CN105849111A - 吡喃并秋葵纤维异甲酚衍生物以及代谢综合征或炎症疾病治疗用药学组成物 - Google Patents
吡喃并秋葵纤维异甲酚衍生物以及代谢综合征或炎症疾病治疗用药学组成物 Download PDFInfo
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- CN105849111A CN105849111A CN201480070935.5A CN201480070935A CN105849111A CN 105849111 A CN105849111 A CN 105849111A CN 201480070935 A CN201480070935 A CN 201480070935A CN 105849111 A CN105849111 A CN 105849111A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Landscapes
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Abstract
本发明公开一种吡喃并秋葵纤维异甲酚衍生物、其药理可用之盐,或者其溶剂化物。并且,公开一种包括它们的用于预防或者治疗代谢综合征或炎症疾病的药学组成物。据此可有效治疗或预防代谢综合征或炎症疾病,而且其化学性质稳定。
Description
技术领域
本发明涉及一种能够有效地预防或者治疗代谢综合征或者炎症疾病的新型吡喃并秋葵纤维异甲酚衍生化合物以及用于预防或者治疗代谢综合征的该化合物的用途。
背景技术
人体内存在200亿以上的脂肪细胞,并且在人体能量供应远大于能量需求的情况下,能量以中性脂肪储存于脂肪细胞中,然后在能量枯竭的情况下,被分解成游离脂肪酸和葡萄糖而使用为能源。
现代人中的30%~40%所具有的肥胖在因上述过程的不均衡而产生过度的能量储存的情况下发生,其现象为脂肪细胞的大小的变大或者其数量增加。最近,随着经济发展、生活水平提高、卫生环境改善,快餐的经常摄取和以肉食为主的饮食生活变化导致了体内储存过多热能。这种现代人的饮食生活变化加上运动不足导致的热量消耗的减少,诱发了肥胖人口的快速增加倾向。这种肥胖与代谢综合征高度相关,以至于被用于诊断代谢综合征。
代谢综合征(metabolic syndrome)是将各种心血管疾病和第二型糖尿病的危险因素彼此形成集群的现象概念化成一种疾病的概念。这是一个能够概括说明胰岛素抵抗性及其与此相关的复杂多样的多种代谢紊乱和临床特征的有用的概念,并且指胖症,糖尿病,脂肪肝和高甘油三脂血症等危险因子一起增加的综合征。因此,在患代谢综合征的情况下,心血管疾病或第二型糖尿病的发病危险程度也增加。根据2001年公布的美国NECP(美国国家胆固醇教育计划,National Cholesterol EducationProgram)的ATPIII,当患者在以下危险因素中表现3个以上时,可以判断为代谢综合征:腰围在男性40英寸(102厘米)、女性35英寸(88厘米)以上的腹部肥胖;甘油三酯(triglycerides)在150mg/dL以上;HDL胆固醇为男性40mg/dL、女性50mg/dL以下;血压在130/85mmHg以上;空腹血糖(fastingglucose)在110mg/dL以上等。
胰岛素抵抗性指即使胰岛素在体内正常分泌,胰岛素所执行的细胞内的葡萄糖供应作用无法正常发挥的现象,其表现为血液中的葡萄糖无法进入细胞内而导致高血糖症状,并且细胞因为葡萄糖不足而无法执行正常功能,最终导致代谢综合征症状。由此产生的糖尿病症状被称为第二型糖尿病(T2DM,非胰岛素依赖型糖尿病:NIDDM),从而与因胰岛素不足而引起的1型糖尿病(胰岛素依赖型糖尿病)进行区分。因此,治疗第二型糖尿病的最优选的方法是改善胰岛素抵抗性而使胰岛素发挥正常功能。即便如此,用于改善胰岛素抵抗性的治疗药目前几乎没有被开发。目前使用中或者正在开发的大部分第二型糖尿病治疗药的目的在于进一步提高胰岛素的分泌量而补充因胰岛素抵抗性而丧失的胰岛素功能。但是,如果我们身体中的胰岛素分泌量增加,则显然会诱发肥胖和炎症等,并且伴随着癌症发生率增加等多种副作用,因此如果无法根本性地改善胰岛素抵抗性问题,虽然可以期待暂时的血糖正常化,但是会导致健康逐渐恶化。因此,目前的实情为,对能够改善胰岛素抵抗性而正常化血糖的第二型糖尿病治疗药的社会需求在逐渐增加。
另外,专利文献1中,公开了光甘草定(glabridin)用于预防或者治疗包括高脂血症、脂肪肝、糖代谢异常、糖尿病、肥胖的代谢综合征的用途。
已知光甘草定在包括高脂血症、脂肪肝、糖代谢异常、糖尿病、肥胖的代谢综合征、以及抗炎症作用、抗癌作用等的预防治疗中有效果,但是容易因阳光、湿度、酸性、碱性、氧气、热等而被分解等的低化学稳定性(low chemical stability),从而导致利用光甘草定的产品开发存在诸多困难(非专利文献1)。
根据目前的研究成果,在肥胖以及第二型糖尿病(T2DM)的原因中,瘦蛋白抵抗性和胰岛素抵抗性分别为重要的原因,但是引起这些抵抗性的代表性的发明机理为,在瘦蛋白受体(leptin receptor)和胰岛素受体(insulin receptor,IR)中的信号传递(signaling)过程产生问题,并且这些共同地与PTP1B(protein tyrosine phosphatase1B;蛋白酪氨酸磷酸酶1B)有着密切的联系(非专利文献2)。
凭借着在我们的身体中与能量储存有关的最重要的荷尔蒙即瘦蛋白(促进食物的摄取和能量消耗的信号传递物质)和胰岛素(促进碳水化物的吸收的脂质的合成的信号传递物质)的信号传递过程都与PTP1B(protein tyrosine phosphatase 1B;蛋白酪氨酸磷酸酶1B)有关的事实,PTP1B足够作为对肥胖和糖尿病的最重要治疗目标而受人们的关注。并且,实际上在明确确定对PTP1B的作用机理的2000年以后,PTP1B作为用于治疗第二型糖尿病和癌症的药理机制而最受瞩目。即,能够任意地控制PTP1B的活性PTP1B抑制剂被开发成通过改善瘦蛋白和胰岛素的抵抗性而正常化瘦蛋白和胰岛素的活性的肥胖及第二型糖尿病的治疗药的可能性非常高(非专利文献3、4)。
根据通过各种研究结果而揭示的研究结果,PTP1B被发现除了肥胖和糖尿病,也与各种炎症疾病、心脏疾病、内质网应激(Endoplasmic Reticulum Stress)疾病、***癌以及***癌等有着密切的联系。如上所述,随着发现通常意义上被认作成人病的各种慢性疾病与PTP1B有着直接或者间接的关系,PTP1B作为用于治疗这些成人病的重要根本的治疗目标而备受瞩目。因此,将PTP1B称为形成多种成人病的原因中的最基本且基础的病因也非夸张(非专利文献5)。
[现有技术文献]
[专利文献]
(专利文献1)l.国际公开专利WO07/058480
[非专利文献]
(非专利文献1)M.Ao、Natural Product Communication 5(2010)、1907~1912.
(非专利文献2)D.Popov;Biochem Biophys Res Commun.410(2011)、377~381.
(非专利文献3)A.P.Combs;J.Med.Chem.53(2010)、2333~2344.
(非专利文献4)T.O.Johnson、J.Ermolieff、M.Jirousek;Nature Reviews1(2002)、696~709.
(非专利文献5)M.Feldhammer、N.Uetani、D.Miranda-Saavedra、M.L.Tremblay;Crit.Rev.Biochem.Mol.Biol.48(2013)430~445.
发明内容
技术问题
本发明的目的在于提供一种新型吡喃并秋葵纤维异甲酚衍生物,其具有优秀的抗肥胖效果、抗糖尿病效果以及抗炎症效果、可有效治疗高脂血等,并且在包括氧的一般大气条件以及酸性或者碱性条件下的化学性质稳定。
本发明的目的还在于提供一种用于预防或者治疗代谢综合征或者炎症疾病的药学组成物。
技术方案
为了实现上述目的,根据本发明的一方面,提供一种如下述式(I)的化合物、其药理可用(或谓“药理准用”)之盐或者其溶剂化物。
[化学式1]
在上述式中各个符号的含义如下:
R1是氢原子、甲基、甲氧基或卤原子。
R2是氢原子;取代或未被取代、直链或支链的C1-C6烷基;卤原子;取代或未被取代、直链或支链的C1-C6烷氧基;或者取代或未被取代、直链或支链的C1-C4硫代烷基。
R3以及R4分别独立地为氢原子或者C1-C2烷基。
对于所述取代烷基、取代烷氧基以及取代硫代烷基而言,所述取代基是直链或支链C1-C5烷基、卤原子、直链或支链C1-C5烷氧基或者直链或支链C1-C3硫代烷基。
根据本发明的另一方面,提供一种包括如下述式(I')的化合物、其药理可用之盐或者其溶剂化物的用于预防或者治疗代谢综合征或炎症疾病的药学组成物。
在上述式中各个符号的含义如下:
R1是氢原子、甲基、甲氧基或卤原子。
R2是氢原子;羟基;取代或未被取代、直链或支链的C1-C6烷基;卤原子;取代或未被取代、直链或支链的C1-C6烷氧基;或者取代或未被取代、直链或支链的C1-C4硫代烷基。
R3以及R4分别独立地为氢原子或者C1-C2烷基。
对于所述取代烷基、取代烷氧基以及取代硫代烷基而言,所述取代基是直链或支链C1-C5烷基、卤原子、直链或支链C1-C5烷氧基、或者直链或支链C1-C3硫代烷基。
有益效果
根据本发明的一实施例的包括吡喃并秋葵纤维异甲酚衍生物的药学组成物在代谢综合征或者炎症疾病的治疗或者预防中,有效且化学性质稳定。
附图说明
图1是示出根据本发明的吡喃并秋葵纤维异甲酚(pyranochromenyl phenol)衍生物的PTP1B抑制实验结果的图表。
图2a是将本发明的化合物16给药6周后,在最终淘汰后进行剖检而提取的老鼠肝组织的用H&E(hematoxylinand eosin;苏木精和伊红)染色的显微镜照片(放大100倍)。图2b是没有给药化合物16的对照组的显微镜照片。
图3a是将本发明的化合物16给药6周后,在最终淘汰后进行剖检而提取的老鼠肝组织的用H&E(hematoxylin and eosin;苏木精和伊红)染色的显微镜照片(放大200倍)。图3b是没有给药化合物16的对照组的显微镜照片。
图4a是将本发明的化合物16给药6周后,在最终淘汰后进行剖检而提取的老鼠肝组织的用脂滴包被蛋白抗体(perilipin antibody)染色的显微镜照片(放大100倍)。图4b是没有给药化合物16的对照组的显微镜照片。
图5a是将本发明的化合物16给药6周后,在最终淘汰后进行剖检而提取的老鼠肝组织的用脂滴包被蛋白抗体(perilipin antibody)染色的显微镜照片(放大200倍)。图5b是没有给药化合物16的对照组的显微镜照片。
图6是示出根据本发明的吡喃并秋葵纤维异甲酚衍生物的抗炎症功效确认实验结果的图表。
图7是示出根据本发明的吡喃并秋葵纤维异甲酚衍生物在酸性溶液中的稳定性的曲线图。
图8是示出根据本发明的吡喃并秋葵纤维异甲酚衍生物在碱性溶液中的稳定性的曲线图。
具体实施方式
以下,对本发明进行更加详细的说明。
本发明中使用的所有技术术语在没有其他定义的情况下,以等同于本发明的相关领域中具有基础知识的从业人员所理解的含义而被使用。并且,本发明的范围包括记载的优选方法或者样本,以及与其相似或者等同的概念。作为本说明书的参考文献而被记载的所有出版物中的整体内容作为参考被整合到本说明书中。
根据本发明的一方面的吡喃并秋葵纤维异甲酚(pyranochromenyl phenol)衍生物可以用下述式1表示。
[化学式1]
在所述式中,各个符号的含义如下:
R1是氢原子、甲基、甲氧基或卤原子。
R2是氢原子;取代或未被取代的直链或支链C1-C6烷基;卤原子;取代或未被取代的直链或支链C1-C6烷氧基;或者取代或未被取代的直链或支链C1-C4硫代烷基。
R3以及R4分别独立地为氢原子或者C1-C2烷基。
对于所述取代烷基、取代烷氧基以及取代硫代烷基而言,所述取代基是卤原子、直链或支链C1-C5烷基、直链或支链C1-C5烷氧基或者直链或支链C1-C3硫代烷基。
根据本发明的一实施例的吡喃并秋葵纤维异甲酚衍生物相比光甘草定,在预防或者治疗肥胖、糖尿病、高脂血症、脂肪肝等代谢综合征或者炎症疾病时,具有更优良的效果,同时在化学稳定性方面具有更优良的效果。
根据本发明的一实施例,在所述式(I)中,所述R1可以是氢原子,R2可以是甲基、乙基、正丙基、异丙基、正丁基、正戊基、2-甲氧基乙基、三氟甲基、氟、氯、溴、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、正戊氧基、甲氧基甲氧基等。
根据本发明的另一实施例,所述式(I)中,在所述R1为卤原子的情况下,可以是氟、氯或者溴。
根据本发明的另一实施例,所述式(I)的化合物可以是下述化合物中的1种以上的化合物。
所述式(I)的化合物与游离酸一起形成盐,因此所述在药理可用之盐可以以酸加成盐的形式存在。所述式(I)的化合物可以通过本技术领域中公知的常规的方法而形成药学中可接受的酸加成盐。所述游离酸可使用有机酸或者无机酸,所述无机酸可使用盐酸、氢溴酸、硫酸或者磷酸等,所述有机酸可以使用柠檬酸(citric acid)、乙酸、乳酸、酒石酸(tartariac acid)、马来酸、富马酸(fumaric acid)、甲酸、丙酸(propionic acid)、草酸、三氟乙酸、苯甲酸、葡糖酸、甲磺酸、乙醇酸、琥珀酸、4-甲苯磺酸、半乳糖醛酸、扑酸、谷氨酸或者天冬氨酸等。
所述药理可用之盐可以作为所述式(I)的化合物的无机盐而存在。所述式(I)的化合物可以通过本技术领域中公知的常规方法而形成药学中可接受的无机盐。所述无机盐中包括铝、铵、钙、铜、铁、锂、镁、锰、钾、钠、锌或者锌的盐,但是不限于此,并且优选铵、钙或者钠盐。
并且,根据本发明的所述式(I)的化合物不仅包括在药理可用之盐,还可以包括可以用常规方法制造的所有盐以及包括水化物的溶剂化物。
所述式(I)中的化合物的制造方法不受特殊限制,但可以根据本发明人开发的(±)-光甘草定的合成方法(Bull.Korean Chem.Soc.2007(28)481~484)而制造。
[反应式1]
在所述反应式中,OBz是苯甲酰氧基、Me是甲基、R1、R2与上述说明相同,P指苯甲基、甲氧基甲基、三烷基硅氧等保护基(protecting group),DEAD指二乙基偶氮二羧酸酯。其中,在P为苯甲基的情况下,可以在氢的附加反应过程中同时进行去保护过程,而不用安排专门的去保护(deprotection)过程。
在有机化学领域中具有基础知识的人员显然可以根据上述反应式1以及下述实施例的制造方法,通过改变取代基而制造所述式(I)的化合物。本说明书中,对式(I)中化合物制造方法的一个实施例进行了说明,但是在有机化学领域具有基础知识的人员可以通过适当地改变起始原料、反应路径、反应条件而利用与本说明书中记载的方法不同的方法制造式(I)的化合物。
根据本发明的另一方面的用于预防和治疗代谢综合征疾病或者治疗炎症疾病的药学组成物包括:下述式(I')所示的化合物、其药理可用之盐或者其溶剂化物。
在所述式中,各个符号的含义如下:
R1是氢原子、甲基、甲氧基或卤原子。
R2是氢原子;羟基;取代或未被取代的直链或支链C1-C6烷基;卤原子;取代或未被取代的直链或支链C1-C6烷氧基;或者取代或未被取代的直链或支链C1-C4硫代烷基。
R3以及R4分别独立地为氢原子或者C1-C2烷基。
对于所述取代烷基、取代烷氧基以及取代硫代烷基而言,所述取代基是直链或支链C1-C5烷基、卤原子、直链或支链C1-C5烷氧基或者直链或支链C1-C3硫代烷基。
根据本发明的一实施例,在所述式(I')中,所述R1可以是氢原子,R2可以是氢原子、羟基、取代或未被取代的直链或支链C1-C5烷基、直链或支链C1-C5烷氧基、或者直链或支链C1-C4硫代烷基。
根据本发明的另一实施例,在所述式(I')中,所述R1可以是氢原子,R2可以是甲基、乙基、正丙基、异丙基、正丁基、正戊基、2-甲氧基乙基、三氟甲基、氟、氯、溴、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、正戊氧基、甲氧基甲氧基等。
根据本发明的又一实施例,所述式(I')中,在所述R1为卤原子的情况下,其可以是氟、氯或者溴。
根据本发明的又一实施例,所述式(I')的化合物可以是下述化合物中的1种以上的化合物。
所述代谢综合征可以是肥胖、糖尿病、高脂血症以及脂肪肝中的一种以上。并且,所述糖尿病可以是第二型糖尿病(T2DM)。
并且,所述代谢综合征可以是第二型糖尿病和肥胖的复合疾病。
本说明书中,“代谢综合征”指在代谢综合征时使危险性增加的疾病,例如指高甘油三脂血症、脂肪肝、糖尿病以及肥胖等危险因素增加的疾病,但不限于此。
根据本发明的一实施例的药学组成物能够预防或者治疗上述第二型糖尿以及肥胖的复合疾病,因此较为完美。
并且,所述炎症疾病可以是类风湿性关节炎;退行性关节炎;以及由哮喘、过敏、糖尿或者心肌梗塞引发的炎症疾病中的一种以上。
所述药学组成物可以被调配成本技术领域中公知的常规药学制剂。所述制剂包括口服制剂、注射剂、栓剂、透皮制剂、以及经鼻给药制剂,但也可以被调配成任意制剂而给药,优选被调配成口服制剂和注射剂。
在被调配成所述各个制剂时,可以添加各个制剂的调配中所需要的药学中可接受的载体而制造。本说明书中,术语“药理准用载体(意同‘药理可用载体’;pharmaceuticallyacceptable carrier)”为了指除药学活性成分之外的任一构成成分而被使用。“药学中可接受的”指不与组成物中存在的其他构成成分相互作用(例如,载体彼此之间或者药学活性成分和载体之间的相互作用)而引起药学上不利变化的性质。所述药学中可接受载体的选择可以根据对于特定给药制剂的特性、给药方式、溶解度以及稳定性的所述载体的效果等因素而不同。
在一实施例中,口服用的药学组成物中所包含的药学中可接受的载体可以是稀释剂、粘合剂、助滑剂(或润滑剂)、崩解剂、稳定剂、溶解助剂、甜味剂,着色剂、调味剂中选择的一种以上,但不限于此。
稀释剂(diluent)指为了增加组成物体积而形成适当的大小而添加的任意赋形剂。所述稀释剂可以使用淀粉(例如,马铃薯淀粉、玉米淀粉、小麦淀粉、预胶化淀粉)、微晶纤维素(例如,低水合微晶纤维素)、乳糖(例如乳糖一水化物、无水乳糖、喷雾乳糖)、葡萄糖、山梨醇、甘露糖醇,蔗糖、藻酸盐、碱土金属盐、粘土,聚乙二醇以碳酸二钙、无水磷酸氢钙、二氧化硅等的单体或者混合物,但不限于此。本发明中,所述赋形剂可以在相对组成物总量5重量%至50重量%的范围内使用,并且为了调配以及维持质量,例如可以相对组成物总量取用10重量%至35重量%。
粘合剂(binder)指为了给粉末状的物质赋予粘着性而使黏着更容易并改善流动性而使用的物质。所述粘合剂可以是淀粉、微晶纤维素、高分散性二氧化硅、甘露醇、乳糖、聚乙二醇、聚乙烯吡咯烷酮、纤维素衍生物(例如,羟基丙基甲基纤维素、羟基丙基纤维素、低取代度羟基丙基纤维素)、天然树胶、合成树胶,聚维酮、共聚维酮以及明胶中选择的一种以上,但不限于此。本发明中,所述粘合剂可以在相对组成物总量2重量%至15重量%的范围内使用,并且为了调配以及维持质量,例如可以相对组成物总量取用1重量%至3重量%。
崩解剂(disintegant)指为了使体内给药后的固体制剂的崩溃或者崩解容易而添加的物质。所述崩解剂可以使用羧基乙酸淀粉钠、玉米淀粉、马铃薯淀粉或者预胶化淀粉等淀粉或改性淀粉、膨润土、蒙脱石、硅酸铝镁(veegum)等如粘土(clay)、微晶纤维素、羟基丙基纤维素或者羧甲基纤维素等纤维素、藻酸钠或者藻酸等藻酸类、交联羧甲纤维素(croscarmellose)钠等交联纤维素、瓜耳胶或黄原胶等树胶、交联聚维酮(crospovidone)等交联聚合物、碳酸氢钠、柠檬酸等泡腾剂中的一个或者混合多个而使用,但不限于此。本发明中,所述崩解剂可以在相对药学组成物总量2重量%至15重量%的范围内使用,例如可以相对组成物总量取用4重量%至10重量%。
助滑剂(glidant)或润滑剂(lubricant)指发挥防止粉末贴附于压缩设备并改善流动的功能的物质。所述助滑剂可以使用硬质无水硅酸、滑石、硬脂酸、硬脂酸金属盐(镁盐或钙盐等)、月桂基硫酸钠、氢化植物油、苯甲酸钠,富马酸硬脂钠,山嵛酸甘油酯、单硬脂酸甘油酯或者聚乙二醇中的一个或者混合多个而使用,但不限于此。本发明中,所述润滑剂可以在相对药学组成物总量0.1重量%至5重量%的范围内使用,例如为了调配以及维持质量,可以相对组成物总量取用1重量%至3重量%。
吸附剂(adsorbant)可以使用水合二氧化硅、硬质无水硅酸、胶体二氧化硅、硅酸铝酸镁、微晶纤维素、乳糖或者交联聚乙烯吡咯烷酮中的一个或者混合多个而使用,但不限于此。
稳定剂(stabilizer)可以选择丁基羟基茴香醚、丁基羟基甲苯、胡萝卜素、视黄醇、抗坏血酸、生育酚、生育酚聚乙二醇琥珀酸或者丙基没食子酸等抗氧化剂;环糊精、羧乙基环糊精、羟丙基环糊精、磺基丁基醚或者环糊精等糖类环状化合物;磷酸、乳酸、乙酸、柠檬酸、酒石酸、琥珀酸、马来酸、富马酸、乙醇酸、丙酸、葡糖酸或者葡萄糖醛酸等有机酸中的一种以上,但不限于此。
选择性地,可以包含用于提升美观而提高适口性的公知的添加剂。例如,可以使用三氯蔗糖、蔗糖、果糖、赤藓醇、乙酰磺胺酸钾、糖醇、蜂蜜、山梨糖醇或者阿司帕坦等甜味剂而更有效地隐藏苦味并维持制剂的稳定性和质量。并且,可以使用柠檬酸、柠檬酸钠等酸化剂;李子香、柠檬香、菠萝香、香草香等天然香料;天然果汁、叶绿酸、类黄酮等天然色素。
所述口服用药学组成物可以是口服用的固体制剂、半固体制剂或者液态制剂。口服用固体制剂例如有片剂、丸剂、硬或软胶囊剂、散剂、细粒、颗粒、用于重构溶液或者悬浮液的粉末、含片、圆片、口服片(oral strip)糖衣丸(dragee)以及咀嚼胶(chewable gum)等,但不限于此。用于口服的液态制剂包括:溶液、悬浮液、乳液、糖浆、酏剂、酒精制剂、芳香水剂、柠檬水剂、提液、沉淀剂,酊剂和油药剂。半固体制剂包括气雾剂、霜剂、凝胶(gel)等,但不限于此。
所述根据本发明的药学组成物可以被调配成注射剂,在被调配成注射剂的情况下,可以包括作为稀释剂的与血液等渗的无毒性缓冲溶液,例如,pH7.4的磷酸缓冲溶液等。所述药学组成物在缓冲溶液之外,可以包括其他稀释剂或者添加剂。
所述提到的制剂中使用的载体和制剂的制造方法可以根据本技术领域中公知的技术选择并制造,例如可以根据Remington's Pharmaceutical Science(雷明顿氏制药科学)最新版中记载的方法制造。
根据如上所述的本发明的药学组成物的给药量以及给药时期可以根据给药对象的年龄、性别、疾病种类、状态、体重、给药路径、给药次数、药的形态而不同。每日给药量为0.1~1000mg/kg,且优选1mg/kg至100mg/kg。所述给药量可以根据疾病的种类、癌症发展程度、给药路径、性别、年龄、体重等而适当地增减。
为了取得代谢综合征或者糖尿病以及肥胖的复合疾病的预防以及治疗效果,为了使以成人为基准的有效成分化合物的每日总给药量达到0.1~1000mg/kg,可以将根据本发明的药学组成物分成任意次数而给药。所述给药量可以根据欲治疗或者预防的疾病的种类、疾病的发展程度、给药路径、性别、年龄、体重、健康状况等而适当地增减。
对于所述根据本发明的药学组成物而言,根据本发明的所述式(I′)的化合物的含量可以占总重量的0.0001~10重量%,优选0.001~1重量%。
以下,根据下述实施例以及实验例对本发明进行更具体的说明。但其目的仅在于帮助理解本发明,其在任何含义下都不限制本发明的范围。
所述制造例以及实施例中使用的试剂在没有相反表示的情况下,为购自西格玛奥德里奇(Sigma-Aldrich)公司的试剂级。
制造例1:光甘草定的制造
购入销售中的从甘草(Licorice)提取并被精制成40%含量水平的光甘草定,并用硅胶柱色谱法精制而得到了纯净的光甘草定。
制造例2:化合物1的制造
使从所述制造例1得到的光甘草定基于文献(Archives of PharmacalResearch32(2009)647~654)进行加氢反应(H2,Pd/C),而得到了3",4"-二氢光甘草定(化合物1)。
制造例3:6-甲酰基-2,2-二甲基-2H-苯并吡喃-5-基苯甲酸的合成
根据[Tetrahedron,57(2001),5335~5338]的方法准备5-羟基-2,2-二甲基-2H-苯并吡喃-6-甲醛后,在20ml CH2Cl2融化2.04g(10.mmol)后,在添加1ml TEA和1.54g(11.0mmol)苯甲酰氯状态下,在常温搅拌5个小时。在其中添加10ml NaHCO3饱和水溶液后,再搅拌10分钟后,分离了水层和有机层。使用10ml CH2Cl2再次萃取分离的水层后,与有机层混合而用MgSO4处理,然后过滤并浓缩。利用异丙基乙醇(IPA)将通过上述方法浓缩的固体再结晶而得到了纯6-甲酰基-2,2-二甲基-2H-苯并吡喃-5-基苯甲酸(8.1mmol)。
1H-NMR(CDCl3):9.92(s,1H),8.25(m,2H),7.71(d,1H),7.68(m,1H),7.55(t,2H),6.83(d,1H),6.38(d,1H),5.69(d,1H),1.49(s,6H)。
制造例4:(2-甲氧甲氧基苯基)乙酸甲酯的合成
在20ml甲醇中融化2-羟基苯乙酸3.04g(20.0mmol)后,添加了1.0ml的浓硫酸。使反应溶液换流10个小时后,进行减压蒸馏并浓缩。将浓缩液柱层析而得到了2.78g(16.7mmol)(2-羟基苯)乙酸甲酯。将其再次融化于20ml丙酮后添加2.8g(20.0mmol)K2CO3,然后在常温下剧烈搅拌30分钟的同时添加2.40g(30.0mmol)的氯甲基甲基醚(chloromethyl methyl ether),然后连夜剧烈搅拌。然后,过滤反应液而去除固体成分,减压蒸馏过滤液并浓缩后,利用硅胶柱层析精制浓缩液而得到了(2-甲氧甲氧基苯)乙酸甲酯2.56g(12.3mmol)。
1H-NMR(CDCl3):7.239(t,1H,J=8.0Hz),7.201(d,1H,J=8.0Hz),7.099(d,1H,J=8.0Hz),6.973(t,1H,J=8.0Hz),5.191(s,2H),3.687(s,3H),3.666(s,2H),3.459(s,3H)。
制造例5:(2-苄氧基-4-甲基苯基)乙酸甲酯的合成
在30ml的CH2Cl2中融化3.01g(20.0mmol)的2'-羟基-4'-甲基苯乙酮(2'-hydroxy-4'-methylacetophenone)后,添加了5ml的15%NaOH水溶液和1.0g的四丁基溴化铵(tetrabutylammonium bromide)。将反应溶液剧烈搅拌的同时添加3.42g(20.0mmole)的溴苄(benzyl bromide)后,连夜剧烈搅拌并进行换流。将反应溶液彼此分离而用20ml的CH2Cl2萃取一次后,带着CH2Cl2层一起减压蒸馏而进行浓缩。将浓缩液色谱而得到了3.89g(16.2mmol)的2'-苄氧基-4'-甲基苯乙酮。使其完全融化于20ml的甲醛后,在溶液中添加3ml的HClO4并在常温下拌匀。然后在常温下剧烈搅拌30分钟通过上述方法准备的反应溶液的同时逐渐添加7.33g(16.5mmol)的硝酸铊(Tl(NO3)3·3H2O)后,在常温下再搅拌1个小时。然后,在反应溶液中添加30ml的NaHCO3饱和水溶液而进行中和,然后真空蒸馏而去除了MeOH。在反应溶液中添加20ml的CH2Cl2而萃取有机层并浓缩后,将浓缩液色谱而得到了3.70g(13.7mmol)的(2-苄氧基-4-甲基苯基)乙酸甲酯。
1H-NMR(CDCl3):7.28~7.45(m,5H),7.088(d,1H,J=8.0Hz),6.767(s,1H)6.761(d,1H,J=8.0Hz),5.065(s,2H),3.644(s,2H),3.625(s,3H),2.334(s,3H)。
制造例6:(2-苄氧基-4-乙基苯基)乙酸甲酯的合成
在150ml的CH2Cl2中融化12.2g(100.0mmole)的3-乙基苯酚并搅拌,同时在1个小时内缓慢添加15ml的三乙胺。在冰浴中缓慢添加11.2g(220.0mmole)的无水乙酸(aceticanhydride)1个小时后,剧烈搅拌2个小时。在反应液中缓慢添加饱和盐水200ml后,剧烈搅拌10分钟,然后分离有机层后进行减压蒸馏并浓缩。在专门准备的瓶子内添加16.7g(110.0mmole)的无水AlCl3后,利用机械搅拌机(mechanical stirrer)剧烈搅拌的同时缓慢滴加上文中准备的浓缩液,然后继续剧烈搅拌并加热到165℃,然后在此状态下维持1个小时。将反应混合物冷却至常温后,缓慢添加500ml的饱和盐水以使反应混合物溶于水而完全释放。当溶液中的固体融化而完全消失的时候,利用500ml的CH2Cl2进行萃取。将有机层分离而浓缩后,再次融化于150ml的CH2Cl2,然后添加15%的NaOH水溶液25ml和3.0g的四丁基溴化铵(tetrabutylammonium bromide)。在剧烈搅拌反应液的同时,添加18.82g(110.0mmole)的溴苄(benzyl bromide),并连夜剧烈搅拌的同时进行换流。使反应液彼此分离后用50ml的CH2Cl2萃取水层一次后,带着CH2Cl2层一起进行一次减压蒸馏并浓缩。在高真空下将浓缩液蒸馏(155~160℃/0.01mmHg)而得到了18.70g(73.6mmol)的2'-苄氧基-4'-乙基苯乙酮。使其充分溶解于10ml的甲醇后,在溶液中添加15ml的HClO4并在常温下混合。在常温下剧烈搅拌通过上述方法准备的反应液的同时,60分钟内缓慢添加33.33g(75.0mmol)的Tl(NO3)3·3H2O后,在常温下再次搅拌5个小时。然后,进行真空蒸馏而去除了MeOH。在反应液中添加80ml的CH2Cl2而提取有机层并浓缩后,利用硅胶柱色谱法精制浓缩液而得到了17.86g(62.8mmol)的(2-苄氧基-4-乙基苯基)乙酸甲酯。
1H-NMR(CDCl3):7.28~7.45(m,5H),7.116(d,1H,J=8.0Hz),6.787(m,2H),5.078(s,2H),3.649(s,2H),3.627(s,3H),2.630(q,2H,J=8.0Hz),1.228(t,3H,J=8.0Hz)。
制造例7:(2-苄氧基-4-丙基苯基)乙酸甲酯的合成
除了用15.22g(100mmole)的3-丙基苯酚代替3-乙基苯酚之外,通过与上述制造例6相同的方法得到了(2-苄氧基-4-丙基苯基)乙酸甲酯。
1H-NMR(CDCl3):7.28~7.45(m,5H),7.109(d,1H,J=8.0Hz),6.764(d,1H,J=8.0Hz)6.763(s,1H),5.073(s,2H),3.650(s,2H),3.627(s,3H),2.561(t,2H,J=4.0Hz),1.628(m,2H),0.936(t,3H,J=7.6Hz)。
制造例8:(2-苄氧基-4-丁基苯基)乙酸甲酯的合成
除了用3-丁基苯酚代替3-乙基苯酚之外,通过与上述制造例6相同的方法得到了(2-苄氧基-4-丁基苯基)乙酸甲酯。
1H-NMR(CDCl3):7.30~7.43(m,5H),7.110(d,1H,J=8.0Hz),6.768(d,1H,J=8.0Hz),6.766(s,1H),5.079(s,2H),3.653(s,2H),3.632(s,3H),2.589(t,2H,J=8.0Hz),1.588(m,2H),1.348(m,2H),0.925(t,3H,J=7.4Hz)。
制造例9:(2-苄氧基-4,5-二甲基苯基)乙酸甲酯的合成
除了用3,4-二甲基苯酚代替3-乙基苯酚之外,通过与上述制造例6相同的方法得到了(2-苄氧基-4,5-二甲基苯基)乙酸甲酯。
1H-NMR(CDCl3):7.28~7.46(m,5H),7.007(s,1H),6.785(s,1H)5.083(s,2H),3.670(s,3H),2.272(s,3H),2.228(s,3H)。
制造例10:(2-苄氧基-4-甲氧基苯基)乙酸甲酯的合成
在30ml的CH2Cl2中融化4.9g(21.7mmol)的2'-羟基-4'-甲氧基苯乙酮后,添加了15%的NaOH水溶液5ml和1.0g的四丁基溴化铵(tetrabutylammoniumbromide)。在剧烈搅拌反应液的同时,添加3.42g(20.0mmole)的溴苄(benzylbromide),并在连夜剧烈搅拌的同时进行换流。使反应液彼此分离后用20ml的CH2Cl2萃取水层一次后,带着CH2Cl2层一起进行一次减压蒸馏并浓缩。将浓缩液用柱层析法精制后,得到了4.27g(15.8mmol)的2'-苄氧基-4'-甲氧基苯乙酮。将其再次与1.76g(20.0mmol)的吗啉(morpholine)、1.5g的硫磺混合后,在160℃下连夜剧烈搅拌了混合物。将反应液冷却至常温后,直接通过硅胶柱层析法得到了4.24g(11.4mmol)的2-(2-苄氧基)-4-甲氧基苯基)-1-吗啉基乙烷硫酮。将其添加到30ml的NaOH饱和乙醇溶液后,进行8小时的换流,然后在冷却至0℃的状态下,缓慢加入浓盐酸而使PH降到1以下。然后将其减压蒸馏而利用30ml的CH2Cl2和20ml的水融化浓缩的固态物后,再次进行分离。利用30m的CH2Cl2再次萃取水层后,对它们一起进行浓缩。在浓缩的固态物中添加20ml的甲醛并融化后,在添加1ml的浓硫酸的状态下,换流10和小时。使反应液融化于30m的CH2Cl2后,用盐水清洗并浓缩后,利用硅胶柱层析法精制而得到了(2-苄氧基-4-甲氧基苯基)乙酸甲酯。
1H-NMR(CDCl3):7.27~7.43(m,5H),7.100(d,1H,J=8.0Hz),6.511(d,1H,J=2.0Hz),6.461(dd,1H,J=8.0,2.0Hz),5.040(s,2H),3.763(s,3H),3.619(s,3H),3.605(s,2H)。
制造例11:(2-苄氧基-4-乙氧基苯基)乙酸甲酯的合成
除了用2'-羟基-4'-乙氧基苯乙酮代替2'-羟基-4'-甲氧基苯乙酮之外,通过与上述制造例10相同的方法得到了(2-苄氧基-4-乙氧基苯基)乙酸甲酯。
1H-NMR(CDCl3):7.28~7.45(m,5H),7.117(d,1H,J=8.0Hz),6.546(d,1H,J=2.4Hz)6.483(dd,1H,J=8.0,2.4Hz),5.073(s,2H),4.028(q,2H,J=6.8Hz),3.653(s,3H),3.635(s,2H),1.421(t,3H,J=7.8Hz)。
制造例12:(2-苄氧基-4-丙氧基苯基)乙酸甲酯的合成
除了用2'-羟基-4'-丙氧基苯乙酮代替2'-羟基-4'-甲氧基苯乙酮之外,通过与上述制造例11相同的方法得到了(2-苄氧基-4-丙氧基苯基)乙酸甲酯。
1H-NMR(CDCl3):7.28~7.45(m,5H),7.098(d,1H,J=8.0Hz),6.538(d,1H,J=2.4Hz)6.469(dd,1H,J=8.0,2.4Hz),5.055(s,2H),3.898(t,2H,J=6.4Hz),3.632(s,3H),3.616(s,2H),1.795(m,2H),1.033(t,3H,J=6.8Hz)。
制造例13:(2-苄氧基-4-丁氧基苯基)乙酸甲酯的合成
除了用2'-羟基-4'-丁氧基苯乙酮代替2'-羟基-4'-甲氧基苯乙酮之外,通过与上述制造例11相同的方法得到了(2-苄氧基-4-丁氧基苯基)乙酸甲酯。
1H-NMR(CDCl3):7.28~7.45(m,5H),7.083(d,1H,J=8.0Hz),6.518(d,1H,J=2.0Hz)6.456(dd,1H,J=8.0,2.0Hz),5.040(s,2H),3.925(t,2H,J=6.4Hz),3.618(s,3H),3.602(s,2H),1.746(m,2H),1.475(m,2H),0.975(t,3H,J=7.2Hz)。
制造例14:6-甲酰基-2,2-二乙基-2H-苯并吡喃-5-基苯甲酸的合成
以制造例3中参考的文献[Tetrahedron,57(2001),5335~5338]的方法为准,在合成5-羟基-2,2-二甲基-2H-苯并吡喃-6-甲醛的过程中,除了用3-乙基-2-戊烯醇(3-ethylpent-2-enal)代替3-甲基丁烯醛(3-methylcrotonaldehyde=3-methylbut-2-enal)之外,通过与上述制造例3相同的方法得到了6-甲酰基-2,2-二乙基-2H-苯并吡喃-5-基苯甲酸。
1H-NMR(CDCl3):9.893(s,1H),8.251(m,2H),7.688(d,1H,J=8.4Hz),7.686(m,1H),7.551(t,2H,J=7.2Hz),6.813(d,1H,J=8.4Hz),6.496(d,1H,J=10.2Hz),5.544(d,1H,J=10.2Hz),1.804(m,2H),1.657(m,2H),0.949(t,6H)。
根据下述反应式制造出化合物2至化合物23。
其中,可以根据需要改变加氢反应以及去保护基过程(deprotecting process)的顺序。并且,在保护基为苄或者被取代的苄的情况下,可以同时进行加氢反应和去保护基的过程,因此无需区分专门的过程。
实施例1:3-(2-羟基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡
喃(化合物2)的合成
(1)2-(2-(甲氧基甲氧基)苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烯酸甲酯的制造
在氮气氛围下,利用干冰-丙酮浴将3颈圆底烧瓶冷却至-78℃。在其中添加45ml的1.0M二异丙基氨基锂(LDA)THF溶液后,在30分钟内缓慢加入将所述制造例4中制造的6.30g(30.0mmol)的(2-甲氧基甲氧基苯基)乙酸甲酯溶于100ml的THF的溶液后,再搅拌了30分钟。
在上述反应液中,在30分钟内缓慢加入下述溶液后再搅拌30分钟,在20ml的THF溶液中融化从所述制造例3制造的9.24g(30.0mmol)的5-苯甲酰-2,2-二甲基-6-甲酰-2H-1-苯并吡喃的溶液。将所述圆底烧瓶从干冰-丙酮浴去除后,进行加热以使所述反应液的温度缓慢上升至0℃。在此状态下,将100ml的盐水加入到所述反应液,然后在常温下剧烈搅拌30分钟。分离有机层后,利用100ml的乙酸乙酯再一次萃取水层。将通过上述方法从乙酸乙酯萃取的有机层与上文中分离的有机层合在一起并用无水硫酸钠干燥后,通过减压蒸馏而浓缩。利用硅胶柱层析法精制该浓缩液后,得到了5.16g(13.02mmol)的2-(2-(甲氧基甲氧基)苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯(Yield:43%)。
1H-NMR(CDCl3):8.007(s,1H),7.293(td,1H,J=8.0,1.6Hz),7.170(d,1H,J=8.0Hz),7.035(dd,1H,J=7.6,1.6Hz),6.940(t,1H,J=7.6Hz),6.605(d,1H,J=10.0Hz),6.603(d,1H,J=8.8Hz),6.147(d,1H,J=8.8Hz),6.136(s,1H),5.536(d,1H,J=10.0Hz),5.113(s,2H),3.757(s,3H),3.377(s,3H),1.376(s,6H)。
13C-NMR(CDCl3):168.902,155,066,154.906,150.589,135.977,131.065,130.067,129.723,128.882,128.364,125.824,122.271,116.345,114.951,114.730,109.460,109.101,94.793,76.144,55.986,52.340,27.834。
(2)2-(2-(甲氧基甲氧基)苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烷-1-醇的制造
在20ml的THF中融化3.96g(10.0mmol)的从所述(1)中获得的2-(2-(甲氧基甲氧基)苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯后,加入60ml的LiBH41.0M THF溶液后,换流5个小时。用冰浴使反应液冷却后,缓慢加入1N HCL 50ml,然后利用100ml的CH2Cl2萃取。利用无水硫酸镁干燥有机层后,通过减压蒸馏进行浓缩。利用硅胶柱层析法精制浓缩液后,得到了2.42g(6.53mmol)的2-(2-(甲氧基甲氧基)苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷(Yield:65%)。
1H-NMR(CDCl3):7.621(b,1H),7.366(td,1H,J=8.0,1.6Hz),7.228(d,1H,J=8.0Hz),7.160(dd,1H,J=7.6,1.6Hz),7.036(t,1H,J=7.6Hz),6.773(d,1H,J=10.0Hz),6.739(d,1H,J=8.0Hz),6.333(d,1H,J=8.0Hz),5.583(d,1H,J=10.0Hz),5.245(s,2H),3.866(dd,1H,J=10.8,4.0Hz),3.810(dd,1H,J=10.8,2.8Hz),3.494(s,3H),3.398(m,1H),3.070(dd,1H,J=14.4,10.4Hz),2.741(dd,1H,J=14.4,4.0Hz),1.433(s,3H),1.420(s,3H)。
13C-NMR(CDCl3):154.418,152.473,150.851,131.444,130.606,128.825,128.015,127.881,122.053,117.835,117.451,114.135,110.286,108.500,94.599,75.540,63.321,56.333,41.798,30.759,27.802,27.585。
(3)3-(2-(甲氧基甲氧基)苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡
喃{2'-(甲氧基甲氧基)-4'-脱氧光甘草定}的制造
在10ml的THF中融化1.31g(3.53mmol)的从所述(2)中获得的2-(2-(甲氧基甲氧基)苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇后,加入0.995g(3.80mmol)的三苯基膦(Ph3P)后加热,从而使THF缓慢换流。维持该状态并缓慢加入3.8ml的二乙基偶氮二羧酸酯(DEAD)1.0M甲苯溶液后,剧烈搅拌一个小时。将反应液冷却至常温后,通过减压蒸馏浓缩,然后利用硅胶柱层析法将其精制而得到了1.14g(3.24mmol)的3-(2-(甲氧基甲氧基)苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃(Yield:92%)。
1H-NMR(CDCl3):7.231(td,1H,J=7.2,1.6Hz),7.13~7.17(m,2H),7.010(td,1H,J=7.2,0.8Hz),6.847(d,1H,J=8.0Hz),6.677(d,1H,J=10.0Hz),6.396(d,1H,J=8.0Hz),5.578(d,1H,J=10.0Hz),5.235(s,2H),4.408(ddd,1H,J=10.4,2.4,1.2Hz),4.058(t,1H,J=10.4Hz),3.702(m,1H),3.491(s,3H),3.015(dd,1H,J=15.2,11.2Hz),2.881(ddd,1H,J=15.2,3.6,1.6Hz),1.447(s,3H),1.426(s,3H)。
13C-NMR(CDCl3):155.027,151.925,149.737,130.100,129.161,128.933,127.885,127.229,121.987,116.912,114.337,114.066,109.896,108.692,94.419,75.557,70.069,56.135,32.114,30.721,27.798,27.511。
(4)3-(2-(羟基)苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃的制造
在80ml的异丙醇中融化从所述(3)中获得的7.05g(20.0mmol)的3-(2-(甲氧基甲氧基)苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃后,加入0.3ml的浓盐酸并在常温下搅拌5个小时。通过减压蒸馏而浓缩反应溶液后,利用硅胶柱层析法精制该溶液而得到了2.82g(9.16mol)的3-(2-(羟基)苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃(Yield:46%)。
1H-NMR(CDCl3):7.11~7.16(m,2H),6.933(dt,1H,J=7.6,1.2Hz),6.848(d,1H,J=8.4Hz),6.759(dd,1H,J=8.0,0.8Hz),6.676(d,1H,J=10.0Hz),6.398(d,1H,J=8.4Hz),5.578(d,1H,J=10.0Hz),5.059(s,1H),4.434(ddd,1H,J=10.4,3.2,2.0Hz),4.087(t,1H,J=10.4Hz),3.607(m,1H),3.037(dd,1H,J=15.2,10.8Hz),2.904(ddd,1H,J=15.2,5.2,1.6Hz),1.449(s,3H),1.431(s,3H)。
13C-NMR(CDCl3):153.405,151.802,149.721,129.190,128.943,127.792,127.617,127.557,121.128,116.934,115.417,114.335,109.935,108.720,75.659,69.781,32.202,30.388,27.732,27.490。
(5)3-(2-羟基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃的制造
将从所述(4)中获得的2.82g(9.16mol)的3-(2-(羟基)苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃放入100ml的压力容器后,加入20ml的乙醇并使其充分溶解,然后在混合100mg的10%PD/C的状态下,在2气压氢下剧烈搅拌15个小时。过滤反应液而去除催化剂后,通过减压蒸馏浓缩,然后利用硅胶柱层析法将其精制而得到了2.78g(8.97mmol)的3-(2-羟基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物2)(Yield=98%)。
1H-NMR(CDCl3):7.218(t,1H,J=7.6Hz),6.842(d,1H,8.4Hz),6.813(d,1H,7.6Hz),6.751(dd,1H,J=7.6,2.0Hz),6.652(d,1H,J=2.0Hz),6.419(d,1H,J=8.4Hz),5.330(s,1H),4.366(ddd,1H,J=10.4,3.6,0.4Hz),3.936(t,1H,J=10.4Hz),3.128(m,1H),2.903(d,2H,J=8.4Hz),2.667(m,2H),1.794(t,2H,J=7.2Hz),1.361(s,3H),1.338(s,3H)。
13C-NMR(CDCl3):155.875,152.714,151.978,143.459,129.903,127.478,119.797,114.227,113.953,112.644,109.480,109.428,74.053,70.774,38.666,32.296,32.034,26.880,26.222,17.116。
实施例2:3-(2-羟基-4-甲基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]
苯并吡喃(化合物3)的合成
(1)2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙
烯酸甲酯的制造
在氮气氛围下维持气氛,与此同时在3颈圆底烧瓶中添加45ml的1.0MLDA THF溶液后,利用-78℃的干冰-丙酮浴进行冷却。使从所述制造例5中制造的8.10g(30.0mmol)的(2-苄氧基-4-甲基苯基)乙酸甲酯{(methyl2-benzyloxy-4-methylphenyl)acetate}溶于150ml的THF后,在30分钟内缓慢加入到之前准备的1.0M LDA THF溶液中,并再次搅拌30分钟。使从所述制造3中制造的9.24g(30.0mmol)的5-苯甲酰-2,2-二甲基-6-甲酰-2H-1-苯并吡喃溶于20ml的THF后,在30分钟内将其缓慢加入到之前准备的反应液后,再搅拌30分钟。将圆底烧瓶从干冰-丙酮浴分离而放置,从而将反应溶液逐渐加热到0℃。在此状态下,加入100ml的盐水后,在常温下剧烈搅拌30分钟。分离有机层后,利用200ml的乙酸乙酯再次萃取水层。将通过上述方法利用乙酸乙酯萃取的有机层与之前分离的有机层合在一起后,用无水硫酸镁干燥,然后通过减压蒸馏而浓缩。利用硅胶柱层析法精制该浓缩液而得到了5.79g(12.70mmol)的2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯(Yield:42.3%)。
1H-NMR(CDCl3):7.879(s,1H),7.26~7.36(m,5H),6.932(d,1H,J=7.6Hz),6.806(s,1H),6.712(d,1H,J=7.6Hz),6.680(d,1H,J=8.4Hz),6.585(d,1H,J=10.0Hz),6.183(d,1H,J=8.4Hz),5.701(s,1H),5.533(d,1H,J=10.0Hz),5.037(s,2H),3.696(s,3H),2.345(s,3H),1.392(s,6H)。
13C-NMR(CDCl3):168.893,156,193,154.704,150.259,139.893,136.992,135.674,130.963,130.160,128.842,128.721,127.668,126.965,122.024,121.948,116.543,114.971,113.332,109.470,109.040,76.115,70.023,52.253,27.872,21.790。
(2)2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙
烷-1-醇的制造
在20ml的THF中融化4.56g(10.0mmol)的从所述(1)中获得的2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯后,加入60ml的LiBH41.0M THF溶液后,换流5个小时。用冰浴使反应液冷却后,缓慢加入1N HCL 50ml,然后利用100ml的CH2Cl2萃取。利用无水硫酸镁干燥有机层后,通过减压蒸馏进行浓缩,并利用硅胶柱层析法精制而得到了2.35g(5.47mmol)的2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇(Yield:54.7%)。
1H-NMR(CDCl3):7.687(b,1H),7.33~7.43(m,5H),7.158(d,1H,J=7.6Hz),6.845(s,1H),6.807(d,1H,J=7.6Hz),6.737(d,1H,J=10.0Hz),6.707(d,1H,J=8.0Hz),6.309(d,1H,J=8.0Hz),5.562(d,1H,J=10.0Hz),5.105(s,2H),3.845(dd,1H,J=10.8,3.6Hz),3.737(dd,1H,J=10.8,2.8Hz),3.323(m,1H),3.118(dd,1H,J=14.0,10.4Hz),2.702(dd,1H,J=14.0,4.0Hz),2.360(s,3H),1.431(s,3H),1.410(s,3H)。
13C-NMR(CDCl3):155.793,152.415,150.979,137.841,136.457,130.688,128.734,128.596,128.429,128.333,128.231,127.633,121.824,118.070,117.591,113.116,110.289,108.436,75.478,70.517,63.463,42.569,30.581,27.910,27.575,21.394。
(3)3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃
的制造
在10ml的THF中融化1.57g(3.65mmol)的从所述(2)中获得的2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇后,加入0.995g(3.80mmol)的三苯基膦(Ph3P)后加热,从而使THF缓慢换流。维持该状态并缓慢加入3.9ml的二乙基偶氮二羧酸酯(DEAD)1.0M甲苯溶液后,剧烈搅拌一个小时。将反应液冷却至常温后,通过减压蒸馏而浓缩,然后利用硅胶柱层析法将其精制而得到了1.31g(3.17mmol)的3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃(Yield:86.8%)。
1H-NMR(CDCl3):7.32~7.45(m,5H),7.052(d,1H,J=7.2Hz),6.838(d,1H,J=8.0Hz),6.811(s,1H),6.796(d,1H,J=7.2Hz),6.666(d,1H,J=10.0Hz),6.384(d,1H,J=8.0Hz),5.567(d,1H,J=10.0Hz),5.116(s,2H),4.394(ddd,1H,J=10.0,3.2,2.0Hz),4.059(t,1H,J=10.0Hz),3.717(m,1H),2.991(dd,1H,J=14.0,6.8Hz),2.894(dd,1H,J=14.0,5.2Hz),2.348(s,3H),1.446(s,3H),1.432(s,3H)。
13C-NMR(CDCl3):156.291,151.838,149.853,137.757,137.128,129.167,128.775,128.592,127.814,127.112,126.958,121.666,116.989,114.446,112.924,109.849,108.577,75.527,70.115,70.065,31.587,30.704,27.784,27.594,21.426。
(4)3-(2-羟基-4-甲基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并
吡喃的制造
将从所述(3)中获得的4.12g(10.0mol)的3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃放入100ml的压力容器后,加入50ml的乙醇并使其充分溶解,然后在混合150mg的5%PD/C的状态下,在5气压氢下剧烈搅拌25个小时。过滤反应溶液而去除催化剂后,通过减压蒸馏而浓缩,然后在硅胶下色谱而得到了2.67g(8.23mmol)的3-(2-羟基-4-甲基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物3)(Yield=82%)。
1H-NMR(CDCl3):7.017(d,1H,J=8.0Hz),6.850(d,1H,J=7.6Hz),6.755(dd,1H,J=7.6,0.4Hz),6.593(d,1H,J=0.4Hz),6.407(d,1H,J=8.0Hz),4.931(s,1H),4.422(ddd,1H,J=10.4,3.6,2.0Hz),4.058(t,1H,J=10.4Hz),3.556(m,1H),3.044(dd,1H,J=15.6,11.2Hz),2.890(ddd,1H,J=15.6,5.2,2.0Hz),2.657(m,2H,J=6.8,2.4Hz),2.294(s,3H),1.809(t,2H,J=6.8Hz),1.351(s,3H),1.337(s,3H)。
13C-NMR(CDCl3):153.271,152.801,152.130,137.818,127.458,127.414,124.618,121.826,116.214,112.830,109.315,109.274,73.743,69.904,32.337,32.050,30.577,26.807,26.408,20.920,17.132。
实施例3:3-(2-羟基-4-乙基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]
苯并吡喃(化合物4)的合成
(1)2-(2-苄氧基-4-乙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙
烯酸甲酯的制造
除了用从所述制造例6中制造的2-苄氧基-4-乙基苯乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2(1)相同的方法得到了2-(2-苄氧基-4-乙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯。
1H-NMR(CDCl3):7.889(s,1H),7.26~7.36(m,5H),6.957(d,1H,J=7.6Hz),6.882(s,1H),6.740(d,1H,J=7.6Hz),6.657(d,1H,J=8.4Hz),6.589(d,1H,J=10.0Hz),6.170(d,1H,J=8.4Hz),5.789(s,1H),5.534(d,1H,J=10.0Hz),5.045(s,2H),3.696(s,3H),2.645(q,2H,J=7.6Hz),1.391(s,6H),1.233(t,3H,J=7.6Hz)。
13C-NMR(CDCl3):168.965,156,246,154.681,150.298,146.182,137.036,135.651,131.006,130.842,130.202,128.874,128.272,127.674,126.938,122.123,120.702,116.555,115.022,112.147,109.477,109.025,76.132,70.033,52.294,28.988,27.880,15.164。
(2)2-(2-苄氧基-4-乙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙
烷-1-醇的制造
除了用从所述(1)中获得的2-(2-苄氧基-4-乙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯,通过与上述实施例2(2)相同的方法得到了2-(2-苄氧基-4-乙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇。
1H-NMR(CDCl3):7.33~7.45(m,5H),7.198(d,1H,J=7.6Hz),6.875(s,1H),6.841(d,1H,J=7.6Hz),6.749(d,1H,J=10.0Hz),6.717(d,1H,J=8.0Hz),6.321(d,1H,J=8.0Hz),5.568(d,1H,J=10.0Hz),5.125(s,2H),3.852(dd,1H,J=10.8,3.6Hz),3.733(dd,1H,J=10.8,2.8Hz),3.328(m,1H),3.132(dd,1H,J=14.0,10.4Hz),2.712(dd,1H,J=14.0,4.0Hz),2.662(q,2H,J=4.4Hz),1.441(s,3H),1.417(s,3H),1.263(t,3H,J=4.4Hz)。
13C-NMR(CDCl3):155.799,152.370,150.984,144.227,136.439,130.670,128.711,128.653,128.578,128.355,128.217,127.661,120.499,118.115,117.587,111.897,110.281,108.412,75.465,70.476,63.352,42.565,30.497,28.755,27.899,27.538,15.477。
(3)3-(2-苄氧基-4-乙基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃
的制造
除了用从所述(2)中获得的2-(2-苄氧基-4-乙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇,通过与上述实施例2(3)相同的方法得到了3-(2-苄氧基-4-乙基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃。
1H-NMR(CDCl3):7.32~7.45(m,5H),7.081(d,1H,J=8.0Hz),6.82~6.86(m,3H),6.663(d,1H,J=10.0Hz),6.384(d,1H,J=8.0Hz),5.568(d,1H,J=10.0Hz),5.128(s,2H),4.402(m,1H),4.062(t,1H,J=10.4Hz),3.724(m,1H),2.997(dd,1H,J=15.6,10.2Hz),2.890(dd,1H,J=15.6,3.2Hz),2.642(q,2H,J=6.8Hz),1.446(s,3H),1.431(s,3H),1.246(t,3H,J=6.8Hz)。
13C-NMR(CDCl3):156.322,151.802,149.827,144.159,137.124,129.167,128.791,128.578,127.807,127.150,127.069,120.340,116.970,114.463,111.727,109.835,108.551,75.526,70.103,70.036,31.571,30.686,28.799,27.772,27.566,15.474。
(4)3-(2-羟基-4-乙基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并
吡喃的制造
除了用从所述(3)获得的3-(2-苄氧基-4-乙基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃来代替3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃,通过与上述实施例2(4)相同的方法得到了3-(2-羟基-4-乙基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物4)。
1H-NMR(CDCl3):7.054(d,1H,J=8.0Hz),6.860(d,1H,J=8.0Hz),6.789(d,1H,J=8.0Hz),6.616(s,1H),6.421(d,1H,J=8.0Hz),5.097(s,1H),4.443(m,1H),4.069(t,1H,J=10.4Hz),3.567(m,1H),3.059(dd,1H,J=15.6,11.2Hz),2.901(m,1H),2.596(q,2H,J=6.8Hz),1.802(t,2H,J=6.8Hz),1.809(t,2H,J=6.8Hz),1.362(s,3H),1.347(s,3H),1.231(t,3H,J=6.8Hz)。
13C-NMR(CDCl3):153.373,152.716,152.102,144.205,127.472,127.415,124.773,120.499,114.963,112.898,109.310,109.248,73.795,69.897,32.308,32.054,30.532,28.276,26.784,26.374,17.120,15.308。
实施例4:3-(2-羟基-4-丙基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]
苯并吡喃(化合物5)的合成
(1)2-(2-苄氧基-4-丙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙
烯酸甲酯的制造
除了用从所述制造例7制造的(2-苄氧基-4-丙基苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与所述实施例2(1)相同的方法得到了2-(2-苄氧基-4-丙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯。
1H-NMR(CDCl3):7.902(s,1H),7.26~7.36(m,5H),6.952(d,1H,J=7.6Hz),6.803(s,1H),6.719(d,1H,J=7.6Hz),6.636(d,1H,J=8.8Hz),6.589(d,1H,J=10.0Hz),6.156(d,1H,J=8.8Hz),5.835(s,1H),5.531(d,1H,J=10.0Hz),5.041(s,2H),3.699(s,3H),2.578(t,2H,J=7.2Hz),1.641(m,2H,J=7.2Hz),1.392(s,6H),0.920(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):169.056,156,132,154.677,150.477,144.567,137.010,135.689,130.894,130.144,128.652,128.542,128.368,127.617,126.983,122.191,121.353,116.536,115.058,112.732,109.488,108.916,76.091,69.985,52.257,38.120,27.833,24.166,13.678。
(2)2-(2-苄氧基-4-丙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙
烷-1-醇的制造
除了用从所述(1)中获得的2-(2-苄氧基-4-丙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯,通过与上述实施例2(2)相同的方法得到了2-(2-苄氧基-4-丙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇。
1H-NMR(CDCl3):7.721(s,1H),7.33~7.45(m,5H),7.189(d,1H,J=8.0Hz),6.859(s,1H),6.824(d,1H,J=8.0Hz),6.761(d,1H,J=10.0Hz),6.715(d,1H,J=8.4Hz),6.329(d,1H,J=8.4Hz),5.575(d,1H,J=10.0Hz),5.126(s,2H),3.858(m,1H),3.743(m,1H),3.339(m,1H),3.132(dd,1H,J=14.0,10.4Hz),2.728(dd,1H,J=14.0,4.4Hz),2.605(t,2H,J=7.6Hz),1.676(m,2H,J=7.6Hz),1.450(s,3H),1.429(s,3H),0.982(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):155.670,152.304,150.940,142.630,136.425,130.674,128.675,128.583,128.564,128.192,128.173,127.629,121.125,118.119,117.563,112.389,110.255,108.386,75.452,70.407,63.289,42.432,37.925,30.462,27.859,27.512,24.455,13.840。
(3)3-(2-苄氧基-4-丙基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃
的制造
除了用从所述(2)中获得的2-(2-苄氧基-4-丙基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇,通过与上述实施例2(3)相同的方法得到了3-(2-苄氧基-4-丙基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃。
1H-NMR(CDCl3):7.32~7.47(m,5H),7.088(d,1H,J=8.0Hz),6.869(d,1H,J=8.0Hz),8.833(s,1H),6.820(d,1H,J=8.0Hz),6.695(d,1H,J=10.4Hz),6.409(d,1H,J=8.0Hz),5.589(d,1H,J=10.4Hz),5.142(s,2H),4.421(m,1H),4.079(t,1H,J=10.4Hz),3.743(m,1H),3.008(dd,1H,J=15.6,11.2Hz),2.914(m,1H,J=15.6,3.2Hz),2.595(t,2H,J=7.2Hz),1.668(m,2H,J=7.2Hz),1.469(s,3H),1.454(s,3H),0.980(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):156.250,151.832,149.850,142.593,137.148,129.164,128.756,128.563,127.790,127.144,127.031,127.031,121.034,116.993,114.471,112.342,109.836,108.556,75.509,70.122,70.070,38.008,31.627,30.718,27.785,27.583,24.437,13.858。
(4)3-(2-羟基-4-丙基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并
吡喃的制造
除了用从所述(3)获得的3-(2-苄氧基-4-丙基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃来代替3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃,通过与上述实施例2(4)相同的方法得到了3-(2-羟基-4-丙基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物5)。
1H-NMR(CDCl3):7.029(d,1H,J=8.0Hz),6.842(d,1H,J=8.0Hz),6.755(d,1H,J=8.0Hz),6.597(s,1H),6.390(d,1H,J=8.4Hz),4.804(s,1H),4.423(m,1H,J=10.4,2.4Hz),4.046(t,1H,J=10.4Hz),3.537(m,1H),3.042(dd,1H,J=15.6,11.2Hz),2.886(m,1H),2.652(m,2H),2.518(t,2H,J=7.6Hz),1.781(t,2H,J=6.8Hz),1.612(m,2H,J=7.2Hz),1.338(s,3H),1.323(s,3H),0.947(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):153.296,152.802,152.143,142.679,127.463,127.331,124.838,121.188,115.572,112.888,109.322,109.286,73.749,69.933,37.502,32.366,32.149,30.605,26.809,26.411,24.276,17.141,13.846。
实施例5:3-(2-羟基-4-异丙基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-
f]苯并吡喃(化合物6)的合成
除了用(2-苄氧基-4-异丙基-苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过进行与上述实施例2相同的一系列过程得到了3-(2-羟基-4-异丙基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物6)。
1H-NMR(CDCl3):7.058(d,1H,J=8.0Hz),6.853(d,1H,J=8.0Hz),6.812(dd,1H,J=8.0,1.2Hz),6.641(d,1H,J=1.2Hz),6.408(d,1H,J=8.0Hz),4.973(s,1H),4.444(m,1H,J=10.4,3.2,2.0Hz),4.060(t,1H,J=10.4Hz),3.552(m,1H),3.056(dd,1H,J=15.6,11.2Hz),2.892(m,1H,J=15.6,5.2,1.6Hz),2.859(m,1H,J=6.8Hz),2.668(m,2H),1.794(t,2H,J=6.8Hz),1.352(s,3H),1.337(s,3H),1.235(d,6H,J=6.8Hz)。
13C-NMR(CDCl3):153.331,152.780,152.123,148.947,127.471,127.408,124.870,119.166,113.559,112.857,109.310,109.268,73.751,69.902,33.597,32.334,32.124,30.566,26.813,26.395,23.853,17.139。
实施例6:3-(2-羟基-4-丁基)苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-
f]苯并吡喃(化合物7)的合成
(1)2-(2-苄氧基-4-丁基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙
烯酸甲酯的制造
除了用从所述制造例8制造的(2-苄氧基-4-丁基苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2(1)相同的方法得到了2-(2-苄氧基-4-丁基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯。
1H-NMR(CDCl3):7.879(s,1H),7.26~7.36(m,5H),6.934(d,1H,J=7.6Hz),6.791(s,1H),6.711(d,1H,J=7.6Hz),6.631(d,1H,J=8.8Hz),6.572(d,1H,J=10.0Hz),6.151(d,1H,J=8.8Hz),5.835(s,1H),5.525(d,1H,J=10.0Hz),5.026(s,2H),3.692(s,3H),2.585(t,2H,J=7.2Hz),1.579(m,2H),1.381(s,6H),1.325(m,2H),0.909(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):169.031,156,107,154.715,150.380,144.868,136.989,135.667,130.929,130.174,128.689,128.451,128.387,127.656,127.037,122.061,121.309,116.561,114.980,112.704,109.546,108.977,76.146,70.034,52.285,35.796,33.226,27.857,22.300,14.054。
(2)2-(2-苄氧基-4-丁基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙
烷-1-醇的制造
除了用从所述(1)中获得的2-(2-苄氧基-4-丁基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯,通过与上述实施例2(2)相同的方法得到了2-(2-苄氧基-4-丁基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇。
1H-NMR(CDCl3):7.422(b,1H),7.33~7.45(m,5H),7.161(d,1H,J=8.0Hz),6.827(s,1H),6.797(d,1H,J=8.0Hz),6.723(d,1H,J=10.0Hz),6.697(d,1H,J=8.4Hz),6.296(d,1H,J=8.4Hz),5.547(d,1H,J=10.0Hz),5.101(s,2H),3.837(m,1H),3.718(m,1H),3.295(m,1H),3.107(dd,1H,J=14.0,10.4Hz),2.689(dd,1H,J=14.0,4.4Hz),2.591(t,2H,J=7.6Hz),1.588(m,2H,J=7.6Hz),1.417(s,3H),1.394(s,3H),1.350(m,2H),0.930(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):155.716,152.389,151.010,142.936,136.424,130.671,128.723,128.581,128.275,128.231,127.680,121.140,118.095,117.604,112.428,110.294,108.422,75.476,70.476,63.366,42.697,35.576,33.545,30.468,27.915,27.551,22.360,13.952。
(3)3-(2-苄氧基-4-丁基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃
的制造
除了用从所述(2)中获得的2-(2-苄氧基-4-丁基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇,通过与上述实施例2(3)相同的方法得到了3-(2-苄氧基-4-丁基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃。
1H-NMR(CDCl3):7.32~7.45(m,5H),7.064(d,1H,J=8.0Hz),6.837(d,1H,J=8.0Hz),8.808(s,1H),6.798(d,1H,J=8.0Hz),6.667(d,1H,J=10.4Hz),6.381(d,1H,J=8.0Hz),5.567(d,1H,J=10.4Hz),5.124(s,2H),4.402(m,1H),4.057(t,1H,J=10.4Hz),3.728(m,1H),2.996(dd,1H,J=15.6,11.2Hz),2.885(m,1H,J=15.6,3.2Hz),2.595(t,2H,J=7.2Hz),1.599(m,2H,J=7.2Hz),1.446(s,3H),1.431(s,3H),1.380(m,2H),0.941(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):156.222,151.797,149.827,142.813,137.127,129.165,128.773,128.563,127.787,127.146,127.060,127.028,120.952,116.973,114.480,112.247,109.829,108.540,75.517,70.112,70.017,35.609,33.538,31.573,30.693,27.772,27.561,22.368,13.948。
(4)3-(2-羟基-4-丁基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并
吡喃的制造
除了用从所述(3)获得的3-(2-苄氧基-4-丁基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃来代替3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃,通过与上述实施例2(4)相同的方法得到了3-(2-羟基-4-丁基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物7)。
1H-NMR(CDCl3):7.033(d,1H,J=8.0Hz),6.851(d,1H,J=8.0Hz),6.761(d,1H,J=8.0Hz),6.596(s,1H),6.407(d,1H,J=8.4Hz),4.904(s,1H),4.434(m,1H,J=10.4,2.4Hz),4.056(t,1H,J=10.4Hz),3.538(m,1H),3.051(dd,1H,J=15.6,11.2Hz),2.892(m,1H),2.667(m,2H),2.546(t,2H,J=7.6Hz),1.792(t,2H,J=6.8Hz),1.599(m,2H,J=7.2Hz),1.375(m,2H),1.351(s,3H),1.336(s,3H),0.939(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):153.256,152.765,152.114,142.906,127.463,127.331,124.724,121.142,115.492,112.866,109.302,109.253,73.751,69.910,35.084,33.380,32.321,32.085,30.565,26.805,26.387,22.351,17.131,13.932。
实施例7:3-(2-羟基-4-正戊基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-
f]苯并吡喃(化合物8)的合成
除了用(2-苄氧基-4-正戊基苯基)乙酸甲酯代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2相同的方法得到了3-(2-羟基-4-正戊基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物8)。
1H-NMR(CDCl3):7.033(d,1H,J=8.0Hz),6.850(d,1H,J=8.0Hz),6.761(dd,1H,J=8.0,1.2Hz),6.598(d,1H,J=1.2Hz),6.404(d,1H,J=8.0Hz),4.898(s,1H),4.436(m,1H,J=10.4,3.2,2.0Hz),4.054(t,1H,J=10.4Hz),3.551(m,1H),3.048(dd,1H,J=15.6,11.2Hz),2.906(m,1H,J=15.6,5.2,1.6Hz),2.664(m,2H),2.536(t,2H,J=4.4H),1.790(t,2H,J=6.8Hz),1.599(m,2H),1.35(m,4H),1.348(s,3H),1.333(s,3H),0.908(t,3H,J=7.4Hz)。
13C-NMR(CDCl3):153.255,152.794,152.125,142.957,127.457,127.344,124.740,121.145,115.485,115.485,112.842,109.258,73.726,69.913,35.383,32.934,32.483,32.333,32.103,30.935,30.581,26.811,26.399,22.519,17.134,14.010。
实施例8:3-(2-羟基-4-(2-甲氧基乙基)苯基)-8,8-二甲基-2,3,4,8,9,10-六氢
吡喃[2,3-f]苯并吡喃(化合物9)的合成
除了用(2-苄氧基-4-(2-甲氧基乙基)苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2相同的方法得到了3-(2-羟基-4-(2-甲氧基乙基)苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物9)。
1H-NMR(CDCl3):7.043(d,1H,J=8.0Hz),6.843(d,1H,J=8.0Hz),6.773(dd,1H,J=8.0,2.0Hz),6.636(d,1H,J=2.0Hz),6.398(d,1H,J=8.0Hz),5.762(s,1H),4.416(m,1H,J=10.4,2.4Hz),4.035(t,1H,J=10.4Hz),3.647(t,2H,J=6.8Hz)3.549(m,1H),3.391(s,3H),3.033(dd,1H,J=15.6,11.2Hz),2.864(m,1H,J=15.6,5.2,1.6Hz),2.831(t,2H,J=6.8Hz)2.654(m,2H),1.783(t,2H,J=6.8H),1.343(s,3H),1.328(s,3H)。
13C-NMR(CDCl3):153.701,152.748,152.100,138.669,127.490,127.449,125.554,121.052,115.967,112.828,109.283,109.227,73.716,73.396,69.838,58.624,35.501,32.294,32.062,30.413,26.787,26.381,17.111。
实施例9:3-(2-羟基-3,4-二甲基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,
3-f]苯并吡喃(化合物10)的合成
除了用(2-苄氧基-3,4-二甲基苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2相同的方法得到了3-(2-羟基-3,4-二甲基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物10)。
1H-NMR(CDCl3):6.901(d,1H,J=8.0Hz),6.857(d,1H,J=8.4Hz),6.790(d,1H,J=8.0Hz),6.411(d,1H,J=8.4Hz),4.834(s,1H),4.430(m,1H,J=10.0,3.2,2.0Hz),4.051(t,1H,J=10.0Hz),3.543(m,1H),3.036(dd,1H,J=15.6,11.2Hz),2.896(m,1H,J=15.6,5.2,2.0Hz),2.672(m,2H),2.297(s,3H),2.199(s,3H),1.798(t,2H,J=6.8Hz),1.357(s,3H),1.344(s,3H)。
13C-NMR(CDCl3):152.849,152.105,151.536,136.143,127.431,124.846,124.061,122.329,121.519,112.767,109.275,73.652,69.998,32.353,32.311,30.781,26.811,26.404,20.154,17.124,11.743。
实施例10:3-(2-羟基-4,5-二甲基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃
[2,3-f]苯并吡喃(化合物11)的合成
(1)2-(2-苄氧基-4,5-二甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-
基)丙烯酸甲酯的制造
除了用从所述制造例9中制造的(2-苄氧基-4,5-二甲基苯基)乙酸甲酯{methyl2-benzyloxy-4,5-dimethylphenylacetate}来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2(1)相同的方法得到了2-(2-苄氧基-4,5-二甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯。
1H-NMR(CDCl3):7.894(s,1H),7.26~7.36(m,5H),6.795(s,1H),6.766(s,1H),6.677(d,1H,J=8.4Hz),6.591(d,1H,J=10.0Hz),6.161(d,1H,J=8.4Hz),5.512(d,1H,J=10.0Hz),4.994(s,2H),3.680(s,3H),2.223(s,3H),2.072(s,3H),1.375(s,6H)。
13C-NMR(CDCl3):169.257,154,688,154.284,150.592,137.994,137.204,135.640,131.947,130.210,129.084,128.604,128.387,128.339,127.573,126.895,122.056,116.624,115.140,114.154,109.504,108.956,76.039,70.161,52.294,27.830,27.781,20.240,18.763。
(2)2-(2-苄氧基-4,5-二甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-
基)丙烷-1-醇的制造
除了用从所述(1)中获得的2-(2-苄氧基-4,5-二甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯,通过与上述实施例2(2)相同的方法得到了2-(2-苄氧基-4,5-二甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇。
1H-NMR(CDCl3):7.30~7.43(m,5H),6.999(s,1H),6.792(s,1H),6.721(d,1H,J=10.0Hz),6.699(d,1H,J=8.0Hz),6.293(d,1H,J=8.0Hz),5.528(d,1H,J=10.0Hz),5.054(s,2H),3.800(dd,1H,J=11.2,3.6Hz),3.691(dd,1H,J=11.2,2.8Hz),3.249(m,1H),3.090(dd,1H,J=14.0,10.4Hz),2.668(dd,1H,J=14.0,4.0Hz),2.232(s,3H),2.188(s,3H),1.406(s,3H),1.385(s,3H)。
13C-NMR(CDCl3):153.764,152.283,150.928,136.498,135.796,130.637,129.835,128.952,128.661,128.528,128.448,128.142,127.587,118.246,117.584,113.911,110.276,108.349,75.432,70.689,63.407,42.833,30.722,27.840,27.480,19.817,18.873。
(3)3-(2-苄氧基-4,5-二甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并
吡喃的制造
除了用从所述(2)中获得的2-(2-苄氧基-4,5-二甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇,通过与上述实施例2(3)相同的方法得到了3-(2-苄氧基-4,5-二甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃。
1H-NMR(CDCl3):7.32~7.45(m,5H),6.935(s,1H),6.857(d,1H,J=8.0Hz),6.810(s,1H),6.697(d,1H,J=10.0Hz),6.407(d,1H,J=8.0Hz),5.591(d,1H,J=10.0Hz),5.115(s,2H),4.414(m,1H,J=10.0,3.2,2.0Hz),4.060(t,1H,J=10.0Hz),3.721(m,1H),3.028(dd,1H,J=14.0,6.8Hz),2.877(dd,1H,J=14.0,5.2Hz),2.272(s,3H),2.229(s,3H),1.470(s,3H),1.455(s,3H)。
13C-NMR(CDCl3):154.383,151.764,149.792,137.275,135.831,129.162,128.772,128.742,128.544,128.519,127.727,127.064,126.960,116.982,114.536,113.786,109.823,108.514,75.504,70.246,70.192,31.530,30.793,27.746,27.536,19.883,18.973。
(4)3-(2-羟基-4,5-二甲基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]
苯并吡喃的制造
除了用从所述(3)获得的3-(2-苄氧基-4,5-二甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃来代替3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃,通过与上述实施例2(4)相同的方法得到了3-(2-羟基-4,5-二甲基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物11)。
1H-NMR(CDCl3):6.886(s,1H),6.857(d,1H,J=4.8Hz),6.579(s,1H),6.418(d,1H,J=4.8Hz),4.965(s,1H),4.433(dd,1H,J=6.0Hz),4.053(t,1H,J=6.0Hz),3.534(m,1H),3.067(dd,1H,J=8.8,6.8Hz),2.873(ddd,1H,J=8.8,2.4,0.8Hz),2.680(m,2H),2.203(s,6H),1.803(t,2H,J=4.0Hz),1.364(s,3H),1.348(s,3H)。
13C-NMR(CDCl3):152.711,152.083,151.311,135.979,128.741,128.608,127.462,124.557,116.894,112.952,109.284,109.207,73.761,69.985,32.239,32.018,30.643,26.781,26.368,19.374,18.905,17.122。
实施例11:3-(2-羟基-4-氟苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]
苯并吡喃(化合物12)的合成
除了用(2-苄氧基-4-氟苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与所述实施例2相同的方法得到了3-(2-羟基-4-氟苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物12)。
1H-NMR(CDCl3):7.045(dd,1H,J=8.8,6.6Hz),6.834(d,1H,J=8.4Hz),6.620(m,1H,J=8.4,2.4Hz),6.501(dd,1H,J=9.6,2.4Hz),6.396(d,1H,J=8.4Hz),5.400(s,1H),4.379(m,1H,J=10.0,3.2,2.0Hz),4.039(t,1H,J=10.0Hz),3.523(m,1H),2.997(dd,1H,J=15.6,11.2Hz),2.892(m,1H,J=15.6,5.2,2.0Hz),2.642(m,2H),1.777(t,2H,J=6.8Hz),1.335(s,3H),1.321(s,3H)。
13C-NMR(CDCl3):163.144,160.705,154.402,152.812,152.061,128.471,127.447,123.663,112.574,109.401,107.644,103.157,73.880,69.704,32.297,31.821,30.520,26.784,26.390,17.103。
实施例12:3-(2-羟基-4-氯苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]
苯并吡喃(化合物13)的合成
除了用(2-苄氧基-4-氯苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2相同的方法得到了3-(2-羟基-4-氯苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物13)。
1H-NMR(CDCl3):7.026(d,1H,J=8.4Hz),6.888(dd,1H,J=8.4,2.0Hz),6.832(d,1H,J=8.4Hz),6.759(d,1H,J=2.0Hz),6.397(d,1H,J=8.4Hz),5.256(s,1H),4.375(m,1H,J=10.0,3.2,2.0Hz),4.047(t,1H,J=10.0Hz),3.532(m,1H),2.988(dd,1H,J=15.6,11.2Hz),2.848(m,1H,J=15.6,5.2,2.0Hz),2.637(m,2H),1.775(t,2H,J=6.8Hz),1.333(s,3H),1.320(s,3H)。
13C-NMR(CDCl3):154.027,152.821,152.035,132.695,128.594,127.445,126.551,121.205,115.699,112.435,109.442,109.408,73.892,69.487,32.274,31.905,30.318,26.776,26.393,17.093。
实施例13:3-(2-羟基-4-甲氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,
3-f]苯并吡喃(化合物14)的合成
(1)2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烯酸甲酯的制造
除了用从上述制造例10中制造的(2-苄氧基-4-甲氧基苯基)乙酸甲酯{methyl(2-benzyloxy-4-methoxyphenyl)acetate}来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与实施例2(1)相同的方法得到了2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯。
1H-NMR(CDCl3):7.875(s,1H),7.24~7.36(m,5H),6.958(d,1H,J=8.4Hz),6.697(d,1H,J=8.4Hz),6.598(d,1H,J=10.0Hz),6.551(d,1H,J=2.4Hz),6.426(dd,1H,J=8.4,2.4Hz),6.195(d,1H,J=8.4Hz),5.783(s,H),5.536(d,1H,J=10.0Hz),5.030(s,2H),3.777(s,3H),3.700(s,3H),1.395(s,6H)。
13C-NMR(CDCl3):169.002,160,933,157.315,154.665,150.202,136.701,135.651,131.736,130.213,128.726,128.489,128.440,127.733,126.958,117.352,116.537,114.996,109.468,109.063,105.279,100.143,76.114,70.097,55.259,52.262,27.855。
(2)2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烷-1-醇的制造
除了用从所述(1)中获得的2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯,通过与上述实施例2(2)相同的方法得到了2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇。
1H-NMR(CDCl3):7.617(s,1H),7.33~7.42(m,5H),7.150(d,1H,J=8.0Hz),6.725(d,1H,J=10.0Hz),6.680(d,1H,J=8.4Hz),6.582(d,1H,J=2.4hz),6.488(dd,1H,J=8.0,2.4Hz),6.294(d,1H,J=8.4Hz),5.550(d,1H,J=10.0Hz),5.075(s,2H),3.820(m,1H),3.787(s,3H),3.719(m,1H),3.292(m,1H),3.085(dd,1H,J=14.0,10.4Hz),2.692(dd,1H,J=14.0,4.0Hz),2.407(m,1H),1.416(s,3H),1.398(s,3H)。
13C-NMR(CDCl3):159.512,156.744,152.398,150.989,136.245,130.750,128.848,128.768,128.648,128.291,127.616,123.685,118.015,117.588,110.284,108.446,104.573100.232,75.508,70.493,63.479,55.380,42.052,30.536,27.905,27.593。
(3)3-(2-苄氧基-4-甲氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡
喃的制造
除了用从所述(2)获得的2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇,通过与上述实施例2(3)相同的方法得到了3-(2-苄氧基-4-甲氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃。
1H-NMR(CDCl3):7.30~7.45(m,5H),7.047(d,1H,J=8.0Hz),6.821(d,1H,J=8.4Hz),6.642(d,1H,J=10.0Hz),6.544(d,1H,J=2.0Hz),6.476(dd,1H,J=8.4,2.0Hz),6.361(d,1H,J=8.0Hz),5.550(d,1H,J=10.0Hz),5.295(s,1H),5.087(s,2H),4.369(m,1H),4.023(t,1H,J=10.0Hz),3.773(s,3H),3.650(m,1H),2.963(dd,1H,J=15.6,10.8Hz),2.883(dd,1H,J=15.6,4.4Hz),1.425(s,3H),1.410(s,3H)。
13C-NMR(CDCl3):159.505,157.258,151.862149.841,136.860,129.178,128.834,128.647,127.913,127.725,127.152,122.328,116.978,114.469,109.857,108.582,104.588,100.013,75.558,70.196,70.088,55.347,31.315,30.733,27.795,27.579。
(4)3-(2-羟基-4-甲氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯
并吡喃的制造
除了用从所述(3)中获得的3-(2-苄氧基-4-甲氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃来代替3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃,通过与上述实施例2(4)相同的方法得到了3-(2-羟基-4-甲氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物14)。
1H-NMR(CDCl3):7.022(d,1H,J=8.4Hz),6.837(d,1H,J=8.0Hz),6.488(dd,1H,J=8.0,2.4Hz),6.388(d,1H,J=8.4Hz),6.364(d,1H,J=2.4Hz),5.059(s,1H),4.392(m,1H,J=10.0,2.0Hz),4.024(t,1H,J=10.0Hz),3.768(s,3H),3.488(m,1H),3.017(dd,1H,J=15.6,11.2Hz),2.875(m,1H,J=15.6,6.8,2.0Hz),2.645(m,2H),1.778(t,2H,J=6.8Hz),1.335(s,3H),1.321(s,3H)。
13C-NMR(CDCl3):159.257,154.516,152.772,152.160,128.184,127.546,120.182,112.994,109.394,109.340,105.957,102.118,73.917,70.069,55.340,32.391,31.811,30.671,26.833,26.459,17.187。
实施例14:3-(2-羟基-4-乙氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,
3-f]苯并吡喃(化合物15)的合成
(1)2-(2-苄氧基-4-乙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烯酸甲酯的制造
除了用从上述制造例11中制造的(2-苄氧基-4-乙氧基苯基)乙酸甲酯{methyl(2-benzyloxy-4-ethoxyphenyl)acetate}来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与实施例2(1)相同的方法得到了2-(2-苄氧基-4-乙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯。
1H-NMR(CDCl3):7.842(s,1H),7.24~7.36(m,5H),6.937(d,1H,J=8.4Hz),6.699(d,1H,J=8.4Hz),6.578(d,1H,J=10.0Hz),6.548(s,1H),6.411(d,1H,J=8.4Hz),6.193(d,1H,J=8.4Hz),5.719(s,H),5.532(d,1H,J=10.0Hz),5.016(s,2H),3.994(q,2H,J=6.8Hz),3.693(s,3H),1.389(s,6H),1.389(t,3H)。
13C-NMR(CDCl3):168.924,160,391,157.312,154.649,150.070,136.734,135.557,131.731,130.243,128.734,128.692,128.438,127.728,126.969,117.117,116.553,114.983,109.481,109.084,105.879,100.527,76.126,70.096,63.462,52.237,27.863,14.767。
(2)2-(2-苄氧基-4-乙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烷-1-醇的制造
除了用从所述(1)中获得的2-(2-苄氧基-4-乙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯,通过与上述实施例2(2)相同的方法得到了2-(2-苄氧基-4-乙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇。
1H-NMR(CDCl3):7.676(s,1H),7.33~7.42(m,5H),7.139(d,1H,J=8.0Hz),6.734(d,1H,J=10.0Hz),6.692(d,1H,J=8.4Hz),6.594(d,1H,J=2.4hz),6.484(dd,1H,J=8.0,2.4Hz),6.303(d,1H,J=8.4Hz),5.559(d,1H,J=10.0Hz),5.077(s,2H),4.019(q,2H,J=7.2Hz),3.826(m,1H),3.729(m,1H),3.291(m,1H),3.096(dd,1H,J=14.0,10.4Hz),2.696(dd,1H,J=14.0,4.0Hz),2.457(b,1H),1.425(s,3H),1.416(t,3H),1.406(s,3H)。
13C-NMR(CDCl3):158.871,156.742,152.390,150.988,136.262,130.727,128.823,128.744,128.609,128.261,127.598,123.504,118.006,117.584,110.268,108.422,105.250,100.663,75.481,70.479,63.550,63.495,42.148,30.525,27.897,27.584,14.812。
(3)3-(2-苄氧基-4-乙氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡
喃的制造
除了用从所述(2)中获得的2-(2-苄氧基-4-乙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇,通过与上述实施例2(3)相同的方法得到了3-(2-苄氧基-4-乙氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃。
1H-NMR(CDCl3):7.30~7.45(m,5H),7.047(d,1H,J=8.0Hz),6.841(d,1H,J=8.4Hz),6.665(d,1H,J=10.0Hz),6.566(d,1H,J=2.0Hz),6.482(dd,1H,J=8.4,2.0Hz),6.385(d,1H,J=8.0Hz),5.571(d,1H,J=10.0Hz),5.096(s,2H),4.384(m,1H),4.026(q,2H,J=6.8Hz),4.009(t,1H,J=10.0Hz),3.661(m,1H),2.980(dd,1H,J=15.6,10.8Hz),2.878(dd,1H,J=15.6,4.4Hz),1.446(s,3H),1.430(s,3H),1.411(t,3H,J=6.8Hz)。
13C-NMR(CDCl3):158.825,157.218,151.784,149.811,136.871,129.153,128.783,128.598,127.850,127.652,127.097,122.093,116.957,114.469,109.814,108.531,105.203,100.385,75.515,70.183,70.013,63.462,31.277,30.706,27.767,27.549,14.809。
(4)3-(2-羟基-4-乙氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯
并吡喃的制造
除了用从所述(3)中获得的3-(2-苄氧基-4-乙氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃来代替3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃,通过与上述实施例2(4)相同的方法得到了3-(2-羟基-4-乙氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物15)。
1H-NMR(CDCl3):6.989(d,1H,J=8.4Hz),6.825(d,1H,J=8.0Hz),6.458(dd,1H,J=8.0,2.4Hz),6.387(d,1H,J=8.4Hz),6.324(d,1H,J=2.4Hz),5.355(s,1H),4.386(m,1H,J=10.4,3.2,2.0Hz),4.007(t,1H,J=10.4Hz),3.954(q,2H,J=7.2Hz),3.484(m,1H),3.006(dd,1H,J=15.6,11.2Hz),2.852(m,1H,J=15.6,4.8,1.6Hz),2.641(m,2H),1.770(t,2H,J=6.8Hz),1.378(t,2H,J=6.8Hz),1.331(s,3H),1.316(s,3H)。
13C-NMR(CDCl3):158.552,154.340,152.719,152.091,128.075,127.465,119.882,112.909,109.305,109.248,106.572,102.504,73.798,70.018,63.450,32.311,31.749,30.614,26.776,26.390,17.116,14.781。
实施例15:3-(2-羟基-4-丙氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,
3-f]苯并吡喃(化合物16)的合成
(1)2-(2-苄氧基-4-丙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烯酸甲酯的制造
除了用从所述制造例12制造的(2-苄氧基-4-丙氧基苯基)乙酸甲酯{methyl(2-benzyloxy-4-propoxyphenyl)acetate}来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2(1)相同的方法得到了2-(2-苄氧基-4-丙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯。
1H-NMR(CDCl3):7.816(s,1H),7.24~7.36(m,5H),6.928(d,1H,J=8.4Hz),6.705(d,1H,J=8.4Hz),6.562(d,1H,J=10.0Hz),6.552(d,1H,J=2.0Hz),6.408(dd,1H,J=8.4,2.0Hz),6.195(d,1H,J=8.4Hz),5.599(b,H),5.526(d,1H,J=10.0Hz),5.012(s,2H),3.880(t,2H,J=6.4Hz),3.687(s,3H),1.785(m,2H),1.385(s,6H),1.024(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):169.032,160,423,157.356,154.638,150.111,136.730,135.529,131.711,130.229,128.714,128.632,128.426,127.724,126.989,117.177,116.564,114.994,109.488,109.066,105.932,100.492,76.117,70.086,69.489,52.236,27.857,22.534,10.495。
(2)2-(2-苄氧基-4-丙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烷-1-醇的制造
除了用从所述(1)中得到的2-(2-苄氧基-4-丙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯,通过与上述实施例2(2)相同的方法得到了2-(2-苄氧基-4-丙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇。
1H-NMR(CDCl3):7.401(b,1H),7.33~7.42(m,5H),7.128(d,1H,J=8.0Hz),6.722(d,1H,J=10.0Hz),6.682(d,1H,J=8.4Hz),6.595(d,1H,J=2.4hz),6.480(dd,1H,J=8.0,2.4Hz),6.291(d,1H,J=8.4Hz),5.548(d,1H,J=10.0Hz),5.070(s,2H),3.899(t,2H,J=6.8Hz),3.816(m,1H),3.706(m,1H),3.282(m,1H),3.085(dd,1H,J=14.0,10.4Hz),2.687(dd,1H,J=14.0,4.0Hz),2.432(b,1H),1.798(2H,m),1.415(s,3H),1.396(s,3H),1.035(t,3H)。
13C-NMR(CDCl3):159.071,156.734,152.376,150.986,136.252,130.727,128.818,128.740,128.600,128.264,127.621,123.437,118.025,117.586,110.267,108.415,105.290,100.625,75.480,70.480,69.615,63.494,42.178,30.515,27.895,27.571,22.555,10.529。
(3)3-(2-苄氧基-4-丙氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡
喃的制造
除了使用从所述(2)中获得的2-(2-苄氧基-4-丙氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇,通过与上述实施例2(3)相同的方法得到了3-(2-苄氧基-4-丙氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃。
1H-NMR(CDCl3):7.30~7.45(m,5H),7.045(d,1H,J=8.0Hz),6.834(d,1H,J=8.4Hz),6.664(d,1H,J=10.0Hz),6.575(d,1H,J=2.0Hz),6.498(dd,1H,J=8.4,2.0Hz),6.380(d,1H,J=8.0Hz),5.562(d,1H,J=10.0Hz),5.097(s,2H),4.376(m,1H),4.0346(t,1H,J=10.0Hz),3.899(t,2H,J=6.4Hz),3.663(m,1H),2.982(dd,1H,J=15.6,10.8Hz),2.874(dd,1H,J=15.6,4.4Hz),1.785(m,2H),1.444(s,3H),1.429(s,3H),1.041(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):159.044,157.236,151.790,149.823,136.889,128.784,128.598,127.855,127.647,127.124,122.042,116.967,114.482,109.821,108.532,105.286,100.380,75.523,70.199,70.036,69.553,31.287,30.720,27.773,27.560,22.549,10.525。
(4)3-(2-羟基-4-丙氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯
并吡喃的制造
除了用从所述(3)中获得的3-(2-苄氧基-4-丙氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃来代替3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃,通过与上述实施例2(4)相同的方法得到了3-(2-羟基-4-丙氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物16)。
1H-NMR(CDCl3):6.976(d,1H,J=8.4Hz),6.817(d,1H,J=8.0Hz),6.452(dd,1H,J=8.0,2.0Hz),6.392(d,1H,J=8.4Hz),6.316(d,1H,J=2.0Hz),5.600(s,1H),4.380(d,1H,J=10.0Hz),4.000(t,1H,J=10.0Hz),3.812(t,2H,J=6.4Hz),3.488(m,1H),2.997(dd,1H,J=15.6,11.2Hz),2.837(dd,1H,J=15.6,4.4Hz),2.640(m,2H),1.782(t,2H,J=6.8Hz),1.765(m,2H),1.329(s,3H),1.314(s,3H),0.994(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):158.678,154.412,152.596,152.054,128.015,127.483,119.827,113.016,109.299,109.226,106.588,102.460,73.888,70.014,69.537,32.287,31.702,30.552,26.728,26.349,22.453,17.096,10.458。
实施例16:3-(2-羟基-4-异丙氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃
[2,3-f]苯并吡喃(化合物17)的合成
除了用(2-苄氧基-4-异丙氧基苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2相同的方法得到了3-(2-羟基-4-异丙氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物17)。
1H-NMR(CDCl3):7.000(d,1H,J=8.4Hz),6.845(d,1H,J=8.0Hz),6.472(dd,1H,J=8.0,2.4Hz),6.404(d,1H,J=8.4Hz),6.344(d,1H,J=2.4Hz),5.333(s,1H),4.450(m,1H,J=6.0Hz),4.409(m,1H,J=10.4,3.2,2.0Hz),4.026(t,1H,J=10.4Hz),3.498(m,1H),3.026(dd,1H,J=15.2,11.2Hz),2.871(m,1H,J=15.2,4.8,1.6Hz),2.669(m,2H),1.789(t,2H,J=6.8Hz),1.378(t,2H,J=6.8Hz),1.349(s,3H),1.331(s,3H),1.324(d,6H,J=6.0Hz)。
13C-NMR(CDCl3):157.519,154.443,152.755,152.116,128.071,127.463,119.886,112.931,109.311,109.266,107.931,103.837,73.778,70.102,70.044,32.349,31.818,30.655,26.787,26.401,22.044,17.128。
实施例17:3-(2-羟基-4-丁氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,
3-f]苯并吡喃(化合物18)的合成
(1)2-(2-苄氧基-4-丁氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烯酸甲酯的制造
除了用从所述制造例13中制造的(2-苄氧基-4-丁氧基苯基)乙酸甲酯{methyl(2-benzyloxy-4-butoxyphenyl)acetate}来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2(1)相同的方法得到了2-(2-苄氧基-4-丁氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯。
1H-NMR(CDCl3):7.836(s,1H),7.24~7.36(m,5H),6.928(d,1H,J=8.4Hz),6.698(d,1H,J=8.4Hz),6.577(d,1H,J=10.0Hz),6.546(d,1H,J=2.0Hz),6.407(dd,1H,J=8.4,2.0Hz),6.188(d,1H,J=8.4Hz),5.726(b,H),5.523(d,1H,J=10.0Hz),5.010(s,2H),3.918(t,2H,J=6.4Hz),3.683(s,3H),1.752(m,2H),1.468(m,2H),1.383(s,6H),0.986(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):169.062,160,539,157.338,154.664,150.278,136.737,135.556,131.694,130.196,128.667,128.450,128.405,127.968,126.968,117.138,116.575,115.049,109.499,109.022,105.911,100.487,76.090,70.061,67.676,52.223,31.263,28.050,19.191,13.802。
(2)2-(2-苄氧基-4-丁氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)
丙烷-1-醇的制造
除了用从所述(1)中得到的2-(2-苄氧基-4-丁氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯,通过与上述实施例2(2)相同的方法得到了2-(2-苄氧基-4-丁氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇。
1H-NMR(CDCl3):7.401(b,1H),7.33~7.42(m,5H),7.128(d,1H,J=8.0Hz),6.723(d,1H,J=10.0Hz),6.682(d,1H,J=8.4Hz),6.588(d,1H,J=2.4hz),6.479(dd,1H,J=8.0,2.4Hz),6.291(d,1H,J=8.4Hz),5.547(d,1H,J=10.0Hz),5.068(s,2H),3.940(t,2H,J=6.8Hz),3.814(m,1H),3.704(m,1H),3.280(m,1H),3.084(dd,1H,J=14.0,10.4Hz),2.681(dd,1H,J=14.0,4.0Hz),2.43(b,1H),1.767(2H,m),1.489(m,2H),1.415(s,3H),1.396(s,3H),0.977(t,3H)。
13C-NMR(CDCl3):159.068,156.721,152.360,150.973,136.220,130.726,128.799,128.729,128.596,128.249,127.611,123.425,118.039,117.579,110.259,108.407,105.271,100.606,75.473,70.464,67.782,63.477,42.119,31.286,30.521,27.884,27.566,19.228,13.838。
(3)3-(2-苄氧基-4-丁氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡
喃的制造
除了使用从所述(2)中获得的2-(2-苄氧基-4-丁氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇来代替2-(2-苄氧基-4-甲基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇,通过与上述实施例2(3)相同的方法得到了3-(2-苄氧基-4-丁氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃。
1H-NMR(CDCl3):7.30~7.45(m,5H),7.022(d,1H,J=8.0Hz),6.813(d,1H,J=8.4Hz),6.640(d,1H,J=10.0Hz),6.548(d,1H,J=2.0Hz),6.465(dd,1H,J=8.4,2.0Hz),6.357(d,1H,J=8.0Hz),5.544(d,1H,J=10.0Hz),5.075(s,2H),4.359(m,1H),4.012(t,1H,J=10.0Hz),3.919(t,2H,J=6.4Hz),3.641(m,1H),2.956(dd,1H,J=15.6,10.8Hz),2.856(dd,1H,J=15.6,4.4Hz),1.739(m,2H),1.473(m,2H),1.422(s,3H),1.407(s,3H),0.964(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):159.063,157.233,151.793,149.826,136.896,128.782,128.600,127.856,127.644,127.126,122.031,116.970,114.483,109.823,108.534,105.279,100.378,75.521,70.201,70.038,67.725,31.291,30.723,27.774,27.561,19.231,13.833。
(4)3-(2-羟基-4-丁氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯
并吡喃的制造
除了用从所述(3)中获得的3-(2-苄氧基-4-丁氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃来代替3-(2-苄氧基-4-甲基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃,通过与上述实施例2(4)相同的方法得到了3-(2-羟基-4-丁氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物18)。
1H-NMR(CDCl3):7.009(d,1H,J=8.4Hz),6.847(1d,1H,J=8.0Hz),6.482(dd,1H,J=8.0,2.0Hz),6.408(d,1H,J=8.4Hz),6.355(d,1H,J=2.0Hz),5.313(s,1H),4.407(m,1H,J=10.0Hz),4.027(t,1H,J=10.0Hz),3.906(t,2H,J=6.4Hz),3.503(m,1H),3.027(dd,1H,J=15.6,11.2Hz),2.874(dd,1H,J=15.6,4.4Hz),2.662(m,2H),1.70~1.90(m,4H),1.482(m,2H),1.351(s,3H),1.337(s,3H),0.977(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):158.793,154.331,152.721,152.092,128.047,127.461,119.777,112.909,109.299,109.248,106.628,102.511,73.786,70.023,67.738,32.317,31.756,31.227,30.626,26.777,26.390,19.193,17.117,13.807。
实施例18:3-(2-羟基-4-正戊氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃
[2,3-f]苯并吡喃(化合物19)的合成
除了用(2-苄氧基-4-正戊氧基苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2相同的方法得到了3-(2-羟基-4-正戊氧基苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物19)。
1H-NMR(CDCl3):7.008(d,1H,J=8.0Hz),6.847(d,1H,J=8.0Hz),6.482(dd,1H,J=8.0,2.4Hz),6.409(d,1H,J=8.0Hz),6.355(d,1H,J=2.4Hz),5.324(s,1H),4.408(m,1H,J=10.4Hz),4.029(t,1H,J=10.4Hz),3.897(t,2H,J=6.4Hz),3.494(m,1H),3.028(dd,1H,J=15.6,11.2Hz),2.875(m,1H,J=15.6,4.4Hz),2.663(m,2H),1.71~1.88(m,4H),1.35~1.50(m,4H),1.353(s,3H),1.338(s,3H),0.941(t,3H,J=7.2Hz)。
13C-NMR(CDCl3):158.726,154.374,152.646,152.062,128.017,127.468,119.767,112.957,109.290,109.222,106.546,102.460,73.833,70.016,68.022,32.287,31.706,30.571,28.862,28.121,26.750,26.362,22.403,17.102,13.997。
实施例19:3-(2-羟基-4-(3-甲基丁氧基)苯基)-8,8-二甲基-2,3,4,8,9,10-六氢
吡喃[2,3-f]苯并吡喃(化合物20)的合成
除了用(2-苄氧基-4-(3-甲基丁氧基)苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2相同的方法得到了3-(2-羟基-4-(3-甲基丁氧基)苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物20)。
1H-NMR(CDCl3):7.001(d,1H,J=8.4Hz),6.833(d,1H,J=8.4Hz),6.477(dd,1H,J=8.4,2.4Hz),6.381(d,1H,J=8.4Hz),6.352(d,1H,J=2.4Hz),4.852(s,1H),4.387(m,1H,J=10.4,2.0,1.2Hz),4.015(t,1H,J=10.4Hz),3.939(t,2H,J=6.4Hz),3.470(m,1H),3.014(dd,1H,J=15.6,11.2Hz),2.866(m,1H,J=15.6,3.6,1.6Hz),2.659(m,2H),1.802(m,1H),1.774(t,2H,J=6.4Hz),1.654(q,2H,J=6.4Hz),1.331(s,3H),1.317(s,3H),0.951(d,6H,J=6.4Hz)。
13C-NMR(CDCl3):158.881,154.197,152.861,152.137,128.120,127.459,119.736,112.789,109.298,109.284,106.724,102.561,73.700,70.031,66.431,37.940,32.345,31.805,30.710,26.839,26.434,25.031,22.573,17.150。
实施例20:3-(2-羟基-4-(甲氧基甲氧基)苯基)-8,8-二甲基-2,3,4,8,9,10-六氢
吡喃[2,3-f]苯并吡喃(化合物21)的合成
除了用(2-苄氧基-4-(甲氧基甲氧基)苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2相同的方法得到了3-(2-羟基-4-(甲氧基甲氧基)苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物21)。
1H-NMR(CDCl3):7.023(d,1H,J=8.4Hz),6.839(d,1H,J=8.4Hz),6.615(dd,1H,J=8.4,2.4Hz),6.524(d,1H,J=2.4Hz),6.396(d,1H,J=8.4Hz),5.443(s,1H),5.142(s,2H),4.400(m,1H,J=10.4,3.2,2.4Hz),4.028(t,1H,J=10.4Hz),3.514(m,1H),3.487(s,3H),3.020(dd,1H,J=15.6,11.2Hz),2.892(m,1H,J=15.6,5.2,1.6Hz),2.653(m,2H),1.783(t,2H,J=6.8Hz),1.342(s,3H),1.327(s,3H)。
13C-NMR(CDCl3):156.730,154.424,152.790,152.106,128.178,127.448,121.402,112.808,109.314,109.295,108.608,103.952,94.398,73.752,69.932,55.957,32.337,31.833,30.573,26.783,26.405,17.123。
实施例21:3-(2-羟基-4-(2-甲氧基乙氧基)苯基)-8,8-二甲基-2,3,4,8,9,10-六
氢吡喃[2,3-f]苯并吡喃(化合物22)的合成
除了用(2-苄氧基-4-(2-甲氧基乙氧基)苯基)乙酸甲酯来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,通过与上述实施例2相同的方法得到了3-(2-羟基-4-(2-甲氧基乙氧基)苯基)-8,8-二甲基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物22)。
1H-NMR(CDCl3):6.976(d,1H,J=8.4Hz),6.833(d,1H,J=8.4Hz),6.489(d,1H,J=2.4Hz),6.433(dd,1H,J=8.4,2.4Hz),6.386(d,1H,J=8.4Hz),6.170(s,1H),4.388(m,1H,J=10.4,2.4Hz),4.083(t,2H,J=4.4Hz),3.997(t,1H,J=10.4Hz),3.784(t,2H,J=4.4Hz),3.500(m,1H),3.475(s,3H),3.006(dd,1H,J=15.6,11.2Hz),2.853(m,1H,J=15.6,3.6Hz),2.650(t,2H),1.777(t,2H,J=6.8Hz),1.336(s,3H),1.322(s,3H)。
13C-NMR(CDCl3):158.296,154.797,152.783,152.137,127.862,127.448,120.507,112.917,109.274,109.231,105.465,103.206,73.683,71.131,66.834,59.012,32.346,31.791,30.559,26.802,26.410,17.130。
实施例22:3-(2-羟基-4-甲氧基苯基)-8,8-二乙基-2,3,4,8,9,10-六氢吡喃[2,
3-f]苯并吡喃(化合物23)的合成
(1)2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二乙基-5-羟基-2H-1-苯并吡喃-6-基)
丙烯酸甲酯的制造
除了用从所述制造例10中制造的(2-苄氧基-4-甲氧基苯基)乙酸甲酯{methyl(2-benzyloxy-4-methoxyphenyl)acetate}来代替(2-苄氧基-4-甲基苯基)乙酸甲酯,并用从所述制造例14中制造的6-甲酰基-2,2-二乙基-2H-苯并吡喃-5-基苯甲酸来代替6-甲酰基-2,2-二甲基-2H-苯并吡喃-5-基苯甲酸,通过进行与上述实施例2相同的过程得到了2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二乙基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯。
1H-NMR(CDCl3):7.857(s,1H),7.24~7.36(m,5H),6.973(d,1H,J=8.4Hz),6.677(d,1H,J=10.0Hz),6.675(d,1H,J=8.4Hz),6.550(d,1H,J=2.4Hz),6.441(dd,1H,J=8.4,2.4Hz),6.172(d,1H,J=8.4Hz),5.620(s,H),5.412(d,1H,J=10.0Hz),5.022(s,2H),3.783(s,3H),3.700(s,3H),1.699(m,2H),1.602(m,2H),0.901(t,6H)。
13C-NMR(CDCl3):168.950,160,945,157.335,155.775,150.135,136.737,135.601,131.781,130.240,128.438,128.128,127.719,126.973,126.210,117.719,117.451,114.573,109.176,108.622,105.334,100.176,81.856,70.123,55.273,52.218,32.165,7.907。
(2)2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二乙基-5-羟基-2H-1-苯并吡喃-6-基)
丙烷-1-醇
除了用从所述(1)中获得的2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二乙基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯来代替2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烯酸甲酯,通过与上述实施例13(2)相同的方法得到了2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二乙基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇。
1H-NMR(CDCl3):7.547(s,1H),7.33~7.42(m,5H),7.181(d,1H,J=8.0Hz),6.829(d,1H,J=10.0Hz),6.680(d,1H,J=8.0Hz),6.599(d,1H,J=2.4hz),6.508(dd,1H,J=8.0,2.4Hz),6.295(d,1H,J=8.0Hz),5.452(d,1H,J=10.0Hz),5.086(s,2H),3.817(m,1H),3.800(s,3H),3.741(m,1H),3.311(m,1H),3.083(dd,1H,J=14.0,10.4Hz),2.696(dd,1H,J=14.0,4.0Hz),2.427(b,1H),1.721(m,2H),1.666(m,2H),0.953(t,3H),0.938(t,3H)。
13C-NMR(CDCl3):159.490,156.750,153.281,150.879,136.250,130.632,128.794,128.736,128.381,128.248,127.598,123.780,118.861,117.559,109.991,107.937,104.604,100.237,81.040,70.494,63.501,55.350,42.006,31.828,31.773,30.589,8.051,7.920。
(3)3-(2-苄氧基-4-甲氧基苯基)-8,8-二乙基-2,3,4,8-四氢吡喃[2,3-f]苯并吡
喃的制造
除了用从所述(2)中获得的2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二乙基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇来代替2-(2-苄氧基-4-甲氧基苯基)-3-(2,2-二甲基-5-羟基-2H-1-苯并吡喃-6-基)丙烷-1-醇,通过与上述实施例13(3)相同的方法得到了3-(2-苄氧基-4-甲氧基苯基)-8,8-二乙基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃。
1H-NMR(CDCl3):7.28~7.45(m,5H),7.095(d,1H,J=8.0Hz),6.846(d,1H,J=8.0Hz),6.789(d,1H,J=10.0Hz),6.598(d,1H,J=2.0Hz),6.531(dd,1H,J=8.0,2.0Hz),6.400(d,1H,J=8.0Hz),5.482(d,1H,J=10.0Hz),5.134(s,1H),5.087(s,2H),4.412(m,1H),4.061(t,1H,J=10.0Hz),3.817(s,3H),3.702(m,1H),3.002(dd,1H,J=15.6,10.8Hz),2.899(dd,1H,J=15.6,4.4Hz),1.65~1.83(m,4H),0.96~1.02(m,6H)。
13C-NMR(CDCl3):159.490,157.254,152.699,149.752,136.848,129.098,128.615,127.877,127.684,127.134,126.304,122.359,118.237,113.980,109.504,108.073,104.606,100.012,81.135,70.175,70.077,55.300,31.834,31.825,31.334,30.742,8.029,7.965。
(4)3-(2-羟基-4-甲氧基苯基)-8,8-二乙基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯
并吡喃的制造
除了用从所述(3)中获得的3-(2-苄氧基-4-甲氧基苯基)-8,8-二乙基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃来代替3-(2-苄氧基-4-甲氧基苯基)-8,8-二甲基-2,3,4,8-四氢吡喃[2,3-f]苯并吡喃,通过与上述实施例13(4)相同的方法得到了3-(2-羟基-4-甲氧基苯基)-8,8-二乙基-2,3,4,8,9,10-六氢吡喃[2,3-f]苯并吡喃(化合物23)。
1H-NMR(CDCl3):7.027(d,1H,J=8.4Hz),6.843(d,1H,J=8.4Hz),6.493(dd,1H,J=8.4,2.4Hz),6.422(d,1H,J=8.4Hz),6.357(d,1H,J=2.4Hz),5.184(s,1H),4.398(m,1H,J=10.4,2.0,1.2Hz),4.026(t,1H,J=10.4Hz),3.766(s,3H),3.498(m,1H),3.022(dd,1H,J=15.6,11.2Hz),2.896(m,1H,J=15.6,6.8,2.0Hz),2.619(m,2H),1.787(t,2H,J=6.8Hz),1.55~1.75(m,4H),0.88~0.95(m,6H)。
13C-NMR(CDCl3):159.248,154.383,152.918,152.031,128.137,127.390,120.145,112.642,109.810,109.416,105.987,102.114,77.969,70.004,55.290,31.826,30.665,28.123,27.794,27.458,16.489,7.592。
实验例1:PTP1B抑制实验
对于PTP1B,比较了光甘草定、制造例2(化合物1)、实施例2(化合物3)、实施例3(化合物4)、实施了4(化合物5)、实施例13(化合物14)、实施例14(化合物15)、实施例15(化合物16)、实施了17(化合物18)、实施例18(化合物19)及实施例20(化合物21)中的化合物的抑制程度(IC50)。为此,将2mM p-NPP(p-nitrophenyl phosphate)用作基质而测量了脱碳酸化程度,从而调查了对PTP1B的抑制活性度。首先,将用蒸馏水稀释的PTP1B与2mM p-NPP{p-nitrophenyl phosphate,0.1M NaCl,1mM EDTA,50mM citrate pH6.0,1mMdithiothreitol(DTT)}及多种浓度的化合物1在30℃下反应30分钟后,用1N-氢氧化钠(NaOH)溶液终结了反应。测量通过上述方法准备的样本的吸光度(405nm)而确认了根据化合物1的浓度的PTP1B活性度抑制程度(IC50)。对光甘草定、化合物3、化合物4、化合物5、化合物14、化合物15、化合物16、化合物18、化合物19及化合物21实施了相同方法。其结果如表1和图1所示。
[表1]
实验组 | IC50=μM |
光甘草定 | 48 |
化合物1 | 46 |
化合物3 | 7.0 |
化合物4 | 2.9 |
化合物5 | 2.8 |
化合物14 | 6.5 |
化合物15 | 8.6 |
化合物16 | 1.9 |
化合物18 | 3.4 |
化合物19 | 1.2 |
化合物21 | 2.3 |
如所述表1和图1所示,相比光甘草定,根据本发明的化合物对PTP1B的抑制程度理想到5~10倍。
实验例2:DIO老鼠(DIO-mice)的抗肥胖效果实验
购入5周龄的雌性C57BL/6老鼠(NARA biotech)并在最小十周以上的时间内只用高脂肪饲料养殖而诱导了DIO(diet induced obeisity,饮食诱导肥胖)。将制造例1(光甘草定)和本发明的实施例的化合物(化合物1~5、7、9、11、14~16、21、23)根据剂量而准确地取样本后放入离心管(Falcon tube)后添加0.5%的甲基纤维素溶液3ml后,用涡流混合器(vortex)轻度混合一次后,在添加0.5%的甲基纤维素水溶液1.5ml的状态下,利用均质器(30,000rpm,T10Basic,IKA)处理了3分钟。用一次性塑料注射器将通过上述方法准备的样本每日一次地口腔给药(oral gavage)28日(4周)。通过上述方法饲养DIO老鼠并每周2次地称了体重。以通过上述方法得出的数据为基础,根据如下定义的数学式计算了抗肥胖效果(%)。
抗肥胖效果={(对照组体重)-(实验组体重)}/(对照组体重)×100
将通过上述方法得到的结果示于表2中。
[表2]
化合物编号 | 抗肥胖效果(%) | 给药时间及用量 |
光甘草定 | 2 | 4周,150mg/kg |
化合物1 | 8 | 4周,150mg/kg |
化合物2 | 8 | 4周,200mg/kg |
化合物3 | 19 | 4周,200mg/kg |
化合物4 | 18 | 4周,150mg/kg |
化合物5 | 19 | 4周,150mg/kg |
化合物7 | 14 | 4周,150mg/kg |
化合物9 | 10 | 4周,150mg/kg |
化合物11 | 8 | 4周,150mg/kg |
化合物14 | 12 | 4周,150mg/kg |
化合物15 | 14 | 4周,150mg/kg |
化合物16 | 7 | 4周,150mg/kg |
化合物21 | 16 | 4周,150mg/kg |
化合物23 | 11 | 4周,200mg/kg |
如上述表2所示,根据本发明的吡喃并秋葵纤维异甲酚衍生物的抗肥胖活性比光甘草定明显更优。
如上所述,在实验28日(4周)后,最终淘汰实验动物并取血液的同时,提取不同脏器(肝、心脏、肾脏、胰脏、脂肪组织)等而称重,并观察了特殊事项。
[表3]
Dose:剂量
BMI:Body Mass Indes(体重指数)
Liver:肝的重量
Fat:从副睾丸及肾脏周围提取的脂肪的重量
AST:Aspartate aminotransferase;天冬氨酸转氨酶
ALT:Alanine aminotransferase;丙氨酸转氨酶
LDL:Low density lipoprotein;低密度脂蛋白
FFA:Free fatty acid;游离脂肪酸
在上述表3中,为了区分在不同时期进行的实验而使用了{}、()等。没有括号的实验都是在相同条件下同时进行的实验。
如上述表3所示,在将本发明的吡喃并秋葵纤维异甲酚衍生物给药的期间内,DIO老鼠的体重减少与脂肪组织的重量减少有着密切的联系,因此可以确认随着DIO老鼠的BMI减少,生物化学指标也都在向更好的方向改善。
实验例3:C 2C12 细胞中的葡萄糖吸收(uptake)实验
将本发明的实施例14的化合物(化合物15)作为对象而将C2C12细胞中的葡萄糖吸收能力与现有的作为糖尿病治疗药使用过或者使用中的的罗格列酮(Rosiglytazone)和二甲双胍(Metformin)进行了比较。在5%的CO2下,在含有10%的胎牛血清(FBS)、青霉素(120unit/mL)和链霉素(75μg/mL)的培养基(dulbecco's modified eagle medium;DMEM)中培养C2C12细胞,用于分化的培养基为包含1%的马血清(horse serum)的DMEM培养基,并培养了C2C12细胞四天。将通过上述方法培养的细胞在含有2-[N-(7-硝基苯-2-氧-1,3-二唑-4-基)氨基]-2-脱氧-d-葡萄糖(2-NBDG)的低-糖无血清(low-glucose、serum-free)培养基中,与化合物15一起处理24个小时,并利用荧光检测器而在激发波长485nm和发射波长535nm下测量了葡萄糖吸光度。对罗格列酮和二甲双胍也实施了相同方法。实验结果示于下述表4中。
[表4]
如上表4所示,相比现有的糖尿治疗药,化合物15的葡萄糖吸收促进能力更优良。
实验例4:db/db老鼠(db/db-mice)抗糖尿效果实验
购入C57BLKS/J-db/db、雄性、5周龄(中央实验动物)并驯化2周,其后用在本实验中。将在本发明的实施例中的实施例4和实施例15中准备的化合物(化合物5、16)根据剂量而取准确的样本后,放入离心管,并将冷藏保管中的0.5%的甲基纤维素水溶液放置于室温下,然后使赋形剂变成室温后,在各个50ml的离心管分别添加16ml,然后用涡流混合器轻轻地混合一次后,利用均质器(30,000rpm,CPT-1600E,Kinemtica,Sweitzerland)而处理3分钟,从而使其悬浮并均质化,然后再进行了30分钟的超声波处理。将通过上述方法准备的样本利用贴附口服用探测器一次性注射器而在42日(6周)内每日一次地口腔给药(oralgavage)。
通过上述方法饲养db/db老鼠,并测量了糖化血红蛋白(HbA1c)。在组分离2日前、给药后第4周以及给药后第6周进行了糖化血红蛋白测量,期中,在测量当日绝食4个小时后,在将各个物质给药之前,从尾静脉抽血并用糖化血红蛋白测量仪(SD A1cCare,SDBiosensor,Inc.,Korea)进行了测量。其测量结果示于下述表5中。
[表5]
如上表5所示,根据本发明的吡喃并秋葵纤维异甲酚衍生物可以将血糖调整到几乎正常的水平(正常血糖:HbA1c 6.0以下)。
本实施例中,在将化合物16给药6周后,在最终淘汰后进行了剖检,在将提取的老鼠肝切开后,用H&E(hematoxylin and eosin;苏木精和伊红)及脂滴包被蛋白抗体(perilipin antibody)分别染色后,用显微镜观察了组织,并将结果示于图2和图5中。为了比较将化合物16给药的情形的显微镜照片(图2a、3a、4a、5a),而示出了没有给药任何药物的对照组的照片(图2b、3b、4b、5b)。
图2a是将本发明的化合物16给药6周后,在最终淘汰后进行剖检而提取的老鼠肝组织的用H&E(hematoxylin and eosin;苏木精和伊红)染色的显微镜照片(放大100倍)。图2b是没有给药化合物16的对照组的显微镜照片。图3a是将本发明的化合物16给药6周后,在最终淘汰后进行剖检而提取的老鼠肝组织的用H&E(hematoxylin and eosin;苏木精和伊红)染色的显微镜照片(放大200倍)。图3b是没有给药化合物16的对照组的显微镜照片。图4a是将本发明的化合物16给药6周后,在最终淘汰后进行剖检而提取的老鼠肝组织的用脂滴包被蛋白抗体(perilipin antibody)染色的显微镜照片(放大100倍)。图4b是没有给药化合物16的对照组的显微镜照片。图5a是将本发明的化合物16给药6周后,在最终淘汰后进行剖检而提取的老鼠肝组织的用脂滴包被蛋白抗体(perilipin antibody)染色的显微镜照片(放大200倍)。
如图2至图5所示,对照组中巨大脂肪细胞占较多空间且能够发现较多的坏死细胞,与此不同地,将化合物16给药的老鼠的肝组织中,脂肪细胞较小且致密,因此在整体全面的水平上健康。
实验例5:BV2细胞NO assay实验(抗炎症功效确认实验)
在96孔板中,以1×104细胞/孔的浓度培养BV2microglia细胞(小胶质细胞)24小时后,在不抑制细胞增殖的3浓度(对光甘草定而言,为5μM、10μM及20μM;对化合物4、化合物5、化合物15、化合物16及化合物18而言,为2.5μM、5μM及10μM的浓度)下,将化合物预处理3个小时。在预处理后,额外添加0.5mg/ml的MTT(Sigma,M2128)试剂。在5%CO2的培养基中培养4个小时后,去掉上清液后添加150μl的DMSO后,摇晃30分钟,然后利用ELISA酶标仪(ELISA micro plate reader;Bio Rad Laboratories Inc.,California,USA,Model 680)在540nm的波长下测量了吸光度。分别利用3次的重复实验值而计算相对对照组的细胞保护率后取平均值而得到了所有实验值,并在不产生细胞毒性的浓度下对各个化合物进行了NO生成抑制实验。
在5×105细胞/孔的水平下在24孔板中培养BV2microglia细胞(小胶质细胞)24小时后,在不抑制细胞增殖的3浓度(对光甘草定而言,为5μM、10μM及20μM;对化合物4、化合物5、化合物15、化合物16及化合物18而言,为2.5μM、5μM及10μM的浓度)下,将化合物预处理3个小时,然后进行LPS(1μg/ml)处理,并在24小时后利用格里斯(Griess)试剂(0.1%(w/v)N-(1-naphathyl)-ethylenediamine and 1%(w/v)sulfanilamide in 5%(v/v)phosphoric acid)反应了从培养基分配出来的NO的量。反应过后,利用ELISA酶标仪(ELISAmicro plate reader;Bio Rad Laboratories Inc.,California,USA,Model 680)在540nm下进行了测量。利用实验组的相对对照组的NO生成量的差异而计算了抑制率,如下表6和图6所示,本发明的化合物4、5、15、16、18等的NO生成抑制效果出众,效果甚至于达到光甘草定的5~9倍。
[表6]
化合物 | BV2(IC50)(μM) |
光甘草定 | 19.6 |
化合物4 | 3.7 |
化合物5 | 3.8 |
化合物15 | 2.7 |
化合物16 | 2.3 |
化合物18 | 2.8 |
实施例6:RAW264.7巨噬细胞的NO assay实验(抗炎症功效确认实验)
在96孔板中,以1×104细胞/孔的浓度培养RAW264.7巨噬细胞24小时,并在不抑制细胞增殖的3浓度(对光甘草定而言,为10μM、20μM及40μM;对化合物4、化合物5、化合物15、化合物16及化合物18而言,为5μM、10μM及20μM的浓度)下,将化合物预处理3个小时。在预处理后,添加了0.5mg/ml浓度的MTT(Sigma,M2128)试剂。在5%CO2的培养基中培养4个小时后,去掉上清液后添加150μl的DMSO后,摇晃30分钟,然后利用ELISA酶标仪(ELISA microplate reader;Bio Rad Laboratories Inc.,California,USA,Model 680)在540nm的波长下测量了吸光度。分别利用3次的重复实验值而计算相对对照组的细胞保护率后取平均值而得到了所有实验值,并在不产生细胞毒性的浓度下对各个化合物进行了NO生成抑制实验。
在5×105细胞/孔的水平下在24孔板中培养RAW264.7巨噬细胞24小时,并在不抑制细胞增殖的3浓度(对光甘草定而言,为10μM、20μM及40μM;对化合物4、化合物5、化合物15、化合物16及化合物18而言,为5μM、10μM及20μM的浓度)下,将化合物预处理3个小时,然后进行LPS(1μg/ml)处理,并在24小时后利用格里斯(Griess)试剂(0.1%(w/v)N-(1-naphathyl)-ethylenediamine and 1%(w/v)sulfanilamide in 5%(v/v)phosphoricacid)反应了从培养基分配出来的NO的量。反应过后,利用ELISA酶标仪(ELISA microplate reader;Bio Rad Laboratories Inc.,California,USA,Model 680)在540nm下进行了测量。利用实验组的相对对照组的NO生成量的差异而计算了抑制率,如下表7所示,本发明的化合物4、5、15、16、18等的NO生成抑制效果出众。
[表7]
实验例7:化学稳定性比较实验
比较了制造例1的光甘草定以及实施例3(化合物4)、实施例4(化合物5)及实施例14(化合物15)的相对化学稳定性程度。即,对光甘草定、化合物4、化合物5及化合物15分别进行50mg的准确的检重,并在50ml的1%HCl的MeOH溶液以及10ml的1%NaOH的MeOH溶液中融化后,在第0小时、第8小时、第12小时、第24小时、第48小时、第72小时的时候用HPLC得到了其浓度。此时,利用内部标准(internal standard)(实施例13的化合物14)决定了1%HCl以及1%NaOH的MeOH溶液中残留的试剂的浓度。即,准确地对10mg的化合物14进行检重后在100ml的乙腈中融化后,将9ml的该溶液与在不同时刻分别取得的1ml的试剂混合,并将其HPLC分析,从而通过与初始值比较而确定了内部标准的浓度和分别取得的试剂中残留的浓度。
这些试料的按时段的1%HCl的MeOH溶液中的试剂的残留浓度如下表8和图7,1%NaOH的MeOH溶液中的残留浓度如下表9和图8。
下表8和表9中,超过100%的数值指比初始测量值稍微高的测量浓度,这是因为没有考虑到测量时产生的统计误差而单纯地用测量值的平均值表示。大约95%以上的测量值可以认为没有事实上的浓度变化,因此本发明中化合物的化学稳定性优良。
[表8]
1%HCl的MeOH溶液 | 0 | 8h | 24h | 48h | 72h |
光甘草定 | 100% | 99% | 94% | 82% | 74% |
化合物4 | 100% | 99% | 101% | 101% | 100% |
化合物5 | 100% | 102% | 102% | 101% | 101% |
化合物15 | 100% | 98% | 100% | 98% | 100% |
[表9]
1%NaOH的MeOH溶液 | 0 | 8h | 24h | 48h | 72h |
光甘草定 | 100% | 71% | 38% | 23% | 13% |
化合物4 | 100% | 101% | 101% | 99% | 100% |
化合物5 | 100% | 101% | 102% | 100% | 102% |
化合物15 | 100% | 100% | 100% | 98% | 100% |
如所述表8和表9所示,与光甘草定不同地,根据本发明的化合物4、化合物5及化合物15在1%HCl的MeOH溶液及1%NaOH的MeOH溶液条件下,在三天(72小时)之内相当稳定。
Claims (17)
1.一种如下述化学式(I)的化合物、其药理可用之盐、或者其溶剂化物,
[化学式1]
在上述化学式中,
R1是氢原子、甲基、甲氧基或卤原子,
R2是氢原子、取代或未被取代的直链或支链C1-C6烷基、卤原子、取代或未被取代的直链或支链C1-C6烷氧基、或者取代或未被取代的直链或支链C1-C4硫代烷基,
R3和R4分别独立地为氢原子或者C1-C2烷基,
其中,对于取代烷基、取代烷氧基以及取代硫代烷基而言,取代基是直链或支链C1-C5烷基、卤原子、直链或支链C1-C5烷氧基、或者直链或支链C1-C3硫代烷基。
2.如权利要求1所述的化学式(I)的化合物、其药理可用之盐、或者其溶剂化物,其中,
所述R1是氢原子;
所述R2是氢原子、直链或支链C1-C6烷基、直链或支链C1-C5烷氧基、或者直链或支链C1-C3硫代烷基。
3.如权利要求2所述的化学式(I)的化合物、其药理可用之盐、或者其溶剂化物,其中,
所述R1是氢原子;
所述R2是甲基、乙基、正丙基、正丁基、乙氧基、正丙氧基、正丁氧基、或者甲氧基甲氧基。
4.如权利要求1所述的化学式(I)的化合物、其药理可用之盐、或者其溶剂化物,其中,所述化学式(I)所示的化合物是以下化合物中的任意一个化合物:
5.一种代谢综合征的预防或治疗用药学组成物,包括如下述化学式(I')的化合物、其药理可用之盐、或者其溶剂化物,
在上述化学式中,
R1是氢原子、甲基、甲氧基或卤原子,
R2是氢原子、羟基、取代或未被取代的直链或支链C1-C6烷基、卤原子、取代或未被取代的直链或支链C1-C6烷氧基、或者取代或未被取代的直链或支链C1-C4硫代烷基,
R3和R4分别独立地为氢原子或者C1-C2烷基,
其中,对于取代烷基、取代烷氧基以及取代硫代烷基而言,取代基是直链或支链C1-C5烷基、卤原子、直链或支链C1-C5烷氧基、或者直链或支链C1-C3硫代烷基。
6.如权利要求5所述的代谢综合征的预防或治疗用药学组成物,其中,在所述化学式(I')中,
R1是氢原子;
R2是氢原子、羟基、直链或支链C1-C6烷基、直链或支链C1-C5烷氧基、或者直链或支链C1-C3硫代烷基。
7.如权利要求6所述的代谢综合征的预防或治疗用药学组成物,其中,在所述化学式(I')中,
R1是氢原子;
R2是甲基、乙基、正丙基、正丁基、乙氧基、正丙氧基、正丁氧基、或者甲氧基甲氧基。
8.如权利要求5所述的代谢综合征的预防或治疗用药学组成物,其中,所述化学式(I')的化合物为下述化合物中的一种以上的化合物:
9.如权利要求5所述的代谢综合征的预防或治疗用药学组成物,其中,所述代谢综合征是肥胖、糖尿病、高脂血症以及脂肪肝中的一种以上。
10.如权利要求9所述的代谢综合征的预防或治疗用药学组成物,其中,所述糖尿病是第二型糖尿病。
11.如权利要求5所述的代谢综合征的预防或治疗用药学组成物,其中,所述代谢综合征是第二型糖尿病与肥胖的复合疾病。
12.一种炎症疾病的预防或治疗用药学组成物,包括如下述化学式(I')的化合物、其药理可用之盐、或者其溶剂化物,
在所述化学式中,
R1是氢原子、甲基、甲氧基或卤原子,
R2是氢原子、羟基、取代或未被取代的直链或支链C1-C6烷基、卤原子、取代或未被取代的直链或支链C1-C6烷氧基、或者取代或未被取代的直链或支链C1-C4硫代烷基,
R3和R4分别独立地为氢原子或者C1-C2烷基,
其中,对于取代烷基、取代烷氧基以及取代硫代烷基而言,取代基是直链或支链C1-C5烷基、卤原子、直链或支链C1-C5烷氧基、或者直链或支链C1-C3硫代烷基。
13.如权利要求12所述的炎症疾病的预防或治疗用药学组成物,其中,在所述化学式(I')中,
R1是氢原子;
R2是氢原子、羟基、直链或支链C1-C6烷基、直链或支链C1-C5烷氧基、或者直链或支链C1-C3硫代烷基。
14.如权利要求12所述的炎症疾病的预防或治疗用药学组成物,其中,在所述化学式(I')中,
R1是氢原子;
是甲基、乙基、正丙基、正丁基、乙氧基、正丙氧基、正丁氧基、或者甲氧基甲氧基。
15.如权利要求12所述的炎症疾病的预防或治疗用药学组成物,其中,所述化学式(I')所示的化合物是下述化合物中的1种以上的化合物:
16.如权利要求12所述的炎症疾病的预防或治疗用药学组成物,其中,在所述化学式(I')中,
R1是氢原子;
R2是甲基、乙基、正丙基、正丁基、乙氧基、正丙氧基、正丁氧基、或者甲氧基甲氧基。
17.如权利要求12所述的炎症疾病的预防或治疗用药学组成物,其中,所述炎症疾病是如下疾病中的一种以上的疾病:
类风湿性关节炎;
退行性关节炎;以及
由哮喘、过敏、糖尿或者心肌梗塞引发的炎症疾病。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109863152A (zh) * | 2016-10-04 | 2019-06-07 | 格拉斯如睦株式会社 | 3-苯基-2,3,4,8,9,10-六氢吡喃并[2,3-f]色烯衍生物以及用于合成其光学异构体的方法 |
TWI731998B (zh) * | 2016-06-29 | 2021-07-01 | 南韓商格雷森伍股份有限公司 | 光學活性吡喃並苯並吡喃基苯酚衍生物及包含其的醫藥組成物 |
CN113507927A (zh) * | 2019-02-28 | 2021-10-15 | 格拉斯如睦株式会社 | 神经***疾病的预防或治疗用药物组合物 |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102344479B1 (ko) * | 2013-12-24 | 2021-12-29 | 주식회사 글라세움 | 피라노크로메닐페놀 유도체, 및 대사증후군 또는 염증 질환 치료용 약학 조성물 |
TWI804600B (zh) * | 2018-04-03 | 2023-06-11 | 南韓商格雷森伍股份有限公司 | 3-苯基-2,8-二氫吡喃[2,3-ƒ]苯并哌喃衍生物的合成方法 |
WO2019194583A1 (ko) * | 2018-04-03 | 2019-10-10 | 주식회사 글라세움 | 3-페닐-2,8-디히드로피라노[2,3-f]크로멘 유도체 및 이를 포함하는 약학적 조성물 |
KR20210014521A (ko) | 2019-07-30 | 2021-02-09 | 주식회사 글라세움 | 2-((6-(히드록시메틸)크로멘-5-일)옥시)-1-페닐에타논 유도체의 합성 방법 |
KR20220166203A (ko) | 2021-06-08 | 2022-12-16 | 주식회사 글라세움 | 퇴행성 안질환의 예방 또는 치료용 약학적 조성물 |
CN113616548B (zh) * | 2021-09-02 | 2023-04-28 | 河南科技大学 | 一种水溶性光甘草定包合物及其制备方法 |
CN114903879B (zh) * | 2022-06-23 | 2023-10-31 | 东北大学 | 3-烃基苯酚衍生物在制备预防或治疗高脂血症及相关代谢性疾病产品中的用途 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007058480A1 (en) * | 2005-11-16 | 2007-05-24 | Md Bioalpha Co., Ltd. | Composition having effect on treatment and prevention of diseases syndrome treatment with glabridin |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20050035142A (ko) | 2001-10-11 | 2005-04-15 | 카네카 코포레이션 | 페록시좀 증식제 응답성 수용체 리간드제 및 그 제조 방법 |
KR100565423B1 (ko) * | 2003-10-20 | 2006-03-30 | 빅 바이오 주식회사 | 이소플라반 유도체 또는 이소플라벤 유도체의 제조방법 |
JP2006008604A (ja) * | 2004-06-25 | 2006-01-12 | Kuraray Co Ltd | イソフラバン誘導体の製造方法 |
KR102344479B1 (ko) * | 2013-12-24 | 2021-12-29 | 주식회사 글라세움 | 피라노크로메닐페놀 유도체, 및 대사증후군 또는 염증 질환 치료용 약학 조성물 |
-
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- 2014-12-23 JP JP2016540481A patent/JP6620096B2/ja active Active
- 2014-12-23 DK DK14873860.2T patent/DK3098224T3/da active
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-
2016
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-
2018
- 2018-03-23 JP JP2018056783A patent/JP2018135343A/ja active Pending
-
2019
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007058480A1 (en) * | 2005-11-16 | 2007-05-24 | Md Bioalpha Co., Ltd. | Composition having effect on treatment and prevention of diseases syndrome treatment with glabridin |
Non-Patent Citations (4)
Title |
---|
FANIE R. VAN HEERDEN ET AL.: "Structure and Synthesis of Some Complex Pyranoisoflavonoids from the Bark of Dalbergia nitidula Welw. ex Bak.", 《J.C.S. PERKIN I》 * |
FEIHUA WU ET AL.: "Hypoglycemic effects of glabridin, a polyphenolic flavonoid from licorice, in an animal model of diabetes mellitus", 《MOLECULAR MEDICINE REPORTS》 * |
OHAD NERYA ET AL.: "Glabrene and Isoliquiritigenin as Tyrosinase Inhibitors from Licorice Roots", 《J. AGRIC. FOOD CHEM.》 * |
WARUNEE JIRAWATTANAPONG ET AL.: "Synthesis of Glabridin Derivatives as Tyrosinase Inhibitors", 《ARCH PHARM RES》 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI731998B (zh) * | 2016-06-29 | 2021-07-01 | 南韓商格雷森伍股份有限公司 | 光學活性吡喃並苯並吡喃基苯酚衍生物及包含其的醫藥組成物 |
US11332475B2 (en) | 2016-06-29 | 2022-05-17 | Glaceum, Inc. | Optically active pyranochromenyl phenol derivative and pharmaceutical composition comprising same |
CN109863152A (zh) * | 2016-10-04 | 2019-06-07 | 格拉斯如睦株式会社 | 3-苯基-2,3,4,8,9,10-六氢吡喃并[2,3-f]色烯衍生物以及用于合成其光学异构体的方法 |
CN109863152B (zh) * | 2016-10-04 | 2021-12-03 | 格拉斯如睦株式会社 | 3-苯基-2,3,4,8,9,10-六氢吡喃并[2,3-f]色烯衍生物以及用于合成其光学异构体的方法 |
CN113507927A (zh) * | 2019-02-28 | 2021-10-15 | 格拉斯如睦株式会社 | 神经***疾病的预防或治疗用药物组合物 |
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CN105849111B (zh) | 2018-05-04 |
NZ720328A (en) | 2018-02-23 |
EP3098224A1 (en) | 2016-11-30 |
IL245908A0 (en) | 2016-08-02 |
EP3098224A4 (en) | 2017-07-05 |
PT3098224T (pt) | 2019-04-26 |
EP3098224B1 (en) | 2019-01-30 |
ES2718878T3 (es) | 2019-07-05 |
BR112016011281A2 (zh) | 2017-08-08 |
CY1121554T1 (el) | 2020-05-29 |
US20160272650A1 (en) | 2016-09-22 |
JP2017501163A (ja) | 2017-01-12 |
US9783551B2 (en) | 2017-10-10 |
KR20150075030A (ko) | 2015-07-02 |
SG11201604371PA (en) | 2016-07-28 |
IL245908B (en) | 2020-08-31 |
JP2018135343A (ja) | 2018-08-30 |
MX2016008429A (es) | 2017-02-23 |
CA2929001C (en) | 2018-02-20 |
AU2014370697A1 (en) | 2016-06-16 |
HUE043902T2 (hu) | 2019-10-28 |
CA2929001A1 (en) | 2015-07-02 |
HRP20190573T1 (hr) | 2019-05-17 |
DK3098224T3 (da) | 2019-05-13 |
AU2014370697B2 (en) | 2017-01-19 |
JP6620096B2 (ja) | 2019-12-11 |
TWI585093B (zh) | 2017-06-01 |
WO2015099392A1 (ko) | 2015-07-02 |
KR102344479B1 (ko) | 2021-12-29 |
PL3098224T3 (pl) | 2019-07-31 |
TW201607949A (zh) | 2016-03-01 |
BR112016011281B1 (pt) | 2021-11-16 |
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