CN109608371B - O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物、制备方法及用途 - Google Patents

O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物、制备方法及用途 Download PDF

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CN109608371B
CN109608371B CN201910039234.XA CN201910039234A CN109608371B CN 109608371 B CN109608371 B CN 109608371B CN 201910039234 A CN201910039234 A CN 201910039234A CN 109608371 B CN109608371 B CN 109608371B
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牟伊
张鑫
刘静
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Abstract

本发明公开了O2‑4‑(3‑(4‑胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物、制备方法及用途，本发明提供的O2‑4‑(3‑(4‑胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物能够不同程度地抑制肿瘤细胞的增殖，且与4‑(3‑(4‑氟苯基)脲)苯磺酰胺(SCL‑0111)相比，本发明提供的部分化合物(I5、I6和I10)对肝癌细胞(HepG2，Bel‑7402，SMMC‑7721)和胃癌细胞(MGC803)的增殖抑制活性更为优异。因此，本发明提供的O2‑4‑(3‑(4‑胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物可以用于制备抗肿瘤药物。

Description

O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物、制 备方法及用途
技术领域
本发明属于药化领域，具体涉及一种O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物、制备方法及抗肿瘤用途。
背景技术
癌症，医学上又称为恶性肿瘤，是由于细胞生长失调而引起的疾病。作为一个人口占世界五分之一的大国，我国的癌症形势十分严峻。据统计，全球20％的新发癌症患者在中国， 24％的癌症死亡病人也在中国。据全国肿瘤登记中心发布的《2012中国肿瘤登记年报显示》，在中国每天有8550人成为癌症患者，每分钟就有6人，这是一个相当触目惊心的数字。在我国，癌症每年造成的直接经济损失超过千亿元。综上可见，癌症已成为全球性的挑战与难题，与癌症的抗争任重而道远。
一氧化氮(NO)是哺乳动物体内重要的信使分子，参与多种生理和病理过程，在心血管、神经、免疫等系统等发挥极其重要的功能，其中NO的抗肿瘤作用已成为癌症研究与治疗的热点之一。研究表明，NO可以通过诱导肿瘤细胞凋亡、抑制肿瘤细胞增殖、抑制肿瘤血管生成、抑制肿瘤细胞的转移、抗氧化等多种机制发挥抗肿瘤作用[19]。偶氮鎓二醇盐是一类重要的NO供体，在生理条件下能够接受质子，释放出NO，产生抗肿瘤活性，但是偶氮鎓二醇盐活性较高，在生理条件下能够快速释放NO，不能有效到达肿瘤组织，需要对其进行O2未保护，提高在肿瘤部位的释放比例。
碳酸酐酶(carbonic anhydrase,CA)是一类普遍存在于生物体内的含锌金属酶,其主要生理功能是催化二氧化碳的可逆水合反应,维持细胞内外pH的平衡，其中碳酸酐酶IX(CA IX)是一个肿瘤相关蛋白，特异性在多种肿瘤组织中高度表达而在正常组织几乎不表达。肿瘤组织由于其快速增殖，导致肿瘤微环境处于缺氧和弱酸性状态，而CAIX通过胞外催化CO2水合反应而产生HCO3-和H+,使胞外pH下降，而产生的HCO3 -则在转运蛋白的协助下进入胞内,中和分子内的H+，能够降低肿瘤细胞内的酸性，对维持肿瘤微环境的稳定、促进肿瘤生长迁移具有重要作用，因此碳酸酐酶IX抑制剂的开发对于肿瘤治疗具有重要意义。化合物SLC-0111为选择性CAIX抑制剂，对多种实体瘤均显示明显的增殖抑制作用，目前国外正开展SLC-0111与传统细胞毒药物吉西他滨联用治疗转移性胰腺癌的二期临床试验(https://www.clinicaltrials.gov/ct2/show/NCT03450018)。
由于CAIX抑制剂细胞毒活性降低，往往需要与传统细胞毒药物联合使用，增加了临床使用难度。为了提高SLC-0111的抗肿瘤活性，同时提高偶氮鎓二醇盐在肿瘤部位的选择性释放NO，本发明采用拼合原理，将SLC-0111与偶氮鎓二醇盐进行连接，设计合成了一种O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物。
发明内容
为了克服现有技术的不足，本发明第一目的在于提供一种O2-4-(3-(4-胺磺酰基苯基)脲) 苯基偶氮鎓二醇盐衍生物；本发明第二目的在于提供该衍生物的制备方法；本发明第三目的在于提供该衍生物的抗肿瘤用途。
本发明的上述目的是通过下面的技术方案得以实现的：
一种O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物，化学式如式(I)所示：
Figure BDA0001946961560000021
R代表NR1R2；
R1和R2相同或不同，并独立代表氢原子、C1-C4烷基、R1和R2与其所连接的氮原子一起形成5至7元脂肪杂环或芳杂环，该脂肪杂环或芳杂环可任意地由下述相同或不同的取代基单取代至五取代，所述取代基为C1-C6烷基、C1-C6烷氧基、羟基或卤素。
优选地，R1和R2独立代表氢原子、二甲胺基、二乙胺基、二丙胺、二正丁胺基、吡咯基、哌啶基、吗啡啉基、咪唑基、4-羟基哌啶基、4-甲基哌啶基或N-甲基哌嗪基。
上述衍生物的旋光异构体，对映体、非对映体、外消旋体或外消旋混合物，或其药学上可接受的盐或酯。
上述衍生物的制备方法：首先将4-(3-(4-氟苯基)脲)苯磺酰胺溶于丙酮制成丙酮溶液，冰浴降至0℃，然后将偶氮鎓二醇盐溶于5％的NaHCO3水溶液中，并在N2保护下缓慢滴至丙酮溶液中，反应液自然升至常温搅拌，监测反应进程至反应完成，最后浓缩除去反应液中的丙酮，过滤，滤饼用水洗涤得到粗品，经乙醇重结晶得纯品；
合成路线如下：
Figure BDA0001946961560000022
R代表NR1R2；
R1和R2相同或不同，并独立代表氢原子、C1-C4烷基、R1和R2与其所连接的氮原子一起形成5至7元脂肪杂环或芳杂环，该脂肪杂环或芳杂环可任意地由下述相同或不同的取代基单取代至五取代，所述取代基为C1-C6烷基、C1-C6烷氧基、羟基或卤素。
优选地，R1和R2独立代表氢原子、二甲胺基、二乙胺基、二丙胺、二正丁胺基、吡咯基、哌啶基、吗啡啉基、咪唑基、4-羟基哌啶基、4-甲基哌啶基或N-甲基哌嗪基。
上述衍生物用于制备抗肿瘤药物的医药用途。
有益效果：
本发明提供的O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物能够不同程度地抑制肿瘤细胞的增殖，且与4-(3-(4-氟苯基)脲)苯磺酰胺(SCL-0111)相比，本发明提供的部分化合物(I5、I6和I10)对肝癌细胞(HepG2，Bel-7402，SMMC-7721)和胃癌细胞(MGC803) 的增殖抑制活性更为优异。
具体实施方式
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐合成通法：
4-(3-(4-氟苯基)脲)苯磺酰胺(SLC-0111)(309mg,1mmol)溶于15mL丙酮，冰浴降至0℃。偶氮鎓二醇盐(1.1mmol)溶于15mL 5％的NaHCO3水溶液中，在N2保护下缓慢滴至丙酮溶液中。偶氮鎓溶液一经滴入后，溶液颜色立刻变为黄色。反应液自然升至常温搅拌，通过TLC监测反应进程直至SLC-0111全部消失。浓缩除去反应液中的丙酮，过滤，滤饼用水洗数次得到粗品，经乙醇重结晶得纯品。
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-二甲胺基偶氮鎓二醇盐(I1)
Figure BDA0001946961560000031
产率68％，黄色固体mp 253-255℃；1H NMR(d6-DMSO,300MHz)δ8.41(s,1H, NH-C＝O),8.35(s,1H,NH-C＝O),7.74(d,J＝11.6Hz,2H,ArH),7.54(m,4H,ArH),7.22(d,J＝11.2Hz,1H,ArH),6.89(s,2H,NH2)3.44(s,3H,CH3),3.36(s,3H,CH3)；ESI-MS 395.4[M+H]+；HRMS calculated for C15H18N6O5S[M+H]+395.1138,found 395.1140,PPM error 0.6.
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-二乙胺基偶氮鎓二醇盐(I2)
Figure BDA0001946961560000032
产率42％，黄色固体mp 253-255℃；1H NMR(d6-DMSO,300MHz)δ8.40(s,1H, NH-C＝O),8.34(s,1H,NH-C＝O),7.75(d,J＝11.6Hz,2H,ArH),7.60(m,4H,ArH),7.23(d,J＝11.2Hz,1H,ArH),6.90(s,2H,NH2),3.38-3.45(m,4H,2×CH2),1.16(t,J＝6.3Hz,6H,2×CH3),；ESI-MS 423.4[M+H]+；HRMS calculated for C17H22N6O6S[M+H]+423.1451,found423.1249,PPM error 0.6.
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-(N-甲基乙醇胺基)偶氮鎓二醇盐(I3)
Figure BDA0001946961560000041
产率42％，黄色固体mp 253-255℃；1HNMR(d6-DMSO,300MHz)δ8.43(s,1H,NH-C＝O), 8.37(s,1H,NH-C＝O),7.76(d,J＝11.6Hz,2H,ArH),7.56(m,4H,ArH),7.24(d,J＝11.2Hz,1H, ArH),6.89(s,2H,NH2)3.78(t,J＝4.5Hz,2H),3.66(t,J＝4.5Hz,2H),3.38(s,3H,CH3)； ESI-MS 425.1[M+H]+；HRMS calculated for C16H20N6O6S[M+H]+425.1243,found425.1245, PPM error 0.6.
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-哌啶基偶氮鎓二醇盐(I4)
Figure BDA0001946961560000042
产率61％，黄色固体：mp 265-267℃；1H NMR(d6-DMSO,300MHz)δ8.45(s,1H, NH-C＝O),8.41(s,1H,NH-C＝O),7.78(d,J＝11.6Hz,2H,ArH),7.59(m,4H,ArH),7.25(d,J＝11.2Hz,2H,ArH),6.91(s,2H,NH2),3.65(t,J＝5.6Hz,4H,piperidine),1.79-1.86(m,6H,piperidine)；ESI-MS 456.2[M+Na]+；HRMS calculated for C18H22N6O5S[M+H]+434.1453,found 434.1455,PPM error 0.4.
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-(4-羟基)哌啶基偶氮鎓二醇盐(I5)
Figure BDA0001946961560000043
产率52％，黄色固体：mp 271-273℃；1H NMR(d6-DMSO,300MHz)δ8.46(s,1H, NH-C＝O),8.43(s,1H,NH-C＝O),7.80(d,J＝11.6Hz,2H,ArH),7.61(m,4H,ArH),7.27(d,J＝11.2Hz,2H,ArH),6.92(s,2H,NH2),4.00-4.10(m,1H,piperidine),3.83-3.97(m,2H,piperidine), 3.61-3.75(m,2H,piperidine),2.00-2.12(m,2H,piperidine),1.78-1.95(m,2H,piperidine)； ESI-MS 468.5[M+NH4]+；HRMS calculated for C18H22N6O6S[M+H]+451.1400,found 451.1401, PPM error 0.2.
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-吡咯烷基偶氮鎓二醇盐(I6)
Figure BDA0001946961560000051
产率48％，黄色固体：mp 249-251℃；1H NMR(d6-DMSO,300MHz)δ8.43(s,1H, NH-C＝O),8.38(s,1H,NH-C＝O),7.76(d,J＝11.6Hz,2H,ArH),7.58(m,4H,ArH),7.19(d,J＝11.2Hz,2H,ArH),6.91(s,2H,NH2),3.78-3.83(m,4H,pyrrolidine),2.05-2.12(m,4H,pyrrolidine)；ESI-MS 421.2[M+H]+；HRMS calculated for C17H20N6O5S[M+H]+421.1294,found 421.1295,PPM error 0.4.
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-(2-羟甲基)吡咯烷基偶氮鎓二醇盐(I7)
Figure BDA0001946961560000052
产率43％，黄色固体：mp 257-259℃；1H NMR(d6-DMSO,300MHz)δ8.41(s,1H, NH-C＝O),8.36(s,1H,NH-C＝O),7.74(d,J＝11.6Hz,2H,ArH),7.55(m,4H,ArH),7.17(d,J＝11.2Hz,2H,ArH),6.89(s,2H,NH2),3.84-3.86(m,1H,prolinol),3.73-3.79(m,4H,pyrrolidine), 2.03-2.26(m,4H,prolinol)；ESI-MS 451.2[M+H]+；HRMS calculated forC18H22N6O6S[M+H]+ 451.1400,found451.1401,PPM error 0.2.
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-(4-N-甲基)哌嗪基偶氮鎓二醇盐(I8)
Figure BDA0001946961560000053
产率55％，黄色固体：mp 271-273℃；1H NMR(d6-DMSO,300MHz)δ8.46(s,1H, NH-C＝O),8.43(s,1H,NH-C＝O),7.80(d,J＝11.6Hz,2H,ArH),7.61(m,4H,ArH),7.27(d,J＝11.2Hz,2H,ArH),6.92(s,2H,NH2),3.70-3.73(m,4H,piperazin),2.65-2.68(m,4H,piperazin), 2.37(s,3H,CH3)；ESI-MS 450.5[M+H]+；HRMS calculated for C18H24N7O5S[M+H]+450.1560, found 450.1562,PPM error 0.6
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-(4-N-羟甲基)哌嗪基偶氮鎓二醇盐(I9)
Figure BDA0001946961560000061
产率55％，黄色固体：mp 284-286℃；1H NMR(d6-DMSO,300MHz)δ8.43(s,1H, NH-C＝O),8.39(s,1H,NH-C＝O),7.78(d,J＝11.6Hz,2H,ArH),7.59(m,4H,ArH),7.25(d,J＝11.2Hz,2H,ArH),6.90(s,2H,NH2),,3.66-3.73(m,6H,piperazin,CH2OH),2.77-2.79(m,4H, piperazin),2.64(t,J＝5.2Hz,2H,NCH2)；ESI-MS 480.2[M+H]+；HRMS calculated forC19H25N7O5S[M+H]+480.1665,found480.1663,PPM error 0.8
O2-4-(3-(4-胺磺酰基苯基)脲)苯基-1-(4-N-苄基)哌嗪基偶氮鎓二醇盐(I10)
Figure BDA0001946961560000062
产率59％，黄色固体：mp 286-288℃；1H NMR(d6-DMSO,300MHz)δ8.45(s,1H, NH-C＝O),8.42(s,1H,NH-C＝O),7.81(d,J＝11.6Hz,2H,ArH),7.62(m,4H,ArH),7.28-7.39(m,5H,ArH),7.26(d,J＝11.2Hz,2H,ArH),6.93(s,2H,NH2),3.68-3.72(m,4H,piperazin),3.61(s, 2H,PhCH2),2.63-2.66(m,4H,piperazin)；ESI-MS 526.5[M+H]+；HRMS calculatedfor C24H27N7O5S[M+H]+526.1873,found 526.1874,PPM error 0.4
效果实施例：抗肿瘤活性测试
取处于指数生长期状态良好的细胞，加入0.25％的胰蛋白酶消化液，消化使贴壁细胞脱落，计数2×104-4×104个/mL，制成细胞悬液。取细胞悬液接种于96孔板上(180μL/孔)，置恒温CO2培养箱中培养24小时。换液，加入受试药物(20μL/孔)，培养24-72小时。将MTT加入96孔板中(20μL/孔)，培养箱中反应4小时。吸去上清液，加入DMSO(150μL /孔)，平板摇床上振摇10分钟。用酶联免疫检测仪在波长为490nm处测定每孔的吸光值 (OD)，并以此计算药物对肿瘤细胞生长的抑制率以及IC50值。
Figure BDA0001946961560000063
测试结果：表1中列出了部分化合物对肝癌细胞(HepG2，Bel-7402)和胃癌细胞(MGC803) 增殖抑制活性的IC50值，阳性对照药为SCL-0111。
表1化合物对肿瘤细胞增殖抑制活性的IC50值
Figure BDA0001946961560000071
以上药理学数据显示，本发明涉及O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐类化合物能够不同程度的抑制肿瘤细胞的增殖，与SCL-0111相比，本发明提供的部分化合物(I5、 I6和I10)在对肝癌细胞(HepG2，Bel-7402，SMMC-7721)和胃癌细胞(MGC803)的具有更高的增殖活性。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。

Claims (5)

1.一种O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物，化学式如式(I)所示：
Figure FDA0002786319750000011
R代表NR1R2；
R1和R2相同或不同，并独立代表氢原子、C1-C4烷基、R1和R2与其所连接的氮原子一起形成5至7元脂肪杂环或芳杂环，该脂肪杂环或芳杂环可任意地由下述相同或不同的取代基单取代至五取代，所述取代基为C1-C6烷基、C1-C6烷氧基、羟基或卤素。
2.根据权利要求1所述的衍生物，其特征在于：R代表二甲胺基、二乙胺基、二丙胺、二正丁胺基、吡咯基、哌啶基、吗啡啉基、咪唑基、4-羟基哌啶基、4-甲基哌啶基或N-甲基哌嗪基。
3.权利要求1所述衍生物的制备方法，其特征在于：首先将4-(3-(4-氟苯基)脲)苯磺酰胺溶于丙酮制成丙酮溶液，冰浴降至0℃，然后将偶氮鎓二醇盐溶于5％的NaHCO3水溶液中，并在N2保护下缓慢滴至丙酮溶液中，反应液自然升至常温搅拌，监测反应进程至反应完成，最后浓缩除去反应液中的丙酮，过滤，滤饼用水洗涤得到粗品，经乙醇重结晶得纯品；
合成路线如下：
Figure FDA0002786319750000012
R代表NR1R2；
R1和R2相同或不同，并独立代表氢原子、C1-C4烷基、R1和R2与其所连接的氮原子一起形成5至7元脂肪杂环或芳杂环，该脂肪杂环或芳杂环可任意地由下述相同或不同的取代基单取代至五取代，所述取代基为C1-C6烷基、C1-C6烷氧基、羟基或卤素。
4.根据权利要求3所述的制备方法，其特征在于：R代表二甲胺基、二乙胺基、二丙胺、二正丁胺基、吡咯基、哌啶基、吗啡啉基、咪唑基、4-羟基哌啶基、4-甲基哌啶基或N-甲基哌嗪基。
5.权利要求1或2所述的衍生物用于制备抗肿瘤药物的医药用途。
CN201910039234.XA 2019-01-16 2019-01-16 O2-4-(3-(4-胺磺酰基苯基)脲)苯基偶氮鎓二醇盐衍生物、制备方法及用途 Active CN109608371B (zh)

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