CN1228080A - 新的治疗免疫剂及其在降低细胞因子水平中的应用 - Google Patents

新的治疗免疫剂及其在降低细胞因子水平中的应用 Download PDF

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CN1228080A
CN1228080A CN97197251A CN97197251A CN1228080A CN 1228080 A CN1228080 A CN 1228080A CN 97197251 A CN97197251 A CN 97197251A CN 97197251 A CN97197251 A CN 97197251A CN 1228080 A CN1228080 A CN 1228080A
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phenyl
methoxy
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dimethoxyphenyl
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CN1263731C (zh
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G·W·米勒
M·夏尔
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Celgene Corp
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Abstract

式(Ⅰ)的取代的苯乙烯的氰基和羧基衍生物，其中Y是－COZ、－C≡N，或1—5个碳原子的低级烷基；Z是－OH、－NR6R6、－R7或－OR7；X、R1、R2、R3、R4、R5、R6和R7在说明书中给出，它是肿瘤坏死因子α、核因子κB和磷酸二酯酶的抑制剂，并可用来抗恶病质、内毒素性休克、逆转录病毒复制、哮喘和炎性症状。典型的例子是3，3－二－(3，4－二甲氧基苯基)丙烯腈。

Description

新的免疫治疗剂及其在降低细胞因子水平中的应用
发明背景
本发明涉及一种减少哺乳动物中细胞因子及其前体的方法，以及用于该方法的化合物和组合物。本发明尤其涉及一类介导磷酸二酯酶(尤其是PDEⅡ和PDEⅣ)的作用以及TNFα和NFκB形成的化合物。
肿瘤坏死因子α(TNFα)是主要由单核吞噬细胞应答免疫刺激剂而释放的细胞因子。当将其施加于动物或人时，TNFα会引起炎症、发热、心血管影响、出血、凝血以及类似于急性感染和休克时所见的急性反应。
核因子κB(NFκB)是多效转录激活剂(Lenardo等，Cell 1989,58,27-29)，已经证实它会参与各种疾病和炎症。NFκB被认为能调节细胞因子(包括但不限于TNFα)的水平，并且也是HIV转录的激活剂(Dbaibo等，J.Biol.Chem.1993,17762-66；Duh等，Proc,.Natl.Acad.Sci.1989,86,5974-78；Bachelerie等，Nature1991,350,709-12；Boswas等，J.Acquired Immune Deficiency Syndrome 1993,6,778-786；Suzuki等，Biochem.And Biophys.Res.Comm.1993.193.277-83；SuZuki等，Biochem.And Biophys.Res Comm.1992.189,1709-15；Suzuki等，Biochem.Mol.Bio.Int.1993,31(4),693-700；Shakhov等，Proc.Natl.Acad.Sci.USA 1990,171,35-47；和Staal等，Proc.Natl.Acad.Sci.USA 1990,87,9943-47)。因此，NFκB结合的抑制可调节细胞因子基因的转录，通过这一调节和其他机制，它能用于抑制众多疾病。TNFα和NTκB水平受逆反馈环的影响。
很多细胞功能由3′,5′-环磷酸腺苷(cAMP)水平介导。这些细胞功能可造成炎性状态和包括哮喘、炎症和其他病状在内的疾病(Lowe和Cheng,Drugs of theFuture,17(9),799-807,1992)。现已证明，炎性白细胞中cAMP水平的升高抑制了这些细胞的激活以及炎性介体(包括TNFα和NFκB)的随后释放。cAMP水平的升高还导致呼吸道平滑肌的松驰。cAMP灭活的主要细胞机制是cAMP被称为环核苷酸磷酸二酯酶(PDE)的同工酶家族破坏，该家族中有7种酶是已知的。例如，认为Ⅳ型PDE的抑制在炎性介体释放抑制和呼吸道平滑肌松弛中是特别有效的。因此，抑制PDE Ⅳ的化合物能表现出所需的炎症抑制和呼吸道平滑肌松弛，而只有最少程度的不希望产生的副作用(如心血管或抗血小板效应)。现在已经知道，TNFα产生的抑制是PDE Ⅳ抑制的结果。(L.J.Lombarbo,CurrentPharmaceutical design,1,255-268(1995))。
很多疾病状态均伴有TNFα产生过量或失控。这些疾病包括内毒素血症和/或中毒性休克综合征{Tracey等，Nature 330,662-664(1987)和Hinshaw等，Circ.Shock 30,279-292(1990)}；恶病质{Dezube等，Lancet,335(8690),662(1990)}和成人呼吸窘迫综合征(ARDS)(其中从ARDS患者肺呼出气中检出TNFα的浓度超出12,000pg/mL){Millar等，Lancet 2(8665),712-714(1989)}.重组TNFα全身输注也会导致ARDS中所见的变化{Ferrai-Baliviera等，Arch.Surg.124(12),1400-1405(1989)}。
TNFα似乎还涉及骨吸收疾病(包括关节炎)，已经测得，当发作时，白细胞会产生骨吸收活性，资料表明TNFα与该发作有关{Bertolini等，Nature 319,516-518(1986)和Johnson等，Endocrinology 124(3),1424-1427(1989)}。在体内、外试验中已经测得，TNFα通过刺激成骨细胞的形成和激活，并同时抑制成骨细胞功能，从而刺激骨吸收，抑制骨生成。尽管TNFα可能涉及很多骨吸收疾病(包括关节炎)，但最令人非信不可的与疾病的联系是肿瘤或宿主组织产生TNFα与伴有高钙血症的恶性肿瘤之间的联系{Calci.Tissue Int.(US)46(Suppl.),S3-10(1990)}。在移植物对宿主反应中，血清TNFα水平的提高与急性同种异型骨髓移植后的主要并发症有关{Holler等，Blood,75(4),1011-1016(1990)}。
脑疟疾是伴有TNFα高血浓度的致死性超急性神经综合征，是疟疾患者中出现的最严重的并发症。血清TNFα水平与患急性疟疾患者疾病的严重程度和预后直接相关{Grau等N.Engl.J.Med.320(24),1586-1591(1989)}。
已知巨噬细胞诱导的血管生成由TNFα介导。Leibovich等{Nature,329,630-632(1987)}证明，在大鼠角膜和发育中的小鸡绒毛尿囊膜上，很低剂量的TNFα即可引起体内毛细血管的形成，提示TNFα在炎症、伤口修复和肿瘤生长上是诱导血管生成的候选物。TNFα的产生还与癌性疾病、特别是诱发肿瘤相关联{Ching等，Brit.J.Cancer,(1955)72,339-343和Koch,Progress in MedicinalChemistry,22,166-242(1985)}。
TNFα还在慢性肺部炎症性疾病方面起作用。硅石颗粒的沉积导致硅肺，一种纤维变性反应引起的进行性呼吸衰竭疾病。抗TNFα抗体完全阻断小鼠体内硅石诱导的肺纤维变性{Pignet等，Nature,344:245-247(1990)}。在硅石和石棉引起的纤维变性的动物模型中已经得到证明，血清和分离出的巨噬细胞中有高水平TNFα的产生{Bissonnette等，Inflammation 13(3),329-339(1989)}。还有人发现，从肺部肉瘤病患者获得的肺泡巨噬细胞与来自正常供体的巨噬细胞相比，会自发性地释放大量TNFα{Baughman等，J.Lab.Clin.Med.115(1),36-42(1990)}。
TNFα还与再灌注后的炎症反应(称作再灌注损伤)有关，是缺血流后组织损伤的主要原因{Vedder等，PNAS 87,2643-2646(1990)}。TNFα还能改变内皮细胞的性质，具有各种促凝血活性，如提高组织因子促凝血活性和抑制抗凝血蛋白C途径，以及下调血栓调节蛋白(thrombomodulin)的表达{Sherry等，J.Cell Biol.107,1269-1277(1988)}。TNFα具有促炎症活性，该活性与TNFα的早期产生(在炎症初期)使其更象是几种重要疾病(包括但不限于心肌梗塞、中风和循环休克)中组织损伤的介质。特别重要的是TNFα诱导的粘合分子(如细胞间粘合分子(ICAM)或内皮白细胞粘合分子(ELAM))在内皮细胞上的表达{Munro等，Am.J.Path.135(1),121-132(1989)}。
用抗TNFα单克隆抗体封闭TNFα已被证明对类风湿性关节炎{Elliot等，Int.J.Pharmac.1995 17(2),141-145}有益。高水平的TNFα与克罗恩氏病{vonDullemen等，Gastroenterology,1995 109(1),129-135}有关，通过TNFα抗体的治疗已经获得了临床效果，从而确认了TNFα在疾病中的重要性。
此外，现已知道，TNFα是逆转录病毒复制(包括HIV-1激活)的潜在激活剂{Duh等，Proc.Nat.Acad.Sci.86,5974-5978(1989)；Poll等，Proc.Nat.Acad.Sci.87,782-785(1990)；Monto等，Blood 79,2670(1990)；Clouse等，J.Immunol.142,431-438(1989)；Poll等，AIDS Res.Hum.Retrovirus,191-197(1992)}。AIDS由人免疫缺陷病毒(HIV)感染T淋巴细胞而引起。至少有三种类型或三株HIV已被鉴定出来，即HIV-1,HIV-2和HIV-3。作为HIV感染的结果，T细胞介导的免疫受损，受感染的个体出现严重的机会性感染和/或异常新生物。HIV进入T淋巴细胞需要T淋巴细胞激活。其他病毒(如HIV-1和HIV-2)在T细胞激活后感染T淋巴细胞，这些病毒蛋白的表达和/或复制由这种T细胞激活所介导或维持。一旦被激活的T淋巴细胞被HIV感染，该T淋巴细胞必须继续维持激活状态，以使HIV基因表达和/或HIV复制。细胞因子，特别是TNFα，通过在维持T淋巴细胞活化上起作用而参与活化T细胞介导的HIV蛋白表达和/或病毒复制。因此，在HIV感染的个体上，诸如通过阻止或抑制细胞因子(值得注意的是TNFα)的产生来干扰细胞因子的活性，有助于限制HIV感染引起的T淋巴细胞激活的维持。
单核细胞、巨噬细胞和相关的细胞(如枯否氏细胞和胶质细胞)也参与HIV感染的维持。这些细胞象T细胞一样，是病毒复制的靶细胞，病毒复制的水平依赖于细胞的激活状态{Rosenberg等，The Immunopathogenesis of HIV Infection,Advances inImmunology,57(1989)}。细胞因子(如TNFα)已被证明在单核细胞和/或巨噬细胞上激活HIV复制{Poli等，Proc.Natl.Acad.Sci.,87,782-784(1990)}，因此，阻止或抑制细胞因子的产生或其活性有助于限制上述的HIV侵入T细胞。另外的研究将TNFα鉴定为体外HIV激活的共同因子，并提供了细胞的胞质中已发现的核调节蛋白起作用的明确的作用机制(Osborn等，PNAS 86 2336-2340)。该证据揭示，TNFα合成的减少通过减少转录从而减少病毒产生，可在HIV感染中具有抗病毒效应。
潜伏在T细胞和巨噬细胞株内的HIV的AIDS病毒复制可被TNFα诱导{Folks等，PNAS 86,2365-2368(1989)}。有人提出，该病毒诱导活性的分子机理是通过TNFα激活细胞胞质中所见基因调节蛋白(NFκB)的能力，其能通过结合病毒调节基因序列(LTR)而促进HIV复制{Osborn等，PNAS 86:2336-2340(1989)}。有人提出，伴有恶病质的AIDS中TNFα系患者血清TNFα的提高及外周血液单核细胞中高水平自发性TNFα产生所致{Wright等，J.Immunol.14l(1).99-104(1988)}。
出于上述提到的类似的理由，TNFα参与其他病毒{如细胞肥大包涵体病毒(CMV)、流感病毒、腺病毒和疱疹病毒族}感染。
已经认识到，抑制TNFα的效果在各种疾病中是有益的，在过去，类固醇(如地塞米松和脱氢可的松)以及多克隆和单克隆抗体{Beutler等，Science 234,470-474(1985)；WO92/11383}已经用于该目的。需要抑制TNFα的疾病包括脓毒性休克、脓毒症、内毒索性休克、血液动力学休克和脓毒综合征、缺血后再灌注损伤、疟疾、分支杆菌感染、脑脊膜炎、牛皮癣、充血性心力衰竭、纤维化疾病、恶病质、移植物排斥、癌症、自身免疫性疾病、AIDS中的机会性感染、类风湿性关节炎、类风湿性脊椎炎、骨关节炎、其他关节炎病症、克罗恩氏病、溃疡性结肠炎、多发性硬化、全身红斑狼疮、麻风中的ENL、放射损伤、哮喘和高氧性肺泡损伤。
细胞核内NFκB作用的抑制可用于治疗各种疾病，包括但不局限于类风湿性关节炎、类风湿性脊椎炎、骨关节炎、其它关节炎病症、脓毒性休克、脓毒症、内毒素性休克、移植物抗宿主疾病、消耗性疾病、克罗恩氏病、溃疡性结肠炎、多发性硬化、全身性红斑狼疮、麻风中的ENL、HIV、AIDS及AIDS中的机会感染。
详述
本发明的化合物影响磷酸二酯酶、TNFα和NFκB的水平，方法为通过给予下式化合物来调节磷酸二酯酶、TNFα和NFκB的水平：
Figure A9719725100111
其中：
(a)X是-O-或-(CnH2n)-，其中n的值为0、1、2或3,R1是1-10个碳原子的烷基、最多有10个碳原子的单环烷基、最多有10个碳原子的多环烷基或最多有10个碳原子的苯并环烷基，或
(b)X是-CH=,R1是最多有10个碳原子的亚烷基、最多有10个碳原子的单环亚烷基或最多有10个碳原子的双环亚烷基；
R2是氢，硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、低级烷基、低级亚烷基甲基、低级烷氧基或卤素；
R3是(ⅰ)未取代的或被一个或多个取代基取代的苯基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基或被1-3个碳原子的烷基取代的氨基甲酰基、乙酰氧基、羧基、羟基、氨基、被1-5个碳原子的烷基取代的氨基、最多有10个碳原子的烷基，最多有10个碳原子的环烷基、最多有10个碳原子的烷氧基、最多有10个碳原子的环烷氧基、最多有10个碳原子的亚烷基甲基、最多有10个碳原子的环亚烷基甲基、苯基或亚甲二氧基；(ⅱ)吡啶、取代的吡啶、吡咯烷、咪唑(imidizole)、萘或噻吩；(ⅲ)未取代的或被一个或多个取代基取代的4-10个碳原子的环烷基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基，甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、取代的氨基、1-10个碳原子的烷基、1-10个碳原子的烷氧基、苯基；
R4和R5各自独立为氢，或R4和R5结合在一起形成碳-碳键；
Y是-COZ、-C≡N，或1-5个碳原子的低级烷基；
Z是-OH、-NR6R6、-R7或-OR7；
R6是氢或低级烷基；和
R7是烷基或苄基。
较佳的一组式Ⅰ化合物是，其中R1是烷基、最多有10个碳原子的单环烷基、最多有10个碳原子的多环烷基或最多有10个碳原子的苯并环烷基；X是-(CH2)n-或-O-，其中n为0、1、2或3；R2是氢、硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、低级烷基、低级烷氧基、卤素；R4、R5、R6和R7如本文所确定。
第二组较佳的化合物是式Ⅰ中R3是(ⅰ)未取代的或被一个或多个取代基取代的苯基或萘，这些取代基独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基或被1-3个碳原子的烷基取代的氨基甲酰基、乙酰氧基、羧基、羟基、氨基、被1-5个碳原子的烷基取代的氨基、1-10个碳原子的烷基或环烷基、1-10个碳原子的烷氧基或环烷氧基；或(ⅱ)未取代的或被一个或多个取代基取代的4-10个碳原子的环烷基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、取代的氨基、1-10个碳原子的烷基、1-10个碳原子的烷氧基或苯基。
特别佳的腈类是有下式的化合物
Figure A9719725100121
ⅡA或
Figure A9719725100122
ⅡB
其中：
(a)X是-O-或-(CnH2n)-，其中n的值为0、1、2或3,R1是最多有10个碳原子的烷基、最多有10个碳原子的单环烷基、最多有10个碳原子的多环烷基或最多有10个碳原子的苯并环烷基，或
(b)X是-CH=,R1是最多有10个碳原子的亚烷基或最多有10个碳原子的单环亚烷基；
R2是氢、硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、低级烷基、低级烷氧基或卤素；和
R3是(ⅰ)未取代的或被一个或多个取代基取代的苯基或萘基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基或被1-3个碳原子的烷基取代的氨基甲酰基、乙酰氧基、羧基、羟基、氨基、被1-5个碳原子的烷基取代的氨基、1-10个碳原子的烷氧基或环烷氧基；或(ⅱ)未取代的或被一个或多个取代基取代的4-10个碳原子的环烷基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、取代的氨基、1-10个碳原子的烷基、1-10个碳原子的烷氧基、苯基。
特别佳的链烷酸衍生物是有下式的化合物：ⅢA或
Figure A9719725100132
ⅢB
其中：
(a)X是-O-或-(CnH2n)-，其中n的值为0、1、2或3,R1是最多有10个碳原子的烷基、最多有10个碳原子的单环烷基、最多有10个碳原子的多环烷基或最多有10个碳原子的苯并环烷基，或
(b)X是-CH=,R1是最多有10个碳原子的亚烷基或最多有10个碳原子的单环亚烷基；
R2是氢、硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、低级烷基、低级烷氧基或卤素；
R3是(ⅰ)未取代的或被一个或多个取代基取代的苯基或萘基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基或被1-3个碳原子的烷基取代的氨基甲酰基、乙酰氧基、羧基、羟基、氨基、被1-5个碳原子的烷基取代的氨基、1-10个碳原子的烷基或环烷基、1-10个碳原子的烷氧基或环烷氧基；或(ⅱ)未取代的或被一个或多个取代基取代的4-10个碳原子的环烷基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、取代的氨基、1-10个碳原子的烷基、1-10个碳原子的烷氧基或苯基；和
Z是-OH、-NR6R6、-R7或-OR7，其中R6是氢或低级烷基；和R7是烷基或苄基。
这里所用的术语烷基指单价饱和的直链或支链烃。除非另有所述，这些链可以含有1-18碳原子。这些烷基的典型例子是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基、己基、异己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基等。当定为“低级”时，烷基则含有1-6个碳原子。相同的碳含量适用于母代术语“链烷”和衍生物术语如“烷氧基”。
这里所用的环烷基指单价饱和的环烃链。除非另有所述，这些链最多含有18个碳原子。单环烷基指有一个环的基团。多环烷基指含有两个或多个环体系(常见的有两个或多个环碳原子)的烃体系。苯并环烷基指与苯并基团稠合的单环烷基。单环烷基的典型例子是环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、环十三烷基、环十四烷基、环十五烷基、环十六烷基、环十七烷基和环十八烷基。多环烷基的典型例子包括双环[2.2.1]庚基、双环[3.2.1]辛基和双环[2.2.2]辛基。苯并环烷基的典型例子是四氢萘基、2,3-二氢化茚基和1,2-苯并环庚酰基。
化合物可用已知的制备二芳基链烯的通用方法来制得。例如，可用氰基甲基磷酸二烷酯来处理合适取代的二(芳基)酮，生成相应的二芳基丙烯腈。它本身可用已知的方法水解成相应的羧酸、酯和酰胺。或者，取代的二(芳基)酮可用二取代的膦酰基乙酸烷酯或二取代的氨基甲酰基甲基膦酸酯和六甲基二硅氮化锂(lithium hexamethyldisilazide)处理，分别直接形成酯或酰胺。取代的二(芳基)酮也可用合适的三苯基亚磷酸盐处理。
Figure A9719725100141
二(芳基)酮本身也可用已知的方法(例如在路易斯酸存在下与酰基氯发生弗瑞德-克来福特酰化作用)制得。
这些化合物的典型例子包括3,3-二-(3,4-二甲氧基苯基)丙烯腈、3,3-二-(3-乙氧基-4-甲氧基苯基)丙烯腈、3,3-二(3-乙氧基-4-甲氧基苯基)丙烯酸甲酯、3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙烯酸甲酯、3-(3-丙氧基-4-甲氧基苯基)-3-苯基丙烯腈、3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙烯腈、3,3-二-(3-环戊氧基-4-甲氧基-苯基)丙烯腈、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙烯酸甲酯、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙烯腈、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙烯、1-(3-环戊氧基-4-甲氧基苯基)-1-苯基-丙烷、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙腈、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙酸甲酯、3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙腈、3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙酸甲酯、3,3-二-(3,4-二甲氧基苯基)丙腈、3,3-二-(3-乙氧基-4-甲氧基苯基)丙腈、3-(3,4-二甲氧基苯基)-3-苯基丙烯腈、3-(3-乙氧基-4-甲氧基苯基)-3-萘基丙腈、3-(3,4-二甲氧基苯基)-3-苯基丙腈和3-(3,4-二甲氧基苯基)-3-(3-乙氧基-4-甲氧基苯基)丙腈。
另一组较佳的化合物包括4,4-二-(3,4-二甲氧基苯基)-丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-(3-乙氧基-4-甲氧基苯基)丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-苯基丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-(3-环戊氧基-4-甲氧基苯基)丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-(3-2,3-二氢化茚-2-基氧-4-甲氧基苯基)丁-3-烯-2-酮、4-(3-乙氧基-4-甲氧基苯基)-4-(4-吡啶基)丁-3-烯-2-酮、4-(3-乙氧基-4-甲氧基苯基)-4-(4-吡啶基)丁-2-酮、4-(3-环戊氧基-4-甲氧基苯基)4-(4-吡啶基)丁-3-烯0-酮、4-(3-环戊氧基-4-甲氧基苯基)-4-(4-吡啶基)丁-2-酮；3-(3-环戊氧基-4-甲氧基苯基)-3-(4-吡啶基)丙-2-烯酸甲酯、3-(3-乙氧基-4-甲氧基苯基)-3-(4-吡啶基)丙-2-烯酸甲酯、3-(3-乙氧基-4-甲氧基苯基)-3-(4-吡啶基)丙酸甲酯、4-(-3-乙氧基-4-甲氧基苯基)-4-(2-呋喃基)丁-3-烯-2-酮、3-(3-乙氧基-4-甲氧基苯基)-3-(2-呋喃基)丙-2-烯腈、3-(3-乙氧基-4-甲氧基苯基)-3-(4-吡啶基)丙-2-烯腈、3-(3-乙氧基-4-甲氧基苯基)-3-(4-吡啶基)丙腈、3-(3-环戊氧基-4-甲氧基苯基)-3-(4-吡啶基)丙-2-烯腈、3-(3-环戊氧基-4-甲氧基苯基)-3-(4-吡啶基)丙腈、4-(3,4-二甲氧基苯基)-4-(4-甲氧基-3-丙-1-烯苯基)丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-(4-甲氧基-3-丙-1-烯苯基)丁-3-烯-2-酮、4,4-二-(3,4-二甲氧基苯基)丁-2-酮、4-(3,4-二甲氧基苯基)-4-(3-乙氧基-4-甲氧基苯基)丁-2-酮、4-(3,4-二甲氧基苯基)-4-(3-(环亚戊基甲基)-4-甲氧基苯基)丁-2-酮、4-(3,4-二甲氧基苯基)-4-(4-甲氧基-3-丙-1-烯苯基)丁-2-酮、4,4-二-(3-乙氧基-4-甲氧基苯基)丁-3-烯-2-酮、3-(3,4-二甲氧基苯基)-3-(3-(环亚戊基甲基)-4-甲氧基苯基)丙-2-烯腈、3-(3-(环亚戊基甲基)-4-甲氧基苯基)-3-苯基-丙-2-烯腈、1-(3,4-二甲氧基苯基)-1-(3-乙氧基-4-甲氧基苯基)戊-3-酮、1-(3,4-二甲氧基苯基)-1-(3-乙氧基-4-甲氧基苯基)戊-1-烯-3-酮、1,1-二-(3,4-二甲氧基苯基)戊-3-酮、3-(3,4-二甲氧基-苯基)-3-(3-(环亚戊基甲基)-4-甲氧基苯基)丙-2-烯腈、3-(3-(环亚戊基甲基)-4-甲氧基苯基)-3-苯基-丙腈、3,3-二-(3-(环亚戊基甲基)-4-甲氧基苯基)丙腈、3,3-二-(3-(环亚戊基甲基)-4-甲氧基苯基)丙-2-烯腈、3-(3,4-二甲氧基苯基)-3-(3-(环亚戊基甲基)-4-甲氧基苯基)丙-2-烯酰胺、3-(3-(环亚戊基甲基)-4-甲氧基苯基-3-苯基)丙酰胺、3,3-二-(3-(环亚戊基甲基)-4-甲氧基苯基)丙酰胺、3,3-二-(3-(环亚戊基甲基)-4-甲氧基-苯基)丙-2-烯酰胺、3-(3,4-二甲氧基苯基)-3-(3-乙氧基-4-甲氧基苯基)-丙-2-烯酰胺、3,3-二-(3-乙氧基-4-甲氧基苯基)丙-2-烯酰胺、3,3-二-(3,4-二甲氧基苯基)丙-2-烯酰胺、3,3-二-(3-乙氧基-4-甲氧基苯基)丙酰胺、3,3-二-(3,4-二甲氧基苯基)丙酰胺、4-(3,4-二甲氧基苯基)-4-(4-甲氧基-3-外-降冰片氧基苯基)丁-3-烯-2-酮、3-(3,4-二甲氧基苯基)-3-(4-甲氧基-3-外-降冰片氧基苯基)丙-2-烯腈、3-(3,4-二甲氧基苯基)-3-(3,4-亚甲二氧基苯基)丙-2-烯腈、3-(4-氨基苯基)-3-(3,4-二甲氧基苯基)-丙-2-烯腈和3-(4-氨基苯基)-3-(3-乙氧基-4-二甲氧基苯基)丙-2-烯腈。
这些化合物具有一个或多个手性中心，因此可以存在旋光异构体。这些异构体的外消旋体和各异构体本身以及非对映异构体(当有两个或多个手性中心时)包括在本发明范围内。外消旋体可直接使用，或可用物理方法，如通过使用手性吸附剂的色谱法将其分离成各个异构体。或者，可以将各个异构体制成手性形式，或用化学方法，通过与手性酸成盐从混合物中分离各个异构体，例如，10-樟脑磺酸、樟脑酸、α-溴代樟脑酸、甲氧基乙酸、酒石酸、二乙酰基酒石酸、苹果酸、吡啶烷酮-5-羧酸等的各个对映体，然后使解析的一种或两种碱游离出来，任意地重复此过程，以获得基本不含另一种的任何一种或两种异构体，即光学纯度＞95％的形式。另外，R4和R5结合在一起形成碳-碳键的化合物可以以顺式(Z)和反式(E)异构体存在。
在专业技术人员的管理下，该化合物可用来抑制TNFα、NFκB和磷酸二酯酶的不良效应。化合物可以单独地或与其它包括抗生素、类固醇等在内的治疗剂组合对需要治疗的哺乳动物进行口服给药、直肠给药或肠胃外给药。
口服剂型包括片剂、胶囊剂、糖衣剂，及类似形状的压制的药物剂型。可用含20-100mg/ml的等渗盐水溶液作为非胃肠道给药，包括肌肉、鞘内、静脉和动脉途径给药。使用从常规载体如可可脂制成的栓剂可进行直肠给药。
剂量方案必须根据患者特定的适应征、年龄、体重和总的生理状况和需要的应答来定，但是剂量通常在约1-1000毫克/天内，一天可给药一次或几次。通常，最初的治疗方案可以来自用本发明化合物治疗其它TNFα介导的病征使有效干扰TNFα活性的已知量。定期检查受治疗者的T细胞数目和T4/T8比，和/或测定病毒血症如逆转录酶或病毒蛋白的水平，和/或细胞因子介导的疾病伴随的问题(如恶病质或肌肉退化)的进展。如果在正常治疗方案后没有观察到有任何效果，则增加细胞因子活性干扰剂的给药量，例如1星期增加50％。
本发明的化合物还可局部用于由过量TNFα的产生分别介导或加剧的局部病症的治疗或预防，例如病毒感染(如由疱疹病毒引起的感染)或病毒性结膜炎、牛皮癣、其它皮肤疾病等。
这些化合物还可用于需要阻止或抑制TNFα产生的人以外的哺乳动物的兽医治疗。处理(治疗或预防)TNFα介导的动物体内的疾病包括上面所述的那些病症，但特别是病毒感染。例子包括猫免疫缺陷病毒、马感染性贫血病毒、羊关节炎病毒、绵羊脱髓鞘性脑白质炎病毒和羊进行性间质肺炎病毒，以及其它慢病毒(lentiviruse)。
这些化合物对PDEⅢ、PDEⅣ、TNFα和NFκB的抑制作用可方便地用该领域已知方法来测定，例如酶免疫测定、放射免疫测定、免疫电泳、亲和标记等，其中下面的测定方法是典型方法。
TNFα的酶联免疫吸附测定
PBMC分离：用Ficoll-Hypaque密度离心从正常供体中获得PBMC。将细胞培育在补加10％AB+血清、2mM L-谷氨酰胺、100U/mL青霉素和100mg/mL链霉素的RPMI中。
PBMC悬液：将药物溶解在二甲亚砜(Sigma Chemical)中，然后稀释在补加的RPMI中。PBMC悬液中有或没有药物存在时的二甲亚砜最终浓度均为0.25％(重量)。以半对数稀释、起始为50mg/mL来测定药物。在加入LPS前一小时，将药物加入96孔板的PBMC(106细胞/mL)中。
细胞刺激：用1mg/mL来自明尼苏达沙门氏菌(Salmonella minnesota)R595(List Biological Labs,Campbell,CA)的LPS处理来刺激有或没有药物存在的PBMC(106细胞/mL)。然后将细胞培育在37℃下18-20小时。收获上清液，立即测定TNFα水平或保藏在-70℃(不超过4天)下直至测定。
TNFα测定：
用人TNFα ELISA试剂盒(ENDOGEN,Boston,MA)根据生产商的说明测定上清中的TNFα浓度。
磷酸二酯酶可用常规模型来测定。例如，用Hill和Mitchell的方法，使人的前单核细胞系的U937细胞生长至1×106细胞/mL，离心收集。用磷酸盐缓冲的盐水溶液洗涤1×109细胞的细胞沉淀，然后冷冻在-70℃下，以便以后的纯化或立即在冷的匀浆缓冲液(20mM Tris-HCl,pH7.1,3mM 2-巯基乙醇，1mM氯化镁，0.1mM乙二醇-二-(β-氨基乙基醚)-N,N,N′,N′-四乙酸(EGTA),1μM苯基甲基磺酰氟(PMSF)和1μg/mL亮抑蛋白酶肽)中进行裂解。使细胞在Dounce匀浆机中打击20次进行匀浆，离心获得含有胞质级分的上清液。然后将上清液上样于匀浆缓冲液平衡过的Sephacryl S-200柱。用匀浆缓冲液以约0.5mL/分钟的的速度洗脱膦酸二酯酶，并测定磷酸二酯酶活性-/+环戊苯吡酮的级分。合并含有磷酸二酯酶活性(环戊苯吡酮敏感)的级分并等分，以便以后的使用。
磷酸二酯酶的测定根据Hill和Mitchell描述的步骤进行。测定在100μl的总体积中进行，总体积中含有各种浓度的测试化合物、50mM Tris-HCl,pH7.5,5mM氯化镁和1μM cAMP(其中1％是3H cAMP)。使反应物在30℃下培育30分钟，然后煮沸2分钟终止反应。用于这些试验的含有磷酸二酯酶Ⅳ的抽提物的量是预先确定的，以使反应在线性范围内，并消耗少于15％的总底物。在反应终止后，使样品在4℃冷却，然后在30℃用10μl 10mg/mL蛇毒处理15分钟。然后加入200μl季铵离子交换树脂(AGI-X8,BioRad)维持15分钟，除去未用的底物。然后使样品在3000rpm下旋转5分钟，取50μl水相进行计算。每个数据点重复进行两次，活性用对照百分比表达。然后从最少三个独立试验的剂量响应曲线确定化合物的IC50。
下列实施例用来进一步列举本发明的特征，但是不应认为其限制了本发明的范围，本发明的范围只由所附权利要求确定。
                      实施例1
           3,3-二-(3,4-二甲氧基苯基)丙烯腈
A．3,4,3′,4′-四甲氧基二苯甲酮
在氮气下搅拌的冰浴冷却的藜芦醚(veratole)(2.07g,15.0mg,在30mL二氯甲烷中)溶液中加入氯化铝(2.20g,16.5mmol)。稍有放热。然后在反应混合物中加入3,4-二甲氧基苯甲酰氯(30.1g,15.0mmol)和20mL二氯甲烷。然后将反应物温热至室温，回流加热3.5小时，然后在室温下搅拌16小时。然后将反应混合物倒入50mL冰水中，搅拌15分钟。用二氯甲烷萃取该混合物(2次，每次25mL)。合并的萃取物用硫酸钠干燥，并真空浓缩成褐色固体的粗品。粗品用闪蒸色谱(硅胶，4/96乙酸乙酯/二氯甲烷)纯化，形成白色粉末状的产物2.97g(66％):1HNMR(CDCl3)δ7.4(m,4H),6.91(m,2H),3.97(s,6H),3.95(s,6H)；13C NMR(DMSO-d6)δ194.4,152.5,148.8,130.7,124.7,112.2,109.7,56.0.分析计算值为C17H18O5。理论值：C,67.54；H,6.00。实测值：C,67.42；H,6.03。
B．3,3-二-(3′,4′,-二甲氧基苯基)丙烯腈
在冰浴冷却的、搅拌的、氢化钠(5.0mmol，在20mL四氢呋喃中)悬浮液中通过注射器滴加入0.8mL氰基甲基膦酸二乙酯。将混合物温热至室温，然后加入3,4,3′,4′-四甲氧基二苯甲酮(1.51g,5.00mmol)和10mL四氢呋喃。搅拌混合物5天，然后用100mL水淬灭。然后用二氯甲烷萃取该反应混合物(50mL和25mL)。用硫酸钠干燥合并的萃取物，并浓缩成油状粗品。粗品用闪蒸色谱纯化，获得白色蜡状产物：1H NMR(CDCl3)δ7.95(br m,6H),5.57(s,1H),3.94(s,3H),3.92(s,3H),3.87(s,3H),3.84(s,3H)；13C NMR(DMSO-d6)δ162.4,151.0,150.5,148.8,148.5,131.8,129.5,123.2,122.2,118.6,112.7,111.4,110.7,110.7,91.9,56.0,55.9,55.9。
                           实施例2
  顺式和反式3-(3,4-二甲氧基苯基)-3-(3-乙氧基-4-甲氧基苯基)丙烯腈
A．3,4-二甲氧基-3-乙氧基-4-甲氧基二苯甲酮
在冰浴冷却的、搅拌的3-乙氧基-4-甲氧基苯甲酸(0.98g,5.0mmol，在20mL二氯甲烷中)悬浮液中加入草酰氯(0.44mL,5.0mmol)和2滴N,N-二甲基甲酰胺(二甲基甲酰胺)。在室温下搅拌获得的黄色混合物35分钟，此时形成一溶液。使溶液在冰浴中冷却，然后加入藜芦醚(0.64mL,5.0mmol)，再加入氯化铝(0.73g,5.5mmol)。移去冰浴，在室温下搅拌混合物。用HPLC(Waters Nova-Pak/C,8柱3.9×150mm,4微米，1mL/分钟，35/65丙烯腈/0.1％水性磷酸)控制反应，37小时后反应完成。将反应混合物倒入30mL冰中，搅拌30分钟，然后用二氯甲烷萃取(3×20mL)。依次用水性碳酸氢钠(30mL)、水(2×50mL)和盐水(50mL)洗涤二氯甲烷萃取物。然后对有机层进行硫酸镁干燥、过滤和真空浓缩，获得棕色固体1.05g。粗品用闪蒸色谱(硅胶，5％乙酸乙酯/二氯甲烷)纯化，然后真空干燥(60℃,＜1mmHg)获得的产物，得0.8g(51％)产物：熔点122-124.5℃；1H NMR(CDCl3)δ7.48-7.34(m,4H),6.98-6.86(m,2H),4.16(q,J=7Hz,2H),3.96(s,3H),3.96(s,3H),3.94(s,3H),1.49(t,J=7Hz,3H)；13C NMR(CDCl3)δ194.4,152.8,152.2,148.8,148.0,130.7,130.6,124.6,124.5,113.5,112.2,109.9,109.7,64.3,55.9,55.9,14.6；HPLC(Waters Nova-Pak/C,8柱3.9×150mm,4微米，1mL/分钟，35/65丙烯腈/0.1％水性磷酸)8分钟，99％；分析计算值为C18H20O5。理论值：C,68.34；H,6.37。实测值：C,68.56；H,6.51。
B．顺式和反式3-(3,4-二甲氧基苯基)-3-(3-乙氧基-4-甲氧基苯基)丙烯腈
在冰浴冷却的搅拌的氰基甲基膦酸二乙酯(0.9mL,5.5mmol,15mL四氢呋喃中)溶液中加入1.3M的六甲基二硅氮化锂(4.2mL,5.5mmol，四氢呋喃中)溶液。将溶液温热至室温，搅拌30分钟，然后加入20mL四氢呋喃中的3,4-二甲氧基-3-乙氧基-4-甲氧基二苯甲酮(1.58g,5.00mmol)淤浆。反应混合物在室温下搅拌21小时，然后用100mL水淬灭。获得的混合物用二氯甲烷萃取(2×50mL)。合并的萃取物用水洗涤，用硫酸镁干燥并真空浓缩，获得橙色油状粗品。粗品用闪蒸色谱(硅胶，3％乙酸乙酯/二氯甲烷)纯化，然后从己烷/乙基中重结晶出来。然后真空干燥(40℃,＜1mmHg)获得的产物，获得0.6g(35％)白色固体产物：熔点103-106℃；1H NMR(CDCl3)δ7.10-6.75(m,6H),5.55(s,1H),4.17-3.76(m,11H),1.54-1.36(m,3H)；13C NMR(CDCl3)δ162.5,151.0,150.8,150.5,148.8,148.6,148.1,147.8,131.9,131.7,129.6,129.5,123.2,123.1,122.1,122.0,118.6,114.2,112.9,112.8,111.4,110.9,110.9,110.7,91.8,64.5,56.0,55.9,14.6；HPLC(Waters Nova-Pak/C,8柱3.9×150mm,4微米，1mL/分钟，45/55丙烯腈/0.1％水性磷酸)7分钟，100％；分析计算值为C20H21NO4。理论值：C,70.78；H,6.24；N,4.13。实测值：C,70.62；H,6.21；N,4.07。
                      实施例3
         3-(3,4-二甲氧基苯基)-3-苯基乙酸酯
A．3,4-二甲氧基二苯甲酮
3,4-二甲氧基二苯甲酮的制备与3,4,3′,4′-四甲氧基二苯甲酮类似，采用藜芦醚(2mL,15mmol)、氯化铝(2.2g,16.5mmol)和苯甲酰氯(1.8mL,15.5mmol)。粗品混合物用闪蒸柱色谱(硅胶，3％乙酸乙酯/二氯甲烷)纯化，获得3.44g(93％)白色固体产物：熔点99-100℃；1H NMR(CDCl3)δ7.82-7.30(m,7H),6.95-6.85(m,1H),3.96(s,3H),3.94(s,3H)；13C NMR(CDCl3)δ195.5,153.0,149.0,138.2,131.8,130.2,129.6,128.1,125.4,112.1,109.7,56.0,56.0；分析计算值为C15H14O3。理论值：C,74.36；H,5.82。实测值：C,74.21；H,6.01。
B．3-(3,4-二甲氧基苯基)-3-苯基乙酸酯(反式和顺式异构体)
3-(3,4-二甲氧基苯基)-3-苯基乙酸酯的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸酯类似，采用3,4-二甲氧基二苯甲酮(4.8g,20mmol)、三甲基膦酰基乙酸酯(4.1g,22mmol)和六甲基二硅氮化锂(22mL,22mmol,1M)，在回流下反应138小时。粗品混合物用闪蒸柱色谱(硅胶，1％乙酸乙酯/二氯甲烷)纯化，获得14.39g(73％)油状的反式和顺式异构体的混合物。异构体通过其它纯化(硅胶，1％乙酸乙酯/二氯甲烷)来分离，获得各异构体的纯样品。
异构体1:1H NMR(CDCl3)δ7.40-7.36(m,3H),7.62-7.20(m,2H),6.88(s,1H),6.80(s,2H),6.30(s,1H),3.88(s,3H),3.82(s,3H),3.60(s,3H)；13C NMR(CDCl3)δ166.5,156.9,150.4,148.7,138.9,133.4,129.1,128.1,128.0,127.8,122.1,114.9,110.8,110.6,55.9,55.8,51.1；分析计算值为C18H18O4。理论值：C,72.47；H,6.08。实测值：C,72.08；H,6.11。
异构体2:1H NMR(CDCl3)δ7.35-7.32(m,5H),6.90-6.83(m,2H),6.73(s,1H),6.30(s,1H),3.92(s,3H),3.81(s,3H),3.64(s,3H)；13C NMR(CDCl3)δ166.6,156.7,149.2,148.3,141.2,131.1,129.4,128.5,128.3,122.4,116.4,112.7,110.4,55.8,55.7,51.2；分析计算值为C18H18O4。理论值：C,72.47；H,6.08。实测值：C,72.28；H,5.94。
                            实施例4
    3-苯基-3-(3′-乙氧基-4-甲氧基苯基)丙烯酰胺(反式和顺式异构体)
丙烯酰胺的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸酯类似,采用3-乙氧基-4-甲氧基二苯甲酮(0.3g,1.2mmol)，氨基甲酰基甲基膦酸二乙酯(0.25g,1.3mmol)和六甲基二硅氮化锂(1mL,1.3mmol,1.3M)，在回流下反应54小时。粗品混合物用闪蒸柱色谱(硅胶，45％乙酸乙酯/二氯甲烷)纯化，获得0.06g(17％)油状的反式和顺式异构体的混合物：1H NMR(CDCl3)δ7.54-7.19(m,10H),7.00-6.65(m,6H),6.34(s,2H),5.54(s,1H),5.55(s,1H),5.24(s,1H),5.04(s,1H),4.16(m,4H),3.92(s,3H),3.87(s,3H),1.60-1.33(m,6H)；13C NMR(CDCl3)δ168.7,168.6,150.8,150.4,149.7,148.4,148.0,140.7,138.2,133.0,130.2,129.2,129.1,128.8,128.3,128.0,121.9,121.6,120.0,113.7,111.9,111.4,110.8,64.4,64.3,55.9,14.6；分析计算值为C18H19NO3·0.35H2O。理论值：C,71.19；H,6.54；N,4.61。实测值：C,71.19；H.6.68；N.4.45。
                         实施例5
    1-(3,4-二甲氧基苯基)-1-苯基丙-1-烯(反式和顺式异构体)
1-(3,4-二甲氧基苯基)-1-苯基丙-1-烯的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸甲酯类似，用3,4-二甲氧基二苯甲酮(3g,12.4mmol)，(乙基)三苯基溴化鏻(5,1g,13.6mmol)和六甲基二硅氮化锂(13.6mL,13.6mmol,1M)，在室温下反应4小时。粗品混合物用闪蒸柱色谱(硅胶，10％己烷/二氯甲烷)纯化，获得1.3g(41％)反式和顺式异构体的白色固体混合物：熔点72-73℃；1H NMR(CDCl3)δ7.40-6.80(m,16H),6.16-6.08(m,2H),3.90-3.80(m,12H),1.97-1.73(m,6H)；13C NMR(CDCl3)δ148.6,148.5,148.1,147.8,142.9,142.3,142.0,140.0,136.0,132.5,129.9,128.0.128.0,127.1,126.7,126.6,123.8,122.6,122.5,119.8,113.6,110.8,110.7,110.4,55.8,55.8,55.7,15.7,15.5；分析计算值为C17H18O2。理论值：C,80.28；H,7.13。实测值：C,79.94；H,7.12。
                             实施例6
1-(3,4-二甲氧基苯基)-1-(3-乙氧基-4-甲氧基苯基)丙-1-烯(反式和顺式异构体)
1-(3,4-二甲氧基苯基)-1-(3-乙氧基-4-甲氧基苯基)丙-1-烯的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸甲酯类似，用3,4-二甲氧基-3′-乙氧基-4′-甲氧基二苯甲酮(1.6g,5mmol)，(乙基)三苯基溴化鏻(2.04g,5.5mmol)和六甲基二硅氮化锂(4.2mL,5.5mmol,1.3M)，在室温下反应24小时。粗品混合物用闪蒸柱色谱(硅胶，10％己烷/二氯甲烷)纯化，获得0.8g(49％)反式和顺式异构体的白色固体混合物：熔点65.5-68℃；1H NMR(CDCl3)δ6.95-6.65(m,12H),6.14-6.00(m,2H),4.11-3.78(m,22H),1.86-1.74(m,6H),1.50-1.36(m,6H)；13C NMR(CDCl3)δ148.5,148.4,148.1,147.7,141.8,141.7,136.1,136.0,132.6,132.5,122.5,122.3,119.7,114.7,113.1,111.9,111.0,110.7,110.4,55.9,55.8,55.8,55.7,15.7,14.7；分析计算值为C20H24O4。理论值：C,73.15；H,7.37。实测值：C,73.33；H,7.39。
                          实施例7
1-(3,4-二甲氧基苯基)-1-(3-乙氧基-4-甲氧基苯基)丁-1-烯(反式和顺式异构体)
1-(3,4-二甲氧基苯基)-1-(3-乙氧基-4-甲氧基苯基)丁-1-烯的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸甲酯类似，用3,4-二甲氧基-3′-乙氧基-4′-甲氧基二苯甲酮(1g,3.2mmol)，丙基三苯基溴化鏻(1.34g,3.5mmol)和六甲基二硅氮化锂(2.7mL,3.5mmol,1.3M)，在室温下反应2.5小时。粗品混合物用闪蒸柱色谱(硅胶，二氯甲烷)纯化，然后进行Kugelrohr蒸馏，获得0.77g(71％)反式和顺式异构体的油状混合物：1H NMR(CDCl3)δ6.92-6.65(m,12H),6.02-5.89(m,2H),4.12-3.96(m,4H),3.92(s,3H),3.91(s,3H),3.86(s,3H),3.85(s,3H),3.82(s,3H),3.81(s,3H),2.22-2.04(m,4H),1.51-1.38(m,6H),1.14-0.98(m,6H)；13C NMR(CDCl3)δ148.5,148.1,147.8,147.7,140.4,140.4,136.0,135.9,133.0,132.9,130.1,130.0,122.2,119.8,114.6,113.1,112.0,111.0,110.7,110.4,64.3,64.2,55.9,23,2,14.8,14.7；分析计算值为C21H26O4。理论值：C,73.66；H,7.65。实测值：C,73.32；H,7.26。
                           实施例8
    3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙烯腈(反式和顺式异构体)
3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙烯腈的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸酯类似，用3-乙氧基-4-甲氧基二苯甲酮(1.3g,5mmol)，二乙基氰基甲基膦酸酯(0.9g,5.5mmol)和六甲基二硅氮化锂(4.2mL,5.5mmol,1.3M)，在室温下反应24小时。粗品混合物用闪蒸柱色谱(硅胶，二氯甲烷)纯化，获得1.35g(96％)反式和顺式异构体的白色固体混合物：熔点74-77℃；1H NMR(CDCl3)δ7.50-7.24(m,10H),7.07-6.75(m,6H),5.67(s,1H),5.60(s,1H),4.15-3.95(m,4H),3.92(s,3H),3.89(s,3H),1.50-1.36(m,6H)；13C NMR(CDCl3)δ162.8,162.7,151.4,150.9,148.1,147.1,147.9,139.3,137.1,131.3,130.2,129.9,129.5,129.3,128.6,128.5,128.4,123.1,122.0,118.3,118.2,113.9,112.5,110.9,93.9,92.9,64.4,55.9,55.9,14.6；分析计算值为C18H17NO2。理论值：C,77.40；H,6.13；N,5.01。实测值：C,77.14；H,6.06；N,4.75。
                          实施例9
             3-(3-乙氧基-甲氧基苯基)-3-苯基丙腈
在3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙烯腈(0.9g,3.2mmol，在乙醇/乙酸乙酯(20mL/30mL)的混合物中)溶液中加入0.5g 10％钯碳催化剂。使混合物在Parr-Shaker装置中55-60psi氢气氛下氢化12天。使反应混合物通过塞利石过滤，将滤液真空浓缩成粗品。粗品用闪蒸柱色谱(硅胶，4％己烷/二氯甲烷)纯化，获得0.15g(15％)油状产物：1H NMR(CDCl3)δ7.40-7.16(m,5H),6.88-6.78(m,3H),4.32(t,J=7.5Hz,1H),4.03(q,J=7Hz,2H),3.85(s,3H),3.00(d,J=7.5Hz,2H),1.42(t,J=7Hz,3H)；13C NMR(CDCl3)δ148.7,148.5,141.5,133.7,128.8,127.4,127.3,119.5,118.5,112.7,111.6,64.4,55.9,46.7,24.5,14.7；分析计算值为C18H17NO2。理论值：C,76.84；H,6.81；N,4.98。实测值：C,76.53；H,6.92；N,4.95。
                        实施例10
  3-(3,4-二甲氧基苯基)-3-(3′,5′-二甲氧基苯基)丙烯腈(反式和顺式异构体)
A．3,4,3′,5′-四甲氧基二苯甲酮
3,4,3′,5′-四甲氧基二苯甲酮的制备与4-(3,4-二甲氧基苯甲酰基)吡啶类似，用丁基锂(9mL,22mmol,2.5M),4-溴藜芦醚(2.9mL,20mmol)和3,5-二甲氧基苄腈(3.75g,23mmol)。粗品用闪蒸柱色谱(硅胶，二氯甲烷)纯化，获得1.54g(26％)产物：熔点107-110℃；1H NMR(CDCl3)δ7.53-7.39(m,2H),6.95-6.84(m,3H),6.70-6.60(m,1H),3.96(s,3H),3.95(s,3H),3.83(s,6H)；13C NMR(CDCl3)δ195.0,160.4,153.0,148.9,140.1,130.0,125.4,112.0,109.7,107.5,104.1,56.0,55.5；分析计算值为C17H18O5。理论值：C,67.54；H,6.00。实测值：C,67.38；H,5.96。
B．3-(3,4-二甲氧基苯基)-3-(3′,5′-二甲氧基苯基)丙烯腈
3-(3,4-二甲氧基苯基)-3-(3′,5′-二甲氧基苯基)丙烯腈的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸酯类似，用3,4,3′,5′-四甲氧基二苯甲酮(0.7g,2.3mmol)，二乙基氰基甲基膦酸酯(0.42mL,2.5mmol)和六甲基二硅氮化锂(1.9mL,2.5mmol,1.3M)，在室温下反应60小时。粗品用闪蒸柱色谱(硅胶，1％乙酸乙酯/二氯甲烷)纯化，获得0.66g(81％)反式和顺式异构体的白色固体混合物：熔点88-90℃；1HNMR(CDCl3)δ7.10-6.80(m,6H),6.61-6.40(m,6H),5.66(s,1H),5.61(s,1H),3.94(s,3H),3.91(s,3H),3.87(s,3H),3.84(s,3H),3.80(s,3H),3.77(s,6H)；13C NMR(CDCl3)δ162.7,162.5,160.7,160.6,151.1,150.6,148.8,148.5,141.3,138.9,131.1,129.2,123.2,122.1,118.2,118.0,112.6,110.9,110.7,110.7,107.6,107.0,102.1,102.0,93.4,93.1,56.0,55.9,55.5,55.4；分析计算值为C19H19NO4。理论值：C,70.14；H,5.89；N,4.30。实测值：C,70.33；H,5.89；N,4.03。
                          实施例11
       3-(3,4-二甲氧基苯基)-3-(3′-硝基苯基)丙烯腈
A．3,4-二甲氧基-3′-硝基二苯甲酮
在氮气下搅拌的冰浴冷却的藜芦醚(2.55mL,20mmol，在二氯甲烷(30mL)中)溶液中加入氯化铝(2.93g,22mmol)。稍有放热。在获得的混合物中加入在30mL二氯甲烷中的3-硝基苯甲酰氯(3.8g,20mmol)。然后将反应温热至室温，然后回流加热。回流5小时后，使反应物冷却至室温并搅拌72小时。然后将反应混合物倒入100mL冰水中搅拌20分钟。用CH2Cl2萃取该混合物(3×60mL)。用硫酸镁干燥有机层，真空浓缩，获得绿色固体粗品。粗品用闪蒸柱色谱(硅胶，CH2Cl2)纯化，获得2.21g(39％)黄色固体产物：熔点133-135℃；1H NMR(CDCl3)δ8.64-8.56(m,1H),8.49-8.39(m,1H),8.10-8.05(m,1H),7.76-7.65(m,1H),7.55-7.47(m,1H),7.36-7.29(m,1H),7.00-6.87(m,1H),3.99(s,3H),3.97(s,3H)；13C NMR(CDCl3)δ192.8,153.8,149.4,147.9,139.7,135.2,129.5,128.9,126.2,125.6,124.4,11.8,110.0,56.2,56.1；分析计算值为C15H13NO4。理论值：C,67.72；H,4.56；N,4.88。实测值：C,62.74；H,4.59；N,4.89。
B．3-(3,4-二甲氧基苯基)-3-(3′-硝基苯基)丙烯腈
3-(3,4-二甲氧基苯基)-3-(3′-硝基苯基)丙烯腈的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸甲酯类似，用3,4-二甲氧基-3′-硝基二苯甲酮(1.44g,5mmol)，二乙基氰基甲基膦酸酯(0.91mL,5.5mmol)和六甲基二硅氮化锂(4.2mL,5.5mmol,1.3M)，在室温下反应24小时。粗品混合物用闪蒸柱色谱(硅胶，3％己烷/二氯甲烷)纯化，获得1.12g(72％)反式和顺式异构体的黄色固体混合物：熔点117.5-120℃；1H NMR(CDCl3)δ8.40-8.17(m,4H),7.90-7.55(m,4H),7.08-6.89(m,6H),5.84(s,1H),5.71(s,1H),3.95(s,3H),3.92(s,3H),3.88(s,3H),3.85(s,3H)；13CNMR(CDCl3)δ160.2,160.1,151.7,151.1,149.2,148.3,148.2,141.0,138.8,135.4,134.4,129.9,129.7,129.7,128.1,124.8,124.6,124.4,123.3,123.1,122.3,117.4,117.3,112.3,111.0,110.4,95.7,94.8,56.0,55.9；分析计算值为C17H14N2O4。理论值：C,65.80；H,4.55；N,9.03。实测值：C,65.57；H,4.64；N,8.92。
                          实施例12
    3-(3′-氨基苯基)-3-(3,4-二甲氧基苯基)丙烯腈(反式和顺式异构体)
在3-(3,4-二甲氧基苯基)-3-(3′-硝基苯基)丙烯腈(0.7g,2.3mmol，在40mL乙酸乙酯中)溶液中加入0.1g 10％钯碳催化剂。使混合物在Parr-Shaker装置中55-60psi氢气氛下氢化2.5小时。使反应混合物通过塞利石过滤，将滤液真空浓缩成粗品。粗品用闪蒸柱色谱(硅胶，15％乙酸乙酯/二氯甲烷)纯化，获得0.25g(56％)反式和顺式异构体的黄色固体混合物：熔点100-101℃；1H NMR(CDCl3)δ7.30-6.59(m,14H),5.63(s,1H),5.59(s,1H),3.94(s,3H),3.91(s,3H),3.87(s,3H),3.84(s,3H)；13C NMR(CDCl3)δ163.1.162.9,151.1,150.5,148.8,148.7,146.5,146.4,140.4,138.2,131.5,129.5,129.5,129.4,123.2,122.1,119.9,119.0,118.4,118.2,116.8,116.6,115.9,115.0,112.7,11 1.0,110.7,93.3,92.7,56.1,56.0,55.9；分析计算值为C17H16N2O3。理论值：C,72.84；H,5.75；N,9.99。实测值：C,72.48；H,6.05；N,9.58。
                      实施例13
           3,4-二甲氧基-3′-氨基二苯甲酮
在3,4-二甲氧基-3′-硝基二苯甲酮(0.5g,1.7mmol，在40mL乙酸乙酯中)溶液中加入0.05g 10％钯碳催化剂。使混合物在Parr-Shaker装置中55-60psi氢气氛下氢化1.5小时。使反应混合物通过塞利石过滤，将滤液真空浓缩成粗品。粗品用闪蒸柱色谱(硅胶，10％乙酸乙酯/二氯甲烷)纯化，获得0.17g(38％)黄色固体产物：熔点157-175℃；1H NMR(CDCl3)δ7.56-6.80(m,7H),3.95(s,3H),3.94(s,3H)；13C NMR(CDCl3)δ195.7,152.9,148.9,146.4,139.3,130.3,128.9,125.4,120.1,118.4,115.6,112.1,109.7,56.0,56.0；分析计算值为C15H15NO3。理论值：C,70.02；H,5.88；N,5.44。实测值：C,70.00；H,6.10；N,5.13。
                            实施例14
    3-(3,4-二甲氧基苯基)-3-(4-硝基苯基)丙烯腈(反式和顺式异构体)
A．3,4-二甲氧基-4′-硝基二苯甲酮
3,4-二甲氧基-4′-硝基二苯甲酮的制备与3,4-二甲氧基-3′-硝基二苯甲酮类似，采用藜芦醚(3.8mL,30mmol)，氯化铝(4.4g,33mmol)和4-硝基苯甲酰氯(5.7g,30mmol)，回流反应48小时。粗品混合物用闪蒸柱色谱(硅胶，4％乙酸乙酯/二氯甲烷)纯化，获得1.69g(78％)白色固体产物：熔点172-173℃；1H NMR(CDCl3)δ8.43-8.31(m,2H),7.97-7.86(m,2H),7.55-7.46(m,1H),7.40-7.40(m,1H),7.00-6.89(m,1H),3.99(s,3H),3.96(s,3H)；13C NMR(CDCl3)δ193.4,153.8,149.4,149.3,143.8,130.2,130.0,125.8,123.4,111.7,109.9,56.1,56.0；分析计算值为C15H13NO5。理论值：C,62.72；H,4.56；N,4.88。实测值：C,62.49；H,4.68；N,4.86。
B．3-(3,4-二甲氧基苯基)-3-(4′-硝基苯基)丙烯腈
3-(3,4-二甲氧基苯基)-3-(4′-硝基苯基)丙烯腈的制备与3,3-二-(3′,4′-二甲氧基苯基)丙烯酸甲酯类似，采用3,4-二甲氧基-4′-硝基二苯甲酮(4g,14mmol)，二乙基氰基甲基膦酸酯(2.5mL,15.4mmol)和六甲基二硅氮化锂(11.8mL,15.4mmol,1.3M),在室温下反应17小时。粗品用色谱(硅胶，3％己烷/二氯甲烷)纯化，获得2.38g(55％)反式和顺式异构体混合物的黄色固体产物：熔点117.5-120℃；1HNMR(CDCl3)δ8.40-8.20(m,4H),7.70-7.46(m,4H),7.06-6.75(m,6H),5.84(s,1H),5.70(s,1H),3.95(s,3H),3.93(s,3H),3.88(s,3H),3.85(s,3H)；13C NMR(CDCl3)δ160.3,151.7,149.2,148.9,148.7,148.5,148.5,143.5,130.6,129.9,129.6,128.2,123.7,123.1,122.2,117.4,117.3,112.3,111.0,110.5,96.2,94.9,56.0,56.0；分析计算值为C17H14N2O4。理论值：C,65.80；H,4.55；N,9.03。实测值：C,65.45；H,4.66；N,8.82。
                         实施例15
       3-(4-氨基苯基)-3-(3,4-二甲氧基苯基)丙烯腈
3-(4-氨基苯基)-3-(3,4-二甲氧基苯基)丙烯腈的制备与3-(3,4-二甲氧基苯基)-3-(3-氨基苯基)丙烯腈类似，采用3-(3,4-二甲氧基苯基)-3-(4-硝基苯基)丙烯腈(1.24g,4mmol)，和100mL乙酸乙酯中10％钯碳催化剂0.15g。粗品混合物用闪蒸柱色谱(硅胶，5％乙酸乙酯/二氯甲烷)纯化，获得0.19g(17％)反式和顺式异构体黄色固体混合物：熔点150-152℃；1H NMR(CDCl3)δ7.38-6.56(m,14H),5.51(s,1H),5.44(s,1H),3.97(br s,4H),3.93(s,3H),3.91(s,3H),3.85(s.3H),3.82(s,3H)；13CNMR(CDCl3)δ162.8,162.6,150.8,150.3,148.8,148.7,148.5,148.4,132.4,131.4,130.1,129.5,129.9,128.6,126.7,123.0,122.1,114.4,114.3,112.8,111.6,110.7,90.3,89.9,56.0,55.9；分析计算值为C17H16N2O3。理论值：C,72.84；H,5.75；N,9.99。实测值：C,72.79；H,5.83；N,9.59。
                         实施例16
             3,4-二甲氧基-4′-氨基二苯甲酮
3,4-二甲氧基-4′-氨基二苯甲酮的制备与3,4-二甲氧基-3′-硝基二苯甲酮类似，采用3,4-二甲氧基-4′-硝基二苯甲酮(1g,3.5mmol)和110mL乙酸乙酯中的10％钯碳催化剂0.1g。粗品用闪蒸柱色谱(硅胶，12％乙酸乙酯/二氯甲烷)纯化，获得0.32g(36％)黄色固体产物：熔点189-191℃；.1H NMR(CDCl3)δ7.80-7.62(m,2H),7.45-7.29(m,2H),6.96-6.80(m,1H),6.75-6.61(m,2H),4.14(s,2H),3.95(s,3H),3.93(s.3H)；13C NMR(CDCl3)δ194.2,152.2,150.5,148.8,132.6,131.3,128.0,124.3,113.6,112.3,109.7,56.0；分析计算值为C15H15NO3。理论值：C,70.02；H,5.88；N,5.44。实测值：C,69.95；H,6.18；N,5.13。
                        实施例17
       3-(3,4-二甲氧基苯基)-3-(4-甲基苯基)丙烯腈
A．3,4-二甲氧基-4′-甲基二苯甲酮
标题化合物的制备与3,4,3′,4′-四甲氧基二苯甲酮类似，采用藜芦醚(3.9mL,28mmol)、氯化铝(4.1g,31mmol)和4-甲基苯甲酰氯(4.6mL,29mmol)，在室温下反应6小时。粗品混合物用闪蒸柱色谱(硅胶，2％乙酸乙酯/二氯甲烷)纯化，获得4.22g(59％)白色固体产物：熔点121.5-122℃；1H NMR(CDCl3)δ7.70-7.67(d,J=8Hz,2H),7.48-7.26(m,4H),6.91-6,88(d,J=8.3Hz,1H),6.96(s,3H),3.94(s,3H),2.44(s,3H)；13C NMR(CDCl3)δ195.1,152.6,148.8,142.4,135.3,130.3,129.8,128.7,125.0,112.0,109.6,55.9,55.8,21.4；分析计算值为C16H16O3。理论值：C,74.98；H,6.29。实测值：C,74.84；H,6.43。
B．3-(3,4-二甲氧基苯基)-3-(4-甲基苯基)丙烯腈
3-(3,4-二甲氧基苯基)-3-(4-甲基苯基)丙烯腈的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸甲酯类似，采用3,4-二甲氧基-4′-甲基二苯甲酮(2.3g,9mmol)，二乙基氰基甲基膦酸酯(1.8mL,9.9mmol)和六甲基二硅氮化锂(10mL,9.9mmol,1M)，在室温下反应22小时。粗品用色谱(硅胶，1％乙酸乙酯/二氯甲烷)纯化，获得1.83g(73％)反式和顺式异构体的白色固体混合物：熔点83.5-86.5℃；.1HNMR(CDCl3)δ7.35-7.20(m,8H),7.04-6.81(m,6H),5.62(s,1H),5.59(s,1H),3.90(s,3H),3.90(s,3H),3.88(s,3H),3.82(s,3H),2.41(s,3H),2.39(s,3H)；13C NMR(CDCl3)δ162.7,162.6,160.0,l50.4,148.8,148.5,140.6,140.1,136.3,134.1,131.6,129.5,129.2,129.0,128.5,123.0,122.1,118.4,118.3,112.6,111.1,110.7,92.6,92.4,55.9,55.9,55.8,21.3,21.2；分析计算值为C18H17NO2。理论值：C,77.40；H,6.13；N,5.01。实测值：C,77.64；H,5.93；N,5.01。
                       实施例18
       3-(4-联苯基)-3-(3,4-二甲氧基苯基)丙烯腈
A．3,4-二甲氧基-4′-苯基二苯甲酮
3,4-二甲氧基-4′-苯基二苯甲酮的制备与3,4,3′,4′-四甲氧基二苯甲酮类似，采用藜芦醚(2.4g,17mmol)、氯化铝(2.5g,19mmol)和4-联苯基羰酰氯(4g,18mmol)，在室温下反应24小时。粗品用闪蒸柱色谱(硅胶，2％乙酸乙酯/二氯甲烷)纯化，获得3.86g(70％)白色固体产物：熔点103-104℃；1H NMR(CDCl3)δ7.88-7.84(m,2H),7.73-7.64(m,4H),7.52-7.40(m,5H),6.93-6.90(m,1H),3.97(s,3H),3.96(s,3H)；13C NMR(CDCl3)δ194.9,152.9,148.9,144.5,139.8,136.8,130.2,130.2,128.8,127.9,127.1,126.7,125.2,112.0,109.7,55.9,55.9；分析计算值为C21H18O3。理论值：C,79.23；H,5.70。实测值：C,78.91；H,5.87。
B．3-(4-联苯基)-3-(3,4-二甲氧基苯基)丙烯腈
3-(4-联苯基)-3-(3,4-二甲氧基苯基)丙烯腈的制备与3,3-二-(3′,4′-二甲氧基苯基)丙烯酸甲酯类似，采用3,4-二甲氧基-4′-苯基二苯甲酮(2.33g,7.32mmol)，二乙基氰基甲基膦酸酯(1.5mL,8.1mmol)和六甲基二硅氮化锂(8.1mL,8.1mmol,1M)，反应22小时。粗品用色谱(硅胶，1％乙酸乙酯/二氯甲烷)纯化，获得1.76g(70％)反式和顺式异构体的白色固体混合物：熔点132.0-134℃；.1H NMR(CDCl3)δ7.70-7.39(m,18H),7.10-6.80(m,6H),5.69(s,1H),5.68(s,1H),3.95(s,6H),3.93(s,3H),3.89(s,3H),3.85(s,3H)；13C NMR(CDCl3)δ162.2,151.1,148.8,148.6,143.0,142.6,140.0,137.9,135.9,131.4,130.1,129.3,129.1,128.8,128.8,127.9,127.1,127.0,126.0,126.9,123.1,122.2,118.3,118.2,112.6,111.1,110.7,93.2,92.9,56.0,55.9,55.8；分析计算值为C23H19NO2。理论值：C,80.92；H,5.61；N,4.10。实测值：C,80.55；H,5.80；N,3.95。
                       实施例19
       3-(3,4-二甲氧基苯基)-3-(4′-氟苯基)丙烯腈
3-(3,4-二甲氧基苯基)-3-(4′-氟苯基)丙烯腈的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸甲酯类似，采用3,4-二甲氧基-4′-氟二苯甲酮(1.3g,5mmol)，二乙基氰基甲基膦酸酯(0.91mL,5.5mmol)和六甲基二硅氮化锂(5.5mL,5.5mmol,1M),在室温下反应22小时。粗品用色谱(硅胶，1％乙酸乙酯/二氯甲烷)纯化，获得2.38g(55％)反式和顺式异构体的白色固体混合物：熔点100-102℃；.1H NMR(CDCl3)δ7.54-6.74(m,14H),5.67(s,1H),5.57(s,1H),3.94(s,3H),3.92(s,3H),3.87(s,3H),3.83(s,3H)；13C NMR(CDCl3)δ166.0,165.6,162.0,161.6,151.3,150.7,148.9,148.7,135.4,135.4,133.2,133.1,131.7,131.6,131.3,130.7,130.5,129.2,123.1,122.1,118.1,118.0,115.8,115.8,115.5,115.4,112.6,111.0,110.8,93.4,93.2,56.0,56.0,55.9；分析计算值为C17H14FNO2。理论值：C,72.07；H,4.98；N,4.94。实测值：C,71.91；H,4.98；N,4.79。
                         实施例20
    3-(3,4-二甲氧基苯基)-3-萘-2-基丙烯腈(反式和顺式异构体)
A．2-(3,4-二甲氧基苯甲酰基)萘
2-(3,4-二甲氧基苯甲酰基)萘的制备与3,4,3′,4′-四甲氧基二苯甲酮类似，采用藜芦醚(2.6mL,20mmol)、氯化铝(2.9g,22mmol)和2-萘甲酰氯(3.9g,20mmol)，回流反应4小时。粗品用闪蒸柱色谱(硅胶，2.5％乙酸乙酯/二氯甲烷)纯化，获得4.52g(77％)白色固体产物：熔点120-121.5℃；1H NMR(CDCl3)δ8.24(s,1H),8.03-7.84(m,4H),7.68-7.40(m,4H),7.00-6.87(m,1H),3.97(s,3H),3.95(s,3H)；13CNMR(CDCl3)δ195.5,153.0,149.0,135.5,134.9,132.2,131.0,130.4,129.2,128.1,128.0,127.8,126.7,125.9,125.4,112.2,109.8,56.1,56.0；分析计算值为C19H16O3。理论值：C,78.06；H,5.52。实测值：C,77.73；H,5.69。
B．3-(3,4-二甲氧基苯基)-3-萘-2-基丙烯腈
3-(3,4-二甲氧基苯基)-3-萘-2-基丙烯腈的制备与3,3-二-(3′,4′-二甲氧基苯基)丙烯酸甲酯类似，采用2-(3,4-二甲氧基苯甲酰基)萘(2.9g,10mmol)，二乙基氰基甲基膦酸酯(1.8mL,11mmol)和六甲基二硅氮化锂(8.5mL,11mmol,1.3M)，回流反应1小时。粗品用色谱(硅胶，二氯甲烷)纯化，获得2.93g(93％)反式和顺式异构体的白色固体混合物：熔点121-123℃；.1H NMR(CDCl3)δ8.11-6.78(m,20H),5.76(s,1H),5.75(s,1H),3.96(s,3H),3.92(s,3H),3.85(s,3H),3.80(s,3H)；13CNMR(CDCl3)δ162.7,162.7,151.2,150.6,148.9,148.7,136.6,134.5,134.0,133.8,132.8,131.5,129.7,129.4,129.0,128.6,128.6,128.3,128.1,127.7,127.7,127.4,127.2,126.8,126.6,125.4,123.2,122.2,118.4,118.2,112.7,111.1,110.8,93.9,93.4,56.0,56.0,55.9；分析计算值为C21H17FNO2。理论值：C,79.98；H,5.43；N,4.44。实测值：C,79.90；H,5.65；N,4.46。
                         实施例21
  3-(3,4-二甲氧基苯基)-3-(3,4-亚甲二氧基苯基)丙烯腈(反式和顺式异构体)
A．1-(3,4-二甲氧基苯甲酰基)-3,4-亚甲二氧基苯
1-(3,4-二甲氧基苯甲酰基)-3,4-亚甲二氧基苯的制备与3,4,3′,4′-四甲氧基二苯甲酮类似，采用藜芦醚(1.3mL,10mmol)、氯化铝(1.5g,11mmol)和胡椒酰氯(1.9g,10mmol)，室温下反应2.5小时。粗品用闪蒸柱色谱(硅胶，5％乙酸乙酯/二氯甲烷)纯化，获得1.99g(69％)白色固体产物：熔点164-165℃；1H NMR(CDCl3)δ7.46-7.26(m,4H),6.95-6.82(m,2H),6.06(s,2H),3.96(s,3H),3.94(s,3H)；13CNMR(CDCl3)δ193.9,152.7,151.0,148.9,147.8,132.4,130.6,126.1,124.8,112.2,109.9,109.7,107.6,101.7,56.0,56.0；分析计算值为C16H14O5。理论值：C,67.13；H,4.93。实测值：C,66.86；H,5.11。
B．3-(3,4-二甲氧基苯基)-3-(3,4-亚甲二氧基苯基)丙烯腈
3-(3,4-二甲氧基苯基)-3-(3,4-亚甲二氧基苯基)丙烯腈的制备与3,3-二-(3′,4′-二甲氧基苯基)丙烯酸甲酯类似，采用1-(3,4-二甲氧基苯甲酰基)-3,4-亚甲二氧基苯(1.43g,5mmol)，二乙基氰基甲基膦酸酯(0.91mL,5.5mmol)和六甲基二硅氮化锂(4.2mL,5.5mmol,1.3M)，回流反应1小时，然后在室温下反应24小时。粗品用色谱(硅胶，2％乙酸乙酯/二氯甲烷)纯化，获得0.97g(51％)反式和顺式异构体的类白色固体混合物：熔点121-123℃；.1H NMR(CDCl3)δ7.10-6.73(m,12H),6.13-5.94(m,4H),5.57(s,1H),5.53(s,1H),3.94(s,3H),3.92(s,3H),3.87(s,3H),3.84(s,3H)；13C NMR(CDCl3)δ162.3,151.0,150.5,149.6,149.1,148.8,148.5,147.9,133.2,131.6,130.8,129.4,124.3,123.5,123.1,122.1,118.5,118.3,112.6,111.1,110.7,109.9,108.5,108.2,101.6,101.5,92.2,92.2,56.0,55.9,55.9；分析计算值为C18H15NO4。理论值：C,69.89；H,4.89；N,4.53。实测值：C,69.61；H,5.01；N,4.37。
                            实施例22
    3-(3,4-二甲氧基苯基)-3-吡啶-4-基丙烯腈(反式和顺式异构体)
A．4-(3,4-二甲氧基苯甲酰基)吡啶
在氮气氛、-70℃下，将丁基锂(9mL,22mmol,2.5M)的己烷溶液缓慢加入4-溴藜芦醚(2.9mL,20mmol，在40mL四氢呋喃中)的搅拌溶液中，15分钟后，在反应混合物中加入在12mL四氢呋喃中的4-氰基吡啶，继续搅拌45分钟。然后将反应温热至-10℃，小心地用盐酸(45mL,1N)淬灭反应。在室温下搅拌混合物30分钟。然后用50mL10％氢氧化钠水溶液将pH调至12。用乙醚萃取混合物(3×50mL)。合并的乙醚萃取物用盐水(100mL)洗涤，然后用硫酸镁干燥，并真空浓缩成棕色固体。粗品用闪蒸柱色谱(硅胶，3％甲醇/二氯甲烷)纯化，在真空干燥(60℃,1mm)后获得1.9g(39％)产物：熔点117-118℃；1H NMR(CDCl3)δ8.85-8.76(m,2H),7.60-7.50(m,3H),7.40-7.30(m,1H),6.97-6.88(m,1H),3.98(s,3H),3.96(s,3H)；13C NMR(CDCl3)δ193.7,153.9,150.1,149.3,145.2,128.7,125.9,122.6,111.5,109.9,56.1,56.0；分析计算值为C14H13NO3。理论值：C,69.12；H,5.39；N,5.76。实测值：C,69.05；H,5.39；N,5.85。
B．3-(3,4-二甲氧基苯基)-3-吡啶-4-基丙烯腈
3-(3,4-二甲氧基苯基)-3-吡啶-4-基丙烯腈的制备与3,3-二-(3′,4′-二甲氧基苯基)丙烯酸甲酯类似，采用4-(3,4-二甲氧基苯甲酰基)吡啶(1g,4mmol)，二乙基氰基甲基膦酸酯(0.73mL,4.4mmol)和六甲基二硅氮化锂(3.4mL,4.4mmol,1.3M)，室温下反应24小时。粗品在10mL己烷中形成淤浆。过滤该混合物，固体用己烷洗涤，空气干燥，然后再真空干燥，获得0.91g(85％)反式和顺式异构体的类白色固体混合物：熔点116-125℃；.1H NMR(CDCl3)δ8.80-8.63(m,4H),7.40-7.20(m,4H),7.04-6.74(m,6H),5.81(s,1H),5.70(s,1H),3.94(s,3H),3.92(s,3H),3.87(s,3H),3.84(s,3H)；13C NMR(CDCl3)δ160.1,157.0,151.6,151.1,150.3,149.2,148.9,146.7,144.9,129.6,127.8,123.7,123.1,122.7,122.1,117.4,117.1,112.3,111.0,110.5,96.1,94.8,56.0,56.0；分析计算值为C16H14N2O2。理论值：C,72.17；H,5.30；N,10.52。实测值：C,72.35；H,5.43；N,10.47。
                         实施例23
          3-(3,4-二甲氧基苯基)-3-吡啶-2-基丙烯腈
A．2-(3,4-二甲氧基苯甲酰基)吡啶
2-(3,4-二甲氧基苯甲酰基)吡啶的制备与4-(3,4-二甲氧基苯甲酰基)吡啶类似，采用2-氰基吡啶。粗品混合物用闪蒸柱色谱(硅胶，1％甲醇/二氯甲烷)纯化，在真空干燥(60℃,1mm)后获得1.67g(34％)产物：熔点91.5-93℃；1HNMR(CDCl3)δ8.76-8.70(m,1H),8.05-7.71(m,4H),7.55-7.45(m,1H),7.00-6.89(m,1H),3.96(s,3H),3.96(s,3H)；13C NMR(CDCl3)6 192.1,155.7,153.3,148.7,148.2,136.9,128.9,126.7,125.7,124.4,112.6,109.8,56.0,55.9；分析计算值为C14H13NO3。理论值：C,69.12；H,5.39；N,5.76。实测值：C,68.96；H,5.47；N,5.66。
B．3-(3,4-二甲氧基苯基)-3-吡啶-2-基丙烯腈
3-(3,4-二甲氧基苯基)-3-吡啶-2-基)丙烯腈的制备与3,3-二-(3′,4 ′-二甲氧基苯基)丙烯酸甲酯类似，采用2-(3,4-二甲氧基苯甲酰基)吡啶(lg,4mmol)，二乙基氰基甲基膦酸酯(0.73mL,4.4mmol)和六甲基二硅氮化锂(3.4mL,4.4mmol,1.3M)，在室温下反应17小时。粗品用闪蒸柱色谱(硅胶，1％甲醇/二氯甲烷)纯化，获得0.8g(75％)反式和顺式异构体的棕色固体混合物。异构物进行进一步纯化(硅胶，10％乙酸乙酯/二氯甲烷)，获得各异构体的纯样品。
异构体1：熔点125-126℃；.1H NMR(CDCl3)δ8.75-8.65(m,1H),7.75-7.60(m,1H),7.41-7.16(m,2H),7.10-6.90(m,3H),6.52(s,1H),3.95(s,3H),3.89(s,3H)；13CNMR(CDCl3)δ159.9,154.9,150.4,149.9,148.9,136.7,128.0,124.6,124.1,122.6,118.1,112.4,111.1,97.8,56.1,56.0；分析计算值为C16H14N2O2。理论值：C,72.17；H,5.30；N,10.52。实测值：C,71.90；H,5.28；N,10.33。
异构体2：熔点134.5-135.5℃；.1H NMR(CDCl3)δ8.82-8.70(m,1H),7.88-7.76(m,1H),7.60-7.34(m,2H),6.94-6.80(m,3H),5.82(s,1H),3.91(s,3H),3.83(s,3H)；13C NMR(CDCl3)δ160.8,155.3,151.2,149.9,149.0,136.6,130.2,124.9,124.3,122.1,117.6,110.9,95.4,56.0；分析计算值为C16H14N2O2。理论值：C,72.17；H,5.30；N,10.52。实测值：C,72.13；H,5.23；N,10.40。
                           实施例24
    3-(3,4-二甲氧基苯基)-3-(2-呋喃基)丙烯腈(反式和顺式异构体)
A．2-(3,4-二甲氧基苯甲酰基)呋喃
2-(3,4-二甲氧基苯甲酰基)呋喃的制备与3,4,3′,4′-四甲氧基二苯甲酮类似，采用藜芦醚(1.3mL,10mmol)、氯化铝(1.5g,10mmol)和2-呋喃甲酰氯(1.1mL,10mmol)，回流反应2小时。粗品用闪蒸柱色谱(硅胶，4％乙酸乙酯/二氯甲烷)纯化，获得1.69g(78％)白色固体产物：熔点112-114℃；1H NMR(CDCl3)δ7.78-7.66(m,2H),7.59-7.52(m,1H),7.26-7.17(m,1H),6.96-6.90(m,1H),6.63-6.55(m,1H),3.97(s,3H),3.96(s,3H)；13C NMR(CDCl3)δ180.9,153.0,152.5,148.9,146.5,129.8,124.0,119.6,112.0,111.7,110.0,56.0,55.9；分析计算值为C13H12O4。理论值：C,67.23；H,5.21。实测值：C,67.09；H,5.21。
B．3-(3,4-二甲氧基苯基)-3-(2-呋喃基)丙烯腈
3-(3,4-二甲氧基苯基)-3-(2-呋喃基)丙烯腈的制备与3,3-二-(3′,4′-二甲氧基苯基)丙烯酸甲酯类似，采用2-(3,4-二甲氧基苯甲酰基)呋喃(0.87g,4mmol)，二乙基氰基甲基膦酸酯(0.73mL,4.4mmol)和六甲基二硅氮化锂(3.4mL,4.4mmol,1.3M)，在室温下反应3小时。粗品用色谱(硅胶，2％乙酸乙酯/二氯甲烷)纯化，获得0.78g(76％)反式和顺式异构体的类白色固体混合物：熔点78-82℃；.1HNMR(CDCl3)δ7.68-7.73(m,2H),7.16-6.75(m,7H),6.54-6.39(m,3H),5.87(s,1H),5.30(s,1H),3.93(s,3H),3.93(s,3H),3,91(s,3H),3.88(s,3H)；13C NMR(CDCl3)δ152.0,150.7,150.5,150.4,149.3,148.8,148.7,148.7,145.2,145.0,129.6,126.7,122.1,121.6,118.1,118.0,116.5,115.6,112.5,112.1,112.0,111.5,110.9,110.8,90.5,90.2,55.9,55.9,55.9,55.8；分析计算值为C15H13NO3。理论值：C,70.58；H,5.13；N,5.49。实测值：C,70.61；H,5.09；N,5.18。
                          实施例25
    3-(3,4-二乙基苯基)-3-苯基丙烯腈(反式和顺式异构体)
A．3,4-二乙基二苯甲酮
在氮气下、搅拌的冰浴冷却的二乙苯(1.7mL,10mmol，在30mL二氯甲烷中)溶液中加入氯化铝(2.93g,22mmol)。稍有放热。在获得的反应混合物中加入苯甲酰氯(1.2mL,10mmol)。然后将反应温热至室温，在室温下搅拌1.5小时。将反应混合物倒入60mL冰水中搅拌20分钟。用二氯甲烷萃取获得的混合物(2×40mL)。用硫酸镁干燥合并的萃取物，真空浓缩，获得橙色油状粗品。粗品用闪蒸柱色谱(硅胶，2.5％乙酸乙酯/己烷)纯化，获得1.22g(51％)黄色油状产物：1HNMR(CDCl3)δ7.85-7.41(m,7H),7.30-7.20(m,1H),2.83-2.61(m,4H),1.35-1.17(m,6H)；13C NMR(CDCl3)δ196.8,147.0,141.9,138.1,135.3,132.1,132.1,130.1,130.0,128.1,128.1,25.6,25.4,15.1,15.0；分析计算值为C17H18O。理论值：C,85.67；H,7.61。实测值：C,85.38；H,7.42。
B．3-(3,4-二乙基苯基)-3-苯基丙烯腈
3-(3,4-二乙基苯基)-3-苯基丙烯腈的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸甲酯类似，采用3,4-二乙基二苯甲酮(0.95g,4mmol)，二乙基氰基甲基膦酸酯(0.73mL,4.4mmol)和六甲基二硅氮化锂(3.4mL,4.4mmol,1.3M)，在室温下反应2小时。粗品用闪蒸柱色谱(硅胶，8％乙酸乙酯/二氯甲烷)纯化，获得一种油，将油搅拌在己烷中直至其固化。对获得的淤浆进行过滤，固体用己烷洗涤，空气干燥，然后真空干燥，获得0.6g(57％)反式和顺式异构体的白色固体混合物：熔点63-64℃；.1H NMR(CDCl3)δ7.51-6.99(m,16H),5.72(s,2H),2.76-2.55(m,8H),1.32-1.14(m,12H)；13C NMR(CDCl3)δ163.3,144.7,142.2,137.3,136.5,130.2,129.8,129.6,128.6,128.5,128.4,128.3,127.2,126.2,118.2,93.9,93.7,25.5,25.3,15.2,15.0。
                        实施例26
     3-(3,4-二乙基苯基)-3-(3,4-二甲氧基苯基)丙烯腈
A．3′,4′-二乙基-3,4-二甲氧基二苯甲酮
3,′4′-二乙基-3,4-二甲氧基二苯甲酮的制备与3,4-二乙基二苯甲酮类似，采用二乙苯(2.5mL,15mmol)、氯化铝(2.2g,16.5mmol)和3,4-二甲氧基苯甲酰氯(3g,15mmol)，回流反应3小时。粗品用闪蒸柱色谱(硅胶，1.5％乙酸乙酯/己烷)纯化，获得0.84g(20％)橙色固体产物：熔点60-61℃；.1HNMR(CDCl3)δ7.74-7.15(m,5H),7.00-6.80(m,1H),3.96(s,3H),3.94(s,3H),2.93-2.60(m,4H),1.43-1.15(m,6H)；13CNMR(CDCl3)δ195.5,152.7,148.8,146.3,141.7,135.9,130.6,129.8,128.0,127.7,125.1,112.2,109.7,56.0,25.6,25.4,15.1,15.0；分析计算值为C19H22O3。理论值：C.76.48；H,7.43。实测值：C,76.53；H,7.34。
B．3-(3,4-二乙基苯基)-3-(3,4-二甲氧基苯基)丙烯腈
3-(3,4-二乙基苯基)-3-(3,4-二甲氧基苯基)丙烯腈的制备与3,3-二-(3,4-二甲氧基苯基)丙烯酸甲酯类似，采用3′,4′-二乙基-3,4-二甲氧基二苯甲酮(0.51g,1.7mmol)，二乙基氰基甲基膦酸酯(0.31mL,1.9mmol)和六甲基二硅氮化锂(1.4mL,1.9mmol,1.3M)，在室温下反应60小时。粗品用色谱(硅胶，1％乙酸乙酯/二氯甲烷)纯化，获得一种油，将油搅拌在己烷中直至其固化。对获得的淤浆进行过滤，固体用己烷洗涤，空气干燥，真空干燥，获得0.31g(57％)反式和顺式异构体的类白色固体混合物：熔点78-82℃；.1H NMR(CDCl3)δ7.30-6.75(m,12H),5.61(s,1H),5.60(s,1H),3.94(s,3H),3.92(s,3H),3.87(s,3H),3.83(s,3H),2.80-2.59(m,8H),1.35-1.14(m,12H)；13C NMR(CDCl3)δ163.0,163.0,151.0,150.5,148.8,148.6,144.6,143.9,142.1,141.8,136.8,134.5,131.9,129.7,128.6,128.5,128.2,127.3,126.3,123.2,122.2,118.7,118.6,112.8,111.3,110.7,92.5,92.2,56,1.56.0.25.5,25.4,25.4,25.3,15.3,15.2,15.0,14.9；分析计算值为C21H23NO2。理论值：C,78.47；H,7.21；N,4.36。实测值：C,77.80；H,7.25；N,4.68。
                         实施例27
         4-(3-乙氧基-4-甲氧基苯基)-4-苯基-3-丁-2-酮
在-70℃、氮气氛下，在氰化亚铜(0.21g,2.3mmol，在8mL四氢呋喃中)悬浮液中加入苯基锂的环己基/乙醚溶液(2.6mL,4.6mmol,1.8M)。45分钟后，将10mL四氢呋喃中的4-(3-乙氧基-4-甲氧基苯基)-3-丁烯-2-酮(0.51g,2.3mmol)缓慢加入反应混合物中。在-78℃下1小时后，使混合物温热至室温。然后用10mL氯化铵水溶液小心淬灭反应混合物。用二氯甲烷萃取获得的混合物(3×10mL)。用硫酸镁干燥合并的有机萃取物，真空浓缩，获得0.7g粗品。粗品用色谱(硅胶，2％乙酸乙酯/二氯甲烷)纯化，获得0.41g(60％)固化的油状产物：熔点57-58℃；.1HNMR(CDCl3)δ7.31-7.13(m,5H),6.89-6.69(m,3H),4.48(t,J=7.5Hz,1H),4.03(q,J=7Hz,2H),3.82(s,3H),3.13(d,J=7.5Hz,2H),2.07(s,3H),1.41(t,J=7Hz,3H)；13CNMR(CDCl3)δ207.0,148.2,148.0,144.2,136.4,128.6,127.6,126.4,119.4,113.0,111.5,64.3,55.9,49.9,45.6,30.6,14.8；分析计算值为C19H22O3。理论值：C,76.48；H,7.43。实测值：C,76.81；H,7.44。
                         实施例28
            3-(3,4-二甲氧基苯基)-3-(萘-1-基)丙烯腈
1-(3,4-二甲氧基苯甲酰基)萘的制备与3,4,3′,4′-四甲氧基二苯甲酮类似，采用藜芦醚(1.3mL,10mmol)、氯化铝(1.5g,11mmol)和1-萘甲酰氯(1.5mL,10mmol)，在室温下反应24小时。粗品用闪蒸柱色谱(硅胶，2.5％乙酸乙酯/二氯甲烷)纯化，获得1.85g(63％)白色固体产物：熔点92.5-94.5℃；1H NMR(CDCl3)δ8.06-7.84(m,3H),7.80-7.39(m,5H),7.31-7.21(m,1H),6.84-6.74(m,1H),3.94(s,3H),3.91(s,3H)；13C NMR(CDCl3)δ196.6,153.5,149.0,136.8,133.6,131.1,130.9,130.5,128.2,126.9,126.7,126.3,126.3,125.6,124.3,111.3,109.7,56.0,55.9；分析计算值为C19H16O3。理论值：C,78.06；H,5.52。实测值：C,77.97；H,5.66。
3-(3,4-二甲氧基苯基)-3-(萘-1-基)丙烯腈按照实施例20所述方式制备。
                       实施例29
     3-(3,4-二甲氧基苯基)-3-(2,5-二氯苯基)丙烯腈
2′,5′-二氯-3,4-二甲氧基二苯甲酮的制备与3,4,3′,4′-四甲氧基二苯甲酮类似，采用藜芦醚(2.15mL,15mmol)、氯化铝(2.2g,16.5mmol)和2,5-二氯苯甲酰氯(1.9mL,15mmol)，回流反应3小时。粗品用闪蒸柱色谱(硅胶，2.5％乙酸乙酯/二氯甲烷)纯化，获得3.88g(83％)白色固体产物：熔点129-130℃；1H NMR(CDCl3)δ7.65-7.56(m,1H),7.41-7.12(m,4H),6.89-6.81(m,1H),3.96(s,3H),3.94(s,3H)；13CNMR(CDCl3)δ191.1,154.4,149.6,137.9,132.0,130.5,128.7,128.0,125.7,110.2,56.1,56.0；分析计算值为C15H12Cl2O3。理论值：C,57.90；H,3.89。实测值：C,57.58；H,3.87。
3-(3,4-二甲氧基苯基)-3-(2,5-二氯苯基)丙烯腈的制备与实施例26中以5′-二氯-3,4-二甲氧基二苯甲酮为起始的制备方法类似。
                       实施例30
             2′,6′,3,4-四甲氧基二苯甲酮
2′,6′,3,4-四甲氧基二苯甲酮的制备与3,4,3′,4′-四甲氧基二苯甲酮类似，只是采用藜芦醚(1.3mL,10mmol)、氯化铝(1.47g,11mmol)和2,6-二甲氧基苯甲酰氯(2.0mL,10mmol)，在室温下反应24小时。粗品用闪蒸柱色谱(硅胶，4％乙酸乙酯/二氯甲烷)纯化，获得2.11g(70％)白色固体产物：熔点128-129℃；1HNMR(CDCl3)δ7.66-7.60(m,1H),7.40-7.20(m,2H),6.88-6.79(m,1H),6.67-6.65(m,2H),3.93(s,3H),3.91(s,3H),3.71(s,6H)；13C NMR(CDCl3)δ193.8,157.4,153.4,148.9,130.9,130.5,125.3,118.0,110.2,109.9,104.0,55.9,55.8；分析计算值为C17H18O5。理论值：C,67.54；H,6.00。实测值：C,66.51；H,5.91。
3-(3,4-二甲氧基苯基)-3-(2,6-二甲氧基苯基)丙烯腈的制备与实施例10中以2′,6′,3,4-四甲氧基二苯甲酮所述的制备方法类似。
                      实施例31
按照以下方式能够获得每片含50mg活性组分的片剂。
组成(1000片)
    活性组分                                  50.0g
    乳糖                                      50.7g
    麦淀粉                                    7.5g
    聚乙二醇6000                          5.0g
    滑石粉                                5.0g
    硬脂酸镁                              1.8g
    软化水                                q.s.
首先，使固体组分通过孔径为0.6mm的筛子，然后混合活性组分、乳糖、滑石粉、硬脂酸镁和一半量的淀粉，另一半淀粉被悬浮在40mL水中，将该悬浮液加入100mL沸腾的聚乙二醇水溶液中，将所得糊状物加入粉末状物质中，并将混合物制成颗粒，如有必要，还可添加水。然后在35℃的温度下干燥颗粒物过夜，再通过孔径为1.2mm的筛子整粒，压片，获得直径为6mm、且两边内凹的片剂。
                      实施例32
按照以下方式步骤能够获得每片含100mg活性组分的片剂。
组成(1000片)
    活性组分                         100.0g
    乳糖                             100.0g
    麦淀粉                           47.0g
    硬脂酸镁                         3.0g
首先，使所有固体组分通过孔径为0.6mm的筛子。然后混合活性组分、乳糖、硬脂酸镁和一半量的淀粉，另一半淀粉悬浮在40mL水中，将该悬浮液加入100mL沸水中，将所得糊状物加入粉末状物质中，并将混合物制成颗粒，如有必要，还可添加水。然后在35℃的温度下干燥颗粒物过夜，再通过孔径为1.2mm的筛子整粒，压片，获得直径为6mm、两边内凹的片剂。
                      实施例33
按照以下方式能够获得每片含有75mg活性组分的咀嚼片剂。
组成(1000片)
    活性组分                           75.0g
    甘露糖醇                           230.0g
    乳糖                               150.0g
    滑石粉                             21.0g
    甘氨酸                               12.5g
    硬脂酸                               10.0g
    糖精                                 1.5g
    5％明胶溶液                          q.s.
首先，使所有固体组分通过孔径为0.25mm的筛子。混合甘露糖醇和乳糖，在其中加入明胶溶液，造粒，再通过孔径为2mm的筛子，在50℃下干燥，再次通过孔径为1.7mm的筛子。接着，小心地混合活性组分、甘氨酸和糖精，加入甘露糖醇、乳糖颗粒，硬脂酸和滑石粉，充分混合，压成直径为10mm、两边凹陷、上面有一个槽的片剂。
                      实施例34
按照以下方式能够获得每片含10mg活性组分的片剂。
组成(1000片)
    活性组分                          10.0g
    乳糖                              328.5g
    玉米淀粉                          17.5g
    聚乙二醇6000                      5.0g
    滑石粉                            25.0g
    硬脂酸镁                          4.0g
    软化水                            q.s.
首先，使所有固体组分通过孔径为0.6mm的筛子。然后充分混合活性组分、乳糖、滑石粉、硬脂酸镁和一半量的淀粉。另一半淀粉悬浮在65mL水中，再将该悬浮液加入260mL沸腾的聚乙二醇水溶液中。将所得糊状物加入到粉末状物质中，混合并造粒，如有必要，还可添加水。然后在35℃下干燥颗粒物过夜，再通过孔径为1.2mm的筛子整粒，压片，获得直径为6mm、两边内凹、且上面有槽的片剂。
                          实施例35
按照以下方式能够获得每个胶囊含100mg活性组分的明胶干填胶囊剂。
组成(1000片)
    活性组分                               100.0g
    微晶纤维素                             30.0g
    十二烷基硫酸钠                         2.0g
    硬脂酸镁                               8.0g
首先，使十二烷基硫酸钠通过孔径为0.2mm的筛子加入活性组分中，使两组分充分混合10分钟。再使微晶纤维素通过孔径为0.9mm的筛子加入上述混合物中，然后充分混合10分钟。最后，使硬脂酸镁通过孔径为0.8mm的筛子加入，再混合3分钟后，将混合物装入0号(拉长型)的明胶干填胶囊中，每个胶囊中装140mg。
                  实施例36
例如，按照以下方式能够获得0.2％注射剂或输液：
    活性组分                         5.0g
    氯化钠                           22.5g
    pH7.4的磷酸缓冲液                300.0g
    软化水                           加到2500.0mL
首先将活性组分溶于1000mL水中，通过微孔滤膜过滤或在1000mL水中形成淤浆。加入缓冲液，然后加水使总容量达到2500mL。将溶液装入玻璃安瓿中，每个瓶装入1.0或2.5mL溶液，即分别含2.0或5.0mg活性组分。

Claims (9)

1．一种有下式的化合物：
其中：
(a)X是-O-或-(CnH2n)-，其中n的值为0、1、2或3，R1是1-10个碳原子的烷基、最多有10个碳原子的单环烷基、最多有10个碳原子的多环烷基或最多有10个碳原子的苯并环烷基，或
(b)X是-CH=,R1是最多有10个碳原子的亚烷基、最多有10个碳原子的单环亚烷基或最多有10个碳原子的双环亚烷基；
R2是氢、硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、低级烷基、低级亚烷基甲基、低级烷氧基或卤素；
R3是(ⅰ)未取代的或被一个或多个取代基取代的苯基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基或被1-3个碳原子的烷基取代的氨基甲酰基、乙酰氧基、羧基、羟基、氨基、被1-5个碳原子的烷基取代的氨基、最多有10个碳原子的烷基、最多有10个碳原子的环烷基、最多有10个碳原子的烷氧基、最多有10个碳原子的环烷氧基、最多有10个碳原子的亚烷基甲基、最多有10个碳原子的环亚烷基甲基、苯基或亚甲二氧基；(ⅱ)吡啶、取代的吡啶、吡咯烷、咪唑、萘或噻吩；(ⅲ)未取代的或被一个或多个取代基取代的4-10个碳原子的环烷基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、取代的氨基、1-10个碳原子的烷基、1-10个碳原子的烷氧基、苯基；
R4和R5各自独立为氢，或R4和R5结合在一起形成碳-碳键；
Y是-COZ、-C≡N，或1-5个碳原子的低级烷基；
Z是-OH、-NR6R6、-R7或-OR7；
R6是氢或低级烷基；和
R7是烷基或苄基。
2．根据权利要求1所述的化合物，其中R1是烷基、最多有10个碳原子的单环烷基、最多有10个碳原子的多环烷基或最多有10个碳原子的苯并环烷基；X是-(CH2)n-或-O-，其中n为0、1、2或3；R2是氢、硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、低级烷基、低级烷氧基、卤素；R4、R5、Y、Z、R6和R7如本文所确定。
3．根据权利要求1所述的化合物，其中R3是(ⅰ)未取代的或被一个或多个取代基取代的苯基或萘，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基或被1-3个碳原子的烷基取代的氨基甲酰基、乙酰氧基、羧基、羟基、氨基、被1-5个碳原子的烷基取代的氨基、1-10个碳原子的烷基或环烷基、1-10个碳原子的烷氧基或环烷氧基；或(ii)未取代的或被一个或多个取代基取代的4-10个碳原子的环烷基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、取代的氨基、1-10个碳原子的烷基、1-10个碳原子的烷氧基或苯基。
4．根据权利要求1所述的化合物，该化合物是有下式的腈：
Figure A9719725100031
或
Figure A9719725100032
其中：
(a)X是-O-或-(CnH2n)-，其中n的值为0、1、2或3,R1是最多有10个碳原子的烷基、最多有10个碳原子的单环烷基、最多有10个碳原子的多环烷基或最多有10个碳原子的苯并环烷基，或
(b)X是-CH=,R1是最多有10个碳原子的亚烷基或最多有10个碳原子的单环亚烷基；
R2是氢、硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、低级烷基、低级烷氧基或卤素；和
R3是(ⅰ)未取代的或被一个或多个取代基取代的苯基或萘基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基或被1-3个碳原子的烷基取代的氨基甲酰基、乙酰基、羧基、羟基、氨基、被1-5个碳原子的烷基取代的氨基、1-10个碳原子的烷基或环烷基、1-10个碳原子的烷氧基或环烷氧基；或(ⅱ)未取代的或被一个或多个取代基取代的4-10个碳原子的环烷基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、取代的氨基、1-10个碳原子的烷基、1-10个碳原子的烷氧基、或苯基。
5．根据权利要求1所述的化合物，该化合物是有下式的链烷酸衍生物：
Figure A9719725100041
或
其中：
(a)X是-O-或-(CnH2n)-，其中n的值为0、1、2或3,R1是最多有10个碳原子的烷基、最多有10个碳原子的单环烷基、最多有10个碳原子的多环烷基或最多有10个碳原子的苯并环烷基，或
(b)X是-CH=,R1是最多有10个碳原子的亚烷基或最多有10个碳原子的单环亚烷基；
R2是氢、硝基、氰基、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、低级烷基、低级烷氧基或卤素；
R3是(ⅰ)未取代的或被一个或多个取代基取代的苯基或萘基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基或被1-3个碳原子的烷基取代的氨基甲酰基、乙酰氧基、羧基、羟基、氨基、被1-5个碳原子的烷基取代的氨基、1-10个碳原子的烷基或环烷基、1-10个碳原子的烷氧基或环烷氧基；或(ⅱ)未取代的或被一个或多个取代基取代的4-10个碳原子的环烷基，这些取代基各自独立选自硝基、氰基、卤素、三氟甲基、乙酯基、甲酯基、丙酯基、乙酰基、氨基甲酰基、乙酰氧基、羧基、羟基、氨基、取代的氨基、1-10个碳原子的烷基、1-10个碳原子的烷氧基或苯基；和
Z是-OH、-NR6R6、R7或-OR7，其中R6是氢或低级烷基；和R7是烷基或苄基。
6．根据权利要求1所述的化合物，该化合物是3,3-二-(3,4-二甲氧基苯基)丙烯腈、3,3-二-(3-乙氧基-4-甲氧基苯基)丙烯腈、3,3-二-(3-乙氧基-4-甲氧基苯基)丙烯酸甲酯、3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙烯酸甲酯、3-(3-丙氧基-4-甲氧基苯基)-3-苯基丙烯腈、3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙烯腈、3,3-二-(3-环戊氧基-4-甲氧基苯基)丙烯腈、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙烯酸甲酯、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙烯腈、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙烯、1-(3-环戊氧基-4-甲氧基苯基)-1-苯基丙烷、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙腈、3-(3-环戊氧基-4-甲氧基苯基)-3-苯基丙酸甲酯、3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙腈、3-(3-乙氧基-4-甲氧基苯基)-3-苯基丙酸甲酯、3,3-二-(3,4-二甲氧基苯基)丙腈、3,3-二-(3-乙氧基-4-甲氧基苯基)丙腈、3-(3,4-二甲氧基苯基)-3-苯基丙烯腈、3-(3-乙氧基-4-甲氧基苯基)-3-萘基丙腈、3-(3,4-二甲氧基苯基)-3-苯基丙腈或3-(3,4-二甲氧基苯基)-3-(3-乙氧基-4-甲氧基苯基)丙腈。
7．根据权利要求1所述的化合物，该化合物是4,4-二-(3,4-二甲氧基苯基)-丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-(3-乙氧基-4-甲氧基苯基)丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-苯基丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-(3-环戊氧基-4-甲氧基苯基)丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-(3-2,3-二氢化茚-2-基氧-4-甲氧基苯基)丁-3-烯-2-酮、4-(3-乙氧基-4-甲氧基苯基)-4-(4-吡啶基)丁-3-烯-2-酮、4-(3-乙氧基-4-甲氧基苯基)-4-(4-吡啶基)丁-2-酮、4-(3-环戊氧基-4-甲氧基苯基)-4-(4-吡啶基)丁-3-烯-2-酮、4-(3-环戊氧基-4-甲氧基苯基)-4-(4-吡啶基)丁-2-酮；3-(3-环戊氧基-4-甲氧基苯基)-3-(4-吡啶基)丙-2-烯酸甲酯、3-(3-乙氧基-4-甲氧基苯基)-3-(4-吡啶基)丙-2-烯酸甲酯、3-(3-乙氧基-4-甲氧基苯基)-3-(4-吡啶基)丙酸甲酯、4-(3-乙氧基-4-甲氧基苯基)-4-(2-呋喃基)丁-3-烯-2-酮、3-(3-乙氧基-4-甲氧基苯基)-3-(2-呋喃基)丙-2-烯腈、3-(3-乙氧基-4-甲氧基苯基)-3-(4-吡啶基)丙-2-烯腈、3-(3-乙氧基-4-甲氧基苯基)-3-(4-吡啶基)丙腈、3-(3-环戊氧基-4-甲氧基苯基)-3-(4-吡啶基)丙-2-烯腈、3-(3-环戊氧基-4-甲氧基苯基)-3-(4-吡啶基)丙腈、4-(3,4-二甲氧基苯基)-4-(4-甲氧基-3-丙-1-烯苯基)丁-3-烯-2-酮、4-(3,4-二甲氧基苯基)-4-(4-甲氧基-3-丙-1-烯苯基)丁-3-烯-2-酮、4,4-二-(3,4-二甲氧基苯基)丁-2-酮、4-(3,4-二甲氧基苯基)-4-(3-乙氧基-4-甲氧基苯基)丁-2-酮、4-(3,4-二甲氧基苯基)-4-(3-(环亚戊基甲基)-4-甲氧基苯基)丁-2-酮、4-(3,4-二甲氧基苯基)-4-(4-甲氧基-3-丙-1-烯苯基)丁-2-酮、4,4-二-(3-乙氧基-4-甲氧基苯基)丁-3-烯-2-酮、3-(3,4-二甲氧基苯基)-3-(3-(环亚戊基甲基)-4-甲氧基苯基)丙-2-烯腈、3-(3-(环亚戊基甲基)-4-甲氧基苯基)-3-苯基-丙-2-烯腈、1-(3,4-二甲氧基苯基)-1-(3-乙氧基-4-甲氧基苯基)戊-3-酮、1-(3,4-二甲氧基苯基)-1-(3-乙氧基-4-甲氧基苯基)戊-1-烯-3-酮、1,1-二-(3,4-二甲氧基苯基)戊-3-酮、3-(3,4-二甲氧基苯基)-3-(3-(环亚戊基甲基)-4-甲氧基苯基)丙-2-烯腈、3-(3-(环亚戊基甲基)-4-甲氧基苯基)-3-苯基-丙腈、3,3-二-(3-(环亚戊基甲基)-4-甲氧基苯基)丙腈、3,3-二-(3-(环亚戊基甲基)-4-甲氧基苯基)丙-2-烯腈、3-(3,4-二甲氧基苯基)-3-(3-(环亚戊基甲基)-4-甲氧基苯基)丙-2-烯酰胺、3-(3-(环亚戊基甲基)-4-甲氧基苯基-3-苯基)丙酰胺、3,3-二-(3-(环亚戊基甲基)-4-甲氧基苯基)丙酰胺、3,3-二-(3-(环亚戊基甲基)-4-甲氧基苯基)丙-2-烯酰胺、3-(3,4-二甲氧基苯基)-3-(3-乙氧基-4-甲氧基苯基)-丙-2-烯酰胺、3,3-二-(3-乙氧基-4-甲氧基苯基)丙-2-烯酰胺、3,3-二-(3 ,4-二甲氧基苯基)丙-2-烯酰胺、3,3-二-(3-乙氧基-4-甲氧基苯基)丙酰胺、3,3-二-(3,4-二甲氧基苯基)丙酰胺、4-(3,4-二甲氧基苯基)-4-(4-甲氧基-3-外-降冰片氧基苯基)丁-3-烯-2-酮、3-(3,4-二甲氧基苯基)-3-(4-甲氧基-3-外-降冰片氧基苯基)丙-2-烯腈、3-(3,4-二甲氧基苯基)-3-(3,4-亚甲二氧基苯基)丙-2-烯腈、3-(4-氨基苯基)-3-(3,4-二甲氧基苯基)丙-2-烯腈或3-(4-氨基苯基)-3-(3-乙氧基-4-二甲氧基苯基)丙-2-烯腈。
8．一种方法，该方法包括对哺乳动物给予有效量的权利要求1所述的化合物，以抑制磷酸二酯酶的酶作用、TNFα水平和NFκB对细胞核易位中的至少一种，该方法包括通过给予有效量的权利要求1所述的化合物来减少哺乳动物体内的磷酸二酯酶、TNFα和NFκB水平。
9．一种药物组合物，该组合物包括权利要求1所述的化合物与药学载体的组合，有效量的化合物单剂量或多剂量使用可抑制磷酸二酯酶的酶作用、TNFα水平和NFκB对细胞核易位中的至少一种。
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