CN104387378A - 新的4-噻唑烷酮类衍生物及其应用 - Google Patents
新的4-噻唑烷酮类衍生物及其应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
本发明涉及通式Ⅰ所示的新的4-噻唑烷酮衍生物、其几何异构体及其药学上可接受的盐,其中取代基R1、R2、R3、R4、n具有在说明书中给出的含义。本发明还涉及通式Ⅰ的化合物在制备治疗和/或预防癌症的药物中的用途。
Description
技术领域
本发明属于医药技术领域,涉及新的4-噻唑烷酮类衍生物及其药学上可接受的盐,包括它们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该衍生物用于制备治疗和/或预防癌症的药物中的用途。
背景技术
含有4-噻唑烷酮结构的化合物具有广泛的生物学活性,如抗菌、抗真菌、抗病毒、抗炎、降血糖、强心以及抗肿瘤作用等。J.K.Choi等人报道了具有PRL-3抑制作用的5-取代苯基次甲基罗丹宁衍生物,该系列化合物体外活性最好的化合物IC50为0.9μM。N.S.Cutshall等人报道了一类N-取代苯基-5-取代苯基次甲基罗丹宁衍生物,该类化合物对JSP-1有抑制作用,该类化合物体外活性最好的化合物IC50为1.3μM。A.Geronikaki等人报道了将噻唑-2-亚胺基、苯并[d]噻唑-2-亚胺基以及苯并[d]异噻唑-2-亚胺基引入4-噻唑烷酮的2位得到了一系列化合物,该类化合物对SHP-2有较强的抑制作用。
本发明人设计并合成了一系列含有吲哚酮的4-噻唑烷酮类衍生物,经体外对多种肿瘤细胞株进行抗肿瘤活性筛选,结果表明其具有抗肿瘤活性。
发明内容:
本发明涉及通式Ⅰ的衍生物、其几何异构体、前药及其药学上可接受的盐,
其中,
R1为氢或为1-3个选自羟基、卤素、三氟甲基、三氟甲氧基、氰基、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烯基、(C1-C4)炔基、(C1-C3)亚烷基二氧基的取代基;
R2和R3相同或不同,分别独立地选自氢、(C1-C10)烷基、(C3-C7)环烷基,或R2和R3与和它们所连接的氮原子一起形成5-10元杂环基;
所述杂环基除了与R2和R3连接的氮原子外,还可以含有1-4个选自N、O或S的杂原子,或所述杂环基还可以任选包括1或2个碳碳双键或叁键;
R4为氢或为1-4个选自羟基、卤素、三氟甲基、三氟甲氧基、氨基、羧基、氰基、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烯基、(C1-C4)炔基、(C1-C3)亚烷基二氧基的取代基;
n为1-4的整数,选自1、2、3或4。
本发明优选的通式Ⅰ的衍生物、其几何异构体及其药学上可接受的盐,其中,
R1为氢或为1-3个选自卤素、(C1-C4)烷基的取代基,优选氢、氯、氟、甲基;
优选地,R2和R3相同或不同,分别独立地选自氢、(C1-C4)烷基,或R2和R3与和它们所连接的氮原子一起形成哌啶基、四氢吡咯基、哌嗪基、4-甲基-1-哌嗪基、吗啉基和硫代吗啉基;
进一步地,R2和R3同为甲基或乙基,或R2和R3与和它们所连接的氮原子一起形成四氢吡咯基、哌嗪基、4-甲基-1-哌嗪基、吗啉基;
R4为氢或为1-4个选自卤素、三氟甲基、三氟甲氧基、(C1-C4)烷基、(C1-C4)烷氧基的取代基,优选氢、氟、氯、三氟甲基;
更为优选地,n为3。
本发明特别优选为结构式如下的通式Ⅰ的衍生物、其几何异构体及其药学上可接受的盐:
5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(2,4-二氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-苯基-1H-吲哚-3-基)次甲基)-3-(3-(二乙氨基)丙基)-2-(5-氟-吲哚2-酮-3-亚基)噻唑-4-酮;
5-((1-苯基-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-甲基-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-三氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-吗啉丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-吗啉丙基)-2-(5-甲基-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-苯基-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-苯基-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-甲基-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(2,4-二氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(2,4-二氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5,6-二氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5,6-二氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5,6-二氟-2-吲哚酮-3-亚基)噻唑-4-酮。
本发明衍生物可以以几何异构体形式存在,这些几何异构形式可以是通式Ⅰ中双键构型为2Z,5Z、2Z,5E、2E,5E以及2E,5Z。本发明既涉及单一构型的衍生物,也涉及它们各自的混合物。
此外,本发明还包括本发明衍生物的前药。依据本发明,前药是通式Ⅰ的衍生物,它们自身可能具有较弱的活性或甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
除非另外指出,本发明所用的术语“卤素”是指氟、氯、溴或碘原子;“烷基”是指直链或支链的烷基;“亚烷基”是指直链或支链的亚烷基;“环烷基”是指取代或未取代的环烷基。
本发明包括药物组合物,该组合物含有通式Ⅰ的4-噻唑烷酮类化合物、其几何异构体、及其药学上可接受的盐作为活性成分,以及药学上可接受的赋型剂。所述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成分组合使用,只要它们不产生其他不利的作用,例如过敏反应。
本发明的药物组合物可配制成若干种剂型,其中含有药学领域中常用的一些赋形剂;例如,口服制剂(如片剂,胶囊剂,溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射用水可立即使用);局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药学领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂等;可注射制剂用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其配制成肠衣片剂。
我们已发现本发明化合物体外具有抑制肿瘤细胞生长活性,因此,它可以用作制备治疗和/或预防癌症的药物。尤其治疗乳腺癌和非小细胞肺癌。本发明化合物也被期望可以用于治疗其他疾病如糖尿病、真菌感染、细菌感染、病毒感染、慢性炎症等。另外预期本发明的4-噻唑烷酮类化合物将具有抗白血病、恶性淋巴瘤和固体肿瘤如在组织如肝、肾、前列腺和胰腺中的癌和肉瘤范围的活性。
根据本发明的衍生物可作为活性成分用于制备治疗和/或预防各种癌症,本发明也提供治疗或预防上述疾病的方法,包括给予患有或易患有此病的病人治疗有效量的根据本发明的衍生物。通式Ⅰ的4-噻唑烷酮类化合物用于患者的临床剂量必需依赖被治疗的主体、给药的具体途径、被治疗疾病的严重性而变化,而最佳剂量由治疗具体患者的医生确定。
本发明活性化合物可作为唯一的抗癌药物使用,或者可以与一种或多种其它抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下面合成路线A描述了本发明的通式Ⅰ化合物的制备,所有的原料都是通过这些路线中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些路线中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。这些路线中应用的全部可变因数如下文的定义或如权利要求中的定义。
按照本发明的通式Ⅰ化合物,在通式Ⅰ化合物的制备路线中,其中取代基R1、R2、R3、R4和n具有在说明书中给出的含义。
通式Ⅰ化合物的制备路线
化合物1与二硫化碳反应生成化合物2,化合物2与氯乙酸反应生成化合物3,化合物3在浓硫酸催化下发生环合反应生成化合物4,化合物4与取代苯甲醛发生Knoevenagel缩合反应生成化合物5,化合物5在三氟化硼乙醚作用下与原甲酸三乙酯发生乙基化反应生成化合物6,化合物6与化合物7发生缩合生成通式Ⅰ所示衍生物。
上述路线中,原料1、7可以通过有机化学领域普通技术人员熟知的方法制备或者可商购。
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。本发明中所制备化合物的核磁共振氢谱用BrukerARX-300测定,质谱用Agilent 1100LC/MSD测定;所用试剂均为分析纯或化学纯。
表1.实施例1-20的结构式
实施例1:
5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮
步骤A 2-硫代-(3-(二乙氨基)丙基)-4-噻唑烷酮的制备
将13.0g(0.1mol)N,N-二乙基丙二胺加入200mL无水乙醚中,然后滴加二硫化碳7.6g(0.1mol)的乙醚(50mL)溶液,滴毕继续搅拌30min,抽滤,乙醚洗涤,干燥后,将固体加入反应器,依次加入200mL水,50mL甲醇。向该混悬液中滴加预先配好的碳酸钾氯乙酸水溶液(碳酸钾6.9g(0.05mol),氯乙酸9.4g(0.1mol),水40mL),滴毕,30℃反应7-8h,滤除不溶物,然后向反应液中滴加浓硫酸11mL,滴毕,30℃反应10h。反应完毕将反应液蒸干,向残余液中乙醇100ml,升温回流30min,趁热抽滤,,将滤液蒸干,得2-硫代-(3-(二乙氨基)丙基)-4-噻唑烷酮14.5g,收率59%。
步骤B 5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-噻唑烷-4-酮的制备
将22-硫代-(3-(二乙氨基)丙基)-4-噻唑烷酮2.46g(0.01mol)加入15mL乙醇,然后依次加入4-氯苯基-1H-吲哚-3-甲醛2.69(0.01mol),哌啶0.85g(0.01mol),升温至80℃反应2h,反应毕,冷却,析出固体,抽滤,滤饼用少量乙醇洗涤,干燥,得黄色固体2.5g,收率51%。
步骤C 5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(乙巯基)-4-氧代-4,5-二氢-4-4-噻唑啉鎓盐的制备
将5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-噻唑烷-4-酮2.19g(0.0044mol)加入40mL二氧六环,然后依次加入原甲酸乙酯4.38mL,三氟化硼乙醚溶液6.57mL,80℃反应2h,反应毕,冷却,抽滤,滤饼用少量二氧六环,乙醚洗涤,干燥,得黄色固体1.90g,收滤82%。
步骤D 5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮的制备
冰浴下将5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(乙巯基)-4-氧代-4,5-二氢-4-4-噻唑啉鎓盐0.65g(1.23mmol)与5-氟-2-吲哚酮0.19g(1.23mmol)依次加入4mL乙腈中,滴加0.28mL三乙胺,冰浴下继续反应4h,反应毕,抽滤,滤饼依次用少量甲醇,少量乙醚洗涤,得固体0.19g,收率25%。
ESI-MS:m/z,615.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.80(s,1H),10.61(s,0.6×1H),8.40(s,0.6×1H),8.17(s,0.6×1H),8.07(s,2H),7.98(m,(1+0.6×1)H),7.66(dd,0.6×1H),7.54(d,(1+0.6×1)H),7.41(m,0.6×2H),7.40(d,2H),7.29(m,7H),7.01(m,2H,(1+0.6×1)H),6.87(m,2H,(1+0.6×1)H),5.69(s,(2+0.6×2)H),4.67(t,0.6×2H),4.32(t,2H),2.40(m,(6+0.6×6)H),1.75(m,(2+0.6×2)H),0.88(t,0.6×6H),0.77(t,6H).
按照实施例1的方法,选择合适的原料和试剂,分别制得实施例2-20的化合物。当提到特定的反应原料时,应该理解的是,精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例2:5-((1-(2,4-二氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,631.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.79(s,1H),10.61(s,0.7×1H),8.21(s,0.7×1H),8.14(s,0.7×1H),8.01(m,(2+1+0.7×1)H),7.81(d,0.7×1H),7.73(d,0.7×2H),7.47(m,3H),7.36(m,2H),7.29(m,3H),7.16(m,(1+0.7×1)H),7.07(m,0.7×1H),7.00(m,1H),6.93(m,(1+0.7×1)H),6.77(m,(1+0.7×1)H),5.75(s,(2+0.7×2)H),4.69(t,0.7×2H),4.33(t,2H),2.31(m,(6+0.7×6)H),1.74(m,(2+0.7×2)H),0.86(t,0.7×6H),0.75(t,6H)。
实施例3:5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,615.2(M+H)+,1H-NMR(400MHz,DMSO)δ10.93(s,1H),10.74(s,0.5×1H),8.40(s,0.5×1H),8.18(s,0.5×1H),8.10(s,1H),8.08(s,1H),7.99(m,(1+0.5×1)H),7.78(d,0.5×1H),7.62(d,0.5×1H),7.57(d,1H),7.42(m,1H),7.39(m,(1+0.5×1)H),7.28(m,3H),7.19(m,2H),7.12(m,3H),7.06(d,1H),6.90(dd,(1+0.5×1)H),5.72(s,2H),5.69(s,0.5×2H),4.64(t,0.5×2H),4.29(t,2H),2.45(m,0.5×2H),2.32(m,6H),1.77(s,(2+0.5×2)H),0.88(t,0.5×6H),0.79(t,6H)。
实施例4:5-((1-苯基-1H-吲哚-3-基)次甲基)-3-(3-(二乙氨基)丙基)-2-(5-氟-吲哚2-酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,581.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.81(s,1H),10.63(s,0.6×1H),8.37(s,0.6×1H),8.17(s,0.6×1H),8.07(s,2H),7.98(m,(1+0.6×1)H),7.64(d,0.6×1H),7.56(d,(1+0.6×1)H),7.30(m,13H),7.00(m,2H),6.87(s,(1+0.6×1)H),5.68(s,(2+0.6×2)H),4.67(t,0.6×2H),4.32(t,2H),2.33(m,(6+0.6×6)H),1.75(m,(2+0.6×2)H),0.87(t,0.6×6H),0.76(t,6H)。
实施例5:5-((1-苯基-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-甲基-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,577.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.68(s,1H),10.49(s,0.5×1H),8.29(s,0.5×1H),8.13(s,0.5×1H),8.03(s,2H),7.97(m,(1+0.5×1)H),7.65(s,0.5×1H),7.60(d,0.5×1H),7.55(d,1H),7.40–7.30(m,4H),7.31–7.18(m,8H),6.98(m,(1+0.5×1)H),6.79(m,(1+0.5×1)H),5.67(m,(2+0.5×2)H),4.68(t,0.5×2H),4.34(t,2H),2.34(m,(3+0.5×3+6+0.5×6)H),1.73(m,(2+0.5×2)H),0.86(t,3H),0.77(t,7H)。
实施例6:5-((1-(3-三氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,665.0(M+H)+,1H-NMR(400MHz,DMSO)δ10.94(s,1H),10.74(s,0.4×1H),8.44(s,0.4×1H),8.19(s,0.4×1H),8.15(s,1H),8.08(s,1H),8.00(m,(1+0.4×1)H),7.77(s,1H),7.73(s,1H),7.65(m,2H),7.59(m,3H),7.48(m,1H),7.42(s,1H),7.28(m,3H),7.20(m,2H),6.90(m,(1+0.4×1)H),5.80(m,(2+0.4×2)H),4.66(t,0.4×1H),4.29(t,2H),2.32(m,(6+0.4×6)H),1.77(m,(2+0.4×2)H),0.85(t,0.4×6H),0.78(t,6H)。
实施例7:5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-吗啉丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,595.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.78(s,1H),10.60(s,0.6×1H),8.32(s,0.6×1H),8.14(s,0.6×1H),8.07(s,1H),8.05(s,1H),7.98(m,(1+0.6×1)H),7.87(d,0.6×1H),7.56(d,(1+0.6×1)H),7.40(m,3H),7.33–7.21(m,3H),7.20–6.98(m,8H),6.91(dd,(1+0.6×1)H),5.72(s,(2+0.6×2)H),4.79(t,0.6×2H),4.40(t,2H),3.42(s,0.6×4H),3.24(s,4H),2.27–2.02(m,(6+0.6×6)H),1.82–1.71(m,2+0.6×2H)。
实施例8:5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-吗啉丙基)-2-(5-甲基-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,609.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.68(s,1H),10.49(s,0.5×1H),8.33(s,0.5×1H),8.14(s,0.5×1H),8.07(s,1H),8.04(s,1H),7.90(m,(1+0.5×1)H),7.66(s,1H),7.63(d,0.5×1H),7.56(d,1H),7.38(m,(1+0.5×1)H),7.34–7.20(m,5H),7.15(m,3H),7.05(m,1H),6.98(m,2H,(1+0.5×1)H),6.80(dd,(1+0.5×1)H),5.71(s,(2+0.5×2)H),4.77(t,0.5×2H),4.39(t,2H),3.43(s,0.5×4H),3.28(s,4H),2.41(s,0.5×3H),2.34(s,3H),2.15(m,(6+0.5×6)H),1.79(s,2+0.5×2H)。
实施例9:5-((1-苯基-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,536.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.80(s,1H),10.59(s,1H),8.27(s,0.8×1H),8.13(s,0.8×1H),8.05(s,2H),7.98(m,(1+0.8×1)H),7.88(m,0.8×1H),7.55(m,(1+0.8×1)H),7.46(m,1H),7.30(m,14H),7.18(m,2H),7.09(m,1H),7.02(m,1H),6.93(m,(1+0.8×1)H),5.69(s,(2+0.8×2)H),4.72(t,0.8×2H),4.34(t,2H),2.09(m,(8+0.8×8)H2),1.75(s,(2+0.8×2)H)。
实施例10:5-((1-苯基-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-甲基-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,549.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.70(s,1H),10.48(s,0.6×1H),8.29(s,0.6×1H),8.12(s,0.6×1H),8.03(s,2H),8.01–7.92(m,(1+0.6×1)H),7.66(s,0.6×1H),7.60(d,0.6×1H,),7.56(d,1H),7.39–7.31(m,5H),7.26(m,8H),6.98(t,(1+0.6×1)H),6.80(m,(1+0.6×1)H),5.67(m,(2+0.6×2)H),4.71(t,0.6×2H),4.31(t,2H),2.42(s,0.6×3H),2.34(s,3H),2.15(m,(2+0.8×2)H),2.03(s,0.6×6H),2.00(s,6H),1.77(m,(2+0.6×2)H)。
实施例11:5-((1-(2,4-二氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,603.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.82(s,1H),10.61(s,0.8×1H),8.22(s,0.8×1H),8.14(s,0.8×1H),8.04(m,2H),7.82(d,0.8×1H),7.75(d,2H),7.47(m,3H),7.37(m,2H),7.29(m,4H),7.17(m,2H),7.10(m,1H),7.04(m,1H),6.96–6.87(m,2H),6.82–6.72(m,2H),5.75(m,(2+0.8×2)H),4.72(s,0.8×2H),4.33(s,2H),2.19(m,0.8×2H),2.10(m,2H),2.04(s,0.8×6H),1.98(s,6H),1.74(m,(2+0.8×2)H)。
实施例12:5-((1-(2,4-二氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,638.8(M+H)+,1H-NMR(400MHz,DMSO)δ10.93(s,1H),10.73(s,0.7×1H),8.23(s,0.7×1H),8.16(s,0.7×1H),8.06(s,1H),8.05(s,1H),8.00(m,(1+0.7×1)H),7.74–7.69(m,(1+0.7×2)H),7.58(d,0.7×1H),7.49(d,1H),7.42–7.39(m,1H),7.37(m,0.7×1H),7.34(d,0.7×1H),7.29(m,4H),7.19(td,(1+0.7×1)H),7.01(d,0.7×1H),6.90(dd,(1+0.7×1)H),6.78(d,1H),5.74(m,(2+0.7×2)H),4.65(t,0.7×2H),4.29(t,2H),2.38(t,0.7×2H),2.24(t,2H),2.18(s,0.7×6H),2.08(s,6H),1.81(m,(2+0.7×2)H)。
实施例13:5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,569.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.82(s,1H),10.61(s,0.8×1H),8.32(s,0.8×1H),8.13(s,0.8×1H),8.07(s,1H),8.04(s,1H),7.98(m,4H),7.89(d,1H),7.53(m,2H),7.42(m,5H),7.27(m,9H),7.18(m,2H),7.10(m,1H),7.02(m,1H),6.92(dd,2H),5.69(s,(2+0.8×2)H),4.70(s,0.8×2H),4.34(s,2H),2.41(m,0.8×2H),2.22(m,(2+0.8×6)H),2.07(s,6H),1.84(m,0.8×2H),1.77(m,2H)。
实施例14:5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5,6-二氟-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,605.0(M+H)+,1H-NMR(400MHz,DMSO)δ10.93(s,1H),10.71(s,0.8×1H),8.41(s,0.8×1H),8.15(s,0.8×1H),8.06(m,2H),7.96(m,1+0.8×1H),7.83(dd,0.8×1H),7.52(m,2H),7.41(m,4H),7.28(m,9H),6.90(dd,1+0.8×1H),5.68(s,(2+0.8×2)H),4.67(t,0.8×2H),4.29(t,2H),2.18(m,0.8×2H),2.11(s,2H),2.03(s,0.8×6H),1.98(s,6H),1.74(m,(2+0.8×2)H)。
实施例15:5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,571.0(M+H)+,1H-NMR(400MHz,DMSO)δ10.81(s,1H),10.60(s,0.8×1H),8.39(s,0.8×1H),8.16(s,0.8×1H),8.09(s,1H),8.06(s,1H),7.98(t,1+0.8×1H),7.65(d,1H),7.56(d,1+0.8×1H),7.38(m,2H),7.28(m,5H),7.17(d,1H),7.12(m,4H),7.06(d,1H),7.03–6.94(m,2H),6.88(dd,1+0.8×1H),5.70(m,(2+0.8×2)H),4.69(t,0.8×2H),4.30(t,2H),2.30(t,0.8×2H),2.16(t,2H),2.12(s,0.8×6H,),2.02(s,6H),1.78(m,(2+0.8×2)H)。
实施例16:5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,587.0(M+H)+,1H-NMR(400MHz,DMSO)δ10.95(s,1H),10.72(s,0.6×1H),8.39(s,0.6×1H),8.17(s,0.6×1H),8.10(s,1H),8.07(s,1H),7.99(t,(1+0.6×1)H),7.78(m,0.6×1H),7.62(d,0.6×1H),7.56(d,1H),7.41(m,3H),7.18(m,10H),6.91(dd,1+0.6×1H),5.70(m,(2+0.6×2)H),4.69(m,0.6×2H),4.26(m,2H),2.17(m,(2+0.6×2)H),2.02(s,(6+0.6×6)H),1.78(m,(2+0.8×2)H)。
实施例17:5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5,6-二氟-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,589.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.93(s,1H),10.71(s,0.75×1H),8.41(s,0.75×1H),8.16(s,0.75×1H),8.07(s,1H),8.05(s,1H),7.98(t,(1+0.75×1)H),7.83(dd,0.75×1H),7.56(d,(1+0.75×1)H),7.50(dd,1H),7.39(m,(1+0.75×1)H),7.27(m,(2+0.75×2)H),7.18(d,1H),7.12(m,(2+0.75×2)H),7.07(d,1H),6.90(dd,(1+0.75×1)H),5.71(s,(2+0.75×2)H),4.67(t,0.75×2H),4.29(t,2H),2.19(t,0.75×2H),2.11(t,2H),2.03(s,0.75×6H),1.98(s,6H),1.74(m,(2+0.8×2)H)。
实施例18:5-((1-(3-氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,621.3(M+H)+,1H-NMR(400MHz,DMSO)δ10.83(s,1H),10.61(s,0.85×1H),8.45(s,0.85×1H),8.17(s,0.85×1H),8.15(s,1H),8.07(s,1H),7.99(t,(1+0.85×1)H),7.80(s,1H),7.73(s,1H),7.66(m,(1+0.85×2)H),7.58(m,5H),7.48(m,1H),7.29(m,5H),7.00(m,2H),6.88(m,2H),5.81(m,(2+0.85×2)H),4.70(m,0.85×2H),4.31(m,2H),2.28(m,0.85×2H),2.16(s,2H),2.11(s,0.85×6H,),2.02(s,6H),1.78(m,(2+0.85×2)H)。
实施例19:5-((1-(3-氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,637.1(M+H)+,1H-NMR(400MHz,DMSO)δ10.94(s,1H),10.72(s,0.6×1H),8.43(s,0.6×1H),8.18(s,0.6×1H),8.14(s,1H),8.07(s,1H),7.99(t,(1+0.6×1)H),7.78(s,1H),7.73(s,1H),7.66(d,2H),7.61–7.54(m,(2+0.6×2)H),7.48(d,1H),7.42(s,1H),7.28(m,(2+0.6×2)H),7.19(m,(1+0.6×1)H),6.92(d,1H),6.89(d,0.6×1H),5.80(m,(2+0.6×2)H),4.68(t,0.6×2H),4.27(t,2H),2.19(m,(2+0.6×2)H),2.06(s,0.6×6),2.02(s,6H),1.79(m,(2+0.6×2)H)。
实施例20:5-((1-(3-氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5,6-二氟-2-吲哚酮-3-亚基)噻唑-4-酮
ESI-MS:m/z,639.0(M+H)+,1H NMR(400MHz,DMSO)δ10.96(s,1H),10.74(s,0.8×1H),8.47(s,0.8×1H),8.16(s,0.8×1H),8.14(s,1H),8.06(s,1H),7.99(t,1+0.8×1H),7.80(s,1H),7.73(s,1H),7.66(d,2H),7.63–7.55(m,5H),7.49(m,2H),7.28(m,4H),6.91(m,2H),5.80(m,(2+0.8×2)H),4.67(t,0.8×2H),4.29(t,2H),2.26(t,0.8×2H),2.14(t,2H),2.09(s,0.8×6H),2.00(s,6H),1.82-1.70(m,(2+0.8×2)H)。
本发明产物的药理研究
对按照本发明的上式Ⅰ的含有吲哚酮的4-噻唑烷酮类衍生物进行了体外抗肿瘤活性筛选。
体外抗肿瘤活性测试
(1)将MDA-MB-231(人乳腺癌细胞)、HT-29(结肠癌)和H460(非小细胞肺癌细胞)三种细胞株分别复苏并传代2-3次稳定后,用胰蛋白酶溶液(0.25%)使其从培养瓶底部消化下来。将细胞消化液倒入离心管中而后加入培养液以终止消化。将离心管在1300r/min下离心3min,轻轻弃去上清液后加入5mL培养液,吹打混匀细胞,吸取10μL细胞混悬液加入细胞计数板中计数,调整细胞浓度为104个/孔。96孔板中除A1孔为空白孔不加细胞外,其余皆加入100uL细胞混悬液。将96孔板放入培养箱中培养24h。
(2)用50μL二甲基亚砜溶解受试样品,然后加入适量培养液,使样品溶解成2mg/mL药液。然后在24孔板中将样品稀释为100,20,4,0.8,0.16μg/mL。每个浓度加入3孔,其中周围两行两列细胞长势受环境影响较大,只作为空白细胞孔使用。将96孔板放入培养箱中培养72H。
(3)将96孔板中带药培养液弃去,用磷酸缓冲溶液(PBS)将细胞冲洗两遍,在每孔中加入MTT(四氮唑)(0.5mg/mL)100μL放入培养箱中4h后,弃去MTT溶液,加入二甲基亚砜100μL。在磁力振荡器上振荡使存活细胞与MTT反应产物甲臜充分溶解,放入酶标仪中测定结果,通过Bliss法可求出药物IC50值。
化合物的体外抗肿瘤细胞活性结果见表2。
表2.化合物的体外抗肿瘤细胞活性结果
Claims (10)
1.通式Ⅰ的衍生物、其几何异构体、前药及其药学上可接受的盐,
其中,
R1为氢或为1-3个选自羟基、卤素、三氟甲基、三氟甲氧基、氰基、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烯基、(C1-C4)炔基、(C1-C3)亚烷基二氧基的取代基;
R2和R3相同或不同,分别独立地选自氢、(C1-C10)烷基、(C3-C7)环烷基,或R2和R3与和它们所连接的氮原子一起形成5-10元杂环基;
所述杂环基除了与R2和R3连接的氮原子外,还可以含有1-4个选自N、O或S的杂原子,或任选包括1或2个碳碳双键或叁键;
R4为氢或为1-4个选自羟基、卤素、三氟甲基、三氟甲氧基、氨基、羧基、氰基、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烯基、(C1-C4)炔基、(C1-C3)亚烷基二氧基的取代基;
n为1-4的整数。
2.权利要求1的通式Ⅰ的衍生物、其几何异构体、前药及其药学上可接受的盐,
其中,
R1为氢或为1-3个选自卤素、(C1-C4)烷基的取代基,优选氢、氯、氟、甲基。
3.权利要求1或2的通式Ⅰ的衍生物、其几何异构体、前药及其药学上可接受的盐,
其中,
R2和R3相同或不同,分别独立地选自氢、(C1-C4)烷基,或R2和R3与和它们所连接的氮原子一起形成哌啶基、四氢吡咯基、哌嗪基、4-甲基-1-哌嗪基、吗啉基或硫代吗啉基。
4.权利要求1-3任何一项的通式Ⅰ的衍生物、其几何异构体、前药及其药学上可接受的盐,
其中,
R2和R3同为甲基或乙基,或R2和R3与和它们所连接的氮原子一起形成四氢吡咯基、哌嗪基、4-甲基-1-哌嗪基、吗啉基。
5.权利要求1-4任何一项的通式Ⅰ的衍生物、其几何异构体、前药及其药学上可接受的盐,
其中,
R4为氢或为1-4个选自卤素、三氟甲基、三氟甲氧基、(C1-C4)烷基、(C1-C4)烷氧基的取代基,优选氢、氟、氯、三氟甲基。
6.权利要求1-5任何一项的通式Ⅰ的衍生物、其几何异构体、前药及其药学上可接受的盐,
其中,
n为3。
7.权利要求1-6任何一项的通式Ⅰ的衍生物、其几何异构体、前药及其药学上可接受的盐:
5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(2,4-二氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-苯基-1H-吲哚-3-基)次甲基)-3-(3-(二乙氨基)丙基)-2-(5-氟-吲哚2-酮-3-亚基)噻唑-4-酮;
5-((1-苯基-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-甲基-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-三氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-(二乙氨基)丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-吗啉丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-吗啉丙基)-2-(5-甲基-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-苯基-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-苯基-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-甲基-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(2,4-二氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(2,4-二氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(4-氯苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5,6-二氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5,6-二氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氟-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5-氯-2-吲哚酮-3-亚基)噻唑-4-酮;
5-((1-(3-氟甲基苯基)-1H-吲哚-3-基)亚甲基)-3-(3-二甲氨基丙基)-2-(5,6-二氟-2-吲哚酮-3-亚基)噻唑-4-酮。
8.一种药用组合物,包含权利要求1-7任何一项的4-噻唑烷酮类化合物、其几何异构体、前药及其药学上可接受的盐作为活性成分以及药学上可接受的赋形剂。
9.权利要求1-7中任何一项的4-噻唑烷酮类化合物及其几何异构体、前药及其药学上可接受的盐或权利要求8所述的组合物在制备治疗和/或预防各种癌症的药物中的应用。
10.权利要求1-7中任何一项的4-噻唑烷酮类化合物及其几何异构体、前药及其药学上可接受的盐或权利要求8所述的组合物在制备治疗和/或预防乳腺癌、结肠癌或非小细胞肺癌的药物中的应用。
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WO2000027832A2 (en) * | 1998-11-11 | 2000-05-18 | Glaxo Group Limited | Thiazole derivatives as ppar gamma ligands |
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WO1995018797A1 (en) * | 1994-01-03 | 1995-07-13 | The Wichita State University | Novel serine protease inhibitors: derivatives of isothiazolidin-3-one-1,1 dioxide and 3-oxo-1,2,5-thiadiazolidine-1,1-dioxide |
WO2000027832A2 (en) * | 1998-11-11 | 2000-05-18 | Glaxo Group Limited | Thiazole derivatives as ppar gamma ligands |
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CN102532118A (zh) * | 2010-12-24 | 2012-07-04 | 沈阳药科大学 | 含有吲哚酮的4-噻唑烷酮类衍生物及其应用 |
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