CN115677704B - 含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂及制备方法和应用 - Google Patents
含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂及制备方法和应用 Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一类含有7H‑吡咯并[2,3‑d]嘧啶结构的组蛋白去乙酰化酶6抑制剂及其制备方法和应用。所述的组蛋白去乙酰化酶6抑制剂,具有如下通式(I)所示的结构。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HDAC6活性或表达异常相关疾病的药物中的应用。
Description
技术领域
本发明涉及一类含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6(HDAC6)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
组蛋白去乙酰化酶(HDAC)是一类重要的癌症治疗靶标,它包含18个家族成员,其中 HDAC1-11属于锌离子依赖性HDAC。与其它锌离子依赖性HDAC成员不同,HDAC6是唯一含有两个催化结构域(CD1和CD2)的组蛋白去乙酰化酶,主要分布在胞质内而不是细胞核内,并且在组蛋白的翻译后修饰中无明显作用,而是主要参与调节α-微管蛋白(α-tubulin),皮层肌动蛋白(cortactin),热休克蛋白90(HSP-90)和过氧化物还原酶I/II(peroxiredoxinsI/II)等非组蛋白的乙酰化状态。
越来越多的研究表明,HDAC6是肿瘤、自身免疫性疾病和神经退行性疾病的潜在治疗靶标(Kalin,J.H.etc.J.Med.Chem.2013,56,6297-6313)。目前,ACY-1215和ACY-241等多个HDAC6抑制剂已进入了临床研究阶段,用于多发性骨髓瘤、黑色素瘤、慢性淋巴性白血病、非小细胞肺癌、乳腺癌、胆道癌、亨廷顿氏舞蹈症、类风湿性关节炎、进行性神经性腓骨肌萎缩症、疼痛性糖尿病周围神经病变等疾病的治疗(Zhang,X.etc.J.Med.Chem.2021,64,1362-1391)。然而,ACY-1215和ACY-241的HDAC6选择性均不高,与HDAC1/2/3相比仅有10-20倍(Santo,L.etc.Blood,2012,16,2579-2589;Huang,P.etc.Oncotarget,2017,8,2694-2707),仍无法完全避免抑制其它HDAC亚型引起的毒副作用。
发明内容
本发明针对现有技术的不足,提供一类含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6(HDAC6)抑制剂及其制备方法和应用。
本发明的技术方案如下:
一、含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6(HDAC6)抑制剂
含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂,其药学上可接受的盐具有如下结构通式(I)所示的:
其中:
Z是p为4~7;
n为0~2;
R是碳原子数为1~3的脂肪烃基或氢。
根据本发明优选的,其中:
Z是处于苯环对位或间位的p为5或6;
n为0或1;
R是甲基或H。
进一步优选的,上述化合物为下列之一:
二、含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6(HDAC6)抑制剂的制备方法
本发明组蛋白去乙酰化酶6(HDAC6)抑制剂的制备方法包括以下步骤:
起始原料1与各种氨基苯甲酸甲酯通过亲核取代反应得到2,再水解得到关键中间体3,将中间体3与各种氨基烷酸甲酯盐酸盐缩合得到4,而后在新鲜配制的NH2OK的甲醇溶液中转化为异羟肟酸类目标产物5;中间体3还可以通过与O-(四氢-2H-吡喃-2-基)羟基胺缩合得到关键中间体6,然后在HCl/EtOAc的条件下脱去保护基团后得到异羟肟酸类目标化合物7;起始原料1经4-甲苯磺酰氯保护得到关键中间体8,化合物8与各种氨基苯甲酸甲酯通过缩合反应得到9,根据2合成7的方法,中间体9可以转化为异羟肟酸类目标化合物12;同时,将化合物9进行甲基化得中间体13,这些中间体也可以通过类似的方法合成异羟肟酸类目标化合物16。
合成路线如下:
上述合成路线中的试剂及反应条件:(a):氨基苯甲酸甲酯,异丙醇,浓盐酸;(b):甲醇, 2.5N氢氧化钠;(c):氨基烷酸甲酯盐酸盐,O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸,三乙胺,N,N-二甲基甲酰胺;(d):盐酸羟胺,氢氧化钾,甲醇;(e):O-(四氢-2H-吡喃-2-基) 羟基胺,(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,1-羟基苯并***,三乙胺,N,N-二甲基甲酰胺;(f):HCl/EtOAC;(g):4-甲苯磺酰氯,4-二甲氨基吡啶,三乙胺,二氯甲烷;(h):碳酸铯,碘甲烷,N,N-二甲基甲酰胺。
以上合成路线中n和p同通式(I)中所述。
本领域技术人员可以对上述步骤进行优化以提高收率,他们可根据本领域的基本知识制订合成路线,如选择反应物、溶剂和温度,可通过使用各种保护基团以避免副反应的发生从而提高收率。这些常规的保护方法可参见T.Greene,Protecting Groups inOrganic Synthesis。
三、含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6(HDAC6)抑制剂的应用
本发明还提供了含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6(HDAC6)抑制剂在制备预防或治疗与HDAC6活性或表达异常相关的疾病的药物中的应用;
所述的与HDAC6活性或表达异常相关疾病为各种肿瘤和非肿瘤疾病。
所述的各类肿瘤为多发性骨髓瘤、黑色素瘤、慢性淋巴性白血病、非小细胞肺癌、乳腺癌、胆道癌等,非肿瘤疾病为亨廷顿氏舞蹈症、类风湿性关节炎、进行性神经性腓骨肌萎缩症、疼痛性糖尿病周围神经病变等。
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)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。
说明书附图
图1是0.5μM化合物5b6和12a1对RPMI 8226细胞内Ac-Tub和Ac-HH4水平的影响;
图2是体内肿瘤生长曲线,与阴性对照组相比*P<0.05;
图3是裸鼠的体重曲线。
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5a5、5a6、5b5和5b6的制备,以化合物5a5为例
具体合成方法和步骤如下:
(1)中间体2a:4-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)苯甲酸甲酯的制备
在25℃下,将4-氯吡咯并嘧啶(1,0.50g,1.0eq,3.25mmol)和4-氨基苯甲酸甲酯(0.54g,1.2eq,3.58mmol)溶于20ml异丙醇,滴加两滴浓盐酸,加热回流10小时,TLC 监测反应完成后减压蒸除大部分溶剂,浓缩并通过柱层析(甲醇/二氯甲烷,1/50-1/20)提纯,得到化合物2a,为白色固体(0.50g,57%产率)。1H NMR(400MHz,DMSO-d6)δ12.65(s,1H), 11.05(s,1H),8.49(s,1H),8.03(d,J=8.5Hz,2H),7.95(d,J=8.5Hz,2H),7.45(t,J=2.8Hz,1H),7.07(dd,J=3.5,1.7Hz,1H),3.87(s,3H).ESI-MS,m/z=269.13[M+H]+.
(2)中间体3a:4-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)苯甲酸的制备
在25℃下,将化合物2a(0.22g,1eq,0.82mmol)溶于20ml甲醇,并加入5ml 2.5NNaOH,回流2小时,TLC监测反应完成后旋蒸除去甲醇,所得溶液在冰浴下用1N HCl调节PH到2并有沉淀析出,所得沉淀过滤并用水洗涤,真空干燥,得到化合物3a,为白色固体(0.16g,76%产率)。1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),10.99(s,1H),8.46(s,1H),8.01(d,J=8.4 Hz,2H),7.89(d,J=8.4Hz,2H),7.45(t,J=2.8Hz,1H),7.07–6.98(m,1H).ESI-MS,m/z= 253.06[M-H]-.
(3)中间体4a5:6-(4-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)苯甲酰胺基)己酸甲酯的制备
在0°下,将化合物3a(0.25g,1eq,0.98mmol)溶于20ml N,N-二甲基甲酰胺,向此溶液中加入TBTU(0.38g,1.2eq,1.18mmol),随之滴加三乙胺(0.15g,1.2eq,1.47mmol),在0°下活化30分钟后,加入6-氨基己酸甲酯盐酸盐(0.21g,1.2eq,1.08mmol)与三乙胺(0.15g,1.2eq,1.47mmol),室温反应6h,TLC监测反应完成,将反应液用水稀释,并用乙酸乙酯萃取3次,合并有机相,用饱和碳酸氢钠与饱和食盐水洗涤,用无水硫酸钠干燥过夜,过滤并浓缩,粗产物通过柱层析(甲醇/二氯甲烷,1/50-1/20)提纯,得到化合物4a5,为黄色固体(0.25g,67%产率)。1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),9.52(s,1H),8.34(s,1H),8.29(t,J=5.6Hz,1H),8.00(d,J=8.7Hz,2H),7.83(d,J=8.7Hz,2H),7.30-7.26(m,1H),6.84(dd,J=3.3, 1.8Hz,1H),3.58(s,3H),3.24(q,J=6.7Hz,2H),2.32(t,J=7.4Hz,2H),1.55(dp,J=15.1,7.3 Hz,4H),1.32(p,J=7.5,6.9Hz,2H).
(4)化合物5a5:(4-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-N-(6-羟基胺基)-6-氧代己基-)苯甲酰胺的制备
分别在70mL和120mL的甲醇中溶解氢氧化钾(28.55g,509mmol)和盐酸羟胺(23.84g, 343mmol),得到溶液A和溶液B,在冰浴下,将溶液A滴加到溶液B中,过滤沉淀,得到羟胺钾溶液。将化合物4a5(0.20g,1eq,0.52mmol)溶解在30mL羟胺钾溶液中搅拌2h,TLC监测反应完成后真空浓缩,加入少量水,并用1N HCl调节体系PH为6,所得沉淀过滤后干燥得到粗产物,粗产物通过重结晶得到化合物5a5,为白色固体(0.20g,83%产率)。Mp:210-212℃. 1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),10.36(s,1H),9.54(s,1H),8.68(s,1H),8.34(s, 1H),8.31(t,J=5.7Hz,1H),8.02(d,J=8.5Hz,2H),7.84(d,J=8.5Hz,2H),7.28(t,J=2.5Hz, 1H),6.86(d,J=3.4Hz,1H),3.25(q,J=6.7Hz,2H),1.97(t,J=7.4Hz,2H),1.53(dd,J=10.6, 5.0Hz,4H),1.30(q,J=7.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ169.57,166.25,153.63, 151.49,151.10,143.58,128.24,128.10,123.06,119.28,104.54,99.28,32.73,29.50,26.63,25.43. HRMS(AP-ESI)m/z calcd for C19H22N6O3[M+H]+383.1826,found 383.1829.
实施例2.化合物7a和7b的制备,以化合物7a为例
(1)中间体6a:(4-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-N-((四氢-2H-吡喃-2-基)氧代)苯甲酰胺的制备
在0°下,将化合物3a(0.45g,1eq,1.77mmol)溶于50ml N,N-二甲基甲酰胺,向此溶液中加入EDCI(0.41g,1.2eq,2.12mmol),HOBT(0.29g,1.2eq,2.12mmol),并滴加三乙胺(0.42g,2.4eq,4.24mmol),活化30分钟后,加入O-(四氢-2H-吡喃-2-基)羟胺(0.25g,1.2eq,2.12mmol),室温反应12小时,TLC监测反应完成,将反应液用水稀释,并用乙酸乙酯萃取3次,合并有机相,用饱和碳酸氢钠与饱和食盐水洗涤,用无水硫酸钠干燥过夜,过滤并浓缩,得到化合物6a,为白色固体(0.12g,20%产率)。1H NMR(400MHz,DMSO-d6)δ 11.85(s,1H),11.51(s,1H),9.57(s,1H),8.35(s,1H),8.03(d,J=8.6Hz,2H),7.77(d,J=8.7Hz,2H),7.29(t,J=2.9Hz,1H),6.85(dd,J=3.5,1.9Hz,1H),5.00(t,J=3.0Hz,1H),4.06-4.00(m, 1H),3.55–3.50(m,1H),1.78-1.67(m,3H),1.60-1.52(m,3H).ESI-MS,m/z=352.15[M-H]-.
(2)化合物7a:(4-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-N-羟基苯甲酰胺的制备
在25℃下,将化合物6a(0.1g,0.28mmol)溶于4ml乙酸乙酯,滴加4mL HCl/EtOAc,室温反应,TLC监测反应完成,所得沉淀经过滤干燥,得到化合物7a,为白色固体(0.028g,37%产率)。Mp:>240℃.1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),11.48(s,1H),8.44(s,1H),7.89(d,J=8.4Hz,2H),7.74(d,J=8.3Hz,2H),7.48(t,J=2.9Hz,1H),7.05(s,1H).13CNMR(101MHz,DMSO-d6)δ163.87,151.10,144.00,139.39,130.57,128.57,125.43,123.97,103.67,102.95.HRMS(AP-ESI)m/z calcd for C13H11N5O2[M+H]+270.0986,found270.0989.
实施例3.化合物12a1、12b1、16a0、16a1、16b0和16b1的制备,以化合物16a0为例
(1)中间体8:4-氯-7-甲苯磺酰基-7H-吡咯[2,3-d]嘧啶的制备
将4-氯吡咯并嘧啶(1,1.0g,1eq,6.5mmol)溶于50ml二氯甲烷中,冰浴下加入对甲苯磺酰氯(1.3g,1.06eq,6.9mmol),然后加入三乙胺(1.30g,2.0eq,1.3mmol)和4-二甲氨基吡啶(0.03g,0.03eq,0.2mmol),室温反应5小时,TLC监测反应完成后,将反应液用二氯甲烷稀释,有机相分别用水,1N柠檬酸,饱和食盐水洗涤,有机相用无水硫酸镁干燥,过滤并浓缩,得到化合物8,为灰白色固体(1.81g,95%产率)。1H NMR(400MHz,DMSO-d6)δ 8.82(s,1H),8.13(d,J=4.0Hz,1H),8.08-8.03(m,2H),7.48(d,J=8.1Hz,2H),6.97(d,J=4.0 Hz,1H),2.37(s,3H).
(2)中间体9a0:4-((-7-甲苯磺酰基-7H-吡咯[2,3-d]嘧啶-4-基)氨基)苯甲酸甲酯的制备
在25℃下,将化合物8(0.61g,1.0eq,2.00mmol)和4-氨基苯甲酸甲酯(0.34g,1.1eq, 2.20mmol)溶于25ml异丙醇,滴加两滴浓盐酸,加热回流2小时,TLC监测反应完成,将反应液冷却到室温,过滤并用异丙醇洗涤1-2次,干燥得到化合物9a0,为黄色色固体(0.76g, 89%产率)。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.51(s,1H),8.02(d,J=8.5Hz,4H), 7.96(d,J=8.8Hz,2H),7.78(d,J=4.0Hz,1H),7.46(d,J=8.1Hz,2H),7.18(d,J=4.0Hz,1H), 3.83(s,3H),2.36(s,3H).ESI-MS,m/z=421.13[M-H]-.
(3)中间体13a0:4-(甲基(7-甲苯磺酰基-7H-吡咯[2,3-d]嘧啶-4-基)氨基)苯甲酸甲酯的制备
在25℃下,将化合物9a0(0.30g,1eq,0.71mmol)溶于10ml N,N-二甲基甲酰胺,向此溶液中加入碳酸铯(0.46g,1.42mmol),在氮气条件下搅拌反应混合物30分钟。加入碘甲烷 (0.78g,5.48mmol),室温下搅拌反应混合物2小时,将反应混合物倒入冰水中搅拌30分钟,过滤并用水洗涤,得到化合物13a0,为黄色固体(0.23g,74%产率)。1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.08-8.03(m,2H),7.96(d,J=8.1Hz,2H),7.53–7.50(m,2H),7.46-7.42 (m,3H),5.00(d,J=4.1Hz,1H),3.89(s,3H),3.53(s,3H),2.36(s,3H).ESI-MS,m/z=437.10 [M+H]+.
(4)中间体14a0:4-(甲基(7H-吡咯[2,3-d]嘧啶-4-基)氨基)苯甲酸的制备
在25℃下,将化合物13a0(0.36g,1eq,0.82mmol)溶于20ml甲醇,并加入5ml 2.5NNaOH,65℃回流2小时,TLC监测反应完成后除去甲醇,所得溶液在并于下用1N HCl调节PH到2至有沉淀析出,所得沉淀过滤并用水洗涤,真空干燥,得到化合物14a0,为黄色固体(0.14g,65%产率)。1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.13(s,1H),7.90(d, J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),7.12(t,J=2.9Hz,1H),6.50(d,J=3.5Hz,1H),5.08(s,2H),3.35(s,3H).ESI-MS,m/z=281.08[M-H]-.
(5)中间体15a0:4-(甲基(7H-吡咯[2,3-d]嘧啶-4-基)氨基)-N-((四氢-2H-吡喃-2-基)氧代)苯甲酰胺的制备
在0℃下,将化合物14a0(0.47g,1eq,1.77mmol)溶于50ml N,N-二甲基甲酰胺,向此溶液中加入EDCI(0.41g,1.2eq,2.12mmol),HOBT(0.29g,1.2eq,2.12mmol),并滴加三乙胺(0.42g,2.4eq,4.24mmol),活化30分钟后,加入O-(四氢-2H-吡喃-2-基)羟胺(0.25g,1.2eq,2.12mmol),室温反应12小时,TLC监测反应完成,将反应液用水稀释,并用乙酸乙酯萃取3次,合并有机相,用饱和碳酸氢钠与饱和食盐水洗涤,用无水硫酸钠干燥过夜,过滤并浓缩,得到化合物15a0,为黄色固体(0.40g,61%产率)。1H NMR(400MHz,DMSO-d6) δ11.74(s),11.69(s,1H,NH),8.32(s),7.89-7.83(m),7.48-7.42(m),6.96(dd,J=3.5,2.4Hz,1H), 5.03(t,J=2.9Hz),4.85(dd,J=3.5,1.9Hz),4.15-4.02(m),3.56(s,3H),3.55-3.51(m,1H,),1.74 (s,3H,),1.62-1.51(m,3H).ESI-MS,m/z=366.15[M-H]-.
(6)化合物16a0:N-羟基-4-(甲基(7H-吡咯[2,3-d]嘧啶-4-基)氨基)苯甲酰胺的制备
分别在70mL和120mL的甲醇中溶解氢氧化钾(28.55g,509mmol)和盐酸羟胺(23.84g, 343mmol),得到溶液A和溶液B,在冰浴下,将溶液A滴加到溶液B中,过滤沉淀,得到羟胺 钾溶液。25℃下,将化合物15a0(0.40g,1eq,1.09mmol)溶解在30mL羟胺钾溶液中搅拌2h, TLC监测反应完成后真空浓缩,加入少量水,并用1N HCl调节体系PH为6,所得沉淀过滤后 干燥得到粗产物,粗产物通过重结晶得到化合物16a0,为白色固体(0.20g,66%产率)。Mp: 228-230℃.1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),11.44(s,1H),8.51(s,1H),7.98(d,J =8.2Hz,2H),7.65(d,J=8.3Hz,2H),7.21(t,J=3.0Hz,1H),4.86(s,1H),3.72(s,3H).13C NMR (101MHz,DMSO-d6)δ166.93,163.43,145.93,143.91,133.63,131.64,129.30,128.04,124.63, 103.31,102.62,41.79.HRMS(AP-ESI)m/z calcd for C14H13N5O2[M+H]+284.1142,found 284.1147.
实施例4.目标化合物体外HDAC抑制活性评价实验
以已知HDAC抑制剂SAHA和Tubastatin A作为阳性对照,我们测试了目标化合物对HDAC2、HDAC6、HDAC8的抑制活性和选择性。
表1实验结果表明,大多数目标化合物在0.5μM下对HDAC6的抑制率超过50%,IC50测定结果进一步证实了它们有效的HDAC6抑制活性。值得注意的是,活性最强的HDAC6 抑制剂12a1(IC50=0.010μM)显示出比SAHA(IC50=0.082μM)和Tubastatin A(IC50=0.085 μM)更强的HDAC6抑制活性。更重要的是,化合物12a1还具有很好的HDAC6选择性。
表1.体外HDAC抑制活性评价结果
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a在重复条件下(n≥2)进行,IC50的SD值小于20%平均值。b未测试
实施例5.目标化合物对人多发性骨髓瘤抗增殖实验
进一步评价了高活性HDAC6抑制剂5b6、7a、12a1和16a1对多发性骨髓瘤细胞株的体外抗增殖活性。
从表2的结果可以看出,四个受试化合物均表现出优于阳性对照Tubastatin A的抗增殖活性。
表2.选定化合物的体外抗增殖活性
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a在重复条件下(n≥3)进行,值显示为平均值±SD值
实施例6.免疫印迹分析实验
进一步利用免疫印迹实验评价化合物5b6和12a1对RPMI 8226细胞内HDACs的抑制活性和选择性。
从图1结果中可以发现,化合物12a1可以显著升高RPMI 8226细胞内HDAC6底物乙酰-α-微管蛋白(Ac-Tub)的水平,而不影响Ⅰ类HDACs(HDAC1/2/3)底物乙酰-组蛋白H4 (Ac-HH4)的水平。化合物5b6则可以同时升高Ac-Tub和Ac-HH4的水平。
实施例7.体内抗肿瘤活性
基于化合物12a1良好的体外抗多发性骨髓瘤活性和HDAC6选择性,我们建立了裸鼠 RPMI 8226异种移植模型来评价12a1的体内抑瘤活性。
表3和图2的结果显示,12a1单独给药或与bortezomib联用均能有效抑制多发性骨髓瘤的体内生长。与12a1和bortezomib单独给药组相比,联合用药组显示出了更强的体内抑瘤活性。如图3所示,与阴性对照组相比,各给药组小鼠的体重均无显著差异,这初步表明了受试化合物良好的安全性。
表3.化合物12a1、bortezomib和联合用药在RPMI 8226异种移植模型中的体内抗肿瘤活性
a与阴性对照组相比P<0.05。
Claims (9)
1.含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂,其药学上可接受的盐,具有如下结构通式(I)所示的结构:
其中:
Z是p为4~7;
n为0~2;
R是碳原子数为1~3的脂肪烃基或氢。
2.如权利要求1所述的含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂,其特征在于:
Z是处于苯环对位或间位的p为5或6;
n为0或1;
R是甲基或H。
3.如权利要求1或2所述的含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂,其特征在于是下述化合物之一:
4.如权利要求1或2所述的含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂的制备方法,包括以下步骤:
起始原料1与各种氨基苯甲酸甲酯通过亲核取代反应得到2,再水解得到关键中间体3,将中间体3与各种氨基烷酸甲酯盐酸盐缩合得到4,而后在新鲜配制的NH2OK的甲醇溶液中转化为异羟肟酸类目标产物5;中间体3还可以通过与O-(四氢-2H-吡喃-2-基)羟基胺缩合得到关键中间体6,然后在HCl/EtOAc的条件下脱去保护基团后得到异羟肟酸类目标化合物7;起始原料1经4-甲苯磺酰氯保护得到关键中间体8,化合物8与各种氨基苯甲酸甲酯通过缩合反应得到9,根据2合成7的方法,中间体9可以转化为异羟肟酸类目标化合物12;同时,将化合物9进行甲基化得中间体13,这些中间体也可以通过类似的方法合成异羟肟酸类目标化合物16;
合成路线如下:
上述合成路线中的试剂及反应条件:(a):氨基苯甲酸甲酯,异丙醇,浓盐酸;(b):甲醇,2.5N氢氧化钠;(c):氨基烷酸甲酯盐酸盐,O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸,三乙胺,N,N-二甲基甲酰胺;(d):盐酸羟胺,氢氧化钾,甲醇;(e):O-(四氢-2H-吡喃-2-基)羟基胺,(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,1-羟基苯并***,三乙胺,N,N-二甲基甲酰胺;(f):HCl/EtOAC;(g):4-甲苯磺酰氯,4-二甲氨基吡啶,三乙胺,二氯甲烷;(h):碳酸铯,碘甲烷,N,N-二甲基甲酰胺;
以上合成路线中n和p同通式(I)中所述。
5.如权利要求1-3任一所述的含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂在制备预防或治疗与HDAC6活性或表达异常相关疾病的药物中的应用。
6.如权利要求5所述的应用,其特征在于,所述的与HDAC6活性或表达异常相关的疾病为各种肿瘤和非肿瘤疾病。
7.如权利要求6所述的应用,其特征在于,所述的各种肿瘤为多发性骨髓瘤、黑色素瘤、慢性淋巴性白血病、非小细胞肺癌、乳腺癌、胆道癌。
8.如权利要求6所述的应用,其特征在于,所述的非肿瘤疾病为亨廷顿氏舞蹈症、类风湿性关节炎、进行性神经性腓骨肌萎缩症、疼痛性糖尿病周围神经病变。
9.一种适于口服或胃肠外给药的药物组合物,包含权利要求1-3任一所述的含有7H-吡咯并[2,3-d]嘧啶结构的组蛋白去乙酰化酶6抑制剂和一种或多种药学上可接受的载体或赋形剂。
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