CN110669054A - 胰岛素样生长因子-1受体酪氨酸激酶抑制剂及其用途 - Google Patents
胰岛素样生长因子-1受体酪氨酸激酶抑制剂及其用途 Download PDFInfo
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- CN110669054A CN110669054A CN201810711045.8A CN201810711045A CN110669054A CN 110669054 A CN110669054 A CN 110669054A CN 201810711045 A CN201810711045 A CN 201810711045A CN 110669054 A CN110669054 A CN 110669054A
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- trimethoxyphenyl
- dioxol
- naphtho
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Abstract
本发明公开了一类可作为胰岛素样生长因子‑1受体酪氨酸激酶抑制剂的化合物,制备它们的方法,包含所述化合物的药物组合物及其药物组合物在预防或治疗肿瘤,尤其脑部胶质瘤的应用。
Description
技术领域
本发明涉及药物化学领域,具体涉及胰岛素样生长因子-1受体酪氨酸激酶抑制剂及其用途。
背景技术
胰岛素样生长因子-1受体(IGF-1R)是酪氨酸蛋白激酶家族的成员,其信号传导途径与肿瘤发生密切相关,在恶性细胞的增生、对抗细胞凋亡及转变中起着重要作用。
环木脂体鬼臼毒素(Podophyllotoxin)是从小蘖科鬼臼属植物中提取的天然产物,其可以与β-微管蛋白结合以引起微管聚集抑制和有丝分裂的停顿,但其毒副作用阻碍了其在抗癌药物领域的发展。
专利文献WO2002102804A显示,鬼臼毒素在内酯环上具有顺式结构的立体异构体鬼臼苦素(Picropodophyllin,PPP)具有良好的IGF-1R抑制的活性,并且由于其空间构型与微管结合的低亲和性,其毒性与鬼臼毒素相比大大降低。
血脑屏障(blood brain barrier,BBB)是指脑毛细血管壁与神经胶质细胞形成的血浆与脑细胞之间的屏障和由脉络丛形成的血浆和脑脊液之间的屏障,这些屏障能够阻止某些物质由血液进入脑组织,它在保护中枢神经系统免受外来物质干扰和伤害的同时,也阻碍了许多潜在的中枢神经系统药物进入中枢,增加了中枢神经系统药物研发的难度。
PPP虽然具有良好的IGF-1R抑制的活性和较低的毒性,但在研究中发现,其BBB通透性不佳,难以在脑部胶质瘤中发挥作用,如星形细胞瘤。
发明内容
本发明公开了一类可作为胰岛素样生长因子-1受体酪氨酸激酶抑制剂的化合物,具有如预防或治疗肿瘤,尤其脑部胶质瘤的用途。
一方面,本发明提供式(I)化合物、其立体异构体或其药学上可接受的盐:
在一些实施例中,两个R1分别独立的选自氢、卤素、取代或非取代的C1-8烷基;或者两个R1与连接它们的碳原子一起形成非取代或取代的具有0-4个独立选自氮、氧或硫杂原子的单环或二环;且两个R1不同时为氢;
R2和R3分别独立的选自氢、氘、卤素、羟基、取代或非取代的C1-8烷基、-ORa、-O(C=O)Ra、-O(C=O)NRaRb;
Ra和Rb分别独立的选自取代或非取代的C1-8烷基,取代基选自氘或卤素;
R4和R5分别独立的选自氢、氘、C1-8烷基、
在另一些实施例中,两个R1分别独立的选自氟或甲基;
R2和R3分别独立的选自氢、氘、卤素、羟基、甲氧基或乙酰氧基;
R4和R5分别独立的选自氢、氘、C1-8烷基、
在另一些实施例中,R4和R5分别独立的选自氢和
在另一些实施例中,两个R1都为氟。
在另一些实施例中,所述化合物选自:
Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮;
Rel-(5R,5aR,8aS,9R)-2,2-二氟-8-氧代-9-(3,4,5-三甲氧基苯基)-5,5a,6,8,8a,9-六氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-5-基乙酸酯;
Rel-(5R,5aS,8aR,9S)-2,2,9-三氟-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮;
Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-甲氧基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4'6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮;
Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮-9-氘;
(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮;
(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮-9-氘;
(5R,5aR,8aS,9R)-2,2-二氟-8-氧代-9-(3,4,5-三甲氧基苯基)-5,5a,6,8,8a,9-六氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-5-基乙酸酯;
(5R,5aS,8aR,9S)-2,2,9-三氟-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮;
(5R,5aS,8aR,9R)-2,2-二氟-9-甲氧基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4'6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮。
在另一些实施例中,所述化合物具有如下相对构型的结构:
在另一些实施例中,所述化合物具有如下绝对构型的结构:
另一方面,本发明提供一种药物组合物,所述药物组合物包括本发明化合物、其立体异构体或其药学上可接受的盐,和药学上可用的载体。
另一方面,本发明提供前述化合物、其立体异构体或其药学上可接受的盐在制备胰岛素样生长因子-1受体酪氨酸激酶抑制剂类药物中的用途。
另一方面,本发明提供前述化合物、其立体异构体或其药学上可接受的盐在制备预防或治疗抗肿瘤药物中的用途。
在一些实施例中,所述肿瘤为脑部胶质瘤。
在另一些实施例中,所述脑部胶质瘤为星形细胞瘤。
下面简写词的使用贯穿本发明:
THF:四氢呋喃;
LDA:二异丙基氨基锂;
EtOAc:乙酸乙酯;
PE:石油醚;
DCM:二氯甲烷;
CDCl3:氘代氯仿;
Et3N:三乙胺;
Tf2O:三氟甲磺酸酐;
PPh3:三苯基膦;
MeOH:甲醇;
FBS:染色缓冲液;
EDTA:乙二胺四乙酸;
DMSO:二甲亚砜;
SDS-PAGE:十二烷基硫酸钠聚丙烯酰胺凝胶电泳;
PVDF:聚偏二氟乙烯。
附图说明
图1为实验例2化合物透过血脑屏障实验-IGF1R信号通路生物标志物检测的全自动化学发光/荧光图像分析系统成像图;
图2为本发明化合物2与PPP(苦鬼臼毒素)以50mg/kg灌胃给药1-3小时后在小鼠脑组织和血浆中的含量图;
图3为本发明化合物5与化合物6以50mg/kg灌胃给药1-3小时后在小鼠脑组织和血浆中的含量图;
图4为本发明化合物6以50mg/kg灌胃给药1-24小时在小鼠脑组织和血浆中的含量图;
图5为本发明化合物7以25mg/kg灌胃给药1-24小时在小鼠脑组织和血浆中的含量图。
具体实施方式
实施例1
化合物1:Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,
8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮
中间体1.1的合成:4-乙烯基二氢呋喃-2(3H)-酮
搅拌下将2-丁烯-1,4-二醇(206.4g,2.34mol,1.0e.q.)溶于原乙酸三乙酯(546.7g,3.4mol,1.4e.q.)中,加入催化氢醌(54.00g,0.49mol,0.2e.q.),并将所得混合物加热至120℃。原位形成的乙醇连续馏出直至不再有乙醇产生。将温度升至150℃,并将反应混合物再搅拌48小时。通过真空蒸馏(70~75℃,2~3mmHg)收集中间体1.1,为无色油状物(170.0g,收率65%)。1HNMR(400MHz,CDCl3)δ(ppm)2.36(dd,J=17.4Hz,8.7Hz,1H),2.69(dd,J=17.7Hz,8.4Hz,1H),3.19-3.29(m,1H),4.01-4.14(m,1H),4.43-4.47(m,1H),5.17-5.23(m,2H),5.75-5.84(m,1H)。
中间体1.2的合成:Rel-(3S,4R)-3-(羟基(3,4,5-三甲氧基苯基)甲基)-4-乙烯基
二氢呋喃-2(3H)-酮
在-78℃和氮气条件下,搅拌下将中间体1.1(170.0g,1.52mol,1.0e.q.)溶于THF中(1500mL),搅拌滴加LDA(2.0M,834mL,1.67mol,1.1e.q.)将反应混合物再搅拌30分钟。在相同条件下滴加3,4,5-三甲氧基苯甲醛(327.6g,1.67mol,1.1e.q.)的THF(1500mL)溶液,并将所得混合物再搅拌3小时,然后逐渐升温至环境温度过夜。将反应混合物冷却至-78℃,并用饱和氯化铵水溶液淬灭。所得混合物用EtOAc萃取,用盐水洗涤有机相,用硫酸镁干燥,过滤并浓缩。通过柱色谱法(200~300目硅胶,PE/EtOAc=5/1~1/1)纯化,得到中间体1.2,为浅黄色固体(190.1g,收率41%)。1HNMR(400MHz,CDCl3)δ(ppm)2.75-2.80(m,1H),2.91-2.96(m,0.5H),3.26-3.31(m,0.5H),3.84(s,3H),3.89(s,6H),3.92(t,1H),4.30-4.40(m,1H),4.86-4.93(m,2H),6.59(s,1H),6.61(s,1H)。
中间体1.3的合成:Rel-(3R,4R)-3–((R)-(2,2-二氟-6-羟基苯并[d][1,3]间二氧
杂环戊烯-5-基)(3,4,5-三甲氧基苯基)甲基)-4-乙烯基二氢-2(3H)-呋喃酮
搅拌下将中间体1.2(106.7g,0.41mol,1.0e.q.)和2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-醇(107.6g,0.61mol,1.5e.q.)溶于DCM(2000mL)中,加入FeCl3(34.06g,0.20mol,0.5e.q.),并将混合物加热至40℃反应2~3小时。将反应混合物用饱和碳酸氢钠水溶液淬灭,并将水相用另外的DCM萃取。用盐水洗涤有机相,用硫酸镁干燥,过滤并浓缩。通过柱色谱法(200~300目硅胶,PE/EtOAc=5/1~1/1)纯化,得到中间体1.3(153.4g,收率45%),为灰白色固体。1HNMR(400MHz,CDCl3)δ(ppm)3.02-3.06(m,1H),3.19-3.21(m,1H),3.83(s,6H),3.88(s,3H),4.04-4.07(m,1H),4.25-4.29(m,1H),4.73-4.75(d,J=4.8Hz,1H),5.14-5.22(m,2H),5.55(brs,1H),5.80-5.84(m,1H),6.51-6.59(m,2H),6.82-6.96(m,1H),7.29(s,1H)。
中间体1.4的合成:Rel-2,2-二氟-6-((R)-((3R,4R)-2-氧代-4-乙烯基四氢呋喃-
3-基)(3,4,5-三甲氧基苯基)甲基)苯并[d][1,3]间二氧杂环戊烯-5-基三氟甲磺酸酯
搅拌下将中间体1.3(120.0g,0.26mol,1.0e.q.)溶于DCM(1500mL)中,加入Et3N(52.62g,0.52mol,2.0e.q.),接着滴加Tf2O(110.0g,0.39mol,1.5e.q.),并在相同温度下将所得混合物再搅拌30分钟。将反应混合物用饱和碳酸氢钠溶液淬灭,并将水相用另外的DCM萃取。将合并的有机相用2M盐酸洗涤,用盐水洗涤有机相,用硫酸镁干燥,过滤并浓缩。通过柱色谱法(200~300目硅胶,PE/EtOAc=6/1~3/1)纯化,得到中间体1.4(120.0g,收率61%),为白色固体。1HNMR(400MHz,CDCl3)δ(ppm)2.97-3.06(m,1H),3.13-3.17(m,1H),3.84(s,6H),3.85(s,3H),4.03-4.08(m,1H),4.37-4.41(m,1H),4.64-4.66(d,J=8.3Hz,1H),5.08-5.20(dt,2H),5.71-5.80(m,1H),6.58(s,2H),7.04(s,1H),7.23(s,1H)。
中间体1.5的合成:Rel-(5R,5aR,8aS)-2,2-二氟-9-亚甲基-5-(3,4,5-三甲氧基
苯基)-5,8,8a,9-四氢呋喃并[3',4':6.7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮
搅拌下将中间体1.4(120.0g,0.20mol,1.0e.q.)溶于乙腈(1500mL),加入PPh3(15.83g,60.0mmol,0.3e.q.),碳酸钾(82.93g,0.60mol,3.0e.q.)和醋酸钯(4.49g,20.0mmol,10mol%),并将所得混合物加热至80℃反应20小时。过滤反应混合物,滤饼用DCM洗涤。将合并的有机相浓缩,通过柱色谱法(200~300目硅胶,PE/EtOAc=5/1~1/1)纯化,得到中间体1.5(76.13g,收率61%),为白色固体。1HNMR(400MHz,CDCl3)δ(ppm)3.31-3.34(dd,1H),3.65-3.68(t,1H),3.76(s,6H),3.84(s,3H),4.21-4.24(dd,1H),4.57-4.59(m,2H),5.21-5.22(d,1),5.57(s,1H),6.31(s,2H),6.95(s,1H),7.27(s,1H)。
中间体1.6的合成:Rel-(5aR,8aR,9R)-2,2-二氟-9-(3,4,5-三甲氧基苯基)-5a,
6,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-5,8-二酮
搅拌下将中间体1.5(79.04g,0.18mol,1.0e.q.)和N-甲基吗啉-N-氧化物(168.7g,0.72mol,3.0e.q.)加入DCM(1200mL)中,加入四氧化锇(4.00g,15.7mmol,8mol%),并将反应混合物在室温下搅拌12小时。分批加入固体高碘酸钠(77.00g,0.36mol,2.0e.q.),并将得到的混合物再搅拌1小时。在冰水浴温度下,用饱和硫代硫酸钠水溶液(300mL)淬灭反应混合物,用DCM萃取水相。将合并的有机相用盐水洗涤,有机相用硫酸镁干燥,过滤并浓缩。通过柱色谱法(200~300目硅胶,PE/EtOAc=5/1~1/1)纯化,得到中间体1.6(48.80g,收率60%),为白色固体。1HNMR(400MHz,CDCl3)δ(ppm)3.37-3.42(m,2H),3.78(s,6H),3.82(s,3H),4.38-4.42(m,1H),4.79-4.80(d,J=2.8Hz,2H),6.22(s,2H),7.02(s,1H),7.80(s,1H)。
化合物1的合成:Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯
基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮
在-78℃和氮气条件下,搅拌下将中间体1.6(43.30g,98.9mmol,1.0e.q.)溶于乙醚(1500mL),滴加三叔丁氧基氢化铝锂(200mL,197mmol,2.0e.q.),并将所得混合物逐渐升温至室温过夜。在冰水浴温度下用2M盐酸淬灭反应,并用另外的DCM萃取水相。将合并的有机相用盐水洗涤,有机相用硫酸镁干燥,过滤并浓缩。将获得的粗品从EtOAc中重结晶,得到呈白色固体的化合物1(33.10g,收率74%)。1HNMR(400MHz,CDCl3)δ(ppm)7.38(s,1H),6.53(s,1H),6.47(s,2H),4.67(d,J=0.9Hz,1H),4.55-4.43(m,2H),4.03(d,J=6.4Hz,1H),3.89(s,3H),3.85(s,6H),3.26(q,1H),2.96(d,J=6.9Hz,1H),2.66(m,1H)。
实施例2
化合物2:Rel-(5R,5aR,8aS,9R)-2,2-二氟-8-氧代-9-(3,4,5-三甲氧基苯基)-5,
5a,6,8,8a,9-六氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-5-基乙酸酯
搅拌下将化合物1(1.15g,2.55mmol,1.0e.q.)溶于DCM(30mL),加入Et3N(770mg,7.6mmol,3.0e.q.),4-二甲氨基吡啶(310mg,2.55mmol,1.0e.q.),在冰水浴温度下加入乙酰氯(400mg,5.1mmol,2.0e.q.),并将所得混合物在环境温度下搅拌12小时。将反应混合物用饱和氯化铵水溶液淬灭,并将水相用另外的DCM萃取。将合并的有机相用盐水洗涤,有机相用硫酸镁干燥,过滤并浓缩。将获得的粗品从PE/EtOAc重结晶,得到呈白色固体的化合物2(810mg,65%收率)。1HNMR(400MHz,CDCl3)δ(ppm)7.02(s,1H),6.76(s,1H),6.41(s,2H),5.81(d,J=6.3Hz,1H),4.48-4.34(m,3H),3.87(s,3H),3.84(s,6H),3.32(d,1H),3.01(m,1H),2.12(s,3H)。
实施例3
化合物3:Rel-(5R,5aS,8aR,9S)-2,2,9-三氟-5-(3,4,5-三甲氧基苯基)-5,8,8a, 9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮
搅拌下将化合物1(700mg,1.60mmol,1.0e.q.)溶于DCM(20mL)中,滴加二乙胺基三氟化硫(520mg,3.20mmol,2.0e.q.),并将所得混合物在室温下搅拌12小时。将反应混合物用饱和碳酸氢钠水溶液淬灭,再搅拌30分钟。分离有机相,并用另外的DCM萃取水相。将合并的有机相用盐水洗涤,有机相用硫酸镁干燥,过滤并浓缩。通过柱色谱法(200~300目硅胶,DCM/MeOH=100/1~50/1)纯化,得到呈白色固体的化合物3(130mg,18%收率)。1HNMR(400MHz,CDCl3)δ(ppm)7.27(s,1H),6.66(s,1H),6.44(s,2H),5.49-5.34(m,1H),4.60-4.47(m,2H),4.20(d,J=5.0Hz,1H),3.88(s,3H),3.84(s,6H),3.28(m,1H),3.01(m,1H)。
实施例4
化合物4:Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-甲氧基-5-(3,4,5-三甲氧基苯基)- 5,8,8a,9-四氢呋喃并[3',4'6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮
搅拌下将化合物1(600mg,1.33mmol,1.0e.q.)溶于DCM(15mL)中,加入三甲基氧鎓四氟硼酸(246mg,1.66mmol,1.2e.q.),并将所得混合物在室温下搅拌20小时。反应用饱和碳酸氢钠水溶液淬灭,并再搅拌30分钟。分离有机相,并用另外的DCM萃取水相。将合并的有机相用盐水洗涤,有机相用硫酸镁干燥,过滤并浓缩。通过柱色谱(200~300目硅胶,DCM/MeOH=100/1~50/1)纯化,得到呈白色固体的化合物4(65mg,11%收率)。1HNMR(400MHz,CDCl3)δ(ppm)7.16(s,1H),6.74(s,1H),6.41(s,2H),4.45-4.36(m,3H),4.34(d,J=4.3Hz,1H),3.88(s,3H),3.83(s,6H),3.42(d,1H),3.31(s,3H),3.14(m,1H)。
实施例5
化合物5:Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5, 8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d]x[1,3]间二氧杂环戊烯-6-(5aH)-酮-9-氘
搅拌下将中间体1.6(400mg,0.89mmol,1.0e.q.)溶于甲醇(10mL),分批加入硼氘化钠(37.5mg,0.89mmol,1.0e.q.),并将所得混合物搅拌4小时。反应用水淬灭,并浓缩。将获得的残余物用水稀释,并用EtOAc萃取。将合并的有机相用盐水洗涤,有机相用硫酸镁干燥,过滤并浓缩。将获得的粗品从PE/EtOAc重结晶,得到呈白色固体的化合物5(140mg,35%收率)。1HNMR(400MHz,CDCl3)δ(ppm)7.38(s,1H),6.57(s,1H),6.47(s,2H),4.66(d,J=9.8Hz,1H),4.47(m,1H),4.06(d,J=6.2Hz,1H),3.89(s,3H),3.87(s,6H),3.27(d,1H),2.68(m,1H),2.44(s,1H)。
实施例6
化合物6:(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8, 8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮
通过在手性柱色谱上手性分离化合物1来制备化合物6,色谱条件如下:
仪器:Waters,SFC200
色谱柱:Daicel Chiralcel AD,250×50mm I.D.,10μm
流动相:A、CO2,B、异丙醇
梯度:B 20%
流速:150mL/min
背压:100bar
柱温:38℃
波长:220nm
循环时间:6.5分钟
样品制备:将化合物溶于约600mL MeOH中
注射:每次注射3mL
1HNMR(400MHz,CDCl3)δ(ppm)7.38(s,1H),6.53(s,1H),6.47(s,2H),4.67(d,J=0.9Hz,1H),4.55-4.43(m,2H),4.03(d,J=6.4Hz,1H),3.89(s,3H),3.85(s,6H),3.26(q,1H),2.96(d,J=6.9Hz,1H),2.66(m,1H);e.e.=98.56%;[α]=11.94°(MeOH,c=0.88g/100mL)。
实施例7
化合物7:(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8, 8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮-9-氘
通过在手性柱色谱上手性分离化合物5来制备化合物7,色谱条件如下:
仪器:水SFC200
柱:Daicel Chiralcel AD,250×50mm I.D.,10μm
流动相:A、CO2,B、异丙醇
梯度:B 20%
流速:150mL/min
背压:100bar
柱温:38℃
波长:220nm
循环时间:6.5分钟
样品制备:将化合物溶于约600mL MeOH中
注射:每次注射3mL
1HNMR(400MHz,CDCl3)δ(ppm)7.38(s,1H),6.57(s,1H),6.47(s,2H),4.66(d,J=9.8Hz,1H),4.47(m,1H),4.06(d,J=6.2Hz,1H),3.89(s,3H),3.87(s,6H),3.27(d,1H),2.68(m,1H),2.44(s,1H)。
实施例8
化合物8:(5R,5aR,8aS,9R)-2,2-二氟-8-氧代-9-(3,4,5-三甲氧基苯基)-5,5a, 6,8,8a,9-六氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-5-基乙酸酯
通过在手性柱色谱上手性分离化合物2来制备化合物8,色谱条件参考实施例6。
1HNMR(400MHz,CDCl3)δ(ppm)7.02(s,1H),6.76(s,1H),6.41(s,2H),5.81(d,J=6.3Hz,1H),4.48-4.34(m,3H),3.87(s,3H),3.84(s,6H),3.32(d,1H),3.01(m,1H),2.12(s,3H)。
实施例9
化合物9:(5R,5aS,8aR,9S)-2,2,9-三氟-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四 氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮
通过在手性柱色谱上手性分离化合物3来制备化合物9,色谱条件参考实施例6。
1HNMR(400MHz,CDCl3)δ(ppm)7.27(s,1H),6.66(s,1H),6.44(s,2H),5.49-5.34(d,J=50.8Hz,1H),4.60-4.47(m,2H),4.20(d,J=5.0Hz,1H),3.88(s,3H),3.84(s,6H),3.28(m,1H),3.01(m,1H)。
实施例10
化合物10:(5R,5aS,8aR,9R)-2,2-二氟-9-甲氧基-5-(3,4,5-三甲氧基苯基)-5, 8,8a,9-四氢呋喃并[3',4'6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮
通过在手性柱色谱上手性分离化合物4来制备化合物10,色谱条件参考实施例6。
1HNMR(400MHz,CDCl3)δ(ppm)7.16(s,1H),6.74(s,1H),6.41(s,2H),4.45-4.36(m,3H),4.34(d,J=4.3Hz,1H),3.88(s,3H),3.83(s,6H),3.42(d,1H),3.31(s,3H),3.14(m,1H)。
表1:本发明部分化合物的NMR、MS数据
实验例1:化合物体外药效学试验
试验方法与材料
细胞来源:人脑星形胶质母细胞瘤/胶质瘤细胞U-87MG(简称U87)购自中国科学院细胞库(上海),货号TCHu138;人胶质瘤细胞DBTRG-05MG(简称DBTRG)来自美国组织培养库ATCC,货号CRL-2020;人胶质瘤细胞KNS-81来自AcceGen Biotech,货号ABC-TC0535。
细胞培养和传代:上述细胞均贴壁培养于含完全培养基[含DMEM高糖基础培养液(#SH30243.01B,HyClone)加入终浓度为10%FBS(#1101-500,上海普飞)和Penicillin-Streptomycin双抗(#SV30010,HyClone)]的6cm培养皿(#430166,Corning)或T75培养瓶(#3276,Corning)中,培养皿(瓶)置于37℃,5%CO2,饱和湿度的细胞培养箱(#3111,ThermoFisher Scientific)中培养。传代时,先吸走培养基,用PBS磷酸缓冲盐溶液(#GNM-10944,杭州吉诺)洗涤2次,然后加入适量0.25%胰酶-0.02%EDTA(#25200-072,Gibco),摇晃培养皿(瓶)使之均匀覆盖细胞,置于相差显微镜下观察。待大多数细胞回缩变圆,轻摇即脱落时,迅速加入两倍胰酶体积的完全培养基终止,并轻轻将细胞吹打成单细胞。将细胞悬液移到合适大小的离心管内,800rpm离心5min。弃上清,用新鲜的完全培养重悬细胞团块,重新吹打成单细胞,以1:3-1:6的比率传代接种至新的培养皿(瓶)并补足完全培养基。置于37℃,5%CO2的细胞培养箱中培养。
细胞加药处理:将上述每种细胞消化、计数,均按5000细胞/200μL培养液的密度接种至96孔细胞培养板(#3988,Corning)的每个孔中,置于37℃,5%CO2的细胞培养箱中培养24h使细胞充分贴壁。然后分别将含梯度稀释后的各种待测化合物(每种化合物每个浓度设置3个重复孔)以及DMSO(#D5879,Sigma-Aldrich)溶剂对照的完全培养液替换掉原来的培养液,继续培养72h。
药效学测定和统计:先用倒置相差显微镜(X71,Olympus)对上述化合物处理后的细胞进行形态观察和拍照记录。然后分别将含CCK-8检测试剂(#E606335,上海生工)的无酚红培养液替换掉原来的培养液,培养箱中继续培养2h。然后在多功能酶标仪(168-1130,Bio-Rad)上测量OD450nm吸光值(OD值)。受试化合物处理细胞后,细胞生存率(cellsurvival rate)或细胞增殖率(cell growth rate)的计算公式为:生存率=加药组OD值/对照组OD值×100%;化合物对细胞增殖的抑制率(growth inhibition rate)计算公式为:抑制率=(对照组OD值-加药组OD值)/对照组OD值×100%。进一步根据抑制率数值在SPSS中计算出各化合物的IC50。
表2:本发明化合物与苦鬼臼毒素在U87细胞系的IC50数据
实验例2:化合物透过血脑屏障实验-IGF1R信号通路生物标志物检测
试验方法与材料
实验动物来源:SPF级雌性ICR小鼠订购自南京大学-南京生物医药研究院,小鼠周龄为3至5周。
实验动物给药处理:将受试化合物溶解在DMSO(#D5879,Sigma-Aldrich)中,配制成50mg/mL母液。用PBS稀释受试化合物母液,以100mg/kg剂量对小鼠进行灌胃,每种受试化合物设置3只小鼠的实验重复。
检测样品制备:给药3小时后,颈椎脱臼法处死小鼠,取其右脑,加入800μL预冷的细胞裂解液(#P0013,碧云天,新鲜添加入蛋白酶和磷酸酶抑制剂#78444,Thermo FisherScientific),冰浴上充分匀浆,12000rpm离心10分钟后,取上清。用BCA法测定样品的蛋白浓度,加入相应量的4×Laemmli上样缓冲液(#161-0747,Bio-Rad),以3:1体积混合成为脑组织裂解液蛋白样品,100℃金属浴变性8min,12000rpm离心2分钟,取上清进行下列Western blot(免疫印迹试验)检测。
IGF1R信号通路生物标志物检测:将4-15%预制梯度胶(456-8084,Bio-Rad)安装到电泳槽中,加入足量1×SDS-PAGE电泳缓冲液。使用20μL的移液枪加入20μL上述细胞裂解液蛋白样品。将电泳槽盖子盖上,并接通电源,先以80V电压电泳约30min,待样品中溴酚蓝在浓缩胶与分离胶分界线压成一条细线时将电压调至120V,根据目标蛋白以及内参蛋白条带的大小调整电泳持续时间。将预冷1×转膜缓冲液倒入合适大小的容器中,按照说明书组装好泡沫垫-滤纸-胶-PVDF膜-滤纸-泡沫垫的“三明治”结构,装入电泳槽中。加入冰块且整个电泳槽冰浴,连通电源进行转膜,250mA,2h。将PVDF膜(IPVH00010,Millipore)放入由1×TBST配制的5%脱脂奶粉中室温封闭1h。然后依次进行不同一抗(anti-pIGF1R-Y1135/Y1136,#3024S,CST;anti-pAKT-T308,#13038,CST;anti-pAKT-S473,#4060,CST;anti-GAPDH[HRP],#A00191-40,GenScript)和二抗(anti-Mouse IgG HRP-linked antibody,#7076,CST;anti-Rabbit IgG HRP-linked antibody,#7074,CST)的孵育(分别室温孵育1h)与洗膜(1×TBST洗膜3次,每次5min)。最后,将PVDF膜放至塑料膜中间,加入ECL膜上反应3min,盖上另一层塑料膜,在全自动化学发光/荧光图像分析系统(5200-Multi,天能)中曝光。
对照物结构如下所示:
表3:对照物结构
如图1所示,以100mg/kg剂量灌胃给药的化合物1组小鼠,3小时后显著下调了脑组织中的磷酸化IGF1R/AKT等IGF1R信号通路中关键的生物标志物,显著优于其他对照物。
实验例3:化合物透过血脑屏障实验-受试化合物HPLC检测
实验材料与方法
实验动物来源:雄性或雌性BALB/c品系裸鼠订购自上海斯莱克实验动物有限责任公司,小鼠周龄为7周;SPF级雌性ICR小鼠订购自南京大学-南京生物医药研究院,小鼠周龄为5周。
实验动物给药处理:将受试化合物溶解在DMSO(#D5879,Sigma-Aldrich)中,配制成50mg/mL母液。用PBS稀释受试化合物母液,以25mg/kg或50mg/kg剂量对小鼠进行灌胃。
检测样品制备:小鼠分别给药1,3,6,12或24小时后,按250μL/20g体重的剂量腹腔注射4%水合氯醛水溶液,麻醉小鼠,颈动脉取血300μl至肝素管,混匀后,4000rpm 5分钟离心,取上清200μL,加入600μL乙腈,混匀超声20分钟,12000rpm离心10分钟,上清4℃静置过夜,然后12000rpm离心10分钟,取上清作为“血浆检测样品”;取0.3-0.5g左右全脑,用预冷的PBS迅速漂洗3次,加1mL乙腈匀浆(PRIMA手持式匀浆机PB100,35000rpm,1分钟),超声20分钟,12000rpm离心10分钟,上清4℃静置过夜,12000rpm离心10分钟,取上清作为“脑组织检测样品”。
HPLC检测:取上述“血浆检测样品”和“脑组织检测样品”,设置各受试化合物的标准品对照、HPLC流动相空白对照等,用高效液相色谱仪(Hitachi Chromaster-5430检测器,Hitachi Chromaster-5310柱温箱,Hitachi Chromaster-5210自动进样器,HitachiChromaster-5110泵)分析样品中受试化合物的含量。
如图2和图3显示,本发明化合物2、化合物5、化合物6在以50mg/kg灌胃给药1-3小时后在小鼠脑组织和血浆中均可以检测到有效量的化合物,而PPP(苦鬼臼毒素)以50mg/kg灌胃给药1-3小时后在脑组织中检测不到有效量化合物。
如图4和图5显示,本发明化合物6在以50mg/kg灌胃给药后24小时内可以检测到有效量的化合物,化合物7在以25mg/kg灌胃给药后12小时内可以检测到有效量的化合物。
Claims (12)
3.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于:
R4和R5分别独立的选自氢和
4.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于:两个R1都为氟。
5.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于所述化合物选自:
Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮;
Rel-(5R,5aR,8aS,9R)-2,2-二氟-8-氧代-9-(3,4,5-三甲氧基苯基)-5,5a,6,8,8a,9-六氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-5-基乙酸酯;
Rel-(5R,5aS,8aR,9S)-2,2,9-三氟-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮;
Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-甲氧基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4'6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮;
Rel-(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮-9-氘;
(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮;
(5R,5aS,8aR,9R)-2,2-二氟-9-羟基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮-9-氘;
(5R,5aR,8aS,9R)-2,2-二氟-8-氧代-9-(3,4,5-三甲氧基苯基)-5,5a,6,8,8a,9-六氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-5-基乙酸酯;
(5R,5aS,8aR,9S)-2,2,9-三氟-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6(5aH)-酮;
(5R,5aS,8aR,9R)-2,2-二氟-9-甲氧基-5-(3,4,5-三甲氧基苯基)-5,8,8a,9-四氢呋喃并[3',4'6,7]萘并[2,3-d][1,3]间二氧杂环戊烯-6-(5aH)-酮。
6.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其特征在于:所述化合物具有如下相对构型的结构:
8.一种药物组合物,包括权利要求1-7任一项所述的化合物、其立体异构体或其药学上可接受的盐,和药学上可用的载体。
9.权利要求1-7任一项所述的化合物、其立体异构体或其药学上可接受的盐在制备胰岛素样生长因子-1受体酪氨酸激酶抑制剂类药物中的用途。
10.权利要求1-7任一项所述的化合物、其立体异构体或其药学上可接受的盐在制备预防或治疗抗肿瘤药物中的用途。
11.根据权利要求10所述的用途,其特征在于:所述肿瘤为脑部胶质瘤。
12.根据权利要求11所述的用途,其特征在于:所述脑部胶质瘤为星形细胞瘤。
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