WO2022042641A1 - Entecavir medicinal salt, preparation method therefor, pharmaceutical composition thereof, and application thereof - Google Patents

Entecavir medicinal salt, preparation method therefor, pharmaceutical composition thereof, and application thereof Download PDF

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WO2022042641A1
WO2022042641A1 PCT/CN2021/114753 CN2021114753W WO2022042641A1 WO 2022042641 A1 WO2022042641 A1 WO 2022042641A1 CN 2021114753 W CN2021114753 W CN 2021114753W WO 2022042641 A1 WO2022042641 A1 WO 2022042641A1
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entecavir
acid
salt
organic
pharmaceutically acceptable
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PCT/CN2021/114753
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French (fr)
Chinese (zh)
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应述欢
陈志祥
刘璐
张贤
朱涛
王婷婷
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上海博志研新药物技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to a pharmaceutical salt of entecavir and its preparation method, pharmaceutical composition and application.
  • Entecavir is a 2'-pentacyclodeoxyguanosine analog with the chemical name 2-amino-9-[(1S,3S,4S)-4-hydroxy-3-hydroxymethyl -2-Methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one, the molecular formula is C 12 H 15 N 5 O 3 , the molecular weight is 277.3, and the structural formula is shown below.
  • Entecavir is a deoxyguanosine analog that can effectively inhibit the replication of hepatitis B virus, and has a strong anti-hepatitis B (HBV) effect.
  • HBV anti-hepatitis B
  • very low concentrations of entecavir can inhibit the replication of hepatitis B virus, and its cytotoxicity is very low, has a very good selective therapeutic index.
  • Patent document CN1566118A discloses entecavir base salts, such as entecavir ammonium salt, calcium salt, sodium salt and preparation method thereof.
  • its alkali salt is not an addition salt formed by an organic acid and a base, but after the enolization of entecavir, the hydroxyl group in the enol has a weak acidity and can react with a strong base such as sodium hydroxide or potassium hydroxide to form An enolate in which the guanosine moiety of entecavir has been substantially altered.
  • the enolate is easily dissociated into entecavir molecules in solution, and may be more easily oxidized and degraded than entecavir itself.
  • Patent document CN101003536A discloses various acid addition salts and base addition salts of entecavir, wherein the acid addition salts include hydrochloride, hydrobromide, mesylate, benzenesulfonate, sulfate and phosphate, The solubility in water is all greater than 150mg/mL, and the alkali salts include magnesium salts and barium salts, which are also enolate salts, and there is a risk of easy dissociation or easy oxidation.
  • Patent document CN1872853A discloses a variety of acid addition salts of entecavir, such as hydrobromide, hydrochloride, mesylate, maleate, etc. Compared with entecavir, these salts have significantly enhanced solubility under the same conditions , for example, the solubility of hydrochloride in aqueous solution and neutral physiological buffer at room temperature is greater than 165 mg/mL, while the solubility of entecavir is 2.4 mg/mL.
  • Patent document CN1907987A discloses various acid addition salts of entecavir, especially hydrochloride and maleate, and discloses the melting points of both. In aqueous solution at room temperature or neutral physiological buffer solution, the solubility of these salts is greater than or equal to 100 mg/mL, which is more than 10 times higher than that of entecavir.
  • Patent document CN101781300A discloses entecavir p-toluenesulfonate, the water solubility at normal temperature and pressure is greater than 130 mg/mL, which is far greater than that of entecavir.
  • entecavir due to the high solubility of entecavir and various existing salts of entecavir, it is easy to cause its release rate in the preparation to be too fast, and frequent administration is required to maintain the blood drug concentration, which makes the patient's compliance poor.
  • the pharmaceutical salt form of entecavir suitable for sustained-release administration, high stability, good clinical effect and suitable for commercialization is a technical problem that needs to be solved urgently at present.
  • the present invention provides a kind of entecavir medicinal salt, and the entecavir medicinal salt is the salt formed by entecavir free base (formula I) and an organic acid having more than six carbons;
  • the organic acid with more than six carbons can be a C6-C30 organic acid.
  • C6 ⁇ C30 organic acids include but are not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid , myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid ( arachidic acid), oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, heptacosanoic acid, Octadecanoic acid, nonaco
  • the palmitate refers to a structure after palmitic acid is esterified with at least one hydroxyl group of a compound containing both carboxyl and hydroxyl groups (such as pamoic acid);
  • the naphthalate refers to naphthalene A structure in which an acid is esterified with at least one hydroxyl group of a compound containing both carboxyl and hydroxyl groups, such as pamoic acid.
  • the pharmaceutically acceptable salt of entecavir may be in crystalline, polymorphic or amorphous form.
  • polymorphism refers to different crystal forms and other solid-state molecular forms of the same compound, for example, comprising two or more crystal forms and/or the pharmaceutically acceptable salts of entecavir. Amorphous form of solid.
  • the pharmaceutically acceptable salt of entecavir includes its solvate formed with a solvent.
  • the solvates include hydrates of entecavir pharmaceutically acceptable salts and solvates formed by entecavir pharmaceutically acceptable salts and organic solvents.
  • the "organic solvent” described in the "solvate formed by a pharmaceutical salt of entecavir and an organic solvent” includes but is not limited to one, two or more selected from ethanol, acetone and dimethyl sulfoxide. kind.
  • the molar ratio of entecavir to the organic acid with more than six carbons is preferably 1:1.
  • the pharmaceutically acceptable salt of entecavir is entecavir 1-hydroxy-2-naphthoate salt having the structure shown in the following formula II.
  • the present invention also provides the preparation method of the pharmaceutical salt of entecavir, which comprises the following steps: respectively forming an entecavir free base solution and an organic acid solution in a first solvent, then mixing and reacting the two, adding a second solvent or removing The first solvent obtains the medicinal salt of entecavir.
  • the first solvent is selected from ethanol, water, N,N-dimethylformamide or a mixture thereof.
  • the second solvent is isopropyl ether, methyl tert-butyl, n-heptane, toluene, or a mixture thereof.
  • the molar ratio of entecavir and organic acid is 1:1.1 ⁇ 1:1.2.
  • the mixing is adding the organic acid solution to the entecavir free base solution.
  • the reaction is carried out at room temperature.
  • the preparation method of the pharmaceutically acceptable salt of entecavir can also be carried out under solvent-free conditions.
  • the organic acid with more than six carbons can be a C6-C30 organic acid.
  • Described C6 ⁇ C30 organic acids include but are not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid , myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid ( arachidic acid), oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, heptacosanoi
  • the present invention also provides a pharmaceutical composition comprising the entecavir pharmaceutically acceptable salt.
  • the pharmaceutical composition comprises a therapeutically effective amount of the pharmaceutically acceptable salt of entecavir and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of a compound to an organism such as a human or other mammal.
  • the dosage form of the pharmaceutical composition is selected from injections, such as long-acting injections.
  • the injection can be an aqueous suspension, an oil suspension or a suspension powder.
  • the suspension powder can be dispersed into a suspension by using a specific diluent immediately before use.
  • the concentration of the entecavir pharmaceutical salt in the entecavir long-acting injection is not less than 5 mg/mL, wherein the concentration refers to the ratio of the mass of the entecavir pharmaceutical salt to the volume of the entecavir long-acting injection .
  • the particle size of the powder in the compounded powder may be, for example, ⁇ 1 mm.
  • the pharmaceutically acceptable adjuvants include one or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
  • the present invention also provides the application of the entecavir medicinal salt in preparing a medicine for treating and/or preventing hepatitis B.
  • the present invention also provides the application of the pharmaceutical salt of entecavir in the preparation of a medicine for inhibiting hepatitis B virus.
  • the present invention also provides the application of the pharmaceutical composition in the preparation of a medicine for treating and/or preventing hepatitis B, which comprises administering the pharmaceutical composition to the user.
  • the application may comprise administering the pharmaceutically acceptable salt of entecavir or a pharmaceutical composition thereof to the user.
  • the present invention also provides a method for treating and/or preventing hepatitis B, comprising administering the entecavir pharmaceutically acceptable salt or its pharmaceutical composition to the user.
  • the present invention also provides a method for inhibiting hepatitis B virus, comprising administering the entecavir pharmaceutically acceptable salt or its pharmaceutical composition to the user.
  • the terms "pharmaceutically acceptable”, “carrier”, “diluent”, “vehicle” or “excipient” refer to a substance (or substances), It can be included with certain pharmaceutical agents to form a pharmaceutical composition, and can be solid or liquid.
  • the solid carriers include but are not limited to starch, calcium sulfate dihydrate, terra alba, talc, lactose, sucrose, mica, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • the liquid carrier includes, but is not limited to, syrup, peanut oil, olive oil, saline solution, water, and the like.
  • the carrier or diluent may include delayed or timed release materials known in the art, such as monostearic acid alone or in combination with waxes, ethyl cellulose, hypromellose, methyl methacrylate, and the like Glycerides or Glyceryl Distearate.
  • the term "solvate” includes a molecular complex of a drug and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (eg, ethanol).
  • solvent molecules eg, ethanol
  • the solvent content will depend on humidity and drying conditions. In such cases, the complex will generally be non-stoichiometric.
  • the term “hydrate” describes a solvate comprising a drug with a stoichiometric or non-stoichiometric amount of water.
  • relative humidity refers to the ratio, expressed as a percentage, of the amount of water vapor at a specified temperature to the maximum amount of water vapor that can be held at that temperature and pressure.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the room temperature refers to an ambient temperature ranging from 10°C to 35°C.
  • the entecavir medicinal salt of the present invention achieves lower solubility, unexpectedly improves the technical problem that the drug is released too fast and needs frequent administration to maintain the blood drug concentration, and significantly improves the medication compliance of patients.
  • the entecavir medicinal salt has good stability, and adopts organic acid to form a salt, which avoids the adverse effect on stability caused by the enol structure formed by entecavir and an alkali salt, and has high bioavailability and marketization prospects. good.
  • Fig. 1 is the 1 H-NMR chart of entecavir 1-hydroxy-2-naphthoate of the present invention
  • Fig. 2 is the XRPD pattern of entecavir 1-hydroxy-2-naphthoate of the present invention.
  • the salt compounds of the examples were tested by nuclear magnetic resonance ( 1 H-NMR), high performance liquid chromatography (HPLC) and X-ray powder diffraction (XRPD) respectively, and the test parameters were as follows:
  • entecavir Take 500mg of entecavir, add 20mL of DMF to dissolve to obtain entecavir free base solution; take 360mg of 1-hydroxy-2-naphthoic acid, add 12mL of DMF to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir After the reaction was carried out for 18-24 hours, 180 mL of methyl tert-butyl ether was added, stirred for 18-24 hours, filtered, and dried under vacuum at 40° C. to obtain 780 mg of entecavir 1-hydroxy-2-naphthoate.
  • the above sample was tested by XRPD and showed to be amorphous.
  • entecavir Take 10mg of entecavir, add 2mL of ethanol to dissolve to obtain entecavir free base solution; take 7.2mg of 1-hydroxy-2-naphthoic acid, add 0.5mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution , stir the reaction for 18-24 hours, add 8 mL of toluene, stir for 18-24 hours, filter, and vacuum dry at 40°C to obtain 15 mg of entecavir 1-hydroxy-2-naphthoate.
  • entecavir Take 25 mg of entecavir, add 5 mL of water, dissolve at 60 °C to obtain entecavir free base solution; take 20 mg of 1-hydroxy-2-naphthoic acid, add 1 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution , the reaction was stirred for 18-24 hours, filtered, and dried under vacuum at 40° C. to obtain 37 mg of entecavir 1-hydroxy-2-naphthoate.
  • entecavir Take 25mg of entecavir, add 10mL of ethanol to dissolve to obtain entecavir free base solution; take 18mg of 1-hydroxy-2-naphthoic acid, add 2mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir The reaction was carried out for 18 to 24 hours, and concentrated under reduced pressure at 40° C. until the solvent was dry to obtain 35 mg of entecavir 1-hydroxy-2-naphthoate.
  • entecavir Take 25mg of entecavir, add 10mL of ethanol to dissolve to obtain entecavir free base solution; take 18mg of 1-hydroxy-2-naphthoic acid, add 2mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir The reaction was carried out for 18-24 hours, and the solvent was evaporated to dryness at 40° C. to obtain 38 mg of entecavir 1-hydroxy-2-naphthoate.
  • entecavir Take 25mg of entecavir, add 10mL of ethanol to dissolve to obtain entecavir free base solution; take 18mg of 1-hydroxy-2-naphthoic acid, add 2mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir The reaction was carried out for 18 to 24 hours, 20 mL of n-heptane was added, and the mixture was stirred and crystallized for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 28 mg of entecavir 1-hydroxy-2-naphthoate.
  • the samples prepared in Examples 2-6 have the same or similar 1 H-NMR and XPRD spectra as those in Example 1, indicating that the samples in Examples 2-6 are the same salt as the sample in Example 1.
  • entecavir Take 50 mg of entecavir, add 7 mL of methanol to dissolve, to obtain entecavir free base solution; take 38 mg of sebacic acid, add 0.4 mL of methanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stirring and reacting for 18-24 After 1 hour, after volatilizing until a large amount of solid was precipitated, it was filtered and dried under vacuum at 40°C to obtain 61 mg of entecavir sebacate.
  • entecavir Take 50 mg of entecavir, add 7 mL of methanol to dissolve, to obtain entecavir free base solution; take 25 mg of heptanoic acid, add 0.1 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, and stir for 18 to 24 hours. , 21 mL of methyl tert-butyl ether was added, stirred for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 51 mg of entecavir enanthate.
  • entecavir Take 50 mg of entecavir, add 7 mL of methanol to dissolve, to obtain entecavir free base solution; take 35 mg of heptanoic acid, add 0.5 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stirring and reacting for 18 to 24 hours , 21 mL of toluene was added, stirred for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 51 mg of entecavir undecanoate.
  • entecavir Take 50mg of entecavir, add 7mL of methanol to dissolve, to obtain entecavir free base solution; take 48mg of palmitic acid, add 0.5mL of methanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir and react for 18-24 hours, filtered, and dried under vacuum at 40°C to yield 70 mg of entecavir palmitate.
  • Example 15 Pharmaceutical composition of entecavir
  • Entecavir 1-hydroxy-2-naphthoate suspension injection is obtained by mixing entecavir 1-hydroxy-2-naphthoate and each auxiliary material under aseptic conditions according to the above-mentioned prescription amount, and grinding by grinding.
  • Entecavir 1-hydroxy-2-naphthoate prepared in Example 1 Entecavir palmitate prepared in Example 11, Entecavir oleate prepared in Example 12, and Entecavir prepared in Example 13.
  • Laurate and entecavir were added to the corresponding medium respectively, shaken at 37°C for 24 hours, filtered with a 0.45 ⁇ m aqueous filter, collected the filtrate, and used high performance liquid phase for solubility determination.
  • pH3 and pH5 are acetate buffer solutions
  • pH7 and pH9 are phosphate buffer solutions
  • Table 1 the solubility test results are shown in Table 1.
  • the entecavir 1-hydroxy-2-naphthoate salt of the present invention as an example, its solubility is moderate, and the release rate can be less dependent on pH, thereby avoiding its release rate in the pH environment of different regions in the body It can avoid the sudden release phenomenon or the high blood drug concentration in the local area of the body, and reduce the drug release variability among individuals.
  • the entecavir 1-hydroxy-2-naphthoate and entecavir prepared in Example 1 were respectively taken, placed in an environment of 2-8° C., and sampled at corresponding time points for XRPD detection to investigate their stability.
  • Table 2 shows that the entecavir 1-hydroxy-2-naphthoate salt of the present invention has good stability and remains amorphous after being placed at 2-8° C. for 30 days.

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Abstract

An entecavir medicinal salt, a preparation method therefor, a pharmaceutical composition thereof, and an application thereof. The entecavir medicinal salt is a salt formed by an entecavir free base (I) and an organic acid having more than six carbons. The entecavir medicinal salt has low solubility, good stability, high bioavailability, and good market prospects.

Description

恩替卡韦药用盐及其制备方法、药物组合物和应用Entecavir medicinal salt and preparation method, pharmaceutical composition and application thereof
本申请要求享有2020年8月26日向中国国家知识产权局提交的申请号为202010870716.2，名称为“恩替卡韦药用盐、制备方法、含其的药物组合物及应用”的发明专利申请的优先权。该申请的全文以引用的方式并入本文。This application claims to enjoy the priority of the invention patent application with the application number 202010870716.2 and the title of "Entecavir medicinal salt, preparation method, pharmaceutical composition containing it and application" submitted to the State Intellectual Property Office of China on August 26, 2020. The entirety of this application is incorporated herein by reference.
技术领域technical field
本发明涉及恩替卡韦药用盐及其制备方法、药物组合物和应用。The present invention relates to a pharmaceutical salt of entecavir and its preparation method, pharmaceutical composition and application.
背景技术Background technique
恩替卡韦(Entecavir，式I)是一种2’-戊环脱氧鸟嘌呤核苷类似物，化学名称为2-氨基-9-[(1S,3S,4S)-4-羟基-3-羟甲基-2-亚甲基环戊基]-1,9-二氢-6H-嘌呤-6-酮，分子式C 12H 15N 5O 3，分子量277.3，结构式如下所示。 Entecavir (Formula I) is a 2'-pentacyclodeoxyguanosine analog with the chemical name 2-amino-9-[(1S,3S,4S)-4-hydroxy-3-hydroxymethyl -2-Methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one, the molecular formula is C 12 H 15 N 5 O 3 , the molecular weight is 277.3, and the structural formula is shown below.
Figure PCTCN2021114753-appb-000001
Figure PCTCN2021114753-appb-000001
恩替卡韦是一种能有效抑制乙肝病毒复制的脱氧鸟苷类似物，具有较强的抗乙肝(HBV)作用。体外试验中，极低浓度的恩替卡韦即可抑制乙肝病毒的复制，而其细胞毒性则很低，有着十分优良的选择性治疗指数。Entecavir is a deoxyguanosine analog that can effectively inhibit the replication of hepatitis B virus, and has a strong anti-hepatitis B (HBV) effect. In vitro experiments, very low concentrations of entecavir can inhibit the replication of hepatitis B virus, and its cytotoxicity is very low, has a very good selective therapeutic index.
专利文献CN1566118A公开了恩替卡韦碱盐，如恩替卡韦铵盐、钙盐、钠盐及其制备方法。但是，其碱盐不是有机酸与碱所形成的加成盐，而是 恩替卡韦通过烯醇化作用之后，烯醇中的羟基具有弱的酸性，可与强碱如氢氧化钠或氢氧化钾反应形成一种烯醇盐，其中恩替卡韦的鸟嘌呤核苷结构部分已经发生了较大的改变。该烯醇盐在溶液中易解离为恩替卡韦分子，且有可能比恩替卡韦本身更容易被氧化而降解。Patent document CN1566118A discloses entecavir base salts, such as entecavir ammonium salt, calcium salt, sodium salt and preparation method thereof. However, its alkali salt is not an addition salt formed by an organic acid and a base, but after the enolization of entecavir, the hydroxyl group in the enol has a weak acidity and can react with a strong base such as sodium hydroxide or potassium hydroxide to form An enolate in which the guanosine moiety of entecavir has been substantially altered. The enolate is easily dissociated into entecavir molecules in solution, and may be more easily oxidized and degraded than entecavir itself.
专利文献CN101003536A公开了恩替卡韦的多种酸加成盐和碱加成盐，其中酸加成盐包括盐酸盐、氢溴酸盐、甲磺酸盐、苯磺酸盐、硫酸盐和磷酸盐，水中的溶解度均大于150mg/mL，碱盐包括镁盐和钡盐，也是烯醇盐，存在易解离或易氧化的风险。Patent document CN101003536A discloses various acid addition salts and base addition salts of entecavir, wherein the acid addition salts include hydrochloride, hydrobromide, mesylate, benzenesulfonate, sulfate and phosphate, The solubility in water is all greater than 150mg/mL, and the alkali salts include magnesium salts and barium salts, which are also enolate salts, and there is a risk of easy dissociation or easy oxidation.
专利文献CN1872853A公开了恩替卡韦多种酸加成盐，如氢溴酸盐、盐酸盐、甲磺酸盐、马来酸盐等，这些盐与恩替卡韦相比，在相同条件下具有显著增强的溶解度，如在室温水溶液和中性生理缓冲液中盐酸盐溶解度大于165mg/mL，而恩替卡韦溶解度为2.4mg/mL。Patent document CN1872853A discloses a variety of acid addition salts of entecavir, such as hydrobromide, hydrochloride, mesylate, maleate, etc. Compared with entecavir, these salts have significantly enhanced solubility under the same conditions , for example, the solubility of hydrochloride in aqueous solution and neutral physiological buffer at room temperature is greater than 165 mg/mL, while the solubility of entecavir is 2.4 mg/mL.
专利文献CN1907987A公开了恩替卡韦多种酸加成盐，特别是盐酸盐和马来酸盐，且公开了两者的熔点。在室温水溶液或中性生理缓冲溶液中，这些盐的溶解度大于等于100mg/mL，比恩替卡韦的数值增加在10倍以上。Patent document CN1907987A discloses various acid addition salts of entecavir, especially hydrochloride and maleate, and discloses the melting points of both. In aqueous solution at room temperature or neutral physiological buffer solution, the solubility of these salts is greater than or equal to 100 mg/mL, which is more than 10 times higher than that of entecavir.
专利文献CN101781300A公开了恩替卡韦对甲苯磺酸盐，常温常压下的水溶性大于130mg/mL，远远大于恩替卡韦的水溶性。Patent document CN101781300A discloses entecavir p-toluenesulfonate, the water solubility at normal temperature and pressure is greater than 130 mg/mL, which is far greater than that of entecavir.
但是，由于恩替卡韦及现有的恩替卡韦各种盐溶解度过高，容易导致其在制剂中的释放速度过快，需要频繁给药以维持血药浓度，使得患者的依从性差，故寻找溶解度较低且适宜缓释给药、稳定性高、临床效果好、适合于商品化的恩替卡韦药用盐型是目前亟需解决的技术问题。However, due to the high solubility of entecavir and various existing salts of entecavir, it is easy to cause its release rate in the preparation to be too fast, and frequent administration is required to maintain the blood drug concentration, which makes the patient's compliance poor. The pharmaceutical salt form of entecavir suitable for sustained-release administration, high stability, good clinical effect and suitable for commercialization is a technical problem that needs to be solved urgently at present.
发明内容SUMMARY OF THE INVENTION
为改善上述技术问题，本发明提供了一种的恩替卡韦药用盐，所述的恩替卡韦药用盐为恩替卡韦游离碱(式I)与六个碳以上的有机酸形成的盐；In order to improve the above-mentioned technical problems, the present invention provides a kind of entecavir medicinal salt, and the entecavir medicinal salt is the salt formed by entecavir free base (formula I) and an organic acid having more than six carbons;
Figure PCTCN2021114753-appb-000002
Figure PCTCN2021114753-appb-000002
根据本发明的实施方案，所述的六个碳以上的有机酸可以为C6～C30的有机酸。所述的C6～C30的有机酸包括但不限于：己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、十一烷酸、月桂酸(十二烷酸)、十三烷酸、肉豆蔻酸(十四烷酸)、十五烷酸、棕榈酸(十六烷酸)、十七烷酸、硬脂酸(十八烷酸)、十九烷酸、二十烷酸(花生酸)、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸(蜂花酸)、甘油三乙酸、木质酸、双羟萘酸(棕榈酸酯)、1-羟基-2萘甲酸以及萘酸衍生物(包括但不限于萘酸酯)。According to an embodiment of the present invention, the organic acid with more than six carbons can be a C6-C30 organic acid. Described C6～C30 organic acids include but are not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid , myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid ( arachidic acid), oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, heptacosanoic acid, Octadecanoic acid, nonacosanoic acid, triaconoic acid (melisic acid), triglyceride, lignin, pamoic acid (palmitate), 1-hydroxy-2 naphthoic acid and naphthoic acid derivatives substances (including but not limited to naphthoate).
根据本发明的实施方案，所述棕榈酸酯是指棕榈酸与既包含羧基又包含羟基的化合物(诸如双羟萘酸)的至少一个羟基成酯后的结构；所述萘酸酯是指萘酸与既包含羧基又包含羟基的化合物(诸如双羟萘酸)的至少一个羟基成酯后的结构。According to an embodiment of the present invention, the palmitate refers to a structure after palmitic acid is esterified with at least one hydroxyl group of a compound containing both carboxyl and hydroxyl groups (such as pamoic acid); the naphthalate refers to naphthalene A structure in which an acid is esterified with at least one hydroxyl group of a compound containing both carboxyl and hydroxyl groups, such as pamoic acid.
根据本发明的实施方案，所述的恩替卡韦药用盐可以为晶体、多晶或无定型的形式。According to an embodiment of the present invention, the pharmaceutically acceptable salt of entecavir may be in crystalline, polymorphic or amorphous form.
根据本发明的实施方案，所述的术语“多晶”是指同一化合物的不同晶体形式和其他固态分子形式，例如包含所述的恩替卡韦药用盐的两种或两种以上晶型和/或无定型形式的固体。According to an embodiment of the present invention, the term "polymorphism" refers to different crystal forms and other solid-state molecular forms of the same compound, for example, comprising two or more crystal forms and/or the pharmaceutically acceptable salts of entecavir. Amorphous form of solid.
根据本发明的实施方案，所述的恩替卡韦药用盐包括其与溶剂形成的溶 剂合物。所述的溶剂合物包括恩替卡韦药用盐的水合物和恩替卡韦药用盐与有机溶剂形成的溶剂合物。所述的“恩替卡韦药用盐与有机溶剂形成的溶剂合物”中所述的“有机溶剂”包括但不限于选自乙醇、丙酮和二甲基亚砜中的一种、两种或更多种。According to an embodiment of the present invention, the pharmaceutically acceptable salt of entecavir includes its solvate formed with a solvent. The solvates include hydrates of entecavir pharmaceutically acceptable salts and solvates formed by entecavir pharmaceutically acceptable salts and organic solvents. The "organic solvent" described in the "solvate formed by a pharmaceutical salt of entecavir and an organic solvent" includes but is not limited to one, two or more selected from ethanol, acetone and dimethyl sulfoxide. kind.
根据本发明的实施方案，所述的恩替卡韦药用盐中，恩替卡韦与所述六个碳以上的有机酸的摩尔比优选为1:1。According to an embodiment of the present invention, in the pharmaceutical salt of entecavir, the molar ratio of entecavir to the organic acid with more than six carbons is preferably 1:1.
根据本发明的实施方案，所述的恩替卡韦药用盐为具有如下式II所示结构的恩替卡韦1-羟基-2-萘甲酸盐。According to an embodiment of the present invention, the pharmaceutically acceptable salt of entecavir is entecavir 1-hydroxy-2-naphthoate salt having the structure shown in the following formula II.
Figure PCTCN2021114753-appb-000003
Figure PCTCN2021114753-appb-000003
本发明还提供了所述的恩替卡韦药用盐的制备方法，其包括以下步骤：分别在第一溶剂中形成恩替卡韦游离碱溶液和有机酸溶液，再将两者混合反应，添加第二溶剂或除去第一溶剂得到恩替卡韦药用盐。The present invention also provides the preparation method of the pharmaceutical salt of entecavir, which comprises the following steps: respectively forming an entecavir free base solution and an organic acid solution in a first solvent, then mixing and reacting the two, adding a second solvent or removing The first solvent obtains the medicinal salt of entecavir.
根据本发明的实施方案，所述第一溶剂选自乙醇、水、N,N-二甲基甲酰胺或其混合物。According to an embodiment of the present invention, the first solvent is selected from ethanol, water, N,N-dimethylformamide or a mixture thereof.
根据本发明的实施方案，所述第二溶剂为异丙醚、甲基叔丁基、正庚烷、甲苯或其混合物。According to an embodiment of the present invention, the second solvent is isopropyl ether, methyl tert-butyl, n-heptane, toluene, or a mixture thereof.
根据本发明的实施方案，所述恩替卡韦和有机酸的摩尔比为1:1.1～1:1.2。According to an embodiment of the present invention, the molar ratio of entecavir and organic acid is 1:1.1˜1:1.2.
根据本发明的实施方案，所述混合为将有机酸溶液加入到恩替卡韦游离碱溶液中。According to an embodiment of the invention, the mixing is adding the organic acid solution to the entecavir free base solution.
根据本发明的实施方案，所述反应在室温下进行。According to an embodiment of the present invention, the reaction is carried out at room temperature.
根据本发明的实施方案，所述的恩替卡韦药用盐的制备方法还可以在无 溶剂的条件下进行。According to an embodiment of the present invention, the preparation method of the pharmaceutically acceptable salt of entecavir can also be carried out under solvent-free conditions.
根据本发明的实施方案，所述的恩替卡韦药用盐的制备方法中，所述的六个碳以上的有机酸可以为C6～C30的有机酸。所述的C6～C30的有机酸包括但不限于：己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、十一烷酸、月桂酸(十二烷酸)、十三烷酸、肉豆蔻酸(十四烷酸)、十五烷酸、棕榈酸(十六烷酸)、十七烷酸、硬脂酸(十八烷酸)、十九烷酸、二十烷酸(花生酸)、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸(蜂花酸)、甘油三乙酸、木质酸、双羟萘酸(棕榈酸酯)、1-羟基-2萘甲酸以及萘酸衍生物(包括但不限于萘酸酯)。According to an embodiment of the present invention, in the preparation method of the pharmaceutical salt of entecavir, the organic acid with more than six carbons can be a C6-C30 organic acid. Described C6～C30 organic acids include but are not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid , myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid ( arachidic acid), oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, heptacosanoic acid, Octadecanoic acid, nonacosanoic acid, triaconoic acid (melisic acid), triglyceride, lignin, pamoic acid (palmitate), 1-hydroxy-2 naphthoic acid and naphthoic acid derivatives substances (including but not limited to naphthoate).
本发明还提供了一种药物组合物，其包括所述的恩替卡韦药用盐。The present invention also provides a pharmaceutical composition comprising the entecavir pharmaceutically acceptable salt.
根据本发明的实施方案，所述的药物组合物包括治疗有效量的所述的恩替卡韦药用盐以及药学上可接受的辅料。According to an embodiment of the present invention, the pharmaceutical composition comprises a therapeutically effective amount of the pharmaceutically acceptable salt of entecavir and pharmaceutically acceptable excipients.
根据本发明的实施方案，所述的药物组合物的目的是促进化合物向诸如人或其他哺乳动物的生物体的给药。According to an embodiment of the invention, the purpose of the pharmaceutical composition is to facilitate the administration of a compound to an organism such as a human or other mammal.
根据本发明的实施方案，所述的药物组合物的剂型选自注射剂，例如长效注射剂。所述的注射剂可以为水混悬剂、油混悬剂或者混悬粉末。According to an embodiment of the present invention, the dosage form of the pharmaceutical composition is selected from injections, such as long-acting injections. The injection can be an aqueous suspension, an oil suspension or a suspension powder.
根据本发明的实施方案，所述的混悬粉末可以在临用时采用特定的稀释剂分散成混悬剂。According to an embodiment of the present invention, the suspension powder can be dispersed into a suspension by using a specific diluent immediately before use.
根据本发明的实施方案，所述的恩替卡韦药用盐在恩替卡韦长效注射剂中的浓度不低于5mg/mL，其中所述的浓度是指恩替卡韦药用盐的质量与恩替卡韦长效注射剂体积的比值。According to an embodiment of the present invention, the concentration of the entecavir pharmaceutical salt in the entecavir long-acting injection is not less than 5 mg/mL, wherein the concentration refers to the ratio of the mass of the entecavir pharmaceutical salt to the volume of the entecavir long-acting injection .
根据本发明的实施方案，所述混选粉末中粉末的粒径可以是例如≤1mm。According to an embodiment of the present invention, the particle size of the powder in the compounded powder may be, for example, < 1 mm.
根据本发明的实施方案，所述的药学上可接受的辅料包括生理或药学上可接受的载体、稀释剂、媒介物和/或赋形剂中的一种或多种。According to an embodiment of the present invention, the pharmaceutically acceptable adjuvants include one or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
本发明还提供所述的恩替卡韦药用盐在制备治疗和/或预防乙型肝炎的药物中的应用。The present invention also provides the application of the entecavir medicinal salt in preparing a medicine for treating and/or preventing hepatitis B.
本发明还提供所述的恩替卡韦药用盐在制备抑制乙型肝炎病毒的药物中的应用。The present invention also provides the application of the pharmaceutical salt of entecavir in the preparation of a medicine for inhibiting hepatitis B virus.
本发明还提供了所述的药物组合物在制备治疗和/或预防乙型肝炎的药物中的应用，其包括给施用者使用所述的药物组合物。The present invention also provides the application of the pharmaceutical composition in the preparation of a medicine for treating and/or preventing hepatitis B, which comprises administering the pharmaceutical composition to the user.
根据本发明的实施方案，所述应用可以包括给施用者使用所述的恩替卡韦药用盐或其药物组合物。According to an embodiment of the present invention, the application may comprise administering the pharmaceutically acceptable salt of entecavir or a pharmaceutical composition thereof to the user.
本发明还提供一种治疗和/或预防乙型肝炎的方法，包括给施用者使用所述的恩替卡韦药用盐或其药物组合物。The present invention also provides a method for treating and/or preventing hepatitis B, comprising administering the entecavir pharmaceutically acceptable salt or its pharmaceutical composition to the user.
本发明还提供一种抑制乙型肝炎病毒的方法，包括给施用者使用所述的恩替卡韦药用盐或其药物组合物。The present invention also provides a method for inhibiting hepatitis B virus, comprising administering the entecavir pharmaceutically acceptable salt or its pharmaceutical composition to the user.
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：Unless otherwise specified, the following terms appearing in the present specification and claims have the following meanings:
根据本发明的实施方案，所述的术语“药学上接受的”、“载体”、“稀释剂”、“媒介物”或“赋形剂”指这样的一种物质(或多种物质)，其可与特定药剂一起被包含从而形成药物组合物，并且可以是固体或液体。所述的固体载体包括但不限于淀粉、硫酸钙二水合物、石膏粉、滑石粉、乳糖、蔗糖、云母、明胶、琼脂、果胶、***胶、硬脂酸镁、硬脂酸等。所述的液体载体包括但不限于糖浆、花生油、橄榄油、盐水溶液和水等。所述的载体或稀释剂可包括本领域已知的延时或定时释放材料，如单独或与蜡、乙基纤维素、羟丙甲纤维素、甲基丙烯酸甲酯等一起的单硬脂酸甘油酯或二硬脂酸甘油酯。According to embodiments of the present invention, the terms "pharmaceutically acceptable", "carrier", "diluent", "vehicle" or "excipient" refer to a substance (or substances), It can be included with certain pharmaceutical agents to form a pharmaceutical composition, and can be solid or liquid. The solid carriers include but are not limited to starch, calcium sulfate dihydrate, terra alba, talc, lactose, sucrose, mica, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. The liquid carrier includes, but is not limited to, syrup, peanut oil, olive oil, saline solution, water, and the like. The carrier or diluent may include delayed or timed release materials known in the art, such as monostearic acid alone or in combination with waxes, ethyl cellulose, hypromellose, methyl methacrylate, and the like Glycerides or Glyceryl Distearate.
根据本发明的实施方案，所述的术语“溶剂合物”包含药物和化学计量或非化学计量量的一种或多种溶剂分子(如乙醇)的分子复合物。当溶剂与药物紧密结合时，所得的复合物会具有与湿度无关的明确限定的化学计量。然而， 当溶剂与药物弱结合时，与在通道溶剂合物(channelsolvate)和吸湿性化合物中一样，溶剂含量会取决于湿度和干燥条件。在这样的情况下，复合物通常会是非化学计量性的。According to an embodiment of the invention, the term "solvate" includes a molecular complex of a drug and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (eg, ethanol). When the solvent is intimately bound to the drug, the resulting complex will have a well-defined stoichiometry independent of humidity. However, when the solvent is weakly bound to the drug, as in channel solvates and hygroscopic compounds, the solvent content will depend on humidity and drying conditions. In such cases, the complex will generally be non-stoichiometric.
根据本发明的实施方案，所述的术语“水合物”描述包含药物与化学计量或非化学计量量的水的溶剂合物。术语“相对湿度”指在指定温度下的水蒸气的量与在该温度和压力下可以保持的水蒸气的最大量的比率，以百分比表示。According to an embodiment of the present invention, the term "hydrate" describes a solvate comprising a drug with a stoichiometric or non-stoichiometric amount of water. The term "relative humidity" refers to the ratio, expressed as a percentage, of the amount of water vapor at a specified temperature to the maximum amount of water vapor that can be held at that temperature and pressure.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
根据本发明的实施方案，所述的室温是指环境温度为10℃～35℃。According to an embodiment of the present invention, the room temperature refers to an ambient temperature ranging from 10°C to 35°C.
有益效果beneficial effect
本发明的恩替卡韦药用盐取得了较低的溶解度，出人意料地改善了该药物的释放速度过快，需要频繁给药以维持血药浓度的技术问题，显著改善了患者的用药依从性。所述恩替卡韦药用盐的稳定性好，且采用有机酸进行成盐，避免了恩替卡韦与碱成盐形成的烯醇式结构对稳定性造成的不利影响，而且其生物利用度高，市场化前景良好。The entecavir medicinal salt of the present invention achieves lower solubility, unexpectedly improves the technical problem that the drug is released too fast and needs frequent administration to maintain the blood drug concentration, and significantly improves the medication compliance of patients. The entecavir medicinal salt has good stability, and adopts organic acid to form a salt, which avoids the adverse effect on stability caused by the enol structure formed by entecavir and an alkali salt, and has high bioavailability and marketization prospects. good.
附图说明Description of drawings
图1为本发明恩替卡韦1-羟基-2-萘甲酸盐的 1H-NMR图； Fig. 1 is the 1 H-NMR chart of entecavir 1-hydroxy-2-naphthoate of the present invention;
图2为本发明恩替卡韦1-羟基-2-萘甲酸盐的XRPD图。Fig. 2 is the XRPD pattern of entecavir 1-hydroxy-2-naphthoate of the present invention.
具体实施方式detailed description
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
分别采用核磁共振( 1H-NMR)、高效液相色谱(HPLC)和X-射线粉末 衍射(XRPD)对实施例的盐型化合物进行测试，测试参数如下： The salt compounds of the examples were tested by nuclear magnetic resonance ( 1 H-NMR), high performance liquid chromatography (HPLC) and X-ray powder diffraction (XRPD) respectively, and the test parameters were as follows:
(1) 1H-NMR测试在布鲁克型号为Bruker Advance III 500M核磁共振谱仪中进行，测量频率为400Mz，使用溶剂为氘代DMSO。 (1) The 1 H-NMR test was performed in a Bruker Advance III 500M nuclear magnetic resonance spectrometer, the measurement frequency was 400 Mz, and the solvent was deuterated DMSO.
(2)XRPD测量在布鲁克型号为D8Advance X-射线粉末衍射仪中进行，并使用圆形零背景的单晶硅样品台。扫描参数如下：电压40kv，电流40mA，扫描范围3°～45°，扫描步长0.02°，扫描模式为连续扫描。(2) XRPD measurements were performed in a Bruker model D8Advance X-ray powder diffractometer using a circular zero-background single crystal silicon sample stage. The scanning parameters are as follows: voltage 40kv, current 40mA, scanning range 3°-45°, scanning step size 0.02°, and scanning mode is continuous scanning.
(3)HPLC测量在Waters高效液相色谱仪中进行，色谱柱为Waters Symmetry Shield TM RP18，4.6mm*250mm，5μm，检测波长为254nm，流动相为水/乙腈(90/10v/v)，流速为1mL/min，柱温为30℃，进样盘温度为37℃，进样量为5μL，洗脱时间为20min。 (3) HPLC measurement was carried out in Waters high performance liquid chromatograph, the chromatographic column was Waters Symmetry Shield ™ RP18, 4.6mm*250mm, 5μm, the detection wavelength was 254nm, and the mobile phase was water/acetonitrile (90/10v/v), The flow rate was 1 mL/min, the column temperature was 30 °C, the temperature of the injection tray was 37 °C, the injection volume was 5 μL, and the elution time was 20 min.
实施例1恩替卡韦1-羟基-2-萘甲酸盐的制备Example 1 Preparation of entecavir 1-hydroxy-2-naphthoate
取500mg恩替卡韦，加入20mL DMF溶解，得到恩替卡韦游离碱溶液；取360mg 1-羟基-2-萘甲酸，加入12mL DMF溶解，得到有机酸溶液；将有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，加入180mL甲基叔丁基醚，搅拌18～24小时，过滤，40℃真空干燥，得到780mg恩替卡韦1-羟基-2-萘甲酸盐。Take 500mg of entecavir, add 20mL of DMF to dissolve to obtain entecavir free base solution; take 360mg of 1-hydroxy-2-naphthoic acid, add 12mL of DMF to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir After the reaction was carried out for 18-24 hours, 180 mL of methyl tert-butyl ether was added, stirred for 18-24 hours, filtered, and dried under vacuum at 40° C. to obtain 780 mg of entecavir 1-hydroxy-2-naphthoate.
通过核磁共振氢谱证实了本发明所述的恩替卡韦1-羟基-2-萘甲酸盐的结构及摩尔比。The structure and molar ratio of entecavir 1-hydroxy-2-naphthoate of the present invention were confirmed by proton nuclear magnetic resonance spectrum.
1H-NMR(400MHz,DMSO-d6):δ10.63(s,1H),8.28(dd,2H),7.89(d,2H),7.78–7.71(m,3H),7.67(ddd,2H),7.57(ddd,2H),7.38(d,2H),6.46(s,2H),5.37(ddd,1H),5.11(t,1H),4.58(t,1H),4.24(dt,1H),3.54(d,2H),2.54(d,1H),2.23(ddd,1H),2.10–2.00(m,1H)。 1 H-NMR (400MHz, DMSO-d6): δ10.63 (s, 1H), 8.28 (dd, 2H), 7.89 (d, 2H), 7.78–7.71 (m, 3H), 7.67 (ddd, 2H) ,7.57(ddd,2H),7.38(d,2H),6.46(s,2H),5.37(ddd,1H),5.11(t,1H),4.58(t,1H),4.24(dt,1H), 3.54(d,2H), 2.54(d,1H), 2.23(ddd,1H), 2.10–2.00(m,1H).
1H-NMR显示恩替卡韦和1-羟基-2-萘甲酸以摩尔比1:1成盐。 1 H-NMR showed that entecavir and 1-hydroxy-2-naphthoic acid formed a salt in a molar ratio of 1:1.
上述样品进行XRPD检测，显示为无定型。The above sample was tested by XRPD and showed to be amorphous.
实施例2恩替卡韦1-羟基-2-萘甲酸盐的制备The preparation of embodiment 2 entecavir 1-hydroxy-2-naphthoate
取10mg恩替卡韦，加入2mL乙醇溶解，得到恩替卡韦游离碱溶液；取7.2mg 1-羟基-2-萘甲酸，加入0.5mL乙醇溶解，得到有机酸溶液；将有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，加入8mL甲苯，搅拌18～24小时，过滤，40℃真空干燥，得到15mg恩替卡韦1-羟基-2-萘甲酸盐。Take 10mg of entecavir, add 2mL of ethanol to dissolve to obtain entecavir free base solution; take 7.2mg of 1-hydroxy-2-naphthoic acid, add 0.5mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution , stir the reaction for 18-24 hours, add 8 mL of toluene, stir for 18-24 hours, filter, and vacuum dry at 40°C to obtain 15 mg of entecavir 1-hydroxy-2-naphthoate.
实施例3恩替卡韦1-羟基-2-萘甲酸盐的制备Example 3 Preparation of entecavir 1-hydroxy-2-naphthoate
取25mg恩替卡韦，加入5mL水，60℃溶解，得到恩替卡韦游离碱溶液；取20mg 1-羟基-2-萘甲酸，加入1mL甲醇溶解，得到有机酸溶液；将有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，过滤，40℃真空干燥，得到37mg恩替卡韦1-羟基-2-萘甲酸盐。Take 25 mg of entecavir, add 5 mL of water, dissolve at 60 °C to obtain entecavir free base solution; take 20 mg of 1-hydroxy-2-naphthoic acid, add 1 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution , the reaction was stirred for 18-24 hours, filtered, and dried under vacuum at 40° C. to obtain 37 mg of entecavir 1-hydroxy-2-naphthoate.
实施例4恩替卡韦1-羟基-2-萘甲酸盐的制备Example 4 Preparation of entecavir 1-hydroxy-2-naphthoate
取25mg恩替卡韦，加入10mL乙醇溶解，得到恩替卡韦游离碱溶液；取18mg 1-羟基-2-萘甲酸，加入2mL乙醇溶解，得到有机酸溶液；将有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，40℃减压浓缩至溶剂干，得到35mg恩替卡韦1-羟基-2-萘甲酸盐。Take 25mg of entecavir, add 10mL of ethanol to dissolve to obtain entecavir free base solution; take 18mg of 1-hydroxy-2-naphthoic acid, add 2mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir The reaction was carried out for 18 to 24 hours, and concentrated under reduced pressure at 40° C. until the solvent was dry to obtain 35 mg of entecavir 1-hydroxy-2-naphthoate.
实施例5恩替卡韦1-羟基-2-萘甲酸盐的制备Example 5 Preparation of entecavir 1-hydroxy-2-naphthoate
取25mg恩替卡韦，加入10mL乙醇溶解，得到恩替卡韦游离碱溶液；取18mg 1-羟基-2-萘甲酸，加入2mL乙醇溶解，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，40℃敞口挥发至溶剂干，得到38mg恩替卡韦1-羟基-2-萘甲酸盐。Take 25mg of entecavir, add 10mL of ethanol to dissolve to obtain entecavir free base solution; take 18mg of 1-hydroxy-2-naphthoic acid, add 2mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir The reaction was carried out for 18-24 hours, and the solvent was evaporated to dryness at 40° C. to obtain 38 mg of entecavir 1-hydroxy-2-naphthoate.
实施例6恩替卡韦1-羟基-2-萘甲酸盐的制备Example 6 Preparation of entecavir 1-hydroxy-2-naphthoate
取25mg恩替卡韦，加入10mL乙醇溶解，得到恩替卡韦游离碱溶液；取18mg 1-羟基-2-萘甲酸，加入2mL乙醇溶解，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，加入20mL正庚烷，搅拌析晶18～24小时，过滤，40℃真空干燥，得到28mg恩替卡韦1-羟基-2-萘甲酸盐。Take 25mg of entecavir, add 10mL of ethanol to dissolve to obtain entecavir free base solution; take 18mg of 1-hydroxy-2-naphthoic acid, add 2mL of ethanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir The reaction was carried out for 18 to 24 hours, 20 mL of n-heptane was added, and the mixture was stirred and crystallized for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 28 mg of entecavir 1-hydroxy-2-naphthoate.
实施例2～6制备的样品具有与实施例1相同或相似的 1H-NMR和XPRD图谱，说明实施例2～6样品与实施例1样品是相同的盐。 The samples prepared in Examples 2-6 have the same or similar 1 H-NMR and XPRD spectra as those in Example 1, indicating that the samples in Examples 2-6 are the same salt as the sample in Example 1.
实施例7恩替卡韦癸二酸盐的制备The preparation of embodiment 7 entecavir sebacate
取50mg恩替卡韦，加入7mL甲醇溶解，得到恩替卡韦游离碱溶液；取38mg癸二酸，加入0.4mL甲醇溶解，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，挥发至析出大量固体后，过滤，40℃真空干燥，得到61mg恩替卡韦癸二酸盐。Take 50 mg of entecavir, add 7 mL of methanol to dissolve, to obtain entecavir free base solution; take 38 mg of sebacic acid, add 0.4 mL of methanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stirring and reacting for 18-24 After 1 hour, after volatilizing until a large amount of solid was precipitated, it was filtered and dried under vacuum at 40°C to obtain 61 mg of entecavir sebacate.
1H-NMR检测显示恩替卡韦和癸二酸以摩尔比1:1成盐。 1 H-NMR analysis showed that entecavir and sebacic acid formed a salt in a molar ratio of 1:1.
实施例8恩替卡韦癸琥珀酸盐的制备The preparation of embodiment 8 entecavir decanosuccinate
取50mg恩替卡韦，加入7mL甲醇溶解，得到恩替卡韦游离碱溶液；取22mg琥珀酸，加入0.2mL甲醇溶解，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，挥发至析出大量固体后，过滤，40℃真空干燥，，得到50mg恩替卡韦琥珀酸盐。Take 50 mg of entecavir and add 7 mL of methanol to dissolve to obtain entecavir free base solution; take 22 mg of succinic acid and add 0.2 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, and stir for 18 to 24 hours , volatilized until a large amount of solid was precipitated, filtered, and dried under vacuum at 40 °C to obtain 50 mg of entecavir succinate.
1H-NMR检测显示恩替卡韦和琥珀酸以摩尔比1:1成盐。 1 H-NMR analysis showed that entecavir and succinic acid formed a salt in a molar ratio of 1:1.
实施例9恩替卡韦己酸盐的制备The preparation of embodiment 9 entecavir caproate
取50mg恩替卡韦，加入7mL甲醇溶解，得到恩替卡韦游离碱溶液；取22mg己酸，加入0.1mL甲醇溶解，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，加入21mL甲基叔丁基醚，搅拌18～24小时，过滤，40℃真空干燥，得到40mg恩替卡韦己酸盐。Take 50 mg of entecavir and add 7 mL of methanol to dissolve to obtain entecavir free base solution; take 22 mg of hexanoic acid, add 0.1 mL of methanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir and react for 18 to 24 hours , 21 mL of methyl tert-butyl ether was added, stirred for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 40 mg of entecavir hexanoate.
1H-NMR检测显示恩替卡韦和己酸以摩尔比1:1成盐。 1 H-NMR analysis showed that entecavir and hexanoic acid formed a salt in a molar ratio of 1:1.
实施例10恩替卡韦庚酸盐的制备The preparation of embodiment 10 entecavir enanthate
取50mg恩替卡韦，加入7mL甲醇溶解，得到恩替卡韦游离碱溶液；取25mg庚酸，加入0.1mL甲醇溶解，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，加入21mL甲基叔丁基醚，搅拌18～24小时，过滤，40℃真空干燥，得到51mg恩替卡韦庚酸盐。Take 50 mg of entecavir, add 7 mL of methanol to dissolve, to obtain entecavir free base solution; take 25 mg of heptanoic acid, add 0.1 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, and stir for 18 to 24 hours. , 21 mL of methyl tert-butyl ether was added, stirred for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 51 mg of entecavir enanthate.
1H-NMR检测显示恩替卡韦和庚酸以摩尔比1:1成盐。 1 H-NMR analysis showed that entecavir and heptanoic acid formed a salt in a molar ratio of 1:1.
实施例11恩替卡韦十一烷酸盐的制备Example 11 Preparation of Entecavir Undecanoate
取50mg恩替卡韦，加入7mL甲醇溶解，得到恩替卡韦游离碱溶液；取35mg庚酸，加入0.5mL甲醇溶解，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，加入21mL甲苯，搅拌18～24小时，过滤，40℃真空干燥，得到51mg恩替卡韦十一烷酸盐。Take 50 mg of entecavir, add 7 mL of methanol to dissolve, to obtain entecavir free base solution; take 35 mg of heptanoic acid, add 0.5 mL of methanol to dissolve to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stirring and reacting for 18 to 24 hours , 21 mL of toluene was added, stirred for 18 to 24 hours, filtered, and dried under vacuum at 40° C. to obtain 51 mg of entecavir undecanoate.
1H-NMR检测显示恩替卡韦和十一烷酸以摩尔比1:1成盐。 1 H-NMR analysis showed that entecavir and undecanoic acid formed a salt with a molar ratio of 1:1.
实施例12恩替卡韦软脂酸盐的制备The preparation of embodiment 12 entecavir palmitate
取50mg恩替卡韦，加入7mL甲醇溶解，得到恩替卡韦游离碱溶液；取48mg软脂酸，加入0.5mL甲醇溶解，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，过滤，40℃真空干燥，得到70mg恩替卡韦软脂酸盐。Take 50mg of entecavir, add 7mL of methanol to dissolve, to obtain entecavir free base solution; take 48mg of palmitic acid, add 0.5mL of methanol to dissolve to obtain organic acid solution; add organic acid solution dropwise to entecavir free base solution, stir and react for 18-24 hours, filtered, and dried under vacuum at 40°C to yield 70 mg of entecavir palmitate.
1H-NMR检测显示恩替卡韦和软脂酸以摩尔比1:1成盐。 1 H-NMR analysis showed that entecavir and palmitic acid formed a salt in a molar ratio of 1:1.
实施例13恩替卡韦油酸盐的制备Example 13 Preparation of Entecavir Oleate
取50mg恩替卡韦，加入7mL甲醇溶解，得到恩替卡韦游离碱溶液；取53mg油酸，加入1mL甲醇稀释，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，过滤，40℃真空干燥，得到45mg恩替卡韦油酸盐。Take 50 mg of entecavir and add 7 mL of methanol to dissolve to obtain entecavir free base solution; take 53 mg of oleic acid, add 1 mL of methanol to dilute to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, Filtration and vacuum drying at 40°C yielded 45 mg of entecavir oleate.
1H-NMR检测显示恩替卡韦和油酸以摩尔比1:1成盐。 1 H-NMR analysis showed that entecavir and oleic acid formed a salt in a molar ratio of 1:1.
实施例14恩替卡韦月桂酸盐的制备Example 14 Preparation of entecavir laurate
取50mg恩替卡韦，加入7mL甲醇溶解，得到恩替卡韦游离碱溶液；取38mg月桂酸，加入1mL甲醇稀释，得到有机酸溶液；加有机酸溶液滴加到恩替卡韦游离碱溶液中，搅拌反应18～24小时，加入21mL甲苯，搅拌18～24小时，过滤，40℃真空干燥，得到56mg恩替卡韦月桂酸盐。Take 50 mg of entecavir and add 7 mL of methanol to dissolve to obtain the entecavir free base solution; take 38 mg of lauric acid, add 1 mL of methanol to dilute to obtain an organic acid solution; add the organic acid solution dropwise to the entecavir free base solution, stir and react for 18 to 24 hours, 21 mL of toluene was added, stirred for 18-24 hours, filtered, and dried under vacuum at 40° C. to obtain 56 mg of entecavir laurate.
1H-NMR检测显示恩替卡韦和月桂酸以摩尔比1:1成盐。 1 H-NMR analysis showed that entecavir and lauric acid formed a salt in a molar ratio of 1:1.
实施例15恩替卡韦的药物组合物Example 15 Pharmaceutical composition of entecavir
组分component 用量(mg)Dosage (mg)
恩替卡韦1-羟基-2萘甲酸盐Entecavir 1-Hydroxy-2 Naphthoate 450(以恩替卡韦计)450 (in terms of entecavir)
***胶 gum arabic 100100
聚维酮K30 Povidone K30 1010
羧甲基纤维素钠 Sodium carboxymethyl cellulose 2020
吐温80Tween 80 3030
甘露醇Mannitol 490490
注射用水Water for Injection qs10.0mLqs10.0mL
按照上述处方量取恩替卡韦1-羟基-2-萘甲酸盐和各辅料在无菌条件下混合，通过研磨，即得恩替卡韦1-羟基-2-萘甲酸盐混悬注射剂。Entecavir 1-hydroxy-2-naphthoate suspension injection is obtained by mixing entecavir 1-hydroxy-2-naphthoate and each auxiliary material under aseptic conditions according to the above-mentioned prescription amount, and grinding by grinding.
测试例1溶解度比较Test Example 1 Solubility Comparison
对本发明的恩替卡韦药用盐与恩替卡韦(已知的恩替卡韦加成盐的溶解度均高于恩替卡韦，故选择溶解度最低的恩替卡韦进行比较)进行溶解度对比。The solubility comparison of the entecavir medicinal salt of the present invention and entecavir (the solubility of the known entecavir addition salt is higher than that of entecavir, so the entecavir with the lowest solubility is selected for comparison).
分别取实施例1制得的恩替卡韦1-羟基-2-萘甲酸盐、实施例11制得的恩替卡韦软脂酸盐、实施例12制得的恩替卡韦油酸盐、实施例13制得的恩替卡韦月桂酸盐、恩替卡韦分别加入到相应介质中，在37℃条件下振荡24小时，0.45μm水相滤膜过滤，收集滤液，采用高效液相进行溶解度测定。其中，pH3和pH5为醋酸缓冲溶液、pH7和pH9为磷酸缓冲溶液，溶解度测试结果见表1。Take Entecavir 1-hydroxy-2-naphthoate prepared in Example 1, Entecavir palmitate prepared in Example 11, Entecavir oleate prepared in Example 12, and Entecavir prepared in Example 13. Laurate and entecavir were added to the corresponding medium respectively, shaken at 37°C for 24 hours, filtered with a 0.45 μm aqueous filter, collected the filtrate, and used high performance liquid phase for solubility determination. Among them, pH3 and pH5 are acetate buffer solutions, pH7 and pH9 are phosphate buffer solutions, and the solubility test results are shown in Table 1.
表1溶解度测试结果Table 1 Solubility test results
Figure PCTCN2021114753-appb-000004
Figure PCTCN2021114753-appb-000004
上述实验结果表明，本发明的恩替卡韦1-羟基-2-萘甲酸盐、恩替卡韦软脂酸盐、恩替卡韦油酸盐和恩替卡韦月桂酸盐在介质中的溶解度均低于恩替卡韦，更适用于制备各类缓释剂型，提高患者的依从性和生物利用度，市场前景好。并且，本发明的恩替卡韦药用盐各自独立地在不同pH介质中取得了相当的溶解度，释放速度可以最小程度的依赖于pH，从而避免在体内不同区域的pH环境中对其释药速率的影响，避免造成突释现象或体内局部区域血药浓度过高，以及降低个体间释药差异性。如果溶解度过大，容易导致其在制剂中的释放速度过快，需要频繁给药以维持血药浓度，使得患者的依从性差；而如溶解度过低，又容易导致其在制剂中的释放速度过慢，血药浓 度偏低，达不到治疗效果。因此，以本发明的恩替卡韦1-羟基-2-萘甲酸盐为例，其溶解度适中，释放速度可以更小程度地依赖于pH，从而避免在体内不同区域的pH环境中对其释药速率的影响，避免造成突释现象或体内局部区域血药浓度过高，以及降低个体间释药差异性。The above experimental results show that the solubility of entecavir 1-hydroxy-2-naphthoate, entecavir palmitate, entecavir oleate and entecavir laurate in the medium of the present invention is lower than that of entecavir, and is more suitable for the preparation of various entecavir. It is a kind of sustained-release dosage form, which can improve patient compliance and bioavailability, and has a good market prospect. Moreover, the pharmaceutical salts of entecavir of the present invention have achieved considerable solubility in different pH media independently, and the release rate can be minimally dependent on pH, thereby avoiding the influence of its release rate in the pH environment of different regions in the body. , to avoid the phenomenon of sudden release or high blood concentration in the local area of the body, and to reduce the variability of drug release between individuals. If the solubility is too large, it will easily lead to its release rate in the preparation too fast, requiring frequent dosing to maintain the blood concentration, resulting in poor patient compliance; and if the dissolution rate is too low, it is easy to cause its release rate in the preparation to be too high Slow, the blood concentration is low, and the therapeutic effect cannot be achieved. Therefore, taking the entecavir 1-hydroxy-2-naphthoate salt of the present invention as an example, its solubility is moderate, and the release rate can be less dependent on pH, thereby avoiding its release rate in the pH environment of different regions in the body It can avoid the sudden release phenomenon or the high blood drug concentration in the local area of the body, and reduce the drug release variability among individuals.
测试例2稳定性比较Test example 2 stability comparison
分别取实施例1制得的恩替卡韦1-羟基-2-萘甲酸盐和恩替卡韦，置于2～8℃环境中，于相应时间点取样进行XRPD检测，考察其稳定性。The entecavir 1-hydroxy-2-naphthoate and entecavir prepared in Example 1 were respectively taken, placed in an environment of 2-8° C., and sampled at corresponding time points for XRPD detection to investigate their stability.
结果见表2，显示本发明的恩替卡韦1-羟基-2-萘甲酸盐稳定性较好，2～8℃放置30天仍为无定型。The results are shown in Table 2, which shows that the entecavir 1-hydroxy-2-naphthoate salt of the present invention has good stability and remains amorphous after being placed at 2-8° C. for 30 days.
表2稳定性测试结果Table 2 Stability test results
Figure PCTCN2021114753-appb-000005
Figure PCTCN2021114753-appb-000005

Claims (10)

  1. 一种恩替卡韦药用盐，其特征在于：所述的恩替卡韦药用盐为恩替卡韦游离碱I与六个碳以上的有机酸形成的盐；A medicinal salt of entecavir, characterized in that: the medicinal salt of entecavir is the salt formed by entecavir free base I and an organic acid having more than six carbons;
    优选的，所述的恩替卡韦药用盐可以为晶体、多晶或无定型的形式；Preferably, the pharmaceutically acceptable salt of entecavir can be in the form of crystal, polymorph or amorphous;
    Figure PCTCN2021114753-appb-100001
    Figure PCTCN2021114753-appb-100001
  2. 如权利要求1所述的恩替卡韦药用盐，其特征在于：所述的六个碳以上的有机酸为C6～C30的有机酸。The pharmaceutical salt of entecavir according to claim 1, wherein the organic acid with more than six carbons is a C6-C30 organic acid.
  3. 如权利要求2所述的恩替卡韦药用盐，其特征在于：所述的C6～C30的有机酸包括但不限于：己酸、庚酸、辛酸、壬酸、壬二酸、癸酸、十一烷酸、月桂酸、十三烷酸、肉豆蔻酸、十五烷酸、棕榈酸、十七烷酸、硬脂酸、十九烷酸、二十烷酸、油酸、二十一烷酸、二十二烷酸、二十三烷酸、二十四烷酸、二十五烷酸、二十六烷酸、二十七烷酸、二十八烷酸、二十九烷酸、三十烷酸、甘油三乙酸、木质酸、双羟萘酸、1-羟基-2萘甲酸以及萘酸衍生物；优选地，所述的恩替卡韦药用盐为具有如下式II所示结构的恩替卡韦1-羟基-2-萘甲酸盐The pharmaceutical salt of entecavir according to claim 2, wherein the organic acids of C6-C30 include but are not limited to: caproic acid, heptanoic acid, caprylic acid, nonanoic acid, azelaic acid, capric acid, undecanoic acid Alkanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid, oleic acid, behenic acid , behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, behenic acid, heptadecanoic acid, octacosanoic acid, nonacosanoic acid, three Decanoic acid, triglyceride, lignin, pamoic acid, 1-hydroxy-2 naphthoic acid and naphthoic acid derivatives; preferably, the entecavir pharmaceutically acceptable salt is entecavir having the structure shown in the following formula II 1-Hydroxy-2-naphthoate
    Figure PCTCN2021114753-appb-100002
    Figure PCTCN2021114753-appb-100002
  4. 如权利要求1-3任一项所述的恩替卡韦药用盐，其特征在于：所述恩替卡韦药用盐中，恩替卡韦与所述六个碳以上的有机酸的摩尔比为1:1；The entecavir medicinal salt according to any one of claims 1-3, wherein: in the entecavir medicinal salt, the molar ratio of entecavir to the organic acid with more than six carbons is 1:1;
    和/或，and / or,
    所述的恩替卡韦药用盐包括其与溶剂形成的溶剂合物；优选的，所述的溶剂合物包括恩替卡韦药用盐的水合物和恩替卡韦药用盐与有机溶剂形成的溶剂合物；进一步优选，所述的“恩替卡韦药用盐与有机溶剂形成的溶剂合物”中所述的“有机溶剂”包括但不限于选自乙醇、丙酮和二甲基亚砜中的一种、两种或更多种。Described entecavir pharmaceutically acceptable salt includes solvate formed with solvent; preferably, described solvate includes entecavir pharmaceutically acceptable salt hydrate and entecavir pharmaceutically acceptable salt solvate formed with organic solvent; further preferred , the "organic solvent" described in the "solvate formed by a pharmaceutical salt of entecavir and an organic solvent" includes, but is not limited to, one, two or more selected from ethanol, acetone and dimethyl sulfoxide. variety.
  5. 一种如权利要求1-4任一项所述的恩替卡韦药用盐的制备方法，其特征在于：分别在第一溶剂中形成恩替卡韦游离碱溶液和有机酸溶液，再将两者混合反应，添加第二溶剂或除去第一溶剂得到恩替卡韦药用盐。A method for preparing a medicinal salt of entecavir as claimed in any one of claims 1 to 4, wherein the entecavir free base solution and the organic acid solution are respectively formed in the first solvent, and then the two are mixed and reacted, adding The second solvent or the first solvent is removed to obtain a pharmaceutically acceptable salt of entecavir.
  6. 如权利要求5所述的恩替卡韦药用盐的制备方法，其特征在于：所述第一溶剂可以选自甲醇、乙醇、水、N,N-二甲基甲酰胺或其混合物；The method for preparing a pharmaceutical salt of entecavir according to claim 5, wherein the first solvent can be selected from methanol, ethanol, water, N,N-dimethylformamide or a mixture thereof;
    所述第二溶剂可以选自异丙醚、甲基叔丁基、正庚烷、甲苯或其混合物；The second solvent can be selected from isopropyl ether, methyl tert-butyl, n-heptane, toluene or a mixture thereof;
    所述恩替卡韦和有机酸的摩尔比可以为1:1.1～1:1.2；The molar ratio of entecavir and organic acid can be 1:1.1～1:1.2;
    所述混合为将有机酸溶液加入到恩替卡韦游离碱溶液中；The mixing is adding the organic acid solution to the entecavir free base solution;
    所述反应在室温下进行。The reaction is carried out at room temperature.
  7. 一种药物组合物，其特征在于包括权利要求1-4任一项所述的恩替卡韦药用盐及药学上可接受的辅料。A pharmaceutical composition, characterized in that it comprises the entecavir pharmaceutically acceptable salt of any one of claims 1-4 and a pharmaceutically acceptable adjuvant.
  8. 如权利要求7所述的药物组合物，其特征在于：所述药物组合物选自注射剂，如长效注射剂。The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is selected from injections, such as long-acting injections.
  9. 如权利要求8所述的组合物，其特征在于：所述注射剂为水混悬剂、油混悬剂或者混悬粉末。The composition of claim 8, wherein the injection is an aqueous suspension, an oil suspension or a suspension powder.
  10. 权利要求1-4任一项所述的恩替卡韦药用盐或权利要求7-9任一项 所述的药物组合物在制备治疗和/或预防乙型肝炎的药物中的应用。Application of the pharmaceutical salt of entecavir according to any one of claims 1-4 or the pharmaceutical composition according to any one of claims 7-9 in the preparation of a medicine for treating and/or preventing hepatitis B.
PCT/CN2021/114753 2020-08-26 2021-08-26 Entecavir medicinal salt, preparation method therefor, pharmaceutical composition thereof, and application thereof WO2022042641A1 (en)

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