CN1143629A - 芪衍生物和含有它们的药物组合物 - Google Patents
芪衍生物和含有它们的药物组合物 Download PDFInfo
- Publication number
- CN1143629A CN1143629A CN96107344A CN96107344A CN1143629A CN 1143629 A CN1143629 A CN 1143629A CN 96107344 A CN96107344 A CN 96107344A CN 96107344 A CN96107344 A CN 96107344A CN 1143629 A CN1143629 A CN 1143629A
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- China
- Prior art keywords
- amino
- trimethoxyphenyl
- phenyl
- methoxy
- mixture
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/33—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- C07C255/44—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms at least one of the singly-bound nitrogen atoms being acylated
Abstract
式(I)芪衍生物或其可药用盐是有效的制癌药并具有低毒性:其中X表示氢原子或氰基,且Y表示氨基酸酰基。
Description
本发明涉及顺式茋衍生物,它们作为药物的应用以及尤其是含有它们作为活性成分的制癌物。
已知含有顺式茋作为其基本骨架的Combre-tastatins具有强有力的有丝分裂抑制活性和强细胞毒性。然而,由于这些化合物在水中几乎不溶,故迄今它们仍未被实际用作药物。因此人们研究了有关其衍生物的进展情况(Molecular Pharmacology 34,Chii,M,Lin等,200-206,1988,J.Med,Chem.,Mark Cushman等,1991,34,2579-2588,International Laid-Open Patent WO92/16486,J.Med.Chem.,Marck Cushman等,1992,35,2293-2306,International Laid-Open Patent WO93/23357,J.Med.Chem.,Mark Cushman等,1993,36,2817-2821,和Bioorg.Med.Chem,Let.,Ryuichi Shirai等,Vol.4,No.5,pp699-704,1994)。尽管如此仍未发现有效化合物。
本发明涉及易被合成的Combretastatin衍生物,它们具有低毒性并具有药物作用,本申请还提供了包含它们的制癌物。
本申请发明人员研究了各种含有氨基酸酰基的茋衍生物并从中筛选出制癌化合物。从而它们发现下述式(I)化合物在动物试验中显示出惊人的制癌作用并具有低毒性。其中X表示氢原子或氰基,且Y表示氨基酸酰基。
式(1)中,氨基酸酰基表示派生于氨基酸的酰基。氨基酸包括α-氨基酸,β-氨基酸和γ-氨基酸。优选的氨基酸实例包括甘氨酸,丙氨酸,亮氨酸,丝氨酸,赖氨酸,谷氨酸,天冬氨酸,苏氨酸,缬氨酸,异亮氨酸,鸟氨酸,谷氨酰胺,天冬酰胺,酪氨酸,苯丙氨酸,胱氨酸,蛋氨酸,精氨酸,β-丙氨酸,色氨酸,脯氨酸,以及组氨酸。就药物作用和安全性而论,特别优选苏氨酸和丝氨酸。这些氨基酸可以是L-异构体或D-异构体。优选L-异构体。
本发明化合物优选的实例包括:(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-甘氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-丙氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-β-丙氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-亮氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-丝氢酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-苏氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-缬氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-异亮氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-脯氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-甲硫氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-谷氨酰胺酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-谷氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-天冬氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-天冬酰胺酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-赖氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-组氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-精氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-半胱氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-色氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-丙氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-亮氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-丝氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-苏氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-缬氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-异亮氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-脯氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氢基苯基)-乙烯-D-谷氨酰胺酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-谷氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-天冬氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-天冬酰胺酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-赖氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-组氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-精氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-半胱氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-甲硫氨酰胺(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-D-色氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-甘氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-丙氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-β-丙氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-亮氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-异亮氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-丝氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-苏氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-苯丙氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-酪氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-脯氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-赖氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-组氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-精氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-半胱氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-甲硫氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-色氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-α-天冬氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-β-天冬氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-天冬酰氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-α-谷氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-γ-谷氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-谷氨酰胺酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-丙氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-亮氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-异亮氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-丝氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-苏氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-苯丙氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-酪氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-脯氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-赖氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-组氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-精氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-半胱氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-甲硫氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-色氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-α-天冬氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-β-天冬氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-天冬酰氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-α-谷氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-γ-谷氨酰胺(E)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-D-谷氨酰胺酰胺
本发明式(5)化合物可通过下述方法形成:使式(2)(Z)-1-(3-氨基-4-甲氧苯基)-2-(3,4,5-三甲氧苯基)-乙烯与式(3)N-α-9-芴基甲氧羰基氨基酸衍生物在室温下于二甲基甲酰胺并在二环己基碳二亚胺(DCC)和1-羟基苯并三唑(HOBt)存在下反应6至12小时,然后通过色谱等其它方式纯化反应混合物,得到中间体(4),且将该中间体用氢氧化钠水溶液脱保护。
本发明式(10)化合物可通过下述方法形成:例如,在1-乙基-3-(3-二甲氨基丙基)碳二亚胺(WSCI)存在下将式(6)(E)-3-(3-氨基-4-甲氧苯基)-2-(3,4,5-三甲氧苯基)-丙-2-烯腈与式(7)N-α-叔丁氧羰基氨基酸衍生物在50℃下于二甲基甲酰胺中反应4小时,得到式(9)化合物,然后将此化合物用氢氯酸和二噁烷混合物脱保护。另一方面,式(10)化合物还可通过下述方法形成:在六氟合磷氢酸苯并三唑-1-基-氧-三(二甲氨基)鏻(Bop试剂)和三乙胺存在下使式(6)化合物与式(3)氨基酸衍生物在乙腈中于60℃反应24小时,形成式(8)化合物,然后用氢氧化钠水溶液或哌啶使式(8)化合物脱保护。
按上述方法所制的本发明茋衍生物还容易从反应混合物中分离出来并通过用溶剂提取,色谱层析,结晶等其它方式纯化。
当上述茋衍生物在本发明中用作抗肿瘤剂时,该药剂可通过口服或非肠道途径(肌内,皮下,静脉内途径,以栓剂等其它形式)给药。药剂剂量因疾病的发展程度而异,成人通常在1和3000mg之间。一般该药剂以1至9000mg/天的剂量分次给用。
当本发明茋衍生物配制成口服制剂时,如果需要,可向其中加入赋形剂,粘合剂,崩解剂,润滑剂,着色剂,矫味剂等,并将所形成的混合物制成片剂,涂层片剂,粒剂,胶囊等剂型。赋形剂的实例包括乳糖,玉米淀粉,糖类,葡萄糖,山梨醇,以及结晶纤维素。粘合剂的实例包括聚乙烯醇,聚乙烯醚,乙基纤维素,甲基纤维素,阿拉伯树胶,黄耆胶,明胶,紫胶,羟丙基纤维素,羟丙基淀粉,以及聚乙烯吡咯烷酮。崩解剂的实例包括淀粉,琼脂,凝胶粉,结晶纤维素,碳酸钙,碳酸氢钠,柠檬酸钙,环糊精,以及果胶。润滑剂的实例包括硬脂酸镁,滑石,聚乙二醇,硅石,以及硬化植物油。着色剂的实例包括允许加到药品中的色素。矫味剂的实例包括可可粉,薄荷醇,薄荷油,精制冰片,以及肉桂。如果需要,这些片剂和粒剂可用蔗糖,明胶等包衣。
当制备注射液时,可加入pH调节剂,稳定剂,防腐剂等。按常规方式制成皮下,肌内或静脉内注射液。
本发明茋衍生物可以与无机酸或有机酸形成药学上可接受的酸加成盐,所述无机酸如盐酸,硫酸和磷酸,有机酸如草酸,富马酸,马来酸,苹果酸,柠檬酸,酒石酸和谷氨酸。
实施例
本发明用下述实施例加以具体说明,但是,本发明并不局限于这些实施例。实施例1
合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-甘氨酰氨步骤1
合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-Fmoc-甘氨酰氨
将2g(6.3mmols)(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯,2.3gFmoc-Gly和11g(25mmols)BOP试剂溶于40ml二甲基甲酰胺中,且将混合物在60℃加热2小时。反应混合物冷却后,向其中加入饱和碳酸氢钠水溶液。所形成的混合物用二氯甲烷提取三次。提取物用无水硫酸钠干燥,减压浓缩至干。产物通过硅胶柱色谱纯化(1∶2的乙酸乙酯和己烷混合物洗脱),得1.63g最终产物,产率43.5%。
1H-NMR(CDCl3)δ;8.29(1H,s),8.11(1H,s),7.76(2H,d,J=7.5),7.60(2H,d,J=7.5),7.39(2H,t,J=7.2),7.30(2H,m),7.00(1H,dd,J=1.8,8.7),6.70(1H,d,J=8.7),6.51(1H,d,J=12,3),6.44(1H,d,J=12.3),4.44(2H,d,J=6.6),4.25(1H,m),4.04(2H,2H,br),3.84(3H,s),3.79(3H,s),3.68(6H,s)MS(m/Z):594(m+)。步骤2
合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-甘氨酰胺
将(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-Fmoc-甘氨酰胺(1.08g,1.82mmols)溶于20ml甲醇内并向其内加入1.0ml(2.0mmols)Z-N氢氧化钠水溶液。混合物搅拌3小时。加入饱和碳酸氢钠溶液,并将混合物用二氯甲烷提取三次。提取液用无水硫酸钠干燥,并减压浓缩至干。产物用硅胶板纯化(5-%甲醇和二氯甲烷的混合物为洗脱剂),得479mg最终产物,产率70.7%。
1H-NMR(CDCl3)δ;9.61(1H,brs),8.36(1H,d,J=1.8),7.00(1H,dd,J=1.8,8.4),6.72(1H,d,J=8.4),6.51(2H,s),6.53(1H,d,J=12.0),6.42(1H,d,J=12.0),3.87(3H,s),3.83(3H,s),3.68(6H,s)MS(m/Z):373(MH+);高分辨质谱,计算值-373.1763,实测值-373.1751。实施例2
合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-丙氨酰胺步骤1
合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-Fmoc-丙氨酰胺
将(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯(2.2g,6.9mmols),2.7g(8.3mmols)Fmoc-L-Ala和12.1g(27.6mmols)BOP试剂溶于22ml二甲基甲酰胺中,并将混合物在60℃加热4小时。待反应混合物冷却之后,向其中加入饱和碳酸氢钠水溶液,并将形成的混合物用二氯甲烷提取三次。提取液用无水硫酸钠干燥,并减压浓缩至干。产物通过硅胶柱色谱纯化(用1∶2的乙酸乙酯和己烷混合物洗脱),得1.79g最终产物,产率41.4%。
1H-NMR(CDCl3)δ;8.32(1H,d,J=1.8),8.19(1H,brs),7.76(2H,d,J=7.2),7.59(2H,d,J=7.2),7.39(2H,t,J=6.9),7.32(2H,m),7.01(1H,dd,J=1.8,8.7),6.69(1H,d,J=8.4),6.52(2H,s),6.51(1H,d,J=12.0),6.44(1H,d,J=12.0),5.35(1H,brs),4.42(3H,br),4.24(1H,m),3.84(3H,s),3.79(3H,s),3.69(6H,s),1.48(3H,d,J=6.9)质谱m/Z:60.8(M+)。步骤2
合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-丙氨酰胺
1g(1.6mmols)(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-Fmoc-L-丙氨酰胺溶于10ml甲醇中,并向其内加入0.9ml(1.76mmols)2-N氢氧化钠水溶液。混合物搅拌3小时。加入饱和氯化钠水溶液,并将所形成的混合物用二氯甲烷提取三次,提取液用无水硫酸钠干燥,并减压浓缩至干。产物用硅胶板纯化(5%甲醇和二氯甲烷混合物为洗脱剂),得543mg最终产物,产率87.9%。
1H-NMR(CDCl3)δ;9.72(1H,brs),8.39(1H,d,J=2.1),6.99(1H,dd,J=2.1,8.4),6.71(1H,d,J=8.4),6.52(1H,d,J=12.3),6.52(2H,s),6.42(1H,d,J=12.3),3.86(3H,s),3.83(3H,s),3.68(6H,s),3.64(1H,m),1.43(3H,d,J=7.2)质谱m/Z:387(MH+);高分辨质谱,计算值-387.1920,实测值-387.1922。实施例3合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-亮氨酰胺步骤1合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯Fmoc-L-亮氨酰胺
将(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯(1.92g,6.1mmols),2.58g(7.3mmols)Fmoc-L-Leu,1.5g(7.3mmols)DCC和1.1g(7.3mmols)HOBtH2O溶于40ml二甲基甲酰胺内,并将混合物室温反应12小时。反应混合物用乙酸乙酯稀释,然后过滤并浓缩。产物通过硅胶柱色谱纯化(用1∶2乙酸乙酯和己烷混合物洗脱),得到3.05g最终产物,产率76.9%。
1H-NMR(CDCl3)δ;8.32(1H,d,J=2.1),8.19(1H,s),7.75(2H,d,J=7.5),7.58(2H,d,J=7.5),7.39(2H,t,J=6.9),7.29(2H,m),7.00(1H,dd,J=2.1,8.4),6.69(1H,d,J=8.4),6.51(2H,s),6.50(1H,d,J=12.3),6.43(1H,d,J=12.3),5.29(1H,brs),4.43(2H,d,J=6.9),4.23(1H,t,J=6.9),3.83(3H,s),3.79(3H,s),3.68(6H,s),1.75(2H,br),11.55(1H,br),0.95(6H,br)质谱m/z:650(M+)步骤2合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-亮氨酰胺
1克(1.54mmols)(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-Fmoc-L-亮氨酰胺溶于10ml甲醇和10ml二氯甲烷内,并向其中加入0.9ml(1.7mmols)2-N氢氧化钠水溶液。混合物搅拌3小时。向其中加入饱和氯化钠水溶液,并将形成的溶液用二氯甲烷提取三次。提取液用无水硫酸钠干燥,并减压浓缩至干。产物通过硅胶柱色谱纯化(用10%用甲醇和二氯甲烷混合物洗脱),得到560mg最终产物,产率84.9%。
1H-NMR(CDCl3)δ;9.78(1H,brs),8.41(1H,d,J=1.8),6.99(1H,dd,J=1.81,8.4),6.70(1H,d,J=8.4),6.52(1H,d,J=12.3),6.52(2H,s),6.42(1H,d,J=8.4),3.87(3H,s),3.83(3H,s),3.68(6H,s),3.51(1H,m),1.80(2H,m),1.42(1H,m),0.98(6H,t,J=6.6)
质谱m/z:429(MH+);高分辨质谱,计算值-429.2389,实测值-429. 2391实施例4合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-丝氨酰胺步骤1合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-Fmoc-L-丝氨酰胺
将(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯(1.5g,4.76mmols),2.1g(5.7mmols)Fmoc-L-Ser(Ac),1.2g(5.7mmols)DCC和0.87g(5.7mmols)HOBt.H2O溶于30ml二甲基甲酰胺内,并将混合物室温反应5小时,反应混合物用乙酸乙酯稀释,然后过滤并浓缩。产物通过硅胶柱色谱纯化(用1∶2乙酸乙酯和己烷混合物洗脱),得到1.96g最终产物,产率61.8%。
1H-NMR(CDCl3)δ;8.38(1H,br),8.30(1H,d,J=1.8),7.76(2H,d,J=7.8),7.59(2H,d,J=7.8),7.40(2H,t,J=7.2),7.32(2H,m),7.03(1H,dd,J=1.8,8.7),6.71(1H,d,J=8.7),6.51(2H,s),6.51(1H,d,J=12.3),6.45(1H,d,J=12.3),5.53(1H,brs),4.62(1H,br),4.45(2H,d,J=6.9),4.25(1H,m),3.83(3H,s),3.80(3H,s),3.69(6H,s),2.65(2H,d,J=9.3),2.1(3H,s)质谱m/z:666(M+)步骤2合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-丝氨酰胺
将(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯Fmoc-L-丝氨酰胺(1.04g,1.56mmols)溶于10ml甲醇和10ml二氯甲烷内,并向其中加入1.7ml(3.4mmols)2-N氢氧化钠水溶液。混合物室温搅拌24小时。向其中加入饱和氯化钠水溶液,并将形成的溶液用二氯甲烷提取三次。提取液用无水硫酸钠干燥,并减压浓缩至于。产物通过硅胶板纯化(用5%甲醇和二氯甲烷混合物洗脱),得到315mg最终产物,产率50.2%。
1H-NMR(CDCl3)δ;9.77(1H,brs),8.34(1H,d,J=2.1),7.01(1H,dd,J=2.1,8.7),6.73(1H,d,J=8.7),6.52(2H,s),6.51(1H,d,J=12.3),6.43(1H,d,J=12.3),3.98(1H,dd,J=4.8,11.1),3.87(3H,s),3.84(3H,s),3.79(1H,dd,J=5.4,11.1),3.69(6H,s),3.59(1H,dd,J=5.1,5.4)
质谱m/z:403(MH+);高分辨质谱,计算值-403.1896,实测值-403.1826实施例5合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-苏氨酰胺步骤1合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-Fmoc-L-苏氨(AC)酰胺
将(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯(1.5g,4.76mmols),2.2g(5.7mmols)Fmoc-L-Thr(Ac),1.2g(5.7mmols)DCC和0.87g(5.7mmols)HOBtH2O溶于30ml二甲基甲酰胺内,并将混合物室温反应6小时。反应混合物用50ml乙酸乙酯稀释,然后过滤并浓缩。产物通过硅胶柱色谱纯化(用1∶2乙酸乙酯和己烷混合物洗脱),得到2.97g最终产物,产率91%。
1H-NMR(CDCl3)δ;8.36(1H,brs),8.29(1H,d,J=2.4),7.77(2H,m),7.61(2H,m),7.28-7.44(4H,m),7.02(1H,dd,J=2.1,8.7),6.72(1H,d,J=8.7),6.51(2H,s),6.51(1H,d,J=12.0),6.45(1H,d,J=12.0),5.72(1H,m),5.40(1H,m),4.48(2H,m),4.25(1H,m),3.83(3H,s),3.82(3H,s),3.69(6H,s),2.08(3H,s),1.24(3H,m)质谱m/z:680(M+)步骤2合成(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-L-苏氨酰胺
1克(1.47mmols)(Z)-1-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-乙烯-Fmoc-L-苏氨(AC)酰胺溶于20ml二噁烷内,并向其中加入1.76ml(3.5mmols)2-N氢氧化钠水溶液。混合物搅拌24小时。向其中加入饱和氯化钠水溶液,并将形成的溶液用二氯甲烷提取三次。提取液用无水硫酸钠干燥,并减压浓缩至干。产物使用硅胶板纯化(用7.5%甲醇和二氯甲烷混合物洗脱),得到448mg最终产物,产率73.4%。
1H-NMR(CDCl3)δ;9.86(1H,brs),8.37(1H,d,J=2.1),7.01(1H,dd,J=2.1,8.7),6.72(1H,d,J=8.7),6.52(2H,s),6.52(1H,d,J=12.0),6.43(1H,d,J=12.0),4.42(1H,m),3.87(3H,s),3.84(3H,s),3.69(6H,s),3.38(1H,m),1.25(3H,d,J=6.3)
质谱m/z:417(MH+);高分辨质谱,计算值-417.2026,实测值-417.2050实施例6合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-甘氨酰胺盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-甘氨酰胺
700mg(1.86mmols)(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈盐酸盐,478mgWSCI,375mgHOBt.H2O和486mgBoc-Gly溶于100ml二甲基甲酰胺,并向其中加入0.35ml三乙胺。混合物在50℃反应3.5小时。向其中加入700毫升水,并将形成的混合物用乙酸乙酯提取。随后乙酸乙酯层用水洗涤三次,无水硫酸钠干燥,并减压浓缩。产物用硅胶柱色谱纯化(洗脱剂,乙醚),然后溶于少量二氯甲烷内。向其中加入乙醚进行结晶,得1.71mmols最终产物,产率92%。
1H-NMR(CDCl3)δ;1.481(s,9H),3.759(s,6H),3.855(s,3H),3.883(s,3H),3.901(d,J=5.7Hz),5.1(br,1H),6.603(s,2H),6.696(d,J=8.5Hz,1H),6.892(d-d,J=1.8Hz,8.5Hz,1H),7.245(s,1H),8.295(br.s,1H),8.333(d,J=1.8Hz,1H)
质谱m/z:497(M+)步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-甘氨酰胺盐酸盐。
将800毫克(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-甘氨酰胺溶于3ml二氯甲烷内,并向其中加入3ml4-M氢氯酸和二噁烷的溶液。混合物室温反应2小时。向其中加入30毫升乙醚,并将形成的混合物过滤。将如此得到的粉末用氯仿,异丙醇和甲苯(6∶8∶20)混合物热洗涤,得483mg(1.11mmols)最终产物,产率65%。
1H-NMR(CD3OD)δ;3.735(s,6H),3.807(br,2H),3.812(s,3H),3.888(s,3H),6.662(s,2H),6.978(d,J=8.6Hz,1H),7.102(d-d,J=2.1Hz,8.6Hz,1H),7.346(s,1H),8.018(d,J=2.1Hz,1H)
高分辨质谱,计算值-398.1716,实测值-398.1723。实施例7合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-鸟氨酰胺二盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-鸟氨酰胺
700mg(1.86mmols)(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈盐酸盐,463mgWSCI,463mgHOBt.H2O和767mgBoc2L-Orn溶于70ml二甲基甲酰胺内,并向其中加入0.35ml三乙胺。混合物在50℃反应41小时。向其中加入400毫升水,并将形成的混合物用乙醚提取。随后乙醚层用水洗涤三次,无水硫酸钠干燥,并减压浓缩。产物用硅胶柱色谱纯化(洗脱剂,乙醚),然后溶于少量二氯甲烷内。向其中加入乙醚进行结晶,得737mg(1.13mmols)最终产物,产率61%。
1H-NMR(CDCl3)δ;1.432(s,9H),1.451(s,9H),1.5(m,2H),1.65(m,1H),1.9(m,1H),3.2(m,2H),3.764(s,6H),3.857(s,3H),3.875(s,3H),4.2(br,1H),4.8(br,1H),5.1(br,1H),6.600(s,2H),6.704(d,J=8.6Hz,1H),6.901(d-d,J=2.1Hz,8.6Hz,1H),7.236(s,1H),8.266(d,J=2.1Hz,1H),8.329(br.s,1H)
质谱m/z:654(M+)步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-鸟氨酰胺盐酸盐
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-鸟氨酰胺(730mg,1.11mmols)溶于5ml二氯甲烷内,并向其中加入5ml4-M氢氯酸的二噁烷溶液。混合物室温反应1小时。向其中加入100毫升乙醚,并将形成的混合物过滤,将如此得到的粉末用1∶1的甲醇和乙酸乙酯混合物重结晶,得286mg(0.542mmols)最终产物,产率48%。
1H-NMR(CDCl3)δ;1.7(m,2H),1.9(m,2H),2.973(d,J=6.3Hz,1H),3.003(d,J=6.3Hz,1H),3.768(s,6H),3.820(s,3H),3.898(s,3H),4.176(t,J=6.3Hz,1H),6.675(s,2H),7.014(d,J=8.5Hz,1H),7.173(d-d,J=2.0Hz,8.5Hz,1H),7.368(s,1H),7.801(d,J=2.0Hz,1H)
高分辨质谱,计算值-455.2288,实测值-455.2300。实施例8合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-苯丙氨酰胺盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-苯丙氨酰胺
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈盐酸盐(998mg,2.65mmols),1.290mgBOP试剂和777mgBoc-L-Phe溶于50ml乙腈内,并向其中加入0.8ml三乙胺。混合物在室温反应18小时并在50℃反应20小时.向其中加入100毫升水,并将形成的混合物用乙酸乙酯提取,随后提取液用无水硫酸钠干燥,并减压浓缩。产物用硅胶柱色谱纯化(洗脱剂,二氯甲烷),然后溶于少量二氯甲烷内,向其中加入乙醚和己烷进行结晶,得1082mg(1.84mmols)最终产物,产率69%。
1H-NMR(CDCl3)δ;1.426(s,9H),3.12(br.t,2H),3.744(s,3H),3.766(s,6H),3.888(s,3H),4.4(br,1H),5.1(br,1H),6.613(s,2H),6.639(d,J=8.8Hz,1H),6.875(d-d,J=2.1Hz,8.8Hz,1H),7.18-7.36(m,5H),8.030(br.s,1H),8.34 5(d,J=2.1Hz,1H)
质谱m/z:587(M+)步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-苯丙氨酰胺盐酸盐
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-苯丙氨酰胺(1082mg,1.11mmols)溶于10ml二氯甲烷内,并向其中加入5ml4-M氢氯酸的二噁烷溶液。混合物室温反应1小时。向其中加入100毫升乙醚,并将形成的混合物过滤。将如此得到的粉末用4∶1∶4的氯仿,甲醇和乙酸乙酯混合物重结晶,得450mg(0.859mmols)最终产物,产率77%。
1H-NMR(CD3OD)δ;3.106(d,J=7.3Hz,1H),3.119(d,J=7.3Hz,1H),4.312(t,J=7.3Hz,1H),3.751(s,6H),3.792(s,3H),3.819(s,3H),6.672(s,2H),6.936(d,J=8.7Hz,1H),7.173(d-d,J=2.2Hz,8.7Hz,1H),7.2(m,2H),7.3(m,3H),7.339(s,1H),7.87 8(d,J=2.2Hz,1H)
高分辨质谱,计算值-488.2186,实测值-488.2162。实施例9合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-脯氨酰胺盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-脯氨酰胺
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈盐酸盐(998mg,2.65mmols),1300mgBOP试剂和605mgBoc-L-Pro溶于50ml乙腈内,并向其中加入0.8ml三乙胺。混合物在室温反应18小时并在50℃反应20小时。向其中加入100毫升水和少量碳酸氢钠,并将形成的混合物用乙酸乙酯提取。随后提取液用无水硫酸钠干燥,并减压浓缩。产物用硅胶柱色谱纯化(洗脱剂,二氯甲烷),然后浓缩,得1310mg(2.44mmols)最终产物,产率92%。
1H-NMR(CDCl3)δ;1.4-1.5(br,9H),1.9(br,2H),2.1-2.3(br,1H),2.3-2.5(br,1H),3.3-3.5(br,2H),3.753(s,6H),3.838(s,3H),3.876(s,3H),4.2-4.5(br,1H),6.609(s,2H),6.677(d,J=8.4Hz,1H),6.871(m,1H),7.238(s,1H),8.39(br.s,1H),9.2(br,1H)
质谱m/z:537(M+)步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-脯氨酰胺盐酸盐
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-脯氨酰胺(1250mg,2.33mmols)溶于10ml二氯甲烷内,并向其中加入5ml4-M氢氯酸的二噁烷溶液。混合物室温反应1小时。向其中加入100毫升乙醚,并将混合物过滤。将得到的粉末通过中压液相色谱纯化(ODS,用70∶30的水和乙腈洗脱),所得产物用1∶10的氯仿和乙酸乙酯混合物重结晶三次,得465mg(0.980mmols)最终产物,产率42%。
1H-NMR(CDCl3)δ;2.0(m,3H),2.4(m,1H),3.4(m,2H),3.745(s,6H),3.805(s,3H),3.895(s,3H),4.45(m,1H),6.660(s,2H),6.997(d,J=8.6Hz,1H),7.143(d-d,J=2.1Hz,8.6Hz,1H),7.349(s,1H),7.839(d,J=2.1Hz,1H)
高分辨质谱,计算值-438.2029,实测值-438.2033。实施例10合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-丙氨酰胺盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-丙氨酰胺
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈盐酸盐(1053mg,2.65mmols),1300mgBOP试剂和554mgBoc-L-Ala溶于50ml乙腈内,并向其中加入0.8ml三乙胺。混合物在60℃反应17小时。向其中加入100毫升水和少量碳酸氢钠,并将形成的混合物用乙酸乙酯提取。随后提取液用饱和氯化钠水溶液洗涤,然后用无水硫酸钠干燥,并减压浓缩。产物用硅胶柱色谱纯化(洗脱剂,20∶1的二氯甲烷和乙酸乙酯混合物),然后浓缩,得1085mg(2.12mmols)最终产物,产率80%。步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-丙氨酰胺盐酸盐
将1000mg(1.95mmols)(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-丙氨酰胺溶于10ml二氯甲烷内,并向其中加入5ml4-M氢氯酸的二噁烷溶液。混合物室温反应1小时.向其中加入100毫升乙醚,并将形成的混合物过滤。将得到的粉末用20∶2∶30的氯仿,甲醇和乙酸乙酯混合物重结晶两次,将如此得到的粉末通过中压液相色谱纯化(ODS,用75∶25的水和乙腈混合物洗脱)。将纯化得到的粉末溶于少量甲醇内,并加入乙醚。过滤收集沉淀,得280mg(0.625mmols)最终产物,产率32%。
1H-NMR(CD3OD)δ;1.503(d,J=7.0Hz,3H),3.736(s,6H),3.808(s,3H),3.888(s,3H),4.129(q,J=7.0Hz,1H),6.662(s,2H),6.985(d,J=8.6Hz,1H),7.122(d-d,J=2.3Hz,8.6Hz,1H),7.345(s,1H),7.900(d,J=2.3Hz,1H)
高分辨质谱,计算值-412.1873,实测值-412.1873。实施例11合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-苏氨酰胺盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-苏氨酰胺
1000mg(2.65mmols)(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈盐酸盐,1300mg BOP试剂和880mgBoc-L-Thr(OtBu)溶于50ml乙腈内,并向其中加入0.8ml三乙胺。混合物在60℃反应21小时。向其中加入100毫升水和少量碳酸氢钠,并将形成的混合物用乙酸乙酯提取。随后提取液用饱和氯化钠水溶液洗涤,然后用无水硫酸钠干燥,并减压浓缩。产物用硅胶柱色谱纯化(洗脱剂,5∶1的乙酸乙酯和己烷混合物),然后浓缩,得870(mg(1.46mmols)最终产物,产率55%。
1H-NMR(CD3OD)δ;1.044(d,J=6.0Hz,3H),1.315(s,9H),1.463(s,9H),3.760(s,6H),3.844(s,3H),3.887(s,3H),4.15(br.m,1H),4.22(br,1H),5.64(br.d,1H),6.617(s,2H),6.857(d,J=8.5Hz,1H),6.897(d-d,J=2.2Hz,8.5Hz,1H),7.22 8(s,1H),8.404(d,J=2.2Hz,1H),9.3(br.s,1H)
质谱m/z:597(M+)步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-苏氨酰胺盐酸盐
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-苏氨酰胺(810mg,1.95mmols)溶于10ml二氯甲烷内,并向其中加入5ml 4-M氢氯酸的二噁烷溶液。混合物在60℃反应3小时。向其中加入100毫升乙醚,并将形成的混合物过滤。将如此得到的粉末通过中压液相色谱纯化两次(ODS,用75∶25的水和乙腈混合物洗脱),并溶于少量甲醇内,加入乙腈和乙酸乙酯混合物。过滤收集沉淀,得290mg(0.607mmols)最终产物,产率31%。
1H-NMR(CD3OD)δ;1.240(d,J=6.3Hz,3H),3.9(1H),3.739(s,6H),3.810(s,3H),3.892(s,3H),4.012(m,1H),6.658(s,2H),6.996(d,J=8.5Hz,1H),7.133(d-d,J=2.2Hz,8.5Hz,1H),7.350(s,1H),7.923(d,J=2.2Hz,1H)
高分辨质谱,计算值-442.1978,实测值-442.1973。实施例12合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-赖氨酰胺二盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-BOC-L-赖氨酰胺
1000mg(2.65mmols)(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈盐酸盐和1462mgBoc2-L-LysoSu溶于50ml乙腈内,并向其中加入0.8ml三乙胺。混合物在60℃反应20小时。加入600mgHOBt和1300mgBOP试剂,并将混合物进一步在60℃反应21小时。向其中加入100毫升水和少量碳酸氢钠,并将形成的混合物用乙酸乙酯提取。随后提取液用饱和氯化钠水溶液洗涤,然后用无水硫酸钠干燥,并减压浓缩。产物用硅胶柱色谱纯化(洗脱剂,二氯甲烷),然后浓缩,得1170mg(1.74mmols)最终产物,产率66%。
1H-NMR(CDCl3)δ;1.438(s,9H),1.450(s,9H),1.4-1.5(br,4H),1.7(br,1H),1.9(br,1H),3.1(br,2H),3.756(s,6H),3.852(s,3H),3.874(s,3H),4.2(br,1H),4.7(br,1H),5.2(br,1H),6.604(s,2H),6.685(d,J=8.7Hz,1H),6.884(d-d,J=2.2Hz,8.7Hz,1H),7.231(s,1H),8.348(br,1H)
质谱m/z:668(M+)步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-赖氨酰胺二盐酸盐
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Boc-L-赖氨酰胺(1100mg,1.64mmols)溶于10ml二氯甲烷内,并向其中加入5ml4-M氢氯酸的二噁烷溶液。混合物在60℃反应3小时。向其中加入100毫升乙醚,并将形成的混合物过滤。将如此得到的粉末通过中压液相色谱纯化(ODS,用95∶5至85∶15的水和乙腈混合物洗脱)。并溶于少量甲醇内,并加入乙腈和乙酸乙酯混合物,过滤收集沉淀,得300mg(0.554mmols)最终产物,产率34%。
1H-NMR(CD3OD)δ;1.4(m,2H),1.7(m,2H),1.9(m,2H),2.95(m,2H),3.756(s,6H),3.811(s,3H),3.896(s,3H),4.131(t,J=6.3),6.667(s,2H),7.010(d,J=8.9Hz,1H),7.164(d-d,J=2.3Hz,8.9Hz,1H),7.3 61(s,1H),7.834(d,J=2.3Hz,1H)
高分辨质谱,计算值-469.2451,实测值-469.2454。实施例13合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-丝氨酰胺盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Fmoc-L-丝氨酰胺
(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈盐酸盐(1007mg,2.65mmols),1105mgFmoc-L-Ser(OtBu)OH,1370mgBOP试剂和618mgHOBt.H2O溶于50ml乙腈内,并向其中加入0.8ml三乙胺。混合物在60℃反应42小时。向其中加入100毫升水和少量碳酸氢钠,并将形成的混合物用乙酸乙酯提取。随后提取液用饱和氯化钠水溶液洗涤,然后用无水硫酸钠干燥,并减压浓缩。产物用硅胶柱色谱纯化(洗脱剂,2∶3的乙酸乙酯和己烷混合物),然后浓缩,得1486mg(2.14mmols)最终产物,产率81%。
1H-NMR(CDCl3)δ;1.241(s,9H),3.243(t,J=8.5Hz,1H),3.760(s,6H),3.832(s,3H),3.874(s,3H),4.247(m,1H),4.33(br,1H),4.42(m,2H),5.8(br,1H),6.61 7(s,2H),6.704(d,J=8.8Hz,1H),6.904(d-d,J=2.2Hz,8.8Hz,1H),7.252(s,1H),7.32(m,2H),7.407(t,J=7.5Hz,2H),7.612(d,J=7.5Hz,2H),7.772(d,J=7.2Hz,2H),8.406(d,J=2.2Hz),9.0(br.s,1H)
质谱m/z:705(M+)步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-丝氨酰胺盐酸盐
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Fmoc-L-丝氨酰胺(1430mg,2.07mmols)溶于5ml三氯甲烷和2ml哌啶内。反应进行1小时,然后将产物用硅胶柱纯化(洗脱剂,1∶1的乙酸乙酯和二氯甲烷混合物)。将如此纯化的产物减压浓缩至干,然后溶于10ml4-M氢氯酸的二噁烷溶液内。所形成的混合物在70℃反应1小时。向其中加入100毫升乙醚,并过滤收集形成的沉淀。将如此得到的粉末通过中压液相色谱纯化(ODS,用75∶25的水和乙腈混合物洗脱),并热溶于氯仿和甲醇(5∶1)混合物内,得460mg(0.992mmols)最终产物,产率48%。
1H-NMR(CD3OD)δ;3.737(s,6H),3.813(s,3H),3.892(s,3H),3.9(m,2H),4.123(d-d,J=5.1Hz,6.3Hz,1H),6.662(s,2H),6.981(d,J=8.5Hz,1H),7.109(d-d,J=2.2Hz,8.5Hz,1H),7.344(s,1H),7.998(d,J=2.2Hz,1H)
高分辨质谱,计算值-428.1822,实测值-428.1806。实施例14合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-天冬氨酰胺盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Fmoc-L-天冬氨酰胺
900mg(2.65mmols)(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈,1400mgFmoc-L-Asp(OBn),1300mgBOP试剂和660mgHOBt.H2O溶于50ml乙腈内,并向其中加入0.5ml三乙胺。混合物在室温反应86小时。向其中加入100毫升水和少量碳酸氢钠,并将形成的混合物用乙酸乙酯提取。随后提取液用饱和氯化钠水溶液洗涤,然后用无水硫酸钠干燥,并减压浓缩,产物用硅胶柱纯化(洗脱剂,1∶10的乙酸乙酯和二氯甲烷混合物),然后浓缩,得1319mg(1.80mmols)最终产物,产率68%。
1H-NMR(CDCl3)δ;2.76(br.d-d,1H),3.15(br.d,1H),3.747(s,9H),3.869(s,3H),4.231(t,J=7.0Hz,1H),4.457(m,2H),4.72(br,1H),5.133(d,J=12.3Hz,1H),5.206(d,J=12.3Hz,1H),6.607(s,2H),6.662(d,J=9.0Hz,1H),6.896(d-d,J=2.1Hz,9.0Hz,1H),7.20-7.45(m,4H),7.342(s,1H),7.58(br.d,2H),7.7 62(d-d,J=2.5Hz,7.3Hz,2H),8.327(d,J=2.1Hz),8.7(br.s,1H)
质谱m/z:767(M+)步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-天冬氨酰胺盐酸盐
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Fmoc-L-天冬氨酰胺(1210mg,1.65mmols)溶于30ml二噁烷内,并加入2ml 2-M氢氧化钠水溶液.混合物室温反应1小时,加入100ml乙醚。过滤收集所形成的沉淀。此沉淀再溶于30ml二噁烷,并加入0.5ml 2-M氢氧化钠水溶液和1.5ml水。混合物室温反应1小时。然后向其中加入100毫升乙醚,并过滤收集形成的沉淀。将如此得到的产物分小批通过中压液相色谱的纯化(ODS,用75∶25∶0.3的水,甲醇和12-N盐酸混合物洗脱)。将含90%或更高纯度的部分浓缩,并溶于200ml2-M氢氯酸和甲醇(10∶1)混合物内.溶液用2-M氢氧化钠水溶液中和,并使之放置40分钟。过滤收集形成的沉淀。将如此得到的产物溶于少量含有0.3ml4-M氢氯酸的二噁烷溶液的甲醇内。加入乙酸乙酯并过滤收集形成的沉淀,得292mg(0.594mmols)最终产物,产率36%。
1H-NMR(CD3OD)δ;3.08(m,2H),3.752(s,6H),3.812(s,3H),3.868(s,3H),4.256(t,J=5.4Hz,1H),6.646(s,2H),6.94 8(d,J=8.6Hz,1H),7.086(d-d,J=2.0Hz,8.6Hz,1H),7.330(s,1H),7.821(d,J=2.0Hz,1H)
高分辨质谱,计算值-456.1771,实测值-456.1775。实施例15合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-谷氨酰胺盐酸盐步骤1合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Fmoc-L-谷氨(OBn)酰胺
900mg(2.65mmols)(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈,1500mgFmoc-L-Glu(OBn),1300mgBOP试剂和643mgHOBt.H2O溶于50ml乙腈内,并向其中加入0.5ml三乙胺。混合物在室温反应64小时。向其中加入100毫升水和少量碳酸氢钠,并将形成的混合物用二氯甲烷提取。随后提取液用饱和氯化钠水溶液洗涤,然后用无水硫酸钠干燥,并减压浓缩,产物用硅胶柱纯化(洗脱剂,二氯甲烷),然后浓缩,得1950mg(2.55mmols)最终产物,产率97%。
1H-NMR(CDCl3)δ;1.9-2.1(br.m,1H),2.1-2.3(br.m,1H),2.4-2.7(br.m,2H),3.745(s,6H),3.788(s,3H),3.868(s,3H),3.85-3.95(m,1H),4.207(t,J=6.9Hz,1H),4.408(d,J=6.9Hz,2H),5.137(s,2H),5.6-5.7(br.s,1H),6.603(s,2H),6.675(d,J=8.7Hz,1H),6.899(d-d,J=2.0Hz,8.7Hz,1H),7.2-7.4(m,10H),7.577(d,J=7.5Hz,2H),7.754(d,J=7.5Hz,2H),8.320(m,2H)
质谱m/z:781(M+)步骤2合成(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-L-谷氨酰胺盐酸盐
将(E)-3-(3-氨基-4-甲氧基苯基)-2-(3,4,5-三甲氧基苯基)-丙-2-烯腈-Fmoc-L-谷氨酰胺(1940mg,2.55mmols)溶于50ml二噁烷内,并加入3.7ml 2-M氢氧化钠水溶液。混合物室温反应1小时,加入100ml乙醚。过滤收集所形成的沉淀。此沉淀再溶于30ml二噁烷内,并加入0.5ml 2-M氢氧化钠水溶液和1.5ml水。混合物室温反应1小时。灰后向其中加入20毫升甲醇,并将混合物倒入250ml乙醚内,。过滤收集形成的沉淀。将如此得到的产物分小批通过中压液相色谱的纯化(ODS,用75∶25∶0.3的水,乙腈和12-N盐酸混合物洗脱)。浓缩如此纯化的产物,不用蒸干。当溶液量达到约50ml时,将溶液加到乙酸乙酯和乙醚(1∶1)的混合物内,并沉淀。在上清液弃去之后,向残余物中依次加入110ml乙腈和350ml乙醚。过滤形成的沉淀,用乙醚洗涤,并减压干燥,得436mg(0.838mmols)最终产物,产率33%。
1H-NMR(CD3OD)δ;2.120(q,J=7.0Hz,2H),2.468(m,2H),3.735(s,6H),3.808(s,3H),3.888(s,3H),4.131(t,J=6.3Hz,1H),6.658(s,2H),6.995(d,J=8.6Hz,1H),7.143(d-d,J=2.2Hz,8.6Hz,1H),7.349(s,1H),7.8 61(d,J=2.2Hz,1H)
高分辨质谱,计算-470.1927,实测值-470.1914。实施例16
细胞毒性评估
P388型小鼠白血病细胞用作癌细胞,且在孵育过程中使用含有5-μM 2-巯基乙醇和10%牛胎盘血清的RPMI-1640培养基。上述细胞在含有1×104细胞/50μl/孔量的96-孔微量滴定板中接种,并向其中加入试验化合物水溶液(4μg/ml),加入量为25μl/孔。混合物在37℃孵育2天。然后利用MTT方法计数活细胞数量,制备剂量-反应曲线。根据剂量-反应曲线计算试验化合物的50%生长抑制浓度(IC50)。本发明化合物的IC50值见下表所列。注射后立即引起急性死亡的最低剂量也可见下表所示。实施例17
小鼠药物作用试验
将皮下克隆在小鼠中的结肠26用剪刀切下并借助套针皮下移植到小鼠体内。一周后,利用测径器测量肿瘤大小,并计算肿瘤体积。将小鼠分组(每组包含3只小鼠)。试验化合物用二甲亚砜溶解并用5%吐温80/生理盐水稀释。在移植后的第7,第11和第15天每天一次注射0.2ml上述溶液。移植后的第21天测量肿瘤体积。采用下列公式计算肿瘤体积及肿瘤生长抑制率(I.R.)。 [表1]a)在第7,第11及第15天每天一次静脉给药b)注射后立即显示死亡的最低剂量。[表2]a)在第7,第11及第15天每天一次静脉给药b)注射后立即显示死亡的最低剂量。[表3]a)在第7,第11及第15天每天一次静脉给药b)注射后立即显示死亡的最低剂量。[表4]a)在第7,第11及第15天每天一次静脉给药b)注射后立即显示死亡的最低剂量。
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DE (1) | DE69604714T2 (zh) |
DK (1) | DK0731085T3 (zh) |
ES (1) | ES2137628T3 (zh) |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Families Citing this family (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2267255T3 (es) * | 1998-04-03 | 2007-03-01 | Ajinomoto Co., Inc. | Agentes antitumorales. |
US7105552B2 (en) * | 1998-05-08 | 2006-09-12 | Theracos, Inc. | Heterocyclic analogs of diphenylethylene compounds |
US6624197B1 (en) | 1998-05-08 | 2003-09-23 | Calyx Therapeutics, Inc. | Diphenylethylene compounds |
US6331633B1 (en) | 1998-05-08 | 2001-12-18 | Calyx Therapeutics Inc. | Heterocyclic analogs of diphenylethylene compounds |
US6245814B1 (en) | 1998-05-08 | 2001-06-12 | Calyx Therapeutics, Inc. | Diphenylethylene compounds |
US7407978B2 (en) * | 1999-04-06 | 2008-08-05 | Theracos, Inc. | Heterocyclic analogs of diphenylethylene compounds |
US6849656B1 (en) | 1999-09-17 | 2005-02-01 | Baylor University | Indole-containing and combretastatin-related anti-mitotic and anti-tubulin polymerization agents |
US20020002200A1 (en) * | 2000-02-04 | 2002-01-03 | Bishwagit Nag | Novel diphenylethylene compounds |
US6525093B1 (en) * | 1999-11-08 | 2003-02-25 | Calyx Therapeutics Inc. | Compounds to treat diabetes and associated conditions |
US7323496B2 (en) * | 1999-11-08 | 2008-01-29 | Theracos, Inc. | Compounds for treatment of inflammation, diabetes and related disorders |
US20080108825A1 (en) * | 1999-11-08 | 2008-05-08 | Theracos, Inc. | Compounds for treatment of inflammation, diabetes and related disorders |
US20080103302A1 (en) * | 2000-02-04 | 2008-05-01 | Theracos, Inc. | Compounds for treatment of inflammation, diabetes and related disorders |
JP2004505888A (ja) | 2000-03-10 | 2004-02-26 | ベイラー・ユニバーシテイ | チューブリン結合リガンドおよび対応するプロドラッグ構造 |
WO2001068587A1 (fr) * | 2000-03-17 | 2001-09-20 | Ajinomoto Co., Inc. | Nouveau derive de cristal de stilbene et son procede d'obtention |
US6670344B2 (en) | 2000-09-14 | 2003-12-30 | Bristol-Myers Squibb Company | Combretastatin A-4 phosphate prodrug mono- and di-organic amine salts, mono- and di- amino acid salts, and mono- and di-amino acid ester salts |
US20050153939A1 (en) * | 2003-09-10 | 2005-07-14 | Bristol-Myers Squibb Company | Combretastatin A-4 phosphate prodrug mono-and di-organic amine salts, mono-and di-amino acid salts, and mono-and di-amino acid ester salts |
YU29803A (sh) | 2000-10-27 | 2006-05-25 | Aventis Pharma S.A. | Kombinacija kamptotekina i derivata stilbena za lečenje raka |
US20020183266A1 (en) * | 2001-03-15 | 2002-12-05 | Aventis Pharma, S.A. | Combination comprising combretastatin and anticancer agents |
CN101816794A (zh) * | 2001-06-25 | 2010-09-01 | 味之素株式会社 | 抗肿瘤剂 |
JPWO2003041740A1 (ja) * | 2001-11-16 | 2005-03-03 | 味の素株式会社 | 腫瘍壊死剤 |
FR2838437B1 (fr) * | 2002-04-11 | 2004-06-04 | Aventis Pharma Sa | Procedes de preparation de combretastatines |
US6759555B2 (en) * | 2002-04-11 | 2004-07-06 | Aventis Pharma S.A. | Process for the preparation of combretastatins |
US20040224768A1 (en) * | 2002-09-24 | 2004-11-11 | Saied Hussaini | Video game controller with integrated status indicators |
US20040063502A1 (en) * | 2002-09-24 | 2004-04-01 | Intec, Inc. | Power module |
KR20050096954A (ko) * | 2003-02-04 | 2005-10-06 | 가부시키가이샤 야쿠루트 혼샤 | 유방암 내성 단백 저해제 |
WO2004078126A2 (en) * | 2003-02-28 | 2004-09-16 | Oxigene, Inc. | Compositions and methods with enhanced therapeutic activity |
GB2403949A (en) * | 2003-07-18 | 2005-01-19 | Sigma Tau Ind Farmaceuti | Combretastatin derivatives |
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 |
EP1746087A1 (de) | 2005-07-21 | 2007-01-24 | Universitaet Regensburg | 3-Indolylmethylen-Derivate mit cytostatischer Wirkung |
FR2895258B1 (fr) * | 2005-12-22 | 2008-03-21 | Aventis Pharma Sa | Combinaison comprenant de la combretastatine et des agents anticancereux |
CN101139358B (zh) * | 2006-09-07 | 2011-10-12 | 浙江大德药业集团有限公司 | 乙氧基康普立停及其前药的制备和用途 |
AU2008242626B2 (en) | 2007-04-20 | 2012-04-12 | Acucela Inc. | Styrenyl derivative compounds for treating ophthalmic diseases and disorders |
WO2009067706A1 (en) | 2007-11-21 | 2009-05-28 | Oxigene, Inc. | Method for treating hematopoietic neoplasms |
FR2945210B1 (fr) | 2009-05-07 | 2011-07-01 | Sanofi Aventis | Combinaison antitumorale comprenant l'ave8062 et le sorafenib |
EP2576514A1 (en) | 2010-06-04 | 2013-04-10 | Exonhit Sa | Substituted isoquinolines and their use as tubulin polymerization inhibitors |
EP2481404A1 (en) | 2010-11-15 | 2012-08-01 | Sanofi | An antitumoral combination comprising ombrabulin, a taxane derivative and a platinum derivative |
EP2397135A1 (en) | 2010-06-18 | 2011-12-21 | Sanofi | An antitumoral combination comprising ombrabulin, a taxane derivative and a platinum derivative |
CN103140224A (zh) | 2010-06-18 | 2013-06-05 | 赛诺菲 | 包含奥瑞布林、紫杉烷衍生物和铂衍生物的抗肿瘤组合 |
EP2407161A1 (en) | 2010-07-13 | 2012-01-18 | Sanofi | An antitumoral combination comprising ombrabulin and bevacizumab |
FR2968557A1 (fr) | 2010-12-09 | 2012-06-15 | Sanofi Aventis | Combinaison antitumorale comprenant un derive de la famille des combretastatines et le cetuximab |
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 |
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WO2020247054A1 (en) | 2019-06-05 | 2020-12-10 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL124588C (zh) * | 1959-04-08 | |||
GB9106177D0 (en) | 1991-03-22 | 1991-05-08 | Aston Molecules Ltd | Substituted diphenylethylenes and analogues or derivatives thereof |
EP0641301A1 (en) | 1992-05-21 | 1995-03-08 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
JP3180127B2 (ja) * | 1993-03-10 | 2001-06-25 | 森永乳業株式会社 | スチルベン誘導体とスチルベン同族体誘導体及びそれらの用途 |
TW325458B (en) * | 1993-09-08 | 1998-01-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer |
-
1996
- 1996-03-05 TW TW085102704A patent/TW334418B/zh not_active IP Right Cessation
- 1996-03-06 ES ES96301517T patent/ES2137628T3/es not_active Expired - Lifetime
- 1996-03-06 DE DE69604714T patent/DE69604714T2/de not_active Expired - Lifetime
- 1996-03-06 EP EP96301517A patent/EP0731085B1/en not_active Expired - Lifetime
- 1996-03-06 AT AT96301517T patent/ATE185792T1/de active
- 1996-03-06 DK DK96301517T patent/DK0731085T3/da active
- 1996-03-06 PT PT96301517T patent/PT731085E/pt unknown
- 1996-03-07 US US08/612,416 patent/US5674906A/en not_active Expired - Lifetime
- 1996-03-07 KR KR1019960005884A patent/KR100352048B1/ko not_active IP Right Cessation
- 1996-03-07 CA CA002171275A patent/CA2171275C/en not_active Expired - Lifetime
- 1996-03-07 CN CN96107344A patent/CN1066713C/zh not_active Expired - Lifetime
-
2000
- 2000-01-04 GR GR20000400011T patent/GR3032311T3/el unknown
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US9682921B2 (en) | 2014-02-03 | 2017-06-20 | Quadriga Biosciences, Inc. | β-substituted γ-amino acids and analogs as chemotherapeutic agents |
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US9861599B2 (en) | 2014-02-03 | 2018-01-09 | Quadriga Biosciences, Inc. | Beta-substituted beta-amino acids and analogs as chemotherapeutic agents |
US9937139B2 (en) | 2014-02-03 | 2018-04-10 | Quadriga Biosciences, Inc. | β-substituted γ-amino acids and analogs as chemotherapeutic agents |
US10034847B2 (en) | 2014-02-03 | 2018-07-31 | Quadriga Biosciences, Inc. | Beta-substituted beta-amino acids and analogs as chemotherapeutic agents |
US10245246B2 (en) | 2014-02-03 | 2019-04-02 | Quadriga Biosciences, Inc. | β-substituted β-amino acids and analogs as chemotherapeutic agents |
US9783487B2 (en) | 2015-08-03 | 2017-10-10 | Quadriga Biosciences, Inc. | Beta-substituted beta-amino acids and analogs as chemotherapeutic agents and uses thereof |
US10017459B2 (en) | 2015-08-03 | 2018-07-10 | Quadriga Biosciences, Inc. | β-substituted β-amino acids and analogs as chemotherapeutic agents and uses thereof |
US10246406B2 (en) | 2015-08-03 | 2019-04-02 | Quadriga Biosciences, Inc. | Beta-substituted beta-amino acids and analogs as chemotherapeutic agents and uses thereof |
CN112225673A (zh) * | 2020-11-13 | 2021-01-15 | 义乌市华耀医药科技有限公司 | 氨基康普立停衍生物及其应用 |
CN112225673B (zh) * | 2020-11-13 | 2022-08-02 | 义乌市华耀医药科技有限公司 | 氨基康普立停衍生物及其应用 |
Also Published As
Publication number | Publication date |
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US5674906A (en) | 1997-10-07 |
KR100352048B1 (ko) | 2003-05-12 |
EP0731085A1 (en) | 1996-09-11 |
CA2171275C (en) | 2005-12-20 |
DE69604714T2 (de) | 2000-06-15 |
PT731085E (pt) | 2000-04-28 |
KR960034164A (ko) | 1996-10-22 |
GR3032311T3 (en) | 2000-04-27 |
EP0731085B1 (en) | 1999-10-20 |
CN1066713C (zh) | 2001-06-06 |
TW334418B (en) | 1998-06-21 |
DK0731085T3 (da) | 2000-04-17 |
CA2171275A1 (en) | 1996-09-08 |
ES2137628T3 (es) | 1999-12-16 |
DE69604714D1 (de) | 1999-11-25 |
ATE185792T1 (de) | 1999-11-15 |
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