WO2016011932A1 - 替诺福韦前药新多晶型及其制备方法和用途 - Google Patents

替诺福韦前药新多晶型及其制备方法和用途 Download PDF

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WO2016011932A1
WO2016011932A1 PCT/CN2015/084671 CN2015084671W WO2016011932A1 WO 2016011932 A1 WO2016011932 A1 WO 2016011932A1 CN 2015084671 W CN2015084671 W CN 2015084671W WO 2016011932 A1 WO2016011932 A1 WO 2016011932A1
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methyl
isopropoxycarbonyl
methoxy
propyl
amino
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PCT/CN2015/084671
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English (en)
French (fr)
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陈明
田承耀
赵明礼
余俊
杨宝海
吕爱锋
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江苏豪森医药集团连云港宏创医药有限公司
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Application filed by 江苏豪森医药集团连云港宏创医药有限公司 filed Critical 江苏豪森医药集团连云港宏创医药有限公司
Priority to BR112017000605-7A priority Critical patent/BR112017000605B1/pt
Priority to US15/326,126 priority patent/US9840525B2/en
Priority to JP2017500324A priority patent/JP6872179B2/ja
Priority to MX2017000516A priority patent/MX370639B/es
Priority to EP15825169.4A priority patent/EP3173417A4/en
Priority to KR1020177002578A priority patent/KR102476361B1/ko
Priority to AU2015292050A priority patent/AU2015292050B2/en
Priority to CN201580035392.8A priority patent/CN106536532B/zh
Priority to RU2017102321A priority patent/RU2701728C2/ru
Priority to CA2954395A priority patent/CA2954395C/en
Publication of WO2016011932A1 publication Critical patent/WO2016011932A1/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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
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    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
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    • 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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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

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  • the invention relates to the field of medical chemistry, in particular to tenofovir prodrug 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl) A new crystalline form of amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate and a process for the preparation thereof, comprising a therapeutically effective amount of a pharmaceutical composition of the compound and its pharmaceutical use.
  • Adenine fumarate is a nucleoside reverse transcriptase inhibitor and a prodrug of tenofovir (PMPA).
  • the PMPA structure resembles the natural nucleoside monophosphate, which is rapidly converted into the active metabolite PMPA diphosphate (PMPApp) in vivo; PMPApp competes with the natural 5′-deoxyadenosine triphosphate and is incorporated into the viral DNA strand, but due to the lack of 3′ of PMPApp The OH group can no longer undergo 5', 3' phosphodiester bond coupling, resulting in delayed DNA strand elongation and ultimately blocking viral replication (Figure 1). Studies have shown that PMPA has anti-human immunodeficiency virus (HIV) and hepatitis B virus (HBV) activity.
  • HIV anti-human immunodeficiency virus
  • HBV hepatitis B virus
  • PMPA contains a phosphate group, which is usually negatively charged under physiological pH conditions and is too polar to pass through the biofilm, resulting in poor oral bioavailability, low tissue distribution coefficient, and certain nephrotoxicity. Therefore, in the development of such drugs, it is necessary to use the principle of prodrugs to mask the negative charge of the phosphate group, thereby eliminating the shortage of such drugs.
  • TDF significantly improves the pharmacokinetic properties of PMPA to a certain extent, but it is rapidly hydrolyzed by non-specific esterases that are widely present in plasma in vivo, especially in the rapid water interpretation of intestinal mucosal epithelial cells.
  • Release PMPA High concentrations of PMPA in plasma are rapidly excreted due to poor membrane permeability, and it is difficult to maintain sufficient concentration in the infected site.
  • PMPA is a substrate for the renal anion epithelial cell organic anion transporter (hOAT), a high concentration of PMPA in plasma. It is easy to accumulate in the proximal tubular epithelial cells of the kidney, causing a certain risk of nephrotoxicity.
  • hOAT renal anion epithelial cell organic anion transporter
  • the new generation of monophosphoramide monoester prodrugs overcomes the shortcomings of TDF described above, is stable in plasma, and is not easily hydrolyzed by esterases; but is absorbed into cells; immediately in serine protease (cathepsinA) and in vivo specific amides It is converted to PMPA by the action of enzymes, so it has better tissue permeability and lymphoid tissue and cell targeting.
  • the monophosphoramide monoester prodrug GS7340 (refer to patent WO2013052094A 2 ) developed by Gilead has successfully entered the phase III clinical trial. The results show that GS7340 has stronger antiviral ability and more than 30 times of TDF. Good security.
  • the adenine fumarate (I) releases the active ingredient PMPA in the cell.
  • the auxiliary group is ingeniously designed, and the structure is different from that of GS7340.
  • the mechanism and manner of the auxiliary group in the cell are basically the same as those of GS7340.
  • HS-10234 will exert its efficacy as an active ingredient PMPA more effectively than prodrugs such as TDF due to its absorption and distribution advantages, and it is the most promising new generation of PMPA prodrugs for the benefit of the majority of patients.
  • the polymorphic form of the drug has become an indispensable and important part of the drug research process and the quality control and detection process of the finished drug product.
  • the study of drug polymorphs contributes to the selection of biological activity of new drug compounds, helps to improve bioavailability, enhance clinical efficacy, facilitates the selection and design of drug delivery routes, and determines the process parameters of pharmaceutical preparations. Improve the quality of pharmaceutical production.
  • Bioavailability may vary significantly depending on the crystal form of the same drug. With the same drug, some crystal forms may have higher biological activity than other crystal forms. Obtaining a tenofovir prodrug crystal form with higher biological activity and more suitable for medical application is a technical problem that the medical field has been expecting to solve.
  • the object of the present invention is to solve the above problems and provide 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]benzene)
  • the XRPD pattern of the crystalline form A of the present invention contains at least 2 ⁇ 0.20° of diffraction peaks of 5.08, 12.44, 13.18, 22.37, 23.37, 28.56.
  • the 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl) group contains at least 2 ⁇ 0.20°: diffraction peaks of 5.08, 7.42, 10.15, 12.44, 13.18, 22.37, 23.37, 28.56. More preferably, it also contains diffraction peaks of 2 ⁇ ⁇ 0.20° of 16.35, 18.23, 21.36, 25.00, 31.68.
  • the XRPD pattern of the crystalline form A is shown in Figure 1.
  • Another object of the present invention is to provide 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyoxyl
  • a method for preparing crystalline form A of phosphino]methoxy]propyl]adenine fumarate comprises the following steps:
  • the organic solvent is selected from the group consisting of acetonitrile, anhydrous methanol, absolute ethanol, isopropanol, anhydrous methanol/n-heptane, absolute ethanol/n-heptane, isopropanol/n-heptane, anhydrous methanol.
  • the organic solvent is heated and dissolved at a temperature of generally 30 ° C to reflux temperature, preferably back The flow temperature; the crystallization temperature is preferably -40 to 40 ° C, and most preferably 0 ° C to 10 ° C.
  • Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of said Form A, optionally further comprising a pharmaceutically acceptable carrier.
  • compositions of the present invention include routes of administration suitable for oral and injection, preferably oral routes of administration.
  • Dosage forms include tablets, capsules, dispersions and suspensions, preferably tablets.
  • Another object of the present invention is to provide the use of the crystalline form A and the pharmaceutical composition containing the crystalline form A in the preparation of a medicament for treating AIDS or hepatitis B virus.
  • the new crystal form A of the invention has the characteristics of high bioavailability, remarkable drug effect, good stability, high yield and high purity.
  • the novel crystal form of the present invention contributes to the selection and design of the drug administration route, as well as the determination of the process parameters of the pharmaceutical preparation, thereby improving the quality of the drug production.
  • Figure 1 is a 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl] group] XRPD pattern of a new crystalline form of methoxy]propyl]adenine fumarate.
  • Figure 2 is a 9-[(R)-2-[[(S)-[[[1-(isopropoxycarbonyl)-1-methyl]ethyl]amino]phenoxyphosphinyl] group] DSC pattern of a new crystalline form of methoxy]propyl]adenine fumarate.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 1 Embodiment 2 Embodiment 3 Angle of repose 36° 35° 34°
  • the absolute bioavailability as determined by intravenous administration and oral administration of rats was as high as 81%. Experiments have shown that the new crystal form prepared by the present invention has a high bioavailability.

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Abstract

本发明涉及9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐新晶形及其制备方法和用途。具体地，本发明涉及式（I）所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型，其特征在于，所述晶型XRPD图谱中至少包含2θ±0.20°为：5.08，12.44，13.18，22.37，23.37，28.56的衍射峰。本发明晶型具有生物利用度高，药效显著，稳定性好，收率高，纯度高等特点，有助于药物给药途径的选择与设计，以及药物制剂工艺参数的确定，从而提高药品生产质量。

Description

替诺福韦前药新多晶型及其制备方法和用途 技术领域
本发明涉及医药化学领域，具体涉及替诺福韦前药9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐新晶型及其制备方法，含有治疗有效量的该化合物的药物组合物及其制药用途。
背景技术
9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(I)。具备如下结构：
Figure PCTCN2015084671-appb-000001
9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(I)是一种核苷类逆转录酶抑制剂，是替诺福韦(PMPA)的前药。PMPA结构类似天然核苷单磷酸，在体内迅速转化为活性代谢产物PMPA二磷酸(PMPApp)；PMPApp与天然5′三磷酸脱氧腺苷竞争，掺入到病毒DNA链中，但由于PMPApp缺乏3′OH基团，无法再进行5′，3′磷酸二酯键偶联，从而导致DNA链延长受阻，最终阻断病毒的复制(图1)。研究证明PMPA具有抗人免疫缺陷病毒(HIV)和乙型肝炎病毒(HBV)活性。
但PMPA含有磷酸基团，在生理pH条件下通常带负电荷而极性太强不易通过生物膜，导致该类药物口服生物利用度差、组织分布系数低，并且具有一定的肾毒性。因此在开发该类药物时，需要运用前药原理将磷酸基团的负电荷掩蔽，消除该类药物的不足。吉利德公司开发的PMPA的双酯前药，富马酸PMPA二吡伏酯 (tenofovirdisoproxilfumarate,TDF)分别于2001年被美国食品药品管理局(FDA)批准用于治疗HIV感染。
TDF在一定程度上显著改善了PMPA的药代动力学属性，但它在体内还是很快被血浆中广泛存在的非特异性酯酶水解，尤其是在肠黏膜上皮细胞碳酸酯酶作用下迅速水解释放出PMPA。血浆中高浓度PMPA由于其膜透过性差而被迅速排出体外，难以在感染部位保持足够的浓度；此外，PMPA是肾近端小管上皮细胞有机阴离子转运体(hOAT)的底物，血浆中高浓度PMPA易在肾近端小管上皮细胞中累积，造成一定的肾毒性风险。
而新一代的单磷酰胺单酯类前药克服了上述TDF的缺点，在血浆中很稳定，不易被酯酶水解；但被吸收进入细胞内；立即在丝氨酸蛋白酶(cathepsinA)以及体内特异性酰胺酶的作用下转化为PMPA，因此有更好的组织透过性及淋巴组织和细胞靶向性。吉利德公司开发的单磷酰胺单酯类前药GS7340(参考专利WO2013052094A2)已经顺利进入Ⅲ期临床试验，结果显示GS7340与30倍剂量的TDF相比，还具有更强的抗病毒能力和更好的安全性。
9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐(I)和GS7340一样，在细胞内都会释放出活性成分PMPA。其辅助基团设计巧妙，结构上和GS7340只有一个甲基的区别，辅助基团在细胞内的脱落机制和方式与GS7340基本相同。可以预见，HS-10234由于吸收和分布上优势，将比TDF等前药更为有效地发挥其活性成分PMPA的药效，作为最有潜力的新一代PMPA前药造福于广大患者。
本领域技术人员知道，药物的多晶型已经成为药物研究过程和药品成品质量控制及检测过程中必不可少的重要组成部分。对药物多晶型的研究有助于新药化合物生物活性的选择，有助于提高生物利用度，增进临床疗效，有助于药物给药途径的选择与设计，以及药物制剂工艺参数的确定，从而提高药品生产质量。同一药物晶型不同，生物利用度可能差异显著。同一种药物，某些晶型可能比其他晶型具备更高的生物活性。获得一种生物活性更高，更适合医药应用的替诺福韦前药晶型是医药领域一直期待解决的技术问题。
发明内容
本发明的目的在于解决上述技术问题，提供9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的一种新晶型，本发明将其命名为晶型A。
本发明所述晶型A的XRPD图谱中至少包含2θ±0.20°为：5.08，12.44，13.18，22.37，23.37，28.56的衍射峰。
优选的，所述的9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A的XRPD图谱中至少包含2θ±0.20°为：5.08，7.42，10.15，12.44，13.18，22.37，23.37，28.56的衍射峰。更优选的，还包含2θ±0.20°为16.35，18.23，21.36，25.00，31.68的衍射峰。
特别优选的，所述晶型A的XRPD图谱如图1所示。
本发明所述的9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐晶型A的差热分析结果表明，在110.9℃出现一个尖锐的吸热熔融峰。
本发明的另一目的在于提供9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的晶型A的制备方法，包括如下步骤：
①将任意形态的9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐在有机溶剂中加热溶解；
②将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的溶解液冷却析晶；
③过滤晶体得到晶型A。
优选的，所述有机溶剂选自乙腈、无水甲醇、无水乙醇、异丙醇、无水甲醇/正庚烷、无水乙醇/正庚烷、异丙醇/正庚烷、无水甲醇/甲基叔丁基醚、无水乙醇/甲基叔丁基醚、异丙醇/甲基叔丁基醚、无水甲醇/异丙醚、无水乙醇/异丙醚、异丙醇/异丙醚、无水甲醇/乙醚、无水乙醇/乙醚或异丙醇/乙醚，其中优选无水甲醇/正庚烷。
优选的，有机溶剂加热溶解温度一般为30℃至回流温度，优选回 流温度；析晶温度优选-40～40℃，最优选0℃～10℃。
本发明的另一目的还在于提供一种包含有效量的所述晶型A的药物组合物，任选的，所述组合物中还包含药学上可接受的载体。
本发明的组合物包括适于口服和注射等给药途径，优选口服给药途径。剂型包括片剂，胶囊，分散剂和混悬剂，优选片剂。
本发明的另一目的还在于提供所述晶型A及含有晶型A的药物组合物在在制备治疗艾滋病或乙型病毒性肝炎药物中的应用。
本发明的新晶型A具有生物利用度高，药效显著，稳定性好，收率高，纯度高等特点。本发明的新晶型有助于药物给药途径的选择与设计，以及药物制剂工艺参数的确定，从而提高药品生产质量。
附图说明
图1是本发明9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐新晶型的XRPD图谱。
图2是本发明9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐新晶型的DSC图谱。
具体实施方式
为体现本发明的技术方案及其所取得的效果，下面将结合具体实施例对本发明做进一步说明，但本发明的保护范围并非局限于具体实施例。
实施例一：
将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐5.0g，无水甲醇20.0ml和正庚烷5ml置于反应瓶中，加热至回流，使固体完全溶解，关闭加热，降温至0～10℃搅拌析晶2h，过滤固体得到晶型A。
经检测验证，其X射线粉末衍射图谱如图1所示，其DSC图谱与图2吻合，证明了所得晶型为晶型A。
实施例二：
将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐5.0g，无水乙醇20.0ml置于反应瓶 中，加热至回流，使固体完全溶解，关闭加热，降温至0～10℃搅拌析晶2h，过滤固体得到晶型A。
经检测验证，其X射线粉末衍射图谱与图1吻合，其DSC图谱与图2吻合，证明了所得晶型为晶型A。
实施例三：
将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐5.0g，异丙醇20.0ml和甲基叔丁基醚5ml置于反应瓶中，加热至回流，使固体完全溶解，关闭加热，降温至0～10℃搅拌析晶2h，过滤固体得到晶型A。
经检测验证，其X射线粉末衍射图谱与图1吻合，其DSC图谱与图2吻合，证明了所得晶型为晶型A。
实验例：稳定性考察
对本发明实施例一的方法制备的新晶型进行稳定性考察，结果表明，本发明的新晶型晶型A在稳定性试验中没有发生转晶，同时也没有发生化学降解，在室温下是稳定的，符合药物及制剂需求，详见下表：
Figure PCTCN2015084671-appb-000002
实施例：流动性考察
对本发明实施例一、二、三制备的新晶型进行流动性考察，结果表明，本发明的新晶型晶型A流动性良好。
  实施例一 实施例二 实施例三
休止角 36° 35° 34°
实施例：绝对生物利用度测定
对本发明制备的新晶型晶型A，通过大鼠静脉注射给药和口服给药测定的绝对生物利用度高达81％。实验表明本发明制备的新晶型具有较高的生物利用度。

Claims (12)

  1. 式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型，
    Figure PCTCN2015084671-appb-100001
    其特征在于，所述晶型XRPD图谱中至少包含2θ±0.20°为：5.08，12.44，13.18，22.37，23.37，28.56的衍射峰。
  2. 根据权利要求1所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型，其特征在于，所述晶型的XRPD图谱中至少包含2θ±0.20°为：5.08，7.42，10.15，12.44，13.18，22.37，23.37，28.56的衍射峰，进一步优选的，还包含16.35，18.23，21.36，25.00，31.68的衍射峰。
  3. 根据权利要求1所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型，其特征在于，所述晶型的差热分析结果表明，在110.9℃出现一个尖锐的吸热熔融峰。
  4. 根据权利要求1-3中任意一项所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型，其中所述的晶体具有与图1基本一致的X射线衍射图。
  5. 如权利要求1-3任意一项所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤 富马酸盐的新晶型的制备方法，包括如下步骤：
    1)将任意形态的9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐在有机溶剂中加热溶解；
    2)将9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的溶解液冷却析晶；
    3)过滤晶体得到目标晶型。
  6. 根据权利要求5所述的制备方法，其特征在于，所述有机溶剂选自乙腈、无水甲醇、无水乙醇、异丙醇、无水甲醇/正庚烷、无水乙醇/正庚烷、异丙醇/正庚烷、无水甲醇/甲基叔丁基醚、无水乙醇/甲基叔丁基醚、异丙醇/甲基叔丁基醚、无水甲醇/异丙醚、无水乙醇/异丙醚、异丙醇/异丙醚、无水甲醇/乙醚、无水乙醇/乙醚或异丙醇/乙醚，其中优选无水甲醇/正庚烷。
  7. 根据权利要求5所述的制备方法，其特征在于，有机溶剂加热溶解温度一般为30℃至回流温度，优选回流温度。
  8. 根据权利要求5所述的制备方法，其特征在于，冷却析晶温度为-40～40℃，其中优选0～10℃。
  9. 药物组合物，其包含如权利要求1-4任意一项所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型，任选的，还包含药学可接受的载体。
  10. 根据权利要求9所述的药物组合物，其特征在于，所述组合物适于口服和注射等给药途径，优选口服给药途径。
  11. 根据权利要求9所述的药物组合物，其特征在于，所述组合物可以制成片剂，胶囊，分散剂和混悬剂，优选片剂。
  12. 根据权利要求1-4任意一项所述的式(I)所示9-[(R)-2-[[(S)-[[[1-(异丙氧基羰基)-1-甲基]乙基]氨基]苯氧基氧膦基]甲氧基]丙基]腺嘌呤富马酸盐的新晶型，或权利要求9-11任意一项所述的药物组合物用于制备治疗或预防艾滋病或乙型病毒性肝炎药物的用途。
PCT/CN2015/084671 2014-07-21 2015-07-21 替诺福韦前药新多晶型及其制备方法和用途 WO2016011932A1 (zh)

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