CN113754591B - 一种hdac、jak和bet三靶点抑制剂及其制备方法和应用 - Google Patents
一种hdac、jak和bet三靶点抑制剂及其制备方法和应用 Download PDFInfo
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- CN113754591B CN113754591B CN202010503272.9A CN202010503272A CN113754591B CN 113754591 B CN113754591 B CN 113754591B CN 202010503272 A CN202010503272 A CN 202010503272A CN 113754591 B CN113754591 B CN 113754591B
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 24
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 5
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Abstract
本发明公开了一种HDAC、JAK和BET三靶点抑制剂及其制备方法和应用。所述的HDAC、JAK和BET三靶点抑制剂,其结构通式为(I)或(II)所示。本发明还提供该类化合物的制备方法以及在制备预防或治疗与HDAC、JAK和BET活性或表达异常相关的疾病的药物中的应用。
Description
技术领域
本发明涉及一种HDAC、JAK和BET三靶点抑制剂及其制备方法和应用,属于有机化合物合成与医药应用技术领域。
背景技术
联合用药和多靶点药物都可以通过协同作用显著提高对肿瘤的治疗效果。相比于联合用药,多靶点药物还在改善药代动力学性质、避免不良药物-药物相互作用和提高病人的依从性等方面具有明显优势(J Med Chem,62(2019)420-444;J Med Chem,62(2019)8881-8914)。
组蛋白去乙酰化酶(Histone deacetylase,HDAC)、含溴结构域和额外终端域蛋白(Bromodomain and extra-terminal,BET)和JAK激酶(Janus kinase,JAK)已经成为治疗各种肿瘤重要的生物靶标。截至目前,共有5个HDAC抑制剂被批准上市用来治疗各种血液瘤;共有6个JAK抑制剂被批准上市,用来治疗类风湿性关节炎和骨髓纤维化;虽然目前没有BET抑制剂被批准上市,但有多个BET抑制剂已经处于治疗各种血液瘤和实体瘤的临床研究阶段。
尽管已经有5个HDAC抑制剂被批准上市用来***,但是HDAC抑制剂对实体瘤的治疗效果十分有限,这严重制约了HDAC抑制剂在***方面的应用。文献报道在乳腺癌等实体瘤细胞中HDAC抑制剂SAHA会增强白血病抑制因子受体(leukemia inhibitoryfactor receptor,LIFR)基因启动子上的组蛋白乙酰化作用,后者会“招募”表观遗传修饰识别因子BRD4,上调LIFR表达并激活JAK1-STAT3信号通路,促进了BCL-2,MCL-1等抗凋亡基因的表达,从而大大减弱了HDAC抑制剂对乳腺癌等实体瘤的治疗效果(Cancer Cell,30(2016)459-473)。因此,阻断实体瘤细胞中的BRD4-JAK1-STAT3-BCL-2/MCL-1耐药信号通路有望提高HDAC抑制剂对实体瘤的治疗效果。文献报道JAK抑制剂菲卓替尼(Fedratinib)和TG101209都有中等强度的BRD4抑制活性(Nat Chem Biol,10(2014)305-312;ACS ChemBiol,9(2014)1160-1171)。因此,我们以JAK抑制剂菲卓替尼(Fedratinib)和TG101209为分子模板,分析了它们与JAK和BET之间的结合模式,结合HDAC抑制剂的药效团模型,设计了一个系列的HDAC、JAK和BET三靶点抑制剂。
发明内容
针对现有技术的不足,本发明提供了一种HDAC、JAK和BET三靶点抑制剂及其制备方法和应用。
本发明的技术方案为:
一、HDAC、JAK和BET三靶点抑制剂
具有如下结构通式(I)或(II)的HDAC、JAK和BET三靶点抑制剂,其药学上可接受的盐,溶剂合物或前药:
其中:X是
Y是
R1是氢,各种脂肪烃基,各种卤素;
R2是六元芳基,对位取代六元芳基,六元杂芳基,对位取代六元杂芳基;
R3是六元芳基,对位取代六元芳基,六元杂芳基,对位取代六元杂芳基;
根据本发明优选的,其中:
X是
Y是
R1是甲基,氯原子;
R2是
R3是
进一步优选的,上述化合物为下列之一:
二、HDAC、JAK和BET三靶点抑制剂的制备方法
具有通式(I)或(II)结构的化合物的制备方法如下路线之一所示:
(一)以化合物1为起始原料,与叔丁胺反应得到化合物2,化合物2通过硝基还原反应得到中间体3,中间体3与2,4-二氯-5-甲基嘧啶或2,4,5-三氯嘧啶发生亲核取代反应得到关键中间体4a-4b;化合物4a-4b在酸的催化下与对氨基苯甲酸或间氨基苯甲酸发生亲核取代反应得到化合物5a-5d,然后中间体5a-5d与O-(四氢-2H-吡喃-2-基)羟胺发生酰胺缩合得到中间体6a-6d,然后在酸性条件下脱去化合物6a-6d的THP保护基团得到异羟肟酸类终产物7a-7d;化合物5a,5c与邻苯二胺经过酰胺缩合得到邻苯二胺类终产物8a-8b;化合物4a-4b分别与对氨基肉桂酸乙酯发生酸催化的亲核取代反应得到中间体9a-9b,9a与新鲜制备的羟胺钾甲醇溶液反应得到终产物10a,而中间体9b经过酯水解反应、酰胺缩合反应,最后在酸性条件下脱去THP保护基得到终产物11a;化合物5a-5d与水合肼发生酰胺缩合,得到中间体12a-12d,然后在经过还原胺化得到酰肼类终产物13a-13d;
合成路线一如下:
上述合成路线中的试剂及反应条件:a)叔丁胺,四氢呋喃,25℃;b)钯碳,80%水合肼,乙醇,回流;c)2,4-二氯-5-甲基嘧啶或2,4,5-三氯嘧啶,甲醇和水,45℃;d)3-氨基苯甲酸或4-氨基苯甲酸或4-氨基肉桂酸乙酯,浓盐酸,异丙醇,回流;e)O-(四氢-2H-吡喃-2-基)羟胺,三乙胺,1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐,1-羟基苯并***,N,N-二甲基甲酰胺,25℃;f)氯化氢饱和的乙酸乙酯;g)邻苯二胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;h)羟胺钾甲醇溶液,25℃;i)氢氧化锂,四氢呋喃,甲醇,水,60℃;j)1)O-(四氢-2H-吡喃-2-基)羟胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;2)氯化氢饱和的乙酸乙酯;k)80%水合肼,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,二氯甲烷,25℃;l)1)丙醛,硫酸镁,无水乙醇,25℃;2)氰基硼氢化钠或硼氢化钠,无水甲醇,25℃。
(二)以化合物14为原料,与对硝基酚在碱性条件下经过亲核取代反应、硝基还原反应得到中间体16,化合物17a-17c与2,4-二氯-5-甲基嘧啶或2,4,5-三氯嘧啶发生亲核取代反应得到关键中间体18a-18f;中间体18a-8f与化合物16经过酸催化发生亲核取代得到关键中间体19a-19f,中间体19a-19d与新鲜制备的羟胺钾甲醇溶液反应得到异羟肟酸类终产物20a-20d,而中间体19e-19f经过与邻苯二胺的缩合反应得到邻苯二胺类终产物20e-20f;化合物19e与水合肼发生酰胺缩合得到中间体21,然后经过还原胺化得到酰肼类终产物22;
合成路线二如下:
上述合成路线中的试剂及反应条件:a)4-硝基苯酚,碳酸铯,N,N-二甲基甲酰胺,氮气,100℃;b)钯/碳,氢气,甲醇,25℃;c)2,4-二氯-5-甲基嘧啶或2,4,5-三氯嘧啶,甲醇,水,45℃;d)浓盐酸,异丙醇,85℃或浓盐酸,异丁醇,100℃;e)羟胺钾甲醇溶液;f)邻苯二胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;g)80%水合肼,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,二氯甲烷,25℃;h)1)丙醛,硫酸镁,无水乙醇,25℃;2)硼氢化钠,无水甲醇,25℃。
(三)以化合物23为起始原料,化合物23经过Boc酸酐保护氨基、硝基还原、和叔丁基亚磺酰氯缩合反应得到化合物26,又经过氧化反应、酸性条件下脱Boc保护基、和2,4-二氯-5-甲基嘧啶亲核取代反应得到化合物29;化合物29在酸性条件下与对氨基苯甲酸发生亲核取代反应得到中间体30,中间体30一方面和O-(四氢-2H-吡喃-2-基)羟胺发生酰胺缩合、在酸性条件下脱THP保护基得到终产物31;另一方面又和邻苯二胺发生酰胺缩合得到终产物32;中间体29与对氨基肉桂酸乙酯发生酸介导的亲核取代反应得到中间体33,然后经过酯水解反应、酰胺缩合、在酸性条件下脱THP保护基得到终产物35;化合物30与水合肼发生酰胺缩合,得到中间体36,然后经过还原胺化得到酰肼类终产物37;
合成路线三如下:
上述合成路线中的试剂及反应条件:a)二碳酸二叔丁酯,叔丁醇,60℃;b)三氯化铁,80%水合肼,活性炭,甲醇,回流;c)叔丁基亚磺酰氯,吡啶,0℃;d)间氯过氧苯甲酸,二氯甲烷,25℃;e)三氟乙酸,二氯甲烷,25℃;f)2,4-二氯-5-甲基嘧啶,甲醇和水,45℃;g)4-氨基苯甲酸,浓盐酸,异丁醇,100℃;h)1)O-(四氢-2H-吡喃-2-基)羟胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;2)氯化氢饱和的乙酸乙酯;i)邻苯二胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;j)4-氨基肉桂酸乙酯,浓盐酸,异丁醇,100℃;k)氢氧化锂,四氢呋喃,甲醇,水,60℃;l)80%水合肼,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,二氯甲烷,25℃;m)1)丙醛,硫酸镁,无水乙醇,25℃;2)硼氢化钠,无水甲醇,25℃。
(四)中起始原料38a-38b在碱性条件下与N-甲基哌嗪发生反应,经过硝基还原得到中间体40a-40b,中间体40a-40b在酸性条件下与化合物18a发生亲核取代反应后,一方面和羟胺钾甲醇溶液反应得到终产物41a-41b;另一方面发生酯水解反应得到中间体42,中间体42与邻苯二胺和正丙基肼盐酸盐分别发生酰胺缩合得到终产物43和44;
合成路线四如下:
上述合成路线中的试剂及反应条件:a)N-甲基哌嗪,碳酸钾,二甲基亚砜,25℃;b)钯碳,80%水合肼,乙醇,60℃;c)1)18a,浓盐酸,异丁醇,100℃;2)羟胺钾甲醇溶液,25℃;d)1)18a,浓盐酸,异丁醇,100℃;2)氢氧化锂,四氢呋喃,甲醇,水,60℃;e)邻苯二胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;f)正丙基肼盐酸盐,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃。
三、HDAC、JAK和BET三靶点抑制剂的应用
本发明还提供了HDAC、JAK和BET三靶点抑制剂在制备预防或治疗与HDAC、JAK和BET活性或表达异常相关的疾病的药物中的应用;
所述的与HDAC、JAK和BET活性或表达异常相关疾病为各种血液瘤、实体瘤和自身免疫性疾病等。
所述的各种血液瘤和实体瘤为骨髓纤维化、黑色素瘤、多发性骨髓瘤、皮肤T细胞淋巴瘤、人红细胞白血病、人慢性髓细胞性白血病、乳腺癌、胰腺癌、胃癌、肺癌、直肠癌、结肠癌和***癌等,自身免疫性疾病为类风湿性关节炎、炎症等。
此外,本发明还包括适于口服或胃肠外给药的药物组合物,包含本发明通式(I)或(II)所述的化合物或其药学上可接受的盐以及一种或多种药学上可接受载体或赋形剂。
具体实施方式
下面结合实施例对本发明做进一步的说明,但不限于此。
实施例1、化合物7a-7d,8a-8b,10a,11a,13a-3d的制备方法,分别以化合物7a,8a,10a,11a,13a为例,具体步骤如下:
(1)中间体2:N-(叔丁基)-3-硝基苯磺酰胺的制备
25℃下,将3-硝基苯磺酰氯(1,5.0g,22.56mmol)加入到50mL四氢呋喃中,加入叔丁胺(4.95g,67.68mmol)。加毕后,25℃下继续搅拌0.5小时,TLC监测反应进程,反应结束后,在0℃下用1M盐酸调节溶液pH为2,减压蒸除反应液,所得固体用石油醚/乙酸乙酯打浆,过滤,滤饼用适量水洗涤3次,所得固体真空干燥,得到5.15g黄色固体,产率88%。ESI-MS,m/z=257.10[M-H]-。
(2)中间体3:3-氨基-N-(叔丁基)苯磺酰胺的制备
25℃下,将化合物2(5.00g,19.36mmol)溶解在80mL乙醇中,加入10%钯碳(0.50g)和80%水合肼(3.63g,58.08mmol)。在氩气保护下,回流反应3小时,反应结束后,减压蒸除溶剂,所得固体用二氯甲烷溶解,用水洗涤2次,合并有机相用无水硫酸镁干燥,过滤,浓缩,真空干燥得到3.35g白色固体,产率76%。ESI-MS,m/z=227.13[M-H]-。
(3)中间体4a:N-(叔丁基)-3-((2-氯-5-甲基嘧啶-4-基)氨基)苯磺酰胺的制备
25℃下,将化合物3(2.3g,10.00mmol)和2,4-二氯-5-甲基嘧啶(1.9g,11.50mmol)加入到甲醇和水(v:v=1:1.5,50mL)中,45℃下反应20小时,反应过程中逐渐有固体析出,TLC监测反应结束后,将反应液静置至室温,过滤,所的固体用甲醇和水(v:v=1:1.5)洗涤2次,真空干燥得到2.96g白色固体,产率83%。ESI-MS,m/z=353.29[M-H]-。
化合物4b的制备方法与化合物4a类似。
(4)中间体5a:4-((4-((3-(N-(叔丁基)氨磺酰基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯甲酸的制备
25℃下,将化合物4a(0.35g,1.00mmol)和对氨基苯甲酸(0.21g,1.50mmol)加入到16mL异丙醇中,加入2-3滴浓盐酸,85℃下回流反应3小时,反应过程中逐渐有固体析出,TLC监测反应结束后,将反应液静置至室温,过滤,所得固体依次用异丙醇和乙酸乙酯洗涤1-2次,真空干燥得到0.37g白色固体,产率81%。ESI-MS,m/z=454.27[M-H]-。
化合物5b-5d的制备方法与化合物5a类似。
(5)中间体6a:4-((4-((3-(N-(叔丁基)氨磺酰基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)-N-((四氢-2H-吡喃-2-基)氧苯甲酰胺的制备
0℃下,将化合物5a(0.45g,1.0mmol)溶于30mL N,N-二甲基甲酰胺中,依次加入三乙胺(0.15g,1.5mmol),1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(0.30g,1.5mmol),1-羟基苯并***(0.20g,1.5mmol)加毕,0℃下继续搅拌30分钟,然后加入O-(四氢-2H-吡喃-2-基)羟胺(0.18g,1.5mmol),加毕,撤去冰浴,25℃下搅拌反应12小时,TLC监测反应结束后,将反应液倾入大量水中,用乙酸乙酯萃取3次,合并有机相依次用饱和NaHCO3和饱和NaCl水溶液洗涤2次,有机相用无水硫酸镁干燥,过滤,浓缩,真空干燥,得到0.30g白色固体,产率55%。ESI-MS,m/z=555.13[M+H]+。
化合物6b-6d的制备方法与化合物6a类似。
(6)化合物7a:4-((4-((3-(N-(叔丁基)氨磺酰基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)-N-羟基苯甲酰胺的制备
25℃下,将化合物6a(0.18g,0.32mmol)加入到20mL乙酸乙酯中,加入0.33mL氯化氢饱和的乙酸乙酯,继续搅拌1小时,TLC监测反应结束后,将反应液过滤,真空干燥得到0.13g白色固体,产率87%。1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.70(s,1H),10.04(s,1H),8.02(s,1H),7.93-7.88(m,2H),7.77(d,J=7.9Hz,1H),7.67-7.60(m,4H),7.45(d,J=8.4Hz,2H),2.21(s,3H),1.10(s,9H)。13C NMR(101MHz,DMSO-d6)δ164.14,162.13,151.35,145.40,142.15,140.20,138.15,129.76,129.32,128.82,128.31,128.17,124.36,122.97,120.10,108.49,53.87,30.22,13.88。HRMS(AP-ESI),calcd for C22H26N6O4S[M+H]+471.1814,found 471.1810。
化合物7b-7d的制备方法与化合物7a类似。
(7)化合物8a:N-(2-氨基苯基)-4-((4-((3-(N-(叔丁基)氨磺酰基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯甲酰胺的制备
将化合物5a(0.23g,0.50mmol)溶于15mL无水N,N-二甲基甲酰胺中,0℃下加入O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯(0.20g,0.60mmol)和三乙胺(0.08g,0.75mmol),加毕,继续搅拌活化30分钟,加入邻苯二胺(0.08g,0.75mmol),加毕,25℃下搅拌反应,TLC监测反应结束后,将反应液倾入大量水中,用乙酸乙酯萃取3次,有机相分别用饱和NaHCO3和饱和NaCl溶液洗涤2-3次,合并有机相用无水硫酸镁干燥,过滤,浓缩,柱层析(二氯甲烷/甲醇=30:1)纯化,真空干燥,得到0.10g黄色固体,产率37%。1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),9.35(s,1H),8.68(s,1H),8.19-8.16(m,1H),8.10(d,J=2.4Hz,1H),8.02(s,1H),7.84(d,J=8.7Hz,2H),7.80(d,J=8.8Hz,2H),7.60-7.51(m,3H),7.16(d,J=7.8Hz,1H),7.02-6.93(m,1H),6.78(d,J=7.9Hz,1H),6.60(t,J=7.5Hz,1H),4.85(s,2H),2.17(s,3H),1.13(s,9H)。13C NMR(101MHz,DMSO-d6)δ165.39,159.55,158.09,156.42,144.99,144.54,143.56,140.77,129.39,128.93,127.05,126.69,126.41,125.71,124.24,120.85,119.70,117.50,116.78,116.64,107.57,53.73,30.26,14.05。HRMS(AP-ESI),calcd for C28H31N7O3S[M+H]+546.2287,found 546.2280.
化合物8b的制备方法与化合物8a类似。
(8)中间体9a:(E)-3-(4-((4-((3-(N-(N-(叔丁基)氨磺酰基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯基)丙烯酸乙酯的制备
将化合物4a(0.27g,0.76mmol)和对氨基肉桂酸乙酯(0.13g,0.69mmol)加入到10mL异丁醇中,加入53μL浓盐酸,加毕,100℃下反应4小时,反应结束后,反应液静置至室温,过滤,真空干燥,得到0.25g白色固体,产率71%。ESI-MS,m/z=510.40[M+H]+。
中间体9b的制备方法与化合物9a类似。
(9)化合物10a:(E)-3-(4-((4-((3-(N-(N-(叔丁基)氨磺酰基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯基)-N-羟基丙烯酰胺的制备
25℃下,将化合物9a(0.20g,0.39mmol)加入到8mL新鲜制备的羟胺钾甲醇溶液中,25℃下搅拌反应2小时,反应结束后,将反应液浓缩,用1M盐酸调节溶液pH值为6,将析出的固体过滤,所得固体用乙酸乙酯打浆,过滤,真空干燥,得到0.13g灰白色固体,产率68%。1HNMR(600MHz,DMSO-d6)δ10.64(s,1H),9.26(s,1H),8.93(s,1H),8.66(s,1H),8.14-8.12(m,1H),8.10(d,J=2.0Hz,1H),7.99(s,1H),7.72(d,J=8.3Hz,2H),7.58(s,1H),7.56-7.51(m,2H),7.42-7.31(m,3H),6.28(d,J=15.7Hz,1H),2.15(s,3H),1.13(s,9H)。13C NMR(101MHz,DMSO-d6)δ163.84,159.55,158.14,156.41,144.98,142.86,140.81,138.86,129.36,128.51,127.35,125.73,120.83,119.76,118.63,116.11,107.30,53.73,30.26,14.02。HRMS(AP-ESI),calcd for C24H28N6O4S[M+H]+497.1971,found 497.1973。
(10)化合物10b:(E)-3-(4-((4-((3-(N-(叔丁基)氨磺酰基)苯基)氨基)-5-氯嘧啶-2-基)氨基)苯基)丙烯酸的制备
25℃下,将化合物9b(0.20g,0.38mmol)溶于15mL四氢呋喃,甲醇和水(v:v:v=1:1:1)混合溶剂中,加入氢氧化锂(0.16g,3.77mmol)加毕,60℃下加热反应1小时,TLC监测反应结束后,将反应液浓缩,用1M盐酸调节溶液pH值为4-5,所得固体过滤,真空干燥,得到0.16g浅黄色固体,产率85%。ESI-MS,m/z=502.19[M+H]+。
实施例2、化合物20a-20d,20e-20f和22的制备方法,分别以化合物20a,20e和22为例,具体步骤如下:
(1)中间体15:1-(2-(4-硝基苯氧基)乙基)吡咯烷的制备
将对硝基苯酚(0.70g,5.0mmol)溶于20mL无水N,N-二甲基甲酰胺中,加入化合物1(0.86g,5.0mmol)和Cs2CO3(2.4g,7.5mmol),加毕,在氮气保护下,100℃下反应4小时,TLC监测反应结束后,将反应液静置至室温,过滤,滤液加入到适量冰水中,用乙酸乙酯萃取,有机相用饱和Na2CO3和NaCl溶液洗涤,合并有机相,用无水硫酸镁干燥,过滤,浓缩,得到0.40g棕黄色油状物,产率34%。ESI-MS,m/z=237.10[M+H]+。
(2)中间体16:4-(2-(吡咯烷-1-基)乙氧基)苯胺的制备
将化合物15(0.75g,3.17mmol)溶于50mL无水甲醇中,加入10%钯碳,在H2下,室温反应12小时,TLC监测反应结束后,用硅藻土过滤除去钯碳,蒸除溶剂,干燥,得到0.65g黄色油状物,产率98%。
(3)中间体18a:4-((2-氯-5-甲基嘧啶-4-基)氨基)苯甲酸甲酯的制备
0.55g灰白色固体,产率64%。1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.15(s,1H),7.96(d,J=8.5Hz,2H),7.86(d,J=8.6Hz,2H),3.84(s,3H),2.22(s,3H)。ESI-MS,m/z=276.19[M-H]-。
中间体18a-18f的制备方法与化合物4a类似。
(4)中间体19a:4-((5-甲基-2-((4-(2-(吡咯烷基-1-基)乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯盐酸盐的制备
25℃下,将化合物18a(0.25g,0.90mmol)和化合物16(0.20g,0.97mmol)加入到10mL异丙醇中,加入浓盐酸(90μL,1.08mmol),加毕,在85℃下加热反应4小时,TLC监测反应结束后,将反应液静置至室温,过滤,所得固体用异丙醇和乙酸乙酯分别洗涤,真空干燥得到0.26g灰白色固体,产率65%。ESI-MS,m/z=448.24[M+H]+。
中间体19b-19f的制备方法与化合物19a类似
(5)化合物20a:N-羟基-4-((5-甲基-2-((4-(2-(吡咯烷基-1-基)乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酰胺的制备
25℃下,将化合物19a(0.09g,0.2mmol)加入到5mL新鲜制备的羟胺钾甲醇溶液中,加毕,25℃下继续反应1.5小时,TLC监测反应结束后,将反应液浓缩,用1M盐酸调节溶液pH=7-8,析出固体,过滤,真空干燥,得到15mg黄色固体,产率17%。Mp:144-146℃。1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.36(s,1H),7.89(s,1H),7.82(d,J=8.5Hz,2H),7.71(d,J=8.5Hz,2H),7.55(d,J=8.9Hz,2H),6.81(d,J=8.9Hz,2H),4.01(t,J=6.0Hz,2H),2.76(t,J=6.0Hz,2H),2.12(s,3H),1.72-1.65(m,4H)。13C NMR(101MHz,DMSO-d6)δ164.42,159.24,158.82,156.58,153.45,134.73,127.54,120.96,120.89,114.67,106.15,67.35,54.95,54.47,23.62,14.07。HRMS(AP-ESI),calcd for C24H28N6O3[M+H]+449.2301,found449.2299。
化合物20b-20d的制备方法与化合物20a类似。
(6)化合物20e:N-(2-氨基苯基)-4-((5-甲基-2-((4-(2-(吡咯烷基-1-基)乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酰胺的制备
0.11g黄色固体,产率50%。1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.91(s,1H),8.47(s,1H),7.99-7.91(m,5H),7.57(d,J=8.5Hz,2H),7.19(d,J=7.8Hz,1H),6.98(t,J=7.7Hz,1H),6.85(d,J=8.6Hz,2H),6.80(d,J=7.9Hz,1H),6.61(t,J=7.5Hz,1H),4.91(s,2H),4.05(t,J=5.8Hz,2H),2.90(t,J=6.0Hz,2H),2.64(s,4H),2.14(s,3H),1.74-1.67(m,4H)。13C NMR(101MHz,DMSO-d6)δ165.30,159.20,158.87,156.71,153.44,143.60,143.55,134.75,128.65,128.23,127.05,126.75,124.20,121.10,120.70,116.80,116.69,114.74,106.19,67.09,54.82,54.45,23.57,14.02。HRMS(AP-ESI),calcd for C30H33N7O2[M+H]+524.2774,found 524.2771。
化合物20e-20f的制备方法与化合物8a类似。
(7)中间体21:4-((5-甲基-2-((4-(2-(吡咯烷-1-基)乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯并肼的制备
0.37g灰白色固体,产率97%。1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),9.55(s,1H),9.04(s,1H),8.00-7.82(m,5H),7.50(d,J=8.6Hz,2H),7.03-6.91(m,2H),4.32(t,J=5.0Hz,2H),3.57(t,J=5.1Hz,2H),2.16(s,3H),1.97(s,4H).ESI-MS,m/z=448.23[M+H]+。
中间体21的制备方法与化合物12a类似。
(8)化合物22:4-((5-甲基-2-((4-(2-(吡咯烷基-1-基)乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N'-丙基苯甲酰肼的制备
0.02g灰白色固体,产率7%。1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.87(s,1H),8.40(s,1H),7.93-7.83(m,3H),7.79(d,J=8.6Hz,2H),7.55(d,J=8.7Hz,2H),6.83(d,J=8.5Hz,2H),5.06(s,1H),4.03(t,J=5.8Hz,2H),2.84(brs,2H),2.75(t,J=7.2Hz,2H),2.59(brs,4H),2.12(s,3H),1.70(brs,4H),1.48(h,J=7.6Hz,2H),0.92(t,J=7.4Hz,3H)。HRMS(AP-ESI),calcd for C27H35N7O2[M+H]+490.2930,found 490.2928。
化合物22的制备方法与化合物13a类似。
实施例3、化合物31,32,35和37的制备方法,具体步骤如下:
(1)中间体24:(4-氯-3-硝基苯基)氨基甲酸叔丁酯的制备
25℃下,将化合物23(1.72g,10.00mmol)加入到15mL叔丁醇中,加入(Boc)2O(2.40g,11.00mmol),加毕,60℃下反应15小时,将反应液浓缩,粗产物柱层析纯化(石油醚/乙酸乙酯=30:1),真空干燥,得到1.76g浅黄色固体,产率65%。
(2)中间体25:(3-氨基-4-氯苯基)氨基甲酸叔丁酯的制备
25℃下,将化合物24(1.00g,3.67mmol),三氯化铁(0.10g,0.37mmol)和活性炭(0.5g)加入到30mL甲醇中,回流反应10分钟后,缓慢加入80%水合肼(734μL,14.68mmol),加毕,继续回流反应,TLC监测反应结束后,将反应液静置至室温,用硅藻土过滤,滤液浓缩,将所得残留物溶于乙酸乙酯中,依次用水,饱和NaCl溶液洗涤,有机相用无水硫酸镁干燥,过滤,浓缩,真空干燥,得到0.73g白色固体,产率85%。
(3)中间体26:(3-((叔丁基亚磺酰基)氨基)-4-氯苯基)氨基甲酸叔丁酯的制备
25℃下,将叔丁基亚磺酰氯(0.25mL,2.00mmol)和化合物25(0.49g,2.00mmol)分别溶于2mL和3mL吡啶中,0℃下,将叔丁基亚磺酰氯的吡啶溶液缓慢滴加到化合物25的吡啶溶液中,加毕,0℃下继续反应,TLC监测反应结束后,向反应液中加入乙酸乙酯,依次用1M盐酸和饱和NaCl溶液洗涤2次,合并有机相并用无水硫酸镁干燥,过滤,浓缩,柱层析(石油醚/乙酸乙酯=5:1)纯化,得到0.42g浅黄色固体,产率61%。
(4)中间体27:(4-氯-3-(((1,1-二甲基乙基)磺酰胺基)苯基)氨基甲酸叔丁酯的制备
25℃下,将化合物26(0.80g,2.31mmol)溶于15mL二氯甲烷中,加入85%m-CPBA(0.42g,2.42mmol),加毕,继续搅拌反应4小时,TLC监测反应结束后,用饱和Na2CO3溶液调节反应液pH为8,有机相用饱和NaCl溶液洗涤2次,合并有机相并用无水硫酸镁干燥,过滤,浓缩,柱层析(二氯甲烷/甲醇=100:1),真空干燥,得到0.60g黄色固体,产率72%。
(5)中间体28:N-(5-氨基-2-氯苯基)-2-甲基丙烷-2-磺酰胺的制备
将化合物27(0.60g,1.65mmol)溶于4mL二氯甲烷中,加入4mL三氟乙酸,加毕,25℃下搅拌反应1小时,反应结束后,用饱和Na2CO3溶液调节反应液pH大于7,向反应液中加入20mL二氯甲烷,用饱和Na2CO3和NaCl溶液依次洗涤2次,有机相用无水硫酸镁干燥,过滤,浓缩,真空干燥,得到0.30g棕色固体,产率70%。
(6)中间体29:N-(2-氯-5-((2-氯-5-甲基嘧啶-4-基)氨基)苯基)-2-甲基丙烷-2-磺酰胺的制备
0.32g棕黄色固体,产率73%。1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),9.01(s,1H),8.10(s,1H),7.95(d,J=2.5Hz,1H),7.59(dd,J=8.9,2.5Hz,1H),7.46(d,J=8.8Hz,1H),2.19(s,3H),1.35(s,9H)。
中间体29的制备方法与化合物4a类似。
(7)中间体30:4-((4-((4-氯-3-((1,1-二甲基乙基)磺酰胺基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯甲酸的制备
25℃下,将化合物29(0.30g,0.77mmol)和对氨基苯甲酸(0.12g,0.85mmol)加入到15mL异丁醇中,加入浓盐酸(96.70μL,1.16mmol),加毕,100℃下反应6小时,反应结束后,静置至室温,过滤,滤饼用异丁醇洗涤2次,真空干燥,得到0.25g白色固体,产率66%。
(8)化合物31:4-((4-((4-氯-3-((1,1-二甲基乙基)磺酰胺基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)-N-羟基苯甲酰胺的制备
25℃下,将化合物30(0.25g,0.51mmol)溶于10mL N,N-二甲基甲酰胺中,加入O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯(0.25g,0.76mmol)和三乙胺(107.0μL,0.76mmol),加毕,活化20分钟,加入O-(四氢-2H-吡喃-2-基)羟胺(71.50mg,0.61mmol),继续搅拌反应,TLC监测反应结束后,向反应液中加入100mL水,用乙酸乙酯萃取,有机相用饱和Na2CO3和饱和NaCl洗涤2次,并用无水硫酸镁干燥,过滤,浓缩,得到白色固体,用少量乙酸乙酯溶解,加入5mL氯化氢饱和的乙酸乙酯,室温反应1小时,过滤,真空干燥,产率43%。1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),10.95(s,1H),10.07(s,1H),9.58(s,1H),8.03(s,1H),7.76(d,J=2.2Hz,1H),7.66(d,J=8.3Hz,2H),7.57(d,J=8.5Hz,1H),7.53-7.44(m,3H),2.19(s,3H),1.30(s,9H)。13C NMR(101MHz,DMSO-d6)δ164.06,162.03,150.93,141.28,140.06,136.81,136.37,129.93,128.43,128.18,125.09,124.28,123.66,120.09,108.54,61.18,24.27,13.98。HRMS(AP-ESI),calcd for C22H25ClN6O4S[M+H]+505.1425,found505.1410。
(9)化合物32:N-(2-氨基苯基)-4-((4-((4-氯-3-((1,1-二甲基乙基)磺酰胺基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯甲酰胺的制备
0.10g浅黄色固体,产率38%。1H NMR(400MHz,DMSO-d6)δ9.40(d,J=10.7Hz,2H),9.34(s,1H),8.61(s,1H),8.01(s,1H),7.92(s,1H),7.87(d,J=8.5Hz,2H),7.84-7.75(m,3H),7.45(d,J=8.8Hz,1H),7.18(d,J=7.8Hz,1H),6.98(t,J=7.6Hz,1H),6.80(d,J=8.0Hz,1H),6.62(t,J=7.5Hz,1H),4.89(s,2H),2.16(s,3H),1.34(s,9H)。13C NMR(101MHz,DMSO-d6)δ165.39,159.47,158.11,156.48,143.59,139.63,135.85,129.47,128.95,127.12,126.73,126.36,124.20,121.56,121.28,121.13,117.43,116.77,116.61,107.44,61.07,24.34,14.06。HRMS(AP-ESI),calcd for C28H30ClN7O3S[M+H]+580.1898,found580.1878。
化合物32的制备方法与化合物8a类似。
(10)中间体33:(E)-3-(4-((4-((4-氯-3-((1,1-二甲基乙基)磺酰胺基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯基)丙烯酸乙酯的制备
0.23g浅黄色固体,产率66%。ESI-MS,m/z=542.31[M-H]-。
中间体33的制备方法和化合物30类似。
(11)中间体34:(E)-3-(4-((4-((4-氯-3-((1,1-二甲基乙基)磺酰胺基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯基)丙烯酸的制备
80mg灰白色固体,产率39%。ESI-MS,m/z=516.35[M+H]+。
中间体34的制备方法和化合物10b类似。
(12)化合物35:(E)-3-(4-((4-((4-氯-3-((1,1-二甲基乙基)磺酰胺基)苯基)氨基)-5-甲基嘧啶-2-基)氨基)苯基)-N-羟基丙烯酰胺的制备
45mg黄色固体,产率63%。1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),10.05(s,1H),9.64(s,1H),8.00(s,1H),7.79(d,J=2.3Hz,1H),7.66-7.37(m,7H),6.39(d,J=15.8Hz,1H),2.18(s,3H),1.29(s,9H)。13C NMR(101MHz,DMSO-d6)δ163.34,162.10,150.91,141.29,138.40,138.16,136.84,136.42,131.05,130.05,128.66,125.13,124.28,123.83,120.99,118.43,108.34,61.20,24.28,13.91。HRMS(AP-ESI),calcd for C24H27ClN6O4S[M+H]+531.1581,found 531.1563。
化合物35的制备方法与化合物31类似。
(13)中间体36:N-(2-氯-5-((2-((4-(肼基羰基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯基)-2-甲基丙烷-2-磺酰胺的制备
0.17g白色固体,产率66%。1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),9.35(d,J=18.2Hz,2H),8.64(s,1H),7.98(s,1H),7.86(d,J=2.5Hz,1H),7.79-7.68(m,5H),7.45-7.42(m,1H),2.14(s,3H),1.33(d,J=3.8Hz,9H)。
中间体36的制备方法与化合物12a类似。
(14)化合物37:N-(2-氯-5-((5-甲基-2-((4-(2-丙基肼-1-羰基)苯基)氨基)嘧啶-4-基)氨基)苯基)-2-甲基丙烷-2-磺酰胺的制备
20mg灰白色固体,产率11%。1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.35(s,1H),9.27(s,1H),8.60(s,1H),7.98(s,1H),7.86(s,1H),7.79-7.67(m,5H),7.44(d,J=8.7Hz,1H),5.03(s,1H),2.75(t,J=7.2Hz,2H),2.14(s,3H),1.48(h,J=7.5Hz,2H),1.33(s,9H),0.92(t,J=7.4Hz,3H)。HRMS(AP-ESI),calcd for C25H32ClN7O3S[M+H]+546.2054,found546.2008.
化合物37的制备方法与化合物13a类似。
实施例4、化合物41a,41b,43和44的制备方法,具体步骤如下:
(1)中间体39a:1-甲基-4-(4-硝基苯基)哌嗪的制备方法
将化合物38a(1.00g,7.09mmol)和K2CO3(1.17g,8.50mmol)加入到15mL DMSO中,25℃下搅拌30分钟,缓慢滴加N-甲基哌嗪(865.5μL,7.80mmol),加毕,继续搅拌反应,TLC监测反应结束后,将反应液倾入大量冰水中,产物析出,过滤,真空干燥,得到1.50g黄色固体,产率95%。ESI-MS,m/z=222.20[M+H]+。
中间体39b的制备方法与化合物39a类似。
(2)中间体40a:4-(4-甲基哌嗪-1-基)苯胺的制备
0.42g***固体,产率61%。ESI-MS,m/z=192.20[M+H]+。
中间体40a和40b的制备方法与化合物3类似。
(3)化合物41a:N-羟基-4-((5-甲基-2-(((4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯甲酰胺的制备
将化合物40a(0.20g,0.72mmol)和18a(0.15g,0.79mmol)加入到10mL异丁醇中,加入180μL浓盐酸,加毕,100℃下加热反应10小时,静置至室温,过滤,得到粗产物,向粗产物中加入5mL新鲜制备的羟胺钾甲醇溶液,室温反应1小时,将反应液过滤,浓缩,用1M盐酸调节pH值为7,产物析出,过滤,用乙酸乙酯打浆,过滤,得到60mg红棕色固体,产率19%。1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.96(s,1H),8.79(s,1H),8.37(s,1H),7.89(d,J=9.9Hz,3H),7.71(d,J=8.3Hz,2H),7.50(d,J=8.5Hz,2H),6.84(d,J=8.5Hz,2H),3.05(t,J=5.0Hz,4H),2.46(t,J=4.9Hz,4H),2.23(s,3H),2.12(s,3H)。13C NMR(101MHz,DMSO-d6)δ164.55,159.15,158.90,156.62,146.25,143.33,133.76,130.17,127.64,126.41,120.74,116.37,105.95,55.21,49.55,46.26,14.00。HRMS(AP-ESI),calcd for C23H28N7O2[M+H]+434.2304,found 434.2285。
化合物41b的制备方法与41a类似。
(4)中间体42:4-((2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯甲酸的制备
将化合物40a(0.20g,0.72mmol)和18a(0.15g,0.79mmol)加入到10mL异丁醇中,加入149μL浓盐酸,加毕,100℃下加热反应,反应结束后,将反应液浓缩,加入水,用饱和NaHCO3溶液调节pH=8,用乙酸乙酯萃取,有机相用饱和NaCl洗涤2次,用无水硫酸镁干燥,过滤,浓缩,得到的粗产物用石油醚和乙酸乙酯混合溶剂打浆,得到0.19g白色固体,将所得的固体溶于15mL甲醇,水和四氢呋喃(v:v:v=1:1:1)混合溶剂中,加入氢氧化锂(0.19g,4.44mmol),60℃下反应1小时,反应结束后,将反应液浓缩,用1M盐酸调节pH=7,产物析出,过滤真空干燥,得到0.16g白色固体,产率52%。ESI-MS,m/z=437.48[M+H]+。
(5)化合物43:N-(2-氨基苯基)-4-((2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯甲酰胺的制备
0.10g灰白色固体,产率56%。1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),9.09(s,1H),8.51(s,1H),8.02-7.94(m,3H),7.92(d,J=8.5Hz,2H),7.69(d,J=15.4Hz,1H),7.30(d,J=8.8Hz,1H),7.20(d,J=7.8Hz,1H),6.98(t,J=7.7Hz,1H),6.91(t,J=9.4Hz,1H),6.81(d,J=8.0Hz,1H),6.62(t,J=7.6Hz,1H),4.89(s,2H),2.93(t,J=4.8Hz,4H),2.45(t,J=4.8Hz,4H),2.21(s,3H),2.16(s,3H)。13C NMR(101MHz,DMSO-d6)δ165.29,159.30,158.41,156.58,156.47(d,1JCF=241.0Hz),143.55,143.47,137.00(d,3JCF=11.0Hz),133.70(d,3JCF=9.0Hz),128.73,128.48,127.04,126.78,124.20,120.99,119.55(d,4JCF=4.0Hz),116.84,116.73,114.98,107.43(d,2JCF=26.0Hz,2C),106.85,55.27,50.96,50.93,46.26,14.01。HRMS(AP-ESI),calcd for C29H31FN8O[M+H]+527.2683,found 527.2665。
化合物43和44的制备方法与化合物8a类似。
实施例5、目标化合物体外HDAC抑制活性评价实验
我们使用了Class I HDAC1和Class II HDAC6作为酶源,测试了目标化合物对HDAC的体外抑制活性,以已批准上市的非选择性HDAC抑制剂伏立诺他(SAHA)作为阳性对照。首先测试了目标化合物在0.5μM下对HDAC1/6的抑制率,根据初筛结果选取了部分活性较好的化合物进一步测试了其对HDAC1/6的IC50值。
实验结果(表1)表明,本发明的大部分目标化合物表现出较好的HDAC抑制作用。化合物7a对HDAC6的IC50值为52nM,与阳性对照SAHA的活性相当;化合物8a,13a和13c对HDAC1具有良好的选择性和抑制活性,IC50值分别为270nM,122nM和283nM;而化合物31对HDAC1/6均表现出较好的抑制活性,IC50值分别为402nM和431nM。
表1.体外HDAC抑制活性评价结果
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a抑制率@0.5μM或IC50。IC50值以三次独立重复试验平均值±SD值形式来表示。
实施例6、目标化合物体外JAK1抑制活性评价实验
我们采用激酶发光实验来测试目标化合物对JAK1的抑制活性,以已经上市的JAK抑制剂鲁索替尼(Ruxolitinib)为阳性对照。首先测试了目标化合物在0.5μM浓度下对JAK1的抑制率,然后综合考虑化合物对HDAC和JAK1的抑制活性,挑选了14个目标化合物进一步测试了其对JAK1的IC50值。
实验结果(表2)表明,大部分目标化合物对JAK1表现出非常好的抑制活性。化合物7a,8a,13a,20a,20c,20e,22和31对JAK1的抑制活性要优于或者与菲卓替尼(Fedratinib)相当,其中化合物7a对JAK1的IC50值为4.5nM明显优于菲卓替尼(Fedratinib)。
表2.体外JAK1抑制活性评价结果
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a抑制率@0.5μM或IC50。IC50值以三次独立重复试验平均值±SD值形式来表示。
实施例7、目标化合物体外BRD4抑制活性评价实验
我们采用均相时间分辨荧光技术(HTRF)测试了目标化合物对BRD4的抑制活性,以菲卓替尼(Fedratinib)为阳性对照。首先测试了目标化合物在10μM下对BRD4-BD1的抑制率,抑制率大于50%的化合物又进一步测试了IC50值。
实验结果(表3)表明,大部分目标化合物对BRD4-BD1表现出一定的抑制活性。化合物20a,22和31对BRD4-BD1抑制活性优于或者与菲卓替尼(Fedratinib)相当,其中化合物31表现出最好的BRD4-BD1抑制活性,IC50值为412nM。
表3.体外BRD4抑制活性评价结果
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a抑制率@10μM或IC50。IC50值以三次独立重复试验平均值±SD值形式来表示。
实施例8、体外抗肿瘤细胞增殖实验
我们采用了较为经典的MTT法测试了部分目标化合物对HEL和MDA-MB-231细胞株的抗增殖活性。
实验结果(表4)表明,所选的大部分化合物对HEL和MDA-MB-231均具有较好的抗增殖活性。化合物8a,8b和32对HEL的抗增殖活性优于阳性对照菲卓替尼(Fedratinib)和鲁索替尼(Ruxolitinib),而与阳性对照伏立诺他(SAHA)表现出相当的抗增殖活性。化合物8a,13a,20c和31对MDA-MB-231的抗增殖活性明显优于阳性对照伏立诺他(SAHA)和鲁索替尼(Ruxolitinib),与阳性对照菲卓替尼(Fedratinib)活性相当。
表4.体外抗肿瘤细胞增殖实验结果
a数值以三次独立重复试验平均值±SD值形式来表示。
Claims (5)
1.HDAC、JAK和BET三靶点抑制剂,以及其药学上可接受的盐,具有如下通式(I)或(II)所示结构的:
X是
Y是
R1是甲基,氯原子;
R2是
R3是
2.如权利要求1所述的HDAC、JAK和BET三靶点抑制剂,其特征在于是下述化合物之一:
3.如权利要求2所述的HDAC、JAK和BET三靶点抑制剂的制备方法,如下路线之一所示:
(一)以化合物1为起始原料,与叔丁胺反应得到化合物2,化合物2通过硝基还原反应得到中间体3,中间体3与2,4-二氯-5-甲基嘧啶或2,4,5-三氯嘧啶发生亲核取代反应得到关键中间体4a-4b;化合物4a-4b在酸的催化下与对氨基苯甲酸或间氨基苯甲酸发生亲核取代反应得到化合物5a-5d,然后中间体5a-5d与O-(四氢-2H-吡喃-2-基)羟胺发生酰胺缩合得到中间体6a-6d,然后在酸性条件下脱去化合物6a-6d的THP保护基团得到异羟肟酸类终产物7a-7d;化合物5a,5c与邻苯二胺经过酰胺缩合得到邻苯二胺类终产物8a-8b;化合物4a-4b分别与对氨基肉桂酸乙酯发生酸催化的亲核取代反应得到中间体9a-9b,9a与新鲜制备的羟胺钾甲醇溶液反应得到终产物10a,而中间体9b经过酯水解反应、酰胺缩合反应,最后在酸性条件下脱去THP保护基得到终产物11a;化合物5a-5d与水合肼发生酰胺缩合,得到中间体12a-12d,然后在经过还原胺化得到酰肼类终产物13a-13d;
合成路线一如下:
上述合成路线中的试剂及反应条件:a)叔丁胺,四氢呋喃,25℃;b)钯碳,80%水合肼,乙醇,回流;c)2,4-二氯-5-甲基嘧啶或2,4,5-三氯嘧啶,甲醇和水,45℃;d)3-氨基苯甲酸或4-氨基苯甲酸或4-氨基肉桂酸乙酯,浓盐酸,异丙醇,回流;e)O-(四氢-2H-吡喃-2-基)羟胺,三乙胺,1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐,1-羟基苯并***,N,N-二甲基甲酰胺,25℃;f)氯化氢饱和的乙酸乙酯;g)邻苯二胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;h)羟胺钾甲醇溶液,25℃;i)氢氧化锂,四氢呋喃,甲醇,水,60℃;j)1)O-(四氢-2H-吡喃-2-基)羟胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;2)氯化氢饱和的乙酸乙酯;k)80%水合肼,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,二氯甲烷,25℃;l)1)丙醛,硫酸镁,无水乙醇,25℃;2)氰基硼氢化钠或硼氢化钠,无水甲醇,25℃;
(二)以化合物14为原料,与对硝基酚在碱性条件下经过亲核取代反应、硝基还原反应得到中间体16,化合物17a-17c与2,4-二氯-5-甲基嘧啶或2,4,5-三氯嘧啶发生亲核取代反应得到关键中间体18a-18f;中间体18a-8f与化合物16经过酸催化发生亲核取代得到关键中间体19a-19f,中间体19a-19d与新鲜制备的羟胺钾甲醇溶液反应得到异羟肟酸类终产物20a-20d,而中间体19e-19f经过与邻苯二胺的缩合反应得到邻苯二胺类终产物20e-20f;化合物19e与水合肼发生酰胺缩合得到中间体21,然后经过还原胺化得到酰肼类终产物22;
合成路线二如下:
上述合成路线中的试剂及反应条件:a)4-硝基苯酚,碳酸铯,N,N-二甲基甲酰胺,氮气,100℃;b)钯碳,氢气,甲醇,25℃;c)2,4-二氯-5-甲基嘧啶或2,4,5-三氯嘧啶,甲醇,水,45℃;d)浓盐酸,异丙醇,85℃或浓盐酸,异丁醇,100℃;e)羟胺钾甲醇溶液;f)邻苯二胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;g)80%水合肼,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,二氯甲烷,25℃;h)1)丙醛,硫酸镁,无水乙醇,25℃;2)硼氢化钠,无水甲醇,25℃;
(三)以化合物23为起始原料,化合物23经过Boc酸酐保护氨基、硝基还原、和叔丁基亚磺酰氯缩合反应得到化合物26,又经过氧化反应、酸性条件下脱Boc保护基、和2,4-二氯-5-甲基嘧啶亲核取代反应得到化合物29;化合物29在酸性条件下与对氨基苯甲酸发生亲核取代反应得到中间体30,中间体30一方面和O-(四氢-2H-吡喃-2-基)羟胺发生酰胺缩合、在酸性条件下脱THP保护基得到终产物31;另一方面又和邻苯二胺发生酰胺缩合得到终产物32;中间体29与对氨基肉桂酸乙酯发生酸介导的亲核取代反应得到中间体33,然后经过酯水解反应、酰胺缩合、在酸性条件下脱THP保护基得到终产物35;化合物30与水合肼发生酰胺缩合,得到中间体36,然后经过还原胺化得到酰肼类终产物37;
合成路线三如下:
上述合成路线中的试剂及反应条件:a)二碳酸二叔丁酯,叔丁醇,60℃;b)三氯化铁,80%水合肼,活性炭,甲醇,回流;c)叔丁基亚磺酰氯,吡啶,0℃;d)间氯过氧苯甲酸,二氯甲烷,25℃;e)三氟乙酸,二氯甲烷,25℃;f)2,4-二氯-5-甲基嘧啶,甲醇和水,45℃;g)4-氨基苯甲酸,浓盐酸,异丁醇,100℃;h)1)O-(四氢-2H-吡喃-2-基)羟胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;2)氯化氢饱和的乙酸乙酯;i)邻苯二胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;j)4-氨基肉桂酸乙酯,浓盐酸,异丁醇,100℃;k)氢氧化锂,四氢呋喃,甲醇,水,60℃;l)80%水合肼,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,二氯甲烷,25℃;m)1)丙醛,硫酸镁,无水乙醇,25℃;2)硼氢化钠,无水甲醇,25℃;
(四)中起始原料38a-38b在碱性条件下与N-甲基哌嗪发生反应,经过硝基还原得到中间体40a-40b,中间体40a-40b在酸性条件下与化合物18a发生亲核取代反应后,一方面和羟胺钾甲醇溶液反应得到终产物41a-41b;另一方面发生酯水解反应得到中间体42,中间体42与邻苯二胺和正丙基肼盐酸盐分别发生酰胺缩合得到终产物43和44;
合成路线四如下:
上述合成路线中的试剂及反应条件:a)N-甲基哌嗪,碳酸钾,二甲基亚砜,25℃;b)钯碳,80%水合肼,乙醇,60℃;c)1)18a,浓盐酸,异丁醇,100℃;2)羟胺钾甲醇溶液,25℃;d)1)18a,浓盐酸,异丁醇,100℃;2)氢氧化锂,四氢呋喃,甲醇,水,60℃;e)邻苯二胺,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃;f)正丙基肼盐酸盐,O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯,三乙胺,N,N-二甲基甲酰胺,25℃。
4.如权利要求1或2任一所述的HDAC、JAK和BET三靶点抑制剂在制备预防或治疗与HDAC、JAK和BET活性或表达异常相关的人红细胞白血病、乳腺癌药物中的应用。
5.一种适于口服或胃肠外给药的药物组合物,包含权利要求1或2任一所述的HDAC、JAK和BET三靶点抑制剂和一种或多种药学上可接受的赋形剂。
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