CN108727234A - 多肽类化合物及其在制备组织蛋白酶d抑制剂中的用途 - Google Patents

多肽类化合物及其在制备组织蛋白酶d抑制剂中的用途 Download PDF

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CN108727234A
CN108727234A CN201710271831.6A CN201710271831A CN108727234A CN 108727234 A CN108727234 A CN 108727234A CN 201710271831 A CN201710271831 A CN 201710271831A CN 108727234 A CN108727234 A CN 108727234A
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CN108727234B (zh
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张伟
李英霞
周扬
艾菁
唐帅
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Fudan University
Shanghai Institute of Materia Medica of CAS
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Abstract

本发明属化学合成领域，涉及一类新的可抑制组织蛋白酶D活性、具有通式I结构的化合物或其药学上可接受的盐，及其制备方法；本发明还涉及包含此类化合物或其药学上可接受的盐的药物组合物，以及该化合物或其药学上可接受盐及其药物组合物在制备防治癌症的药物中的应用。本发明的化合物其药学上可接受的盐可有效抑制组织蛋白酶D的活性，有防治肿瘤的潜在应用价值。

Description

多肽类化合物及其在制备组织蛋白酶D抑制剂中的用途
技术领域
本发明属医药学及化学合成领域，涉及与肿瘤相关的组织蛋白酶D抑制剂；尤其涉及一类新型的多肽类化合物(通式I)或其药学上可接受的盐及其制备方法和用途；本发明进一步涉及包含此类化合物或其药学上可接受的盐的药物组合物，以及该化合物或其药学上可接受的盐及其药物组合物在制备组织蛋白酶D抑制的药物中的应用。
背景技术
现有技术公开了组织蛋白酶D(Cathepsin D,Cath D)是天冬氨酸蛋白酶家族的主要成员，几乎存在与所有的哺乳动物组织和细胞内。研究显示，Cath D是一种溶酶体肽链内切酶，在正常情况下，以低浓度存在于细胞内，其作用是参与蛋白质和多肽的降解；在恶性肿瘤细胞中，Cath D过表达并过度分泌至胞外，参与肿瘤细胞入侵、增殖扩散、转移和凋亡等过程，此外，它还参与阿尔兹海默症等人类神经退行性疾病和动脉粥样硬化等疾病的病理过程。因此有专家认为，该蛋白酶极有可能成为恶性肿瘤治疗的一个重要且全新的分子靶点(Tandon,A.K.et al.Proc.Natl.Acad.Sci.USA.1993,90,6796-6800；Hu,L.etal.Cancer Res.2008,68,4666-4673；Chaudhary,H.et al.J.Phys.Pharm.Adv.2012,2,87-96.)。有研究显示，目前的Cath D小分子抑制剂存在活性不够突出、选择性差等缺点；基于现有技术的现状，本申请的发明人拟提供一类具有高活性的Cath D抑制剂，其对Cath D同族的其它蛋白酶抑制率较低，具有良好的选择性。
发明内容
本发明的目的视为克服现有技术的缺陷，提供一类具有高活性的一类具有高活性的Cath D抑制剂。
本发明通过对Cath D蛋白与小分子的共晶结构[Tandon,A.K.etal.Proc.Natl.Acad.Sci.USA.1993,90,6796-6800]的分析，设计合成了一系列化合物并进行了组织蛋白D抑制活性的测试，提供了一类对Cath D有显著抑制活性且对同家族蛋白酶有高度选择性、进而具有防治癌症的化合物。
具体的，本发明提供一类具有通式I结构的多肽类化合物或其药学上可接受的盐，该类化合物可以有效地抑制Cath D的活性，从而发挥治疗癌症的作用。
进一步，本发明提供了通式I所示化合物的制备方法。
更进一步，本发明提供了包含通式I所示化合物或其药学上可接受的盐的药物组合物。
本发明还提供通式I所示化合物或其药学上可接受盐在制备防治癌症的药物中的应用。
本发明提供了具有如下通式I所示化合物或其药学上可接受的盐：
其中，R基团可以是异丁基、环丙基、间甲氧基苄基。
通式I所代表的化合物，其制备方法如下所示进行并包括如下步骤：
(1)片段A和B缩合制得化合物C，所用缩合方法可以为酰氯法，酰氟法，混合酸酐法或使用如下缩合剂：N,N-二环己基亚胺、1-[3-二甲氨基]-丙基-3-乙基碳二酰亚胺盐酸盐或7-氮杂苯并唑-1-基-氧(三-(二甲胺基)膦)六氟磷酸盐；
(2)化合物C脱除叔丁酯保护基后再与胺缩合得通式I的化合物，其中脱除叔丁酯保护基所用试剂为浓盐酸、氯化氢乙酸乙酯溶液、氯化氢二氧六环溶液、氟化氢、三氟乙酸或其组合；所用的胺包括异丁基胺、环丙基胺、间甲氧基苄胺；所用缩合方法可以为酰氯法，酰氟法，混合酸酐法或使用如下缩合剂：N,N-二环己基亚胺、1-[3-二甲氨基]-丙基-3-乙基碳二酰亚胺盐酸盐或7-氮杂苯并唑-1- 基-氧(三-(二甲胺基)膦)六氟磷酸盐。
本发明提供了一类具有通式I结构的多肽类化合物或其药学上可接受的盐，该类化合物可以有效地抑制Cath D的活性，可进一步制备防治癌症的药物。
具体实施方式
实施例1：
将化合物A(0.8mmol)和B(0.8mmol)溶于150mL无水二氯甲烷中，冰浴下加入N,N-二异丙基乙胺(0.59mL,3.488mmol)、EDC(669mg,3.488mmol)、HOAt(475mg,3.488mmol)。维持冰浴30min后恢复至室温反应20h。减压浓缩除去溶剂，加入100mL乙酸乙酯溶解残渣，然后依次用10％柠檬酸、5％碳酸氢钠溶液、水、饱和食盐水洗涤，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析(PE:EA＝5:1-1:2)后得纯品C(410mg,63.8％)。1HNMR(DMSO-d6,400MHz)δ:9.01(d,J＝7.9Hz,1H),8.34(d,J＝8.8Hz,1H),8.23(s,1H),8.11(d,J＝7.6Hz,1H),7.98(s,1H),7.93(s,1H),7.41-7.16(m,10H),5.22-5.17(m,1H),5.13(d,J＝5.4Hz,1H),4.28-4.21(m,1H),4.13(dd,J＝14.7,7.5Hz,1H),4.07-4.03(m,1H),3.34(s,3H),3.02(s,3H),2.96(dd,J＝13.9,5.4Hz,1H),2.88-2.82(m,1H),2.33-2.23(m,2H),1.99(s,1H),1.66-1.58(m,1H),1.50(d,J＝7.0Hz,3H),1.45-1.41(m,2H),1.37(s,9H),0.88(d,J＝6.6Hz,3H),0.82(d,J＝6.5Hz,3H)；13C NMR(CDCl3,151MHz)δ:172.7,172.0,166.2,164.9,143.1,142.3,138.1,136.4,135.5,129.4,128.8,128.7,128.0,127.8,127.6,126.7,126.4,124.7,82.6,69.4,60.5,55.7,51.6,49.8,41.6,40.8,38.1,35.9,28.2,25.1,22.9,22.1,21.8,14.3；HRESIMS calcd for C39H52N4O8S[M+Na]+759.3398,found759.3394.。
实施例2：
将化合物C(130mg,0.1764mmol)溶于1mL二氯甲烷中，缓缓加入1mL三氟乙酸，室温反应2h。TLC显示反应完毕后，减压蒸馏除去溶剂，向残留物中加入二氯甲烷重蒸两次，得固体粉末，真空干燥3h后溶于50mL无水四氢呋喃中，冰浴下加入异丁胺(10.42μL,0.1175mmol)、N,N-二异丙基乙胺(40μL,0.2350mmol)、HATU(90mg,0.2350mmol)、HOAt(32mg,0.2350mmol)。维持冰浴30min后恢复至室温反应20h。减压浓缩除去溶剂，加入100mL乙酸乙酯溶解残渣，然后依次用10％柠檬酸、5％碳酸氢钠溶液、水、饱和食盐水洗涤，有机相用无水硫酸钠干燥，减压浓缩，硅胶柱层析(DCM:MeOH＝50:1-10:1)后共获得通式I中R＝异丁基的目标化合物，为白色固体18mg，收率50.0％。1HNMR(CDCl3,400MHz)δ:8.18(s,1H),7.93(s,1H),7.80(s,1H),7.51(d,J＝10.3Hz,1H),7.29-7.12(m,10H),7.01(d,J＝8.0Hz,1H),6.71(br,1H),5.29-5.22(m,1H),4.31-4.25(m,1H),4.21-4.15(m,1H),4.07-4.02(m,1H),3.27(s,3H),3.11-3.06(m,1H),2.99(dd,J＝13.3,6.1Hz,1H),2.83(s,3H),2.76-2.71(m,1H),2.25-2.16(m,1H),2.07-2.01(m,1H),1.61-1.54(m,1H),1.51-1.47(m,2H),1.48(d,J＝7.1Hz,3H),0.85(d,J＝6.7Hz,3H),0.83(d,J＝6.6Hz,3H),0.73-0.71(m,2H),0.56-0.48(m,2H)；13C NMR(CDCl3,151MHz)δ:174.4,172.3,166.4,165.2,143.3,142.1,138.2,136.4,135.9,135.5,130.0,129.4,128.7,128.2,127.9,127.4,126.7,126.4,125.6,124.9,69.8,56.1,52.0,49.9,41.3,40.9,38.1,37.8,35.8,30.5,29.8,24.9,23.0,22.1,21.8,14.2,6.6,6.4；HRESIMS calcd for C38H49N5O7S[M+H]+720.3425,found720.3444.。
实施例3：
将实施例2中异丁胺替换为环丙胺，其它操作方法相同，可得通式I中R＝环丙基的目标产物。该产物为黄色固体，收率51.0％。1HNMR(CDCl3,400MHz)δ:8.18(s,1H),7.93(s,1H),7.80(s,1H),7.51(d,J＝10.3Hz,1H),7.29-7.12(m,10H),7.01(d,J＝8.0Hz,1H),6.71(br,1H),5.29-5.22(m,1H),4.31-4.25(m,1H),4.21-4.15(m,1H),4.07-4.02(m,1H),3.27(s,3H),3.11-3.06(m,1H),2.99(dd,J＝13.3,6.1Hz,1H),2.83(s,3H),2.76-2.71(m,1H),2.25-2.16(m,1H),2.07-2.01(m,1H),1.61-1.54(m,1H),1.51-1.47(m,2H),1.48(d,J＝7.1Hz,3H),0.85(d,J＝6.7Hz,3H),0.83(d,J＝6.6Hz,3H),0.73-0.71(m,2H),0.56-0.48(m,2H)；13C NMR(CDCl3,151MHz)δ:174.4,172.3,166.4,165.2,143.3,142.1,138.2,136.4,135.9,135.5,130.0,129.4,128.7,128.2,127.9,127.4,126.7,126.4,125.6,124.9,69.8,56.1,52.0,49.9,41.3,40.9,38.1,37.8,35.8,30.5,29.8,24.9,23.0,22.1,21.8,14.2,6.6,6.4；HRESIMS calcd for C38H49N5O7S[M+H]+720.3425,found 720.3444.。
实施例4：
将实施例2中异丁胺替换为间甲氧基苄胺，其它操作方法相同，可得通式I中R＝间甲氧基苄基的目标产物。该产物为白色固体，收率65.0％。1HNMR(CDCl3,400MHz)δ:8.15(s,1H),7.92(s,1H),7.78(s,1H),7.50(d,J＝7.6Hz,1H),7.27-7.12(m,10H),7.06(d,J＝7.6Hz,1H),6.91(br,1H),6.83-6.75(m,3H),5.28-5.20(m,1H),4.54-4.49(m,2H),4.43-4.37(m,1H),4.32(dd,J＝14.9,4.9Hz,1H),4.20-4.13(m,1H),4.05-4.03(m,1H),3.72(s,3H),3.25(s,3H),3.08-3.03(m,1H),2.95(dd,J＝13.7,6.4Hz,1H),2.79(s,3H),2.21-2.15(m,1H),2.04-2.00(m,3H),1.62-1.54(m,1H),1.46(d,J＝6.9Hz,3H),0.86(d,J＝6.4Hz,3H),0.84(d,J＝6.4Hz,3H)；13C NMR(CDCl3,151MHz)δ:172.7,172.3,166.2,165.1,160.0,143.3,142.2,139.5,138.1,136.4,135.5,129.9,129.4,128.8,128.1,127.8,127.5,126.7,126.4,124.8,119.9,113.4,113.0,69.7,56.0,55.3,52.2,49.8,43.8,41.3,40.9,38.1,37.9,35.8,24.9,23.0,22.1,21.8；HRESIMS calcd for C43H53N5O8S[M+Na]+822.3507,found 822.3499.。
实施例5：通式I所示化合物的Cath D抑制活性及对同族蛋白酶的选择性实验
以Pepstatin A做阳性对照；实验前向新鲜制备的反应缓冲液中加入1％DMSO。所用缓冲液：100mM NaOAc/100mM NaCl(pH 3.5)。将酶加入到反应缓冲液至设定的终浓度(Cat D的终浓度：2μg/mL)，然后将待测样品的DMSO溶液加入。样品浓度从10μM起3倍稀释，共设12个浓度梯度；DMSO总用量不超过2％，随后加入相应底物引发反应(Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH2，底物终浓度为10μM。)，室温下120min测试荧光强度(激发波长320nm，发射波长405nm)，得出酶活抑制率，计算IC50，每个样品至少重复测试2次。
表1为测试结果(半数抑制浓度IC50，单位nM)：

Claims (8)

1.具有通式I结构的多肽类化合物或其药学上可接受的盐：
其中，R基团是异丁基、环丙基、间甲氧基苄基。
2.如权利要求1所述的具有通式I结构的多肽类化合物或其药学上可接受的盐，其特征在于，所述的化合物按下式方法制备，
包括步骤：
(1)片段A和B缩合制得化合物C，
(2)化合物C脱除叔丁酯保护基后与胺缩合得通式I的化合物。
3.如权利要求2所述的具有通式I结构的多肽类化合物或其药学上可接受的盐，其特征在于，所述的制备方法步骤(1)中，采用缩合方法为酰氯法，酰氟法，混合酸酐法或使用缩合剂：N,N-二环己基亚胺、1-[3-二甲氨基]-丙基-3-乙基碳二酰亚胺盐酸盐或7-氮杂苯并唑-1-基-氧(三-(二甲胺基)膦)六氟磷酸盐。
4.如权利要求2所述的具有通式I结构的多肽类化合物或其药学上可接受的盐，其特征在于，所述的制备方法步骤(2)中，脱除叔丁酯保护基采用试剂为浓盐酸、氯化氢乙酸乙酯溶液、氯化氢二氧六环溶液、氟化氢、三氟乙酸或其组合；
所用的胺包括异丁基胺、环丙基胺、间甲氧基苄胺；
所用缩合方法为酰氯法，酰氟法，混合酸酐法或使用缩合剂：N,N-二环己基亚胺、1-[3-二甲氨基]-丙基-3-乙基碳二酰亚胺盐酸盐或7-氮杂苯并唑-1-基-氧(三-(二甲胺基)膦)六氟磷酸盐。
5.一种药物组合物，其特征是，该组合物含有治疗有效量的权利要求1所述的多肽类化合物或其药学上可接受的盐。
6.据权利要求5所述的药物组合物，其特征是，所述的多肽类化合物或其药学上可接受的盐占该药物组合物总重量的20％～99％。
7.据权利要求5或6所述的药物组合物，其特征是，该组合物进一步包括一种或多种药学上可接受的载体、气味剂、香味剂、赋形剂或稀释液。
8.权利要求1所述的具有通式I结构的多肽类化合物或其药学上可接受的盐在制备组织蛋白酶D抑制剂的药物中的用途。
CN201710271831.6A 2017-04-24 2017-04-24 多肽类化合物及其在制备组织蛋白酶d抑制剂中的用途 Active CN108727234B (zh)

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