease, an immunological disease, or a pathological condition involving an immunological component and a fibrotic disease.
  • a disease or condition selected from a neoplastic disease, an immunological disease, or a pathological condition involving an immunological component and a fibrotic disease.
  • Another aspect of the present application provides a method for preparing the above nidanib diacetyl sulfonate type A crystal or the above crystal composition, comprising:
  • the organic solvent is a C1-C6 alkyl alcohol, preferably methanol or ethanol, more preferably methanol.
  • the amount of the organic solvent can dissolve nidanib and ethanesulfonic acid or nidanib cloth diethyl sulfonate.
  • 10-40 ml of an organic solvent preferably 10-15 ml of an organic solvent, is added per 1 mol of nidanib or nidanib.
  • the molar ratio of ethanesulfonic acid to nidanib is from 2 to 5:1, preferably 3:1.
  • the nidanib diacetyl sulfonate is an amorphous nidanib dimethanesulfonate or other crystalline form of nidanib diacetyl sulfonate. , such as nidanib cloth diethyl sulfonate crystals prepared according to WO2012068441.
  • the volume of acetone is more than twice the volume of the organic solvent in step (a), preferably 2-8 times. Preferably, it is heated to 50 °C.
  • step (b) above acetone is added to the crystals under agitation (40-60 ° C). That is, the temperature was maintained at 40 to 60 ° C during the addition of acetone to the crystallization.
  • the method of the above nidanib diacetyl sulfonate type A crystal or the above crystalline composition further comprises:
  • the X-ray powder diffraction spectrum of the sample was measured under the following conditions: Instrument: Bruker D2 X-ray diffractometer; Test conditions: 30 kV 10 mA; Slit: 0.6 mm/3 mm/0.8 mm; Target type: Cu; Angle range : 5-40°; step length 0.1s/0.02°.
  • the DSC spectrum was measured under the following conditions: Instrument: Mettler type 1 differential thermal analyzer; temperature range: 30-270 ° C; heating rate: 10 ° C / min.
  • the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystal form, wherein the relative intensity of the band (especially at a low angle) may be due to the crystal.
  • the dominant orientation effect due to the difference in conditions, particle size, and other measurement conditions varies. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystal form to be targeted.
  • the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of the XRD spectrum have similarities as a whole, and the relative intensity error may be large.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting.
  • the thermal transition temperature and melting point error is typically within about 5 ° C, usually within about 3 ° C, when we say a compound has a given DSC At the peak or melting point, this means the DSC peak or melting point ⁇ 5 °C.
  • DSC provides an auxiliary method for identifying different crystal forms. Different crystal morphology can be identified based on their different transition temperature characteristics. It should be noted that for the mixture, the DSC peak or melting point can be Can change in a larger range.
  • the melting temperature is related to the rate of temperature increase due to decomposition during the melting of the substance.
  • nidanib can be prepared by referring to the method disclosed in CN1671660A.
  • the nidanib diethyl sulfonate type A crystal of the present application has a basic moisture content after being placed under high humidity (25 ° C, 92.5% RH) and accelerated test (40 ⁇ 2 ° C, 75% ⁇ 5% RH) for 10 days.
  • the water content of the nidanib cloth diethyl sulfonate salt produced under the same conditions was significantly increased according to WO2012068441, and the wettability was also observed from the traits.
  • Fig. 1 The XRD pattern of the obtained nidanib diacetyl sulfonate type A crystal is shown in Fig. 1, and the DSC spectrum is shown in Fig. 2.
  • nidanib diethyl sulfonate crystals prepared according to WO2012068441 were added to 15 mL of methanol, dissolved by heating, and stirred under stirring at 50 ° C, and slowly added to 40 mL of acetone to crystallize, and filtered to obtain nidanib. Acid salt type A crystal.
  • the nidanib diethyl sulfonate type A crystal prepared in Example 1 and the nidani obtained according to WO2012068441 are referred to the method of the influencing factor test of the drug substance in the Appendix XIX C of the Chinese Pharmacopoeia 2010 (Part 2).
  • the cloth diethyl sulfonate crystals (existing crystals) were subjected to high humidity (25 ° C, 92.5% RH), light (10000 lx ⁇ 500 lx) and accelerated (40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5%) tests, respectively.
  • the investigation time was 10 days, and the purity of the samples was sampled on the 0th, 5th, and 10th days to examine the stability.
  • the test results are shown in Table 1.
  • nidanib epoxide salt A crystal prepared in Example 1 and the nidanib ethanesulfonate crystal prepared according to WO2012068441 (existing crystallization) were prepared by the intrinsic dissolution dial method of the United States Pharmacopoeia 1087. The intrinsic dissolution measurement was carried out, and the results are shown in Table 2.
  • Dissolution medium 700 ml of 0.1 mol/L hydrochloric acid solution, rotation speed: 300 rpm, detection wavelength: 287 nm, medium temperature: 37 °C.

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Abstract

本申请涉及式(II)所示的尼达尼布二乙磺酸盐的A型晶体，还涉及包含该晶体的晶体组合物、药物组合物，以及它们的制备方法和用途。本申请的尼达尼布二乙磺酸盐A型晶体的X-射线粉末衍射光谱用2θ值表示在约14.64、18.79、19.31、20.11、21.20、22.45、26.71°处有衍射峰。本申请的尼达尼布二乙磺酸盐的A型晶体性质稳定，不易降解、不吸潮，特别适合药物生产。

Description

尼达尼布二乙磺酸盐晶体及其制备方法和用途
相关申请的交叉引用
本申请要求于2015年3月13日向中国国家知识产权局提交的第201510112909.0号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请涉及医药化学领域。具体而言，本申请涉及尼达尼布二乙磺酸盐晶体、晶体组合物、药物组合物，及其制备方法和用途。
背景技术
尼达尼布(nintedanib/intedanib)，化学名称为3-Z-[1-(4-(N-((4-甲基哌嗪-1-基)-甲基羰基)-N-甲基氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮，结构如式(I)所示：
Figure PCTCN2016076110-appb-000001
尼达尼布在各种激酶上有抑制作用，特别是受体酪氨酸激酶，如VEGFR1，VEGFR2，VEGFR3，PDGFRα，PDGFRβ，FGFR1，FGFR3，EGFR，HER2，c-Kit，IGF1R，Flt-3及HGFR，可用于治疗肿瘤性疾病、免疫性疾病或涉及免疫成分的病理学病症或纤维变性疾病，尤其是特发性肺纤维变性。
WO2012068441公开了式(II)的尼达尼布二乙磺酸盐的无定形形态及一种结晶。
Figure PCTCN2016076110-appb-000002
然而，上述尼达尼布二乙磺酸盐结晶储存时不稳定，易吸潮，并且储存时杂质含量出现明显增加。从获得一种商业上可行的生产方法的角度或者从生产含有活性化合物的药用组合物的角度出发，活性成分的化学稳定性、固态稳定性和储存期限均是非常重要的因素。因此，提供一种具有所需性质的药物的合适形式对于药物生产、储存是十分重要的。
发明内容
本申请的一方面提供了式(II)所示的尼达尼布二乙磺酸盐A型晶体，
Figure PCTCN2016076110-appb-000003
其特征是其X-射线粉末衍射光谱用2θ值表示在约14.64、18.79、19.31、20.11、21.20、22.45、26.71°处有衍射峰。
本申请的另一方面提供了晶体组合物，其中上述尼达尼布二乙磺酸盐A型晶体占所述晶体组合物重量的50％以上，较好是80％以上，更好是90％以上，最好是95％以上。
本申请的另一方面提供了药物组合物，其中包含治疗有效量的上述尼达尼布二乙磺酸盐A型晶体，或上述晶体组合物。
本申请的另一方面提供了上述尼达尼布二乙磺酸盐A型晶体，上述晶体组合物，或上述药物组合物在制备用于预防或治疗选自肿瘤性疾病、免疫性疾病或涉及免疫学成份的病理学病症及纤维变性疾病的疾病或病症的药物中的用途，尤其是在制备治疗非小细胞肺癌或特发性肺纤维变性的药物中的用途。
本申请的另一方面提供了预防或治疗选自肿瘤性疾病、免疫性疾病或涉及免疫学成份的病理学病症及纤维变性疾病的疾病或病症的方法，其包括向有需要的哺乳动物给予治疗有效量的上述尼达尼布二乙磺酸盐A型晶体，上述晶体组合物，或上述药物组合物。
本申请的另一方面提供了用于预防或治疗选自肿瘤性疾病、免疫性疾 病或涉及免疫学成份的病理学病症及纤维变性疾病的疾病或病症的上述尼达尼布二乙磺酸盐A型晶体，上述晶体组合物，或上述药物组合物。
本申请的另一方面提供了上述尼达尼布二乙磺酸盐A型晶体或上述晶体组合物的制备方法，其包括：
(a)将尼达尼布和乙磺酸溶于有机溶剂中，或者将尼达尼布二乙磺酸盐溶于有机溶剂中；
(b)加热至40-60℃，加入丙酮析晶。
附图说明
图1为实施例1制得的尼达尼布二乙磺酸盐A型晶体的X-射线粉末衍射图谱。
图2为实施例1制得的尼达尼布二乙磺酸盐A型晶体差示扫描量热(DSC)测量图。
发明详述
定义
当用于本申请的说明书与所附的权利要求中时，除非有相反的指定，否则下列术语具有所指示的意义：
“哺乳动物”包括人和家畜如实验室哺乳动物与家庭宠物(例如猫、狗、猪、牛、绵羊、山羊、马、家兔)，及非驯养哺乳动物，如野生哺乳动物等。
术语“药物组合物”是指本发明化合物与本领域中通常接受的用于传递生物活性化合物至哺乳动物例如人的介质的制剂。所述介质包括所有供其使用的药物可接受的载体。药物组合物有利于化合物向生物体的给药。
术语“载体”定义为有利于将化合物引入细胞或组织的化合物。例如二甲亚砜(DMSO)通常用作载体，这是因为它易于将某些有机化合物引入生物体的细胞或组织中。
“药物可接受的载体”包括但不限于任何被国家药品管理机构批准为可接受用于人或家畜的佐剂、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等张剂、溶剂或乳化剂。
“治疗有效量”是指本发明化合物的量，当其被给予哺乳动物，优选为 人时，足以如下文定义地在哺乳动物，优选为人中实现对病毒感染的治疗。构成“治疗有效量”的本发明化合物的量，根据化合物、疾病状态及其严重性、给药方式以及要治疗的哺乳动物的年龄而改变，但可常规地由本领域一般技术人员根据其自有知识及本公开内容而决定。
本文中使用的“治疗”涵盖对患有病毒感染的哺乳动物，优选为人中的病毒感染的治疗，且包括：
(i)抑制病毒感染，即阻止其发展；
(ii)缓解病毒感染，即引起病毒感染的复原；或
(iii)缓解由病毒感染引发的症状。
具体实施方式
本申请的一方面提供了式(II)所示的尼达尼布二乙磺酸盐A型晶体，
Figure PCTCN2016076110-appb-000004
其特征是其X-射线粉末衍射光谱用2θ值表示在约14.64、18.79、19.31、20.11、21.20、22.45、26.71°处有衍射峰；典型地在5.84、12.27、14.64、17.27、17.61、18.12、18.79、19.31、20.11、21.20、22.45、24.57、26.71°处有衍射峰；更典型地在5.84、12.27、13.22、14.64、15.54、17.27、17.61、18.12、18.79、19.31、20.11、21.20、21.88、22.45、23.13、23.95、24.57、26.71°处有衍射峰。
在本申请的一个实施方式中，本申请的尼达尼布二乙磺酸盐A型晶体的X-射线粉末衍射光谱具有如下表所示的衍射峰。
序号 2θ(°) I/I0
1 5.84 10
2 12.27 20
3 13.22 17
4 14.64 27
5 15.54 20
6 17.27 31
7 17.61 30
8 18.12 31
9 18.79 100
10 19.31 61
11 20.11 39
12 21.20 36
13 21.88 36
14 22.45 42
15 23.13 26
16 23.95 23
17 24.57 26
18 26.71 32
在本申请的一个实施方式中，本申请的尼达尼布二乙磺酸盐A型晶体的X-射线粉末衍射光谱如图1所示。
在本申请的一个实施方式中，本申请的尼达尼布二乙磺酸盐A型晶体的差示扫描量热(DSC)测量图在约257℃处有吸收峰。
在本申请的一个实施方式中，本申请的尼达尼布二乙磺酸盐A型晶体的差示扫描量热(DSC)测量图如图2所示。
本申请的另一方面提供了晶体组合物，其中上述尼达尼布二乙磺酸盐A型晶体占所述晶体组合物重量的50％以上，较好是80％以上，更好是90％以上，最好是95％以上。
本申请的另一方面提供了药物组合物，其中包含治疗有效量的上述尼达尼布二乙磺酸盐A型晶体，或上述晶体组合物。所述药物组合物可以包含至少一种药学上可接受的载体。
本申请的另一方面提供了上述尼达尼布二乙磺酸盐A型晶体，上述晶体组合物，或上述药物组合物在制备用于预防或治疗选自肿瘤性疾病、免疫性疾病或涉及免疫学成份的病理学病症及纤维变性疾病的疾病或病症的药物中的用途，尤其是在制备治疗非小细胞肺癌或特发性肺纤维变性的药物中的用途。
本申请的另一方面提供了预防或治疗选自肿瘤性疾病、免疫性疾病或涉及免疫学成份的病理学病症及纤维变性疾病的疾病或病症的方法，其包括向有需要的哺乳动物给予治疗有效量的上述尼达尼布二乙磺酸盐A型晶体，上述晶体组合物，或上述药物组合物。哺乳动物优选为人类。
本申请的另一方面提供了用于预防或治疗选自肿瘤性疾病、免疫性疾病或涉及免疫学成份的病理学病症及纤维变性疾病的疾病或病症的上述尼达尼布二乙磺酸盐A型晶体，上述晶体组合物，或上述药物组合物。
本申请的另一方面提供了上述尼达尼布二乙磺酸盐A型晶体或上述晶体组合物的制备方法，其包括：
(a)将尼达尼布和乙磺酸溶于有机溶剂中，或者将尼达尼布二乙磺酸盐溶于有机溶剂中；
(b)加热至40-60℃，加入丙酮析晶。
在某些实施方案中，上述步骤(a)中，有机溶剂为C1-C6烷基醇，优选甲醇或乙醇，更优选甲醇。有机溶剂的用量能溶解尼达尼布和乙磺酸或者尼达尼布二乙磺酸盐即可。在某些实施方案中，每1mol尼达尼布或尼达尼布二乙磺酸盐加入10-40ml有机溶剂，优选为10-15ml有机溶剂。
在某些实施方案中，上述步骤(a)中，乙磺酸与尼达尼布的摩尔比为2-5∶1，优选为3∶1。
在某些实施方案中，上述步骤(a)中，尼达尼布二乙磺酸盐为无定形的尼达尼布二乙磺酸盐或其它晶型的尼达尼布二乙磺酸盐，如根据WO2012068441制得的尼达尼布二乙磺酸盐晶体。
在某些实施方案中，上述步骤(b)中，丙酮的体积为步骤(a)中有机溶剂体积的2倍以上，优选2-8倍。优选地，加热至50℃。
在某些实施方案中，上述步骤(b)中，在保温(40-60℃)搅拌下，加入丙酮析晶。即，在加入丙酮析晶的过程中，温度保持为40-60℃。
在某些实施方案中，上述尼达尼布二乙磺酸盐A型晶体或上述晶体组合物的方法还包括：
(c)过滤；
(d)干燥。
本申请中，样品的X-射线粉末衍射光谱在下述条件下测定：仪器：Bruker D2X射线衍射仪；测试条件：30kv 10mA；狭缝：0.6mm/3mm/0.8mm；靶型：Cu；角度范围：5-40°；步长0.1s/0.02°。
本申请中，DSC光谱在下述条件下测定：仪器：Mettler 1型差热分析仪；温度范围：30-270℃；升温速率：10℃/min。
需要说明的是，在X-射线粉末衍射光谱中，由晶体化合物得到的衍射谱图对于特定的晶型往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为晶体条件、粒径和其它测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的晶型并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的相对位置而不是它们的相对强度。此外，对任何给定的晶型而言，峰的位置可能存在轻微误差，这在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品移动、或仪器的标定等，峰的位置可以移动，2θ值的测定误差有时约为±0.2°。因此，在确定每种结晶结构时，应该将此误差考虑在内。在XRD图谱中通常用2θ角或晶面距d表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面距，λ代表入射X射线的波长，θ为衍射角。对于同种化合物的同种晶型，其XRD谱的峰位置在整体上具有相似性，相对强度误差可能较大。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的晶体是特征性的。
DSC测定当晶体由于其晶体结构发生变化或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内，通常在约3℃之内，当我们说一个化合物具有一给定的DSC峰或熔点时，这是指该DSC峰或熔点±5℃。DSC提供了一种辨别不同晶型的辅助方法。不同的晶体形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰或熔点可 能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。
本申请中，尼达尼布可以参照CN1671660A中公开的方法制备得到。
本申请的尼达尼布二乙磺酸盐A型晶体在高湿(25℃，92.5％RH)和加速试验(40±2℃，75％±5％RH)条件下放置10天后水分含量基本不变，而根据WO2012068441制得尼达尼布二乙磺酸盐结晶在相同条件下水分含量出现了明显增加，从性状上也可明显看出其引湿成团。
下面通过实施例进一步详述本申请，但本申请并不限于下述的实施例。
实施例1尼达尼布二乙磺酸盐A型晶体的制备
将5.4g尼达尼布加入到11mL甲醇中，搅拌下，加入约3.3g乙磺酸，溶清后，升温至50℃，保温搅拌下，缓慢加入45mL丙酮析晶，过滤即得尼达尼布二乙磺酸盐A型晶体。
所得尼达尼布二乙磺酸盐A型晶体的XRD图谱见图1，DSC图谱见图2。
实施例2尼达尼布二乙磺酸盐A型晶体的制备
将根据WO2012068441制得的尼达尼布二乙磺酸盐结晶7.6g加入到15mL甲醇中，加热溶解，50℃保温搅拌下，缓慢加入40mL丙酮析晶，过滤即得尼达尼布二乙磺酸盐A型晶体。
实施例3稳定性试验
参照中国药典2010年版(二部)的附录XIX C中原料药影响因素试验的方法，将实施例1制备得到的尼达尼布二乙磺酸盐A型晶体和根据WO2012068441制得的尼达尼布二乙磺酸盐结晶(现有结晶)分别进行高湿(25℃，92.5％RH)、光照(10000lx±500lx)和加速(40℃±2℃、相对湿度75％±5％)试验。考察时间为10天，分别于第0天、5天和第10天取样检测样品纯度，以考察其稳定性，试验结果如表1所示。
表1稳定性试验结果
Figure PCTCN2016076110-appb-000005
实施例4尼达尼布二乙磺酸盐A型晶体溶出速率
采用美国药典1087章节固有溶出度转盘法对实施例1制备得到的尼达尼布二乙磺酸盐A型晶体和根据WO2012068441制得的尼达尼布二乙磺酸盐结晶(现有结晶)进行固有溶出测定，结果如表2所示。溶出介质：0.1mol/L盐酸溶液700ml，转速：300rpm，检测波长：287nm，介质温度：37℃。
Figure PCTCN2016076110-appb-000006
本申请说明书中所引用的所有专利、专利申请公开、专利申请及非专利出版物，均以其全文并入本文供参考。
自前文可以理解，虽然为了说明的目的在本文中描述了本发明的具体实施方案，但可在不偏离本发明的精神与范围下进行各种修正。因此，本发明的范围应当仅受所附的权利要求的限定。

Claims (14)

  1. 式(II)所示的尼达尼布二乙磺酸盐A型晶体，
    Figure PCTCN2016076110-appb-100001
    其特征是其X-射线粉末衍射光谱用2θ值表示在约14.64、18.79、19.31、20.11、21.20、22.45、26.71°处有衍射峰。
  2. 权利要求1所述的尼达尼布二乙磺酸盐A型晶体，其特征是其X-射线粉末衍射光谱用2θ值表示在约5.84、12.27、14.64、17.27、17.61、18.12、18.79、19.31、20.11、21.20、22.45、24.57、26.71°处有衍射峰。
  3. 权利要求2所述的尼达尼布二乙磺酸盐A型晶体，其特征是其X-射线粉末衍射光谱用2θ值表示在约5.84、12.27、13.22、14.64、15.54、17.27、17.61、18.12、18.79、19.31、20.11、21.20、21.88、22.45、23.13、23.95、24.57、26.71°处有衍射峰。
  4. 权利要求1-3中任一项所述的尼达尼布二乙磺酸盐A型晶体，其特征是，其DSC测量图在约257℃处有吸收峰。
  5. 晶体组合物，其中权利要求1-4中任一项所述的尼达尼布二乙磺酸盐A型晶体占所述晶体组合物重量的50％以上，较好是80％以上，更好是90％以上，最好是95％以上。
  6. 药物组合物，其包含权利要求1-4中任一项所述的尼达尼布二乙磺酸盐A型晶体或权利要求5所述的晶体组合物。
  7. 权利要求1-4中任一项所述的尼达尼布二乙磺酸盐A型晶体、权利要求5所述的晶体组合物、权利要求6所述的药物组合物在制备用于预防或治疗选自肿瘤性疾病、免疫性疾病或涉及免疫学成份的病理学病症及纤维变性疾病的疾病或病症的药物中的用途。
  8. 权利要求1-4中任一项所述的尼达尼布二乙磺酸盐A型晶体的制备方法，包括：
    (a)将尼达尼布和乙磺酸溶于有机溶剂中，或者将尼达尼布二乙磺酸盐溶于有机溶剂中；
    (b)加热至40-60℃，加入丙酮析晶。
  9. 权利要求8所述的制备方法，其中步骤(a)中所述有机溶剂为C1-C6烷基醇，优选甲醇或乙醇，更优选甲醇。
  10. 权利要求8所述的制备方法，其中步骤(a)中每1mol尼达尼布或尼达尼布二乙磺酸盐加入10-40ml有机溶剂，优选为10-15ml有机溶剂。
  11. 权利要求8所述的制备方法，其中步骤(a)中所述乙磺酸与所述尼达尼布的摩尔比为2-5∶1，优选为3∶1。
  12. 权利要求8所述的制备方法，其中步骤(b)中所述丙酮的体积为步骤(a)中所述有机溶剂体积的2倍以上，优选2-8倍。
  13. 权利要求8所述的制备方法，其中步骤(b)中在加入丙酮析晶的过程中，温度保持为40-60℃。
  14. 权利要求8所述的制备方法，其还包括：
    (c)过滤；
    (d)干燥。
PCT/CN2016/076110 2015-03-13 2016-03-11 尼达尼布二乙磺酸盐晶体及其制备方法和用途 WO2016146020A1 (zh)

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Publication number Priority date Publication date Assignee Title
DE10233500A1 (de) * 2002-07-24 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylen]-6-methoxycarbonyl-2-indolinon-Monoethansulfonat und dessen Verwendung als Arzneimittel
EP1870400A1 (en) * 2006-06-08 2007-12-26 Boehringer Ingelheim Pharma GmbH & Co. KG Salts and crystalline salt forms of an 2-indolinone derivative
NZ585799A (en) * 2007-12-03 2012-04-27 Boehringer Ingelheim Int Process for the manufacture of an indolinone derivative in particular 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012068441A2 (en) * 2010-11-19 2012-05-24 Ratiopharm Gmbh Intedanib salts and solid state forms thereof

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US10292965B2 (en) 2019-05-21
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