CN114698374A - 用于改善维生素e的易分解且相连的氧化还原惰性的类似物 - Google Patents
用于改善维生素e的易分解且相连的氧化还原惰性的类似物 Download PDFInfo
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- CN114698374A CN114698374A CN202180005851.3A CN202180005851A CN114698374A CN 114698374 A CN114698374 A CN 114698374A CN 202180005851 A CN202180005851 A CN 202180005851A CN 114698374 A CN114698374 A CN 114698374A
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- vitamin
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- tocotrienol
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- 239000011709 vitamin E Substances 0.000 title claims abstract description 94
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- FGYKUFVNYVMTAM-UHFFFAOYSA-N (R)-2,5,8-trimethyl-2-(4,8,12-trimethyl-trideca-3t,7t,11-trienyl)-chroman-6-ol Chemical group OC1=CC(C)=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-UHFFFAOYSA-N 0.000 claims description 4
- GZIFEOYASATJEH-UHFFFAOYSA-N D-delta tocopherol Chemical group OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-UHFFFAOYSA-N 0.000 claims description 4
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
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- FGYKUFVNYVMTAM-YMCDKREISA-N beta-Tocotrienol Chemical group Oc1c(C)c2c(c(C)c1)O[C@@](CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)(C)CC2 FGYKUFVNYVMTAM-YMCDKREISA-N 0.000 claims description 4
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- 125000005456 glyceride group Chemical group 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明提供了一种合成维生素E类似物和有用衍生物的新方法。本发明提供了用于衍生维生素E以产生具有改进的生物利用度、用于诊断用途的放射性标记能力分子的新方法,以及用于从天然植物油源中分离或纯化维生素E的改进方法。
Description
技术领域
本发明涉及天然产品、营养保健品和抗氧化剂的化学改性领域,适用于维生素E。
背景技术
本申请中引用的所有出版物、专利和专利申请均以引用的方式整体并入本文,其程度与每一单独出版物、专利申请或专利的公开内容被具体和单独指出通过引用全部并入相同。
维生素E家族由八种色原醇类似物组成,它们分为两个亚家族:生育酚(TPs)和生育三烯酚(T-3s)(图1)。这些家族通过色原醇-C2的烃链进一步识别和区分。尽管T-3s具有带有三个非共轭双键(C3'-C4'、C7'-C8'、C11'-C12')的C-2类异戊二烯侧链,而TPs具有相同但完全饱和的链。四种天然存在的TP和T-3类似物(α-、β-、γ-、δ-)仅通过芳族色原醇环上C5、C7和C8处甲基取代的变化而相互区别。
维生素E类似物是重要的天然抗氧化剂,通过与自由基相互作用来保护细胞。越来越多的证据表明,包括抗癌、抗炎和神经保护活性在内的其他维生素E药用特性可能与其抗氧化作用同样重要。特定的生化相互作用可以降低血液中的胆固醇和血压,逆转动脉粥样硬化,最大限度地减少中风相关的脑损伤,刺激头发再生,并防止晒伤皮肤。维生素E类似物y-T-3,存在于许多植物油中,尤其是棕榈油、胭脂树(annatto)油和米糠油;癌症研究人员特别感兴趣。
维生素E的药理学、代谢作用和分子生物学仍然是科学研究的主题。通常,双环(色原醇)部分负责抗氧化特性,而C2的烃侧链有两个功能:近端部分赋予信号活性,远端(末端)烃尾赋予额外的疏水性,促进与亲脂性细胞成分的相互作用(图2)。侧链末端受到C-13'处的细胞色素P4504F2(CYP4F2)的氧化攻击,导致ω-羟基化,随后从C-13'开始的一系列连续β氧化,破坏侧链并留下水溶性羧乙基羟基色满(carboxyethylhydroxychroman)或羧甲基丁基羟基色满(carboxymethylbutyl hydroxychroman)核心。据报道,色满部分芳环的氧化也会产生少量代谢物。
本领域需要新的维生素E类似物,以支持其在生物基质中的体内、体外和原位检测和定量。此外,本领域需要改善用于分离维生素E的方法,以及改善的原药,促进其从肠腔中吸收并改善跨质膜的一般运输。
发明内容
本发明提供了维生素E类似物的新衍生物的合成。这些新的维生素E加合物包括但不限于能够在体内进行药理学、药物学、组织病理学和分子研究的化合物,以及那些简化或改善维生素E从其天然来源的回收、以及改善动物或人类摄入后的口服生物利用度的化合物。
此外,本发明提供了生产营养学、药理学和药学活性化合物,包括有助于诊断和治疗文献中归因于维生素E的临床病症的化合物,作为有助于发现维生素E的药理学和药代动力学特征的试剂,作为有助于从天然来源中分离维生素E的中间药剂,以及有助于改善天然维生素E的口服吸收和生物利用度。
在一个方面,本发明提供了式(I)的化合物,
维生素E——LNK——REG (I)
其中,维生素E是α-生育酚、β-生育酚、γ-生育酚、δ-生育酚、α-生育三烯酚、β-生育三烯酚、γ-生育三烯酚或δ-生育三烯酚;其中LNK是通过醚键、氨基甲酸酯键或酯键与维生素E组分上的C6氧连接的直链烃或支链烃或取代烃,并且具有适合被亲核报告元素置换的反应中心;以及其中REG是报告元素或基团,其是化学亲核试剂。在一个实施方案中,REG是充当荧光基团、发色基团、放射性元素或核磁共振响应中心的卤化物、叠氮化物、报告基团。在另一个实施方案中,卤化物是碘、溴、氟或氯。在另一个实施方案中,卤化物是碘、溴、氟、氯的放射性同位素。在另一个实施方案中,核磁共振响应中心是单氟化、二氟化、三氟化或多氟化实体。在另一个实施方案中,荧光团是硝基苯并恶二唑或5氟硫氰酸(sulfo-cyanine5 fluor)。在另一个实施方案中,发色基团是活化芳族。在另一个实施方案中,活化芳族是硝化芳族。
在另一方面,本发明提供式(II)的化合物
维生素E——LNK——GRP (II)
其中维生素E是α-生育酚、β-生育酚、γ-生育酚、δ-生育酚、α-生育三烯酚、β-生育三烯酚、γ-生育三烯酚;其中LNK是通过醚键、氨基甲酸酯键或酯键与维生素E组分上的C6氧连接的直链烃或支链烃或取代烃,并且具有适合被亲核报告元素置换的反应中心;并且其中GRP是改变化合物的维生素E组分性质的功能元素。在一个实施方案中,GRP是单糖、二糖、多糖、甘油酸、氨基酸或无机酸;导致化合物的维生素E组分的亲脂性降低。在另一个实施方案中,单糖、二糖或多糖是糖醛酸、葡糖酸、葡萄糖醛酸、抗坏血酸、乳糖醛酸或糖酸。在另一个实施方案中,GRP在哺乳动物提供改善的口服吸收。在另一个实施方案中,LNK通过二酯与维生素E组分上的C6氧连接,并且GRP是甘油酯。在另一个实施方案中,GRP在哺乳动物中提供改善的口服生物利用度。在另一个实施方案中,LNK通过二酯与维生素E成分上的C6氧连接,并且GRP是甘油酯。在另一个实施方案中,LNK通过与甘油酸的单酯化或经由二甲酸酯连接剂的单酯化与维生素E组分上的C6氧连接,从而使得该化合物可经酸水解产生维生素E、甘油和二甲酸盐。
在另一个方面,本发明提供了一种从含有维生素E的天然植物油馏出物中分离维生素E的方法,包括通过添加三氟乙酸酯使葡萄糖醛酸糖上的羟基酯化产生受保护的葡萄糖醛酸,将受保护的葡萄糖醛酸添加到所述天然植物油馏出物中产生维生素E葡萄糖醛酸盐,将稀释的氟乙酸盐添加到所述维生素E葡萄糖醛酸盐中,并用水从所得混合物中提取维生素E。在一个实施方案中,用水从所得混合物中提取维生素E,还包括添加乙醚和稀释的碳酸钠水溶液。
另一方面,本发明提供式(III)的化合物
其中R1为H或CH3;R2是H或CH3;R3是H或CH3;R4是H、维生素C或H2NC(CH2OH)3。
另一方面,本发明提供式(IV)的化合物
其中R1为H或CH3;R2是H或CH3;R3是H或CH3;R4是H、维生素C或H2NC(CH2OH)3。
附图说明
图1显示了维生素E的八种天然类似物的化学结构示意图;
图2显示了γ-生育三烯酚(γ-T-3)的化学结构和其主要结构域的一般分子生物学;
图3显示了本发明化合物的通用合成方法的示意图;
图4显示了使用甲苯磺酸酯和甲磺酰基并以F/[18F]作为报告元素/基团(REG)合成F-γ-T-3和[18F]F-γ-T-3的通用方法的示意图;
图5显示了放射性氟化后由γ-T-3合成的F-γ-T-3和TsO-γ-T-3反应混合物的代表性HPLC放射性-紫外共色谱图;
图6显示了F-γ-T-3的部分1H NMR光谱;
图7显示了尾静脉注射[18F]F-γ-T-3后的F-18在小鼠体内的生物分布正电子发射断层扫描(PET)图像;
图8显示了合成亲水性维生素E衍生物的通用方法的示意图;
图9显示了设计用于跨质膜转运的维生素E酯的合成示意图;
图10显示了在叠氮化物和炔烃衍生的维生素E上“点击”插入报告元素(REs)的示意性反应;
图11显示了使用本发明的方法产生的化合物的化学结构;
图12显示了涉及炔烃和叠氮化物的一般铜催化“点击”反应;
图13显示了制备NBD-APy-T-3的反应示意图;和
图14显示了能够使用本发明的方法生产的其他示例性化合物。
具体实施方式
本发明部分地提供了用于维生素E体内研究的放射性标记示踪剂的制备,包括但不限于放射性标记的γ-生育三烯酚(γ-T-3)。
如本文所用,“维生素E”是指维生素E家族的所有8种天然类似物,并用作该色原醇家族的所有8种天然类似物(4种生育酚和4种生育三烯酚)的统称;所有这些都根据IUPAC/IUB术语(1982,Eur J Biochem 123:473-475)进一步描述并呈现在图1中。生育酚(TP)和生育三烯酚(T-3)的缩写是由1973年IUPAC-IUB生化命名委员会(CBN)的建议提供的,具有异戊二烯侧链的醌类命名法(1975,Eur.J.Biochem.53:15-18)。
如本文所用,“烷基”是指具有1-12个碳原子的直链或支链烷基,最常见的是1-4个碳原子。烷基可以是取代或未取代的环烷基或带有一个或多个取代基的短烷基,例如羟基、烷氧基、芳基、巯基、卤素、三氟甲基、氰基、硝基、氨基、羧基、氨基甲酸酯(carbamate)、磺酰基(sulfonyl)、磺酰胺(sulfonamide)等。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基、环己基等。
如本文所用,“烷氧基”是指式RO-的化合物,其中R是如上所述的烷基(其可以是取代的或未取代的,除非另有说明)。
如本文所用,“烯基”是指直链或支链烃基,例如上述的烷基(包括取代基)并且具有至少一个碳-碳双键。
如本文所用,“炔基”是指直链或支链烃基,例如烷基、取代的和未取代的、饱和的和不饱和的,并且具有至少一个碳-碳三键。
如本文所用,“芳基”是指具有一个或多个芳香环的单环碳环系统或双环碳环稠环系统,包括但不限于萘基、苯基、四氢萘基等。芳基可以被取代或未被取代,并且当被取代时可以被1、2、3、4或5个取代基取代,这些取代基选自多种取代基,例如烷基、烯基、烯氧基、烷氧基、烷氧基烷氧基(alkoxyalkoxy)、烷氧基羰基(alkoxycarbonyl)、烷基羰基(alkylcarbonyl)、烷基磺酰基、烷硫基、炔基、芳基、芳氧基、叠氮基、芳基烷氧基、芳烷基、芳氧基、羧基、氰基、甲酰基、卤素、卤代烷基、卤代烷氧基、羟基、羟烷基(hydroxyalkyl)、巯基、硝基、磺酸盐(sulfonate)。
如本文所用,“卤素”是指选自氟、氯、溴和碘的原子。
如本文所用,“LEG”是指包括亲核物质的离去组分,其接受来自亲核试剂的一对电子(电子供体,本文称为报告元素/基团,REG)。LEGs包括但不限于卤化物(例如I、Br、Cl)、磺酸(例如甲苯磺酰基(tosyl)、甲磺酰基(nosyl)、甲磺酸盐(mesyl))、羧酸和质子化胺。
如本文所用,“REG”是指化学亲核体的报告元素/基团,可以通过亲核反应置换LEG。包括卤化物(包括I、Br、F、Cl的放射性同位素)、叠氮化物、充当荧光基团的报告部分(REs)(包括但不限于NBD、Cy5和其他普通荧光试剂)、发色基团(包括但不限于硝化芳烃和其他活化芳族)、放射性(包括但不限于F-18、F-19、I-123、I-124、I-125、I-131)和NMR响应中心(包括单氟化、二氟化、三氟化和多氟化实体)。
如本文所用,“CG”是指点击基团,其包括可用于通过“点击”化学反应引入报道元件(CCR)的活性组分(参见例如,Angew.Chem.Int.Ed.,2002,41:2596)。LNK上的CG(叠氮化物或“炔(yne)”碳三键)与相应的“炔(yne)”或叠氮化物(CCR)反应形成所需的Vit E-CCR(方程式1)。
Vit E-LNK-CG’+CCR(‘yne’或N3,各自地)→Vit E-LNK-CCR方程式1
如本文所用,“CCR”是指点击化学报告分子,是报告部分,包括荧光基团(包括但不限于NBD、Cy5和其他常见的荧光试剂)、发色基团(包括但不限于硝化芳烃和其他活化的芳烃)、放射性同位素(包括但不限于F-19、I-123、I-124、I-125、I-131)和NMR响应中心(包括单氟化、二氟化、三氟化和多氟化实体)。这些CCRs的区别在于具有叠氮化物或“yne”焦点,它们将与Vit E-LNK-N3/'yne'合成子上的“yne”或叠氮化物反应。
如本文所用,“亲核体”是指提供电子对以形成与反应相关的化学键的化学物质。实例包括但不限于卤化物、硫醇、叠氮化物、胺和腈。
如本文所用,“LNK”是指通过醚键、氨基甲酸酯键或酯键与C6-O-连接的直链烃或支链烃或取代烃(C=1-12)(例如,烷基、烯基、炔基、芳基),并具有适合被亲核报告元素(RE;例如卤素;放射性卤素;荧光基团、NMR报道分子、发色基团)置换的反应中心(离去元素/基团,LEG,例如磺酰基、叠氮化物、卤化物)。
本发明提供了将报告元素/基团(REG)并入通常描述为REG-LNK-维生素E的维生素E结构中的新方法。通过本发明的方法产生的新型化合物在维生素E在细胞、组织和整个生物体中分布的非侵入性成像、空间和动力学分析中具有特别的用途,并且在该成像中提供了更大的可及性、敏感性和特异性;不破坏维生素E类似物的固有特性。本领域技术人员将认识到使用本文所述的REG-LNK-维生素E结构的已知报告元素/基团的效用,用于全身成像(放射性-PET、SPECT和平面;光学-荧光测定;磁共振-MRI、MRS)、组织病理学和分子分析,用于药理学、药代动力学、药物代谢和分子生物学治疗疾病。
本发明进一步提供了从天然来源(包括但不限于植物油)中回收维生素E的新方法。尽管目前的方法需要蒸馏和色谱序列,在维生素E上使用的C6-O-原位酯衍生化将高度亲脂的维生素E转化为更亲水的加合物,这些加合物可以通过水萃取从原始油中去除,并通过水溶性部分的简单水萃取回收并留下原始浓缩的亲脂性维生素E类似物。本发明提供了多元酸作为所述亲水性加合物的用途,包括但不限于葡萄糖醛酸、抗坏血酸、糖酸以及天然和合成的多羟基化单体、二聚体和聚合物,包括合适的糖衍生物。
本发明还提供了合成维生素E-甘油单酸酯(mono-glyceric acid ester)的新方法及其用作维生素E生物利用度增强剂的应用。如图9所示的示意图,通过在C6-O处与甘油酸酯化对维生素E进行衍生化,所得甘油单酯加合物成为天然脂质的结构模拟物,并因此利用身体的自然方法使脂质跨膜移动(例如,肠上皮;一般的质膜)。此外,C6-O与多元酸(例如,葡萄糖醛酸(gluronate))的酯化,使维生素E在肠腔内可以通过自缔合、胶束形成和乳化获得更大的分散。
如现有技术中已知的,将报道元素/基团(REG)如放射性同位素、荧光物质和NMR响应性全氟部分引入维生素E类似物的可选择方式非常少:维生素E的化学结构及其被赋予的区域结构-活性关系受到很大限制。放射性标记选项分为两大类:影响氧化还原电位和生物氧化特性的选项(例如,C6-OH的改变/取代),以及改变归因于C2链的信号、对接和代谢降解的选项(例如,T-3s的类异戊二烯双键上的取代)。后一种选择不适用于TPs,而对于T-3s,需要在链的某处创建一个反应中心;这需要大量的化学合成,并对这些分子的生物物理特性产生关键的改变。在C6-O以外的芳香烃位点加入示踪元素同样需要进行大量的化学修饰,这是一项繁琐而困难的练习,导致化合物与膜和大分子靶标的相互作用被调节,以及吸收和生物分布模式被改变。许多报道的天然TPs和T-3s的合成衍生物是基于C6-OH上的取代。本发明提供了一种在C6-O处的修复连接臂(prosthetic linking arm)引入REGs(放射性标记、荧光物质、氟化组分)的新方法,作为报道标记所有维生素E类似物的有效方法。图7展示了F-18PET图像,显示了在尾静脉注射(intravenous tail veil injections)本发明化合物[18F]F-y-T-3(左图)和参照物[18F]氟-D-葡萄糖(FDG,右图)后小鼠体内放射性的生物分布情况。[18F]F-γ-T-3图像是在注射2小时后拍摄的,而[18F]氟-D-葡萄糖是在注射后90分钟获得的,在[18F]F-γ-T-3研究24小时后使用同一只动物。
本发明考虑了连接结构LNK的各种组成;作为非限制性示例,烷基1C至12C;LNK在C6-O处的化学选择(例如,O-烷基;O-氨基甲酸酯)和和反应条件对本领域技术人员是显而易见的。本领域技术人员将认识到,产品的化学结构取决于特定的起始化合物(维生素E类似物)和功能成分(例如,LNKs、LEGs、REGs、催化剂、引发剂);除非明确说明,否则本文披露的反应条件可能不会针对特定起始化合物和功能成分的产率或纯度进行优化。使用本文所述方法合成化合物过程中所使用的试剂质量、反应时间和温度将落入其他(非维生素E)化合物通常报道的范围内。“点击”反应(如本文进一步描述的)被设计为与C6-O-烷基叠氮基或C6-O-炔基中间体(LNKs)及其反试剂(分别为炔基官能部分和叠氮基官能部分)共同作用。
本发明提供但不限于一种通过LNK部分在C6-O处与维生素E结合适当LEG键的亲核置换方法。LEG的这种亲核置换受REG影响,从而将REG引入结构中。在放射性氟化以制备[18F]F-维生素E的情况下,通过亲核REG置换适当的维生素E合成物上的LEG(图3和式2)。一般方法获得的产物如图3所示,特别适用于制备具有改善的生物利用度、溶解度、无损成像(non-invasive imaging)的维生素E类似物,并在式2中提供了有效的中间体:
Vitamin E-LNK-LEG+REG→Vitamin E-LNK-REG+LEG式2。
本发明提供了一种使用双功能LNKs将亲核REGs引入维生素E的新方法,如本领域已知的和通过非限制性示例的方法18F(CH2)nX(n=1-3,X=Br,OMes,OTos)(1988,J LabelCompd Radiopharmaceut.25:201-216)。这种合成是通过首先将REG连接到LNK,然后将LNK连接到C6-O处的维生素E(式3)来实现的。例如,放射性氟化物和甲磺酸盐丙醇制备成1-甲磺酰基-3-氟丙烷,然后将其连接到T-3以制备18F]F-γ-T-3:
Vitamin E+LEG-LNK-REG→Vitamin E-LNK-REG+LEG 式(3)
本领域技术人员将认识到,式2和式3中提供的合成方法能够产生相同的产物,并且两种方法都旨在生产本发明的化合物,基于特定的需要和反应条件选择合成方法。
本发明提供但不限于使用本领域已知的双功能LNKs结构将亲核REGs引入维生素E的新方法。通过非限制性示例,图3提供了反应的一般示意图,图4提供了3-氟-1-丙醇的甲磺酰化,然后用γ-T-3对其甲磺酰基进行亲核取代,以61%的产率完成目标F-γ-T-3(试剂和条件:(a)MsCl,E13N,DCM,室温(r.t.),30min,92.7%;(b)CSC03、DMF、r.t.)和TsO-γ-T-3的放射氟化提供了足够的放射化学产率(RCY 12%),无需进一步优化。高效液相色谱(HPLC)提供0.5-1GBq高纯度(RCP>99%)[18F]F-γ-T-3。一种特定的梯度HPLC方法产生高放射性色谱纯度产品,没有检测到放射化学杂质。通过亲核放射性氟化获得的高比活性产物不能通过紫外光吸收检测,但添加内部标准F-γ-T-3能够在14.4分钟处产生一个峰值,直接低于共色谱时[18F]F-γ-T-3的放射性峰(图5)。如图5所示,在14.4分钟洗脱的291nm和254nm峰以及放射性峰(14.4分钟;痕量501)代表反应混合物中的真实F-γ-T-3(痕量502)和产物[18F]F-γ-T-3的共混物。痕量503中的吸收峰(291nm)对应于甲基取代的6-色原醇(苯并吡喃)环系统(例如,F-γ-T-3,TsO-γ-T-3)的主要紫外吸收带,痕量504(254nm)是一个选择性较差的芳香性指标。主要紫外吸收峰505在10.1分钟洗脱(291nm和254nm)代表未消耗的TsO-γ-T-3;在早期洗脱的吸收峰是未被识别的。这些化合物的标准检测需要注意其在硅胶色谱下的潜在不稳定性和对紫外线的敏感性。
作为非限制性示例,F-γ-T-3和TsO-γ-T-3由γ-T-3合成,可接受的化学产率分别为61%和48%(图4)。为这项工作开发的等度HPLC系统在TsO-γ-T-3和F-γ-T-3之间提供了良好的分离。TsO-γ-T-3和F-γ-T-3的混合物的色谱图显示存在几种未鉴定的少量杂质(图5)。图6表明F-γ-T-3的部分1HNMR图谱显示出C6-O处氟丙氧基取代基的独特耦合模式;特别是F-γ-T-3的CH2-1,它显示出独特的dt(三重态双峰(doublet of triplet))耦合模式,耦合常数J=47.1和5.9Hz,分别表示F-H和H-H耦合。这些共振与其他脂肪族-H共振完全分离,因此可用于区分F-γ-T-3和未取代的T-3s。
作为非限制性实例,[18F]F-y-T-3以未添加载体的(NCA)比活度(SA)生产和使用。NCA[18F]氟化物的理论SA为6.3TBq/μmol,但实际上,由于试剂和材料中普遍存在氟,无需额外添加氟,将NCA产品的氟含量减少到30-150GBq(1-5Ci/μmol),尽管已经报道了SA为0.1-1.9TBq(3-51Ci)/μmol(J Nucl Med 2012,53:434)。在150GBq/mmol时,14.8MBq的注入放射性剂量代表约1nmol的Fy-T-3,该剂量不太可能调节大多数维生素E相关过程,并与组织中发现的低维生素E浓度一致。至少在人体中,维生素E类似物的药代动力学参数在大剂量范围内似乎没有剂量依赖性,因此特定的活性可能对于标记的维生素E类似物作为诊断剂的有效性不是关键的。
实施例1:制备的常规条件。
为了制备、分析和量化实施例中呈现的化合物,采用以下常规条件。本领域技术人员将认识到,这些是常规反应条件和程序,能够按照本领域已知情况进行变化。
反应用的溶剂在氩气氛围下连续通过氧化铝和铜柱进行纯化。试剂购自商业来源,除非另有说明,否则无需进一步纯化即可使用。所有反应均在正压氩气气氛下进行,通过薄层色谱法(TLC)在Whatman MK6P硅胶微TLC板(25μm厚)或硅胶G-25UV254(0.25mm)微孔板上使用己烷:EtOAc(1:3,v/v)(溶剂系统A)和己烷:EtOAc(1:1,v/v)(溶剂体系B)作为显影溶剂进行监测。TLC斑点在紫外光(uv)下和/或通过用茴香醛在乙醇、乙酸和H2SO4中的溶液炭化来检测。在Merck 7734硅胶上进行柱层析(100-200μm粒径)。
为了分析,1H和13C NMR光谱分别记录在498.118MHz和125.266MHz,而19F NMR光谱记录在468.652MHz。1H/19F NMR化学位移参照TMS(0.0,CDCb)和13C NMR化学位移参照CDCl(d 77.23)。1H NMR数据被报告为一阶数据,并且峰值分配基于2D-NMR(1H-1H COZY和HMQC)实验(图6)。在Agilent 1100LC/MS上使用Agilent Zorbax C-18色谱柱(2.1×50mm,5μM)或带有Xcalibur数据采集和解释软件的Q ExactiveTMHybrid Quadrupole-OrbitrapTM质谱仪记录质谱。
用于放射性氟化的乙腈(CH3CN)和Kryptofix2.2.2(K222)购自Merck(Da rmstadt,Germany),干燥的二甲基亚砜(DMSO)购自Sigma Aldrich。Sep-Pak light、Accell PlusQMA和Alumina N暗盒(cartridges)来自美国Wa ters。Phenomenex Luna预柱(C18/2,50×10mm;5μm),Phenomenex Nucl eosil柱(C18,250×10mm;5μm和C18,250×4.6mm)和0.22μmMillex GS和LX过滤器来自美国Millipore公司。NCA[18F]氟化物通过180(p,n)18F核反应从PETtrace 16.5MeV回旋加速器获得,该回旋加速器包括高压铌靶(Cyc1otek(AUST)Pty.Ltd.)。用0.5M K2CO3预处理F-18分离柱(Waters Acc ell Plus QMA Sep-Pak Light,Kent,UK),随后用水冲洗。使用Shimadz u HPLC(SCL-1OA VP系统控制器、SIL-10ADVP自动进样器、LC-10AT VP溶剂输送单元、CV-10AL控制阀、DGU-14A脱气机和SPD-10A VPV检测器,MD,USA)进行放射性HPLC分析,Q6耦合到闪烁探测器(Ortec276光电倍增管底座,带前置放大器、Ortec 925-SCINTACE mate前置放大器、放大器、BIAS supply电源和SCA,以及Bicron1M 11/2光电倍增管)。
图11提供了使用本文所述的方法和使用所披露的实施例中提供的那些方法和条件制备的示例化合物;而图14提供了可通过使用本文描述的方法产生的其他化合物。
实施例2(R)-6-(3-氟丙氧基)-2,7,8-三甲基-2-(4,8,12-三甲基十三烷-3,7,11-三烯-1-基)-色烷((R)-6-(3-Fluoropropox)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-l-yl)-chromane)(F-γ-T-3)
将粉末状的CS2CO3(3.18g,9.77mmol)添加到含有3-氟丙基甲磺酸(1.52g,9.77mmol)和γ-T-3(1.50g,3.66mmol)在DMF(15mL)中的混合物。将所得混合物在室温下搅拌过夜,然后用Et2O(100mL)稀释并用水(50mL)洗涤。水溶液用Et2O(2×50mL)萃取,所得有机溶液用盐水(50mL)洗涤,经无水Na2SO4干燥并过滤。将滤液浓缩并通过硅胶柱色谱纯化,用0-5%的EtOAc在己烷中洗脱,得到F-γ-T-3,为淡黄色油状物(1.05g,61%):19FNMR(468.652MHz,CDCl3):δ=-11.71(tt,J=47.1,25.5Hz);lH NMR(498.118MHz,CDCl3)δ=6.50(s,1H,Ar),5.27-5.12(m,3H),4.72(dt,J=47.1,5.9Hz,2H,CH2-1),4.06(t,J=6.0Hz,2H,CH2-3),2.85-2.72(m,2H),2.28-2.17(m,10H,包括CH2-2,2.17-2.10(m,4H),2.05(dd,J=8.6,4.9Hz,4H),1.83(ddt,J=36.5,13.2,6.8Hz,2H),l.75(d,J=l.4Hz,3H),1.71(dd,J=9.1,7.6Hz,1H),1.69-1.64(m,9H),1.64-1.59(m,1H),1.33(s,3H);13C NMR(125.266MHz,CDCl3)δ=149.82,145.95,135.07,134.95,131.21,125.98,124.62,124.26,117.51,109.97,81.74,80.43,77.33,77.08,76.82,75.27,64.57,64.52,39.89,39.77,39.75,31.53,30.92,30.76,26.82,26.66,25.73,24.06,22.66,22.28,17.72,16.04,15.93,11.91,11.89;HRMS(ESI):计算C31H48FO2 m/z:471.3638[M+H+];得到:471.3630。
实施例3:(R)-6-(3-碘丙氧基)-2,7,8-三甲基-2-(4,8,12-三甲基-3,7,11-三烯-1-基)-色烷((R)-6-(3-Iodopropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-l-yl)-chromane)(I-γ-T-3)
将γ-T-3(0.30g)添加到含有1,3-二碘丙烷(2eq)和CS2CO3(2eq)9.77在DMF(15mL)中的混合物中;在室温下搅拌过夜,然后用Et2O(100mL)稀释并用水(50mL)洗涤。将其水溶液用Et2O(2×50mL)萃取,所得有机溶液用盐水(50mL)洗涤,经无水Na2SO4干燥并过滤。将滤液浓缩并通过硅胶柱色谱法纯化,用0-5%的EtOAc在己烷中洗脱,得到F-γ-T-3,为不纯的淡黄色油状物(83%)。通过硅胶柱色谱法用0~10%EtOAc/己烷进行再纯化,得到(I-γ-T-3);162毫克;质量579.5[M+H]+,C31H47IO2计算值578.26。
实施例4:(R)-6-(3-甲苯磺酰丙氧基)-2,7,8-三甲基-2-(4,8,12-三甲基-十三烷-3,7,11-三烯-1-基)色满((R)-6-(3-Tosyl-propoxy)-2,4,8-trimethyl-2-(4,8,12-trimethyl-trideca-3,7,11-trien-l-yl)chroman)(TsO-γ-T-3)
将粉末状的CS2CO3(4.24g,13.0mmol)添加到含有γ-T-3(2g,4.87mmol)和1,3-二甲苯磺基丙烷(ditosylpropane)(5g,13.0mmol)在DMF(20mL)中的混合物。将所得混合物在室温下搅拌过夜。然后将混合物用EtOAc(20mL)和水(50mL)稀释,最后用EtOAc(2×20mL)萃取。合并的有机溶液用水(50mL)洗涤。有机溶液用Na2SO4干燥。过滤后,将滤液浓缩并通过硅胶柱色谱纯化,用DCM洗脱,得到黄色油状物TsO-γ-T-3,产率为48%(1.45g):1HNMR(498.118MHz,CDCl3):δ=7.78(d,J=8.2Hz,2H,Ar),7.27(d,J=7.8Hz,2H,Ar),6.34(s,1H,Ar),5.40-4.97(m,2H),4.28(t,J=6.1Hz,2H,CH2-1),3.89(t,J=5.8Hz,2H,CH2-3),2.78-2.66(m,2H),2.41(s,3H,CH3),2.20-2.07(m,6H,包括CH2-2,2.02-1.94(m,5H),1.87-1.49(m,18H),1.35-1.17(m,6H),1.09-0.83(m,3H);13C NMR(125.266MHz,CDCl3)δ=182.23,149.44,145.89,144.65,132.92,129.76,127.85,125.84,124.30,117.42,109.56,77.31,77.06,76.80,75.27,71.42,67.48,63.88,39.88,39.72,36.93,35.00,31.48,29.22,25.71,24.07,23.09,22.63,22.23,21.59,17.70,16.55,15.82,11.88,11.74;HRMS(ESI):计算C38H54O5S的m/z:623.3765[M+H]+;得到:623.3760。
实施例5:(R)-6-(3-[18F]氟丙氧基)-2,7,8-三甲基-2-(4,8,12-三甲基十三烷-3,7,11-三烯-1-基)-色烷((R)-6-(3-[18F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-l-yl)-chromane)([18F]F-γ-T-3)的辐射合成
将H2[18O]O中的[18F]氟化物被转移到Tracerlab PXFN放射合成模块,并通过预处理的QMA暗盒。使用由在CH3CN和H2O(1mL,80:20)中K2C2O4(2.5mg)、K222(10mg)和K2CO3(10mL的5mg/mL溶液)将捕获的[18F]氟化物(3-7GBq)洗脱到反应器中。将该溶液在氦气流和真空下于65℃蒸发7分钟至干燥,然后在真空下于120℃加热7分钟。将CH3CN中的甲苯磺酸盐前体(TsO-y-T-3;10mg)添加到无水K[18F]F/K222残余物中,然后在100℃下加热10分钟。然后用流动相(EtOH-H2O,1.5mL)稀释放射性反应混合物并转移到环形注射瓶中。制备型HPLC(图4)[(Nucleosil C18,300mm×16mm),流动相H2O:EtOH(90:10),流速3mL/min]得到[18F]F-γ-T-3(0.5-1.0GBq;12%RCY;>99%RCP),总制备时间为45min。[18F]F-γ-T-3在EtOH:丙二醇(PPG):盐水(0.9%)(25:25:50)中配制,并直接用于小动物成像研究。
实施例6:(R)-6-(3-叠氮-丙氧基)-2,7,8-三甲基-2-(4,8,12-三甲基-癸-3,7,11-三烯-1-基)-色烷((R)-6-(3-azido-propoxy))-2,7,8-trimethyl-2-(4,8,12-trimethyltri-deca-3,7,11-trien-1-yl)-chromane)(N3-T-3).
将CS2CO3(3.18g,9.77mmol)加入到含有3-叠氮丙基甲磺酸盐(3-azidopropylmesylate)(1.75g,9.77mmol)和γ-T-3(1.50g,3.66mmol)在DMF(15mL)中的混合物中。将得到的混合物在室温下过夜搅拌。混合物用100mL的Et2O稀释并用水(50mL)洗涤。用Et2O(2×50mL)萃取水溶液。合并的有机溶液用盐水(50mL)洗涤。有机溶液用Na2SO4干燥。过滤之后,将滤液浓缩并通过硅胶柱色谱法纯化,用0-5%EtOAc在己烷中洗脱,得到黄色油状物N3-T-3,产率为67.8%(1.22g)。
实施例7:(R)-6-(3-(4-氨基-NBD-丙氧基))-2,7,8-三甲基-2-(4,8,12-三甲基十三烷-3,7,11-三烯-1-基)-色烷((R)-6-(3-(4-amino-NBD-propoxy))-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane)(NBDA-T-3).
将Ph3P(210mg,0.768mmol)添加到含有4-氨基-(3-羟丙基)-NBD(64.5mg,0.256mmol)和γ-T-3(100mg,0.244mmol)的THF(5mL)溶液中,然后加入DIAD(156mg,0.768mmol)。得到的混合物在室温下搅拌过夜。除去溶剂后,通过柱色谱法纯化残余物,用0-5%的EtOAc在DCM中洗脱,得到橙色固体NBDA-γ-T-3,产率为12%(20mg)。1H NMR和LC-MS(m/z645.4)。
实施例8:(R)-6-(3-(4-氨基吡咯烷-1-基-NBD)-丙氧基))-2,7,8-三甲基-2-(4,8,12-三甲基十三烷-3,7,11-三烯-1-基)-色烷((R)-6-(3-(4-aminopyrolidin-1-yl-NBD)-propoxy))-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane)(NBD-APy-T-3).
图13显示制备NBD-APy-T-3的反应示意图。将含有TsO-γ-T-3(0.15g,0.25mmol)的DMF(1mL)加入到含有NBD-APy(0.57mmol)和Et3N(0.1mL,0.741mmol)混合物的DMF(4mL)中。将得到的混合物在室温下搅拌3h。然后,添加CS2CO3(0.24g,0.74mmol)并在室温下搅拌16h。将混合物用水(20mL)淬灭,并用Et2O(3×25mL)和EtOAc(2×25mL)萃取。将水溶液浓缩并与有机溶液合并,然后用Na2SO4干燥。过滤后,将滤液浓缩通过硅胶柱色谱法纯化,用0-50%的EtOAc在己烷中洗脱,得到橙色半油状物NBD-APy-T-3,产率为8.9%(15mg)。
实施例9:亲水性维生素E酯
棕榈油馏出物是中等分子量、高度亲油性化合物的混合物;典型的分析可能是TPs9-13%、T-3s 38-42%、胡萝卜素<1%、甾醇2-4%、角鲨烯7-10%、三油酸甘油酯(tri-oleins)30-45%。葡萄糖醛酸的羟基被三氟乙酸酐酯化,然后馏出物中的维生素E(γ-T-3)被保护的葡萄糖醛酸酯化,形成维生素E葡萄糖醛酸。该酯用稀释的氟乙酸盐原位脱保护,并用水从油性混合物中提取维生素E-葡萄糖醛酸。图8表明加入二乙醚(diethyl ether)并用稀碳酸钠水溶液后处理产生双层,有机相含有从油馏分中提取的维生素E,水相含有氟乙酸钠和其他水溶性组分。
图8进一步显示了另一种提取过程,其中维生素E在馏出物中通过双功能连接剂(马来酸)原位连接到糖上。维生素E的回收遵循类似的提取和脱保护顺序,以获得原始维生素E。
实施例10:维生素E的吸收增强配方。
维生素E的肠道吸收是通过复杂的生物分子机制实现的,包括细胞内转运蛋白、核受体调节和ATP结合盒转运蛋白,以及其在肠腔中的生物物理分散。分散与胶束和乳液的形成有关,这是通过维生素E(两亲物)的自组装特性产生的。维生素E的亲油性结构由长的饱和(TP)或不饱和(T-3)烃链和非离子的微亲水性羟基头组成,这使它们能够通过缔合形成胶束来降低界面张力(表面活性剂特性),这些胶束作为肠道吸收所需的乳化剂和分散剂发挥着重要作用。胶束的特性取决于这些两亲分子的亲油性和亲水性。维生素E有一个小的、弱亲水性的头部(每个分子只有一个羟基),因此它在肠腔中形成胶束的能力需要胆汁盐和胰腺排泄物。从胶束吸收维生素E的分散体成分等同于脂肪酸和脂肪酸甘油酯的吸收机制。维生素E的生物利用度不仅取决于其在肠腔中的分散,而且还取决于脂肪酸和植物甾醇的共同摄取、通过基因调节肠道摄取、通过细胞内运输和通过维生素E的脂蛋白分泌;如本领域中所述(Adv.Condensed Matter Physics,2015,Article ID 151683:22;J Obstet Gynαecol Cαn,2009,31:210-217;Free Radic Res Commun,1991,14:229-246;J Clin Invest,1967,46:1695-1703)。
“分散模型”和维生素E的低生物利用度共同构成了合成具有更多亲水性头部的维生素E分子(如糖醛酸酯)的基本原理,以通过胶束形成实现更有效的分散,从而改善其吸收。脂肪酸/脂肪酸单甘油酯吸收模型的扩展,包括维生素E-单甘油酯和更多其他具有更多亲水头部的维生素E酯,从而改善了维生素E从肠道的吸收。通过利用天然代谢酸形成这些酯,维生素E在体内水解后的再生将仅产生相关的生理亲水酸,从而消除了产生有毒副产物的担忧。
图12显示了提高维生素E类似物生物利用度的一般反应。甘油酸首先与三氟乙酸酐酯化,然后与维生素E反应生成受保护的维生素E甘油酯。将其用稀释的三氟乙酸水解,加入二乙醚中,醚部分用水洗涤,得到所需的甘油单酯。
实施例11:维生素E衍生物和荧光报告基团之间的点击反应。
一般的铜催化反应涉及炔烃和叠氮化物,如图12所示的通用方案中描述。
使用标准反应条件,根据本发明中描述的方法制备的叠氮化物或炔烃衍生的维生素E可以通过点击化学与报告元素反应。因此,任何功能衍生的维生素E类似物都可以用任何经过适当修饰的市售RE(例如荧光染料)进行标记,如图10所示。此程序可用于制备维生素E-RE加合物,其中RE是一种荧光染料,具有特定发色基团的部分、NMR响应部分或具有其他所需性质的部分。
尽管上文已经描述了本发明的特定实施例,应当理解,其他实施例在本发明的范围内是可能的并且旨在被包括在本文中。本领域的任何技术人员将清楚,在不背离通过示例性实施例所展示的本发明的宗旨的情况下,对本发明(未示出)的修改和调整是可能的。因此,本发明被认为仅受所附权利要求的范围限制。
Claims (21)
1.一种化合物,如式(I)所示,
维生素E-LNK-REG (I)
其中,维生素E是α-生育酚、β-生育酚、γ-生育酚、δ-生育酚、α-生育三烯酚、β-生育三烯酚、γ-生育三烯酚或δ-生育三烯酚;
其中,LNK是通过醚键、氨基甲酸酯键或酯键与维生素E组分上的C6氧连接的直链烃或支链烃或取代烃,并且具有适合被亲核报告元素置换的反应中心;以及
其中,REG是化学亲核体的报告元素或基团。
2.根据权利要求1所述的化合物,其中,所述REG是卤化物、叠氮化物、作为荧光基团的报告基团、发色基团、放射性元素或核磁共振响应中心。
3.根据权利要求2所述的化合物,其中,所述卤化物是碘、溴、氟或氯。
4.根据权利要求2所述的化合物,其中,所述卤化物是碘、溴、氟、氯的放射性同位素。
5.根据权利要求2所述的化合物,其中,所述核磁共振响应中心是单氟化、二氟化、三氟化或多氟化实体。
6.根据权利要求2所述的化合物,其中,所述荧光基团是硝基苯并噁二唑或5氟硫氰酸。
7.根据权利要求2所述的化合物,其中,所述发色基团是活化芳族。
8.根据权利要求7所述的化合物,其中,所述活化芳烃是硝化芳族。
9.一种化合物
10.一种化合物,如式(II)所示,
维生素E-LNK-GRP (II)
其中,维生素E是α-生育酚、β-生育酚、γ-生育酚、δ-生育酚、α-生育三烯酚、β-生育三烯酚、γ-生育三烯酚或δ-生育三烯酚;
其中,LNK是通过醚键、氨基甲酸酯键或酯键与维生素E组分上的C6氧连接的直链烃或支链烃或取代烃,并且具有适合被亲核报告元素置换的反应中心;以及
其中,GRP是一种功能元素,所述功能元素改变所述化合物中维生素E组分的特性。
11.根据权利要求10所述的化合物,其中,所述GRP是单糖、二糖、多糖、甘油酸、氨基酸或无机酸;所述GRP导致所述化合物中维生素E组分的亲脂性降低。
12.根据权利要求10所述的化合物,其中,所述单糖、所述二糖或所述多糖是糖醛酸、葡萄糖酸、葡萄糖醛酸、抗坏血酸、乳糖醛酸或糖酸。
13.根据权利要求10所述的化合物,其中,所述GRP在哺乳动物中提供改善的口服吸收。
14.根据权利要求13所述的化合物,其中,所述LNK通过二酯与所述维生素E组分上的C6氧连接,并且所述GRP是甘油酯。
15.根据权利要求10所述的化合物,其中,所述GRP在哺乳动物中提供改善的口服生物利用度。
16.根据权利要求13所述的化合物,其中,所述LNK通过二酯与所述维生素E组分上的C6氧连接,并且所述GRP是甘油酯。
17.根据权利要求10所述的化合物,其中,所述LNK通过甘油酸单酯化或通过二甲酸酯连接剂单酯化与维生素E组分上的C6氧连接,以使所述化合物可经酸水解产生维生素E、甘油和二甲酸酯。
18.一种从含有维生素E的天然植物油馏出物中分离维生素E的方法,所述方法包括通过添加三氟乙酸酯使葡萄糖醛酸糖上的羟基发生酯化反应,生成受保护的葡萄糖醛酸;将所述受保护的葡萄糖醛酸添加到所述天然植物油馏出物中,生成维生素E葡萄糖醛酸盐;将稀释的氟乙酸盐添加到所述维生素E葡萄糖醛酸盐中,并用水从所得混合物中提取维生素E。
19.根据权利要求18所述的方法,其中,用水从所得混合物中提取维生素E还包括添加二乙醚和稀释的碳酸钠水溶液。
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Citations (6)
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JPH09278770A (ja) * | 1996-04-17 | 1997-10-28 | Pacific Corp | 陽イオン性ビタミンe誘導体及びその製造方法、並びにこれを用いて形成した抗酸化作用を有する両親媒性高分子ベシクル |
US6136851A (en) * | 1997-05-14 | 2000-10-24 | Lvmh Recherche | Tocopherol esters and their cosmetic and pharmaceutical uses |
CN1529701A (zh) * | 2000-02-11 | 2004-09-15 | �������о�����չ˽������˾ | 生育酚、生育三烯酚、其它苯并二氢吡喃和侧链衍生物,及其用途 |
WO2011097481A1 (en) * | 2010-02-05 | 2011-08-11 | First Tech International Limited | Tocotrienol esters |
CN104211674A (zh) * | 2014-08-20 | 2014-12-17 | 江苏科鼐生物制品有限公司 | 一种利用水解还原方法生产高含量天然维生素e的工业化生产方法 |
CN104870432A (zh) * | 2012-11-16 | 2015-08-26 | 美国健康及人类服务部 | 作为溶酶体贮积症的修复剂的生育酚和生育酚衍生物 |
-
2021
- 2021-10-27 WO PCT/CA2021/051518 patent/WO2022087735A1/en active Application Filing
- 2021-10-27 CN CN202180005851.3A patent/CN114698374A/zh active Pending
- 2021-10-27 CA CA3135920A patent/CA3135920A1/en active Pending
- 2021-10-27 US US17/761,978 patent/US20240051932A1/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH09278770A (ja) * | 1996-04-17 | 1997-10-28 | Pacific Corp | 陽イオン性ビタミンe誘導体及びその製造方法、並びにこれを用いて形成した抗酸化作用を有する両親媒性高分子ベシクル |
US6136851A (en) * | 1997-05-14 | 2000-10-24 | Lvmh Recherche | Tocopherol esters and their cosmetic and pharmaceutical uses |
CN1529701A (zh) * | 2000-02-11 | 2004-09-15 | �������о�����չ˽������˾ | 生育酚、生育三烯酚、其它苯并二氢吡喃和侧链衍生物,及其用途 |
WO2011097481A1 (en) * | 2010-02-05 | 2011-08-11 | First Tech International Limited | Tocotrienol esters |
CN104870432A (zh) * | 2012-11-16 | 2015-08-26 | 美国健康及人类服务部 | 作为溶酶体贮积症的修复剂的生育酚和生育酚衍生物 |
CN104211674A (zh) * | 2014-08-20 | 2014-12-17 | 江苏科鼐生物制品有限公司 | 一种利用水解还原方法生产高含量天然维生素e的工业化生产方法 |
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CA3135920A1 (en) | 2022-04-28 |
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