WO2017219994A1 - 9-氨基甲基取代的四环素类化合物的晶型及其制备方法 - Google Patents

9-氨基甲基取代的四环素类化合物的晶型及其制备方法 Download PDF

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WO2017219994A1
WO2017219994A1 PCT/CN2017/089470 CN2017089470W WO2017219994A1 WO 2017219994 A1 WO2017219994 A1 WO 2017219994A1 CN 2017089470 W CN2017089470 W CN 2017089470W WO 2017219994 A1 WO2017219994 A1 WO 2017219994A1
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formula
compound
vii
crystal form
crystal
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PCT/CN2017/089470
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English (en)
French (fr)
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黄振华
洪梅
姜辰
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山东亨利医药科技有限责任公司
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Priority to PE2018003293A priority Critical patent/PE20190810A1/es
Priority to SG11201811499WA priority patent/SG11201811499WA/en
Application filed by 山东亨利医药科技有限责任公司 filed Critical 山东亨利医药科技有限责任公司
Priority to ES17814732T priority patent/ES2906885T3/es
Priority to BR112018076726-3A priority patent/BR112018076726A2/pt
Priority to AU2017282891A priority patent/AU2017282891B2/en
Priority to KR1020187037477A priority patent/KR102205843B1/ko
Priority to EP17814732.8A priority patent/EP3476831B8/en
Priority to CA3028014A priority patent/CA3028014C/en
Priority to NZ749495A priority patent/NZ749495B2/en
Priority to RU2019101248A priority patent/RU2764723C2/ru
Priority to JP2018567683A priority patent/JP6883593B2/ja
Priority to CN201780026902.4A priority patent/CN109563035B/zh
Priority to IL263868A priority patent/IL263868B/en
Priority to MX2019000086A priority patent/MX2019000086A/es
Priority to US16/312,404 priority patent/US10633337B2/en
Priority to MYPI2018002825A priority patent/MY186900A/en
Publication of WO2017219994A1 publication Critical patent/WO2017219994A1/zh
Priority to PH12018502680A priority patent/PH12018502680A1/en
Priority to ZA2019/00274A priority patent/ZA201900274B/en
Priority to CONC2019/0000513A priority patent/CO2019000513A2/es

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    • 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
    • C07D209/52—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 condensed with a ring other than six-membered
    • 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
    • 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
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D209/54—Spiro-condensed
    • 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 a crystal form of a 9-aminomethyl-substituted tetracycline compound and a process for the preparation thereof, and a crystal form of the compound for preparing a drug for treating and/or preventing a disease caused by a tetracycline-sensitive bacteria and/or a drug-resistant bacteria Application in .
  • Tetracycline antibiotics are a class of oral broad-spectrum antibiotics produced by the fermentation of Actinomyces Streptomyces, against rickettsia, many Gram-positive and Gram-negative bacteria, pathogenic lymphogranuloma pathogens, inclusion body conjunctivitis Pathogens and parrot fever pathogens have good pharmacological effects.
  • Tigecycline has a broad spectrum of antibacterial activity, which not only has the antibacterial activity of early tetracyclines, but also has antibacterial activity against tetracycline-resistant pathogens due to efflux mechanism and ribosome protection mechanism.
  • tigecycline drugs available for oral administration.
  • WO2013013505 A1 also describes a process for preparing a compound of the formula (1), whereby a crystalline form of the compound of the formula (1) which can be obtained by obtaining an amorphous form of the compound of the formula (1) (Fig. 13).
  • the compound represented by the formula (1) is extremely liable to form an unstable solvate, resulting in unsatisfactory purity, content and stability.
  • the present inventors conducted intensive studies on the crystal form of the compound represented by (1), and finally found a crystal form of the compound represented by the formula (1).
  • the object of the present invention is to provide a crystal form of the compound represented by the formula (1).
  • Another object of the present invention is to provide a process for the preparation of a crystalline form of the compound of the formula (1) and a method for its mutual conversion.
  • a further object of the present invention is to provide a use of a crystalline form of the compound of the formula (1) for preventing and/or treating a drug caused by a tetracycline-like sensitive bacteria and/or a drug-resistant bacterium, wherein the tetracycline-like drug Diseases caused by susceptible bacteria and/or resistant bacteria are, for example, infections, cancer, diabetes, and other diseases that have been found to be treatable and/or preventable with other tetracyclines.
  • the amorphous form of the compound of the formula (1) was obtained according to the method described in WO2013013505 A1, and its XRPD pattern is shown in FIG.
  • the compound represented by the formula (1) has a low amorphous content and is difficult to purify.
  • the crude product was purified by column chromatography at a content of 84.8%, and after repurification, it was 87.7%. After repeated purification, the content still failed to meet the requirements for preparation of the drug.
  • the amorphous form of the compound represented by the formula (1) is not high in itself, and the stability is poor under high temperature, high humidity, and light conditions, and therefore, the amorphous form of the compound represented by the formula (1) is not suitable for preparation. drug.
  • the amorphous form of the compound represented by the formula (1) cannot satisfy the requirements for the preparation of a drug, and it is not necessary to find a crystalline form of a drug having a higher purity, content, and stability.
  • the present inventors further conducted extensive studies on the crystal form of the compound represented by the formula (1), and found the crystal forms I, II, III, IV, V, VI, VII, and VIII of the compound represented by the formula (1). In particular, it is not possible to predict the eight different crystal forms according to the chemical formula of the compound represented by formula (1), nor to predict the structure or properties of any one crystal form.
  • Form I 10.6 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °;
  • Form III 11.7 ° ⁇ 0.2 °, 16.6 ° ⁇ 0.2 °, 20.5 ° ⁇ 0.2 °, 27.3 ° ⁇ 0.2 °;
  • Form IV 6.8 ° ⁇ 0.2 °, 10.0 ° ⁇ 0.2 °, 11.1 ° ⁇ 0.2 °, 21.5 ° ⁇ 0.2 °;
  • Form V 9.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 23.8° ⁇ 0.2°;
  • Form VII 11.7 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °;
  • Form VIII 4.8 ° ⁇ 0.2 °, 9.7 ° ⁇ 0.2 °, 19.6 ° ⁇ 0.2 °.
  • Form I 9.0 ° ⁇ 0.2 °, 10.6 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 23.6 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °;
  • Form II 9.3 ° ⁇ 0.2 °, 10.2 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 24.1 ° ⁇ 0.2 °;
  • Form III 9.5 ° ⁇ 0.2 °, 11.7 ° ⁇ 0.2 °, 16.6 ° ⁇ 0.2 °, 20.5 ° ⁇ 0.2 °, 22.1 ° ⁇ 0.2 °, 27.3 ° ⁇ 0.2 °;
  • Form IV 6.8 ° ⁇ 0.2 °, 10.0 ° ⁇ 0.2 °, 11.1 ° ⁇ 0.2 °, 20.1 ° ⁇ 0.2 °, 20.5 ° ⁇ 0.2 °, 21.5 ° ⁇ 0.2 °;
  • Form V 9.7° ⁇ 0.2°, 11.8° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.8° ⁇ 0.2°;
  • Form VI 7.7 ° ⁇ 0.2 °, 15.5 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.2 ° ⁇ 0.2 °, 19.5 ° ⁇ 0.2 °, 21.2 ° ⁇ 0.2 °;
  • Form VII 11.7 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.1 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °;
  • Form VIII 4.8 ° ⁇ 0.2 °, 9.7 ° ⁇ 0.2 °, 14.6 ° ⁇ 0.2 °, 19.6 ° ⁇ 0.2 °, 22.0 ° ⁇ 0.2 °, 24.5 ° ⁇ 0.2 °.
  • Form I 9.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.9° ⁇ 0.2°, 18.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, 21.3° ⁇ 0.2 °, 23.6 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °;
  • Form II 9.3 ° ⁇ 0.2 °, 10.2 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, 23.0 ° ⁇ 0.2 °, 24.1 ° ⁇ 0.2 °, 24.8 ° ⁇ 0.2 °, 27.7 ° ⁇ 0.2 °;
  • Form III 9.5° ⁇ 0.2°, 11.7° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.5 ⁇ 0.2°, 16.6° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.5° ⁇ 0.2°, 22.1° ⁇ 0.2° 23.5° ⁇ 0.2°, 27.3° ⁇ 0.2°, 27.7° ⁇ 0.2°;
  • Form IV 6.8 ° ⁇ 0.2 °, 10.0 ° ⁇ 0.2 °, 11.1 ° ⁇ 0.2 °, 11.8 ° ⁇ 0.2 °, 13.9 ° ⁇ 0.2 °, 14.9 ° ⁇ 0.2 °, 15.5 ° ⁇ 0.2 °, 20.1 ° ⁇ 0.2 °, 20.5 ° ⁇ 0.2 °, 21.5 ° ⁇ 0.2 °;
  • Form V 7.1 ° ⁇ 0.2 °, 9.7 ° ⁇ 0.2 °, 11.8 ° ⁇ 0.2 °, 16.5 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, 22.1 ⁇ 0.2 °, 23.1 ° ⁇ 0.2 °, 23.8 ° ⁇ 0.2 °, 24.9 ° ⁇ 0.2 °;
  • Form VI 7.7° ⁇ 0.2°, 15.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.2° ⁇ 0.2 °, 22.0 ° ⁇ 0.2 °, 29.5 ° ⁇ 0.2 °;
  • Form VII 11.0° ⁇ 0.2°, 11.7° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.9° ⁇ 0.2°, 20.1° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, 25.6 ° ⁇ 0.2 °;
  • Form VIII 4.8 ° ⁇ 0.2 °, 9.7 ° ⁇ 0.2 °, 14.6 ° ⁇ 0.2 °, 19.6 ° ⁇ 0.2 °, 22.0 ° ⁇ 0.2 °, 24.5 ° ⁇ 0.2 °.
  • Form I has a differential scanning calorimetry graph that absorbs heat in the range of 180-220 ° C;
  • Form II has a differential scanning calorimetry graph that absorbs heat in the range of 195-215 ° C;
  • Form III has a differential scanning calorimetry graph that absorbs heat in the range of 150-190 ° C;
  • Form VII has a differential scanning calorimetry chart that absorbs heat in the range of 165-205 °C.
  • the crystal form of the compound represented by the formula (1) is characterized in that
  • the preparation method of the crystal form I of the compound of the formula (1) the compound of the formula (1) is slurried in anhydrous acetonitrile or stirred in tetrahydrofuran to precipitate a solid, and the crystal form I is obtained by filtration.
  • Process for the preparation of Form II of the compound of formula (1) placing the compound of formula (1) in a lower alcohol or ethyl acetate or acetone or methanol and water (1:1 to 9:1, v/v) The mixture is slurried in a mixed solution or dissolved in tetrahydrofuran to precipitate a solid in an isopropanol or n-heptane atmosphere, and then filtered to obtain a crystal form II.
  • a method for preparing the crystalline form III of the compound of the formula (1) the compound represented by the formula (1) is washed in a mixed solution of acetonitrile and water in a ratio of 1:1 to 4:1 at 0 to 70 ° C, Filtration gave Form III as an acetonitrile solvent compound.
  • a method for preparing the crystalline form IV of the compound of the formula (1) the compound represented by the formula (1) is placed in a mixed solution of acetonitrile and water at a ratio of 9:1, and washed at 70 to 90 ° C to obtain a crystalline form IV.
  • the method for preparing the crystalline form V of the compound of the formula (1) the compound represented by the formula (1) is slowly volatilized in a mixed solution of tetrahydrofuran and isopropyl acetate; or the compound represented by the formula (1) is dissolved. In tetrahydrofuran, isopropyl acetate was added dropwise to precipitate a solid, which was filtered to give crystal form V as isopropyl acetate solvate.
  • the preparation method of the crystalline form VI of the compound represented by the formula (1) the compound represented by the formula (1) is slowly volatilized in a chloroform solution; or the compound represented by the formula (1) is dissolved in chloroform, and the mixture is placed in a different form. Precipitating a solid in a propanol or n-heptane atmosphere; or dissolving the compound of formula (1) in chloroform, passing polyvinyl acetate, polyphenylene sulfide, 1,3-dimethylimidazolium methanesulfonate Or 1,3-dimethylimidazoline perchlorate induction, volatile chloroform precipitated solid to obtain crystal form VI, which is a chloroform solvate.
  • Form VII of the compound of the formula (1) The compound represented by the formula (1) is slurried and filtered in a mixed solution of acetonitrile to water in a ratio of 1:1 to 9:1 (v/v). Drying under vacuum gave Form VII. Alternatively, the crystalline form III of the compound of the formula (1) is dried under vacuum to obtain the form VII.
  • crystal forms III, V, VI, and VIII are solvent compounds, respectively containing a non-medicinal organic solvent acetonitrile (second type solvent, limit 410 ppm), chloroform (second type solvent, limit 60 ppm), acetic acid Propyl ester (three types of solvents, the amount of residual solvent does not exceed 0.5%).
  • second type solvent second type solvent, limit 410 ppm
  • chloroform second type solvent, limit 60 ppm
  • acetic acid Propyl ester three types of solvents, the amount of residual solvent does not exceed 0.5%).
  • the invention adopts a high content of the crystalline form of the compound represented by the formula (1) as a raw material to obtain an amorphous substance having a high medicinal content (content: 97.1%), and it is found that the amorphous content is decreased during the conversion process (as in the first embodiment). Shown).
  • the crystal forms I, II, III, IV, V, VI, VII, VIII of the compound of the formula (1) are not all better than the amorphous stability.
  • the compound content decreased by about 10% after being placed under high humidity conditions of 40 ° C / 75% ⁇ 5% RH for 14 days. It can be seen that under high humidity conditions, the stability of Form III is worse than amorphous.
  • the stability study of Form IV the content was lowered by 23.1% under light conditions of 4500 Lx ⁇ 500 Lx for 15 days, and the content was decreased by nearly 10% after being placed at a high temperature of 60 ° C for 15 days.
  • the above experimental results show that the stability of Form IV under illumination and high temperature is inferior to that of amorphous.
  • crystal forms I, II, III, IV, V, VI, VII, and VIII of the compound represented by the formula (1) do not all satisfy the medicinal requirements.
  • the present invention provides stable crystalline form I, crystalline form II and crystalline form VII of the compound of formula (1).
  • Form I 10.6 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °;
  • Form VII 11.7 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °.
  • Form I 9.0 ° ⁇ 0.2 °, 10.6 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 23.6 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °;
  • Form II 9.3 ° ⁇ 0.2 °, 10.2 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 24.1 ° ⁇ 0.2 °;
  • Form VII 11.7 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.1 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °.
  • Form I 9.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.9° ⁇ 0.2°, 18.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, 21.3° ⁇ 0.2 °, 23.6 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °;
  • Form II 9.3 ° ⁇ 0.2 °, 10.2 ° ⁇ 0.2 °, 14.0 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, 23.0 ° ⁇ 0.2 °, 24.1 ° ⁇ 0.2 °, 24.8 ° ⁇ 0.2 °, 27.7 ° ⁇ 0.2 °;
  • Form VII 11.0° ⁇ 0.2°, 11.7° ⁇ 0.2°, 13.8° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.9° ⁇ 0.2°, 20.1° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, 25.6 ° ⁇ 0.2 °.
  • Form I has a differential scanning calorimetry graph that absorbs heat in the range of 180-220 ° C;
  • Form II has a differential scanning calorimetry graph that absorbs heat in the range of 195-215 ° C;
  • Form VII has a differential scanning calorimetry chart that absorbs heat in the range of 165-205 °C.
  • the crystal form of the compound represented by the formula (1) is characterized in that
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form or amorphous form of the compound of the formula (1), and a pharmaceutically acceptable carrier, wherein the crystalline form comprises a crystalline form I , II, VII or a combination thereof.
  • the pharmaceutical composition of the present invention wherein the crystalline form is present in pure form.
  • Including, but not limited to, the content of Form I, II, VII, or a combination thereof is not less than 94.5% or 95% or 96% or 98% or 99%, such as less than about 5.5%, about 5%, less than about 4%, less than about 2% or less than about 1% impurities.
  • impurities include, but are not limited to, degradation products, oxidation products, epimers, solvents, and/or other undesirable impurities.
  • the invention further provides a pharmaceutical formulation of a crystalline form of a compound of formula (1) and one or more pharmaceutically acceptable carriers and/or diluents, which are pharmaceutically acceptable in any dosage form.
  • the present invention also provides a crystalline form of the compound of the formula (1) which can be formulated into a pharmaceutical preparation together with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical preparation refers to a conventional preparation for clinical use, and can be administered to a patient in need of such treatment by oral or parenteral administration. For oral administration, it can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule or the like; or an oral liquid preparation such as an oral solution, an oral suspension, a syrup or the like.
  • parenteral administration it can be prepared as an injection, including an injection, a sterile powder for injection, a concentrated solution for injection, a suspension for injection, and the like.
  • rectal administration it can be made into a suppository or the like.
  • pulmonary administration it can be made into an inhalant or a spray.
  • topical or transdermal administration it can be formulated into ointments, pastes, creams, lotions, gels, powders, solutions or transdermal patches.
  • These preparations can be prepared by a conventional method by adding a pharmaceutically acceptable carrier such as an excipient, a binder, a moisturizing agent, a disintegrating agent, a thickening agent and the like.
  • the crystalline form comprises Form I, II, VII or a combination thereof.
  • the present invention also provides the use of a crystalline form of the compound of the formula (1) for the preparation of a medicament for treating and/or preventing a disease caused by a tetracycline-like susceptible bacteria and/or a resistant bacteria, wherein the "tetracycline-like drugs" Diseases caused by susceptible bacteria and/or resistant bacteria are, for example, infections, cancer, diabetes, and other diseases that have been found to be treatable and/or preventable with other tetracyclines, including crystalline forms I, II, VII or a combination thereof.
  • the crystalline form of the compound of the formula (1) of the present invention can be used for the treatment and/or prevention of diseases which are sensitive to tetracyclines, and the diseases which are sensitive to tetracyclines include infections (for example, rickettsial infection, sexually transmitted lymphogranuloma, Inclusion body conjunctivitis, parrot fever pathogen infection and other tetracycline compound-resistant infections, cancer, diabetes, and other diseases that have been found to be treatable and/or preventable with tetracyclines.
  • infections for example, rickettsial infection, sexually transmitted lymphogranuloma, Inclusion body conjunctivitis, parrot fever pathogen infection and other tetracycline compound-resistant infections, cancer, diabetes, and other diseases that have been found to be treatable and/or preventable with tetracyclines.
  • the compound of the formula (1) of the invention has broad antibacterial spectrum and strong antibacterial activity, and has good antibacterial activity against Gram-positive and negative bacteria including aerobic bacteria and
  • the crystal form of the compound of the formula (1) of the present invention has the following advantages as compared with the closest prior art:
  • the crystalline form I, II, VII or a combination thereof of the compound of the formula (1) of the present invention has good stability, wherein the stability of the crystalline forms I and II is better than that of the crystalline form VII, and the thermal stability of the crystalline form I is good.
  • Form II In Form II;
  • the crystalline form I, II, VII or a combination thereof of the compound of the formula (1) of the present invention has good physical and chemical properties, stable quality, high content and purity, stable particle size, and is easy to carry out large-scale industrial production.
  • the crystalline form I, II, VII or a combination thereof of the compound of the formula (1) according to the present invention is characterized in that physical properties such as stability, solubility, hygroscopicity and dissolution rate are suitable for clinical and therapeutic dosage forms; Physical properties such as crystalline morphology, compressibility, particle size and hardness are suitable for the preparation of solid dosage forms.
  • the above properties can be determined by techniques known in the art such as X-ray diffraction, microscopy, IR spectroscopy, thermal analysis, and hygroscopicity analysis.
  • the crystalline form of the compound affects the solubility, dissolution, bioavailability, chemical and physical stability, fluidity, fragmentation and compressibility of the compound as well as the safety and efficacy of the compound-based pharmaceutical product (Knapman, Modern Drug Discovery, 2000, 3 (2): 53). Therefore, it has become very important to prepare and market pure drugs which are present in their thermodynamically most stable crystalline form and which are substantially free of other crystalline forms.
  • the crystalline form of the compound with the best physical and chemical properties will facilitate the development of the active compound as a drug.
  • the most useful physical and chemical properties include: easy and reproducible preparation, crystallinity, non-hygroscopicity, water solubility, stability to visible and ultraviolet light, low degradation rate under accelerated temperature and humidity conditions, The rate of low isomerization between isomer forms and long-term safety to the human body. So you need to show the advantages of each crystal form in the example.
  • the present invention relates to the crystalline form I, II, VII or a combination thereof of the compound of the formula (1), which has storage stability, suitable crystal morphology, compressibility, fluidity, imperceptibility to sticking, and density.
  • the particle size stability, dissolution properties and the like are advantageous for the preparation, formulation, use in the formulation and bioavailability of the compound represented by the formula (1).
  • crystal forms I, II, III, IV, V, VI, VII, VIII and amorphous form of the compound of the formula (1) according to the present invention can be mutually converted under certain conditions, and the present invention also provides the crystal form I, The conversion relationship between Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII and amorphous.
  • the amorphous form is obtained by slurry washing at 0-70 ° C in a mixed solution of acetonitrile and water in a ratio of 1:1 to 4:1;
  • Form II is washed in anhydrous acetonitrile to obtain crystal form I;
  • Form VII is recrystallized from methanol to obtain Form II;
  • Forms V, VI and VIII are dried to give an amorphous shape.
  • Figure 8 XRPD pattern of the crystalline form V of the compound of the formula (1);
  • Figure 10 XRPD pattern of the crystalline form VII of the compound of the formula (1);
  • Figure 12 XRPD pattern of the crystalline form VIII of the compound of the formula (1);
  • Figure 13 XRPD pattern of the amorphous form of the compound of formula (1);
  • Figure 14 Conversion diagram between the crystalline form I, the crystalline form II, the crystalline form III, the crystalline form IV, the crystalline form V, the crystalline form VI, the crystalline form VII, the crystalline form VIII and the amorphous form of the compound of the formula (1). ,among them:
  • the slurry is washed in a mixed solution of acetonitrile and water in a ratio of 1:1 to 4:1;
  • the slurry is washed in a mixed solution of acetonitrile and water in a ratio of 9:1;
  • the chloroform solution slowly volatilizes or induces crystallization of polyvinyl acetate, polyphenylene sulfide, 1,3-dimethylimidazolium methanesulfonate or 1,3-dimethylimidazolium perchlorate in chloroform solution. ;
  • the slurry washing according to the present invention means that a large amount of solid is stirred and washed with a small amount of a solvent.
  • the lower alcohol of the present invention means an alcohol having 1 to 6 carbon atoms, and includes methanol, ethanol, propanol, isopropanol, butanol, isobutanol, n-butanol, pentanol, hexanol and the like.
  • Form II of the compound of formula (1) (content 95.6%) was dissolved in an appropriate amount of dichloromethane, and dropped into n-heptane system at 0-5 ° C, stirred for 30 min, suction filtered, and dried in vacuo.
  • the compound represented by the formula (1) was amorphous (content was 93.3%).
  • Form II (content: 97.0%) of the compound represented by formula (1) is dissolved in an appropriate amount of methylene chloride, dropped into n-heptane system at 0-5 ° C, stirred for 30 min, suction filtered, and dried under vacuum.
  • the compound of the formula (1) was amorphous (content was 93.9%).
  • Form II (content: 98.4%) of the compound represented by formula (1) is dissolved in an appropriate amount of dichloromethane, and dropped into n-heptane system at 0-5 ° C, stirred for 30 min, suction filtered, and dried under vacuum.
  • the compound of the formula (1) was amorphous (content was 97.1%).
  • the solid was characterized as amorphous by XRPD, as shown in Figure 13.
  • the compound of the formula (1) obtained in Example 1 was amorphous 0.5 g (content 87.7%, purity 96.2%), placed in 5 mL acetonitrile or 2 mL THF, heated to 55 ° C and stirred for 0.5 h, and filtered to obtain a solid. It was placed in a vacuum drying oven and dried under vacuum at 50 ° C for 12 h to obtain Form I. The content was 97.0% and the purity was 98.2%.
  • XRPD X-ray powder diffraction
  • Method 1 The amorphous form of the compound of the formula (1) obtained in Example 1 was obtained in an amount of 1.0 g (content: 87.7%, purity: 96.2%), dissolved in 10 mL of methanol, stirred at 55 ° C for 1-2 h, and filtered. The solid was placed in a vacuum drying oven and dried under vacuum at 50 ° C for 12 h to obtain Form II, the content was 94.5%, and the purity was 96.4%.
  • Method 2 The amorphous form of the compound of the formula (1) obtained in Example 1 was obtained in an amount of 1.0 g (content: 87.7%, purity: 96.2%). After repeated purification, it was dissolved in 10 mL of methanol and stirred at 55 ° C for 1-2 h. After filtration, the obtained solid was placed in a vacuum drying oven and dried under vacuum at 50 ° C for 12 h to obtain Form II with a content of 98.4%.
  • Method 3 15 mg of the obtained compound of the formula (1) was placed in a 3 mL vial, and the vial was placed in a 20 mL large glass bottle containing 4 mL of methanol. After standing at room temperature for 10 days, the solid was Form II.
  • Method 4 15 mg of the obtained compound of the formula (1) was placed in a 3 mL vial, dissolved in 0.6 mL of THF, and the vial was placed in a 20 mL large glass vial containing 4 mL of n-heptane. After standing at room temperature for 4 days, a solid precipitated and was filtered to obtain crystal form II.
  • XRPD X-ray powder diffraction
  • Method 1 500 mg (87.7%, purity: 96.2%) of the amorphous compound of the formula (1) obtained in Example 1 was placed in a mixed solution of acetonitrile and water (1:1), and stirred at 5 ° C for 2 h.
  • the crystal form III was obtained by filtration, and the content was 90.1%, and the purity was 97.7%.
  • the data of the stability study are as described above.
  • Method 2 16.1 mg (content: 97.1%) of the amorphous compound of the formula (1) obtained in the preparation of Example 1 was placed in a mixed solution of 0.15 mL of acetonitrile and 0.15 mL of water, stirred at 5 ° C for 2 h, and filtered to obtain a crystal form. III.
  • XRPD X-ray powder diffraction
  • Example 1 15 mg of the amorphous compound represented by the formula (1) obtained in Example 1 was placed in a mixed solution of 0.9 mL of acetonitrile and 0.1 mL of water, and stirred at 80 ° C for 2 hours, and filtered to obtain crystal form IV. Crystal form IV is unstable and poor reproducibility.
  • XRPD X-ray powder diffraction
  • Method 1 14.8 mg of the compound of the formula (1) obtained in Example 1 was dissolved in 0.7 mL of THF and 0.7 mL of isopropyl acetate, and the solvent was slowly evaporated at 5 ° C or room temperature to precipitate a solid, which was filtered to obtain a crystal form V. .
  • Method 2 15 mg of the compound of the formula (1) obtained in Example 1 was dissolved in 1.0 mL of THF, and then 4 mL of isopropyl acetate was added dropwise to precipitate a solid, which was filtered to give crystals.
  • XRPD X-ray powder diffraction
  • Method 1 15 mg of the compound of the formula (1) obtained in the preparation of Example 1 was dissolved in 0.5 mL of chloroform, and slowly evolved to form Form VI at room temperature.
  • Method 2 16.1 mg of the compound of the formula (1) obtained in the preparation of Example 1 was placed in a 3 mL vial and dissolved in 0.8 mL of chloroform. The vial was placed in a 20 mL large glass bottle, and the large glass bottle contained 4 mL. Isopropanol or n-heptane. After standing at room temperature for 4 days, the precipitated solid was crystalline form VI.
  • Method 3 15 mg of the compound of the formula (1) obtained in the Example (Form II) was placed in a 3 mL vial, and the vial was placed in a 20 mL large glass bottle containing 4 mL of chloroform. After standing at room temperature for 10 days, the solid was crystalline form VI.
  • Method 4 15 mg of the compound of the formula (1) was placed in a 3 mL vial, dissolved in 0.5 mL of chloroform, and then 2.98 mg of polyphenylene sulfide was added, and the solid was slowly evolved to form a crystal form VI at room temperature.
  • Method 5 15 mg of the compound of the formula (1) was placed in a 3 mL vial, dissolved in 0.5 mL of chloroform, and then 3 mg of 1,3-dimethylimidazolium methanesulfonate was added, and the solid was slowly evolved at room temperature.
  • Form VI 15 mg of the compound of the formula (1) was placed in a 3 mL vial, dissolved in 0.5 mL of chloroform, and then 3 mg of 1,3-dimethylimidazolium methanesulfonate was added, and the solid was slowly evolved at room temperature.
  • XRPD X-ray powder diffraction
  • Method 1 16.1 mg of the amorphous compound represented by the formula (1) obtained in Example 1 was placed in a mixed solution of 0.15 mL of acetonitrile and 0.15 mL of water, stirred at 5 ° C for 2 h, filtered and dried under vacuum to obtain a crystal form. VII.
  • Method 2 15 mg of the compound of the formula (1) obtained in the Example (Form II) was placed in a mixed solution of 0.8 mL of acetonitrile and 0.2 mL of water (ACN/H 2 O, V/V, 4:1) at room temperature. The reaction was filtered, and after vacuum drying at 50 ° C for 2 h, the solid was crystal form VII.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • Test sample compound represented by formula (1) is amorphous, crystal form I, crystal form II, form VII: obtained by the examples;
  • the compound of formula (1) is amorphous, crystal form I, crystal form II, and form VII are placed in a dry clean surface dish and placed at 60 ° C ⁇ 5 ° C for 14 days, respectively Samples were taken on days 7 and 14 to determine the content and purity of the compound of formula (1), which was compared with the sample of 0 day;
  • High-humidity test the compound of formula (1) is amorphous, crystal form I, crystal form II, and form VII are plated in a dry clean surface dish at 25 ° C ⁇ 2 ° C, RH 75% ⁇ 5%, 40 ° C After being placed at ⁇ 2 ° C and RH 75% ⁇ 5% for 14 days, samples were taken on days 7 and 14, respectively, and the content and purity of the compound represented by the formula (1) were measured and compared with the samples of 0 day.
  • the compound of formula (1) is amorphous, crystal form I, crystal form II, and form VII are placed in a dry clean surface dish, placed in a light box, and placed under irradiation for 4 days at 4500Lx ⁇ 500Lx. The samples were sampled on the 7th and 14th days respectively, and the content and purity of the compound represented by the formula (1) were measured and compared with the sample of 0 day.
  • the amorphous form of the compound represented by formula (1) is high temperature, high humidity and light.
  • the content and purity vary greatly, indicating that the compound of formula (1) is amorphous and unstable, but the crystal forms I, II and VII of the compound represented by formula (1) are high temperature, high humidity and light.
  • the content and purity change little, indicating that the crystal forms I, II and VII of the compound represented by formula (1) have high stability, which is convenient for preparation, storage and transportation of the drug, and is more effective for ensuring the effectiveness of the drug. And security.
  • Test product the compound of the formula (1), Form II, Form IV: obtained by the examples;
  • High-humidity test crystal form II and form IV of the compound represented by formula (1) are placed in a dry clean surface dish at 25 ° C ⁇ 2 ° C, RH 92.5% ⁇ 5%, 25 ° C ⁇ 2 ° C, RH75 % ⁇ 5%, 40°C ⁇ 2°C, RH75% ⁇ 5% for 15 days, samples were taken on days 5 and 15, respectively, and the content and purity of the compound represented by formula (1) were determined, and the samples were subjected to 0 days. Comparison.
  • the crystal form II and crystal form IV of the compound represented by formula (1) were placed in a dry clean surface dish, placed in a light box, and placed under the illumination of 4500 Lx ⁇ 500 Lx for 15 days, respectively, at 5, 15 The sample was taken in a day, and the content and purity of the compound represented by the formula (1) were measured and compared with the sample of 0 day.
  • the crystal form IV of the compound represented by the formula (1) has a large change in the content of the compound represented by the formula (1) under the conditions of high temperature, high humidity and light, and the crystal of the compound represented by the formula (1). Under the conditions of high temperature, high humidity and light, the content of the compound represented by formula (1) changes little, indicating that the crystal form II of the compound represented by formula (1) has higher stability than that of crystal form IV. Sexuality facilitates the preparation, storage and transportation of drugs, and is more conducive to ensuring the effectiveness and safety of drug use.

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Abstract

涉及9-氨基甲基取代的四环素类化合物的晶型及其制备方法，具体涉及式(1)所示的化合物晶型、式(1)所示的化合物晶型的制备方法及其晶型在制备治疗和/或预防四环素敏感菌和/或耐药菌引起的感染疾病药物中的应用。

Description

9-氨基甲基取代的四环素类化合物的晶型及其制备方法 技术领域
本发明涉及9-氨基甲基取代的四环素类化合物的晶型及其制备方法，以及该化合物的晶型在制备治疗和/或预防四环素类药物敏感菌和/或耐药菌引起的疾病的药物中的应用。
背景技术
四环素类抗生素是由放线菌链霉菌属发酵产生的一类口服广谱抗生素，对立克次氏体、许多革兰氏阳性菌和革兰氏阴性菌、性病淋巴肉芽肿病原体、包涵体结膜炎病原体和鹦鹉热病原体有很好的药理学效应。
20世纪90年代初研发了新一类四环素类药物——甘氨酰环素类药物(glycyclines)，代表药物为替加环素(tigecylcine，GAR-936)。替加环素抗菌谱广，不但具有早期四环素类的抗菌活性，而且对因外排机制和核糖体保护机制而对四环素类耐药的病原菌也具抗菌活性。目前还没有可以口服的替加环素类药物上市。
Figure PCTCN2017089470-appb-000001
另外，WO2013013505 A1中还公开了下述式(1)所示化合物，
Figure PCTCN2017089470-appb-000002
其化学名称为(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲 基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代-1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺，该化合物的抗菌谱广，抗菌活性强。
WO2013013505 A1中还记载了式(1)所示化合物的制备方法，由此方法可以得到式(1)所示化合物的无定形(图13)，而无法得到的式(1)化合物的晶型。
发明内容
在式(1)所示的化合物的研究开发过程中，发现式(1)所示的化合物极易生成不稳定的溶剂化物，导致其纯度、含量以及稳定性不能令人满意。为了得到高纯度、高含量、稳定性好的晶型，本发明人对(1)所示化合物的晶型进行了悉心的研究，最终发现了式(1)所示化合物的晶型。
本发明目的在于提供式(1)所示化合物的晶型。
本发明目的还在于提供式(1)所示化合物的可药用的晶型。
本发明目的另外在于提供式(1)所示化合物的晶型的制备方法及其相互转化方法。
本发明的再一目的在于提供式(1)所示化合物的晶型在预防和/或治疗四环素类药物敏感菌和/或耐药菌引起的疾病的药物中的应用，其中所述四环素类药物敏感菌和/或耐药菌引起的疾病例如是感染、癌症、糖尿病和已经发现的可以用其他四环素类化合物治疗和/或预防的其他疾病。
本发明人对(1)所示化合物的晶型进行了悉心研究，结果发现：
(1)无定形
根据WO2013013505 A1记载的方法制备得到式(1)所示化合物的无定形，其XRPD图谱如图13所示。
式(1)所示的化合物的无定形含量低，不易纯化。如实施例1所述的工艺中，粗品经过柱层析的纯化，含量为84.8％，再次纯化后为87.7％，多次纯化后含量仍达不到制备药物的要求。
研究还发现，式(1)所示的化合物的无定形稳定性极差，如表1所示，高温60℃下14天含量下降了6.6％，高湿条件40℃/75％±5％RH下14天含量下降7.5％，而光照条件4500lx±500lx下，14天含量下降 了12.1％。式(1)所示的化合物的无定形其制备中的含量本身不高，在高温、高湿、光照条件下稳定性差，因此，式(1)所示的化合物的无定形不适合用于制备药物。
综上所述，式(1)所示的化合物的无定形不能满足用于制备药物的要求，亟需找到纯度、含量以及稳定性更好的药物用晶型。
(2)晶型
本发明人进一步对式(1)所示的化合物的晶型进行了大量研究，发现了式(1)所示的化合物的晶型I、II、III、IV、V、VI、VII、VIII。特别需要指出的是，这8种不同的晶型无法根据式(1)所示的化合物的化学式进行预测，也不可能预测到任何一种晶型的结构或者性质。
式(1)所示化合物的晶型，使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，分别在以下位置有特征峰：
晶型I：10.6°±0.2°、13.3°±0.2°、15.9°±0.2°、24.0°±0.2°；
晶型II：10.2°±0.2°、15.9°±0.2°、17.9°±0.2°、24.1°±0.2°；
晶型III：11.7°±0.2°、16.6°±0.2°、20.5°±0.2°、27.3°±0.2°；
晶型IV：6.8°±0.2°、10.0°±0.2°、11.1°±0.2°、21.5°±0.2°；
晶型V：9.7°±0.2°、17.9°±0.2°、19.2°±0.2°、23.8°±0.2°；
晶型VI：7.7°±0.2°、15.5°±0.2°、15.9°±0.2°、19.5°±0.2°；
晶型VII：11.7°±0.2°、15.1°±0.2°、15.9°±0.2°、17.9°±0.2°；
晶型VIII：4.8°±0.2°、9.7°±0.2°、19.6°±0.2°。
所述的式(1)所示化合物的晶型，使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，分别在以下位置有特征峰：
晶型I：9.0°±0.2°、10.6°±0.2°、13.3°±0.2°、15.9°±0.2°、23.6°±0.2°、24.0°±0.2°；
晶型II：9.3°±0.2°、10.2°±0.2°、14.0°±0.2°、15.9°±0.2°、17.9°±0.2°、24.1°±0.2°；
晶型III：9.5°±0.2°、11.7°±0.2°、16.6°±0.2°、20.5°±0.2°、22.1°±0.2°、27.3°±0.2°；
晶型IV：6.8°±0.2°、10.0°±0.2°、11.1°±0.2°、20.1°±0.2°、20.5°±0.2°、21.5°±0.2°；
晶型V：9.7°±0.2°、11.8°±0.2°、17.9°±0.2°、19.2°±0.2°、22.1°±0.2°、23.8°±0.2°；
晶型VI：7.7°±0.2°、15.5°±0.2°、15.9°±0.2°、17.2°±0.2°、19.5°±0.2°、21.2°±0.2°；
晶型VII：11.7°±0.2°、15.1°±0.2°、15.9°±0.2°、17.9°±0.2°、20.1°±0.2°、21.8°±0.2°；
晶型VIII：4.8°±0.2°、9.7°±0.2°、14.6°±0.2°、19.6°±0.2°、22.0°±0.2°、24.5°±0.2°。
所述的式(1)所示化合物的晶型，使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，分别在以下位置有特征峰：
晶型I：9.0°±0.2°、10.6°±0.2°、13.3°±0.2°、14.3°±0.2°、15.9°±0.2°、18.0°±0.2°、20.0°±0.2°、21.3°±0.2°、23.6°±0.2°、24.0°±0.2°；
晶型II：9.3°±0.2°、10.2°±0.2°、14.0°±0.2°、15.9°±0.2°、17.9°±0.2°、20.8°±0.2°、23.0°±0.2°、24.1°±0.2°、24.8°±0.2°、27.7°±0.2°；
晶型III：9.5°±0.2°、11.7°±0.2°、12.7°±0.2°、13.5±0.2°、16.6°±0.2°、19.8°±0.2°、20.5°±0.2°、22.1°±0.2°、23.5°±0.2°、27.3°±0.2°、27.7°±0.2°；
晶型IV：6.8°±0.2°、10.0°±0.2°、11.1°±0.2°、11.8°±0.2°、13.9°±0.2°、14.9°±0.2°、15.5°±0.2°、20.1°±0.2°、20.5°±0.2°、21.5°±0.2°；
晶型V：7.1°±0.2°、9.7°±0.2°、11.8°±0.2°、16.5°±0.2°、17.9°±0.2°、19.2°±0.2°、22.1°±0.2°、23.1°±0.2°、23.8°±0.2°、24.9°±0.2°；
晶型VI：7.7°±0.2°、15.5°±0.2°、15.9°±0.2°、17.2°±0.2°、18.0°±0.2°、19.5°±0.2°、20.6°±0.2°、21.2°±0.2°、22.0°±0.2°、29.5°±0.2°；
晶型VII：11.0°±0.2°、11.7°±0.2°、13.8°±0.2°、14.3°±0.2°、15.1°±0.2°、15.9°±0.2°、17.9°±0.2°、20.1°±0.2°、21.8°±0.2°、25.6°±0.2°；
晶型VIII：4.8°±0.2°、9.7°±0.2°、14.6°±0.2°、19.6°±0.2°、22.0°±0.2°、24.5°±0.2°。
所述的式(1)所示化合物的各晶型中，
晶型I其差示扫描量热热分析图在180-220℃范围内吸热；
晶型II其差示扫描量热热分析图在195-215℃范围内吸热；
晶型III其差示扫描量热热分析图在150-190℃范围内吸热；
晶型VII其差示扫描量热热分析图在165-205℃范围内吸热。
式(1)所示化合物的晶型，其特征分别在于，
晶型I其X-射线粉末衍射图谱如图1所示；
晶型II其X-射线粉末衍射图谱如图3所示；
晶型III其X-射线粉末衍射图谱如图5所示；
晶型IV其X-射线粉末衍射图谱如图7所示；
晶型V其X-射线粉末衍射图谱如图8所示；
晶型VI其X-射线粉末衍射图谱如图9所示；
晶型VII其X-射线粉末衍射图谱如图10所示；
晶型VIII其X-射线粉末衍射图谱如图12所示。
式(1)所示化合物的晶型I的制备方法：将式(1)所示化合物置于无水乙腈中浆洗或四氢呋喃中搅拌析出固体，过滤得到晶型I。
式(1)所示化合物的晶型II的制备方法：将式(1)所示化合物置于低级醇或乙酸乙酯或丙酮或甲醇与水(1∶1-9∶1，v/v)混合溶液中浆洗，或者溶于四氢呋喃中置于异丙醇或正庚烷氛围中析出固体后，过滤得到晶型II。
式(1)所示化合物的晶型III的制备方法：将式(1)所示的化合物置于乙腈与水比例为1∶1-4∶1的混合溶液中于0-70℃下浆洗，过滤得到晶型III，为乙腈溶剂化合物。
式(1)所示化合物的晶型IV的制备方法：将式(1)所示的化合物置于乙腈与水比例为9∶1的混合溶液中于70-90℃下浆洗得晶型IV。
式(1)所示化合物的晶型V的制备方法：将式(1)所示的化合物置于四氢呋喃与乙酸异丙酯混合溶液中缓慢挥发；或将式(1)所示的化合物溶于四氢呋喃中，然后滴加乙酸异丙酯，析出固体，过滤得到晶型V，为乙酸异丙酯溶剂化物。
式(1)所示化合物的晶型VI的制备方法：将式(1)所示的化合物置于氯仿溶液中缓慢挥发；或将式(1)所示的化合物溶于氯仿中，置于异丙醇或正庚烷氛围中析出固体；或将式(1)所示的化合物溶于氯仿中，通过聚醋酸乙烯酯、聚苯硫醚、1，3-二甲基咪唑啉甲烷磺酸盐或1，3-二甲基咪唑啉高氯酸盐诱导，挥发氯仿析出固体得到晶型VI，为氯仿溶剂化物。
式(1)所示化合物的晶型VII的制备方法：将式(1)所示的化合物置于乙腈与水比例为1∶1-9∶1(v/v)的混合溶液中浆洗、过滤，在真空下干燥得晶型VII。或者将式(1)所示的化合物的晶型III在真空下干燥得晶型VII。
式(1)所示化合物的晶型VIII的制备方法：将式(1)所示的化合 物置于乙酸异丙酯中浆洗，过滤得到晶型VIII，为乙酸异丙酯溶剂化物。
进一步研究发现，上述晶型III、V、VI、VIII属于溶剂化合物，分别含有非药用的有机溶剂乙腈(二类溶剂，限度为410ppm)、氯仿(二类溶剂，限度为60ppm)、乙酸异丙酯(三类溶剂，残留溶剂的量不超过0.5％)。经过测定，晶型III、V、VI、VIII的残留溶剂均超过药用限度，不符合药用要求。
为进一步测定符合药用含量的无定形的稳定性，需要制备含量高的无定形。本发明以含量高的式(1)所示的化合物晶型为原料制得药用含量高的无定形(含量为97.1％)，发现在转化过程中，无定形的含量下降(如实施例1所示)。
研究还发现，式(1)所示化合物的的晶型I、II、III、IV、V、VI、VII、VIII相比于无定形的稳定性，并非都更好。具体而言，在晶型III的稳定性考察中，于高湿条件40℃/75％±5％RH下放置14天后，化合物含量下降了10％左右。由此可以看出：高湿条件下，晶型III的稳定性比无定形差。另外，在晶型IV的稳定性考察中，于光照条件4500Lx±500Lx下放置15天，其含量下降了23.1％，另外，于高温60℃下放置15天，其含量下降近10％。上述实验结果说明晶型IV在光照、高温条件下的稳定性比无定形的差。
因此，式(1)所示化合物的晶型I、II、III、IV、V、VI、VII、VIII并非都能满足药用要求。
(3)可药用的晶型
基于上述的研究，本发明提供了式(1)所示化合物的稳定的晶型I、晶型II和晶型VII。
本发明的优选的技术方案概述如下：
式(1)所示化合物(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代-1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺的晶型
使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，分别在以下位置有特征峰：
晶型I：10.6°±0.2°、13.3°±0.2°、15.9°±0.2°、24.0°±0.2°；
晶型II：10.2°±0.2°、15.9°±0.2°、17.9°±0.2°、24.1°±0.2°；
晶型VII：11.7°±0.2°、15.1°±0.2°、15.9°±0.2°、17.9°±0.2°。
式(1)所示化合物的晶型，使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，分别在以下位置有特征峰：
晶型I：9.0°±0.2°、10.6°±0.2°、13.3°±0.2°、15.9°±0.2°、23.6°±0.2°、24.0°±0.2°；
晶型II：9.3°±0.2°、10.2°±0.2°、14.0°±0.2°、15.9°±0.2°、17.9°±0.2°、24.1°±0.2°；
晶型VII：11.7°±0.2°、15.1°±0.2°、15.9°±0.2°、17.9°±0.2°、20.1°±0.2°、21.8°±0.2°。
式(1)所示化合物的晶型，使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，分别在以下位置有特征峰：
晶型I：9.0°±0.2°、10.6°±0.2°、13.3°±0.2°、14.3°±0.2°、15.9°±0.2°、18.0°±0.2°、20.0°±0.2°、21.3°±0.2°、23.6°±0.2°、24.0°±0.2°；
晶型II：9.3°±0.2°、10.2°±0.2°、14.0°±0.2°、15.9°±0.2°、17.9°±0.2°、20.8°±0.2°、23.0°±0.2°、24.1°±0.2°、24.8°±0.2°、27.7°±0.2°；
晶型VII：11.0°±0.2°、11.7°±0.2°、13.8°±0.2°、14.3°±0.2°、15.1°±0.2°、15.9°±0.2°、17.9°±0.2°、20.1°±0.2°、21.8°±0.2°、25.6°±0.2°。
式(1)所示化合物的各晶型中，
晶型I其差示扫描量热热分析图在180-220℃范围内吸热；
晶型II其差示扫描量热热分析图在195-215℃范围内吸热；
晶型VII其差示扫描量热热分析图在165-205℃范围内吸热。
式(1)所示化合物的晶型，其特征分别在于，
晶型I其X-射线粉末衍射图谱如图1所示；
晶型II其X-射线粉末衍射图谱如图3所示；
晶型VII其X-射线粉末衍射图谱如图10所示。
本发明还提供一种药物组合物，所述药物组合物含有所述的式(1)所示化合物的晶型或无定型，和药用可接受的载体，其中所述晶型包括晶型I、II、VII或其组合。
本发明所述的药物组合物，其中所述的晶型以纯的形式存在。包括但不仅限于，晶型I、II、VII或其组合的含量不低于94.5％或者95％或者96％或者98％或者99％，例如存在少于约5.5％、约5％、少于约4％、少于约2％或少于约1％的杂质。这样的杂质包括但不仅限于降解产物、氧化产物、差向异构体、溶剂和/或其它不合需要的杂质。
本发明还提供式(1)所示化合物的晶型和一种或多种药用载体和/或稀释剂的药用制剂，其为药学上可接受的任一剂型。本发明还提供式(1)所示化合物的晶型可以与一种或者多种药用载体制成药物制剂。所述的药物制剂指临床上使用的常规制剂，可以口服或肠胃外给药等方式施用于需要这种治疗的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射无菌粉末、注射用浓溶液、注射用混悬剂等。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或者喷雾剂等。用于局部或经皮给药时，可制成软膏剂、糊剂、霜剂、洗剂、凝胶剂、粉剂、溶液或透皮贴剂等。这些制剂可以通过常规方法，添加药用载体如赋形剂、黏合剂、增湿剂、崩解剂、增稠剂等制备而成。其中所述晶型包括晶型I、II、VII或其组合。
本发明还提供式(1)所示化合物的晶型在制备治疗和/或预防对四环素类药物敏感菌和/或耐药菌引起的疾病的药物中的应用，其中所述“对四环素类药物敏感菌和/或耐药菌引起的疾病”例如是感染、癌症、糖尿病和已经发现的可以用其他四环素类化合物治疗和/或预防的其他疾病，其中所述晶型包括晶型I、II、VII或其组合。
本发明式(1)所示化合物的晶型能够用于治疗和/或预防对四环素类药物敏感的疾病，对四环素类药物敏感的疾病包括感染(例如立克次体感染，性病淋巴肉芽肿，包涵体结膜炎，鹦鹉热病原体感染及其它四环素化合物耐药性感染)、癌症、糖尿病和已经发现可以用四环素类化合物治疗和/或预防的其它疾病。本发明式(1)所示化合物的晶型抗菌谱广，抗菌活性强，对革兰氏阳性、阴性菌包括需氧菌和厌氧菌均具有良好的抗菌活性；且具有较好的药代动力学特征。
本发明式(1)所示化合物的晶型与最接近的现有技术相比，具有以下优点：
(1)本发明式(1)所示化合物的晶型I、II、VII或其组合稳定性好，其中晶型I、II的稳定性好于晶型VII，晶型I的热稳定性好于晶型II；
(2)本发明式(1)所示化合物的晶型I、II、VII或其组合，残留溶剂少，毒性和副作用低；
(3)本发明化合物式(1)所示化合物的晶型I、II、VII或其组合，理化性质好，质量稳定，含量和纯度高，粒径稳定，易于进行大规模工业生产。
本发明涉及的式(1)所示化合物的晶型I、II、VII或其组合为其特征在于物理性质如稳定性、溶解性、吸湿性和溶出率适合于临床和治疗剂型；其特征还在于物理性质例如结晶形态学、可压缩性、粒度和硬度适合于制备固体剂型。上述性质可采用本领域已知的技术例如X-射线衍射、显微镜学、IR光谱学、热分析和吸湿性分析测定。
化合物的晶型影响化合物的溶解性、溶出率、生物利用度、化学和物理稳定性、流动性、破碎性和可压缩性以及基于化合物的药物产品的安全性和效力(Knapman，Modern Drug Discovery，2000，3(2)：53)。因此，制备和上市以其热力学最稳定的晶型存在的、基本上不含其它晶型的纯的药物变得非常重要。
具有最佳物理和化学性质的化合物的晶型将促进活性化合物做为药物的开发。最有用的物理和化学性质包括：容易和可再生式制备、结晶性、非吸湿性、水溶性、对可见和紫外光的稳定性、在温度和湿度的加速稳定性条件下低得降解速率、同分异构体形式之间的低异构化速率和长期给予人体的安全性等。所以需要在实例里展示各个晶型的优势。
本发明涉及的式(1)所示化合物的晶型I、II、VII或其组合，其储存稳定性、合适的晶体形状(crystal morphology)、可压缩性、流动性、不容易粘冲、密度、粒径稳定性、溶出性质等对式(1)所示化合物的制备、配制、制剂中的使用和生物利用度是有益的。
本发明所述的式(1)所示化合物的晶型I、II、III、IV、V、VI、VII、VIII及无定形在一定条件下可以相互转化，本发明还提供了晶型I、晶型II、晶型III、晶型IV、晶型V、晶型VI、晶型VII、晶型VIII与无定形之间的转化关系。
无定形在无水乙腈中浆洗或在四氢呋喃重结晶制得晶型I；
无定形在甲醇中浆洗制得晶型II；
无定形在乙腈与水比例为1∶1-4∶1的混合溶液中0-70℃浆洗制得晶型III；
无定形在乙腈与水比例为9∶1的混合溶液中70-90℃浆洗制得晶型 IV；
无定形在乙酸异丙酯中浆洗制得晶型VIII；
晶型II在无水乙腈中浆洗制得晶型I；
晶型III真空干燥制得晶型VII；
晶型VII在甲醇中重结晶制得晶型II；
晶型V、VI和VIII干燥后制得无定形。
附图说明
图1：式(1)所示化合物晶型I的XRPD图谱；
图2：式(1)所示化合物晶型I的DSC图谱；
图3：式(1)所示化合物晶型II的XRPD图谱；
图4：式(1)所示化合物晶型II的DSC图谱；
图5：式(1)所示化合物晶型III的XRPD图谱；
图6：式(1)所示化合物晶型III的DSC图谱；
图7：式(1)所示化合物晶型IV的XRPD图谱；
图8：式(1)所示化合物晶型V的XRPD图谱；
图9：式(1)所示化合物晶型VI的XRPD图谱；
图10：式(1)所示化合物晶型VII的XRPD图谱；
图11：式(1)所示化合物晶型VII的DSC图谱；
图12：式(1)所示化合物晶型VIII的XRPD图谱；
图13：式(1)所示化合物无定型的XRPD图谱；
图14：式(1)所示化合物晶型I、晶型II、晶型III、晶型IV、晶型V、晶型VI、晶型VII、晶型VIII与无定形之间的转化关系图，其中：
1.甲醇中浆洗或甲醇与水(1∶1-9∶1，v/v)的混合溶液中浆洗；
2.乙腈或四氢呋喃中浆洗；
3.乙腈与水比例为1∶1-4∶1的混合溶液中浆洗；
4.乙腈与水比例为9∶1的的混合溶液中浆洗；
5.乙酸异丙酯中浆洗；
6.氯仿溶液缓慢挥发或在氯仿溶液中聚醋酸乙烯酯、聚苯硫醚、1，3-二甲基咪唑啉甲烷磺酸盐或1，3-二甲基咪唑啉高氯酸盐诱导结晶；
7.四氢呋喃与乙酸异丙酯(1∶1，v/v)混合溶液中缓慢挥发；
8.加热干燥。
本发明所述浆洗是指大量固体用少量溶剂搅拌洗涤。
本发明所述低级醇是指含有1-6个碳原子的醇，包括甲醇、乙醇、丙醇、异丙醇、丁醇、异丁醇、正丁醇、戊醇、己醇等。
4、具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲 基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代 -1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺无定形的制备
参照专利WO2013013505A1记载的方法合成(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代-1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺8g。粗品含量为84.8％。
将8g粗品溶于1.5L水中，加入三氟乙酸调pH＝2-4溶解后加入氨水调pH＝6.5-7.5，上样后用(1‰TFA/水)/乙腈(6％)体系制备分离，收集含产物流分。水相用氢氧化钠水溶液调pH＝7.5～8.5，保持水相温度25-30℃，用二氯甲烷萃取三次，二氯甲烷相合并。二氯甲烷相浓缩，滴入正庚烷中降温至0～5℃搅拌10-30min，抽滤，得到化合物3.17g，含量为87.7％，纯度为96.2％。
分子式：C29H36N4O7
1H-NMR(CD3OD，400MHz)δ：8.48(s，1H)，4.54(brs，2H)，4.22(s，1H)，3.65(brs，4H)，3.46(m，1H)，3.35(s，6H)，3.25(m，1H)，3.10(s，3H)，3.05(s，1H)，3.00(s，3H)，2.60(m，1H)，2.37(m，1H)，1.87-1.97(m，2H)，1.68(m，1H)，1.07(m，1H)，0.78(m，1H).
为了制备含量高的(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代-1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺的无定形，本发明还尝试下列工艺：
将式(1)所示化合物的晶型II(含量为95.6％)溶于适量二氯甲烷中，在0-5℃下滴入正庚烷体系中，搅拌30min，抽滤，固体真空干 燥得式(1)所示化合物无定形(含量为93.3％)。
将式(1)所示化合物的晶型II(含量为97.0％)溶于适量二氯甲烷中，在0-5℃下滴入正庚烷体系中，搅拌30min，抽滤，固体真空干燥得式(1)所示化合物无定形(含量为93.9％)。
将式(1)所示化合物的晶型II(含量为98.4％)溶于适量二氯甲烷中，在0-5℃下滴入正庚烷体系中，搅拌30min，抽滤，固体真空干燥得式(1)所示化合物无定形(含量为97.1％)。
固体用XRPD表征为无定形，如图13所示。
实施例2(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲 基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代 -1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺晶型I的制备
将实施例1制备所得式(1)所示化合物无定形0.5g(含量87.7％，纯度为96.2％)，置于5mL乙腈或2mL THF中，加热至55℃搅拌0.5h，过滤，得到的固体放置于真空干燥箱中50℃真空干燥12h，获得晶型I。含量为97.0％，纯度为98.2％。
晶型I的X-射线粉末衍射(XRPD)图谱如图1中所示，其中主要参数如下：
Figure PCTCN2017089470-appb-000003
式(1)所示化合物晶型I的DSC图谱如图2所示。
实施例3(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲 基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代 -1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺晶型II的制备
方法1：将实施例1制备所得式(1)所示化合物的无定形1.0g(含量87.7％，纯度为96.2％)，溶于10mL甲醇中，55℃下搅拌1-2h，过滤，得到的固体放置于真空干燥箱中50℃真空干燥12h，得晶型II，含量为94.5％，纯度为96.4％。
方法2：将实施例1制备所得式(1)所示化合物的无定形1.0g(含量87.7％，纯度为96.2％)，多次纯化后，溶于10mL甲醇中，55℃下搅拌1-2h，过滤，得到的固体放置于真空干燥箱中50℃真空干燥12h，得晶型II，含量为98.4％。
方法3：将所得式(1)所示化合物15mg置于3mL小玻璃瓶中，将该小瓶置于20mL大玻璃瓶内，大玻璃瓶含4mL甲醇。室温下放置10天后，固体为晶型II。
方法4：将所得式(1)所示化合物15mg置于3mL小玻璃瓶中，溶于0.6mL THF中，将该小瓶置于20mL大玻璃瓶内，大玻璃瓶含4mL正庚烷。室温下放置4天，析出固体，过滤得晶型II。
晶型II的X-射线粉末衍射(XRPD)图谱如图3中所示，其中主要参数如下：
Figure PCTCN2017089470-appb-000004
实施例4(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲 基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代 -1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺晶型III(乙腈溶剂化物)的 制备
方法1：将实施例1制备所得式(1)所示无定型化合物500mg(含量87.7％，纯度为96.2％)，置于乙腈和水(1∶1)的混合溶液中，5℃下搅拌2h，过滤得晶型III，含量为90.1％，纯度为97.7％。稳定性考察的数据如前述。
方法2：将实施例1制备所得式(1)所示无定型化合物16.1mg(含量97.1％)，置于0.15mL乙腈和0.15mL水的混合溶液中，5℃下搅拌2h，过滤得晶型III。
晶型III的X-射线粉末衍射(XRPD)图谱如图5中所示，DSC图谱如图6所示，其中主要参数如下：
Figure PCTCN2017089470-appb-000005
实施例5(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲 基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代 -1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺晶型IV的制备
将实施例1制备所得式(1)所示无定型化合物15mg，置于0.9mL乙腈和0.1mL水的混合溶液中，80℃下搅拌2h，过滤得晶型IV。晶型 IV不稳定，重现性差。
晶型IV的X-射线粉末衍射(XRPD)图谱如图7中所示，其中主要参数如下：
Figure PCTCN2017089470-appb-000006
实施例6(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲 基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代 -1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺晶型V(乙酸异丙酯的溶剂 化物)的制备
方法1：将实施例1制备所得式(1)所示化合物14.8mg，溶于0.7mL THF和0.7mL乙酸异丙酯中，5℃或室温下溶剂缓慢挥发后析出固体，过滤得晶型V。
方法2：将实施例1制备所得式(1)所示化合物15mg，溶于1.0mLTHF中，然后滴加4mL乙酸异丙酯，析出固体，过滤得晶型。
晶型V的X-射线粉末衍射(XRPD)图谱如图8中所示，其中主要参数如下：
Figure PCTCN2017089470-appb-000007
实施例7(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲 基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代 -1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺晶型VI(氯仿的溶剂化物) 的制备
方法1：将实施例1制备所得式(1)所示化合物15mg溶于0.5mL氯仿中，室温下缓慢挥发析出为晶型VI。
方法2：将实施例1制备所得式(1)所示化合物16.1mg，置于3mL小玻璃瓶中，溶于0.8mL氯仿中，将该小瓶置于20mL大玻璃瓶内，大玻璃瓶含4mL异丙醇或正庚烷。室温下放置4天，析出固体为晶型VI。
方法3：将实施例制备所得式(1)所示化合物15mg(晶型II)，置于3mL小玻璃瓶中，将该小瓶置于20mL大玻璃瓶内，大玻璃瓶含4mL氯仿。室温下放置10天后，固体为晶型VI。
方法4：将式(1)所示化合物15mg置于3mL小玻璃瓶中，加入0.5mL氯仿溶解，然后加入2.98mg聚苯硫醚，室温下缓慢挥发析出固体为晶型VI。
方法5：将式(1)所示化合物15mg置于3mL小玻璃瓶中，加入0.5mL氯仿溶解，然后加入3mg 1，3-二甲基咪唑啉甲烷磺酸盐，室温下缓慢挥发析出固体为晶型VI。
晶型VI的X-射线粉末衍射(XRPD)图谱如图9中所示，其中主要参数如下：
Figure PCTCN2017089470-appb-000008
实施例8(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代-1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺晶型VII的制备
方法1：将实施例1制备所得式(1)所示无定型化合物16.1mg，置于0.15mL乙腈和0.15mL水的混合溶液中，5℃下搅拌2h，过滤后在真空下干燥得晶型VII。
方法2：将实施例制备所得式(1)所示化合物15mg(晶型II)置于0.8mL乙腈和0.2mL水(ACN/H2O，V/V，4∶1)混合溶液中，室温反应，过滤后50℃下真空干燥2h后，固体为晶型VII。
方法3：将实施例制备所得式(1)所示化合物晶型III在真空下干燥得晶型VII。
晶型VII的X-射线粉末衍射(XRPD)图谱如图10中所示，其中主要参数如下：
Figure PCTCN2017089470-appb-000009
实施例9(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲 基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代 -1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺晶型VIII(乙酸异丙酯溶剂化 物)的制备
将实施例1制备所得式(1)所示化合物15mg(无定形)置于1mL乙酸异丙酯中，5℃下搅拌2h后，过滤后固体为晶型VIII。
晶型VIII的X-射线粉末衍射(XRPD)图谱如图12中所示，其中主要参数如下：
Figure PCTCN2017089470-appb-000010
以下通过无定形及各晶型的稳定性实验进一步阐述本发明化合物有益效果，但不应将此理解为本发明化合物仅具有下列有益效果。
实验例1 本发明化合物无定形及各晶型的稳定性
供试品：式(1)所示化合物无定形、晶型I、晶型II、晶型VII：通过实施例制得；
影响因素试验考察条件：
高温试验：将式(1)所示化合物无定形、晶型I、晶型II、晶型VII平铺于干燥洁净表面皿中，在60℃±5℃条件下放置14天，分别于 第7、14天取样，测定式(1)所示化合物的含量和纯度，与0天的样品进行比较；
高湿试验：将式(1)所示化合物无定形、晶型I、晶型II、晶型VII平铺于干燥洁净表面皿中，在25℃±2℃、RH75％±5％，40℃±2℃、RH75％±5％条件下放置14天，分别于第7、14天取样，测定式(1)所示化合物的含量和纯度，与0天的样品进行比较。
光照试验：将式(1)所示化合物无定形、晶型I、晶型II、晶型VII平铺于干燥洁净表面皿中，置光照箱内，于照度为4500Lx±500Lx条件下放置14天，分别于第7、14天取样，测定式(1)所示化合物的含量和纯度，与0天的样品进行比较。
含量：按照中国药典2010版附录VD高效液相色谱法，采用外标法进行测定。
纯度：按照中国药典2010版附录VD高效液相色谱法，采用面积归一化法进行测定。
试验结果：见下表1。
表1 式(1)所示化合物无定形及晶型的影响因素试验考察结果
Figure PCTCN2017089470-appb-000011
由试验结果可知，式(1)所示化合物的无定形在高温、高湿和光 照的条件下，含量和纯度变化较大，表明式(1)所示化合物的无定形不稳定，但式(1)所示化合物的晶型I、II、VII在高温、高湿和光照的条件下，含量和纯度变化很小，表明式(1)所示化合物的晶型I、II、VII具有较高的稳定性，便于药品的制备、储存和运输，更利于保证药物使用的有效性和安全性。
实验例2 本发明化合物晶型II、晶型IV的稳定性
供试品：式(1)所示化合物晶型II、晶型IV：通过实施例制得；
影响因素试验考察条件：
高温试验：将式(1)所示化合物晶型II、晶型IV平铺于干燥洁净表面皿中，在60℃±5℃条件下放置15天，分别于第5、15天取样，测定式(1)所示化合物的含量和纯度，与0天的样品进行比较；
高湿试验：将式(1)所示化合物晶型II、晶型IV平铺于干燥洁净表面皿中，在25℃±2℃、RH92.5％±5％，25℃±2℃、RH75％±5％，40℃±2℃、RH75％±5％条件下放置15天，分别于第5、15天取样，测定式(1)所示化合物的含量和纯度，与0天的样品进行比较。
光照试验：将式(1)所示化合物晶型II、晶型IV平铺于干燥洁净表面皿中，置光照箱内，于照度为4500Lx±500Lx条件下放置15天，分别于第5、15天取样，测定式(1)所示化合物的含量和纯度，与0天的样品进行比较。
含量：按照中国药典2010版附录VD高效液相色谱法，采用外标法进行测定。
纯度：按照中国药典2010版附录VD高效液相色谱法，采用面积归一化法进行测定。
试验结果：见表2。
表2 式(1)所示化合物晶型的影响因素试验考察结果
Figure PCTCN2017089470-appb-000012
由试验结果可知，式(1)所示化合物的晶型IV在高温、高湿和光照的条件下，式(1)所示化合物的含量变化较大，而式(1)所示化合物的晶型II在高温、高湿和光照的条件下，式(1)所示化合物的含量变化很小，表明式(1)所示化合物的晶型II与晶型IV相比，具有较高的稳定性，便于药品的制备、储存和运输，更利于保证药物使用的有效性和安全性。

Claims (10)

  1. 式(1)所示化合物(4S，4aS，5aR，12aS)-9-(3-氮杂双环[3.1.0]己烷-3-基甲基)-4，7-双(二甲氨基)-3，10，12，12a-四羟基-1，11-二氧代-1，4，4a，5，5a，6，11，12a-八氢并四苯-2-甲酰胺的晶型，
    Figure PCTCN2017089470-appb-100001
    其特征在于，使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，分别在以下位置有特征峰：
    晶型I：10.6°±0.2°、13.3°±0.2°、15.9°±0.2°、24.0°±0.2°；
    晶型II：10.2°±0.2°、15.9°±0.2°、17.9°±0.2°、24.1°±0.2°；
    晶型VII：11.7°±0.2°、15.1°±0.2°、15.9°±0.2°、17.9°±0.2°。
  2. 如权利要求1所述的式(1)所示化合物的晶型，其特征在于，使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，分别在以下位置有特征峰：
    晶型I：9.0°±0.2°、10.6°±0.2°、13.3°±0.2°、15.9°±0.2°、23.6°±0.2°、24.0°±0.2°；
    晶型II：9.3°±0.2°、10.2°±0.2°、14.0°±0.2°、15.9°±0.2°、17.9°±0.2°、24.1°±0.2°；
    晶型VII：11.7°±0.2°、15.1°±0.2°、15.9°±0.2°、17.9°±0.2°、20.1°±0.2°、21.8°±0.2°。
  3. 如权利要求1或2所述的式(1)所示化合物的晶型，其特征在于，使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，分别在以下位置有特征峰：
    晶型I：9.0°±0.2°、10.6°±0.2°、13.3°±0.2°、14.3°±0.2°、15.9°±0.2°、18.0°±0.2°、20.0°±0.2°、21.3°±0.2°、23.6°±0.2°、24.0°±0.2°；
    晶型II：9.3°±0.2°、10.2°±0.2°、14.0°±0.2°、15.9°±0.2°、17.9°±0.2°、20.8°±0.2°、23.0°±0.2°、24.1°±0.2°、24.8°±0.2°、27.7°±0.2°；
    晶型VII：11.0°±0.2°、11.7°±0.2°、13.8°±0.2°、14.3°±0.2°、15.1°±0.2°、15.9°±0.2°、17.9°±0.2°、20.1°±0.2°、21.8°±0.2°、25.6°±0.2°。
  4. 如权利要求1、2或3所述的式(1)所示化合物的晶型，其特征分别在于，
    晶型I其X-射线粉末衍射图谱基本上如图1所示；
    晶型II其X-射线粉末衍射图谱基本上如图3所示；
    晶型VII其X-射线粉末衍射图谱基本上如图10所示。
  5. 如权利要求1-4所述的式(1)所示化合物的晶型，其特征分别在于，
    晶型I其差示扫描量热热分析图在180-220℃范围内吸热；
    晶型II其差示扫描量热热分析图在195-215℃范围内吸热；
    晶型VII其差示扫描量热热分析图在165-205℃范围内吸热。
  6. 如权利要求1-5所述的式(1)所示化合物的晶型I、II、VII的制备方法，其特征分别在于，
    将式(1)所示化合物置于无水乙腈中浆洗或四氢呋喃中搅拌析出固体，过滤得到晶型I；
    将式(1)所示化合物置于低级醇或乙酸乙酯或丙酮或甲醇与水比例为1∶1-9∶1(v/v)混合溶液中浆洗，或者溶于四氢呋喃中置于异丙醇或正庚烷氛围中析出固体后，过滤得到晶型II；
    将式(1)所示化合物置于乙腈与水比例为1∶1-9∶1(v/v)的混合溶液中浆洗、过滤，在真空下干燥得晶型VII。
  7. 一种药物组合物，其特征在于，所述药物组合物含有式(1)所示化合物的晶型I、II、VII或其组合，和药用可接受的载体。
  8. 如权利要求7所述的药物组合物，其中所述的晶型的含量不低于94.5％。
  9. 含有权利要求1-8任一项所述的式(1)所示化合物的晶型I、II、VII或其组合，和一种或多种药用载体和/或稀释剂的药用制剂，为药学上可接受的任一剂型。
  10. 权利要求1-9任一项所述的式(1)所示化合物的晶型在制备治疗和/或预防四环素类药物敏感菌和/或耐药菌引起的疾病的药物中的应用，其所述四环素类药物敏感菌和/或耐药菌引起的疾病选自感染、癌症、糖尿病和已经发现的可以用其他四环素类化合物治疗和/或预防的其他疾病，其中所述晶型选自晶型I、II、VII或其组合。
PCT/CN2017/089470 2016-06-22 2017-06-22 9-氨基甲基取代的四环素类化合物的晶型及其制备方法 WO2017219994A1 (zh)

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MYPI2018002825A MY186900A (en) 2016-06-22 2017-06-22 Crystal forms of a 9-aminomethyl substituted tetracycline compound and preparation method therefor
PH12018502680A PH12018502680A1 (en) 2016-06-22 2018-12-18 Crystal forms of 9-aminomethyl substituted tetracycline compound and preparation method thereof
ZA2019/00274A ZA201900274B (en) 2016-06-22 2019-01-15 Crystal forms of a 9-aminomethyl substituted tetracycline compound and a preparation method thereof
CONC2019/0000513A CO2019000513A2 (es) 2016-06-22 2019-01-18 Formas cristalinas de un compuesto de tetraciclina sustituido con 9-aminometilo y un método de preparación de las mismas

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CN102417465A (zh) * 2011-10-27 2012-04-18 宫宁瑞 替加环素新晶型及其制备方法
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WO2004064728A2 (en) * 2003-01-16 2004-08-05 Paratek Pharmaceuticals, Inc. Use of specific tetracycline compounds in therapy
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SI2220033T1 (sl) * 2007-11-14 2015-07-31 Sandoz Ag Kristalna oblika tigeciklin hidroklorida
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