CN115521254B - 一种茚达特罗衍生物及其制备方法和应用 - Google Patents
一种茚达特罗衍生物及其制备方法和应用 Download PDFInfo
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- CN115521254B CN115521254B CN202211179749.8A CN202211179749A CN115521254B CN 115521254 B CN115521254 B CN 115521254B CN 202211179749 A CN202211179749 A CN 202211179749A CN 115521254 B CN115521254 B CN 115521254B
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- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 20
- PJVZAXRWCFBQFH-UHFFFAOYSA-N 5-acetyl-8-hydroxy-1h-quinolin-2-one Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2C(=O)C PJVZAXRWCFBQFH-UHFFFAOYSA-N 0.000 claims abstract description 5
- -1 compound indacaterol derivative Chemical class 0.000 claims description 38
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 6
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
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- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
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- FLHFTXCMKFVKRP-UHFFFAOYSA-N bromomethylcyclobutane Chemical group BrCC1CCC1 FLHFTXCMKFVKRP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明公开了一种结构通式为(I)的茚达特罗衍生物,其制备方法为:以5‑乙酰基‑2,8‑二羟基喹啉与溴卞为原始原料,通过八步反应得到式(I)的茚达特罗衍生物;该茚达特罗衍生物通过对R1和R2进行改变,合成了一系列新的化合物,对结直肠肿瘤细胞具有明显的抑制作用,作用于结直肠癌细胞系SW620,其中IC50最小为1.716μM。
Description
技术领域
本发明涉及一种药物及其制备方法与应用,特别涉及一种茚达特罗衍生物及其制备方法和应用。
背景技术
结直肠癌(Colorectal cancer,CRC)是由结肠或直肠内壁上形成的常见消化道恶性肿瘤,是当今世界对人类生存和健康构成极大威胁的恶性肿瘤之一,发病率居所有恶性肿瘤第三位,死亡率居第二位。世界卫生组织癌症研究中心的GLOBOCAN项目估计,2018年全球新发结直肠癌病例数约为180万,死亡人数约为880,000。导致个体易患结直肠癌的主要风险因素包括遗传因素以及生活方式因素,如不良饮食和肥胖,且主要好发于40岁以上的中老年人。近年来,我国结直肠癌的发病率和死亡率呈上升趋势,应引起足够重视。
结直肠癌的基本治疗是手术切除和淋巴清扫,进展期病人需要接受辅助性化疗。化疗采用5-氟尿嘧啶、伊立替康、奥沙利铂等药物,以及贝伐单抗、西妥昔单抗、帕尼单抗等分子靶向药物也是治疗方式之一,近年来,对微卫星不稳定性结直肠癌试用免疫治疗。但化疗一般都有较严重的副作用,影响用药和生活质量。并且上述方法并非都有效,仍有一部分病人对化疗、靶向治疗过程抵抗。因此开发新的药物意义重大。
茚达特罗是用于成人慢性阻塞性肺疾病(COPD)患者的药物,而有研究表明,茚达特罗可以抑制结直肠肿瘤细胞系的增殖、侵袭、迁移,能够在小鼠模型中显著降低肿瘤病灶的大小。但在体外活性研究中,茚达特罗的IC50只有20~30μM。
发明内容
发明目的:本发明第一目的为提供一种提高结直肠肿瘤作用效果的茚达特罗衍生物;第二目的为提供所述茚达特罗衍生物的制备方法;第三目的是提高所述茚达特罗衍生物的应用。
技术方案:本发明所述的茚达特罗衍生物,化学结构式为:
其中R1选自a、b、c选自C或N,R3、R4选自H、C1~C4烷基、卤素取代的C1~C4烷基、卤素取代的C1~C4烷氧基、卤素或硝基;d、e、f选自C、N、O或S,R5、R6选自H或C1~C4烷基;g选自C3~C8环烷基;R2选自/> h、k选自C或N,R7选自H、卤素或/>手性中心*为S构型或R构型。
优选的,所述中a、b、c均为C或至少含有一个N。
优选的,所述为/>
优选的,所述为/>
优选的,所述为/>
R1基团为苄基或取代苄基时具有优秀活性,更换为杂环或芳杂环同样具有较好活性,且当基团的疏水性增加,化合物的活性会不同程度的相应增加。
本发明所述的茚达特罗衍生物的制备方法,包括以下步骤:
(1)5-乙酰基-2,8-二羟基喹啉与溴卞反应后苯环上的羟基被苄基保护,然后加入溴化剂对末端伯碳进行溴化,得到化合物II;
(2)以(R)/(S)-2-甲基-CBS-噁唑硼烷为手性催化剂,硼烷为还原剂,化合物II发生还原反应,苯环上的羰基被选择性地还原为羟基,得到化合物III;
(3)化合物III在碱性条件下发生分子内环合反应,得到化合物IV;
(4)化合物IV与亲核试剂R2H反应得到化合物V;
(5)化合物V与Boc酸酐反应得到化合物VI;
(6)化合物VI在钯碳/氢气条件下脱去苄基得到化合物VII;
(7)化合物VII与R1X反应后得到化合物VIII;
(8)最后化合物VIII被酸脱去Boc得到目标化合物茚达特罗衍生物I;合成路线如下:
其中R1选自a、b、c选自C或N,R3、R4选自H、C1~C4烷基、卤素取代的C1~C4烷基、卤素取代的C1~C4烷氧基、卤素或硝基;d、e、f选自C、N、O或S,R5、R6选自H或C1~C4烷基;g选自C3~C8环烷基;R2选自/> h、k选自C或N,R7选自H、卤素或/>手性中心*为S构型或R构型。
优选的,步骤(1)中,反应溶剂选自乙腈、二氯甲烷、氯仿、丙酮、水、四氢呋喃、甲醇、N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种;碱选自碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾或三乙胺;溴化剂选择四丁基三溴化铵;反应温度45~60℃。反应过程TLC监测反应进程,展开剂为二氯甲烷:甲醇=15:1。
优选地,步骤(2)中,还原反应溶剂选自乙腈、二氯甲烷、氯仿、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜中的一种或多种;反应温度-20℃至25℃;根据其手性要求,分别选择(R)或(S)-CBS类手性催化剂,搭配硼烷进行不对称还原。反应过程TLC监测反应进程,展开剂为二氯甲烷:甲醇=15:1。
优选地,步骤(3)中,反应溶剂选自乙腈、二氯甲烷、氯仿、丙酮、四氢呋喃、甲醇、N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种,碱选自碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾或三乙胺,回流反应。反应过程TLC监测反应进程,展开剂为二氯甲烷:乙酸乙酯=1:1。
优选的,步骤(4)中,反应溶剂选自乙腈、N,N-二甲基甲酰胺、二甲亚砜、正丁醇或二乙二醇二甲醚;反应温度60℃至150℃。反应过程TLC监测反应进程,展开剂为二氯甲烷:乙酸乙酯=1:1。
优选的,步骤(5)中,反应溶剂选自二氯甲烷、氯仿、二氧六环、水、甲醇、乙醇、乙腈、N,N-二甲基甲酰胺或四氢呋喃中的一种或多种;碱可选自三乙胺、氢氧化钠、碳酸氢钠、碳酸钾或4-二甲氨基吡啶,回流反应。反应过程TLC监测反应进程,展开剂为二氯甲烷:甲醇=15:1。
优选的,步骤(6)中,反应溶剂选自甲醇、乙醇、四氢呋喃或乙酸乙酯中的一种或多种;反应温度25℃至35℃。反应过程TLC监测反应进程,展开剂为二氯甲烷:甲醇=15:1。
优选的,步骤(7)中,反应溶剂选自N,N-二甲基甲酰胺、乙腈、丙酮、四氢呋喃或二甲亚砜中的一种或多种;碱选自碳酸钾、碳酸铯、碳酸钠、三乙胺;回流反应。反应过程TLC监测反应进程,展开剂为二氯甲烷:甲醇=15:1。
优选的,步骤(8)中,反应溶剂选自二氯甲烷、二氧六环、甲醇或乙酸乙酯中的一种或多种;酸选自三氟乙酸、盐酸;反应温度为25℃至35℃。反应过程TLC监测反应进程,展开剂为二氯甲烷:甲醇=15:1。
本发明的茚达特罗衍生物在治疗肿瘤药物中的应用,所述肿瘤为结直肠肿瘤。
有益效果:与现有技术相比,本发明具有如下显著优点:(1)该茚达特罗衍生物通过对R1和R2进行改变,合成了一系列新的化合物,对结直肠肿瘤细胞具有明显的抑制作用,作用于结直肠癌细胞系SW620,其IC50最小为1.716μM;(2)将茚达特罗衍生物的R构型羟基替换为S构型,消除了其β2受体激动作用;(3)将衍生物制备路线进行了优化,先用苄基将R1基团处封闭待连接R2基团后再脱去,大量合成中间体后连接不同R1基团,使衍生物制备效率显著增加,并实现一些敏感基团连接至R1基团处。
附图说明
图1是本发明代表化合物I6经静脉注射(5mg/kg)后大鼠体内血药浓度-时间曲线(n=3);
图2是本发明代表化合物I6经灌胃给药(50mg/kg)后大鼠体内血药浓度-时间曲线(n=3)。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1
本发明的茚达特罗衍生物,其化学名称为(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((5-氟-2-甲基苄基)氧基)喹啉-2(1H)-酮(I1),其合成路线如下所示:
(1)中间体II1的合成
将5-乙酰基-8-羟基喹啉-2(1H)-酮1g(4.92mmol)和无水碳酸钾816mg(5.91mmol)加入反应瓶后,加入丙酮15mL并升温至回流,在回流条件下加入2-甲基-5-氟溴苄1.2g(5.91mmol),充分搅拌后收集滤饼产物1.44g。
将滤饼产物1.43g(4.40mmol)加入反应瓶后,加入无水THF28.60mL和无水甲醇11.44mL并升温至40℃并充分搅拌,再分批次缓慢加入四丁基三溴化铵2.97g(6.15mmol),对末端伯碳进行溴化,得到代表性中间体5-(2-溴乙酰基)-8-((5-氟-2-甲基苄基)氧基)喹啉-2(1H)-酮(化合物II1)1.58g,收率为89.05%。1H NMR(300MHz,DMSO-d6)δ11.24(s,1H),8.52(d,J=10.0Hz,1H),7.93(d,J=8.6Hz,1H),7.54(d,J=9.7Hz,1H),7.36(d,J=9.0Hz,1H),7.28(t,J=6.6Hz,1H),7.10(t,J=8.4Hz,1H),6.70(d,J=10.0Hz,1H),5.39(s,2H),4.97(s,2H),2.35(s,3H)。
(2)中间体III1的合成
氮气保护条件下,将化合物II11.58g(3.91mmol)加入到100mL双颈反应瓶中,加入无水THF23.70 mL和催化量的(S)-2-甲基-CBS-噁唑硼烷162.50mg(0.59mmol),置于-10℃冷阱中充分搅拌。10min后,量取硼烷-四氢呋喃络合物1M(4.77mL,4.77mmol),在半小时内缓慢滴入反应体系,在此温度下继续搅拌15min,TLC监测反应完成,用15mL甲醇淬灭反应。通过减压浓缩除去溶剂后,向瓶中加入1M盐酸溶液(50mL),室温搅拌过夜后过滤,收集滤饼,真空干燥后得白色固体III1 1.55g,收率为97.61%。1H NMR(300MHz,DMSO-d6)δ10.89(s,1H),8.22(d,J=10.0Hz,1H),7.54(dd,J=10.1,2.8Hz,1H),7.24(d,J=7.2Hz,3H),7.07(td,J=8.6,2.9Hz,1H),6.58(d,J=9.9Hz,1H),5.99(s,1H),5.26(s,3H),3.74–3.60(m,2H),2.33(s,3H)。
(3)中间体IV1的合成
将化合物III11.52g(3.74mmol)加入到100mL单口反应瓶中,加入丙酮15mL、水0.15mL和无水碳酸钾1.03g(7.48mmol),加热至回流,充分搅拌。4h后TLC监测反应完成,过滤,用丙酮洗涤滤饼,收集合并滤液。滤液减压浓缩除去溶剂后,加入正庚烷进行重结晶,得到淡黄色固体IV1 900mg,收率为73.94%。1H NMR(300MHz,DMSO-d6)δ11.04(s,1H),8.23(d,J=9.9Hz,1H),7.55(dd,J=10.1,2.8Hz,1H),7.25(dd,J=8.5,6.0Hz,2H),7.06(td,J=8.6,2.9Hz,1H),6.99(d,J=8.3Hz,1H),6.63(d,J=9.8Hz,1H),5.25(s,2H),4.43–4.35(m,1H),3.16(dd,J=5.5,4.1Hz,1H),2.80(dd,J=5.5,2.6Hz,1H),2.32(s,3H)。
(4)目标产物I1的合成
将化合物IV1308mg(0.95mmol)与5,6-二乙基-2,3-二氢-1H-茚-2-胺233mg(1.23mmol)加入到单口反应瓶中,加入3mL正丁醇将其溶解后升温至95℃,在此温度下充分搅拌5h,TLC监测反应完成。将反应液浓缩后通过硅胶柱层析纯化,得到目标产物I1 105mg,收率为21.55%。1H NMR(300MHz,DMSO-d6)δ8.24(d,J=10.0Hz,1H),7.54(dd,J=10.2,2.8Hz,1H),7.30–7.19(m,3H),7.06(td,J=8.6,2.9Hz,1H),6.95(s,2H),6.58(d,J=9.9Hz,1H),5.25(s,2H),5.15(t,J=6.2Hz,1H),3.62(t,J=6.9Hz,1H),3.03(dt,J=15.7,7.8Hz,2H),2.83(d,J=5.8Hz,2H),2.68(dd,J=15.6,6.5Hz,2H),2.59–2.51(m,4H),2.33(s,3H),1.12(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO-d6)δ161.47,143.96,139.64,139.34,139.29,137.40,137.16,133.29,132.42,132.38,132.01,131.90,129.65,124.68,124.64,122.56,119.96,117.28,115.31,115.02,114.71,112.41,68.76,68.35,59.41,55.49,39.00,38.88,25.34,18.25,16.14.MS(ESI)m/z=515.2[M+H]+(C32H35FN2O3)。
实施例2
本发明的茚达特罗衍生物,其化学名称为(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((2-硝基苄基)氧基)喹啉-2(1H)-酮(I2),其合成路线如下所示:
(1)中间体II2的合成
将5-乙酰基-8-羟基喹啉-2(1H)-酮10g(49.21mmol)和无水碳酸钾8.16g(59.06mmol)加入反应瓶后,加入丙酮150mL并升温至回流,在回流条件下加入溴苄7.01ml(59.06mmol),充分搅拌后收集滤饼13.40g。
将滤饼13.40g(45.68mmol)加入反应瓶后,加入无水THF201mL和无水甲醇80.4mL并升温至40℃并充分搅拌,再分批次缓慢加入四丁基三溴化铵30.84g(63.96mmol),对末端伯碳进行溴化,得到代表性中间体8-(苄氧基)-5-(2-溴乙酰基)喹啉-2(1H)-酮(化合物II2)12.59g,收率为74.04%。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.51(d,J=9.9Hz,1H),7.87(d,J=8.5Hz,1H),7.60(d,J=7.0Hz,2H),7.42–7.37(m,2H),7.34(dd,J=6.8,1.9Hz,1H),7.30(d,J=8.7Hz,1H),6.68(d,J=10.1Hz,1H),5.44(s,2H),4.92(s,2H)。
(2)中间体III2的合成
氮气保护条件下,将化合物II212.58g(33.80mmol)加入到500mL双颈反应瓶中,加入无水THF190 mL和催化量的(S)-2-甲基-CBS-噁唑硼烷1.41g(5.07mmol),置于-10℃冷阱中充分搅拌。10min后,量取硼烷-四氢呋喃络合物1M(41.23mL,41.23mmol),在半小时内缓慢滴入反应体系,在此温度下继续搅拌15min,TLC监测反应完成,用甲醇(50mL)淬灭反应。通过减压浓缩除去溶剂后,向瓶中加入1M盐酸溶液(250mL),室温搅拌过夜后过滤,收集滤饼,真空干燥后得白色固体III2 11.76g,收率为92.98%。1H NMR(300MHz,DMSO-d6)δ10.74(s,1H),8.19(d,J=9.9Hz,1H),7.58(d,J=6.6Hz,2H),7.42–7.30(m,3H),7.20(s,2H),6.57(d,J=9.9Hz,1H),5.96(d,J=4.7Hz,1H),5.31(s,2H),5.22(dt,J=7.2,4.8Hz,1H),3.72–3.58(m,2H)。
(3)中间体IV2的合成
将化合物III211.70g(31.26mmol)加入到500mL单口反应瓶中,加入丙酮180mL、水1.80ml和无水碳酸钾8.64g(62.53mmol),加热至回流,充分搅拌。4h后TLC监测反应完成,过滤,用丙酮洗涤滤饼,收集合并滤液。滤液减压浓缩除去溶剂后,加入正庚烷进行重结晶,得到淡黄色固体IV2 8.43g,收率为91.93%。1H NMR(300MHz,DMSO-d6)δ10.88(s,1H),8.21(d,J=9.8Hz,1H),7.57(d,J=6.7Hz,2H),7.41–7.28(m,3H),7.19(d,J=8.4Hz,1H),6.94(d,J=8.3Hz,1H),6.62(d,J=9.8Hz,1H),5.31(s,2H),4.41–4.31(m,1H),3.14(dd,J=5.5,4.1Hz,1H),2.78(dd,J=5.5,2.6Hz,1H).
(4)中间体V2的合成
将化合物IV2 5g(17.05mmol)与5,6-二乙基-2,3-二氢-1H-茚-2-胺4.19g(22.16mmol)加入到单口反应瓶中,加入10mL正丁醇将其溶解后升温至95℃,在此温度下充分搅拌10h,TLC监测反应完成。将反应液浓缩后通过硅胶柱层析纯化,得到中间体V26.78g,收率为82.41%。1H NMR(300MHz,DMSO-d6)δ10.91(s,1H),8.32(d,J=10.1Hz,1H),7.59(d,J=7.4Hz,2H),7.39(tt,J=14.8,7.2Hz,3H),7.24(s,2H),6.99(s,2H),6.59(d,J=9.8Hz,1H),5.42(d,J=7.9Hz,1H),5.32(s,2H),3.88(p,J=7.8Hz,1H),3.15(dt,J=16.2,8.2Hz,2H),2.95(dd,J=24.1,10.5Hz,4H),2.56(t,J=7.6Hz,4H),1.12(t,J=7.5Hz,6H).
(5)中间体VI2的合成
将化合物V2 6.78g(14.05mmol)加入到250ml单口反应瓶中并用二氯甲烷102ml溶解,加入三乙胺5.86ml(42.14mmol)和二碳酸二叔丁酯6.13g(28.10mmol),氮气保护。在室温下充分搅拌5小时后TLC监测反应完成,加水萃取三次,将有机层用无水硫酸钠干燥,减压浓缩后通过硅胶柱层析纯化,得到中间体VI2 5.82g,收率为71.09%。1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.22(d,J=33.0Hz,1H),7.57(d,J=7.5Hz,2H),7.33(dd,J=25.1,11.0Hz,3H),7.11(d,J=48.5Hz,2H),6.90(d,J=24.4Hz,2H),6.49(s,1H),5.59(s,1H),5.29(d,J=15.1Hz,2H),4.40(d,J=19.5Hz,1H),3.34(s,2H),3.05(d,J=121.0Hz,4H),2.55(d,J=7.1Hz,4H),1.29(s,9H),1.19–1.00(m,6H)。
(6)中间体VII2的合成
将化合物VI2 3g(5.15mmol)加入到100ml单口反应瓶中用无水甲醇35ml溶解,加入10%Pd/C 345mg,连接事先充气的氢气袋,置换空气。室温搅拌12小时,TLC监测反应完成,用硅藻土过滤,滤液减压浓缩得到淡黄色固体VII2 2.25g,收率为88.72%。1H NMR(400MHz,DMSO-d6)δ10.31(s,2H),8.19(s,1H),7.07(s,1H),6.96–6.86(m,3H),6.46(s,1H),5.54(s,1H),5.14(d,J=53.6Hz,1H),4.41(s,1H),3.33(s,2H),3.16–2.78(m,4H),2.60–2.52(m,4H),1.31(s,9H),1.12(q,J=7.5Hz,6H)。
(7)中间体VIII2的合成
将化合物VII2 200mg(0.41mmol)和无水碳酸钾84.17mg(0.61mmol)加入双颈反应瓶后,加入N,N-二甲基甲酰胺2mL并升温至80℃,在回流条件下逐滴加入1ml N,N-二甲基甲酰胺溶解的2-硝基溴苄96.48mg(0.45mmol),充分搅拌至TLC监测反应完成。加水用乙酸乙酯萃取,有机层用无水硫酸钠干燥后减压浓缩,通过硅胶柱层析纯化,得到中间体VIII2100mg,收率为39.24%。
1H NMR(300MHz,DMSO-d6)δ10.87(s,1H),8.19(d,J=8.1Hz,2H),7.94(d,J=7.8Hz,1H),7.79(t,J=7.8Hz,1H),7.65(d,J=8.1Hz,1H),7.19(s,2H),6.91(d,J=17.7Hz,2H),6.53(s,1H),5.61(s,3H),5.18(d,J=42.2Hz,1H),4.39(s,1H),3.35(s,4H),2.91(s,2H),2.57(d,J=6.9Hz,4H),1.30(s,9H),1.13(d,J=8.4Hz,6H)。
(8)目标产物I2的合成
将化合物VIII2 100mg(0.16mmol)加入单口反应瓶后用二氯甲烷2ml溶解,室温加入三氟乙酸0.24ml(3.19mmol)并插上气球收集生成气体,搅拌30min后TLC监测反应完成。将反应液70℃减压浓缩,加入饱和碳酸氢钠溶液调至碱性,用二氯甲烷萃取,有机相用无水硫酸钠干燥后减压浓缩,通过硅胶柱层析纯化,得到目标产物I2 18mg,收率为21.42%。1HNMR(300MHz,DMSO-d6)δ8.22(dd,J=17.6,9.0Hz,2H),7.96(d,J=7.7Hz,1H),7.80(t,J=7.5Hz,1H),7.64(t,J=7.7Hz,1H),7.21(s,2H),6.96(s,2H),6.58(d,J=9.8Hz,1H),5.62(s,2H),5.16(t,J=6.0Hz,1H),3.63(p,J=6.9Hz,1H),3.03(dt,J=15.6,7.7Hz,2H),2.84(d,J=4.7Hz,2H),2.70(dd,J=15.6,6.5Hz,2H),2.54(d,J=7.6Hz,4H),1.12(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO-d6)δ161.47,147.79,143.78,139.65,139.31,137.18,134.56,133.64,132.69,130.19,129.67,129.59,125.33,124.68,122.62,119.99,112.59,68.67,67.99,59.36,55.43,38.91,38.78,25.34,16.14.MS(ESI)m/z=528.2[M+H]+(C31H33N3O5)。
实施例3
本发明的茚达特罗衍生物,其化学名称为(S)-8-((3,5-双(三氟甲基)苄基)氧基)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)喹啉-2(1H)-酮(I3),其合成路线如下所示:
制备方法包括以下步骤:
(1)中间体VIII3的合成
将化合物VII2 350mg(0.71mmol)和无水碳酸钾147.29mg(1.07mmol)加入双颈反应瓶后,加入N,N-二甲基甲酰胺2mL并升温至80℃,在回流条件下逐滴加入1ml N,N-二甲基甲酰胺溶解的3,5-双三氟甲基溴苄239.96mg(0.78mmol),充分搅拌至TLC监测反应完成。加水用乙酸乙酯萃取,有机层用无水硫酸钠干燥后减压浓缩,通过硅胶柱层析纯化,得到中间体VIII3 480mg,收率为94%。1H NMR(300MHz,DMSO-d6)δ11.15(s,1H),8.41(s,2H),8.24(d,J=25.1Hz,1H),8.07(s,1H),7.29(d,J=8.2Hz,1H),7.14(d,J=23.3Hz,1H),6.90(d,J=17.1Hz,2H),6.51(s,1H),5.63(s,1H),5.45(s,2H),5.15(d,J=44.6Hz,1H),4.40(s,1H),3.24(s,2H),2.93(s,4H),2.60–2.52(m,4H),1.23(s,9H),1.11(td,J=7.6,3.7Hz,6H)。
(2)目标产物I3的合成
将化合物VIII3 480mg(0.67mmol)加入单口反应瓶后用二氯甲烷2ml溶解,室温加入三氟乙酸0.89ml(12.02mmol)并插上气球收集生成气体,搅拌30min后TLC监测反应完成。将反应液70℃减压浓缩,加入饱和碳酸氢钠溶液调至碱性,用二氯甲烷萃取,有机相用无水硫酸钠干燥后减压浓缩,通过硅胶柱层析纯化,得到目标产物I3 73mg,收率为17.67%。1HNMR(300MHz,DMSO-d6)δ11.10(s,1H),8.40(d,J=1.8Hz,2H),8.22(d,J=10.0Hz,1H),8.08(s,1H),7.32–7.18(m,2H),6.94(d,J=2.5Hz,2H),6.56(d,J=9.8Hz,1H),5.45(s,3H),5.07(t,J=6.1Hz,1H),3.54(q,J=6.6Hz,1H),2.98(dt,J=15.8,7.9Hz,2H),2.76(d,J=6.1Hz,2H),2.66–2.51(m,6H),1.12(t,J=7.5Hz,6H).13CNMR(75MHz,DMSO-d6)δ161.60,143.52,140.66,139.72,139.67,139.45,137.20,134.12,130.78,130.34,129.87,124.68,124.64,122.53,122.08,119.86,117.44,112.67,69.37,68.92,59.65,56.02,25.33,16.14.MS(ESI)m/z=619.3[M+H]+(C33H32F6N2O3)。
实施例4
本发明的茚达特罗衍生物,其化学名称为(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((4-(三氟甲氧基)苄基)氧基)喹啉-2(1H)-酮(I4),其合成路线如下所示:
在实施例3的基础上以4-三氟甲氧基溴苄替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I4。1H NMR(300MHz,DMSO-d6)δ10.74(s,1H),8.21(d,J=10.0Hz,1H),7.74(d,J=8.7Hz,2H),7.39(d,J=7.5Hz,2H),7.20(d,J=1.6Hz,2H),6.94(d,J=2.4Hz,2H),6.56(d,J=9.9Hz,1H),5.32(s,3H),5.06(t,J=6.1Hz,1H),3.53(t,J=6.7Hz,1H),2.99(dt,J=15.7,7.8Hz,2H),2.76(d,J=6.1Hz,2H),2.65–2.51(m,6H),1.12(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO-d6)δ161.44,143.59,139.69,139.64,139.47,137.25,136.66,133.66,130.25,129.76,124.69,124.64,122.45,121.38,119.87,117.34,112.41,69.29,59.64,55.98,25.34,16.14.MS(ESI)m/z=567.3[M+H]+(C32H33F3N2O4)。
实施例5
本发明的茚达特罗衍生物,其化学名称为(S)-8-((3,5-二叔丁基苄基)氧基)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)喹啉-2(1H)-酮(I5),其合成路线如下所示:
在实施例3的基础上以3,5-二叔丁基溴苄替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I5。1H NMR(300MHz,DMSO-d6)δ8.20(d,J=9.9Hz,1H),7.38(d,J=1.8Hz,2H),7.33(d,J=1.9Hz,1H),7.26–7.16(m,2H),6.93(d,J=2.6Hz,2H),6.54(d,J=9.8Hz,1H),5.45(s,1H),5.25(s,2H),5.05(t,J=6.1Hz,1H),3.54–3.48(m,1H),3.03–2.92(m,2H),2.74(d,J=6.1Hz,2H),2.62–2.52(m,6H),1.27(s,18H),1.12(t,J=7.5Hz,6H).13CNMR(75MHz,DMSO-d6)δ161.27,150.70,139.75,139.70,139.43,137.33,136.29,133.64,129.97,124.69,122.83,122.26,121.85,119.88,117.25,113.08,71.42,69.47,59.68,56.13,34.98,31.71,25.34,16.15.MS(ESI)m/z=595.4[M+H]+(C39H50N2O3)。
实施例6
本发明的茚达特罗衍生物,其化学名称为(S)-8-(环丙基甲氧基)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)喹啉-2(1H)-酮(I6),其合成路线如下所示:
在实施例3的基础上以溴甲基环丙烷替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I6。1H NMR(300MHz,DMSO-d6)δ8.22(d,J=10.1Hz,1H),7.20(d,J=8.3Hz,1H),7.11(d,J=8.5Hz,1H),6.94(s,2H),6.55(d,J=10.1Hz,1H),5.07(t,J=5.9Hz,1H),3.96(d,J=7.0Hz,2H),3.52(q,J=6.8Hz,1H),2.99(dt,J=16.0,8.0Hz,2H),2.69(dd,J=41.4,6.1Hz,4H),2.59–2.52(m,4H),1.40–1.32(m,1H),1.12(t,J=7.4Hz,6H),0.58(d,J=7.8Hz,2H),0.37(d,J=5.1Hz,2H).13C NMR(75MHz,DMSO-d6)δ161.26,144.22,139.71,139.66,139.45,137.39,133.24,129.64,124.69,124.64,122.27,120.01,117.16,112.22,73.76,69.40,59.66,56.08,25.34,16.15,10.49,3.75.MS(ESI)m/z=447.3[M+H]+(C28H34N2O3)。
实施例7
本发明的茚达特罗衍生物,其化学名称为(S)-8-(环丁基甲氧基)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)喹啉-2(1H)-酮(I7),其合成路线如下所示:
在实施例3的基础上以溴甲基环丁烷替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I7。1H NMR(300MHz,DMSO-d6)δ10.52(s,1H),8.24(d,J=9.9Hz,1H),7.24(d,J=8.3Hz,1H),7.14(d,J=8.4Hz,1H),6.96(s,2H),6.57(d,J=9.9Hz,1H),5.77(s,1H),5.21(dd,J=8.1,4.3Hz,1H),4.08(d,J=6.8Hz,2H),3.70(p,J=7.0Hz,1H),3.06(dt,J=15.9,7.9Hz,2H),2.93–2.70(m,5H),2.59–2.51(m,4H),2.17–2.03(m,2H),1.96–1.80(m,4H),1.12(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO-d6)δ161.33,144.64,139.79,138.99,137.17,132.28,129.51,124.67,122.51,120.05,117.03,111.74,73.13,68.15,59.10,55.01,38.33,38.23,34.31,26.81,25.34,25.06,18.67,16.13.MS(ESI)m/z=461.3[M+H]+(C29H36N2O3)。
实施例8
本发明的茚达特罗衍生物,其化学名称为(S)-8-(环戊基甲氧基)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)喹啉-2(1H)-酮(I8),其合成路线如下所示:
在实施例3的基础上以溴甲基环戊烷替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I8。1H NMR(300MHz,DMSO-d6)δ10.56(s,1H),8.24(d,J=9.9Hz,1H),7.23(d,J=8.3Hz,1H),7.13(d,J=8.4Hz,1H),6.96(s,2H),6.57(d,J=9.9Hz,1H),5.21(dd,J=7.9,4.3Hz,1H),3.98(d,J=7.1Hz,2H),3.70(p,J=7.1Hz,1H),3.06(dt,J=15.9,7.9Hz,2H),2.92–2.70(m,4H),2.59–2.51(m,4H),2.44(q,J=7.5Hz,1H),1.93–1.80(m,2H),1.67–1.50(m,4H),1.33(dt,J=10.5,6.8Hz,2H),1.12(t,J=7.5Hz,6H).13CNMR(75MHz,DMSO-d6)δ161.35,144.67,139.79,138.99,138.95,137.17,132.21,129.44,124.67,124.64,122.51,120.04,111.60,73.16,68.15,59.10,55.01,38.88,38.32,38.22,29.56,26.81,25.38,25.34,16.13.MS(ESI)m/z=475.3[M+H]+(C30H38N2O3)。
实施例9
本发明的茚达特罗衍生物,其化学名称为(S)-8-(环己基甲氧基)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)喹啉-2(1H)-酮(I9),其合成路线如下所示:
在实施例3的基础上以溴甲基环己烷替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I9。1H NMR(300MHz,DMSO-d6)δ10.67(s,1H),8.24(d,J=9.8Hz,1H),7.22(d,J=8.5Hz,1H),7.10(d,J=7.9Hz,1H),6.95(s,2H),6.56(d,J=9.6Hz,1H),5.75(s,2H),5.17(s,1H),3.87(s,2H),3.65(s,1H),3.03(q,J=8.1Hz,2H),2.84(s,2H),2.76–2.66(m,2H),2.57(d,J=8.3Hz,4H),1.92(d,J=11.6Hz,3H),1.70(t,J=14.3Hz,4H),1.35–1.16(m,4H),1.11(d,J=8.0Hz,6H).13C NMR(75MHz,DMSO-d6)δ161.43,144.70,139.68,139.22,137.21,132.38,129.41,124.65,122.45,120.02,117.05,111.36,74.33,68.54,59.28,55.37,38.76,38.64,37.21,29.70,26.82,26.50,25.88,25.34,16.14.MS(ESI)m/z=489.3[M+H]+(C31H40N2O3)。
实施例10:
本发明的茚达特罗衍生物,其化学名称为(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-(吡啶-4-基甲氧基)喹啉-2(1H)-酮(I10),其合成路线如下所示:
在实施例3的基础上以4-氯甲基吡啶替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I10。1H NMR(300MHz,DMSO-d6)δ10.94(s,1H),8.60–8.54(m,2H),8.23(d,J=9.9Hz,1H),7.68–7.55(m,2H),7.19(d,J=2.0Hz,2H),6.96(s,2H),6.58(d,J=9.9Hz,1H),5.35(s,2H),5.15(d,J=7.2Hz,1H),3.63(p,J=7.1Hz,1H),3.03(dt,J=15.5,7.7Hz,2H),2.89–2.63(m,4H),2.56(t,J=7.5Hz,4H),1.12(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO-d6)δ161.49,150.06,146.15,143.59,139.65,139.26,137.13,133.45,129.74,124.66,122.53,119.88,117.34,112.43,68.71,59.35,55.40,38.91,38.78,25.34,16.14.MS(ESI)m/z=484.3[M+H]+(C30H33N3O3)。
实施例11
本发明的茚达特罗衍生物,其化学名称为(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-(吡啶-3-基甲氧基)喹啉-2(1H)-酮(I11),其合成路线如下所示:
在实施例3的基础上以3-氯甲基吡啶替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I11。1H NMR(300MHz,DMSO-d6)δ10.90(s,1H),8.80(d,J=2.2Hz,1H),8.54(dd,J=4.8,1.7Hz,1H),8.23(d,J=9.9Hz,1H),8.05(dt,J=7.9,2.0Hz,1H),7.42(ddd,J=7.8,4.8,0.9Hz,1H),7.26(q,J=8.4Hz,2H),6.97(s,2H),6.58(d,J=9.9Hz,1H),5.33(s,2H),5.23(dd,J=8.5,3.9Hz,1H),3.73(p,J=7.2Hz,1H),3.08(dt,J=15.8,7.9Hz,2H),2.85(ddt,J=28.6,14.8,7.6Hz,4H),2.60–2.51(m,4H),1.12(t,J=7.5Hz,6H).13CNMR(75MHz,DMSO-d6)δ161.47,149.84,149.61,143.81,139.88,138.81,136.98,136.45,132.75,132.59,129.89,124.66,123.93,122.75,119.89,117.22,112.61,68.05,67.82,58.97,54.68,38.00,37.90,25.33,16.12.MS(ESI)m/z=484.3[M+H]+(C30H33N3O3)。
实施例12
本发明的茚达特罗衍生物,其化学名称为(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-(吡啶-2-基甲氧基)喹啉-2(1H)-酮(I12),其合成路线如下所示:
在实施例3的基础上以2-氯甲基吡啶替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I12。1H NMR(300MHz,DMSO-d6)δ10.91(s,1H),8.59(ddd,J=4.9,1.8,0.9Hz,1H),8.25(d,J=10.0Hz,1H),7.84(td,J=7.6,1.8Hz,1H),7.75(dt,J=7.9,1.2Hz,1H),7.35(ddd,J=7.5,4.9,1.3Hz,1H),7.21(d,J=1.1Hz,2H),6.97(s,2H),6.60(d,J=9.9Hz,1H),5.35(s,2H),5.24(dd,J=8.5,3.9Hz,1H),3.73(p,J=7.2Hz,1H),3.08(dt,J=15.8,7.8Hz,2H),2.96–2.85(m,2H),2.79(dt,J=15.2,6.7Hz,2H),2.60–2.52(m,4H),1.12(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO-d6)δ165.76,161.41,156.81,149.36,144.08,139.87,138.82,138.78,137.45,137.04,132.98,129.93,124.65,123.52,122.73,122.38,119.97,117.27,113.02,71.73,67.84,58.98,54.69,38.01,37.92,26.81,25.33,16.12.MS(ESI)m/z=484.3[M+H]+(C30H33N3O3).
实施例13
本发明的茚达特罗衍生物,其化学名称为(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-(噻唑-4-基甲氧基)喹啉-2(1H)-酮(I13),其合成路线如下所示:
在实施例3的基础上以4-(氯甲基)噻唑替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I13。1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),9.14(d,J=2.0Hz,1H),8.22(d,J=10.0Hz,1H),8.13(d,J=2.0Hz,1H),7.30(d,J=8.4Hz,1H),7.22(d,J=8.4Hz,1H),6.94(d,J=3.6Hz,2H),6.56(d,J=9.9Hz,1H),5.46(s,1H),5.39(s,2H),5.06(t,J=6.0Hz,1H),3.50(q,J=6.6Hz,1H),2.98(ddd,J=15.3,12.1,6.9Hz,2H),2.75(d,J=6.2Hz,2H),2.62–2.56(m,2H),2.54(d,J=7.6Hz,4H),1.12(t,J=7.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.38,154.90,152.82,143.76,139.82,139.77,139.41,137.34,134.13,129.71,124.70,124.65,122.36,119.95,118.43,117.35,112.97,69.54,67.23,59.74,56.19,25.34,16.16.MS(ESI)m/z=490.2[M+H]+(C28H31N3O3S)。
实施例14:
本发明的茚达特罗衍生物,其化学名称为(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((3,5-二甲基异恶唑-4-基)甲氧基)喹啉-2(1H)-酮(I14),其合成路线如下所示:
在实施例3的基础上以4-(氯甲基)-3,5-二甲基异噁唑替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I14。1H NMR(300MHz,DMSO-d6)δ10.75(s,1H),8.21(d,J=10.0Hz,1H),7.23(d,J=0.9Hz,2H),6.95(d,J=2.4Hz,2H),6.53(d,J=9.9Hz,1H),5.39(d,J=48.2Hz,1H),5.06(d,J=12.8Hz,3H),3.53(q,J=6.7Hz,1H),2.99(dt,J=15.6,7.8Hz,2H),2.77(d,J=6.1Hz,2H),2.65–2.52(m,6H),2.42(s,3H),2.25(s,3H),1.12(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO-d6)δ168.30,161.47,160.40,143.83,139.74,139.68,139.46,137.21,133.73,129.74,124.70,124.65,122.43,119.84,117.25,112.36,110.54,69.40,60.14,59.69,56.11,25.34,16.16,11.22,10.29.MS(ESI)m/z=502.3[M+H]+(C30H35N3O4)。
实施例15
本发明的茚达特罗衍生物,其化学名称为(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((4-甲基嘧啶-2-基)氧基)喹啉-2(1H)-酮(I15),其合成路线如下所示:
在实施例3的基础上以2-氯-4-甲基嘧啶替换3,5-双三氟甲基溴苄,其他条件不变,得到目标产物I15。1H NMR(300MHz,DMSO-d6)δ8.40(d,J=5.0Hz,1H),8.26(d,J=10.0Hz,1H),7.34–7.24(m,2H),7.15(d,J=5.0Hz,1H),6.96(d,J=2.0Hz,2H),6.56(d,J=9.9Hz,1H),5.69(d,J=44.1Hz,1H),5.18(t,J=6.1Hz,1H),3.58(p,J=6.7Hz,1H),3.02(dt,J=15.4,7.6Hz,2H),2.89–2.76(m,2H),2.69–2.51(m,6H),2.41(s,3H),1.13(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO-d6)δ170.51,165.16,161.76,159.32,139.69,139.63,139.50,138.95,136.95,132.97,124.71,124.66,123.22,122.59,120.09,116.82,69.19,59.67,55.93,25.35,24.00,16.16.MS(ESI)m/z=485.3[M+H]+(C29H32N4O3)。
实施例16
本发明的茚达特罗衍生物,其化学名称为8-(苄氧基)-5-((1S)-2-(6,6-二甲基-3-氮杂双环[3.1.0]己烷-3-基)-1-羟乙基)喹啉-2(1H)-酮(I16),其合成路线如下所示:
参照实施例2中步骤(4)的方法,将茚达特罗中间体(S)-8-(苄氧基)-5-(环氧乙烷-2-基)喹啉-2(1H)-酮200mg(0.68mmol)和6,6-二甲基-3-氮杂双环[3.1.0]己烷0.11ml(0.89mmol)反应,经硅胶柱层析纯化后,得到目标产物I16 55mg,收率为19.94%。1HNMR(300MHz,DMSO-d6)δ10.65(s,1H),8.24–8.18(m,1H),7.57(d,J=7.4Hz,2H),7.34(dt,J=14.5,8.8Hz,3H),7.20–7.05(m,2H),6.54(dd,J=9.8,2.7Hz,1H),5.29(s,2H),4.96(d,J=7.2Hz,1H),2.86–2.61(m,6H),1.16(s,2H),0.94(d,J=19.5Hz,6H).13CNMR(75MHz,DMSO-d6)δ161.35,143.58,137.50,137.16,133.62,129.75,128.78,128.31,128.26,122.23,120.29,117.49,112.48,70.19,69.17,63.26,53.96,53.89,28.70,28.58,27.28,20.05,14.75.MS(ESI)m/z=405.2[M+H]+(C25H28N2O3)。
实施例17
本发明的茚达特罗衍生物,其化学名称为(S)-8-(苄氧基)-5-(1-羟基-2-(吡啶-2-基氨基)乙基)喹啉-2(1H)-酮(I17),其合成路线如下所示:
参照实施例2中步骤(4)的方法,将茚达特罗中间体(S)-8-(苄氧基)-5-(环氧乙烷-2-基)喹啉-2(1H)-酮200mg(0.68mmol)和吡啶-2-胺83.43mg(0.89mmol)反应,经硅胶柱层析纯化后,得到目标产物I17 113mg,收率为42.77%。1H NMR(300MHz,DMSO-d6)δ8.48(s,1H),8.30(d,J=9.9Hz,1H),7.68(s,1H),7.58(d,J=7.1Hz,3H),7.36(dt,J=15.2,7.6Hz,4H),7.16(d,J=12.4Hz,2H),6.62–6.50(m,2H),5.37(d,J=26.7Hz,3H),4.60–4.13(m,2H).13C NMR(75MHz,DMSO-d6)δ161.37,155.50,144.22,141.62,141.16,137.35,137.05,130.24,129.93,128.80,128.35,128.30,122.62,120.86,117.75,115.86,112.46,111.16,70.19,66.46,58.72.MS(ESI)m/z=388.2[M+H]+(C23H21N3O3)。
实施例18
本发明的茚达特罗衍生物,其化学名称为(S)-8-(苄氧基)-5-(2-((6-氟吡啶-3-基)氨基)-1-羟乙基)喹啉-2(1H)-酮(I18),其合成路线如下所示:
参照实施例2中步骤(4)的方法,将茚达特罗中间体(S)-8-(苄氧基)-5-(环氧乙烷-2-基)喹啉-2(1H)-酮200mg(0.68mmol)和2-氟-5-氨基吡啶99.37mg(0.89mmol)反应,经硅胶柱层析纯化后,得到目标产物I18 60mg,收率为21.70%。1H NMR(300MHz,DMSO-d6)δ10.68(s,1H),8.34(d,J=9.9Hz,1H),7.57(d,J=7.3Hz,2H),7.35(t,J=10.6Hz,4H),7.10(dq,J=23.2,8.4Hz,3H),6.80(d,J=9.0Hz,1H),6.62(d,J=9.8Hz,1H),6.41(d,J=6.2Hz,1H),5.25(s,2H),5.04(s,1H),4.93(s,1H),3.63(t,J=9.1Hz,2H).13CNMR(75MHz,DMSO-d6)δ161.33,143.83,142.95,137.15,136.65,130.50,130.30,129.90,129.78,128.81,128.36,128.32,125.85,125.77,122.70,120.00,118.17,112.60,109.63,109.11,70.21,65.94,55.64,26.81.MS(ESI)m/z=406.2[M+H]+(C23H20FN3O3)。
实施例19
本发明的茚达特罗衍生物其化学名称为(S)-5-(2-((4-(二乙氨基)苯基)氨基)-1-羟乙基)-8-((4-氟苄基)氧基)喹啉-2(1H)-酮(I19),其合成路线如下所示:
参照实施例2中步骤(4)的方法,将(S)-8-((4-氟苄基)氧基)-5-(环氧乙烷-2-基)喹啉-2(1H)-酮250mg(0.80mmol)和N,N-二乙基对苯二胺0.17ml(1.04mmol)反应,经硅胶柱层析纯化后,得到目标产物I19 36mg,收率为9.43%。1H NMR(300MHz,DMSO-d6)δ10.69(s,1H),8.35(d,J=9.8Hz,1H),8.17(s,1H),7.64(p,J=3.8Hz,2H),7.19(d,J=9.3Hz,4H),6.60(d,J=9.8Hz,1H),6.42(s,4H),5.22(s,2H),4.79(s,1H),3.56(s,2H),3.07(s,4H),0.92(s,6H).13C NMR(75MHz,DMSO-d6)δ163.89,161.39,160.66,143.46,136.68,133.36,130.71,130.60,122.56,115.72,115.43,112.68,69.47.MS(ESI)m/z=476.2[M+H]+(C28H30FN3O3)。
应用
1、化合物I对结直肠癌细胞系的抑制作用
以茚达特罗为阳性对照,配制10、20、30、40μM的浓度梯度,将其对SW620的IC50固定在20-25μM之间。化合物I以同样浓度梯度配制后进行初筛,具有相较茚达特罗更低IC50的化合物进行二次筛选,二次筛选时化合物的浓度梯度为1、2、4、8μM。
两轮筛选均作用于结直肠癌细胞系SW620,初始细胞数为每孔5000个,直接测定第48h的细胞存活率,最终确定化合物的IC50。
细胞存活率=[(实验组读数-空白组读数)/(对照组读数-空白组读数)]×100%。
表1化合物I对SW620抑制作用
化合物 | IC50(μM) | 化合物 | IC50(μM) |
茚达特罗 | 23.95 | I8 | 4.855 |
I1 | 2.711 | I9 | 3.868 |
I2 | 5.762 | I10 | 4.667 |
I3 | 2.132 | I11 | 10.52 |
I4 | 1.716 | I12 | 6.281 |
I5 | 2.393 | I13 | 4.194 |
I6 | 3.617 | I14 | 6.714 |
I7 | 4.489 |
2、化合物I6在大鼠体内药物代谢动力学研究
考察I6(LYS-7)在大鼠体内的整体药代动力学特征,获得其在大鼠体内的主要的药动学参数,为药物的进一步开发提供参考。按5mg/kg静脉注射、50mg/kg灌胃两种方式给药大鼠(n=3),在既定时间收集血浆,分别建立HPLC-MS/MS方法测定化合物在大鼠血浆中的浓度,利用WinNonlin软件计算药动学参数,得到数据结果如下:
表2化合物I6经给药后在大鼠体内的主要药代动参数(n=3)
表3化合物I6经静脉注射(5mg/kg)后大鼠体内血药浓度(ng/mL)
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表4化合物I6经灌胃给药(50mg/kg)后大鼠体内血药浓度(ng/mL)
注:“ND”为低于定量下限的点,为异常点,绘图与参数计算时均剔除。
根据样品测定结果及参数分析结果显示:
(1)静脉注射(5mg/kg)给予化合物I6后,2min(试验过程得到的Cmax)测得的血药浓度平均值为233.67±23.31ng/mL,提示化合物I6在体内可能迅速向组织分布,导致浓度较低。
(2)化合物I6经静脉注射后的AUC(0-∞)为632.08±42.37h·μg/L,清除率为7.94±0.55L/h/kg,表观分布容积约为39.03±0.8L/kg,提示化合物I6暴露量较低可能与其存在特异性组织分布有关。
(3)静注给药(5mg/kg)后,化合物I6在1h左右存在浓度峰值,分析原因可能由于组织再释放所致。
(4)灌胃给药(50mg/kg)后,根据血药浓度-时间曲线显示,化合物I6在1h内达到吸收峰值,提示化合物可能在体内存在快速吸收。而Cmax为167.17±59.62μg/L,结合静注给药数据,提示药物可能在组织中快速分布。同时,化合物在12h的浓度有明显提升,且浓度高于吸收峰值,结合静注给药(5mg/kg)后化合物I6在1h左右存在浓度峰值,提示可能存在组织再释放。
综上所述,基于茚达特罗对结直肠癌的抑制作用,我们筛选了先导化合物LYW-1并对结构进行了设计优化,合成了新的系列化合物I。体外研究发现其可显著抑制结直肠癌细胞的发生发展;体内药物代谢动力学实验结果为化合物的结构改造提供药动学的指导意见,为后续药效、毒理研究提供数据支撑;为结直肠癌的小分子抗肿瘤药的成药提供了可能,具有良好的应用前景。
Claims (8)
1.一种茚达特罗衍生物,其特征在于,化学结构式为:
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2.根据权利要求1所述的茚达特罗衍生物,其特征在于,结构式为
、/>、/>、/>、/>、或/>。
3.根据权利要求1所述的茚达特罗衍生物,其特征在于,其特征在于,结构式为。
4.根据权利要求1所述的茚达特罗衍生物的制备方法,其特征在于,包括以下步骤:
(1)5-乙酰基-2,8-二羟基喹啉与溴苄反应后苯环上的羟基被苄基保护,然后加入溴化剂对末端伯碳进行溴化,得到化合物II;
(2)以(R)/(S)-2-甲基-CBS-噁唑硼烷为手性催化剂,硼烷为还原剂,化合物II发生还原反应,苯环上的羰基被选择性地还原为羟基,得到化合物III;
(3)化合物III在碱性条件下发生分子内环合反应,得到化合物IV;
(4)化合物IV与亲核试剂R2H反应得到化合物V;
(5)化合物V与Boc酸酐反应得到化合物VI;
(6)化合物VI在钯碳/氢气条件下脱去苄基得到化合物VII;
(7)化合物VII与R1X反应后得到化合物VIII;
(8)最后化合物VIII被酸脱去Boc得到目标化合物茚达特罗衍生物I;合成路线如下:
;
其中,R1和R2对应于权利要求1具体化合物相应位置处的取代基团;手性中心*为S构型。
5.根据权利要求4述的茚达特罗衍生物的制备方法,其特征在于,步骤(4)中,反应溶剂选自乙腈、N,N-二甲基甲酰胺、二甲亚砜、正丁醇或二乙二醇二甲醚;反应温度60℃至150℃。
6.根据权利要求4所述的茚达特罗衍生物的制备方法,其特征在于,步骤(7)中,反应溶剂选自N,N-二甲基甲酰胺、乙腈、丙酮、四氢呋喃或二甲亚砜中的一种或多种;反应中使用的碱选自碳酸钾、碳酸铯、碳酸钠或三乙胺;回流反应。
7.权利要求1~3任一项所述的茚达特罗衍生物在制备治疗肿瘤疾病药物中的应用。
8.根据权利要求7所述的应用,其特征在于,所述肿瘤为结直肠肿瘤。
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