WO2018049632A1 - 奥扎莫德的晶型、其制备方法及药物组合物 - Google Patents

奥扎莫德的晶型、其制备方法及药物组合物 Download PDF

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WO2018049632A1
WO2018049632A1 PCT/CN2016/099137 CN2016099137W WO2018049632A1 WO 2018049632 A1 WO2018049632 A1 WO 2018049632A1 CN 2016099137 W CN2016099137 W CN 2016099137W WO 2018049632 A1 WO2018049632 A1 WO 2018049632A1
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ozamod
crystal form
solvent
preparation
crystal
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PCT/CN2016/099137
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English (en)
French (fr)
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盛晓红
盛晓霞
郑剑锋
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杭州领业医药科技有限公司
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Priority to PCT/CN2016/099137 priority Critical patent/WO2018049632A1/zh
Priority to CN201680056784.7A priority patent/CN108137516A/zh
Priority to US16/333,287 priority patent/US11117875B2/en
Publication of WO2018049632A1 publication Critical patent/WO2018049632A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

  • This application relates to the field of medicinal chemical crystallization technology.
  • the present application relates to crystalline forms of Ozamod and methods for their preparation and use, as well as pharmaceutical compositions comprising the crystalline forms.
  • Ozamod is a selective nitramine 1 phosphate (S1P) receptor modulator developed for the treatment of autoimmune diseases. In clinical trials, Ozamod has strong pharmacokinetics and drugs. Effectiveness and safety data to meet differential development strategies.
  • S1P selective nitramine 1 phosphate
  • Ozamod also known as RPC1063
  • RPC1063 has the chemical name 5-[3-[(1S)-2,3-dihydro-1-(2-hydroxyethylamino)-1H-indol-4-yl]-1 , 2,4-oxadiazol-5-yl]-2-isopropoxybenzonitrile
  • English name is Ozanimod
  • molecular formula is C 23 H 24 N 4 O 3
  • molecular weight is 404.46
  • CAS number 1306760-87-1 Its chemical structural formula is as shown in the following formula (I):
  • Ozamod compounds, methods for their preparation, and pharmaceutical compositions thereof are disclosed in the patents CN102118972B and CN102762100B.
  • the novel crystalline form of the present invention has one or more improved properties compared to known Ozamod compounds, particularly in the presence of good crystallinity and stability.
  • the Ozamod solid form of the present invention has at least one or more superior properties compared to known solid forms of Ozamod compounds.
  • Specific improved properties include, for example, higher crystallinity, higher solubility, higher dissolution rate, lower moisture absorption, better storage stability, better fluidity, and favorable processing and handling characteristics.
  • the solid form of the invention has a higher degree of crystallinity and better stability.
  • the present invention provides Ozamod's Form 1 (abbreviated as "Form 1" in the present invention).
  • the crystal form 1 is an anhydride, and its structural formula is as shown in the formula (I):
  • the X-ray powder diffraction pattern of Form 1 expressed in 2 ⁇ angle has the following characteristic peaks: 5.7 ⁇ 0.2 °, 8.6 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 13.3 ⁇ 0.2 °, 16.2 ⁇ 0.2 ° and 19.5 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form 1 represented by the 2 ⁇ angle has characteristic peaks at the following positions: 5.7 ⁇ 0.2°, 8.6 ⁇ 0.2°, 11.5 ⁇ 0.2°, 13.3 ⁇ 0.2°, 13.9 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 16.2 ⁇ 0.2 °, 19.5 ⁇ 0.2 °, 24.6 ⁇ 0.2 °, 25.3 ⁇ 0.2 °, 26.1 ⁇ 0.2 ° and 26.9 ⁇ 0.2 °.
  • the crystal form 1 has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • a typical example of the Form 1 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of Form 1 has characteristic peaks at wave numbers of 1485, 1461, 1370, 1349, 1287, 1104, 1066, 943, 831, and 758 cm -1 .
  • the present invention provides a process for the preparation of Form 1, characterized in that the preparation method employs any one of the following methods:
  • the solvent is selected from the group consisting of diethyl ether, ethanol, acetonitrile, water, methanol, dichloromethane, nitromethane, n-heptane or mixtures thereof.
  • the preparation method has an operating temperature of 10 to 40 ° C, more preferably room temperature;
  • the drying temperature is 10 to 60 ° C, more preferably 10 to 40 ° C;
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the mass-to-volume ratio of ozzamod to solvent in the preparation method is 5 to 100 mg: 1 mL, more preferably 20 to 50 mg: 1 mL.
  • the solvent is selected from the group consisting of a mixed solvent of nitromethane and n-heptane, a mixed solvent of acetonitrile and water, and a mixed solvent of dichloromethane and methanol.
  • the volatilization temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the concentration of the Ozamod solution is 0.5 to 1 times, more preferably 0.8 to 1 times, the solubility of Ozamod in the solvent.
  • the solvent is selected from the group consisting of nitromethane, acetonitrile, chloroform or mixtures thereof.
  • the heating temperature in the preparation method is 40 to 70 ° C, more preferably 50 to 70 ° C;
  • the low temperature is -10 to 30 ° C, more preferably -10 to 0 ° C.
  • the drying temperature is 10 to 40 ° C, more preferably 10 to 30 ° C;
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the mass to volume ratio of ozzamod to solvent is 5 to 15 mg: 1 mL, more preferably 7 to 15 mg: 1 mL.
  • the crystal form 1 has the following beneficial effects:
  • Ozamod's Form 1 of the present invention has a higher degree of crystallinity than the known Ozamod's amorphous solid.
  • the known Ozamod amorphous solids will appear diffraction peaks, the Ozamod crystal form 1 of the present invention can maintain the crystal form unchanged, therefore, the Ozamo of the present invention De crystal type 1 has better stability.
  • the Ozamod crystal form 1 of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged.
  • the Ozamod crystal form 1 of the invention has good stability, can better ensure that the pharmaceutically active ingredient itself and the formulation dosage form containing Ozamod are avoided and reduced in quality during the manufacture and/or storage of the drug, Safety and stability issues, such as uneven content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the present invention provides Ozamod crystal form 2 (abbreviated as "Form 2" in the present invention).
  • the crystal form 2 is an anhydride, and its structural formula is as shown in (I):
  • the X-ray powder diffraction pattern of the Form 2 expressed in terms of 2 ⁇ angle has the following characteristic peaks: 4.2 ⁇ 0.2°, 16.0 ⁇ 0.2°, 23.4 ⁇ 0.2°, 26.7 ⁇ 0.2°, and 30.3 ⁇ 0.2. °.
  • the X-ray powder diffraction pattern of the crystal form 2 represented by the 2 ⁇ angle has characteristic peaks at the following positions: 4.2 ⁇ 0.2°, 8.2 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.6 ⁇ 0.2 °, 19.1 ⁇ 0.2 °, 20.5 ⁇ 0.2 °, 23.4 ⁇ 0.2 °, 26.7 ⁇ 0.2 ° and 30.3 ⁇ 0.2 °.
  • the crystal form 2 has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • a typical example of the crystal form 2 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of Form 2 has characteristic peaks at wave numbers of 1616, 1487, 1460, 1283, 1260, 1097, 1045, 939, 808, and 761 cm -1 .
  • the present invention provides a process for the preparation of Form 2, characterized in that the preparation method employs any one of the following methods:
  • the Ozamod solid is in a C 1 -C 4 alcohol, water, acetone, alkane, C 3 -C 5 ether, C 2 -C 6 ester, acetonitrile, toluene, dimethyl sulfoxide or a mixed solvent thereof.
  • the suspension was formed, stirred and crystallized, and the precipitated crystals were separated and dried to obtain the Ozamod crystal form 2.
  • the stirring time is 3 to 7 days.
  • the solvent is selected from the group consisting of methanol, ethanol, water, acetone, dichloromethane, diisopropyl ether, ethyl acetate, tetrahydrofuran, toluene, acetonitrile, dimethyl sulfoxide, n-heptane or mixtures thereof.
  • the preparation method has an operating temperature of 10 to 40 ° C, more preferably room temperature;
  • the agitation time is 5 to 7 days.
  • the drying temperature is 10 to 60 ° C, more preferably 10 to 40 ° C;
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the mass-to-volume ratio of ozzamod to solvent in the preparation method is 10 to 100 mg: 1 mL, more preferably 20 to 50 mg: 1 mL.
  • the solvent is selected from the group consisting of methanol, ethanol, acetone, isopropyl acetate, toluene, dimethyl sulfoxide or mixtures thereof.
  • the volatilization temperature is 20 to 60 ° C, and more preferably 20 to 40 ° C.
  • the concentration of the Ozamod solution is 0.5 to 1 times, more preferably 0.8 to 1 times, the solubility of Ozamod in the solvent.
  • the C 3 -C 4 ether does not include a cyclic ether.
  • the solvent is selected from the group consisting of isopropanol, ethanol, water, isopropyl acetate, toluene, dimethyl sulfoxide, and isopropyl Ether or a mixture thereof.
  • the heating temperature in the preparation method is 40 to 70 ° C, more preferably 50 to 70 ° C;
  • the low temperature is -10 to 10 °C, more preferably -10 to 0 °C.
  • the drying temperature is 10 to 40 ° C, more preferably 10 to 30 ° C;
  • the drying time is from 10 to 48 hours, more preferably from 10 to 24 hours.
  • the mass to volume ratio of ozzamod to solvent is 5 to 20 mg: 1 mL, more preferably 7 to 20 mg: 1 mL.
  • the crystal form 2 has the following beneficial effects:
  • the Ozamod's Form 2 of the present invention has a higher crystallinity than the known Ozamod's amorphous solid.
  • the Ozamod crystal form 2 of the present invention can maintain the crystal form unchanged, and the known Ozamod solids can be converted into the Ozamod crystal form 2 of the present invention.
  • This property makes the Ozamod crystal form 2 of the present invention more suitable for the wet granulation process of the solid preparation or the oral suspension dosage form, and can be stabilized during the manufacture and/or storage of the drug.
  • the Ozamod crystal form 2 of the present invention is left in an environment of room temperature and relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point are unchanged.
  • the Ozamod crystal form 2 of the present invention has good stability, and can better ensure that the pharmaceutically active ingredient itself and the formulation dosage form containing Ozamod are avoided or reduced in quality during the manufacture and/or storage of the drug, Safety and stability issues, such as uneven content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the present invention provides Ozamod crystal form 3 (abbreviated as "Form 3" in the present invention).
  • the crystal form 3 is an anhydride, and its structural formula is as shown in (I):
  • the X-ray powder diffraction pattern of the crystal form 3 expressed in terms of 2 ⁇ angle has the following characteristic peaks: 4.6 ⁇ 0.2°, 9.1 ⁇ 0.2°, 13.6 ⁇ 0.2°, 18.1 ⁇ 0.2°, and 22.7 ⁇ 0.2. °.
  • the X-ray powder diffraction pattern of the crystal form 3 represented by the 2 ⁇ angle has characteristic peaks at the following positions: 4.6 ⁇ 0.2°, 8.0 ⁇ 0.2°, 9.1 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.1 ⁇ 0.2 °, 13.6 ⁇ 0.2 °, 18.1 ⁇ 0.2 °, 19.3 ⁇ 0.2 °, 22.7 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °.
  • the crystal form 3 has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • a typical example of the crystal form 3 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier infrared spectrum of Form 3 has characteristic peaks at wave numbers of 1616, 1487, 1459, 1350, 1284, 1151, 1126, 1103, 943, and 758 cm -1 .
  • the present invention provides a process for the preparation of Form 3, which comprises the steps of: dissolving the Ozamod solid in a solvent of ethyl acetate, cyclic ether, acetonitrile, halogenated alkane or a mixture thereof, and removing The liquid was evaporated to dryness to obtain the Ozamod crystal form 3.
  • the solvent is selected from the group consisting of ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane or a mixture thereof.
  • the preparation method has a volatilization temperature of 0 to 40 ° C, more preferably room temperature.
  • the concentration of the Ozamod free solution is 0.5 to 1 times, more preferably 0.8 to 1 times the solubility of Ozamod in the solvent.
  • the crystal form 3 has the following beneficial effects:
  • the Ozamod crystal form 3 of the present invention has a higher crystallinity than the known Ozamod's amorphous solid.
  • the Ozamod crystal form 3 of the present invention can maintain the crystal form unchanged, and the known Ozamod noisy solid can be converted into the present invention.
  • the Ozamod crystal form 3 of the invention has good stability, and can better ensure that the pharmaceutically active ingredient itself and the formulation dosage form containing Ozamod are avoided or reduced in quality during the manufacture and/or storage of the drug, Safety and stability issues, such as uneven content of active ingredients, impurities, and the like. Avoid special and expensive packaging.
  • the present inventors have also developed Ozamod crystal form 4 and form 5 and their preparation methods in the study.
  • the above Ozamod crystal forms 4 and 5 have one or more improved properties compared to known Ozamod solid forms, such as higher crystallinity, better solubility, and dissolution rate.
  • the Ozamod crystal form 4 is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern has a diffraction angle 2 ⁇ of 4.3 ⁇ 0.2°, 7.5 ⁇ 0.2°, 10.6 ⁇ 0.2°, and 12.2 ⁇ 0.2. Characteristic peaks at °, 12.9 ⁇ 0.2 °, 17.3 ⁇ 0.2 °, 17.7 ⁇ 0.2 °, 18.3 ⁇ 0.2 °, 21.6 ⁇ 0.2 °, 22.5 ⁇ 0.2 °, and 24.6 ⁇ 0.2 °.
  • the invention also provides a method for preparing Ozamod crystal form 4, which adopts any one of the following methods:
  • the Ozamod solid is suspended in methanol and stirred and crystallized at a certain temperature to precipitate crystals.
  • the Ozamod crystal form 4 was obtained by leaving and drying.
  • the temperature is 10 to 40 ° C
  • the stirring time is 3 to 7 days
  • the drying temperature is 10 to 40 ° C.
  • the Ozamod solid is heated and dissolved in a mixed solvent of methanol or methanol, and the supernatant is stirred and crystallized at a low temperature, and the precipitated crystal is separated and dried to obtain the Ozamod crystal form.
  • the heating temperature in the preparation method is 50 to 60 ° C
  • the low temperature is -10 to 10 ° C
  • the drying temperature is 10 to 40 ° C.
  • the Ozamod crystal form 5 is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern has diffraction angles of 6.7 ⁇ 0.2°, 6.9 ⁇ 0.2°, 10.3 ⁇ 0.2°, and 10.7 ⁇ 0.2°. Characteristic peaks at 11.3 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.1 ⁇ 0.2°, 16.6 ⁇ 0.2°, 18.9 ⁇ 0.2°, 20.6 ⁇ 0.2°, and 22.6 ⁇ 0.2°.
  • the invention also provides a preparation method of Ozamod crystal form 5, comprising the steps of: forming a suspension of the Ozamod free solid in a mixed solvent of methyl ethyl ketone or butanone, stirring and crystallization at a certain temperature, and precipitating The crystals were separated and dried to obtain the Ozamod crystal form 5.
  • the operating temperature in the preparation method is from -10 to 60 °C.
  • the Ozamod crystal form 1, the crystal form 2, the crystal form 3, the crystal form 4 and the crystal form 5 of the present invention all have improved properties of one or more of the following, as compared with the known Ozamod. : It has higher crystallinity, better solubility, dissolution rate, better crystal morphology, better thermal stability and storage stability, lower hygroscopicity, higher active ingredient content, better flow. Sexual and better formulation processability, can be more easily prepared under room temperature conditions or low temperature conditions, and is more conducive to industrialization of products.
  • room temperature means a temperature of 10 to 30 °C.
  • the "cyclic ether” may be tetrahydrofuran or 1,4-dioxane.
  • the "halogenated alkane” may be dichloromethane, chloroform or carbon tetrachloride.
  • the “stirring” may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation" can be carried out by conventional methods in the art, such as centrifugation or filtration.
  • the filtration under reduced pressure is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the "drying" can be accomplished by conventional techniques in the art, such as drying at ambient temperature, blast drying or reduced pressure drying; it can be reduced or at atmospheric pressure, preferably at a pressure of less than 0.09 MPa.
  • the drying apparatus and method are not limited and may be a fume hood, a blast oven, a spray dryer, a fluidized bed drying or a vacuum oven; it may be carried out under reduced pressure or no reduced pressure, preferably at a pressure of less than 0.09 MPa.
  • the starting material Ozamod can be prepared by the method described in the example [0388-0399] of the patent document CN102762100B, and is also commercially available, which is incorporated herein by reference in its entirety.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more crystalline forms of Ozamod of the present invention or Ozamo prepared by the method of the present invention
  • the crystalline form of De and at least one pharmaceutically acceptable carrier.
  • the new crystal form of Ozamod includes Ozamod crystal form 1, crystal form 2 and crystal form 3.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable crystalline forms of Ozamod (eg, Form 4 and Form 5).
  • Excipients in the pharmaceutical compositions are well known to those skilled in the art, and the choice of species, usage, and amount is well known to those skilled in the art.
  • examples include sugars, cellulose and its derivatives, starch or modified starch, solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulfate, calcium carbonate, semi-solids such as lipids or paraffins, Mixtures such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, glidants such as colloidal silica, light anhydrous silicic acid, Crystalline cellulose, talc or stearin
  • disintegrants such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, dry cornstarch, lubricants such as stearic acid, magnesium stearate, stearin Sodium fulfumarate
  • the administration route of the pharmaceutical combination includes oral administration, intravenous subcutaneous injection, injection into tissue administration, transdermal administration, rectal administration, intranasal administration, and the like.
  • the pharmaceutical combination may be prepared into a certain dosage form depending on the route of administration or need, and may be solid or liquid.
  • Solid oral dosage forms including, for example, tablets, granules, powders, pills, and capsules; liquid oral dosage forms, including, for example, solutions, syrups, suspensions, dispersions, and emulsions; injectable preparations including, for example, solutions, dispersions And lyophilizate.
  • the formulation may be suitable for immediate, sustained or controlled release of the active ingredient of the drug. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the Ozamod crystal form 1, Form 2 or Form 3 of the invention is admixed with one or more pharmaceutically acceptable excipients, optionally with pharmaceutically acceptable Other crystalline forms, amorphous forms of Ozamod are mixed, optionally in combination with one or more other pharmaceutically active ingredients.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • the present invention provides one or more crystalline forms of Ozamod, or a crystalline form of Ozamod, obtained by the process of the present invention, for the preparation and/or prevention of one or more conditions or Use in a conditional drug, which is medically required to modulate, activate, agonize, inhibit or antagonize a selective sphingosine-1-phosphate receptor, wherein the condition or condition includes Multiple sclerosis, transplant rejection, or adult respiratory distress syndrome.
  • the crystal form of the Ozamod is included in the Ozamod crystal form 1, the crystal form 2, the crystal form 3, the crystal form 4, and the crystal form 5 of the present invention.
  • the present invention provides a method of treating and/or preventing one or more conditions or conditions, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the crystal of Ozamod of the present invention.
  • a combination thereof, or a pharmaceutical composition thereof, for use, activation, agonism, inhibition or antagonism in a medicament for medically requiring selective modulation of a sphingosine-1-phosphate sphingosine receptor The condition or adverse condition includes multiple sclerosis, ulcerative colitis, arthritis, transplant rejection or adult respiratory distress syndrome.
  • the crystal form of the Ozamod is including Ozamod crystal form 1, crystal form 2, crystal form 3, form 4 and form 5.
  • Such patients include, but are not limited to, mammals.
  • Example 2 is an X-ray powder diffraction pattern of Ozamod crystal form 1 prepared in Example 2 of the present invention.
  • Example 3 is a DSC chart of Ozamod crystal form 1 prepared in Example 2 of the present invention.
  • Example 4 is a TGA pattern of Ozamod crystal form 1 prepared in Example 2 of the present invention.
  • Example 5 is an IR spectrum of Ozamod crystal form 1 prepared in Example 2 of the present invention.
  • Figure 6 is an X-ray powder diffraction pattern of Ozamod Seed Form 2 prepared in Example 10 of the present invention.
  • Figure 7 is a DSC chart of Ozamod crystal form 2 prepared in Example 10 of the present invention.
  • Example 8 is a TGA pattern of Ozamod crystal form 2 prepared in Example 10 of the present invention.
  • Figure 9 is an IR spectrum of the Ozamod crystal form 2 prepared in Example 10 of the present invention.
  • Figure 10 is an X-ray powder diffraction pattern of Ozamod crystal form 3 prepared in Example 19 of the present invention.
  • Figure 11 is a DSC chart of Ozamod crystal form 3 prepared in Example 19 of the present invention.
  • Figure 12 is a TGA pattern of Ozamod crystal form 3 prepared in Example 19 of the present invention.
  • Figure 13 is an IR spectrum of Ozamod crystal form 3 prepared in Example 19 of the present invention.
  • Figure 14 is an X-ray powder diffraction pattern of Ozamoded Form 4 prepared in Example 24 of the present invention.
  • Figure 15 is an X-ray powder diffraction pattern of Ozamoded Form 5 prepared in Example 26 of the present invention.
  • X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. The samples were tested at room temperature. The detection conditions are as follows, the angle range is 3 to 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • Differential thermal analysis data was taken from the TA Instruments Q200 MDSC.
  • the detection method is as follows: a sample of 1 to 10 mg is placed in a small-pore aluminum crucible, and the sample is raised from room temperature to 200 to 250 ° C under the protection of 40 mL/min dry N 2 at a heating rate of 10 ° C/min.
  • Thermogravimetric analysis data was taken from the TA Instruments Q500TGA.
  • the detection method is as follows: 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to a temperature of 10 ° C/min under the protection of 40 mL/min dry N 2 by means of segmented high-resolution detection. 350 ° C.
  • Infrared spectroscopy (IR) data was taken from Bruker Tensor 27 using an ATR apparatus and infrared absorption spectra were acquired in the range of 600-4000 cm -1 .
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 300 MHz NMR spectrometer. A sample of 1 to 5 mg was weighed and dissolved in a nuclear magnetic sample tube with about 0.5 mL of deuterated reagent for detection.
  • Ozamod was prepared according to the method described in Example [0388-0399] of the patent document CN102762100B.
  • the X-ray powder diffraction pattern is shown in Figure 1. It is shown that the Ozamod prepared according to the method described in the examples of the patent document CN102762100B is amorphous.
  • Ozamod crystal form 1 can be obtained by replacing the solvent in Example 3 with the following table.
  • Ozamod crystal form 1 can be obtained by replacing the solvent in Example 6 with the following table.
  • Ozamod crystal form 1 can be obtained by replacing the solvent in Example 8 with the following table.
  • the samples prepared in Examples 2 to 9 have the same or similar XRPD patterns, DSC patterns, TGA patterns, and IR patterns (not shown) as the samples of Examples 2 to 9 and the samples of Example 1. It is the same crystal form.
  • Ozamod crystal form 2 can be obtained by replacing the solvent in Example 12 with the following table.
  • Example 2 5 mg of the Ozamod crystal form 1 of the present invention obtained in Example 1 was dissolved in 1.0 mL of sec-butanol, and evaporated to dryness at 30 ° C to obtain Ozamod crystal form 2.
  • Example 2 5 mg of the Ozamod crystal form 1 of the present invention obtained in Example 1 was added to 1.0 mL of toluene, and evaporated to dryness at 50 ° C to obtain Ozamod crystal form 2.
  • Ozamod crystal form 2 can be obtained by replacing the solvent in Example 15 with the following table.
  • Ozamod crystal form 2 can be obtained by replacing the solvent in Example 17 with the following table.
  • the samples prepared in Examples 11 to 18 had the same or similar XRPD patterns, DSC patterns, TGA patterns, and IR patterns (not shown) as the samples of Examples 11 to 18 and the samples of Example 10. It is the same crystal form.
  • the samples prepared in Examples 20 to 23 had the same or similar XRPD patterns, DSC patterns, TGA patterns, and IR patterns (not shown) as the samples of Examples 19 to 23 and the samples of Example 19. It is the same crystal form.
  • the X-ray powder diffraction pattern was the same as that of the sample of Example 24 (not shown) and was Ozamod crystal form 4.
  • the solid sample of Obazol obtained in Preparation Example 1 was 15 mg, 0.5 mL of methyl ethyl ketone was added to form a suspension, and the mixture was stirred at room temperature for 3 days, and then filtered under reduced pressure. The solid was dried at 30 ° C for 16 hours under vacuum to obtain Ozamod crystal form 5 .
  • a typical tablet that can be prepared by conventional tabletting techniques can include:
  • Example 27 The Ozamod crystal form 1 of Example 27 was replaced with Ozamod crystal form 2, Ozamod crystal form 3, Ozamod crystal form 4 and Ozamo, respectively, as described herein.
  • De crystal form 5 the free base in the formulation and the free base in the Ozamod form 1 are the same molar amount, and the other components in each formula are also the same as in the case of Example 27, and the preparation steps of each tablet are also the same.
  • a typical capsule for oral administration comprises 11 mg of the Ozamod crystal form of the invention, 75 mg of lactose and 2 mg of magnesium stearate. The mixture was passed through a 60 mesh screen and filled into size 4 gelatin capsules.
  • Example 32 The Ozamod crystal form 1 of Example 32 was replaced with Ozamod crystal form 2, Ozamod crystal form 3, Ozamod crystal form 4 and Ozamo, respectively, as described herein.
  • De crystal form 5 the free base in the formulation and the free base in the Ozamod crystal form 1 are used in the same molar amount, and the other components in each formulation are also the same as in the embodiment 32, and the preparation steps of the capsules are also the same.
  • a typical injection is prepared by placing 1 mg of Ozamod's Form 1 of the present invention in a vial under sterile conditions, aseptically freeze-dried and sealed. In use, the contents of the vial were mixed with 2 mL of sterile physiological saline to prepare an injection.
  • Example 37 The Ozamod crystal form 1 of Example 37 was replaced with Ozamod crystal form 2, Ozamod crystal form 3, Ozamod crystal form 4 and Ozamo, respectively, as described herein.
  • De crystal form 5 the free base in the formulation and the free base in the Ozamod crystal form 1 are used in the same molar amount, and the other components in each formulation are also the same as in the embodiment 37, and the preparation steps of the respective injections are also carried out.
  • Example 37 The Ozamod crystal form 1 of Example 37 was replaced with Ozamod crystal form 2, Ozamod crystal form 3, Ozamod crystal form 4 and Ozamo, respectively, as described herein.
  • De crystal form 5 the free base in the formulation and the free base in the Ozamod crystal form 1 are used in the same molar amount, and the other components in each formulation are also the same as in the embodiment 37, and the preparation steps of the respective injections are also carried out.
  • the known Ozamod was prepared in Preparation Example 1 and the Ozamod crystal Form 1 solid prepared in Example 1 was subjected to a crystal stability test.
  • the specific operation was as follows: 20 mg of the sample was placed in an environment of 50 ° C, respectively. The crystal form stability was examined.
  • the Ozamod crystal form 1 of the present invention has better crystal form stability at high temperatures than the Ozamod obtained in the prior art.
  • the known Ozamod was prepared in Preparation Example 1 and the Ozamod crystal 2 solid prepared in Example 10 was subjected to a crystal stability test in water.
  • the specific operation was as follows: 20 mg of the sample was placed in water and stirred. Its crystal form stability.
  • the Ozamod crystal form 2 of the present invention can maintain the original crystal form without being stirred for 3 days in the water compared with the Ozamod prepared in the prior art, and thus has higher water stability. Sex.
  • the Ozamod crystal form 3 of the present invention can maintain the original crystal form in a 97% RH environment for 10 days as compared with the Ozamod prepared in the prior art, and thus has a more High stability.

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Abstract

本发明涉及奥扎莫德的晶型，与已知的奥扎莫德相比，本发明的奥扎莫德晶型具有一种或多种改进的特性。本发明还涉及奥扎莫德晶型的制备方法、其药物组合物及其用于制备在医学上需要选择性鞘氨醇-1-磷酸酯受体的调节、活化、激动、抑制或拮抗的病症或不良状况的药物中的用途。

Description

奥扎莫德的晶型、其制备方法及药物组合物 技术领域
本申请涉及药物化学结晶技术领域。具体而言，本申请涉及奥扎莫德的晶型及其制备方法和用途，以及包含所述晶型的药物组合物。
背景技术
奥扎莫德是一种选择性硝氨醇1磷酸(S1P)受体调节剂，开发用于自身免疫性疾病的治疗，在临床试验中，奥扎莫德具有强的药代动力学、药效及安全性数据，能够满足差异性开发战略。
奥扎莫德，又名RPC1063，化学名称为5-[3-[(1S)-2,3-二氢-1-(2-羟乙基氨基)-1H-茚-4-基]-1,2,4-噁二唑-5-基]-2-异丙氧基苄腈，英文名称为Ozanimod，分子式为C23H24N4O3，分子量为404.46，CAS号1306760-87-1，其化学结构式如下式(I)所示：
Figure PCTCN2016099137-appb-000001
专利CN102118972B和CN102762100B中公开了奥扎莫德化合物、其制备方法及其药物组合物。
本发明人在研究过程中发现根据先有技术CN102762100B专利提供的信息制备得到的奥扎莫德固体具有结晶度低、晶型稳定性差的缺陷。
鉴于现有技术尚存不足，需开发具有更多优势性能的奥扎莫德固体形态。
发明内容
本发明的目的是提供奥扎莫德的新晶型及其制备方法和用途，以及包含所述奥扎莫德新晶型的药物组合物。与已知奥扎莫德化合物相比，本发明新晶型具有一种或多种改进的特性，特别是表现在具备良好的结晶度和稳定性。
与已知的奥扎莫德化合物固体形态相比，本发明的奥扎莫德固体形态具有至少一种或多种更优越的性能。具体的改进性能例如，具有较高的结晶度、较高的溶解度、较高的溶解速度、较低的吸湿性、较好的贮存稳定性、较好的流动性和有利的加工与处理特性等。优选的是，本发明的固体形态具有较高的结晶度和较好的稳定性。
根据本发明的目的，本发明提供奥扎莫德晶型1(在本发明中简称为“晶型1”)。
所述晶型1为无水物，其结构式如式(I)所示：
Figure PCTCN2016099137-appb-000002
使用Cu-Kα辐射，所述晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰： 5.7±0.2°、8.6±0.2°、11.5±0.2°、13.3±0.2°、16.2±0.2°和19.5±0.2°。
更优选地，所述晶型1以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：5.7±0.2°、8.6±0.2°、11.5±0.2°、13.3±0.2°、13.9±0.2°、14.5±0.2°、16.2±0.2°、19.5±0.2°、24.6±0.2°、25.3±0.2°、26.1±0.2°和26.9±0.2°。
进一步优选地，所述的晶型1，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2016099137-appb-000003
非限制性地，所述晶型1的一个典型实例具有如图2所示的X-射线粉末衍射(XRPD)图谱。
所述晶型1的傅里叶红外光谱在波数为1485、1461、1370、1349、1287、1104、1066、943、831和758cm-1处具有特征峰。
根据本发明的目的，本发明提供晶型1的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
(1)将奥扎莫德固体在C4～C6醚、C1～C4醇、环醚、腈类、水、烷烃、硝基甲烷或其混合溶剂中形成悬浮液，搅拌析晶，将析出的晶体分离、干燥，得到所述的奥扎莫德晶型1。所述搅拌的时间为1～2天。
优选地，所述溶剂选自乙醚、乙醇、乙腈、水、甲醇、二氯甲烷、硝基甲烷、正庚烷或其混合物。
优选地，所述制备方法的操作温度为10～40℃，更优选为室温；
优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
优选地，所述制备方法中奥扎莫德与溶剂的质量体积比为5～100mg：1mL，更优选为20～50mg：1mL。
(2)将奥扎莫德固体在硝基甲烷与烷烃的混合溶剂或C1～C4醇与烷烃的混合溶 剂或环醚与水的混合溶剂中形成溶液，挥发析晶，得到所述的奥扎莫德晶型1。
优选地，所述溶剂选自硝基甲烷与正庚烷的混合溶剂、乙腈和水的混合溶剂、二氯甲烷和甲醇的混合溶剂。
优选地，所述挥发温度为10～60℃，更优选为10～40℃。
优选地，所述奥扎莫德溶液的浓度为奥扎莫德在所述溶剂中溶解度的0.5～1倍，更优选为0.8～1倍。
(3)将奥扎莫德固体在硝基甲烷、卤代烷烃、环醚、乙腈或其混合溶剂中加热溶清，将清液置于低温下搅拌析晶，将析出的晶体分离、干燥，得到所述的奥扎莫德晶型1。
优选地，所述溶剂选自硝基甲烷、乙腈、氯仿或其混合物。
优选地，所述制备方法中的加热温度为40～70℃，更优选为50～70℃；
优选地，所述低温为-10～30℃，更优选为-10～0℃。
优选地，所述干燥的温度为10～40℃，更优选为10～30℃；
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
优选地，所述制备方法中奥扎莫德与溶剂的质量体积比5～15mg：1mL，更优选为7～15mg：1mL。
所述晶型1具有以下有益效果：
①本发明的奥扎莫德晶型1与已知的奥扎莫德无定型固体相比，具有更高的结晶度。
②在50℃环境中放置1天，已知的奥扎莫德无定型固体会出现衍射峰，本发明的奥扎莫德晶型1能维持晶型不变，因此，本发明的奥扎莫德晶型1具有更好的稳定性。
③本发明的奥扎莫德晶型1在室温、相对湿度10％～90％的干燥器中放置4个月，其外观、XRPD和熔点都不变。
说明本发明的奥扎莫德晶型1具有好的稳定性，能够更好地保证药物活性成分自身和含有奥扎莫德的制剂剂型避免和减少药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
根据本发明的目的，本发明提供奥扎莫德晶型2(在本发明中简称为“晶型2”)。
所述晶型2为无水物，其结构式如图(I)所示：
Figure PCTCN2016099137-appb-000004
使用Cu-Kα辐射，所述晶型2以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.2±0.2°、16.0±0.2°、23.4±0.2°、26.7±0.2°和30.3±0.2°。
更优选地，所述晶型2以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.2±0.2°、8.2±0.2°、16.0±0.2°、17.9±0.2°、18.6±0.2°、19.1±0.2°、20.5±0.2°、23.4±0.2°、26.7±0.2°和30.3±0.2°。
进一步优选地，所述晶型2，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2016099137-appb-000005
非限制性地，所述晶型2的一个典型实例具有如图6所示的X-射线粉末衍射(XRPD)图谱。
所述晶型2的傅里叶红外光谱在波数为1616、1487、1460、1283、1260、1097、1045、939、808和761cm-1处具有特征峰。
根据本发明的目的，本发明提供晶型2的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
(1)将奥扎莫德固体在C1～C4醇、水、丙酮、烷烃、C3～C5醚、C2～C6酯、乙腈、甲苯、二甲亚砜或其混合溶剂中形成悬浮液，搅拌析晶，将析出的晶体分离、干燥，得到所述奥扎莫德晶型2。所述搅拌的时间为3～7天。
优选地，所述溶剂选自甲醇、乙醇、水、丙酮、二氯甲烷、异丙醚、乙酸乙酯、四氢呋喃、甲苯、乙腈、二甲亚砜、正庚烷或其混合物。
优选地，所述制备方法的操作温度为10～40℃，更优选为室温；
优选地，所述搅拌的时间为5～7天。
优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
优选地，所述制备方法中奥扎莫德与溶剂的质量体积比为10～100mg：1mL，更优选为20～50mg：1mL。
(2)将奥扎莫德固体在C1～C4醇、C3～C4酮、乙酸异丙酯、甲苯、二甲亚砜或其混合溶剂中形成清液，再挥发析晶，得到所述奥扎莫德晶型2。
优选地，所述溶剂选自甲醇、乙醇、丙酮、乙酸异丙酯、甲苯、二甲亚砜或其混合物。
优选地，所述挥发温度为20～60℃，更优选为20～40℃。
优选地，所述奥扎莫德溶液的浓度为奥扎莫德在所述溶剂中溶解度的0.5～1倍，更优选为0.8～1倍。
(3)将奥扎莫德固体在C2～C4醇、C2～C6酯、甲苯、二甲亚砜、C3～C4醚或其混合溶剂中加热溶清，将清液置于低温下搅拌析晶，将析出的晶体分离、干燥，得到所述的奥扎莫德晶型2。
优选地，所述C3～C4醚不包括环醚。
优选地，所述溶剂选自异丙醇、乙醇、水、乙酸异丙酯、甲苯、二甲亚砜、异丙 醚或其混合物。
优选地，所述制备方法中的加热温度为40～70℃，更优选为50～70℃；
优选地，所述低温为-10～10℃，更优选为-10～0℃。
优选地，所述干燥的温度为10～40℃，更优选为10～30℃；
优选地，所述干燥的时间为10～48小时，更优选为10～24小时。
优选地，所述制备方法中奥扎莫德与溶剂的质量体积比5～20mg：1mL，更优选为7～20mg：1mL。
所述晶型2具有以下有益效果：
①与已知的奥扎莫德无定型固体相比，本发明的奥扎莫德晶型2具有更高的结晶度。
②在水中搅拌3天，本发明的奥扎莫德晶型2能能维持晶型不变，已知的奥扎莫德固体会转为的本发明的奥扎莫德晶型2。这一性质使得本发明的奥扎莫德晶型2更适合固体制剂的湿法制粒工艺或制成口服悬浮液剂型，在药物制造和/或存储等过程中能够保持稳定。
③本发明的奥扎莫德晶型2在室温、相对湿度10％～90％的环境中放置4个月，其外观、XRPD和熔点都不变。
说明本发明的奥扎莫德晶型2具有好的稳定性，能够更好地保证药物活性成分自身和含有奥扎莫德的制剂剂型避免或减少药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
根据本发明的目的，本发明提供奥扎莫德晶型3(在本发明中简称为“晶型3”)。
所述晶型3为无水物，其结构式如图(I)所示：
Figure PCTCN2016099137-appb-000006
使用Cu-Kα辐射，所述晶型3以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.6±0.2°、9.1±0.2°、13.6±0.2°、18.1±0.2°和22.7±0.2°。
更优选地，所述晶型3以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.6±0.2°、8.0±0.2°、9.1±0.2°、11.2±0.2°、13.1±0.2°、13.6±0.2°、18.1±0.2°、19.3±0.2°、22.7±0.2°和26.2±0.2°。
进一步优选地，所述的晶型3，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2016099137-appb-000007
Figure PCTCN2016099137-appb-000008
非限制性地，所述晶型3的一个典型实例具有如图10所示的X-射线粉末衍射(XRPD)图谱。
所述晶型3的傅里叶红外光谱在波数为1616、1487、1459、1350、1284、1151、1126、1103、943和758cm-1处具有特征峰。
根据本发明的目的，本发明提供晶型3的制备方法，其包括以下步骤：将奥扎莫德固体在乙酸乙酯、环醚、乙腈、卤代烷烃或其混合物的溶剂中溶清，取清液挥发干，得到所述奥扎莫德晶型3。
优选地，所述溶剂选自乙酸乙酯、四氢呋喃、乙腈、二氯甲烷或其混合物。
优选地，所述制备方法的挥发温度为0～40℃，更优选为室温。
优选地，所述奥扎莫德游离态溶液的浓度为奥扎莫德在所述溶剂中溶解度的0.5～1倍，更优选为0.8～1倍。
所述晶型3具有以下有益效果：
①本发明的奥扎莫德晶型3与已知的奥扎莫德无定型固体相比，具有更高的结晶度。
②在室温、相对湿度97％的环境中放置3天，本发明的奥扎莫德晶型3能维持晶型不变，已知的奥扎莫德无定型固体会转为的本发明的奥扎莫德晶型3。
说明本发明的奥扎莫德晶型3具有好的稳定性，能够更好地保证药物活性成分自身和含有奥扎莫德的制剂剂型避免或减少药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
本发明人在研究中还开发了奥扎莫德晶型4和晶型5以及它们的制备方法。
与已知的奥扎莫德固体形态相比，上述奥扎莫德晶型4和晶型5具有一种或多种改进的特性，例如：更高的结晶度、更好的溶解度、溶解速度、较佳的结晶形态、较好的热稳定性和贮存稳定性、较低的吸湿性、较好的可流动性和有利的加工与处理特性。
所述奥扎莫德晶型4，其特征在于，使用Cu-Kα辐射，其X-射线粉末衍射图谱在衍射角2θ为4.3±0.2°、7.5±0.2°、10.6±0.2°、12.2±0.2°、12.9±0.2°、17.3±0.2°、17.7±0.2°、18.3±0.2°、21.6±0.2°、22.5±0.2°和24.6±0.2°处具有特征峰。
本发明还提供奥扎莫德晶型4的制备方法，所述制备方法采用下述方法中的任意一种：
(1)将奥扎莫德固体在甲醇中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分 离、干燥，得到所述奥扎莫德晶型4。优选地，所述温度为10～40℃，所述搅拌时间为3～7天，所述干燥温度为10～40℃。
(2)将奥扎莫德固体在甲醇或含甲醇的混合溶剂中加热溶清，将清液置于低温下搅拌析晶，将析出的晶体分离、干燥，得到所述奥扎莫德晶型4。优选地，所述制备方法中的加热温度为50～60℃,所述低温为-10～10℃，所述干燥温度为10～40℃。
所述奥扎莫德晶型5，其特征在于，使用Cu-Kα辐射，其X-射线粉末衍射图谱在衍射角为6.7±0.2°、6.9±0.2°、10.3±0.2°、10.7±0.2°、11.3±0.2°、12.7±0.2°、13.1±0.2°、16.6±0.2°、18.9±0.2°、20.6±0.2°和22.6±0.2°、处具有特征峰。
本发明还提供奥扎莫德晶型5的制备方法，包括以下步骤：将奥扎莫德游离态固体在丁酮或含丁酮的混合溶剂中形成悬浮液，一定温度下搅拌析晶，将析出的晶体分离、干燥，得到所述奥扎莫德晶型5。优选地，所述制备方法中的操作温度为-10～60℃。
与已知的奥扎莫德相比，本发明的奥扎莫德晶型1、晶型2、晶型3、晶型4和晶型5都具有以下一种或多种的改进性能，例如：具有更高的结晶度、较好的溶解度、溶解速度、较佳的结晶形态、较好的热稳定性和贮存稳定性、较低的吸湿性、更高的活性成分含量、更好的流动性和更好的制剂可加工性，可在室温条件或低温条件下更简便地制备，更有利于产品的工业化。
本发明的奥扎莫德晶型1、晶型2、晶型3、晶型4和晶型5的任何制备方法中：
除非特殊注明，“室温”是指10～30℃的温度。
所述“环醚”可以是四氢呋喃、1,4-二氧六环。
所述“卤代烷烃”可以是二氯甲烷、氯仿、四氯化碳。
所述“搅拌”，可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50～1800转/分，优选为300～900转/分。
所述“分离”可以采用本领域的常规方法，例如离心或过滤。优选减压过滤，一般是在室温下以小于大气压的压力进行抽滤，优选压力小于0.09MPa。
所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥；可以减压或常压，优选压力小于0.09MPa。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；可以在减压或不减压下进行，优选为压力小于0.09Mpa。
起始原料奥扎莫德可参照专利文献CN102762100B中实施例[0388-0399]所描述的方法制备得到，亦可由市售购买得到，该文献通过引用其全文的方式并入到本申请中。
进一步地，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的一种或多种本发明奥扎莫德的晶型或者由本发明方法制备得到的奥扎莫德的晶型，以及至少一种药学上可接受的载体。其中，所述奥扎莫德新晶型包括奥扎莫德晶型1、晶型2和晶型3。此外，所述药物组合物还可以包含奥扎莫德的其它可药用的晶型(例如晶型4和晶型5)。
所述药物组合物中的赋形剂，是本领域技术人员公知的，其种类、用法、用量的选择也是本领域技术人员公知的。例如包括糖类，纤维素及其衍生物，淀粉或改性淀粉，固体无机物如磷酸钙、磷酸氢二钙、羟基磷灰石、硫酸钙、碳酸钙，半固体如脂质或石蜡，粘合剂如微晶纤维素、乙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素，助流剂如胶态二氧化硅、轻质无水硅酸、结晶纤维素、滑石粉或硬脂 酸镁，崩解剂如乙醇酸淀粉钠、交聚维酮、交联羧甲基纤维素、羧甲基纤维素钠、干玉米淀粉，润滑剂如硬脂酸、硬脂酸镁、硬脂酰富马酸钠、聚乙二醇。
所述药物组合的给药途径包括口服、静脉皮下注射、注射入组织给药、透皮给药、直肠给药、滴鼻给药等。所述药物组合可以根据给药途径或需要，制备成一定的剂型，可为固态或液态。固体口服剂型，例如包括片剂、颗粒剂、散剂、丸剂和胶囊剂；液体口服剂型，例如包括溶液剂、糖浆剂、混悬剂、分散剂和乳剂；可注射制剂，例如包括溶液剂、分散剂和冻干剂。配方可适于药物活性成分的速释、缓释或可控释放。可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速熔化的制剂。
所述药物组合物可以使用本领域技术人员公知的方法来制备。制备药物组合物时，将本发明的奥扎莫德晶型1、晶型2或晶型3与一种或多种药学上可接受的赋形剂相混合，任选地与可药用的奥扎莫德的其它晶型、无定型物相混合，任选地与一种或多种其他的药物活性成分相混合。固体制剂可以通过直接混合、制粒等工艺来制备。
进一步地，本发明提供一种或多种本发明奥扎莫德的晶型或者由本发明制备方法得到的奥扎莫德的晶型在制备用于治疗和/或预防一种或多种病症或不良状况的药物中的用途，所述病症或不良状况是在医学上需要选择性鞘氨醇-1-磷酸酯受体的调节、活化、激动、抑制或拮抗，其中所述病症或不良状况包括多发性硬化、移植排斥或成人呼吸窘迫综合症。其中所述奥扎莫德的晶型包括本发明的奥扎莫德晶型1、晶型2、晶型3、晶型4和晶型5。
进一步地，本发明提供一种治疗和/或预防一种或多种病症或不良状况的方法，所述方法包括给予需要的患者治疗和/或预防有效量的本发明的奥扎莫德的晶型或其组合或其药物组合物，所述病症或不良状况是在医学上需要选择性调节鞘氨醇-1-磷酸酯鞘氨醇受体的药物中的用途活化、激动、抑制或拮抗，其中所述病症或不良状况包括多发性硬化、溃疡性结肠炎、关节炎、移植排斥或成人呼吸窘迫综合症等。其中所述奥扎莫德的晶型包括奥扎莫德晶型1、晶型2、晶型3、晶型4和晶型5。所述患者包括但不限于哺乳动物。
附图说明
图1为按照专利文献CN102762100B中实施例[0388-0399]所描述的方法制备的已知的奥扎莫德的X-射线粉末衍射图。
图2为本发明实施例2制备得到的奥扎莫德晶型1的X-射线粉末衍射图。
图3为本发明实施例2制备得到的奥扎莫德晶型1的DSC图谱。
图4为本发明实施例2制备得到的奥扎莫德晶型1的TGA图谱。
图5为本发明实施例2制备得到的奥扎莫德晶型1的IR谱图。
图6为本发明实施例10制备得到的奥扎莫德晶型2的X-射线粉末衍射图。
图7为本发明实施例10制备得到的奥扎莫德晶型2的DSC图谱。
图8为本发明实施例10制备得到的奥扎莫德晶型2的TGA图谱。
图9为本发明实施例10制备得到的奥扎莫德晶型2的IR谱图。
图10为本发明实施例19制备得到的奥扎莫德晶型3的X-射线粉末衍射图。
图11为本发明实施例19制备得到的奥扎莫德晶型3的DSC图谱。
图12为本发明实施例19制备得到的奥扎莫德晶型3的TGA图谱。
图13为本发明实施例19制备得到的奥扎莫德晶型3的IR谱图。
图14为本发明实施例24制备得到的奥扎莫德晶型4的X-射线粉末衍射图。
图15为本发明实施例26制备得到的奥扎莫德晶型5的X-射线粉末衍射图。
具体实施方案
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明的内容。
检测仪器及方法：
X-射线粉末衍射(XRPD)：仪器为Bruker D8Advance diffractometer。样品在室温下测试。检测条件如下，角度范围：3～40°2θ，步长：0.02°2θ，速度：0.2秒/步。
差热分析数据采自于TA Instruments Q200MDSC。检测方法为：取1～10毫克的样品放置于小孔铝坩埚内，以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至200～250℃。
热重分析数据采自于TA Instruments Q500TGA。检测方法为：取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至350℃。
红外光谱分析(IR)数据采自于Bruker Tensor 27，采用ATR设备，在600-4000cm-1范围内，采集红外吸收光谱。
核磁氢谱数据(1HNMR)采自于Bruker Avance II DMX 300MHz核磁共振波谱仪。称量1～5mg样品，用约0.5mL氘代试剂溶解到核磁样品管中进行检测。
除非特殊注明，实施例均在室温下操作，溶剂比均为体积比。
实施例中所用的各种试剂如无特别说明均为市售购买。
制备例1(制备奥扎莫德)
根据专利文献CN102762100B中实施例[0388-0399]所描述的方法制备得到奥扎莫德。
1HNMR(300MHz,CDCl3-CH3OD)：8.33(d,1H),8.26(dd,1H),7.99(d,1H),7.47(d,1H),7.33(t,1H),7.07(d,1H),4.74(t,1H),4.27(t,1H),3.62(q,2H),3.37-3.32(m,1H),3.18-3.10(m,1H)，2.79(t,2H)，2.48-2.37(m,1H)，1.92-1.85(m,1H)，1.40(d,6H)，显示为已知的奥扎莫德。
X射线粉末衍射图谱如图1所示。显示：根据专利文献CN102762100B中实施例所描述的方法制备得到的奥扎莫德为无定型。
实施例1
取制备例1所得奥扎莫德固体样品15mg，加入0.5mL乙醚形成混悬液，室温下搅拌2天后，减压过滤，固体40℃真空干燥10小时，得到14.2mg奥扎莫德晶型1，收率94.6％。
其X-射线粉末衍射图谱如图2所示。
其DSC图谱如图3所示。
其TGA图谱如图4所示。
其IR图谱如图5所示。
实施例2
取制备例1所得奥扎莫德固体样品15mg，加入1.5mL乙腈:水(1:2)的混合溶剂形 成混悬液，40℃下搅拌2天后，减压过滤，固体60℃真空干燥48小时，得到13.1mg奥扎莫德晶型1，收率87.3％。
实施例3
取制备例1所得奥扎莫德固体样品20mg，加入1.0mL乙醇形成混悬液，室温下搅拌1天后，减压过滤，固体10℃真空干燥24小时，得到18.3mg奥扎莫德晶型1，收率91.5％。
实施例4
对实施例3中的溶剂按以下表格进行替换均可获得奥扎莫德晶型1。
Figure PCTCN2016099137-appb-000009
实施例5
取制备例1所得奥扎莫德固体样品10mg，加入1.0mL甲醇:二氯甲烷(1:9)的混合溶剂溶清，20℃挥发至干，得到奥扎莫德晶型1。
实施例6
取制备例1所得奥扎莫德固体样品10mg，加入3mL乙腈:水(2:1)的混合溶剂溶清，40℃挥发至干，得到奥扎莫德晶型1。
实施例7
对实施例6中的溶剂按以下表格进行替换均可获得奥扎莫德晶型1。
Figure PCTCN2016099137-appb-000010
实施例8
取制备例1所得奥扎莫德固体样品15mg，加入1.5mL硝基甲烷在70℃环境下溶清，将样品转至-10℃环境中搅拌至析出固体，将析出的固体减压过滤，30℃真空干燥24小时，得到13.8mg奥扎莫德晶型1，收率92.0％。
实施例9
对实施例8中的溶剂按以下表格进行替换均可获得奥扎莫德晶型1。
Figure PCTCN2016099137-appb-000011
Figure PCTCN2016099137-appb-000012
实施例2～9制备得到的样品与实施例1的样品具有相同或相似的XRPD图谱、DSC图谱、TGA图谱、IR图谱(未示出)，说明实施例2～9样品与实施例1的样品是相同的晶型。
实施例10
取制备例1所得奥扎莫德固体样品100mg，加入2.0mL乙醇形成混悬液，室温下搅拌5天后，减压过滤，固体40℃真空干燥24小时，得到96.8mg奥扎莫德晶型2，收率96.8％。
其X-射线粉末衍射图谱如图6所示。
其DSC图谱如图7所示。
其TGA图谱如图8所示。
其IR图谱如图9所示。
实施例11
取制备例1所得奥扎莫德固体样品15mg，加入0.5mL丙酮形成混悬液，室温下搅拌7天后，减压过滤，固体10℃真空干燥10小时，得到14.1mg奥扎莫德晶型2，收率94.0％。
实施例12
取制备例1所得奥扎莫德固体样品15mg，加入0.2mL异丙醚形成混悬液，40℃下搅拌3天后，减压过滤，固体60℃真空干燥48小时，得到12.1mg奥扎莫德晶型2，收率80.6％。
实施例13
对实施例12中的溶剂按以下表格进行替换均可获得奥扎莫德晶型2。
Figure PCTCN2016099137-appb-000013
实施例14
取实施例1所得本发明的奥扎莫德晶型1样品5mg，加入1.0mL仲丁醇溶清，30℃下挥发至干，得到奥扎莫德晶型2。
实施例15
取实施例1所得本发明的奥扎莫德晶型1样品5mg，加入1.0mL甲苯溶清，50℃下挥发至干，得到奥扎莫德晶型2。
实施例16
对实施例15中的溶剂按以下表格进行替换均可获得奥扎莫德晶型2。
Figure PCTCN2016099137-appb-000014
实施例17
取制备例1所得奥扎莫德固体样品15mg，加入0.75mL乙醇:水(4:1)的混合溶剂，50℃加热溶清后，将反应液转至-10℃搅拌至析出固体，减压过滤，固体30℃真空干燥24小时，得到14.1mg奥扎莫德晶型2，收率94％。
实施例18
对实施例17中的溶剂按以下表格进行替换均可获得奥扎莫德晶型2。
Figure PCTCN2016099137-appb-000015
实施例11～18制备得到的样品与实施例10的样品具有相同或相似的XRPD图谱、DSC图谱、TGA图谱、IR图谱(未示出)，说明实施例11～18样品与实施例10的样品是相同的晶型。
实施例19
取实施例10所得本发明的奥扎莫德晶型2样品5mg，加入2.0mL乙酸乙酯溶清，室温下挥发至干，得到奥扎莫德晶型3。
其X-射线粉末衍射图谱如图10所示。
其DSC图谱如图11所示。
其TGA图谱如图12所示。
其IR图谱如图13所示。
实施例20
取制备例1所得奥扎莫德固体样品5mg，加入0.2mL四氢呋喃溶清，0℃挥发至干，得到奥扎莫德游离态晶型3。
实施例21
取制备例1所得奥扎莫德固体样品5mg，加入1.0mL乙腈溶清，40℃挥发至干，得到奥扎莫德游离态晶型3。
实施例22
取制备例1所得奥扎莫德固体样品5mg，加入0.6mL二氯甲烷/四氢呋喃(1:1)的混合溶剂溶清，5℃挥发至干，得到奥扎莫德晶型3。
实施例23
取制备例1所得奥扎莫德固体样品5mg，加入1.5mL氯仿/1,4-二氧六环(2:1)的混合溶剂溶清，36℃挥发至干，得到奥扎莫德晶型3。
实施例20～23制备得到的样品与实施例19的样品具有相同或相似的XRPD图谱、DSC图谱、TGA图谱、IR图谱(未示出)，说明实施例20～23样品与实施例19的样品是相同的晶型。
实施例24
取制备例1所得奥扎莫德固体样品15mg，加入0.5mL甲醇形成混悬液，室温下搅拌7天后，减压过滤，固体10℃真空干燥24小时，得到奥扎莫德晶型4。
其X-射线粉末衍射图谱如图14所示。
实施例25
取制备例1所得奥扎莫德固体样品15mg，加入0.4mL甲醇:乙酸乙酯(2:3)的混合溶剂60℃加热溶清，将反应液转至-10℃搅拌至析出固体，减压过滤，固体40℃真空干燥24小时，得到奥扎莫德晶型4。
其X-射线粉末衍射图谱与实施例24的样品相同(未示出)，为奥扎莫德晶型4。
实施例26
取制备例1所得所得奥扎莫德固体样品15mg，加入0.5mL丁酮形成混悬液，室温下搅拌3天后，减压过滤，固体30℃真空干燥16小时，得到奥扎莫德晶型5。
其X-射线粉末衍射图谱如图15所示。
实施例27
可通过常规压片技术制备的典型片剂可包含：
Figure PCTCN2016099137-appb-000016
*酰化甘油单酯，用作薄膜包衣的增塑剂。
实施例28～31
药片：将实施例27的奥扎莫德晶型1分别替换为将本申请所述的奥扎莫德晶型2、奥扎莫德晶型3、奥扎莫德晶型4和奥扎莫德晶型5，配方中的游离碱和奥扎莫德晶型1中游离碱的摩尔用量相同，各配方中的其他组分也与实施例27中的相同，各片剂的制备步骤也同实施例27。
实施例32
供口服施用的典型胶囊包含本发明的奥扎莫德晶型1 1mg、乳糖75mg和硬脂酸镁2mg。将混合物通过60目筛并填装到4号明胶胶囊中。
实施例33～36
胶囊：将实施例32的奥扎莫德晶型1分别替换为将本申请所述的奥扎莫德晶型2、奥扎莫德晶型3、奥扎莫德晶型4和奥扎莫德晶型5，配方中的游离碱和奥扎莫德晶型1中游离碱的摩尔用量相同，各配方中的其他组分也与实施例32中的相同，各胶囊剂的制备步骤也同实施例32。
实施例37
典型的注射剂是通过将1mg本发明的奥扎莫德晶型1在无菌条件下置于小瓶中，无菌冷冻干燥和密封而制备的。使用时，将小瓶的内容物与2mL无菌生理盐水混合以制备注射剂。
实施例38～41
注射剂：将实施例37的奥扎莫德晶型1分别替换为将本申请所述的奥扎莫德晶型2、奥扎莫德晶型3、奥扎莫德晶型4和奥扎莫德晶型5，配方中的游离碱和奥扎莫德晶型1中游离碱的摩尔用量相同，各配方中的其他组分也与实施例37中的相同，各注射剂的制备步骤也同实施例37。
对比例1
取制备例1制备的已知的奥扎莫德和实施例1制备的奥扎莫德晶型1固体进行晶型稳定性对比实验，具体操作如下：分别取20mg样品放置于50℃环境中，考察其晶型稳定性。
表1：对比例1对比实验数据统计
Figure PCTCN2016099137-appb-000017
由表1可知，与现有技术制备得到的奥扎莫德相比，本发明的奥扎莫德晶型1在高温下的晶型稳定性更好。
对比例2
取制备例1制备的已知的奥扎莫德和实施例10制备的奥扎莫德晶型2固体进行水中晶型稳定性对比实验，具体操作如下：分别取20mg样品放置于水中搅拌，考察其晶型稳定性。
表2：对比例2对比实验数据统计
起始样品 水中搅拌3天
本发明的奥扎莫德晶型2 保持晶型2
已知的奥扎莫德 转变为晶型2
由表1可知，与现有技术制备得到的奥扎莫德相比，本发明的奥扎莫德晶型2在水中搅拌3天能维持原有晶型不变，因此具有更高的水中稳定性。
对比例3
取制备例1制备的已知的奥扎莫德和实施例19制备的奥扎莫德晶型3固体进行 97％相对湿度环境下的晶型稳定性对比实验，具体操作如下：分别取20mg样品放置于97％相对湿度环境下，考察其晶型稳定性。
表3：对比例3对比实验数据统计
Figure PCTCN2016099137-appb-000018
由表1可知，与现有技术制备得到的奥扎莫德相比，本发明的奥扎莫德晶型3在97％RH环境下放置10天能维持原有晶型不变，因此具有更高的稳定性。
本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，均通过引用以其全文并入本文中。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。

Claims (18)

  1. 结构式如式(I)所示的奥扎莫德晶型1，
    Figure PCTCN2016099137-appb-100001
    其特征在于，所述晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.7±0.2°、8.6±0.2°、11.5±0.2°、13.3±0.2°、16.2±0.2°和19.5±0.2°。
  2. 根据权利要求1所述的奥扎莫德晶型1，其特征在于，所述晶型1以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.7±0.2°、8.6±0.2°、11.5±0.2°、13.3±0.2°、13.9±0.2°、14.5±0.2°、16.2±0.2°、19.5±0.2°、24.6±0.2°、25.3±0.2°、26.1±0.2°和26.9±0.2°。
  3. 根据权利要求2所述的奥扎莫德晶型1，其特征在于，所述晶型1以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
    Figure PCTCN2016099137-appb-100002
  4. 根据权利要求1～3中任一项所述奥扎莫德晶型1，其特征在于，所述晶型1的傅里叶红外光谱在波数为1485、1461、1370、1349、1287、1104、1066、943、831和758cm-1处具有特征峰。
  5. 根据权利要求1～4所述的奥扎莫德晶型1的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
    (1)将奥扎莫德固体在C4～C6醚、C1～C4醇、环醚、腈类、水、烷烃、硝基甲烷或其混合溶剂中形成悬浮液，搅拌析晶，将析出的晶体分离、干燥，得到所述的奥扎莫德晶型1；所述搅拌的时间为1～2天；
    优选地，所述溶剂选自乙醚、乙醇、乙腈、水、甲醇、二氯甲烷、硝基甲烷、正庚烷或其混合物；
    优选地，所述制备方法的操作温度为10～40℃，更优选为室温；
    优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时；
    优选地，所述制备方法中奥扎莫德与溶剂的质量体积比为5～100mg：1mL，更优选为20～50mg：1mL；
    (2)将奥扎莫德固体在硝基甲烷与烷烃的混合溶剂或C1～C4醇与烷烃的混合溶剂或环醚与水的混合溶剂中形成溶液，挥发析晶，得到所述的奥扎莫德晶型1；
    优选地，所述混合溶剂选自硝基甲烷与正庚烷的混合溶剂、乙腈和水的混合溶剂、二氯甲烷和甲醇的混合溶剂；
    优选地，所述挥发温度为10～60℃，更优选为10～40℃；
    优选地，所述奥扎莫德溶液的浓度为奥扎莫德在所述溶剂中溶解度的0.5～1倍，更优选为0.8～1倍；
    (3)将奥扎莫德固体在硝基甲烷、卤代烷烃、环醚、乙腈或其混合溶剂中加热溶清，将清液置于低温下搅拌析晶，将析出的晶体分离、干燥，得到所述的奥扎莫德晶型1；
    优选地，所述溶剂选自硝基甲烷、乙腈、氯仿或其混合物；
    优选地，所述制备方法中的加热温度为40～70℃，更优选为50～70℃；
    优选地，所述低温为-10～30℃，更优选为-10～0℃；
    优选地，所述干燥的温度为10～40℃，更优选为10～30℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时；
    优选地，所述制备方法中奥扎莫德与溶剂的质量体积比为5～15mg：1mL，更优选为7～15mg：1mL。
  6. 结构式如式(I)所示的奥扎莫德晶型2
    Figure PCTCN2016099137-appb-100003
    其特征在于，所述晶型2以2θ角度表示的X-射线粉末衍射图具有以下特征峰:4.2±0.2°、16.0±0.2°、23.4±0.2°、26.7±0.2°和30.3±0.2°。
  7. 根据权利要求6所述的奥扎莫德晶型2，其特征在于，所述晶型2以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.2±0.2°、8.2±0.2°、16.0±0.2°、17.9±0.2°、18.6±0.2°、19.1±0.2°、20.5±0.2°、23.4±0.2°、26.7±0.2°和30.3±0.2°。
  8. 根据权利要求7所述的奥扎莫德晶型2，其特征在于，所述晶型2以2θ角度表示 的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2016099137-appb-100004
  9. 根据权利要求6～8中任一项所述奥扎莫德晶型2，其特征在于，所述晶型3的傅里叶红外光谱在波数为1616、1487、1460、1283、1260、1097、1045、939、808和761cm-1处具有特征峰。
  10. 根据权利要求6～9中任一项所述奥扎莫德晶型2的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
    (1)将奥扎莫德固体在C1～C4醇、水、丙酮、烷烃、C3～C5醚、C2～C6酯、乙腈、甲苯、二甲亚砜或其混合溶剂中形成悬浮液，搅拌析晶，将析出的晶体分离、干燥，得到所述奥扎莫德晶型2；所述搅拌的时间为3～7天；
    优选地，所述溶剂选自甲醇、乙醇、水、丙酮、二氯甲烷、异丙醚、乙酸乙酯、四氢呋喃、甲苯、乙腈、二甲亚砜、正庚烷或其混合物；
    优选地，所述制备方法的操作温度为10～40℃，更优选为室温；
    优选地，所述搅拌的时间为5～7天；
    优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时；
    优选地，所述制备方法中奥扎莫德与溶剂的质量体积比为10～100mg：1mL，更优选为20～50mg：1mL；
    (2)将奥扎莫德固体在C1～C4醇、C3～C4酮、乙酸异丙酯、甲苯、二甲亚砜或其混合溶剂中形成清液，挥发析晶，得到所述奥扎莫德的晶型2；
    优选地，所述溶剂选自甲醇、乙醇、丙酮、乙酸异丙酯、甲苯、二甲亚砜或其混合物；
    优选地，所述挥发温度为20～60℃，更优选为20～40℃；
    优选地，所述奥扎莫德溶液的浓度为奥扎莫德在所述溶剂中溶解度的0.5～1倍，更优选为0.8～1倍；
    (3)将奥扎莫德固体在C2～C4醇、C2～C6酯、甲苯、二甲亚砜、C3～C4醚或其混合溶剂中加热溶清，将清液置于低温下搅拌析晶，将析出的晶体分离、干燥，得到所述的奥扎莫德晶型2；
    优选地，所述C3～C4醚不包括环醚；
    优选地，所述溶剂选自异丙醇、乙醇、水、乙酸异丙酯、甲苯、二甲亚砜、异丙 醚或其混合物；
    优选地，所述制备方法中的加热温度为40～70℃，更优选为50～70℃；
    优选地，所述低温为-10～10℃，更优选为-10～0℃；
    优选地，所述干燥的温度为10～40℃，更优选为10～30℃；
    优选地，所述干燥的时间为10～48小时，更优选为10～24小时；
    优选地，所述制备方法中奥扎莫德与溶剂的质量体积比5～20mg：1mL，更优选为7～20mg：1mL。
  11. 结构式如式(I)所示的奥扎莫德晶型3，
    Figure PCTCN2016099137-appb-100005
    其特征在于，所述晶型3以2θ角度表示的X-射线粉末衍射图具有以下特征峰:4.6±0.2°、9.1±0.2°、13.6±0.2°、18.1±0.2°和22.7±0.2°。
  12. 根据权利要求11所述的奥扎莫德晶型3，其特征在于，所述晶型3以2θ角度表示的X-射线粉末衍射图具有以下特征峰：4.6±0.2°、8.0±0.2°、9.1±0.2°、11.2±0.2°、13.1±0.2°、13.6±0.2°、18.1±0.2°、19.3±0.2°、22.7±0.2°和26.2±0.2°。
  13. 根据权利要求12所述的奥扎莫德晶型3，其特征在于，所述晶型3以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2016099137-appb-100006
  14. 根据权利要求11～13中任一项所述奥扎莫德晶型3，其特征在于，所述晶型3的傅里叶红外光谱在波数为1616、1487、1459、1350、1284、1151、1126、1103、943和758cm-1处具有特征峰。
  15. 根据权利要求11～14中任一项所述奥扎莫德晶型3的制备方法，包括以下步骤：将奥扎莫德固体在乙酸乙酯、环醚、乙腈、卤代烷烃或其混合物的溶剂中溶清，取清液挥发干，得到所述奥扎莫德晶型3；
    优选地，所述溶剂选自乙酸乙酯、四氢呋喃、乙腈、二氯甲烷或其混合物；
    优选地，所述制备方法的挥发温度为0～40℃，更优选为室温；
    优选地，所述奥扎莫德溶液的浓度为奥扎莫德在所述溶剂中溶解度的0.5～1倍，更优选为0.8～1倍。
  16. 一种药物组合物，其包含治疗和/或预防疾病有效量的一种或多种的选自权利要求1～5中任一项所述的奥扎莫德晶型1、权利要求6～10中任一项所述的奥扎莫德晶型2、权利要求11～15中任一项所述的奥扎莫德晶型3，以及至少一种药学上可接受的载体。
  17. 权利要求1～5中任一项所述的奥扎莫德晶型1、权利要求6～10中任一项所述的奥扎莫德晶型2、权利要求11～15中任一项所述的奥扎莫德晶型3或权利要求16所述药物组合物在制备用于治疗和/或预防一种或多种病症或不良状况的药物中的用途，所述病症或不良状况是在医学上需要选择性鞘氨醇-1-磷酸酯受体的调节、活化、激动、抑制或拮抗，其中所述病症或不良状况包括多发性硬化、溃疡性结肠炎、关节炎、移植排斥或成人呼吸窘迫综合症等。
  18. 一种治疗和/或预防一种或多种病症或不良状况的方法，所述方法包括给予需要的患者治疗和/或预防疾病有效量的一种或多种的选自权利要求1～5中任一项所述的奥扎莫德晶型1、权利要求6～10中任一项所述的奥扎莫德晶型2、权利要求11～15中任一项所述的奥扎莫德晶型3；所述病症或不良状况是在医学上需要选择性鞘氨醇-1-磷酸酯受体的调节、活化、激动、抑制或拮抗，其中所述病症或不良状况包括多发性硬化、溃疡性结肠炎、关节炎、移植排斥或成人呼吸窘迫综合症等。
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US11680050B2 (en) 2016-06-14 2023-06-20 Receptos Llc Crystalline forms of ozanimod and ozanimod hydrochloride, and processes for preparation thereof
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