CN104250247B - 新型槐定碱类衍生物槐定酸、槐定醇、槐定酯、槐定醚及其制备方法和用途 - Google Patents
新型槐定碱类衍生物槐定酸、槐定醇、槐定酯、槐定醚及其制备方法和用途 Download PDFInfo
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- CN104250247B CN104250247B CN201310268482.4A CN201310268482A CN104250247B CN 104250247 B CN104250247 B CN 104250247B CN 201310268482 A CN201310268482 A CN 201310268482A CN 104250247 B CN104250247 B CN 104250247B
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- Prior art keywords
- diimmonium
- chloride
- acid
- methyl ester
- acid methyl
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- 239000002253 acid Substances 0.000 title claims abstract description 67
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 76
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及新型槐定碱类衍生物槐定酸、槐定醇、槐定酯、槐定醚及其制备方法和用途。本发明第一方面涉及式I的化合物,或其药学可接受的盐或溶剂合物,其中R1选自丁酸、丁酸甲酯或乙酯、丁醇、丁基甲醚或乙醚;以及R2选自氢、苯甲基、苯乙基、4‑吡啶甲基、2‑呋喃甲基、C1‑5直链或支链的烷基、萘甲基、或蒽基甲基,所述苯基任选地被一个或多个选自下列的取代基取代:C1‑2烷氧基、卤素。本发明还涉及式I化合物的制备方法,包含它们的药物组合物,以及它们在制备用于治疗肿瘤或癌症的药物中的应用。
Description
技术领域
本发明属于医药化学领域,具体涉及一类新的用于肿瘤或癌症治疗的化合物,特别涉及一类具有抗肿瘤活性的槐定碱衍生物及其制备方法,以及此类化合物在作为药物特别是用于肿瘤或癌症治疗的药物的应用。
背景技术
槐定碱可以从豆科植物苦豆草提取所得。其具有如下结构式:
槐定碱的体外抑菌试验证明,对志贺氏,宋内氏,福氏,斯密氏等15种痢疾菌株均有抑制作用。目前已经有研究证明槐定碱可以作为活性成分用于治疗人肺癌和消化道癌。
中国专利第93100881号公开了一种抗癌新药及其制取方法,其特征是将从中药苦豆子中提取的槐定碱作为活性成分与药用载体及添加剂混合制成针剂、片剂、胶囊和其他制剂。其制取方法是取苦豆子地上部分经浸泡、渗滤、离子交换、碱化、洗脱、一次转盐、游离、萃取、二次转盐、游离、萃取、三次转盐、游离、萃取、粗结晶、精制得到槐定碱,然后加盐酸制成注射液。加赋形剂制成片剂、胶囊等,所制得的抗癌药对绒癌、恶葡、肺癌、消化道癌抗癌作用明显而稳定,毒副反应低。且苦豆子资源丰富,槐定碱含量高,提取的成本低,是一种很有价值的抗癌新药。
但是,人们仍然期待发现新的且有效的抗癌药物用于癌症治疗。
发明内容
本发明的目的是寻找具有有效的抗癌活性的新化合物。本发明人出于意料地发现,具有式I结构的化合物具有令人惊讶的效果,该式I结构的化合物是从天然提取的槐定碱修饰改造得到的。本发明基于此发现而完成。
为此,本发明的第一方面提供了式I化合物:
或其药学可接受的盐或溶剂合物,其中
R1选自丁酸、丁酸甲酯或乙酯、丁醇、丁基甲醚或乙醚;以及
R2选自氢、苯甲基、苯乙基、4-吡啶基甲基、2-呋喃甲基、C1-5直链或支链的烷基、萘甲基、或蒽基甲基,所述苯基任选地被一个或多个选自下列的取代基取代:C1-2烷氧基、卤素。
根据本发明的式I化合物,其中所述式I的化合物选自:
根据本发明的式I化合物,其为选自下列的化合物:
12-N-(2-甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(4-甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(4-甲基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-氟苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(3-氟苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(4-氟苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(4-氯苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-氯苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-苄基槐定丁醇-1,12-二鎓氯化物;
12-N-(3-甲氧基-4-乙氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-氯-3-甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-氯-3,4-二甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-苯乙基槐定丁醇-1,12-二鎓氯化物;
12-N-(4-吡啶甲基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-呋喃甲基)槐定丁醇-1,12-二鎓氯化物;
12-N-丙基槐定丁醇-1,12-二鎓氯化物;
12-N-正丁基槐定丁醇-1,12-二鎓氯化物;
12-N-新戊基槐定丁醇-1,12-二鎓氯化物;
12-N-异丁基槐定丁醇-1,12-二鎓氯化物;
12-N-(3,4,5-三甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(9-蒽甲基)槐定丁醇-1,12-二鎓氯化物;
12-N-(1-萘甲基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-萘甲基)槐定丁醇-1,12-二鎓氯化物;
槐定丁酸甲酯-1,12-二鎓氯化物;
槐定丁酸乙酯-1,12-二鎓氯化物;
12-N-(2-甲氧基苄基)槐定丁酸甲酯;
12-N-(4-甲氧基苄基)槐定丁酸甲酯;
12-N-(2-氟苄基)槐定丁酸甲酯;
12-N-(3-氟苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(4-氟苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(3-甲氧基苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(4-氯苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(3-氯苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(4-溴苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(3,4-二甲氧基苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(2-氯-3,4-二甲氧基苄基)槐定丁酸甲酯;
12-N-(4-吡啶甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(2-呋喃甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-丙基槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-异丁基槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(3,4,5-三甲氧基苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(9-蒽甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(1-萘甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(2-萘甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(2-甲氧基苄基)槐定丁酸;
12-N-(2-氟苄基)槐定丁酸;
12-N-(3-氟苄基)槐定丁酸;
12-N-(4-氟苄基)槐定丁酸;
12-N-(4-氯苄基)槐定丁酸;
12-N-(3-氯苄基)槐定丁酸;
12-N-苄基槐定丁酸;
12-N-(4-溴苄基)槐定丁酸;
12-N-(2,3-二甲氧基苄基)槐定丁酸;
12-N-(4-吡啶甲基)槐定丁酸;
12-N-丙基槐定丁酸;
12-N-异丁基槐定丁酸;
12-N-(3,4,5-三甲氧基苄基)槐定丁酸;
12-N-(1-萘基)槐定丁酸;
12-N-(2-萘基)槐定丁酸;
12-N-(4-氟苄基)槐定丁基甲醚;
12-N-(4-氟苄基)槐定丁基乙醚;
12-N-(4-氯苄基)槐定丁基甲醚;
12-N-(4-氯苄基)槐定丁基乙醚;
12-N-苄基槐定丁基甲醚;
12-N-苄基槐定丁基乙醚。
本发明第二方面提供了制备本发明第一方面的式I化合物的方法,其包括以下步骤:
将槐定碱与酸反应后,加入甲醇进行反应,得到槐定甲酯;
在槐定甲酯中依次加入无水1,2-二氯乙烷、无水三乙胺、硫酸钠回流,加入醛回流,加入三乙酰基硼氢化钠反应,抽滤蒸干后,用乙酸乙酯和饱和碳酸氢钠水溶液萃取,将乙酸乙酯层蒸干后用减压硅胶柱分离纯化,可选地加入盐酸乙醚,得到该式I-1的化合物或其盐;
将式I-1的化合物溶解在无水四氢呋喃中,在氮气保护下,于0℃加入到含四氢铝锂的无水四氢呋喃溶液中,之后升室温反应,依次加入水,10-20%NaOH溶液,水,搅拌,蒸干,用减压硅胶柱分离纯化,可选地加入盐酸乙醚,得到该式I-2的化合物或其盐;
将式I-1的化合物于10-20%NaOH溶液中回流,0℃调PH至6-7,蒸干,用减压硅胶柱分离纯化得到式I-3化合物;
将式I-2化合物于绝对无水四氢呋喃中溶解,加入苯磺酸甲酯或者苯磺酸乙酯后常温反应,蒸干溶剂后用减压硅胶柱分离纯化,加入盐酸乙醚,得到该式I-4的化合物或其盐。本发明的第三方面提供了一种药物组合物,其包含权利要求1至6中任一项所述化合物,以及任选的一种或多种药学可接受的载体或赋形剂。
本发明的第四方面提供了式I化合物在制备用于治疗肿瘤或癌症的药物中的应用。所述癌症的一个实例为肝癌。
本发明的任一方面的任一实施方案,可以与其他实施方案进行组合,只要它们不会出现矛盾。此外,在本发明任一方面的任一实施方案中,任一技术特征可以适用于其它实施方案中的该技术特征,只要它们不会出现矛盾。
下面对本发明作进一步的描述。
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。
术语“卤素”或“卤代”是指氟、氯、溴、和碘。
在本发明合成式I化合物的方法中,反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的,或者是可以通过文献公知的方法制得的,或者是可以通过商业购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。或者,本领域技术人员也可以根据本发明第二方面方法合成本发明未具体列举的其它式I化合物。
本发明的式I化合物可以与其它活性成分组合使用,只要它不产生其他不利作用,例如过敏反应。
本发明式I所示的活性化合物可作为唯一的抗癌药物使用,或者可以与一种或多种其他抗癌药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
本文所用的术语“组合物”意指包括包含指定量的各指定成分的产品,以及直接或间接从指定量的各指定成分的组合产生的任何产品。在本发明中,术语“组合物”可以与“药物组合物”互换使用。
词语“药学可接受的盐”指在可靠的医学判断范围内,适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等,且与合理的效果/风险比相称的盐。药学可接受的盐是本领域公知的。例如,S.M.Berge,et al.,J.Pharmaceutical Sciences,1977,66:1中对药学可接受的盐进行了详细描述。
本发明式I化合物还包括其异构体、消旋体、对映体、非对映体、对映体富集物、溶剂合物,本发明式I化合物以及它的异构体、消旋体、对映体、非对映体、对映体富集物、溶剂合物还可以形成溶剂合物,例如水合物、醇合物等。上述化合物还可以是前药或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。一般来说,对于本发明的目的,与药学可接受的溶剂如水、乙醇等的溶剂合物形式与非溶剂合物形式相当。
可改变本发明药物组合物中各活性成分的实际剂量水平,以便所得的活性化合物量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据具体化合物的活性、给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。但是,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。
当用于上述治疗和/或预防或其他治疗和/或预防时,治疗和/或预防有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的酯或前药形式(在存在这些形式的情况下)应用。或者,所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂的药物组合物给药。词语“治疗和/或预防有效量”的本发明化合物指以适用于任何医学治疗和/或预防的合理效果/风险比治疗障碍的足够量的化合物。但应认识到,本发明化合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径和排泄率;治疗持续时间;与所采用的具体化合物组合使用或同时使用的药物;及医疗领域公知的类似因素。例如,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。
运用本领域技术人员熟悉的药物载体可以制备成含有效剂量的本发明化合物的药物组合物。因此本发明还提供包含与一种或多种无毒药物可接受载体配制在一起的本发明化合物的药物组合物。所述药物组合物可特别专门配制成以固体或液体形式供口服给药、供胃肠外注射或供直肠给药。
所述的药物组合物可配制成许多剂型,便于给药,例如,口服制剂(如片剂、胶囊剂、溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射水可立即使用)。所述的药物组合物中载体包括:口服制剂使用的粘合剂(如淀粉,通常是玉米、小麦或米淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮),稀释剂(如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素,和/或甘油),润滑剂(如二氧化硅、滑石、硬脂酸或其盐,通常是硬脂酸镁或硬脂酸钙,和/或聚乙二醇),以及如果需要,还含有崩解剂,如淀粉、琼脂、海藻酸或其盐,通常是藻酸钠,和/或泡腾混合物,助溶剂、稳定剂、悬浮剂、无色素、矫味剂等,可注射的制剂使用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可以将其配制成肠衣片剂。
更具体地说,本发明的药物组合物可通过口服、直肠、胃肠外、池内、阴道内、腹膜内、局部(如通过散剂、软膏剂或滴剂)、口颊给予人类和其他哺乳动物,或者作为口腔喷雾剂或鼻腔喷雾剂给予。本文所用术语“胃肠外”指包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输液的给药方式。
适合于胃肠外注射的组合物可包括生理上可接受的无菌含水或非水溶液剂、分散剂、混悬剂或乳剂,及供重构成无菌可注射溶液剂或分散剂的无菌散剂。合适的含水或非水载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、植物油(如橄榄油)、可注射有机酯如油酸乙酯及它们的合适混合物。
这些组合物也可含有辅料,如防腐剂、湿润剂、乳化剂和分散剂。通过各种抗细菌剂和抗真菌剂,例如尼泊金酯类、三氯叔丁醇、苯酚、山梨酸等,可确保防止微生物的作用。还期望包括等渗剂,例如糖类、氯化钠等。通过使用能延迟吸收的物质,例如单硬脂酸铝和明胶,可达到可注射药物形式的延长吸收。
混悬剂中除活性化合物外还可含有悬浮剂,例如乙氧基化异十八醇、聚氧乙烯山梨醇和聚氧乙烯失水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶或者这些物质的混合物等。
在一些情况下,为延长药物的作用,期望减慢皮下或肌内注射药物的吸收。这可通过使用水溶性差的晶体或无定形物质的液体混悬剂来实现。这样,药物的吸收速度取决于其溶解速度,而溶解速度又可取决于晶体大小和晶型。或者,胃肠外给药的药物形式的延迟吸收通过将该药物溶解于或悬浮于油媒介物中来实现。
可注射贮库制剂形式可通过在生物可降解聚合物如聚丙交酯-聚乙交酯(polylactide-polyglycolide)中形成药物的微胶囊基质来制备。可根据药物与聚合物之比和所采用的具体聚合物的性质,对药物释放速度加以控制。其他生物可降解聚合物的实例包括聚原酸酯类和聚酐类。可注射贮库制剂也可通过将药物包埋于能与身体组织相容的脂质体或微乳中来制备。
可注射制剂可例如通过用滤菌器过滤或通过掺入无菌固体组合物形式的灭菌剂来灭菌,所述固体组合物可在临用前溶解或分散于无菌水或其他无菌可注射介质。
本发明化合物或其组合物可用口服方法或非胃肠道给药方式。口服给药可以是片剂、胶囊剂、包衣剂,肠道外用药制剂有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟悉的方法制备的。为了制造片剂、胶囊剂、包衣剂所用的辅料是常规用的辅料,例如淀粉、明胶、阿拉伯胶,硅石,聚乙二醇,液体剂型所用的溶剂如水、乙醇、丙二醇、植物油(如玉米油、花生油、橄榄油等)。含有本发明化合物的制剂中还有其它辅料,例如表面活性剂,润滑剂,崩解剂,防腐剂,矫味剂和色素等。在片剂、胶囊剂、包衣剂、注射剂和栓剂中含有本发明式I化合物的剂量是以单元剂型中存在的化合物量计算的。具体地说,本发明可以提供的供口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中,活性化合物可与至少一种惰性的药物可接受赋形剂或载体如柠檬酸钠或磷酸二钙和/或以下物质混合:a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;b)粘合剂如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯树胶;c)保湿剂如甘油;d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶液阻滞剂如石蜡;f)吸收加速剂如季铵化合物;g)湿润剂如鲸蜡醇和甘油单硬脂酸酯;h)吸附剂如高岭土和膨润土以及i)润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠和它们的混合物。在胶囊剂、片剂和丸剂的情况下,所述剂型中也可包含缓冲剂。
相似类型的固体组合物使用赋形剂例如乳糖及高分子量聚乙二醇等,也可用作软胶囊和硬胶囊中的填充物。
片剂、糖衣丸剂、胶囊剂、丸剂和颗粒剂的固体剂型可与包衣和壳料如肠溶衣材和医药制剂领域公知的其他衣材一起制备。这些固体剂型可任选含有遮光剂,且其组成还可使其只是或优先地在肠道的某个部位任选以延迟方式释放活性成分。可以使用的包埋组合物的实例包括高分子物质和蜡类。如果适合,活性化合物也可与一种或多种上述赋形剂配成微囊形式。
供口服给药的液体剂型包括药学可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。液体剂型除含有活性化合物外还可含有本领域常用的惰性稀释剂,例如水或其他溶剂,增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯及它们的混合物。口服组合物除包含惰性稀释剂外还可包含辅料,例如湿润剂、乳化剂和悬浮剂、甜味剂、矫味剂和香味剂。
供直肠或阴道给药的组合物优选是栓剂。栓剂可通过将本发明化合物与合适的非刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合来制备,它们在室温下为固体,但在体温下则为液体,因此可在直肠腔或阴道腔内熔化而释放出活性化合物。
本发明的化合物及其组合物还考虑用于局部给药。供局部给予本发明化合物的剂量形式包括散剂、喷雾剂、软膏剂和吸入剂。在无菌条件下将活性化合物与药学可接受的载体和任何所需的防腐剂、缓冲剂或推进剂混合。眼用制剂、眼软膏剂、散剂和溶液剂也被考虑在本发明范围内。
本发明化合物也可以脂质体形式给药。如本领域所公知,脂质体通常用磷脂或其他脂类物质制得。脂质体由分散于含水介质中的单层或多层水化液晶所形成。任何能够形成脂质体的无毒、生理上可接受和可代谢的脂质均可使用。脂质体形式的本发明组合物除含有本发明化合物外,还可含有稳定剂、防腐剂、赋形剂等。优选的脂类是天然和合成的磷脂和磷脂酰胆碱(卵磷脂),它们可单独或者一起使用。形成脂质体的方法是本领域公知的。参见例如Prescott,Ed.,Methods in Cell Biology,Volume XIV,Academic Press,NewYork,N.Y.(1976),p.33。
本发明人惊奇地发现,式I的化合物对HepG2细胞有抗增殖活性。因此,本发明的化合物可用于治疗和/或预防哺乳动物(包括人)的肿瘤或癌症。
具体实施方式
下面通过具体的制备实施例和生物学试验例进一步说明本发明,但是,应当理解为,这些实施例和试验例仅仅是用于更详细具体地说明之用,而不应理解为用于以任何形式限制本发明。
本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的,但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚,在下文中,如果未特别说明,本发明所用材料和操作方法是本领域公知的。
实施例1.化合物槐定甲(乙)酯的合成
取槐定碱4.96g(0.02mol),加入100ml盐酸(6mol/L),加热回流8h,减压浓缩蒸干后,加入甲醇100ml,常温搅拌6小时,减压蒸干得粗品槐定甲酯,此白色固体以二氯甲烷/甲醇为流动相,用减压硅胶柱分离纯化,得到白色产物(5.20g92%),试验中将该白色产物用HDZ-0A表示。HDZ-0A即为槐定甲酯。
取槐定碱4.96g(0.02mol),加入100ml盐酸(6mol/L),加热回流8h,减压浓缩蒸干后,加入乙醇100ml,常温搅拌6小时,减压蒸干得粗品槐定乙酯,此白色固体以二氯甲烷/甲醇为流动相,用减压硅胶柱分离纯化,得到白色产物(5.10g90%),试验中将该白色产物用HDZ-0B表示。HDZ-0B即为槐定乙酯。
实施例2:式I-1化合物或HDZ系列化合物的合成
取HDZ-0A2.81g(0.01mol),依次加入150ml无水1,2-二氯乙烷、5ml无水三乙胺、10g硫酸钠,回流溶解后,加入相应的醛(0.02mol),回流4h后,缓慢加入三乙酰基硼氢化钠4.22g(0.02mol),继续回流4h后停止反应,抽滤,滤液蒸干后,用乙酸乙酯和饱和碳酸氢钠溶液萃取,将乙酸乙酯层蒸干后用减压硅胶柱分离纯化得黄色油状液体或固体,如为液体,则加入盐酸乙醚(1mol/L)后析出白色固体,抽滤得白色产物,即式I-1化合物,试验中将该白色产物用HDZ系列表示。
HDZ-0A与不同的醛进行还原氨化反应生成了不同的HDZ化合物。举例而言,HDZ-01化合物是通过HDZ-0A与邻甲氧基苯甲醛反应得到的。本领域技术人员根据表1中列出的HDZ系列化合物的结构,可以确定反应所需要的醛。
实施例3:式I-2化合物或者HDC系列化合物的合成
取上述HDZ化合物(0.005mol),用25ml无水四氢呋喃溶解后,干燥氮气保护条件下,于0℃缓慢滴加到含四氢铝锂(600mg0.015mol)的无水四氢呋喃溶液中,滴加完毕后缓慢升至室温反应4小时后,依次加入0.6ml水,0.6ml15%NaOH溶液,1.8ml水,室温搅拌1小时后,蒸干用减压硅胶柱分离纯化得黄色油状液体或固体,如为液体,则加入盐酸乙醚(1mol/L)后析出白色固体,抽滤得白色产物,即式I-2化合物,试验中将该白色产物用HDC系列表示。
实施例4:式I-3化合物或者化合物HDS系列的合成
取上述HDZ化合物(0.005mol)于15%NaOH溶液中回流4小时,0℃调PH6-7,蒸干蒸干用减压硅胶柱分离纯化得白色固体,即式I-3化合物,试验中将该白色产物用HDS系列表示。
实施例5:式I-4化合物或者化合物HDJM及HDYM系列的合成
取上述HDC化合物(0.005mol)于30ml绝对无水四氢呋喃中溶解,缓慢加入苯磺酸甲酯或者苯磺酸乙酯(0.02mol)后常温反应8小时,蒸干溶剂后用减压硅胶柱分离纯化得黄色油状液体,加入盐酸乙醚后得黄色粘稠状固体HDJM或HDYM。
从槐定碱生成各衍生物的反应路线如下:
以上反应路线中的式4、式5、式6、式7、式8(分别对应HDZ,HDC,HDS,HDJM和HDYM)的结构和理化参数参见表1。
表1
试验例1:抗增殖活性的测定
用本发明的式I化合物,具体地式I-1、式I-2、式I-3和式I-4的化合物(在表1中表示为HDZ系列、HDC系列、HDS系列、HDJM和HDYM系列)(10μg/mL)处理HepG2细胞48h。用MTT实验确定前述化合物的抗增殖活性。数据表示在表2中,用三次重复实验的平均值±SD表示。
MTT实验方法为:将对数生长期的细胞消化计数后接种于96孔培养板,4000个/孔/100μL,24h后换上含有相应浓度的化合物的培养基,每组浓度设3个复孔,并设DMSO溶媒对照孔和无细胞调零孔。于37℃、5%CO2条件下培养48h,随后每孔加入10μL5mg/ml的MTT,继续培养4小时,弃去培养基,每孔加入DMSO,待溶解后在Bio TEK Gen5酶标仪上用490nm波长测定吸光度OD值。
细胞存活率计算公式为:抑制率(%)=(对照孔OD490–给药孔OD490)/对照OD490×100%。
用HepG2细胞测定本发明部分化合物的IC50值。IC50为50%抑制浓度,即化合物作用后存活细胞数与对照组细胞数之比等于50%时所对应的浓度。
IC50值计算:将不同的浓度及相应的存活率输入Sigmaplot软件中,计算IC50值。
本发明化合物的抗癌活性通过抗HepG2细胞增殖活性和IC50值来表示。表2显示,本发明的化合物具有非常显著的抗肝癌细胞活性。
表2
本系列槐定碱衍生物具有较广泛的抗瘤谱,以HDC-06、HDC-08、HDZ-06、HDZ-08为例,对多种类型的肿瘤细胞都具有活性,且在部分细胞中优于阳性药TPT,见表3。
表3:槐定碱结构类似物抗瘤谱分析
Claims (2)
1.一种制备式I-1~I-4的化合物或其药学可接受的盐的方法,其包括如下步骤:
将槐定碱与酸反应后,加入甲醇进行反应,得到槐定甲酯;
在槐定甲酯中依次加入无水1,2-二氯乙烷、无水三乙胺、硫酸钠回流,加入醛回流,加入三乙酰基硼氢化钠反应,抽滤蒸干后,用乙酸乙酯和饱和碳酸氢钠水溶液萃取,将乙酸乙酯层蒸干后用减压硅胶柱分离纯化,加入盐酸乙醚,得到式I-1的化合物或其盐;
将式I-1的化合物溶解在无水四氢呋喃中,在氮气保护下,于0℃加入到含四氢铝锂的无水四氢呋喃溶液中,之后升室温反应,依次加入水,10-20%NaOH溶液,水,搅拌,蒸干,用减压硅胶柱分离纯化,加入盐酸乙醚,得到式I-2的化合物或其盐;
将式I-1的化合物于10-20%NaOH溶液中回流,0℃调pH至6-7,蒸干,用减压硅胶柱分离纯化得到式I-3化合物;
将式I-2化合物于绝对无水四氢呋喃中溶解,加入苯磺酸甲酯或者苯磺酸乙酯后常温反应,蒸干溶剂后用减压硅胶柱分离纯化,加入盐酸乙醚,得到式I-4的化合物或其盐;
其中,
R2选自苯甲基、苯乙基、4-吡啶基甲基、2-呋喃甲基、C1-5直链或支链的烷基、萘甲基、或蒽基甲基,所述苯甲基任选地被一个或多个选自下列的取代基取代:C1-2烷氧基、卤素。
2.根据权利要求1的制备方法,所述式I-1~I-4为选自下列的化合物:
12-N-(2-甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(4-甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-氟苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(3-氟苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(4-氟苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(4-氯苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-氯苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-苄基槐定丁醇-1,12-二鎓氯化物;
12-N-(3-甲氧基-4-乙氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-氯-3-甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-氯-3,4-二甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-苯乙基槐定丁醇-1,12-二鎓氯化物;
12-N-(4-吡啶甲基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-呋喃甲基)槐定丁醇-1,12-二鎓氯化物;
12-N-丙基槐定丁醇-1,12-二鎓氯化物;
12-N-正丁基槐定丁醇-1,12-二鎓氯化物;
12-N-新戊基槐定丁醇-1,12-二鎓氯化物;
12-N-异丁基槐定丁醇-1,12-二鎓氯化物;
12-N-(3,4,5-三甲氧基苄基)槐定丁醇-1,12-二鎓氯化物;
12-N-(9-蒽甲基)槐定丁醇-1,12-二鎓氯化物;
12-N-(1-萘甲基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-萘甲基)槐定丁醇-1,12-二鎓氯化物;
12-N-(2-甲氧基苄基)槐定丁酸甲酯;
12-N-(4-甲氧基苄基)槐定丁酸甲酯;
12-N-(2-氟苄基)槐定丁酸甲酯;
12-N-(3-氟苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(4-氟苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(3-甲氧基苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(4-氯苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(3-氯苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(4-溴苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(3,4-二甲氧基苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(2-氯-3,4-二甲氧基苄基)槐定丁酸甲酯;
12-N-(4-吡啶甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(2-呋喃甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-丙基槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-异丁基槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(3,4,5-三甲氧基苄基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(9-蒽甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(1-萘甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(2-萘甲基)槐定丁酸甲酯-1,12-二鎓氯化物;
12-N-(2-甲氧基苄基)槐定丁酸;
12-N-(4-氟苄基)槐定丁酸;
12-N-(4-氯苄基)槐定丁酸;
12-N-(3-氯苄基)槐定丁酸;
12-N-苄基槐定丁酸;
12-N-(4-溴苄基)槐定丁酸;
12-N-(2,3-二甲氧基苄基)槐定丁酸;
12-N-(4-吡啶甲基)槐定丁酸;
12-N-丙基槐定丁酸;
12-N-异丁基槐定丁酸;
12-N-(3,4,5-三甲氧基苄基)槐定丁酸;
12-N-(4-氟苄基)槐定丁基甲醚;
12-N-(4-氟苄基)槐定丁基乙醚;
12-N-(4-氯苄基)槐定丁基甲醚;
12-N-(4-氯苄基)槐定丁基乙醚;
12-N-苄基槐定丁基甲醚;
12-N-苄基槐定丁基乙醚。
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