WO2018165865A1 - 3-z-[1-(4-(n-((4-甲基-哌嗪-1-基)-甲羰基)-n-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的晶型 - Google Patents

3-z-[1-(4-(n-((4-甲基-哌嗪-1-基)-甲羰基)-n-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的晶型 Download PDF

Info

Publication number
WO2018165865A1
WO2018165865A1 PCT/CN2017/076648 CN2017076648W WO2018165865A1 WO 2018165865 A1 WO2018165865 A1 WO 2018165865A1 CN 2017076648 W CN2017076648 W CN 2017076648W WO 2018165865 A1 WO2018165865 A1 WO 2018165865A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
nidanib
methyl
ray powder
powder diffraction
Prior art date
Application number
PCT/CN2017/076648
Other languages
English (en)
French (fr)
Inventor
刘飞
张翠霞
姜伟明
赖清裕
阮新
张豪龙
Original Assignee
新源生物科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 新源生物科技股份有限公司 filed Critical 新源生物科技股份有限公司
Priority to JP2019542699A priority Critical patent/JP7306697B2/ja
Priority to EP17900817.2A priority patent/EP3597636A4/en
Priority to CN202310090866.5A priority patent/CN116063221A/zh
Priority to PCT/CN2017/076648 priority patent/WO2018165865A1/zh
Priority to CN201780077637.2A priority patent/CN110072849A/zh
Publication of WO2018165865A1 publication Critical patent/WO2018165865A1/zh
Priority to US16/570,710 priority patent/US10961203B2/en
Priority to JP2021124466A priority patent/JP2021176899A/ja

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-
  • Nidanib is a potent inhibitor of the receptor tyrosine kinase family (RTK).
  • RTK receptor tyrosine kinase family
  • Nidanib is capable of inhibiting platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) and Fms-like tyrosine kinase-3 (FLT3).
  • FGFR, PDGFR and VEGFR have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • nidanib can reduce the progression of IPF disease by reducing the rate of decline in lung function.
  • WO 2016/209555 discloses ophthalmic formulations comprising nidanib for the treatment of diseases of the ocular surface.
  • An object of the present invention is to provide nidanib (chemical name: 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-) A new crystalline form of benzyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indanone).
  • Another object of the present invention is to provide a process for the preparation of the crystal form of the nidanib.
  • Another object of the present invention is to provide a pharmaceutical preparation containing the crystalline form of the nidanib.
  • Another object of the invention is to provide a crystalline form of the nidanib and the use of the formulation.
  • the invention provides a 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-benzene)
  • the crystal form of nidanib provided by the present invention includes: Form B, Form C, Form D, Form E, Form F.
  • the crystalline form of nidanib of the present invention has an X-ray powder diffraction (XRPD) pattern having a characteristic diffraction peak at a 2 ⁇ value of 6.4 ⁇ 0.2, and is selected from the group consisting of At least one correspondence of the 2 ⁇ values has characteristic diffraction peaks: 16.6 ⁇ 0.2, 17.4 ⁇ 0.2, 17.8 ⁇ 0.2, and 19.9 ⁇ 0.2.
  • Such crystal forms include Form C, Form D, Form E, Form F.
  • the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2 ⁇ values: 6.4 ⁇ 0.2, 16.6 ⁇ 0.2, 17.4 ⁇ 0.2, 17.8 ⁇ 0.2 and 19.9 ⁇ 0.2.
  • Such crystal forms include Form C, Form E, Form F.
  • the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2 ⁇ values: 6.4 ⁇ 0.2, 12.0 ⁇ 0.2, 16.6 ⁇ 0.2, 17.4 ⁇ 0.2, 17.8 ⁇ 0.2 and 19.9 ⁇ 0.2.
  • Such crystal forms include Form E and Form F.
  • the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2 ⁇ values: 6.4 ⁇ 0.2, 12.0 ⁇ 0.2, 16.6 ⁇ 0.2, 17.4 ⁇ 0.2, 17.8 ⁇ 0.2 and 19.9 ⁇ 0.2; and the crystalline form has a melting point temperature of 245 ° C ⁇ 5 ° C.
  • This crystal form is named crystal form E in the present invention.
  • the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2 ⁇ values: 6.4 ⁇ 0.2, 12.0 ⁇ 0.2, 16.6 ⁇ 0.2, 17.4 ⁇ 0.2, 17.8 ⁇ 0.2 and 19.9 ⁇ 0.2; and the crystalline form has a melting point temperature of 255 ° C ⁇ 5 ° C.
  • This crystal form is named as Form F in the present invention.
  • the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2 ⁇ values: 6.4 ⁇ 0.2, 16.6 ⁇ 0.2, 17.4 ⁇ 0.2, 17.8 ⁇ 0.2, 19.9 ⁇ 0.2 and 23.3 ⁇ 0.2.
  • a crystal form having these characteristic diffraction peaks is named as Form C.
  • the crystal form of nidanib of the present invention has an XRPD pattern having characteristic diffraction peaks at the corresponding 2 ⁇ values: 4.8 ⁇ 0.2, 5.6 ⁇ 0.2, 6.4 ⁇ 0.2, 17.4 ⁇ 0.2 and 19.9 ⁇ 0.2.
  • a crystal form having these characteristic diffraction peaks is named as Form D.
  • the present invention also provides another crystal form of nidanib having an XRPD spectrum having characteristic diffraction peaks at the correspondence of the following 2 ⁇ values: 11.2 ⁇ 0.2, 14.8 ⁇ 0.2, 16.4 ⁇ 0.2, 17.0 ⁇ 0.2, and 21.0 ⁇ 0.2.
  • a crystal form having these characteristic diffraction peaks is named as Form B.
  • the crystal form of the nidanib of the present invention is Form E, the XRPD pattern of which is substantially as shown in Figures 12, 14, 19, 20, 21 or 22.
  • substantially as shown in Figure n means having a characteristic diffraction peak at a corresponding position of a specific 2 ⁇ value of ⁇ 0.2 as indicated in Figure n.
  • the crystal form of the nidanib of the present invention is Form E, and the differential scanning calorimetry (DSC) pattern of the crystal form is substantially as shown in FIG.
  • the crystalline form of nidanib of the present invention is Form F, the XRPD pattern of which is substantially as shown in Figure 15 or Figure 23.
  • the crystalline form of nidanib of the present invention is Form F, the DSC pattern of which is substantially as shown in FIG.
  • the crystal form of the nidanib of the present invention is a crystalline form C, and the XRPD pattern of the crystalline form is substantially as shown in FIGS. 3, 4, 5, 6, 7, and 8.
  • the crystal form of nidanib of the present invention is Form D, the XRPD pattern of which is substantially as shown in FIG.
  • the crystal form of nidanib of the present invention is Form B, the XRPD pattern of which is substantially as shown in FIG.
  • the present invention also provides a process for the preparation of the crystal form of nidanib of the present invention, wherein a commercially available free base crystal form or a specific salt of nidanib can be used as a starting material in different solvent systems.
  • Various crystal forms of nidanib as described in the present invention are obtained by suspension stirring, slow evaporation, and the like.
  • the method for preparing the nedanib of the present invention comprises: adding nidanib ethanesulfonate to a saturated aqueous solution of sodium carbonate, extracting with dichloromethane, and then washing with water until Neutral, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to give a nidanib.
  • the method for preparing the nedanib of the present invention comprises: adding nidanib to acetone, vortexing for several minutes, and then passing through a 0.22 ⁇ m organic filter to obtain a filtrate.
  • the solid after the filtrate was evaporated to dryness was the nidanib form C.
  • the method for preparing the nedanib of the present invention comprises: adding nidanib to a solvent, suspending, magnetically stirring, and then centrifuging the supernatant, and drying.
  • the solid obtained was a nidanib crystal form C.
  • the solvent is selected from the group consisting of acetonitrile, isopropanol, n-propanol, 2-butanone, 1,4-dioxane/water mixed solvent, heptane, methanol/water mixed solvent, and acetone/water mixed solvent.
  • the solvent is selected from the group consisting of acetonitrile, isopropanol, n-propanol, 2-butanone, 1,4-dioxane/water mixed solvent, heptane, methanol/water mixed solvent, and acetone/water mixed solvent.
  • the method for preparing the nedanib of the present invention comprises: adding nidanib to dichloromethane, vortexing for several minutes, and then passing through a 0.22 ⁇ m organic filter. The filtrate, the solid after the filtrate was evaporated to dryness, was the nedanib form D.
  • the method for preparing the nedanib of the present invention comprises: adding nidanib form A to water or acetone/water (9/1, v/v), Vortex, pass 0.22 ⁇ m filter, the filtrate is added to nidanib form B, vortex, pass 0.22 ⁇ m filter, the filtrate is added to nidanib form C, vortex, pass 0.22 ⁇ m filter, filtrate is added to Nepal Danibu Form A, Form B and Form C, magnetically stirred, centrifuged to discard the supernatant, and evaporated to give a solid of Nidanib Form E.
  • the method for preparing the nedanib of the present invention comprises: adding nidanib ethanesulfonate to water, and adjusting the pH of the solution to about 10 with a saturated sodium carbonate solution.
  • Dichloromethane was added to the suspension solution, stirred, and allowed to stand for separation. The aqueous layer was back-extracted with dichloromethane, and the organic phases were combined. Dilute, liquid, dry anhydrous sodium sulfate, dilute the solvent under reduced pressure, dry to obtain nidanib free base, add the nidanib free base to ethanol, suspend stirring, filter, and dry to obtain crystal form F .
  • the method for preparing the nedanib of the present invention comprises: adding nidanib form F to water, magnetically stirring uniformly, adding a small amount of crystal form E as a seed crystal, room temperature Under magnetic stirring, centrifuge to take a solid and dry to obtain nidanib crystal form E.
  • the method for preparing the nedanib of the present invention comprises: mixing nidanib form F with a 0.2% tyloxapol solution, and using nidanib The mixture of tyloxapol and the 200 micron zirconia grinding beads were ground, ground, separated and centrifuged and dried to obtain a nedanib crystal form E.
  • nidanib of the present invention possesses valuable pharmacological properties and can be used in the pharmaceutical industry for the production of pharmaceutical compositions for use in human medicine.
  • the invention also provides the use of the crystalline form of nidanib of the invention for the preparation of a medicament, in particular for the manufacture of a medicament for the treatment and/or prevention of an ocular condition.
  • the invention also provides a pharmaceutical composition comprising a crystalline form of nidanib of the invention.
  • the present invention provides an ophthalmic formulation comprising: a crystalline form of nidanib of the present invention (including Form B, Form C, Form D, Form E) One or more of Form F), and one or more pharmaceutically acceptable carriers.
  • the present invention provides the use of the ophthalmic preparation for the preparation of a medicament for treating an ocular disease selected from the group consisting of age-related macular degeneration (AMD), anterior ocular angiogenesis such as the cornea Corneal angiogenesis after inflammation, corneal transplantation or keratoplasty, atrophy of retinal pigment epithelium (RPE), choroidal neovascularization (CNV), choroidal retinal vein occlusion, Slow-proliferating conjunctival degeneration (cleavage plaque), conjunctival papilloma, corneal angiogenesis caused by hypoxic retinal detachment, diabetic macular edema, diabetic retinopathy, hyperremeia, pterygium Related hypopremeia associated with pterygium, hyperthyroidism-induced hyperremia, hypertrophy of retinal pigment epithelium (RPE), immune or surgery-related dry eye, retinal edema, macular edema, macular
  • the ophthalmic formulation of the invention comprising the nedanib crystalline form is for use in the treatment of an angiogenic ocular disorder.
  • the desired pharmacological effect can be achieved by administering to the individual in need the crystalline form of the nidanib.
  • the individual is preferably a mammal or human in need of treatment for a particular condition or disease.
  • the crystalline form of nidanib of the present invention has enhanced thermodynamic stability.
  • Figure 1 is an XRPD pattern of the nedanib in Form B of the present invention.
  • Figure 2 is an XRPD pattern of Form A of a commercially available nidanib.
  • 3 to 10 are XRPD patterns of the nidanib form C of Experiment Nos. 0227-05-A01 to 0227-05-A08, respectively.
  • Figure 11 is an XRPD pattern of the nidanib form D of the present invention.
  • Figure 12 is an XRPD pattern of Nidanib Form E (Experiment No. 0271-71-A04) of the present invention.
  • Figure 13 is a DSC chart of Nidanib Form E (Experiment No. 0271-71-A04) of the present invention.
  • Figure 14 is an XRPD pattern of Nidanib Form E (Experiment No. 0271-71-A05) of the present invention.
  • Figure 15 is an XRPD pattern of the nidanib form F of the present invention.
  • Figure 16 is a DSC chart of the nedanib in Form F of the present invention.
  • Figure 17 is an XRPD pattern of Nidanib Form C (Experiment No. 0227-06-A01) of the present invention.
  • Figure 18 is an XRPD pattern of Nidanib Form C (Experiment No. 0227-06-A02) of the present invention.
  • Figure 19 is an XRPD pattern of Nidanib Form E of Example 7 of the present invention.
  • Figure 20 is an XRPD pattern of the nidanib form E of Example 8 of the present invention.
  • Figure 21 is an XRPD pattern of the Nidanib Form E of Example 8 of the present invention after being placed in a 60 ° C incubator for 28 days.
  • Figure 22 is an XRPD pattern of the Nidanib Form E of Example 8 of the present invention after being placed in a 4 ° C incubator for 28 days.
  • Figure 23 is an XRPD pattern of Nidanib Form F after standing at room temperature for three months in accordance with another embodiment of the present invention.
  • X-ray powder diffraction experiment using a Bruker D8advance diffractometer, using Cu Ka at room temperature Filling tube (40kV, 40mA) as X-ray source with wide-angle goniometer, 0.6mm divergence slit, 2.5° primary cable slit, 2.5° secondary cable slit, 8mm anti-scatter slit, 0.1mm Detector slits and LynxEye detectors.
  • 2 ⁇ continuous scan mode data acquisition was performed at a scan speed of 2.4°/min, in a range of 3°-40° with a scan step of 0.02°.
  • DSC experiments Data collection was done using TA Q200, Mettler DSC 1+ and Mettler DSC 3+ under N 2 protection at a flow rate of 50 mL/min, before warming from room temperature to degradation temperature at 10 C/min.
  • Nidanib various crystal forms and preparation methods thereof
  • nidanib ethanesulfonate (Shanghai Haote Pharmaceutical Technology Co., Ltd.) was added to a saturated aqueous solution of sodium carbonate to adjust the pH to 9, extracted three times with 20 ml of dichloromethane, and washed three times with 30 ml of water to neutral, organic layer. It was dried over anhydrous sodium sulfate. After drying for 0.5 h, the solvent was evaporated to dryness under reduced pressure and the solvent was evaporated to give 20 g of Nidanib.
  • nidanib which is commercially available (Shanghai Haote Pharmaceutical Technology Co., Ltd.), was determined, and the crystal form was named as crystal form A (see Fig. 2 for XRPD pattern).
  • Nidanibu available from Shanghai Haotein Pharmaceutical Technology Co., Ltd.
  • the vial Seal the vial containing the filtrate with parafilm, poke 5-6 small holes, and slowly evaporate in the fume hood.
  • the dry solid is Nidanib Form D.
  • the experimental data and measurement results are shown in the table below.
  • the nidanib form A in the following experiment was obtained from a commercially available (Shanghai Haote Pharmaceutical Technology Co., Ltd.); the nidanib form B was obtained by the preparation method of Example 1; the nidanib form C was The preparation method of Example 2 was obtained.
  • nidanib crystal form A weigh 2-3 mg of nidanib crystal form A, add 1 mL of water, vortex for a few minutes, pass through a 0.22 ⁇ m filter, and add the filtrate to a 1.8 mL HPLC vial containing 2-3 mg of nidanib form B.
  • Vortex for a few minutes pass through a 0.22 ⁇ m filter, and add the filtrate to a 1.8 mL HPLC vial containing 2-3 mg of nidanib C, vortex for a few minutes, pass through a 0.22 ⁇ m filter, and add the filtrate to Shengni
  • a 1.8 mL HPLC vial of 10 mg each of Danibu Form A, Form B and Form C after magnetic stirring for 72 hours, the supernatant was centrifuged, and the obtained solid was placed in a fume hood and evaporated at room temperature to obtain a solid. It is a nidanib crystal type E.
  • the experimental data and measurement results are shown in the table below.
  • nidanib ethanesulfonate 30 g was added to 300 ml of water, and the pH of the solution was adjusted to about 10 with a saturated sodium carbonate solution under stirring at room temperature.
  • 200 ml of dichloromethane was added to the suspension solution, and the mixture was stirred for 15 minutes, and the mixture was allowed to stand for separation.
  • the aqueous layer was back-extracted once more with 50 ml of dichloromethane, the organic phase was combined, and the organic phase was washed twice with 100 ml of water, and the mixture was separated.
  • the aqueous solution was dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • nidanib commercially available from Shanghai Haotein Pharmaceutical Technology Co., Ltd.
  • acetone/water 9/1, v/v
  • the solid obtained was a nidanib form C.
  • the experimental data and measurement results are shown in the table below.
  • Nidanib form B was obtained by the preparation method of Example 1, 500 mg of nidanib form B was weighed, 15 mL of acetone/water (9/1, v/v) was added, and the mixture was suspended and stirred at room temperature for 72 hours, and then centrifuged. The supernatant was discarded, and the obtained solid was placed in a fume hood and evaporated at room temperature to obtain a nedanib crystal form C.
  • the experimental data and measurement results are shown in the table below.
  • nidanib form F in the following experiment was obtained by the preparation method of Example 5.
  • nidanib form F obtained by the preparation method of Example 5 was weighed at room temperature, and dispersed and mixed by stirring in 200 ml of a 0.2% tyloxapol solution. Then, the mixture of nidanib and tyloxapol is MINICER's 160 ml chamber was ground with 200 micron zirconia beads. The grinding speed and time are adjusted to vary the specific characteristics of the formulation composition, such as the particle size distribution. The exemplary speed and time used was 20 minutes at 3000 revolutions per minute (rpm). After grinding, the particle size distribution of the nidanib particles was evaluated. After separation and centrifugation and drying, the obtained solid was found to be nidanib crystal form E (the XRPD pattern is shown in Fig. 20) after XRPD measurement.
  • the nidanib nanosuspension prepared by the above ball milling method was subjected to a stability test, and the nidanib nanosuspension sample was placed in a 60 ° C and 4 ° C incubator for 28 days, respectively, and then taken out, centrifuged, and washed with water. Remove the residual auxiliary solution, take the solid, and blast dry at 30 °C for 1-2 days. When there is no obvious water residue on the surface of the sample, take it out and measure XRPD. The results show that the above nanosuspension maintains its stability under different storage environments, and its crystal form remains crystal form E.
  • the results of the XRPD pattern after 28 days in a 60 ° C incubator are shown in Fig. 21.
  • the results of the XRPD pattern after 28 days in a 4 ° C incubator are shown in Fig. 22.
  • the nidanib form F was obtained by the preparation method of Example 5.
  • the crystal form F is placed in a polyethylene plastic bag, and then the plastic bag is placed in a humidity-free drier and placed at room temperature for three months (April 12 to July 12), respectively.
  • the XRPD patterns on April 12 and July 12 (see Figure 15 for the XRPD pattern before placement and Figure 23 for the XRPD pattern after three months). The results are all for Form F.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Indole Compounds (AREA)

Abstract

多种3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲羰基)-N-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的游离碱晶型及其制备方法，还提供了含有所述晶型的药物制剂及其用于治疗疾病特别是用于治疗血管生成性眼部疾病的用途。

Description

3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲羰基)-N-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的晶型 技术领域
本发明是关于3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲羰基)-N-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的新游离碱晶型及其制备方法、含有所述晶型的药物制剂及其作为药物的用途。
背景技术
3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲羰基)-N-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮，药品名称尼达尼布(Nintedanib)，是受体酪氨酸激酶家族(RTK)的有效抑制剂。尼达尼布能够抑制血小板源性生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)和血管内皮生长因子受体(VEGFR)和Fms样酪氨酸激酶-3(FLT3)。FGFR，PDGFR和VEGFR已涉及特发性肺纤维化(IPF)发病机制，通过阻断这些参与纤维化进程的信号转导通路，尼达尼布能够通过减少肺功能下降速度、从而减缓IPF疾病进展。WO 2016/209555公开了包含尼达尼布的用于治疗眼表面疾病的眼用制剂。
发明内容
本发明的一个目的是提供尼达尼布(化学名：3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲羰基)-N-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮)的新晶型。
本发明的另一目的是提供所述尼达尼布的晶型的制备方法。
本发明的另一目的是提供含有所述尼达尼布的晶型的药物制剂。
本发明的另一目的是提供所述尼达尼布的晶型及所述制剂的用途。
一方面，本发明提供了一种3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲羰基)-N-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的游离碱晶型，即尼达尼布的晶型。本发明提供的尼达尼布的晶型包括：晶型B、晶型C、晶型D、晶型E、晶型F。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型，其X-射线粉末衍射(XRPD)图谱在2θ值为6.4±0.2对应处具有特征衍射峰，并且在选自以下2θ值的至少一对应处具有特征衍射峰：16.6±0.2，17.4±0.2，17.8±0.2以及19.9±0.2。这样的晶型包括晶型C、晶型D、晶型E、晶型F。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型，其XRPD图谱在以下2θ值的对应处具有特征衍射峰：6.4±0.2，16.6±0.2，17.4±0.2，17.8±0.2以及19.9±0.2。这样的晶型包括晶型C、晶型E、晶型F。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型，其XRPD图谱在以下2θ值的对应处具有特征衍射峰：6.4±0.2，12.0±0.2，16.6±0.2，17.4±0.2，17.8±0.2以及19.9±0.2。这样的晶型包括晶型E、晶型F。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型，其XRPD图谱在以下2θ值的对应处具有特征衍射峰：6.4±0.2，12.0±0.2，16.6±0.2，17.4±0.2，17.8±0.2以及19.9±0.2；并且，该晶型的熔点温度为245℃±5℃。本发明中将该晶型命名为晶型E。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型，其XRPD图谱在以下2θ值的对应处具有特征衍射峰：6.4±0.2，12.0±0.2，16.6±0.2，17.4±0.2，17.8±0.2以及19.9±0.2；并且，该晶型的熔点温度为255℃±5℃。本发明中将该晶型命名为晶型F。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型，其XRPD图谱在以下2θ值的对应处具有特征衍射峰：6.4±0.2，16.6±0.2，17.4±0.2，17.8±0.2，19.9±0.2以及23.3±0.2。本发明中将具有这些特征衍射峰的晶型命名为晶型C。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型，其XRPD图谱在以下2θ值的对应处具有特征衍射峰：4.8±0.2，5.6±0.2，6.4±0.2，17.4±0.2以及19.9±0.2。本发明中将具有这些特征衍射峰的晶型命名为晶型D。
本发明还提供了尼达尼布的另一种晶型，该晶型的XRPD谱在以下2θ值的对应处具有特征衍射峰：11.2±0.2，14.8±0.2，16.4±0.2，17.0±0.2以及21.0±0.2。本发明中将具有这些特征衍射峰的晶型命名为晶型B。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型为晶型E，其XRPD图谱基本如图12、图14、图19、图20、图21或图22所示。本发明中“基本如图n所示”是指于如图n中所标示出具体2θ值±0.2的对应处具有特征衍射峰。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型为晶型E，该晶型的差示扫描量热法(DSC)图谱基本如图13所示。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型为晶型F，该晶型的XRPD图谱基本如图15或图23所示。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型为晶型F，该晶型的DSC图谱基本如图16所示。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型为晶型C，该晶型的XRPD图谱基本如图3、图4、图5、图6、图7、图8、图9、图10、图17或图18所示。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型为晶型D，该晶型的XRPD图谱基本如图11所示。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型为晶型B，该晶型的XRPD图谱基本如图1所示。
另一方面，本发明还提供了本发明的尼达尼布的晶型的制备方法，其中可通过尼达尼布的市购游离碱晶型或特定盐类作为起始物质在不同的溶剂体系中悬浮搅拌，缓慢挥发等方法得到本发明中所述的尼达尼布各种晶型。在本发明的一些具体实施方案中，本发明的尼达尼布的晶型的制备方法包括：将尼达尼布乙磺酸盐加入饱和碳酸钠水溶液中，加入二氯甲烷萃取，之后水洗至中性，有机层用无水硫酸钠干燥，蒸干溶剂，制备得到尼达尼布晶型B。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型的制备方法包括：将尼达尼布加入丙酮中，涡旋数分钟，之后过0.22μm有机滤膜，得滤液，滤液经挥干溶剂后的固体为尼达尼布晶型C。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型的制备方法包括：将尼达尼布加入溶剂中，混悬，磁力搅拌，之后离心弃上清液，挥干，得到的固体为尼达尼布晶型C。具体地，所述溶剂选择乙腈、异丙醇、正丙醇、2-丁酮、1,4-二恶烷/水混合溶剂、庚烷、甲醇/水混合溶剂、丙酮/水混合溶剂中的一种或多种。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型的制备方法包括：将尼达尼布入二氯甲烷中，涡旋数分钟，之后过0.22μm有机滤膜，得滤液，滤液经挥干溶剂后的固体为尼达尼布晶型D。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型的制备方法包括：将尼达尼布晶型A加入水或丙酮/水(9/1,v/v)中，涡旋，过0.22μm滤膜，滤液加入尼达尼布晶型B，涡旋，过0.22μm滤膜，滤液加入尼达尼布晶型C，涡旋，过0.22μm滤膜，滤液加入尼达尼布晶型A、晶型B和晶型C，磁力搅拌，离心弃上清液，挥干，得到的固体为尼达尼布晶型E。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型的制备方法包括：将尼达尼布乙磺酸盐加入水中，用饱和碳酸钠溶液调节溶液的pH至10左右，向混悬溶液中加入二氯甲烷，搅拌，静置分液，水层再用二氯甲烷反萃，合并有机相，有机相用水洗 涤，分液，无水硫酸钠干燥，减压蒸除溶剂，干燥得尼达尼布游离碱，将该尼达尼布游离碱加入到乙醇中，悬浮搅拌，过滤，干燥，得到晶型F。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型的制备方法包括：将尼达尼布晶型F加入水，磁力搅拌均匀后加入少量晶型E作为晶种，室温下磁力搅拌，离心取固体，烘干，得到尼达尼布晶型E。
在本发明的一些具体实施方案中，本发明的尼达尼布的晶型的制备方法包括：将尼达尼布晶型F与0.2％泰洛沙泊溶液混合分散，并将尼达尼布及泰洛沙泊的混合物与200微米氧化锆研磨珠一起研磨，研磨后，分离离心并烘干，得到的固体为尼达尼布晶型E。
本发明的尼达尼布的晶型具备有价值的药理学性质，并且可以用于制药工业中用于生产用于人类医学的药物组合物。
另一方面，本发明还提供了本发明的尼达尼布的晶型在制备药物中的用途，特别是制备用于治疗和/或预防眼病的药物中的用途。
另一方面，本发明还提供了含有本发明的尼达尼布的晶型的药物组合物。
在本发明的一些具体实施方案中，本发明提供了一种眼用制剂，其包含：本发明的尼达尼布的晶型(包括晶型B、晶型C、晶型D、晶型E、晶型F中的一种或多种)，以及一种或多种药学上可接受的载体。
另一方面，本发明还提供了所述的眼用制剂在制备用于治疗选自以下的眼部疾病的药物中的用途：年龄相关性黄斑变性(AMD)，眼睛前部的血管生成如角膜炎、角膜移植(corneal transplantation)或角膜移植术(keratoplasty)后的角膜血管生成，视网膜色素上皮(RPE)的萎缩变化，脉络膜新生血管形成(CNV)，脉络膜视网膜静脉阻塞(choroidal retinal vein occlusion)，慢增殖的结膜变性(睑裂斑)，结膜乳头状瘤(conjunctival papilloma)，由缺氧视网膜脱离引起的角膜血管生成，糖尿病性黄斑水肿，糖尿病性视网膜病变，眼充血(hyperremeia)，翼状胬肉相关的眼充血(hyperemeia associated with pterygium)，甲状腺机能亢进引起的眼充血(hyperthyroidism-induced hyperremia)，视网膜色素上皮(RPE)的肥大变化，免疫或手术相关的干眼，视网膜水肿，黄斑水肿，视网膜静脉阻塞的黄斑水肿，新生血管性青光眼(NVG)，眼癌，翼状胬肉结膜(pterygium conjunctivae)，翼状胬肉复发(pterygium recurrence)，史蒂文约翰逊综合征(Steven Johnson syndrome)，麦粒肿(stye)和视网膜下水肿。
在本发明的一些具体实施方案中，本发明的包含所述尼达尼布的晶型的眼用制剂是用于治疗血管生成性眼部疾病。
通过向需要的个体施予所述的尼达尼布的晶型，可用于实现所需的药理学效果。出于本发明的目的，所述个体优选是需要治疗特定病症或疾病的哺乳动物或人。
本发明的尼达尼布的晶型的有益效果：
本发明的尼达尼布的晶型，具有增强的热力学稳定性。
附图说明
图1为本发明的尼达尼布晶型B的XRPD图谱。
图2为市购尼达尼布的晶型A的XRPD图谱。
图3至图10分别为本发明中实验编号0227-05-A01至0227-05-A08的尼达尼布晶型C的XRPD图谱。
图11为本发明的尼达尼布晶型D的XRPD图谱。
图12为本发明的尼达尼布晶型E(实验编号0227-11-A04)的XRPD图谱。
图13为本发明的尼达尼布晶型E(实验编号0227-11-A04)的DSC图谱。
图14为本发明的尼达尼布晶型E(实验编号0227-11-A05)的XRPD图谱。
图15为本发明的尼达尼布晶型F的XRPD图谱。
图16为本发明的尼达尼布晶型F的DSC图谱。
图17为本发明的尼达尼布晶型C(实验编号0227-06-A01)的XRPD图谱。
图18为本发明的尼达尼布晶型C(实验编号0227-06-A02)的XRPD图谱。
图19为本发明实例7的尼达尼布晶型E的XRPD图谱。
图20为本发明实例8的尼达尼布晶型E的XRPD图谱。
图21为本发明实例8的尼达尼布晶型E于60℃恒温箱内放置28天后的XRPD图谱。
图22为本发明实例8的尼达尼布晶型E于4℃恒温箱内放置28天后的XRPD图谱。
图23为本发明的另一实施例的尼达尼布晶型F于室温放置三个月后的XRPD图谱。
具体实施方式
以下通过具体实施例进一步详述本发明，但本发明并不限于下述实施例。
各实例中，X-射线粉末衍射实验：使用Bruker D8advance衍射仪，室温下使用Cu Ka(波长
Figure PCTCN2017076648-appb-000001
)填充管(40kV,40mA)作为具有广角测角仪的X射线源、0.6mm 发散狭缝、2.5°初级索拉狭缝、2.5°次级索拉狭缝、8mm防散射狭缝、0.1mm探测器狭缝和LynxEye探测器。在2θ连续扫描模式下，以2.4°/分的扫描速度、在3°-40°的范围内以0.02°的扫描步长完成数据采集。
DSC实验：使用TA Q200，Mettler DSC 1+和Mettler DSC 3+，在50mL/min的流速的N2保护下，以10C/min从室温升温至降解温度前，完成数据采集。
尼达尼布各晶型及其制备方法实施例
实例1尼达尼布晶型B及其制备方法
将尼达尼布乙磺酸盐(上海佰特因医药科技有限公司)22g加入饱和碳酸钠水溶液，调节pH值至9，加入20ml二氯甲烷萃取三次，30ml水洗涤三次至中性，有机层用无水硫酸钠干燥。干燥0.5h后减压蒸干溶剂，旋转蒸发溶剂，得20g尼达尼布晶型B。
尼达尼布晶型B的XRPD图谱参见图1。
实例2尼达尼布晶型C及其制备方法
测定市购(上海佰特因医药科技有限公司)尼达尼布的晶型，将该晶型命名为晶型A(XRPD图谱参见图2)。
称取市购(上海佰特因医药科技有限公司)尼达尼布8份各约30mg，至8个高效液相色谱法(HPLC)小瓶中，分别加入1mL下表中的溶剂至各HPLC小瓶中，混悬，磁力搅拌72小时。72小时之后离心弃上清液，将固体置通风橱，室温下挥干，得到的固体为尼达尼布晶型C。实验数据和测定结果见下表。各实验编号的XRPD图谱见图3至图10。
Figure PCTCN2017076648-appb-000002
实例3尼达尼布晶型D及其制备方法
称取市购(上海佰特因医药科技有限公司)尼达尼布约20mg，加入至10mL西林瓶中。加入二氯甲烷3mL，涡旋数分钟，之后过0.22μm有机滤膜，得滤液至10mL 西林瓶中。将盛有滤液的西林瓶用parafilm封口，戳5-6个小孔，置通风橱里缓慢挥发。挥干的固体为尼达尼布晶型D。实验数据和测定结果见下表。
Figure PCTCN2017076648-appb-000003
尼达尼布晶型D的XRPD图谱参见图11。
实例4尼达尼布晶型E及其制备方法
下述实验中的尼达尼布晶型A由市购(上海佰特因医药科技有限公司)取得；尼达尼布晶型B由实例1的制备方法取得；尼达尼布晶型C由实例2的制备方法取得。
称取2-3mg尼达尼布晶型A，加入1mL水，涡旋数分钟，过0.22μm滤膜，滤液加至盛有2-3mg尼达尼布晶型B的1.8mL HPLC小瓶中，涡旋数分钟，过0.22μm滤膜，滤液加至盛有2-3mg尼达尼布晶型C的1.8mL HPLC小瓶中，涡旋数分钟，过0.22μm滤膜，滤液加至盛有尼达尼布晶型A、晶型B和晶型C各10mg的1.8mL HPLC小瓶中，磁力搅拌72小时后，离心弃上清液，得到的固体置通风橱，室温下挥干，得到的固体为尼达尼布晶型E。实验数据和测定结果见下表。
称取3-5mg尼达尼布晶型A，加入1mL丙酮/水(9/1,v/v)，涡旋数分钟，过0.22μm滤膜，滤液加至盛有3-5mg尼达尼布晶型B的1.8mL HPLC小瓶中，涡旋数分钟，过0.22μm滤膜，滤液加至盛有3-5mg尼达尼布晶型C的1.8mL HPLC小瓶中，涡旋数分钟，过0.22μm滤膜，滤液加至盛有尼达尼布晶型A、晶型B和晶型C各10mg的1.8mL HPLC小瓶中，磁力搅拌72小时后，离心弃上清液，得到的固体置通风橱，室温下挥干，得到的固体为尼达尼布晶型E。实验数据和测定结果见下表。
实验编号 溶剂 目标称重(mg) 实际称重(mg) 晶型
0227-11-A04 水 10+10+10 10.0+9.2+10.1 晶型E
0227-11-A05 丙酮/水(9/1) 10+10+10 12.1+10.5+15.2 晶型E
尼达尼布晶型E(0227-11-A04)的XRPD图谱参见图12；DSC图谱(0227-11-A04)参见图13。
尼达尼布晶型E(0227-11-A05)的XRPD图谱参见图14。
实例5尼达尼布晶型F及其制备方法
将30g尼达尼布乙磺酸盐加入300ml水中，室温搅拌下用饱和碳酸钠溶液调节溶液的pH至10左右，向混悬溶液中加入200ml二氯甲烷，搅拌15分钟，静置分液，水层再用50ml二氯甲烷反萃一次，合并有机相，有机相用100ml水洗涤2次，分液，无 水硫酸钠干燥，减压蒸除溶剂，鼓风45℃干燥8小时得尼达尼布游离碱27g。将27g上述样品加入到140ml乙醇中，悬浮搅拌3天，过滤，鼓风烘干45℃干燥15-16小时。得到晶型F。
晶型F的XRPD图谱参见图15；DSC图谱参见图16。
尼达尼布晶型的放大制备实施例
实例6尼达尼布晶型C的放大制备
称取市购(上海佰特因医药科技有限公司)尼达尼布500mg，加入15mL丙酮/水(9/1,v/v)，室温下悬浮搅拌72小时后，离心弃上清液，得到的固体置通风橱，室温下挥干，得到的固体为尼达尼布晶型C。实验数据和测定结果见下表。
由实例1的制备方法取得尼达尼布晶型B，称取500mg尼达尼布晶型B，加入15mL丙酮/水(9/1,v/v)，室温下悬浮搅拌72小时后，离心弃上清液，得到的固体置通风橱，室温下挥干，得到的固体为尼达尼布晶型C。实验数据和测定结果见下表。
Figure PCTCN2017076648-appb-000004
尼达尼布晶型C(0227-06-A01)的XRPD图谱参见图17。尼达尼布晶型C(0227-06-A02)的XRPD图谱参见图18。
实例7尼达尼布晶型E的放大制备
下述实验中的尼达尼布晶型F由实例5的制备方法取得。
称取约500mg晶型F至30ml西林瓶中，加入15ml水，磁力搅拌均匀后加入少量晶型E作为晶种，室温下磁力搅拌72小时后，离心取固体，40℃烘干2天，得到的固体为尼达尼布晶型E(其XRPD图谱参见图19)。
尼达尼布晶型的稳定性试验
实例8尼达尼布纳米悬浮液的稳定性试验
在室温下，称取约4.0克由实例5的制备方法取得的尼达尼布晶型F，在200毫升的0.2％泰洛沙泊溶液中藉由搅拌而被分散及混合。接着，尼达尼布及泰洛沙泊的混合物在
Figure PCTCN2017076648-appb-000005
MINICER的160毫升的腔室中与200微米氧化锆研磨珠一起研磨。调整研磨速度及时间以改变调配物组合物的特定特性，如，粒径分布。使用的示例性速度 及时间为3000转/分钟(rpm)进行20分钟。研磨后，评估尼达尼布粒子的粒径分布。分离离心并烘干后，得到的固体经XRPD测定后发现为尼达尼布晶型E(其XRPD图谱参见图20)。
根据上述球研磨法制造的一示例性尼达尼布纳米悬浮液的粒径及组合物示于下表。
成分 数值w/v(％)
尼达尼布 1
泰洛沙泊 0.1
乙二胺四乙酸二钠 0.01
氯化钠 0.75
氯化芐二甲烃铵 0.005
悬浮剂 0.5
磷酸钾缓冲液(10mM) 0.136
研磨速度及时间 3000rpm,20分钟
D10/50/90(微米) 0.251/0.386/0.619
对上述球研磨法制造的尼达尼布纳米悬浮液进行稳定性试验，将该尼达尼布纳米悬浮液样品分别放置在60℃和4℃恒温箱内28天，之后取出，离心，并用水洗去残留的辅料溶液，取固体，30℃下鼓风干燥1-2天，待样品表面没有明显水分残留时取出，测XRPD。结果表明上述纳米悬浮液在不同的储存环境下仍维持其稳定度，其晶型仍保持为晶型E。60℃恒温箱内放置28天后的XRPD图谱的测定结果见图21。4℃恒温箱内放置28天后的XRPD图谱的测定结果见图22。
实例9尼达尼布晶型F的稳定性试验
由实例5的制备方法取得尼达尼布晶型F。将晶型F放置在聚乙烯材质的塑料袋中，之后将该塑料袋放置在无湿度控制的干燥器中，在室温下放置三个月(4月12日至7月12日)，分别测定4月12日和7月12日的XRPD图谱(放置前的XRPD图谱参见图15、放置三个月后的XRPD图谱参见图23)，测定结果皆为晶型F。

Claims (18)

  1. 3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲羰基)-N-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的游离碱晶型，该晶型的X-射线粉末衍射图谱在2θ值为6.4±0.2对应处具有特征衍射峰，并且在选自以下2θ值的至少一对应处具有特征衍射峰：16.6±0.2，17.4±0.2，17.8±0.2以及19.9±0.2。
  2. 根据权利要求1所述的晶型，该晶型的X-射线粉末衍射图谱在以下2θ值的对应处具有特征衍射峰：6.4±0.2，16.6±0.2，17.4±0.2，17.8±0.2以及19.9±0.2。
  3. 根据权利要求1所述的晶型，该晶型的X-射线粉末衍射图谱在以下2θ值的对应处具有特征衍射峰：6.4±0.2，12.0±0.2，16.6±0.2，17.4±0.2，17.8±0.2以及19.9±0.2。
  4. 根据权利要求3所述的晶型，该晶型的熔点温度为245℃±5℃。
  5. 根据权利要求3所述的晶型，该晶型的熔点温度为255℃±5℃。
  6. 根据权利要求2所述的晶型，该晶型的X-射线粉末衍射图谱在以下2θ值的对应处具有特征衍射峰：6.4±0.2，16.6±0.2，17.4±0.2，17.8±0.2，19.9±0.2以及23.3±0.2。
  7. 根据权利要求1所述的晶型，该晶型的X-射线粉末衍射图谱在以下2θ值的对应处具有特征衍射峰：4.8±0.2，5.6±0.2，6.4±0.2，17.4±0.2以及19.9±0.2。
  8. 3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲羰基)-N-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的游离碱晶型，该晶型的X-射线粉末衍射图谱在以下2θ值的对应处具有特征衍射峰：11.2±0.2，14.8±0.2，16.4±0.2，17.0±0.2以及21.0±0.2。
  9. 根据权利要求1所述的晶型，该晶型的X-射线粉末衍射图谱基本如图12、图14、图19、图20、图21或图22所示。
  10. 根据权利要求1或9所述的晶型，该晶型的DSC图谱基本如图13所示。
  11. 根据权利要求1所述的晶型，该晶型的X-射线粉末衍射图谱基本如图15或图23所示。
  12. 根据权利要求1或11所述的晶型，该晶型的DSC图谱基本如图16所示。
  13. 根据权利要求1所述的晶型，该晶型的X-射线粉末衍射图谱基本如图3、图4、图5、图6、图7、图8、图9、图10、图17或图18所示。
  14. 根据权利要求1所述的晶型，该晶型的X-射线粉末衍射图谱基本如图11所示。
  15. 根据权利要求8所述的晶型，该晶型的X-射线粉末衍射图谱基本如图1所示。
  16. 一种眼用制剂，其包含：权利要求1-15中任一项所述的晶型，以及一种或多种药学上可接受的载体。
  17. 根据权利要求16所述的眼用制剂在制备用于治疗选自以下的眼部疾病的药物中的用途：年龄相关性黄斑变性(AMD)，眼睛前部的血管生成如角膜炎、角膜移植(corneal transplantation)或角膜移植术(keratoplasty)后的角膜血管生成，视网膜色素上皮(RPE)的萎缩变化，脉络膜新生血管形成(CNV)，脉络膜视网膜静脉阻塞(choroidal retinal vein occlusion)，慢增殖的结膜变性(睑裂斑)，结膜乳头状瘤(conjunctival papilloma)，由缺氧视网膜脱离引起的角膜血管生成，糖尿病性黄斑水肿，糖尿病性视网膜病变，眼充血(hyperremeia)，翼状胬肉相关的眼充血(hyperemeia associated with pterygium)，甲状腺机能亢进引起的眼充血(hyperthyroidism-induced hyperremia)，视网膜色素上皮(RPE)的肥大变化，免疫或手术相关的干眼，视网膜水肿，黄斑水肿，视网膜静脉阻塞的黄斑水肿，新生血管性青光眼(NVG)，眼癌，翼状胬肉结膜(pterygium conjunctivae)，翼状胬肉复发(pterygium recurrence)，史蒂文约翰逊综合征(Steven Johnson syndrome)，麦粒肿(stye)和视网膜下水肿。
  18. 根据权利要求17所述的用途，其中，所述眼用制剂是用于治疗血管生成性眼部疾病。
PCT/CN2017/076648 2017-03-14 2017-03-14 3-z-[1-(4-(n-((4-甲基-哌嗪-1-基)-甲羰基)-n-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的晶型 WO2018165865A1 (zh)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2019542699A JP7306697B2 (ja) 2017-03-14 2017-03-14 ３－ｚ－［１－（４－（ｎ－（（４－メチル－ピペラジン－１－イル）－メチルカルボニル）－ｎ－メチル－アミノ）－フェニルアミノ）－１－フェニル－メチレン］－６－メトキシカルボニル－２－インドリノンの結晶形
EP17900817.2A EP3597636A4 (en) 2017-03-14 2017-03-14 CRYSTAL FORMS OF 3-Z- [1- (4- (N - ((4-METHYL-PIPERAZINE-1-YL) -METHYLCARBONYL) -N-METHYL-AMINO) -PHENYLAMINO) -1-PHENYL-METHYLENE] -6- METHOXYCARBONYL-2-INDOLINONE
CN202310090866.5A CN116063221A (zh) 2017-03-14 2017-03-14 尼达尼布的晶型
PCT/CN2017/076648 WO2018165865A1 (zh) 2017-03-14 2017-03-14 3-z-[1-(4-(n-((4-甲基-哌嗪-1-基)-甲羰基)-n-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的晶型
CN201780077637.2A CN110072849A (zh) 2017-03-14 2017-03-14 3-z-[1-(4-(n-((4-甲基-哌嗪-1-基)-甲羰基)-n-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的晶型
US16/570,710 US10961203B2 (en) 2017-03-14 2019-09-13 Crystalline forms of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
JP2021124466A JP2021176899A (ja) 2017-03-14 2021-07-29 ３−ｚ−［１−（４−（ｎ−（（４−メチル−ピペラジン−１−イル）−メチルカルボニル）−ｎ−メチル−アミノ）−フェニルアミノ）−１−フェニル−メチレン］−６−メトキシカルボニル−２−インドリノンの結晶形

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2017/076648 WO2018165865A1 (zh) 2017-03-14 2017-03-14 3-z-[1-(4-(n-((4-甲基-哌嗪-1-基)-甲羰基)-n-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的晶型

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/570,710 Continuation US10961203B2 (en) 2017-03-14 2019-09-13 Crystalline forms of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone

Publications (1)

Publication Number Publication Date
WO2018165865A1 true WO2018165865A1 (zh) 2018-09-20

Family

ID=63523471

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/076648 WO2018165865A1 (zh) 2017-03-14 2017-03-14 3-z-[1-(4-(n-((4-甲基-哌嗪-1-基)-甲羰基)-n-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的晶型

Country Status (5)

Country Link
US (1) US10961203B2 (zh)
EP (1) EP3597636A4 (zh)
JP (2) JP7306697B2 (zh)
CN (2) CN116063221A (zh)
WO (1) WO2018165865A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113024439A (zh) * 2021-03-28 2021-06-25 郑州大学 尼达尼布乙磺酸盐新晶型ⅰ的制备

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7306697B2 (ja) 2017-03-14 2023-07-11 オールジェネシス バイオセラピューティクス インコーポレイテッド ３－ｚ－［１－（４－（ｎ－（（４－メチル－ピペラジン－１－イル）－メチルカルボニル）－ｎ－メチル－アミノ）－フェニルアミノ）－１－フェニル－メチレン］－６－メトキシカルボニル－２－インドリノンの結晶形
AU2020346812A1 (en) * 2019-09-10 2022-01-27 Cloudbreak Therapeutics, Llc Methods for alleviating pterygium-associated worry about eye appearance

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009071523A1 (en) * 2007-12-03 2009-06-11 Boehringer Ingelheim International Gmbh Process for the manufacture of an indolinone derivative
CN104844499A (zh) * 2015-06-05 2015-08-19 北京康立生医药技术开发有限公司 一锅法制备尼达尼布的合成方法
WO2016037514A1 (zh) * 2014-09-09 2016-03-17 苏州明锐医药科技有限公司 尼泰达尼的制备方法
CN105461609A (zh) * 2015-12-25 2016-04-06 杭州新博思生物医药有限公司 一种尼达尼布的制备方法
CN105837493A (zh) * 2016-04-08 2016-08-10 东南大学 尼达尼布的合成方法及其中间体
WO2016178064A1 (en) * 2015-05-06 2016-11-10 Suven Life Sciences Limited Polymorph of nintedanib ethanesulphonate, processes and intermediates thereof
WO2016209555A1 (en) 2015-06-22 2016-12-29 Allgenesis Biotherapeutics Inc. Ophthalmic formulations of tyrosine kinase inhibitors, methods of use thereof, and preparation methods thereof
WO2017016530A1 (en) * 2015-07-29 2017-02-02 Zentiva, K.S. A method for preparing methyl (z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl] amino]phenyl]amino]phenylmethylene)-oxindole-6-carboxylate (intedanib, nintedanib)
WO2017077551A2 (en) * 2015-11-03 2017-05-11 Mylan Laboratories Limited An amorphous nintedanib esylate and solid dispersion thereof
CN106748961A (zh) * 2016-11-30 2017-05-31 瑞阳制药有限公司 尼达尼布的杂质化合物、制备方法、应用及其检测方法
CN106748960A (zh) * 2016-11-30 2017-05-31 瑞阳制药有限公司 尼达尼布的潜在杂质化合物、制备方法、应用及其检测方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
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
CN106008308A (zh) * 2015-03-13 2016-10-12 正大天晴药业集团股份有限公司 尼达尼布乙磺酸盐结晶
ES2911678T3 (es) * 2015-11-14 2022-05-20 Sunshine Lake Pharma Co Ltd Forma cristalina de un compuesto de quinolina sustituida y composiciones farmacéuticas de la misma
JP7306697B2 (ja) * 2017-03-14 2023-07-11 オールジェネシス バイオセラピューティクス インコーポレイテッド ３－ｚ－［１－（４－（ｎ－（（４－メチル－ピペラジン－１－イル）－メチルカルボニル）－ｎ－メチル－アミノ）－フェニルアミノ）－１－フェニル－メチレン］－６－メトキシカルボニル－２－インドリノンの結晶形

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009071523A1 (en) * 2007-12-03 2009-06-11 Boehringer Ingelheim International Gmbh Process for the manufacture of an indolinone derivative
WO2016037514A1 (zh) * 2014-09-09 2016-03-17 苏州明锐医药科技有限公司 尼泰达尼的制备方法
WO2016178064A1 (en) * 2015-05-06 2016-11-10 Suven Life Sciences Limited Polymorph of nintedanib ethanesulphonate, processes and intermediates thereof
CN104844499A (zh) * 2015-06-05 2015-08-19 北京康立生医药技术开发有限公司 一锅法制备尼达尼布的合成方法
WO2016209555A1 (en) 2015-06-22 2016-12-29 Allgenesis Biotherapeutics Inc. Ophthalmic formulations of tyrosine kinase inhibitors, methods of use thereof, and preparation methods thereof
WO2017016530A1 (en) * 2015-07-29 2017-02-02 Zentiva, K.S. A method for preparing methyl (z)-3-[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl] amino]phenyl]amino]phenylmethylene)-oxindole-6-carboxylate (intedanib, nintedanib)
WO2017077551A2 (en) * 2015-11-03 2017-05-11 Mylan Laboratories Limited An amorphous nintedanib esylate and solid dispersion thereof
CN105461609A (zh) * 2015-12-25 2016-04-06 杭州新博思生物医药有限公司 一种尼达尼布的制备方法
CN105837493A (zh) * 2016-04-08 2016-08-10 东南大学 尼达尼布的合成方法及其中间体
CN106748961A (zh) * 2016-11-30 2017-05-31 瑞阳制药有限公司 尼达尼布的杂质化合物、制备方法、应用及其检测方法
CN106748960A (zh) * 2016-11-30 2017-05-31 瑞阳制药有限公司 尼达尼布的潜在杂质化合物、制备方法、应用及其检测方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113024439A (zh) * 2021-03-28 2021-06-25 郑州大学 尼达尼布乙磺酸盐新晶型ⅰ的制备

Also Published As

Publication number Publication date
JP7306697B2 (ja) 2023-07-11
EP3597636A4 (en) 2020-10-21
JP2021176899A (ja) 2021-11-11
JP2020508979A (ja) 2020-03-26
CN110072849A (zh) 2019-07-30
EP3597636A1 (en) 2020-01-22
US20200002294A1 (en) 2020-01-02
CN116063221A (zh) 2023-05-05
US10961203B2 (en) 2021-03-30

Similar Documents

Publication Publication Date Title
JP2021176899A (ja) ３−ｚ−［１−（４−（ｎ−（（４−メチル−ピペラジン−１−イル）−メチルカルボニル）−ｎ−メチル−アミノ）−フェニルアミノ）−１−フェニル−メチレン］−６−メトキシカルボニル−２−インドリノンの結晶形
CN109311851A (zh) 二氢嘧啶基苯并氮杂*甲酰胺化合物
JP2023098936A (ja) 新規ペプチド及びその新規ペプチドを活性成分として含む眼疾患の治療のための医薬組成物
CN110636845A (zh) 卢美哌隆对甲苯磺酸盐的无定形形式和固体分散体
WO2018157803A1 (zh) 维奈妥拉的晶型及其制备方法
TWI632133B (zh) ３－ｚ－［１－（４－（ｎ－（（４－甲基－哌嗪－１－基）－甲羰基）－ｎ－甲基－胺基）－苯胺基）－１－苯基－亞甲基］－６－甲氧羰基－２－吲哚啉酮的晶型
TWI676617B (zh) 3-z-[1-(4-(n-((4-甲基-呱嗪-1-基)-甲羰基)-n-甲基-胺基)-苯胺基)-1-苯基-亞甲基]-6-甲氧羰基-2-吲哚啉酮的晶型
KR20010052332A (ko) 2-프탈이미디노글루타르산 유사체 및 안기오게네시스억제제로서의 이의 용도
US8637514B2 (en) Polymorphs of brimonidine pamoate
JP2012006918A (ja) イソキノリンスルホニル誘導体を有効成分として含有する網脈絡膜変性疾患の予防または治療剤
CA3144226A1 (en) Compounds for treatment of cancer
CN112272667A (zh) 盐形式
US10875857B2 (en) 1-amino-triazolo(1,5-A)pyridine-substituted urea derivative and uses thereof
WO2017219688A1 (zh) 一种嘧啶类化合物的盐酸盐及其制备方法和用途
KR20130130802A (ko) 보르트만닌 유사체의 결정질 형태의 조성물 및 이의 사용 방법
US10253045B2 (en) Crystalline forms of a therapeutic compound and uses thereof
JPH09512007A (ja) １−［５−メタンスルホンアミドインドリル−２−カルボニル］−４−［３−（１−メチルエチルアミノ）−２−ピリジニル］ピペラジンの新規結晶形
JP2021500346A (ja) Ｒｅｔ９及びｖｅｇｆｒ２阻害剤
WO2019034048A1 (zh) 一种vegfr抑制剂晶型及其制备方法

Legal Events

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

Ref document number: 17900817

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019542699

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017900817

Country of ref document: EP

Effective date: 20191014