CN105399771A - 替诺福韦前药晶型及其制备方法和用途 - Google Patents
替诺福韦前药晶型及其制备方法和用途 Download PDFInfo
- Publication number
- CN105399771A CN105399771A CN201410349141.4A CN201410349141A CN105399771A CN 105399771 A CN105399771 A CN 105399771A CN 201410349141 A CN201410349141 A CN 201410349141A CN 105399771 A CN105399771 A CN 105399771A
- Authority
- CN
- China
- Prior art keywords
- methyl
- ethyl
- amino
- group
- phosphinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title description 22
- 239000000651 prodrug Substances 0.000 title description 10
- 229940002612 prodrug Drugs 0.000 title description 10
- 229960004556 tenofovir Drugs 0.000 title 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 28
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229930024421 Adenine Natural products 0.000 claims abstract description 26
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229960000643 adenine Drugs 0.000 claims abstract description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 26
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 26
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 4
- 208000030507 AIDS Diseases 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000004455 differential thermal analysis Methods 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000002672 hepatitis B Diseases 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000006166 lysate Substances 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000000857 drug effect Effects 0.000 abstract description 3
- 238000001228 spectrum Methods 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 241000700605 Viruses Species 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000004926 tubular epithelial cell Anatomy 0.000 description 2
- 108010013043 Acetylesterase Proteins 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 108010020856 N-terminal nucleophile hydrolase Proteins 0.000 description 1
- 102000007990 Organic Anion Transporters Human genes 0.000 description 1
- 108010089503 Organic Anion Transporters Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- -1 glycoside monophosphate Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 230000008316 intracellular mechanism Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000003589 nefrotoxic effect Effects 0.000 description 1
- 231100000381 nephrotoxic Toxicity 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- 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
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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：
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：
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，
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。
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410349141.4A CN105399771B (zh) | 2014-07-21 | 2014-07-21 | 替诺福韦前药晶型及其制备方法和用途 |
| EP15825169.4A EP3173417A4 (en) | 2014-07-21 | 2015-07-21 | New polycrystalline form of tenofovir prodrug, and preparation method and application therefor |
| US15/326,126 US9840525B2 (en) | 2014-07-21 | 2015-07-21 | Crystal form of tenofovir prodrug, preparation method thereof, and method of use thereof |
| BR112017000605-7A BR112017000605B1 (pt) | 2014-07-21 | 2015-07-21 | Forma policristalina do pró-fármaco de tenofovir, seu método de preparação e seu uso, e composição farmacêutica |
| CN201580035392.8A CN106536532B (zh) | 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 |
| RU2017102321A RU2701728C2 (ru) | 2014-07-21 | 2015-07-21 | Новая поликристаллическая форма пролекарства тенофовира и способ ее получения и ее применение |
| TW104123520A TWI718990B (zh) | 2014-07-21 | 2015-07-21 | 替諾福韋前藥新多晶型及其製備方法和用途 |
| PCT/CN2015/084671 WO2016011932A1 (zh) | 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 |
| CA2954395A CA2954395C (en) | 2014-07-21 | 2015-07-21 | New polycrystalline form of tenofovir prodrug, and preparation method and application therefor |
| MX2017000516A MX370639B (es) | 2014-07-21 | 2015-07-21 | Nueva forma policristalina de profármaco tenofovir, y método de preparación y aplicación del mismo. |
| AU2015292050A AU2015292050B2 (en) | 2014-07-21 | 2015-07-21 | New polycrystalline form of tenofovir prodrug, and preparation method and application therefor |
| JP2017500324A JP6872179B2 (ja) | 2014-07-21 | 2015-07-21 | テノホビルプロドラッグの新規な多結晶形並びにその製造方法及び用途 |
| KR1020177002578A KR102476361B1 (ko) | 2014-07-21 | 2015-07-21 | 테노포비르 프로드럭의 신규 다결정형 및 이의 제조방법 및 적용 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410349141.4A CN105399771B (zh) | 2014-07-21 | 2014-07-21 | 替诺福韦前药晶型及其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105399771A true CN105399771A (zh) | 2016-03-16 |
| CN105399771B CN105399771B (zh) | 2020-11-24 |
Family
ID=55162513
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410349141.4A Active CN105399771B (zh) | 2014-07-21 | 2014-07-21 | 替诺福韦前药晶型及其制备方法和用途 |
| CN201580035392.8A Active CN106536532B (zh) | 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 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580035392.8A Active CN106536532B (zh) | 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 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US9840525B2 (zh) |
| EP (1) | EP3173417A4 (zh) |
| JP (1) | JP6872179B2 (zh) |
| KR (1) | KR102476361B1 (zh) |
| CN (2) | CN105399771B (zh) |
| AU (1) | AU2015292050B2 (zh) |
| BR (1) | BR112017000605B1 (zh) |
| CA (1) | CA2954395C (zh) |
| MX (1) | MX370639B (zh) |
| RU (1) | RU2701728C2 (zh) |
| TW (1) | TWI718990B (zh) |
| WO (1) | WO2016011932A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794530A (zh) * | 2017-04-26 | 2018-11-13 | 上海医药工业研究院 | 一种替诺福韦丙酚酰胺盐晶型及其制备方法和用途 |
| CN111096954A (zh) * | 2018-10-29 | 2020-05-05 | 江苏豪森药业集团有限公司 | 一种用于抗病毒感染的药物组合物及制备方法 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4081217A1 (en) | 2019-12-24 | 2022-11-02 | F. Hoffmann-La Roche AG | Pharmaceutical combination of antiviral agents targeting hbv and/or an immune modulator for treatment of hbv |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665043A (zh) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | 一种替诺福韦前药及其在医药上的应用 |
| CN103842366A (zh) * | 2011-10-07 | 2014-06-04 | 吉联亚科学公司 | 制备抗病毒核苷酸类似物的方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2396079A1 (en) * | 2000-01-07 | 2001-07-19 | Transform Pharmaceuticals, Inc. | High-throughput formation, identification, and analysis of diverse solid-forms |
| AU2004206821C1 (en) * | 2003-01-14 | 2009-10-01 | Gilead Sciences, Inc. | Compositions and methods for combination antiviral therapy |
| CN102240295B (zh) * | 2005-06-13 | 2013-04-03 | 博瑞生物医药技术(苏州)有限公司 | 泰诺福韦衍生物及用途 |
| CN100396689C (zh) * | 2006-03-07 | 2008-06-25 | 中国医学科学院医药生物技术研究所 | 一组具有抑制hiv-1/hbv病毒复制活性的替诺福韦单酯化合物 |
| AU2011288091B2 (en) | 2010-08-01 | 2016-06-09 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Crystals of Tenofovir disoproxil fumarate |
| KR101703258B1 (ko) | 2014-12-30 | 2017-02-06 | 한미정밀화학주식회사 | 고순도의 (r)-9-[2-(포스포노메톡시)프로필]아데닌의 제조방법 |
-
2014
- 2014-07-21 CN CN201410349141.4A patent/CN105399771B/zh active Active
-
2015
- 2015-07-21 AU AU2015292050A patent/AU2015292050B2/en active Active
- 2015-07-21 CA CA2954395A patent/CA2954395C/en active Active
- 2015-07-21 CN CN201580035392.8A patent/CN106536532B/zh active Active
- 2015-07-21 WO PCT/CN2015/084671 patent/WO2016011932A1/zh active Application Filing
- 2015-07-21 MX MX2017000516A patent/MX370639B/es active IP Right Grant
- 2015-07-21 KR KR1020177002578A patent/KR102476361B1/ko active IP Right Grant
- 2015-07-21 BR BR112017000605-7A patent/BR112017000605B1/pt active IP Right Grant
- 2015-07-21 EP EP15825169.4A patent/EP3173417A4/en not_active Withdrawn
- 2015-07-21 JP JP2017500324A patent/JP6872179B2/ja active Active
- 2015-07-21 TW TW104123520A patent/TWI718990B/zh active
- 2015-07-21 RU RU2017102321A patent/RU2701728C2/ru active
- 2015-07-21 US US15/326,126 patent/US9840525B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103842366A (zh) * | 2011-10-07 | 2014-06-04 | 吉联亚科学公司 | 制备抗病毒核苷酸类似物的方法 |
| CN103665043A (zh) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | 一种替诺福韦前药及其在医药上的应用 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794530A (zh) * | 2017-04-26 | 2018-11-13 | 上海医药工业研究院 | 一种替诺福韦丙酚酰胺盐晶型及其制备方法和用途 |
| CN111096954A (zh) * | 2018-10-29 | 2020-05-05 | 江苏豪森药业集团有限公司 | 一种用于抗病毒感染的药物组合物及制备方法 |
| CN111386104A (zh) * | 2018-10-29 | 2020-07-07 | 江苏豪森药业集团有限公司 | 一种用于抗病毒感染的药物组合物及制备方法 |
| TWI827715B (zh) * | 2018-10-29 | 2024-01-01 | 大陸商江蘇豪森藥業集團有限公司 | 一種用於抗病毒感染的醫藥組成物及製備方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2017102321A3 (zh) | 2018-12-06 |
| CA2954395A1 (en) | 2016-01-28 |
| CN106536532B (zh) | 2019-09-03 |
| CA2954395C (en) | 2022-08-16 |
| RU2017102321A (ru) | 2018-08-21 |
| US20170204125A1 (en) | 2017-07-20 |
| MX2017000516A (es) | 2017-09-01 |
| AU2015292050B2 (en) | 2019-01-31 |
| KR20170033862A (ko) | 2017-03-27 |
| EP3173417A1 (en) | 2017-05-31 |
| KR102476361B1 (ko) | 2022-12-09 |
| BR112017000605B1 (pt) | 2023-04-18 |
| RU2701728C2 (ru) | 2019-10-01 |
| US9840525B2 (en) | 2017-12-12 |
| CN105399771B (zh) | 2020-11-24 |
| CN106536532A (zh) | 2017-03-22 |
| JP6872179B2 (ja) | 2021-05-19 |
| MX370639B (es) | 2019-12-17 |
| WO2016011932A1 (zh) | 2016-01-28 |
| TWI718990B (zh) | 2021-02-21 |
| AU2015292050A1 (en) | 2017-02-02 |
| EP3173417A4 (en) | 2018-01-03 |
| BR112017000605A2 (pt) | 2017-11-07 |
| JP2017522301A (ja) | 2017-08-10 |
| TW201623323A (zh) | 2016-07-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102057751B1 (ko) | 테노포비르 전구약물 및 그의 약학적 용도 | |
| KR101470715B1 (ko) | 다사티닙 다결정체 및 그의 제조방법과 약물 조성물 | |
| CN102240297B (zh) | 泰诺福韦的晶体 | |
| CN101778855A (zh) | 替诺福韦酯半富马酸共晶体 | |
| UA125655C2 (uk) | Терапевтичні дендримери | |
| IL238217A (en) | Phosphonate ester derivatives and their synthesis methods | |
| CN106458881A (zh) | 类胡萝卜素衍生物、其药学上可接受的盐或者其药学上可接受的酯类或酰胺类 | |
| CN104804042B (zh) | 核苷酸膦酸酯类化合物、其药物组合物、制备方法及用途 | |
| CN105399771A (zh) | 替诺福韦前药晶型及其制备方法和用途 | |
| CN107445994A (zh) | 替诺福韦艾拉酚胺半富马酸盐新晶型 | |
| CN108101943B (zh) | 一种替诺福韦前药或可药用盐及其在医药上的应用 | |
| CN110407878A (zh) | 替诺福韦前药晶型及其制备方法和用途 | |
| CN109790154A (zh) | 用于治疗病毒感染和另外的疾病的嘧啶前药 | |
| CN102485229A (zh) | 抗病毒药物 | |
| JP5589097B2 (ja) | ダサチニブ多結晶体、並びにその調製方法及び薬物組成物 | |
| CN102491995A (zh) | 一种替诺福韦单酯的制备方法 | |
| CN116903658A (zh) | 含氮稠杂环类化合物晶型及其制备方法和应用 | |
| CN103804416A (zh) | 阿昔洛韦的磷酸酯衍生物及其医药用途 | |
| CN117510543A (zh) | 艾米替诺福韦马来酸盐晶型及其制备方法和应用 | |
| US20150175640A1 (en) | Forms of cidofovir | |
| CN111909205A (zh) | 一种替诺福韦双丙酸酯基氨基磷酸酯化合物及其药物组合物和用途 | |
| CN103641857A (zh) | 一种替诺福韦新晶型及其制备方法 | |
| KR20150005818A (ko) | 신규한 테노포비어 디소프록실 오로테이트 및 이의 제조방법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160314 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222006 Jiangsu province Lianyungang Kaitai Dapu Industrial Zone, economic and Technological Development Zone Road Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. |
|
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20201105 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Changzhou Hengbang Pharmaceutical Co.,Ltd. Address before: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |