CN112225673A - 氨基康普立停衍生物及其应用 - Google Patents
氨基康普立停衍生物及其应用 Download PDFInfo
- Publication number
- CN112225673A CN112225673A CN202011271276.5A CN202011271276A CN112225673A CN 112225673 A CN112225673 A CN 112225673A CN 202011271276 A CN202011271276 A CN 202011271276A CN 112225673 A CN112225673 A CN 112225673A
- Authority
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- China
- Prior art keywords
- pharmaceutically acceptable
- ethylene
- trimethoxyphenyl
- amino
- propionamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- -1 Amino combretastatin derivative Chemical class 0.000 title claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 58
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- 238000002360 preparation method Methods 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 15
- 150000004677 hydrates Chemical class 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 3
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- 108090000704 Tubulin Proteins 0.000 claims abstract description 3
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- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 66
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
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- 238000002474 experimental method Methods 0.000 description 6
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 5
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- 206010009944 Colon cancer Diseases 0.000 description 4
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
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- 208000029742 colonic neoplasm Diseases 0.000 description 4
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- 208000014018 liver neoplasm Diseases 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
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- 201000011549 stomach cancer Diseases 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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Abstract
Description
技术领域
本发明属于药物化合物的合成制备领域,特别是涉及抗癌类药物化合物的合成、制备,更为具体的说是涉及氨基康普立停衍生物及其合成方法和应用。
背景技术
Combretastatins系列化合物最初是从南非Combretumcaffrum树干中提取分离得到的,该系列化合物具有顺式1,2-二苯乙烯结构。其中CombretastatinA-4,即CA-4(顺式-1-(3,4,5-三甲氧基)苯基-2-(3’-羟基-4’-甲氧基)苯基乙烯)具有最强的抑制微管聚合作用。1997年日本味之素株式会社(AjinomotoCo.)T.Hatanaka等人发现把CA-4的3′位的羟基改造成氨基,其抗癌活性大大提高。但是,Combretastatins系列化合物的水溶性很差,特别是将CA-4的3’位改造为氨基后,其水溶性进一步降低。日本味之素株式会社将氨基CA-4用氨基酸进行了修饰,增加了其水溶性,使其成为针剂能对癌症病人使用。但是研究表明,氨基CA-4用氨基酸进行了修饰后,其分子的毒性会大大增加,人体耐受量降低,不适于临床使用。
因此,对氨基康普立停结构式进行进一步改造,从而在满足不同制剂的水溶性要求,特别是口服制剂类药物剂型的水溶性要求的前提下,降低分子毒性,提高耐受量,保证药物疗效,是本领域技术人员,特别是针对康普立停的研究领域中技术人员关注的重点问题和亟待解决的技术难题。
发明内容
本发明所要解决的技术问题是如何能够改善氨基康普立停的水溶性,并且同时保证提供较好的临床可接受的药物毒性和耐受量。
为了解决上述技术问题,本发明提供了通式(I)所示的化合物,其药学上可接受的盐,其水合物、其药学上可接受的盐的水合物,其溶剂化物、其药学上可接受的盐的溶剂化物,以及其异构体,所述的通式(I)结构式如下:
其中,R1选自C1-C3烷基或C1-C3卤代烷基;
R2,R3分别独立地选自C1-C6烷基、C1-C6卤代烷基、或者C1-C6醇基。
进一步优选的,所述R1选自甲基、乙基、二氟甲基或三氟乙基。
在一个优选的技术方案中,所述R2,R3分别独立地选自甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、丙烯基、丙炔基。
在一个优选的技术方案中,所述R2,R3均为甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、丙烯基或丙炔基。
进一步优选的,本发明还公开了所述的化合物优选为,(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-乙氧基苯基)乙烯,或(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-三氟乙氧基苯基)、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2,2-二氟乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2,2-二甲氧基乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯。
本发明所说的药学上可接受的盐是指一个或者一个以上的碱性成盐基团与酸形成的盐。所述的酸可以为有机酸也可以为无机酸。其中较为优选的方案是与盐酸、硫酸、磷酸、乙酸、丙酸三氟乙酸、乙醇酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、草酸、氨基酸、苯甲酸、水杨酸、4-氨基水杨酸、扁桃酸肉桂酸、烟酸、异烟酸、甲磺酸、三氟甲磺酸、乙磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、2-萘磺酸中的一种或者几种成盐。进一步优选的技术方案是所述的药学上可接受的盐为盐酸盐,硫酸盐,磷酸盐,柠檬酸盐或者酒石酸盐。
需要说明的是,本发明中所说的溶剂化物包括有机溶剂化物和无机溶剂化物。本发明包含通式(I)所示化合物及其药学上可接受的盐的溶剂化物、水合物以及非溶剂化物或非水合物等不同物理形式。
异构体有混合物形式或者纯形式的异构体,本发明中所说的异构体既包括混合物形式的立体异构体也包括纯形式的立体异构体,即包含有所有可能的立体异构体及其混合物。进一步优选的,这里的异构体指具有特定活性的光学异构体,通常为可分离的具有外消旋形式的光学异构体。
同时,在本发明中还进一步公开了通式(I)所示化合物的合成方法,反应方程式如下:
本发明所述的合成方法通过化合物溴代、与三苯基膦反应后得到VI,再通过维蒂希反应得到顺式的化合物V。再用二溴二辛基联吡啶和金属钐粉作为还原剂将化合物V中的硝基还原成氨基,得到氨基康普立停A-4。然后以氨基康普立停A-4为原料,在DMTMM催化下接2-溴丙酸,得到化合物III。将化合物III与胺类化合物在高温下反应即得化合物II。
进一步优选的是,所述化合物II进一步与酸成盐,形成药学上可接受的盐产物。
进一步优选的是,还包括有光学异构体分离,将化合物II的光学异构体通过物理方法进行拆分,或者在成盐步骤中进行拆分。具体的物理方法可以参考现有技术中的光学异构体拆分方法,譬如对非对映异构体衍生物进行分级结晶、分离或者通过手性色谱柱进行分离。在成盐步骤中拆分可以参考现有的成盐拆分方法,譬如利用具有光学活性的酸成盐,接着通过结晶的方式,从外消旋体得到单独的光学异构体。
本发明还提供了通式(I)所示的化合物,其药学上可接受的盐,以及其水合物或其药学上可接受的盐的水合物,和其溶剂化物或其药学上可接受的盐的溶剂化物,以及其异构体所制备得到的药物或药物组合物。
优选的,所述药物或药物组合物为局部、肠内或肠外给药剂型。
在制备成制剂形式时,可以是无机的,也可以是有机的,可以是固态的,也可以是液态的。譬如,当用于口服时,可以制备成常规的固体制剂,比如片剂、胶囊剂、丸剂、颗粒剂,也可以制备成常见的液体制剂,比如口服液溶剂、口服混悬液、糖浆剂等。又譬如,以肠胃外给药形式或者以针剂形式被适用时,优选等渗水溶液或乳液,如在仅由活性成分和一种载体组成的冻干组合物的情况下,此类溶液可以在使用前制备。这些药物组合物可以式无菌的,或包含赋形剂的,或加溶剂、调节渗透压的盐。
优选的,本发明公开通式(I)所示的化合物,其药学上可接受的盐,以及其水合物或其药学上可接受的盐的水合物,和其溶剂化物或其药学上可接受的盐的溶剂化物,以及其异构体所制备得到的片剂或叫胶囊剂。
当制备片剂或者胶囊剂时,这种片剂或胶囊包含活性成分和稀释剂(如乳糖、葡萄糖、蔗糖、甘露醇糖、山梨醇、纤维素、丙三醇)、润滑剂(如滑石、硬脂酸盐),聚乙二醇。片剂包含粘合剂、淀粉、明胶、甲基纤维素、羧甲基纤维素和聚乙烯吡咯烷酮,必要时还可以包含粉碎剂(如淀粉、琼脂、藻酸及其盐),泡腾混合物或吸附剂、染料、调味剂、增填剂。
进一步的,在本发明中还公开了通式(I)所示的化合物,其药学上可接受的盐,以及其水合物或其药学上可接受的盐的水合物,和其溶剂化物或其药学上可接受的盐的溶剂化物,以及其异构体在制备用于治疗由非正常新生血管引起的疾病的药物中的应用。
目前已经证实的由非正常新生血管引起的疾病包括肺癌、小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、肾癌、胆管癌、前列腺癌、睾丸癌、结肠癌、膀胱癌、子宫颈癌、支气管癌、黑色素瘤、腺癌、汗腺癌、乳头状癌、乳头状腺癌、鳞状细胞癌、基底细胞癌、囊性腺癌、胶质细胞癌、星形细胞瘤、成神经细胞瘤、成神经细胞管瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、少突神经胶质瘤、脑膜瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、粘液肉瘤、粘液囊瘤、脂肪瘤、脂肪腺瘤、软骨肉瘤、软骨癌、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛血管瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、破骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、股囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管瘤、血管肉瘤、淋巴管肉瘤、淋巴管瘤、淋巴瘤、内皮瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、横纹肌瘤、横纹肌肉瘤、急性淋巴性白血病、急性骨髓性白血病、慢性白血病、红细胞增多症、多发性骨髓瘤在内的各种肿瘤,风湿性关节炎、糖尿病视网膜病、早熟视网膜病、视网膜静脉闭塞、牛皮癣、红斑痤疮、卡波济肉瘤、特异性反应性角膜炎、流行性角膜结膜炎、新生血管性青光眼、细菌性溃疡、真菌性溃疡、单纯性疱疹感染、带状疱疹感染、原生动物感染、分枝杆菌感染、多动脉炎、肉样瘤、巩膜炎、潮红、口干眼燥、关节炎综合症、全身性红斑狼疮、艾滋病综合症、梅毒等。
同时,本发明还公开了通式(I)所示的化合物,其药学上可接受的盐,以及其水合物或其药学上可接受的盐的水合物,和其溶剂化物或其药学上可接受的盐的溶剂化物,以及其异构体在制备微管蛋白聚集抑制剂中的应用。
具体实施方式
下面将详细描述本发明的示例性实施方案。这些实施方案仅为说明目的,并不旨在限制本发明的范围。
以下是本说明书中使用的术语的定义。
除非另有说明,本专利就基团或术语而言提供的初始定义适用于在说明书通篇中的所述基团或者术语,不论是单独使用还是作为另一基团部分使用。
术语“烷基”是指直链的或支链的未取代的烃基,其具有1-20个碳原子,优选的是1-6个碳原子,尤其指甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)等。
术语“烯基”是指具有一个或多个碳碳双键的烯烃,如乙烯基、丙烯基、1,3-丁二烯、顺丁烯、反丁烯等。
术语“炔基”是指具有一个或多个碳碳三键的炔烃,如乙炔基、丙炔基等。
术语“卤素”或“卤代”是指氟、氯、溴、碘。
术语羟基是指基团-OH。
术语羧基是指基团-COOH。
术语氨基是指基团-NH2。
术语硝基是指基团-NO2。
术语烷氧基是指基团-OR4,其中R4指烷基。
术语氨甲酰基是指基团R5C(=O)NH2,其中R5指烷基。
术语氰基是指基团-CN。
术语酰胺基是指基团-C(=O)NH-。
术语烷氧羰基是指基团-C(=O)OR6,其中R6指烷基。
术语酰氧基是指基团-OC(=O)R7,其中R7指烷基。
术语巯基是指基团-SH。
“取代的”意味着随后描述的基团可以被一些常见的基团(如氢、卤素、羟基、氨基、巯基、硝基、氰基、芳基、杂环基、杂环烷基、羧基、酰胺基等)取代。
“可选的”意味着随后描述的事件或情况可以发生或者不发生,所描述的包括其中所述事件或者情况发生的例子和其中不发生的例子。
本文所用的“药学可接受的载体”包括全部的溶剂、分散介质、包衣、抗细菌和抗真菌药剂、等渗和吸收延迟剂等。这样的介质和药剂用于药学活性物质在本领域是众所周知的。除非任何常规介质或者药剂与活性成分不相容,其在治疗组合物中的应用可预期的。补充的活性成分也可并入组合物中。
实施例1
(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的合成
步骤1:溴化三甲氧基苄基三苯基膦的合成
将3,4,5-三甲氧基苄醇320g溶于2L甲苯,搅拌溶解后降温到-5到0℃,恒压滴液漏斗滴加100ml溴化磷,保持反应温度-5到0℃。滴加完毕后,继续低温反应2h,再恢复室温,反应过夜。
加纯化水1.4L淬灭反应,搅拌30min,静置分液。取上层有机相用饱和碳酸氢钠溶液洗涤pH值至7.5-8,加无水硫酸镁干燥并过滤,得到三甲氧基苄溴的甲苯溶液。
在此溶液中加入三苯基磷0.56kg,搅拌48h以上,有固体析出,过滤即得粗产物。再用无水乙醇重结晶。
步骤2:(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯的合成
在反应釜中,通入氩气保护,将溴化三甲氧基苯基亚甲基三苯膦15g溶于300ml无水THF,冷却至-15℃左右,滴入1.6mol/L的正丁基锂环己烷溶液22ml,反应1h。然后将5.7g3-硝基-4-乙氧基苯甲醛的24mlTHF溶液缓慢滴加入反应液。反应温度逐渐升至室温,搅拌过夜,TLC点板跟踪。反应结束后将反应降温至-5℃,加入饱和食盐水淬灭反应。分液,将有机层浓缩干,硅胶过柱(正己烷:乙酸乙酯=4:1)分离得到6.5g浅黄色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-硝基-4-乙氧基苯基)乙烯,产率50%到60%。
在干燥的1L四颈瓶中通氩气保护,加入700ml无水异丙醇,后小心加入二溴二锌基联吡啶10g和金属钐粉24g,最后加入(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-硝基-4-乙氧基苯基)乙烯10g,搅拌加热回流,TLC点板跟踪反应直至反应结束。反应结束后,抽滤并将滤液浓缩,硅胶柱过柱(石油醚:乙酸乙酯=4:1)。收率30%到40%。
步骤3:(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯的合成
将10g(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯溶于无水乙醇,加入20g DMTMM,溶清后再加入5.58g溴丙酸。室温反应,TLC点板跟踪。反应结束后迅速低温浓缩干,加乙酸乙酯溶解并用水洗涤。洗涤后合并有机相,浓缩干后用乙酸乙酯和石油醚=1:4重结晶,得到白色或者米黄色固体,收率60%到70%。
步骤4:(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的合成
称取2g(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯溶解在10ml乙醇中,加入0.53g二丙胺和2ml三乙胺,升温至60℃搅拌反应。TLC点板跟踪。反应结束后,浓缩干,乙酸乙酯:石油醚=1:6过常压硅胶柱。浓缩干后得到1.65g白色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯,收率80%左右。
MS(m/Z)=484.30。1HNMR(ppm)δ:7.08(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);4.18(q,2H,-CH2);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3);2.74(t,2H,-CH2);2.36(dt,4H,-NCH2-);2.33(t,2H,-COCH2);1.43(m,4H,-CH2-);1.33(t,3H,-CH3);0.96(t,6H,-CH3)。
实施例2
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯盐酸盐的制备
将1g(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯溶于10ml甲醇,加入0.2ml盐酸,加热至35℃搅拌1h。冷却后浓缩干加入10ml水搅拌10min后静置过夜。抽滤,所得白色滤饼冷冻干燥后即为(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯盐酸盐。
实施例3
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯的制备
步骤1:溴化三甲氧基苄基三苯基膦的合成
将3,4,5-三甲氧基苄醇320g溶于2L甲苯,搅拌溶解后降温到-5到0℃,恒压滴液漏斗滴加100ml溴化磷,保持反应温度-5到0℃。滴加完毕后,继续低温反应2h,再恢复室温,反应过夜。
加纯化水1.4L淬灭反应,搅拌30min,静置分液。取上层有机相用饱和碳酸氢钠溶液洗涤pH值至7.5-8,加无水硫酸镁干燥并过滤,得到三甲氧基苄溴的甲苯溶液。
在此溶液中加入三苯基磷0.56kg,搅拌48h以上,有固体析出,过滤即得粗产物。再用无水乙醇重结晶。
步骤2:(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-甲氧基苯基)乙烯的合成
在反应釜中,通入氩气保护,将溴化三甲氧基苯基亚甲基三苯膦15g溶于300ml无水THF,冷却至-15℃左右,滴入1.6mol/L的正丁基锂环己烷溶液22ml,反应1h。然后将5.5g3-硝基-4-甲氧基苯甲醛24mlTHF溶液缓慢滴加入反应液。搅拌过夜,反应温度逐渐升至室温,TLC点板跟踪。次日,将反应降温至-5℃,加入饱和食盐水淬灭反应。分液,将有机层浓缩干,硅胶过柱(正己烷:乙酸乙酯=4:1)分离得到6.0g浅黄色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-硝基-4-甲氧基苯基)乙烯,产率50%到60%。
在干燥的1L四颈瓶中,通氩气保护,加入700ml无水异丙醇,后小心加入二溴二锌基联吡啶10g和金属钐粉24g,最后加入(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-硝基-4-甲氧基苯基)乙烯10g,搅拌加热回流,TLC点板跟踪反应直至反应结束。反应结束后,抽滤并将滤液浓缩,硅胶柱过柱(石油醚:乙酸乙酯=4:1)。收率30%到40%。
步骤3.按照实施例1所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯。MS(m/Z)=470.28。1HNMR(ppm)δ:7.08(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);3.86(s,3H,4-OCH3);3.73(s,3H,-OCH3);3.70(s,6H,3,5-OCH3);2.74(t,2H,-CH2);2.36(dt,4H,-NCH2-);2.33(t,2H,-COCH2);1.43(m,4H,-CH2-);0.96(t,6H,-CH3)。
实施例4
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的制备
步骤1:按照实施例1所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯。
步骤2:(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的合成
称取2g(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯溶解在10ml乙醇中,加入0.56g二乙胺和2ml三乙胺,升温至60℃搅拌反应。TLC点板跟踪。反应结束后,浓缩干,乙酸乙酯:石油醚=1:6过常压硅胶柱。浓缩干后得到1.65g白色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯,收率80%左右。
MS(m/Z)=456.26。1HNMR(ppm)δ:7.08(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);4.18(q,2H,-CH2);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3);3.68(t,2H,-CH2N=);3.01(dt,4H,-NCH2-);2.55(t,2H,-COCH2);1.33(t,3H,-CH3);1.15(t,6H,-CH3)。
实施例5
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的制备
步骤1:按照实施例1所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯。
步骤2:(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的合成
称取2g(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-乙氧基苯基)乙烯溶解在10ml乙醇中,加入0.56g二丁胺和2ml三乙胺,升温至60℃搅拌反应。TLC点板跟踪。反应结束后,浓缩干,乙酸乙酯:石油醚=1:6过常压硅胶柱。浓缩干后得到1.65g白色晶体即为(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯,收率80%左右。
MS(m/Z)=512.33。1HNMR(ppm)δ:7.08(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);4.18(q,2H,-CH2);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3);2.74(t,2H,-CH2);2.36(dt,4H,-NCH2-);2.33(t,2H,-COCH2);1.40(m,4H,-CH2-);1.35(m,4H,-CH2-);1.33(t,3H,-CH3);0.96(t,6H,-CH3)。
实施例6
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-甲氧基苯基)乙烯的制备
步骤1:按照实施例3所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-溴丙酰胺)-4-甲氧基苯基)乙烯。
步骤2:按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯。MS(m/Z)=498.31。1HNMR(ppm)δ:7.08(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);3.86(s,3H,4-OCH3);3.73(s,3H,-OCH3);3.70(s,6H,3,5-OCH3);2.74(t,2H,-CH2);2.36(dt,4H,-NCH2-);2.33(t,2H,-COCH2);1.40(m,4H,-CH2-);1.33(m,4H,-CH2-);0.96(t,6H,-CH3)。
实施例7
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯的制备
步骤1:按照实施例1所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-三氟乙氧基苯基)乙烯。
步骤2:按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯。MS(m/Z)=538.27。1HNMR(ppm)δ:7.08(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);4.46(d,2H,-OCH2CF3);3.86(s,9H,3,4,5-OCH3);2.74(t,2H,-CH2);2.36(dt,4H,-NCH2-);2.33(t,2H,-COC H2);1.40(m,4H,-CH2-);0.96(t,6H,-CH3)。
实施例8
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯的制备
步骤1:按照实施例3所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-二氟甲氧基苯基)乙烯。
步骤2:按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯。MS(m/Z)=506.26。1HNMR(ppm)δ:7.36(d,1H,-CHF2);7.08(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);3.73(s,9H,3,4,5-OCH3);2.74(t,2H,-CH2);2.36(dt,4H,-NCH2-);2.33(t,2H,-CO CH2);1.43(m,4H,-CH2-);0.96(t,6H,-CH3)。
实施例9
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯的制备
步骤1:按照实施例1所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-三氟乙氧基苯基)乙烯。
步骤2:按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯。MS(m/Z)=566.30。1HNMR(ppm)δ:7.08(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);4.46(d,2H,-OCH2CF3);3.86(s,9H,3,4,5-OCH3);2.74(t,2H,-CH2);2.36(dt,4H,-NCH2-);2.33(t,2H,-COC H2);1.40(m,4H,-CH2-);1.33(m,4H,-CH2-);0.96(t,6H,-CH3)。
实施例10
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯的制备
步骤1:按照实施例3所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-二氟甲氧基苯基)乙烯。
步骤2:按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯。MS(m/Z)=534.29。1HNMR(ppm)δ:7.36(d,1H,-CHF2);7.08(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);3.73(s,9H,3,4,5-OCH3);2.74(t,2H,-CH2);2.36(dt,4H,-NCH2-);2.33(t,2H,-CO CH2);1.39(m,4H,-CH2-);1.33(m,4H,-CH2-);0.96(t,6H,-CH3)。
实施例11
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯的制备
步骤1:按照实施例1所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯。
步骤2:按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯。MS(m/Z)=488.25。1HNMR(ppm)δ:7.68(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);3.98(-OCH2-);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3);3.63(q,4H,-CH2OH);2.74(q,2H,-CH2N-);2.55(dt,4H,-NCH2-);2.33(q,2H,-COCH2-);1.33(q,3H,-CH3)。
实施例12
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯的制备
步骤1:按照实施例3所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-甲氧基苯基)乙烯。
步骤2:按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯。MS(m/Z)=474.24。1HNMR(ppm)δ:7.68(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);3.86(s,3H,4-OCH3);3.70(s,9H,3,3’,5-OCH3);3.63(q,4H,-CH2OH);2.74(q,2H,-CH2N-);2.55(dt,4H,-NCH2-);2.33(q,2H,-COCH2-)。
实施例13
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2,2-二氟乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯的制备
步骤1:按照实施例1所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯。
步骤2:按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2,2-二氟乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯。MS(m/Z)=464.21。1HNMR(ppm)δ:7.68(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);5.39(t,1H,-CHF2);3.98(q,2H,-OCH2);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3);2.93(m,2H,-CH2-);2.91(t,2H,-NCH2-);2.35(t,2H,-COCH2);1.33(t,3H,-CH3)。
实施例14
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2,2-二甲氧基乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯的制备
步骤1:按照实施例1所示的方法,合成(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)乙烯。
步骤2:按照实施例1所示的方法合成(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2,2-二甲氧基乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯。MS(m/Z)=488.25。1HNMR(ppm)δ:7.68(d,1H,2’-H);6.92(d,1H,6’-H);6.76(d,1H,5’-H);6.62(s,2H,2,6’-H);6.49(d,1H,J=12.2Hz,1a-H);6.43(d,1H,J=12.2Hz,1a’-H);4.43(t,1H,-CH-);3.98(q,2H,-OCH2-);3.86(s,3H,4-OCH3);3.70(s,6H,3,5-OCH3);3.24(s,6H,-OCH3);2.93(t,2H,-NCH2-);2.85(t,2H,-CH2-);2.35(t,2H,-COCH2);1.33(t,3H,-CH3)。
实施例15药物制剂配方
本发明提供了几种与新生血管异常增生相关疾病的药物组合配方,其药物组合主要有片剂,胶囊等口服制剂。以下“活性化合物”即为本发明中所述的通式(I)所示化合物,其药学上可接受的盐,以及其水合物或其药学上可接受的盐的水合物,和其溶剂化物或其药学上可接受的盐的溶剂化物,以及其异构体。
实施例16动物急性毒性试验
选取ICR小鼠,体重23±2g清洁级,雄性。给药途径采用灌胃(ig)给药,这与临床拟用口服途径一致。
小鼠按体重随机分为8组:分别为空白对照组、实施例1组、实施例5组、实施例11组、实施例12组、实施例13组、实施例14组及对照品组,其中对照品组采用氨基康普立停丝氨酰胺盐酸盐作为对照品(以下称对照品)。
实施例组中所用药物的制备:按照实施例2中公开的盐酸盐的方法,将实施例1、实施例3、实施例4、实施例5、实施例6、实施例7、实施例8、实施例9、实施例10、实施例11、实施例12、实施例13、实施例14中得到化合物制备成盐酸盐产物。
对照品的制备:以氨基乙氧基康普立停(即本专利实施例1步骤2所得产物)为原料,通过以下方法制备:
(1)将氨基乙氧基康普立停、Fmoc-丝氨酸以及DCC和HOBt溶于DMF中。在搅拌下,反应混合物室温反应5小时,TLC跟踪。反应完成后,冷却,加入乙酸乙酯稀释,混合均匀。过滤,经无水硫酸镁干燥,减压浓缩。然后,经快速柱层析分离得到白色泡沫状物质。
(2)取上述得到的(Z)-1-(3,4,5-三甲氧基苯基)-2-(3-氨基-4-乙氧基苯基)-乙烯-Fmoc-丝氨酰胺溶于甲醇和二氯甲烷混合溶剂中。在搅拌下,加入2N氢氧化钠溶液,室温反应24小时,TLC跟踪。反应完成后,冷却,加入饱和氯化钠溶液,混合均匀。用二氯甲烷萃取3次,有机层经无水硫酸镁干燥,减压浓缩。然后,经常压柱层析分离得到无色泡沫状物质,即得。
预实验:取上述小鼠48只,实验前禁食不禁水12h,按体重随机分组,每组10只。各药物组按0.25ml/10g小鼠体重灌胃给药1次,水对照组灌胃等体积的蒸馏水。找出LD100值(100%死亡量)、LD0(0死亡量)和相应的剂量组间距r值,进行LD50的测定。
正式实验:取上述小鼠160只,按体重随机分为8组,每组20只。实验前禁食不禁水12h后,各给药组按照0.3ml/10g小鼠体重灌胃给药1次,12h后无死亡情况发生,故进行第二次给药,对照组灌胃等体积水。计算各组一日内给药量;对照组灌胃等体积的水,进行急性毒性实验反应观察并记录14d内小鼠每日体重。通过计算,各药物的经口LD50计算结果如表1所示:
表1:
结果表明,本发明所示化合物在氨基康普立停的氨基侧链改进后,小鼠LD50提高5-6倍,表明本发明所示的化合物可以显著降低急性毒性,对于临床使用的安全性有明显提升。
实施例17裸小鼠移植瘤的疗效实验
BALB/cA-nude裸小鼠,6-7周,♀,购自上海斯莱克实验动物有限责任公司。裸小鼠皮下分别接种人肝癌Bel-7402细胞、结肠癌HT-29细胞、胃癌SGC-7901细胞和非小细胞肺癌A549细胞,待肿瘤生长至100-250mm3后,将动物随机分组(d0)。每周测2-3次瘤体积,称鼠重,记录数据。肿瘤体积(V)计算公式为:
V=1/2×a×b2
T/C(%)=(T-T0)/(C-C0)×100
其中a、b分别表示长、宽;T、C为实验结束时的肿瘤体积;T0、C0为实验开始时的肿瘤体积。
将所试样品均用50%PEG400蒸馏水稀释成所需浓度。用药方式为每天给药1次,50mg/kg小鼠灌胃给药,对照品为50mg/kg小鼠连用21天。分别将实施例1、3、4、5、6、7、8、9、10、11、12、13、14、对照品中得到的化合物参考实施例2公开的方法制备形成对应化合物的盐酸盐作为给药药物,考察其对人肝癌Bel-7402、结肠癌HT-29细胞、胃癌SGC-7901细胞和非小细胞肺癌A549细胞的裸小鼠移植瘤的疗效,并与对照品(制备方法同实施例16)进行比较。结果如表2所示。
表2:
结论:本发明所示化合物可以在灌胃给药的条件下明显抑制人肝癌Bel-7402、结肠癌HT-29细胞、胃癌SGC-7901细胞和非小细胞肺癌A549细胞裸小鼠移植瘤的生长,且其抑制率比对照品有显著地提高。
以上所述是本发明的具体实施方式。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也视为本发明的保护范围。
Claims (9)
2.根据权利要求1所述的通式(I)所示的化合物,其药学上可接受的盐,其水合物、其药学上可接受的盐的水合物,其溶剂化物、其药学上可接受的盐的溶剂化物,以及其异构体,其特征是:
所述R1选自甲基、乙基、二氟甲基或三氟乙基;
所述R2,R3分别独立地选自甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、丙烯基、丙炔基;特别优选的是,所述R2=R3,进一步优选的是R2,R3同时选自甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、丙烯基或丙炔基中的一种。
3.根据权利要求1所述的通式(I)所示的化合物,其药学上可接受的盐,其水合物、其药学上可接受的盐的水合物,其溶剂化物、其药学上可接受的盐的溶剂化物,以及其异构体,其特征是,所述的化合物为:
(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-乙氧基苯基)乙烯,或(Z)-1-(3,4,5- 三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-三氟乙氧基苯基)、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丙基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-三氟乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-正丁基)氨基)丙酰胺)-4-二氟甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(双(2-羟乙基)氨基)丙酰胺)-4-甲氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2,2-二氟乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯、(Z)-1-(3,4,5-三甲氧基苯基)-2-((3-(2,2-二甲氧基乙基氨基)丙酰胺)-4-乙氧基苯基)乙烯。
4.根据权利要求1所述的通式(I)所示的化合物,其药学上可接受的盐,其水合物、其药学上可接受的盐的水合物,其溶剂化物、其药学上可接受的盐的溶剂化物,以及其异构体,其特征是:所述药学上可接受的盐是指一个或者一个以上的碱性成盐基团与酸形成的盐,所述的酸为有机酸和/或无机酸。
5.权利要求1至4中任意一项所述的通式(I)所示的化合物,其药学上可接受的盐,其水合物、其药学上可接受的盐的水合物,其溶剂化物、其药学上可接受的盐的溶剂化物,以及其异构体所制备得到的药物或药物组合物。
6.根据权利要求5所述的药物或药物组合物,其特征是,所述药物或药物组合物为局部、肠内或肠外给药剂型。
7.根据权利要求6所述的药物或药物组合物,其特征是,通式(I)所示的化合物,其药学上可接受的盐,其水合物、其药学上可接受的盐的水合物,其溶剂化物、其药学上可接受的盐的溶剂化物,以及其异构体所制备得到药物或药物组合物为片剂或胶囊剂。
8.权利要求1至4中任意一项所述的通式(I)所示的化合物,其药学上可接受的盐,其水合物、其药学上可接受的盐的水合物,其溶剂化物、其药学上可接受的盐的溶剂化物,以及其异构体在制备用于治疗由非正常新生血管引起的疾病的药物中的应用。
9.权利要求1至4中任意一项所述的通式(I)所示的化合物,其药学上可接受的盐,其水合物、其药学上可接受的盐的水合物,其溶剂化物、其药学上可接受的盐的溶剂化物,以及其异构体在制备微管蛋白聚集抑制剂中的应用。
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CN202011271276.5A CN112225673B (zh) | 2020-11-13 | 2020-11-13 | 氨基康普立停衍生物及其应用 |
CA3196777A CA3196777A1 (en) | 2020-11-13 | 2021-11-02 | Amino-combretastatin derivative and use thereof |
PCT/CN2021/128275 WO2022100487A1 (zh) | 2020-11-13 | 2021-11-02 | 氨基康普立停衍生物及其应用 |
KR1020237012257A KR20230088358A (ko) | 2020-11-13 | 2021-11-02 | 아미노 컴브리태스태틴(Amino combretastatin) 유도체 및 이의 응용 |
EP21891014.9A EP4245750A1 (en) | 2020-11-13 | 2021-11-02 | Amino-combretastatin derivative and use thereof |
AU2021378005A AU2021378005B2 (en) | 2020-11-13 | 2021-11-02 | Amino-combretastatin derivative and use thereof |
JP2023522350A JP2023545151A (ja) | 2020-11-13 | 2021-11-02 | アミノコンブレタスタチン誘導体及びその応用 |
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WO2022100487A1 (zh) * | 2020-11-13 | 2022-05-19 | 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 |
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AU2021378005A1 (en) | 2023-05-25 |
KR20230088358A (ko) | 2023-06-19 |
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