CN1826330A - 具有细胞毒性作用的考布他汀衍生物 - Google Patents
具有细胞毒性作用的考布他汀衍生物 Download PDFInfo
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- CN1826330A CN1826330A CNA2004800207571A CN200480020757A CN1826330A CN 1826330 A CN1826330 A CN 1826330A CN A2004800207571 A CNA2004800207571 A CN A2004800207571A CN 200480020757 A CN200480020757 A CN 200480020757A CN 1826330 A CN1826330 A CN 1826330A
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- hydrogen
- phenyl
- methoxyl group
- trimethoxy
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Abstract
本文所述的发明涉及通过全合成得到并具有以下通式(I)的新的考布他汀衍生物,其中的基团如在本文以下的描述中定义。该化合物虽然与顺式/反式-考布他汀的结构是化学相关的,并不总是结合微管蛋白,但表现出在肿瘤领域作为抗癌和/或抗血管生成剂的令人感兴趣的细胞毒性活性。
Description
本文所述的发明涉及通过全合成得到的新的考布他汀衍生物,它们的制备方法,它们作为药物的应用和包含它们的组合物。
对各种产物的开发策略选自:(i)用异噁唑或4,5-二氢-3-R-异噁唑型杂环取代烯键,或者ii)用氟取代烯键上存在的一个或两个H,和/或iii)用苯并呋喃、苯并噻吩、吲哚和吲唑、呋喃或噻吩型芳香杂环残基或者用萘基(具有任选官能化的取代基)取代芳族残基,和/或iv)用其它取代基取代三甲氧基苯基上的一个或多个甲氧基残基。该化合物虽然与顺式/反式-考布他汀的结构化学相关,并不总是结合微管蛋白,但表现出在肿瘤领域作为抗癌和/或抗血管生成剂的令人感兴趣的细胞毒性活性。
抗微管蛋白活性不被认为是抗癌活性必需的必要条件,事实上考布他汀的抗癌活性是一系列药效学和药代动力学类型组分的结果。
发明背景
成人血管生成通常是静止的,但它构成例如在伤口的愈合或在女性生殖周期中重建子宫内膜中一种正常功能。血管功能降低和组织灌注不足时生理性刺激血管生成反应。
更为一般地,可以认为在生理条件下的血管生成构成一种对灌注不足或氧和营养物供应减少作出反应的正反馈形式,例如在动脉闭塞的情况下,在组织物生长的情况下(例如与肌组织形成相伴的新血管形成),和在与氧和营养物需求增加有关的工作负荷增加的情况下。在局部缺血期间,由于动脉的部分或完全闭塞,需要形成侧副管以保持灌注。
已知肿瘤组织的良好血管形成促进原发性肿瘤的生长。氧和营养物供应充足促进肿瘤自身的快速生长。已表明新血管生成的程度是肿瘤预后中的一个非常不利的因素(van Hinsbergh,V.W.,Collen,A.,Koolwijk,P.:Anrc.On-col.,10 Suppl.,4:60-3,199;uolezmwini,J.K:Curr.,Opin.,Chers.,Biol.,3(4):500-9,1999)。
旨在发现新一代化学治疗剂的研究已确定微管蛋白是一种可能的细胞靶体。能够改变微管聚集的物质也能够抑制细胞增殖。
微管在细胞结构、细胞分裂和细胞代谢的调节中起重要作用。真核细胞的微管系统包括基体的聚集和解聚动态机构,其中微管蛋白杂二聚体聚合形成癌细胞和正常细胞中的微管。能够改变微管的聚合或解聚的细胞毒性剂证明是有效的化学治疗剂。
从非洲柳树品种矮生柳树(Combretum caffrum)(使君子科)中分离的考布他汀A-4(CA-4)(Pettit,G.R.等人,:Experientia,1989,45,209)表现出具有抗微管机制的有希望的抗癌潜能,在非常类似于秋水仙碱结合的部位强力地结合微管蛋白(Lin,C.N等人,Biochemistry,1989,28,6984)。所述与微管蛋白的结合防止它聚合成微管,具有抗有丝分裂作用。CA-4即使在毫微摩尔数量级的极低浓度下也抑制细胞生长。
CA-4的磷酸盐-″CA-4P″(Pettit,G.R.等人;Anti-cancer DrugDes.1995,10,299)-是水溶性的,且目前进入II期临床试验。
考布他汀选择性损伤肿瘤新血管生成的能力使这种化合物明显地令人感兴趣,并促使寻找新的和更有效的化合物。
目前,许多研究已表明大量的具有抗血管生成活性的化合物,例如CA-4P,在良好表征的视网膜病形式的鼠模型中能够抑制视网膜的新血管形成。这些研究表明CA-4P和新的衍生物可以有用地用作肿瘤学和眼科学领域中的抗血管生成剂(Griggs J.等人,:Am.J Pathol.2002,160(3),1097-103)。
然而,考布他汀的非常显著的细胞毒性效力不可能仅归于它的抗微管蛋白效果。存在类似结构的化合物,这些化合物虽然表现出显著的细胞毒性,但不产生同等高程度的抗微管蛋白活性。
除了药代动力学方面之外,许多药效学方面仍然是充分研究的对象,且按照目前的情况没有获得足够的文献数据提供确定的反应(LeWang等人,:J.Med.Chem,2002,45,1697-1711)。
根据化学观点,已知考布他汀、秋水仙碱或它们的衍生物的两个芳环之间的距离构成这类化合物的抗微管蛋白性能的不变的必要条件(McGown,A.T.等人;a)Bioorg.Med.Chem.Lett.,1988,8(9),1051-6;b)Bioorg.Med.Chem.Lett.2001,11(1),51-4)。
吲哚基噁唑啉残基取代双键(Qun Li,Q.等人,:Bioorg.Med.Chem.Lett.,2002,12(3),465-9)已产生考布他汀衍生物,A-289099,(其中的芳环还被N-Me-吲哚残基取代),具有相当于比较参照产物的抗癌活性。
抑制微管蛋白聚合的茋和二氢茋衍生物在Cushing等人的工作(J.Med.Chem.,1991,34,2579-2588;1992,35,2293-2306,US 5,430,062),Woods等人(British Journal of Cancer,1995,71,705-711),US 5,512,678,US 5,525,632和Ohsumi等人(J.Med.Chem.,1998,41,3022-3032),Hatanaka等人(Bioorganic &Medicinal Chemistry Letters,1998,8,3371-3374),Maya等人(Bioorganic Medicinal Chemistry Letters,2000,10,2549-2551),Li等人(Bioorganic & Medicinal Chemistry Letters,2002,12,465-469),Hori等人(British Journal of Cancer,2002,86,1604-1614),WO 02/50007,Petti t等人(J.Med.Chem.,2003,46(4),525-531),Wang等人(J.Med.Chem.,2002,45,1697-1711),Kim等人(Chem.Pharm.Bull.,2003,51(5),516-521)中作了描述。
在癌症领域中同样已知肿瘤细胞的生物学基本阶段是它们获得导致转移的能力。
转移的肿瘤细胞具有丧失与周围结构的粘附、侵入血液和淋巴管和定居其它远处组织然后它们在那里继续繁殖的能力。
转移扩散也是疾病的临床病史中一个重要的事件,是癌症致死的主要原因。它与肿瘤部位或相邻区域存在血管组织密切相关,并受其促进。
事实上,癌细胞迁移通过周围结构允许细胞到达肿瘤的血管,不管其是预先存在的还是由于新血管生成而形成的,然后它们从那里进入血流(Ray,J.M.,Stetler-Stevenson,W.G.:Eur.Respir.J.,1994,7(11):2062-72;Stetler-Stevenson,W.G.,Liotta,L.A.,Kleiner D.E.Jr.:FASEB J.,1993,7(15):1434-41)。
淋巴管和血管之间通讯通道的存在使癌细胞在两种脉管系统中移动。
近来的研究已表明在血管生成和关节炎病之间存在直接的关系(Koch,A.E.:Arthritis and Rheumatism,1998,41:951-962)。具体而言,已表明关节软骨的新血管形成在血管翳的形成和关节炎的进展中起重要的作用。正常软骨不具有血管,而关节炎患者的滑液含有由内皮细胞产生的血管生成刺激因子(内皮细胞刺激血管生成因子=ESAF)。
这种因子的存在与血管形成和软骨降解有关。
其它疾病也与异常血管生成有关。
已发现受累组织的新血管形成是促进糖尿病性视网膜病(Histol.Histopathol.,1999;14(4):1287-94)、牛皮癣(Br.J.Dermatol.,1999 141(6):1054-60)、慢性炎症和动脉粥样硬化(Planta Med.,1998;64(8):686-95)的诱发因素。
因此,控制新血管形成是控制和治疗这些疾病的一个基本要素。
尽管在过去数年内在赋予抗血管生成活性的新药物的领域已取得进展,药物领域的许多专家认为此研究领域仍是发现治疗以异常血管生成为特征的疾病,特别是肿瘤的新药物的最有希望的领域之一。
事实上,对于这些疾病,甚至更为强烈地感受到需要表现出更少副作用并能够阻断或妨碍上述疾病潜在的异常机理,从而允许治疗这些疾病的新化合物。
已令人惊奇地发现,通过修饰考布他汀的双烯键和芳环,产生本文下述的具有抗微管蛋白和/或细胞毒性性能的通式(I)化合物,该化合物是治疗由异常血管生成导致的疾病和肿瘤的有用药剂。
根据本发明的衍生物以完全意外的方式表明,即使在存在低抗微管蛋白活性或不存在抗微管蛋白活性的情况下细胞毒性活性仍可以是非常显著的。
发明概述
本发明的一个目的是式(I)化合物、它们的对映异构体、非对映异构体、各自的混合物和它们的药学上可接受的盐
其中
各个R1、R2、R3和R4可以相同或不同,为H、OH、OPO3H2或OCH2OPO3H2和它们的二钠盐、OMe、OCH2O、NO2、F、Cl、Br;
-R1-R2-还可以一起为:-CR8=CR9-X-
Y为选自以下的基团:
:顺式或反式
R5和R6可以相同或不同,为H或卤素;
R7为H、OMe、SO2Ph;
Ar为选自以下的基团:
R8、R9和R10可以相同或不同,为H、OH、OPO3H2或OCH2OPO3H2和它们的二钠盐、OR11、OCH2O、NH2、NHR11、NO2、烷基(C1-C4)、C6H5、C5H4N或卤素;
R11为C1-C4烷基或酰基、氨基酸残基;
X为O、S、N、NR12;
R12为H、CH3、CH2Ph;
Z为CH、N;
条件是式(I)化合物不是考布他汀A-1、考布他汀A-2、考布他汀A-4,和它们的磷酸二钠衍生物,并排除以下化合物:
2-苯基-6-反式-苯乙烯基-苯并[b]呋喃;
2,3-二苯基-6-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-6-(4-甲氧基)-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-6-(3,4-二甲氧基)-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-6-(3,4,5-三甲氧基)-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-6-(3,4-亚甲二氧基)-反式-苯乙烯基-苯并[b]呋喃;
2,3-二苯基-6-(4-甲氧基)-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-5-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-5-(4-甲氧基)-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-5-(3,4-亚甲二氧基)-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-6-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-6-(4-甲氧基)-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-6-(4-氯)-反式-苯乙烯基-苯并[b]噻吩;
Piceatannol;
1-(3-呋喃基)-2-(3,4,5-三甲氧基苯基)乙烯;
1-(3-噻吩基)-2-(3,4,5-三甲氧基苯基)乙烯;
1-(2-呋喃基)-2-(3,4,5-三甲氧基苯基)乙烯;
并且条件是:
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为2-氯时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为三甲氧基,Y为双键,R5和R6为H,Ar为苯基时,R8-R10中至少一个不为氢;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-氯、4-溴、4-硝基、4-羟基、4-乙酰基、4-乙氧基、4-C1-C4烷基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-硝基或4-氨基时,R10不为3-氯、3-甲氧基、3-甲基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-硝基或3-氨基时,R10不为3-氯、3-甲氧基、3-甲基;
-当R1为氢,而R2-R4为2,3,4-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,至少一个R8为氢,R9为3-甲氧基时,R10不为5-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基时,R8-R10不为甲氧基;
-当R1和R2为氢,而R3-R4为3,4-二甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-甲氧基;
-当R1和R2为氢,而R3-R4为3,4-二甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢时,R9-R10不为3,5-二甲氧基;
-当R1和R2为氢,而R3-R4为3,4-二甲氧基,Y为双键,R5和R6为H,Ar为苯基时,R8-R10中至少一个不为氢;
-当R1和R2为氢,而R3-R4为3,5-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-甲氧基;
-当R1和R2为氢,而R3-R4为3,5-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-乙酰基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H时,Ar不为吡啶基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基,R10为4-NHR11时,R11不为丝氨酸残基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为具有1-3个碳原子的4-烷氧基或具有1-4个碳原子的4-烷基或卤原子;
-当R1为氢,而R2-R3为3,4-亚甲二氧基,R4为5-甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为2,3,4-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为NHR11,R11为丝氨酸残基时,R10不为4-甲氧基;
-当R1为氢,而R2-R3为3,4-亚甲二氧基,R4为4-甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为NHR11,R11为氨基酸半胱氨酸、甘氨酸、苯丙氨酸、丝氨酸、色氨酸(triptophan)、酪氨酸、缬氨酸的残基时,R10不为4-甲氧基;
-当R1为氢,而R2-R3为3,4-亚甲二氧基,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为NO2或NH2时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基时,R8-R10中至少一个不为氢;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-氟;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲基时,R10不为3-氟或3-羟基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为3-氟,R9为4-甲氧基时,R10不为2-或5-氟;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-羟基或3-氨基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-氟或3-溴;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-羟基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-甲基时,R10不为4-甲基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-羟基;
-当R1-R2为氢,而R3-R4为3,5-二羟基,Y为反式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-羟基时,R10不为5-羟基;
-当R1-R3为氢,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9和R10为3,4-二甲基时,R4不为4-甲氧基;
-当R1-R2为氢,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9和R10为3,4-二甲基,R4为4-甲氧基时,R3不为3-氟或3-溴或3-硝基或3-羟基;
-当R1-R2为氢,Y为双键,R5和R6为H,Ar为苯基,R8-R10为3,4,5-三乙氧基,R4为4-甲氧基时,R3不为3-氟或3-氯或3-溴或3-羟基;
-当R1-R2为氢,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8-R9为4,5-二甲氧基,R10为3-羟基时,R3不为3-氟或3-羟基;
-当R1-R2为氢,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8-R9为4,5-二甲氧基,R10为3-甲氧基时,R3不为3-氟;
-当R1为氢,R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为2-萘基时,R8-R10中至少一个不为氢;
-当R1和R2为氢,R3为3-羟基,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为2-萘基时,R8-R10中至少一个不为氢;
-当R1为氢,R2-R4为3,4,5-三甲氧基,Y为
Ar为吲哚基时,其中R8-R10中至少一个不为氢。
本发明涉及新的式(I)化合物在医学领域作为药物的应用。
本发明的另一目的是包含式(I)化合物作为它们的活性成分和至少一种药学上可接受的赋形剂或稀释剂的药物组合物。
本发明的另一目的是式(I)化合物用于制备具有细胞毒性型抗癌活性的药物的应用。
本发明的另一目的是式(I)化合物用于制备具有抗血管生成型抗癌活性的药物的应用。
本发明的另一目的是式(I)化合物用于制备用于预防和减少癌症转移的药物的应用。
本发明的另一方面是式(I)化合物用于制备具有抗癌活性的药物的应用,其中该癌症选自肉瘤、癌、类癌、骨癌、内分泌癌、淋巴白血病、髓细胞白血病、单核细胞白血病、巨核细胞白血病或何杰金病。
本发明的另一目的是式(I)化合物用于制备治疗与异常血管生成有关的疾病的药物的应用,其中该疾病选自关节炎病、肿瘤、转移性扩散、糖尿病性视网膜病、牛皮癣、慢性炎症,和动脉粥样硬化。
发明详述
根据本发明,药学上可接受的盐是所有本领域专业人员能够制备的盐,在所述盐用作药物时所利用的酸或碱不产生不期望的副作用。
特别优选的化合物为:
2-甲氧基-5-[3-甲氧基-5-(3,4,5-三甲氧基-苯基)-4,5-二氢-4-异噁唑基]-苯酚-ST1996;
2-甲氧基-5-[3-甲氧基-4-(3,4,5-三甲氧基-苯基)-4,5-二氢-5-异噁唑基]-苯酚-ST1998;
5-[3-苯磺酰基-4-(3,4,5-三甲氧基-苯基)-4,5-二氢-4-异噁唑基]-2-甲氧基-苯酚-ST1995;
5-[3-苯磺酰基-5-(3,4,5-三甲氧基-苯基)-4,5-二氢-5-异噁唑基]-2-甲氧基-苯酚-ST1997;
2-甲氧基-5-[3-(3,4,5-三甲氧基-苯基)-4,5-二氢-5-异噁唑基]-苯酚-ST1999;
2-甲氧基-5-[5-(3,4,5-三甲氧基-苯基)-4,5-二氢-3-异噁唑基]-苯酚-ST2001;
2-甲氧基-5-[5-(3,4,5-三甲氧基-苯基)-3-异噁唑]-苯酚-ST2002;
顺式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-4-醇-ST2151;
反式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-4-醇-ST2152;
顺式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-ST2049;
反式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-ST2050;
顺式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-4-醇-ST2179;
反式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-4-醇-ST2180;
顺式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-ST2051;
反式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-ST2052;
顺式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-7-醇-ST2487;
反式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-7-醇-ST2488;
顺式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-7-醇-ST2491;
反式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-7-醇-ST2492;
顺式-1-甲氧基-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘-ST2053;
甲氧基-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘-ST2054;
顺式-7-甲氧基-1-甲基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-1H-吲唑-ST2055;
反式-7-甲氧基-1-甲基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-1H-吲唑-ST2056;
2-硝基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-噻吩-ST2057;
2-硝基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-呋喃-ST2058;
顺式-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘-1-醇-ST2181;
反式-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘-1-醇-ST2182;
6[(Z)-2-(3,4,5-三甲氧基-苯基)乙烯基]-1-苯并噻吩-4-醇4-O-磷酸二钠-ST2495;
6[(Z)-2-(3,4,5-三甲氧基苯基)乙烯基]-1-苯并呋喃-4-醇4-O-磷酸二钠-ST2496;
6-[(Z)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇-ST2892;
6-[(E)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇-ST2891;
6[(Z)-2-(3-甲氧基-4,5-亚甲二氧基-苯基-1-基)-乙烯基]-1-苯并呋喃-4-醇-ST2933;
6[(E)-2-(3-甲氧基-4,5-亚甲二氧基-苯基-1-基)-乙烯基]-1-苯并呋喃-4-醇-ST2934;
6[(Z)-2-(3,4,5-三甲氧基-苯基)乙烯基]-1-苯并噻吩-4-醇4-O-甲氧基磷酸二钠;
6[(Z)-2-(3,4,5-三甲氧基苯基)乙烯基]-1-苯并呋喃-4-醇4-O-甲氧基磷酸二钠;
6-[(Z)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇-ST2892;
顺式-2-甲氧基-5-[2-(4-甲氧基-苯并呋喃-6-基)-乙烯基]-苯酚-ST2897;
顺式-2-甲氧基-5-[2-(7-甲氧基-苯并呋喃-5-基)-乙烯基]-苯酚-ST2898;
顺式-2-甲氧基-5-[2-(4-甲氧基-苯并[b]噻吩-6-基)-乙烯基]-苯酚-ST2899;
顺式-6-[2-(3,5-二甲氧基-苯基)-乙烯基]-苯并[b]噻吩-4-醇-ST2900;
顺式-5-[2-(3,5-二甲氧基-苯基)-乙烯基]-苯并呋喃-7-醇-ST2901;
顺式-6-[2-(3,5-二甲氧基-苯基)-乙烯基]-苯并呋喃-4-醇-ST2902。
本发明所述的化合物根据合成方案1-15制备。
具体而言,Y为异噁唑啉环,而R7为苯基磺酸残基的式(I)化合物,例如称为ST1995和ST1997的化合物,根据方案1通过在适宜保护的考布他汀上硝基衍生物2产生的硝酰氧的偶极环加成反应[3+2]-来制备。除去保护基,例如叔丁基-二甲基甲硅烷基,产生目标化合物ST1995和ST1997。
另一方面,在R7基团为甲氧基的情况下,例如在称为ST1996和ST1998的化合物中,通过与甲氧基化钠反应取代如前述化合物ST1995和ST1997中的苯基磺酸基来得到该化合物。
区域异构的(regioisomeric)异噁唑啉衍生物,例如ST1999和ST2001,根据合成方案2和3,分别通过由肟5和10产生的硝酰氧与烯烃组分6和9之间的偶极环加成反应[3+2]-来制备。
再通过使根据合成方案2和3适宜保护的上述异噁唑啉进行二氧化锰介导的氧化来制备区域异构异噁唑衍生物,例如ST2000和ST2002。除去保护基,例如叔丁基-二甲基甲硅烷基,产生目标产物。
根据合成方案4和5所述的合成方法得到Ar为苯并噻吩或苯并呋喃残基的式(I)化合物,例如化合物ST2151、ST2152、ST2049、ST2050、ST2179、ST2180、ST2051、ST2052、ST2487、ST2488、ST2491和ST2492。
具体而言,在醛17a-d和磷鎓盐18之间进行Wittig反应,然后除去叔丁基-二甲基甲硅烷基保护基,能够得到目标衍生物(方案4)。以相同的方式,在醛26a、b和磷鎓盐18之间进行Wittig反应,然后除去适宜的保护基,例如叔丁基-二甲基甲硅烷基,能够得到目标衍生物,例如ST2487、ST2488、ST2491和ST2492(方案5)。
用类似的方法,通过适宜的醛29a-d和磷鎓盐18之间的Wittig反应来制备Ar为萘、吲唑、硝基噻吩或硝基呋喃残基的衍生物,例如ST2053、ST2054、ST2055、ST2056、ST2181、ST2057、ST2058和ST2182(方案6)。
最后,根据方案7所述的合成方法,从对应的酚衍生物例如ST2151和ST2179开始,得到R8或R9为磷酸酯基的式(I)化合物,例如ST2495和ST2496。
根据方案12-13所述的合成方法,从对应的酚或胺衍生物开始,得到其它前药形式和/或更具水溶性的衍生物。
在医学领域,已知涉及同时或顺序地(例如作为细胞周期同步化的函数)施用多于一种的抗癌药的治疗方案的应用,肿瘤学专业人员对此是十分熟悉的。
在治疗方案中需要施用多于一种的抗癌药是因为药物通过在不同的代谢水平起作用而在某些情况下促进癌症的完全缓解,和在其它情况下延长生命和/或改善治疗患者的生活质量。根据本发明的联合使其本身与一种或多种已知的抗癌药物相伴使用以治疗肿瘤。
因此,本发明的另一目的是式(I)化合物单独或者与选自以下的其它已知的抑制生长(antiblastic)药联合的应用:烷化剂、拓朴异构酶抑制剂、抗微管蛋白剂、嵌入剂、抗代谢药、天然产物例如长春花属生物碱,表鬼臼毒素、抗生素、酶、紫杉烷类和抗癌疫苗。
以下实施例进一步例示本发明。
实验部分所用的缩写:TBDMSiCl(叔丁基二甲基氯硅烷);TBAF(氟化四正丁基铵);NCS(N-氯琥珀酰亚胺);Hex(己烷);DAST(三氟化二乙基氨基硫);DIPEA(二异丙基乙基胺);PyBroP(溴-三吡咯烷基-磷鎓-六氟-磷酸盐);TAEA(三(2-氨基-乙基)胺);BTMS(溴三甲基硅烷)。
实施例1
制备ST1995、ST1996、ST1997和ST1998
根据本文下述的合成方案1制备这些化合物:
方案1
制备异噁唑啉3和4
往含有根据Wade等人(J.Org.Chem.1981,46,765-770)所述的方法制备的氮酸酯2的烧瓶加入溶于CH2Cl2(6ml)的烯1(600mg,1.4mmol)和对甲苯磺酸一水合物(270mg,1.4mmol)。将反应物在氩气氛下回流30分钟。在使溶液变回室温后加入CH2Cl2(15ml),用5%NaOH(10ml)、H2O(10ml)和盐水(10ml)洗涤。在减压下蒸发用Na2SO4脱水的有机相。将粗产物色谱纯化可以得到产物3和4,总产率为20%。
制备ST1996和ST1998
将金属Na(130mg,0.6mmol)溶于MeOH(10ml),将如此得到的溶液加到适宜的苯基-磺酰基衍生物3,4(0.15mmol),并使反应物在室温下放置6小时。
在浓缩乙醇和用CH2Cl2(15ml)稀释后,用H2O(8ml)和盐水(8ml)进行萃取。在减压下蒸发用Na2SO4脱水的有机溶液。
用色谱法纯化所得的粗产物。
2-甲氧基-5-[3-甲氧基-5-(3,4,5-三甲氧基-苯基)-4,5-二氢-4-异噁唑基]-苯酚-ST1996
产率:70%,m.p.=160-162℃;
1HNMR(CDCl3)δ3.84(s,9H),3.91(s,6H),4.19(d,1H,J=9.2Hz),5.38(d,1H,J=9.3Hz),5.69(s,1H),6.54(s,2H),6.69-6.74(m,1H),6.84-6.88(m,2H)。
2-甲氧基-5-[3-甲氧基-4-(3,4,5-三甲氧基-苯基)-4,5-二氢-5-异噁唑基]-苯酚-ST1998
产率:65%.油。
1HNMR(CDCl3)δ3.86(s,9H),3.91(s,6H),4.14(d,1H,J=9.1Hz),5.40(d,1H,J=9.1Hz),5.68(br,1H),6.43(s,2H),6.84(s,2H),6.95(s,1H)。
制备ST1995、ST1997
将适宜的甲硅烷基衍生物(0.1mmol)3,4溶于MeOH(10ml),并将H2O(1/2ml)和HCl 5%(10滴)加到溶液。在室温下放置过夜后,蒸发甲醇,用CH2Cl2(15ml)萃取粗产物,并用H2O(10ml)和盐水(10ml)洗涤。将有机溶液脱水并蒸发至干,产生一种粗产物,用硅胶色谱法将其纯化。
5-[3-苯磺酰基-4-(3,4,5-三甲氧基-苯基)-4,5-二氢-4-异噁唑基]-2-甲氧基-苯酚-ST1995
产率:95%.油。
1HNMR(CDCl3)δ3.67(s,6H),3.82(s,3H),3.91(s,3H),4.58(d,1H,J=6.5Hz),5.56(d,1H,J=6.5Hz),5.62(br,1H),6.15(s,2H),6.79-6.84(m,3H),7.37-7.43(m,2H),7.55(d,1H,J=8.1Hz),7.61-7.65(m,2H)。
5-[3-苯磺酰基-5-(3,4,5-三甲氧基-苯基)-4,5-二氢-5-异噁唑基]-2-甲氧基-苯酚-ST1997
产率:85%.油。
1HNMR(CDCl3)δ3.82(s,6H),3.84(s,3H),3.89(s,3H),4.56(d,1H,J=6.6Hz),5.55(d,1H,J=6.5Hz),5.57(br,1H),6.39(s,2H),6.56-6.58(m,1H),6.62(d,1H,J=2,1Hz),6.71(d,1H,J=8,1Hz),7.37-7.44(m,2H),7.55-7.59(m,1H),7.66-7.72(m,2H)。
实施例2
制备ST1999、ST2000、ST2001和ST2002
根据本文下述的合成方案2和3制备这些化合物:
方案2
方案3
7和11的一般制备方法
往含有无水CHCl3(7ml)的烧瓶加入NCS(1mmol,133mg)、吡啶(0.1mmol,7.9mg,8μl)和适宜的肟5、10(1mmol)。将反应物在50℃下搅拌1小时。然后在室温下加入对应的烯6、9(1.1mmol),并非常缓慢滴加TEA(1.5mmol,152mg,0.2ml)。将反应混合物搅拌2小时。然后加入CH2Cl2(20ml),并用H2O(15ml)、2.5%HCl(10ml)、H2O(10ml)和盐水(10ml)洗涤。用Na2SO4将有机相脱水,并在减压下浓缩。用色谱法纯化粗反应产物得到目标异噁唑啉。环加成产率:70-75%。
异噁唑8和12的一般制备方法
将异噁唑啉7、11(50mg,0.1mmol)溶于苯(15ml),将MnO2(450mg,5.17mmol)加到溶液,并将该混合物与Dean-Stark一起在剧烈搅拌下回流6小时。
用C盐将变回至室温的反应混合物过滤,并在减压下浓缩滤液。
用色谱法纯化如此得到的粗产物得到异噁唑衍生物。氧化产率:80-85%。
由对应的前体7、8、11和12,经以上关于ST1997和ST1995所述进行的去甲硅烷基化得到最终化合物ST1999、ST2000、ST2001和ST2002。
2-甲氧基-5-[3-(3,4,5-三甲氧基-苯基)-4,5-二氢-5-异噁唑基]-苯酚-ST1999
产率:85%,油,
1H-NMR(CDCl3)δ:3.30(dd,1H,J=8.2Hz,16.2Hz),3.74(dd,1H,J=10.9Hz,16.3Hz),3.89(s,12H),5.65(dd,1H,J=8.2Hz,10.8Hz),5.63(br,1H),6.85-6.95(m,5H)。
2-甲氧基-5-[3-(3,4,5-三甲氧基-苯基)-5-异噁唑基]-苯酚-ST2000
产率:95%,m.p.:183-185℃,
1H-NMR(CDCl3)δ:3.91(s,3H),3.95(s,3H),3.96(s,9H),5.80(br,1H),5.82(s,1H),6.94(d,1H,J=8.9Hz),7.08(s,2H),7.37-7.41(m,2H)。
2-甲氧基-5-[5-(3,4,5-三甲氧基-苯基)-4,5-二氢-3-异噁唑基]-苯酚-ST2001
产率:90%,m.p.:128-130℃,
1H-NMR(CDCl3)δ:3.30(dd,1H,J=8.4Hz,16.2Hz),3.75(dd,1H,J=10.4Hz,16.4Hz),3.86(s,3H),3.90(s,6H),3.96(s,3H),5.65(dd,1H,J=8.2Hz,10.2Hz),5.68(br,1H),6.62(s,2H),6.90(d,1H,J=8.1Hz),7.22(dd,1H,J=2.1Hz,8.2Hz),7.28(d,1H,J=2.1Hz)。
2-甲氧基-5-[5-(3,4,5-三甲氧基-苯基)-3-异噁唑]-苯酚-ST2002
产率:80%,m.p.:205-206℃,
1H-NMR(CDCl3)δ:3.90(s,3H),3.95(s,9H),5.80(br,1H),6.70(s,1H),6.93(d,1H,J=8.3Hz),7.04(s,2H),7.36(d,1H,J=2Hz),7.43(dd,1H,J=1.9Hz,8.2Hz)。
实施例3
制备ST2151、ST2152、ST2179、ST2180、ST2049、ST2050、ST2051、ST2052、ST2487、ST2488、ST2491、ST2492[和ST2900、ST2901、ST2902]
根据本文下述的合成方案4和5制备这些化合物:
方案4
方案5
获得15a,b和23a,b的一般方法
往在t-BuOH(50mL)中的t-BuOK(17g.;150mmol,3当量)的悬浮液加入在琥珀酸二乙酯(32mL,225mmol,4.5mmol)中的醛13a-b、21a-b(50mmol)的混合物。将该反应物回流45分钟。此段时间后加入相同量的t-BuOK、t-BuOH和琥珀酸二乙酯,并再将该混合物回流45分钟。然后使其转变为室温,并用HCl水溶液(20%v/v)酸化(pH2)。用5%HCl(100mL)稀释混合物,并用EtOAc(3×100mL)萃取。然后有机相用10%Na2CO3水溶液(4×50mL)萃取;用Et2O(50mL)洗涤汇集的水相,然后用HCl(20%v/v)酸化至pH=2。最后用EtOAc(4×50mL)萃取水相,并在减压下浓缩脱水的汇集的有机萃取物,以定量产率得到酸酯14a-b、22a-b。将用前述反应得到的粗产物(14a-b、22a-b)(50mmol)溶于由乙酸酐(100mL)和无水CH3CO2Na(200mmol,4当量)组成的混合物。将如此得到的溶液煮沸5小时,然后将其蒸发至干。
用Na2CO3(15%)的水溶液(75mL)萃取残余物,并用EtOAc(3×50mL)萃取。用盐水(50mL)洗涤汇集的有机萃取物,脱水(Na2SO4),并用硅胶快速色谱法纯化。
将在EtOH(20mL)中的乙酰基衍生物(10mmol)和无水K2CO3(1.4g.,10mmol)的悬浮液回流18小时,然后过滤,并将滤液蒸发至干。将残余物溶于水(20mL),用HCl(10%v/v)将水相酸化(pH=2),然后用EtOAc(3×20mL)萃取。将汇集的有机萃取物脱水(Na2SO4),在减压下浓缩,并用硅胶快速色谱法纯化。
15a:褐色固体,m.p.=134-136℃;15b:白色固体,m.p.=105-107℃;23a:褐色固体,m.p.=145-147℃;23b:白色固体,m.p.=165-167℃。
制备16b、16d
往由在THF(20mL)中的化合物15a,b(5mmol)和无水K2CO3(5mmol,690mg,1当量)组成的悬浮液加入Me2SO4(5mmol,630mg,0.48mL),并将所得的溶液煮沸8小时。此段时间后过滤混合物,蒸发至干,并用EtOAc(20mL)和水(5mL)的混合物萃取残余物。用盐水(5mL)洗涤有机相,脱水并真空浓缩。用硅胶快速色谱法纯化所得的残余物。得到衍生物16b,d,为无色油。
制备16a,c和24a,b
往在DCM(10mL)中的酚15a-b、23a-b(3mmol)的溶液加入TBDMSCl(3.6mmol,1.2当量,550mg)和咪唑(7.5mmol,2.5当量,510mg)。将该混合物在室温下放置18小时,然后用DCM(10mL)稀释,用水(5mL)和盐水(5mL)洗涤,并将有机相脱水。浓缩后,用硅胶快速色谱法纯化残余物。得到衍生物16a、16c、24a和24b,为无色油。
制备17a-d和26a,b
在0℃下将溶于THF(5mL)的适宜的酯16a-d、24a,b(2mmol)滴加到在10mL THF中的LiAlH4(3mmol,114mg,1.5当量)的悬浮液。完成添加时,将反应物于0℃下再放置30分钟,然后在室温下放置2小时。然后再次用水和冰浴冷却反应物,用苏打水溶液(5%)分解过量的LiAlH4:用C盐过滤反应混合物,并用EtOAc(15mL)和水(5mL)萃取滤液。然后用盐水(5mL)冼涤有机相,脱水(Na2SO4),并蒸发至干。用快速硅胶色谱法纯化所得的产物。往在CCl4(25mL)中的通过色谱法得到的醇衍生物(1mmol)的溶液加入MnO2(1.1mmol,1.1当量)。室温下2小时后,将混合物过滤,将滤液蒸发至干,并不经任何进一步的纯化用于下一步反应。
制备ST2151、ST2152、ST2179、ST2180、ST2049、ST2050、ST2051和ST2052
往在10mL无水THF中的醛17a-d、26a,b(2mmol)的溶液加入磷鎓盐18(2mmol,1.05g,2当量)。用水和冰浴冷却如此得到的悬浮液,然后加入NaH(50%,在矿物悬浮液中,2.2mmol,1.1当量,110mg)。将其在室温下搅拌24小时,用C盐床过滤,用THF洗涤。进行蒸发,用DCM(15mL)萃取残余物,并用水(5mL)和盐水(5mL)洗涤有机相,脱水并再次蒸发。
对于其中的酚羟基作为TBDMS醚保护的衍生物,将残余物溶于DCM(10mL),并加入TBAF(6mmol,3当量)。室温下1小时后,用DCM(5mL)稀释混合物,用水(3×5mL)和盐水(5mL)洗涤,并脱水(Na2SO4)。浓缩后,用快速硅胶色谱法纯化残余物。
为纯化这些产物,使用硅胶色谱法,采用以下类型的洗脱梯度:EtOAc∶石油醚1∶9,2∶8,3∶7。
顺式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-4-醇-ST2151:
白色固体,m.p.=145-147℃;
1H-NMR(CDCl3)δ:3.64(s,6H),3.83(s,3H),5.34(s,1H),6.50(d,J=12.6Hz,1H),6.54(s,2H),6.60(d,J=12.6Hz,1H),6.69(s,1H),7.32(d,J=5.6Hz,1H),7.41(d,J=5.6Hz,1H),7.42(s,1H)。
反式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-4-醇-ST2152:
黄色固体,m.p.=67-69℃;
1H-NMR(CDCl3)δ:3.88(s,6H),3.92(s,3H),5.50(s,1H),6.74(s,2H),6.93(s,1H),7.03(s,2H),7.35(d,J=5.2Hz,1H),7.43(d,J=5.2Hz,1H),7.56(s,1H)。
顺式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-ST2049:
黄色固体。
1H-NMR(CDCl3)δ:3.65(s,6H),3.76(s,3H)3.84(s,3H),6.55(s,2H),6.58(d,J=11.2Hz,1H),6.64(d,J=11.2Hz,1H),6.70(s,1H),7.31(d,J=5.0Hz,1H),7.42(d,J=5.0Hz,1H),7.44(s,1H)。
FAB-MS(MALDI-TOF):356.4[M+1]。
反式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-ST2050:
黄色固体;m.p.=171-173℃。
1H-NMR(CDCl3)δ:3.89(s,6H),3.94(s,3H),4.03(s,3H),6.78(s,2H),6.95(s,1H),7.10(s,2H),7.33(d,J=5.6Hz,1H),7.47(d,J=5.6Hz,1H),7.58(s,1H)。
FAB-MS(MALDI-TOF):356.3[M+1]。
顺式-6-[2-(3,4,5-三甲氧基--苯基)-乙烯基]-苯并呋喃-4-醇-ST2179:
白色固体;m.p.=134-136℃。
1H-NMR(CDCl3)δ:3.57(s,6H),3.77(s,3H),5.12(s,1H),6.42(d,J=12Hz,1H),6.44(s,2H),6.53(d,J=12Hz,1H),6.56(s,1H),6.72(d,J=2.2Hz,1H),7.00(s,1H),7.45(d,J=2.2Hz,1H)。
FAB-MS(MALDI-TOF):327.2[M+1]。
反式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基-苯并呋喃-4-醇-ST2180:
浅黄色固体,m.p.=142-143℃。
1H-NMR(CDCl3)δ:3.89(s,6H),3.92(s,3H),5.50(s,1H),6.74(s,2H),6.93(s,1H),7.03(s,2H),7.35(d,J=5.2Hz,1H),7.43(d,J=5.2Hz,1H),7.56(s,1H)。
顺式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-ST2051:
黄色油。
1H-NMR(CDCl3)δ:3.65(s,6H),3.74(s,3H),3.83(s,3H),6.52(s,2H),6.55(d,J=11.2Hz,1H),6.62(d,J=11.2Hz,1H),6.63(s,1H),6.80(s,1H),7.10(s,1H),7.51(s,1H)。
FAB-MS(MALDI-TOF):356.4[M+1]。
反式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-ST2052:
黄色固体,m.p.=152-153℃。
1H-NMR(CDCl3)δ:3.88(s,6H),3.94(s,3H),4.00(s,3H),6.76(s,2H),6.84(s,2H),7.08(s,2H),7.28(d,J=2.2Hz,1H),7.54(d,J=2.2Hz,1H)。
FAB-MS(MALDI-TOF):340.6[M+1]。
顺式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-7-醇-ST2487:
褐色固体,m.p.=152-154℃。
1H-NMR(CDCl3)δ:3.63(s,6H),3.83(s,3H),5.51(s,1H),6.48(d,J=12.2Hz,1H),6.52(s,2H),6.64(d,J=12.2Hz,1H),6.73(s,1H),7.29(d,J=3.2Hz,1H),7.41(d,J=3.2Hz,1H),7.43(s,1H)。
反式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-7-醇-ST2488:
浅黄色固体,m.p.=172-174℃;
1H-NMR(CDCl3)δ:3.89(s,6H),3.92(s,3H),5.63(s,1H),6.74(s,2H),6.94(s,1H),7.02(d,J=2.8Hz,1H),7.32(d,J=5.2Hz,1H),7.45(d,J=5.2Hz,1H),7.53(s,1H)。
顺式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-7-醇-ST2491(27b):
白色固体,m.p.=140-141℃;
1H-NMR(CDCl3)δ:3.63(s,6H),3.83(s,3H),5.20(s,1H),6.46(d,J=12.2Hz,1H),6.52(s,2H),6.57(d,J=12.4Hz,1H),6.69(d,J=2.2Hz,1H),6.82(s,1H),7.12(s,1H),7.58(d,J=2.2Hz,1H)。
反式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-7-醇-ST2492(28b):
白色固体,m.p.=173-175℃;
1H-NMR(CDCl3)δ:3.89(s,6H),3.92(s,3H),6.01(s,1H),6.74(s,2H),6.97(s,1H),7.06(d,J=3.2Hz,1H),7.26(d,J=5.2Hz,1H),7.45(d,J=5.2Hz,1H),7.60(s,1H)。
通过类似的方法得到:
顺式-6-[2-(3,5-二甲氧基-苯基)-乙烯基]-苯并[b]噻吩-4-醇-ST2900。
1H NMRδ(CDCl3):3.63(s,6H),5.06(s,1H),6.32-6.34(m,1H),6.45(d,J=2.2Hz,2H),6.53(d,J=12.4Hz,1H),6.60-6.66(m,2H),7.34(s,1H),7.38-7.40(m,2H)。
顺式-5-[2-(3,5-二甲氧基-苯基)-乙烯基]-苯并呋喃-7-醇-ST2901。
1H NMRδ(CDCl3):3.62(s,6H),5.07(s,1H),6.30-6.32(m,1H),6.43(d,J=2.2Hz,2H),6.48(d,J=12.2Hz,1H),6.64(d,J=12.2Hz,1H),6.67.6.69(m,1H),6.78(d,J=1.4Hz,1H),7.10(s,1H),7.57(d,J=2.2Hz,1H)
顺式-6-[2-(3,5-二甲氧基-苯基)-乙烯基]-苯并呋喃-4-醇-ST2902。
1H NMRδ(CDCl3):3.64(s,6H),4.93(s,1H),6.31-6.34(m,1H),6.43(d,J=2.4Hz,2H),6.53(d,J=12.2Hz,1H),6.57(s,1H),6.63(d,J=12.2Hz,1H),6.78(dd,J=2.2Hz,J=1Hz,1H),7.05(s,1H),7.51(d,J=2.2Hz,1H)。
实施例4
制备ST2053、ST2054、ST2055、ST2056、ST2057、ST2058、ST2181和ST2182
根据本文下述的合成方案6制备这些化合物:
用在所有方面与用于制备醛17a,d(方案4)类似的合成方法制备醛29a,b。
方案6
顺式-1-甲氧基-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘-ST2053:
无色油。
1H-NMR(CDCl3)δ:3.63(s,6H),3.75(s,3H),3.83(s,3H),6.57(s,1H),6.66(d,J=13.2Hz,1H),6.71(d,J=13.2Hz,1H),6.75(s,1H),7.44(m,4H),7.69(m,1H),8.12(m,1H)。
FAB-MS(MALDI-TOF):350.3[M+1]。
反式-1-甲氧基-3-[2-3,4,5-三甲氧基-苯基]-乙烯基]-萘-ST2054:
黄色固体;m.p.=166-168℃。
1H-NMR(CDCl3)δ:3.89(s,3H),3.95(s,6H),4.09(s,3H),6.80(s,2H),7.06(s,1H),7.16(s,2H),7.46(m,3H),7.76(dd,J=9.2e 1.8Hz,1H),8.20(dd,J=9.2e 1.8Hz,1H)。
FAB-MS(MALDI-TOF):350.3[M+1]。
顺式-7-甲氧基-1-甲基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-1H-吲唑-ST2055:
白色固体,m.p.182-183℃;
1H-NMR(CDCl3)δ:3.64(s,3H),3.67(s,3H),3.82(s,3H),4.23(s,3H),6.51(d,J=12.5Hz,1H),6.53(s,2H),6.59(d,J=12.5Hz,1H),7.19(s,1H),7.80(s,2H)。
反式-7-甲氧基-1-甲基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-1H-吲唑-ST2056:
油;
1H-NMR(CDCl3)δ:3.86(s,3H),3.91(s,6H),4.01(s,3H),4.28(s,3H),6.73(s,2H),6.94(d,J=15.8Hz,1H),7.06(d,J=15.8Hz,1H),7.31(s,1H),7.86(s,2H)。
2-硝基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-噻吩-ST2057:
微黄色油,
1H NMR(CDCl3)δ3.89(s,3H),3.93(s,6H),6.73(s,2H),6.99(d,1H,J=4.4Hz),7.06(s,2H),7.85(d,1H,J=4.4Hz)。
2-硝基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]呋喃-ST2058:
微黄色油。
1H NMR(CDCl3)δ3.90(s,3H),3.92(s,6H),6.53(d,1H,J=3.7Hz),6.76(s,2H)7.28(s,2H),7.38(d,1H,J=3.6Hz)。
顺式-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘-1-醇-ST2181:
黄色固体,m.p.=163-165℃。
1H-NMR(CDCl3)δ:3.62(s,6H),3.84(s,3H),5.56(s,1H),6.53(d,J=12.4Hz,1H),6.56(s,2H),6.68(d,J=12.4Hz,1H),6.79(s,1H),7.38(s,1H),7.45(m,2H),7.72(dd,J=9.8e 3.6Hz,1H),8.11(dd,J=9.8e 3.6Hz,1H)。
反式-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘-1-醇-ST2182:
黄色固体,m.p.=176-178℃。
1H-NMR(CDCl3)δ:3.90(s,3H),3.93(s,6H),5.73(s,1H),6.77(s,2H),7.07(m,3H),7.46(m,3H),7.80(dd,J=9.6e 2.8Hz,1H),8.14(dd,J=9.6e 2.8Hz,1H)。
实施例5
方案7
获得34和35的一般方法
往冷却至-25℃的在5mL无水CH3CN中的1.2mmol ST2151(或ST2179)的溶液加入581μL(6mmol;5当量)CCl4。大约10分钟后,按所示的顺序加入以下物质:429μL(2.59mmol;2.1当量)二异丙基乙基胺、15mg(0.12mmol;0.1当量)二甲基氨基吡啶和383μL(1.74mmol;1.45当量)二苄基-亚磷酸酯(phosphyte)。-10℃下2小时后反应完全,加入20mL KH2PO4 0.5M,并将水相与AcOEt(3×10mL)一起振荡。用无水Na2SO4干燥有机相,并在SiO2上用己烷∶AcOEt 75∶25将粗产物色谱纯化,得到1.05mmol:产率:88%的预期产物,为一种黄色油。
6[(Z)-2-(3,4,5-三甲氧基苯基)乙烯基]-1-苯并噻吩-4-醇4-O-二苄基-磷酸酯(34)。
Fr=0.11,在己烷/AcOEt 8∶2中,MS-IS:[M+H]+=603.2
1H-NMR(300MHz,CDCl3)δ:3.6(s,6H,2xOCH3),3.8(s,3H,OCH3),5.05(s,2H,CH2),5.1(s,2H,CH2),6.5(s,2H,2xCHar),6.6(bs,2H,2xCHar),7.2-7.4(m,11H,11xCHar)7.6(s,1H,CHar)。
13C-NMR(75MHz,CDCl3)δ:56.1;61.1;70.3;106.4;115.9;119.7;120.4;127.1;128.2;128.8;128.9;129.0;131.1;131.6;132.2;134.9;135.6;153.2。
6[(Z)-2-(3,4,5-三甲氧基苯基)乙烯基]-1-苯并呋喃-4-醇-4-O-二苄基-磷酸酯(35)。
Fr=0.20,在己烷/AcOEt 7∶3中,MS-IS:[M+H]+=587.2
1H-NMR(300MHz,CDCl3)δ:3.6(s,6H,2xOCH3),3.8(s,3H,OCH3),5.05(s,2H,CH2),5.1(s,2H,CH2),6.45(s,2H,2xCHar),6.55(bs,2H,2xCHar),6.75(bs,1H,CHar),7.05(s,1H,CHar),7.2-7.4(m,11H,11xCHar),7.5(bs,1H,CHar)。
13C-NMR(75MHz,CDCl3)δ:56.1;61.1;70.3;98.8;104.3;106.4;109.1;115.1;119.9;128.2;128.8;128.9;129.2;130.9;132.3;134.7;135.5;145.5;153.2;156.5。
获得ST2495和ST2496的一般方法
室温下往在7mL无水CH3CN中的1.2mmol的二苄基酯34(或35)的溶液加入36mg(2.4mmol;2当量)NaI,然后加入在1mL无水CH3CN中的303μL(2.4mmol;2当量)的Me3SiCl的溶液。2小时后反应完全,加入用于溶解盐的最少量的水和10%Na2S2O3溶液直至实现反应混合物的脱色。将如此得到的溶液与AcOEt一起振荡,直至在有机相中完全萃取产物;用Na2SO4干燥有机相,并在真空下除去溶剂。
可以通过BTMS[S.Lazar等人,Synthetic Comm.1992,22(6),923-31]除去苄基酯,但该反应不如用NaI快速。
将如此得到的粗油溶于4mL无水MeOH,并将130mg(2.4mmol;2当量)的NaOMe加到溶液。将该混合物于室温下放置20小时,直至实现完全成盐。然后在真空下除去溶剂,并用Et2O洗涤残余物,得到1.1mmol(产率:92%)的产物,为一种白色固体。
作为可替代的选择,可以在NaOH 1N溶液中制备钠盐。
6[(Z)-2-(3,4,5-三甲氧基苯基)乙烯基]-1-苯并噻吩-4-醇-4-O-磷酸二钠-ST2495。
T dec=226°,MS-IS:[M-1]-=419。
1H-NMR(300MHz,D2O)δ:3.4(s,3H,OCH3),3.1(s,3H,OCH3),3.75(s,3H,OCH3),6.4-6.45(d,1H,CHolef),6.5(s,2H,2xCHar),6.1-6.15(d,1H,CHolef),7.25-7.5(m,4H,4xCHar)。
13C-NMR(75MHz,D2O)δ:30.4;55.7;56.0;56.2;61.1;104.1;106.9;115.5;116.6;121.5;121.6;126.1;126.3;127.6;128.3;128.6;128.9;129.9;130.7;132.6;132.7;133.6;134.3;134.7;136.1;140.9;141.6;149.2;152.3;152.8。
6[(Z)-2-(3,4,5-三甲氧基苯基)乙烯基]-1-苯并呋喃-4-醇4-O-磷酸二钠-ST2496.
T dec=212°,MS-IS:[M-1]-=403。
1H-NMR(300MHz,D2O)δ:3.5(s,6H,2xOCH3),3.6(8,3H,OCH3),6.4-6.45(d,1H,CHolef),6.5(s,2H,2xCHar),6.6-6.65(d,1H,CHolef),6.85-7.1(m,3H,3xCHar),7.5(s,1H,CHar)。
13C-NMR(75MHz,D2O)δ:30.4;55.8;56.0;56.2;61.1;98.8;104.1;104.2;104.8;105.9;106.8;114.9;120.3;127.6;128.0;128.6;129.7;130.9;133.7;134.2;136.1;145.2;147.4;152.1;152.3;152.8;156.0。
本发明的目的还在于方案4和5中所述的中间合成产物15a,b、16a-d、17a-d、23a,b、24a,b和26a,b。
制备43(ST2898)、44、45a,b(ST2899,ST2897)和46a,b
根据本文下述的方案8和9制备该化合物。
方案8
方案9
获得37和40的一般方法
0℃下往溶于THF(15mL)的适宜的醇36或39a,b(1.8mmol)加入CBr4(2.87mmol,953mg,1.6当量)和P(Ph)3(2.87mmol,754mg,1.6当量)。将反应物于室温下放置1.5小时;然后用EtOAc(10mL)稀释混合物,用水(5mL)和盐水(5mL)洗涤,并干燥有机相。浓缩后,通过硅胶快速色谱法纯化残余物。得到衍生物37和40a,b,为无色油。
5-溴甲基-7-甲氧基-苯并呋喃
产率:54%。油。
1HNMR(CDCl3)δ4.03(s,3H),4.61(s,2H),6.74(d,1H,J=2.2Hz),6.84(d,1H,J=1.6Hz),7.23(d,1H,J=1.4),7.64(d,1H,J=1.8)。
6-溴甲基-4-甲氧基-苯并呋喃
产率:80%。油。
1HNMR(CDCl3)δ3.96(s,3H),4.62(s,2H),6.69(d,1H,J=1.2Hz),6.83-6.84(m,1H),7.18(s,1H),7.5(d,1H,J=2.2Hz)。
6-溴甲基-4-甲氧基-苯并噻吩
产率:60%.油。
1HNMR(CDCl3)δ3.97(s,3H),4.63(s,2H),6.69(d,1H,J=1.3Hz),6.89(s,1H),7.22(s,1H),7.59(s,1H)。
获得38和41的一般方法
往在二甲苯(10ml)中的37或40a,b(0.97mmol)的溶液加入P(Ph)3(1.65mmol,433mg,1.7当量),将所得的悬浮液煮沸12小时。将悬浮液过滤,用二乙醚洗涤残余物,并用甲醇-二乙醚结晶。得到盐38和41a,b,为无色固体物质,其m.p.超过180℃并分解。
7-甲氧基-苯并呋喃-5-基甲基)-三苯基-磷鎓
产率:85%,1H-NMR(CDC l3)δ:3.66(s,3H),5.50(d,2H,J=13.6Hz),6.55(d,1H,J=2Hz),6.78(s,1H),6.93(s,1H),7.54-7.81(m,16H)。
4-甲氧基-苯并呋喃-6-基甲基)-三苯基-磷鎓
产率:83%。
1H-NMR(CDCl3)δ:3.63(s,3H),5.49(d,2H,J=14.2Hz),6.74-6.78(m,3H),7.57-7.67(m,16H)。
4-甲氧基-苯并[b]噻吩-6-基甲基-三苯基-磷鎓
产率:80%,1H-NMR(CDCl3)δ:3.65(s,3H),5.48(d,2H,J=14.1Hz),6.75-6.79(m,3H),7.58-7.68(m,16H)。
获得43(ST2898)、44、45a,b(ST2899、ST2897)和46a,b的一般方法
往在10mL的无水THF中的醛42(359.6mg,1.35mmol)的溶液加入膦酸盐38或41a,b(1.35mmol,1当量)。在冰浴中冷却如此得到的悬浮液,然后加入NaH(50%,在矿物悬浮液中,1.62mmol,1.2当量,77mg)。将反应物在室温下搅拌2小时,然后用C盐床过滤,并用THF洗涤。完成蒸发,用DCM(15mL)萃取残余物,并用水(5mL)和盐水(5mL)洗涤,然后干燥并再次蒸发。将残余物溶于DCM(10mL),并加入TBAF(6mmol,3当量)。室温下1小时后,用DCM(5mL)稀释溶液,用水(3×5mL)和盐水(5mL)洗涤,然后干燥(Na2SO4)。浓缩后,用快速硅胶色谱法,使用EtOAc-石油醚2-8纯化残余物。
顺式-2-甲氧基-5-[2-(7-甲氧基-苯并呋喃-5-基)-乙烯基]-苯酚-ST2898
油。
1H-NMR(CDCl3)δ:3.81(s,3H),3.86(s,3H),5.47(s,1H),6.48(d,J=12Hz,1H),6.60(d,J=12.2Hz,1H),6.68(d,J=2Hz,1H),6.72(s,1H),6.75-6.76(m,2H),6.88(d,J=2Hz,1H),7.1(s,1H),7.57(d,J=2Hz,1H)。
反式-2-甲氧基-5-[2-(7-甲氧基-苯并呋喃-5-基)-乙烯基]-苯酚
油。
1H-NMR(CDCl3)δ:3.92(s,3H),4.1(s,3H),5.62(s,1H),6.75(d,J=1.8Hz,1H),6.83-6.86(m,2H),6.95-7.02(m,4H),7.2(s,1H),7.61(d,J=2Hz,1H)。
顺式-2-甲氧基-5-[2-(4-甲氧基-苯并呋喃-6-基)-乙烯基]-苯酚-ST2897
油。
1H-NMR(CDCl3)δ:3.76(s,3H),3.86(s,3H),5.52(br,1H),6.50(d,J=12Hz,1H),6.56-6.64(m,2H),6.73(s,1H),6.78-6.80(m,2H),6.91(d,J=2Hz,1H),7.01(s,1H),7.49(d,J=2Hz,1H)。
反式-2-甲氧基-5-[2-(4-甲氧基-苯并呋喃-6-基)-乙烯基]-苯酚
油。
1H-NMR(CDCl3)δ:3.85(s,3H),3.92(s,3H),5.53(s,1H),6.75-6.77(m,3H),6.92(d,J=2,1H),6.96(s,3H),7.1(d,J=2.2Hz,1H),7.45(d,J=2.2Hz,1H)。
顺式-2-甲氧基-5-[2-(4-甲氧基-苯并[b]噻吩-6-基)-乙烯基]-苯酚-ST2899
油。
1H-NMR(CDCl3)δ:3.74(s,3H),3.87(s,3H),5.50(s,1H),6.52(d,J=12Hz,1H),6.60(d,J=12.Hz,1H),6.68-6.72(m,2H),6.78(d,J=2Hz,1H),6.91(d,J=2Hz,1H),7.29(d,J=5.4Hz,1H),7.37-7.44(m,2H)。
反式-2-甲氧基-5-[2-(4-甲氧基-苯并[b]噻吩-6-基)-乙烯基]-苯酚
油。
1H-NMR(CDCl3)δ:3.85(s,3H),3.95(s,3H),5.54(s,1H),6.76-6.85(m,3H),6.98(s,2H),7.10(d,J=2Hz,1H),7.19(s,1H),7.36-7.39(m,1H),7.47(s,1H)。
通过光化学异构化制备19a(ST2151)和19c(ST2179)
根据下述方案10中的合成制备该化合物。
方案10
获得47a,c的一般方法
往在二氯甲烷(4,8ml)中的20a(ST2152)或20c(ST2180)(1,2mmol)的溶液加入吡啶(2,1当量)和4-二甲基氨基吡啶(催化量),并在干燥的烧瓶中搅拌。
在0℃下滴加溶于二氯甲烷(1,9ml)的乙酰氯(2当量),并将混合物于室温下搅拌过夜。
用二氯甲烷稀释反应物,用HCl(10%水溶液)洗涤2次,用水洗涤2次,用饱和碳酸氢盐溶液洗涤2次,并用饱和盐水洗涤1次。用无水硫酸钠干燥有机层,并在真空下浓缩。不经进一步纯化使用粗物质。
获得48a,c的一般方法
将粗品47分成300mg部分,并溶于甲醇(300ml ca.),所有部分如下处理:将UV-VIS灯浸在溶液中并打开。大约45分钟后关灯,将灯取出,并排空溶剂。合并所得的粗物质,并不经进一步纯化使用。
用于19a(ST2151)的一般方法
0℃下往在THF(3ml)、甲醇(1ml)和水(1ml)中的48(1mmoli)的搅拌的溶液加入氢氧化锂(3当量)。室温下1小时后,在真空下浓缩混合物,用水稀释,并用二乙醚洗涤(两次)。将水层酸化,用二乙醚萃取(三次),并用无水硫酸钠干燥。用硅胶柱色谱法纯化产物。从20a,c开始的总产率为大约50%。
光化学异构化:药物和前药形式的茋衍生物-本发明的目的-可以通过与电磁辐射,特别是紫外-可见光接触而光异构化。在有机溶液(MeOH、AcOEt等)中,在氩气氛下,存在独立于E/Z起始异构体的光化学异构化,且通常E/Z比率为70∶30。
获得化合物54和55的一般方法
可以如关于ST2151和ST2179所述的相同方式获得这些化合物(方案11)。
方案11
a:X=S,R1=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br;R2=H
b:X=S,R1=H;R2=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br;R2=H
c:X=O,R1=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br;R2=H
d:X=O,R1=H;R2=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br;
a:X=S,R1=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br;R2=H;R3=TBDMSi
b:X=S,R1=H;R2=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br;R3=TBDMSi
c:X=O,R1=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br,R2=H;R3=TBDMSi
d:X=O,R1=H;R2=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br;R3=TBDMSi
a:X=S,R1=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br,R2=H;R3=TBDMSi
b:X=S,R1=H;R2=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br,R2=H;R3=TBDMSi
c:X=O,R1=CH3,CH3CH2,(CH3)2CH,C6H6,C6H6,OCH3,OCH2CH3,C5H5N,Br;R2=H;R3=TBDMSi
d:X=O,R1=H;R2=CH3,CH3CH2,(CH3)2CH,C6H6,OCH3,OCH2CH3,C5H5N,Br;R3=TBDMSi
获得化合物56的一般方法
通过方案12所述的路线制备前药56。首先用典型的甲氧基-磷酸化方法,用氢化钠处理酚残基,然后用如所述的方法[Mantyla A.等人,Tetrahedron Lett.2002,43,3793-4]制备的受保护的磷酸氯甲酯处理。使用饱和EtOAc/HCl溶液除去保护基,然后在NaOH/H2O溶液中制备二钠盐。
方案12
获得化合物57的一般方法
从氨基茋衍生物开始,通过Fmoc路线产生与氨基酸的偶合,然后裂解α-氨基保护基[G.R.Pettit等人,J.Med.Chem 2002,46,525-31]。
方案13
方案14
获得ST2891、ST2892、化合物ST2933和ST2934的一般方法
往NaH的悬浮液(80%,在矿物悬浮液中,7.4mmol,3.7当量,220mg)加入磷鎓盐(62)(8mmol,4.06g.,4当量),并将混合物于室温下搅拌30分钟。然后将在10mL无水THF中的醛17a-c(2mmol)的溶液加到反应先前冷却至4℃的反应混合物。将其于室温下搅拌1.5小时,并用C盐床过滤,用THF洗涤。进行蒸发,用DCM(15mL)萃取残余物,并用水(5mL)和盐水(5mL)洗涤有机相,脱水并再次蒸发。
对于其中的酚羟基作为TBDMS醚保护的衍生物,将残余物溶于DCM(10mL),并加入TBAF(6mmol,3当量)。室温下1小时后,用DCM(5mL)稀释混合物,用水(3×5mL)和盐水(5mL)洗涤,并脱水(Na2SO4)。为纯化这些产物,使用硅胶色谱法,采用以下类型的洗脱梯度:己烷/EtOAc 99∶1,9∶1,85∶15。
6-[(Z)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇-ST2892;
白色固体,m.p.=121-123℃。
1H-NMR(CDCl3)δ:3.68(s,3H),5.93(s,2H),6.49(d,J=12.3Hz,1H),6.51(s,2H),6.56(d,J=12.3Hz,1H),6.67(s,1H),7.33(d,J=5.5Hz,1H),7.39(s,1H),7.40(d,J=5.5Hz,1H)。
6-[(E)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇-ST2891
白色固体,m.p.=148-150℃。
1H-NMR(CDCl3)δ:3.95(s,3H),5.99(s,2H),6.66(s,1H),6.76(s,1H),6.90(s,1H),6.98(s,2H),7.34(d,J=5.5Hz,1H),7.42(d,J=5.5Hz,1H),7.53(s,1H)。
6-[(Z)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇-ST2933;
浅黄色油。
1H-NMR(CDCl3)δ:3.72(s,3H),5.95(s,2H),6.48(d,J=9.3Hz,1H),6.49(s,2H),6.53(d,J=9.3Hz,1H),6.61(s,1H),6.81(d,J=2.2Hz,1H),7.07(s,1H),7.54(d,J=2.2Hz,1H)。
MS=309[M-1]
6-[(E)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇-ST2934。
白色固体。
1H-NMR(CDCl3)δ:3.96(s,3H),6.01(s,2H),6.66(d,J=1.5Hz,1H),6.76(d,J=1.5Hz,1H),6.85(s,1H),6.86(d,J=2.2Hz,1H),6.97(s,2H),7.23(s,1H),7.56(d,J=2.2Hz,1H)。MS=309[M-1]
方案15
获得61的一般方法
4℃下将NaBH4(65.4mmol,1.2当量,2.47g)加到化合物60(54.5mmol,9.82g)的溶液。反应在1小时内完成,减压下除去溶剂,然后在EtOAc和水之间洗涤残余物,并用硅胶色谱法,使用以下梯度纯化粗产物:己烷/EtOAc 9∶1,7∶3,65∶35。
白色固体,m.p.=64-66℃。
1H-NMR(CDCl3)δ:2.24(s,1H),3.92(s,3H),4.58(s,2H),5.98(s,2H),6.56(s,2H)。
获得62的一般方法
4℃下往在THF(100mL)中的61(53.8mmol,9.8g)和吡啶(0.260mL)的溶液加入PBr3(134.5mmol,12mL,2.5当量)。在此温度下3小时后反应完成,并在水和二乙醚之间洗涤反应混合物,用饱和NaHCO3中和收集的有机层,并用Na2SO4脱水。在减压下除去溶剂。
将在二甲苯(100mL)中的PPh3(64.5mmol,16.93g,1.2当量)的溶液滴至在二甲苯(120mL)中的粗品溴化物的溶液;将反应混合物回流1.5小时,直至反应完全。将悬浮液冷却至室温,并过滤得到目标产物,为一种白色固体。
白色固体,m.p.=159-162℃。
1H-NMR(CD3OD)δ:3.56(s,3H),5.93(s,2H),6.17-6.22(m 2H),7.64-7.98(m,17H)。
细胞培养和细胞毒性试验
在系列人和鼠细胞系中评价我们的衍生物的细胞毒性作用。
将购自BioWhit-taker公司的人脐静脉内皮细胞(HUVEC)保存在EGM-2培养基(BioWhit-taker)中。
将分离自牛肾上腺的牛微循环内皮细胞(BMEC)保存在含有20%FBS、50μg/ml牛脑提取物(BBE),50单位/ml肝素(SIGMA)、100单位/ml庆大霉素(SIGMA)和10mg/ml L-谷氨酰胺(Hyclone)的DMEM中培养。在加有10%FBS和庆大霉素的DMEM中培养购自巴里大学生物医学科学和人肿瘤学学部(University of Bari Department of BiomedicalSciences and Human Oncology)的EA-hy926-一种HUVEC和腺癌细胞的永生杂交瘤。
根据制造商的指示培养购自ATCC的以下细胞系:MeWo人黑素瘤、NCI-H460人肺癌、LoVo人结肠腺癌、PC3人前列腺癌、MES-SA人子宫肉瘤、HCT 116人结肠直肠癌、MCF-7人乳腺癌。
在含有10%FBS和抗生素的RPMI中培养购自米兰肿瘤研究所(Milan Tumour Institute)的M109鼠肺癌系、HT29人结肠腺癌系、A2780人卵巢癌系。
在含有10%FBS和抗生素的DMEM中培养购自米兰的M.Negri研究所的B16/BL6鼠黑素瘤系。
对于细胞毒性试验,根据细胞类型在96孔平板中以可变的密度将细胞接种于正常培养基中(200μl/孔),并在37℃下温育24小时。在第二天,以标量浓度加入研究物质,并将细胞于37℃和含有5%CO2的潮湿气氛下再培养24小时。在培养期结束时,除去含有物质的培养基,并用PBS洗涤三次。在洗涤结束时,加入200μl/孔的新鲜培养基,并将该平板于37℃下再培养48小时。在此培养期结束时,通过翻转平板移出培养基,并加入200μl/孔PBS和50μl 80%冷三氯乙酸(TCA)。然后在冰上温育平板。1小时后移出TCA,通过在蒸馏水中浸泡将平板洗涤三次,并首先在吸墨纸上干燥,随后在烘箱中干燥。然后,将200μl在1%乙酸中的0.4%硫代若丹明(sulforodamine)B加到所有孔。将该平板在室温下再温育30分钟。通过翻转来移出硫代若丹明B,通过在1%乙酸中浸泡来洗涤该平板三次,然后首先在吸墨纸上干燥,随后在烘箱中干燥。接着,将200μl Tris碱10mM加到所有的孔,并将该平板搅拌至少20分钟。用分光光度读出装置在540nm下测定光密度。
表1显示ST2151和ST2179的IC50值,即能够抑制细胞存活达50%的浓度,该浓度用ALLFIT软件处理。在相同的表中报道了ST2897、ST2898和ST2899对BMEC的IC50。
表1
IC50±SE(nM) | ||||
细胞系 | ST2151 | ST2179 | ST2495 | ST2496 |
BMEC | 87±1 | 49±1 | 640±40 | 340±16 |
HUVEC | 49±0.64 | n.d. | 83±2.06 | 85±1.2 |
EAHY.926 | 52±4.9 | 40±3.9 | - | - |
NCI-H460 | 74±2.9 | 53±1.3 | 620±65 | 780±3.4 |
M109 | 490±30 | 93±6 | - | - |
HT29 | 900±65 | 990±40 | >10000 | 3900±70 |
LoVo | 360±0.01 | 490±0.04 | - | - |
PC3 | 120±0.01 | 100±0.01 | - | - |
B16/BL6 | 85±0.5 | 44±3.8 | >10000 | 4140±490 |
A2780 | 70±2 | 50±2 | 500±20 | 260±6 |
MeWo | 68±5 | 71±17 | 830±0.13 | 820±7.7 |
MESSA | 86±10 | 40±4 | 1420±49 | 500±50 |
HCT-116 | 84±3.8 | 54±9 | 3000±102 | 1680±70 |
MCF-7 | 66±2.7 | 38±3 | 693±21 | 646±29 |
IC50±SE(nM) | ||||
细胞系 | ST2897 | ST2898 | ST2899 | |
BMEC | 35±1.8 | 35±0.3 | <<40 |
微管蛋白聚合抑制试验
如Shiff等人(Biochemistry,1981,20:3247-3252)所述,并进行一些改变,在ST2151存在下进行微管蛋白聚合试验。简言之,将富含微管相关蛋白(MAP)的微管蛋白在含有1mM GTP(GPEM)的PEM缓冲液[100mM PIPES(pH6.9),1mM EGTA和1mM MgCl2]中稀释至浓度为3mg/ml并在冰上保存。将溶液置于37℃,并在340nm下每25秒用配备电子温度控制仪的分光光度计(Cobas-Mira Analyzer)测定吸光度来监测聚合反应。5分钟后,当聚合微管蛋白达到稳态时,加入5μM紫杉醇、1,35μM秋水仙酰胺或ST2151,并再测定吸光度15分钟。通过非线性回归分析,使用″Prism GraphPad″软件测定IC50值。结果表示为相对于未处理的对照而言对微管蛋白聚合的抑制%。
表2所示的值为3次独立测定的平均值。
表2
化合物 对微管蛋白聚合的抑制%
ST2151 37.1
ST2179 44.0
评价抗癌活性
在人肺癌的动物模型中分析ST2495和ST2496的抗癌活性。
在此模型中,以3×106细胞/小鼠的密度将人NCI-H460肺癌细胞皮下注射在CD1裸鼠的右胁。从接种肿瘤细胞后第4天开始,用不同剂量的研究分子并根据不同的治疗方案(参见表)治疗动物。
在治疗期间将所有动物称重以调节药物给药体积和记录体重降低百分率(%BWL)。
通过每周二次周游标卡尺测定各个肿瘤的较短的直径(宽度)和较长的直径(长度)来评价肿瘤生长,并根据肿瘤生长抑制百分率评价抗癌活性。用下式计算肿瘤体积:以mm3为单位的肿瘤体积(TV)=[长度(mm)×宽度(mm)2]/2。根据以下方程计算抑制百分率(%TVI):100-[(治疗组的平均肿瘤体积/对照组的平均肿瘤体积)×100]。P≤0.05的值被认为在统计学上是显著的。
用ST2495和ST2496进行的实验的结果分别表示在表3和4中。
表3
%TVI肿瘤接种后天数 | |||||
治疗 | n | %BWL | 死亡率 | 15 | 22 |
载体(5%葡萄糖溶液) | 8 | 0 | 0/8 | / | / |
ST2495i.p 30mg/kg | 8 | 4 | 0/8 | 32** | 38* |
ST2495i.p 30mg/kg两次/天 | 8 | 0 | 0/8 | 75** | 72** |
载体(5%葡萄糖溶液) | 8 | 11 | 0/8 | / | / |
ST2495p.o 30mg/kg两次/天 | 8 | 0 | 0/8 | 42** | 30* |
ST2495p.o 60mg/kg两次/天 | 8 | 1 | 0/8 | 79** | 67** |
载体(5%葡萄糖溶液) | 8 | 2 | 0/8 | / | / |
ST2495i.v.60mg/kg | 8 | 1 | 0/8 | 84** | 73** |
ST2495i.v.90mg/kg | 8 | 00 | 0/8 | 81** | 62** |
从第4天至第22天根据方案qd5x/w每天一次或两次腹膜内或经口施用ST2495,从第4天至第16天根据方案q2dx6进行静脉内施用。
*P<0.05,**P<0.01(Mann Whithney′s检验)
表4
%TVI肿瘤接种后天数 | |||||
治疗 | n | %BWL | 死亡率 | 14 | 21 |
载体(盐水) | 8 | 1 | 0/8 | / | / |
ST2496p.o.30mg/kg | 8 | 1 | 0/8 | 48* | 46* |
载体(5%葡萄糖溶液) | 8 | 1 | 0/8 | / | / |
ST2496i.v.60mg/kg | 8 | 1 | 0/8 | 48** | 53** |
ST2496i.v.90mg/kg | 8 | 11 | 0/8 | 57*** | 56* |
从接种肿瘤之后第4天至第14天根据qdx5/w方案以所示的剂量经口(p.o.)施用化合物,或者从第5天至第17天根据q2dx6方案以所示的剂量静脉内施用化合物。
*P<0.05;**P<0.01,***P<0.001
从表中可以看出,ST2495采用所有的给药途径都证明具有活性。值得注意的是,当每天两次施用化合物时,i.p.和p.o.治疗中的体积抑制%明显增加。
口服或静脉内给药的ST2496与对照组相比也产生明显的肿瘤抑制作用。
心血管参数的评价
最近来自I期研究的数据表明考布他汀A4-P避免不了副作用,表现出限制剂量的毒性的发作,包括急性冠脉综合征的病例(CancerRes.,62:3408-3416,2002)。基于这些结果,且由于心血管副作用代表抗血管剂的主要问题,我们决定研究我们所选择的化合物对心血管参数的影响。
考布他汀A4、它的前药ST2494和我们选择的水溶性化合物ST2495和ST2496,在盐水溶液中稀释至剂量为20或40mg/kg,或者对于考布他汀A4在5%DMSO中稀释,将其注射至用55mg/kg戊巴比妥麻醉的Wistar大鼠颈静脉。所考虑的参数为血压和心率。考布他汀A4和它的前药ST2494在给药后不久即引起血压明显增高和心率进行性降低。相比之下,ST2495和ST2496没有表现出对所考虑的参数具有显著的影响(图1)。
与本发明的另一目的一致的是,药物组合物包含至少一种式(I)化合物作为活性成分,其量为在不导致心血管副作用的情况下产生明显的治疗效果。本发明涵盖的组合物完全是常规的,并使用在制药工业中常规实施的方法获得,所述方法例如在Remington′sPharmaceutical Science Handbook,Mack Pub.N.Y.-最新版中作了说明。根据选择的给药途径,该组合物可以是固体或液体剂型,适于口、肠胃外或静脉内给药。根据本发明的组合物包含活性成分和至少一种药学上可接受的载体或赋形剂。它们可以具体为制剂中的有用助剂,例如增溶剂、分散剂、助悬剂和乳化剂。
Claims (18)
1.式(I)化合物、它们的对映异构体、非对映异构体、各自的混合物和它们的药学上可接受的盐
其中
各个R1、R2、R3和R4可以相同或不同,为H、OH、OPO3H2或OCH2OPO3H2和它们的二钠盐、OMe、OCH2O、NO2、F、Cl、Br;
-R1-R2-还可以一起为:-CR8=CR9-X-
Y为选自以下的基团:
R5和R6可以相同或不同,为H或卤素;
R7为H、OMe、SO2Ph;
Ar为选自以下的基团:
R8、R9和R10可以相同或不同,为H、OH、OPO3H2或OCH2OPO3H2和它们的二钠盐、OR11、OCH2O、NH2、NHR11、NO2、烷基(C1-C4)、C6H5、C5H4N或卤素;
R11为C1-C4烷基或酰基、氨基酸残基;
X为O、S、N、NR12;
R12为H、CH3、CH2Ph;
Z为CH、N;
条件是式(I)化合物不是考布他汀A-1、考布他汀A-2、考布他汀A-4,和它们的磷酸二钠衍生物,并排除以下化合物:
2-苯基-6-反式-苯乙烯基-苯并[b]呋喃;
2,3-二苯基-6-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-6-(4-甲氧基)-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-6-(3,4-二甲氧基)-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-6-(3,4,5-三甲氧基)-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-6-(3,4-亚甲二氧基)-反式-苯乙烯基-苯并[b]呋喃;
2,3-二苯基-6-(4-甲氧基)-反式-苯乙烯基-苯并[b]呋喃;
2-苯基-5-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-5-(4-甲氧基)-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-5-(3,4-亚甲二氧基)-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-6-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-6-(4-甲氧基)-反式-苯乙烯基-苯并[b]噻吩;
2-苯基-6-(4-氯)-反式-苯乙烯基-苯并[b]噻吩;
Piceatannol;
1-(3-呋喃基)-2-(3,4,5-三甲氧基苯基)乙烯;
1-(3-噻吩基)-2-(3,4,5-三甲氧基苯基)乙烯;
1-(2-呋喃基)-2-(3,4,5-三甲氧基苯基)乙烯;
并且条件是:
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为2-氯时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为三甲氧基,Y为双键,R5和R6为H,Ar为苯基时,R8-R10中至少一个不为氢;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-氯、4-溴、4-硝基、4-羟基、4-乙酰基、4-乙氧基、4-C1-C4烷基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-硝基或4-氨基时,R10不为3-氯、3-甲氧基、3-甲基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-硝基或3-氨基时,R10不为3-氯、3-甲氧基、3-甲基;
-当R1为氢,而R2-R4为2,3,4-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,至少一个R8为氢,R9为3-甲氧基时,R10不为5-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基时,R8-R10不为甲氧基;
-当R1和R2为氢,而R3-R4为3,4-二甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-甲氧基;
-当R1和R2为氢,而R3-R4为3,4-二甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢时,R9-R10不为3,5-二甲氧基;
-当R1和R2为氢,而R3-R4为3,4-二甲氧基,Y为双键,R5和R6为H,Ar为苯基时,R8-R10中至少一个不为氢;
-当R1和R2为氢,而R3-R4为3,5-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-甲氧基;
-当R1和R2为氢,而R3-R4为3,5-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-乙酰基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H时,Ar不为吡啶基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基,R10为4-NHR11时,R11不为丝氨酸残基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为具有1-3个碳原子的4-烷氧基或具有1-4个碳原子的4-烷基或卤原子;
-当R1为氢,而R2-R3为3,4-亚甲二氧基,R4为5-甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为2,3,4-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为NHR11,R11为丝氨酸残基时,R10不为4-甲氧基;
-当R1为氢,而R2-R3为3,4-亚甲二氧基,R4为4-甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为NHR11,R11为氨基酸半胱氨酸、甘氨酸、苯丙氨酸、丝氨酸、色氨酸、酪氨酸、缬氨酸的残基时,R10不为4-甲氧基;
-当R1为氢,而R2-R3为3,4-亚甲二氧基,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为NO2或NH2时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基时,R8-R10中至少一个不为氢;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-氟;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲基时,R10不为3-氟或3-羟基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为3-氟,R9为4-甲氧基时,R10不为2-或5-氟;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-羟基或3-氨基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-氟或3-溴;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-羟基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-甲基时,R10不为4-甲基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-羟基;
-当R1-R2为氢,而R3-R4为3,5-二羟基,Y为反式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-羟基时,R10不为5-羟基;
-当R1-R3为氢,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9和R10为3,4-二甲基时,R4不为4-甲氧基;
-当R1-R2为氢,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9和R10为3,4-二甲基,R4为4-甲氧基时,R3不为3-氟或3-溴或3-硝基或3-羟基;
-当R1-R2为氢,Y为双键,R5和R6为H,Ar为苯基,R8-R10为3,4,5-三乙氧基,R4为4-甲氧基时,R3不为3-氟或3-氯或3-溴或3-羟基;
-当R1-R2为氢,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8-R9为4,5-二甲氧基,R10为3-羟基时,R3不为3-氟或3-羟基;
-当R1-R2为氢,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8-R9为4,5-二甲氧基,R10为3-甲氧基时,R3不为3-氟;
-当R1为氢,R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为2-萘基时,R8-R10中至少一个不为氢;
-当R1和R2为氢,R3为3-羟基,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为2-萘基时,R8-R10中至少一个不为氢;
-当R1为氢,R2-R4为3,4,5-三甲氧基,Y为
Ar为吲哚基时,其中R8-R10中至少一个不为氢。
2.根据权利要求1的化合物,选自:
2-甲氧基-5-[3-甲氧基-5-(3,4,5-三甲氧基-苯基)-4,5-二氢-4-异噁唑基]-苯酚;
2-甲氧基-5-[3-甲氧基-4-(3,4,5-三甲氧基-苯基)-4,5-二氢-5-异噁唑基]-苯酚;
5-[3-苯磺酰基-4-(3,4,5-三甲氧基-苯基)-4,5-二氢-4-异噁唑基]-2-甲氧基-苯酚;
5-[3-苯磺酰基-5-(3,4,5-三甲氧基-苯基)-4,5-二氢-5-异噁唑基]-2-甲氧基-苯酚;
2-甲氧基-5-[3-(3,4,5-三甲氧基-苯基)-4,5-二氢-5-异噁唑基]-苯酚;
2-甲氧基-5-[5-(3,4,5-三甲氧基-苯基)-4,5-二氢-3-异噁唑基]-苯酚;
2-甲氧基-5-[5-(3,4,5-三甲氧基-苯基)-3-异噁唑]-苯酚;
顺式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-4-醇;
反式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-4-醇;
顺式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩;
反式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩;
顺式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-4-醇;
反式-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-4-醇;
顺式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃;
反式-4-甲氧基-6-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃;
顺式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-7-醇;
反式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并[b]噻吩-7-醇;
顺式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-7-醇;
反式-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-苯并呋喃-7-醇;
顺式-1-甲氧基-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘;
甲氧基-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘;
顺式-7-甲氧基-1-甲基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-1H-吲唑;
反式-7-甲氧基-1-甲基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-1H-吲唑;
2-硝基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-噻吩;
2-硝基-5-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-呋喃;
顺式-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘-1-醇;
反式-3-[2-(3,4,5-三甲氧基-苯基)-乙烯基]-萘-1-醇;
6[(Z)-2-(3,4,5-三甲氧基-苯基)乙烯基]-1-苯并噻吩-4-醇4-O-磷酸二钠;
6[(Z)-2-(3,4,5-三甲氧基苯基)乙烯基]-1-苯并呋喃-4-醇4-O-磷酸二钠;
6-[(Z)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇;
6-[(E)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇;
6[(Z)-2-(3-甲氧基-4,5-亚甲二氧基-苯基-1-基)-乙烯基]-1-苯并呋喃-4-醇;
6[(E)-2-(3-甲氧基-4,5-亚甲二氧基-苯基-1-基)-乙烯基]-1-苯并呋喃-4-醇;
6[(Z)-2-(3,4,5-三甲氧基-苯基)乙烯基]-1-苯并噻吩-4-醇4-O-甲氧基磷酸二钠;
6[(Z)-2-(3,4,5-三甲氧基苯基)乙烯基]-1-苯并呋喃-4-醇4-O-甲氧基磷酸二钠;
6-[(Z)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇;
6-[(E)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇;
6[(Z)-2-(3-甲氧基-4,5-亚甲二氧基-苯基-1-基)-乙烯基]-1-苯并呋喃-4-醇;
6[(E)-2-(3-甲氧基-4,5-亚甲二氧基-苯基-1-基)-乙烯基]-1-苯并呋喃-4-醇;
6[(Z)-2-(3,4,5-三甲氧基-苯基)乙烯基]-1-苯并噻吩-4-醇4-O-甲氧基磷酸二钠;
6[(Z)-2-(3,4,5-三甲氧基苯基)乙烯基]-1-苯并呋喃-4-醇4-O-甲氧基磷酸二钠;
6-[(Z)-2-(7-甲氧基-1,3-苯并间二氧杂环戊烯-5-基)乙烯基]-1-苯并噻吩-4-醇;
顺式-2-甲氧基-5-[2-(4-甲氧基-苯并呋喃-6-基)-乙烯基]-苯酚;
顺式-2-甲氧基-5-[2-(7-甲氧基-苯并呋喃-5-基)-乙烯基]-苯酚;
顺式-2-甲氧基-5-[2-(4-甲氧基-苯并[b]噻吩-6-基)-乙烯基]-苯酚;
顺式-6-[2-(3,5-二甲氧基-苯基)-乙烯基]-苯并[b]噻吩-4-醇;
顺式-5-[2-(3,5-二甲氧基-苯基)-乙烯基]-苯并呋喃-7-醇;
顺式-6-[2-(3,5-二甲氧基-苯基)-乙烯基]-苯并呋喃-4-醇;
它们的对映异构体、非对映异构体、各自的混合物和它们的药学上可接受的盐。
3.式(I)化合物、它们的对映异构体、非对映异构体、各自的混合物和它们的药学上可接受的盐作为药物的应用,
其中
各个R1、R2、R3和R4可以相同或不同,为H、OH、OPO3H2或OCH2OPO3H2和它们的二钠盐、OMe、OCH2O、NO2、F、Cl、Br;
-R1-R2-还可以一起为:-CR8=CR9-X-
Y为选自以下的基团:
顺式或反式
R5和R6可以相同或不同,为H或卤素;
R7为H、OMe、SO2Ph;
Ar为选自以下的基团:
R8、R9和R10可以相同或不同,为H、OH、OPO3H2或OCH2OPO3H2和它们的二钠盐、OR11、OCH2O、NH2、NHR11、NO2、烷基(C1-C4)、C6H5、C5H4N或卤素;
R11为C1-C4烷基或酰基、氨基酸残基;
X为O、S、N、NR12;
R12为H、CH3、CH2Ph;
Z为CH、N;
条件是式(I)化合物不为考布他汀A-1、考布他汀A-2、考布他汀A-4和它们的磷酸二钠衍生物,并排除以下化合物:
Piceatannol;
1-(3-呋喃基)-2-(3,4,5-三甲氧基苯基)乙烯;
1-(3-噻吩基)-2-(3,4,5-三甲氧基苯基)乙烯;
1-(2-呋喃基)-2-(3,4,5-三甲氧基苯基)乙烯;
并且条件是
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为2-氯时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为三甲氧基,Y为双键,R5和R6为H,Ar为苯基时,R8-R10中至少一个不为氢;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-氯、4-溴、4-硝基、4-羟基、4-乙酰基、4-乙氧基、4-C1-C4烷基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-硝基或4-氨基时,R10不为3-氯、3-甲氧基、3-甲基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-硝基或3-氨基时,R10不为3-氯、3-甲氧基、3-甲基;
-当R1为氢,而R2-R4为2,3,4-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,至少一个R8为氢,R9为3-甲氧基时,R10不为5-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基时,R8-R10不为甲氧基;
-当R1和R2为氢,而R3-R4为3,4-二甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-甲氧基;
-当R1和R2为氢,而R3-R4为3,4-二甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢时,R9-R10不为3,5-二甲氧基;
-当R1和R2为氢,而R3-R4为3,4-二甲氧基,Y为双键,R5和R6为H,Ar为苯基时,R8-R10中至少一个不为氢;
-当R1和R2为氢,而R3-R4为3,5-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-甲氧基;
-当R1和R2为氢,而R3-R4为3,5-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-乙酰基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H时,Ar不为吡啶基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基,R10为4-NHR11时,R11不为丝氨酸的残基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为具有1-3个碳原子的4-烷氧基或具有1-4个碳原子的4-烷基或卤原子;
-当R1为氢,而R2-R3为3,4-亚甲二氧基,R4为5-甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为2,3,4-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-氨基时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为NHR11,R11为丝氨酸残基时,R10不为4-甲氧基;
-当R1为氢,而R2-R3为3,4-亚甲二氧基,R4为4-甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为NHR11,R11为氨基酸半胱氨酸、甘氨酸、苯丙氨酸、丝氨酸、色氨酸、酪氨酸、缬氨酸的残基时,R10不为4-甲氧基;
-当R1为氢,而R2-R3为3,4-亚甲二氧基,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为NO2或NH2时,R10不为4-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基时,R8-R10中至少一个不为氢;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-氟;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲基时,R10不为3-氟或3-羟基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-甲氧基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为3-氟,R9为4-甲氧基时,R10不为2-或5-氟;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-羟基或3-氨基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-氟或3-溴;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8和R9为氢时,R10不为4-羟基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-甲基时,R10不为4-甲基;
-当R1为氢,而R2-R4为3,4,5-三甲氧基,Y为顺式双键,R5和R6为H,Ar为苯基,R8为氢,R9为4-甲氧基时,R10不为3-羟基;
-当R1-R2为氢,而R3-R4为3,5-二羟基,Y为反式双键,R5和R6为H,Ar为苯基,R8为氢,R9为3-羟基时,R10不为5-羟基;
-当R1-R3为氢,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9和R10为3,4-二甲基时,R4不为4-甲氧基;
-当R1-R2为氢,Y为双键,R5和R6为H,Ar为苯基,R8为氢,R9和R10为3,4-二甲基,R4为4-甲氧基时,R3不为3-氟或3-溴或3-硝基或3-羟基;
-当R1-R2为氢,Y为双键,R5和R6为H,Ar为苯基,R8-R10为3,4,5-三乙氧基,R4为4-甲氧基时,R3不为3-氟或3-氯或3-溴或3-羟基;
-当R1-R2为氢,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8-R9为4,5-二甲氧基,R10为3-羟基时,R3不为3-氟或3-羟基;
-当R1-R2为氢,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为苯基,R8-R9为4,5-二甲氧基,R10为3-甲氧基时,R3不为3-氟;
-当R1为氢,R2-R4为3,4,5-三甲氧基,Y为双键,R5和R6为H,Ar为2-萘基时,R8-R10中至少一个不为氢;
-当R1和R2为氢,R3为3-羟基,R4为4-甲氧基,Y为双键,R5和R6为H,Ar为2-萘基时,R8-R10中至少一个不为氢;
-当R1为氢,R2-R4为3,4,5-三甲氧基,Y为
Ar为吲哚基时,其中R8-R10中至少一个不为氢。
4.根据权利要求3的应用,用于制备治疗肿瘤类型疾病的药物。
5.根据权利要求3的应用,用于制备治疗对细胞毒性活性有反应的癌症的药物。
6.根据权利要求5的应用,其中该癌症选自肉瘤、癌、类癌、骨癌、神经内分泌癌、淋巴白血病、髓细胞白血病、单核细胞白血病、巨核细胞白血病或何杰金病。
7.根据权利要求1的化合物用于制备治疗与异常血管生成有关的疾病的药物的应用。
8.根据权利要求7的应用,其中该疾病选自关节炎病、对抗血管生成活性有反应的肿瘤、转移扩散、糖尿病性视网膜病、牛皮癣、慢性炎症和动脉粥样硬化。
9.根据权利要求4-8之任一项的应用,其中在肿瘤的治疗中,将该药物与至少一种其它抑制生长药联合。
10.根据权利要求9的应用,其中该抑制生长药选自烷化剂;拓朴异构酶抑制剂;抗微管蛋白剂;嵌入剂;抗代谢药;天然产物例如长春花属生物碱、表鬼臼毒素、抗生素、酶、紫杉烷类和抗癌疫苗。
11.药物组合物,含有作为活性成分的根据权利要求1-2或者在权利要求3中公开的化合物与药学上可接受的赋形剂或稀释剂的混合物。
15.具有下式的化合物作为中间产物用于制备根据权利要求1-2的化合物的应用,
其中X为氧或硫。
18.根据权利要求13-14和16-17的化合物作为中间产物在制备根据权利要求1-2的化合物中的应用。
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BRPI0607688A2 (pt) | 2005-02-17 | 2009-09-22 | Synta Pharmaceuticals Corp | método para inibir a polimerização de tubulina em uma célula; método para tratar ou prevenir um distúrbio proliferativo em um indivìduo; método para bloquear, ocluir ou de outro modo romper o fluxo sangüìneo na neovasculatura; composto; composição farmacêutica e uso do referido método e composto |
AU2006272652B2 (en) * | 2005-07-25 | 2011-06-16 | Synta Pharmaceuticals Corp. | 1,2,3-triazoles inhibitors of tubulin polymerization for the treatment of proliferative disorders |
US7781580B2 (en) * | 2007-04-23 | 2010-08-24 | Virginia Commonwealth University | Stilbene derivatives as new cancer therapeutic agents |
EP2219451B1 (en) | 2007-11-21 | 2014-11-12 | Oxigene, Inc. | Method for treating hematopoietic neoplasms |
CN102026634B (zh) | 2008-04-10 | 2014-01-22 | 弗吉尼亚州立邦联大学 | 诱导肿瘤缺氧以治疗癌症 |
CN102863388B (zh) * | 2011-07-05 | 2015-04-29 | 南京圣和药业股份有限公司 | 肿瘤靶向药物Combretastatin A4衍生物 |
WO2013047813A1 (ja) | 2011-09-30 | 2013-04-04 | 大鵬薬品工業株式会社 | 1,2,4-トリアジン-6-カルボキサミド誘導体 |
PL220039B1 (pl) * | 2012-03-29 | 2015-08-31 | Univ Medyczny Im Karola Marcinkowskiego W Poznaniu | Nowe pochodne (Z)-1,2-difenyloetenu |
CN102993115B (zh) * | 2012-12-08 | 2015-09-30 | 南京师范大学 | 一种3,5–二取代异噁唑啉衍生物及其合成方法和应用 |
JP2018523712A (ja) | 2015-08-18 | 2018-08-23 | マテオン セラピューティクス, インク.Mateon Therapeutics, Inc. | 腫瘍に対する免疫調節療法を向上させる為のvdasの使用 |
AU2017383102B2 (en) * | 2016-12-23 | 2023-05-11 | The University Of Queensland | Inhibitors of SOX18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases |
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FR2558158B1 (fr) * | 1984-01-13 | 1986-05-16 | Roussel Uclaf | Derives de l'indole ethenyl phenol, leurs sels, procede de preparation, application a titre de medicaments, compositions les renfermant et intermediaires |
US5468898A (en) * | 1990-09-10 | 1995-11-21 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted naphthylene compounds exhibiting selective leukotriene B4 antagonist activity |
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CN102249987B (zh) * | 2011-05-06 | 2013-07-24 | 兰州大学 | 一种考布他汀类化合物及其制备方法和用途 |
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AR045700A1 (es) | 2005-11-09 |
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ITRM20030355A1 (it) | 2005-01-19 |
WO2005007635A3 (en) | 2005-08-11 |
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KR20060039001A (ko) | 2006-05-04 |
JP2007530427A (ja) | 2007-11-01 |
EP1646616A2 (en) | 2006-04-19 |
WO2005007635A8 (en) | 2005-05-12 |
MXPA06000625A (es) | 2006-04-19 |
CA2531389A1 (en) | 2005-01-27 |
US20060160773A1 (en) | 2006-07-20 |
AU2004257011A1 (en) | 2005-01-27 |
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