CN1177596A - 苯并二氢吡喃基抗坏血酸衍生物及其制备和用途 - Google Patents
苯并二氢吡喃基抗坏血酸衍生物及其制备和用途 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
本发明涉及通式Ⅰ的苯并二氢吡喃基抗坏血酸,其中:R1是具有1至12个C原子的有机基团,特别是甲基;R2是具有8至30个C原子的未取代的或被官能团取代有机基团,特别是植基;和R3是-PO3H2-或苷基;R3、R4和R5各自是氢或烷基或具有1至20个C原子的酰基,特别是氢;以及R6是氢或酰基;通过相应的5-氯甲基或5-溴甲基苯并二氢吡喃衍生物与相应于式Ⅰ的抗坏血酸或抗坏血酸衍生物的碱金属或碱土金属盐反应制备上述化合物的方法;以及该粉末化合物作为药物或化妆品活性化合物或食品添加剂、作为生物抗氧剂用途。
Description
本发明涉及通式I苯并二氢吡喃基抗坏血酸衍生物其中R1是具有1至12个C原子的有机基团,例如支链或直链、饱和或不饱和的具有1至12个C原子的脂族烃基,或具有4至12个C原子的环烷基、芳基或杂环基,所述基团是未取代的或被一个或多个烷基、烷氧基、羟基、氨基、单烷基氨基或二烷基氨基取代;R2是具有8至30个C原子的有机基团,例如支链或直链、饱和或不饱和的具有8至30个C原子,优选具有12至24个C原子的脂族烃基、具有1至6个C原子的烷基,所述基团是未取代的或被羧基取代;或是具有4至20个C原子的环烷基、芳基或杂环基,所述基团是未取代的或被一个或多个烷基、烷氧基、羟基、氨基、单烷基氨基或二烷基氨基取代;R3是-PO3H2-或苷基;R3、R4和R5各自是氢或烷基、环烷基、芳基、芳烷基或环烷基烷基或具有1至20个C原子的式-CO-R7-表示的酰基;或R4和R5一起形成未取代的或被一个或多个烷基取代的亚烷基;R6是氢或式-CO-R7-表示的酰基,以及R7是具有1至20个C原子的饱和或不饱和的脂族烃基或苯乙烯基。
优选的通式I的苯并二氢吡喃基抗坏血酸衍生物是,其中R1是具有1至4个C原子的脂族烃基;R2是直链或带甲基支链的、饱和或不饱和的具有12至24个C原子的脂族烃基;以及R3、R4和R5是氢,或具有1至4个C原子的烷基或酰基;和R6是氢或具有1至20个C原子的酰基;
由于具有抑制氧化和清除自由基作用,所以苯并二氢吡喃衍生的α-生育酚(维生素E)和抗坏血酸(维生素C)及抗坏血酸衍生物在生物体系中起重要作用,而且可以各种方式应用于药物或化妆品中;根据其极性结构,维生素E在亲油相中优先起自由基清除剂作用,而维生素C及其它抗坏血酸衍生物在水相中则起还原剂作用;由于这两组化合物的作用协同互补,它们经常一起使用;当使用二化合物的混合物时,由于二氢苯并吡喃衍生物(例如维生素E)和抗坏血酸衍生物(例如维生素C)的极性大不相同,它们将阻止最佳的相互作用和潜在作用的全面发挥;物理现象(例如扩散过程、粒径和粒径分布)同样会很不利地影响它们的活性;因此,目前市售的维生素E制剂仅仅利用了给药剂量的小部分。
维生素E用作抗氧、热和光的损害作用的塑料稳定剂的用途例如已经在DE-A1136100和DE-A1114319以及DE-A36169中公开;同样还公开了维生素E对在食品中的脂肪和油类的稳定作用(参见UllmannsEncyklopadie der technischen Chemi [Ullmann′s Encyclopedia ofIndustrial Chemistry],第23卷,第649页)。
已知的二氢苯并吡喃衍生物还有关于活性、亲水体系中的溶解性、体内的分布和可分散性以及在挥发性方面的问题有待于解决。
因此,本发明的目的是制得新的二氢苯并吡喃衍生物,该衍生物能够避免已知化合物的上述缺点或将其控制在相对小的程度。
特别地,本发明的目的是提供可有助于提高维生素E在人或动物体的吸收能力的新的身体可耐受的维生素E衍生物。
在人体内,维生素E在肠道被吸收;就市售的维生素E制剂而言,目前给药的维生素E剂量仅有大约10%可被吸收,剩余物被没有改变地排泄掉,而造成这种问题的重要原因是该制剂在碱性肠介质中严重凝结。
在人体中,pH值在胃和肠道之间明显下降;当pH值在胃中低于3(即在酸性范围)时,而在肠道中则通常是碱性介质(pH>9);为了提高维生素E的可吸收能力,该活性化合物至少在短期内要以良好的分散形式存在;由于这难于以物理方式实现,所以本发明的特别目的是提供可使维生素E以良好的分散形式在肠道化学释放的维生素E衍生物,当然在该释放过程中所涉及和形成的所有物质,必须是生理上可接受的。
令人惊讶的是,我们成功地在5a-位将维生素E偶合在维生素C上;所生成的式Ia化合物在酸性介质中(例如在胃中)稳定;但是,在碱性介质中(例如在肠道中),用生成邻醌甲基化物而将抗坏血酸根阴离子从式Ia化合物中消除;然后,抗坏血酸根阴离子还原邻醌甲基化物中间体为维生素E,该维生素E现在以良好的分散形式存在因而可容易地被吸收;“沉淀的”维生素E的收率基于所使用的式Ia化合物为大约80%,并可以通过进一步加入维生素C(即未与维生素E结合的形式的维生素C)而进一步提高。
在这种式Ia化合物的碱诱导的分裂中,除了作为主产物形成的良好分散的维生素E和氧化形式的维生素C外,仅仅释放出对-生育醌和非氧化的维生素C;由于在身体中对-生育醌也通常作为维生素E的降解产物出现,因此,从式Ia偶合产物释放的所有物质都是生理上可接受的。
式Ia化合物和通式I的其它苯并二氢吡喃基抗坏血酸衍生物的制备是相当简单的。
本发明还涉及通式I的苯并二氢吡喃基抗坏血酸衍生物的制备方法,该方法包括使通式II的5-卤代甲基苯并二氢吡喃其中R1、R2和R6具有上述定义和X是Br或Cl,与通式III抗坏血酸自身或抗坏血酸衍生物的碱金属盐或碱土金属盐反应,其中R3至R5具有上述定义。
特别有益的是,本发明制备通式I苯并二氢吡喃基抗坏血酸衍生物、特别是式Ia化合物的方法是通过就地制备抗坏血酸衍生物或抗坏血酸自身的碱金属盐或碱土金属盐来进行的,即在反应混合物中,利用碱的存在并随后使之反应来进行。
按照本发明方法,用作起始化合物的通式II的5-卤代甲基苯并二氢吡喃是已知化合物并例如可通过下述方法制备,即在惰性有机溶剂(例如己烷、庚烷、辛烷或甲苯)中,选择性地溴化或氯化维生素E或苯并二氢吡喃衍生物的5-甲基;适合的其中R6为酰基的通式II的5-卤代甲基苯并二氢吡喃特别是相应的乙酸酯、棕榈酸酯、山梨酸酯、油酸酯、亚油酸酯和肉桂酸酯。
为了进行本发明的方法,通常使用下述步骤,将抗坏血酸或抗坏血酸衍生物和抗坏血酸的碱金属盐或碱土金属盐或抗坏血酸衍生物的碱金属盐或碱土金属盐或碱金属或碱土金属的氢氧化物在强烈混合下溶于通用溶剂(例如二甲基亚砜)中,冷却溶液至室温,然后用5a-溴代-α-生育酚或其盐之一处理并在惰性气体保护下边搅拌边在40-60℃加热2至6小时,优选2.5至3.5小时;以常规的方式处理反应混合物,例如,通过用正己烷和水萃取和继而在Al2O3上色谱分离;抗坏血酸钠和5a-溴代-α-生育酚或其盐以近似等摩尔比使用;但是,进一步向反应混合物中加入抗坏血酸有益于阻止副反应(例如生育醌的生成);每摩尔5a-溴代-α-生育酚另加的抗坏血酸的量通常是0.5至2摩尔。
如果在制备溶液中立即使用通式II的5-卤代甲基苯并二氢吡喃,则将特别有益于该方法的进行。
本发明还涉及通式I的苯并二氢吡喃基抗坏血酸衍生物(特别是式Ia化合物)作为药物或化妆品的活性化合物或食品添加剂、或作为生物抗氧剂的用途。
此外,本发明还涉及通式I的苯并二氢吡喃基抗坏血酸衍生物(特别是式Ia化合物)对有机物(特别是食品、药物或化妆制剂或塑料)抗氧、热和/或光的稳定作用的用途。
通式I的苯并二氢吡喃基抗坏血酸衍生物(特别是式Ia化合物)在与抗坏血酸或抗坏血酸衍生物作为混合物使用时,上述用途特别有效。
下述实施例用以更详尽地说明本发明方法。实施例1
在装有有效电磁搅拌器的250ml烧瓶中,在60℃将2.18g(11mmol)干燥细粉状的抗坏血酸钠、2.64g(15mmol)粉末状的抗坏血酸和50ml二甲基亚砜(DMS)的混合物搅拌2小时(h),然后将反应混合物冷却至室温(RT);在2小时过程中,在惰性气体保护下搅拌的同时,加入于10ml四氢呋喃(THF)和10mlDMS的混合物中的5.1g(10mmol)5a-溴代-α-生育酚溶液;而后,将混合物在50℃搅拌3h后冷却至RT;继而,用100ml正己烷和50ml水处理反应混合物,萃取该混合物,分离所形成的相;将含有主要量DMS的水相用10ml正己烷萃取后,用每次20ml水将合并的有机相洗至不含DMS;将有机相仔细地用Na2SO4干燥后,用20g中性Al2O3和50ml无水正己烷处理;搅拌混合物直至溶剂无色;随后,利用多孔玻璃过滤器分离掉黄色Al2O3,用50ml乙醚洗涤直至滤液呈无色;然后,用100ml甲醇从黄色Al2O3中萃取出所需的式Ia产物;得到纯的5a-苯并二氢吡喃基抗坏血酸(Ia)的甲醇溶液,由此在室温下减压除去甲醇,得到纯的5a-苯并二氢吡喃基抗坏血酸(Ia),收率为基于所使用的5a-溴代-α-生育酚理论值的63%;通过元素分析和13C-NMR、1HNMR、FAB-MS和MALDI-TOF-MS确定其如式Ia所示的结构。1H-NMR(DMSO-d6/CDCI3):δ2.11(s,3H,CH3-Ar),2.13(s,3H,CH3-Ar),2.63(t,2H,Ar-CH2-CH2),3.6(d,2H,-CH-CH(OH)-CH2OH),37(m,1H,-CH-CH(OH)-CH2OH),4.63(s,2H,Ar-CH2-O),4.77(d,1H,-CH-CH(OH)-CH2OH).
未显示类异戊二烯侧链在2.0ppm以下的强共振。13C-NMR(DMSO-d6/CDCl3):δ11.8(C-8b),12.1(C-7a),19.5(C-4a′),19.6(C-8a′),20.8(C-4),21.0(C-2′),22.5(C-13′),22.6(C-12a′),23.6(C-2a),24.5(C-6′),24.8(C-10′),27.9(C-12′),31.6(C-3),32.6(C-8′),32.7(C-4′),37.3(C-7′),37.4(C-5′),37.5(C-9′),37.6(C-3′),39.4(C-11′),39.8(C-1′),61.9(-CO2OH),71.0(-CH(OH)-CH2OH),74.3(C-2),77.9(-CH-CH(OH)-CH2OH),115.1(CAr),116.1(CAr),119.5(=C-O-CH2),123.0(CAr),125.5(CAr),144.6(CAr),147.3(CAr),156.8(=C-OH),173.8(CO)MALDI-TOF-MS m/z:606(M+H+)
5a-生育酚基抗坏血酸作为活性化合物在化妆品配方中的用途实施例实施例2脱脂防晒凝胶组合物质量含量(重量%)0.40 丙烯酸酯/C10-C30丙烯酸烷基酯交联聚合物0.25 羟乙基纤维素8.00 辛基甲氧基肉桂酸酯1.00 4-甲基亚苄基樟脑0.50 5a-生育酚基抗坏血酸(Ia)0.20 乙二胺四乙酸二钠5.00 甘油0.15 香料0.30 咪唑烷基脲0.25 甲基-对-羟基苯甲酸钠0.15 丙基-对-羟基苯甲酸钠5.00 PEG-25 PABA0.10 氢氧化钠加至100 水实施例3保湿霜组合物质量含量(重量%)6.00 PEG-7-氢化蓖麻油5.00 棕榈酸异丙酯6.00 矿物油5.00 西蒙得木油5.00 杏仁油1.00 5a-生育酚基抗坏血酸(Ia)0.60 硬脂酸镁2.00 PEG 45/十二烷基二醇共聚物5.00 甘油0.25 甲基-对-羟基苯甲酸0.15 丙基-对-羟基苯甲酸5.00 咪唑烷基脲0.15 香料0.20 乙二胺四乙酸二钠加至100 水实施例4不含防腐剂的晚霜组合物质量含量(重量%)5.00 PEG-7-氢化蓖麻油4.00 棕榈酸异丙酯4.00 辛/癸酸甘油三酯3.00 5a-生育酚基抗坏血酸(Ia)1.50 PEG-45/十二烷基二醇共聚物0.50 硬脂酸镁1.50 双甲酮(Dimethicone)4.00 1,2-丙二醇4.00 甘油8.00 611醇0.15 香料加至100 水实施例5抗皱霜组合物质量含量(重量%)6.00 PEG-7-氢化蓖麻油5.00 棕榈酸异丙酯1.00 矿物油3.00 辛/癸酸甘油三酯0.60 硬脂酸镁1.00 N-氨基羰基-2,3-O-异丙基-L-酮古洛糖酰胺1.00 乙酸生育酚酯2.00 PEG-45/十二烷基二醇共聚物0.20 视黄醇1.50 5a-生育酚基抗坏血酸(Ia)0.30 甘油0.70 硫酸镁0.25 甲基-对-羟基苯甲酸0.15 丙基-对-羟基苯甲酸0.20 抗坏血酸单磷酸钠0.10 α-生育酚0.10 抗坏血酸棕榈酸酯0.15 香料加至100 水实施例6保湿日霜组合物质量含量(重量%)2.00 Cremophor A62.00 Cremophor A2510.00 矿物油3.00 辛/癸酸甘油三酯3.00 异硬脂酸3.00 N-氨基羰基-2,3-O-异丙基-L-酮古洛糖酰胺1.50 乙酸生育酚酯2.00 D-panthenol USP2.50 5a-生育酚基抗坏血酸(Ia)0.20 视黄醇0.30 甘油0.15 二溴氰基丁烷0.20 抗坏血酸单磷酸钠0.10 α-生育酚0.10 抗坏血酸棕榈酸酯0.15 香料加至100 水
Claims (10)
1、通式I的苯并二氢吡喃基抗坏血酸衍生物其中R1是支链或直链、饱和或不饱和的具有1至12个C原子的脂族烃基,或具有4至12个C原子的环烷基、芳基或杂环基,所述基团是未取代的或被一个或多个烷基、烷氧基、羟基、氨基、单烷基氨基或二烷基氨基取代;R2是支链或直链、饱和或不饱和的具有8至30个C原子、优选具有12至24个C原子的脂族烃基,具有1至6个C原子的烷基,所述基团是未取代的或被羧基取代;或是具有4至20个C原子的环烷基、芳基或杂环基,所述基团是未取代的或被一个或多个烷基、烷氧基、羟基、氨基、单烷基氨基或二烷基氨基取代;R3是-PO3H2-或苷基;R3、R4和R5各自是氢或烷基、环烷基、芳基、芳烷基或环烷基烷基或具有1至20个C原子的式-CO-R7-表示的酰基;或R4和R5一起形成未取代的或被一个或多个烷基取代的亚烷基;R6是氢或基团-CO-R7-,以及R7是氢、具有1至20个C原子的饱和或不饱和的脂族烃基或苯乙烯基。
2、如权利要求1所要求的通式I的苯并二氢吡喃基抗坏血酸衍生物,其中R1是具有1至4个C原子的烃基;R2是直链或带甲基支链的、饱和或不饱和的具有12至24个C原子的脂族烃基;和R3、R4和R5是氢,或具有1至4个C原子的烷基或酰基;以及R6是氢或具有1至20个C原子的酰基。
3、如权利要求1所要求的通式I的苯并二氢吡喃基抗坏血酸衍生物,其中R1是甲基;R2是植基以及R3、R4、R5和R6各自是氢。
5、如权利要求4所要求的制备通式I的苯并二氢吡喃基抗坏血酸衍生物的方法,其中抗坏血酸或抗坏血酸衍生物的碱金属盐或碱土金属盐是就地(在反应化合物中)制备,然后进行反应。
6、如权利要求1所要求的通式I的苯并二氢吡喃基抗坏血酸衍生物作为药物或化妆品的活性化合物或食品添加剂的用途。
7、如权利要求1所要求的通式I的苯并二氢吡喃基抗坏血酸衍生物作为生物抗氧剂的用途。
8、如权利要求1所要求的通式I的苯并二氢吡喃基抗坏血酸衍生物用于稳定有机物以抗氧、热和/或光的损害作用的用途。
9、如权利要求1所要求的通式I的苯并二氢吡喃基抗坏血酸衍生物用于稳定食品或药物或化妆品制剂以抗氧、热和/或光的损害作用的用途。
10、如权利要求1所要求的通式I的苯并二氢吡喃基抗坏血酸衍生物的用途,其中包括作为与抗坏血酸或抗坏血酸衍生物的混合物来使用。
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DE19633560A DE19633560A1 (de) | 1996-08-21 | 1996-08-21 | Chromanyl-ascorbinsäurederivate, deren Herstellung und Verwendung |
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DE4000397A1 (de) * | 1990-01-09 | 1991-07-11 | Hoechst Ag | Lipidselektive antioxidantien sowie deren herstellung und verwendung |
JPH0499772A (ja) * | 1990-08-17 | 1992-03-31 | Kanebo Ltd | トコフェロール―5,6―0―イソプロピリデン―l―アスコルビン酸―2―ジカルボン酸ジエステル,及びその製造方法,並びにそれより成るビタミンc・ビタミンe補給剤 |
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EP0825191A2 (de) | 1998-02-25 |
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US5962701A (en) | 1999-10-05 |
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