CN104829554B - 吩噻嗪类化合物及其制备方法和应用 - Google Patents
吩噻嗪类化合物及其制备方法和应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—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
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Abstract
本发明涉及一种具有抗癌作用的吩噻嗪类化合物和该化合物的制备方法,此外,本发明还涉及该类化合物在制备抗癌药物中的应用,以及该类化合物作为有效成分的抗癌药物。本发明通过对吩噻嗪三元连环母核进行修饰得到具有广谱抗癌作用的化合物,合成方法简单、产率高;该类吩噻嗪化合物对于人乳腺癌细胞株MCF‑7和人肝癌细胞株Hep‑G2均有一定的抑制作用,为满足临床需求的新药提供新思路。
Description
技术领域
本发明属于抗癌药物领域,涉及一种具有抗癌作用的吩噻嗪类化合物和该化合物的制备方法,此外,本发明还涉及该类化合物在制备抗癌药物中的应用,以及含有该类化合物作为有效成分的抗癌药物。
背景技术
过去20多年来,各种实体瘤及血癌的癌症干细胞也被陆续分离出来。癌症干细胞(CSC:CancerStemCell)是指肿瘤细胞中的一小部分细胞亚群(约0.1%-5%),具有类似于干细胞的特征,具有自我更新、无限增殖以及高致瘤性等特点,大多数处于休眠状态(G0),具有极强的耐药性,传统的化疗或放疗不能对其杀灭,最终导致肿瘤复发和转移。从2009年美国哈佛大学和麻省理工学院的白头研究所进行以盐霉素杀灭乳腺癌干细胞的活体实验起,小分子抗癌症干细胞药物的研究获得了飞速发展。迄今为止,已有近30个抗癌症干细胞药物被推向临床一、二、三期。
吩噻嗪类药物是应用广泛、较为成熟的一种抗精神病类药物,其主要作用于中枢的多巴胺受体,具有镇静、镇吐、抗精神病和降低体温等作用。近年来的研究表明,吩噻嗪类药物具有抑制肿瘤干细胞的作用。美国专利US2013/0065887A1公开了一种用于治疗急性骨髓性白血病的多巴胺受体拮抗剂,该拮抗剂是吩噻嗪类衍生物甲硫哒嗪或氯哒嗪,其具有选择靶向性,可以针对性的损害血癌干细胞并不对其他细胞进行侵害。在吩噻嗪类药物处理淋巴瘤细胞的研究中,有报道显示,在临床常用剂量下,氯丙嗪及三氟拉嗪能够促进淋巴瘤细胞的凋亡而对正常淋巴细胞无影响。中国专利申请CN104114175公开了用于清除癌干细胞的医药组合物,该组合物包含吩噻嗪类衍生物如三氟拉嗪可以抑制肺癌干细胞。以往的研究也发现精神分裂症患者的患癌概率较正常人低,也证实该类化合物具有潜在的抗肿瘤效应。以上证据均表明,吩噻嗪类化合物及其衍生物具有抑制肿瘤增殖或者抑制肿瘤干细胞的作用。因而对于吩噻嗪类化合物其广谱抗癌作用的研究已成为业界工作者努力专研的方向之一,具有广谱、高效、低毒的新型吩噻嗪类衍生物是研究热点所在,设计并筛选具有新化学结构、新作用机制或新作用靶位的此类抗癌药成为亟待解决的问题。
发明内容
本发明人经过对吩噻嗪类化合物构效关系的研究和筛选,合成出具有抗癌作用的吩噻嗪类化合物,实验证明,该化合物对于人乳腺癌细胞株MCF-7和人肝癌细胞株Hep-G2均有一定的抑制作用。
本发明的技术方案是这样实现的:一种吩噻嗪类化合物,该化合物结构如通式(Ⅰ)所示:
其中,A为哌嗪基、哌啶基、三氮唑基、四氮唑基、吡咯基、胍基、吗啉基及其衍生物基团;R为C2-3的直链饱和烷基;B可独立的为Cl、甲硫基或三氟甲基。
进一步的,当B为甲硫基时,A为哌嗪基、三氮唑基、四氮唑基、吡咯基、胍基、吗啉基及其衍生物基团,或哌啶基或N(CH3)2;当B为三氟甲基时,A为吗啉基、哌啶基、吡咯基及其衍生物基团,或哌嗪基;当B为Cl时,A为哌啶基、三氮唑基、四氮唑基、吡咯基、胍基、吗啉基及其衍生物基团,或哌嗪基。
本发明还请求保护上述吩噻嗪类化合物的制备方法,前驱体具有通式(Ⅱ)的化学结构,该前驱体的T1基团与配体基团在有机溶剂中发生取代反应;其中T1选自卤代丙烷及其衍生物基团,T2选自Cl、甲硫基或三氟甲基;
所述的配体基团包括:哌啶基、哌嗪基、三氮唑基、四氮唑基、吡咯基、胍基、吗啉基及其衍生物基团。
另一种制备上述吩噻嗪类化合物的方法是:M与具有通式(Ⅲ)的化合物在有机溶剂中发生取代反应;
其中,M选自被哌啶基或其衍生物基团所取代的卤代乙烷及其衍生物,B可独立的为Cl、甲硫基或三氟甲基。
上述方法中通式(I)或(II)的哌啶基、哌嗪基及其衍生物基团被一个或连续两个氨基酸通过酰胺化或酯化反应连接。
进一步的,所述的有机溶剂如醚、烷烃、芳香烃、酰胺类、腈类、胺类、醇类或酮类溶剂中的一种或上述溶剂的混合物,如THF、甲苯、DMF、乙腈、三乙胺、丙酮或乙醇。
本发明提供上述吩噻嗪类化合物的新用途。
一方面,所述的吩噻嗪类化合物用于制备抗人乳腺癌细胞株MCF-7的药物。
另一方面,所述的吩噻嗪类化合物用于制备抗人肝癌细胞株Hep-G2的药物。
一种抗癌药物组合物,其中含有上述吩噻嗪类任一化合物或它们的混合物作为有效成分,以及一种或多种药学上可接受的载体。
进一步的,该药物组合物可以制成任何一种药学上可接受的剂型,注射剂、喷雾剂、吸入剂或口服剂。
本发明的部分具体化合物如表1所示。
表1 化合物列表
本发明合成的上述吩噻嗪类化合物,合成方法简单、产率高,通过对吩噻嗪三元连环母核10位、2位进行修饰,得到具有与所预期的广谱抗癌作用,该类吩噻嗪化合物对于人乳腺癌细胞株MCF-7和人肝癌细胞株Hep-G2均有一定的抑制作用,为满足临床需求的新药提供新思路。
具体实施方式
下面通过具体实施例对本发明进行说明,但本发明并不局限于此。下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和生物材料,如无特殊说明,均可从商业途径获得。
实施例1:制备2-21-2
2-10:
取2-三氟甲基吩噻嗪(2.00g,7.4831mmol)置于500mL烧瓶中,加入经无水K2CO3干燥的THF(100mL),然后在N2保护下依次加入60%的NaH矿物油(1.1973g,29.9323mmol)和1-溴-3-氯丙烷(2.9601mL,29.9323mmol),在65℃浴温回流过夜。冷却至室温,然后将反应液倒入冰水混合物中,用乙酸乙酯萃取(300mL+100mL×2),合并有机相,用无水MgSO4干燥,过滤除去固体,然后将滤液旋干,再加入乙酸乙酯(50mL)溶解,向溶液中加入硅胶粉(20g)旋干,干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度洗脱,收集产品,旋干,真空干燥得到产品2-10(4.9444g,产率69.8%)。+c ESI Q1MS:[M+H+]344.00。
2-21-2:
取2-10(250mg,0.7272mmol)置于30mL直筒瓶中,然后加入吗啉(95.0mg,1.0908mmol),三乙胺(0.30mL,2.1816mmol)和乙腈(10mL),于80℃下搅拌过夜。冷却至室温,直接旋干,将粗产品用甲醇溶解,过滤,往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-21-2(108.5mg,产率31.5%)。1H-NMR(400MHz,CDCl3)δ7.23-7.10(m,4H),7.04(s,1H),7.00-6.89(m,2H),4.00(t,J=6Hz,2H),3.76-3.62(m,4H),2.61-2.39(m,6H),2.08-1.92(m,2H);+c ESI Q1MS:[M+H+]395.09。
实施例2:制备2-21-6
在30mL直筒瓶里,加入2-10(250mg,0.7272mmol)、脯氨醇(110.3mg,1.0908mmol)、三乙胺(0.5mL)和乙腈(10mL),于80℃下搅拌过夜。冷却至室温,直接旋干,将粗产品用甲醇溶解,过滤,往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-21-6(138.9mg,产率38.9%)。1H-NMR(400MHz,CDCl3)δ7.25-7.13(m,4H),7.05(s,1H),7.01-6.89(m,2H),4.05-3.96(m,2H),3.68-3.60(m,1H),3.51-3.42(m,1H),3.33-3.23(m,1H),3.14-3.03(m,1H),2.81-2.69(m,1H),2.61-2.50(m,1H),2.35-2.24(m,1H),2.16-2.05(m,2H),1.85-1.72(m,3H),1.28-1.23(m,2H);+c ESI Q1MS:[M+H+]409.11。
实施例3:制备2-163、2-172
2-21-1:
取2-10(300mg,0.8726mmol)置于30mL直筒瓶中,然后加入1-叔丁氧羰基哌嗪(243.8mg,1.3089mmol),三乙胺(0.37ml,2.6178mmol)和乙腈(10mL),于80℃条件下反应过夜。冷却至室温,直接蒸干,将粗产品用甲醇溶解,然后往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用乙酸乙酯、石油醚和三乙胺梯度洗脱,收集产品,旋干,真空干燥得产品2-21-1(63.4mg,产率40.2%)。1H-NMR(400MHz,CDCl3)δ7.24-7.10(m,5H),7.04(s,1H),7.00-6.88(m,1H),4.08-3.95(m,2H),3.60-3.25(m,4H),2.70-2.25(m,6H),2.12-1.90(m,2H),1.44(s,9H);+c ESI Q1MS:[M+H+]494.20。
2-163:
在100mL烧瓶中,将2-21-1(2.4458g,4.9569mmol)溶于CH2Cl2(50mL),加入TFA(4mL),室温下搅拌过夜。浓缩除去溶剂和大部分TFA,粗产品用甲醇溶解,然后加入NaHCO3中和过量的TFA,过滤除去固体,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用NH3·H2O,CH3OH和CH2Cl2梯度洗脱,收集产品,旋干,真空干燥得产品2-163(2.4346g,产率100%)。1H-NMR(400MHz,CDCl3)δ=7.23-7.10(m,4H),7.03(s,1H),6.99-6.93(t,J=6Hz,1H),6.92-6.87(d,J=8Hz,1H),3.99(t,J=4Hz,2H),3.10-2.95(m,4H),2.70-2.47(m,6H),1.95-1.86(m,2H)。+c ESI Q1MS:[M+H+]394.25。
2-169:
将2-163(1.9146g,4.8681mmol)置于200mL烧瓶中,然后加入Boc-甘氨酸(Boc-Gly)(0.9381g,5.3549mmol),HBTU(2.7404g,7.3022mmol),HOBT(986.7mg,7.3022mmol)和DMF(50mL),在0℃条件下滴加DIEA(3.8159mL,21.9065mmol),然后移至室温下搅拌过夜。将反应液倒入到饱和NaHCO3溶液(500mL)中,用乙酸乙酯(500mL)萃取,水相再用乙酸乙酯萃取(200mL×3)分相;合并有机相,然后用饱和NaHCO3溶液清洗(200mL×2),再用饱和NaCl溶液清洗(200mL×2);分相后有机相用无水MgSO4干燥,过滤除去固体,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-169(2.6138g,产率97.54%)。1H-NMR(400MHz,CDCl3)δ7.21-7.10(m,4H),7.03(s,1H),6.97-6.89(m,2H),3.99(t,J=4Hz,2H),3.93-3.88(d,J=4Hz,2H),3.56-3.51(m,2H),3.29-3.24(m,2H),2.48(t,J=6Hz,2H),2.40-2.33(m,4H),1.95-1.88(m,2H),1.44(s,9H)
2-172:
将2-169(2.5949g,4.7140mmol)置于100mL烧瓶中,然后加入CH2Cl2(20mL)溶解,再加入TFA(5mL)搅拌过夜。旋干,将粗产品用CH3OH溶解,然后加入NaHCO3中和多余的TFA;过滤除去固体,将滤液旋干,粗产品再次用CH2Cl2溶解,湿法上样过硅胶柱纯化,用NH3·H2O、甲醇和二氯甲烷进行梯度淋洗,收集产品,旋干,真空干燥得产品2-172(1.3303g,产率62.8%)。1H-NMR(400MHz,CDCl3)δ7.22-7.11(m,4H),7.04(s,1H),6.98-6.89(m,2H),4.00(t,J=6Hz,2H),3.56(t,J=4Hz,2H),3.42(s,2H),3.27(t,J=4Hz,2H),2.49(t,J=4Hz,2H),2.37(t,J=4Hz,4H),1.97-1.89(m,2H),1.25(s,2H);+c ESI Q1MS:[M+H+]451.39。
实施例4:制备2-21-4、2-162
2-21-4:
以2-10(250mg,0.7272mmol)、哌啶-4-醇(110.3mg,1.0908mmol)、三乙胺(0.5mL)和乙腈(10mL),于80℃下搅拌过夜。冷却至室温,直接旋干,将粗产品用甲醇溶解,过滤,往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-21-4(232.5mg,产率65.1%)。1H-NMR(400MHz,CDCl3)δ7.24-7.10(m,4H),7.04(s,1H),6.99-6.90(m,2H),3.97(t,J=6Hz,2H),3.79-3.66(m,2H),2.82-2.72m,2H),2.60-2.50(m,2H),2.32-2.14(m,2H),1.98-1.86(m,2H),1.63-1.50(m,2H),1.14(t,J=8Hz,2H);+c ESI Q1MS:[M+H+]409.13。
2-154:
取2-21-4(1.6316g,3.9947mmol)置于250mL烧瓶中,加入Boc-Gly(839.7mg,4.7936mmol),DMAP(48.8mg,0.3995mmol)和CH2Cl2(200mL),将反应液置于0℃下搅拌30分钟,再加入DCC(2.4727g,11.9841mmol),然后转至室温下搅拌过夜。过滤除去固体杂质;加入甲醇将粗产品溶解,向溶液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度洗脱,收集产品,旋干,真空干燥得产品2-154(3.2987g,产率100%)。1H-NMR(400MHz,CDCl3)δ7.21-7.09(m,4H),7.04(s,1H),6.97-6.89(m,2H),4.86-4.77(m,1H),3.96(t,J=4Hz,2H),2.70-2.58(m,2H),2.52-2.42(m,2H),2.28-2.16(m,2H),1.98-1.89(m,4H),1.87-1.80(m,2H),1.77-1.70(m,4H),1.45(s,9H);+c ESI Q1MS:[M+H+]551.42。
2-162:
取2-154(3.1691g,5.6029mmol)置于100mL烧瓶中,加入CH2Cl2(50mL)溶解,再加入TFA(2.15mL,28.0143mmol),室温下搅拌过夜。旋干除去CH2Cl2,将粗产品用甲醇溶解,搅拌下加入NaHCO3中和多余的TFA,过滤除去固体,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用NH3·H2O、CH3OH和CH2Cl2进行梯度淋洗,收集产品,旋干,真空干燥得产品2-162(1.5027g,产率57.7%)。1H-NMR(400MHz,CDCl3)δ7.22-7.10(m,4H),7.04(s,1H),6.98-6.90(m,2H),4.84-4.75(m,1H),3.96(t,J=4Hz,2H),3.41(s,2H),2.70-2.60(m,2H),2.47(t,J=6Hz,2H),2.25-2.16(m,2H),1.97-1.89(m,2H),1.89-1.81(m,2H),1.68-1.57(m,4H);+c ESI Q1MS:[M+H+]466.38。
实施例5:制备4-215
7-78:
将2-(哌啶-2-基)乙烷-1-醇(20.00g,154.8947mmol)置于500mL烧瓶中,加CH2Cl2(300mL)溶解,然后加入三乙胺(45mL,309.7894mmol),搅拌下加入Boc2O(40.5669g,185.8736mmol),室温下反应4小时。直接旋干,将粗产品用CH3OH溶解,加入NaHCO3中和多余的TFA,过滤,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度淋洗,收集产品,浓缩,真空干燥得产品7-78(36.2772g,产率100%)。ITMS+c ESI[M+H+]230.18。
7-80:
取7-78(15.00g,65.4094mmol)置于500mL烧瓶中,加入经无水K2CO3干燥的THF(150mL)、三苯基磷(27.7142g,105.6623mmol),在0℃搅拌下分批加入NBS(18.8058g,105.6623mmol),转移至室温下搅拌3天。直接旋干,粗产品用CH2Cl2溶解,向溶液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度淋洗,收集产品,浓缩,真空干燥得产品7-80(12.0956g,产率63.26%)。1H-NMR(500MHz,CDCl3)δ4.44-4.35(m,1H),4.09-3.94(m,1H),3.41-3.28(m,2H),2.80-2.66(m,1H),2.40-2.29(m,1H),1.98-1.84(m,1H),1.76-1.61(m,3H),1.58-1.43(m,12H)。
4-197:
取三氟拉嗪(1.00g,3.7415mmol)置于100mL三颈圆底烧瓶中,加入经无水碳酸钾干燥过的THF(50mL),在N2保护下加入60%的矿物油保护的NaH(359.2mg,14.966mmol)、7-80(1.0975g,3.7415mmol),于60℃加热条件下回流过夜。反应结束后,停止反应,冷却至室温,将反应液倒入200mL冰水中,用乙酸乙酯萃取(200mL×3),合并有机相用无水硫酸镁干燥,过滤,向滤液中加入(3g)硅胶粉制成固体溶液,干法上样过硅胶柱纯化,硅胶柱:2.5×20cm,用石油醚做溶剂匀浆湿法装柱,干法上样,用乙酸乙酯与石油醚梯度淋洗,收集产品,旋干,真空干燥得纯品4-197(1.40g,产率78%)。ITMS+c ESI[M+H+]479.12。4-215:
取4-197(1.30g,2.7050mmol)置于100mL烧瓶中,加入二氯甲烷(50mL),搅拌下加入TFA(2.0727ml,27.0498mmol),室温搅拌过夜。直接蒸干,将粗产品用甲醇溶解,加入NaHCO3中和多余的TFA;过滤,向滤液中加入硅胶粉制成固体溶液,过硅胶柱纯化。用NH3·H2O,甲醇和二氯甲烷梯度淋洗,收集产品,旋干,真空干燥得产品4-215(539.2mg,产率53%)。1H-NMR(500MHz,CDCl3)δ7.26-7.14(m,4H),7.10-7.07(m,1H),7.01-6.92(m,2H),4.08-3.94(m,3H),3.12-3.02(m,1H),2.73-2.59(m,2H),1.92-1.85(m,2H),1.84-1.76(m,1H),1.72-1.64(m,2H),1.44-1.34(m,2H);ITMS+c ESI:[M+H+]379.20。
实施例6 制备2-30-3
2-133:
取2-甲硫基吩噻嗪(10.00g,40.8163mmol)置于500mL烧瓶中,加入经无水K2CO3干燥的THF(250mL),在N2保护下加入60%的矿物油保护的NaH(6.5306g,163.2653mmol)和1-溴-3-氯丙烷(16.15mL,163.2653mmol),在65℃下回流过夜。冷却至室温,将反应液倒入冰水中,粗产品用乙酸乙酯萃取(300mL+100mL×2),合并有机相用无水MgSO4干燥,过滤除去固体,旋干,然后加入乙酸乙酯(50mL)将组产品溶解,向溶液中加入硅胶粉(20g)制成固体溶液。干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-133(13.798g,产率100%)。1H-NMR(400MHz,CDCl3)δ7.20-7.14(m,2H),7.07(d,J=8Hz,1H),6.97-6.88(m,2H),6.87-6.81(m,2H),4.08(t,J=6Hz,2H),3.67(t,J=6Hz,2H),2.47(s,3H),2.27-2.21(m,2H);+c ESI Q1MS[M+H+]322.13。
2-30-3:
以2-133(300mg,0.9320mmol)、二甲胺盐酸盐(114mg,1.3980mmol)、三乙胺(0.39mL,2.7961mmol)和乙腈(10mL),于80℃下搅拌过夜。冷却至室温,直接旋干,将粗产品用甲醇溶解,过滤,往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-30-3(83.2mg,产率24.3%)。1H-NMR(400MHz,CDCl3)δ7.18-7.10(m,2H),7.07-7.01(m,1H),6.94-6.86(m,2H),6.84-6.78(m,3H),3.93-3.85(m,2H),2.46(s,3H),2.42-2.36(m,2H),2.22-2.19(s,6H),1.98-1.90(m,2H);+c ESI Q1MS:[M+H+]331.10,[M+NH3]347.08。
实施例7 制备2-30-2
取2-133(300mg,0.9320mmol)、吗啉(121.8mg,1.3981mmol)、三乙胺(0.39mL,2.7961mmol)和乙腈(10mL),于80℃下搅拌过夜。冷却至室温,直接旋干,将粗产品用甲醇溶解,过滤,往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-30-2(121mg,产率33.5%)。1H-NMR(400MHz,CDCl3)δ7.18-7.09(m,2H),7.08-7.01(m,1H),6.95-6.86(m,2H),6.85-6.78(m,2H),3.94(t,J=6Hz,2H),3.71-3.61(m,4H),2.51-2.34(m,9H),1.99-188(m,2H);+c ESIQ1MS:[M+H+]373.23。
实施例8 制备2-30-4
以2-133(300mg,0.9320mmol)、哌啶-4-醇(141.4mg,1.3979mmol)、三乙胺(0.39mL,2.7961mmol)和乙腈(10mL),于80℃下搅拌过夜。冷却至室温,直接旋干,将粗产品用甲醇溶解,过滤,往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-30-4(126.1mg,产率35.0%)。+c ESI Q1MS:[M+H+]387.16。
实施例9 制备2-30-5
以2-133(300mg,0.9320mmol)置于30ml直筒瓶中,加入1-(2-羟乙基)吡嗪(182mg,1.3980mmol),三乙胺(0.39mL,2.7961mmol)和乙腈(10mL),于80℃下搅拌过夜。停止反应,冷却至室温,旋干,将粗产品用甲醇溶解,往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-30-5(106mg,产率27.4%)。+c ESI Q1MS:[M+H+]416.15。
实施例10 制备2-30-6
取2-133(300mg,0.9320mmol)置于30mL直筒瓶中,加入脯氨醇(141.4mg,1.3979mmol),三乙胺(0.39mL,2.7961mmol)和乙腈(10mL),于80℃下搅拌过夜。冷却至室温,旋干,将粗产品用甲醇溶解,往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-30-6(88.3mg,产率24.5%)。+c ESI Q1MS:[M+H+]387.16。
实施例11 制备2-58
取2-133(0.3126g,0.9712mmol),置于30mL直筒瓶中,加入乙醇溶剂(20mL),盐酸胍(185.5mg,1.9423mmol),然后将NaOH(77.7mg,1.9423mmol)溶于H2O(1mL)中再加入直筒瓶中,密封后在80℃条件下搅拌过夜。湿法上样过硅胶柱纯化,用氨水、甲醇和二氯甲烷梯度淋洗,收集产品,旋干,真空干燥得产品2-58(141mg,产率38.1%)。+c ESI Q1MS:[M+H+]345.30。
实施例12 制备2-60
将2-133(0.2964g,0.9208mmol)加入到30mL直筒瓶中,加入1,2,4-三氮唑(0.1272g,1.8417mmol),K2CO3(0.7636g,5.5250mmol),KI(15.3g,0.09208mmol)和丙酮(10mL),密封后在60℃条件下搅拌过夜。过滤,将滤液旋干,将粗产品用二氯甲烷溶解,向溶液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用甲醇和二氯甲烷梯度淋洗,收集产品,旋干,真空干燥得产品2-60(179.0mg,产率54.8%)。1H-NMR(400MHz,CDCl3)δ7.94(s,1H),7.88(s,1H),7.24-7.10(m,3H),7.04-6.94(m,1H),6.90-6.78(m,2H),6.77-6.74(m,1H),4.35-4.24(m,2H),3.85-3.74(m,2H),2.50-2.34(m,5H);+c ESI Q1MS:[M+H+]355.18,[M+Na+]377.11。
实施例13 制备2-138
将2-133(300mg,0.9320mmol)加入到100ml烧瓶中,加入5-甲基-1H-四氮唑(156.6mg,1.8640mmol),K2CO3(0.7729g,5.5921mmol),KI(15.4mg,0.09320mmol)和丙酮(15ml)。在60℃条件下搅拌回流过夜。冷却至室温,过滤,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-138(71.3mg,产率20.7%)。1H-NMR(400MHz,CDCl3)δ7.20-7.11(m,2H),7.09(d,J=8Hz,1H),6.97-6.92(m,1H),6.89-6.80(m,2H),6,76-6.74(m,1H),4.68(t,J=6Hz,2H),3.98(t,J=6Hz,2H),2.52-2.44(m,8H)。
实施例14 制备2-139
将2-133(0.2964g,0.9208mmol)加入到100mL烧瓶中,加入1,2,3-三氮唑(0.11mL,1.8640mmol),K2CO3(0.7729g,5.5961mmol),KI(15.4mg,0.09320mmol)和丙酮(15mL)。在60℃条件下搅拌回流过夜。冷却至室温,过滤,将滤液浓缩后加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度洗脱,收集产品,旋干,真空干燥得产品2-139(202.5mg,产率61.3%)。1H-NMR(400MHz,CDCl3)δ7.59-7.58(m,2H),7.21-7.02(m,3H),7.00-6.68(m,4H),4.59(t,J=6Hz,2H),4.02-3.84(m,2H),2.54-2.36(m,5H)。
实施例15 制备2-149
将2-133(300mg,0.9320mmol)加入到100mL烧瓶中,加入1H-四氮唑(0.1306mg,1.8640mmol),K2CO3(0.7729g,5.5921mmol),KI(15.4mg,0.09320mmol)和丙酮(50mL)。在60℃条件下搅拌过夜。冷却至室温,过滤,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化。用乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-149(44.1mg,产率13.3%)。+c ESI Q1MS:[M+H+]356.13,[M+Na+]378.11。
实施例16 制备2-72
2-30-1:
取2-12(300mg,0.9320mmol)置于30mL直筒瓶中,然后加入1-叔丁氧羰基哌嗪(260.4mg,1.3980mmol),三乙胺(0.39mL,2.7961mmol)和乙腈(10mL),密封后在80℃条件下搅拌过夜。冷却至室温,旋干,将粗产品用甲醇溶解,往滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品2-30-1(75.1mg,产率17.08%)。+c ESI Q1MS:[M+H+]472.13,[M+NH3]488.11。
2-72:
取2-30-1(75.1mg,0.1522mmol)置于100mL烧瓶中,加入CH2Cl2(50mL)溶解,再加入TFA(4mL,52.2014mmol),室温下搅拌过夜。旋干,将粗产品用甲醇溶解,然后加入NaHCO3中和多余的TFA,过滤,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用NH3·H2O、CH3OH和CH2Cl2梯度淋洗,收集产品,旋干,真空干燥得产品2-72(46.2mg,产率84.5%)。1H-NMR(400MHz,CDCl3)δ7.18-7.10(m,2H),7.05(d,J=8Hz,1H),6.95-6.76(m,4H),3.94(t,J=6Hz,2H),3.10-3.02(m,4H),2.71-2.59(m,4H),2.58-2.50(m,2H),3.46(s,3H);+c ESIQ1MS[M+H+]373.23。
实施例17 制备7-4
7-2:
取Boc-Gly(0.8453g,4.8251mmol)置于500mL烧瓶中,加入2-30-4(1.6955g,4.3865mmol),HBTU(2.4693g,6.5798mmol)和HOBT(0.8891g,6.5798mmol);在0℃条件下滴加DIEA(3.4384mL,19.7393mmol),30分钟后转至室温下搅拌过夜。将反应液直接倒入饱和NaHCO3溶液(500mL)中,用乙酸乙酯萃取(500mL+200mL×3+100mL),合并有机相,先用饱和NaHCO3溶液清洗(300mL×2),再用饱和食盐水清洗(300mL×2);有机相用无水MgSO4干燥,过滤,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品7-2(2.3893g,产率100%)。1H-NMR(400MHz,CDCl3)δ7.20-7.10(m,2H),7.08-7.02(m,1H),6.96-6.86(m,2H),6.85-6.78(m,2H),4.88-4.81(m,1H),3.96-3.91(m,2H),2.75-2.65(m,2H),2.60-2.50(m,2H),2.47(s,3H),2.40-2.25(m,2H),2.02-1.84(m,4H),1.82-1.63(m,4H),1.45(s,9H);+c ESI Q1MS:[M+H+]544.32。
7-4:
将7-2(2.3082g,4.2453mmol)置于200mL烧瓶中,加入CH2Cl2(15mL),磁力搅拌下加入TFA(3.25mL,42.4527mmol),室温下搅拌过夜。旋干,将粗产品用CH3OH溶解,加入NaHCO3中和多余的TFA,过滤,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用NH3·H2O、CH3OH和CH2Cl2梯度淋洗,收集产品,旋干,真空干燥得产品7-4(896.6mg,产率47.7%)。1H-NMR(400MHz,CDCl3)δ7.18-7.10(m,2H),7.08-7.02(m,1H),6.94-6.87(m,2H),6.85-6.78(m,2H),4.85-4.77(m,1H),3.92(t,J=4Hz,2H),3.41(s,2H),2.72-2.62(m,2H),2.52-2.43(m,5H),2.29-2.16(m,2H),2.00-1.83(m,4H),1.73-1.62(m,4H)。
实施例18 制备7-86、7-92、7-147
7-82:
取2-甲硫基吩噻嗪(10.1029g,41.2362mmol)置于500mL烧瓶中,加入经无水K2CO3干燥过的THF(200mL),在N2保护下先后加入60%的矿物油保护的NaH(6.5978g,164.9448mmol)和7-80(12.0956g,41.2362mmol)。在60℃条件下回流过夜。冷却至室温,将反应液倒入冰水混合物中,用乙酸乙酯萃取(500mL×3),合并有机相用无水MgSO4干燥,过滤,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用乙酸乙酯和石油醚梯度洗脱,旋干,真空干燥得产品7-82(19.1176g,产率100%)。1H-NMR(500MHz,CDCl3)δ7.18-7.12(m,2H),7.08-7.03(m,1H),6.96-6.89(m,1H),6.88-6.80(m,2H),6.79-6.74(m,1H),4.41(s,1H),4.10-3.95(m,1H),3.94-3.75(m,2H),2.80(t,J=15Hz,1H),2.46(s,3H),2.28-2.14(m,1H),1.94-1.82(m,1H),1.61-1.53(m,3H),1.51-1.34(m,12H)。7-86:
在100mL烧瓶中,将7-82(19.00g,41.5459mmol)溶于二氯甲烷(20mL),加入TFA(15.92mL,207.7297mmol),在室温下搅拌过夜。旋干,将粗产品用甲醇溶解,然后加入NaHCO3中和多余的TFA,过滤,向滤液中加入硅胶粉制成固体溶液,过硅胶柱纯化。用NH3·H2O、CH3OH和CH2Cl2梯度淋洗,收集产品,旋干,真空干燥得产品7-86(19.0062g,产率100%)。1H-NMR(500MHz,CDCl3)δ7.20-7.13(m,2H),7.11-7.06(m,1H),6.98-6.92(m,1H),6.88-6.82(m,2H),6.80-6.77(m,1H),3.96(t,J=7.5Hz,2H),3.22-3.12(m,1H),3.00-2.92(m,1H),2.74-2.64(m,1H),2.46(s,3H),2.25-2.13(m,1H),2.02-1.90(m,1H),1.85-1.75(m,1H),1.72-1.55(m,3H),1.54-1.33(m,2H)。
7-88:
取Boc-Gly(10.2309g,58.4025mmol)置于500mL烧瓶中,加入7-86(18.9118g,53.0932mmol),HBTU(29.8880g,79.6398mmol),HOBT(10.9609g,79.7398mmol)和DMF(200mL),在0℃条件下滴加DIEA(41.62mL,238.9194mmol),30分钟后转至室温下搅拌过夜。将反应液直接倒入饱和NaHCO3溶液(500mL)中,用乙酸乙酯萃取(500mL+200mL×3+100mL),合并有机相用饱和NaHCO3溶液清洗(300mL×2),再用饱和食盐水溶液清洗(300mL×2)。有机相用无水MgSO4干燥,过滤,向滤液中加入硅胶粉制成固体溶液,过硅胶柱纯化。用乙酸乙酯和石油醚梯度洗脱,收集产品,旋干,真空干燥得产品7-88(19.1364g,产率70.2%)。1H-NMR(500MHz,CDCl3)δ7.22-7.02(m,3H),6.97-6.89(m,1H),6.88-6.80(m,2H),6.79-6.70(m,1H),4.05-3.80(m,4H),3.75-3.65(m,1H),3.60-3.40(m,1H),3.14-3.05(m,1H),2.47(s,3H),2.25-2.10(m,1H),1.95-1.85(m,1H),1.62-1.30(m,15H)。
7-92:
将7-88(19.0825g,37.1703mmol)置于200mL烧瓶中,加入二氯甲烷(20mL)溶解,然后加入TFA(14.24mL,185.8516mmol),室温下搅拌过夜。旋干,将粗产品用甲醇溶解,加入NaHCO3中和多余的TFA。过滤,向滤液中加入硅胶粉制成固体溶液,过硅胶柱纯化。用NH3·H2O、甲醇和二氯甲烷梯度淋洗,收集产品,旋干,真空干燥得产品7-92(13.6454g,产率89.05%)。1H-NMR(500MHz,CDCl3)δ7.24-7.10(m,2H),7.08-7.03(m,1H),7.00-6.77(m,3H),6.76-6.70(m,1H),3.93-3.81(m,2H),3.65-3.47(m,2H),3.40-3.32(m,1H),3.26-3.19(m,1H),3.13-3.04(m,1H),2.46(s,3H),2.25-2.05(m,2H),1.70-1.28(m,6H)。
7-145:
取Boc-Gly(2.7978g,15.9708mmol)置于500ml烧瓶中,加入7-92(6.00g,14.5189mmol),HBTU(8.1732g,21.7784mmol),HOBT(2.9427g,21.7784mmol)和DMF(200mL);在0℃条件下滴加DIEA(11.38mL,65.3351mmol),30分钟后转至室温下搅拌过夜。将反应液直接倒入饱和NaHCO3溶液(500mL)中,用乙酸乙酯萃取(500mL+200mL×3+100mL),合并有机相用饱和NaHCO3溶液清洗(200mL×2),再用饱和食盐水清洗(200mL×2);有机相用无水MgSO4干燥,过滤,向滤液中加入硅胶粉制成固体溶液,过硅胶柱纯化。用乙酸乙酯和石油醚梯度淋洗,收集产品,旋干,真空干燥得产品7-145(7.67g,产率93%)。1H-NMR(500MHz,CDCl3)δ7.22-6.60(m,9H),5.03-4.93(m,1H),4.05-3.70(m,6H),2.45(s,3H),1.72-1.56(m,6H),1.48(s,9H)。
7-147:
将7-145(7.57g,13.2706mmol)置于500mL烧瓶中,加入二氯甲烷(20mL)溶解,然后加入TFA(10.17mL,132.7057mmol),室温下搅拌过夜。旋干,将粗产品用甲醇溶解,然后加入NaHCO3中和多余的TFA,过滤,向滤液中加入硅胶粉制成固体溶液,干法上样过硅胶柱纯化,用NH3·H2O、甲醇和二氯甲烷梯度淋洗,收集产品,旋干,真空干燥得产品7-147(5.3975g,产率86.48%)。1H-NMR(500MHz,CDCl3)δ7.80-7.55(m,1H),7.22-7.09(m,2H),7.08-7.02(m,1H),6.97-6.89(m,1H),6.87-6.79(m,2H),6.79-6.69(m,1H),5.03-4.94(m,1H),4.08-4.01(m,1H),3.96-3.85(m,2H),3.84-3.65(m,1H),3.58-3.47(m,1H),3.40-3.29(m,2H),3.16-3.06(m,1H),2.47(s,3H),2.27-2.08(m,1H),1.95-1.82(m,1H),1.62-1.13(m,6H);ITMS+cESI[M+H+]571.19,[M+Na+]593.31。
实施例19 制备6-78
6-71:
在氮气保护下,于500ml烧瓶中加入2-氯吩噻嗪(5.00g,21.3mmol),用THF溶解,然后加入60%的矿物油保护的NaH(4.2786g,106.966mmol),放出大量气泡,然后加入1-溴-3-氯丙烷(10.57mL,106.966mmol)。在65℃的油浴中回流过夜。停止反应,将反应液倒到冰水混合物(500mL)中,用乙酸乙酯萃取(300mL×3),合并有机相用无水硫酸镁干燥,过滤。柱层析,用乙酸乙酯和石油醚梯度淋洗,收集产品点,减压浓缩得产品6-71(6.6377g,产率59.11%)。+c ESI Q1 MS:[M+H+]310.10
6-78:
在圆筒瓶中加入6-71(500mg,1.6117mmol),哌啶-4-醇(244.5mg,2.4175mmol),用CH3CN(15mL)溶解,最后加入三乙胺(0.67mL,4.8346mmol),密封后在80℃油浴中回流72小时。旋干,然后用甲醇溶解,加入NaHCO3中和,过滤。柱层析,用三乙胺、乙酸乙酯和石油醚梯度淋洗,收集产品点,减压浓缩,真空干燥得产品6-78(541.6mg,产率89.6%)。1H-NMR(400MHz,CDCl3)δ7.18-7.09(m,2H),7.01(d,J=8Hz,1H),6.95-6.83(m,4H),3.89(t,J=6Hz,2H),3.72-3.62(m,1H),2.78-2.68(m,2H),2.46(t,J=6Hz,2H),2.20-2.06(m,2H),1.98-1.83(m,4H),1.59-1.50(m,2H)。
实施例20 制备6-80
在圆筒瓶中加入6-71(500mg,1.6117mmol)和脯氨醇(244.5mg,2.4175mmol),用CH3CN(15mL)溶解,最后加入三乙胺(0.67mL,4.8346mmol),密封后在80℃油浴中回流72小时。停止反应,直接蒸干,然后用甲醇溶解,加入NaHCO3中和,过滤,浓缩。柱层析,用乙酸乙酯和石油醚梯度淋洗,收集产品点,减压浓缩真空干燥得产品6-80(307.1mg,产率50.8%)。1H-NMR(400MHz,CDCl3)δ7.20-7.12(m,2H),7.06-7.01(m,1H),6.97-6.92(m,1H),6.92-6.87(m,2H),6.86-6.83(m,1H),3.92(t,J=6Hz,2H),3.60-3.55(m,1H),3.36-3.31(m,1H),3.19-3.13(m,1H),2.97-2.89(m,1H),2.59-2.52(m,1H),2.40-2.32(m,1H),2.24-2.16(m,1H),2.06-1.90(m,3H),1.87-1.81(m,1H),1.77-1.68(m,3H)。
实施例21 制备6-86
在圆筒瓶中加入6-71(500mg,1.6117mmol),盐酸胍(168.4mg,1.7728mmol),用乙醇/水(10mL)溶解氢氧化钠(70.9mg,1.7728mmol),然后在80℃油浴中回流72小时。停止反应,直接蒸干。柱层析,用氨水、甲醇和二氯甲烷梯度淋洗,收集产品,减压浓缩真空干燥得产品6-86(513.9mg,产率100%)。1H-NMR(400MHz,CDCl3)δ7.23-7.14(m,2H),7.07(d,J=8Hz,1H),7.00-6.88(m,4H),3.97(t,J=6Hz,2H),3.28-3.19(m,2H),2.10-2.02(m,2H)。
实施例22 制备6-87
在圆筒瓶中加入6-71(500mg,1.6117mmol),1,2,4-三氮唑(222.6mg,3.2234mmol),用丙酮(5mL)溶解,然后加入碳酸钾(1.3365g,9.6701mmol)和碘化钾(18.7mg,0.1612mmol),然后在80℃油浴中回流72小时。停止反应,直接蒸干。柱层析,用乙酸乙酯和石油醚梯度淋洗,收集产品,减压浓缩,真空干燥得产品6-87(552.6mg,产率100%)。1H-NMR(400MHz,CDCl3)δ7.90(s,1H),7.81(s,1H),7.23-7.14(m,2H),7.10(d,J=8Hz,1H),7.02-6.91(m,2H),6.84-6.76(m,2H),4.26(t,J=6Hz,2H),3.78(t,J=6Hz,2H),2.42-2.34(m,2H)。
实施例23 制备6-88
在圆筒瓶中加入6-71(500mg,1.6117mmol)和四氮唑(225.7mg,3.2234mmol),用丙酮(5mL)溶解,然后加入碳酸钾(1.3365g,9.6701mmol)和碘化钾(18.7mg,0.1612mmol),然后在80℃油浴中回流72小时。停止反应,直接蒸干。柱层析,石油醚和乙酸乙酯梯度淋洗,收集产品,减压浓缩,真空干燥得产品6-88(554.2mg,产率43.09%)。1H-NMR(400MHz,CDCl3)δ8.47(s,1H),7.21-7.15(m,2H),7.08(d,J=8Hz,1H),7.01-6.91(m,2H),6.85-6.78(m,2H),4.77(t,J=6Hz,2H),3.97(t,J=6Hz,2H),2.55-2.47(m,2H)。
实施例24 制备6-89
在圆筒瓶中加入6-71(500mg,1.6117mmol),5-甲基-1H-四氮唑(270.7mg,3.2234mmol),用丙酮(5mL)溶解,然后加入碳酸钾(1.3365g,9.6701mmol)和碘化钾(18.7mg,0.1612mmol),然后在80℃油浴中回流72小时。停止反应,直接蒸干。柱层析,用石油醚和乙酸乙酯梯度淋洗,收集产品,减压浓缩,真空干燥得产品6-89(511.4mg,产率88.67%)。1H-NMR(400MHz,CDCl3)δ7.20-7.14(m,2H),7.07(d,J=8Hz,1H),7.00-6.90(m,2H),6.86-6.77(m,2H),4.68(t,J=6Hz,2H),3.95(t,J=6Hz,2H),2.51-2.44(m,5H)。:
实施例25 制备6-109
6-81:
在圆筒瓶中加入6-71(500mg,1.6117mmol),1-叔丁氧羰基哌嗪(244.5mg,2.4175mmol,),用CH3CN(15mL)溶解,最后加入三乙胺(0.67mL,4.8346mmol),迅速密封,然后在80℃油浴中回流72小时。停止反应,直接蒸干,然后用甲醇溶解,加入NaHCO3中和,过滤,浓缩。柱层析,用乙酸乙酯和石油醚梯度淋洗,收集产品,减压浓缩,真空干燥得产品6-81(741.4mg,产率100%)ITMS+ESI:[M+H+]460.19。
6-109:
在50mL的烧瓶中,加入6-81(877.7mg,1.9079mmol),用二氯甲烷溶解(10mL),然后再加入TFA(0.73mL,9.5395mmol),室温搅拌过夜。停止反应蒸干,用甲醇溶解,然后加入过量NaHCO3中和多余的TFA,抽滤,向滤液中加入硅胶粉浓缩蒸干,干法上样柱层析。用氨水、甲醇和二氯甲烷梯度淋洗,收集产品点,减压浓缩得产品6-109(558.3mg,产率81%)。1H-NMR(400MHz,CDCl3)δ7.18-7.09(m,2H),7.01(d,J=8Hz,1H),6.95-6.83(m,4H),3.91(t,J=6Hz,2H),2.95-2.88(m,4H),2.51-2.42(m,6H),1.97-1.88(m,2H)。
实施例26 制备4-219
4-195:
取2-氯吩噻嗪(1.00g,4.2786mmol)置于100mL三颈圆底烧瓶中,加入经无水碳酸钾干燥过的THF(25mL),在N2保护下加入60%矿物油保护的NaH(410.7mg,17.1145mmol)和4-170(1.2550g,4.2786mmol),在60℃加热条件下回流过夜。反应结束后,停止反应,冷却至室温,将反应液倒入冰水(200mL)中,用乙酸乙酯萃取(200mL×3),合并有机相用无水硫酸镁干燥,过滤,在滤液中加入硅胶粉,干燥做成固体溶液,干法上样柱层析,用乙酸乙酯和石油醚梯度淋洗,收集产品,蒸干得纯品4-195(0.70g,产率47%)。ITMS+c ESI:[M+H+]445.17。4-219:
取4-195(1.50g,3.1444mmol)置于100mL烧瓶中,加入二氯甲烷(50mL),在磁力搅拌下加入TFA(2.41mL,31.4436mmol),室温下过夜反应。停止反应蒸干,粗产品用甲醇溶解,加入过量NaHCO3中和TFA,过滤,加入二氯甲烷将组产品溶解,湿法上样柱层析。用NH3·H2O、甲醇和二氯甲烷梯度淋洗,收集产品,浓缩,干燥得到产品4-219(654.4mg,产率60%)。1H-NMR(500MHz,CDCl3)δ7.20-7.165(m,2H),7.09-7.055(m,1H),7.00-6.95(m,1H),6.95-6.915(dd,1H),6.91-6.87(d,1H),6.865-6.85(d,1H),4.00-3.94(t,2H),3.81-3.42(m,2H),2.975-2.9425(s,1H),2.9025-2.8675(s,1H)2.26-2.12(m,1H),2.005-1.8975(m,1H),1.768-1.665(m,2H),1.635-1.505(m,2H),1.495-1.40(m,2H);ITMS+c ESI:[M+H+]345.22。
生物测试及结果
本专利针对人乳腺癌细胞株MCF-7和人肝癌细胞株Hep-G2对所合成化合物的细胞毒性进行了详细的测试。MCF-7和Hep-G2细胞株所用的培养基为含有10%NCS,1%双抗的DMEM-F12,中溶液。培养细胞至其指数生长期,使用细胞计数板对细胞悬液计数,使用培养液调节细胞浓度为20000个/mL,然后将细胞悬液接种到96孔板中,每孔接种100μL,并留出4个孔作为空白对照,然后将培养板放置于5%CO2、37℃培养箱中培养24小时使细胞贴壁。取出培养板将其中的培养液移除,然后依次加入各个浓度(按所需量称取各个化合物,然后将各个化合物先用50μlDMSO溶解,然后用空白培养液依次稀释至100μmol/L、50μmol/L、25μmol/L、12.5μmol/L、6.25μmol/L、3.125μmol/L、1.5625μmol/L)的含药的培养液,空白对照孔加入空白培养液,放入培养箱继续培养72小时。将已知的抗癌药物阿霉素、紫杉醇分别与本发明制备的化合物作阳性对照,取出培养板,相应孔中分别加入5mg/mL的MTT试剂(20μL/孔),再将培养板重新放人5%CO2、37℃培养箱中继续培养4小时,取出培养板,将所有孔中的培养液移除,然后加入DMSO(150μL/孔),使用酶联免疫检测仪在波长490nm处测量细胞的OD值,然后用IC50计算软件计算各个化合物的IC50值,如表2所示。根据本发明,不可预期的发现,本发明制备所得的化合物对于MCF-7和Hep-G2细胞株均会产生一定的抑制作用。
表2 吩噻嗪类化合物IC50值
Claims (3)
1.一种吩噻嗪类化合物的应用,其特征在于,用于制备同时抗人乳腺癌细胞株MCF-7和抗人肝癌细胞株Hep-G2的药物,该化合物结构如通式(Ⅰ)所示:
其中,R为C2-3的直链饱和烷基;B可独立的为Cl、甲硫基或三氟甲基;当B为甲硫基时,A为三氮唑基、四氮唑基、吡咯基、胍基、吗啉基;当B为三氟甲基时,A为吗啉基、吡咯基;当B为Cl时,A为三氮唑基、四氮唑基、吡咯基、胍基、吗啉基。
2.一种抗癌药物组合物,其特征在于,其中含有权利要求1中通式(Ⅰ)所示的吩噻嗪类化合物作为有效成分,以及一种或多种药学上可接受的载体;其中所述的抗癌药物组合物能够同时抗人乳腺癌细胞株MCF-7和抗人肝癌细胞株Hep-G2。
3.一种如权利要求2所述的抗癌药物组合物,其特征在于,可制成药学上可接受的注射剂、喷雾剂、吸入剂或口服剂。
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IT201900015809A1 (it) * | 2019-09-06 | 2021-03-06 | Univ Degli Studi Padova | Composti analoghi della tioridazina |
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