WO2020078205A1 - 康泰唑胺酯的药物晶体及其制备方法和应用 - Google Patents

康泰唑胺酯的药物晶体及其制备方法和应用 Download PDF

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WO2020078205A1
WO2020078205A1 PCT/CN2019/109063 CN2019109063W WO2020078205A1 WO 2020078205 A1 WO2020078205 A1 WO 2020078205A1 CN 2019109063 W CN2019109063 W CN 2019109063W WO 2020078205 A1 WO2020078205 A1 WO 2020078205A1
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crystal
sodium
crystal compound
compound
ray powder
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PCT/CN2019/109063
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English (en)
French (fr)
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张学亮
王星海
刘进前
高德福•M•F
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上海盟科药业有限公司
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Priority to CA3116783A priority Critical patent/CA3116783A1/en
Priority to KR1020217014195A priority patent/KR20210076065A/ko
Priority to US17/285,889 priority patent/US20220153767A1/en
Priority to JP2021519592A priority patent/JP2022502464A/ja
Priority to EP19872651.5A priority patent/EP3868768B1/en
Publication of WO2020078205A1 publication Critical patent/WO2020078205A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • 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 invention provides a contezolid acefosamil medicinal crystal and a preparation method and application thereof.
  • Oxazolidinone compounds are a new class of synthetic compounds with activity against various pathogenic microorganisms.
  • Linezolid the first drug in this class, has been approved for the treatment of Gram-positive infections.
  • Linezolid has good antibacterial activity, but as noted in the "Warning" section of the linezolid drug prescription, bone marrow suppression and amine oxidase inhibition are the main factors limiting the use of linezolid.
  • Chinese patent publication CN105612166A discloses that conzazodine is a new oxazolidinone compound with excellent safety characteristics and good antibacterial activity.
  • the Chinese patent publication CN105612166A discloses a therapeutic water-soluble (O-carbonyl) phosphoramidate prodrug, which has good water solubility.
  • X-ray powder diffraction analysis is in the range of 0 ⁇ No diffraction peaks are shown between 40 ° 2 ⁇ ( Figure 1), which are all amorphous powders with poor stability and easy to cause decomposition.
  • the present invention provides crystals or crystal compounds of conzazod and its preparation method.
  • the stability of the obtained conzazod is better than that of amorphous powder, and can meet the requirements of clinical use of pharmaceutical preparation .
  • the invention provides a crystal or crystal compound of a compound of formula I, wherein R is selected from hydrogen, sodium, or a compound in any ratio.
  • R is selected from sodium, ONa and O - Na + are equivalent.
  • the crystal or crystal compound provided by the present invention greatly improves the stability of conzazod, and is beneficial to the production and transportation of this drug, and the routine delivery of this drug to patients or mammals in need of treatment for bacterial infections, thereby To ensure the practical application of the safe and effective neooxazolidinone in clinical.
  • the crystal or crystal compound shows at least one diffraction peak at about 5.0-40 ° 2 ⁇ in the X-ray powder diffraction pattern.
  • the crystal or crystal compound shows at least two diffraction peaks in an X-ray powder diffraction pattern at about 20.0-25 ° 2 ⁇ .
  • the crystal or crystal compound shows a diffraction peak at about 20.0 to 21.0 ° 2 ⁇ in the X-ray powder diffraction pattern.
  • the crystal or crystal compound shows a diffraction peak at about 23.0 to 24.0 ° 2 ⁇ in the X-ray powder diffraction pattern.
  • the crystal or crystal compound shows a diffraction peak at about 6.9 °, 14.7 °, 15.5 °, 16.5 °, 20.2 °, 22.9 °, 23.7 ° 2 ⁇ in an X-ray powder diffraction pattern.
  • the melting point of the crystal or crystal compound is 220 ⁇ 10 ° C.
  • the content of sodium in the crystal or crystal compound is 0-6% by weight.
  • the present invention provides a method for preparing any of the above crystals or crystal compounds, including the following steps:
  • the inorganic salt or organic solvent can be added selectively to separate the product phase to remove part or all of the volatile substances.
  • the organic solvent can be added selectively to crystallize to obtain crystals;
  • the organic solvent is preferably selected from at least one of acetonitrile, acetone, methanol, ethanol, propanol, isopropanol, butanol, and tetrahydrofuran.
  • the inorganic salt is selected from sodium chloride, sodium bromide, sodium iodide, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, sodium sulfate, sodium carbonate, At least one of sodium bicarbonate, sodium acetate, and hydrates thereof.
  • the organic solvent is selected from acetonitrile, acetone, methanol, ethanol, propanol, butanol, isopropanol, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran At least one of them.
  • the present invention provides the use of any of the above-mentioned crystals or crystal compounds in the preparation of antibiotic drugs.
  • the present invention also provides a method for treating infection using the above crystal or crystal compound.
  • the invention also provides the application of any of the above preparation methods in preparing antibiotic medicine.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above-mentioned crystals or crystal compounds and a pharmaceutically acceptable carrier.
  • FIG. 1 is an X-ray powder diffraction analysis chart of product form 2 of Example 1.
  • FIG. 1 is an X-ray powder diffraction analysis chart of product form 2 of Example 1.
  • FIG. 2 is an X-ray powder diffraction analysis chart of the product form 3 (crystal) of Example 1.
  • FIG. 3 is an X-ray powder diffraction analysis chart of the product form 1 of Example 1.
  • FIG. 4 is a differential thermal scanning analysis diagram of product form 3 (crystal) of Example 1.
  • FIG. 4 is a differential thermal scanning analysis diagram of product form 3 (crystal) of Example 1.
  • Fig. 5 is a differential thermal scanning analysis diagram of a product obtained by re-dissolving crystals in water lyophilization.
  • the term "about” when used in reference to the peak position of an X-ray powder diffraction pattern refers to the inherent variability of the peak, which depends on, for example, the calibration of the equipment used, the method used to produce the polymorph, the life of the crystalline material, etc. Depends on the instrument used. In this case, the measurement variability of the instrument is about ⁇ 0.2 ° 2 ⁇ . Those skilled in the art can understand the use of "about” in this case.
  • mamal refers to all mammals, including humans, domestic animals, and pets.
  • Treatment includes: (1) prevention of the disease, for example, preventing the development of clinical symptoms of the disease in mammals that may be exposed or predisposed to the disease but have not experienced or shown symptoms of the disease, (2) inhibiting the disease For example, to prevent or reduce the development of the disease or its clinical symptoms, or (3) to alleviate the disease, for example, to degenerate the disease or its clinical symptoms.
  • “Therapeutically effective amount” means that when administered to a mammal for the treatment of a disease, the dose of the compound is sufficient to effect such treatment of the disease.
  • the “therapeutically effective amount” may vary with the compound, disease and severity, and the age, weight, etc. of the mammal being treated.
  • crystal compound refers to a mixture of pharmaceutically acceptable crystals containing certain crystals.
  • the crystal content can account for 50-90% in products including amorphous, moisture, and solvated organic solvents.
  • composite refers to a mixture or co-crystal.
  • solvate of a compound means that the compound contains a certain pharmaceutically acceptable solvent, whether it is chemically bonded, such as a crystalline solvate, or remains, or as an additive, such as in a wetted or lubricated solid.
  • solvent refers to dispersing a solid into a liquid with or without stirring until a liquid is obtained, which may be a single phase, a layered multi-phase solution, or an imperfectly transparent turbid solution or suspension.
  • Volatile substances refers to substances with a low boiling point, especially organic solvents and water, such as acetonitrile, acetone, ethanol, isopropanol, ethyl acetate, hexane, cyclohexane, petroleum ether, methyl ethyl ketone, Or a mixture of them.
  • salt of a compound refers to a pharmaceutically acceptable salt having the desired pharmacological activity of the parent compound.
  • Such salts include salts formed under the following conditions: when the acid protons in the parent compound are replaced by metal ions, the metal ions are, for example, alkali metal ions, alkaline earth metal ions, zinc, or aluminum ions; or the acid protons in the parent compound are Organic base coordination, such as glutamic acid, lysine, ethanolamine, diethanolamine, triethanolamine, trimethanolamine, N-methylglucamine, etc.
  • R is selected from hydrogen, sodium, or a mixture in any ratio.
  • R is selected from sodium, ONa and O - Na + are equivalent.
  • the content of sodium in the crystal or crystal compound is 1-10% by weight, more preferably 3.2-6% by weight. This can improve the crystallinity of the compound.
  • the crystal or crystal compound of the present disclosure shows a plurality of sharp diffraction peaks between 0 and 40 ° 2 ⁇ in X-ray powder diffraction analysis (XRPD) (FIG. 2).
  • the crystal or crystal compound exhibits at least one X-ray powder diffraction peak at about 5.0-40 ° 2 ⁇ .
  • the crystal or crystal compound exhibits at least two diffraction peaks at about 20.0-25 ° 2 ⁇ .
  • the crystal or crystal compound exhibits a sharp X-ray powder diffraction peak at about 6.0-8.0 ° 2 ⁇ .
  • the crystal or crystal compound exhibits an X-ray powder diffraction peak at about 20.0 to 21.0 ° 2 ⁇ .
  • the crystal or crystal compound exhibits an X-ray powder diffraction peak at about 23.0-24.0 ° 2 ⁇ .
  • the crystal or crystal compound of the present disclosure greatly enhances the stability of conzazod, for example, it can be substantially free of decomposition at room temperature for 24 hours.
  • the increased stability of the sample also confirmed the formation of the crystal or crystal compound.
  • the melting point of the crystal or crystal compound is between 220 ⁇ 10 ° C.
  • the crystal or crystal compound of the present disclosure may contain one crystal form, or may contain multiple crystal forms.
  • the crystal or crystal compound of the present disclosure may contain one or more crystal forms or a mixture thereof.
  • the preparation method of the above crystal or crystal compound is also disclosed here.
  • the compound of formula I (crude contazolomide of formula I) is dissolved in a mixed solution of an organic solvent and water; an inorganic salt is added, and then the product phase is separated) to remove some or all of the volatility Substance, adding organic solvent, crystallization to obtain crystals.
  • the crude product of conazole oxalate of formula I can be prepared by the method disclosed in CN105612166A.
  • the ratio of organic solvent to water is preferably 1: 9 to 4: 6.
  • the organic solvent may be selected from acetonitrile, acetone, methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, isopropyl acetate, n-heptane, hexane, cyclohexane, petroleum At least one of ether, methyl ethyl ketone, and tetrahydrofuran.
  • the organic solvent may be at least one selected from acetonitrile, ethanol, butanol, isopropanol, acetone, methyl ethyl ketone, and tetrahydrofuran.
  • the method of dissolving the compound of formula I in a mixed solution of an organic solvent and water may be stirring and dissolving.
  • an inorganic salt is also added to the mixed solution of organic solvent and water.
  • the inorganic salt may be, for example, sodium chloride, sodium bromide, sodium iodide, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, sodium sulfate, sodium carbonate, sodium bicarbonate, sodium acetate and the like At least one of hydrates.
  • the concentration of the crystallization solution, the rate and temperature at which the crystals precipitate out can be controlled.
  • the volatile materials such as organic solvents and water are removed from the product phase.
  • the removal method is, for example, azeotrope, vacuum distillation and the like.
  • a second organic solvent is added to the product phase to perform crystallization.
  • the second organic solvent may be at least one selected from acetonitrile, acetone, methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, and tetrahydrofuran.
  • the added amount of the second organic solvent may be 2-50 times the weight of the substrate.
  • the product phase is cooled to about -30 ° C to about 20 ° C to precipitate crystals.
  • the product can be isolated to obtain crystals or crystal compounds. Further, the obtained crystal or crystal compound may be dried.
  • the crystals are physically separated or filtered.
  • the separated crystals are vacuum dried to obtain crystals or crystal compounds.
  • the temperature during vacuum drying may be about 15 ° C to about 80 ° C, preferably about 20 ° C to about 50 ° C.
  • a method of providing the above crystal or crystal compound for use in treating a mammalian microbial infection or bacterial infection includes administering to the mammal a therapeutically effective amount of the crystal or crystal compound.
  • the crystal or crystal compound may be administered orally, parenterally, percutaneously, topically, rectally or intranasally to a mammal in the form of a pharmaceutical composition.
  • the microorganism infects a Gram-positive microorganism.
  • the crystal or crystal compound of the present invention is a useful antimicrobial drug and may be effective against many human and animal pathogenic bacteria, including Gram-positive aerobic bacteria such as multi-resistant Staphylococcus aureus, enterococci, streptococcus And anaerobic microorganisms such as Bacteroides and Clostridia, and acid-fast microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium.
  • Gram-positive aerobic bacteria such as multi-resistant Staphylococcus aureus, enterococci, streptococcus And anaerobic microorganisms such as Bacteroides and Clostridia
  • acid-fast microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium.
  • the crystal or crystal compound provided by the present disclosure can be conveniently added to the pharmaceutical composition in a conventional manner.
  • the pharmaceutical composition or medicament may further comprise a pharmaceutically acceptable diluent, excipient, disintegrant, lubricant or carrier.
  • a pharmaceutically acceptable carrier may be solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Illustrative examples of pharmaceutically acceptable formulations and methods for preparing some pharmaceutical compositions are found in, for example, "The Science and Practice” (The Science and Practice) of Pharmacy, edited by A. Gennaro, Lippincott Williams & Wilkins, Baltimore, Maryland (Baltimore, Md. ., 2000).
  • the crystal or crystal compound can be made into various pharmaceutically acceptable compositions such as water, D5W injection solution, or other tablets, and used in the treatment or prevention of various infections.
  • X-ray powder diffraction analysis XPERT-3 X-ray diffractometer of Panalytical (Panalytical) was used. Approximately 10 mg of the sample was evenly spread on the single crystal silicon sample tray, and the XRPD test was performed with the following described parameters:
  • TA2000Q2000 differential scanning calorimeter is used for DSC analysis with the following description parameters:
  • Example 1 Product Form 1: The crude product of Example 1 was stirred in 5% EtOH / DCM (1000 ml), filtered, and the mother liquor was concentrated under reduced pressure. The residue was beaten with ethyl acetate: methyl tert-butyl ether (3: 1,300 ml). Filter, wash (residue ethyl acetate: methyl tert-butyl ether), and dry in vacuo to give a yellow solid as product form 1. MS: 531 [M + H]. Product X-ray powder diffraction analysis is shown in Figure 3.
  • Example 1 Product form 2: The crude product of Example 1 was dissolved in water and purified by reverse-phase HPLC (C18) gradient. The mobile phases are water and acetonitrile. The fraction containing Example 1 was collected. Freeze-drying to obtain a white solid as product form 2. MS: 531 [M + H]. Product X-ray powder diffraction analysis is shown in Figure 1.
  • the crystal or crystal compound of the product of Example 1 (product form 3): 146 g of the crude product of Example 1 was dissolved in 582 mL of water and 169 mL of acetonitrile at room temperature, dissolved by stirring, and 349 g of sodium dihydrogen phosphate dihydrate was added, dissolved after stirring The product phase was taken out, concentrated under reduced pressure until there was no obvious fraction, then added 550 mL of acetone to dissolve, cooled and crystallized with stirring. Filtration and vacuum drying gave a white solid with a sodium content of 4.3%.
  • the product X-ray powder diffraction analysis is shown in Figure 2, and the DSC analysis result is shown in Figure 4.
  • the X-ray powder diffraction data of the product obtained by the preparation method provided by the present invention are shown in Table 1 and the diffraction analysis chart is shown in FIG. 2.
  • the stability of the crystal of the present invention was determined by HPLC method.
  • One is the product obtained by HPLC purification and lyophilization (Example 1 product form 2); the other is the product obtained by the method for preparing the crystal form provided by the present invention (Example 1 product form 3).
  • the results are shown in Table 2.
  • DSC differential thermal scanning
  • the product Compared with the differential thermal scanning analysis diagram of the crystal in Fig. 4, the product obviously has the characteristics of a narrow melting range containing a single crystal or a crystal compound whose crystal is the main component.
  • the method for preparing the crystal form of the present invention is unique, and can be achieved by non-traditional crystallization operations (solvent heating and dissolution, cooling crystallization).
  • solvent heating and dissolution, cooling crystallization For example, acetonitrile, one of the solvents used for extraction in some embodiments, is not used in general extraction operations.
  • the crystal or crystal compound of the oxazolidinone compound of the present invention exhibits effective in vivo activity against various microorganisms, including Gram-positive microorganisms.
  • the pathogenic Staphylococcus aureus strain SAU1018 was used, which was given to the infected animals by intravenous injection of a saline solution containing these crystals suitable for clinical or therapeutic use, showing a high activity in vivo
  • the ED 50 (effective dose for 50% animal survival in the test) value is 10 mg / kg.
  • the crystal or crystal compound of the present invention can also be administered in a convenient oral manner.
  • the compound When administered orally to animals of the mouse model infected with Staphylococcus aureus as described above, the compound showed high antibacterial efficacy, with an ED 50 value of about 8 mg / kg.
  • the crystal of the present invention or the crystal comprising the present invention and its composition possess useful antibacterial properties. Therefore, the crystals of the present invention are useful antimicrobial drugs and may be effective against many human and animal pathogenic bacteria, including Gram-positive aerobic bacteria such as multi-resistant Staphylococcus aureus, enterococci, streptococci, and anaerobic microorganisms For example, Bacteroides and Clostridium, and acid-fast microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium. These pharmaceutical compositions can be administered by various routes such as intravenous injection, oral administration, parenteral administration, transdermal administration, local administration, rectal administration, and intranasal administration.

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Abstract

本发明提供康泰唑胺酯的药物晶体及其制备方法和应用。一种式I化合物的晶体或晶体合物，其中，R选自氢、钠或其任意比例的合物，

Description

康泰唑胺酯的药物晶体及其制备方法和应用 技术领域
本发明提供一种康泰唑胺酯(contezolid acefosamil)的药物晶体及其制备方法和应用。
背景技术
噁唑烷酮类化合物是一类新的具有抗多种致病微生物活性的合成化合物。该类首个药物利奈唑胺(Linezolid)已经被批准应用于治疗革兰氏阳性感染菌的药物。利奈唑胺具有良好的抗菌活性、但是就如利奈唑胺药物处方说明书中“警示”部分注明的一样，骨髓抑制和胺氧化酶抑制是限制利奈唑胺应用的主要因素。中国专利公布文本CN105612166A公开了康泰唑胺酯是一种具有优异的安全特征，并有很好抗菌活性的新噁唑烷酮类化合物。
除了所需的抗菌活性和安全性外，有效的抗菌药物必须具备适合于实际应用的溶解度和稳定性。中国专利公布文本CN105612166A公开了一种治疗用水溶性(O-羰基)氨基磷酸酯前药，该类化合物具有良好的水溶性。然而，按此公布文本提供的康泰唑胺酯的制备方法，无论是实验室传统操作处理例如萃取，减压去溶剂，或者HPLC纯化冻干所得到的产物，X-射线粉末衍射分析在0～40°2θ之间未显示任何衍射峰(图1)，都为无定形粉末，稳定性差，易导致分解。
发明内容
针对上述问题，本发明提供康泰唑胺酯的晶体或晶体合物及其制备方法，得到的康泰唑胺酯晶体的稳定性相比无定形粉末有显著的提高，可以满足药物制剂临床使用的要求。
一方面，本发明提供式I化合物的晶体或晶体合物，其中，R选自氢、钠或其任意比例的合物。当R选自钠时，ONa和O -Na +是等同的。
Figure PCTCN2019109063-appb-000001
本发明提供的晶体或晶体合物极大地提高了康泰唑胺酯的稳定性，有利于这种药物的生产、运输，和将这种药物常规输送给需要治疗细菌感染的患者或哺乳动物，从而确保了该安全有效新噁唑烷酮在临床中的实际应用。
优选地，所述晶体或晶体合物在X射线粉末衍射图谱中在约5.0～40°2θ显示至少一个衍射峰。
优选地，所述晶体或晶体合物在X射线粉末衍射图谱中在约20.0～25°2θ显示至少两个衍射峰。
优选地，所述晶体或晶体合物在X射线粉末衍射图谱中在约20.0～21.0°2θ显示衍射峰。
优选地，所述晶体或晶体合物在X射线粉末衍射图谱中在约23.0～24.0°2θ显示衍射峰。
优选地，所述晶体或晶体合物在X射线粉末衍射图谱中在约6.9°、14.7°、15.5°、16.5°、20.2°、22.9°、23.7°2θ显示衍射峰。
优选地，所述晶体或晶体合物的熔点在220±10℃。
优选地，以重量计，所述晶体或晶体合物中钠的含量在0-6％。
第二方面，本发明提供制备上述任一晶体或晶体合物的方法，包括如下步骤：
(1)制备有式I的化合物的粗品；
(2)将有式I的化合物的粗品溶解于有机溶剂和水的混合溶液；
(3)可选择性地加入无机盐或有机溶剂，分出产物相，去除部分或全部挥发性物质，可选择性地加入有机溶剂，结晶得到晶体；
(4)分离出有式I的化合物的晶体。
优选地，步骤(2)中，所述有机溶剂，优选自乙腈、丙酮、甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃中的至少一种。
优选地，步骤(3)中，所述无机盐选自氯化钠、溴化钠、碘化钠、柠檬酸钠、磷酸二氢钠、磷酸氢二钠、磷酸钠、硫酸钠、碳酸钠、碳酸氢钠、醋酸钠及其水合物中的至少一种。
优选地，步骤(3)中，所述有机溶剂选自乙腈、丙酮、甲醇、乙醇、丙醇、丁醇、异丙醇、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚、四氢呋喃中的至少一种。
第三方面，本发明提供上述任一晶体或晶体合物在制备抗生素药物中的应用。
本发明还提供利用上述晶体或晶体合物治疗感染的方法。
本发明还提供上述任一制备方法在制备抗生素药物中的应用。
第四方面，本发明提供一种药物组合物，其含有上述任一晶体或晶体合物和药学上可接受的载体。
附图说明
图1是实施例1产品形态2的X-射线粉末衍射分析图。
图2是实施例1产品形态3(晶体)的X-射线粉末衍射分析图。
图3是实施例1产品形态1的X-射线粉末衍射分析图。
图4是实施例1产品形态3(晶体)的差热扫描分析图。
图5是晶体重新溶解于水冻干所得到的产物的差热扫描分析图。
具体实施方式
以下结合附图和下述实施方式进一步说明本发明，应理解，附图和下述实施方式仅用于说明本发明，而非限制本发明。
术语
术语“约”在涉及X射线粉末衍射图峰位置使用时是指峰的固有变异性，其取决于(例如)所用设备的校准、用于产生多晶型物的方法、结晶材料的寿命等，取决于所用仪器。在此情形中，仪器的测量变异性为约±0.2°2θ。本领域技术人员可理解“约”在此情况中的使用。
术语“哺乳动物”指所有的哺乳动物，包括人、家畜以及宠物。
疾病的“处理”或“治疗”包括：(1)预防疾病，例如，在可能暴露或预先处置于疾病但尚未经历或显示疾病症状的哺乳动物中使疾病临床症状不发展，(2)抑制疾病，例如，阻止或降低疾病或其临床症状的发展，或者(3)缓解疾病，例如，使疾病或其临床症状退化。
“治疗有效量”表示当给予哺乳动物用于治疗疾病时，化合物的该剂量足以实施对疾病的这种治疗。“治疗有效量”可以随化合物、疾病和严重性、以及进行治疗的哺乳动物的年龄、体重等变化。
术语“晶体合物”指含有一定晶体的药学上可接受的晶体混合物。晶体含量在包括不定型物、水分、和溶剂化有机溶剂的产品中可占50～90％。
术语“合物”指混合物或共结晶物。
术语化合物的“溶剂化物”指所述化合物含有一定的药学上可接受的溶剂，无论是化学键合的如晶体溶剂化物，还是残留的，或作为添加物，如在润湿或润滑的固体中。
术语“溶解”指用搅拌或不用搅拌将固体分散到液体中至得到液体，可能是一相，也可能是分层的多相溶液，也可能是不完全透明的混浊溶液或悬浮液。
“挥发性物质”指沸点低的物质，特别是指有机溶剂和水，像乙腈、丙酮、乙醇、异 丙醇，乙酸乙酯、己烷、环己烷、石油醚、甲基乙基酮、或它们的混合物。
术语化合物的“盐”指药学上可接受的、具有母化合物的所需药理学活性的盐。这类盐包括在以下条件下形成的盐：当母化合物中的酸质子被金属离子取代时，金属离子例如是碱金属离子、碱土金属离子、锌或者铝离子；或者母化合物中的酸质子与有机碱配位，例如谷氨酸、赖氨酸、乙醇胺、二乙醇胺、三乙醇胺、三甲醇氨基甲烷、N-甲基葡糖胺等。
本文揭示的化合物一般按照IUPAC或CAS命名体系命名。
晶体或晶体合物
由于康泰唑胺酯结构中N-磷酰和O-乙酰基磷酸的特殊性，康泰唑胺酯作为前药在一些条件下不稳定，传统加热溶解，冷却结晶的方法经常导致分解。在此公开一种康泰唑胺酯(式I)的新颖晶体或晶体合物。该晶体室温下稳定，且晶体性质明显。
式I中，R选自氢、钠、或其任意比例的混合物。当R选自钠时，ONa和O -Na +是等同的。
在一些实施方式中，晶体或晶体合物是R＝氢的式I和R＝钠的式I的0～50％任意比例的混合物。
在一些实施方式中，R＝氢的式I化合物的含量小于5％(重量计)。这样可以提高化合物的结晶性。
在一些实施方式中，晶体或晶体合物中钠的含量在1-10％(重量计)，更优选为3.2-6％(重量计)。这样可以提高化合物的结晶性。
本公开的晶体或晶体合物在X-射线粉末衍射分析(XRPD)中在0～40°2θ之间显示多个尖锐的衍射峰(图2)。
在一些实施方式中，晶体或晶体合物在约5.0～40°2θ显示至少一个X-射线粉末衍射峰。
在一些实施方式中，晶体或晶体合物在约20.0～25°2θ显示至少两个衍射峰。
在一些实施方式中，晶体或晶体合物在约6.0～8.0°2θ显示一个尖锐的X-射线粉末衍射峰。
在一些实施方式中，晶体或晶体合物在约20.0～21.0°2θ显示出X-射线粉末衍射峰。
在一些实施方式中，晶体或晶体合物在约23.0～24.0°2θ显示出X-射线粉末衍射峰。
本公开的晶体或晶体合物极大地提升了康泰唑胺酯的稳定性，例如能使其室温下在24小时基本无分解。样品稳定性的提高也证实了该晶体或晶体合物的形成。
在一些实施方式中，晶体或晶体合物的熔点范围在220±10℃之间。
本公开的晶体或晶体合物可含有一种晶型，也可含有多种晶型。
本公开的晶体或晶体合物可含有一种或多种晶型或其混合物。
制备
在此还公开上述晶体或晶体合物的制备方法。在一些实施方式中，将有式I的化合物(式I的康泰唑胺酯的粗品)溶解于有机溶剂和水的混合溶液；加入无机盐，然后分离出产物相)，去除部分或全部挥发性物质，加入有机溶剂，结晶得到晶体。式I的康泰唑胺酯的粗品可以通过CN105612166A公开的方法制备。
有机溶剂和水的比例体积比，优选为1：9～4：6。
在一些实施方式中，有机溶剂可选自乙腈、丙酮、甲醇、乙醇、丙醇、异丙醇，丁醇、乙酸乙酯、乙酸异丙酯、正庚烷、己烷、环己烷、石油醚、甲基乙基酮、四氢呋喃中的至少一种。
在更优选的实施方式中，有机溶剂可选自乙腈、乙醇、丁醇、异丙醇、丙酮、甲基乙基酮、四氢呋喃中的至少一种。
将有式I的化合物溶解于有机溶剂和水的混合溶液的方式可为搅拌溶解。
可选地，在有机溶剂和水的混合溶液中，还加入无机盐。所述无机盐例如可为氯化钠、溴化钠、碘化钠、柠檬酸钠、磷酸二氢钠、磷酸氢二钠、磷酸钠、硫酸钠、碳酸钠、碳酸氢钠、醋酸钠及其水合物中的至少一种。
在结晶过程中，可以控制结晶溶液的浓度，结晶析出的速度和温度。
可选地，去除产物相中的部分或者全部挥发性物质如有机溶剂和水。去除方式例如为共沸、减压蒸馏等。
可选地，在产物相中加入第二有机溶剂，进行结晶。第二有机溶剂可选自乙腈、丙酮、甲醇、乙醇、丙醇、异丙醇、丁醇、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚、四氢呋喃中的至少一种。第二有机溶剂的加入量可为底物重量的2～50倍。
可选地，将产物相冷却到约-30℃至约20℃以析出结晶。
结晶后，可分离出产物，得到晶体或晶体合物。进一步地，可对得到的晶体或晶体合物进行干燥。
在一些实施方式中，对结晶进行物理分离或过滤。
在一些实施方式中，对分离出的结晶进行真空干燥得到晶体或晶体合物。真空干燥时的温度可为约15℃至约80℃，优选为约20℃至约50℃。
在一些实施方式中，提供上述晶体或晶体合物用于治疗哺乳动物微生物感染或细菌感 染的方法，包括对所述哺乳动物施用治疗有效量的晶体或晶体合物。所述晶体或晶体合物可以药物组合物形式通过口服，肠胃外，经皮，局部，直肠或鼻内施用于哺乳动物。在一些或任意实施方式中，所述方法中，所述微生物感染革兰氏阳性微生物。因此，本发明的晶体或晶体合物是有用的抗微生物药物，并且可能对许多人体和动物病原菌有效，包括革兰氏阳性需氧菌例如多重耐药金黄色葡萄球菌，肠球菌，链球菌，以及厌氧微生物例如拟杆菌和梭状芽胞杆菌，和抗酸微生物例如结核分枝杆菌和鸟型结核分支杆菌。
本公开提供的晶体或晶体合物可采用常规方式方便地加入药物组合物中。所述药物组合物或药剂可以进一步包含药学上可接受的稀释剂、赋形剂、崩解剂、润滑剂或载体。
制备含有本公开的晶体或晶体合物的药物组合物，药学上可接受的载体可以是固体或液体。固体形式的制剂包括粉剂、片剂、可分散的细粒、胶囊剂、扁胶囊和栓剂。片剂、粉剂、扁胶囊和胶囊可以用作适合于口服给药的固体剂型。药学上可接受的制剂和一些药物组合物的制备方法的说明性示例在例如《药学科学与实践》(The Science and Practice of Pharmacy),A.Gennaro编著,Lippincott Williams&Wilkins,马里兰州巴尔的摩(Baltimore,Md.,2000)中有描述。
在一些实施方式中，晶体或晶体合物可以制成各种例如水、D5W注射溶液或其他的片剂等药学上可接受的组合物，应用于治疗或预防各种感染。
下面进一步例举实施例以详细说明本发明。同样应理解，以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。下述示例具体的工艺参数等也仅是合适范围中的一个示例，即本领域技术人员可以通过本文的说明做合适的范围内选择，而并非要限定于下文示例的具体数值。
以下实施例中的测试方法如下：
X射线粉末衍射分析：采用Panalytical(帕纳科)公司的XPERT-3型X射线衍射仪。将约10mg样品均匀平铺在单晶硅样品盘上，用以下描述参数进行XRPD测试：
Figure PCTCN2019109063-appb-000002
DSC分析：采用TA Q2000差示扫描量热仪，用以下描述参数进行DSC分析：
样品盘 铝盘，压盖
温度范围/℃ 25-350℃
扫描速率 10
保护气体 氮气
。
实施例1
合成路线：
Figure PCTCN2019109063-appb-000003
实施例1的化合物：在氮气保护下，在0-10℃将三甲基碘硅烷(14.4g)滴加到中间体1(10.5g，根据CN105612166A中间体2的方法制备)的DCM(105mL)溶液中，室温搅拌2小时。反应液减压浓缩，残留物用甲基叔丁基醚漂洗(100ml)，过滤，真空干燥。所得产物重新溶解在DMSO/MeCN(10.5ml/105ml)中，加入NaOAc(36.7g)和Ac 2O(5.9g)，搅拌1小时。加入MTBE(700ml)，搅拌，过滤，真空干燥，得到实施例1的化合物粗品。
实施例1产品形态1：实施例1的粗品在5％EtOH/DCM(1000ml)中搅拌，过滤，母液减压浓缩。残留物用乙酸乙酯：甲基叔丁基醚(3:1,300ml)打浆。过滤，洗涤(残留物用乙酸乙酯：甲基叔丁基醚)，真空干燥，得黄色固体，作为产品形态1。MS:531[M+H]。产品X-射线粉末衍射分析如图3。
实施例1产品形态2：实施例1的粗品溶解于水，用反相HPLC(C18)梯度纯化。流动相是水和乙腈。收集包含实施例1的馏分。冷冻干燥，得白色固体，作为产品形态2。MS:531[M+H]。产品X-射线粉末衍射分析如图1。
实施例1产品的晶体或晶体合物(产品形态3)：实施例1的粗品146g在室温下溶解于582mL水和169mL乙腈，搅拌溶解，加入磷酸二氢钠二水合物349g，搅拌溶解后分出产物相，减压浓缩至无明显馏分，然后加入550mL丙酮溶解，冷却，搅拌析晶。过滤，真空干燥，得白色固体，钠含量为4.3％。产品X-射线粉末衍射分析如图2，DSC分析结果如图4。
测试和应用
在contezolid acefosamil(康泰唑胺酯)的早期开发研究中，实验室传统操作处理例如 萃取，减压去溶剂所得的产物，室温储藏不稳定。即使是HPLC纯化冻干所得到的产物稳定性亦不足，X-射线粉末衍射显示为无衍射峰。惊奇的是，本发明发现的制备方法所得到的产物，X-射线粉末衍射分析在0-40°2θ之间显示很多尖锐的衍射峰，并且差热扫描(DSC)分析结果也表明狭窄熔解范围，特征为晶体，尤为重要的是，所得的晶体产物具有比无定形粉末更好的稳定。详细数据如下。
本发明提供的制备方法所得到的产物X射线粉末衍射数据见表1和衍射分析图见图2。
表1本发明的晶体X射线粉末衍射主要峰列表
角度(2θ°) 相对强度(％)
6.9 100
14.7 29.5
15.5 29.3
16.5 31.2
20.2 50.8
22.9 42.1
23.7 54.4
。
从表1和图2可以看出该产物有明显的多个尖锐峰。说明产物有明显的晶面反射X-射线的晶体特性。是一种之前实验室传统操作溶剂重结晶，或者HPLC纯化冻干所无法得到的新晶体。
本发明晶体的稳定性：用HPLC方法测定了两种样品在室温条件下九个月内的纯度变化(稳定性)。一种是HPLC纯化冻干所得到的产物(实施例1产品形态2)；另一种是本发明提供的制备该晶型的方法所得到的产物(实施例1产品形态3)。结果见表2。
表2产物的九个月内的稳定性(HPLC纯度，％)
Figure PCTCN2019109063-appb-000004
从表2可以看出两种产物都慢慢分解，在室温下，产品形态3(晶体)明显较产品形态2(无定形粉末)更稳定，并在九个月时更显著(95.81％和83.21％)。样品稳定性的大幅增加也证实了该晶体或晶体合物的存在。
另一方面，差热扫描(DSC)分析结果也佐证了晶体的存在。图5是晶体(实施例1产品形态3)重新溶解于水冻干所得到产物的差热扫描分析图。
与图4晶体的差热扫描分析图相比，该产物明显具有狭窄熔解范围的含有单一晶体或晶体占主要成分的晶体合物的特征。
本发明的制备该晶型的方法独特，非传统析晶操作(溶剂加热溶解，冷却结晶)能达到。例如，一些实施方式中所采用的用于萃取的溶剂之一乙腈是一般萃取操作所不采用的。
本发明的噁唑烷酮类化合物的晶体或晶体合物显示了对多种微生物有效的体内活性，包括革兰氏阳性微生物。为测定本发明晶体或晶体合物有效的治疗活性，遵循Marra等在Current Protocols in Pharmacology(2005),13A.4.1-13A.4.13中描述的通用程序使用了一种在小鼠腹膜炎感染模型中的测试方法。
在这个感染模型中使用了病原性的金黄色葡萄球菌株SAU1018，通过静脉注射适合临床或治疗用的含有这些晶体的食盐水溶液给予感染动物，显示了很高的体内活性，晶体或晶体合物的ED 50(试验中50％动物存活的有效剂量)值为10mg/kg。
本发明的晶体或晶体合物也能采用方便的口服方式给药。通过口服的方式给予以上所述感染了金黄色葡萄球菌的小鼠模型的动物时，该化合物显示了很高的抗菌功效，其ED 50值为约8mg/kg。
据此，本发明的晶体或包含有本发明的晶体及其组合物拥有有用的抗菌性质。因此，本发明的晶体是有用的抗微生物药物，并且可能对许多人体和动物病原菌有效，包括革兰氏阳性需氧菌例如多重耐药金黄色葡萄球菌，肠球菌，链球菌，以及厌氧微生物例如拟杆菌和梭状芽胞杆菌，和抗酸微生物例如结核分枝杆菌和鸟型结核分支杆菌。这些药物组合物可以通过静脉注射、口服、非肠道给药、透皮给药、局部给药、直肠给药和鼻内给药等多种不同途径给药。
以上描述的各个方面是对本发明的简要陈述，本领域具有常规技能的人员在阅读了前述的说明书后，能够对在此提出的发明进行改变，等价取代和其他类型的改变。但本发明不会限于在此描述的陈述和实例。本发明的晶体或晶体合物及其制备方法许多修改和变化可以不脱离它的精神和范围而实现，对本领域的技术人员也是显而易见的。在本发明范围内功能上相当的方法，除了在此列举的以外，基于前面的描述，对本领域的技术人员也是显而易见的。可以理解本发明不会限于特定的方法，溶剂，盐，操作顺序，工艺条件等当然可以变化的因素。同样可以理解此处使用的术语是仅为了描述特定的方面，并不作为限制条件。因此，说明书应该被看作是示例性的。

Claims (14)

  1. 一种式I化合物的晶体或晶体合物，其中，R选自氢、钠或其任意比例的合物，
    Figure PCTCN2019109063-appb-100001
  2. 根据权利要求1所述的晶体或晶体合物，其特征在于，所述晶体或晶体合物在X射线粉末衍射图谱中在约5.0～40°2θ显示至少一个衍射峰。
  3. 根据权利要求1或2所述的晶体或晶体合物，其特征在于，所述晶体或晶体合物在X射线粉末衍射图谱中在约20.0～25°2θ显示至少两个衍射峰。
  4. 根据权利要求1至3中任一项所述的晶体或晶体合物，其特征在于，所述晶体或晶体合物在X射线粉末衍射图谱中在约20.0～21.0°2θ显示衍射峰。
  5. 根据权利要求1至4中任一项所述的晶体或晶体合物，其特征在于，所述晶体或晶体合物在X射线粉末衍射图谱中在约23.0～24.0°2θ显示衍射峰。
  6. 根据权利要求1至5中任一项所述的晶体或晶体合物，其特征在于，所述晶体或晶体合物在X射线粉末衍射图谱中在约6.9°、14.7°、15.5°、16.5°、20.2°、22.9°、23.7°2θ显示衍射峰。
  7. 根据权利要求1至6中任一项所述的晶体或晶体合物，其特征在于，所述晶体或晶体合物的熔点在220±10℃。
  8. 根据权利要求1至7中任一项所述的晶体或晶体合物，其特征在于，以重量计，所述晶体或晶体合物中钠的含量在0～6％。
  9. 一种制备如权利要求1至8中任一项所述的晶体或晶体合物的方法，其特征在于，包括如下步骤：
    (1)制备有式I的化合物的粗品；
    (2)将有式I的化合物的粗品溶解于有机溶剂和水的混合溶液；
    (3)加入无机盐或有机溶剂，分出产物相，去除部分或全部挥发性物质，加入有机溶剂，结晶得到晶体；
    (4)分离出有式I的化合物的晶体。
  10. 根据权利要求9所述的方法，其特征在于，步骤(2)中，所述有机溶剂选自乙腈、丙酮、甲醇、乙醇、丙醇、异丙醇、丁醇、四氢呋喃中的至少一种。
  11. 根据权利要求9或10所述的方法，其特征在于，步骤(3)中，所述无机盐选自氯化 钠、溴化钠、碘化钠、柠檬酸钠、磷酸二氢钠、磷酸氢二钠、磷酸钠、硫酸钠、碳酸钠、碳酸氢钠、醋酸钠及其水合物中的至少一种。
  12. 根据权利要求9至11中任一项所述的方法，其特征在于，步骤(3)中，所述有机溶剂选自乙腈、丙酮、甲醇、乙醇、丙醇、异丙醇、丁醇、乙酸乙酯、乙酸异丙酯、甲基叔丁基醚、四氢呋喃中的至少一种。
  13. 一种如权利要求1至8中任一项所述的晶体或晶体合物在制备抗生素药物中的应用。
  14. 一种药物组合物，含有权利要求1至8中任一项所述的晶体或晶体合物和药学上可接受的载体。
PCT/CN2019/109063 2018-10-15 2019-09-29 康泰唑胺酯的药物晶体及其制备方法和应用 WO2020078205A1 (zh)

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