CN113185486B - 用于治疗癌症的抗肿瘤剂3-芳基-4h-色烯-4-酮 - Google Patents
用于治疗癌症的抗肿瘤剂3-芳基-4h-色烯-4-酮 Download PDFInfo
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- CN113185486B CN113185486B CN202110445673.8A CN202110445673A CN113185486B CN 113185486 B CN113185486 B CN 113185486B CN 202110445673 A CN202110445673 A CN 202110445673A CN 113185486 B CN113185486 B CN 113185486B
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
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- C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
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- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明公开了用于治疗癌症的抗肿瘤剂3‑芳基‑4H‑色烯‑4‑酮，具体而言，本发明公开了用于治疗前列腺癌，或者治疗或抑制前列腺癌转移的异黄酮或其药学上可接受的盐或其药学上接受的组合物。
Description
本申请是申请日为2016年5月11日、申请号为201680027279.X(PCT/US2016/031789)、发明名称为“用于治疗癌症的抗肿瘤剂3-芳基-4H-色烯-4-酮”的中国专利申请的分案申请。
相关申请的交叉参考
本申请要求2015年5月11日提交的美国临时申请第62/159,669号的权利，其全部内容通过引入本文而并入。
关于联邦资助研究的声明
本发明是在政府支持下根据由国立卫生研究院颁布的第2P20RR020171号合同做出的。政府享有发明中一定的权利。
发明领域
本发明涉及具有抗肿瘤活性的化合物。具体而言，本发明涉及3-芳基-4H-色烯-4-酮，通常指的是异黄酮，以及该化合物抑制有此需要的患者的癌细胞(例如，前列腺癌)生长的用途。
背景技术
前列腺癌代表着重要的医疗保健负担，是男性癌症相关死亡率的第二大主要原因。参见Siegel,R.；Ma,J.；Zou,Z.；Jemal,A.CA Cancer J.Clin.2014,64,9。这一领域的挑战是在雄激素剥夺治疗(即去势)后复发性前列腺癌的问题。医学去势最初消耗雄性激素，如睾丸激素及其还原形式5α-二氢睾酮。然而，癌症不可避免地复发，一个以前未被认可但又非常危险的后门途径(Fiandalo,M.V.；Wilton,J.；Mohler,J.L.Int.J.Bio.l Sci.2014,10,596)将胆固醇代谢中的中间体17α-氢孕酮首先转化为4-雄甾烯-3,17-二酮，然后转化为二氢睾酮，而不经过睾丸激素。因此，仍然需要开发降低这些雄激素水平的升高的疗法来作为治疗复发性前列腺癌的手段。
发明内容
本发明公开的优点包括3-芳基-4H-色烯-4-酮或其可接受的盐或其药学上可接受的组合物及其用于制备治疗前列腺癌或者用于治疗/抑制复发性前列腺癌药物中的应用。
这些或其他优点至少部分地被具有式(I)的3-芳基-4H-色烯-4-酮或其药学上可接受的盐所满足：
其中Ar是芳基或杂芳基；n为1-5的整数，每个X独立地为卤素或烷氧基，或Ar上多于一个的X一起形成环醚结构；并且其中化合物在C-2位上被H、烷基、环烷基或烷氧基取代，在C-5、C-6、C-7和C-8位独立地被H、羟基(OH)、烷基、环烷基、烷氧基取代，或者C-6和C-7或C-7和C-8上的取代基一起形成取代或未取代的、饱和或不饱和的环状或多环结构，其包括至少一个氧族元素，例如氧或硫。烷基、环烷基、烷氧基和环结构可以是未取代的或取代的。这些取代基包括一个或多个胺基(NR2R3)、羟基、酯，例如乙酰氧基、烷氧基、羰基。
实施方式包括单独的一个或多个以下特征或其组合。例如，本发明的实施方式包括3-芳基-4H-色烯-4-酮，其中Ar是杂芳基，例如吡啶基、二嗪基、嘧啶基、噁唑基或咪唑基。在一些实施方式中，Ar为芳基，例如苯基。在其它实施方式中，3-芳基-4H-色烯-4-酮具有式(II)：
在各种实施方式中，3-芳基-4H-色烯-4-酮(II)上的取代基包括：其中C-2取代基为氢H或甲基；在Ar上包括一个或两个X基团的芳基，X基团可以是卤素(例如氟或氯)或烷氧基(例如甲氧基)或一起形成环结构(例如亚甲二氧基或二亚甲基二氧基)；C-5取代基是氢H、羟基(OH)或烷氧基(OR1)，其中R1是烷基或环烷基；C-6取代基是氢H；C-7取代基是羟基或烷氧基(OR1)，其中R1是烷基或环烷基；C-8是氢H、甲基、烷基或取代的烷基，如烷基-Y，其中Y表示(NR2R3)、羟基、酯，例如乙酰氧基、烷氧基，其中R2和R3独立地为H、烷基(例如C1-8烷基)、或者C-6和C-7一起形成包含一个氧的环结构、或者C-7和C-8一起形成包含一个氧的环结构。
本发明的另一方面包括本发明的一种或多种3-芳基-4H-色烯-4-酮或其一种或多种药学上可接受的盐的药物组合物，例如一种或多种式(I)和/或式(II)的化合物和/或一种或多种根据式(I)和/或(II)的化合物的药学上可接受的盐与药学上可接受的添加剂(例如药学上可接受的载体或赋形剂)的组合。在本发明的一个方面，药物组合物包含有效量的至少一种3-芳基-4H-色烯-4-酮或其药学上可接受的盐。
本发明的另一方面包括在制备治疗前列腺癌药物中的应用。该应用包括向有此需要的患者施用有效量的本发明的一种或多种3-芳基-4H-色烯-4-酮或其药学上可接受的盐或其药物组合物。
对本领域技术人员而言本发明的另外的优点将从下面的详细描述中变得显而易见，其中仅通过预期实现本发明的最佳模式来示出和描述本发明的优选实施方式。如将认识到的，本发明能够具有其他和不同的实施方式，并且在不脱离本发明的情况下，其多个细节能够在各种显而易见的方面进行修改。
具体实施方式
本发明涉及能用于治疗前列腺癌的3-芳基-4H-色烯-4-酮。围绕与富含异黄酮家族的天然产物的食品消费相关的健康益处有相当多的学问。特别地，含有7-羟基异黄酮(例如黄豆苷原(A)和染料木黄酮(B))的大豆产品引起了关于癌症预防和前列腺癌治疗的所谓益处的关注。参见(a)Munro,I.C；Harwood,M.；Hlywka,J.J.；Stephen,A.M.；Doull,J.；Flamm,W.G.；Adlercreutz,H.Nutr.Rev.2003,61,1；(b)Adlercreutz,H.Scand.J.Clin.Lab.Invest.1990,50,3；(c)Andres,S.；Abraham,K.；Appel,K.E.；Lampen,A.Crit.Rev.Toxicol.2011,41,463。可惜的是，天然存在的异黄酮及其代谢物拥有众多的生物学活性，包括对雄激素受体表达和与雄激素代谢相关的酶的作用。Hamilton-Reeves,J.M.；Rebello,S.A.；Thomas,W.；Slaton,J.W.；Kurzer,M.S.J.Nutr.2007,137,1769。
我们发现，从这些天然产物中去除一些羟基并且用有氢键合和范德华相互作用力的官能团替代这些基团导致具有独特生物学目标的新试剂。
本发明的优点包括可用于治疗前列腺癌或在有此需要的患者中治疗或抑制复发性前列腺癌的3-芳基-4H-色烯-4-酮或其药学上可接受的盐。本发明的3-芳基-4H-色烯-4-酮包括式(I)的化合物或其药学上可接受的盐：
其中Ar表示芳基，例如苯基，或杂芳基，例如吡啶、二嗪基、嘧啶基、噁唑基或咪唑基。变量n表示Ar上X基团的数目，其可以使1-5的整数。每个X，例如X 1、X2、X3、X4和/或X5独立地为卤素，例如氟、氯或溴，或烷氧基(-OR1，其中R1是烷基或环烷基)，或者Ar上多于一个X一起形成环醚结构，例如Ar上的X1和X2一起形成-O-R-或-O-R-O-环，其中R为双自由基有机基团。这些基团的实例包括亚甲二氧基、二亚甲基二氧基等。3-芳基-4H-色烯-4-酮在其C-2、C-5、C-6、C-7、C-8位各自被取代。这些位置上的每个取代基可以相同或不同，并且包括氢H；羟基(OH)；烷基或环烷基；例如甲基、乙基、环丙基；烷氧基；-COR1，例如乙酰基(-COCH3)；酯等。此外，C-6和C-7上的取代基或C-7和C-8上的取代基可以一起形成取代或未取代的、饱和或不饱和的环状或多环结构，其包括至少一种氧族元素，例如氧或硫。在本发明的一个实施方式中，化合物在C-2位被H、烷基或环烷基取代，在C-5、C-6、C-7和C-8位置独立地被H、羟基(OH)、烷基或环烷基、烷氧基(-OR1，其中R1是烷基或环烷基)取代，或者C-6和C-7上的取代基或C-7和C-8上的取代基一起形成取代或未取代的、饱和或不饱和的环状或多环结构，其包括至少一个氧族元素。
对各种基团和取代基而言所述的烷基、环烷基、烷氧基和环结构可以是未取代的或取代的。例如，烷基、环烷基、烷氧基和环结构可以被胺(NR2R3)、羟基、酯(例如乙酰氧基、烷氧基、羰基)取代，其中R2和R3独立地表示H、烷基，例如C1-8烷基。在一些实施方式中，C-7和C-8独立地可以是CH2OY1，其中Y1是氢、烷基，例如甲基、乙酰基等。
在本发明的一个实施方式中，3-芳基-4H-色烯-4-酮是式(II)的化合物或其药学上可接受的盐：
其中C-2、C-5、C-6、C-7、C-8、X和n如上定义，包括其所有实施方式。
包括式(I)和式(II)化合物的本发明化合物，可以通过本文发明的方法或其他本领域已知的方法制备。例如，向苯酚和β-萘酚应用Betti反应(也称为曼尼希反应)的立体选择性提供了一系列取代的芳族体系，并且在本发明中适用于制备取代的3-芳基-4H-色烯-4-酮。参见(a)M.Betti,Gazz.Chim.Ital.,1900,30,301-309；(b)M.Betti,Gazz.Chim.Ital,1900,30,310-316；(c)M.Betti,Gazz.Chim.Ital,1906,36,392-394；(d)L.O.Paquette,Ed.,Encyclopedia of Reagents for Organic Synthesis,1995,Wiley,UK,4,2582。天然异黄酮，如来自大豆的染料木黄酮(B)，用于前列腺癌预防和治疗的临床试验。参见Perabo,et al.,Prostate Cancer and Prostate Diseases,2008,11,6-12。
在开发合成3-芳基-4H-色烯-4-酮作为抗肿瘤剂的过程中，我们探讨了Betti反应在异黄酮中的应用。开发这些新的3-芳基-4H-色烯-4-酮的理论基础来源于天然存在的异黄酮作为抗肿瘤剂的低效能和天然存在的异黄酮及其代谢物的非特异性生物学效应。天然存在的染料木黄酮(B)在不同癌细胞系中的IC50仅为约15-100μM，天然异黄酮作为抗肿瘤药物的具体生物学靶标尚不清楚。在本发明中，使用前列腺癌PC3细胞系的增殖测定法提供了在C-2位取代的，或者在C-6或C-8位乙酰氧基甲基-、羟甲基-和甲氧基甲基-取代的3-芳基-7-羟基-4H-色烯-4-酮1和2以及环状对应物(其中在C-6和C7或C7和C8之间存在取代或未取代的、饱和或不饱和的环状或多环结构的，其包括至少一个氧族元素，例如氧或硫)内查看构效关系(SAR)的合理替代(方案1)。
方案1.生物活性的3-芳基-4H-色烯-4-酮1和2
相关天然产物中抗肿瘤活性的文献报道包括色酮如8-(甲氧基甲基)异丁香酚，其显示出对P388白血病细胞的中等细胞毒性。参见Y.Feng,J.W.Blunt,A.L.J.Cole and M.Η.G.Munro,J.Nat.Prod.2002,65,1681-1682。像这样的报道是有限的，因为在自然界中不容易发现8-(羟甲基)异黄酮。因此，本发明揭示了这些各种取代的类似物以及可用于治疗前列腺癌的生物活性化合物的通用合成途径。
使用双(N,N-二甲氨基)甲烷在1,4-二氧六环中在70℃下将Betti反应应用于羟基化的3-芳基-4H-色烯-4-酮提供了进入二甲氨基甲基取代体系的途径，并且随后的操作提供所需的乙酰氧基甲基、羟甲基和烷氧基甲基衍生物用于生物学评估。参见例如Tramontini et al.,Mannich Bases-Chemistry and Uses,1994,CRC Press,Boca Raton,FL。合适的起始材料的合成包括在碳酸钾存在下使用硫酸二甲酯使5,7-二羟基异黄酮中C-7羟基的立体选择性甲基化，以得到5-羟基-2',7-二甲氧基异黄酮(3a)和4',7-二甲氧基染料木黄铜(3b)(方案2)。方案2.3-芳基-4H-色烯-4-酮或3-芳基-2-甲基-4H-色烯-4-酮3的Betti反应。图例：a.CH2(N(CH3)2)2，DMF，回流。
与经历双-氨甲基化的5,7-二羟基取代的3-芳基-4H-色烯-4-酮相反，5-羟基取代的3-芳基-4H-色烯-4-酮3a和3b在1,4-二氧六环中与双(N,N-二甲氨基)甲烷经历单-氨甲基化，以分别得到6-和8-(N,N-二甲基氨甲基)衍生物4a-4b和5a-5b的混合物，(方案2)其中C-6异构体占支配地位。这些异构体的结构通过HMBC NMR光谱法进行评估。6-(N,N-二甲氨基)甲基衍生物4a和4b具有H-2与C-8a以及H-8与C-8a的交叉峰。在化合物5a和5b中观察到相似的H-2与C-8a以及C-8处的亚甲基质子与C-8a的交叉峰。C-7羟基化的3-芳基-4H-色烯-4-酮3c-3e与双(N,N-二甲氨基)甲烷在异丙酮或1,4-二氧六环中的氨甲基化仅得到了8-N,N-二甲氨基的衍生物5c-5e。总之，5-羟基化和7-羟基化的3-芳基-4H-色烯-4-酮以双(N,N-二甲氨基)甲烷经历所需的氨甲基化，并在C-5羟基化的情况下表现出区域选择性，有利于C-8(二甲氨基)甲基衍生物4，以及在C-7羟基化的情况下表现出立体选择性，有利于C-6(二甲氨基)甲基衍生物5。
将Betti碱4和5直接转化成相应的C-6或C-8乙酰氧基甲基衍生物包括在乙酸钾存在下加热Betti碱4a-4b或5a-5e与乙酸酐，以良好的产率得到相应的二乙酸酯6和7(方案3)。
方案3.将Betti碱4和5分别转化成乙酰氧基甲基衍生物6和7。图例：a，Ac2O，KOAc。
用比例为2:1的0.2M含水硫酸在1,4-二氧六环中对6a-6b或7a-7e进行水解，分别提供了相应的羟甲基3-芳基-4H-色烯-4-酮8a-8b或9a-9e(方案4)。在甲醇中用盐酸对二乙酸盐6和7进行水解直接分别导致了C-6或C-8-甲氧基甲基3-芳基-4H-色烯-4-酮10和11。甲醇的乙醇或异丙醇替代如所预期的导致了其他烷氧基甲基取代的类似物。在甲醇中用盐酸处理8-羟甲基3-芳基-4H-色烯-4-酮提供了8-甲氧基甲基类似物，在甲醇中用氢氧化钠处理8-乙酰氧基甲基衍生物也导致了8-甲氧基甲基3-芳基-4H-色烯-4-酮(方案4)。
方案4.乙酰氧基甲基衍生物6和7向羟甲基和羟甲基衍生物的转化。图例：a，
0.2M H2SO4，aq.1,4-二氧六环；b，HC1，MeOH；c，NaOH，MeOH。
使用体外PC3前列腺癌细胞系的筛选程序显示，数个具有C-8乙酰氧基甲基、羟甲基或烷氧基甲基取代基的7-羟基化3-芳基-4H-色烯-4-酮2在1-10μM范围内表现出抗肿瘤活性(表1)。通常，我们观察到C-8取代的类似物7、9和11分别比C-6取代的类似物6、8和10在10μM浓度下更有效。在C-8系列中，乙酰氧基甲基和羟甲基-3-芳基-4H-色烯-4-酮比相应的烷氧基甲基取代的3-芳基-4H-色烯-4-酮更有效。同样在C-8系列中，具有4-甲氧基苯基的3-芳基-4H-色烯-4-酮通常优于具有2-甲氧基苯基的那些。例如，3-芳基-4H-色烯-4-酮7d和7e比7c更有效；3-芳基-4H-色烯-4-酮9b、9d和9e比9c更有效；3-芳基-4H-色烯-4-酮11b比11c更有效。还探索了3-苯基上的除甲氧基以外的其它取代基，并且具有卤素的取代基也具有生物活性。最后，在C-8系列中，具有7-羟基取代基以及8-乙酰氧基甲基或8-羟甲基(例如7d和7e，9d和9e)的3-芳基-4H-色烯-4-酮通常比具有5-羟基-7-甲氧基的3-芳基-4H-色烯-4-酮(例如，7b和9b)更有效。具有C-8乙酰氧基甲基的3-芳基-4H-色烯-4-酮7d作为有希望的主导结构出现，其即使在1mM浓度下仍保留效力。
表1在通过异黄酮的前列腺癌PC3细胞测定中的增殖抑制百分比。
| 异黄酮 | C-6或C-8取代基 | 在10μM下的抑制(％) |
| 6a | 6-乙酰氧基甲基 | 17.1±5.9 |
| 6b | 6-乙酰氧基甲基 | 51.7±5.7 |
| 7b | 8-乙酰氧基甲基 | 20.2±2 |
| 7c | 8-乙酰氧基甲基 | 20.6±3.8 |
| 7d | 8-乙酰氧基甲基 | 99.2±0.4 |
| 7e | 8-乙酰氧基甲基 | 98.2±1.5 |
| 8a | 6-羟甲基 | 14.6±3.2 |
| 8b | 6-羟甲基 | 0±16 |
| 9b | 8-羟甲基 | 79.5±3.6 |
| 9c | 8-羟甲基 | 0±16 |
| 9d | 8-羟甲基 | 99.5±0.2 |
| 9e | 8-羟甲基 | 99.5±0.5 |
| 10a | 6-甲氧基甲基 | 53.4±8 |
| 10b | 6-甲氧基甲基 | 0±27 |
| 11a | 8-甲氧基甲基 | 0±1.3 |
| 11b | 8-甲氧基甲基 | 96.8±0.8 |
| 11c | 8-甲氧基甲基 | 0±7.4 |
| 11d | 8-甲氧基甲基 | 34.9±3.3 |
总之，3-芳基-4H-色烯-4-酮的C-5或C-7羟基化的Betti反应提供了易于转化为乙酰氧基甲基、羟甲基或烷氧基甲基取代的3-芳基-4H-色烯-4-酮的N,N-(二甲氨基)甲基衍生物。特别地，5-羟基化的3-芳基-4H-色烯-4-酮3a-3b立体选择性地提供了C-6Betti碱4a-4b，其通过二乙酸盐6a-6b导致C-6烷氧基甲基衍生物10a-10b。7-羟基化3-芳基-4H-色烯-4-酮3c-3e的类似反应立体选择性地提供了C-8Betti碱5c-5e，并且源自这些曼尼希碱的二乙酸盐7c-7e经过取代，导致所需的C-8烷氧基甲基衍生物11c-11e。在前列腺癌PC3细胞增殖测定中，数个C-8乙酰氧基甲基、羟甲基或烷氧基甲基取代的3-芳基-4H-色烯-4-酮在低的微摩尔范围内具有有希望的效力。
除了具有上述多种取代基的异黄酮外，我们制备了其中C-6和C-7上的取代基或C-7和C-8上的取代基一起形成取代的或未取代的、饱和或不饱和的环或多环结构(至少包括一个氧原子)的3-芳基-4H-色烯-4-酮。我们还展示了这些异黄酮中的某些的抗肿瘤活性。
嵌入3-芳基-4H-色烯-4-酮平台内的邻亚甲基苯醌的产生和Diels-Alder反应被用来制备具有这些环状排列的3-芳基-4H-色烯-4-酮的稠环类似物。在这方面，我们合成了各种稠环类似物，如取代的3-芳基-9,10-二氢吡喃并[2,3-f]色烯-4-(8H)-酮12和3-芳基-10-甲基-3,4-二氢-2H,6H-吡喃并[3,2-g]色烯-6-酮13(方案5)。
方案5.代表性的3-芳基-4H-色烯-4-酮的稠环类似物12和13
本发明前述Betti反应提供了所需的邻亚甲基苯醌前体的获得，转而又导致了3-芳基-4H-色烯-4-酮的稠环类似物。在回流下在异丙醇中将Betti反应应用至7-羟基异黄酮14与二(N,N-二甲氨基)甲烷，以良好的收率立体选择性地提供了C-8取代的N,N-二甲氨基甲基类似物15(方案6)。如预期的那样，7-羟基-8-甲基异黄酮16得到了异构体C-6类似物17。
方案6.7-羟基化3-芳基-4H-色烯-4-酮14和16的立体选择性氨甲基化。图例：a，CH2(N(CH3)2)2，异丙醇，80℃。
加热N,N-二甲氨基甲基取代的异黄酮15或17，分别产生截留各种二烯亲和物(包括2,3-二氢呋喃、3,4-二氢-2H-吡喃、3-(N,N-二甲氨基)-5,5-二甲基-2-环己烯-1-酮、1-吗啉环戊烯和1-吗啉环己烯)的中间体邻-亚甲基苯醌18和19(方案7)，并以随二烯亲和物反应性变化的产率获得Diels-Alder加合物20-26(方案8和9)(表2)。
二甲氨基甲基取代的3-芳基-7-羟基-4H-色烯-4-酮15和17与二烯亲和物的Diels-Alder反应。图例：a，二烯亲和物，DMF，回流。
C-7a处的乙缩醛质子和C-10a桥头质子之间的偶联常数3J与由C-8N,N-二甲氨基甲基取代的3-芳基-4H-色烯-4-酮15产生的顺式稠合加合物20和21的结构一致。C-6N,N-二甲氨基甲基取代的3-芳基-4H-色烯-4-酮17的异构反应也导致顺式稠合的加合物16。15和17与3-(N,N-二甲氨基)-5,5-二甲基-2-环己烯-1-酮的Diels-Alder反应导致初始加合物遭受二甲胺的热消除，以高产率分别提供分离的加合物22和26。如表2所示，15a与3-(N,N-二甲氨基)-5,5-二甲基-2-环己烯-1-酮在各种溶剂中的反应的研究导致选择回流的N,N-二甲基甲酰胺作为这些反应的最佳条件。最终，与1-吗啉环戊烯和1-吗啉环己烯的Diels-Alder反应发生了不同的转变，并分别导致加合物23和24。导致这些加合物的机理包括初始环加成、吗啉的β-消除、以及中间体烯醇醚的水解或者烯胺亲核加成到邻亚甲基苯醌中且随后亚铵离子水解。在1-吗啉环戊烯的情况下，加合物采用开链互变异构体23，在1-吗啉环己烯的情况下，加合物优选为环状半缩醛24。导致这些加合物的烯醇醚或亚铵离子的水解发生在分离和纯化过程中。
方案8.源自Betti碱15或17与多种二烯亲和物的热反应的Diels-Alder加合物20-22。
方案9.更多源自Betti碱15或17与多种二烯亲和物的热反应的Diels-Alder加合物23-26。
使用前列腺癌PC3细胞系的增殖研究显示，由2,3-二氢呋喃或3,4-二氢-2H-吡喃与源自C-8N,N-二甲氨基甲基取代的异黄酮15的邻亚甲基苯醌形成的Diels-Alder加合物产生了最活跃的加合物20和21(表3)。一般来说，加合物21比其他加合物活性更高，除了少数例外。在这种一般化的例外中，加合物20a和20e的活性与21a和21e相当。类似地，加合物24g的活性略高于21g。关于异黄酮骨架上的取代基，含有3-(4'-甲氧基苯基)、3-(3',4'-二甲氧基苯基)、3-(3',4'-亚甲二氧基苯基)或3-(4'-氯苯基)取代基的那些加合物通常是最活跃的。在C-2处存在额外的甲基对活性影响相对较小，但加合物24g除外，其活性高于24a。最令人惊奇的是，使用3-(N,N-二甲氨基)-5,5-二甲基-2-环己烯-1-酮产生的加合物通常是不溶性的，除了加合物22b外，其在10μM处显示86％的抑制作用，在1μM处显示31％的抑制作用。
表2来自二烯亲合物与源自18和19的邻亚甲基苯醌反应的Diels-Alder加合物20-26。
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表3在通过含有3-芳基-4H-色烯-4-酮基Diels-Alder加合物的前列腺癌PC3细胞测定中的增值抑制百分比。
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总之，在回流下在异丙醇中3-芳基-7-羟基-4H-色烯酮14或3-芳基-7-羟基-8-甲基-4H-色烯酮16与双(N,N-二甲氨基)甲烷的立体选择性缩合分别提供了氨甲基化衍生物15或17。来自这些Betti碱15和16的二甲胺的热消除产生了捕获各种二烯亲和物的邻亚甲基苯醌中间体，以良好的产率得到各种Diels-Alder加合物20-26。这些加合物，特别是源自2,3-二氢呋喃，3,4-二氢-2H-吡喃或3-(N,N-二甲基氨基)-5,5-二甲基-2-环己烯-1-酮的加合物在使用前列腺癌PC3细胞系的增殖测定中显示良好的活性。
本发明的另一方面包括本发明任何一种或多种3-芳基-4H-色烯-4-酮或其一种或多种药学上可接受的盐的药物组合物，例如，一种或多种式(I)和/或式(II)和/或一种或多种根据式(I)和/或(II)的化合物的药学上可接受的盐，与药学上可接受的添加剂(例如药学上可接受的载体或赋形剂)的组合。在本发明的一个方面，药物组合物包含有效量的至少一种3-芳基-4H-色烯-4-酮或其药学上可接受的盐。
虽然本发明的化合物可能在没有添加剂的情况下而被施用，但优选将其呈现为药物组合物。根据另一方面，本发明提供了一种药物组合物，其包括式(I)和/或式(II)的化合物或化合物的混合物或其药学上可接受的盐、溶剂化物或水合物，与一种或多种药学上可接受的添加剂(例如药学上可接受的载体或赋形剂)以及任选的一种或多种其它治疗成分。在与制剂的其他成分相容的意义上，添加剂必须是“可接受的”，并且对其接受者无害。术语“药学上可接受的载体”包括载体和稀释剂。
本发明的另一方面包括治疗前列腺癌的方法。该方法包括向对此治疗有需要的患者施用有效量的一种或多种3-芳基-4H-色烯-4-酮，包括根据本发明在C-6和C-7具有稠环的那些或在C-7和C-8具有稠环的那些，或其药学上可接受的盐或其药物组合物。
因此，本发明的化合物和/或组合物可用作治疗作为患者的动物、特别是包括人类在内的哺乳动物。因此，患有过度增殖性疾病、特别是前列腺癌的人和其它动物(特别是哺乳动物)，可以通过向患者施用有效量的根据本发明的一种或多种异黄酮或其药学上可接受的盐，其任选地单独或与其他已知的药剂相结合在药学上可接受的添加剂中。根据本发明的治疗还可以通过将本发明的化合物和/或组合物与其它常规癌症疗法(例如放疗或外科手术或施用其它抗癌药剂)一起施用。
实施例
以下实施例旨在进一步说明本发明的某些优选实施方式并且本质上不是限制性的。本领域技术人员将认识到、或能够使用不超过常规的实验来确定本文所述的具体物质和方法的多种等同方式。
表征：在Varian 500(500MHz/125MHz)、Varian 400(400MHz/100MHz)光谱仪上分别在CDCl13或DMSO-d6中记录1H和13C NMR光谱。结构也用HMBC技术证实。在Bruker Vertex70FT/IR光谱仪上记录IR光谱。使用Buchi B-535仪器测定熔点，未校正。使用Agilent 1100光谱仪在化学电离模式下获得质谱。在Merck硅胶60上进行色谱。
3-芳基-4H-色烯-4-酮3a和3b甲基化的一般过程.用5mmol的3、2.07g(15mmol)的无水碳酸钾和0.5mL(5.2mmol)的硫酸二甲酯在10mL的丙酮中将KIM的过程重复6小时，以提供产物3a或3b。参见Kim et al.Org.Lett.2013,15,658。
5-羟基-7-甲氧基-3-(2-甲氧基苯基)-4H-色烯-4-酮(3a).浅黄色固体(产率89％)；mp 153-154℃；IR(KBr):vmax 2993,2942,2839,1662,1583,1495,1439,1260,1181,748cm-1；1H NMR(400MHz,DMSO-d6):δ3.79(s,3H,2'-OCH3)。3.88(s,3H,7-OCH3),6.33(s,1H,6-H),6.49(s,1H,8-H),6.94-7.07(m,2H,3',5'-H),7.20-7.28(m,1H,6'-H),7.32-7.41(m,1H,4'-H),8.06(s,1H,2-H),12.76ppm(s,1H,5-OH)；13C NMR(100MHz,DMSO-d6)：δ55.54,56.06,92.50,98.06,105.25,111.29,119.56,120.13,120.73,129.99,131.55,155.59,157.42,157.52,161.59,165.24,179.90ppm；MS(CI):m/z 299.2(MH+,100)。分析计算C17H14O5:C,68.45；H,4.73。发现：C,68.12；H,4.97。
5-羟基-7-甲氧基-3-(4-甲氧基苯基)-4H-色烯-4-酮(3b).浅黄色固体(产率73％)；mp 142-143℃；IR(KBr):vmax 2964,2936,2833,1658,1618,1579,1516,1244,1192,1151,1051cm-1；1H NMR(400MHz,DMSO-d6):δ3.79(s,3H,4'-OCH3)。3.86(s,3H,7-OCH3),6.41(d,1H,J＝2.2Hz,8-H),6.65(d,1H,J＝2.2Hz,6-H),7.00(d,2H,J＝8.8Hz,3',5'-H),7.51(d,2H,J＝8.7Hz,2',6'-H),8.44(s,1H,2-H),12.92ppm(s,1H,5-OH)；13C NMR(101MHz,DMSO-d6):δ55.14,56.06,92.40,98.03,105.37,113.68,122.13,122.73,130.11,154.61,157.45,159.17,161.70,165.21,180.25ppm；MS(CI):m/z299.1(MH+,100)。分析计算C17H14O5:C,68.45；H,4.73。发现：C,68.73；H,4.94。
合成Betti碱4a-4b和5a-5b的一般过程.向2mmol 3a-3b在10mL1,4-二氧六环中的悬浮液中加入1.36mL(10mmol)双(N,N-二甲氨基)甲烷。将混合物回流24-30小时，冷却并浓缩。异构的曼尼希碱4a-4b和5a-5b的混合物用1:50甲醇-二氯甲烷进行色谱分离。
6-[(二甲氨基)甲基]-5-羟基-7-甲氧基-3-(2-甲氧基苯基)-4H-色烯-4-酮(4a).浅黄色固体(产率48％)；mp 130-131℃；IR(KBr):vmax 2937,2809,2759,1659,1585,1457,1282,1222,1120,1078cm-1；1H NMR(400MHz,CDCl3):δ2.31(s,6H,N(CH3)2),3.52(s,2H,6-CH2),3.81(s,3H,2'-OCH3),3.92(s,3H,7-OCH3),6.43(s,1H,8-H),6.97-7.06(m,2H,3',5'-H),7.28-7.32(m,1H,6-H'),7.35-7.42(m,1H,4'-H),7.87(s,1H,2-H),13.12ppm(s,1H,5-OH)；13C NMR(101MHz,CDCl3):δ45.42,49.70,55.71,56.17,89.45,106.06,109.83,111.25,119.66,120.57,121.37,130.05,131.58,154.11,157.37,157.45,160.53,164.22,180.42ppm；MS(CI):m/z 356.2(MH+,100).分析计算C20H21NO5:C,67.59；H,5.96；N,3.94。发现：C,67.87；H,6.17；N,4.17。
6-[(二甲氨基)甲基]-5-羟基-7-甲氧基-3-(4-甲氧基苯基)-4H-色烯-4-酮(4b).浅黄色固体(产率69％)；mp 140-142℃；IR(KBr):vmax 2933,2817,2757,1653,1610,1514,1254,1221,1123,832cm-1；1H NMR(400MHz,CDCl3):δ2.31(s,6H,N(CH3)2),3.53(s,2H,6-CH2),3.85(s,3H,4'-OCH3),3.92(s,3H,7-OCH3),6.42(s,1H,8-H),6.98(d,2H,J＝8.8Hz,3',5'-H),7.46(d,2H,J＝8.8Hz,2',6'-H),7.88(s,1H,2-H),13.10ppm(s,1H,5-OH)；13CNMR(101MHz,CDCl3):δ45.38,49.65,55.27,56.15,89.41,105.96,109.81,114.00,122.95,123.77,130.04,152.32,157.30,159.67,160.55,164.29,180.69ppm；MS(CI):m/z 356.3(MH+,100)。分析计算C20H21NO5；C,67.59；H,5.96；N,3.94。发现：C,67.42；H,6.14；N,4.23。
8-[(二甲氨基)甲基]-5-羟基-7-甲氧基-3-(2-甲氧基苯基)-4H-色烯-4-酮(5a).浅黄色固体(产率25％)；mp 92-93℃；IR(KBr):vmax 2924,2853,1654,1583,1460,1312,1200,1083,1017cm-1；1H NMR(400MHz,CDCl3):δ2.32(s,6H,N(CH3)2),3.62(s,2H,8-CH2),3.82(s,3H,2'-OCH3),3.92(s,3H,7-OCH3),6.45(s,1H,6-H),6.98-7.06(m,2H,3',5'-H),7.29-7.32(m,1H,6'-H),7.36-7.42(m,1H,4'-H),7.94(s,1H,2-H),13.12ppm(s,1H,5-OH)；13C NMR(101MHz,):δ43.66,49.05,55.70,56.45,95.23,105.73,111.21,119.04,120.57,121.19,130.23,131.54,154.62,156.14,157.40,163.89,164.02,180.67ppm；MS(CI):m/z356.3(MH+,100)。分析计算C20H21NO5:C,67.59；H,5.96；N,3.94。发现：C,67.83；H,6.21；N,4.13。
8-[(二甲氨基)甲基]-5-羟基-7-甲氧基-3-(4-甲氧基苯基)-4H-色烯-4-酮(5b).浅黄色固体(产率28％)；mp 126-127℃；IR(KBr):vmax 2934,2832,1653,1578,1513,1298,1248,1200,1178,1039cm-1；1H NMR(400MHz,CDCl3):δ2.30(s,6H,N(CH3)2),3.58(s,2H,8-CH2),3.84(s,3H,4'-OCH3),3.92(s,3H,7-OCH3),6.44(s,1H,6-H),6.98(d,2H,J＝8.8Hz,3',5'-H),7.46(d,2H,J＝8.8Hz,2',6'-H),7.95(s,1H,2-H),13.13ppm(s,1H,5-OH)；13CNMR(101MHz,CDCl3):δ45.21,49.78,55.23,56.14,95.06,104.76,105.48,113.96,122.86,122.88,129.97,152.94,155.73,159.62,162.35,163.94,181.16ppm；MS(CI):m/z 356.3(MH+,100)。分析计算C20H21NO5:C,67.59；H,5.96；N,3.94。发现：C,67.65；H,5.77；N,3.75。
合成Betti碱5c-5e的一般过程.向搅拌的2mmol 3c-3e在10ml异丙醇的悬浮液中加入0.3mL(2.2mmol)双(N,N-二甲氨基)甲烷。将混合物在80℃下加热4-6小时，并冷却以诱导结晶或浓缩，然后用己烷研磨以诱导结晶。将化合物从异丙醇-己烷中重结晶。
8-[(二甲氨基)甲基]-7-羟基-3-(2-甲氧基苯基)-4H-色烯-4-酮(5c).浅黄色固体(产率91％)；mp 120-121℃；1H NMR(400MHz,CDCl3):δ2.43(s,6H,N(CH3)2),3.81(s,3H,2'-OCH3),3.99(s,2H,8-CH2),6.89(d,1H,3J＝8.8Hz,6-H),6.96-7.06(m,2H,3',5'-H),7.29-7.40(m,2H,4',6'-H),7.88(s,1H,H-2),8.19(d,1H,3J＝8.8Hz,5-H),12ppm(br.s,1H,7-OH)；13C NMR(125MHz,CDCl3):δ44.41,54.87,55.20,107.27,113.80,115.44,116.89,124.22,124.32,126.67,130.00,151.25,154.96,159.41,163.97,175.74ppm；IR(KBr):vmax3448,2951,1626,1427,1246,1178,1028cm-1；MS(CI):m/z 326.2(MH+,100)。分析计算C19H19NO4:C,70.14；H,5.89；N,4.30。发现:C,70.27；H,5.77；N,4.17。
8-[(二甲氨基)甲基]-7-羟基-3-(4-甲氧基苯基)-4H-色烯-4-酮(5d).浅黄色固体(产率83％)；mp 174-176℃；IR(KBr):vmax 3448,2951,1626,1427,1246,1178,1028cm-1；1H NMR(400MHz,CDCl3):δ2.44(s,6H,N(CH3)2),3.85(s,3H,4'-OCH3),3.99(s,2H,8-CH2),6.90(d,1H,3J＝8.8Hz,6-H),6.97(d,2H,3J＝8.8Hz,3',5'-H),7.50(d,2H,3J＝8.8Hz,2',6'-H),7.89(s,1H,2-H),8.14(d,1H,3J＝8.8Hz,5-H),10.21ppm(br.s,1H,7-OH)；13C NMR(125MHz,CDCl3):δ44.41,54.87,55.20,107.27,113.80,115.44,116.89,124.22,124.32,126.67,130.00,151.25,154.96,159.41,163.97,175.74ppm；MS(CI):m/z 326.1(MH+,100)。分析计算C19H19NO4:C,70.14；H,5.89；N,4.30。发现：C,69.88；H,5.97；N,4.39。
8-[(二甲氨基)甲基]-7-羟基-3-(4-甲氧基苯基)-2-甲基-4H-色烯-4-酮(5e).浅黄色固体(产率91％)；mp 185-187℃(分解)；IR(KBr):vmax3450,2958,1626,1603,1255,1176,1016cm-1；1H NMR(400MHz,CDCl3):δ2.30(s,3H,2-CH3),2.44(s,6H,N(CH3)2),3.84(s,3H,4'-OCH3),3.98(s,2H,8-CH2),6.85(d,1H,3J＝8.8Hz,6-H),6.97(d,2H,3J＝8.7Hz,3',5'-H),7.20(d,2H,3J＝8.7Hz,2',6'-H),8.04(d,1H,3J＝8.8Hz,5-H),11.30ppm(br.s,1H)；13C NMR(125MHz,CDCl3):δ19.28,44.44,54.85,55.21,106.83,113.78,115.03,115.89,122.51,125.33,126.74,131.51,154.68,158.99,161.76,163.69,176.47ppm；MS(CI):m/z340.1(MH+,100)。分析计算C20H21NO4:C,70.78；H,6.24；N,4.13。发现:C,70.91；H,5.95；N,4.33。
二乙酸酯6a-6b或7a-7e的一般合成方法.将Betti碱4a-4b或5a-5e(2mmol)和200mg(2mmol)乙酸钾在5mL乙酸酐中的混合物回流5分钟并冷却至室温。将混合物用水稀释，并从乙腈-水中收集并重结晶沉淀物。
5-乙酰氧基-6-(乙酰氧基甲基)-7-甲氧基-3-(2-甲氧基苯基)-4H-色烯-4-酮(6a).白色固体(产率96％)；mp 143-145℃；IR(KBr):vmax 2945,2836,1767,1738,1650,1617,1451,1280,1235,1127cm-1；1H NMR(400MHz,CDCl3):δ2.04(s,3H,C-6CH2OCOCH 3),2.41(s,3H,C-5OCOCH3),3.78(s,3H,2'-OCH3),3.96(s,3H,7-OCH3),5.21(br.s,2H,6-CH2),6.80(s,1H,8-H),6.93-7.03(m,2H,3',5'-H),7.24-7.29(m,1H,6'-H),7.32-7.38(m,1H,4'-H),7.80ppm(s,1H,2-H)；13C NMR(101MHz,CDCl3):δ20.85,21.10,54.69,55.68,56.35,97.13,111.34,111.69,115.90,120.52,120.52,123.43,129.85,131.67,150.12,152.45,157.40,158.93,161.92,169.32,170.80,174.02ppm；MS(CI):m/z 413.2(MH+,100)。分析计算C22H20O8:C,64.08；H,4.89。发现:C,64.27；H,5.11。
5-乙酰氧基-6-(乙酰氧基甲基)-7-甲氧基-3-(4-甲氧基苯基)-4H-色烯-4-酮(6b).白色固体(产率97％)；mp 167-169℃；IR(KBr):vmax 2962,2834,1734,1629,1513,1453,1248,1182,1123cm-1；1H NMR(400MHz,CDCl3):δ2.04(s,3H,C-6CH2OCOCH3),2.44(s,3H,C-5OCOCH3),3.83(s,3H,4'-OCH3),3.96(s,3H,7-OCH3),5.20(s,2H,6-CH2),6.80(s,1H,8-H),6.94(d,2H,J＝8.8Hz,3',5'-H),7.39(d,2H,J＝8.8Hz,2',6'-H),7.81ppm(s,1H,2-H)；13C NMR(101MHz,CDCl3):δ20.83,21.08,54.62,55.25,56.35,97.06,111.53,113.91,116.01,123.58,125.95,130.25,150.18,150.85,158.88,159.58,162.00,169.38,170.77,174.40ppm；MS(CI):m/z 413.2(MH+,100)。分析计算C22H20O8:C,64.08；H,4.89。发现:C,63.89；H,5.17。
[7-(乙酰氧基)-3-(4-甲氧基苯基)-8-甲基-4-氧代-4H-色烯-6-基乙酸甲酯(6c).白色固体(产率93％)；mp 136-138℃；IR(KBr):vmax 3074,2839,1767,1742,1642,1291,1232,1176cm-1；1H NMR(400MHz,CDCl3):δ2.09(s,3H,C-8CH2OCOCH3),2.30(s,3H,8-CH3),2.41(s,3H,7-OCOCH3),2.40(s,3H,C-7OCOCH3),3.85(s,3H,4'-OCH3)5.14(s,2H,6-CH2),6.99(d,2H,3J＝8.8Hz,3',5'-H),7.51(d,2H,3J＝8.8Hz,2',6'-H),8.04(s,1H,H-2),8.26ppm(s,1H,5-H)；13C NMR(100MHz,CDCl3):δ9.44,20.49,20.82,55.29,61.28,113.90,121.05,122.21,123.59,124.80,125.08,126.11,129.93,151.10,152.36,154.89,159.54,168.03,170.35,175.75ppm；MS(CI):m/z 397.2(MH+,100)。分析计算C21H18O7:C,66.66；H,5.09。发现：C,66.91；H,4.89。
5-乙酰氧基-8-(乙酰氧基甲基)-7-甲氧基-3-(2-甲氧基苯基)-4H-色烯-4-酮(7a).白色固体(产率98％)；mp 1 16-118℃；IR(KBr):vmax 2946,1759,1652,1537,1389,1254,1157,1022cm-1；1H NMR(400MHz,CDCl3):δ2.09(s,3H,C-8CH2OCOCH 3),2.40(s,3H,C-5OCOCH3),3.79(s,3H,2'-OCH3),3.96(s,3H,7-OCH3),5.36(s,2H,8-CH2),6.67(s,1H,6-H),6.94-7.10(m,2H,3',5'-H),7.24-7.29(m,1H,6'-H),7.24-7.28(m,1H,4'-H),7.86ppm(s,1H,2-H)；13C NMR(101MHz,CDCl3):δ20.74,20.98,54.38,55.39,56.12,103.49,109.19,110.93,111.38,119.87,120.18,122.50,129.53,131.34,151.37,152.36,156.56,156.99,161.36,169.18,170.72,173.95ppm；MS(CI):m/z 413.2(MH+,100)。分析计算C22H20O8:C,64.08；H,4.89。发现:C,64.32；H,5.07。
5-乙酰氧基-8-(乙酰氧基甲基)-7-甲氧基-3-(4-甲氧基苯基)-4H-色烯-4-酮(7b).白色固体(产率88％)；mp 124-126℃；IR(KBr):vmax 2943,2840,1763,1740,1645,1515,1411,1304,1247,1182,1026cm-1；1H NMR(400MHz,CDCl3):δ2.09(s,3H,C-8CH2OCOCH 3),2.44(s,3H,C-5OCOCH3),3.84(s,3H,4'-OCH3),3.97(s,3H,7-OCH3),5.37(s,2H,8-CH2),6.68(s,1H,6-H),6.96(d,2H,J＝8.8Hz,3',5'-H),7.41(d,2H,J＝8.8Hz,2',6'-H),7.87ppm(s,1H,2-H)；13C NMR(101MHz,CDCl3):δ20.95,21.21,54.57,55.28,56.41,103.95,109.54,111.61,113.97,123.49,125.46,130.27,151.07,151.86,156.91,159.63,161.83,169.59,171.02,174.73ppm；MS(CI):m/z413.3(MH+,100)。分析计算C22H20O8:C,64.08；H,4.89。发现：C,63.85；H,4.61。
7-(乙酰氧基)-8-(乙酰氧基甲基)-3-(2-甲氧基苯基)-4H-色烯-4-酮(7c).白色固体(产率98％)；mp 122-124℃；IR(KBr):vmax 3076,1759,1741,1660,1255,1236and1178cm-1；1H NMR(400MHz,CDCl3):δ2.08(s,3H,C-8CH2OCOCH 3),2.40(s,3H,C-7OCOCH3),3.82(s,3H,2'-OCH3)5.40(s,2H,8-CH2),6.97-7.07(m,2H,3',5'-H),7.21(d,1H,3J＝8.8Hz,6-H),7.30-7.35(m,1H,6'-H),7.37-7.42(m,1H,4'-H),8.04(s,1H,H-2),8.35ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(125MHz,CDCl3):δ20.70,20.79,54.46,55.29,114.03,117.52,120.31,122.54,123.47,125.16,128.06,130.03,152.28,153.65,155.38,159.77,168.63,170.52,175.59ppm；MS(CI):m/z 383.1(MH+,100)。分析计算C21H18O7:C,65.97；H,4.75。发现：C,65.83；H,4.95。
7-(乙酰氧基)-8-(乙酰氧基甲基)-3-(4-甲氧基苯基)-4H-色烯-4-酮(7d).浅黄色固体(产率84％)；mp 141-143℃；IR(KBr):vmax 3076,1759,1741,1660,1255,1236和1178cm-1；1H NMR(400MHz,CDCl3):δ2.07(s,3H,C-8CH2OCOCH 3),2.40(s,3H,C-7OCOCH3),3.85(s,3H,4'-OCH3)5.39(s,2H,8-CH2),6.99(d,2H,3J＝8.8Hz,3',5'-H),7.21(d,1H,3J＝8.8Hz,6-H),7.51(d,2H,3J＝8.8Hz,2',6'-H),8.06(s,1H,2-H),8.36ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(125MHz,CDCl3):δ20.69,20.78,54.45,55.29,114.02,117.51,120.30,122.53,123.46,125.15,128.05,130.02,152.27,153.64,155.37,159.77,168.62,170.51,175.59ppm；MS(CI):m/z 383.1(MH+,100)。分析计算C21H18O7:C,65.97；H,4.75。发现:C,66.21；H,4.51。
7-(乙酰氧基)-8-(乙酰氧基甲基)-3-(4-甲氧基苯基)-2-甲基-4H-色烯-4-酮(7e).白色晶体(产率77％)；mp 142-144℃；IR(KBr):vmax 2922,1765,1737,1645,1223,1199,1180cm-1；1H NMR(400MHz,CDCl3):δ2.08(s,3H,C-8CH2OCOCH 3),2.36(s,3H,2-CH3),2.39(s,3H,C-7OCOCH3),3.85(s,3H,4'-OCH3),5.40(s,2H,8-CH2),6.98(d,2H,3J＝8.3Hz,3',5'-H),7.16(d,1H,3J＝8.8Hz,6-H),7.21(d,2H,3J＝8.3Hz,2',6'-H),8.28ppm(d,1H,3J＝8.8Hz,5-H)；；13C NMR(125MHz,CDCl3):δ19.45,20.72,20.78,54.55,55.24,113.93,117.08,119.84,121.51,123.30,124.57,127.94,131.42,153.46,154.92,159.22,163.21,168.66,170.50,176.11ppm；MS(CI):m/z 397.2(MH+,100)。分析计算C22H20O7:C,66.66；H,5.09。发现:C,66.41；H,5.27。
用于合成羟甲基衍生物8a-8b、9a-9b和9d-9e的一般过程.向含有6或7(1mmol)的10mL 1,4-二氧六环中加入20mL 0.2M硫酸水溶液。将混合物在50-60℃加热6-8小时。将混合物冷却并用水稀释，通过过滤收集所得沉淀。将粗产物用1:20甲醇-二氯甲烷层析，并从乙腈重结晶。
5-羟基-6-(羟甲基)-7-甲氧基-3-(2-甲氧基苯基)-4H-色烯-4-酮(8a).白色固体(25％)；mp 100-101℃；IR(KBr):vmax 2938,2837,1654,1583,1494,1283,1220,1129,1076cm-1；1H NMR(400MHz,CDCl3):δ3.81(s,3H,2'-OCH3),3.93(s,3H,7-OCH3),4.81(s,2H,6-CH 2OH),6.43(s,1H,8-H),6.94-7.08(m,2H,3',5'-H),7.27-7.45(m,2H,4',6'-H),7.88(s,1H,2-H),13.19ppm(s,1H,5-OH)；13C NMR(101MHz,CDCl3):δ53.71,55.70,56.07,89.67,106.18,111.24(111.92),119.37,120.57,121.38,130.15,131.54,154.40,157.40,157.57,159.90,163.20,180.53ppm；MS(CI):m/z 329.1(MH+,100)。分析计算C18H16O6:C,65.85；H,4.91。发现：C,65.93；H,5.07。
5-羟基-6-(羟甲基)-7-甲氧基-3-(4-甲氧基苯基)-4H-色烯-4-酮(8b).白色固体(产率37％)；mp 138-139℃；IR(KBr):vmax 2930,2833,1645,1611,1513,1253,1223,1179,836cm-1；1H NMR(400MHz,CDCl3):δ3.80(s,3H,4'-OCH3),3.92(s,3H,7-OCH3),4.48(s,2H,6-CH 2OH),6.74(s,1H,8-H),6.96-7.05(m,2H,3',5'-H),7.47-7.58(m,2H,2',6'-H),8.48(s,1H,2-H),13.23ppm(s,1H,5-OH)；13C NMR(101MHz,CDCl3):δ53.68,55.31,56.08,89.65,106.12,111.99,114.07,122.73,123.84,130.04,152.57,157.53,159.80,159.98,163.34,180.83ppm；MS(CI):m/z(％):329.2(MH+,100)。分析计算C18H16O6:C,65.85；H,4.91。发现:C,65.56；H,4.87。
7-羟基-6-(羟甲基)-3-(4-甲氧基苯基)-8-甲基-4H-色烯-4-酮(8c).白色结晶(产率72％)；mp 153-155℃；IR(KBr):vmax 2929,1636,1580,1512,1231,1174,1112,1084cm-1；1H NMR(400MHz,DMSO-d6):δ2.29(s,3H,8-CH3),3.79(s,3H,4'-OCH3),4.64(s,3H,6-CH 2OH),5.45(s,3H,6-CH2OH),6.99(d,2H,3J＝8.7Hz,3',5'-H),7.52(d,2H,3J＝8.7Hz,2',6'-H),7.96(s,1H,5-H),8.42(s,1H,2-H),9.73ppm(s,1H,7-OH)；13C NMR(100MHz,DMSO-d6):δ8.44,55.11,59.02,111.01,113.51,116.50,120.73,122.66,124.32,127.94,129.97,153.01,154.21,156.84,158.77,174.92ppm；MS(CI):m/z 313.3(MH+,100)。分析计算C18H16O5:C,69.22；H,5.16。发现：C,69.01；H,5.45。
5-羟基-8-(羟甲基)-7-甲氧基-3-(4-甲氧基苯基)-4H-色烯-4-酮(9b).白色固体(产率48％)；mp 139-141℃；IR(KBr):vmax 2938,2835,1656,1610,1582,1514,1250,1178,1040,831cm-1；1H NMR(400MHz,CDCl3):δ3.85(s,3H,4'-OCH3),3.96(s,3H,7-OCH3),4.86(s,2H,8-CH 2OH),6.44(s,1H,6-H),6.99(d,2H,3J＝8.8Hz,3',5'-H),7.46(d,2H,3J＝8.8Hz,2',6'-H),7.94(s,1H,2-H),13.14ppm(s,1H,5-OH)；13C NMR(101MHz,CDCl3):δ56.35,55.36,56.25,95.22,105.56,106.97,114.08,122.70,123.29,130.03,152.66,154.91,159.76,163.03,163.56,181.11ppm；MS(CI):m/z 329.2(MH+,100)。分析计算C18H16O6:C,65.85；H,4.91。发现:C,65.68；H,5.11。
7-羟基-8-(羟甲基)-3-(2-甲氧基苯基)-4H-色烯-4-酮(9c).白色晶体(产率63％)；mp 163-165℃；IR(KBr):vmax 2953,1627,1603,1441,1267,1237cm-1；1H NMR(400MHz,DMSO-d6):δ3.71(s,3H,2'-OCH3),4.72(s,2H,8-CH 2OH),6.82(d,1H,3J＝8.8Hz,6-H),6.95-7.02(m,1H,5'-H),7.04-7.10(m,1H,3'-H),7.19-7.25(m,1H,6'-H),7.32-7.39(m,1H,4'-H),7.75(d,1H,3J＝8.8Hz,5-H),8.12ppm(s,1H,H-2)；13C NMR(125MHz,DMSO-d6):δ51.39,55.13,113.60,114.59,114.87,116.60,122.88,124.25,125.91,130.06,153.10,155.85,158.94,160.51,174.86ppm；MS(CI):m/z(％)299.2(MH+,100)。分析计算C17H14O5:C,68.45；H,4.73。发现:C,68.55；H,4.93。
7-羟基-8-(羟甲基)-3-(4-甲氧基苯基)-4H-色烯-4-酮(9d).白色晶体(产率69％)；mp 150-152℃(分解)；IR(KBr):vmax 2953,1627,1603,1441,1267,1237cm-1；1H NMR(400MHz,DMSO-d6):δ3.79(s,3H,4'-OCH3),4.70(s,2H,8-CH2),4.91(br s,1H,8-CH2OH),6.95-7.05(m,3H,6,3',5'-H),7.52(d,2H,3J＝8.8Hz,2',6'-H),7.93(d,1H,3J＝8.8Hz,5-H),8.41(s,1H,2-H),10.77ppm(s,1H,7-OH)；13C NMR(125MHz,DMSO-d6):δ51.39,55.13,113.60,114.59,114.87,116.60,122.88,124.25,125.91,130.06,153.10,155.85,158.94,160.51,174.86ppm；MS(CI):m/z(％)299.1(MH+,100)。分析计算C17H14O5:C,68.45；H,4.73。发现:C,68.72；H,4.58.。
7-羟基-8-(羟甲基)-3-(4-甲氧基苯基)-2-甲基-4H-色烯-4-酮(9e).白色晶体(产率58％)；mp 212-214℃(分解)；IR(KBr):vmax 2958,1633,1589,1438,1246,1066cm-1；1HNMR(400MHz,DMSO-d6):δ2.28(s,3H,2-CH3),3.79(s,3H,4'-OCH3),4.71(s,2H,8-CH2),4.89(br.s,1H,8-CH2OH),6.92-7.05(m,3H,6,3',5'-H),7.19(d,2H,3J＝8.8Hz,2',6'-H),7.82(d,1H,3J＝8.8Hz,5-H),10.68ppm(s,1H,7-OH)；13C NMR(125MHz,DMSO-d6):δ19.18,51.48,55.02,113.43,114.13,114.55,115.51,121.43,125.33,125.64,131.62,155.27,158.47,160.30,162.37,175.19ppm；MS(CI):m/z(％)313.1(MH+,100)。分析计算C18H16O5:C,69.22；H,5.16。发现:C,68.95；H,5.31。
用于合成烷氧基甲基衍生物10a-10b或11a-11e的一般程序.将二乙酸酯8a-8c或9a-9f(2mmol)和0.1mL浓盐酸的混合物在10ml甲醇中回流16-24小时。将混合物冷却并用水稀释，通过过滤收集所得沉淀。产物使用1:20的甲醇-二氯甲烷的层析纯化。
5-羟基-7-甲氧基-6-(甲氧基甲基)-3-(2-甲氧基苯基)-4H-色烯-4-酮(10a).白色固体(产率53％)；mp 123-124℃；IR(KBr):vmax 2934,2880,1656,1585,1494,1450,1284,1220,1137,1078cm-1；1H NMR(400MHz,DMSO-d6):δ3.23(s,3H,6-CH2OCH 3),3.75(s,3H,2'-OCH3),3.93(s,3H,7-OCH3),4.41(s,2H,6-CH 2OCH3),6.78(s,1H,8-H),6.94-7.09(m,2H,3',5'-H),7.28-7.34(m,1H,6'-H),7.35-7.43(m,1H,4'-H),8.37(s,1H,2-H),13.24(s,1H,5-OH)；13C NMR(101MHz,CDCl3):δ55.70,56.17,58.14,61.58,89.56,106.10,109.02,111.26,119.49,120.57,121.46,130.12,131.53,154.23,157.43,157.99,160.95,164.22,180.45；MS(CI):m/z 343.3(MH+,100)。分析计算C19H18O6:C,66.66；H,5.30。发现:C,66.58；H,5.17。
5-羟基-7-甲氧基-6-(甲氧基甲基)-3-(4-甲氧基苯基)-4H-色烯-4-酮(10b).白色固体(产率95％)；mp 180-181℃；IR(KBr):vmax 2969,2835,1655,1622,1579,1516,1264,1225,1138,1097cm-1；1H NMR(400MHz,DMSO-d6):δ3.24(s,3H,6-CH2OCH 3),3.81(s,3H,4'-OCH3),3.93(s,3H,7-OCH3),4.43(s,2H,6-CH 2OCH3),6.74(s,1H,8-H),7.01(d,2H,3J＝8.8Hz,3',5'-H),7.53(d,2H,3J＝8.8Hz,2',6'-H),8.46(s,1H,2-H),13.29ppm(s,1H,5-OH)；13C NMR(101MHz,DMSO-d6):δ55.16,56.50,57.28,60.84,90.31,105.06,108.41,113.72,122.33,122.68,130.17,154.67,157.45,159.22,159.97,164.11,180.40ppm；MS(CI):m/z 343.2(MH+,100)。分析计算C19H18O6:C,66.66；H,5.30。发现:C,66.87；H,5.56。
7-羟基-6-(甲氧基甲基)-3-(4-甲氧基苯基)-8-甲基-4H-色烯-4-酮(10c).白色晶体(产率68％)；mp 143-145℃；IR(KBr):vmax 2929,1636,1580,1512,1231,1174,1112,1084cm-1；1H NMR(400MHz,DMSO-d6):δ2.30(s,3H,8-CH3),3.36(s,3H,6-CH2OCH 3),3.79(s,3H,4'-OCH3),4.52(s,3H,6-CH 2OCH3),6.99(d,2H,3J＝8.8Hz,3',5'-H),7.51(d,2H,3J＝8.8Hz,2',6'-H),7.89(s,1H,5-H),8.42(s,1H,2-H),9.79ppm(s,1H,7-OH)；13C NMR(100MHz,DMSO-d6):δ8.61,55.12,57.79,69.15,111.47,113.52,116.49,122.24,122.72,124.24,124.26,130.00,153.12,154.56,157.15,158.81,174.89ppm；MS(CI):m/z 327.1(MH+,100)。分析计算C19H18O5:C,69.93；H,5.56。发现:C,70.11；H,5.38。
5-羟基-7-甲氧基-8-(甲氧基甲基)-3-(2-甲氧基苯基)-4H-色烯-4-酮(11a).白色固体(产率28％)；mp 154-155℃；IR(KBr):vmax 2922,2835,1664,1558,1377,1311,1285,1239,1095,1031cm-1；1H NMR(400MHz,DMSO-d6):δ3.25(s,3H,8-CH2OCH 3),3.74(s,3H,2'-OCH3),3.93(s,3H,7-OCH3),4.51(s,2H,8-CH 2OCH3),6.61(s,1H,6-H),6.98-7.05(m,1H,5'-H),7.07-7.15(m,1H,3'-H),7.24-7.31(m,1H,6'-H),7.36-7.44(m,1H,4'-H),8.37(s,1H,2-H),13.14ppm(s,1H,5-OH)；13C NMR(101MHz,DMSO-d6):δ55.51,56.49,57.23,60.89,95.23,104.03,104.45,111.23,119.37,120.04,120.28,129.88,131.45,155.31,155.56,157.29,162.04,163.65,180.10ppm；MS(CI):m/z 343.3(MH+,100)。分析计算C19H18O6:C,66.66；H,5.30。发现:C,66.93；H,5.12。
5-羟基-7-甲氧基-8-(甲氧基甲基)-3-(4-甲氧基苯基)-4H-色烯-4-酮(11b).白色固体(产率41％)；mp 126-128℃；IR(KBr):vmax 2938,2838,1662,1610,1585,1541,1246,1204,1072,1042cm-1；1H NMR(400MHz,DMSO-d6):δ3.25(s,3H,8-CH2OCH 3),3.79(s,3H,4'-OCH3),3.92(s,3H,7-OCH3),4.50(s,2H,8-CH 2OCH3),6.60(s,1H,6-H),7.01(d,2H,J＝8.8Hz,3',5'-H),7.52(d,2H,J＝8.8Hz,2',6'-H),8.51(s,1H,2-H),13.24ppm(s,1H,5-OH)；13C NMR(101MHz,DMSO-d6):δ55.16,56.53,57.28,60.92,95.30,103.96,104.65,113.72,121.85,122.66,130.17,154.76,155.38,159.19,162.36,163.81,180.64ppm；MS(CI):m/z 343.3(MH+,100)。分析计算C19H18O6:C,66.66；H,5.30。发现:C,66.43；H,5.22。
7-羟基-8-(甲氧基甲基)-3-(2-甲氧基苯基)-4H-色烯-4-酮(11c).白色晶体(产率78％)；mp 164-166℃；IR(KBr):vmax 2937,1624,1579,1427,1284,1259cm-1；1H NMR(400MHz,DMSO-d6):δ3.29(s,3H,8-CH2OCH 3),3.71(s,3H,2'-OCH3),4.62(s,2H,8-CH 2OCH3),6.91-7.02(m,2H,6,5'-H),7.04-7.10(m,1H,3'-H),7.20-7.24(m,1H,6'-H),7.33-7.40(m,1H,4'-H),7.82(d,1H,3J＝8.8Hz,5-H),8.17ppm(s,1H,H-2)；13C NMR(125MHz,DMSO-d6):δ55.07,57.45,61.37,111.24,113.55,114.45,116.53,122.95,124.13,126.70,130.01,153.03,156.16,158.92,161.10,174.71ppm；MS(CI):m/z313.2(MH+,100)。分析计算C18H16O5:C,69.22；H,5.16。发现:C,68.88；H,5.27。
7-羟基-8-(甲氧基甲基)-3-(4-甲氧基苯基)-4H-色烯-4-酮(11d).白色晶体(产率89％)；mp 167-169℃分解；IR(KBr):vmax 2937,1624,1579,1427,1284,1259cm-1；1H NMR(400MHz,DMSO-d6):δ3.30(s,3H,8-CH2OCH 3),3.79(s,3H,4'-OCH3),4.62(s,2H,8-CH 2OCH3),6.99(d,2H,3J＝8.8Hz,3',5'-H),7.05(d,1H,3J＝8.8Hz,6-H),7.53(d,2H,3J＝8.8Hz,2',6'-H),7.98(d,1H,3J＝8.8Hz,5-H),8.40(s,1H,2-H),10.83ppm(s,1H,2-H)ppm；13C NMR(125MHz,DMSO-d6):δ55.07,57.45,61.37,111.24,113.55,114.45,116.53,122.95,124.13,126.70,130.01,153.03,156.16,158.92,161.10,174.71ppm；MS(CI):m/z 313.1(MH+,100)。分析计算C18H16O5:C,69.22；H,5.16。发现:C,69.01；H,4.92。
7-羟基-8-(甲氧基甲基)-3-(4-甲氧基苯基)-2-甲基-4H-色烯-4-酮(11e).白色结晶(产率89％)；mp 215-217℃分解；IR(KBr):vmax 2927,1614,1585,1406,1294,1246,1065cm-1；1H NMR(400MHz,DMSO-d6):δ2.27(s,3H,2-CH3),3.29(s,3H,8-CH2OCH 3),3.79(s,3H,4'-OCH3),4.61(s,2H,8-CH 2OCH3),6.98(d,2H,3J＝8.8Hz,3',5'-H),7.00(d,1H,3J＝8.8Hz,6-H),7.20(d,2H,3J＝8.8Hz,2',6'-H),7.87(d,1H,3J＝8.8Hz,5-H),10.85ppm(s,1H)ppm；13C NMR(125MHz,DMSO-d6):δ19.13,55.01,57.48,61.40,110.99,113.41,114.03,115.43,121.52,125.21,126.48,131.60,155.70,158.48,160.89,162.25,175.08ppm；MS(CI):m/z 327.1(MH+,100)。分析计算C19H18O5:C,69.93；H,5.56。发现:C,70.23；H,5.28。
细胞增殖测定：在DMEM/F-12HAM混合物(Sigma D8437)、10％胎牛血清(AtlantaBiological S11150)中培养PC3前列腺癌细胞。在治疗之前，以每孔3.5×104个将细胞分至12孔板。24小时后，向各孔中加入10μM的各化合物。DMSO用作对照。本实验一式三份进行。使用Vi-Cell XR细胞活力分析仪(Beckman Coulter)分析细胞活力和数量。
用于合成Betti碱15和17的一般过程.在70℃向搅拌下的14或16在10mL异丙醇(2mmol)的悬浮液中加入0.3mL(2.2mmol，1.1当量)的双(N,N-二甲氨基)甲烷。将混合物在80℃下加热2小时，并冷却至沉淀，通过重力过滤收集。在不结晶的情况下，将残余物用己烷研磨以诱导结晶。将Betti碱14和16从异丙醇-己烷重结晶。
8-[(N,N-二甲氨基)甲基]-7-羟基-3-(4-甲氧基苯基)-4H-色烯-4-酮(15a).浅黄色固体(产率83％)；mp 174-176℃；IR(KBr)vmax 3448,2951,1626,1427,1246,1178,1028cm-1；1H NMR(400MHz,CDCl3)δ2.44(s,6H,N(CH3)2),3.85(s,3H,4'-OCH3),3.99(s,2H,8-CH2),6.90(d,1H,3J＝8.8Hz,6-H),6.97(d,2H,3J＝8.8Hz,3',5'-H),7.50(d,2H,3J＝8.8Hz,2',6'-H),7.89(s,1H,2-H),8.14(d,1H,3J＝8.8Hz,5-H),10.21ppm(br s,1H,7-OH)；13C NMR(125MHz,CDCl3)δ44.41,54.87,55.20,107.27,113.80,115.44,116.89,124.22,124.32,126.67,130.00,151.25,154.96,159.41,163.97,175.74ppm；MS(CI):m/z326.1(MH+,100)。分析计算C19H19NO4:C,70.14；H,5.89；N,4.30。发现:C,69.88；H,5.97；N,4.39。
3-(3,4-二甲氧基苯基)-8-[(N,N-二甲氨基)甲基]-7-羟基-4H-色烯-4-酮(15b).浅黄色固体(产率77％)；mp 154-155℃；IR(KBr)vmax 2948,1636,1602,1517,1266,1145,1024cm-1；1H NMR(400MHz,CDCl3)δ2.44(s,6H,N(CH3)2),3.91,3.93(2s,6H,3',4'-OCH3),3.99(s,2H,8-CH2),6.86-6.96(m,2H,6,6'-H),7.00-7.07(m,1H,5'-H),7.18-7.23(m,1H,2'-H),7.92(s,1H,2-H),8.13(d,1H,3J＝8.8Hz,5-H),9.79ppm(s,1H,7-OH)；13C NMR(125MHz,CDCl3)δ44.52,55.04,55.88,55.89,107.40,111.04,112.46,1 15.58,116.93,120.90,124.45,124.70,126.68,148.64,148.95,151.44,154.93,164.05,175.86ppm；MS(CI):m/z 356.2(MH+,100)。分析计算C20H21NO5:C,67.59；H,5.96；N,3.94。发现:C,67.88；H,5.97；N,4.39。
3-(l,3-苯并二噁戊环-5-基)-8-[(N,N-二甲氨基)甲基]-7-羟基-4H-色烯-4-酮(15c).浅黄色固体(产率73％)；mp 160-161℃；IR(KBr)vmax 2960,2987,1639,1488,1425,1246,1017cm-1；1H NMR(400MHz,CDC13)δ2.44(s,6H,N(CH3)2),3.98(s,2H,8-CH2),5.98(s,2H,3',4'-OCH2O),6.80-7.00(m,3H,6,5',6'-H),7.06-7.13(m,1H,2'-H),7.86(s,1H,2-H),8.11(d,1H,3J＝8.8Hz,5-H),9.95ppm(s,1H,7-OH)；13C NMR(125MHz,CDCl3)δ44.60,55.15,101.13,107.49,108.34,109.78,115.62,116.94,122.34,124.61,125.78,126.78,147.56,147.62,151.46,154.97,164.12,175.73ppm；MS(CI):m/z 340.3(MH+,100)。分析计算C19H17NO5:C,67.25；H,5.05；N,4.13。发现:C,67.48；H,4.97；N,4.39。
3-(2,3-二氢-l,4-苯并二氧六环-6-基)-8-[(N,N-二甲氨基)甲基]-7-羟基-4H-色烯-4-酮(15d).浅黄色固体(产率68％)；mp 179-180℃；IR(KBr)；vmax 3072,2955,1643,1602,1509,1289,1060,1027cm-1；1H NMR(400MHz,CDCl3)δ2.42(s,6H,N(CH3)2),3.97(s,2H,8-CH2),4.27(s,4H,3',4'-OCH2CH2O),6.88(d,1H,3J＝8.7Hz,6-H),6.91(d,1H,3J＝8.4Hz,8'-H),7.02(dd,1H,3J＝8.7Hz,4J＝2.0Hz,7'-H),7.09(d,1H,4J＝2.0Hz,5'-H),7.86(s,1H,2-H),8.11(d,1H,3J＝8.7Hz,5-H),10.04ppm(s,1H,7-OH)；13C NMR(125MHz,CDCl3)δ44.39,54.63,64.24,64.38,107.04,115.54,116.87,117.16,1 17.88,122.08,124.27,125.10,126.94,143.32,143.57,151.46,155.02,164.03,175.67ppm；MS(CI):m/z 354.2(MH+,100)。分析计算C20H19NO5:C,67.98；H,5.42；N,3.96。发现:C,68.10；H,5.67；N,4.79。
3-(4-氯苯基)-8-[(N,N-二甲氨基)甲基]-7-羟基-4H-色烯-4-酮(15e).浅黄色固体(产率78％)；mp 174-176℃；IR(KBr)vmax 3061,2958,2838,1881,1632,1590,1466,1378,1257,1204,1176,1011,824cm-1；1H NMR(400MHz,CDCl3)δ2.43(s,6H,N(CH3)2),3.97(s,2H,8-CH2),6.90(d,1H,3J＝8.8Hz,6-H),7.36-7.41(m,2H,3',5'-H),7.46-7.52(m,2H,2',6'-H),7.89(s,1H,H-2),8.11(d,1H,3J＝8.8Hz,5-H),12.48ppm(s,1H,7-OH)；13C NMR(100MHz,CDCl3)δ44.59,55.14,107.55,115.79,116.89,123.84,126.75,128.60,130.21,130.51,134.01,151.79,155.00,164.32,175.37ppm；MS(CI):m/z 330.2(MH+,100),332.2(MH+,28)。分析计算C18H16ClNO3:C,65.56；H,4.89；N,4.25。发现:C,65.81；H,5.07；N,4.47。
8-[(N,N-二甲氨基)甲基]-7-羟基-2-甲基-3-苯基-4H-色烯-4-酮(15f).浅黄色固体(产率81％)；mp 168-170℃；IR(KBr)vmax 3052,2952,1633,1599,1399,1287,1258,1018cm-1；1H NMR(400MHz,CDCl3)δ2.29(s,3H,2-CH3),2.44(s,6H,N(CH3)2),3.98(s,2H,8-CH2),6.84(d,1H,3J＝8.8Hz,6-H),7.24-7.47(m,5H,3-Ph),8.05(d,1H,3J＝8.8Hz,5-H),11.79ppm(s,1H,7-OH)；13C NMR(125MHz,CDCl3)δ19.32,44.41,54.67,106.69,115.12,115.83,122.95,126.83,127.58,128.24,130.38,133.17,154.73,161.90,163.78,176.29ppm；MS(CI):m/z 310(MH+,100)。分析计算C19H19NO3:C,73.77；H,6.19；N,4.53。发现:C,73.92；H,5.99；N,4.43。
8-[(N,N-二甲氨基)甲基]-7-羟基-3-(4-甲氧基苯基)-2-甲基-4H-色烯-4-酮(15g).浅黄色固体(产率91％)；mp 185-187℃分解；IR(KBr)Vmax 3450,2958,1626,1603,1255,1176,1016cm-1；1H NMR(400MHz,CDCl3):δ2.30(s,3H,2-CH3),2.44(s,6H,N(CH3)2),3.84(s,3H,4'-OCH3),3.98(s,2H,8-CH2),6.85(d,1H,3J＝8.8Hz,6-H),6.97(d,2H,3J＝8.7Hz,3',5'-H),7.20(d,2H,3J＝8.7Hz,2',6'-H),8.04(d,1H,3J＝8.8Hz,5-H),11.30ppm(br s,1H)；13C NMR(125MHz,CDCl3):δ19.28,44.44,54.85,55.21,106.83,113.78,115.03,115.89,122.51,125.33,126.74,131.51,154.68,158.99,161.76,163.69,176.47ppm；MS(CI):m/z 340.1(MH+,100)。分析计算C20H21NO4:C,70.78；H,6.24；N,4.13。发现:C,70.91；H,5.95；N,4.33。
3-(3,4-二甲氧基苯基)-8-[(N,N-二甲氨基)甲基]-7-羟基-2-甲基-4H-色烯-4-酮(15h).浅黄色固体(产率87％)；mp 150-152℃；IR(KBr)vmax2995,2841,1635,1516,1393,1262,1020cm-1；1H NMR(400MHz,CDCl3):δ2.31(s,3H,2-CH3),2.45(s,6H,N(CH3)2),3.87,3.91(2s,6H,3',4'-OCH3),3.99(s,2H,8-CH2),6.78-6.83(m,2H,2',6'-H),6.85(d,1H,3J＝8.8Hz,6-H),6.92(d,1H,3J＝8.7Hz,5'-H),8.05ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(125MHz,CDCl3):δ19.39,44.62,55.24,55.88,55.89,107.14,111.11,113.67,115.11,115.94,122.76,122.80,125.84,126.64,148.50,148.70,154.61,161.89,163.78,176.50ppm；MS(CI):m/z 370.3(MH+,100)。分析计算C21H23NO5:C,68.28；H,6.28；N,3.79。发现:C,67.97；H,6.14；N,4.56。
3-(4-氯苯基)-8-[(N,N-二甲氨基)甲基]-7-羟基-2-甲基-4H-色烯-4-酮(15i).浅黄色固体(86％)；mp 174-175℃；IR(KBr)vmax 2974,2835,1631,1407,1371,1285,1258,1014cm-1；1H NMR(400MHz,CDCl3)δ2.29(s,3H,2-CH3),2.44(s,6H,N(CH3)2),3.98(s,2H,8-CH2),6.86(d,1H,3J＝8.8Hz,6-H),7.19-7.25(m,2H,3',5'-H),7.36-7.42(m,2H,2',6'-H),8.03(d,1H,3J＝8.8Hz,5-H),12.14ppm(s,7-OH)；13C NMR(100MHz,CDCl3)δ19.32,44.63,55.24,107.18,115.29,115.80,121.99,126.65,128.54,131.76,131.88,133.61,154.63,161.76,163.99,176.03ppm；MS(CI):m/z344.3(MH+,100),346.3(MH+,29)。分析计算C19H18ClNO3:C,66.38；H,5.28；N,4.07。发现:C,66.10；H,4.99；N,3.85。
6-[(N,N-二甲氨基)甲基]-7-羟基-3-(4-甲氧基苯基)-8-甲基-4H-色烯-4-酮(17a).在70℃下向2mmol 16a在10ml2-甲氧基乙醇中的悬浮液中加入1mL(7.4mmol)双(N,N-二甲氨基)甲烷。将混合物在124℃下加热16小时，冷却，用己烷稀释。收集沉淀物，得到672mg(99％)为黄色固体的17a：mp182-183℃；IR(KBr)vmax 3069,2954,2831,1627,1512,1461,1369,1290,1223,1176,830cm-1；1H NMR(400MHz,CDCl3)δ2.32(s,3H,8-CH3),2.37(s,6H,N(CH3)2),3.78(s,2H,6-CH2),3.84(s,3H,4'-OCH3),6.97(d,2H,3J＝8.7Hz,3',5'-H),7.50(d,2H,3J＝8.7Hz,2',6'-H),7.81(s,1H,5-H),7.97(s,1H,2-H),9.81ppm(br s,1H,7-OH)；13C NMR(125MHz,CDCl3)δ7.81,44.21,55.30,62.37,111.80,113.88,116.63,120.31,122.69,124.02,124.60,130.07,152.01,155.76,159.38,161.30,176.30ppm；MS(CI):m/z340.3(MH+,100)。分析计算C20H21NO4:C,70.87；H,6.24；N,4.13。发现:C,70.62；H,6.43；N,4.11。
6-[(N,N-二甲氨基)甲基]-7-羟基-3-(4-甲氧基苯基)-2,8-二甲基-4H-色烯-4-酮(17g).重复对17a所述的步骤，得到509mg的白色固体17g(产率72％)；mp 176-177℃；IR(KBr)vmax 3039,2952,2834,1643,1606,1511,1397,1239,1158cm-1；1H NMR(400MHz,CDCl3)δ2.32(s,6H,2,8-CH3),2.36(s,6H,N(CH3)2),3.76(s,2H,6-CH2),3.85(s,3H,4'-OCH3),6.97(d,2H,3J＝8.7Hz,3',5'-H),7.21(d,2H,3J＝8.7Hz,2',6'-H),7.74ppm(s,1H,5-H)；13CNMR(125MHz,CDCl3)δ7.83,19.43,44.20,55.23,62.34,111.39,113.77,115.55,119.84,122.14,122.62,125.67,131.55,155.31,158.87,161.02,162.34,176.92ppm；MS(CI):m/z354.2(MH+,100)。分析计算C21H23NO4:C,71.37；H,6.56；N,3.96。发现:C,71.46；H,6.31；N,4.17。
合成Diels-Alder加合物20或25的一般过程。向2mmol 15或17在10mL N,N-二甲基甲酰胺溶液中加入2mL(26mmol，13当量)2,3-二氢呋喃。将溶液回流24-40小时。真空蒸发溶剂和过量的2,3-二氢呋喃，残余物通过使用1:50的甲醇-二氯甲烷的色谱法纯化，得到加合物20或25。
3-(4-甲氧基苯基)-9,10,10a,11-四氢-4H,7aH-呋喃并[2,3-b]吡喃并[2,3-f]色烯-4-酮(20a).浅黄色固体(产率70％)；mp 201-202℃；IR(KBr)vmax 2903,2844,1643,1610,1510,1435,1295,1242,1205,1052cm-1；1H NMR(400MHz,CDCl3)δ1.69-1.82(m,1H,10α-CH),2.10-2.20(m,1H,10β-CH),2.75-2.86(m,1H,10a-CH),3.09(dd,1H,2J＝17.5Hz,3J＝6.2Hz,11α-CH),3.19(dd,1H,2J＝17.5Hz,3J＝2.0Hz,11β-CH),3.85(s,3H,4'-OMe),4.01-4.10(m,1H,9α-CH),4.16-4.24(m,1H,9β-CH),5.68(d,1H,3J＝4.2Hz,7a-CH),6.94(d,1H,3J＝8.8Hz,6-H),6.96-7.00(m,2H,3',H-5'-H),7.48-7.54(m,2H,2',H-6'-H),7.96(s,1H,2-H),8.10ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.46,27.72,36.27,55.34,68.45,100.86,107.02,113.95,115.55,118.49,124.19,124.79,125.49,130.11,151.74,155.39,157.14,159.57,175.95ppm；MS(CI):m/z 351.2(MH+,100)。分析计算C21H18O5:C,71.99；H,5.18。发现:C,72.17；H,4.92。
3-(3,4-二甲氧基苯基)-9,10,10a,11-四氢-4H,7aH-呋喃并[2,3-b]吡喃并[2,3-f]色烯-4-酮(20b).浅黄色固体(产率29％)；mp 193-195℃；IR(KBr)vmax 2900,2843,1637,1607,1510,1437,1398,1290,1244,1057,1025,840cm-1；1H NMR(400MHz,CDCl3)δ1.68-1.82(m,1H,10α-CH),2.10-2.21(m,1H,10β-CH),2.75-2.86(m,1H,10a-CH),3.09(dd,1H,2J＝17.5,3J＝6.0Hz,11α-CH),3.14-3.24(m,1H,11β-CH),3.92(s,3H,3'-OMe),3.93(s,3H,4'-OMe),4.01-4.12(m,1H,9α-CH),4.15-4.24(m,1H,9β-Η),5.68(d,1H,3J＝4.1Hz,7a-CH),6.91-6.98(m,2H,6,5'-H),7.03-7.09(m,1H,6'-H),7.22(d,IH,4J＝1.8Hz,2'-H),7.99(s,1H,2-H),8.10ppm(d,1H,3J＝8.9Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.47,27.71,36.26,55.96,55.99,68.46,100.87,107.03,111.15,112.52,115.65,118.47,121.01,124.62,124.85,125.47,148.76,149.10,151.94,155.38,157.21,176.00ppm；MS(CI):m/z 381.2(MH+,100)。分析计算C22H20O6:C,69.46；H,5.30。发现:C 69.21；H,5.01。
3-(l,3-苯并二氧戊环-5-基)-9,10,10a,11-四氢-4H,7aH-呋喃并[2,3-b]吡喃并[2,3-f]色烯-4-酮(20c).浅黄色固体(产率64％)；mp 203-205℃；IR(KBr)vmax2986,2903,1641,1600,1490,1435,1245,1226,1056,1032cm-1；1H NMR(400MHz,CDCl3)δ1.67-1.81(m,1H,10α-CH),2.10-2.20(m,1H,10β-CH),2.75-2.86(m,1H,10a-CH),3.09(dd,1H,2J＝17.6,3J＝6.2Hz,11α-CH),3.19(dd,1H,2J＝17.6,3J＝2.0Hz,11β-CH),4.00-4.11(m,1H,9α-CH),4.14-4.24(m,1H,9β-CH),5.68(d,1H,3J＝4.2Hz,7a-CH),6.00(s,2H,OCH2O),6.87(d,1H,3J＝8.0Hz,7'-H),6.94(d,1H,3J＝8.8Hz,6-H),6.98(dd,1H,3J＝8.0,4J＝1.7Hz,6'-H),7.10(d,1H,3J＝1.7Hz,4'-H),7.95(s,1H,2-H),8.09ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.46,27.71,36.26,68.46,100.87,101.16,107.04,108.36,109.75,115.63,118.41,122.35,124.93,125.50,125.64,147.63,147.66,151.91,155.37,157.21,175.79ppm；MS(CI):m/z 365.1(MH+,100)。分析计算C21H16O6:C,69.23；H,4.43。发现:C69.52；H,4.18。
3-(2,3-二氢-l,4-苯并二氧六环-6-基)-9,10,10a,11-四氢-4H,7aH-呋喃并[2,3-b]吡喃并[2,3-f]色烯-4-酮(20d).浅黄色固体(产率75％)；mp 188-189℃；IR(KBr)vmax2936,2862,1656,1611,1512,1437,1281,1219,1198,1138cm-1；1H NMR(400MHz,CDCl3)δ1.68-1.82(m,1H,10α-CH),2.09-2.20(m,1H,10β-CH),2.75-2.86(m,1H,10a-CH),3.09(dd,1H,2J＝17.4,3J＝6.4Hz,11α-CH),3.19(dd,1H,2J＝17.4,3J＝2.0Hz,11β-CH),3.99-4.09(m,1H,9α-CH),4.14-4.23(m,1H,9β-CΗ),4.25-4.32(m,4H,OCH2CH2O),5.68(d,1H,3J＝4.2Hz,7a-CH),6.90-6.96(m,2H,6,8'-H),7.04(dd,1H,3J＝8.3,4J＝2.0Hz,7'-H),7.11(d,1H,3J＝2.0Hz,2'-H),7.94(s,1H,7-H),8.09ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.45,27.70,36.25,64.32,64.46,68.45,100.87,107.05,115.55,117.25,117.94,118.46,122.13,124.63,125.09,125.48,143.42,143.69,151.92,155.35,157.15,175.79ppm；MS(CI):m/z 379.2(MH+,100)。分析计算C22H18O6:C,69.84；H,4.79。发现:C,70.07；H,4.95。
3-(4-氯苯基)-9,10,10a,11-四氢-4H,7aH-呋喃并[2,3-b]吡喃并[2,3-f]色烯-4-酮(20e).浅黄色固体(产率55％)；mp 194-195℃；IR(KBr)vmax 2961,2899,1637,1598,1492,1438,1377,1244,1092,1064,1012,819cm-1；1H NMR(400MHz,CDCl3)δ1.70-1.82(m,1H,10α-CH),2.12-2.21(m,1H,10β-CH),2.77-2.86(m,1H,10a-CH),3.09(dd,1H,2J＝17.5,3J＝6.3Hz,11α-CH),3.19(dd,1H,2J＝17.5,3J＝2.0Hz,11β-CH),4.02-4.11(m,1H,9α-CH),4.16-4.25(m,1H,9β-CH),5.69(d,1H,3J＝4.2Hz,7a-CH),6.96(d,1H,3J＝8.9Hz,6-H),7.39-7.44(m,2H,3',5'-H),7.49-7.55(m,2H,2',6'-H),7.99(s,1H,2-H),8.10ppm(d,1H,3J＝8.9Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.46,27.70,36.22,68.48,100.90,107.10,115.83,118.38,124.19,125.50,128.65,130.22,130.36,134.15,152.27,155.42,157.40,175.50ppm；MS(CI):m/z 355.2(MH+,100),357.1(MH+,30)。分析计算C20H15ClO4:C,67.71；H,4.26。发现:C,67.55；H,4.43。
2-甲基-3-苯基-9,10,10a,11-四氢-4H,7aH-呋喃并[2,3-b]吡喃并[2,3-f]色烯-4-酮(20f).浅黄色固体(产率73％)；mp 181-182℃；IR(KBr)vmax 2966,2900,1634,1607,1579,1510,1437,1398,1244,1057,840cm-1；1H NMR(400MHz,CDCl3)δ1.70-1.83(m,1H,10α-CH),2.11-2.21(m,1H,10β-CH),2.32(s,3H,2-CH3),2.75-2.85(m,1H,10a-CH),3.10(dd,1H,2J＝17.4,3J＝6.1Hz,11α-CH),3.21(dd,1H,2J＝17.4,3J＝2.0Hz,11β-CH),4.01-4.10(m,1H,9α-CH),4.16-4.23(m,1H,9β-CH),5.68(d,1H,3J＝4.2Hz,7a-CH),6.91(d,1H,3J＝8.8Hz,6-H),7.27-7.30(m,2H,2',6'-H),7.46-7.34(m,3H,3',4',5',H),8.02ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.39,19.52,27.76,36.31,68.44,100.84,106.71,115.15,117.44,123.38,125.40,127.68,128.33,130.42,133.20,155.01,157.00,162.28,176.34ppm；MS(CI):m/z 335.2(MH+,100)。分析计算C21H18O4:C,75.43；H,5.43。发现:C 75.85；H,5.72。
3-(4-甲氧基苯基)-2-甲基-9,10,10a,11-四氢-4H,7aH-呋喃并[2,3-b]吡喃并[2,3-f]色烯-4-酮(20g).浅黄色固体(产率62％)；mp 227-229℃；IR(KBr)vmax 2900,2825,1634,1607,1510,1437,1398,1290,1244,1057,1025cm-1；1H NMR(400MHz,CDCl3)δ1.68-1.82(m,1H,10α-CH),2.09-2.20(m,1H,10β-CH),2.33(s,3H,2-CH3),2.74-2.85(m,1H,10a-CH),3.09(dd,1H,2J＝17.4,3J＝6.2Hz,11α-CH),3.19(dd,1H,2J＝17.4,3J＝1.6Hz,11β-CH),3.85(s,3H,4'-OMe),4.00-4.09(m,1H,9α-CH),4.15-4.22(m,1H,9β-CH),5.67(d,1H,3J＝4.2Hz,7a-CH),6.90(d,1H,3J＝8.8Hz,6-H),6.97(d,2H,3J＝8.7Hz,3',5'-H),7.21(d,2H,3J＝8.7Hz,2',6'-H),8.01ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.41,19.53,27.78,36.33,55.29,68.43,100.84,106.69,113.87,115.08,117.43,122.92,125.31,125.42,131.55,154.98,156.94,159.07,162.22,176.55ppm；MS(CI):m/z 365.1(MH+,100)。分析计算C22H20O5:C,72.51；H,5.53。发现:C,72.80；H,5.82。
3-(3,4-二甲氧基苯基)-2-甲基-9,10,10a,11-四氢-4H,7aH-呋喃并[2,3-b]吡喃并[2,3-f]色烯-4-酮(20h).浅黄色固体(产率56％)；mp 217-219℃；IR(KBr)vmax 2936,2859,1634,1602,1578,1506,1436,1386,1242,1216,1067cm-1；1H NMR(400MHz,CDCl3)δ1.69-1.82(m,IH,10α-CH),2.10-2.19(m,1H,10β-CH),2.33(s,3H,2-CH3),2.75-2.84(m,1H,10a-CH),3.10(dd,1H,2J＝17.5,3J＝6.1Hz,11α-CH),3.20(dd,1H,2J＝17.5,2J＝2.0Hz,11β-CH),3.88(s,3H,3'-OMe),3.92(s,3H,4'-OMe),4.02-4.10(m,1H,9α-CH),4.15-4.23(m,1H,9β-CH),5.68(d,1H,3J＝4.2Hz,7a-CH),6.80-6.83(m,2H,2',6'-H),6.90(d,1H,3J＝8.8Hz,6-H),6.93(d,1H,3J＝8.6Hz,5'-H),8.02ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.45,19.53,27.77,36.32,55.90,55.92,68.43,100.85,106.68,111.18,113.68,115.16,117.42,122.80,123.14,125.41,125.73,148.60,148.77,154.99,156.99,162.44,176.57ppm；MS(CI):m/z 395.3(MH+,100)。分析计算C23H22O6:C,70.04；H,5.62。发现:C,69.85；H,5.90。
3-(4-氯苯基)-2-甲基-9,10,10a,11-四氢-4H,7aH-呋喃并[2,3-b]吡喃并[2,3-f]色烯-4-酮(20i).浅黄色固体(产率60％)；mp 266-268℃；IR(KBr)vmax 2971,2903,1641,1605,1582,1491,1438,1399,1251,1088,1068cm-1；1H NMR(400MHz,CDCl3)δ1.69-1.83(m,1H,10α-CH),2.11-2.20(m,1H,10β-CH),2.32(s,3H,2-CH3),2.75-2.85(m,1H,10a-CH),3.10(dd,1H,2J＝17.4,3J＝6.3Hz,11α-CH),3.20(dd,1H,2J＝17.4,2J＝2.1Hz,11β-CH),4.02-4.11(m,1H,9α-CH),4.16-4.23(m,1H,9β-CH),5.68(d,1H,3J＝4.2Hz,7a-CH),6.91(d,1H,3J＝8.8Hz,6-H),7.19-7.25(m,2H,3',5'-H),7.38-7.44(m,-2',6'-H),8.01ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.38,19.52,27.74,36.28,68.45,100.87,106.75,115.32,117.27,122.34,125.38,128.59,131.65,131.86,133.71,155.01,157.16,162.32,176.10ppm；MS(CI):m/z 369.1(MH+,100).,371.1(MH+,29)。分析计算C21H17ClO4:C,68.39；H,4.65。发现:C,68.70；H,4.87。
3-(4-甲氧基苯基)-11-甲基-6a,7,8,9a-四氢-4H,6H-呋喃并[2,3-b]吡喃并[3,2-g]色烯-4-酮(25a).浅黄色固体(产率27％)；mp 155-157℃；IR(KBr)vmax 2963,2907,1640,1606,1512,1462,1289,1219,1176,1056cm-1；1H NMR(400MHz,CDCl3)δ1.53-1.67(m,1H,7α-CH),2.00-2.14(m,1H,7β-CH),2.33(s,3H,11-CH3),2.79-2.93(m,2H,6a-CH,6α-CH),3.10(dd,2J＝16.4,3J＝5.9Hz,1H,6β-CH),3.83(s,3H,4'-OCH3),3.88-3.98(m,2H,8-CH2),5.83(d,1H,3J＝5.1Hz,9a-CH),6.98(d,2H,3J＝8.8Hz,3',5'-H),7.51(d,2H,3J＝8.8Hz,2',6'-H),7.91(s,1H,5-H),8.00ppm(s,1H,2-H)；13C NMR(100MHz,CDCl3)δ8.20,26.53,27.97,37.67,55.34,68.33,102.87,113.96,118.62,120.49,123.20,124.19,124.49,130.11,152.27,154.78,155.98,159.49,176.33ppm；MS(CI):m/z 365.3(MH+,100)。分析计算C22H20O5:C,72.51；H,5.53。发现:C,72.80；H,5.35。
3-(4-甲氧基苯基)-2,11-甲基-6a,7,8,9a-四氢-4H,6H-呋喃并[2,3-b]吡喃并[3,2-g]色烯-4-酮(25g).浅黄色固体(产率24％)；mp 155-157℃；IR(KBr)vmax 2933,2837,1635,1608,1513,1462,1238,1932cm-1；1H NMR(400MHz,CDCl3)δ1.52-1.62(m,1H,7α-CH),2.02-2.12(m,1H,7β-CH),2.33,2.35(2s,3H,3H,2,11-CH3),2.80-2.91(m,2H,6a-CH,6α-CH),3.09(dd,2J＝16.0,3J＝5.7Hz,1H,6β-CH),3.84(s,3H,4'-OCH3),3.88-3.99(m,2H,8-CH2),5.83(d,1H,3J＝5.3Hz,9a-CH),6.97(d,2H,3J＝8.6Hz,3',5'-H),7.21(d,2H,3J＝8.6Hz,2',6'-H),7.82ppm(s,1H,5-H)；13C NMR(100MHz,CDCl3)δ8.24,19.50,26.54,28.03,37.76,55.29,68.32,102.91,113.60,113.88,117.58,120.15,122.38,123.09,125.59,131.59,154.37,155.79,159.00,162.77,176.94ppm；MS(CI):m/z 365.3(MH+,100)。分析计算C22H20O5:C,72.51；H,5.53。发现:C,72.80；H,5.35。
用于合成Diels-Alder加合物21的一般方法.向2mmol 18在10mL N,N-二甲基甲酰胺中的溶液中加入2mL(22mmol，11当量)的2H,3,4-二氢吡喃。将溶液回流24-40小时。真空蒸发溶剂和过量的2,3-二氢呋喃，残余物用1:50的甲醇-二氯甲烷通过色谱纯化，得到21。
3-(4-甲氧基苯基)-10,11,11a,12-四氢-4H,7aH,9H-二吡喃并[2,3-b:2',3'-f]色烯-4-酮(21a).浅黄色固体(产率30％)；mp 182-183℃；IR(KBr)vmax 2966,2933,1636,1598,1511,1437,1248,1205,1178,1090,1029cm-1；1H NMR(400MHz,CDCl3)δ1.47-1.92(m,4H,10,11-CH2),2.24-2.40(m,1H,11a-CH),2.90(dd,1H,2J＝17.4Hz,3J＝4.2Hz,12α-CH),3.01(dd,1H,2J＝17.4,3J＝6.1Hz,12β-CH),3.75-3.82(m,1H,9α-CH),3.85(s,3H,4'-OMe),3.95-4.09(m,1H,9β-CH),5.44(d,1H,3J＝2.0Hz,7a-CH),6.93-7.02(m,3H,6,3',5'-H),7.50(d,2H,3J＝8.7Hz,2',6'-H),7.96(s,1H,2-H),8.10ppm(d,1H,3J＝8.8Hz,5-H)；13CNMR(400MHz,CDCl3)δ23.17,23.57,24.02,30.62,55.33,62.58,96.94,107.86,113.94,115.27,118.45,124.19,124.79,125.29,130.13,151.79,155.37,157.15,159.55,176.07ppm；MS(CI):m/z 365.1(MH+,100)。分析计算C22H20O5:C,72.51；H,5.53。发现:C,72.38；H,5.67。
3-(3,4-二甲氧基苯基)-10,11,11a,12-四氢-4H,7aH,9H-二吡喃并[2,3-b:2',3'-f]色烯-4-酮(21b).浅黄色固体(产率54％)；mp 177-178℃；IR(KBr)vmax 3076,2925,1642,1600,1515,1436,1267,1249,1139,1090,1023cm-1；1H NMR(400MHz,CDCl3)δ1.61-1.82(m,4H,10,11-CH2),2.27-2.37(m,1H,11a-CH),2.91(dd,1H,2J＝17.3,3J＝4.1Hz,12α-CH),2.99(dd,1H,2J＝17.3,3J＝6.1Hz,12β-CH),3.76-3.83(m,1H,9α-CH),3.92(s,3H,3'-OMe),3.93(s,3H,4'-OMe),4.00-4.08(m,1H,9β-CH),5.45(d,1H,3J＝2.0Hz,7a-CH),6.93(d,1H,3J＝8.3Hz,5'-H),6.98(d,1H,3J＝8.9Hz,6-H),7.04(dd,1H,3J＝8.3,4J＝2.0Hz,6'-H),7.22(d,1H,4J＝2.0Hz,2'-H),7.99(s,1H,2-H),8.09ppm(d,1H,3J＝8.9Hz,5-H)；13CNMR(400MHz,CDCl3)δ23.15,23.56,24.05,30.64,55.96,55.98,62.61,96.97,107.89,111.16,112.55,115.34,118.46,121.02,124.67,124.83,125.26,148.76,149.10,151.96,155.35,157.22,176.06ppm；MS(CI):m/z 395.3(MH+,100)。分析计算C23H22O6:C,70.04；H,5.62。发现:C,70.27；H,5.90。
3-(l,3-苯并二氧戊环-5-基)-10,11,11a,12-四氢-4H,7aH,9H-二吡喃并[2,3-b:2',3'-f]色烯-4-酮(21c).浅黄色固体(产率25％)；mp179-181℃；IR(KBr)vmax 2925,1637,1599,1434,1247,1142,1033cm-1；1H NMR(400MHz,CDCl3)δ1.68-1.84(m,4H,10,11-CH2),2.25-2.37(m,1H,l la-CH),2.83-3.08(m,2H,12α,12β-CH),3.75-3.85(m,1H,9α-CH),4.00-4.09(m,1H,9β-CH),5.44(d,1H,3J＝2.4Hz,7a-CH),6.00(s,2H,OCH2O),6.88(d,1H,3J＝8.0Hz,7'-H),6.95-7.01(m,2H,6,6'-H),7.10(d,1H,3J＝1.7Hz,4'-H),7.95(s,1H,2-H),8.09ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ23.19,23.58,24.05,30.63,62.58,96.91,101.11,107.82,108.31,109.71,115.29,118.30,122.31,124.86,125.23,125.56,147.53,147.55,151.88,155.25,157.13,175.82ppm；MS(CI):m/z 379.2(MH+,100)。分析计算C22H18O6:C,69.84；H,4.79。发现:C,70.07；H,4.61。
3-(2,3-二氢-l,4-苯并二氧六环-6-基)-10,11,11a,12-四氢-4H,7aH,9H-二吡喃并[2,3-b:2',3'-f]色烯-4-酮(21d).浅黄色固体(产率36％)；mp 160-162℃；IR(KBr)vmax2943,2924,2860,1635,1599,1507,1436,1303,1287,1249,1091cm-1；1H NMR(400MHz,CDCl3)δ1.67-1.82(m,4H,10,11-CH2),2.27-2.35(m,1H,11a-CH),2.91(dd,1H,2J＝17.3,3J＝4.1Hz,12α-CH),2.99(dd,1H,2J＝17.3,3J＝6.1Hz,12β-CH),3.75-3.83(m,1H,9α-CH),4.00-4.09(m,1H,9β-CH),4.27-4.31(m,4H,OCH2CH2O),5.44(d,1H,3J＝2.4Hz,7a-CH),6.93(d,1H,3J＝8.3Hz,8'-H),6.97(d,1H,3J＝8.9Hz,6-H),7.03(dd,1H,3J＝8.3,4J＝2.1Hz,7'-H),7.10(d,1H,4J＝2.1Hz,5'-H),7.94(s,1H,2-H),8.09ppm(d,1H,3J＝8.9Hz,5-H)；13CNMR(400MHz,CDCl3)δ23.19,23.58,24.01,30.63,62.56,64.32,64.46,96.94,107.85,115.27,117.28,117.96,118.45,122.18,124.67,125.12,125.32,143.42,143.68,151.93,155.33,157.17,175.90ppm；MS(CI):m/z 393.2(MH+,100)。分析计算C23H20O6:C,70.40；H,5.14。发现:C,70.15；H,5.40。
3-(4-氯苯基)-10,11,11a,12-四氢-4H,7aH,9H-二吡喃并[2,3-b:2',3'-f]色烯-4-酮(21e).浅黄色固体(产率19％)；mp 195-197℃；IR(KBr)vmax 2930,1643,1597,1437,1256,1206,1094,826cm-1；1H NMR(400MHz,CDCl3)δ1.67-1.84(m,4H,10,11-CH2),2.28-2.38(m,IH,11a-CH),2.85-3.07(m,2H,12α,12β-CH),3.76-3.85(m,1H,9α-CH),3.99-4.11(m,1H,9β-CH),5.45(d,1H,2J＝2.4Hz,7a-CH),6.99(d,1H,3J＝8.8Hz,6-H),7.42(d,2H,3J＝8.7Hz,3',5'-H),7.52(d,2H,3J＝8.7Hz,2',6'-H),7.99(s,1H,2-H),8.09ppm(d,1H,3J＝8.9Hz,5-H)；13C NMR(400MHz,CDCl3)δ23.20,23.59,24.05,30.61,62.60,96.93,107.89,115.47,118.33,124.13,125.25,128.60,130.16,130.32,134.06,152.16,155.28,157.28,175.27ppm；MS(CI):m/z 369.2(MH+,100),371.2(MH+,25)。分析计算C21H17ClO4:C,68.39；H,4.65。发现:C,68.17；H,4.43。
2-甲基-3-苯基-10,11,11a,12-四氢-4H,7aH,9H-二吡喃并[2,3-b:2',3'-f]色烯-4-酮(21f).浅黄色固体(产率33％)；mp 165-167℃；IR(KBr)vmax 2927,1626,1600,1440,1400,1255,1139,1090cm-1；1H NMR(400MHz,CDCl3)δ1.66-1.81(m,4H,10,11-CH2),2.32(s,4H,2-CH3,11a-CH),2.86-3.08(m,2H,12α,12β-CH),3.75-3.86(m,1H,9α-CH),4.01-4.11(m,1H,9β-CH),5.45(d,1H,3J＝2.4Hz,7a-CH),6.94(d,1H,3J＝8.8Hz,6-H),7.28-7.32(m,2H,2',6'-H),7.36(t,1H,3J＝7.3Hz,4'-H),7.44(t,2H,3J＝7.3Hz,3',5'-H),8.02ppm(d,1H,3J＝8.9Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.43,23.24,23.62,24.09,30.72,62.58,96.86,107.44,114.77,117.37,123.30,125.15,127.59,128.25,130.36,133.16,154.87,156.87,162.15,176.26ppm；MS(CI):m/z 349.2(MH+,100)。分析计算C22H20O4:C,75.84；H,5.79。发现:C,76.01；H,5.95。
3-(4-甲氧基苯基)-2-甲基-10,11l,11a,12-四氢-4H,7aH,9H-二吡喃并[2,3-b:2',3'-f]色烯-4-酮(21g).浅黄色固体(产率34％)；mp 199-200℃；IR(KBr)vmax 2931,2901,1637,1606,1510,1440,1397,1255,1243,1136,1091,1030cm-1；1H NMR(400MHz,CDCl3)δ1.61-1.82(m,4H,10,11-CH2),2.28-2.35(m,4H,2-CH3,11a-CH),2.92(dd,1H,2J＝17.3,3J＝4.2Hz,12α-CH),3.00(dd,1H,2J＝17.3,3J＝6.3Hz,12β-CH),3.76-3.83(m,1H,9α-CH),3.85(s,3H,4'-OMe),4.00-4.10(m,1H,9β-CΗ),5.44(d,1H,3J＝2.2Hz,7a-CH),6.93(d,1H,3J＝8.8Hz,6-H),6.97(d,2H,3J＝8.7Hz,3',5'-H),7.21(d,2H,3J＝8.7Hz,2',6'-H),8.01ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.41,23.18,23.58,24.06,30.69,55.28,62.59,96.90,107.48,113.84,114.76,117.38,122.88,125.19,125.32,131.55,154.94,156.91,159.02,162.25,176.63ppm；MS(CI):m/z 379.3(MH+,100)。分析计算C23H22O5:C,73.00；H,5.86。发现:C,73.18；H,6.02。
3-(3,4-二甲氧基苯基)-2-甲基-10,11,11a,12-四氢-4H,7aH,9H-二吡喃并[2,3-b:2',3'-f]色烯-4-酮(21h).浅黄色固体(产率15％)；mp 209-210℃；IR(KBr)vmax 2934,1636,1581,1513,1438,1394,1258,1138cm-1；1H NMR(400MHz,CDCl3)δ1.56-1.82(m,4H,10,11-CH2),2.27-2.35(m,4H,2-CH3,11a-CH),2.98(dd,1H,2J＝17.2,3J＝4.4Hz,12α-CH),3.00(dd,1H,2J＝17.2,3J＝6.3Hz,12β-CH),3.75-3.83(m,1H,9α-CH),3.88(s,3H,3'-OMe),3.92(s,3H,4'-OMe),4.00-4.10(m,1H,9β-CΗ),5.44(d,1H,3J＝2.4Hz,7a-CH),6.79-6.83(m,2H,2',6'-H),6.91-6.95(m,2H,6,5'-H),8.02ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.45,23.17,23.57,24.08,30.69,55.90,55.91,62.61,96.93,107.51,111.17,113.68,114.86,117.37,122.81,123.12,125.19,125.76,148.58,148.76,154.97,156.99,162.51,176.68ppm；MS(CI):m/z 409.2(MH+,100)。分析计算C24H24O6:C,70.58；H,5.92。发现:C,70.69；H,6.17。
3-(4-氯苯基)-2-甲基-10,11,11a,12-四氢-4H,7aH,9H-二吡喃并[2,3-b:2',3'-f]色烯-4-酮(21i).浅黄色固体(产率15％)；mp 205-206℃；IR(KBr)Vmax 2927,1635,1605,1439,1398,1257,1139,1094,895cm-1；1H NMR(400MHz,CDCl3)δ1.82-1.64(m,4H,10,11-CH2),2.28-2.37(m,4H,2-CH3,l la-CH),2.84-3.07(m,2H,12α,12β-CH),3.75-3.84(m,1H,9α-CH),4.00-4.10(m,1H,9β-CH),5.44(d,1H,3J＝2.5Hz,7a-CH),6.95(d,1H,3J＝8.8Hz,6-H),7.20-7.25(m,2H,2',6'-H),7.38-7.43(m,2H,3',5'-H),8.01ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(400MHz,CDCl3)δ19.38,23.12,23.51,24.03,30.60,62.59,96.90,107.55,115.03,117.15,122.27,125.16,128.57,131.59,131.83,133.67,154.96,157.15,162.44,176.20ppm；MS(CI):m/z 383.2(MH+,100),385.2(MH+,25)。分析计算C22H19ClO3:C,72.03；H,5.22。发现:C,72.31；H,5.43。
合成Diels-Alder加合物22和26的一般过程.向1mmol 18或19的溶液中加入1.25mmol(1.25当量)3-(N,N-二甲氨基)-5,5-二甲基环己-2-烯-1-酮在10mL N,N-二甲基甲酰胺中的溶液。将溶液回流4小时。将混合物用20mL甲醇稀释，通过过滤收集沉淀物，并从N,N-二甲基甲酰胺-甲醇中重结晶得到22或26。
3-(4-甲氧基苯基)-9,9-二甲基-8,9,10,12-四氢-4H,11H-吡喃并[2,3-a]氧杂蒽-4,11-二酮(22a).米白色固体(产率92％)；mp 223-225℃；IR(KBr)vmax 2949,1647,1606,1511,1438,1237,1032cm-1；1H NMR(400MHz,DMSO-d6)δ1.10(s,6H,9-CH3),2.33(s,2H,10-CH2),2.53(2,2H,8-CH2),3.52(s,2H,12-CH2),3.81(s,3H,4'-OCH3),7.01(d,2H,3J＝8.6,3',5'-H),7.18(d,1H,Д,3J＝8.8,6-H),7.54(d,2H,3J＝8.6,2',6'-H),8.00(d,2H,3J＝8.8,5-H),8.50ppm(s,1H,2-H)；13C NMR(125MHz,CDCl3和DMSO-d6 1:1)δ16.01,27.89,31.67,40.57,50.07,54.80,107.61,109.39,113.36,113.84,120.34,123.22,124.36,124.84,129.51,151.86,152.47,153.99,159.01,163.63,174.96,196.87ppm；MS(CI):m/z403.2(MH+,100)。分析计算C25H22O5:C,74.61；H,5.51。发现:C,74.47；H,5.27。
3-(3,4-二甲氧基苯基)-9,9-二甲基-8,9,10,12-四氢-4H,11H-吡喃并[2,3-a]氧杂蒽-4,11-二酮(22b).米白色固体(产率75％)；mp 196-198℃；IR(KBr)vmax 2955,1654,1640,1516,1440,1261,1237,1195cm-1；1H NMR(400MHz,CDCl3)δ1.17(s,6H,9-CH3),2.39(s,2H,10-CH2),2.50(s,2H,8-CH2),3.65(s,2H,12-CH2),3.93,3.94(2s,6H,3',4'-OCH3),6.94(d,1H,3J＝8.3Hz,5'-H),7.02-7.10(m,2H,6,6'-H),7.21(d,1H,4J＝1.8Hz,2'-H),8.04(s,1H,2-H),8.15ppm(d,1H,3J＝8.3Hz,5-H)；13C NMR(400MHz,CDCl3)δ16.51,28.42,32.20,41.17,50.60,55.94,55.96,108.31,109.99,111.18,112.39,114.45,121.02,121.07,124.17,125.20,125.60,148.80,149.24,152.51,153.12,154.62,164.28,175.76,197.69ppm；MS(CI):m/z 433.3(MH+,100)。分析计算C26H24O6:C,72.21；H,5.59。发现:C,72.49；H,5.22。
3-(l,3-苯并二氧戊环-5-基)-9,9-二甲基-8,9,10,12-四氢-4H,11H-吡喃并[2,3-a]氧杂蒽-4,11-二酮(22c).米白色固体(产率80％)；mp258-260℃；IR(KBr)vmax 2950,2897,1649,1599,1429,1240,1194,1037cm-1；1H NMR(400MHz,CDCl3)δ1.17(s,6H,9-CH3),2.39(s,2H,10-CH2),2.50(s,2H,8-CH2),3.64(s,2H,c,12-CH2),6.00(s,2H,OCH2O),6.88(d,1H,3J＝8.0Hz,5'-H),6.99(dd,1H,4J＝1.7Hz,3J＝8.0Hz,6'-H),7.05(d,1H,3J＝8.8Hz,6-H),7.10(d,1H,4J＝1.7Hz,2'-H),8.00(s,1H,2-H),8.15ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(100MHz,CDCl3)δ16.52,28.43,32.21,41.19,50.61,101.22,108.33,108.45,109.71,110.01,114.46,120.99,122.42,125.23,125.32,125.69,147.74,147.81,152.49,153.15,154.65,164.28,175.62,197.69ppm；MS(CI):m/z 417.3(MH+,100)。分析计算C25H20O6:C,72.11；H,4.84。发现:C,72.29；H,5.11。
2,9,9-三甲基-3-苯基-8,9,10,12-四氢-4H,11H-吡喃并[2,3-a]氧杂蒽-4,11-二酮(22f).米白色固体(产率84％)；mp 265-266℃；IR(KBr)vmax3047,2947,2885,1646,1590,1390,1235,1215,700cm-1；1H NMR(400MHz,CDCl3)δ1.17(s,6H,9-CH3),2.35(s,3H,2-CH3),2.40(s,2H,10-CH2),2.51(s,2H,8-CH2),3.66(s,2H,12-CH2),7.01(d,1H,3J＝8.8Hz,6-H),7.26-7.30(m,2H,2',6'-H),7.35-7.40(m,1H,4'-H),7.41-7.47(m,2H,3',5'-H),8.08ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(100MHz,CDCl3)δ16.48,19.55,28.42,32.20,41.22,50.64,108.34,109.56,113.99,120.04,123.73,125.56,127.85,128.41,130.34,132.82,152.94,154.29,163.30,164.46,176.08,197.89ppm；MS(CI):m/z 387.3(MH+,100)。分析计算C25H22O4:C,77.70；H,5.74。发现:C,77.92；H,5.88。
3-(4-甲氧基苯基)-2,9,9-三甲基-8,9,10,12-四氢-4H,11H-吡喃并[2,3-a]氧杂蒽-4,11-二酮(22g).米白色固体(产率90％)；mp 236-237℃；IR(KBr)vmax 2958,2890,1653,1586,1515,1440,1393,1239,1174,1026cm-1；1H NMR(400MHz,CDCl3)δ1.14(s,6H,9-CH3),2.32(s,3H,2-CH3),2.36(s,2H,10-CH2),2.47(s,2H,8-CH2),3.62(s,2H,12-CH2),3.82(s,3H,4'-OCH3),6.92-6.99(m,3H,6,3',5'-H),7.15-7.21(m,2H,2',6'-H),8.04ppm(d,1H,3J＝8.8Hz,5-H)；13C NMR(100MHz,CDCl3)δ16.47,19.56,28.42,32.19,41.23,50.65,55.28,108.36,109.52,113.92,113.93,120.02,123.28,124.91,125.56,131.50,152.90,154.26,159.17,163.25,164.46,176.30,197.86ppm；MS(CI):m/z 417.3(MH+,100)。分析计算C26H24O5:C,74.98；H,5.81。发现:C,74.70；H,6.10。
3-(4-甲氧基苯基)-9,9,12-三甲基-6,8,9,10-四氢-4H,7H-吡喃并[3,2-b]氧杂蒽-4,7-二酮(26a).米白色固体(产率80％)；mp 230-232℃；IR(KBr)Vmax 3079,2958,2835,1645,1612,1514,1463,1391,1296,1220,1179cm-1；1H NMR(400MHz,CDCl3)δ1.16(s,6H,9-CH3),2.35(s,2H,8-CH2),2.39(s,3H,12-CH3),2.52(s,2H,10-CH2),3.62(s,2H,6-CH2),3.84(s,3H,4'-OCH3),6.97(d,2H,3J＝8.8Hz,3',5'-H),7.50(d,2H,3J＝8.8Hz,2',6'-H),7.96(s,1H,5-H),8.00ppm(s,1H,2-H)；13C NMR(100MHz,CDCl3)δ8.32,20.97,28.45,32.20,41.29,50.62,55.34,109.16,113.99,114.18,118.85,120.88,124.05,124.16,124.49,130.05,151.43,152.48,153.96,159.62,163.91,175.92,197.56ppm；MS(CI):m/z 417.3(MH+,100)。分析计算C26H14O5:C,74.98；H,5.81。发现:C,75.22；H,5.64。
3-(4-甲氧基苯基)-2,9,9,12-四甲基-6,8,9,10-四氢-4H,7H-吡喃并[3,2-b]氧杂蒽-4,7-二酮(26g).米白色固体(产率72％)；mp 270-272℃；IR(KBr)vmax 2954,2878,1642,1609,1395,1238,1220,1142cm-1；1H NMR(400MHz,CDCl3)δ1.16(s,6H,9-CH3),2.34(s,3H,2-CH3),2.36(s,2H,8-CH2),2.40(s,3H,12-CH3),2.52(2H,10-CH2),3.61(s,2H,6-CH2),3.85(s,3H,4'-OCH3),6.97(d,2H,3J＝8.7Hz,3',5'-H),7.20(d,2H,3J＝8.7Hz,2',6'-H),7.89ppm(s,1H,5-H)；13C NMR(100MHz,CDCl3)δ8.33,19.54,20.95,28.47,32.20,41.33,50.63,55.29,109.19,113.70,113.91,118.35,119.84,122.75,124.08,125.16,131.54,151.26,153.58,159.11,163.11,163.96,176.53,197.61ppm；MS(CI):m/z 431.1(MH+,100)。分析计算C27H26O5:C,75.33；H,6.09。发现:C,75.52；H,5.87。
合成Diels-加合物23和24的一般过程.向2mmol 18在10mL N,N-二甲基甲酰胺中的溶液中加入2.2mmol(1.1当量)的1-吗啉代环戊烯或1-吗啉代环己烯。将混合物在154℃加热4小时。真空蒸发溶剂，残留物用1:50的甲醇-二氯甲烷进行色谱分离，得到23或24。
7-羟基-3-(4-甲氧基苯基)-2-甲基-8-[(2-氧杂环戊基)甲基]-4H-色烯-4-酮(23g).浅黄色固体(产率58％)；mp 210-211℃；IR(KBr)vmax 2960,1735,1631,1580,1512,1436,1291,1244cm-1；1H NMR(400MHz,CDCl3)δ1.62-2.25(m,4H,4",5"-CH2),2.33(s,3H,2-CH3),2.38-2.63(m,2H,3"-CH2),3.01-3.17(m,2H,8-CH2),3.37-3.74(m,1H,1”-H),3.84(s,3H,4'-OCH3),6.91-7.00(m,3H,6,3',5'-H),7.21(d,2H,3J＝8.6Hz,2',6'-H),7.99ppm(d,1H,3J＝8.7Hz,5-H)；13C NMR(125MHz,DMSO-d6)δ19.15,20.05,22.40,28.91,37.40,48.03,55.04,113.25,113.43,113.69,115.56,121.25,124.27,125.31,131.67,155.07,158.46,159.94,162.29,175.36,219.25ppm；MS(CI):m/z 379.1(MH+,100)。分析计算C23H22O5:C,73.00；H,5.86。发现:C,73.26；H,5.62。
3-(3,4-二甲氧基苯基)-7-羟基-2-甲基-8-[(2-氧杂环戊基)甲基]-4H-色烯-4-酮(23h).浅黄色固体(产率53％)；mp 88-90℃；IR(KBr)vmax 2924,1736,1633,1515,1440,1265cm-1；1H NMR(400MHz,DMSO-d6)δ1.51-2.07(m,4H,4",5"-CH2),2.27(s,3H,2-CH3),2.66-3.16(m,4H,8,3"-CH2),3.36-3.60(m,1H,1"-H),3.74,3.79(2s,6H,3',4'-OCH3),6.74-6.88(m,2H,2',6'-H),6.93-7.03(m,2H,6,5'-H),7.76(d,1H,3J＝8.7Hz,5-H),10.64ppm(s,1H,7-OH)；13C NMR(125MHz,DMSO-d6)δ19.63,20.47,29.33,37.83,48.43,55.93,55.97,111.89,113.68,114.12,114.80,116.05,122.01,123.24,124.70,126.17,148.54,148.68,155.50,160.34,162.85,175.75,219.65ppm；MS(CI):m/z 409.2(MH+,100)。分析计算C24H24O6:C,70.58；H,5.92。发现:C,70.28；H,6.18。
7a-羟基-3-(4-甲氧基苯基)-8,9,10,11,11a,12-六氢-4H,7aH-吡喃并[2,3-a]杂蒽-4-酮(24a).浅黄色固体(产率91％)；mp 222-223℃；IR(KBr)vmax 2987,1613,1513,1439,1251,1030cm-1；1H NMR(400MHz,CDCl3)δ1.30-2.18(m,9H,8,9,10,11-CH2,11a-CH),2.35-3.26(m,2H,12-CH2),3.85(s,3H,4'-OCH3),6.81-6.89(m,1H,6-H),6.98(d,2H,3J＝8.6Hz,3',5'-H),7.51(d,2H,3J＝8.6Hz,2',6'-H),7.96(s,1H,2-H),8.02-8.09ppm(m,1H,5-H)；13C NMR(125MHz,DMSO-d6)δ21.82(21.73),22.82(23.00),24.93(24.30),29.11(28.59),36.33(35.45),37.51(37.28),55.13,98.10(97.70),111.20(108.97),113.58,115.63(115.65),117.11(117.33),123.13(123.18),123.84,124.16,130.06(130.08),153.15,154.26(154.95),156.84(156.37),158.96,174.88(174.86)ppm；MS(CI):m/z349.2(MH+,100)。分析计算C23H22O5:C,73.00；H,5.86。发现:C,72.71；H,5.98。
3-(3,4-二甲氧基苯基)-7a-羟基-8,9,10,11,11a,12-六氢-4H,7aH-吡喃并[2,3-a]杂蒽-4-酮(24b).浅黄色固体(产率85％)；mp 214-216℃；IR(KBr)vmax 2930,1629,1612,1516,1439,1263,1143,1027cm-1；1H NMR(400MHz,DMSO-d6)δ1.40-2.62(m,9H,8,9,10,11-CH2,11a-CH),2.70-3.60(m,2H,12-CH2),3.75(s,6H,3',4'-OCH3),6.84-6.99,7.07-7.19(2m,4H,6,2',5',6'-H),7.81-7.87(m,1H,5-H),8.42,8.43ppm(2s,1H,2-H)；13C NMR(125MHz,DMSO-d6)δ22.22(22.13),23.25(23.42),25.35(24.73),29.54(29.02),36.76(35.87),37.94(37.71),55.96,55.96,98.54(98.13),109.39(109.30),111.95(111.62),113.17,116.10(116.07),117.56(117.78),121.63(121.66),123.63(123.63),124.28,124.90(124.91),148.68,149.03,153.79,154.63(155.32),157.27(156.79),175.28(175.26)ppm；MS(CI):m/z 409.2(MH+,100)。分析计算C24H24O6:C,70.58；H,5.92。发现:C,70.31；H,6.21。
3-(l,3-苯并二氧戊环-5-基)-7a-羟基-8,9,10,11,11a,12-六氢-4H,7aH-吡喃并[2,3-a]杂蒽-4-酮(24c).浅黄色固体(产率76％)；mp 197-197℃；IR(KBr)vmax 2937,1630,1587,1435,1251,1027cm-1；1H NMR(400MHz,DMSO-d6)δ1.23-2.62(m,9H,8,9,10,11-CH2,11a-CH),2.70-3.60(m,2H,12-CH2),6.05(s,2H,OCH2O),6.88-7.18(2m,4H,6,2',5',6'-H),7.81-7.99(m,1H,5-H),8.41,8.45ppm(2s,1H,2-H)；13C NMR(125MHz,DMSO-d6)δ22.24(22.14),23.24(23.42),25.35(24.72),29.53(29.02),36.76(35.88),37.95(37.70),98.56(98.15),101.45,108.51,109.83(109.86),111.65,116.13(116.10),117.49(117.72),122.81(122.84),123.58(123.63),124.29,126.11(126.13),147.34,147.41,153.86(153.64),154.64(155.33),157.32(156.86),175.16(175.15)ppm；MS(CI):m/z393.2(MH+,100)。分析计算C23H20O6:C,70.40；H,5.14。发现:C,70.14；H,4.85。
7a-羟基-3-(4-甲氧基苯基)-2-甲基-8,9,10,11,11a,12-六氢-4H,7aH-吡喃并[2,3-a]杂蒽-4-酮(24g).浅黄色固体(产率69％)；mp 212-213℃；IR(KBr)vmax 2924,1632,1608,1514,1435,1251,1177cm-1；1H NMR(400MHz,CDCl3)δ1.57-2.17(m,9H,8,9,10,11-CH2,11a-CH),2.33(s,3H,2-CH3),2.54-3.27(m,2H,12-CH2),3.85(s,3H,4'-OCH3),6.70-6.81(m,1H,6-H),6.97(d,2H,3J＝8.5Hz,3',5'-H),7.21(d,2H,3J＝8.5Hz,2',6'-H),7.87-7.97ppm(m,1H,5-H)；13C NMR(400MHz,CDCl3)δ19.43(19.44),22.12(21.97),23.09(23.34),25.51(24.92),29.44(29.13),36.64(38.54),37.80(37.85),55.29,97.93(97.76),110.68(108.50),113.85,115.24(115.21),116.93(117.14),122.74(122.77),124.61(124.70),125.50(125.51),131.61,154.48(155.18),155.81(156.39),159.02,162.51(162.51),177.10(177.07)ppm；MS(CI):m/z 393.2(MH+,100)。分析计算C24H24O5:C,73.45；H,6.16。发现:C,73.18；H,6.42。
3-(3,4-二甲氧基苯基)-7a-羟基-2-甲基-8,9,10,11,11a,12-六氢-4H,7aH-吡喃并[2,3-a]杂蒽-4-酮(24h).浅黄色固体(产率51％)；mp 193-194；IR(KBr)vmax 2938,1631,1610,1577,1514,1437,1264,1028cm-1；1H NMR(400MHz,CDCl3)δ1.30-2.16(m,9H,8,9,10,11-CH2,11a-CH),2.34(s,3H,2-CH3),2.53-3.28(m,2H,12-CH2),3.88,3.92(2s,6H,3',4'-OCH3),6.62-6.99(m,1H,6-H),6.78-6.86,6.90-6.96(2m,3H,2',5',6'-H),7.84-7.92ppm(m,1H,5-H)；13C NMR(125MHz,DMSO-d6)δ19.19(19.21),21.76(21.69),22.80(22.99),24.96(24.32),29.10(28.59),36.36(35.46),37.57(37.31),55.47,55.50,97.97(97.58),110.87(108.64),111.41,114.31,115.20(115.17),116.05(116.27),122.02(122.08),122.80,123.64,125.65(125.67),148.13,148.22,153.81(154.50),156.65(156.16),162.53,175.20(175.17)ppm；MS(CI):m/z 423.2(MH+,100)。分析计算C25H26O6:C,71.07；H,6.20。发现:C,71.33；H,6.07。
在本发明中仅示出和描述了本发明的优选实施方式及其多功能性实施例。应当理解，本发明能够在各种其他组合和环境中使用，并且能够在本文所表达的本发明构思的范围内进行改变或修改。因此，例如，本领域技术人员将认识到、或者能够使用不超过常规实验来确定本文所述的具体物质、方法和布置的许多等价方式。这种等价方式被认为在本发明的范围内，并且由所附权利要求书覆盖。
Claims (3)
1.一种具有式(VI)的化合物或其药学上可接受的盐：
C-2＝H，Ar’＝C6H4-4-OCH3，C-7＝OCH3，C-5＝OH，或
C-2＝H，Ar’＝C6H4-4-OCH3，C-7＝OH，C-5＝H。
2.一种药学上可接受的组合物，其包括权利要求1所述的化合物或其药学上可接受的盐以及药学上可接受的添加剂。
3.一种药学上可接受的组合物在制备治疗前列腺癌药物中的应用，其特征在于，所述组合物包括权利要求1所述的化合物或其药学上可接受的盐。
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